Marker degradation
Encyclopedia
The Marker degradation is a three-step synthetic route
in steroid
chemistry developed by American chemist Russell Earl Marker in 1938–40. It is used for the production of cortisone
and mammalian sex hormones (progesterone
, estradiol
, etc.) from plant steroids, and established Mexico
as a world center for steroid production in the years immediately after World War II
. The discovery of the Marker degradation allowed the production of substantial quantities of steroid hormones for the first time, and was fundamental in the development of the contraceptive pill and corticosteroid
anti-inflammatory
drugs. In 1999, the American Chemical Society
and the Sociedad Química de México
named the route as a National Historic Chemical Landmark.
The first large-scale application of the route took place in 1943, when Russell Earl Marker collected 10 tons of yam
tuber
s to synthesize 3 kilograms (6.6 lb) of progesterone
, which was the largest single amount of progesterone that had been produced by that time. That single batch had a value of US
$240,000 (approximately $3 million in 2009) at the time it was synthesized.
The discovery of the Marker degradation led to the development of a fine chemical
industry in Mexico
which, starting from scratch and in less than ten years, supplied more than half the human sex hormones sold in the United States. The booming industry caused a huge expansion in chemical education in Mexico.
) was directed towards finding synthetic routes to steroid hormones from "relatively inexpensive starting materials". While working on a series of plant steroids called sapogenin
s, he realized that the structure of the side chainSteroids are characterized by four fused rings of carbon atoms (three six-membered rings and one five-membered ring). Many steroids also have a "side chain" of carbon atoms, usually attached to the five-membered ring. of one of the compounds, sarsasapogenin
, had been incorrectly described in the literature: rather than having an unreactive "double-tetrahydrofuran
" side chain, it actually had a much more reactive "ketone
spiro
acetal
" side chain. While the ketone spiro acetal was unreactive in basic or neutral conditions, it could be degraded
under acidic conditions: indeed, Marker described it as "unusually reactive". In showing the true nature of the sarsasapogenin side chain, Marker had discovered the first of the steps in what would become known as the Marker degradation.
Sarsasapogenin was too expensive to be a commercial precursor to other steroids, so Marker set about looking for richer sources of sapogenins which were more closely related to progesterone. He identified one candidate in Trillium erectum
("Beth root" or "Wake-robin"), a sapogenin called diosgenin
which had previously been found in Japan
ese yam
s (Dioscorea tokoro
). Marker showed that both sarsasapogenin and diosgenin could be converted into both progesterone and other steroid hormones.Although it wasn't known at the time, the use of progesterone
as a precursor for other steroid hormones closely mimics the biosynthetic
pathway. Human males synthesize progesterone as a precursor to testosterone
, and human females synthesize testosterone as a precursor to the various estrogen
s. Cortisone
is also sythesized from progesterone in the human body, as in the industrial process developed after the discovery of the Marker degradation. The quantities of diosgenin that could be extracted from T. erectum were still unsatisfactory, so Marker looked for richer sources. He eventually hit upon another species of Dioscorea
, a Mexican
yam known locally as cabeza de negro,Not to be confused with the fruit known as cabeza de negro or ilama
(Annona purpurea
). whose tuber
s were reported to grow up to 100 kg (220 lbs) in weight.
The first step is the reaction that led Marker to discover that the sapogenins had a ketone spiro acetal structure in their side chain. Acetals are inert in basic conditions, but can be hydrolysed in acidic conditions. Marker uses acetic anhydride
to block the hydroxyl group formed by opening the six-membered pyran
ring.
The five.-membered furan ring is then oxidatively opened with chromic acid
. This forms the acetyl side chain of progesterone and an esterified hydroxyl group on the steroid nucleus.
The ester is then hydrolyzed under strongly basic conditions. The use of ethanol
ic sodium hydroxide leads to the elimination of water to form a double bond.
The resulting 3-hydroxypregna-5,16-dien-20-one can be converted into progesterone
in four steps involving the hydrogenation of the double bond in the five-membered ring, the oxidation of the hydroxyl group and the shifting of the other double bond from ring B to ring A. It can also be converted into testosterone
, estrone
and estradiol
.
, a leading American pharmaceutical company now part of Pfizer
. However, Marker realized that it made more sense commercially to produce steroids in Mexico, near to the raw material (Mexican Dioscorea sp.; D. mexicana
would come to be the preferred species), than to ship the tubers back to the United States. Parke-Davis did not believe that it was scientifically feasible to operate a fine chemicals production facility in Mexico, and the collaboration foundered. Instead, Marker decided to look for Mexican partners himself, and resigned his academic post on December 1, 1943. One consequence of this split was that the Marker degradation was never patent
ed.
