Note: Descriptions are shown in the official language in which they were submitted.
_ ! ORTH 379
~8~
1--
Synthes s of Dioxabi~y~1O[3.2.1~0ctanes and Oxe~anes
The synthesis of optically active 4-(4,3-dimethyl-5-
hydroxy-7-nonenyl)-4-methyl-3,8-dioxabicyclo[3.2.1]-
oc~ane-l-acetic acid ~I)
J~ ~ X2COO~
from an optically active component of the zoapatle plant
is described in U.S. Patent No. 4,102,895. The present
invention relates to the C-4 alkyl analogs of racemic
(lRS,4SR,5RS)~4-(4,8-dimethyl-5-hydroxy-7-nonenyl)-4-
methyl-3,8-dioxabicyclo[3.2.1~octane-1-acetic acid and the
corresponding (lRS,4RS,5RS) derivative and to a method of
synthesizing the C-4 alkyl analogs. The novel C-4 alkyl
analogs which are the subject of this inven~ion have the
following chemical configuration.
~ ~ ~2C~
R II
wherein R is a straight or branched chain alkyl or alkenyl
group of from 1-12 carbon atoms such as ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, pentyl, hexyl, octyl, nonyl,
nonenyl, n-decyl, dimethyl decyl and the like, and the
pharmaceutically acceptable acid addition salts thereof.
The alkyl chain ~ay be substituted with a lower
alkanoyloxy group having 2-5 carbon atoms such as an
acetyloxy or propionyloxv group.
The novel dioxabicyclo[3.2.1~octanes are prepared by a
synthetic route comprised o~ several steps which are
summarized in the following schematic diagram:
ORTlH 379
~ 034~
LDA~--fSi (C.~3) 3
3 R 1~ ~3
~S
l)f'f
~¦~m-CP3A
~ ~ ~f
~ C~2Br ~ 3
~+~(~)3
~2~3r ~ ~ ~C~3
R CY3
OE
R ~3
ORT7~ :~ 7 q
3~
~H
5~
~ I '~
c~3 ~ C~13
8a 8b
~`
~0) 3P~5 C~I3 \~
~,COOH
~C~2Coo~2~5 R~
R~ 11
g \~ R~I2COO}I
c~3
~ ORT~I 379
f~
wherein R is a straight or branched chain alkyl or alkenyl
group of from 1-1~ carbon atoms, LDA is li~hium
diisopropylamide; NBS is N-bromo~uccinimide; and m-CP~A is
m-chloroperbenzoic acid.
The first step in the synthssis of ~he.bicyclic acid (II)
involves the conversion of the unsaturated ketone (1) to
the silyl enol ether (2). The conversion is carried out
by first reacting the ketone with lithium diisopropylamide
in a suitable solvent such as tetrahydrofuran, dimethoxy-
ethane and dioxane. The reaction is carried out a temper-
a~ure between -80C and ~20C. The preferred temperature
range is betwaen -70 and 0C~ The resulting enolate is
then reacted with a trialkylsilyl halide such as, for
example, trimethylsilyl chloride in the presence of a mild
base such as triethylamine or pyridine. The reaction
product ~2) is obtained by techniques known to those
skilled in the art. The silyl enol ether (2) is then
brominated with a brominating agent such as N-bromosuc-
cinimide, for example, to ~ive the bromo-ketone (3). The
reaction is carried out in a suitable solvent such as
tetrahydrofuran, dimethoxyethan~ and dioxane at a temper-
ature between -80C and 0C. The preferred reaction
temperatu~e is about -78C. Epoxidation of the bromo-
ketone (3~ with a peracid such as m-chloroperbenzoic acid,
perbenzoic acid, monoperphthalic acid, peracetic acid and
trifluoroperacetic acid in a suitable solvent such as, for
example, methylene chloride, chloroform, ether and
dichloroethane gives the epoxide (4) which is converted to
the hemi-ketal (5) upon treatment with dilute acid in a
suitable solvent. Acids which may be employed include
dilute hydrochloric acid, perchloric acid, phosphoric acid
and sulfuric acid. As the solvents acetone, butanol and
tetrahydrofuran may be employed. The hemi-ketal (5) is
then converted to the ke~al (6) by treatment with a
trialkylorthoformate such as, for example, trime~hyl-
` ORT~ 379
3~
orthoformate and triethylorthoformate and a weakly acidicalcoholic solution. Acids such as sulfuric acid, hydro-
chloric acid and phosphoric acid may be employed.
Cyclization of the ketal (6~ with an alXali metal
hydroxide or oxide such as potassium hydroxide, sodium
hydroxide, potassium tert. butoxide or sodium methoxide or
wi~h a metal hydride such as sodium hydride, in a suitable
solvent such as dimethyl sulfoxide, dimethylformamide or
tetrahydrofuran-hexamethylphosphoramide gives the bicyclic
oxido-oxepane (7).
