25,37 synthesis Ergoline

An improved synthesis of Uhle s ketone (54), a useful intermediate in ergoline synthesis, has been described,36 in which the closure of the ketone ring is accomplished by the Dieckmann reaction this route is also applicable to the homologous ketone. 

Figure 8 Intact incorporation of [N- CH3]MeDMAT into elymoclavine establishes methylation of DMAT as the second step of the ergoline synthesis pathway...

Palmisano, G., Danieli, B., Lesma, G. and Fiori, G. (1987) Electrochemical synthesis of 2-halo-ergolines. Synthesis, 1987, 137-139. 

Sauei G., Haffei G. and Wachtel, H. (1986) Reduction 8a-suhstituted 9,10-didehydro ergolines. Synthesis, 1007-1010. 

Chemoselective C-alkylation of the highly acidic and enolic triacetic acid lactone 104 (pAl, = 4.94) and tetronic acid (pA, = 3.76) is possible by use of DBU[68]. No 0-alkylation takes place. The same compound 105 is obtained by the regioslective allylation of copper-protected methyl 3,5-dioxohexano-ate[69]. It is known that base-catalyzed alkylation of nitro compounds affords 0-alkylation products, and the smooth Pd-catalyzed C-allylation of nitroalkanes[38.39], nitroacetate[70], and phenylstilfonylnitromethane[71] is possible. Chemoselective C-allylation of nitroethane (106) or the nitroacetate 107 has been applied to the synthesis of the skeleton of the ergoline alkaloid 108[70]. 

The technical aspect of 2-bromo-a-ergocryptine synthesis, including the characterisation and significance of the impurities obtained in the production process, were reviewed. In the continuation new ergolene and ergoline compounds were synthesized and tested for the pharmacological activity. 

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphi-noxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereo- and enantioselective allylation of substituted nitroalkanes has also been reported.9513... 

Cyclialkylation has been applied in the synthesis of iV-heterotri- and tetracycles. Reimann et al.332 have performed the stereoselective ring closing of the diastereo-meric mixture of piperidinols 101 and isolated the product ergoline with a C/D cis configuration in low yield [Eq. (5.130)]. It was also observed, however, that one of the isomers afforded the product quantitatively under identical conditions, whereas the other slowly decomposed. 

A considerable amount of attention has been paid during the past year to the synthesis of ergot alkaloids, particularly the simpler ergoline or seco-ergoline bases. Reviews on this subject have been contributed by Horwell320 and by Kozikowski.326... 

Synthesis of tritium and carbon-14 labelled N-(3-dimethylaminopropyl)-N-(ethylaminocarbonyl)-6-(2-propen- 1-yl)ergoline-8p-carboxamide (cabergoline)... 

Ohno S, Koumori M, Adachi Y, Mizukoshi K, Nagasaka M, Ichihara K. Synthesis and structure-activity relationships of new (5R,8S,10R)-ergoline derivatives with antihypertensive or dopaminergic activity. Chem Pharm Bull 42 2042-2048, 1994. 

Scheme 37 (73IZV2572). This pyrrole synthesis proved to be general and was used in the synthesis of bi- and tricyclic ergoline dopamine agonists (80JMC481). A recent report claims that tetramethylammonium glycinate is a better reagent than the metal salts (91SC1971).

The tricyclic system has also been constructed from an indole via electrophilic substitution reactions at positions 3 and/or 4. Synthesis of tricyclic ergoline synthons from 5-methoxy-lH-indole-4-carboxaldehyde has been described [45]. Sodium cyanoborohydride mediated reductive amination provided easy access to l,3,4,5-tetrahydrobenz[cd]indole-4-amines, compounds which show specificity for serotonin and dopamine receptors. 

Syntheses of potent 5-HT agonists were accompUshed in several steps from a 6-iodo partial ergoline alkaloid. A new and general methodology critical for the construction of oxazole-containing alkaloids was developed for the synthesis of the 5-HT agonists using a novel palladium(O)- and copper(I)-cocatalyzed cyanation reaction [56]. 

Bemardi L, Gandini E, Temperilli A (1974) Ergoline Derivatives. XIV. Synthesis of Clavine Alkaloids. Tetrahedron 30 3447... 

En route to a new synthesis of the ergoline skeleton, Parker and colleagues developed a new cyclization of 4-unsubstituted indoles. Indole 235 was reduced to a mixture of indoline epimers under standard triethylsilane/ trifluoroacetic acid conditions proteaion of indoline 236 with benzoyl chloride delivered 237 in 85% yield over two steps. Finally, palladium-catalyzed cyclization afforded desired tetracyclic indole structure 238 in 86% yield (130L2598). 

An easy synthesis of the ergoline synthon 274 has been described by Genet and Grisoni.f i The key step involved C-5/C-6 intramolecular alkylation of allylic nitro compounds. The starting aldehyde 275 was submitted to a Homer-Einmons reaction with... 

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