Marker set up a Mexican company – Syntex
Now part of Hoffmann–La Roche. – in early 1944 in association with two Mexican investors, Emeric Somlo and Federico Lehmann. Marker is said to have partly paid for his 40% stake in Syntex with progesterone, then valued at about $80/gram. Within the year, Syntex was selling progesterone for $50/gram. However Marker split with his partners in May 1945 in a row over profits, and set up a new company called Botanica-mex, which would later be sold to Gedeon Richter Ltd.
and renamed Hormonosynth (later Diosynth).
The difficulties in fine chemicals manufacture in Mexico were indeed considerable: there was a severe shortage of trained chemists and indeed no doctoral program
in chemistry at any Mexican university. When Marker left Syntex, his associates found no instructions for the production process and reagent bottles labeled in code. They hired George Rosenkranz
, a Hungarian organic chemist trained at the Swiss Federal Institute of Technology
(ETH Zürich) who had been stranded in Cuba
by the entry of the United States into World War II, to replace Marker. Rosenkranz would have to virtually reinvent the production process for progesterone from diosgenin: he also established an Institute of Chemistry at the National Autonomous University of Mexico
, where one of the first research students was Luis E. Miramontes
, later to become a pivotal researcher at Syntex.
Rosenkranz also hired foreign talent for Syntex, including the Austria
n Jewish refugee (and naturalized
American) Carl Djerassi
and the Uruguay
an Alejandro Zaffaroni
. In 1951, Djerassi, Miramontes and Rosencranz synthesized norethindrone at Syntex, the first orally active progesterone analog and a vital ingredient of the first oral contraceptive pills. By this time, Syntex and its Mexican competitors (including Percy Lavon Julian, the first African-American chemist inducted into the U.S. National Academy of Sciences
) were supplying more than half the human sex hormones sold in the United States,The availability of (relatively) cheap progesterone in (relatively) large quantities created a market, and had the effect of spurring other manufacturers to improve their production processes for steroid hormones: this is best seen in the case of cortisone
, where Merck's
original 36-step synthesis from ox
bile
was improved to remain competitive with cortisone prepared from Mexican yams. and the price of progesterone had dropped to $2/gram. Fortune
ran a story that same year (1951) headlined "Syntex makes the biggest technological boom ever heard south of the border": by 1999, and with the benefit of hindsight, this was considered to be an understatement by the American Chemical Society
, not least because of the truly global impact of the Syntex production and research. The impact of the Syntex research can be seen from in the authoritative 1959 monograph Steroids by Louis
and Mary Fieser: Syntex accounted for 30% of all papers cited from industrial laboratories.
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
in steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
chemistry developed by American chemist Russell Earl Marker in 1938–40. It is used for the production of cortisone
Cortisone
Cortisone is a steroid hormone. It is one of the main hormones released by the adrenal gland in response to stress. In chemical structure, it is a corticosteroid closely related to corticosterone. It is used to treat a variety of ailments and can be administered intravenously, orally,...
and mammalian sex hormones (progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
, estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
, etc.) from plant steroids, and established Mexico
Mexico
The United Mexican States , commonly known as Mexico , is a federal constitutional republic in North America. It is bordered on the north by the United States; on the south and west by the Pacific Ocean; on the southeast by Guatemala, Belize, and the Caribbean Sea; and on the east by the Gulf of...
as a world center for steroid production in the years immediately after World War II
World War II
World War II, or the Second World War , was a global conflict lasting from 1939 to 1945, involving most of the world's nations—including all of the great powers—eventually forming two opposing military alliances: the Allies and the Axis...
. The discovery of the Marker degradation allowed the production of substantial quantities of steroid hormones for the first time, and was fundamental in the development of the contraceptive pill and corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
drugs. In 1999, the American Chemical Society
American Chemical Society
The American Chemical Society is a scientific society based in the United States that supports scientific inquiry in the field of chemistry. Founded in 1876 at New York University, the ACS currently has more than 161,000 members at all degree-levels and in all fields of chemistry, chemical...
and the Sociedad Química de México
Sociedad Química de México
The Chemical Society of Mexico is a learned society based in Mexico which supports scientific inquiry and education in the field of chemistry....
named the route as a National Historic Chemical Landmark.
