合成路线1

The synthesis of the C16-C34 fragment of tacrolimus (FK-506), the key intermediate on the total synthesis of tacrolimus has been described: 1) The reaction of (Z)-2-butene (I) with (­)-beta-methoxydiisopinocamphenylborane (IPCB-OCH3; II) by means of potassium tert-butoxide and butyllithium in THF gives the butenyl borane (III), which is condensed with 2-benzyl-acetaldehyde (IV) by means of BF3 ethearate in ether to yield the monobenzylated diol (V). The silylation of (V) with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole affords the fully protected olefine (VI), which is oxidized with OsO4 and N-methylmorpholine N-oxide (NMO) in acetone/water/benzene to give a diastereomeric mixture of the diols (VII) and (VIII) separated by column chromatography. The epoxidation of (VII) with NaH and tosyl imidazole in THF afforded epoxide (IX), which was condensed with the protected furfuryl alcohol (X) by means of butyllithium and BF3 ethearate in THF giving the diol (XI). The oxidation of (XI) with m-chloroperbenzoic acid (MCPBA) with simultaneous trapping of the intermediate with 2-methoxypropene (XII) afforded the spiroenone (XIII), which was condensed with alkyne (XIV) by means of trimethylaluminum and a zircornium complex yielding the expected spiroketone (XV). 2) The alkyne intermediate (XIV) has been obtained by condensation of the chiral tosylate (XXVII) with lithium acetylide giving the chiral pentynol ether (XVIII). (XVIII) then was deprotected with p-toluenesulfonic acid and silylated with TBDMS-Cl. 3) The undesired diol (VIII) can also be converted into the epoxide (IX) by reaction with benzoyl chloride and dimethylaminopyridine (DMAP) to give the expected benzoate, which was subsequently treated with methanesulfonyl chloride and DMAP, and finally epoxidized with sodium methoxide in methanol. 4) The diol (VII) can be selectively obtained by reaction of methyl 5-O-benzyl-beta-D-ribofuranoside (XXIV) with methylmagnesium chloride and copper bromide giving methyl 5-O-benzyl-3-deoxy-3-C-methyl-beta-D-xylofuranoside (XXV). (XXV) was treated with ethanethiol and TBDMS-Cl in the presence of imidazole and a catalytic amount of DMAP affording the dithioacetal (XXVI). Finally, this compound is treated with HgCl2 and CaCO3, and reduced with NaBH4 in THF/methanol to afford the desired diol (VII). 5) The intermediate vinyl bromide (XXIII) has been obtained according to a previously reported method (Ragan, J.A. et al. J Org Chem 1989, 54(18): 4267) .

合成路线2

Cyclization of 2,2-dichloroisobutyraldehyde (I) - obtained by reaction of isovaleraldehyde (II) with chlorine in DMF - with 2-benzyloxyacetaldehyde (III) - produced by reaction of 2-butene-1,4-diol (IV) with benzyl chloride by means of NaOH in water, followed by ozonolysis in MeOH and finally reduction with triphenylphosphine in ethyl acetate - and aqueous NH4OH in methanol gives the imidazole derivative (VI), which is iodinated with I2 and NaOH in dichloromethane to yield the 5-iodoimidaz-ole derivative (VII). Condensation of compound (VII) with bis(3,5-dichlorophenyl)disulfide (VIII) by means of LiH in DMSO affords the dichlorophenylsulfanyl imidazole (IX), which is alkylated with 4-(chloromethyl)pyridine (X) and K2CO3 in DMF to provide the fully substituted imidazole (XI). Debenzylation of compound (XI) with conc. HCl in refluxing ethanol gives the carbinol (XII), which is finally treated with trichloroacetyl isocyanate and triethylamine in methanol/water.

合成路线3

The O-silylated 4-hydroxy-delta-caprolactam (XXXIV) was reduced with borane and the resulting piperidine was protected as the N-Boc derivative (XXXV). Lithiation employing sec-butyllithium and TMEDA, followed by addition of aldehyde (XXXIII) produced an inseparable 3:1 mixture of the alcohol epimers (XXXVIIa-b) and the trans-oxazolidinone (XXXVI). Acylation of the mixture with m-(trifluoromethyl)benzoyl chloride afforded a diastereomeric mixture of (trifluoromethyl)benzoates (XXXVIIIa-b), separable by column chromatography. Deprotection of the Boc group from the syn-isomer of (XXXVIII) by means of trimethylsilyl triflate and lutidine gave the free amine (XXXIX). Subsequent cyclization of (XXXIX) with AgNO3 afforded the desired cis-quinolizidine (XL) with very high diastereoselectivity. Reductive cleavage of the (trifluoromethyl)benzoyl group of (XL), followed by treatment of the free alcohol with methanesulfonyl chloride provided mesylate (XLI).

合成路线4