The Journal of Organic Chemistry
Article
NMR spectra were consistent with those previously reported within
18.0, −4.8, −4.8 ppm. HRMS (EI) m/z: calculated for C H O Si
1
5
25
4
60
literature.
E)-13-Bromo-3-(tert-butyldimethylsilyloxy)-5-oxotridec-6-
enoic Acid (28). A stirring solution of dimethyl methylphosphonate
[(M − t-Bu)] 297.1522, observed 297.1518 (Δ = 0.4 mmu).
(
(E)-4-Hydroxyoxacyclotetradec-7-ene-2,6-dione (15). To a
1.5 mL polypropylene Eppendorf tube charged with macrolactone 29
(16 mg, 0.045 mmol, 1.0 equiv) were added acetonitrile (450 μL, 0.1
M) and pyridine (18 μL, 0.225 mmol, 5.0 equiv). The reaction mixture
was vortexed to homogeneity, upon which 48% HF (82 μL, 0.450
mmol, 50 equiv) was added. The reaction mixture was again vortexed,
then centrifuged, and left for 5 h. The reaction was quenched with
water (2 × 1 mL) and diluted with ethyl acetate (2 × 2 mL). The
aqueous layer was re-extracted with ethyl acetate, and the combined
(
750 μL, 6.70 mmol, 3.7 equiv) in dry THF (8 mL) was cooled to −78
°C under an inert atmosphere. To this solution 2.5 M nBuLi (2.5 mL,
6
.25 mmol, 3.5 equiv) was added dropwise to effect a yellow color,
followed by stirring for 2 h. Addition of acid 26 (500 mg, 1.81 mmol,
.0 equiv) in THF (4 mL) via cannula yielded a clear, orange solution.
1
The solution was brought to rt, and product formation was observed
via TLC (silica gel, 5% MeOH in methylene chloride), where the
product was bright red under visualization with p-anisaldehyde stain.
Upon completion, the reaction was quenched with 1.0 M HCl solution
organic layers were washed with brine, dried (MgSO ), filtered, and
4
concentrated to dryness in vacuo. The product was purified by column
chromatography (silica gel, 20% ethyl acetate in hexanes) to afford
(
3 × 3 mL), diluted in ethyl acetate (3 × 20 mL), and separated. The
combined organic layers were washed with brine, dried (MgSO4),
10.8 mg of 15 (0.045 mmol, > 99%) as a clear, colorless oil. R = 0.28
f
filtered, and concentrated to afford 645.6 mg of crude phosphonate as
a pale yellow oil, which was spectroscopically pure enough for use in
silica gel, 40% ethyl acetate in hexanes); 1H NMR (400 MHz,
(
CDCl ): δ 6.81 (dt, J = 16.0, 7.3 Hz, 1H), 6.07 (dt, J = 16.0, 1.4 Hz,
3
the following step. R = 0.24 (silica gel, 5% MeOH in methylene
f
1H), 4.33−4.27 (m, 1H), 4.17 (t, J = 5.4 Hz, 2H), 3.73 (br s, 1H),
2.92 (d, J = 5.7 Hz, 2H), 2.62 (dd, J = 16.1, 3.6 Hz, 1H), 2.52 (dd, J =
1
chloride; p-anisaldehyde stain); H NMR (300 MHz, CDCl ): δ 4.54
3
(
p, J = 5.8 Hz, 1H), 3.78 (d, J = 11.3 Hz, 3H), 3.77 (d, J = 11.3 Hz,
1
6.1, 8.4 Hz, 1H), 2.36 (dd, J = 7.1, 1.6 Hz, 1H), 2.32 (dd, J = 7.1, 1.4
3
H), 3.11 (d, J = 22.7 Hz, 2H), 2.89 (d, J = 6.1 Hz, 2H), 2.58 (dd, J =
.9, 15.4 Hz, 1H), 2.49 (dd, J = 5.5, 15.4 Hz, 1H), 0.84 (s, 9H), 0.09
13
Hz, 1H), 1.66−1.57 (m, 4H), 1.44−1.31 (m, 4H) ppm; C NMR
5
(100 MHz, CDCl ): δ 201.5, 171.8, 151.9, 132.5, 66.7, 64.4, 41.6, 39.6,
s, 3H), 0.06 (s, 3H) ppm; 31P NMR (121 MHz, CDCl ): δ 19.6 ppm.
3
(
3
3
2.6, 27.8, 27.7, 25.9, 25.6 ppm. HRMS (EI) m/z: calculated for
HRMS (EI) m/z: calculated for C H O PSi [M − t-Bu] 311.0716,
10
20
7
C H O [M] 240.1362, observed 240.1348 (Δ = 1.4 mmu).
