SYNTHESIS
April 1998
487
in 40% (140 mg, 0.60 mmol), and 25% (87.5 mg, 0.37 mmol) isolated
yield, respectively; Rf (hexane/EtOAc, 7:3) 0.25.
(2R,6S)-2-[(Benzyloxy)methyl]-6-methylhexahydropyridine (49):
A solution of 45 (7.486g, 30.51 mmol) in anhyd 1,2-dichlorobenzene
(50 mL) was heated for 3 h at 165˚C under N2 atmosphere. The mix-
ture was cooled to r.t. and the solvent was removed by distillation,
giving the crude imine 48, which was used immediately in the follow-
ing reduction without purification.
IR (film): ν = 2930, 2857, 1756, 1686, 1447, 1387, 1326, 1222, 1051,
1032, 922, 908, 759, 718, 689 cm–1.
MS: m/z (rel.intensity, %) = 234 ([M]+., 6), 219 (3), 216 (16), 190
(31), 173 (10), 161 (100), 145 (18), 133 (21), 105 (32), 91 (70), 77
(25), 65 (13), 43 (16).
1H NMR (500 MHz, CDCl3): δ = 1.28 (m, 1 H), 1.58 (m, 1 H), 1.78
(m, 1 H), 1.85 (m, 1 H), 1.93 (s, 3 H), 2.04–2.16 (m, 2 H), 3.38 (AXd,
1 H, JAX = 8.7, J = 8.1), 3.53 (m, 1 H), 3.74 (AXd, 1 H, JAX = 9.1, J =
4.8), 4.55 (AB, 1 H, JAB = 12.3), 4.61 (AB, 1 H, JAB = 12.3), 7.28–7.36
(m, 5 H).
1H NMR (500 MHz, CDCl3): endo-adduct 5: δ = 1.10–1.40 (m, 3 H),
1.41 (d, 3 H, J = 6.1), 1.49–1.75 (m, 3 H), 1.80 (m, 2 H), 2.31 (m, 1
H), 2.46 (m, 1 H, ΣJ = 29.0), 2.55 (ddd, 1 H, J = 10.9, 9.3, 4.4), 2.93
(ddd, 1 H, J = 9.3, 9.2, 3.2), 4.15 (dq, 1 H, J = 9.2, 6.1), 6.72 (dd, 1 H,
J = 3.8, 3.2), 9.74 (d, 1 H, J = 4.4); exo-adduct 26: δ = 1.10–1.40 (m,
5 H), 1.45 (d, 3 H, J = 6.1), 1.80 (m, 4 H), 2.12 (m, 1 H, ΣJ = 25.0),
2.73 (ddd, 1 H, J = 10.6, 10.4, 4.3), 2.88 (ddd, 1 H, J = 10.4, 9.2, 3.4),
4.42 (dq, 1 H, J = 9.2, 6.1), 6.72 (dd, 1 H, J = 3.4, 3.0), 9.69 (d, 1 H,
J = 4.3).
To a suspension of LiAlH4 (8.535 g, 213.61 mmol) in anhyd THF
(250 ml) at –78°C under N2 atmosphere was slowly added a solution of
48 in THF (50 mL), followed by the dropwise addition of a 2 M hexane
solution of Me3Al (106.8 mL, 213.61 mmol) over 30 min. The mixture
was stirred for 30 min at –78˚C, 1 h at –45˚C, 1 h at –20˚C and finally
1 h at 0˚C. Still at 0˚C, the solution was diluted with Et2O (200 mL), af-
ter which NaF (35.875 g, 854.4 mmol) was added. Then H2O (11.54 g,
640.8 mmol) was added very carefully, after which the slurry was
stirred for 15 min. After filtration over Celite, the residue was dried
(MgSO4). The crude product was purified by column chromatography
(Et2O/Et3N, 99:1) to afford 49 (5.018 g, 22.88 mmol, 75%) as a colour-
less oil; Rf (Et2O/Et3N, 99:1) 0.31; [α]D +8.92 (c = 1.11, CHCl3). The
cis-piperidine 50 was obtained when no Me3Al was used in the reaction.
IR (film): ν = 3322, 3088, 3030, 2929, 2861, 1496, 1454, 1367, 1330,
1207, 1098, 1028, 946, 736, 680 cm–1.
