合成路线:1) The condensation of (S)-L-malic acid (I) and cyclohexanone (II) by means of boron trifluoride etherate gives the cyclic lactone (III),which is reduced by borane and treated with tert-butyldiphenylchlorosilane yielding the silyl ether (IV).The transesterification of (IV) with sodium methoxide in methanol affords 4-(tert-butyldiphenylsilyloxy)-2(S)-hydroxybutyric acid methyl ester (V),which is reduced with borane as before and esterified with naphthalenesufonyl chloride to give the sulfonate (VI).The treatment of (VI) with sodium methoxide affords the epoxide (VII),which is alkylated with decyllithium yielding 1-(tert-butyldiphenylsilyloxy)tetradecan-3(R)-ol (VIII).The benzylation of (VIII) with benzyl trichloroacetimidate (BTA) gives the benzyl ether (IX),which is desilylated with HF in acetonitrile yielding 3(R)-benzyloxytetradecan-1-ol (X).The oxidation of (X) with PDC gives 3(R)-benzyloxytetradecanal (XI),which is condensed with 1-(trimethylsilyl)-2(E)-nonene (XII) by means of a titanium dichloride complex yielding the diastereoisomeric mixture of alcohols (3R,4S,6R)- (XIII) and (3S,4S,6R)- (XIV),which are separated by column chromatography.The silylation of both isomers with tert-butyldimethylsilyl chloride affords both isomers (XV) and (XVI),which are ozonolyzed with O3 and oxidized with NaClO2 to yield the corresponding acids (XVII) and (XVIII).The desilylation of (XVII) and (XVIII) with HF in acetonitrile gives the hydroxy acids (XIX) and (XX),which are cyclized by means of benzenesulfonyl chloride and pyridine to the isomeric oxetanones (XXI) and (XXII).The unwanted isomer (XXII) can be isomerized by means of lithium diisopropylamide in THF to the correct isomer (XXI).The debenzylation of (XXI) by hydrogenation with H2 over Pd/C affords (3S,4S)-3-hexyl-4-[2(R)-hydroxytridecyl]oxetan-2-one (XXIII),which is finally condensed with N-formyl-L-leucine (XXIV) by means of diethyl azodicarboxylate (DEAD) in THF.
合成路线:The chiral aldehyde (XI) can also be obtained as follows:The reaction of dodecanal (XXV) with allylmagnesium bromide (XXVI) in THF gives 1-pentadecen-4-ol (XXVII) as a racemic mixture,which is esterified with 2(R)-acetoxy-2-phenylacetic acid (XXVIII) by means of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) to yield the diastereoisomeric mixture of esters (XXIX) and (XXX),which are separated by flash chromatography.The hydrolysis of (XXIX) and (XXX) with KOH in methanol affords the alcohols (XXXI) and (XXXII).The unwanted isomer (XXXII) can be isomerized to (XXXI) through the formation of the 4-nitrobenzoyl ester and hydrolysis with K2CO3.The benzylation of (XXXI) with benzyl bromide and KH in THF gives the benzyl ether (XXXIII),which is finally ozonolyzed to the desired aldehyde (XI) with O3 in methanol-dichloromethane.
参考文献标题:Total synthesis of (-)-tetrahydrolipstatin
文献作者:Tehim,A.; Chen,P.; Hanessian,S.
参考来源:J Org Chem 1993,58(27),7768-81
合成路线:1) The condensation of (S)-L-malic acid (I) and cyclohexanone (II) by means of boron trifluoride etherate gives the cyclic lactone (III),which is reduced by borane and treated with tert-butyldiphenylchlorosilane yielding the silyl ether (IV).The transesterification of (IV) with sodium methoxide in methanol affords 4-(tert-butyldiphenylsilyloxy)-2(S)-hydroxybutyric acid methyl ester (V),which is reduced with borane as before and esterified with naphthalenesufonyl chloride to give the sulfonate (VI).The treatment of (VI) with sodium methoxide affords the epoxide (VII),which is alkylated with decyllithium yielding 1-(tert-butyldiphenylsilyloxy)tetradecan-3(R)-ol (VIII).The benzylation of (VIII) with benzyl trichloroacetimidate (BTA) gives the benzyl ether (IX),which is desilylated with HF in acetonitrile yielding 3(R)-benzyloxytetradecan-1-ol (X).The oxidation of (X) with PDC gives 3(R)-benzyloxytetradecanal (XI),which is condensed with 1-(trimethylsilyl)-2(E)-nonene (XII) by means of a titanium dichloride complex yielding the diastereoisomeric mixture of alcohols (3R,4S,6R)- (XIII) and (3S,4S,6R)- (XIV),which are separated by column chromatography.The silylation of both isomers with tert-butyldimethylsilyl chloride affords both isomers (XV) and (XVI),which are ozonolyzed with O3 and oxidized with NaClO2 to yield the corresponding acids (XVII) and (XVIII).The desilylation of (XVII) and (XVIII) with HF in acetonitrile gives the hydroxy acids (XIX) and (XX),which are cyclized by means of benzenesulfonyl chloride and pyridine to the isomeric oxetanones (XXI) and (XXII).The unwanted isomer (XXII) can be isomerized by means of lithium diisopropylamide in THF to the correct isomer (XXI).The debenzylation of (XXI) by hydrogenation with H2 over Pd/C affords (3S,4S)-3-hexyl-4-[2(R)-hydroxytridecyl]oxetan-2-one (XXIII),which is finally condensed with N-formyl-L-leucine (XXIV) by means of diethyl azodicarboxylate (DEAD) in THF.
