N-Phosphinyl Imine Chemistry (I): Design and Synthesis of Novel N-Phosphinyl Imines and their Application to Asymmetric aza-Henry Reaction Suresh Pindi, Parminder Kaur, Gaurav Shakya and Guigen Li* Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA *Corresponding author: Guigen Li, guigen.li@ttu.edu Novel chiral N-phosphinamide and N-phosphinyl imines have been designed, synthesized and applied to asymmetric aza-Henry reaction to give excellent chemical yields (92% – quant.) and diastereoselectivity (91% to >99%de). The reac- tion showed a great substrate scope in which aromatic ⁄ aliphatic aldehyde- and ketone-derived N-phosphinyl imines can be employed as electro- philes. The chiral N-phosphinamide can be stored at room temperature for more than 2 months with- out inert gas protection, and chiral N-phosphinyl imines were also proven to be highly stable at room temperature for a long period under inert gas protection. The N-phosphinyl group enabled the product purification to be performed simply by washing crude product with EtOAc and hexane. This reaction joined other eight GAP (Group-Assis- tant-Purification) chemistry processes that were developed in our laboratories. The absolute config- uration has been unambiguously determined by converting a b-nitroamine product into a known N- Boc sample. Key words: aza-Henry reaction, chiral N-phosphinamide, GAP (Group-Assistant-Purification) chemistry, N-phosphinyl imines Received 19 August 2010, revised 15 September 2010 and accepted for publication 19 September 2010 Imine chemistry has been playing a crucial role for drug develop- ment and discovery because most drugs and their precursors con- tain amino functionality; this places imine chemistry among the most important and active research areas in modern organic, bioor- ganic, and medicinal chemistry (1–12). b-Nitroamines are particu- larly important synthetic precursors because of their easy conversion into many other useful building blocks, such as vicinal diamines and a-amino acids (13–17). The vicinal diamine motif has been proven to play crucial roles in many biological systems. For example, the diamine functionality of some opioid ligands is responsible for their selective binding onto their receptors of l, d, and j types for pharmacological studies in central and peripheral nervous systems (18–20). The diamine functionality was also found to exist in chemotherapeutical bleomycin A 2 and B 2 (21), glycopep- tides (21) and edeine A 1 and B 1 of antibiotics (22). The evidence indicates that chirality of diamine ligands also plays critical roles in biological processes (20). In this work, we have shown a simple and facile methodology for the formation of the S-enantiomer of b-nitroamines in high enantioselectivity. There are many approaches to chiral diamine compounds (23,24), particularly those involving N-protected imine starting materials with various protect- ing groups, such as Ar 2 CH- ⁄ Bn- (4,25–27), alkoxycarbonyl (7,28,29), Ar 2 PO- (30,31), Aryl- (32–34), and ArSO 2 , (35–38) can be employed as both electrophiles and dienophiles for asymmetric reactions (4– 14). These protecting groups were often found to be crucial during N P N R R O N R 1 Ph Ph P R R O N R 1 + H 3 C NO 2 LiHMDS, THF –78 °C, 6 – 8 h P O NH R H(CH 3 ) NO 2 P O N R H(CH 3 ) 92% - quant. yields and 91% to >99% de 20 Chem Biol Drug Des 2011; 77: 20–29 Research Article ª 2010 John Wiley & Sons A/S doi: 10.1111/j.1747-0285.2010.01047.x