J. Chem. Research (S), 1997, 36–37 J. Chem. Research (M), 1997, 0301–0313 Synthesis of Enantiopure 4-Amino-6-fluoro- 3-(hydroxymethyl)chromanes via Intramolecular Nitrone Cycloadditions Gianluigi Broggini,a Luca Bruch�e,*b Enrico Cappellettia and Gaetano Zecchia aDipartimento di Chimica Organica e Industriale, Universit`a, via Golgi 19, 20133 Milano, Italy bDipartimento di Chimica, Politecnico, via Mancinelli 7, 20131 Milano, Italy Enantiopure 4-amino-6-fluoro-3-(hydroxymethyl)chromanes are synthesised starting from 5-fluorosalicylaldehyde and using (R)-(+)-(1-phenylethyl)hydroxylamine as chiral auxiliary. 4-Aminochromane derivatives are becoming increasingly utilised in the medicinal chemistry field of potassium channel openers,1–5 and the fundamental role of the absolute con- figuration in their physiological activity is well documented. 6–9 In a continuation of our research aimed at the synthesis of fluorinated heterocyclic compounds via intramolecular nitrone cycloadditions,10 we describe here a version of this strategy leading to enantiopure 4-amino-6-fluoro- 3-(hydroxymethyl)chromanes. Nitrones derived from allyl-type ethers of 5-fluorosalicylaldehyde and (R)-(+)-(1-phenylethyl)hydroxylamine (1) were envisioned as appropriate intermediates.Accordingly, 36 J. CHEM. RESEARCH (S), 1996 *To receive any correspondence. Scheme 1 Reagents and conditions: i, CaCl2, toluene, reflux; ii, H2, Pd/C, acetic acid, r.t. Scheme 2 Reagents and conditions: i, CaCl2, toluene, reflux; ii, H2, Pd/C, acetic acid, r.t.we synthesised compounds 2 and 8 and treated them with hydroxylamine 1, Schemes 1 and 2.Hydrogenolytic treatment of the cycloadducts resulted in both the removal of the benzyl-like N-pendant and the cleavage of the isoxazolidine ring, so disclosing the masked functionalities and resulting in the optically active amino alcohols 6, 7, 14–17, as three pairs of enantiomers. Their enantiomeric purity was proven to be E98% by NMR analysis in the presence of (R)-O-acetylmandelic acid.We thank the C.N.R. (Rome) and the MURST for financial support. Techniques used: IR, 1H NMR, mass spectrometry, microanalysis, polarimetry References: 14 Schemes: 2 Received, 27th September 1996; Accepted, 22nd October 1996 Paper E/6/06616J References cited in this synopsis 1 V. A. Ashwood, R. E. Buckingham, F. Cassidy, J. M. Evans, E. A. Faruk, T.C. Hamilton, D. J. Nash, G. Stemp and K. Willcocks, J.Med. Chem., 1986, 29, 2194; J. M. Evans and G. Stemp, Chem. Br., 1991, 439. 2 A. H. Weston, in The Pharmacology of Antihypertensive Therapeutics, ed. D. Ganter and P. J. Mulrow, Springer, Heidelberg, 1989, p. 643. 3 D. W. Robertson and M. I. Steinberg, J. Med. Chem., 1990, 33, 1529. 4 N. Taka, H. Koga, H. Sato, T. Ishizawa, T. Takahashi and J. Imagawa, Biomed. Chem. Lett., 1994, 4, 2893. 5 C. Z. Ding and A. V. Miller, Tetrahedron Lett., 1996, 37, 4447. 6 M. R. Attwood, B. S. Brown, R. M. Dansdon, D. N. Hurst, P. S. Jones and P. B. Kay, Biomed. Chem. Lett., 1992, 2, 229. 7 R. M. Soll, P. J. Dollings, R. J. McCaully, T. M. Argentieri, N. Lodge, G. Oshiro, T. Colatsky, N. W. Norton, D. Zebick, C. Havens and N. Halaka, Biomed. Chem. Lett., 1994, 4, 769. 8 R. C. Gadwood, L. M. Thomasco, V. E. Groppi, B. A. Burnett, S. J. Humphrey, M. P. Smith and W. Watt, Biomed. Chem. Lett., 1995, 5, 2101. 9 T. H. Brown, C. A. Campbell, W. N. Chan. J. M. Evans, R. T. Martin, T. O. Stean, G. Stemp, N. C. Stevens, M. Thompson, N. Upton and A. K. Vong, Biomed. Chem. Lett., 1995, 5, 2563. 10 A. Arnone, L. Bruch�e, L. Garanti and G. Zecchi, J. Chem. Res. (S), 1995, 282; A. Arnone, P. Bandiera, P. Bravo, L. Bruch�e and M. Zanda, Gazz. Chim. Ital., 1996, 126, 773. J. CHEM. RESEARCH (S), 1