合成路线:The chiral aldehyde (XI) can also be obtained as follows:The reaction of dodecanal (XXV) with allylmagnesium bromide (XXVI) in THF gives 1-pentadecen-4-ol (XXVII) as a racemic mixture,which is esterified with 2(R)-acetoxy-2-phenylacetic acid (XXVIII) by means of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) to yield the diastereoisomeric mixture of esters (XXIX) and (XXX),which are separated by flash chromatography.The hydrolysis of (XXIX) and (XXX) with KOH in methanol affords the alcohols (XXXI) and (XXXII).The unwanted isomer (XXXII) can be isomerized to (XXXI) through the formation of the 4-nitrobenzoyl ester and hydrolysis with K2CO3.The benzylation of (XXXI) with benzyl bromide and KH in THF gives the benzyl ether (XXXIII),which is finally ozonolyzed to the desired aldehyde (XI) with O3 in methanol-dichloromethane.
合成路线:The oxetanone (XXIII) can also be obtained as follows:The condensation of 3(R)-benzyloxytetradecanal (XI) with octanoic acid (XXXIV) by means of lithium diisopropylamide gives 5(R)-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid (XXXV),which is deprotected by hydrogenation with H2 over Pd/C yielding the dihydroxy acid (XXXVI).The lactonization of (XXXVI) with p-toluenesulfonic acid affords the hydroxy lactone (XXXVII),which is oxidized with CrO3 H2SO4 to 3-hexyl-6(R)-undecyltetrahydropyran-2,4-dione (XXXVIII).Hydrogenation of (XXXVIII) with H2 over PtO2/C in ethylacetate gives (3S,4S,6R)-3-hexyl-4-hydroxy-6-undecyltetrahydropyran-2-one (XXXIX),which is benzylated with benzyl trichloroacetimidate to the 4-benzyloxy derivative (XL).Ring opening of (XL) with KOH in dioxane-water yields the hydroxy acid (XLI),which is esterified with benzyl bromide to the benzyl ester (XLII).The reaction of (XLII) with dihydropyran (DHP) by means of p-toluenesulfonic acid in dichloromethane affords (2S,3S,5R)-3-benzyloxy-2-hexyl-5-(tetrahydropyran-2-yloxy)hexadecanoic acid benzyl ester (XLIII),which is debenzylated by hydrogenation with H2 over Pd/C in THF to the hydroxy acid (XLIV).The cyclization of (XLIV) with p-toluenesulfonyl chloride in pyridine gives (3S,4S)-3-hexyl-4-[2(R)-(tetrahydropyran-2-yloxy)tridecyl]oxetan-2-one (XLV),which is finally deprotected with pyridinium p-toluenesulfonate in ethanol to afford the oxetanone (XXIII),already obtained in scheme 11082301a.
合成路线:Oxetanone (XLV) can also be obtained as follows:The reaction of 3(R)-hydroxytetradecanoic acid tert-butyl ester (XLVI) with DHP and p-toluenesulfonic acid gives the corresponding tetrahydropyranyl ether (XLVII),which is reduced with dibutylaluminum hydride (DIBAL) in toluene to the aldehyde (XI),already obtained.Compound (XI) is condensed with 2-(p-toluenesulfinyl)acetic acid tert-butyl ester (XLVIII) by means of tert-butylmagnesium bromide in ether-THF affording the sulfinylhydroxy ester (II),which is treated with aluminum amalgam in THF-water to yield the hydroxy ester (L).The alkylation of (L) with hexyl bromide (LI) by means of butyllithium and diisopropylamine in THF-hexane affords 2-hexyl-3(S)-hydroxy-5(R)-(tetrahydropyranyloxy)hexadecanoic acid tert-butyl ester (LII),which is hydrolyzed with KOH in methanol to the corresponding free acid (LIII).The lactonization of (LIII) with pyridinium p-toluenesulfonate in hot ethanol affords oxetanone (LIV) as a diastereomeric mixture,which is separated by column chromatography,finally yielding oxetanone (XLV),previously obtained in scheme 11082301c.
