Syntheses of Macrolide Antibiotics
J. Am. Chem. Soc., Vol. 120, No. 24, 1998 5933
CDCl3) δ 7.09 (d, J ) 8.5 Hz, 2H), 6.72 (d, J ) 8.5 Hz, 2H),
4.58 (q, J ) 5.5 Hz, 1H), 4.40 (d, J ) 10.3 Hz, 1H), 4.28 (d,
J ) 10.3 Hz, 1H), 3.89 (dt, J ) 5.3, 1.8 Hz, 1H), 3.71 (dd, J
) 2.5, 9.3 Hz, 1H), 3.68 (s, 3H), 2.10 (m, 1H), 1.52 (m, 1H),
1.48-1.32 (m, 2H), 1.42 (d, J ) 5.5 Hz, 3H), 0.84 (d, J ) 7.0
Hz, 3H), 0.80 (s, 9H), 0.69 (t, J ) 7.5 Hz, 3H), 0.64 (d, J )
6.9 Hz, 3H), 0.09 (s, 9H), -0.01 (s, 3H), -0.06 (s, 3H); TLC
Rf ) 0.80 (20% EtOAc/hexanes). HRMS (FAB) m/z could not
be obtained due to the instability of the product.
matography (3 × 12 cm, linear gradient 20 to 25% EtOAc/
hexanes) to afford 492 mg (95%) of a clear colorless oil: [R]23
D
-33.6° (c 0.25, CH2Cl2); IR (neat) 3476, 2936, 2856, 1784,
1695, 1614, 1514, 1 cm-1;1H NMR (500 MHz, CDCl3) δ 7.40-
7.10 (m, 7H), 6.83 (d, J ) 8.5 Hz, 2H), 4.67 (m, 1H), 4.64 (d,
J ) 11.1 Hz, 1H), 4.58 (d, J ) 11.0 Hz, 1H), 4.20 (app t, J )
9.1, 8.9 Hz, 1H), 4.18 (dd, J ) 11.1, 2.7 Hz, 1H), 4.10 (dd, J
) 9.3, 1.8 Hz, 1H), 3.98 (m, 1H), 3.90 (dq, J ) 3.0, 7.0 Hz,
1H), 3.84 (m, 2H), 3.78 (m, 2H), 3.78 (s, 3H), 3.22 (dd, J )
13.3, 3.2 Hz, 1H), 2.73 (dd, J ) 13.4, 9.6 Hz, 1H), 1.88-1.75
(m, 4H), 1.62-1.45 (m, 3H), 1.42 (s, 3H), 1.36 (s, 3H), 1.28
(d, J ) 7.0 Hz, 3H), 0.92 (d, J ) 7.0 Hz, 3H), 0.90 (s, 9H),
0.85-0.72 (m, 15H), 0.08 (s, 3H, 0.06 (s, 3H); TLC Rf ) 0.33
(35% EtOAc/hexanes). HRMS (FAB) m/z calcd for [M + Na]+
878.5214, found 878.5223.
(4R)-4-Benzyl-3-[(2R)-2-[(4S,5R6S)-6-[(1S,2S,3R,5R,6S,-
7R,8R)-8-(tert-butyldimethylsiloxy)-2-hydroxy-6-[(p-meth-
oxybenzyl)oxy]-1,3,5,7-tetramethyl-4-oxodecyl)]-2,2,5-tri-
methyl-m-dioxan-4-yl]propionyl]-2-oxazolidinone (15).
A
mixture of 244 mg of silyl enol ether (0.481 mmol) and 319
mg of aldehyde (0.769 mmol) was azeotropically dried twice
with 25 mL of benzene before dissolution in 12 mL of CH2Cl2.