The ketal protecting group is removed from the oxido
oxepane by reaction with dilute acid such as aqueous
hydrochloric acid, sulfuric acid or acetic acid to ~ive a
mixture of epimeric hemi-ketals (8a and 8b). The epimers
can ~e separated by physical means such as chromatography,
for example, to give the desired lRS,4RS,SSR epimer (8a)
and the lRS,4SR,5SR epimer (8b). When the series of
reactions is carried out on the unsaturated ketone (1)
having the E- configuration only the hemi-ketal having the
lRS,4RS,5SR configuration is obtained. Thé hemi-ketal
(8a) is then converted to the bicyclic ester (9) by
reaction wi~h a carbalkoxymethylene-triphenylphosphorane
such as carbethoxymethylenetriphenylphosphorane for
example. The reaction is preferably carried out at
elevated temperatures in an inert atmosphere such as
nitrogen. When the reaction is carried out at elevated
temperatures, a temperature ranging from 50 to 120C may
be empioyed. ~he preferred temperature range is 90 -
120C. The bicylic ester is then hydrolyzed to thecorresponding acid (II) by techniques known to those
skilled in the art. The hydrolysis reaction is preferably
carried out with an alkali metal or alkaline earth metal
base such as sodium hydroxide, potassium hydroxide and
calcium hydroxide in an aqueous or alcoholic aqueous
solution at a temperature between about 0C and 20C. In
ORTH 379
3~1
a similar fashion, the corresponding epimer (8b) is
converted to ~he free acid (11). The free acid (II) and
the esters are useful as contragestational agents.
The unsaturated ketone (1) which is used as the starting
material is prepared as a mixture of isomers (E:Z) from
2 heptanone by the method of Kovalev [Kovalev, B.G. et al.
Zh.OrgO ~him., 11, 1183-87 (1975)]. Alternatively, the
pure E isomer can be synthesi~ed by the method describe~
in Canadian Patent No. 1,149,403 in the name of the
present inventors, granted July 5, 1983.
- The hemi-ketal (8a3 can be converted to the 3-alkyloxy-6-
oxo-oxepane according to the following scheme:
0~ OC~ 3
~1
8 12 1
~(~3)2
R3 ~ 0C~3
R ~ 0
13
~ ~+
R ~ 0 R30
14a l~b
` OR~H 379
~8~3~
wherein R is as previously defined and R3 is an
alkanoyl group having 2-5 carbon atoms.
In the first step in the preparation of the oxepane analog
the hemi-ketal is first treated with a mild base such as
potassium acetate in a suitable solvent such as methanol
and then reacted with methoxyamine hydrochloride to form
the alcohol (12). The alcohol is then converted to the
ester (13) by acylation with an acylating agent such as
acetic anhydride, propionic anhydride and butyric
anhydride in the presence of a base such as pyridine.
Reaction of the ester derivative with dilu~e acid, such as
for example hydrochloric acid, gives the 3-alkyloxy-6-
oxooxepane analog (14a and 14b) in the form of C-3
isomers. The C-3 isomers can be separated by the
chromatographic method described in copending Canadian
application Serial No. 374,092 of Hajos et al, March 27,
1981. The oxepane analogs are useful as intermediates
in the preparation of zoapatanol and its analogs.
The invention is further described in the following
examples of more preferred embodiments thereof which are
presented for the purpose of illustration and not by way
of limitins the scope of the invention.
ORTH 379
~L~8~3~
Example 1
6-Methyl-2-trimethylsiloxy-undec-1,5-diene (2)
Triphenylmethane indicator (50 mg) is added to
isopropylamine ~9.15 ml, O.Q65 moles) in anhydrous
tetrahydrofuran (80 ml). The solution is cooled to 0C
and a solution of n~butyllithium (2.34 m) in hexane (28.5
ml, 0.065 moles) i~ added carefully while stirring at 0 -
5C. The mixture is kept at 0C for 20 minutes and then
cooled to -70C. 6-Methyl-2-oxo-;-undecene (9.1 g, 0.05
moles, 60:40 E:Z mixture) is dissolved in anhydrous
tetrahydrofuran ~9.~ ml.~ and added to the above solution
of lithium diisopropylamide in tetrahydrofuran while
stirring at -70C within 15 minutes (-70 - 65C). To th~
resultant enolate solution is added immediately at -70C
while stirring a freshly prepared and centrifuged solu~ion
o trimethylsilyl chloride (15 ml, ~ .12 moies) and
triethylamine (4.0 ml, 0.029 moles) i~ tetrahydrofuran (25
ml). The solution is Xept at 70C for 1.5 hours. Solid
sodium bicarbonate (10 9) is added. The solution is then
allowed to come to 10C, and a saturated aqueous sodium
bicarbonate solution (60 ml) is added. The solution is
then allowed to come to room temperature, the
tetrahydrofuran layer is separated, and the aqueous layer
is re-extracted wi~h etherO The combined orsanic extract
is washed with satur2ted aqueous chloride solution, dried
with sodium sulfate, filtered, and evaporated in vacuo.
Drying in high vacuo gives crude
6-methyl~2-trimethylsiloxy-undec-1,5-diene (13.75 g).
IR (neat): 1640-1660 cm~l (enol silyl ether);
NMR (CDC13)~j 5.15 ~m, lH, -E~C=CH2), 4.07 (s, 2H,
-C=CH2 ),
1.70, 1.62 [2 x s, 3H total, (40/60 Z:E), H3-C=CH-],
ORT~ 379
3~
0,90 [dist'd t, 3H, CH3-(C~2)4-]
GC/MS = two fractions (~J40/60 ratio), showing iden~ical
mass spectra. M+ 252, M-CH3 = 239, M-nC5H11 ~ 183.
