Synthesis of cortistatins A, J, K and L


The cortistatins are a recently identified class of marine natural products characterized by an unusual steroidal skeleton, which have been found to inhibit differentially the proliferation of various mammalian cells in culture by an unknown mechanism. We describe a comprehensive route for the synthesis of cortistatins from a common precursor, which in turn is assembled from two fragments of similar structural complexity. Cortistatins A and J, and for the first time K and L, have been synthesized in parallel processes from like intermediates prepared from a single compound. With the identification of facile laboratory transformations linking intermediates in the cortistatin L synthetic series with corresponding intermediates to cortistatins A and J, we have been led to speculate that somewhat related paths might occur in nature, offering potential sequencing and chemical detail for cortistatin biosynthetic pathways.

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Figure 1: Cortistatins A, J, K and L and their IC50 values measured in cultured HUVECs.
Figure 2: A key precursor to cortistatins and its retrosynthetic disconnection.
Figure 3: Preparation of the o-vinyl benzylzinc reagent 8.
Figure 4: Synthesis of azido alcohol 5 from α-methylene ketone 15.
Figure 5: Synthetic pathways to 17-keto precursors to cortistatins A, J, K and L from azido alcohol 5.
Figure 6: Syntheses of cortistatins A, L, J and K.
Figure 7: Chemical interconversions among intermediates of cortistatin series A, J and L and a hypothesized parallel biosynthetic sequence.


  1. 1

    Aoki, S. et al. Cortistatins A, B, C and D, anti-angiogenic steroidal alkaloids, from the marine sponge Corticium simplex. J. Am. Chem. Soc. 128, 3148–3149 (2006).

  2. 2

    Watanabe, Y., Aoki, S., Tanabe, D., Setiawan, A. & Kobayashi, M. Cortistatins E, F, G and H, four novel steroidal alkaloids from marine sponge Corticium simplex. Tetrahedron 63, 4074–4079 (2007).

  3. 3

    Aoki, S. et al. Cortistatins J, K, L, novel abeo-9(10-19)-androstane-type steroidal alkaloids with isoquinoline unit, from marine sponge Corticium simplex. Tetrahedron Lett. 48, 4485–4488 (2007).

  4. 4

    Aoki, S. et al. Structure–activity relationship and biological property of cortistatins, anti-angiogenic spongean steroidal alkaloids. Bioorg. Med. Chem. 15, 6758–6762 (2007).

  5. 5

    Shenvi, R. A., Guerrero, C. A., Shi, J., Li, C.-C. & Baran, P. S. Synthesis of (+)-cortistatin A. J. Am. Chem. Soc. 130, 7241–7243 (2008).

  6. 6

    Nicolaou, K. C., Sun, Y. P., Peng, X. S., Polet, D. & Chen, D. Y. K. Total synthesis of (+)-cortistatin A. Angew. Chem. Int. Ed. 47, 7310–7313 (2008).

  7. 7

    Lee, H. M., Nieto-Oberhuber, C. & Shair, M. D. Enantioselective synthesis of (+)-cortistatin A, a potent and selective inhibitor of endothelial cell proliferation. J. Am. Chem. Soc. 130, 16864–16866 (2008).

  8. 8

    Simmons, E. M., Hardin, A. R., Guo, X. & Sarpong, R. Rapid construction of the cortistatin pentacyclic core. Angew. Chem. Int. Ed. 47, 6650–6653 (2008).

  9. 9

    Yamashita, S., Iso, K. & Hirama, M. A concise synthesis of the pentacyclic framework of cortistatins. Org. Lett. 10, 3413–3415 (2008).

  10. 10

    Craft, D. T. & Gung, B. W. The first transannular [4 + 3] cycloaddition reaction: synthesis of the ABCD ring structure of cortistatins. Tetrahedron Lett. 49, 5931–5934 (2008).

  11. 11

    Dai, M. J. & Danishefsky, S. J. A concise synthesis of the cortistatin core. Tetrahedron Lett. 49, 6610–6612 (2008).

  12. 12

    Dai, M. J., Wang, Z. & Danishefsky, S. J. A novel α,β–unsaturated nitrone-aryne [3 + 2] cycloaddition and its application in the synthesis of the cortistatin core. Tetrahedron Lett. 49, 6613–6616 (2008).

  13. 13

    Kotoku, N., Sumii, Y., Hayashi, T. & Kobayashi, M. Synthesis of CD-ring structure of cortistatin A, an anti-angiogenic steroidal alkaloid from marine sponge. Tetrahedron Lett. 49, 7078–7081 (2008).

