Phosphoramidate auxiliaries

General procedure for the synthesis of a-aminophosphonates using chiral phosphoramidate auxiliaries In a dry vial, under inert gas protection, diethyl H-phosphonate (1.5 mmol) was dissolved in 3 mL of THF. The vial was cooled to —78 °C and into the resulting solution LHMDS (1.5 M in THF, 1.5 mmol) was added dropwise. The reaction solution was stirred at —78 C for 15 minutes, and corresponding chiral A -phosphoryl imine (e.g., 98, 1.00 mmol in 3-mL THF) was added to the reaction mixture at 78 C. The reaction mixture was stirred for another 2 hours before it was quenched by adding saturated ammonium chloride... 

SCHEME 47.22. Diastereoselective synthesis of a-aminophosphonates using chiral phosphoramidate auxiliaries. 

The excellent enantioselectivity and wide scope of the CBS reduction have motivated researchers to make new chiral auxiliaries [3]. Figure 1 depicts examples of in situ prepared and preformed catalyst systems reported since 1997. Most of these amino-alcohol-derived catalysts were used for the reduction of a-halogenated ketones and/or for the double reduction of diketones [16-28]. Sulfonamides [29,30], phosphinamides [31], phosphoramides [32], and amine oxides [33] derived from chiral amino alcohols were also applied. The reduction of aromatic ketones with a chiral 1,2-diamine [34] and an a-hydroxythiol [35] gave good optical yields. Acetophenone was reduced with borane-THF in the presence of a chiral phosphoramidite with an optical yield of 96% [36]. 

Another chiral phosphoramidate 16, which possesses stereogenic centers at both phosphorus and carbon atoms, was examined in asymmetric HWE olefination reactions [53]. By fine-tuning of the N-substituents in the structure of the auxiliary,... 

Of the catalysts listed in Figures 15.1 and 15.2, 12, 18, 22, and 26 are the most efficient in terms of diastereo- and enantioselectivity, catalyst loading, and reaction rate. While 18 is synthesized in seven steps (including resolution or the use of a chiral auxiliary) [26], the other three are accessible in a more straightforward way. Thus, phosphoramide 12 was prepared in four steps (including resolution) from pyrrolidine (42) (Scheme 15.7) [22f]. The key step here is the photochemical dimerization of pyrrolidine (42 —> 43), originally reported by Crabtree [51]. 

---