Type II Polyketide Synthases: A Bioinformatics-Driven Approach.

Bioinformatics has become an indispensable tool for natural products research in the genomic era. One of the key challenges is to accurately convert sequence data of a biosynthetic gene cluster into chemical information such as the enzymatic function or the biosynthetic product structure. Type II polyketide synthase is the most bioinformatically well-studied class of non-modular biosynthetic machinery and represents a model system to showcase bioinformatic applications in natural products research. This review takes a bioinformatics-centered perspective and summarizes the past advances and future opportunities of bioinformatics-guided research on type II polyketide synthases. How bioinformatics has contributed to deepen the chemical understanding of type II PKSs will be discussed with the focus on enzymology, evolution, structural prediction of the biosynthetic products, genome mining, and the global analyses of their polyketide products.

13-Step Total Synthesis of Atropurpuran.

Herein, we report a concise total synthesis of atropurpuran, a unique and synthetically challenging pentacyclic diterpene that bears a tetracyclo[5.3.3.04,9.04,12]-tridecane skeleton that is unprecedented among natural terpenes. This 13-step approach features a strategy that include early stage rapid skeleton formation and the late-stage introduction of reactive functional groups, thus allowed a high overall synthetic efficiency with minimal use of PGs. The key transformations of our work include a facile construction of the spiro[5.5]undecane moiety through an ring-closing enyne metathesis reaction and an efficient formation of the tetracyclo[5.3.3.04,9.04,12]-tridecane scaffold via an regioselective double oxidative dearomatization/intramolecular Diels-Alder reaction cascade. This efficient approach should also inspire further advances in the synthesis of related complex diterpenes and diterpenoid alkaloids.

Stereoselective Synthesis of the ABC Ring System of Aspterpenacids.

Aspterpenacids A and B are sesterterpenoids that possess a unique and highly congested 5/3/7/6/5 fused ring system. These compounds also contain a sterically encumbered isopropyl trans-hydrindane motif and a cyclopropane motif bearing two quaternary centers, which make them remarkably challenging synthetic targets. Herein, we report the successful construction of the key highly substituted ABC ring system in a stereoselective manner.

Total Synthesis of Astellatol.

A nearly-30-year-old unanswered synthetic puzzle, astellatol, has been solved in an enantiospecific manner. The highly congested pentacyclic skeleton of this rare sesterterpenoid, which possesses a unique bicyclo[4.1.1]octane motif, ten stereocenters, a cyclobutane that contains two quaternary centers, an exo-methylene group, and a sterically encumbered isopropyl trans-hydrindane motif, makes astellatol arguably one of the most challenging targets for sesterterpenoid synthesis. An intramolecular Pauson-Khand reaction was exploited to construct the right-hand side scaffold of this sesterterpenoid. An unprecedented reductive radical 1,6-addition, mediated by SmI2 , forged the cyclobutane motif. Last, a strategic oxidation/reduction step provided not only the decisive solution for the remarkably challenging late-stage transformations, but also a highly valuable unravelling of the notorious issue of trans-hydrindane synthesis. Importantly, the synthesis of astellatol showcases a rapid, scalable strategy to access diverse complex isopropyl trans-hydrindane sesterterpenoids.

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.