Total Synthesis of Cortistatin A and Analogues Kai Hong Morken Group Topic Talk November 17 th, 2011
Topic Overview Discovery and Bioactivity of Cortistatins Synthetic challenge Total syntheses Baran: Semisynthesis from Nature Steroid Shair: Aza-Prins Cyclization Nicolaou: 1,4-Addition/Aldol Reaction Myers: Ring-Closing Metathesis Funk: [4+3] Cyclization Formal Syntheses Summary
Discovery and Bioactivity Cortistatins A-J: a group of steroidal alkaloids first isolated in 2006 by Kobayashi group from the marine sponge Corticium simplex Highly selective antiangiogenic activity against human umbilical vein endothelial cells (HUVECs): IC 50 = 0.0018 mm (cortistatin A) Angiogenesis: A process that involves the formation of new blood vessels from pre-existing ones, is fundamental and vital to growth, development, and wound healing but also to cancer metastasis. in vivo studies have not been published due to its low availability Kobayashi, M. J. Am. Chem. Soc. 2006, 128, 3148 Baran, P. J. Am. Chem. Soc. 2011, 133, 8014
Kobayashi, M. J. Am. Chem. Soc. 2006, 128, 3148 Baran, P. J. Am. Chem. Soc. 2011, 133, 8014
Synthetic Challenges Unusal 9(10,19)-abeo-androstane skeleton, which contains the 6-7-6-5 ring system Oxabicyclo[3.2.1]octene core Contiguous trans stereocenters on A-Ring 8 stereocenters Isoquinoline motif
Baran, P. J. Am. Chem. Soc. 2008, 130, 7241 Baran, P. J. Am. Chem. Soc. 2011, 133, 8014 Baran: Retrosynthesis via (+)-Cortistatinone Considerations: redox-neutral conversion from commercial steroid to target (the same oxidation state) a strategic sacrifice has to be made to oxidize C19 methyl introduction of isoquinoline at late stage the price of the starting material (prednisone $1.2/g) Challenges to be addressed: control of all four A-ring stereocenters oxidation of the unfunctionalized C19 and C8 centers expansion of the B-ring chemo-/stereoselective installation of the side chain
Baran: A-Ring Functionalization epoxidation: > 30 g scale amination: hydride attacks the b face epoxide opening: 2:1 ratio, minor regioisomer recycled by DMAP Rationale for the Selectivity of Mukaiyama Hydration Baran, P. J. Am. Chem. Soc. 2008, 130, 7241 Baran, P. J. Am. Chem. Soc. 2011, 133, 8014
Baran: B-Ring Expansion initially proposed by Kobayashi in the plausible biogenesis of cortistatins in-situ generate acetoxy hypobromite (BrOAc) bromide on cyclopropane is not necessary for ring-expansion 1 st example of an alcohol-directed, geminal dihalogenation of an unactivated hydrocarbon. radical opening of the three-membered ring using SmI 2 TBCHD: 2,4,4,6-tetrabromo-2,5-cyclohexadienone, Br + source Lewis acid promoted ring closure Baran, P. J. Am. Chem. Soc. 2008, 130, 7241 Baran, P. J. Am. Chem. Soc. 2011, 133, 8014
Baran: Isoquinoline Installation Attempted installation at early stages of the synthesis prevented the desired diversification Barton s vinyl iodide preparation Numerous conditions failed in the last step: either over-reduction or no reaction SmI 2 /Et 3 N/H 2 O, over-reduction Pd/C, H 2, over-reduction Pd/CaCO 3, H 2, over-reduction RhCl(PPh 3 ) 3, NaOH, i-proh, no reaction KO 2 CN=NCO 2 K, no reaction 101 was found nearly equipotent to 11 in all biological assays tested 16 steps, 2.1% overall yield Baran, P. J. Am. Chem. Soc. 2008, 130, 7241 Baran, P. J. Am. Chem. Soc. 2011, 133, 8014
Shair: Aza-Prins Bicyclization The synthesis plan was guided by a desire to produce Cortistatins A, C, J for biological and medicinal studies and generate diverse analogues To discover molecules less complex than Cortistatin A but that maintain the biological activity Key step: aza-prins cyclization via iminium ion with transannular cyclization Shair, M. D. J. Am. Chem. Soc. 2008, 130, 16864
Shair: Forward Synthesis (a) NaH; 2-(2-bromoethyl)-2-methyl-1,3-dioxolane; (b) TBSOTf, 2,6-lutidine; (c) H 2 (1 atm), Pd/C; (d) m-cpba, NaHCO 3 ; HF (66% over 4 steps); (e) MEMCl, iprnet2 (88%); (f) PPTS; (g) NaOMe (49% over 2 steps); (h) SOCl 2, pyridine; (i) NaHMDS, PhNTf 2 ; (j) Me 3 SiCH 2 MgBr for 10a or Me(OiPr) 2 SiCH 2 MgCl for 10b, Pd(PPh 3 ) 4 (62% over 3 steps). Shair, M. D. J. Am. Chem. Soc. 2008, 130, 16864
