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 Literature August 18, 2007 John Maciejewski @ Wipf Group 1 10/29/2007
Isolation and Brief History Kinamycins A, B, C, and D isolated from fermentation broth of 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 OR 2 R 1 O O OR 3 OR 4 N OH O N Kinamycin scaffold Kinamycin A : R 1 = H, R 2 = Ac, R 3 = Ac, R 4 = Ac Kinamycin B : R 1 = H, R 2 = H, R 3 = Ac, R 4 = H Kinamycin C : R 1 = Ac, R 2 = Ac, R 3 = H, R 4 = Ac Kinamycin D : R 1 = H, R 2 = Ac, R 3 = H, R 4 = Ac Ito, S.; J. Antibiot. 1970 , 23 , 315 Hata, T; J. Antibiot. 1971 , 24 , 353 Gould, S. J.; Chem. Rev. 1997 , 97 , 2499 John Maciejewski @ Wipf Group 2 10/29/2007
Initial Structural Assignment of Kinamycin Core OR 2 R 1 O OR 2 R 1 O O O OR 3 OR 3 initial assignment OR 4 N OR 4 X C OH O Y OH O N Z cyanobenzo[ b ]carbazole system Used IR, 1 H, 13 C, 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(?)) Hata, T.; Isr. J. Chem. 1972 , 10 , 173 Dmitrienko, G. I.; J. Am. Chem. Soc . 1994 , 116 , 2207 - 2208 John Maciejewski @ Wipf Group 3 10/29/2007
Structural Revisions Gould and Dmitrienko independently revised structure based upon (original) X-ray structure, as well as indepth IR, NMR, and synthetic studies. Original assignment of kinamycin core Scaffolds prepared by Dmitrienko OR 2 R 1 R 1 O O R 1 R 2 O OR 3 R 2 R 3 compared to… N N OR 4 N C C R 4 O C OH O N N N cyanobenzo[ b ]carbazole system 22 N- cyanoindole derivatives (Dmitrienko): Kinamycin spectral data (Hata): - IR range (2237 - 2245 cm -1 ) - IR range (2119 - 2170 -1 ) - 13 C NMR ( δ 105 - 108) for cyanamide carbon - 13 C NMR ( δ 78.5 - 83.7) “cyanamide” carbon 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 John Maciejewski @ Wipf Group 4 10/29/2007
Structural Revisions Original assignment of kinamycin core Revised kinamycin core (Hata) (Gould & Dmitrienko) OR 2 OR 2 R 1 O R 1 O O O OR 3 OR 3 reassignment OR 4 OR 4 N C C N OH O OH O N N cyanobenzo[ b ]carbazole system diazobenzo[ b ]fluorene ring system Kinamycin spectral data: Diazo bands - IR (2119 - 2170 -1 ) -C=N=N 13 C NMR ( δ 78.5 - 83.7) diazo carbon Crystal structure of kinamycin D (Gould) Gould, S.; J. Am. Chem. Soc . 1994 , 116 , 2207 - 2210. Dmitrienko, G. I.; J. Am. Chem. Soc . 1994 , 116 , 2207 - 2208 John Maciejewski @ Wipf Group 5 10/29/2007
Proposed mechanism-of-action Pathways to DNA cleavage HO HO HO O HO OH OH OH CH 3 CH 3 CH 3 CH 3 e - -N 2 DNA-H DNA N OH O N H OH O OH O OH O N N prekinamycin Experimental observations HO O HO HO Bu 3 SnO OH CH 3 CH 3 Bu 3 SnH, AIBN CH 3 workup 80 O C, benzene N OH O Ph Ph OH O OH O N multiple aromatic solvents were screened 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 John Maciejewski @ Wipf Group 6 10/29/2007
