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Computations (SCS-MP2//B3LYP) reveal that the asymmetric synthesis of highly substituted γ-lactams with three stereogenic centers, including one quaternary center, proceeds through a Mannich reaction between the enol form of the anhydride and the E-imine, followed by a transannular acylation. This new mechanistic picture accounts for both the observed reactivity and stereoselectivity. CH-O and hydrogen bonding interactions in the Mannich step and torsional steering effects in the acylation step are responsible for stereocontrol. It is demonstrated that this new mechanistic picture applies to the related reactions of homophthalic anhydrides with imines and presents new vistas for the design of a new reaction to access complex molecular architectures.

A reaction between imines and anhydrides has been developed with chiral disubstituted anhydrides and chiral imines. The synthesis of highly substituted γ-lactams with three stereogenic centers, including one quaternary center, proceeds at room temperature in high yield and with high diastereoselectivity in most cases. Enantiomerically pure alkyl-substituted anhydrides proceed with no epimerization, thus providing access to enantiomerically pure penta-substituted lactam products.

Peptidomimetics are emerging as a promising class of potent and selective therapeutics. Among the current approaches to these compounds, the utilization of constrained lactams is a key element in enforcing the active peptide conformation, and the development of efficient and stereocontrolled methods for generating such lactam building blocks is an important objective. Current methods typically rely on the elaboration of existing α-amino acids, and in so doing, the side chain is sacrificed during the ring-forming process. We report a new asymmetric approach to lactam-constrained α-amino acid building blocks bearing a range of polar and hydrophobic side chains. The chemistry is amenable to rapidly generating di- and tripeptides, and the potential for these lactams to stabilize type II β-turns is demonstrated in the synthesis of the melanocyte-inhibiting factor peptidomimetic.

A protocol for palladium-catalyzed C-H carbonylation of readily available free primary benzylamines using NH2 as the chelating group under an atmospheric pressure of CO has been achieved, providing a general, atom- and step-economic approach to benzolactams, an important structural motif found in many biologically active compounds. Application of this new method is also exemplified in the concise syntheses of two bioactive molecules. [ABSTRACT FROM AUTHOR]

A synthetic method for the efficient construction of β-hydroxylactones and lactams bearing α-quaternary carbon centers is described. This transformation relies on an electronically differentiated Lewis base catalyst, which is uniquely capable of promoting a reductive aldol reaction of a,a-disubstituted and α,α,β-trisubstituted enones. This approach provides a valuable synthetic alternative for carbon-carbon bond formation in complex molecular settings due to its orthogonal reactivity compared to that of traditional aldol reactions. Based on this method described herein, lactones, lactams, and morpholine amides bearing α-quaternary carbon centers are accessible in yields up to 85% and 50:1 dr. [ABSTRACT FROM AUTHOR]

A formal α-addition of N-propiolamide and 2-bromoacetate is reported for the synthesis of α-methylene-β-lactam in good yields. The transformation proceeds smoothly in the presence of K2CO3 as a base and KI as an additive. An excellent reaction scope is observed. A 2 mmol scaled synthesis of α-methylene-β-lactams and synthetic applications of α-methylene-β-lactams are also reached. In the process, it is believed that an intramolecular 1,2-addition of N-propiolamide and sequential C-C bond migrating cleavage are involved. [ABSTRACT FROM AUTHOR]

This work develops a photocatalysis method for the synthesis of γ-spirolactams through a tandem intramolecular 1,5-HAT reaction-cyclization process. A variety of novel γ-spirolactams are prepared in good to excellent yields with this method. This transformation features mild reaction conditions and exceptional functional group tolerance. Additionally, γ-terpinene is applied to this transformation as a hydrogen atom donor for the first time. [ABSTRACT FROM AUTHOR]

Asymmetric and site-selective formal [3 + 2]-annulations of γ-alkyl-β,γ-unsaturated γ-lactams with α,β-unsaturated aldehydes have been developed. These organocatalysed transformations yield high value enantioenriched bicyclic γ-lactams with up to four new stereocenters (sometimes including a quarternary carbon). The overall transformation starts from simple and readily accessible furans and oversees a rapid, controlled, and dramatic enhancement in 3D complexity. [ABSTRACT FROM AUTHOR]

A photoredox catalytic approach to synthetically valuable N-acyl-N'-aryl-N,N'-aminals is described. This method uses the addition of a radical precursor to enamides, with subsequent interception of the cationic iminium intermediate with an arylamine. The reaction has been shown to be compatible with electron-rich and electron-deficient arylamines, and moderate to good levels of diastereoselectivity can be attained using a chiral enamide. Furthermore, the N-acyl-N'-aryl-N,N'-aminal reaction products can be readily cyclized, providing a novel synthetic route to valuable γ-lactams. [ABSTRACT FROM AUTHOR]

