Lewis acid promoted highly diastereoselective Petasis Borono-Mannich reaction: efficient synthesis of optically active β,γ-unsaturated α-amino acids

An efficient and straightforward method for the preparation of highly enantiomerically enriched β,γ-unsaturated α-amino acid derivatives by a Lewis acid promoted diastereoselective Petasis reaction of vinylboronic acid, N-tert-butanesulfinamide, and glyoxylic acid has been developed. The synthetic utilities of the approach were demonstrated by the rapid and convenient construction of challenging cyclopenta[c]proline derivatives.     

The use of two optically active N-sulfinyl α-imino esters in the stereoselective aza-Diels-Alder reaction

Diastereoselective aza-Diels-Alder (aza-DA) reactions of ethyl (S)-N-(tert-butanesulfinyl)iminoacetate (2a) and ethyl (S)-N-(p-toluenesulfinyl)iminoacetate (2b) with different dienes including activated, non-activated, cyclic, and acyclic dienes in the presence of Lewis acids are described. Reactions with 2a were found to be more selective. Reactions of unactivated dienes (acyclic and cyclic) with stoichiometric amounts of TMSOTf as Lewis acid afforded the aza-DA adducts in modest yields and in diastereoselectivities up to 99%. A strong preference for Re-approach was observed for 2a. Cyclic dienes gave the exo adducts as major products. For the aza-DA reaction with activated Danishefsky type dienes poor diastereoselectivities were observed. In these cases, the best results were obtained using stoichiometric amounts of BF₃·Et₂O as Lewis acid (up to 69% de, 76% yield). The absolute configurations of six of the addition products were established by chemical correlation with known compounds. Acidic cleavage of the sulfinyl group occurred without racemization to optically active non-proteinogenic α-amino acid ethyl esters.     

Studies on the reaction of α-imino esters with organometallic compounds

Benzylzinc reagent reacted with α-imino ester (2) at the α-carbon exclusively, though other organometallic reagents such as Mg. Al, Cu, Tl, and B derivatives reacted at the nitrogen atom. Use of the (S)-amine as a chiral auxiliary of 2 created the R chirality at the imino carbon. Very high chiral Induction was realized In the reaction of prenylzinc reagent wlih α-imino 8-(-)phenylmenthyl ester (10). The reaction of 2 with heteroatom substituted allylic organometalic compounds (15) gave the corresponding α-heterostom substituted amino acid derivatives (16). Here again, the allylic zinc reagent gave the adduct in higher yield than the corresponding Tl, Al, and B reagents.     

Organocatalytic conjugate addition of α-nitroacetates to β,γ-unsaturated α-keto esters and subsequent decarboxylation: synthesis of optically active δ-nitro-α-keto esters

Organocatalytic asymmetric conjugate addition of tert-butyl nitroacetates to β,γ-unsaturated α-keto esters has been developed. The subsequent in situ hydrolysis-decarboxylation of the adducts provided 5-nitro-2-oxopentanoates. A pyrrolidine-based thiourea-tertiary amine was identified as the best catalyst. A number of γ-aryl, γ-alkyl, and γ-heteroaryl β,γ-unsaturated α-keto esters and α-substituted tert-butyl nitroacetates were examined in the transformation. Generally 5-nitro-2-oxopentanoates were obtained in good yields (up to 97%) and enantioselectivities (up to 94% ee). The products were readily transformed to chiral proline derivatives by catalytic hydrogenation.     

Efficient synthesis of optically active α-quaternary amino acids by highly diastereoselective [2,3]-rearrangement of allylic ammonium ylides

A pincer-like chiral auxiliary strategy for synthesizing various optically active α,α-disubstituted amino acids in high yields with excellent enantioselectivities is described.     

Silver-catalyzed decarboxylative cross-coupling of α-keto acids with alkenes giving approach to chalcones

A silver-catalyzed decarboxylative cross-coupling of α-keto acids with alkenes is reported. The method, with a wide range of substrate tolerance and mild operational conditions, can produce various chalcone derivatives in moderate to high yields from easily available starting materials.     

A highly stereoselective conversion of α,β-epoxy esters to α-hydroxy esters. An efficient route to optically active α-hydroxyesters

α,β-Epoxy esters were cleanly converted to α-hydroxy esters with retention of the configurations at the α-carbon atoms via MgI₂-promoted regioselective oxirane ring-opening followed by tributyltin hydride-reduction.     

Copper-bipyridine-catalyzed enantioselective α-amination of β-keto esters

The Cu(OTf)₂-bipyridine-catalyzed, enantioselective, direct α-amination of β-keto esters and β-diketones with diethyl azodicarboxylate (DEAD) has been studied. Exceptionally high enantioselectivities of up to 99% ee were found for 1-indanone-based β-keto esters in particular even for substrates and reagents carrying conventional ester groups such as methyl and ethyl.     

