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Robinson, Woodward and the synthesis of cholesterol
Robinson, Woodward and the synthesis of cholesterol Greg Mulheirn The synthesis of cholesterol is one of the great achievements of 20th century chemistry. However, its synthesis was reported almost simultaneously by two groups, those of Robinson in Oxford and of Woodward at Harvard. This article describes the race that developed between these two groups to be the first to succeed.
Cholesterol is a fundamental natural steroid found in all animal tissues. Its laboratory synthesis was one of the milestones in 20th century synthetic chemistry. Achieved simultaneously and independently in 1951 by Sir Robert Robinson in Oxford and R.B. Woodward at Harvard, it represented the culmination of many years of research into steroids. This research began in the 19th century with Chevreul’s attempts to characterize cholesterol isolated from gall stones. Woodward completed his synthesis in just over two years but Robinson’s interest in the problem stretched back to 1932, the year he was appointed to the Waynflete Chair at Oxford. In the early years of their research, Robinson and his group at Oxford made many significant contributions to synthetic organic chemistry. They laid the foundations for successful syntheses achieved later both in Oxford and elsewhere. 1941 was a turning point as John Cornforth, working with Robinson, made a breakthrough that opened the way to the final stage of the synthesis. After World War II, the synthesis project became more focused on the final goal and was completed by Cornforth and Robinson in 1951. Woodward’s synthesis coincided almost exactly with that of Cornforth and Robinson. Despite the complexity of the problem, Woodward was able to complete his project in a remarkably short period, which was testimony both to his brilliance and to the support his group received from the pharmaceutical industry. As the Woodward group realized that Robinson and Cornforth were also coming close to the complete synthesis, a ‘race’ mentality developed, which was particularly evident in the final stages before Woodward’s announcement at the Chemical Society in London in April 1951. It is no coincidence that one of the most significant chemical problems of the time drew the attention of two of the greatest chemists of the 20th century. Both men were attracted by the intricate polycyclic structure of the molecule and the synthetic challenges it presented. It was the most complex organic molecule to have been Greg Mulheirn Was educated at Lady Margaret Hall, Oxford and began research into the history of chemistry under Allan Chapman. He currently lives in Shanghai, where he works for ICI, studies Chinese and maintains an interest in the history of science.
synthesized up to that time and finding a synthetic route to it paved the way for the synthesis of many related steroid hormones. Robinson and Cornforth at Oxford Robinson’s researches into steroids was stimulated by a breakthrough in structural understanding by Rosenheim and King1. During the 1930s, his group experimented with various ways of building up the steroid skeleton. In 1941, a major breakthrough was made when Cornforth, with Rita Cornforth and Robinson, published a paper entitled ‘The preparation of -tetralone from -naphthol and some analogous transformations’2. Cornforth’s critical insight was that by using a little known hydrolysis developed by von Braun3 on a product from one of Robinson’s earlier experiments he might produce an intermediate that would provide a route to the complete synthesis. They subsequently converted a dihydro-derivative of 2:6dimethoxynaphthalene to the 6-methoxytetralone, and the analogous conversion was then performed on the 1:6dimethoxynaphthalene to give a tetralone from which Cornforth could see a route to the steroid nucleus. However, at this stage, work had to be suspended until after the war as Cornforth was asked to work on penicillin. When he was able to return to steroid synthesis, Cornforth’s next major achievement was the synthesis of the Reich diketone. This compound had been obtained from natural sources by Reich4 and so comparison with the natural product would enable the correct stereoisomer to be selected from the synthetic racemate. Cornforth and Robinson also hoped that sufficient quantity of the Reich diketone would be available from natural sources for it to be used for the next stage of the synthesis without having laboriously to synthesize a large quantity of it. Using a naturally available compound in this way is known as using a relay. The use of relays was important because, for every experiment that is successful, there are many that are not and so a large amount of substrate is needed at each stage in the synthesis. As the number of stages increases, more and more time has to be spent keeping the synthetic ‘front line’ supplied with the necessary substrate. Through the use of relays, they were able to save many valuable man-hours synthesizing substrate in the lab.
