Trans-Concerted Addition to Alkynes: the case of Ynamide Silylzincation.

An original concerted antarafacial mechanism for the addition of diorganosilyl-zinc reagents across the C-C triple bond of ynamides is computationally investigated using DFT calculations. This concerted mechanism, leading to a trans-product in only one step, results in the formation of a Si-C and a Zn-C σ-bond on opposite sides of the π-system. We demonstrate that the mechanism going through a η-vinyl intermediate and the proposal of a radical chain pathway are energetically unsustainable.

α-(Aminomethyl)acrylates as acceptors in radical-polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping.

We demonstrate that α-(aminomethyl)acrylates are suitable acceptors for 1,4-additions of dialkylzincs in aerobic conditions. The air-promoted radical-polar crossover process involves the 1,4-addition of an alkyl radical followed by homolytic substitution at the zinc atom of dialkylzinc. Coordination of the nitrogen atom to zinc enables this S2 process which represents a rare example of alkylzinc-group transfer to a tertiary α-carbonyl radical.

Transition-Metal-Free Synthesis of Enantioenriched Tertiary and Quaternary α-Chiral Allylsilanes.

Access to enantioenriched tertiary and quaternary α-chiral allysilanes without any transition-metal catalyst is reported. This was achieved by enantioselective allylic displacement of γ-silylated allylic bromides through Lewis base activation of Grignard reagents by a bidentate chiral NHC ligand. The process afforded both high γ-regio- and enantioselectivity and is compatible with a wide range of silyl groups on the substrates.

Modular access to substituted germoles by intramolecular germylzincation.

Intramolecular alkyne germylzincation giving access to a wide range of germoles is achieved from triarylhydrogermanes in the presence of diethylzinc and AIBN as radical initiator. The reaction proceeds through activation of the Ge-H bond, leading to a heteroarylzinc intermediate after cyclisation, which can then be involved in a post-functionalisation reaction. Our results show that only 5- cyclizations occur, with benzogermoles being exclusively obtained.

Radical Germylzincation of Aryl- and Alkyl-Substituted Internal Alkynes.

The stereoselective germylzincation of internal alkynes delivering trisubstituted vinylgermanes is achieved via a radical chain process involving PhGeH and EtZn with AIBN as the initiator. Excellent levels of regiocontrol are observed for nonsymmetric (aryl, alkyl)-substituted alkynes and for propargylic alcohols with aryl-, alkyl-, or silyl-substituted alkynes. The germylzincation reaction can be combined in one pot with the Cu(I)-mediated electrophilic substitution of the C(sp)-Zn bond to obtain synthetically challenging tetrasubstituted vinylgermanes.

Radical Germylzincation of α-Heteroatom-Substituted Alkynes.

The regio- and stereoselective addition of germanium and zinc across the C-C triple bond of nitrogen-, sulfur-, oxygen-, and phosphorus-substituted terminal and internal alkynes is achieved by reaction with a combination of RGeH and EtZn. Diagnostic experiments support a radical-chain mechanism and the β-zincated vinylgermanes that show exceptional stability are characterized by NMR spectroscopy and X-ray crystallography. The unique feature of this new radical germylzincation reaction is that the C(sp)-Zn bond formed remains available for subsequent in situ Cu(I)- or Pd(0)-mediated C-C or C-heteroatom bond formation with retention of the double bond geometry.

Catalytic Chemoselective and Stereoselective Semihydrogenation of Alkynes to E-Alkenes Using the Combination of Pd Catalyst and ZnI.

An efficient E-selective semihydrogenation of internal alkynes was developed under low dihydrogen pressure and low reaction temperature from commercially available reagents: ClPd(PPh), Zn, and ZnI. Kinetic studies and control experiments underline the significant role of ZnI in this process under H atmosphere, establishing that the transformation involves syn-hydrogenation followed by isomerization. This simple and easy-to-handle system provides a route to E-alkenes under mild conditions.

Stereodivergent Silylzincation of α-Heteroatom-Substituted Alkynes.

Zinc reagents (Me2PhSi)2Zn and [(Me3Si)3Si]2Zn undergo highly regio- and stereoselective addition across the carbon-carbon triple bond of nitrogen-, sulfur-, oxygen-, and phosphorus-substituted terminal alkynes in the absence of copper or any other catalyst. Both reagents yield exclusively β-isomers, and the stereoselectivity is determined by the silyl group: Me2PhSi for cis or (Me3Si)3Si for trans. These stereodivergent silylzincation protocols offer an efficient access to heteroatom-substituted vinylsilanes with either double bond geometry, including trisubstituted vinylsilanes by one-pot electrophilic substitution of the intermediate C(sp(2))-Zn bond by copper(I)-mediated carbon-carbon bond formation.

