Open Access
Camp, Jason Eliot
Graduate Program:
Doctor of Philosophy
Document Type:
Date of Defense:
December 18, 2007
Committee Members:
  • Steven M Weinreb, Committee Chair
  • Raymond Lee Funk, Committee Member
  • Ken S Feldman, Committee Member
  • Ming Tien, Committee Member
  • total synthesis
  • alkaloids
  • marine natural products
  • N-vinylation
Chapter 1 In work directed towards a total synthesis of the chartellamides, several strategies were investigated to construct the pentacyclic core of this marine alkaloid with the correct relative stereochemistry at C9,20. The first approach involved intermolecular addition of aryl Grignard reagents to in situ generated N-acyliminium ions. Thus, N-acyl hemiaminals 77a-c were synthesized from the addition of alkyl Grignards to the carbonyl of γ-lactam 76. Unfortunately, in situ formation of N-acyliminium ion 81 from N-acyl hemiaminals 77a-c, followed by addition of aryl Grignard 82 did not give the desired C9 addition product 80. Alternatively, an intramolecular cyclization approach towards diastereoselectively forming the C9,20 adjacent quaternary centers was examined. Cyclization precursor 117 was synthesized from γ-lactam 84 in five steps via addition of a lithio acetylide to the C9 carbonyl group of sulfonamide 115 followed by a Meyer-Schuster rearrangement of the resulting hemiaminal 116. However, attempts to cyclize arylbromide 117 using either radical or reductive Heck conditions resulted in ring opening of the β-lactam to form undesired indole products 119 or 122, respectively. Finally, a novel method for the construction of the bromoenamide moiety of the chartellamides was developed based on an extension of the known copper catalyzed coupling of amides with vinylhalides. In this study, haloenamides were constructed both inter- and intramolecularly via a halogen-selective N-vinylation reaction. Chapter 2 In work directed towards a total synthesis of the marine alkaloids chartelline A-C (1-3), a model system was explored to probe the formation of the 10-membered macrocycle via RCM. After an initial model study demonstrated that ketone enolates add effectively to the carbonyl of activated N-acyl γ-lactams, the requisite ketoimidazole 292 was synthesized from known aldehyde imidazole 259 in 4 steps and 50% overall yield. However, addition of the enolate of ketoimidazole 292 to the C12 carbonyl of N-acyl γ-lactam 293 resulted in formation of vinylogous amide 297 rather than the desired hemiaminal 295. An alternative route was therefore examined in which the bond between C11 and C12 would be formed via the addition of a metallated (Z)-alkene to the activated carbonyl group. Simple model reactions between the metallated alkene of vinyliodide 310 and γ-lactams 96 and 76 gave hemiaminals 311 and 312, respectively. After this successful model study the requisite iodovinylimidazole 302 was synthesized from either alcohol imidazole 314 or alkynyl imidazole 262. Unfortunately, formation of the metallated anion of 302 followed by addition of N-acyl γ-lactam 231 resulted in formation of alkyne hemiaminal 263 rather than the desired alkene hemiaminal 310. We next turned to an alternative approach in which the chloroenamide moiety of the chartellines would first be constructed and then the macrocycle would be closed via either the intramolecular addition of a ketone enolate or a metallated (Z)-alkene to the activated C12 γ-lactam carbonyl moiety. Thus, ketoimidazole 317 and related imidazoles 324, 325, 330 were synthesized through functional group manipulations of aldehyde imidazole 259 or isobutenyl imidazole 281. Unfortunately, coupling of these imidazoles, which contained the C9-C11 functionality found in the chartellines, with NH-β-lactams 260, 316, or 334 did not give any of the desired haloenamide products. Fortunately, imidazoles 247, 370, and 403, containing the C9,10 functionality of the chartellines, were found to couple with NH-β-lactams to form the desired chloroenamide products. Efforts are being made to utilize these chloroenamide products to construct the 10-membered macrocycle towards completion of a total synthesis of the chartellines.