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It seems that, despite his brilliance, Robinson’s style of In 1946, Cornforth moved from Oxford. His deafness running the research program had the effect of slowing prevented him from taking on teaching responsibilities progress to some extent. In contrast to Woodward, within the University and so he moved to the National Robinson was at the end of his career as the head of a Institute for Medical Research at Mill Hill. The director, laboratory. He had been due to retire from the Waynflete Charles Harrington, allowed the collaboration with Chair of Chemistry in 1951. However, owing to the Robinson to continue and, throughout the late 1940s, disruption caused by World War II, he applied for and was there was copious correspondence between them and ocawarded an extension of four years. He liked to keep casional visits to Oxford by Cornforth (J.W. Cornforth, direct control of the projects that were being undertaken pers. commun.). Unfortunately, little of this correspondence in his lab and was always reluctant to delegate remains in the Robinson archive. responsibility even to experienced colleagues. This lack The practical work for the synthesis was mainly carried of autonomy led to a ‘brain drain’ of people with exout by Cornforth and his collaborators, although there perience in a specific area as they moved to other places were some disagreements with Robinson about strategy. where they could pursue their own The discovery that the Köster– interests14. Logemann (KL) ketone5 was availWoodward had a natural able in large quantities as a byRobinson also had a tendency to instinct for cultivating product of an industrial preparation dismiss ideas from senior colindustrial relations. of sex hormones led Robinson to leagues if he was thinking along think that it could be used as another different lines himself. He was relay. To do this, a method had to be found to convert constantly generating new ideas for synthetic routes but the Reich diketone to the KL ketone. Cornforth thought would often not pursue them when he came up against that this would be difficult and favoured a more direct obstacles, preferring to try a different idea. These two approach. However, they found a route using Birch6 and factors left the way open for other groups to improve on and extend his ideas, and to go on to achieve major Dauben’s7 conversion of cholestanone to cholesterol as a synthetic goals. For example, the synthesis of equilenin model. by Bachmann, Cole and Wilds15 was built on a step that The last part of the synthesis was the closure of the fourth ring starting from a derivative of the KL ketone. This was Robinson had discarded as being of little use because of achieved using the Arndt–Eistert and Blanc methods, reits low yield. Bachmann had developed the process, sulting in the formation of epiandrosterone acetate. Walden however, until it gave a yield sufficiently high to be of inversion at position 3 of epiandrosterone led to androsterpractical use in the synthesis. one, from which 2-bromoandrostanedione, androstenedione In fact, it was the synthesis of equilenin by Bachmann, and testosterone had already been obtained by Ruzicka, Cole and Wilds in 1937 that stimulated American interest Plattner and Aeschbacher8. From androstenedione, they in steroid synthesis. This was the first complete synthesis of a steroid and, moreover, it was the first major complete found a route to dehydroepiandrosterone, which they were synthesis of a natural product by an American group. As able to use as a relay, as it had been obtained from etioa result, it created significant interest, particularly in the bilienic acid by Kuwada and Nakamura9. USA. At this stage the medical importance of the steroid Butenandt and Schmidt-Thomé10 had already found a hormones was already appreciated, oestrogens, for exroute to 3-hydroxypregn-5-en-20-one. Robinson and his ample, being widely used. collaborators tried to introduce the alkyl side chain, charAfter World War II, the next major achievement in acteristic of cholesterol, at C22 but they were unsuccessful. steroid synthesis was the synthesis of oestrone by Anna Instead, they were able to introduce the required side chain and Miescher16 in 1948 in Switzerland. Oestrone was still into allopregnanolone (thus following Woodward et al.), which had already been obtained from 3-hydroxypregn-5an aromatic steroid, however, and the method used was en-20-one by Plattner, Heusser and Angliker11. By successfundamentally similar to that of Bachmann. The major goal in steroid synthesis was the non-aromatic steroid nucleus, fully achieving this, they obtained 3-acetoxycholestwith all its stereochemical complications. It was natural 17(20)-ene. They converted this to cholestanyl acetate, that Woodward, whose major interest was in synthesis, which they showed to be identical to a product derived should have addressed himself to this, the biggest problem from natural sources. From here, transformations to cholof the day, some time in 1948. estanol, cholestanone, cholest-4-enone and cholesterol were already well known. According to Cornforth, they became aware of the threat Woodward collaborating with industry at from Woodward and his group at Harvard in 1950. At this Harvard point, Cornforth persuaded Robinson to let him take over Woodward had a natural instinct for cultivating industrial the work entirely in the interests of speed. The preliminary relations. His steroid work benefited immensely from the notice of the total synthesis was published in Chemistry support of pharmaceutical companies, in terms of both and Industry in 195112, only a couple of weeks after funding and supply of raw materials and intermediates. Industrial interest in the project was easy to understand. Woodward’s announcement of his synthesis at the ChemiThe medical importance of steroids, particularly the sex cal Society Centenary Lecture (subsequently, preliminary hormones, had been demonstrated in the 1930s and they notice of the synthesis was published in the Journal of the were widely used in medicine. When, in 1949, Hench and American Chemical Society13).
