Cinchona Derivatives as Bifunctional H‐bonding Organocatalysts in Asymmetric Vinylogous Conjugate Addition Reactions

Abstract

Asymmetric vinylogous conjugate addition reactions constitute an essential class of enantioselective CÀ C bond-forming transformations characterized by remote functionalization of substrates and the construction of distal stereocenters. After the renaissance of organocatalysis in 2000, vinylogous addition methodologies have seen new horizons of development. Cinchona alkaloids and some of their derivatives have appeared as efficient chiral catalysts in several organic transformations. Their non-toxicity, low cost, availability in pseudo-enantiomeric forms, and "open flask" reaction procedures have been the main reasons behind their success in asymmetric synthesis. These organocatalysts have also shown remarkable applications in vinylogous chemistry. This mini-review covers the developments of asymmetric vinylogous conjugate addition (VCA) reactions under bifunctional cinchona alkaloids/derivatives catalysis.

Organocatalytic Asymmetric Direct Vinylogous Michael Initiated Ring Closure Reaction of 4-Nitroisoxazole Derivatives to 3-Isopropylidene Oxindoles

“…The product 3aa was isolated in 27% yield with a 10:1 dr and 8% ee for the major diastereomer. Next, a series of cinchona alkaloid-based bifunctional organocatalysts (including urea, thiourea, and squaramide) C2– C9 were screened under the same reaction conditions and the expected product was obtained in moderate to good yield with excellent stereoselectivities in all cases (Table , entry 2–9). Among various catalysts, C4 proved to be the best catalyst, as it produced the desired product 3aa in 73% yield with 99% ee and >20:1 dr (Table , entry 4).…”

Synthesis of D-Fructose-Based Bifunctional Primary Amine-Thiourea Organocatalysts and Their Applications in Asymmetric Reactions

“…With the catalyst 6a at hand, the enantioselective addition of ketones to derivatives of nitroalkenes was conducted and the corresponding Michael adducts 8h-l were obtained in high yields (73-85%) with good enantioselectivities (between 71 and 81%) (Table 3, entries 5-9). Additionally, the reactions of substituted and electron-neutral nitroolefins with cyclohexanone could be completed, giving moderate yields (up to 55%) and stereoselectivities (up to 83% ee and 68:32% dr) (Table 3, entries [11][12][13].…”

“…Significant efforts have been made in recent years to produce metal-free organocatalysts that are capable of promoting these asymmetric processes with exceptionally high yields and stereoselectivity [6][7][8]. In this context, the applications of chiral bifunctional amine-thioureas have emerged as a promising prospect and they have been successfully employed for a number of asymmetric transformations [9][10][11][12][13][14]. Their high efficacy in stereoselective synthesis is mainly attributed to their unique capability of multiple hydrogen-bonding donors as well as the readily accessible chiral diamines [15].…”

Biomacromolecule-Assisted Screening for Reaction Discovery and Catalyst Optimization

“…However, this same chiral element has been used in non- C 2 -symmetric applications as well. For example, in the process of building an asymmetric Strecker catalyst to generate a more enzyme-like system, Jacobsen and Sigman very effectively incorporated this trans- 1,2-diaminocyclohexane motif into a chiral thiourea. ,, This work, along with the impressive performance of non- C 2 -symmetric chiral elements such as the cinchona alkaloids, − inspired the Berkowitz group to explore non- C 2 -symmetric salens for the HKR reaction, as has been described. − In what follows, we describe one such catalyst that has proven particularly versatile for target-directed synthesis.…”