Catalytic enantioselective reductive alkynylation of amides enables one-pot syntheses of pyrrolidine, piperidine and indolizidine alkaloids.

The primary objective in synthetic organic chemistry is to develop highly efficient, selective, and versatile synthetic methodologies, which are essential for discovering new drug candidates and agrochemicals. In this study, we present a unified strategy for a one-pot, catalytic enantioselective synthesis of α-alkyl and α,α'-dialkyl pyrrolidine, piperidine, and indolizidine alkaloids using readily available amides and alkynes. This synthesis is enabled by the identification and development of an Ir/Cu/N-PINAP catalyzed highly enantioselective and chemoselective reductive alkynylation of α-unbranched aliphatic amides, which serves as the key reaction. This reaction is combined with Pd-catalyzed tandem reactions in a one-pot approach, enabling the collective, catalytic enantioselective total syntheses of eight alkaloids and an anticancer antipode with 90-98% ee. The methodology's enantio-divergence is exemplified by the one-step access to either enantiomer of alkaloid bgugaine.

Concise Total Synthesis of (-)-Quinocarcin Enabled by Catalytic Enantioselective Reductive 1,3-Dipolar Cycloaddition of Secondary Amides.

A concise asymmetric total synthesis of (-)-quinocarcin has been accomplished with high step economy from commercially available starting materials. A catalytic enantioselective reductive 1,3-dipolar cycloaddition reaction of N-heteroaryl secondary amides with reactive dipolarophiles using iridium/copper relay catalysis was developed to prepare the key chiral pyrrolidine intermediate with three stereocenters. This protocol features excellent regio-, exo- and enantioselectivities, broad substrate scope, and good functional group tolerance. The high efficiency was also ensured by a RhIII -catalyzed C-H activation/cyclization and a tandem diastereoselective hydrogenation/cyclization to construct the tetrahydroisoquinoline-pyrrolidine tetracyclic core unit of quinocarcin.

Multicatalysis protocol enables direct and versatile enantioselective reductive transformations of secondary amides.

The catalytic asymmetric geminal bis-nucleophilic addition to nonreactive functional groups is a type of highly desirable yet challenging transformation in organic chemistry. Here, we report the first catalytic asymmetric reductive/deoxygenative alkynylation of secondary amides. The method is based on a multicatalysis strategy that merges iridium/copper relay catalysis with organocatalysis. A further combination with the palladium-catalyzed alkyne hydrogenation allows the one-pot enantioselective reductive alkylation of secondary amides. This versatile protocol allows the efficient synthesis of four types of α-branched chiral amines, which are prevalent structural motifs of active pharmaceutical ingredients. The protocol also features excellent enantioselectivity, chemoselectivity, and functional group tolerance to be compatible with more reactive functional groups such as ketone and aldehyde. The synthetic utility of the method was further demonstrated by the late-stage functionalization of two drug derivatives and the concise, first catalytic asymmetric approach to the κ-opioid antagonist aticaprant.

Ir-Catalyzed Chemoselective Reductive Condensation Reactions of Tertiary Amides with Active Methylene Compounds.

The catalytic reductive condensation reactions of tertiary amides with active methylene compounds leading to multifunctionalized non-N-containing products is described. The reactions proceed through sequential iridium-catalyzed hydrosilylation of the amides followed by acid-mediated condensation with the active methylene compounds. This scalable method is broad in scope and shows remarkable chemoselectivity for the amide group in the presence of several sensitive or even more reactive functionalities such as ester, cyano, nitro, silyl dienol ether, and ketone.

One-Pot Synthesis of α-Amino Bisphosphonates from Nitriles via Tf2O/HC(OR)3-Mediated Interrupted Ritter-Type Reaction.

A versatile synthesis of α-amino bisphosphonates has been achieved through one-pot interrupted Ritter-type reaction under mild conditions. The reactive Ritter intermediate nitrilium is in situ generated by treatment of nitrile with readily accessible Tf2O/HC(OR1)3, which is trapped by phosphite ester to deliver the desired product. This protocol is efficient, scalable, and well compatible with a broad scope of substrates. In addition, plentiful characteristic JP-C couplings including unusual five-bond long-range 5JP-C and 3JP-C across quaternary carbon and hetero (N) atoms were observed in 13C NMR spectra.

Tf2O-Mediated Cyclization of 7-Enamides: Bioinspired Construction of Fused Eight-Membered Carbocyclic Enimines and Enones.

In this paper, we document the construction of functionalized and fused eight-membered carbocycles by the triflic anhydride-mediated cyclization of 7-enamides. Taking advantage of the high electrophilicity of the nitrilium ion intermediates, generated in situ from secondary N-(2,6-dimethyl)anilides, the nonactivated, trisubstituted alkene-nitrilium cyclization reactions proceeded smoothly to afford nonconjugated ß,γ-enimines (for fused 6/6/8 ring systems), conjugated α,ß-enimines (for 6/5/8), or fused 5/8 ring systems in good yields. When the cyclization reactions were followed by one-pot acidic hydrolysis, the reaction led directly to the corresponding α,ß-enones. For some substrates, the reaction afford an efficient access to pendent cyclic ß,γ-enimines/enones.

