Diazoacetylation

The (diazoacetyl)dihydropyrazole 4a is converted into the 1 //-l, 2-diazepin-6(7//)-one 5a in hot acetic acid 73 a somewhat similar reaction affords the diphenyl analog 5b.74... 

Acetoacetyl-3,4-dihydro-2(lF/)-qumoxahnone (211) with mesyl azide gave 4-(2-diasoacetoacetyl)-3,4-dihydro-2(lF/)-quinoxahnone (212) (Et3N, MeCN, 20°C, 8 h 91% of crude), which underwent deacetylation to afford 4-diazoacetyl-3,4-dihydro-2(lF/)-qumoxalmone (213) (NaOH, THF, H2O, 20°C, 1 h 69%) ... 

There are two catalytically active residues in pepsin Asp-32 and Asp-215. Their ionizations are seen in the pH-activity profile, which has an optimum at pH 2 to 3, and which depends upon the acidic form of a group of pKa 4.5 and the basic form of a group of pKa 1.1.160,161 The pKa values have been assigned from the reactions of irreversible inhibitors that are designed to react specifically with ionized or un-ionized carboxyl groups. Diazo compounds—such as A-diazoacetyl-L-phenylalanine methyl ester, which reacts with un-ionized carboxyls—react specifically with Asp-215 up to pH 5 or so (equation 16.28).162-164 Epoxides, which react specifically with ionized carboxyls, modify Asp-32 (equation 16.29). 

Optical induction emanating from a chiral diazoacetamide is apparently not much higher. The 2-phenylcyclopropanecarboxylates cis-222 and trans-222, obtained in low yield from (N-diazoacetyl)oxazolidones 220,221 and styrene in the presence of Rh2(OAe)4 followed by ethanolysis, showed only small enantiomeric excesses 215). Starting with either diazo compound, the (1/ ) enantiomer was predominant in both cis- and trans-222. 

Whereas pyrrole was reported not to give N/H insertion by ketocarbenoids, such a reaction mode does occur with imidazole Copper-catalyzed decomposition of ethyl diazoacetate at 80 °C in the presence of imidazole gives ethyl imidazol- 1-ylacetate exclusively (93 %) small amounts of a C-alkylated imidazole were obtained additionally under purely thermal conditions 244). N/H insertion also takes place at benzimidazole 245 a). The reaction is thought to begin with formation of an N3-ylide, followed by N1 - C proton transfer leading to the formal N/H insertion product. Diazomalonic raters behave analogously however, they suffer complete or partial dealkoxycarbonylation under the reaction conditions 244) (Scheme 34). N-alkylation of imidazole and benzimidazole by the carbenoids derived from co-diazoacetophenone and 2-(diazoacetyl)naphthalene has also been reported 245 b>. 

Buten-l-yl diazoacetate, 2377 tert-Butyl diazoacetate, 2423 tert-Butyl 2-diazoacetoacetate, 3009 5-/er/-Butyl-3-diazo-3//-pyrazole, 2831 Cyanodiazoacetyl azide, 1346 5-Cyano-4-diazo-4//-l,2,3-triazole, 1345 Diazoacetaldehyde, 0710 Diazoacetonitrile, 0675 Diazoacetyl azide, 0679... 

Although diazoacetamides are usually converted into p-lactams upon diazodecomposition, with some substrates pyrrolidinones can be the main product (Table 4.6) [1101,1102,1140,1141]. For instance, l-diazoacetyl-2-ethylpyrrolidine yields, upon treatment with rhodium(II) complexes only l-methyl-3-pyrrolizidinone (i.e. 

A similar desymmetrization approach was applied to the synthesis of bridged bicyclic systems. Reaction of 2-diazoacetyl-l,3-dioxane in the presence of a chiral rhodium catalyst allow the construction of the bicycle in 27-54% yield, but poor ee (4-12%) (Equation 51) <2003TA929>. 

Suga et al. (197) reported the first stereocontrolled 1,3-dipolar cycloaddition reactions of carbonyl ylides with electron-deficient alkenes using a Lewis acid catalyst. Carbonyl ylides are highly reactive 1,3-dipoles and cannot be isolated. They are mainly generated through transition metal carbenoid intermediates derived in situ from diazo precursors by treatment with a transition metal catalyst. When methyl o-(diazoacetyl)benzoate is treated with A-methylmaleimide at reflux... 

Reactions of the same carbonyl ylide intermediate with aldehydes are even more fruitful. The Rh2(OAc)2 catalyzed reaction proceeds at room temperature in the presence of 2 mol% of the catalyst, but the diastereoselectivity is disappointingly low (endo/exo = 49 51, Scheme 11.56). However, when 10 mol% of the cocatalyst Yb(OTf)3 is added, the reaction becomes highly exo-selective (endo/ exo = 3 97) (198). Suga has extended this Lewis acid catalyzed carbonyl ylide cycloaddition reaction to catalyzed asymmetric versions. The chiral cocatalyst employed is ytterbium(III) tris(5)-1,1 -binaphthyl-2,2 -diyl phosphonate, Yb[(S) BNP]3 (10 mol%). In the reaction of methyl o-(diazoacetyl)benzoate with benzyloxyacetaldehyde in the presence of Rh2(OAc)2 (2 mol%) at room temperature with the chiral Yb catalyst, the diastereoselectivity is low (endo/exo = 57 43) and the enantiopurity of the endo-cycloadduct is 52% ee. 

The diazo compound 0-(2-diazoacetyl)-L-serine, known also as azaserine (see Fig. 22-48), is a powerful inhibitor of glutamine amidotransferases. If growing cells are treated with azaserine, what intermediates of nucleotide biosynthesis would accumulate Explain. 

Another good example of the use of affinity labels involves pepsin, and is illustrated in Chapter 16, equations 16.28 and 16.29. The enzyme has two catalyt-ically important aspartic acid residues, one ionized and the other un-ionized. The ionized carboxylate is trapped with an epoxide, which, of course, requires the reaction of a nucleophilic group. The un-ionized carboxyl is trapped with a diazoacetyl derivative of an amino acid ester ... 

Stereosectivity is a broad term. The stereoselectivity in cyclopropanation which has been discussed in the above subsection, in fact, can also be referred to as diastereoselectivity. In this section, for convenience, the description of diastereoselectivity will be reserved for selectivity in cyclopropanation of diazo compounds or alkenes that are bound to a chiral auxiliary. Chiral diazoesters or chiral Ar-(diazoacetyl)oxazolidinone have been applied in metal catalysed cyclopropanation. However, these chiral diazo precursors and styrene yield cyclopropane products whose diastereomeric excess are less than 15% (equation 129)183,184. The use of several a-hydroxy esters as chiral auxiliaries for asymmetric inter-molecular cyclopropanation with rhodium(II)-stabilized vinylcarbenoids have been reported by Davies and coworkers. With (R)-pantolactone as the chiral auxiliary, cyclopropanation of diazoester 144 with a range of alkenes provided c yield with diastereomeric excess at levels of 90% (equation 130)1... 

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 ... 

On the other hand, rhodium(II) can catalyze intramolecular C—H insertion of 1-methyl-3-silyloxy-l-(diazoacetyl)cyclohexanes63. The ratio of the products through C5—H versus C3—H insertions increases from 2.2 1 to 6 1 when the bulkier (i-Pr)3Si group is used to replace the (t-Bu)Me2Si group (entry 51 of Table 1). 

---