Diastereomeric Fluoroolefins as Peptide Bond Mimics Prepared by Asymmetric Reductive Amination of α‐Fluoroenones

Abstract

Among the numerous peptide bond analogues, monofluorinated olefins are considered to be ideal mimics because of their close steric and electronic similarities.[1] Moreover, fluoroolefins are not affected by chemical or enzymatic hydrolysis. [1c, d, 2] Another important feature is the lack of rotational freedom of this peptidic bond isostere: "transoid" and "cisoid" conformation effects can be estimated separately. Since the pioneering work of Allmendinger et al., [2b] useful synthetic methods have been developed to prepare fluoroolefins as peptide bond analogues. These include classical olefination reactions (aldol, [3] Horner-WadsworthEmmons, [1d, 4] and Peterson [5] reactions) and elegant defluorination reactions.[6] Nevertheless, stereochemical control of the fluoroalkene configuration as well as the chiral centers a to the double bond are still important issues to be addressed.In our project we proposed a stereoselective and mild method to obtain both E and Z isomers of the dipeptide mimics 3. Our strategy was based on an efficient Negishi-type reaction with easily accessible bromofluoroalkenes, [7] allowing us access to both Z and E fluoroenones 2 (Scheme 1).[8] At this stage, we were interested in short sequences to transform unsaturated ketones 2 into chiral allylic primary amines 3, which are potential dipeptide mimics. To our knowledge, no reductive aminations of a-fluoro a,b-unsaturated ketones 2 had been described. Moreover, there are only few examples of either nonstereoselective [9] or asymmetric [10,11] amination reactions of enones in the literature. Since our first attempts as enantioselective reduction studies gave only moderate results, [12] we turned our attention to diastereoselective processes. Only two chiral agents have been used for the diastereoselective reduction of enones : a-methylbenzylamine [11a,b] and Ellmans sulfinamide.[11c] The facile deprotection of the latter and the high diastereoselectivity induced by this auxiliary prompted us to test this method.[11c, 13] Herein we report the first diastereoselective reductive amination of afluoroenones 2 and their transformation into dipeptide mimics.Preliminary tests were made with the aromatic compound 2 a. A one-pot procedure for sulfinyl imine synthesis [14] and subsequent reduction was developed, and we obtained compounds 4 in good yields and high diastereoselectivities (Scheme 2, Table 1). When the imines were purified and isolated before reduction, no significant change in the diastereoselectivity was observed, indicating that the presence of Ti(OEt) 4 does not affect the reduction process. Different metal hydrides were tested for the reductive amination of compound 2 a. Common coordinating reagents such as NaBH 4 , BH 3 , 9-borabicyclo[3.3.1]nonane (9-BBN), and diisobutylaluminum hydride (DIBAL-H) furnished amines 4 a in yields up to 79 % and with excellent diastereoselectivities of up to 97 % de for the crude mixture (entries 1-4, Table 1). It should be noted that in each case a single chromatographic purification on silica...

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