When in the above procedure 6-methyl-2-oxo-5 nonene and
6-methyl-2-oxo-5-decene are employed in place of
6-methyl-2-oxo-5-undecene, the corresponding
6-methyl-2-trimethylsiloxy-non-1,5-diene and
6-methyl-2-trimethylsiloxy-dec-1,5-diene are obtained.
~ xample 2
l-Bromo-6-methyl-2--oxo-undec-5-ene (3)
Anhydrous solid sodium bicarbonate t5.0 g) i5 added to
crude 6-methyl-2-trimethylsiloxy-undec-1,5-diene (13.75 g,
max. 0.05 moles) dissolved in tetrahydrofuran (150 ml).
The mixture is cooled to -78C under argon and stirred.
Solid N-bromosuccinimide (9.1 g, ~0.05 moles) is added
within 5 minutes with the exclusion of light and moisture.
The reaction mixture is stirred a~ -78C for 2 hours and
then cannulated into a stirred mixture of an ice cold 10
aqueous sodium bicarbonate solution and ether. The
organic 1 yer is separated, washed with 10% aqueous sodium
- bicarbonate solution then with saturated aqueous sodium
chloride. The solution is dried with sodium sulfate,
filtered, and evaporated in vacuo. Drying in high vacuo
gives l-bromo-6-methyl-2-oxo-undec-5-ene (13.05 g).
IR (neat): 1710 cm~l ~CO of ketone):
NMR ~CDC13)~ 5.07 (m, 1~, HC-CH2-), 3.90 (s, 2H,
-CO-C~2-Br), 1~72, ~.67 L2Xs, 3H total, (40/60 Z:E),
C=CH-l, 0.8g ~dist'd t, 3H, CH3(CH2)4-].
O~TH 379
3~
--10--
~C/MS = two frac~ions ~J40/60 ra~io), showing identical
mass spectra M+ 260, M-Br a 181, BP 55.
When in the above procedure 6-methyl-2-trime~hylsiloxy-
octa-1,5-diene and 6-methyl-2-trimethylsiloxyhept-1,5-
diene are employed in place of 5-methyl-2-trimethylsiloxy-
undec-1,5-diene, the corresponding 1-bromo-6-methyl-2~oxo-
oct-5-ene and l~bromo-6-methyl-2-oxo-hept-5-ene are obtained.
Example 3
1-8romo-5,6-epoxy-6-me~hyl-undecan-2-one (4)
l-Bromo-6-methyl-2-oxo-undec-5-ene (10.4 g, 0.04 mole) i~
dissolved in methylene chloride tlOO ml). ~he solution is
cooled ~o 0C and m-chloroperbenzoic acid (7.9 g, 0.04
mole of 85% pure substance) in methylene chloride (180 ml)
is added while stirring at +5 - 10C within 25 minutes.
After stirring for 3 hours at 0C, the reaction mixture is
stored at +5C for 16 hours. It is then filtered through
a sintered glass funnel, and the filtrate is washed first
with saturated aqueous sodium bicarbonate, and then 5
times with sodium sulfite ~60 g in 500 ml of H20).
~he solution is washed with saturated aqueous sodium
chloride, dried with sodium sulfate, filtered, and
evaporated in vacuo to give 1-bromo-5,6-epoxy-6-methyl-
undecan~2-one (10.63 g).
IR (neat): 1724 cm~l (CO of ketone);
NMR (CDC13)~ 3.90 (s, 2H, -CO-CH2-Br), 2.78 (q, 2H,
-CO-CH2-CH2~), 2.7 (m, lH, C5-H), 0.92 [dist'd t,
3H, CH3(c~2)4 ]
GC/MS = two fractions (~40/60 ratio). M+ ~76 not visible,
M-CsHll = 20C~ 3P = 83.
ORTH 379
3~
When in the above procedure l-bromo-6-methyl-2-oxo oct-5-
ene and l-bromo-6-methyl-2-oxo-non-5~ene are employed in
place of l-bromo-6-methyl-2-oxG-undec-5-ene, the
corresponding 1-bromo-5,6-epoxy-6~methyl octan-2-one and
1-bromo-6-methyl-nonan-2-one are obtained.
Example 4
2-[2-~romomethyl-2-hydxoxy-tetrah~drofuran-5'-yl]-
he~an-2~ol (5)
Aqueous hydrochloric acid (0.2 N, 1.5 ml) is added to
l-bromo-5,6-epoxy-6-methyl-undecan-2-one (3.26 g, 11.8
mmole) in acetone (9.0 ml) while stirring at 0C. After 5
minutes of stirring, the solution is kept at 0C for 5
days. The acetone is evaporated in vacuo, the re~idue is
dissolved in methylene chloride, and washed with saturated
sodium bicarbonate-water, then with saturated sodium
chloride~water, dried with sodium sul~ate, filtered, and
evaporated in vacuo to sive 2-[2-bromomethyl-2-hydroxy-
tetrahydrofuran-5'-yl]-heptan-2-ol (3.46 g of crude
hemiketal).
IR (neat): 3400 (OH), 900-1150 cm~l (ether bands);
NMR (CDC13)~ 4.0 (m, lH, H-~-O-), 3.53 (s, 2H, -CH2-Br).
GC/MS = two fractions ( ~40/60 ratio), showing identical
mass spectra. M~ 294 not visible, [M-H2O-CsHll]=
205/7, BP 83.
