Improved asymmetric S(N)Ar reaction of beta-dicarbonyl compounds catalyzed by quaternary ammonium salts derived from cinchona alkaloids

The scope and limitation of the asymmetric nucleophilic aromatic substitution reaction of alpha-substituted 1,3-dicarbonyl compounds and activated aromatic systems catalyzed by N-benzyl-O-benzoylcinchoninium or cinchonidinium salts are presented. Several novel O-benzoylcinchona alkaloid derived salts have been prepared and evaluated as catalysts in this reaction, which can proceed with enantioselectivites up to 96% ee. Various 1,3-dicarbonyl compounds and activated aromatic systems are evaluated for the aromatic nucleophilic substitution reaction, and it has been found that the yield and enantioselectivity are very dependent on the substrate and reagent. The scope of the functionalization of the products to, e.g., spiro-oxoindole, a ring-opening reaction of 1,3 alpha,alpha-disubstituted dicarbonyl compounds with several nucleophiles, and the diastereoselective reduction of the keto functionality in the optically active S(N)Ar product are reported.     

Synthesis of novel alpha-substituted and alpha,alpha-disubstituted amino acids by rearrangement of ammonium ylides generated from metal carbenoids

[reaction: see text] A new and general four-step synthesis of protected alpha-substituted and alpha,alpha-disubstituted amino acids has been developed. The key step involves intramolecular ammonium ylide generation from a copper carbenoid with concomitant [2,3] rearrangement. The aromatic template serves as a tether, protecting group, and activating group for peptide coupling. The ylide rearrangement products can be converted into protected cyclic amino acids by ring-closing metathesis.     

Enantioselective synthesis of alpha-substituted ketones by asymmetric addition of chiral zinc enamides to 1-alkenes

A zinc enamide of a chiral imine derived from a ketone and (S)-valinol or (S)-t-leucinol undergoes addition to 1-alkene to generate a gamma-zincioimine intermediate, which reacts with a carbon electrophile to give upon hydrolysis an optically active alpha-substituted ketone in good yield. The stereoselectivity of the addition reaction may reach 99% for the reaction of a cyclohexanone imine with ethylene.     

Synthesis of the new mannosidase inhibitors, diversity-oriented 5-substituted swainsonine analogues, via stereoselective Mannich reaction

5alpha-substituted swainsonine analogues were synthesized by Mannich reaction of an in situ generated (-)-swainsonine iminium ion intermediate. 5alpha-substituted swainsonine analogues were epimerized to their 5beta-isomers in protic solvent. [reaction: see text]     

Facile synthesis of alpha-substituted acrylate esters

Treatment of 5-monosubstituted Meldrum's acids with dimethylmethyleneimmonium iodide (Eschenmoser's iodide salt) in methanol gives alpha-substituted acrylate methyl esters in good yields. Easy access to 5-monosubstituted Meldrum's acids allowed us to synthesize a wide variety of alpha-substituted acrylate methyl esters. The reaction conditions are mild and tolerate many functional groups commonly used in organic synthesis; thus, this new method has potential as an alternative to conventional preparative methods for alpha-substituted acrylate esters.     

Use of odorless thiols: formal asymmetric Michael addition of hydrogen sulfide to alpha-substituted alpha,beta-unsaturated carbonyl compounds

[reaction: see text] The Michael addition to alpha-substituted alpha,beta-unsaturated esters and amides using complex A containing a chiral odorless thiol proceeded diastereoselectively. The Michael adducts were converted to beta-mercapto esters and amides via a Wagner-Meerwein rearrangement with boron trifluoride etherate and a thiol exchange reaction using odorless 1-dodecanethiol. This conversion constitutes a formal asymmetric Michael addition of hydrogen sulfide to alpha,beta-unsaturated carbonyl compounds using odorless thiols instead of the toxic hydrogen sulfide.     

A new method for the stereoselective synthesis of alpha-substituted serine amino acid analogues

[reaction: see text]. A new method was developed for the stereoselective synthesis of alpha-substituted serine amino acids. The strategy utilizes a common enantiomerically enriched intermediate obtained through an enzymatic desymmetrization. A variety of amino acids were synthesized in good ee's through nucleophilic acetylide addition reactions and palladium-catalyzed Sonogashira couplings.     

A rapid 1H NMR assay for enantiomeric excess of alpha-substituted aldehydes

In situ derivatization of a variety of alpha-substituted aldehydes via reaction with chiral amines allows convenient and efficient determination of enantiomeric excess. (1)H NMR analysis of the imine diastereomer ratio can be conducted immediately after the aldehyde and amine have been mixed. The results correlate well with ee values determined by more traditional (and slower) methods. This approach may be broadly applicable to alpha-substituted aldehydes. [reaction: see text]     

Ruthenium-catalyzed hydrogenation of alkynylstannanes with migration of the stannyl group

Molecular hydrogen adds to aliphatic and aromatic alkynylstannanes in the presence of a ruthenium catalyst, pushing the stannyl group to the adjacent carbon atom to give alpha-substituted vinylstannanes. This is the first achievement of hydrogenation of alkynylstannanes, which is applicable also to the deuteration affording precursors for an important class of deuterium-labeled compounds.     

