Synthesis of Pladienolide B and Its 7-Epimer
(3R,6R,7R,8E,10S,11S,12E)-Macrolactone 41: To a solution of
macrolactone 40 (0.016 g, 0.024 mmol) in MeOH (0.3 mL) was
added PPTS (0.018 g, 0.072 mmol). The reaction mixture was
heated to 50 °C and stirred overnight. After cooling to room temp.,
the solvent was removed in vacuo, and the residue purified by pre-
parative TLC (petroleum ether/EtOAc, 1:2) to give deprotected
lactone 41 (0.007 g, 63%) as a colorless oil; Rf = 0.26 (petroleum
ether/EtOAc, 1:2). [α]2D1 = –69.1 (c = 1.7, CHCl3), 1H NMR
(400 MHz, CDCl3): δ = 0.87 (d, J = 6.8 Hz, 3 H, 10-CH3), 1.24 (s,
ditional 5 h. The mixture was then treated with a saturated NH4Cl
solution (0.5 mL). The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (3ϫ 0.5 mL). The combined organic
layers were washed with a saturated NaCl solution, dried with
MgSO4, filtered, and concentrated in vacuo. Purification by flash
chromatography (petroleum ether/EtOAc, 5:1) delivered the desired
allylic alcohol 43 (0.023 g, 68%; dr 4:1, determined by mass after
separation of the isomers) as a colorless oil; Rf = 0.18 (petroleum
ether/Et2O, 2:1). [α]2D5 = –16.0 (c = 0.8, CHCl3). 1H NMR
3 H, 6-CH3), 1.55–1.66 (m, 4 H, 4-H, 5-H), 1.82 (s, 3 H, 12-CH3), (400 MHz, CDCl3): δ = 0.01 [s, 3 H, Si(CH3)2], 0.05 [s, 3 H, Si-
2.13 (s, 3 H, OAc), 2.52–2.63 (m, 3 H, 2-H, 10-H), 3.72 (br. s, 1 H,
3-H), 5.13–5.21 (m, 2 H, 7-H, 9-H), 5.27 (d, J = 10.6 Hz, 1 H, 11-
H), 5.87 (dd, J = 15.4, 2.3 Hz, 1 H, 8-H), 6.46 (s, 1 H, 13-H) ppm.
(CH3)2], 0.54 [q, J = 7.9 Hz, 6 H, Si(CH2CH3)3], 0.85 [s, 9 H,
C(CH3)3], 0.89–0.93 [m, 12 H, 10-CH3, Si(CH2CH3)3], 1.11 (s, 3 H,
6-CH3), 1.48–1.63 (m, 3 H, 4-H, 5-H), 1.73 (d, J = 1.0 Hz, 3 H,
13C NMR (100 MHz, CDCl3): δ = 16.6 (10-CH3), 19.0 (12-CH3), 12-CH3), 1.76–1.86 (m, 1 H, 5-H), 2.26–2.35 (m, 1 H, 10-H), 2.42–
21.0 (OAc), 24.8 (6-CH3), 29.9 (C-4), 36.1 (C-5), 38.7 (C-10), 40.7
(C-2), 69.4 (C-3), 74.1 (C-13), 77.7 (C-6), 80.4 (C-7), 83.9 (C-11),
2.44 (m, 2 H, 2-H), 3.37 (s, 3 H, OCH3), 3.54 (t, J = 4.4 Hz, 2
H, OCH2CH2OCH3), 3.64 (s, 3 H, 1-OCH3), 3.66–3.73 (m, 1 H,
127.4 (C-8), 130.0 (C-9), 143.6 (C-12), 169.7 (C=O), 171.8 (C- OCH2CH2OCH3), 3.75–3.82 (m, 1 H, OCH2CH2OCH3), 3.90 (d,
1) ppm. HRMS (ESI): calcd. for C18H27IO6 [M + Na]+ 489.074453;
found 489.074137.
J = 6.32 Hz, 1 H, 11-H), 4.01 (d, J = 7.1 Hz, 1 H, 7-H), 4.11–4.16
(m, 1 H, 3-H), 4.72 (d, J = 7.8 Hz, 1 H, OCH2O), 4.86 (d, J =
7.8 Hz, 1 H, OCH2O), 5.38 (dd, J = 15.4, 6.8 Hz, 1 H, 8-H), 5.72
(dd, J = 15.4, 7.5 Hz, 1 H, 9-H), 6.10 (s, 1 H, 13-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = –4.9 [Si(CH3)2], –4.4 [Si(CH3)2], 4.7
[Si(CH2CH3)3], 6.8 [Si(CH2CH3)3], 15.3 (10-CH3), 18.0 [C(CH3)3],
20.2 (12-CH3), 20.5 (6-CH3), 25.8 [C(CH3)3], 29.1 (C-4), 30.9 (C-
5), 41.0 (C-2), 42.3 (C-10), 51.4 (1-OCH3), 59.0 (OCH3), 65.9 (C-
3), 67.6 (OCH2CH2OCH3), 69.7 (OCH2CH2OCH3), 71.7 (C-7),
77.8 (C-11), 78.4 (C-13), 81.4 (C-6), 89.9 (OCH2O), 128.2 (C-8),
135.5 (C-12), 149.3 (C-9), 172.3 (C-1) ppm. HRMS (ESI): calcd.
