CA1179358A - Total synthesis of the utero-evacuant substance d,l- zoapatanol - Google Patents
Total synthesis of the utero-evacuant substance d,l- zoapatanolInfo
- Publication number
- CA1179358A CA1179358A CA000401602A CA401602A CA1179358A CA 1179358 A CA1179358 A CA 1179358A CA 000401602 A CA000401602 A CA 000401602A CA 401602 A CA401602 A CA 401602A CA 1179358 A CA1179358 A CA 1179358A
- Authority
- CA
- Canada
- Prior art keywords
- dimethyl
- methyl
- give
- mixture
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Abstract
ABSTRACT
TOTAL SYNTHESIS OF THE UTERO-EVACUANT
SUBSTANCE D,L-ZOAPATANOL
A method of synthesizing 2S*, 3R*-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol, one of the active ingredients in the zoapatle plant, is described. The natural product is useful as a utero-evacuant agent.
TOTAL SYNTHESIS OF THE UTERO-EVACUANT
SUBSTANCE D,L-ZOAPATANOL
A method of synthesizing 2S*, 3R*-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol, one of the active ingredients in the zoapatle plant, is described. The natural product is useful as a utero-evacuant agent.
Description
~7~35~3 TOTAL SYNTHESIS OF THE UTERO-EVACUANT
SUBSTANCE D,L-ZOAPATANOL
The zoapatle plant is a bush about 2 meters high that grows wild in Mexico. Botanically, it is known as Montanoa tomentosa according to Cervantes, Fam.
Compositae, Tribe Heliantheae; another variety o the . .
species is Montanoa florlbunda. The plant is described in great detail in Las Plantas ~edicinales de Mexico, Third Edition, Ediciones Botas ~1944).
The plant has be4n used for centuries in the form of a "tea" or other crude aqueous preparations pr.imarily as a labor inducer or menses inducer for humans. Its use as a utero-evacuant has been documented in the literature.
In U.S. Patent No. 4,086,358, a method is described ~or the isolation of the active ingredients in the zoapatle plant. One of the active ingredients is 2S, 3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol. This compound, referred to as zoapatanol, has the following structural formula:
~0,~
~~0 c~3 The present invention relates to a method for the total synthesis of 2S*, 3R*-6~-(2~hydroxyethy].idene)-[*The asterisk indicates the xacemic nature of the compoundand refers to the relative configuration of the ~ ral centers.]
' 7~35~3 -
SUBSTANCE D,L-ZOAPATANOL
The zoapatle plant is a bush about 2 meters high that grows wild in Mexico. Botanically, it is known as Montanoa tomentosa according to Cervantes, Fam.
Compositae, Tribe Heliantheae; another variety o the . .
species is Montanoa florlbunda. The plant is described in great detail in Las Plantas ~edicinales de Mexico, Third Edition, Ediciones Botas ~1944).
The plant has be4n used for centuries in the form of a "tea" or other crude aqueous preparations pr.imarily as a labor inducer or menses inducer for humans. Its use as a utero-evacuant has been documented in the literature.
In U.S. Patent No. 4,086,358, a method is described ~or the isolation of the active ingredients in the zoapatle plant. One of the active ingredients is 2S, 3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol. This compound, referred to as zoapatanol, has the following structural formula:
~0,~
~~0 c~3 The present invention relates to a method for the total synthesis of 2S*, 3R*-6~-(2~hydroxyethy].idene)-[*The asterisk indicates the xacemic nature of the compoundand refers to the relative configuration of the ~ ral centers.]
' 7~35~3 -
2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.
Many of the intermediates employed in the synthesis of zoa~atanol are novel compounds and are included as part of the invention.
The synthesis is comprised of several steps which are summarized in the following schematic diagram:
M M
Br Mg ~ ~ ~ MgBr (1) ~ (2) ~ OH
TH ~ ~ ,OH
~ O
r ,-OH OH
~_ U IlG~r~
R20/PYr i1`
OR
(4) M RO", ~ OR~ RO ~ OR
~ ~oJ ~ ~J
~6) t7) H~
,~
" " . .
(8) ~L~7~3s~3 `
RO" ~ OR RO, ~ OR
(6) ~ ~ J CrO3- ~SO4 ~ 0 J
(8) (9) ~Hydrolysis O ~", ~ OH
~OJ
(1 0 ) Wherein M is a protecting group selected from the group consistinq of an O-tetrahYdropyranyl qrou~ and an O-ethoxyethyl group, R is an acyl group having 2-5 carbon atoms and X is selected from the group consist-ing of bromo, chloro, iodo, tosyl, mesyl and brosyl.
As seen rom the diagram, the first step in the synthesis involves the preparation of the Grignard reagent (2) from the corresponding halo compound 8-bromo-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy),-2-octene (1). For purposes of describing the invention, the process will be described using a 2-tetrahydropyranyl group as the protecting group. The reaction with magnesium is carried out in the standard fashion, pre~erably in an organic solvent such as ether or tetrahydrofuran. The Grignard reagent is preferably uced in the next step without isolation.
The coupled product ~3) is prepared by reacting the Grignard reagent with a substituted 6,7-oxido-2-octen-l-ol. The reaction is carried out in an organic solvent such as ether or tetrahydrofuran at a temperature between about -20 and 0C. It is preferred to carry out 7~3~8 the reaction In the presence of a catalytic amount of a copper salt such as, ~or example, cuprous iodide, cuprous bromide and lithium copper chloride. The coupled product ~3) can be used directly in the cyclization step or it can be purified first by convert ing it to the diacyl deri~ative (4) by reaction with a suitable acylating agent such as acetic anhydride in a base such as pyridine.
The product obtained from the coupling reaction
Many of the intermediates employed in the synthesis of zoa~atanol are novel compounds and are included as part of the invention.
The synthesis is comprised of several steps which are summarized in the following schematic diagram:
M M
Br Mg ~ ~ ~ MgBr (1) ~ (2) ~ OH
TH ~ ~ ,OH
~ O
r ,-OH OH
~_ U IlG~r~
R20/PYr i1`
OR
(4) M RO", ~ OR~ RO ~ OR
~ ~oJ ~ ~J
~6) t7) H~
,~
" " . .
(8) ~L~7~3s~3 `
RO" ~ OR RO, ~ OR
(6) ~ ~ J CrO3- ~SO4 ~ 0 J
(8) (9) ~Hydrolysis O ~", ~ OH
~OJ
(1 0 ) Wherein M is a protecting group selected from the group consistinq of an O-tetrahYdropyranyl qrou~ and an O-ethoxyethyl group, R is an acyl group having 2-5 carbon atoms and X is selected from the group consist-ing of bromo, chloro, iodo, tosyl, mesyl and brosyl.
As seen rom the diagram, the first step in the synthesis involves the preparation of the Grignard reagent (2) from the corresponding halo compound 8-bromo-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy),-2-octene (1). For purposes of describing the invention, the process will be described using a 2-tetrahydropyranyl group as the protecting group. The reaction with magnesium is carried out in the standard fashion, pre~erably in an organic solvent such as ether or tetrahydrofuran. The Grignard reagent is preferably uced in the next step without isolation.
The coupled product ~3) is prepared by reacting the Grignard reagent with a substituted 6,7-oxido-2-octen-l-ol. The reaction is carried out in an organic solvent such as ether or tetrahydrofuran at a temperature between about -20 and 0C. It is preferred to carry out 7~3~8 the reaction In the presence of a catalytic amount of a copper salt such as, ~or example, cuprous iodide, cuprous bromide and lithium copper chloride. The coupled product ~3) can be used directly in the cyclization step or it can be purified first by convert ing it to the diacyl deri~ative (4) by reaction with a suitable acylating agent such as acetic anhydride in a base such as pyridine.
The product obtained from the coupling reaction
(3) is then converted to a mixture of epimeric oxepanes (5) upon treatment with a catalytic amount of a Lewis acid such as boron trifluoride etherate, alumlnum chloridel and zinc chloride, for example, or a protic acid such as ~-toluenesulfonic acid and trifluoroacetic acid. l~e reaction may be carried out in an organ~c solvent such as ether or tetrahydrofuran, for example, at a temperature between about 0 and 30C.
The mixture of oxepanes can also be prepared from the diacyl derivative (4) by ~irst hydrolyzing the ester groups~ith a mild base such as potassium carbonate, for example, and then reacting the product of the hydrolysis with a Lewis acid.
The mixture of epimeric oxepanes (5) is converted -to a mixture of diacyl derivatives (6 and 7) by reaction 25 with an acylating agent such as, for example,acetic anhydride, propionic anhydride or butyric anhydride and acyl halides, such as for example, acetyl chloride, propionyl chloride and butyryl chloride in a basic medium such ~s pyridine.
The mixture o~ diacyl derivatives i5 separated by physical means prior to the next step. A preerred method o~
Reparation is preparat~e thin layer chromatography on a suitable adsorbent such as silica gel, alumina or 35 10risil~ However~ any suitable method of separating the epi~erlc compounds may be employed. Other suitable methods include column chromatography and high pressure liquid chromatography. The compounds are epimeric at the 3-position.
~ .. -~7~3~;8 Hydrolysis o~ the tetrahydropyranyl deriva-tive (6) to the hydroxyl compound (8) is accomplished by treating the tetrahydro;~yranyl deri~at~ve with an acidic solvent system. Suitable acidic solvent systems include tetrahydrofuran-water-acetic acid, acetonitrile-water-acetic acid, and tetrahydrofuran water-sulfuric acid.
