Journal article

Total asymmetric synthesis of doubly branched carba-hexopyranoses and amino derivatives starting from the Diels-Alder adducts of maleic anhydride to furfuryl esters

The Diels-Alder adducts of maleic anhydride to furfuryl esters were reduced into 7-oxabicyclo[2.2.l]hept-5-ene-1.2-exo,3-exo-trimethanol (+/-)-15 and enantiomerically pure (-)-15 (Scheme 1). The tripivalate of (+/-)-15 was converted into (1RS,2RS,3RS,4RS,5SR,6SR)-1,5,6-tris(hydroxymethyl)cyclohexane-1,2,3,4-t etrol ((+/-)-23; Scheme 2). Reaction of BBr3 with the triacetate (+/-)-30 of (+/-)-15 gave (1RS,2RS,5RS,6RS)-5-bromo-6-hydroxycyclohex-3-ene-1,2,3-trimethyl triacetate ((+/-)-31) at -78 degrees, and (1RS,2RS,5SR,8SR)-2-endo-hydroxy-6-oxabicylo[3.2.l]oct-3-ene-5,8-dimethy l diacetate ((+/-)-32) at 0 degrees (Scheme 3). Single-crystal X-ray diffraction of (1RS,2RS,5SR,8SR)-2-acetoxy-6-oxabicyclo[3.2.1]oct-3-ene-5,8-dimethyl diacetate ((+/-)-33) was carried out. Displacement of bromide (+)-31 (derived from (-)-15) with azide anion gave (+)-38 which was transformed into (+)-( 1R,2R,5S,6S)-5-amino-6-hydroxycyclohex-3-ene-1,2,3-trimethanol ((+)-40) (Scheme 4). Reaction of (+/-)-31 with BBr3 at 0 degrees, followed by azide disubstitution led to (1RS,2RS,5SR,6SR)-5-amino-3-(aminomethyl)-6-hydroxycyclohex-3-ene-1,2-di methanol ((+/-)-45). Dihydroxylation of (+/-)-38 and further transformations gave (1RS,2RS,3SR,4RS,5SR,6RS)-5-amino-1,4,6-trihydroxycyclohexane-1,2,3-trim ethanol ((+/-)-49) and (1RS,2RS, 3SR,4RS,5SR,6RS)-2,3-dihydroxy-7-oxabicyclo[4.1.0]heptane-2,3,4-trimetha nol ((+/-)-55) (Schemes 5 and 6). Expoxidation of the 4-nitrobenzoate (+/-)-61 of (+/-)-38 allowed the preparation of (1RS,2RS,3SR,4RS,5RS)-5-amino-4-amino-1.4-dihydroxycyclohexane-1,2,3-tri methanol ((+)-65) and of (1RS,2RS,3SR,4RS,5SR,6RS)-5-amino-4-hydroxy-7-oxabicyclo[4.1.0]heptane-1 ,2,3 ((+/-)-67) (Scheme 7). The new unprotected polyols and aminopolyols were tested for their inhibitory activity toward commercially available glycohydrolases. At 1 mM concentration, 34, 30, and 31% inhibition of beta-galactosidase from bovine liver was observed for (+/-)-40, (+/-)-65, and (1)-67, respectively.


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