Note: Descriptions are shown in the official language in which they were submitted.
12395
PROSTAGLAN~IN INTERMEDIATES
This invention relates to intermediates for use in the synthesis
of prostaglandins containing ~everal types of ring system.
In Cana~ian Patent Application Number 380,307 a group of
biologicaliy active compounds is described and claimed which
05 contain a substituted bicyclo [2,2,2] octane, bicyclo [2,2,2J
oct-2~-ene t 6,6-dimethyl-bicyclo [3,1,1] heptane, 7-oxa-bicyclo
[2,2,~ heptane, 7-oxa-bicyclo ~2,2,1] hept-2Z-ene, cyclohexene,
cyclohexane or hydroxycyclopentane ring system. The compounds of
the present invention constitute intermediates in a synthetic
route of particular value for the preparation of various of these
biologically active compounds.
According to the present invention a process for the preparation
of a compound of formula tI)
I~P~
X I (I)
--¦~C~R2)~'
H W
H
~C
wherein ¦ represents one of the divalent cyclic
X I groups
I
H
;~@
.
lo
-- 2 --
I' I, SHEA
O O
SHEA
OH
~8L23L
the letters a and b indicating in each case the points of attachment
of the substituents R and C(R ) W respectively; R represents
a 6-carboxyhex-2-enyl group or a modification thereof in which the
group is altered by one, or where appropriate by a combination,of
05 the following: (a) reduction of the double bond optional.ly
accompanied by replacement of a carbon atom at the 1, 2 or 3
position by a sulphur or oxygen atom, (b) alteration of the
position of the double bo~d, (c) shortening or lengthening of
the carbon chain by one or two methylene groups, and (d) formation
of an amide, ester or salt derivative of the carboxy group;
R represents hydrogen~ a C1 10 aliphatic hydrocarbon group or
a C1 10 aliphatic hydrocarbon group substituted directly or
through an oxygen or sulphur atom by an aromatic group Ar, where
Ar is a phenyl, napthyl, fluorenyl, dibenzocyclohexyl, dibenzo-
cycloheptyl, pyridyl, benzothiazolyl, dihydrobenzothiazolyl,
N-methyldihydrobenzothiazoly~ benzoxazolyl, dihydrobenzoxazolyl
or N-methyldihydrobenzoxazolyl group or such a group substituted
by one or more substituents selected from Cl 10 alkoxy, halogen,
C1 10 halogen substituted alkyl, sulphamoyl, amino, hydroxyl,
nitro and C1 10 alkyl groups; and either V and W together rapresent
the oxygen atom of a carbonyl group or, when R is other than hydrogen,
V represents hydrogen and W represents a hydroxy group; with the
proviso that when R is hydrogen then the divalent cyclic group
is a bicyclo [2,2,2] octane, a bicyclo ~2,2,2] oct-2Z-ene or a
6,6-dimethyl-bicyclo ~3,1,1] heptane ring system which comprises
reacting a compound of formula (II)
C~ Y
X (II)
H
~;
2~
-- 4 --
in which Z represents (a) a formyl group in acetal form, (b) a
hydroxymethyl group, (c) a formyl group or (d) a group CH(R )OH,
Y is either R1as defined for (I) or a precursor for R and and
R are as defined for (I), the said reaction consisting of
05 (a) effecting hydrolysis of the acetal to give a formyl group,
(b) effecting oxidation of the hydroxymethyl group to give a
formyl group, (c) effecting a Grignard reaction involving the
fsrmyl group and a reagent R2MgHalogen to give a group CH(R OH),
or (d) effecting oxidation of the group CH(R OH) to give a group
C(R )=O, and where appropriate converting the group Y in the
resultant product into a group Rl, the process optionally involving
a change of stereochemistry of (I) to that of (II).
The various bridged ring systems indicated above may
alternatively be represented in planar form, i.e. in the same
order as
'
~1
5 --
(the two free valencies ln the third and fourth formulQe indicating
methyl groups), bu~ ~he more usual convention has generally been
followed throughout the speciflcation of representing these systems
in non-pla~r form. It will be apprec~ated, however, that the
05 compounds (I) may e~ist in varlous stereoisomeric forms, which
are included wlthin the ~cope of the invention, and in particular
~hat each geometric isomer of a bridged ring c~mpound (I) will
exi~t in two enantiomorphic forms. These two forms will have the
6tr~cture illustrated hereinbefore and the mirror image of that
structure. Taking the vicinally disubstituted bicyclo [2,2~2]
oct-2Z-enP ring system as an example, such pairs of enantiomorphs
may be shown as foll~s (the rings being numbered according to the
system used herein).
3 3
2 6 2
For the sake of added clarity it might be mentioned that alterna-
tive, equivalent, modes of showing these non-planar structures may
be used. Thus the right hand of ehe two formulae shown directly
above is equivalent to
7 3
2 *~d ~Iso 3
" ~l989L2~
It will be seen that the modif~catlons of ehe 6-carboxyhex-
2-enyl group which may be made in compo~nds according to the
present ~nvention are of two types. Thus, the modiflcatlons
elther involve ~he hex-2 enyl group or the 6-carboxy group. ~mong
~5 modifications of the firs~ fonm, wh~ch sre listed under (a) to (c)
above, certain preferences may be lndicated. Ihu~, ~here the
double bond 15 reduced and a carbon atom replac~d, the replacemen~
- is convenlently by an oxygen rather than a sulphur ~om and al80
is conveniently at ~he 2 or 3 position. ~oreover, where the
position of the double bond is altered, thls is convenien~ly to
the 3,4 posltion and where the carbon chain is shortened or
leng~hened, this is conveniently at the end of the chain ad~acent
to the carboxy group. Among the second fonm of modificatiou,
listed under (d) above, examples of amide, ~ster and salt deriva-
tives of partlcular interest are to be found in the prostaglandinart and ~nclude esters such as alkyl esters, amides 6uch as ~hose
con~aining the group CONHS02CH3 and Yariants thereon, and sal~s
wl~h var~ous physiologically acceptable cations. Specific examples
of salts are those formed with an alkali metal such as sodium or
with quaternary ammonium ions or amines cuch as tris (the symbol
tris represents the compound 2-amino-2-hydroxymethylpropane-~,3-diol).
Examples of specific groups Rl are -CH2-CH=CH-(CH~)3C02~,
-~CH2)6C02H and -(CH)20(cH~)3Co2H, as well as amide,~salt and
partlcularly ster derivatives of both groups.
Groups R other than hydrogen are fully described in Canadian
Patent Application Number 38Q,907, aliphatic hydrocarbon groups
substituted directly by an aromatic group and particularly
unsubstituted aliphatic hydrocarbon groups being of most interest.
The size of the group R can however influence the ease with which
the final biologically active compounds may be prepared a~d R is
preferably either hydrogen or one of the smaller alkyl groups, for
example of 1 to 3 carbon atoms, in substituted form, or particularly
in unsubstituted form3 for example ethyl and especially methyl. The
hydrocarbon and heterocyclic aromatic groups present in groups R are
described in further detail in Canadian Application 380,907 but
342~
-- 7 --
pyridyl groups such as pyrid-l-yl and especi~lly phenyl and
substituted phenyl groups are of particular interest. When the
group R contains an aliphatic hydrocarbon gorup directly substituted
by an aromatic group, then it is preferred that the aromatic group is
05 not attached to a carbon atom of the aliphatic group which is itself
attached directly to the carbon atom of the group C(R )~ W Thus,
for example, a 2-phenylethyl group is preferred to a l-phenylethyl
or phenylmethyl (benzyl) group. Good levels of biological activity
have been achieved with compounds prepared from intermediates of
formula (I) in which R2 is one of hydrogen, ethyl and especially methyl.
