1,2;3,4-Di-O-isopropylidene-L-galactose synthesis from its D-enantiomer Bogdan Doboszewski   , Piet Herdewijn ⇑ Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium article info Article history: Received 30 November 2011 Revised 14 February 2012 Accepted 20 February 2012 Available online 28 February 2012 Keywords: L-Galactose D-Galactose Acetyl migration abstract Easy procedure was devised to obtain di-O-isopropylidene-L-galactose from di-O-isopropylidene-D- galactose. Ó 2012 Elsevier Ltd. All rights reserved. D-Galactose is an easily available hexose whose alditol has a plane of symmetry. This implies an enantiotopic relation between both terminal hydroxymethyl groups in galactitol, and enables a transformation of D-galactose into L-galactose or vice versa as shown in the Scheme 1. The same applies to other sugars like erythrose, xylose, ribose, and allose. Transformation of D-Gal into L-Gal based on this principle is known 1–4 and requires sodium amalgam as a critical reducer. Due to current environmental concerns, the use of large quantities of mercury is unacceptable. Consequently we searched for an alter- native method of synthesis of L-Gal starting from D-Gal. L-Galactose can be obtained from natural sources (flaxseed, 5 galactogen 6 , or seaweeds 7 ), from L-ascorbic acid, 8 from 1-deoxy- 1-nitro-L-galactitol 9 (obtainable from L-xylose), from 1-L-(À)-2-O- methyl-chiroinositol (quebrachitol), 10 via total synthesis using either furfural 11 or allyl alcohol, 12 or via enzymatic processes which use either galactitol 13–15 or L-sorbose 16 as substrates. Dithioacetals of D-Gal were used to mask the carbonyl function during conversion into L-Gal, 17,18 and finally 6,7-dideoxy-1,2;3,4;-di-O-isopropyli- dene-a-D-galacto-hept-6-enose was used. 19 Total syntheses of carbohydrates in general have been reviewed. 20–22 Our interest in L-galactose results from a possibility to use it as a source of the C3 chiral fragment 1, as shown in the Figure 1. Since enantiomeric 2 can be obtained from D-galactose, the procedure would be stereospecific and would allow accessing both 1 and 2 via uniform procedures. Our initial approach to get L-Gal from D-Gal is shown in the Scheme 2. The known 6-O-t-butyldiphenylsilyl-D-galactopyranose 3 23,24 was sequentially reduced with NaBH 4 (?4) and conventionally acetylated (?5). Apparently simple desilylation with Bu 4 NF for 20 min at rt furnished 1,2,3,5,6-penta-O-acetyl-D-galactitol 7 as the only product. Evidently, under slightly basic conditions acetyl group migration took place in initially formed 6 presumably via a chair-like conformation 8 which approximates 6-OH group and the carbonyl group of the 4-OAc. The position of the acetates was established by heteronuclear multiple bond correlation (HMBC) spectrum, which shows no cross-peak joining the signal of the H4 and a carbonyl group via three bonds. It should be stressed that in the substrate 5, there is no correlation between the signals of both –CH 2 -OSitBuPh 2 hydrogen atoms and a carbonyl group which proves that no silicon migration took place during either a reduction (?4) or during acetylation (?5). As a point of interest: bulky tBuPh 2 Si– prefers primary versus secondary positions by ca 8–9 kJ/mol. 25 Migrations of the acetyl (acyl) groups are a known phenomenon which can take place in basic, acidic, or neutral med- ium, 26 occur in acyclic 27,28 or cyclic compounds, 29–35 and can be either intra- or intermolecular. 32 Such migrations are a frequent nuisance during desilylations using tetrabutylammonium fluoride (TBAF) due to the presence of water which makes it basic and promotes migrations via transient orthoesters. 27,28,31,32 Neutraliza- tion of TBAF with acetic acid is known to suppress this process 36–38 but due to variable quantities of water in commercial reagents, this is rather inconvenient. It should be firmly stressed that acetyl migrations are known even in neutral medium. 26 Anhydrous organic sources of the fluoride anion are known, for example, tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), 39 tetrabutylammonium tetra(t-butanol) fluoride 40 or genuinely 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2012.02.091 ⇑ Corresponding author. Tel.: +32 16 337387; fax: +32 16 337340. E-mail address: piet.herdewijn@rega.kuleuven.be (P. Herdewijn).   Permanent address: Departamento de Química, Universidade Federal Rural de Pernambuco, 52171-900 Recife, PE, Brazil. Tetrahedron Letters 53 (2012) 2253–2256 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet