Organocatalytic asymmetric 5-hydroxyisoxazolidine synthesis: a highly enantioselective route to beta-amino acids

The highly chemo- and enantioselective organocatalytic tandem reaction between N-protected hydroxyl amines and alpha,beta-unsaturated aldehydes is presented; the reaction provides access to 5-hydroxyisoxazolidines and beta-amino acids in high yields and with 90-99% ee.     

Lewis base activation of Lewis acids: catalytic, enantioselective vinylogous aldol addition reactions

The generality of Lewis base catalyzed, Lewis acid mediated, enantioselective vinylogous aldol addition reactions has been investigated. The combination of silicon tetrachloride and chiral phosphoramides is a competent catalyst for highly selective additions of a variety of alpha,beta-unsaturated ketone-, 1,3-diketone-, and alpha,beta-unsaturated amide-derived dienolates to aldehydes. These reactions provided high levels of gamma-site selectivity for a variety of substitution patterns on the dienyl unit. Both ketone- and morpholine amide-derived dienol ethers afforded high enantio- and diastereoselectivity in the addition to conjugated aldehydes. Although alpha,beta-unsaturated ketone-derived dienolate did not react with aliphatic aldehydes, alpha,beta-unsaturated amide-derived dienolates underwent addition at reasonable rates affording high yields of vinylogous aldol product. The enantioselectivities achieved with the morpholine derived-dienolate in the addition to aliphatic aldehydes was the highest afforded to date with the silicon tetrachloride-chiral phosphoramide system. Furthermore, the ability to cleanly convert the morpholine amide to a methyl ketone was demonstrated.     

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.     

Asymmetric multicomponent domino reactions and highly enantioselective conjugated addition of thiols to alpha,beta-unsaturated aldehydes

An organocatalytic asymmetric multicomponent domino and a conjugated addition reaction to alpha,beta-unsaturated aldehydes are presented. The development is based, first, on an organocatalyzed highly enantioselective nucleophilic thiol addition to the beta-carbon atom in the iminium ion intermediate, followed by an electrophilic amination of the alpha-carbon atom to the enamine intermediate. The multicomponent reactions proceed to give enantiopure amino-thiols in moderate to good yields. Furthermore, the organocatalyzed thiol addition to alpha,beta-unsaturated aldehydes takes place in good yields and excellent enantioselectivities.     

Asymmetric synthesis and applications of beta-amino Weinreb amides: asymmetric synthesis of (S)-coniine

Conjugate addition of lithium (S)-N-benzyl-N-alpha-methylbenzylamide to a range of alpha, beta-unsaturated Weinreb amides proceeds with high levels of diastereoselectivity (>95% de). The beta-amino Weinreb amide products may be transformed into beta-amino ketones via reactions with Grignard reagents, while treatment with DIBAL-H furnishes beta-amino aldehydes. Trapping of the aldehyde via Wadsworth-Emmons reaction and subsequent manipulation offers an efficient route to homochiral delta-amino acid derivatives and 2-substituted piperidines. The application of this methodology for the synthesis of (S)-coniine is demonstrated.     

Organocatalytic asymmetric epoxidation reactions in water-alcohol solutions

The diastereo- and enantioselective organocatalytic epoxidation of alpha,beta-unsaturated aldehydes in aqueous solutions is presented. By the screening of the reaction conditions for the epoxidation of cinnamic aldehyde applying hydrogen peroxide as the oxidant and 2-[bis-(3,5-bis-trifluoromethyl-phenyl)-trimethylsilanyloxy-methyl]-pyrrolidine as the catalyst, a highly stereoselective reaction has been developed. The scope of the diastereo- and enantioselective organocatalytic epoxidation in aqueous solutions is documented by the asymmetric epoxidation of alpha,beta-unsaturated aldehydes with enantioselectivities up to 96% ee.     

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.     

The first enantioselective organocatalytic Mukaiyama-Michael reaction: a direct method for the synthesis of enantioenriched gamma-butenolide architecture

The first enantioselective organocatalytic Mukaiyama-Michael reaction using alpha,beta-unsaturated aldehydes has been accomplished. The use of iminium catalysis has provided a new strategy for the enantioselective addition of 2-silyloxy furans to unsaturated aldehydes to generate a variety of butenolide systems, an important chiral synthon found among many natural isolates. The (2S,5S)-5-benzyl-2-tert-butyl-imidazolidinone amine catalyst has been found to mediate the conjugate addition of a wide variety of substituted and unsubstituted silyloxy furans to unsaturated aldehydes. A diverse range of aldehyde substrates can be accommodated in this new organocatalytic transformation. Application of this new asymmetric technology to the enantioselective total synthesis of spiculisporic acid and the corresponding 5-epi-spiculisporic acid analogue is also discussed.     

Direct amination of homoenolates catalyzed by N-heterocyclic carbenes

N-Heterocyclic carbenes derived from N-mesityl-N-methyltriazolium salts are effective catalysts for generating homoenolate species from alpha,beta-unsaturated aldehydes. The unique intermediate adds to the electrophilic nitrogen of 1-acyl-2-aryldiazenes, and the resulting activated carbonyl unit undergoes an intramolecular acylation event. This formal [3+2] cycloaddition between alpha,beta-unsaturated aldehydes and acylaryldiazenes, catalyzed by an N-heterocyclic carbene, produces substituted pyrazolidinones in good yields. This new NHC-catalyzed reaction accommodates aromatic and alkyl alpha,beta-unsaturated aldehydes and various aromatic diazenes. A chiral triazolium salt catalyzes the formation of the pyrazolidinone product in moderate yield and good enantioselectivity. The pyrazolidinones can undergo reductive N-N bond cleavage to give beta-amino acid derivatives.     

