A.C. Bissember, M.G. Banwell / Tetrahedron 65 (2009) 8222–8230
8229
(410 mg, 99%) as a clear, yellow oil [Found: (MþH)þ, 228.1592.
immediately above) and 4-(N,N-dimethylamino)pyridine (43 mg,
0.36 mmol) in diethyl ether (30 mL) maintained under nitrogen at
18 ꢀC. After 22 h the reaction mixture was concentrated under
reduced pressure and the ensuing yellow oil was subjected to flash
chromatography (silica, 9:1 v/v hexane/ethyl acetate elution).
Concentration of the appropriate fractions (Rf¼0.5, 9:1 v/v
dichloromethane/ethyl acetate) afforded an indeterminable mix-
ture of the epimers of the title compound 25 (1.99 g, 91% over 3
steps) as a clear, light-yellow oil [Found: (MþH)þ, 296.1863.
C16H25NO4 requires (MþH)þ, 296.1862]. 1H NMR (300 MHz)
C12H21NO3 requires (MþH)þ, 228.1600]. 1H NMR (300 MHz)
d 6.05–
5.95 (m, 1H), 5.83–5.65 (m, 1H), 5.52 (dd, J¼9.9, 1.5 Hz, 1H), 5.23–
5.08 (m, 2H), 4.58 (s, 2H), 3.67–3.50 (m, 3H), 3.40–3.33 (m, 2H), 3.35
(s, 3H), 3.10–3.04 (m,1H), 2.95–2.84 (m, 2H), 2.72 (td, J¼10.5, 3.9 Hz,
1H), 2.26–2.10 (m, 1H), 2.04–1.90 (m, 1H); 13C NMR (75 MHz)
d
136.7,130.0,128.7,116.6, 96.5, 68.2, 62.7, 61.3, 55.3, 51.5, 42.8, 25.4;
nmax (NaCl) 3423, 2921,1149,1107,1038, 917 cmꢂ1; MS (ESI) m/z 250
[(MþNa)þ, 19%], 228 [(MþH)þ, 39], 196 (7), 166 (22), 148 (30), 70
(100).
Step iii. A solution of dimethyl sulfoxide (1.51 mL, 21.3 mmol) in
dichloromethane (5 mL) was added dropwise to a magnetically stir-
red solution of oxalyl chloride (1.24 mL, 14.2 mmol) in dichloro-
methane (40 mL) maintained under nitrogen at ꢂ78 ꢀC. After 0.25 h
a solution of the {1-allyl-2-[(methoxymethoxy)methyl]-1,2,5,6-tet-
rahydropyridin-2-yl}methanol (1.60 g, 7.10 mmol) in dichloro-
methane (30 mL) was added dropwise over 0.25 h. After 1 h
a solution of triethylamine (3.95 mL, 28.4 mmol) in dichloromethane
(15 mL) was added and the reaction mixture was then warmed to
18 ꢀC and maintained at this temperature for a further 1 h. Sodium
bicarbonate (20 mL of a saturated solution) wasadded and the phases
separated. The aqueous layer was extracted with dichloromethane
(3ꢁ30 mL) and the combined organic phases were dried (MgSO4),
filtered, and concentrated under reduced pressure to give aldehyde 23
as a clear, colorless oil [Found: (MþH)þ, 226.1438. C12H19NO3 requires
d 6.05–5.90 (m, 2H), 5.75–5.60 (m, 2H), 5.60–5.45 (m, 1H), 5.20–
5.00 (m, 3H), 4.60–4.50 (m, 2H), 3.75–3.60 (m, 2H), 3.51 (d,
J¼10.5 Hz, 1H), 3.34 (s, 3H), 3.12–2.92 (m, 1H), 2.84–2.74 (m, 1H),
2.64–2.53 (m, 1H), 2.09 (s, 3H), 2.00–1.84 (m, 3H); 13C NMR
(75 MHz)
d 169.8, 137.3, 134.1, 129.2, 127.9, 126.7, 117.0, 115.7, 96.8,
95.4, 73.5, 68.7, 67.8, 62.0, 55.3, 52.8, 42.9, 25.7, 21.1 (thirteen
signals obscured or overlapping); nmax (NaCl) 2925, 2825, 1743,
1641, 1370, 1238, 1149, 1109, 1039, 918 cmꢂ1; MS (ESI) m/z 318
[(MþNa)þ, 5%], 296 [(MþH)þ, 29], 236 (66), 206 (14), 174 (51), 105
(63), 70 (100).
