S. Hishiyama et al. / Tetrahedron Letters 53 (2012) 842–845
843
(
a
R,bR)-threo-GGE,
(
a
R,bS)-erythro-GGE, and (
a
S,bS)-threo-GGE]
t-butyldimethylsilyl (TBS) groups, the resulting benzylic alcohol 4
was esterified with CDPA in the presence of N,N0-dicyclohexylcar-
bodiimide and 4-dimethylaminopyridine. 1H NMR measurements
revealed that the obtained ester 5 was a ca. 1:1 mixture of diaste-
reomers. High-performance thin-layer chromatography analysis of
the mixture showed a clear difference between Rf values. The value
of less polar moiety 5a was 0.29 and that of the more polar moiety
5b was 0.27, when hexane/ethyl acetate (5/1) was used as the elu-
ent. Fortunately, the separation of the diastereomers was possible
with a few repetitions of silica gel open column chromatography
using above eluent.
The absolute configuration of the less polar compound 5a was
determined by application of the modified Mosher’s method.10
Treatment of 4a, which was obtained by removing the CDPA group
of the less polar ester 5a, with (R)-(ꢀ)- and (S)-(+)-2-methoxy-2-
trifluoro-2-phenylacetyl chloride (MTPACl) gave the (S)- and (R)-
MTPA esters of 4a. The 1H NMR data for each diastereomer were
assigned by analysis of the 1H–1H COSY spectra, and the chemical
and both enantiomers of erone [(bS)-erone and (bR)-erone]. In
our recent study, using these compounds, we succeeded in proving
the stereospecificity of four C
a-dehydrogases (LigD, Lig L, LigN, and
LigO).5
Results and discussion
Synthetic methods to produce racemic lignin model compounds
with b-O-4 linkage including GGE have been reported in previous
studies.7 In addition, several synthetic approaches to prepare chiral
8-O-40 type neolignans, whose chemical structures are quite simi-
lar to GGE, have been reported.8 However, stereoselective synthe-
ses of GGE in enantiopure form and determinations of their
stereochemistry have not been published to date. It was thought
that the most obvious route to enantiopure GGE (accompanied
with determination of its stereochemistry) would be optical reso-
lution of racemic erythro-GGE. Furthermore, it was thought that
the erythro-GGE 1 could be converted into threo-GGE and erone
without inversion of stereochemistry at the b-carbon atom. To re-
solve racemic erythro-GGE, chiral diclorophthalicacid (CDPA) was
selected as a chiral auxiliary (Scheme 1). CDPA is a powerful
resolving agent for racemic alcohols.9 We planned to convert the
racemate into the diastereomeric mixture by condensing the chiral
secondary alcohol at benzylic position of GGE 1 with CDPA.
The synthesis of the racemic erythro-GGE 1 commenced with
acetovanilone in accordance with the previously described proce-
dure.7 After selective protection of phenolic hydroxyl group and
shift differences (
for protons on the left side had negative signs, whereas positive
signs were observed for protons on the right side, suggesting that
D
d = dS ꢀ dR) were shown in Scheme 2.
Dd values
C-a possessed an S-configuration. An irregular value was observed
on C-b(ꢀ0.05); however, it was attributed to the anisotropic effect
of aromatic ring, so it can be neglected in the determination of
absolute configuration.11 Given the already known relative config-
uration, the absolute configuration of 4a was assigned as
aSbR.
Similarly, antipode 4b, whose absolute configuration is RbS, was
a
obtained from 5b by removing the CDPA group. Scheme 3 shows
the synthetic steps to prepare enantiopure 2 and 1.12 For the syn-
primary hydroxyl group at
c-position of racemic erythro-GGE with
thesis of enantiopure 2, (aS,bR)-erythro-4a was oxidized by tetra-
n-propylammonium perruthenate in the presence of N-methyl-
morpholine-N-oxide and 4 Å molecular sieves, and the TBS groups
of the obtained
cally pure (bR)-2, whose optical rotation is (ꢀ), ([
ing the same procedure to the enantiomer, (
delivered the optically pure (bS)-2, whose optical rotation is (+),
([ +27.9). Reduction of the benzylic ketone in (bR)-2 with so-
dium borohydride gave a diastereomixture of (bR)-1[(
thro-1 and ( R,bR)-threo-1]. It was difficult to separate these
isomers by silica gel column chromatography, so the 1,3-diol was
converted by acetonization into six membered ring structures 7a
and 7b, which enhanced the separation of these diastereomers
by silica gel chromatography. After separation of the diastereo-
meric mixture, conformational analysis of both compounds were
performed by NMR spectroscopy, revealing that the more polar
acetonide, which had a small coupling constant (J = 2.0 Hz), corre-
a
-keto compound 6a were removed to afford opti-
D ꢀ28.5). Apply-
R,bS)-erythro-4b,
Cl
Cl
a
a
]
N
O
a
]
D
S
O
aS,bR)-ery-
O
OH
O
a
Chiral Dichlorophthalic acid (CDPA)
N-(2-Carboxy-4,5-dichlorobenzoyl)-(-)-10,2-camphorsultam
rac- erythro-1
Cl
Cl
a
N
S
OH
O
O
O
O
O
MeO
sponded to (
which had a large coupling constant (J = 8.8 Hz), corresponded to
S,bR)-erythro-1. Removal of the acetonide in 7a and 7b under
acidic conditions13 delivered the desired optically pure (
S,bR)-er-
ythro-1, whose optical rotation is (ꢀ), ([ ꢀ8.5), and optically
pure (
R,bR)-threo-1, whose optical rotation is (ꢀ), ([
aR,bR)-threo-1, whereas the less polar acetonide,
OTBS
MeO
OTBS
O
b
TBSO
(a
O
TBSO
a
MeO
a]
MeO
D
rac-erythro-4
a
a
]
D
ꢀ39.2).
erythro-5 (diastereomeric mixture)
(separable)
5a (less polar)
5b (polar)
d
-0.05
-0.01
c
+0.05,
+0.15
OMTPA
-0.21
-0.04
MeO
MTPACl
OTBS
-0.10
OH
O
OH
+0.13
4a
O
-0.18
MeO
+0.08
+0.09
MeO
TBSO
OTBS
OTBS
O
MeO
TBSO
+0.07
TBSO
+0.02
Δδ values [Δδ(in ppm)=δS-δR] obtained
from (S)- and (R)-MTPA esters of 4a.
MeO
MeO
4a [αS,βR]
4b [αR,βS]
[
α βR] configuration
S,
Scheme 1. Resolution of ( )-erythro-GGE (1). Reagents and conditions: (a) TBSCl,
imidazole 99%; (b) DCC, DMAP 75%; (c) K2CO3, MeOH, 100%; (d) K2CO3, MeOH 100%.
Scheme 2. Determination of stereochemistry of 4a by advanced Mosher’s method.