The increase in biological activity resulting from the presence of a
group R which is methyl rather than hydrogen has been found to be
particularly marked in the case of those compounds described in
Canadian Applieation 380,907 containing a group derived from the
group C(~ ) ~W of the intermediate which is of the form C(R )=N-NHCO.NHR
or C(R )=N-NHCS.NHR .
As lndicated above, compounds according to the present inven-
tlon may contain, in the order shown previously, one of the following
types of ring syste~: b~cyc lo [2,2~2~ octane, bicyclo [2, 2,2]
20-; oct-~Z-ene, 6,6-dimethyl-bicyclo [3,1,11 heptane, 7-oxa-bicyclo
~2,291] heptane, 7-oxa-b1cyclo [2,2,1~ hept-2Z-ene, cyclohexane,
~yclohexene and hydroxycyclopentane. The 6,6-dimethyl-bicyclo
13,1,11 heptane ring system, unlike the others, may be substituted
in either of two ways, corresponding to reversal of the substituents
shown at the a and b positions. It will be appreciaeed that the
bridged ring systems present in compounds according to the present
invention show a range of degrees of asymmetry. Thus, the
6,6-dime~hyl-bicyclo [3,1,1] heptane ring system is sufficiently
asymmetric for reversal of the substituents at the a and b positions
3~ to resul~ in a different structural isomer and thus a different
compound (I), both types of compound (I) containing the 6,6-dimethyl-
bicyclo 13,1,1] heptane ring system being covered by ~he present
~nvention. In the case of the 7-oxa-bicyclo [2,2,1~ hep~ane and
7-oxa-bicyclo 12,2,1] hept-2Z-ene ring systems, h~ever, reversal
of these substituents would merely provide a struc~ure whleh
represents an alternative stereoisomer, the invention, as has
z~
_ 8 --
p eviously been indlcated, extending ~o the compounds (I) in their
various stereolsomeric forms. The situstion with the b~c~clo [2,2,2]
oct-2~-ene ring system is Qnalogous to thQt pertaining in the case
of the 7-oxa-bicyclo 12,2,13 heptane and hept-2Z-ene rlng sgstems
05 but the bicyclo [2,2,2] octane rln~ system hRs a ~ufflcient degree
of symmetry for such reYersal of the a and b 6ubstituents to glve
the same compound ~) of identical stereochem~stry. Amang these
ring systems, ~he bridged rlng systems are of particular interest
and of the~e the blcyclo 12,2,21 octane and the 6,6-di~enthyl-bicyclo
~3,1,1] heptane ring subs~ituted at the 2-position by the group
C~R ) W rather than the group R may be mentioned particularly.
Among those brldged rlng systems which may be ~aturated or unsatu-
rated, ~he for~er are usually preferred, particularly in the case
of the compounds con~aining an oxygen bridging group, as ~nsaturation
generally confers lower stab~lity wh~lst the level of biological
activity of the final compounds prepared fr~ intermediates of this
invention is generslly substantially slmllar.
It will be appreciated that the ~tructures of the compounds
described above prov~de varlous opportunities for the occurrence
of stereoisomerism. The substituent groups R1 and C(R ) = m~y
be in the cis or trans rela~ionship to each other, compounds of
the latter configuration more generally being preferred. Moreover~
when the ring system is one which ls br~dged or contains a hydrogen
substituent then, in m~st cases~ diferent isomers will exlst
which vary a~cording to the way in which the substituent groups R
and C~R ) V are disposed in relation to the ~ridging groups or
the substituent. Isomers of particular interest are shown below
ln one of the two enantiomorphic forms which can exist in each
case, the other enantiomorph having a structure which is the
mirror ~mage of that shown. Ihe unsaturated rlng system is
illustrated ~here the ring system may be saturated or unsatur~ted
and the symbol B represents -C~2CH2-(positions 7 and 8) nr
-0-~position 7). As indicated above, the bicyclo [2,2,2] ~ctane
system possesses a greater degree of symmPtry than the o~her
bridged ring systems~ 8S the two bridging groups at$ached $oge~her
st the bridge positions (1 ~nd 4~ are identical, both being -CH2CH2-.
~.g8~
In this case therefore, although the trans isomer is preferred and
can exist in two enantiomorphic Eorms, the endo, exo type isomerism
which can occur with the other bridged ring systems cannot arise.
It will be seen that in the s~ructures shown below the numbering
05 applied herein to the various positions of the ring system has been
indicated. It should be noted that the system of numbering adopted
for the bridged ring systems which can exist in both saturated
and unsatura~ed form is chosen so that the double bond in the
unsaturated ring system receives the lowet number possible (2),
the substituents Rl and C(R2) = V then being at the 5 and 6 positions,
respectively. For conformity, a similar system of numbering is
followed for the analogous saturated ring systems, the substituents
again being described as at the 5 and 6, rather than the 2 and 3
positions as in the 6,6-dimethyl [39]~]] heptane system.
B B
V ~o V
5-exo~ 6-endo W ~-endo~ 6-~xo
-
~RI or C(R~\
C~3 \~ C(~2~W or ~1
3Clc 9 ~oC
(RZ)~W
C(k~3~ or Rl
20c>~, 60c
~.
2~
--10--
OH
~RI
`C(R J~W
~,2,~, 30
0
~RI
~C¢R J<~
oc, 3"~
Among the isomers illustrated above in two forms, one form is
usually preferred to a somewhat greater extent than the other. In
the case of the S-exo, 6-endo and 5~endo, 6-exo isomers the latter
is most usually preferred but in the case where B is -O- the
05 5-exo, 6-endo isomer is also of considerable interest. In the
case of the 2~, 3~, 6~, and 2~, 3~, 6~, isomers the latter is of
most interest. [The convention applied herein for naming the
compounds (I) containing a 6,6-dimethyl-bicyclo [3,1,1] heptane
ring sy5 tem is the use of and to indicate the directions in
which the substituents at the 2- and 3-positions are directed. In
the designations used above the position of the bridging carbon
atom at position 6 has for simplicity also been indicated by
an or (the position of the gem dimethyl groups at the 6-position
-
84~
is dlctated by that of the carbon atom to ~hlch they are attached)].
In the case of the , 2B9 3a and 1~, 2a~ 3~isomers the latter is
agal~ of ~o~t lnt~re~t.
~here the substituen~ R ls a 6~carboxyhex-2-enyl group or a
05 group ~odified there~rom but stlll contalning the double bond,
~hen ~he configuration about this bond is preferably c16 (Z)
rather than trans (E). In add~tion to the foregoing lsomerism, as
indicated pre~iougly the compounds of the present lnvention wlll
ln ~ost cases additlonally be resolvable i~to enantiomorphic forms
aod one among these may be preferred by virtue of blological
- activity or phycical properties of the final compoun~s prepared
from lntermediates of the present invent~on. Single enant~amers
~ay be obtained either by ~he use of an optically active starting
material or by resolution of a pair of enantiomorphs.
It ~ill be appreciated, however, that certain of the compounds
of the present lnvent~on are capable of ep~meri~ation under parti-
cular conditions and that in a few cases, as wlll be seen from
Canadian Application 380,907, the stereochemistry of an intermediate
may undergo some modification during conversion to a final,
biologically active, compound.
Compounds of formula (I) in which R is hydrogen are of value
not only for direct use as an intermediate in the preparation of
biologically active compounds in which R is hydrogen but also as a
suitable intermediate for the preparation of those compounds of formula (I)
in which R is other than hydrogen. The preparation of such compounds
in which the substituent C(R2)' W is a formyl group, is described in
detail in the Examples and at the end of the Examples for various of
the nine ring systems described hereinbefora. The formyl group may be
generated by one of the two procedures referred to previously involving
the hydrolysis, for example with aqueous hydrochloric acid, of a formyl
group in acetal form, for example an acekal formed with ethylene glycol,
methanol or ethanol, or the oxidation of a group CH(R2)0H, for example
with pyridinium dichromate, the procedure used for any particular
ring system depending upon the ease of synthesis of the precursor (II).
