Synthesis of R-Methylomuralide
the crude azido alcohol 7 (31.2 g, 90%) as a viscous oil. The
crude product was pure enough for next step. A small amount
of azido alcohol was purified by silica gel column to give
analytically pure 7 as a colorless oil. Data for 7: Rf 0.75 (Hex-
32.6, 17.5, 17.4; LRMS (m/z) 248.1 (100) (M + H+),178.2 (50);
EIMS m/z calcd for C14H17NO3 247.2897, found 247.2896.
Con ver sion of tr a n s-(4S, 5R)-P h en yloxa zolin e to P r i-
m a r y Alcoh ol 11. To a flame-dried flask was added LiHMDS
(1.5 m.mol, 2.27 mL, 0.66 M stock solution in THF), which
was then then cooled to -78 °C, immersed in THF (10 mL),
and treated dropwise with a solution of oxazoline 10 (4.0 g,
16.2 mmol) in THF (20 mL) to give the yellow transparent
solution. Stirring was continued for another 1 h. After the
enolate formation was complete, it was subjected to formyla-
tion by adding freshly prepared formaldehyde (160 mL, 1 M
stock solution in ether, through pre cooled cannula with dry
ice)32 solution at -78 °C, and stirring was continued for 3 h.
The mixture was rapidly quenched with water (20 mL) and
warmed to room temperature. The organic phase was sepa-
rated, the aqueous layer was extracted with EtOAc (3 × 200
mL),and the combined organic layers were dried over Na2SO4
and concentrated in vacuo. The pure alcohol 11 (3.59 g, 81%)
was obtained as a white powder by flash column chromatog-
raphy using Hex-EtOAc (25% neat EtOAc in hexane) as
eluent: mp 76-78 °C; Rf 0.18 (Hex-EtOAc 50:50); [R]23D -4.4
(c 1.0, CHCl3); FTIR (film) νmax 3356, 2978, 1742, 1628, 1498,
1253, 1020, 865 cm-1; 1H NMR (CDCl3, 600 MHz) δ 7.84 (2H,
d, J ) 8.4 Hz), 7.41 (1H, m), 7.32 (2H, m), 4.40 (1H, d, J ) 7.2
Hz), 3.97 (1H, dd, J ) 12.0, 6.6 Hz), 3.79 (1H, dd, J ) 11.8,
6.4 Hz), 3.69 (3H, s), 3.10 (1H, t, 6.5 Hz), 1.97 (1H, m), 0.95
(3H, d, J ) 6.6 Hz), 0.94 (3H, d, J ) 6.5 Hz); 13C NMR (CDCl3,
100 MHz) δ 171.6, 166.6, 132.0, 128.7, 128.5, 127.1, 89.3, 80.4,
67.0, 52.6, 29.8, 19.7, 18.9; LRMS (m/z) 277.0 (100) (M+), 250.1
(60), 178.2 (35), 165.2 (25); EIMS m/z calcd for C15H19NO4
277.3157, found 277.3152.
EtOAc 50:50); [R]23 -47.6 (c 1.1, CHCl3); FTIR (film) νmax
D
3498, 2964, 2118, 1744, 1434, 1513, 1256, 980 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 3.90 (1H, d, J ) 6.4 Hz), 3.80 (3H, s),
3.65 (1H, q, J ) 6.2 Hz), 2.56 (1H, br s, -OH), 1.89 (1H, m),
0.97 (3H, d, J ) 6.8 Hz), 0.95 (3H, d, J ) 6.5 Hz); 13C NMR
(CDCl3, 100 MHz) δ 170.3, 76.6, 64.0, 52.9, 30.4, 19.5, 16.7;
LRMS (m/z) 210.0 (70) (M + Na)+, 165.2 (100), 129.4 (40);
EIMS m/z calcd for C7H14N3O3 188.2044, found (M + H)+
188.2039.
