Catalytic Asymmetric CN Bond Formation: Phosphine‐Catalyzed Intra‐ and Intermolecular γ‐Addition of Nitrogen Nucleophiles to Allenoates and Alkynoates

Abstract

The first examples are described of catalyzed -additions of nitrogen nucleophiles to -substituted alkynoates or allenoates that proceed with good efficiency, specifically, intra-and intermolecular processes that employ distinct and useful families of nitrogen nucleophiles (anilines and 2,2,2-trifluoroacetamide), catalyzed by spirophosphine 1. Furthermore, the first demonstrations are reported of asymmetric reactions, affording interesting classes of target molecules such as enantioenriched pyrrolidines, indolines, and -amino-, -unsaturated carbonyl compounds. Keywords amination; asymmetric catalysis; heterocycles; organocatalysis; phosphanesThe use of chiral phosphines as nucleophilic catalysts represents an important second dimension to their utility in catalytic asymmetric synthesis, [1] in addition to their more familiar role as ligands for transition metals. [2] Cognizant of the paucity of general methods for the catalytic enantioselective -functionalization of carbonyl compounds, [3] we have recently pursued the development of phosphine-catalyzed processes that couple nucleophiles with allenoates and related compounds in the -position (Figure 1). [4][5][6] Given the ready availability of the starting allenes, along with the plethora of methods for stereoselectiveand -functionalization of , -unsaturated carbonyl compounds, [7,8] this approach should provide straightforward access to highly functionalized, stereochemically rich, target molecules ( Figure 1).To date, we have established the viability of this approach with oxygen (intramolecular additions to alkynes), carbon (intermolecular/allenes), and sulfur (intermolecular/allenes) nucleophiles. [4] In view of the biological significance of amines, [9,10] including -amino-, -unsaturated carbonyl compounds, [11][12][13] achieving catalytic enantioselective -additions with nitrogen nucleophiles is a particularly important objective. [14] However, attempts to effect phosphine-catalyzed -addition (even non-enantioselective) of nitrogen nucleophiles to -substituted 2,3-allenoates and 2-alkynoates (and related compounds) have been unsuccessful (≤30% yield), [15] due in part to the propensity of such electrophiles to isomerize to 1,3-dienes. [16] In this report, we demonstrate that spirophosphine 1 not only can achieve C-N bond formation in good yield for the first time, but it can also provide good enantioselectivity, both for intra-and for intermolecular processes [Eq. (1) and Eq. (2); CPME = cyclopentyl methyl ether; TBME = tbutyl methyl ether].(1) (2) From the outset of our investigation of phosphine-catalyzed -additions of nitrogen nucleophiles, we decided to address simultaneously the two key challenges: accomplishing C-N bond formation and controlling the stereochemistry of the -carbon. Upon examining an array of conditions for the enantioselective cyclization of the amino-alkyne illustrated in entry 1 of Table 1, we developed a method whereby spirophosphine 1 [17][18][19] catalyzes the desired intramolecular -addition to generate the target pyrro...

Phosphine‐Catalyzed Enantioselective γ‐Addition of 3‐Substituted Oxindoles to 2,3‐Butadienoates and 2‐Butynoates: Use of Prochiral Nucleophiles

“…Recently, Fu and co‐workers described enantioselective γ‐addition reactions of oxygen,8a carbon,8b,c sulfur,8d and nitrogen8e pronucleophiles to γ‐substituted allenoates and/or alkynoates by utilizing C 2 ‐symmetric chiral phosphine catalysts. To date, γ‐substituted allenes have been employed in a vast majority of the reported phosphine‐mediated γ‐additions, and only the enantioselective formation of stereocenters at the γ‐position was successfully demonstrated.…”