most of the difficulties associated with conventional silica
gel chromatography. The objective of the experiments
described herein is to demonstrate the feasibility of the
proposed approach for efficient product isolation.
treated with aqueous HBF4 to remove the acetal protection
without affecting the DBn ether, whose acid sensitivity is
similar to that of the well-known p-methoxybenzyl ether.9
The diol 8 so formed was converted to the benzoate 10 using
a standard protocol involving cyclic ortho ester formation
at HO-2 and -3 with trimethyl orthobenzoate/CSA (f9)
followed by mild, acetic acid hydrolysis.10 The lipophilic
compound 10 was purified by solid-phase extraction using
a Waters Preparative C18 125 Å column made in 80%
aqueous MeOH. This solvent completely eluted the impuri-
ties. Compound 10 was eluted with MeCN. Because of the
formation of an isomeric benzoate (11) that coeluted from
the C18 adsorbent with 10 as expected, the final purification
was done on a silica gel column to afford 10 in an overall
yield of 52% for five steps (from 5).
The synthesis of the new lipophilic p-alkoxybenzyl
chloride 4 is outlined in Scheme 1.7 Reaction of the
commercially available p-(dodecyloxy)benzoic acid (1) with
Cs2CO3 followed by MeI afforded the methyl ester 2.
Reduction of 2 with LiAlH4 under the usual conditions
provided the alcohol 3 as a solid material. Chlorination of
compound 3 using HCl yielded the chloride 4, which was
isolated as a crystalline product from methyl alcohol.
Compound 4 showed no sign of decomposition at 0 °C after
several weeks.
Scheme 1
Scheme 2
In a representative test, the new p-(dodecyloxy)benzyl
chloride (4; DBnCl) was condensed with the thiorhamnoside
6 obtained from the triol8 5 by treatment with p-methoxy-
benzaldehyde dimethylacetal/CSA (Scheme 2). The etheri-
fication followed the established method for benzyl ether
formation using NaH in DMF to convert the alcohol to its
sodium salt and proceeded to completion with only a small
excess of 4. The resulting p-(dodecyloxy)benzyl ether 7 was
(7) Procedure for the Synthesis of Compound 4. To a solution of 4-(n-
dodecyloxy)benzoic acid (20 g, 65.2 mmol) in hot MeOH (300 mL) was
added Cs2CO3 (12.0, 36.8 mmol) in 10:1 MeOH-H2O (110 mL). After
dissolution of the solids the solution was concentrated. To the residue were
added DMF (100 mL) and MeI (30 mL) at 25 °C. After 1 h, the solution
was concentrated. The residue was equilibrated between CHCl3 and H2O,
and the organic layer was dried (Na2SO4) and concentrated. A solution of
the solid so obtained in dry THF (100 mL) was treated with LiAlH4 (3.5
g): then the mixture was stirred under reflux for 1 h. The usual workup
afforded a solid that was recrystallized from EtOAc. The mixture was kept
at 0 °C for 1 day before filtration to give 3 (13.5 g, 71% for three steps) as
a white crystalline solid: mp 68-69 °C; 1H NMR (CDCl3) δ 7.27 (d, 2 H,
J ) 8.6 Hz), 6.88 (d, 2 H, J ) 8.6 Hz), 4.61 (s, 2 H), 3.95 (t, 2 H, 6.5 Hz),
1.78 (m, 2 H), 1.62 (s, 1 H), 1.55-1.20 (m, 18 H), 0.88 (t, 3 H, J ) 5.8
Hz); 13C NMR (CDCl3) δ 128.6, 114.5, 68.0, 65.1, 31.9, 29.6, 29.5, 29.4,
29.3, 29.2, 26.0, 22.7, 14.1. Dry HCl gas was bubbled through a solution
of 3 (16.5 g) in toluene (100 mL) at 25 °C for 6 h; then the solution was
kept at 0 °C for 24 h. The solution was concentrated. The crystalline residue
was triturated in MeOH at 0 °C. Filtration afforded 4 (14.0 g, 80%): mp
38-40 °C; 1H NMR (CDCl3) δ 7.27 (d, 2 H, J ) 8.7 Hz), 6.86 (d, 2 H, J
) 8.7 Hz), 4.56 (s, 2 H), 3.95 (t, 2 H, 6.5 Hz), 1.77 (m, 2 H), 1.6-1.2 (m,
18 H), 0.88 (t, 3 H, J ) 6.8 Hz); 13C NMR (CDCl3) δ 114.7, 68.1, 46.4,
31.9, 29.6, 29.5, 29.4, 29.3, 29.2, 26.0, 22.7, 14.1.
The use of the lipophilic protecting group-tagged acceptor
in the synthesis of a disaccharide is shown in Scheme 3.
Thus, the rhamnosyl donor11 12 (2 equiv) was combined with
the lipophilic acceptor 10 under AgOTf activation using
standard conditions (DTBMP, 4 Å molecular sieves, CH2-
Cl2, -60 to -10 °C). TLC analysis of the reaction mixture
showed complete conversion of 10 within 30 min, thus
(13) NMR data for 13: 1H (CDCl3), δ (selected) 5.66 (dd, 1 H), 5.63
(dd, 1 H), 5.57 (d, 1 H, J ) 1.5 Hz), 5.38 (t, 1 H, J ) 9.7 Hz), 5.32 (d, 1
H, J ) 1.8 Hz), 4.81 and 4.61 (2 d, 2 H, J ) 10.4 Hz), 4.52 and 4.36 (2
d, 2 H, J ) 12.5 Hz), 1.75 (m, 2 H), 1.36 and 1.20 (2 d, 2 × 3 H, J ≈ 6.2
Hz), 0.88 (t, 3 H); 13C (CDCl3), δ 165.6, 165.5, 159.0, 137.5-128.5, 114.5,
99.7 (JH-1,C-1 ) 172 Hz), 85.6 (JH-1,C-1 ) 168 Hz), 80.0, 77.5, 75.4, 74.5,
74.0, 72.8, 71.1, 69.3, 69.1, 68.0, 67.6, 31.9, 29.6-29.2, 26.0, 22.7, 18.0,
17.5, 14.1.
(8) Pozsgay, V. Carbohydr. Res. 1992, 235, 295.
(9) Johannson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans 1 1984,
2371.
(10) King, J. F.; Allbutt, A. D. Can. J. Chem. 1970, 48, 1754.
(11) Pozsgay, V. J. Am. Chem. Soc. 1995, 117, 6673.
(12) Pozsgay, V.; Dubois, E. P.; Pannell, L. J. Org. Chem. 1997, 62,
2832.
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Org. Lett., Vol. 1, No. 3, 1999