合成路线1

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2

3) The esterification of L-malic acid (XX) with methanol and acetyl chloride gives the dimethyl ester (XXI), which is reduced with borane-dimethyl sulfide in THF yielding 3(S),4-dihydroxybutyric acid methyl ester (XXII). Partial protection of (XXII) with trityl chloride in pyridine affords 3(S)-hydroxy-4-(trityloxy) butyric acid methyl ester (XXIII), which is hydrolyzed with NaOH to the corresponding free acid (XXIV). The condensation of (XXIV) with succinic acid monoallyl ester, magnesium salt (XXV) by means of the carbonyl diimidazole (DCI) in THF gives 5(S)-hydroxy-3-oxo-6-(trityloxy)hexanoic acid allyl ester (XXVI), which is reduced with triethylborane and NaBH4 in THF and treated with H2O2 at -70 C to afford 3(R),5(S)-6-(trityloxy)hexanoic acid allyl ester (XXVII). The protection of the hydroxyl groups of (XXVII) with tert-butyldiphenylsilyl chloride and imidazole in DMF gives the fully protected ester (XXVIII), which is treated with trifluoroacetic acid in dichloromethane yielding erythro-3(R),5(S)-bis(tert-butyldiphenylsilyloxy)-6-hydroxyhexanoic acid allyl ester (XXIX). The oxidation of (XXIX) with pyridinium chlorochromate in dichloromethane affords the oxo-ester (XXX), which is condensed with phosphonate (X), as in method 2 above, to give ester (XXXI). The hydrolysis of (XXXI) with triphenylphosphine and palladium tetrakis triphenylphosphine as before yields the protected acid (XXXII), which is finally deprotected with tetrabutylammonium fluoride, also as before. [3(R),5(S)-erythro-isomer].

合成路线3

The reaction of (S)-malic acid (I) with dimethoxypropane (II) and Ts-OH gives the carboxymethyldioxolanone (III), which is reduced with BH3/DMS and Ts-OH in toluene, yielding the chiral 2-hydroxybutyrolactone (IV). The silylation of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V), which is methylated to the lactol (Via) by means of methyl lithium in THF. The condensation of the partially silylated dihydroxypentanone (VIb) (tautomer of (VIa)) with thiazolylphosphonium salt (VII) by means of LiHMDS in THF provides the unsaturated primary alcohol (VIII), which by Swern oxidation is converted into the corresponding aldehyde (IX). The condensation of (IX) with phosphonate (X) by means of KHMDS in THF furnishes the heptadienoic ester (XI), which is reduced with DIBAL in THF to give the primary alcohol (XII). The reaction of (XII) with I2 and PPh3 in acetonitrile/Et2O gives the allylic iodide (XIII), which is condensed with sulfone (XIV) by means of KHMDS and Na/Hg in MeOH/THF, yielding the protected diol (XVII). The sulfone (XIV) has been obtained by condensation of the chiral propanol (XV) with methylphenylsulfone (XVI) by means of Ts-Cl and BuLi. The selective deprotection of the primary silyl ether of (XVIII) with CSA in methanol/dichloromethane affords the primary alcohol (XVIII), which is finally oxidized with DMP in dichloromethane to afford the target intermediate carbaldehyde (XIX).

合成路线4

The esterification of L-malic acid (VII) with methanol in acidic medium gives the dimethyl ester (VIII), which is chemoselectively reduced with BH3, Me2S and NaBH4 yielding the diol (IX). The reaction of (IX) with trimethyl orthoformate affords the cyclic orthoester (X), which is reduced with DIBAL to the aldehyde (XI). The methylation of (XI) with MeLi provides the isopropanol derivative (XII), which is submitted to a Swern oxidation to afford the corresponding ketone (XIII). The enolization of (XIII) with TBDMS-OTf and DIEA gives the silylated enol ether (XIV), which is finally cyclized to the target ketone (IV) by means of Lewis acids such as TiCl4, BF3.Et2O, SnCl4 or Et2AlCl, the best yields being obtained with the last mentioned reagent.

