Hygrin

A/ -Methoxycarbonyl-2-pyrroline undergoes Vilsmeier formylation and Friedel-Crafts acylation in the 3-position (82TL1201). In an attempt to prepare a chloropyrroline by chlorination of 2-pyrrolidone, the product (234) was obtained in 62% yield (8UOC4076). At pH 7, two molecules of 2,3-dihydropyrrole add together to give (235), thus exemplifying the dual characteristics of 2,3-dihydropyrroles as imines and enamines. The ability of pyrrolines to react with nucleophiles is central to their biosynthetic role. For example, addition of acetoacetic acid (possibly as its coenzyme A ester) to pyrroline is a key step in the biosynthesis of the alkaloid hygrine (236). 

Convolvulus haxnadoe. The roots eontained 0-42, from whieh he isolated hygrine and euscohygrine (p. 103) and a third alkaloid hamadine, still awaiting detailed description. 

When the final methylation of either product is effected with formaldehyde, oxidation of the secondary alcohol group occurs simultaneously in each case, and of the two resulting ketones that from product (XIX) proved to be dZ-hygrine, which must therefore have formula (XVII) given above. Another synthesis of dZ-hygrine has been effected recently by Sorm. ... 

Hygrinc, Cj Hj ONj. This, the second fraction of Lossen s hygrine, decomposes when distilled imder atmospheric pressure, but boils at... 

Anet et al. ( 04) obtained in 1947 the alkaloids hygrine (191) and kusk-hygrine (192) in a very good yield by treatment of y-methylaminobutyralde-hyde with acetoacetic or acetonedicarboxylic acids at pH 7. The same reaction was later accomplished by Galinovsky et al. (305-307), who prepared the starting aldehyde by partial reduction of 1-methyl-2-pyrroli-done with lithium aluminum hydride. He used acetonedicarboxylic acid for the synthesis of both alkaloids and showed that a mixture of both alkaloids is formed, the composition of which depends on the ratio of components. 

Scheme 24. d(+)-Hygrine (209a) and l(—)-hygrine (209b) as synthetic intermediates. 

The mechanism of acetoacetate coupling in the biosynthesis of hygrine (209) has been studied by feeding sodium [3-14C]- and [4-14C] acetoacetate to Nicandra physaloides 134). 

In view of this finding, it was proposed (135-138) (Scheme 22) that in the case of cocaine (98) the ornithine (201) is incorporated through free putrescine (202), which is a symmetrical intermediate and therefore would afford the pyrrolinium salt 206 equally labeled at C-2 and C-5. As above, condensation of the (V-methyl-A1 -pyrrolinium salt (206) with acetyl coenzyme A leads to the coenzyme A ester of hygrine-1 -carboxylic acid (207), which by transester-... 

Two reviews on pyrrolidine alkaloids have appeared in volumes I (7) and VI (2) of this series. At that time, the only alkaloids mentioned were hygrine (1), hygroline (2), cuscohygrine (3), stachydrine (4), and betonicine (5). Carpaine,... 

Hygrine (1) and hygroline (2) were known compounds when the first reviews on pyrrolidine alkaloids in this series were written. Since 1950, the configurations of 1 and 2 have been determined and new sources of the alkaloids have been found. 

New sources of hygrine are the roots of Nicandra physaloides (L.) Gaertn. (Solanaceae) (9, JO), Dendrobium chrysanthum Wall. (Orchidaceae) (11), and Cochlearia arctica Slecht (Cruciferae) (12). Hygroline was also isolated from this latter source as well as from Carallia brachiata (Lour.) Merr. (Rhi-zophoraceae), a plant from eastern Asia, New Guinea, and Queensland (13), and... 

Syntheses of hygrine will be detailed in a separate section but it is worth noting here that the intriguing problem of the Hess synthesis of hygrine has been solved (15, 16). Hygrine is no longer synthesized from 2-(p-hydroxypropyl) pyrrolidine, HC1, and CH2OI... 

Structures of alkaloids 25, 26, and 27 were established by spectroscopic means (UV, IR, NMR, and mass) and by chemical correlations. All three compounds had a zero optical rotation, which might be attributed to an easy racemization of their unique stereo centers this was also observed for hygrine. 

Chemical degradations have allowed the identification of both extremities of peripentadenine, hexanoic acid (present as an amide) and 2-hydroxy-6-meth-ylacetophenone. 13C NMR showed that the rest of the molecule included two nitrogen atoms, six methylenes, and one methine arranged in a (3-propylami-no)-l-pyrrolidine unit substituted at C-2. This formula was definitively proved by chemical degradations as well as by two total syntheses. As noted before in the cases of hygrine and of the ruspolinone alkaloids, peripentadenine is optically inactive. 

Dehydrodarlingianine (69) and dehydrodarlinine (72) were synthetized by base-catalyzed reaction of hygrine with cinnamaldehyde and benzaldehyde, respectively. The relative stereochemistry of darlingianine (65) was established by X-ray diffraction (111). The structure of the other bases was established by chemical correlations as well as by spectroscopic methods. The absolute configurations of these bases remain to be determined. 

The pivotal role of hygrine in the biosynthesis of cuscohygrine and of the tropane alkaloids has justified numerous investigations. The following scheme represents the now generally admitted pattern of formation of these bases. Ornithine (119) is first converted to putrescine or V-methylputrescine (120)... 

Scheme 9. Incorporation of acetate and acetoacetate in hygrine and cusecohygrine.

The viability of these biosynthetic schemes were supported by several enzymatic (155, 156) or chemical (757) biomimetic syntheses of cuscohygrine and of hygrine (Scheme 11). 

Although no experiment has yet been reported to support the idea, it seems clear that a majority of the pyrrolidine alkaloids arise from the ornithine, pu-trescine, and proline pool. This could be the case for ficine (61) and isoficine (62), vochysine (63), and phyllospadine (64) but also of the Darlingia alkaloids, which share common features with hygrine this assertion probably also holds for the ruspolinone (25) and odorine-roxburghlin (59) families. Peripentadenine, isolated from a plant of the family Elaeocarpaceae, bears resemblance to other alkaloids of the elaeocarpus type such as isoelaeocarpicine (124) (161). It cannot be excluded, however, that spermidine may be a biosynthetic intermediate instead of putrescine. The question of the origin of ant alkaloid substances remains so far without an obvious answer. 

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