Synthesis of Novel Allocolchicine Analogues with a Pyridine C-Ring through Intermolecular Vollhardt Diyne-Nitrile Cyclotrimerization

Abstract

A short synthesis of new allocolchicinoids with a pyridine C-ring and an oxa-B-ring was developed exploiting a cobalt-catalyzed intermolecular [2+2+2] cycloaddition (diyne-nitrile cyclotrimerization). Starting from readily accessible 3,4,5-trimethoxy­benzaldehyde or 3,4,5-trimethoxyacetophenone, the (racemic) target compounds were regioselectively obtained in 15-20% overall yield (five steps).

Key words

heterocycles - cycloaddition - regioselectivity - microwave - transition metal catalysis - natural product analogues

References and Notes

• 1a Capraro HG. Brossi A. In The Alkaloids   Vol. 23:  Brossi A. Academic Press; Orlando: 1984.  Chap. 1.
• 1b Boyé O. Brossi A. In The Alkaloids   Vol. 41:  Brossi A. Cordell GA. Academic Press; San Diego: 1992.  Chap. 3.
• 1c Le Hello C. In The Alkaloids   Vol. 53:  Cordell GA. Academic Press; San Diego: 2000.  Chap. 5.
• 1d Davis PD. Dougherty GJ. Blakey DC. Galbraith SM. Tozer GM. Holder AL. Naylor MA. Nolan J. Stratford MRL. Chaplin DJ. Hill SA. Cancer Res.  2002,  62:  7247 
• 1e Jordan MA. Wilson L. Nat. Rev. Cancer  2004,  4:  253 
• 1f Tozer GM. Kanthou C. Baguley BC. Nat. Rev. Cancer  2005,  5:  423 
• For selected examples on recent synthetic work in the field of allocolchicinoids, see:
• 2a Vorogushin AV. Predeus AV. Wulff WD. Hansen H.-J. J. Org. Chem.  2003,  68:  5826 
• 2b Bergemann S. Brecht R. Büttner F. Guénard D. Gust R. Seitz G. Strubbs MT. Thoret S. Bioorg. Med. Chem.  2003,  11:  1269 
• 2c Büttner F. Bergemann S. Guénard D. Gust R. Seitz G. Thoret S. Bioorg. Med. Chem.  2005,  13:  3497 
• 2d LeBlanc M. Fagnou K. Org. Lett.  2005,  7:  2849 
• 2e Besong G. Jarowicki K. Kocienski PJ. Sliwinski E. Boyle FT. Org. Biomol. Chem.  2006,  4:  2193 
• 2f Djurdjevic S. Green JR. Org. Lett.  2007,  9:  5505 
• 2g Boyer F.-D. Hanna I. Org. Lett.  2007,  9:  715 
• 2h Joncour A. Décor A. Liu J.-M. Tran Huu Dau M.-E. Baudoin O. Chem. Eur. J.  2007,  13:  5450 
• 2i Joncour A. Liu J.-M. Décor A. Thoret S. Wdzieczak-Bakala J. Bignon J. Baudoin O. ChemMedChem  2008,  3:  1731 
• 3a Graening T. Friedrichsen W. Lex J. Schmalz H.-G. Angew. Chem. Int. Ed.  2002,  41:  1524 
• 3b Graening T. Bette V. Neudörfl J. Lex J. Schmalz H.-G. Org. Lett.  2005,  7:  4317 
• 3c Graening T. Schmalz H.-G. Angew. Chem. Int. Ed.  2004,  43:  3230 
• 4 Nicolaus N. Zapke J. Riesterer P. Neudörfl J.-M. Prokop A. Oschkinat H. Schmalz H.-G. ChemMedChem  2010,  5:  661 
• 5 Nicolaus N. Strauß S. Neudörfl J.-M. Prokop A. Schmalz H.-G. Org. Lett.  2009,  11:  341 
• For selected references, see:
• 6a Vollhardt KPC. Bergman RG. J. Am. Chem. Soc.  1974,  96:  4996 
• 6b Naiman A. Vollhardt KPC. Angew. Chem. Int. Ed.  1977,  16:  708 
• 6c Bönnemann H. Angew. Chem. Int. Ed.  1978,  17:  505 
• 6d Vollhardt KPC. Angew. Chem. Int. Ed.  1984,  23:  539 
• 6e Heller B. Sundermann B. Buschmann H. Drexler H.-J. You J. Holzgrabe U. Heller E. Oehme G. J. Org. Chem.  2002,  67:  4414 
• 6f Varela JA. Saá C. Chem. Rev.  2003,  103:  3787 
• 6g Gutnov A. Heller B. Fischer C. Drexler H.-J. Spannenberg A. Sundermann B. Sundermann C. Angew. Chem. Int. Ed.  2004,  43:  3795 
• 6h Zhou Y. Porco JA. Snyder JK. Org. Lett.  2007,  9:  393 
• 6i Young DD. Deiters A. Angew. Chem. Int. Ed.  2007,  46:  5187 
• 6j Heller B. Hapke M. Chem. Soc. Rev.  2007,  36:  1085 
• 6k Turek P. Hocek M. Pohl R. Klepetářová B. Kotora M. Eur. J. Org. Chem.  2008,  3335 
• 6l Geny A. Agnet N. Iannazzo L. Malacria M. Aubert C. Gandon V. Angew. Chem.  2009,  121:  1842 
• 6m Meißner A. Groth U. Synlett  2010,  1051 
• 7a Agenet N. Buisine O. Slowinski F. Gandon V. Aubert C. Malacria M. In Organic Reactions   Vol. 68:  Overman L. Wiley; New Jersey: 2007.  p.1 
• 7b Kase K. Goswami A. Ohtaki K. Tanabe E. Saino N. Okamoto S. Org. Lett.  2007,  9:  931 
• 8 For a regioselective cyclotrimerization using a silicon tether, see: Groth U. Huhn T. Kesenheimer C. Kalogerakis A. Synlett  2005,  1758 
• 9 Bonaga LVR. Zhang H.-C. Maryanoff BE. Chem. Commun.  2004,  2394 
• 10 Chopade PR. Louie J. Adv. Synth. Catal.  2006,  348:  2307 

