Scheme 1.
Centro di Studio C.N.R. sulla Chimica e la Struttura dei Composti Eterociclici e loro Applicazioni (CSCEA), Dipartimento di Chimica organica "Ugo Schiff", Universita di Firenze, via G. Capponi 9, I-50121 Firenze, Italy. Tel: (39) 55-2757610, Fax: (39) 55-2476964, goti@risc1.chimorg.unifi.it
Received: 15 July 1997 / Uploaded: 23 July 1997
We have recently reported the synthesis of enantiopure 3-heterosubstituted pyrroline N-oxides of type 1 and 2 (Scheme 1) obtained by oxidation of the corresponding hydroxylamines, in turn available in large amounts from L-malic and L-aspartic acids, respectively.1
Scheme 1.
Scheme 2.
The final oxidation step of hydroxylamines 3 produced two regioisomeric nitrones 4 and 5 (Scheme 2).1 An unexpected high preference for oxidation at the position vicinal to the substituent to afford compound 4 has been found. The amount of this regioisomer increased consistently with the ability of the substituent to stabilize a negative charge. This effect was rationalized on the basis of the stabilizing stereoelectronic effect provided by an adjacent electronegative group in the TS of the rate-determining step of the oxidation, from the nitrosonium cation to the final nitrone, which requires the removal of a proton, as indicated in Figure 1.1
Figure 1.
In this communication we report the application of nitrones 1 and 2 to the synthesis of enantiopure pyrrolizidines and structurally related compounds by means of 1,3-dipolar cycloaddition reactions to dimethyl maleate and -crotonolactone. 2,3
The reaction of nitrone 1 with dimethyl maleate (6) in benzene at room temperature for 3 days gave three cycloadducts in a 5:1:1 ratio (Scheme 3), which were assigned structures 7a-c, respectively, on the basis of 2D-NMR NOESY spectra. As expected on the basis of previous findings on related cycloadditions of substituted pyrroline N-oxides,1,3 the major adduct 7a derived from the less encumbered exo-anti TS. The minor adducts 7b and 7c arose from roughly equi-energetic endo-anti and exo-syn TS, respectively, while formation of the fourth possible adduct was prevented by the sterically unfavored endo-syn approach (Figure 2).4
Scheme 3.
The analogous cycloaddition of nitrone 2 to 6 gave only two adducts 8a-b in 4:1 ratio (Scheme 3), with structural assignment based on analogy and a NOESY spectrum of 8b. The bulkier dibenzylamino group with respect to tert-butoxy can account for the lack of formation of products deriving from the sterically more hindered syn approaches at all (Figure 2).
Figure 2
-Crotonolactone (9) has been chosen as another suitable dipolarophile for synthesizing the pyrrolizidine target compounds.5 Indeed, 9 and butenolides in general are known to give an unique regioisomer,5,6 usually with a better exo/endo selectivity in cycloadditions to cyclic nitrones than maleic acid derivatives,5,6a likely due to the loss of favorable secondary orbital interactions in the TS. Indeed, the reaction of nitrone 1 with 9 gave only two adducts in the same 5:1 ratio (Scheme 4). These compounds were assigned the structures 10a and 10c, as deriving from the two possible exo approaches, anti and syn to the substituent on nitrone, respectively, once again on the basis of NOESY spectra.
Scheme 4.
The transformation of adducts 7 and 8 into the desired pyrrolizine skeleton requires a simple opening of the isoxazolidine ring by reductive cleavage of the N-O bond, since re-closure to form a lactam moiety by attack of nitrogen to the -carboxylic carbon atom occurs spontaneously.7,5 A mild method consisting in refluxing the isoxazolidine in aqueous acetonitrile in presence of molybdenum hexacarbonyl has been used to perform this transformation.8 The separated isoxazolidines 7a and 7c gave good to excellent yields of 11a and 11c, respectively, in this step (Scheme 5). The mixture of isoxazolidines 8a-b turned out to be inseparable by flash column chromatography and was subjected directly to the reductive ring-opening, which afforded only the pyrrolizidinone 12, corresponding to the major adduct 8a (Scheme 5).
Scheme 5.
The same cycloaddition-reductive ring-opening procedure has been utilized very recently for a formal EPC synthesis of (-)-hastanecine (15),9,10 the necine base of several pyrrolizidine alkaloids, starting from nitrone 13 (Scheme 6).
Scheme 6
Due to the biological relevance of polyhydroxypyrrolizidines and pyrrolidines as inhibitors of glycosidases and consequently as potential therapeutic (antibiotic, antiviral, antitumoral) agents,11,12 we pursued the synthesis of such compounds and their structural analogues from the pyrrolizidinone 11a and the cycloadduct 10a (Scheme 7). Reduction of 11a with LiAlH4 in Et2O gave the monoprotected pyrrolizidine triol 16, which represents a new, non-natural stereoisomer of the necine bases rosmarinecine and croalbinecine. Reduction of the adduct 10a under the same conditions was not able to accomplish the cleavage of the isoxazolidine ring, giving the pyrrolo[1,2-b]isoxazole derivative 17 in good yields. This compound is also interesting, representing a structural oxygenated analogue of polyhydroxypyrrolizidines. On the other hand, under reflux in THF, the reduction proceeded to give the monoprotected tetrahydroxypyrrolidine 18, which in turn was deprotected to 19 or cyclized to 16 by treatment with PPh3 in CCl4 (Scheme 7).
