CA1180340A - Synthesis of dioxabicylo (3.2.1)octanes and oxepanes - Google Patents
Synthesis of dioxabicylo (3.2.1)octanes and oxepanesInfo
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Abstract
Synthesis of Dioxabicyclo[3.2.1]Octanes and Oxepanes ABSTRACT
The synthesis of C-4 alkyl analogs of racemic (1RS,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 (1RS,4RS,5RS)- derivative is described. The dioxabicyclo[3.2.1]octanes are useful as contragestational agents. The intermediate oxepane analogs are useful as intermediates in the preparation of the contragestational agent zoapatanol.
The synthesis of C-4 alkyl analogs of racemic (1RS,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 (1RS,4RS,5RS)- derivative is described. The dioxabicyclo[3.2.1]octanes are useful as contragestational agents. The intermediate oxepane analogs are useful as intermediates in the preparation of the contragestational agent zoapatanol.
Description
_ ! ORTH 379 ~8~
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 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 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
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 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 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 ~(~3)2 R3 ~ 0C~3 R ~ 0 ~ ~+
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.
~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
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 ~(~3)2 R3 ~ 0C~3 R ~ 0 ~ ~+
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.
~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~
~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.
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.
3~
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.
11~1qJ3~
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.
3~
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-
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~
~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.
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.
3~
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.
11~1qJ3~
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.
3~
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).
3~
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~
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-4-3~3 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)-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~
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).
3~
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 ~8~34~;D
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).
.
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.
3~
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~
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-4-3~3 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)-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~
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).
3~
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 ~8~34~;D
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).
.
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.
Claims (13)
1. The process for the preparation of compounds of the formula:
which comprises reacting a compound of the formula:
with lithium diisopropylamide followed by reaction of the intermediate with trimethylsilyl chloride to form a silyl enol ether of the formula:
reacting the enol ether with N-bromosuccinimide to form a bromide of the formula:
reacting the bromide with a peracid to form an epoxide of the formula:
reacting the epoxide with an acid to form a hemi-ketal of the formula:
reacting the hemi-ketal with a trialkylorthoformate to form a ketal of the formula:
reacting the ketal with a cyclizing agent to form an oxido oxepane of the formula:
reacting the oxido oxepane with dilute acid to give a mixture of epimeric hemi-ketals of the formula:
separating the epimers by physical means and i. reacting Compound A with a carbalkoxymethylenetriphenyl-phosphorane to form an ester of the formula:
and hydrolyzing the ester with a base; and ii. reacting compound B with a carbalkoxymethylenetriphenyl-phosphorane to form an ester of the formula:
and hydrolyzing the ester with a base, wherein R is a straight or branched chain alkyl group having 1-12 carbon atoms and R1 and R2 are lower alkyl having 1-5 carbon atoms.
which comprises reacting a compound of the formula:
with lithium diisopropylamide followed by reaction of the intermediate with trimethylsilyl chloride to form a silyl enol ether of the formula:
reacting the enol ether with N-bromosuccinimide to form a bromide of the formula:
reacting the bromide with a peracid to form an epoxide of the formula:
reacting the epoxide with an acid to form a hemi-ketal of the formula:
reacting the hemi-ketal with a trialkylorthoformate to form a ketal of the formula:
reacting the ketal with a cyclizing agent to form an oxido oxepane of the formula:
reacting the oxido oxepane with dilute acid to give a mixture of epimeric hemi-ketals of the formula:
separating the epimers by physical means and i. reacting Compound A with a carbalkoxymethylenetriphenyl-phosphorane to form an ester of the formula:
and hydrolyzing the ester with a base; and ii. reacting compound B with a carbalkoxymethylenetriphenyl-phosphorane to form an ester of the formula:
and hydrolyzing the ester with a base, wherein R is a straight or branched chain alkyl group having 1-12 carbon atoms and R1 and R2 are lower alkyl having 1-5 carbon atoms.
2. The process of claim 1 wherein the acid is hydro-chloric acid.
3. The process of claim 1 wherein the cyclizing agent is potassium hydroxide.
4. The process of claim 1 wherein the carbalkoxymethylene triphenylphosphorane is carbethoxymethylenetriphenylphosphorane.
5. The process of claim 1 wherein the base is potassium hydroxide.
6 . The process according to claim 1 wherein the dilute acid is selected from hydrochloric acid, sulfuric acid and acetic acid.
7 . The process of claim 1 wherein the peracid is m-chloroperbenzoic acid.
8 . The process of claim 1 wherein the trialkylortho-formate is trimethylorthoformate.
9 . The process for the preparation of compounds of the formula which comprises reacting a ketal of the formula:
with a cyclizing agent to form an oxido-oxepane of the formula:
reacting the oxido-oxepane with dilute acid to give a mixture of epimeric hemi-ketals of the formula:
separating the epimers by physical means and i. reacting Compound A with a carbalkoxymethylenetriphenyl-phosphorane to form an ester of the formula:
and hydrolyzing the ester with a base; and ii. reacting Compound B with a carbalkoxymethylene triphenylphosphorane to form an ester of the formula:
and hydrolyzing the ester with a base, wherein R is a straight or branched chain alkyl group having 1-12 carbon atoms and R1 and R2 are lower alkyl having 1-5 carbon atoms.
with a cyclizing agent to form an oxido-oxepane of the formula:
reacting the oxido-oxepane with dilute acid to give a mixture of epimeric hemi-ketals of the formula:
separating the epimers by physical means and i. reacting Compound A with a carbalkoxymethylenetriphenyl-phosphorane to form an ester of the formula:
and hydrolyzing the ester with a base; and ii. reacting Compound B with a carbalkoxymethylene triphenylphosphorane to form an ester of the formula:
and hydrolyzing the ester with a base, wherein R is a straight or branched chain alkyl group having 1-12 carbon atoms and R1 and R2 are lower alkyl having 1-5 carbon atoms.
10. The process of claim 9 wherein the cyclizing agent is potassium hydroxide.
11. The process of claim 9 wherein the carbalkoxymethylene triphenylphosphorane is carbethoxymethylenetriphenylphosphorane.
12. The process of claim 9 wherein the base is sodium hydroxide.
13. The process of claim 9 wherein the dilute acid is selected from hydrochloric acid, sulfuric acid and acetic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000442914A CA1180340A (en) | 1980-07-31 | 1983-12-08 | Synthesis of dioxabicylo (3.2.1)octanes and oxepanes |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/174,070 US4276216A (en) | 1980-07-31 | 1980-07-31 | Synthesis of dioxabicyclo[3.2.1]octanes and oxepanes |
| US174,070 | 1980-07-31 | ||
| US23374881A | 1981-02-12 | 1981-02-12 | |
| US233,748 | 1981-02-12 | ||
| CA000382365A CA1171422A (en) | 1980-07-31 | 1981-07-23 | Synthesis of dioxabicylo (3.2.1)octanes and oxepanes |
| CA000442914A CA1180340A (en) | 1980-07-31 | 1983-12-08 | Synthesis of dioxabicylo (3.2.1)octanes and oxepanes |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000382365A Division CA1171422A (en) | 1980-07-31 | 1981-07-23 | Synthesis of dioxabicylo (3.2.1)octanes and oxepanes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1180340A true CA1180340A (en) | 1985-01-02 |
Family
ID=27426318
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000442914A Expired CA1180340A (en) | 1980-07-31 | 1983-12-08 | Synthesis of dioxabicylo (3.2.1)octanes and oxepanes |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1180340A (en) |
-
1983
- 1983-12-08 CA CA000442914A patent/CA1180340A/en not_active Expired
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