(2S)-1-(Benzyloxy)hept-6-en-2-ol (44):
To a suspension of Mg (4.007 g, 164.84 mmol) in Et2O (10 mL) was
added dropwise under argon atmosphere a solution of 4-bromobut-1-
ene (20.230 g, 149.85 mmol) in Et2O (100 mL). After 30 min, the
mixture was cooled to –78˚C, and a 0.1 M THF solution of lithium
tetrachlorocuprate (50 mL, 5.00 mmol) was added, followed by the
dropwise addition of 43 (7.710 g, 49.95 mmol). The mixture was
stirred overnight, while the temperature was allowed to warm to r.t.
The dark solution was cooled to 0˚C, and a satd aq solution of NH4Cl
(200 mL) was added carefully. The mixture was extracted with Et2O
(3 × 250 mL), the combined organic phases were dried (MgSO4) and
the solvent was removed under vacuum. The product was further pu-
rified by distillation (137˚C/ 0.7 Torr) to give 44 as a colourless oil
(9.794 g, 44.46 mmol, 89%); Rf (isooctane/EtOAc, 4:1) 0.32;
[α]D –3.65 (c = 1.07, CHCl3).
1H NMR (500 MHz, CDCl3): 2,6-trans-piperidine 49: δ = 1.07 (d, 3
H, J = 6.2), 1.23 (m, 1 H), 1.32 (m, 1 H), 1.44 (m, 1 H), 1.54–1.63 (m,
3 H), 3.01 (qdd, 1 H, J = 6.6, 6.2, 3.2), 3.20 (m, 1 H), 3.35 (dd, 1 H, J
= 9.1, 4.3), 3.54 (app t, 1 H, J = 9.1), 4.52 (AB, 1 H, J = 12.1), 4.54
(AB, 1 H, J = 12.1), 7.27–7.37 (m, 5 H); cis-piperidine 50: δ = 1.07
(d, 3 H, J = 6.3), 1.27–1.41 (m, 2 H), 1.50 (m, 1 H), 1.59 (m, 1 H),
1.78 (m, 1 H), 1.85 (m, 1H), 2.62 (qdd, 1 H, J = 6.3, 4.7, 2.6), 2.84
(ddt, 1 H, J = 11.3, 8.7, 2.8), 3.33 (AXd, 1 H, JAX = J = 8.9), 3.46
(AXd, 1 H, JAX = 9.0, J = 3.4), 4.47 (AB, 1 H, JAB = 11.8), 4.55 (AB,
1 H, JAB = 11.8), 7.26–7.37 (m, 5 H).
IR (film): ν = 3445, 3065, 3030, 2929, 2860, 1640, 1496, 1454, 1364,
1310, 1255, 1206, 1098, 1028, 997, 911, 737, 698 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.40–1.60 (m, 4 H), 2.07 (m, 2 H),
3.33 (AXd, 1 H, JAX = 9.3, J = 7.9), 3.51 (AXd, 1 H, JAX = 9.4, J =
3.0), 3.82 (m, 1 H), 4.56 (s, 2 H), 4.89 (br d, 1 H, J = 17.0), 5.01 (br
d, 1 H, J = 10.2), 5.80 (ddt, 1 H, J = 16.9, 10.2, 6.7), 7.29–7.38 (m, 5
H).
13C NMR + DEPT (50 MHz, CDCl3): trans-piperidine 49: δ = 19.50
(CH2), 20.95 (CH3), 26.94 (CH2), 32.34 (CH2), 45.28 (CH), 50.03
(CH), 71.72 (CH2), 72.92 (CH2), 127.30 (CH), 127.35 (CH), 128.08
(CH), 138.16 (C).
13C NMR + DEPT (50 MHz, CDCl3): δ = 24.75 (CH2), 32.48 (CH2),
33.67 (CH2), 70.25 (CH), 73.32 (CH2), 74.58 (CH2), 114.65 (CH2),
127.72 (CH), 127.78 (CH), 128.45 (CH), 137.94 (C), 138.57 (CH).
MS: m/z (rel.intensity, %) = 220 ([M]+., 1), 189 (1), 171 (1), 129 (1),
122 (5), 121 (4), 107 (13), 91 (100), 81 (51), 65 (18), 55 (26).
