8
Tetrahedron
ACCEPTED MANUSCRIPT
20 min. Et3N (0.50 mL, 3.55 mmol) was added dropwise to the
reaction mixture and stirred at –78 °C for 2.5 h, and the reaction
mixture was allowed to warm to room temperature and stirred for
30 min. The reaction was quenched with saturated NH4Cl and the
whole mixture was extracted with CH2Cl2 (3 x 10 mL). The
combined organic layers were washed with water (10 mL) and
brine (10 mL), and dried over anhydrous MgSO4. Filtrate was
concentrated in vacuo, and the residue was purified by column
chromatography (silica gel, 10% EtOAc in hexane) to provide 22
(361 mg, 96%) as a colorless oil: [α]D19 –6.3 (c 1.00, CHCl3); IR
(film, cm–1) ν 3422, 1733, 1714, 1502; 1H NMR (400 MHz,
CDCl3) δ 9.52 (s, 1H), 7.68–7.63 (m, 4H), 7.47–7.38 (m, 6H),
5.12 (s, 1H), 4.56 (s, 1H), 4.20 (d, J = 11.0 Hz, 1H), 4.09 (d, J =
12.0 Hz, 1H), 4.04 (d, J = 10.4 Hz, 1H), 3.84 (d, J = 11.0 Hz,
1H), 1.52 (s, 3H), 1.44 (s, 3H), 1.36 (s, 9H), 1.09 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 171.1, 154.9, 135.6, 135.5, 132.5,
132.4, 130.02, 129.97, 127.9, 99.7, 76.4, 63.9, 62.9, 60.3, 56.1,
28.3, 28.2, 26.8, 21.0, 19.2; HRMS (EI) m/z calcd for
C29H41NO6SSi (M)+ 527.2703, found 527.2692.
yl]-3-butenyl acetate (24). Ac2O (4 mL) was added to a solution
of 23 (408 mg, 0.71 mmol) in pyridine (4 mL) at room
temperature. After stirring overnight, the solvent was removed in
vacuo. The resulting residue was solved with EtOAc (20 mL),
and washed water (10 mL) and brine (10 mL), and dried over
anhydrous MgSO4. Filtrate was concentrated in vacuo, and the
residue was purified by column chromatography (silica gel, 10%
EtOAc in hexane) to provide 24 (417 mg, 96%) as a colorless oil:
[α]D21 +50.0 (c 0.50, CHCl3); IR (film, cm–1) ν 3441, 3074, 3051,
1
1748, 1722, 1496; H NMR (400 MHz, CDCl3) δ 7.67–7.61 (m,
4H), 7,47–7.36 (m, 6H), 5.64 (br s, 1H), 5.48 (br s, 1H), 5.39 (br
s, 1H), 5.11 (d, J = 17.6 Hz, 1H), 5.06 (d, J = 10.0 Hz, 1H), 4.41
(s, 1H), 4.30 (d, J = 10.8 Hz, 1H), 4.16 (m, 1H), 4.00 (d, J = 10.8
Hz, 1H), 3.84 (d, J = 10.8 Hz, 1H), 2.39 (t, J = 6.4 Hz, 2H), 2.08
(s, 3H), 1.50 (s, 3H), 1.46 (s, 3H), 1.34 (s, 9H), 1.08 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 170.0, 154.7, 135.6, 135.5, 133.2,
132.7, 129.9, 127.82, 127.81, 118.5, 99.4, 78.9, 70.2, 70.0, 63.5,
62.9, 55.6, 44.3, 36.1, 29.2, 28.3, 27.0, 21.0, 19.2, 18.8; HRMS
(EI) m/z calcd for C34H49NO7SSi (M)+ 611.3278, found 611.3238.
4.4. Total synthesis of myriocin (1)
4.4.3.
