Tropane skeleton, synthesis

The organic synthesis of alkaloids has a long history and numerous synthetic approaches of the tropane skeleton have been developed, from the classical synthesis of tropine by Willstatter at the beginning of the century and comprehensively reviewed by Holmes [46], to the most recent developments dealing with asymmetric deprotonation of tropinone, with chiral lithium amide bases for the enantioselective synthesis of a range of tropanes [47]. New synthetic methods are periodically reviewed and readers interested in this area may refer to specialized literature. 

The Hajos-Parrish-Eder-Sauer-Wiechert synthesis (Scheme 5) was the first example of an intramolecular proline-catalyzed asymmetric aldol reaction. Systematically, this reaction can be described as a 6-enolendo cyclization. In 2003, List et al. described the first example of an intramolecular enolexo aldolization 85). This approach was then used by Pearson and Mans for the synthesis of (-i-)-cocaine 92, starting from the weso-dialdehyde 90 on treatment with (S)-12 86). This desymmetrization process gave 91 as a mixture of epimers with good enantio-selectivity. The tropane skeleton 91 could be further transformed into +)-92 by conventional means (Scheme 21). 

Other Reactions Oxallyls, formed from a,a -dibromoketones and Fe2(CO)9, react with alkenes, enamines, enol ethers, amides, or dienes to give a variety of [3 + 2] and [3 + 4] cycloaddition products (Eq. 14.71). This provides a very short synthesis of the tropane skeleton from acetone and pyrrole (Eq. 14.72). As shown in Eq. 14.71, an oxallyl resembles trimeth-ylenemethane (5.22) except that one =CH2 of 5.22 is replaced by =0. 

Cycloaddition of oxyallyl cations to N-methylpyrrole and furan leads to novel analogues of cocaine (Scheme 74). ° In a somewhat related synthesis the tropane skeleton has been prepared using bromo-ketone-iron carbonyl coupling to pyrroles (Scheme 75). ° ... 

The first biomimetic synthesis of the tropane skeleton was reported by Robert Robinson (Nobel Prize, 1947) in 1917 initially, the yield was only of the order of 20 % but it was later improved to 90 %. Write a mechanism for the process ... 

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]. 

This reaction type is useful for the synthesis of tropane-like azabicycles (equations 94 and 95). Allyl-and propargyl-silanes are excellent nucleophiles in this process.Enone (125) is probably first transformed into an enol ether (c/. equation 70) before it cyclizes to the homotropane skeleton, which is eventually isolated as a mixture of enone (126) and chloride (127). 

Davies has further exploiled his previously reporied approach to (he tropanc skeleton related to cocaine based on the rhodium catalyzed decomposition of the vinyidiazomethane 81 in the presence of A/-Boc-pyrroIe (82) <01BMCL487>. Reduction of the non-conjugated double bond followed by A -deprotection and N-alkylation provided substrate 83 which was susceptible to conjugate addition of nucleophiles such as 84 in the presence of CuBr to afford 3-p-aryl tropanes which exhibited potent binding affinity for both the dopamine and serotonin transporters. Additionally, this author described the synthesis of various methyl heteroaryldiazoacetate analogues of 81, (me of which possessed an indole function, for use in catalytic asymmetric cyclopropanations . 

The starting material for the synthesis of the lupin alkaloids is the amino acid lysine, which is first decarboxylated to give its biogenic amine cadaverine. Two units of cadaverine are then joined via a still hypothetical intermediate to give lupinin. Addition of another cadaverine unit to lupinin gives sparteine, which then can be oxidized to lupanin and, further, to hydroxylupanin. The C skeleton of the quinolizidine alkaloids is derived entirely from lysine. We shall now consider two further groups of alkaloids, the nicotiana alkaloids and the tropane alkaloids, which derive only a part of their C skeleton from the aliphatic amino acids ornithine or lysine. 

Noyori et al. have reported a general synthesis of tropane alkaloids from a,a -dibromo ketones. Reaction of tetrabromoace-tone, /V-methoxycarbonylpyrrole, and Fc2(CO)9 (3 1 1.5 mol ratio) in benzene (50 C, Nj) produces two isomeric cycloadducts in a 2 1 mixture, which can be used in the preparation of the alcohol (46), a key intermediate in the synthesis of scopine and other tropane alkaloids. A more recent example gives access to the bicyclo[5.2.0]nonene skeleton. ... 

Over the past few decades, the biosyntheses of tropane alkaloids such as (—)-hyoscyamine, (—)-scopolamine, and (—)-cocaine have been studied extensively [18]. The skeletons of all these alkaloids feature the tropinone moiety, produced by oxidation and subsequent cyclization of (-b)-hygrine (17) [19]. It was envisioned that RCM could be invoked in order to develop an enantioselective synthesis of 17 [20]. As depicted in Scheme 2.5, a phase-transfer catalytic allylation reaction with methaUyl bromide converted t-butyl ester 13 into product 14 with 97% ee. Metathesis precursor 15 was then prepared in six more steps, including transformation of the t-butyl ester of 14 into a terminal olefin. Dihydropyrrole 17 was formed in quantitative yield by RCM employing [Ru]-II (8 mol%). Subsequent hydrogenation and deprotection of 16 led to (-l-)-hygrine 17 with overall yield of 29% and an ee of 97%. 

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