MS: m/z (rel.intensity, %) = 219 ([M]+., 1), 218 ([M]+. –1, 1), 204 (2),
199(2), 126 (3), 113 (4), 111 (5), 105 (4), 98 (100), 91 (34), 65 (12),
55 (18).
(2R,6S)-(6-Methylhexahydro-2-pyridinyl)methanol (37):
Ammonia (20 mL) was distilled into a dry flask and cooled to –78˚C.
Na (50 mg) was added, which turned the solution deep blue. A solu-
tion of 49 (250 mg, 1.14 mmol) in Et2O (5 mL) was added dropwise,
followed by the addition of tert-butyl alcohol (150 mg). The cooling
bath was removed, and the mixture was refluxed at –30˚C. After 2 h,
solid NH4Cl was added until the blue colour disappeared. The ammo-
nia was removed by a stream of air, after which the residue was taken
up in CH2Cl2 and filtered over Celite. After removal of the solvents,
the amino alcohol 37 (127 mg, 0.983 mmol, 86%) was obtained as a
light yellow oil; Rf [hexane/acetone (2% aq NH3), 55:45] 0.11.
IR (film): ν = 3299, 2930, 2864, 1633, 1442, 1378, 1330, 1125, 1051,
955, 824 cm–1.
(6R)-6-Azido-7-(benzyloxy)hept-1-ene (45):
Zinc diazide bipyridine adduct (9.310 g, 30.27 mmol), prepared as de-
scribed by Viaud and Rollin,39 was added to a solution of 44 (8.890 g,
40.35 mmol) and PPh3 (21.167 g, 80.70 mmol) in anhyd toluene
(250 mL) under argon atmosphere. Diisopropyl azodicarboxylate
(16.318 g, 80.70 mmol) was added dropwise to the above mixture,
causing a slight exothermic reaction. After 3 h, the mixture was fil-
tered over silica gel. Further purification was effected by column
chromatography (pentane/EtOAc, 19:1) which gave 45 as a colour-
less oil (8.909 g, 36.32 mmol, 90%); Rf (isooctane/EtOAc, 9:1) 0.63;
[α]D –20.10 (c = 3.88, CHCl3).
IR (film): ν = 3065, 3030, 2938, 2860, 2106, 1640, 1496, 1454, 1364,
1340, 1272, 1207, 1115, 1028, 995, 912, 737, 698, 626 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.41–1.57 (m, 4 H), 2.67 (m, 2 H),
3.49 (ABd, 1 H, JAB = 8.7, J = 8.6), 3.52 (m, 1 H), 3.57 (ABd, 1 H,
JAB = 8.7, J = 2.7), 4.58 (s, 2 H), 4.98 (br d, 1 H, J = 10.2), 5.02 (br d,
1 H, J = 17.2), 5.78 (ddt, 1 H, J = 17.0, 10.2, 6.7), 7.28–7.38 (m, 5 H).
13C NMR + DEPT (50 MHz, CDCl3): δ = 25.08 (CH2), 30.12 (CH2),
33.23 (CH2), 61.60 (CH), 72.69 (CH2), 73.14 (CH2), 114.88 (CH2),
127.40 (CH), 127.57 (CH), 128.28 (CH), 137.71 (C), 137.95 (CH).
MS: m/z (rel.intensity, %) = 244 ([M]+. –1, 1), 216 (4), 186 (2), 174
(2), 148 (7), 140 (4), 105 (4), 91 (100), 65 (15), 41 (26).
1H NMR (500 MHz, CDCl3): δ = 1.08 (d, 3 H, J = 6.6), 1.15–1.70 (m,
6 H), 3.00 (m, 2 H), 3.42 (dd, 1 H, J = 10.3, 4.7), 3.62 (dd, 1 H, J =
10.3, 9.6).
MS: m/z (rel.intensity, %) = 129 ([M]+·, 6), 128 (8), 114 (10), 106
(10), 98 (100), 81 (9), 70 (10), 56 (20), 44 (20).
tert-Butyl (2R,6S)-2-[(Benzyloxy)methyl]-6-methylhexahydro-1-
pyridinecarboxylate (51):
To a solution of di-tert-butyl dicarbonate (3.497 g, 16.02 mmol) in an-
hyd CH2Cl2 (100 mL) at 0˚C under N2 atmosphere was added the pi-