C2-Alkylation and Alkenylation of Indoles Catalyzed by a Low-Valent Cobalt Complex in the Absence of Reductant.

Herein an extremely versatile, well-defined, low-valent cobalt catalyst [Co(PMe3)4] capable of intermolecular and intramolecular imine-directed C2-alkylation and alkenylation of indoles is reported. The reaction proceeds in the absence of reducing agents or additives, affording a range of substituted indoles and dihydropyrroloindoles in high yields and regioselectivities. With the aid of deuterium labeling studies and DFT (Density Functional Theory) calculations, a mechanism is proposed that is based on a Ligand-to-Ligand Hydrogen Transfer pathway.

tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon-Nitrogen Bond Forming Reactions.

The use of tert-butanesulfinamides as nitrogen nucleophiles in carbon-nitrogen bond forming reactions is reviewed. This field has grown in the shadow of the general interest in N-tert-butanesulfinyl imines for asymmetric synthesis and occupies now an important place in its own right in the chemistry of the chiral amine reagent tert-butanesulfinamide. This article provides an overview of the area and emphasizes recent contributions wherein the tert-butanesulfinamides act as chiral auxiliaries or perform as nitrogen donors in metal-catalyzed amination reactions.

C-H activation/functionalization catalyzed by simple, well-defined low-valent cobalt complexes.

A facile C-H activation and functionalization of aromatic imines is presented using low-valent cobalt catalysts. Using Co(PMe3)4 as catalyst we have developed an efficient and simple protocol for the C-H/hydroarylation of alkynes with an anti selectivity. Deuterium-labeling experiments, DFT calculations coupled with the use of a well-defined catalyst have for the first time shed light on the elusive black box of cobalt catalyzed C-H functionalization.

Trans-selective radical silylzincation of ynamides.

The silylzincation of terminal ynamides is achieved through a radical-chain process involving (Me3Si)3SiH and R2Zn. A potentially competing polar mechanism is excluded on the basis of diagnostic control experiments. The unique feature of this addition across the C≡C bond is its trans selectivity.

Radical zinc-atom-transfer-based carbozincation of haloalkynes with dialkylzincs.

The formation of alkylidenezinc carbenoids by 1,4-addition/carbozincation of dialkylzincs or alkyl iodides based on zinc atom radical transfer, in the presence of dimethylzinc with β-(propargyloxy)enoates having pendant iodo- and bromoalkynes, is disclosed. Formation of the carbenoid intermediate is fully stereoselective at -30 °C and arises from a formal anti-selective carbozincation reaction. Upon warming, the zinc carbenoid is stereochemically labile and isomerizes to its more stable form.

Three-carbon homologation of diorganozincs with lithiated acetylenic epoxides.

Reaction of dialkylzincs with lithiated acetylenic epoxides is described to give zincates that undergo a 1,2-metallate rearrangement by an anti-S(N)2' pathway. This rearrangement occurs with the transfer of an alkyl or a silyl group affording allenylzinc intermediates. Allenic and/or homopropargylic alcohols are obtained upon hydrolysis.

Synthesis of (-)-swainsonine and (-)-8-epi-swainsonine by the addition of allenylmetals to chiral α,β-alkoxy sulfinylimines.

The asymmetric synthesis of (-)-swainsonine and (-)-8-epi-swainsonine is reported through the addition of either the allenylzinc or the allenyl lithio cyanocuprate reagents derived from [3-(methoxymethoxy)prop-1-ynyl]trimethylsilane to enantiopure α,β-dialkoxy N-tert-butanesulfinylimines derived from d-erythronolactone.

Cyclization of zincated α-N-homoallylamino nitriles: a new entry to enantiopure 2,3-methanopyrrolidines.

Stereoselective cyclization of zincated α-N-homoallylamino nitriles has been developed. Following treatment with lithium diisopropylamide (LDA) and transmetalation with zinc bromide, α-N-(1-phenylethyl)-N-homoallylamino nitriles lead to 2,3-methanopyrrolidines in moderate to good yields (up to 66 %) and excellent selectivities (up to >98:2). With substrates derived from α-branched homoallylic amines, a stereospecific inversion of the homoallylic stereogenic center was observed.

High-yielding synthesis of sphingoid-type bases.

