Biotechnol. J. 2008, 3, 449–451
com
Biotech History
Mexico, the father of the pill and the race for cortisone
The son of
Jewish
physicians,
Carl Djerassi
(born 1923),
grew up in
pre-war
Vienna and
fled the Nazis
in 1938.
When he was 16 years old, he
arrived in New York penniless.
A few years later, he graduated
Phi Beta Kappa from Kenyon
College in Ohio. His first job
was as a junior chemist with the
Swiss pharmaceutical company
CIBA, where he was part of the
team discovering the antihista-
mine pyribenzamine. He ob-
tained his PhD at the Universi-
ty of Wisconsin and then went
to work at a little known Syntex
lab in Mexico City. This Mexi-
can lab became a center of
steroid research and synthesis
within a short time. They joined
the worldwide race to synthe-
size cortisone. It was here, that
Djerassi directed the synthesis
of the first oral contraceptive
for women and became known
throughout the world as the
‘Father of the birth-control
pill’.
In the following, Carl Dje-
rassi describes the exciting
hunt for cortisone (extracted
Carl Djerassi at
Syntex with his
assistant Arelina
Gomez.
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Mexican yams
Carl Djerassi with Alejan-
dro Zaffaroni pointing at
the key chemical feature
of all steroid contracep-
tives.
and shortened from two of his
memoirs by me RR):
The telegram dated 8 June 1951,
bore the name of Tadeusz Reich-
stein, who the year before had
shared the Nobel Prize in medi-
cine for his isolation and structur-
al elucidation of cortisone. The
telegram – sent from Basel to
Mexico City, then the site of tiny
Syntex, S. A.-said only, “No de-
pression.”
It signified that the melting
point of the authentic steroid, iso-
lated by Reichstein from adrenal
glands, was not depressed when
mixed with the synthetic speci-
men we had dispatched to
Switzerland. (In 1951, a “mixed
melting point” was one of the
standard ways of establishing
identity between two crystalline
chemicals.)
Thus, our unknown research
group – the oldest member of
which, was, at age thirty-four, sev-
en years my senior – won the race.
www.biotechnology-journal.
BTJ-FORUM
Those were the days of unre-
strained optimism, when corti-
sone was believed to be a wonder
drug for treating arthritis and
other inflammatory diseases.
Philip Hench, one of Reichstein’s
fellow Nobel Prize winners from
the Mayo Clinic, had shown
movies in 1949 of helpless arthrit-
ics receiving cortisone and then,
in days, getting up to dance. The
only problem was that cortisone
cost nearly $200 per gram, and
depended on not readily available
starting material: slaughterhouse
animals. In 1944, it had taken
Lewis H. Sarett of Merck & Com-
pany in Rahway, New Jersey, 36
chemical steps to synthesize cor-
tisone from cattle bile. Thus, a po-
tentially unlimited source for cor-
tisone was needed: if not through
total synthesis – building from
scratch from air, coal or petrole-
um, and water – then through
partial synthesis, starting with a
naturally occurring steroid and
449
 Biotechnology
Journal
transforming it chemically into
BTJ-FORUM
cortisone. Sarett had prepared the
first few grams of cortisone by
such a partial synthesis – some-
what akin to the conversion of a
barn into a villa, the bile acid be-
ing his barn, cortisone his villa.
Here I shall try to emulate Ein-
stein’s dictum: “We should make
things as simple as possible, but
not simpler.” The starting materi-
al our Syntex team chose, as a
more widely available alternative
to Sarett’s bile acid, was dios-
genin.
At first glance, the choice
seems to make neither chemical
nor geographical sense. While its
chemical structure does contain
the four rings typical of steroids,
diosgenin is burdened by extra-
neous chemical appendixes, en-
compassed by two more rings at-
tached to positions 16 and 17 (see
Figure, rings E and F).
