Reprogramming of the biosynthetic network of Daphniphyllum alkaloids into a chemically synthetic network through generalized biomimetic strategies

Abstract

Biomimetic synthesis is a fundamental approach to the chemical synthesis of natural products, which, due to the intrinsic correlation between the biogenesis and the structure of natural products, offers many advantages. Conventional biomimetic strategies have evolved on a principle featuring “(essentially) the same substrates, similar reactions, and similar pathways”, which defines the pattern of biomimetic synthesis from the structural, mechanistic, and sequential perspectives. In practice, such highly imitative approaches have proved considerably feasible and efficient. However, applicability of this type of approach is also limited by the principle. To enhance the power of biomimetic synthesis, we envision generalized biomimetic strategies focusing on the key bond formation/cleavage sites implied by the biogenesis of natural products, which allow us to take full advantage of altered substrates, reactions, and pathways while retaining the inherent advantages of biomimetic synthesis. In this study, we showcased the utility of generalized biomimetic strategies in the synthesis of fourteen Daphniphyllum alkaloids from the macrodaphniphyllamine, calyciphylline A, daphnilongeranin A, and daphnicyclidin D subfamilies. The biosynthetic network of these alkaloids was reprogrammed into a powerful chemically synthetic network through substrate-, reaction-, and pathway-altering biomimetic strategies.

Total Syntheses of Calyciphylline A-Type Alkaloids (−)-10-Deoxydaphnipaxianine A, (+)-Daphlongamine E and (+)-Calyciphylline R via Late-Stage Divinyl Carbinol Rearrangements

“…Followed by an interesting amide reduction tactic via an O -alkyloxime-masked enone, these key transformations eventually paved the way to the total synthesis of (−)-10-deoxydaphnipaxianine A. Our synthetic strategy would allow flexible accesses to various calyciphylline A-type alkaloids, and the novel methodic findings in our approach may also be inspiring in the chemical synthesis of many other natural products …”

Five-membered carbocycle construction in the synthesis of Daphniphyllum alkaloids: recent strategic and methodological advances

“…2 Since Heathcock's landmark, biomimetic syntheses (Fig. 1B), 3 impressive efforts from the groups of Carreira, 4 A. Li, 5 Smith, 6 Fukuyama/Yokoshima, 7 Dixon, 8 Zhai, 9 Qiu, 10 Gao, 11 Sarpong, 12 C. Li 13 and Lu 14 culminated in many elegant total syntheses. Moreover, beautiful synthesis of a putative natural Daphniphyllum alkaloid, isodaphlongamine H, has been reported by the Hanessian lab 15 and the Sarpong lab.…”

“…In 2018, Zhai's lab reported an impressive total synthesis of calyciphylline A-type alkaloids daphnilongeranin B and daphenylline (Scheme 4), also highlighting a Lu's [3 + 2] cycloaddition 29 that formed the five-membered carbocycle and the vicinal all-carbon quaternary centers. 9 Subjecting known enone 23 5 and tert -butyl-2-butynoate to Lu's [3 + 2] cycloaddition conditions (PBu 3 ) 29 produced tetracyclic compound 24 in 83% yield. Sequential construction of the seven-membered ring and the cyclopentenone moiety followed by the reduction of the amide functionality finally afforded daphnilongeranin B. Interestingly, treating compound 26 with p -TsOH triggered an unusual Wagner–Meerwein rearrangement to produce benzofuran 27 , which can be further converted to another calyciphylline A-type alkaloid, daphenylline.…”

Total Synthesis of Yuzurine-type Alkaloid Daphgraciline

“…These alkaloids have attracted great interest from synthetic chemists . After Heathcock’s pioneering work, the groups led by Carreira, A. Li, Smith, Fukuyama, Hanessian, Dixon, Zhai, Qiu, Xu, Gao, Sarpong, C. Li, and Lu have completed the remarkable total syntheses of a number of Daphniphyllum alkaloids. Notably, the yuzurine-type subfamily (Figure , 1 ), one of the largest subfamilies in Daphniphyllum alkaloids, includes ∼50 members .…”