SmI2-Mediated Reduction of γ,γ-Difluoro-α,β-enoates with Application to the Synthesis of Functionalized (Z)-Fluoroalkene-Type Dipeptide Isosteres

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Abstract
A samarium diiodide (SmI2)-mediated reduction of γ,γ-difluoro-α,β-enoates (15, 29, and 34) was successfully applied to the synthesis of (Z)-fluoroalkene dipeptide isosteres (23, 30, and 35), which have served as potential dipeptide mimetics. Reduction of the γ,γ-difluoro-α,β-enoates by SmI2 proceeded via successive two-electron transfers to form dienolate species which upon kinetically controlled trapping with t-BuOH yielded Xaa-Gly-type fluoroalkene isosteres exemplified by 23, 30, and 35. Replacement of the t-BuOH kinetic trapping agent with aldehydes or ketones provided access to α-substituted fluoroalkene isosteres (43 and 45) through aldol reactions of Sm-dienolates with the carbonyl compounds. Of particular note, the use of the SmI2−HCHO reagent system with chiral enoate 34 provided d-Phe-ψ[(Z)-CFCH]-d/l-Ser isosteres (45), which could be converted to enantiomerically pure isosteres (49−52) that bore a variety of side chain functionalities at the α-position. This was achieved by a sequence of manipulations consisting of β-lactone formation followed by chromatographic separation and ring-opening with soft nucleophiles. Included in the present work is the first utilization of a Rh-catalyzed Reformatsky reaction of chiral imines for the stereoselective preparation of α,α-difluoro-β-amino acid derivatives (28 and 33). The appropriate choice of reagents (carbonyl compounds for kinetic trapping or ring-opening nucleophiles and imines for Reformatsky reactions) allows the presented methodology to yield various fluoroalkene isosteres possessing a wide range of side chain functionalities.

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