Sterically Hindered and Deconjugative α‐Regioselective Asymmetric Mannich Reaction of Meinwald Rearrangement‐Intermediate

Abstract

Compared to γ‐addition, the α‐addition of α‐branched β,γ‐unsaturated aldehydes faces larger steric hindrance and disrupts the π–π conjugation, which might be why very few examples are reported. In this article, a highly diastereo‐ and enantioselective α‐regioselective Mannich reaction of isatin‐derived ketimines with α‐, β‐ or γ‐branched β,γ‐unsaturated aldehydes, generated in situ from Meinwald rearrangement of vinyl epoxides, is realized by using chiral N,N′‐dioxide/ScIII catalysts. A series of chiral α‐quaternary allyl aldehydes and homoallylic alcohols with vicinal multisubstituted stereocenters are constructed in excellent yields, good d.r. and excellent ee values. Experimental studies and DFT (density functional theory) calculations reveal that the large steric hindrance of the ligand and the Boc (tButyloxy carbonyl) protecting group of imines are critical factors for the α‐regioselectivity.

Progress in catalytic asymmetric α-functionalization of vinylogous nucleophilic species

“…49 In this context, Feng and Lin disclosed an α-regioselective asymmetric Mannich reaction of in situ-formed β,γ-unsaturated aldehyde (Scheme 36). 50 Conducting the reaction in the presence of Sc(III)/N,N′-dioxide catalysts in THF at 10 °C, various chiral α-quaternary allyl aldehydes 147 and their derivatives 148 were given in generally excellent results. In their report, DFT calculations were performed to account for the perfect α-selectivity of the reaction (not shown).…”

Bimetallic tandem catalysis-enabled enantioselective cycloisomerization/carbonyl–ene reaction for construction of 5-oxazoylmethyl α-silyl alcohol

“…Next, a multi-metallic catalyst system via the combination of IPrAuCl/AgNTf 2 and a chiral Lewis acid catalyst was investigated. The screening of Lewis acids coordinating with an l - proline - derived chiral N , N ′-dioxide ligand 13 L 3 -PrEt 3 showed that Sc(OTf) 3 and Fe(OTf) 2 gave extremely low yields and ee values (Table 1, entries 2 and 3), but Zn(OTf) 2 promoted this reaction resulting in 65% yield with 96% ee (Table 1, entry 4), and the Co(OTf) 2 / L 3 -PrEt 3 complex provided the best result (Table 1, entry 5, 84% yield with 99% ee). The chiral N , N ′-dioxide ligands were then evaluated (Table 1, entries 6–8, see Table S4 in the ESI for details†); a higher yield (88%) and the same ee value were obtained with the use of the l -pipecolic acid-derived L 3 -PiPr 2 , which possessed larger steric hindrance at the 2,6-position of the phenyl group of the amide unit (Table 1, entry 8).…”

Harnessing Dpp-Imine as a Powerful Achiral Cocatalyst to Dramatically Increase the Efficiency and Stereoselectivity in a Magnesium-Mediated Oxa-Michael Reaction

“…Imines are important and basic synthetic feedstocks in chemical synthesis and are widely utilized as model substrates in many classic reactions, including under catalytic asymmetric patterns (Scheme , A). − On the other hand, the nonactive imine, usually called Schiff base, represents one of the mainstream ligands that are employed in a series of metal-catalyzed transformations. It is well-known that the usual Schiff base ligands possessing multiple coordination sites are always generated from primary aromatic or aliphatic amines. − However, attempts of applying active and easily accessed imines, including Boc-, Ts-, or Dpp-imine, as ligands in metal catalysis is still elusive, given that these imines are often utilized as model substrates in asymmetric reactions. − There exist several potential challenges for utilizing these active monoimines as ligands in metal catalysis: (a) active monoimines might not be as enough as ligands; (b) these active imines are typically electrophiles which are prone to react with a wide scope of given nucleophiles; (c) in the situation of asymmetric reactions, it might be hard to introduce valid chiral elements in the classic structure of active monoimines; and (d) the inflexible impression of these types of imines as “classic model substrates”. On consideration of these above reasons, we wondered whether it is possible to explore these active imines as ligands or coligands in metal-catalyzed reactions, which might benefit the discovery of new types of active imine ligands in organic synthesis.…”