Tricyclic ergolines

Asymmetric cyclization to tricyclic ergolines. The ergoline system of ergot alkaloids can be obtained in fairly high enantioselectivity by cyclization of 2 catalyzed by Pd(0) complexed with a chiral ligand and a base. The ligands BINAP,... 

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. 

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... 

A nitroalkane has also served as nucleophile in the cyclizadon as shown in Scheme 8E.32 to give the ergoline ring system in high diastereo- and enantioselecdvity. The initially obtained modest enanitoselectivity (66% ee) by using a catalyst derived from Pd2(dba)3 CHCl3 and (5, 5 )-chiraphos (2) was optimized to 95% ee by using a complex of (S)-BINAP (ent-4) and Pd(OAc)2 [169,170], The obtained tricyclic alkylation product provided an expeditious access to (-)-chanoclavine I. 

Similarly, irradiation of the tricyclic enamide 226 for over 96 hr afforded the lactam 227, in 42% yield, which was reduced with LAH and then acetylated to give the compound 228, with an ergoline skeleton in good yield. This method provided a simple route for constructing the clavine skeleton (130) (Scheme 86). 

In contrast to the tricyclic partial ergolines, the tetracyclic ergolines such as d-LSD (pK =8.7), lisuride (pKj=9.1) or pergolide (pKj=8.7) bind with high affinity to 5-HT1A receptors but they lack selectivity. 

In an attempt to gain insight into the pharmacophore moiety of the ergot alkaloids, aza-transposed ergolines were synthesized [55] with the nitrogen atom in the 9-position by alkylation-amination of a tricyclic enamine in the presence of ethyl a,a,-bis(dibromomethyl)acetate, triethylamine, and methyl-amine which led to the construction of the azatransposed ergoline. 

Irradiation of an enamide, which was readily prepared from the imine of the tricyclic Komfeld s ketone by acylation with 3-furoyl chloride, in the presence of sodium borohydride, yielded die skeletal structure of the ergoline alkaloids, which was readily converted by conventional procedures to lysergic acid (1). This photochemical route offered a wide potential for triplication to variously substituted analogs of lysergic acid (1) having high synthetic interest. 

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