edited by:
LEONARDFINE Columbia University New York. NY 10027
ERICS. PROSKAUER
My Journey from Organic to Bioorganic Chemistry Theodor Wagner-Jauregg Bonenwilerstrasse 23, CH-4800 Zofingen, Switzerland My interest in chemistry probably has genetic roots. As my father told me, he had chemical inclinations in his youth but, more or less by chance, he became a well-known Vienna psychiatrist ( 1 ) . At the Unlversity of Vienna and Munich (1921-26)
Born in 1903, I started studvina at the Universitv of Vienna in 1921. My main interest w=s &amc c h ~ m i s t r i b u unfort tunately at that time its ~rofessorshipwas vacant. W.Schlenk had just gone to Berlin and his successor E. S p i t h was only nominated as chief of the department of organic chemistry quite a few years later. That's why in 1923 I moved to the University of Munich where chemistry was in high esteem under the leadership of R. W. Willstatter. However, when I was ready to start my doctor's thesis Willstitter retired prematurely for political reasons. He recommended me to his favorite scholar Richard Kuhn, who a few years before had moved from his native town, Vienna, to Munich. Between the two of us developed a close cooperation lasting 12 years and a life-long friendship. An excellent short biography of Kuhn has been written by his pupil Otto Westphal (2). My reminiscences of Kuhn will be oublished later in the frame of mv own autobiography. At Munich. Kuhn was mainlv occunied with stereochemical and enzymatic subjects. The problem of my doctor's thesis, which I started under his direction at the beginning of 1925, dealt with the so-called y-methylglucoside of Emil Fischer. For this purpose I studied the reaction rates concerning the permanganate oxidation of sugars (3) and the action of enzymes on y-methylglucoside. Thts was my first brief contact with biochemistry. In the fall of 1926, Kuhn was appointed as a full Professor at the Institute of Chemistry of the Eidgenossische Technische Hochschule, Zurich, Switzerland, on recommendation of his teacher, Willstatter. I was very lucky in that he offered me a research assistantship at his new position. At the Eidgenossische Technische Hochschule (ETH) Ziirlch (1926-30) With our first investigation a t Ziirich we were able t o demonstrate in which phase of the Waldensche Umkehr reaction the stereochemical inversion of the suhstituents takes place (5). Kuhn proposed as the next attractive goal, the production of optically active substances without the aid of other optically active materials. For this purpose he intended to destrov ~artiallvracemic comnounds bv illumination with circular p&arized"light (asymmetric destruction). We considered monobromo succinic acid esters as a suitable material for this investigation. However, its optically active forms very easily undergo autoracemization (P. Walden, 1898). I soon
592
Journal of Chemical Education
found that trarrs of hydrogen bromide or bromide anions, formed by. slight - decomposition of the ester, caused the phenomenon of autoracemizition. The mechanism of this reaction corresponds in principle to the change of configuration via the Walden inversion. Using finely dispersed silver, the autoracemization could he stopped. This was my first independent DaDer. . . . which I nublished in 1926 (6).It awakened mv further interest in the study of catalytic iincluding enzymatic) phenomena. While I was busy with further preliminary work for our attemot a t asvmmetric destruction we were forestalled hv ~ e r n e r~ u h n ,a Swiss physicochemist, working in K. Freudenbera's institute a t Heidelhere. He was able to obtain opt~rnllyariive material hy ex pus in&^-bromopropionicvcid e*rer or N,N-dimethvl-n-nzi~lor~rouionir acid amide to the action of circular light ( j ) .Thus, the first asymmetric destruction became connected with the name of Werner Kuhn, which was, I suppose, a big disappointment for Richard Kuhn. However, I was happy that my stereochemical epoch bad come to an end, because up to then my opportunity to ohtain experience in classical organic chemistry, which at that time was my main interest, had been rather small. In 1928 the sensational paper by 0. Diels and K. Alder on diene additions appeared. We applied this new method to the diphenylpolyenes of R. Kuhn and A. Winterstein and ohtained the expected results (8).More interesting were three incidental observations that I made during the execution of this project. For my experiments I employed the help of two young students. One of them was supposed to study the reaction of maleic anhydride with stilhene (the first member of the diphenylpolyene series). By heating a small amount of the mixture of both comoounds in an inert solvent he obtained a few crystals. Their elementary analysis, however, did not make anv sense. That's whv, I r e.~ e a t e dthis exoeriment on a Iar:w sc31e. H. Kuhn, whom I hnd informrd about the problem. did not want tn miss the birth of the mvstrrious substance and eagerly watched the flask with the boiling solution. However, no crystals but, rather, cheesy shreds appeared which settled down a s curd-like crumbs. Kuhn reacted exactly as on similar occasions: he retired disappointed and sad. but without saying a word. I was not unhappy because on t h a t Saturday morning I had an appointment for a skiing trip with some colleagues and the chiefs departure gave me the opportunitv to leave the laboratory in sufficient time. The folI8,wing Monday I WHS prepared-to pour out the unpleasant mixture. Hut suddenly the thought flashed through my mind that 11 learned chemist should be nblr to interpret unexpected reactions also. The product formed was i s o l n t ~as ~ i an amurphous, high-meltmg powder. According to the chnentary analysis and molecular wright determination it was a pt,lymeric addition product of stilhenc and maleic anhydride in
a ratio of approximately 1:l for which I proposed the structure I (9). I t is recorded in the literature as the first example of alternating copolymerization (96).
me a position. However, first I had to go through a few medical tests. A trace of protein was found in my urine, probably hecause shortly before I had been ill with a severe angina. Therefore, I was told that my contract unfortunately could not be signed until my kidneys were again 0.k. because they had prev~ouslyhad bad expe&=nreswith similar cases. At the end of 1927 something happened that made it easy for to forget an industrid nosition. M\'father received the - - -me -~Nobel Prize in Medicine, so.1 no longecfelt hesitant about accepting a monthly financial allowance from him and happily continued my scientific work in the laboratories of R. Kuhn, who soon also ex~eriencedan eauallv haDDv sur~rise:At the end of 1929 he wes nominated &rector $;he chemistry DeDartment at a new Kaiser Wilhelm Institute (KWI) for medical research, to he built a t Heidelherg. In the spring of 1930 we both moved there and our research program received a closer orientation toward bioorganic chemistry. ~~
~
The chemistry of polymers at that time hecame increasingly significant, mainly thrnugh the publications of H. Staudinger. I Hoon met him a t a meetine and he. as well as others in industrial circles, encouraged me by their interest in my paper. Kranzlein and Hopf of the Farbwerke Hoechst invited me for a discussion meeting. They obviously were happy that I had not filed for a patent and rewarded me for this omission with a good meal and an excellent wine and their everlasting henevolence. The I.G. Farhenindustrie A.G. a t that time had claimed patents on related copolymers (10). (Synthetic rubber "Buna S" was ~roducedsoon afterwards hv co~olvmerization of styrene a n d butadiene.) However, conirary td structure I these ~ r o d u c t contained s onlv one normallv. un~olvmerizable . . cornp(.)nent along with a polimerizable one. Sincestilhene and maleic anhvdride (MA) reacted insuch a remarkable manner i t seemed worthwhile to study also the behavior of asymmetric diphenyl ethylene (11) toward MA. They reacted with formation of 111 (eqn.(l)) (11):
-
+
-~
~
At the KWI Heldelberg (1930-36)
R. Kuhn, together with A. Winterstein, M. Hoffer, E. Lederer, H. Brockmann, Ch. Grundmann and others mainly worked on polyenes and carotinoids, as well as on cbromatography. I myself (later together with H. Arnold and M. Lennartz) (17) studied the synthesis of terpenes (e.g., geraniol, a-terpineol-1.4,1.4- and 1.8-cineol, farnesol, diterpene alcohols) fmm isoprene in the presence of water containing acetic, sulfuric, or phosphoric acid as catalysts. The formation of terpenes in our in vitro model experiments obviously happened primarily by addition of acids (HX) to isoprene, which forms A3-isopentenylic esters W a n d the isomeric y,y-dimethylallylic esters (IV) (eqn. (3)).
-
I t was the first example of a (4 2) 6-cycloaddition with the participation of an aromatic nucleus. This type of reaction was studied later more thoroughly by F. Bergmann and J. Szmuszkowicz (12) and by Alder et al. (13). Since that time, many similar examples of the same type have been verified (14~). In my paper (9a) I described the reaction of 2 mol of maleic anhydride with 1mol of benzaldazine according to a criss-cross addition (15), (eqn. (2)):
vn active isoprene
I t was the first example of a criss-cross addition by participation of a dienophile and an early example of 1,3-cycloadditions. Later on R. Huisee demonstrated the eeneral sianificance of this reaction type for the synthesis of heterocycles (16).A wide varietv of new criss-cross additions were discovered not long ago by K. Burger in Germany (14b.c) and A. E. Tipping in England (14d). My salary a t the E T H Ziirich a t that time was between 200 and 240 Swiss Francs per month. This was not very muchand one could not expect any further substantial increase. Since I did not want to rely for a long period on a supplemental allowance from my father I applied in the second half of 1927 for anosition a t the Badische Anilin- und Sodafabrik (BASF) at 1.udwigshafen. Rhn. There, on the orcnsim of my personal visit after sounding out my chemirnl knowledge, K. H. Meycr and H. Mark, the chirfs of the research department, offered
Twentv-sixvears later. F. Lvnen ( 1 8 ~demonstrated ) that the key s;hst&ce for the bingenesis of all the natural terpenes, the masked isonrene. is identical with A3-iso~entenvl~vrophosphoric acid ( ~ 1 1and ) the isomeric 3,3-dimethylall&vro~hosohoricacid (VI) (eun. (411.These two com~oundsserve asAfirsihuildingblocks fdr all compounds that are governed by the "isoprene rule"of 0.Wallach (1885) and the "hiogenetic isoprene rule" of L. Ruzicka (186). Our former attempts to produce terpenes from isoprene by acidic catalysts were, so t o speak, an in vitro model of the reaction taking place in living cells viapyrophosphoric acid esters. Referring to this, Lynen once wrote to me: "It really is a nice confirmation of the biosynthetic way, that one can produce also in vitro terpenes from dimethyl-allyl alcohol in the presence of acidic catalysts." My paper "synthesis of terpenes from isoprene" was accepted a t the beginning of 1932 by Freudenberg to grant me a uenia legendi a t the University of Heidelherg. However, I Volume 62 Number 7 July 1985
593
had to wait another year to give my first lecture because a t that time there were too manv Dozenten in the Chemistrv Department. In January 1932, R. Kuhn suggested I investigate the ability of carotinoids to form addition compounds. I was not very keen on this subject and informed him about my intention to work in a rather unexplored field of biochemistry, namely the water-soluble vitamins. I started searching the literature on this suhject when R. Kuhn proposed to try the isolation of vitamin Bz. The pediatrician Paul Gyorgy was supposed tornrry nut theanimal experiments. I donot know whether the idea for this new subject originated from CyBrgy or Kuhn. However, ihey both, with the experimenlal chemical aid oiLederer were already attempting 11, isolate the vitamin H. an antiseborrheir skin fartor. tirst described bv. CvGrrv. . 1tlater turned out to be identical with biotin (19).Since vitamin B? was considered to be the antioellama vitamin its comparison with the antidermatitic vitamin H seemed to he logical. At that time the only known characteristic property of vitamin Bz was its heat stability, representing the main difference from vitamin B1. How I succeeded in isolating riboflavin a t the end of 1932 has already been described elsewhere (20). In the same year, 0. Warburg and W. Christian had discovered the "yellow enzyme." Its prostethic group turned out to be identical with rihoflavin. This was the first example of a vitamin exerting the function of a coenzyme. The isolation of rihoflavin represented to me a most exciting scientific adventure: out of the darkness a natural product of universal importance had been brought to the daylight. At the beginning of this project, I never would have expected having complete success in the short time of one year. The love for riboflavin bas remained with me for the re& of mv life. Even today, I get excited when, out of a commercial polyvitamin solution, the fluorescing greenish-yellow color of riboflavin "smiles" a t me. The synthesis of riboflavin was performed by R. Kubn and F. Weygand a t Heidelberg and simultaneously by P. Karrer and coworkers a t Zurich. The latter. in cooneration with H. von Euler (Srockholm~had started ;he isoiarion of vitamin D? indeuendentlv from us. but somewhat later. We obtained a first hint of their project on the occasion of a visit of von Euler to Heidelbere. When he saw the vellow solutions of riboflavin with their greenish fluorescence standing on my work bench and we told him about our work on riboflavin. be obviuuslv wa< ronfounded. Karrer must have bem prpsenr when I reported the isolntr,nof vitiunin LLnt Altdorf cSwitzrrlandJ in 1933 (21). I t was not until 1934 that the first vitamin Bz ~ublicationsof vou Euler and Karrer ameared in Heluetica chimica Acta, but Karrer obviously didnot mind my competition in the vitamin BZfield. When, a t a later time, I lived in Switzerland I was even invited to the festival of his 70th birthday a t Zurich. Synthetic riboflavin, on the basis of its vitamin activity, in the course of time became a very important product commercially. In 1973 the estimated worldwide demand was more than 100 tons per year, and for 1980 i t was twice that amount. In 1955 a very interesting new chapter of flavin chemistry was opened. V. N. Boukine and D. E. Green demonstrated that by ordinary extraction methods not all the flavin could be removed from bacteria. olants. and animal tissue. A conafter proteolytic digessiderable amount was liherited tion. In 1960, after degrading succinnte debydrogenase from beetheart by trypsi11and cbymotrypsin, h
