Huicai Huang

Highly Diastereo‐ and Enantioselective Synthesis of 5‐Substituted 3‐Pyrrolidin‐2‐ones: Vinylogous Michael Addition under Multifunctional Catalysis

molecules display marvelous biological properties including antiviral, pesticidal, and antitumor activity, as well as other pharmacological properties, which undoubtably contribute greatly to their importance in the field of organic chemistry both in terms of their chemical synthesis and in the development of synthetic methodologies. As one of the efficient chemical precursors to 5-substituted 3-pyrrolidin-2-one derivatives, a,b-unsaturated g-butyrolactam has recently appeared as one of the most attractive reactants in various chemical reactions including Mannich, Aldol, Michael, and other simple transformations of either direct or Mukaiyama-type reactions. Even more attractive are the diastereoor enantioenriched products that could be further utilized as versatile building blocks towards more functionalized pyrrolidin-2-ones. However, stereoselective transformations involving this interesting molecule still remain rare, both in the field of organocatalytic synthesis and organometallic catalysis, compared with other important nucleophilic reagents. The scarcity of reactions is partially due to the difficulties in the chemoselective activation of the a, b-unsaturated vinylogous system either as a donor or as an acceptor in chemical reactions, and the challenges in the enantioand diastereoselectivity during those processes. Satisfactory results were achieved in the recent report of Shibasaki and co-workers in the asymmetric vinylogous Mannich and Michael reaction of this a,b-unsaturated g-butyrolactam with N-Boc imines and nitroolefins involving a dinuclear nickel catalytic system. Furthermore, Chen and co-workers have presented an asymmetric Michael addition with a,b-unsaturated aldehydes under the well-established iminium activation using the catalyst developed by Jørgensen and Hayashi. However, to the best of our knowledge, the vinylogous Michael additions of this a,b-unsaturated g-butyrolactam to a,bunsaturated ketones has never been reported and still represents a challenging task regarding the reactivity and stereoselectivity of the two relatively inert reactants. Herein, we report our investigations on this transformation under a multifunctional catalytic system, as well as some explorations into the use of the resulting products to demonstrate the potential utility of this strategy in the pharmaceutical and organic synthesis fields. Our initial investigations were carried out using a series of catalysts (1–3) for the model reaction of benzalacetone 4a and a,b-unsaturated g-butyrolactam 5a in CH2Cl2 at room temperature (Table 1, entries 1–11). Experimental data showed that the cyclohexane-1,2-diamine catalysts 1a and 1b could promote the reaction more effectively than other types of catalysts, with conversions of up to 93% after 72 hours, but with low stereoselectivity (entries 1 and 2). The 9-amino-epiquinine 2 a and its derivative 2b afforded the products with slightly increased ee values, but still with unsatisfactory reaction conversions or stereoselectivity (entries 3 and 4). Then our attention turned to another type of iminium-activation catalyst bearing a chiral 1,2-diphenylethane-1,2-diamine fragment with the hope that it would provide an improvement in this transformation. Attractive ee values were attained using the simple (R,R)-1,2-diphenylScheme 1. Several natural products that contain the fragments of 5-substituted 3-pyrrolidin-2-one derivatives.

Asymmetric vinylogous Michael reaction of alpha,beta-unsaturated ketones with gamma-butenolide under multifunctional catalysis.

A general and direct organocatalytic asymmetric vinylogous Michael reaction of gamma-butenolide with alpha,beta-unsaturated ketones was investigated with a multifunctional primary amine salt as catalyst. The reaction enables straightforward access toward synthetically versatile gamma-substituted butenolides from simple 2(5H)-furanone with satisfactory yields, diastereo- and enantioselectivities (up to 30:1 dr and 95-99% ee).

Diastereo- and enantioselective synthesis of oxazine and oxazolidine derivatives with a chiral quaternary carbon center under multifunctional catalysis.

An easy one-pot, multistep cascade reaction which could afford a series of substituted benzo[d]pyrido[2,1-b]oxazolidine and [1,3]oxazine derivatives in a highly enantio- (up to 98% ee) and diastereoselective (4:1 to >20:1 dr) manner with generally good to excellent yields (up to 99%) has been developed. This well designed strategy could be applied to a wide scope of substrates under mild conditions with simple operations.

Aminocatalyzed asymmetric Diels–Alder reaction of 2,4-dienals and rhodanine/hydantoin derivatives

Aminocatalyzed asymmetric Diels-Alder reaction between 2,4-dienals and rhodanine/hydantoin derivatives via trienamine mechanism has been developed to synthesize various spirocyclic compounds with good yields (up to 98%) and excellent stereoselectivities (up to 99% ee and >19 : 1 dr).

Catalytic asymmetric Michael addition with curcumin derivative

Catalytic asymmetric Michael additions with curcumin derivatives were achieved by a new series of tertiary amine-thiourea organocatalysts to afford the Michael adducts in high yields and excellent enantioselectivities.

Highly Diastereo‐ and Enantioselective Cross‐Cascade Reactions of Different Enones

Cascading ketones! The first highly efficient asymmetric cross-cascade reaction of different α,β-unsaturated ketones catalyzed by an easily prepared bulky primary amine salt has been developed. It affords the corresponding diverse products containing three to four contiguous stereocenters with excellent enantio- and diastereoselectivities (see scheme).