Synthetic Studies of the Zoanthamine Alkaloids: The Total Syntheses of Norzoanthamine and Zoanthamine

Highly effective : We report herein the first and highly efficient total syntheses of norzoanthamine and zoanthamine in full detail, which involves stereoselective synthesis of the requisite triene for an intramolecular Diels–Alder reaction via three‐component coupling reactions, the intramolecular Diels–Alder reaction, and subsequent crucial bis‐aminoacetalization as the key steps.

     

Asymmetric Total Synthesis of Indole Alkaloids Containing an Indoline Spiroaminal Framework

The total synthesis of the indole alkaloids, neoxaline, oxaline and meleagrin A, all containing a unique indoline spiroaminal framework, was accomplished through the stereoselective introduction of a reverse prenyl group to the congested benzylic carbon of furoindoline, a two‐pot transformation of indoline (containing three nitrogen atoms at appropriate positions) to the featured indoline spiroaminal framework, and elimination of carbonate assisted by the adjacent imidazole moiety to construct the (E)‐dehydrohistidine. The absolute stereochemistry of neoxaline was elucidated through our total synthesis. In addition, we evaluated the bioactivity, especially the anti‐infectious properties, of neoxaline and oxaline, and of some synthetic intermediates.     

A Flexible Approach to Grandisine Alkaloids: Total Synthesis of Grandisines B,D, and F

This article describes in detail the first total synthesis of grandisine alkaloids, grandisines B, D, and F, which show affinity for the human δ‐opioid receptor. The key steps in this synthesis are construction of the isoquinuclidinone moiety of 2 by intramolecular imine formation and the tetracyclic ring system of 4 by stereoselective ring closure of the enolate of amine 8 generated by 1,4‐addition of ammonia to 9 . Synthesis of key intermediate 9 featured a highly stereoselective Brønsted acid mediated Morita–Baylis–Hillman (MBH) reaction via the N‐acyl iminium ion.     

Collective Total Synthesis of 4-Azafluorenone Alkaloids

4-Azafluorenones are typically obtained by acid-mediated cyclization of 2-arylnicotinates. However, this approach fails to give 5-oxygenated 4-azafluorenones due to lactonization of 2-(2-alkoxy)phenylnicotinate intermediates. Herein, we report two modifications of established approaches to 4-azafluorenone synthesis that, either in combination or by themselves, enable the flexible preparation of 4-azafluorenones with diverse oxygenation patterns in the benzenoid ring. Undesired lactonization was circumvented via tert-butyl hydroperoxide (TBHP)-mediated radical cyclization of 2-aryl-3-(hydroxymethyl)pyridines. In the absence of suitable protecting groups for phenolic intermediates, bromide substituents were regioselectively introduced as latent hydroxy groups and later converted under palladium catalysis. We present the first total syntheses of five 4-azafluorenone alkaloids muniranine, darienine, 5,8-dimethoxy-7-hydroxyonychine, 5,6,7,8-tetramethoxyonychine, and 6,8-dihydroxy-7-methoxyonychine in addition to new total syntheses of six 4-azafluorenone alkaloids and one related pyridocoumarin alkaloid.     

百部生物碱的全合成

百部生物碱是从直立百部(Stemona sessilifolia)和其近缘植物的根部分离得到一类生物碱。在分子结构上,这类生物碱通常具有[1, 2-b]吡咯并[1, 2-a]氮杂卓的母核结构,并且由于在母核的多个位置有不同的取代基,从而表现出结构及生物活性的多样性,因而百部生物碱的全合成研究引起国内外化学家的关注。但是由于百部生物碱结构中具有复杂的多环结构及多个手性中心,此类天然产物的全合成研究具有较大的挑战。近年来,化学家们相继开发并应用高对映选择性的反应及串联反应等高效的策略,完成了多个百部生物碱的全合成研究,为百部生物碱进行深入生物活性研究及开发利用奠定了坚实的基础。本文基于本课题组的相关研究内容,综述了各种类型百部生物碱近年来的全合成研究进展。     

Bio-inspired Total Synthesis of Twelve Securinega Alkaloids: Structural Reassignments of (+)-Virosine B and (−)-Episecurinol A

The so-called Securinega alkaloids constitute a class of tetracyclic biologically active specialised metabolites isolated principally from subtropical plants belonging to the Phyllanthaceae family. Following a strategy based on alternative hypotheses for their biosynthesis, an easy and time-efficient divergent synthesis enabled access to twelve of those alkaloids featuring (neo)(nor)securinane skeletons. Moreover, this work permitted to reassign the absolute configurations of (+)-virosine B and (−)-episecurinol A.     

