Preparation of diastereomerically pure dilignol model compounds

Article abstract of DOI:10.1002/chem.201101579

A gram-scale synthetic access to diastereomerically pure dilignol β-O-4 type model compounds, which represent valuable candidates for studies of lignin cleavage and valorization, is described. Following a straightforward procedure both diastereoisomers of 1,3-dilignols can be prepared. In the key-step, tert-butyl aryloxy esters are used as enolate precursors for additions on aldehydes. After separation, the resulting erythro and threo β-hydroxy esters are independently reduced to afford the target compounds in high yields.

Full text of DOI:10.1002/chem.201101579

FULL PAPER
DOI: 10.1002/chem.201101579
Preparation of Diastereomerically Pure Dilignol Model Compounds
Julien Buendia, Jakob Mottweiler, and Carsten Bolm*[a]
Dedicated to Professor Eun Lee on the occasion of his 65th birthday
Abstract: A gram-scale synthetic access to diastereomerically pure dilignol b-O-4
type model compounds, which represent valuable candidates for studies of lignin
cleavage and valorization, is described. Following a straightforward procedure
both diastereoisomers of 1,3-dilignols can be prepared. In the key-step, tert-butyl
aryloxy esters are used as enolate precursors for additions on aldehydes. After sep-
aration, the resulting erythro and threo b-hydroxy esters are independently re-
duced to afford the target compounds in high yields.
Keywords:
hydrides
organic chemistry · reduction
diastereoselectivity
lignin derivatives
·
·
·
Introduction
catalysts. Having straightforward access to diastereomerical-
ly homogeneous model compounds is therefore of prime in-
terest for such studies.
Over the last decades, considerable effort has been put into
the valorization of lignocellulosic biomass as a feedstock for
fuels, chemicals and energy.[1,2] Being abundant and renewa-
ble, lignocellulose is currently regarded as one of the most
promising alternatives to fossil energy resources. While the
selective conversion of cellulose and hemicellulose has ex-
tensively been studied,[3] the valorization of lignin, which
represents 15 to 30% of the lignocellulosic biomass, is still
in its infancy.[4,5] This can mainly be attributed to the diffi-
culty in achieving selective cleavage reactions of the various
linkages present in this rather complex natural polymer.[6]
However, besides the very fundamental scientific challenges,
practical aspects appear to hamper rapid progress in this
area as well. For example, very often the resulting reaction
mixtures are difficult to analyze due to the high complexity
and structural variability of the starting material and the
plethora of products obtained from the degradation of
lignin.[6] To circumvent such problems, studies of lignin
cleavage mostly involve dilignol model compounds.[7] In this
context, substrates with b-O-4 linkages are particularly rele-
vant, because this bonding type is the most dominant in
lignin (30–50%, depending on the wood type).[5,6] The use
of diastereomerically pure model compounds simplifies such
cleavage studies and reduces the analytical challenges. The
goal is then to build on the knowledge gained in those inves-
tigations and to develop a deeper insight into the mechanis-
tic details, leading to a sound understanding of the underly-
ing principles of lignin degradation by enzymes and metal
Various synthetic strategies have been reported for the
preparation of erythro and threo dilignol model com-
pounds.[8–10] One of the two most frequently used routes
(Scheme 1) was originally described by Adler et al.[8] The
first step is the bromination of acetophenone derivatives 1
to give bromoketones 2. Subsequent substitution of 2 with
phenols provided keto aryl ethers 3. After aldol condensa-
tion with formaldehyde and reduction of the resulting b-hy-
droxy ketones 4 with NaBH4, 1,3-diols 5 were obtained as
mixtures of erythro and threo diastereomers 5E and 5T, re-
spectively.
