PAPER
Synthetic Studies towards the Total Synthesis of Providencin
3813
1H NMR (400 MHz, CDCl3): d = 1.65 (s, 3 H, H–C13), 1.84–1.93
(m, 1 H, H–C2), 2.05–2.13 (m, 1 H, H–C11), 2.25–2.34 (m, 1 H, H–
C11), 2.60–2.76 (m, 3 H, H–C2, H–C3, H–C6), 2.77–2.87 (m, 1 H,
H–C6), 3.09 (t, J = 8.9 Hz, 1 H, H–C4), 3.26 (dd, J = 9.4, 5.0 Hz, 1
H, H–C4), 3.42–3.52 (m, 1 H, H–C7), 3.80 (s, 3 H, OCH3), 3.95–
4.01 (m, 1 H, H–C10), 4.20, 4.39 (AB, J = 11.6 Hz, 2 H,
CH2C6H4CH3), 4.65 (s, 1 H, H–C14), 4.75 (s, 1 H, H–C14), 5.34–
5.40 (m, 1 H, H–C1), 6.13 (ddd, J = 16.0, 4.5, 1.1 Hz, 1 H, H–C8),
6.51 (dt, J = 16.0, 6.0 Hz, 1 H, H–C9), 6.81–6.86 (m, 2 H,
C6H4CH3), 7.13–7.18 (m, 2 H, C6H4CH3), 7.19–7.25 (m, 9 H,
CPh3), 7.33–7.39 (m, 2 H, Ph), 7.41–7.45 (m, 6 H, CPh3), 7.48–7.53
(m, 1 H, Ph), 7.78–7.83 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): d = 23.2, 31.5, 31.6, 35.8, 37.2, 43.8,
55.7, 64.2, 69.3, 71.1, 76.9, 86.9, 113.8, 114.2, 127.4, 128.2, 128.7,
129.0, 129.7, 129.9, 130.3, 130.4, 130.6, 133.2, 141.6, 144.4, 145.8,
159.6, 166.1, 198.8.
ESI-HRMS: m/z [M + Na]+ calcd for C38H48O6Na: 743.3349; found:
743.3343.
C11), 2.28–2.43 (m, 1 H, H–C11), 2.57–2.77 (m, 2 H, H–C2, H–
C3), 2.84–3.00 (m, 1 H, H–C4), 3.17–3.39 (m, 2 H, H–C4, H–C7),
3.78–3.92 (m, 1 H, H–C10), 3.83 (s, 3 H, OCH3), 4.24, 4.46 (AB,
J = 11.6 Hz, 2 H, CH2C6H4CH3), 4.71 (s, 1 H, H–C14), 4.77 (s, 1 H,
H–C14), 5.25–5.58 (m, 4 H, H–C1, H–C5, H–C8, H–C9), 6.83–
6.91 (m, 2 H, C6H4CH3), 7.18–7.38 (m, 11 H, C6H4CH3, CPh3),
7.40–7.54 (m, 8 H, Ph, CPh3), 7.55–7.64 (m, 1 H, Ph), 7.90–7.99
(m, 2 H, Ph).
13C NMR (63 MHz, CDCl3): d = 21.6, 23.3, 29.5, 31.7, 32.9, 38.4,
44.4, 55.7, 64.5, 70.2, 70.3, 73.4, 77.7, 87.1, 113.2, 114.1, 127.4,
128.2, 128.8, 129.1, 129.7, 130.0, 130.6, 131.0, 131.5, 133.3, 134.0,
142.4, 144.5, 159.5, 166.3, 170.6.
ESI-HRMS: m/z [M + Na]+ calcd for C50H52O7Na: 787.3611; found:
787.3626.
(1SR,2RS,3RS)-2-{(E,5S)-2-Acetoxy-5-[(4-methoxybenzyl)oxy]-
7-methylocta-3,7-dienyl}-3-(hydroxymethyl)cyclobutyl Ben-
zoate (31)
Trityl ether 30 (72 mg, 0.094 mmol) in MeOH (2 mL) was detrity-
lated with TsOH (4 mg, 0.019 mmol) for 2 h at 25 °C. Workup as
described for 22 followed by chromatography (silica gel, hexane–
EtOAc, 1:2) gave 31 as an inseparable diastereomeric mixture. The
NMR data provided below are for the major diastereomer [Rf = 0.45
(hexane–EtOAc, 1:2)].
