Diazomethyl ketones

Intramolecular insertion reactions show a strong preference for formation of five-membered rings.219 This was seen in a series of a-diazomethyl ketones of increasing chain length. With only one exception, all of the products were five-membered lactones.220 In the case of n = 3, the cyclization occurs in the side chain, again forming a five-membered ring. 

The main synthetic application of the Wolff rearrangement is for the one-carbon homologation of carboxylic acids.242 In this procedure, a diazomethyl ketone is synthesized from an acyl chloride. The rearrangement is then carried out in a nucleophilic solvent that traps the ketene to form a carboxylic acid (in water) or an ester (in alcohols). Silver oxide is often used as a catalyst, since it seems to promote the rearrangement over carbene formation.243... 

Intramolecular oxonium ylide formation is assumed to initialize the copper-catalyzed transformation of a, (3-epoxy diazomethyl ketones 341 to olefins 342 in the presence of an alcohol 333 . The reaction may be described as an intramolecular oxygen transfer from the epoxide ring to the carbenoid carbon atom, yielding a p,y-unsaturated a-ketoaldehyde which is then acetalized. A detailed reaction mechanism has been proposed. In some cases, the oxonium-ylide pathway gives rise to additional products when the reaction is catalyzed by copper powder. If, on the other hand, diazoketones of type 341 are heated in the presence of olefins (e.g. styrene, cyclohexene, cyclopen-tene, but not isopropenyl acetate or 2,3-dimethyl-2-butene) and palladium(II) acetate, intermolecular cyclopropanation rather than oxonium ylide derived chemistry takes place 334 ). 

Synthesis of [12-3H]-farnesoic acid and [13-3H]-farnesyl diazomethyl ketone... 

The tritium-labelled famesoic acid [3H]-MF, 111, and its diazomethyl ketone analogue, [3H]-FDK, 112, which can be used for the photoaffinity labelling of MF binding... 

Silyl-substituted diazoketones 29 cycloadd with aryl isocyanates to form 1,2,3-triazoles 194 (252) (Scheme 8.44). This reaction, which resembles the formation of 5-hydroxy-l,2,3-triazoles 190 in Scheme 8.43, has no analogy with other diazocarbonyl compounds. The beneficial effect of the silyl group in 29 can be seen from the fact that related diazomethyl-ketones do not react with phenyl isocyanate at 70 °C (252). Although the exact mechanistic details are unknown, one can speculate that the 2-siloxy-1-diazo-1-alkene isomer 30 [rather than 29 (see Section 8.1)] is involved in the cycloaddition step. With acyl isocyanates, diazoketones 29 cycloadd to give 5-acylamino-l,2,3-thiadiazoles 195 by addition across the C=S bond (252), in analogy with the behavior of diazomethyl-ketones and diazoacetates (5). 

Reaction of diazomethyl ketone with ketene acetals to form 2,2-di-alkoxy-l,2-dihydropyrans [178]. 

Preparation of an N-Protected Amino Add Diazomethyl Ketone (e.g., 100) General Procedure 142 ... 

C-Terminal ketone derivatives of peptides have been used as effective inhibitors for a variety of proteases including serine, cysteine, and aspartyl proteases. 271 This class of peptides includes diazomethyl ketones (Section 15.1.2), halomethyl ketones (Section 15.1.3), and fluoromethyl ketones (Section 15.1.4). In general, the A -amino group and side chain must be protected. The diazomethyl ketones serve as good intermediates for conversion into chloromethyl and bromomethyl ketones. Fluoromethyl ketones, the most widely known class of peptide haloketones, can also be prepared from diazomethyl ketones or by halogen-exchange reactions. Other methods for the synthesis of fluoromethyl ketones are described in Section 15.1.4. 

The diazomethyl ketone functional group was first observed to be an affinity label by Buchanan and co-workers who showed that the antibiotic azaserine, an O-diazoacetyl derivative, 9 inhibited an enzyme in the biosynthesis of purine by alkylation of a cysteine residue. 10 The acid protease pepsin was then observed to be inhibited by peptidyl diazomethyl ketones in the presence of copper ions with the resulting esterification of an aspartate residue. 11 Two peptidyl diazomethyl ketones, Z-Phe-CHN2 and Z-Phe-Phe-CHN2, were found to irreversibly inactivate papain, a cysteine protease. 12 Since these reports, many peptidyl diazomethyl ketones have been prepared primarily as inhibitors of various cysteine proteases. 7 Peptidyl diazomethyl ketones are also synthetic intermediates and have been used to prepare chloromethyl ketones (Section 15.1.3), 13 bromomethyl ketones (Section 15.1.3), acyloxymethyl ketones, 14 and (i-peptides. 15 A few peptidyl diazoalkyl ketones have been reported. 16,17 ... 

