Ketoamides residues

Peptide mimetics containing the a-ketoamide moiety are very important because they act as cysteine protease inhibitors. In fact, the a-ketoamide residue forms hemithioacetals with the -SH group of the cysteine residue of the enzyme [32], Nakamura et al. [26b] reported the preparation of a 100-member combinatorial library of a-ketoamides by means of a two-step one-pot synthesis. The first step consisted of the Ugi-4CR between (+/— )lactic acid, amines, isocyanides, and aldehydes leading to the formation of the lactamides 40 which were oxidized to the corresponding pyruvamides 41. This one-pot procedure was performed in THF since the PDC oxidation was incompatible with the presence of methanol. Five a-ketoamides showed an 80% average purity (Scheme 2.17). 

Scheme 2.18. Synthesis of peptide mimetics containing the a-ketoamide residue.

The a-ketoamide group is a well-known electrophile for the inhibition of both serine and cysteine proteases. Introducing a pyrazole as the N-substituent of the ketoamide provides potent inhibitors of Cat K [50]. SAR exploration of the P2-P3 residues in a series of Cat K inhibitors led to the identification of the pyrrolidine... 

Cysteine proteases play key roles in the pathogenesis of a variety of disease states including osteoporosis [49], muscular dystrophy [50] and several CNS-related disorders [51]. A 100-member library of a-ketoamides 50 was generated via a two-step one-pot synthesis, in which the initial condensation was followed by a pyridinium dichromate (PDC) oxidation (Scheme 11.9). Yields were respectable, ranging from 53 to 75%. Note that a-ketoamides are potential reversible inhibitors with the ability to form hemi-thioacetals with the active thiol of cysteine residues. 

The oxidative modification of peptides is a most interesting topic, but there is no suitable method available. The mthenium-catalyzed oxidation with peracetic acid provides a useful method for modification. For example, the reaction of N,C-pro-tected peptides containing glycine residues with peracetic acid in the presence of RUCI3 catalyst gives a-ketoamides 69 derived from oxidation at the Cf position of the glycine residue selectively (81%, conv. 70%) (Eq. 3.81) [139]. 

Using a similar strategy, oxazoles and thiazoles were prepared starting from dipeptide-bound Wang resin 60 (Scheme 9.8). The hydroxyl group on the threonine residue was oxidized with 3 equiv of Dess-Martin periodinane to give the corresponding p-ketoamide intermediate 61. Treatment of 61 with triphenylphosphine in the presence of iodine and diisopropylethylamine (DIEA) in DCM for 12 h afforded the resin-bound oxazoles 62,... 

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