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New metal-mediated synthetic methods

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One of the major current challenges of organometallic chemistry is to establish new processes that meet economic needs and environmental welfare. In this context, the use of organozinc reagents has regained significant interest from the chemical community. Inexpensive and barely non-toxic, their use offers the possibility to develop new reactions that are more efficient and selective and thus reduce the number of synthetic steps to achieve a given transformation. Over the last few years, our group has actively developed new synthetic methodologies based on zinc-mediated reactions. More specifically, the carbometallation of unactivated alkenes and alkynes by zinc enolate derivatives including radical zinc atom transfer reactions and the development of new organometallic species of carbenoidic type have been studied. A brief overview of our activity in this field for the period 2007-2009 is described hereafter.

Carbometallation of Unactivated Alkenes and Alkynes by Addition of Zinc Enolates or by Radical Zinc Atom Transfer

The carbometalation reaction of zinc enolates on unactivated double bonds has emerged over the past decade as a mechanistically interesting (apparently contra-thermodynamic) and synthetically useful reaction. Our recent mechanistic studies have shown that in addition to the "classical" polar carbozincations, radical-polar crossover processes can also take place.

Review : Chem. Rev., 2010, 110, 2366-2447 ; New J. Chem., 2008, 32, 594-606.

Radical-Polar Crossover Domino Reaction Involving Alkynes : A stereoselective Zinc Atom Radical Transfer. A new domino 1,4 addition / alkyne carbozincation has been developed with dialkylzincs. This radical-polar crossover sequence involves a novel stereoselective radical zinc atom transfer that leads to a vinyl zinc species that can be reacted with electrophiles, thus offering a new multicomponent approach to polysubstituted alkylidene tetrahydrofurans.

Chem.-Eur. J., 2008, 14, 8784-8788. Synthesis, 2011, 1347-1360.

Diastereo- and Enantiocontrolled Synthesis of 3,4-Disubstituted β-Prolines. Enantioenriched 3,4-disubstituted β-prolines have been prepared with a high diastereocontrol through a carbometallation reaction or through a radical-polar domino Michael addition/ carbometallation reaction.

J. Org. Chem., 2007, 72, 398-406.

Radical-polar Crossover Domino Reactions Involving Organozinc Reagents and β-(Allyloxy)-enoates. Organozinc reagents (organozinc halides, diorganozincs and mixed copper-zinc reagents) react with β-(allyloxy)-enoates via a radical-polar crossover process to afford substituted furans in one single synthetic step following a domino reaction involving Michael addition and carbocyclisation. Reversal of diastereoselectivity can be obtained varying the organometallic and/or the reaction conditions.

Tetrahedron Lett. 2008, 49, 3963-3966.


The condensation reaction of allenyl metals with carbonyl derivatives provides a highly efficient entry to propargylic derivatives 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-amino alcohols and homopropargylic amines. The combination of allenylzincs and chiral tert-butylsulfinylimines has emerged as a fruitful marriage for synthesis. Our progress in this field from a methodological stand point are presented hereafter.

Reviews : Tetrahedron : Asymmetry, 2010, 21, 1147-1153 ; Chem.Soc.Rev. 2009, 38, 1-25 New J. Chem., 2007, 31, 1552-1567.

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.

Organometallics. 2012, 31, 4876-4885.

Diastereoselective Synthesis of Homopropargylic N-tert-Butylsulfinylamines. The reaction between N-tert-butylsulfinylimines and 1-trimethylsilyl allenylzinc bromide provides a new entry to the diastereoselective synthesis of enantiopure chiral homopropargylic amines.

Synlett. 2012, 23, 1374-1378.

Stereoselective Synthesis of syn–Β-Amino Propargylic Ethers. We have disclosed the stereoselective synthesis of syn Β-amino propargylic ethers by the addition of racemic lithio 3-(methoxymethoxy)allenylcoppers, and more particularly (cyano) and (mesityl)cuprates, to enantiopure chiral N-tert-butylsulfinylimines. The usefulness of the methodology for the synthesis of compounds having a syn 1,2-aminoalcohol unit has been shown through the development of the asymmetric syntheses of (+)-Β-conhydrine and of an advanced intermediate of (–)-balanol

Adv. Synth. Catal. 2011, 353, 2137-2151.

Stereoselective synthesis of 2-amino-1,3-diol stereotriads. The high-yielding and highly efficient stereoselective synthesis of enantiopure anti,anti and syn,anti acetylenic 2-amino-1,3-diol stereotriads from α-alkoxy-tert-butanesulfinylimines bearing a stereocenter α to the imino group was reported. An excellent kinetic resolution of the racemic allenylzinc species was also observed, allowing a high stereocontrol.

Org. Lett. 2009, 11, 931-934.

Stereoselective synthesis of anti- and syn-acetylenic 1, 2-aminoalcohols
We have recently shown that the stereoselective and enantioselective synthesis of anti- and syn-acetylenic aziridines can be achieved by using the condensation of enantiopure N-tert-butane sulfimines with a racemic allenylzinc carbenoid. Aziridines are obtained in high d.e. and e.e. through the in situ ring closure of the corresponding chloro zinc amide. These azirdines can be opened by water under acidic conditions to give regioselectively and stereospecifically the corresponding anti- and syn-acetylenic 1, 2-aminoalcohols.

Chem.Soc.Rev. 2008, 38, 1-25
New J. Chem., 2007, 31, 1552-1567.
Synlett, 2006, 1039

Acetylenic 1,2-aminoethers anti can also be synthesized stereo- and enantioselectively by the condensation of sulfinimines with the racemic methoxymethylallenylzinc

Synthesis, 2007, 8, 1235-1241

Applications to the synthesis of bio-active natural cyclic alkaloids

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 special interest due to their biological activities as potential antiviral, antitumor, and immunomodulating agents. To illustrate the synthetic usefulness of the methodology of enantioselective addition of allenylzinc carbenoid to tert-butanesulfinimines, we have proposed 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 occuring bioactive related compounds, amongst which the hydrolysis product of clavaminol H and two spisulosines. (see <article316>) 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 recently achieved.


Cyclization of zincated α-N-homoallylamino nitriles : a new entry to enantiopure 2,3-methanopyrrolidines. The stereoselective cyclization of zincated α-N-homoallylamino nitriles has been developed. Following treatment with LDA and transmetalation with zinc bromide, α-N-(homoallyl)amino nitriles lead to 2,3-methanopyrrolidines in moderate to good yields (up to 71%) and excellent selectivities (up to > 98:2). With substrates derived from α-branched homoallylic amines, the formation of trans adducts in excellent diastereoselectivities (up to > 98:2) is observed. The absolute configuration and enantiomeric excess are dependent on the nitrogen protecting-group. In the case of α-N-(1-phenyl-ethyl)-N- homoallylamino nitriles a stereospecific inversion of the homoallylic stereogenic center has been observed. To account for it, a mechanistic rationale involving the formation of zincioiminium ions from zincated α-amino nitriles is put forward. 2,3-Methanopyrrolidines should then arise from a sequence involving an aza-Cope rearrangement providing a configurationally stable (2-azoniaallyl)zinc that then undergoes a [3+2] cycloaddition reaction.

Chem.-Eur. J., 2010, 16, 12668-12677 ; Synlett, 2012, 23, 1374-1378