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제124회 대한화학회 학술발표회, 총회 및 기기전시회 안내 Total Synthesis of PGF2α and 6,15-Diketo-PGF1α and Formal Synthesis of 6-Keto-PGF1α via Three-Component Coupling

2019년 8월 29일 14시 16분 19초
ORGN.P-438 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
10월 18일 (금요일) 11:00~12:30
Organic Chemistry
저자 및
Taehyeong Kim, Do Hyun Ryu*
Department of Chemistry, Sungkyunkwan University, Korea

Prostaglandins (PGs) are a group of naturally occurring lipid compounds. They exist in animals and human-beings and mediate various physiological functions[1]. PGs contain 20 carbon atoms including a five-membered carbon ring and have several types of analogues which vary in carbon ring and upper and lower side chain structures. Due to their wide array of bioactivities[2], PGs have attracted considerable attention from synthetic chemists and numerous synthetic explorations have been implemented over several decades[3]. Our research group interested in synthesis of PGF2α which is known for its luteolytic effect (degradation of the corpus luteum) in cattle[4] and prostacyclin (PGI2) which has excellent ability to inhibit platelet aggregation and vasodilation[2]. One of the PGF2α analogues, latanoprost (Xalatan) is using for treatment of glaucoma and quickly became a “blockbuster” drug for Pfizer, with sales of $1.75 billion in 2010[5]. Because PGI2 is unstable in aqueous conditions and rapidly decomposed to its metabolites; for instance, 6,15-diketo-PGF1α and 6-keto-PGF1α are known metabolites of prostacyclin[6]. Compared with PGF2α, synthetic studies on PGI2 and its stable metabolites, 6,15-diketo-PGF1α and 6-keto-PGF1α have rarely been reported[3(b)]. To the best of our knowledge, there is no synthetic example for 6,15-diketo-PGF1α and only one example of total synthesis of 6-keto-PGF1α from simple starting material was reported[7] in spite of their many analytical studies[6(c),8]. Considering the same core structures of them, we envisioned that three target compounds would be synthesized from common intermediate because appropriate functional groups can be easily introduced for the installation of both side chains. Herein, we reported an efficient synthetic route to PGF2α, 6,15-diketo-PGF1α and 6-keto-PGF1α with high levels of stereoselectivity from a common synthetic intermediate. References : 1. (a) Gibson, K. H. Chem. Soc. Rev. 1977, 6, 489-510; (b) Curtis-Prior, P. B. Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids, Churchill Livingstone, New York, 1988; (c) Marks, F.; Fürstenberger, G. Prostaglandins, Leukotrienes and other Eicosanoids, Wiley-VCH, Verlag, New York, 1999 and references therein; (d) Dams, I.; Wasyluk, J.; Prost, M.; Kutner, A. Prostaglandins Other Lipid Mediators 2013, 104-105, 109-121. 2. Collins, P. W.; Djuric, S. W. Chem. Rev. 1993, 93, 1533-1564. 3. (a) Das, S.; Chandrasekhar, S.; Yadav, J. S.; Grée, R. Chem. Rev. 2007, 107, 3286-3337; (b) Peng, H.; Chen, F.-E. Org. Biomol. Chem. 2017, 15, 6281-6301. 4. (a) Lauderdale, J. W. J. Anim. Sci. 2008, 87, 801. (b) Rowson, L. E. A.; Tervit, R.; Brand, A. J. Reprod. Fertil. 1972, 29, 145. 5. Full-year results for 2010 were reported by pfizer: http://www.pfizer.com/Files/investors/presentations/q4performance_020111.pdf 6. (a) Cho, M. J.; Allen, M. A. Prostaglandins 1978, 15, 943-954; (b) Armstrong, J. M.; Thirsk, G.; Salmon, J. A. Hypertension 1979, 1, 309-315; (c) Etingin, O. R.; Weksler, B. B.; Hajjar, D. P. J. Lipid. Res. 1986, 27, 530-536. 7. Tanaka, T.; Hazato, A.; Bannai, K.; Okamura, N.; Sugiura, S.; Manabe, K.; Toru, T.; Kurozumi, S.; Suzuki, M.; Kawagishi, T.; Noyori, R. Tetrahedron 1987, 43, 813-824. 8. (a) Falardeau, P.; Oates, J. A.; Brash, A. R. Anal. Biochem. 1981, 115, 359. (c) Rosenkranz, B.; Fischer, C.; Weimer, K. E.; Froelich, J. C. J. Biol. Chem. 1980, 255, 10194.