合成路线:A new synthesis of orlistat has been described:The ozonolysis of 3(R)-(tetrahydropyranyloxy)-6-heptenoic acid ethyl ester (LV) with O3 gives the corresponding terminal aldehyde (LVI),which is submitted to a Wittig condensation with octyl triphenylphosphonium bromide (LVII) and butyllithium in ether-THF yielding 3(R)-(tetrahydropyranyloxy)-6(Z)-tetradecenoic acid ethyl ester (LVIII).The reduction of (LVIII) with DIBAL in toluene-dichloromethane affords the corresponding aldehyde (LIX),which is condensed with octanoic acid (XXXIV) by means of butyllithium and diisopropylamine in THF to give 2-hexyl-3-hydroxy-5(R)-(tetrahydropyranyloxy)-8(Z)-hexadecenoic acid (LX),which is lactonized with benzenesulfonyl chloride in pyridine to the protected oxetanone (LXI).The deprotection of (LXI) with pyridinium p-toluenesulfonate in hot ethanol affords 3-hexyl-4-[2(R)-hydroxy-5(Z)-tridecenyl]oxetan-2-one (LXII) as a mixture of diastereomers,which are separated by column chromatography yielding the (3S,4S,2'R)-isomer (LXIII).The condensation of (LXIII) with N-formyl-L-leucine (XXIV) as before gives dihydrolipstatin (LXIV),which is finally hydrogenated with H2 over Pd/C in THF.
合成路线:The esterification of optical active (-)-N-methylephedrine (LXV) with octanoyl chloride (LXVI) in tert-butyl methyl ether gives the corresponding ester (LXVII),which is treated with trimethylsilyl chloride and butyllithium-diisopropylamine in THF to yield the enolic trimethylsilyl ether (LXVIII).The condensation of (LXVIII) with the previously obtained aldehyde,3(R)-(benzyloxy)tetradecanal (XI) (scheme 11082301a),by means of TiCl4 in dichloromethane affords,after chromatography,(2S,3S,5R)-5-(benzyloxy)-2-hexyl-3-hydroxyhexadecanoic acid 2(S)-(dimethylamino)-1(R)-phenylpropyl ester (LXIX),which is finally hydrolyzed with methanolic KOH to (2S,3S,5R)-5-(benzyloxy)-2-hexyl-3-hydroxy-hexadecanoic acid (XIX),obtained in scheme 11082301a.The previously obtained 3(R)-(benzyloxy)tetradecanal (XI) can also be obtained by benzylation of 3(R)-hydroxytetradecanoic acid methyl ester (LXX) as usual,to the protected (LXXI),which is then reduced with DIBAL as before.Tetrahydrolipstatin can also be obtained from natural lipstatin by hydrogenation with H2 over Pd/C in ethanol.
参考文献标题:Orlistat
文献作者:Prous,J.; Mealy,N.; Castar,J.
参考来源:Drugs Fut 1994,19(11),1003
合成路线:A new synthesis of orlistat has been described:The ozonolysis of 3(R)-(tetrahydropyranyloxy)-6-heptenoic acid ethyl ester (LV) with O3 gives the corresponding terminal aldehyde (LVI),which is submitted to a Wittig condensation with octyl triphenylphosphonium bromide (LVII) and butyllithium in ether-THF yielding 3(R)-(tetrahydropyranyloxy)-6(Z)-tetradecenoic acid ethyl ester (LVIII).The reduction of (LVIII) with DIBAL in toluene-dichloromethane affords the corresponding aldehyde (LIX),which is condensed with octanoic acid (XXXIV) by means of butyllithium and diisopropylamine in THF to give 2-hexyl-3-hydroxy-5(R)-(tetrahydropyranyloxy)-8(Z)-hexadecenoic acid (LX),which is lactonized with benzenesulfonyl chloride in pyridine to the protected oxetanone (LXI).The deprotection of (LXI) with pyridinium p-toluenesulfonate in hot ethanol affords 3-hexyl-4-[2(R)-hydroxy-5(Z)-tridecenyl]oxetan-2-one (LXII) as a mixture of diastereomers,which are separated by column chromatography yielding the (3S,4S,2'R)-isomer (LXIII).The condensation of (LXIII) with N-formyl-L-leucine (XXIV) as before gives dihydrolipstatin (LXIV),which is finally hydrogenated with H2 over Pd/C in THF.
参考文献标题:Syntheses of tetrahydrolipstatin and absolute configuration of tetrahydrolipstatin and lipstatin
文献作者:Barbier,P.; Schneider,F.
