Chemistry 125: Lecture 74 (and last!)

April 30, 2010

Review:Synthesis of Cortisone,

a Natural Product This

For copyright notice see final page of this file

Cortisone

based on Fieser & FieserAdvanced Organic ChemistryReinhold (1961) pp. 594-599

O

O

CH3

CH3

H

H H

OHCO

CH2OH

Louis F. Fieser (1899-1977)

htt

p://

no

bel

pri

ze.o

rg

Philip Hench Nobel Address

htt

p://

no

bel

pri

ze.o

rg

Philip Hench Nobel Address

htt

p://

no

bel

pri

ze.o

rg

Reichstein

Tadeus Reichstein Nobel Address

Fishhook to Extract Ketones :

H2N-NH-C-CH2-N(CH3)3

O+

H2N-NH-R+

EtO-C-CH2-N(CH3)3

O+

EtO-C-CH2-ClO

Cl-C-CH2-ClO

HO-C-CH3

O

H2NNH2

EtOHP/Cl2

N(CH3)3

htt

p://

no

bel

pri

ze.o

rg

5 were Previously

Known

Cortisol (hydrocortisone)

11

17

29 Steroids from

Adrenal Cortex

htt

p://

no

bel

pri

ze.o

rg

O

O

CH3

CH3

H

H H

OHCO

CH2OH

11

htt

p://

no

bel

pri

ze.o

rg

Woodward "Total" Synthesis (1951)

O

O

CH3

CH3

H

H H

OHCO

CH2OH

"Total" Synthesis Woodward (1951)

C D

BA

O

O

CH3

CH3

H

H H

OHCO

CH2OH

LiAlH4

reduction

D?C

O

CH3O

CH3

OH

D?C

O

CH3O

CH3

OH

OH

OH

D?C

CH3O

CH3

HOH

D?C

O

CH3

H

H+/H2O

OH

D?C

CH3O

CH3

HOH

CH3

C

O

CH3O

O

H

H

OH-

H

H+

+

D?C

O

CH3

H

Ac2O

Why losethe top OH

not one of these?hemiacetal

Diels-Alder

via enolate

OH allylic rearrangement

known andreadily available

+ +

CH3CO

Zn:+2

CH3CO2-

H+

cis

trans

trans

Zn

“handle”for B

“handle”for 11C=O

“handle” to modify D

Redox Analysis

D?C

O

CH3

H

"Total" Synthesis Woodward (1951)

C D

BA

O

O

CH3

CH3

H

H H

OHCO

CH2OH

D?C

O

CH3

H

OO

D?C

CH3

H

H

B

OsO4

O

D?C

CH3

H

H

B

OH

OH

O

D?C

CH3

H

H

B

O

O

H+ O=C(CH3)2

(ketal)

O

D?C

CH3

H

H

B

O

OH2 / Pd

enolate-

-

-

“Michael” (1,4 or conjugate)

addition

aldol

Robinson annulation

Robinson and Woodward after an MIT seminar on the Robinson annulation

(photo J.D. Roberts, 1951)

Protecting C=C

“handle”for A

“handle”for 11C=O

protection for D?

O

C

CH3

H

H

B

CH3

"Total" Synthesis Woodward (1951)

C D

BA

O

O

CH3

CH3

H

H H

OHCO

CH2OHO

D?C

CH3

H

H

B

O

O

Abbreviate Ring D(while we work on A)

Protectthe more

reactive position

"Total" Synthesis Woodward (1951)

C D

BA

O

O

CH3

CH3

H

H H

OHCO

CH2OH

O

C

CH3

H

H

B

CH3

O

C

CH3

H

H

B

CH3

N(CH3)PhHO

C

CH3

H

H

B

N(CH3)PhHN

CH3

C

-

-OH-

(catalytic)

NC

C

B

O

CH3

CH3

H

H

OCH3

conjugate addition

H-N(CH3)Ph

OB

H

OCH3

O

B

H O

OB

H OHO

N(CH3)Ph

- -

:

like aldol -unsaturated ketone(also an enamine)

like Claisen

HH

HH

"vinylogous”

H

LORE!

readyfor A

closerto 11C=O

H+

Protectthe more

reactive position

"Total" Synthesis Woodward (1951)

C D

BA

O

O

CH3

CH3

H

H H

OHCO

CH2OH

O

C

CH3

H

H

B

CH3

O

C

CH3

H

H

B

CH3

N(CH3)PhHO

C

CH3

H

H

B

N(CH3)PhHN

CH3

C

- OH-

(catalytic)

NC

OH- (strong)

H2O

ON

C

CH3

H

H

B

CH3

C OO

CH3MgBr H+C

B

O

CH3

CH3

H

H

OCH3

C

CH3

H

H

B

CH3

OO

conjugate addition

A?-

O

N(CH3)PhHlose

HOH+

++

H +H

+

HCH3enolate

"Total" Synthesis Woodward (1951)

CH3

O

C

B

O

CH3

CH3

H

H

D?

