Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
11;~8430
The invention relates to the preparation of novel cy-
clisation substrates for steroidal compounds, and also relates
to the conversion of these cyclisation substrates into novel
steroidal compounds, in particular, 11 6~-substituted steroids
of the oestrane series.
The ll~-alkyl-l9-nor-steroids are biologically active
compounds to which access by synthetic routes is difficult for
those in the art. For example, in 41 J. ORG. CHEM 531 (1976),
an unsuccessful attempt is described to prepare ll-alkyl-substi-
tuted steroids by a total synthesis according to the method ofTorgov. The cyclisation by the Johnson method of 2-(5'7'-di-
methyl-trideca 3'(E),7'(E)-dien-ll-ynyl)-3-methyl-cyclopent-2-
enol to ll-methyl-steroids is described in the dissertation of
T.M. Yarnell, (Stanford University, July 1975, in DISSERTATION
ABSTRACTS INTERN, B 36 (1976) no. 10 at page 5054. The 5'-meth-
yl group in the cyclisation substrate is the "pro-C-ll" substi-
tuent. In this cyclisation, in addition to a range of other
products, the ll~-methyl-steroid and the ll~-methyl-isomer were
shown to be formed in approximately equal proportions. Stereo-
selectivity was described as absent, and this synthesis there-
fore had little practical value.
Also, Johnson discloses in U.S. Pat. 4,032,579 various
cyclopentenyl alcohols which can be cyclized to ll-chalcogen-
substituted steroids (see especially col. 17, line 64 to col. 20,
line 12), although there is no disclosure of an A-ring interme-
diate. Hughes (U.S. Pats. 3,417,105 and 3,547,909) disclose
aryl cyclopentanediones which are cyclized to gonene compounds.
Bertin et al (U.S. Pat. 3,526,648) and Bucourt (U.S. Pat.
3,906,096 disclose ll~-alkoxy steroids.
Of interest also in U.S. Pat. 3,778,434 to Coombs,
directed to the preparation of 9~,11-dimethyl-substituted es-
tranes from the corresponding estane-17-ones.
-- ~13~430
The stereospecific cy~lisation of a compound of formu-
la XX:
fH3
H3C ~ 1 3 ~
~ lJ
H3C , where R = CH3
(~C)
into a compound of formula XXI:
CI H 3
CH C = O
R ~
,1
H3C , where R = CH3
(XXI)
is described in 98 J.A.C.S. 1038 (1976).
Only the equatorial ll~-methyl derivative is formed.
The cyclisation of a (pro)-ll-hydroxy compound also results ex-
clusively in the ll~-hydroxy steroid (98 J.A.C.S. 1038-1039
(1976)).
Again it iS mentioned that when this cyclisation is
performed in the (pro)-l9-nor-series (R is H), it proves that no
stereo-selectivity occurs (see T.M. Yarnell, Dissertion, Stanford
University, July 1975, in 1976 DISSERTATION ABSTRACTS INTERN,
1976, B35 no. 10, page 5054). A mixture 11~- and ll~-substitu-
ted steroids in molar proportions of about 1:1 is formed.
Distantly related compounds by structure (7-substituted
compounds) to those of formulae II-III of the instant invention
are disclosed in Anner et al, U.S. Patent 3,660,435 (7A-methyl-
3,16~, 17~-trihydroxy- ~1'3'5(10)-oestratrienes for controlling
.
' ~
113~430
fertility) and U.S. Patent 3,804,866 (3-cyclopentyl ether of 7~-
methyl-3, 16A,17A,~-trihydroxy- ~1,3,5(10) oestratrienes and
their 16,17-diacetates for controlling fertility. See also U.S.
Patent 3,345,570 (to Anner et al (isolation of 7A-methyl-3-oxo-
~ steroids from mixtures of the epimeric 7-methyl-compounds):
U.S. Patent 3,627,894 to Babcock (novel 7A-methylestrones); U.S.
Patent 3,928,398 to Grunwell et al (7A-methylestr-4-ene-3~,17~-
diols as antiprogestational and antifertility agents); U.S. Pat-
ent 3,574,197 (1-hydroxy-7A-methyl-estranes); 3,944,576 (7~-
methoxy-methyl-estranes); and U.S. Patents 3,318,925/26/27/28/29
(7A-methyl- ~1'3'5(10)-estratrienes).
A method of producing analogues of the compounds
(II, III) unsubstituted in ring C, is disclosed in British Pat.
1,448,873 (producing oestrone by cyclizing 2-~(E)-6-aryl-3-hexen-
yl~-cyclopentenols of which the hexenyl group has not been sub-
stituted). See also 95 J.A.C.S. 7501-7504 (1973).
The following stereo-selective synthesis was described
in 22 Tetrahedon at 1019-1025 (1966):
O ~ ~ H3C0 ~ ~ ~
CH3 c~3
(I) (II) (III)
The main product obtained was the 6~-methyl compound (yield 25%~
40% by weight) in addition to traces of the 6A-methyl compound.
Since the 6A-methyl compounds are the most valuable, attempts
were made to isomerise the 6~-methyl compounds to 6A-methyl com-
pounds, after the A-ring had been converted to a 3-oxo- ~4-system:
` 1138430
H 1 ~ H t "
oJ~J ~
H3 3
(IV) (V)
This isomerisation occurs only in part, and the 6~-
methyl compound can only be obtained in low yield by this route.
The circuitous route via the enol acetate gives higher yields
(see 90 Recueil 849 (1971)).
Other distantly related art by structure (6-substituted)
includes U.S. Patent 3,137,689 to Dorfmann et al, which teaches
preparation of 6~-methyl-pregnenolones (anti-ovulatory activity),
U.S. Patent 3,257,427 to Bowers for 6-alkyl-3-desoxy- ~ ' ' ( )
estratriene substituted in the 17 position by keto or hydroxy
(anti-androgenic action, low feminizing effects; for fertility
control and menstrual disorders), U.S. Patent 3,816,481 to Dou~as
et al for 6~-methyl-4-gonenes (progestational activity), and
British Patent 1,448,873 (cyclisation of (arylhexenyl)-cyclopen-
tenols to A1~3~5(10),13(17) gOnatetraenes unsubstituted in posi-
tion 6).
This invention relates to new cyclisation substrates of
the formula:
R~ R3
5(1)
(I) :
wherein:
(a) Rl is H or alkyl of one to four carbon atoms, -
-- 4 --
113~4~30
(b) R2 is H or alkyl of one to four carbon atoms, with
the proviso that Rl is H when R2 is alkyl, and with the proviso
that R2 is H when Rl is alkyl,
(c) R3 is a suitable leaving group selected from the
group consisting of hydroxy, alkoxy of one to four carbons, al-
koxyalkoxy of two to four carbons, acyloxy of one to about seven
carbon atoms, and trialkylsilyloxy of less than fifteen carbons,
(d) R4 is hydrocarbyl of one to four carbons, and
(e) R5(1) and R5(2) are each H, alkyl of one to eight
carbons, or an optionally esterified or etherified hydroxy group
selected from the group consisting of hydroxy, alkoxy of one to
four carbons, alkoxyalkoxy of two to four carbons, trialkyl-
silyloxy of one to fifteen carbons, acyloxy of one to seven
carbons, cycloalkoxy of four to eight carbons, or heterocyclic
ether of five to seven atoms and four to six carbons, with the
proviso that at least one of R5(1) and R5(2) is H.