Because the direct separation of diastereomers 5E and
5T proved difficult, they were converted to the correspond-
ing acetonides (not shown), which were isolated by column
chromatography. Their separate hydrolysis finally afforded
the two 1,3-diols 5E and 5T in diastereomerically pure
form.[8d,9c]
For the reduction of hydroxy ketones 4 (Scheme 1, last
step) two elegant procedures were described by Helm et
al.,[11] who found that the use of specific metal hydrides
opened direct access to both diastereomers (erythro and
[a] Dr. J. Buendia, J. Mottweiler, Prof. Dr. C. Bolm
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52056 Aachen (Germany)
Fax : (+49) 241-8092391
E-mail: Carsten.Bolm@oc.rwth-aachen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101579.
Scheme 1. Adlerꢀs route for the preparation of dilignol model compounds
5.
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threo) of protected alcohols in good yields and with high ste-
reoselectivities.
Although the aforementioned methods lead to the desired
products, it is fair to say that they all have significant practi-
cal drawbacks due to the number of synthetic steps and
moderate overall yields.
An alternative approach towards dilignol model com-
pounds was described by Nakatsubo and co-workers
(Scheme 2).[9] Beginning with the additions of readily avail-
able lithio enolates of esters 8 to aldehydes 9, erythro-en-
riched mixtures of the resulting b-hydroxy esters 10 were
obtained. Isolation by column chromatography or recrystal-
lization afforded the pure erythro hydroxy esters 10E in
moderate to good yields. threo compounds 10T, however,
proved more difficult to obtain, and often those diastereo-
mers could only be isolated in minute quantities.[9b,e] Al-
though the subsequent LiAlH4 reductions of 10 worked
well, the overall access to the threo diastereomers 5T by Na-
katsuboꢀs method remained problematic due to the limited
availability of 10T.
Scheme 3. Synthetic access of erythro diastereomer dilignol 5aE.
b-hydroxy ester 10a as an erythro-enriched diastereomeric
mixture. Its recrystallization from ethyl acetate afforded
10aE with an erythro-to-threo ratio of greater than 98:2 in
52% yield. This convenient protocol allowed to perform the
reaction on a multi-gram scale. Finally, reduction of 10aE
with LiAlH4 in THF or NaBH4 in a THF/water mixture led
to dilignol 5aE in 90% yield.[12]
This procedure was further applied to reactions of other
aldehydes (Table 1), and in this manner various functional-
ized b-hydroxy esters were obtained in good yields. In
agreement with the findings of Nakatsubo et al., the product
mixtures were erythro-enriched with diastereomeric ratios
ranging from 3:1 to 5:1 (erythro/threo).[9a] Unfortunately,
with the exception of 10b, which could be recrystallized
from ethanol/hexane to give the pure erythro diastereoiso-
mer (erythro/threo>98:2) in 30% yield, all other products
remained diastereomeric mixtures, which could neither be
separated by recrystallization nor column chromatography.
Following the latter technique only small amounts of the er-
ythro isomers were obtained in pure form, and the threo dia-
stereomers could not be isolated at all.
Hypothesizing that the ester group would affect the dia-
stereoselectivity of the addition process and hoping that the
resulting stereoisomers could be separated by recrystalliza-
tion or chromatography to yield stereochemically homoge-
neous products, guaiacylacetates 8b and 8c bearing an ada-
mantyl and an amyl group, respectively, were prepared via
acid 11 (Figure 1). Gratifyingly, our hypothesis was con-
firmed, and addition of the lithio enolate of 8b to VAD
(9a) gave a 1:1 mixture of the corresponding erythro and
threo diastereoisomers (12aE and 12aT) in 80% yield. The
isomers could be almost quantitatively separated by column
chromatography. In an analogous manner, the lithio enolate
of 8c reacted with 9a affording b-hydroxy esters 12bE and
12bT (in a 1:1 ratio) in 75% yield. Also here, separation of
the diastereomers led to stereochemically homogeneous
samples.[13]
Scheme 2. Nakatsuboꢀs route for the preparation of dilignol model com-
pounds 5.
With the goal to improve the accessibility of stereochemi-
cally well-defined lignin model compounds, we searched for
synthetic alternatives and developed a protocol, which
allows to obtain both erythro and threo 1,3-dilignols. Prepa-
rative details of this study and respective analytical data are
presented here.
