Owing to high strain energy, molecules with trans -fused bicyclo3.3.0octane ring systems are very difficult to synthesize, and there are very few approaches to access them. Recently, a number of ...natural products with such ring systems have been made by the synthetic community. However, there has been no review in this field before. This review provides a systematic and comprehensive discussion on the synthesis of natural products containing trans -fused bicyclo3.3.0octanes and the historical context of this work. The prospects for future research in this field are also discussed. Covering the literature before 2021, this review aims to offer a helpful reference for total synthesis of highly strained natural products containing trans -fused bicyclo3.3.0octane ring systems.
Convergent approach: The total syntheses of (−)‐flueggine A and (+)‐virosaine B (see scheme) have been accomplished in a concise and convergent manner. Key steps in these approaches were relay ...ring‐closing metathesis reactions for rapid construction of the key intermediates, and 1,3‐dipolar cycloaddition reactions for the formation of the natural products.
Natural products containing eight-membered carbocycles constitute a class of structurally intriguing and biologically important molecules such as the famous diterpenes taxol and vinigrol. Such ...natural products are being increasingly investigated because of their fascinating architectural features and potent medicinal properties. However, synthesis of natural products with cyclooctane moieties has proved to be highly challenging. This review highlights the recently completed total syntheses of natural products with eight-membered carbocycles with a focus on strategic considerations. A collection of 27 representative studies from the literature covering the decade from 2009 to 2019 is described in chronological order with relevant studies grouped together, including syntheses of the same natural product by different research groups using different strategies. Finally, a summary and outlook including a discussion of the major features of each strategy used in the syntheses are presented. This review illustrates the diversity and creativity in the elegant synthetic designs of eight-membered carbocycles. We hope this review will provide timely illumination and beneficial guidance for future synthetic efforts for organic chemists who are interested in this area.
Hetero-Diels-Alder (HDA) reaction is an important synthetic method for many natural products. An iron(III) catalyst was developed to catalyze the challenging HDA reaction of unactivated aldehydes and ...dienes with high selectivity. Here we report extensive density-functional theory (DFT) calculations and molecular dynamics simulations that show effects of iron (including its coordinate mode and/or spin state) on the dynamics of this reaction: considerably enhancing dynamically stepwise process, broadening entrance channel and narrowing exit channel from concerted asynchronous transition states. Also, our combined computational and experimental secondary KIE studies reveal unexpectedly large KIE values for the five-coordinate pathway even with considerable C-C bond forming, due to equilibrium isotope effect from the change in the metal coordination. Moreover, steric and electronic effects are computationally shown to dictate the C=O chemoselectivity for an α,β-unsaturated aldehyde, which is verified experimentally. Our mechanistic study may help design homogeneous, heterogeneous and biological catalysts for this challenging reaction.
Conspectus Natural products containing bridged ring systems are widely identified and show significant biological activity. The development of efficient synthesis reactions and strategies to ...construct bridged ring systems is a long-standing but very significant challenge in organic chemistry. In 2014, our group developed a unique type II 5 + 2 cycloaddition reaction that provides a facile and direct methodology for constructing highly functionalized bridged bicyclo4.3.1, bicyclo4.4.1, bicyclo5.4.1, bicyclo6.4.1, and other bicyclom.n.1 systems containing a strained bridgehead double bond. In this Account, we summarize the methodology development and report the results of application of our unique strategy for the total synthesis of several natural products with bridged ring systems (i.e., cyclocitrinol, cerorubenic acid-III, and vinigrol) during the past 5 years in our laboratory. In the first part, we introduce the logic behind the design and discovery of type II 5 + 2 cycloadditions. The substrates can be easily synthesized by a modular approach, followed by base-promoted group elimination under heat to form an oxidopyrylium ylide, which can undergo cycloaddition under relatively mild conditions with a variety of double bonds to generate bridged bicyclom.n.1 frameworks in high yield. The diastereocontrol and unique endo selectivity of this methodology are favorable for further application to the synthesis of complex natural products. In the second part, we highlight our endeavors in the total synthesis of several different types of molecules bearing bridged ring systems using our methodology. The bridged bicyclo4.4.1 system is the core structure of two different types of natural products, cyclocitrinol and cerorubenic acid-III, that can be efficiently constructed by type II 5 + 2 cycloadditions. The development of suitable strategies and methods for site-selective cleavage of the C–O bond of the oxa-3.2.1 ring system in the products of type II 5 + 2 cycloadditions is also discussed and highlighted during the syntheses. Moreover, the bridged bicyclo5.3.1 system is the core structure of vinigrol, which can be constructed through a novel ring contraction sequence of the bicyclo5.4.1 system formed by a type II 5 + 2 cycloaddition. By combining with a ring contraction cascade, we believe that type II 5 + 2 cycloadditions have the potential to be used as a unified approach to constructing natural products containing bridged bicyclom.n.1 frameworks.
