Balancing skeleton and functional groups in total syntheses of complex natural products: a case study of tigliane, daphnane and ingenane diterpenoids

Liu, Zhi; Ding, Zhengwei; Chen, Kai; Xu, Min; Yu, Tao; Tong, Guanghu; Zhang, Hailong; Li, Pengfei

doi:10.1039/d0np00086h

Cited by 29 publications

(26 citation statements)

References 112 publications

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“…TMS-dithiane (87) was prepared by treating dithiane (88) with n-butyl lithium (nBuLi) and quenching the resulting anion with trimethylsilyl chloride (TMSCl). Subsequent treatment of TMS-dithiane (87) with nBuLi provided the TMS-dithiane anion (89), which when reacted with epoxide 84, followed by addition of epi-chlorohydrin (86), afforded the desired disubstituted dithiane (90). Interestingly, unmasking the acyl anion equivalent (i.e.…”

Section: Linear Synthesismentioning

confidence: 99%

“…1), [89] and in turn attracted considerable synthetic attention. [90] Partial Synthesis Partial synthesis (or semi-synthesis) relates to natural product synthesis using a mixture of biosynthetic, degradation, and FGI-inspired retrosynthetic concepts. This often means that the skeleton is already (or mostly) intact and that FGI chemistry is then deployed to achieve the synthesis of the target.…”

Section: Chemical Degradationmentioning

confidence: 99%

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The Future of Retrosynthesis and Synthetic Planning: Algorithmic, Humanistic or the Interplay?

Williams

Dallaston

2021

Aust. J. Chem.

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The practice of deploying and teaching retrosynthesis is on the cusp of considerable change, which in turn forces practitioners and educators to contemplate whether this impending change will advance or erode the efficiency and elegance of organic synthesis in the future. A short treatise is presented herein that covers the concept of retrosynthesis, along with exemplified methods and theories, and an attempt to comprehend the impact of artificial intelligence in an era when freely and commercially available retrosynthetic and forward synthesis planning programs are increasingly prevalent. Will the computer ever compete with human retrosynthetic design and the art of organic synthesis?

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Section: Linear Synthesismentioning

confidence: 99%

Section: Chemical Degradationmentioning

confidence: 99%

The Future of Retrosynthesis and Synthetic Planning: Algorithmic, Humanistic or the Interplay?

Williams

Dallaston

2021

Aust. J. Chem.

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“…For instance, picato (ingenol 3-angelate), a protein kinase C activator isolated from E. peplus, has been approved by FDA in 2012 as the first-in-class drug for the treatment of actinic keratosis. 8 Its precursor, ingenol, has been elaborately total synthesized by many research groups, [9][10][11][12] among which Baran and co-workers reported a highly stereocontrolled synthesis in only 14 steps using a two-phase strategy. 11 Euphorbia stracheyi Boiss is a perennial herbaceous plant distributed in some southern provinces of China.…”

Section: Introductionmentioning

confidence: 99%

Euphorstranoids A and B, two highly rearranged ingenane diterpenoids from Euphorbia stracheyi: structural elucidation, chemical transformation, and lipid-lowering activity

et al. 2022

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“…The remarkable biological activities and architecturally complex structures, rhamnofolane, tigliane, and daphnane diterpenoids, have drawn considerable attention from organic chemists. , Numerous laboratories over several decades have together provided many creative strategies for constructing the unique 5/7/6-ring system. To date, the groups of Wender, Cha, Baran, Li, Liu, and Inoue have reported successful total syntheses of these molecules by applying a series of powerful and selective transformations.…”

Section: Introductionmentioning

confidence: 99%

Unified Total Syntheses of Rhamnofolane, Tigliane, and Daphnane Diterpenoids

et al. 2021

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Rhamnofolane, tigliane, and daphnane diterpenoids are structurally complex natural products with multiple oxygen functionalities, making them synthetically challenging. While these diterpenoids share a 5/7/6-trans-fused ring system (ABC-ring), the three-carbon substitutions at the C13- and C14-positions on the C-ring and appending oxygen functional groups differ among them, accounting for the disparate biological activities of these natural products. Here, we developed a new, unified strategy for expeditious total syntheses of five representative members of these three families, crotophorbolone (1), langduin A (2), prostratin (3), resiniferatoxin (4), and tinyatoxin (5). Retrosynthetically, 1–5 were simplified into their common ABC-ring 6 by detaching the three-carbon units and the oxygen-appended groups. Intermediate 6 with six stereocenters was assembled from four achiral fragments in 12 steps by integrating three powerful transformations, as follows: (i) asymmetric Diels–Alder reaction to induce formation of the C-ring; (ii) π-allyl Stille coupling reaction to set the trisubstituted E-olefin of the B-ring; and (iii) Eu(fod)3-promoted 7-endo cyclization of the B-ring via the generation of a bridgehead radical. Then 6 was diversified into 1–5 by selective installation of the different functional groups. Attachment of the C14-β-isopropenyl and isopropyl groups led to 1 and 2, respectively, while oxidative acetoxylation and C13,14-β-dimethylcyclopropane formation gave rise to 3. Finally, formation of an α-oriented caged orthoester by C13-stereochemical inversion and esterification with two different homovanillic acids delivered 4 and 5 with a C13-β-isopropenyl group. This unified synthetic route to 1–5 required only 16–20 total steps, demonstrating the exceptional efficiency of the present strategy.

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Balancing skeleton and functional groups in total syntheses of complex natural products: a case study of tigliane, daphnane and ingenane diterpenoids

Abstract: The fruitful advancement in synthetic chemistry of the title families of complex diterpenes has stimulated and enjoyed strategic balance between building the skeletons and installing the functional groups.

Cited by 29 publications

References 112 publications

The Future of Retrosynthesis and Synthetic Planning: Algorithmic, Humanistic or the Interplay?

The Future of Retrosynthesis and Synthetic Planning: Algorithmic, Humanistic or the Interplay?

Euphorstranoids A and B, two highly rearranged ingenane diterpenoids from Euphorbia stracheyi: structural elucidation, chemical transformation, and lipid-lowering activity

Unified Total Syntheses of Rhamnofolane, Tigliane, and Daphnane Diterpenoids

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