The solution was cooled to -95 °C before 0.591 mL of BF3‚
Et2O (4.81 mmol) was added dropwise down the inside of the
flask. Following warming to -78 °C, the solution was stirred
for 1.5 h before it was quenched by the addition of ∼3 mL of
Et3N and warmed to ambient temperature. The solution was
partitioned between 20 mL of deionized water and 20 mL of
CH2Cl2. The aqueous layer was extracted with CH2Cl2 (2 ×
25 mL), and the combined organic layers were washed with
brine (1 × 20 mL), dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash
chromatography (5 × 11 cm, linear gradient 18 to 35% EtOAc/
hexanes followed by 3 × 14.5 cm, linear gradient of 2 to 3%
acetone/CH2Cl2), affording 333 mg (83%) of a clear colorless
oil as a single isolated diastereomer. Data for the isolated
(4R)-4-Benzyl-3-[(2R)-2-[(4S,5R,6S)-6-[(1S,2R,3R)-3-[(2R,-
4S,5S,6R)-6-[(1R,2R)-2-(tert-butyldimethylsiloxy)-1-methyl-
butyl]-2-(p-methoxyphenyl)-5-methyl-m-dioxan-4-yl]-2-hy-
droxy-1-methylbutyl]-2,2,5-trimethyl-m-dioxan-4-yl]propionyl]-
2-oxazolidinone (17). To mixture of 383 mg (0.448 mmol) of
the diol and ∼500 mg Mg2SO4 in 4.5 mL of CH2Cl2 at ambient
temperature was added via cannula an orange solution of 122
mg (0.538 mmol) of DDQ in 5.0 mL of CH2Cl2 (followed by
a 1 mL rinse) standing over ∼250 mg of Mg2SO4. After 10
min, 10 mL of a saturated aqueous NaHCO3 solution was added
to the green mixture. The layers were separated and the aqueous
layer extracted with CH2Cl2 (2 × 10 mL). The combined
organic layers were dried over Na2SO4, filtered, and concen-
trated in vacuo to afford 382 mg (>99%) of a clear, colorless
oil which required no further purification: [R]23D -49.6° (c 0.93,
CH2Cl2); IR (neat) 3522, 3031, 2935, 2856, 1783, 1695, 1615,
1517, 1456 cm-1;1H NMR (400 MHz, C6D6) δ 7.80 (d, J )
10.0 Hz, 2H), 7.15-6.88 (m, 7H), 6.06 (s, 1H), 4.50 (m, 1H),
4.47 (dd, J ) 9.8, 1.9 Hz), 4.33 (m, 1H), 4.26 (m, 1H), 4.22
(dd, J ) 10.2, 1.2 Hz, 1H), 4.09 (dd, J ) 9.9, 17 Hz, 1H), 3.94
(br, 1H), 3.90 (app d, J ) 10.1, 1H), 3.44 (dd, J ) 9.1, 2.6 Hz,
1H), 3.32 (s, 3H), 3.16 (app t, J ) 8.6 Hz, 1H), 2.99 (dd, J )
13.2, 3.2 Hz, 1H), 2.62 (m, 1H), 2.30 (dd, J ) 13.3, 9.5 Hz,
1H), 2.07 (m, 2H), 1.98-1.85 (m, 2H), 1.76 (br d, J ) 7.1 Hz,
1H), 1.67-1.49 (m, 2H), 1.60 (d, J ) 7.0 Hz, 3H), 1.50 (s,
3H), 1.40 (s, 3H), 1.39 (d, J ) 7.0 Hz, 3H), 1.31 (d, J ) 7.0
Hz, 3H, 1.18 (d, J ) 7.0 Hz, 3H), 1.08 (s, 9H), 0.51 (app t, J
) 7.0 Hz, 6H), 0.82 (t, J ) 6.0, 3H), 0.20 (s, 3H), 0.14 (s, 3H);
TLC Rf ) 0.49 (35% EtOAc/hexanes). HRMS (FAB) m/z calcd
for [M + Na]+ 876.5058, found 876.5050.
diastereomer: [R]23 -82.1° (c 1.2, CH2Cl2); IR (neat) 3533,
D
2935, 2884, 1784, 1695, 1633, 1586, 1514, 1456 cm-1;1H NMR
(500 MHz, CDCl3) δ 7.33-7.16 (m, 7H), 6.34 (d, J ) 8.5 Hz,
2H), 4.67 (m, 1H), 4.34 (d, J ) 10.3 Hz, 1H), 4.30 (d, J )
10.2 Hz, 1H), 4.20 (app t, J ) 8.0 Hz, 1H), 4.17 (dd, J ) 9.1,
2.7 Hz, 1H), 4.08 (dd, J ) 9.7, 1.6 Hz, 1H), 3.98-3.85 (m,
4H), 3.78 (s, 3H), 3.76 (dd, J ) 8.7, 1.8 Hz, 1H), 3.21 (dd, J
) 13.3, 3.2 Hz, 1H), 3.10 (app quint, J ) 6.3, 1H), 2.81 (dq,
J ) 7.0, 1.0 Hz, 1H), 2.73 (dd, J ) 13.3, 9.6 Hz, 1H), 2.57 (d,
J ) 4.6 Hz, 1H), 1.71 (m, 1H), 1.67-1.45 (m, 4H), 1.42 (s,
3H), 1.36 (s, 3H), 1.28 (d, J ) 7.0 Hz, 3H), 1.20 (d, J ) 7.0
Hz, 3H), 1.10 (d, J ) 7.0 Hz, 3H), 0.90 (s, 9H), 0.85-0.70 (m,
12H), 0.08 (s, 3H), 0.06 (s, 3H); TLC Rf ) 0.43 (35% EtOAc/
hexanes). HRMS (FAB) m/z calcd for [M + Na]+ 876.5058,
found 876. 5043.