Results and Discussion
The three-step procedure described by Nakatsubo et al.
served as basis for our investigations.[9a,b] A rapid optimiza-
tion with guaiacol (2-methoxyphenol, 6a) and ethyl bromoa-
cetate (7a) as representative starting materials revealed that
ester 8a could be obtained in 90% yield using K2CO3 as
base in acetone under reflux for 8 h (Scheme 3). Important-
ly, the same yield was achieved when the condensation reac-
tion was performed on a 20 g scale.
Lithiation of 8a with LDA in THF at ꢀ788C and trapping
In order to follow the general concept of using substrates
with bulky carboxy ester groups, and with the goal to simpli-
of the resulting enolate with veratraldehyde (VAD, 9a) gave
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Synthesis of Dilignol Model Compounds
FULL PAPER
Table 1. Addition of the lithio ethyl ester enolate of 8a to various alde-
hydes 9.[a]
droxy esters 12cE and 12cT in high yield (Table 2, entry 1).
Thus in this manner, both diastereomers were accessible
using a short and highly productive reaction sequence.
Subsequently, this protocol was applied for the synthesis
of various derivatives (Table 2). By combining aryloxy-sub-
stituted tert-butyl esters with functionalized benzaldehydes,
several tert-butyl b-hydroxy esters could be prepared in high
yields (83–95%). The diastereomer ratios varied favoring
the erythro isomer in most cases. The only two exceptions
were compounds 12h and 12i, which yielded the threo dia-
stereomers in excess (entries 6 and 7). Presumably, the steric
hindrance of the corresponding aldehydes [2,4,6-trimethoxy-
benzaldehyde (9 f) and mesityl aldehyde (9g)] caused
changes of the reaction path leading to the preferential for-
mation of the commonly under-represented diastereomer.
With the exception of 12k all stereoisomer pairs could be
separated by column chromatography, thus providing signifi-
cant amounts of both erythro and threo products.
Next, we focused on the reduction of the tert-butyl hy-
droxy-esters leading to the corresponding dilignol model
compounds. Initial attempts using NaBH4 as reducing agent
remained unsatisfying. Even with a large excess of reagent
(10 equiv), full conversion could not be achieved with the er-
ythro tert-butyl ester 12cE (at 608C for 24 h). Gratifyingly,
the use of LiAlH4 (2.5 equiv at 608C for 3 h) led to better
results, providing the two diastereomeric diols of 5a in high
yields (90 and 80% for 5aE and 5aT, respectively; Table 3,
entries 1 and 2). In both cases, the stereochemistry remained
unaffected.
Entry Product
Aldehyde Yield [%] erythro/threo
1
9b
9c
9d
84[b]
5:1
3:1
4:1
2
3
80
78
4
9e
83
5:1
Also the other tert-butyl esters reacted well, leading to
the corresponding diols in yields higher than 76% (Table 3).
Due to the reduction of the two carboxyl groups, the conver-
sions of esters 12 f required 5 equiv of LiAlH4 leading to the
erythro and threo products 5dE and 5dT in 86 and 84%
yield, respectively (entries 7 and 8). In order to get more re-
alistic model compounds, the products from the reductions
of 12g with LiAlH4 were directly debenzylated by Pd/C-cat-
alyzed hydrogenations, affording the corresponding erythro
and threo dilignols 5eE and 5eT in yield of 90 and 80%, re-
spectively (entries 9 and 10).
[a]The reactions were performed on a 10 mmol scale. [b]The diastereo-
merically pure erythro isomer of 10b was obtained in 30% yield by re-
crystallization from an ethanol/hexane mixture (3:2).
Conclusion
An efficient method for the preparation of dilignol b-O-4
type model compounds was developed. It gives access to
both erythro and threo diastereomers in only three synthetic
steps and does not require any additional protection or deri-
vatization. Furthermore, the high yielding procedure is con-
venient for gram-scale preparations, since the reactions are
performed under standard conditions using inexpensive and
commercially available reagents. Lignin cleavage studies
with model compounds have been initiated,[14] and the re-
sulting data will be reported in due course.
