Funding for this project was provided by the Fisher College of Science and Mathematics (Towson University) through an undergraduate research grant. This work was also supported by instrumentation provided through the National Science Foundation under Grant Nos. 0923051 and 1531562.
The enantioselective total synthesis of the alkaloid aristoquinoline has been achieved in seven steps and 26% overall yield. A new preparation of the useful synthetic building block (–)-α-terpinyl amine was also developed in order to avoid stoichiometric mercury reagents or azide-containing intermediates. Key steps in the optimized synthetic route include an intramolecular nitrilium ion cyclization to form the characteristic azabicyclo[3.3.1]nonane ring system and a diastereoselective reduction of the resulting imine mixture to afford the natural product. An isomer of aristoquinoline containing an exocyclic alkene was also obtained and found to exhibit unusual chromatographic and spectroscopic properties.
Key words
total synthesis -
natural product -
alkaloid -
nitrilium ion -
quinoline
Supporting Information
Supporting information for this article is available online at https://doi.org/10.1055/s-0041-1737276.
23
Lahm GP,
Smith BK.
WO Patent 2014099837, 2014 ; The initially formed product is a brick-red insoluble copper complex from which 4-cyanoquinoline can be liberated via partitioning between diethyl ether and aqueous ammonium hydroxide.
26 The observed diastereoselectivity is also consistent with the Fürst–Plattner rule in which axial delivery of hydride minimizes torsional strain in the transition state. A similar effect was observed in the last step of Kenney’s synthesis of hobartine, which involves an analogous borohydride reduction of an imine (see ref. 13).
27 Interestingly, Riley proposes that the absolute configuration of 1 may have been misassigned based on correlations between the reported biological activity of natural aristoquinoline and that observed for synthetic 1 and its enantiomer. For further details, see ref. 12.
28 Butler has synthesized a series of compounds in which a 1,1-disubstituted exocyclic alkene is forced into the proximity of one or more benzene rings within a rigid molecular scaffold. The most extreme example is a bridged pentacene derivative containing a so-called ‘entombed olefin’ in which the 1H NMR chemical shift of the alkene protons is 2.58 ppm. This remarkable diamagnetic shielding effect is, to our knowledge, the current record for hydrogens attached to an sp2-hybridized carbon in a neutral organic compound. For further details, see:
Butler DN,
Gupta I,
Ng WW,
Nyburg SC.
J. Chem. Soc., Chem. Commun. 1980; 596
