Total Synthesis of Platensimycin

Zhensheng Ding October 19 2007

Nicolaou, K. C. Angew. Chem. Int. Ed., 2006, 45, 7086-90 Nicolaou, K. C. Angew. Chem. Int. Ed., 2007, 46, 3942-5 Nicolaou, K. C. Angew. Chem. Int. Ed., 2007, 46, 4712-4 Nicolaou, K. C. Chem. Commun., 2007, 1922-3 Zou, Y.; Snider, B. Org. Lett., 2007, 9, 1825-8 Heretsch, P.; Giannis, A. Synthesis 2007, 2614-6 Ghosh, A. Org. Lett., 2007, 9, 4013-6 Kaliappan, K. P. and Ravikumar, V. Org. Lett., 2007, 9, 2417-9 Li, P.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9534 –5 Mulzer, J. Angew. Chem. Int. Ed. 2007, 46, 8074-5 Corey, E. J. Org. Lett., 2007, xxxx

O O

O

NH

HO

OH

COOH

Introduction

Super Drug: Platensimycin and Its Structure Features

http://www.chemistry.msu.edu/courses/cem958/FS06_SS07/irosha.pdf

O∗

∗

∗

∗

∗

O

O

NH

HO

OH

COOH

*

Tetracyclic motif Cage-like 6 chiral centers 3 tertiary carbons Ether linkage

Tetra-substituted resorcine Amino acid

Introduction

Outline

O

O

O

O

ketyl radical cyclization/ etherification

O O

OFnFn

O

H

FnFn

Fn= functional groups

O O

O

NH

HO

OH

COOH

amide bond formation

O O

O

H2N

HO

OH

COOH

OH +

O O

O

Fn Fn

Fn

Nicolaou

Introduction

NicolaouCorey

Nicolaou, K. C.; Angew. Chem., Int. Ed. 2002, 41, 996-1000.

Summary: Enone Synthesis from Ketone

Introduction

Summary: Enone Synthesis from Ketone

R

O

Base

TMSClR

OTMSPd(OAc)2 R

OPdOAc +TMSOAc

R R R

R

O

R

R

O

R

PhSeBr

BaseR

OSePh

R

OxidationR

OSePh

H

O

R

R

O

R

R

OOH

H

NaOHH2O

R

O

RR

Yamamoto

Nicolaou

Nicolaou

R

OOH

H

R

O

RRSnider

R

OOTf

HR

Tf2OBase

Base

Nicolaou’s

Nicolaou’ s Racemic Synthesis: Retrosynthesis

Nicolaou, K. C. Angew. Chem. Int. Ed., 2006, 45, 7086-90

O

O

Me

4

O

O

6

Synthesis

Nicolaou’s

92%, 1:1 diastereomeric ratio

89%, two steps 84%, two steps

68%, two steps85%

Nicolaou, K. C. Angew. Chem. Int. Ed., 2006, 45, 7086-90

Synthesis

Nicolaou’s

O

O

2.2 eq SmI2

1.5 eq (CF3)2CHOHTHF/ HMPA (10:1)-78 °C, 1min

O

14

OH

646%, ca. 2:1 d.r.

OSmI2

OSm (III) OSm (III) O

E+

H

E

R

RRh+

R

RRh+

R

[Rh]

R

Large-scale Synthesis of Monomer 5 of VAPOL

87%

88%

79%

85% 6:1 E/ Z

95% 95%

Nicolaou’s

Nicolaou, K. C. Angew. Chem. Int. Ed., 2006, 45, 7086-90

Nicolaou, K. C. Angew. Chem. Int. Ed., 2007, 46, 3942-5

Nicolaou’s

Nicolaou’ s Asymmetric Synthesis: Retrosynthesis

Xumu Zhang’s chemistry

A. G. Myers’s chemistry

Nicolaou’ s Asymmetric Synthesis

Nicolaou’s

91% 90%

49%, 3 steps 90%

Nicolaou, K. C. Angew. Chem. Int. Ed., 2007, 46, 3942-5

Summary

Pathway a) was able to scale up; expensive and toxic reagents; multiple step.

Cr(CO)6: $266/ 50g, toxic and carcinogen; BuLi: $107/ 800mL (2.5M), corrosive, highly sensitive to air

Pathway b) Moderate yield, one step synthesis; hard to purify, not suitable for old VAPOL synthesis.

Purpose: To find an efficient way to prepare both ligands with inexpensive starting materials.

How to optimize pathway b) ?

1)  Solvent---must be high bp, inert, easily removable;

2)  Lower the reaction temperature (base);

3)  None-toxic reagents;

4)  More efficient

Nicolaou’s

Nicolaou’ s Asymmetric Synthesis: Another Pathway

Redic, R.; Schuster, G. Journal of Photochemistry and Photobiology, A: Chemistry, 2006, 179, 66-74.

