Aspidophytine Synthesis Essay

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3. a) Kam T-S, Anuradha S. Phytochemistry. 1995;40:313–316.b) Lien TP, Ripperger H, Porzel A, Merzweiler K, Sung TV, Adam G. Phytochemistry. 1998;49:1457–1461.c) Merzweiler K, Lien TP, Sung TV, Ripperger H, Adam G. J Prakt Chem. 1999;341:69–71.

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5. A semi-synthesis of (−)-mehranine (2) has been reported:Éles J, Kalaus G, Greiner I, Katjár-Peredy M, Szabó P, Keserû GM, Szabó L, Szántay C. J Org Chem. 2002;67:7255–7260.[PubMed]

6. a) Medley JW, Movassaghi M. Angew Chem. 2012;124:4650–4654.Angew. Chem. Int. Ed. 2012, 51, 4572–4576.b) Medley JW, Movassaghi M. Org Lett. 2013;15:3614–3617.[PubMed]

7. The dihydropyridinium fragment in intermediate 9 makes it more sensitive compared to diiminium intermediate 8 and the forcing conditions required for the second cyclization led to decomposition

8. a) Stork G, Dolfini JE. J Am Chem Soc. 1963;85:2872–2873.b) Yoshida K, Sakuma Y, Ban Y. Heterocycles. 1987;25:47–50.

9. Morales MR, Mellem KT, Myers AG. Angew Chem. 2012;124:4646–4649.Angew. Chem. Int. Ed.2012, 51, 4568–4571.

10. Iodide 19 was prepared in four steps from commercially available 2-iodoaniline in an overall yield of 72%. See the Supporting Information for further details.

11. The chiral auxiliary (+)-pseudoephenamine (22) was recovered in 94% yield in the same step.

12. Righi M, Topi F, Bartolucci S, Bedini A, Piersanti G, Spadoni G. J Org Chem. 2012;77:6351–6357.[PubMed]

13. Kumar A, Akula HK, Lakshman MK. Eur J Org Chem. 2010:2709–2715.

14. Garber SB, Kingsbury JS, Gray BL, Hoveyda AH. J Am Chem Soc. 2000;122:8168–8179.

15. Jones SB, Simmons B, MacMillan DWC. J Am Chem Soc. 2009;131:13606–13607.[PMC free article][PubMed]

16. CCDC 997229 [(+)-13] contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif

17. Two similar conformations are present in the unit cell with C12–C19 distances of 3.22 and 3.24 Å, respectively.

18. See the Supporting Information for further details.

19. The geometries in the gas phase were optimized with molecular modeling (MMFF) followed by density functional theory at B3LYP level with 6–31G(d) as basis set (Spartan ’14, Version 1.1.1, by Wavefunction, INC.).

20. For example, m-CPBA/HClO4 led to full N-oxide formation at N9.

21. The epoxidation conditions described in ref. 5 were utilized in the total synthesis of (−)-conophylline:Hanya Y, Tokuyama H, Fukuyama T. Angew Chem. 2011;123:4986–4989.Angew. Chem. Int. Ed.2011, 50, 4884–4887.

22. Milborrow BV, Djerassi C. J Chem Soc C. 1969:417–424.

23. For related amide reductions involving electrophilic amide activation, see:a) Borch F. Tetrahedron Lett. 1968;9:61–65.b) Atta-ur-Rahman, Basha A, Waheed N, Ahmed S. Tetrahedron Lett. 1976;17:219–222.c) Kuehne ME, Shannon PJ. J Org Chem. 1977;42:2082–2087.d) Barbe G, Charette AB. J Am Chem Soc. 2008;130:18–19.[PubMed]e) Xiang S-H, Hu J, Yuan H-Q, Huang P-Q. Synlett. 2010:1829–1832.for a formamide reduction in the total synthesis of aspidophytine, see:f) Marino JP, Cao G. Tetrahedron Lett. 2006;47:7711–7713.

24. The opening of the epoxide is evident by the coupling constant of the C6 and C7 methine protons (3J6,7) which is 4.0 Hz in cis-configured (−)-2 and 9.3 Hz in trans-configured (+)-3

25. For a general procedure for the preparation of bis(dialkylamino)methanes and their use in Mannich and Morita–Baylis–Hillman reactions, see:a) Porzelle A, Williams CM. Synthesis. 2006:3025–3030.for the synthesis and characterization of bis(4-piperazin-1-yl)methane, see:b) Mrug GP, Bondarenko SP, Khilya VP, Frasinyuk MS. Chem Nat Comp. 2013;49:235–241.for a related dimerization of N-methylpyrrole, see:c) Eyley SC, Heaney H, Papageorgiou G, Wilkins RF. Tetrahedron Lett. 1988;29:2997–3000.

+

CH2Cl2, Et3N

RT, 60 min, 97%

i-PrOH

40 °C, 3 h, 57% (2 steps)

H2O, THF

RT, 35 min, 98%

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