S. Flock et al. / Tetrahedron 72 (2016) 4518e4522
4521
3
.3. (2E,6Z,9Z,12Z)-1-Phenylsulfonyl-2,5,9,12-
3.5. Diastereomer 13a
(20% EtOAc/hexane): 0.32; [
pentadecatetraene (12)
2
5
R
f
a
]
D
¼þ4.6 (c¼0.32, CH
3
OH); IR:
3
2
.3.1. Method A. To
6.2 mmol) and thiophenol (1.7 g, 15.5 mmol) in MeOH (130 mL)
a
stirred solution of LiOHꢂH
2
O(1.1 g,
3506 (broad), 3443, 3388, 3008, 2973, 2933, 1710, 1501, 1447, 1299,
1167, 1144 cm ; H NMR (300 MHz, CDCl
1.17 (d, J¼6.0 Hz, 3 H), 1.39 (s, 9 H), 1.86e2.10 (m, 6 H), 2.63e2.81
(m, 4 H), 3.46 (t, J¼9.8 Hz, 1 H, H-4), 3.58e3.74 (m, 1 H, H-2), 4.17 (s,
1 H, OH), (4.26 m, 1 H, H-3), 4.26 (d, J¼9.8 Hz, 1 H, H-3), 5,01e5.46
(m, 9 H), 7.44e7.54 (m, 2 H), 7.57e7.65 (m, 1 H), 7.73e7.86 (m, 2 H);
ꢀ
1 1
3
)
d
0.93 (t, J¼7.5 Hz, 3 H),
was added, at room temperature, a solution of the bromide 6 (4.0 g,
4.1 mmol) in MeOH (20 mL). After stirring for 3 h at rt, water
100 mL) was added and the mixture extracted with hexane. The
extract was washed with brine and dried (MgSO ). Evaporation of
1
(
4
13
solvents under reduced pressure followed by filtration through
a plug of silica (hexane as eluent) gave (2E, 6Z, 9Z, 12Z)-1-
C NMR (75 MHz, CDCl
(4ꢂCH ), 28.3 (3ꢂCH ), 32.5 (CH
(CHSO
3
)
d
12.3, 14.2 (2ꢂCH
3
), 20.6, 25.4, 25.5, 26.1
2
3
2
), 47.6 (CHNH), 70.1 (CHOH), 72.8
Phenylthio-2,5,9,12-pentadecatetraene (4.1 g, 93%) as an oil. R
f
2
Ph), 79.3 (CO), 118.4, 126.7, 127.7, 128.3, 128.5 (5ꢂCH]),
(
20% EtOAc/hexane): 0.80; IR: 3011, 2962, 2931, 1652, 1585, 1480,
128.8 (3ꢂCH]), 129.3 (2ꢂCH]), 132.0 (CH]), 134.1 (CH]), 136.5
ꢀ1
1
þ
1
2
5
452 cm
;
H NMR (300 MHz, CDCl
3
)
d
0.95 (t, J¼7.5 Hz, 3 H),
(C), 141.2 (CH]), 155.0 (C]O). m/z (CI): 518 (M þ1, 0.9), 57 (100);
þ
.03e2.21 (m, 6 H), 2.75e2.93 (m, 4 H), 3.43e3.52 (m, 2 H),
.20e5.44 (m, 7 H), 5.45e5.55 (1 H), 7.17e7.25 (m, 1 H), 7.27e7.40
(HRMS (Electrospray): found: M þ1, 518.2938. C29
5
H44NO S re-
quires 518.2935).
(
m, 4 H); 13C NMR (75 MHz, CDCl
3
)
d14.2 (CH
3
), 20.5, 25.5, 25.6,
2
6.8, 32.2, 36.4 (6ꢂCH
2
), 125.4, 126.0, 127.0, 128.0, 128.2, 128.3
3.6. Diastereomer 13b
(
1
6ꢂCH]), 128.6 (2ꢂCH]), 129.1 (CH]), 129.8 (2ꢂCH]), 131.9,
þ
25
33.5 (2ꢂCH]), 136.2 (C]); m/z (EI) 312 (M , 8%), 203 (22), 79
R
f
(20% EtOAc/hexane): 0.20; [
a
]
D
¼ꢀ2.45 (c¼0.41, CH
3
OH); IR:
þ
(
100) (HRMS: found: M 312,1919. C21
H28S requires 312, 1912).