for C33H65IO8Si2 [M + Na]+ 795.315487; found 795.315977.
7-epi-Pladienolide B (42): To a solution of Pd2(dba)3 (1 mg,
0.001 mmol), Ph3As (5 g, 0.017 mmol), LiCl (0.9 mg, 0.021 mmol),
and vinylstannane 39 (11 mg, 0.023 mmol) in degassed NMP
(0.4 mL) was added a solution of lactone 41 (7 mg, 0.015 mmol) in
NMP (0.4 mL). The resulting green reaction mixture was stirred at
room temp. for 24 h. Then Pd2(dba)3 (1 mg, 0.001 mmol) and
Ph3As (5 mg, 0.017 mmol) were added again, and the mixture was
stirred for an additional 24 h. The reaction was quenched by the
addition of H2O (0.5 mL). The layers were separated, and the aque-
ous layer was extracted with EtOAc (3ϫ 0.5 mL). The combined
organic layers were washed with a saturated NaCl solution, dried
with MgSO4, filtered, and concentrated in vacuo. The residue was
purified by preparative TLC (n-hexane/EtOAc, 3:7) to afford 7-epi-
pladienolide B (42, 2.2 mg, 18%) as a white oil; Rf = 0.20 (n-hex-
ane/EtOAc, 3:7). [α]2D7 = +2.3 (c = 0.05, CH3OH). 1H NMR
(400 MHz, CD3OD): δ = 0.86 (d, J = 6.8 Hz, 3 H, 10-CH3), 0.89
(d, J = 7.1 Hz, 3 H, 20-H), 0.93 (t, J = 7.5 Hz, 3 H, 23-H), 1.08
(d, J = 6.8 Hz, 3 H, 16-CH3), 1.16–1.21 (m, 1 H, 20-H), 1.19 (s, 3
H, 6-CH3), 1.42–1.53 (m, 6 H, 4-H, 5-H, 17-H, 22-H), 1.60–1.68
(m, 2 H, 4-H, 17-H), 1.74 (s, 3 H, 12-CH3), 2.12 (s, 3 H, OAc),
2.44–2.57 (m, 3 H, 2-H, 16-H), 2.56–2.66 (m, 1 H, 10-H), 2.62–
2.66 (m, 1 H, 19-H), 2.70–2.73 (m, 1 H, 18-H), 3.43–3.53 (m, 1 H,
21-H), 3.73–3.79 (m, 1 H, 3-H), 4.99 (d, J = 10.6 Hz, 1 H, 11-H),
5.17 (s, 1 H, 7-H), 5.23 (ddd, J = 15.5, 9.7, 2.0 Hz, 1 H, 9-H), 5.64
(dd, J = 15.0, 8.5 Hz, 1 H, 15-H), 5.87 (dd, J = 15.4, 2.5 Hz, 1 H,
8-H), 6.08 (d, J = 10.9 Hz, 1 H, 13-H), 6.32 (dd, J = 14.6, 10.9 Hz,
1 H, 14-H) ppm. 13C NMR (100 MHz, CD3OD): δ = 10.8 (20-
CH3), 10.9 (12-CH3), 11.9 (C-23), 17.2 (10-CH3), 20.9 (OAc), 21.7
(16-CH3), 24.6 (6-CH3), 28.6 (C-22), 30.8 (C-4), 36.7 (C-16), 37.2
(C-5), 40.7 (C-2), 40.7 (C-17), 41.7 (C-10), 42.8 (C-20), 58.5 (C-18),
63.0 (C-19), 70.8 (C-3), 74.6 (C-6), 75.3 (C-21), 79.3 (C-7), 84.3 (C-
11), 125.9 (C-14), 128.1 (C-8), 132.0 (C-13), 132.2 (C-9), 132.8 (C-
12), 142.2 (C-15), 171.6 (C=O), 171.9 (C-1) ppm. HRMS (ESI):
calcd. for C30H48O8 [M + Na]+ 559.32414; found 559.32383.
