Thirty‐Three Years Member of the Group Vasella by Bruno Bernet

Dear Andrea, I thank you very much for the opportunity to have assisted you in your carbohydrate research projects. In 1975, I was at the end of my diploma stay in the group of Professor Albert Eschenmoser and asked the professor for a doctoral research study in his group. But he answered: ‘I am sorry, I have no free space and no money, but there is a young researcher in the house who is looking for a collaborator. His name is Andrea Vasella. A young supervisor may be an advantage as he can teach you more than me. Will you ask him for a doctoral research study?’ Thus, I went and saw Andrea in his laboratory. First, he asked me about my diploma work. I was astonished that he had specific questions and advice to all steps. Then he asked me about my preferences. I answered that I like to do a synthetic work, but not carbohydrate chemistry, since Professor Oskar Jeger had told in his lecture that carbohydrates are terrible mixtures of hardly crystallizing compounds. Then he replied: ‘I do not carbohydrate chemistry, I do organic chemistry with carbohydrates.’ Later on, I have understood this fine difference as carbohydrates are organic molecules with several hydroxy groups. I left his laboratory with the intention to investigate sugars as I will benefit a lot from the knowledge of this young researcher. Andrea had just started his own research after returning from the postdoctoral stays in the groups of the Professors Jack E. Baldwin and Robert B. Woodward. He had selected Professor Albert Eschenmoser as his mentor and followed regularly the tea breaks of this group in the cafeteria. Andrea analyzed the diastereoselectivity of the cycloaddition of glycosyl nitrones. In 1977, he was elected as an Assistant Professor of the University of Freiburg im Üechtland. The second doctoral student Heinrich Steinlin and me, we transported the equipment of the group laboratory into the new university building in Pérolles. In my thesis, I investigated a new method for opening of glycopyranosides where the C(5)−O bond is broken. A reductive fragmentation of 6-halopyranosides led to hex-5-enoses which in the presence of N-alkylhydroxylamines were transformed into cyclopentisoxazolidines. The first step was adapted by many groups worldwide as e. g. to selectively cleave oligosaccharides and to transform carbohydrate derivatives into carbocyles (e. g. prostaglandin analogs and cyclohexenes) and piperidines. In 1979, I left the group for a postdoctoral stay in the laboratories of Professor Pierre Deslongchamps in Sherbrooke (Québec). Interestingly, I worked with the same compound as Andrea in the postdoctoral stay in the Woodward group, namely with erythromycin A. The knowledge of carbohydrates helped me a lot since this antibiotic is also a polyhydroxylated compound. I tended to an industrial career, but in 1980, the large Swiss chemical companies had personal stops due to internal reorganizations and the few free positions were appointed to applicants with industrial experience. Andrea informed me that he was elected as an Associate Professor of the university of Zürich and offered me the position of the scientific assistant (Oberassistent) which I accepted with pleasure since I like research very much and could stay in Zürich. Hence, the group equipment was moved into the new laboratories of the Irchel campus. At the universities of Freiburg and Zürich, Andrea exploited the chemistry of glycosyl nitrones. Thus, a variety of products were prepared, e. g. 5-oxaprolines, α-aminophosphonates, nojirimycin, glycosylidene oximes, 1-nitrosoglycosyl chlorides which upon a Diels-Alder reaction gave bicyclic oxazines, and 1-nitro-1-deoxyglycoses. These nitro derivatives allowed the synthesis of higher monosaccharides, especially of neuraminic acid, a C9 saccharide, whose chemistry and biological function were at this time a research goal in carbohydrate chemistry. An equally strong inhibitor of neuraminidase as Tamiflu® from F. Hoffmann-La Roche AG was synthesized albeit by a commercially uninteresting route. Protection of the double bond by a triple bond in a Sharpless oxidation led to a short and efficient asymmetric synthesis of d-erythro-sphingosine. At the university of Zürich, the Vasella group implemented computers for making electronic manuscripts. We were pioneers for using ChemDraw, Word, and EndNote on the early cubic Macintoshes SEs. Gone the time for the preparation of drawings with formula stencils, ink, Letraset, and stencil paper. Selective glycosylation is a central topic in carbohydrate chemistry. Andrea found a promoter-free variant, the addition of alcohols to carbenes obtained from glycosylidene diazirines. This method is especially useful for sterically hindered alcohols, phosphines, and di- and triols where the kinetically most acidic OH group is preferentially attacked. This led to an extensive investigation of intramolecular hydrogen bonding in partially protected glycosides and inositols. The inclusion of fluorinated carbohydrates refined the famous statement of Professor Jack Dunitz: ‘Organic fluorine hardly ever accepts hydrogen bonds’ to ‘Organic fluorine accepts hydrogen bonds in the absence of a better hydrogen bond acceptor’. A scalar coupling between F and OH, present only in apolar solvents, proved that there is indeed a hydrogen bond and not only a dipolar interaction. Later on, molecular modeling of other groups corroborated this finding. Addition of glycosylidene carbenes to olefins yielded spirocyclopropanes. At the International