Asymmetric synthesis of syn-propargylamines and unsaturated β-amino acids under Brønsted base catalysis

Abstract

Propargylamines are important intermediates for the synthesis of polyfunctional amino derivatives and natural products and biologically active compounds. The classic method of synthesizing chiral propargylamines involves the asymmetric alkynylation of imines. Here, we report a significant advance in the catalytic asymmetric Mannich-type synthesis of propargylamines through catalytic asymmetric addition of carbon nucleophiles to C-alkynyl imines, culminating in a highly syn-selective catalytic asymmetric Mannich reaction of C-alkynyl imines that provide syn-configured propargylamines with two adjacent stereogenic centres and a transition metal-free organocatalytic asymmetric approach to β-alkynyl-β-amino acids with high efficiency and practicality, via a chiral Brønsted base-catalysed asymmetric Mannich-type reaction of in situ generated challenging N-Boc C-alkynyl imines from previously unreported C-alkynyl N-Boc-N,O-acetals, with α-substituted β-keto esters and less-acidic malonate (thio)esters as nucleophiles, respectively. A catalytic activation strategy is also disclosed, which may have broad implications for use in catalysis and synthesis.

Recent Developments in the Stereoselective Synthesis of Nitrogen‐Containing Heterocycles using N‐Acylimines as Reactive Substrates

“…α,β‐Unsaturated aldehydes give satisfactory results in the synthesis of biscarbamates 4 , but modest yields are recorded in the formation of amido sulfones 5 because of a concomitant conjugate addition of the sulfinate anion . Propargyl aldehydes can be efficiently converted into alkoxy derivatives 3 , and biscarbamates 4 . Carboxylic acid amides, carbamates and substituted ureas can be profitably employed as nitrogen‐containing reactants leading to a diversified set of derivatives with peculiar electrophilic reactivities.…”

Direct asymmetric N-propargylation of indoles and carbazoles catalyzed by lithium SPINOL phosphate

“…We first explored the N-propargylation of carbazole 2a with our C-alkynyl N,O-acetal 1a (Table 1). Chiral bifunctional Brønsted base catalysts such as BB1 and BB2, which have been shown to be efficient in the asymmetric reaction of C-alkynyl N,O-acetals with carbon-based nucleophiles 32 , failed to promote the reaction, while chiral phosphoric acids 33 promoted the model reaction between C-alkynyl N,O-acetal 1a and carbazole 2a but with very poor enantioselectivity ( Table 1, entries 1 and 2). These results highlight the challenges of developing the proposed catalytic asymmetric N-propargylation.…”

“…We recently introduced C-alkynyl N-Boc-and N-Cbzprotected N,O-acetals as a class of coupling partners for asymmetric catalytic transformations; to date, these transformations have been limited to the formation of C-C bonds with the use of carbon-based nucleophiles ( Fig. 2a) [32][33][34][35] . However, the corresponding asymmetric reaction of C-alkynyl N,O-acetals through carbon-heteroatom bond formation has remained an unmet task.…”

Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)‐Sitagliptin

“…As another class of reactivity-enhancedt hioester enolates, dithiomalonates (DTMs) were successfully introduced by Tanand co-workers in 2007 for asymmetric catalysis. [8] However,t oo ur knowledge,c atalytic enantioselective Mannich reactions of dithiomalonates with N-protected primary alkyl imines or alkyl a-amidosulfones have not been attempted to date. [7] Quite recently,Wang et al also utilized MTMs and DTMs in chiral Brønsted base catalyzed Mannich reactions of alkynyl imine precursors.…”

“…[7] Quite recently,Wang et al also utilized MTMs and DTMs in chiral Brønsted base catalyzed Mannich reactions of alkynyl imine precursors. [8] However,t oo ur knowledge,c atalytic enantioselective Mannich reactions of dithiomalonates with N-protected primary alkyl imines or alkyl a-amidosulfones have not been attempted to date.…”