Total Synthesis of Ingenol€¦ · Synthetic Approaches toward Ingenol A time axis: Numerous...

Total Synthesis of Ingenol

Reporter: Yong Lu

Supervisors: Prof. Yang

Prof. Chen

Prof. Tang

2012.12.07

1. Introduction

2. Synthetic Approaches toward Ingenol

3. Summary

4. Acknowledgements

Contents

1

1. Introduction

2. Synthetic Approaches toward Ingenol

3. Summary

4. Acknowledgements

Contents

2

Introduction

Ingenol: isolated from the genus Euphorbia

(大戟属) in 1968 by Hecker

Remarkable Biological Properties:

antitumor

anti-leukemic

anti-HIV properties

Synthetic Challenges:

highly strained in-out stereochemistry of the bicyclo[4.4.1] system

cis-triol of the AB ring

Ingenol

3

Introduction

Park, C. H.; Simmons, H. E. J. Am. Chem. Soc. 1972, 94, 7184.

Small or common-sized rings

Medium (7- to 12- membered) and large rings

Gassman, P. G.; Thummel, R. P. J. Am. Chem. Soc. 1972, 94, 7183.

Gassman, P. G.; Korn, S. R.; Thummel, R. P. J. Am. Chem. Soc. 1974, 96, 6948

4

Introduction

Simmons, H. E.; Park, C. H. J. Am. Chem. Soc. 1968, 90, 2428.

First introduced for bridged bicyclic compounds by Simmons

macrocyclic diamine

(k, l, and m: 6-10)

In-out isomerism:

5

Introduction

In-out isomerism:

bicyclo[4.4.1] undecane

In-out isomerism in Natural Products:

out-out isomer:

no bioactivity

Kato, T.; Hirukawa, T.; Uyehara, T.; Yamamoto, Y. Tetrahedron Lett. 1987, 28, 1439.

Hirukawa, T.; Shudo, T.; Kato, T. J. Chem. Soc., Perkin Trans. 1 1993, 217.

Kato, T.; Hirukawa, T.; Yamamoto, Y. J. Chem. Soc., Chem. Commun. 1987, 977

Hirukawa, T.; Koarai, A.; Kato, T. J. Org. Chem. 1991, 56, 4520.

6

Introduction

Key Players in the Ingenol Field

Core Synthesie:

Total Synthesis:

2004

Wood

total synthesis of (+) - ingenol

2004

Cha

tetracyclic ring system

1987

Winkler

1st tricyclic ring system

2000

Kigoshi

tricyclic ring system

1993

Funk

1st tetracyclic ring system

2001

Wood

tetracyclic ring system

2002

Rigby

tricyclic ring System

2002

Winkler

1st total synthesis of (±) ingenol

2003

Kuwajima

total synthesis of (±) ingenol

2004

Kigoshi

formal synthesis of (+) - ingenol

1997

Kuwajima

tetracyclic ring system

2005

Winkler

tricyclic ring system

2004

Grainger

tricyclic ring system

7

1. Introduction

2. Synthetic Approaches toward Ingenol

3. Summary

4. Acknowledgements

Contents

8

1993

Funk: 1st

tetracyclic ring system

2002

Winkler: 1st

racemic synthesis

2003

Kuwajima: 2nd

racemic synthesis

2004

Wood: 1st

asymmetric synthesis

2004

Kigoshi: Formal

asymmetric synthesis

2002

Rigby:

tricyclic ring system

1968

Hecker: isolation

and characterization

Synthetic Approaches toward Ingenol

A time axis:

Numerous reports on core strategies

9

2002

Winkler: 1st

racemic synthesis

2003

Kuwajima: 2nd

racemic synthesis

2004

Wood: 1st

asymmetric synthesis

2004

Kigoshi: Formal

asymmetric synthesis

1968

Hecker: isolation

and characterization

Synthetic Approaches toward Ingenol

A time axis:

Numerous reports on core strategies

1993

Funk: 1st

tetracyclic ring system

2002

Rigby:

tricyclic ring system

10

Concept:

Funk’s Core Synthesis

Claisen-Ireland Rearrangement

Funk, R. L.; Olmstead, J. A.; Parvez, M.; Stallman, B. J. J. Org. Chem. 1993, 58, 5873. 11

Funk’s Core Synthesis

Claisen-Ireland

Rearrangement 1st tetracyclic ring system

Funk, R. L.; Olmstead, J. A.; Parvez, M.; Stallman, B. J. J. Org. Chem. 1993, 58, 5873. 12

2002

Winkler: 1st

racemic synthesis

2003

Kuwajima: 2nd

racemic synthesis

2004

Wood: 1st

asymmetric synthesis

2004

Kigoshi: Formal

asymmetric synthesis

1968

Hecker: isolation

and characterization

Synthetic Approaches toward Ingenol

A time axis:

Numerous reports on core strategies

2002

Rigby:

tricyclic ring system

1993

Funk: 1st

tetracyclic ring system

1993

Funk: 1st

tetracyclic ring system

13

Rigby’s Core Synthesis

Strategy:

1, 5-H shift

Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799.

out/out in/out

out/out in/out

14

Rigby’s Core Synthesis

Alkoxide-accelerated [1,5]-hydrogen shift

out/out

in/out

not

Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799. 15

2004

Wood: 1st

asymmetric synthesis

2004

Kigoshi: Formal

asymmetric synthesis

1968

Hecker: isolation

and characterization

Synthetic Approaches toward Ingenol

A time axis:

Numerous reports on core strategies

2003

Kuwajima: 2nd

racemic synthesis

2002

Winkler: 1st

racemic synthesis

1993

Funk: 1st

tetracyclic ring system

1993

Funk: 1st

tetracyclic ring system

2002

Rigby:

tricyclic ring system

16

Winkler’s racemic synthesis

De Mayo Reaction

Intramolecular dioxenone/alkene [2+2] Photocycloaddition-Fragementation Sequence

pseudo boat

pseudo chair 1st tricyclic ring system

Winkler, J. D.; Henegar, K. E. J. Am. Chem. Soc. 1987, 109, 2850. 17

Winkler’s racemic synthesis

Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T.