Cascade radical cyclization of 1,6-enynes for the synthesis of biologically important γ-lactams containing alkenyl C-X bonds is reported. In these radical cascade processes, three new chemical bonds, including C-S, C-C, and C-X bonds, are formed in one step. The method is attractive and valuable due to its mild reaction conditions, broad substrate scope, and the importance of the corresponding γ-lactam products. [ABSTRACT FROM AUTHOR]

A diastereoselective (up to >99%) route to all carbon quaternary stereocenters at the C-3 position of cyclic lactams has been developed via Johnson-Claisen rearrangement of γ-hydroxy-α,β-unsaturated lactams. It has been observed that olefin geometry plays an important role in the development of the absolute stereochemistry of the product. Dependence of product configuration on the olefin geometry is explained by postulating probable transition states. The success of this method has been shown for multigram-scale synthesis of these substituted lactams from commercially available cheap starting materials. The synthetic usefulness of this method is also demonstrated by carrying out the total synthesis of (-)-physostigmine. [ABSTRACT FROM AUTHOR]

A synthesis of (+)-gephyrotoxin 287C using (S)-phenylglycinol-derived tricyclic lactam 7 as the starting enantiomeric scaffold is reported. From the stereochemical standpoint, the key steps are the generation of the DHQ C-5 stereocenter by hydrogenation of the C-C double bond, removal of the chiral inductor to give a cis-DHQ, introduction of the DHQ C-2 substituent, completion of the (Z)-enyne moiety, and generation of the C-1 stereocenter during closure of the pyrrolidine ring. [ABSTRACT FROM AUTHOR]

An alkoxide-catalyzed reduction of benzolactams to isoindoles with silanes was realized. With t-BuOK as the catalyst and Ph2SiH2 as the reductant, a series of benzolactams containing different functional groups were reduced to the corresponding isoindoles, which could be captured by N-phenyl maleimide to form Diels-Alder products in moderate to good yields. Deuterium labeling studies and the hydrosilylation of benzolactam in DMF indicated that the deprotonation of benzolactams took place at C3 potion during the reduction. [ABSTRACT FROM AUTHOR]

A novel palladium-catalyzed intramolecular hydroaminocarbonylation of aminoalkynes has been developed. This direct and operationally simple protocol provides a rapid and reliable approach to a diverse array of valuable seven- and eight-membered lactams with high chemoselectivity and regioselectivity. The high selectivity might be attributed to rational tuning the electronic nature of the amine moiety and the palladium catalyst, which enabled this transformation to proceed in the absence of acidic or any other additives under fairly mild reaction conditions. This method paves the way for the synthesis of medium-sized lactams. [ABSTRACT FROM AUTHOR]

The nickel-catalyzed reduction of secondary and tertiary amides to give amine products is reported. The transformation is tolerant of extensive variation with respect to the amide substrate, proceeds in the presence of esters and epimerizable stereocenters, and can be used to achieve the reduction of lactams. Moreover, this methodology provides a simple tactic for accessing medicinally relevant α-deuterated amines. [ABSTRACT FROM AUTHOR]

Chiral γ-lactams have been synthesized in excellent yields and enantioselectivities (up to 99% yield and 96% ee) from easily accessible racemic γ-hydroxy γ-lactams via an iridium-phosphoramidite catalyzed asymmetric hydrogenation. The reaction was designed based on insight into the reaction mechanism demonstrated in previous work and can be carried out at a reduced catalyst loading of 0.1 mol % on a gram scale. Several potential bioactive compounds can be synthesized from the reduced products. Mechanistic studies indicated that the reduced products were obtained via the hydrogenation of the N-acyliminium cations, generated from γ-hydroxy γ-lactams. [ABSTRACT FROM AUTHOR]

An efficient asymmetric hydrogenation of β,γ-unsaturated γ-lactams using an iridium-phosphoramidite complex is reported. The chiral γ-lactams were obtained in excellent yields and enantioselectivities (up to 99% yield and 99% ee). The mechanistic studies indicated that the reduced products were obtained via the hydrogenation of the N-acyliminium cations, generated from β,γ-unsaturated γ-lactams, which was verified by ¹H NMR analysis. The reaction was carried out at a reduced catalyst loading of 0.1 mol %, and the reduced products can be transformed to two potential bioactive compounds. A new route is provided for the synthesis of chiral γ-lactams. [ABSTRACT FROM AUTHOR]

