Robinson, tropine synthesis

Atropine can be synthesized from tropi-none and tropic acid as starting materials. Tropinone can be prepared by Robinson s synthesis (68) and reduced under proper conditions to tropine. ( )-Tropic acid can be prepared from ethyl phenylacetate (69, 70) or acetophenone (71). The 0-acetyl derivative of tropyl chloride reacts with tropine to yield O-acetyl of atropine hydrochloride, from which the acetyl group hydrolyzes spontaneously in aqueous solution (72). 

Robinson s synthesis of tropine (210) on the other hand was as direct (two steps) as Willstatter s was long but it involved the use of the very sensitive succinic dialdehyde (from pyrrole) (157, 219). The fragments from the hypothetical fission of the symmetrical tropinone (XLVI) suggested to Robinson the possibility of obtaining this ketone by the condensation of succinic dialdehyde and methylamine with acetone. The primary reaction was considered to be the combination of succinic dialdehyde with methyl-amine and the resulting biscarbinolamine (XLIX) in turn condensed with acetone. This synthesis was realized when these reactants, in aqueous... 

Blount and Robinson have extended this mode of synthesis to the preparation of iV-methyl/iomogranatonine (XXII) by the use of adipaldehyde, CHO. [CH2]4. CHO. The base, on reduetion with sodium in butyl aleohol, yields A -methyl/mmogranatoline (XXII CO — CHOH), the benzoyl derivative of which possesses marked local anaesthetic aetion. Similarly Blount, by eondensing /3-(o-formylphenyl)propaldehyde, CHO. CgH4. CHj. CHj. CHO, with methylamine and calcium acetonedicarboxylate, has prepared 8 9-benz-d - -feomogranatene-3-one (XXIII), which was reduced to the -alcohol (cf. reduction of tropinone to -tropine) and the latter converted to the benzoyl-derivative (m.p. 98°),... 

Though the dialdehyde-tropinone synthesis does not succeed when the dialdehyde is replaced by a diketone, Blount and Robinson have shown that 1-methyltropinone (XXXV) can be obtained by the interaction of the keto-aldehyde, laevulinaldehyde. Me. CO. CH. CH. CHO, with methylamine and calcium acetonedicarboxylate, and from this by reduction to 1-methyl- -tropine and benzoylation, 1-methyl tropacocaine (b.p. 210°/15 mm. picrate, m.p. 163-4°) has been prepared. 

Mannich reactions, or a mechanistic analog, are important in the biosynthesis of many nitrogen-containing natural products. As a result, the Mannich reaction has played an important role in the synthesis of such compounds, especially in syntheses patterned after the biosynthesis, i.e., biomimetic synthesis. The earliest example of the use of the Mannich reaction in this way was Sir Robert Robinson s successful synthesis of tropinone, a derivative of the alkaloid tropine, in 1917. 

But the most reliable biomimetic type of synthesis of tropine was achieved in 1S17 by Robinson (27). In this method, succindialdehyde, methylamine and acetone dicarboxylic acid were mixed at pH 5.6 for 30 minutes to give tropinone in one step which was then reduced to tropine by an established process (25). A much better yield (almost 40%) was obtained by using calcium acetcndicarboxy-late the calcium salt so produced is converted into tropinone by warming with hydrochloric acid (23). 

From analytical data the structure for tropine appears to be well established and this has been confirmed by synthesis. The classical S3mthe-sis of this alkaloid by Willstatter was followed in rapid succession by the shorter and more direct methods both of Robinson and of Willstatter. 

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