Asymmetric Alkaloid Synthesis: A One‐Pot Organocatalytic Reaction to Quinolizidine Derivatives

Abstract

Ein Topf + zwei Stufen=drei Stereozentren: Eine kurze enantioselektive Syntheseroute zum Indolo[2,3a]chinolizidin‐ und Benzo[a]chinolizidin‐Gerüst wurde entwickelt (siehe Schema; R1=aromatisch, R2=3‐Indoyl oder 3,4‐Dimethoxyphenyl). Die Sequenz besteht aus einer organokatalytischen konjugierten Addition und einer nachfolgenden Azid‐katalysierten Cyclisierung des Acyliminiumions.

Diverse Asymmetric Quinolizidine Synthesis: A Stereodivergent One‐Pot Approach

“…The corresponding reactions of the ethyl ester 3b and cinnamaldehyde 1a gave similar yields and diastereoselectivity but a pronounced increase in enantioselectivity (Table 8, entries 5 and 6). The same trend of increased enantioselectivity was also observed for the corresponding reactions with o-nitrocinnamaldehyde 1b and p-methoxycinnamaldehyde 1c (Table 8, entries [7][8][9][10][11][12][13][14]. The diastereoselectivity in the reaction with tin(IV) chloride turned out to be independent of which cinnamaldehyde was used and gave the thermodynamic product 11bb-10 with approximately 75:25 diastereomeric ratio (Table 8) with the exception of the methyl ester 3a in combination with o-nitrocinnamaldehyde 1b that gave 11ba-10ba and 11bb-10bb in a 1:1 mixture (Table 8, entry 8).…”

“…For the one-pot reaction of p-methoxycinnamaldehyde 1c with the methyl and ethyl esters 14a, b under kinetic and thermodynamic conditions gave 11ba-20ca, cb and 11bb-20ca, cb, respectively, in good diastereoselectivity. As been previously observed for the methoxy derivatives (vide supra), the methyl ester derivative 11ba-20ca was isolated in moderate enantioselectivity whereas the selectivity increased substantially for the corresponding ethyl ester derivative 11ba-20cb (Table 7, entries [11][12][13][14].…”

“…Recently, the asymmetric organocatalytic a-carbon addition of activated amides to a,b-unsaturated aldehydes was independently developed by our group [14] and Rios et al [16g] In our study towards the one-pot reaction to quinolizidine derivatives, we found that conjugate addition of indole-substituted amide 2a to cinnamaldehyde 1a catalyzed by pyrrolidine derivative (S)-4 preformed best in DCM at 3 8C to give the hemiaminal intermediate 7.…”

“…[8i] Recently in our group we developed an enantioselective one-pot reaction to the 12ba-indoloA C H T U N G T R E N N U N G [2,3-a]quinolizidine 9 and the 11ba-benzo[a]quinolizidine 10 skeleton (Scheme 1). [14] The one-pot reaction sequence is based on a domino organocatalytic conjugate addition [15,16] /hemiaminal formation. [17] Acidification of the resulting reaction mixture initiates an intramolecular N-acyliminiumion cyclization [18,19] to give indoloA C H T U N G T R E N N U N G [2,3-a]quinolizidines (9) and benzo [a]quinolizidines (10).…”

“…-a]quinolizidine 9 was obtained in 89% ee from the methyl ester 2a and in > 99% ee from the ethyl ester 2b (Table 3, entries [11][12][13][14].…”