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New metal-mediated synthetic methods

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Our group develops active research in the area of synthetic methodology focusing on metal-mediated transformations. We currently study the reactivity of main-group organometallic reagents in order to develop synthetic tools for carbon–carbon bond formation under reaction conditions that tolerate the presence of functional groups. Such tools are interesting as they offer the synthetic chemist the possibility to design more direct and efficient strategies to prepare a given target. Furthermore, by using readily available and environmentally benign metals, our research embraces the overall effort to make organic synthesis meet economic needs and environmental welfare. The challenge and originality of our approach is to work with functionalized organometallic reagents and particularly with species that have a reactive functional group in close vicinity of the organometallic linkage. A brief overview of our recent activity in this field is described hereafter.

Radical zinc-transfer-based carbo- and silylzincations of alkynes

Unexpensive and barely toxic, organozinc reagents have regained considerable interest from the chemical community as moderately reactive nucleophiles having a high functional group tolerance. A significant feature of alkylzincs is their dual character that makes that, depending on the reaction conditions, they can react either as carbanions or as alkyl radical precursors. Looking for an entry into the field of step-economical multi-bond forming processes, we have combined these two forms of reactivity in radical-polar cross over sequences. Specifically, we have developed a new entry into the chemistry of alkyne carbozincation based on a chain radical process involving an alkylzinc group-transfer. Synthetically, this approach has been proved useful for the straightforward three-component synthesis of 3-alkylidene carbo- and heterocycles, including alkylidene β-prolines.

More recently, the concept has been extended to the silylzincation of alkynes. Our first results using ynamides as substrates demonstrate that a radical approach can provide a general solution to achieve the silylmetalation of alkynes with trans stereoselectivity, a process that is otherwise difficult to perform.

Functionalization of alkynes by addition of element–metal bonds

  • Silylzincation of alkynes

We have recently demonstrated that disilylzinc reagents (Me2PhSi)2Zn and [(Me3Si)3Si]2Zn react with nitrogen-, sulfur-, oxygen- and phosphorous-substituted terminal alkynes, in the absence of copper or any other catalyst, to provide regio- and stereoselectively the corresponding silylzincation adducts. Both reagents yield β-isomers, and the stereoselectivity is determined by the silyl group : Me2PhSi for cis or (Me3Si)3Si for trans. This reversal of selectivity is attributed to a mechanistic dichotomy. While (Me2PhSi)2Zn reacts through a conventional anionic silicon transfer mechanism, the addition with [(Me3Si)3Si]2Zn occurs following an uncommon radical transfer.

  • Synthesis and reactivity of functionalized δ-chiral allenyl metals

We are also interested in the preparation and reactivity of functionalized δ-chiral allenylmetals having a hetero-substituent in the δ position. In a first approach, we have considered the opening of acetylenic epoxides and aziridines by intramolecular nucleophilic substitution. The process developed implements the rearrangement (intramolecular SN2’) of a zincate intermediate obtained by reaction of a lithiated acetylenic epoxide or aziridine with Zn(SiMe2Ph)2. The resulting allenyl/propargyl zinc intermediate can react subsequently with electrophiles and thus leads to homopropargylic alcohols or amines.

In a second approach, we have demonstrated that silylzincates and silylcuprates react directly and stereospecifically with acetylenic N-(tert-butanesulfinyl)-aziridines as well as with propargylic acetates to afford the corresponding chiral enantiopure δ-aminoallenyl silanes.

Novel synthetic methods with sp3-bimetallic species

Given their functional group tolerance, zinc gem-bimetallic species offer many interesting opportunities to develop domino reactions. In our first foray in this area, we have taken advantage of the compatibility between Matsubara’s reagent (CH2(ZnI)2) and Wilkinson’s complex (ClRh(PPh3)3) to achieve the methylenation–hydrogenation cascade reaction of aldehydes or ketones through a domino process involving two ensuing steps in one pot. The developed protocol is applicable to aromatic and aliphatic aldehydes as well as to ketones.