The acylated derivative (8) is then converted to the derivatized utero-ev~cuant material (9) ~y treat-ment with a suitable oxidizing agent such as, for example,chromium trioxide-sulfuric ~cid, chromium trioxide-acetic acid or chromium trioxide-pvridine. The oxidation is pre-ferably carried out in a suitable organic solvent such as acetone, 2-butanone, chloroform or methylené chloride.
The particular solvent employed will depend upon the particular oxidi~ing agent employed in the oxidation step.
The residue o~tained from the oxidation reaction is then converted to the underivatized utero-evacuant material (10 by hydrolysis with a suitable base such as, for example, sodium hydroxide, potassium hydroxide, potassium carbonate and tetra n-butyl ammonium hydroxide. The hydrolysis step is preferably carried out in an organic solvent such as, fox example, methanol, ethanol, isopropanol, benzene, ether and tetrahydrofuran. However, aqueous media may also be employed for the hydrolysis step. The reaction is preferably carried out in an inert atmosphere such as, or example, nitrogen or argon. The reaction is generally carried out at room temperature al~hough elevated temperatures such as the re1ux temperature of the solvent~ for example, may also be employed. The crude product of the hydrolysis can be further purified by column chromatography oYer an adsorbent material~ such as silica gel, alumi:na or Florisi ~
The bromo compound,8-bromo-2,6-dimethyl-5-~2-~ .ra-hydropyran-2-yloxy?j-Z-octene,used to prepare the Grignard reagent in the first step in the synthesis is prepared by a ~1~';' ~g3S~ ' series of reacttons using 5~bromo-2-methyl-2-pentene as the starting material, The bromide is first converted to 2-methyl-5-nitro-2-pentene by reaction with sodium nitrite in dimethylsulfoxide.The nitro compound is then reacted with methyl crotonate to form methyl 3,7-dimethyl-4-nitro-6-octenoate. Reaction of the octenoate derivative with titanous chloride results in the formation of the oxo compound, methyl 3,7-dimethyl-4-oxo-6-octenate. The oxo compound is then reacted with lithium aluminum hydride 10 to form 3,7-dimethyl-4-hydroxy-6-octen-1-ol. The diol is converted to the mono-acetate by reaction with acetic anhydride and the mono-acetate is then converted to the tetrahydro-pyranyl derivative by reaction with dihydropyran. The tetrahydropyranyl derivati~e is converted to the corresponding 15 alcohol by reaction with potassium carbonate in a mixture of methanol and water. The bromo compound is then obtained by reacting the alcohol 3,7-dimethyl-4-[Z~tetrahydropyran-2-yloxy)1-6-octen-1-ol with phosphorous tribromide or tri-phenylphosphine and carbon tetrabromide.
The substituted 6,7-oxido~2-octen-1-ol compound employed to prepare the coupled product (3) is itself pre-pared by a series of reactions using myrcene as the starting material. 8-Hydroxy-7-methyl-3-methylene-1,6-(E)-octadiene is first synthesized from myrcene by the method of G. Buchi 25 and H. Wuest, Helv. Chim. Acta, 50,2440 (1967). The octadiene compound is then converted to the hydroxy epoxide by xeaction with a peracid such as m-chloroperbenzoic acid or peracetic acid. The hydroxy epoxide is then converted to the diac~l derivative by reaction with an e~uivalent amount 30 of a halogen~ such as bromine~ followed by an excess of an acetate salt, such as potassium acetate. The major product of the reaction is the compo~md having the E configuration, however~ about 20% of the compound hav~ng the Z configuration is also formed, Treatment of the diacyl derivative with a slight excess of ~-toluenesulfonyl chloride in the presence llt7~33~ `
of a base affords the corresponding tosylate. Reaction of the tosylate with potassium bromide or sodium bromide in 2-butanone at reflux temperature gives the corresponding bromo derivative. The tosylate or the bromide derivative is then hydrolyzed to the diol, 7-methyl-3-hydroxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octen-1-ol or 7-methyl-3-hydroxymethyl-6,7-oxido-8-bromo-(E)~2-octen-1-ol by treatment with a base such as sodium hydroxide, potassium carbonate or tetra-_-butyl ammonium hydroxide. During the workup of the reaction mixture, the compound having the Z configuration forms a complex with magnesium sulfate which results in a product having only the E configuration. Those compounds wherein X is brosyl and mesyl are prepared in the same manner in which the corresponding tosylate is prepared except that p-bromotoluenesulfonyl chloride and methane-sulfonyl chloride are employed in place of ~-toluenesulfonyl chloride. The compound (1) wherein M is O-ethoxyethyl is prepared in the same manner as the compound wherein P~ is O-tetrahydro-pyranyl except that ethyl vinylether is employed in place of dihydropyran. --The following examples describe the invention in greater detail and are inten~ed to be a way of illustrating and not limiting the invention.
~L~7935~
EXAMPLE I
8-Hydroxy-7~methyl-3-methylene~6,7-oxido-1-octene A solution of sodium acetate (25 g, 0.03 m) in 40%peracetic acid (85 ml) is added to a mixture of 8-hydroxy-7-methyl-3-methylene-1,6-(E)-octadiene (50.0 g, 0.33 m), sodium carbonate (42.4 g, 0.40 m) and methylene chloride (500 ml) at 0.
The resulting mixture is allowed to come to room temperature and is stirred for an additional hour after which it is filtered/ diluted with methylene chloride (1 1) and washed with 5~ sodium bicarbonate (2 1). The organic layer is dried (Na2SO4), and evaporated _ vacuo to give the crude product (49.5 g).
The crude product is purified by column chromatography on silica gel (600 g; ethyl acetate/
hexane 1:9) to give 8-hydroxy 7-methyl-3-methylene-6,7-oxido-1-octene (23.2 g, 42%), ir (neat): 3448, 1592 cm nmr (CDC13) ~ : 1.25 (s, 3H, CH3-C~-,CH), 3.03 (t, J=6 Hz, lH, /~-,CH), 3.56 (s,2H,-CH2-OH), 4.90 - 6.58 (m, 5H, ~=~H2, -CH=CH2).
EX~MPLE 2 l-Ac toxy-8-hydroxy-7-methyl-3-acetoxymethyl~-6_7-oxido-(E~-2 octene Bromine (56.8 g, 0.355 m) is added to a solution of 8-hydroxy-7-methyl-3-methylene-6,7-oxido-l-octene (59.7 g, 0.355 m) in methylene chloride (1 1) under nitrogen at 0. The resulting mixture is allowed to warm to room temperature and then washed with water (500 ml). The oryanic layer is dried (Na2SO4) and the solvent is removed to give the crude dibromide (117.0 g).
A portion of this crude dibromide (57.2 g) in . .
31L~7935~3 `
EXAMPLE 2 (Cont'd) carbon tetrachloride (50 ml) is added to a solution of potassium acetate (59.8 g, 0.61 m) and adogen 464 (15.0 g) in water at 60. The resulting mixture is stirred overnight, after which it is cooled to room temperature, diluted with ether (1 1) and washed with water (500 ml). The organic layer is dried (Na2SO4) and evaporated in vacuo to give crude diacetate (64.0 g).
The crude product is further purified by column chromatography on silica gel (2 kg, ethyl acetate/hexane
The mixture of oxepanes can also be prepared from the diacyl derivative (4) by ~irst hydrolyzing the ester groups~ith a mild base such as potassium carbonate, for example, and then reacting the product of the hydrolysis with a Lewis acid.
The mixture of epimeric oxepanes (5) is converted -to a mixture of diacyl derivatives (6 and 7) by reaction 25 with an acylating agent such as, for example,acetic anhydride, propionic anhydride or butyric anhydride and acyl halides, such as for example, acetyl chloride, propionyl chloride and butyryl chloride in a basic medium such ~s pyridine.
The mixture o~ diacyl derivatives i5 separated by physical means prior to the next step. A preerred method o~
Reparation is preparat~e thin layer chromatography on a suitable adsorbent such as silica gel, alumina or 35 10risil~ However~ any suitable method of separating the epi~erlc compounds may be employed. Other suitable methods include column chromatography and high pressure liquid chromatography. The compounds are epimeric at the 3-position.
~ .. -~7~3~;8 Hydrolysis o~ the tetrahydropyranyl deriva-tive (6) to the hydroxyl compound (8) is accomplished by treating the tetrahydro;~yranyl deri~at~ve with an acidic solvent system. Suitable acidic solvent systems include tetrahydrofuran-water-acetic acid, acetonitrile-water-acetic acid, and tetrahydrofuran water-sulfuric acid.
The acylated derivative (8) is then converted to the derivatized utero-ev~cuant material (9) ~y treat-ment with a suitable oxidizing agent such as, for example,chromium trioxide-sulfuric ~cid, chromium trioxide-acetic acid or chromium trioxide-pvridine. The oxidation is pre-ferably carried out in a suitable organic solvent such as acetone, 2-butanone, chloroform or methylené chloride.
The particular solvent employed will depend upon the particular oxidi~ing agent employed in the oxidation step.