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Kendall at the Mayo Institute demonstrated the dramatic effect that cortisone could have in the treatment of rheumatoid arthritis, the demand for this substance quickly outstripped supply. Steroids were big business in the pharmaceutical industry and a company that discovered viable ways to produce them stood to make huge profits. The fact that people were suffering from a crippling disease and could not be treated because of a short supply of the appropriate medicine was also a great incentive to find effective methods of production. At that time, steroids were produced by the chemical conversion of steroids extracted from natural sources. This was an extremely expensive process as the natural concentration of steroids is low. For example, the early production of cortisone was from cholic acid obtained from cattle, a method developed by Lew Sarrett (Merck and Co.), and required 40 cattle to produce 1 g of pharmaceutical grade cortisone – a daily dose. In 1949, a gram cost US$200 to produce. Although complete synthesis might require over 30 stages and, as a result, have a tiny yield, it was generally believed that, even so, it would provide a cheaper and quicker method of production of the drug. Research like Woodward’s was therefore given extremely high priority. The result was that Woodward was able to build up his steroid group relatively quickly. Merck provided him with funding for two postdoctoral fellows from 1949 and Monsanto funded another. Monsanto, to whom Woodward had acted as a consultant since 1948, were also invaluable when, in 1950, his group synthesized a tricyclic ketone that was to be a key intermediate to the final stages of the synthesis. Monsanto agreed to produce the intermediate on a pilot plant scale and supply it to Woodward. This gave Woodward a virtually unlimited supply of the tricyclic ketone and saved the group a large amount of time. Where Robinson and Cornforth had resorted to using relays, Woodward was able to rely on support from Monsanto. By funding Woodward, Monsanto and Merck were able to use the knowledge they gained from his research as a head start in developing their own processes for the production of useful compounds. Monsanto was particularly willing to provide intermediates for Woodward as it gave them the opportunity to begin working on the scaling up of a total synthesis to an industrial scale. They also had scientists closely following Woodward’s work and improving on the number of steps and the yields at each stage so as to optimize the process for industrial use. The synthesis itself13 used the CD→BCD→ABCD route rather than the BC→ABC→ABCD route used by Robinson. Woodward’s starting point was 2-methyl-5methoxy-1,4-quinone, which was to form ring C in the final structure. Ring D was neatly added using a Diels– Alder reaction. The closure of ring B and the introduction of the third chiral centre were achieved in the early part of 1950. In a letter in May of that year, Woodward suggested to Monsanto that they might be able to synthesize this intermediate in order to help with research into the final stages: ‘in order to make further progress efficiently, it has now become essential to carry out the early stages of the synthesis on a considerably larger scale than is feasible
Figure 1
The Robinson–Cornforth synthesis.
