Cofactor-mimetic aerobic oxidation has conceptually merged with catalysis of syngas reactions to form a wide range of Markovnikov-selective olefin radical hydrofunctionalizations. We cover the development of the field and review contributions to reaction invention, mechanism, and application to complex molecule synthesis. We also provide a mechanistic framework for understanding this compendium of radical reactions.

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Mn-, Fe-, and Co-Catalyzed Radical Hydrofunctionalizations of Olefins

The divergent total syntheses of complex natural products from a common intermediate have attracted enormous attention in the chemical community in the past few years because it can improve the efficiency of chemical synthesis. A number of powerful and unified strategies have been developed by emulating the natural biosynthesis or through innovative transformations. This review focuses on the total synthesis of natural products by applying divergent strategies and the literature covering from 2013 to June 2017. On the basis of where the diversity comes from, the examples are grouped into three parts and discussed in detail. In each group, the examples that synthesize natural products belonging to the same subfamily are put together to contrast with one another.

Divergent Strategy in Natural Product Total Synthesis.

The pool of abundant chiral terpene building blocks (i.e., “chiral pool terpenes”) has long served as a starting point for the chemical synthesis of complex natural products, including many terpenes themselves. As inexpensive and versatile starting materials, such compounds continue to influence modern synthetic chemistry. This review highlights 21st century terpene total syntheses which themselves use small, terpene-derived materials as building blocks. An outlook to the future of research in this area is highlighted as well.

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

Macrocyclic scaffolds are commonly found in bioactive natural products and pharmaceutical molecules. So far, a large number of macrocyclic natural products have been isolated and synthesized. The construction of macrocycles is generally considered as a crucial and challenging step in the synthesis of macrocyclic natural products. Over the last several decades, numerous efforts have been undertaken toward the synthesis of complex naturally occurring macrocycles and great progresses have been made to advance the field of total synthesis. The commonly used synthetic methodologies toward macrocyclization include macrolactonization, macrolactamization, transition metal-catalyzed cross coupling, ring-closing metathesis, and click reaction, among others. Selected recent examples of macrocyclic synthesis of natural products and druglike macrocycles with significant biological relevance are highlighted in each class. The primary goal of this review is to summarize currently used macrocyclic drugs, highlight the therapeutic potential of this underexplored drug class and outline the general synthetic methodologies for the synthesis of macrocycles.

https://www.mdpi.com/1420-3049/18/6/6230/pdf

Macrocyclic Drugs and Synthetic Methodologies toward Macrocycles

First-row transition-metal-mediated reactions constitute an important and growing area of research due to the low cost, low toxicity, and exceptional synthetic versatility of these metals Currently, there is considerable effort to replace existing precious-metal-catalyzed reactions with first-row analogs More importantly, there are a plethora of unique transformations mediated by first-row metals, which have no classical second- or third-row counterpart Herein, the application of first-row metal-mediated methods to the total synthesis of natural products is discussed This Review is intended to highlight strategic uses of these metals to realize efficient syntheses and highlight the future potential of these reagents and catalysts in organic synthesis

Methods Utilizing First-Row Transition Metals in Natural Product Total Synthesis.

Few examples of [4 + 2] cycloaddition with unmasked ortho-benzoquinones (UMOBs) as carbodiene have been reported in complex molecule synthesis. Herein we report that this cycloaddition with podocarpane-type UMOB was developed and applied to construct fully functionalized bicyclo[2.2.2]octanes. Based on this methodology, divergent total syntheses of atisane-type diterpenoids, including (±)-crotobarin, crotogoudin, atisane-3β,16α-diol, and 16S,17-dihydroxy-atisan-3-one, were accomplished in 14, 14, 12, and 16 steps, respectively. Key elements in these total syntheses include: (1) FeCl3-catalyzed cationic cascade cyclization to construct podocarpane-type skeleton; (2) Mn(III)/Co(II)-catalyzed radical hydroxylation of alkene with high regio-, diastereo-, and chemoselectivities; (3) and a ketal-deprotection/lactone-opening/deprotonation/lactonization cascade. Additionally, the synthetic utility of the fully functionalized bicyclo[2.2.2]octane framework was further elucidated by applying ring distortion strateg...

Total Synthesis of Atisane-Type Diterpenoids: Application of Diels–Alder Cycloadditions of Podocarpane-Type Unmasked ortho-Benzoquinones

Most sesterterpenoids feature unprecedented structural complexity and fascinating bioactivities, which continue to inspire synthetic chemists to develop elegant approaches for their synthesis. Since 2010, leucosceptroids A–D, as well as their natural siblings, have been isolated and identified from Leucosceptrum canum. These sesterterpenoids exhibit interesting bioactivities, including potent antifungal and antifeedant effects, impressive antiangiogenic activity, and inhibition of prolyl endopeptidase. Leucosceptroids A–D consist of a tricyclic system that contains a fully functionalized tetrahydrofuran ring and eight contiguous stereogenic centers (Scheme 1). With a carbonyl group present in the six-

Asymmetric total synthesis of leucosceptroid B.

Construction of the cyclophane core of the hirsutellones via a RCM strategy.

Toward the synthesis of hirsutellone B via an intramolecular Diels–Alder/ketene-trapping strategy

The synthesis of strained paracyclophanes is challenging and generally delivers low yields. A novel strategy of installing an ortho-substituent group to the ethereal oxygen is developed to facilitate the formation of oxygen-containing [10]paracyclophane via RCM macrocyclization. By rationally modulating the electronic and steric effects in the single and double ortho-substitution modes, efficient RCM macrocyclization was achieved for different substrates to form the corresponding [10]paracyclophane products, in which all newly generated double bonds were in the E-form. The development of this methodology will enrich the chemistry of ring-closing metathesis related to the formation of strained macrocycles.

Liqiang Song

Papers

Total Synthesis of Atisane-Type Diterpenoids: Application of Diels–Alder Cycloadditions of Podocarpane-Type Unmasked ortho-Benzoquinones

Asymmetric total synthesis of leucosceptroid B.

Construction of the cyclophane core of the hirsutellones via a RCM strategy.

Toward the synthesis of hirsutellone B via an intramolecular Diels–Alder/ketene-trapping strategy

Exploiting ortho-substitution effect on formation of oxygen-containing [10]paracyclophane through ring-closing metathesis