The residue o~tained from the oxidation reaction is then converted to the underivatized utero-evacuant material (10 by hydrolysis with a suitable base such as, for example, sodium hydroxide, potassium hydroxide, potassium carbonate and tetra n-butyl ammonium hydroxide. The hydrolysis step is preferably carried out in an organic solvent such as, fox example, methanol, ethanol, isopropanol, benzene, ether and tetrahydrofuran. However, aqueous media may also be employed for the hydrolysis step. The reaction is preferably carried out in an inert atmosphere such as, or example, nitrogen or argon. The reaction is generally carried out at room temperature al~hough elevated temperatures such as the re1ux temperature of the solvent~ for example, may also be employed. The crude product of the hydrolysis can be further purified by column chromatography oYer an adsorbent material~ such as silica gel, alumi:na or Florisi ~
The bromo compound,8-bromo-2,6-dimethyl-5-~2-~ .ra-hydropyran-2-yloxy?j-Z-octene,used to prepare the Grignard reagent in the first step in the synthesis is prepared by a ~1~';' ~g3S~ ' series of reacttons using 5~bromo-2-methyl-2-pentene as the starting material, The bromide is first converted to 2-methyl-5-nitro-2-pentene by reaction with sodium nitrite in dimethylsulfoxide.The nitro compound is then reacted with methyl crotonate to form methyl 3,7-dimethyl-4-nitro-6-octenoate. Reaction of the octenoate derivative with titanous chloride results in the formation of the oxo compound, methyl 3,7-dimethyl-4-oxo-6-octenate. The oxo compound is then reacted with lithium aluminum hydride 10 to form 3,7-dimethyl-4-hydroxy-6-octen-1-ol. The diol is converted to the mono-acetate by reaction with acetic anhydride and the mono-acetate is then converted to the tetrahydro-pyranyl derivative by reaction with dihydropyran. The tetrahydropyranyl derivati~e is converted to the corresponding 15 alcohol by reaction with potassium carbonate in a mixture of methanol and water. The bromo compound is then obtained by reacting the alcohol 3,7-dimethyl-4-[Z~tetrahydropyran-2-yloxy)1-6-octen-1-ol with phosphorous tribromide or tri-phenylphosphine and carbon tetrabromide.
The substituted 6,7-oxido~2-octen-1-ol compound employed to prepare the coupled product (3) is itself pre-pared by a series of reactions using myrcene as the starting material. 8-Hydroxy-7-methyl-3-methylene-1,6-(E)-octadiene is first synthesized from myrcene by the method of G. Buchi 25 and H. Wuest, Helv. Chim. Acta, 50,2440 (1967). The octadiene compound is then converted to the hydroxy epoxide by xeaction with a peracid such as m-chloroperbenzoic acid or peracetic acid. The hydroxy epoxide is then converted to the diac~l derivative by reaction with an e~uivalent amount 30 of a halogen~ such as bromine~ followed by an excess of an acetate salt, such as potassium acetate. The major product of the reaction is the compo~md having the E configuration, however~ about 20% of the compound hav~ng the Z configuration is also formed, Treatment of the diacyl derivative with a slight excess of ~-toluenesulfonyl chloride in the presence llt7~33~ `
of a base affords the corresponding tosylate. Reaction of the tosylate with potassium bromide or sodium bromide in 2-butanone at reflux temperature gives the corresponding bromo derivative. The tosylate or the bromide derivative is then hydrolyzed to the diol, 7-methyl-3-hydroxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octen-1-ol or 7-methyl-3-hydroxymethyl-6,7-oxido-8-bromo-(E)~2-octen-1-ol by treatment with a base such as sodium hydroxide, potassium carbonate or tetra-_-butyl ammonium hydroxide. During the workup of the reaction mixture, the compound having the Z configuration forms a complex with magnesium sulfate which results in a product having only the E configuration. Those compounds wherein X is brosyl and mesyl are prepared in the same manner in which the corresponding tosylate is prepared except that p-bromotoluenesulfonyl chloride and methane-sulfonyl chloride are employed in place of ~-toluenesulfonyl chloride. The compound (1) wherein M is O-ethoxyethyl is prepared in the same manner as the compound wherein P~ is O-tetrahydro-pyranyl except that ethyl vinylether is employed in place of dihydropyran. --The following examples describe the invention in greater detail and are inten~ed to be a way of illustrating and not limiting the invention.
~L~7935~
EXAMPLE I
8-Hydroxy-7~methyl-3-methylene~6,7-oxido-1-octene A solution of sodium acetate (25 g, 0.03 m) in 40%peracetic acid (85 ml) is added to a mixture of 8-hydroxy-7-methyl-3-methylene-1,6-(E)-octadiene (50.0 g, 0.33 m), sodium carbonate (42.4 g, 0.40 m) and methylene chloride (500 ml) at 0.
The resulting mixture is allowed to come to room temperature and is stirred for an additional hour after which it is filtered/ diluted with methylene chloride (1 1) and washed with 5~ sodium bicarbonate (2 1). The organic layer is dried (Na2SO4), and evaporated _ vacuo to give the crude product (49.5 g).
The crude product is purified by column chromatography on silica gel (600 g; ethyl acetate/
hexane 1:9) to give 8-hydroxy 7-methyl-3-methylene-6,7-oxido-1-octene (23.2 g, 42%), ir (neat): 3448, 1592 cm nmr (CDC13) ~ : 1.25 (s, 3H, CH3-C~-,CH), 3.03 (t, J=6 Hz, lH, /~-,CH), 3.56 (s,2H,-CH2-OH), 4.90 - 6.58 (m, 5H, ~=~H2, -CH=CH2).
EX~MPLE 2 l-Ac toxy-8-hydroxy-7-methyl-3-acetoxymethyl~-6_7-oxido-(E~-2 octene Bromine (56.8 g, 0.355 m) is added to a solution of 8-hydroxy-7-methyl-3-methylene-6,7-oxido-l-octene (59.7 g, 0.355 m) in methylene chloride (1 1) under nitrogen at 0. The resulting mixture is allowed to warm to room temperature and then washed with water (500 ml). The oryanic layer is dried (Na2SO4) and the solvent is removed to give the crude dibromide (117.0 g).
A portion of this crude dibromide (57.2 g) in . .
31L~7935~3 `
EXAMPLE 2 (Cont'd) carbon tetrachloride (50 ml) is added to a solution of potassium acetate (59.8 g, 0.61 m) and adogen 464 (15.0 g) in water at 60. The resulting mixture is stirred overnight, after which it is cooled to room temperature, diluted with ether (1 1) and washed with water (500 ml). The organic layer is dried (Na2SO4) and evaporated in vacuo to give crude diacetate (64.0 g).
The crude product is further purified by column chromatography on silica gel (2 kg, ethyl acetate/hexane
4:6) to give 1-acetoxy-8-hydroxy-7-methyl-3-acetoxymethyl-6,7-oxido-(E)-2-octene (9.5 g; 18~).
ir (neat) 3484, 1730 cm 1; nmr (CDC13)S: 1.28 (s, 3H, ~ ~ Q
CH3-C--CH), 2.05 and 2.07 (each s, 6H, CH3-C-O-), 3.00 (t, J=6 Hz, lH, -C--CH), 3.58 (bs, 2H, -CH2-OH), 4.50-4.73 (m, 4H, ~C=CHCH2OAc and ~ C=C-CH2OAc), 5.63 (t, J-7 Hz, lH,,JC=CHCH2OAc).
EXAMP~E 3 l-Acetoxy-7-methyl-3-acetoxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octene Triethylamine (10 ml) and tosyl chloride ~13.78 g, 0.072 m) are added to a solution of l-acetoxy-8-hydroxy-7-methyl-3-acetoxymethyl-6,7-oxido-(E)-2-octene (10.34 g, 0.036 m) in dry tetrahydrofuran (300 ml).
The resulting mixture is stirred at room temperature under nitrogen for 6 days. The mixture is then diluted with ether t800 ml) and washed with 5% sodium bicar-bonate (800 ml) and water (800 ml). The organic layer is dried (Na2SO4) and evaporated ln vacuo to give the crude product (18~3 g). The crude material is purified by column chromatography on silica gel (600 g; ethyl acetate/hexane; 40:60) to give 1-acetoxy-7-methyl-3-acetoxymethyl-6,7-oxido-8-tosyloxy-~E)-2-octene (10.12 g, 64%).
3SI~ ~
EXAMPLE 3 (Cont'd) ir (neat) 1730, 1595 cm 1; nmr (CDC13)~: 1.23 (s, 3H, CH3-C\--CH), 2.03 and 2.07 (each s, 6H, C_ 3-C~o )~ 2.43 (s, 3H, CH3 ~ )~ 2.78 (t, J=6 Hz, lH, ~ -CH), 3.90 o (s, 2H, -CH2OTs), 4.47 - 4.70 (m, 4H, ~C=CH-CH2OAc and ~ C=C - CH2OAc), 5.62 (bt, J=6 Hz, lH, C=C~cH OAc) 7-Methyl-3-hydroxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octen-1-ol A mixture of l-acetoxy-7-methyl-3-acetoxymethyl-10 6,7-oxido-8-tosyloxy-(E)-2-octene (4.0 g, 9.1 mmole), methanol (150 ml), water (5 ml) and saturated po~assium carbonate solution (5 ml) is stored at room temperature for 2 hours. ~ost of themethanol is then removed m vacuo and the resulting mixture is extracted wlth ethyl acetate (3x20 ml). The ccmbined organic 15 layer is dried (MgSO4) and evaporated ln vacuo to give an oil (3.4 g). The crude oil is further purified by column chromatography on silica gel (20 g, isopropanol/
chloroform 2:98) to give 7-methyl-3-hydroxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octen-1-ol as a colorless oil --(2.24 g, 69%).
ir (neat) 3424, 1597 cm 1; nmr (CDC13)~: 1.28 (s, 3H, CH3-C--CH), 2.43 (s, 3H, CH3 ~ ), 2.83 (t, J=6 Hz, ~C ~ H)' 3 90 (s, 2H, -CH2-OTs), 5.70 (bt, J=6 Hz, lH, o =f-~H2-OH)~
H
2-Methyl-5~nitro-2-pentene
ir (neat) 3484, 1730 cm 1; nmr (CDC13)S: 1.28 (s, 3H, ~ ~ Q
CH3-C--CH), 2.05 and 2.07 (each s, 6H, CH3-C-O-), 3.00 (t, J=6 Hz, lH, -C--CH), 3.58 (bs, 2H, -CH2-OH), 4.50-4.73 (m, 4H, ~C=CHCH2OAc and ~ C=C-CH2OAc), 5.63 (t, J-7 Hz, lH,,JC=CHCH2OAc).
