Organocatalytic and direct asymmetric vinylogous Michael addition of alpha,alpha-dicyanoolefins to alpha,beta-unsaturated aldehydes

The first highly regio-, chemo-, diastereo- and enantioselective direct vinylogous Michael addition of alpha,alpha-dicyanoolefins to alpha,beta-unsaturated aldehydes is described, employing readily available chiral alpha,alpha-diarylprolinol salts as iminium organocatalysts.     

Indium-mediated beta-allylation,beta-propargylation,and beta-allenylation onto alpha,beta-unsaturated ketones: reactions of in-situ-generated 3-tert-butyldimethylsilyloxyalk-2-enylsulfonium salts with in-situ-generated organoindium reagents

3-tert-Butyldimethylsilyloxyalk-2-enylsulfonium salts, generated in situ from the reaction of alpha,beta-enones with dimethyl sulfide in the presence of TBSOTf, underwent a novel nucleophilic substitution with allylindiums to give silyl enol ethers of delta,epsilon-alkenyl ketones in good yields, which correspond to formal Michael addition products. In a similar manner, 1,4-propargylation of propargylindiums onto the sulfonium salts produced the corresponding silyl enol ethers of delta,epsilon-alkynyl ketones in good yields. Organoindium reagents derived from gamma-substituted propargyl bromide and indium afforded the corresponding silyl enol ethers of beta-allenyl ketones in good yields. The reaction proceeds via an addition-substitution mechanism involving the formation of allylic sulfonium salts. The presence of the intermediate sulfonium salt was confirmed by observation of the low-temperature (1)H NMR spectra.     

Simple alkenes as substitutes for organometallic reagents: nickel-catalyzed, intermolecular coupling of aldehydes, silyl triflates, and alpha olefins

A nickel-catalyzed method for the three-component coupling of alkenes (ethylene and alpha olefins), aldehydes, and silyl triflates is described, and this process represents the first catalytic method for coupling aldehydes and alkenes to give allylic alcohol derivatives. Conceptually, the alkene functions as a replacement for an alkenylmetal reagent.     

Diphenylprolinol silyl ether as catalyst of an asymmetric, catalytic, and direct Michael reaction of nitroalkanes with alpha,beta-unsaturated aldehydes

A catalytic enantioselective direct conjugate addition of nitroalkanes to alpha,beta-unsaturated aldehydes using diphenylprolinol silyl ether as an organocatalyst has been developed. Using this methodology as a key step, short syntheses of therapeutically useful compounds have also been accomplished.     

A theoretical study on the mechanism, regiochemistry, and stereochemistry of hydrosilylation catalyzed by cationic ruthenium complexes

Density functional calculations have been carried out to understand the anti-addition stereochemistry and Markovnikov regiochemistry of the hydrosilylation of terminal alkynes and the endo-dig product of intramolecular hydrosilylation of homopropargyl alcohols catalyzed by cationic cyclopentadienyl-ruthenium complexes. It has been found that hydride or silyl insertion is concerted with the oxidative addition of the H-Si bond. Hydride insertion is much more favorable than silyl insertion. Such a hydride insertion nicely reproduces the observed regioselectivity, while silyl insertion would predict the opposite result. The hydride insertion leads to the formation of a eta(2)-vinylruthenium intermediate for the reaction of acetylene or a metallacyclopropene intermediate for the reaction of propyne. In the formation of both intermediates, there is a C(alpha)-C(beta) bond rotation so that the transferring hydride becomes anti to the silyl group. This is followed by a facile reductive alpha-silyl migration transition state, which results in the overall anti-addition stereochemistry. The proposed mechanism also rationalizes the observed regio- and stereochemistry of the intramolecular reaction.     

Enantioselective organocatalytic Mukaiyama-Michael addition of silyl enol ethers to alpha,beta-unsaturated aldehydes

[reaction: see text] A highly enantioselective, organocatalytic Mukaiyama-Michael addition reaction of silyl ethers and alpha,beta-unsaturated aldehydes has been developed. The process, catalyzed by MacMillan's chiral imidazolidinone, affords delta-keto aldehydes in high yields (56-87%) and high enantioselectivities (85-97% ee). Moreover, the reaction is applicable to a wide range of silyl ethers and alpha,beta-unsaturated aldehydes and, as such, provides access to a range of important synthetic building blocks.     

Tandem intramolecular silylformylation and silicon-assisted cross-coupling reactions. synthesis of geometrically defined alpha,beta-unsaturated aldehydes

The palladium- and copper-catalyzed cross-coupling reactions of cyclic silyl ethers with aryl iodides are reported. Silyl ethers 3 were readily prepared by intramolecular silylformylation of homopropargyl silyl ethers 2 under a carbon monoxide atmosphere. The reaction of cyclic silyl ethers 3with various aryl iodides 7 in the presence of [(allyl)PdCl](2), CuI, a hydrosilane, and KF.2H(2)O in DMF at room temperature provided the alpha,beta-unsaturated aldehyde coupling products 8 in high yields. The need for copper in this process suggested that transmetalation from silicon to copper is an important step in the mechanism. Although siloxane 3 and the product 8 are not stable under basic conditions, KF.2H(2)O provided the appropriate balance of reactivity toward silicon and reduced basicity. The addition of a hydrosilane to [(allyl)PdCl](2) was needed to reduce the palladium(II) to the active palladium(0) form.     