Alkenyl C-H insertion of iodonium ylides into pyrroles: studies toward the total syntheses of tolmetin and amtolmetin guacil

The thermal-catalyzed or photochemical reaction of iodonium ylides with pyrroles yields exclusively alpha-substituted pyrroles in moderate to good yields. [reaction: see text]     

Synthesis of alpha-substituted beta-amino acids using pseudoephedrine as a chiral auxiliary

[reaction: see text] beta-Amino acids are becoming increasingly attractive as intermediates in the synthesis of a variety of molecular structures. However, few methods are available for the synthesis of alpha-substituted beta-amino acids that are both readily scalable and highly stereoselective. Herein we report a new method for synthesizing alpha-substituted beta-amino acids that satisfies both of these requirements using enantiomerically pure pseudoephedrine as a chiral auxiliary.     

Hydrosilylation of terminal alkynes with alkylidene ruthenium complexes and silanes

[reaction: see text] Ruthenium alkylidene complexes 1-3 mediate hydrosilylation of alkynes with silanes. When triethoxy- or triphenylsilanes are used as silylating agents, the reaction affords alpha-substituted vinylsilanes as major products.     

Fluoride-assisted regioselective conversion of functionalized furans to alpha-substituted gamma-hydroxybutenolides using singlet oxygen

A facile synthesis of alpha-substituted gamma-hydroxybutenolides from 3-furfural was achieved using a Baylis-Hillman reaction followed by singlet oxygen oxidation. The regioselectivity of this conversion was controlled by using TBAF.     

Microbial deracemization of alpha-substituted carboxylic acids

An enzyme system of Nocardia diaphanozonaria JCM 3208 catalyzes the inversion of the chirality of various alpha-substituted carboxylic acids, such as 2-phenylpropanoic acid and 2-phenoxypropanoic acid derivatives, via a novel deracemization reaction.     

One-pot three-component reaction for the synthesis of alpha-(aminoethyl)-alpha,beta-enones

[reaction: see text] The synthesis of alpha-substituted alpha,beta-enones by a new metal iodide-promoted one-pot three-component reaction involving commercially available cyclopropyl ketones, aldehydes, and secondary amines followed by base treatment is described.     

Stille cross-coupling reaction of an alpha-stannyl enamide.

The Stille cross-coupling reaction of an N-tosyl alpha-stannyl enamine is clearly exemplified for the first time with a wide range of halogeno derivatives. This gives access to functionalized alpha-substituted enamines in fair yields.     

Efficient synthesis of enantiomerically pure beta2-amino acids via chiral isoxazolidinones

We report a practical and scalable synthetic route for the preparation of alpha-substituted beta-amino acids (beta(2)-amino acids). Michael addition of a chiral hydroxylamine, derived from alpha-methylbenzylamine, to an alpha-alkylacrylate followed by cyclization gives a diastereomeric mixture of alpha-substituted isoxazolidinones. These diastereomers are separable by column chromatography. Subsequent hydrogenation of the purified isoxazolidinones followed by Fmoc protection affords enantiomerically pure Fmoc-beta(2)-amino acids, which are useful for beta-peptide synthesis. This route provides access to both enantiomers of a protected beta(2)-amino acid.     

Intramolecular Nucleophilic Acyl Substitution Reaction of 3,4-Alkadienyl Carbonates Mediated by Ti(O-i-Pr)(4)/2 i-PrMgCl Reagent. Efficient Synthesis of Optically Active beta,gamma-Unsaturated Esters with an alpha-Substituent

Treatment of 3,4-alkadienyl carbonates 2a-i with a low-valent titanium reagent diisopropoxy(eta(2)-propene)titanium (1), readily generated by the reaction of Ti(O-i-Pr)(4) with 2 i-PrMgCl, resulted in an intramolecular nucleophilic acyl substitution (INAS) reaction to afford vinyltitanium compounds 3 which, in turn, reacted with H(3)O(+), D(2)O, or iodine to give alpha-substituted beta,gamma-unsaturated esters 4 in good to excellent yields. The olefin moiety of the hydrolysis product 4 has (Z)-geometry mainly except for 4h. Starting from chiral 2f or 2g, the reaction proceeded stereospecifically to give optically active alpha-substituted beta,gamma-unsaturated ester 4f or 4g having (Z)-olefin geometry exclusively.     

Zinc-mediated ring-expansion and chain-extension reactions of beta-keto esters

[Chemical reaction: see text] The reaction of cyclic beta-keto esters with CF3CO2ZnCH2I provided the corresponding ring-expanded products in moderate to good yields. Although alpha-substituted acyclic beta-keto esters reacted with much less efficient, chain-extension reaction of simple beta-keto esters also proceeded effectively to generate gamma-keto esters in high yields.     

GaCl3-promoted ethenylation of silylated beta-dicarbonyl compound with silylethyne. Synthesis of ethenylmalonate

[reaction: see text]. In the presence of GaCl3, silyl enol ethers derived from alpha-substituted beta-ketoesters or malonates are ethenylated at the alpha-carbon atom with trimethylsilylethyne in high yields. Ethenylmalonates can also be synthesized by this method.