EXAMP~E 3 l-Acetoxy-7-methyl-3-acetoxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octene Triethylamine (10 ml) and tosyl chloride ~13.78 g, 0.072 m) are added to a solution of l-acetoxy-8-hydroxy-7-methyl-3-acetoxymethyl-6,7-oxido-(E)-2-octene (10.34 g, 0.036 m) in dry tetrahydrofuran (300 ml).
The resulting mixture is stirred at room temperature under nitrogen for 6 days. The mixture is then diluted with ether t800 ml) and washed with 5% sodium bicar-bonate (800 ml) and water (800 ml). The organic layer is dried (Na2SO4) and evaporated ln vacuo to give the crude product (18~3 g). The crude material is purified by column chromatography on silica gel (600 g; ethyl acetate/hexane; 40:60) to give 1-acetoxy-7-methyl-3-acetoxymethyl-6,7-oxido-8-tosyloxy-~E)-2-octene (10.12 g, 64%).
3SI~ ~
EXAMPLE 3 (Cont'd) ir (neat) 1730, 1595 cm 1; nmr (CDC13)~: 1.23 (s, 3H, CH3-C\--CH), 2.03 and 2.07 (each s, 6H, C_ 3-C~o )~ 2.43 (s, 3H, CH3 ~ )~ 2.78 (t, J=6 Hz, lH, ~ -CH), 3.90 o (s, 2H, -CH2OTs), 4.47 - 4.70 (m, 4H, ~C=CH-CH2OAc and ~ C=C - CH2OAc), 5.62 (bt, J=6 Hz, lH, C=C~cH OAc) 7-Methyl-3-hydroxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octen-1-ol A mixture of l-acetoxy-7-methyl-3-acetoxymethyl-10 6,7-oxido-8-tosyloxy-(E)-2-octene (4.0 g, 9.1 mmole), methanol (150 ml), water (5 ml) and saturated po~assium carbonate solution (5 ml) is stored at room temperature for 2 hours. ~ost of themethanol is then removed m vacuo and the resulting mixture is extracted wlth ethyl acetate (3x20 ml). The ccmbined organic 15 layer is dried (MgSO4) and evaporated ln vacuo to give an oil (3.4 g). The crude oil is further purified by column chromatography on silica gel (20 g, isopropanol/
chloroform 2:98) to give 7-methyl-3-hydroxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octen-1-ol as a colorless oil --(2.24 g, 69%).
ir (neat) 3424, 1597 cm 1; nmr (CDC13)~: 1.28 (s, 3H, CH3-C--CH), 2.43 (s, 3H, CH3 ~ ), 2.83 (t, J=6 Hz, ~C ~ H)' 3 90 (s, 2H, -CH2-OTs), 5.70 (bt, J=6 Hz, lH, o =f-~H2-OH)~
H
2-Methyl-5~nitro-2-pentene
5-Bromo-2-methyl-2-pentene (120 g, 0.736 m) is added dropwise to a solution of sodium nitrite (60.9 g, 0.883 m) in dimethylsu~oxide (700 ml) at room temperature under nitrogen. The mixture is stirred for 1 hour and ....
~7913S8 EXAMPLE 5 (Cont'd) treated with water (500 ml) and petroleum ether (1 1).
The organic layer is dried (Na2SO4) and evaporated in vacuo to give a pale yellow liquid (80.7 g). This material is purified by column chromatography on silica gel (800 g, petroleum ether) to give 2-methyl-5-nitro-2-pentene as a colorless liquid (45.4 g, 48~).
ir (neat) 1550 cm 1; nmr (CDC13)S: 1.70 and 1.73 (both s, 6H, (CH3)2-C=C ), 2.50^-2.93 (m, 2H, -CH2-N02), 4.35 (t, J=8 Hz, 2H, -CH2-CH2-NO2), 5.05 (bt, J=7 Hz, lH, ~C=CH).
Methyl 3,7-dimel~yl-4-nitro-6-octenoate 1,5-Diazabicyclo[5,4,0]undec-5-ene (4 ml) is added to a solution of 2-methyl-5-nitro-2-pentene (25.0 g, 0.193 m) in methanol (200 ml). The resulting mixture is heated to 60 and methyl crotonate (30.85 g, 0.308 m) is added under nitrogen. The mixture is then stirred for 6 days at 60 after which it is cooled to room temperature and most of the methanol is removed _ vacuo. The residue is treated with ether (500 ml) and washed with 2N HCl (250 ml) and water (250 ml).
The organic layer is dried (Na2SO4) and evaporated ln vacuo to give 42.~ of crude product. The crude pro- --duct is purified by column chromatography on silica gel (500 g, ethyl acetate/h~xane 2:98) to give methyl 3,7-dimethyl-4-nitro-6-octenoate (8.65 g, 42~).
ir ~neat): 1736, 1547 cm 1; nmr (CDC13)~: 1.62 and 1.68 (both s, 6H, (CH3)2C=CH), 3.67 (s, 3H,-OCH3), 4.22-4.42 (m, lH, CH-NO2),4.95 (bt, J=7 Hz, lH, ~ C=CH).
Methyl 3_7-dimeth~1-4-oxo-6-octenoate A solution o methyl 3,7-dimethyl-4-nitro-
~7913S8 EXAMPLE 5 (Cont'd) treated with water (500 ml) and petroleum ether (1 1).
The organic layer is dried (Na2SO4) and evaporated in vacuo to give a pale yellow liquid (80.7 g). This material is purified by column chromatography on silica gel (800 g, petroleum ether) to give 2-methyl-5-nitro-2-pentene as a colorless liquid (45.4 g, 48~).
ir (neat) 1550 cm 1; nmr (CDC13)S: 1.70 and 1.73 (both s, 6H, (CH3)2-C=C ), 2.50^-2.93 (m, 2H, -CH2-N02), 4.35 (t, J=8 Hz, 2H, -CH2-CH2-NO2), 5.05 (bt, J=7 Hz, lH, ~C=CH).
Methyl 3,7-dimel~yl-4-nitro-6-octenoate 1,5-Diazabicyclo[5,4,0]undec-5-ene (4 ml) is added to a solution of 2-methyl-5-nitro-2-pentene (25.0 g, 0.193 m) in methanol (200 ml). The resulting mixture is heated to 60 and methyl crotonate (30.85 g, 0.308 m) is added under nitrogen. The mixture is then stirred for 6 days at 60 after which it is cooled to room temperature and most of the methanol is removed _ vacuo. The residue is treated with ether (500 ml) and washed with 2N HCl (250 ml) and water (250 ml).
The organic layer is dried (Na2SO4) and evaporated ln vacuo to give 42.~ of crude product. The crude pro- --duct is purified by column chromatography on silica gel (500 g, ethyl acetate/h~xane 2:98) to give methyl 3,7-dimethyl-4-nitro-6-octenoate (8.65 g, 42~).
ir ~neat): 1736, 1547 cm 1; nmr (CDC13)~: 1.62 and 1.68 (both s, 6H, (CH3)2C=CH), 3.67 (s, 3H,-OCH3), 4.22-4.42 (m, lH, CH-NO2),4.95 (bt, J=7 Hz, lH, ~ C=CH).
Methyl 3_7-dimeth~1-4-oxo-6-octenoate A solution o methyl 3,7-dimethyl-4-nitro-
6-octenoate (24.55 g, 0~107 m) in methanol (10 ml) is added dropwise to a solution of sodium methoxide (6.37 g, 0.118 m) in methanol (250 ml) at room tempera-ture under nitrogen. The mixture is stirred for 1 hour, added to a mixture of 20~ titanous chloride (170 ml, ~ ~9~5~
EXAMPL~ 7 (Cont'd) 0.267 m) and pH 7 buffer (potassium phosphate monobasic-sodium hydroxide buffer) solution (340 ml). The resulting mixture is stirred for 30 minutes after which it is treated with ether (1 1). The organic phase is separated, dried (Na2SO4) and evaporated in vacuo to give the crude product (15.4 g). This material is purified by column chromatography on silica gel (300 g, 2~ ethyl acetate in hexane)to give methyl 3,7-dimethyl-4-oxo-6~octenoate as a colorless liquid (6.8 g, 35~).
ir (neat) 1705 and 1735 cm 1; nmr (CDC13)~ : 1.15 (d, J=7 Hz, 3H, CH3- ~H), 3.2 (bd, J=7 Hz~ 2H~
3.63 (s, 3H, CH30-), 5.30 (bt, J=7 Hz, lH, ~ CH-).
3,7-Dimethyl-4-hydroxy-6-octen-1-ol Methyl 3,7-dimethyl-4-oxo-6-octenoate (6~ g, 34mmole) in ether (10 ml) is added to a mixture of lithium aluminum hydride (1.3g, 34 mmole) and ether (150 ml) at 0.
After the addition is complete the mixture is allowed to warm to room temperature and stirred for 1 hour, after which it is cooled to 0 and carefully added to a 5% aqueous sodium bicarbona~e solution (50 ml). The resulting mixture is treated with water (100 ml) and ethyl acetate (300 ml). The organic phase is separated, dried (Na2SO4) and the solvent is removed ln vacuo to give a colorless oil (50.6 g, 94~). This material shows one spot on TLC ~silica gel 50% ethyl acetate in hexane) and is not further purified.
ir (neat) 3225 cm 1.
