Tropinone syntheses

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. 

Teloidine, the basic hydrolytic product of meteloidine, has been synthesised recently under physiological conditions by Schdpf and Arnold, on the lines of the tropinone synthesis, mesotartaric aldehyde (CHOH. CHO)j, being condensed at 25° with aeetonediearboxylic acid bnd methylamine hydrochloride to teloidinone (5-keto-l 2-dihydroxy-tropane) whieh on eatalytic hydrogenation yielded teloidine (1 2 5-trihydroxytropane). 

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

Table 4.30 Summary of reaction metrics and synthesis tree parameters for tropinone synthesis plans ranked according to overall kernel (maximum) RME. ...

BICYCLIC KETONES FOR TROPINONE SYNTHESIS 2a,4a-DIMETHYL-8-OXABICYCLO[3.2.1]OCT-6-EN-3-ONE... 

Bicyclic and cyclic ketones are also useful intermediates and a series of preparations are given in BICYCLIC KETONES FOR TROPINONE SYNTHESIS 2a,4a-DIMETHYL-8-OXABI-CYCLO[3.2.1 ]OCT -6-EN-3-ONE CYCLOPENTENONES... 

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. 

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. 

Bicyclic and cyclic ketones are also useful intermediates and a series of preparations are given in BICYCLIC KETONES FOR TROPINONE SYNTHESIS 2a,4a-DIMETHYL-8-OXABI-CYCLO[3.2.1]OCT -6-EN-3-ONE CYCLOPENTENONES FROM a,a -DIBROMOKETONES AND ENAMINES 2,5-DI-METHYL-3-PHENYL-2-CYCLOPENTEN-1-ONE y-KETO-ESTER TO PREPARE CYCLIC DIKETONES 2-METHYL-1,3-CYCLOPENTANEDIONE, with the companion preparation y-KETOESTERS FROM ALDEHYDES VIA DIETHYL ARYLSUCCINATES 4-OXOHEXANOIC ACID ETHYL ESTER, which gives the procedure used to prepare the needed... 

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. 

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." ... 

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]. 

---