O

OA

aldol C D

BA

O

O

CH3

CH3

H

H H

OHCO

CH2OHnow work on D

A all set

"Total" Synthesis Woodward (1951)

CH3

H

D?

O

O

C D

BA

O

O

CH3

CH3

H

H H

OHCO

CH2OH

CH3

H

D?

OH

OH

H+

H2O

CH3

H

O

H

O H

CH3

H

D?

O

O

I

H

HO

O-

O

Formal (or "Relay")

This conversion was known from previous cortisone studies!

1) K2Cr2O7

OB

A

C-OHCH3

H

D

O

CH3 HC

BH4-

CCH3

H

D!

O

aldol

base

-H2O

I

OO-

O

O

H/ resolved (1909 method)

/ H2-cat

-IO3- pericyclic

H

2) CH2=N2

hydrolyze acetal

new “acetal”

reduces ketone

not ester

CH3

not(luck)

not

precipitated 3 from 90% EtOHby natural “digitonin”

J. Am. Chem. Soc.

H2

Pd

1) NaBH4

2) Ac2O

4 5 6 7 8

O

OH

But What Was the Yield?

Intellectual Problem Solved.

Sequential (40 steps @ 80%) 0.01% yield

Convergent (4x9 steps + 2) 9% yield99

99

A

B

C

D

Product

E

F

Cortisone Synthesis (Practical)

Choose an appropriate,readily availablestarting material.

properlymethylatedtetracyclic

carbonskeleton

with properstereochemistryat key positions

and functionalgroups at or near

some of the proper positions

but

from ox bile1946-49

Merck made 1 kg cortisonefrom 600 kg

of this bile acid

?

Br?Br

Br

?O

1949Merck

$200/gm

Cortisone Synthesis (Practical)

Pregnancyhormone

~1955$0.48/gm

Abundant ina Mexican yam

Russell Marker

Vitamin B12

(1973)

Albert Eschenmoser

ETH Zurich

Robert Burns Woodward

(1917-1979) Harvard

During this work RBW discovered control of stereochemistry by orbital symmetry(pericyclic reactions)

with ~100 co-workersincluding…

postdoctoral Woodward collaborator

Yoshito Kishi(instructor Nagoya Univ.)

WOODWARD, PURE APPL CHEM 25: 283 (1971)

Kishi joined and then succeeded Woodward as professor at Harvard.

Palytoxin 62 Stereogenic Centers

42 Functional GroupsProtected 8 Different Ways

Convergent from 8 Pieces

Kishi et al. 1994

1020 stereoisomers7 E/Z Double Bonds

C123H213NO53

E7389 being developed commercially for breast cancer by Eisai Pharmaceutical

O

O

O

O O

O

O

O

O

HO

HO

MeO

O

H

H H

MeH

H

H

O O

OMe

OO

O

O

O

OO

Me

HH

H

H

H2N

OH

E7389halichondrin B C.1-C.38 macrolide

"In Vitro and In Vivo Anticancer Activities of Synthetic Macrocyclic Ketone Analogues of Halichondrin B"M.J. Towle, K.A. Salvato, J. Budrow, B.F. Wels, G. Kuznetsov, K.K. Aalfs, S. Welsh, W. Zheng, B.M.Seletsky, M.H. Palme, G.J. Habgood, L.A. Singer, L.V. DiPietro, Y.Wang, J.J. Chen, D.A. Quincy, A.DavisK. Yoshimatsu, Y. Kishi, M.J. Yu, and B.A. Littlefield, Cancer Res., February 1, 2001; 61(3): 1013-1021

SARActive Fragment

of Halichondrin B

"Simplified" Versionof Active Fragmentis Drug Candidate

E7389

~ 100,000 configurational isomers!

Friedrich Wöhler(1800-1882)

Organic Synthesis has comea long way from urea.

"Perhaps you still remember the experiment I carried out in that fortunate time when I was working with you, in which I found that whenever one tries to react cyanic acid with ammonia a crystalline substance appears which is inert, behaving neither like cyanate nor like ammonia."

To Berzelius (1828)

Good Luck on the Final Exam

Review at Class Time Monday

End of Lecture 74April 30, 2010

Copyright © J. M. McBride 2010. Some rights reserved. Except for cited third-party materials, and those used by visiting speakers, all content is licensed under a Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0).

Use of this content constitutes your acceptance of the noted license and the terms and conditions of use.

Materials from Wikimedia Commons are denoted by the symbol .

Third party materials may be subject to additional intellectual property notices, information, or restrictions. 

The following attribution may be used when reusing material that is not identified as third-party content: J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0