Total Synthesis of Kinamycins C, F, and J OR 2 R 1 O O OR 3 OR 4 N - - PowerPoint PPT Presentation

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Total Synthesis of Kinamycins C, F, and J OR 2 R 1 O O OR 3 OR 4 N - - PowerPoint PPT Presentation

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Total Synthesis of Kinamycins C, F, and J OR 2 R 1 O O OR 3 OR 4 N OH O N Kinamycin scaffold K.C. Nicolaou, Hongming Li, Andrea L. Nold, Doron Pappo, and Achim Lenzen J. Am. Chem. Soc., 2007 , ASAP John Maciejewski Wipf Group Current

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SLIDE 1

Total Synthesis of Kinamycins C, F, and J

K.C. Nicolaou, Hongming Li, Andrea L. Nold, Doron Pappo, and Achim Lenzen

  • J. Am. Chem. Soc., 2007, ASAP

John Maciejewski Wipf Group Current Literature August 18, 2007

OH OR4 OR3 N R1O OR2 O O N Kinamycin scaffold

John Maciejewski @ Wipf Group 1 10/29/2007

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SLIDE 2

Isolation and Brief History

Kinamycins A, B, C, and D isolated from fermentation broth

  • f Streptomyces murayamaensis (Ito, Hata)

Assignment of core structure subject of controversy Installation of densely oxygenated cyclohexane D-ring and diazo functionality present synthetic challenges Kinamycin family known to possess antibiotic and antitumor activities

Ito, S.; J. Antibiot. 1970, 23, 315 Hata, T; J. Antibiot. 1971, 24, 353 Gould, S. J.; Chem. Rev. 1997, 97, 2499

OH OR4 OR3 N R1O OR2 O O N Kinamycin scaffold Kinamycin A: R1 = H, R2 = Ac, R3 = Ac, R4 = Ac Kinamycin B: R1 = H, R2 = H, R3 = Ac, R4 = H Kinamycin C: R1 = Ac, R2 = Ac, R3 = H, R4 = Ac Kinamycin D: R1 = H, R2 = Ac, R3 = H, R4 = Ac

John Maciejewski @ Wipf Group 2 10/29/2007

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SLIDE 3

Initial Structural Assignment of Kinamycin Core

Hata, T.; Isr. J. Chem. 1972, 10, 173 Dmitrienko, G. I.; J. Am. Chem. Soc. 1994, 116, 2207 - 2208

Used IR, 1H, 13C, and X-ray analysis to assign kinamycin core

  • Poor quality X-ray data of kinamycin C
  • Could not unambiguously assign X-Y-Z connectivity
  • Either cyanide or isocyanide (diazo connectivity not considered(?))

OH OR4 OR3 X Y R1O OR2 O O Z initial assignment OH OR4 OR3 N C R1O OR2 O O N cyanobenzo[b]carbazole system

John Maciejewski @ Wipf Group 3 10/29/2007

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SLIDE 4

Structural Revisions

Gould and Dmitrienko independently revised structure based upon (original) X-ray structure, as well as indepth IR, NMR, and synthetic studies.

Dmitrienko, G. I.; Tet. Lett. 1990, 31, 3681 Gould, S.; J. Am. Chem. Soc. 1994, 116, 2207 - 2210. Dmitrienko, G. I.; J. Am. Chem. Soc. 1994, 116, 2207 - 2208

22 N-cyanoindole derivatives (Dmitrienko):

  • IR range (2237 - 2245 cm-1)
  • 13C NMR (δ 105 - 108) for cyanamide carbon

Kinamycin spectral data (Hata):

  • IR range (2119 - 2170-1)
  • 13C NMR (δ 78.5 - 83.7) “cyanamide” carbon

compared to…

OH OR4 OR3 N C R1O OR2 O O N Original assignment of kinamycin core cyanobenzo[b]carbazole system N R1 R2 O O C N N R2 R3 C N R1 R4 Scaffolds prepared by Dmitrienko

John Maciejewski @ Wipf Group 4 10/29/2007

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SLIDE 5

Structural Revisions

Gould, S.; J. Am. Chem. Soc. 1994, 116, 2207 - 2210. Dmitrienko, G. I.; J. Am. Chem. Soc. 1994, 116, 2207 - 2208

Kinamycin spectral data: Diazo bands - IR (2119 - 2170-1) -C=N=N

13C NMR (δ 78.5 - 83.7) diazo carbon

OH OR4 OR3 N C R1O OR2 O O N Original assignment of kinamycin core (Hata) cyanobenzo[b]carbazole system OH OR4 OR3 C N R1O OR2 O O N diazobenzo[b]fluorene ring system Revised kinamycin core (Gould & Dmitrienko) reassignment

Crystal structure of kinamycin D (Gould)

John Maciejewski @ Wipf Group 5 10/29/2007

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SLIDE 6

Proposed mechanism-of-action

Pathways to DNA cleavage

Feldman, K. S.; J. Am. Chem. Soc. 2005, 127, 15344 Melander, C.; Bioorg. Med. Chem. Lett. 2006, 16, 5148 Arya, D. P.; J. Org. Chem. 1995, 3268