The first large-scale application of the route took place in 1943, when Russell Earl Marker collected 10 tons of yam
Yam (vegetable)
Yam is the common name for some species in the genus Dioscorea . These are perennial herbaceous vines cultivated for the consumption of their starchy tubers in Africa, Asia, Latin America and Oceania...
tuber
Tuber
Tubers are various types of modified plant structures that are enlarged to store nutrients. They are used by plants to survive the winter or dry months and provide energy and nutrients for regrowth during the next growing season and they are a means of asexual reproduction...
s to synthesize 3 kilograms (6.6 lb) of progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
, which was the largest single amount of progesterone that had been produced by that time. That single batch had a value of US
United States dollar
The United States dollar , also referred to as the American dollar, is the official currency of the United States of America. It is divided into 100 smaller units called cents or pennies....
$240,000 (approximately $3 million in 2009) at the time it was synthesized.
The discovery of the Marker degradation led to the development of a fine chemical
Fine chemicals
Fine chemicals are pure, single chemical substances that are commercially produced with chemical reactions for highly specialized applications. Fine chemicals produced can be categorized into active pharmaceutical ingredients and their intermediates, biocides, and specialty chemicals for technical...
industry in Mexico
Mexico
The United Mexican States , commonly known as Mexico , is a federal constitutional republic in North America. It is bordered on the north by the United States; on the south and west by the Pacific Ocean; on the southeast by Guatemala, Belize, and the Caribbean Sea; and on the east by the Gulf of...
which, starting from scratch and in less than ten years, supplied more than half the human sex hormones sold in the United States. The booming industry caused a huge expansion in chemical education in Mexico.
Early development
Marker's research at Pennsylvania State College (now Pennsylvania State UniversityPennsylvania State University
The Pennsylvania State University, commonly referred to as Penn State or PSU, is a public research university with campuses and facilities throughout the state of Pennsylvania, United States. Founded in 1855, the university has a threefold mission of teaching, research, and public service...
) was directed towards finding synthetic routes to steroid hormones from "relatively inexpensive starting materials". While working on a series of plant steroids called sapogenin
Sapogenin
Sapogenins are the aglycones, or non-saccharide, portions of the family of natural products known as saponins. Sapogenins contain steroid or other triterpene frameworks as their key organic feature. For example, steroidal sapogenins like tiggenin, neogitogenin, and tokorogenin have been isolated...
s, he realized that the structure of the side chainSteroids are characterized by four fused rings of carbon atoms (three six-membered rings and one five-membered ring). Many steroids also have a "side chain" of carbon atoms, usually attached to the five-membered ring. of one of the compounds, sarsasapogenin
Sarsasapogenin
Sarsasapogenin is a steroidal sapogenin, that is the aglycosidic portion of a plant saponin. It is named after sarsaparilla , a family of climbing plants found in subtropical regions. It was one of the first sapogenins to be identified, and the first spirostan steroid to be identified as such...
, had been incorrectly described in the literature: rather than having an unreactive "double-tetrahydrofuran
Tetrahydrofuran
Tetrahydrofuran is a colorless, water-miscible organic liquid with low viscosity at standard temperature and pressure. This heterocyclic compound has the chemical formula 4O. As one of the most polar ethers with a wide liquid range, it is a useful solvent. Its main use, however, is as a precursor...
" side chain, it actually had a much more reactive "ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
spiro
Spiro
Spiro or Spyro may refer to:* ARA Spiro , the corvette of the Argentine Navy named after Samuel Spiro, a Greek tanker in service 1974-75* Spiro Agnew, thirty-ninth Vice President of the United States* Spiro curves, i.e...
acetal
Acetal
An acetal is a molecule with two single-bonded oxygen atoms attached to the same carbon atom.Traditional usages distinguish ketals from acetals...
" side chain. While the ketone spiro acetal was unreactive in basic or neutral conditions, it could be degraded
Chemical decomposition
Chemical decomposition, analysis or breakdown is the separation of a chemical compound into elements or simpler compounds. It is sometimes defined as the exact opposite of a chemical synthesis. Chemical decomposition is often an undesired chemical reaction...
under acidic conditions: indeed, Marker described it as "unusually reactive". In showing the true nature of the sarsasapogenin side chain, Marker had discovered the first of the steps in what would become known as the Marker degradation.
