Sugasawa reaction

4) The Sugasawa reaction (ortho-acylation of aniline) was optimized for this route using a combination of BCl3/GaCl3. 

5) Installation of an N-protecting group was optimized to suppress formation of O-benzylation. 

6) A classical chiral resolution method was established, prior to investigation of the asymmetric addition of lithium acetylide to the ketimine 5. 

7) The novel asymmetric nucleophilic substitution to the ketimine was discovered and optimized for this preparation. 

8) The ANM group was selected as the nitrogen protecting group for the novel asymmetric nucleophilic substitution providing the optimum enantioselectivity. 

---

The large scale preparation of the drug candidate 2 was accomplished via the Sugasawa reaction (an ortho-selective Friedel-Craft acylation on anilines) and the asymmetric addition to ketimines. Understanding the reaction mechanism and reaction parameters is the only way to gain confidence that the reactions will perform as required upon scale up. Below we discuss both subjects in detail. 

The first time we encountered the Sugasawa reaction was in the early 1990s, when we worked on anti-MRSA carbapenem projects. We were very interested in this... 

Elucidation of the reaction mechanism of the Sugasawa reaction was initiated under the initiative of Dr. Alan Douglas who was the head of our NMR group [13], The results are summarized in Scheme 1.9. 

Further Optimization of the Sugasawa Reaction Based on the Reaction Mechanism... 

Table 7.7 Other auxiliary Lewis acids for the Sugasawa reaction.

---