Hygrinic acid esters

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

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. ... 

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. 

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). 

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-... 

All that remains to form hygrine is the hydrolysis of the CoA thiol ester and decarboxylation of the keto-acid. This is standard chemistry, but you should ensure that you can draw the mechanisms for these steps. 

The cyclized form of this amino-aldehyde is the y-methyl-A -pyrrol-inium salt (6). Condensation of this iminium salt with aceto-acetyl coenzyme A yields the coenzyme A ester of hygrine-1 -carboxylic acid (10). Hydrolysis of this ester and decarboxylation of the resultant 3-keto-acid (9) affords hygrine (8), which has been shown to be a precursor of tropine which is plausibly formed... 

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