Note: Descriptions are shown in the official language in which they were submitted.
34~
The object of this invention is 9-deoxy-9a-methylene-isosteres of
PGI2, also known as 6,9a-oxide-11~,15(S)-dihydroxy-prosta-5(Z),13(E)-
dienoic acid, including a procedure for their preparation as well as pharm-
aceutical and veterinary compositions containing them.
Compounds covered by this invention have the following general
formula I
CH~J(cH2)m -D (CH2)m2
/c \
(CH2) B (CH2)
H H
my
Rl 2 R3 R5
C-(cH2)n X(C 2 n2 7
R4 R6
wherein R is chosen from the group (a) a free or esterified carboxy group;
(b) -C(OR')3, where each R' group is independently Cl-C6-alkyl or phenyl;
(c) -CH2-R", where R" is hydroxy or C2-C7-alkoxy; (d) -CON R where Ra
and Rb are chosen independently from the group hydrogen, Cl-C6-alkyl, C2-C6-
alkanoyl and phenyl; (e) -C-N; (f) a O ¦¦ radical; (g) -CHO; (h) a
X'R' NH-N
-CH ~X'R' radical where each X' is independently -O- or -S- and the R' and
R'b groups, whether the same or different, are Cl-C6-alkyl or together form
a straight or branched C2-C6-alkylene chain; D is chosen from the group:
-CH2-, -CH-OH, -CH=CH- (cis), -CH=CH- (trans), -C_C-, ,C=O, -O-, -S- and
,N-R , where R may be hydrogen, Cl-C6-alkyl or C2-C6-alkanoyl; one of Rl
and R2 and, independently, one of R3 and R4 is hydrogen, Cl-C6-alkyl, C2-C10-
alkenyl, C2-C10-alkynyl, phenyl, or aryl-Cl-C6-alkyl and the other is hydro-
gent hydroxy, Cl-C6-alkoxy or aryl-Cl-C6-alkoxy, or, Rl and R2 and, independ-
ently, R3 and R4 together form an oxo group; each R5 and R6, whether the
same or different, may be hydrogen, Cl-C6-alkyl or halogen, preferably
fluorine, or R5, R6 and the carbon atom to which they are bound form a
,C=CH2 or ,C - CH radical; Y is chosen from the group: -CH2-CH2-, -CH=CH-
12~13A
~(trans) or -CH=CZ- (cis) where z is hydrogen; X is chosen from the group:
-(CH2) - in which m3 is zero or l, -CH._CH- (cis), -CH=CH- (trans), -0-,
-S- and `N-R wherein R is as defined above; ml, m2, nl and n2, whether the
same or different, may be zero or an integer between 0 and 12 such that each
sum ml + m2 and nl + n2 is less than or equal to 15; p and q are independent-
ly zero or an integer between l and 3 such that the sum p + q is an integer
of l to 6; R7 is hydrogen or Cl-C4-alkYl.
This invention also covers lactones derived from compounds with
formula I, as well as pharmaceutically or veterinarily acceptable salts,
optical antipodes, and geometric isomers and diastereoisomers of compounds
with formula I, plus their mixtures.
In this discussion, a dashed line (lll ) refers to substituents on
a ring in the configuration, that is, below the plane of the ring, to sub-
stituents on a bicyclo [(p+q+1).3.0] alkane system (composed of condensed
rings A and B) in the endo configuration, and to substituents on a chain in
the S configuration. A wedged line ( _ ), on the other hand, refers to a
ring substituent in the configuration, that is above the plane of the ring,
to a bicyclo [(p+q+1).3.0] alkane substituent in the exo configuration, and
to a side chain substituent in the R configuration. A wavy line ( )
indicates a substituent of undefined stereochemistry: ring substituents may
be or I, becycloalkane substituents may be endo or exo, and side chain
substituents may be R or S.
The compounds with formula I and their derivatives described here
have a cis junction between condensed rings A and B; the hydrogen atoms bound
to the bicyclic system at the junction are both outside the dihedral angle
formed by the rings in the natural configuration.
The side chain on cyclopentane ring A (the chain) is trans with
respect to ring B and exo with respect to the bicyclic system.
In the compounds covered by this invention, there are two possible
geometric isomers arising from the configuration of the double bond exocyclic
to ring B, depending on whether the chain bound to this double bond (chain I)
is on the same side as or the opposite side from the chain on cyclopentane
- 2 -
lZQ$J 34
ring A (chain I): in the first case, the exocyclic double bond is defined
as cis; in the second, it is trans. In both formula I and the formulae which
follow, the symbol means that both geometric isomers are covered by this
invention, both separately and in mixtures.
The above notation refers to natural compounds. However, the
enantiomers covered by this invention show stereochemistry at all asymmetric
sites which is the opposite of that found in the natural compounds. They are
thus mirror images of the latter, and their names include the prefix "ent"
to indicate precisely that. d,l mixtures contain equimolar quantities of
the natural compounds and the corresponding enantiomers.
The alkyl, alkenyl, alkynyl, alkoxy and alkanoyloxy groups may be
straight or branched, unsubstituted or substituted with one or more of the
following: halogen, Cl-C6-alkoxy and aryl, phenyl in particular.
R is preferably a free or esterified carboxylic group, or its
derivative salt. A C1-C6-alkyl group is preferably methyl, ethyl or propyl.
A C2-C7-acyloxy group is preferably C2-C6-alkanoyloxy, for example, acetoxy,
propionyloxy, or benzoyloxy. A C2-C6-alkanoyl group is preferably acetyl or
propionyl. A C2-C6-alkylene radical is preferably ethylene or propylene. A
Cl-C6-alkoxy group is preferably methoxy, ethoxy or propoxy. An aryl-Cl-C6-
alkyl group is preferably benzyl. An aryl-Cl-C6-alkoxy group is preferably
benzyloxy. A C2-C10-alkenyl group is preferably -CH=CH-R8, where R8 is
hydrogen or straight or branched Cl-C8-alkyl, but preferably a vinyl group.
A C2-C10-alkynyl group is preferably -C-C-R8, where R8 is as defined above,
but preferably an ethynyl group. A halo-Cl-C6-alkyl group is preferably
trihalo-Cl-C6-alkyl, particularly trifluoromethyl. Preferably, R5 and R6
are independently chosen from hydrogen, Cl-C6-alkyl and fluorine. When R7
is Cl-C4-alkyl, methyl is preferred. When R is an esterified carboxyl group,
-COORg is preferred, where Rg is a Cl-C12-alkyl radical, particularly methyl,
ethyl, propyl, heptyl or C2-C12-alkenyl, allyl in particular. Preferably,
ml, m2, nl and n2 are independently zero, 1, 2 or 3.
Pharmaceutically or veterinarily acceptable salts of compounds
with formula I may be formed with both inorganic and organic acids and bases.
PA 3 _
12Q$134
Pharmaceutically or veterinarily acceptaole inorganic acids include
hydrochloric, hydrobromic and sulfuric; while organic acids include citric,
fumaric, tartaric, malic, maleic, methanesulfonic and ethanesulfonic. Ac-
cepta`ole inorganic bases may be the hydroxides of alkali or alkaline earth
metals, zinc and aluminum. Acceptable organic bases may be amines like
methylamine, diethylamine, trimethylamine, ethylamine, dibutylamine, triiso-
propylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine,
crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine,
~-phenylethylamine, ~-phenylethylamine, ethylenediamine, diethylenetriamine,
and other similar aliphatic, aromatic and heterocyclic amines like piperi-
dine, morpholine, pyrrolidine, piperazine, as well as substituted derivatives
like l-methylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine, 2-methyl-
pyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, hydrophilic deriv-
atives like mono-, di- and triethanolamine, 2-amino-2-butanol, 2-amino-1-
butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris-
(hydroxymethyl)-aminomethane, N-phenylethanolamine, N-(p-tert.-amylphenyl)-
diethanolamine, ephedrine, procain, and and amino acids like lysine and
arginine.
Under this invention, the preferred salts are compounds of formula
I in which R is -COORd, where Rd is a pharmaceutically or veterinarily
acceptable cation derived from one of the bases listed above.
In this discussion, the compounds covered by the invention will be
referred to as bicyclo [(p+q+1).3.0] alkane derivatives, or, preferably, as
derivatives of a 20 carbon atom compound, the prostacyclanoic acid, with the
following formula:
COOH
o~6\7
1 0~
1 20
in which the position of the oxygen atom is called the 9a-position.
- 4 -
!
lZ~134
Therefore, a compound with formula I in which p=q=l is a bicyclo
[3.3.0]octyl derivative or, preferably, a derivative of a 9a-deoxy-9a-
methylene prostacyclanoic acid, since a methylene group has taken the place
of the heteroatom in position 9a of the prostacyclanoic acid. A compound
with formula I in which p=2 and q=l is a bicycloL4.3.0]nonyl derivative, or,
preferably, a derivative of 9a-deoxy-9a,9b-dimethylene prostacyclanoic acid,
since two methylene groups have substituted the heteroatom in position 9a of
the prostacyclanoic acid. Analogously, a compound with formula I in which
p=3 and q=l is a bicyclo[5.3.0]dodecyl derivative or, preferably, a deriva-
- l0 tive of 9a-deoxy-9a,9b,9c-trimethylene prostacyclanoic acid.
Analogous prostacyclanoic acid derivatives in which q=2 or q=3
are called "7a-homo" or "7a,7b-dihomo" respectively, while compounds with
formula I with p or q equal to zero are called "9a-nor-methylene" or "7-nor-
methylene" respectively.
The same notation (homo, dihomo, nor, dinor, etc.) is used to
indicate lengthening (the former) or shortening (the latter) of the and
chains by one, two or more carbon atoms, relative to the number of carbon
atoms in prostacyclanoic acid.
As examples of this nomenclature, the following two compounds (Ia)
and (Ib) are named in full:
HOOC C
11
C \ (Ia)
'I, 8
1 H
OH 13 OH 17 19
- 5 -
12~134
\ 5~lcooH
9a / 6 a (Ib)
CH3
OH
OH
(Ia): 7-endo-hydroxy-6-exo-(3"S-hydroxy-oct-l'-trans-l'--enyl)-bicyclo-
[3.3.0]octyl-3(5')-pent-5'-trans-enoic acid; or 5t,13t-11,15S-dihydroxy-9a-
deoxy-9a-methylene-prostacyclan-5,13-dienoic acid; (Ib): 8-endo-hydroxy-7-
exo(3"R-hydroxy-4'S-methyl-non-l'-yl)-bicycloL4.3..0]nonyl-3(6')-hex-6'-cis-
enoic aeid; or5c-11,15R-dihydroxy-16S,20-dimethyl-9a-deoxy-9a-mmethylene-
7a,2a-dihomo-prostacyel-5-enoie aeid.
Under this invention, preferred compounds with formula I are those
in whieh R is a free or salified earboxy group; R7 is a straight or bran-
ched Cl-C4-alkyl and the other substituents have the meanings reported
above.
The following compounds are particularly preferred under this
invention:5e,13t-11,15S-dihydroxy-9a-deoxy-9a-methylene-proostaeyela-5,13-
dienoie aeid;5e,13t-11,15R-dihydroxy-9a-deoxy-9a-methylene-proostaeyela-
5,13-dienoic acid;5e-11,15S-dihydroxy-9a-deoxy-9a-methylene-prostaeeyel-5-
enoie acid, and its 15R epimer; a 16S-methyl derivative of the above
mentioned aeids; a 20-methyl derivative of the above mentioned acids; 5e,13t-
4-oxo-11,15S-dihydroxy-9a-deoxy-9a-methylene-prosstaeyela-5,13-dienoie aeid;
5e,13t-4S,11,15S-trihydroxy-9a-deoxy-9a-methylenee-prostaeyela-5,13-dienoie
aeid-1,4-y-laetone, and its 4R epimer; sodium salt of 5e,13t-4S,11,15S-
trihydroxy-9a-deoxy-9a-methylene-prostaeycla-5,13--dienoic aeid, and its 4R
epimer;5e,13t-11,15(S)-dihydroxy-9a-deoxy-9a-methylene-116-methyl-16-
butoxy-18,19,20-trinor-prostaeyela-5,13-dienoie acid; 5t,13t-11,15S-di-
hydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dieenoic acid; 5t,13t-11,15R-
P
- 6 -
12~34
dihydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-ddienoic acid 5t-lla,15S-
dihydroxy-9a-deoxy-9a-methylene-prostacycl-5-enoicc acid and its 15R epimer;
a 16S-methyl derivative of the above mentioned acids; a 20-methyl derivative
of the above mentioned acids; 5t,13t-4-oxo-lla,15S-dihydroxy-9a-deoxy-9a-
methylene-prostacycla-5,13-dienoic acid; 5t,13t-4S,11~,15S-trihydroxy-9a-
deoxy-9a-methylene-prostacycla-5,13-dienoic acid-1,4-y-lactone, and its 4R
epimer; sodium salt of5t,13t-4S,lla,15S-trihydroxy-9a-deoxy-9a-methylenee-
prostacycla-5,13-dienoic acid, and its 4R epimeri 5t,13t-lla,15S-dihydroxy-
9a-deoxy-9a-methylene-16-methyl-16-butoxy-18,19,200-trinor-prostacycla-5,13-
dienoic acid;5c,13t-lla,15S-dihydroxy-9a-deoxy-9a-nor-methylenee-prostacycla-
5,13-dienoic acid;5c,13t-lla,15S-dihydroxy-9a-deoxy-7-nor-methylene--prost-
acycla-5,13-dienoic acid;5c,13t-lla,15S-dihydroxy-9a-deoxy-9a,9b-dimethylenne-
prostacycla-5,13-dienoic acid; 5c~13t-lla~15S-dihydroxy-9a-deoxy-9a~7a-homo-
dimethylene-prostacycla-5,13-dienoic acid; 5c,13t-lla,15S-dihydroxy-9a-deoxy-
9a,7a-homo-dimethylene-15-methyl-prostacycla-5,13--dienoic acid; 5c,13t-lla,
15S-dihydroxy-9a-deoxy-9a,7a-homo-dimethylene-16S--methyl-prostacycla-5,13-
dienoic acid and the 16R-methyl isomer thereof; 5c,13t-lla,15S-dihydroxy-9a-
deoxy-9a,9b,7a-homo-trimethylene-2-nor-prostacyclaa-5,13-dienoic acid; 5t,13t-
lla,15S-dihydroxy-9a-deoxy-9a-nor-methylene-prostaacycla-5,13-dienoic acid;
5t,13t-lla,15S-dihydroxy-9a-deoxy-7-nor-methylene--prostacycla-5,13-dienoic
acid;5t,13t-lla,15S-dihydroxy-9a-deoxy-9a,9b-dimethylenne-prostacycla-5,13-
dienoic acid;5t,13t-lla,15S-dihydroxy-9a-deoxy-9a,7a-homo-dimetthylene-
prostacycla-5,13-dienoic acid; 5t,13t-lla,15s-dihydroxy-9a-deoxy-9a,7a-homo-
dimethylene-15-methyl-prostacycla-5,13-dienoic acid; 5t,13t-lla,15S-di-
hydroxy-9a-deoxy-9a,7a-homo-dimethylene-16S-methyll-prostacycla-5,13-dienoic
acid and the 16R-methyl isomer thereof; 5t,13t-lla,15S-dihydroxy-9a-deoxy-
9a,9b,7a-homo-trimethylene-2-nor-prostacycla-5,13--dienoic acid; as well as
the ll-deoxy-derivatives, the ll-epimers, the 15R-hydroxy isomers and all
the enantiomers of the compounds indicated above as well as their pharmaceu-
tically or veterinarily acceptable salts.
The compounds covered by this invention are prepared by a process
which comprises
- 7 -
~2~34
alkylation of compound II
/c \
(C P B (CH2)q
H H
< A II
R'l R~3 R5
2 C-(CH2)n ~~ X (CH2)n2 7
R~4 R6
wherein p, q, Y, nl, n2, X, R5, R6 and R7 are as defined above; one of R~
and R'2 and, independently, one of R'3 and R'4 is hydrogen, Cl-C6-alkyl,
C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl and the other is
hydrogen, hydroxy, Cl-C6-alkoxy, aryl-C1-C6-alkoxy or a protecting group
bound to the bicyclic system or the side chain through an ether linkage, or
R'l and R'2 and, independently, R'3 or R'4 together form a protecting group
for the ketone function, with a compound with formula III
E-CH-(CH2)m D (CH2)m2 III
wherein D, m1 and m2 are as defined above; E is a (C6H5)3P- or a
(R O)2P~(O)- group where each R may independently be C1-C6-alkyl or phenyl;
R"' is (a") a carboxylic group, free, esterified or as its salt;
(b") -C(OR')3, where R' is as defined above; (c") -CH2-R , where R is
C2-C7-acyloxy or a protecting group bound to -CH2- through an ether linkage;
(d") -CON a, where R and Rb are as defined above; (e") -C--N; (f") a
- Rb a X'R'
O ¦¦ radical; (g ) a -CH X~R~ radical where X', R' and R'b are as
- defined above, followed if required by the removal of any protecting group
present; or, if required, a compound of formula I in which Y is -CH=CZ-
where Z is hydrogen, is reduced to give, after the protecting groups are
removed, a compound of formula I in which Y is -CH2-CH2-; or, if required,
subjecting to nucleophilic addition the free carbonyl on the chain of a
compound of formula I in which Y is -CH2-CH2- or -CH=CZ- and Z is as defined
above, and R3 and R4 together form an oxo group to afford, upon removal of
A- - 8 -
12~S.34
any protecting groups, a compound of formula I in which Y is -CH2-CH2- or
-CH=CZ- and Z is as defined above, and one of R3 and R4 is hydroxy while the
i h drogen C -C -alkyl, C2-C10-alkeny 2 l
aryl-Cl-C6-alkyl and, if required, preparing the ether derivative from a
compound of formula I in which Y is -CH2-CH2- or -CH=CZ- wherein Z is as
defined above, one of R3 and R4 is hydroxy while the other is hydrogen,
C -C -alkyl, C -C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl, and
any other hydroxyl groups present are protected to give after removal of any
protecting groups a compound of formula I in which Y is -CH2-CH2- or -CH=CZ-
where Z is as defined above and one of R3 and R4 is Cl-C6-alkoxy or aryl-
Cl-C6-alkoxy while the other is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl,
C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl; or, if required, converting a
compound of formula I into another or to the lactone or pharmaceutically or
veterinarily acceptable salt or, if required, converting a salt of a com-
pound of formula I to the free compound or, if required, separating a mixture
of isomeric compounds of formula I into individual isomers.
Protecting groups for the hydroxyl functions are ether or ester
residues readily converted to hydroxyl groups under mild conditions, for
instance acid hydrolysis. Preferred groups include silyl ethers: for
instance trialkylsilyl ethers like trimethyl, dimethyl-tert.-butyl, dimethyl-
isopropyl, or dimethylethylsilyl ether; and also acetal and enol ether res-
idues: for instance, tetrahydropyranyl ether, tetrahydrofuranyl ether,
dioxanyl ether, oxathianyl ether,
a - ~0 Alk 0-Alk
where Alk is cl-C6-alkyl.
Ketone protecting groups are preferably ketal and thio-ketal
residues: O x R a groups in which X', R' and R'b are as defined
above.
Alkylation of a compound II with a compound III is carried out by
using at least a 1.1 molar equivalent excess of III per mole of II. The
A g
~Z~S134
reaction may be run in any inert solvent e.g. in a linear or cyclic ether
like diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane; in an ali-
phatic or aromatic hydrocarbon like n-hexane, n-heptane, benzene or toluene;
in a halogenated hydrocarbon like dichloromethane or carbon tetrachloride,
as well as in mixtures of these solvents.
Especially when E in compound III is (C6H5)3P-, dimethylsulfoxide~
hexamethylphosphoramide, and other aprotic solvents are particularly useful.
Dimethylsulfoxide jives the dimethylsulfinyl carbanion upon reaction with an
alkali hydride which in turn can venerate carbanions with formula III from
the corresponding phosphoranes and phosphonates; this solvent is thus par-
ticularly preferred, since carbanions III can then be generated ln situ.
For the alkylations described above, the reaction temperature may
range from the freezing point to the boiling point of water, although room
temperature is particularly preferred.
Reaction of a compound II with a compound III gives a mixture of
geometric isomers, in that the new exocyclic double bond formed in the
reaction may be cis or trans. If desired, the individual geometric isomers
may be separated by fractional crystallization from a suitable solvent or by
chromatography, either thin layer, column or liquid-liquid at low, medium or
2Q high pressure. Silica gel or magnesium silicate may be used as support with
a solvent like cyclohexane, n-hexane, benzene, methylene chloride, ethyl
ether, isopropyl ether, ethyl acetate or methyl acetate as the mobile phase.
When necessary, the ether protecting groups may be removed from
the hydroxyl functions with mild acid hydrolysis, for instance with mono- or
polycarboxylic acids like acetic, formic, citric, oxalic, or tartaric in a
solvent like water, acetone, tetrahydrofuran, dimethoxyethane or a low
molecular weight alcohol, or with a sulfonic acid like p-toluene-sulfonic
in a low molecular weight alcohol like anhydrous ethanol or methanol, or
with a polystyrene-sulfonic resin. For example, a 0.1-0.25N polycarboxylic
acid (like oxalic or citric) is used with a suitable low-boiling solvent
miscible with water and readily removable under vacuum at the end of the
reaction.
,~ - 10-
12~134
Silyl ether residues may be selectively removed in the presence of
other protecting groups with F ions in solvents like tetrahydrofuran and
dimethylformamide.
Ester protecting groups may be removed by following typical
saponification procedures.
Ketal and thioketal protecting groups for ketones are generally
removed as are acetal or thioacetal groups, with mild acid hydrolysis as
described above.
Thioketals and thioacetals may be selectively removed in the
presence of other protecting groups with, for instance, mercuric chloride in
aqueous acetone or acetonitrile, or a mixture of them, in the presence of an
alkaline earth carbonate like that of calcium or magnesium.
The optional reduction of a compound I in which Y is -CH=CZ-
wherein Z is hydrogen, to afford, after any protecting groups are removed,
a compound I in which Y is -CH2-CH2- is preferably run in liquid ammonia,
with or without a co-solvent (for instance, an aliphatic alcohol like tert.-
butanol or a 2-Cl-C4-alkylpropan-2-ol, or a cyclic ether like tetrahydro-
furan or dioxane), with an excess of an alklai or alkaline earth metal like
lithium, sodium, potassium or calcium. At the end of the reaction, a weak
acid like ammonium chloride or sulfate or an aliphatic alcohol like ethanol
or propanol is used as a protons source. The reaction temperature may range
from -70C to that of the solvent at reflux.
Nucleophilic addition to the free carbonyl group on the chain
in a compound I in which Y is -CH2-CH2- or -CH=CZ-, Z is as defined above,
and R3 and R4 together form an oxo group gives a secondary or tertiary
alcohol, depending on the nucleophile.
