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The Journey of Azadirachtin. --- Dead Ends and Detours. Supervisors: Prof. Zhen Yang & Jiahua Chen. Reporter: Weiwu Ren 2008-01-11. Introduction. Dead Ends and Detours – An Example. Total Synthesis of Azadirachtin. Summary. Acknowledgement. Contents. Introduction.

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The Journey of Azadirachtin

--- Dead Ends and Detours

Supervisors: Prof. Zhen Yang & Jiahua Chen

Reporter: Weiwu Ren

2008-01-11


Introduction

Dead Ends and Detours – An Example

Total Synthesis of Azadirachtin

Summary

Acknowledgement

Contents


Introduction

Dead Ends and Detours – An Example

Total Synthesis of Azadirachtin

Summary

Acknowledgement

Contents


Guanacastepene

IMDA

Tandem Cyclization

Heck

RCM/Robinson

TandemRCM

Stille/[2+2]


Dead Ends and Detours

Planning

Starting

Materials

Target

Molecule

Dead Ends

Detours


Our Attitudes

Reality

Several Steps

Condition B

Starting

Materials

Condition A

Product

Condition C

OR


Introduction

Dead Ends and Detours – An Example

Total Synthesis of Azadirachtin

Summary

Acknowledgement

Contents


Brevetoxin B

Brevetoxin B

A marine neurotoxin

First reported by Nakanishi in 1981

23 stereocenters

All trans-contiguous ether rings

Lin, Y.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773.


First-generation Retrosynthetic Analysis

Nicolaou, K. C.; Hwang, C. -K.. J. Am. Chem. Soc. 1986, 108, 6800.


Work with Model

Nicolaou, K. C.; Hwang, C. -K. J. Am. Chem. Soc.1990, 112,3040.


But…

Nightmare!!!


Is the Strategy Useless?

Unfortunately, however, all attempts to achieve the bis(thionation) of the macrodilactone precursor failed… The lactone carbonyl flanked by the methyl group, defiantly resists the action of Lawesson’s reagent, presumably due to its hindered nature…

------ K. C. Nicolaou

Significance:

1. Investigation of the chemistry of the molecule

Brevetoxin B and the basis of the following total

synthesis;

2. Developing a full body of methodology to build

fused seven-membered rings;


Introduction

Dead Ends and Detours – An Example

Total Synthesis of Azadirachtin

Summary

Acknowledgement

Contents


Azadirachtin

16 Contiguous Stereogenic Centers

7 Tetrasubstituted Carbons

4 Different Ester Groups

2 Hydroxy Groups

1 Acid and Base-Sensitive Hemiketal

1 Strained and Sterically-hindered Epoxide

2 Intramolecular Hydrogen Bonds (strong: C11OH - O13 weak: C7OH – C20OH)


1986

1968

1986

1996

1996

2006

2006

2007

2007

Story Line

Beginning

Isolation and Structure Determination of Azadirachtin


1985-1986

The correct structure was submitted and was confirmed by X-ray analysis

1975

The first complete structure was reported but not correct

1968

First report of the isolation of Azadirachtin by Morgan group

Hop Skip and Jump


First Isolation

Isolated from the seeds of Azadirachta indica A. Juss in India

( 印度苦楝树 )

Named Azadirachtin

( Azadirachta indica )

High activity against the desert locust(沙漠蝗虫)

Molecular formula:C29H38O16(642.222)

Butterworth, J. H.;Morgan,E. D. J. Chem. Soc., Chem. Commun. 1968, 23.


Right Molecular Formula & Partial Structure

Butterworth, J. H.;Morgan,E. D. J. Chem. Soc., Chem. Commun. 1968, 23.

Molecular Formula : C35H44O16 (Triterpenoid)

Butterworth, J. H.; Morgan, E. D. J. Chem. Soc., Perkin Trans. I 1972, 2445.


The First Complete Structure

Nakanishi’s Azadirachtin

Correct Structure

Based on: PRFT/CWD 13C NMR

Hypothetical Relationship with Known Terpenoids

Zanno, P. R.; Muira, I.; Nakanishi, K. J. Am. Chem. Soc.1975, 97,1975.


Ley’s Modification

Ley’s Modification

Correct Structure

Based on: 1D NOE & 2D NOESY

Bilton, J. N.; Broughton, H. B.; Ley, S. V. J. Chem. Soc., Chem. Commun. 1985, 986.


Azadirachtin

Finally, the Correct Structure

W. Kraus.; M. Bokel.; A. Klenk.; H. P. Khnl. Tetrahedron Lett. 1985, 26, 6435.

Broughton, H. B.; Ley, S. V. J. Chem. Soc. Chem. Commun. 1986, 46.