here in our laboratory.’17 Monsanto were able to scale up the process and were supplying the ketone to Woodward’s group by July. A key intermediate in the synthesis was obtained by Sondheimer on Christmas Day of 1950. Woodward’s high pressure style of leadership, combined with the sense of success being just around the corner, obviously led to irregular working hours. The compound was dubbed ‘Christmasterone’ by Woodward and he went on to develop several other syntheses from it. The final hurdle was the contraction of ring D from a six-membered to a five-membered ring. Treatment of Christmasterone with periodic acid in dioxane followed by heating the product in the presence of a catalytic amount of piperidine acetate gave DL-9(11),16-bisdehydro20-norprogesterone, from which a route to cholesterol was known. Competition It would seem that, in the last year or so of the total synthesis project, a strongly competitive spirit arose in the Woodward group with respect to Robinson and Cornforth. At the start of the project, the opinion was that Robinson would not complete the synthesis. He had been producing papers on the synthesis of steroids for almost 20 years and had yet to achieve the non-aromatic steroid nucleus. Coupled with the fact that he was close to retirement, the Woodward group doubted that he would be a threat. However, when Cornforth became involved, the prospect of Endeavour Vol. 24(3) 2000
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the Oxford team producing a synthesis was put back on the agenda. The Christmasterone story suggests the sense of urgency that was prevalent in the Harvard group. On 18 April 1951, Woodward left for England on a two month visit. He was due to give the Centenary Lecture of the Chemical Society, at Burlington House on 26 April, at which he intended to announce the total synthesis. This he did, and it appears to have stimulated Cornforth and Robinson into swiftly publishing a preliminary notice of their synthesis in Chemistry and Industry on 19 May. Woodward’s group seems to have been intending to publish their preliminary notice in June. On 26 May, Woodward sent a telegram to Sondheimer back in Harvard: ‘June communication urgent if at all possible. RR communication appeared here Tuesday… In view of urgency communication please phone me’. On 19 June, in the covering letter to the communication entitled The Total Synthesis of Cholesterol, Sondheimer wrote to Marshall Gates, the editor of the Journal of the American Chemical Society. ‘You probably know that Sir R. Robinson is also aiming at cholesterol, and due to the historic importance of this substance, I think it would be valuable to get the communication published as quickly as possible.’ The communication was published in July of 1951. Media response The fame of cortisone led to some media interest in the synthesis. Just over a year since cortisone had first appeared on the market, the shortage of cortisone led Merck to issue a memorandum at the beginning of March explaining the situation. ‘Before cortisone can be made in sufficient quantities, a new, more plentiful starting material will have to be found, or a complete synthesis discovered by the chemists and research workers.’18 This interest led to the heralding of the Woodward synthesis on American radio. ‘It now seems reasonable to expect mass production of this wonder-working hormone within a short time, as a result of the greatest international race in modern chemistry – the race to achieve the total synthesis of a steroid.’19 The only media interest when Cornforth and Robinson announced their synthesis was from a News of the World reporter who had noticed, and misunderstood, the term ‘sex hormones’. The story never made it to press.
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Summary The synthesis of the steroid nucleus was one of the major challenges in synthetic organic chemistry in the late 1940s. As such, Woodward found it impossible to resist. His synthesis is notable not only for its technical brilliance but also the speed with which it was completed. Woodward was a very fast worker and kept intense pressure on his group, which enabled the group to complete the synthesis in a remarkably short period of time. The other notable feature of Woodward’s work, which contrasts with Robinson’s, is Woodward’s relationship with industry. The industrial support that Woodward was able to raise, in terms of both funding postdoctoral fellows and also supplying raw materials and, most importantly, key intermediates, was essential for the steroid synthesis to have been completed on the timescale that it was. Without it, the synthesis would have taken much longer and Woodward would probably have had to resort to using relays in the synthesis, in the same way that Robinson did. References 1 Rosenheim, O. and King, H. (1932) Nature 130, 315 2 Cornforth, J.W. (1992) Selected Research Papers with Commentaries (Golding, B.T., ed.), p. 15, Pergamon Press 3 Von Braun (1930) Chem. Ber. 63, 3052 4 Reich (1945) Helv. Chim. Acta 28, 892 5 Koster and Logemann (1940) Chem. Ber. 73, 299 6 Birch, A. (1950) J. Chem. Soc. 2325 7 Dauben and Eastham (1950) J. Am. Chem. Soc. 72, 2305 8 Ruzicka et al. (1946) Helv. Chim. Acta 21, 886 9 Kuwada and Nakamura (1938) J. Pharm. Soc. Jpn 58, 235 10 Butenandt and Schmidt-Thomé (1939) Chem. Ber. 72, 182 11 Plattner et al. (1946) Helv. Chim. Acta 29, 468 12 Cardwell, H.M.E. et al. (1951) Chem. Ind. 389 13 Woodward, R.B. et al. (1952) J. Am. Chem. Soc. 74, 4223 14 Birch, A. (1995) To See the Obvious, American Chemical Society 15 Bachmann, W.E. et al. (1939) J. Am. Chem. Soc. 61, 974 16 Anner, G. and Miescher, K. (1948) Helv. Chim. Acta 31, 2073 17 Woodward, R.B. (1950) Letter to C.A. Hochwalt of Monsanto dated 4 May 18 Merck & Co. (1951) Memorandum on cortisone dated 1 March 19 American Chemical Society News Service (1951) Transcript of 191st of a series of weekly news broadcasts on station WNYC aired on 1 May at 5.30pm