: Surprisingly, it has now been found that the cyclisa-
tion of a cyclisation substrate of formula (I):
Rl R3
5(1)
(I)
leads stereoselectively to equatorially-substituted steroid com-
pounds of formulae II and III having R4 and R5 (one of R5tl) or
R5(2) which may or may not be hydrogen) as described above:
-- 5 --
113~430
~6 ~ ~ ^ ~6
II III
"para" "ortho"
which may be represented in shorthand notation by the following
formula (positions indicated in small arabic numerals):
~J~6
R5(l)
(II-III)
which is more recognizable by those in the art. R6 is an alkyl
moiety of one to four carbon atoms. '
In formulae I, II and III, most preferably Rl and R2
are H or CH3, R3 is OH, R4 is CH3, one of R5(1) and R5(2) is hy-
drogen and the other OCH3 or trialkylsilyloxy of three to twelve
carbon atoms, and R6 is CH3.
When R5(1) is R5(2), the resultant compounds are ofcourse identical, but when R5(1) is not R5(2), two isomers result
from the cyclisation: the proportions of which are strongly in-
fluenced by the cyclisation conditions and the choice of the sub-
stituents R5(1) and R5(2).
The cyclisation substrates of structure I are novel com-
pounds which may be prepared in several ways, the individual steps
of each way being known to those skilled in the art. The inven-
tion is therefor characterized by the preparation of novel com-
pounds with the general formula I by steps which are in themselvesknown to those in the art. The invention is also characterized by
- 113~430
the cyclisation of the novel cyclisation substrates of formula I
to the novel and biologically active steroid compounds substitu-
ted equatorially in position 11, with the structures II and III.
Referring to the Flow Diagram below, the cyclisation
substrate I may, for example, be prepared by condensing in Reac-
tion (or Step) (a) an 8-R2-2-R4-5,5,8,8-tetra-alkoxy-(or-aikylene-
dioxy)-octanal (V) with a 3-aryl-propylidene-triaryl-phosphorane
(Wittig reagent IV), or by condensing an 8-R2-2-R4-5,5,8,8-tetra-
alkoxy-(or -alkylene-dioxy)-octylidene-tri-aryl-phosphorane (V)
with a 3-aryl-propanal (IV) under conditions which favor the (E)-
configuration (Wittig-Schlosser reaction, see for example the
German Pat. Specifications Nos. 1,270,545 and 1,279,678 and 5
ANGEW CHEMIE, Int. Ed. (1966) 126. Instead of the tetra-alkoxy
or alkylene-dioxy reagent, use may also be made of the thio ana-
logues known to those in the art.
The (E)-olefine-bis-ketal (VI) obtained is hydrolysed
in step (b) under weakly acid conditions to a l-aryl-5-R4-8,11-
dioxo-ll-R2-3-undecene (VII), after which the dioxo compound (VII)
is condensed to give a 2-(2'-R4-6'-aryl-3'-hexenyl)-3-R2-2-cyclo-
pentenone (VIII) (Step (c)).
In step (d), if R2 is alkyl of one to four carbons, theketone obtained is reduced to an alcohol, and when R2 is H, the
ketone is reacted with a compound RlLi or RlMg-halogen (where Rl
is alkyl of one to four carbons) giving a tertiary alcohol. The
OH-group is optionally further esterified or converted to an ether
in ways known to those in the art.
The cyclisation substrate (I) obtained in Reaction (d)
is subsequently cyclised with a Lewis acid under suitable acid
conditions, giving a tetracyclic compound with an equatorial R4-
substituent.
The invention therefore also relates to a method ofpreparing a cyclisation substrate compound of the formula:
113843~0
R R3
R4vu~
R ~ 2
5(1) (I)
wherein:
(a) Rl is H or alkyl of one to four carbons;
(b) R2 is H or alkyl of one to four carbon atoms, with
the proviso that Rl is H when R2 is alkyl, and with the proviso
that R2 is H when Rl is alkyl;
(c) R3 is a suitable leaving group selected from the
group consisting of hydroxy, alkoxy of one to four carbons, alk-
oxyalkoxy of two to four carbons, acyloxy of one to about seven
carbon atoms, and trialkylsiloxy of less than fifteen carbons;
(d) R4 is hydrocarbyl of one to four carbons; and
(e) R5(1) and R5(2) are each H, alkyl of one to eight
carbons, or optionally esterified or etherified hydroxy selected
from the group consisting of hydroxy, alkoxy of one to four atoms,
alkoxyalkoxy of two to four carbons, trialkylsilyloxy of one to
fifteen carbons, cycloalkoxy of four to eight carbons,
acyloxy of one to seven carbons, or heterocyclic ether of five to
- seven atoms and four to six carbons, with the proviso that at .
least one of R5(1) and R5(2) is hydrogen~
which comprises ~ -
condensing an 8-R2-2-R4-5,5,8,8-tetraalkoxy-(or-alkyl-
ene-dioxy)-octanal of formula:
: (Z)2
R~
Y=CH (V)
with a 3-aryl-propylidene-tri-aryl-phosphorane of formula:
-- 8 --
- - -
38430
,f~ HC-X
R ~ (IV)
wherein R2, R4 and R5 are the same as defined above,
X is 0 or P(R7)3,
wherein R7 is an aryl hydrocarbon residue having 6 or 7
carbon atoms,
Y is 0 or P(R7)3
wherein R7 is the same as defined above,with the proviso
that Y is O when X is P(R7)3 and vice-versa,
Z is an alkyl-chalcogen group having one to four carbon
atoms, or
condensing an 8-R2-2-R4-5~5~8l8-tetra-alkoxy-(or-alkylene
dioxy)-octylidene-tri-aryl-phosphorane of formula V with a tri-
aryl-propanal of formula IV
wherein R2, R4, R5, R7, X, Y and Z are the same as de-
fined above under conditions which favor the (E)-configuration,
to give an (E)-olefine-bis-ketal of formula:
(~2
R ~ ~
~ R ~ (VI)
wherein R2, R4, R5 and Z are the same as defined above,
hydrolysing the compound of formula (VI) under weakly
acid conditions to give a l-aryl-5-R4-8,11-dioxo-11-R2-3-undecene
of formula:
0
R4
~ ~ R ~
R5. (VII)
- - -
--- 113f~43V
wherein R2, R4 and R5 are the same as defined above, or
reacting a 2-R4-4-(5'-R2-2'-furyl)-butanol of formula:
R4~--~2
X =CH (IX)
wherein X is 0, R2 and R4 are the same a~ defined above,
with a phosphorane of formula IV
wherein X is P(R7)3 in which R7 is the same as defined
above or
reacting a 2-R4-4-(5'-R2-2'-furyl)-butylidene-triaryl-
phosphorane of formula IX in which X is P(R7)3, R7 being thesame as defined above with an aldehyde of formula IV tX being 0)
to give a furyl-(E)-olefine of formula:
R4 ~ ~2 ~ ~
~ I ,, .
