The porphyrins (e.g., porphine, 1) are of ubiquitous biological importance and remain among the most widely studied of all known macrocycles. Increasingly, however, attention is being devoted to the study of larger pyrrole-containing macrocycles.Such larger systems, the so-called "expanded porphyrins",1 appear attractive with regard to a variety of biomedical applications ranging from magnetic resonance imaging (MRI)1-3 and photodynamic therapy (PDT)1•* 1234•5 to anion chelation and drug delivery.1•6While there are now a number of expanded porphyrins known,1 including penta-and hexapyrrolic macrocycles such as sapphyrin,7 pentaphyrin,8 hexaphyrin,9 and rubyrin,10 none is easy to prepare.
An efficient method for the preparation of N-aryl amides from anilines, esters or lactones promoted by NaHMDS is described. Advantages of this new method include high yields and mild reaction conditions which tolerate functional groups such as ketones and halides.
The process development and the kilogram-scale synthesis of BMS-587101 (1) are described. The synthesis features a [3 + 2] azomethine ylide cycloaddition to efficiently build the spirocyclic core in a diastereoselective fashion followed by a classical resolution which affords the desired enantiomer in >98% enantiomeric excess. The target was prepared in four steps in an overall yield of 22%.
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