P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
6355
13
73.8, 71.7, 59.9, 59.3, 56.3, 48.2, 27.1, 25.4, 8.5 ppm; HRMS calcd. For
C41H47N2O7S (MHþ) 711.3104 Da. Found 711.3113 Da.
s), 1.32 (C24, 9H, s) ppm; C NMR (125 MHz, toluene-d8, 100 ꢂC):
167.8, 153.6, 152.4, 151.5, 145.7, 139.7, 138.3, 137.9, 137.5, 135.3, 132.7
(C16), 129.3, 128.9, 128.6, 128.4, 128.0, 127.7, 127.4, 125.5, 124.8,
124.7, 116.1 (C17), 81.3 (C23), 75.5 (C20), 73.9 (C18), 73.6 (C19), 60.6
(C5-OMe), 60.2 (C7-OMe), 58.6 (C3), 57.8 (C13), 50.6 (C1), 41.2
(C15), 28.5 (C24), 28.2 (C4), 9.6 (C6-Me) ppm; HRMS calcd for
C44H51N2O7S (MHþ) 751.3417 Da. Found 751.3419 Da.
4.2. Synthesis of ( )-lemonomycinone amide (8)
4.2.1. Allyl alkylated product 47. To a stirred solution of thioaminal
46 (30 mg, 0.042 mmol) in THF (0.33 mL) at ꢁ78 ꢂC was added
LiHMDS (0.57 M in THF, 86 mL, 0.049 mmol) dropwise within
5 min. The yellow solution was stirred for 15 min at ꢁ78 ꢂC, and
allyl bromide (4.1 mL, 0.049 mmol) added. After 20 min the re-
action was quenched with satd aq NH4Cl (5 mL) and extracted with
EtOAc (2ꢃ10 mL). The combined extracts were washed with satd aq
NaCl (5 mL), dried (Na2SO4), filtered, and concentrated under vac-
uum. The resulting pale yellow oil was purified by flash column
chromatography (SiO2, 10e30% EtOAcehexane) to afford product
47 (22 mg, 70% yield) as a white solid: recrystallized from benzene
and hexanes; X-ray (CCDC 28815); mp 119e122 ꢂC; Rf¼0.38 (30%
EtOAc in hexanes); IR (thin film): 2976, 2935, 2865, 1703, 1661,
4.2.3. Alkylated product 50. To a stirred solution of thioaminal 46
(3.04 g, 4.28 mmol) in THF (21 mL) at ꢁ78 ꢂC was added KHMDS
(0.5 M in toluene, 10.3 mL, 5.14 mmol) dropwise within 5 min. The
pale orange clear solution was stirred for 5 min and iodide 49 (1.9 g,
5.56 mmol) was added dropwise. No color change was observed.
The reaction appeared complete by TLC analysis after 10 min. The
reaction was quenched with water (10 mL), diluted with satd aq
NH4Cl (75 mL), and extracted with EtOAc (3ꢃ150 mL). The com-
bined extracts were washed with satd aq NaCl (100 mL), dried
(Na2SO4), filtered, and concentrated under vacuum. The resulting
pale yellow oil was purified by flash column chromatography (SiO2,
5e10% EtOAcehexane) to afford alkylated product 51 (3.10 g, 78%
yield) as a colorless oil and starting material 46 (0.31 g, 10% yield).
