Carboxylic acid derivatives diazomethane

A practicable strategy to provide access to chiral pyrazolidine-3-carboxylic acid (16) makes use of asymmetric dipolar cycloaddition of diazoalkanes to u,p-unsaturated carboxylic acid derivatives. For this purpose a chiral auxiliary of the alkene component is used, e.g. Op-polzer s1166 1671 (lf )-2,10-camphorsultam.t164l As shown in Scheme 7, by reaction of (tri-methylsilyl)diazomethane (41) with /V-( aery I oy I )cam p h ors u 11 am (42), the AL(4,5-dihy-dropyrazoline-5-carbonyl)camphorsultam (43) is obtained. Reduction of 44 with sodium cyanoborohydride leads to A-(pyrazolidine-3-carbonyl)camphorsultam (45) as the 35-dia-stereoisomer (ee 9 1) in 65 to 80% yields.[164] The camphorsultam 45 is then converted into the methyl ester 46 by reaction with magnesium methylate without racemizationj1641... 

The Arndt-Eistert Synthesis allows the formation of homologated carboxylic acids or their derivatives by reaction of the activated carboxylic acids with diazomethane and subsequent Wolff-Rearrangement of the intermediate diazoketones in the presence of nucleophiles such as water, alcohols, or amines. 

Diphenyl-1-benzoylcyclopropane and its derivatives (Scheme 2) provide ideal vehicles for testing the solid-state ionic chiral auxiliary approach to asymmetric synthesis. Early work by Zimmerman and Flechtner had shown that the parent unsubstituted compound, which is achiral, undergoes very efficient (d> = 0.94) photoisomerization in solution to afford the chiral cisjrans isomer [10]. Accordingly, we prepared the j9-carboxylic acid derivative 5a and treated this with a variety of optically pure amines to give salts 5b-5f. Irradiation of crystals of these salts followed by diazomethane workup yielded methyl ester 6, which was analyzed by chiral HPLC for enantiomeric excess. The results are summarized in Table 1 [11]. 

In palladium-catalyzed reactions with diazomethane A -enoylsultams have been successfully used for the synthesis of cyclopropane carboxylic acid derivatives. The cleavage of the auxiliary was achieved by treatment of the cycloadducts with a. Ti(0 Pr)4, PhCHzOH b. Na0H/H20. 

Julia substrate 41 was prepared as follows. Cyclopropylketone 42 was converted to the corresponding /3-ketoester using sodium hydride and dimethyl carbonate. The anion derived from the /3-ketoester was alkylated with allylic bromide 43 to provide 44a. Ester hydrolysis, decarboxylation of the intermediate /3-ketoacid, and esterification of the terminal carboxylic acid using diazomethane, gave ketone 44b (CJH-5). 

The methyl ester (100, R = CH3), derived from this A-nor acid by treatment with diazomethane, is different from the ester (102) obtained either by Favorskii rearrangement of 2a-bromo-5a-cholestan-3-one (101) or by the action of cyanogen azide on 3-methoxy-5a-cholest-2-ene (103) followed by hydrolysis on alumina. The ketene intermediate involved in photolysis of (99) is expected to be hydrated from the less hindered a-side of the molecule to give the 2j -carboxylic acid. The reactions which afford (102) would be expected to afford the 2a-epimer. These configurational assignments are confirmed by deuteriochloroform-benzene solvent shifts in the NMR spectra of esters (100) and (102). ... 

The second example described here is dormant seeds from Rosa canina. Extracts of these seeds also inhibit germination of seeds of several plants (10). In Figure 5 a scheme is given for extraction and separation oF"three different inhibitor compounds. All these are present in the acid fraction. The first essential step is chromatography on Sephadex LH-20, which separates inhibitor I from inhibitor II and III. Inhibitor I was identified as abscisic acid. The other two inhibitors were separated by methylation with diazomethane, fractional distillation, and column chromatography. The second inhibitor is the a-pyrone 1 . Reaction with diazomethane transforms it into the bi-cyclic compound 19. This bicyclic compound is even more active than the parent a-pyrone 1 . Since we sought structural requirements for bioactivity here also,we tested several synthetic a-pyrones ( 0 - 22) for bioactivity. These compounds had no inhibitory activity. We alio tested the cyclopropane derivatives 23 and 24 In Table II, the bioactivity of the bicyclic compound T9 and two such derivatives is compared. The presence of several carboxylic acid groups seems to be essential (or at least helpful) for bioactivity in this case also. 

Special attention was given to the characterization of the radioactive metabolites found in the strawberry fruits where no parent compound was detectable. Unidentified, very polar metabolites accounted for 83% of the material while 3% was identified as thiazolidine-2-thione-4-carboxylic acid by two-dimensional thin-layer chromatography. Treatment with diazomethane allowed for GC-MS confirmation of the latter as the methylated derivatives of the thiazolidine. 

Acyl substituents at the 3- and/or 4-positions result in decreased hydrolytic stability compared with the alkyl and aryl derivatives described above. Despite this constraint most of the usual reactions of the carbonyl group are possible. Aldehydes <9ILA1211> and ketones are oxidized to the carboxylic acid, borohydride reduction affords the expected alcohols, and epoxides are formed on reaction with diazomethane. Oximes and arylhydrazones are formed with hydroxylamine and arylhydrazines, and the products may subsequently undergo monocyclic rearrangement involving the oxadiazole to give the corresponding isomeric furazans and 1,2,3-triazoles (Section 4.05.5.1.4). 

Esters of racemic pyrazolidine-3-carboxylic acid (5-azaproline, 16) are obtained by a two-step reaction via addition of diazomethane to acrylic acid esters to form the corresponding dihydropyrazoline derivatives, which are converted into the desired pyrazolidine-3-carb-oxylic acid derivative by hydrogenation over palladium on charcoal,11621 or by reduction with sodium cyanoborohydride,[164l or with zinc in acetic acid. Details are given in Table 6J1651... 

A few natural products which contain the cyclopropyl ring have been synthesized through metal catalysed cyclopropanation using dicarbonyl diazomethanes. ( )-Cycloeudesmol 63, isolated from marine alga Chondria oppositiclada, was synthesized via a sequence involving a copper catalysed cyclopropanation of a-diazo-/8-ketoester 61 to give the key intermediate 62 (equation 73)1 7,108. Similarly, the bicyclo[3.1.0]hexane derivative 65 was synthesized from the corresponding a-diazo-/8-ketoester 64 via the catalytic method and was converted into ( )-trinoranastreptene 66 (equation 74)109. Intramolecular cyclopropanation of -diazo-/i-ketoesters 67 results in lactones 68 which are precursors to 1-aminocyclopropane-l-carboxylic acids 69 (equation 75)110. 

Phenols (like carboxylic acids Section 24-7C and Table 18-6) are converted to methoxy derivatives with diazomethane ... 

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