C. Tacon et al. / Bioorg. Med. Chem. 20 (2012) 893–902
899
reaction mixture was raised to 25 °C and epichlorohydrin (5 equiv)
was added dropwise over 2 min. The reactions were complete after
12 h as confirmed via TLC. The mixture was diluted with water
(100 ml), extracted with EtOAc (3 Â 100 ml) and dried over MgSO4.
Excess epichlorohydrin and EtOAc was removed in vacuo to yield an
oil which was purified by silica gel column chromatography.
1590 (C@C aromatic); 1H NMR dH (400 MHz; CDCl3) 7.00 (d, J = 8.8,
H-11), 6.51 (d, J = 8.8, H-12), 4.11 (m, H-22), 3.98 (dd, J = 12.4, 6.4,
H-21a), 3.91 (dd, J = 12.4, 6.8, H-21b), 3.30 (sept, J = 7.2, H-15), 2.94
(dd, J = 17.0, 6.2, H-7b), 2.75 (m, H-7
2.34–2.56 (m, H-24, H-25, H-26, H-27), 2.30 (s, H-28), 2.23 (br d,
J = 11.6, H-1b), 1.92 (dd, J = 7.7, 1.6, H-6 ), 1.73 (dt, J = 13.7, 3.3,
H-2b), 1.55–1.70 (m, H-6b), 1.49 (dt, J = 13.2, 3.2, H-2 ), 1.47 (br
d, J = 13.2, H-3b), 1.36 (d, J = 7.1, H-17), 1.34 (d, J = 7.1, H-16),
1.18 (s, H-20), 1.17–1.24 (m, H-1 , H-3 , H-5), 0.95 (s, H-18),
a), 2.57–2.60 (m, H-23),
a
a
5.1.1. Compound 8
11.1 g (3.88 mmol) of totarol (3), 0.14 g (5.82 mmol) NaH and
1.52 (19.41 mmol) epichlorohydrin used, resulting oil purified via
silica gel chromatography, eluting with Et2O/Hex (1:12), Rf = 0.56,
giving an isolated yield of 84% (1.12 g). 1H NMR dH (400 MHz; CDCl3)
7.07 (d, J = 8.8, H-11), 6.67 (d, J = 8.8, H-12), 4.16 (t, J = 10.9, 3.0,
H-21a), 4.14 (t, J = 10.9, 3.0, H-21b), 3.98 (ddd, J = 10.8, 5.2, 2.4,
a
a
0.92 (s, H-19). 13C NMR dC (100.6 MHz; CDCl3) 155.1 (C-13),
143.3 (C-9), 133.7 (C-8), 133.2 (C-14), 122.7 (C-11), 109.8 (C-12),
80.0 (C-21), 70.1 (C-22), 65.9 (C-23), 65.7 (C-24), 61.0 (C-28),
55.1 (C-25), 53.2 (C-26), 49.5 (C-5), 45.9 (C-3), 41.5 (C-1), 39.6
(C-10), 37.6 (C-4), 33.1 (C-18), 28.7 (C-7), 27.4 (C-15), 22.9 (C-
20), 21.5 (C-19), 20.6 (C-16, C-17), 19.4 (C-2), 19.3 (C-6), 17.0 (C-
28); APCI m/z 443.5 (M+1)+. Found: C, 76.0; H, 10.0; N, 6.2.
C28H46N2O2 requires C, 76.0; H, 10.5; N, 6.3. Mp 123 °C.
H-23
J = 7.2, H-15), 2.95 (dd, J = 16.9, 6.0, H-7b), 2.75 (m, H-7
J = 11.6, H-1b), 1.91 (dd, J = 7.9, 1.9, H-6 ), 1.73 (dt, J = 13.4, 3.9, H-
2b), 1.55–1.72 (m, H-6b), 1.49 (dt, J = 13.2, 3.2, H-2 ), 1.47 (br d,
J = 13.2, H-3b), 1.36 (d, J = 7.1, H-17), 1.34 (d, J = 7.1, H-16), 1.18 (s,
a), 3.95 (ddd, J = 10.8, 5.2, 2.4, H-23b), 3.36 (m, H-22), 3.3 (sept,
a), 2.24 (br d,
a
a
5.2.2. Compound 12c
H-20), 1.16–1.30 (m, H-1a, H-3a, H-5), 0.95 (s, H-18), 0.92 (s,
76.8 mg (0.22 mmol) of totarol epoxide (8) used, 0.027 ml
(0.25 mmol) benzylamine used, resulting oil purified via silica gel
chromatography, eluting with DCM/MeOH (9:1), Rf = 0.55, giving
an isolated yield of 30.5% (30.5 mg). IR mmax (KBr)/cmÀ1 3687
(OH), 2953 (CH aliphatic), 1603, 1453 (C@C), 707 (C–N); 1H NMR
dH (400 MHz; CDCl3) 7.26–7.37 (m, H-26, H-27, H-28, H-29, H-
30), 7.00 (d, J = 8.8, H-11), 6.51 (d, J = 8.8, H-12), 4.16 (m, H-22),
4.00 (dd, J = 9.5, 5.4, H-21a), 3.92 (dd, J = 9.5, 5.4, H-21b), 3.50 (s,
H-19). Compound previously reported.16
5.1.2. Compound 9
Reaction was performed at 50 °C. 1.07 g (11.39 mmol) of phenol
(5), 0.82 (34.17 mmol) NaH and 4.45 ml (56.95 mmol) epichloro-
hydrin used, resulting oil purified via silica gel chromatography,
eluting with EtOAc/Hex (1:12), Rf = 0.48, giving an isolated yield
of 88% (1.50 g). 1H NMR dH (400 MHz; CDCl3) 4.21 (dd, J = 14.8,
4.4, H-7a), 3.98 (dd, J = 11.1, 5.4, H-7b), 3.33–3.38 (m, H-8), 2.90
H-24), 3.28 (br s, H-15), 2.94 (m, H-7b), 2.75 (m, H-7
2.96–3.00 (m, H-23), 2.23 (br d, J = 11.6, H-1b), 1.92 (dd, J = 13.2,
7.6, H-6 ), 1.73 (dt, J = 13.7, 3.3, H-2b), 1.55–1.70 (m, H-6b), 1.47
(dt, J = 13.2, 3.2, H-2 ), 1.47 (br d, J = 13.2, H-3b), 1.36 (d, J = 3.6,
H-17), 1.34 (d, J = 1.34, H-16), 1.19 (s, H-20), 1.20–1.39 (m, H-1
H-3
H-5), 0.96 (s, H-18), 0.93 (s, H-19). 13C NMR dC
a),
(m, H-9a
), 2.75 (dd, J = 5.1, 3.3, H-9b). 13C NMR dC (100.6 MHz;
CDCl3) 69.0 (C-7), 50.2 (C-8), 44.7 (C-9).
a
a
a,
5.1.3. Compound 10
a
,
1.02 g (7.08 mmol) of 1-naphthol (6), 0.25 g (10.5 mmol) NaH
and 2.74 ml (35 mmol) of epichlorohydrin used, resulting oil puri-
fied via silica gel chromatography, eluting with Et2O/Hex (3:7),
Rf = 0.40, giving an isolated yield of 76% (1.08 g). 1H NMR dH
(400 MHz; CDCl3) 4.40 (dd, J = 11.2, 3.2, H-9a), 4.17 (dd, J = 11.0,
(100.6 MHz; CDCl3) 155.0 (C-13), 143.5 (C-9), 138.5 (C-25), 133.8
(C-8), 133.1 (C-14), 128.4 (C26, C-27, C-28, C-29, C-30), 122.8 (C-
11), 115.5 (C-12), 80.0 (C-21), 70.1 (C-22), 53.4 (C-23), 51.3 (C-
24), 49.5 (C-5), 41.5 (C-3), 39.6 (C-1), 37.6 (C-10), 33.2 (C-4), 33.1
(C-18), 28.7 (C-7), 27.3 (C-15), 25.1 (C-16, C-17), 21.5 (C-20), 20.7
(C-19), 19.4 (C-2), 19.3 (C-6); EIMS m/z 449 (M+). Mp 69–74 °C.
5.4, H-9b), 3.48–3.51 (m, H-10), 2.97 (dd, J = 5.0, 4.2, H-11a),
2.85 (dd, J = 5.0, 2.6, H-11b). 13C NMR dC (100.6 MHz; CDCl3) 69.0
(C-9), 50.2 (C-10), 44.7 (C-11).
