RESEARCH Making Penicillins—Natural and Synthetic Key step i n synsyn thesis of p e n i c i l - lin V is c y c l i z a tion of p e n i c i l l o i c a c i d . A n a liphatic carbodï imîde d o e s i t by j o i n i n g under m i l d c o n ditions a c a r b o n and n i t r o g e n to f o r m the u n s t a b l e penicillin structure
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Ten new s y n t h e t i c p e n i c i l l i n s have been m a d e by c h a n g i n g c o n d i t i o n s s l i g h t l y in t h e (as! h a l f of t h e r e a c t i o n sequence l e a d i n g t o p e n i c i l l i n V. W h i l e the s i d e chain acyl g r o u p o f p e n i c i l l i n s m a d e b y f e r m e n t a t i o n is an a c e t i c a c i d d e r i v a t i v e , t h e new m e t h o d p e r m i t s o t h e r side c h a i n s — sulfonic a c i d ( s h o w n here) a n d c a r b o n i c acid d e r i v a t i v e s
Penicillin V Synthesized Penicillin V synthesized by MIT's S h e e h a n : 10 n e w synthetic penicillins b e i n g tested f o r m e d i c a l use J P E N I C I L L I N -v, t h e m o r e acid-stable
form of the antibiotic, has b e e n syn thesized, thus solving what M I T terms "one of the m o s t baffling problems in chemistry." C u l m i n a t i n g nine years of research, Jolm C . Sheehan succeeded in synthesizing t h e unstable, t h o u g h not particularly complex, molecule. W h i l e the n e w methods probably cannot compete with t h e established fermentation process, they provide a route t o new synthetic penicillins which might b e : • Effective against organisms resist ant to natural penicillin. • Effective a g a i n s t a wider variety of organisms. • Less likely t o produce allergic r e actions. Using S h e e h a n ' s techniques, Merck 32
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Sharp & D o h m e Research Laboratories has already made 2 to 5 grams each of 10 new active synthetic penicillins; ani mal tests are u n d e r way. Included are compounds in which t h e side chain is a sulfonic acid o r a carbonic acid deriva tive. T h e 30 o d d penicillins made by fermentation h a v e only minor differ ences in the side chain; all are deriva tives of acetic acid. T h e n e w syn thetics have activity similar in type to natural penicillin, although there are differences which m a y prove advan tageous. T h e n e w compounds are more stable t o acid than the natural penicillins. Because t h e reaction conditions are mild, Sheehan believes his n e w tech niques and reagents may prove useful in studying other materials of biological interest—enzymes and intermediary metabolites, for example.
> $ 2 0 Million Project. While at Merck during W o r l d W a r I I , Sheehan w a s o n e of the thousand chemists work i n g in 39 laboratories i n t h e U. S. a n d Great Britain on t h e problem of syn thesizing penicillin. Conservative esti mates place cost of t h e effort a t $ 2 0 million. According to M I T , one group d i d p r o d u c e a microscopic quantity. H o w the reaction proceeded w a s not k n o w n ; t h e structure of t h e penicillin molecule h a d not y e t b e e n determined fully. Practical production was out of t h e question. Sheehan's w a r t i m e efforts bore fruit —he was instrumental in devising a practical synthesis of penicillamine, a key c o m p o u n d in t h e synthesis of peni cillin V, a n d penillic acid, a rearrange ment product of t h e antibiotic. By 1948, m a n y chemists, skeptical t h a t penicillin could ever be synthe sized, gave u p t h e task; S h e e h a n took it up in earnest, a i d e d by a long line of g r a d u a t e a n d postdoctoral students. Working with h i m in the final stages of t h e penicillin V synthesis w a s re s e a r c h associate K. R. Henery-Logan. Penicillin is n o t an unusually com plex molecule—similar structures such a s quinine, m o r p h i n e , cortisone, a n d sucrose, for example, have b e e n syn thesized. The problem is its instability, particularly a t t h e last stage w h e n penicilloic acid is cyclized to phenoxymethylpenicillin, penicillin V. Earlier researchers h a d gotten this far, only to get yields of a b o u t 0 . 0 1 % on t h e final reaction. T o solve this problem, Sheehan d r e w on h i s research, unrelated to h i s work on penicillin, on p e p t i d e synthesis. T h e instability problem is common t o b o t h projects, although more acute with penicillin. I n his peptide work, Shee han found that aliphatic carbodiimides can form amide bonds in aqueous solu tion directly from t h e amine a n d carboxyl components under mild condi tions. This reaction completes t h e penicillin V synthesis, with a yield of 10 t o 1 2 % i n t h e final step. Earlier steps average about 8 0 % . T h e total synthesis consists of a ser ies of 10 reactions; t h e last five a r e at room temperature or below, unusual in synthetic organic chemistry, Sheehan says the current ( M a r c h 5 ) J ACS. T o make t h e n e w synthetics, the last half of t h e reaction series is changed slightly. Sheehan makes more extensive use of blocking groups (in cluding phthalyl, feri-butyl, a n d ben zyl) and also uses a stronger cyclizing agent, thionyl chloride. Working w i t h Sheehan on this p h a s e of t h e work w e r e Dale R . Hoff a n d P . A. Cruickshank. Sheehan's w o r k was aided financially by Bristol Laboratories. •
