Journal of Natural Products
Article
2H), 2.08 (q, 2H), 1.66 (m, 2H), 0.95 (s, 18H), 0.25 (s, 2H); 13C
NMR (125 MHz, CDCl3) δ 173.31, 131.62, 129.65, 58.33, 35.49,
27.51, 26.58, 24.84, 20.28, −7.51; HREIMS m/z 283.2089 [M − OH]+
(calcd for C16H31 O2Si, 283.2093).
( E ) - D i - t e r t - b u t y l ( m e t h y l ) s i l y l 5 - ( 4 - ( 3 - ( ( t e r t -
butyldimethylsilyl)oxy)oct-1-en-1-yl)-2,5-dioxo-2,5-dihydro-
furan-3-yl)hept-6-enoate (3′). To a solution of 4′ (42 mg, 0.056
mmol) in toluene (5.0 mL) was added SiO2 (360 mg). The solution
was boiled under reflux under argon for about 6 h, then cooled to rt
and then diluted with 10 mL of CH2Cl2, and filtered through a pad of
Celite. The solution was concentrated under vacuum. The crude
product 3 was used for the next step without further purification (33.0
Di-tert-butyl(methyl)silyl (Z)-7-Bromohept-5-enoate (7).
Methanesulfonyl chloride (343 mg, 3.0 mmol) was added dropwise
to a chilled solution of 13 (500 mg, 0.166 mmol) and triethylamine
(337 mg, 3.33 mmol) in CH2Cl2 (6.0 mL) at −50 °C. The resulting
white suspension was stirred for 45 min and then treated with a
solution of lithium bromide (577 mg, 6.64 mmol) in THF (2.0 mL).
The colorless mixture was then warmed slowly to −20 °C and stirred
for 1 h. Then the reaction mixture was poured over H2O and extracted
with pentane. The pentane extracts were washed with H2O, then brine,
and then dried and concentrated by rotary evaporation to deliver crude
allylic bromide. The crude product was purified by flash chromatog-
raphy with EtOAc/hexanes (1:25) to give pure 7 (503 mg, 83.3%) as a
clear oil: Rf = 0.20 (25:1 hexanes/EtOAc); 1H NMR (400 MHz,
CDCl3) δ 5.76 (m, 1H), 5.59 (dt, 1H), 3.99 (d, 2H), 2.37 (t, 2H), 2.20
(q, 2H,), 1.74 (m, 2H), 1.02 (s, 18H), 0.32 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 173.08, 134.80, 126.47, 35.72, 27.73, 27.15, 26.49,
24.71, 20.49, −7.28; HREIMS m/z 305.0575, 307.0553 [M − C4H9]+
(calcd for C12H22BrO2Si, 305.0572, 307.0552).
Three-Component Coupling Product 4 and Its Regioisomer
4′. A solution of (E)-tert-butyldimethyl((1-(tributylstannyl)oct-1-en-
3-yl)oxy)silane (5)41 (160 mg, 0.3 mmol) in dry THF (1.0 mL) at
−78 °C was treated with n-BuLi (1.6 M, 0.12 mL, 0.3 mmol). After 40
min, the light yellow solution was transferred dropwise via a cannula to
a solution of copper cyanide (14 mg, 0.15 mmol) in anhydrous THF
(2.0 mL) at −78 °C. The resulting clear soltion was stirred at −78 °C
for 2 h. Then a solution of di-tert-butyl acetylenedicarboxylate (68 mg,
0.3 mmol) in anhydrous THF (1.0 mL) was slowly added via cannula
to the cuprate at −78 °C. The mixture was stirred at −78 °C for 50
min. Freshly distilled HMPA (480 mg, 2.7 mmol) in THF was then
added. After 15 min, Pd(PPh3)4 (12 mg, 0.01 mmol) in THF (1.0 mL)
was added by cannula, followed by the addition of 6 (55 mg, 0.15
mmol) in THF (1.0 mL). Stirring was continued overnight at −78 °C,
and the mixture was then warmed to −45 °C and stirred for one more
hour. Then the reaction mixture was quenched by addition of aqueous
saturated NH4Cl/NH4OH (pH 9, 5 mL) and slowly warmed to 0 °C.
Diethyl ether was used to extract the mixture. The crude product was
purified by flash chromatography with hexanes/Et2O (40:1 to 20:1) to
give 4 and 4′ (60 mg, yield = 54%) as a clear oil: Rf = 0.25 (20:1
hexanes/Et2O). Products 4 and 4′ were then separated by HPLC
(Luna C18 5 μm, 10 × 250 mm, gradient elution with CH3CN/2-
propanol).
