A Concise Synthesis of a Very Late Antigen-4 Antagonist <i>trans</i>-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4<i>S</i>)-methoxy-(2<i>S</i>)-pyrrolidinylmethoxy]cyclohexanecarboxylic Acid <i>via</i> Reductive Etherification

Abstract

This contribution describes a concise synthesis to ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy] cyclohexanecarboxylate (2b) as a key intermediate of very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1). The synthesis employs a reductive etherification as a key reaction using (2S,4S)-1-benzyloxycarbonyl-4-methoxypyrrolidine-2-carboxyaldehyde (12) and trans-4-triethylsilyloxycyclohexanecarboxilic acid ethyl ester (13b). This synthesis provides 2b in 6 steps with 38% overall yield from commercially available starting material.Key words 4-hydroxycyclohexanecarboxylic acid; reductive etherification; antagonistWe have discovered a VLA-4 (very late antigen-4, integrin α 4 β 1 ) antagonist, trans-4- [1-[[2,5-dichloro-4-(1-methyl- (1) 1,2) shown in Fig. 1. On the basis of its favorable profile, 1,2) compound 1 was advanced into clinical trials for the treatment of asthma.Compounds 2a-c are key intermediates for accessing 1. Originally, we prepared 2a, b via Route A as shown in Chart 1, which features Mitsunobu etherification of 3, Rh/Al 2 O 3 catalized high pressured hydrogenation of the benzene ring of 4, and the following isomerization of cis-5 to trans-5. On top of that, HPLC or flash column chromatography using a large amount of silica gel was necessary for separation of trans-5 from a mixture of cis-5 and trans-5. To address the troublesome separation, we next established Route B 3) in Chart 1, where we set out tert-butyl trans-4-hydroxycyclohexanecarboxylate (7) as a starting material. At first, the ester 7 was subjected to basic etherification with epichlorohydrin to give the ether 8, which was transformed to the amide 9 by utilization of the sequential 4 steps procedure; nucleophilic addition with vinyl magnesium bromide, amination via a pthalimide, and benzoylation. Next, the pyrrolidine ring construction by means of iodine mediated cyclization 4,5) and the following modification on 4-position substituent of the pyrrolidine successfully provided the amine 2c. However, Route B needed a total of 13 steps to 2c. In continuation of our work on the synthesis of 1, we have now developed a more concise synthetic route to 1 than Route A and B. Herein, we describe the new approach to 1 via the synthesis of ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy] cyclohexanecarboxylate (2b) based on a stereo defined method using reductive etherification.Reductive etherification 6-16) of silyl ethers with carbonyl compounds using triethylsilane as a reductive agent and Lewis acids such as trimethylsilyl trifluoromethanesulfonate (TMSOTf), 6,7) trimethyl iodosilane (TMSI), 8,9) TrClO 4 , 10) BiBr 3 , 11) BiCl 3 , 12) CuOTf, 13) InCl 3 , 14) FeCl 3 15,16) as a catalyst, is a useful transformation reaction in organic synthesis. It is well known that the etherification works well even in case of a secondary alkoxy silyl ethers with ketone in Chart 2.9,16) At this point, we considered that compou...