A secondary alcohol is preferably prepared with an alkali or alka-
line earth (like sodium, lithium, calcium or magnesium) borohydride or with
zinc borohydride to give, after any protecting groups are removed, a com-
pound I in which Y is -CH2-CH2- or -CH=CZ-, Z is as defined above, and one
of R3 and R4 is hydrogen and the other is hydroxy. 0.5-6 moles of reducing
agent are used per mole of the carbonyl derivative I, in an aqueous or
-- 11 --
12~134
anhydrous solvent; for instance, a linear or cyclic ether like ethyl ether,
tetrahydrofuran,dimethoxyethane or dioxane, an aliphatic or aromatic hydro-
carbon like n-heptane or benzene, a halogenated hydrocarbon like methylene
chloride, or a hydroxyl-containing solvent like methyl, ethyl or isopropyl
alcohol, as well as mixtures of these. The reaction temperature may range
from -40 C to the boiling point of the solvent, but is preferably between
-25C and +25 C.
A tertiary alcohol is prepared by reaction with an organometallic
derivative to give, aster any protecting groups are removed, a compound I in
which Y is -CH2-CH2- or -CH=CZ-, Z is as defined above, and one of R3 and R4
is Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl
while the other is hydroxy. The organometallic may be a magnesium deriva-
tive like RlOMg~al (in which Rlo is Cl-C6-alkyl, C2-C10-alkenyl, phenyl or
aryl-Cl-C6-alkyl and Hal is halogen, preferably chlorine or bromine), a
lithium cuprate like RloCuLi (Rlo as above), an organolithium derivative
like RloLi (Rlo as above), or an alkali or alkaline earth acetylide
(Rll-C-C-) M (in which n is 1 or 2, Rll is hydrogen, straight or branched
Cl-C8-alkyl, aryl-Cl-C6-alkyl, or aryl, particularly phenyl, and M is an
alkali or alkaline earth metal). The reaction between the carbonyl compound
and one of these organometallic derivatives is preferably run with 1.05
moles (or slightly more) of reagent per mole of compound, in an anhydrous
solvent: for instance, an aprotic solvent like dimethylsulfoxide or hexa-
methylphosphoramide, a linear or cyclic ether like ethyl ether, tetrahydro-
furan, anisole, dioxane or dimethoxyethane, or an aliphatic or aromatic
hydrocarbon like n-heptane, n-hexane, benzene or toluene. The reaction
temperature may range from approximately -70 C to the boiling point of the
solvent, but is preferably between -60 C and 20 C.
Whether it is a secondary or tertiary alcohol, the product of this
nucleophilic addition is a mixture of the epimeric S and R alcohols. The
individual S (I O 2) and R (I O R ) alcohols (in which R12 is hydrogen,
C -C -alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl) may
be separated as desired using the fractional crystallization and chromato-
, .
- 12 -
~2~134
graphy techniques described above.
The optional preparation of ethers from these secondary and
tertiary alcohols to give, after any protecting groups are removed, compounds
with formula I in which Y is -CH2-CH2- or -CH=CZ-, Z is as defined above,
and one of R3 and R4 is Cl-C6-alkoxy or aryl-Cl-C6-alkoxY while the other is
hydrogen Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-
alkyl, may be effected by reaction with an optionally aryl-substituted
diazoalkane in the presence of a catalyst like fluoroboric acid or boron
trifluoride in an organic solvent like dichloromethane. Alternatively, it
may be done by reaction of the hydroxyl group (either free or as its salt)
with an alkyl or arylalkyl halide in the presence of a base like silver
oxide, in a solvent like dimethylsulfoxide or dimethylformamide.
The following reactions are all run using standard procedures:
optional transformation of a compound with formula I into another, optional
lactone or salt preparation, preparation of the free compound I from its
salt, and separation of individual isomers from a mixture.
For example, a compound with formula I in which R3 and R4 are both
hydrogen may be prepared from one in which one of R3 and R4 is hydrogen while
the otheris hydroxy by preparing the tosylate from the alcohol, for instance
by treatment with tosyl chloride in the presence of base, and reducing the
tosylate with NaBH4 or NaB(CN)H3 in water, aqueous alcohol or dimethyl-
formamide or with LiAlH4 in an anhydrous solvent like ethyl ether or tetra-
hydrofuran, at a temperature ranging from room temperature to the boiling
point of the solvent. Analogously, a compound with formula I in which Rl
and R2 are both hydrogen may be prepared from one in which one of Rl and R2
is hydrogen while the other is hydroxy, and a compound I in which D is
-CH2- may be prepared from one in which D is ~CH-OH.
A compound with formula I in which R3 and R4 together form an oxo
group may be prepared from one in which one of R3 and R4 is hydrogen while
the other is hydroxy by selective oxidation with excess activated MnO2 in an
inert, preferably chlorinated solvent like methylene chloride or chloroform
at room temperature or, alternatively, with 1.1-1.2 molar equivalents of
,~
- 13 -
12~34
dichlorodicyanobenzoquinone in an inert solvent like dioxane, benzene or a
mixture at a temperature ranging from 40 C to the boiling point of the sol-
vent.
In an analogous fashion a compound with formula I in which Rl and
R2 together form an oxo group may be prepared from one in which one of Rl
and R2 is hydrogen while the other is hydroxy, and a compound I in which D
is ~C=O may be prepared from one in which D is ~CH-OH.
When only one of several secondary alcohol functions is to be
oxidized, the others must be protected as described above; the protecting
groups are then removed at the end of the reaction.
A compound with formula I in which one of Rl and R2 is Cl-C6-
alkoxy or aryl-Cl-C6-alkoxy may be prepared from one in which one of Rl and
R2 is hydroxy through etherification analogous to that described for a com-
pound with formula I in which one of R3 and R4 is hydroxy. Again, when only
one of several secondary alcohol functions is to react, the others must be
protected; the protecting groups are then removed at the end of the reaction.
A compound with formula I in which R is a carboxylic ester group
(for instance, a Cl-C12-alkoxycarbonyl) may be prepared from one in which R
is a free carboxylic group by following standard procedures, for example
reaction with an appropriate alcohol, like a Cl-C12-aliPhatic alcohol, in
the presence of an acid catalyst, like p-toluenesulfonic acid, or alterna-
tively, treatment with a diazoalkane.
The optional conversion of a compound with formula I in which R is
an esterified carboxyl group (i.e., a Cl-C12-alkoxycarbonyl) to one in which
R is a free carboxyl group may be effected using standard saponification
procedures: treatment with an alkali or alkaline earth hydroxide in water
or aqueous alcohol, followed by acidification.
The optional preparation of a compound with formula I in which R
is -CH2-R" (R"=hydroxy) from one in which R is a free or esterified carboxyl
group may be effected by reduction of the ester with LiAlH4 in ethyl ether
or tetrahydrofuran at reflux.
The optional conversion of a compound with formula I in which R is
12~34
a free carboxyl group to one in which R is -CO-N~R (R and Rb as defined
above) may be effected by treatment with an amine HNR Rb in the presence of
a condensing agent, for instance a carbodiimide like dicyclohexylcarbodiimide.
A compound with formula I in which R is a carboxylic ester may be converted
into one in which R is -CON Ra by treatment with an amine HNR Rb in a suit-
able organic solvent at reflux for 2-3 hours.
The optional preparation of a compound with formula I in which R
N-N
is a O radical from one in which R is a free carboxyl group may be
NH-N
effected by forming first the corresponding acid halide (preferably chloride,
perhaps with thionyl or oxalyl chloride in refluxing dichloroethane or diox-
ane), then the amide derivative (for example, with ammonia), followed by
dehydration to the nitrile (for instance with p-toluenesulfonyl chloride in
pyridine at 90-100 C) and finally reaction of the nitrile with sodium azide
and ammonium chloride in dimethylformamide at a temperature ranging from
room temperature to 100 C. This reaction of the carboxyl group to give -CN
N-N
or O is preferably run on the starting material.
\ NH-N
The optional conversion of a compound with formula I in which R is
a free or esterified carboxyl group into one in which R is -CHO may be
effected using standard procedures, for instance the preparation of the cor-
responding chloride from the acid or ester and subsequent Rosenmund reaction
as described in Org. Reactions,4,362(1948).
A compound with formula I in which R is -C(OR')3 (R' as defined
above) may be prepared from one in which R is a free or esterified carboxyl
group by reacting the hydrochloride of the carboximide ester (prepared with
standard methods) with a suitable alcohol, according to the procedure des-
cribed in J. Amer. Chem. Soc.,64,1827(1942), for example.
Acetalization, for example the optional preparation of a compound
X'R'
with formula I in which R is -CH ~x~R~a (where X' is oxygen and R' and R'b
are as defined above) is effected by reaction of the aldehyde with an alcohol
or glycol in the presence of a catalyst like p-toluenesulfonic acid or a sul-
fonic resin in a solvent which allows the removal of the water formed by
A
- 15 -
12~34
azeotropic distillation, by an exchange reaction with acetone-dioxolane in
which acetone is removed as it forms, or by reaction with an ortho-ester in
which the alcohol is distilled away as it forms. The acetal may also be
prepared from the corresponding thioacetal by reaction with a suitable
alcohol or glycol in the presence of a mercuric salt (preferably HgC12)
as an exchange catalyst and an alkaline earth carbonate, in an inert solvent.
Thioacetalization, for example the optional preparation of a com-
pound with formula I in which R is -CH X'R' (where X' is sulfur and R' and
R'b are as defined above) from one in which R is -CHO, is preferably
effected by reaction with a mono- or dimercaptan like methylmercaptan, ethyl-
mercaptan, dithioethyleneglycol or dithiopropyleneglycol in the presence of
a catalyst like boron trifluoride etherate in an inert solvent, preferably
a halogenated or aromatic hydrocarbon (methylene chloride, chloroform,
ben~ene, toluene).
The corresponding ketals and thioketals may be prepared from
ketones by following the procedure described above for acetals and thio-
acetals.
Lactone and salt preparation from a compound with formula I, as
well as preparation of compound I from its salt, are performed using standard
procedures.
Individual isomers are separated from mixtures of isomeric com-
pounds I using standard techniques like fractional crystallization and
chromatography.
Compounds with formula III in which E is (R O)2P~(O)- (R as
defined above) are prepared by reacting a compound VII
R O \ O
P-CH2-(CH2)m D (CH2)m2 VII
ReO
in which R , ml, D, m2 and R"' are as defined above, with at least one molar
equivalent of one of the following bases: an alkali or alkaline earth
hydride like sodium, potassium, lithium or calcium hydride, an alkali or
alkaline earth alcoholate like sodium or potassium tert.-butylate, an alkali
- 16 -
213~
or alkaline earth amide like sodium amide, or an alkali or alkaline earth
salt of a carboxyamide, like N-sodioacetamide and N-sodiosuccinimide.
Compounds with Eormula III in which E is (C6H5)3P- are prepared
by reacting a compound with formula VIII
Hal-CH2~(cH2)m D (C 2)m2 VIII
in which ml, D, m2 and R"' are as defined above and Hal is halogen with
1.1-1.3 molar equivalents of triphenylphosphine in an organic solvent like
benæene, acetonitrile or diethyl ether and then treating the product
phosphonium salt with an equivalent quantity of an inorganic base like
NaOH~ KOH~ Na2C3 or NaHco3.
Compounds with formula VII are prepared using standard methods,
for example those described by Corey et al. in J. Amer. Chem. Soc.,90,3247
(1968) and 88,5654(1966). Compound VIII are also prepared following standard
procedures.
Compounds with formula II are new compounds covered by this inven-
tion, as are procedures for their preparation.
Compounds with formula II in which Y is -CH2-CH2-, or -CH=CZ-,
z as defined above, are prepared in a procedure involving:
(a ) reaction of a compound with formula XI
G \
(CH2)p (CH2)q
H H XI
I
R 1 R' CHO
wherein p, q, R'l and R'2 are as defined above and G is a protected carbonyl
group or a group ,CH~OG' wherein G' is a silyl ether or acetal ether
residue, with a compound of formula V
t =5
E-CH-c-(cH2)m X (CH2)m2 7 V
O R
B. wherein E, z, I, R5, R6, X, and R7 are as defined above, to afford a
- 17 -
12~34
compound of formula XII
( CH 2 ) p OH 2 ) q
H H
XII
C=C-C-(CH2)n X (C 2)n2 7
H O R6
1 2 l R5, R6, X, n2 and R7 are as defined above;
(b ) optional conversion of a compound with formula XII into a
compound of formula XIII
/ \
H H
/ XIII
= 3 -5
R'l R y~-C-(CH2)n X (CH2)n2 7
R~4 R6
1 2' 3~ R 4, nl, R5, R6, X, n2 and R7 are as defined
above, and Y' is -CH2-CH2- or -CH=CZ-, Z as defined above;
(c ) removal of the protecting group in G to afford a compound
of formula XIV
/ Go
( CH 2 ) p ( CH 2 ) q
H H
R' R XIV
y~-c-(CH2)n ~~ X (CH2)n2 7
R' R6
1' 2' , R 3, R 4, nl, R5, R6, X, n2 and R7 are as defined
above and G" is,CH~HOH or ~C=O;
(d ) optional oxidation of a compound of Iormula XIV wherein G"
is ~CH~OH and the other hydroxy groups, if present, are protected as
- 18 -
lZ0~34
reported above.
The reaction between a compound with formula XI and one with
formula V is run in the same way as that reported above for the reaction
between compounds II and compounds III.
The optional conversion of a compound with formula XII into one
with formula XIII is effected with reactions analogous to those described
above for the preparation of one compound with formula I from another: for
example, nucleophilic addition to the carbonyl on the chain, etherifica-
tion of the product alcohols and hydrogenation.
As stated above, when G is a group ,CH~OG', the protecting group
G' may be a silyl ether residue (for instance, a trialkylsilyl ether like
trimethyl, dimethyl-tert.-butyl, dimethylisopropyl, or dimethylethylsilyl
ether, but preferably dimethyl-tert.-butyl) or an acetal ether residue
(for instance, tetrahydropyranyl ether, tetrahydrofuranyl ether, dioxanyl
ether, oxathianyl ether, but preferably tetrahydropyranyl).
The protecting group G' in a compound with formula XIII is removed
as described previously: that is, selectively, with F for a silyl ether
and with acid hydrolysis for an acetal ether. When a protecting group G'
must be removed in the presence of other labile ether groups, these latter
should be acetal ethers when -OG' is a silyl ether or silylethers when -OG'
is an acetal ether.
When G is a protected carbonyl group it is preferably protected as
acetal or thioacetal, for example a dimethoxyacetal, a diethoxyacetal, a
dimethylthioacetal, a diethylthioacetal, preferably a dimethoxyacetal, or as
ketal, or thioketal, for example a ethylenedioxyketal OH O , a propylene-
dithioketal 1 2) S a propylenedioxyketal (CH ) O , a ethylenedithio-
ketal IH S preferably a ethylenedioxyketal.
The removal of said protecting groups in a compound of formula
XIII as well as the optional protection of the free hydroxy groups in a com-
pound of formula XIV, e.g. as acetal ethers or silyl ethers, may be effected
as previously reported.
The optional oxidation of a compound of formula XIV wherein G" is
- 19-
~2'~ 34
hydroxy, may be effected using standard oxidation procedures for secondary
alcohols: for example treatment of the alcohol in an organic solvent like
acetone with a solution of chromic anhydride in sulfuric acid, following
normal procedures,
Compounds with formula XI are prepared with a procedure involving:
(a ) conversion of a compound XXIA or XXIB
OH G"'
(CH2)p (CH2)q ~,2 P 2 q
'I, _ H by Y H
XXIA XXIB
O OH
in which p and q are as defined above and G"' is a protected carbonyl group
as reported above, into a compound XXII
/ G
XXII
in which p, q and G are as defined above;
(b ) reaction of compound XXII with a compound O=C(OR13)2 in
which R13 is a Cl-C6-alkyl or aryl-Cl-C6-alkyl to give a compound with
formula XXIII
G
( C"H 2 ) p t CH 2 )
H H
XXIII
O COOR13
in which p, q, G and R13 are as defined above;
(c ) reduction of the product compound XXIII to a compound with
formula XXIV
- 20 -
12~34
H H
XXIV
H OH COOR13
in which G, p, q and R13 are as defined above;
(d ) optional separation of compound XXIV into the individual
optical antipodes;
(e ) optional conversion of compound XXIV into a compound with
formula XXV
/ G
(CH2)p (CH2)
H ~7 H
XXV
- COOR13
OH H
in which G, p, q and R13 are as defined above;
(f ) transformation of a compound XXIV or XXV into a compound
with formula XXVI
~"2 p 2 q
H H
/ XXVI
R' . ECHO
1 R 2
wherein G, p, q, R'l and R'2 are as defined above.
A compound of formula XXII wherein G is a group, CH~OG', in which
G' is as defined above may be prepared from one of formula XXIA by known
methods, e.g. by reaction in the presence of base, with a silyl halide, a
silazane or a silyl trifluoroacetamide or, for example, by reaction with a
vinyl ether X~=JO where X" is -O-, -S- or -(CH2) (r=0,1), according to
'A'
- 21 -
;lZ~134
known procedures.
A compound of formula XXII, in which G is a protected carbonyl,
may be prepared from one of formula XXIB by oxidation in pyridine with an
excess of the pyridine-chromic anhydride complex, or by oxidation according
to Moffatt in a mixture of benzene and dimethylsulphoxide with dicyclohexyl-
carbodiimide in the presence of pyridinium trifluoroacetate.
The reaction between a compound with formula XXII and O=C(OR13)2
(R13 as defined above, but preferably methyl) is run in the presence of
2-4 moles of a base like sodium methoxide, sodium ethoxide, sodium or
potassium hydride or potassium tert.-butoxide, with an excess of 6-12 moles
of carbonic diester per mole of ketone, neat or in an inert solvent in an
oxygen- and water-free atmosphere. The temperature may range from approxi-
mately 0 -80 C (preferably 60-80 C) for a period between 10 minutes and l
hour. The yield varies from 5% to 90%, depending on the temperature, the
reaction time and the concentration.
A compound with formula XXIII may be reduced with an alkali or
alkaline earth borohydride in aqueous solution, preferably at a pH between
5.3 and 7.2, or at -20 C with ethanolic NaBH4 in methylene chloride/ethanol.
Generally, the reduction is complete in 30 minutes and the excess reagent is
quenched by adding a readily reducable species, like acetone, and a proton
donor, like acetic acid.
The individual optical antipodes of a compound with formula XXIV,
in which G is as defined above, may be separated by saponifying the ester
using standard procedures, forming a salt of the product acid with an opti-
cally active base like quinine, chinconine, ephedrine, l-phenyl-l-amino-
ethane, dihydroabietylamine, amphetamine or arginine, and separating the
resulting diastereomeric salts by fractional crystallization, for example.
The optically active acid is then recovered by conversion to the sodium salt
and subsequently acidification of its aqueous solution to a pH which does
not interfere with the protecting group in G.
Optionally the hydrolysis of the protecting groups may precede the
optical resolution: the protecting groups are then restored at the end of
En
A - 22 -
12~34
the separation process.
The optically active free acid prepared in this way is then con-
verted to an optically active ester XXIV using standard procedures, for
instance treatment with a suitable diazoalkane.
If desired, using an identical procedure, a racemic mixture of
compounds XXV may be separated into individual optical antipodes.
Alternatively, compounds XXIV and XXV wherein G is a protected
carbonyl group may be resolved into their optical antipodes deprotecting
the carbonyl group in G, reacting this with an optically active primary
amine, for example arginine, lysine, alanine, l-phenyl-l-ethyl-amine, 1-
phenyl-l-propyl-amine and similar, to give the corresponding optically
active diastereoisomeric Schiff bases; these may be separated by known
methods, e.g. by fractionate crystallization or by ~PLC, the imino group may
be hydrolized to ~C=O in a known manner then the separated optically active
keto-esters may be transformed into the optical antipodes XXIV and XXV by
ketalization or acetalization in a conventional way.
The optional conversion of a compound with formula XXIV to one
with formula XXV may be done on either a racemic mixture or the individual
isomers separated as described above. In this transformation, the configura-
tion of the free hydroxyl on the cyclopentane ring is inverted. The proce-
dure involves esterification of the hydroxyl, for example by treatment with
2-4 molar equivalents of triphenylphosphine and 2-4 molar equivalents of a
carboxylic acid like acetic, benzoic or p-phenylbenzoic, or with 2-4 molar
equivalents of ethyl azo-bis-carboxylate in an inert solvent like an aromatic
hydrocarbon, perhaps halogenated, like benzene or chlorobenzene, or a cyclic
ether like tetrahydrofuran, and subsequent selective saponification of the
ester function formed in this way, for example by transesterification in an
inert alcohol R13OH in the presence of an alkali carbonate, preferably
K2C03 -
A compound with formula XXVI is prepared from a compound XXIV or
XXV using known methods. For example, the free hydroxyl group in compound
XXIV or XXV may be converted to a Cl-C6-alkoxy, an aryl-Cl-C6-alkoxy or a
- 23 -
34
labile ether like a silyl or acetal ether using the etherpreparation tech-
niques already described for the analogous reactions of compounds with
formula I.
The free hydroxyl group in a compound with formula XXIV or xxV
may be oxidized to an oxo group, and the product ketone may be converted to
a ketal or thioketal according to the procedure described above for compounds
with formula I to afford a tertiary alcohol.
A hydrogen atom may replace the free hydroxyl group in a compound
with formula XXIV or XXV, for example, by treatment with a sulfonic acid
chloride like p-toluenesulfonyl, methanesulfonyl or benzenesulfonyl chloride
and subsequent reduction of the product sulfonate, for instance with LiAlH4
in standard methods. In this case the carboxylic ester group (-COOR3) is
reduced at the same time to the primary alcohol (-CH2OH), which may then be
oxidized to the aldehyde with Moffatt's reagent.
A product compound with formula XXVII
G \
(CH2)p (_ 2)q
H H
XXVII
R"l C 13
in which one of R"l and R"2 is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, aryl
or aryl-Cl-C6-alkyl while the other is hydroxy, Cl-C6-alkoxy, aryl-Cl-C6-
alkoxy or a labile ether group, or R"l and R"2 together form a ketone pro-
teeting group may be eonverted to the eorresponding compound with formula
XXVI by reduction following standard procedures, for example, with diiso-
butylaluminum hydride or lithium diisobutylaluminum hydride.
When a compound XXVII is reduced with LiAlH4 following standard
procedures, the product is the corresponding primary alcohol which may also
be prepared from the free acid by standard reduetion with BH3 in tetrahydro-
furan. The free acid is prepared by saponification of the ester. This pri-
mary alcohol may then be oxidized to the aldehyde, with Moffatt's reagent,
- 24 -
~2~34
for example, as mentioned previously.
Compounds with formula XXIA and XXIB are prepared with known
methods. For example, a compound XXIA in which p=q=l is prepared by selec-
tive reduction of bicyclo[3.3.0]octane-3,7-dione (J. Amer. Chem. Soc.,82,
6347(1960)) or by reduction of bicyclo[3.3.0]octane-3,7-dione-monoketal
(J. Org. Chem.,39,2377(1974)), followed by removal of the ketal from the
carbonyl function. In both cases, the product hydroxy ketone XXI with p=q=l
is a mixture of the endo-hydroxy and exo-hydroxy derivatives, with approxi-
mately 80% endo. The two isomers may readily be separated, using the corres-
ponding racemic silyloxy derivative, by fractional crystallization or
chromatography, as described several times above.
A compound with formula XXI in which p=l and q=2 is prepared frombicyclo[4.3.0]non-7-en-3-one XXVIII
o XXVIII
H
which has a cis junction between the two rings, in a procedure involving the
protection of the ketone as a ketal or thioketal (as described above),
standard hydroboration of the double bond, and subsequent removal of the
ketone protecting group as described above.