1
mg, yield = 95%). 3′: clear oil; Rf = 0.80 (10:1 hexanes/EtOAc); H
NMR (500 MHz, CDCl3) δ 7.28 (ddd, 1H, J = 4 Hz, J = 5 Hz), 6.57
(ddd, 1H, J = 16 Hz, J = 7 Hz, J = 2 Hz), 5.96 (m, 1H), 5.13 (m, 2H),
4.37 (t,1H), 3.43 (q, 1H), 2.34 (m, 2H), 1.82 (m, 2H), 1.66 (m, 1H)
1.55 (m, 3H), 1.37−1.25 (m, 6H), 1.00 (s, 18H), 0.93 (d, 9H), 0.89 (t,
3H) 0.31 (d, 3H), 0.09 (s, 3H), 0.04(s, 3H); 13C NMR (125 MHz,
CDCl3) δ 172.49, 164.75, 164.26, 149.94, 140.31, 136.53, 135.86,
117.85, 114.31, 72.28, 41.18, 37.49, 35.63, 31.95, 31.82, 27.49, 25.85,
24.64, 23.25, 22.55, 20.25, 18.25, 14.02, −4.64, −4.76, −7.52; ESIMS
m/z 643.20 [M + Na]+ (calcd for C34H60O6Si2Na, 643.38).
(Z)-Di-tert-butyl(methyl)silyl 7-(4-((E)-3-((tert-
butyldimethylsilyl)oxy)oct-1-en-1-yl)-2,5-dioxo-2,5-dihydro-
furan-3-yl)hept-5-enoate (3). To a solution of 4 (21 mg, 0.028
mmol) in toluene (2.5 mL) was added SiO2 (200 mg). The solution
was boiled under reflux under argon for about 6 h, then cooled to rt
and diluted with 5 mL of CH2Cl2, and filtered through a pad of Celite.
The solution was concentrated under vacuum. The crude product 3
was used for the next step without further purification (16.0 mg, yield
1
= 91%). 3: clear oil; Rf = 0.80 (10:1 hexanes/EtOAc); H NMR (500
MHz, CDCl3) δ 7.22 (dd, 1H, J = 16 Hz, J = 4.0 Hz), 6.54 (dt, 1H, J =
16 Hz), 5.56 (dt, 1H), 5.38 (dt, 1H), 4.37 (dd,1H, J = 4.0 Hz), 3.26
(d, 2H), 2.36 (t, 2H), 2.21 (m, 2H), 1.72 (tt, 2H) 1.56 (m, 2H), 1.37−
1.25 (m, 6H), 1.02 (s, 18H), 0.93 (s, 9H), 0.88 (t, 3H) 0.32 (s, 3H),
0.06 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 173.05, 165.81, 164.67,
149.75, 138.12, 136.68, 133.33, 122.62, 114.64, 72.48, 37.66, 35.69,
31.96, 27.65, 26.92, 25.98, 24.79, 24.71, 22.70, 22.48, 20.41, 18.38,
14.18, −4.45, −4.64, −7.36; HREIMS m/z 563.3226 [M − C4H9]+
(calcd for C30H51O6Si2, 563.3224).
( E ) - D i - t e r t - b u t y l ( m e t h y l ) s i l y l 5 - ( 4 - ( 3 - ( ( t e r t -
butyldimethylsilyl)oxy)oct-1-en-1-yl)-5-hydroxy-5-methyl-2-
oxo-2,5-dihydrofuran-3-yl)hept-6-enoate (1p′) and (E)-di-tert-
butyl(methyl)silyl 5-(4-(3-((tert-butyldimethylsilyl)oxy)oct-1-
en-1-yl)-2-hydroxy-2-methyl-5-oxo-2,5-dihydrofuran-3-yl)-
hept-6-enoate (2p′). Methyllithium (57.5 μL, 1.6 M in diethyl ether,
3.0 equiv) was added to 3′ (19 mg) in dry THF (3.5 mL) at −94 °C.
The reaction was kept at −94 °C for 15 min. The reaction mixture was
quenched with aqueous NH4Cl. Diethyl ether was used to extract the
mixture. The crude product was purified by flash chromatography with
hexanes/EtOAc (5:1) to give a mixture of hydroxylactones 1p′ and
2p′ (8.2 mg, yield = 52% based on recovered starting material) as a
(4Z,7Z,9E)-7,8-Di-tert-butyl 1-(di-tert-butyl(methyl)silyl) 11-
((tert-butyldimethylsilyl)oxy)hexadeca-4,7,9-triene-1,7,8-tri-
carboxylate (4): 1H NMR (500 MHz, CDCl3) δ 6.41 (d, 1H, J = 15.8
Hz), 5.99 (dd, 1H, J = 15.8 Hz, J = 5.2 Hz), 5.40 (m, 1H), 5.31 (m,
1H), 4.22 (q, 1H, J = 5.2 Hz), 3.11 (d, 2H), 2.35 (t, 2H), 2.15 (m,
2H), 1.72 (m, 2H), 1.49 (m, 20H), 1.31−1.26 (m, 6H), 1.01 (s, 18H)
0.89 (m, 12H), 0.31 (s, 3H), 0.03 (d, 6H); 13C NMR (125 MHz,
CDCl3) δ 173.18, 167.65, 166.41, 141.92, 139.75, 130.56, 130.27,
126.92, 122.01, 81.77, 81.29, 73.08, 38.15, 35.84, 31.95, 28.22, 28.15,
27.66, 27.05, 26.54, 25.99, 25.13, 24.81, 22.74, 20.41, 18.34, 14.17,
−4.23, −4.66, −7.36; HREIMS m/z 694.4463 [M − C4H8]+ (calcd for
C38H70O7Si2, 694.4460).