When in the above procedure l-bromo-5,6-epoxy-6-methyl-
dodecan-2-one and 1-bromo-5,6-epoxy-6-methyl-tridecan-
2-one are employed in place of 1-bromo-5,6-epoxy-6-methyl-
undecan-2 one, the corresponding 2-[2-bromomethyl-2-
hydroxy-tetrahydrofuran-5'-yll-octan-2-ol and 2-[2-bromo-
methyl-2-hydroxy-tetrahydrofuran-5'-yl]-nonan-2-ol are
obtained.
ORTH 379
3~
-12-
Example 5
2--[2-Bro~omethyl-2-methoxy-tetrahydrofuran-5l-xl-]
S To 2-[2~bromomethyl-2-hydroxy-tetrahydrofuran-5'-yl]-
heptan-2-ol [3.46 g, 11.78 mmole) in trimethylorthoformate
(4.~ ml,~37 mmole), methanolic sulfuric acid t2.0 ml of a
solution of 0.27 ml of conc. sulfuric acid and 99.7 ml of
methanol) is added while stirring at 0C. After 15
minutes of stirring, the solution is stored at 0C for 48
hours and is then added dropwise to saturated aqueous
sodium bicarbona~e and methylene chloride, while stirring
in the cold. Tbe methylene chloride extract is washed
with saturated aqueous sodium chloride, dried with sodium
sulfate, filtered, and evaporated in vacuo to give crude
cis and trans 2-[2-bromomethyl-2-methoxy-tetrahydrofuran-
5'-yl]-heptan~2-ol (3.17 g~.
NMR (CDC13)~ 3.93 (m, lH, H-C-O-), 3.53 (s, 70% of 2H,
-CH2~Br of cis), 3052 (q, 30% of 2H, -CH2Br of trans), 3.3
(s, 30% of 3H, -OC~3), 3.23 ts, 70% of 3H, -OCH3), ~dist'd t,
3H, CH3(CH2)4 ]
When in the above procedure 2-[2-bromomethyl-2-hydroxy-
tetrahydrofuran-5'-yl]-tetradecan-2-ol and 2-[2-bromQ-
methyl-2-hydroxy-tetrahydrofuran-5'-yl]pen~adecan-2-ol are
employed in place of 2-[2-bromomethyl-2-hydroxy-tetra-
hydrofuran-5'-yl]-heptan-2-ol, the corresponding 2-[2-bro-
momethyl-2-methoxy-tetrahydrofuran-S'-yl]-tetradecan-2-ol
and 2-[2-bromomethyl-2-methoxy-tetrahydrofuran-5l-yl]-
pentadecan-2-ol are obtained.
ORTH 379
11~1qJ3~
-13-
Example 6
lRS,4RS,5SR-l-Methoxy-4-methyl-4-~-p~nt~1-3,8-dioxabicyclo
~3.2.1~octane and lRS,4SR,SSR-l-methoxy-4-methyl-4-~-
ent 1 3,8 dioxabicvclo[3~2.1]octane (7)
~ _ _ _
KOH pellets (7.1 ~, 0.13 mole) are added to the mixture of
cis and trans 2-[2-bromomethyl 2-methoxy tetrahydrofuran-
5'-yl]-heptan-2-ol (3.02 g, 9.8 mmole) in
dimethylsulfoxide (25 ml) within 5 minutes, while stirring
at ~21C under nitrogen. It is then heated to +28C, and
the stirring is continued for 10 days at this
temperature~
The mixture is then cooled to room temperature; methylene
chloride ~100 ml) is added and the mixture is filtered
through"Celite *on a sintered glass funnel. The filtrate
is washed with water, then with saturated aqueous sodium
chloride, dried with sodium sulfate, filtered, and
evaporated in vacuo at ~25~C, then at +45C at 0.5 mm for
__
16 hours to give an oily residue (2.0; g). The residue is
chromatographed on"SilicAR CC-7"**(200 g). Elution with
chloroform affords the bicyclic ketals, 1RS,4RS,5SR-l-
methoxy-4-methyl 4-n-pentyl-3,8-dioxabicyclo[3.2.1]octane
and lRS,4SR,5SR-l-methoxy-4-methyl-4-n-pentyl-3,8-
dioxabicyclo{3.2.1]octane (959 mg) as the faster moving
component.
IR (neat): 1020-1130 cm~l (ether bands);
NMR (CDC13)~ 3.93 (m, lH, H-C-O), 3.73 (m, 2H, OCH2-C-O),
3.43 (s, 3~, OCH2), 1.97 (m, 4H, -C~2C~2-), 1.07 (s,3H,
CH3-C-O-), 0.95 [dist'd t, 3H, CH~(CH2)4-].
The slower component of the column chromatography is the
trans bromo-hydroxy ketal, 2-[2-bromomet~yl-2-methoxy-
tetrahydrofuran-5'-yl]-heptan-2-ol (8Ç0 mg~.
* Trademark for diatomaceous earth products used as
filtering ag~nts.
** Trademark for silica gel.
ORTH 379
3~
-14-
IR ~neat): 3400 (OH~,900~1154 cm~l ether bands);
NMR (CDC13)~ 4~0 (m, lH, ~-C-O), 3.5 (~, 2H, -CH2 Br),
3~33 (s, 3H, OC~3)1 0.90 [dist'd t, 3H, CH35CH2)4-].
GC/MS M+ 308 not visible, M-OC~3 = 277, BP 83.
