Formal total synthesis of haouamine A

Article abstract of DOI:10.1021/jo802787j

A synthesis of the indenotetrahydropyridine unit of haouamine A is described. The construction of a diaryl quaternary center and tricyclic framework of this compound was achieved by an intramolecular cascade Mizoroki-Heck reaction.

Full text of DOI:10.1021/jo802787j

Formal Total Synthesis of Haouamine A
Tsuyoshi Taniguchi, Hisaaki Zaimoku, and Hiroyuki Ishibashi*
School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health
Sciences, Kanazawa University, Kanazawa 920-1192, Japan
isibasi@p.kanazawa-u.ac.jp
Supporting Information
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Table of Contents
General methods
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S3-S5
Experimental procedures for 4-8
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1H NMR and C NMR spectrum of 4
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1H NMR and C NMR spectrum of 5
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1H NMR and C NMR spectrum of 6
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S12-S13
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1H NMR and C NMR spectrum of 7
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1H NMR and C NMR spectrum of 8
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1H NMR and C NMR spectrum of 9
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1H NMR and C NMR spectrum of 10
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1H NMR and C NMR spectrum of 12
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1H NMR and C NMR spectrum of 13
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1H NMR and C NMR spectrum of 14
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General methods. Reactions were carried out in flame-dried glassware under
nitrogen atmosphere. Ether and THF were distilled over sodium/benzophenone.
Dichloromethane was distilled over calcium hydride. All reagents were purchased
commercially and used without further purification. Melting points are uncorrected. IR
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spectra were recorded on a commercial FT/IR spectrometer. H NMR spectra were
recorded at 500 MHz or 270 MHz spectrometer; chemical shifts (δ) are quoted relative
to tetramethylsilane. 13C NMR spectra were recorded at 125 MHz or 67.5 MHz
spectrometer with complete proton decoupling; chemical shift (δ) are quoted relative to
the residual signals of chloroform. Silica gel column chromatography was carried out on
silica gel 60N. Mass spectra were recorded on a high-resolution mass spectrometer in
electron impact mode.
tert-Butyl N-benzyl-N-[2-(2-iodo-3-methoxyphenyl)-1-methoxycarbonyl]ethyl-
carbamate (4). To a solution of 3 (1.80 g, 6.44 mmol) in THF (20 mL) was added
dropwise a 1.0 M solution of lithium hexamethyldisilazide (7.0 mL, 7.0 mmol) at -78
°C. After the mixture was stirred at the same temperature for 1 h, a solution of
2-iodo-3-methoxybenzyl bromide (2.40 g, 7.30 mmol) in THF (7 mL) was added, and
the mixture was warmed to room temperture. The reaction mixture was quenched with a
saturated NH4Cl solution and extracted with AcOEt, and the organic layer was washed
with brine. After drying (MgSO4), the mixture was concentrated and chromatographed
on silica gel (hexane/AcOEt, 6:1) to give 4 (2.95 g, 87%) as a colorless oil: IR (CHCl3)
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υ 1690, 1740 cm-1; rotamers of 4 were observed by H NMR and C NMR. H NMR
(270 MHz, CDCl3) δ 1.44, 1.49 (total 9H, both s), 3.32-3.86 (5H, m), 3.88 (3H, s),
4.24-4.40 (2H, m), 4.50 (1H, d, J = 15.2 Hz), 6.66-6.84 (2H, m), 7.09-7.23 (6H, m); 13C
NMR (67.8 MHz, CDCl3) δ 28.4, 41.0, 52.0, 56.44, 56.45, 58.3, 80.8, 109.1, 123.9,
127.1, 128.0, 128.7, 128.9, 129.1, 136.9, 142.3, 151.3, 155.1, 158.0, 171.1; HRMS
calcd for C23H28NIO5 525.1012, found: 525.1011.