(2S,3S)-3-Hyd r oxyleu cin e Meth yl Ester , 8. A solution
of azido alcohol 7 (24 g, 0.13 mol) in 20% EtOH-EtOAc (0.5
L) at room temperature was treated with 10% Pd-C (5 g)
under an argon atmosphere. The reaction setup was kept
under vacuum and purged with H2 gas (four times); the
resulting dark suspension was stirred vigorously in an atmo-
sphere of H2 (1 atm, H2 balloon). After 24 h, the reaction
mixture was filtered through Celite and concentrated in vacuo
to give the crude amino alcohol 8 (20.8 g, 99%) as a yellow
viscous oil and subjected to the next step without further
purification. Data for 8: Rf 0.10 (neat EtOAc); [R]23 +8.6 (c
D
0.7, CHCl3); FTIR (film) νmax 3494, 2898, 1738, 1513, 1252,
988 cm-1; 1H NMR (CDCl3, 400 MHz) δ 4.10 (1H, m), 3.79 (3H,
s), 3.69 (1H, d, J ) 6.5 Hz), 3.01 (3H, bs), 1.72 (1H, m), 0.98
(3H, d, J ) 4.6 Hz), 0.92 (3H, d, J ) 4.2 Hz); 13C NMR (CDCl3,
100 MHz) δ 175.1, 80.1, 57.6, 52.1, 31.5, 20.4, 18.2; LRMS (m/
z) 162.1 (40) (M + H+), 128.4 (50), 112.1 (30); EIMS m/z calcd
for C7H15NO3 161.1989, found 161.1987.
Met h yl (4S,5S)-5-Isop r op yl-2-p h en yl-4,5-d ih yd r oox-
a zole-4-ca r boxyla te, 9. To a mixture of (2S,3S)-3-hydroxy-
leucine methyl ester (16.7 g, 0.1 mol) and p-TsOH‚H2O (19.0
g, 0.1 mol) in dimethoxyethane (250 mL) was added trimethyl
orthobenzoate (53.7 mL, 0.313 mol), and the mixture was
refluxed for 4 h. After completion, the reaction mixture was
diluted with water (200 mL), and the aqueous layer was
separated and extracted with ether (3 × 150 mL). The
combined organic layers were washed with water and brine
and dried over Na2SO4. The solvent was removed in vacuo to
give crude oxazoline 9 and excess orthobenzoate. Flash column
chromatography on silica gel column (eluent 10-60% EtOAc-
hexane) afforded the pure oxazoline 9 (21.8 g, 85%) as viscous
Con ver sion of P r im a r y Alcoh ol 11 to Ald eh yd e 12
(Mod ified Sw er n Oxid a tion ). To a solution of oxalyl chloride
(875 µL, 10.0 mmol) in CH2Cl2 (50 mL) was added dropwise a
solution of dry DMSO (1.0 mL, 15.0 mmol) in CH2Cl2 (30 mL)
at -78 °C. Stirring was continued for 30 min at this temper-
ature. The above preformed Swern reagent was carefully
transferred through a cannula (wrapped with dry ice alumi-
num foil) to a solution containing the mixture of alcohol 11
(1.38 g, 5.0 mmol) and excess Et3N (3.45 mL, 25.0 mmol) at
-78 °C. After 3 h of vigorous stirring, the excess solvent was
pumped off in vacuo and the reaction mixture was diluted with
pentane (30 mL). The resulting white crystalline Et3N‚HCl salt
was filtered off under argon through a sintered funnel fitted
with a dry round-bottom flask and nitrogen inlet. The flask
was washed with pentane portionwise (3 × 30 mL) and the
supernatant solution decanted through a syringe and filtered.
The combined filtrates were condensed in vacuo under argon
atmosphere (vacuum pump 2 mmHg at rt) to give the aldehyde
12 (pure by 1H NMR analysis) 1.37 g (99%): Rf 0.28-0.35
oil. Data for 9: Rf 0.55 (Hex-EtOAc 50:50); [R]23 -74.4 (c
D
1.8, CHCl3); FTIR (film) νmax 2950, 1746, 1544, 1358, 1186,
1
1010 cm-1; H NMR (CDCl3, 400 MHz) δ 7.92 (2H, d, J ) 8.9
Hz), 7.39 (1H, m), 7.34 (2H, m), 4.87 (1H, d, J ) 8.9 Hz), 4.45
(1H, dd, J ) 10.0, 8.0 Hz), 3.67 (3H, s), 1.94 (1H, m), 0.96 (3H,
d, J ) 6.5 Hz), 0.93 (3H, d, J ) 6.4 Hz); 13C NMR (CDCl3, 100
MHz) δ 170.7, 166.8, 131.9, 128.7, 128.4, 127.4, 87.7, 70.6, 52.3,
29.4, 19.8, 18.9; LRMS (m/z) 248.1 (M + H+) (100), 171.1 (90),
158.3 (20); EIMS m/z calcd for C14H17NO3 247.2897, found
247.2892.
