Diastereoselective formal total synthesis of (±)-triptolide via a novel cationic cyclization of 2-alkenyl-1,3-dithiolane

Abstract

A concise and diastereoselective formal total synthesis of triptolide, a natural product with a wide range of biological properties, is described. The key reaction is an unprecedented 6-endo-Trig cationic cyclization of a 2-alkenyl-1,3-dithiolane precursor induced by TMSOTf as Lewis acid.

Catalytic Asymmetric Formal Total Synthesis of (−)-Triptophenolide and (+)-Triptolide

“…Hydrogenation of 19 furnished key intermediate 4 in 93 % yield and the ee value of 4 was determined to be 83 %. The spectra of 4 were identical with reported data [28–30]. From 4 , (+)-TP and (−)-Triptophenolide could be synthesized with reported methods [28].…”

“…Unlike precedent methods including biogenetic cascade radical [21, 27] or cationic [28–30] cyclization and alkylation of benzocyclohexanone derivatives, [18, 24] or Diels–Alder reaction [25] to construct the quaternary center, we envisioned that it could be formed enantioselectively via arylboronic acid addition to cyclic enone, a methodology pioneered by Prof. Lu [31] and developed by Prof. Stoltz [32–34].

Scheme 1Retrosynthetic analysis of 1 and 2

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“…As illustrated in scheme 1, TP and triptophenolide could be synthesized from tetracycle 3 , [28] the butenolide installation could be accomplished from key intermediate tricyclic ketone 4 ,1 [35–38] which is accessible by a 3-step transformation including Claisen rearrangement, alkene oxidation and aldol cyclization. Trans -cyclization could be realized if dehydration occurs at C6-C7 after diasteroselective aldol reaction.…”

An efficient one-pot four-step domino reaction for the synthesis of C2-substituted 3-methylcyclohex-2-enones

“…Importantly, C2-substituted 3-methylcyclohex-2-enones 1 have also been used as key synthetic intermediates in numerous total synthesis of natural products, such as (þ/À)-dichroanal B, 8 umbrosone, 9 (þ/À)-isopisiferin 10 and more recently (þ/À)-triptolide 7 (Fig. 2 The important feature of this class of versatile compounds (1) is the chemical nature of the nucleophilic functionality introduced at the C2 position that participates to the cyclization event.…”

“…2). 7 The synthesis of the key C2-substituted 3-methylcylohex-2-enone cyclization precursor relied on an efficient one-pot four-step domino reaction of a substituted b-ketoester. Herein, we described the optimization of this protocol and the result of our studies on the scope and application of this domino process that affords efficiently C2-substituted 3-methylcyclohex-2-enones 1.…”