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R. B. Woodward R . B . W O O D W A R D Recent advances in the chemistry of natural products Nobel Lecture, December 11, 1965 The Nobel Prize in Chemistry for 1965 has been awarded for contributions to the art of chemical synthesis. It gives me much pleasure to record here my gratification with the citation, which properly signalizes an exciting and signif- icant aspect of synthetic activity. But that aspect is one which is more readily - and I dare say more effectively - exemplified and epitomized than it is articulated and summarized. Having here this morning the responsibility of delivering a lecture on a topic related to the work - for which the Prize was awarded, I have chosen to present an account of an entirely new and hitherto unreported investigation which, I hope, will illuminate many facets of the spirit of contemporary work in chemical synthesis. Cephalosporin C, a product of the metabolism of Cephalosporium acre- monium, was isolated in 1955 by Newton and Abraham 1 in an investigation notable for its perspicacity as well as its painstaking attention to detail. The investigation of the structure of the metabolite was successfully concluded in 1961 through studies in which both chemical 2 and X-ray crystallographic 3 techniques were employed. The molecular array (I) thus laid bare strikes one at once as having affinities with a hitherto well-known class of substances which has constituted one of the most challenging and recalcitrant synthetic objectives of our generation. I refer of course to the penicillins, of which penicillin G (II) - one of the earliest known and one which has been widely used in medicine - may serve as an example. There can be few organic chemists THE CHEMISTRY OF NATURAL PRODUCTS 101 who do not know the fascinating history of the penicillins 4. How, following up an early observation of Alexander Fleming, Chain and Florey isolated the first penicillin shortly after the outbreak of the Second World War. How the powerful practical desiderata of those trying times led to the establishment of a mammoth British/American program which had as its objectives the deter- mination of the structure and the synthesis of the penicillins. How the chemical investigations, and especially the X-ray crystallographic studies of Dorothy Hodgkin conquered the structural problem, and how despite the best efforts of probably the largest number of chemists ever concentrated upon a single objective the synthetic problem had not been solved when the program was brought to a close at the end of the War. Many chemists continued to be fascinated by the problem, and some were still willing to gamble their skill against its obstinacy. In 1959, after more than a decade of intensive investi- gation, John Sheehan 5 succeeded in the development of methods by which penicillins could be prepared by total synthesis. That these methods have not come into practical use does not detract from this major achievement, but only emphasizes that the challenge presented to the synthetic chemist by the penicillins has not been exhausted. A parenthesis is probably desirable at this point in order to allay some con- cern among those who have not been initiated in these matters. I have used the plural term "penicillins" because Nature provides several closely related substances, differing only in the acyl group attached to the nitrogen atom which is itself situated a to the lactam carbonyl group of the general structure (III). Furthermore, chemists have found ways of removing these acyl groups from the natural representatives of the class, and attaching entirely new and III 102 1965 ROBERT BURNS WOODWARD different groupings to the nitrogen atom thus freed. In this way, many hun- dreds of artificial penicillins have been prepared. The situation is similar in respect to cephalosporin C, in that a whole class of cephalosporins has been created by replacement of the residue of the natural metabolite by numerous other acyl groups. In both classes - the peni- cillins and the cephalosporins - some of the derived substances possess prop- erties which confer on them special utility in medicine. Thus, cephalosporin C itself possesses antimicrobial activity of a relatively low order of magnitude, which, however, early attracted special interest because it persisted against organisms which had become resistant to the penicillins. In some of the derived cephalosporins this especially interesting aspect of the antimicrobial activity is retained, while at the same time the level of activity is much heightened. Further, the activity extends over the range of Gram-negative and Gram- positive organisms. Consequently, some of these substances, of which ceph- alothin (IV) may serve as an example 6, have already achieved utility in medicine as broad-spectrum antibiotics of low toxicity, effective against penicillin-resistant organisms. in considering the development of a plan for the synthesis of any compli- cated substance, it is always desirable to look at the problem from an entirely fresh point of view. Nevertheless, in the case at hand, it