The role of fluorine in the stereoselective tandem Aza-Michael addition to acrylamide acceptors: An experimental and theoretical mechanistic study

Aza-Michael additions of alpha-amino esters to fluorinated acceptors take place in a highly stereoselective manner, to give partially modified Psi-[NHCH2]retropeptides incorporating a hydrolytically stable trifluoroalanine mimic. The reaction mechanism has been investigated experimentally and theoretically, in order to explain the effect of the trifluoromethyl group on the reactivity and the origins of the experimentally observed stereocontrol. The reaction is a two-step process, involving a tandem aza-Michael addition followed by a stereoselective hydrogen transfer. Both steps are base-catalyzed. The high level of stereocontrol is the result of a combination of electrostatic interactions a…

Highly stereoselective tandem aza-Michael addition-enolate protonation to form partially modified retropeptide mimetics incorporating a trifluoroalanine surrogate.

Fluorous (Trimethylsilyl)ethanol:  A New Reagent for Carboxylic Acid Tagging and Protection in Peptide Synthesis

Starting with a fluorous analogue of 2-(trimethylsilyl)ethanol, we have designed an easy method for preparing a new fluorous tag ((F)TMSE) for the protection of carboxylic acids. Because mild conditions are employed in the tag cleavage (TBAF in the presence of 4 A molecular sieves, which prevent racemization), this tag can be advantageously used in the synthesis of peptides and modified peptides, as we have demonstrated with several examples, including the fluorous synthesis of short alpha- and beta-peptides as well as of modified fluorinated retropeptides.

New approaches to the synthesis of organofluorine nitrogenated derivatives

Fluorinated carboxylic acids are valuable building blocks for several types of organofluorine nitrogenated derivatives. In this review paper, several strategies that use these compounds as starting materials are described. First, fluorinated seven-membered cyclic β-amino esters can be diastereoselectively synthesized from these compounds with a ring-closing metathesis (RCM) reaction as the key step. The use of the RCM reaction in a different approach enables the preparation of fluorinated cyclic α-amino acid derivatives. Fluorinated carboxylic acids also constitute the starting material for the asymmetric synthesis of fluorinated allylic amines. Finally, a solution and solid-phase synthesis…

Stereoselective Access to Fluorinated and Non-fluorinated Quaternary Piperidines: Synthesis of Pipecolic Acid and Iminosugar Derivatives

The preparation of optically pure quaternary piperidines, both fluorinated and non-fluorinated, has been achieved from a chiral imino lactone derived from (R)-phenylglycinol. In the case of the fluorinated derivatives, the addition of (trifluoromethyl)trimethylsilane (TMSCF(3)) followed by iodoamination and migration of the CF(3) group allowed access to four derivatives of α-(trifluoromethyl)pipecolic acid. A theoretical study of the CF(3)-group rearrangement has been carried out to help establish the reaction mechanism of this uncommon transformation. Moreover, a route to trifluoromethyl-substituted iminosugars was also developed through the diastereoselective dihydroxylation of suitable s…

New Fluorinated Peptidomimetics through Tandem Aza-Michael Addition to α-Trifluoromethyl Acrylamide Acceptors: Synthesis and Conformational Study in Solid State and Solution

A range of partially modified retro (PMR) psi[NHCH(2)] peptide mimetics containing a hydrolytically stable CH(2)CH(CF(3))CO unit have been synthesized. The first kind of peptidomimetics is obtained from the highly efficient aza-Michael addition of different amines to alpha-trifluoromethyl acrylamide acceptors. Subsequent deprotection of the amino group furnishes the key common intermediate for the synthesis of other families of peptidomimetics: dipeptides, tripeptides, peptidomimetics containing a urea moiety, and structures containing two units of alpha-trifluoromethyl-beta(2)-alanine. Finally, a conformational study of several of the newly synthesized peptidomimetics, performed with the a…

Stereocontrolled solid-phase synthesis of fluorinated partially-modified retropeptides via tandem aza-Michael/enolate-protonation

N-Acylation of Wang resin-bound l-α-amino acids with 2-trifluoromethyl-propenoyl chloride, followed by asymmetric tandem aza-Michael/enolate-protonation by a series of l-α-amino esters and final release from the resin, afforded a representative library of partially-modified retropeptides incorporating a stereodefined trifluoroalanine surrogate. The stereocontrol can be dramatically improved (up to 15:1) by using apolar solvents like carbon tetrachloride and DABCO as base.