total synthesis of cortistatin a and related structures

Total Synthesis of Cortistatin A and Analogues

Kai Hong

Morken Group Topic Talk

November 17th, 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):

IC50 = 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: 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, P. J. Am. Chem. Soc. 2008, 130, 7241


Baran: A-Ring Functionalization

• Rationale for the Selectivity of Mukaiyama Hydration

• epoxidation: > 30 g scale

• amination: hydride attacks the b face

• epoxide opening: 2:1 ratio, minor regioisomer recycled by DMAP



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

• 1st example of an alcohol-directed, geminal dihalogenation of an unactivated hydrocarbon.

• radical opening of the three-membered ring using SmI2

• 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: 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

– SmI2/Et3N/H2O, over-reduction

– Pd/C, H2, over-reduction

– Pd/CaCO3, H2, over-reduction

– RhCl(PPh3)3, NaOH, i-PrOH, no reaction

– KO2CN=NCO2K, no reaction

• 101 was found nearly equipotent to 11 in all biological assays tested

• 16 steps, 2.1% overall yield



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) H2 (1 atm), Pd/C;

• (d) m-CPBA, NaHCO3; HF (66% over 4 steps);

• (e) MEMCl, iPrNEt2 (88%);

• (f) PPTS; (g) NaOMe (49% over 2 steps);

• (h) SOCl2, pyridine;

• (i) NaHMDS, PhNTf2;

• (j) Me3SiCH2MgBr for 10a or Me(OiPr)2SiCH2MgCl for 10b, Pd(PPh3)4 (62% over 3 steps).


(a) CHBr3, KOtBu; (b) TASF (66% over two steps); (c) 13, Pd(PPh3)4, K2CO3 (84%); (d) K2OsO4·2H2O, (DHQD)2PHAL, K3Fe(CN)6, K2CO3, MeSO2NH2, 10:1 d.r.; (e) Ac2O, NEt3, DMAP (51% over two steps); (f) HF/pyr; (g) DMP; (h) Me2NH, ZnBr2 (65% over three steps); (i) TBAF (70%); (j) TPAP, NMO (quant.); (k) K2CO3 (82%); (l) N2H4·H2O, NEt3; NEt3, I2; (m) Pd(PPh3)4, 7-isoquinolinestannane, LiCl, CuCl (61% over three steps); (n) 2,4,6-triisopropylbenzenesulfonyl hydrazide, NEt3 (20%).

Forward Synthesis: Continued


• 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

• 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


• 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)

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

• 8: 5 steps form Hajors-Parrish ketone

• Ohira-Bestman reagent generated alkyne

• Installation of isoquinoline at early stage prevented the hydrogenation of alkyne



73%

87%

72%

79%

86%

70%

72%

45%

85%

64%

125 oC, 12 h 52%

• 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



63%

80%

60% 88%

50%

46%

70%

80%, 1:1 100%

45% 36%

60%

81%

40% yield, 45% sm

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

Completion of Synthesis


Funk: (±)-Cortistatin J from Furan

Funk, R. L. J. Am. Chem. Soc. 2011, 133, 12451

Overman, L. E. Tetrahedron Lett. 1984, 25, 5739

Funk, R. L. Org. Lett. 2001, 3, 3553

• A-ring: exocyclic iminium ion/vinylsilane cyclization: Overman protocol

• endo [4+3] cyclization

Tetracyclic Core Synthesis


single diastereomer

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


Total Syntheses Summary

Formal Syntheses

Sorensen, E. J. Org. Lett. 2009, 11, 5394

Danishefsky, S. J. Tetrahedron Lett. 2008, 49, 6613

Sarpong, R. ACIE, 2008, 47, 6650

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.

Thank you!

SmI2 mediated B-Ring Expansion Mechanism

Myers: Synthesis of Zinc Reagent 8

total synthesis of cortistatin a and related structures

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