Bioassay-guided metabolomic analyses led to the characterization of four new 20-membered glycosylated polyketide macrolactams, macrotermycins A-D, from a termite-associated actinomycete, Amycolatopsis sp. M39. M39's sequenced genome revealed the macrotermycin's putative biosynthetic gene cluster. Macrotermycins A and C had antibacterial activity against human-pathogenic Staphylococcus aureus and, of greater ecological relevance, they also had selective antifungal activity against a fungal parasite of the termite fungal garden. [ABSTRACT FROM AUTHOR]

A metal-free strategy for the formation of lactams via selective oxidation of cyclic secondary and tertiary amines is described. Molecular iodine facilitates both chemoselective and regioselective oxidation of C-H bonds directly adjacent to a cyclic amine. The mild conditions, functional group tolerance, and substrate scope are demonstrated using a suite of diverse small molecule cyclic amines, including clinically approved drug scaffolds. [ABSTRACT FROM AUTHOR]

In the search for new antiprotozoal substances, hoshinolactam, an antitrypanosomal lactam, was isolated from a marine cyanobacterium. The gross structure was elucidated by spectroscopic analyses, and the absolute configuration was determined by the first total synthesis. Hoshinolactam showed potent antitrypanosomal activity with an IC50 value of 3.9 nM without cytotoxicity against human fetal lung fibroblast MRC-5 cells (IC50 > 25 μM). [ABSTRACT FROM AUTHOR]

A tetracyclic compound with the ABCD ring framework of calyciphylline A-type alkaloids was synthesized from a cis-3a-methyloctahydroindole triggered by a 5-endo radical cyclization. The synthesis required two additional ring-forming steps: the construction of a seven-membered ring by aldol cyclization and the azabicyclic fragment by a radical ring closure of a trichloroacetamide-tethered enol acetate followed by a diastereoselective α-methylation of the lactam group. [ABSTRACT FROM AUTHOR]

The new ansa macrolide antibiotics 1 to 4 have been isolated from cultures of a Micromonospora sp. obtained from a marine sediment. Rifamycins 1 and 2 are the first natural ansa macrolides to have a 3-amino substituent. Sporalactams A (3) and B (4) are comprised of a heterocylic core 5 and a 14-membered ansa bridge that are both unprecedented. Sporalactam B (4) shows selective and potent inhibition of Mycobacterium tuberculosis. [ABSTRACT FROM AUTHOR]

The facile synthesis of 6- to 8-membered pyrrololactams has been developed using a ring expansion of spiro-2H-pyrroles, the products of intermolecular alkyne-isocyanide click reactions. The key to successful ring expansion of spiro-2H-pyrroles to pyrrololactams is the enforced orbital overlap between the internal alkene and the amide carbonyl group through the conformationally locked bicyclic structures. The newly disclosed a-isocyano lactams, substrates for click reactions, should find their utility in the synthesis of pharmaceutically important heterocyclic compounds. [ABSTRACT FROM AUTHOR]

A highly efficient Ir-catalyzed asymmetric hydrogenation of racemic β-keto lactams via dynamic kinetic resolution (DKR) for the synthesis of optically active β-hydroxyl lactams has been described. With the Ir-SpiroSAP catalyst, a series of racemic β-keto lactams including β-keto γ-, δ-, and ε-lactams were hydrogenated to chiral β-hydroxy lactams in high yields (87-99%) with excellent enantio- and diastereoselectivity (83-99.9% ee, syn/anti: 97:3->99:1) at low catalyst loading under mild reaction conditions. This efficient method has been successfully applied in the synthesis of the chiral intermediate of fluoroquinolone antibiotic premafloxacine. [ABSTRACT FROM AUTHOR]

An iron-catalyzed direct aerobic α,β-dehydrogenation of carbonyls has been reported. The combination of tert -butyl nitrite and N -hydroxyphthalimide worked as the organo cocatalyst system; thus, no extra transition metal reagents are required. A large variety of lactams and flavanones as well as lactone and thiochromen-4-one could be produced via this method in high yields.

