10.1002/asia.201800903
Chemistry - An Asian Journal
FULL PAPER
“d” (doublet), “dd” (doublet of doublets), “ddd” (doublet of doublets of
doublets), “t” (triplet), and “m” (multiplet). Where distinct from those due to
the major diastereomer, resonances due to minor diastereomers are
denoted by an asterisk. 1H and 13C NMR resonances were assigned using
a combination of DEPT 135, COSY, HSQC, HMBC, and NOESY spectra.
Infrared (IR) spectra were recorded using a thin film on a composite of zinc
selenide and diamond crystal on an FT-IR system transform spectrometer.
Melting points are uncorrected. High-resolution mass spectrometry
(HRMS) was performed using a spectrometer operating at a nominal
accelerating voltage of 70 eV or a TOF-Q mass spectrometer.
Na2CO3 (5 mL) was added and the aqueous phase was extracted with
CH2Cl2 (3 × 5 mL). The combined organic phases were concentrated in
vacuo and the crude oil was purified by flash chromatography (20% EtOAc
in pet. ether) to give adduct 16 as a clear oil (23 mg, 84%). IR (film) νmax
2971, 2931, 1711, 1457, 1386, 1369, 1240, 1166 cm-1; 1H NMR (400 MHz,
CDCl3) δ 9.61 (s, 1H), 6.72 (dd, J = 10.2, 1.8 Hz, 1H), 6.04 (d, J = 10.2 Hz,
1H), 2.34 (dd, J = 14.5, 1.8 Hz, 2H), 1.82 (d, J = 14.5 Hz, 1H), 1.27 (s, 3H)
1.16 (s, 3H), 1.02 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 203.4, 201.5,
148.0, 128.8, 48.6, 43.9, 41.4, 26.7, 25.7, 24.0; HRMS (ESI+) [M + H]+
167.0714 calcd for C10H15O2 167.1067.
Ketone 13. A suspension of 3-methyl-2-butanone (6.21 mL, 58.1 mmol),
ethyl formate (8.58 mL, 116 mmol) and NaH (1.53 g, 63.9 mmol, 60%
dispersion in mineral oil) in THF (120 mL) was heated to reflux and allowed
to stir for 30 min. The solution turned cloudy grey to yellow, then was
allowed to cool to rt before concentration in vacuo. The resultant yellow
gum was dissolved in DMSO (120 mL) under an inert atmosphere, then
dimethyl sulfate (5.51 mL, 58.1 mmol) was added and the reaction was left
to stir for 4 h at rt. The reaction was quenched with H2O (150 mL) then
extracted with CH2Cl2 (3 × 150 mL); the collected organic fractions were
then dried over MgSO4 and concentrated in vacuo. The resultant oil was
purified by vacuum distillation (80 °C, 1.5 mbar) to give ketone 13 (5.92 g,
80%, E/Z 4:1) as a clear oil. 1H NMR (400 MHz, CDCl3) 7.60 (d, J = 12.6
Hz, 1H), 6.40* (d, J = 7.2 Hz, 0.24H), 5.62 (d, J = 12.5 Hz, 1H), 5.08* (d, J
= 7.2 Hz, 0.23H), 3.85* (s, 0.83H), 3.70 (s, 3H), 2.87* (dq, J = 13.9, 6.9 Hz,
0.23H), 2.65 (dq, J = 7.0 Hz, 1H), 1.10 (s, 3H), 1.09 (s, 3H), 1.07* (s, 0.74H),
1.05* (s, 0.68H); 13C NMR (101 MHz, CDCl3) 203.6, 162.7, 158.2*,
105.3*, 103.5, 57.7, 41.2, 39.7*, 18.8, 18.6 *minor isomer. Spectroscopic
data were in good agreement with those previously reported.6
Ketone 18. To a solution of diene 8a (40 mg, 0.16 mmol) and methyl
methacrylate (35 L, 0.32 mmol) in CH2Cl2 (0.5 mL) at -78 ºC was added
SnCl4 (0.1 M in CH2Cl2, 30 L. 0.06 mmol). The resulting solution was
stirred for 3 h at -78 °C, then warmed to 0 ºC and stirred for a further 1 h
before addition of NEt3 (69 L, 0.49 mmol). The reaction mixture was then
concentrated in vacuo and purified by flash chromatography (20% EtOAc
in pet. ether) to afford dimer 18 as a clear oil (yield). IR (film) νmax 2973,
2936, 1672, 1270, 1032, 816; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J =
12.1 Hz, 1H), 6.95 (d, J = 16.1 Hz, 1H), 6.21 (d, J = 16.0 Hz, 1H), 5.73 (d,
J = 12.1 Hz, 1H), 3.71 (s, 3H), 2.85 (sept, J = 6.9 Hz, 1H), 1.30 (s, 6H),
1.12 (d, J = 7.0 Hz, 6 H); 13C NMR (101 MHz, CDCl3) δ 203.9, 199.8,
164.2, 150.2, 126.9, 100.7, 58.3, 49.6, 39.0, 23.9, 18.5.
