A sequential reaction process to assemble polysubstituted indolizidines, quinolizidines and quinolizidine analogues
Graphical abstract
Introduction
Fused nitrogen heterocyclic units of indolizidine and quinolizidine are found in a rather large class of alkaloids isolated from diverse natural sources and in human-made substances.1, 1(a), 1(b) These compounds exhibit a considerable range of biological functions including neurological,1, 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 3, 3(a), 3(b) antiviral,4, 4(a), 4(b) immunosuppressive,5 antimalarial6 and anti-tumor7, 7(a), 7(b) activities. Because of the very limited amounts available to us from natural sources, total synthesis of natural indolizidines and quinolizidines has greatly facilitated their structural elucidation, as well as evaluation of their pharmacological profile in the past decades.1, 1(a), 1(b), 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f) In order to assemble quickly the bicyclic skeletons of these compounds, several elegant methods have been developed and found extensive applications in the total synthesis of the targeted alkaloids.8, 8(a), 8(b), 8(c), 8(d), 8(e), 8(f), 8(g), 8(h), 8(i), 8(j), 9, 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), 9(g), 9(h), 10, 10(a), 10(b), 10(c), 10(d), 11, 11(a), 11(b), 11(c), 12, 12(a), 12(b), 12(c), 13, 13(a), 13(b), 13(c), 13(d), 13(e), 13(f), 13(g), 13(h), 13(i), 13(j), 13(k), 13(l), 13(m) However, more efficient protocols are still highly required to merit the increasing need for rapidly synthesizing these natural products, and their analogues for drug development and chemical biology.
During the studies aimed at synthesizing pyrrolizidine indolizidine and quinolizidine alkaloids,14, 14(a), 14(b), 14(c) we have developed a sequential SN2/Michael addition/condensation reaction process14a to enantiopure quinolizidinones and indolizidinones 3 by refluxing enantiopure β-amino esters 2 and ω-iodo-α,β-alkynoates 1 in acetonitrile under the action of K2CO3 (Scheme 1). A plausible mechanism was that the amino group in a β-amino ester 2 first attacked the terminal carbon of ethyl 7-iodo-2-heptynoate 1a or ethyl 7-iodo-2-hexynoate 1b to form a secondary amine, which spontaneously attacked the electron-deficient triple bond to provide a heterocyclic intermediate A. Finally the vinylogous anion of A generated in the Michael addition step reacted with the carbonyl group of the β-amino ester 2 to give the bicyclic product 3. Unfortunately, the efficiency of this process was greatly decreased by formation of a side product 4 through proton abstraction in intermediate A, although 4 could be converted into 3 through the mixed anhydrides 5.14a In this article, we wish to report a new cascade process, which could deliver the desired bicyclic products exclusively in most cases.15
Section snippets
Sequential SN2/Michael addition/SN2/SN2 reaction process to indolizidines and quinolizidines
As depicted in Scheme 1, the successful transformation of 4 to 3 through the mixed anhydrides 5 implied that the lower reactivity of the ester moiety in 4 was the cause for incomplete conversion of the above sequential reaction process. One can easily think that increasing the reactivity of nucleophilic moiety of the bifunctional agents 2 would provide a cure for the above drawback. However, such substrates would probably lead to an intramolecular reaction between the amine group and this
Conclusions
In conclusion, we have demonstrated here a sequential SN2/Michael addition/SN2/SN2 reaction process, which allows effectively assembling polysubstituted indolizidines, or quinolizidines and their analogues with a great diversity. This process should find further application in the total synthesis of natural products and designed molecules for biological evaluation.
(R)-1-Chloro-3-octylamine hydrochloride salt (7b)
To a stirred suspension of LAH (544 mg, 14.3 mmol) in dry diethyl ether (40 mL) was added dropwise β-amino ester 9b (5.5 g, 14.3 mmol) in dry diethyl ether (40 mL) at 0 °C. After the reaction mixture was stirred at 20 °C for 1 h, water (0.57 mL), 15% NaOH (0.57 mL) and more water (1.71 mL) was added successively. Stirring was continued until a white precipitate formed, then it was filtered through Celite, and the filtrate was dried over MgSO4, concentrated and purified via chromatography to give 4.85 g
Acknowledgements
The authors are grateful to the Chinese Academy of Sciences, National Natural Science Foundation of China (grants 20321202 & 20132030), and Science and Technology Commission of Shanghai Municipality (grants 02JC14032 & 03XD14001) for their financial support.
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