Diastereoselective Total Synthesis of the Euphorbia Diterpenoid Pepluanol A: A Reductive Annulation Approach

Abstract

A new titanium(III)-catalyzed reductive annulation constructed a series of diversely functionalized 1,5-diols in good to excellent yields with respect to a wide scope of vinyl epoxide-aldehyde substrates. Taken together with a Diels-Alder reaction and a substrate-controlled diastereoselective cyclopropanation as additional key steps, the synthetic utility of this novel method has been preliminarily explored by the first and concise total synthesis of the Euphorbia diterpenoid (±)-pepluanol A.

Total Synthesis of (−)‐Pepluanol B: Conformational Control of the Eight‐Membered‐Ring System

“…The unique fused polycyclic skeletons with a high oxidation level and six to eight stereogenic centers render these natural products formidable synthetic targets. Thus far, only the total synthesis of (±)‐pepluanol A ( 2 ) has been accomplished by Ding and co‐workers by exploiting an elegant Ti III ‐catalyzed reductive annulation . Herein, we report the first total synthesis of pepluanol B in both racemic and asymmetric form in 20 steps.…”

Diastereoselective Synthesis of the Hydroperoxide–Keto Form of (±)-Steenkrotin B

“…We reasoned that the endoperoxide in (±)- 2 might be constructed from tricycle 3 through a regio- and diastereoselective Schenck ene reaction . A new titanium­(III)-catalyzed reductive annulation reaction on the vinyl epoxide–aldehyde 5 was expected to yield 3 via the intermediacy of 4 , which is analogous to our concise total synthesis of pepluanol A . The preparation of 5 could be traced back to the cycloheptenone 7 and Rawal’s diene 8 by taking advantage of a Diels–Alder reaction and global functionalization of the corresponding adduct 6 .…”

“…2 In 2008, steenkrotins A (1) and B (2) bearing two unprecedented skeletons, which exhibit moderate antiplasmodial activities, were isolated by Hussein and co-workers from this genus (Figure 1). 3 The relative configuration of steenkrotin A (1) was unambiguously established by X-ray diffraction analysis, featuring a compact [3,5,5,6,7] pentacyclic carbon framework containing a sterically congested tetrahydrofuran moiety. The structure of steenkrotin B (2) was originally assigned through a combination of one-and two-dimensional NMR experiments, which apparently revealed an unusual and highly oxygenated [5,6,6,7] tetracyclic skeleton embedded with an endoperoxide subunit.…”

“…3 The relative configuration of steenkrotin A (1) was unambiguously established by X-ray diffraction analysis, featuring a compact [3,5,5,6,7] pentacyclic carbon framework containing a sterically congested tetrahydrofuran moiety. The structure of steenkrotin B (2) was originally assigned through a combination of one-and two-dimensional NMR experiments, which apparently revealed an unusual and highly oxygenated [5,6,6,7] tetracyclic skeleton embedded with an endoperoxide subunit. Both molecules share a common [5,6,7] tricyclic steenkrotane core that consists of eight stereogenic centers, six of which are contiguous including one quaternary.…”

Diastereoselective Total Synthesis of the Euphorbia Diterpenoid Pepluanol A: A Reductive Annulation Approach

“…Pleasingly,the desired tricyclic diol 7 was obtained in 91 %yield as a1 :1 mixture of diastereomers,w hose structures were unambiguously confirmed by X-ray crystallographic analysis of its C3a-OH isomer (Scheme 3). [22] As ac omparison, Molandersr eaction conditions afforded 7 in only 15 % yield as a1:1 mixture of diastereomers.…”