(4R)-4-Benzyl-3-[(2R)-2-[(4S,5R6S)-6-[(1S,2R,3S,4S,5S,6R,-
7R,8R)-8-(tert-butyldimethylsiloxy)-2,4-dihydroxy-6-[(p-meth-
oxybenzyl)oxy]-1,3,5,7-tetramethyldecyl)]-2,2,5-trimethyl-m-
dioxan-4-yl]propionyl]-2-oxazolidinone (16). To a solution
of 520 mg (0.610 mmol) of aldol adduct in 6 mL of CH2Cl2 at
0 °C was added 30 mL (6.10 mmol, 0.20 M in Et2O) of Zn-
(BH4)2. After 1.0 h, 10 mL each of pH 7 buffer and MeOH
was added slowly, and the resultant mixture warmed to ambient
temperature and stirred for 12 h. The mixture was extracted
by CH2Cl2 (3 × 15 mL), and the combined organic extracts
were dried over Mg2SO4, filtered, and concentrated. The residue
was taken up in 50 mL of MeOH and stirred at ambient
temperature for 24 h. Following concentration, the residue was
partitioned between 20 mL of saturated aqueous NH4Cl and 20
mL of CH2Cl2. The aqueous layer was extracted with CH2Cl2
(2 × 20 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. 1H NMR spec-
troscopy analysis of the unpurified product showed >98:2
diastereoselectivity. The residue was purified by flash chro-
(4R)-4-Benzyl-3-[(2R)-2-[(4S,5R,6S)-6-[(1S)-1-[(4R,5S,6R)-
6-[(1R,2R,3R,4R)-4-(tert-butyldimethylsiloxy)-2-[(p-methoxy-
benzyl)oxy]-1,3-dimethylhexyl]-2,2,5-trimethyl-m-dioxan-4-
yl]ethyl]-2,2,5-trimethyl-m-dioxan-4-yl]propionyl]-2-oxa-
zolidinone (18). To a solution of 4.2 mg (4.9 × 10-3 mmol)
of diol in 1.0 mL of 2,2-dimethoxypropane at ambient temper-
ature was added ∼1 mg of CSA. After 1.0 h, the reaction was
quenched by the addition of 5 drops of Et3N and the resultant
solution filtered through a plug of silica. Concentration in vacuo
afforded 3.5 mg (80%) of a clear colorless residue: [R]23
D
-21.1° (c 0.18, CH2Cl2); IR (neat) 2933, 2855, 1785, 1695,
1513, 1458 cm-1;1H NMR (500 MHz, C6D6) δ 7.52 (d, J )
10.0 Hz, 2H), 7.12-7.02 (m, 3H), 6.94 (d, J ) 10.0 Hz, 2H),
6.49 (d, J ) 10.0 Hz, 2H), 5.01 (d, J ) 11.7 Hz, 1H), 4.99 (d,
J ) 11.8 Hz, 1H), 4.50 (m, 1H, 4.41 (dd, J ) 9.8, 1.8 Hz),
4.29 (app d, J ) 9.4, 1H), 4.26 (m, 2H), 4.07 (dd, J ) 9.9, 1.7
Hz, 1H), 3.82 (dd, J ) 6.6, 1.7 Hz, 1H), 3.68 (dd, J ) 9.6, 1.7
Hz, 1H), 3.44 (dd, J ) 9.9, 2.6 Hz, 1H), 3.18 (app t, J ) 8.4
Hz, 1H), 2.98 (dd, J ) 13.3, 3.2 Hz, 1H), 2.30 (dd, J ) 13.3,