T. Fortunati et al. / Tetrahedron 71 (2015) 2357e2362
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at room temperature. Then, the mixture was quenched with water
and extracted with dichloromethane (3ꢃ20 mL). The organic layer
was dried over Na2SO4 and concentrated under vacuum. Purifica-
tion of the crude material on flash column chromatography, eluting
with petroleum ether/diethyl ether 97/3, gave pure 11 (1.539 g,
96%) as colourless oil.
chromatography, eluiting with petroleum ether/diethyl ether from
85/15 to 7/3, yielding pure 6 (714 mg, 62%) as colourless oil.
Compound (6): 1H NMR (CDCl3, 400 MHz):
d
5.35 (1H, dt, J¼11.2
and 5.8 Hz), 5.32 (1H, dt, J¼11.2 and 5.8 Hz), 4.11 (2H, q, J¼7.1 Hz),
3.63 (2H, t, J¼6.6 Hz), 2.28 (2H, t, J¼7.6 Hz), 2.00 (4H, m), 1.62 (2H,
m), 1.55 (2H, m), 1.34e1.28 (14H, m), 1.24 (3H, t, J¼7.1 Hz). 13C NMR
Compound (11): 1H NMR (CDCl3, 400 MHz):
d
3.65 (3H, s,
(100.03 MHz CDCl3): d 173.9 (C), 130.0 (CH), 129.5(CH), 62.9 (CH2),
eOCH3), 3.58 (2H, t, J¼6.5 Hz), 2.29 (2H, t, J¼7.7 Hz), 1.61 (2H, m),
60.1 (CH2), 34.3 (CH2), 32.7 (CH2), 29.6 (CH2), 29.4 (CH2), 29.3 (CH2),
29.1 (t), 28.7 (CH2), 27.1 (CH2), 26.9 (CH2), 25.7 (CH2), 24.8 (CH2),
14.2 (CH3). ES-MS (m/z): 321 [MþNa]þ, 299 [MþH]þ.
1.49 (2H, m), 1.29 (8H, m), 0.88 (9H, s), ꢂ0.03 (6H, s). 13C NMR
(62.89 MHz CDCl3):
d 174.3 (C), 63.2 (CH2), 21.4 (CH3), 34.1 (CH2),
32.8 (CH2), 29.2 (CH2), 29.1 (CH2), 26.0 (3 CH3), 25.7 (CH2), 24.9
(CH2), 18.3 (C), ꢂ5.3 (2 CH3). ES-MS (m/z): 325 [MþNa]þ, 303
[MþH]þ.
4.4.5. Ambrettolide (5). The reaction vessel containing a suspen-
sion of 50 mg of enzyme CALB (lipase B acrylic resin from C. ant-
arctica (EC 3.1.1.3, 10,000 U/g) in 40 mL of cyclohexane was placed
in a closed chamber containing a saturated solution of salt hydrates
(Na2HPO4$7H20/2H20) and kept overnight in indirectly contact,
4.4.2. Aldehyde 7. To a stirred solution of 11 (1.40 g, 4.37 mmol) in
anhydrous CH2Cl2 (10 mL), under N2 atmosphere, DIBAL-H (10 mL,
10.5 mol/L in CH2Cl2) was added dropwise during 2 h, at ꢂ78 ꢀC.
Then, the resulted solution was warmed to 0 ꢀC and quenched
with a saturated solution of Na/K tartrate (10 mL) and extracted
with dichloromethane (3ꢃ20 mL). The organic layer was dried
over Na2SO4, and concentrated under vacuum. Purification of the
crude material on flash column chromatography, eluting with
pentane/diethyl ether 99/1, gave aldehyde 7 (1.060 g, 89%) as
colourless oil.
under vigorous agitation. Then, hydroxy-ester
6 (12 mg,
0.04 mmol) was added and the reaction was vigorously stirred at
40 ꢀC for 3 h. At the end, the enzyme was removed by filtration and
the filtrate was concentrated under vacuum. Purification of the
crude material on flash column chromatography, eluting with pe-
troleum ether/chloroform 8/2, gave. ambrettolide 5 (8.4 mg, 83%) as
colourless oil.
Ambrettolide (5): Rf (50% CHCl3/hexane) 0.62; IR (cmꢂ1): 2927,
Compound (7): 1H NMR (CDCl3, 250 MHz):
d
9.75 (1H, s), 3.58
1738, 1468. 1H NMR (CDCl3, 400 MHz):
d
5.32 (2H, m), 4.13 (2H, m),
2.32 (2H, t, J¼6.6 Hz), 2.08e1.99 (4H, m), 1.66e1.57 (4H, m),
1.44e1.19 (14H, m). 13C NMR (CDCl3, 100 MHz):
173.9 (C), 130.2
(2H, t, J¼6.5 Hz), 2.30 (2H, dt, J¼7.4, 1.8 Hz), 1.62 (2H, m), 1.49 (2H,
m), 1.29 (8H, m), 0.88 (9H, s), ꢂ0.03 (6H, s). 13C NMR (62.89 MHz
d
CDCl3):
d
202.7 (CH), 63.1 (CH2), 43.7 (CH2), 32.6 (CH2), 29.1 (CH2),
(CH), 130.0 (CH), 63.7 (CH2), 34.5 (CH2), 29.4 (CH2), 28.8 (CH2), 28.7
(CH2), 28.5 (CH2), 28.4 (CH2), 28.3 (CH2), 27.6 (CH2), 26.9 (CH2), 26.8
(CH2), 25.3 (CH2), 25.2 (CH2). MS (m/z): 253 [MþH]þ. Anal. Calcd for
C16H28O2: C, 76.14; H, 11.18. Found: C, 76.02; H, 11.27.
29.0 (CH2), 28.9 (CH2), 25.8 (3 CH3), 25.5 (CH2), 21.9 (CH2), 18.2 (C),
ꢂ5.4 (2 CH3). ES-MS (m/z): 295 [MþNa]þ, 273 [MþH]þ.
4.4.3. Phosphonium salt (8). A mixture containing ethyl 7-bromo
heptanoate (1.35 g, 5.7 mmol), triphenilphosphine (1.5 g,
6.3 mmol) and 15 mL of CH3CN was refluxed for 48 h. Upon cooling,
the solution was concentrated under vacuum and subjected to flash
column chromatography (petroleum ether/diethyl ether 97/3 and
then with chloroform/methanol 95/5) to give phosphonium salt 8
(2.56 g, 90%).
4.5. Synthesis of (15R)-15-hexadecanolide (21)
4.5.1. TBS-protected alcohol (rac)-14. To a stirred solution of (rac)-
ethyl-3-hydroxybutanoate (1.00 g, 7.57 mmol) in dry dichloro-
methane (8.0 mL) was added imidazole (0.67 g, 9.84 mmol) and
then TBSCl (1.5 g, 9.95 mmol). The resulting solution was stirred
overnight at room temperature. Then, the mixture was quenched
with water and extracted with dichloromethane (3ꢃ20 mL). The
organic layer was dried over Na2SO4 and concentrated under vac-
uum. Purification of the crude material on flash column chroma-
tography, eluting with petroleum ether/diethyl ether 95/5, gave
pure (rac)-14 (1.59 g, 85%) as colourless oil.