Asymmetric three- and [2 + 1]-component conjugate addition reactions for the stereoselective synthesis of polysubstituted piperidinones

The efficiency and stereoselectivity of the conjugate addition of lithium (Z)- or (E)-beta-amino ester enolates, generated by lithium amide conjugate addition to an alpha,beta-unsaturated ester or deprotonation of a beta-amino ester, respectively, to a range of alpha,beta-unsaturated acceptors has been investigated. Deprotonation of a beta-amino ester with LDA, followed by conjugate addition to a chiral alpha,beta-unsaturated oxazolidinone gives high 2,3-anti selectivity ( approximately 90% d.e.), with hydrogenolysis and purification to homogeneity generating stereodefined trisubstituted piperidinones as single stereoisomers. Asymmetric three-component couplings of alpha,beta-unsaturated esters and alkylidene malonates initiated by lithium amide conjugate addition proceeds with high levels of 2,3-anti stereoselectivity, with hydrogenolysis giving tetrasubstituted piperidinones.     

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.     

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.     

Enantioselective addition of diethylzinc to aldehydes catalyzed by N-(9-phenylfluoren-9-yl) beta-amino alcohols

A set of secondary N-phenylfluorenyl beta-amino alcohols have been prepared and evaluated as catalysts for the enantioselective addition of diethylzinc to benzaldehyde. The influence of the substituents on the stereogenic centers of the ligand has been studied, and enantioselectivities up to 97% have been obtained. Those ligands with bulky groups in the carbinol stereocenter and small groups alpha to the nitrogen atom displayed the best catalytic activity and enantioselectivity. The most enantioselective ligand (4e) was found to possess general applicability for the enantioselective addition of diethylzinc to a variety of aromatic and aliphatic aldehydes.     

Fluoroalkyl alpha,beta-unsaturated imines. Valuable synthetic intermediates from primary fluorinated enamine phosphonates

[reaction: see text] A simple method for the preparation of fluoroalkyl allylamines or alpha,beta-unsaturated ketones by an olefination reaction of primary enamine phosphonates and aldehydes, followed by selective reduction with hydrides or hydrolysis, is reported. Fluorinated beta-amino nitriles are also obtained by an olefination reaction of primary enamine phosphonates with aldehydes and subsequent addition of metalated acetonitrile.     

Enantioselective organocatalytic intramolecular ring-closing Friedel-Crafts-type alkylation of indoles

An enantioselective organocatalytic intramolecular ring-closing Friedel-Crafts-type alkylation of indolyl alpha,beta-unsaturated aldehydes has been developed. This powerful new strategy allows enantioselective access to THPIs and THBCs in a straightforward and atom-economical manner.     

Enantioselective organocatalytic double Michael addition reactions

[reaction: see text] A novel organocatalytic, enantioselective domino double Michael addition reaction of alpha,beta-unsaturated aldehydes with ethyl 4-mercapto-2-butenoate has been developed. The process is promoted by chiral diphenylprolinol TMS ether to give chiral tetrahydrothiophenes in high to excellent levels of enantioselectivities.     

Highly enantioselective conjugate additions to alpha,beta-unsaturated ketones catalyzed by a (salen)Al complex

Chiral (salen)Al complex 1a catalyzes the highly enantioselective conjugate addition of carbon- and nitrogen-based nucleophiles to acyclic alpha,beta-unsaturated ketones. This methodology is tolerant of substantial variation of the ketone structure, providing access to a wide range of useful chiral building blocks in high yield and enantiomeric excess. Synthetic manipulations of the conjugate addition products are demonstrated, including the straightforward preparation of beta-amino ketones and highly enantioenriched carbo- and heterocyclic compounds.     

Dienamine catalysis: organocatalytic asymmetric gamma-amination of alpha,beta-unsaturated aldehydes

A new concept in organocatalysis is presented, the direct asymmetric gamma-functionalization of alpha,beta-unsaturated aldehydes. We disclose that secondary amines can invert the usual reactivity of alpha,beta-unsaturated aldehydes, enabling a direct gamma-amination of the carbonyl compound using azodicarboxylates as the electrophilic nitrogen-source. The scope of the reaction is demonstrated for the enantioselective gamma-amination of different alpha,beta-unsaturated aldehydes, giving the products in moderate to good yields and with high enantioselectivities up to 93% ee. Experimental investigations and DFT calculations indicate that the reaction might proceed as a hetero-Diels-Alder cycloaddition reaction. Such a mechanism can explain the "unexpected" stereochemical outcome of the reaction.     

Asymmetric synthesis of gamma-hydroxy alpha,beta-unsaturated aldehydes via enantioselective direct addition of propargyl acetate to aldehydes

We report the first example of enantioselective and diastereoselective aldehyde additions of propargyl acetate to aldehydes using the methodology recently reported from our laboratories. Subsequent O-silyl protection, Pd-catalyzed isomerization, AcOH addition, and hydrolysis result in optically active gamma-hydroxy alpha,beta-unsaturated aldehydes as powerful building blocks. Reaction: see text.     

The enantioselective organocatalytic 1,4-addition of electron-rich benzenes to alpha,beta-unsaturated aldehydes

The first enantioselective organocatalytic alkylation of electron-rich benzene rings with alpha,beta-unsaturated aldehydes has been accomplished. The use of iminium catalysis has provided a new strategy for the enantioselective construction of benzylic stereogenicity, an important chiral synthon for natural product and medicinal agent synthesis. The (2S,5S)-5-benzyl-2-tert-butylimidazolidinone amine catalyst has been found to mediate the conjugate addition of a wide variety of substituted and unsubstituted anilines to unsaturated aldehydes. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 10 mol % were generally employed in this study, successful alkylations conducted with catalyst loadings as low as 1 mol % are described.