Direct Access to 6/5/7/5- and 6/7/5/5-Fused Tetracyclic Triterpenoids via Divergent Transannular Aldol Reaction of Lanosterol-Derived Diketone

Abstract

In an effort to access biologically relevant chemical space, a complex natural product-derived non-symmetrical diketone was prepared as a substrate for divergent transannular aldol reactions. The use of common aldol conditions resulted in predominant syn-addition via pathway a, while the use of alumina provided access to the anti-adduct. Screening of a range of Lewis acids of varying strength unexpectedly resulted in the formation of aldol products with 6/7/5/5-fused molecular skeleton via pathway b.

Aphananoid A is an Anti-Inflammatory Limonoid with a New 5/6/5 Fused Ring Featuring a C24 Carbon Skeleton from Aphanamixis polystachya

“…Triterpenes have been considered to be the origin of all tetranortriterpenoids. After multiple oxidations and C-30 methyl transfers, the basic limonoid skeleton was formed, and the A/B ring simultaneously ruptured via oxidations, which led to intermediate 1 . , After checking the related literature, − we deduced that decarbonization was divided into two steps, and ring B was formed by comparatively rational aldol condensation. The C-8–C-30 olefin was oxidized to form a C-8 ketone .…”

“…The C-8–C-30 olefin was oxidized to form a C-8 ketone . Then, an aldol condensation occurred between C-6 and C-8 . Subsequently, the C-8–C-14 olefinic bond formed underwent dehydration.…”

Underexplored Opportunities for Natural Products in Drug Discovery

“…In recent years, several research groups have expanded on this theme, demonstrating that diverse sets of complex natural product-based libraries can be accessed via the architectural remodeling of natural product cores . Hergenrother and co-workers have reported on the application of ring cleavage, expansion, fusion, and rearrangement reactions of gibberellic acid, andrenosterone, quinine, abietic acid, and pleuromutilin, a strategy they coined complexity-to-diversity (CtD). − A similar strategy has been applied to lanosterol and bryonolic acid by Tochtrop and co-workers. − …”

Asymmetric Total Synthesis of Twin Bufogargarizins A and B

“…3a It will be difficult to predict its reactivity and the C4, C10 diastereoselectivity of the transannular aldol reaction. 12 Alternatively, 2 could be synthesized from [5−7− 6−5] with the desired C5 carbonyl group could be directly constructed from 5 by the intramolecular transition metalcatalyzed [5 + 2] cycloaddition reaction 16 of a vinyl ether cyclopropane-yne. However, there are no reports on such a [5 + 2] cycloaddition with a vinyl ether cyclopropane (VECP) moiety (highlighted in red in 5) instead of a typical vinyl cyclopropane (VCP) moiety (highlighted in the Box B).…”

“…However, the interconversion between twin bufogargarizins A and B has not been reported, and the proposed biogenetic pathway is to be confirmed . It will be difficult to predict its reactivity and the C4, C10 diastereoselectivity of the transannular aldol reaction . Alternatively, 2 could be synthesized from [5–7–6–5] tetracyclic 4 , which was proposed to be reassembled from [7–5–6–5] tetracyclic 3 at early stage, although there are no reports on a [7–5–X] skeleton reassembling to generate a [5–7–X] skeleton (highlighted in the box A).…”