3501(broad), 3447, 2970, 2932, 1716, 1499, 1441, 1297, 1158,
ꢀ
1 1
To an ice-cooled solution of the sulfide (4.0 g, 12.8 mmol) in
1136 cm ; H NMR (300 MHz, CDCl
3
)
d
0.92 (t, J¼7.5 Hz, 3 H), 1.17
MeOH (30 mL) and dioxane (20 mL) was added dropwise an
aqueous solution of oxone (23.7 g, 38.4 mmol). The mixture was left
stirring at rt overnight. Water (50 mL) was added and the mixture
(d, J¼6.7 Hz, 3 H), 1.34 (s, 9 H), 1.83e2.08 (m, 6 H), 2.60e2.78 (m,
4 H), 3.56e3.77 (m, 2 H, H-2 and H-4), 4.09 (d, J¼9.5 Hz, 1 H, H-3),
4.33 (s, 1 H, OH), 4.72e4.93 (m, 1 H, NH), 4,95e5.43 (m, 8 H),
13
extracted with CHCl
MgSO ). Evaporation of solvents under reduced pressure followed
by flash chromatography (silica gel, 8:2 hexane/EtOAc) gave the
sulfone 12 (2.7 g, 62%) as an oil. R (30% EtOAc/hexane): 0.45; IR:
000, 2965, 2923, 1445, 1318, 1306, 1152 cm ; H NMR (500 MHz,
CDCl
0.92 (t, J¼7.5 Hz, 3 H), 1.91e2.08 (m, 6 H), 2.62e2.81 (m,
H), 3.71 (d, J¼7.2 Hz, 2 H), 5.12e5.51 (m, 8 H), 7.49e7.57 (m, 2 H),
3
. The extract was washed with brine and dried
7.41e7.52 (m, 2 H), 7.53e7.64 (m, 1 H), 7.77e7.84 (m, 2 H); C NMR
(75 MHz, CDCl ), 20.5, 25.4, 25.5, 25.9 (4ꢂCH ),
14.2, 18.7 (2ꢂCH
28.2 (3ꢂCH ), 32.5 (CH ), 47.7 (CHNH), 71.4 (CHOH), 72.9
(CHSO
(
4
3
)
d
3
2
3
2
f
2
Ph), 78.9 (CO), 117.9, 126.9, 127.8, 128.4, 128.7 (5ꢂCH]),
ꢀ
1 1
3
128.8 (3ꢂCH]), 129.1 (2ꢂCH]), 132.0, 133.9 (2ꢂCH]), 137,0 (C),
þ
3
)
d
141.6 (CH]), 154.8 (C]O). m/z (CI): 518 (M þ1, 0.6), 57 (100). m/z
þ
4
(EI): 461 (1.4), 44 (100); (HRMS (Electrospray): found: M þ1,
13
7
d
.58e7.62 (m, 1 H), 7.78e7.86 (m, 2 H); C NMR (75 MHz, CDCl
14.2 (CH ), 20.4 (CH ), 25.4 (CH ), 25.5 (CH ), 26.2 (CH ), 32.4
CH ), 59.9 (CH
), 116.3, 126.8, 127.7 (3ꢂCH]), 128.4 (2ꢂCH]),
3
)
5
518.2934. C29H44NO S requires 518.2935).
3
2
2
2
2
(
2
2
3.7. Mixture of diastereomers 13c and 13d
1
28.5 (2ꢂCH]), 128.5 (CH]), 128.9 (2ꢂCH]), 131.9, 133.5
þ
1
(
2ꢂCH]),138.2 (C]),140.8 (CH]); m/z (EI) 344 (M , 3%), 203 (82),
R
f
(20% EtOAc/hexane): 0.12; H NMR (300 MHz, CDCl
3
)
d0.92 (t,
þ
7
9 (100) (HRMS: found: M 344,1802. C21
28
H O
2
S requires 344,
J¼7.5 Hz, 2ꢂ3 H), 1.12 (d, J¼6.7 Hz, 3 H), 1.34 (d, J¼6.5 Hz, 3 H), 1.37
1810).
