11-Step Enantioselective Synthesis of ( )-Lomaiviticin Aglycon

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1 11-Step Enantioselective Synthesis of ( )-Lomaiviticin Aglycon Seth B. erzon, Liang Lu, Christina M. Woo, and Shivajirao L. Gholap J. Am. Chem. Soc. ASAP DI /ja200034b Melissa Sprachman Current Literature February 26, 2011 Published in: Seth B. erzon; Liang Lu; Christina M. Woo; Shivajirao L. Gholap; J. Am. Chem. Soc. Article ASAP DI: /ja200034b Copyright 2011 American Chemical Society Melissa Wipf Group Page 1 of 13 2/28/2011

2 Isolation and Preliminary Biological Activity 2 Me Me 2 Me 2 Me lomaiviticin A Me 2 Me 2 lomaiviticin B The lomaiviticins (red solids) were isolated from the fermentation broth of an actinomycetes strain LL , which was initially isolated from the core a host ascidian. The fermentation broth exhibited potent DA-damaging activity (detected by biochemical induction assay) and was cytotoxic against a number of cancer cell lines. Lomaiviticin A exhibited activity against a variety of cancer cell lines (IC 50 values of ng/ml). e et al. J. Am. Chem. Soc. 2001, 123, Melissa Wipf Group Page 2 of 13 2/28/2011

3 Related atural Products: The Kinamycins R 4 R 3 R 1 R 2 R 3 R 4 2 R 1 C 3 R 2 K pke, T.; Zaleski, J. M. Anticancer Agents Med. Chem. 2008, 8, kinamycin A Ac Ac Ac kinamycin B Ac kinamycin C Ac Ac Ac kinamycin D Ac Ac kinamycin E Ac kinamycin F kinamycin G Ac CiPr Ac Ac kinamycin CiPr Ac Ac kinamycin I CiPr CiPr Ac kinamycin J Ac Ac Ac Ac Completed Syntheses: Kinamycin C: Lei, X.; Porco, J. A. J. Am. Chem. Soc. 2006, 128, Kinamycins C, F, and J: icolaou et al. J. Am. Chem. Soc. 2007, 129, (John s Current Literature August 2007). Kinamycin F: erzon et al. J. Am. Chem. Soc. 2010, 132, Melissa Wipf Group Page 3 of 13 2/28/2011

4 Model Systems and Construction of the Central Bond Me2 C C 2 Me Mea, Me MgBr, CeCl 3 + C 2 Me 17% Me 2 C C 2 Me C 2 Me 57% C 2 Me 12% (3:1) C 2 Me BM BM BM Pb(Ac) 4 C 2 Cl 2, 25 ºC 91% BM BM 1. LiB 4 (60 equiv) TF, 25 ºC, 16 h 2. Pb(Ac) 4 25 ºC, 10 min 66% (2 steps) (ca. 3:1 dr) BM TPAP, M C 2 Cl 2, 25 ºC, 55% BM BM Pb(Ac) 4 (2 equiv) 25 ºC, 10 min 95% 3, Me 40% icolaou et al. Angew. Chem. Int. Ed. 2006, 45, Melissa Wipf Group Page 4 of 13 2/28/2011

5 Model Systems and Construction of the Central Bond Bn TBS 1. m-cpba, C 2 Cl 2 23 ºC, 20 min SPh 2. neat, 50 ºC, 3 d 3:1 dr, 53% (2 steps) TBS Bn S 2 Ph TBS S 2 Ph LiMDS, MPA TF, -78 ºC, 1.5 h TBS then [Cp 2 Fe]PF 6 (3 equiv) -20 ºC, 20 h 45-51% S 2 Ph S 2 Ph TBS exhibited instability to chromatography on Si % F (aq), MeC 2. DMP, C 2 Cl 2 26% (2 steps) Ph 2 S S 2 Ph very stable to chromatography on Si 2 K 2 C 3, Me 0 ºC to 23 ºC 3 h, 14% Me lomaiviticin A core Me Sc(Tf) 3 (cat.) Me, 65 ºC or Ts (cat.) 4 Å MS, C 6 6, 80 o C Me Me lomaiviticin B core Key Findings: -Fully stereoselective oxidative enolate coupling -Stability of the lomaiviticin A core as the hydrate Krygowski, E. S.; Murphy-Benenato, K.; Shair, M.D. Angew. Chem. Int. Ed. 2008, 47, Melissa Wipf Group Page 5 of 13 2/28/2011

6 erzon Group Forward Synthesis Me Me TIPS 1. Li, 3, 98% 2. (DQD) 2 PAL K 2 s 4, K 3 Fe(C) 6 62%, 91% ee TIPS 2, Pd(Ac) 2 DMS, 24 o C 92% PPTS C 3 C, 24 o C to 50 o C 85%, 1:1 dr 1. TMSC 2 MgCl, CuI, TMSCl then Pd(Ac) 2 82% TMS 2 F S 2 3 C Si 2 3 C F MM C 2 81% Br MM MM Br Br MM C 2 Cl 2, -78 o C Pd(Ac) 2 Ag 2 C 3 PPh 3 toluene, 80 o C 95% MM MM Tf 3, DMAP C 3 C, -20 o C 51%, 1:1 dr MM MM Melissa Wipf Group Page 6 of 13 2/28/2011