[1R,1(4R,5R),3E]-1-Acetoxy-1-[5-(tert-
butyldiphenylsilyloxy)methyl-2,2-dimethyl-5-(1,1-
4.4.1. [1R,1(4R,5R)]-1-[5-(tert-Butyldiphenylsilyloxy)methyl-2,2-
dimethyl-5-(1,1-dimethylethoxycarbonyl)amino-1,3-dioxane-4-
dimethylethoxycarbonyl)amino-1,3-dioxane-4-yl]heptadec-3-en-
11-one (25). Pentadec-1-en-9-one (5,11 88 mg, 0.42 mmol) and
second generation Grubbs catalyst (4.5 mg, 0.0053 mmol) were
added to a solution of alkene 24 (64 mg, 0.11 mmol) in CH2Cl2
(3.3 mL). After stirring at reflux for 5.5 h, the solvent was
removed in vacuo. The resulting residue was purified by column
chromatography (silica gel, 5% EtOAc in hexane) to provide 25
(81 mg, 96%) as a colorless oil: [α]D13 +33.5 (c 1.00, CHCl3); IR
(film, cm–1) ν 3450, 3073, 1745, 1718, 1499; 1H NMR (400
MHz, CDCl3) δ 7.67–7.62 (m, 4H), 7.45–7.36 (m, 6H), 5.49 (br
s, 2H), 5.37 (br s, 1H), 5.26 (br s, 1H), 4.40 (s, 1H), 4.28 (d, J =
10.0 Hz, 1H), 4.17 (m, 1H), 4.00 (d, J = 11.2 Hz, 1H), 3.83 (d, J
= 10.0 Hz, 1H), 2.38 (t, J = 7.6 Hz, 4H), 2.33 (m, 1H), 2.07 (br s,
3H), 1.93 (d, J = 5.6 Hz, 2H), 1.55 (dd, J = 14.4, 7.2 Hz, 2H),
1.55 (m, 1H), 1.50 (s, 3H), 1.46 (s, 3H), 1.33 (s, 9H), 1.20 (br s,
11H), 1.08 (s, 9H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 211.5, 169.9, 154.6, 150.0, 135.5, 134.7, 132.7, 129.9,
127.8, 124.3, 124.2, 99.4, 78.8, 70.5, 70.1, 63.4, 62.9, 55.7, 49.3,
42.8, 34.9, 32.5, 31.6, 29.2, 29.1, 28.9, 26.9, 23.82, 23.76, 23.6,
22.5, 21.1, 19.2, 18.8, 14.0; HRMS (FAB) m/z calcd for
C47H74NO7SSi (M+H)+ 808.5184, found 808.5166.
yl]-3-butene-1-ol
(23)
[1S,1(4R,5R)]-1-[5-(tert-
Butyldiphenylsilyloxy)methyl-2,2-dimethyl-5-(1,1-
dimethylethoxycarbonyl)amino-1,3-dioxane-4-yl]-3-butene-1-ol
(23'). MgI2 (37 mg, 0.13 mmol) was added to a solution of
aldehyde 22 (35 mg, 0.066 mmol) in DMF (1.0 mL) at room
temperature and stirred for 30 min. Indium (11 mg, 0.099 mmol),
a solution of allyl bromide (16 mg, 0.13 mmol) in DMF (1.0
mL), and tetrabutylammonium iodide (TBAI, 24 mg, 0.066
mmol) were added to the reaction mixture. After stirring
overnight, the reaction was quenched with saturated NH4Cl and
the whole mixture was extracted with Et2O (3 x 10 mL). The
combined organic layers were washed with water (10 mL) and
brine (10 mL), and dried over anhydrous MgSO4. Filtrate was
concentrated in vacuo, and the residue was purified by column
chromatography (silica gel, 10% EtOAc in hexane) to provide 23
15
(27 mg, 73%) and 23' (4 mg, 11%) as a colorless oil. 23: [α]D
+17.5 (c 1.00, CHCl3); IR (film, cm–1) ν 3553, 3377, 3073, 1710,
1511; H NMR (400 MHz, CDCl3) δ 7.64–7.61 (m, 4H), 7.43–
1
7.36 (m, 6H), 6.66 (s, 1H), 5.71 (m, 1H), 5.09 (d, J = 17.9 Hz,
1H), 5.08 (d, J = 10.0 Hz, 1H), 4.25 (d, J = 10.8 Hz, 1H), 4.06
(ddd, J = 9.9, 8.0, 6.0 Hz, 1H), 3.99 (s, 2H), 3.97 (d, J = 9.8 Hz,
1H), 3.89 (d, J = 10.8 Hz, 1H), 2.37 (m, 1H), 2.34 (d, J = 9.8 Hz,
1H), 2.19 (m, 1H), 1.44 (s, 3H), 1.42 (s, 3H), 1.37 (s, 9H), 1.07
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.2, 135.6, 135.5,
134.1, 132.8, 132.7, 129.9, 129.8, 127.8, 127.7, 118.0, 99.5, 78.9,
70.9, 68.9, 63.9, 63.4, 57.1, 40.1, 28.4, 27.0, 26.9, 20.8, 19.2;
HRMS (FAB) m/z calcd for C32H47NO6SSi (M+H)+ 570.3251,
4.4.4.
