Stereoselective Carbon-carbon Bond Formation Research Articles

Chiral, air stable, and reliable Pd(0) precatalysts applicable to asymmetric allylic alkylation chemistry

Stereoselective carbon-carbon bond formation via palladium-catalyzed asymmetric allylic alkylation is a crucial strategy to access chiral natural products and active pharmaceutical ingredients. However, catalysts based on the privileged Trost and Pfaltz-Helmchen-Williams PHOX ligands often require high loadings, specific preactivation protocols, and excess chiral ligand. This makes these reactions uneconomical, often unreproducible, and thus unsustainable. Here we report several chiral single-component Pd(0) precatalysts that are active and practically-applicable in a variety of asymmetric allylic alkylation reactions. Despite the decades-long history and widespread use of Trost-type ligands, the precatalysts in this work are the only reported examples of stable, isolable Pd(0) complexes with these ligands. Evaluating these precatalysts across nine asymmetric allylic alkylation reactions reveals high reactivity and selectivity at low Pd loading. Importantly, we also report an unprecedented Pd-catalyzed enantioselective allylation of a hydantoin, achieved on gram scale in high yield and enantioselectivity with only 0.2 mol% catalyst.

Direct Catalytic Enantioselective Benzylation from Aryl Acetic Acids.

We demonstrate that metal-catalyzed enantioselective benzylation reactions of allylic electrophiles can occur directly from aryl acetic acids. The reaction proceeds via a pathway in which decarboxylation is the terminal event, occurring after stereoselective carbon-carbon bond formation. This mechanistic feature enables enantioselective benzylation without the generation of a highly basic nucleophile. Thus, the process has broad functional group compatibility that would not be possible employing established protocols.

Synthesis of Aryl C-Glycosides via Iron-Catalyzed Cross Coupling of Halosugars: Stereoselective Anomeric Arylation of Glycosyl Radicals.

We have developed a novel diastereoselective iron-catalyzed cross-coupling reaction of various glycosyl halides with aryl metal reagents for the efficient synthesis of aryl C-glycosides, which are of significant pharmaceutical interest due to their biological activities and resistance toward metabolic degradation. A variety of aryl, heteroaryl, and vinyl metal reagents can be cross-coupled with glycosyl halides in high yields in the presence of a well-defined iron complex, composed of iron(II) chloride and a bulky bisphosphine ligand, TMS-SciOPP. The chemoselective nature of the reaction allows the use of synthetically versatile acetyl-protected glycosyl donors and the incorporation of various functional groups on the aryl moieties, producing a diverse array of aryl C-glycosides, including Canagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), and a prevailing diabetes drug. The cross-coupling reaction proceeds via generation and stereoselective trapping of glycosyl radical intermediates, representing a rare example of highly stereoselective carbon-carbon bond formation based on iron catalysis. Radical probe experiments using 3,4,6-tri-O-acetyl-2-O-allyl-α-d-glucopyranosyl bromide (8) and 6-bromo-1-hexene (10) confirm the generation and intermediacy of the corresponding glycosyl radicals. Density functional theory (DFT) calculations reveal that the observed anomeric diastereoselectivity is attributable to the relative stability of the conformers of glycosyl radical intermediates. The present cross-coupling reaction demonstrates the potential of iron-catalyzed stereo- and chemoselective carbon-carbon bond formation in the synthesis of bioactive compounds of certain structural complexity.

The Organocatalytic Vinylogous Aldol Reaction: Recent Advances

Over the past decade, organocatalysis has emerged as a powerful tool for stereoselective carbon-carbon bond formation under exceptionally mild conditions. The organocatalytic versions of a large number of traditional synthetic transformations are now well established and the quest for new applications of the basic concepts of organocatalysis continues. This review addresses the emergent interest in the organocatalytic vinylogous aldol reaction. While noteworthy progress has been made in this area, significant challenges lie ahead.

Chemical and enzymatic routes to dihydroxyacetone phosphate

Stereoselective carbon-carbon bond formation with aldolases has become an indispensable tool in preparative synthetic chemistry. In particular, the dihydroxyacetone phosphate (DHAP)-dependent aldolases are attractive because four different types are available that allow access to a complete set of diastereomers of vicinal diols from achiral aldehyde acceptors and the DHAP donor substrate. While the substrate specificity for the acceptor is rather relaxed, these enzymes show only very limited tolerance for substituting the donor. Therefore, access to DHAP is instrumental for the preparative exploitation of these enzymes, and several routes for its synthesis have become available. DHAP is unstable, so chemical synthetic routes have concentrated on producing a storable precursor that can easily be converted to DHAP immediately before its use. Enzymatic routes have concentrated on integrating the DHAP formation with upstream or downstream catalytic steps, leading to multi-enzyme arrangements with up to seven enzymes operating simultaneously. While the various chemical routes suffer from either low yields, complicated work-up, or toxic reagents or catalysts, the enzymatic routes suffer from complex product mixtures and the need to assemble multiple enzymes into one reaction scheme. Both types of routes will require further improvement to serve as a basis for a scalable route to DHAP.

L‐Proline Catalyzed Asymmetric Aldol Reactions of Protected Hydroxyacetone.

AbstractFor Abstract see ChemInform Abstract in Full Text.

