Downloaded from orbit.dtu.dk on: Dec 17, 2017 Methods for Shortening and Extending the Carbon Chain in Carbohydrates Monrad, Rune Nygaard; Madsen, Robert Publication date: 2008 Document Version Publisher's PDF, also known as Version of record Link back to DTU Orbit Citation (APA): Monrad, R. N., & Madsen, R. (2008). Methods for Shortening and Extending the Carbon Chain in Carbohydrates. 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Methods for Shortening and Extending the Carbon Chain in Carbohydrates Ph.D. Thesis By Rune Nygaard Monrad December 2008 Department of Chemistry Technical University of Denmark Methods for Shortening and Extending the Carbon Chain in Carbohydrates Rune Nygaard Monrad Ph.D. Thesis December 2008 Department of Chemistry Technical University of Denmark Kemitorvet Building 201 DK-2800 Kgs. Lyngby Denmark Preface Preface This thesis describes the work carried out during my three years as a Ph.D. student in Center for Sustainable and Green Chemistry at the Technical University of Denmark. In addition to research within the fields of organometallic and carbohydrate chemistry at the Technical University of Denmark, I had the opportunity to become acquainted with chemical biology during a six months research stay at University of Oxford. My period as a Ph.D. student has been very fruitful for me not only by means of education and achieving academic and technical qualifications, but also with respect to personal development as an individual and as a scientist. Many people have contributed to the present work, and most of all, I would like to express my gratitude to professor Robert Madsen. During the last three years of Ph.D. study, my theoretical and experimental skills have improved considerably. In particular, Robert Madsen’s support and guidance through critical decisions and his ability to suggest improvements of both overall strategies and specific reaction conditions have had a huge impact on the success of the projects I have been involved in. The decarbonylation team: Mike Kreis and Esben Taarning are thanked for good discussions, and Charlotte B. Pipper and Mette Fanefjord are acknowledged for collaborations on the calystegine and gabosine projects. A special thanks goes to Lars Linderoth for lots of fun and great company in the lab. The Department of Chemistry building 201, in particular the Madsen group, are gratefully acknowledged for invaluable help and for always maintaining an enthusiastic and positive spirit. I would like to thank professor Benjamin G. Davis for giving me the opportunity to work within such an interesting field of research in an interdisciplinary and highly dynamic group. The entire Davis group, in particular James, Conor, Justin and Nicola are thanked for invaluable help and good times in the lab. I am grateful to professor Andrew V. Stachulski for providing acyl glucuronide samples. Furthermore, Katja Rohr-Gaubert and Thomas Jensen are thanked for proofreading parts of this thesis. Last but not least, the Technical University of Denmark, Center for Sustainable and Green Chemistry, Danish Chemical Society, Civilingeniør Frants Allings Legat, Vera & Carl Johan Michaelsens Legat, Ulla & Mogens Folmer Andersens Fond, Krista & Viggo Petersens Fond, Fabrikant P. A. Fiskers Fond, Knud Højgaards Fond, Otto Mønsteds Fond and Oticon Fonden are gratefully acknowledged for financial support. _____________________ Rune Nygaard Monrad Lyngby, December 2008 i Rune Nygaard Monrad – Ph.D. Thesis Abstract Carbohydrates play a central role in a variety of physiological and pathological processes such as HIV, cancer and diabetes. The understanding of these processes and the development of specific therapeutic agents is relying on the ability to chemically synthesize unnatural sugars, glycoconjugates and carbohydrate mimetics. Such polyhydroxylated compounds are conveniently synthesized from carbohydrates, however, due to the scarcity of many sugars from nature, efficient methods for transformation of readily available carbohydrates into valuable chiral building blocks are required. The work presented in this thesis focuses on the development and application of transition metal mediated methods for shortening and extending the carbon chain in carbohydrates thereby providing access to lower and higher sugars. A new catalytic procedure for shortening unprotected sugars by one carbon atom has been developed. By means of