Asymmetric Deoxygenative Alkynylation of Tertiary Amides Enabled by Iridium/Copper Bimetallic Relay Catalysis.

A variety of inert tertiary amides have been successfully transformed into synthetically important chiral propargylamines in high yields with good to excellent enantioselectivities via a relayed sequence of Ir catalyzed partial reduction and Cu/GARPHOS catalyzed asymmetric alkynylation with terminal alkynes. The reaction was readily extended to some drug molecules and the transformations of representative products have been demonstrated, thus attesting the practical utilities and the robust nature of the protocol.

Tf2O/TTBP (2,4,6-Tri-tert-butylpyrimidine): An Alternative Amide Activation System for the Direct Transformations of Both Tertiary and Secondary Amides.

Ten types of Tf2O/TTBP-mediated amide transformation reactions were investigated. The results showed that compared with pyridine derivatives 2,6-di-tert-butyl-4-methylpyridine (DTBMP) and 2-fluoropyridine (2-F-Pyr.), TTBP can serve as an alternative amide activation system for the direct transformation of both secondary and tertiary amides. For most surveyed examples, higher or comparable yields were generally obtained. In addition, Tf2O/TTBP combination was used to promote the condensation reactions of 2-(tert-butyldimethylsilyloxy)furan (TBSOF) with both tertiary and secondary amides, the one-pot reductive Bischler-Napieralski-type reaction of tertiary lactams, and Movassaghi and Hill's modern version of the Bischler-Napieralski reaction. The value of the Tf2O/TTBP-based methodology was further demonstrated by the concise and high-yielding syntheses of several natural products.

Chemoselective Reactions of Isocyanates with Secondary Amides: One-Pot Construction of 2,3-Dialkyl-Substituted Quinazolinones.

A facile method for the preparation of 2,3-dialkyl-substituted quinazolinones from readily available N-arylamides and commercial isocyanates was developed. This one-pot procedure involves the chemoselective activation of the secondary amide with Tf2O/2-Br-Pyr, the sequential addition of isocyanate, and cyclization. The mild reaction is general for a wide range of substrates and can be run on a gram scale.

Enantioselective Reductive Cyanation and Phosphonylation of Secondary Amides by Iridium and Chiral Thiourea Sequential Catalysis.

The combination of transition-metal catalysis and organocatalysis increasingly offers chemists opportunities to realize diverse unprecedented chemical transformations. By combining iridium with chiral thiourea catalysis, direct enantioselective reductive cyanation and phosphonylation of secondary amides have been accomplished for the first time for the synthesis of enantioenriched chiral α-aminonitriles and α-aminophosphonates. The protocol is highly efficient and enantioselective, providing a novel route to the synthesis of optically active α-functionalized amines from the simple, readily available feedstocks. In addition, the reactions are scalable and the thiourea catalyst can be recycled and reused.

Enantioselective Total Syntheses of the Proposed and Revised Structures of Methoxystemofoline: A Stereochemical Revision.

This article describes the full details of our synthetic efforts toward the enantioselective total synthesis of the complex alkaloid methoxystemofoline. The enantioselective construction of the tetracyclic core features: (1) the Keck allylation at the N-α bridgehead carbon to forge the tetrasubstituted stereocenter; (2) an olefin cross-metathesis reaction for the side-chain elongation that is amenable for the synthesis of congeners and analogues; and (3) a regioselective aldol addition reaction with methyl pyruvate that ensured the subsequent regioselective cyclization reaction to construct the fourth ring. Overman's method was employed to install the 5-(alkoxyalky1idene)-3-methyl-tetronate moiety. In the last step, a nonstereoselective reaction resulted in the formation of both the proposed structure of methoxystemofoline and its E-stereoisomer, the natural product (revised structure), in a 1:1 ratio. We suggest to rename the natural product as isomethoxystemofoline, and report for the first time the complete 1H NMR data for this natural product.

Photoredox-Catalyzed Decarboxylative Cross-Coupling of α-Amino Acids with Nitrones.

A decarboxylative cross-coupling reaction of α-amino acids with nitrones via visible-light-induced photoredox catalysis has been established for easy access to ß-amino hydroxylamines and vicinal diamines with structural diversity, which is featured with simple operation, mild conditions, readily available α-amino acids, and a broad scope of nitrone substrates. The application of this protocol can furnish efficient synthetic strategies for some valuable vicinal diamine-containing molecules.