_ 12 --
Co~pounds (II) containing the unsaturated blcyclo [2,2,23 ~ct-2X-ene
rlng sys~em may be prepared by ~he procedure descrlbed in Example 1
for the preparation of a blcyclo [2,2,2] octane (II) but omitting
the H2~Pd-C reduction step whlch is described in sectlon (4),
05 thereby retaining the double bond present in the bicyclo 12,2,2]
oct-2~-ene of section (3). Such a procedure ls similar to the
synthesis of ~he analogous compound containing a bicyclo ~2,2,1]
hept-2Z-ene ring system ~A~hich is described in detail and illu-
s~rated in UK Pa~ent Application 8000279, published under the
serial number GB 2039909A, except that for the eight membered ring
system it is preferred to use an acetal prepared from ethylene
glycol rather than ethanol since the equil~brium of the reaction
wi~h ethanol does not lie sufficiently towards the ring closed
form. The compound (II~ containing the cyclohe~ane ring system
l5 may be obtained by the introductlon of a H2~pd-C reduction step
into the synth&sis of the equivalent cyclohexene compound, reducing
the cis-4~5-bis-hydroxymethylcyclohex~l-ene to give cis-4,5-bis-
hydroxymethylcyclohexane before proceeding with the forma~ion of
the monobenzyl ether. Alternatively, cyclohexane 1,2-dicarboxylic
acid anhydride may be used as the starting materlal. The 7-oxa-
bicyclo [2,2,1~ heptane and hept-2Z-ene compounds of formula ~II)
are obtainable, for example in the 5-endo, 6-exo form, by routes
described in th~ literature ~hich yield compounds containing a
6-carboxyhex-2'Z-enyl or 6-carboxyhexyl substi~uent R , for example
Eggelte et al, J.C.S. Perkin I, 1978, 980 Sprague et al, Advances
in Prostaglandin and Thromboxane Research, 1980, 6, 493.
Other stereoisomers are obtainable by modified r~outes. Thus,
for examp]e a-pinene ~ay be obtained in both optically active
forms thus providing a route to ~+)-nopol and (+)-myrtenol as
alternative starting materials for use in the routes described in
Examples 3, 4 and 5. Also, in the case of the 7-oxa-bicyclo
[2,2,1] heptane compounds and their rlng unsaturated analogues
modifications of the routes described in ~he literature may be
used to produce other stereoisomers.
Modification of the 6-carboxyhex-2-enyl group may be effected
~hrough the initial introduction of a group R in modified form or
t3 -
by modificat~on of this group during or at the end of the 6ynthesls.
Thus, ester formation may conveniently be effected by esterlficatlon
of a free carboxy group ~ust prior to conversion of an acetal
group to a formyl group, for example using diazomethane to form
05 the ~ethyl ester. Amides may similarly be prepared by conventional
procedures. Indeed, the procedures for effectlng the various
modiflcations indicated above will be apparent from the considerable
literature existing on prostaglandin chemistry. Thus, for example,
in the case of a sa~urated ring system, where a precursor of
structure
~/ =\/~/\CO 11
X
C
¦ CH0 (in acetal form)
is involved in the synthesis of compounds containing a 6-carboxy-
hex-2-enyl group, then a convenient rou~e to the analogous contain-
ing a 6-carboxyhexyl group involves the reduction of this precursor,
for example with H2/Pd-C. The preparation of compounds containing
a 6-carboxyhexyl group in this ~anner is described in GB 2039909A.
Where the synthetic route initially involves compounds con~aining
the corresponding unsaturated ring lt may be possible, if desired,
to reduce both the ring and chain double bonds at this stage in
one step. In the case of other ring systems, particularly the
unsaturated ring syste~s, a 6-carboxyhexyl group is best introduced
at an earlier stage of the synthesis, for example by a modification
of the initial Diels Alder reaction where such a reaction is
employed. Introduction of a 3-oxa-6-carboxyhexyl group is similarly
best effected at an early stage of the synthesis. A convenient
route for doing this involves the use of a compound of structure
11 2 2
11 .
CH
~3 '
Z'~
_ 14
~herein the resldue ls a ~aturated one, such as 6,6-d~me~hyl-2-
.. (2'-hydroxyethyl)-bicyclo [3,1,11 hept-2-ene, a6 8 ~tar~ing material.
Reac~lon ~ith ~crylonitrlle in the presence of Triton B ~benzyl-
methylammonlu~ hydroxlde~ in a Michael reactlon i6 then used to
05 modify the 2 substitutent to fonm a 5' cyano-3'-oxapentyl gro~p
whlch is then chain extended using, ~n turn, lithlum ~luminium
hydride, toluene sulphonyl tTs) chloride in pyridine, sod~um
hydride followed by Ts chlorlde, and cyanide ion to give a 6'-cya~o-
3'-oxahexyl group by the sequence of reactions
-(CH2)20(CH2)2 CN (cH2)2o~cH2)2cH2NH~ -(cH2)2o(cH2)3NHTs
( -(C~2~20(CH2)3MT (C~2)2(cH2~3cN
(2)'r~CL
Acid hydrolysig and esterification are then used to con~ert the
cyano ~roup to a methoxycarbonyl ~roup snd the reactsnt 9-borabicyclo
13,3,1] nonane ls finally employed to effec~ reaction ~t the
double bond to yield a compound of the ~ype (II) descrlbed herein-
before having the structure
H/\~ C~2C~13
/~
¦ \ C~O
When the desired compound of formula (I) contains a substituent
C(R ) ~W in which R is other than hydrogen, its formation from the
compound (II) may conveniently be effected by a Grignard reaction
using a reagent of the form R MgHalogen, followed by oxidation of the
resulting secondary alcohol of formula (II) in which Z is CH(R )OH,
for example using Jones reagent, to give the desired compound of
formula (I).
T~a~ U~C
It will be appreciated that the methods described above are
not the only ones which may be ~sed for the preparation of compounds
according to the present inventlon and that various alternatlve
procedures ~ay be used as will be apparent to those skilled in the
S art o~ prostaglandin chemistry.
The compounds (I) are used for the preparation of the compounds
of Canadian Application 380,907 in procedures which are
described therein.
This inYention is illustrated by the following Examples.
Where possible, t'ne stereochemistry whi~h the compounds are believed
to possess has been indicated. However, some contam~natioa of a
minor nature by other isomers may often be present i.e. by the
other of the pairs of preferred isomers shown hereinbefore or
particularly by the corresponding cis isomer. It ~ill be appreciated
that the proportion of such con~aminants does not necessarily
depend upon the ~tereochemical nature of the inter~ediaces in
earlier stages of the synthesls. Thus, certain compounds are
eapable of epimerisation under particular conditions, and the
formyl compounds (II) in particular can undergo an epimerisation
involving the formyl group, for example at the stage in the
synthesis of so~e of these compounds where the formyl group is
generated by the action oE acid on an acetal~
In most cases the compounds are obtained in the form of a
racemic mixture but in the case of the compounds of Examples 3, 4
and 5 sn optically active starting ~aterial is used and these
compounds are therefore also optically active. It should also be
noted that the full ~tereochemistry has not been designated in the
names of the compounds of Examples 3 and 4 in as far as no attempt
has been ~ade to indicate the orien~ation of the substituents R
and C(R )' W relative eo the two bridging groups -CH2- and -C(CH3)~-,
the full orientation being as shown in the structure designated
, 3~, 6x, shown hereinbeEore. In the case of Example 5, this is
also true for the stereochemistry of the compounds of sect;ons S
and 6, although in admixture with another isomer, but reference
~hould be made to the note at the end of this Example as regards
the stereochemistry of the title ~ompound thereof.
-
!
