Chemistry 125: Lecture 75
April 29, 2011
Review:
Synthesis of Cortisone,
a Natural Product
This
For copyright
notice see final
page of this file
CH2OH
CH3 CO
OH
O
H
CH3
H
H
O
based on Fieser & Fieser
Advanced Organic Chemistry
Reinhold (1961) pp. 594-599
Louis F. Fieser
(1899-1977)
Cortisone
Mikael Häggström
Steroid work was awarded four Nobel Prizes between 1927 and 1950.
Closely related work earned another three between 1965 and 1975.
The awards in 1927 and 1928 were for determiningwrong
the structure.
http://nobelprize.org
http://nobelprize.org
Philip Hench Nobel Address
http://nobelprize.org
Philip Hench Nobel Address
Reichstein
Cf Lect 6511 slide 3
O
+
H2N-NH-C-CH2-N(CH3)3
O
HO-C-CH3
+
H2N-NH-R
H2NNH2
O
+
EtO-C-CH2-N(CH3)3
Tadeus Reichstein Nobel
Address
N(CH
3)3
P/Cl2
O
Cl-C-CH2-Cl
EtOH
O
EtO-C-CH2-Cl
http://nobelprize.org
Fishhook to Extract Ketones :
17
Cortisol (hydrocortisone)
11
http://nobelprize.org
29 Steroids
from
5 were
Adrenal
Previously
Cortex
Known
CH2OH
CH3 CO
OH
O 11
H
O
H
http://nobelprize.org
H
CH3
Woodward "Total" Synthesis (1951)
CH2OH
CH3 CO
OH
O
H
CH3
H
O
H
O
O
CH3
CH3
H
CH3O
CH3O
H
Diels-Alder
O
O
known and
readily available
Zn:
O
“handle” H
CH113CO
OH
for
C=O
CH
CH CO
3
2
D?
C
O
Zn
3
OH
hemiaceta
l
OH
D?
+
CH3O
+
D?
C
not oneH OH
of these?
“handle” to
modify D
H
C
CH3
O
CH2OH
CH3 CO
OH
O
A
reduction
+
H+/H2O
H
"Total" Synthesis
Woodward (1951)
LiAlH4
Why lose OH
OH allylic
the top OH
H
CH3
rearrangement
H
“handle”trans
for B
Ac2O
3
Redox
C
Analysis
CH O
H
O
CH3
D?
C
D?
C
cis
H+
CH3
CH3O
H
CH3
+2
OH-
D?
C
C
O
via enolate
D
H
H
B
H
trans
Robinson
annulation
CH3
C
-
-
O
B
C
H
(ketal)
CH3
C
O
protection
for D?
H2 / Pd
O
H
B
O
CH2OH
CH3 CO
OH
O
H
"Total" Synthesis
Woodward (1951)
O
D?
H
D?
C
OH
H+ O=C(CH3)2
O
D?
H
D?
B
Protecting C=C
CH3
OH
H
O
addition
“handle”CH
3
O
for A
C
H
O
(1,4 or conjugate)
“handle”
for 11C=O
OsO4
H
B
enolate
“Michael”
-
O
D?
H
aldol
CH3
C
CH3
A
O
D
H
H
B
H
CH3
C
D?
H
CH3
B
O
H
O
O
CH2OH
Abbreviate Ring D
CH3 CO
OH
O
(while we work on A)
"Total" Synthesis
Woodward (1951)
C
CH3
A
O
D
H
H
B
H
"vinylogous”
H

H
CH3
C
Protect
the more
H
CH3
H
B
O
H H
reactive
 position
CH3
C
-B
H
:
O
H
H
N
O
H
N(CH3)Ph
OH
N(CH3)Ph
H
CH2OH
O
CH3
ready for
aldol to A
CH3
LORE!
CH3
closer
OCH3
H-N(CH3)Ph
to 11C=O
C
CH3 H
B
B
H
O
H
C
B ketone
like(catalytic)
aldol C
-unsaturated
(also an enamine)
N(CH3)Ph
like Claisen
O
O
conjugate
addition
OH-
H
B
H O-
CH3
C
N
H
O

B
O
-
CH3
CH3 CO
OH
O
"Total" Synthesis
Woodward (1951)
C
CH3
A
O
D
H
H
B
H
CH3
CH3
C
Protect
the more
H
CH3
H
B
reactive
 position
CH3
C
CH3
C
N
H
-B
conjugate
addition
(catalytic)
O
O
C
CH3
OH- (strong)
B
O
O
CH3
N(CH3)Ph
H2O
CH3
CH3MgBr
H
N(CH3)Ph
H
lose
CH3
H
O
O
H
H
B
C
N
N(CH3)Ph
H
CH3
OH-
H
C
H
CH3
A?
O
B
+
O
HO+H+H
CH3 enolate
"Total" Synthesis
Woodward (1951)
C
H+
H
CH3
CH3
C
H
H
B
+C O
H
CH2OH
+ +
H- O
HO
N
CH3 CO
OH
O
C
CH3
A
O
D
H
H
B
H
CH3
C
CH3
A
O
O
CH3
D?
H
B
O
H
O
CH2OH
now work on D
O
aldol
A all set
CH3 CO
OH
"Total" Synthesis
Woodward (1951)
C
CH3
A
O
D
H
H
B
H
O
CH3
H+
D?
H2O
-H2O
OH
hydrolyze H
acetal
new “acetal”
O
CH3
A
D
H
H D?
B
HO
BH4- / resolved
reduces(1909 method)
ketone
(or "Relay")
not ester
CH3 C H
1) K2Cr2O7
O
H
O
CH3
base
O
aldol
(luck)
H
not
H
O
O
pericyclic
D!
2) CH2=N2
O
H
-IO3-
O
CH3
CH3 C-OH
C
precipitated 3
90%
H EtOH
CHfrom
3
I O
O
O
by natural “digitonin”
O
I OD?
OH O
H
H
This conversion was known from CH OH
2
previous cortisone studies!
Formal "Total" Synthesis
Woodward (1951)
CH3 CO
OH
O
C
CH3
A
O
D
H
H
B
H
J. Am. Chem. Soc.
O
H2
1) NaBH4
Pd
2) Ac2O
HO
45678
Intellectual/Artistic Problem Solved
But What Was the Yield?
Sequential (39 steps @ 80%) 0.01% yield
Convergent
9
9
9
9
(4x9 steps + 2)
A
B
E
Product
C
D
9% yield
F
Cortisone Synthesis (Practical)
Br
Br
?
?
?
from ox bile
O
Br
1946-49
Merck made
1 kg cortisone
from 600 kg
of this bile acid
properly
methylated
tetracyclic
carbon
skeleton
1949
Merck
$200/gm
with proper
stereochemistry
at key positions
and functional
groups at or near
some of the
proper positions
Choose an appropriate,
readily available
starting material.
but
Cortisone Synthesis (Practical)
Russell Marker
Abundant in
a Mexican yam
(1943) 10 tons
Pregnancy
hormone
~1955
$0.48/gm
3 kg ($250,000)
1954 Strychnine Synthesis
“Woodward’s style is polished showing an insight and
Nobel
"for his
achievements
sense(1965)
of proportion
thatoutstanding
afford him strong
convictions, and
indramatic
the art of
organic
synthesis”
. (1969)
a well developed
sense.”
Bartlett,
Westheimer, Büchi
Photos courtesy M. Saunders
M. Saunders
Vitamin B12
V. Kisakürek H.C.A.
(1973)
Robert Burns
Woodward
(1917-1979)
Harvard
During this work RBW
discovered control of
stereochemistry by
orbital symmetry
(pericyclic reactions)
Albert
with ~100 co-workers
including…
Eschenmoser
ETH Zurich
WOODWARD, PURE APPL CHEM 25: 283 (1971)
postdoctoral Woodward collaborator
Yoshito Kishi
(instructor Nagoya Univ.)
Kishi joined and then succeeded Woodward as professor at Harvard.
Palytoxin
Kishi et al. 1994
62 Stereogenic Centers
1020 stereoisomers
7 E/Z Double Bonds
C123H213NO53
Convergent from 8 Pieces
42 Functional Groups
Protected 8 Different Ways
The FDA approved Eribulin for metastatic
breast cancer on November 15, 2010
HO
O
HO
H
H
Active Fragment
of Halichondrin B
OMe
Me
OH
O
O
O
H
O
O
H
O
H2N
O
O
H
SAR
O
O
O
halichondrin B C.1-C.38 macrolide
Me
H
H
O O
O O
Me
H
O
O
H
O
H
O
"Simplified" Version
of Active Fragment
is Drug Candidate
E7389
E7389
"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.Davis
K. Yoshimatsu, Y. Kishi, M.J. Yu, and B.A. Littlefield, Cancer Res., February 1, 2001; 61(3): 1013-1021
~ 100,000 configurational isomers!
Organic Synthesis has come
a long way from urea.
To Berzelius (1828)
"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."
Friedrich Wöhler
(1800-1882)
C. L. Berthollet
“a tall, thin man with
a small head, a strong
J. L. Gay-Lussac
nose, ice-gray hair,
J. Liebig
and a thin beard”
K. Schmid
W. Ostwald
J. J. Berzelius
Thanks
&
Credits
F. Woehler
R. Fittig
I. Remsen
E. P. Kohler
T. R. Williams
T. W. Richards
G. C. Maxfield
J. B. Conant
L. F. Fieser
P. D. Bartlett
Connecticut Science
Teachers Association
Review at Class Time Monday
in 110 SCL
Good Luck on the Final Exam
w
April 29, 2011
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