Synthesis of 5-(1-Alkoxyalkylidene)tetronates by Direct Condensation Reactions of Tetronates with Thionolactones and Thionoesters.

We report a two-step approach to bicyclic and monocyclic 5-(1-alkoxyalkylidene)tetronates starting from lactones/esters. The method features the use of thionolactones and thionoesters as activated forms of lactones/esters that allows the direct condensation with tetronates via one-pot enolate formation, nucleophilic addition, S-methylation, and DBU-promoted elimination. The value of the method was demonstrated by the stereoselective syntheses of two natural products: 5,6-Z-fadyenolide (Z/E ratio = 6:1) and 9,10-methylenedioxy-5,6-Z-fadyenolide (Z/E ratio = 9:1).

Organocatalytic Asymmetric Synthesis of an Advanced Intermediate of (+)-Sarain A.

The first organocatalytic asymmetric synthesis of an advanced intermediate of (+)-sarain A was achieved. This approach featured the employment of an organocatalytic asymmetric Michael addition reaction and a nitrogen-to-carbon chirality transfer to forge three chiral centers, as well as a catalytic hydrosilylation for the chemoselective reduction of a key lactam intermediate. The tricyclic intermediate contained all the required functionalities for elaborating into (+)-sarain A.

Enantioselective total syntheses of (+)-stemofoline and three congeners based on a biogenetic hypothesis.

The powerful insecticidal and multi-drug-resistance-reversing activities displayed by the stemofoline group of alkaloids render them promising lead structures for further development as commercial agents in agriculture and medicine. However, concise, enantioselective total syntheses of stemofoline alkaloids remain a formidable challenge due to their structural complexity. We disclose herein the enantioselective total syntheses of four stemofoline alkaloids, including (+)-stemofoline, (+)-isostemofoline, (+)-stemoburkilline, and (+)-(11S,12R)-dihydrostemofoline, in just 19 steps. Our strategy relies on a biogenetic hypothesis, which postulates that stemoburkilline and dihydrostemofolines are biogenetic precursors of stemofoline and isostemofoline. Other highlights of our approach are the use of Horner-Wadsworth-Emmons reaction to connect the two segments of the molecule, an improved protocol allowing gram-scale access to the tetracyclic cage-type core, and a Cu-catalyzed direct and versatile nucleophilic alkylation reaction on an anti-Bredt iminium ion. The synthetic techniques that we developed could also be extended to the preparation of other Stemona alkaloids.

Organocatalytic, Enantioselective Reductive Bis-functionalization of Secondary Amides: One-Pot Construction of Chiral 2,2-Disubstituted 3-Iminoindoline.

We report the first catalytic, enantioselective reductive bis-functionalization of common amides, which provides a facile access to a variety of 2,2-disubstituted 3-iminoindolines in good yields and with excellent enantioselectivities. The reaction conditions are quite mild and can be run on a gram scale. In this one-pot reaction, three C-C bonds, one ring, and one nitrogen-containing tetrasubstituted carbon stereocenter are created in a catalytic enantioselective manner.

Double Addition of Alkynyllithium Reagents to Amides/Lactams: A Direct and Flexible Synthesis of 3-Amino-1,4-diynes Bearing an Aza-Quaternary Carbon Center.

An efficient and mild protocol for the direct and flexible synthesis of 3-amino-1,4-diynes bearing an aza-quaternary carbon from tertiary amides and lactams has been established. The one-pot method consists of in situ activation of amides with trifluoromethanesulfonic anhydride, followed by double addition of alkynyllithium reagents at a concentration of 0.5 mol·L-1 in dichloromethane. This constitutes an extension of the method of direct reductive bisalkylation of amides that allows both employing alkynyllithium reagents as the first-addition nucleophiles and incorporating an alkynyl group as the first-introduced group.

Chemoselective Synthesis of α-Amino-α-cyanophosphonates by Reductive Gem-Cyanation-Phosphonylation of Secondary Amides.

A novel approach to α-amino-α-cyanophosphonates has been developed. The method features a Tf2O-mediated reductive geminal cyanation/phosphonylation of secondary amides. Mild reaction conditions, high bond-forming efficiency, inexpensive readily available starting materials, and good to excellent yields with wide functional group compatibility constitute the main advantages of this method. The protocol can be run on a gram scale.

Biomimetic Enantioselective Total Synthesis of (-)-Robustanoids A and B and Analogues.

We report a step-economical, enantioselective total synthesis of (-)-robustanoid B and (-)-robustanoid A and four novel natural product-like compounds. Our strategy relied on our biosynthetic hypothesis and on a novel complexity generation methodology, namely, the one-pot hydroxylative double cyclization reaction. The latter consists of a modified 3,3-dimethyldioxirane-triggered epoxidation-epoxide-ring-opening cyclization reaction cascade and Trost's regioselectivity umpolung methodology ("anti-Michael addition").