Nicolaou’s

100%

87%

91%

92%

94%

100%

90%

Nicolaou’s Analogues Synthesis: Adamantaplatensimycin

Nicolaou’s

Nicolaou, K. C. Angew. Chem. Int. Ed., 2007, 46, 4712-4

Nicolaou’s Analogues Synthesis: Adamantaplatensimycin

Nicolaou’s

Nicolaou, K. C. Angew. Chem. Int. Ed., 2007, 46, 4712-4

51%, 4 steps

65%

88%

86%

Resolution of 12

Nicolaou’s

Nicolaou, K. C. Angew. Chem. Int. Ed., 2007, 46, 4712-4

Outline

Outline

O O

OFnFn

O

H

FnFn

Fn= functional groups

O O

O

NH

HO

OH

COOH

amide bond formation

O O

O

H2N

HO

OH

COOH

OH +

Yamamoto: Asymmetric DA-Robinson Annulation Sequence

Yamamoto’s

OCHO

O

8

Michael addition

OCHO

O OCHO

O

O Oaldol

9O

O

Me9H2O

Yamamoto: Asymmetric DA-Robinson Annulation Sequence

Yamamoto’s

Yamamoto: Asymmetric DA-Robinson Annulation Sequence

Yamamoto’s

O

O

O

O

O

O

O

Baeyerrearrangement O

H

O

3 4

Yamamoto: Asymmetric DA-Robinson Annulation Sequence

Yamamoto’s

O O Michael addition

O O O O

O Oaldol

9O

O

Me9

NH

B:

O O

N N N

Ghosh: Intramolecular Diels-Alder Reaction Retrosynthesis

Ghosh’s (Purdue U.)

O

OMe

Me

EtO2C

Diels-AlderO

OMe

Me

EtO2CO CO2Et

OMe

3

O

(+)-6Hg(OAc)2, THF, H2ONaBH4, MeOH

HOO

6aO

OH6b

OOH

O

mCPBA

OOH

HOHOHO

OO

6c 6d 6e

mCPBA

KOH

Oxidation

O

H

OO 5

a) Srikrishna, A.; Hemamalini, P. J. Org. Chem. 1990, 55, 4883. (b) Weinges, K.; Reichert, H. Synlett 1991, 785. (c) Weinges, K.; et al Liebigs Ann. Chem. 1993, 403. (d) Weinges, K. et al Chem. Ber. 1994, 127, 549.

Ghosh: Intramolecular Diels-Alder Reaction

Ghosh’s (Purdue U.)

Ghosh, A. Org. Lett., 2007, 9, 4013-6

Ghosh’s (Purdue U.)

Continued…

39%

38%

Introduction

Outline

Fn= functional groups

O O

O

NH

HO

OH

COOH

amide bond formation

O O

O

H2N

HO

OH

COOH

OH +

O O

O

Fn Fn

Fn

Starting from decaline derivatives

Retrosynthetic Analysis: Summary

etherification

O

X

HO

ring closure

Mulzer's synthesis

CO2H

OMe

N2CH2TMS

O

O

Me

O O

etherification

O

E+

HO

O

O

O

HO

X

H

C-C bond formation

Kaliappan's synthesisNicolaou's synthesisSnider's synthesis

O

O

MeSN2 elimination

O

OH

E

O

OH

Eetherification

OH

HO

E+

Corey's synthesis

Corey’s Synthesis THF-ring construction first

Corey’s Synthesis Corey’s

Corey, E. J. Org. Lett., 2007, xxxx

Caron-ring construction first

O

O

Me

O O

etherification

O

E+

HO

O

O

O

HO

X

H

C-C bond formation

Kaliappan's synthesisNicolaou's synthesisSnider's synthesis

Nicolaou, K. C. Chem. Commun., 2007, 1922-3 Zou, Y.; Snider, B. Org. Lett., 2007, 9, 1825-8 Kaliappan, K. P. and Ravikumar, V. Org. Lett., 2007, 9, 2417-9

Nicolaou, K. C. Chem. Commun., 2007, 1922-3

Nicolaou’s Synthesis

Caron-ring construction first

64%

1) Protection 2) Oxidation (IBX)

86%

91%

85%

Kaliappan, K. P. and Ravikumar, V. Org. Lett., 2007, 9, 2417-9

Kaliappan’s Retrosynthesis

Caron-ring construction first

O

O

MeetherificationC-C bond formation

Kaliappan, K. P. and Ravikumar, V. Org. Lett., 2007, 9, 2417-9

Kaliappan’s Synthesis

Caron-ring construction first

Snider’s Retrosynthesis

Caron-ring construction first

Zou, Y.; Snider, B. Org. Lett., 2007, 9, 1825-8

C-C bond formation

C-C bond formation etherification

Snider’s Synthesis

Caron-ring construction first

Mulzer’s Synthesis

Caron-ring construction first

1) Mulzer, J. Angew. Chem. Int. Ed. 2007, 46, 8074-5 2) D. J. Beames, T. R. Klose, L. N. Mander, Aust. J. Chem. 1974, 27, 1269. 3) P. Anantha Reddy, G. S. Krishna Rao, Indian J. Chem. Sect. B 1981, 20, 100.

O

O

MeetherificationO

X

HO

ring closure

CO2H

OMe

N2CH2TMS

O O

Mulzer’s Synthesis

Caron-ring construction first

Mulzer, J. Angew. Chem. Int. Ed. 2007, 46, 8074-5

Conclusions

1) Nicolaou’s racemic: 10 steps, 11%;

2) Nicolaou’s asymmetric: 16 steps, 5.6% using chrial catalysis; 11 steps, chiral auxiliary;

3) Snider’s: 7 steps + equilibration + one step for conversion of a diasteromer, 32%;

4) Mulzer’s: protecting-group-free; 5 steps from 7 (overall yield 20%);

5) Corey’s: 14 steps, 25.6%; (calculated by meeeee!)

6) Kaliappan’s: 13 steps, 5.6%; (calculated by meeeee!)

7) Yamamoto’s: 8 steps + one step for conversion of a diasteromer, 18% (calculated by me! not sure!!!)

Total synthesis of platensimycin

O O

O

NH

HO

OH

COOH

Mulzer, J. Angew. Chem. Int. Ed. 2007, 46, 8074-5