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Marker degradation
The Marker degradation is a three-step synthetic route in steroid chemistry developed by American chemist Russell Earl Marker in 1938–1940. 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 an International Historic Chemical Landmark.
The first large-scale application of the route took place in 1943, when Russell Earl Marker collected 10 tons of yam tubers 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.
Marker's research at Pennsylvania State College (now Pennsylvania State University) was directed towards finding synthetic routes to steroid hormones from "relatively inexpensive starting materials". While working on a series of plant steroids called sapogenins, he realized that the structure of the side chain 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 Japanese yams (Dioscorea tokoro). Marker showed that both sarsasapogenin and diosgenin could be converted into both progesterone and other steroid hormones. 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, whose tubers were reported to grow up to 100 kg (220 lbs) in weight.
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 to block the hydroxyl group formed by opening the six-membered pyran ring.
The five-membered furan ring is then oxidatively opened with chromium trioxide. This forms the acetyl side chain of progesterone and an esterified hydroxyl group on the steroid nucleus.
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Marker degradation
The Marker degradation is a three-step synthetic route in steroid chemistry developed by American chemist Russell Earl Marker in 1938–1940. 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 an International Historic Chemical Landmark.
The first large-scale application of the route took place in 1943, when Russell Earl Marker collected 10 tons of yam tubers 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.
Marker's research at Pennsylvania State College (now Pennsylvania State University) was directed towards finding synthetic routes to steroid hormones from "relatively inexpensive starting materials". While working on a series of plant steroids called sapogenins, he realized that the structure of the side chain 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 Japanese yams (Dioscorea tokoro). Marker showed that both sarsasapogenin and diosgenin could be converted into both progesterone and other steroid hormones. 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, whose tubers were reported to grow up to 100 kg (220 lbs) in weight.
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 to block the hydroxyl group formed by opening the six-membered pyran ring.
The five-membered furan ring is then oxidatively opened with chromium trioxide. This forms the acetyl side chain of progesterone and an esterified hydroxyl group on the steroid nucleus.