Enantioselective Total Syntheses of Manzamine A and Related Alkaloids

John M. Humphrey, Yusheng Liao, Amjad Ali, Tobias Rein, Yue-Ling Wong,

Hui-Ju Chen, Anne K. Courtney, and Stephen F. Martin*

Presented by: Jixin Liu

Stephen F. Martin

M. June and J. Virgil Waggoner Regents Chair in Chemistrynow at The University of Texas at Austin

B.S. University of New Mexico (1968)Ph.D. Princeton University (1972) with Professor Edward C. TaylorPostdoctoral work at the University of Munich with Professor Rudolf

Gompper, and further work with Professor George Büchi at the MIT.

Known for his work in alkaloid synthesis;Current research is directed toward the syntheses of natural and

unnatural products that are of biological or structural interest

J. AM. CHEM. SOC. 2002, 124, 8584 8592

Manzamine A, a structurally unique β-carboline alkaloid derived from marine sponge Haliclona sp., exhibiting a high level of antimalarial activity in vivo when tested in

Plasmodium berghei (ANKA)-infected mice.

Manzamine A

N

H

N

H

H

OH

NNH

1

3D

Manzamine A

N

H

N

H

H

OH

NNH

A B

D C

E

Retro synthesis

Key Steps

• Intramolecular Diels Alder reactions to produce the tricyclic ABC core of the manzamines

• Ring-Closing Metathesis of E ring

Key steps

D-A reaction

Key steps Ring-Closing

Ring Closing

Ring-Closing

Forward Synthesis

Forward Synthesis

Forward Synthesis

Forward Synthesis

N

H

HN O

CH(OMe)2

O

OO

N

H

HN O

CH(OMe)2

O

OO

CH2CH2CH CH2LiN

H

HN O

CH(OMe)2

O

OO

N

H

H

N O

CH(OMe)2

O

O

Forward Synthesis

Forward Synthesis

NH

N

H

H

OH

N NH

1

H2N

HNN

CHO

H

N

H

H

OH

5

NH

NH

OH

HN

NH

H2O

CF3CO2H

NH

NH

OH

NH

NHN

H

N

H

H

OH

HN NHH

NH

N

H

H

OH

HN NHH

NH

N

H

H

OH

HN NH

NC

NC

Cl

Cl

O

O

NC

NC

Cl

Cl

OH

OH

-

NH

N

H

H

OH

N NH

1

Pictet-Spengler

Conclusion

• The longest linear sequence was 21 steps• The concise approach highlights a novel

strategy for assembling the tricyclic ABC ring core by a Diels Alder reaction.

• 13- and 8-membered heterocyclic rings were synthesized via RCM.