3.2.17. Compounds 26 and 27. Grubbs’ second generation catalyst
(572 mg, 0.67 mmol) was added to a magnetically stirred solution
of the epimeric forms of compound 25 (1.99 g, 6.74 mmol) in
dichloromethane (335 mL) maintained under nitrogen at 18 ꢀC. The
ensuing mixture was heated at reflux for 46 h then cooled and
treated with dimethyl sulfoxide (2.38 mL, 33.5 mmol) and trie-
thylamine (4.66 mL, 33.5 mmol). After a further 23 h the reaction
mixture was concentrated under reduced pressure and the ensuing
brown oil was subjected to flash chromatography (silica, 9:1/ 4:1
v/v hexane/ethyl acetate elution) affording three major fractions, A,
B, and C.
(MþH)þ, 226.1443]. 1H NMR (300 MHz)
d 9.28 (s, 1H), 6.24–6.13 (m,
1H), 5.86–5.72 (m, 1H), 5.40–5.32 (m, 1H), 5.28–5.08 (m, 2H), 4.61 (s,
2H), 3.86 (d, J¼10.5 Hz,1H), 3.80 (d, J¼10.5 Hz,1H), 3.36 (s, 3H), 3.32–
3.16 (m, 2H), 2.98–2.88 (m,1H), 2.82–2.72 (m,1H), 2.32–2.18 (m,1H),
2.14–2.02 (m, 1H); 13C NMR (75 MHz)
d 201.0, 136.4, 132.0, 127.9,
123.3, 117.0, 96.7, 69.3, 67.3, 55.4, 54.3, 42.3, 25.9; nmax (NaCl) 3421,
2924,1722,1440,1262,1212,1150,1110,1045, 919 cmꢂ1; MS (ESI) m/z
248 [(MþNa)þ, 2%], 240 (100), 226 [(MþH)þ, 43], 210 (28), 194 (28),
178 (40), 164 (52), 146 (24), 109 (82).
This somewhat unstable aldehyde was immediately subjected to
the vinylation reaction described directly below.
Concentration of fraction A (Rf¼0.6 in 9:1 v/v dichloromethane/
ethyl acetate) afforded the starting triene 25 (847 mg, 43% re-
covery) as a clear, light-yellow oil.
Concentration of fraction B (Rf¼0.2, 1:1 v/v hexane/ethyl ace-
tate) afforded title compound 27 (169 mg, 16% at 57% conversion) as
a clear, light-yellow oil (Found: (MþH)þ, 268.1549. C14H21NO4 re-
3.2.16. Compound 25. Step i. Vinyl magnesium bromide (21.3 mL of
a 1.0 M solution in THF, 21.3 mmol) was added, dropwise, to
a magnetically stirred solution of aldehyde 23 (obtained as de-
scribed immediately above) in THF (60 mL) maintained under ni-
trogen at ꢂ78 ꢀC. After 0.5 h the reaction mixture was warmed to
0 ꢀC and maintained at this temperature for a further 2 h, then
warmed to 18 ꢀC. After a further 1 h the reaction mixture was
cooled to 0 ꢀC and water (12 mL) followed by ammonium chloride
(8 mL of a saturated aqueous solution) were added then the phases
separated. The aqueous layer was extracted with dichloromethane
(3ꢁ30 mL) and the combined organic phases were dried (MgSO4),
filtered, and concentrated under reduced pressure to give a ca. 3:1
mixture of the epimers of the alcohol 24 as a light-yellow oil
[Found: (MþH)þ, 254.1755. C14H23NO3 requires (MþH)þ,
quires (MþH)þ, 268.1549]. 1H NMR (300 MHz)
d 5.97–5.90 (m, 1H),
5.90–5.80 (m, 1H), 5.64 (d, J¼9.6 Hz, 1H), 5.50 (d, J¼10.2 Hz, 1H),
5.30 (s, 1H), 4.63 (d, J¼6.3 Hz, 1H), 4.58 (d, J¼6.3 Hz, 1H), 3.98 (d,
J¼10.8 Hz, 1H), 3.62 (d, J¼10.8 Hz, 1H), 3.50–3.15 (m, 3H), 3.36 (s,
3H), 2.76–2.65 (m, 1H), 2.42–2.26 (m, 1H), 2.08 (s, 3H), 2.04–1.97
(m, 1H); 13C NMR (75 MHz)
d 170.3, 128.3, 128.1, 127.0, 125.0, 96.7,
73.9, 66.0, 57.0, 55.3, 50.0, 46.4, 25.2, 21.2; nmax (NaCl) 2924, 1746,
1370, 1231, 1150, 1109, 1041 cmꢂ1; MS (ESI) m/z 268 [MþH)þ, 51%],
208 (12), 176 (21), 148 (51), 146 (100).
