13 エポキシアルコールへの立体および位置選択的アミノ基導入の新手法 : α-置換セリン構造を持つ天然物の合成(口頭発表の部)

概要

論文の詳細を見る
α-Substituted serine derivatives have recently attracted so much attention from the view points of the design and the synthesis of enzyme inhibitors. Isolation of natural products having α-substituted serine structures such as conagenin (1), myriocin (2), and lactacystin (3) has also spurred much research on synthetic approaches to this class of α-amino acids due to their potent biological activities. For the purpose of developing an efficient method for the preparation of chiral α-substituted serines, we examined Lewis acid mediated cyclizations of seven imidates 5 prepared from the corresponding epoxy alcohols 4 (Table 1). Upon treatment of imidates 5 either with 0.5 equimolar of BF_3・Et_2O or Et_2AlCl in CH_2Cl_2, the cyclization turned out to occur at the more polarized center of the epoxide with complete inversion of the stereochemistry in the cases of trisubstituted epoxy imidates and the imidate derived from cinnamyl alcohol. In the case of disubstituted epoxy imidates, the reaction took place in 5-exo mode rather than 6-endo mode again with complete inversion of the stereochemistry. Interestingly, BF_3・Et_2O always caused the formation of the trichloroacetamides 8 along with the cyclized products 6 or 7, while Et_2AlCl allowed exclusive formation of the cyclized products 6 or 7. Having developed the new stereo- and regioselective cyclization reaction of epoxy imidates 5 which would be useful for the preparation of α-substituted serines, we then investigated the syntheses of conagenin (1) and myriocin (2). Our synthesis of conagenin (1) took the following convergent approach. The carboxylic acid moiety 12 was prepared starting with propiophenone and acetaldehyde by the sequence involved asymmetric aldol reaction followed by in situ syn-selective reduction, acetylation, and RuO_4 induced oxidative cleavage of the benzene ring. For the synthesis of α-methylserine moiety, the above-mentioned methodology was employed. Thus, Et_2AlCl mediated cyclization of the epoxy imidate 13 prepared from methallyl alcohol gave the dihydrooxazole 15 which, upon sequential functional group interconversions, afforded α-methylserine benzyl ester 19. Condensation of the carboxylic acid 12 with α-methylserine benzyl ester 19 followed by alkaline hydrolysis led to the first total synthesis of (+)-conagenin (1). Furthermore, a stereoselective route to the promising precursor of myriocin 31 has been developed based on the combination of Lewis acid mediated cyclization of an epoxy imidate and the chemistry of allenylmethyltrimethylsilanes which we have recently established. TiCl_4 mediated addition of allenylmethyltrimethylsilane to the aldehyde 21 followed by VO(acac)_2 catalyzed epoxidation gave the epoxy alcohol 24 with excellent stereoselectivity. After conversion of 24 into the epoxy imidate 25, successive treatment of 25 with BF_3・Et_2O and acid hydrolysis afforded the diol 27 having all required asymmetric centers with correct absolute streochemistries. Conversion of the diol 27 into the aldehyde 29 followed by Wittig reaction allowed the formation of 31, a protected form of myriocin (2). The synthesis of myriocin (2) from 31 is now in progress.
天然有機化合物討論会の論文
1995-09-01

13 エポキシアルコールへの立体および位置選択的アミノ基導入の新手法 : α-置換セリン構造を持つ天然物の合成(口頭発表の部)

スポンサーリンク

概要

著者

関連論文

スポンサーリンク