I. Introduction 893 A. The Drug Discovery Process 895 B. Characteristics of Privileged Substructures 896 C. Scope of the Review 897 II. Phenyl-Substituted Monocycles 898 A. Biphenyls 898 B. Arylpiperidines 899 C. Arylpiperazines 901 D. 1,4-Dihydropyridines 901 E. Dihydropyrimidones 902 III. Fused [7−6] Ring Systems 904 A. 1,4-Benzodiazepin-2-ones 904 B. 1,5-Benzodiazepin-2-ones 905 C. 1,4-Benzodiazepin-2,5-diones and Pyrrolo-[2,1-c][1,4]benzodiazepin-5,11-diones 906 D. 1,4-Benzothiazepin-5-ones 907 E. 5,11-Dihydro-benzo[e]pyrido[3,2-b][1,4]diazepin-6-ones 907 IV. Fused [6−6] Ring Systems 908 A. Benzopyrans, Chromones, Coumarins, and Pyranocoumarins 908 1. Benzopyrans 908 2. Chromones 909 3. Coumarins 911 4. Pyranocoumarins 911 B. Quinoxalines/Quinazolines 913 1. 3,4-Dihydroquinoxalin-2-ones (Benzopiperazinones) 913 2. Quinazolinones 915 3. Quinazolindiones 916 4. Imidazoquinoxalines 917 V. Fused [5−6] Ring Systems 919 A. Indoles 919 B. Benzimidazoles 921 C. Benzofurans 922 D. Benzothiophenes 924 VI. Conclusions 925 VII. Acknowledgments 925 VIII. References 925

For Abstract see ChemInform Abstract in Full Text.

[reaction: see text] Cyclic tetrapeptides are an intriguing class of natural products. To synthesize highly strained cyclic tetrapeptides we developed a macrocyclization strategy that involves the inclusion of 2-hydroxy-6-nitrobenzyl (HnB) group at the N-terminus and in the "middle" of the sequence. The N-terminal auxiliary performs a ring closure/ring contraction role, and the backbone auxiliary promotes cis amide bonds to facilitate the otherwise difficult ring contraction. Following this route, the all-L cyclic tetrapeptide cyclo-[Tyr-Arg-Phe-Ala] was successfully prepared.

Cyclic peptides comprise a large and important class of biologically active molecules. They are generally synthesized through amide bond-forming reactions of the C-and N-termini under high dilution conditions. Yields of such processes are highly dependent on the size of the ring being formed and on the particular amino acids of the linear precursor, giving rise to the well-known sequence-dependent effect of cyclization. To overcome this problem, we have developed a peptide cyclization strategy that proceeds through a ring closure/ring contraction process. The linear peptide Ala-Phe-Leu-Pro-Ala, which does not generate monocyclic product under conventional cyclization conditions, was used as a model to probe a range of auxiliaries. This has led to the development of a new photolabile peptide cyclization auxiliary. The 6-nitro-2-hydroxybenzyl group is readily and quantitatively introduced at the N-terminus via a reductive alkylation. Cyclization of the auxiliary-peptide initially proceeds through a cyclic nitrophenyl ester that preorganizes the peptide for lactamization. As the C-and N-termini are in close proximity, lactamization is achieved via an intramolecular O-N acyl transfer step to produce the N-substituted target cycle. The auxiliary is then removed by mild photolysis to produce the target cyclic peptide, cyclo-[Ala-Phe-Leu-Pro-Ala], in good yield. This strategy should find further useful applications in the assembly of libraries of small cyclic peptides.