  14. 14

    Kurti, L., Czako, B. & Corey, E. J. A short, scalable synthesis of the carbocyclic core of the anti-angiogenic cortistatins from (+)-estrone by B-ring expansion. Org. Lett. 10, 5247–5250 (2008).

  15. 15

    Dai, M. J. & Danishefsky, S. J. An oxidative dearomatization cyclization model for cortistatin A. Heterocycles 77, 157–161 (2009).

  16. 16

    Liu, L. Z. et al. A model study for the concise construction of the oxapentacyclic core of cortistatins through intramolecular Diels–Alder and oxidative dearomatization–cyclization reactions. Chem. Commun. 662–664 (2009).

  17. 17

    Magnus, P. & Littich, R. Intramolecular cyclopropene-furan [2 + 4] cycloaddition followed by a cyclopropylcarbinyl rearrangement to synthesize the BCD rings of cortistatin A. Org. Lett. 11, 3938–3941 (2009).

  18. 18

    Frie, J. L., Jeffrey, C. S. & Sorensen, E. J. A hypervalent iodine-induced double annulation enables a concise synthesis of the pentacyclic core structure of the cortistatins. Org. Lett. 11, 5394–5397 (2009).

  19. 19

    Yamashita, S., Kitajima, K., Iso, K. & Hirama, M. Efficient and stereoselective installation of isoquinoline: formal total synthesis of cortistatin A. Tetrahedron Lett. 50, 3277–3279 (2009).

  20. 20

    Simmons, E. M., Hardin-Narayan, A. R., Guo, X. & Sarpong, R. Formal total synthesis of (±)-cortistatin A. Tetrahedron 66, 4696–4700 (2010).

  21. 21

    Nicolaou, K. C. et al. Total synthesis and biological evaluation of cortistatins A and J and analogues thereof. J. Am. Chem. Soc. 131, 10587–10597 (2009).

  22. 22

    Shi, J. et al. Stereodivergent synthesis of 17-α and 17-β-aryl steroids: application and biological evaluation of D-ring cortistatin analogues. Angew. Chem. Int. Ed. 48, 4328–4331 (2009).

  23. 23

    Czako, B., Kurti, L., Mammoto, A., Ingber, D. E. & Corey, E. J. Discovery of potent and practical antiangiogenic agents inspired by cortistatin A. J. Am. Chem. Soc. 131, 9014–9019 (2009).

  24. 24

    Cee, V. J., Chen, D. Y. K., Lee, M. R. & Nicolaou, K. C. Cortistatin A is a high-affinity ligand of protein kinases ROCK, CDK8 and CDK11. Angew. Chem. Int. Ed. 48, 8952–8957 (2009).

  25. 25

    Berk, S. C., Knochel, P. & Yeh, M. C. P. General approach to highly functionalized benzylic organometallics of zinc and copper. J. Org. Chem. 53, 5789–5791 (1988).

  26. 26

    Pearson, D. E., Cowan, D. & Beckler, J. D. A study of the entrainment method for making Grignard reagents. J. Org. Chem. 24, 504–509 (1959).

  27. 27

    Isaacs, R. C. A., Digrandi, M. J. & Danishefsky, S. J. Synthesis of an enantiomerically pure intermediate containing the CD substructure of taxol. J. Org. Chem. 58, 3938–3941 (1993).

  28. 28

    Hajos, Z. G. & Parrish, D. R. (+)-(7aS)-7a-methyl-2,3,7,7a-tetrahydro-1H-indene-1,5-6H-dione. In Organic Syntheses, Vol. 63, 26–31 (Wiley & Sons, 1985).

  29. 29

    Evans, D. A., Hurst, K. M. & Takacs, J. M. New silicon-phosphorus reagents in organic synthesis: carbonyl and conjugate addition reactions of silicon phosphite esters and related systems. J. Am. Chem. Soc. 100, 3467–3477 (1978).

  30. 30

    Kozikowski, A. P. & Jung, S. H. Phosphoniosilylation: an efficient and practical method for the β-functionalization of enones. J. Org. Chem. 51, 3400–3402 (1986).

  31. 31

    Mi, Y., Schreiber, J. V. & Corey, E. J. Total synthesis of (+)-α-onocerin in four steps via four-component coupling and tetracyclization steps. J. Am. Chem. Soc. 124, 11290–11291 (2002).

  32. 32

    Walker, S. D., Barder, T. E., Martinelli, J. R. & Buchwald, S. L. A rationally designed universal catalyst for Suzuki–Miyaura coupling processes. Angew. Chem. Int. Ed. 43, 1871–1876 (2004).

  33. 33

    Scholl, M., Ding, S., Lee, C. W. & Grubbs, R. H. Synthesis and activity of a new generation of ruthenium-based olefin metathesis catalysts coordinated with 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene ligands. Org. Lett. 1, 953–956 (1999).