R ~ (X) ~ -
in which R2, R4 and R5 are the same as defined above, :
hydrolysing the compound of formula (X) to give a com-
pound of formula VII,
. opening the furan or ring in the furyl-(E)-olefine of
20 formula X with the aid of a strong acid in the presence of a
ketal-forming agent to give a compound of formula VI in which R2
is H, and converting compound of formula VI to a compound of
formula VII,
condensing the dioxo compound of formula (VII) to give
a Z-(2'-R4-6'-aryl-3'-hexenyl)-3-R2-2-cyclopentenone of formula:
-- 10 --
_ .
1138430
4~ ~ ~ R2
~ b ~J
101
R ~ (VIII)
wherein R2, R4 and R5 are the same as defined above
when R2 in the compound of formula (VIII) is alkyl of
one to four carbons, reducing the ketone of formula VIII to an
alcohol of formula I,and
when R2 in the compound of formula (VIII) is H, reacting
the ketone of formula VIII with a compound RlLi or RlMg-halogen
in which Rl is alkyl of one to four carbon atoms to give a ter-
tiary alcohol of formula I.
The invention also relates to a method of preparing
compounds of the formulae: .
~ and ~ 6
R5
(II) (III)
: from the compound:
Rl 3
J~
5(1) (I)
wherein:
(a) Rl is H or alkyl of one to four carbon atoms
(b) R2 is H or alkyl of one to four carbon atoms, with
the proviso that Rl is H when R2 is alkyl, and with the proviso
that R2 is H when Rl is alkyl,
113843(1
(c) R3 is a suitable leaving group selected from the
group consisting of hydroxy, alkoxy of one to four carbons, alk- :
oxyalkoxy of two to four carbons, acyloxy of one to about seven
carbons, and trialkylsilyloxy of less than fifteen carbons,
(d) R4 is hydrocarbyl of one to four carbons,
(e) R5(1) and R5(2) are each H, OH, alkyl of one to
eight carbons, or optionally esterified hydroxy selected from
the group consisting of hydroxy, alkoxy of two to four carbon
atoms, alkoxyalkoxy of two to four carbons, trialkylsilyloxy of
one to fifteen carbons, cycloalkoxy of four to eight carbons,
acyloxy of one to seven carbons, or heterocyclic ether of
five to seven atoms and four to six carbons, with the proviso that
at least one of R5(1) and R5(2) is hydrogen; and ::
(f) R6 is alkyl of one to about four carbon atoms, ;
which comprises the step of: -
cyclising compound I in a suitable solvent with an ef-
fective amount of one or more of the acids consisting of the
suitable protic and suitable aprotic Lewis acids at a temperature
below about room temperature and above about -150C.
The preparation indicated above is summarized by the
following reaction scheme:
FLOW DIAGRAM
C=X R~
(IV) (V)
R ~ R4
R5 ~ R5 ~
(VI) (VII)
- 12 -
-- 1138~30
,~J
(VIII) (I)
R ~ 6 ~ 6
(II) (III)
In this Flow Diagram, Rl, R2, R3, R4, 5 6
the meanings already assigned above. X is 0 or P(R7)3, where R7
is an aryl hydrocarbon residue with 6 or 7 carbon atoms and is a
preferably phenyl; Y is 0 or P(R7)3, where R7 has the meaning
assigned above, with the proviso that Y is 0 when X is P(R7)3 and
vice versa. Z is an alkyl-chalcogen group, that is: alkoxy or
alkylthio, each with one to four carbon atoms, preferably one to
two carbon atoms. Preferably, (Z)2 is an alkylene-dichalcogen
group, that is: alkylene-dioxy or alkylene-dithio, with two to
three carbon atoms, for example ethylene dioxy.
For the preparation of the dioxo compound with the
structure VII, it is also possible to react a 2-R4-4-(5'-R2-2'-
furyl)-butanal (X) with a phosphorane of formula IV (X is P(R)),
or a 2-R4-4-(5'-R2-2'-furyl)-butylidene-triaryl-phosphorane with
an aldehyde of formula IV (X is 0), by the Wittig-Schlosser re-
action, giving a furyl-(E)-olefine (X), according to the reaction
scheme:
- 13 -
~13~430
~ C=X 4
R Y=CH
(IV) (IX)
R4 ~ 2
~ ~ VII ___--XVIII~
R (X) VI (b),(c~vI~)
after which the furyl-~E)-olefine of formula (X) obtained is hy-
drolysed (step g) to the dioxo compound of formula VII. This last
hydrolysis may constitute a problem, since the reaction is diffi-
cult and the keto-aldehyde of formula VII (R2 is H) obtained is
not very stable. In this case, a preferred method (step h) con-
stitutes opening of the furan ring in the furyl-(E)-olefine with
the aid of a suitable strong acid known to those in the art for
reactions of this type, for example p-toluene-sulphonic acid, in
the presence of a ketal-forming agent known to those in the art,
for example glycol, such that a ketal-acetal of formula VI
(R2 = H) is obtained which can then be converted in the way indi-
cated above into a cyclisation substrate.
With respect to the substituents Rl to R6 inclusive,
the following may further be noted:
Rl or R2 is generally methyl or ethyl, preferably meth-
yl, whereby the other substituent is then H. R3 as a suitable
"leaving" group known to those in the art is generally alkoxy of
one to four carbons, for example methoxy: otherwise (1) alkoxy-
alkoxy of two to four carbons, for example methoxymethoxy
or l'-ethoxyethoxy: (2) acyloxy of one to seven carbons, for
example acetoxy, propionyloxy, butyroxy, pivaloyloxy, valeryloxy,
benzoyloxy: or (3) trialkylsiloxy of less than fifteen carbons,
- 14 -
- . .
113f~430
for example, trimethylsilyloxy.
R4 is a hydrocarbyl (hydrocarbon) group of one to four
carbon atoms, where hydrocarbyl is ~mderstood to mean: a mono-
valent radical consisting of hydrogen and carbon atoms and which
is a saturated or unsaturated aliphatic or alicyclic residue.
Examples of hydrocarbyl groups for R4 are: methyl,
ethyl, isopropyl, cyclopropyl, butyl, allyl, propargyl. R4 is
preferably methyl.
One of R5(1) and R5(2) is hydrogen and the other
("active" R5 moiety) is preferably hydroxy, or in the alternative,
optionally etherified or esterified hydroxy of less than ten car-
bon atoms; for example, (1) hydrocarbyloxy of one to eight car-
bons such as methoxy, ethoxy, cyclopentoxy, cyclohexenyloxy, benz-
yloxy, (2) ~-alkoxyalkoxy of two to four carbons, such as meth-
oxymethoxy, ~-ethoxyethoxy, (3) trimethylsilyloxy or tetrahydro-
pyranyloxy, and (4) acyloxy of one to seven carbons, such
as acetoxy, pivaloyloxy or benzoyloxy.