tert-Butyl N-benzyl-N-[2-(2-iodo-3-methoxyphenyl)-1-(N’-methoxy-N’-methyl-
cabamoyl)]ethylcarbamate (5). To a solution of 4 (2.00 g, 3.81 mmol) and
N-methoxy-N-methylamine hydrochloride (557 mg, 5.71 mmol) in THF (30 mL) was
added a 1.0 M solution of lithium hexamethyldisilazide (11.2 mL, 11.4 mmol) at -78 °C,
and the mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with
a saturated NH4Cl solution and extracted with AcOEt, and the organic layer was washed
with brine. After drying (MgSO4), the mixture was concentrated and chromatographed
on silica gel (hexane/AcOEt, 3:1) to give 5 (1.98 g, 94%) as a colorless oil: IR (CHCl3)
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υ 1663, 1684 cm-1; rotamers of 5 were observed by H NMR and C NMR. H NMR
(500 MHz, CDCl3) δ 1.15, 1.25 (total 9H, both s), 2.66 (2/3 × 3H, br-s), 2.87 (1/3 × 3H,
br-s), 3.13 (1/3H, br-d, J = 14.6 Hz), 3.22-3.31 [(1 + 2/3)H, m], 3.56 (3H, s), 3.88 (3H,
s), 4.29 (2/3H, d, J = 15.3 Hz), 4.49 (1/3H, d. J = 15.3 Hz), 4.67 (1/3H, d, J = 15.3 Hz),
4.86 (2/3H, d, J = 15.3 Hz), 5.43 (2/3H, br), 5.72 (1/3H, br), 6.63-6.83 (2H, m),
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7.15-7.29 (6H, m); C NMR (125 MHz, CDCl3) δ 28.1, 31.7, 39.9, 45.9, 53.6, 56.5,
61.6, 79.6, 93.8, 109.2, 123.7, 126.7, 127.0, 127.9, 128.0, 138.5, 142.7, 155.2, 158.1;
HRMS calcd for C24H31N2IO5 554.1278, found: 554.1274.
tert-Butyl N-benzyl-N-[3-(2-iodo-3-methoxyphenyl)-1-(3-methoxyphenyl)]-
1-oxoprop-2-ylcarbamate (6). To a solution of 5 (1.70 g, 3.07 mmol) in Et2O (30 mL)
was added a 1.0 M solution of 3-methoxyphenylmagnesium bromide (6.0 mL, 6.00
mmol) at room temperature, and the mixture was heated at reflux for 1 h. The reaction
mixture was quenched with saturated NH4Cl solution and extracted with AcOEt, and the
organic layer was washed with brine. After drying (MgSO4), the mixture was
concentrated and chromatographed on silica gel (hexane/AcOEt, 6:1) to give 6 (1.42 g,
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77%) as a colorless oil: IR (CHCl3) υ 1685 cm-1; rotamers of 6 were observed by H
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NMR and 13C NMR. H NMR (500 MHz, CDCl3) δ 1.25, 1.29 (total 9H, both s),
3.28-3.38 [(1 + 3/5)H, m), 3.46 (2/5H, dd, J = 13.9, 5.6 Hz), 3.74, 3.77 (total 3H, both
br-s), 3.85, 3.89 (total 3H, both br-s), 4.30-4.34 [(1 + 3/5)H, m), 4.48 (2/5H, d, J = 15.4
Hz), 5.85 (3/5H, dd, J = 10.0, 4.6 Hz), 6.04 (2/5H, t, J = 6.6 Hz), 6.64-7.42 (12H, m);
13C NMR (125 MHz, CDCl3) δ 28.06, 28.13, 39.5, 39.7, 47.6, 48.6, 55.2, 55.3, 56.5,
58.4, 58.8, 80.5, 80.8, 101.5, 106.2, 107.8, 109.1, 109.2, 111.9, 112.7, 119.4, 120.4,
120.7, 121.0, 123.2, 123.7, 126.6, 126.8, 127.4, 127.9, 128.4, 128.7, 129.0, 129.2, 130.0,
137.7, 142.7, 158.2, 159.6, 197.6; HRMS calcd for C29H32NIO5 601.1325, found:
601.1319.