(1SR,2RS,3RS)-2-{(E,5S)-2-Hydroxy-5-[(4-methoxyben-
zyl)oxy]-7-methylocta-3,7-dienyl}-3-[(trityloxy)methyl]cyclo-
butyl Benzoate (29)
Ketone 28 (91 mg, 0.13 mmol) and CeCl3·H2O (48 mg, 0.13 mmol)
were stirred for 30 min in MeOH (4 mL) at –78 °C. NaBH4 (6 mg,
0.14 mmol) was added and the mixture was stirred for 3 h at –78 °C.
Usual workup with NH4Cl, H2O, and Et2O followed by chromatog-
raphy (silica gel, hexane–EtOAc, 1:1) gave 29 as an inseparable
diastereomeric mixture. The NMR data provided below are for the
major diastereomer [Rf = 0.38 (hexane–EtOAc, 1:1)].
Yield: 40 mg (81%); colorless oil.
IR (film): 3467, 2935, 2870, 1718, 1612, 1513, 1452, 1371 (m),
1275, 1248, 1175, 1111, 1071, 1027 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.70 (s, 3 H, H–C13), 1.86–2.03
(m, 3 H, H–C2, H–C6), 2.02 (s, 3 H, CH3CO), 2.11–2.27 (m, 1 H,
H–C11), 2.33–2.68 (m, 3 H, H–C2, H–C3, H–C11), 2.81–2.96 (m,
1 H, H–C7), 3.70–3.99 (m, 3 H, H–C4, H–C10), 3.82 (s, 3 H,
OCH3), 4.31, 4.49 (AB, J = 11.4 Hz, 2 H, CH2C6H4CH3), 4.72 (s, 1
H, H–C14), 4.78 (s, 1 H, H–C14), 5.28–5.40 (m, 1 H, H–C1), 5.41–
5.53 (m, 1 H, H–C5), 5.59–5.68 (m, 2 H, H–C8, H–C9), 6.83–6.92
(m, 2 H, C6H4CH3), 7.20–7.31 (m, 2 H, C6H4CH3), 7.42–7.52 (m, 2
H, Ph), 7.55–7.65 (m, 1 H, Ph), 8.02–8.13 (m, 2 H, Ph).
13C NMR (63 MHz, CDCl3): d = 21.6, 23.3, 29.7, 31.3, 34.3, 38.4,
44.4, 55.7, 63.5, 69.0, 70.4, 73.2, 77.7, 113.3, 114.2, 126.9, 128.8,
129.7, 130.0, 130.5, 131.2, 133.5, 134.0, 142.4, 159.5, 170.9.
ESI-HRMS: m/z [M + Na]+ calcd for C31H38O7Na: 545.2515; found:
545.2498.
Yield: 73 mg (78%); colorless oil.
IR (film): 3468, 3061, 2934, 2862, 1717, 1612, 1514, 1490, 1450,
1368, 1314, 1276, 1249, 1174, 1111, 1069, 1033 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.58–1.76 (m, 2 H, H–C6, OH),
1.70 (s, 3 H, H–C13), 1.76–1.96 (m, 2 H, H–C2, H–C6), 2.11–2.24
(m, 1 H, H–C11), 2.29–2.45 (m, 1 H, H–C11), 2.59–2.78 (m, 2 H,
H–C2, H–C3), 2.98–3.14 (m, 1 H, H–C4), 3.17–3.30 (m, 1 H, H–
C4), 3.31–3.41 (m, 1 H, H–C7), 3.82 (s, 3 H, OCH3), 3.84–3.95 (m,
1 H, H–C10), 4.06–4.21 (m, 1 H, H–C5), 4.31, 4.50 (AB, J = 11.4
Hz, 2 H, CH2C6H4CH3), 4.73 (s, 1 H, H–C14), 4.78 (s, 1 H, H–C14),
5.29–5.65 (m, 3 H, H–C1, H–C8, H–C9), 6.83–6.93 (m, 2 H,
C6H4CH3), 7.17–7.38 (m, 11 H, C6H4CH3, CPh3), 7.39–7.53 (m, 8
H, Ph, CPh3), 7.54–7.64 (m, 1 H, Ph), 7.87–7.97 (m, 2 H, Ph).
