Stereocontrolled approaches to 2-2-aminoalkyl)-1-hydroxycyclopropanes Mark S. Baird, a,p Florian A. M. Huber a and William Clegg b a Department of Chemistry, University of Wales, Bangor, Gwynedd, LL57 2UW Wales, UK b Department of Chemistry, University of Newcastle upon Tyne, NE1 7RU Newcastle upon Tyne, UK Received 20 July 2001; accepted 18 October 2001 Abstract Ð1S,2S)-2[S)-Amino4-methoxyphenyl)methyl]cyclopropan-1-ol together with a range of racemic 2-2-aminoalkyl)-1-hydroxy- cyclopropanes were prepared by a stepwise procedure involving a 1,3-dipolar cycloaddition of a nitrile oxide to a cyclopropene followed by reduction of the derived bicycle. q 2001 Elsevier Science Ltd. All rights reserved. Isoxazolines are readily obtained by cycloaddition of nitrile oxides to alkenes. The reduction of the ring is known to provide access to g-aminoalcohols, in some cases with a high degree of stereo-control, 1±3 in a reaction effectively amounting to selective 1-hydroxy-2-aminoalkylation of an alkene Scheme 1). With alkyl or other non-coordinating groups at C-4 or C-5 of the isoxazoline, hydrogen addition takes place predomi- nantly anti trans) to the substituents to give the syn-1,3- disubstituted aminoalcohol. Hydroxyl or hydroxymethyl- substituents, however, direct the reducing agent to the syn face of the CvN bond, leading predominantly to the anti- aminoalcohol. 4,5 Although there has been considerable interest in the formation of isoxazolines by the cyclo- addition of nitrile oxides to cyclopropenes, little is known about their subsequent ring-opening to 2-aminoalkyl-1- hydroxycyclopropanes. In view of the considerable range of biological activity shown by amino-substituted cyclo- propanes, 6 we now report the results of such an examination. Cycloadducts between a number of cyclopropenes and nitrile oxides were prepared by standard methods. 7 The adduct 1), formed from 2,4,6-trimethoxybenzonitrile oxide and 3-methyl-3-phenyl-cyclopropene did not react with lithium aluminium hydride Scheme 2). However, the corresponding adduct of 4-methoxybenzo- nitrile oxide, compound 2) was reduced to a single aminoalcohol 8) in reasonable yield 51%), as a pair of enantiomers. The structure of this product was con®rmed by a single crystal X-ray determination, and is shown in Fig. 1. This can be explained in terms of a selective addition of hydride to the convex face of the azabicycle, ®xing the stereochemistry at C-4, followed by N±O cleavage Scheme 3). Presumably in the case of 1), the two o-OMe groups cause the aryl group to be twisted out of the plane of the CvN Tetrahedron 57 2001) 9849±9858 Pergamon TETRAHEDRON 0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved. PII: S0040-402001)00996-6 Scheme 1. Scheme 2. Keywords: isoxazolines; allyl alcohol; cyclopropenes; cyclopropanes. p Corresponding author. Tel.: 144-1248-382-374; fax: 144-1248-370- 528; e-mail: chs028@bangor.ac.uk