Compound XXVIII may be synthesized, for example, as described by
J.P. Vidal in "Stereochimie et Selectivite Reactionelle en Serie Bicyclo-
[n.3.0]alcanique", presented at the Universite de Sciences et Tecniques du
Languedoc, Academie de Montpelier, n d'orde C.N.R.S.A.O. 11257(1975).
A compound with formula XXIA in which p=l and q=2 (prepared, for
example, as described above) may be converted to other XXI derivatives by
successive detalization or thioketalization, oxidation, Bayer-Willinger and
formulation of the product using methods analogous to those reported above.
A compound of formula XXIB wherein p is zero and q is 1 or p is 1
and q is zero may be prepared from the bromidrine 5-exo-bromo-6-endo-hydroxy-
- 25 -
12~:9.'t34
bicyclo[3.2.0]heptan-2-one [J. Chem. Soc., Perkin, l, 1767 (1965)] by known
methods: for example said bromidrine may be converted into its acetal, thio-
acetal, ketal or thioketal, then dehalogenated to the compound XXIB using
the known methods of organic chemistry such as, for example, the reduction
with chromium (II) salts, the catalytic hydrogenation in the presence of
Pd/CaCO3 or Pd/C and in the presence ofanhalohydric acid acceptor, or the
reduction with tributyl tin hydride.
A compound of formula XXIB wherein p is 2 and q is l or q is 2 and
p is l, may be prepared, e.g., from a compound of formula XXVIII by a process
comprising: reducing the carbonyl group to alcohol, e.g. with LiAlH4 in
ethyl ether, protecting the alcoholic group, e.g. as tetrahydropyranylether
or silyl ether, hydroborating, by conventional methods, the olefinic double
bond, oxidizing, deblocking the protected hydroxy group, following the
acetalization or ketalization.
A compound of formula XXIB wherein p=q=2 may be prepared by known
methods e.g. from 2-hydroxy-perhydro-azulen-6-one which in turn may be
obtained as described by D.IC. Banerjee and lC. Sankara Ram. in Ind. J. of
Chem. vol. X, page l tl972).
The compound of formula XXVIII may be used as starting material
also for the preparation of the compounds of formula XI wherein G is a group
~CH~OG' wherein G' is the residue of a silyl ether and wherein, when one of
R'l and R'2 is hydrogen and the other is hydroxy, the latter is preferably
protected as acetal ether or as ester, following the reaction scheme reported
below:
- 26 -
12~ 34
CO CH
2 3 OH 2 3
O O
(XXVIII) (XXIX) (XXX)
2 3 2 3 C2CH3
O-Acetal O-Acetal O-Acetal
(XXXI) (XXXIIa : G'=H) (XXXIIIa : G'=H)
(XXXIIb : G'=silyl- (XXXIIIb : G'=silyl-
ether residue) ether residue)
The compound XXVIII, by known methods, e.g. those previously
reported, is converted into the ~-keto ester XXIX which is reduced to the I-
hydroxy ester XXX wherein the hydroxy group is protected as acetal ether;
the obtained compound XXXI is then submitted, in a conventional manner. to
the hydroboration at the olefinic double bond to give the alcohols XXXIIa and
XXXIIIa which are then resolved by chromatography or by fractionate crystal-
lization, converted into the corresponding silyl ethers XXXIIb and XXXIIIb
and finally transformed into the compounds of formula XI by reduction with
diisobutylaluminium hydride in toluene according to known methods.
The compounds of formula I show the same pharmacological activities
as the natural prostacyclin, or PGI2 but, as compared with PGI2, the com-
pounds covered by this invention have a particular advantage in their
greater stability in the range of pH between zero and 11, in particular, at
physiologic pH: this leads to longer lasting and more constant biological
activity. The source of this greater stability is the different chemical
structure of these compounds as compared to natural prostacyclin. Since
there is an oxygen heteroatom in the 2-oxa-bicyclo[3.3.0]octane system,
natural prostacyclin is an exocyclic enol ether and so is extremely acid
- 27 -
`~ ~2`~34
sensitive. The product of reaction with acid, 6-keto-PGFl , shows almost
none of the biological activity characteristic of natural prostacyclin. On
the other hand, the compounds covered by this invention have no oxygen in
the bicyclic system and so are not enol ethers. Since they are not highly
labile as are the natural derivatives, they may be administered by mouth.
In addition, compounds of formula I in which there is a hindering
group, such as a Cl-C6-alkyl group or an electron receptor group, e.g.
fluorine, near the hydroxyl in position 15 (R3 or R4 = hydroxy) are more
resistant to enzyme-induced (for instance, 15-PG-dehydrogenase) metabolic
degradation than natural prostacyclin.
The pharmacological actions of natural prostacyclin are known.
Thus, for example, when inhaled in asthmatic patients, prostacyclin prevents
aspecifically induced (e.g. by nebulized water or by effort) bronchocostric-
tion [S. Bianco et al, J. Res. Medical Science, 6, 256 (1978)]; when infused
in man, it shows hypotensive and vasodilator activity and also shows blood
platelet anti-aggregant and disaggregant properties LSzekely et al, Pharm.
Res. Comm. 10, 545 (1978)]; prostacyclin also possess uterus stimulant action
in the monkey and in woman; furthermore, prostacyclin exhibits luteolytic
activity in test animals and is able to protect the gastric mucous membrane
from ulcers induced by non-steroidal anti-inflammatory substances, e.g.
acetyl salicyclic acid (ASA) and indomethacin, in test animals, e.g. the rat.
In natural prostacyclin these activities are combined with a marked
chemical instability which is unsuitable for pharmaceutical use. As already
reported, the compounds of formula I have pharmacological actions similar to
those of natural prostacyclin but the undesired chemical instability of
PGI2, is absent in the compounds of the invention.
The following Table shows the ln vitro inhibitory effect on plate-
let aggregation induced by 10 em ADP in platelet rich plasma and the hypo-
tensive effect on the anaesthetized rat of two compounds of the invention
and PGI2.
tp~,
- 28 -
12~13~
ln vitro antiaggregant hypotensive effect
effect
IC50 mg/ml potency ratio
(1) 1 100
(2)25 1.15
(3)20 0.25
tl) PGI2
(2) 5t,13t-11,15S-dihydroxy-9a-deoxy-9a-methylene-proostacycla-
5,13-dienoic acid
(3) 5t,13t-11~,15S-dihydroxy-9a-deoxy-9a,7a-homo-dimetthylen-
prostacycla-5,13-dienoic acid.
IC50 = 50~ platelet aggregation inhibiting concentration.
A comparison between PGI2 and the compound dl-5,13t-11,15S-
dihydroxy-9a-deoxy-7-nor-methylene-prostacycla-5,113-dienoic acid shows that,
for equi-active antiaggregant doses, the antiulcerogenic activity of the
latter is ten times greater than that of PGI2.
As to their prostacyclin- and prostaglandin-like activity the com-
pounds covered by this invention may be used in human and veterinary medicine
when natural prostacyclin and prostaglandins are indicated therapeutically.
For instance, these compounds are useful in treating asthma because
of their pronounced bronchodilatory effect. In this application, they may be
administered by various routes:
- 29 -
-,`t $~3~
- 30 -
orally in tablets, capsules, pills, or liquids like drops or
syrups; rectally, in suppositories, intravenously, intra-
muscularly or subcutaneously; by inhalation as aerosols or
vaporizer solutions; or by insufflation as powders. Doses of
approximately 0.01-4mg/kg may be given from 1 to 4 times daily,
but the exact dose depends on the age, weight and condition of
the patient as well as the administration method.
For anti-asthmatic applications the compounds covered
by this invention may be combined with other anti-asthmatics:
simpaticomimetics like isoproterenol, ephedrine, etc.; xanthine
derivatives like theophillin and aminophillin; and
corticosteroids like prednisolone and ACTH.
In addition the compounds covered by this invention
exhibit oxytocic activity and so may be used in place of
oxytocin to induce labor or expel a dead fetus, both in human
and veterinary obstetrics. For this application, the compounds
are given intravenously at a dose of approximately O.Ol~g/kg/
minute until the end of labor, or by mouth.
The compounds covered by this invention are also
luteolytic and so are useful in fertility control, with the
advantage that they stimulate the smooth muscles much less and
so are free of the side effects of natural prostaglandins like
vomiting and diarrhea.
Further, these compounds are anti-ulcerogenic and thus
may be used to reduce and control excessive gastric secretion in
mammals. In this way they minimize or eliminate the formation
of gastrointestinal ulcers and accelerate the cure of any ulcers
already present in the gastrointestinal tract. They are admin-
istered in this case by intravenous infusion or by intravenous,
subcutaneous or intramuscular injection; doses for intravenous
12(~34
- - 31 -
infusion range from O.l~g to 500~g/kilo/minute. The total daily
dose for both injection and infusion is on the order of 0.1-
20mg/kg depending on the age, weight and condition of the
patient or animal and on the administration method.
However, like natural prostacyclines, the most impor-
tant pharmacological property of the compounds covered by this
invention is their platelet anti-aggregant activity, that is,
the capacity to inhibit platelet aggregation, to decrease adhe-
sion, to prevent clot formation and to dissolve recently-formed
clots. This platelet anti-aggregant activity is also associated
with a relaxing of the coronary arteries. For these reasons,
these compounds are useful in preventing and treating myocardial
infarctions and, in general, in treating and preventing
thromboses, in treating conditions like atherosclerosis,
arteriosclerosis and, more generally, dihyperlipidemia.
Normal administration methods are used in this applica-
tion: that is, intravenous, subcutaneous, intramuscular, etc.
In emergency situations intravenous administration is preferred,
in doses ranging from 0.005 to 20mg/kg/day, again depending on
the age, weight and condition of the patient and on the adminis-
tration method. As mentioned above, the compounds covered by
this invention are useful in human and veterinary therapy, with
several administration methods. They may be given orally in
tablets, capsules, drops or syrups; rectally in suppositories;
parenterally, in solutions or suspensions gives subcutaneously
or intramuscularly; intravenously, as preferred in emergencies;
by inhalation in aerosols or vaporizer solutions; in sterile
grafts for prolonged action; or endovaginally, for instance in
vaginal suppositories.
Pharmaceutical and veterinary compositions of the com-
lZ~3~
- 32 -
pounds covered by this invention may be prepared conventionally
using common carriers and/or diluents. For example, sterile and
isotonic aqueous solutions are preferred for intravenous injec-
tion or infusion. Sterile aqueous solutions or suspensions in
aqueous or nonaqueous medium are used for subcutaneous or intra-
muscular injections. A sterile compress or a silicon rubber
capsule containing or impregnated with the active ingredient may
be used for sterile grafts.
Conventional carriers and diluents include water,
gelatine, lactose, dextrose, sucrose, mannitol, sorbitol, cellu-
lose, talc, stearic acid, calcium and magnesium stearate,
glycols, starch, gum arabic, gum adragant, alginic acid,
alginates, lecithin, polysorbates, vegetable oils, etc.
The compounds may be given with a vaporizer using an
aqueous suspension or solution of them, preferably in their salt
forms, for instance the sodium salt. Or the compounds may be
suspended or dissolved in one of the common liquified propel-
lants like dichlorodifluoromethane or dichlorotetrafluoroethane
and given with a pressurized container like an aerosol bomb.
When the compound is not soluble in the propellant, a co-solvent
must be added to the pharmaceutical formulation: for instance,
ethanol, dipropyleneglycol and/or a tensioactive substance.
In the following examples, THP, DMtB, DIOX, THF, DMSO,
DIBA and DMF refer respectively to tetrahydropyranyl, dimethyl-
tert-butyl, 1,4-diox-2-enyl, tetrahydrofuran, dimethylsulphoxide,
diisobutylaluminiumhydride and dimethylformamide.
The following examples illustrate but do not in any
way limit the present invention.
Example 1
l.lg of sodium borohydride (0.029 mol) is added with
~2~34
- 33 -
stirring to a solution of 11.6g of bicyclo[3.3.0]octane-3,7-
dione (8.4xlO mol) in lOOml of methylene chloride and lOOml of
ethanol. After 45 minutes at this temperature, the excess rea-
gent is decomposed by slowly adding 20ml of acetone. The mix-
ture is then neutralized with 1.4ml of acetic acid, and evapor-
ated under vacuum to afford a residue which is taken up in water
and methylene chloride. The organic phase is evaporated to dry-
ness and filtered on silica gel (70:30 hexane:ethyl ether as
eluent) to afford 9.lg of 7~-hydroxy-bicyclo[3.3.0]octan-3-one.
A solution of this compound (0.065mol) in 27ml of
anhydrous dimethylformamide is treated with 12.8g of dimethyl-
tert-butylsilyl chloride and 8.85g of imidazole. The resulting
mixture is heated to 60 C for 5 hours, cooled diluted with two
volumes of water and extracted with ethyl ether (3x40ml and
2x20ml). The combined organic extract is washed with 5% NaHCO3
and then water until neutral, and evaporate to dryness to give
15.8g of crude product (95% yield). Purification on silica gel
affords 2.85g of 7-exo-hydroxy-bicyclo[3.3.0]octan-3-one-
dimethyl-tert-butylsilyl ether and 11.8g of 7-endo-hydroxy-
bicyclo[3.3.0]octan-3-one-7-dimethyl-tert-butylsillyl ether.
A solution of the latter (11.8g, 4.63xlO mol) in
295ml of methyl carbonate (Me2CO3) is stirred with the exclusion
of water in an inert atmosphere and treated cautiously with
6.95g of 80% sodium hydride. When hydrogen evolution ceases,
the reaction mixture is heated at 75-80C for forty minutes.
After cooling, the mixture is diluted with two volumes of ethyl
ether and cautiously treated with 13g of glacial acetic acid.
The organic phase is then separated with pH 5.2-5.5 buffer and
the aqueous layer is extracted with ethyl ether. The combined
organic extract is dried over Na2SO4 and evaporated to dryness
120$~34
- 34 -
to give 12.82g of d,1-7-endo-hydroxy-bicyclo[3.3.0]octan-3-one-
2-carboxymethylester-7-dimethyl-tert-butylsilyl ether (85% of
the 14.49g theoretical yield), which after purification on
silica gel (45g/g, with 97:3 hexane:ethyl ether as eluent)
affords 10.81g of the pure product; ~maX=254m~,E=7,000.
Starting with the exo isomer, the same procedure
affordsd,l-7-exo-hydroxy-bicyclo[3.3.0]octan-3-one-2-carbboxy-
methylester-7-dimethyl-tert-butyl silylether; ~maX=254m~=6~500.
Example 2
A solution of 7.5g of d,l-7-endo-hydroxy-bicyclo-
[3.3.0]octan-3-one-2-carboxymethylester-7-dimethyll-tert-butyl
silylether (DMtB-silylether) in 75ml of dichloromethane and 75ml
of ethanol is cooled to -20C and treated with stirring with
O.9g of sodium borohydride. After stirring for 15 minutes, the
excess reagent is destroyed by adding 12ml of acetone. The mix-
ture is brought to 0C, 20ml of 20~ KH2PO4 is added, the solvent
is evaporated under vacuum and the residue is extracted several
times with ethyl ether. The combined organic extract is washed
with 5ml of water and evaporated to dryness to afford a residue
which is crystallized from n-hexane to give 4.8g of d,l-3,7-endo-
dihydroxy-bicyclo[3.3.0]octane-2-exo-carboxymethyllester-7-DMtB-
silylether, m.p.=68-70C. The mother liquor is adsorbed on 25g
of silica gel; elution with 90:10 n-heptane:ethyl ether gives
another 2g of product pure enough to be used as is.
A solution of 6g of d,l-3,7-endo-dihydroxy-bicyclo-
E3.3.o]octane-2-exo-carboxymethylester-7-DMtB-silyylether in
lOOml of 80:20 methanol:water is treated with 2g of potassium
hydroxide and heated to reflux for 30 minutes. After concentra-
tion under vacuum, the mixture is acidified to pH 5.1 and ex-
tracted with ethyl acetate. Evaporation of the organic layer
æ
1 l ~3 4
- 35 -
gives 5.lg of d,1-3,7-endo-dihydroxy-2-carboxy-bicyclo[3,3,0]-
octane-7-DMtB-silylether. A solution of this compound in 150ml
of acetonitrile is then treated with 2.81g of d-(+)-ephedrine.
4 hours at room temperature afford 2.9g of a salt which is cry-
stallized twice from acetonitrile to give 1.85g of (+)-3,7-endo-
dihydroxy-2-exo-carboxy-bicyclo[3.3.0]octane-7-DMttB-silylether-
dt+)-ephedrine salt. All the mother liquors are collected and
evaporated to dryness to give a residue which is dissolved in
water and treated with 0.68g of sodium hydroxide in water. The
d-(~)-ephedrine is recovered in a benzene extraction, and the
sodium salt solution is acidified to pH5 and extracted with
ethyl acetate. The organic phase is evaporated to dryness to
give a residue which is treated with 2.2g of l-ephedrine to
afford after several crystallizations 2.3g of (-)-3,7-endo-
dihydroxy-2-exo-carboxy-bicyclo[3.3.03octane-7-DMttB-silylether-l-
ephedrine salt.
Example 3
A solution of 6.28g of d,1-3,7-endo-dihydroxy-bicyclo-
[3.3.0]octane-7-DMtB-silylether-2-exo-carboxymethyylester in 30ml
of anhydrous methylene chloride is treated with 2.19g of 2,3-
dihydropyran and 39mg of p-toluenesulfonic acid. After 3 hours
at room temperature, the reaction mixture is washed with 5%
NaHCO3 (2xSml). Evaporation of the organic phase to dryness
gives 8g ofd,l-3,7-endo-dihydroxy-bicyclo13.3.0]octane-7-DMtBB-
silylether-3-THP-ether-2-carboxymethyl ester, which is then
dried by being taken up in anhydrous benzene (2xl5ml) and evapor-
ated to dryness. This product in 30ml of anhydrous ethyl ether
is added dropwise, in 15 minutes, to a stirred suspension of
0.6g of LiAlH4 in 40ml of anhydrous ethyl ether. Stirring is
continued for 30 minutes before the excess reagent is destroyed
l 34
- 36 -
by the cautious addition of 5ml of acetone followed by water-
saturated ethyl ether. 10g of anhydrous sodium sulfate is then
added. Filtration of the organic solution and evaporation to
dryness afford 7.2g of d,l-3,7-endo-dihydroxy-2-exo-hydroxy-
methylbicyclo[3.3.0]octane-7-DMtB-silylether-3-THP-etherr.
The following compounds are prepared in this way from
optically active starting materials:
nat-3,7-endo-dihydroxy-2-exo-hydroxymethyl-bicycloo[3.3.0]octane-
7-DMtB-silylether-3-THP-ether;
ent-3,7-endo-dihydroxy-2-exo-dihydroxymethyl-bicycclo[3.3.0]-
octane-7-DMtB-silylether-3-THP-ether.
If 1,4-diox-2-ene is used instead of 2,3-dihydropyran,
the corresponding 3(2'-DIOX)-ethers are obtained.
Example 4
A solution of 3.8g of d,l-3,7-endo-dihydroxy-bicyclo-
[3.3.0]octane-2-exo-carboxymethylester-7-DMtB-silyylether in 40ml
of benzene is treated first with 3.66g of benzoic acid and 7.9g
of triphenylphosphine, and then, with stirring, with 5.30g of
ethyl azo-bis-carboxylate in 15ml of benzene. After 40 minutes
~0 of stirring, the organic phase is washed with 2N sulfuric
(2x20ml), and then sodium carbonate (3xl5ml) and finally water
until neutral. Evaporation to dryness affords a mixture of d,l-
3-exo-7-endo-dihydroxy-bicyclo[3.3.0]octane-2-exo--carboxymethyl-
ester-7-DMtB-silylether-3-benzoate and d,l-7-endo-hydroxy-
bicyclo[3.3.0]oct-3-ene-2-exo-carboxymethylester-77-DMtB-silyl-
ether.
The crude reaction product is dissolved in anhydrous
methanol, stirred for 3 hours, and treated with 0.5g of
anhydrous potassium carbonate. Evaporation to dryness affords a
residue which is taken up in ethyl acetate and saturated KH2PO4.
~2~3~
The organic phase is washed until neutral and evaporated to dry-
ness. The residue is adsorbed on silica gel and eluted with
hexane and hexane:ethyl ether to give:
a) 1.01g ofd,1-7-endo-hydroxy-bicyclo[3.3.0]oct-3-ene-2-carbooxy-
methylester-7-DMtB-silylether, which is dissolved in methanol,
treated with 0.3g of 5% Pd on CaCO3 and hydrogenated at room
temperature and pressure to give d,1-7-endo-hydroxy-bicyclo-
[3.3.0]octane-2-carboxymethylester-7-DMtB-silylethher;
b) 2.01g ofd,l-3-exo-7-endo-dihydroxy-bicyclo[3.3.0]octane-2--
carboxymethylester-7-DMtB-silylether, which is saponified as des-
cribed in Example 2 with 5% potassium carbonate in 80:20
methanol:water to give d,l-3-exo-7-endo-dihydroxy-bicyclo[3.3.0]-
octane-2-exo-carboxy acid-7-DMtB-silylether. This is then
separated into individual optical antipodes with (+) and (-)
amphetamine.
Reaction with ethereal diazomethane converts (+)-3-exo-
7-endo-dihydroxy-bicyclo[3.3.0]octane-2-exo-carboxxy acid-7-DMtB-
silylether into the methyl ester derivative. Subsequent reac-
tion with 2,3-dihydropyran followed by reduction with LiAlH4 in
ethyl ether gives (+)-3-exo-7-endo-2-exo-hydroxymethyl-bicyclo-
[3.3.0]octane-3-THP-ether-7-DMtB-silylether.
The (-) enantiomers and the racemic mixture are pre-
pared analogously.
Example 5
5g of d,l-7-endo-hydroxy-bicyclo[3.3.0~octane-DMtB-
silylether-3-exo-carboxymethylester in 100ml of aqueous methanol
is saponified with 2g of KOH, at reflux. After the methanol is
removed under vacuum, the aqueous solution of the potassium salt
is extracted to remove neutral impurities, acidified, and ex-
tracted with ethyl ether. The latter extracts are combined and
~2~13~
- 38 -
evaporated to dryness to give 4.5g of the d,l acid which is then
separated into optical antipodes with (+) and (-) ephedrine.
1.32g of (-)-7-endo-hydroxy-bicyclo[3.3.0]octane-7-
DMtB-silylether-2-exo-carboxy acid is then dissolved in 20ml of
THF and treated with 10ml of lM sH3 in THF. After 4 hours at
room temperature, the excess reagent is destroyed by the cau-
tions addition of 20ml of 1.5N NaOH. The THF is then removed
under vacuum and the aqueous phase is extracted with ethyl ether.
The combined organic extract is washed until neutral and evapor-
ated to dryness to afford 1.02g of (-)-7-endo-hydroxy-2-exo-
hydroxymethyl-bicyclo[3.3.0]octane-7-DMtB-silylethher.
The (+) isomer and the racemic mixture are prepared
analogously.