Lewis base activation of Lewis acids: catalytic, enantioselective addition of glycolate-derived silyl ketene acetals to aldehydes

A catalytic system involving silicon tetrachloride and a chiral, Lewis basic bisphosphoramide catalyst is effective for the addition of glycolate-derived silyl ketene acetals to aldehydes. It was found that the sense of diastereoselectivity could be modulated by changing the size of the substituents on the silyl ketene acetals. In general, the trimethylsilyl ketene acetals derived from methyl glycolates with a large protecting group on the alpha-oxygen provide enantiomerically enriched alpha,beta-dihydroxy esters with high syn-diastereoselectivity, whereas the tert-butyldimethylsilyl ketene acetals derived from bulky esters of alpha-methoxyacetic acid provide enantiomerically enriched alpha,beta-dihydroxy esters with high anti-diastereoselecitvity.     

Alpha,beta-unsaturated delta-lactones from copper-catalyzed asymmetric vinylogous Mukaiyama reactions of aldehydes: scope and mechanistic insights

A direct regio-, diastereo-, and enantiocontrolled access to alpha,beta-unsaturated delta-lactones is described, based on the reaction of a silyl dienolate and an aldehyde in the presence of 10 % of Carreira's catalyst. The scope and limitations of this reaction, as well as mechanistic insights concerning the reactivity of an allyl copper species, are discussed.     

Regio- and stereospecific cleavage of silyl- and disilylepoxides with lithium diphenylphosphide

Unsubstituted or alpha- and beta-C-substituted silylepoxides react stereospecifically with lithium diphenylphosphide, optionally followed by methylation, to give vinylphosphonium iodides or vinylphosphine oxides resulting from alpha-opening and silyl enol ethers, vinylsilanes or alpha-hydroxysilanes by beta-opening. On the other hand, alpha,beta- or alpha,alpha-disilylepoxides afforded beta-silyl vinylphosphine oxides or alpha-silylated silyl enol ethers by alpha- and beta-cleavage, respectively. All compounds are interesting synthons in organic chemistry.     

Efficient pyrrole synthesis using double nucleophilic addition to alpha,beta-unsaturated imines with plural nucleophiles

[reaction: see text] 2,3,5-Trisubstituted pyrroles were prepared in a regioselective manner using the double nucleophilic addition of alpha,alpha-dialkoxy ketene silyl acetals and ketene sily thioacetals or trimethylsilyl cyanide to alpha,beta-unsaturated imines followed by acid-promoted cyclization and oxidation with DDQ. Using this methodology an imidazole glycerol phosphate dehydratase inhibitor (IGPDI) possessing a monopyrrole aldehyde moiety was synthesized.     

Nickel-Catalyzed Tandem Coupling of alpha,beta-Enones, Alkynes, and Alkynyltins for the Regio- and Stereoselective Synthesis of Conjugated Enynes

The nickel-catalyzed reaction of alpha,beta-enones 2 with alkynes 1, alkynyltins 6, and Me(3)SiCl was carried out by the successive construction of two carbon-carbon bonds to give enol silyl ethers 5, which were then hydrolyzed to conjugated enynes 7, with high regio- and stereoselectivities (isomeric purities: 92-98%).     

A Lewis acid-catalyzed formal [3 + 3] cycloaddition of alpha,beta-unsaturated aldehydes with 4-hydroxy-2-pyrone, diketones, and vinylogous esters

[reaction: see text] A Lewis acid-catalyzed formal cycloaddition of alpha,beta-unsaturated aldehydes with 6-methyl-4-hydroxy-2-pyrone, 1,3-diketones, and vinylogous silyl esters is described here.     

Organocatalytic asymmetric synthesis of alpha,alpha-disubstituted alpha-amino acids and derivatives

It is shown that racemic oxazolones are excellent reagents for the synthesis of chiral quaternary amino acids and its derivatives by the diastereo- and enantioselective nucleophilic addition to alpha,beta-unsaturated aldehydes catalyzed by diarylprolinol silyl ethers. The scope of this new organocatalytic reaction is demonstrated for different oxazolones having aromatic and alkyl groups at the reactive carbon atom and different aromatic and aliphatic substituted alpha,beta-unsaturated aldehydes, for which the stereoselective reaction proceeds with good yield, moderate to good to very high diastereoselectivity, and very high enantioselectivity. The potential of the reaction is shown for the synthesis of optically active alpha,alpha-disubstituted alpha-amino acids, alpha-quaternary proline derivatives, amino alcohols, lactams, and tetrahydropyranes. Furthermore, we have calculated by DFT-methods the transition-state structures that account for both the diastereo- and enantioselectivity observed for the addition of oxazolones to the alpha,beta-unsaturated aldehydes. For one class of compounds, the stereoselectivity is controlled by a hydrogen-bonding interaction of the enolate-form of the oxazolone with an ortho-hydroxy-phenyl substituent of the alpha,beta-unsaturated aldehyde, whereas the benzhydryl-protecting group in the oxazolone determines the diastereo- and enantioselectivity in a more general manner for both aromatic and aliphatic alpha,beta-unsaturated aldehydes.     

