Indolo- quinolizidine preparation

A series of papers have been published by Lounasmaa et al. (122-128) on the synthesis of different alkaloid-like indolo[2,3-a]quinolizidine derivatives by means of reduction and subsequent cyclization of A-[2-(indol-3-yl)ethyl]piridi-nium salts, developed as a general method for indole alkaloid synthesis by Wenkert and co-workers (129, 130). Aimed at the total synthesis of vallesiachotamine (9), valuable model studies were reported (131-133). Reduction of pyridinium salts 183 and 184 with sodium dithionite and subsequent acid-induced cyclization represents a convenient method for preparing val-lesiachotamine-type derivatives 185 and 186, respectively. 

When pyridinium salt 187 was transformed to an indolo[2,3-a]quinolizidine compound in a similar way and the unsaturated lactone 188 was hydrogenated over platina catalyst, a mixture of vallesiachotamine-type compounds (189 di-astereomers) epimeric at C-20 was formed (134). These compounds have also been prepared in optically active form from vallesiachotamine (9), thus producing the first chemical correlation between synthetic and natural vallesiachotamine derivatives (134). 

To test the necessity of aromatic n electrons in the epimerization reaction, indolo[2,3-a]quinolizidines with different substituents at C-10 were prepared [14]. Subjecting these compounds to epimerization conditions (TFA, 90°C, 60 min) gave the following results, Table 1. 

Another way to test the operation of Mechanism 1 is to subject C-l2b alkyl substituted indolo[2,3-a]quinolizidines to epimerization conditions. Should Mechanism 1 be operative, these compounds could not epimerize. Thus, C-l2b methyl substituted indoloquinolizidines 20 - 25 with different structural features were prepared by Lounasmaa and co-workers [22], Fig. (3). As well as testing Mechanism 1, they investigated the effect of different structural features on the epimerization reaction in general. 

Preparation of the dodecahydro benz[/]indolo[2,3-a]quinolizidine ring structure relied on the Fry reaction [39] of salt 52, which, after subsequent acid-induced cyclization, yielded three compounds, 53 - 55, Scheme (13). 

Indolo[3,2-Z)]quinolizidine (240) was obtained from the Pictet-Spengler ring closure of (239) (Equation (58)) <57JA5686, 72CPB1745>. The indolo[2,3-i]quinolizidine ring can be prepared analogously <62BRP891157>. 

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