Construction of Tetracyclic 3-Spirooxindole through Cross-Dehydrogenation of Pyridinium: Applications in Facile Synthesis of (±)-Corynoxine and (±)-Corynoxine B

Abstract

A facile and straightforward method was developed to construct the fused tetracyclic 3-spirooxindole skeleton, which exists widely in natural products. The formation of the tetracyclic 3-spirooxindole structure was achieved through a transition-metal-free intramolecular cross-dehydrogenative coupling of pyridinium, which were formed in situ by the condensation of 3-(2-bromoethyl)indolin-2-one derivatives with 3-substituted pyridines. As examples of the application of this new methodology, two potentially medicinal natural products, (±)-corynoxine and (±)-corynoxine B, were efficiently synthesized in five scalable steps.

Collective formal synthesis of (±)-rhynchophylline and homologues

“…Unlike corynoxine (7) and corynoxine B (8) which the cis-substituents of C15 and C20 were installed by Johnson-Claisen rearrangement of allylic alcohol 12 with trimethyl orthoacetate in situ. 7 The trans-substituents of C15 and C20 of 1-6 could be introduced by a one-pot stereoselective Michael/Krapcho sequence of ketone 13 with methyl malonate. Intermediates 12 and 13 could be formed by dearomatization of pyridinium salt 9.…”

“…Oxidation of commercially available tryptophol followed by bromination with N-bromosuccinimide (NBS) provided 3-(2-bromoethyl)indolin-2-one (11) in 69.6 % yield over 2 steps. 7 Then an improved synthesis of 12 and 13 started from a one-pot N-alkylation/CDC protocol which was initiated by heating 11 with 3-acetyl pyridine (10) at 70 °C for 3 h, removing the unreacted 3-acetyl pyridine by adding large amount of ether that contained 10% of MeOH, pouring out of the solvent after stirring vigorously for 30 min. The rest ether was evaporated to give the residue in the flask.…”

“…3 Moreover, Rhynchophylline (1) has been identified as an inhibitor of the receptor tyrosine kinase EphA4, and is implicated in rescuing hippocampal synaptic dysfunctions in AD. 4 The biological significance and structural complexity of 3-spirooxindole moiety prompted synthetic organic chemists to take up the research project towards the synthesis of rhynchophylline (1) and its homologues (2)(3)(4)(5)(6)(7)(8). 6,7 Ban et al…”

“…6f More recently, we described a crossdehydrogenative coupling (CDC) approach which provided the direct access to the tetracyclic 3-spirooxindole system and to the application in the facile synthesis of (±)-7 and (±)-8. 7 Herein, a collective formal synthesis of six oxindole alkaloids including rhynchophylline (1) and its homologues (2-6) was completed based upon a one-pot N-alkylation/crossdehydrogenative coupling sequence and a one-pot stereoselective Michael/Karpocho sequence.…”

Construction of Spirooxindole Skeleton Through Intramolecular Dieckmann Cyclization

“…Other synthetic strategies of the spiro-pyrrolidone-3,3′-oxoindole frameworks also include Michael cyclization reaction [19–23] and C-selective SnAr reactions [24–26]. Besides, in our previous study, a completely different method has been achieved for the construction of the tetracyclic 3-spirooxindole through a transition-metal-free intramolecular cross-dehydrogenative coupling of pyridinium [27].

Scheme 1The general synthetic strategies of spirooxindoles

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