Toward a Unified Total Synthesis of the Xiamycin and Oridamycin Families of Indolosesquiterpenes

Abstract

A unified synthetic strategy toward the oridamycin and xiamycin families of natural products was designed, aiming to access several natural products from a common synthetic intermediate readily prepared from geranyl acetate. Part of this strategy was successfully realized, culminating in the synthesis of oridamycin A and oridamycin B. Key steps include a Mn(III)-mediated oxidative radical cyclization to construct the trans-decalin ring, and a 6π-electrocyclization/aromatization sequence to produce the 2,3-fused carbazole. Oridamycin B was accessed through a late-stage, C-H oxidation that converted the C16 methyl to a hydroxymethyl. A variety of strategies were explored to form a chelated radical intermediate en route to xiamycin A, including enolate SET oxidation, oxo-vanadium oxidation, and atom-transfer cyclization. Unfortunately, none of these strategies provided the desired C16-epimeric trans-decalin. Exploratory studies on photoredox-catalyzed radical cyclizations yielded interesting results, including the formation of a bicyclic lactone arising from oxidative termination of the photoredox-catalyzed radical cyclization, and a double 6-endo cyclization with catalyst loadings as low as 0.01 mol%.

Trends in carbazole synthesis – an update (2013–2023)

“…This is illustrated by the push in the 2010s to prepare xiamycin, a pentacyclic indolosesquiterpene with selective anti-HIV activity, 79 and oridamycin. [80][81][82][83] In 2015, Li reported the electrocyclization of a sesquiterpene-substituted indole starting material 43 that yielded the core of these natural products 44 (Scheme 12, eqn (1)). 84 The conversion of the triene starting material 43 can be completed either with heating in air or under the action of palladium and benzoquinone.…”

“…In the same year, Trotta used a similar thermally initiated electrocyclization strategy to these xiamycin and ori-damycin that differed by the generation of the triene in situ. 85,86 In a later contribution, Sarpong broke with convention by using a 2-substituted indole 45. 87 This change required a photochemical isomerisation of the starting material to yield the desired product.…”

Recent progress in catalytic acyloxylation of C(sp3)‐H bonds

“…Trotta utilized oxime-directed C(sp 3 )-H acetoxylation in the synthesis of bioactive indolosesquiterpene Oridamycin B. [45,46] The key acetoxylation step was accomplished using 10 mol. % of palladium diacetate and 2 equiv.…”

Recent Developments in Polyene Cyclizations and Their Applications in Natural Product Synthesis

“…Trotta reported attempts to employ photoredox catalysts as polyene cyclization initiators during his studies on the total synthesis of xiamycin A (193). 55 While earlier work on (±)-oridamycin A (188) showed that manganese(III)-mediated cyclization gave the trans-decalin 187 with the methoxy ester in the axial position (Scheme 43); photoredox catalysts were able to convert an α-bromo-βketo ester 216 into the same trans-decalin compound 187.…”