When in the above procedure 2-[2-bromomethyl-2-methoxy-
tetrahydrofuran-5' yl]~hexan-2-ol and 2-[2-bromomethyl-2-
methoxy-t~trahydrofuran-5'-yl]-butan-2-ol are employed in
place of 2-[2-bromomethyl-2-methoxy-tetrahydrofuran~5'-
yl]-heptan-2-ol, the corresponding lRS,4RS,5SR and
lRS,4SR,5SR-l-methoxy-4-butyl-4-methyl-3,8-dioxabicyclo-
[3.2.1]octane and lRS,4RS,5SR and lRS,4SR,5SR-l-methoxy-
~-ethyl-4-methyl-3,8-dioxabicyclo-[3.2.1]octane are
obtained.
Example 7
lRS,4RS,5SR-l-Hydroxy-4-methyl-4-~-pentyl-~,8-dioxabicyclo
[3O2.1]octane and lRS,4SR,SSR-l-hydroxy-4-methyl-4-~
penty~-3,8-dioxabicyclo[3.2.1]octane (8)
2N Aqueous hydrochloric acid (2 ml) is added to the
bicyclic methoxy ketals, lRS,4RS,5SR-1 methoxy-4-methyl-
4-n-pentyl-3,8-dioxabicyclo[3.2.1]octane and lRS,4SR,5SR-
1-methoxy-4-methyl-4-n-pentyl-3,8-dioxabicyclo[3.2.1]-
octane (315 mg, 1.38 mmole) in acetone (2 ml) and the
mixture is stirred at +20C for 48 hours. The acetone is
eva~orated in vacuo, and the residue is dissolved in
-
methylene chloride, washed with saturated aqueous sodium
chloride, dried with sodium sulfate, filtered and
evaporated in vacuo to give lRS,4RS,5SR-l-hydroxy-4-
methyl-4-n-pentyl- 3,8-dioxabicyclo~3.2.1]octane and
lRS,4SR,5SR-l-hydroxy-4-methyl-4-n-pentyl-3,8-dioxabicyclo-
[3.2.1]octane ~259.9 mg; 88%, 60/40 mixture of C4
epimers).
ORTH 379
3~
-15-
IR (CC14) 3600 and 3200-3500 (OH), 1720 (CO), 1050-1260 cm~
(ether bands).
NMR (CDC13)6 3.93 (m, lH, H-C-O), 3~5 (2xq, -O-CH2-C-OH),
1.33 (s, 60% of 3H, CH3-C-O), 1.03 (s, 40% of 3H, C~3-C-O),
0.9 [dist'd t, 3H, CH3(CH2)~-].
The bicyclic hemi-ketal (4.1 g) is chromatographed on
SilicAR CC-7 (196 g) usin~ 5~ ether-methylene chloride as
the eluent. The earlier eluting ~ractions give the
hemi-ketal lRS,4SR,5SR-l-hydroxy-4-methyl-4-n-pentyl-3,8-
dioxabicyclo[3.2.1]octane (353 mg~, followed by a 1:1
mixture of epimers (1.57 g) and then the lRS,4RS,SSR-l-
hydroxy-4-methyl-4-n-pentyl-3,8-dioxabicyclo[3.2.1]octane
lS (1.2 9) in the later eluting fraction~.
lRS,4RS,5SR - hemi-ketal, NMR (CDC13)~ 1.33 (s, 3H, CH3C-O),
3.5 (q, OCH2C-OH).
2Q lRS,4SR,5SR - hemi~ketal, NMR (CDC13)~ 1.03 (s, 3H, CH3-C-O),
3.5 (q, QCH2C-OH).
When in the above procedure 1RS,4RS,55R-l-methoxy-4-methyl-
4-n-propyl-3,8-dioxabicyclo[3.2.1]octane and lRS,4SR,5SR-
1-methoxy-4-methyl-4-n-propyl-3,8-dioxabicyclo[3.2.1]oc~ane
are employed in place of 1RS,4RS,5SR-l-methoxy-4-methyl-4-
n-pentyl-3,8-dioxabicyclo[3.2.1]octane and 1RS,4SR,5SR-l-
methoxy-4-methyl-4-n-pentyl-3,8-dioxabicyclo[3.2.1]octane,
the corresponding lRS,4RS,5SR-l-hydroxy-4-methyl-4-n-
propyl-3,8-dioxabicyclo[3.2.1]oc~ane and lRS,4SR,5SR-l-
hydroxy-4-methyl-4-n-propyl-3,8-dioxabicyclo[3.2.1]octane
are obtained.
-- ORT~ 379
3~
-16-
Exam~le 8
..
lRS,4SR!SRS-4-Methyl-4-n-pe~yl-3,8-dioxabicyclo[3.2.13-
octane-l-acetlc acid, ethyl ester (9)
A mixture of lRS,4RS/5SR-l-hydroxy-4-methyl-4-n-pentyl-3,8-
dioxabicyclo[3.~.l]octane (647 mg, 3.02 mmole) and
~carbethoxymethylene)triphenylphosphorane (2.10 g, 6.02
mmole) i~ heated to 90C for 3 days under nitrogen. After
adding 50 ml of petroleum ether, the resulting suspension
is refluxed for 30 minutes, and Shen filtered. The
petroleum ether is evaporated ln vacuo, and the crude
residue (750 mg~ is chromatographed on"SilicAR CC-7"
(40 g). The column is eluted with 10~ ethyl ether in
methylene chloride to give lRS,45R,5RS-4-methyl-4-n-
pentyl-3,8-dioxabicyclol3.2.1]octane-1-acetic acid, ethyl
ester (400 mg, 46%) as a light yellow oil.