Scheme 7.
In conclusion, a straightforward and versatile access to polyhydroxypyrrolizidines, pyrrolidines and structural analogues has been outlined. Application of related procedures to the synthesis of natural products and biologically interesting compounds is underway in our laboratories, as well as biological screening of the products against a variety of glycosidic enzymes.
Acknowledgment: The authors thank C.N.R. (Consiglio Nazionale delle Ricerche - Italy, Progetto Strategico "Tecnologie Chimiche Innovative") and M.U.R.S.T. (Ministero dell'Universit[daggerdbl] e della Ricerca Scientifica e Tecnologica - Italy) for financial support.
References and Notes
1. (a) Goti, A.; Cicchi, S.; Fedi, V.; Nannelli, L.; Brandi, A. J. Org. Chem. 1997, 62, 3119-3125. (b) Cicchi, S.; Goti, A.; Brandi, A. J. Org. Chem. 1995, 60, 4743-4748.
2. For a synthesis of hydroxyindolizidines from nitrone 1, see ref. 1b.
3. For cycloadditions of related enantiomerically pure pyrroline N-oxides, see: (a) Mc Caig, A. E.; Wightman, R. H. Tetrahedron Lett. 1993, 34, 3939-3942. (b) Cordero, F. M.; Cicchi, S.; Goti, A.; Brandi, A. Tetrahedron Lett. 1994, 35, 949-952. (c) Brandi, A.; Cicchi, S.; Goti, A.; Koprowski, A.; Pietrusiewicz, K. M. J. Org. Chem. 1994, 59, 1315-1318. (d) Brandi, A.; Cicchi, S.; Cordero, F. M.; Frignoli, R.; Goti, A.; Picasso, S.; Vogel, P. J. Org. Chem. 1995, 60, 6806-6812. (e) Goti, A.; Cardona, F.; Brandi, A.; Picasso, S.; Vogel, P. Tetrahedron: Asymmetry 1996, 7, 1659-1674. (f) Goti, A.; Cardona, F.; Brandi, A. Synlett 1996, 761-763. (g) Ishikawa, T.; Tajima, Y.; Fukui, M.; Saito, S. Angew. Chem. Int. Ed. Engl. 1996, 35, 1863-1864. (h) Hall, A.; Meldrum, K. P.; Therond, P. R.; Wightman, R. H. Synlett 1997, 123-125.
4. Syn and anti refer to the approaches of dipolarophile from the same or the opposite face of the substituent at C-3 of the nitrone, respectively.
5. Tufariello, J. J.; Tette, J. P. J. Org. Chem. 1975, 40, 3866-3869.
6. (a) Cid, P.; de March, P.; Figueredo, M.; Font, J.; Milan, S.; Soria, A.; Virgili, A. Tetrahedron 1993, 49, 3857-3870. (b) de Lange, B.; Feringa, B. L. Tetrahedron Lett. 1988, 29, 5317-5320. (c) Banerji, A.; Basu, S. Tetrahedron 1992, 48, 3335-3344. (d) Saito, S.; Ishikawa, T.; Kishimoto, N.; Kohara, T.; Moriwake, T. Synlett 1994, 282-284.r 7. Huisgen, R.; Hauck, H.; Grashey, R.; Seidl, H. Chem. Ber. 1968, 101, 2568-2584.
8. Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F. Tetrahedron Lett. 1990, 31, 3351-3354.
9. Goti, A.; Cicchi, S.; Fedi, V.; Nannelli, L.; Brandi, A. Synlett 1997, 577-579.
10. Denmark, S. E.; Thorarensen, A. J. Org. Chem. 1994, 59, 5672-5680.
11. Reviews: (a) Elbein, A. D. Ann. Rev. Biochem. 1987, 56, 497-534. (b) Vogel, P. Chimica Oggi 1992, 10 (August-September), 9-15. (c) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2, 199-210. (d) Legler, G. Adv. Carbohydr. Chem. Biochem. 1990, 48, 319-384.
12. (a) Hartmann, T.; Witte, L. Chemistry, Biology and Chemoecology of the Pyrrolizidine Alkaloids In Alkaloids: Chemical & Biological Perspectives; Pelletier, S. W., Ed.; Pergamon: Oxford, 1995; vol. 9, p. 155-233. (b) Mattocks, A. R. Chemistry and Toxicology of Pyrrolizidine Alkaloids; Academic Press: New York, 1986.
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