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DOI: 10.1055/s-2002-35584
Asymmetric Synthesis of the Polyol Portion of the Polyene Macrolide Antibiotic RK-397
Publication History
Publication Date:
20 November 2002 (online)
Abstract
A highly convergent and asymmetric synthesis of a fully functionalized polyol portion of the new polyene macrolide antibiotic RK-397 has been achieved taking advantage of a novel polyol synthesis.
Key words
RK-397 - polyene macrolide antibiotics - total synthesis - aldol reaction - Cope rearrangement
- 1
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References
Experimental Procedure: An
amount of 149 mg (0.39 mmol) of methyl ketone 7 was
dissolved in 4 mL diethyl ether and cooled to -78 °C.
For enolization 0.59 mL (0.59 mmol) of a 1 M solution of dibutylboron
triflate in dichloromethane were added and subsequently 92 µL
(0.66 mmol) triethyl-amine and the resulting solution was stirred for
30 min at -78 °C and for 30 min at 0 °C.
Then the solution was cooled to -100 °C
and 122 mg (0.27 mmmol) of aldehyde 8,
dissolved in 1 mL diethyl ether, were added with a syringe. Stirring
was continued for 3 h at -100 °C and 3
h at -78 °C after which the reaction
was quenched with pH 7 buffer. After separation of the phases the
aq phase was repeatedly extracted with diethyl ether, the combined organic
extracts were dried over MgSO4, filtered and evaporated
in vacuo. Purification of the crude mixture through flash chromatography
with diethyl ether/pentane (1:2) as eluent yielded 145
mg (65%) of the desired aldol product 9 as
a colourless oil (84:16 mixture of stereo-isomers) along with 34
mg (27%) of unreacted aldehyde 8 and
44 mg (30%) of methyl ketone 7 both
of which were used again in the aldol reaction. [α]D
20 +19.7
(c 0.58, CHCl3);
IR(film): ν = 3471 (OH), 2992,
2949, 2857 (CH), 1741 (C=O), 1712 (C=O) cm-1; 1H
NMR (300 MHz, CDCl3): δ = 0.05
(s, 6 H, SiMe2), 0.90 (s, 9 H, t-Bu),
1.07-1.33 (m, 2 H), 1.36, 1.40, 1.41 [3 s, 12
H, 2 × C(CH3)2], 1.50-1.97
(m, 10 H), 2.37 (dd, J = 15.5,
6.0 Hz, 1 H, 2-H), 2.43-2.65 (m, 4 H) 2.73 (dd, J = 15.5,
7.0 Hz, 1 H, 2-H), 3.68 (s, 3 H, OMe), 3.65-4.29 (m, 9
H), 4.45, 4.48, 4.55, 4.56 (4 × d, J = 11.5 Hz,
4 H, 2 × OBn), 7.25-7.36 (m,
10 H, 2 × Ph); 13C
NMR (75 MHz, CDCl3): δ = -5.35,
18.30, 19.81, 19.84, 25.94, 30.11, 30.26, 36.86, 37.41, 39.45, 40.20,
40.47, 41.18, 42.39, 49.29, 50.81, 51.60, 58.77, 65.28, 65.48, 65.76,
65.87, 66.49, 70.36, 72.44, 71.93, 74.63, 98.36, 98.81, 127.70,
127.80, 128.00, 128.10, 128.40, 138.10, 138.30, 171.30, 209.40;
MS (200 eV, DCI/NH3):
m/z
(%) = 847(100) [M + NH4
+];
calcd for C46H72O11Si (829.15):
C, 66.63; H, 8.75. Found: C, 66.82; H, 8.50.
Spectroscopic Data of 2: [α]D 20 0 (c 0.2, CHCl3); IR(film): ν = 2990, 2938, 2857 (CH), 1745 (C=O) cm-1; 1H NMR (500 MHz, C6D6): δ = 0.06, 0.08 (2 × s, 6 H, SiMe2), 0.98 (s, 9 H, t-Bu), 1.10-1.60 (m, 14 H), 1.32, 1.37, 1.47, 1.49, 1.50, 1.54, 1.55 [7 s, 24 H, 8 × C(CH3)2], 1.67 (s, 3 H, OAc), 1.73-1.82 (m, 1 H), 2.06 (quint, J = 7.0 Hz, 1 H), 3.68 (dt, J = 10.0, 5.0 Hz, 1 H, CH2OTBS), 3.82 (ddd, J = 10.0, 8.5, 5.0 Hz, 1 H, CH2OTBS), 3.83-3.89 (m, 1 H), 3.96-4.34 (m, 9 H); 13C NMR (150 MHz, C6D6): δ = -5.38, 18.49, 19.82, 19.92, 19.97, 20.42, 24.86, 26.13, 30.39, 30.63, 30.67, 37.60, 37.80, 39.46, 40.16, 42.80, 43.08, 43.59, 59.20, 62.55, 62.69, 64.86, 65.34, 65.60, 65.71, 65.76, 67.38, 67.70, 98.54, 98.59, 98.80, 100.50, 170.10; MS (200 eV, EI): m/z (%) = 715(34) [M+ - CH3], 414(4), 380(5), 337(10), 256(18), 149(21), 57(100) [C4H9]; HRMS calcd for C38H70O11Si: for [M+ - CH3] 715.4453. Found: 715.4531.