Cascade radical cyclization of 1,6-enynes for the construction of biologically important polycyclic γ-lactams and related heterocycles is reported. In these radical cascade processes, three new C-C bonds are formed and transition metals are not required to run these sequences. The mild reaction conditions, broad substrate scope, and the importance of the heterocyclic products render the approach valuable. [ABSTRACT FROM AUTHOR]

Developing new on-DNA reactions is paramount to the development of new encoded libraries in the pursuit of novel pharmaceutical lead compounds. Lactam-containing molecules have been shown to be effective in a wide range of therapeutic areas and therefore represent a promising target for further investigation by DNA-encoded library screening. In pursuit of this motif, we report a novel method for the introduction of lactam-containing structures onto a DNA headpiece through the Ugi four-center three-component reaction (4C-3CR). This novel method is successful in three different approaches to give unique on-DNA lactam structures: on-DNA aldehyde coupled with isonitriles and amino acids; on-DNA isonitrile coupled with aldehydes and amino acids; and on-DNA isonitrile coupled with amines and acid aldehydes.

Enantio- and diastereoselective hydrogenation of β-keto-γ-lactams with a ruthenium-BINAP catalyst, involving dynamic kinetic resolution, has been employed to provide a general, asymmetric approach to β-hydroxy-γ-lactams, a structural motif common to several bioactive compounds. Full conversion to the desired β-hydroxy-γ-lactams was achieved with high diastereoselectivity (up to >98% de) by addition of catalytic HCl and LiCl, while β-branching of the ketone substituent demonstrated a pronounced effect on the modest to excellent enantioselectivity (up to 97% ee) obtained. [ABSTRACT FROM AUTHOR]

The ability to affect asymmetric reduction of heterocyclic β-aminoacrylates 1 (n = 1-3) has been assessed with pyrrolidine and piperidone variants generating the corresponding N-heterocyclic β²-amino acids 3b and 5b with high enantioselectivity (≥97% ee) using a Rh/WALPHOS catalyst combination. The use of the carboxylic acid substrate was essential; the corresponding esters do undergo reduction but led to racemic products. The seven-ring azepanone variant (as the carboxylic acid 9b) underwent reduction, but only a minimal level of asymmetric induction was observed. [ABSTRACT FROM AUTHOR]

In the presented method, a one-pot metal-free access to β-lactams is provided. The developed strategy employs a hypervalent iodine(III)-triggered bromination/rearrangement/cyclization cascade reaction that allows the straightforward synthesis of a broad range of structurally different lactams from cheap and easily available imides. This triple cascade reaction is furthermore extendable by an in situ ring-opening reaction, giving direct access to isoserine derivatives from simple imines in a four-step, one-pot reaction. [ABSTRACT FROM AUTHOR]

The first total synthesis of (-)-L-755,807 and its three stereoisomers was achieved by our Horner-Wadsworth-Emmons reaction for stereoselective formation of trisubstituted olefins, highly diastereoselective Darzens condensation to construct the epoxy-γ-lactam ring, and late-stage coupling of the ring and side-chain segments for efficient convergent synthesis. This synthesis shows that the originally proposed structure of natural (-)-L-755,807 was incorrect and establishes its relative and absolute configurations. [ABSTRACT FROM AUTHOR]

A new aerobic intramolecular palladium(II)-based catalytic system that triggers aminopalladation/dehydropalladation of N-sulfonylalkenylamides to give the corresponding methylidene γ-lactams has been identified. Use of triphenylphosphine and chloride anion as ligands is mandatory for optimal yields, and molecular oxygen can be used as the sole terminal oxidant. Scope and limitations of the methods are described. A mechanism is proposed on the basis of experimental results as well as density functional theory calculations. [ABSTRACT FROM AUTHOR]

A total synthesis of huperzine R was accomplished. Intramolecular cycloaddition of a nitrile oxide and reductive cleavage of the resulting isoxazoline induced sequential cleavage of the C-C and C-O bonds to form the characteristic bicyclic lactam core with an enone moiety. Construction of the butenolide moiety from the enone afforded huperzine R. [ABSTRACT FROM AUTHOR]

An efficient route to isoindolinonesand isoquinolinones has beenachieved via a domino Ni-catalyzed homoallylation/lactamization from in situprepared imines, derived from o-formyl benzoates and o-formyl arylacetates, withconjugated dienes promoted by diethylzinc. The reaction proceeds smoothlyat room temperature for a variety of aldehydes, amines, and dienes.The method involves one C–C and two C–N bond formingevents under operationally simple conditions. [ABSTRACT FROM AUTHOR]

Thefirst example of the synthesis of β-lactam-triflones is described.Treatment of 2-diazo-1-aryl-2-(trifluoromethylsulfonyl)ethanones 1cfwith imines 2undercatalyst-free heating conditions provides pharmaceutically attractivemultisubstituted β-lactam-triflones 3in good tohigh yields with regio- and diastereoselectivities. A successiveWolff rearrangement and Staudinger [2 + 2] cycloaddition reactionare key elements for the success of this transformation. [ABSTRACT FROM AUTHOR]