The active R5 moiety may be heterocyclic ether wherein
the heterocyclic member has five to seven atoms, is monohetero-
cyclic (one non-carbon member in the ring) or diheterocyclic
(two non-carbon members) and has from four to six carbon atoms,
and is unsubstituted.
If the active R5 moiety is an oxy group, then the posi-
tions 2, 4 and 6 of the phenyl nucleus are activated in the cy-
clisation.
Due to steric factors, position 4 takes no part in the
reaction, and for the case R5(1) is not equal to R5(2), two pro-
ducts may therefore be formed as indicated above by the formulae
II and III. As previously noted, the ratio of formation of these
two products can be changed considerably in favor of one thereof
by a suitable choice of R5(1) and/or R5(2). If R5(1) is, for
example, trimethylsilyloxy and R5(2) is H, then much more "para"
- 1138430
(position 6) product is formed than "ortho" (position 2) product.
If use is made as starting material of a phosphorane
with R5(1) and/or R5(2) being a protected hydroxy group, then the
protective group may remain intact during the various reaction
steps, but it may also undergo modification. Certain protective
groups known to those in the art are preferred for some reaction
steps, while again other protective groups are preferred for
other reaction steps. In the steps (a) and (b), for example,
R5(1) and/or R5(2) is preferably methoxy or methoxymethoxy. In
steps (c) and (d)~ R5(1) and/or Rs(2) may without objection be
hydroxy, while in step (e) R5(1) and/or R5(2) is preferably tri-
methylsilyloxy if the interest is primarily for the "position 6"
product. Specifically, the "para" product (R5(2) is H) is most
preferred since it may be used for the preparation of steroids
similar to those occurring in nature.
The cyclisation substrate contains two asymetric cen-
ters, namely, the carbon atom carrying the substituent Rl and the
carbon atom with the substituent R4. The stereochemistry of the
cyclisation product proves to be governed predominantly by the
latter center in the cyclisation product. The substituent R4
surprisingly proves to occur predominantly in the equatorial con-
figuration.
If use is made of a racemic cyclisation substrate as
starting material, i.e., a material with nearly equal amounts of
the (R)-R4-substituted and the (S)-R4-substituted compounds,
then a racemic tetracyclic product is formed, consisting of 2-
enantiomers is shown to be formed, while on grounds of the two
asymmetric centers, without optical induction, four stereoiso-
mers in equal amounts would be formed. That the chiral center
with the substituent Rl has little, if any, influence on the
stereochemistry of the end-product may be proved by the fact that
the (S)-Rl-(R)-R4-substituted cyclisation substrate gives the
- 16 -
113~43~0
same R4-equatorially-substituted cyc:Lisation product as the
(R)-Rl-(R)-R4-substituted cyclisation substrate. Thus, for ex-
ample, both l(S)-3-methyl-2-~2'(R)-methyl-6'-(m-methoxyphenyl)-
3'(E)-hexenyl7-2-cyclo-pentenol and 1(R)-3-methyl-2-~2'(R)-
methyl-6'-(m-methoxyphenyl)-3'(E)-hexenyl7-2-cyclopentenol give
the natural 3-methoxy-ll~-methyl- ~1,3,5(10),13(17) t t
on cyclisation.
It has been indicated in formula I that the substituent
R4 may be present in the (R)-configuration or the (S)-configura-
10 tion. If a racemate is used as starting material and the ortho/para isomerism of the aromatic ring is ignored, then a racemate
of the R4-equatorially substituted steroid compound with the
structure II is formed in the cyclisation. If an optically act-
ive cyclisation substrate is used, for example the (R)-R4-com-
pound (R4 = CH3), then an optically active compound of formula
II is formed, that is, a "natural" ll~-CH3-l~ ' ' ( )' 3( )-
gonatetraene.
By epoxizing of this 13(17) olefine (II-III), prefer-
ably by conversion into a 13,17-halohydrin, preferably a chloro-
20 or bromohydrin, and treatment of the halohydrin with a base, thecorresponding 11~<-CH3-13-~, 17-~-epoxy compound of formula XI below
is formed (if the epoxidation is performed directly with a per-
acid, the 13,~,17~-epoxy compound is formed). Opening the -~-
epoxide ring under weakly acid conditions, preferably by use of
an aprotic Lewis acid, for example BF3/diethyl ether, initiates
migration of the substituent R6 from the 17-position to the 13
position such that the corresponding ll~<-CH3-13~-R6-17-ketone of
formula XII is formed from the -C-epoxide XI.
1~38430
(I ~ ~ r~ ~
(XI) (XII)
(The antipode can be converted into the ent-3-R5-11~-R4-13~-R6-
~1'3'5(1)-gonatrien-17-one in a corresponding fashion). When
R5(~is methoxy, R5(2) is hydrogen and R6 is methyl, the 3-methyl
ether of ll~-alkyl-oestrone is obtained in this way.
The internal condensation of the dioxo compound VII
(Step (c))may be brought about in the usual way, for example,
with alkaline ethanol or with trimethylbenzyl-ammonium hydroxide.
In the cyclisation Reaction (step e), an effective a-
mount of an aprotic or a protic Lewis acid is used and the reac-
tion is performed in a non-nucleophilic protic or aprotic solvent.
Examples of suitable solvents are formic acid, acetic acid, tri-
fluoro-acetic acid, trifluoro-ethanol, benzene, saturated hydro-
carbons such as pentane, hexane, cyclohexane, and halogenatedhydrocarbons such as dichloromethane.
Examples of protic Lewis acids are carboxylic acids
with a pK (20C) of less than about 4, and preferably less than
about 2, such as, for example, trifluoro-acetic acid, trichloro-
acetic acid, formic acid.
Examples of aprotic Lewis acids are stannic chloride,
titanium tetrachloride, zinc chloride, zinc bromide, boron tri-
fluoride. Aprotic Lewis acids are stannic chloride, titanium
tetrachloride, zinc chloride, zinc bromide, boron trifluoride.
Aprotic Lewis acids are preferably used, in an amount of about
0.1 to about 10 moles per mole cyclisation substrate, and prefer-
ably about 0.5 to about 5 moles per mole. Stannic chloride is
preferable.
- 18 -
~13~430
The cyclisation reaction is usually carried out at a
temperature below room temperature (about 20-22C) and above
-150C, preferably at a temperature between about +10C and
about -100C.
The mixtures of "ortho"- and "para"- products ("ortho"
means A-aromatic steroid substituted in position 1, "para" means
A-aromatic steroid substituted in position 3) of compound II-III
obtained in the cyclisation step (e) may be separated in the
usual way known to those in the art, for example, by chromato-
graphy or by crystallization. Racemates of intermediate or final
products may be resolved to give the optical antipodes in the
usual way.
11~ lk 1 ~ 1l3~5(lo)~l3(l7)-gonatetraenes obtained
in the cyclisation, and the 13~, 17~-epoxy compounds which can be
prepared from these, are new. These compoundshave hormonal pro-
perties and are furthermore of value as starting materials for
known, biologically active ll~-alkyl steroids.