(Hex-EtOAc 50:50, decomposes on TLC); [R]23 -3.4 (c 1.7,
D
CHCl3); FTIR (film) νmax 2943, 2860, 1728, 1608, 1416, 1228,
1
cm-1; H NMR (CDCl3, 400 MHz) δ 9.71 (1H, s), 7.91 (2H, d,
J ) 8.1 Hz), 7.42 (1H, m), 7.34 (2H, m), 4.84 (1H, d, J ) 8.4
Hz), 3.70 (3H, s), 2.01 (1H, m), 1.03 (3H, d, J ) 6.4 Hz), 0.87
(3H, d, J ) 6.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 192.2, 168.3,
167.3, 132.5, 128.8, 128.5, 126.9, 86.8, 85.3, 53.0, 41.0, 29.4,
19.2, 19.1; LRMS (m/z) 276.1 (45) (M+), 249.1 (20), 220.2 (100)
(45), 171.1 (20), 133.3 (35).
Met h yl (4R,5S)-5-Isop r op yl-2-p h en yl-4,5-d ih yd r oox-
a zole-4-ca r boxyla te, 10. A solution of oxazoline 9 (11.8 g,
48.0 mmol) in CH2Cl2 (100 mL) was treated with 1,8-
diazabicyclo[5.4.0]undec-7-ene (360 µL, 2.4 mmol) at room
temperature. After 12 h, the reaction mixture was diluted with
ether (250 mL) and washed with water (3×) and brine. The
organic layer was dried over Na2SO4, and removal of the
solvent in vacuo afforded the crude trans-oxazoline 10 (11.4
g, 96%) as a yellow viscous oil. A small amount of compound
was purified by flash column chromatography (eluent 10-60%
EtOAc-hexane) to give pure compound for analytical pur-
poses. Data for 10: Rf 0.50 (Hex-EtOAc 50:50); [R]23D -106.8
(c 3.0, CHCl3); FTIR (film) νmax 2964, 1746, 1644, 1256, 938
Con ver sion of Ald eh yd e 12 to Ald ol P r od u ct 13. A
solution of LiClO4 (580 mg, 5.5 mmol) in CH2Cl2 (20 mL) was
treated with freshly prepared aldehyde 12 (1.37 g, 5.0 mmol)
at 0 °C, and the dimethyl ketene acetal (10 mL, 1 M solution
in CH2Cl2, 10.0 mmol) was added dropwise at this tempera-
ture. After 5 h, the reaction mixture was quenched with
saturated NaHCO3 (20 mL), the aqueous layer was extracted
with CH2Cl2 (3 × 25 mL), and the combined organic layers
were washed with water and brine and dried over Na2SO4.
The crude product was obtained by solvent removal and
purified by silica gel column to give the pure aldol product 13
(1.3 g, 67%) as a single diastereomer. Data for 13: Rf 0.50
1
cm-1; H NMR (CDCl3, 400 MHz) δ 7.98 (2H, d, J ) 6.8 Hz),
7.47 (1H, m), 7.39 (2H, m), 4.66 (1H, apparent t, J ) 6.4 Hz),
4.56 (1H, d, J ) 6.8 Hz), 3.78 (3H, s), 1.94 (1H, m), 1.02 (3H,
d, J ) 6.8 Hz), 0.98 (3H, d, J ) 6.5 Hz); 13C NMR (CDCl3, 100
MHz) δ 172.3, 165.9, 131.9, 128.7, 128.5, 127.4, 87.3, 71.4, 52.8,
(Hex-EtOAc 60:40); [R]23 -18.2 (c 1.8, CHCl3); FTIR (film)
D
J . Org. Chem, Vol. 68, No. 7, 2003 2763