Pierfrancesco Bravo

New fluorinated chiral synthons

Abstract the syntheses of new optically pure poly-halo and poly-fluoro oxiranes 5b-e by addition of diazomethane on the corresponding β-ketoγ-fluorosubstituted sulphoxide intermediates, both in keto 3 , hydrate 4 or in keto/ hydrate form are described. Syntheses of sulphur-free fluorinated oxiranes 18b-e , β-hydroxy-β-trifluoromethyl amine 21d , α- acid 25d and β,γ-dihydroxy-β-trifluoro- and -chlorodifluoromethyl amines 26c and 26d are shown as examples of their chemical versatility

Chiral sulfoxide controlled asymmetric additions to CN double bond. An efficient approach to stereochemically defined α-fluoroalkyl amino compounds

Abstract This paper presents a full account of studies into the asymmetric addition reactions between α-lithium derivatives of enantiomerically pure methyl and benzyl p-tolyl sulfoxides and the N-(p-methoxyphenyl)aldimines, bearing trifluoromethyl, pentafluoroethyl and ω-hydrotetrafluoroethyl groups, to afford the corresponding α-fluoroalkyl β-sulfinylamines, synthetically versatile precursors of a series of enantiomerically pure biomedicinally important α-fluoroalkylalkylamines and α-fluoroalkyl-β-hydroxyalkylamines. The addition reactions were found to proceed under mild conditions allowing for convenient preparation of the corresponding α-fluoroalkyl β-sulfinylamines in excellent yields and good enantiomeric purity. The stereochemical outcomes of these reactions were shown to be subject to kinetic control, that is in sharp contrast to the corresponding reactions of fluorine-free imines. The absolute configurations of the addition products suggest that the fluoroalkyl group on starting imines plays a role of enantiodirecting, sterically larger substituent causing realization of an unusual for this type of reactions transition states.

Synthesis of optically pure (R)- and (S)-α-trifluoromethyl-alanine

Abstract (+)-(R)- and (−)-(S)-3,3,3-trifluoro-2-methyl-alanine (1) were synthesized from (+)-(R)-methyl-p-tolyl-sulphoxide (5) and N-alkoxycarbonylimino derivatives 4 of methyl 3,3,3-trifluoropyruvate (3). The absolute configuration was determined by X-ray analyses of two synthetic intermediates (2S,RS)-6a and (2R,RS-6c.

Palladium(II) complexes with sulphonium ylides

Keto-stabilized sulphonium ylides displace styrene and benzonitrile from their adducts with PdCl2 to give stable 21 ylideue5f8PdCl2 complexes. Evidence is given for epimeric equilibrium between trans square-planar structures of these new complexes in solution. n nA 11 ylideue5f8PdI2 complex, obtained from dimethylsulphonium methylide, is also described.

Palladium(II) complexes with keto-stabilized phosphonium, arsonium and pyridinium ylides☆

Complexes of the general formula (Ylide)2 · PdCl2 arise in high yields when keto-stabilized alkylphosphoranes (XY2P=CHCOR), arsonanes (Ph3As=CHCOR) and pyridinium ylides (C5H5N+ue5f8C−HCOR) are treated with styrene- or benzonitrile-PdCl2 complexes. Evidence is given for a trans square planar structure in the solid state and for epimeric equilibrium between trans square planar structures in solution for all the new complexes. Cross exchange experiments between ligands of different series are also described.

Asymmetric synthesis of α-arylglycinols via additions of lithium methyl p-tolyl sulfoxide to N-(PMP)arylaldimines followed by “non oxidative” Pummerer reaction

Abstract The results presented in this paper demonstrate that the stereochemical outcome of the reversible additions of lithium (R)-methyl p-tolyl sulfoxide to N-arylidene-p-anisidines (N-PMP imines) is a function of a) the reaction conditions used and b) the electronic properties of the arylidene moiety on the starting imine. High kinetically controlled (2S,RS) diastereoselectivity (−70 °C) was achieved for additions of imines bearing relatively electron-rich N-arylidene groups, while an electron-deficient nature of this group was found to favor the opposite stereochemical outcome. On the other hand, the reactions run under thermodynamically controlled conditions (0 °C) afforded equimolar mixtures of the diastereomeric products regardless of the pattern of substitution on the starting imines. Enantiopure α-arylglycinols were readily synthesized by “non-oxidative” Pummerer rearrangement of diastereomerically pure β-aryl-β-N-(acyl)aminoalkyl sulfoxides, prepared from the corresponding N-PMP derivatives.

Solution/solid-phase synthesis of partially modified retro-ψ[NHCH(CF3)]-peptidyl hydroxamates

Abstract The synthesis of a novel family of partially-modified (PM) retropeptidyl hydroxamates incorporating a [CH(CF 3 )CH 2 CO] unit as a surrogate of the conventional malonyl group, has been accomplished both in solution and in solid-phase. The key step is the Michael-type N -addition of free or polymer bound α-amino hydroxamates to 3-( E -enoyl)-1,3-oxazolidin-2-ones, which takes place very effectively, although with low stereocontrol. A number of tri- and tetra-peptidyl hydroxamates were obtained either in diastereomerically pure form (by solution-phase synthesis, after chromatographic purification), or as mixtures of two epimers in very good chemical purity (by solid-phase, after release from the resin), demonstrating that this method is suitable for preparing combinatorial libraries of PM retro- ψ [NHCH(CF 3 )]-peptidyl hydroxamates for screening as metalloprotease inhibitors.

Total synthesis of a pepstatin analog incorporating two trifluoromethyl hydroxymethylene isosteres (Tfm-GABOB) and evaluation of Tfm-GABOB containing peptides as inhibitors of HIV-1 protease and MMP-9

Abstract We describe the asymmetric total synthesis of a trifluoromethyl (Tfm) analogue of the aspartate protease inhibitor pepstatin incorporating two γ-Tfm-γ-amino-β-hydroxybutyric acid (γ-Tfm-GABOB) units instead of the natural statine units. The title compound as well as several Tfm-substituted precursors were tested as inhibitors of HIV-1 protease and Gelatinase B (MMP-9)

Enantiomerically pure α-fluoroalkyl-α-amino acids: Synthesis of (R)-α-difluoromethyl-alanine and (S)-α-difluoromethyl-serine

Abstract Hydrocyanation of enantiomerically pure N-Cbz α-fluoroalkyl β-sulfinylenamines 1 occurs smoothly by treatment with KCN or by addition of trimethylsilycyanide or diethyl phosphorocyanidate to preformed sodium derivatives of 1. The diastereoisomeric difluoro α-aminonitriles 2b have been transformed in the unnatural amino acids (R)-α-difluoromethyl-alanine and (S)-α-difluoromethyl-serine.

The “Non-Oxidative” Chloro-Pummerer Reaction: Novel Stereospecific Entry to Vicinal Chloroamines and Aziridines

This article describes a new, useful synthetic tool, the “Non-Oxidative” Chloro-Pummerer Reaction (NOCPR), which allows for the use of enantiomerically pure α-Li alkylsulfoxides as chiral α-chloroalkyl carbanions with N-protected imines. In this reaction the sulfinyl group of N-alkoxycarbonyl-β-sulfinylamines derived from aryl-, fluoroalkyl- and alkylimines is displaced by a chlorine atom in a one-pot reaction with clean stereoinversion at carbon. Several 1,2-chloroamines produced via NOCPR were transformed into the corresponding aziridines. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)