OH N O O N HO CH3 OH O HO CH3 Bu3SnH, AIBN 80OC, benzene Ph Bu3SnO multiple aromatic solvents were screened OH OH O HO CH3 Ph workup OH N O O N HO CH3 prekinamycin OH N OH O N HO CH3 e-

  • N2

OH OH O HO CH3 DNA-H OH OH O HO CH3 H DNA

Experimental observations

John Maciejewski @ Wipf Group 6 10/29/2007

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SLIDE 7

First Enantioselective Synthesis of Kinamycin C

Porco, J. A.; J. Am. Chem. Soc. 2006, 128, 14790

OHC OH Br OH O O O O Br TBSO OH 7 steps Me4NBH(OAc)3, AcOH, 90% MsCl, collidine, 85% OH O O O Br TBSO OMs Super-Hydride, 95% K-10 clay, 90% OH O Br TBSO O O O OH Br MOMCl, DIEA, 85% Na2S2O4, Et2O, then MOMCl, 70% Pd(PPh3)4, (Bu3Sn)2, 70% OR OMOM OMOM R = MOM SnBu3

Synthesis of two main fragments

John Maciejewski @ Wipf Group 7 10/29/2007

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SLIDE 8

First Enantioselective Synthesis of Kinamycin C

Porco, J. A.; J. Am. Chem. Soc. 2006, 128, 14790

OR OMOM OMOM R = MOM SnBu3 OH O Br TBSO O Pd2(dba)3, AsPh3, 70% Super-Hydride, 80% (dr >10:1) Ti(OiPr)4, nBu4NOAc, 60% OR OMOM OMOM R = MOM OH OH OTBS HO OAc Ac2O, py Et3N-3HF, 67% (2 steps) OR OMOM OR R = MOM OAc OH OH AcO OAc TPAP, NMO, then NaClO2, NaH2PO4, 88% (2 steps) OR OR OR R = MOM OAc OH O AcO OAc HO TFAA, 90% CBr4, then Pd/C, air, 70% (2 steps) OH OAc OH O AcO OAc O O TBSNHNHTBS, Sc(OTf)3 PhIF2, 35% (2 steps) OH OAc OH N AcO OAc O O N Kinamycin C

John Maciejewski @ Wipf Group 8 10/29/2007

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SLIDE 9

Kinamycins C, F, and J

Nicolaou, K. C.; J. Am. Chem. Soc., 2007, ASAP

Assembling the kinamycin core

O O Br OH vinyl acetic acid, AgNO3 (cat.) (NH4)2S2O8, 75% O O Br OH BnBr, Ag2O, 92% Na2S2O4, then NaH, MeI, 82% t-BuOK, 98% OsO4, NaIO4, 84% OMe OMe Br OBn CHO MeMgBr, CuBr-Me2S, TMSCl then Pd(OAc)2, (cat.), O2, 90% OsO4, NMO, 76%, >98% ee 2-MeO-propene, CSA, 95% LHMDS, TMSCl then Pd(OAc)2, (cat.), O2, 84% I2, py, 92% O OTBS O OTBS CH3 O CH3 O O O OTBS CH3 O O I OMe OMe Br OBn CHO O OTBS CH3 O O OMe OMe OBn CHO Pd2(dba)3 (cat.) CuI (cat.), Cu, 83% N N N C6F5 BF4 NEt3, catalyst, 78% OH OTBS CH3 O O OMe OMe OBn O TBSO

John Maciejewski @ Wipf Group 9 10/29/2007

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SLIDE 10

Kinamycins C, F, and J

Nicolaou, K. C.; J. Am. Chem. Soc., 2007, ASAP

OH OTBS CH3 O O OMe OMe OBn O Ac2O, Et3N, 95% SmI2, MeOH, then Et3N SeO2 58% (3 steps) OTBS CH3 O O OMe OMe OBn O HO (aq.) HF, ACN, (then Ac2O, 89% (2 steps) Pd/C, H2, 99% OAc CH3 OAc OH OMe OMe OH O AcO TBSCl, imid., 94% TsNHNH2, aq. HCl, 95% CAN, 42% OH OAc OH N AcO OAc O O N Kinamycin C OAc OH N AcO OAc O O N

  • aq. HCl, ACN 95%

OH OH OH N HO OH O O N Kinamycin F

  • aq. LiOH, THF, 92%

Ac2O, Et3N

  • aq. HCl, ACN, 80%

(2 steps) OH OAc OAc N AcO OAc O O N Kinamycin J TBSO

John Maciejewski @ Wipf Group 10 10/29/2007

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SLIDE 11

Conclusions

Nicolaou synthesis summary:

  • further manipulates kinamycin C to analogs F and J
  • innovative benzoin-like addition to form C-ring
  • used enantiomerically pure enone to control D-ring stereochemistry
  • utilized CAN oxidation* to install quinone and diazo moiety

Porco synthesis summary:

  • used proposed biomimetic approach to form C-ring
  • uses asymmetric epoxidation to control stereochemistry of D-ring

OH OAc OH C N AcO OAc O O N Kinamycin C

*Kumamoto, T.; Tetrahedron 2007, 63, 5189 John Maciejewski @ Wipf Group 11 10/29/2007