Sarsasapogenin was too expensive to be a commercial precursor to other steroids, so Marker set about looking for richer sources of sapogenins which were more closely related to progesterone. He identified one candidate in Trillium erectum
Trillium erectum
Trillium erectum, also known as Wake-robin, red trillium, purple trillium, Beth root or Stinking Benjamin, is a spring-flowering perennial plant native to the east and north-eastern areas of North America. The flowers are a deep red colour, and the plant takes its name Wake-robin by analogy with...
("Beth root" or "Wake-robin"), a sapogenin called diosgenin
Diosgenin
Diosgenin, a steroid sapogenin, is the product of hydrolysis by acids, strong bases, or enzymes of saponins, extracted from the tubers of Dioscorea wild yam, such as the Kokoro...
which had previously been found in Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
ese yam
Yam (vegetable)
Yam is the common name for some species in the genus Dioscorea . These are perennial herbaceous vines cultivated for the consumption of their starchy tubers in Africa, Asia, Latin America and Oceania...
s (Dioscorea tokoro
Dioscorea
Dioscorea is a genus of over 600 species of flowering plants in the family Dioscoreaceae, native throughout the tropical and warm temperate regions of the world. The vast majority of the species are tropical, with only a few species extending into temperate climates...
). Marker showed that both sarsasapogenin and diosgenin could be converted into both progesterone and other steroid hormones.Although it wasn't known at the time, the use of progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
as a precursor for other steroid hormones closely mimics the biosynthetic
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
pathway. Human males synthesize progesterone as a precursor to testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
, and human females synthesize testosterone as a precursor to the various estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
s. Cortisone
Cortisone
Cortisone is a steroid hormone. It is one of the main hormones released by the adrenal gland in response to stress. In chemical structure, it is a corticosteroid closely related to corticosterone. It is used to treat a variety of ailments and can be administered intravenously, orally,...
is also sythesized from progesterone in the human body, as in the industrial process developed after the discovery of the Marker degradation. The quantities of diosgenin that could be extracted from T. erectum were still unsatisfactory, so Marker looked for richer sources. He eventually hit upon another species of Dioscorea
Dioscorea
Dioscorea is a genus of over 600 species of flowering plants in the family Dioscoreaceae, native throughout the tropical and warm temperate regions of the world. The vast majority of the species are tropical, with only a few species extending into temperate climates...
, a Mexican
Mexico
The United Mexican States , commonly known as Mexico , is a federal constitutional republic in North America. It is bordered on the north by the United States; on the south and west by the Pacific Ocean; on the southeast by Guatemala, Belize, and the Caribbean Sea; and on the east by the Gulf of...
yam known locally as cabeza de negro,Not to be confused with the fruit known as cabeza de negro or ilama
Ilama (fruit)
The ilama is a tropical fruit tree found in Central America. The name is derived from the Spanish from the Nahuatl ilamatzapotl, of which the rough translation is "old woman's sapote". The name is also applied to a similar fruit, soncoya or cabeza de negro The ilama (also known as the tree of...
(Annona purpurea
Annona purpurea
Annona purpurea is an edible fruit and medicinal plant in the Annonaceae family. It is native to Mexico, Central America, and parts of South America. Its common names include soncoya, sincuya, and cabeza de negro. It is a tree reaching 6 to 10 meters in maximum height. It has hairy leaves and...
). whose tuber
Tuber
Tubers are various types of modified plant structures that are enlarged to store nutrients. They are used by plants to survive the winter or dry months and provide energy and nutrients for regrowth during the next growing season and they are a means of asexual reproduction...
s were reported to grow up to 100 kg (220 lbs) in weight.
Route from diosgenin
As with much steroid chemistry, the Marker degradation relies heavily on kinetic control to degrade the sapogenin side chain while leaving similar functional groups on the steroid nucleus (relatively) unaffected.The first step is the reaction that led Marker to discover that the sapogenins had a ketone spiro acetal structure in their side chain. Acetals are inert in basic conditions, but can be hydrolysed in acidic conditions. Marker uses acetic anhydride
Acetic anhydride
Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula 2O. Commonly abbreviated Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis...
to block the hydroxyl group formed by opening the six-membered pyran
Pyran
In chemistry, a pyran, or oxine, is a six-membered heterocyclic, non-aromatic ring, consisting of five carbon atoms and one oxygen atom and containing two double bonds. The molecular formula is C5H6O. There are two isomers of pyran that differ by the location of the double bonds...
ring.