[1R,1(4R,5S),3E]-1-Acetoxy-1-[2,2-dimethyl-5-(1,1-
dimethylethoxycarbonyl)amino-5-hydroxymethyl-1,3-dioxane-4-
yl]heptadec-3-en-11-one (33). Tetrabutylammonium fluoride
(TBAF, 0.14 mL, 1 M in THF, 0.14 mmol) and a solution of
acetic acid (8 mg, 0.14 mmol) in THF (0.2 mL) were added to a
solution of 25 (37 mg, 0.046 mmol) in THF (0.24 mL) at 0 °C.
After stirring at 50 °C for 24 h, the reaction was quenched with
water and the whole mixture was extracted with EtOAc (3 x 5
mL). The combined organic layers were washed with water (5
mL) and brine (5 mL), and dried over anhydrous MgSO4. Filtrate
was concentrated in vacuo, and the residue was purified by
column chromatography (silica gel, 10% EtOAc in hexane) to
23
found 570.3216. 23': [α]D –2.50 (c 0.5, CHCl3); IR (film, cm–
1) ν 3432, 3073, 1695, 1506; 1H NMR (400 MHz, CDCl3)
δ 7.67–7.64 (m, 4H), 7.45–7.34 (m, 6H), 5.90 (m, 1H), 5.30 (s,
1H), 5.07 (d, J = 17.6 Hz, 1H), 5.06 (d, J = 10.0 Hz, 1H), 4.69 (br
s, 1H), 4.53 (d, J = 10.6 Hz, 1H), 3.90 (s, 2H), 3.79 (d, J = 10.6
Hz, 1H), 3.65–3.57 (m, 2H), 2.48–2.44 (m, 2H), 2.15 (ddd, J =
13.6, 12.3, 10.2 Hz, 1H), 1.42 (s, 3H), 1.40 (s, 3H), 1.36 (s, 9H),
1.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 156.5, 135.6, 135.1,
132.9, 132.8, 129.8, 129.7, 127.7, 127.6, 117.0, 98.8, 79.9, 74.6,
70.0, 66.8, 63.0, 56.7, 37.7, 28.34, 28.29, 26.8, 19.3; HRMS
(FAB) m/z calcd for C32H48NO6SSi (M+H)+ 570.3251, found
570.3267.
13
provide 33 (22 mg, 84%) as a colorless oil: [α]D +56.6 (c 1.00,
CHCl3); IR (film, cm–1) ν 3438, 1744, 1711, 1701; 1H NMR (400
MHz, CDCl3) δ 5.61 (s, 1H), 5.50 (dt, J = 15.2, 6.8 Hz, 1H), 5.26
(dt, J = 15.2, 6.8 Hz, 1H), 5.02 (t, J = 6.8 Hz, 1H), 4.75 (d, J =
9.6 Hz, 1H), 4.08 (d, J = 12.4 Hz, 1H), 4.00 (d, J = 12.0 Hz, 1H),
3.75 (d, J =12.4 Hz, 1H), 3.75 (d, J =12.0 Hz, 1H), 3.45 (t, J =
10.8 Hz, 1H), 2.39 (t, J = 7.2 Hz, 4H), 2.30–2.26 (m, 2H), 2.10
(s, 3H), 2.01–1.95 (m, 2H), 1.57–1.54 (m, 3H), 1.52 (s, 3H), 1.43
(s, 12H), 1.27 (br s, 12H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 211.5, 169.9, 156.4, 135.2, 123.9, 99.6,
4.4.2. [1R,1(4R,5R)]-1-[5-(tert-Butyldiphenylsilyloxy)methyl-2,2-
dimethyl-5-(1,1-dimethylethoxycarbonyl)amino-1,3-dioxane-4-