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Five- and six-membered cyclic amide structures with an embedded endocyclic α-aza group (α-aza-lactams) not only represent masked or protected forms of α-amino acids, but also form the core of other medicinally relevant compound families such as (thio)hydantoins and di(tri)ketopiperazines. In recent years, catalytic methods have been discovered to synthesize these molecular scaffolds, particularly those bearing an α-stereogenic tri- or tetrasubstituted carbon center, enantioselectively. The wide variety of methods and catalytic activation strategies that have been successfully applied to this end in a short period of years is notable. This short review covers the most significant, highlighting their differences and complementarities. The methods are organized according to the disconnection approach to the target α-aza-lactam structure, which in most cases is deeply bound to the type of catalysis applied. 1 Introduction 2 Catalyst-Controlled Cα –H Functionalization (Approach a) 3 Decarboxylative α-AAA Reactions (Approach b) 4 Cα –X Substitution Reactions (Approach c) 5 De Novo Synthesis from Acyclic Precursors (Approach d) 6 Hydrogenation of (Addition to) α-Alkyliden-α-aza-lactams (Approach e) 7 Kinetic Resolution and Deracemization (Approach f) 8 Conclusions [ABSTRACT FROM AUTHOR]

Chiral Brønsted base (BB) catalyzed asymmetric transformations constitute an important tool for synthesis. A meaningful fraction of these transformations proceeds through transiently generated enolate intermediates, which display quite versatile reactivity against a variety of electrophiles. Some years ago, our group became interested in developing BB‐catalyzed asymmetric reactions of enolizable carbonyl substrates that involve π‐extended enolates in which, besides control of reaction diastereo and enantioselectivity, the site‐selectivity control is an additional issue in most cases. In the examples covered in this account the opportunities deployed, and the challenges posed, by these methods are illustrated, with a focus on the generation of quaternary carbon stereocenters. In the way, new bifunctional BB catalysts as well as achiral templates were developed that may find further applications. [ABSTRACT FROM AUTHOR]

An attempt was made to explore a new type of sugar-amino acid hybrid, which was comprised of a sugar unit (gluco-galacto-, or mannopyranose) linked through a C-glycosidic linkage to the beta-position of an alpha-unsubstituted beta-amino acid unit. The synthetic strategy used is based on a new Mannich-type reaction between a chiral acetate enolate equivalent and alpha-amido sulfones derived from the corresponding sugar-C-glycoside aldehydes.

Research demonstrates a general strategy to access alpha,beta-dihydroxy alpha-amino acid- derived N-carboxy anhydrides and peptides derived from them. Results show that the method comprises of sequential application of the [2+2]ketone-imine cycloaddition, the Sharpless AD reaction, and a ring expansion of 3-hydroxy beta-lactams.

Research has been conducted on the synthesis of dihydroxyhomotyrosine amino acid segment that is ready for peptide coupling. Enantioselective AD reaction of 4-methoxycinnamic acid methyl ester is described.

Research has been conducted on lithium enolates of alpha-hydroxy ketones. The authors evaluate them for asymmetric aldol reactions in the presence of lithium chloride.

The use of N-Selectride with CuX2.SMe2 halides is capable of promoting enolate trapping and conjugate reduction with glyoxylate imines. This process can lead to the production of beta-lactam intermediates that possess remarkable enentioselectivity attributes. The procedure is expected to aid in the development of stereocontrolled synthesis of beta-lactams, a development that will greatly improve the production of the antimicrobial beta-lactam antibiotics.

Research was conducted to derive a synthesis for N-carboxy anhydride formally derived from polyhydroxylated alpha-amino acides using non-alpha-amino acid precursors. Results demonstrate that the approach sets the basis for the development of a practical and concise access to simultaneously amino-protected and carboxy-activated forms of polyhydroxylated alpha-amino acids.

A study was conducted to characterize an epimerization-free pathway toward beta,beta-disubstituted beta-amino acid-containing peptides. The integration of 1-aminocylclobutylacetic acid and cycloalkyl homologies into small peptide segments were also analyzed in the study. Results indicated that potassium cyanide correlates with the ring opening of beta-lactams through the generation of an acyl cyanide intermediate.

The diastereoselective cycloaddition of N-Boc-alpha-amino aldehydes with alpha-(silyloxy) aldehydes and dicholoroketene led to the synthesis of alpha, alpha-dichloro beta-lactones. The synthetic process involves the coupling of the intermediate product from highly diastereoselective cycloaddition with alpha-amino acid esters leading to the formation of peptide mimics after dehalogenation with H2. The alpha, alpha-dichloro beta-lactones from single synthetic step also undergo omicron-acyl fission with alpha-amino acid esters.

The kinetics of the reaction between homochiral ketene with homochiral aldehyde was analyzed to determine the stereochemical characteristics of the synthetic process for beta-lactams. The formation of beta-lactams involves cycloaddition reactions that are mediated by the acid chlorides and triethylamine of chiral aminoketenes with chiral imines. The synthetic process leads to the direct formation of cis-beta-lactams with an absolute stereochemistry that is affected by the ketene component.