The five.-membered furan ring is then oxidatively opened with chromic acid
Chromic acid
The term chromic acid is usually used for a mixture made by adding concentrated sulfuric acid to a dichromate, which may contain a variety of compounds, including solid chromium trioxide. This kind of chromic acid may be used as a cleaning mixture for glass. Chromic acid may also refer to the...
. This forms the acetyl side chain of progesterone and an esterified hydroxyl group on the steroid nucleus.
The ester is then hydrolyzed under strongly basic conditions. The use of ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
ic sodium hydroxide leads to the elimination of water to form a double bond.
The resulting 3-hydroxypregna-5,16-dien-20-one can be converted into progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
in four steps involving the hydrogenation of the double bond in the five-membered ring, the oxidation of the hydroxyl group and the shifting of the other double bond from ring B to ring A. It can also be converted into testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
, estrone
Estrone
Estrone is an estrogenic hormone secreted by the ovary as well as adipose tissue.Estrone is one of several natural estrogens, which also include estriol and estradiol...
and estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
.
Mexican steroid industry
Marker's early developmental work was supported by Parke-DavisParke-Davis
Parke-Davis is a subsidiary of the pharmaceutical company Pfizer. Although no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history.- History :...
, a leading American pharmaceutical company now part of Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
. However, Marker realized that it made more sense commercially to produce steroids in Mexico, near to the raw material (Mexican Dioscorea sp.; D. mexicana
Dioscorea mexicana
Mexican yam or barbasco de placa is a species of yam in the genus Dioscorea. It ranges from the state of Veracruz in Mexico south to Panama. It is notable for its production of diosgenin, which is a precursor for the synthesis of hormones such as progesterone. Russell Marker developed the...
would come to be the preferred species), than to ship the tubers back to the United States. Parke-Davis did not believe that it was scientifically feasible to operate a fine chemicals production facility in Mexico, and the collaboration foundered. Instead, Marker decided to look for Mexican partners himself, and resigned his academic post on December 1, 1943. One consequence of this split was that the Marker degradation was never patent
Patent
A patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....
ed.
Marker set up a Mexican company – Syntex
Syntex
Laboratorios Syntex SA was a pharmaceutical company formed in Mexico City in 1944 by Russell Marker to manufacture therapeutic steroids from the Mexican yam....
Now part of Hoffmann–La Roche. – in early 1944 in association with two Mexican investors, Emeric Somlo and Federico Lehmann. Marker is said to have partly paid for his 40% stake in Syntex with progesterone, then valued at about $80/gram. Within the year, Syntex was selling progesterone for $50/gram. However Marker split with his partners in May 1945 in a row over profits, and set up a new company called Botanica-mex, which would later be sold to Gedeon Richter Ltd.
Gedeon Richter Ltd.
Gedeon Richter Plc. , the largest pharmaceutical factory in Hungary, was established by Mr. Gedeon Richter, a pharmacist in 1901. Mr. Richter is not only the founder of the company, but the establishment of his firm also marked the beginning of the development of the Hungarian pharmaceutical industry...
and renamed Hormonosynth (later Diosynth).
Doctor of Philosophy
Doctor of Philosophy, abbreviated as Ph.D., PhD, D.Phil., or DPhil , in English-speaking countries, is a postgraduate academic degree awarded by universities...
in chemistry at any Mexican university. When Marker left Syntex, his associates found no instructions for the production process and reagent bottles labeled in code. They hired George Rosenkranz
George Rosenkranz
George Rosenkranz is a Mexican scientist in steroid research and a professional bridge player. He was born in Hungary, educated in Switzerland and lived in Mexico for 66 years...
, a Hungarian organic chemist trained at the Swiss Federal Institute of Technology
ETH Zurich
The Swiss Federal Institute of Technology Zurich or ETH Zürich is an engineering, science, technology, mathematics and management university in the City of Zurich, Switzerland....
(ETH Zürich) who had been stranded in Cuba
Cuba
The Republic of Cuba is an island nation in the Caribbean. The nation of Cuba consists of the main island of Cuba, the Isla de la Juventud, and several archipelagos. Havana is the largest city in Cuba and the country's capital. Santiago de Cuba is the second largest city...
by the entry of the United States into World War II, to replace Marker. Rosenkranz would have to virtually reinvent the production process for progesterone from diosgenin: he also established an Institute of Chemistry at the National Autonomous University of Mexico
National Autonomous University of Mexico
The Universidad Nacional Autónoma de México is a university in Mexico. UNAM was founded on 22 September 1910 by Justo Sierra as a liberal alternative to the Roman Catholic-sponsored Royal and Pontifical University of Mexico The Universidad Nacional Autónoma de México (UNAM) (National Autonomous...