Example 6
2.7g of d,1-7-endo-hydroxy-2-exo-hydroxymethyl-bicyclo-
[3.3.0]octane-7-DMtB-silylether in 20ml of methylene chloride is
treated with 0.95g of 2,3-dihydropyran and 20mg of p-toluene-
sulfonic acid for 3 hours at room temperature. After being
washed with 7~ aqueous NaHCO3 and then water, the organic phase
is evaporated to dryness to give crude d,l-7-endo-hydroxy-2-exo-
tetrahydropyranyloxymethyl-bicyclo[3.3.0]octane-7--DMtB-silyl-
ether. This is dissolved in 15ml of THF and treated with 4.5g
of tetrabutylammonium fluoride for 10 hours, with stirring. The
reaction mixture is then concentrated under vacuum, adsorbed on
silica gel and eluted with benzene:ethyl ether to give 2.lg of
d,1-7-endo-hydroxy-2-exo-THP-oxymethyl-bicyclo[3.33.0]octane. A
solution of this product in 25ml of acetone is cooled to -20 C -
-8 C with stirring and treated with 4.2ml of 8~ Jones' reagent
(CrO3 in aqueous sulfuric acid) over a period of 15 minutes,
until a slight pink color persists. After an additional 14-20
12~3~
- 39 -
minutes of stirring, 1.5ml of isopropanol is added dropwise and
the resulting green solution is diluted with 6 volumes of
benzene. The organic phase is washed with 20% (NH4)2SO4 until
neutral, and the combined aqueous phase is re-extracted with
benzene. The combined benzene extract is dried and evaporated
to dryness to afford 1.82g of d,l-2-exo-THP-oxymethyl-bicyclo-
[3.3.0]octan-7-one.
The nat- and enant- isomers are prepared analogously.
Example 7
With external cooling and stirring to keep the reac-
tion temperature near 20-22C, a solution of 6.57g of potassium
tert-butylate in 65ml of DMSO is added dropwise to 6.76g of
4-carboxybutyl-triphenyl-phosphonium bromide in 40ml of DMSO.
After the addition, the mixture is diluted with an equal volume
of water, acidified to pH 5 and extracted with ethyl ether. The
aqueous phases are discarded, and the combined organic extract
is re-extracted several times with 0.5N NaOH. The alkaline
aqueous phases are acidified to pH5 and re-extracted with 50:50
ethyl ether:pentane. This combined organic extract is brought
to small volume, treated with ethereal diazomethane until a yel-
low coloration persists, and then evaporated to dryness. The
residue is then dissolved in 50ml of acetone, treated with 20ml
of 2N aqueous oxalic acid, and held at 40-45 C for 8 hours.
After the acetone is removed under vacuum, the aqueous phase is
extracted with ethyl acetate, and the combined organic extract
is evaporated to dryness. Purification of the resulting residue
on silica gel with ethyl ether as eluent gives a mixture of d,l-
5-cis,trans-[2'-exo-hydroxymethyl-bicyclo[3.3.0]occt-7'-enyl]-
pentenoic acid methyl ester (1.75g). The individual isomers may
be separated with high pressure liquid-liquid chromatography to
134
- 40 -
the 5-trans-d,l and the 5-cis-d,l isomers; the latter is named
5-cis-~(20~12)-octanor-12-hydroxymethyl-9a-deoxy-99a-methylene-
prostacycl-5-enoic acid methyl ester.
If the 4-carboxybutyltriphenylphosphonium bromide in
the above procedure is replaced by one of the following Wittig
reagents (3-carboxypropyltriphenylphosphonium bromide, 5-carboxy-
pentyltriphenylphosphonium bromide, 4-carboxy-2-oxabutyltri-
phenylphosphonium bromide), the methyl esters of the following
acids are prepared:
d,1-5-cis-~(20>12)-octanor-2 nor-12~-hydroxymethyl-9a-deoxy-9a-
methylene-prostacycl-5-enoic acid;
d,l-5-cis-~(20~12)-octanor-2ahomo-12~-hydroxymethyyl-9a-deoxy-9a-
methylene-prostacycl-5-enoic acid;
d,l-5-cis-~(20~12)-octanor-3-oxa-12~-hydroxymethyll-9a-deoxy-9a-
methylene-prostacycl-5-enoic acid;
as well as their 5-trans isomers and the individual nat- and
enant- antipodes.
Example 8
A stirred solution of 7.16g of 5-cis-~(20~12)-octanor-
12~-hydroxymethyl-9a-deoxy-9a-methylene-prostacycll-5-enoic acid
methyl ester in 80ml of 75:25 benzene:dimethylsulfoxide is
treated with 8.9g of dicyclohexylcarbodiimide and then with
14.2ml of a pyridinium trifluoroacetate solution (prepared by
adding 25ml of 75:25 benzene:DMSO to lml of trifluoroacetic acid
and 2ml of pyridine). After four hours of stirring, the reac-
tion mixture is diluted with lOOml of benzene and 3g of oxalic
acid in water is added dropwise. The dicyclohexylurea is re-
moved by filtration, the organic phase is separated and washed
with water (5x6ml). Reduction in volume gives a benzene solu-
tion of the 12~-formyl derivative which is added all at once to
:~L2r~3
- 41 -
a solution of (2-oxo-heptyl)dimethyl phosphonate sodium salt.
The latter is prepared by adding dropwise 7.58g of ~2-oxo-
heptyl)-dimethyl phosphonate in 4Oml of anhydrous benzene to a
stirred solution of 1.02g of sodium hydride (80% mineral oil dis-
persion) in an inert gas atmosphere, continuing stirring until
H2 evolution ceases. After the addition of the formyl deriva-
tive to this sodium phosphonate salt, stirring is continued for
20 minutes. The reaction mixture is then neutralized with satur-
ated monosodium phosphate solution. The organic phase is separ-
ated, reduced to small volume, adsorbed on silica gel and eluted
with cyclohexane: ethyl ether to give 6.4g of 5-cis-13-trans-9a-
deoxy-9a-methylene-15-oxo-prostacycla-5,13-dienoicc acid methyl
ester.
Using an analogous 12~-hydroxymethyl derivative from
example 7 gives the methyl esters of the following acids:
5-cis-13-trans-9a-deoxy-9a-methylene-15-oxo-2-nor--prostacycla-
5,13-dienoic acid;
5-cis-13-trans-9a-deoxy-9a-methylene-15-oxo-2ahomoo-prostacycla-
5,13-dienoic acid;
5-cis-13-trans-9a-deoxy-9a-methylene-15-oxo-3-oxa--prostacycla-
5,13-dienoic acid;
as well as their 5-trans geometric isomers, in the nat-, enant-
and d,l forms.
Example 9
A stirred and cooled (5-8C) solution of 1.35g of
2-exo-hydroxymethyl-7-endo-hydroxy-bicyclo[3.3.0]ooctane-DMtB-
silylether in 5ml of pyridine is treated with 0.82g of benzoyl
chloride. After 8 hours at room temperature, 2N H2SO4 is added
and the mixture is extracted with ethyl ether to give 2-exo-
benzoyloxymethyl-7-endo-hydroxy-bicyclo[3.3.0]octaane-7-DMtB-
12~34
- 42 -
silylether. This silylether group is removed by reflux in 20ml
of acetone with 8ml of 2N oxalic acid. The acetone is removed
under vacuum and the residue is extracted with ethyl ether to
afford, after purification on silica gel, l.llg of 2-exo-benzoyl-
oxymethyl-7-endo-hydroxy-bicyclo[3.3.0]octane. This is dis-
solved in pyridine and then added to a solution of lg of CrO3 in
lOml of pyridine. After 6 hours at room temperature, this mix-
ture is diluted with 20ml of benzene and filtered. The filtrate
is evaporated under vacuum and the residue is taken up in 2N
sulfuric acid and benzene. After being washed with 2N H2SO4 and
water until neutral, the organic extract is evaporated to dry-
ness to afford 0.98g of 2-exo-benzoyloxymethyl-bicyclo~3.3.0]-
octan-7-one. A solution of this compound in 5ml of anhydrous
THF is then added to a solution of (2-oxo-5-trimethoxy-pentyl)-
dimethyl phosphonate sodium salt, prepared by adding dropwise a
suspension of 0.23g of 80% sodium hydride in THF to a solution
of 2.12g of (2-oxo-5-trimethoxy-pentyl)-dimethyl phosphonate in
6ml of anhydrous THF. After 10 hours of stirring, the mixture
is neutralized with 15% KH2PO4, the THF is evaporated under
vacuum and the residue is extracted with ethyl ether. The com-
bined extract is concentrated in volume, adsorbed on silica gel
and eluted with hexane:ether to afford l.lg of 2'-benzoyloxy-
methyl-bicyclo[3.3.0]oct-7-enyl-1,1,1-trimethoxy-ppent-5-en-4-one,
or12~-benzoyloxymethyl-~(20~12)-octanor-4-oxo-9a-deooxy-9a-
methylene-prostacycl-5-enoic acid-orthomethylester, as a mixture
of the 5-cis and 5-trans olefins which are then separated by
high pressure liquid-liquid chromatography.
Subsequent treatment with aqueous methanol and H2SO4
gives the corresponding methyl ester derivatives. Reaction of
0.3g of methyl ester with 0.25ml of 1,3-ethanedithiol in
12~134
- 43 -
methylene chloride and a catalytic amount of BF3-etherate for 15
minutes at 0C then affords 12~-benzoyloxymethyl-~20~12)-
octanor-4,4-ethylenedithio-9a-deoxy-9a-methylene-pprostacycl-5-
enoic acid methyl ester.
Example 10
0.8g of 12~-benzoyloxymethyl-~(20~12)-octanor-4-oxo-9a-
deoxy-9a-methylene-prostacycl-5-enoic acid methyl ester in 10ml
of methanol is selectively de-benzoylated upon treatment with
stirring with 0.15g of anhydrous K2CO3. After the solvent is
evaporated, the residue is taken up in 15~ aqueous KH2PO4 and
methylene chloride to afford upon evaporation of the organic
phase12~-hydroxymethyl-~20)12)-octanor-4-oxo-9a-deoxy-99a-
methylene-prostacycl-5-enoic acid methylester. A solution of
this compound in 10ml of CH2C12 and 10ml of ethanol cooled to
-20 C is treated with 90mg of NaBH4 and stirred for two hours.
Excess reagent is then destroyed with 15~ aqueous acetic acid,
the solvent is evaporated and the residue is adsorbed on silica
gel. Elution with ethyl ether affords 0.21g of 12~-hydroxy-
methyl-~(20~12)-octanor-4S-hydroxy-9a-deoxy-9a-metthylene-
prostacycl-5-enoic acid methyl ester and 0.13g of the 4R-hydroxy
isomer.
The individual products are then saponified with 20%
aqueous methanol and 19~ potassium carbonate to afford, after
acidification and extraction with ethyl acetate, 0.18g of
12~-hydroxymethyl-~(20tl2)-octanor-4S-hydroxy-9a-ddeoxy-9a-
methylene-prostacycl-5-enoic acid-1,4-~-lactone and 0.11g of the
4R isomer. Oxidation of these following the procedure in
example 8 gives the 12-formyl derivatives.
Example 11
0.28g of 4,4-ethylenetithio-12~-benzoyloxymethyl-
~Z~3~
- 44 -
~(20>12)-octanor-9a-deoxy-9a-methylene-prostacycl--5-enoic acid
methyl ester is selectively de-benzoylated upon methanolysis
with K2CO3 in anhydrous methanol to give the corresponding
12~-hydroxymethyl derivative. This is then oxidized to the
aldehyde according to the procedure in example 8 to give the
12~-formyl derivative.
Reaction of 0.12g of this compound in benzene with the
phosphonate prepared from 0.177g of (2-oxo-3,3-dimethyl-heptyl)-
dimethyl phosphonate and 20mg of 80~ NaH, as described in
example 8, gives 5,13t-16,16-dimethyl-4,4-dithioethylenedioxy-
15-oxo-9a-deoxy-9a-methylene-prostacycla-5,13-diennoic acid
methylester.
In an analogous fashion, using (4-cyclohexyl-2-oxo-
butyl)-dimethyl phosphonate as the phosphonate and the 4S-
lactone from example 10 as the aldehyde affords 5,13t-4S-hydroxy-
15-oxo-9a-deoxy-9a-methylene-17-cyclohexyl-18,19,220-trinor-
prostacycla-5,13-dienoic acid-1,4-~-lactone. Or, with (3-
phenoxy-2-oxo-propyl)-dimethyl phosphonate, 5,13t-4S-hydroxy-15-
oxo-9a-deoxy-9a-methylene-17,18,19,20-tetranor-16--phenoxy-
prostacycla-5,13-dienoic acid-1,4-~-lactone is prepared.
Example 12
Using (2-oxo-3S-methyl-heptyl)-dimethyl phosphonate
and (2-oxo-3S-fluoro-heptyl)-dimethyl phosphonate as the phos-
phonates and12~-formyl-~(20~12)-octanor-4R-hydroxy-9a-deoxy-9aa-
methylene-prostacycl-5-enoic acid-1,4-~-lactone as the aldehyde,
tne procedures of examples 8 and 11 afford:
5,13t-4R-hydroxy-15-oxo-9a-deoxy-9a-methylene-16S--methyl-
prostacycla-5,13-dienoic acid-1,4-~-lactone;
5,13t-4R-hydroxy-15-oxo-9a-deoxy-9a-methylene-16S--fluoro-
prostacycla-5,13-dienoic acid-1,4-~-lactone.
2~ 34
- 45 -
Example 13
A solution of 0.7g of 5c,13t-15-oxo-9a-deoxy-9a-
methylene-prostacycla-5,13-dienoic acid methyl ester in 7ml of
methylene chloride and 7ml of ethanol cooled to -20C is treated
with 38mg of sodium borohydride. After 20 minutes of stirring,
the reaction is quenched with 2ml of acetone and 2.5ml of 20%
aqueous NaH2PO4. The mixture is then reduced in volume under
vacuum and extracted with methylene chloride. The combined
organic extract is evaporated to dryness to give a residue which
is purified on silica gel with ethyl ether as eluent to afford
0.32g of5c,13t-15S-hydroxy-9a-deoxy-9a-methylene-prostacyccla-
5,13-dienoic acid methylester and 0.26g of the 15R isomer.
This same procedure for reducing the 15-oxo deriva-
tives from examples 8, 11 and 12 affords the methyl esters of
the following acids:
5cis,13-trans-9a-deoxy-9a-methylene-lSS-hydroxy-2--nor-
prostacycla-5,13-dienoic acid;
5cis,13trans-9a-deoxy-9a-methylene-15S-hydroxy-2ahhomo-
prostacycla-5,13-dienoic acid;
5cis,13trans-9a-deoxy-9a-methylene-15S-hydroxy-3-ooxa-prostacycla-
5,13-dienoic acid;
5cis,13trans-9a-deoxy-9a-methylene-4,4-diethioethyylenedioxy-15S-
hydroxy-prostacycla-5,13-dienoic acid;
and the 1,4-lactones of the following acids:
5c,13t-9a-deoxy-9a-methylene-4S,14S-dihydroxy-17-ccyclohexyl-
18,19,20-~-trinor-prostacycla-5,13-dienoic acid;
5c,13t-9a-deoxy-9a-methylene-4S,15S-dihydroxy-16-pphenoxy-
17,18,19,20-~-tetranor-prostacycla-5,13-dienoic acid;
5c,13t-9a-deoxy-9a-methylene-4R,15S-dihydroxy-16S--methyl-
prostacycla-5,13-dienoic acid;
lZ~34
- 46 -
5,13t-9a-deoxy-9a-methylene-4R,15S-dihydroxy-16S-ffluoro-
prostacycla-5,13-dienoic acid;
as well as their 5-trans geometric isomers, in the nat-, enant-
and d,l forms.
Example 14
A solution of 0.35g of 5c,13t-15-oxo-9a-deoxy-9a-
methylene-prostacycla-5,13-dienoic acid methylester in lOml of
2:1 ethyl ether:toluene is cooled to -30C and treated with stir-
ring with 5ml of 5% methyl magnesium iodide in ethyl ether.
After 4 hours of stirring, the mixture is brought to 0 C and
quenched with 20% aqueous ammonium chloride. The organic phase
is washed with water, sodium bicarbonate and water, dried over
MgSO4, treated with O.lml of pyridine, and evaporated under
vacuum to give a mixture of the 15S and 15R alcohols. Separa-
tion on silica gel with 80:20 ethyl ether:isopropyl ether as
eluent affords O.lg of 5c,13t-15S-hydroxy-9a-deoxy-9a-methylene-
prostacycla-5,13-dienoic acid methylester and O.lg of the 15R
isomer.
Example 15
With the same substrate but anhydrous THF as solvent,
reaction with 8ml of 0.3M ethynyl magnesium bromide in THF gives,
after chromatography on silica gel, 5c,13t-15-ethynyl-15S-
hydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dieenoic acid
methylester and its 15R isomer.
With 0.3M vinyl magnesium bromide, 5c,13t-15-vinyl-15S-
hydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dieenoic acid
methylester and its 15R isomer are prepared.
Example 16
A solution of 0.26g of 5c,13t-9a-deoxy-9a-methylene-
4R,15S-dihydroxy-16S-methyl-prostacycla-5,13-dienooic acid-1,4-~-
:12~134
- 47 -
lactone in methylene chloride is cooled to -10 -8 C and treated
with stirring with 0.3ml of boron trifluoride etherate
(1.2xlO M in anhydrous methylene chloride) and then 5% diazo-
methane in methylene chloride until a yellow color persists.
The solution is washed with 5% aqueous NaHCO3 and then water
until neutral, evaporated to dryness, and purified on silica gel
(3g) to give 0.21g of 5c,13t-9a-deoxy-9a-methylene-4R,15S-
dihydroxy-16S-methyl-prostacycla-5,13-dienoic acid-1,4-~-lactone-
15-methylether.
Example 17
A solution of 0.74g of d,1-2-exo-hydroxymethyl-3-exo-
THP-oxy-7-endo-DMtB-silyloxy-bicyclol3.3.0]octane in 15ml of
anhydrous methylene chloride is added all at once to a solution
of 3.1g of Collin's reagent (C5H5N2)2.CrO3 in 40ml of anhydrous
methylene chloride, with stirring and cooling to 0-5C. Filter-
ing earth is added after 15 minutes of stirring and the mixture
is filtered to give a clear solution of the corresponding d,l-2-
exo-formyl derivative. After the solvent is evaporated under
vacuum, the residue is taken up in anhydrous benzene and added
to a solution of sodium dimethyl-(2-oxo-octyl)-phosphonate.
This latter is prepared by adding 0.59g of (2-oxo-octyl)-
dimethyl phosphonate in lOml of benzene dropwise to a suspension
of 0.07g of 80% NaH in 20ml of benzene and stirring the result-
ing mixture for approximately 1 hour, until hydrogen evolution
ceases. Stirring is continued for 20 minutes after the aldehyde
is added to the phosphonate carbanion solution. The organic
phase is then neutralized with excess 25% aqueous NaH2PO4 and
separated. After drying, it is evaporated to dryness to give a
residue which is purified on silica gel (cyclohexane:ethyl ether
as eluent) to afford 0.81g of d,l-2-exo-[3'-oxo-non-1'-trans-1'-
enyl]-3-exo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo[33.3.0]octane.
12i~34
- 48 -
Example 18
A solution of 1.05g of d,1-2-exo-hydroxymethyl-3-endo-
THP-oxy-7-endo-DMtB-silyloxy-bicyclo[3.3.0]octane in 8ml of
75:25 benzene:DMSO is treated with 0.89g of dicyclohexylcarbodi-
imide and then, with stirring, with 1.42ml of a pyridinium tri-
fluoroacetate solution. After 3 hours of stirring, 20ml of
benzene are added and excess carbodiimide is quenched with 0.13g
of oxalic acid in 3.8ml of water. The benzene phase is separ-
ated, washed until neutral, and concentrated under vacuum to
give a solution of 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-
silyloxy-bicyclo[3.3.0]octane.
The d,l-nat- and enantio-formyl derivatives are pre-
pared using this procedure. In the same way, if 7-exo-hydroxy-
bicyclo[3.3.0]octan-3-one-7-dimethyl-tert-butylsillylether is
used in the procedures of examples 1, 2 and 3, 2-exo-formyl-3-
endo-THP-oxy-7-exo-DMtB-siloxy-bicyclo[3.3.0]octanne is obtained.
Example 19
A solution of 322mg of (2-oxo-heptyl)-dimethyl phos-
phonate in 5ml of benzene is added to a suspension of 43.5mg of
80~ NaH in lOml of benzene, and the resulting mixture is stirred
until hydrogen evolution ceases. In the dark, 258mg of finely
divided N-bromosuccinimide are added and stirring is continued
for another 5 minutes. 0.37g of 2-exo-formyl-3-endo-THP-oxy-7-
endo-DMtB-silyloxy-bicyclo[3.3.0]octane in 5ml of benzene is
then added and the resulting mixture is stirred for another 15
minutes, after which the reaction mixture is partitioned between
benzene and 15% NaH2PO4. The organic phase is dried, concen-
trated to small volume, adsorbed on silica gel and eluted with
80:20 cyclohexane:ethyl ether to afford 0.42g of 2-exo-[2'-bromo-
3'-oxo-oct-1'-enyl]-3-endo-THP-oxy-7-endo-DMtB-sillyloxy-bicyclo-
[3.3.0]octane (~max=251m~,=9,250).
a
~LZ~34
- 49 -
If (2-oxo-3R-fluoro-heptyl)-dimethyl phosphonate is
used, the corresponding 2-exo-[2'-bromo-3'-oxo-4'R-fluoro-oct-l'-
trans-enyl]- derivative is obtained.
Example 20
A solution of 0.3g of [2-oxo-4(2')-tetrahydrofuryl-
butyl]-dimethyl phosphonate is added dropwise to a stirred sus-
pension of 36mg of 80% sodium hydride in 5ml of benzene. Stirr-
ing is continued until hydrogen evolution ceases, and then a
solution of 0.37g of 2-exo-formyl-3-endo-THP-oxy-7-exo-DMtB-
silyloxy-bicyclo[3.3.0]octane is added. After another 20
minutes of stirring, the mixture is taken up in benzene and 20%
aqueous monosodium phosphate. The organic phase is separated,
concentrated to small volume, adsorbed on silica gel and eluted
with benzene:ethyl ether to give 0.35g of 2-exo-[3'-oxo-5'(2")-
tetrahydrofuryl-pent-l'-trans-enyl]-3-endo-THP-oxyy-7-exo-DMtB-
silyloxy-bicyclo[3.3.0]octane (~max=229m~=8, 800) .
Example 21
If 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-
bicyclo[3.3.0]octane was the 2-exo-formyl-7-exo-bicyclo deriva-
tive used in the procedure described in example 20, and if the
following phosphates were used:
(2-oxo-heptyl)-dimethyl phosphonate;
(2-oxo-octyl)-dimethyl phosphonate;
(2-oxo-3S-methyl-heptyl)-dimethyl phosphonate;
(2-oxo-4-cyclohexyl-butyl)-dimethyl phosphonate;
(2-oxo-4-phenyl-butyl)-dimethyl phosphonate;
(2-oxo-3-m-trifluoromethylphenoxy-propyl)-dimethyll phosphonate;
(2-oxo-3-methyl-3-butoxy-butyl)-dimethyl phosphonate;
then the following compounds were prepared:
3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-~oxo--oct-1'-trans-1'-
enyl)-bicyclo~3.3.0]octane;
12~:134
- 50 -
3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo-nnon-1'-trans-1'-
enyl)-bicyclo[3.3.0~octane;
3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo-44'S-methyl-oct-
l'-trans-l'-enyl)-bicyclo[3.3.0~octane;
3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo-55'-cyclohexyl-
pent-l'-trans-l'-enyl)-bicyclo[3.3.0]octane;
3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo-55'-phenyl-pent-
l'-trans-l'-enyl)-bicyclo[3.3.0]octane;
3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo-44'-m-trifluoro-
methylphenoxy-but-1'-trans-1'-enyl)-bicyclo[3.3.0]]octane;
3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo-44'-methyl-4'-
butoxy-pent-l'-trans-l'-enyl)-bicyclo[3.3.0]octanee.