First Enantioselective Synthesis of Kinamycin C Synthesis of two main fragments OH O Br O O O O Br Me 4 NBH(OAc) 3 , AcOH, 90% Br Br Super-Hydride, 95% O O O TBSO OHC MsCl, collidine, 85% TBSO 7 steps TBSO K-10 clay, 90% OH OH OMs O OH OH O OMOM Br SnBu 3 MOMCl, DIEA, 85% Na 2 S 2 O 4 , Et 2 O, then MOMCl, 70% Pd(PPh 3 ) 4 , (Bu 3 Sn) 2 , 70% OH O OR OMOM R = MOM Porco, J. A.; J. Am. Chem. Soc. 2006 , 128 , 14790 John Maciejewski @ Wipf Group 7 10/29/2007
First Enantioselective Synthesis of Kinamycin C HO OMOM OMOM OAc O Ac 2 O, py SnBu 3 OH Br Pd 2 (dba) 3 , AsPh 3 , 70% O Et 3 N-3HF, 67% (2 steps) TBSO Super-Hydride, 80% (dr >10:1) OH Ti(O i Pr) 4 , n Bu 4 NOAc, 60% OR OMOM OR OMOM OTBS OH R = MOM R = MOM AcO OR AcO OAc OR OAc OH OH TFAA, 90% TPAP, NMO, then CBr 4 , then Pd/C, air, 70% (2 steps) HO NaClO 2 , NaH 2 PO 4 , 88% (2 steps) OAc OAc OR OMOM OH OR OR O R = MOM R = MOM OAc AcO OAc AcO O OH O OH TBSNHNHTBS, Sc(OTf) 3 OAc PhIF 2 , 35% (2 steps) OAc O OH O N OH O N Kinamycin C Porco, J. A.; J. Am. Chem. Soc. 2006 , 128 , 14790 John Maciejewski @ Wipf Group 8 10/29/2007
Kinamycins C, F, and J Assembling the kinamycin core O O OMe Br Br Br BnBr, Ag 2 O, 92% vinyl acetic acid, AgNO 3 (cat.) Na 2 S 2 O 4 , then NaH, MeI, 82% (NH 4 ) 2 S 2 O 8 , 75% CHO OH O t -BuOK, 98% OH O OBn OMe OsO 4 , NaIO 4 , 84% O O O LHMDS, TMSCl O MeMgBr, CuBr-Me 2 S, TMSCl OsO 4 , NMO, 76%, >98% ee then Pd(OAc) 2 , (cat.), O 2 , 84% O then Pd(OAc) 2 , (cat.), O 2 , 90% CH 3 2-MeO-propene, CSA, 95% I 2 , py, 92% CH 3 OTBS OTBS TBSO OTBS OMe O O O OMe CH 3 OMe Br I O O O NEt 3 , catalyst, 78% Pd 2 (dba) 3 (cat.) CH 3 O CHO O OH CuI (cat.), Cu, 83% OTBS CH 3 CHO N OBn OMe OTBS O N OBn OMe OBn OMe N C 6 F 5 BF 4 Nicolaou, K. C.; J. Am. Chem. Soc., 2007 , ASAP John Maciejewski @ Wipf Group 9 10/29/2007
Kinamycins C, F, and J OTBS OTBS HO OMe CH 3 OMe CH 3 Ac 2 O, Et 3 N, 95% O O (aq.) HF, ACN, (then Ac 2 O, 89% (2 steps) SmI 2 , MeOH, then Et 3 N O O Pd/C, H 2 , 99% OH SeO 2 58% (3 steps) O O OBn OMe OBn OMe OAc AcO OAc AcO O O OH OH OAc AcO OMe CH 3 TBSCl, imid., 94% aq. HCl, ACN 95% OAc OH OAc TsNHNH 2 , aq. HCl, 95% N OH O N O CAN, 42% OAc TBSO N N O OH OMe Kinamycin C aq. LiOH, THF, 92% Ac 2 O, Et 3 N aq. HCl, ACN, 80% (2 steps) OH HO OAc AcO O O OH OAc OH OAc Kinamycin J N OH O N OH O N N Kinamycin F Nicolaou, K. C.; J. Am. Chem. Soc., 2007 , ASAP John Maciejewski @ Wipf Group 10 10/29/2007
Conclusions OAc AcO O OH OAc C N OH O N Kinamycin C 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 * Kumamoto, T.; Tetrahedron 2007 , 63 , 5189 John Maciejewski @ Wipf Group 11 10/29/2007
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