a rhodium-catalyzed decarbonylation of the aldehyde functionality, aldoses are converted into their corresponding lower alditols in yields around 70%. The reaction is performed with 8% of the catalyst Rh(dppp) 2Cl in the presence of small amounts of pyridine to facilitate mutarotation. The procedure has been employed as the key step in a short five-step synthesis of the unnatural sugar L-threose in 74% overall yield from D-glucose. R OH O 8% Rh(dppp)2Cl OH HO OH 6% pyridine OH + CO diglyme/DMA HO OH 162 °C OH R R = H, CH3, CH2OH A zinc-mediated one-pot fragmentation-allylation reaction has been used to elongate D-glucose and D-ribose by three carbon atoms thereby producing carbohydrate-derived α,ω-dienes, which have been converted into the natural products calystegine A 3 and gabosine A. The glycosidase inhibitor calystegine A 3 was produced by two similar routes from commercially available methyl α-D-glucopyranoside in 13 and 14 steps with 8.3 and 5.3% overall yield, respectively. The present work thereby constitutes the shortest synthesis of enantiomerically pure calystegine A 3, and furthermore, it enables the absolute configuration of the natural product to be determined. Gabosine A has been prepared in nine steps and 13.9% overall yield from D-ribose, and this synthesis provides the first route to gabosine A from an abundant carbohydrate precursor. ii Abstract OH 13 steps HO NH D-glucose HO calystegine A3 9 steps D-ribose HO O HO OH gabosine A During an external stay at University of Oxford, the metabolism of nonsteroidal anti-inflammatory drugs (NSAIDs) has been investigated. It was found that known acyl glucuronide metabolites of ibuprofen and several analogues modify human plasma protein under conditions encountered in therapy. Two different kinds of protein modification occur depending on the structure of the parent drug. The obtained results strongly suggest that irreversible modification of human proteins takes place during treatment with carboxylic acid containing drugs such as NSAIDs. Furthermore, the observed reactivity of these metabolites with respect to protein modification may provide an explanation for the severe toxicity that has led to the withdrawal of certain carboxylate drugs. OH O O O HO O Transacylation HO O + Protein Protein Lys N Drug HO Drug H Acyl migration OH OH O O O O HO Glycosylation HO O O + Protein O O Lys Protein HO N HO OH H Drug Drug iii Rune Nygaard Monrad – Ph.D. Thesis Resumé Kulhydrater spiller en central rolle i mange forskellige fysiologiske og patologiske processer såsom HIV, cancer og diabetes. Forståelsen af disse processer samt udviklingen af specifikke lægemidler afhænger i høj grad af kemisk at kunne syntetisere unaturlige sukkerstoffer samt stoffer, der imiterer kulhydrater. Ideelt set fremstilles sådanne polyhydroxylerede forbindelser fra kulhydrater, men på grund af meget lav tilgængelighed af mange sukkerstoffer fra naturens side, er der behov for effektive metoder til at omdanne tilgængelige kulhydrater til værdifulde kemiske byggeblokke. Det arbejde, der præsenteres i denne afhandling, fokuserer på udvikling og anvendelse af metoder, hvor overgangsmetaller benyttes til at forkorte og forlænge sukkerstoffers kulstofkæde og dermed giver adgang til ellers utilgængelige kulhydrater. En ny katalytisk metode til at forkorte ubeskyttede kulhydrater med ét kulstofatom er blevet udviklet. Ved hjælp af en rhodium-katalyseret decarbonylering af aldehyd-gruppen kan monosakkarider omdannes til de tilsvarende forkortede polyoler i udbytter omkring 70%. Reaktionen udføres med rhodium-katalysatoren Rh(dppp) 2Cl i tilstedeværelse af en lille smule pyridin, der katalyserer mutarotation mellem kulhydratets hemiacetal- og aldehydform. Den udviklede metode er blevet anvendt som nøgletrin i en kort syntese af det unaturlige sukkerstof L-threose i 74% samlet udbytte i fem trin fra D-glukose. R OH O 8% Rh(dppp)2Cl OH HO OH 6% pyridin OH + CO diglyme/DMA HO OH 162 °C OH R R = H, CH , CH OH 3 2 Som en del af fremstillingen af naturstofferne calystegin A3 og gabosin A er D-glukose og D-ribose blevet forlænget med tre kulstofatomer ved hjælp af en zink-medieret fragmentering- allyleringsreaktion. Calystegin A 3 blev fremstillet på to lidt forskellige måder i 13 og 14 trin med henholdsvis 8,3 og 5,3% overordnet udbytte fra D-glukose. Herved er det lykkedes at udvikle den hidtil korteste syntese af naturligt forekommende calystegin