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M. Dai, S. J. Danishefsky / Tetrahedron Letters 49 (2008) 6610–6612
OTBS
O
Me
O
TBSO
Me
O
a
+
b
Br
OHC
O
O
22
OTBS
O
O
23
9
OTBS
NEt2
HO
Me
O
8
O
24
O
OH
TBSO
TBSO
c
Me
23
9
Me
e,f
g
8
O
O
or
d
O
O
O
O
26
25
TBSO
OMs
Me
O
O
O
O
27
Scheme 4. Synthesis of the pentacyclic core of cortistatin A. Reagents and conditions: (a) tBuLi, Et2O, À78 °C, 30 min, then 22, then heated to 80 °C, overnight, 44%; (b) TBAF,
THF, 0 °C, 2 h, 96%; (c) THF, 130 °C, overnight, 100%; (d) tBuLi, Et2O, À78 °C, 30 min, then 22, then heated to 130 °C, overnight, 71%; (e) I2, MeOH/THF (1/1), rt, 2 h, 83%;
(f) MsCl, Pyridine, CH2Cl2, 0 °C?rt, 94%; (g) TBAF, THF, rt, 5 min, then 130 °C, 20 min, 88%.
2. (a) Folkman, J. New Engl. J. Med. 1995, 333, 1757; (b) Folkman, J.; Shing, Y. J. Biol.
Chem. 1992, 267, 10931.
3. When we were preparing this manuscript, three elegant syntheses of the
In summary, we have devised and reduced to practice a concise
and efficient route to the core matrix of the cortistatins. Critical to
its success was an orchestration of carbanion chemistry, an O?O
acyl transfer driven rearrangement, quinomethide formation,19
and electrocyclic re-aromatization setting the stage for alkylative
dearomatization (see 9?27). This chemistry could well be extended
to a total synthesis of the cortistatin family of steroids. Equally
important, it sets the stage for realistic SAR work based on diverted
total synthesis.7
cortistatin core were reported see: (a) Yamashita, S.; Iso, K.; Hirama, M. Org.
Lett. 2008, 10, 3413; (b) Simmons, E. M.; Hardin, A. R.; Guo, X.; Sarpong, R.
Angew. Chem., Int. Ed. 2008, 47, 6650; (c) Craft, D. T.; Gung, B. W. Tetrahedron
Lett. 2008, 49, 5931.
4. Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,
130, 7241.
5. Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Angew. Chem., Int.
Ed. 2008, 47, 7310.
6. Dai, M.; Danishefsky, S. J. Heterocycles; published online, April 17th, 2008.
COM-08-S(F)6.
7. (a) Njardarson, J. T.; Gaul, C.; Shan, D.; Huang, X.-Y.; Danishefsky, S. J. J. Am.
Chem. Soc. 2004, 126, 1038; (b) Wilson, R. M.; Danishefsky, S. J. J. Org. Chem.
2006, 71, 8329.
8. (a) Masamune, S. J. Am. Chem. Soc. 1961, 83, 1009; (b) Lalic, G.; Corey, E. J. Org.
Lett. 2007, 9, 4921.
9. (a) Chauder, B. A.; Kalinin, A. V.; Taylor, N. J.; Snieckus, V. Angew. Chem., Int. Ed.
1999, 38, 1435; (b) Chauder, B. A.; Kalinin, A. V.; Snieckus, V. Synthesis 2001,
140.
10. (a) Kranich, R.; Eis, K.; Geis, O.; Mühle, S.; Bats, J. W.; Schmalz, H.-G.
Chem. Eur. J. 2000, 6, 2874; (b) Alvarez-Manzaneda, E. J.; Chahboun, R.;
Pérez, I. B.; Cabrera, E.; Alvarez, E.; Alvarez-Manzaneda, R. Org. Lett. 2005,
7, 1477.
Acknowledgments
Financial support for this research was provided by the National
Institutes of Health (HL25848 and CA103823). M.D. thanks the gen-
erous support of the Guthikonda Fellowship in Organic Chemistry,
the Bristol-Myers Squibb Graduate Fellowship in Synthetic Organic
Chemistry, and the Sylvia & Victor Fourman Fellowship. We thank
Daniela Buccella and Aaron Sattler (Parkin Group) for the crystal
structure analysis and the National Science Foundation (CHE-
0619638) for acquisition of an X-ray diffractometer. Ms. Rebecca
Wilson is thanked for valuable help in editing the manuscript.
11. (a) Gagnier, S. V.; Larock, R. C. J. Am. Chem. Soc. 2003, 125, 4804; (b)
Chandraratna, R. A. S.; Okamura, W. H. J. Am. Chem. Soc. 1982, 104, 6114; (c)
Yadav, V. K.; Senthil, G.; Babu, K. G.; Parvez, M.; Reid, J. L. J. Org. Chem. 2002, 67,
1109.
12. Smith, A. B., III; Sperry, J. B.; Han, Q. J. Org. Chem. 2007, 72, 6891.
13. Hajos, Z. G.; Micheli, R. A.; Parrish, D. R.; Oliveto, E. P. J. Org. Chem. 1967, 32,
3008.
14. Senanayake, C. H.; Bill, T. J.; DiMichele, L. M.; Chen, C. Y.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1993, 34, 6021.
15. Snider, B. B.; Vo, N. H.; O’Neil, S. V.; Foxman, B. M. J. Am. Chem. Soc. 1996, 118,
7644.
16. More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
17. CCDC 696105 contains the supplementary crystallographic data for compound
24.
18. CCDC 696762 contains the supplementary crystallographic data for compound
27.
Supplementary data
Supplementary data associated with this article can be found, in
References and notes
1. (a) Aoki, S.; Watanabe, Y.; Sanagawa, M.; Setiawan, A.; Kotoku, N.; Kobayashi,
M. J. Am. Chem. Soc. 2006, 128, 3148; (b) Watanabe, Y.; Aoki, S.; Tanabe, D.;
Setiawan, A.; Kobayashi, M. Tetrahedron 2007, 63, 4074; (c) Aoki, S.; Watanabe,
Y.; Tanabe, D.; Setiawan, A.; Arai, M.; Kobayashi, M. Tetrahedron Lett. 2007, 48,
4485.
19. Van De Water, R. W.; Magdziak, D. J.; Chau, J. N.; Pettus, T. R. R. J. Am. Chem. Soc.
2000, 122, 6502.