Chapter 7: Seven-membered rings
Introduction
The chemistry and biological activities of seven-membered heterocyclic compounds continues to command significant attention in 2007. In this chapter both fused and non-fused heterocycles are addressed with an emphasis on N, O, and S as the heteroatoms of the seven-membered ring components. Particular emphasis has been placed on research describing the construction of these systems. A continuing trend has been the synthesis of seven-membered derivatives of biologically active molecules such as carbohydrates and nucleic acids. Many synthetic methods for the synthesis of seven-membered rings are simply extensions of methodology for the lower homologues, therefore, particular attention has been given to synthetic methods that specifically target the titled systems. Reviews focussing on the featured systems during 2007 have covered the medicinal chemistry of the 1,4-diazepines <07RMC793>, and the synthesis of macrocyclic shellfish toxins containing spiroimine moieties <07NPR869>.
Section snippets
Azepines and derivatives
Denmark reported a protocol for the formation of 3-substituted azepines 4 from nitro acylsilanes 3, which were formed by the conjugate addition of an acylsilane-derived dienol-ether 2 to nitroalkenes 1 <07JOC7050>. The reaction of the nitro acylsilane with aluminium-amalgam gave a mixture of azepines and lactams, however, this was overcome by conversion of the acylsilane to an aldehyde prior to the reductive cyclisation.
The radical mediated cyclisation of
Diazepines and fused derivatives
The synthesis of diazepines remains of great interest in the development of biologically active compounds and coverage of the entire field in 2007 is beyond the scope of this forum, therefore, we have chosen to concentrate on articles were synthetic outcomes are the key focus. The reaction of 2-oxobenzo[h]chromeme 72 with hydrazine hydrate at room temperature in the absence of solvent gives pyrazole 71. However, under more forcing conditions, tetraazanaphtho[2,1-e]azulen-12-one 73 is isolated <
Systems with N, S and or/O
Several new polysulfide metabolites 164 and 165 bearing a trisulfide ring have been isolated from an Indonesian acidian along with the known metabolites lissoclinotoxin F and the pentasulfide N,N-dimethyl-5-(methylthio)varacin 166 <07JNP439>, while three monocyclic trithiepine compounds 167-169 have been identified amongst other polysulfide metabolites produced by Cytophaga bacteria which was isolated from biofilms found in the North Sea <07JOC3776>. A fused trithiepine 170 was synthesised from
Seven-Membered Systems of Pharmacological Significance
Pharmacologically active compounds incorporating 7-membered heterocyclic components continue to flourish.
In the field of cardiovascular/metabolic health, examples include spirobenzodiazepines as vasopression V1a/V2 receptor antagonists with a candidate currently undergoing human trials for treating diseases such as congestive heart failure <07BMCL6623>, pyrrolo-fused azepinones as novel conformationally restricted HMG-CoA reductase inhibitors that act as potent inhibitors of cholesterol
Future Directions
Research into seven membered heterocycles is likely to remain active with a key focus on structurally novel drug leads, either seven-membered analogues of the corresponding five and six membered systems or the introduction of extra heteroatoms into the ring. The seven membered heterocycles are likely to continue as useful scaffolds for highly functionalised drugs and for the developing field of peptidomimetics. The synthesis of more complex structures will benefit by research into development
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