7 End Game: xidative Dimerization General Strategy R 1 R 2 R 2 R 1 MM MM Both diastereomers and derivatives > 1500 experiments MM Desired Product not formed MM MM TMSTf, 3 C 2 Cl 2, 0 o C MM MM TMS Ph, 21 o C MM MM MM + MM 26% MM MM 12% MM Melissa Wipf Group Page 7 of 13 2/28/2011

8 Formation of Lomaiviticin Aglycon MM MM MM TFA, TBP C 2 Cl 2, -35 o C, 12 h 39% MM 8 : 1 (reaction course) (isolated) MM MM MM TFA C 3, 50 ºC 41% MM Melissa Wipf Group Page 8 of 13 2/28/2011

9 Proposed Mechanism of Action and Diazonium Character C 3 C 3 9-diazofluorene 2,1-naphthoquinodiazide υ = 1906 cm -1 (C- 2 ) υ = 2056 cm -1 (C- 2 ) υ = 2087 cm -1 (C- 2 ) - = Å - = Å - = Å υ = 2101 cm -1 (C- 2 ) - = Å υ = 2125 cm -1 (C- 2 ) - = Å C 3 Ac Cl Isoprekinamycin υ = 2139 cm -1 (C- 2 ) - = Å ab initio calculations at F theory level using 6-31G and LanL2DZ basis sets. The trend in diazonium character parallels the trend in antiobiotic and antitumor activity. Kinamycin B υ = 2188 cm -1 (C- 2 ) - = Å Isoprekinamycin υ = 2139 cm -1 (C- 2 ) - = Å C 3 Model for lomaiviticin A υ = 2212 cm -1 (C- 2 ) - = Å Kinamycin B υ = 2188 cm -1 (C- 2 ) - = Å υ = 2212 cm -1 (C- 2 ) - = Å Laufer, R. S.; Dmitrienko, G. I. J. Am. Chem. Soc. 2002, 124, Ac < Lovaiviticin A Melissa Wipf Group Page 9 of 13 2/28/2011

10 Proposed Mechanism of Action (Continued) The authors also provided experimental evidence for relative electrophilicities and a proposal that deazetation by nucleophilic attack followed by -atom abstraction is a possible MA. C 3 C 3 C 3 Cs 2 C 3 TF, 0 ºC 61% Cs 2 C 3 TF, 0 o C R a 2 P 4 /a 2 P 4 buffer, p 9, relux quant. Laufer, R. S.; Dmitrienko, G. I. J. Am. Chem. Soc. 2002, 124, u - 2 u u K pke, T.; Zaleski, J. M. Anticancer Agents Med. Chem. 2008, 8, Melissa Wipf Group Page 10 of 13 2/28/2011

11 A Second Proposal: 1-electron reduction An alternative proposal involves 1-e - reduction followed by -atom abstraction. 3 C Bu 3 Sn AIB, 80 ºC 3 C Relative rate (relative to benzene) X C 3 Cl C C 3 C (1:1) X C 3 Ar rate Additionally, yields of solvent incorporation dropped with increasing equivalents of Bu 3 Sn. The authors estimate the rate constant for sp 2 radical addition to the aromatic solvent to be 10 7 M -1 s -1. The reported rate constant for addition of phenyl radical to chlorobenzene is ~10 6 M -1 s -1.. Feldman, K. S.; Eastman, K. J. J. Am. Chem. Soc. 2005, 127, Melissa Wipf Group Page 11 of 13 2/28/2011

12 Experimental Evidence of DA Strand Cleavage Type II icked DA Type I Supercoiled DA DA kinamycin D + DA/DTT (1.0 M) S S Dithiothreitol (DTT) The authors compared the DA cleavage ability of kinamycin D to a variety of diazoflourene probes. 2 kinamycin D 2 Ac Me 2 R 1 2 C 3 2 % DA cleavage 18 ± 8 28 ± 7 41 ± 6 (44 ± 7 with no DTT) Ac R 2 < 5% R 1 = Cl or 2, R 2 = R 1 =, R 2 = Cl or 2 Melander et al. Bioorg. Med. Chem. Lett. 2006, 16, Melissa Wipf Group Page 12 of 13 2/28/2011

13 Summary and utlook erzon and coworkers have completed the first synthesis of lomaiviticin aglycon in 11 linear steps. Several operations are amenable to large-scale preparative work. As of the online publication date, the group has synthesized 15 mg of lomaiviticin aglycon. After exhaustive screening, the authors demonstrated the feasibility of an oxidative dimerization using Mn(hfacac) 3. Their report is the first use of this reagent in an oxidative enoxysilane coupling.. erzon and coworkers previously reported the synthesis of the sugar residues (rg. Lett. 2009, 11, ) and demonstrated formation of the glycosidic bonds on a model system. With the aglycon in hand, elaboration to form usable quantities of the natural products is a possibility. The ability to produce useful quantities of the core may lead to analog development and future application to important antibiotics and/or cancer therapeutics. Further probing of the lomaiviticins MA via some of the same assays used to study the kinamycins is also a possibility with synthetic access to the materials. Melissa Wipf Group Page 13 of 13 2/28/2011

Nine-Step Enantioselective Total Synthesis of (+)-Minfiensine

Nine-Step Enantioselective Total Synthesis of (+)-Minfiensine ine-step nantioselective Total Synthesis of (+)-Minfiensine Jones, S. B.; Simmons, B.; MacMillan, D. W. C.* J. Am. Chem. Soc. 2009, ASAP. DI: 10.1021/ja906472m Kara George Wipf Group - Current Literature