Example 22
A solution of 0.3g of d,l-2-exo-(2'-bromo-3'-oxo-4'R-
fluoro-oct-l'-trans-l'-enyl)-3-endo-THP-oxy-7-endoo-DMtB-
silyloxy-bicycloL3.3.0]octane in lOml of anhydrous ether is
added dropwise in 15 minutes to a O.lM solution of zinc boro-
hydride in ethyl ether (lOml). After stirring for two hours,
the reaction mixture is quenched with saturated sodium chloride
and 2N sulfuric acid. The ether layer is separated and washed
with water, 5~ NaHC03, and then water. Evaporation to dryness
affords a mixture of the 3'S and 3'R hydroxy alcohols which are
separated by liquid-liquid chromatography with isopropyl ether
as solvent to give O.llg of d,l-2-exo-(2'-bromo-3'S-hydroxy-4'R-
fluoro-oct-l'-trans-l'-enyl)-3-endo-THP-oxy-7-endoo-DMtB-
silyloxy-bicyclo[3.3.0]octane and O.g of the 3'R epimer.
Example 23
A solution of 0.3g of 2-exo-[3'-oxo-5'(2")-tetrahydro-
furyl-pent-l'-trans-l'-enyl]-3-endo-THP-oxy-7-exo--DMtB-silyloxy-
bicyclo[3.3.0]octane in 3ml of methylene chlGride and 3ml of
1~3~34
- 51 -
ethanol is cooled to -10-15C and then treated with 25mg of
NaBH4. After 30 minutes of stirring, the reaction mixture is
quenched with 1.5ml of acetone and 3ml of saturated NaH2PO4,
evaporated under vacuum, and then extracted with methylene
chloride. The organic phase is dried over Na2SO4 and evaporated
to dryness to give a residue which is purified on silica gel
(hexane:ethyl ether as eluent) to afford O.lg of 2-exo-~3'S-
hydroxy-5'(2")-tetrahydrofuryl-pent-1'-trans-1'-ennyl]-3-endo-THP-
oxy-7-exo-DMtB-silyloxy-bicyclo[3.3.0]octane and O.llg of the
3'R isomer.
Example 24
By following the procedure of examples 22 and 23 using
one of the unsaturated ketones prepared as in examples 19,
20 and 21, the following compounds were prepared:
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(2'-brommo-3'S-hydroxy-
oxt-l'-trans-l'-enyl)-bicyclo[3.3.0]octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hyddroxy-oct-l'-
trans-l'-enyl)-bicyclo[3.3.0]octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hyddroxy-4'S-
methyl-oct-1'-trans-1'-enyl)-bicyclo[3.3.0]octane;;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hyddroxy-non-l'-
trans-l'-enyl)-bicyclo[3.3.0]octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hyddroxy-cyclo-
hexyl-pent-l'-trans-l'-enyl)-bicyclo~3.3.0]octane;;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hyddroxy-5'-phenyl-
pent-l'-trans-l'-enyl)-bicyclo[3.3.0]octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hyddroxy-4'-m-tri-
fluoromethylphenoxy-but-l'-trans-l'-enyl)-bicyclo[[3.3.0]octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hyddroxy-4'-methyl-
4'-butoxy-pent-1'-trans-1'-enyl)-bicyclo[3.3.0]octtane;
~2~34
- 52 -
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(2'-brommo-3'R-hydroxy-
oct-l'-trans-l'-enyl)-bicyclo[3.3.0]octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hyddroxy-oct-l'-
trans-l'-enyl)-bicyclo[3.3.0]octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hyddroxy-4'S-
methyl-oct-l'-trans-l'-enyl)-bicyclo[3.3.0]octane;;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hyddroxy-non-l'-
trans-l'--enyl)-bicyclo[3.3.0]octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hyddroxy-5'-cyclo-
hexyl-pent-1'-trans-1'-enyl)-bicyclo[3.3.0]octane;;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hyddroxy-5'-phenyl-
pent-l'-trans-l'-enyl)-bicyclo[3.3.0]octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hyddroxy-4'-m-tri-
fluoromethylphenoxy-but-l'-trans-l'-enyl)-bicyclo[[3.3.0loctane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'4-hyddroxy-4'-methyl-
4'-butoxy-pent-1'-trans-1'-enyl)-bicyclo[3.3.0]octtane.
Example 25
A solution of 1.17g of 2-exo-(3'S-hydroxy-oct-l'-trans-
l'-enyl)-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicycclo[3.3.0]-
octane in 12ml of anhydrous methylene chloride is treated with
120mg of 2,3-dihydropyran and 5mg of p-toluenesulfonic acid.
After 4 hours at room temperature, the organic phase is washed
successively with 5% NaHCO3 and water and then evaporated to dry-
ness to give 1.45g of crude 2-exo-(3'S-THP-oxy-oct-l'-trans-l'-
enyl)-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo[[3.3.0]octane.
This product is dissolved in 12ml of THF and treated with 2g of
tetrabutylammonium fluoride. The resulting mixture is stirred
for 12 hours at room temperature and concentrated to small
volume to give a residue which is purified on silica gel (ethyl
ether as eluent) to afford 920mg of 2-exo-(39S-hydroxy-oct-l'-
34
- 53 -
trans-l'-enyl)-3-endo-7-endo-dihydroxy-bicyclo[3.33.0]octane-3,3'-
bis-THP-ether.
Example 26
Using the procedure of example 25 with compounds pre-
pared according to examples 22, 23 and 24, the following bicyclo-
[3.3.0]octane-3,3'-bis-THP-ether-derivatives were prepared:
2-exo-(2'-bromo-3'S-hydroxy-4'-fluoro-oct-1'-transs-1'-enyl)-3-
endo-7-endo-dihydroxy;
2-exo-(2'-bromo-3'R-hydroxy-4'R-fluoro-oct-l'-tranns-l'-enyl)-3-
endo-7-endo-dihydroxy;
2-exo-(3'S-hydroxy-5'(2")-tetrahydrofuryl-pent-1'--trans-1'-enyl)-
3-endo-7-exo-dihydroxy;
2-exo-(3'R-hydroxy-5'(2")-tetrahydrofuryl-pent-1'--trans-1'-enyl)-
3-endo-7-exo-dihydroxy;
2-exo-(2'-bromo-3'S-hydroxy-oct-l'-trans-l'-enyl)--3-endo-7-endo-
dihydroxy;
2-exo-(2'-bromo-3'R-hydroxy-oct-l'-trans-l'-enyl)--3-endo-7-endo-
dihydroxy;
2-exo-(3'S-hydroxy-oct-l'-trans-l'-enyl)-3-endo-7--endo-dihydroxy;
2-exo-(3'R-hydroxy-oct-l'-trans-l'-enyl)-3-endo-7--endo-dihydroxy;
2-exo-(3'S-hydroxy-4'S-methyl-oct-l'-trans-l'-enyll)-3-endo-7-
endo-dihydroxy;
2-exo-(3'R-hydroxy-4'S-methyl-oct-l'-trans-l'-enyll)-3-endo-7-
endo-dihydroxy;
2-exo-(3'S-hydroxy-non-l'-trans-l'-enyl)-3-endo-7--endo-dihydroxy;
2-exo-(3'R-hydroxy-non-l'-trans-l'-enyl)-3-endo-7--endo-dihydroxy;
2-exo-(3'S-hydroxy-5'-cyclohexyl-pent-1'-trans-1'--enyl)-3-endo-
7-endo-dihydroxy;
2-exo-(3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-enyll)-3-endo-7-
endo-dihydroxy;
~LZ~ 3~
- 54 -
2-exo-~3'R-hydroxy-5'-phenyl-pent-1'-trans-1'-enyll)-3-endo-7-
endo-dihydroxy;
2-exo-13'S-hydroxy-4'-m-trifluoromethylphenoxy-butt-1'-trans-1'-
enyl)-3-endo-7-endo-dihydroxy;
2-exo-(3'R-hydroxy-4'-m-trifluoromethylphenoxy-butt-1'-trans-1'-
enyl)-3-endo-7-endo-dihydroxy;
2-exo-(3'S-hydroxy-4'-methyl-4'-butoxy-pent-1'-traans-1'-enyl)-3-
endo-7-endo-dihydroxy;
2-exo-(3'R-hydroxy-4'-methyl-4'-butoxy-pent-1'-traans-1'-enyl)-3-
endo-7-endo-dihydroxy.
Example 27
Successive portions of a solution of 0.4g of chromic
anhydride are added with stirring to 4ml of pyridine. Once the
complex is formed, this mixture is treated with 0.36g of 2-exo-
(3'S-hydroxy-5'(2")-tetrahydrofuryl-pent-1'-trans--1'-enyl)-3-
endo-7-exo-dihydroxy-bicyclo[3.3.0]octane-3,3'-biss-THP-ether in
4ml of pyridine. The reaction mixture i5 held overnight at
room temperature, diluted with 3 volumes of benzene, and
filtered. The filtrate is then evaporated to give a residue
which is partitioned between benzene and 2N sulfuric acid. The
aqueous portion is re-extracted with benzene, washed succes-
sively with water, NaHCO3 and water, and evaporated to dryness
to give 0.31g of 2-exo-(3'S-hydroxy-5'(2")-tetrahydrofuryl-pent-
l'-trans-l'-enyl)-3-endo-hydroxy-bicyclo[3.3.0]octtan-7-one-3,3'-
bis-THP-ether.
Example 28
A stirred and cooled (-10-6 C) solution of 0.8g of
2-exo-(3'S-hydroxy-oct-l'-trans-l'-enyl)-3-endo-7--endo-dihydroxy-
bicyclo[3.3.0]octane-3,3'-bis-THP-ether in 20ml of acetone is
treated with 1.6ml of Jones' reagent in 15 minutes. After an-
ED
lZ~34
- 55 -
other 15 minutes of stirring, 80ml of benzene is added. The
organic phase is separated, washed with 15% aqueous (NH4)2SO4
until neutral, dried and evaporated to dryness to afford 0.71g
of2-exo-(3'S-hydroxy-oct-l'-trans-l'-enyl)-endo-hydrroxy-bicyclo-
[3.3.0]octan-7-one-3,3'-bis-tetrahydropyranyletherr.
Example 29
Using either of the oxidation procedures described in
examples 27 and 28 on the triols of example 26, the following
3-endo-hydroxy-bicyclo[3.3.0]octan-7-one-3,3'-bis--THP-esters are
prepared:
2-exo-(2'-bromo-3'S-hydroxy-4'R-fluoro-oct-l'-tranns-l'-enyl);
2-exo-(2'-bromo-3'R-hydroxy-4'R-fluoro-oct-l'-tranns-l'-enyl);
2-exo-(3'S-hydroxy-5'(2")-tetrahydrofuryl-pent-1'--trans-1'-enyl);
2-exo-(3'R-hydroxy-5'(2")-tetrahydrofuryl-pent-1'--trans-1'-enyl);
2-exo-(2'-bromo-3'S-hydroxy-oct-l'-trans-l'-enyl);;
2-exo-(2'-bromo-3'R-hydroxy-oct-l'-trans-l'-enyl);;
2-exo-(3'S-hydroxy-oct-l'-trans-l'-enyl);
2-exo-(3'R-hydroxy-oct-l'-trans-l'-enyl);
2-exo-(3'S-hydroxy-4'S-methyl-oct-l'-trans-l'-enyll);
2-exo-(3'R-hydroxy-4'S-methyl-oct-l'-trans-l'-enyll);
2-exo-(3'S-hydroxy-non-l'-trans-l'-enyl);
2-exo-(3'R-hydroxy-non-l'-trans-l'-enyl);
2-exo-(3'S-hydroxy-5'-cyclohexyl-pent-1'-trans-1'--enyl);
2-exo-(3'R-hydroxy-5'-cyclohexyl-pent-1'-trans-1'--enyl);
2-exo-(3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-enyll);
2-exo-(3'R-hydroxy-5'-phenyl-pent-1'-trans-1'-enyll);
2-exo-(3'S-hydroxy-4'-m-trifluoromethylphenoxy-butt-1'-trans-1'-
enyl);
2-exo-(3'R-hydroxy-4'-m-trifluoromethylphenoxy-butt-1'-trans-1'-
enyl);
~Z~34
- 56 -
2-exo-(3'S-hydroxy-4'-methyl-~'-butoxy-pent-1'-traans-1'-enyl);
2-exo-(3'R-hydroxy-4'-methyl-4'-butoxy-pent-1'-traans-1'-enyl);
Example 30
A solution of 2.lg of d,1-2-exo-(3'-oxo-non-1'-trans-
l'-enyl)-3-exo-THP-oxy-7-endo-DMtB-silyloxy-bicycllo[3.3.0]octane
(prepared according to example 17) is reduced at -15 C in
methylene chloride:ethanol with 0.17g of NaBH4, following the
procedure of example 23, to afford 2.01g of d,l-2-exo-(3'(S,R)-
hydroxy-non-l'-trans-l'-enyl)-3-exo-THP-oxy-7-endoo-DMtB-silyloxy-
bicyclo[3.3.0]octane. Without separating the 3'S and 3'R
alcohols, this product is reacted in 30ml of methylene chloride
with 0.4g of 2,3-dihydropyran in the presence of 25mg of
p-toluenesulfonic acid to give the corresponding d,l-exo-(3'(S,R)-
hydroxy-non-l'-trans-l'-enyl)-3-exo-hydroxy-7-endoo-DMtB-silyloxy-
bicyclo[3.3.0]octane-3,3'-bis-THP-ether. With no further puri-
fication, this product is treated with 2.5 molar equivalents of
tetrabutyl ammonium fluoride in THF to remove the silyl ether.
The product d,l-2-exo-(3'(S,R)-hydroxy-non-l'-trans-l'-
enyl)-3-exo-7-endo-dihydroxy-bicyclo[3.3.0]octane--3,3'-bis-THP-
ether (1.660g) is then oxidized with pyridine - chromic
anhydride to give 1.25g of d,l-2-exo-(3'(S,R)-hydroxy-non-l'-
trans-l'-enyl)-3-exo-hydroxy-bicyclo[3.3.0]octan-77-one-3,3'-bis-
THP-ether.
Example 31
A solution of (2-oxo-5,5,5-trimethoxy-pentyl)-dimethyl
phosphonate in lOml of THF is added dropwise to a stirred suspen-
sion of 68mg of NaH (80%) in lOml of anhydrous THF. Stirring is
continued until hydrogen evolution ceases, and then a solution
of 0.67g ofd,1-2-exo-(3'(S,R),-hydroxy-non-l'-trans-l'-enyl)--3-
exo-hydroxy-bicyclo[3.3.0]octan-7-one-3,3'-bis-THPP-ether in 5ml
lZ0~34
- 57 -
of THF is added. After 6 hours of stirring at 40-45C, 20ml of
20~ NaH2PO4 is added and the THF is removed under vacuum. The
residue is extracted with ethyl ether, and the organic extract
is dried over Na2SO4 and evaporated. Adsorption of the residue
on silica gel and elution with cyclohexane:ethyl ether afford
0.76g ofd,l-5t,13t-4-oxo-11~,15(S,R)-dihydroxy-20-methyl-99a-
deoxy-9a-methylene-prostacycla-5,13-dienoic acid-trimethylortho-
ester-11,15-bis-THP-ether.
A solution of this product in 15ml of anhydrous
methanol is treated with 6mg of p-toluenesulfonic acid for 5
hours at room temperature. O.lml of pyridine is added, the solu-
tion is evaporated to dryness, and the residue is purified on
silica gel (isopropyl ether:ethyl ether as eluent) to afford
0.20g of d,1-5t,13t-4-oxo~ ,15S-dihydroxy-20-methyl-9a-deoxy-
9a-methylene-prostacycla-5,13-dienoic acid-trimethylorthoester
and 0.21g of the 15R epimer.
Example 32
Following the procedure of example 31 with a bicyclo-
[3.3.0]octan-7-one prepared as in examples 27, 28 and 29, the
following trimethylorthoesters were prepared:
5,13t-4-oxo-11~,15S-dihydroxy-9a-deoxy-9a-methylenne-prostacycla-
5,13-dienoic acid;
5,13t-5-oxo-lla,15S-dihydroxy-9a-deoxy-9a-methylenne-20-methyl-
prostacycla-5,13-dienoic acid;
5,13t-4-oxo-11~,15S-dihydroxy-9a-deoxy-9a-methylenne-17(2')-tetra-
hydrofuryl-18,19,20-trinor-prostacycla-5,13-dienoiic acid;
5,13t-4-oxo-11~,15S-dihydroxy-9a-deoxy-9a-methylenne-16-m-tri-
fluoromethylphenoxy-17,18,19,20-tetranor-prostacyccla-5,13-
dienoic acid;
as well as their 15R epimers.
lZ~ 34
- 58 -
Each of the ortho-esters of examples 31 and 32 is then
converted to its methyl ester by refluxing it in methanol
(15ml/g) with 2ml of 0.2N oxalic acid and recovering the product
by evaporating the methanol and extracting with ethyl ether.
Subsequent saponification with 2% KHC03 in 80% aqueous methanol
gives the free acid.
Example 33
A solution of 0.45g of 5,13t-4-oxo-lla,15S-dihydroxy-
9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid-trimethyl-
orthoester (~maX=244m~ r =9 850) in 6ml of methanol and 1.2ml of
0.2N oxalic acid is refluxed for two hours. Evaporation of the
methanol under vacuum and extraction with ethyl ether give 0.42g
of the corresponding methyl ester.
A solution of this product in 6ml of anhydrous ethyl
ether is added dropwise to a stirred O.lM solution of zinc boro-
hydride (lOml) in 10 minutes. After 1 hour of stirring at room
temperature, the reaction is quenched with 2N sulfuric acid.
The organic phase is separated, washed until neutral, and evapor-
ated to dryness to give 0.4g of 5,13t-4(S,R),lla,15S-trihydroxy-
9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid methyl ester.
Chromatographic separation on silica gel (ethyl ether:ethyl
acetate as eluent) affords O.llg of 5,13t-4S,lla,15S-tr hydroxy-
9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid methyl ester
and 0.14g of the 4R-epimer methyl ester.
A solution of the latter compound in 5ml of methanol
is treated with 0.05g of lithium hydrate and 0.3ml of H20 and
then stirred at room temperature for 6 hours. Removal of the
methanol under vacuum, acidification of pH 5.6 and rapid extrac-
tion with ethyl acetate afford 5,13t-4R,lla,15S-trihydroxy-9a-
deoxy-9a-methylene-prostacycla-5,13-dienoic acid. Treatment of
~2~134
- 59 -
a stirred ethyl acetate solution of this compound with 0.5 parts
of a polystyrenesulfonic resin (hydrogen ion form) gives 5,13t-
4R,11~,15S-trihydroxy-9a-deoxy-9a-methylene-prostaacycla-5,13-
dienoic acid-1,4-~-lactone quantitatively.
The 4S epimer-~-lactone was prepared analogously.
Example 34
A solution of 0.8g of 5,13t-4-oxo-11~,15S-dihydroxy-20-
methyl-9a-deoxy-9a-methylene-prostacycla-5,13-diennoic acid-
trimethylorthoester-11,15-bis-THP-ether in 20ml of methylene
chloride:ethanol is cooled to -20C and treated with 50mg of
NaBH4. After 30 minutes of stirring, the reaction is quenched
with 2ml of acetone and 5ml of saturated monosodium phosphate.
Evaporation of the methylene chloride and ethanol under vacuum
and repeated extraction with ethyl ether afford, after the com-
bined organic extract is dried and evaporated, 0.75g of 5,13t-
4(S,R),11,15S-trihydroxy-20-methyl-9a-deoxy-9a-meethylene-
prostacycla-5,13-dienoic acid-trimethylorthoester-11,15-bis-THP-
ether.
This crude product is dissolved in 2.2ml of methane-
sulfonyl chloride. The reaction mixture is held overnight atroom temperature and then partitioned between iced 2N sulfuric
acid and ethyl ether. The combined organic extract is washed
with brine, dried and evaporated at low temperature to give
5,13t-4(S,R),11~,15S-trihydroxy-20-methyl-9a-deoxyy-9a-methylene-
prostacycla-5,13-dienoic acid-trimethylorthoester-4-mesylate-
11,15-bis-THP-ether.
With no further purification, this product is dis-
solved in anhydrous ethyl ether and treated with 50mg of lithium
aluminum hydride in ethyl ether. After stirring for 2 hours at
room temperature and 1 hour at reflux, the reaction mixture is
.~
12~134
- 60 -
quenched with 2ml of ethyl acetate and then wet ethyl ether.
Drying over Na2SO4 and evaporating the ethyl ether give 0.5g of
crude5,13t-11,15S-dihydroxy-20-methyl-9a-deoxy-9a-methhylene-
prostacycla-5,13-dienoic acid-trimethylorthoester-11,15-bis-THP-
ether.
After treatment at reflux with 12ml of methanol and
4ml of 0.3N aqueous oxalic acid, standard work-up gives 0.2g of
5,13t-11~,15(S)-dihydroxy-20-methyl-9a-deoxy-9a-meethylene-
prostacycla-5,13-dienoic acid methyl ester. Liquid-liquid
chromatography shows that the product is mainly trans (85~),
with 15~ of the cis isomer.
Example 35
In an inert gas atmosphere, a stirred suspension of
0.4g of NaH (75% mineral oil dispersion) in 13.5ml of DMSO is
heated to 60-65 C for 4 hours. The mixture is then cooled to
room temperature and held at 20-22C while 2.6g of 4-carboxy-
butyl-triphenyl phosphonium bromide in 6ml of DMSO and 0.85g of
2-exo-(3'S-hydroxy-non-l'-trans-l'-enyl)-3-endo-hyydroxy-bicyclo-
[3.3.0]octan-7-one-3,3'-bis-THP-ether are added successively.
After stirring for 3 hours, the mixture is diluted with 35ml of
water and the aqueous phase is extracted with ethyl ether
(5xl2ml) and ethyl ether:benzene (7xl2ml). The combined organic
extract is re-extracted with 0.5N NaOH (3xl5ml) and then water
until neutral, and then discarded. The combined aqueous
alkaline extract is acidified to pH 5.3 and extracted with 1:1
ethyl ether:pentane. Washing until neutral, drying over Na2SO4
and removing the solvent afford 0.86g of 5,13t-11~,15S-dihydroxy-
9a-deoxy-9a-methylene-20-methyl-prostacycla-5,13-ddienoic acid-
11,15-bis-THP-ether. This product is then esterified by treat-
ment with diazomethane, and the pyranyl protecting groups areremoved, as follows:
121~134
- 61 -
The methyl ester is dissolved in anhydrous methanol
and treated with a solution of 10 2 molar equivalents of
p-toluenesulfonic acid. After 4 hours, the p-toluenesulfonic
acid is neutralized with pyridine and the mixture is evaporated
to dryness. Purification on silica gel affords 5,13t~ ,15S-
dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacyycla-5,13-
dienoic acid methyl ester, which is then separated into the
individual 5c,13t and 5t,13t isomers by liquid-liquid chromato-
graphy.