8-Acetoxy-2,6-dimethyl-5-hydroxy-2-octene A mixture of 3,7-dimethyl-~-hydroxy-6-octen-1-ol (5.06g, 29 mmole), acetic anhydride (3.06 g, 30 mmole), pyridi~e (4.75g, 60 mmole) and ether (100 ml) i5 stirred at room temperature for 16 hours. The resulting mixture is treated with ether (200 ml) and washed with saturated ~7~3S~
EXAMPLE 9 (Cont'd) cupric sulfate solution (2xlO0 ml). The organic phase is dried (Na2SO4) and evaporated ln vacuo to give 8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene as a colorless oil (2.27 g, 45%).
ir (neat) 3508; 1738 cm 1; nmr (CDC13)~ : 0.93 (d, J=7 /~
Hz, 3H, CH3-CH), 2.0 (s, 3H, CH3-C-0-), 4.10 (t, J=7 Hz, 2H, -CH2-OAc), 5.10 (bt, lH, /C=CH).
8-Acetoxy-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene A mixture of 8-acetoxy-2,6-dimethyl-5-hydroxy~
2-octene (2.27g, 10.6 mmole), dihydropyran (0.98 g, 11.4 mmole), p-toluenesulfonic acid monohydrate (catalytic amount) and ether (50 ml) is stirred at room temperature for 16 hours. The resulting mixture is treated with ether (150 ml) and washed with 5% sodium bicarbonate solution (2xlO0 ml). The organic phase is dried (Na2SO4), and evaporated in vacuo to give the crude product (3.27 g). This material is further puriied by column chromatography on silica gel (25 g, 5~ ethyl acetate in hexane) to give 8-acetoxy-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene as a colorless oil (2.67 g, 89~). ,0 ir (neat) 1739 cm 1; nmr (CDC13)~: 2.07 (s, 3H, CH3-C~
4.61 tbr, lH, ~ 0/ ), 5.2 (br, lH, ~C=CH).
H
3,7-Dimethyl 4-~2-(tetrahydropyran-2-yloxy)]-6-octen-1-ol) A mixture of 8-acetoxy-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene (2.67 g, 0.5 mmole), saturated potassium carbonate solution (9 ml), water 793S~ ~
EXAMPLE 11 (Cont'd) (6 ml) and methanol (100 ml) is stirred for 3 hours at room temperature. Most of the methanol is removed _ vacuo and the residue is treated with ethyl acetate (500 ml) and water (200 ml). The organic phase is dried (Na2SO4) and evaporated ln vacuo to give the crude product ~2.5 g). This material is further purified by column chromatography on silica gel (25 g, 15%
ethyl acetate in hexane) to give 3,7-dimethyl-4-~2-(tetrahydropyran~2-yloxy)]-6-octen-1-ol as a colorless oil (1.5 g, 60~).
ir (neat) 3434 cm 1, nmr (CDC13)~: 4.62 (br,LH, Q ~ )~
\ / H
5.2 (br, lH, ~C=CH).
8=Bromo-2,6-dimethyl-5-~2-(tetrahydropyran-2-yloxy)]-2-octene Triphenylphosphine (1.83 g, 7.02 mmole) in methylene chloride (30 ml) is added to a mixture of 3,7~dimethyl-4-[2-(tetrahydropyran-2-yloxy)]-6-octen-1-ol (1.20g, 4.7 mmole), carbon tetrabromide (1.94 g, 5.85mmole), pyridine (2 ml) and methylene chloride (30 ml) at 0 under nitrogen. The mixture is allowed to warm to room temperature and stirred for 4 hours, after which it is treated with methylene chloride (100 ml) and washed with 5~ sodi~m bicarbonate solution. The organic phase is dried (Na2SO4) and evaporated in vacuo to give the crude product ~5.6 g) This material is ~urther purified by column chromatography on silica gel (100 g, ~% ethyl acetate in hexane) to give 8-bromo-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene as a colorless oil (0~7 g, 46%).
nmr (CDC13)~: 4.61 (br, lH~ 5.15 ~br, lH, /
/C=CH).
~,~
35~
3,7-Dimethyl-4-[2-(tetrahydropyran-2-yloxy)]-6-octenyl magnesium bromide The Grignard reagent is prepared from 8-bromo-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene (8.5g, 26.7 mmole) and magnesiumt650m~, 27.1 mmole) in tetrahydrofuran (35 ml) at room temperature under argon. The reagent is not isolated but is used directly in the next step.
1-Acetoxy-3-acetoxymethyl-7,11,15-~trimethyl-_ _ 12-[2-~tetrahydropyran-2-yloxy)] (E)-2,14-hexadecadiene An excess of the Grignard reagent is added to a solution of 7-methyl-3-hydroxymethyl-6,7-oxido-8 tosyloxy-(E)-2-octen-1-ol (423.3 mg, 1.3 mmole) in tetrahydrofuran at 0, followed by Li2CuC14 (0.1 mmole) and the mixture is stirred for 1.5 hours at 0. The mixture is allowed to warm to room temperature and then treated wlth ice water (125 ml) and ethyl acetate ~400 ml). The organic phase is separated, dried (Na2SO4) and evaporated ln vacuo to give the crude product. This material is then treated with acetic anhydride (10 ml) and pyridine (2 ml) and stirred for 16 hours at room temperature. The resulting mixture is treated with ether (100 ml) and then washed with saturated cupric sulfate solution (100 ml) and 5%
sodium bicarbonate solution (100 ml). The organic phase is dried (Na2SO4) and evaporated ln vacuo to give an oil (210 mg) which is further puri~ied by column chromatography on silica gel (7 g, 7% ethyl acetate in hexane) to give 1-acetoxy-3-acetoxymethyl-7,11,15-trimethyl-12-[2-(tetrahydropyran-2-yloxy)]-(E)-2,14-hexadecadiene as a colorless oil (41 mg, 9%).
ir (neat) 1735 cm 1; nmr (CDC13)S: 1.23 (s, 3H, CH3 ~ ~ H , 2.0 and 2.03 ~both s, 6h, CH3-C~
~'7~335~
EXAMPLE 14 (Cont'd) 2.66 (bt, J=6 Hz, lH ~ , 5.60 (bt, J=6 Hz~ lH, \C~C
\CH20Ac ) -2S*, 3R*-3-Acetoxy-6E~acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5-(2-tetrahydropyran-2-yloxy)-7-nonenvl]-_ . .
oxepane and 2S*, 3$*-3-acetoxy6E-(2-acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5-(2-tetrahydropyran-2_yloxy)
EXAMPL~ 7 (Cont'd) 0.267 m) and pH 7 buffer (potassium phosphate monobasic-sodium hydroxide buffer) solution (340 ml). The resulting mixture is stirred for 30 minutes after which it is treated with ether (1 1). The organic phase is separated, dried (Na2SO4) and evaporated in vacuo to give the crude product (15.4 g). This material is purified by column chromatography on silica gel (300 g, 2~ ethyl acetate in hexane)to give methyl 3,7-dimethyl-4-oxo-6~octenoate as a colorless liquid (6.8 g, 35~).
ir (neat) 1705 and 1735 cm 1; nmr (CDC13)~ : 1.15 (d, J=7 Hz, 3H, CH3- ~H), 3.2 (bd, J=7 Hz~ 2H~
3.63 (s, 3H, CH30-), 5.30 (bt, J=7 Hz, lH, ~ CH-).
3,7-Dimethyl-4-hydroxy-6-octen-1-ol Methyl 3,7-dimethyl-4-oxo-6-octenoate (6~ g, 34mmole) in ether (10 ml) is added to a mixture of lithium aluminum hydride (1.3g, 34 mmole) and ether (150 ml) at 0.
After the addition is complete the mixture is allowed to warm to room temperature and stirred for 1 hour, after which it is cooled to 0 and carefully added to a 5% aqueous sodium bicarbona~e solution (50 ml). The resulting mixture is treated with water (100 ml) and ethyl acetate (300 ml). The organic phase is separated, dried (Na2SO4) and the solvent is removed ln vacuo to give a colorless oil (50.6 g, 94~). This material shows one spot on TLC ~silica gel 50% ethyl acetate in hexane) and is not further purified.
ir (neat) 3225 cm 1.
8-Acetoxy-2,6-dimethyl-5-hydroxy-2-octene A mixture of 3,7-dimethyl-~-hydroxy-6-octen-1-ol (5.06g, 29 mmole), acetic anhydride (3.06 g, 30 mmole), pyridi~e (4.75g, 60 mmole) and ether (100 ml) i5 stirred at room temperature for 16 hours. The resulting mixture is treated with ether (200 ml) and washed with saturated ~7~3S~
EXAMPLE 9 (Cont'd) cupric sulfate solution (2xlO0 ml). The organic phase is dried (Na2SO4) and evaporated ln vacuo to give 8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene as a colorless oil (2.27 g, 45%).
ir (neat) 3508; 1738 cm 1; nmr (CDC13)~ : 0.93 (d, J=7 /~
Hz, 3H, CH3-CH), 2.0 (s, 3H, CH3-C-0-), 4.10 (t, J=7 Hz, 2H, -CH2-OAc), 5.10 (bt, lH, /C=CH).
