Schmidt degradation

Of the classical Hofmann, Curtius, Lossen and Schmidt degradations, only a rare example of the first is known, hypobromite converting 4,7-diamino-2-phenyl-6-pteridinecar-boxamide (208) into 8-amino-2,3-dihydro-6-phenyl-l//-imidazo[4,5-g]pteridin-2-one (209 equation 64) (63JOC1203). 

Putrescine dihydrochloride has been prepared by the Hofmann degradation of adipamide 3.. s by the Curtius degradation of adipyl hydrazide through the urethane by the Curtius degradation of adipyl azide obtained from adipyl chloride and sodium azide by the Schmidt degradation of adipic acid with hydrogen azide by the reduction of succinonitrile, succinaldoxime, or 7-phthalimidobutyronitrile with sodium and from N-ben-zoyl-7-iodobutylamine ... 

Caution Hydrazoic acid, which is used in Part C of this procedure, is very toxic. Consequently, the conversion of methyl cycloundec-l-enecarboxy-late to cycloundecanone by the Schmidt degradation, including hydrolysis and subsequent steam distillation, should be conducted in a well-ventilated hood. 

Schmidt degradation of acyl azides (obtained from carboxylic acids)... 

Schmidt degradation of inandenin-10-one (63), isolated from the stem bark of Oncinotis nilida, followed by hydrolysis and analysis of the resulting mixture in a manner analogous to that described in the case of inandenin-12- and -13-one (see Scheme 11) was the basis of its structure elucidation (26). 

Scheme 11. Schmidt degradation reaction of the inandenine mixture 53/54.

Preliminary experiments on the alkaloids of Oncinotis nigra have afforded a fantastic mixture of related compounds. Besides small amounts of inandeninones, several inandeninols were isolated as an inseparable mixture. To identify the compounds in the mixture, two reactions were performed a transamidation reaction and Schmidt degradation of the ketones prepared by Cr03 oxidation of the natural alcohols. The structures 65-72 were proposed on the basis of the two reactions and MS and GC/MS identification of the mixed degradation products. It was not possible to determine the ratios of these alkaloids (74). 

SCHMIDT DEGRADATION Sodium azide. SILYLATION Trimethylsilyldiethylamine. SIMMONS-SMITH REAGENT, which see. SOMMELET REACTION Hexamethylenetetramine. 

Radioactive sparteine (II) was incorporated in good yield when lysine (2-14C) and cadaverine (l 5-i4C) were administered to L. luteus and Sarothamnus scoparius L. When the alkaloid was degraded by chromic oxide oxidation it gave succinic acid and a mixture of amino acids. The Schmidt degradation of the former generated carbon dioxide and ethylenediamine. The amino acid mixture contained jS-alanine and y-aminobutyric acid, which was further degraded to carbon dioxide and trimethy lenediamine. 

So little has been described of the chemistry of amino-furans that general comment on their reactivity is difficult to make it seems likely that simple amino-furans are too unstable to be isolable, though 2-acylamino-furans have been described, for example Boc-masked 2-aminofuran is obtained via a Schmidt degradation of the carbonyl azide in i-butanol. Heavily substituted amino-furans, in particular those with electron-withdrawing substituents on the ring or on the nitrogen are known. For example methyl 2-aminofuran-5-carboxylate is relatively stable it undergoes Diels-Alder cycloadditions in the usual manner (cf. 18.7). ... 

Upon oxidation of 32 with chromic acid to benzoic acid (35), followed by a Schmidt degradation of the benzoic acid, it was demonstrated that the carboxyl group of 35 contained 1/7, whereas the phenyl group contained 6/7 of the total molar radioactivity, a result consistent with the intervention of the tropylium ion (C). 

For the degradation of carboxylic acid, factors that may affect the reaction outcome are the ratio of sulfuric acid/carboxylic acid, the reaction temperature and the dilution extent of sulfuric acid. Even though some of the Schmidt degradations of carboxylic... 

TABLE 1. Analysis by Schmidt degradation to predict biosynthetic pathways for fatty acid biosynthesis from [2- C]acetate in various oil seeds. 

