DedicatedtoP rofessor Emeritus Miha Tišler, University of Ljubljana,ont he occasion of his 90 th birthday.Supporting information for this article is availableonthe WWW under http://dx.Abstract: Chiral 1,2-diamines are privileged structural motifsi no rganocatalysis,w herease fficient 1,3-diamine-derivedo rganocatalystsa re very rare.H erein we report ah ighly efficient camphor-1,3-diamine-derived squaramide organocatalyst.I ts catalytic activity in Michaela dditions of 1,3-dicarbonyl nucleophiles to trans-b-nitrostyrene derivatives provides excellent enantioselectivities (up to > 99% ee).

AbstractΔ2‐Pyrrolin‐4‐ones undergo organocatalyzed sulfa‐Michael/aldol domino spirocyclizations with mercaptoacetaldehyde dimer. The products contain three contiguous stereocenters (ee up to 99%, dr up to 95:5, 25 examples) and can be transformed into analogues of natural products. With the use of a single catalyst, the absolute configuration of the products were determined by the configuration of the exocyclic double bond of the starting material. These results point at the possibility of a widespread use of unsaturated Δ2‐pyrrolin‐4‐ones in various (organo)catalyzed (cascade) transformations for accessing libraries of 3D‐rich pyrrolone‐based (spiro)heterocycles.magnified image

Nonbiaryl atropisomers are molecules defined by a stereogenic axis featuring at least one nonarene moiety. Among these, scaffolds bearing a conformationally stable C­(sp2)–C­(sp3) stereogenic axis have been observed in natural compounds; however, their enantioselective synthesis remains almost completely unexplored. Herein we disclose a new class of chiral C­(sp2)–C­(sp3) atropisomers obtained with high levels of stereoselectivity (up to 99% ee) by means of an organocatalytic asymmetric methodology. Multiple molecular motifs could be embedded in this class of C­(sp2)–C­(sp3) atropisomers, showing a broad and general protocol. Experimental data provide strong evidence of the conformational stability of the C­(sp2)–C­(sp3) stereogenic axis (up to t 1/2 25 °C >1000 y) in the obtained compounds and show kinetic control over this rare stereogenic element. This, coupled with density functional theory calculations, suggests that the observed stereoselectivity arises from a Curtin–Hammett scenario establishing an equilibrium of intermediates. Furthermore, the experimental investigation led to evidence of the operating principle of central-to-axial chirality conversions.

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.