The Enantioselective Total Synthesis of Bisquinolizidine Alkaloids: A Modular “Inside‐Out” Approach

Bisquinolizidine alkaloids are characterized by a chiral bispidine core (3,7‐diazabicyclo[3.3.1]nonane) to which combinations of an α,N‐fused 2‐pyridone, an endo‐ or exo‐α,N‐annulated piperidin(on)e, and an exo‐allyl substituent are attached. We developed a modular “inside‐out” approach that permits access to most members of this class. Its applicability was proven in the asymmetric synthesis of 21 natural bisquinolizidine alkaloids, among them more than ten first enantioselective total syntheses. Key steps are the first successful preparation of both enantiomers of C₂‐symmetric 2,6‐dioxobispidine by desymmetrization of a 2,4,6,8‐tetraoxo precursor, the construction of the α,N‐fused 2‐pyridone by using an enamine‐bromoacrylic acid strategy, and the installation of endo‐ or, optionally, exo‐annulated piperidin(on)es.     

Total Synthesis of Pulchellalactam via an RCM Strategy

Total synthesis of (Z) pulchellalactam, a CD protein tyrosine phosphatase inhibitor, from commercially available methallyl chloride employing ring‐closure metathesis (RCM) as a key step is described.     

Total Synthesis of Bryostatin 8 Using an Organosilane‐Based Strategy

Convergent total synthesis of bryostatin 8 has been accomplished by an organosilane‐based strategy. The C ring is constructed stereoselectively through a geminal bis(silane)‐based [1,5]‐Brook rearrangement, and the B ring through geminal bis(silane)‐based Prins cyclization, thus efficiently joining the northern and southern parts of the molecule.     

Total Synthesis of (+)‐Minfiensine: Construction of the Tetracyclic Core Structure by an Asymmetric Cascade Cyclization

A new method for one‐step construction of the tetracyclic core structure of the indole alkaloid (+)‐minfiensine was developed utilizing a palladium‐catalyzed asymmetric indole dearomatization/iminium cyclization cascade. An efficient total synthesis of (+)‐minfiensine was realized using this strategy. The present method enables access to the common core structure of a series of monoterpene indole alkaloids, such as vincorine, echitamine, and aspidosphylline A.     

Synthetic Studies on Erythrina Alkaloids: Formal Total Synthesis of (+)-3-Demethoxyerythratidinone

A formal asymmetric synthesis of (+)-3-demethoxyerythratidinone (1) is reported using the key intermediate 3 as the starting material, which is available from L-malic acid by a known method.

Concise Total Synthesis of Dehaloperophoramidine

Perophoramidine, dehaloperophoramidine, and communesin F are structurally related alkaloids having intriguing polycyclic structures. A strategy for the synthesis of dehaloperophoramidine has been developed. In this synthesis all skeletal atoms and all functional groups required to reach the target molecule are incorporated early in the sequence. This approach led to the discovery of two novel substrate‐specific domino processes, one encompassing four steps and the other comprising five steps, thus resulting in an eight‐step synthesis of dehaloperophoramidine.     

Total Synthesis of (±)-Corymine

The first total synthesis of the hexacyclic indole alkaloid (±)-corymine is described. Starting from the readily available N-protected tryptamine, the title compound was achieved in 21 steps in 3.4 % overall yield. Key steps of the synthesis include: a) the addition of a malonate to a 3-bromooxindole to afford 3,3-disubstituted oxindole, b) the formation of a 12-membered cyclic enol ether by intramolecular O-propargylation, immediately followed by propargyl Claisen rearrangement to provide the α-allenyl ketone stereospecifically, c) DMDO oxidation to install a hydroxy group in a highly stereoselective manner, and d) the SmI₂-mediated reductive C−O bond cleavage to remove the α-keto carboxyl group.     

A Configurational Switch Based on Iridium‐Catalyzed Allylic Cyclization: Application in Asymmetric Total Syntheses of Prosopis,Dendrobate, and Spruce Alkaloids

A method for the stereoselective synthesis of 2,6‐disubstituted piperidines has been developed that is based on the use of an intramolecular iridium‐catalyzed allylic substitution as a configurational switch. The procedure allows the preparation of 2‐vinylpiperidines with enantiomeric excesses (ee) of greater than 99 %. As applications, total syntheses of piperidine alkaloids have been elaborated, most often by using Ru‐catalyzed cross‐metatheses as a key step for introduction of a side chain. Asymmetric total syntheses of the prosopis alkaloids (+)‐prosopinine, (+)‐prosophylline, (+)‐prosopine, and of the dendrobate alkaloid (+)‐241D and its C6 epimer are described.     

Total Synthesis of Marinomycin A Based on a Direct Dimerization Strategy

The asymmetric total synthesis of (+)‐marinomycin A, a 44‐membered macrodiolide antitumor agent and antibiotic isolated from a marine actinomycete, Marinispora strain CNQ‐140, is reported. The key features of the synthesis include the highly convergent stereocontrolled construction of the monomeric hydroxy salicylate starting from asymmetric epoxidation of the σ‐symmetrical dialkenyl carbinol, and an unprecedented direct dimerization through NaHMDS‐promoted double transesterification.