11

Representative Procedure for the [2+2+2] Cycloaddition; 9,10,11-Trimethoxy-4,7-dimethyl-2-phenyl-5,7-dihydrobenzo[5,6]oxepino[3,4- c ]-pyridine (3b): In a flame-dried microwave vessel the diyne 4b (106 mg, 370 mmol) was dissolved in anhydrous chlorobenzene followed by addition of benzonitrile (76 mg, 740 mmol). After degassing the solution three times, CpCo(CO)₂ (7.3 mL, 73 mmol) was added via syringe. The reaction vessel was transferred into a microwave reactor (CEM, Discover) and the mixture was irradiated for 15 min (150 ˚C, 300 W). Finally, the solvent was evaporated in vacuo (100 ˚C) and the residue was purified by flash chromatography (cyclohexane-EtOAc = 3:1, R _f 0.5) to afford compound 3b as a yellowish solid (75 mg, 193 mmol, 52%). IR (ATR): 2927 (m), 2853 (m), 1730 (w), 1590 (s), 1541 (s), 1488 (s), 1463 (s), 1401 (s), 1310 (s), 1248 (m), 1194 (m), 1158 (m), 1119 (s), 1083 (s), 1054 (s), 920 (w), 835 (w), 773 (m), 694 (m). ^¹H NMR (300 MHz, CDCl₃): δ = 1.56 (d, ^³ J = 6.3 Hz, 3 H), 2.79 (s, 3 H, OMe), 3.71 (s, 3 H), 3.95 (s, 6 H), 3.97 (d, ^² J = 11.7 Hz, 1 H), 4.16 (q, ^³ J = 6.3 Hz, 1 H), 4.83 (d, ^² J = 11.7 Hz, 1 H), 6.85 (s, 1 H), 7.36-7.48 (m, 3 H), 7.84 (s, 1 H), 8.04 (d, ^³ J = 7.2 Hz, 2 H). ^¹³C NMR (300 MHz, CDCl₃): δ = 17.8 (q), 22.8 (q), 56.1 (q), 61.1 (q), 61.2 (q), 62.9 (t), 68.6 (d), 104.6 (d), 119.0 (d), 125.0 (s), 126.6 (s), 127.1 (d), 128.7 (d), 133.8 (s), 139.7 (s), 142.4 (s), 146.1 (s), 150.6 (s), 154.1 (s), 155.5 (s), 156.5 (s). HRMS (EI): m/z [M]⁺ calcd for C₂₄H₂₅NO₄: 391.1783; found: 391.178.