When in the above procedure lRS,4RS,5SR-l-hydroxy-4-
methyl-4-n-propyl-3,8-dioxabicyclo[3.2.1]oc~ane and
lRS,4RS,5SR-4-ethyl-1-hydroxy-4-me~hyl-3,8-dioxabicyclo-
[3.2.1]octane are employed in place of lRS,4RS~5SR-l-
hydroxy-4-me~hyl-4-n-pentyl-3,8-dioxabicyclo[3.2.1~octane,
the corresponding lRS,4SR,5RS-l-hydroxy-4-methyl-4-n-
propyl-3,8-dioxabicyclo[3.2.1]octane-1-acetic acid, ethyl
ester and lRS,4SR,5RS-4-ethyl-1-hydroxy-4-methyl-3,8-
dioxabicyclo[3.2.1]octane-1-acetic acid, ethyl ester are
obtained.
Example 9
lRS,4RS,5RS-4-Methyl-4-g-pentyl-3,8-dioxabicyclo[3.2.1]
octane-l-acetic acid, ethyl ester (10~
When in the above procedure lRS,4SR,5SR-l-hydroxy-4-
methyl-4-n-pentyl-3,8-dioxabicyclo~3.2.1]octane (350 mg)
and (carbethoxymethylene)triphenylphosphorane (1.8 g) is
refluxed in xylene (10 ml) for two days, lRS,4RS,5RS-4-
ORTH 379
3~3
ol7--
methyl-4-n-pentyl-3,3 dioxabicyclo[3.2.1]octane-1-acetic
acid ethyl ester (470 mg, 96%) is obtained as a light
yellow Oiln
When in the above procedure lRS,4SR,5SR-l-hydroxy-4-
methyl-4-n-propyl-3,8-dioxabicyclo[3.2.1]octane and
lRS,4SR,5SR-4-ethyl-1-hydroxy-4-methyl-3,8-dioxabicyclo-
[3.2.1]octane are employed in place of lRS,4SR,5$R-l-
hydroxy-4-methyl-4-n-pentyl-3,8-dioxabicyclo[3.2.1]octane,
the corresponding lRS,4RS,5RS-1 hydroxy-4~methyl-4-n-
propyl-3,8-dioxabicyclo[3.2.1]octane-1-acetic acid, ethyl
ester and lRS,4RS,5RS-4-ethyl-1-hydroxy-4-methyl-3,8-
dioxabicyclo[3.~,1]octane-1-acetic acid, ethyl ester are
obtained.
, 15
Example 10
lRS,4SR,5RS-4-Methyl-4-~-pentyl-3,8 dioxabicyclol3.2.1]-
octane-l-acetic acid (II)
2N 50dium hydroxide in water (5 ml) is added to
lRS,4SR,5RS-4-methyl-4-n-pen~yl-3,8-dioxabicyclo[3.2.1~-
octane-l-acetic acid, ethyl ester (860 mg, 3.0 mmole) in
methanol (5 ml) while stirring at 0C wi~hin 2 minutes.
The mixture is allowed to come to 20C and stirring is
continued for 3 days under nitrogen. The solvent is
evaporated in vacuo, and the residue is extracted with
methylene chloride. The methylene chloride solution is
extracted with water and then with sodium chloride-water.
The basic, aqueous solution is carefully acidified with 2N
hydrochloric-water (5.0 ml). The cloudy solution is
extracted with methylene chloride, and the extract is
washed with water and with sodium chloride-water, dried
with sodium sulfate and filtered through "Celite" on a
sintered glass funnel to give lRS,4SX,5RS-4-methyl-4-n-
pentyl-3,8-dioxabicyclo[3.2.1]octane-1wacçtic acid (762.7
mg)-
ORTH 379
-18-
IR (CHC13) 3100-3600, 2400-2600 (OH), 1750 and 1715
(CO of acid),
NMR (CDC13)~ 3.88 (t, lH, -O-CH-CH2-), 3.60 (q, 2H,
-O-CH2-C-O), 2.63 (brs, 2H, -C~2-CO2H), 1.~2-2.08
(m, 4~r -C~2-C~2-)~ 1.33 (s~ 3H, CH3-C-O-), 0.88 [dist'd
t~ 3H~ CH3(CH2)4-]-
M't 3213~ M-CH3= 313~ M--H20 = 310~ CsHll =
0 257 ~ M--TMS--OH = 23B; EIP ~ 73 .
When in the above procedure 1RS,4SR,5RS-4-methyl~4-propyl-
3,8-dioxabicyclo[3.2.1]octane l-acetic acid, e~hyl ester
and lRS,4SR,5RS-4-n-hexyl-4-methyl-3,8-dioxabicyclo-
[3.2.1]octane-1 acetic acid, ethyl ester are employed in
place of lRS,4SR,5RS-4-methyl-4-n-pentyl-3,8-dioxabicyclo-
[3.2~1]oc~ane-1-acetic acid, ethyl ester, the
corresponding lRS,4SR,5RS-4-methyl-4-propyl 3,8-
dioxabicyclo[3.2.1]octane-1-acetic acid and lRS,4SR,5RS-
4-n-hexyl-4-methyl-3,8-dioxabi~yclo[3.2.1]octane-1-acetic
acid are ob~ained.
