Tetsuo Nozoe: Chemistry and Life

Abstract

On May 16, 1902, a baby was born in Sendai, Japan, and named Tetsuo by his parents Juichi and Toyo† Nozoe (Figure 1). The name Tetsuo Nozoe would one day become well known in the chemical world. His father, Juichi, was a lawyer and a politician, who at one time served as a member of the National Diet. As is common in Japan, Nozoe's family is Buddhist. But his mother, Toyo, was a devout Christian. Tetsuo was the sixth child with ten brothers and sisters (Figure 2), and thus the family could not enjoy a quiet life. More details of Nozoe's youth and life can be found in his autobiography[1] and in other biographical materials.[2-8] Tetsuo Nozoe on his second birthday, May 16, 1904, Sendai. Nozoe family portrait at home, Sendai, 1910. Tetsuo is standing at the far right. Other identifications and additional family history is found in Nozoe's autobiography from which this and other photos in this article appear.[1] Nozoe told us that, as a youngster, he was not healthy all the time. Thus, he loved solitude and developed hobbies like listening to classic music, especially operas. He had already developed an interest in chemistry in his junior high school days, and he had set up a laboratory in a section of a storehouse and performed daily experiments.[4] This interest led him to the Chemistry Department, Faculty of Science of the Tohoku Imperial University, where he started studying organic chemistry under Professor Riko Majima, renowned as the father of modern organic chemistry in Japan (Figure 3). Riko Majima on his 88th (Beiju) birthday. Majima was, for Nozoe, a life-long mentor and the best and most powerful supporter. Foreseeing the young man's bright future, Majima suggested “the synthesis of thyroxin” for his thesis project, and urged him to conduct the research with his own initiative. Professor Majima advised him repeatedly that research is to be conducted always with an infant's curiosity and open-minded modesty. However, the chemical structure proposed for thyroxin those days was incorrect; Nozoe's synthetic effort was naturally unsuccessful. Half a year after Nozoe's graduation, without consulting him, Professor Majima had arranged a job for the young chemist in Taipei on the island of Formosa (as the island was then known, also then under Japanese control), and urged Nozoe to take it. The truth behind the plan was that the Japanese government had decided to found an Imperial University in Taipei, and Majima wanted to keep the promising young man away from his father's political activity. Upon finding the truth later, Nozoe could not stop showing his gratitude for his mentor's deep consideration towards himself. In Formosa, Nozoe started working at the Monopoly Bureau on the essential oil of taiwanhinoki (Chamaecyparis taiwanensis) under the guidance of Dr. Kinzo Kafuku (Figure 4). Kafuku only emphasized what is essential in research, saying “Never forget to maintain originality in chemical research. You must concentrate on your own research work, while I teach you how to drink sake.” Although not a good student in drinking, Nozoe had indeed concentrated in his research, keeping in his mind the recommendations he received from his two life-long mentors. Indeed, Nozoe was focused 100% on his science, as he spent both day and night in his laboratory. “Dr. Kinzo Kafuku in his office at the Central Research Institute of the Formosan Government-General in Taipei, 1926. He is wearing his official uniform.”[1] After a few years, Nozoe moved with Dr. Kafuku to become an assistant professor at the newly started Taihoku Imperial University. Nozoe kept himself busy in setting up the new laboratories, giving lectures and laboratory instructions in addition to his own research work (Figure 5). During these days, Nozoe had conducted research on saponins, sapogenins, and animal skin fat including wool wax. Notably he proposed new and correct planar structures for oleanolic acid and hederagenin in 1937,[9] correcting Ruzicka's previous structures.[10] Nozoe established the tetracyclic nature of lanosterol,[11] and isolated various branched-chain fatty acids.[12,13] The utilization of UV spectroscopy in the 1930s is another of his noteworthy contributions to natural product chemistry. Tetsuo Nozoe (seated at far right) with colleagues and students from the chemistry department at Taihoku Imperial University in Taipei, 1935.[1] For identifications, see Nozoe's autobiography.[1] In 1935, overcoming all difficulties, Nozoe isolated a phenolic compound with the empirical formula C10H12O2 from the essential oil of Ch. taiwanensis and named this compound hinokitiol. This seemingly simple compound provided a great difficulty in its structural study because of its peculiar behavior. For example, hinokitiol dissolves in concentrated sulfuric acid and is recovered by neutralization; its sodium salt is very stable in strong alkaline conditions; and its acetate and methyl ether are hydrolyzed exceptionally easily. These behaviors puzzled him even after the seven-membered cyclic trienolone structure was established for the compound. Though no foreign scientific books or journals were accessible in Taiwan in 1941, Nozoe had a chance to read Pauling's “The Nature of the Chemical Bond” and arrived at the conclusion that the resonance of two nearly equal Kekulé structures is responsible for the unusual stability of hinokitiol and its derivatives. It was the dawn of a new aromatic chemistry. The development of the war, however, resulted in a shortage of resources and forced the evacuation of the laboratories and the interruption of research activities until the end of World War II in August 1945. “Thank you, Professor Nozoe! Best of luck, Professor! Sayonara! Sayonara! Sayonara!!” They even sang farewell songs in Japanese, despite a prohibition of speaking Japanese in public.[1] All this showed their emotional appreciation for his contribution to the chemistry in Taiwan and his unfailing love of young people, and how they were reluctant to say goodbye to their beloved teacher. Even though the discovery of hinokitiol and the work thereafter were carried out for 22 years entirely in Formosa and then Taiwan, it contributed to the renaissance of Hückel's rule, and resulted in an entirely new field of organic chemistry. Therefore it was quite natural for Nozoe to keep his special affection and courtesy to Taiwan and the people there. He extended financial help to them privately on many occasions. He also invited Taiwanese chemists to Japan for postdoctorate or graduate studies. The study of hinokitiol was resumed immediately after his return to Japan (Figure 6) despite all the difficulty in post-war Japan, and soon flourished in the field of colorful non-benzenoid aromatic chemistry. It was thus possible to synthesize not only hinokitiol, but also tropolone, tropone and tropylium ion, the basic seven-membered ring systems, to reveal their electrophilic as well as nucleophilic substitutions, rearrangements, and to establish pathways to azulenoids, heteroazulenoids, and heptafulvenes. Professor Riko Majima (seated) with Tetsuo Nozoe standing in front, to the right in the photograph, with other faculty of the Department of Chemistry, Tokoku University, Sendai, 1958. Further identifications can be found in Nozoe's autobiography.[1] Realizing that a symposium was going to be held on tropolone and the related compounds in London in November 1950, Nozoe wrote a summary of his study to Professor J. W. Cook, the chairman of the meeting. To this, Professor Cook replied kindly saying that: 1) he was not aware of such a research work carried out in Japan; 2) the study was worthwhile for publishing; and 3) he would try to publish the whole summary in Nature as a special contribution. That breakthrough paper appeared in Nature in 1951.[14] It is not hard to imagine how grateful Nozoe was to the fair, kind and respectful attitude of Professor Cook, who was a potential rival of the research. Professor Holger Erdtman, one of the lecturers at the meeting, made an announcement during his talk and surprised the audience. He said: “I know now that there is a man who had discovered a tropolone eight years before I have discovered thujaplicin.” He added: “He is Professor Tetsuo Nozoe of Japan. His hinokitiol was proved identical with my β-thujaplicin.” In fact Erdtman became aware of Nozoe's work through Chemical Abstracts, which carried an abstract in the analytical chemistry section describing that hinokitiol was a β-diketone with an unsaturated seven-membered ring, and forms metal complexes with various ions. He immediately sent an inquiry to Nozoe through his old friend Professor Shigehiko Sugasawa of Tokyo University. This first acquaintance was followed by many mutual visits; see Figure 7. Nozoe and Erdtman and their wives were to become life-long friends. This heartwarming anecdote and their friendship were described in a Japanese primary school textbook as the finest example of international friendship. Tetsuo Nozoe, second from the left, in the Hiba forest, Aomori prefecture, Japan, with Professor and Mrs. Holger Erdtman, looking for plant material containing hinokitiol. Professor Erdtman is in the foreground, kneeling to inspect a grub containing hinokitiol, June 1958.[1] “Ein lieber Besuch aus einem schönen, fremden Land erfreute uns und zeigt wie völkerverbindend die Wissenschaft ist. Viele gute Wünsche für die weitere Reise!” [“A delightful visit from a beautiful distant land which gives us joy and shows just how science brings cultures together. Many best wishes for your further travels.”] Clemens Schőpf. Professor and Mrs. Schőpf made the first entries in the Nozoe autograph books on July 19, 1953. For a translation of the entry, see the text. Photograph courtesy of the Schőpf family. Schőpf's entry was followed by autographs, comments, poems, caricatures, cartoons and just about anything, contributed by thousands of chemists. As Nozoe always carried his autograph book whenever and wherever he went, over time it grew up to 9 volumes when he left us, containing nearly 4000 autographs including those of at least 32 Nobel laureates. The original notebooks are kept in the Archives of Tohoku University. The collected autographs speak themselves of Nozoe's earnest, thoroughgoing and uncompromising character, and at the same time, of his warm temperament which attracted so many chemists to make their warm-hearted contributions from time to time. In short, the autograph book is his chemistry and his life in a crystallized form. In 1961, Professor Ronald Breslow (Columbia University) proposed to hold a symposium in order to commemorate Nozoe's retirement from Tohoku University. Though reluctant to have a meeting on such a personal occasion, Nozoe organized the International Symposium on the Chemistry of Non-benzenoid Aromatic Compounds (abbreviated ISNA) in 1970, being well aware of the necessity of international cooperation for the development of the chemistry of Japan. As the symposium's chairman, Nozoe kept his eye on every detail of the meeting, and thus he led it to a great success. For a listing of the speakers of ISNA-1, see Table 1. Based on the meeting's success, it was decided to continue the meetings, while the title was changed into International Symposium on Novel Aromatic Compounds (abbreviated again ISNA). Nozoe's participation continued up to and including the 8th meeting (Braunshweig), where he presented a poster. Nozoe was 93 years of age at the time and enjoyed a discussion with much younger chemists of the age of his son or grandsons (Figure 9). After his death, the Nozoe Lectureship was established in his memory within ISNA. The next ISNA-15 scheduled for 2013 will be held in Taipei, a place associated with memories of Nozoe. As exemplified in his attitude towards ISNA, Nozoe has made a great contribution to international friendship. Tetsuo Nozoe explaining some of his recent chemistry of the quinones of azulene to Larry Scott at ISNA-8, Braunschweig, 1995. Photograph courtesy L. Scott. Nozoe always carried a notebook to describe various ideas of new projects, and the possible mechanisms of the ongoing reactions. He talked almost on every respect of his research with the foreign guests, at the breakfast in hotels in Tokyo, or in the Sinkansen trip to Osaka; his research instructions by midnight fax were a nightmare for his students and collaborators. He was not good at remembering the names of his students, but once their theses were mentioned, the Master declared with confidence, “It sure is Mr. So-and-so's Master thesis.” “As a pure chemist, it is a shame to leave an unsolved problem intact” was his habitual saying in later days. Tetsuo Nozoe: “Do we have some money, a good round sum, Kyoko?” Kyoko Nozoe: “Yes, we do. Your yearly pension for the Cultural Merit is untouched, and, besides, we have some savings.” Tetsuo Nozoe: “Is the money available for my use?” Kyoko Nozoe: “Yes, it is, as your yearly pension will be available soon. We will manage to live with it.” Tetsuo Nozoe: “To tell you the truth, I would like to found a research laboratory.” Kyoko Nozoe: “This is fine idea, but is the money enough altogether?” Tetsuo Nozoe: “It may not be.” Kyoko Nozoe: “Why don't you use your retirement lump amount?” Tetsuo Nozoe: “Is it OK to use, too?” Kyoko Nozoe: “Yes, please use it if you wish.”[7] Tetsuo Nozoe at his retirement ceremony, Tohoku University, Sendai, 1966. (Left to right) Toyonobu Asao, Ichiro Murata, Hiroyuki Abe (18th President of Tohoku University), and Shô Itô at the monument to troponoid chemistry on the grounds of Tohoku University, November 1999. Note the heptagonal design of the monument. Photograph courtesy Asao, Murata, and Itô. This conversation certainly demonstrates Kyoko's extraordinary devotion and collaboration to her husband, besides Nozoe's extraordinary affection to his chemistry. After Nozoe's retirement from Tohoku University, Kao Co., Ltd provided him with the Nozoe Laboratories, which consisted of an office and laboratory space. Thus, Nozoe kept interest and devotion to chemistry all through his life. Chemistry, especially the beautifully colored non-benzenoid aromatic chemistry, was indeed his priority in his life. Even after his retirement from Tohoku University, he pursued his research in the synthesis of more exotic members, such as tropocoronands[15] and their metal complexes,[16] cycloheptabenzoxazines,[17] benzothiazines[18] and azulenoquinones.[19] Nozoe never stopped dreaming up more advanced chemistry of his own, until his death on April 4, 1996. Nozoe's research was helped by as many as 200 students and many more Japanese and foreign collaborators. However, one should not fail to mention the financial support by private enterprises as well as grants-in-aid from governmental sources. Over many years, many companies and agencies supported Nozoe and his students with no expected rewards, on the basis of the understanding that a university is the place to carry out non-profitable basic research in science. This attitude originated from Nozoe's pure and impartial character, and his sincere attitude toward research, but one can catch a glimpse also of the dignified attitude of these companies. Such are the Takasago Perfumery Industry Co., Ltd for camphor oil and Taiwan hinoki oil; the Kao Co., Ltd for wool fat and other surface oils, and the Sankyo Co., Ltd for troponoid research. Nozoe had a son and three daughters with his lovable wife, Kyoko. His son, Shigeo, succeeded his father as an organic chemist at the Faculty of Pharmacy of Tohoku University, while his eldest daughter, Takako, married an organic chemist, the late Professor Satoru Masamune who taught for many years at the Massachusetts Institute of Technology (MIT). See Figure 12. Nozoe had many grandchildren; one granddaughter, Hiroko Masamune, followed the organic chemistry tradition, received her Ph.D. at UCLA with Robert V. Stevens and did postdoctoral studies at MIT with Barry Sharpless. Nozoe's second daughter, the late Yoko, was a chemist and professor at Hakuho University, Japan, and married Professor Hisayuki Ishikura (Jichi Medical University). Nozoe's youngest daughter, Yuriko, is married to Genichiro Higashihara, a businessman in Tokyo. The sagacious wife, Kyoko, took every care to support her husband's research activity (Figure 13). Sadly, she passed away on October 13, 2006 at the age of 97. (Left to right) Nozoe family photograph, ca. 1970. Mrs. Shigeo (Masako) Nozoe, Mrs. Yuriko (Nozoe) Higashihara, Mrs. Yoko Ishikura with her daughter, Hisayuki Ishikura, Tetsuo Nozoe, Kyoko Nozoe holding Shigeo Nozoe's baby, and Shigeo Nozoe. The Masamune family are not in this photograph. Identifications by Takako Masamune. Kyoko and Tetsuo Nozoe at the ISNA-6 banquet, Toyonaka, Osaka, August 1989. Nozoe's major hobby was listening to classical music, especially operas. Even as a youth in Sendai, the young Nozoe would travel 12 hours to Tokyo to hear special concerts. Nozoe also drew very casual sketches of wild flowers (Figure 14). His hobby of sketching wild flowers was not known by us until we found them in his possessions after his passing. Many of these sketches are used as illustrations in the booklet entitled A Straight Path—In Memory of Professor Nozoe.[3] After his retirement, Nozoe also enjoyed gardening at his cottage in Izu Peninsula every weekend. Some passers-by envied Nozoe's wife, saying to her, “You are so lucky having an excellent gardener!” Flower drawings by Tetsuo Nozoe, Banff, Canadian Rockies, Summer 1971. Starting as a natural product chemist, Nozoe created the seven-membered ring aromatic chemistry all through the hardship of wartime and of the post-war period, and finally established a new discipline in organic chemistry. Furthermore, he made a major contribution to international cooperation, as shown in the autograph books, for upgrading of the research environment in Japan, and strived to ensure the eventual development of fundamental chemistry. He was indeed one of a few who kept their keen interest toward nature to the end. It is needless to say that he received numerous recognitions, both domestic and international, for his contribution to chemistry, including the Order of Cultural Merit, and the 1st Order of the Sacred Treasure from the Japanese Government. “In the evening of March 27, 1996, the authors visited Professor Tetsuo Nozoe in a hospital in Tokyo. His bed side was half covered by chemistry periodicals, domestic and foreign. He looked and sounded much better than we had feared, and, though hoarse in voice, he told us about his current research work and the proofreading of his review article on azulenequinone[20] as enthusiastically as ever. As we had doctor's permission to visit him for only 30 minutes, we became anxious that the long conversation might fatigue him, and after an hour, we reluctantly mentioned that we ought to leave him, but he held out his hand, gesturing for us to stay for ‘just another five minutes!’ He then continued to talk about his chemistry for another 30 minutes. “Only eight days after our visit, Professor Nozoe quietly passed away at 4:40 in the afternoon of April 4 [1996], just before his 94th birthday. He had ended his stormy life entirely dedicated to chemical science, like an old, big tree falling down. Despite his age, his death struck unbelievable surprise and enormous sadness into his collaborators, friends, and students, who had seen him walking around in a lively manner, discussing chemistry tirelessly, to make them believe that he really was an ‘iron man’ who never dies, as his name Tetsuo means in Japanese.”[4] (Left to right) Toyonobu Asao, Shô Itô, Shigeo Nozoe, and Ichiro Murata at Tetsuo Nozoe's grave, April 21, 2004. We are grateful to Dr. Jeffrey I. Seeman, guest editor of The Chemical Record, for his eager and continuous encouragement and useful suggestions. Professor Ichiro Murata was born in Tokyo in 1929. He received his B. Sc. from the Chemistry Department, Tohoku University (1952) and D. Sc. from Tohoku University (1960). Following postdoctoral studies with R. Breslow (Columbia University, 1961–1962), he returned to the Chemistry Department, Tohoku University (Associate Professor, 1964–1967;), then moved to the Chemistry Department, Osaka University (Professor, 1967–1992; Professor Emeritus, 1992—present). He was Professor at Fukui University of Technology (1992–2001). Professor Shô Itô was born in Tokyo in 1924. He received his B. Pharm. from the Chiba College of Pharmacy (1944), B. Sc. from the Chemistry Department, Tohoku University (1950) and D. Sc. from Tohoku University (1956). Following postdoctoral studies with K. Wiesner (University of New Brunswick, 1956–1958) and with R. B. Woodward (Harvard, 1958–1959), he returned to the Chemistry Department, Tohoku University (Associate Professor, 1963–1965; Professor, 1965–1988; Professor Emeritus, 1988–present). In 1988, he became Professor at Tokushima Bunri University and, since 2000, is also Professor Emeritus at that University. Professor Toyonobu Asao was born in Yamagata, Japan in 1932. He received his B. Sc. (1954) and D. Sc. (1959) from the Chemistry Department, Tohoku University. Following postdoctoral studies with G. Buchi (MIT, 1962–1964), he returned to the Chemistry Department, Tohoku University (Associate Professor, 1966–1970; Professor, Liberal Arts, 1970–1993; and Professor, Chemistry Department, 1993–1995; Professor Emeritus, 1995—present). He then joined the Educational Department, Iwate University (Professor, 1995–1996). From 2007–2010, Asao was President, Tohoku Seikatsu Bunka University.