Adduct 21. To a solution of ethyl 3-methyl-4-oxocrotonate (44 µL, 0.33
mmol) and Sc(OTf)3 (16 mg, 20 mol %) in CH2Cl2 at -78 °C was added
diene 8a (40 mg, 0.16 mmol). The resultant mixture was stirred for 3 h,
then allowed to warm to rt and quenched with NEt3 (69 L, 0.49 mmol).
The reaction mixture was extracted with sat. aq. NH4Cl, washed with brine,
and dried over Mg4SO4. The organic phase was then concentrated in
vacuo and purified by flash chromatography (30% EtOAc in pet. ether) to
give adduct 21 as a clear oil (23 mg, 43%). IR (film) νmax 2978, 2937, 1716,
1466, 1385, 1369, 1269, 1162 cm-1 ;1H NMR (400 MHz, CDCl3) 7.35 (dd,
J = 6.6 Hz, 1H), 5.94 (q, J = 1.1 Hz, 1H), 5.39 (d, J = 5.9 Hz, 1H), 4.54 (s,
1H), 4.19 (q, J = 7.1 Hz, 2H), 2.25 (d, J = 1.5, 3H), 1.30 (t, J = 7.1 Hz, 3H),
1.11 (s, 3H) 1.06 (s, 3H); 13C NMR (101 MHz, CDCl3) 197.6, 166.0, 161.5,
151.1, 120.7, 105.5, 90.4, 60.3, 44.8, 20.0, 19.0, 18.0, 14.4; HRMS (ESI+)
[M + Na] 261.1091 calcd for C13H18NaO4 261.1097.
Diene 8a. To a stirred solution of ketone 13 (2.50 g, 15.6 mmol) and NEt3
(6.52 mL, 46.8 mmol) in Et2O (50 mL) at 0 °C under nitrogen was added
TBSOTf (5.38 mL, 23.4 mmol) dropwise. After 10 min, the solution was
allowed to warm to rt and stir for 3 h by which point two clear layers had
formed. The bottom layer was removed by pipette and the top layer was
concentrated in vacuo. The resultant crude oil was then purified by flash
chromatography on neutral alumina (6% EtOAc in pet. ether) to give diene
1
8a (3.75 g, 99%) as a clear oil. H NMR (400 MHz, CDCl3) 6.63 (d, J =
12.3 Hz, 1H), 5.63 (d, J = 12.4 Hz, 1H), 3.58 (s, 3H), 1.67 (s, 6H), 0.99 (s,
9H), 0.10 (s, 6H); 13C NMR (101 MHz, CDCl3) 149.4, 140.2, 111.2, 101.0,
56.7, 26.2, 19.1, 19.0, 18.5, -3.3. A small impurity corresponding to TBS-
X persists after purification as per report by Rawal et al. Spectroscopic
data were in good agreement with those previously reported by Rawal et
al. 6
Adduct 22. A solution of diene 8a (61 mg, 0.25 mmol) and freshly sublimed
maleic anhydride (49 mg, 0.50 mmol) in toluene (1 mL) was stirred at
100 °C in a round-bottom flask for 2 hours. After cooling to rt, the solution
was concentrated in vacuo and purified by flash chromatography (15%
EtOAc in pet. ether) to afford adduct 14 (31 mg, 36%) as a colorless oil. IR
(film) νmax 2933, 1715, 1637, 1255, 1089 cm-1; 1H NMR (400 MHz, CDCl3)
