Lipase-mediated synthesis of enantiomeric 2,5,6-trideoxy- 2,5-iminohexitols q Isidoro Izquierdo * , Marı ´a T. Plaza, Juan A. Tamayo * , Francisco Franco, Fernando Sa ´ nchez-Cantalejo Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada,18071 Granada, Spain article info Article history: Received 25 February 2008 Received in revised form 25 March 2008 Accepted 26 March 2008 Available online 29 March 2008 Dedicated to Professor Vicente Gotor on the occasion of his 60th anniversary abstract Syntheses of 2,5,6-trideoxy-2,5-imino-D-alditol (2, 6-deoxy-DADP) and its enantiomer (3) from tri- orthogonally protected derivatives of DADP have been developed employing lipase-mediated kinetic desymmetrization and protecting group manipulations. Thus, and as an example, the starting DADP derivative (4) was transformed into a new symmetrical 2,5-bis(hydroxymethyl)pyrrolidine (6) by sequential N-protection and bis-O-desilylation. The lipase-mediated desymmetrization of 6 was best carried out under acetylation conditions to give (2R)-acetyloxymethyl derivative 7 . The absolute con- figuration and ee of 7 were unambiguously established by chemical correlation with a homochiral sample. Compound 7 was straightforwardly transformed into the target 2,5,6-trideoxy-2,5-iminohexitol 3. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Several 5-methylpyrrolidine-triols (1) of the type displayed in Figure 1 show potent inhibitory activity versus glycosidases in general 2 as well as a-L-fucosidases 3 in particular. They are also rather weak a-[1,3]-fucosyl-transferase inhibitor with a potent synergistic effect in the presence of GDP, 4 and have been prepared employing chemo-enzymatic 2,5 and chemical methods. 1,6 In the case of 2,5,6-trideoxy-2,5-imino-D-allitol (2, 6-deoxy- DADP), only two chemical syntheses have been reported to date, one by Defoin et al., 7 using a chiral 1,2-oxazines as starting material, and a second by Ja ¨ger and Palmer, 8 where a nitrone approach was the methodology of choice. To the best of our knowledge, no syn- thesis for ent-2 (3) has been reported so far, and taking into account the influence of the chirality of this type of compounds on the specificity and inhibition potency, 9 we considered that the synthesis of 3 would be of interest for future enzymatic assays. From a synthetic point of view, the symmetrical character of (2R,3R,4S,5S)-3,4-dibenzyloxy-2,5-bis(tert-butyldiphenylsilyloxy- methyl)pyrrolidine (4), recently prepared from the carbohydrate chiral pool (D-fructose) by our group, 10 makes it an appropriate starting material, suitable for further desymmetrization, to achieve the previously mentioned iminohexitol 3. A lipase-mediated regioselective transesterification at the hydroxylmethyl groups on the corresponding N-protected, bis-O-desilylated derivative 6, obtained from pyrrolidine 4, was the methodology of choice in order to obtain the required chirality. Although chemo-enzymatic desymmetrizations have been described on different N-protected acyclic 11 and cyclic aminodiols, 12 to the best of our knowledge, the only example of this methodology applied to a pyrrolidinic skeleton has been done by Donohoe et al. 13 on a 2,5-bis(hydroxymethyl)- D 3 -pyrroline. We described another approach of this method performed on more complex pyrrolidines together with the use of the resulting products in the enantiosynthesis of 2,5,6-trideoxy- 2,5-iminohexitols 2 and 3. H N HO OH H N HO OH 6-Deoxy-DADP (2) Ent-2 (3) Not described HO OH H N HO OH 1 OH H N BnO OBn 4 (PG = TBDPS) OPG PGO Figure 1. General structure for 5-methylpyrrolidine-triols (1), the enantiomers of 6-deoxy-DADP (2 and 3), and an orthogonally protected derivative (4) of 2,5-dideoxy- 2,5-imino-D-allitol. q Part VII: Polyhydroxylated pyrrolidines. For Part VI, see Ref. 1. * Corresponding authors. Tel.: þ34 958 249583; fax: þ34 958 243845 (I.I.); tel.: þ34 958 243846; fax: þ34 958 243845 (J.A.T.). E-mail addresses: isidoro@ugr.es (I. Izquierdo), jtamayo@ugr.es (J.A. Tamayo). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet Tetrahedron 64 (2008) 4993–4998 Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.03.089