Compound 50: Rf¼0.34 (20% EtOAc in hexanes); IR (thin film):
2940, 2865, 1701, 1663, 1457, 1414, 1367, 1337, 1304, 1164,
1455, 1414, 1368, 1338, 1289, 1163, 1115 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): 7.57e7.15 (15H, m), 5.92 (1H, t, J¼5.2 Hz), 5.73e5.54 (2H,
m), 5.06e4.92 (4H, m), 4.53e4.36 (3H, m), 3.85e3.77 (6H, m),
3.71e3.52 (4H, m), 3.26e3.10 (1H, m), 3.05e2.85 (1H, m), 2.66 (1H,
br s), 2.25 (3H, s), 1.41 (4.5H, s), 1.14 (4.5H, s) ppm; 1H NMR
(500 MHz, toluene-d8, 100 ꢂC): 7.55 (PhS-ortho, 2H, d, J¼6.7 Hz),
7.10e6.94 (13H, m), 6.23 (C1, 1H, t, J¼5.2 Hz), 5.79e5.71 (C11, C16,
2H, m), 5.07 (C20, 1H, d, J¼11.0 Hz), 4.99 (C20, 1H, d, J¼11.0 Hz),
4.98e4.95 (C17-Ha, 1H, m), 4.83e4.80 (C17-Hb, 1H, m), 4.59 (C13,
1H, br s), 4.41 (C19, 1H, d, J¼12.0 Hz), 4.34 (C19, 1H, d, J¼12.1 Hz),
4.03 (C18, 2H, d, J¼5.0 Hz), 3.85e3.80 (C3, 1H, m), 3.61 (C7-OMe,
3H, s), 3.40e3.34 (C4-Ha, 1H, m), 3.36 (C5-OMe, 3H, s), 2.98 (C4-Hb,
1H, dd, J¼14.7, 3.4 Hz), 2.80e2.73 (C15, 2H, m), 2.23 (C6-Me, 3H, s),
1106 cmꢁ1 1H NMR (300 MHz, CDCl3): 7.60e7.15 (15H, m), 5.98
;
(1H, t, J¼5.3 Hz), 5.71 (1H, br s), 5.03 (2H, s), 4.51 (2.5H, br s), 4.30
(0.5H, br s), 3.95e3.84 (2H, m), 3.82 (3H, s), 3.64e3.54 (6H, m),
3.23e3.14 (1.5H, m), 3.02e2.90 (0.5H, m), 2.27 (3H, s), 2.05e1.95
(1H, m), 1.80e1.48 (3H, m), 1.42 (6H, br s), 1.16 (3H, br s), 1.06e0.99
(21H, m) ppm; 13C NMR (75 MHz, CDCl3): 168.3, 151.1, 150.2, 145.3,
138.3, 137.4, 134.6, 133.1, 128.9, 128.8, 128.4, 128.2, 128.1, 128.0,
127.8, 127.7, 127.3, 127.2, 126.9, 124.6, 122.8, 81.1, 74.7, 72.4, 62.9,
60.7, 60.0, 55.7, 48.4, 28.1, 27.9,17.8,17.5,13.5,11.7, 9.2 ppm; 1H NMR
(500 MHz, DMSO-d6, 90 ꢂC): 7.52 (2H, d, J¼7.6 Hz), 7.43 (2H, d,
J¼7.2 Hz), 7.39e7.27 (6H, m), 7.19e7.16 (3H, m), 7.11e7.09 (2H, m),
5.83 (1H, t, J¼5.4 Hz), 5.79 (1H, s), 4.99 (1H, d, J¼10.9 Hz), 4.91 (1H,
d, J¼10.9 Hz), 4.42 (1H, d, J¼12.3 Hz), 4.39 (1H, d, J¼12.1 Hz), 4.14
(1H, dd, J¼7.5, 4.2 Hz), 3.95 (1H, ddd, J¼11.9, 4.0, 1.6 Hz), 3.78e3.74
(1H, m), 3.76 (3H, s), 3.64 (1H, dd, J¼9.4, 6.9 Hz), 3.61e3.59 (2H, m),
3.60 (3H, s), 3.19 (1H, br s), 3.05e2.99 (1H, m), 2.18 (3H, s),
1.90e1.78 (2H, m),1.61e1.54 (1H, m),1.48e1.39 (1H, m),1.27 (9H, s),
1.01e0.91 (21H, m) ppm; HRMS calcd for C53H73N2O8SiS (MHþ)
925.4857 Da. Found 925.4833 Da.
13
1.24 (C24, 9H, s) ppm; C NMR (125 MHz, toluene-d8, 100 ꢂC):
168.2, 153.5, 151.5, 146.1, 139.8, 138.5, 137.9, 137.5, 135.2, 134.8, 134.4
(C16), 129.3, 128.9, 128.6, 128.4, 128.0, 127.7, 127.3, 125.5, 124.8,
124.1, 118.1 (C17), 81.2 (C23), 75.8 (C20), 73.7 (C18), 73.4 (C19), 69.5
(C11), 60.5 (C5-OMe), 60.1 (C7-OMe), 59.1 (C13), 56.9 (C3), 50.3
(C1), 38.9 (C15), 28.4 (C24), 9.6 (C6-Me) ppm; HRMS calcd for
C44H51N2O7S (MHþ) 751.3417 Da. Found 751.3410 Da.