Cholesterol is a fundamental natural steroid found in all animal tissues. Its laboratory synthesis was one of the milestones in 20th century synthetic chemistry. Achieved simultaneously and independently in 1951 by Sir Robert Robinson in Oxford and R.B. Woodward at Harvard, it represented the culmination of many years of research into steroids. This research began in the 19th century with Chevreul’s attempts to characterize cholesterol isolated from gall stones. Woodward completed his synthesis in just over two years but Robinson’s interest in the problem stretched back to 1932, the year he was appointed to the Waynflete Chair at Oxford. In the early years of their research, Robinson and his group at Oxford made many significant contributions to synthetic organic chemistry. They laid the foundations for successful syntheses achieved later both in Oxford and elsewhere. 1941 was a turning point as John Cornforth, working with Robinson, made a breakthrough that opened the way to the final stage of the synthesis. After World War II, the synthesis project became more focused on the final goal and was completed by Cornforth and Robinson in 1951. Woodward’s synthesis coincided almost exactly with that of Cornforth and Robinson. Despite the complexity of the problem, Woodward was able to complete his project in a remarkably short period, which was testimony both to his brilliance and to the support his group received from the pharmaceutical industry. As the Woodward group realized that Robinson and Cornforth were also coming close to the complete synthesis, a ‘race’ mentality developed, which was particularly evident in the final stages before Woodward’s announcement at the Chemical Society in London in April 1951. It is no coincidence that one of the most significant chemical problems of the time drew the attention of two of the greatest chemists of the 20th century. Both men were attracted by the intricate polycyclic structure of the molecule and the synthetic challenges it presented. It was the most complex organic molecule to have been Greg Mulheirn Was educated at Lady Margaret Hall, Oxford and began research into the history of chemistry under Allan Chapman. He currently lives in Shanghai, where he works for ICI, studies Chinese and maintains an interest in the history of science.
synthesized up to that time and finding a synthetic route to it paved the way for the synthesis of many related steroid hormones. Robinson and Cornforth at Oxford Robinson’s researches into steroids was stimulated by a breakthrough in structural understanding by Rosenheim and King1. During the 1930s, his group experimented with various ways of building up the steroid skeleton. In 1941, a major breakthrough was made when Cornforth, with Rita Cornforth and Robinson, published a paper entitled ‘The preparation of -tetralone from -naphthol and some analogous transformations’2. Cornforth’s critical insight was that by using a little known hydrolysis developed by von Braun3 on a product from one of Robinson’s earlier experiments he might produce an intermediate that would provide a route to the complete synthesis. They subsequently converted a dihydro-derivative of 2:6dimethoxynaphthalene to the 6-methoxytetralone, and the analogous conversion was then performed on the 1:6dimethoxynaphthalene to give a tetralone from which Cornforth could see a route to the steroid nucleus. However, at this stage, work had to be suspended until after the war as Cornforth was asked to work on penicillin. When he was able to return to steroid synthesis, Cornforth’s next major achievement was the synthesis of the Reich diketone. This compound had been obtained from natural sources by Reich4 and so comparison with the natural product would enable the correct stereoisomer to be selected from the synthetic racemate. Cornforth and Robinson also hoped that sufficient quantity of the Reich diketone would be available from natural sources for it to be used for the next stage of the synthesis without having laboriously to synthesize a large quantity of it. Using a naturally available compound in this way is known as using a relay. The use of relays was important because, for every experiment that is successful, there are many that are not and so a large amount of substrate is needed at each stage in the synthesis. As the number of stages increases, more and more time has to be spent keeping the synthetic ‘front line’ supplied with the necessary substrate. Through the use of relays, they were able to save many valuable man-hours synthesizing substrate in the lab.