L-Proline catalyzed asymmetric aldol reactions of protected hydroxyacetone

We extended the proline-catalyzed asymmetric direct aldol reactions to the TBDMS protected hydroxyacetone. This important donor provides a ready access to optically active monoprotected 1,2-diol units simultaneously accompanied by stereoselective carbon-carbon bond formation in 40–90% yield and in up to 95% ee.

Total synthesis of paniculide A from d-glucose

The chiral total synthesis of paniculide A ( 1), a highly oxygenated sesquiterpene possessing a bisabolane skeleton, starting from D-glucose is described. The two different approaches, both involved Ferrier's carbocyclization reaction to construct the cyclohexane unit in 1, were explored. The first approach, employing the carbocyclization of bicyclic substrate furnished the formal total synthesis. The second approach, designed to suppress the undesired side reactions observed in the first one, adopted the carbocyclization of a monocyclic substrate, and Claisen rearrangement for the stereoselective carbon-carbon bond formation. The successful total synthesis of 1 revealed the effectiveness of the combination of Ferrier's carbocyclization and Claisen rearrangement for the chiral synthesis of highly oxygenated natural products possessing cyclohexane units.

Preparation and synthetic utility of oxasilacyclopentane acetals derived from siliranes

The insertion of formamides into a CSi bond of silirane trans- 1 provides a facile route to the oxasilacyclopentane acetate 5 (86% overall yield). Stereoselective carbon-carbon bond formation on the derived oxonium ion was achieved by addition of the silyl enol ether of acetophenone (92:8 selectivity, 79% yield) and 3-pentanone (92:5:3 selectivity, 100% yield). These results demonstrate the potential of siliranes as intermediates in organic synthesis.

Dynamic kinetic resolution utilizing a chiral auxiliary by stereoselective SN2 alkylation with malonic ester enolate

Dynamic kinetic resolution by highly stereoselective carbon-carbon bond formation utilizing 2-oxoimidazolidine-4-carboxylate as a chiral auxiliary was exploited. The reaction of tert-butyl(4 S)-1-methyl-3-(2-bromopropionyl)-2-oxoimidazolidine-4-carboxylate ( 1) with sodium dimethyl malonate in HMPA at room temperature predominantly afforded tert-butyl(4 S)-1-methyl-3-((2 R)-2-methyl-3,3-bis(methoxycarbonyl)propionyl)-2-oxoimidazolidine-4-carboxylate ( (S,R)- 2a ) in a good yield.

CsF in Organic Synthesis. Malonic Ester Synthesis Revisited for Stereoselective Carbon-Carbon Bond Formation

CsF in Organic Synthesis. Malonic Ester Synthesis Revisited for Stereoselective Carbon-Carbon Bond Formation

Regio- and stereoselective carbon-carbon bond formation through transition metal catalysis. The influence of catalyst chirality on selective ethylmagnesiation of chiral, nonracemic alcohols and ethers

The authors investigate the catalytic effects of zirconium complexes. The ethylmagnesations of alcohols and ethers were studied.

Lewis acid promoted stereoselective carbon-carbon bond formation of 3-formyl-.DELTA.2-isoxazolines

4,5-Disubstituted 3-formyl-Δ 2 -isoxazolines undergo the aldol, allylation, and carbonyl ene reactions in the presence of appropriate Lewis acid to give the adducts with an effective 1,3-asymmetric induction. The stereoselectivity of the reaction mainly depends on the nature of the Lewis acid and the relative configuration of the ring. It is remarkable that both diastereomers can be readily prepared stereoselectively

Stereo- and regio-controlled carbon–carbon bond formation mediated by tungsten in the s-trans-η4-diene cationic intermediates

The tungsten-η3-2-substituted pentadienyl complexes WC5H5(CO)2(syn-η3-R-C5H6)(R = COOMe; CMeCH2) undergo BF3-catalysed stereoselective carbon-carbon bond formation with aldehydes to afford isolable s-trans-diene cations which after hydrolysis produces tungsten-η3-allyl-1,3-diols; utilization of the diols for stereoselective synthesis of α-methylene-γ-butyrolactones, furanone skeletons, have been reported in good yields (> 80%).

Nickel enolates in the Ni(CO) 4 -induced carbonylation of gem-dibromocyclopropanes with silylamine or silylsulfide

Silyl compounds (N,N-dialkyltrimethylsilylamine, 1-(trimethylsilyl)-imidazole and phenylthiotrimethylsilane) were successfully used in the Ni(CO) 4 -induced carbonylation reactions of gem-dibromocyclopropanes. The nickel carbenoid and enolate complexes are considered to be involved as key intermediates. Protonation afforded the cyclopropanecarboxylic acid derivatives. The presence of an electrophile achieved another stereoselective carbon-carbon bond formation via the nickel enolate intermediate.

Acyclic Stereoselective Synthesis of Carbohydrates

Abstract This review examines recent syntheses of carbohydrates in which the target compounds are viewed as acyclic carbon frameworks. The synthetic approaches are divided into two categories in which critical asymmetry is placed either by (a) stereo-selective carbon-carbon bond formation, or (b) stereoselective carbon-heteroatom bond formation. This account focuses its attention on the methodology utilized to place acyclic stereo-centers as the key feature of the synthetic strategy.