A three-component bicyclization strategy for the efficient synthesis of densely functionalized pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidines from readily accessible aryl aldehydes, α-thiocyanate ketones, and pyrazol-5-amines was established. The reaction pathway involves a nucleophilic addition/5-exo-trig/6-endo-trig bicyclization sequence that results in continuous multiple bond-forming events, including the formation of C–N and C–C bonds, to give high levels of molecular complexity.

The group-assisted purification asymmetric synthesis of α,β-diamino acid derivatives was achieved by treating chiral N-phosphonyl imines with a Ni^II-complexed glycine-derived enolate; traditional purification techniques such as chromatography and recrystallization are not required. Successful control of the syn stereochemistry of the vicinal diamino products complements our previous methods that afforded anti stereoisomers; thus, all four individual isomers can be synthesized simply by changing the geometry of the enolate. In contrast to our previous synthesis in which at least 5 equiv. of the glycine Schiff base enolate was required for complete conversion, the new synthesis only needs 1.1 equiv. of the glycine Schiff base enolate to give complete diastereoselectivity (>30:1 dr) and high yields (91–97 %). The absolute stereochemistry was unambiguously determined by X-ray structure analysis.

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 reaction showed a great substrate scope in which aromatic/aliphatic aldehyde- and ketone-derived N-phosphinyl imines can be employed as electrophiles. The chiral N-phosphinamide can be stored at room temperature for more than 2 months without 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-Assistant-Purification) chemistry processes that were developed in our laboratories. The absolute configuration has been unambiguously determined by converting a β-nitroamine product into a known N-Boc sample.

The combinations of N-methyl-p-toluenesulfonamide/NBS and N-ethyl-p-toluenesulfonamide/NBS were found to be good nitrogen/halogen resources for the aminohalogenation of α,β-unsaturated ketones in the presence of Ni(OAc)₂ as the catalyst for the synthesis of vicinal haloamino ketone derivatives. The introduction of N-alkyl groups to the nitrogen resources resulted in excellent regio- and stereoselectivity for both electron-donating and electron-withdrawing group-attached unsaturated ketone substrates. The structure of the resulting products has been unambiguously confirmed by X-ray crystal structure analysis.

Chiral N-phosphonylimines were found to react with lithium phosphites to provide various substituted chiral α-amino phosphonates in excellent yields (94–97%) and diastereoselectivities (93:7–99:1). The types of bases utilized for generating the nucleophile are crucial for the effectiveness of asymmetric induction. In addition, N,N-isopropyl group on chiral N-phosphonylimine auxilliary was proven to be superior to other protecting groups in controlling diastereoselectivity. The absolute configuration was unambiguously determined by converting a chiral α-amino phosphonate into its authentic N-Cbz derivative.

A series of new chiral syn-α-branched β-amino ketones has been synthesized by reacting chiral phosphonyl imines with ketone-derived enolates. The N-protection group on imine auxiliary was found to be crucial to the asymmetric induction. The absolute stereochemistry has been unambiguously determined by converting a product to a known sample.

Various chiral N-phosphonyl β-amino Weinreb amides were synthesized by treating chiral N-phosphonyl imines with the lithium enolate of N-methoxy-N-methylacetamide. The N,N-protection groups on chiral N-phosphonyl imines and the types of deprotonation bases for enolate generation were found to be crucial for the successful synthesis. Eleven Weinreb amides were obtained in excellent chemical yields (92 to 98 %) and good to excellent diastereoselectivities (up to dr = 99:1). The absolute structures were unambiguously determined by converting the products into authentic samples and by comparing their optical rotation values.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

A series of chiral N-phosphonyl imines have been synthesized and utilized successfully in asymmetric aza-Henry reaction. The chiral auxiliary was optimized for this reaction by varying different R groups on the nitrogen atoms. The reaction is convenient to perform to give excellent yields and good diastereoselectivities. The absolute stereochemistry was unambiguously determined by converting a resulting vicinal nitroamine into its N-Boc derivative which serves as a known compound.

Chiral phosphonyl imines attached by 1-naphthyl protection group were found to react with lithium ester enolates smoothly and give chiral β-amino esters in good yields (70–88%) and up to excellent diastereoselectivity (>99:1 dr). Triisopropoxytitanium (IV) chloride was found to enhance diastereoseletivity when used as the Lewis acid promoter. The chiral auxiliary can be readily removed by treating with HBr to give free amino esters. The absolute structure has been unambiguously determined by converting one of the products into an authentic sample. This reaction provides an easy access to β-amino acid derivatives.