8-Acetoxy-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene A mixture of 8-acetoxy-2,6-dimethyl-5-hydroxy~
2-octene (2.27g, 10.6 mmole), dihydropyran (0.98 g, 11.4 mmole), p-toluenesulfonic acid monohydrate (catalytic amount) and ether (50 ml) is stirred at room temperature for 16 hours. The resulting mixture is treated with ether (150 ml) and washed with 5% sodium bicarbonate solution (2xlO0 ml). The organic phase is dried (Na2SO4), and evaporated in vacuo to give the crude product (3.27 g). This material is further puriied by column chromatography on silica gel (25 g, 5~ ethyl acetate in hexane) to give 8-acetoxy-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene as a colorless oil (2.67 g, 89~). ,0 ir (neat) 1739 cm 1; nmr (CDC13)~: 2.07 (s, 3H, CH3-C~
4.61 tbr, lH, ~ 0/ ), 5.2 (br, lH, ~C=CH).
H
3,7-Dimethyl 4-~2-(tetrahydropyran-2-yloxy)]-6-octen-1-ol) A mixture of 8-acetoxy-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene (2.67 g, 0.5 mmole), saturated potassium carbonate solution (9 ml), water 793S~ ~
EXAMPLE 11 (Cont'd) (6 ml) and methanol (100 ml) is stirred for 3 hours at room temperature. Most of the methanol is removed _ vacuo and the residue is treated with ethyl acetate (500 ml) and water (200 ml). The organic phase is dried (Na2SO4) and evaporated ln vacuo to give the crude product ~2.5 g). This material is further purified by column chromatography on silica gel (25 g, 15%
ethyl acetate in hexane) to give 3,7-dimethyl-4-~2-(tetrahydropyran~2-yloxy)]-6-octen-1-ol as a colorless oil (1.5 g, 60~).
ir (neat) 3434 cm 1, nmr (CDC13)~: 4.62 (br,LH, Q ~ )~
\ / H
5.2 (br, lH, ~C=CH).
8=Bromo-2,6-dimethyl-5-~2-(tetrahydropyran-2-yloxy)]-2-octene Triphenylphosphine (1.83 g, 7.02 mmole) in methylene chloride (30 ml) is added to a mixture of 3,7~dimethyl-4-[2-(tetrahydropyran-2-yloxy)]-6-octen-1-ol (1.20g, 4.7 mmole), carbon tetrabromide (1.94 g, 5.85mmole), pyridine (2 ml) and methylene chloride (30 ml) at 0 under nitrogen. The mixture is allowed to warm to room temperature and stirred for 4 hours, after which it is treated with methylene chloride (100 ml) and washed with 5~ sodi~m bicarbonate solution. The organic phase is dried (Na2SO4) and evaporated in vacuo to give the crude product ~5.6 g) This material is ~urther purified by column chromatography on silica gel (100 g, ~% ethyl acetate in hexane) to give 8-bromo-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene as a colorless oil (0~7 g, 46%).
nmr (CDC13)~: 4.61 (br, lH~ 5.15 ~br, lH, /
/C=CH).
~,~
35~
3,7-Dimethyl-4-[2-(tetrahydropyran-2-yloxy)]-6-octenyl magnesium bromide The Grignard reagent is prepared from 8-bromo-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene (8.5g, 26.7 mmole) and magnesiumt650m~, 27.1 mmole) in tetrahydrofuran (35 ml) at room temperature under argon. The reagent is not isolated but is used directly in the next step.
1-Acetoxy-3-acetoxymethyl-7,11,15-~trimethyl-_ _ 12-[2-~tetrahydropyran-2-yloxy)] (E)-2,14-hexadecadiene An excess of the Grignard reagent is added to a solution of 7-methyl-3-hydroxymethyl-6,7-oxido-8 tosyloxy-(E)-2-octen-1-ol (423.3 mg, 1.3 mmole) in tetrahydrofuran at 0, followed by Li2CuC14 (0.1 mmole) and the mixture is stirred for 1.5 hours at 0. The mixture is allowed to warm to room temperature and then treated wlth ice water (125 ml) and ethyl acetate ~400 ml). The organic phase is separated, dried (Na2SO4) and evaporated ln vacuo to give the crude product. This material is then treated with acetic anhydride (10 ml) and pyridine (2 ml) and stirred for 16 hours at room temperature. The resulting mixture is treated with ether (100 ml) and then washed with saturated cupric sulfate solution (100 ml) and 5%
sodium bicarbonate solution (100 ml). The organic phase is dried (Na2SO4) and evaporated ln vacuo to give an oil (210 mg) which is further puri~ied by column chromatography on silica gel (7 g, 7% ethyl acetate in hexane) to give 1-acetoxy-3-acetoxymethyl-7,11,15-trimethyl-12-[2-(tetrahydropyran-2-yloxy)]-(E)-2,14-hexadecadiene as a colorless oil (41 mg, 9%).
ir (neat) 1735 cm 1; nmr (CDC13)S: 1.23 (s, 3H, CH3 ~ ~ H , 2.0 and 2.03 ~both s, 6h, CH3-C~
~'7~335~
EXAMPLE 14 (Cont'd) 2.66 (bt, J=6 Hz, lH ~ , 5.60 (bt, J=6 Hz~ lH, \C~C
\CH20Ac ) -2S*, 3R*-3-Acetoxy-6E~acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5-(2-tetrahydropyran-2-yloxy)-7-nonenvl]-_ . .
oxepane and 2S*, 3$*-3-acetoxy6E-(2-acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5-(2-tetrahydropyran-2_yloxy)
-7-yloxy 7~nonenyl]-oxepane A mixture o 1-acetoxy-3-acetoxymethyl-7,11,15-trimethyl-12-~2-(tetrahydropyran--2-yloxy~]-(E)-2,14-hexadecadiene (lOmg,0.02 mmole), methanol (5 ml), saturated potassium carbonate solution (1 ml) and water (1 ml) is stirred at room temperature for 3 hours. The mixture is then treated with ethyl acetate (15 ml) and water (15 ml). The organic phase is dried (Na2SO4) and the solvent is removed in vacuo to give 3-hydroxymethyl-6,7-oxido-12-~2-(tetrahydropyran-2-yloxy)]-7,11,15-trimethyl-~E)-2,14-hexadecadiene-1-ol as a colorless oil. The oil is dissolved in ether (5 ml)/ treated with boron trifluoride --etherate (5 drops) and stirred for 90 minutes at room temperature. The resulting mixture is treated with pyridine (2 ml) and acetic anhydride ~1 ml) and stirred for 16 hours. Most of the solvent is evapo~ated in vacuo and the residue (15 mg) is purified by column __.
chromatography on silica gel (1 g, 20% ether in petroleum ether to give a mixture of 2S*, 3R*-3-` acetoxy-6E~(2-acetoxyethylidene)-2-methyl-2 [4,8-dimethyl-5-(2-tetrahydropyran-2-yloxy)-7-nonenyl}oxepane and 2S*, 3S*-acetoxy~E-(2-acetoxyethylidene) - 2-methyl-2-~4,8-dimethyl-5-(2-tetrahydropyran-2-yloxy)-7-nonenyl]--oxepane as a colorless oil (2 mg, 20%). The mixture of compounds is separated by preparative thin layer chromatography (silica gel, 30~ ethyl acetate in hexane).
~:~lt7~35;~
2S*, 3R*-3-Acetoxy~E-(2-acetoxyethylidene) ~ 2-methyl-2-- (4~8-dimethyl-5-hydroxy-7-nonenyl)-oxepane 2S*, 3R*-3-Acetoxy~E-(2-acetoxyethyliden~-2-~ethyl~
2-[4,8-dimethyl-5-(2-tetrahydropyran-2-yloxy)-7-nonenyl]-oxepane (2mg, 0.02 mmole) in tetrahydrofuran (2 ml), water (0.3 ml) and glacial acetic acid (2 drops) is heated at 65 (bath temperature) in a well-capped test tube for 2 hours. The mixture is allowed to cool to room temperature and is treated with ether (10 ml) and water (3 ml). The organic phase is dried (Na2SO~) and the solvent is removed _ vacuo to yive a colorless oil (1.5 mg). The oil is homogeneous as determined by thin layer chromatography analysis (30~ ethyl acetate lS in hexane).
ir (nea~); 3497, 1739 cm 1; nmr (CDC13)~; o.sn (d, J=6 Hz, 3H, OEI3-CH), 1.13 (s, 3H, CH3-¢-O-), 1062 and 1.73 [both s, 3H each, (C}I3)2C=CH], 2.03 (s, 6H, CH3CO2), 4.10 (bs, 2H,\O-CH2-C=), 4.60 (d, J=7 Hz, 2H, =C-CH2OAc), 5.32 5m, 2H, /C-CH- and ~=CH-CH2OAc).
2~,3~6E~2-Hydroxyethylidene)-2-methyl-2t~,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol -A. 2S~,3R~3-Acetoxy~æ-(2-acetoxyethylidene)-2-me~hyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane (333 mg) is dissolved in acetone (5 ml) and treated slowly with Jones reagent (2 mmole) at 0 under nitrogen.
The resulting mixture is stirred for 7 minutes and then treated with ether (30 ml) and water (20 ml). The layers are separated and the aqueous layer is extracted with ether (20 ml). The combined organic layer is washed with water (30 ml), dried (MgSO4) and evaporated ln vacuo to give an oil. The crude product is used as such in the next step.