Carbohydrate Symposium 1992 in Paris, Andrea was honored with the Roy L. Whistler Award from the International Carbohydrate Organization and could present the first glycosylated fullerenes. He was also elected as the first non-British organizer of the Gregynog symposium. The buta-1,3-diynyl group is isometric to a pyranosyl unit. Thus, alternating carbohydrate moieties were replaced by buta-1,3-diyn-1,4-diyl groups preventing any intramolecular interaction between the carbohydrate moieties and afforded analogues of oligocelluloses (up to a hexadecamer), oligomers of cellobiose, and of cyclodextrins. An ethynylated and a buta-1,3-diynylated cellooctaosyl moiety were attached to anthraquinone to mimic cellulose I. Indeed, CP/MAS 13C-NMR spectroscopy and X-ray powder-diffraction showed that this model mimics cellulose I. The inhibition of glycosidases and related enzymes by carbohydrate-derived hydroximinolactones and -lactams and by imidazo- to tetrazopiperidines were intensely investigated partly in collaboration with other groups worldwide. In 1993, Andrea was appointed as a Full Professor of the ETH Zürich where he could take the office and laboratories of his well-honored mentor, the Emeritus Professor Albert Eschenmoser. We were lucky that we had hired Thomas Mäder as laboratory technician. He kept the equipment of the group in excellent conditions and repaired many items by himself. Advanced programs allowed to do literature research and synthesis planning directly from the working place. The tedious scrolling in volumes of Chemical Abstracts in the library was now a thing of the past. Force-field calculations with the program Macromodel on a unix work station showed that phosphate-free oligonucleotide analogs where C(5) of the ribose unit is linked by an ethynediyl moiety to C(9) of the purine or C(6) of the pyrimidine base of the next unit can pair. Hence, oligomers with an ethynediyl, thiomethylene, or aminomethylene linker were prepared and their base pairing intensely studied (32 publications in this series). The fourth and last movement was in 2003, when the chemistry department of the ETH left the city center for new buildings on the Hönggerberg campus. The school management had abstained from a cooling system for the offices. Unfortunately, the extremely hot summer in 2003 led in the afternoons to high, uncomfortable room temperatures up to 36 °C. I was able to move my working place into the cooled computer room. Powerpoint replaced slide presentations which had required a special photographic procedure and did not allow last-minute changes. A carbohydrate moiety of the aminoglycoside antibiotics kanamycin and paromomycin was selectively modified. Professor Erik C. Böttger from the university of Zürich investigated the interaction of these modifications with ribosomes featuring single point mutations. From beginning, Andrea was consultant of the chemical industry, first of Sandoz AG, both in Basel and Wien (research on carbohydrates), and later on of F. Hoffmann-La Roche AG and Syngenta AG. After 2000, he had strong consulting projects with university and industrial researchers in France and in India, and therefore got the Honorary Degree of the INSERM and was elected as Honorary Member of the Indian Society for Chemical Research. He was always well prepared for these consulting sessions. Whenever strong differences appeared in a board, he was estimated as conciliator in finding a convenient solution for all. Thus, he helped a lot Helvetica Chimica Acta to get out of a crisis. Andrea has inspired and supervised PhD students and postdoctoral coworkers from all over the world, mostly from European and Asian countries. His laboratories were a place of intense scientific and cultural exchange. I remember with pleasure the group Christmas events when the coworkers prepared specialties from their home countries. At the farewell parties, Andrea always foregrounded the merits of the leaving coworker and handed over the gifts of the group, and the leaving person had to guess the content from the properties of the parcels. A special highlight were the seminaries of the group at the beginning on Thursday evening and afterward late on Friday afternoon. Here, Andrea presented synthetic and mechanistic problems from the actual literature, but always outside carbohydrate chemistry. Together, we should find the best solution. I remember the many sessions in his office where we searched a rationalization for different experimental and spectroscopic data and he formulated the conclusion in a short and concise sentence. In 2008, Andrea was emeritus (Figure 1), and I joined the group of Professor François Diederich who kindly allowed me to help Andrea in the preparation of the last publications in the oligonucleotide series and to continue investigations of intramolecular hydrogen bonding of organofluorine compounds in collaboration with Professor Véronique Gouverneur at the university of Oxford. Pictures taken from the emeritus party 2008 where I have handed over the book ‘The Vasella Group from 1975 to 2008’ to Andrea. Andrea introduced functional groups well known in organic chemistry (many more than mentioned in this article) into carbohydrates ascertaining his statement at my thesis application: ‘I do organic chemistry with carbohydrates’. Thus, he had a huge impact on the renaissance of the carbohydrate chemistry. I thank the destiny which had directed me twice into the Vasella group and I am extremely proud to have spent thirty-three years in this group.

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