tert-Butyl N-benzyl-N-[1-(2-iodo-3-methoxyphenyl)-3-(3-methoxyphenyl)]-
but-3-en-2-ylcarbamate (7). To a suspension of methyltriphenylphosphonium bromide
(2.50 g, 7.00 mmol) in THF (30 mL) was added dropwise a 0.5 M solution of potassium
hexamethyldisilazide (14.0 mL, 7.00 mmol) at -78 °C. After the yellow suspension was
stirred for 15 min at the same temperature, a solution of 6 (1.40 g, 2.33 mmol) in THF
(10 mL) was added and the mixture was stirred at room temperature for 1 h. The
reaction mixture was quenched with saturated a NH4Cl solution and extracted with
AcOEt, and the organic layer was washed with brine. After drying (MgSO4), the
mixture was concentrated and chromatographed on silica gel (hexane/AcOEt, 7:1) to
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give 7 (1.31 g, 94%) as a colorless oil: IR (CHCl3) υ 1682 cm-1; rotamers of 7 were
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observed by H NMR and C NMR. H NMR (500 MHz, CDCl3) δ 1.18 (9H, s), 3.11
(1H, br-t, J = 12.5 Hz), 3.28 (1H, br-d, J = 12.0 Hz), 3.73 (3H, br-s), 3.88 (3H, br-s),
4.17, 4.32 (total 2H, both br), 5.36 (1H, br-s), 5.50 (1H, s), 5.60-5.71 (1H, m), 6.43-7.20
(12H, m); 13C NMR (125 MHz, CDCl3) δ 28.1, 41.9, 46.5, 55.1, 56.5, 56.9, 79.5, 93.9,
109.0, 112.9, 115.4, 119.2, 123.4, 126.4, 127.3, 127.8, 128.2, 128.7, 128.8, 139.3, 141.8,
143.4, 158.1, 159.4; HRMS calcd for C30H34NO4I 599.1533, found: 599.1530.
N-Benzyl-N-[1-(2-iodo-3-methoxyphenyl)-3-(3-methoxyphenyl)]but-3-en-
2-yl-2-phenylacrylamide (8). To a solution of 7 (1.25 g, 2.09 mmol) in CH2Cl2 (8 mL)
was added trifluoroacetic acid (8 mL) at 0 °C, and the mixture was further stirred at the
same temperature for 1 h. The reaction mixture was basified with a saturated NaHCO3
solution and extracted with CH2Cl2, and the organic layer was washed with brine. After
drying (MgSO4), the mixture was concentrated to give crude amine as a brown oil. To a
solution of the crude material, triethylamine (633 mg, 6.26 mmol) and
N,N-dimethylaminopyridine (128 mg, 1.04 mmol) in CH2Cl2 (20 mL) were added
cinnamoyl chloride (522 mg, 3.13 mmol) at 0 °C, and the mixture was further stirred at
room temperture for 2 h. The reaction mixture was diluted with a saturated NaHCO3
solution and extracted with CH2Cl2, and the organic layer was washed with brine. After
drying (MgSO4), the mixture was concentrated and chromatographed on silica gel
(hexane/AcOEt, 4:1) to give 8 (1.16 g, 89%) as a colorless amorphous solid: IR (CHCl3)
1
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υ 1601, 1646 cm-1; rotamers of 8 were observed by H NMR and C NMR. H NMR
(500 MHz, CDCl3) δ 3.19 (2/3H, dd, J = 13.4, 10.7 Hz), 3.30 (1/3H, dd, J = 13.4, 10.7
Hz), 3.33 (1/3H, s, dd, J = 13.4, 10.7 Hz), 3.45 (2/3H, dd, J = 13.7, 2.4 Hz), 3.51 (2/3 ×
3H, s), 3.62 (2/3 × 3H, s), 3.76 (1/3 × 3H, s), 3.85 (1/3 × 3H, s), 4.55-4.58 [(1 + 1/3)H,
m], 4.67 (2/3H, d, J = 14.6 Hz), 5.35 (1/3H, s), 5.56 (2/3H, s), 5.58 (1/3H, s), 5.63
(2/3H, s), 6.28 (2/3H, d, J = 7.6 Hz), 6.34 (2/3H, d, J = 15.1 Hz), 6.39-6.46 (1H, m),
6.53 (1/3H, d, J = 15.1 Hz), 6.63-7.33 (17H, m), 7.56 (1/3H, d, J = 15.1 Hz); 13C NMR
(125 MHz, CDCl3) δ 42.2, 42.4, 45.9, 48.3, 55.0, 55.2, 56.0, 56.4, 58.9, 93.2, 108.9,
109.5, 111.8, 112.1, 113.9, 114.1, 116.8, 116.9, 117.4, 118.7, 118.9, 119.1, 122.1, 124.0,
126.5, 126.7, 126.9, 127.7, 127.8, 128.0, 128.4, 128.5, 128.6, 128.8, 128.9, 129.1, 129.3,
129.4, 135.3, 137.7, 138.8, 141.3, 141.6, 142.1, 142.7, 147.6, 158.0, 159.5, 167.3,
168.3; HRMS calcd for C34H32NIO3 629.1427, found: 629.1426.
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