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clear oil. H NMR data showed there are sets of two peaks, which
indicates that the product is a mixture of two hydroxylactones (1:1)
1
1p′ and 2p′: Rf = 0.30 (5:1 hexanes/EtOAc); H NMR (500 MHz,
CDCl3) δ 7.02 (m, 0.5H, isomer 1), 6.54 (m, 1H, isomer 2), 6.34 (dd,
0.5H, isomer 1), 6.06 (m, 1H, isomer 1), 5.91 (dddt, 1H, isomer 2),
5.08 (m, 2H), 4.31 (m,1H), 3.26 (m, 1H), 2.33 (m, 2H), 1.79 (q, 2H),
1.63−1.72 (m, 3H), 1.49−1.62 (m, 4H), 1.23−1.39 (m, 6H), 1.00 (m,
18H), 0.93 (m, 9H), 0.88 (m, 3H) 0.30 (m, 3H), 0.05 (m, 6H);
ESIMS m/z 659.27 [M + Na]+ (calcd for C35H64O6Si2Na, 659.41).
(Z)-Di-tert-butyl(methyl)silyl 7-(4-((E)-3-((tert-
butyldimethylsilyl)oxy)oct-1-en-1-yl)-5-hydroxy-5-methyl-2-
oxo-2,5-dihydrofuran-3-yl)hept-5-enoate (1p) and (Z)-di-tert-
butyl(methyl)silyl 7-(4-((E)-3-((tert-butyldimethylsilyl)oxy)oct-
1-en-1-yl)-2-hydroxy-2-methyl-5-oxo-2,5-dihydrofuran-3-yl)-
hept-5-enoate (2p). Methyllithium (18 μL, 1.6 M in diethyl ether,
1.2 equiv) was added to 3 (15 mg) in dry THF (5 mL) at −94 °C.
The reaction was kept at −94 °C for 15 min. The reaction mixture was
quenched with aqueous NH4Cl. Diethyl ether was used to extract the
mixture. The crude product was purified by flash chromatography with
hexanes/EtOAc (5:1) to give a 1:6 mixture of hydroxylactones 1p and
2p based on the integrated 1H NMR peak areas for resonances
centered at δ 6.50 and 6.32 (Figure S2), corresponding to H-13 in 1p
and 2p, respectively (4 mg, yield = 57% based on unrecovered starting
(5Z,7E)-5,6-Di-tert-butyl 1-(di-tert-butyl(methyl)silyl) 9-((tert-
butyldimethylsilyl)oxy)-4-vinyltetradeca-5,7-diene-1,5,6-tri-
1
carboxylate (4′): H NMR (500 MHz, CDCl3) δ 6.39 (d, 1H, J =
15.8 Hz), 5.95 (d, 1H, J = 17.0 Hz), 5.89 (1H, ddd, J = 9.9, 6.2, 2.6
Hz), 5.04 (d, 2H, J = 11.8 Hz), 4.21 (s, 1H), 3.27 (q, 1H, J = 7.5 Hz),
2.46−2.17 (m, 2H), 1.77−1.58 (m, 2H), 1.53 (m, 2H), 1.50 (s, 9H),
1.48(s, 9H), 1.37−1.18 (m, 6H), 1.01 (s, 18H) 0.90 (s, 9H), 0.87(t,
3H), 0.31 (s, 3H), 0.04 (d, J = 12.4 Hz, 6H); 13C NMR (125 MHz,
CDCl3) δ 173.00, 167.40, 166.96, 141.25, 138.60, 137.09, 136.07,
121.16, 116.19, 81.77, 81.71, 73.07, 43.68, 38.19, 36.22, 32.68, 31.98,
28.25, 28.15, 27.66, 26.02, 24.84, 24.78, 23.49, 22.76, 20.39, 18.35,
14.18, −4.20, −4.66, −7.37; ESIMS m/z 773.20 [M + Na]+ (calcd for
C42H78O7Si2Na, 773.52).
I
J. Nat. Prod. XXXX, XXX, XXX−XXX