, where one of the first research students was Luis E. Miramontes
Luis E. Miramontes
Luis Ernesto Miramontes Cárdenas , was a Mexican chemist known as the co-inventor of the progestin used in one of the first two oral contraceptives....
, later to become a pivotal researcher at Syntex.
Rosenkranz also hired foreign talent for Syntex, including the Austria
Austria
Austria , officially the Republic of Austria , is a landlocked country of roughly 8.4 million people in Central Europe. It is bordered by the Czech Republic and Germany to the north, Slovakia and Hungary to the east, Slovenia and Italy to the south, and Switzerland and Liechtenstein to the...
n Jewish refugee (and naturalized
Naturalization
Naturalization is the acquisition of citizenship and nationality by somebody who was not a citizen of that country at the time of birth....
American) Carl Djerassi
Carl Djerassi
Carl Djerassi is an Austrian-American chemist, novelist, and playwright best known for his contribution to the development of the first oral contraceptive pill . Djerassi is emeritus professor of chemistry at Stanford University.He participated in the invention in 1951, together with Mexican Luis E...
and the Uruguay
Uruguay
Uruguay ,officially the Oriental Republic of Uruguay,sometimes the Eastern Republic of Uruguay; ) is a country in the southeastern part of South America. It is home to some 3.5 million people, of whom 1.8 million live in the capital Montevideo and its metropolitan area...
an Alejandro Zaffaroni
Alejandro Zaffaroni
Alejandro Zaffaroni is a serial entrepreneur who is responsible for founding several successful biotechnology companies in Silicon Valley....
. In 1951, Djerassi, Miramontes and Rosencranz synthesized norethindrone at Syntex, the first orally active progesterone analog and a vital ingredient of the first oral contraceptive pills. By this time, Syntex and its Mexican competitors (including Percy Lavon Julian, the first African-American chemist inducted into the U.S. National Academy of Sciences
United States National Academy of Sciences
The National Academy of Sciences is a corporation in the United States whose members serve pro bono as "advisers to the nation on science, engineering, and medicine." As a national academy, new members of the organization are elected annually by current members, based on their distinguished and...
) were supplying more than half the human sex hormones sold in the United States,The availability of (relatively) cheap progesterone in (relatively) large quantities created a market, and had the effect of spurring other manufacturers to improve their production processes for steroid hormones: this is best seen in the case of cortisone
Cortisone
Cortisone is a steroid hormone. It is one of the main hormones released by the adrenal gland in response to stress. In chemical structure, it is a corticosteroid closely related to corticosterone. It is used to treat a variety of ailments and can be administered intravenously, orally,...
, where Merck's
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
original 36-step synthesis from ox
Ox
An ox , also known as a bullock in Australia, New Zealand and India, is a bovine trained as a draft animal. Oxen are commonly castrated adult male cattle; castration makes the animals more tractable...
bile
Bile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
was improved to remain competitive with cortisone prepared from Mexican yams. and the price of progesterone had dropped to $2/gram. Fortune
Fortune (magazine)
Fortune is a global business magazine published by Time Inc. Founded by Henry Luce in 1930, the publishing business, consisting of Time, Life, Fortune, and Sports Illustrated, grew to become Time Warner. In turn, AOL grew as it acquired Time Warner in 2000 when Time Warner was the world's largest...
ran a story that same year (1951) headlined "Syntex makes the biggest technological boom ever heard south of the border": by 1999, and with the benefit of hindsight, this was considered to be an understatement by the American Chemical Society
American Chemical Society
The American Chemical Society is a scientific society based in the United States that supports scientific inquiry in the field of chemistry. Founded in 1876 at New York University, the ACS currently has more than 161,000 members at all degree-levels and in all fields of chemistry, chemical...
, not least because of the truly global impact of the Syntex production and research. The impact of the Syntex research can be seen from in the authoritative 1959 monograph Steroids by Louis
Louis Fieser
Louis Frederick Fieser was an organic chemist, professor, and in 1968, professor emeritus at Harvard University. He was renowned as the inventor, in 1943, of a militarily effective form of napalm...
and Mary Fieser: Syntex accounted for 30% of all papers cited from industrial laboratories.