Fluoroolefin dipeptide isosteres

Fluoroolefin Dipeptide isosteres Structure, Syntheses, and Appiications... 

Fluoroolefin Dipeptide Isosteres Stmcture, Syntheses, and Applications 701... 

FLUOROOLEFIN DIPEPTIDE ISOSTERES 2.1. Alkenes as amide bond substitutes... 

The preparations of Glyi/r[CF=CH]Gly (4) and Phei/r[CF=CH]Gly (5) were described by Allmendinger and his coworkers [46,47]. The Gly-Gly fluoroolefin dipeptide isostere (4) was synthesized from cyclic acetal (6), obtained by the procedure of Dehmiow [48] involving a carbene insertion and reexpansion reaction. Further elaboration as detailed in Scheme 1 ultimately afforded the A/-protected amino acids (4). 

Methyl fluoro(diethoxyphosphono)dithioacetate (34) has been prepared from difluorinated precursors [56], Fluorophosphonothioacetamides (35) derived from this dithioester, have been successfully transformed into highly functionalized fluoroalkenes (36). Judicious selection of the aldehyde coupling partner can lead expeditiously to the preparation of fluoroolefin dipeptide isosteres following elaboration of the carboethoxy group and desulfurization (Scheme 11). 

Horner-Emmons. The use of 2-fluoro-2-diethylphosphonoacetic acid (41) or acylfluorodiethylphosphonoacetate to prepare fluoroolefin dipeptide isostere precursors (42)... 

T. Allmendinger, E. Felder, E. Hungerbuehler, Fluoroolefin dipeptide isosteres. II. Enantioselective synthesis of both antipodes of the Phe-Gly dipeptide mimic. Tetrahedron Lett. 31 (1990) 7301-7304. 

Watanabe, D., Koura, M., Saito, A., et al. (2005). A highly stereoselective synthesis of fluoroolefin dipeptide isostere. 125th Annual Meeting of the Pharmaceutical Society of Japan, Tokyo, Japan. Pharmaceutical Society of Japan, Abstract 31-0205. 

Two general routes to a new class of dipeptide mimics, the fluoroolefin dipeptide isosteres, will be presented. They allow the preparation of compounds of formula 2 with a wide variety of residues R, and r3 in racemic or enantiomerically pure form. Some of the mimics have been introduced into small peptides of biological interest. Some preliminary results will also be discussed. 

Using similar reaction sequences we have also prepared the corresponding fluoroolefin dipeptide isosteres 15,16 and 17 of Phe-Phe, Gly-Gly and Phe-Gly respectively scheme 5 shows the key intermediates. Applying the silyliinine strategy to die achiral aldehyde 18, one has only access to the Phe-Gly (or any other AA-Gly) analog in racemic form. To overcome this general limitation an alternate route was developed. 

We have established two routes to a new class of peptide mimics, the fluoroolefin dipeptide isosteres. By appropriate selection of the precursors they allow the preparation of anaolgues of dipeptidic combinations of aminoacids bearing no other functionalities in their side chains, e.g. Gly, Ala, Val, Phe, Pro. 

Allmendinger, T., Felder, E., Hungerbuehler, E. Fluoroolefin dipeptide isosteres. In Selective Fluorination in Organic and Bioorganic Chemistry (Weldi, J. T, Ed.). American Chemical Society Washington, 1991, pp. 186-195. Vol. ACS Symp. 456... 

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