Constrained Ugi Adducts from Bi-functional Precursors

was the first reported monocydic /J-lactam with potentially useful antibacterial activity [67]. The preparation employed the use of chiral /i-amino acids 69, thereby ensuring the correct configuration at the 4-position of the lactam. The carboxylic acid was prepared by conversion of the N-diphenylmethane moiety via N-nitrosoamide formation and decomposition to the corresponding ester, representing an early, if not the most effective, example of a convertible isocyanide. 

Three groups independently reported on this approach in 1997-98 [68]. Harri-man envisioned that compounds containing the constrained peptide-like backbone could be potentially used as modulators of leukocyte trafficking. More specifically, 

The representative example, MC 52201 80 was kinetically well behaved, proving to be a classical competitive, time-independent PTP1B inhibitor after a Lineweaver-Burk analysis. Further studies on this class are reported as on-going. 

Banfi and co-workers have also employed similar methodology to access meso-cyclic yS-turn scaffolds by the tandem U-MCR/RCM procedure generating such macrocyclic structures as 87 [73]. 

Chemically, and in a somewhat analogous fashion to the tetrazole-norstatine libraries described earlier, the intermediate Ugi nitrilium ion may also be trapped by an azide nucleophile, generating racemic monocyclic tetrazoles. Workers at Amgen have reported utilizing this methodology for the generation of a 10000- 

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The earliest reports of constrained Ugi adducts derived from bi-functional precursors appeared in the 1960s with the preparation of penicillin derivatives such as 68, involving sequential Asinger and Ugi four-component reactions (Scheme 11.13). As such, the synthesis represents the shortest preparation of a known penicillin derivative [65], The /Mactam ring is formed after isocyanide addition to the cyclic Schiff base, followed by carboxylate nitrilium ion trapping and acyl transfer to give the final penicillin core. In this example, the amine and carboxylic acid inputs may be considered tethered. 

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