Oxidation of α-diazoketones derived fromL-amino acids and dipeptides using dimethyldioxirane. Synthesis and reactions of homochiral N-protected α-amino glyoxals

Abstract

Homochiral N-protected a-amino glyoxals are readily accessible by oxidation of a-diazoketones derived from natural amino acids and dipeptides using dimethyldioxirane in acetone; the glyoxals can be trapped efficiently in reactions such as Wittig olefination and condensation with amines and vicinal diamines.Without functional group protection amino glyoxals of type 1 would be expected to undergo spontaneous polymerisation. With appropriate N-protection they should be reasonably stable, yet amenable to a range of useful synthetic transformations through the highly electrophilic aldehyde group. They are , for example, potential precursors of hydrolytically stable pseudopeptides or peptide isosteres.1We have developed a general route (Scheme 1) to amino glyoxals in the N-protected form 2 from a range of L-amino acids. The route is equally applicable to any N-protected peptide with a free carboxylic acid group and the reaction conditions appear to tolerate most forms of N-protection. So far we have successfully employed Boc, Z, phthaloyl and ethoxycarbonyl groups. The N-protected amino acids and dipeptides 3 shown in Table 1 were transformed into the corresponding diazoketones 4 using standard procedures.* The key step in the sequence was oxidation of the diazoketones to glyoxals 2 using distilled dimethyldioxirane (DMD) 5 in acetone,3.4 a process recently reported for simple achiral 0 1 Me Me x:5

13C- and 1H-NMR studies of oxyanion and tetrahedral intermediate stabilization by the serine proteinases: optimizing inhibitor warhead specificity and potency by studying the inhibition of the serine proteinases by peptide-derived chloromethane and glyoxal inhibitors

“…Specific substrate-derived glyoxal inhibitors of proteases have been synthesized [31] and shown to be potent reversible inhibitors of chymotrypsin [32][33][34][35], subtilisin [36], papain [37], cathepsin B [35,38], cathepsin L [38], cathepsin S [39] and the proteasome [40]. In substrate-derived glyoxal inhibitors, the peptide carboxy group (RCOOH) is replaced by a glyoxal or keto-aldehyde group (RCOCHO) and the α-keto carbon of the glyoxal should occupy the same position as the hydrolysed peptide carbonyl of a peptide substrate.…”

A 13C-NMR study of the inhibition of papain by a dipeptide-glyoxal inhibitor

“…Specific-substrate-derived glyoxal or α-keto-β-aldehyde (RCOCHO) inhibitors of proteases have been synthesized [1] and shown to be potent inhibitors of chymotrypsin [2][3][4], cathepsin B [3,5], cathepsin L [5], cathepsin S [6] and the proteasome [7]. We have recently [4] used "$C-NMR to study the mechanism of inhibition of chymotrypsin by specific-substrate-derived glyoxal inhibitors.…”

Evaluation of Dipeptide α-Keto-β-aldehydes as New Inhibitors of Cathepsin S

“…Peptidyl diazoketones were treated with a solution of dimethyldioxirane in moist acetone (for preparation of ␣-keto-␤-aldehydes). It has previously been demonstrated that such an approach leads to formation of peptidyl ␣-keto-␤-aldehydes, in almost quantitative yield, by the oxidative cleavage of the diazo-group [13,17]. Compound identity was confirmed by mass spectral and elemental analysis in each instance.…”