Methyl (3R,6R,7S,8E,10S,11S,12E)-7-(Acetyloxy)-3-{[tert-butyl(di-
methyl)silyl]oxy}-13-iodo-6-[(2-methoxyethoxy)methoxy]-6,10,12-tri-
methyl-11-[(triethylsilyl)oxy]trideca-8,12-dienoate (44): Alcohol 43
(0.075 g, 0.097 mmol) was dissolved in CH2Cl2 (0.5 mL), and
DMAP (0.174 g, 0.467 mmol), Et3N (0.016 mL, 0.116 mmol) and
Ac2O (0.014 mL, 0.145 mmol) were added. The resulting reaction
mixture was stirred at room temp. for 2 h. Afterwards, a saturated
NaHCO3 solution (1 mL) was added, and the layers were sepa-
rated. The aqueous layer was extracted with EtOAc (3ϫ 1 mL),
and the combined organic layers were dried with MgSO4, filtered,
and concentrated in vacuo. The residue was purified by flash
chromatography (petroleum ether/Et2O, 3:1) to obtain the desired
acetate 44 (0.078 g, 99%) as colorless oil; Rf = 0.26 (petroleum
ether/Et2O, 2:1). [α]2D6 = +6.7 (c = 0.2, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 0.01 [s, 3 H, Si(CH3)2], 0.05 [s, 3 H, Si-
(CH3)2], 0.53 [q, J = 7.8 Hz, 6 H, Si(CH2CH3)3], 0.85 [s, 9 H,
C(CH3)3], 0.88–0.92 [m, 12 H, 10-CH3, Si(CH2CH3)3], 1.17 (s, 3 H,
6-CH3), 1.34–1.41 (m, 1 H, 5-H), 1.56–1.66 (m, 3 H, 4-H, 5-H),
1.72 (d, J = 0.7 Hz, 3 H, 12-CH3), 2.04 (s, 3 H, OAc), 2.28–2.32
(m, 1 H, 10-H), 2.36–2.48 (m, 2 H, 2-H), 3.37 (s, 3 H, OCH3),
3.51 (t, J = 4.7 Hz, 2 H, OCH2CH2OCH3), 3.60–3.74 (m, 2 H,
OCH2CH2OCH3), 3.65 (s, 3 H, 1-OCH3), 3.89 (d, J = 6.3 Hz, 1 H,
11-H), 4.08–4.15 (m, 1 H, 3-H), 4.69 (d, J = 7.8 Hz, 1 H, OCH2O),
4.86 (d, J = 7.8 Hz, 1 H, OCH2O), 5.27 (d, J = 6.6 Hz, 1 H, 7-H),
5.38–5.44 (m, 1 H, 8-H), 5.71–5.76 (m, 1 H, 9-H), 6.09 (s, 1 H, 13-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = –4.9 [Si(CH3)2], –4.5
[Si(CH3)2], 4.7 [Si(CH2CH3)3], 6.8 [Si(CH2CH3)3], 16.3 (10-CH3),
17.9 [C(CH3)3], 20.1 (OAc), 20.2 (12-CH3), 21.2 (6-CH3), 25.7
[C(CH3)3], 30.8 (C-4), 31.1 (C-5), 40.9 (C-2), 42.4 (C-10), 51.5 (1-
OCH3), 59.0 (OCH3), 67.0 (OCH2CH2OCH3), 69.5 (C-3), 71.8
(OCH2CH2OCH3), 77.6 (C-7), 78.6 (C-11), 78.7 (C-13), 81.3 (C-6),
90.1 (OCH2O), 124.5 (C-8), 136.7 (C-9), 149.2 (C-12), 169.7 (OAc),
172.1 (C-1) ppm. HRMS (ESI): calcd. for C3 5H67 IO9Si2
[M + Na]+ 837.326051; found 837.326287.
Methyl (3R,6R,7S,8E,10S,11S,12E)-3-{[tert-Butyl(dimethyl)-
silyl]oxy}-7-hydroxy-13-iodo-6-[(2-methoxyethoxy)methoxy]-
6,10,12-trimethyl-11-[(triethylsilyl)oxy]trideca-8,12-dienoate (43):
To a solution of ZnCl2 (1 m in Et2O, 0.15 mmol) in Et2O (1 mL)
was added NaBH4 (0.010 g, 0.31 mmol) at 0 °C. The resulting mix-
ture was stirred at room temp. for 12 h and then cooled again to
–15 °C. Then, a solution of enone 17 (0.030 g, 0.03 mmol) in Et2O
(0.8 mL) was added dropwise to the Zn(BH4)2 solution. The mix-
ture was stirred at –15 °C overnight and then at –10 °C for an ad-
Eur. J. Org. Chem. 2014, 1025–1036
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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