Total Synthesis and Late‐Stage C−H Oxidations of ent‐Trachylobane Natural Products

Abstract

Herein, we present our studies to construct seven ent‐trachylobane diterpenoids by employing a bioinspired two‐phase synthetic strategy. The first phase provided enantioselective and scalable access to five ent‐trachylobanes, of which methyl ent‐trachyloban‐19‐oate was produced on a 300 mg scale. During the second phase, chemical C−H oxidation methods were employed to enable selective conversion to two naturally occurring higher functionalized ent‐trachylobanes. The formation of regioisomeric analogs, which are currently inaccessible via enzymatic methods, reveals the potential as well as limitations of established chemical C−H oxidation protocols for complex molecule synthesis.

A simple monoselective C–H oxygenation approach for the synthesis of ursane triterpenoids

“…of PhI(OAc) 2 and 15 mol% Pd(OAc) 2 at 50 °C in AcOH-Ac 2 O overnight afforded an inseparable mixture of monoacetoxylated products (8a and b) in 29.3% yield with a diastereomeric ratio (dr) of 5 : 1; in addition, the C23, C24-diacetoxylated product (8c) was isolated in 30.2% yield (entry 1). The corresponding products (8a-c) maintained the innate Δ 12,13 double bond in the ursane skeleton, which was proved by 1 H NMR spectroscopy. Upon increasing the reaction temperature to 70 °C in AcOH-Ac 2 O, the reaction provided 35.9% of 8a and b with high selectivity for monoacetoxylation (entry 2).…”

“…To date, many methods have been tried for the syntheses of polyhydroxylated ursane triterpenoids, and especially, the siteselective unactivated C(sp 3 )-H bond oxidation in a lipophilic skeleton, such as steroids, sesquiterpenoids, diterpenoids, and triterpenoids, has attracted considerable attention. [8][9][10][11][12][13] As shown in Fig. 1C, ring A of pentacyclic triterpenoids was the primary target for hydroxylation/functionalization, and an often utilized procedure is the remote oxidation of C23 by Baldwin's stoichiometric cyclopalladation protocol [14][15][16] at a temperature of −78 °C.…”

“…It was reported that the intrinsic Δ 12,13 double bond in the pentacyclic triterpenoid skeleton is stable under a variety of oxidation or reduction conditions, 11,15,19 and oxime-directed catalytic C-H oxylation was first reported by Sanford. 20 So, we prepared the ursane derivatives 8-10 with oxime as the DG without any protection of the Δ 12,13 double bond in considerable yields (ESI †), and further optimization studies are shown in Table 1. It was found that the reaction of 8 with 1.7 equiv.…”

Catalyst and Medium Control over Rebound Pathways in Manganese-Catalyzed Methylenic C–H Bond Oxidation

“…oxidations (Figure 2). 20 However, in all the experiments described above, C−H functionalization products deriving from HFIP or nonafluoro tert-butyl alcohol (NFTBA) transfer were never detected, with the role of these fluorinated alcohol solvents that appears to be mainly related to increase the reactivity of the manganese catalysts, presumably via hydrogen bonding 16 and, when employing a carboxylic acid co-ligand, promote the exclusive formation of ester products. Along this line, in order to probe whether the proposed model for carboxylate transfer also holds for TFE, we have studied the oxidation of S1 in this solvent.…”