4.2.2. Epimer product 48. To a solution of 47 (75 mg, 0.10 mmol) in
THF (1.2 mL) at ꢁ78 ꢂC was added t-BuLi (0.9 M in pentane,
0.28 mL, 0.25 mmol). Upon addition of t-BuLi the solution became
orange in color. Within 10 s of complete t-BuLi addition the reaction
was quenched with a solution of butylated hydroxytoluene (0.110 g,
0.50 mmol) in THF (0.5 mL) and the solution became pale yellow in
color. The solution was diluted with H2O (10 mL) and extracted
with EtOAc (3ꢃ10 mL). The extracts were combined, washed with
satd aq NaCl (15 mL), dried (Na2SO4), filtered, and concentrated
under vacuum. The residue was purified by flash column chroma-
tography (SiO2, 10e20% EtOAcehexane) to yield 48 (0.145 g, 73%
yield) as a colorless oil: Rf¼0.41 (30% EtOAc in hexanes); IR (thin
film): 2977, 2935, 2863, 1696, 1653, 1455, 1413, 1382, 1316, 1162,
4.2.4. epi-50. To
a stirred, degassed solution of 50 (0.20 g,
0.22 mmol) in THF (2.2 mL) at ꢁ78 ꢂC was added t-BuLi (1.2 M in
pentane, 0.40 mL, 0.48 mmol). Upon addition of t-BuLi the solution
became brown/orange in color. Within 10 s of complete t-BuLi ad-
dition the reaction was quenched with a solution of butylated
hydroxytoluene (0.19 g, 0.86 mmol) in THF (0.5 mL) and the solu-
tion became pale yellow in color. The solution was diluted with H2O
(15 mL) and extracted with EtOAc (3ꢃ15 mL). The extracts were
combined, washed with satd aq NaCl (15 mL), dried (Na2SO4), fil-
tered, and concentrated under vacuum. The residue was purified by
flash column chromatography (SiO2, very slow gradient of
5e10e20% EtOAcehexane) to yield epi-50 (0.145 g, 73% yield) as
a colorless oil: Rf¼0.38 (20% EtOAc in hexanes); IR (thin film): 2941,
1117 cmꢁ1
;
1H NMR (300 MHz, CDCl3): 7.47e7.45 (2H, m),
7.35e7.23 (8H, m), 7.22e7.15 (5H, m), 6.17 (0.5H, s), 6.08e5.94
(0.5H, m), 5.93e5.73 (2H, m), 5.01e4.93 (3H, m), 4.91e4.79 (1H, m),
4.56e4.51 (0.5H, m), 4.47 (2H, s), 4.44e4.40 (0.5H, m), 3.81 (3H, s),
3.76 (1.0H, d, J¼5.2 Hz), 3.68 (1.0H, d, J¼3.9 Hz), 3.65e3.45 (4H, m),
3.20e2.91 (3H, m), 2.80e2.61 (1H, m), 2.22 (3H, s), 1.40 (6H, s), 1.27
2865, 1698, 1653, 1456, 1414, 1384, 1367, 1310, 1163, 1116 cmꢁ1 1H
;
NMR (300 MHz, CDCl3): 7.52e7.47 (2H, m), 7.37e7.19 (13H, m), 6.17
(0.5H, s), 5.85e5.79 (1.5H, m), 5.06e4.96 (2H, m), 4.50e4.45 (2.5H,
m), 4.34e4.30 (0.5H, m), 3.83 (3H, s), 3.79e3.48 (8H, m), 3.20e2.97
(2H, m), 2.38e2.10 (2H, m), 2.25 (3H, s), 2.05e1.84 (2H, m),1.43 (6H,
br s), 1.27 (3H, br s), 1.07e0.94 (21H, m) ppm; 13C NMR (75 MHz,
CDCl3): 168.3, 153.3, 151.0, 150.2, 144.6, 138.5, 137.1, 133.3, 131.2,
128.8, 128.7, 128.5, 128.3, 128.1, 127.8, 127.7, 127.2, 126.9, 126.8,
124.4, 123.8, 81.3, 74.4, 72.7, 72.3, 63.3, 62.2, 60.8, 60.2, 57.7, 56.7,
49.4, 33.1, 31.8, 31.4, 27.9, 27.7, 26.8, 17.9, 11.8, 9.2 ppm; 1H NMR
1
(3H, s) ppm; H NMR (500 MHz, toluene-d8, 100 ꢂC): 7.52 (PhS-or-
tho, 2H, d, J¼7.7 Hz), 7.09e6.95 (13H, m), 6.26 (C16, 1H, br s), 6.12
(C1, 1H, t, J¼4.8 Hz), 6.08 (C11, 1H, br s), 5.08 (C17-Ha, 1H, d,
J¼16.5 Hz), 5.03 (C20, 2H, s), 4.99 (C17-Hb, 1H, d, J¼9.4 Hz), 4.50
(C13, 1H, br s), 4.40 (C19, 1H, d, J¼12.0 Hz), 4.30 (C19, 1H, d,
J¼12.1 Hz), 3.98 (C18, 1H, dd, J¼9.9, 5.3 Hz), 3.83 (C18, 1H, dd, J¼9.8,
4.0 Hz), 3.66 (C7-OMe, 3H, s), 3.36 (C5-OMe, 3H, s), 3.35e3.29 (C15,
C3, C4-Ha, 3H, m), 2.97e2.87 (C15, C4-Hb, 2H, m), 2.25 (C6-Me, 3H,