Robinson, tropinone synthesis

Scheme 4.21 Robinson Tropinone Synthesis Plan (1 91 7). (a) CaC03, then 2HCI (42%).

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." ... 

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. 

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. 

This complex route to tropinone was imitated as long ago as 1917 in one of the most celebrated reactions of all time, Robinson s tropinone synthesis. Robinson argued on purely chemical grounds that the sequence of imine salts and enols, which later (1970) turned out to be Nature s route, could be produced under natural conditions (aqueous solution at pH 7) from a C4 dialdehyde, MeNH2 and acetone dicarboxylic acid. It worked and the intermediates must be very similar to those in the biosynthesis. 

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... 

Sir Robert Robinson (1886-1975) carried out many famous syntheses at Liverpool and Oxford and has two reactions, this annelation and the tropinone synthesis (Chapter 51), named after him. He won the Nobel prize in 1947. He was brilliantly inventive and the first person to work out mechanistically howto do syntheses. 

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). 

Proline and ornithine would also appear to be the most probable amino acid precursors of 1-hyoscyamine, and, as such, the source of the nitrogen of the tropane nucleus. The biosynthesis of the tropic acid half of the molecule has not yet received attention. Such investigations as have been made up to the present have been based upon Robinson s (113) proposed tropinone synthesis from ornithine plus acetone, and have been principally concerned with the identification of the original nitrogenous precursor. 

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... 

The yield of tropinone by Robinson s synthesis has been demonstrated to be markedly dependent upon experimental conditions (39). Table 1 illustrates the variation in the yield of tropinone with changes of temperature and pH (time of reaction 72 hours). The yield of tropinone at a pH of 13 is 5% or less but an additional 65% may be recovered by decarboxylation of the tropinonedicarboxylic acid formed under these conditions. 

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]. 

In the earliest period of complex natural product synthesis, from Robinson s 1917 tropinone synthesis to Eschenmoser and Woodward s 1973 coenzyme synthesis, metal-catalyzed reactions played no great role. In contrast, modern organic syntheses often involve numerous transition metal-catalyzed steps. Main-group compounds, such as BuLi, MeMgBr, or NaBH4, tend to act in stoichiometric quantity as reagents, while the more expensive transition metals, typically complexes of Pd, Rh, or Ru, tend to be used as catalysts and therefore in much lower amounts, for example, 0.1-5 mol% (mmol catalyst per 100 mmol substrate). 

Based on this simple one-step route to tropinone developed by Robinson, other alkaloids with a common piperidine or pyrrolidine ring moiety became easily accessible. For example, only a few years after the initial discovery of the tropinone synthesis, Robinson developed an analogous one-step synthesis of pseudopeUetierine (48), a ring homolog of tropinone, involving a consecutive inter- and... 

SCHEME 11.43 Revised tropinone synthesis by Robinson [131, 132] and Schopf [133]. 

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°),... 

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. ... 

Tropinone is another classic compound in the history of total synthesis. The celebrated plans of Willstatter and Robinson are shown in Schemes 4.20 and 4.21 and Figure 4.63 shows a synthesis map for different ways this compoimd has been made. The synthesis tree for the three-component Robinson plan is shown in Figure 4.64. Calcium carbonate and hydrochloric acid are added as inputs to complete the balanced chemical equation since these are involved in a neutralization reaction. It is clear from the results summarized in Table 4.30 that the Robinson plan is the clear front-rimner because the synthesis is achieved in a single step even though the reaction yield is modest. Any further improvements to this method would be directed to improving this parameter. 

Figure 4.64 Synthesis tree for Robinson synthesis of tropinone.

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. 

The original Robinson synthesis (66) of tropinone (124), which consists of a reaction between succinaldehyde (140), methylamine (141), and the calcium salt of acetonedicarboxylic acid (142), proceeds in low yield (Scheme 2). However, it has the great merit of being the pioneering achievement in the field of biomimetic syntheses of natural products. 

The domino approach is also used by Nature for the synthesis of several alkaloids, the most prominent example being the biosynthesis of tropinone (0-16). In this case, a biomimetic synthesis was developed before the biosynthesis had been disclosed. Shortly after the publication of a more than 20-step synthesis of tropinone by Willstatter [14], Robinson [15] described a domino process (which was later improved by Schopf [16]) using succinaldehyde (0-13), methylamine (0-14) and acetonedicarboxylic acid (0-15) to give tropinone (0-16) in excellent yield without isolating any intermediates (Scheme 0.5). 

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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