Site-Selective Functionalization of Unactivated Allylic C–H Bonds via Direct Deprotonation with KTMP: Application to the Formal Total Synthesis of (+)-Artemisinin from Amorphadiene

Abstract

The site-selective functionalization of unactivated allylic C–H bonds via direct deprotonation using KTMP is described. The conversion of amorphadiene to artemisinic alcohol via a simple, highly regioselective deprotonation over 4 other possible allylic sites is shown with further extrapolation to the first large-scale telescoped chemical synthesis of artemisinic acid from amorphadiene. Finally, application of the method for the successful site-selective functionalization of unactivated allylic C–H bonds in other terpene-based natural products is also highlighted.

C–H modification of natural products: a minimalist enabling tactic for drug discovery, API processing and bioconjugation

“…In order to augment the plant-based supply of artemisinin ( 32 ) for anti-malarial drug production, a biotransformation driven process for artemisinin was developed at Sanofi, starting from its biosynthetic terpene precursor amorphadiene ( 72 ) (Scheme 16). 57 The critical step involved a highly regioselective allylic oxidation of 72 which was carried out using an enzymatic C–H hydroxylation reaction, a far superior process over chemical methods, 58 to produce the key intermediate artemisinic alcohol ( 73 ).…”

LiN(SiMe3)2/KOtBu-Promoted Synthesis of Isoquinolone Derivatives from 2-Methylaryl Aldehydes and Nitriles

“…Subsequently, Walsh’s group, Guan’s group, Zhao’s group, and Wu and co-workers developed the functionalization of C­(sp 3 )–H bonds via direct deprotonation using MN­(SiMe 3 ) 2 bases (M = Li, Na, K, and Cs). In 2023, Frantz et al described an effective site-selective allylic C­(sp 3 )–H functionalization protocol with KTMP for the total synthesis of (+)-artemisinin from amorphadiene. In continuation with our previous work on the synthesis of N -heterocyclic compounds, we herein report the LiN­(SiMe 3 ) 2 /KO t Bu-promoted formal [4 + 2] cycloaddition reaction for the one-pot synthesis of isoquinolones via C­(sp 3 )–H bond activation (Scheme d).…”

Silylation of Allylic C(sp3)–H Bonds Enabled by the Catalytic Generation of Allylpotassium Complexes

“…Frantz and co-workers have recently demonstrated that a stoichiometric metalation/borylation/oxidation sequence on this substrate selectively affords 10-hydroxyperillyl alcohol 36 by activation of the exocyclic isoprene unit. 24 In sharp contrast, 35 mostly reacted through the allyl alcohol residue with an excess of diazene 1a and tBuOK (30 mol %) to afford the α-hydroxysilane 35a in 45% yield after careful hydrolysis of the O−SiEt 3 linkage. In this case, the endocyclic C�C double bond of 35 did not migrate, presumably because the most favorable pathway involves a retro-[1,2]-Brook rearrangement.…”

“…To further illustrate the synthetic potential of our methodology, we set out to investigate the catalytic silylation of (−)-perillyl alcohol 35 , a naturally occurring terpene that contains up to five potentially reactive allylic positions (Scheme B). Frantz and co-workers have recently demonstrated that a stoichiometric metalation/borylation/oxidation sequence on this substrate selectively affords 10-hydroxyperillyl alcohol 36 by activation of the exocyclic isoprene unit . In sharp contrast, 35 mostly reacted through the allyl alcohol residue with an excess of diazene 1a and t BuOK (30 mol %) to afford the α-hydroxysilane 35a in 45% yield after careful hydrolysis of the O–SiEt 3 linkage.…”