Forward Synthesis: Continued (a) CHBr 3, KOtBu; (b) TASF (66% over two steps); (c) 13, Pd(PPh 3 ) 4, K 2 CO 3 (84%); (d) K 2 OsO 4 2H 2 O, (DHQD) 2 PHAL, K 3 Fe(CN) 6, K 2 CO 3, MeSO 2 NH 2, 10:1 d.r.; (e) Ac 2 O, NEt 3, DMAP (51% over two steps); (f) HF/pyr; (g) DMP; (h) Me 2 NH, ZnBr 2 (65% over three steps); (i) TBAF (70%); (j) TPAP, NMO (quant.); (k) K 2 CO 3 (82%); (l) N 2 H 4 H 2 O, NEt 3 ; NEt 3, I 2 ; (m) Pd(PPh 3 ) 4, 7-isoquinolinestannane, LiCl, CuCl (61% over three steps); (n) 2,4,6-triisopropylbenzenesulfonyl hydrazide, NEt 3 (20%). TASF: tris(diethylamino)sulfonium difluorotrimethylsilicate, F - source 11a generated allylsilane as byproduct >20:1 d.r. in aza-prins cyclization Final step: diimide hydrogenation 24 steps, 0.14% overall yield Shair, M. D. J. Am. Chem. Soc. 2008, 130, 16864
11a: equal mixture of 12 and 20 20 12 failed 11b: disiloxane has a higher propensity for pentacoordinate fluorosilicate silica-directed elimination exclusively 12, 66% yield (2 steps) The forming A-ring exists in a boat conformation The internal methyl iminium ion and C2-H are coplanar to avoid A(1,3) strain C2-OAc blocks addition from the Re face, guiding addition to the Si face Shair, M. D. J. Am. Chem. Soc. 2008, 130, 16864
Nicolaou & Chen s Retrosynthesis Nicolaou, K. C.; Chen, D. Y.-K. ACIE 2008, 47, 7310 Nicolaou, K. C.; Chen, D. Y.-K. J. Am. Chem. Soc. 2009, 131, 10587
Nicolaou & Chen s Forward Synthesis 73% 87% 72% 85% 79% 86% 64% 70% 72% 125 o C, 12 h 52% 45% 8: 5 steps form Hajors-Parrish ketone Ohira-Bestman reagent generated alkyne Installation of isoquinoline at early stage prevented the hydrogenation of alkyne Nicolaou, K. C.; Chen, D. Y.-K. ACIE 2008, 47, 7310 Nicolaou, K. C.; Chen, D. Y.-K. J. Am. Chem. Soc. 2009, 131, 10587
63% 80% 60% 81% 88% 60% 50% 40% yield, 45% sm 100% 70% 80%, 1:1 46% Hydrogenation occurs from the convex face Luche reduction furnished 1:1 isomers, undesired isomer 83 could be recycled by DMP oxidation Final step: 1 in 45% yield, 85 in 36% yield 25+5 steps, < 0.012% overall yield 83 could also be converted to cortistatin J 36% 45% Nicolaou, K. C.; Chen, D. Y.-K. ACIE 2008, 47, 7310 Nicolaou, K. C.; Chen, D. Y.-K. J. Am. Chem. Soc. 2009, 131, 10587
Myers: Cortistatins A, J, K and L from the same intermediate Myers, A. G. Nature Chem. 2010, 2, 886
Synthesis of Azido Alcohol Intermediate 16 g scale Myers, A. G. Nature Chem. 2010, 2, 886
Myers, A. G. Nature Chem. 2010, 2, 886
Completion of Synthesis Myers, A. G. Nature Chem. 2010, 2, 886
Funk: (±)-Cortistatin J from Furan Funk, R. L. Org. Lett. 2001, 3, 3553 A-ring: exocyclic iminium ion/vinylsilane cyclization: Overman protocol endo [4+3] cyclization Funk, R. L. J. Am. Chem. Soc. 2011, 133, 12451 Overman, L. E. Tetrahedron Lett. 1984, 25, 5739
Tetracyclic Core Synthesis single diastereomer Funk, R. L. J. Am. Chem. Soc. 2011, 133, 12451
Completion of the Total Synthesis Alkene reduction of 19 using diimide from potassium azodicarboxylate The presence of isoquinoline didn t complicate subsequent steps The cyclization of A-ring presumably proceeds through iminium ion conformer 6 20 steps, 4.2% overall yield Funk, R. L. J. Am. Chem. Soc. 2011, 133, 12451
Total Syntheses Summary
Formal Syntheses Danishefsky, S. J. Tetrahedron Lett. 2008, 49, 6613 Sarpong, R. ACIE, 2008, 47, 6650 Sorensen, E. J. Org. Lett. 2009, 11, 5394 Stoltz, B. M. Org. Biomol. Chem. 2010, 8, 2915
Summary Five total syntheses of cortistatin A and analogues have been discussed. A number of ring-formation methodologies have been introduced, including: ring expansion, aza-prins cyclization, 1,4-addition/aldol reaction, olefin metathesis, [4+3] cycloaddition, enyne metathesis, [3+2] cycloaddtion, etc. Cross-coupling reactions were widely used in these syntheses, especially the installation of isoquinoline motif.
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SmI 2 mediated B-Ring Expansion Mechanism
Myers: Synthesis of Zinc Reagent 8