A diastereoselective approach to α-allyl-β-amino acids using the Ireland enolate Claisen rearrangement

Abstract

Ireland enolate–Claisen rearrangements of the esters 11 derived from a range of N-alkoxycarbonyland related β-alanines 9 and allylic alcohols (e.g.10) generally lead to good yields of α-allyl-β-amino acid derivatives 13, isolated for convenience as the corresponding esters 14. The N-tert-butoxycarbonyl (BOC) derivatives 15 proved to be especially useful and led to good to excellent yields of the α-allyl-β-amino acid derivatives 16 and 17, with diastereoselectivities usually in excess of 4:1. One set of optimum conditions consists of rearrangements of the N-BOC derivatives 15 by sequential treatment with lithium diisopropylamide and trimethylsilyl chloride [3 equiv. of each] in tetrahydrofuran at –78 °C followed by ∼4 h under reflux. Isolated chemical yields of the derived methyl esters 16 and 17 were generally in the range 70–88%. The stereochemical outcome of the rearrangements was deduced by conversion of the initial silyloxymethyl derivatives 16d and 17d, derived from the esters (E)-15d and (Z)-15d, into the corresponding cis- and trans-butyrolactones 24 and 26, respectively. The synthetic utility was further demonstrated by conversions of the initial hydroxyethyl derivatives 19 and 20 into the valerolactones 28 and 29 and of the syn-isomer 19 into the piperidine 30. A chair-like transition state 31 is consistent with the direct relationship between the allylic alcohol geometry and the nature of the major diastereoisomer of the α-allyl-β-amino acid derivatives (16 and 17) obtained; the E-lithio enolates of the starting esters are presumably favoured due to intramolecular complexation with the enolised carbamate function.