Direct Catalytic Asymmetric Synthesis of Pyrazolidine Derivatives

The importance and increased demand of pharmaceutically active azaheterocycles has urged the development of inexpensive and environmentally benign catalytic asymmetric technologies. 2] In this context, the pyrazolidine and pyrazoline structural motif is present in several compounds with significant bioactivities, such as anti-inflammatory, antidepressant, anticancer, antibacterial and antiviral activities. These types of compounds are also important starting materials for the syntheses of azaprolines and diamines. In their seminal 1887 work, Fisher and Knçvenagel reported that the reaction between acrolein and phenylhydrazine gave the corresponding pyrazoline under acidic conditions (Scheme 1). 7] However, it was not until 2000 that the first enantioselective synthesis of pyrazolines from acrylamides by means of metal-catalyzed enantioselective [1,3]-dipolar cycloaddition was disclosed. The subsequent asymmetric syntheses were also predominantly based on metal-catalyzed [1,3]-dipolar cycloadditions using dipoles and dipole precursors such as diazoalkanes and nitrile imines, respectively, as starting materials. The synthesis of 3-pyridyl-4-aryl pyrazolines was also accomplished by a metal-mediated aza-Michael cyclocondensation cascade transformation with moderate enantioselectivity. Simultaneously, Sibi and coworkers reported an elegant pyrazilidinone synthesis using a metal-catalyzed enantioselective aza-Michael/cyclization cascade transformation. In the realms of metal-free catalysis, List and M ller recently reported the first catalytic asymmetric Fischer synthesis of pyrazolines through a chiral phosphoric acid-catalyzed 6p-electrocyclization of a,b-unsaturated hydrazones. Shortly after, Briere and coworkers reported an elegant enantioselective synthesis of pyrazolines using b-aryl enones as starting materials by means of phase-transfer catalysis. This was recently expanded by Deng and coworkers to aliphatic-substituted enones. Chiral substituted pyrazolidines can also be synthesized by metal and metal-free catalysis. Based on the importance of diazaheterocycles and our research interest in asymmetric synthesis, we decided to embark on the development of a direct enantioselective route to pyrazolidines by metal-free catalysis. The retrocatalytic analysis suggested that a possible asymmetric synthesis of these compounds would be through a chiral amine-catalyzed Michael/hemiaminal cascade reaction between a suitable hydrazine compound and an a,b-unsaturated aldehyde that would favor 1,4-addition over 1,2-addition (Scheme 2). Moreover, we envisioned that the subsequent hemiaminal formation would push the equilibrium of the reversible azaconjugate addition step towards product formation. During our studies one elegant report appeared on the direct catalytic synthesis of pyrazolidines derivatives based on this strategy. Interestingly, this reaction did not work for b-arylsubstituted enals. Herein, we present a highly enantioselective entry to pyrazolidine derivatives with 98–99% ee, which proceeds via a metalfree, catalytic 1,4-specific cascade transformation between di1,2-N-protected hydrazine and a,b-unsaturated aldehydes. We began our studies by investigating the reaction between cinnamic aldehyde 1a and di-1,2-N-tert-butoxycarbonyl (Boc)protected hydrazine 2a using different catalysts and conditions (Table 1). To our delight, the cascade reaction gave the corresponding 3-hydroxypyrazolidine 3a as the only product with high enantioselectivity when bulky, chiral pyrrolidine derivative 4 was used as the catalyst. Notably, the employment of chiral amines 4a–c as catalysts delivered 3a with high to excellent enantioselectivities in toluene, trifluoromethyl benzene (PhCF3) and tetrahydrofuran (THF), respectively (Entries 2, 4, 7–17). For example, protected prolinol 4a catalyzed the assembly of 3a in an asymmetric fashion in 54% yield with 98% ee at Scheme 1. Acrolein and phenylhydrazine give the corresponding pyrazoline under acidic conditions. 7]