Br(?)nsted Acid Catalyzed Asymmetric Cycloaddition And Lewis Acid Catalyzed Darzens Reaction

Optically active substituted pyrrolidine derivatives are very important building blocks for the synthesis of many natural products, bioactive substrates and chiral pharmaceuticals. 1,3-Dipolar cycloaddition reactions is an extremely powerful synthetic methodology to access these structural motifs. In particular, the 1,3-dipolar cycloaddition reaction of azomethine ylides(AMY) with electron-deficient olefins is an efficient and straightforward method for the stereoselective construction of pyrrodine compounds.In this paper, we have established a chiral Br?nsted acid catalyzed asymmetric 1,3-dipolar cycloaddition reaction. Studies on the relationship between the structure of Br?nsted acid and the catalytic performance have revealed that Br?nsted acid 2.1 is the optimal catalyst, tolerating a wide spectrum of substrates. Up to 98% ee has been obtained for different phenyl glycine ester under the optimal conditions. The cycloaddition reaction of phenylalaine ester also delivered the products in good yields and with excellent enantioselectivity. We also found that bisphosphoric acids 2.1, showed excellent levels of both diastereo and enantioselectivities for the reaction of aldehyde, diethyl aminomalonate, and terminal alkenes. In addition, the three-component 1,3-dipolar cycloaddition reaction of aldehyde, diethyl aminomalonate and dimethyl fumarate was also successful, affording moderate dr value and high enantioselectivity (up to 98% ee) by using the toluene as the solvent.Theoretical calculations were performed to explore the intrinsic factors for the 1,3-dipolar cycloaddition reaction, revealing that the two carbonyl groups of the dimethyl maleate forms two hydrogen bonds with the hydroxyl groups of the bisphosphoric acid 2.1 and concomitantly, the phosphoryl oxygen forms an additional hydrogen bonds with N-H of azomethine ylides. We also synthesized a series of bisphosphoric acids through structural modification of phosphoric acid 2.1, and the catalytic performance reveals that 2.1 shows superior catalytic efficiency to its structural anologues.In addition, we also developed an asymmetric Darzens reaction of aldehydes with diazo-N,N-dimethylacetamide catalyzd by an air-stable and storable chiral zirconium Lewis acid catalyst, which is formed from 3,3'-diiodobinaphthol and tetrabutoxyzirconium, giving solely cis-glycidic amides in high yields and with excellent enantioselectivity (76-96% yield, up to >99% ee) for aromatic aldehydes and 98% ee for aliphatic aldehydes. In contrast to the reaction using titanium complex of (R)-binaphthol, the current protocol is easier to operate than the titanium complex and thus provides an important alternative to prepare epoxyamides with high enantiomeric purity. The Darzens reaction could be carried out smoothly on gram-scale under mild conditions with a very subtle erosion of the stereoselectivity.