Scalable Total Syntheses of N-Linked Tryptamine Dimers by Direct Indole-Aniline Coupling: Psychotrimine and Kapakahines B and F

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1 Scalable Total Syntheses of -Linked Tryptamine Dimers by Direct ndole-aniline Coupling: Psychotrimine and Kapakahines B and F tryptamine X electrophilic nitrogen source 2 methodology development innovative application psychotrimine 2 Ph kapakahine F 2 Ph Ph kapakahine B ewhouse, T.; Lewis, C. A.; Eastman, K. J.; Baran, P. S. J. Am. Chem. Soc., 2010,132, John Maciejewski Wipf Group - Current Literature 22 May 2010 John Wipf Group Page 1 of 18 7/10/2010

2 solation of Targets psychotrimine 2 Ph kapakahine F Psychotrimine solated from leaves of Psychotria rostrata in 2004 (Takayama) Shown to possess activity against colon and lung cancers Ph 2 Ph kapakahine B Kapakahines Kapakahine B: 0.3 mg isolated from sponge Cribrochalina olemda in 1995 (Scheuer) Kapakahine F: 0.8 mg isolated from C. olemda in 2003 (Scheuer) Exhibit promising anti-leukemia activity Takayama,. rg. Lett. 2004, 6, 2945 Scheuer, P. J. J. Am. Chem. Soc., 1995, 117, 8271 Scheuer, P. J. rg. Lett. 2003, Synthesis of kapakahine B and F, see Baran, P. J. Am. Chem. Soc., 2009, 131, 6360 Synthesis of psychotrimine, see Baran, P. J. Am. Chem. Soc., 2009, 130, John Wipf Group Page 2 of 18 7/10/2010

3 Bond Connectivity in ndole-based atural Products C-C linkages -C linkages Me 2 C Me vinblastine Ac C2 Me Ph asperazine Ph 2 Ph kapakahine F Ph 2 Ph kapakahine B chimonanthine psychotrimine John Wipf Group Page 3 of 18 7/10/2010

4 Proposed Biosynthetic Routes to the 1-C3 Bond R R " R " radical or cationic-based oxidative dimerization R 2 2 C 2 C 2 C C oxidative [1,5] tautomerization C 2 dimerization C oxidative dimerization of tryptophan C 2 As applied by Baran and Shenvi in the total synthesis of chartelline C For [1,5] rearrangement, see: J. Am. Chem. Soc., 2006, 128, John Wipf Group Page 4 of 18 7/10/2010

5 Direct xidative Dimerization Extensive screening of oxidants did not afford the desired 1-C3 linkage Koser s reagent afforded trace amounts of the desired dimer Attempts at oxidative coupling of 35 to arrive at 36 were not fruitful John Wipf Group Page 5 of 18 7/10/2010

6 Screening for the ndole Cation Equivalent C 2 Me Boc 2 conditions C 2 MeC:Me (20:1), S (1.5 equiv.), -45 o C 79%, >20:1 dr nstead of employing tryptamine dimerization, o-iodoaniline was screened as the nitrogen donor S was the optimal reagent for conversion, isolated yield, diastereoselectivity, and scalability Low temperature and the absence of any amine base were critical John Wipf Group Page 6 of 18 7/10/2010

7 Mechanistic Considerations Figure 7 John Wipf Group Page 7 of 18 7/10/2010

8 Rationalization of Diastereoselectivity rder of addition, as well as the oxidant used effect the diastereoselectivity of the reaction Suggests the halogen may be involved in the stereochemistry-determining step or effect the reaction rate John Wipf Group Page 8 of 18 7/10/2010

9 Rationalization of exo Diastereoselectivity Danishefsky, S. J. J. Am. Chem. Soc., 1999, 121, Crich, J J. rg. Chem. 1999, 64, 7218 John Wipf Group Page 9 of 18 7/10/2010

10 Probing the ature of the Electrophilic Aniline Figure A: aniline addition may occur through addition at C2 followed by migration Figure B: phenylnitrenium and iodide pair react reversibly with tryptamine; explains high diastereoselectivity as well as the dependence on the XS oxidant (X=Cl, Br, or ) John Wipf Group Page 10 of 18 7/10/2010

11 Comparing the nfluence of Substituted Anilines R 1 R 2 R 3 R 4 2 S MeC/Me 20:1 R 1 R 4 R 3 R 2 Br C 2 Me 68% 2 74% C 2 Me C 2 Me 24% Cl F 43% C 2 Me 0% Me C 2 Me Me 2 C Br 67% C 2 Me 63% C 2 Me Br 79% Boc C 2 Me Br 78% Boc Bn C 2 Me Electron-deficient aniline substrates perform better in reaction than electron-rich Supports the presence of an electrophilic phenylnitrenium ion John Wipf Group Page 11 of 18 7/10/2010

12 nitial Route to Psychotrimine Buchwald-Goldberg-Ullmann coupling followed by indole-aniline oxidative coupling afforded 98 in lower than expected yield Larock indolization was employed to afford 107 John Wipf Group Page 12 of 18 7/10/2010

13 Gram-scale Preparation of Psychotrimine ndole-aniline oxidative coupling was performed first to afford 101 Larock indole synthesis was used to efficiently prepare 109 Buchwald-Goldberg-Ullmann coupling installed the final tryptamine moiety John Wipf Group Page 13 of 18 7/10/2010

14 Kapakahines B and F xidative coupling at C3 followed by [1,5] shift to afford 119 Decreased nucleophilicity of amide relative to carbamate Pyrroloindoline core accessible Possibility to equilibrate constitutional isomers ndole-aniline oxidative coupling affords pyrroloindoline core in good yields John Wipf Group Page 14 of 18 7/10/2010

15 Kapakahines B and F Larock indole synthesis affords 123 Peptide coupling affords iodide 127 Unable to isomerize 124 into the desired carboline scaffold John Wipf Group Page 15 of 18 7/10/2010

16 Kapakahines B and F Removal of both the Cbz and benzyl groups allow equilibrium between 136 and 138 John Wipf Group Page 16 of 18 7/10/2010

17 Kapakahines B and F John Wipf Group Page 17 of 18 7/10/2010

18 Conclusions tryptamine X electrophilic nitrogen source 2 methodology development innovative application psychotrimine 2 Ph kapakahine F 2 Ph Ph kapakahine B Biological data on synthetic natural products: Kapakahines B and F did not possess significant cytotoxicity in the C 60-cell line Kapakahine B had an C 50 value of 11.7 µm for breast cancer cells (tested by BMS) Psychotrimine showed broad biological activity between 1.3 and 40 µm in the C 60-cell line This methodology not only broadens our understanding of chemical reactivity, but allows access to complex molecules in quantities that would otherwise be unavailable from traditional isolation practices John Wipf Group Page 18 of 18 7/10/2010