Diastereoselective synthesis of the 5-hydroxy-pyrrolidinone amino acid of the microsclerodermins and model studies for an end-game strategy for microsclerodermin B

Christian Winter,Robert D.C Pullin,Timothy J Donohoe

doi:10.1016/j.tetlet.2016.12.045

Abstract

The first diastereoselective synthesis of the 5-hydroxy-pyrrolidinone amino acid common to eight members of the microsclerodermin family is presented. Our strategy involves formal hydration of an unsaturated precursor via the use of a two-step hydroxybromination-debromination protocol; this procedure provides exclusively the requisite 4,5-cis-pyrrolidinone. Furthermore model studies are presented that indicated the potential viability of this hydration strategy in the context of a synthesis of microsclerodermin B.

Highlights

The microsclerodermins represent an intriguing class of cyclic peptide natural product
In 2003 Ma reported the total synthesis of microsclerodermin E,8 which possesses an unsaturated pyrrolidinone residue and whilst early studies by Shioiri and Hamada demonstrated the synthesis of an isolated 5-hydroxypyrrolidinone amino acid,[9] they found that it dehydrated, in line with previous observations made by Faulkner.[1]
Because of the reported ease with which the 5-hydroxypyrrolidinone dehydrated we reasoned that in order to incorporate this residue into a viable total synthesis, hydration of the unsaturated pyrrolidinone should be conducted as late as possible in any synthetic sequence

Summary

Introduction

The microsclerodermins (assigned as variants A-M) represent an intriguing class of cyclic peptide natural product. In 2003 Ma reported the total synthesis of microsclerodermin E,8 which possesses an unsaturated pyrrolidinone residue and whilst early studies by Shioiri and Hamada demonstrated the synthesis of an isolated 5-hydroxypyrrolidinone amino acid,[9] they found that it dehydrated, in line with previous observations made by Faulkner.[1] As part of our efforts we recently disclosed the total synthesis of microsclerodermin J and dehydromicrosclerodermin B, along with the structural reassignment of the C4 pyrrolidinone stereocentre in both natural products and concurrently the adjacent C5 stereocentre in microsclerodermin B.10. Whilst we have so far been unsuccessful in our attempts to prepare microsclerodermin B (1) itself, our synthetic strategy was designed to incorporate a late-stage hydration of the unsaturated pyrrolidinone amino acid II of dehydromicrosclerodermin B in order to reveal the sensitive c-hydroxypyrrolidinone I (Scheme 1) at a late stage. Proposed hydration strategy to prepare the 5-hydroxypyrrolidinone of microsclerodermin B

Results and discussion

H HN H 54

Conclusion

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