First isolated by Morgan(1968)

Partial structure(1972)

Confirmed by X-ray analysis(1986)

Azadirachtin

The first complete structure

(1975)

Ley’s modification

(1985)

22


1986

1996

2006

2007

Story Line

1968

1986

1996

Ley’s Monodrama(独角戏)

2006

2007


Ley’s Idea

We recognise this coupling involves the formation of a difficult bond, but therein lies the challenge.

---- S. V. Ley

Ley, S. V. Pure Appl. Chem.1994, 66, 2099.


1stSynthesis

Ⅰ. Develop a flexible approach

for the total synthesis

Ⅱ. Study the functional groups

responsible for activity

(potential active center)

Ley, S. V.; Santafianosa, D.Tetrahedron Lett. 1987, 28(2), 221.


Construction of This Fragment

Ley, S. V.; Santafianosa, D.Tetrahedron Lett. 1987, 28(2), 221.


Absolute Configuration

Method:

Modified Mosher methodology using high field FT NMR techniques

Ley, S. V.; Lovell, H.J. Chem. Soc., Chem. Commun. 1992, 1304.


Ley’s Other Work

Azadirachtin


1986

1996

2006

2007

Story Line

1968

1986

1996

Ley

Cambridge

Nicolaou

Scripps

2006

2007

Watanabe

Tokyo

Murai

Hokkaido


Ley’s Attempts on the Direct Coupling

Complex ‘Right’ to Simple ‘Left’

Complex ‘Left’ to Simple ‘Right’

Ley, S. V. Pure Appl. Chem. 2005, 77, 1115.


Ways to Go

Dead Ends

Detour

Connect the two parts through other functional groups and then close the desired bondintramolecularly!

Introduce this bond in an earlier step of the synthesis!

Prof. Ley & Prof. Nicolaou & Prof. Murai

Prof. Watanabe


First Participant — Watanabe

1) Watanabe, H.; Watanabe, T.; Mori, K. Tetrahedron 1996, 52, 13939.

2) Watanabe, H.; Watanabe, T.; Mori, K.;Kitahara, T. Tetrahedron Lett. 1997, 38, 4429.

3) Watanabe, H.; Mori, N.; Itoh, D.; Kitahara, T. Angew. Chem. Int. Ed. 2007, 46, 1512.


Watanabe’s Model

Watanabe, H.; Mori, N.; Itoh, D.; Kitahara, T.; Mori, K. Angew. Chem. Int. Ed. 2007, 46, 1512.


Tandem Radical Cyclization

Watanabe, H.; Watanabe, T.; Mori, K.; Kitahara, T.Tetrahedron Lett.1997, 38, 4429.


Murai’s Model Study

Ireland – Claisen Rearrangement

1) Ishihara, J.; Fukuzaki, T.; Murai, A. Tetrahedron Lett. 1999, 40, 1907.

2) Yamamoto, Y.;Ishihara,J.; Kanoh,N.; Murai, A. Synthesis2000, 1894.

3) Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.


Ireland-Claisen Rearrangement

Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.


Diastereoselectivity

Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.


K. C. Nicolaou’s Model Study

2002

Radical

2002

Organometallic

2005

2003


From Radical Chemistry

Nicolaou, K. C.;Follmann,M.; Roecker, A. J. Angew. Chem. Int. Ed. 2002, 41, 2103.


From Organometallic Chemistry

Nicolaou, K. C.;Roecker, A.; J Follmann,M. Angew. Chem. Int. Ed. 2002, 41, 2107.


Greatest Challenge: C8-C14 Bond

Azadirachtin

Nicolaou

Ley

Murai

Watanabe

Brief Summary


1986

1968

1986

1996

1996

2006

2006

2007

2007

Story Line

Total Synthesis


Relay Study

Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633.


Back to ‘Azadirachtin’

Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633.


Retrosynthetic Analysis

Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.


Left ‘Shoulder’

Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.


Right ‘Arm’

Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.


Total Synthesis

Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.


Total Synthesis

Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.


Introduction

Dead Ends and Detours – An Example

Total Synthesis of Azadirachtin

Summary

Acknowledgement

Contents


Summary

Isolation and Structure Determination (18 years)

Total Synthesis (22 years)

Total Yield: 0.00015%

Ley and More Than 35 Co-workers

71 Steps (longest linear sequence 48 steps)


Summary

Logic!

Convergence!

Accuracy!

Beginning !

Detours?

Dead Ends ?


Introduction

Dead Ends and Detours – An Example

Total Synthesis of Azadirachtin

Summary

Acknowledgement

Contents


Acknowledgement

Prof. Yang & Prof. Chen

Prof. Shi & Prof. Yu

All the Members of Our Lab

All theAudience


No Dead Ends

Less Detours

More success!!!


Thank You!!!


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