216
reported procedure.2 The diol 5 was initially treated with benzaldehyde and zinc chloride to give 2,3-O-
benzylidene derivative 8 (100%) as the sole diastereoisomer.† In the presence of titanium tetrachloride,
2,3-O-benzylidene 8 was treated with sodium cyanoborohydride in acetonitrile to afford 3-O-benzyl
derivative 9 (67%) along with a 2-O-benzyl derivative (27%). Upon exposure of 9 to sodium hexame-
thyldisilazide in tetrahydrofuran, bicyclic methyl ribofuranoside 10 was obtained (95%). Deprotection at
the 5-hydroxy group in 10 (10→11, 100%) followed by substitution by a benzyl group gave 12 (11→12,
92%), which was treated with 10% HCl to give the desired compound 1 successively (100%).‡ From
1
analysis of the H NMR spectrum, 1 was found to exist in an aldehyde form (not a hemiacetal form)
because of the ring strain derived from the 2-O,4-C-methylene bridge.
Scheme 1. Reagents and conditions: (i) TBDPSCl (2.2 equiv.), Et3N, CH2Cl2, rt; (ii) TsCl, Et3N, DMAP, CH2Cl2, rt; (iii)
CF3COOH:THF:H2O (14:8:3), rt; (iv) (Me3Si)2NNa (10 equiv.), THF:benzene (5:2), rt; (v) PhCHO, ZnCl2, rt; (vi) NaBH3CN
(5 equiv.), TiCl4 (5 equiv.), MeCN, rt; (vii) (Me3Si)2NNa, THF, rt; (viii) TBAF, THF, rt; (ix) BnBr, NaH, DMF, rt; (x) 10% HCl,
THF, rt
Next, the aldehyde 1 was coupled with the magnesium and the lithium derivatives of some aromatic
heterocycles as shown in Table 1. The magnesium derivative of 2-phenyl-5-oxazole gave the S-epimer
of compound 13a as a main product, while those of 2-pyridine, N-triisopropylsilyl-3-pyrrole and 2-tert-
butyldiphenylsilyl-1-N,N-dimethylsulfamoyl-5-imidazole afforded the R-epimer of 13b, 13c and 13d,
respectively.§ This stereoselectivity may be explained by the re-face attack of nucleophiles on the
carbonyl group of the chelation model,¶ as illustrated in Fig. 1. On the other hand, the lithium salts
of heterocycles also gave the corresponding products; however, significant stereoselectivities were not
observed.
After separation of the R- and S-epimers of 13a–c by silica gel column chromatography, these
compounds were cyclized under typical Mitsunobu conditions.15–17 As shown in Table 2, S-13a and
R-13b, which were obtained as major products in the coupling reaction of 1 with magnesium salts,
were treated with diethyl azodicarobxylate (DEAD) and triphenylphosphine (TPP) in tetrahydrofuran
‡
Recently, the aldehyde 1 was alternatively prepared by Wengel et al.13,14
§
The stereochemistry of 13 was determined from the structure of their cyclization products 14.
¶
A similar chelation model for 2,3,5-tri-O-benzyl-D-ribofuranose was reported by Yokoyama et al.15