Metallophosphite-catalyzed asymmetric acylation of alpha,beta-unsaturated amides

The l-menthone-derived TADDOL phosphite 6b catalyzes highly enantioselective conjugate additions of acyl silanes to alpha,beta-unsaturated amides. p-Methoxybenzoyl cyclohexyldimethylsilane adds to a variety of N,N-dimethyl acrylamide derivatives in the presence of the lithium salt of 6b. In many instances the alpha-silyl-gamma-ketoamide product undergoes facile enantioenrichment (to 97-99% ee) upon recrystallization. Desilylation with HF.pyr affords the formal Stetter addition products. Baeyer-Villiger oxidation of the desilylated gamma-ketoamides affords useful ester products. An X-ray diffraction study of 6b reveals that the isopropyl group of the menthone ketal influences the position of the syn-pseudoaxial phenyl group in the TADDOL structure. Through a crossover experiment, the silicon migration step in the reaction mechanism is shown to be strictly intramolecular.     

Stereoselective synthesis of (E)-trisubstituted alpha,beta-unsaturated amides and acids

Potassium alkoxides of N-acyl-oxazolidin-2-one-syn-aldols undergo stereoselective elimination reactions to afford a range of trisubstituted (E)-alpha,beta-unsaturated amides in >95% de, that may be subsequently converted into their corresponding (E)-alpha,beta-unsaturated acids or (E)-alpha,beta-unsaturated oxazolines in good yield. syn-Aldols derived from alpha,beta-unsaturated aldehydes gave their corresponding trisubstituted (E)-alpha,beta-unsaturated-amides with poorer levels of diastereocontrol, whilst there was a similar loss in (E)-selectivity during elimination of syn-aldols derived from chiral aldehydes. These elimination reactions proceed via rearrangement of the potassium alkoxide of the syn-aldol to a 1,3-oxazinane-2,4-dione enolate intermediate that subsequently eliminates carbon dioxide to afford a trisubstituted (E)-alpha,beta-unsaturated amide. The (E)-selectivity observed during the E1cB-type elimination step has been rationalised using a simple conformational model that employs a chair-like transition state to explain the observed stereocontrol.     

Convenient synthesis of substituted piperidinones from alpha,beta-unsaturated amides: formal synthesis of deplancheine, tacamonine, and paroxetine

[reaction: see text] An intermolecular aza-double Michael reaction leading to functionalized piperidin-2-ones from simple starting materials has been developed. The method allows alpha,beta-unsaturated amides to be used as a synthon of the piperidine nucleus. In addition, the utility of this methodology is demonstrated by its application to a formal synthesis of the indolo[2,3-a]quinolizidine alkaloids, (+/-)-deplancheine, (+/-)-tacamonine, and the antidepressant paroxetine.     

Diastereoselective intermolecular cobalt-catalyzed reductive aldol reactions of alpha,beta-unsaturated amides with ketones

Under cobalt catalysis, diethylzinc mediates the conjugate reduction of alpha,beta-unsaturated amides to produce ethylzinc enolates that react with ketones in situ to produce tertiary alcohol-containing aldol products with up to >19:1 diastereoselectivity.     

Cobalt-rhodium heterobimetallic nanoparticle-catalyzed synthesis of alpha,beta-unsaturated amides from internal alkynes, amines, and carbon monoxide

The first example of cobalt-rhodium heterobimetallic nanoparticle-catalyzed synthesis of alkenyl amides from alkynes, amines, and carbon monoxide is described.     

Stereospecific and stereoselective alkyl and silylcyclopropanation of alpha,beta-unsaturated amides

A novel chromium-promoted alkyl- and silyl cyclopropanation of (E)- or (Z)-alpha,beta-unsaturated amides in which the C-C double bond is di-, or trisubstituted is described. This process takes place with total stereospecificity, and the new stereogenic center is generated with high or total stereoselectivity. A mechanism is proposed to explain the cyclopropanation reaction.     

Nickel-catalyzed beta-boration of alpha,beta-unsaturated esters and amides with bis(pinacolato)diboron

A nickel catalyst system for beta-boration of alpha,beta-unsaturated esters and amides with bis(pinacolato)diboron has been developed. The catalyst system enables the boration of di-, tri-, and tetrasubstituted substrates in good yields.     

Asymmetric synthesis of beta-amino-gamma-substituted-gamma-butyrolactones: double diastereoselective conjugate addition of homochiral lithium amides to homochiral alpha,beta-unsaturated esters

Chiral alpha,beta-unsaturated esters, containing a single, gamma-stereogenic centre, show modest levels of substrate control upon conjugate addition of lithium dibenzylamide. Double diastereoselective conjugate additions of homochiral lithium N-benzyl-N-(alpha-methylbenzyl)amide to the homochiral alpha,beta-unsaturated esters display "matching" and "mismatching" effects. In each case, however, these additions proceed under the dominant stereocontrol of the lithium amide to give the corresponding beta-amino esters in high de. A remarkable reversal in stereoselectivity is noted by changing the ester functionality to an oxazolidinone. Subsequent O-deprotection and cyclisation of the resultant beta-amino adducts gives access to the corresponding beta-amino-gamma-substituted-gamma-butyrolactones in good yield and high de.     

