ACCEPTED MANUSCRIPT
10
Tetrahedron
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atmosphere. The reaction mixture was warmed to 23 C and
(s, 9H), 0.03 (d, J = 9.0 Hz, 6H). LRMS-ESI (m/z): 581.6
stirred for 2h. Upon completion, the reaction mixture was
purified by silica gel column chromatography (5% EtOAc in
hexane) to give 35 (3.4 mg, 80%) as a colorless oil. H NMR
[M+Na]+.
8-(R)-MTPA ester of 38 (40): 38 (2 mg) was treated with (S)-
(+)-MTPACl (2.2 mg) by following the above esterification
procedure to afford 40 (2.6 mg, 80%) as a colorless oil. 1H NMR
(500 MHz, CDCl3) δ 7.54 – 7.49 (m, 2H), 7.4 – 7.36 (m, 3H),
5.52 (dd, J = 8.4, 5.3 Hz, 1H), 5.11 – 5.08 (m, 2H), 4.12 (p, J =
6.5 Hz, 1H), 3.94 – 3.88 (m, 2H), 3.55 – 3.51 (m, 3H), 2.27 –
2.17 (m, 2H), 2.12 – 2.04 (m, 1H), 1.7 – 1.66 (m, 1H), 1.63 –
1.57 (m, 1H), 1.55 – 1.52 (m, 1H), 1.51 – 1.48 (m, 1H), 1.27 –
1.25 (m, 3H), 0.92 (t, J = 6.4 Hz, 6H), 0.88 (s, 9H), 0.04 (d, J =
5.1 Hz, 6H). LRMS-ESI (m/z): 581.5 [M+Na]+.
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(500 MHz, CDCl3) δ 7.54 – 7.50 (m, 2H), 7.38 (dd, J = 5.2, 1.8
Hz, 3H), 6.29 – 6.21 (m, 1H), 5.84 (dq, J = 9.7, 3.0 Hz, 1H), 5.80
(dd, J = 10.7, 4.3 Hz, 1H), 5.62 – 5.55 (m, 1H), 5.51 (s, 1H), 5.40
(dd, J = 7.3, 5.0 Hz, 1H), 5.04 (s, 2H), 5.00 (d, J = 4.5 Hz, 2H),
4.98 – 4.94 (m, 1H), 4.86 (s, 1H), 4.19 – 4.14 (m, 1H), 3.95 (q, J
= 6.6 Hz, 1H), 3.88 (ddd, J = 8.1, 5.4, 3.9 Hz, 1H), 3.56 (s, 3H),
2.75 (s, 2H), 2.29 – 2.26 (m, 1H), 2.25 (d, J = 4.8 Hz, 1H), 2.22
(d, J = 6.7 Hz, 1H), 2.20 – 2.15 (m, 3H), 2.10 (d, J = 8.0 Hz, 1H),
2.09 – 2.06 (m, 1H), 2.03 (dd, J = 11.1, 4.7 Hz, 1H), 1.88-1.8 (m,
2H), 1.75 (d, J = 1.0 Hz, 3H), 1.68 (s, 3H), 1.53-1.48 (m, 1H),
1.27-1.25 (m, 3H), 0.87 (s, 9H), 0.04 (d, J = 6.4 Hz, 6H). LRMS-
ESI (m/z): 753.7 [M+Na]+.
8-(R)-MTPA ester of 34 (36): 34 (3 mg) was treated with (S)-
(+)-MTPACl (2.2 mg) by following the above esterification
procedure to afford 36 (3.3 mg, 80%) as a colorless oil. 1H NMR
(500 MHz, CDCl3) δ 7.54 – 7.51 (m, 2H), 7.38 (dd, J = 5.3, 1.9
Hz, 3H), 6.29 – 6.22 (m, 1H), 5.87 – 5.82 (m, 1H), 5.80 (dd, J =
11.1, 5.1 Hz, 1H), 5.63 – 5.55 (m, 1H), 5.45 (s, 1H), 5.44 – 5.42
(m, 1H), 5.15 (s, 1H), 5.14 – 5.11 (m, 1H), 5.05 – 5.00 (m, 1H),
4.99 – 4.98 (m, 1H), 4.98 – 4.95 (m, 1H), 4.84 (s, 1H), 4.19 –
4.14 (m, 1H), 3.96 (q, J = 6.6 Hz, 1H), 3.91 (ddd, J = 9.2, 5.5, 3.9
Hz, 1H), 3.54 (s, 3H), 2.75 (s, 2H), 2.31 (dd, J = 15.6, 3.6 Hz,
1H), 2.28 – 2.22 (m, 1H), 2.21 – 2.13 (m, 5H), 1.91 (dt, J = 8.9,
5.9 Hz, 2H), 1.83 – 1.75 (m, 2H), 1.71 (d, J = 1.1 Hz, 3H), 1.68
(s, 3H), 1.55 – 1.49 (m, 1H), 1.27-1.26 (m, 3H), 0.88 (s, 9H),
0.04 (d, J = 6.1 Hz, 6H); LRMS-ESI (m/z): 753.7 [M+Na]+.
