Examination of the organocatalysed reactions between azides and cyclic anhydrides

Abstract

Azide is encountered in organic synthesis as both a functional group and as and an ion, and provides a valuable means of incorporating nitrogen into target compounds. The intrinsic nucleophilicity of azides can be beneficial, but can be equally challenging to harness this reactivity in the context of asymmetric synthesis. Achiral and meso-anhydrides are a useful prochiral starting materials and can be exploited as a powerful means of accessing enantioenriched products through symmetry-breaking desymmetrisation reactions. When influenced by chiral organocatalysts, alcohols and thiols are routinely employed as compatible nucleophilic partners, yet reaction of other nucleophiles with prochiral cyclic anhydrides is underexplored by comparison. Thermally-initiated reactions between azide nucleophiles with cyclic anhydrides have been studied historically, but do not currently provide a useful means of accessing valuable compounds due to the complex reactivity of the intermediates. Furthermore, a catalytic approach to the same reaction has not been reported. Compounds containing the γ-aminobutyric acid skeleton are ubiquitous in biology due to its important role in the central nervous system. Consequently, the same motif is also found in a myriad of both natural product and drug structures as both amino acids and the related cyclised form; lactams. This thesis details findings concerning the synthesis of both classes of compound by the reaction of azides with cyclic achiral and meso-anhydrides in both a racemic and enantioselective manner. Concerning the former, the organocatalytic reactions between glutaric anhydride derivatives and trimethylsilyl azide were first examined. Br?nsted base catalysis was identified as a suitable method of safe and efficient transfer of azide to the anhydride via a hydrogen-bonded complex of HN3 and catalyst, which was supported by mechanistic investigations. The acyl azide products of this reaction could be smoothly transformed via a Curtius rearrangement to compounds that contain both carboxylic acid and isocyanate functionalities; a challenging structural feature to generate by other means. Hydrolysis of the isocyanate moiety resulted in the preparation of seven amino acid active pharmaceutical intermediates, including the previous Pfizer blockbuster drug Lyrica in uniformly high yields. In the same study, it was found that the isocyanate intermediates could undergo efficient and clean conversion to the lactam without any further activating agent, catalysed by DMAP. Mechanistic investigations have found that the lactamisation reaction proceeds through an unconventional amidation methodology involving an N-carboxyanhydride intermediate, derived by the addition of a carboxylic acid to an isocyanate (hitherto unknown in an intramolecular context). Further investigation of this formal ring-contraction-lactamisation reaction resulted in extension of the methodology to encompass other anhydride ring sizes and substitution patterns. Although the preparation of the cyclic forms of anhydrides containing seven or more atoms was complicated by the formation of linear poly(anhydrides), rigidification of the backbone allowed the effective preparation of δ-lactams from seven-membered anhydrides for the first time. Through identification of bifunctional Cinchona alkaloid-based sulfamides as effective promoters of the desymmetrisation reaction, the first asymmetric addition of azide to a carbonyl centre was also realised. The resulting enantioenriched acyl azide derivatives can be readily converted to -lactams of considerable medicinal/pharmaceutical interest via sequential Curtius rearrangement, decarboxylation and lactamisation. While the enantiocontrol possible using the new methodology ranges from 55 to 72% ee, it was shown that after a single recrystallisation, a chiral precursor to two APIs could be obtained in 61% overall yield and >99% ee from 3-phenylglutaric anhydride. The utility of these processes to both biochemical and synthetic communities is highlighted, and mechanistic insights into each of the processes presented also.