A new method for the preparation of alpha-chlorodifluoromethyl-, alpha-bromodifluoromethyl-, and alpha-difluoromethyl-substituted alpha-hydroxy and alpha-amino acid esters 11, 19-21 is described. The key step of the synthesis is the regioselective alkylation of ketones 5, 7-9 and imines 16-18 with C-nucleophiles. The ketones 7-9 are readily available from 3,3,3-trifluorolactate 1 by a five-step procedure. Subsequent removal of the protecting groups from 19-21 provides the corresponding free amino acids 25, 26, 28.

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A convenient synthesis of fluorinated b-amino acids via Morita-Baylis-Hillman reaction is described. Hydrogenation of Morita-Baylis-Hillman adducts or cuprate addition to the double bond provides ready access to a-substituted b,b-bis(trifluoromethyl) b-amino acids.During the last decade b-amino acids have attracted considerable attention because of their numerous biochemical and synthetic applications. b-Amino acids themselves are present in nature, and are constituents of naturally occurring biologically active peptides. [1][2][3] Fluorine-containing b-amino acids have also received a great deal of attention. Useful synthetic approaches have been developed for the synthesis of different classes of fluorine-containing b-amino acids. a-Substituted b-fluoroalkyl b-amino acids were the persistent aim of many synthetic efforts, primarily, due to their biological activities as enzyme inhibitors. [4][5][6][7] As an extension of our studies on the synthesis of fluorinecontaining amino acids as building blocks for peptide mimetics with enhanced lipophilicity and proteolytic stability, we report on a new and efficient two-step approach to a-alkyl b,b-bis(trifluoromethyl) b-amino acids. The key step is a Morita-Baylis-Hillman reaction 8 (MBH) of hexafluoroacetone imines with acrylic esters followed by functionalisation of the double bond by hydrogenation or cuprate addition.Among the hexafluoroacetone imines available, N-tertbutyloxycarbonylimine 1a seems to be the best substrate for a MBH reaction with respect to an orthogonal protection group strategy. The first attempts to obtain MBH products on reaction of hexafluoroacetone N-tert-butyloxycarbonylimine 1a and methyl acrylate using classical MBH reaction conditions (10 mol%, DABCO, THF as solvent) were disappointing because of a low conversion of the educt. A stoichiometric amount of DABCO resulted in an improved conversion. Nevertheless, under these conditions, the reaction could not be brought to completion. Noteworthy, DBU 9 caused a fast decomposition of imine 1a. Scheme 1Finally, we found that addition of CaH 2 to the mixture of imine 1a, methyl acrylate and stoichiometric amounts of DABCO at room temperature in a clean reaction gave product 2a in 65% yield within a reasonable reaction time (Table 1). Benzyl acrylate reacted in the same manner.The role of the additive CaH 2 remains somewhat obscure, although the transition metal hydride complex catalysis of the MBH reaction is well-known. 8 At this stage we reinvestigated the MBH reaction of hexafluoroacetone N-benzoylimine 1b. 10 We found, that catalysis of the MBH reaction with DABCO is very capricious. We could not obtain the stated yield even with stoichiometric amounts of DABCO because of incomplete conversion and formation of by-products.Again, under optimised conditions, the reaction gave the products 2c-e in fair yields in acceptable reaction times. A very striking example of the usefulness of CaH 2 addition was the reaction of imine 1b with tert-butyl acrylate to provide 2f. Indeed, this reaction does not ...

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