Short,Enantioselective Total Synthesis of Highly Oxidized Taxanes

In the realm of natural product chemistry, few isolates have risen to the level of fame justifiably accorded to Taxol ( 1 ) and its chemical siblings. This report describes the most concise route to date for accessing the highly oxidized members of this family. As representative members of taxanes containing five oxygen atoms, decinnamoyltaxinine E ( 2 ) and taxabaccatin III ( 3 ), have succumbed to enantioselective total synthesis for the first time in only 18 steps from a simple olefin starting material. The strategy holistically mimics nature's approach (two‐phase synthesis) and features a carefully choreographed sequence of stereoselective oxidations and a remarkable redox‐isomerization to set the key trans‐diol present in 2 and 3 . This work lays the critical groundwork necessary to access even higher oxidized taxanes such as 1 in a more practical fashion, thus empowering a medicinal chemistry campaign that is not wedded to semi‐synthesis.     

Total Synthesis of (+)‐6‐epi‐Ophiobolin A

The ophiobolin sesterterpenes are notable plant pathogens which have recently elicited significant chemical and biological attention because of their intriguing carbogenic frameworks, reactive functionalities, and emerging anticancer profiles. Reported herein is a total synthesis of (+)‐6‐epi‐ophiobolin A in 14 steps, a task which addresses construction of the synthetically challenging spirocyclic tetrahydrofuran motif as well as several other key stereochemical problems. This work demonstrates a streamlined synthetic platform to complex ophiobolins leveraging disparate termination modes of a radical polycyclization cascade for divergent elaboration and functionalization.     

Biosynthesis and Chemical Synthesis of Presilphiperfolanol Natural Products

Presilphiperfolanols constitute a family of biosynthetically important sesquiterpenes which can rearrange to diverse sesquiterpenoid skeletons. While the origin of these natural products can be traced to simple linear terpene precursors, the details of the enzymatic cyclization mechanism that forms the stereochemically dense tricyclic skeleton has required extensive biochemical, computational, and synthetic investigation. Parallel efforts to prepare the unique and intriguing structures of these compounds by total synthesis have also inspired novel strategies, thus resulting in four synthetic approaches and two completed syntheses. While the biosynthesis and chemical synthesis studies performed to date have provided much insight into the role and properties of these molecules, emerging questions regarding the biosynthesis of newer members of the family and subtle details of rearrangement mechanisms have yet to be explored.     

Reconstitution of Biosynthetic Machinery for the Synthesis of the Highly Elaborated Indole Diterpene Penitrem

Penitrem A is one of the most elaborated members of the fungal indole diterpenes. Two separate penitrem gene clusters were identified using genomic and RNA sequencing data, and 13 out of 17 transformations in the penitrem biosynthesis were elucidated by heterologous reconstitution of the relevant genes. These reactions involve 1) a prenylation‐initiated cationic cyclization to install the bicyclo[3.2.0]heptane skeleton (PtmE), 2) a two‐step P450‐catalyzed oxidative processes forming the unique tricyclic penitrem skeleton (PtmK and PtmU), and 3) five sequential oxidative transformations (PtmKULNJ). Importantly, without conventional gene disruption, reconstitution of the biosynthetic machinery provided sufficient data to determine the pathway. It was thus demonstrated that the Aspergillus oryzae reconstitution system is a powerful method for studying the biosynthesis of complex natural products.     

Biomimetic Synthesis of Complex Flavonoids Isolated from Daemonorops “Dragon's Blood”

The dragonbloodins are a pair of complex flavonoid trimers that have been isolated from the palm tree Daemonorops draco, one of the sources of the ancient resin known as “dragon's blood”. We present a short synthesis that clarifies their relative configurations and sheds light on their origin in Nature. This synthesis features biomimetic cascade reactions that involve both ionic and radical intermediates. The biogenetic relationships between dracorhodin, the dracoflavans C, and the dragonbloodins A1 and A2 are discussed.     

Total Synthesis of Diaporthichalasin by Using the Intramolecular Diels–Alder Reaction of an α,β‐Unsaturated γ‐Hydroxylactam in Aqueous Media

The first total synthesis of diaporthichalasin has been successfully achieved and complete structure elucidation, including the absolute configuration, was also accomplished. The intramolecular Diels–Alder (IMDA) reaction between the diene side chain on the decalin skeleton and α,β‐unsaturated γ‐hydroxy‐γ‐lactam in aqueous media was effectively employed as the key step. From this synthetic study, we found that α,β‐unsaturated γ‐hydroxy‐γ‐lactam is an essential precursor for the construction of the diaporthichalasin‐type pentacyclic skeleton. This important finding strongly suggests that this route is involved in the biosynthetic pathway for diaporthichalasin.     

Concise Synthesis of Astellatol Core Skeleton

A ten‐step, enantiospecific synthesis of the highly challenging core skeleton of sesterterpenoid astellatol has been achieved. Key transformations of this strategy include a facile, convergent construction of the tricyclic motif and a SmI₂‐induced reductive radical cyclization that forms the pivotal cyclobutane ring.     

Total Synthesis of the Isodon Diterpene Sculponeatin N

The total synthesis of sculponeatin N, a bioactive polycyclic diterpene isolated from Isodon sculponeatus, is reported. Key features of the synthesis include diastereoselective Nazarov and ring‐closing metathesis reactions, and a highly efficient formation of the bicyclo[3.2.1]octane ring system by a reductive radical cyclization.     

A Hydrolase‐Catalyzed Cyclization Forms the Fused Bicyclic β‐Lactone in Vibralactone

Vibralactone is isolated from the basidiomycete fungus Boreostereum vibrans as one of the strongest lipase inhibitors. Its unusual β‐lactone‐fused bicycle is derived from an aryl ring moiety by an oxidative ring‐expansion prior to an intramolecular cyclization. Herein, we report the discovery of the cyclase VibC which belongs to the α/β‐hydrolase superfamily and is involved in the vibralactone biosynthesis. Biochemical and crystal studies suggest that VibC may catalyze an aldol or an electrocyclic reaction initiated by the Ser‐His‐Asp catalytic triad. For the aldol and pericyclic chemistry in living cells, VibC is a unique hydrolase performing the carbocycle formation of an oxepinone to a fused bicyclic β‐lactone. This presents a naturally occurring, new enzymatic reaction in both aldol and hydrolase (bio)chemistry that will guide future exploitation of these enzymes in synthetic biology for chemical‐diversity expansion of natural products.     

Tetrodotoxin: History,Biology, and Synthesis

This review provides a comprehensive coverage of the history, biology and chemistry of tetrodotoxin (TTX). It traces the origin of this remarkable molecule all the way back to the ancient Chinese medicine records. The discovery of biological activity, isolation, and a brief overview of structure elucidation are summarized. Next, the biology of TTX is discussed, primarily in the context of its activity in the sodium channels, its anesthetic properties, and its potential use in cancer treatment or drug addiction. Biosynthesis of TTX is covered before the discussion of the total syntheses. All total, formal or partial syntheses are covered but those total syntheses that have been discussed in previous reviews are only briefly summarized. Finally, the synthesis of natural and unnatural derivatives is surveyed, and a conclusion and outlook are provided for this very extensive field of endeavor. To the best of our knowledge the literature coverage is complete up to December 2018.     

Empowering Synthesis of Complex Natural Products

Synthesis of natural products remains a daring task. Their richly diverse and intricate structures often encompass a large degree of unsaturation, contain fused and/or bridged rings, or possess numerous stereogenic centers. Thus, their preparation requires significant synthetic overhead, detracting from their overall practicality as well as hampering the ability of medicinal chemists to synthesize derivatives for pharmaceutical optimization and structure-activity relationship studies. The purpose of this Minireview is to showcase recent examples of efficient total syntheses. Emphasis was not given to the evaluation of ideality or economies (quality), but rather to the practicality (quality with quantity).     

Chemical Synthesis of the Englerins

In the long lasting battle against cancer, Nature sometimes gives a helping hand to researchers to find new drugs for the treatment of diseases and improvement of patients′ well‐being. Englerin A has emerged as a promising anticancer candidate as well as being an exciting synthetic challenge for organic chemists. This focus review summarizes the total syntheses reported to date and the synthetic approaches toward analogues of this fascinating natural product.