TETRAHEDRON: ASYMMETRY Tetrahedron: Asymmetry 12 (2001) 1977–1982 Pergamon Synthesis of enantiomerically pure 4-substituted pyrrolidin-3-ols via asymmetric 1,3-dipolar cycloaddition Staffan Karlsson* and Hans-Erik Ho ¨ gberg* Chemistry, Department of Natural and Environmental Sciences, Mid Sweden University, SE -851 70 Sundsvall, Sweden Received 14 August 2001; accepted 20 August 2001 Abstract—Asymmetric 1,3-dipolar cycloadditions of chiral azomethine ylides to 3-benzyloxy-substituted alkenoylcamphorsultams are described. trans -3,4-Disubstituted pyrrolidines containing a protected hydroxyl group at C(4) of the pyrrolidine ring are obtained in high diastereomeric ratios. Such compounds can serve as chiral building blocks for the syntheses of enantiopure bioactive pyrrolidines. This is exemplified by a short synthetic route to a known glycosidase inhibitor, (3R,4R )-4-(hydroxy- methyl)pyrrolidin-3-ol and its enantiomer. © 2001 Elsevier Science Ltd. All rights reserved. 1. Introduction Asymmetric 1,3-dipolar cycloadditions are among the most efficient reactions for the construction of enan- tiopure five-membered ring heterocycles. 1–3 The chiral- ity of the products of these reactions can be introduced through enantioselective catalysis, e.g. by the use of either chiral Lewis acids 4 or enantiopure organic cata- lysts. 5 Alternatively, chiral auxiliaries can be used. 1,2 Using the latter approach, we have recently studied the reactions of chiral ylides with chiral dipolarophiles in an attempt to improve the diastereoselectivity in reac- tions of azomethine ylides with dipolarophiles, which are attached to chiral auxiliaries. 3b,3c Chiral non- racemic azomethine ylides show significantly higher diastereoselectivity than achiral ones when reacting with some ,-unsaturated cycloalkenoic derivatives attached to chiral auxiliaries. 3c,6 In reactions with acyclic alkenoic substrates, however, the effect of using non-racemic ylides is small. 3b The enantiomers of 1- phenylethylamine, which are comparatively inexpensive starting materials for the preparation of the ylide pre- cursors, can, however, be used with some advantage in place of achiral benzylamine. The reaction of an unstabilised azomethine ylide with a dipolarophile, such as an ,-unsaturated acyl com- pound, is controlled by interaction of the HOMO of the azomethine ylide with the LUMO of the dipolar- ophile. 7 A dipolarophile containing a vinyl ether group (e.g. compounds 3 or 4, Scheme 1) has a higher LUMO energy than the analogous cinnamoyl derivative, because of the electron donating nature of the ether oxygen. Thus, when the reaction is controlled by inter- actions between HOMO (azomethine ylide) and LUMO (dipolarophile), and when a dipolarophile containing an electron-rich vinyl ether is used, lower reactivity should result. We have recently shown that compound 3 can serve as a dipolarophile in a reaction with a sulphur-containing 1,3-dipolar compound, 3d and that the resulting cycloadduct can serve as the starting mate- rial in the synthesis of a pheromone of the pine sawfly. 8 A 1,3-dipolar cycloaddition reaction of a 3-benzyl- oxypropenoyl derivative, e.g. 3 or 4, with an azome- thine ylide (derived from either of the precursors 1 or 2) would result in a pyrrolidine cycloadduct containing an ether group at the 4-position of the heterocyclic ring formed. Substituted pyrrolidines of this type should be useful intermediates for further manipulation into enan- tiopure alkaloids and bioactive substances. For exam- ple, racemic and non-racemic derivatives of such pyrrolidines have been prepared and found to have an inhibitory effect on certain enzymes 9–11 as well as on the glial GABA uptake systems. 12 These pyrrolidines have also been used as building blocks for further syntheses of compounds with antibacterial activity. 13,14 We now present some doubly diastereoselective 1,3- dipolar cycloadditions of the chiral azomethine ylide precursor 1 and its enantiomer 2 to the -benzyloxy- substituted ,-unsaturated compound 3 and its enan- tiomer 4. The diastereoselectivity of these reactions as a function of the solvent polarity is also discussed. * Corresponding authors. Tel.: +46(60)148704; fax: +46(60)148802; e-mail: staffan.karlsson@mh.se; hans-erik.hogberg@mh.se 0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII:S0957-4166(01)00367-6