ConVergent Total Synthesis of (+)-Mycalamide A
Data for 18a: [R]27 +19.09° (c 0.54, CHCl3); IR (neat) 1735
3-(2-Oxocyclooctanyl)-3-phenylpropan-1-al (21, n ) 2). IR
D
cm-1; H NMR (500 MHz, CDCl3) δ 0.06 (s, 9 H), 1.08 (s, 9 H),
(neat) 2855, 1722, 1701, 1452, 702 cm-1; H NMR (400 MHz,
1
1
1.13 (s, 3 H), 1.23 (s, 3 H), 3.60 (s, 3 H), 3.82 (dd, J ) 4.4, 5.5
Hz, 1 H), 3.87 (dd, J ) 4.8, 11.0 Hz, 1 H), 3.89 (t, J ) 4.8 Hz, 1
H), 3.93 (dd, J ) 5.1, 11.0 Hz, 1 H), 4.23 (q, J ) 5.3 Hz, 1 H),
4.45 (d, J ) 5.1 Hz, 1 H), 4.50 (d, J ) 11.7 Hz, 1 H), 4.64 (d, J
) 11.7 Hz, 1 H), 4.77 (d, J ) 5.9 Hz, 1 H), 5.15 (d, J ) 5.9 Hz,
1 H), 7.24-7.44 (m, 11 H), 7.67-7.71 (m, 4 H); 13C NMR (125
MHz, CDCl3) δ 177.5, 138.2, 135.8, 135.7, 133.4, 133.2, 129.9,
128.4, 128.0, 127.9, 127.8, 127.8, 89.9, 75.9, 74.5, 74.3, 71.9, 71.9,
62.7, 51.9, 47.7, 27.0, 21.9, 21.9, 19.4, 0.9; LRMS m/z 649 (M+ -
15); HRMS calcd for C36H49O7Si2: 649.3014, found: 649.3011;
Anal. Calcd for C37H52O7Si2: C, 66.82; H, 7.88. Found: C, 66.84;
H, 7.98.
CDCl3) δ 1.20-1.50 (m, 5 H), 1.53-1.71 (m, 4 H), 1.83-1.94
(m, 2 H), 1.99-2.06 (m, 1 H), 2.23-2.31 (m, 0.3 H), 2.47 (ddd, J
) 3.4, 12.4, 15.6 Hz, 0.3 H), 2.64 (ddd, J ) 1.7, 3.9, 6.4 Hz, 0.7
H), 2.73 (ddd, J ) 2.4, 9.5, 16.8 Hz, 0.7 H), 2.94 (ddd, J ) 1.5,
5.4, 16.8 Hz, 1 H), 3.03 (ddd, J ) 3.4, 9.0, 12.0 Hz, 1 H), 3.42
(ddd, J ) 5.4, 8.8, 14.2 Hz, 0.3 H), 3.50 (ddd, J ) 5.6, 9.3, 14.6
Hz, 0.7 H), 7.12-7.33 (m, 5 H), 9.47 (dd, J ) 1.7, 2.2 Hz, 0.3 H),
9.60 (dd, J ) 1.4, 2.4 Hz, 0.7 H); LRMS m/z 258 (M+); HRMS
calcd for C17H22O2: 258.1619, found: 258.1621.
(4S,5R)-3-(1-Oxo-2-methyl-3-phenylpentan-4-alyl)-4-methyl-
5-phenyl-1,3-oxazolidin-2-one (23). To a mixture of oxazolidinone
22 (57.5 mg, 0.247 mmol), Yb(OTf)3 (15.3 mg, 0.0247 mmol, 10
mol %), and 4 Å molecular sieves (0.30 g) in CH2Cl2 (2 mL) were
added TMSCl (68.9 µL, 0.543 mmol) and benzaldehyde (27.6 µL,
0.271 mmol). The solution was cooled to 0 °C, and Et3N (0.344
mL, 2.47 mmol) was added. The resulting solution was stirred for
65 h and then poured into a slurry of SiO2 (10 mL) in hexanes-
EtOAc (2:1, 15 mL). The resulting suspension was vigorously
stirred for 15 min and filtered through Celite. The filtrate was
concentrated to give a crude oil. Purification of the crude product
by chromatography (33% EtOAc-hexane) provided aldehyde 23
(40.7 mg, 45%) as a colorless oil.