  34. 34

    Murray, R. W. & Singh, M. Synthesis of epoxides using dimethyldioxirane: trans-stilbene oxide. In Organic Syntheses, Vol. 74, 91–100 (Wiley & Sons, 1997).

  35. 35

    Thummel, R. P. & Rickborn, B. Base-induced rearrangement of epoxides. V. Phenyl-substituted epoxides. J. Org. Chem. 37, 3919–3923 (1972).

  36. 36

    Kita, Y., Tohma, H., Kikuchi, K., Inagaki, M. & Yakura, T. Hypervalent iodine oxidation of N-acyltyramines: synthesis of quinol ethers, spirohexadienones and hexahydroindol-6-ones. J. Org. Chem. 56, 435–438 (1991).

  37. 37

    Kogure, T. & Ojima, I. Reduction of carbonyl compounds via hydrosilylation. 4. Highly regioselective reductions of α,β-unsaturated carbonyl compounds. Organometallics 1, 1390–1399 (1982).

  38. 38

    Corey, E. J. & Helal, C. J. Reduction of carbonyl compounds with chiral oxazaborolidine catalysts: a new paradigm for enantioselective catalysis and a powerful new synthetic method. Angew. Chem. Int. Ed. 37, 1986–2012 (1998).

  39. 39

    San Filippo, J., Chern, C. I. & Valentine, J. S. Reaction of superoxide with alkyl halides and tosylates. J. Org. Chem. 40, 1678–1680 (1975).

  40. 40

    Corey, E. J., Nicolaou, K. C., Shibasaki, M., Machida, Y. & Shiner, C. S. Superoxide ion as a synthetically useful oxygen nucleophile . Tetrahedron Lett. 37, 3183–3186 (1975).

  41. 41

    Ishihara, K., Kubota, M., Kurihara, H. & Yamamoto, H. Scandium trifluoromethanesulfonate as an extremely active acylation catalyst. J. Am. Chem. Soc. 117, 4413–4414 (1995).

  42. 42

    Hutchins, R. O., Learn, K. & Fulton, R. P. Reductive displacement of allylic acetates by hydride transfer via catalytic activation by palladium(0) complexes. Tetrahedron Lett. 21, 27–30 (1980).

  43. 43

    Couturier, M., Tucker, J. L., Andresen, B. M., Dube, P. & Negri, J. T. Palladium and Raney nickel catalyzed methanolic cleavage of stable borane–amine complexes. Org. Lett. 3, 465–467 (2001).

  44. 44

    Moon, S. S., Stuhmiller, L. M. & McMorris, T. C. Synthesis of oogoniol. J. Org. Chem. 54, 26–28 (1989).

  45. 45

    Foy, N. et al. Synthesis, receptor binding, molecular modeling and proliferative assays of a series of 17α-arylestradiols. Chembiochem. 4, 494–503 (2003).

  46. 46

    Jang, D. O., Kim, J. G., Cho, D. H. & Chung, C. M. Radical deoxygenation of alcohols via their trifluoroacetate derivatives with diphenylsilane. Tetrahedron Lett. 42, 1073–1075 (2001).

  47. 47

    Kim, J. G., Cho, D. H. & Jang, D. O. Radical deoxygenation of tertiary alcohols via trifluoroacetates. Tetrahedron Lett. 45, 3031–3033 (2004).

  48. 48

    D' Auria, M. V., Minale, L. & Riccio, R. Polyoxygenated steroids of marine origin. Chem. Rev. 93, 1839–1895 (1993).

  49. 49

    Sarma, N. S., Krishna, M. S. R. & Rao, S. R. Sterol ring system oxidation pattern in marine sponges. Mar. Drugs 3, 84–111 (2005).

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Financial support from the National Institutes of Health (Stimulus grant no. CA047148-22S1) is gratefully acknowledged. A.N.F. acknowledges a scholarship from Eli Lilly and Company. We gratefully acknowledge G. Zou for measuring the GI50 values of cortistatins A, J, K and L and A.W.G. Burgett and M.D. Shair for their assistance with these measurements as well as a gift of the HUVEC. We acknowledge helpful discussions with C. T. Walsh and E. Balskus.

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A.N.F., C.S. and A.G.M conceived the synthetic route. A.N.F and C.S. conducted all experimental work and analysed the results. A.N.F., C.S. and A.G.M. wrote the manuscript.

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Correspondence to Andrew G. Myers.

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Flyer, A., Si, C. & Myers, A. Synthesis of cortistatins A, J, K and L. Nature Chem 2, 886–892 (2010).

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