Project 4 Background

Heterocycles are cyclic compounds in which an atom other than carbon is incorporated in the ring. Pyrrole (Figure 1) is one of the most common and biologically important aromatic heterocycles. The pyrrole ring core can be found in a variety of natural products with interesting properties. For example,  the structure of pyrrolomycin B is characteristic of a class of pyrrole-containing compounds originally isolated from soil bacteria. These pyrrolomycins have been found to exhibit potent antimicrobial properties. Students paying attention in their biology courses might recognize the structures of heme or chlorophyll, both of which contain four pyrrole or pyrrole-derived subunits. Finally, pyrrole forms the core structure of  the cholesterol-lowering drug Lipitor, which earns approximately $2 billion in annual revenue for the pharmaceutical company Pfizer.

Figure 1. The structure of pyrrole and some pyrrole-containing compounds with interesting properties.

Given their  importance, chemists have developed a variety of synthetic methods to generate pyrroles. In 1973, Russian chemist S.I. Zav’yalov reported the pyrrole synthesis outlined in Figure 2. Reaction of the aldehyde component of 1 with the amine functionality of 2 generated imine 3.  The direct conversion of imine 3 to pyrrole 5 by reaction with acetic anhydride (4) was unexpected. Despite its simplicity and the use of readily available and non-toxic reagents (especially amino acid 2), this route to pyrroles has remained largely underexploited for over four decades.

Figure 2. The two-step pyrrole synthesis reported by Zav’yalov in 1973.

In Project 4, you will attempt to apply the Zav’yalov methodology to a simple model system. The two-step pyrrole synthesis begins with the reaction of 2,4-pentanedione (6) with the amino acid glycine (7) under strongly basic conditions. You will isolate and characterize the intermediate enamine 8 before generating pyrrole 9 by reaction with acetic anhydride in the presence of triethylamine (NEt3).