was pertinent to examine whether the experience gained and the results achieved in synthetic studies on the penicillins might be usefully applicable to the structurally related cephalosporins. We rejected this possibility at the outset for several reasons. I have already alluded to the fact that the known penicillin syntheses, THE CHEMISTRY OF NATURAL PRODUCTS 103 hard-won, brilliant achievements though they are, are lacking in practicality. Further, the problems which had had to be overcome in devising methods for penicillin synthesis had been quite difficult enough without adding to them the intricacies which would have been associated with the achievement of stereospecificity in the creation of asymmetric intermediates, and this aspect had been slighted. Finally, a special chemical point was of much importance. The -lactam ring common to the penicillins and the cephalosporins is highly susceptible to hydrolytic cleavage. In the case, for example, of penicillin G (II), the product of this hydrolysis is penicilloic acid (V). The synthesis of penicilloic acid and its analogs, at least by non-stereospecific methods, was a relatively simple problem, and by far the largest number of attempts to syn- thesize penicillins - and the only successful ones - involved the deceptively simple task of removing the elements of water from penicilloic acid analogs, with closure of the four-membered ring. In the case of the cephalo- sporins the situation is strikingly different. Here the ring is also easily cleaved, but the proximate product of the hydrolysis, which must have the structure (VI), is not a known substance. Its intricate and delicate con- stitution is such that it does not survive even the mild conditions of its genera- tion from the corresponding lactam. Clearly then, it would be unwise to essay the synthesis of a cepahalosporin from such a hitherto unknown and obviously highly fugitive precursor. Often in the course of synthetic work one or two key ideas set the style, 104 1965 ROBERT BURNS WOODWARD development, and outcome of the investigation, while providing the flexi- bility essential for any long journey through unknown territory, beset with perils which at best can be only dimly foreseen. In planning our synthesis of cephalosporin the first of these definitive concepts was our choice of L(+) - cysteine (VII) as our starting material. This readily available substance pos- nitrogen atom and a β-sulfur atom-in short, it presents in ready-made fashion a large portion of the crucial substituted moiety of the cephalo- spot-ins. Furthermore, it is optically active, and the groups arranged about its one asymmetric carbon atom (starred in VII) are oriented in an absolute stereochemical sense precisely as are the similar groups in the objective; that is to say, as soon as the decision to use cysteine had been made, our stereochem- ical problem was in a sense already halfsolved, since the cephalosporin nucleus contains only one further asymmetric center ( cf. stars in I and IV). On the other hand, advantageous as this choice obviously was in many ways, it was also clear that associated with it was a special problem which could by no means be viewed lightly. The cysteine molecule is a tightly assembled pack- age of highly reactive groupings. The amino group, the sulfhydryl group, the carboxyl group, and the α-methine group each possess characteristic features of chemical reactivity, and represent points at which ready modification of the molecule might be expected. But the only remaining feature of the mole- cule, the simple saturated group, represents a point at which there is little or no precedent for chemical attack. And yet, in the light of our plan we must in some way introduce a nitrogen atom at that point, preferably in a stereospecific manner ( cf. arrow in VII). Further, even assuming that a method should be discovered for overcoming the defences of the molecule at that strong point, it was clear that we should be dealing with intermediates containing two electronegative atoms bound to the same carbon atom - a situation well known for its potentialities in conferring sensitivity and insta- bility upon molecules so constituted. In sum, our initial decision placed us in the exhilarating position of having to make a discovery, and of being prepared to deal with substances of an especially precarious constitution. THE CHEMISTRY OF NATURAL PRODUCTS 105 Our first actual operations consisted quite naturally in so modifying the cysteine structure as to depress the reactivity of the amino, sulfhydryl, and carboxyl groups. Thus, the amino acid was first converted by reaction with acetone into the thiazolidine (VIII)‘, which in its turn reacted with tert- butyloxycarbonyl chloride in the presence of pyridine to give the correspond- ing N-tert- butyloxycarbonyl compound (IX). Some special interest attaches to the fact that the acylation reaction undoubtedly takes place through internal delivery of the N-tert- butyloxycarbonyl group, which first becomes at- tached at the carboxyl site to give the mixed anhydride (X).
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