Figure 1. Products of the additions of the lithio enolates of 8b–d to alde-
hyde 9a.
fy the access of both diastereomers of the dilignol model
compounds, tert-butyl ester 8d was prepared (Figure 1). In
contrast to the syntheses of esters 8b and 8c its preparation
required only a single step from commercially available
starting materials. Thus, condensation of guaiacol (8a) with
tert-butyl bromoacetate gave 8d in 93% yield. Addition of
the lithio enolate of 8d to VAD (9a) gave, as hoped for, a
separable 1:1 mixture of erythro and threo tert-butyl b-hy-
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13879

C. Bolm et al.
Table 2. Additions of lithio enolates of tert-butyl aryloxyesters to func-
tionalized benzaldehydes to give tert-butyl b-hydroxy esters 12c–k.[a]
Table 3. Reduction of the tert-butyl b-hydroxy esters.[a]
Entry Starting material Product
Yield [%]
Entry Product
Aldehyde Yield
[%]
erythro/
threo
1
2
12cE
12cT
90 (erythro)
80 (threo)
1
9a
9c
9d
90
83
84
1:1
3
4
12dE
12dT
91 (erythro)
84 (threo)
2
3
1.2:1
1.3:1
5
6
12eE
12eT
88 (erythro)
91 (threo)
7
8
12 fE
12 fT
86[b] (erythro)
84[b] (threo)
4
5
9e
9b
85
84
1.6:1
1.2:1
9
10
12gE
12gT
90[c] (erythro)
80[c] (threo)
11
12
12hE
12hT
76 (erythro)
82 (threo)
13
14
12iE
12iT
– (erythro)
90 (threo)
6
7
9 f[c]
87
95
1:1.5
15
16
12jE
12jT
93 (erythro)
87 (threo)
9g[d]
1:4.5[b]
[a]The reactions were performed on a 5 mmol scale. [b]Use of 5 equiv of
LiAlH4. [c]Yield after debenzylation of the phenolic hydroxy group.
8
9
9a
9a
85
1:1
Experimental Section
General information: All experiments were carried out under an argon
atmosphere. The starting materials were purchased from commercial sup-
pliers and used without further purification. THF was dried by distillation
over Solvona (sodium on molecular sieves) in the presence of benzophe-
none, and CH2Cl2 was dried by distillation over CaH2. These two solvents
were then stored under an argon atmosphere. Flash column chromatogra-
phy was carried out with silica gel 60 (35–70 mesh). Analytical TLC was
performed with silica gel 60 F254 plates, and the products were visualized
by UV detection. 1H NMR and 13C NMR spectra were recorded either
81[e]
1.6:1
[a]The reactions were performed on a 10 mmol scale. [b]Only the threo
isomer could be isolated in pure form by column chromatography.
[c]2,4,6-Trimethoxybenzaldehyde. [d]Mesitylbenzaldehyde. [e]The eryth-
ro and threo diastereoisomers could not be separated by column chroma-
tography.
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Synthesis of Dilignol Model Compounds
FULL PAPER
on a Varian VNMRS 600, a Varian Inova 400 or a Varian Mercury 300
spectrometer, in CDCl3 using TMS as an internal standard. Chemical
shifts (d) were reported in ppm using TMS as internal standard, and
spin-spin coupling constants (J) were given in Hz. HRMS were recorded
on a FinniganMAT 95 spectrometer (ESI). All compounds gave satisfac-
tory HRMS analyses. The analytical data for the known compounds were
found to match with the literature data.
1H NMR (400 MHz, CDCl3, 258C, TMS): d=7.06 (d, J=8.0 Hz, 1H),
7.05–6.97 (m, 2H), 6.92 (ddd, J=8.0, 8.0, 1.6 Hz, 2H), 6.87–6.82 (m, 2H),
5.15 (brt, J=5.6 Hz, 1H), 4.74 (d, J=4.7 Hz, 1H), 4.14 (q, J=7.3 Hz,
2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.87 (s, 3H), 3.66 (d, J=6.0 Hz, 1H),
1.16 ppm (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=169.3,
150.6, 148.8, 148.7, 147.2, 131.7, 123.9, 121.1, 119.3, 119.0, 112.3, 110.7,
110.1, 83.9, 73.8, 61.2, 55.9, 55.8, 55.8, 14.1 ppm; HRMS (ESI, 70 eV):
m/z calcd for C20H24O7 +Na+: 399.1414 [M+Na+]; found: 399.1414.
