Total Synthesis of (–)-Aristoquinoline via an Intramolecular Nitrilium Ion Cyclization

Abstract

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

Publication History

Received: 03 September 2021

Accepted after revision: 03 October 2021

Article published online:
22 November 2021

• References

• 1 New address: Priyansh D. Gujarati, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
• 2a Misle E, Garrido E, Contardo H, González W. J. Agric. Sci. Technol. B 2011; 1: 473
• 2b Romanucci V, D’Alonzo D, Guaragna A, Di Marino C, Davinelli S, Scapagnini G, Di Fabio G, Zarrelli A. Curr. Pharm. Biotechnol. 2016; 17: 513
• 2c Cespedes CL, Pavon N, Dominguez M, Alarcon J, Balbontin C, Kubo I, El-Hafidi M, Avila JG. Food Chem. Toxicol. 2017; 108: 438
• 2d Zúñiga GE, Tapia A, Arenas A, Contreras RA, Zúñiga-Libano G. Phytochem. Rev. 2017; 16: 1081
• 3 Hai MH, Bick IR. C. Aristotelia Alkaloids . In The Alkaloids, Vol. XXIV. Brossi A. Academic Press; New York: 1985: 113
• 4 Jakupovic J, Tsichritzis F, Cespedes C. Phytochemistry 1993; 34: 881
• 5 Kyburz R, Schöpp E, Bick IR. C, Hesse M. Helv. Chim. Acta 1979; 62: 2539
• 6 Bick IR. C, Hai MA. Heterocycles 1981; 16: 1301
• 7 Anderson BF, Robertson GB, Avey HP, Donovan WF, Bick IR. C, Bremner JB, Finney AJ. T, Preston NW, Gallagher RT, Russel GB. J. Chem. Soc., Chem. Commun. 1975; 511
• 8 Bick IR. C, Hai MA, Preston NW, Gallagher RT. Tetrahedron Lett. 1980; 21: 545
• 9 Silva M, Bhakuni DS, Matlin SA, Sammes PG. Phytochemistry 1976; 15: 574
• 10a Lévy J, Mirand C, Massiot G. J. Org. Chem. 1982; 47: 4170
• 10b Borschberg H.-J, Darbre T, Nussbaumer C. Helv. Chim. Acta 1984; 67: 1040
• 10c Gribble GW, Barden TC. J. Org. Chem. 1985; 50: 5900
• 10d Heathcock CH, Stoermer D. J. Org. Chem. 1993; 58: 564
• 11 Paz C, Arias HR, Ortells MO, Feuerbach D, Burgos V. J. Nat. Prod. 2019; 82: 1953
• 12 Riley AP, Argade MD, Straub CJ, Rusali LE, Santarsiero BD. Org. Lett. 2021; 23: 7693
• 13 Kenney PM, Stevens RV. J. Chem. Soc., Chem. Commun. 1983; 384
• 14a Williams SG, Ung AT, Angeloski A, Ashmore J, Kuzhiumparambil U, Bhadbhade M, Bishop R. Monatsh. Chem. 2014; 145: 983
• 14b Williams SG, Bhadbhade M, Bishop R, Ung AT. Tetrahedron 2017; 73: 116
• 15 For a review of the synthesis and applications of nitrilium ions, see: Lammertsma K, Slootweg JC, van Dijk T. Org. Biomol. Chem. 2017; 15: 10134
• 16a de Mattos MC. S, Kover WB, Aznar F, Barluenga J. Tetrahedron Lett. 1992; 33: 4863
• 16b Carman RM, Derbyshire RP. C. Aust. J. Chem. 2003; 56: 319
• 17 Khuong-Huu Q, Pancrazi A, Kaboré I. Bull. Soc. Chim. Fr. 1977; 162
• 18 Shenvi RA, Pronin SV, Reiher CA. Nature 2013; 501: 195
• 19 Florjancic AS, Dart MJ, Ryther KB, Perez-Medrano A, Carroll WA, Patel MV, Tietje KR, Li T, Kolasa T, Gallagher ME, Peddi S, Frost JM, Nelson DW. US Patent 20100093814, 2010
• 20 Huang P.-Q, Huang Y.-H, Geng H, Ye J.-L. Sci. Rep. 2016; 28801
• 21 Fodor G, Nagubandi S. Tetrahedron 1980; 36: 1279
• 22 Gawley RE, Chemburkar S. Tetrahedron Lett. 1986; 27: 2071
• 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.
• 24 von Braun J. Ber. Dtsch. Chem. Ges. 1904; 37: 3210
• 25 Corey EJ, Winter RA. E. J. Am. Chem. Soc. 1963; 85: 2677
• 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
• 29a Diederich F, Salonen LM. Ellermann M. Angew. Chem. Int. Ed. 2011; 50: 4808
• 29b For an alternative viewpoint of this phenomenon, see: Iverson BL, Martinez CR. Chem. Sci. 2012; 3: 2191
• 30 Suárez AG, Corne V, Sarotti AM, de Arellano CR, Spanevello RA. Beilstein J. Org. Chem. 2016; 12: 1616
• 31 de Mattos MC. S, Coelho RB, Sanseverino AM. Synth. Commun. 2004; 34: 541