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New Synthetic Routes to Tamiflu
E.J. Corey, Ying-Yeung Yeung, and Sungwoo HongJACS ASAP
Masakatsu Shibasaki, Yuhei Fukuta, Tsuyoshi Mita, NobuhisaFukuda, Motomu Kanai
JACS ASAP
Bryan Wakefield @ Wipf Group 1 5/10/2006
Chiral 1,2 Diamines
Natural Products Chiral Ligands
T. Gall, Angew. Chem. Int. Ed., 1998, 2580
Bryan Wakefield @ Wipf Group 2 5/10/2006
Early Example of Desymmetrization of Aziridines
E. Jacobsen, Org. Lett. 1999, 1611
Bryan Wakefield @ Wipf Group 3 5/10/2006
Desymmetrization of meso-Aziridines with TMSN3
Bryan Wakefield @ Wipf Group 4 5/10/2006
Desymmetrization of meso-Aziridines with TMSN3
Bryan Wakefield @ Wipf Group 5 5/10/2006
The Importance of Tamiflu
• There are currently 4 drugs for the treatment of influenzainfections.
• The neuraminidase inhibitors, Zanamivir (Relenza) andOseltamivir (Tamiflu), have little toxicity and do not promotedrug resistance.
• If the H5N1 virus becomes readily transmitted through human-human contact, the treatment of choice would be Tamiflu.
NH3ClNH3Cl
Amantadine Rimantadine
O
HN
CO2H
NH2
NH
AcHN
H
HO
HO
OH
Zanamivir(Relenza)
NH2•H3PO4
AcHN
O CO2Et
Oseltamivir(Tamiflu)
A. Moscona, N. Eng. J. Med., 2005, 353
Bryan Wakefield @ Wipf Group 6 5/10/2006
Bryan Wakefield @ Wipf Group 7 5/10/2006
First Route to Tamiflu
J. Rohloff, J. Org. Chem. 1998, 4545
Bryan Wakefield @ Wipf Group 8 5/10/2006
Second Route to Tamiflu
M. Karpf, J. Org. Chem., 2001, 2044
Bryan Wakefield @ Wipf Group 9 5/10/2006
Third Route to Tamiflu
P. Harrington, Org. Pro. Res. Dev. 2004, 86
Bryan Wakefield @ Wipf Group 10 5/10/2006
Shibasaki Route to Tamiflu
HN
N3O
NO2
NO2
1. Boc2O, DMAP, CH3CN2. 4 M NaOH
98% (2 steps)
1. Ph3P, CH3CN2. Boc2O, Et3N, CH3CN
90% (2 steps)
HN
N3
Boc
HN
NH
Boc
Boc
1. SeO2, DMP, Dioxane2. DMP, DCM
68% (2 steps)
HN
NH
Boc
Boc
O
1. 10 mol% Ni(COD)2, 10 mol% COD, 3 eq TMSCN, THF2. NBS, , Et3N, THF3. LiAlH(OtBu)3, THF
60% (3 steps)
HN
NH
Boc
Boc
OH
NC
1. DEAD, Ph3P, THF, 87%2. 3-pentanol, BF3•OEt2, 52%
HN
NH
Boc
Boc
O
NC
1. Ac2O, DMAP, py, 84%2. 4.2 M HCl-EtOH, 53%3. 85% H3PO4, EtOH, 50%
HN
NH2
Ac
O
EtO2C
NH2
NH
Boc
O
NC
1. TFA, DCM2. Boc2O, Et3N
63% (2 steps)
Bryan Wakefield @ Wipf Group 11 5/10/2006
Corey Route to Tamiflu
Bryan Wakefield @ Wipf Group 12 5/10/2006
Conclusion
• The key step in the Shibasaki synthesis are a catalyticenantioselective desymmetrization of a meso-aziridine.
• The key steps in the Corey route are a enantioselective Diels-Alder, iodo-lactamization and bromoacetamidation.
• Both routes offer a new way to access Tamiflu that does notrequire the use of shikimic acid or quinic acid.
• “Although our route is already very efficient, it’s conceivable thatwhen you put new developments together, you’ll have an evenbetter and cheaper process. I think the Tamiflu supply problemis solved” E.J. Corey C&E News May 5th, 2006
Though the possibility does exist that each route could bemodified, currently due to scalability issues with reagents,neither route offers a viable alternative to process route.
Bryan Wakefield @ Wipf Group 13 5/10/2006