Data for 18b: [R]27 -6.03° (c 1.03, CHCl3); IR (neat) 3500,
D
1720 cm-1; H NMR (300 MHz, CDCl3) δ 1.08 (s, 9 H), 1.17 (s,
1
3 H), 1.19 (s, 3 H), 3.50 (d, J ) 3.8 Hz, 1 H), 3.63 (s, 3 H), 3.74
(t, J ) 3.3 Hz, 1 H), 3.84-3.91 (m, 4 H), 4.16-4.21 (m 1 H),
4.51 (d, J ) 11.5 Hz, 1 H), 4.72 (d, J ) 11.8 Hz, 1 H), 4.86 (d, J
) 5.8 Hz, 1 H), 5.00 (d, J ) 5.8 Hz, 1 H), 7.27-7.48 (m, 11 H),
7.64-7.67 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 177.7, 137.4,
135.7, 135.7, 133.0, 133.0, 130.0, 128.6, 128.3, 128.2, 128.0, 89.4,
76.2, 74.9, 74.5, 72.2, 71.7, 62.4, 51.9, 46.4, 26.8, 21.8, 21.6, 19.1;
LRMS m/z 535 (M+ - 57); HRMS calcd for C30H35O7Si: 535.2150,
found: 535.2147; Anal. Calcd for C34H44O7Si: C, 68.88; H, 7.48.
Found: C, 68.79; H, 7.46.
Representative Procedure for Cross-Aldol Reactions. To a
suspension of Yb(OTf)3 (60.0 mg, 0.0965 mmol) and chlorotri-
methylsilane (0.37 mL, 2.90 mmol) in CH2Cl2 (8 mL) was added
a solution of cyclohexanone (0.096 mL, 0.965 mmol) in CH2Cl2
(2 mL) followed by triethylamine (0.50 mL, 3.62 mmol). After 40
min, benzaldehyde (0.10 mL, 0.98 mmol) was added, and the
resulting solution was stirred for 37 h. A solution of NaHCO3 (10
mL, saturated) was added, and the biphasic solution was poured
into EtOAc (20 mL). The layers were separated, and the aqueous
layer was further extracted with EtOAc (2 × 20 mL). The combined
organic extracts were washed with brine (30 mL), dried (MgSO4),
and concentrated to provide a brown oil. The crude product was
purified by flash chromatography. Elution with a 99:1 mixture of
hexanes-EtOAc afforded the corresponding ether (0.187 g, 70%).
Elution with a 4:1 mixture of hexanes-EtOAc afforded the alcohol
(4.7 mg, 2%) as a colorless oil.
Data for a Major Isomer of 23: IR (neat) 1778, 1730, 1693,
1454, 1344, 1196, 764, 702 cm-1; 1H NMR (300 MHz, CDCl3) δ
0.94 (d, J ) 6.6 Hz, 3 H), 1.00 (d, J ) 6.9 Hz, 3 H), 2.64 (ddd, J
) 1.8, 4.5, 15.9 Hz, 1 H), 2.88 (ddd, J ) 2.4, 9.9, 15.9 Hz, 1 H),
3.55 (dt, J ) 4.8, 10.2 Hz, 1 H), 4.21 (qd, J ) 6.0, 9.3 Hz, 1 H),
4.80 (qd, 6.0, 7.2 Hz, 1 H), 5.68 (d, J ) 7.4 Hz, 1 H), 7.22-7.47
(m, 10 H), 9.53 (t, J ) 2.2 Hz, 1 H); 13C NMR (100 MHz, CDCl3)
δ 200.9, 175.8, 152.7, 140.5, 132.9, 128.8, 128.7, 128.7, 128.3,
127.2, 125.5, 78.9, 55.2, 48.0, 43.4, 42.5, 16.6, 14.7; LRMS m/z
365 (M+); HRMS calcd for C22H23NO4: 365.1627, found: 365.1631.
Data for a Minor Isomer of 23: IR (neat) 1776, 1722, 1697,
1
1342, 1196, 765, 700 cm-1; H NMR (300 MHz, CDCl3) δ 0.19
(d, J ) 6.6 Hz, 3 H), 1.17 (d, J ) 6.9 Hz, 3 H), 2.73-2.78 (m, 2
H), 3.55 (dt, J ) 5.5, 9.0 Hz, 1 H), 4.28 (qd, J ) 6.9, 9.3 Hz, 1 H),
4.51 (qd, J ) 6.6, 7.2 Hz, 1 H), 5.45 (d, J ) 7.4 Hz, 1 H), 7.01-
7.33 (m, 10 H), 9.52 (t, J ) 2.2 Hz, 1 H); 13C NMR (100 MHz,
CDCl3) δ 200.8, 175.3, 152.5, 141.3, 133.1, 128.6, 128.5, 128.4,
128.2, 126.9, 125.5, 78.5, 54.4, 46.2, 43.0, 42.4, 15.2, 13.8; LRMS
m/z: 365 (M+); HRMS calcd for C22H23NO4: 365.1627, found:
365.1630.
2-[Phenyl(trimethylsilyloxy)methyl]-cycloheptan-1-one (20, n
) 1). IR (neat) 1710, 1452, 1250, 1084, 1065, 876, 841, 752, 700
cm-1; 1H NMR (300 MHz, CDCl3) δ -0.02 (s, 5.4 H), 0.03 (s, 3.6
H), 1.07-1.29 (m, 2 H), 1.39-1.48 (m, 1 H), 1.54-1.69 (m, 2 H),
1.71-1.94 (m, 3 H), 2.38-2.64 (m, 2 H), 2.92 (ddd, J ) 4.1, 8.5,
12.4 Hz, 1 H), 4.95 (d, J ) 8.5 Hz, 0.6 H), 5.18 (d, J ) 4.4 Hz,
0.4 H), 7.24-7.36 (m, 5 H); LRMS m/z 290 (M+); HRMS calcd
for C17H26O2Si: 290.1701, found: 290.1706.