0160-9327/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0160-9327(00)01310-7
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It seems that, despite his brilliance, Robinson’s style of In 1946, Cornforth moved from Oxford. His deafness running the research program had the effect of slowing prevented him from taking on teaching responsibilities progress to some extent. In contrast to Woodward, within the University and so he moved to the National Robinson was at the end of his career as the head of a Institute for Medical Research at Mill Hill. The director, laboratory. He had been due to retire from the Waynflete Charles Harrington, allowed the collaboration with Chair of Chemistry in 1951. However, owing to the Robinson to continue and, throughout the late 1940s, disruption caused by World War II, he applied for and was there was copious correspondence between them and ocawarded an extension of four years. He liked to keep casional visits to Oxford by Cornforth (J.W. Cornforth, direct control of the projects that were being undertaken pers. commun.). Unfortunately, little of this correspondence in his lab and was always reluctant to delegate remains in the Robinson archive. responsibility even to experienced colleagues. This lack The practical work for the synthesis was mainly carried of autonomy led to a ‘brain drain’ of people with exout by Cornforth and his collaborators, although there perience in a specific area as they moved to other places were some disagreements with Robinson about strategy. where they could pursue their own The discovery that the Köster– interests14. Logemann (KL) ketone5 was availWoodward had a natural able in large quantities as a byRobinson also had a tendency to instinct for cultivating product of an industrial preparation dismiss ideas from senior colindustrial relations. of sex hormones led Robinson to leagues if he was thinking along think that it could be used as another different lines himself. He was relay. To do this, a method had to be found to convert constantly generating new ideas for synthetic routes but the Reich diketone to the KL ketone. Cornforth thought would often not pursue them when he came up against that this would be difficult and favoured a more direct obstacles, preferring to try a different idea. These two approach. However, they found a route using Birch6 and factors left the way open for other groups to improve on and extend his ideas, and to go on to achieve major Dauben’s7 conversion of cholestanone to cholesterol as a synthetic goals. For example, the synthesis of equilenin model. by Bachmann, Cole and Wilds15 was built on a step that The last part of the synthesis was the closure of the fourth ring starting from a derivative of the KL ketone. This was Robinson had discarded as being of little use because of achieved using the Arndt–Eistert and Blanc methods, reits low yield. Bachmann had developed the process, sulting in the formation of epiandrosterone acetate. Walden however, until it gave a yield sufficiently high to be of inversion at position 3 of epiandrosterone led to androsterpractical use in the synthesis. one, from which 2-bromoandrostanedione, androstenedione In fact, it was the synthesis of equilenin by Bachmann, and testosterone had already been obtained by Ruzicka, Cole and Wilds in 1937 that stimulated American interest Plattner and Aeschbacher8. From androstenedione, they in steroid synthesis. This was the first complete synthesis of a steroid and, moreover, it was the first major complete found a route to dehydroepiandrosterone, which they were synthesis of a natural product by an American group. As able to use as a relay, as it had been obtained from etioa result, it created significant interest, particularly in the bilienic acid by Kuwada and Nakamura9. USA. At this stage the medical importance of the steroid Butenandt and Schmidt-Thomé10 had already found a hormones was already appreciated, oestrogens, for exroute to 3-hydroxypregn-5-en-20-one. Robinson and his ample, being widely used. collaborators tried to introduce the alkyl side chain, charAfter World War II, the next major achievement in acteristic of cholesterol, at C22 but they were unsuccessful. steroid synthesis was the synthesis of oestrone by Anna Instead, they were able to introduce the required side chain and Miescher16 in 1948 in Switzerland. Oestrone was still into allopregnanolone (thus following Woodward et al.), which had already been obtained from 3-hydroxypregn-5an aromatic steroid, however, and the method used was en-20-one by Plattner, Heusser and Angliker11. By successfundamentally similar to that of Bachmann. The major goal in steroid synthesis was the non-aromatic steroid nucleus, fully achieving this, they obtained 3-acetoxycholestwith all its stereochemical complications. It was natural 17(20)-ene. They converted this to cholestanyl acetate, that Woodward, whose major interest was in synthesis, which they showed to be identical to a product derived should have addressed himself to this, the biggest problem from natural sources. From here, transformations to cholof the day, some time in 1948. estanol, cholestanone, cholest-4-enone and cholesterol were already well known. According to Cornforth, they became aware of the threat Woodward collaborating with industry at from Woodward and his group at Harvard in 1950. At this Harvard point, Cornforth persuaded Robinson to let him take over Woodward had a natural instinct for cultivating industrial the work entirely in the interests of speed. The preliminary relations. His steroid work benefited immensely from the notice of the total synthesis was published in Chemistry support of pharmaceutical companies, in terms of both and Industry in 195112, only a couple of weeks after funding and supply of raw materials and intermediates. Industrial interest in the project was easy to understand. Woodward’s announcement of his synthesis at the ChemiThe medical importance of steroids, particularly the sex cal Society Centenary Lecture (subsequently, preliminary hormones, had been demonstrated in the 1930s and they notice of the synthesis was published in the Journal of the were widely used in medicine. When, in 1949, Hench and American Chemical Society13).