Diosgenin, however, had been
the raison d’être for Syntex’s for-
mation just a few years earlier. In
the late 1930s and early 1940s,
Russell E. Marker, a brilliant
but unorthodox chemistry pro-
fessor at Pennsylvania State Uni-
versity, conducted research on a
group of steroids called “sa-
pogenins,” compounds of plant
origin socalled because their
chemical combination with sug-
ars (termed “saponins”) display
soaplike qualities in aqueous sus-
pension. Natives of Mexico and
Central America, where saponin-
containing plants occur wildly
and in abundance, had long used
them for doing laundry and to kill
fish. Marker concentrated on the
chemistry of the steroid sa-
pogenin diosgenin, which was
present in certain types of inedi-
ble yams growing wild in Mexico.
He discovered an exceedingly
simple process whereby the two
complex rings (for us, molecular
garbage) could be degraded to a
substance then easily trans-
formed chemically into the fe-
male sex hormone progesterone.
450 © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
The press conference announcing the first syn-
thesis of cortisone from a plant source at Syntex
im Mexico City, 1951. Left to right: Gilbert Storck,
Juan Pataki, George Rosenkranz, Enrique Batres,
Juan Berlin, Carl Djerassi, and Rosa Yashin.
In 1944, unable to convince
any American pharmaceutical
firm of the commercial potential
of diosgenin, Marker formed a
small Mexican company named
Syntex (from Synthesis and Mex-
ico).
A few months later, Syntex
started to sell to other pharma-
ceutical companies pure, crys-
talline progesterone prepared
from diosgenin by partial synthe-
sis in five steps. Within a year the
partners had a disagreement, and
Marker left the company … His
partners Emeric Somlo and Fe-
derico Lehmann, looking for an-
other chemist who could re-es-
tablish the manufacture of prog-
esterone from diosgenin at
Syntex, recruited Dr. George
Rosenkranz from Havana. A
Hungarian like Somlo, Rosen-
kranz had received his doctorate
under the Nobel laureate Leo-
pold Ruzicka (one of the giants of
early steroid chemistry) and read
Marker’s publications.
Within two years, Rosenkranz
had not only reinstituted at Syn-
tex the large-scale manufacture
of progesterone from diosgenin
but, even more important, had
achieved the large-scale synthe-
sis, from these same Mexican
yams, of the commercially more
valuable male sex hormone
testosterone. Both syntheses were
so much simpler than the meth-
ods used by the European
pharmaceutical companies -such
Biotechnol. J. 2008, 3, 449–451
as CIBA, then dominating the
steroid hormone field- that in a
short while, tiny Syntex broke the
international hormone cartel. As
a result, prices were lowered con-
siderably, and these hormones
became much more available.
In the late 1940s, Syntex
served as bulk supplier to phar-
maceutical companies through-
out the world, but few people out-
side these firms even knew of the
existence of this small chemical
manufacturing operation in Mex-
ico City, which was soon to revolu-
tionize steroid chemistry and the
steroid industry all over the
world. By the spring of 1951, how-
ever, everyone was taking at least
one Mexican coup seriously. By
then our Syntex team had pub-
lished a “Communication” in the
JACS. Another “Communication”
recorded our discovery of a novel
path to the characteristic ring-A
structure of cortisone or of other
hormones, such as progesterone,
from an intermediate that was
particularly suitable to steroidal
sapogenin precursors such as
diosgenin.
At this point, we moved into
the two-shift mode, which led to
the synthetic crystals that were
shipped to Reichstein in Switzer-
land. Within hours of the arrival
of the “no depression” telegram, I
wrote the first draft of our “Com-
munication” entitled “Synthesis of
Cortisone.”
Our successful synthesis of
cortisone from diosgenin had
permanently placed Mexico on
the map of steroid research. It
was, moreover, Upjohn’s require-
ments for tons of progesterone – a
quantity that at that time could be
satisfied only from diosgenin –
that started Syntex on the way to
becoming a pharmaceutical giant.
