An enantioselective Biginelli reaction that proceeds by a dual-activation route has been developed by using a combined catalyst of a readily available trans-4-hydroxyproline-derived secondary amine and a Brønsted acid. Aromatic, heteroaromatic, and fused-ring aldehydes were found to be suitable substrates for this multicomponent reaction. The corresponding dihydropyrimidines were obtained in moderate-to-good yields with up to 98 % ee under mild conditions. Based on the experimental results and the observed absolute configurations of the products, a plausible transition state has been proposed to explain the origin of the activation and the asymmetric induction.

The theoretically inspired development of a Rh-catalyzed [3 + 2 + 1] carbocyclization of carbon- and heteroatom-tethered alkenylidenecyclopropanes (ACPs) with CO for the stereoselective construction of cis-fused bicyclohexenones is described. This study demonstrates that the ring opening of alkylidenecyclopropane proceeds through a Rh(III)-trimethylenemethane complex, which undergoes rate-determining carbometalation through a transition state that accurately predicts the stereochemical outcome for this process. The experimental studies demonstrate the validity of this approach and include the first highly enantioselective reaction involving an ACP to highlight further the synthetic utility of this transformation.

Chiral a-hydroxy phosphonates and phosphonic acids are widely applied in the pharmaceutical industry owing to their biological activity, [1] and intense efforts have been made on the asymmetric hydrophosphonylation of aldehydes. To our knowledge, the first highly enantioselective hydrophosphonylation was realized by the Shibasaki group using heterobimetallic complexes ([LaLi 3 (binaphthoxide) 3 ], [AlLi(binaphthoxide) 2 ]) as tailor-made catalysts.[2] Recently, Kee and co-workers studied the catalytic performance of chiral [Al(salcyen)] and [Al(salcyan)] complexes.[3] Subsequently, the Katsuki group developed an interesting and highly efficient C 1 -symmetric [Al(salalen)] complex for the reaction.[4] An aluminum-binaphthyl Schiff base complex was also found to be effective for the reaction.[5] Although a number of works have appeared on the synthesis of chiral a-hydroxy phosphonates, [6] searching for a catalyst system that could achieve high reactivity and enantioselectivity is still challenging and interesting. As excellent chiral scaffolds, tridentate Schiff base metal complexes, especially those of vanadium, chromium, and iron, have successfully been applied in many asymmetric reactions.[7] Herein, we present a highly efficient asymmetric hydrophosphonylation of various aldehydes catalyzed by chiral tridentate Schiff base Al III complexes. Initially, tridentate Schiff base 1 a (Scheme 1), derived from l-valinol and 3,5-di-tert-butylsalicylaldehyde, reacted in situ with various aluminum(III) reagents to form complexes that catalyze the asymmetric hydrophosphonylation (Table 1, entries 1-3). The counterions of 1 a-Al III complexes showed a decisive effect on the enantioselectivity. [3a, 8] Complex 1 aEt 2 AlCl catalyzed the reaction smoothly, giving the desired products with 86 % ee, while only a racemate product was obtained in the presence of 1 a-AlEt 3 (Table 1, entry 1 vs. 3). It was interesting that catalyst 1 a-Al(OiPr) 3 showed an opposite absolute sense of stereoinduction (Table 1, entry 2). The disparate results were probably caused by the different steric and electronic properties of the counterions (Cl, Et, and OiPr), which each exhibited a different action in the catalytic cycle. [9b,d] To further improve the enantioselectivity of the reaction, [9a] the steric and electronic effects based on 1 were examined (Table 1, entries 1 and 4-8). As shown in Table 1, electron-donating groups at the position para to the OH Scheme 1. Chiral ligands used in the study. Ad = adamantyl. ee [%][c]

Mild conditions: A secondary amine–amide organocatalyst 1 has been applied in the asymmetric Henry reaction of α‐ketophosphonates. A series of aromatic, heteroaromatic, and aliphatic α‐ketophosphonates can be converted into the desired α‐hydroxy‐β‐nitrophosphonates in moderate to high yields with excellent enantioselectivities (up to 99 % ee) under mild conditions. The mechanism of reaction was investigated by theoretical calculations.