A Cooperative Hydrogen Bond Donor–Brønsted Acid System for the Enantioselective Synthesis of Tetrahydropyrans

Abstract

Carbocations stabilized by adjacent oxygen atoms are useful reactive intermediates involved in fundamental chemical transformations. These oxocarbenium ions typically lack sufficient electron density to engage established chiral Brønsted or Lewis acid catalysts, presenting a major challenge to their widespread application in asymmetric catalysis. Leading methods for selectivity operate primarily through electrostatic pairing between the oxocarbenium ion and a chiral counterion. A general approach to new enantioselective transformations of oxocarbenium ions requires novel strategies that address the weak binding capabilities of these intermediates. We demonstrate herein a novel cooperative catalysis system for selective reactions with oxocarbenium ions. This new strategy has been applied to a highly selective and rapid oxa‐Pictet–Spengler reaction and highlights a powerful combination of an achiral hydrogen bond donor with a chiral Brønsted acid.

Mechanism and origins of selectivity in the enantioselective oxa-Pictet–Spengler reaction: a cooperative catalytic complex from a hydrogen bond donor and chiral phosphoric acid

“…1A) furnishes tetrahydropyranoindoles (THPIs) through cooperative chiral phosphoric acid (CPA)/hydrogen bond donor catalysis. 8 This reaction demonstrates high levels of enantioselectivity and good- to-excellent yields for electronically-diverse substrates, with reaction rates substantially higher than previously published enantioselective oxa-Pictet-Spengler reactions (Table 1). Notably, the enhancements to reactivity and selectivity observed in this process were only observed in the presence of a hydrogen-bonding urea.…”

“…Unlike many other reactions proceeding through the oxocarbenium ion, the oxa-Pictet-Spengler reaction has been curiously resistant to enantioselective catalysis. 1,2 This reaction, which has the potential for broad applicability to pharmaceutical and material sciences, 3 has only recently been rendered enantioselective, 4 with excellent contributions from Seidel, 5,6 List, 7 and our own laboratory 8 (Fig. 1A).…”

Indole‐N‐Carboxylic Acids and Indole‐N‐Carboxamides in Organic Synthesis

“…Indole‐ N ‐carboxamides could be also applied in asymmetric synthesis. In 2018, the Scheidt group developed a cooperative hydrogen bond donor‐bronsted acid system for the enantioselective synthesis of tetrahydropyrans from indole‐ N ‐carboxamides (Scheme ) . They prepared a series of enol ether bearing indole‐ N ‐carboxamides 128 and successfully realized an enantioselective cyclization to obtain the products 129 in good yields and high selectivity under the cooperative catalysis of chiral phosphorus acid (CPA) 130 and urea 131 .…”

Asymmetric Aza‐Diels–Alder Reaction with Ion‐Paired—Iron Lewis Acid—Brønsted Acid Catalyst

“…Therefore, we were interested in the combination of FeCl 3 and chiral phosphoric acid, because disproportionation could be induced by the relatively weak Lewis basic phosphoryl oxygen (P=O:), which does not significantly lower the Lewis acidity of the cationic iron species [FeCl 2 ] + . Furthermore, we considered that 1) the Brønsted acid moiety can coordinate to the substrates and 2) the Brønsted acid moiety of chiral phosphoric acid is excellent for multiple binding activation for enantioselectivity due to the rigid chiral scaffold …”

“…[3b, 6, 7] This disproportionation was mediated by coordination of substrates, and the ion-paired Lewis acids howed great catalytic activity for the aza-Diels-Alder reaction of nonactivated substrates, with high TOF and chemoselectivity.T herefore, we were interested in the combination of FeCl 3 and chiral phosphoric acid, [8] because disproportionation could be induced by the relatively weak Lewis basic phosphoryl oxygen (P=O:), which does not significantly lower the Lewis acidity of the cationic iron species [FeCl 2 ] + .F urthermore, we considered that 1) the Brønsted acid moiety can coordinate to the substrates and 2) the Brønsted acid moiety of chiral phosphoric acid is excellent for multiple binding activation for enantioselectivity due to the rigid chiral scaffold. [9,10] To prove our hypothesis, we examined the asymmetric aza-Diels-Alder reaction of N-tosylated aldimine (1a)a nd 2-phenyl-1,3-butadiene (2a); the resultsa re summarized in Ta ble 1. As expected, the reactionp roceeded in an enantioselective manner in 6h in the presence of only 1mol %o fF eCl 3 and chiral phosphoric acid 3a (Ar = 3,5-(CF 3 ) 2 C 6 H 3 ;e ntry 1), whereas FeCl 3 alone catalyzed the reaction to give only the racemic product (entry 2).…”