Organocatalytic Asymmetric Synthesis of Propargylamines with Two Adjacent Stereocenters: Mannich‐Type Reactions of In Situ Generated C‐Alkynyl Imines with β‐Keto Esters

Abstract

Side by side: The title reaction is catalyzed by the chiral Brønsted acid (S)-1, and affords hitherto less accessible chiral propargylamines, having two adjacent stereocenters, in good to excellent diastereo- and enantioselectivities. Boc=tert-butoxycarbonyl.

Development of a syn‐Selective Mannich Reaction of Aldehydes with Propargylic Imines by Dual Catalysis: Asymmetric Synthesis of Functionalized Propargylic Amines

“…[8] Whilst severalc lasses of azomethine functions participate in this and related direct asymmetric Mannich reactions,t oo ur knowledge C-alkynyl imines had essentially not been reported before our work on this subject. [12] We are aware of as ingle report on the catalytic asymmetric Mannich reactioni nvolving alkynyl imines, in which Snapper,H oveyda, and co-workers [13] described the reaction of silyl enol ethers (or silyl ketene acetalsa sa cetate enolatee quivalents) with N-2methoxyphenyl alkynylidenamines using ac hiral silver catalyst as the stereocontrol/activation agent. At the outset of the present investigation, we hypothesized that proline and related bifunctional amine catalysts, knownt o promote Mannich reactions [8] through List-Houk-type transition states [10,14] similar to A (Figure 2), would lead to the corresponding syn-configured propargylic adducts.…”

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

“…During the course of our work of catalytic asymmetric synthesis of Boc-protected chiral β-alkynyl-β-amino acids and derivatives via chiral Brønsted base-catalysed asymmetric Mannich-type reaction of in situ -generated N -Boc C-alkynyl imines from C-alkynyl N -Boc- N , O -acetals with malonate (thio)esters, Maruoka and co-workers reported a related heterogeneous chiral Brønsted acid-catalysed Mannich-type reaction of C-alkynyl N -Boc-aminals with reactive acetylacetone and β-ketoesters as nucleophiles 13 14 . However, when this method was attempted with malonate (thio)esters 2a – d as nucleophiles, we could not obtain the Mannich products (no reactions occurred).…”

“…When the catalyst loading was decreased from 10 mol% to 2 mol%, the yield and stereoselectivity (diastereo- and enantioselectivity) were not affected (entry 2 versus entry 1). This approach also features the lowest catalyst loading reported to date for catalytic asymmetric synthesis of propargylamines with two adjacent stereocenters from C-alkynyl imines 11 12 13 .…”

“…1b ) 8 9 10 11 12 13 14 15 , and the reactions with prochiral nucleophiles to generate chiral propargylamines with two adjacent stereogenic centres are few 11 12 13 . Interestingly, these limited reports provide anti -configured propargylamine Mannich products 11 12 13 , and a syn -selective catalytic asymmetric Mannich reaction of C-alkynyl imines remains unattainable, despite the high synthetic utility. Thus, we became interested in developing the catalytic asymmetric additions of carbon nucleophiles to C-alkynyl imines to target syn -configured chiral propargylamines and pharmaceutically and synthetically important chiral propargylamines, such as β-alkynyl-β-amino acids, which cannot be prepared by the frequently employed alkynylation of imines.…”

An Arylation Strategy to Propargylamines: Catalytic Asymmetric Friedel–Crafts‐type Arylation Reactions of C‐Alkynyl Imines

“…The classic strategy for preparing chiral propargylamines involves the asymmetric nucleophilic alkynylation of imines, thereby creating the chiral propargylic stereocenter in a C(sp)−C(sp 3 ) bond‐forming event (Scheme A) . Recently, several elegant asymmetric syntheses of propargylamines have been developed by utilizing electrophilic alkynyl imines that react with alkyl zinc reagents, silyl enol ethers, silyl ketene acetals,, enolizable aldehydes,– acetylacetone, β‐keto esters, malonate (thio)esters, and glycine Schiff bases as suitable nucleophiles; in these approaches, a C(sp 3 )−C(sp 3 ) bond formation is involved (Scheme B). However, to the best of our knowledge, chiral propargylamines still have not been synthesized in an arylation approach, which would involve a distinctive and complementary C(sp 2 )−C(sp 3 ) bond formation (Scheme C).…”