Total Synthesis of Maoecrystal V: Early-Stage C–H Functionalization and Lactone Assembly by Radical Cyclization

Abstract

A total synthesis of the unusual ent-kaurane maoecrystal V is described. The synthesis strategy features a counterintuitive early disconnection of the lactone subunit to a polycyclic enol ether intermediate in order to preserve the central tetrahydrofuran ring until the beginning stages of the synthesis. This strategy enables an application of C–H functionalization at the early phase of the synthesis during the construction of a dihydrobenzo-furan intermediate.

Recent Applications of Rh‐ and Pd‐Catalyzed C(sp3)–H Functionalization in Natural Product Total Synthesis

“…The Zakarian and Davies groups jointly reported a detailed account of their total synthesis of (–)‐maoecrystal V ( 1 ; Scheme , below) featuring a Rh‐catalyzed insertion into an ethereal C–H bond to form the central oxolane ring of the natural product . With diazo ester 2 as the substrate, Rh 2 OAc 4 (0.1 mol‐%) proved to be an efficient catalyst for the desired C–H insertion (Scheme ), providing racemic dihydrobenzofuran 3 in 74 % yield and with high diastereoselectivity favoring the trans product ( dr = 1:10) . Rendering the reaction enantioselective with the use of chiral rhodium catalysts proved challenging, and an extensive screen did not identify a catalyst that could provide 3 with both high dr and ee .…”

Recent advances in the synthesis of tetrahydrofurans and applications in total synthesis

“…Additionally, one example of C-H insertion was reported by the group of Zakarian for the obtention of the furan ring of Maoecrystal V, 159 where the furan was obtained by a rhodium catalyzed reaction on an α-diazoester (Scheme 47).…”

Asymmetric Total Synthesis of (−)‐Maoecrystal V

“…The remarkable biological activity and complex structure of maoecrystal V together with its unique topology has garnered much interest from the scientific community. An intensive effort has been devoted to its total synthesis, leading to the total synthesis of maoecrystal V by the laboratories of Yang (2010), Danishefsky (2012), and Zakarian (2013), as well as the asymmetric total synthesis from the laboratories of Zakarian (2014) and Thomson (2014) …”

“…The remarkable biological activity and complex structure of maoecrystal Vt ogether with its unique topology has garnered much interestf rom the scientific community.A ni ntensive effort has been devotedt oi ts total synthesis, [6] leading to the [7] Danishefsky (2012), [8] andZ akarian (2013), [9] as well as the asymmetric total synthesis from the laboratories of Zakarian (2014) [10] and . [11] In the asymmetrict otal synthesis of maoecrystal Vb yZ akarian and co-workers, [10] the stereochemistry of the C10 stereogenic centeri ni ntermediate B wasa symmetrically established via aR h-catalyzedc hiral auxiliary-basedC ÀHi nsertion reaction from substrate A in 84 % ee (Reaction 1i nF igure 2).…”