An efficient methodology for the synthesis of sphingoid-type bases is reported. It involves the stereoselective addition of a racemic 3-alkoxy allenylzinc to enantiopure N-tert-butylsulfinyl imines and a cross-metathesis reaction as the key steps. It has been successfully applied to the syntheses of sphinganine and naturally occurring bioactive related compounds, among which the hydrolysis product of clavaminol H and two spisulosines.

tert-Butanesulfinimines: structure, synthesis and synthetic applications.

Since Ellman's seminal works, over the past ten years tert-butanesulfinimines have proved to be useful chiral amino intermediates for organic synthesis. Through highly stereoselective reactions, amongst which reductions, nucleophilic 1,2-additions and ylide condensations, a broad range of nitrogen-containing compounds has been synthesized. Although the stereoselectivity levels are high in most cases, the sense of the stereoinduction is generally not predictable.

Expeditious synthesis of a common intermediate of L-1-deoxyallonojirimycin and L-1-deoxymannojirimycin.

The expeditious synthesis of a common intermediate of L-1-deoxyallonojirimycin (L-allo-DNJ) and L-1-deoxymannojirimycin (L-manno-DNJ) is reported. This intermediate is obtained in highly diastereo- and enantioselectivity with 38.4% overall yield in six steps involving the unprecedented ring-closing metathesis of a tert-butylsulfinyl allylamine as the key step.

Stereo- and enantioselective synthesis of acetylenic 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 alpha-alkoxy-tert-butanesulfinylimines bearing a stereocenter alpha to the imino group is reported. The stereoselectivity of the reaction of these tert-butanesulfinyl (tBS)-imines with allenylzinc (+/-)-1 was found to be controlled only by the configuration of the tBS group. An excellent kinetic resolution of the racemic allenylzinc species was observed, allowing a high stereocontrol no matter what the configuration or the protecting group of the alpha-alkoxy group.

Asymmetric synthesis of (-)-1-hydroxyquinolizidinone, a common intermediate for the syntheses of (-)-homopumiliotoxin 223G and (-)-epiquinamide.

The short and efficient asymmetric synthesis of (-)-1-hydroxyquinolizidinone was achieved in seven steps and 25.2% overall yield from readily available 5-chloropentanal. It is a key intermediate in the formal syntheses of (-)-homopumilotoxin 223G and (-)-epiquinamide.

Short and efficient asymmetric synthesis of (-)-alpha-conhydrine.

The short and efficient synthesis of (-)-alpha-conhydrine was accomplished with 41% overall yield in seven steps and high diastereo- and enantioselectivity. The anti-stereochemistry of the two stereogenic centers has been confirmed by the single-crystal X-ray analysis of an intermediate.

Influence of HMPA on the stereochemical outcome of the addition of a racemic allenylzinc onto enantiopure N-tert-butanesulfinimines: stereoselective access to enantiopure cis-ethynylaziridines.

In the presence of 60 equivalents of HMPA, the condensation of the racemic allenylzinc derived from 1-chloro-3-trimethylsilylpropyne onto enantiopure non-alpha-branched N-tert-butanesulfinimines was proven to give access to the corresponding cis-ethynylaziridines as the major products. The good cis selectivity observed presumably resulted from a high kinetic resolution with the allenylzinc being partially configurationally labile with respect to the time scale defined by the rate of the reaction. Both single crystal X-ray analysis and semiempirical calculations conducted at the MM2 and AM1 levels of theory proved that the reaction certainly occurred through a preferred synclinal transition state in a supra- or antarafacial S(E)2' process.

High kinetic resolution in the addition of a racemic allenylzinc onto enantiopure N-tert-butanesulfinimines: concise synthesis of enantiopure trans-2-ethynylaziridines.

Enantiopure trans-ethynyl N-tert-butanesulfinylaziridines (R(S))-6 were prepared in good to excellent yields by the condensation of the racemic allenylzinc species 1 derived from 3-chloro-1-trimethylsilylpropyne onto the corresponding enantiopure N-tert-butanesulfinimines (R(S))-5. The absolute stereochemistry of enantiopure N-tert-butanesulfinylaziridines (R(S))-6 was shown to be (R(S),2R,3R) and results from a chelate-type transition state in which the zinc atom of allenylzinc 1 is coordinated by both the nitogen and the oxygen atoms of the imine. Further removal of the N-tert-butanesulfinyl auxiliary of alkyl 3-substituted and 3,3-disubstituted ethynyl N-tert-butanesulfinylaziridines (R(S))-6 could be achieved by treatment with HCl in MeOH affording the corresponding deprotected aziridines (2R,3R)-9 and (2R)-9 respectively as enantiomerically pure compounds.