13C NMR (63 MHz, CDCl3): d = 23.3, 31.8, 32.0, 32.8, 38.5, 44.6,
55.7, 64.6, 70.2, 70.4, 71.3, 78.0, 87.2, 113.1, 114.1, 127.4, 128.2,
128.8, 129.0, 129.7, 129.9, 130.6, 131.2, 131.8, 133.4, 136.1, 142.5,
144.4, 159.5, 166.3.
ESI-HRMS: m/z [M + Na]+ calcd for C48H50O6Na: 745.3505; found:
745.3489.
(1SR,2RS,3RS)-2-{(E,5S)-2-Acetoxy-5-[(4-methoxybenzyl)oxy]-
7-methylocta-3,7-dienyl}-3-formylcyclobutyl Benzoate (32)
Alcohol 31 (14 mg, 0.027 mmol) was oxidized with NaHCO3 (10
mg, 0.122 mmol) and DMP (17 mg, 0.040 mmol) in CH2Cl2 (1 mL)
as described above for the synthesis of 17 from 15. Purification by
chromatography (silica gel, hexane–EtOAc, 2:1) gave aldehyde 32.
Yield: 12 mg (85%); colorless oil.
(1SR,2RS,3RS)-2-{(E,5S)-2-Acetoxy-5-[(4-methoxybenzyl)oxy]-
7-methylocta-3,7-dienyl}-3-[(trityloxy)methyl]cyclobutyl Ben-
zoate (30)
IR (film): 2930, 2855, 1717, 1649, 1611, 1512, 1451, 1375, 1315,
1277, 1246, 1178, 1118, 1072, 1027 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.66 (s, 3 H, H–C13), 1.88–1.99
(m, 2 H, H–C6), 2.04 (s, 3 H, CH3CO), 2.15 (dd, J = 13.9, 6.4 Hz,
1 H, H–C11), 2.36 (dd, J = 13.9, 7.3 Hz, 1 H, H–C11), 2.46–2.68
(m, 2 H, H–C2), 3.05–3.31 (m, 2 H, H–C3, H–C7), 3.79 (s, 3 H,
OCH3), 3.82–3.93 (m, 1 H, H–C10), 4.27, 4.45 (AB, J = 11.5 Hz, 2
H, CH2C6H4CH3), 4.69 (s, 1 H, H–C14), 4.75 (s, 1 H, H–C14),
5.21–5.32 (m, 1 H, H–C1), 5.33–5.44 (m, 1 H, H–C5), 5.53–5.59
(m, 2 H, H–C8, H–C9), 6.84, 7.20 (AA¢BB¢, J = 8.5 Hz, 4 H,
C6H4CH3), 7.40–7.50 (m, 2 H, Ph), 7.53–7.63 (m, 1 H, Ph), 8.00–
8.09 (m, 2 H, Ph), 9.99 (s, 1 H, CHO).
Alcohol 29 (82 mg, 0.11 mmol) in CH2Cl2 (5 mL) was treated with
Ac2O (32 mL, 0.34 mmol), Et3N (63 mL, 0.45 mmol), and DMAP (3
mg, 0.02 mmol) for 2 h at 25 °C. Usual workup and chromatogra-
phy (silica gel, hexane–EtOAc, 5:1) gave 30 as an inseparable dia-
stereomeric mixture. The NMR data provided below are for the
major diastereomer [Rf = 0.32 (hexane–EtOAc, 5:1)].
Yield: 84 mg (97%); colorless oil.
IR (film): 3061, 2934, 1737, 1717, 1612, 1514, 1490, 1450, 1370,
1314, 1274, 1247, 1174, 1155, 1111, 1069, 1027 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.66–1.96 (m, 3 H, H–C2, H–C6),
1.69 (s, 3 H, H–C13), 2.02 (s, 3 H, CH3CO), 2.07–2.21 (m, 1 H, H–
Synthesis 2007, No. 24, 3807–3814 © Thieme Stuttgart · New York