(R)-2-(((2R,3S,5R)-3-((Tert-butyldimethylsilyl)oxy)-5-
methyltetrahydrofuran-2-yl)methyl)-5-methylhex-1-en-3-ol
(37): To a degassed (for 15 min with an argon purge) solution of
vinyl iodide 17 (20 mg, 0.05 mmol) and isovaleraldehyde (11 µL,
0.1 mmol) in DMF (1.0 mL) were added NiCl2 (0.7 mg, 0.005
mmol) and CrCl2 (32 mg, 0.26 mmol) at 0 C. The reaction
mixture was stirred at 0 C for 24 h. The reaction mixture was
quenched by the addition of saturated aqueous NH4Cl and
extracted with EtOAc. The extracts were dried over Na2SO4 and
concentrated under reduced pressure to give the curde product in
2:1 mixture of diastereomers. The major diastereomer was
purified by silica gel column chromatography (10% EtOAc in
(S,6E,10E,12E)-2-(((2S,3S,5R)-3-((Tert-butyl-
dimethylsilyl)oxy)-5-methyltetrahydrofuran-2-yl)
methyl)-
6,10-dimethyl-8-methyleneheptadeca-1,6,10,12,16-pentaen-3-
ol (41): To a degassed (for 15 min with an argon purge) solution
of vinyl iodide 22 (4 mg, 0.01 mmol) and aldehyde 415 (3 mg,
0.01 mmol) in DMF (0.5 mL) were added NiCl2 (0.14 mg, 0.001
mmol) and CrCl2 (6 mg, 0.05 mmol) at 0 oC. The reaction
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mixture was warmed to 23 C and stirred for 24 h. The reaction
mixture was quenched by the addition of saturated aqueous
NH4Cl and extracted with EtOAc. The extracts were dried over
Na2SO4 and concentrated under reduced pressure to give the
curde product in 4:1 mixture of diastereomers. The major
diastereomer was purified by silica gel column chromatography
(10% EtOAc in Pentane) to give 41 (3 mg) as a colorless oil.
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[α]D -8.7 (c 0.15, CHCl3); H NMR (500 MHz, CDCl3) δ 6.25
(dd, J = 15.1, 10.8 Hz, 1H), 5.87-5.79 (m, 2H), 5.62 – 5.52 (m,
2H), 5.13 – 4.91 (m, 5H), 4.87 (brs, 1H), 4.29 – 4.25 (m, 1H),
4.00 (ddt, J = 23.4, 12.7, 6.8 Hz, 3H), 3.74 (ddd, J = 10.2, 4.4,
2.8 Hz, 1H), 2.77 (brs, 2H), 2.51 (dd, J = 14.5, 10.3 Hz, 1H),
2.32-2.26 (m, 1H), 2.25-2.11 (m, 5H), 2.1-2.06 (m, 1H), 2.03-
1.97 (m, 1H), 1.83-1.75(m, 3H), 1.74 – 1.70 (m, 1H), 1.69 (brs,
3H), 1.62 – 1.58 (m, 1H), 1.55 (dt, J = 6.5, 3.3 Hz, 1H), 1.35 –
1.29 (d, J = 6.2 Hz, 3H), 0.91 (s, 9H), 0.07 (d, J = 2.3 Hz, 6H);
13C NMR (125 MHz, CDCl3) δ 149.6, 143.9, 138.5, 138.4, 134.6,
132.0, 127.2, 126.5, 125.8, 114.8, 114.5, 114.2, 84.4, 75.5, 74.3,
73.9, 48.4, 43.2, 36.9, 34.7, 33.9, 32.5, 32.0, 25.9, 22.2, 18.3,
18.1, 16.4, -4.4, -4.9; IR: 3400, 2930, 2857, 2360, 2343, 1256,
1067, 836, 775, 668 cm-1; HRMS-ESI (m/z): [M+Na]+ calcd for
C32H54O3SiNa, 537.3740; found 537.3734.
