synthesis of vancomycin from the aglycon
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
Synthesis of Vancomycin from the Aglycon
Christopher Thompson, Min Ge, Daniel KahneJ. Am. Chem. Soc. 1999, 121, 1237-1244
Presented by James Melnyk
O
H2N
OH
O
O
OHOH
OH
O
OO
O
HNH
NH
O
HN
H
H2N
OO
H
NH
O
NH
H
Cl
Cl
H
OH
OHHO
HO
H
H
NH
O
NH
O
HO
O
H
OHH
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
O
H2N
OH
O
O
OHOH
OH
O
OO
O
HNH
NH
O
HN
H
H2N
OO
H
NH
O
NH
H
Cl
Cl
H
OH
OHHO
HO
H
H
NH
O
NH
O
HO
O
H
agylcon
glucose
vancosamine
1,2 trans glycosidic bond
OHH
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
R
OH
+O
AcO
AcOAcO
AcO
Glycosyl AcceptorGlycosidic Donor
O
AcO
AcOAcO
AcO
O
R
base
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
O
AcO
AcOAcO
O
O
AcO
AcOAcO
OO
ROH
O
AcO
AcOAcO
pivO
OR
Beta-glycoside
O
AcO
AcOAcO
OO
ROH
OR
Ortho-ester
O
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 β-glycosidic bond formation in the presence of the sterically bulky 2,4,6-trisubstituted 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
O
RO
RORO SPh
O
O
O
N3
1. Tf2O, DTBMP-78°C to -60°C
2. OH
OMeMeO
-78°C to -40°C
O
RO
RORO OAr
O
O
N3
Nt-Bu t-Bu
Me
,BF3
Vancomycin Synthesis
O
OH
HO
HOHO
HO
H+, MeOH
MeO OMe
O
OH
HO
HOO
OPh
O
SPh
HO
HOO
OPh
1
Py, PhSH, BF3 OEt2
O
SPh
HO
HOO
O
O
SPh
HO
AcOO
O
1. Bu2SnO, benzene, ref lux2. AcCl, 0°C
O
SPh
O
AcOO
OPhPh
Ph
O
N3
HO
O
N3
(ClCO)2, Py, 0°C
1 2 3
p-toluenesulfonic acid, MeOH, rt
O
SPh
O
AcOHO
HO
O
N3
4
O
SPh
O
AcOAcO
AcO
O
N3
5
AcCl, Py, 0°C to rtO
SPh
O
AcOAcO
AcO
O
N3
6
O
m-CPBA, -78°C to 0°C
83%94%
82%
100% 98%
Vancomycin Synthesis
Vancomycin
7
OH
OO
O
HNH
NH
O
HN
H
H2N
OO
H
NH
O
NAlloc
H
Cl
Cl
H
OAll
OAllAllO
HO
H
H
NH
O
NH
O
AllO
O
H
1. Alloc-succinimide, NaHCO3, rt2. Allyl Bromide, NaHCO3, rt3. 1% HBr/HOAc, PhSH, rt
8
O O
O
N
O
O
Cs2CO3, PMBCl, rt
OPMB
OO
O
HNH
NH
O
HN
H
H2N
OO
H
NH
O
NAlloc
H
Cl
Cl
H
OAll
OAllAllO
HO
H
H
NH
O
NH
O
AllO
O
H
9MeO
Cl
OHH
OHH
98% over 4 steps
Vancomycin SynthesisOH
OO
O
HNH
NH
O
HN
H
H2N
OO
H
NH
O
NAlloc
H
Cl
Cl
H
OAll
OAllAllO
AcO
H
H
NH
O
NH
O
AllO
O
H
10
9
1. Ac2O, Py, DMAP, rt2. TFA, rt
95%
OAcH
O
O
OAcOAc
OAc
O
OO
O
HNH
NH
O
HN
H
H2N
OO
H
NH
O
NAlloc
H
Cl
Cl
H
OAll
OAllAllO
AcO
H
H
NH
O
NH
O
AllO
O
H
11
OAcH
O
N3
Tf 2O, DTBMP, 6, -78°C to -60°C, then add to 10 with BF3 OEt2, -78°C to -0°C
11Ph3P, ref luxing dioxane: H2O
HO
O
OAcOAc
OAc
O
OO
O
HNH
NH
O
HN
H
H2N
OO
H
NH
O
NAlloc
H
Cl
Cl
H
OAll
OAllAllO
AcO
H
H
NH
O
NH
O
AllO
O
H
12
OAcH13% over 2 steps
Vancomycin
7
1. Alloc-succinimide, NaHCO3, rt2. 1M HCl/MeOH, rt3. Ac2O, Py, DMAP, rt
56%
O
OMe
OAcAllocHN
O
SPh
OAcAllocHN
PhSH, BF3 OEt2, rt
13 14
88%
m-CPBA then DMS, -78°C to -20°C
O
SPh
OAcAllocHN
O
15
86%
Vancomycin Synthesis
12
O
H2N
OH
O
O
OHOH
OH
O
OO
O
HNH
NH
O
HN
H
H2N
OO
H
NH
O
NH
H
Cl
Cl
H
OH
OHHO
HO
H
H
NH
O
NH
O
HO
O
H
OHH
Vancomycin (7)
1. BF3 OEt2, Tf2O, 15, -78°C to -20°C2. 5% Hydrazine, allyl alcohol:MeOH:THF, rt3. Bu3SnH, PdCl2(PPh3)3, DMF:AcOH, rt
30% over 3 steps
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