Efficient and practical synthesis of Cerageins

ORGN 67

Xinzhong Lai, laixz@chem.byu.edu, Yanshu Feng, Gard Nelson, and Paul B. Savage, paul_savage@byu.edu. Department of Chemistry and Biochemistry, Brigham Young University, C100 BNSN, Provo, UT 84602
Ceragenins, the steroid-based mimics of endogenous antimicrobial peptides, are highly active against Gram-negative and positive bacteria and may be useful in augmenting or replacing the activities of human antimicrobial peptides. As preclinical studies with ceragenins progress, sources of large quantities of lead compounds are required. We have developed an efficient pathway for the large-scale preparation of the ceragenins.

Important features of this synthesis include a facile transetherification reaction of methyl cholate with 3-methoxyacrylonitrile and efficient hydrogenation of both alkene and nitrile groups. In situ protection of the resulting amines with Boc groups is critical to prevent the amines from poisoning the catalysts. Optimization of reaction conditions in the preparation of ceragenin CSA-13 on a large scale (>50 g) will be presented as representative synthesis.