Development of new synthetic methods and its application to total synthesis of nitrogen-containing bioactive natural products

A group of naturally occurring substances containing nitrogen is widely distributed in plants as well as in fungi, animal, marine organisms, and insects, and many exhibit significant biological activity. These natural products with a huge variety of chemical structures include antibiotics, antitumor agents, immunostimulants, drugs affecting the cardiovascular and central nervous systems, analgesics etc. The diverse activities and low natural abundance of this group of natural products when coupled with their molecular complexity warrant development of new and efficient synthetic methods and strategy for the total synthesis of these products, in particular alkaloids. The purpose of this review is to describe some of our achievements in the total synthesis of the naturally-occurring bases including the Dendrobatid alkaloids pumiliotoxin B and allopumiliotoxin A, the anitibiotic streptazolin, the tricyclic marine alkaloids isolated from the ascidians such as fasicularin, lepadiformine, and cylindricine C, and the dimeric monoterpene alkaloid incarvillateine as well as the formal total synthesis of the spirocyclic marine alkaloids halichlorine and pinnaic acid, which are isolated from the Japanese marine sponge and the Okinawan bivalve, respectively.     

Achieving natural product synthesis and diversity via catalytic networking ex vivo

Recent studies on ex vivo synthesis of natural products reveal that even complex multistep pathways can be successfully reconstructed. Genetic engineering of such reconstituted pathways has already been used to generate ‘unnatural’ natural products related to the original compound. In the future, it may be possible to use these approaches to make natural products that are currently inaccessible to conventional synthesis.     

Angucyclinone antibiotics: total syntheses of YM-181741, (+)-ochromycinone, (+)-rubiginone B2, (-)-tetrangomycin, and MM-47755

A concise and highly enantioselective route has been developed for the synthesis of angucyclinone-type natural products. Utilizing this strategy, total syntheses of five natural products YM-181741, (+)-ochromycinone, (+)-rubiginone B2, (-)-tetrangomycin, and MM-47755 have been accomplished in 22%, 23%, 19%, 18%, and 12% overall yields, respectively. Our approach for the synthesis of these natural products having the benz[a]anthraquinone skeleton is based on a sequential intramolecular enyne metathesis, intermolecular Diels-Alder reaction (DAR), and aromatization. The intramolecular enyne metathesis reaction was employed for the synthesis of enantiopure 1,3-dienes in excellent yields. Furthermore, the synthesis of YM-181741 as well as structurally similar angucyclinones such as (+)-ochromycinone and (+)-rubiginone B2 was achieved via asymmetric enolate alkylation of an oxazolidinone in excellent de. The related angucyclinones (-)-tetrangomycin and MM-47755, bearing a labile tertiary alcohol, were synthesized via Sharpless asymmetric epoxidation of a known allylic alcohol followed by opening the epoxide with Red-Al. The introduction of oxygen functionality at C-1 in all these natural products was accomplished by photooxygenation under a positive pressure of oxygen.     

Total synthesis and absolute configuration of otteliones A and B, novel and potent antitumor agents from a freshwater plant

[reaction: see text] The first enantioselective total synthesis of otteliones A and B, biologically important and structurally novel natural products, has been successfully achieved. This total synthesis fully confirms the absolute configuration of these natural products.     

Synthesis of Substituted γ-Butyrolactones: β-Hydroxymethyl-, β-Methylene and Cyclopropane Derivatives

A β-hydroxymethyl-γ-butyrolactone, which is a useful intermediate for the synthesis of several natural products with biological activity, was synthesized with good yield and a reduced number of steps from simple commercially available starting materials. Model compounds of natural products containing the unsaturated γ-butyrolactone unit, such as butenolides and β-methylene-γ-butyrolactones, were also conveniently synthesized from this hydroxymethyl-lactone.     

