Synthesis of Vancomycin from the Aglycon
Christopher Thompson, Min Ge, Daniel Kahne
J. Am. Chem. Soc. 1999, 121, 1237-1244
Presented by James Melnyk
Daniel Kahne
• Born and raised in Lexington Massachusetts
• Initially attended Cornell University to study art and art
art history, however he subsequently left
• His advisor, Roald Hoffmann (Nobel Prize in Chemistry)
convinced him to return and work in the chemistry lab
of a new faculty member which led him to graduate
with his B. S. in Chemistry
• Ph.D. at Columbia University where he studied
tetracycline
– Advisor: Gilbert Stork
• Postdoctoral research – Columbia University
– Clark Still
• Joined Princeton University Faculty in 1988
• Relocated to Harvard University in 2004
• Research focuses on the synthesis of antibiotics that target bacterial cell
wall biosynthesis and the mechanistic study of how they inhibit cellular
processes
Vancomycin
• A glycopeptide antibiotic
• First isolated from a soil sample from the Borneo jungle in 1953
• The bacteria that produced it was eventually named Amycolatopsis
orientalis
• Initially indicated for the treatment of penecillin resistant Staphylococcus
aureus, and later on for the treatment of colitis (intestinal inflammation
from bacteria)
• Often referred to as a “drug of last resort”
• The development of Vancomycin resistant organisms has resulted in a
decrease of its usage
Synthesis of Vancomycin from the Aglycon
• Synthesis of Vancomycin from the agylcon necessitated the development
of a method to make the glycosidic linkage to the 2,4,6-trisubstituted
phenol of amino acid 4 on the aglycon
• Synthesis of the aglycon has been previous reported by both D. A. Evans
and K. C. Nicolaou
– Evans, D. A. et al. Angew. Chem. Int. Ed. 1998, 37, 2700
– Nicolaou, K. C. et al. Angew. Chem. Int. Ed. 1998, 37, 2717
Forming Glycosidic bonds with a Phenol as the
Glycosyl Acceptor
• A common approach with phenols involves displacement of an anomeric
halide and nucleophilic attack at the anomeric carbon in the presence of a
base
• This method of forming glycosidic bonds is not possible with a sterically
hindered phenol group as seen in the Vancomycin aglycon
• Additionally the aglycon is prone to racemization at its amino acids and is
therefore extremely sensitive to basic conditions
Further Complications with Vancomycin Aglycon
• As previously noted the glycosidic bond to the phenol is 1,2 trans (β) in
Vancomycin
• In these cases stereochemical control is achieved by using a C2 ester that
is capable of neighboring group participation to form the β-glycosidic bond
– Requires the use of a large steric ester, like pivaloate, to prevent ortho-ester formation
Further Complications with Vancomycin Aglycon
• Unfortunately the removal of pivaloate protecting groups necessitate the
use of harsh basic or reductive conditions and are therefore incompatible
with the Vancomycin aglycon
• Additionally the large steric bulk of the pivaloate is problematic for βglycosidic bond formation in the presence of the sterically bulky 2,4,6trisubstituted phenol nucleophile
• These complications led the Kahne Lab to adapt the sulfoxide glycosylation
methods so that it could be applied to forming the glycosidic linkage to the
Vancomycin aglycon
Vancomycin Synthesis
Vancomycin Synthesis
Vancomycin Synthesis
Vancomycin Synthesis
Conclusion
• Sulfoxide glycosylation methodology was adapted to synthesize
vancomycin from the aglycon, and expands on the methodologies
applicability for constructing glycosidic bonds
• The aglycon for this synthesis was acquired from Vancomycin however it
can also be synthesized according to the precedent established by D. Evans
and K.C. Nicolaou