Indolo- quinolizidine cyclization

As shown in Scheme 14, a sulfuric acid-catalyzed dehydration-cyclization-elimination domino sequence starting from protonation of the secondary hydroxy group of the indolo[2,3- ]quinolizidine 112 led to the isolation of the pentacyclic compound 113 in good yield <1999EJ03429>. 

Enantiospecific syntheses of amino derivatives of benzo[ ]quinolizidine and indolo[2,3- ]quinolizidine compounds have also been achieved via A-acyliminium ion cyclization reactions, as an alternative to the more traditional Bischler-Napieralski chemistry (see Section 12.01.9.2.2). One interesting example involves the use of L-pyroglutamic acid as a chiral starting material to construct intermediates 240 via reaction with arylethylamine derivatives. Diisobutylaluminium hydride (DIBAL-H) reduction of the amide function in 240 and subsequent cyclization and further reduction afforded piperidine derivatives 241, which stereoselectively cyclized to benzo[ ]quinolizidine 242 upon treatment with boron trifluoride (Scheme 47) <1999JOC9729>. 

The intramolecular Pummerer reaction has been applied to the synthesis of simple quinolizidine alkaloids like lupinine <2000JOC2368>, and also to arenoquinolizine alkaloids. Thus, the 2-(2-piperidyl)indole 284 was converted to indolo[2,3- ]quinolizidine 287 following a protocol that has as the key step the regioselective cyclization onto the indole 3-position of a thionium ion generated by Pummerer reaction from the appropriately substituted compound... 

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. 

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). 

In contrast to the reductive cyclization, the indolo[2,3-a]quinolizidine structure can also be formed from 7V-)8-(3-indolyl)ethylpiperidine derivatives by oxidizing the piperidine moiety to an immonium ion followed by spontaneous cyclization. Unfortunately, chemical yields obtained from this oxidative cyclization tactic were extremely low in most cases <62JOC2283, 62JA4914). An alternative was to form the piperidine A-oxide and then to cyclize it into indolo[2,3-a]quinolizidine using trifluoroacetic anhydride <72CC930> or ferrous sulfate <72JOC1083>. 

Intramolecular ene reactions. Use of Lewis acid catalysts (particularly FeCL, 15,156 16,190-101) has greatly extended the usefulness of intramolecular ene cy-clization. Thus a new diastereoselective route to corynanthe-type alkaloids involves the ene cyclization of 1 to tr s-indolo[2,3-a]-quinolizidine (2), a precursor to methyl corynantheate (3) by demethoxycarbonylation. SnCU (1 equiv.) is the only common Lewis acid that is useful for this particular ene cyclization, and even so, it also requires the presence of trifluoroacetic acid (1.5 equiv.). 

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