Catalysis of highly stereoselective Mannich-type reactions of ketones with α-imino esters by a pyrrolidine-sulfonamide. Synthesis of unnatural α-amino acids

The novel pyrrolidine-sulfonamide I has been prepared and used successfully to catalyze Mannich-type reactions between ketones and α-imino esters. The process is used to efficiently synthesize functionalized α-amino acid derivatives with excellent levels of regio-, diastereo-, and enantio-selectivity.     

Metal-free decarboxylative acylation of isoquinolines using α-keto acids in water

An efficient method for acylation of isoquinolines has been developed using α-ketoacids under metal- and additive-free conditions in water. The protocol involves C(sp²)H functionalization of isoquinolines providing an easy access to C1-benzoylated isoquinolines, which constitute the core structure of a number of biological active compounds and serve as key intermediate in the synthesis of many alkaloids.     

Lewis acid-catalyzed one-pot sequential reaction for the synthesis of α-halogenated β-keto esters

A Lewis acid-catalyzed one-pot sequential transformation of β-keto esters, aromatic aldehydes, and NCS/NBS was reported. The reaction proceeds by way of Knoevenagel condensation/Nazarov cyclization/halogenation to give α-chloro- and α-bromo-β-keto esters in moderate yields with high diastereoselectivities. However, several aromatic aldehydes with electron-withdrawing substituents afforded unexpected α,β′-dichloro-β-keto esters in good to high yields.     

Synthesis of optically active α-benzyl paraconic acids and their esters and assignment of their absolute configuration

The cis- and trans-4-benzylparaconic acids and their ethyl esters were synthesized with high enantiomeric excess by hydrolysis of the corresponding diastereomeric lactonic esters using α-chymotrypsin. Thus, at low conversion values, cis- and trans-4-benzyl-5-oxo-3-tetrahydrofurancarboxylic acids were separately isolated with 99% ee and 92% ee, respectively. Both ethyl ester diastereomers were also obtained in enantiopure form. The absolute configuration of the trans-lactonic acid was assigned by ¹H NMR analysis of its ester derivatives with both enantiomers of 1-(9-anthryl)-2,2,2-trifluoroethanol, while that of the cis-lactonic acid was assigned by means of X-ray analysis of a crystalline derivative. The circular dichroism curves of the products obtained are also reported.     

The reaction of α-stannylmethyllithium with esters

Ketonic compounds were prepared from esters using α-stannylmethyllithium as the reagent.     

Catalytic decarboxylative alkylation of β-keto acids with sulfonamides via the cleavage of carbon-nitrogen and carbon-carbon bonds

An efficient decarboxylative alkylation reaction of β-keto acids with N-benzylic or N-allylic sulfonamides has been developed, for the first time, through sequential cleavage of carbon-nitrogen and carbon-carbon bonds in the presence of 10 mol% of FeCl(3).     

An expedient synthesis of α,α-difluoro-β-hydroxy ketones via decarboxylative aldol reaction of α,α-difluoro-β-keto acids with aldehydes

A novel decarboxylative aldol reaction of α,α-difluoro-β-keto acids with aldehydes in the absence of any base and metal catalysts has been developed. This reaction provides a highly convenient and efficient method for the synthesis of structurally diverse α,α-difluoro-β-hydroxy ketones in good to excellent yields.     

A diastereoselective aza-Diels-Alder reaction of N-aryl-1-azadienes derived from α-amino acids with enamines

A diastereoselective inverse electron demand aza-Diels-Alder reaction of N-aryl-1-azadienes derived from α-amino acids is accomplished using enamine dienophiles. Activation with ytterbium triflate of these azadienes affords dimeric structures through aza-Diels-Alder reaction, where the alkene double bond of 1-azadienes also adopts the role of dienophile. An asymmetric synthesis of functionalised 1,4,5,6-tetrahydropyridine compounds derived from α-amino acids using an optically active enamine is reported.     

A novel annulation reaction of N-substituted-2-nitrosoanilines with esters of α-isocyano acids. A one-pot,two-step route to 2-benzimidazole-substituted esters of α-amino acids

A BF₃-promoted α-addition of isocyanides to both nitrogen atoms of N-aryl-2-nitrosoanilines leads to stable BF₃-complexes of 3-N-hydroxy-(2-alkylimino)benzimidazole derivatives, which, after reduction with Zn in AcOH produce 1-N-aryl-2-alkylaminobenzimidazoles. This two-step annulation proceeds efficiently in a one-pot protocol with isocyanides derived from esters of α-amino acids. The chirality of the latter remains unaffected in the reaction.