(s, 9 H), 1.39 (s, 9 H), 1.29e2.15 (m, 2ꢂ6 H), 2.58e2.28 (m, 2ꢂ4 H),
3
.38e3.77 (m, 2ꢂ2 H), 4.26e4.45 (m, 2ꢂ1 H), 4.58 (d, J¼8.6 Hz,1 H),
3.3.2. Method B. A solution of bromide 6 (4.0 g, 17.0 mmol) and
4.82 (d, J¼9.4 Hz,1 H), 5.05e5.48 (m, 2ꢂ8 H), 5.49e5.64 (m, 2ꢂ1 H),
ꢁ
13
PhSO
2
Na (5.55 g, 34.0 mmol) in DMF (100 mL) was heated at 80 C
7.38e7.62 (m, 2ꢂ3 H), 7.72e7.81 (m, 2ꢂ2 H); C NMR (75 MHz,
for 15 h. Mixture was cooled to rt followed by addition of water
100 mL) and DCM (100 mL). Phases were separated, and the or-
CDCl
3
)
d
14.1, 18.3, 20.4, 25.4 (2ꢂCH
2
), 26.1, 32.5, 32.6, 49.1, 50.3,
(
70.4, 70.5, 71,2, 72.0, 77.2, 79.4, 117.4, 117.6, 126.8, 127.7, 128.4, 128.5,
128.6 (2ꢂCH), 128.7, 128.8, 129.0, 129.2, 131.8, 131.9, 133.5, 133.6,
137.2, 137.3, 140.8, 142.1, 155.2, 155.7.
ganic phase was washed with water (3ꢂ100 mL). Purification by
chromatography (silica gel, 8:2 hexane/EtOAc) gave the sulfone 12
(
4.1 g, 85%) as an oil.
.4. (2R,5E,9Z,12Z,15Z)-N-Boc-2-Amino-3-hydroxy-4-
3.8. (2R,5E,9Z,12Z,15Z)-N-Boc-2-Amino-3-hydroxy-5,9,12,15-
3
octadecatetraene (14a)
phenysulfonyl-5,9,12,15-octadecatetraene (13)
To a solution of compound 13a (0.150 g, 0.29 mmol) and LiBH
4
ꢁ
n-BuLi (1.3 M in hexane, 5.50 mL, 7.15 mmol) was added to
(0.032 g, 1.45 mmol) in dry THF (10 mL), cooled to ꢀ25 C, was
1
0
a solution of the sulfone 12 (2.67 g, 7.76 mmol) in THF (25 mL) at
added a suspension of Pd(PPh
3
)
2
Cl
2
in THF (5 mL). The mixture
ꢁ
ꢁ
ꢀ
78 C. The mixture was stirred for 30 min before a solution of N-
was left stirring at ꢀ25 C overnight. 0.1 M aq NaOH (3 mL) was
added and the mixture extracted with ether/hexane 1:1. The ex-
tract was washed with water until neutral, then with brine and
Boc- -alaninal (5, 0.80 g, 4.62 mmol) in THF (5 mL) was added
D
dropwise (0.5 mL/min using a syringe pump). The reaction mixture
ꢁ
was stirred at ꢀ78 C for 1.5 h before the reaction was quenched by
dried (MgSO
4
). Evaporation of solvents followed by flash chroma-
addition of water and the mixture extracted with ether. The extract
tography (silica gel, 8:2 hexane/EtOAc) gave the compound 14a
2
5
was washed with water (3ꢂ), brine and dried (MgSO
4
). Evaporation
(0.09 g, 82%) as an oil; Rf (40% EtOAc/hexane): 0.60; [
(c¼0.17, CHCl ) IR:3439 (broad), 3010, 2974, 2932, 1690 (broad),
1505, 1366, 1170 cm ; H NMR (300 MHz, CDCl
a
]
D
¼þ11.6
of solvents under reduced pressure gave a residue that contained
a mixture of unreacted 12 and four diastereomers. Purification by
flash chromatography (silica gel, 8:2 hexane/EtOAc) gave the sul-
fone 12 (1.05 g), diastereomer 13a (0.33 g), diastereomer 13b
3
ꢀ1 1
3
) d
0.94 (t, J¼7.5 Hz,
3 H), 1.06 (d, J¼6.7 Hz, 3 H), 1,42 (s, 9 H), 1.90e2.28 (m, 9 H),
2.62e2.81 (m, 4 H), 3.51e3.72 (m, 2 H, H-2 and H-3), 4.68e4.82 (m,
13
(
(
0.62 g), and an inseparable mixture of diastereomers 13c and 13d
0.61 g, 54:46 according to NMR). The combined yield of 13 was 69%
1 H, NH), 5.21e5.60 (m, 8 H); C NMR (75 MHz, CDCl
3
)
d
14.2, 14.5
), 32.5, 37.2
), 50.1 (CHNH), 73.4 (CHOH), 79.3 (CO), 126.3, 127.0, 128.0,
(2ꢂCH
3
2
), 20.5, 25.5, 25.6, 27.0 (4ꢂCH
2
), 28.4 (3ꢂCH
3
based on alaninal.
(2ꢂCH