As to the reaction steps (a) - (e) the following addi-
tional information can be given:
Reaction step (a) is usually carried out at a temper-
ature between about -100C and about 0C, preferably between a-
bout -75C and about -25C. The solvent is usually an etheric
solvent, such as diethyl ether, tetrahydrofuran and mixtures
thereof. A preferred solvent is an 1:1 mixture of diethyl ether
and tetrahydrofuran.
- Reaction step (b) is usually carried out at a temper-
ature between about 20C and 80C, preferably between about 50C
and 60C. The solvent may be an etheric solvent, such as dimeth-
oxyethane, or a mixture of water and an alcohol, such as ethanol.
An 1:2 mixture of water and ethanol containing between 5 and 10
mmol HCl per liter, is very suited.
-- 19 --
~13~43()
Reaction step (c) is usually carried out between about
60C and 80C, preferably at about 80C. The solvent is the same
as used in step (b). An 1:2 mixture of water and ethanol con-
taining between 5 and 10 mmol NaOH or an equivalent amount of KOH
or trimethylbenzyl-ammoniumhydroxide is very suited.
Reaction step (d): The reaction of the ketone to an
alcohol is carried out with a complex metallic hydride, such as
lithiumaluminiumhydride, di-isobutyl-aluminium-hydride, sodium-
di-isobutylboronhydride, at a temperature between about -50C and
0C, preferably between about -25C and 0C. The reaction of the
ketone with a compound RlLi or RlMg halogen is usually carried
out at a temperature between -70C and 0C, preferably between
-70C and -20C. The solvent is usually an etheric solvent, pre-
ferably diethyl ether.
The reaction steps (a), (d), and (e) are preferably
carried out in an inert atmosphere (nitrogen or argon blanket).
Reaction step (e): When using a protic solvent, pre-
ferably a protic Lewis acid is used. A protic solvent, such as
formic acid, trifluoro-acetic acid, trifluoro-ethanol, may also
serve as protic Lewis acid. An aprotic solvent may be combined
with either a protic Lewis acid or an aprotic Lewis acid.
Although the invention has been described with refer-
ence to the specific embodiments about, numerous variations and
modifications will become evident to those skilled in the art,
without departing from the scope and spirit of the invention as
described above, defined in the appended claims, and as shown in
the following Examples:
Example 1
3-(m-methoxyphenyl)-propyl-triphenylphosPhonium bromide (Precursor
of Compound IV)
A solution of m-bromo-anisole (37.4 g, 0.2 mol) in dry
tetrahydrofuran (200 ml) was added dropwise under nitrogen to
- 20 -
~13~43~0
magnesium shavings (4.8 g, 0.2 g.at.).
The solution obtained was stirred for about 1 hour at
room temperature, after which it was added over a period of about
1.5 hours to a solution of 80.1 g (0.4 mol) 1,3-dibromopropane in
80 ml dry tetrafuran, which had been warmed to 50C under nitro-
gen. The mixture obtained was heated at 70C for 16 hours,
cooled, and mixed with ether and an aqueous solution of ammonium
sulphate. The organic layer was separated, dried over anhydrous
sodium sulphate and distilled under vacuum. In this way, dibromo-
10 propane was recovered (48 g, room temperature 66-67C/18mm) and
l-bromo-3-(m-methoxyphenyl)-propane (26.5 g, 58%, boiling point
85-95C/0.7mm) was obtained.
The product was warmed for 8 hours at 120C with tri-
phenylphosphine (40 g 0.15 mol, 1-3 eq) and toluene (30 ml).
Cooling gave a vitreous precipitate. This was dissolved in a
minimum of boiling acetone, and precipitated by cooling and add-
ing ether. 53 g (93O/o yield) of crystalline phosphonium salt was
obtained, melting point 130-134C.
Example II
20 (Examples II-V are used to show a way of preparing Compound V)
Preparation of dl-2-methvl-5-(3-bromobutyl)furan
A solution of 4-(5-methyl-2-furyl)-butan-2-one (16 g,
0.5 mol) in methanol (750 ml) was cooled to the range of about
0-5C, after which 35 ml O.lN sodium hydroxide and 19 g (0.5 mol)
sodium borohydride were added consecutively, the last in portions.
The mixture was stirred for 1.5 hours, after which glacial acetic
acid was added to obtain a pH of 7 (about 0.5 ml). The methanol
was largely removed by distillation under vacuum. The residue
was taken up in ether, washed with water, and dried over anhy-
30 drous magnesium sulphate. Removal of the solvent by evaporationgave 77 g (quantitative yield) dl-2-methyl-5-(3-hydroxybutyl)-
furan.
-- 21 --
113f~430
This product was dissolved in a mixture of dichloro-
methane (750 ml) and pyridine (230 ml), and the resultant solu-
tion was cooled to -15C. Methane-sulphonyl chloride (75 ml)
was then added slowly dropwise with stirring. The mixture ob-
tained was stirred for a further 2.5 hours at about 0C. The
reaction mixture was washed with 2N hydrochloric acid until neu-
tral, dried (anhydrous magnesium sulphate) and evaporated to
dryness, giving in this way 112 g (9~/O) of the mesylate as an oil
which was not purified. The mesylate was dissolved in dry di-
methylformamide (900 ml), after which lithium bromide (192 g, 5
eq.) was added. The mixture was stirred under a nitrogen atmos-
phere at 60C for ahout 1 hour. It was then cooled, poured into
water, and extracted with ether (6 x 100 ml). The ether extracts
were washed with saturated sodium chloride solution, dried
(anhydrous MgS04) and evaporated to dryness. The residue was
distilled under vacuum. In this way, 78 g (77% yield) of the
desired product was obtained, boiling point 61-63C/0.15mm.
Example III
Preparation of dl-8-bromo-2,5-bis(ethYlene-dioxy)nonane
A mixture of dl-2-methyl-5-(3-bromobutyl)furan (44 g,
0.2 mol) from Example II, glycol (175 ml), dry tetrahydrofuran
(175 ml), tri-ethyl orthoformate (70 ml) and p-toluene-sulphonic
acid was heated at about 80C under nitrogen for 3 hours.
The reaction mixture was cooled, mixed with 0.2N sodium
hydroxide (350 ml) and extracted with ether. The extracts were
dried over anhydrous MgS04 and evaporated to dryness. The residue
was chromatographed on silica gel (600 g) with hexane/ethyl ace-
tate, 8:2. The starting material (16.3 g, 37%) was eluted first,
followed by the product (39 g, 60% yield, 96% based on converted
starting material), oil, NMR (CDC13):~ 1.30 (s, protons at C-l),
1.70 (s, protons at C-3 and C-4), 1.70 (d, J = 6.5, CH3-CHBr),
3.93 (s, OCH2CH2O), 4.12 (m, CHBr).
