Total Synthesis of Natural Products Containing a Bridgehead Double Bond

Liu, Junyang; Liu, Xin; Wu, Jianlei; Li, Chuang‐Chuang

doi:10.1016/j.chempr.2019.12.027

Cited by 54 publications

(19 citation statements)

References 161 publications

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“…Bredt’s rule is an experimental guideline for understanding and predicting the stability and reactivity of different bridgehead alkenes or other functional groups in bridged ring systems . The development of a variety of methodologies and strategies to efficiently construct this type of compound is highly valuable to the organic synthesis community. ,, All of the products of type II [5 + 2] cycloadditions contain a bridgehead double bond, so it represents a versatile method for bridgehead olefin formation. However, the bridged bicyclo[4.2.1] ring system ( 2n , Scheme ) cannot be obtained by type II [5 + 2] cycloaddition, and the similar skeleton (bicyclo[4.2.1]non-1(2)-ene) was reported to be unstable and have a very limited retention time for 5 min .…”

Section: Methodology Discovery and Developmentmentioning

confidence: 99%

Total Synthesis of Natural Products with Bridged Bicyclo[m.n.1] Ring Systems via Type II [5 + 2] Cycloaddition

Min

Liu

2020

Acc. Chem. Res.

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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 bicyclo[4.3.1], bicyclo[4.4.1], bicyclo[5.4.1], bicyclo[6.4.1], and other bicyclo[m.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 bicyclo[m.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 bicyclo[4.4.1] 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 bicyclo[5.3.1] system is the core structure of vinigrol, which can be constructed through a novel ring contraction sequence of the bicyclo[5.4.1] 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 bicyclo[m.n.1] frameworks.

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Section: Methodology Discovery and Developmentmentioning

confidence: 99%

Total Synthesis of Natural Products with Bridged Bicyclo[m.n.1] Ring Systems via Type II [5 + 2] Cycloaddition

Min

Liu

2020

Acc. Chem. Res.

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“…Type I IMDA cycloadditions (linked at the 1-position of the diene) are great for synthesizing fused bicyclo[m.4.0] ring systems. The pioneering Shea type II IMDA cycloadditions (linked at the 2-position of the diene) are powerful for the preparation of a few of bridged bicyclo[m.3.1] ring systems 15 – 17 ; however, these are very rarely used for the creation of all-carbon bicyclo[m.2.2] ring systems 18 , because the formation of such bicyclo[m.2.2] ring systems ( m = 3, 4, or 5) also with an unfavorable strained bridgehead olefin 19 (Bredt’s rule) 20 are usually more challenging than their regioisomeric products 21 (Fig. 1b ).…”

Section: Introductionmentioning

confidence: 99%

Facile generation of bridged medium-sized polycyclic systems by rhodium-catalysed intramolecular (3+2) dipolar cycloadditions

Hou

Wong

et al. 2021

Nat Commun

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Bridged medium-sized bicyclo[m.n.2] ring systems are common in natural products and potent pharmaceuticals, and pose a great synthetic challenge. Chemistry for making bicyclo[m.n.2] ring systems remains underdeveloped. Currently, there are no general reactions available for the single-step synthesis of various bridged bicyclo[m.n.2] ring systems from acyclic precursors. Here, we report an unusual type II intramolecular (3+2) dipolar cycloaddition strategy for the syntheses of various bridged bicyclo[m.n.2] ring systems. This rhodium-catalysed cascade reaction provides a relatively general strategy for the direct and efficient regioselective and diastereoselective synthesis of highly functionalized and synthetically challenging bridged medium-sized polycyclic systems. Asymmetric total synthesis of nakafuran-8 was accomplished using this method as a key step. Quantum mechanical calculations demonstrate the mechanism of this transformation and the origins of its multiple selectivities. This reaction will inspire the design of the strategies to make complex bioactive molecules with bridged medium-sized polycyclic systems.

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“…Owing to the scarcity of these isolated natural samples, no further biological activity of these compounds has been determined other than their reported role in insect communication. Structurally, cerorubenic acid-III ( 1 ), the most complex compound in this family, possesses a unique 6/3/7/6 tetracyclic skeleton, featuring a bridged bicyclo[4.4.1]undecene ring system (highlighted in red), and a highly strained vinylcyclopropane moiety with the double bond at the bridgehead position . Furthermore, seven contiguous stereocenters with an all-carbon quaternary stereocenter (C3) make this molecule a formidable synthetic challenge that has attracted much attention from the chemical community .…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Total Synthesis of Cerorubenic Acid-III via Type II [5+2] Cycloaddition Reaction

Liu

et al. 2021

J. Org. Chem.

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The first enantioselective total synthesis of cerorubenic acid-III is described in detail. Different strategies and attempts, based on a type II [5+2] cycloaddition reaction, leading to the bicyclo[4.4.1] ring system with a strained bridgehead double bond, are depicted. Furthermore, sodium naphthalenide was found to be efficient in the chemoselective reduction of 8oxabicyclo[3.2.1]octene, with three transformations completed in one operation. An unusual S N 1 transannular cyclization reaction was applied to construct the synthetically challenging vinylcyclopropane moiety. This strategy enabled the total synthesis of cerorubenic acid-III in 19 steps.

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Total Synthesis of Natural Products Containing a Bridgehead Double Bond

Cited by 54 publications

References 161 publications

Total Synthesis of Natural Products with Bridged Bicyclo[m.n.1] Ring Systems via Type II [5 + 2] Cycloaddition

Total Synthesis of Natural Products with Bridged Bicyclo[m.n.1] Ring Systems via Type II [5 + 2] Cycloaddition

Facile generation of bridged medium-sized polycyclic systems by rhodium-catalysed intramolecular (3+2) dipolar cycloadditions

Enantioselective Total Synthesis of Cerorubenic Acid-III via Type II [5+2] Cycloaddition Reaction

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