_ 16 -
The mass spectroscopy data is generally obtained by direct inlet
except for cases where the compound has a substituent R ~hich
terminates in an ester grouplng when the data i8 obtained by gas
chromatography mass spectroscopy. In certain ca~es, which are
S indicated, the f~eP carboxy group of the substituent R is converted
to a methyl ester group before the mass spectrum i8 run (by gas
chromatography mass spectroscopy). Such conversion is readlly
achieved by solution in methanol, using ~arming and addition of
~aHC03 as necessary, ollowed by ~he addition of an excess of
ethereal diazomethane ~o the methanolic solution, standing, and
the removal of sol~ent.
EXAMPLES
Following ~he Examples, the preparation -Is described of two
compounds, 4-(6'-ethoxycarbonylhex-2'Z-enyl)-5-formylcyclohex-1-ene
and 1-hydroxy~2a-(6'-carboxyhex-2'7-enyl)-3~Lformylcyclopentane,
which may be used in a manner analogous to that of Examples 2 and
4 as starting materials for the preparation of compounds according
to the present in~ention having a group R other than hydrogen and
contain~ng a 4,5-substltuted cyclohex~l-ene or 2,3-substltuted
1-hydroxycyclopentane ring system.
Example 1: ~rans-$-~6'-Carboxyhex-2'Z-enyl)-6-formyl-bicyclo [2,2,2]
octane
(1) aleinaldehydic acid pseudo-ethyl ester
30 g of redistilled furan 2-aldehyde is mixed with 600 ml dry
ethanol and 300 mg of methylene blue is added. Dry air is blown
gently through the solution and the material ~s irradla~ed with a
300 W tungsten lamp for about two days until t.l.c in a silica
gel/ether system shows essentially no remaining starting material.
The solution is then stirred with vanadium pentoxide for four
hours, filtered, and the solvent removed under reduced pressure.
The residual oil is distilled under high vacuum to give the title
compound as an oil (23.6 g, 76%), b.p. 90 - 92 C/0.2 mm.
(2) Diels-Alder reaction between msleinaldehydic acld pseudo-ethyl
ester and cyclohexadlene
Cyclohexadiene t4.5 g) and the maleinaldehydic acid pseudo-ethyl
ester (1) (6.4 g) are heated together in a thick walled glass tube
at 120 C for 10 hours and the produc~ ls distllled to give the
Diels-Alder adduct of these two compounds in over 90~ yleld,
b.p. 95 - 97 C/0.2 mm, M 208.
(3) 5-endo-HydrDx~ethyl 6-exo~(1',3'-dioxacyclopent o
12.2.2J oct-2Z-ene
The Diels-Alder adduct (2) (10 g) is heated under a ~ean and
05 Stark apparatus wlth 12 ml of ethylene glycol in 100 ml toluene con-
~aining a crystal of p-toluenesulphonic acid. After water has ceased
to form, half of the solvent is distilled off and ~he resultant
~olution nf 5-endo-ethoxycarbonyl-6-exo-(1',3'-dloxacyclopent-2'-yl)
bicyclo [2.2,2~ oct-2Z-ene is added to e~cess lithium aluminium
hydride (3 g) in 200 ml ~f dry ether. The addition is perf~rmed
a~ a rate whlch maintains a gentle boiling of the ether (30 to
60 m~nutes). After a further 1 hour of heating ~he excess
hydride is destroyed by the careful addition of wet ether followed
by water. The mixture is then treated with aqueous 10~ w/v sodlum
hydroxide solution to precipitate aluminium salts. The mlxture ls
dried over magnesiu~ sulphate and then filtered. The organic
solvent is evaporated to give the title compound as an oil which
is used directly in step (4).
(4) trans-5-Hydr~y~thyl-6~ 3~-dioxacyclope -
bicyclo ~2,2,2~ octane
The crude alcohol/acetal obtained in (3) is dissolved in
ethanol and hydrogenated at atmospheric pressure over 10~ palladium
on charcoal. one molecular eqllivalent of hydrogen being absorbed.
The catalyst is filtered off and the solvent evaporated. Distilla-
tlon of the residue gives the title compound as a colourless oil
(6.1 g, 60~), b.p. 110 - 112 C/0.15 mm.
(5) trans-5-Cyano-6-(1',3'-dioxacyclopen~-2'-yl)-bicyclo ~2,2,2]
octane
The alcohol/acetal (4~ (7.0 ~) ~n 15 ml dry pyrldine is added
to 7.5 g of p-toluenesulphonyl chloride in 45 m~ of pyridine at
0 C with stirring. After 20 hours the mixture is poured ~nto
ice/water and after 30 minutes stirrin~ the mixture is extracted
with ether to give the tosy~ate ester of the alcohol as a colour-
less oil ln good yield.
34~
he tosylate ester (12.0 g) ln di~ethyl sulphoxide (15 ml) is
added to potassium cyanide (3.0 g) in dimethyl sulphoxide t20 ml).
The mixture is stirred and heated at 100 C under ~itrogen for
6 hours. The rea~tion mlxture is then poured into water and the
05 mixture is ex~racted with ether ~o give the title compound as an
oil (7-2 8). ~max22o5 cm , which i6 purified by passage through a
short Florisil~column with toluene as eluant.
(6) trans-5-Formylmethyl-6-(1',3'-dioxacyclopent-2'-yl)-bicyclo
_2,2,2J octane
The nitrlle/ace~al (5) (7.0 g) is stirred in 100 ml of dry
toluene under nitrogen at -15 C. Di-isobutylaluminlum hydride9
~42.5 ml of lM solu$ion in toluene) is added slowly over 25 minutes
and the mixture ls allowed to wanm slowly to room temperature.
After 1 hour, methanol tlO ml) is slowly added, followed by 200 ml
of saturated aqueous sodium hydrogen tartrate. The mixture is
stirred at 40 C for 2 hours and the upper organic layer is then
separated and the aqueous phase further extracted with ethyl
acetate. The combined organic solutions are dried C~gS04) and
evaporated. The yellow oil obtained i8 chromatographed on Florisil
in toluene to give the title compound as an oil (5.8 B, 83Z~,y a
~film) 1720 cm , ~(CDC13) 9.75 (t, J=2Hz, lH). 4.85 (d, J=8Hz, lH),
3.9 (m, 4H~, 2.8-2~4 (m, 2H), 2.1-1.2 (m, 12H).
(7) trans-5-(6' Carboxyhex-2'Z-enyl)-6-formyl-bicyclo 12,2,2~ octane
4-Carboxy-n-butyltriphenylphosphonium bromide (17.0 g) is
dried at 75 C for 3 hours under vacuum. The solid is cooled and
the vacuum released to argon. Dimethyl sulphoxide (50 ml) is
added and butyllithium (270 ml of a 1.5 M solution in pentane) is
added slowly over 1 hour. The deep red ylide thus formed is
stirred at room temperature for 15 minutes and then the aldehyde/
acetal (6) (4.6 g) is added slowly over 15 minutes. The mlxture
is stirred overnight at room temperature, and then the solvent is
removed at 50 - 60 under vacuum. The residue is dissolved in
water and the aqueous phase is extracted wlth ether to remove
non-acidic material. The water layer is acidified (pH = 4) with 2N
aqueous hydrochloric acid and then extracted with ether. The
i~ ~rQ~e
Li9~Z~L
~9 --
,/ ethereal solution i6 dried and e~aporated to give transr(6'-
carboxyhex-2'Z-enyl)-6 (1',3'-dioxacyclopent-2'-yl)-bicyclo [2,2,2]
octane as an oil t3.5 g, 55%).
The acetal group is removed by stirr~ng this material (3 g)
05 with 200 ml of wa$er/dioxane (1:1 v/v) containlng 0.1N aqueous
hydrochloric acid at 40 C. The mixture is extracted wlth ether
and the ethereal extract is dried (MgSO4~ and evaporated to give a
residue which ls purified by chromatography on 6ilica gel in
toluene~ethyl acetate (g0:10 v/v) to give the title compound as an
oil [2.3 g, 48~ from (6)], v ax (film) 1725 and 1710cm 1, ~(~DC13)
9.73 (6, lH), 5.5-5.3 (m, 2H), and 2.2-1.45 (m, 20H).
Example 2. trans-5-(6'-Carboxyhex-2'Z-enyl)-6-acety~bicyclo [2,2,2]
octane
(1) trans-5-(6'-Carboxyhex-2'Z-enyl)~6-(1'-hydroxyethyl)-bicyclo
12,2,2] oc~ane
trans-5-(6'-Carboxyhex-2'Z-enyl)-6-formyl-bicyclo [2,2,2~
octane is prepared as descrlbed in Example 1. This acidtaldehyde
(2 g) is dissolved in dry tetrahydrofuran (20 ml) at 0 C and
treated under nitrogen with lM solution of methyl magnesium bromide
in ether (23 ml) during 2 hours. The reactlon is quenched by the
addltion of dilute aqueous hydrochloric acid and the mixture is
extracted with ether ~3 x). Ihe ethereal solution is dried and
evapora~ed to gi~e a residue which is chomatographed on silica gel
using increasing proportions o~ ethyl aceta~e in toluene as eluant.
Traces of the starting material are eluted with 20% v/v ethyl
acetate in toluene and 50% v/v ethyl acetate in toluene elutes the
title compound. Evaporation of the solvent from the 50~ v/v ethyl
acetate/toluene gives the title compound as an oil ~1.6 g) which
consists of a mixture of the two epimers differing in configuration
at the asymmetric caroon atom of the group -CHOHCH3.
t2) trans-5-(6'-Carboxyhex-2'Z-enyl)-6-acetyl-bicyclo [2,2,2] octane
A solution of the epimeric alcohols from (1) in acetone
(20 ml) is treated with Jones reagent (2.2 ~1 of a solution prepared
by dissolving 26.7 g of chromic anhydride in 23 ml of concentrated
sulphuric acid and dilutlng to 100 ml with water, followed by
fil~ration~ and oxidation allowed to proceed at O C for 30 minu~es.
- 20 -
The reaction mixture is then poured into water and the product
extracted with ether. The ether solution is dried and evaporated
to give the title compound as an oil (1.3 g), C (CDC13) 5.4 (m, 2H),
2.2 (s, 3H) 2.6-1.3 (m, 20H) M 292 and also 249 (M-43) and 151
05 (M-141) (as methyl ester).
Example 3: 2o-(6'-Carboxyhex-2'Z-enyl)-3~-formyl-6,6-dimethyl-
_icyclo [3,1,1] heptane
(1) 2-(2'-Benzy oxyethyl)-6,6-dimethyl-bicyclo [3,3,1]-hept-2-ene
2-(2'-Hydroxyethyl)-6,6-dimethyl-bicyclo [3,3,1] hept-2-ene
[(-)-nopol] (66 g) is added slowly with stirring to 12.5 g of 80%
sodium hydride dispersion in oil in 300 ml of dimethylformamide at
roum t-~mperature. After addition (ca. 1 hour), stirring is con-
tinued for 4-5 hours until all hydrogen evolution has ceased.
Benzyl chloride (52 g, 46 ml) ls added over 1-2 hours at room
temperature ~hen an exothermic reaction is observed. After the
addition, the mixture is heated at 80 C for 4 hours. The material
is then cooled, poured into water and the product isolated by
ether extraction follo~ed by distillation under vacuum to give the
title compound as an oil (71 g, 70%), b.p. 128 - 131 C/0.2 mm.
(2) 2o-(2'-Benzyloxyethyl)-3~formyl-6,6-dimethyl-bicyclo
[3,17 1] heptane
The benzyl ether (1) (10.2 g) is placed in a large flas~
(1 litre) with 30 ml THF (dry) under argon and 9-bora-bicyclo
[3,3,1] nonane (9-BBN) in THF (90 ml of 0.5M solution) is added
over 5-10 minutes at room ~emperature. The solution is refluxed
for 30 hours maintaining the inert atmosphere, after which most of
the compound has reacted at the double bond.
The hydroborated benzyl ether is cooled to 0 C while the
argon atmosphere is replaced by carbon monoxide. A solution of
lithium trimethoxyaluminium hydride (62 ml of 0.7M) is prepared
from lithium aluminium hydride and methanol in THF and added
oYer 30-60 minutes with vigorous stirring maintaining a posltive
pressure of carbon monoxide in the system. A vigorous uptake of
gas is observed (ca. 1,000 ml) and after a further 1 hour of
vigorous stirring the argon atmosphere is re-established and 82 ml
of pH7 aqueous saturated phosphate buffer (buffer prepared from
~9~
_ 21 --
97.5 g NaH2P0~.2H20 + 108.75 g K2HP04 dissolved ln 250 ml ~ater)
is added with vigorous stirring. Flnally 15 ml of 30% hydrogen
peroxide is carefully added while keeping the temperature of the
mixture below 20 C. The mixture is stirred for a further 10 minutes
05 and then poured into water. The title co~pound is isola~ed by
ether extraction and yurified by chromatography on Florisil eluting
with petrol/ether, being obtained as an oil (8.9 g, 81~ max(film)
1718 cm
(3) 2~-(2'-Ben~yloxyethyl)-3~-(dimethoxymethyl)-6,6-dimethyl-
bicyclo ~3,1,1] heptane
The benzyl ether/aldehyde (2) (10 g) is dissolved in 100 ml
of methanol contalning 10 ml trimethyl orthoformate. A few crystals
of p-toluene sulphonic acid are added and the mixture is kept
overnight. The solution is treated wi~h anhydrous sodium carbonate
(0.5 g) and water (20 ml~ is slowly added with efficient mixing.
The mixture is added to excess water and the title compound isolated
by ether extrac~ion in impure form as an oil in 100% yield, M 342.
(4) 2a-(2'-Hydroxyethyl?~3~-(dimethoxymethyl)-6,6-dimethyl-
bicyclo [3~ heptane
The benzyl ether/acetal (3) (10 g~ is dissolved in 100 ml of
methanol and 300 ~g of 10% palladium on charcoal is added. The
mixture is then hydrogenated at room temperature and atmospheric
pressure. After take up of 1 molar equivalent of hydrogen ~he
title compound is isolated in impure form as an oil in 100% yield
by filtration oE the mixture through Celite~kand eYaporation of the
~ethanol.
(5) 2a-(2~-Formylmethyl)-3~-(dimethoxymethyl)-6,6-dimethyl-
bicyclo 13,1,1~ heptane
The alcohol/acetal (4) (S.0 g) is dissolved in dry methylene
chloride (10 ml) and the solution is added with stirring over 10
* Some samples of catalyst may be found to encourage cyclisa$ion
of the debenzylated compound to give a cyclic acetal. In the event
of this presenting difficulty, an alternatlve procedure is to use
sodium in liquid ammonia for this s~age.
T~ade ~r~
84~
- 22 -
minutes to pyridinium chlorochromate (6.0 g) in 30 ml methylene chloride con-
taining 0.5 g of dry finely divided sodium acetate. After 2 hourst 200 ml of
dry ether is added to the mixture and after a further lS minutes, the mixture is
poured into water. The ether layer is quickly washed with 3% aqueous sodium
hydroxide (2 x 200 ml), followed by brine. The solution is dried over sodiurn
sulphate, the ether evaporated and the residue chromatographed on Florisil with
benzene/ether as eluant to give the title compound (2.1 g, 43%), vmax(film) 1720
cm , M 240.
(6) 2~-(6~-carboxyhex-2~z-enyl)-3~-(dimethoxymethyl)-6~6-dimethyl-bicyclo [3,1,1J
heptane
The aldehyde/acetal (5) (0.5 g) is reacted with 2.2 equivalents of 4-
carboxy-n-butyl-triphenyl-phosphonium bromide in the presence of dimesyl sodium in
dimethyl sulphoxicle. The 4-carboxy-n-butyl-triphenyl-phosphonium bromide is
mixed with 30 ml of dimethyl sulphoxide. A 2M solution of dimesyl sodium in
dimethyl sulphoxide (50 ml) is added slowly while the mixture is maintained at
25C with a water bath. The aldehyde/acetal (5) is reacted with this mixture to
give the title compound in a high purity (0.51 g, 72%)9 M 338.
(7) 2~-(6'-Carboxyhex-2'Z-enyl)-3~-formyl-6,6-dimethyl-bicyclo [3,1,1] heptane
The acid/acetal (6) (0.5 g) is dissolved in 20 ml of dioxane-water
mixture (1:1) and the solution is heated at 40C for 2.5 hours with an excess of
0.2M aqueous hydrochloric acid. The title compound is isolated as an oil by
extraction with ether followed by chromatography on silicic acid eluting with
5% ether in toluene (0.36 g, 72%), v (film) 1720 cm , ~(CDC13) 0.7 (d, lH)~
1.2 (s 3H), 1.5-2.8 (m, 15H), 5.4 (m, 2H), 8.5 (s, very broad, lH), 9.6 (d9 lH),
M 292 (methyl ester).
~.~
2~
- 22a -
Example 4: 2a-(6'-carboxyhex-2~z-enyl)-3~-acetyl-6~6-dimethyl-bicyclo l3,1,1]
heptane
(1) 2a-(6'--Carboxyhex-2'Z-enyl)-3~-(1'-hydroxyethyl)-6,6-dimethyl-bicyclo [3,1,1]
heptane
2~-(6'-Carboxyhex-2'Z-enyl)-3~-formyl-6,6-dimethyl-bicyclo 13,1,1~ heptane
is prepared as described in Example 3. This acid/aldehyde ~1.1 g) is dis-
solved in dry tetrahydrofuran (20 ml) and treated at 0C ~mder nitrogen with a
lM solution of methyl magnesium bromide in diethyl ether (12 ml). The mixture
is stirred overnight and is then allowed to come to room temperature and is
quenched by the addition of dilute aqueous hydrochloric acid. The
-
8~
- 23
mixture is extracted with ether (3x) and the ether solution is
dried and evaporated to give, as an oil the title compound in the
- form of an epimeric mixture differing in configuration at the
asymmetric carbon atom of the group -CHOHCH3.
(2) _~-(6'-Carboxyhex-2'Z-enyl)~3~acetyl-6,6-diMethyl-bicyclo
[3,1,1] heptane
05 The mixture of epimeric alcohols obtained in (1) is dissolved
in acetone and treated at O C slowly whilst stirring with Jones
reagent (1.25 ml, prepared as described in Example 2), the oxidation
at O C being contlnued for 30 minutes. The reaction mixture is
~hen quenched with water and the product immediately extracted
with ether. The ether solution is dried and evaporated and the
oily residue is chromatographed on silica gel using increasing
concentrations of ethyl acetate in toluene as eluant. The bulk of
the desired product is contained in the 20% v¦v ethyl acetate/toluene
frac~ion ~hich is evaporated to give the title compound (0.625 g),
~(CDC13) 5.35 (~, 2H), 218 (s; 3H), 3.0-1.6 (m~ 17H), 1.07 (s, 3H),
1.22 (s, 3H), 0.87 (d, lH), M 306 and also 2~3 (M-43), 165 (M-141)
and 125 ~on ~ethyl ester). The methyl ester-butyl oxime derivative,
unlike the methyl ester, shows twin peaks on gas chromatography
(syn/anti isomers). The major compound on g.c.m.s shows prominent
ions at m/e 377 ~M ), 320 (M-57), 304 (M-73), 142 and 116.
Example 5~: 3~(6'-Carboxyhex-2'~-enyl)-2-formyl-6,6-dimethyl-bicyclo
_,1,1] heptane
(1) 2-(6'-Vinyloxymethyl-6,6-dimeth~_-bicyclo ~3,1~1] hept-2-ene
A mixture of ~-hydroxymethyl-6,6-dimethyl-bicyclo [3,3,1~
hept-2-ene [(-)-myrtenol~ ~26 g), mercuric acetate (2.S g) and
ethyl vinyl ether (500 ~1) ls heated under reflux in an atmosphere
of argon for 16 hours. On cooling, anhydrous potassium carbonate
(4.5 g) is added and the excess ethyl vinyl ether is removed by
distillation. The residue is filt~red, the solid washed with
hexane (2 x 20 ml) and the combined filtrate and washings are
distilled to give the title compound as an oil (22 g, 72%),
b-p- 105 - 109 C/17 mm,~ ma (film) 2975, 2910, 2820 and 1605 cm
318~
- 24 -
(2) _~}(Formyl~ethyl 2-methylene=6~6-dimethyl-blcycio [3,1,1]
heptane
The vinyl ether (1~ (2.0 g) is heated in a sealed tube at
200 C for 7 h~urs. The resultlng yellow oil is purified by chroma~
to~raphy on silica gel ~ith toluene as eluant to glve the title
compound as an oil (1.4 g, 70%),vmax(film) 1720 cm
05 In an alternative procedure whlch may produce higher yields
the vinyl ether (1) is passed in a stream of argon or nitrogen
through a tube (1 cm x 10 cm) packed w~th glass wool aDd heated at
lso c, the product being condensed ln a cold trap and distilled to
give the title compound as an oil, b.p. 70 - 75 C/l mm.
(3) 3-~L(6'-Carboxyhex-21Z-enyl)-2-methylene-6,6-dimethyl-bicyclo
[3 1,1] heptane
(4-Carboxy-n-butyl)triphenylphosphonium bromide (7.0 g) is
dried at 75 C under vacuum for 90 minutes, cooled ~nd the flask
released to dry nitrogen. Dry dimethyl sulphoxide (DMS0) (25 ml)
is added, followed by the slow addition of 18 ml of a 1.6 M solution
of butylllthium in hexane. The temperature is held at 25 C and
the aldehyde ~2~ (1.5 g) in DMS0 (5 ml) ls added to the red ylide
solution. The mixture is stirred overnight under nitrogen, then
poured into 10% w/v aqueous sodium chloride (200 ml). The aqueous
mixture is extracted with e*her (3 x 75 ml), and the aqueous layer
is then acidifled to pH 4 with 2N hydrochloric acid and re-extracted
with ether ~3 x 50 ml). The extracts of the acidified aqueous
layer are dried over magnèsium sulphate and evaporated to give the
title compound as a yellow oil (2.0 g, 86%), ~CDCl3) 0.75 (s, 3H),
1.25 (s, 3H), 4.73 (m, 2H), 5.45 (m, 2H).
~4) 3-~L(6'-~etho~ycarbonylhex-2'Z-enyl)~2-methylene-6,6-dimethyl-
bicyclo [3,1,1] heptane
The acid (3~ (2.0 g) is treated with an ethereal solutio~ of
diazomethane (120 ml) and a few drops of methanol are added. The
solution is stirred for 20 minutes and the solvent is then removed
under vacuu~ to give the title compound as a yellow oil (2.2 g, 100%).