113~430
Example IV
Preparation of dl-2-methyl-5,8-bis(ethylene-dioxy)-pelarqono-
nitrile
The bromide from example III (32.3 g, 0,1 mol) was
dissolved in dry dimethylsulphoxide (250 ml), powdered potassium
cyanide was added, and the mixture obtained was stirred at 60C
under nitrogen for 4 hours.
The reaction mixture was cooled, mixed with water, and
extracted with ether. The extracts were washed with water, dried
over anhydrous MgSO4 and evaporated to dryness. The residue was
chromatographed on silica gel with hexane/ethyl acetate 60:40.
The product was obtained as a colourless oil (22.7 g, 85% yield).
NMR(CDC13): ~ 1.31 (s, protons at C-9 + d, J = 7, CH30H), 1.70 (m),
2.65 (q, J = 7, CHCN), 3.94 (s, OCH2CH20).
Example V
Preparation of dl-2-methyl-5,8-bis(ethylene-dioxy)-nonanal
(Formula V, R2 = methyl, R4 = methyl, (Z)~ = ethylene-dioxy, Y=0)
The nitrile from example IV (13.5 g, 0.05 mol) was
dissolved in dry toluene (250 ml) and cooled under nitrogen to
-78C. Di-isobutyl aluminium hydride (50 ml of a 1.2M solution
in toluene, 0.06 mol) was then added dropwise such that the temp-
erature did not rise above -70C.
After stirring for a further 10 minutes, water (10 ml)
was cautiously added and the mixture thus obtained was slowly
TM
warmed to room temperature. Anhydrous Na2S04 and Hyflo were added,
and the mixture thus obtained was filtered over a layer of Hyflo.
The filter-cake was washed with ether. The combined filtrates
were evaporated to dryness and the residue was chromatographed
on silica gel with hexane/ethyl acetate 70:30, giving the alde-
hyde as a colourless oil tl3.4 g, 98% yield). NMR(CDC13): 1`1.09
(d, J = 7, CH3-CH), 1.30 (s, protons at C-9), 1.70 (s, protons
at C-6 and C-7), 2.33 (m, CHCH0), 3.93 (s, OCH2CH20), 9.61 (d, J =
-- 23 --
113~ 30
1.5, CHO).
Example VI - Step (a)
Preparation of dl-(E)-l-(m-methoxyphenyl)-5-methyl-8,11-bis(eth-
ylenedioxy)-3-dodecene
(Formula VI,R2 = methyl, R~ = methyl, Rs = methoxy, (Z)2_
ethylene-dioxy)
Phenyl-lithium in ether (50 ml of a 1.1 M solution,
0.055 mol) was added dropwise under nitrogen to a stirred suspen-
sion of 3-(m-methoxy-phenyl)-propyl-triphenylphosphonium bromide
10 (27 g, 0.055 mol) in dry tetrahydrofuran (125 ml), cooled in ice.
The orange-red mixture obtained was stirred for a further 15 min-
utes without cooling, after which it was cooled to about -70C.
The aldehyde of Example V (13.6 g, 0.05 mol), dissolved in dry
tetrahydrofuran (25 ml), was added dropwise after which the whole
was stirred for 5 minutes at -70C. A further amount of phenyl-
lithium in ether (90 ml, 1.1 M, 0.10 mol) was added and the red
solution obtained was warmed to about -30C. After about 15
- minutes at -30C, the reaction mixture was poured into water and
extracted with ether. The ether extracts were dried (anhydrous
20 ~a2S04), filtered and evaporated to dryness. The residue was
- chromatographed on silica gel (400 g) with hexane/ethyl acetate
80:20, followed by 60:40 by weight mixture hexane/ethyl acetate
and pure ethyl acetate. The desired product (8.4 g, 42% yield)
was eluted first, followed by the aldehyde (8 g, 59%) used as
starting material. Product: oil, NMR (CDC13): O~0.95 (d, J = 6.5,
CH3CH), 1.30 (s, protons at C-12), 1.70 (s, protons at C-9 and
C-10), 3.78 (s, CH30), 3.92 (s, OCH2CH20), 5.36 (m, CH = CH).
Example VII - stePs (b) and (c)
Preparation of dl-3-methyl-2~(E)-6'-(m-methoxyphenyl)-2'-methyl-
30 3'-hexeny~-2-cyclopentenone
(Formula VIII, R2 = methvl, R4 = methvl, R5 = methoxv)
(a) A solution of the Wittig product from Example VI
-- 24 --
113~
(8.1 9, 0.02 mol) in 95% ethanol (200 ml) and 0.2 N hydrochloric
acid (100 ml) was heated for 2 hours at 50-55C, giving the pro-
duct of formula VII (R2, R4, R5 as before~-
(b) 20 ml 2N potassiumhydroxide solution and 180 ml 95%
ethanol were then added, and the solution obtained was boiled
under reflux for 5 hours. The reaction mixture was evaporated
under vacuum to a volume of about 100 ml and then extracted with
ethyl acetate. The extracts were dried (anhydrous Na2SO4) and
evaporated to dryness. The residue was chromatographed on 150 g
silica gel with hexane/ethyl acetate 90:10. The product was ob-
tained as a colorless oil (5.3 g, 89% yield). NMR (CDC13): ~0.93
(d, J = 6, CH3CH), 1.99 (s, CH3C=C), 3.78 (s, CH30), 5.31 (m,
CH = CH).
Example VIII - Step (d)
Preparation of dl-3-methyl-2-~E)-6'-(m-methoxyphenyl)-2'-methYl-
3'-hexenylJ-2-cyclopentenol
(Formula I, R~ = H, R2 = methyl, R3 = hydroxy, R4 = methyl, R5_
methoxv ) .
Lithium aluminium hydride (0.57 g, 0.015 mol) was slow-
ly added at about -20C to a solution of the cyclopentenone from
Example VII (3.0 g, 0.01 mol) in dry ether (100 ml). The mixture
was warmed with stirring to about 0C over a period of about 30
minutes. The excess hydride was decomposed by cautious addition
of saturated sodium sulphate solution. The ether layer was de-
canted from the resultant suspension which was further extracted
two times with portions of dry ether.
The combined ether solutions were evaporated to dryness
under vacuum in a cold waterbath (less than or about 20C), giv-
ing 3.0 g product (99% yield) in the form of a colorless oil,
NMR (CDC13 + C5D5N):a~0.88 and 0.98 (2 x d, J = 6, CH3CH), 1.60
(s, CH3C=C), 3.76 (s, CH30), 4.46 (m, H-C-OH), 5.30 (m, CH = CH).
-- 25 --
1 1 3~430
Example IX - SteP (e), Cyclisation
Preparation of dl-l- and 3-methoxy-11-~, 17-dimethyl- l~l,3,5(10),
13(17)-aonatetraene
(formulae II and III, R4 = methyl, R5 = methoxy, R6 = methyl)
A solution of stannic chloride (10.5 g, 0.04 mol) in
280 ml dry di-chloromethane was cooled under nitrogen to about
-100C (via acetone/liquid nitrogen). The cyclopentenol from
Example VIII (93.0 g, 0.01 mol), dissolved in 20 ml dry dichloro-
methane was then added dropwise over a period of about 1 hour.
