Tropinone, Mannich reaction

The synthesis of tropinone 14, a precursor of atropine and related compounds, is a classical example. In 1917 Robinson has prepared tropinone 14 by a Mannich reaction of succindialdehyde 11 and methylamine 12 with acetone 13 better yields of tropinone were obtained when he used the calcium salt of acetonedicar-boxylic acid instead of acetone. Modern variants are aimed at control of regio-and stereoselectivity of the Mannich reaction. ... 

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. 

Tropinone is a structural component of several alkaloids, including atropine. The synthesis is based on a double Mannich process with iminium ions as intermediates. The Mannich reaction in itself is a three-component domino process, which is one of the first domino reactions developed by humankind. 

The Mannich reaction consists on the condensation of a CH-activated compound with a primary or a secondary amine and a non-enolizable aldehyde or ketone to afford p-aminocarbonyl derivatives known as Mannich bases (Scheme 20). This sequence is of great use for the constmction of heterocyclic targets, as illustrated for example by the Robinson-Schopf synthesis of tropinone in 1937 or by the preparation of some azabicyclo[3.3.1]nonanones or pyranocoumarine derivatives (Fig. 1) [100]. In the following, representative recent examples of the formation of five- to seven-membered ring heterocycles will be presented. 

L-metilionine to -adenosylmethionine. In this process a positively charged sulphur is produced and facilitates the nucleophilic reaction. By the activity of diamine oxidase, the A -methyl-A -pyrrolinium cation is formed and after that the first alkaloid, hygrine. From hygrine, by way of acetyl CoA, hydrolysis and intramolecular Mannich reactions, other pyrrolidine and tropane alkaloids are synthesized cuscohygrine, hyoscyamine or tropinone, tropine and cocaine. The Mannich reaction involves the combination of an amine, an aldehyde or a ketone with a nucleophilic carbon. This reaction is typical in alkaloid synthesis, and can be written as follows ... 

Robinson synthesis of tropinone (example of Mannich reaction in synthesis)... 

The Mannich reaction is an important biosynthetic route to natural products, mainly alkaloids, and some of these routes have been duplicated in the laboratory. A classic example is the synthesis of tropinone (17) by Robinson in 1917. Robinson synthesized tropinone by a Mannich reaction involving succindialdehyde, methylamine, and acetone 183... 

Pyrrolidines may also be prepared by Mannich reactions, e.g. the formation of tropinone by reaction (34) — (35) reactions of this type are involved in alkaloid biogenesis. 

The first example of the application of the Mannich reaction to natural product synthesis is attributed to Robinson in his synthesis of tropinone R. Robinson, J. Chem. Soc. 1917, 762. 

Decarbomethoxylation. A recent stereoselective synthesis of coccinelline (4), an alkaloid used by the ladybug for defense, has been achieved by use of a variant of the classical Robinson-Schopf synthesis of tropinone. The reaction of 1 with acetonedicarboxylic ester at pH 5.5 yields a single product in 75 % yield, even though five chiral centers are produced. The next step, conversion of 2 to 3, requires neutral conditions in order to avoid retro-Mannich or retro-Michael reactions. This decar-bomethoxylation was accomplished most satisfactorily by NaCl in refluxing wet... 

An interesting pyrrole synthesis involved a retro-Mannich reaction of tropinone derivatives <04EIO1397>. 

This reaction was first reported by Robinson in 1917 and subsequently improved by Schopf in 1935. It is an ingenious one-pot multicomponent synthesis of tropinone from succindialdehyde, acetonedicarboxylic acid and methylamine in aqueous solution involving a double Mannich Reaction This reaction is thus known as the Robinson tropinone synthesis," Robinson synthesis, " Robinson-Schopf reaction,Robinson-Schopf condensation, or Robinson condensation." It has been reported that the Robinson tropinone synthesis can take place without any racemization at the stereogenic center adjacent to the aldehyde group, as demonstrated by the formation of L-a/to-teloidinone from D-tartaraldehyde, and c-a/to-teloidinone from i-tartaraldehyde respectively." ... 

Also, a large number of indole alkaloids are formed by Mannich reactions involving tryptophan or its decarboxylation product tryptamine with various aldehydes. Both the a- and p-position of the indole nucleus are electronegative, and a Mannich reaction with tryptamine can yield a p-carboline derivative or a 3,3-spiroindolenine [30]. A further example is provided by the tropinone biosynthesis (Figure 1.29) [31 ]. 

Figure 1.29 Examples of Mannich reactions, (a) Biosynthesis of alkaloids bearing the 1,2,3,4-tetrahydroisoqumoline ring, (h) biosynthesis of indole alkaloids (P-carboline, 3,3-spiroindolenine), and (c) tropinone biosynthesis.

Another well-known example is the biosynthesis ofatropine within the formation of the central skeleton tropinone. Using a twofold Mannich reaction, tropinone has been prepared in a single process [8] (Scheme 5). 

Mannich reaction between the enol and iminium 10 to give bicycle 11. Finally, action of HCl on bis-carboxylic acid 11 results in double decarboxylation to generate tropinone (4). As shown by Paquette, slight variations in this mechanism may be operative depending on steric compression during ring-closing events. 

Robinson s synthesis of alkaloid tropinone (24), an achiral, wso-structure, represents an elegant application of the Mannich reaction to dialdehyde 21, methyl-amine 22, and C-H acid keto-diester 23 (Scheme 8.9) [42]. 

Scheme 8.9 The three-component Mannich reaction in the synthesis of tropinone 24...

Scheme 6.2 Synthesis of tropinone 7 by the three-component Mannich reaction...

We already described the application and mechanism of the Mannich reaction in Sect. 4.4.2. An elegant application of this reaction is Robinson synthesis of the bicyclic alkaloid tropinone 7 starting from simple building blocks 4-6 and completed with great atom economy (Scheme 6.2) [7]. 

The retro-Mannich reaction of tropinones under the influence of certain catalysts, such as TMS-Br affords pyrroles (eq 50). In these reactions the nitrogen atom of the substrates typically is protected as a carbamate or as a sulfonamide. A basic amine is not conducive to this reaction with this t) e of reagent. The TMS-Br is used catalytically in amounts usually around 10%. The tropinone ketone may be a-substituted with various alkyl groups to give ultimately homologous ketone products. 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

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