Example 36
With stirring and external cooling to keep the reac-
tion temperature at 20-22C, a solution of freshly sublimed
potassium tert-butylate in 12ml of anhydrous DMSO is treated
successively with 1.8g of 4-carboxybutyl-triphenyl phosphonium
bromide in 10ml of DMSO and 0.65g of 2-exo-(2'-bromo-3'S-hydroxy-
oct-l'-trans-l'-enyl)-3-endo-hydroxy-bicyclo[3.3.00]octan-7-one-
3,3'-bis-THP-ether in 5ml of DMSO. After stirring for 8 hours
at room temperature, the mixture is diluted with an equal volume
of water, acidified to pH 5 and extracted with 1:1 ethyl ether:
pentane. The acidic aqueous phase is discarded, and the com-
bined organic extract is extracted with 0.8N NaOH (5x20ml) and
then washed with water until neutral. While this organic phase
is discarded, the aqueous alkaline extract is acidified to pH 5
and extracted with 1:1 ethyl ether:pentane. The combined ex-
tract is dried over Na2SO4, filtered and treated with ethereal
diazomethane until a yellow coloration persists. Evaporation
to dryness gives crude 11,15S-dihydroxy-9a-deoxy-9a-methylene-
prostacycl-5-en-13-ynoic acid methylester-11,15-bis-THP-ether.
Removal of the pyranyl protecting group followed by liquid-
liquid chromatography gives 5c-11~,15S-dihydroxy-9a-deoxy-9a-
12~34
- 62 -
methylene-prostacycl-5-en-13-ynoic acid methyl ester, plus the
5t geometric isomer.
Example 37
When the bicyclo[3.3.0]octan-7-one-3,3'-bis-THP-ethers
prepared according to examples 27,28,29 and 30 were used in the
procedure of examples 35 and 36, the methyl esters of the follow-
ing acids were obtained:
5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-proostacycla-5,13-
dienoic acid;
5c-lla,15S-dihydroxy-9a-deoxy-9a-methylene-16R-fluuoro-prostacycl-
5-en-13-ynoic acid;
5c-11,15S-dihydroxy-9a-deoxy-9a-methylene-16S-fluuoro-prostacycl-
5-en-13-ynoic acid;
5c-lla,15S-dihydroxy-9a-deoxy-9a-methylene-17t2')--tetrahydro-
furyl-18,19,20-trinor-prostacycl-5-en-13-ynoic acid;
5c-lla,15S-dihydroxy-9a-deoxy-9a-methylene-prostaccycl-5-en-13-
ynoic acid;
5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-proostacycla-5,13-
dienoic acid;
5c,13t-lla,15S-dihydroxy-9a-deoxy-9a-methylene-16SS-methyl-
prostacycla-5,13-dienoic acid;
5c,13t-lla,15S-dihydroxy-9a-deoxy-9a-methylene-20--methyl-
prostacycla-5,13-dienoic acid;
5c,13t-lla,15S-dihydroxy-9a-deoxy-9a-methylene-17--phenyl-18,19,
20-trinor-prostacycla-5,13-dienoic acid;
5C,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-16--m-CF3-phenoxy-
17,18,19,20-tetranor-prostacycla-5,13-dienoic acid;
5c,13t-11,15S-dihydroxy-9a-deoxy-9a-methylene-16--methyl-16-
butoxy-18,19,20-trinor-prostacycla-5,13-dienoic acid;
as well as their 5-trans geometric isomers, plus the 15R epimers
of both.
~2~34
- 63 -
These were then saponified to give the free acids.
Example 38
A solution of 0.45g of 2-exo-(3'S-hydroxy-oct-l'-trans-
l'-enyl)-3-endo-hydroxy-bicyclo[3.3.0]octan-7-one--3,3'-bis-THP-
ether in ethyl acetate is hydrogenated at ambient temperature
and pressure in the presence of O.lg of 5~ Pd/CaCO3, until 1.01
equivalents of hydrogen are absorbed. Filtration and evapora-
tion to dryness give 0.42g of 2-exo-(3'S-hydroxy-octan-l'-yl)-3-
endo-hydroxy-bicyclo[3.3.0]octan-7-one-3,3'-bis-THHP-ether.
Treatment of this with the Wittig reagent prepared from
4-carboxy-butyl phosphonium bromide according to examples 35, 36
and 37 affords a product which is esterified with diazomethane
and depyranylized to give 0.12g of 11~,15S-dihydroxy-9a-deoxy-9a-
methylene-prostacycl-5-enoic acid methylester. The 5-cis and
5-trans geometric isomers are separated by liquid-liquid
chromatography.
Example 39
Using (3-carboxy-propyl)-phosphonium bromide in the
procedure of examples 37 and 38 instead of (4-carboxy-butyl)-
phosphonium bromide gave the following acids:
5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-2-nnor-prostacycla-
5,13-dienoic;
5c-lla,15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-pprostacycl-5-
enoic;
5c-11~,15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-pprostacycl-5-en-
13-ynoic acid.
Example 40
By using (5-carboxy-pentyl)-phosphonium bromide in the
procedure of examples 37 and 38, 5c,13t-11~,15S-dihydroxy-9a-
deoxy-9a-methylene-2ahomo-prostacycla-5,13-dienoicc acid and
r~L34
- 64 -
5,13t~,15S-dihydroxy-9a-deoxy-9a-methylene-20-methyl-2ahhomo-
prostacycla-5,13-dienoic acid were prepared.
Example 41
A solution of 0.37g of 5c,13t-11~,15S-dihydroxy-9a-
deoxy-9a-methylene-prostacycla-5,13-dienoic acid methyl ester in
lOml of benzene is heated to 50 C with 250mg of 2,3-dichloro-5,6-
dicyano-benzoquinone for 8 hours. The precipitate is removed by
filtration, and the benzene solution is purified on a short
alumina column to give 0.29g of 5c,13t-11~-hydroxy-15-oxo-9a-
deoxy-9a-methylene-prostacycla-5,13-dienoic acid methyl ester.
A solution of this product in ethyl ether;toluene is
cooled to -20 C and treated with 1.2ml of lM methyl magnesium
bromide in ethyl ether. After 2.5 hours at -20C, the reaction
is quenched with NH4Cl solution. The organic phase is separated,
reduced in volume and purified on silica gel (ethyl ether:ethyl
acetate as eluent) to give O.lg of 5c,13t-11~,15S-dihydroxy-15-
methyl-9a-deoxy-9a-methylene-prostacycla-5,13-diennoic acid
methyl ester and 0.072g of the 15R hydroxy epimer.
Example 42
A solution of 2.2g of 3-endo-hydroxy-bicyclo[3.3.0]-
octan-7-one in lOOml of anhydrous benzene is treated with 4ml of
ethylene glycol and 0.2g of p-toluenesulfonic acid monohydrate
and refluxed for 12 hours while the water which forms during the
reaction is collected. 0.25ml of pyridine is then added and the
mixture is cooled. The organic phase is washed with water,
NaHCO3 and then water, and evaporated to dryness to give 2.32g
of3-endo-hydroxy-bicyclo[3.3.0]octan-7-one-7,7-ethyllenedioxide.
A solution of this product in 40ml of acetone is
cooled to -5 C and treated at this temperature with 4.lml of
Jones' reagent. After 20 minutes at -5 C, excess oxidant is
12~$~ 3~
- 65 -
quenched with 4ml of isopropyl alcohol. 150ml of benzene is
added, and the benzene phase is washed successively with 20~
(NH4)2SO4, water, 5% NaHCO3 and water. Evaporation to dryness
gives 2.lg ofd,l-bicyclo[3.3.0]octan-3,7-dione-2-carboxymethyl--
ester-7,7-ethylenedioxide.
According to the procedure of example 2, a solution of
this product in 20ml of CH2C12 and 20ml of ethanol is reduced
with NaBH4 at -20 C to give 1.72g of d,1-3-endo-hydroxy-bicyclo-
[3.3.0]octan-7-one-2-exo-carboxymethylester-7,7-etthylenedioxide.
A solution of 1.57g of this compound in 3ml of
dimethylformamide is treated with 1.3g of dimethyl-tert-butyl-
silyl chloride and 0.885g of imidazol, and then held at 0C for
5 hours. After cooling, water is added and the usual work-up
affords 2.3g of d,l-3-endo-hydroxy-bicyclo[3.3.0]octan-7-one-2-
exo-carboxymethylester-7,7-ethylenedioxide-3-dimetthyl-tert-butyl-
silyl ether. Subsequent reduction with LiAlH4 in anhydrous ethyl
ether, as described in example 3, gives d,1-3-endo-hydroxy-2-exo-
hydroxymethyl-7,7-ethylenedioxy-bicyclo[3.3.0]octaan-7-one-3-
dimethyl-tert-butyl silyl ether quantitatively.
Example 43
By using dithioethylene glycol in the procedure of
example 42 instead of ethylene glycol, the corresponding 7,7-
ethylenedithio analogues were prepared.
Example 44
1.8g of d,l-3-endo-hydroxy-2-exo-hydroxymethyl-7,7-
ethylenedioxy-bicyclo[3.3.0]octan-7-one-3-dimethyll-tert-butyl
silyl ether is oxidized according to the procedure of example 18
to give the corresponding 2-formyl derivative. This is then
reacted with (2-oxo-heptyl)-dimethyl phosphonate as in example
20 to give 1.23g of d,1-3-endo-hydroxy-2-exo-t3'-oxo-oct-1'-
~213~13~
- 66 -
trans-l'-enyl)-7,7-ethylenedioxy-bicyclo[3.3.0]octtan-7-one-3-
dimethyl-tert-butyl silyl ether (~max=228m~=898~), According
to the procedure in example 22, this is reduced with zinc boro-
hydride in ether to give 1.22g of d,l-3-endo-hydroxy-2-exo-
(3'(S,R)-hydroxy-oct-l'-trans-l'-enyl)-7,7-ethylennddioxy-bicyclo-
~3.3.0]octan-7-one-3-dimethyl-tert-butyl silyl ether.
A solution of this compound in 25ml of methanol is
treated with lOml of lN H2SO4 at reflux for 50 minutes. The
methanol is evaporated under vacuum, the residue is extracted
with ethyl ether, and the organic phase is evaporated to dryness
to afford 0.72g of crude d,l-3-endo-hydroxy-2-exo-(3'(S,R)-
hydroxy-oct-l'-trans-l'-enyl)-bicyclo[3.3.0]octan--7-one. The
individual isomers are separated by chromatography on silica gel
with hexane:ethyl ether as eluent and then converted to the
tetrahydropyranyl ethers by treatment with 2,3-dihydropyran in
methylene chloride as in example 25. In this fashion, a com-
pound identical in all respects to 2-exo-~3'S-hydroxy-oct-l'-
trans-l'-enyl)-3-endo-hydroxy-bicyclo[3.3.0]octan--7-one-3,3'-bis-
tetrahydropyranylether prepared as in example 28 is prepared
from the 3'S-hydroxy isomer.
Similarly, with the procedure of examples 42 and 44,
all the compounds prepared as in examples 27, 28 and 29 were ob-
tained.
Example 45
Saponification of 4.8g of d,l-3-endo-hydroxy-2-exo-
carboxymethylester-7,7-ethylenedioxy-bicyclo[3.3.00]octan-7-one
with lOOml of 2.5% potassium carbonate in 80:20 methanol:water
at reflux for 40 minutes and subsequent work-up as described in
example 2 gave 4.02g of d,1-3-endo-hydroxy-2-exo-carboxy-bicyclo-
[3.3.0]octan-7-one-7,7-ethylenedioxide. This compound is dis-
12~34
- 67 -
solved in 80ml of anhydrous tetrahydrofuran, cooled to -10C,
and treated dropwise with 2.lg of triethylamine in 12ml of
anhydrous tetrahydrofuran and then 2.2g of ethyl chlorocarbonate
in 12ml of anhydrous tetrahydrofuran, while keeping the tempera-
ture at -10 C. After 1 hour of stirring at -10 C, 1.4g of
sodium azide in 12ml of water is added slowly and stirring is
continued for another 25 minutes. The reaction mixture is then
concentrated under vacuum and diluted with water. The 2-exo-
carboxy-azide is isolated rapidly by filtration and dried under
vacuum.
A solution of 4.01g of this compound in 8ml of pyri-
dine is treated with 4ml of acetic anhydride and held at 5-8 C
for 24 hours. The reaction mixture is then partitioned between
ice water, ethyl ether and 2N sulfuric acid. The organic layer
is separated, washed until neutral, dried and evaporated to dry-
ness to give 4.lg of 3-endo-hydroxy-2-exo-carboxyazide-bicyclo-
[3.3.0]octan-7-one-3-acetate-7,7-ethylenedioxide.
This product is suspended in acetic acid (50ml) and
water (8ml), and the mixture is heated to 40C. When hydrogen
evolution is noted, it is heated to 60-70 C for 2 hours, after
which the excess acetic acid is removed by steam distillation.
After cooling, the mixture is extracted with ethyl ether:ethyl
acetate and the aqueous phase is brought to pH 9 with sodium
hydrate. The alkaline phase is washed with saturated salt solu-
tion and evaporated to dryness to give 1.92g of 3-endo-hydroxy-2-
exo-amino-bicyclo[3.3.0]octan-7-one-3-acetate. Reaction of this
with the mixed anhydride from ethoxycarbonyl chloride and 2S-
hydroxy-heptanoic acid-2-acetate affords 3-endo-hydroxy-2-exo-
(2'S-acetoxy-heptanoyl-amide)-bicyclo[3.3.0]octan--7-one-3-
acetate. A solution of this compound in anhydrous dimethyl-
lZ~34
- 68 -
sulfoxide is then reacted with the ylide obtained from 4-carboxy-
butyl-triphenyl phosphonium bromide to give, after saponifica-
tion,5t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-12-aza--13-oxo-
prostacycl-5-enoic acid.
In an analogous fashion the 15R-epi analogue was pre-
pared from the 2'R-hydroxy-heptanoic acid.
Example 46
Ethylene glycol (15ml) and p-toluenesulfonic acid
(0.9g) are added to a solution of 2-exo-bromo-3-endo-hydroxy-
bicyclo[3.2.0]heptane-6-one in benzene and the mixture is re-
fluxed for 12 hours, withdrawing water which forms during the
reaction, then the mixture is added by pyridine (0.6ml) and
cooled at room temperature.
The organic phase is washed with water, 2.5% aqueous
NaHC03 and water, dried. Benzene (lOOml) is partially removed
in vacuum, then the mixture is treated with tributyl tin-hydride
(41g) in N2 atmosphere at 55 for 8 hours.
After cooling at room temperature the organic phase is
washed with saturated aqueous NaH2P04, dried and evaporated to
dryness. Purification of the resulting residue on SiO2 (240g)
with benzene-ethylether as eluent affords 14.9g of 3-endo-
hydroxy-bicyclo[3.2.0]heptane-6-one-6,6-ethylenediioxide.
Example 47
A stirred solution of 3-endo-hydroxy-bicyclo[3.2.0]-
heptane-6-one-6,6-ethylenedioxide (12.75g) in benzene (340ml)
and DMSO (112ml) was treated with dicyclohexylcarbodiimide
(46.35g), pyridine (5.9g) and trifluoroacetic acid (5.4g).
After 6 hours, the mixture is diluted with benzene (600ml) and
water (50ml), filtered from dicyclohexylurea and the organic
phase is washed with water, dried on MgS04 and evaporated to dry-
12(:~134
- 69 -
ness affording bicyclo[3.2.0]heptane-3,6-dione-6,6-diethylene-
dioxide.
A solution of this crude product in dimethylcarbonate
(70ml) is added to a suspension of sodium hydride t80% in
mineral oil, 4g). The mixture is stirred until H2 development
ceases at room temperature then it is warmed for 40 minutes at
75-80 .
After cooling, the reaction mixture is diluted with
benzene t350ml) and acetic acid t8-4g), washed with water, dried
and evaporated to dryness affording a mixture (1:1) of d,l-
bicyclo[3.2.0]heptane-3,6-dione-2-carboxymethylestter-6,6-
ethylenedioxide tp=0, q=l) and d,l-bicyclo[3.2.0]heptane-3,6-
dione-4-carboxymethylester-6,6-ethylenedioxide (p=l, q=0) which
are separated by means of chromatography on SiO2 tFe , Fe
free) using hexane-ethylether as eluents.
Example 48
Using in the procedure of the example 47g 14.85 of 3-
endo-hydroxy-bicyclo[4.3.0]nonane-7-one-7,7-ethyleenedioxide the
oxidation process affords 13.9g of bicyclo[4.3.0]nonane-3,7-
dione-7,7-ethylenedioxide giving the carbomethoxylation process
4.2g ofdl-bicyclol4.3.0]nonane-3,7-dione-2-carboxymethyleester-
7,7-ethylenedioxide (p=l, q=2) and 4.8g of dl-bicyclo[4.3.0]-
nonane-3,7-dione-4-carboxymethylester-7,7-ethyleneedioxide also
named asdl-bicyclo[4.3.0]nonane-3,8-dione-2-carboxymethyleester-
8,8-ethylenedioxide tp=2, q=l).
Example 49
A stirred solution of bicyclo[4.3.0]nonane-7-en-3-one
t90g) in dimethyl carbonate (350ml) is added to a suspension of
sodium hydride (80~ dispersion in mineral oil, 42g) in dimethyl-
carbonate t550ml). After ceasing the hydrogen evolution, the
12~ $134
- 70 -
mlxture is heated for 4.5 hours at 75-80, cooled at r.t.,
diluted with benzene (2.7 1) and washed with 25% aqueous NaH2PO4
solution, evaporated to dryness affording bicyclo[4.3.0]nonane-
7-ene-3-one-2-carboxymethylester (9lg) (~maX=252m~,~=8.200).
A solution of this compound in methylene chloride
(1.2 1) and ethanol (1.2 1) is cooled at -20 and, under stirr-
ing, treated with NaBH4 (14.4g).
The mixture is stirred for 30 minutes, again at -20,
then it is treated with acetic acid (23ml), warmed at room tem-
perature, and the solvents are evaporated in vacuum.
The residue is partitioned between ethyl acetate andwater, the organic phase is dried and evaporated in vacuum
affordingdl-bicyclo[4.3.0]nonane-7-ene-3-endo-hydroxy-2-exoo-
carboxymethylester (64g) which is dissolved in dry tetrahydro-
furan (THF) and treated with 2,3-dihydropyrane (33g) and
p-toluenesulphonic acid (0.63g) for 3 hours at r.t.. Pyridine
(0.4g) is added to the reaction mixture and then, after cooling
at 0 C, under stirring a solution of 1.2M BH3 in THF is also
added during 45 minutes. The stirring goes on for 1 hour at
0 C then water is added to destroy residual hydride. Under
vigorous stirring, with external cooling at -5+0, the formed
borane is oxidized by the slow concurrent addition of llOml of
3M sodium hydroxide and llOml of 30% hydrogen peroxide, main-
taining the internal temperature at 20-25. The oxidation mix-
ture is diluted with benzene (2 1) and the layers are separated.
The aqueous layer is extracted with benzene (2x50). The
organic layers are combined, washed successively with 1% sodium
carbonate, saturated sodium sulphite and saturated sodium
chloride and dried on MgSO4. Evaporation of the solvents
affords a crude mixture of 7 and 8 hydroxy compounds which are
$134
- 71 -
separated by means ox SiO2 (300g) column chromatography, ethyl
ether as eluent, obtaining respectively:
dl-bicyclo[4.3.0]nonane-3-endo, 7~-dihydroxy-2-exo-carboxymethyl-
ester-3-THP-ether (24g) and
dl-bicyclo[4.3.0]nonane-3-endo, 8~-dehydroxy-2-exo-carboxymethyl-
ester-3-THP-ether (27g).
A solution of the 7~-hydroxy alcohol (24g) in dry DMF
(30ml) is treated with dimethyl-ter-butyl-silyl chloride (15.8g)
and imidazole (8.85g1 and then it is heated for 5 hours at 60,
cooled at room temperature, diluted with water (9Oml) and then
extracted with ethyl ether.
The organic layers are collected, washed with water
and evaporated to dryness affording dl-bicyclo[4.3.0]nonane-3-
endo,7~-dihydroxy-2-exo-carboxymethylester-3-THP-ether--7-DMtB-
silylether.
To a stirred solution of this compound in dry toluene
(220ml) cooled at -70 , a solution of 1.4M DIBA in toluene is
added over a period of 45 minutes, maintaining the temperature
between -70+-60 . The stirring is continued for 2 hours, the
residual hydride is destroyed by addition of 2M isopropyl
alcohol in toluene.
The reaction mixture is warmed at room temperature and
successively 30% aqueous NaH2P04 (60ml) and Na2S04 (50g) are
added. After filtration, the organic phase is washed with water
and evaporated in vacuum affording dl-bicyclo[4.3.0]3-endo, 7~-
dihydroxy-2-exo-formyl-3-THP-ether-7-DMB-silyletheer (p=2, q=l).
Using in this procedure the 8~-hydroxy compound, we have ob-
tained:
dl-bicyclo[4.3.0]nonane-3-endo, 8~-dihydroxy-2-exo-carboxymethyl-
ester-3-THP-ether-8-DMB-silylether and
X
34
- 72 -
dl-bicyclo[4.3.0]nonane-3-endo, 8~-dihydroxy-2-exo-formyl-3-THP-
ether, 8-DMB-silylether.
Example 50
A solution of (2-oxo-heptyl)dimethylphosphonate
(0.33g) in dry benzene (5ml) is added to a stirred suspension of
NaH (80% dispersion in mineral oil, 43.5mg) in dry benzene
(lOml). After 1 hour N-Br-succinimide (260mg) is added and then,
after 5 minutes, a solution of bicyclo[4.3.0]nonane-3-endo, 8~-
dihydroxy-2-exo-formyl-3-THP-ether, 8-DMtB-silylether (0.4g) in
toluene (5ml).
The stirring is continued for 15 minutes, then the
reaction mixture is washed with aqueous 15% NaH2P04, dried and
evaporated in vacuum to give 2-exo[2'-bromo-3'-oxo-oct-1'-trans-
enyl]-3-endo-THP-oxy-8~-DMB-silyloxy-bicyclo[4.3.00]nonane,
~maX=25lm~,~=8.90
Example 51
A solution of (3-phenoxy-2-oxo-propyl)dimethyl-
phosphonate (2.85g) in benzene (lOml~ is added to a stirred sus-
pension of NaH (80% mineral oil dispersion, 0.33g) in benzene
(50ml). The stirring is continued for 45 minutes, then a solu-
tion of2-exo-formyl-3-endo-THP-oxy-7~-DMB-silyloxy-bicycllo-
[4.3.0]nonane (3.82g) in toluene is added. After 20 minutes the
organic phase is washed with aqueous 20% NaH2P04 and water,
dried and evaporated to dryness affording after filtration on
SiO2 (38g), using benzene-ethyl ether as eluent, 2-exo-[3'-oxo-
4'-phenoxy-but-1'-trans-enyl]-3-endo-THP-oxy-7~-DMMB-silyloxy-
bicyclo[4.3.0]nonane (3.97g). Using in the procedure (5-cyclo-
hexyl-2-oxo-butyl)-dimethyl phosphonate and starting from the
aldehydes of the example 49 we have obtained:
2-exo[3'-oxo-5'-cyclohexyl-pent-1'-trans-enyl]-3-eendo-THP-oxy-
7~-DM8-silyloxy-bicyclo[4.3.0]nonane ~maX=228m~=9.300
X
12~134
- 73 -
2-exo[3'-oxo-5'-cyclohexyl-pent-1'-trans-enyl]-3-eendo-THP-oxy-8~-
DMB-silyloxy-bicyclo[4.3.0]nonane ~maX=228.6m~,=9.450.
Example 52
The DMB-silylether~ -unsaturated ketones, obtained
in accordance with the procedure of the examples 50, 51 (a) are
reduced to allylic alcohols and (b) the new hydroxy group is pro-
tected as THP-ether; successively (c) the DMs-silylether protect-
ing group is selectively removed giving a secondary alcohol
which (d) is oxidized to ketone; finally after removal (e) of
all the remaining protective groups (f) the epimeric allylic
alcohols are separated by HPLC-chromatography on SiO2. Working
in a 2.10 molar scale, the following procedure is used:
a) reduction: 1.10 2 mole (0.32g) of NaBH4 is added to a stirred
solution of a unsaturated ketone-DMB-silylether (2.10 m) in
methylene chloride-ethanol ~1:1) (180ml) cooled at -10+-15.
After 30 minutes, the residual hydride is destroyed by adding
acetone (lOml) and aqueous saturated NaH2P04 (25ml). The sol-
vents are removed in vacuum and the residue is partitioned be-
tween water and methylene chloride. The organic layer is separ-
ated dried and evaporated to dryness affording a mixture of3'S t 3'R allylic alcohols-silylethers (2.10 2m).
b) protection of allylic alcohols as THP-ethers: the crude mix-
ture of 3'S,3'R-allylic alcohols silylether (2.10 2m) was
treated with methylene chloride (30ml) and to the stirred solu-
tion 2,3-dehydropyrane (2g) and p-toluenesulphonic acid (0.038g)
are added. The reaction is complete after 2 hours stopped by
addition of pyridine (0.5ml) and the solvents are removed by
evaporation in vacuum to give a crude mixture of 3'S,3'R-THP-
ether silylethers.
c) desilylation: a solution of the above obtained material in
$2~$134
- 74 -
dry THF (80ml) is treated for 12 hours at r.t. with dry tetra-
butylammonium fluoride (14g). After concentration in vacuum to
small volume, the residue is absorbed on SiO2 (40g) and follow-
ing elution with ethylether affords the secondary alcohol-3'S,
3'R-THP-ethers (about 2.10 m).
d) oxidation: dicyclohexylcarbodiimide (6.5g), pyridine (lml)
and trifluoro acetic acid (0.5ml) are added successively to a
stirred solution in 75:25 benzene-DMSO (60ml) of the secondary
alcohol-3'S,3'R-THP-ether. After 4.5 hours the reaction mix-
ture is diluted with benzene (lOOml) and with a solution of
oxalic acid (3g) in water. Formed dicyclohexylurea is filtered,
organic layer is washed until neutral, dried and evaporated to
dryness.
e,f) depyranylization and chromatographic separation: a solution
of the 3'S,3'R-THP-ether-ketones in methanol (30ml) is stirred
at r.t. for 3 hours with p-toluenesulphonic acid (0.18g); after
addition of pyridine (0.5ml) it is evaporated to dryness. The
residue is dissolved in cyclohexane-ethyl acetate (80:20) and
injected in HPLC instrument to give the following keto alcohols:
2-exo[2'bromo-3'S-hydroxy-oct-l'-trans-enyl]-3-enddo hydroxy-
bicyclo[4.3.0]nonane-8-one
2-exol2'bromo-3'R-hydroxy-oct-l'-trans-enyl]-3-enddo hydroxy-
bicyclo[4.3.0]nonane-8-one
2-exo[3'S-hydroxy-4'-phenoxy-but-1'-trans-enyl]-3--endo hydroxy-
bicyclo[4.3.0]nonane-7-one
2-exo[3'R-hydroxy-4'-phenoxy-but-1'-trans-enyl]-3--endo hydroxy-
bicyclo[4~3.0]nonane-7-one
2-exo[3'S-hydroxy-5-cyclohexyl-pent-1'-trans-enyl]]-3-endo
hydroxy-bicyclo[4.3.0]nonane-7-one
2-exo[3'R-hydroxy-5-cyclohexyl-pent-1'-trans-enyl]]-3-endo
hydroxy-bicyclo~4.3.0]nonane-7-one
~2Q~134
- 75 -
2-exo[3'S-hydroxy-5-cyclohexyl-pent-1'-trans-enyl]]-3-endo
hydroxy-bicyclo[4.3.0]nonane-8-one
2-exo[3'R-hydroxy-5-cyclohexyl-pent-1'-trans-enyl]]-3-endo
hydroxy-bicyclo[4.3.0]nonane-8-one.
Example 53
Under a N2 atmosphere, a suspension of NaH (80% disper-
sion in mineral oil, 2.lg) in dry DMSO (70ml) is stirred for 4
hours at 65 . After cooling at 25-30, dry 4-carboxy-butyl-
triphenyl phosphonium bromide (13g) is added to it, obtaining a
deep red solution of the ylide.
After addition of a solution of 2-exo[2'bromo-3'S-
hydroxy-oct-l'-trans-enyl]-3-endo hydroxy-bicyclo[4.3.0]nonane-
8-one (1.79g) in dry DMSO (6ml), the reaction mixture is stirred
for 1 hour at 28 and then for 4 hours at 40; afterwards it is
cooled at r.t., diluted with water (80ml), acidified up to pH
4.5 by adding 4N H2SO4 and extracted with ethyl ether (4x50ml,
2x25).
The aqueous layer is discarded, the organic phases are
combined washed with water (this washing is discarded), then
with N NaOH (5xlOml) and water until neutral. The combined
alkaline extracts are acidified up to pH 5 and extracted with
ethyl ether to give 5(zrE)-lla~l5s-dihydroxy-9a-deoxy-9a~9b-
dimethylene-prostacycla-5-en-13-ynoic acid (a mixture of 5c- and
5t-isomers).
The individual geometric isomers are obtained after
chromatographic separation on acidic SiO2 (40g/each g of acid)
using cyclohexane-ethyl acetate as eluents.
Example 54
Under a N2 atmosphere, to a stirred solution of potas-
sium-ter-butoxide (3.36g), freshly sublimated, in dry DMSO
~2~34
- 76 -
(36ml) it is added 6.5g of 4-carboxy-butyl-triphenyl-phosphonium
bromide to give a deep red solution of the ylide. After addi-
tion of a solution of 2-exo[3'R-hydroxy-4'-phenoxy-but-1'-trans-
enyl]3-endo hydroxy-bicyclo[4.3.0]nonane-7-one (0.8g) in dry
DMSO ~3ml), the reaction mixture is stirred for 5 hours at 42 ,
cooled diluted with water (50ml) acidified up to pH 5 and ex-
tracted with ethyl ether (4xlOml). The aqueous phase is dis-
carded the combined ethereal extracts are washed with water
(lOml, this washing is discarded), and with 0.5N NaOH (4x6ml) and
water until neutral. The combined alkaline extracts are
acidified up to pH 5 and extracted with ethyl ether. The
organic phases are combined dried and evaporated to dryness to
give:
5(Z,E),13t-11~,15R-dihydroxy-9a-deoxy-7a-homo-9a-methylenne-16-
phenoxy-17,18,19,20-tetranor-prostacycla-5,13-diennoic acid (a
mixture of 5c and St-geometrical isomers).
The individual geometric isomers are obtained after
chromatographic separation on acidic SiO2 (40g/each g of acid)
using cyclohexane-ethyl acetate as eluents.
Example 55
Using the keto alcohols of the example 52 in the pro-
cedure of the examples 53, 54 we have prepared the following
prostacyclanoic acids:
5c~,15S-dihydroxy-9a-deoxy-9a,9b-dimethylene-prostacyycla-5-en-
13-ynoic acid
5c,13t-11~,15S-dihydroxy-9a-deoxy-7a homo-9a-methylene-16-
phenoxy-17,18,19,20-tetranor-prostacycla-5,13-diennoic acid
5c,13t-11~,15S-dihydroxy-9a-deoxy-9a,9b-dimethylenne-17-cyclo-
hexyl-18,19,20-trinor-prostacycla-5,13-dienoic acid
5c,13t-11~,15S-dihydroxy-9a-deoxy-7a homo-9a-methylene-17-cyclo-
hexyl-18,19,20-trinor-prostacycla-5,13-dienoic acid
~Z~S~34
- 77 -
5t~ ,15S-dihydroxy-9a-deoxy-9a,9b-dimethylene-prostacyycla-5-en-
13-ynoic acid
5t,13t-lla,15S-dihydroxy-9~-deoxy-7a homo-9a-methylene-16-
phenoxy-17,18,19,20-tetranor-prostacycla-5,13-diennoic acid
5t,13t-11,15S-dihydroxy-9a-deoxy-9a,9b-dimethylenne-17-cyclo-
hexyl-18,19,20-trinor-prostacycla-5,13-dienoic acid
5t,13t-11~,15S-dihydroxy-9a-deoxy-7a homo-9a-methylene-17-cyclo-
hexyl-18,19,20-trinor-prostacycla-5,13-dienoic acid.
Example 56
Using the procedure of the example 46, 30g of
2-acetoxyperhydroazulen-6-one, also named as 3-endo-hydroxy-
bicyclo[5.3.0]decane-8-one acetate (obtained in accordance with
D.K. Baner]ee et al. Indian J. Chem. 10, 1, 1972) is transformed
into its ethylenedioxide (29.lg). Then the compound is saponi-
fied by treatment with 2~ K2CO3 in aqueous methanol to give
3-endo-hydroxy-bicyclo[5.3.0]decane-8-one-8,8-ethyylenedioxide
and oxidized using the procedure of the example 47 and treated
with dimethylcarbonate (see the procedure of example 47) to ob-
taindl-bicyclo[5.3.0]decane-3,8-dione-2-carboxymethyleester-8,8-
ethylenedioxide, 21.2g, ~maX=254nm;~=7.000.
Example 57
The bicyclo-~-keto ester-ethylenedioxides obtained in
the examples 47, 48 and 56 are reduced with the following proce-
dure:
NaBH4 (0.9g) is added portionwise to a stirred solution of the
bicyclo-~-keto ester-ethylenedioxides (2.5.10 m) in 1:1
methylene chloride-ethanol (150ml), cooled at -20 . After addi-
tional stirring for 30 minutes at -20, the residual hydride is
destroyed by adding acetone (12ml). The reaction mixture is
warmed at room temperature treated with aqueous 20% KH2PO4 and
~2~ 134
- 78 -
after removal of solvents, and dilution with water (20ml) it is
extracted with methylene chloride. The organic phases are com-
bined, washed until neutral with water, dried and evaporated to
dryness. The residue is equilibrated by treatment with absolute
methanol (20ml) and sodium methoxide (0.54g), for 12 hours at
r.t.; acetic acid (0.59g) addition followed by evaporation of
solvents and extraction with methylene chloride gives about
0.22.lO m of the following bicyclo-~-hydroxy ester-ethylene-
dioxides:
dl-3-endohydroxy-bicyclo[3.2.0]heptane-6-one-2-exo-carboxy--
methylester-6,6-ethylenedioxide
dl-3-endohydroxy-bicyclo13.2.0]heptane-6-one-4-exo-carboxy--
methylester-6,6-ethylenedioxide, also named as: dl-3-endo
hydroxy-bicyclo[3.2.0]heptane 7-one-2-exo-carboxymethylester-7,7-
ethylenedioxide
dl-3-endo hydroxy-bicyclo[4.3.0]nonane-7-one-2-exo-carboxy-
methylester-7,7-ethylenedioxide
dl-3-endo hydroxy-bicyclo[4.3.0]nonane-8 one-2-exo-carboxy-
methylester-8,8-ethylenedioxide
dl-3-endo hydroxy-bicyclo[5.3.0]decane-8-one-2-exo-carboxy-
methylester-8,8-ethylenedioxide.
In the following, a solution of 2.lO m of each of
these compounds in dry methylene chloride, 25ml, is reacted
with 2,3-dihydropyran (2g) and p-toluenesulphonic acid (38mg,
2.lO 4m) for 2 hours at r.t. The reaction is stopped by adding
pyridine (O.lml) and the mixture is evaporated to dryness in
vacuum affording the corresponding 3-THP-ethers which are used
without any further purification.
Example 58
The 3-endo-hydroxy-2-exo-carboxymethylesters and their
$~34
- 79 -
3-THP-ethers, obtained with the procedure of the example 57 are
reduced to give the corresponding 2-exo-hydroxymethyl deriva-
tives with following procedure: a solution of 2.10 m of the
~-ketoester (both alcohol and 3-THP ether) in dry ethylether
(25ml) is added dropwise to a stirred suspension of LiAlH4 (0.4)
in dry ethylether (50ml). After additional stirring for 30
minutes the residual hydride is destroyed by adding acetone
(5ml) and ethylether saturated with water. Dry MgSO4, 12g, is
added to, then the organic phase is filtered and evaporated to
dryness.
We obtain the following 3-endohydroxy-2-exo-hydroxy-
methyl:
bicyclo[3.2.0]heptane-6-one-6,6-ethylenedioxide
bicyclo[3.2.0]heptane-7-one-7,7-ethylenedioxide
bicyclo[4.3.0]nonane-7-one-7,7-ethylenedioxide
bicyclo[4.3.0]nonane-8-one-8,8-ethylenedioxide
bicyclo~5.3.0]decane-8-one-8,8-ethylenedioxide
and their 3-endo-hydroxy-THP-ethers both racemic and optical
active form (nat, ent) when optical active material, coming from
optical resolution successively described, is used in the reduc-
tive process.
Example 59
Free ketone is obtained by treatment of a solution of
3-endohydroxy-2-exo-hydroxymethyl-bicyclo[5.3.0]decane-88-one-
8,8-ethylenedioxide (5g, 2.10 m) in methanol (20ml) and water
(2ml) with p-toluenesulphonic acid (0.3g) for 2 hours at reflux
temperature. The solvents are evaporated in vacuum and the
residue is filtered through a short column of SiO2.
Working in accordance with the procedure of the
example 54, a solution of the so obtained 3-endo-hydroxy-2-exo-
lZ~$~134
- 80 -
hydroxymethyl-bicyclo[5.3.0]8-one (4.7g) in dry DMSO (17ml) is
reacted with the ylide formed from potassium ter-butoxide (27g),
DMSO (280ml) and 3-carboxy-propyl-phosphoniumbromide for 5 hours
at 40 . The reaction mixture is diluted with water (300ml) and
extracted with 80:20 ethylether-benzene to remove triphenyl-
phosphoxide. These extracts are discarded and alkaline phases
are acidified up to pH 5 and repeatedly extracted with ethyl-
ether (8x200) and with 3:1 ethylether-ethylacetate (5xlOO). The
combined organic extracts are dried, concentrated to a small
volume (lOOml) treated with ethereal diazomethane to achieve the
methyl ester and then evaporated to dryness.
The crude material is chromatographed on SiO2 (lOOg)
ethylacetate as eluent) to give 5 (Z,E)-~(20~12) octanor-12~-
hydroxymethyl-ll~-hydroxy-9a-deoxy-7a-homo-9a,9b-ddimethylene-2-
nor-prostacycla-5-enoic acid methylester (4.lg).
By treating this compound in dry DMF (12ml) with
dimethyl-ter-butyl-silyl-chloride (2.2g) and imidazole (1.55g)
at 15 for 24 hours, followed from dilution with water (24ml)
and extraction with ethylether and chromatographic purification
on SiO2 (25g, cyclohexane-ethylether as eluent) we obtain its
mono 12~-DMB-silyloxy methyl-ether (4.31g 80~).
Treatment with pyridine (lOml), acetic anhydride (5ml)
at r.t. for 12 hours and hydrolysis with aqueous methanol and
p-toluenesulphonic acid afford 5tZ,E)-~-(20~12) octanor-12~-
hydroxymethyl-ll~-hydroxy-9~-deoxy-7a-homo-9a,9b-ddimethylene-2-
nor-prostacycla-5-en-oic acid methylester-ll-acetate. Prepara-
tive chromatography (using a HPLC-instrument and monitoring with
refractive index) on SiO2 treated with 3% AgN03 (with methylene-
chloride-ethylacetate as eluent) affords the individual geo-
metric 5c and 5t isomers.
lZ~134
- 81 -
In similar way, 5(Z,E)-~-(20~12) octanor-12~-hydroxy-
methyl -hydroxy-9a-deoxy-7a-homo-9a-methylene-prostacyclaa-5-
enoic acid methyl ester-ll-acetate and their 5c and 5t indivi-
dual geometric isomers are prepared when 3-endo-hydroxy-bicyclo-
[4.3.0]nonane-7-one-2-exo-carboxymethylester-7,7-eethylenedioxide
is used in side of the corresponding per-hydroazulene compound
and the 4-carboxybutylphosphonium bromide is utilized in side of
the 3-carboxypropyl-one.
Example 60
Starting from the 2-exo-hydroxymethyl-THP-ether com-
pounds of the example 58 and from 12~-hydroxymethyl-11-acetate
of the example 59, we have obtained the corresponding aldehydes
by the following oxidative procedure:
Successively, dicyclohexylcarbodiimide (0.64g), pyridine (O.lml)
trifluoroacetic acid (0.05ml) are added to a stirred solution of
the hydroxy-methyl compound (2.10 3m) in 75:25 benzene-DMSO
(6ml). After 4.5 hours, the reaction mixture is diluted with
benzene (20ml) and water (lOml) and stirred for 30 minutes again.
Dicyclohexylurea is filtered off and the organic layer is washed
with water until neutral and the concentrated up to lOml afford-
ing a solution in dry benzene of the following aldehydes:
3-endo-THP-oxy-2-exo-formyl-bicyclo[3.2.0]heptane--6-one-6,6-
ethylenedioxide
3-endo-THP-oxy-2-exo-formyl-bicyclo[3.2.0]heptane--7-one-7,7-
- ethylenedioxide
3-endo-THP-oxy-2-exo-formyl-bicyclo~4.3.0]nonane-77-one-7,7-
ethylenedioxide
3-endo-THP-oxy-2-exo-formyl-bicyclo[4.3.0]nonane-88-one-8,8-
ethylenedioxide
3-endo-THP-oxy-2-exo-formyl-bicyclo~5.3.0]decane-88-one-8,8-
ethylenedioxide
- ~Z~3$~134
- 82 -
~(20~12)octanor-12~-formyl-11~-hydroxy-7-homo-9a,99b-dimethylene-
2-nor-prostacycla-5-enoic acid methylester-ll-acetate (5(Z,E);5c;
5t).
~(20~12)octanor-12~-formyl-11~-hydroxy-9a-deoxy-7aa-homo-9a-
methylene-prostacycla-5-enoic acid methylester-ll-acetate (5(Z,E);
5c;5t).
These compounds are used in the following Wittig-Horner reac-
tions with any further purification.
Example 61
A solution of (2-oxo-heptyl)dimethylphosphonate
(0.49g) in benzene (6ml) is added dropwise to a stirred suspen-
sion of NaH (80% dispersion in mineral oil, 66mg, 2.2.10 m) in
benzene (15ml). After an additional stirring for 45' we add a
solution of 2.10 m of 5t-~(20~12)octanor-12~-formyl~ -hydroxy-
9a-deoxy-7a-homo-9a,9b-dimethylene-2-nor-prostacyccla-5-enoic
acid methylester-ll-acetate in benzene (lOml) to it. After an
additional hour the reaction is stopped by adding a solution of
acetic acid (132mg) in benzene (5ml); the organic phase is
washed with water until neutral, dried and evaporated to dryness.
The residue, 1.2g, is absorbed on SiO2 (lOg), follow-
ing elution with cyclohexane-ethylacetate gives 5t,13t-11-
hydroxy-15-oxo-9a-deoxy-7a-homo-9a,9b-dimethylene--2-nor-
prostacycla-5,13-dienoic acid methyl ester-ll-acetate (0.76g),
lmaX=228m11~ =9- 800-
The following a,~-unsaturated ketones are obtained
when the other aldehydes of the example 60 are used in the above
procedure:
5c,13t-11~-hydroxy-15-oxo-9a-deoxy-7a-homo-9a,9b-ddimethylene-2-
nor prostacycla-5,13-dienoic acid-methylester-ll-acetate
~max=228m~,=9.9OO and the mixture of their 5(Z,E) isomers
~Z~ 134
- 83 -
5t,13t-11-hydroxy-15-oxo-9a-deoxy-7a-homo-9a-methhylene-
prostacycla-5,13-dienoic acid methylester-ll-acetate (~maX=229m~
=10.000) and its 5t and 5(Z,E)-isomers
and the following 2-exo[3'-oxo-oct-1'-trans-enyl]3-endo-hydroxy-
THP-ethers:
bicyclo[3.2.0]heptane-6-one-6,6-ethylenedioxide
bicyclo[3.2.0]heptane-7-one-7,7-ethylenedioxide
bicyclo[4.3.0]nonane-7-one-7,7-ethylenedioxide
bicyclo[4.3.0]nonane-8-one-8,8-ethylenedioxide
bicyclo[5.3.0]decane-8-one-8,8-ethylenedioxide.
Example 62
Using in the procedure of the example 61, different
dimethylphosphonates we have prepared the following ~,~-unsatu-
rated ketones:
a) by reaction of 3-endo-THP-oxy-2-exo-formyl-bicyclo[3.2.0]-
heptane-7-one-7,7-ethylenedioxide (2.10 3m) with (2-oxo-3(S,R)-
fluoro-heptyl)dimethyl phosphonate (0.54g) we obtain 3-endo-THP-
oxy-2-exo[3'-oxo-4'(R,S)fluoro-oct-l'-trans-enyl]bbicyclo[3.2.0]-
heptane-7-one-7,7-ethylenedioxide (0.72g) ~max=229nm,~=9.9OO,
[~]D=~98 (CHC13)
b) by reaction of the heptane-6-one-6,6-ethylenedioxide aldehyde
(2.10 m) with (2-oxo-octyl)dimethylphosphonate we obtain 3-endo-
THP-oxy-2-exo[3'-oxo-non-1'-trans-enyl]bicyclo[3.22.0]heptane-6-
one-6,6-ethylenedioxide ~maX=228nm~ F=9 . 300
c) by reaction with the heptane-7-one-7,7-ethylenedioxide
aldehyde with (2-oxo-4-phenyl-butyl)dimethylphosphonate (0.565g)
we obtain3-endo-THP-oxy-2-exo-[3'-oxo-5'-phenyl-pent-1'-traans-
enyllbicyclo[3.2.0]heptane-7-one-7,7-ethylenedioxiide
d) by reaction with the nonane-7-one-7,7-ethylenedioxide with
0.52g of (2-oxo-3S-methylheptyl) and with (2-oxo-3R-methyl-
$~34
- 84 -
heptyl)dimethyl phosphonate we obtain respectively:
3-endo-THP-oxy-2-exo[3'-oxo-4'S-methyl-oct-l'-tranns-enyl~bicyclo-
[4.3.0]nonane-7-one-7,7-ethylenedioxide and
3-endo-THP-oxy-2-exo[3'-oxo-4'R-methyl-oct-l'-tranns-enyl~bicyclo-
[4.3.0]nonane-7-one-7,7-ethylenedioxide.