Concentration of fraction C (Rf¼0.1 in 1:1 v/v hexane/ethyl ac-
etate) afforded the title compound 26 (49 mg, 48% at 57% conver-
sion) as a clear, light-yellow oil [Found: (MþH)þ, 268.1548.
C14H21NO4 requires (MþH)þ, 268.1549]. 1H NMR (300 MHz)
d 6.03–
254.1756]. 1H NMR (300 MHz)
d
6.10–5.90 (m, 1H), 5.75 (br s, 1H),
5.95 (m, 1H), 5.86–5.74 (m, 2H), 5.53 (d, J¼10.2 Hz, 1H), 5.30 (d,
J¼5.1 Hz, 1H), 4.53 (d, J¼6.6 Hz, 1H), 4.49 (d, J¼6.6 Hz, 1H), 3.68 (d,
J¼9.0 Hz, 1H), 3.54 (d, J¼9.0 Hz, 1H), 3.32–3.18 (m, 2H), 3.26 (s, 3H),
2.97 (td, J¼11.1, 4.5 Hz, 1H), 2.76–2.66 (m, 1H), 2.46–2.30 (m, 1H),
5.60 (dm, J¼10.2 Hz, 1H), 5.34 (dm, J¼17.4 Hz, 1H), 5.22–5.04 (m,
3H), 4.61 (ABq, J¼6.6 Hz, 2H), 4.26 (s, 1H), 3.72 (s, 3H), 3.67 (s, 1H),
3.38 (s, 3H), 3.00–2.80 (m, 3H), 2.65 (m, 1H), 2.20–1.85 (m, 2H); 13C
NMR (75 MHz)
d
138.2, 136.9, 136.7, 136.1, 130.1, 129.2, 128.0, 126.6,
2.06–1.91 (m, 1H), 1.99 (s, 3H); 13C NMR (75 MHz)
d 170.9, 131.5,
117.4, 116.7, 116.2, 115.4, 96.9, 96.8, 73.4, 71.1, 68.7, 67.8, 63.1, 55.6,
53.2, 51.7, 43.7, 43.4, 25.5, 24.9 (two signals obscured or over-
lapping); nmax (NaCl) 3436, 2918, 1641, 1440, 1417, 1384, 1275, 1211,
1150, 1107, 1041, 916 cmꢂ1; MS (ESI) m/z 254 [(MþH)þ, 100%], 228
(14), 210 (5).
128.2, 126.3, 122.3, 96.4, 67.8, 66.0, 58.4, 55.1, 49.6, 45.4, 24.9, 21.1;
nmax (NaCl) 2922, 1731, 1370, 1241, 1140, 1109, 1041, 1022 cmꢂ1; MS
(ESI) m/z 290 [(MþNa)þ, 38%], 268 [(MþH)þ, 17], 236 (4), 208 (12),
148 (40), 146 (100).
This material was immediately subjected to an acetylation re-
action described directly below.
Step ii. Acetic anhydride (1.34 mL, 14.2 mmol) was added to
a magnetically stirred solution of the above-mentioned mixture
of the epimeric forms of alcohol 24 (obtained as described
3.2.18. Compound 28. Potassium carbonate (54 mg, 0.39 mmol)
was added to a magnetically stirred solution of compound 26
(105 mg, 0.39 mmol) in methanol (5 mL) maintained under nitro-
gen at 18 ꢀC. After 15.5 h the reaction mixture was concentrated
under reduced pressure then dichloromethane (10 mL) and water