Compound (8): 1H NMR (CDCl3, 250 MHz):
d 7.85e7.57 (15H, m),
3.98 (2H, q, J¼7.1 Hz), 3.64 (2H, m), 2.14 (2H, t, J¼7.3 Hz), 1.66e1.50
(4H, m), 1.44 (2H, m), 1.24 (2H, m), 1.12 (3H, t, J¼7.1 Hz). 13C NMR
4
(75 MHz CDCl3):
d
173.4 (C), 134.8 (CH, d, JPC¼3 Hz, aromatic car-
3
bon para to phosphorous), 133.4 (CH, d, JPC¼10 Hz, aromatic car-
2
bon meta to phosphorous), 130.3 (CH, d, JPC¼13 Hz, aromatic
1
carbon ortho to phosphorous), 118.0 (C, d, JPC¼86 Hz, quaternary
Compound (rac)-14: 1H NMR (CDCl3, 400 MHz):
d 4.26 (1H, m),
aromatic carbon attached to phosphorous), 59.9 (t), 33.8 (t), 29.7
4.09 (2H, m), 2.45 (1H, dd, J¼14.3, 7.5 Hz), 2.34 (1H, dd, J¼14.3,
2
(CH2, d, JPC¼16 Hz), 28.2 (CH2), 24.1 (CH2), 22.4 (CH2, d,
5.4 Hz), 1.24 (3H, t, J¼7.5 Hz), 1.17 (3H, d, J¼6.1 Hz), 0.84 (9H, s), 0.05
1JPC¼46 Hz), 22.1 (CH2), 14.0 (CH3).
(3H, s), 0.03 (3H, s). 13C NMR (62.89 MHz CDCl3):
d 171.6 (C), 65.8
(CH), 60.1 (CH2), 44.9 (CH2), 25.7 (3 CH3), 23.9 (CH3), 17.9 (C), 14.2
(CH3), ꢂ4.6 (CH3), ꢂ5.1 (CH3). ES-MS (m/z): 269 [MþNa]þ, 247
[MþH]þ.
4.4.4. (Z)-ethyl 16-hydroxyhexadec-7-enoate (6). Phosphonium salt
8 (2.55 g, 5.1 mmol) was dissolved in 10 mL of dry THF at 0 ꢀC
stirring for some minutes. Then, a solution of potassium bis(-
trimethylsilyl)amide (10 mL 0.25 M in toluene) was added. The
reaction mixture was warmed to rt and stirred for 30 min. After
cooling at 0 ꢀC, a solution of aldehyde 7 (1.054 g, 3.87 mmol) in dry
THF (7 mL) was added dropwise. The resulting solution was stirred
for 2 h before it was quenched by acidification with 10 ml of HCl
1.0 M and extracted with diethyl ether. The organic layer was dried
over Na2SO4 and concentrated under vacuum. The crude material
was dissolved in CH3CN (100 mL), in a silicon vessel and 48%
aqueous HF (30 mL) was added at room temperature. The resulting
mixture was stirred for 3 h. Then, NaHCO3 was carefully added until
the mixture was neutralized. The organic solvent was removed in
vacuo and the residual aqueous layer was extracted with ethyl
acetate (3ꢃ20 mL). The combined organic extracts were dried over
Na2SO4, concentrated in vacuo and purified on flash column
4.5.2. Aldehyde (rac)-16. To a stirred solution of (rac)-14 (1.5 g,
6.09 mmol) in anhydrous CH2Cl2 (6 mL), under N2 atmosphere,
DIBAL-H (12 mL, 0.5 mol/L in CH2Cl2) was added dropwise during
2 h, at ꢂ78 ꢀC. Then, the resulted solution was warmed to 0 ꢀC and
quenched with a saturated solution of Na/K tartrate (10 mL) and
extracted with dichloromethane (3ꢃ20 mL). The organic layer was
dried over Na2SO4, and concentrated under vacuum. Purification of
the crude material on flash column chromatography, eluting with
pentane/diethyl ether 99/1, gave aldehyde (rac)-16 (1.082 g, 88%) as
colourless oil.
Compound (rac)-16: 1H NMR (CDCl3, 400 MHz):
d 9.72 (1H, br s),
4.29 (1H, m), 2.48 (1H, ddd, J¼15.6, 6.8, 2.9 Hz), 2.39 (1H, ddd,
J¼15.6, 4.9, 2.0 Hz), 1.17 (3H, d, J¼5.9 Hz), 0.80 (9H, s), 0.01 (3H, s),-
0.01 (3H, s). 13C NMR (75 MHz CDCl3):
d 202.1 (CH), 64.4 (CH), 52.8