Tropane synthesis

An impressively efficient new route to the synthesis of tropane derivatives has been reported during the year. - This involves as key stage the promotion of C—C bond formation by means of transition-metal carbonyls. The known cycloaddition of oxyallyl derivatives of type (10) with 1,3-dienes or furan to give products of structure (11a) or (11b) has not previously been applied to tropane synthesis owing to the fact that iV-methylpyrrole gives preferentially products, e.g. (12), arising by electrophilic substitution. This difficulty has now been overcome... 

As our first model we chose N-benzoylnortropane (12) to investigate construction of the tropane ring system based on [4 + 2] nitroso cycloaddition with a 1 3-cycloheptadiene. A search of the literature indicated that only one example of a Diels-Alder cycloaddition of a nitroso compound with a seven-membered ring diene has been reported (ref. 8). In view of this the present study of tropane synthesis was initiated by the examination of the nitroso Diels-Alder reaction of 1 3-cycloheptadiene (7) (Fig. 1). Thus reaction of 7 with the acylnitroso compound 8 generated in situ from benzohydroxamic acid by oxidation with tetrapropyl-ammonium metaperiodate (ref. 9) was carried out at room temperature, affording the [4 +2] cycloadduct 9 in 85% yield. Reduc-... 

Recent studies have demonstrated (ref. 10) the potential synthetic utility of C-N bond formation via heteromercuration of carbamate derivatives of unsaturated amines. This prompted us to utilize the dehydration products 19a and 20a in the tropane synthesis via intramolecular heteromercuration. Thus the 1 1 mixture of 19a and 20a was treated with mercuric acetate followed by reduction with NaBH to furnish N-carbobenzoxynortropane (26) in 45% yield (based on reacted starting material). The product 26 must result from reductive demercuration of both organomer-curials 24 and 25 initially formed from the asymmetrical and symmetrical olefins 19a and 20a, respectively, via cationic intermediates 22 and 23 as depicted in Fig. 3. Thus separation of the olefin mixture is not necessary since both the olefins can equally be utilized as the reaction substrates in this cycliza-tion. 

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]. 

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). 

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. 

Heckrodt TJ, Mulzer J (2005) Marine Natural Products from Pseudopterogorgia Elisabe-thae Structures, Biosynthesis, Pharmacology and Total Synthesis. 244 1-41 Heinmaa I, see Samoson A (2005) 246 15-31 Helm L,see Toth E (2002) 221 61-101 Helmboldt H, see Hiersemann M (2005) 243 73-136 Hemscheidt T (2000) Tropane and Related Alkaloids. 209 175-206... 

The basic principle of the synthesis involving 143 has been applied for the preparation of many tropane derivatives [e.g., 6-hydroxytropinone (144) and ( + )-cocaine (98)] (69-71). During recent years, especially in China, considerable attention has been paid to practical applications and modifications of this long known method (70-77), illustrated here by the scheme leading to anisodamine (63) (Scheme 4). 

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. 

Kende described an impressive example of the use of the [34-4] cycloaddition in natural product synthesis (Scheme 14.10) [101]. A key nortropinone intermediate for the total synthesis of ( )-isostemofoHne 105 was acquired through the tropane system 104, which was formed from the [34-4] cycloaddition of pyrrole 103 and a siloxy-substituted vinylcarbenoid of 87 in 90% yield. 

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 ... 

Koh, J. S. Ellman, J. A. Palladium-Mediated Three-Component Coupling Strategy for the Solid-Phase Synthesis of Tropane Derivatives, J. Org. Chem. 1996, 61,4494-4495. 

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... 

Sertraline [60], chiral 1,4-cycloheptadienes [61], and select cyclopentenes [62] have been prepared by using these catalysts and vinyldiazocarboxylates, and this approach has also been applied to the enantioselective synthesis of functionalized tropanes [63] and of the four stereoisomers of 2-phenylcyclopropane-l-amino acid [64]. 

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. 

A total synthesis of diastereoisomers of anisodamine, an alkaloid from Anisodus tanguticus, has been claimed17 by Chinese authors. ( )-Acetyltropoylation of ( )-/ -acetoxy-3cr-hydroxytropane, followed by partial deacetylation, led to a diastereoisomeric mixture of 6/ -hydroxy-atropines. (—)-(S)-6/l-Hydroxyhyoscy-amine, a natural tropane, had earlier been obtained by total synthesis.18 In view of this and of the non-identity of the i.r. spectra of synthetic mixture and natural anisodamine , it remains uncertain whether the latter is identical with natural (—)-(5 )-6/ff-hydroxyhyoscyamine.18... 

---