4.97 (d, J = 6.4 Hz, 1H), 4.25 (dd, J = 6.4, 5.0 Hz, 1H), 3.36 (dd, J = 10.8,
4.9 Hz, 1H), 3.21 (s, 3H), 3.18 (d, J = 10.9 Hz, 1H), 1.39 (s, 3H), 1.32 (s,
3H), 0.95 (s, 9H), 0.22 (d, J = 1.0 Hz, 6H); 13C NMR (101 MHz, CDCl3)
171.1, 170.3, 163.1, 97.3, 71.5, 55.5, 49.4, 46.7, 36.8, 28.8, 25.7, 25.2,
18.3, -4.3, -5.1; HRMS (ESI+) [M + Na]+ 363.1598; calc. for C17H28NaO5Si
363.1598.
Diene 8b. To a stirred solution of ketone 13 (1.00 g, 7.80 mmol) and NEt3
(3.26 mL, 23.4 mmol) in Et2O (90 mL) at 0 °C under nitrogen was added
TMSOTf (1.55 mL, 8.58 mmol) dropwise. After 10 min, the solution was
allowed to warm to rt and stir for a further 3 h. The reaction mixture was
quenched by addition of sat. aq. NaHCO3 (30 mL) followed by pentane
(30 mL). The organic layer was then separated and the aqueous phase
was extracted with pentane (30 mL). The combined organic extracts were
then washed with sat. aq. NaHCO3 (2 × 30 mL), H2O (2 × 30 mL), and
brine (2 × 30 mL) and dried over MgSO4. The solvent was removed in
vacuo, and the resultant brown oil was purified by vacuum distillation
(110 °C, 50 mbar) to afford diene 8b (1.20 g, 77%) as a clear oil. IR (film)
νmax 2981, 2936, 1627, 1380, 1045 cm-1; 1H NMR (400 MHz, CDCl3) 6.62
(d, J = 12.6 Hz, 1H), 5.68 (d, J = 12.2 Hz, 1H), 3.58 (s, 3H), 1.66 (s, 3H),
1.66 (s, 3H), 0.18 (s, 9H); 13C NMR (101 MHz, CDCl3) 148.9, 140.6,
111.0, 101.2, 56.8, 18.9, 18.7, 0.82.
Lactone 25 & 26.
Method A. A mixture of diene 8a (1.17 g, 4.82 mmol), distilled citraconic
anhydride (400 mg, 3.57 mmol), and hydroquinone (9.8 mg, 0.09 mmol)
was degassed in a Schlenk tube by prolonged evacuation followed by
back-filling with nitrogen three times. The reaction mixture was then stirred
at 140 °C overnight. After cooling to rt, chloroform (35 mL) and TFA
(1.05 mL) were added and the resulting mixture was stirred for 5 min at rt,
then concentrated in vacuo. The crude mixture was dissolved in AcOH
(40 mL) and NaCNBH3 (1.24 g, 17.9 mmol) was added. The reaction
mixture was stirred at rt for 2 h before concentration in vacuo. The crude
mixture was then dissolved in CH2Cl2 (150 mL) and washed with
Adduct 16. To a solution of methacrolein (30 L, 0.33 mmol) and ZnCl2
(4.5 mg, 0.033 mmol) at 0 ºC in CH2Cl2 (0.5 mL) was added diene 8a
(40 mg, 0.16 mmol). The resultant solution was stirred for 3 h then sat. aq.
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