Insights on the Pseudo‐Enantiomeric Properties of Bifunctional Cinchona Alkaloid Squaramide‐Derived Organocatalyst

Abstract

The use of pseudo enantiomers is a well‐known method of achieving products of complementary stereochemistry. Only rarely can different enantiomers of a product be accessed without modulation of the catalyst. Recently, a system was reported wherein two different enantiomers of spirocycles were obtained by a cascade reaction of unsaturated pyrrolin‐4‐ones with mercaptoacetaldehyde catalyzed by a single optimized cinchona alkaloid squaramide‐derived organocatalyst. It was originally proposed that the E/Z geometry of the unsaturated pyrrolin‐4‐one dictated the stereochemistry of the spirocycle product, but this was not investigated further. In the present work, we have investigated the nature of a pseudo‐enantiomeric organocatalyst conformation applying density functional theory calculations for investigating the transition states for the reaction. Furthermore, the influence of the double‐bond geometry of the pyrrolin‐4‐one has been studied beyond what is possible to test experimentally. The results provide a greater understanding for this class of reactions that may be applicable in future methodology development.

Squaramide Catalyzed Asymmetric Synthesis of Five‐ and Six‐Membered Rings

“…The net cycloaddition comprises of Sulfa‐Michael/Aldol steps catalyzed by C to afford the products with high yields albeit only moderate stereoselectivities (Scheme 83). Ričko and co‐workers demonstrated similar type of domino process involving arylidene‐Δ 2 ‐pyrrolin‐4‐ones 316 and dimeric 2‐mercapto acetaldehyde 313 as the reactants in presence of C as catalyst affording spiro linked tetrahydrothiophene and Δ 2 ‐pyrrolin‐4‐one units 317/317′ [126,127] . The stereochemistry of the product depends on the E/Z configuration of the arylidene moiety in 316 .…”

“…Ričko and co-workers demonstrated similar type of domino process involving arylidene-Δ 2 -pyrrolin-4-ones 316 and dimeric 2-mercapto acetaldehyde 313 as the reactants in presence of C as catalyst affording spiro linked tetrahydrothiophene and Δ 2 -pyrrolin-4one units 317/317'. [126,127] The stereochemistry of the product depends on the E/Z configuration of the arylidene moiety in 316. With N-Ph/Me substitution, E-configured arylidene-Δ 2pyrrolin-4-ones were synthesized in laboratory whereas pure Zisomers for N-unsubstituted analogues were isolated.…”

Double Spirocyclization of Arylidene-Δ2-Pyrrolin-4-Ones with 3-Isothiocyanato Oxindoles

“…The follow-up methylation of compound 3a with iodomethane in the presence of K2CO3 in acetone gave the S-methylated product 4 (Scheme 4). According to the Grayson [72,73] proposal of stereochemistry origin in squaramide-catalyzed asymmetric Michael addition reactions and the observed absolute configuration revealed by X-ray analysis of the major diastereomer of compound 3b (cf. Figure 3), a plausible transition state (TS) leading to the product (as exemplified for the formation of product 3a) can be postulated (Scheme 5).…”

Mechanistic Insights into Annulation of Arylidene‐Δ2‐Pyrrolin‐4‐Ones by Cinchona Squaramide‐Based Organocatalysts

“…[31][32][33][34] The pyrrolone (Δ 2 -pyrrolin-4-one) structural motif, although featured in several natural products and bioactive molecules, [35][36][37][38][39][40] has seldom been employed as a substrate in organocatalyzed transformations. [17,30,[41][42][43][44][45][46] Herein, a successful application of arylidene-Δ 2 -pyrrolin-4-ones [17,45] 1 in the annulation with malononitrile for the enantioselective construction of dihydropyrano [3,2-b]pyrroles 3 and 4, along with detailed mechanistic investigations, is disclosed. Using a single catalyst, the enantioselectivity of the product turned out to be solvent or substrate dependent (Scheme 1).…”