Synthesis of stereoisomeric medium-ring alpha,alpha'-dihydroxy cycloalkanones

The stereochemical course of the epoxidation of the silyl enol ethers of 2-tert-butyldimethylsilyloxycycloheptanone and -cyclooctanone has been investigated and shown to proceed exclusively anti to the existing alpha-substituent. 2-(Benzyloxy)cyclooctanone behaves similarly, and the presence of a transannular double bond does not alter the outcome. Alpha-ketol rearrangements are seen to operate during ensuing fluoride ion-induced removal of the silyl protecting groups in select examples. The preferred means for generating the cis isomers of the alpha,alpha'-dihydroxy cycloalkanones involves methylenation of the monoprotected trans-dihydroxy ketones with the Nysted reagent, followed by oxidation and subsequent reduction with sodium borohydride. Ozonolysis and fluoride ion-induced desilylation complete the route.     

Pd(OH)2/C-mediated selective oxidation of silyl enol ethers by tert-butylhydroperoxide, a useful method for the conversion of ketones to alpha,beta-enones or beta-silyloxy-alpha,beta-enones

[reaction: see text] Pd(OH)2-catalyzed oxidation of silyl enol ethers by t-BuOOH gives either beta-silyloxy-alpha,beta-enones or alpha,beta-enones in good yields depending on the base used.     

Asymmetric acyl-transfer promoted by readily assembled chiral 4-N,N-dialkylaminopyridine derivatives

The development of a new class of chiral 4-N,N-dialkylaminopyridine acyl-transfer catalysts capable of exploiting both van der Waals (pi) and H-bonding interactions to allow remote chiral information to stereochemically control the kinetic resolution of sec-alcohols with moderate to excellent selectivity (s = 6-30). Catalysts derived from (S)-alpha,alpha-diarylprolinol are considerably superior to analogues devoid of a tertiary hydroxyl moiety and possess high activity and selectivity across a broad range of substrates.     

Highly enantioselective michael addition of silyl nitronates to alpha,beta-unsaturated aldehydes catalyzed by designer chiral ammonium bifluorides: efficient access to optically active gamma-nitro aldehydes and their enol silyl ethers

Highly enantioselective Michael addition of silyl nitronates to alpha,beta-unsaturated aldehydes has been accomplished by the utilization of designer N-spiro C2-symmetric chiral quaternary ammonium bifluoride 1 as an efficient catalyst, providing direct access to both optically active gamma-nitro aldehydes, a very useful precursor to various complex organic molecules including aminocarbonyls, and their enol silyl ethers, a Mukaiyama donor of potential synthetic utility for further selective transformations. For instance, the reaction of trimethylsilyl nitronate 2 (R1 = Me) with trans-cinnamaldehyde (R2 = Ph, R3 = H) in toluene in the presence of (R,R)-1 (2 mol %) proceeded smoothly at -78 degrees C to give the desired enol silyl ether 3 (R1 = Me, R2 = Ph, R3 = H) in 90% isolated yield (anti/syn = 83:17) with 97% ee (anti isomer), and simple treatment of 3 thus obtained with 1 N HCl in THF at 0 degrees C afforded the corresponding gamma-nitro aldehyde 4 quantitatively without loss of diastereo- and enantioselectivity.     

Dirhodium(II) tetrakis(perfluorobutyrate)-catalyzed 1,4-hydrosilylation of alpha,beta-unsaturated carbonyl compounds

The use of dirhodium(II) catalysts in the 1,4-hydrosilylation of alpha,beta-unsaturated ketones and aldehydes was explored. Dirhodium(II) tetrakis(perfluorobutyrate), Rh2(pfb)4, proved to be the catalyst of choice for this process, providing the corresponding silyl enol ethers in high yields.     

Powerful Ti-crossed Claisen condensation between ketene silyl acetals or thioacetals and acid chlorides or acids

[Structure: see text] A powerful Ti-crossed Claisen condensation between ketene silyl acetals (KSAs) and acid chlorides was successfully performed to give alpha-monoalkylated esters and thermodynamically unfavorable (less accessible) alpha,alpha-dialkylated beta-keto esters in good yield (46 examples; 41-98% yield). A closely related reaction between ketene silyl thioacetals (KSTAs) and acid chlorides also proceeded smoothly to give alpha-monoalkylated and alpha,alpha-dialkylated beta-keto thioesters (21 examples; 61-97% yield). The present protocol was extended to the direct condensation of KSAs with carboxylic acids (14 examples; 71-97% yield).