合成路线1

The reduction of the chiral propionic acid (VII) with NaBH4 in THF gives the primary alcohol (XXIX), which by reaction with SOCl2 and pyridine in CHCl3 yields the chloride (XXX). Condensation of (XXX) with the butyrolactone intermediate (XXVII) by means of Mg and dibromoethane affords the ketonic adduct (XXXI). Reduction of the exocyclic carbonyl group of (XXXI) with NaBH4 in THF/ methanol provides a 3:1 diastereomeric mixture of the desired chiral alcohol (XXXII) and its OH-epimer (XXXIII) that are separated by flash chromatography. Reaction of (XXXII) with MsCl and TEA, followed by treatment with NaN3, affords the azido derivative (XXXIV), which is condensed with 4-amino-3,3-dimethylbutyramide (XIX) by means of 2-hydroxypyridine and TEA to provide the adduct (XXXV). Finally, the azido group of (XXXV) is reduced with H2 over Pd/ in MeOH to yield the target amino alcohol. An extensive study on the stereoselective reduction of the ketonic adduct (XXXI) has been performed. No better diastereoselectivity than 3:1 has been obtained for the synthesis of the chiral alcohol (XXXII). However, excellent diastereoselectivity (97:3) has been obtained for the synthesis of its OH-epimer, alcohol (XXXIII), with K-selectride in THF, which could potentially provide access to the target amino alcohol via a double inversion protocol.

合成路线2

Alternatively, the chiral phenylpropyl chloride (XXX) can also be prepared as follows: Reduction of the cinnamic acid (XXXVI) with H2 over Pd/C in ethyl acetate gives the phenylpropionic acid (XXXVII), which is treated with oxalyl chloride to yield the acyl chloride (XXXVIII). Condensation of (XXXVIII) with (+)-pseudoephedrine (XXXIX) by means of NaOH in toluene/water affords the chiral amide (XL), which is enantioselectively alkylated with 2-iodopropane (XLI) by means of LDA in THF to provide the adduct (XLII). Reduction of the amide group of (XLII) with BH3/NH3 in THF gives the already reported primary alcohol (XXIX), which is finally treated with POCl3 in hot toluene to afford the phenylpropyl chloride intermediate (XXX).

合成路线3

The condensation of ethyl isovalerate (I) with 1,3-dichloropropene (II) by means of BuLi and DIA in THF gives 5-chloro-2-isopropyl-4-pentenoic acid ethyl ester (III), which is hydrolyzed with NaOH in ethanol to yield the corresponding racemic acid (IV). The optical resolution of (IV) is carried out by means of cinchonidine and TEA in THF to afford 5-chloro-2(S)-isopropyl-4-pentenoic acid (V), which can also be obtained by asymmetric synthesis as follows: Condensation of 4(S)-benzyl-3-(3-methylbutyryl)oxazolidin-2-one (VI) with 3-iodo-1-propenyl chloride (VII) by means of LiHMDS in THF gives 4(S)-benzyl-3-(2(S)-isopropyl-3-methylbutyryl)oxazolidin-2-one (VIII), which is hydrolyzed with LiOH in THF/water to afford the chiral pentanoic acid (V). The reaction of (V) with oxalyl chloride in toluene gives the corresponding acyl chloride (IX), which is treated with dimethylamine and pyridine in dichloromethane to yield the dimethylamide (X). The condensation of (X) with the chiral chloro derivative (XI) (obtained by reaction of the corresponding alcohol (XII) with CCl4 and trioctylphosphine) by means of Mg and 1,2-dibromoethane in THF affords the octenamide (XIII). The cyclization of (XIII) by means of phosphoric acid and simultaneous bromination with NBS in THF provides the chiral bromolactone (XIV), which is opened by means of dimethylamine and Et2AlCl in dichloromethane to give the chiral 5-bromo-4-hydroxy-2,7-diisopropyloctanamide (XV). The reaction of (XV) with acetic anhydride and pyridine in dichloromethane yields the acetoxy derivative (XVI), which is treated with LiN3 to afford the 5(S)-azido derivative (XVII).

合成路线4

The condensation of benzaldehyde (I) with ethyl isovalerate (II) by means of hexyl lithium and DIA in THF gives the hydroxyester (III), which is acylated with Ac2O and DMAP in THF to yield the acetoxy derivative (IV). The elimination reaction in (IV) by means of t-BuOK in THF affords the unsaturated ester (V), which is reduced with diisobutylaluminum hydride in toluene to provide the unsaturated alcohol (VI). Finally, this compound is enantioselectively reduced with H2 over a chiral biphenylyl diphenylphosphine catalyst and a [Rh(norbornadiene)Cl]2 catalyst in toluene to give the target intermediate 2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-1-propanol (VII). (see scheme 26758001d, intermediate (XXIX)).

合成路线5

合成路线6

合成路线7