A convenient synthesis of trans -3-hydroxy-L-proline

Abstract

A simple synthesis of cis-3-hydroxy-L-proline has been achieved starting from b -alanine making use of Sharpless asymmetric epoxidation as a key step in the synthesis. cis-3-Hydroxy-L-proline is a relatively rare b -hydroxy-a -amino acid, which has been found as a component of the antibiotic teleomycin.1 In connection with the synthesis of the natural product cyclothialidine2, we required to synthesize the optically pure cis-3-hydroxy-L-proline in good chemical yield. Several syntheses of cis-3-hydroxy-L-proline have been reported. Apart from the enzymatic resolution3 of cisand trans-3-hydroxy proline, a variety of approaches to the synthesis of this amino acid are reported in the literature with varying degree of success and limitations.4 Most of these utilized enzymatic methods or chiron approach to get the optically pure product. We decided to study a new approach to the asymmetric synthesis of cis-3-hydroxy-Lproline 1 using Sharpless asymmetric epoxidation as a key step in the synthetic strategy. A retrosynthetic analysis of this approach is depicted in scheme-1 Cis-3-hydroxy proline can be derived from trans-3-hydroxy proline which in turn can be formed by an intramolecular cyclisation of an amino epoxide. The chiral epoxide can be generated by Sharpless epoxidation of a suitable allylic alcohol. The allylic alcohol in turn can be derived from b alanine by straightforward synthetic manipulations. The synthetic route was started with the readily available and inexpensive b -alanine. A suitable protective group for the amino group was needed which will be stable to Sharpless epoxidation conditions later in the sequence. It is well documented in the literature5 that the Boc or Cbz protected amines usually lead to the formation of cyclic urethane derivatives under these conditions. Various type of N-protecting groups that would encourage cyclization through nitrogen namely N-tosyl, N-trityl, and even unprotected derivatives have been tried but in all the cases the reaction leads to a complex mixture of products. All the problems are taken care of when nitrogen is protected both with tosyl as well as benzyl group.6 The synthetic route adopted to achieve the synthesis of 1 is presented in scheme-2. The methyl ester of b -alanine was readily converted to the N-protected methylester 2 which on reduction with lithium aluminium hydride in ether (0oC) provided the alcohol 3 in quantitative yield. The alcohol 3 was then oxidized with Dess-Martin periodinane to afford the aldehyde 4 in 97% yield while the Swern oxidation of the same compound gave the product only in 69% yield. The aldehyde 4 was allowed to react with triethylphosphono acetate7 and the trans olefin 5 was obtained in 89% yield. Initially the reduction of the unsaturated ester 5 was tried with lithium aluminium hydride in ether but it led to a mixture of allylic alcohol 6 and the corresponding saturated alcohol. However when the reduction of 5 was carried out with AlH3, generated in situ, the allylic alcohol 6 was the only product obtained in quantitative yield. Now the stage is set for carrying out Sharpless asymmetric epoxidation. The allyl alcohol 6 was treated with titanium tetraisopropoxide, tert-butyl hydroperoxide, and L-(+)-diethyl tartarate8 and the epoxy alcohol 7 was obtained in 92% yield with 98% ee. The enantiomeric excess was estimated by NMR shift reagent [Eu(hfc)3] experiments. Initially the direct oxidation of the epoxy alcohol 7 to the epoxy acid 8 with RuCl3/NaIO4 was carried out but the yield obtained in this reaction was generally poor (45% of corresponding methyl ester). Therefore the epoxy alcohol 7 was first oxidized to the aldehyde with Dess-Martin periodinane followed by oxidation with Ag2O to get the epoxy carboxylic acid 8 (91%). Compound 8 was converted to its methyl ester 9 on treatment with diazomethane in high yield. NMR experiments with chiral shift reagent [Eu(hfc)3] revealed the product 9 to have optical purity of 98% ee.