Asymmetric Synthesis of Dihydrocoumarins Containing Contiguous Quaternary and Tertiary Stereogenic Centers Catalyzed by a Cinchona‐Alkaloid‐Based Bifunctional Thiourea Derivative

Abstract

A series of enantiomerically enriched 3,4‐dihydrocoumarins containing contiguous quaternary and tertiary stereogenic centers has been efficiently constructed via domino asymmetric Michael addition/transesterification reactions of azlactones with o‐hydroxychalcones using a quinine‐derived thiourea as bifunctional organocatalyst. Under mild reaction conditions, the optically active 3,4‐dihydrocoumarins were generally obtained in 63–96% yields with >20:1 dr and 81–96% ee.magnified image

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…Wang and co‐workers recently realized an asymmetric synthesis of 3,4‐dihydrocoumarin derivatives 476 . Similar to Ender's approach presented in Scheme , ortho ‐hydroxychalcones 477 were used as the Michael acceptors (Scheme ).…”

“…According to the proposed mechanism, the tertiary amine moiety of the catalyst assisted deprotonation of the azlactone to form an enolate of 475 . An enantiofacial selective Michael addition of this enolate onto 477 , as governed by the hydrogen bonding between the catalyst and the substrate led to the observed high stereoselectivities in the products . Simultaneously, Zhou and co‐workers also employed ( E )‐2‐(2‐nitrovinyl)phenols 303 and azlactones 475 to achieve a highly stereoselective synthesis of 3,4‐dihydrocoumarin derivatives 478 via a similar domino Michael/transesterification reaction, using the squaramide derivative 479 as the catalyst (Scheme ) …”

Thiourea–Tertiary Amine Promoted Cascade Catalysis: A Tool for Complexity Generation

“…[48] Later in 2016, the same research group i.e., Wang group, came up with a Michael addition-transesterification double cascade between alkyl-substituted azalactones 95 and o-hydroxychalcone derivatives 96 using the bifunctional organocatalyst C-1 (Scheme 26). [49] Mechanistically, the o-hydroxychalcones 96 were activated and orientated through hydrogen bonding between the carbonyl group and the thiourea. The enolates of azalactones 95 generated by the tertiary amine of the quinuclidines do an initial Michael addition on to the 96.…”

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

“…Recently, Wang and co-workers disclosed an asymmetric synthesis of dihydrocoumarins 113 containing adjacent stereogenic centers, utilizing the cinchona-derived bifunctional thiourea 57 [ 55 ]. A wide range of azlactones 112 were tested, as well as a plethora of o -hydroxychalcone derivatives 111 , providing the products in good to excellent yield and good to excellent stereoselectivity ( Scheme 36 ).…”