cyclobutane synthesis and fragmentation. a cascade route...
TRANSCRIPT
Cyclobutane Synthesis and Fragmentation. A Cascade Route to the Lycopodium Alkaloid (–)-Huperzine A
White, J. D *.; Li, Y.; Kim, J.; Terinek, M. J. Org. Chem. 2015, ASAP
DOI : 10.1021/acs.joc.5b01619
Nicolas Volkoff 10/09/2015
N ONH2
H
2
James D. White > Ph.D. at the MIT with G. Büchi in 1965 > Assistant Professor, Harvard University, 1967-1971 > Associate Professor, Oregon State University, 1971-1976 > Professor, Oregon State University, 1976-1992 > Distinguished Professor, Oregon State University, 1992-2003 > Distinguished Professor Emeritus, Oregon State University, 2003-present
> Research interest : Total synthesis of complex natural products
3
Introduction
> Lycopodium alkaloid family > Found in the chinese club moss Huperzia serrata and in the New Zealand
club moss Lycopodium varium > First enantioselective synthesis by Kozikowski et al. in 1991 > Most efficient synthesis by G.Q.Lin and co. in 2012
— 10 Steps 17% overall yield
> Interesting activity against Alzheimer‘s disease
N ONH2
H
4
Retrosynthetic Approach
N ONH2
H N OMeNH
H EWG N
H
H
N OMe
H EWG
O
H
H
R
O
R
Huperzine A
+
aza-Prins
PyridineAnnulation
[2+2]-photoaddition
5
Intramolecular Photocycloaddition
O
OH
O
O O
O
H
H
Ag2O
59%
hν
58%
Br
O
O
H
HO
H
HO
H
H
HOOH
1.PhSeCl,EtOAc
2. NaIO4
81%
Zn, EtOH
53%
DMP
67%
6
Acrylamide Formation
O
O
H
H
O
OTIPS
H
H
O
OTIPS
H
H
N3
O
OTIPS
H
H
HN O
SePh
KHMDSTIPSCl
THF, 0 °C
PhIOTMSN3
CH2Cl2, -19 °C86% (2 steps)
1. LiAlH4, Et2O
3. 5-(O2N)2C6H3COClEt3N, 69%
CO2H
SePh2.
7
Pyridine Formation
OH
H
NH
TIPSOO
SePh
O
O
H
H
HN OH
H SePh
O
O
H
H
HN O
O
O
H
H
N OMe
AlMe3
DCE, 80 °C69%
HF (48%)MeNO2
89%
NaIO4MeOH-H2O
83%
MeIAg2CO3
CHCl391%
O
OTIPS
H
H
HN O
SePh
8
Opening of the THF Ring and Oxidation
O
O
H
H
N OMe
O
H
H
N OMeOH
Zn, NaOHMeOH-H2O
80 °C, 94%
O
H
H
N OMeO
H
O
H
H
N OMeOH
O
H
H
N OMeO
DMPCH2Cl2
93%
MeMgIEt2O, -78 °C
76%
DMPCH2Cl2
92%
9
Selective Methylenation
O
H
H
N OMeO
O
H
H
N OMeOTf
N
Cl
N(SO2CF3)2
KHMDS
THF, 74%
O
H
H
N OMe(Ph3P)4Pd(SnMe3)2
76%
10
Aza-Prins Cyclisation
O
H
H
N OMe
N
H
H
N OMe
CO2Me
N OMeHN
CO2Me
N ONH2
H
H2NCO2Mep-TsOH
C6H6, reflux
37%
TMSI
N
H
H
N OMe
H CO2Me
N OMeNH
H CO2Me
11
Conclusion
> Key Step : Aza-Prins Cyclisation > 17 Steps overall yield of 1%
à Not the most efficient (–)-Huperzine A synthesis
Thank you for your attention
12
β-Azidation
Magnus, P.; Lacour, J. J. Am. Chem. Soc. 1992, 114 (2), 767.