Highly diastereoselective entry into chiral spirooxindole-based 4-methyleneazetidines via formal [2+2] annulation reaction

Abstract

A diastereoselective, DABCO-catalyzed reaction of isatin-derived ketimines with allenoates is described. Exploiting the stereodirecting effect of the bulky tert-butanesulfinyl chiral auxiliary, the method provides an efficient access to single diastereoisomers of unprecedented spirocyclic oxindoles, bearing a 4-methyleneazetidine ring at the spiro junction. The versatility of the method is fully demonstrated by further transformations including the conversion to relevant spirocyclic oxindolo-β-lactams.

Organocatalytic Access to Enantioenriched Spirooxindole-Based 4-Methyleneazetidines

“…The absolute configuration of the major enantiomer of compound 6a was determined through chemical correlation, exploiting a proper conversion of reference compound I [ 13 ] ( Scheme 3 ). More precisely, performing a selective sulfur oxidation, enantiopure compound 6a′ could be easily obtained from compound I .…”

“…In our ongoing work devoted to the asymmetric synthesis of spirooxindoles [ 11 , 12 ], we recently reported the first highly diastereoselective entry into chiral spirooxindole-based 4-methyleneazetidines [ 13 ]. Such compounds can be considered new lead structures in drug discovery and also versatile intermediates, thanks to the presence of the reactive carbon-carbon double bond and of the carboxylic ester moiety ( Scheme 1 a).…”

Advances in the Synthesis of Benzo‐Fused Spiro Nitrogen Heterocycles: New Approaches and Modification of Old Strategies

“…Heterocycles 80 can easily be used for further transformations, such as oxidation at the sulfur atom, reduction of the imino to amino group, and in the Ugi -Joullié three-component reaction with isocyanides in the presence of a carboxylic acid (Scheme 22). [155] The [2 + 2] [158,159] DABCO-catalyzed formal [2 + 2] annulation of butadienoates 81 with N-R 2 substituted ketimines 82 leads exclusively to the (E)-isomers of spiro[2-oxindole-azetidines] 83. In the case of unprotected ketimine (R 2 = H) or its N-acetyl analog (R 2 = Ac), the spirocyclic reaction product 84 was unexpectedly obtained from both the [2 + 2] annulation and the competitive participation of the NH group with allenoate.…”

“…The formation of the same product 84 from the N-acetyl derivative is probably due to the high lability of the protective acetyl group (Scheme 23). [158] Previous [158] (Scheme 23) and citation below, [160] are applications of the known [161] cycloaddition of activated allenes to imines in the presence of organic bases. In the PPh 3 -catalyzed reaction of ketimines 85 with allenoate 86, the [3 + 2] cycloaddition occurs with in situ generated intermediate 87, resulting in dihydrospiro[indoline-3,2'-pyrroles] 88 in the yields in the range of 35-85 %.…”

“…The [2+2] or [3+2] cycloaddition reactions of ketimines and similar systems derived from isatin derivatives are effective in the synthesis of spiro[oxindole‐azetidines], cyclopropane fused furo[2,3‐ b ]indolines or spiro[oxindole‐pyrrolidine/piperidines] [158,159] . DABCO‐catalyzed formal [2+2] annulation of butadienoates 81 with N ‐R 2 substituted ketimines 82 leads exclusively to the ( E )‐isomers of spiro[2‐oxindole‐azetidines] 83 .…”