J. Am. Chem. Soc. 2002, 124, 9726.

Advanced Cycloaddtion Precursor

dioxenone moiety

--- a locked enol tautomer of the β-keto ester

allows further functional groups transformation

Advantages of This Precursor:

A ring

--- higher facial selectivity in the cycloaddition step

Cl subtituent

--- facilitate the introduction of D ring

18

Winkler’s racemic synthesis

Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T.

J. Am. Chem. Soc. 2002, 124, 9726. 19

Winkler’s racemic synthesis

Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T.

J. Am. Chem. Soc. 2002, 124, 9726.

43 steps

average 80% per step

20

2002

Winkler: 1st

racemic synthesis

2004

Wood: 1st

asymmetric synthesis

2004

Kigoshi: Formal

asymmetric synthesis

1968

Hecker: isolation

and characterization

Synthetic Approaches toward Ingenol

A time axis:

Numerous reports on core strategies

2003

Kuwajima: 2nd

racemic synthesis

1993

Funk: 1st

tetracyclic ring system

1993

Funk: 1st

tetracyclic ring system

2002

Rigby:

tricyclic ring system

21

Kuwajima’s racemic synthesis

Hypothetical Pathway to Ingenane Carbocycle

pinacol rearrangement

Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I.

J. Am. Chem. Soc. 2003, 125, 1498.

22

Kuwajima’s racemic synthesis

Advantageous to Induce the Desired Transformation:

two reaction sites are located closely

facile generation of the cationic species

broaden the bond angle to favor a larger ring cyclization

regenerate the C=C bond for attachment of the D ring

Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I.

J. Am. Chem. Soc. 2003, 125, 1498.

23

Kuwajima’s racemic synthesis

weak LA strong LA

Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I.

J. Am. Chem. Soc. 2003, 125, 1498.

24

Kuwajima’s racemic synthesis

Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I.

J. Am. Chem. Soc. 2003, 125, 1498.

Preparation of the Ring Cyclization Precursor

25

Kuwajima’s racemic synthesis

Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I.

J. Am. Chem. Soc. 2003, 125, 1498.

Construction of Ingenane Tetracarbocycle

--- Tandem Cyclization/Deprotonation Methodology

26

pinacol

rearrangement

Kuwajima’s racemic synthesis

Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I.

J. Am. Chem. Soc. 2003, 125, 1498.

27

Kuwajima’s racemic synthesis

Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I.

J. Am. Chem. Soc. 2003, 125, 1498.

28 45 steps, 0.1%

2002

Winkler: 1st

racemic synthesis

2003

Kuwajima: 2nd

racemic synthesis

2004

Wood: 1st

asymmetric synthesis

1968

Hecker: isolation

and characterization

Synthetic Approaches toward Ingenol

A time axis:

Numerous reports on core strategies

2004

Kigoshi: Formal

asymmetric synthesis

2002

Rigby:

tricyclic ring system

1993

Funk: 1st

tetracyclic ring system

1993

Funk: 1st

tetracyclic ring system

29

RCM Strategy toward the Stained Trans-Fused BC Ring Syntem

Kigoshi Wood

D ring --- improve the diastereoselectivity of alkylation

A ring --- constrain the flexible conformation of the pendant

side chain, bring closer the terminal olefins

C6-substituent --- prevent the competing ROM

Watanabe, K.; Suzuki, Y.; Aoki, K.; Sakakura, A.; Suenaga, K.; Kigoshi, H. J. Org. Chem. 2004, 69, 7802.

Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L.

J. Am. Chem. Soc. 2004, 126, 16300.

Synthetic Approaches toward Ingenol

30

Funk’s keto ester

Wood’s asymmetric synthesis

Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L.

J. Am. Chem. Soc. 2004, 126, 16300.

Funk’s keto ester

31

Wood’s asymmetric synthesis

Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L.

J. Am. Chem. Soc. 2004, 126, 16300.

32 steps

0. 2% overall yield

32

Kigoshi’s formal synthesis

Watanabe, K.; Suzuki, Y.; Aoki, K.; Sakakura, A.; Suenaga, K.; Kigoshi, H.

J. Org. Chem. 2004, 69, 7802.

8 steps

12.5%

Funk’s keto ester

Winkler’s aldehyde

33

1. Introduction

2. Synthetic Approaches toward Ingenol

3. Summary

4. Acknowledgements

Contents

34

Summary

Winkler

[2+2] Photocycloaddition

-Fragementation

Funk

Claisen-Ireland Rearrangement

Rigby

1,5-Hydrogen Migration Kuwajima

Cyclization-Pinacol

Rearrangement

Kigoshi and Wood

RCM

35

Acknowledgements

Prof. Zhen Yang, Prof. Jiahua Chen and Prof. Yefeng Tang

Dr. Tianwen Sun, Mr. Dongdong Liu

All members in our lab

Everyone here

36

Thanks for your attention！

Acknowledgements