A recyclable stereoauxiliary aminocatalyzed strategy for one-pot synthesis of indolizine-2-carbaldehydes

Abstract

Indolizine-carbaldehydes with the easily modifiable carbaldehyde group are important synthetic targets as versatile precursors for distinct indolizines. However, the efficient one-pot construction of trisubstituted indolizine-2-carbaldehydes represents a long-standing challenge. Herein, we report an unprecedented recyclable stereoauxiliary aminocatalytic approach via aminosugars derived from biomass, which enable the efficient one-pot synthesis of desired trisubstituted indolizine-2-carbaldehydes via [3+2] annulations of acyl pyridines and α,β-unsaturated aldehyde. Compared to the steric shielding effect from α-anomer, a stereoauxiliary effect favored by β-anomer of D-glucosamine is supported by control experiments. Furthermore, polymeric chitosan containing predominantly β-D-anhydroglucosamine units also shows excellent catalytic performance in aqueous solutions for the conversion of various substrates, large-scale synthesis and catalytic cycling experiments. Thus, our approach advances the existing methodologies by providing a rich library of indolizine-2-aldehydes. In addition, it delivers an efficient protocol for a set of late-stage diversification and targeted modifications of bioactive molecules or drugs, as showcased with 1,2,3-trisubstituted indolizine-2-carbaldehydes.

Weak-coordination-auxiliary aminocatalysis enables directed [3 + 2] cyclization for 2-acylindolizines

“…The ring size of cyclic enones could affect the reaction steps like Michael addition and cyclization. 27 In addition to the internal α,β-unsaturated ketones, the terminal α,β-unsaturated ketone ( pent-1-en-3-one) was also compatible with the standard conditions to give the two products 15 : 16 (15% : 35%). Even the terminal α,β-unsaturated ketone (oct-1-en-3-one) could afford the corresponding product 18 (31%).…”

“…Inspired by the strategies of using an iminium ion and enamine mechanism to activate the carbonyl group with aminocatalysts, [23][24][25][26] our previous glucosamine-catalyzed strategy via a stereoauxiliary-iminium ion/enamine tandem sequence demonstrated the efficient preparation of a rich library of indolizine-2-aldehydes with one-pot [3 + 2] cyclization of 2-acetylpyridine and α,β-unsaturated aldehydes (Scheme 1c). 27 As demonstrated, 27 Lewis-acid mediated Baylis-Hillman reaction (Scheme 1b) 22 cannot tolerate a group of sensitive functional groups (such as the hydroxyl group, N,Ndimethyl group, heterocyclic group, cyclic enone group etc. ), but highlights the ability of the amino-catalyzed method to gain successful access to these α,β-unsaturated aldehydes.…”

“…), but highlights the ability of the amino-catalyzed method to gain successful access to these α,β-unsaturated aldehydes. 27 However, due to less electronic activity and more sterically demanding nature of α,β-unsaturated ketones toward iminium formation with aminocatalysts, [28][29][30] the glucosamine-catalyzed strategy cannot efficiently access α,β-unsaturated ketones for the preparation of 2-acylindolizines. We propose herewith that a weak-coordination-auxiliary strategy involving an aminocatalyst would help overcome the challenges, especially the energy barrier in the intramolecular cyclization step.…”

“…We propose herewith that a weak-coordination-auxiliary strategy involving an aminocatalyst would help overcome the challenges, especially the energy barrier in the intramolecular cyclization step. With our ongoing interest in the carboxylate assisted activation strategy [31][32][33][34] and the preparation of N-heterocyclic compounds by sustainable organic synthesis methods, 27,35,36 herein, we report for the first time glycine-catalyzed [3 + 2] cyclization of α,β-unsaturated ketones and N-heteroaryl ketones for various 2-acylindolizines by a weak-coordination-auxiliary strategy (Scheme 1d).…”

Chiral Phosphoric Acid-Catalyzed Asymmetric Friedel–Crafts Addition of Indolizine to Cyclic N-Sulfonyl Imine

“…Considering their immense synthetic and biological value, elegant strategies have been developed to synthesize and functionalize indolizines . However, approaches to access enantioenriched indolizines still remain limited .…”