Type II intramolecular cycloadditions (4+2, 4+3, 4+4 and 5+2) have emerged recently as an efficient and powerful strategy for the construction of bridged ring systems. In general, type II ...cycloadditions provide access to a wide range of bridged bicyclo
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.1 ring systems with high regio- and diastereoselectivity in an easy and straightforward manner. In each section of this review, an overview of the corresponding type II cycloadditions is presented, which is followed by highlights of method development and synthetic applications in natural product synthesis. The goal of this review is to provide a survey of recent advances in the field covering literature up to 2020. The review will serve as a useful reference for organic chemists engaged in the total synthesis of natural products containing bridged bicyclo
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Type II intramolecular cycloadditions (4+2, 4+3, 4+4 and 5+2) have emerged recently as an efficient and powerful strategy for the construction of bridged ring systems.
A type II intramolecular oxidopyrylium‐mediated 5+2 cycloaddition reaction allows the efficient and diastereoselective formation of various highly functionalized and synthetically challenging bridged ...seven‐membered ring systems (such as bicyclo4.4.1undecane, bicyclo4.3.1decane, bicyclo5.4.1dodecane, and bicyclo6.4.1tridecane). This simple, thermal, direct transformation has a broad substrate scope and is high yielding, with high functional‐group tolerance and unique endo selectivity. The highly strained tricyclic cores of ingenol mebutate (picato) and cyclocitrinol are synthesized efficiently and diastereoselectively using this methodology.
Bridged: The title reaction proceeds via an oxidopyrylium ylide and allows the efficient diastereoselective formation of various synthetically challenging bridged 7‐membered ring systems. This direct transformation has a broad substrate scope with high functional‐group tolerance and unique endo selectivity and gives the bridged ring systems, including the highly strained tricyclic cores of ingenol and cyclocitrinol, in high yields. TMP=2,2,6,6‐tetramethylpiperidine.
A Ni-catalyzed Suzuki-type cross-coupling of boronic acids with epoxides without an exogenous base and with broad substrate scope has been developed. The product selectivity of styrenyl epoxides is ...different from that of previous work. This methodology uses readily available starting materials to access a range of substituted alcohols, which are valuable feedstock chemicals.
A Ni-catalyzed Suzuki-type cross-coupling of boronic acids with epoxides without an exogenous base and with broad substrate scope has been developed.
The first dearomative indole 5+2 cycloaddition reaction with an oxidopyrylium ylide resulted in efficient and diastereoselective construction of some highly functionalized and synthetically ...challenging oxacycloheptabindoles. The protocol proceeds under very mild reaction conditions, thus enabling high functional‐group tolerance and unique endo selectivity.
Bridge construction: The title reaction with an oxidopyrylium ylide resulted in efficient and diastereoselective construction of highly functionalized oxacycloheptabindoles. The procedure proceeded under very mild reaction conditions, thus enabling high functional‐group tolerance and endo selectivity. TBS=tert‐butyldimethylsilyl, Tf=trifluoromethanesulfonyl.
A method for Ni-catalyzed hydroalkylation of internal alkynes with cycloketone oxime esters was developed. The reaction has a broad substrate scope. This hydroalkylation shows excellent regio- and ...stereo-selectivity. This method enables readily available starting materials to be used to access a range of cyano-substituted single-configuration trisubstituted alkenes. These are valuable feedstock chemicals and are widely used in synthetic and medicinal chemistry.
A method for Ni-catalyzed hydroalkylation of internal alkynes with cycloketone oxime esters was developed.
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