Condensation of allenyl metals with carbonyl derivatives

The condensation reaction of allenyl metals with carbonyl derivatives provides a highly efficient entry to propargylic intermediates of high synthetic value. Over the past years we have developed a number of synthetic methodologies providing access to enantiopure acetylenic aziridines, alkynyl 1,2-aminoethers and homopropargylic amines. For Reviews, see : Tetrahedron : Asymmetry, 2010, 21, 1147-1153 ; Chem. Soc. Rev. 2009, 38, 1-25 ; New J. Chem., 2007, 31, 1552-1567.

  • Condensation of allenylmetals and chiral N-tert-butylsulfinylimines

The combination of allenylmetals and chiral tert-butylsulfinylimines has emerged as a fruitful marriage for synthesis. For instance, the reaction between N-tert-butylsulfinylimines and 1-trimethylsilyl allenylzinc bromide provides a new entry to the diastereoselective synthesis of enantiopure chiral homopropargylic amines.

Acetylenic 1,2-aminoethers with anti relative stereochemistry between the newly created stereocenters can be readily prepared in diastereo- and enantiomerically pure form by the condensation of sulfinimines with racemic α-methoxymethyl-1-trimethylsilyl allenylzinc bromide. The condensation is also efficient for 3-alkoxy-tert-butanesulfinylimines bearing a stereocenter α to the imino group and has proved useful for the stereoselective preparation of enantiopure anti,anti and syn,anti acetylenic 2-amino-1,3-diol stereotriads.

A similar approach was also developed for the synthesis of syn β-amino propargylic ethers. To achieve the syn relative stereochemistry between the newly created stereocenters, racemic lithio 3-(methoxymethoxy)-allenyl cyano- or mesitylcuprates were used for the condensation with the N-tert-butylsulfinylimines.

The 1,2-aminoalcohol and 2-amino-1,3-diol structural subunits are ubiquitous in bio-active natural cyclic alkaloids (hydroxylated piperidines and pyrrolizidines, indolizidines) which have all attracted interest due to their biological activities as potential antiviral, antitumor, and immunomodulating agents. To illustrate the synthetic usefulness of the above-described synthetic methodologies we have reported short and efficient total or formal synthesis of natural product such as : (-)-α-conhydrine, (–)-1-hydroxyquinolizidinone, a common intermediate for the syntheses of (–)-homopumiliotoxin 223G and (–)-epiquinamide, L-1-deoxyallonojirimycin, L-1-deoxymannojirimycin and the syntheses of sphinganines and naturally occurring bioactive related compounds, amongst which the hydrolysis product of clavaminol H and two spisulosines (See the theme “Synthesis of Compounds of Synthetic or Pharmaceutical Interest”). Synthesis of natural products (+)-epicastanospermine, (+)-β-conhydrine, (-)-balanol, (-)-swainsonine, and (2S,3R)-3-hydroxy-2-phenylpiperidine, an advanced key intermediate of human non-peptide NK-1 receptor antagonists have also been achieved.

  • Configurational Stability of 3-Chloro-1-Trimethylsilyl- Propargyl and Allenyl Metals : A Comparative Study Between Lithium, Titanium and Zinc.

A comparative study of the metallotropic equilibrium between 1-chloro-3-trimethylsilyl- propargyl and allenyl metals, with lithium, titanium triisopropoxide and zinc bromide as the metal, was undertaken. The lithium and zinc species were shown to exist mainly as their allenic metallotropic forms, whereas the titanium species proved to exist predominantly as it propargylic metallotropic form. The configurational stability of these organometallics was next examined using a modification of the Hoffmann test. In each case, the organometallic was reacted with a chiral enantiopure electrophile. The diastereomeric ratios obtained at low and high conversion rates of the organometallic allows to evaluate its configurational behaviour. The lithium species thus exhibited a configurational lability at –125 °C in Trapp solvent to the time scale of its reaction with (+)-camphor, while the titanium analogue proved to be configurational stable at –40 °C in THF–Et2O in the time scale defined by its reaction with (S)-N-tritylprolinal. With the same electrophile, the zinc bromide species was demonstrated to be at least partially labile from -80 °C in THF and its dynamic kinetic resolution was investigated.