5.2.3. Compound 12d
Reaction was performed at 31 °C. 229.9 mg (0.67 mmol) of tota-
rol epoxide (8) used, 3 equiv (0.3 ml, 3.52 mmol) isopropylamine
used, resulting oil purified via silica gel chromatography, eluting
with DCM/MeOH (9:1), Rf = 0.37, giving an isolated yield of 70%
(189.3 mg). IR mmax (KBr)/cmÀ1 3313 (OH, H bonded), 2960, 2867
(C–H aliphatic), 1590 (C@C aromatic); 1H NMR dH (400 MHz; CDCl3)
7.09 (d, J = 8.8, H-11), 6.72 (d, J = 8.8, H-12), 4.11 (m, H-22), 3.96 (2 X
ddd, J = 9.4, 5.1, 1.8, H-21a and b), 3.30 (br s, H-15), 2.84–3.00 (m, H-
5.1.4. Compound 11
0.5 g (3.47 mmol) of 2-naphthol (7), 0.125 g (5.2 mmol) NaH
and 1.35 ml (17.3 mmol) of epichlorohydrin used, resulting oil
purified via silica gel chromatography, eluting with Et2O/Hex
(3:7), Rf = 0.51, giving an isolated yield of 92% (632.6 mg). 1H
NMR dH (400 MHz; CDCl3) 4.34 (dd, J = 11.0, 3.4, H-9a), 4.09 (dd,
J = 10.8, 5.6, H-9b), 3.42 (m, H-10), 2.94 (dd, J = 4.8, 4.0, H-11a),
2.81 (dd, J = 5.2, 2.8, H-11b). 13C NMR dC (100.6 MHz; CDCl3) 68.8
7b), 2.76–3.00 (m, H-7
H-1b), 1.92 (dd, J = 13.3, 8.1, H-6
1.63–1.72 (m, H-6b), 1.59 (dt, J = 13.6, 3.4, H-2
H-3b), 1.20–1.39 (m, H-1 , H-3 , H-5, H-16, H-17), 1.19 (s, H-20),
a
, H-23), 2.74 (br s, H-24), 2.25 (d, J = 12.4,
), 1.74 (dt, J = 13.6, 3.3, H-2b),
), 1.47 (br d, J = 14.0,
(C-9), 50.1 (C-10), 44.7 (C-11).
a
a
5.2. General procedure for synthesis of b-amino alcohols 12–14
a
a
1.13 (d, J = 6.4, H-25, H-26), 0.95 (s, H-18), 0.93 (s, H-19). 13C NMR
dC (100.6 MHz; CDCl3) 155.1 (C-13), 143.5 (C-9), 133.8 (C-8), 133.2
(C-14), 122.8 (C-11), 110.0 (C-12), 70.2 (C-21), 69.6 (C-22), 49.61
(C-23), 49.59 (C-24), 49.5 (C-5), 49.1 (C-24), 41.6 (C-3), 39.6 (C-1),
37.7 (C-10), 33.2 (C-4), 33.2 (C-18), 28.7 (C-7), 27.4 (C-15), 25.1
(C-16), 22.7 (C-17), 21.6 (C-25), 20.7 (C-26), 20.7 (C-20, C-19), 19.5
(C-2), 19.4 (C-6); APCI m/z 402.5 (M+1)+. Found: C, 77.3; H, 10.2; N,
3.2. C26H43NO2 requires C, 77.8; H, 10.8; N, 3.5. Mp 39–42 °C.
The respective amine (1.1 equiv) was added to 1 equiv of the
respective epoxide in MeOH (1 ml per 0.06 mmol starting mate-
rial). The mixture was stirred at 50 °C, for 12–24 h, until the reac-
tion was complete (verified via TLC). The excess solvent was
removed under reduced pressure and the resulting oil purified
using either preparative TLC or column chromatography.
5.2.1. Compound 12a
101.3 mg (0.30 mmol) of totarol epoxide (8) used, 0.036 ml
(0.33 mmol) N-methylpiperazine used, resulting oil purified using
preparative TLC, DCM/MeOH (9:1), Rf = 0.56, to yield 29%
(38 mg). IR mmax (KBr)/cmÀ1 3134 (OH), 2805–2938 (CH aliphatic),
5.2.4. Compound 13
500 mg (3.61 mmol) of phenyl epoxide (9) used, 0.44 ml
(3.97 mmol) N-methylpiperazine used, resulting oil purified via