Stereoselective Synthesis of 2,3,4,6-Tetrasubstituted Tetrahydropyrans

The construction of stereodefined, highly substituted tetrahydropyrans has attracted a lot of interest over the years since they constitute ubiquitous fragments of numerous biologically active natural products.[1] During the course of our synthetic studies toward ambruticin, a fascinating antibiotic[2] which came back in the front scene with three recent total synthesis, [3] we have been interested in the synthesis of 2,3,4,6-tetrasubstituted tetrahydropyrans 5 (Scheme 1). [4] Moreover, this kind of subunit is found to be embedded in several other natural products such as lasonolide A, polycavernoside A, ratjadone, or concanamycin A.     

Chemoenzymatic Synthesis of Cylindrocyclophanes A and F and Merocyclophanes A and D

Incorporating enzymatic reactions into natural product synthesis can significantly improve synthetic efficiency and selectivity. In contrast to the increasing applications of biocatalytic functional-group interconversions, the use of enzymatic C−C bond formation reactions in natural product synthesis is underexplored. Herein, we report a concise and efficient approach for the synthesis of [7.7]paracyclophane natural products, a family of polyketides with diverse biological activities. By using enzymatic Friedel–Crafts alkylation, cylindrocyclophanes A and F and merocyclophanes A and D were synthesized in six to eight steps in the longest linear sequence. This study demonstrates the power of combining enzymatic reactions with contemporary synthetic methodologies and provides opportunities for the structure–activity relationship studies of [7.7]paracyclophane natural products.     

Biomimetic synthesis of pyrone-derived natural products: exploring chemical pathways from a unique polyketide precursor

Our biomimetic hypothesis proposes that families of diverse natural products with complex core structures such as 9,10-deoxytridachione, photodeoxytridachione and ocellapyrone A are derived in nature from a linear and conformationally strained all-( E) tetraene-pyrone precursor. We therefore synthesized such a precursor and investigated its biomimetic transformation under a variety of reaction conditions, both to the above natural products as well as to diverse isomers which we propose to be natural products "yet to be discovered". We also report herein the first synthesis of the natural product iso-9,10-deoxytridachione.     

Flow “Fine” Synthesis: High Yielding and Selective Organic Synthesis by Flow Methods

The concept of flow “fine” synthesis, that is, high yielding and selective organic synthesis by flow methods, is described. Some examples of flow “fine” synthesis of natural products and APIs are discussed. Flow methods have several advantages over batch methods in terms of environmental compatibility, efficiency, and safety. However, synthesis by flow methods is more difficult than synthesis by batch methods. Indeed, it has been considered that synthesis by flow methods can be applicable for the production of simple gasses but that it is difficult to apply to the synthesis of complex molecules such as natural products and APIs. Therefore, organic synthesis of such complex molecules has been conducted by batch methods. On the other hand, syntheses and reactions that attain high yields and high selectivities by flow methods are increasingly reported. Flow methods are leading candidates for the next generation of manufacturing methods that can mitigate environmental concerns toward sustainable society.     

Total synthesis of spiruchostatin B aided by an automated synthesizer

The total synthesis of a natural product HDAC inhibitor, spiruchostatin B, was successfully achieved. A 5-step synthesis that included an asymmetric aldol reaction was carried out in an automated synthesizer to provide an (E)-(S)-3-hydroxy-7-thio-4-heptenoic acid segment that is the crucial structure of cysteine-containing, depsipeptidic natural products such as spiruchostatins, FK228, FR901375, and largazole for their inhibitory activity against HDACs.     

Brexane骨架的快速合成策略

本文报道了三环[4,4,0,03,7]壬烷(Brexane)的快速合成策略.该方法以双功能路易斯酸介导的Diels-Alder/碳环化串联反应构建了目标环系,且核心反应具有高度立体选择性,该路线共五步反应,总产率为23％.本工作可为具有该骨架的萜类天然产物的全合成提供一可选的策略.     

Novel total synthesis of anserinone A and B

Anserinones A and B are natural products that have been shown to have potential anticancer, antifungal, and antibacterial properties. This work entails the novel synthesis of these natural products.     

A mild and efficient method for the synthesis of vinylogous carbamates from alkyl azides

A mild and efficient one-pot method for the synthesis of vinylogous carbamates is reported starting from alkyl azides under a hydrogen atmosphere using 10% Pd/C. The resulting products are useful intermediates for the synthesis of heterocyclic compounds, natural products, and in peptidomimetics.     