B. The crude product obtained above (161 mg) is dissolved in tetrahydrofuran (5 ml) and water (5 ml).
3Si~ `
EXAMPLE 17 (Cont'd) To this mixture, tetra n-butyl ammonium hydroxide (20~ solution in methanol, 1 ml) is added under nitrogen at room temperature and the resulting mix~ure is stirred for 40 hours. The mixture is treated with ether (S0 ml) and the organic layer is washed with 10~
hydrochloric acid ~2x15 ml), dried (MgSO~) and evaporated ln vacuo to give an oil. This crude product is purified by chromatography on a SilicAR column (5 g). 2S*,3R*-6~~(2-hydroxyethylidene~-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol (81.8 mg) is eluted with ether. Its ir, nmr spectra, Rf on thin layer and retention time on gas chromatography are identical to those o~ the natural product (Compound I~ reported in U.S. Patent No. 4,086,358. The compound has the following physical analysis:
ir (neat) p: 2.91 and 5.88 nmr CTDC13 ~: 5-41 (m, 2H, &=CH-CH2OH and \C=CH-CH2-8-); 4.20 (d, 2H, )C=CH-CH2OH); 4.15 (s, 2EI, C-O-CH2-C-); 3.58 [broad tjl~, ~CH(OH) ]; 3.18 (d, 2H, ~C=CH-CH2-~-); 1.71 [d, 6H, ~C=C-(CH3)2~; 1.15 (s, 3H, ~C-O- I -CH3 ) Mass spec ~m/e]: 320 [M-18], 251, 233, 221, 171, 143, 141, 137, 125, 113, 97, 95, 81, 69 Chemical Ionization: M+ ~ H = 339; M.W. = 338 ~1~93SI~
chromatography on silica gel (1 g, 20% ether in petroleum ether to give a mixture of 2S*, 3R*-3-` acetoxy-6E~(2-acetoxyethylidene)-2-methyl-2 [4,8-dimethyl-5-(2-tetrahydropyran-2-yloxy)-7-nonenyl}oxepane and 2S*, 3S*-acetoxy~E-(2-acetoxyethylidene) - 2-methyl-2-~4,8-dimethyl-5-(2-tetrahydropyran-2-yloxy)-7-nonenyl]--oxepane as a colorless oil (2 mg, 20%). The mixture of compounds is separated by preparative thin layer chromatography (silica gel, 30~ ethyl acetate in hexane).
~:~lt7~35;~
2S*, 3R*-3-Acetoxy~E-(2-acetoxyethylidene) ~ 2-methyl-2-- (4~8-dimethyl-5-hydroxy-7-nonenyl)-oxepane 2S*, 3R*-3-Acetoxy~E-(2-acetoxyethyliden~-2-~ethyl~
2-[4,8-dimethyl-5-(2-tetrahydropyran-2-yloxy)-7-nonenyl]-oxepane (2mg, 0.02 mmole) in tetrahydrofuran (2 ml), water (0.3 ml) and glacial acetic acid (2 drops) is heated at 65 (bath temperature) in a well-capped test tube for 2 hours. The mixture is allowed to cool to room temperature and is treated with ether (10 ml) and water (3 ml). The organic phase is dried (Na2SO~) and the solvent is removed _ vacuo to yive a colorless oil (1.5 mg). The oil is homogeneous as determined by thin layer chromatography analysis (30~ ethyl acetate lS in hexane).
ir (nea~); 3497, 1739 cm 1; nmr (CDC13)~; o.sn (d, J=6 Hz, 3H, OEI3-CH), 1.13 (s, 3H, CH3-¢-O-), 1062 and 1.73 [both s, 3H each, (C}I3)2C=CH], 2.03 (s, 6H, CH3CO2), 4.10 (bs, 2H,\O-CH2-C=), 4.60 (d, J=7 Hz, 2H, =C-CH2OAc), 5.32 5m, 2H, /C-CH- and ~=CH-CH2OAc).
2~,3~6E~2-Hydroxyethylidene)-2-methyl-2t~,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol -A. 2S~,3R~3-Acetoxy~æ-(2-acetoxyethylidene)-2-me~hyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane (333 mg) is dissolved in acetone (5 ml) and treated slowly with Jones reagent (2 mmole) at 0 under nitrogen.
The resulting mixture is stirred for 7 minutes and then treated with ether (30 ml) and water (20 ml). The layers are separated and the aqueous layer is extracted with ether (20 ml). The combined organic layer is washed with water (30 ml), dried (MgSO4) and evaporated ln vacuo to give an oil. The crude product is used as such in the next step.
B. The crude product obtained above (161 mg) is dissolved in tetrahydrofuran (5 ml) and water (5 ml).
3Si~ `
EXAMPLE 17 (Cont'd) To this mixture, tetra n-butyl ammonium hydroxide (20~ solution in methanol, 1 ml) is added under nitrogen at room temperature and the resulting mix~ure is stirred for 40 hours. The mixture is treated with ether (S0 ml) and the organic layer is washed with 10~
hydrochloric acid ~2x15 ml), dried (MgSO~) and evaporated ln vacuo to give an oil. This crude product is purified by chromatography on a SilicAR column (5 g). 2S*,3R*-6~~(2-hydroxyethylidene~-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol (81.8 mg) is eluted with ether. Its ir, nmr spectra, Rf on thin layer and retention time on gas chromatography are identical to those o~ the natural product (Compound I~ reported in U.S. Patent No. 4,086,358. The compound has the following physical analysis:
ir (neat) p: 2.91 and 5.88 nmr CTDC13 ~: 5-41 (m, 2H, &=CH-CH2OH and \C=CH-CH2-8-); 4.20 (d, 2H, )C=CH-CH2OH); 4.15 (s, 2EI, C-O-CH2-C-); 3.58 [broad tjl~, ~CH(OH) ]; 3.18 (d, 2H, ~C=CH-CH2-~-); 1.71 [d, 6H, ~C=C-(CH3)2~; 1.15 (s, 3H, ~C-O- I -CH3 ) Mass spec ~m/e]: 320 [M-18], 251, 233, 221, 171, 143, 141, 137, 125, 113, 97, 95, 81, 69 Chemical Ionization: M+ ~ H = 339; M.W. = 338 ~1~93SI~
8-Acetox -2 6-dimeth 1-5-[(1-ethoxYethoxy)]-2-octene Y ~ Y
A mixture o~ 8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene~2.27g, 10.6 mmole), ethyl vinylether (0.82 g.
11.4 mmole), ~toluenesulfomc acid monohydrate (catalytic amount) and ether (50 ml) is stirred a~ room temperature for 16 hours. The resulting mixture is treated with ether (150 ml) and washed with 5% sodium bicarbonate solution (2X100 ml). The organic phase is dried (Na2SO4), and evaporated in vacuo to give the crude product. The crude material is further purified by column chromatography on silica gel (25 g, 5% ethyl acetate in hexane) to give 8-acetoxy-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene as a colorless oil.
3,7-Dimethyl-4-[(1-ethoxyethoxy)]-6-octen-1-ol 2 A mixture of 8-acetoxy-2,6-dimethyl-5-~(1-ethoxy-ethoxy)]~2-octene (0.5mmol~), saturated potassium carbonate solution (9 ml), water (6 ml) and methanol (100 ml) is stirred for 3 hours at room temperature. Most of the methanol is removed in vacuo and the residue is treated with ethyl acetate (500 ml) and water (200 ml). The organic phase is dried (Na2SO4) and evaporated in vacuo to give the crude product. This material is further purified by column chromatography on silica gel (25 g, 15~ ethyl acetate in hexane) to give 3,7-dimethyl-4-5 [(1-ethoxyethoxy)]-6-octen-1-Ql as a colorless oil.
EXAMP~E 20 8-Bromo-2,6-dimethyl-5 [(1-ethoxyethoxy)]-2-octene Triphenylphosphine (1.83g, 7.02 mmole) in methylene chloride (30 ml) is added to a mixture of 3,7-dimethyl-4-~ ethoxyethoxy)]-6-octen-1-ol (4.7mmQle) carbon tetra-3~ ~
bromide (1.94 g, 5~85 mm), pyridine (2 ml) andmethylene chloride at 0C under nitrogen. The resulting mixture is allowed to warm to room temperature and stirred for 4 hours after which it is treated with methylene chloride (lO0 ml) and washed with 5% sodium bicarbonate solution. The organic phase is dried and evaporated ln vacuo to give the crude product. This material is further purified by column chromatography on silica gel (lO0 g, 2 ethyl acetate in hexane) to give 8~bromo-2,6-dimethyl-5-O [(l-ethoxyethoxy)~-2-octene as a colorless oil.
EXAMPL~ 21 l-Acetoxy-3-acetoxymethyl-7,11,15-trimethyl-12-[(1-ethoxy-ethox )]-(E)-2,14-hexadecadiene Y
The Grignard reagent is prepared from 8-bromo-2,6-15 dimethyl-5-[(l-ethoxyethoxy)]~2-octene(26 mm~le~ and magnesium (27.1mmole)intetrahydrofuran (35 ml) at room temperature under argon. An excess o~ the Grignard reagent is added to a solution of 7-methyl-3-hydroxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octen-l-ol (423.3 mg, 1.3mmole) in 20 tetrahydrofuran at 0C, followed by Li2CuCl4(0.1mmole) and the mixture is stirred for 1.5 hours at 0. The mixture is allowed to warm to room temperature and then treated with ice water (125 ml) and ethyl acetate (400 ml). The organic phase is separated, dried (Na2S04) and evaporated 25 in vacuo to give the crude product. This material is then treated with acetic anhydride (lO ml) and pyridine (2 ml) and stirred for 16 hr. at room temperature. The resulting mixture is treated with ether (lO0 ml) and then washed with saturated cupric sulfate solution (lO0 ml) and 5~
30 sodium bicarbonate solution (lO0 ml). The organic phase is dried (Na2S04) and evaporated ln vacuo to give an oil which is further purified by column chromatography on silica yel ~7~35~
(7 g, 7% ethyl asetate in hexane) to give 1-acetoxy-3-acetoxymethyl-7,11,15-trimethyl~12-[(1-ethoxyethoxy)]
(E)-2,14-hexadecadiene as a colorless oil.