Only one method has been used to prepare various peptidyl diazomethyl ketones. A protected amino acid or peptide acid is activated as the mixed anhydride and reacted with ethereal diazomethane at low temperature. Generally a peptide with the desired sequence is prepared first and then converted into the diazomethyl ketone in the final step of the synthesis. Since the diazomethyl ketone functional group is stable to alkali but unstable to acid, acidic conditions used to deprotect many peptide protecting groups must be avoided. 

Base is frequently used to remove the protecting group (e.g., Fmoc or Tfa) at the N-terminus or in the side chain of the peptide diazomethyl ketones. 

Protected amino acids or peptides are activated at the carboxy group by the mixed anhydride method using isobutyl chloroformate and NMM and reacted with ethereal diazomethane to form the corresponding peptidyl diazomethyl ketone (Scheme 1). The diazomethane solution is prepared from TV-methyl-A -nitroso-d-toluenesulfonamide (Diazald, Aldrich) or l-methyl-3-nitro-l-nitrosoguanidine (MNNG, Aldrich) according to the supplier s instruction (Aldrich information bulletin No. Al-180). No racemization occurs when diazomethyl ketones are prepared by this method. 

The reaction of diazomethane with a mixed anhydride is generally complete within 15 minutes. If the peptide contains Tyr the reaction should be worked up immediately to avoid methylation of the Tyr side-chain hydroxy group. In the assessment of purity of peptidyl diazomethyl ketones using HPLC, it should be noted that the peptidyl diazomethyl ketone, R1CHN2, is converted into RlCH COCFj if TFA is used in the HPLC solvent system. The peak seen in HPLC is the trifluoroacetate derivative, sometimes two peaks appear if the reaction is slowJ71... 

Some peptidyl diazomethyl ketones are not very soluble in water, therefore their stock solutions are often prepared in water-miscible organic solvents such as DMSO, MeCN, or EtOH and these solutions are then diluted into buffers for biological studies. The solid forms... 

Peptidyl bromomethyl ketones (Scheme 2) are synthesized by the same method used to prepare chloromethyl ketones (Scheme 1) namely, the reaction of peptidyl diazomethyl ketones with HBr. 16-18 This reaction proceeds readily for either chloromethyl or bromomethyl ketones, although a contaminant, the N-methylated compound, is usually observed in the final reaction product. 1 A variation of this method involves the use of LiBr, which facilitates the formation of acid-sensitive protected amino acids. 1 As with the chloromethyl synthesis, only Z and Boc should be used to protect the amino acids. 3 Although the reaction of diazo ketones with HBr is well known and relatively simple, only a few compounds have been synthesized (Table 2). 

The diazomethyl ketone Z-L-Ile-CHN2 (1, R = sBu) was prepared from CH2N2 and Z-L-Ile-OH using the mixed anhydride method. A detailed procedure for the preparation of diazomethyl ketones is given in Section 15.1.2. To a cold (0-5 °C) stirred soln of Z-L-Ile-CHN2 (1, R = sBu 0.8g, 2.8mmol) in dry... 

Unlike the synthesis of chloromethyl and bromomethyl ketones, iodomethyl ketones cannot be synthesized simply by reacting a diazomethyl ketone with HI, since this reaction generally leads to the formation of the methyl ketone instead. To resolve this difficulty, iodomethyl ketones 8 are generally synthesized by reacting a chloro- or bromomethyl ketone 7 with Nal in acetone (Scheme 3).[1 3]... 

Fluoromethyl ketones are one of the most widely used classes of peptidyl a-fluoroalkyl ketones, second only to trifluoromethyl ketones. Peptidyl fluoromethyl ketones are very effective as irreversible inhibitors of cysteine proteases the first reported use of a fluoromethyl ketone compound was the use of Z-Phe-Ala-CH2F as an irreversible inhibitor of cathepsin BJ2,31 Today, many lysine and arginine derivatives have been synthesized as potential inhibitors for trypsin and trypsin-like enzymesJ3 There are four basic methods for the synthesis of peptide fluoromethyl ketones (1) the reaction of HF with peptide diazomethyl ketones (Section 15.1.4.1.1), (2) a halogen-exchange reaction with a chloro-, bromo-, or iodomethyl ketone (Section 15.1.4.1.2), (3) a Henry nitro-aldol condensation reaction (Section 15.1.4.1.3), and (4) a modified Dakin-West acylation reaction (Section 15.1.4.1.4). 

Reaction of Hydrogen Fluoride with a Peptide Diazomethyl Ketone... 

Scheme 1 Reaction of Peptidyl Diazomethyl Ketones with Hydrogen Fluoride 41...

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