Values represent the percent radioactivity (of total label in fatty acid) observed in the carboxyl-carbon. In brackets are the number of experiments form which data are summarized followed by the pathway of synthesis (FAS, direct utilization of acetate in FAS or synthesis via aKAE) concluded from the data. The two right hand columns represent percentages predicted if fatty acids were derived from direct utilization of acetate by FAS or aKAE. When label of a particular acid was low, repeated collections form HPLC were pooled to obtain sufficient radioactivity for degradation. The method used for Schmidt degradation was reproducible to about 3% [7]. 

TABLE 2. Analysis by combined a-oxidation and Schmidt degradation to predict biosynthetic pathways for 16 0 and 18 carbon FAs biosynthesis from P- CJacetate in Arabidopsis fruits and soybean seeds. 

Howard (1968b) studied fatty acid synthetic systems in cell-free preparations from squirrel monkey aortas, and the data were similar to those for the rabbit aorta with regard to the mitochondrial system. Acetate or acetyl-CoA was a more efficient precursor than malonyl-CoA, and the Schmidt degradation data indicated that it was primarily an elongation system. The cytosol or HSS was examined, and malonyl-CoA was found to be incorporated into fatty acids 55-200 times more actively than acetyl-CoA, a finding that had been noted previously in liver HSS by Abraham et al. (1962a). Majerus and Lastra (1967) noted that malonyl-CoA was incorporated into fatty acids six or seven times as fast as acetyl-CoA by human leukocytes. The latter authors were unable to find any acetyl-CoA carboxylase activity in leukocytes and reasoned that these cells possess only the fatty acid synthetase. As they pointed out, in the absence of any acetyl-CoA carboxylase, the synthetase alone uses 1 mole of acetyl-CoA plus 7 moles of malonyl-CoA to make 1 mole of palmitate (Wakil... 

Dahlen and Porter (1968), Christ (1968), and Wit-Peeters (1969) have studied heart mitochondria and found only a chain elongation system. Studies by Whereat et al. (1967) with rabbit heart mitochondria led to the suspicion that there might be two synthetic systems. A complete Schmidt degradation by the Phares method (1951) as modified by Rabinowitz (1968) was performed and may explain why our results differed from those of other investigators. The latter method enabled assay of isotopic and nonisotopic carbon in the entire fatty acid chain and, therefore, specific activities of both carboxyl and alkyl were determined. In our hands we never achieved preci-... 

Incorporations of p- C-tryptophan (29a) and p- C-tryptophan (29b) quickly established that this amino acid is the biological precursor to the C and D rings (41). Kuhn-Roth oxidation of labeled (1) derived from (29 a), followed by Schmidt degradation of the resulting acetic acid, located all of the radioaetivity at C-3 of (1). This result was later confirmed by NMR analysis of streptonigrin derived from (29b). Other experiments showed that while methionine had labeled the four methyls of (1) equally, C-3 of serine — the major precursor to the biological one-carbon pool — labeled the three 0-methyls almost exclusively (41). 

In a second degradation sequence, verrucarinolactone (87) was oxidized to (/ )-(-h)-methylsuccinic acid (101). Schmidt degradation of this acid afforded radioinactive 1,2-diaminopropane (102) and two equivalents of active CO2, isolated as BaC03. From these results it was concluded that the carbon skeleton of mevalonate had undergone neither a rearrangement nor an exchange of the state of oxidation of C(l) and C(5), respectively. 

In experiment 1 (Table VII), the precursors emodin (76) and emodin-anthrone (77) were labeled with the same isotope ( " C) in two different positions [at C(3) and C(ll)] by the synthetic procedures described above. After incorporation, the corresponding carbon atoms of the ergochrome EE (2) could be analyzed as acetic acid by Kuhn-Roth oxidation. The specific incorporations were derived from the activities of the two carbon atoms, determined separately by Schmidt degradation of the acetic acid. The results show that emodinanthrone (77) is incorporated into ergochrome EE (2) 4.5 times more effectively than emodin (76). 

On treatment with periodate, the third ozonolysis product, 3-methyloctane-l,7,8-triol(32), yielded formaldehyde [(21)] and 5-methyl-7-hydroxyheptanal (33). The hydroxyaldehyde 33 was oxidized by chromium trioxide to 3-methylpimelic acid (34). Schmidt degradation of the latter gave carbon dioxide [C(14) and C(20)] and l,5-diamino-2-methylpentane (35) (isolated as dipicrate). Kuhn-Roth oxidation of octanetriol (32) yielded one equivalent of acetic acid [C(16) and 16-methyl]. 

---