(+)-(2R,3R,4R,5S)-1-tert-Butyldiphenylsilyloxy-6,6-dimethyl-
3-hydroxy-5-methoxy-2,4-methylenedioxyoct-7-en-3-ol (26). Liq-
uid NH3 (30 mL) was distilled from Na (solid) via cannula to a
-78 °C flask, and Li (solid) (0.130 g, 6.92 mmol) was added,
immediately producing a blue solution. A solution of benzyl ether
25 (0.199 g, 0.346 mmol) in THF (9 mL) was added dropwise over
2 min. The mixture was stirred for 20 min, and then NH4Cl (solid)
was added until the blue color disappeared. The solution was
allowed to warm to room temperature, and then quenched by H2O.
The resulting solution was extracted with EtOAc (50 mL × 3).
The combined organic extracts were washed with brine, dried over
MgSO4, and concentrated to give a crude oil (0.176 g).
3-(2-Oxocycloheptanyl)-3-phenylpropan-1-al (21, n ) 1). IR
1
(neat) 2855, 1722, 1693, 1495, 1452, 702 cm-1; H NMR (400
MHz, CDCl3) δ 1.11-1.30 (m, 2 H), 1.37-1.50 (m, 2 H), 1.74-
1.94 (m, 4 H), 2.08 (ddd, J ) 3.2, 13.4, 15.1 Hz, 1 H), 2.22 (dddd,
J ) 1.0, 3.4, 6.3, 13.4 Hz, 0.9 H), 2.41-2.49 (m, 0.1 H), 2.54-
2.60 (m, 0.1 H), 2.71 (ddd, J ) 3.4, 5.4, 11.4 Hz, 1 H), 2.81 (ddd,
J ) 2.2, 8.8, 17.3 Hz, 1 H), 3.01 (ddd, J ) 1.5, 6.4, 17.3 Hz, 1 H),
3.50 (ddd, J ) 5.6, 8.6, 14.6 Hz, 0.1 H), 3.60 (ddd, J ) 5.8, 8.5,
11.7 Hz, 0.9 H), 7.12-7.36 (m, 5 H), 9.54 (dd, J ) 1.7, 2.0 Hz,
0.1 H), 9.65 (dd, J ) 1.5, 2.2 Hz, 0.9 H); LRMS m/z 244 (M+);
HRMS calcd for C16H20O2: 244.1462, found: 244.1459.
To a solution of the above product (0.176 g) in benzene (10
mL) was added DDQ (0.243 g, 1.04 mmol). The mixture was stirred
for 3.5 h, and then saturated NH4Cl was added. The resulting
solution was filtered through Celite, and the filtrate was extracted
with Et2O (60 mL × 3). The combined organic extracts were
washed with brine, dried over MgSO4, and concentrated to give a
crude oil. Purification of the crude product by flash chromatography
(13% EtOAc-hexane) provided alcohol 26 (0.124 g, 74% for two
steps) as a colorless oil.
2-[Phenyl(trimethylsilyloxy)methyl]-cyclooctan-1-one (20, n
) 2). IR (neat) 1705, 1452, 1250, 1060, 883, 843, 750, 700 cm-1
;
1H NMR (300 MHz, CDCl3) δ -0.10 (s, 6.3 H), -0.01 (s, 2.7 H),
1.06-2.00 (m, 10 H), 2.09-2.24 (m, 1 H), 2.34-2.50 (m, 1 H),
3.02 (ddd, J ) 3.3, 8.1, 11.1 Hz, 0.3 H), 3.11 (ddd, J ) 3.6, 9.6,
12.4 Hz, 0.7 H), 4.78 (d, J ) 8.2 Hz, 0.3 H), 4.79 (d, J ) 9.3 Hz,
0.7 H), 7.22-7.34 (m, 5 H); LRMS m/z 304 (M+); HRMS calcd
for C18H28O2Si: 304.1857, found: 304.1856.
Data for 26: [R]22 +10.28° (c 0.50, CHCl3); IR (neat) 3400,
D
1605 cm-1; H NMR (300 MHz, CDCl3) δ 1.05 (s, 9 H), 1.06 (s,
1
3 H), 1.09 (s, 3 H), 3.20 (d, J ) 4.9 Hz, 1 H), 3.25 (d, J ) 8.2 Hz,
1 H), 3.53 (s, 3 H), 3.82-3.94 (m, 4 H), 4.00-4.05 (m, 1 H), 4.79
J. Org. Chem, Vol. 71, No. 18, 2006 6803