Deciphering the quest in the divergent total synthesis of natural products

Fernandes, Rodney A.

doi:10.1039/d3cc03564f

Cited by 4 publications

(2 citation statements)

References 139 publications

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“…Moreover, we developed different C13,C14-functionalization protocols from common intermediate 6 to synthesize crotophorbolone ( 7 )/langduin A ( 8 ) and resiniferatoxin ( 10 )/tinyatoxin ( 11 ), which belong to the rhamnofolane and daphnane diterpenoid families, respectively . Here, we disclose the collective total syntheses of phorbol ( 13 ) and 11 tiglianes 14 – 24 from tricyclic intermediate 9 . , Efficient syntheses were realized by devising and optimizing the functionalizations of the C5, C6, C7, C12, C13, and C14 positions of highly complex synthetic intermediates. These achievements allowed us to conduct parallel assessment of the HIV latency-reversing activities of 17 compounds ( 7 , 8, 10 – 24 ), revealing the strong activities of 17 , 23 , and 24 for the first time.…”

Section: Introductionmentioning

confidence: 99%

Total Syntheses of Phorbol and 11 Tigliane Diterpenoids and Their Evaluation as HIV Latency-Reversing Agents

Watanabe,

Nagatomo,

Hirose

et al. 2024

J. Am. Chem. Soc.

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Tigliane diterpenoids possess exceptionally complex structures comprising common 5/7/6/3-membered ABCD-rings and disparate oxygen functionalities. While tiglianes display a wide range of biological activities, compounds with HIV latencyreversing activity can eliminate viral reservoirs, thereby serving as promising leads for new anti-HIV agents. Herein, we report collective total syntheses of phorbol ( 13) and 11 tiglianes 14−24 with various acylation patterns and oxidation states, and their evaluation as HIV latency-reversing agents. The syntheses were strategically divided into five stages to increase the structural complexity. First, our previously established sequence enabled the expeditious preparation of ABC-tricycle 9 in 15 steps. Second, hydroxylation of 9 and ring-contractive D-ring formation furnished phorbol (13). Third, site-selective attachment of two acyl groups to 13 produced four phorbol diesters 14−17. Fourth, the oxygen functionalities were regio-and stereoselectively installed to yield five tiglianes 18−22. Fifth, further oxidation to the most densely oxygenated acerifolin A (23) and tigilanol tiglate (24) was realized through organizing a 3D shape of the B-ring. Assessment of the HIV latency-reversing activities of the 12 tiglianes revealed seven tiglianes (14−17 and 22−24) with 20-to 300-fold improved efficacy compared with prostratin (12), a representative latency-reversing agent. Therefore, the robust synthetic routes to a variety of tiglianes with promising activities devised in this study provide opportunities for advancing HIV eradication strategies.

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Section: Introductionmentioning

confidence: 99%

Total Syntheses of Phorbol and 11 Tigliane Diterpenoids and Their Evaluation as HIV Latency-Reversing Agents

Watanabe,

Nagatomo,

Hirose

et al. 2024

J. Am. Chem. Soc.

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“…Subsequent C12-hydroxylation and D-ring formation from 2 led to 1 . We then established synthetic routes from 1 to 11 structurally distinct tiglianes, represented by tigilanol tiglate ( 8 , also known as EBC-46), which exhibits potent anticancer and HIV-latency reversing activities. , The strategically differentiated functional groups of 2 also enabled us to functionalize the C13 and C14 positions of 2 , culminating in the total syntheses of five natural products, including crotophorbolone ( 5 ), resiniferatoxin ( 6 ), and prostratin ( 7 ), in 2021. − Therefore, ABC-ring 2 served as a common intermediate of 17 natural products …”

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confidence: 99%

Conversion of Phorbol into Des-D-Ring Tricycle and Crotonianoid B via Peroxidation Reaction

Watanabe,

Hikone,

Nagatomo

et al. 2024

Org. Lett.

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Phorbol (1) has a tetracyclic ABCD-ring and is readily isolable from a natural source. We previously synthesized 1 and 16 structurally related natural products using common ABC-ring intermediate 2. Here we report a new synthetic route to 2 using 1 as a starting material. Key features of the synthesis are chemoselective removal of the D-ring via cyclopropane opening, peroxidation, and retro-aldol reactions. The high utility of the peroxidation was further demonstrated in the first synthesis of crotonianoid B (9).

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Spokewise Total Syntheses of Four Erythrina Alkaloids and Telescoped Syntheses of Six Additional Alkaloids

Hu,

Gan,

et al. 2024

J. Org. Chem.

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Based on rich sulfur-involving chemical transformations, a novel spokewise synthetic strategy, a subclass of the collective strategies, has been developed to concisely synthesize four erythrina alkaloids through a single-step transformation from a common synthetic precursor. Moreover, six additional erythrina alkaloids have also been synthesized by subsequent 1−2 steps chemical transformations. The current synthetic approaches provide a valuable platform for collective total syntheses of erythrina alkaloids and pseudo-natural erythrina alkaloids.

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Deciphering the quest in the divergent total synthesis of natural products

Abstract: Divergent synthesis of natural products is fast emerging towards achieving the goal of efficiency and economy in total synthesis today. Present day sustainable development in synthesis of natural products do...

Cited by 4 publications

References 139 publications

Total Syntheses of Phorbol and 11 Tigliane Diterpenoids and Their Evaluation as HIV Latency-Reversing Agents

Total Syntheses of Phorbol and 11 Tigliane Diterpenoids and Their Evaluation as HIV Latency-Reversing Agents

Conversion of Phorbol into Des-D-Ring Tricycle and Crotonianoid B via Peroxidation Reaction

Spokewise Total Syntheses of Four Erythrina Alkaloids and Telescoped Syntheses of Six Additional Alkaloids

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