10 After stirring for a further 20 minutes, the reaction was halted
by slowly adding 90 ml of a 5% solution of KOH in methanol (temp.
less than about -85C). The mixture obtained was slowly warmed
to about 20C, washed with water and dried over anhydrous potas-
sium carbonate. The solvent was removed by evaporation and the
residue was chromatographed on 60 g silica gel with hexane/tolu-
ene 90:10 by weight followed by hexane/toluene 80:20 by weight.
The l-methoxy-isomer was eluted first (0.485 g, 17% yield), con-
sisting for 92% of the ll~-methyl derivative. The pure compound
had a melting point of 80C after crystallization from methanol.
20 The 3-methoxy-isomer was subsequently eluted (1.34 g, 50% yield).
This fraction was then chromatographed on silica gel (140 g) im-
pregnated with 20% silver nitrate, with hexane/toluene 80:20 by
weight. In this way, the pure ll~-methyl-isomer was obtained
- (1.01 g, 36% yield), melting point 98-99C (from pentane). The
ll~-methyl-isomer was also isolated in the form of an oil (0.157 g,
5,5% yield).
Example X
Preparation of dl-ll <-methyloestrone, methyl ether
(Formula XII, R4 = CH~ Rs(l) = CH3O~ R5(2) 6 3
A solution of 3-methoxy-11~-methyl-17-methyl-~1'3'5(10)~
3~(17)-gonatetraene (0.282 g, 0.001 mol) in t-butanol/water 2:1
(20 ml was cooled in ice. N-chlorosuccinimide (0.265 g, 0.002
-- 26 --
113~
mol) was added to the suspension thus obtained, after which the
whole was stirred for about 1 hour at room temperature. Sodium
bisulphite (0.10 g) and 5 ml 40% KOH solution were then added
consecutively and the whole was stirred for about 30 minutes at
room temperature (20-25C). Hexane (50 ml) was added and the re-
sultant aqueous layer was removed. The organic layer was evapo-
rated to dryness under vacuum.
The residue, consisting ~ the13~,17~-epoxy derivative,
was taken up in toluene (20 ml) and treated with boron trifluo-
ride etherate (0.2 ml) for 1 minute at room temperature. The darkred reaction mixture was diluted with ether and shaken with sa-
turated sodium bicarbonate solution. The organic layer was
separated, dried over anhydrous Na2SO4, and evaporated to dryness.
The residue was chromatographed on 30 g silica gel with hexane/
ethyl acetate 9:1.
The material obtained was crystallized from ether/
pentane, giving 54 mg (18% yield) product, m.p. 88-90C.
Example XI
PreParation of dl-2-methyl-4(2-furyl)butyronitrile
(Precursor of Formula IX, R2 = H, R4 = CH ~
Methylvinylketone (14 g, 0.2 mol) was added dropwise
over a period of about 2 hours to furan (150 ml), containing a
trace of p-toluene-sulphonic acid, boiling under reflux. The
dark brown reaction mixture was stirred for about 1~ hours at
room temperature. The excess furan was removed by distillation,
after which the residue was distilled under vacuum giving 4-(2-
furyl)butan-2-one (18.5 g, 67% yield). In a way analogous to
that described in Example II, the ketone was reduced to the cor-
responding alcohol and subsequently converted to the mesylate
(28 g, 92% yield).
The mesylate (22.8 g, 0.1 mol) was dissolved in dry
DMSO (100 ml). Potassium cyanide (13 g, 0. 2 mol) was added and
~ 27 --
113~43~
mixed, and the mixture obtained was heated at about 70C under
nitrogen for about 16 hours.
The reaction mixture was poured into water and extract-
ed with ether (4 times, each with 200 ml ether). The ether ex-
tracts were washed with water, dried (anhydrous Na2S04) and eva-
porated to dryness. The residue was chromatographed on silica
gel with hexane/ethyl acetate 80:20 by weight, giving the pure
product as a colorless oil (10.5 g, 70% yield), b.p. 75-76C/
2mm.
Example XII
Preparation of dl-2-methyl-4-(2-furyl)butanal
(formula IX, R2 = H, R1 = methyl: Y = 0
In a way analogous to that described in Example V, the
nitrile of Example XI was reduced to the corresponding aldehyde.
The crude product was chromatographed on silica gel with hexane/
ethyl acetate 80:20 by weight, giving the pure aldehyde in 58%
yield, b.p. 71-72C C/18 mm.
Example XIII - Step (f)
Preparation of dl-(E)-1-(2-furYl)-3-methyl-7-(m-methoxyphenyl)-4-
heptene(Formula X, R2 = H, R~ = methyl, R5 = methoxy)
The aldehyde from Example XII (1.52 g, 0.010 mol) was
reacted with 3-(m-methoxyphenyl)-propyl-triphenyl-phosphonium
bromide (5.4 g, 0.011 mol) in an exact way analogous to that de-
scribed in Example VI. The crude product was chromatographed on
silica gel with a hexane/ethyl acetate 95:5 by weight solution,
giving the pure product as a colorless oil (2.65 g, 93/O yield).
NMR (CDC13):~ 0.97 (d, J = 6, CH3CH), 3.77 (s, CH30), 5.35 (m,
CH = CH), 5.92 (m), 6.25 (m) and 7.27 (m, furan protons).
Example XIV - steP (h)
Preparation of dl-(E)-l-(m-methoxyphenyl)-5-methyl-8,11-bis(ethyl-
ene dioxy)-3-undecene
- 28 -
113~43 o
(Formula VI, R2 = H, R,l = methyl, R5 = methoxy, (Z)2 = ethylene-
dioxy)
The Wittig product from Example XIII (0.284 g, 0.001
mol) was mixed with dry benzene (5 ml), glycol (5 ml) and p-
toluene-sulphonic acid (0.50 g). This mixture was boiled under
nitrogen with vigorous stirring for 2 weeks. The reaction mix-
ture was neutralized with a few drops 0.2N sodium hydroxide and
mixed with water and ether. The organic layer was separated,
dried over anhydrous MgS04 and evaporated to dryness. The resi-
10 due was chromato~raphed on silica gel with hexane/ethyl acetate80:20. The product was obtained as a colorless oil (0.298 g,
77% yield.) NMR (CDC13): d~o.g5 (d, J = 6, CH3CH), 3.77 (s, CH30),
5.35 (m, trans-CH=CH), 7.20 (m, proton at C-3).
Example XV - Steps (b), (c)
Preparation of dl-2~(E)-6'-(m-methoxYPhenYl)-2'-methyl-3~-hexenyl7
-2-cvclopentenone
(Formula VIII, R2 = H, R1 = methyl, R5 = methoxy).
