A. A. Khan, S. H. Chee, B. L. Stocker, M. S. M. Timmer
FULL PAPER
thesis of α-alkenyl-β-hydroxy diesters, 6g was obtained (eluting in
15:1, PE/EA, v/v) as white solid (0.48 g, 1.03 mmol, 49%, anti/syn
= 9:1). Rf = 0.49 (PE/EA, 2:1, v/v). [α]2D2 = +6.0 (c = 1.0, CHCl3).
General Procedure for the Synthesis of α-Alkyl-β-Hydroxy Diesters:
nBuLi (2.0 m in hexanes, 11.5 mL, 23.0 mmol) was added to a solu-
tion of diisoproplyamine (6.3 mL, 25.0 mmol) in THF (20 mL) at
0 °C. After 30 min, the solution was cooled to –78 °C and 5 (1.9 g,
10 mmol) in THF (20 mL) was added. The resulting mixture was
stirred at –78 °C for 1 h, warmed to –20 °C over 1 h and stirred at
IR (film): ν = 3517, 2924, 2853, 1737, 1219, 1032, 970, 772 cm–1.
˜
1H NMR (500 MHz, CDCl3): δ = 5.56 (dt, J5,6 = 15.4 Hz, J6,7a
J6,7b = 6.6 Hz, 1 H, 6-H), 5.40 (dt, J5,6 = 15.4 Hz, J4a,5 = J4b,5
=
=
6.6 Hz, 1 H, 5-H), 4.31–4.22 (m, 3 H, 1-CH2O and 2-H), 4.19–4.10 –20 °C for 20 min. After cooling to –78 °C, alkyl iodide
(m, 2 H, 3-CO2CH2), 2.90 (ddd, J3,4a = J3,4b = 8.8 Hz, J2,3
3.2 Hz, 1 H, 3-H), 2.58–2.52 (m, 1 H, 4a-H), 2.38 (ddd, J4a,4b
15.2 Hz, J3,4b = 8.8 Hz, J4b,5 = 6.6 Hz, 1 H, 4b-H), 1.99 (q, J6,7
=
=
=
(15.0 mmol, 1 equiv.) in THF (20 mL) was added dropwise, and the
reaction stirred for 2 h, during which time the temperature in-
creased to 0 °C, and stirred for a further 2 h at room temperature.
The reaction was quenched using saturated NH4Cl solution and
J7,8 = 6.6 Hz, 2 H, 7a,b-H), 1.32–1.23 (m, 36 H, 8-H–22-H and 2
CH3), 0.89 (t, J = 7.1 Hz, 3 H, 23-CH3) ppm. 13C NMR (125 MHz, extracted with EtOAc (3ϫ100 mL). The combined organic layers
CDCl3): δ = 173.7 (C-1), 172.3 (3-CO2), 134.4 (C-6), 125.8 (C-5), were washed with water (30 mL) and brine (30 mL), dried
70.2 (C-2), 61.8 (CH2O, OEt-1), 60.8 (CH2O, CO2CH2-3), 48.6 (C- (MgSO4), filtered, and the solvent was removed in vacuo to yield
3), 32.2 (C-4), 31.9 (C-7), 31.1 (C-8), 29.7, 29.66, 29.65, 29.5, 29.4,
a yellow oil. Purification of the residue by flash column chromatog-
29.2, 22.7 (C-9–C-22), 14.1 (C-23), 14.1 (CH3, OEt-1), 14.1 (CH3, raphy gave the alkylated product.
CO2Et-3) ppm. HRMS (ESI): calcd. for C28H52O5Na [M + Na]+
491.3712; found 491.3706.
Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonyldecanoate (anti-6b): By the
reaction of 5 (3.97 g, 20.9 mmol) with 1-iodoheptane (5.13 mL,
31.3 mmol) according to the general procedure for the synthesis of
α-alkylated-β-hydroxy diesters, 6b was obtained (eluting in 15:1,
PE/EA, v/v) as a colourless oil (2.24 g, 7.4 mmol, 37%, anti/syn =
7:1). Rf = 0.73 (PE/EA, 2:1, v/v). [α]2D3 = +0.7 (c = 0.1, CHCl3). IR
Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonylpentacos-5-enoate (anti-
6i): By the reaction of 5 (0.53 g, 2.77 mmol) with 1-iododocos-2-
ene (1.80 g, 4.15 mmol) according to the general procedure for the
synthesis of α-alkenyl-β-hydroxy diesters, 6i was obtained (eluting
in 15:1, PE/EA, v/v) as a white solid (0.57 g, 1.16 mmol, 42%,
anti/syn = 9:1). Rf = 0.6 (PE/EA, 2:1, v/v). [α]2D3 = +5.0 (c = 1.0,
(film): ν = 3522, 3020, 2928, 2857, 1734, 1376, 1216, 1027, 754,
˜
1
668 cm–1. H NMR (500 MHz, CDCl3): δ = 4.31–4.21 (m, 3 H, 1-
CH2O and 2-H), 4.14 (q, Ja,b = 7.1 Hz, 2 H, CH2O, 3-CO2CH2),
CHCl ). IR (film): ν = 3523, 2916, 2849, 1735, 1373, 1213, 1032,
˜
3
3.19 (d, J2,OH = 7.6 Hz, 1 H, OH), 2.84 (td, J3,4 = 7.1 Hz, J2,3
3.7 Hz, 1 H, 3-H), 1.85 (ddt, J4a,4b = 14.9 Hz, J3,4a = J4a,5a = J4a,5b
= 7.1 Hz, 1 H, 4a-H), 1.66 (ddt, J4a,4b = 14.9 Hz, J3,4b = J4b,5a
=
969, 756 cm–1. 1H NMR (500 MHz, CDCl3): δ = 5.56 (dt, J5,6
=
15.1 Hz, J6,7a = J6,7b = 6.9 Hz, 1 H, 6-H), 5.39 (dt, J5,6 = 15.1 Hz,
J4a,5 = J4b,5 = 7.3 Hz, 1 H, 5-H), 4.30–4.22 (m, 3 H, CH2O-1 and
2-H), 4.14–4.10 (m, 2 H, 3-CO2CH2), 3.18 (d, J2,OH = 6.9 Hz, 1 H,
OH), 2.90 (ddd, J3,4a = J3,4b = 8.3 Hz, J2,3 = 3.2 Hz, 1 H, 3-H),
=
J4b,5b = 7.1 Hz, 1 H, 4b-H), 1.40–1.24 (m, 16 H, 5-H–9-H, 2 CH3),
0.89 (t, J = 6.9 Hz, 3 H, 10-CH3) ppm. 13C NMR (125 MHz,
CDCl3): δ = 173.5 (C-1), 172.9 (CO2-3), 71.1 (C-2), 61.8 (CH2O,
OEt-1), 60.8 (CH2O, CO2CH2-3), 48.6 (C-3), 31.8 (C-4), 29.4, 29.1,
28.1, 27.4, 22.6 (C-5–C-9), 14.1 (C-10), 14.1 (CH3, OEt-1), 14.1
(CH3, CO2Et-3) ppm. HRMS (ESI): calcd. for C15H28O5Na [M +
Na]+ 311.1833; found 311.1834.
2.58–2.52 (m, 1 H, 4a-H), 2.38 (ddd, J4a,4b = 14.1 Hz, J3,4a
=
8.3 Hz, J4a,5 = 7.3 Hz, 1 H, 4b-H), 1.99 (q, J6,7 = J7,8 = 6.9 Hz, 2
H, 7a,b-H), 1.33–1.21 (m, 40 H, 8-H–24-H and 2 CH3), 0.88 (t, J
= 7.2 Hz, 3 H, 25-CH3) ppm. 13C NMR (125 MHz, CDCl3): δ =
173.7 (C-1), 172.3 (3-CO2), 134.5 (C-6), 125.8 (C-5), 70.2 (C-2),
61.8 (CH2O, OEt-1), 60.8 (CH2O, CO2CH2-3), 48.6 (C-3), 32.5 (C-
4), 31.9 (C-7), 31.1 (C-8), 29.7, 29.66, 29.64, 29.5, 29.4, 29.2, 22.7
(C-9–C-24), 14.1 (C-25), 14.1 (CH3, OEt-1), 14.1 (CH3, CO2Et-3)
ppm. HRMS (ESI): calcd. for C30H56O5Na [M + Na]+ 519.4025;
found 519.4029.
Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonylheptadecanoate (anti-6d):
By the reaction of 5 (0.44 g, 2.35 mmol) with 1-iodotetradecane
(1.14 g, 3.53 mmol) according to the general procedure for the syn-
thesis of α-alkyl-β-hydroxy diesters, 6d was obtained (eluting in
15:1, PE/EA, v/v) as a colourless oil (0.14 g, 0.34 mmol, 15%,
anti/syn = 9:1). Rf = 0.66 (PE/EA, 2:1, v/v). [α]2D3 = +4.0 (c = 1.0,
Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonylheptacos-5-enoate (anti-
6j): By the reaction of 5 (0.55 g, 2.89 mmol) with 1-iodotetracos-2-
ene (2.0 g, 4.32 mmol) according to the general procedure for the
synthesis of α-alkenyl-β-hydroxy diesters, 6j was obtained (eluting
in 15:1, PE/EA, v/v) as a white solid (0.62 g, 1.19 mmol, 41%,
anti/syn = 9:1). Rf = 0.58 (PE/EA, 2:1, v/v). [α]2D2 = +0.1 (c = 1.0,
CHCl ). IR (film): ν = 3514, 3020, 2925, 2584, 1735, 1466, 1369,
˜
3
1216, 755 cm–1. H NMR (500 MHz, CDCl3): δ = 4.29–4.22 (m, 3
1
H, 1-CH2O and 2-H), 4.14 (q, J = 7.1 Hz, 2 H, 3-CO2CH3), 3.19
(d, J2,OH = 7.6 Hz, 1 H, OH), 2.84 (td, J3,4 = 7.2 Hz, J2,3 = 3.5 Hz,
1 H, 3-H), 1.83 (ddt, J4a,4b = 14.0 Hz, J3,4a = J4a,5a = J4a,5b
7.2 Hz, 1 H, 4a-H), 1.66 (ddt, J4a,4b = 14.0 Hz, J3,4b = J4b,5a
=
=
CHCl ). IR (film): ν = 3351, 2922, 2852, 1736, 1376, 1215, 1042,
˜
3
J4b,5b = 7.2 Hz, 1 H, 4b-H), 1.45–1.21 (m, 30 H, 5-H–16-H and 2
CH3), 0.87 (t, J = 6.4 Hz, 3 H, 17-CH3) ppm. 13C NMR (125 MHz,
CDCl3): δ = 173.5 (C-1), 172.9 (CO2-3), 71.1 (C-2), 61.8 (CH2O,
OEt-1), 60.8 (CH2O, CO2CH2-3), 48.6 (C-3), 31.9 (C-4), 29.74,
29.73, 29.71, 29.70, 29.64, 29.62, 29.4, 28.1, 27.4, 22.7 (C-5–C-16),
14.2 (C-17), 14.1 (CH3, OEt-1), 14.1 (CH3, CO2Et-3) ppm. HRMS
(ESI): calcd. for C22H42O5Na [M + Na]+ 409.2931; found 409.2928.
756 cm–1. 1H NMR (500 MHz, CDCl3): δ = 5.56 (dt, J5,6
=
15.1 Hz, J6,7a = J6,7b = 6.8 Hz, 1 H, 6-H), 5.39 (dt, J5,6 = 15.1 Hz,
J4a,5 = J4b,5 = 6.5 Hz, 1 H, 5-H), 4.30–4.22 (m, 3 H, 1-CH2O and
2-H), 4.16–4.12 (m, 2 H, 3-CO2CH2), 3.17 (d, J2,OH = 7.3 Hz, 1 H,
OH), 2.91 (ddd, J3,4a = J3,4b = 9.1 Hz, J2,3 = 3.2 Hz, 1 H, 3-H),
2.58–2.53 (m, 1 H, 4a-H), 2.38 (ddd, J4a,4b = 14.3 Hz, J3,4a
=
9.1 Hz, J4a,5 = 6.5 Hz, 1 H, 4b-H), 2.00 (q, J6,7 = J7,8 = 7.8 Hz, 2
H, 7a,b-H), 1.37–1.18 (m, 44 H, 8-H–26-H and 2 CH3), 0.88 (t, J Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonyltricosanoate (anti-6f): By
= 6.8 Hz, 3 H, 27-CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = the reaction of 5 (0.22 g, 1.15 mmol) with 1-iodoeicosane (0.70 g,
173.7 (C-1), 172.3 (3-CO2), 134.5 (C-6), 125.8 (C-5), 70.2 (C-2), 1.72 mmol) according to the general procedure for the synthesis of
61.8 (CH2O, OEt-1), 60.8 (CH2O, CO2CH2-3), 48.6 (C-3), 32.6 (C- α-alkyl-β-hydroxy diesters, 6f was obtained (eluting in 15:1, PE/EA,
4), 31.9 (C-7), 31.1 (C-8), 29.71, 29.67, 29.65, 29.58, 29.52, 29.37,
v/v) as a white solid (0.02 g, 0.05 mmol, 4%, anti/syn = 6:1). Rf =
29.2, 22.7 (C-9–C-26), 14.2 (C-27), 14.1 (CH3, OEt-1), 14.1 (CH3, 0.58 (PE/EA, 2:1, v/v). [α]2D3 = +2.0 (c = 1.0, CHCl ). IR (film): ν
˜
3
CO2Et-3) ppm. HRMS (ESI): calcd. for C32H60O5Na [M + Na]+
547.4338; found 547.4344.
= 2918, 2850, 1737, 1252, 1182, 1099, 1030, 837, 757 cm–1. 1H
NMR (500 MHz, CDCl3): δ = 4.31–4.21 (m, 3 H, 1-CH2O and 2-
1000
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Eur. J. Org. Chem. 2012, 995–1002