Reduction of pseudoephedrine amides

Reduction of pseudoephedrine amides with metal amide-borane complexes, and lithium amidotrihydroborate (LAB) in particular, furnishes the corresponding primary alcohols in high yield. In the initial report, LAB was prepared by deprotonation of the commercial, solid reagent borane-ammonia complex, using slightly less than 1 equiv of butyllithium as base (eq 11). In... 

Table I. Reduction of Pseudoephedrine Amides with Lithium Pyrrolidinoborohydride...

Figure 4, Reductive cleavage of pseudoephedrine amides with lithium pyrrolidinoborohydride.

In the last entry of Table I, it is noted that the reduction had to be done with lithium aminoborohydride (LiH3BNH2). Myers further expanded the utility of this reagent with additional examples of the reduction of alkylated pseudoephedrine amides to chiral alcohols of high ee (Table II), and the reduction of iV,iV-disubstituted dodecanecarboxamides and 1-adamantanecarbox-amides to the corresponding alcohols, respectively (Table III) (5). 

Pseudoephedrine was used as a chiral auxiliary in Merck s synthesis of neurokinin-1 (NKj receptor antagonists 226. NKi receptor antagonists have been shown to prevent acute delayed chemotherapy-induced nausea and vomiting. The enolate of (f ,f )-pseudoephedrine amide 222 was formed by reaction with LiHMDS in the presence of TMEDA, and subsequent reaction with ot,p-unsaturated ester afforded the desired product 224 in 56% yield with the required diastereoisomer as the major product. Following reduction of the ester functionality, the chiral auxiliary was removed via acid induced cyclisation to afford lactone 225. This was transformed into NKi receptor antagonist 226 in eight steps (Scheme 14.77). 

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