C
G. S. Ghotekar et al.
Paper
Synthesis
hydrogenolysis of compounds (S)-8a and (R)-8b furnished
ligraminol D [(S)-1] and ligraminol E [(R)-2] in 95% and 98%
yield, respectively. The structures of (S)-1 and (R)-2 were
confirmed by means of 1H NMR, 13C NMR, and HRMS spec-
troscopic analyses.
In conclusion, we have developed a short synthesis of li-
graminol D and E [(S)-1 and (R)-2] from commercially avail-
able chiral benzyl glycidyl ethers. Simple procedures, high
yields, and high enantioselectivities are some of the salient
features of this strategy. Further, this simple approach of-
fers flexibility in making other ligraminols or related neoli-
gnans.
1H NMR (500 MHz, CDCl3): = 7.37–7.31 (m, 4 H), 7.31–7.25 (m, 1 H),
6.86 (s, 1 H), 6.83–6.75 (m, 3 H), 6.71 (s, 1 H), 6.66 (d, J = 8.0 Hz, 1 H),
5.96 (tdd, J = 6.7, 10.1, 16.9 Hz, 1 H), 5.13–5.04 (m, 2 H), 4.60–4.53 (m,
2 H), 4.49 (quint, J = 5.5 Hz, 1 H), 3.86 (s, 3 H), 3.81 (s, 6 H), 3.67–3.59
(m, 2 H), 3.33 (d, J = 6.5 Hz, 2 H), 3.11–2.99 (m, 2 H).
l3C{1H} NMR (125 MHz, CDCl3): = 150.5, 148.6, 147.5, 145.9, 138.3,
137.5, 134.0, 130.7, 128.3, 127.6, 127.5, 121.5, 120.6, 117.4, 115.6,
113.0, 112.7, 111.0, 80.4, 73.3, 70.7, 55.8, 55.8, 55.7, 39.8, 37.5.
HRMS (ESI-TOF): m/z calcd for C28H32O5Na [M + Na]+: 471.2142;
found: 471.2142.
(S)-3-(4-{[1-(Benzyloxy)-3-(3,4-dimethoxyphenyl)propan-2-
yl]oxy}-3-methoxyphenyl)propan-1-ol [(S)-8a]
BH3·SMe2 complex (0.42 mL, 4.46 mmol) was slowly added to a solu-
tion of (S)-7a (1.0 g, 2.23 mmol) in THF (50 mL) at 0 °C under argon
atmosphere. After stirring for 30 min, the reaction mixture was
warmed to RT and stirred for another 2 h. The reaction was quenched
at 0 °C with H2O (100 mL), H2O2 (30%, 3.0 mL, 33.4 mmol), and NaOH
(0.17 g, 4.46 mmol); then the mixture was stirred for 90 min. The re-
sulting two layers were separated, and the aqueous layer was extract-
ed with EtOAc (3 × 100 mL), the combined organic layers were
washed with H2O (100 mL) and brine (100 mL), dried (anhyd Na2SO4),
and evaporated under reduced pressure. The crude product was puri-
fied by column chromatography (silica gel, PE/acetone 83:17) to af-
ford (S)-8a as a colorless liquid; yield: 0.94 g (90%); Rf = 0.4 (PE/EtOAc
80:20); []D25 –22.27 (c 1.0, CHCl3).
Solvents were purified and dried by standard procedures prior to use.
1H NMR and 13C NMR spectra were recorded on a Bruker AV-400 and
AV-500 NMR spectrometers. Spectra were obtained in CDCl3. The re-
actions were monitored by using TLC Merck silica gel 60 F254 plates
and visualization with UV light (254 and 365 nm), or with KMnO4 and
anisaldehyde in EtOH as development reagents. Optical rotations
were measured with a JASCO P 1020 digital polarimeter. High-resolu-
tion mass spectrometry (HRMS) was performed on a TOF/Q-TOF mass
spectrometer.
(R)-1-(Benzyloxy)-3-(3,4-dimethoxyphenyl)propan-2-ol [(R)-5a]
1H NMR (400 MHz, CDCl3): = 7.41–7.30 (m, 4 H), 7.29 (d, J = 6.1 Hz, 1
H), 6.85 (s, 1 H), 6.83–6.75 (m, 3 H), 6.72 (s, 1 H), 6.66 (d, J = 7.9 Hz, 1
H), 4.61–4.52 (m, 2 H), 4.49 (t, J = 5.2 Hz, 1 H), 3.86 (s, 3 H), 3.81 (s, 6
H), 3.67 (t, J = 6.4 Hz, 2 H), 3.65–3.58 (m, 2 H), 3.09–3.02 (m, 2 H), 2.99
(s, 1 H), 2.65 (t, J = 7.6 Hz, 2 H), 1.87 (quint, J = 7.0 Hz, 2 H).
l3C{1H} NMR (100 MHz, CDCl3): = 150.5, 148.6, 147.5, 145.8, 138.3,
135.8, 130.7, 128.3, 127.6, 127.5, 121.6, 120.4, 117.4, 113.0, 112.6,
111.0, 80.4, 73.4, 70.8, 62.2, 55.9, 55.7, 42.6, 37.5, 34.3, 31.7.