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Kendall at the Mayo Institute demonstrated the dramatic effect that cortisone could have in the treatment of rheumatoid arthritis, the demand for this substance quickly outstripped supply. Steroids were big business in the pharmaceutical industry and a company that discovered viable ways to produce them stood to make huge profits. The fact that people were suffering from a crippling disease and could not be treated because of a short supply of the appropriate medicine was also a great incentive to find effective methods of production. At that time, steroids were produced by the chemical conversion of steroids extracted from natural sources. This was an extremely expensive process as the natural concentration of steroids is low. For example, the early production of cortisone was from cholic acid obtained from cattle, a method developed by Lew Sarrett (Merck and Co.), and required 40 cattle to produce 1 g of pharmaceutical grade cortisone – a daily dose. In 1949, a gram cost US$200 to produce. Although complete synthesis might require over 30 stages and, as a result, have a tiny yield, it was generally believed that, even so, it would provide a cheaper and quicker method of production of the drug. Research like Woodward’s was therefore given extremely high priority. The result was that Woodward was able to build up his steroid group relatively quickly. Merck provided him with funding for two postdoctoral fellows from 1949 and Monsanto funded another. Monsanto, to whom Woodward had acted as a consultant since 1948, were also invaluable when, in 1950, his group synthesized a tricyclic ketone that was to be a key intermediate to the final stages of the synthesis. Monsanto agreed to produce the intermediate on a pilot plant scale and supply it to Woodward. This gave Woodward a virtually unlimited supply of the tricyclic ketone and saved the group a large amount of time. Where Robinson and Cornforth had resorted to using relays, Woodward was able to rely on support from Monsanto. By funding Woodward, Monsanto and Merck were able to use the knowledge they gained from his research as a head start in developing their own processes for the production of useful compounds. Monsanto was particularly willing to provide intermediates for Woodward as it gave them the opportunity to begin working on the scaling up of a total synthesis to an industrial scale. They also had scientists closely following Woodward’s work and improving on the number of steps and the yields at each stage so as to optimize the process for industrial use. The synthesis itself13 used the CD→BCD→ABCD route rather than the BC→ABC→ABCD route used by Robinson. Woodward’s starting point was 2-methyl-5methoxy-1,4-quinone, which was to form ring C in the final structure. Ring D was neatly added using a Diels– Alder reaction. The closure of ring B and the introduction of the third chiral centre were achieved in the early part of 1950. In a letter in May of that year, Woodward suggested to Monsanto that they might be able to synthesize this intermediate in order to help with research into the final stages: ‘in order to make further progress efficiently, it has now become essential to carry out the early stages of the synthesis on a considerably larger scale than is feasible
Figure 1
The Robinson–Cornforth synthesis.
