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.