合成路线5

The reaction of (S)-malic acid (I) with dimethoxypropane (II) and Ts-OH gives the carboxymethyldioxolanone (III), which is reduced with BH3/DMS and Ts-OH in toluene, yielding the chiral 2-hydroxybutyrolactone (IV). The silylation of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V), which is methylated to the lactol (VIa) by means of methyl lithium in THF. The condensation of the partially silylated dihydroxypentanone (VIb) (tautomer of (VIa)) with thiazolylphosphonium salt (VII) by means of LiHMDS in THF provides the unsaturated primary alcohol (VIII), which by Swern oxidation is converted into the corresponding aldehyde (IX). The condensation of (IX) with phosphonate (X) by means of KHMDS in THF furnishes the heptadienoic ester (XI), which is reduced with DIBAL in THF to give the primary alcohol (XII). The reaction of (XII) with I2 and PPh3 in acetonitrile/Et2O gives the allylic iodide (XIII), which is condensed with sulfone (XIV) by means of KHMDS and Na/Hg in MeOH/THF, yielding the protected diol (XVII). The sulfone (XIV) has been obtained by condensation of the chiral propanol (XV) with methylphenylsulfone (XVI) by means of Ts-Cl and BuLi . The selective deprotection of the primary silyl ether of (XVIII) with CSA in methanol/dichloromethane affords the primary alcohol (XVIII), which is finally oxidized with DMP in dichloromethane to afford the target intermediate carbaldehyde (XIX).

合成路线6

The reduction of (R)-malic acid (I) with BH3/Me2S and NaBH4 gives 1,2(R),4-butane-triol (II), which is treated with benzaldehyde dimethylacetal (III) and Ts-OH to yield the 1,3-dioxane (IV). The oxidation of the hydroxymethyl group of (IV) by means of oxalyl chloride in DMSO/dichloromethane affords the carbaldehyde (V), which is submitted to a Wittig condensation with allyltriphenylphosphonium bromide (VI) and potassium tert-butoxide to provide the butadienyl derivative (VII). The reductive cleavage of the benzylidene acetal (VII) by means of DIBAL, followed by Z/E photoisomerization of the resulting diene gives (E)-3(R)-(benzyloxy)-4,6-heptadien-1-ol (VIII). The reaction of the OH group of (VIII) with TsCl and pyridine yields the corresponding tosylate (IX), which is treated with NaCN in DMSO to afford (E)-4(R)-(benzyloxy)-5 ,7-octadienonitrile (X). The hydrolysis of the CN group of (X) with NaOH in methanol/water provides the carboxylic acid (XI), which is esterified with diazomethane to afford the methyl ester (XII). The reaction of (XII) with hydroxylamine and KOH in methanol provides the hydroxamic acid (XIII), which is oxidized with tetrapropylammonium periodate in water to generate an acylnitroso intermediate (XIV), which undergoes a (4+2) cycloaddition to give the trans-1,2-oxazinolactam (XV) along with some cis isomer that is separated by chromatography. The reductive cleavage of the N-O bond of (XV) by means of sodium amalgam yields the allyl alcohol (XVI), which is silylated with Tbdps-Cl and imidazole affording the silyl ether (XVII). The catalytic dihydroxylation of the double bond of (XVII) by means of OsO4 and NMO provides the diol (XVIII) along with some diastereoisomer that is separated by chromatography. The protection of the OH groups of (XVIII) by reaction of 2,2-dimethoxypropane (XIX) and PPTS gives the acetonide (XX). The reduction of the lactone group of (XX) with LiAlH4 in THF proceeds with simultaneous desilylation yielding the piperidino-alcohol (XXI), which is cyclized by means of CBr4, PPh3 and TEA to provide the indolizidine derivative (XXII). The hydrogenolytic removal of the benzyl group of (XXII) with H2 over PdCl2 gives the alcohol (XXIII), which is finally submitted to hydrolysis of its acetonide group by means of 6N HCl in THF to afford the target swainsonine.

