Total Synthesis of Norzoanthamine

Miyashita, M. et al. Science 2004, 305, 495.

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目 录

1 简介

2 反合成分析

3 Norzoanthamine的合成

4 总结和讨论

1. 简介

( )纽扣珊瑚 Zoanthids

Norzoanthamine (1): R=HZoathamine (2): R=Me

IsolationNorzoanthamine: Rao and Faulker, the coast of India in 1984.Zoanthamine: Uemura, the coast of islands of south of Japan in 1995.Biological activity N th i I hibit h l t l t ti d ti t ti dNorzoanthamine: Inhibits human platelet aggregation and antisteoporotic drug.Zoanthamine: Analgesic and inhibitor of phorbol myristate-induced inflammation.

Synthetic ChallengesSynthetic Challenges

trans-anti-trans-fused perhydro-phenanthrene

three all-carbon quarterary centers in C ring (C9, 12, 22)

two novel aminoacetal structure(D, G ring)

2. 反合成分析O

OH

OO

H1 methylation at C9

Me

O

H

HMe

Me

Me

O O

Me

O

H

HMe

Me

MeCO2H

bis-amino-acetalization

1. methylation at C9

9

2. coupling

H

A BC

DE

N

O

Me

O ONH2

Me

O

O

OH

H

O Me ONBoc

MeMe

FG

Me

OAcO

H

HMe

intramolecularDiels-Alderreaction

OAcOH

CO2Mephotosensitizedoxidation

OAc

OTBS

Me

MeH

HMe

MeCO2H

OTBS

MeH

OTBS

MeMe Me

H

O

Me TBS

O

Me

TBSOHC

OTMS LiCu Me

OTIPS2

O

O TBS

aldol reactionMe

Me

OTIPS conjugate additionMe

2. Norzoanthamine的合成

exo: endo=72:28

1. Dibal2 Ph PCD Br

M

OAc

Me

H

MeOH

Me

OTES

Me

H

MeOTBS

12K-selectride

1. TBSOTf2. Ti(OEt)43. TESOTf

2. Ph3PCD3BrKHMDS

3. 9-BBN,then H2O2

MeH H

O

OMe

H H

O

O74%

13 14

OTESH

OTESH

OTESH(MeO)2C=O

Me

H

H

Me

H

OTBSMe

OH

DD

Me

H

H

Me

H

OTBSMe

OH

DD

Me

H

H

Me

H

OTBS

O

MeD

D

77%

2t-BuOLi,then MeI

92%

(NH4)6Mo7O24

OH

OH

O

OH

OMe O15 16 17

OH O

OH O

MeH

Me

H

O

CO2HMe

Me Me H

Me

H

O

CO2MeMe

Me

1. TMSCHN22.TMSCl,LHMDS3. Pd(AcO)2

96%

AcOH aq.100 oC

OMe

BocN O OMe

BocN O

26 27

OH

MeOH

OH

MeOH

MTFA aq.Me

H

Me

N

HMe

MeCO2Me

CH3CO2

MeH

NH

MeMe

CF3CO2 OO

Norzoanthamine

TFA aq.110 oC Al2O3, MeOH

81%

O

Me

3 2 HO

Me28 29

3. 总结与讨论

41 steps, 3.5% overall yield (average of 92% per step)p , y ( g p p)

Intramolecular Diels-Alder reaction (ABC ring, C12, C22)

Kinetic isotope effect for synthesis of alkyne (not only for mechanism)

Bis-aminoacetalization (DEFG ring, C12, C22)

These distinctive biological properties, combined with novel chemicalstructures, make this family of alkaloids extremely attractive targets forh i l th i H th h i l th i f th th ichemical synthesis. However, the chemical synthesis of the zoanthamine

alkaloids has remained as an unexplored summit, despite great syntheticefforts, owing to their densely functionalized complex stereostructures.g ySynthetic challenges posed by norzoanthamine (1) and zoanthamine (2)include construction of the stereochemically dense C ring that has threeadjacent quaternary asymmetric carbon atoms at the C 9 C 12 and C 22adjacent quaternary asymmetric carbon atoms at the C-9, C-12, and C-22positions; stereoselective synthesis of the ABC carbon framework consistingof the trans-anti-trans-fused perhydrophenanthren skeleton; andstereoselective construction of two novel aminoacetal structures, including abridged -lactone. We set about synthetic studies of norzoanthamine (1) thataimed at developing an efficient synthetic route flexible enough to provideaimed at developing an efficient synthetic route flexible enough to provideaccess to several members of the zoanthamine alkaloids while allowing thesynthesis of various analogs for biological testing. We report herein the stereoselective total synthesis of 1stereoselective total synthesis of 1.

The total yield of synthetic norzoanthamine was 3.5% (an average of 92%yield each step) in 41 steps starting from 3 The synthetic compound wasyield each step) in 41 steps, starting from 3. The synthetic compound wasidentical in all respects with naturally occurring norzoanthamine, includingspectroscopic characteristics [1H and 13C nuclear magnetic resonance (NMR)spectra, infrared spectroscopy, and mass spectra], circular dichroism (CD),and optical rotation [α]24 D = –6.0 (c 0.23, CHCl3); natural norzoanthamine[α]24 D = –6.2 (c 0.23, CHCl3)]. The absolute structure of norzoanthamine (1)[ ] D ( , 3)] ( )was rigorously verified by the present total synthesis. The chemistrydescribed here not only offers a solution to a formidable synthetic challengebut also opens a completely chemical avenue to norzoanthamine otherbut also opens a completely chemical avenue to norzoanthamine, othernaturally occurring zoanthamine alkaloids, and synthetic, designednorzoanthamine derivatives.