A diastereoselective synthesis of beta-lactams with quarternary stereogenic centers was developed based on [2+2] cycloaddition reactions. The synthetic process was based on Staudinger reaction which provided a more chemically efficient route to the construction of the homochiral beta-lactams with quarternary stereogenic centers. Furthermore, the single synthetic step was utilized to produce a wide variety of structurally different C(4)-disubstituted beta-lactams in a single synthetic step.

The diastereoselective cycloaddition of N-Boc-alpha-amino aldehydes with alpha-(silyloxy) aldehydes and dicholoroketene led to the synthesis of alpha, alpha-dichloro beta-lactones. The synthetic process involves the coupling of the intermediate product from highly diastereoselective cycloaddition with alpha-amino acid esters leading to the formation of peptide mimics after dehalogenation with H2. The alpha, alpha-dichloro beta-lactones from single synthetic step also undergo omicron-acyl fission with alpha-amino acid esters.

The kinetics of the reaction between homochiral ketene with homochiral aldehyde was analyzed to determine the stereochemical characteristics of the synthetic process for beta-lactams. The formation of beta-lactams involves cycloaddition reactions that are mediated by the acid chlorides and triethylamine of chiral aminoketenes with chiral imines. The synthetic process leads to the direct formation of cis-beta-lactams with an absolute stereochemistry that is affected by the ketene component.

The oxidation of alpha-hydroxy beta-lactams gives alpha-keto beta-lactams intermediates that undergo Baeyer-Villiger rearrangement to form threonine- and azathreonine N-carboxy anhydrides. The one-pot oxidation-Baeyer-Villiger reaction occurs only in the presence of 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) and sodium hypochlorite. Rearrangement of the alpha-keto beta-lactams produces alpha-amino acid N-carboxy anhydrides (NACs) which readily form the dipeptides. TEMPO effectively catalyzes the cycloexpansion of alpha-hydroxy beta-lactams.

Grignard and organocuprate reagents catalyze ring opening reactions of 3, 4-disubstituted N-BOC-beta-lactams to yield alpha,gamma-disubstituted beta-amino ketones. NMR analysis of the crude mixtures helps estimate the proportion of products generated in the reaction. Nature of Grignard reagents influences the reaction. The disubstituted ketones help synthesize alpha-amino acids and polyhydroxylated nitrogen-containing products.

A novel method was developed to synthesize alpha-amino acid N-carboxy anhydrides (NCA), which were optically active, and their corresponding alpha-amino acid derivatives. The synthesis involved a Baeyer-Villiger rearrangement subsequent to alpha-hydroxy beta-lactam oxidation to the correlating alpha-keto beta-lactams. This reaction methodology facilitated the preparation of various NCAs from non-amino acid precursors.

Studies reveal that asymmetric 1, 4-addition of higher order silylcuprates to Oppolzer's N-enoylsultams is as diastereofacially selective as carbocupration of beta-silyl-substituted N-enoylsultams. Silylcupration efficiently yields enantiomerically pure beta-silyl carboxylic acid. H NMR spectroscopy yields the diastereomeric ratio for the addition reactions after flash chromatography of the initial reaction mixture.

The cyclization of ketenes and imines to beta-lactams is investigated by using the approximate self-consistent-field molecular orbital theory. The reaction between ketene and methanimine is carried out to produce 2-azetidone and the imine effect is assessed by studying the reaction of several selected imines. Results indicate that the reaction between ketenes and imines occurs in two steps and that it takes place via the formation of a N1-C1 bond which leads to ring closure through C3-C4 bond formation.

N-tert-butyloxycarbonyl alpha-amino aldehyde imines are optimal sources for forming patterns of optically active beta-lactams through Staudinger reaction. The Staudinger reaction between ketenes and imines, obtained from homochiral aldehydes possessing bonds between a chiral carbon and electronegative atom, leads to stereochemical product formation. The procedures may be useful in the synthesis and reactions of beta-lactams.

A stereocontrolled synthetic route to racemic thienamycin precursors and beta-(hydroxymethyl)aspartic acid derivatives involves the formation of cis- and trans-3- 1'-(dimethylphenylsilyl)ethyl -4-alkoxycarbonyl beta-lactams. The beta-lactams result from the condensation of glyoxylic ester imines with acid chlorides (which leads to the cis-form) or with organocopper enolates (which leads to the trans-form), using the dimethylphenylsilyl group as a masked hydroxy function.

The high tendency of α‐amino aldehydes to undergo 1,2‐additions and their relatively low stability under basic conditions have largely prevented their use as pronucleophiles in the realm of asymmetric catalysis, particularly for the production of quaternary α‐amino aldehydes. Herein, it is demonstrated that the chemistry of α‐amino aldehydes may be expanded beyond these limits by documenting the first direct α‐alkylation of α‐branched α‐amino aldehydes with nitroolefins. The reaction produces densely functionalized products bearing up to two, quaternary and tertiary, vicinal stereocenters with high diastereo‐ and enantioselectivity. DFT modeling leads to the proposal that intramolecular hydrogen bonding between the NH group and the carbonyl oxygen atom in the starting α‐amino aldehyde is key for reaction stereocontrol. [ABSTRACT FROM AUTHOR]