SmI2-mediated reduction of gamma,gamma-difluoro-alpha,beta-enoates with application to the synthesis of functionalized (Z)-fluoroalkene-type dipeptide isosteres.
A samarium diiodide (SmI(2))-mediated reduction of gamma,gamma-difluoro-alpha,beta-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 gamma,gamma-difluoro-alpha,beta-enoates by SmI(2) 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 alpha-substituted fluoroalkene isosteres (43 and 45) through aldol reactions of Sm-dienolates with the carbonyl compounds. Of particular note, the use of the SmI(2)-HCHO reagent system with chiral enoate 34 provided D-Phe-psi[(Z)-CF[double bond]CH]-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 alpha-position. This was achieved by a sequence of manipulations consisting of beta-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 alpha,alpha-difluoro-beta-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.
Otaka
Akira
A
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. aotaka@pharm.kyoto-u.ac.jp
Watanabe
Junko
J
Yukimasa
Akira
A
Sasaki
Yoshikazu
Y
Watanabe
Hideaki
H
Kinoshita
Takayoshi
T
Oishi
Shinya
S
Tamamura
Hirokazu
H
Fujii
Nobutaka
N
D000475:Alkenes / Q000737:chemistry*; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry; D007097:Imines / Q000737:chemistry; D007454:Iodides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D012493:Samarium / Q000737:chemistry*; D013237:Stereoisomerism
D000475:Alkenes; D004151:Dipeptides; D006845:Hydrocarbons, Fluorinated; D007097:Imines; D007454:Iodides; D012493:Samarium; C409809:samarium diiodide