Hygrinic acid

Hygrinc (CgHisON) is insoluble in aqueous NaOH but soluble in aqueous HCI. It does not react with benzenesulfonyl chloride. It reacts with phenylhydraxine to yield a phenylhydrazone. It reacts with NaOI to yield a yellow precipitate and a carl xylic acid (C7HnO->N). Vigorous oxidation by Cr03 converts hygrine into hygrinic acid (CfiHnOaN). 

The results with [l- C]acetate in S. lurida support this conclusion. Incorporations for this precursor as well as [2- C,<5- N]ornithine, [l,4- C2]putrescine, and [4- H]-iV-methylputrescine were recorded in both cuscohygrine (29) and hyoscyamine (30). Degradation of the cuscohygrine in each case, which was to hygrinic acid (31), showed that the activity from these precursors (excluding acetate) was confined almost entirely to the pyrrolidine ring. 

Hygrine when oxidized with chromic acid in sulfuric acid (14), yields hygrinic acid, CgHnOjN, m.p. 164°, which forms a hydrochloride, m.p. 

The above structure for hygrinic acid has been confirmed by synthesis (16). The reaction in the cold of molar amounts of trimethylene bromide and ethyl sodiomalonate yielded ethyl bromopropylmalonate (II) which readily took up another atom of bromine to form ethyl a,5-dibromo-... 

It is of interest here to note that Z-hygrinic acid, m.p. 116°, Wd = -80° (HjO), has been prepared by oxidation of iV-methylnicotone with chromic acid in sulfuric acid (17). 

Some of the early reactions applied to stachydrine (42), although somewhat drastic, pointed to the presence of a dimethylamino grouping and a pyrrolidine nucleus in this alkaloid. Fusion of stachydrine with potassium hydroxide liberated dimethylamine while the vapors from the pyrolysis of this alkaloid gave a characteristic pyrrole test. This assumption of a pyrrolidine nucleus in the base is further confirmed by the above conversion of stachydrine into hygrinic acid. Schulze and Trier considered stachydrine to be the methylbetaine of hygrinic acid (XXIII). At about the same time Engeland, in elaborating his scheme for the isolation of... 

By following the synthesis for hygrinic acid,we can deduce the structure of hygrine. The first step is the malohic ester synthesis ... 

The next step is decarboxylation by heat to form hygrinic acid ... 

The absolute configuration of brevicolline (9) has been established by a multistep oxidative degradation to hygrinic acid. 

In the above examples, L-a-amino acids induce the natural 13P-chirality. Amines or amino acid derivatives (esters, amides) are much less effective, and a tertiary amino acid, hygrinic acid, was ineffective. For trione 13a, secondary amino acids (e.g., proline) are best for 13b and 13c [R > H, see also the Danishevsky (Scheme 8) and Tsuji (Scheme 10) syntheses below], a primary amino acid (e.g., L-phenylalanine) is preferred. The mechanism of the reaction has not yet been clarified. ... 

In 1925, Paul Karrer succeeded in determining the absolute configuration of nicotine, by deconstructing it to (L)-hygrinic acid, and further to proUne (Fig. 5.203). [531]... 

Methylprolines, A27.3, A27.4 Pipecolic acid, A10.7, A"6 Nipecotinic acid, A30.13 2-Aminohex-4-enoic acid, A10.12 Hygrinic acid. All. 14 Homoproline, A"21.6 Coronamic acid, A"35.6... 

The Hajos and Wiechert research groups looked at a number of other potential proline based catalysts for their intramolecular Robinson annulation. (. -(-)-Hygrinic acid, Af-methylproline 13, was examined, but only the racemic intermediate ketol product 2 was obtained. In a similar manner, the proline methyl ester 14 also produced the racemic ketol intermediate. No reaction was observed with the piperidine analog 15. The homo-proline analog 16 gave the enantiomeric product. An explanation for this change in selectivity has not been provided yet. Please note that the use of (i )-proline provides the enantiomeric product. 

The naturally occurring alkaloid hygrine is easily racemized and, as normally isolated, is only slightly levorotatory. The acids (+)-hygrinic acid and ( )-hygrinic acid obtained from hygrine are not readily racemized. 

Hydroxytremetone, Y1 2-hydroxytryptophan, A20 5-hydroxytryptophan, A20 Hygrine, K19 Hygrinic acid. All Hygroline, K19 Hygrophyllinecic acid, K23 Hymentherenes, Tl Hyoscine, K28 Hyoscyamine, K28... 

Some of the configurational relationships established between different bases and amino acids have a possible biogenetic significance and may be briefly mentioned. Thus Karrer and Widmer (1925) methylated ( —)nicotine (I) on the pyridine nitrogen, (II) and oxidized this compound to l( —)hygrinic acid (III) which could be methylated to stachydrine this betaine is also formed from L-proline. Thus ( —)nicotine may be formed in nature from L-proline. 

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