New access to α-substituted (Z)-fluoroalkene dipeptide isosteres utilizing organocopper reagents under ‘reduction–oxidative alkylation (R–OA)’ conditions

An efficient synthetic method for Z-fluoroalkene dipeptide isosteres: Application to the synthesis of the dipeptide isostere of Sta-Ala

“…Addition of trimethylaluminum did not show any effect on the reaction course obtaining 3a in 64% yield (entry 2). It would be likely that the formation of the reductive defluorination product 3 involves the generation of the enolate intermediate 5 through sequential two electron transfer from lithiocuprate and elimination of fluoride anion [16,20,30]. Therefore, it was expected that the desired a-alkylated g-fluoro-b,g-enoate 2 can be obtained by treating the enolate intermediate 5 with an appropriate alkylating reagent.…”

“…So far, extensive efforts to develop highly stereoselective methods for the preparation of functionalized fluorinated olefins have been reported [8][9][10][11][12][13][14][15][16][17]. We have been also working in this field for a recent couple of years.…”

Synthesis of fluorine‐containing bioisosteres corresponding to phosphoamino acids and dipeptide units

“…Allmendinger's pioneering study on fluoroalkene isosteres employed aldol reaction of α‐fluoro‐α,β‐unsaturated aldehydes with ester enolates, followed by the introduction of nitrogen functionality by an Overman rearrangement 26, 27. Conceptually distinct from the above‐published methodology, the use of organocopper‐mediated reduction of γ,γ‐difluoro‐α,β‐enoates provides a new access to the fluoroalkene isosteres 32, 33. (Treatment of γ,γ‐difluoro‐α,β‐enoates with R 3 Al–Cu(I) reagent proceeds in an S N 2′ manner to afford α‐alkylated γ‐fluoro‐β,γ‐enoates and related work; see Refs.…”

“…The use of higher species [Me 3 Cu(CN)Li 3 ] improved the yield (74%) (Table II, entry 4). Reaction with other alkyl copper reagents derived from n ‐BuLi or sec ‐BuLi, followed by O 2 oxidation, also gave α‐substituted fluoroalkene isosteres ( 41a and 42a , Table II, entry 5 and 6) 33…”

“…In this article, we briefly review our synthetic studies on phosphatase‐resistant phosphoamino acids corresponding to phosphothreonine (pThr) and its incorporation into a peptide with development of deprotecting methodologies suitable for phosphopeptides 8. Additionally, application of an unexpected reaction using an organocopper reagent, which was found during the synthesis of a nonhydrolyzable phosphothreonine mimetic,24 to the preparation of ( Z )‐fluoroalkene dipeptide isosteres,25–31 is summarized 32, 33. The use of our newly found reaction for the preparation of the dipeptide isosteres provides an access to the isosteres conceptually distinct from the methodologies published in the literature 27–31…”