Quinolizidines Mannich reaction

An intramolecular Mannich reaction of carboline derivative 352 afforded a complex bridged system containing an indolo[2,3-tf]quinolizidine moiety, as a mixture of two diastereomers. One of them, 353, was transformed into the alkaloid tacamonine 15 (Scheme 79) <2002T4969>. 

The trans- and cis-fused forms are clearly identifiable by Bohlmann bands in the IR spectra (33, 34) and by the NMR chemical shifts and coupling of the benzylic proton at C-l. In the spectra of trans-fused quinolizidones the diagnostic proton absorbs in the region <5 2.70-3.30 ppm where, as in the cis-fused forms, the absorption is shifted to lower field by 0.5-2 ppm. Condensation under thermodynamic control yields mainly the trans-fused quinolizidine system whereas in a kinetically controled reaction predominantly cis products are obtained (66, 67). The latter isomerize to the corresponding trans forms in an alkaline medium. An isomerization in dilute hydrochloric acid was also reported (68). The stereoselectivity of the reaction was influenced by the solubilities of the starting aldehydes and products, since the first-formed m-quinolizidones isomerize easier in a soluble state. Several mechanism have been suggested for this reaction. Hanaoka et al. (66) have described it as a Mannich reaction. 

Mannich reaction of the piperidine derivative (30) with 3-formylfuran gave a mixture of the four stereoisomeric quinolizidin-2-ones, cf. (31). The major product [as (31), but with a /3-furyl group] was isomerized with base to the most stable ftms-quinolizidinone (31), which on Wolff-Kishner reduction afforded a mixture of alkaloids (27) and (21). 

Isopelletierine (23) undergoes a Mannich reaction with both m-methoxy- and m-hydroxy-benzaldehyde, to give respectively a mixture of the cis (24 R = Me) and trans (25 R = Me) quinolizidines, and exclusively the tran -quinolizidine (25 R = H). The ratio of stereoisomers in the former reaction varies widely with solvent used. ... 

Earlier syntheses of quinolizidines involved Mannich reactions of pelletierine. In a new approach, applied to the synthesis of (+)-vertaline (Scheme 6), allylic strain controls the stereochemical course of cyclisation of the N-acyliminium ion (40) the... 

On the other hand, a direct asymmetric Mannich reaction was reported, in 2009, by Rutjes et al. in the course of developing a synthesis of the bioactive quinolizidine alkaloid lasubine II. Therefore, the key step of this synthesis was the L-proline-catalysed Mannich reaction between acetone, para-mtm-benzaldehyde and veratryl aldehyde, providing the expected Mannich adduct in moderate yield and almost complete enantioselectivity (Scheme 3.5). This chiral p-amino ketone was further converted into the desired (-F )-lasubine II. 

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