Natural Product Synthesis at the Interface of Chemistry and Biology

Nature has evolved to produce unique and diverse natural products that possess high target affinity and specificity. Natural products have been the richest sources for novel modulators of biomolecular function. Since the chemical synthesis of urea by Wöhler, organic chemists have been intrigued by natural products, leading to the evolution of the field of natural product synthesis over the past two centuries. Natural product synthesis has enabled natural products to play an essential role in drug discovery and chemical biology. With the introduction of novel, innovative concepts and strategies for synthetic efficiency, natural product synthesis in the 21st century is well poised to address the challenges and complexities faced by natural product chemistry and will remain essential to progress in biomedical sciences.     

Exploration of the interrupted Fischer indolization reaction

A convergent method to access the fused indoline ring system present in a multitude of bioactive molecules has been developed. The strategy involves the condensation of hydrazines with latent aldehydes to ultimately deliver indoline-containing products by way of an interrupted Fischer indolization sequence. The method is convergent, mild, operationally simple, broad in scope, and can be used to access enantioenriched products. In addition, our approach is amenable to the synthesis of furoindoline and pyrrolidinoindoline natural products as demonstrated by the concise formal total syntheses of physovenine and debromoflustramine B. The strategy will likely enable the synthesis of more complex targets such as the communesin alkaloids.     

Synthetic studies on the DEF-rings of FR182877 and hexacyclinic acid

A synthesis of model DEF-rings of the polyketide anti tumor natural products FR182877 and hexacyclinic acid has been achieved. The key steps in the synthesis are an intramolecular Pd(0) catalyzed allylic substitution reaction, which was used to generate a 9-membered carbocycle, and a novel transannular iodocyclization reaction which furnished the DF-rings of both natural products.     

The enterprise of synthesis: from concept to practice

A retrospective account of natural products synthesis adopting the Chiral Synthon (Chiron) Approach and spanning nearly 50 years of personal research activity is presented highlighting the interplay between the eye and the mind's eye. Synthesis planning is discussed in terms of visual relational and visual reflexive thinking modalities relying on the recognition of naturally occurring nonracemic starting materials such as amino acids, carbohydrates, hydroxy acids, and terpenes in the carbon framework of target molecules. Lessons learned and synthetic methods developed are discussed in the context of selected natural products covered in this Perspective.     

Stereodivergent Aminocatalytic Synthesis of Z‐ and E‐Trisubstituted Double Bonds from Alkynals

A highly diastereoselective synthesis of trisubstituted Z‐ or E‐enals, which are important intermediates in organic synthesis, as well as being present in natural products, is described using different alkynals and nucleophiles as starting materials. Diastereocontrol is mainly governed by the appropriate catalyst. Therefore, those reactions controlled by steric effects, such as the Jørgensen–Hayashi's catalyst, give access to E isomers, and those catalysts that facilitate hydrogen bonding, such as tetrazol‐pyrrolidine Ley's catalyst, allow the synthesis of Z isomers. A stereochemical model based on DFT calculations is proposed.     

Natural products as an inspiration in the diversity-oriented synthesis of bioactive compound libraries

The purpose of diversity-oriented synthesis is to drive the discovery of small molecules with previously unknown biological functions. Natural products necessarily populate biologically relevant chemical space, since they bind both their biosynthetic enzymes and their target macromolecules. Natural product families are, therefore, libraries of pre-validated, functionally diverse structures in which individual compounds selectively modulate unrelated macromolecular targets. This review describes examples of diversity-oriented syntheses which have, to some extent, been inspired by the structures of natural products. Particular emphasis is placed on innovations that allow the synthesis of compound libraries that, like natural products, are skeletally diverse. Mimicking the broad structural features of natural products may allow the discovery of compounds that modulate the functions of macromolecules for which ligands are not known. The ability of innovations in diversity-oriented synthesis to deliver such compounds is critically assessed.