5
1
986.6, 900.2, 752.3, 724.3, 634.7 cm-1; H NMR (300 MHz,
Following the general procedure, the residue was purified by
ACCEPTED MANUSCRIPT
CDCl3) δ 4.47 (dd, J = 12.5, 6.6 Hz, 1H), 3.76 (s, 3H), 2.67 (d, J
= 5.8 Hz, 1H), 1.73 (ddd, J = 7.5, 4.9, 1.5 Hz, 2H), 1.44 (dd, J =
8.4, 5.5 Hz, 2H), 1.35 – 1.23 (m, 8H), 0.92 – 0.82 (m, 3H). 13C
NMR (75 MHz, CDCl3) δ 153.58, 88.22, 75.77, 61.70, 52.41,
36.50, 31.36, 28.75, 28.72, 24.56, 22.23, 13.66. HRMS ESI
[M+Na]+ calcd for C12H20O3Na+ 235.1305, found 235.1305.
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column (98:2 n-hexanes: isopropanol, 1.0 mL/min, 220
nm); major (S)-enantiomer tr = 15.71 min, minor (R)-enantiomer
tr =14.13 min.
silica gel chromatography (hexanes/ethyl acetate 10:1) to offer
25
(S)-20e (0.0911 g, 65% yield, 98% ee) as colorless oil. [α]D
=
+33.7 (c 1.05, CH2Cl2); IR vmax (neat): 3417.9, 3093.5, 3021.2,
2958.1, 2848.4, 2516.2, 2236.8, 1889.6, 1719.9, 1644.2, 1436.5,
1408.3, 1258.6, 1125.1, 1069.6, 1042.1, 988.4, 952.2, 905.4,
828.1, 752.5, 633.9 cm-1; H NMR (300 MHz, CDCl3) δ 5.97
1
(ddd, J = 17.0, 10.2, 5.3 Hz, 1H), 5.58 – 5.47 (m, 1H), 5.32 (d, J
= 10.2 Hz, 1H), 5.02 (dd, J = 6.7, 5.3 Hz, 1H), 3.80 (s, 3H), 2.93
(d, J = 6.7 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 153.46,
134.48, 117.54, 85.55, 76.86, 62.33, 52.56. HRMS ESI [M+Na]+
calcd for C7H8O3Na+ 163.0366, found 163.0366. Enantiomeric
excess was determined by HPLC with a Chiralcel OD-H column
(98:2 n-hexanes: isopropanol, 1.0 mL/min, 220 nm); major
(S)-enantiomer tr = 26.31 min, minor (R)-enantiomer tr = 22.08
min.
4.1.2. Methyl (S)-4-hydroxynon-2-ynoate: (S)-20b
Following the general procedure, the residue was purified by
silica gel chromatography (hexanes/ethyl acetate 10:1) to offer
(S)-20b (0.1308 g, 71% yield, 99% ee) as colorless oil. [α]D25 = -
5.5 (c 1.05, CH2Cl2); IR vmax (neat): 3336.3, 2926.8, 2856.8,
2236.7, 1719.9, 1463.5, 1438.5, 1252.7, 1125.6, 1066.6, 1046.8,
944.32, 912.6, 889.1, 822.3, 796.9, 752.5, 729.1, 691.1, 634.7
cm-1; H NMR (300 MHz, CDCl3) δ 4.47 (q, J = 6.4 Hz, 1H), 3.76
(s, 3H), 2.66 (d, J = 4.7 Hz, 1H), 1.80 – 1.67 (m, 2H), 1.52 – 1.38
(m, 2H), 1.35 – 1.25 (m, 4H), 0.88 (t, J = 6.7 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 153.57, 88.19, 75.78, 61.71, 52.40, 36.46,
30.95, 24.23, 22.08, 13.54. HRMS ESI [M+Na]+ calcd for
C10H16O3Na+ 207.0992, found 207.0992. Enantiomeric excess
was determined by HPLC with a Chiralcel OD-H column (98:2
n-hexanes: isopropanol, 1.0 mL/min, 220 nm); major
(S)-enantiomer tr = 17.07 min, minor (R)-enantiomer tr =14.94
min.