13
20
4
observed 311.0705 (Δ = 1.1 mmu). A solution of the obtained
phosphonate (230 mg, 0.62 mmol, 1.2 equiv) in isopropanol (4 mL,
dried over 4 Å MS) was cooled to 0 °C. Cesium carbonate (390 mg,
trans-4,15-Dioxabicyclo[9.3.1]pentadecane-3,13-dione (30).
To a 5 mm NMR tube charged with 15 (3.5 mg, 14.57 μmol, 1.0
equiv) in CDCl3 (0.5 mL) was added p-toluenesulfonic acid
monohydrate (1.6 mg), of which most did not go into solution.
1
.2 mmol, 1.9 equiv) was added in one portion, and the mixture was
stirred at 0 °C for 2 h. To the reaction mixture a solution of
bromoaldehyde 27 (99 mg, 0.51 mmol, 1.0 equiv) in isopropanol (1
mL, dried over 4 Å MS, 0.1 M overall reaction mixture) was added
dropwise. The reaction mixture was warmed to 30 °C and stirred
overnight. The reaction was diluted with ethyl acetate (10 mL) and
quenched by the addition of 1.0 M HCl solution (4 mL). The mixture
was extracted with ethyl acetate (2 × 10 mL), and the combined
1
Instantaneous conversion of material was realized via H NMR and
TLC (silica gel, 20% ethyl acetate in hexanes) monitoring, at which
point the mixture was filtered, concentrated, and purified by column
chromatography (silica gel, 20% ethyl acetate in hexanes) to afford 2.9
mg of 30 (12.09 μmol, 83%) as a clear, colorless oil. R = 0.19 (silica
f
1
gel, 20% ethyl acetate in hexanes); H NMR (400 MHz, CDCl ): δ
3
4.74 (ddt, J = 12.2, 6.3, 3.8 Hz, 1H), 4.47 (ddd, J = 11.2, 6.4, 2.4 Hz,
1H), 4.17 (dddd, J = 10.8, 8.7, 3.9, 1.9 Hz, 1H), 3.97 (ddd, J = 11.2,
9.4, 1.9 Hz, 1H), 2.71 (dd, J = 12.3, 1.4 Hz, 1H), 2.67 (ddd, J = 14.3,
6.2, 1.2 Hz, 1H), 2.42 (ddd, J = 14.1, 4.1, 1.7 Hz, 1H), 2.34 (dd, J =
organic layers were washed with brine, dried with MgSO , filtered, and
4
concentrated in vacuo. Purification via column chromatography (20%
ethyl acetate/hexanes) yielded 179.9 mg of 28 (0.413 mmol, 81%) as a
clear, colorless oil. R = 0.29 (silica gel, 20% Ethyl acetate in hexanes);
f
1
13.7, 3.4 Hz, 1H), 2.32−2.26 (m, 1H), 2.24 (ddd, J = 14.4, 4.3, 1.7 Hz,
H NMR (400 MHz, CDCl ): δ = 9.70 (br s, 1H), 6.81 (dt, J = 15.9,
3
1
H), 1.92−1.82 (m, 1H), 1.73−1.43 (m, 5H), 1.43−1.26 (m, 4H)
6.9 Hz, 1H), 6.08 (dt, J = 15.9, 1.5 Hz, 1H), 4.59 (p, J = 5.9 Hz, 1H),
3.38 (t, J = 6.7 Hz, 2H), 2.84 (dd, J = 15.9, 6.4 Hz, 1H), 2.72 (dd, J =
15.9, 6.0 Hz, 1H), 2.60 (dd, J = 15.1, 5.5 Hz, 1H), 2.49 (dd, J = 15.1,
6.0 Hz, 1H), 2.24−2.17 (m, 2H), 1.89−1.78 (m, 2H), 1.51−1.29 (m,
8
H), 0.82 (s, 9H), 0.06 (s, 3H), 0.02 (s, 3H) ppm; 13C NMR (100
13
ppm; C NMR (100 MHz, CDCl ): δ 206.5, 170.4, 70.8, 69.9, 66.7,
3
4
8.2, 46.1, 39.6, 33.4, 26.8, 25.4, 25.1, 22.1 ppm. HRMS (EI) m/z:
calculated for C H O [M − H O] 222.1256, observed 222.1270 (Δ
13
18
3
2
= 1.4 mmu).
cis-4,15-Dioxabicyclo[9.3.1]pentadecane-3,13-dione (31). To
a 5 mm NMR tube charged with 15 (4.7 mg, 19.56 μmol, 1.0 equiv) in
MHz, CDCl ): δ = 198.2, 176.5, 148.3, 131.0, 66.0, 46.9, 42.3, 33.7,
3
3
2.5, 32.3, 28.3, 27.8, 27.7, 25.7, 17.9, −4.8, −5.0 ppm. HRMS (EI) m/
CDCl (0.5 mL) was added Amberlyst 15 hydrogen form (5 mg),
3
z: calculated for C H BrO Si [(M − t-Bu)] 377.0784, observed
3
15
26
4
followed by heating to 80 °C for 4 h. The reaction was monitored by
77.0789 (Δ = 0.5 mmu).