合成路线7

The selective monobenzylation of the hydroxysuccinic acid (I) with trifluoroacetic anhydride and benzyl alcohol gives the monoester (II), which is esterified again with 4-methoxybenzyl chloride (PMB-Cl) and K2CO3 in hot DMF yielding the asymetric diester (III). The reaction of (III) with trifluoromethanesulfonic anhydride, CH3SNa and 15-crown-5 affords the methylsulfanyl derivative (IV), which is selectively debenzylated to give the hemiester (V). The condensation of (V) with the intermediate aminomethyl amide (VI) by means of EDAC and HOBT yields the expected amide (VII), which is oxidized with MCPBA or Oxone to afford the methylsulfanyl derivative (VIIIa-b). Unfortunately, during the preceding oxidation, during a variety of conditions, inevitably lead to epimerization of the stereocenter bearing the methylsulfonyl group. Finally (VIIIa-b) is deprotected by hydrogenolysis with Pd/C and formic acid in methanol. The intermediate aminomethyl amide (VI) has been obtained by condensation of N-benzyloxycarbonyl-L-alanine (X) with glycinamide (IX) by means of CDI and TEA in THF to give the dipeptide (XI), which is submitted to an acidic Hofmann rearrangement using I,I-bis(trifluoroacetoxy)iodobenzene (PIFA) yielding the desired aminomethyl amide (VI).

合成路线8

Malic acid (I) was protected as the 1,2-O-isopropylidene derivative (II) upon treatment with acetone in the presence of acid catalyst. Condensation of (II) with paclitaxel (III) using diisopropylcarbodiimide and DMAP produced the 2'-ester (IV). After hydrolytic cleavage of the isopropylidene protecting group of (IV), conversion to the corresponding sodium carboxylate salt furnished the title compound.

合成路线9

The pyrrolidine building blocks are in turn synthesized as shown in Scheme 5. 3(R)-Hydroxypyrrolidine (IV) is protected as the N-Boc derivative (LIV), followed by O-alkylation with benzyl bromide and acidic deprotection of the resulting benzyl ether (LV) to furnish 3(R)-benzyloxypyrrolidine (II). Condensation of pyrrolidine (II) with cyclohexene oxide (XXXI) gives the trans-pyrrolidinocyclohexanol (LVI) as a diastereomeric mixture, which is separated either by crystallization with di-p-toluoyl-L-tartaric acid (DTTA) or by diastereoselective N-oxidation of the undesired diastereoisomer to furnish the target isomer (IX). Alternatively, intermediate (IX) can be obtained by ring opening of epoxide (XXXI) with pyrrolidine (II) in the presence of chiral catalysts. In a different strategy, enantioselective ring opening of cyclohexene oxide (XXXI) with B-bromodiisopinocamphenylborane provides the optically enriched trans-bromohydrin (LVII), which is then condensed with benzyloxypyrrolidine (II) to yield the (1S,2R)-pyrrolidinocyclohexanol (LVIII). Inversion of the configuration of alcohol (LVIII) to produce (IX) is then accomplished by Mitsunobu coupling with formic acid, followed by acidic hydrolysis of the resulting (1R,2R)-formate ester (LIX). Further synthetic strategies leading to the pyrrolidinocyclohexanol (IX) involve cyclization of (R,R)-2-aminocyclohexanol (LX) with 2(R)-benzyloxy-1,4-butanediol ditosylate (LXI), and condensation of (LX) with cyclohexanone (XXVI), followed by asymmetric hydroboration and oxidative work-up of the resulting enamine (LXII) (2). Alternatively, (R,R)-2-aminocyclohexanol (LX) can be converted to the intermediate acetoxysuccinimide (XII) by condensation with 2(R)-acetoxysuccinic anhydride (VI) (prepared from L-malic acid [LXIII] and acetyl chloride) to produce a regioisomeric mixture of succinamic acids (LXIVa) and (LXIVb), which undergoes cyclization to imide (XII) upon heating with acetyl chloride (4). Similarly, racemic trans-2-benzyloxycyclohexylamine (LXV) is resolved by enantioselective N-acylation with isopropyl methoxyacetate in the presence of lipase, followed by hydrolysis of the resulting (R,R)-methoxyacetamide (LXVI) to provide (LXVII) (5). Acylation of (R,R)-2-benzyloxycyclohexylamine (LXVII) with O-acetylmalic anhydride (VI), followed by cyclization with acetyl chloride, yields the N-(2-benzyloxycyclohexyl)succinimide (LXVIII), which is then debenzylated to (XII) by catalytic hydrogenation over Pd/C (4). Scheme 5.

合成路线10