To a pre-cooled (0 °C) solution of (R)-3a (1.0 g, 6.24 mmol) in anhyd
THF (10 mL) was slowly added 3,4-dimethoxyphenylmagnesium bro-
mide (4a; 2.20 g, 9.13 mmol) in the presence of a catalytic amount of
CuCl under argon atmosphere. The reaction mixture was stirred for 2
h at the same temperature and cautiously quenched with sat. aq NH4-
Cl (10 mL). The organic layer was separated, and the aqueous layer
was extracted with EtOAc (2 × 10 mL). The combined organic layers
were dried (anhyd Na2SO4) and the solvent was removed under re-
duced pressure to afford a crude mixture, which was purified by col-
umn chromatography (silica gel, PE/EtOAc 80:20) to afford (R)-5a as a
yellow oil; yield: 1.6 g (85%); Rf = 0.3 (PE/EtOAc 70:30); []D26 –5.4 (c
1.3, EtOH).
1H NMR (400 MHz, CDCl3): = 7.44–7.22 (m, 5 H), 6.83–6.78 (m, 1 H),
6.78–6.71 (m, 2 H), 4.56 (s, 2 H), 4.09–3.99 (m, 1 H), 3.86 (s, 6 H), 3.53
(dd, J = 2.1, 9.5 Hz, 1 H), 3.45–3.38 (m, 1 H), 2.76 (d, J = 6.1 Hz, 2 H),
2.09 (br s, 1 H).
l3C{1H} NMR (100 MHz, CDCl3): = 148.9, 147.6, 137.9, 130.4, 128.4,
127.8, 127.7, 121.2, 112.5, 111.3, 73.6, 73.4, 71.4, 55.9, 55.8, 39.4.
HRMS (ESI-TOF): m/z calcd for C28H34O6Na [M + Na]+: 489.2248;
found: 489.2248.
(S)-3-(3,4-Dimethoxyphenyl)-2-[4-(3-hydroxypropyl)-2-methoxy-
phenoxy]propan-1-ol [Ligraminol D, (S)-1]
To a solution of (S)-8a (0.5 g, 1.07 mmol) in EtOH (5 mL) was added
Pd(OH)2 on activated charcoal (50 mg, 10–20 wt%), and the reaction
mixture was stirred under H2 atmosphere (20 psi) for 6 h. After the
completion of the reaction (indicated by TLC), the catalyst was filtered
over a plug of Celite bed (EtOAc eluent) and the solvent was evaporat-
ed under reduced pressure to give (S)-1 as a colorless liquid; yield:
HRMS (ESI-TOF): m/z calcd for C18H22O4Na [M + Na]+: 325.1410;
found: 325.1410.
25
0.383 g (95%); Rf = 0.2 (PE/EtOAc 80:20); []D –29.09 (c 0.1, MeOH)
{Lit.4 []D25 +9.5 (c 0.1, MeOH)}.
1H NMR (500 MHz, CDCl3): = 6.81 (s, 3 H), 6.74 (s, 1 H), 6.67 (s, 2 H),
4.24–4.18 (m, 1 H), 3.89–3.82 (m, 9 H), 3.72–3.64 (m, 3 H), 3.63–3.58
(m, 1 H), 3.06 (dd, J = 6.7, 13.9 Hz, 1 H), 2.91 (dd, J = 6.9, 14.1 Hz, 1 H),
2.67–2.60 (m, 2 H), 2.42 (br s, 2 H), 1.91–1.82 (m, 2 H).
l3C NMR (125 MHz, CDCl3): = 150.9, 148.9, 147.7, 145.5, 137.2,
130.5, 121.5, 121.0, 119.7, 112.9, 112.4, 111.4, 84.9, 63.4, 62.0, 55.9,
55.8, 55.8, 37.2, 34.2, 31.7, 29.6.
(S)-4-Allyl-1-{[1-(benzyloxy)-3-(3,4-dimethoxyphenyl)propan-2-
yl]oxy}-2-methoxybenzene [(S)-7a]
A solution of DIAD (0.7 mL, 3.97 mmol) was added dropwise to a
solution of (R)-5a (1.0 g, 3.30 mmol), eugenol (6; 0.54 g, 3.30 mmol),
and PPh3 (1 g, 3.97 mmol) in anhyd THF (20 mL) at 0 °C under N2 at-
mosphere. Then, the reaction mixture was stirred at RT for 1 h. The
solvent was removed under reduced pressure, and the residue was
purified by column chromatography (silica gel, PE/EtOAc 93:07) to af-
ford (S)-7a as a colorless oil; yield: 1.33 g (90%); Rf = 0.6 (PE/EtOAc
80:20); []D26 –17.61 (c 1.0, CHCl3).
HRMS (ESI-TOF): m/z calcd for C21H28O6Na [M + Na]+: 399.1778;
found: 399.1776.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–E