The convergent synthesis of polyether ionophore antibiotics: the synthesis of the monensin spiroketal

TLDR: The monensin spiroketal2, a versatile intermediate for the synthesis of polyether ionophore antibiotics, is prepared from D-fructose as discussed by the authors, where the ester enolate Claisen rearrangement of a glycal propionate, expansion of a furanoid to a pyranoid ring, and acid-catalyzed equilibration of a bicyclic ketal to a spirokal are performed.

Abstract: The monensin spiroketal2, a versatile intermediate for the synthesis of polyether ionophore antibiotics, is prepared from D-fructose. Key steps include the ester enolate Claisen rearrangement of a glycal propionate, expansion of a furanoid to a pyranoid ring, and the acid-catalyzed equilibration of a bicyclic ketal to a spiroketal. An alternative approach, entailing the hetero-Diels-Alder condensation of the exocyclic enol ether 15 with acrolein, is thwarted by facile isomerization to the endocyclic enol ether 18. The complex chemistry and potent biological activity of the polyether antibiotics have engaged widespread i n t e r e ~ t . ~ As ionophores, these compounds possess a striking ability to perturb ionic gradients by catalytically transporting cations across lipid barrier^.^ While optimal membrane and ion selectivity remain elusive goals, the commercial use of monensin for control of poultry coccidiosis6 and enhancement of ruminant feed utilization6 have encouraged intensive efforts in the isolation and study of these compounds. Several have demonstrated potential in human medicine, particularly as cardiovascular agent^.^ In addition to their diverse biological activity, these antibiotics display a formidable molecular complexity, and the attendant challenge of total synthesis has been taken up by numerous research groups.' Structurally, most of the polyether ionophores feature linear chains ( I ) Grateful acknowledgement is made for support of this investigation by a grant from NIH (No. HL-23167). Acknowledgement is also made for the use of the Southern California Regional NMR Facility (National Science Foundation Grant CHE-79-16324). (2) Fellow of Deutscher Akademischer Austausendienst. (3) National Science Foundation Research Fellow, 1981-1984. (4) Westley, J. W., Ed. 'Polyether Antibiotics: Naturally Occurring Acid Ionoohores\": Marcel Dekker. Inc.: New York. 1982: Vols. I and 11. ~~ pressman, man, B. C.; Harris, E. J.; Jagger, W. S.f Johnson, J . M. Proc. Natl. Acad. Sci. U.S.A. 1967, 58, 1949. (6) Ruff, Michael D. In \"Polyether Antibiotics: Naturally Occurring Acid Ionophores\"; Westley, J. W., Ed.; Marcel Dekker, Inc.: New York, 1982; Vol. I , Chapter 6. (7) Hanley, H. G.; Slack, J. D., ref 6, Chapter 8. Reed, P. W.; Bokoch, G. M., ref 6, Chapter 9. Osborne, M. W.; Wenger, J.; Zanko, M.; Kovzelove, F.; Cohen, M. R., ref 6, Chapter IO. (8) (a) Calcimycin: Evans, D. A,; Sacks, C. E.; Kleschick, W. A.; Tabor, T. R. J. Am. Chem. SOC. 1979, 101, 6789-6791. Grieco, P. A,; Williams, E.; Tanaka, H.; Gilman, S. J . Org. Chem. 1980, 45, 3537-3539. (b) Lasalocid A: Nakata, T.; Schmid, G.; Vranesic, B.; Okigawa, M.; Smith-Palmer, T.; Kishi, Y. J . Am. Chem. SOC. 1978, 100,2933-2935. Ireland, R. E.; Anderson, R. C.; Badoud, R.; Fitzsimmons, B. J.; McGarvey, G. J.; Thaisrivongs, S.; Wilcox, C. S. Ibid. 1983, 105, 1988-2006. (c) Monensin: Fukuyama, T.; Akasaka, K.; Karanewsky, D. S.; Wang, C.-L. J.; Schmid, G.; Kishi, Y. Ibid. 1979, 101, 259-263. Still, W. C.; McDonald, J.; Collum, D. Ibid. 1980, 102, 21 17-2121. (d) X-14547A: Nicolaou, K. C.; Papahatjis, D. P.; Claremon, D. A.; Dolle, R. E., 111. Ibid. 1981, 103, 6967-6969. Roush, W. R.; Meyers, A. G. J . Org. Chem. 1981, 46, 1509. Edwards, M. P.; Ley, S. V.; Lister, S. G. Tetrahedron Lett. 1981, 361. (e) Narasin: Kishi, Y. Aldrichim. Acta 1980, 13, 23-30. (f) Salinomycin: Kishi, Y.; Hatakeyama, S.; Lewis, M. D. Front. Chem., Plenary Keynote Lect. IUFAC Congr., 28th 1981 (Pub. 1982), 287-304. Laidler, K. J., Ed., Pergamon: Oxford, U.K. (g) General Methods: Walba, D. M.; Stoudt, G. S. Tetrahedron Lett. 1982, 727-730. Amouroux, R.; Folefoc, G.; Chastrette, F.; Chastrette, M. Tetrahedron Lett. 1981, 2259. Walba, D. M.; Wand, M. P. Tetrahedron Lett. 1982, 4995-4998. (h) Reviews: Kishi, Y. In 'Polyether Antibiotics: Naturally Occurring Acid Ionophores\"; Westley, J. W., Ed.; Marcel Dekker, Inc.: New York, 1982; Vol. 11, Chapter 1. Wierenga, W. In \"The Total Synthesis of Natural Products\"; ApSimon, J., Ed.; Wiley: New York, 1981; Vol. IV, p 263q. 0002-786318511507-327 1$01.50/0 of substituted tetrahydropyran and tetrahydrofuran rings. Comparison reveals that nearly a l l these rings recur with high frequency, often in stereochemically indistinguishable sequences. The unified biosynthetic pathway proposed by Cane , Celmer, and Westley underscores the structural identities and combinatorial diversity of these antibiotics.' We have recently developed a versatile, building-block approach to the polyethers in which prefabricated tetrahydrofuran and tetrahydrogen rings are joined via the ester enolate Claisen rearrangement. This work has culminated in the total synthesis of lasalocid Agb and its enantiomerL0 from readily available carbohydrates. In this and the following two papers in this issue, we report the preparation of several additional subunits for the synthesis of naturally occurring polyethers and potentially informative analogues. Serving as rigid bands in the polyether backbone, spiroketals play a critical role in establishing the coordination geometry necessary for ion complexation.\" Since one of the spiro oxygens usually acts as a ligand as well, spiroketals are prominent features of the polyether class.I2 Monensin's13 spiroketal is a particularly a t t ract ive synthetic target, as it occurs in at least eight other ionophores. Disconnection of the C2,3 and C12,13 bonds of monensin generates the common structural subunit 2, and the results of an aldol and ester enolate Claisen transform are shown in Scheme I. Our synthetic plan for this pol yether building block developed out of model studies which demonstrated the value of the hetero-Diels-Alder condensation in the construction of spiroketals (Scheme II).I4 Although the rigidity of the spiroketal system itself can mediate control of relative s t e r e ~ c h e m i s t r y , ' ~ in this (9) Crane, D. E.; Celmer, W. D.; Westley, J. W. J . Am. Chem. SOC. 1983, (10) Ireland, R. E.; Courtney, L.; Fitzsimmons, B. J. J . Org. Chem., 1983, ( 1 1) Dobler, M. \"Ionophores and Their Structures\"; Wiley: New York, 105, 3594-3600.