Research Article: Regio- and stereospecific assembly of di­spiro­[indoline-3,3′-pyrrolizine-1′,5′′-thia­zolidines] from simple precursors using a one-pot procedure: synthesis, spectroscopic and structural characterization, and a proposed mechanism of formation

Date Published: August 01, 2020

Publisher: International Union of Crystallography

Author(s): Pablo Romo, Jairo Quiroga, Justo Cobo, Christopher Glidewell.


Di­spiro­[indoline-3,3′-pyrrolizine-1′,5′′-thia­zolidine]s containing four contiguous stereogenic centres have been synthesized with high regio- and stereoselectivity in a one-pot procedure using simple starting materials. The various modes of supra­molecular assembly depend upon different combinations of N—H⋯N, N—H⋯O, N—H⋯S=C and C—H⋯S=C hydrogen bonds.

Partial Text

An attractive approach to the production of new organic com­pounds exhibiting broad-spectrum biological activity, for agricultural and pharmaceutical applications, is to combine in the same mol­ecule two or more pharmacophores of proven efficacy. We report here on the synthesis, characterization and structure of a new heterocyclic system containing three such units, namely, the spiro-oxindole, pyrrolizine and rhodanine (2-sulfanyl­idene­thia­zolidin-4-one) units. Spiro-oxindoles are an important class of alkaloids derived from indole that are widely distributed in nature, including examples such as elacomine [(2′S,3R)-6-hy­droxy-2′-(2-methyl­prop­yl)spiro­[1H-indole-3,3′-pyrrolidine]-2-one], horsfiline [(3R)-5-meth­oxy-1′-methyl­spiro­[1H-indole-3,3′-pyrrolidine]-2-one] rhynchophylline [methyl (7β,16E,20α)-16-(meth­oxy­methyl­ene)-2-oxocorynoxan-17-oate] and spiro­tryprostatin {(3S,3′S,5′aS,10′aS)-6-meth­oxy-3′-(2-methyl­prop-1-en­yl)spiro­[1H-indole-3,2′-3,5a,6,7,8,10a-hexa­hydro-1H-di­pyrrolo­[1,2-c:1′,4′-f]pyrazine]-2,5′,10′-trione}, and com­pounds of this type exhibit a wide range of biological activity, including anti­bacterial, anti­fungal, anti-oxidant and anti­tumour activity (Russel, 2010 ▸). In addition, pyrrolizines have been found to be promising scaffolds for anti­cancer drugs (Belal & El-Gendy, 2014 ▸), while com­pounds derived from rhodanine have been found to exhibit outstanding levels of anti­bacterial and anti­fungal activity (Sortino et al., 2007 ▸; Tomasić & Masic, 2009 ▸). Hence, the synthesis of new com­pounds containing all three of these mol­ecular fragments, i.e. spiro-oxo­indole, pyrrolizine and rhodanine, is essential, and an efficient route to such com­pounds involves a 1,3-dipolar cyclo­addition reaction between an appropriate derivative of isatin (1H-indole-2,3-dione), an amino acid and an electron-deficient alkene (Ponnala et al., 2006 ▸; Liu et al., 2011 ▸).

Compounds (I)–(III) (Scheme 1) were each isolated as a single stereoisomer in yields of 53% for (I), 49% for (II) and 50% for (III). For all three products, the com­positions were established by elemental analysis, com­plemented by high-resolution mass spectrometry in the case of (I) (§2.1). The 1H and 13C NMR spectra contained all the signals expected for the proposed formulations, and the regioselectivity of the reactions leading to the products was established by analysis of the 1H spectra; it is necessary here to discuss only the analysis for (I), as those for (II) and (III) follow entirely similar lines. For (I), the signal from the proton H2′ bonded to atom C2′ (atom C22 in the crystallographic labeling scheme; see Fig. 1 ▸ and §2.2) was ob­served as a singlet at δ 4.64, while the signal for H7a′ bonded to C7a′ (C27A) was observed as a triplet (J = 7.22 Hz) at δ 4.42. These two signals indicate the formation of the pyrrolizine in (I), singly substituted at position C2′ and doubly substituted at positions C1′ and C3′, so confirming the identity of regioisomer (I) (Scheme 1 and Fig. 1 ▸). Had the alternative regioisomer (Ia) been formed, the appearance of these two pyrrolizine signals would have been different; that for atom H7a′ would have been a doublet of triplets and, crucially, that for atom H1′ would have appeared as a doublet, rather than the singlet actually observed. Entirely similar remarks apply to the spectra of com­pounds (II) and (III) but, in addition, five of the signals in the 13C NMR spectrum of (III) exhibit coupling to the 19F nucleus at position 5, namely, those at δ 159.0 for C5, 131.7 for C7, 116.2 and 112.2 for C4 and C6, and 111.2 for C3A; the four-bond coupling to atom C7A is too small to be resolved.




Leave a Reply

Your email address will not be published.