Catalytic asymmetric epoxidation of alpha,beta-unsaturated amides: efficient synthesis of beta-aryl alpha-hydroxy amides using a one-pot tandem catalytic asymmetric epoxidation-Pd-catalyzed epoxide opening process

The catalytic asymmetric epoxidation of alpha,beta-unsaturated amides using Sm-BINOL-Ph3As=O complex was succeeded. Using 5-10 mol % of the asymmetric catalyst, a variety of amides were epoxidized efficiently, yielding the corresponding alpha,beta-epoxy amides in up to 99% yield and in more than 99% ee. Moreover, the novel one-pot tandem process, one-pot tandem catalytic asymmetric epoxidation-Pd-catalyzed epoxide opening process, was developed. This method was successfully utilized for the efficient synthesis of beta-aryl alpha-hydroxy amides, including beta-aryllactyl-leucine methyl esters. Interestingly, it was found that beneficial modifications on the Pd catalyst were achieved by the constituents of the first epoxidation, producing a more suitable catalyst for the Pd-catalyzed epoxide opening reaction in terms of chemoselectivity.     

CrCl2-promoted stereospecific and stereoselective alkyl- and silylcyclopropanation of alpha,beta-unsaturated amides

An efficient chromium-promoted alkyl- or silylcyclopropanation of alpha,beta-unsaturated amides is described. These reactions can be carried out on (E)- or (Z)-alpha,beta-enamides in which the C-C double bond is di-, or trisubstituted. This process takes place with total stereospecificity and the new stereogenic center is generated with high or total stereoselectivity. Some synthetic applications of the obtained silylcyclopropyl amides are also reported. Two mechanisms based on the generation of carbenoid or carbene complexes have been proposed to explain this cyclopropanation reaction.     

New rearrangement of 4-isoxazoline system: conversion of ketones into alpha,beta-unsaturated amides

A new rearrangement pattern of the 4-isoxazoline system is reported. The reaction, starting from 3,3-disubstituted derivatives and leading to alpha,beta-unsaturated amides, proceeds through the quaternarization of the nitrogen atom and involves the heterolytic cleavage of C(3)-N bond, assisted by the formation of a relatively stable intermediate. The overall process represents a useful conversion of ketones into alpha,beta-unsaturated amides.     

Rhodium/diene-catalyzed asymmetric 1,4-addition of arylboronic acids to alpha,beta-unsaturated Weinreb amides

Rhodium/chiral diene (S,S)- complex has been found to effectively catalyze the 1,4-addition of arylboronic acids to alpha,beta-unsaturated Weinreb amides, furnishing useful beta-chiral Weinreb amides in high enantioselectivity.     

Straightforward synthesis of alpha,beta-unsaturated thioesters via ruthenium-catalyzed olefin cross-metathesis with thioacrylate

The cross-metathesis reaction of S-ethyl thioacrylate with a variety of olefins is effectively catalyzed by using a ruthenium benzylidene olefin metathesis catalyst. This reaction provides a convenient and versatile route to substituted alpha,beta-unsaturated thioesters, key building blocks in organic synthesis.     

Asymmetric synthesis of trifluoromethylated allylic amines using alpha,beta-unsaturated N-tert-butanesulfinimines

[reaction: see text]. The trifluoromethide ion generated in situ from TMSCF(3) and TBAT (tetrabutylammonium triphenyldifluorosilicate), as well as TMAF (tetramethylammonium fluoride), adds to the alpha,beta-unsaturated N-tert-butanesulfinimines exclusively in a 1,2 fashion with high diastereoselectivities, affording the first examples of chiral trifluoromethylated allylic amines.     

One-pot synthesis of alpha-iodo-substituted alpha,beta-unsaturated aldehydes from propargylic alcohols

An efficient one-pot method for the preparation of alpha-iodo-substituted alpha,beta-unsaturated aldehydes (alpha-iodoenals) from propargylic alcohol is developed. The reaction proceeds via an iodoallene intermediate, which is generated in situ by the reaction of propargylic alcohol with aqueous HI. The iodoallene intermediate is further transformed to an alpha-iodoenal derivative in good overall yield by oxidation with molecular O(2).     

Stereoselective synthesis of (Z)-alpha-halo-alpha,beta-unsaturated esters, and amides from aldehydes and trihaloesters or amides promoted by manganese

Preliminary results of a Mn-promoted sequential process directed toward the stereoselective synthesis of different (Z)-alpha-halo-alpha,beta-unsaturated compounds are described.