here in our laboratory.’17 Monsanto were able to scale up the process and were supplying the ketone to Woodward’s group by July. A key intermediate in the synthesis was obtained by Sondheimer on Christmas Day of 1950. Woodward’s high pressure style of leadership, combined with the sense of success being just around the corner, obviously led to irregular working hours. The compound was dubbed ‘Christmasterone’ by Woodward and he went on to develop several other syntheses from it. The final hurdle was the contraction of ring D from a six-membered to a five-membered ring. Treatment of Christmasterone with periodic acid in dioxane followed by heating the product in the presence of a catalytic amount of piperidine acetate gave DL-9(11),16-bisdehydro20-norprogesterone, from which a route to cholesterol was known. Competition It would seem that, in the last year or so of the total synthesis project, a strongly competitive spirit arose in the Woodward group with respect to Robinson and Cornforth. At the start of the project, the opinion was that Robinson would not complete the synthesis. He had been producing papers on the synthesis of steroids for almost 20 years and had yet to achieve the non-aromatic steroid nucleus. Coupled with the fact that he was close to retirement, the Woodward group doubted that he would be a threat. However, when Cornforth became involved, the prospect of Endeavour Vol. 24(3) 2000
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the Oxford team producing a synthesis was put back on the agenda. The Christmasterone story suggests the sense of urgency that was prevalent in the Harvard group. On 18 April 1951, Woodward left for England on a two month visit. He was due to give the Centenary Lecture of the Chemical Society, at Burlington House on 26 April, at which he intended to announce the total synthesis. This he did, and it appears to have stimulated Cornforth and Robinson into swiftly publishing a preliminary notice of their synthesis in Chemistry and Industry on 19 May. Woodward’s group seems to have been intending to publish their preliminary notice in June. On 26 May, Woodward sent a telegram to Sondheimer back in Harvard: ‘June communication urgent if at all possible. RR communication appeared here Tuesday… In view of urgency communication please phone me’. On 19 June, in the covering letter to the communication entitled The Total Synthesis of Cholesterol, Sondheimer wrote to Marshall Gates, the editor of the Journal of the American Chemical Society. ‘You probably know that Sir R. Robinson is also aiming at cholesterol, and due to the historic importance of this substance, I think it would be valuable to get the communication published as quickly as possible.’ The communication was published in July of 1951. Media response The fame of cortisone led to some media interest in the synthesis. Just over a year since cortisone had first appeared on the market, the shortage of cortisone led Merck to issue a memorandum at the beginning of March explaining the situation. ‘Before cortisone can be made in sufficient quantities, a new, more plentiful starting material will have to be found, or a complete synthesis discovered by the chemists and research workers.’18 This interest led to the heralding of the Woodward synthesis on American radio. ‘It now seems reasonable to expect mass production of this wonder-working hormone within a short time, as a result of the greatest international race in modern chemistry – the race to achieve the total synthesis of a steroid.’19 The only media interest when Cornforth and Robinson announced their synthesis was from a News of the World reporter who had noticed, and misunderstood, the term ‘sex hormones’. The story never made it to press.
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Summary The synthesis of the steroid nucleus was one of the major challenges in synthetic organic chemistry in the late 1940s. As such, Woodward found it impossible to resist. His synthesis is notable not only for its technical brilliance but also the speed with which it was completed. Woodward was a very fast worker and kept intense pressure on his group, which enabled the group to complete the synthesis in a remarkably short period of time. The other notable feature of Woodward’s work, which contrasts with Robinson’s, is Woodward’s relationship with industry. The industrial support that Woodward was able to raise, in terms of both funding postdoctoral fellows and also supplying raw materials and, most importantly, key intermediates, was essential for the steroid synthesis to have been completed on the timescale that it was. Without it, the synthesis would have taken much longer and Woodward would probably have had to resort to using relays in the synthesis, in the same way that Robinson did. References 1 Rosenheim, O. and King, H. (1932) Nature 130, 315 2 Cornforth, J.W. (1992) Selected Research Papers with Commentaries (Golding, B.T., ed.), p. 15, Pergamon Press 3 Von Braun (1930) Chem. Ber. 63, 3052 4 Reich (1945) Helv. Chim. Acta 28, 892 5 Koster and Logemann (1940) Chem. Ber. 73, 299 6 Birch, A. (1950) J. Chem. Soc. 2325 7 Dauben and Eastham (1950) J. Am. Chem. Soc. 72, 2305 8 Ruzicka et al. (1946) Helv. Chim. Acta 21, 886 9 Kuwada and Nakamura (1938) J. Pharm. Soc. Jpn 58, 235 10 Butenandt and Schmidt-Thomé (1939) Chem. Ber. 72, 182 11 Plattner et al. (1946) Helv. Chim. Acta 29, 468 12 Cardwell, H.M.E. et al. (1951) Chem. Ind. 389 13 Woodward, R.B. et al. (1952) J. Am. Chem. Soc. 74, 4223 14 Birch, A. (1995) To See the Obvious, American Chemical Society 15 Bachmann, W.E. et al. (1939) J. Am. Chem. Soc. 61, 974 16 Anner, G. and Miescher, K. (1948) Helv. Chim. Acta 31, 2073 17 Woodward, R.B. (1950) Letter to C.A. Hochwalt of Monsanto dated 4 May 18 Merck & Co. (1951) Memorandum on cortisone dated 1 March 19 American Chemical Society News Service (1951) Transcript of 191st of a series of weekly news broadcasts on station WNYC aired on 1 May at 5.30pm