Synthetic Progress of Daphnane-type Diterpenoids

Abstract

Daphnane diterpenoids usually embrace a 5/7/6-tricyclic ring system with poly-hydroxyl groups located at C3, C4, C5, C9, C13, C14, C20 and some special ones have a characteristic orthoester motif located at C9, C13, C14. The daphnane diterpenoids can be categorized into daphnetoxins, 12-hydroxydaphnetoxins, 1-alkyldaphnanes, resiniferonoids, genkwanines and rediocides, based on the oxygen containing functions at rings B and C, as well as the substitution pattern of the ring A. Besides, some daphniphyllum alkaloids are qualified with daphnane and seco-daphnane skeletons. Up to now, more than 100 daphnane diterpenoids have been isolated from Thymelaeaceae and Euphorbiaceae. Their structures have been determined on the basis of chemical correlation, NMR, X-ray diffraction, IR and other spectral analysis. The in-vitro and in-vivo experiments of these compounds have shown that they bear a wide range of biological activities including anti-HIV, anticancer, anti-leukemic, neurotrophic, pesticidal and cytotoxic effects. The biogenic hypothesis postulated that the daphnane-type and the tigliane type diterpenoids can be derived from a common intermediate, and that the tigliane-type can be transferred into the daphnane-type diterpenoids. There have been few papers on the total syntheses of daphnane diterpenoids owing to the synthetic challenges derived from their dense, highly oxygenated and polycyclic skeletons. However, numerous synthetic endeavors have been made in constructing core structures of daphnane diterpenoids based on various methodologies. In this paper, we focus on reviewing the synthetic efforts which have been made for daphnane diterpenoids, and we divide the main body of this paper into two parts, total syntheses and the related methodologies. The first part contains the asymmetric total synthesis of (＋)-resiniferatoxin, the gateway synthesis of C6-C7-epi-yuanhuapin, and the biomimetic synthesis of (±)-methyl-homosecodaphniphyllate. The second part is classified according to the sequence of constructing the ABC core of daphnane diterpenoids, including the [X-BC-ABC] approach, the [X-AB-ABC] approach, the [AX-ABC] approach, the [CX-ABC] approach, the [A'B'C'-ABC] approach and the [X-ABC] approach. Keywords daphnane; diterpenoid; (＋)-resiniferatoxin; total synthesis; synthetic methodology 1 引言 瑞香烷型二萜类天然产物主要分布在瑞香科和大 戟科植物中, 具有 5/7/6 三环骨架 1, 通常在 C3、C4、 C5、C9、C13、C14、C20 位置有羟基, 在 C9、C13、 C14 具有特定的原酸酯结构. 根据 B 环和 C 环的氧化形 式以及 A 环的取代形式, 可将已知的瑞香烷型二萜天然 产物(图 1)分为六类 [1] : daphnetoxins 2、12-hydroxydaphnetoxins 3、1-alkyldaphnanes 4、resiniferonoids 5、 genkwanines 6 和 rediocides 7; 其中, daphnetoxins 通常 在 A 环具有 α-β 不饱和酮结构, 且 B 环具有 C5β 羟基、 C20 羟基、C6α-C7α 环氧结构; 12-hydroxydaphnetoxins 相对于 daphnetoxins 在 C12 处多一个含氧官能团 OR, 并 且 OR 通常为酰氧基; 1-alkyldaphnanes 通常具有饱和的 A 环, 并且原酸酯烷基链末端和 A 环 C1 之间具有一个 大环; resiniferonoids 相对于 daphnetoxins 而言, A 环具有 α-β 不饱和酮结构, B 环 C5 为亚甲基且 C6-C7 之间为双 键, C20 为羟基或者酰氧基; genkwanines 通常在 B 环 C6-C7 之间具有双羟基, 并且饱和 A 环 C3 以及 B 环 C20

Euphorbiaditerpenoids: isolation, structure, bioactivity, biosynthesis, and synthesis (2013–2021)

“…Their intriguing structures, signicant bioactivities, and elaborate syntheses have attracted considerable attention from related scientic communities. [15][16][17][18][19][20][21][22][23][24][25][26] In this period, several reviews on some specic diterpenoid types or on metabolites from certain Euphorbia plants have included some of these Euphorbia diterpenoids, 17,[27][28][29][30][31][32][33] but none has provided a complete and in-depth view of this topic. In this context, we intend to provide an extensive coverage of Euphorbia diterpenoids from 2013 to the end of 2021.…”

“…136 Compound 359 from aerial parts of E. connate possesses a 5,6-epoxy group rather than the commonly observed D 5 double bond in jatrophane diterpenoids. 137 Jatrophane diterpenoids 360-544 are structurally characterized by the presence of a D 6 (17) semicyclic double bond, and E. esula is a rich source of such diterpenoids (445-485, 533-535, 539, and 540). 111,[138][139][140] Compound 511 bearing a rare 19-OH was characterized from the whole plant of E. amygdaloides subsp.…”

“…Commonly, they contain Z/E-D 5 , D 6 (17) , and/or E-D 12 double bonds, and these double bonds can be oxidized to the corresponding epoxy functionalities. Based on the conguration and position of the double bonds, lathyranes can be further classi-ed into ve subtypes A-E.…”

“…155 The further structural modication of K21 afforded a known lathyrane K32 with improved bioactivity. The preliminary SARs showed that the exocyclic D 6 (17) double bond and the aromatic acyl at C-3 were probably critical for their antiinammatory effects. 316 Euphorbia factor L 2 (K18) could alleviate LPS-induced acute lung injury and inammation in mice.…”

Asymmetric Construction of the Core of C6, C7-Epoxy Daphnane Diterpenoid Orthoesters

“…Compared to active synthetic studies and total syntheses of the structurally and biogenetically related tigliane and rhamnofolane diterpenoids, ,, fewer research groups are involved in the syntheses of DDOs. − So far, the groups of Wender, Inoue, and Maimone have completed successful total syntheses of DDOs, focusing on resiniferatoxin without a C 6 , C 7 -epoxy moiety (Scheme ). In 2011, the Wender group reported their synthesis of C 6 , C 7 -epoxy DDOs, albeit as a C 6 , C 7 -epimer of yuanhuapin, in the 41 longest linear steps .…”