参考来源:Helv Chim Acta 1987,70196-202
合成路线:The esterification of optical active (-)-N-methylephedrine (LXV) with octanoyl chloride (LXVI) in tert-butyl methyl ether gives the corresponding ester (LXVII),which is treated with trimethylsilyl chloride and butyllithium-diisopropylamine in THF to yield the enolic trimethylsilyl ether (LXVIII).The condensation of (LXVIII) with the previously obtained aldehyde,3(R)-(benzyloxy)tetradecanal (XI) (scheme 11082301a),by means of TiCl4 in dichloromethane affords,after chromatography,(2S,3S,5R)-5-(benzyloxy)-2-hexyl-3-hydroxyhexadecanoic acid 2(S)-(dimethylamino)-1(R)-phenylpropyl ester (LXIX),which is finally hydrolyzed with methanolic KOH to (2S,3S,5R)-5-(benzyloxy)-2-hexyl-3-hydroxy-hexadecanoic acid (XIX),obtained in scheme 11082301a.The previously obtained 3(R)-(benzyloxy)tetradecanal (XI) can also be obtained by benzylation of 3(R)-hydroxytetradecanoic acid methyl ester (LXX) as usual,to the protected (LXXI),which is then reduced with DIBAL as before.Tetrahydrolipstatin can also be obtained from natural lipstatin by hydrogenation with H2 over Pd/C in ethanol.
参考文献标题:Stereoselective syntheses of tetrahydrolipstatin and of an analogue,potent pancreatic-lipase inhibitors containing a beta-lactone moiety
文献作者:Barbier,P.; Widmer,U.; Schneider,F.
参考来源:Helv Chim Acta 1987,701412-8
合成路线:synthesis of (3S,4S)-3-hexyl-4-[2(S)-hydroxytridecyl]oxetan-2-one (VI),a key intermediate in the synthesis of orlistat has been reported: Reaction of methyl 3(S)-hydroxytetradecanoate (I) with 2-methoxypropene (II) by means of pyridinium p-toluenesulfonate gives the protected ester (III),which is reduced with DIBAL to the aldehyde (IV).Finally,aldehyde (IV) is condensed with the lithium amide-enolate (V) generated from 1-octanoylbenzotriazole and LiHMDS,resulting in a 4:1 mixture of diastereomeric oxetanones (VI) and (VII) separated by flash chromatography.
参考文献标题:Synthesis of enantiomerically pure beta-lactones by the tandem aldol - Lactonization.A highly efficient access to (3S,4S)-3-hexyl-4-[(2S)-2-hydroxytridencyl]oxetan-2-one,the key intermediate for the enzyme inhibitors tetrahydrolipstatin and tetrahydroes
文献作者:Wedler,C.; et al.
参考来源:J Org Chem 1999,64(14),5301
合成路线:A new asymmetric synthesis of orlistat has been described: Reaction of the chiral aminoindanol (I) with octanoyl chloride (II) in pyridine gives the chiral ester (III),which is condensed with cinnamaldehyde (IV) by means of TiCl4,DIEA and Bu2BOTf in dichloromethane yielding,after chromatographic purification,the anti-aldol adduct (V).Hydrolysis of the chiral auxiliary of (V) with lithium hydroperoxide affords the beta-hydroxy acid (VI),which is protected as the 1,3-dioxan-4-one (VIII) by reaction with pivalaldehyde (VII),TMS-OTf and isopropoxytrimethylsilane (TMS-O-i-Pr).Ozonolysis of (VIII) with O3 in dichloromethane yields the aldehyde (IX),which is condensed with 1-nitrododecane (X) by means of TBAF in DMF to provide the nitroaldol (XI).The dehydration of (XI) with DCC and CuCl in hot acetonitrile gives the nitroalkene (XII),which is reduced with Zn/HOAc to oxime (XIII).Oxidative hydrolysis of (XIII) with ceric ammonium nitrate (CAN) and HNO3 yields diketone (XIV),which is hydrolyzed with HCl in THF providing the beta-hydroxy acid (XV).Esterification of (XV) with benzyl iodide and CsCO3 gives the benzyl ester (XVI),which is estereoselectively reduced with Me4NB(OAc)3H in HOAc/acetonitrile yielding the chiral anti-1,3-diol (XVII).The selective protection of (XVII) with TIPS-OTf and 2,6-lutidine affords the monosilylated ester (XVIII),which is treated with H2 over Pd(OH)2 in ethyl acetate/methanol to furnish the free beta-hydroxy acid (XIX).Cyclization of acid (XIX) by means of PhSO2Cl in pyridine affords the beta-lactone (XX),which is desilylated with TBAF and HOAc in THF giving lactone (XXI).Finally,lactone (XXI) is esterified under Mitsunobu conditions with N-formyl-L-leucine (XXII) by means of DIAD and PPh3 in THF.
参考文献标题:Asymmetric synthesis of (-)-tetrahydrolipstatin: An anti-aldol-based strategy
文献作者:Ghosh,A.K.; Fidanze,S.
参考来源:Org Lett 2000,2(16),2405
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