Example 63
Pyridine hydrobromideperbromide (C5H5N.HBr.sr2), 0.8g,
is added to a stirred solution of 3-endo-THP-oxy-2-exo[3'-oxo-
4'(R,S)-fluoro-oct-l'-trans-enyl]bicyclo[3.2.0]hepptane-7-one-7,7-
ethylenedioxide in dry pyridine (15ml). After additional stirr-
ing for 4 hours at r.t., the precipitate is filtered off and the
organic eluate is partitioned among ice, 2N H2SO4 and ethyl-
acetate.
The organic layer is washed with cooled 0.5 NH2SO4,
brine, 1% sodium carbonate, water until neutral affording 0.71g
of 2'bromo-4'(R,S)-fluoro compound, which is a mixture of 2
diasteroisomeric 4'S and 4'R derivatives. HPLC-chromatography
on SiO2 with CH2C12-ethylether (85:15) affords the individual
isomers:0.22g of 3-endo-THP-oxy-2-exo[2'bromo-3'-oxo-4'R-fluoro-
oct-1'-trans-enyl]bicyclo[3.2.0]heptane-7-one-7,7--ethylene-
dioxide ~maX=250nm,~=9.830 and O.l9g of the 4'S-fluoro isomer
=251nm,~=9.750.
Using in the above procedure different unsaturated
ketones, we obtain the followings:
3-endo-THP-oxy-2-exo[2'bromo-3'-oxo-non-1'-trans-eenyl]bicyclo
[3.2.0]heptane-6-one-6,6-ethylenedioxide and
-I 3-endo-THP-oxy-2-exo[2'bromo-3'-oxo-oct-1'-trans-eenyl]bicyclo-
[4.3.0]nonane-7-one-7,7-ethylenedioxide.
Example 64
An ethereal solution of 5% methylmagnesium iodide
lZO$~34
- 85 -
(5ml) is added to a stirred solution of 5t,13t-lla-hydroxy-15-
oxo-9a-deoxy-7a-homo-9a-methylene-prostacycla-5,133-dienoic acid
methylester (0.4g) in 2:1 ethyl ether-toluene (12ml), cooled at
-30 . After stirring for additional 4 hours, the reaction mix-
ture is warmed to O and the residual reagent is destroyed by
adding of 20% aqueous NH4Cl. The organic layer is separated,
washed with water, dried and after addition of pyridine (O.lml)
is evaporated to dryness. The residue dissolved in dry methanol
(lOml) is stirred with anhydrous K2C03 (O.lg) for 2 hours. The
solution is filtered, evaporated in vacuum and the resulting
crude material is partitioned between ethyl acetate 20% NaH2P04.
The organic layer after the usual work-up is concentrated to
small volume; the residue is absorbed on SiO2 (20g). Elution
with 80:20 ethylether:isopropylether gives 5t,13t-lla,15S-
dihydroxy-15-methyl-9a-deo-7a-homo-9a-methylene-prrostacycla-5,13-
dienoic acid methylester (O.lg) and its 15R-isomer (0.085g).
With this procedure it is also obtained:
5t,13t-lla,15S-dihydroxy-15-methyl-9a-deoxy-7a-hommo-9a,9b-
dimethylene-2-nor-prostacycla-5,13-dienoic acid-methylester and
its 15R-epimer.
The free acids are obtained heating at the reflux tem-
perature a solution of methylesters in 80:20 methanol-water in
the presence of 2~ K2C03. The solvent is evaporated in vacuum
and the residue is partitioned between ethylether and water.
The organic layers are reextracted with 0.5% K2C03 and discarded.
The combined alkaline phases are acidified up to pH 6 and ex-
tracted with ethylether. Combined organic phases are washed,
dried on MgS04 and evaporated to dryness to give free acids.
Example 65
Using in the procedure of the example 64 ethynyl
12~134
- 86 -
magnesium bromide, vinyl magnesium bromide and ethyl magnesium
bromide in side of the methyl magnesium iodide, the correspond-
ing 15-ethynyl, 15-vinyl and 15-ethyl prostacycladienoic acids
are obtained.
Example 66
Starting from the a,~-unsaturated ketones of the
examples 61,62,63, secondary allylic alcohols are obtained using
the following procedure:
a solution of a,~-unsaturated ketone (2.10 3m) in dry ethylether
(20ml) is added to a stirred solution of 0.25M zinc borohydride
(48ml) in dry ethylether, dropwise in a period of 30 minutes.
After an additional stirring for 2 hours, the residual hydride
is destroyed by adding saturated NaCl.
The organic layer is separated, washed until neutral,
dried on Na2SO4 and evaporated to dryness. Preparative HPLC-
chromatography on SiO2, using as eluent methylene chloride/
ethylacetate, affords:
5c,13t-lla,15S-dihydroxy-9a-deoxy-7a-homo-9a,9b-diimethylene-2-
nor-prostacycla-5,13-dienoic acid methylester-ll-acetate and its
5(Z,E) and 5t geometric isomers.
5t,13t-lla,15S-dihydroxy-9a-deoxy-7a-homo-9a-methyylene-
prostacycla-5,13-dienois acid methylester-ll-acetate and its
5(Z,E) and 5c-geometric isomers.
The following 2-exo[3'S-hydroxy-oct-l'-trans-enyl]3-
endo-THP-oxy;
bicyclo~3.2.0]heptane-6-one-6,6-ethylenedioxide
bicyclo[3.2.0]heptane-7-one-7,7-ethylenedioxide
bicyclo[4.3.0]nonane-7-one-7,7-ethylenedioxide
bicyclo[4.3.0]nonane-8-one-8,8-ethylenedioxide
and the following 3-endo-THP-oxy:
12~.t39~
- 87 -
2-exo[2'bromo-3'S-hydroxy-4'R-fluoro-oct-1'-trans--enyl]bicyclo-
[3.2.0]heptane-7-one-7,7-ethylenedioxide
2-exo[2'bromo-3'S-hydroxy-4'S-fluoro-oct-l'-trans--enyl]bicyclo-
[3.2.0]heptane-7-one-7,7-ethylenedioxide
2-exo[2'bromo-3'S-hydroxy-non-l'-trans-enyl]bicycllo[3.2.0]-
heptane-6-one-6,6-ethylenedioxide
2-exo[3'S-hydroxy-non-l'-trans-enyl]bicyclo[3.2.0]]heptane-6-one-
6,6-ethylenedioxide
2-exo[3'S-hydroxy-5'-phenyl-pent-1'-trans-enyl]biccyclo[3.2.0]-
heptane-7-one-7,7-ethylenedioxide
2-exo~2'bromo-3'S-hydroxy-oct-l'-trans-enyl]bicycllo[4.3.0]nonane-
7-one-7,7-ethylenedioxide
2-exo[3'S-hydroxy-4'S-methyl-oct-l'-trans-enyl3biccyclo[4.3.0]-
nonane-7-one-7,7-ethylenedioxide
2-exo[3'S-hydroxy-4'R-methyl-oct-l'-trans-enyl]biccyclo[4.3.0]-
nonane-7-one-7,7-ethylenedioxide
5c,13t-lla,15R-dihydroxy-9a-deoxy-7a-homo-9a,9b-diimethylene-2-
nor-prostacycla-5,13-dienoic acid methylester-ll-acetate and its
5(Z,E) and 5t geometric isomers.
5t,13t-lla,15R-dihydroxy-9a-deoxy-7a-homo-9a-methyylene-
prostacycla-5,13-dienoic acid methylester-ll-acetate and its
5(Z,E) and 5c-geometric isomers.
The following 2-exo[3'R-hydroxy-oct-l'-trans-enyl]3-
endo-THP-oxy:
bicyclo[3.2.0]heptane-6-one-6,6-ethylenedioxide
bicyclo[3.2.0]heptane-7-one-7,7-ethylenedioxide
bicyclo[4.3.0]nonane-7-one-7,7-ethylenedioxide
bicyclo[4.3.0]nonane-8-one-8,8-ethylenedioxide
and the following 3-endo-THP-oxy:
2-exo[2'bromo-3'R-hydroxy-4'R-fluoro-oct-l'-trans--enyl]bicyclo-
[3.2.0]heptane-7-one-7,7-ethylenedioxide
3~
- 88 -
2-exo[2'bromo-3'R-hydroxy-4'S-fluoro-oct-l'-trans--enyl]bicyclo-
~3.2.0]heptane-7-one-7,7-ethylenedioxide
2-exo[2'bromo-3'R-hydroxy-non-l'-trans-enyl]bicycllol3.2.0]-
heptane-6-one-6,6-ethylenedioxide
2-exo[3'R-hydroxy-non-l'-trans-enyl]bicyclo[3.2.0]]heptane-6-one-
6,6-ethylenedioxide
2-exo[3'R-hydroxy-5'-phenyl-pent-1'-trans-enyl]biccyclo[3.2.0]-
heptane-7-one-7,7-ethylenedioxide
2-exo[2'bromo-3'R-hydroxy-oct-l'-trans-enyl]bicycllo[4.3.0]-
nonane-7-one-7,7-ethylenedioxide
2-exo[3'R-hydroxy-4'S-methyl-oct-l'-trans-enyl]biccyclo[4.3.0]-
nonane-7-one-7,7-ethylenedioxide
2-exo[3'R-hydroxy-4'R-methyl-oct-l'-trans-enyl]biccyclo[4.3.0]-
nonane-7-one-7,7-ethylenedioxide
Example 67
The individual ll-acetate prostacycladienoic acid
methylesters are converted both in their ll-hydroxy methylesters
by trans esterification in dry methanol with anhydrous K2C03
(0.5 mol equiv) and in their ll-hydroxy free acid by treatment
with K2C03 in 80~ aqueous methanol.
Example 68
Every one of the bicyclo-THP-oxy-ethylenedioxides ob-
tained in the procedure of the example 66 is converted in to the
corresponding prostacyclenoic acids working up with the follow-
ing procedure:
a solution of 1.10 3m of the bicyclo-THP-oxy-ethylenedioxide in
acetone (15ml) is refluxed with N aqueous oxalic acid (lOml) for
8 hours. The acetone is evaporated in vacuum and the aqueous
phase is extracted with ethylether. The combined extracts,
after the usual work-up, are evaporated to dryness affording
~LZ~,134
- 89 -
about 0.6-1.10 m of the hydroxy ketone. A solution of this com-
pound in dry DMSO (2ml) is added to a solution of the ylide ob-
tained so on: in a N2 atmosphere potassium-tert-butoxide (1.35g)
is added to dry DMSO tl5ml), thin to it we added 4-carboxy-butyl-
triphenyl-phosphoniumbromide (2.6g) to obtain a deep-red solu-
tion of the ylide. After addition of the ketone, the reaction
mixture is warmed at 40-42 for 6 hours, cooled, diluted with
water (20ml), acidified up to pH 5.1 and extracted with ethyl-
ether (5x25ml).
The aqueous phase is discarded, and the organic ex-
tracts are collected, washed with water (5ml; this washing is
discarded) and extracted with 0.5N NaOH (6x6ml) and water until
neutral. The combined alkaline extracts are combined, acidified
to pH 5 and extracted with ethylether. The combined organic ex-
tracts are washed with water (2ml), dried on Na2SO4, and evapo-
rated to dryness giving a mixture of the 5Z and 5E acids.
The individual geometric isomers are obtained after
chromatographic separation on acidic SiO2 (Fe +, Fe ++ free)
using CH2C12-ethylacetate as eluent (SiO2 30g for each of 0.2g
of the acid).
In this way we have prepared:
5t,13t-lla,15S-dihydroxy-9a-deoxy-9a-nor-methylenee-prostacycla-
5,13-dienoic acid
5t,13t-lla,15S-dihydroxy-9a-deoxy-9a-nor-methylenee-20-methyl-
prostacycla-5,13-dienoic acid
5t-lla,15S-dehydroxy-9a-deoxy-9a-nor-methylene-20--methyl-
prostacycla-5-en-13-ynoic acid
5t,13t-lla,15S-dihydroxy-9a-deoxy-9a-methylene-7-nnor-methylene-
prostacycla-5,13-dienoic acid
5t,13t-lla,15S-dihydroxy-9a-deoxy-7a-homo-9a-methyylene-
prostacycla-5,13-dienoic acid
12(~34
-- 90 --
5t,13t-11~,15S-dihydroxy-9a-deoxy-9a,9b-dimethylenne-prostacycla-
5,13-dienoic acid
5t-11,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-mmethylene-16S-
fluoro-prostacycla-5-en-13-ynoic acid
5t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-mmethylene-16R-
fluoro-prostacycla-5-en-13-ynoic acid
5t,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nnor-methylene-
17-phenyl-18,19,20-trinor-prostacycla-5,13-dienoicc acid
5t,13t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methyylene-16S-
methyl-prostacycla-5,13-dienoic acid
5t,13t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methyylene-16R-
methyl-prostacycla-5,13-dienoic acid
5t-11,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylenee-prostacycla-5-
en-13-ynoic acid
5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-nor-methylenee-prostacycla-
5,13-dienoic acid
5c,13t-11~,15S-dehydroxy-9a-deoxy-9a-nor-methylenee-20-methyl-
prostacycla-5,13-dienoic acid
5c-11~,15S-dehydroxy-9a-deoxy-9a-nor-methylene-20--methyl-
prostacycla-5-en-13-ynoic acid
5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nnor-methylene-
prostacycla-5,13-dienoic acid
5c,13t~ ,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylene-
prostacycla-5,13-dienoic acid
5c,13t-lla,15S-dihydroxy-9a-deoxy-9a,9b-dimethylenne-prostacycla-
5,13-dienoic acid
5c-11~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-mmethylene-16S-
fluoro-prostacycla-5-en-13-ynoic acid
5c-11~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-mmethylene-16R-
fluoro-prostacycla-5-en-13-ynoic acid
~2~34
-- 91 --
5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nnor-methylene-
17-phenyl-18,19,20-trinor-prostacycla-5,13-dienoicc acid
5c,13t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methyylene-16S-
methyl-prostacycla-5,13-dienoic acid
5c,13t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methyylene-16R-
methyl-prostacycla-5,13-dienoic acid
5c,11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylenee-prostacycla-5-
en-13-ynoic acid and their 15R-isomers.
Example 69
Successively dicyclohexylcarbodiimide (0.32g) pyridine
(0.044ml) and trifluoroacetic acid (0.022ml) are added to a stir-
red solution of 5t,13t-11~,15S-dihydroxy-9a-deoxy-9a,7a-homo-
dimethylene-15-methyl-prostacycla-5,13-dienoic acid methylester
(0.39g) in 75:25 benzene-DMSO (6ml). After 5 hours the reaction
mixture is diluted with benzene (20ml) and 1.2g of oxalic acid
in water (lOml). The stirring is continued for 20 minutes, the
mixture is filtered and the organic phase is washed until
neutral, dried and finally evaporated to dryness.
Chromatographic purification on SiO2 (4g), ethyl ether
as eluent, gives 0.26g of 5t,13t-11-oxo-15S-hydroxy-9a-deoxy-7a-
homo-9a-methylene-15-methyl-prostacycla-5,13-dienooic acid methyl-
ester which is hydrolysed with 2% aqueous K2C03 to give the free
acid.
Example 70
Sodium borohydride (2.5g) in portionwise is added to a
stirred solution of bicyclo[4.3.0]nonane-7-en-3-one (11.42g) in
ethanol (80ml). After an additional stirring for 2 hours,
acetic acid (5ml) is added and the mixture is evaporated to dry-
ness. The residue is partitioned between water and CH2C12, and
the organic layer is evaporated to dryness. A solution of the
L34
- 92 -
resulting bicyclo[4.3.0]nonane-7-en-3-hydroxy (llg) in dry DMF
is heated successively with dimethyl-tert-butyl-silyl-chloride
(15.6g) and imidazole (10.85g), warmed at 60 for 6 hours,
cooled and diluted with water (66ml). After exhaustive extrac-
tion with ethylether and usual work-up we obtain bicyclo[4.3.0]-
nonane-7-ene-3-hydroxy-3-DMB-silyl ether (l9.lg). Its solution
in dry THF (lOOml), cooled at O C is treated (under stirring, in
N2 atmosphere) with M BH3 solution in THF (75ml). After 2 hours,
maintaining the temperature at 25 , we add N NaOH (25ml) and 30%
hydrogen peroxide (25ml). The mixture is heated at 60 for 2
hours, cooled and diluted with benzene (400ml). The organic
layer is washed with l Na2C03, saturated sodium sulphite, satu-
rated NaCl, dried and evaporated to dryness giving crude bicyclo-
[4.3.0]nonane-7(8)~-3-dihydroxy-3-DMB-silylether (20.3g). A
solution of the resulting alcohol in 75/25 benzene-DMSO (150ml)
is treated successively with dicyclohexylcarbodiimide (16g)
pyridine (2ml) trifluoro acetic acid (lml), under stirring.
After 5 hours, the mixture is diluted with benzene (400ml),
water (50ml) with a solution of oxalic acid (6g) in water (75ml),
and after additional stirring for 30 minutes is filtered. The
organic phase is washed with water until neutral affording
bicyclo[4.3.0]nonane-7(8)-one-3-hydroxy-DMB-silyleether (18.25g)
which is dissolved in methanol (60ml) and treated with 1.8g of
p-toluenesulphonic acid. After 12 hours, the mixture is treated
with pyridine (1.95ml) and evaporated to dryness. The residue
is filtered on SiO2 (ethylether-ethylacetate as eluent) to give
bicyclo[4.3.0]nonane-7(8)-one-3-hydroxy (lOg).
A solution of this compound in benzene (50ml) is re-
fluxed in the presence of dry ethylene glycol (5.2g) and
-p-toluenesulphonic acid (0.6 g) withdrawing the water formed dur-
34
- 93 -
ing the reaction. After 14 hours we add pyridine (2ml) and the
organic phase is cooled, washed with water, 2% Na2CO3 and satu-
rated NaCl until neutral. Evaporation of solvents gives bicyclo-
[4.3.0]nonane-7(8)-one-3-hydroxy-7,7~8,8)-ethyleneedioxide.
Example 71
Saponification with 2% K2CO3 in 80% aqueous methanol
of the dl-3-endo-hydroxy-bicyclo[4.3.0]nonane-8-one-8,8-
diethylenedioxide-2-exo-carboxy-methylester (4.5g) gives the
free acid (4.2g).
To a solution of the free acid (4.2g) in acetonitrile
(120ml) it is added d(+)-ephedrine (2.3g); after 4 hours at r.t.
2.8g of salt crystalizes giving after further crystalization
from acetonitrile 2.15g of (+)bicyclo[4.3.0]nonane-8-one-8,8-
ethylenedioxide-3-endo-hydroxy-2-exo-carboxylic acid d(+)-
ephedrinium salt. All the liquor waters are combined, evapor-
ated to dryness; the residue is dissolved in water and treated
with N NaOH up to alkaline pH (12-13). d(+)-Ephedrine is re-
covered by extraction with ether, then alkaline aqueous solution
is acidified to pH 5 extracted with ethylacetate and organic
layer combined are evaporated to dryness. The residue is
diluted in acetonitrile and the procedure is repeated using
(-)ephedrine to give (-)bicyclo[4.3.0]nonane-8-one-8,8-ethylene-
dioxide-3-endo-hydroxy-2-exo-carboxylic acid l(-)ephedrinium
salt. Every one of the salts is separately dissolved in water/
NaOH; the optically active base is recovered by extraction with
ethylether, the alkaline aqueous phase is acidified up to pH 5-5,
1 and extracted with ethylacetate, affording
(+)bicyclo[4.3.0]nonane-8-one-8,8-ethylenedioxide--3-endo-hydroxy-
2-exo-carboxylic acid and
(-)bicyclo[4.3.0]nonane-8-one-8,8-ethylenedioxide--3-endo-hydroxy-
~Z~134
- 94 -
2-exo-carboxylic acid, which are converted into the methylester
with diazomethane treatment.
Example 72
A solution of 26g of dl-3-endo-hydroxy-bicyclo[4.3.0]-
2-exo-carboxymethylester-7-one-7,7-ethylenedioxidee in acetone
(lOOml) is refluxed with 2N H2S04 (20ml) for 4 hours.
Acetone is evaporated in vacuum and aqueous phase is
extracted with ethylacetate. Combined organic extracts are
washed until neutral, dried and evaporated to give 21.2g of
dl-3-endo-hydroxy-bicyclo[4.3.0~-2-exo-carboxymethhylester-7-one.
To a solution of the ketone in dry acetonitrile (250ml) it is
added d-l-phenyl-l-ethyl-amine (12.lg) and solvent is slowly dis-
tilled off recovering 50ml in 30' minutes. The mixture is
slowly cooled at r.t. and then 12.12g of (+) 3-endo-hydroxy-7,7-
(l'-phenyl-l'-ethylidenimino)-2-exo-carboxymethyleester-bicyclo-
[4.3.0] are collected after filtration. The liquor waters are
concentrated further to give 6g of racemic material. Finally, a
further concentration up to 80ml affords 11.42g of (-) 3-endo-
hydroxy-7,7(1'-phenyl-1'-ethylidenimino)-2-exo-carrboxymethyl-
ester-bicyclo[4.3.0].
Separately, the two Schiff bases are cleaved with 80:20
methanol 2N H2S04 (200ml) at reflux temperature for 2 hours.
Solvent is evaporated in vacuum and after extraction with ethyl-
acetate, the combined organic phases are washed until neutral,
dried and evaporated in vacuum to give:
8.lg of (+) 3-endo-hydroxy-bicyclo[4.3.0]2-exo-carboxymethyl-
ester-7-one and 7.2g of (-) 3-endo-hydroxy-bicyclo[4.3.0]2-exo-
carboxymethylester-7-one, respectively.
Using this procedure, all the bicyclo-~-hydroxy-
carboxylic ester-ethylene dioxides of the example 57 are submit-
12Q<;~ 4
- 95 -
ted to optical resolution to give the following 3-endo-hydroxy
alcohols:
(+)bicyclo[3.2.0]heptane-6-one-2-exo-carboxymethylestter
(+)bicyclo[3.2.0]heptane-7-one-2-exo-carboxymethylestter
(+)bicyclo~4.3.0]nonane-7-one-2-exo-carboxymethylesteer
(+)bicyclo[4.3.0]nonane-8-one-2-exo-carboxymethylesteer
(+)bicyclo[5.3.0]decane-8-one-2-exo-carboxymethylesteer
(-)bicyclo[3.2.0]heptane-6-one-2-exo-carboxymethylestter
(-)bicyclo[3.2.0]heptane-7-one-2-exo-carboxymethylestter
(-)bicyclo[4.3.0]nonane-7-one-2-exo-carboxymethylesteer
(-)bicyclo[4.3.0]nonane-8-one-2-exo-carboxyme~hylesteer
(-)bicyclo[5.3.0]decane-8-one-2-exo-carboxymethylesteer
Using the procedure of the example 56; these ketones are con-
verted into their ethylenedioxide derivatives.