A mixture o~ 8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene~2.27g, 10.6 mmole), ethyl vinylether (0.82 g.
11.4 mmole), ~toluenesulfomc acid monohydrate (catalytic amount) and ether (50 ml) is stirred a~ room temperature for 16 hours. The resulting mixture is treated with ether (150 ml) and washed with 5% sodium bicarbonate solution (2X100 ml). The organic phase is dried (Na2SO4), and evaporated in vacuo to give the crude product. The crude material is further purified by column chromatography on silica gel (25 g, 5% ethyl acetate in hexane) to give 8-acetoxy-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene as a colorless oil.
3,7-Dimethyl-4-[(1-ethoxyethoxy)]-6-octen-1-ol 2 A mixture of 8-acetoxy-2,6-dimethyl-5-~(1-ethoxy-ethoxy)]~2-octene (0.5mmol~), saturated potassium carbonate solution (9 ml), water (6 ml) and methanol (100 ml) is stirred for 3 hours at room temperature. Most of the methanol is removed in vacuo and the residue is treated with ethyl acetate (500 ml) and water (200 ml). The organic phase is dried (Na2SO4) and evaporated in vacuo to give the crude product. This material is further purified by column chromatography on silica gel (25 g, 15~ ethyl acetate in hexane) to give 3,7-dimethyl-4-5 [(1-ethoxyethoxy)]-6-octen-1-Ql as a colorless oil.
EXAMP~E 20 8-Bromo-2,6-dimethyl-5 [(1-ethoxyethoxy)]-2-octene Triphenylphosphine (1.83g, 7.02 mmole) in methylene chloride (30 ml) is added to a mixture of 3,7-dimethyl-4-~ ethoxyethoxy)]-6-octen-1-ol (4.7mmQle) carbon tetra-3~ ~
bromide (1.94 g, 5~85 mm), pyridine (2 ml) andmethylene chloride at 0C under nitrogen. The resulting mixture is allowed to warm to room temperature and stirred for 4 hours after which it is treated with methylene chloride (lO0 ml) and washed with 5% sodium bicarbonate solution. The organic phase is dried and evaporated ln vacuo to give the crude product. This material is further purified by column chromatography on silica gel (lO0 g, 2 ethyl acetate in hexane) to give 8~bromo-2,6-dimethyl-5-O [(l-ethoxyethoxy)~-2-octene as a colorless oil.
EXAMPL~ 21 l-Acetoxy-3-acetoxymethyl-7,11,15-trimethyl-12-[(1-ethoxy-ethox )]-(E)-2,14-hexadecadiene Y
The Grignard reagent is prepared from 8-bromo-2,6-15 dimethyl-5-[(l-ethoxyethoxy)]~2-octene(26 mm~le~ and magnesium (27.1mmole)intetrahydrofuran (35 ml) at room temperature under argon. An excess o~ the Grignard reagent is added to a solution of 7-methyl-3-hydroxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octen-l-ol (423.3 mg, 1.3mmole) in 20 tetrahydrofuran at 0C, followed by Li2CuCl4(0.1mmole) and the mixture is stirred for 1.5 hours at 0. The mixture is allowed to warm to room temperature and then treated with ice water (125 ml) and ethyl acetate (400 ml). The organic phase is separated, dried (Na2S04) and evaporated 25 in vacuo to give the crude product. This material is then treated with acetic anhydride (lO ml) and pyridine (2 ml) and stirred for 16 hr. at room temperature. The resulting mixture is treated with ether (lO0 ml) and then washed with saturated cupric sulfate solution (lO0 ml) and 5~
30 sodium bicarbonate solution (lO0 ml). The organic phase is dried (Na2S04) and evaporated ln vacuo to give an oil which is further purified by column chromatography on silica yel ~7~35~
(7 g, 7% ethyl asetate in hexane) to give 1-acetoxy-3-acetoxymethyl-7,11,15-trimethyl~12-[(1-ethoxyethoxy)]
(E)-2,14-hexadecadiene as a colorless oil.
Claims (4)
1. The process for the preparation of a compound of the formula which comprises reacting a compound of the formula with magnesium to produce a compound of the formula reacting the product with a compound of the formula to produce a compound of the formula and reacting the product with a Lewis acid or a protic acid, wherein M is an O-tetrahydropyranyl group or an O-ethoxyethyl group and X is tosyl, mesyl, brosyl, chloro, bromo, and iodo.
2 . The process of Claim 1 wherein the Lewis acid is boron trif1uoride etherate.
3. The process of Claim 1 wherein the protic acid is p-toluenesulfonic acid.
4. A compound of the formula wherein M is an O-tetrahydropyranyl or O-ethoxyethyl group, whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000401602A CA1179358A (en) | 1978-06-29 | 1982-04-23 | Total synthesis of the utero-evacuant substance d,l- zoapatanol |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US920,432 | 1978-06-29 | ||
| US05/920,432 US4177194A (en) | 1978-06-29 | 1978-06-29 | Total synthesis of the utero-evacuant substance D,L-zoapatanol |
| CA330,241A CA1125775A (en) | 1978-06-29 | 1979-06-21 | Total synthesis of the utero-evacuant substance d,l-zoapatanol |
| CA000401602A CA1179358A (en) | 1978-06-29 | 1982-04-23 | Total synthesis of the utero-evacuant substance d,l- zoapatanol |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA330,241A Division CA1125775A (en) | 1978-06-29 | 1979-06-21 | Total synthesis of the utero-evacuant substance d,l-zoapatanol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1179358A true CA1179358A (en) | 1984-12-11 |
Family
ID=27166299
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000401602A Expired CA1179358A (en) | 1978-06-29 | 1982-04-23 | Total synthesis of the utero-evacuant substance d,l- zoapatanol |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1179358A (en) |
-
1982
- 1982-04-23 CA CA000401602A patent/CA1179358A/en not_active Expired
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5625078A (en) | Processes for the production of 13-ether derivatives of milbemycins and novel intermediates therefor | |
| JPH0560835B2 (en) | ||
| Guindon et al. | Preparation of ethyl 5 (s), 6-epoxy-3 (r)-(methoxymethoxy) hexanoate: a key chiral intermediate for mevinolin and compactin. | |
| Nakata et al. | Stereoselective acyclic ketone reduction: synthesis of the synthons having three consecutive chiral centers | |
| Satoh et al. | . ALPHA.,. BETA.-Epoxy sulfoxides as useful intermediates in organic synthesis. II. A novel synthesis of. ALPHA.-sulfenylated ketones and. ALPHA.-sulfenylated aldehydes from. ALPHA.,. BETA.-epoxy sulfoxides. | |
| Bartels et al. | A selectivity study of activated ketal reduction with borane dimethyl sulfide | |
| CA1179358A (en) | Total synthesis of the utero-evacuant substance d,l- zoapatanol | |
| Kametani et al. | Stereocontrolled synthesis of the brassinolide side chain via a pyranone derivative | |
| CA1125775A (en) | Total synthesis of the utero-evacuant substance d,l-zoapatanol | |
| Matsumoto et al. | The synthesis of ar-abietatrien-12, 16-oxide and its C-15 epimer. | |
| Labadie et al. | Studies toward the total synthesis of saudine: simple and stereoselective synthesis of a model caged ketal backbone | |
| ITOKAWA et al. | A novel sesquiterpene peroxide from Alpinia japonica (Thunb.) MIQ. | |
| US4182717A (en) | Total synthesis of the utero-evacuant substance d,l-zoapatanol | |
| EP0585104B1 (en) | A method of preparing a saturated monocyclic hydrocarbon compound and an intermediate therefor | |
| NAKATA et al. | A total synthesis of (±)-warburganal | |
| Bennis et al. | A new route to some enantiomerically pure substituted morpholines from D-ribono-and D-gulono-1, 4-lactones | |
| JPH0121146B2 (en) | ||
| Asakawa et al. | Sesquiterpene lactones of Eremanthus incanus and Porella japonica. Crystal structure and stereochemistry of eregoyazidin | |
| TANAKA et al. | Synthetic studies on a picrotoxane sesquiterpene, coriamyrtin. II. An effective stereocontrolled synthesis of the picrotoxane skeleton except for a C1 unit at the C9 position and functionalization of the five-membered ring | |
| Ponthieux et al. | Preparation of α, α-bis (phenylseleno) ketones | |
| Hagiwara et al. | A total synthesis of (-)-sacculatal. | |
| Fronza et al. | Carbohydrate-like chiral synthons: Synthesis of the N-trifluoroacetyl derivatives of 4-amino-2, 4, 6-trideoxy-L-lyxo-,-L-arabino, and-L-ribo-hexose from the (2S, 3R)-2, 3-diol formed from cinnamaldehyde in fermenting baker's yeast | |
| US5434300A (en) | Method for preparing dodecahydro-3A,6,6,9A-tetramethylnaphtho [2,1-B]furan and novel haloethyl decalin derivatives | |
| Angle et al. | Stereoselective synthesis of 3-hydroxy-2-sulfonyltetrahydrofurans from β-(triethylsilyloxy) aldehydes and p-tolylsulfonyldiazomethane | |
| Baker et al. | Stereoselective synthesis of (±)-ancistrofuran and its stereoisomers |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |