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SYNTHESIS OF BIOACTIVE TERPENES FROM WIELAND-MIESCHER KETONE AND ITS METHYL ANALOG.?
A. K. Banerjee* and M. Laya-Mimo
Abstract - The Wieland-Miescher ketone (1) and its methyl analog (2) have been utilized for the synthesis of several sesquiterpenes like warburganal, muzigadial, albicanol, etc. Similarly several bioactive diterpenes like taxodione, pisiferic acid, aphidicolin, etc., have been synthesized from these ketones. The utility of several reagents in the total synthesis of terpenoid compounds has been documented. The developments of several routes for a single terpene from these ketones have been discussed.
? To the memory of Professor D. H. R. Barton whose work and worth will not be forgotten.
1- Introduction
The organic chemists are frequently acquainted with the fact that a wise choice of starting material is essential in the design phase of the synthesis of organic compounds, specially complex natural products. Judging by the chemical literature one can observe that the Wieland-Miescher ketone (1) and its methyl analog (2) have been utilized for the synthesis of several bioactive terpenes owing to the presence of several interesting functional groups (saturated carbonyl, a,b-unsaturated carbonyl and angular methyl group).
The Wieland-Miescher ketone (1) can be commercially obtained or prepared1,2 in the laboratory. Its methyl analog (2) is probably not commercially available but can be prepared in the laboratory by the published procedure.3,4 The aim of the present review is to describe briefly the synthesis of several bioactive terpenes from these ketones (1) and (2). It describes only the synthesis (total and formal) of bioactive di- and sesquiterpenes. It is necessary to mention that the review does not claim to include the synthesis of all bioactive terpenes from the above mentioned ketones.
2. SYNTHESIS OF SESQUITERPENES
2.1 WARBURGANAL
Warburganal (12)5, a sesquiterpene dialdehyde, shows a strong antifeedant activity against African armyworms, and exhibits heliocidal and cytotoxic activity. As a result of its interesting biological properties warburganal (12) has received great attention from the synthetic chemists. A number of total syntheses of warburganal have been developed by quite a number of organic chemists.6,7
An elegant synthesis of Warburganal (12) from the ketone (2) was reported by Kende and Blacklock8 as depicted in "Fig (1)". The ketone (2), prepared3 by
"Fig.(1)"- The transformation of the ketone (2) to the decalone (6) is described. The decalone (6) is converted to the adduct (10) and (11). Epoxidation of (10) followed by hydrolysis leads the formation of warburganal (12) and epiwarburganal (13), whereas the adduct (11) on similar treatment yields only the warburganal (12).
Reagents: (i) (CH2OH)2, p-TSOH, C6H6 (ii) Li/Liq. NH3, MeI, (iii) N2H4, DEG, KOH, (iv) HCl, MeCOOH, THF, (v) HCO2Et, NaH, THF, (vi) DDQ, C6H6, (vii) (viii) Me3SiCHLiOMe, (viii) KH, THF, (ix) MCPBA, CH2Cl2, NaHCO3,(x) H3O?
Robinson annelation of the 2-methyl-1,3-cyclohexanedione with ethyl vinyl ketone, on ketalization afforded (3) which was converted to the trans-decalone (4) by the reductive methylation procedure of Stork.9 Wolff-Kishner reduction of (4) produced the ketal (5), which without purification was hydrolyzed with acid to obtain the trans-decalone (6)10 in excellent yield. The present method for the synthesis of the decalone (6) appears more efficient and convenient than the methods previously reported11,12, considering the overall yield and the stereoselectivity.
The formyl derivative of the decalone (6) on mild dehydrogenation afforded the unsaturated keto aldehyde (7), which was previously obtained in low yield by Kitahara.13 Selective ketalization of (7) to obtain the monoketal (8) in good yield was possible owing to the hindered nature of the ketone (7). The ketal (8) did not react satisfactorily with Ph3P=CH2, (EtO)POCHOHCH2CH2OMe, or Tosmic but it underwent 1,2-addition with methyl lithium, vinyl lithium and methyl magnesium bromide to afford high yields of the corresponding alcohols. This has also been observed by Goldsmith and Kezar14 in the realization of warburganal by a different route as can be observed in "Fig (2)". The ketal (8) was converted to the diastereomeric mixture of alcohols (9) by treatment with lithium methoxy(trimethylsilyl)methylide. These alcohols, not readily separable by chromatography, underwent smooth elimination to afford the mixture of adducts (10) and (11). Epoxidation of (10) afforded a mixture of epoxy ether adducts which on mild acid hydrolysis afforded warburganal (12) and epi-warburganal (13). Epoxidation of the adduct (11) yielded only one epoxy ether which was converted to warburganal (12) by acid hydrolysis in excellent yield. The present synthesis of warburganal (12) is interesting because it involves only seven steps from the
"Fig.(2)"- An alternative route for the conversion of the decalone (6) to aldehyde (7) is described. Its transformation to the alcohol (19) was carried out by protection of the aldehyde and reaction with methyllithium. On subjection to dehydration and hydroxylation the alcohol (19) was converted to diol (21) whose transformation to warburganal (12) was achieved by oxidation and acid hydrolysis.
Reagents: (i) NaBH4, MeOH, (ii) Li, liq. NH3, MeI, (iii) N2H4, DEG, KOH, (iv) CrO3, H2SO4, (v) NaH, HCOOEt, (vi) PhSeCl, Py, CHCl3, (vii) 30% H2O2, (viii) (HOCH2)2CH2, p-TsOH, (ix) MeLi, Et2O,, (x) MeO2CNSO2NEt3, Et3N, THF, (xi) OsO4, Py, (xii) CrO3, Py, (xiii) H3O?
decalone (6) and is satisfactory compared to the other methods for these bioactive terpenes.
Goldsmith and Kezar14 developed an alternative synthesis of warburganal (12) by a route depicted in "Fig (2)". These authors utilized the same decalone (6) used by Kende8 but did not prepare by the method of Watt.10 In the present method the ketone (2) was converted to the alcohol (14) by reduction and this on reductive methylation of Stork9 yielded the already reported3 compound (15) whose conversion to the decalone (6) was accomplished by Wolff-Kishner reduction and then oxidation. Its transformation to the already reported keto aldehyde (7) was accomplished by a different route. The formyl derivative (16) of the decalone (6), on treatment with phenylselenium chloride in pyridine yielded a mixture of the unsaturated keto aldehyde (7) and the phenylselenyl ketone (17). Oxidation of the crude mixture and elimination of the resulting selenide produced the already described keto aldehyde (7) in quantitative yield. Selective acetalization with propylene glycol yielded the acetal derivative (18) which was converted to the tertiary alcohol (19) with methyl lithium. No rigorous proof of the stereochemistry of the alcohol (19) was provided but on consideration of the accessibility of either face of the carbonyl group one can assume the addition of the nucleophile should occur preferentially from the a-side. Dehydration of (19) with Burguess reagent15 produced the diene (20) quantitatively. This transformation could not be achieved by Wittig reagent. Hydroxylation of (20) with osmium tetroxide produced the known diol (21)16. No diol epimeric at C-9 was obtained and thus this reagent was specific for warburganal stereochemistry. The transformation of the diol (21) to warburganal (12) was carried out by oxidation with Collins reagent followed by acid hydrolysis.
De Groot17 also developed an interesting method for the synthesis of warburganal (12) from Wieland-Miescher ketone (1). The ketone (1) was converted to the alcohol (24) without difficulty by the published procedure12 as depicted in "Fig (3)" via the intermediate (22) and (23) and thus requires no comments. The transformation of the alcohol (24) to the saturated ketone (27) via the intermediates (25) and (27) can easily be realized by dehydration, allylic oxidation and catalytic hydrogenation respectively. Formylation of the ketone (27) followed by selenylation and deselenylation14,18 yielded the a,b-unsaturated aldehyde (28) which on conjugate cyanation19 afforded the 9a-cyano ketone (29). Its (n-butylthio)-methylene derivative (30) on reduction
followed by hydrolysis produced the compound (31) and this on subjection to protection and reduction, respectively, yielded the 9a-aldehyde (32) in excellent yield. Its epimerization to 9a-aldehyde (33) was essential for its subsequent transformation to warburganal (12). After a long trial the epimerization was effected in high yield by treatment of (32) with a large amount of potassium t-butoxide in t-butanol. The resulting 9b-aldehyde (33) on hydroxylation20 followed by hydrolysis afforded warburganal (12).
It is important to mention that the epimerization of the aldehyde (32) to (33) was indispensable because otherwise the hydroxylation process could not have been achieved. This can be explained by assuming that the steric crowding around 9b-proton of (32) allowed the nucleophilic attack on the relatively exposed 9a-aldehyde (32). The salient feature of the present synthesis is the epimerization of the 9a-aldehyde (32) to 9b-aldehyde (33). Banerjee and Vera21 developed an alternative route for the synthesis of the diester (42) as depicted in "Fig (4)" whose conversion to warburganal (12) has already been reported.20 The
"Fig. (3) - The conversion of Wieland-Miescher ketone (1) to the ketone (27) utilising the standard reactions is described. On subjection to a series of reactions like formylation, selenylation, deselenylation, cyanation the ketone (27) was converted to the compound (31) whose conversion to warburganal (12) was effected by protection of the aldehyde group, reduction epimerization of the a-aldehyde to the b-aldehyde and acid hydrolysis respectively.
Reagents: (i) NaBH4, MeOH, BzCl, Py, (ii) MeI, C4H9OK, C4H9OH, (iii) N2H4, DEG, KOH, (iv) 10% Pd-C, (v) TsCl, Py, LiBr, Li2CO3, DMF, (vi), CrO3-Py, CH2Cl2, (vii) NaH, HCOOEt, (viii) PhSeCl, Py, H2O2, (ix) KCN, MeOH, (x) N-BuSH, H?, (xi) NaBH4, H3O?, Hg2Cl2, (xii) (CH2OH)2, H?, DIBAL, (xiii) C4H9OK, C4H9OH, (xiv) LDA, MoO5-MMPA-Py, H3O?.
starting material for the present synthesis was the ketone (1) which was converted to the alcohol (24) by procedure12 as shown in "Fig (3)" and this on oxidation with Jones reagent afforded the ketone (6) whose alternative preparation has already been reported.10 The ketone (6) on treatment with methyllithium in ether yielded a tertiary alcohol, which on heating with dimethylsulfoxide underwent dehydration affording the trisubstituted alkene (34). Its preparation by an alternative route has also been reported.22 In order to synthesize the diester (42), the alkene (34) was oxidized to obtain the a,b-unsaturated ketone (35), which on hydrogenation at atmospheric pressure yielded the saturated ketone (36). The assignment of the b-configuration of the two methyl groups (C-4 and C-4a) follows from analogy. Reduction of the carbonyl group with lithium aluminium hydride produced in 90% yield the alcohol (37). Irradiation of the cyclohexane solution of the alcohol (37) containing lead tetraacetate and iodine with a 250 W tungsten lamp yielded the cyclic ether (38), which on oxidation with chromic acid in acetic acid at room temperature afforded the ketoacid (39).23 To the best of our knowledge this is the first synthesis of the racemic ketoacid (39).
Esterification of the ketoacid (39) with diazomethane afforded the ketoester (40). This, on treatment with sodium hydride and diethyl carbonate in 1,2-dimethoxyethane, furnished (41) whose 1H NMR spectrum was rather complicated, probably due to contamination with a small amount of tautomer. Reduction of the free carbonyl group with sodium borohydride led to the formation of alcohol whose tosyl derivative on heating with lithium bromide and lithium carbonate in dimethylformamide gave the diester (42). Its spectroscopic properties were identical with those of the one reported.20 As the diester (42) has already been converted to ee carbonyl group with sodium borohydride led to the formation of alcohol whose
SYNTHESIS OF BIOACTIVE TERPENES FROM WIELAND-MIESCHER KETONE AND ITS METHYL ANALOG.?
A. K. Banerjee* and M. Laya-Mimo
Abstract - The Wieland-Miescher ketone (1) and its methyl analog (2) have been utilized for the synthesis of several sesquiterpenes like warburganal, muzigadial, albicanol, etc. Similarly several bioactive diterpenes like taxodione, pisiferic acid, aphidicolin, etc., have been synthesized from these ketones. The utility of several reagents in the total synthesis of terpenoid compounds has been documented. The developments of several routes for a single terpene from these ketones have been discussed.
? To the memory of Professor D. H. R. Barton whose work and worth will not be forgotten.
1- Introduction
The organic chemists are frequently acquainted with the fact that a wise choice of starting material is essential in the design phase of the synthesis of organic compounds, specially complex natural products. Judging by the chemical literature one can observe that the Wieland-Miescher ketone (1) and its methyl analog (2) have been utilized for the synthesis of several bioactive terpenes owing to the presence of several interesting functional groups (saturated carbonyl, a,b-unsaturated carbonyl and angular methyl group).
The Wieland-Miescher ketone (1) can be commercially obtained or prepared1,2 in the laboratory. Its methyl analog (2) is probably not commercially available but can be prepared in the laboratory by the published procedure.3,4 The aim of the present review is to describe briefly the synthesis of several bioactive terpenes from these ketones (1) and (2). It describes only the synthesis (total and formal) of bioactive di- and sesquiterpenes. It is necessary to mention that the review does not claim to include the synthesis of all bioactive terpenes from the above mentioned ketones.
2. SYNTHESIS OF SESQUITERPENES
2.1 WARBURGANAL
Warburganal (12)5, a sesquiterpene dialdehyde, shows a strong antifeedant activity against African armyworms, and exhibits heliocidal and cytotoxic activity. As a result of its interesting biological properties warburganal (12) has received great attention from the synthetic chemists. A number of total syntheses of warburganal have been developed by quite a number of organic chemists.6,7
An elegant synthesis of Warburganal (12) from the ketone (2) was reported by Kende and Blacklock8 as depicted in "Fig (1)". The ketone (2), prepared3 by
"Fig.(1)"- The transformation of the ketone (2) to the decalone (6) is described. The decalone (6) is converted to the adduct (10) and (11). Epoxidation of (10) followed by hydrolysis leads the formation of warburganal (12) and epiwarburganal (13), whereas the adduct (11) on similar treatment yields only the warburganal (12).
Reagents: (i) (CH2OH)2, p-TSOH, C6H6 (ii) Li/Liq. NH3, MeI, (iii) N2H4, DEG, KOH, (iv) HCl, MeCOOH, THF, (v) HCO2Et, NaH, THF, (vi) DDQ, C6H6, (vii) (viii) Me3SiCHLiOMe, (viii) KH, THF, (ix) MCPBA, CH2Cl2, NaHCO3,(x) H3O?
Robinson annelation of the 2-methyl-1,3-cyclohexanedione with ethyl vinyl ketone, on ketalization afforded (3) which was converted to the trans-decalone (4) by the reductive methylation procedure of Stork.9 Wolff-Kishner reduction of (4) produced the ketal (5), which without purification was hydrolyzed with acid to obtain the trans-decalone (6)10 in excellent yield. The present method for the synthesis of the decalone (6) appears more efficient and convenient than the methods previously reported11,12, considering the overall yield and the stereoselectivity.
The formyl derivative of the decalone (6) on mild dehydrogenation afforded the unsaturated keto aldehyde (7), which was previously obtained in low yield by Kitahara.13 Selective ketalization of (7) to obtain the monoketal (8) in good yield was possible owing to the hindered nature of the ketone (7). The ketal (8) did not react satisfactorily with Ph3P=CH2, (EtO)POCHOHCH2CH2OMe, or Tosmic but it underwent 1,2-addition with methyl lithium, vinyl lithium and methyl magnesium bromide to afford high yields of the corresponding alcohols. This has also been observed by Goldsmith and Kezar14 in the realization of warburganal by a different route as can be observed in "Fig (2)". The ketal (8) was converted to the diastereomeric mixture of alcohols (9) by treatment with lithium methoxy(trimethylsilyl)methylide. These alcohols, not readily separable by chromatography, underwent smooth elimination to afford the mixture of adducts (10) and (11). Epoxidation of (10) afforded a mixture of epoxy ether adducts which on mild acid hydrolysis afforded warburganal (12) and epi-warburganal (13). Epoxidation of the adduct (11) yielded only one epoxy ether which was converted to warburganal (12) by acid hydrolysis in excellent yield. The present synthesis of warburganal (12) is interesting because it involves only seven steps from the
"Fig.(2)"- An alternative route for the conversion of the decalone (6) to aldehyde (7) is described. Its transformation to the alcohol (19) was carried out by protection of the aldehyde and reaction with methyllithium. On subjection to dehydration and hydroxylation the alcohol (19) was converted to diol (21) whose transformation to warburganal (12) was achieved by oxidation and acid hydrolysis.
Reagents: (i) NaBH4, MeOH, (ii) Li, liq. NH3, MeI, (iii) N2H4, DEG, KOH, (iv) CrO3, H2SO4, (v) NaH, HCOOEt, (vi) PhSeCl, Py, CHCl3, (vii) 30% H2O2, (viii) (HOCH2)2CH2, p-TsOH, (ix) MeLi, Et2O,, (x) MeO2CNSO2NEt3, Et3N, THF, (xi) OsO4, Py, (xii) CrO3, Py, (xiii) H3O?
decalone (6) and is satisfactory compared to the other methods for these bioactive terpenes.
Goldsmith and Kezar14 developed an alternative synthesis of warburganal (12) by a route depicted in "Fig (2)". These authors utilized the same decalone (6) used by Kende8 but did not prepare by the method of Watt.10 In the present method the ketone (2) was converted to the alcohol (14) by reduction and this on reductive methylation of Stork9 yielded the already reported3 compound (15) whose conversion to the decalone (6) was accomplished by Wolff-Kishner reduction and then oxidation. Its transformation to the already reported keto aldehyde (7) was accomplished by a different route. The formyl derivative (16) of the decalone (6), on treatment with phenylselenium chloride in pyridine yielded a mixture of the unsaturated keto aldehyde (7) and the phenylselenyl ketone (17). Oxidation of the crude mixture and elimination of the resulting selenide produced the already described keto aldehyde (7) in quantitative yield. Selective acetalization with propylene glycol yielded the acetal derivative (18) which was converted to the tertiary alcohol (19) with methyl lithium. No rigorous proof of the stereochemistry of the alcohol (19) was provided but on consideration of the accessibility of either face of the carbonyl group one can assume the addition of the nucleophile should occur preferentially from the a-side. Dehydration of (19) with Burguess reagent15 produced the diene (20) quantitatively. This transformation could not be achieved by Wittig reagent. Hydroxylation of (20) with osmium tetroxide produced the known diol (21)16. No diol epimeric at C-9 was obtained and thus this reagent was specific for warburganal stereochemistry. The transformation of the diol (21) to warburganal (12) was carried out by oxidation with Collins reagent followed by acid hydrolysis.
De Groot17 also developed an interesting method for the synthesis of warburganal (12) from Wieland-Miescher ketone (1). The ketone (1) was converted to the alcohol (24) without difficulty by the published procedure12 as depicted in "Fig (3)" via the intermediate (22) and (23) and thus requires no comments. The transformation of the alcohol (24) to the saturated ketone (27) via the intermediates (25) and (27) can easily be realized by dehydration, allylic oxidation and catalytic hydrogenation respectively. Formylation of the ketone (27) followed by selenylation and deselenylation14,18 yielded the a,b-unsaturated aldehyde (28) which on conjugate cyanation19 afforded the 9a-cyano ketone (29). Its (n-butylthio)-methylene derivative (30) on reduction
followed by hydrolysis produced the compound (31) and this on subjection to protection and reduction, respectively, yielded the 9a-aldehyde (32) in excellent yield. Its epimerization to 9a-aldehyde (33) was essential for its subsequent transformation to warburganal (12). After a long trial the epimerization was effected in high yield by treatment of (32) with a large amount of potassium t-butoxide in t-butanol. The resulting 9b-aldehyde (33) on hydroxylation20 followed by hydrolysis afforded warburganal (12).
It is important to mention that the epimerization of the aldehyde (32) to (33) was indispensable because otherwise the hydroxylation process could not have been achieved. This can be explained by assuming that the steric crowding around 9b-proton of (32) allowed the nucleophilic attack on the relatively exposed 9a-aldehyde (32). The salient feature of the present synthesis is the epimerization of the 9a-aldehyde (32) to 9b-aldehyde (33). Banerjee and Vera21 developed an alternative route for the synthesis of the diester (42) as depicted in "Fig (4)" whose conversion to warburganal (12) has already been reported.20 The
"Fig. (3) - The conversion of Wieland-Miescher ketone (1) to the ketone (27) utilising the standard reactions is described. On subjection to a series of reactions like formylation, selenylation, deselenylation, cyanation the ketone (27) was converted to the compound (31) whose conversion to warburganal (12) was effected by protection of the aldehyde group, reduction epimerization of the a-aldehyde to the b-aldehyde and acid hydrolysis respectively.
Reagents: (i) NaBH4, MeOH, BzCl, Py, (ii) MeI, C4H9OK, C4H9OH, (iii) N2H4, DEG, KOH, (iv) 10% Pd-C, (v) TsCl, Py, LiBr, Li2CO3, DMF, (vi), CrO3-Py, CH2Cl2, (vii) NaH, HCOOEt, (viii) PhSeCl, Py, H2O2, (ix) KCN, MeOH, (x) N-BuSH, H?, (xi) NaBH4, H3O?, Hg2Cl2, (xii) (CH2OH)2, H?, DIBAL, (xiii) C4H9OK, C4H9OH, (xiv) LDA, MoO5-MMPA-Py, H3O?.
starting material for the present synthesis was the ketone (1) which was converted to the alcohol (24) by procedure12 as shown in "Fig (3)" and this on oxidation with Jones reagent afforded the ketone (6) whose alternative preparation has already been reported.10 The ketone (6) on treatment with methyllithium in ether yielded a tertiary alcohol, which on heating with dimethylsulfoxide underwent dehydration affording the trisubstituted alkene (34). Its preparation by an alternative route has also been reported.22 In order to synthesize the diester (42), the alkene (34) was oxidized to obtain the a,b-unsaturated ketone (35), which on hydrogenation at atmospheric pressure yielded the saturated ketone (36). The assignment of the b-configuration of the two methyl groups (C-4 and C-4a) follows from analogy. Reduction of the carbonyl group with lithium aluminium hydride produced in 90% yield the alcohol (37). Irradiation of the cyclohexane solution of the alcohol (37) containing lead tetraacetate and iodine with a 250 W tungsten lamp yielded the cyclic ether (38), which on oxidation with chromic acid in acetic acid at room temperature afforded the ketoacid (39).23 To the best of our knowledge this is the first synthesis of the racemic ketoacid (39).
Esterification of the ketoacid (39) with diazomethane afforded the ketoester (40). This, on treatment with sodium hydride and diethyl carbonate in 1,2-dimethoxyethane, furnished (41) whose 1H NMR spectrum was rather complicated, probably due to contamination with a small amount of tautomer. Reduction of the free carbonyl group with sodium borohydride led to the formation of alcohol whose tosyl derivative on heating with lithium bromide and lithium carbonate in dimethylformamide gave the diester (42). Its spectroscopic properties were identical with those of the one reported.20 As the diester (42) has already been converted to ee carbonyl group with sodium borohydride led to the formation of alcohol whose
"Fig. (4) - An alternative route of the alkene (35) is described.Its transformation to cyclic eter (38) was achieved in moderate yield whose conversion to ketoacid (39) was done by oxidation. Its conversion to diester (42) was carried out by standard organic reactions which proved a valuable intermediate for warburganal.
Reagents: ( i ) MeLi, Et2O, DMSO; (ii) CrO3-3,5-dimethyl pyrazole; (iii) 10% Pd-C, H2 ; (iv) LiAlH4, THF, (v) Pb(OAc)4, I2, C6H12; (vi) CrO3, AcOH; (vii) CH2N2, Et2O; (viii) CO(COOMe)2, NaH, 1,2-dimethoxyethame; (ix) NaBH4, MeOH, TsCl, Py, LiBr, Li2CO3.
warburganal (12), the present route for the diester (42) constitutes a formal total synthesis of warburganal.
2.2 MUZIGADIAL
Muzigadial (58), a drimane sesquiterpene isolated from the bark of East African plant Warburgia ugandensis and W. stuhlmanii24,25 shows potent activity against the African armyworms. In addition, muzigadial (58) exhibits a broad antibiotic spectrum as well as helicocidal activity.24
Muzigadial provides a challenge to the organic chemists since it possesses an exomethylene group at C-5 and the chiral center at C-6. Meinwald26 developed a first total synthesis of muzigadial (58) by a route as depicted in "Fig (5)". The starting material of the present synthesis was the Wieland-Miescher ketone (1) which on selective acetalization with 2-methyl-2-ethyl-1,3-dioxolane (MED) afforded 95% of the monoacetal (42). Previous workers could not obtain this excellent yield27,28 by the use of conventional reagents ethylene glycol and p-toluenesulfonic acid. The diene (43), obtained from the monoacetal (42) by Wittig reaction, on reduction with lithium in liquid ammonia afforded a mixture of monoenones (44), (45) and (46) in a 58:23:19 ratio. These mixtures on subjection to oxidative hydroboration provided a mixture of diastereomeric alcohols (47) in 81% yield which on oxidation furnished a mixture of decalones (48) in a 6:53:41 ratio as revealed by GLC analysis. Epimerization of (48) under basic conditions followed by subjection of the resulting product under Wittig reaction produced the exomethylene acetal (49) in 95% yield. Hydrolysis of the acetal group (49) was effected with a mixture of hydrochloric acid, glacial acetic acid and tetrahydrofuran in a ratio 1:2:3 to obtain the decalone (50). It is important to mention that the migration of the exocyclic double bond was avoided by the use of the mixture of acid and solvent in the mentioned deacetalization. An alternative route was also developed for the synthesis of the decalone (50) but was found not efficient compared to the described above mentioned. The ketone (50) was fully characterized by its m.p., IR, 1H NMR, 13C NMR and MS spectra, some of which were missing in the previously published work.29
In order to accomplish the transformation of the decalone (50) to muzigadial (58), it was converted to its hydroxymethylene derivative (51), which was found to exist in two tautomeric forms on the basis of its spectroscopic properties. The selenenation of (51) followed by oxidation of the resulting product yielded the a,b-unsaturated aldehyde (52) in 95% yield. The yield of the aldehyde (52) was also obtained in 53% yield when the hydroxymethylene derivative (51) was subjected to dehydrogenation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Selective protection of the aldehyde moiety of (52) as dimethoxymethylene acetal afforded ke toacetal (53) in 85% yield. This was made to react with lithium salt of (methoxymethyl)diphenylphosphine oxide to obtain the adduct (54) which underwent decomposition under the reaction conditions to afford the enol ether (55) with Z configuration in 75% yield. Several attempts were made to introduce the hydroxyl group into (55). Successful hydroxylation was achieved by using osmium tetroxide in presence of tert-butyl hydroperoxide (TBHP), tetraethylammonium hydroxide (Et4NOH) and tert-butanol. The resulting product was a mixture of hydroxy aldehydes (56) and (57) in a 10:1 ratio and obtained in 85% yield. On subjection to acid hydrolysis (?)-muzigadial (58) and (?)-epi-muzigadial (59) in 76% and 7% yield, respectively. The overall yield of (?)-muzigadial (58) from the Wieland-Miescher ketone (1) was 11%.
2.3 ALBICANOL
Albicanol (66), a drimane-type sesquiterpene, was isolated from the liverworts
"Fig.(5)"- An alternative synthesis of the decalone (50) from the Wieland-Miescher ketone (1) is described. Its hydroxymethylene derivative on subjection to selenenation followed by oxidation afforded the unsaturated aldehyde (52) in excellent yield. The protection of the aldehyde moiety of (52) followed by the conversion of the resulting product to the adduct (54) led to the formation of the enol ether (55) which on hydroxylation yielded a mixture of hydroxy-aldehyde (56) and (57). This on acid hydrolysis afforded muzgadial (58) in 85% yield.
Reagents: (i) MED, (CH2OH)2, (ii) CH2=PPh3, (iii) Li/liq. NH3, (iv) BH3-THF, H2O2, NaOH, (v) CrO3-Py, (vi) NaOMe-MeOH, (vii) 1N HCl- AcOH-THF, (viii) HCO2Et/NaOEt, (ix) PhSeCl-Py, 30% H2O2,
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