Example 11
lRS,4RS,5RS 4-methyl-4-_-pentyl-3_,8-dioxabicyclo[3.2.1]
octane l-acetic acid (11)
Following the procedure of Example 9, to lRS,4RS,SRS-4-
methyl-4-n-pentyl-3,8-dioxabicyclo[3.2.1]octane-1-acetic
acid, ethyl ester (470 mg, 1.65 mm) in methanol (5 ml) is
added while stirring at 0C under nitrogen 2N NaOH-H2O
(5 ml). The mixture is then stirrad at ~20C for three
days under nitrogen. The solven~ is evaporated in vacuo,
~nd the residue ex~racted with methylene chloride. The
basic, aqueous solution is carefully acidified wi~h 2N
HCl-H2O, extracted with methylene chloride, washed
I ORT~ 379
~L8~3~
--19--
with water and with NaCl H2O, dried with Na2SO4,
filtered, and evaporated to give 1RS,4RS,SRS-4-methyl-
4 n-pentyl-3,8-dioxabicyclo[3.2.1]oc~ane-1-acetic acid
(210 mg, 50.0%). IR (neat) 3100-3600, 2600-2900 (OH),
1748 and 1715 cm-l (CO of acid). NMR ( CDC13)~ :
3.90 tt, 1~, -O-CH-C~2), 3.56 (q, 2H, -O-CH2-C-O),
2.63 (s, -CH2-CO2H), 1.03 (s, 3H, CH3-CO-),
0.9 [distd. t, 3H, CH3(CH2)4-]. GC/MS of ~MS
derivative; M+ - 328; ~P - 73.
Example 12
2RS,3SR~ and 2RS,3RS-3-Hydroxy-6-methoxyimino-2
methyl-2-a-pentyl-oxepane (12)
Anhydrous potassium acetate (68.6 mg, 0.7 m~) is added to
a mixture of 1RS,4RS,5SR and 1~S,4SR,5SR-l-hydroxy-4-
methyl-4-n-pentyl-3,8-dioxabicyclo[3.2.1]octane (106.Q mg,
0.49 mM) in methanol (1.0 ml) while stirring at +21C.
Methoxyamine hydrochloride (64.0 mg, 0.65 mM) is added to
this solution and stirring is continued for four days
under nitrogen. The methanol is evaporated in vacuo and
the residue dissolved in methylene chloride. The solution
is wsshed with water, dried with Na2SO4, fil~ered
and evaporated in vacuo to give 2RS, 3SR- snd
2RS,3RS-3-hydroxy-6-methoxyimino-2-methyl-2-n-pentyl-
oxepane (109.1 mg, 91.6%) NMR (CDC13)~: 3.80, 3.77
(2xs, 3H total, 40/60 =N-OCH3), 3.57 (m, lH, -CHOH);
IR (neat) 2975 (OH), 1630 (=NOCH3), 1150 and 1100
cm~l (ether CO). GC/MS - two fractions (40/60 ratio.
M+ 243 not visible, M-CH2CBOH = 199, BP 128).
ORTH 379
3~
--20--
Example _13
2RS,35R- and 2RS,3RS-3-acetoxy-6-methox~mino-2-m~thyl-
2-~-pentyl-oxepane (13)
A mixture of pyridine (0.6 ml) and acetic anhydride ~0.3
ml) is added to 2RS,3SR- and 2RS,3R~-3-hydroxy 6-
methoxyimino-~-methyl-2-n-pentyl-oxepane (53.2 mg, 0.2 mM)
at 21C. After stirring under nitrogen at 21C for
sixteen hours the system is evaporated in vacuo. The
residue is dissolved in methylene chloride, washed with
10 ~ saturated NaCl/H2O containing a few drops of 2N HCl
(pH 2.0). It is then washed with NaCl/H,O free of
acid, dried with Na2SO4, filtered, and evaporated
in vacuo to give 2RS,3SR- and 2RS-3RS-3-acetoxy-
6-methoxyimino-2-methyl-2-n-pentyl~oxepane t53.3 mg,
93.5%). IR (neat): 1750 (CO of acetate), 1630
(-C=NOCH3), 1250 (acetate), 1150, 11~0 and 1050
cm~l ~ether bands). NMR (CDC13)~ 4.82 ~m, 0.6 H,
ax H of -CHOAc), 4.47 (m,-0.4 H, eq H of -CHOAc), 3.8~ ,
3.83 (2xs, 3H, ~NOCH3), 2.13, 2.10 (2xs, 3H,
-O-CO~CH3).
Example 14
2RS,3SR- and 2RS,3RS-3-Acetoxy-2-methyl-2-~-pentyl-oxepa_
6-one t60/40 isomer ratio) (14a and 14b)
The acetoxy oxime-ether (53.0 mg, 0.19 mm) obtained in
Example 13 above in acetone (7.6 ml) and 2N aqueous
hydrochloric acid (0.4 ml) is stirred and refluxed under
nitrogen for three hours. The mixture is evaporated
ln vacuo and the residue is dissolved in CH2C12.
