Prostaglandins (PGs) are a group of naturally occurring lipid compounds. They exist in animals and human-beings and mediate various physiological functions. 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, PGs have attracted considerable attention from synthetic chemists and numerous synthetic explorations have been implemented over several decades.
Our research group interested in synthesis of PGF2α which is known for its luteolytic effect (degradation of the corpus luteum) in cattle and prostacyclin (PGI2) which has excellent ability to inhibit platelet aggregation and vasodilation. 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. 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. 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 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.
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.