Vincent Levacher

Deracemization of diarylmethanes via lateral lithiation–protonation sequences by means of sparteine

Abstract Deracemization of diarylmethane derivatives was investigated by lateral lithiation–protonation mediated by (−)-sparteine. Treatment of racemic 4-phenyltetrahydroisoquinoline 1 with s-butyllithium–(−)-sparteine followed by protonation of the resulting anion afforded (R)-phenyltetrahydroisoquinoline 1 in up to 88% e.e. Following the same procedure, racemic 2-(1-phenylethyl)pyridine 2 was subjected to the lithiation–protonation sequence. The stereochemical outcome of the sequence proved to be highly dependent on the proton sources giving either (S)- or (R)-2-(1-phenylethyl)pyridine 2 with EtOH or t-BuOH respectively in up to 50% e.e.

Preparation of new axially chiral bridged 2,2'-bipyridines and pyridyl monooxazolines (pymox). Evaluation in copper(I)-catalyzed enantioselective cyclopropanation.

This work reports the synthesis of new axially chiral bridged 2,2-bipyridines 1 and pyridylmonooxazolines (pymox) 2. The potential of these new axially chiral N,N-ligands was evaluated in asymmetric catalytic cyclopropanation of styrene derivatives 22a-c with diazoesters 21a,b. While 2,2-bipyridines 1a-c afforded the corresponding cyclopropanes 23a-f in up to 65% ee, pymoxs 2a-e gave somewhat lower enantioselectivities (up to 53% ee). Both classes of ligands produced trans-cyclopropanes 23a-f as the major isomer, although with modest diasteroselectivities (56 : 44 to 78 : 22). A structure-stereoselectivity relationship study of ligands 1 and 2 identified the chiral biaryl axis as being mostly responsible for the enantioselective performances of these ligands.

BROMINE-LITHIUM EXCHANGE ON BROMO-8-HYDROXYQUINOLINES VIA FORMATION OF THEIR SODIUM SALTS

Abstract A short and versatile method is reported for the preparation of 8-hydroxyquinoline derivatives by reaction of n-butyllithium with 5,7-dibromo-8-hydroxyquinoline 2 and 7-bromo-8-hydroxyqumoline 1 as their sodium salts. Thus, bromine-lithium exchange reaction on compound 2 , highly regioselective, gave after addition of various electrophiles, 5-substituted 7-bromo-8-hydroxyquinolines 4a-j in moderate to good yields. The same procedure was also applicable to 7-bromo-8-hydroxyquinoline 1 which led to 7-substituted 8-hydroxyquinolines 3a-b .

Synthesis of strained cyclic peptides via an aza-Michael-acyl-transfer reaction cascade

A new method is presented to prepare strained lactams. Esterification of the C-terminus of a dipeptide with β-nitrostyrene or quinoline-type auxiliaries is followed by lactam formation by an intramolecular aza-Michael-acyl-transfer reaction cascade. Ultimately, the cyclic tetrapeptide cyclo[Phe-Tyr-Ala-Gly] has been prepared.

Rational design of central selective acetylcholinesterase inhibitors by means of a “bio-oxidisable prodrug” strategy

This work deals with the design of a bio-oxidisable prodrug strategy for the development of new central selective acetylcholinesterase inhibitors. This prodrug approach is expected to reduce peripheral anticholinesterase activity responsible for various side effects observed with presently marketed AChE inhibitors. The design of these new AChE inhibitors in quinoline series is roughly based on cyclic analogues of rivastigmine. The key activation step of the prodrug involves an oxidation of an N-alkyl-1,4-dihydroquinoline 1 to the corresponding quinolinium salt 2 unmasking the positive charge required for binding to the catalytic anionic site of the enzyme. The synthesis of a set of 1,4-dihydroquinolines 1 and their corresponding quinolinium salts 2 is presented. An in vitro biological evaluation revealed that while all reduced forms 1 were unable to exhibit any anticholinesterase activity (IC50 > 10(6) nM), most of the quinolinium salts 2 displayed high AChE inhibitory activity (IC50 ranging from 6 microM to 7 nM). These preliminary in vitro assays validate the use of these cyclic analogues of rivastigmine in quinoline series as appealing chemical tools for further in vivo development of this bio-oxidisable prodrug approach.

Diastereoselective alkylation of homochiral 1,2,3,4-tetrahydroisoquinolin-3-one. A potential route to enantiomerically pure 4-substituted tetrahydroisoquinolines

Abstract Enantiomerically pure 1,4-dihydroisoquinolin-3-one 1 was prepared in four steps with an overall yield of 60%. Alkylation of the corresponding lactam enolate has been studied and has proven to be highly diastereoselective. Thus, 4-substituted-1,4-dihydroisoquinolin-3-ones 7a-d were obtained in high chemical yields with up to 97% diastereoisomeric excesses.

Solid phase synthesis of a redox delivery system with the aim of targeting peptides into the brain

A solid phase approach for the preparation of peptides attached to a redox chemical delivery system derived from stable annulated NADH models is reported. The synthesis starts with the grafting on a Merrifield resin of quinoline 4b, precursor of the redox carrier. From the resulting quinoline supported resin 4d, the stepwise SPPS of both octapeptide OP (RPGLLDLK) and octadecaneuropeptide ODN (QATVGDVNTDRPGLLDLK), two neuropeptides exhibiting anorexigenic effects, was successfully achieved by conventional methods. Quaternization of the quinoline moiety prior to cleavage of the modified OP and ODN peptides from the resin, led to the expected quinolinium salt 8a and 8b respectively linked to OP or ODN peptides. Finally, the reduction with NaBH4 monitored by UV-vis, provided the desired annulated NADH models as peptides carriers with either the OP (11a,b) or ODN (12a,b) moiety.

Chiral Quaternary Ammonium Salts in Organocatalysis

The acceleration of a reaction by means of a substoichiometric amount of small chiral organic molecules emerged as a powerful asymmetric synthetic methodology during the early 2000s. As testified by the increasing number of publications, organocatalysis has become the third pillar of catalysis beside metallocatalysis and biocatalysis. In a modern society looking for both efficient and environmentally benign processes, catalysis, especially when making use of usually environmentally benign organic-based catalysts, stands out when talking of a contemporary sustainable chemistry. The term organocatalysis was coined in 2000, along with the conceptualization of generic modes of activation allowing the classification of organocatalytic processes. Nevertheless, the occurrences of organic catalysts in synthesis dated back much before this period of time. Quaternary ammonium salts (R 4 N + X – ) is a representative example of this nonlinear historical evolution. In the late 1960s, leading works by Starks, Makosza and Brandstrom established that amphiphilic quaternary phosphonium or ammonium salts, having long alkyl chains R, were able to accelerate a reaction occurring in a biphasic mixture, either solid/liquid or liquid/liquid immiscible phases. In 1971, Starks proposed the term “phase-transfer catalysis” (PTC) to account for the ability of R 4 N + cation (i) to accelerate the transport a polar nucleophile Nu – species from one polar phase (a solid phase such as a mineral base or an aqueous phase) into a non-polar organic solvent (liquid 2) and (ii) to facilitate/accelerate the addition reaction to a given electrophile E + .