~he solution is washed with saturated NaCl/H2O
containing a few drops of NaHCO3/H2O to make it
basic, then with NaCl/H2O, dried with Na2SO4,
filtered, and evaporated in vacuo to give 43.8 mg (90~) of
a mixture. The mixture is dissolved in 0.5 ml of
methylene chloride and applied to one 20x20x0.1 cm silica
ORTH 379
~8~34~;D
-21-
gel plate with fluorescen~ indicator (Analab) using 10
ether in methylene chloride developi~g mixture to give
25.4 mg ~73%~ of the keto acetate in the form of the C-3
isomers, as indicated by nmr spectroscopy. NMR
S (CDC13)~;: 4.9 (m, lE~, -CE~OAc), 4.08 (s, 2H,
-O-CH2-CO-), 2.1, 2.07 (2xs, 3H, -OCOCH3), 1.25,
1.17 (2xs, 3~1, CH3~ ), 0.90 [distd. t, 3}1,
C113 ( CH 2 ~ 4 ] -
Example 15
(2RS,35R)-3-~ydroxy~6(E,Z)-methoxy-Lmino-2-methyl-2-(5-
acetoxy-4,8-dimethyl-&-nonen-1-yl)oxeF.ane
Potassium a~etate ~182 mg, 1.~6 mm) is added to lRS,4SR,
15 5 _-4-(5-acetoxy-4,8 dimethyl-~-nonenyl)-1-hydroxy-4-
methyl-3,8-dioxabicyclo[3.2.1]octane (460 mg, 1.30 mm)
while stirring at room temperature. After stirring for
10 minutes at room temperature, m~thoxyamine hydro-
chloride (156 mg, 1.87 mm) is added and stirring is con-
tinued for 4 days at room temperature under nitrogen.
~he methanol is evaporated in vacuo and the residue is
dis olved in methylene dichloride. The solution is washe~
with water, NaCl-H2O, drieæ (~a~SO4), filtered, an~
evaporated ln vacuo to give (2RS,35R)-3-hydroxy-6(E,Z)-
25 methoxy-imino-2-methyl-2-~5 acetoxy-4,"~dimethyl-8-nonen-
l-yl)oxepane (459.7 mg, 92.0%) a light yellow oil. T~C
(ether) R~=0.57 (minor spot, Z-oxime ether)-, 0.43 (major
s~ot, E-oxime ether). ~MR (CDC13)~ : 4.&7 (m, lH,
-C~-OAc), 4.70 (m, 2H, CH2=C~-), 4.38 (s, 70% of 2H,
30 -O-CH2- of E-isomer), 4.12 (s, 30% of 2H, -O-CH2- of
Z-isomer), 3.82 (s, 30% of 3~, =NOCH3, Z-isome~), 3.78
(s, 70% of 3H, =NOCH3, E-isomer), 3.53 (m, lH, -CH-OH),
2.03 (s, 3H, OCOCH3), 1.73 (br.s, 3H, CH2= C-CH3), 1.13
(s, 3H, CH3-C), 0.92 ~d, 3H, CH3-CH~. IR (neat) 3300-
35 3450 (OH), 2980 (C=C), 1740 and 1730 (CO), 1660 (C=C),
1640 (C=N), 1~50 ~OAc), 1060 ~C-O), 900cm ~C=C).
ORTH 379
.
-22
Exam~le 16
(2RS,3S~) _-Acetoxy-6IE~z)-methoxy-imlno-2-methyl~2-(5
A mixture of pyridine (3 ml) and acetic anhydride (1.5 ml)
is added to (2RS,3SR)-3-hydroxy-6~,Z)-methoxy-imino-2-
methyl-2-(5-acetoxy-4,S-dimethyl-~-nonen-l-yl)oxep~ne (374
mg, 0.98 mm) with stirring. After stirring for 16 hours at
room temperature under nitrogen, the solvent is evaporated
at +40C and 0.3 mm. The residue is dissolved in CH2C12,
washed with saturated N~Cl/H20 containing a few drops of 2N
~Cl (pH 2.0). The residue is then washed with NaCl/H2O free
of acid, dried (Na25O4), fil ered, and evaporatPd in vacuo
to give ~he diacetate (408.3 mg). The ~ample was charcoaled
with NUCHAR*in CH2C12 to give (2~S,3SR)-3-acetoxy-6(E,Z)-
methoxy-Lmino-2-methyl-2-(5-acetoxy-4,8-dimethyl-&-nonen-1-
yl)oxepane (368 mg, 88.7%), a light yellow oil. TLC on 0.25
mm silica gel. MN with 10% ether in CH2C12 showe~. Rf=0.57
~30%, Z-isomer) and R~=0.39 ~70%, E-isomer). IR (neat)
1740, 1650, 1630, 1450, 1370, 1235, 1100, 1050, 1020 and 890
cm 1 N~R (CDC13)~: 4.93 (m, 2H, 2x -CHOCOCH3), 4.67
(br.s, 2H, CH2=C-), 4.38 (m, 70% of 2H, -O-CH2-), 4.13 (m,
30% of 2H, -O-CH2-), 3.82 (s, 30% of 3H, =NOCH3), 3.78 (s,
70% of 3H, =NOCH3), 2.03 (s, 6H, 2x OCOCH3), 1.72 (br.s, 3H,
CH=C-CH3), 1.15 (s, 3H, CH3-C O).
The ~tarting material is prepared according to the proce~ure
described i~ ~.S~ Patent No. 4,237, 055. The conversion of
the oxepane analogs to zoapatanol is described in co-pending
Canadian application Serial No. 374,092 of Hajos et al,
filed on March 27, 1981.
* Trademark for activated charcoal.
