Stereoselective Synthesis of anti‐β‐Hydroxy‐α‐amino Acids through Dynamic Kinetic Resolution

Abstract

-Hydroxy-a-amino acids are valuable constituents of a variety of biologically active natural products and medicinally important compounds, and many approaches for their enantioselective synthesis have been reported. [1][2][3][4] In connection with our ongoing research into the total synthesis of cyclodepsipeptides, [5] papuamides, and polyoxypeptins with biologically interesting activities, we needed a new method for the preparation of a large amount of (2R,3R)-and (2S,3S)-3-hydroxyleucine bearing the skeleton of an anti-b-hydroxy-aamino acid, with control of both relative and absolute configuration. It is reported that syn-b-hydroxy-a-amino acid derivatives have been efficiently synthesized with high diastereo-and enantioselectivities from chirally labile aamino-b-keto esters through dynamic kinetic resolution with the Ru-BINAP catalyst (BINAP = 2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl), which was originally developed by Noyori and co-workers. [3,4,6] Using this methodology, we have achieved stereoselective synthesis of all four stereoisomers of 3-hydroxyleucine. [3i] In this method, the syn isomer 2 of 3-hydroxyleucine was directly prepared by the asymmetric hydrogenation, but the anti isomer 4 needed to be constructed from 2 by two additional steps, oxazoline formation with internal Sn2 inversion and acid hydrolysis (Scheme 1). To our knowledge, direct preparation of the anti-b-hydroxy-a-amino acids from the a-amino-b-keto esters by using an Ru-chiralphosphane catalyst has not been reported. Herein, we describe the highly anti-selective hydrogenation of a-aminob-keto esters through dynamic kinetic resolution with the Ru-BINAP catalyst. We envisioned hydrogenation through the five-membered transition state 5 (Scheme 1) with the 2-amino substituent of a-amino-b-keto ester 3 as a directing group; this reaction would directly produce anti-b-hydroxy-a-amino acid 4 in place of the syn product 2 that is produced through the six-membered transition state 6.Hydrogenation of methyl 2-amino-4-methyl-3-oxo-pentanoate (3, where R = Me), the substrate producing 3-hydroxyleucine, was examined in detail, and the results are shown in Table 1. Reactions were carried out with the Ru-(S)-BINAP catalyst (4.2 mol %) at 50 8C under 100 atm of hydrogen. The absolute and relative configurations of the hydrogenated product were established, after transformation into benzoylamide derivative 7, by comparison with authentic samples. [3i] In the preliminary experiment with the TsOH salt in methanol we were pleased to find that excellent anti selectivity (97:3) was observed by 1 H NMR analysis, although the enantioselectivity needed to be improved (Table 1, entry 1). With this encouraging result in hand, we extensively surveyed the conditions for the anti-selective hydrogenation with high enantioselectivity. First, the effect of counter anions in ammonium salts was investigated. The hydrochloric acid salt showed high anti diastereoselectivity with modest enantioselectivity (Table 1, entry 3). Interestingly, the tetrafluoroboric acid...

Transition Metal‐Catalyzed Homogeneous Asymmetric Hydrogenation

“…7.34 ). The reverse syn / anti selectivity was believed to be attributed to the unprotected amino group, which coordinated with Ru and served as a stronger directing substituent than the ester group [261] . Excellent dynamic kinetic resolution was observed for anti -selective hydrogenation of racemic α - …”

Equilibrium Studies on Reactive Extraction of α‐Cyclohexyl‐mandelic Enantiomers Using Hydrophilic β‐Cyclodextrin Derivatives Extractants

“…1 Many researchers have attempted the separation of optically active compounds. [2][3][4][5][6][7][8] The most used method in industry is diasteriomeric crystallisation. However, crystallisation is generally inflexible and thus its development for each new racemic mixture is quite time consuming.…”

Enantioselective Partitioning of Racemic Ibuprofen in a Biphasic Recognition Chiral Extraction System

“…2,3 Many researchers have attempted the separation of optically active compounds. [4][5][6][7][8][9][10][11][12][13] Such chiral separation technologies as crystallization, chromatography, kinetic resolution, etc. accelerate researches about chiral compounds, but there still exist some defects for most racemic compounds.…”