4.2. Synthesis of virol A (Method A and Method B)
4.2.1. Synthesis of (S)-oct-1-yn-3-ol: (S)-1b
(Method A) A solution of (S)-20b 0.9211g (5 mmol) and THF
(60 mL) were cooled to 0 °C, 1M aq LiOH (25 mmol, 5 eq) was
added at a slow rate. The solution was warmed to rt and stirred
for an additional 1 h before it was quenched with 1M aq NaHSO4
(50 mL) . The aqueous phase was extracted by ethyl acetate. The
combined organic phases were dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The residue was dissolved
in acetonitrile (12 mL), CuCl (6 mmol, 1.2 eq) was added in one
portion to the mixture. The mixture was allowed to warm to rt
and stirred for another 13h. The aqueous phase was extracted by
ether. The combined organic phases were dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue
was purified by silica gel chromatography (hexanes/ehthyl
acetate 20:1) to give (S)-1b (0.536 g, 85% yield) as a colorless
oil. [α]D25 = –6.3(c 0.70, CHCl3); IR vmax (neat): 3336.3, 2926.8,
2856.8, 2731.7, 2114.9, 1710.9, 1632.3, 1436.5, 1379.6, 1337.3,
1312.3, 1276.6, 1184.5, 1046.8, 1027.8, 968.4, 896.4, 726.5,
4.1.3. Methyl (S)-4-hydroxyhept-2-ynoate: (S)-20c
Following the general procedure, the residue was purified by
silica gel chromatography (hexanes/ethyl acetate 10:1) to offer
(S)-20c (0.1047 g, 67% yield, 99% ee) as colorless oil. [α]D25 = -
6.1 (c 1.05, CH2Cl2); IR vmax (neat): 3417.9, 2958.1, 2875.8,
2236.8, 1719.9, 1436.5, 1383.5, 1258.6, 1123.4, 1102.6, 1071.5,
1042.8, 985.3, 965.9, 905.4, 879.7, 852.7, 826.6, 795.6, 752.5,
692.9, 633.9 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.51 (d, J = 6.0
Hz, 1H), 3.79 (s, 3H), 3.02 (d, J = 5.8 Hz, 1H), 1.83 – 1.66 (m,
2H), 1.58 – 1.41 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ 153.64, 88.29, 75.69, 61.40, 52.45, 38.47, 17.88,
13.22. HRMS ESI [M+Na]+ calcd for C8H12O3Na+ 179.0679,
found 179.0679. Enantiomeric excess was determined by HPLC
with a Chiralcel OD-H column (98:2 n-hexanes: isopropanol, 1.0
mL/min, 220 nm); major (S)-enantiomer tr = 19.49 min, minor
(R)-enantiomer tr =17.45 min.
654.1, 627.9 cm-1; H NMR (300 MHz, CDCl3) δ 4.30 (m, 1H),
1
3.10 (s, 1H), 2.40 (d, J = 2.1 Hz, 1H), 1.75 – 1.54 (m, 2H), 1.46 –
1.33 (m, 2H), 1.33 – 1.11 (m, 4H), 0.83 (t, J = 7.0 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ 84.82, 72.31, 61.71, 37.15, 31.03,
24.33, 22.11, 13.53. HRMS ESI [M+Na]+ calcd for C8H14ONa+
149.0937, found 149.0942.
4.2.2. Synthesis of
(S,E)-1-chlorodec-1-en-3-yn-5-ol: (S)-19
(Method A) A solution of CuI (57 mg, 0.3 mmol), Pd(PPh3)4
(86 mg, 0.75mmol), trans-1,2-Dichloroethylene(1.1 mL, 1.5
mmol) in benzene (3 mL) were cooled to 0 °C, (S)-1b (189 mg,
1.5mmol) and piperidine (0.3 mL,3 mmol) were added
sequentially. The solution was warmed to rt and stirred for an
additional 6 h before it was quenched with aq NH4Cl (3 mL). The
aqueous phase was extracted by ether. The combined organic
phases were dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (hexanes/ehthyl acetate 10:1) to give (S)-19
(0.238 g, 85% yield) as a colorless oil. [α]D25 = +8.0 (c 0.57,
CHCl3), lit34 [α]D25 = +7.0 (c 0.57, CHCl3); IR vmax (neat): 3336.3,
3074.6, 3026.5, 2926.8, 2856.8, 2731.2, 2214.1, 2140.6, 1704.3,
1585.5, 1463.5, 1408.8, 1379.6, 1335.3, 1229.4, 1163.1, 1112.3,
1046.8, 1026.4, 917.4, 848.6, 725.6, 657.1 cm-1.1H NMR (300
MHz, CHCl3) δ 6.53 (dd, J = 13.7, 0.4 Hz, 1H), 5.95 (dd, J =
13.7, 1.9 Hz, 1H), 4.47 (d, J = 5.9 Hz, 1H), 2.00 (d, J = 4.9 Hz,
1H), 1.71 (dd, J = 6.6, 5.4 Hz, 2H), 1.43 (ddd, J = 12.9, 9.3, 6.8
Hz, 2H), 1.37 – 1.26 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 130.30, 112.92, 92.61, 79.47, 62.53, 37.29,
4.1.4. Methyl (S)-4-hydroxyhex-2-ynoate: (S)-20d
Following the general procedure, the residue was purified by
silica gel chromatography (hexanes/ethyl acetate 10:1) to offer
(S)-20d (0.1009 g, 71% yield, 99% ee) as colorless oil. [α]D25 = -
5.8 (c 1.05, CH2Cl2); IR vmax (neat): 3336.3, 2926.8, 2856.8,
2732.2, 2236.2, 1720.1, 1463.5, 1436.1, 1379.1, 1250.1, 1113.6,
1048.9, 955.9, 917.8, 825.5, 752.3, 726.2, 634.8 cm-1;1H NMR
(300 MHz, CDCl3) δ 4.45 (dd, J = 12.4, 6.5 Hz, 1H), 3.79 (s,
3H), 3.09 (d, J = 5.8 Hz, 1H), 1.87 – 1.75 (m, 2H), 1.04 (t, J =
7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 153.64, 88.07, 75.76,
62.84, 52.45, 29.64, 8.88. HRMS ESI [M+Na]+ calcd for
C7H10O3Na+ 165.0522, found 165.0528. Enantiomeric excess was
determined by HPLC with a Chiralcel OD-H column (98:2
n-hexanes: isopropanol, 1.0 mL/min, 220 nm); major
(S)-enantiomer tr = 16.95 min, minor (R)-enantiomer tr =15.15
min.
4.1.5. Methyl (S)-4-hydroxyhex-5-en-2-ynoate:
(S)-20e