total synthesis of epothilone a: the olefin metathesis approach
DESCRIPTION
Total Synthesis of Epothilone A: The Olefin Metathesis Approach. Zhen Yang, Yun He, Dionisios Vourloumis, Hans Vallberg, and K. C. Nicolaou Angew. Chem. Int. Ed. 1997, 36, 166-168 Presented by: Steven Rossi April 03, 2012. K. C. Nicolaou. 1946: Born in Karavas, Cyprus - PowerPoint PPT PresentationTRANSCRIPT
Total Synthesis of Epothilone A: The Olefin Metathesis Approach
Zhen Yang, Yun He, Dionisios Vourloumis, Hans Vallberg, and K. C. Nicolaou
Angew. Chem. Int. Ed. 1997, 36, 166-168
Presented by: Steven RossiApril 03, 2012
K. C. Nicolaou
• 1946: Born in Karavas, Cyprus• 1969: B.S. University of London• 1972: Ph.D. under F. Sondheimer and P.J. Garret at Univeristy of
London• 1972: Postdoc T. J. Katz• 1974: Postdoc E. J. Corey• 1976: Joined the Faculty at UPenn• Sloan Fellowship while at UPenn• 1989: Joined the faulty at UC: San Diego• 1989: Joined the Scripps Research Institute• Currently Active at both institutions
2
Epothilone A
• Isolated from Sorangium Cellulosum, soil dwelling myxobacteria • Structure determined in 1996 via X-Ray • Prevent cancer cell division • Similar in biological activity to Taxens, but milder side effects with
higher efficiency• Epothilone A-F have been isolated to date
3
Epothilones
A: R= H C: R= HB: R= Me D: R= Me
E: R= HF: R= Me
4
Epothilone A
5
O
MeMeMe
Me
HO
O
Me
N
SMe
O OOH
1
Previous Synthesis
• Danishefsky (1996)
• Schinzer (1997)
• Mulzer (2000)
• Carreira (2001)
6
Retrosynthesis
7
O
MeMeMe
Me
HO
O
Me
N
SMe
O OOH
1
O
MeMeMe
Me
HO
Me
N
SMe
O OOH
2
Me
O
Me MeOH
OOTBS
OMe
OH
Me
N
SMe
A
B
C
Synthesis of Fragment A
8
MeO
Me Me
O
Me
Me Me
O OH
Me
Me Me
O OTBS
Me
Me Me
O
O
OTBS
Me
Me Me
O
O
OHOTBS
A
(+)Ipc2B(allyl)
Et2O/Pentane
-100°C
TBSOTf
DCM, rt
1) O3
DCM, -78°C2) PPh3
NaClO2
2-methyl-2-butene
NaH2PO4
tBuOH/H2O
74% 98%
82% 93%
B
Me
Me
Me
2
(+)-Ipc2B(allyl)
Synthesis of Fragment B
9
SN O
MeO O
+
SN
O O
O
Me
HO O
NaHMDS
HMPA-78°C
LAH
TPAP
NMOB
I
60%, 2 Steps95%
J. Am. Chem. Soc. 1997, 119, 7960-7973
Synthesis of Fragment C
10
N
S
EtO
O
N
S
O
PPh3
Me
C6H6
80°C
N
S
O
N
S
OHC
DIBAL
-78°C
(+)Ipc2B(allyl)
Et2O/Pentane
-100°C
90% 90%
96%
Fragment Additions
11
Me
Me Me
O
O
OHOTBS
A
+O
B
O
OH
MeMeMeHO
Me
OOTBS
N
S
OHC
O
MeMeMe
Me
HO
Me
N
SMe
O O
O
MeMeMe
Me
HO
Me
N
SMe
O OOTBS OTBS
O
MeMeMe
Me
HO
Me
N
SMe
O OOH
3 Products
LDA
-78°C
DCC
DMAP
3CF3COOH
DCM
mCPBA
C6H6
Ru ClCl
Cy3P
PCy3
3
Final Products
12
O
MeMeMe
Me
HO
O
Me
N
SMe
O OOH
1
O
MeMeMe
Me
HO
O
Me
N
SMe
O OOH
O
MeMeMe
Me
HO
Me
N
SMe
O OOH
O
55%20%
20%
Conclusions
• Vital Step: Intramolecular Olefin Metathesis
• Fairly Steroselective
• Relatively short and high yielding Total Synthesis
13
Questions?
14