The process was accelerated by
our synthesis – a few months
later, again in Mexico City – of the
first oral contraceptive. Reich-
stein’s telegram, “No depression,”
of just a few months earlier ap-
Biotechnol. J. 2008, 3, 449–451
plied to cortisone, but not to us.
We were elated: Que viva México!
Life magazine featured our
team, most in immaculate white
lab coats, grouped around a
gleaming glass table and appar-
ently mesmerized by an enor-
mous yam root, which over-
whelmed the molecular model of
cortisone lying next to it.
Rosenkranz held a test tube, filled
almost to the brim with white
crystals – the chemist’s equivalent
of the climber’s flag on top of
Mount Everest. For the photogra-
pher’s benefit, the tube had been
filled with ordinary table salt, be-
cause at that time we had synthe-
sized only milligram quantities of
cortisone.
Ironically, none of the corti-
sone triumphs from our laborato-
ry and those of our competitors at
Harvard and Merck that appeared
in the August 1951 issue of the
Journal of the American Chemistry
Society contributed to the treat-
ment of a single arthritic patient
because of the appearance of a
newcomer, whose participation in
the race was not even known. A
few months after our publication,
Syntex’s management received
an inquiry from the Upjohn Com-
pany of Kalamazoo (in South
Africa), asking whether we could
supply them with 10 tons of prog-
esterone.
Since the world’s entire annu-
al production at that time was
probably less than one-hun-
dredth that amount, such a re-
quest seemed outlandish. No one
in our group could conceive of a
medical application of proges-
terone that could require tons of
the stuff. We concluded that Up-
john was planning to use proges-
terone as a chemical intermediate
rather than as a therapeutic hor-
mone.
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Our conclusion proved correct
when, a few weeks later, we
learned through a patent issued
to Upjohn in South Africa (where
patents are granted much more
rapidly than in the United States)
that two of its scientists, Durey H.
Peterson and Herbert C. Mur-
ray, had made a sensational dis-
covery: fermentation of proges-
terone with certain microorgan-
isms resulting in an one-step key
transformation on the way to cor-
tisone.
What we chemists had accom-
plished laboriously through a se-
ries of complicated chemical con-
versions, Upjohn’s microorgan-
ism with its own enzymes did in a
single step!
Only a few months later,
Djerassi found solace by syn-
thesizing with Georg Rosen-
kranz and Luis E. Miramontes
the progestin norethindrone
which, unlike progesterone, re-
mained effective when taken
orally and was far stronger than
the naturally occurring hor-
mone. Djerassi remarked later
that “not in our wildest dreams
… did we imagine (it)”, though
he is now referred to as the Fa-
ther of the pill.
Author of over 1200 scientific pub-
lications and seven monographs,
Carl Djerassi is one of the few
American scientists to have been
awarded both the National Medal
of Science (1973, for the discovery
of oral contraceptives – ‘the pill’)
www.biotechnology-journal.com
and the National Medal of Technol-
BTJ-FORUM
ogy (in 1991, for promoting the new
approaches to insect control). He
was inducted into the National In-
ventors Hall of Fame. Since 1959,
Djerassi has been Professor of
Chemistry at Stanford University.
In his second career, multi-tal-
ent Djerassi has turned from prac-
ticing chemistry to writing five “sci-
ence-in fiction” novels. Recently he
has embarked on a trilogy of plays
with emphasis on contemporary
cutting-edge research in the bio-
medical sciences.
Cited Literature:
[1] Djerassi, C., The Pill, Pygmy Cimps,
and Degas Horse, BASICBOOKS, New
York 1992
[2] Djerassi, C., This Man’s Pill, Oxford
University Press, 2001. Excerpts
reprinted by permission of Oxford
University Press
www.djerassi.com
By Reinhard Renneberg, Hong Kong
E-mail: chrenneb@ust.hk
Reprinted with permission from
BIOTECHNOLOGY FOR BEGINNERS
Academic press (Elsevier),
New York 2007, 360 pp.,
ISBN-13: 978-0-12-373581-2
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