- 25 -
(5) _-~-(Hydroxymethyl-3-~-(6'-methoxycarbonylhex-2'Z-enyl)-6,6-
_imethyl-bicyclo [3,1,1 _heptane and 2-~-Hydro~ymethyl-3-~-
( methoxycarbonylhex-2'Z-enyl)-6,6-dimethyl-bicyclo [3,1,1
heptalle
The ester (4) (0.92 g) is placed in a dry 100 ml round-bottomed
flask under nitrogen and is treated at 0 C over 5 minutes using
magnetic stirring with 9-bora-bicyclo 13,3,1] nonane (a-BBN) in
tetrahydrofuran (20 ml of 0.5M solution). The reaction mixture is
05 stirred at room temperature for 3 hours, and then 3N aqueous
sodium hydroxide (3.3 ml, 10 mmol) is added, followed by 30~ v/v
aqueous hydrogen peroxide r3.3 ml) over a period of 10 minutes,
cooling being required to control the resulting exothermic reaction.
Th ixture is then stirred under air for 15 minutes, treated with
potassium carbonate (3 g), and the organic upper layer separated
off and dried over potassium carbonate. Evaporation of the solvent
gives a cloudy yellow oil, ~hich is stirred overnigh~ in a 10:1 v/v
toluene:light petroleum mixture (30 ml). The upper layer is
decanted and evaporated to give a mixture of the title compounds
as an oil (0.4 g, 41~ (CDC13) 0.92 (s) and 0.98 (s, total
of 3H), 1.23 (s, 3H), 3.6-3.9 ~m, 2H), 3.67 (s, 3~) 5.42 (m, 2H).
(6) 2~-(Formyl-3~-~6'-methoxycarbonyl-hex-2'Z-enyl)-6,6-dimethyl-
bicyclo 13?1,1] heptane and 2~-formyl-3~-(6'-methoxycarbonyl-
hex-2'Z-enyl)-6,6-dimethyl-bicyclo [3,1~1J heptane
The mixture of epimeric alcohols (5) (0.~94 g) is dissolved
in dry dichloromethane (1.5 ml) and pyridinlum dichromate (0.6 g)
is added. The mixture is stirred for 22 hours at room tempera~ure
and then dry ether (3 ml) and hexane (3 ml) are added. Stirring
ls continued for 15 minutes, and the mixture is then filtered.
The last traces of the chromium salt are removed by passing the
filtrate through anhydrous magnesium sulphate (5 g). Evaporation
of the filtrate gives a mixture of the title compounds as an oil
(0-075 g, 25.4~), S(CDC13) 0.75 (s) and 0.96 (s, total of 3H),
1.21 (s, 3H), 3.67 (s, 3H), 5.42 (m, 2H), 9.70 (d~ and 9.87 (d, total
of 1~.
:~L9~3~Z~
- 26 _
(7) 3~-(6'-Carboxyhex-2'Z-enyl)-2-formyl-6,6-dimethyl-bicyclo
[3,1~1] heptane
The aldehyde ester (6) (0.075 g) is treated with 0.2N 5~ v/v
aqueous methanolic potassium hydroxide at 40 C for 2 hours. The
solution is then neutraliæed with 2N aqueous hydrochloric acid and
extracted with ether (3 x 20 ml). The extracts are dried over
05 magnesium sulphate and the solvent evaporated to give the title
compound as sn oil (0.065 g, 65~ (CDC13) 0.75 (s, 3H), 1.22
(s, 3H), 5.45 (m, 2H)t 9.6 (br, lH), 9.71 (s or finely split d, lH).
This aldehyde/acid (7) is obtained as a compound having a
2-formyl substituent with either the aor ~configuration. The
formation of a single compound from the aldehyde ester (6) which
is a mixture of compounds having a 2-formyl substituent with
either an exo or an endo configuration is due to the epimerisation
resulting from the use of the base to effect de-esterifica~ion.
It has not been possib]e, however, ~o identify which of the two
]5 configurations should be assigned to the 2-formyl substituent of
the aldehyde acid.
PREPARATIO~ OF FORMYL SUBSTITUTED STARTING MATERIAL
(A) Preparation of 4-(6'-ethoxycarbonylhex-2'~-enyl)-
5-formylcyclohex-1-ene
~1) cis-4,5-bis-Hydroxymethylcyclohex-l-ene
A solution of the anhydride of 3,4-dicarboxycyclohex-1-ene
t25.8 g~ in THF (150 ml) is added with cooling to a stirred suspen-
sion of LiAlH4 (~ g) in THF (200 ml) under N2 at a rate such as to
maintain the temperatura at O C. After stirring for 18 hours at
room temperature the mixture is gently refluxed for 1 hour and
cooled in ice. The excess lithium aluminium hydride is decomposed
by the careful addi~ion of 1:1 THF-H2o mixture (100 ml). After
dilut~on with chloroform (150 ml) the resulting mixture is filtered
a~d ~he solid is washed with chlorofom ~3 x 25 ml). Concentration
of ~he filtrate under reduced pressure yields an~oily residue
which ls dissolved in benzene, dried over (MgS04) and reconcentrated
in vacuo to give the title compound as an oil (22 g, ca. 90X),
~fllm) 3350 cm
max
`` 11984~
- 27 -
(2) cis-4-Hydroxymethyl-5-benzyloxymethylcyclohex-1-e~e
The diol (1) (16.2 g) ln dimethylEormamide (50 ml) is added
dropwise to sodium hydride (3.1 g) in dimethylformamide tDMF)
(50 ml)~ The mixture is stirred for 20 minutes and then benzyl
chloride (16 g) is added and stirring is continued for a further
05 1~ hours at 70 C. After removing the DMF in vacuo~ water is added
and the mixture is extracted with ether. The combine extracts are
dried (MgS04) and the solvent is evaporated to give a residue
which is distilled under reduced pressure to give the title compound
as an oil (16.5 g, ca. 60%), b.p. 140 - 145 C/0.03 mm,v a (film)
10 3440 and 1600 cm 1.
(3) cis-4-p-Toluenesulphonyloxymethyl-5-benzyloxymethyl-
cyclohex-l-ene
The alcohol/benzyl ether (2) (10 g) in 20 ml of dry pyridine
is added slowly at 0 C to p-toluenesulphonyl chloride ~10.4 g) in
pyridine (60 ml). The mixture is kept overnight at room temperature
and is then quenched by pouring over crushed ice with vigorous
shaking. The product is extracted with ether, washed consecutively
with water, 0.1 M sodium carbonate and brine, dried (MgS04), and
concentrated in vacuo at room temperature. The crude product is
purified on a silica gel column, eluting with benzene-ethyl acetate
(95~: 5% v/v) to give the title compound (14 g, 90%). The i.r.
spectrum shows the absence of a hydroxyl group.
(4) cis-4-Cyanomethyl-5-benzyloxymethylcyclohex-1-en_
The p-toluene sulphonyl ester/benzyl ether (3) (12 g) in
dimethylsulphoxide (DMS0) (15 ml) is added with stirring to potas-
sium cyanide (3 g) in DMS0 ~20 ml). The mixture is heated at
100 C under nitrogen for 6 hours and is ~hen cooled, poured into
water and the product extracted with ether. The solvent is removed
and the residue purified on a Plorisil column, eluting with petroleum
ether-ben~ene (1:1) to give the tit~e compound as an oil (6.5 g,
ca. B0~) v (film) 2220 and 1600 cm 1
max
(5) cis-4-Formylmethyl-5-benzyloxymethylcyclohex-1-ene
Di-isobutyl aluminium hydride (25 ml of a lM solution in
hexane) is added with stirring over a 15 minute period to the
cyano/benzyl ether (4) (5.0 g) in dry toluene ~70 ml) at -10 C
- 28 _
under N2. After stirring for a further one hour at room tempera-
ture, the reaction is terminated by the cautious addition of
methanol (6 ml), followed by saturated aqueous sodium hydrogPn
tartrate (95 ml). The mixture is then stirred and heated at 40 C
05 for 2 hours. The organic phase is separated and the aqueous layer
is further extracted with ethyl acetate, the combined arganic
solutions being dried and the solven-t evaporated to give an oil.
Chro~atography of the oil on Florisil, eluting with benzene gives
the pure title compound as an oil (3.0 g 60%), a (film) 1715 cm 1.