E)-4-(tert-Butyldimethylsilyloxy)oxacyclotetradec-7-ene-
,6-dione (29). To a flask charged with bromoacid 28 (120 mg, 0.28
1
H NMR and TLC, and upon consumption of starting material the
(
mixture was filtered, concentrated, and purified by column
chromatography (silica gel, 10% ethyl acetate in hexanes) to afford
2
mmol, 1.0 equiv) in anhydrous DMF (28 mL, 0.01 M) was added
cesium carbonate (162.1 mg, 0.50 mmol, 1.8 equiv) under an Ar
atmosphere at 0 °C. The reaction was left to warm to room
temperature as it was stirred overnight. The reaction mixture was then
diluted with ethyl acetate (40 mL) and washed with brine. The
aqueous layer was re-extracted with ethyl acetate, and the combined
organic layers were washed with water (3 × 40 mL) and brine, dried
3
(
.6 mg of 31 (14.87 μmol, 76%) as a clear, colorless oil. R = 0.25
f
silica gel, 20% ethyl acetate in hexanes); 1H NMR (300 MHz,
CDCl ): δ 4.32 (ddd, J = 11.0, 10.1, 2.9 Hz, 1H), 4.18 (ddd, J = 11.0,
3
4
1
.7, 4.0 Hz, 1H), 3.95 (dddd, J = 11.5, 7.7, 6.4, 2.7 Hz, 1H), 3.58 (m,
H), 2.51 (d, J = 7.7 Hz, 1H), 2.50 (d, J = 6.4 Hz, 1H), 2.41 (ddd, J =
14.4, 2.7, 1.6 Hz, 1H), 2.32 (ddd, J = 14.4, 3.1, 1.6 Hz, 1H), 2.36−2.18
1
3
(
MgSO ), filtered, and concentrated to dryness in vacuo. The residue
(m, 2H), 1.93−1.78 (m, 1H), 1.77−1.27 (m, 9H) ppm; C NMR
(100 MHz, CDCl ): δ 206.1, 171.0, 77.2, 74.3, 64.4, 48.3, 47.1, 42.3,
33.6, 26.1, 25.2, 24.4, 24.2 ppm. HRMS (ESI+ TOF) m/z: calculated
4
was purified by column chromatography (silica gel, 10% ethyl acetate
in hexanes) to afford 66.3 mg of macrolactone 29 (0.19 mmol, 68%) as
3
+
a clear, pale yellow oil. R = 0.54 (silica gel, 10% ethyl acetate in
for C13
mmu). Alternatively, to a 5 mm NMR tube charged with 30 (2.7 mg,
11.24 μmol, 1.0 equiv) in CDCl (0.5 mL) was added Amberlyst 15
H O Na [(M + Na) ] 263.1259, observed 263.1276 (Δ = 1.7
20 4
f
1
hexanes); H NMR (400 MHz, CDCl ): δ 6.80 (ddd, J = 16.0, 8.1, 6.6
3
Hz, 1H), 6.05 (dt, J = 16.0, 1.4 Hz, 1H), 4.54 (ddt, J = 8.2, 4.3, 6.0 Hz,
3
1
H), 4.15 (ddd, J = 11.1, 7.3, 3.1 Hz, 1H), 4.08−4.01 (m, 1H), 3.00
hydrogen form (5 mg) and heated to 80 °C for 4 h. The reaction was
1
(
dd, J = 13.8, 8.2 Hz, 1H), 2.70 (dd, J = 13.8, 6.0 Hz, 1H), 2.52 (dd, J
monitored by H NMR, following key proton shifts in the range of δ
=
14.7, 4.3 Hz, 1H), 2.47 (dd, J = 14.7, 6.1 Hz, 1H), 2.39−2.21 (m,
4.74−3.58 (H3, H7, H13A, H13B). Upon completion, the reaction
mixture was filtered and purified by column chromatography (silica
gel, 10% ethyl acetate in hexanes) to afford 2.2 mg of 31 (9.33 μmol,
83%) as a clear, colorless oil.
2
3
1
H), 1.65−1.54 (m, 4H), 1.48−1.39 (m, 4H), 0.85 (s, 9H), 0.06 (s,
H), 0.05 (s, 3H) ppm; 13C NMR (100 MHz, CDCl ): δ 198.8, 170.4,
3
49.5, 131.8, 67.3, 64.7, 47.0, 42.5, 32.2, 27.4, 27.2, 25.8, 25.7, 25.5,
G
J. Org. Chem. XXXX, XXX, XXX−XXX