Tropane alkaloids synthesis

It is now accepted that iV-methyl-A1 -pyrrolinium salt is the common precursor of not only tropane alkaloids but also of the N-methylpyrrolidine ring of nicotine, hygrine and cuscohygrine, as shown in Fig. 4. Purification of several enzymes involved in the tropane alkaloid synthesis and the use of radiolabelled precursors have considerably improved our understanding of the biosynthetic pathway. 

The wM-diacetate 363 can be transformed into either enantiomer of the 4-substituted 2-cyclohexen-l-ol 364 via the enzymatic hydrolysis. By changing the relative reactivity of the allylic leaving groups (acetate and the more reactive carbonate), either enantiomer of 4-substituted cyclohexenyl acetate is accessible by choice. Then the enantioselective synthesis of (7 )- and (S)-5-substituted 1,3-cyclohexadienes 365 and 367 can be achieved. The Pd(II)-cat-alyzed acetoxylactonization of the diene acids affords the lactones 366 and 368 of different stereochemistry[310]. The tropane alkaloid skeletons 370 and 371 have been constructed based on this chemoselective Pd-catalyzed reactions of 6-benzyloxy-l,3-cycloheptadiene (369)[311]. 

A divergent synthesis of tropane alkaloid ferruginine was reported by Node and coworkers [59]. The P-ketoester intermediate was prepared by a novel PLE-catalyzed asymmetric dealkoxycarbonylation (hydrolysis followed by a decarboxylation) of a symmetric tropinone-type diester (Figure 6.12). Dimethyl sulfoxide was added to the phosphate buffer pH 8 (1 9) to reduce the activity of PLE and prevent over-deal-koxycarbonylation leading to tropinone. 

Noyori and co-workers have developed a new and useful general synthesis of the tropane alkaloids (89-91). The Fe2(CO)9-aided reaction of tetra-bromoacetone and Af-carbomethoxypyrrole (165) (3 3 1 ratio) in benzene at... 

It was pointed out that 6,7-dehydro-3a-hydroxytropane (168), in particular, is a very important intermediate for the synthesis of several tropane alkaloids (e.g., 1,26,44, and 85), as well as of their congener 170 (Scheme 11). 

Scheme 11. 6,7-Dehydro-3a-hydroxytropane (168) as an intermediate in the synthesis of several tropane alkaloids. 

Synthesis of scopolamine (Fig. 4), a tropane alkaloid of known anticholinergic properties, was induced hy fivefold in hairy root cultures of Atropa belladonna overexpressing hyoscianine 6[3-hydroxilase. ... 

The Mannich reaction was used for the first synthesis of tropine, the parent alcohol of the tropane alkaloids. One of the natural tropane alkaloids used medicinally is hyoscyamine, sometimes in its racemic form atropine. Hyoscyamine is an anticholinergic, competing with acetylcholine for the muscarinic site of the parasympathetic nervous system, and thus prevendng the passage of nerve impulses. 

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 ... 

The a-methoxylated derivatives are shown to be versatile synthons because of the reactivity of the methoxy group near the nitrogen atom, a-Methoxycarbamates, prepared by anodic oxidation, were used as key intermediates in the synthesis of a-amino acids,200 a new carbon-phosphorus bond-forming reaction,200 and in a new method of acylation of aliphatic amines at the -position.201 The application of this reaction to the synthesis of pyrrolidine, piperidine, and tropane alkaloids is also described.202... 

Elicitation is effective in enhancing metabolite synthesis in some cases, such as in production of paclitaxel by Taxus cell suspension cultures [2] and tropane alkaloid production by suspension cultures of Datura stramonium [3]. Increasing the activity of metabolic pathways by elicitation, in conjunction with end-product removal and accumulation in an extractive phase, has proven to be a very successful strategy for increasing metabolite productivity [4]. For example, two-phase operation with elicitation-enhanced alkaloid production in cell suspension cultures of Escherichia californica [5,6]. 

A clever total synthesis of both enantiomers of animated 6a-carbahexoseptanoses 336 and ent-336, the immediate precursors of the tropane alkaloids calystegines A3 (337 and ent-337), was accomplished by Johnson and Bis [77], which centered upon the enzymatic desymmetrization of meso aminotropanediol 333. 

As a rule of thumb, we can assume that all parts of an alkaloidal plant contain alkaloids, although the site of synthesis is often restricted to a particular organ, such as the roots or leaves. Translocation via the phloem, xylem, or apoplastically must have therefore occurred. Phloem transport has been demonstrated for quinolizidine, pyrrolizidine, and indolizidine alkaloids, and xylem transport for nicotine and tropane alkaloids 36,39,511). 

The synthesis of a variety of tropane alkaloids has been achieved via 6,7-dehydrotropines (105), derived from (82) by stereoselective reduction with diisobutylaluminum hydride. Suteequent ap[ opriate modification of the double bond leads to several naturally occurring tropane alkaloids, including tropine (106), scopine (107), tropanediol (108) and teloidine (109) (Scheme 25). ... 

In a synthesis of tropane alkaloid 57, the strategy started with the diastereoselective 1,4-diacetoxylation of diene 51 (Scheme 8-18) [73]. The diacetate 52 obtained was converted to... 

Scheme 8-18 Synthesis of tropane alkaloids via diacetoxylation-desymmetrization.

Majewski, M., Lazny, R. Stereoselective synthesis of tropane alkaloids. Physoperuvine and dihydroxytropanes. Synlett 1996, 785-786. 

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