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(-)-Amphirionin-4 (1): To a solution of 41 (3 mg, 0.006 mmol)
in THF/pyridine (0.4 mL/0.6 mL) in a plastic vessel was added
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pentane) to give 37 (12 mg, 67 %)as a light yellow oil. [α]D
+50.7 (c 0.38, CHCl3); H NMR (500 MHz, CDCl3) δ 5.05 (s,
1
o
HF•py complex (0.3 mL) at 0 C under argon atmosphere. The
reaction mixture was warmed to 23 C and stirred for 9 h. Upon
completion, the reaction mixture was quenched by the addition of
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1H), 4.93 (s, 1H), 4.21 (dt, J = 7.9, 6.3 Hz, 1H), 4.18 – 4.13 (m,
1H), 3.97 (q, J = 7.0 Hz, 1H), 3.81 (ddd, J = 9.5, 6.0, 3.3 Hz,
1H), 3.70 (s, 1H), 2.33 – 2.18 (m, 3H), 1.68 (dp, J = 13.3, 6.7 Hz,
1H), 1.58 – 1.47 (m, 2H), 1.32 – 1.28 (m, 1H), 1.27 (d, J = 6.2
Hz, 3H), 0.93 – 0.90 (m, 6H), 0.89 (s, 9H), 0.07 (d, J = 4.1 Hz,
6H): 13C NMR (125 MHz, CDCl3) δ 149.2, 114.0, 84.9, 73.7,
45.5, 42.6, 35.3, 25.9, 24.7, 23.1, 22.6, 22.2, 18.1, -4.3, -4.6.
LRMS-ESI (m/z): 365.3 [M+Na]+.
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saturated aqueous NaHCO3 at 0 C and stirred for 15 min at 23
oC. The mixture was extracted with EtOAc (×3) and concentrated
under reduced pressure. The crude product was purified by silica
gel column chromatography (40% EtOAc in Hexane) to give (˗)-
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amphirionin-4 (1) (2.1 mg, 90%) as a colorless oil. [α]D -6 (c
0.1, CHCl3); H NMR (500 MHz, C6D6) δ 6.34 (dd, J = 15.0,
1
8-(S)-MTPA ester of 38 (39): To a stirred solution of 38 (2 mg)
in CH2Cl2 (1.0 mL) were added DMAP (0.07 mg), triethylamine
(10 µL) and (R)-(˗)-MTPACl (2.2 mg) at 0 oC under argon
atmosphere. The reaction mixture was warmed to 23 oC and
stirred for 4h. Upon completion, the reaction mixture was
purified by silica gel column chromatography (5% EtOAc in
10.8 Hz, 1H), 5.98 (brd, J = 10.8 Hz, 1H), 5.81 (brs, 1H), 5.76
(ddd, J = 17.0, 6.4, 3.8 Hz, 1H), 5.58 (brdt, J = 14.4, 6.7 Hz, 1H),
5.12 – 5.08 (m, 1H), 5.06 (brs, 1H), 5.05 – 5.01 (m, 1H), 5.01 –
5.00 (m, 1H), 4.99 – 4.96 (m, 1H), 4.92 (brs, 1H), 4.15 – 4.10 (m,
1H), 3.77 (dt, J = 6.2, 3.5 Hz, 1H), 3.61 – 3.56 (m, 1H), 3.48 (dt,
J = 8.6, 4.4 Hz, 1H), 2.83 (brs, 2H), 2.63 (dd, J = 14.5, 8.8 Hz,
1H), 2.29 – 2.24 (m, 1H), 2.22 (dd, J = 8.6, 5.6 Hz, 1H), 2.20 –
2.13 (m, 1H), 2.13 – 2.09 (m, 2H), 2.09 – 2.03 (m, 2H), 1.90 –
1.87 (m, 1H), 1.85 (dd, J = 6.0, 3.3 Hz, 1H), 1.84 – 1.79 (m, 3H),
1.77 – 1.72 (m, 1H), 1.72 – 1.67 (m, 3H), 1.19 (ddd, J = 13.5,
6.7, 2.4 Hz, 1H), 1.14 (d, J = 6.2 Hz, 3H); 13C NMR (125 MHz,
C6D6) δ 150.1, 144.3, 138.7, 138.5, 134.2, 132.1, 127.5, 127.4,
126.3, 114.9, 114.8, 112.8, 84.2, 75.2, 73.9, 73.4, 48.8, 43.2,
37.2, 35.0, 34.2, 32.8, 31.6, 22.0, 18.2, 16.4; IR: 3394, 2925,
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hexane) to give 39 (2.6 mg, 80%) as a colorless oil. H NMR
(500 MHz, CDCl3) δ 7.53 – 7.49 (m, 2H), 7.40 – 7.36 (m, 3H),
5.56 (dd, J = 8.7, 4.7 Hz, 1H), 5.22 (s, 1H), 5.19 – 5.17 (m, 1H),
4.16 (h, J = 6.3 Hz, 1H), 3.94 (pd, J = 5.2, 1.5 Hz, 2H), 3.54 –
3.52 (m, 3H), 2.37 – 2.28 (m, 1H), 2.28 – 2.21 (m, 1H), 2.17 –
2.09 (m, 1H), 1.66 – 1.62 (m, 1H), 1.55 – 1.50 (m, 1H), 1.47 –
1.42 (m, 2H), 1.27 (d, J = 6.2 Hz, 3H), 0.90 – 0.87 (m, 6H), 0.87