(6) cis-4-(6'-Carboxyhex-2'Z-enyl)-5-benzyloxymethylcyclohex-1-ene
(4-Carboxyl-n-butyl)-triphenylphosphonium bromide (7.0 g) is
dried at 75 C under vacuum for 2 hours. The white solid is cooled,
the vacuum is released to dry nitrogen and DMSO ~lO ml) is added
followed by 9 ml of 2M solution of dimesyl sodium in DMS0. The
temperature is maintained at 25 C and the aldehyde/benzyl ether
(5) (1.5 g) in DMSO is added to the deep red ylide solution.
After stirring overnight the solvent is removed at 55 - 60 C under
reduced pressure. The residue is dissolved in water, extracted
with ether, and the aqueous phase carefully acidified to pH 4 with
2N HCl. The mixture is extracted with ether and the ethereal
solution dried (MgSO4) and concentrated in vacuo to give the title
compound (10 g), vma (film) 1700 cm
(7) cis-4-(6~-Carboxyhex-2'Z-enyl)-5-hydroxymethylcyclohex-1-ene
To a stirred suspension of 1.5 g of the acidtbenzyl ether (6)
in lO0 ml of liquid ammonia is added a total of 1 g of sodium in
portions over 10 - 12 mislutes at the end of which tlme the charac-
teristic deep blue colour persists. The mixture is stirred for30 minutes, the blue colour is then dlscharged by the careful
addition of ammonium chloride and the reaction mixture is evaporated
to dryness under a stream of nitrogen. The solid residue is
triturated with 50 ml of benzene (to remove benzyl alcohol) and it
3Q ls then dissolved in 40 ml of water. The aqueous solution is
treated ~ith Nori then acidified with acetic acid and extracted
with chloroform. Evaporation of the solvent gives the title
compound as an oil (0.9 g), v a (film) 3350-3450 and 1700 cm 1.
r~R~
L91~Z~
- 29
(8) cis-4-(6'-Ethoxycarbonylhex-2'Z-enyl)-5_hydro~.y~ethyl~yclo-
hex-]-ene
The acid/alcohol (7) (0.75 g) is dissolved in ethanol, 0.3 ml
o~ concentrated sulphuric acid is added and the mixture is heated
under rerlux for 18 hours. The mixture is then diluted with water
and extracted with ether. The ethereal extracts are washed with
05 water, saturated aqueous sodium bicarbonate and aqueous sodium
chloride, and then dried (MgS04). Evaporation of the solvent
gives the title compound as an oil (0.8 g),v (film) 1725 cm 1
(9) 4 6'-Ethoxycarbonylhex-2'Z-enyl)-5-formylcyclohex-1-ene
The ester/alcohol (8) (1.3 g), dicyclohexylcarbiimide (3.5 g)
DMS0 (5 ml) and dry benzene ~10 ml) are placed in a 125 ml flask
under nitrogeD. Pyridinium trifluoroacetate (0.8 g) is added in
one portion and the mixture is stirred for 18 hours. Ethyl acetate
(50 ml) is added and the reaction mixture is then filtered. The
filtrate is washed with water, saturated aqueous sodium chloride,
and dried (Na2SO4). The solvent is evaporated to give a slurry
]5 residue which is redissolved in ben~ene. Solid particles separate
fr~m the solution and the solvent is then evaporated to give the
title compound as aD oil (l . O g), v tfilm) 1715 cm , ~(CDC13)
1.61-2.06 (m) 2.15-2.28 (t, lH). 2.4Q ~t, 2H), 5.40 (m, 2H), 5.70
(s, 2H~, 9.79 (d, lH~, M 250 (as methyl ester).
(B) P paration of l~-hydroxy-2~-~6'-Carboxyhex-2'Z-enyl)-
3~-formylcyclopentane
(1) 6-(1',3'-Dioxacyclopent-2'-yl)-2-oxabicyclo 13,3,0] octane-3-one
6-Formyl-2-oxabicyclo [3,3,03 octane-3-one ~2.0 g~ is heated
at 6Q C in benzene (50 ml) with ethylene glycol (1 ml) and a trace
of toluene-p-sulphonic acid under a Dean and Stark head. When
reaction ceases, the reaction mixture is cooled and treated with
water ~20 ml) and 10% w/v aqueous NaHC03 (20 ml). The organic
phase is separated, washed with ~ater, dried and concentrated to
give the title compound in 95% yield,v a (film) 1750 cm 1.
The starting msterial is prepared by the treatment of
1,3-cyclohexadiene with dichloroacetyl chloride, followed by
dechlorination with ~inc and acetic acid of the resulting adduct
to ~ive bicyclo 14,2,0]-oct-2-en-7-one. This compound is subjected
2~L
- - 30 -
to Baeyer-Villiger oxidation to give 7-oxablcyclo l4,3,0] non-2-en-
~-one which is ~reated with thallium (III) nitrat~ under carefully
controlled oonditions to give 6-formyl-2-oxabicyclo 13,3,0]
octane-3~one having properties identical with those reported by
~5 Corey and Ravindranathan, Tetrahedron ~etters, 1971, 4753.
(2) 6-(1',3'-Dioxacyclopent-2'-yl)-3 hydroxy-2-oxabicyclo 13,3,0
octane
The lactone/acetal (1) (0.5 g) in dry toluene is cooled to
-60 C and treated under N2 dropwise from a syringe with 2 ml of a
25% ~/v ~olution of diisobu~ylaluminium hydried in toluene. The
reac~ion is quenched at -60 C after 2.5 hours by the careful
addition of methanol (1 ml). The resction mixture is then diluted
with ether (50 ml~ and is warmed to room temperature. Water
(0.5 ml~ is added and stirring ls continued for 40 minutes followed
by drying over anhydrous MgS04. Evaporation of the solvent in
vacuo gives the tltle compound as an oil (0.42 g), v a (f~lm)
15 3400 cm
(3)~ 1~-Hydroxy-2a-(6'-carboxyhex-2'Z-enyl)-3~-(1',3'-dioxa-
cyclopent-2t-yl)-cyclopentane
Dimesyl sodium in DMS0 (2.05 ml) is added dropwise to a
solution of (4-carboxy-n-butyl)-triphenylphosphonium bromide
(2.3 g3 (dried before use) in 3 ml of DMS0. To the resultant red
solution of the ylide is added dropwise a solution of the hydroxy/
20 acetal (2) (0.5 g~ in 5 ml of DMS0 and the m~xture is stirred
overnight. The reaction mixture is then dil~ted wlth water ~50 ml)
and extracted with ethyl acetate. The cooled aqueous layer is
acidified with dilute HCl to pH 4 and extracted with e~hyl aceta~eO
The or~anic extracts are washed with water, dried ~MgS04) and
2~ concentrated. The resulting erude product ~s pu~ified by chroma-
tography on Unisil using toluene-ether (1:1 v/v) as eluant to yield
the title compound as sn oil (0-4 g)~ vma ~film~ 3350-3420 cm
(4) la-Hydroxy-2~-(6'-carboxyhex-2'Z-enyl)-3~-formylcyclopentane
The hydroxylacid/acetal (3) (0.15 g) Is hydrnlysed by d~ssolving
it in 20 ml of dioxane-water mixture (1:1 v/v) and heated at 40 C
30 with 0.05M aqueous HCl for 3 hours. 100 ml of water is added and
the product extracted with ether. The solve~t ~s e~aporated and
the residue purified by silica gel chromatography, eluting with a
gradient fro~ 10% v/v ethyl acetate in toluene to pure ethyl
acetate, to give the title compound as an oil (95 mg),
35 ~(CDCl3) 4.30 (br, lH) 5.40 (m, 2H), 6.70 (br, lH), 9.60 (d, lH).
~de ~Q
,
.