The product from Example XIV (0.30 g, 0.77 mol) was
dissolved in a mixture of dimethoxyethane (20 ml) and lN hydro- ;~
20 chloric acid (7 ml). The solution was heated at about 50C under
nitrogen for about 3 hours. The reaction mixture was diluted
with water and extracted with ethyl acetate. Evaporation of the
extracts to dryness yielded 0.23 g of keto-aldehyde. This was
dissolved in 20 ml absolute ethanol, after which 0.4 ml 40% tri-
TM
methylbenzylammonium hydroxide ("TRITON B") was added. The mix-
ture was warmed at about 40C under nitrogen for about 1 hour,
after which saturated sodium chloride solution and ether were
added. The ether layer was separated and the aqueous layer was
extracted again twice with ether. The extracts were dried by
30 anhydrous Na2S04 evaporated to dryness. The dark brown residue
was rapidly chromatographed on silica gel (20 g) with hexane/
ethyl acetate 90:10. The product was obtained as an unstable
-- 29 --
1 13~34.30
oil (0.15 g, 69% yield. NMR (CDC13): ~0.95 (d, J = 6, CH3CH),
3.77 (s, CH30), 5.35 (m, trans-CH=CH), 7.20 (m, proton at C-3).
Example XVI - Step (d)
Preparation of dl-2~(E)-6'-(m-methoxyphenyl)-2'-methyl-3'-
hexenyl~-l-methyl-2-cyclopenten-1-ol
(Formula I, R1 = methyl, R2 = H, R3 = hydroxy, R4 = methyl, R5 _
methoxy)
The product from Example XV (0.142 g, 0.50mmol) was
dissolved in dry ether (10 ml) and cooled under nitrogen to about
-70C. A solution of methyl-lithium in ether (1.5 ml, lM, 3 eq.)
was added and the resultant mixture was stirred for about a fur-
ther 10 minutes. A few drops of water were added, after which
the reaction mixture was warmed to room temperature and dried
with the aid of anhydrous Na2SO4. Filtration and evaporation
under vacuum at less than about 20C gave 0.15 g product in the
form of an unstable colorless oil. NMR (CDC13 + C5D5N):~ 0.88
and 0.95 (2 x d, J = 6, CH3CH), 1.25 and 1.29 (2 x s, CH3-C-OH),
3.75 (s, CH30), 5.2-5.6 (m, olefinic protons).
Example XVII - SteP (e), Cyclisation
Preparation of dl-l- and -3-methoxv-11~, 17-dimethyl- ~1~3~5(10)~
13(17)-qonatetraene
(Formula II and III, R4 = methyl, R = methoxy, R6 = methyl
The product from Example XVI (0.15 g, 0.50 mmol) was
cyclized with stannic chloride in dichloromethane at about -70C
in the way described in Example IX, giving 15.6 mg (11% yield) of
the l-methoxy-isomer and 44.4 mg (31% yield) of the 3-methoxy-
isomer. The products consisted of 85% and 80% respectively of the
ll~-methyl isomer, which was isolated in the way described in
Example IX.
Example XVIII - Step (d)
Preparation of dl-2-~(E)-6'-(m-methoxyphenvl)-2'-methyl-3'-
hexenyl7-1-ethyl-2-cyclopenten-1-ol
- 30 -
1138430
(Formula I, Rl = ethyl, R2 = H, R3 = hydroxy, R~ = methyl, R5_
methoxy)
The cyclopentenone from Example XV is caused to react
with ethyl-lithium in the way described in Example XVII to give
the corresponding l-ethyl-2-cyclopentenol.
Example XIX - Step (e)
Preparation of dl-l- and -3-methoxy-11~-methyl-17-ethyl-~ 1,3,5
(10),13(17)_qOnatetraene
(Formula II and III, R4 = methyl, R5 = methoxy, R6 = ethyl)
The l-ethyl-2-cyclopentenol of Example XVIII was cy-
clized to the gonatetraene product named above in the exact way
described in Example XVII.
Example XX - Steps (a) - (d)
Preparation of dl-3-methyl-2-~(E)-6'-(m-methoxyphenyl)-2'-ethYl-
3'-hexenyl~-2-cyclopentenol
(Formula I, Rl = H; R2 = methyl, R3 = hydroxv, R4 = ethyl: R5_
methoxy)
In the way described in Example VI, 3-(m-methoxyphenyl)
propyl-triphenylphosphonium bromide was first caused to react
with phenyl-lithium to give the yield of formula IV (X = P
(C6H5)3), after which the yield was condensed with dl-2-ethyl-
5,8-bis(ethylene-dioxy)nonanal (obtained in the way described in
the Examples II to V inclusive, starting from 1-(5-methyl-2-
furyl)-pentan-3-one), followed by hydrolysis, cyclodehydration
and reduction in the way described in Examples VII and VIII.
Example XXI - Step (f)
Preparation of dl-(E)-1-(2-furyl)-3-methyl-7-(m-methoxyphenyl)-4- `
heptene ~
(Formula X, R2 = H, R4 = methyl, R5 = methoxy) ~:
In the way described in the last paragraph of Example I,
dl-l-iodo-2-methyl-4-(2-furyl)butane (obtained by reducing the
butanal of Example XII to the corresponding butanol, followed by
- 31 -
113t~43(~
conversion with methane-sulphonic acid chloride into the mesylate
and reaction of the latter with lithium iodide) was converted
with triphenylphosphine into dl-2-methyl-4-(2-furyl)-butyl-tri-
phenyl-phosphonium iodide, which was converted with phenyl-li-
thium, in the way described in Example VI, into the yield of
formula IX (R2 = H, R4 = methyl, Y = P(C6H5)3), followed by con-
densation of the yield with 3-(m-methoxyphenyl)propanal, giving
the product, which was identical with the product of Example XIII.
Example XXII - Step (f)
10 Preparation of dl-(E)-1-(5-methyl-2-furyl)-3-methyl-7-(m-methoxy-
phenyl)-4-heptene (Formula X, R2 = methyl; R" = methyl, R5_
methoxy).
In the way described in Example II, using lithium iodide
instead of lithium bromide, dl-2-methyl-5-(3-iodobutyl)-furan was
prepared, which was converted with triphenylphosphine, as de-
scribed in the last paragraph of Example I, into dl-2-methyl-4-
(5-methyl-2-furyl)-butyltriphenylphosphoniumiodide. (m.p. 133-
135C). This compound was converted with phenyl lithium, in the
way as described in Example VI, into the yield of formula IX (R2 =
20 methyl, R4 = methyl, Y = P(C6H5/3), followed by condensation of
the yield with 3-(m-methoxyphenyl)-propanal, giving the product
in the form of an oil, NMR (CDC13): c~ 0.97 (d, J = 6.5, CH3CH),
2.22 (s, CH3 at furan), 3.77 (s, CH30), 5.33 (m, CH=CH), 5.80
(m, protons at furan).
Example XXIII - Steps (h), (b) - (d)
Preparation of dl-3-methyl-2-~(E)-6'-(m-methoxyphenyl)-2l-methyl-
3'-hexenyl7-2-cyclopentenol (Formula I, Rl = H: R2 = methyl: R3_
hydroxy, R4 = methyl: R5 = methoxy).
In the way described in the Examples XIV - XVI, the
30 Wittig product from Example XXII was converted into the product,
which was identical to the product of Example VIII.
This application is a division of Canadian Application
No. 314,203, filed October 25, 1978.
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