Procedure for the syntheses of aryloxy esters 8a and 8d
tert-Butyl 3-(3,4-dimethoxyphenyl)-3-hydroxy-2-(2-methoxyphenoxy)pro-
panoate (12c): The product was prepared following the same procedure
as for compound 10a (using 10 mmol of 8d), and the purification was
performed by flash chromatography (pentane/ethyl acetate 5:1!1:1)
yielding erythro (46%, 1.86 g, white solid) and threo (44%, 1.78 g, color-
less syrup) diastereomers of 12c.
Ethyl (2-methoxyphenoxy)acetate (8a): A dry and argon-flushed 1 L
three-necked flask equipped with a magnetic stirrer, a reflux condenser,
an argon inlet and a septum was charged with dry K2CO3 (13.82 g, 0.1
mol, 1 equiv), 2-methoxyphenol (12.41 g, 0.1 mol, 1 equiv) and acetone
(500 mL). The mixture was stirred at ambient temperature during 15 min,
and cooled to 08C. Ethyl bromoacetate (16.70 g, 0.1 mol, 1 equiv) was
added dropwise with a syringe in 5 min, and the reaction mixture was
subsequently warmed at reflux during 8 h. Then, the solution was allowed
to cool at ambient temperature, and filtered over a pad of celite (washed
with acetone). The filtrate was evaporated under reduced pressure until
almost dryness, and diluted in diethyl ether (200 mL). The organic layer
was washed with an aqueous NaOH solution (5% w/w, 3ꢂ50 mL), water
(50 mL) and brine (50 mL). The organic layer was dried with MgSO4, fil-
tered and evaporated under reduced pressure. The crude residue was pu-
rified by flash chromatography (pentane/Et2O 2:1) yielding ethyl (2-me-
thoxyphenoxy)acetate (18.85 g, 90%) as a slightly yellow oil. 1H NMR
(400 MHz, CDCl3, 258C, TMS): d=6.97 (ddd, J=8.0, 7.2, 1.6 Hz, 1H),
6.92–6.82 (m, 3H), 4.67 (s, 2H), 4.24 (q, J=7.3 Hz, 2H), 3.86 ppm (s,
3H), 1.27 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3, 258C, TMS):
d=169.0, 149.7, 147.3, 122.5, 120.7, 114.5, 112.1, 66.6, 61.2, 55.9,
14.1 ppm; HRMS (ESI, 70 eV): m/z calcd for C11H14O4 +K+: 249.0524
[M+K+]; found: 249.0524.
1
erythro (upper spot; 12cE): m.p. 103–1048C; H NMR (400 MHz, CDCl3,
258C, TMS): d=7.12 (d, J=8.0 Hz, 1H), 7.04–6.98 (m, 2H), 6.95 (dd, J=
8.0, 1.6 Hz, 1H), 6.91 (dd, J=8.0, 1.6 Hz, 1H), 6.88–6.82 (m, 2H), 5.12
(dd, J=6.0, 4.7 Hz, 1H), 4.68 (d, J=4.7 Hz, 1H), 3.89 (s, 3H), 3.87 (s,
3H), 3.87 (s, 3H), 3.71 (d, J=6.0 Hz, 1H), 1.32 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3, 258C, TMS): d=168.1, 150.5, 148.7, 148.6, 147.4,
131.8, 123.6, 121.0, 119.6, 118.5, 112.3, 110.6, 110.4, 83.8, 82.3, 73.8, 55.9,
55.8, 55.8, 27.8 ppm (3C); HRMS (ESI, 70 eV): m/z calcd for C22H28O7 +
Na+: 427.1727 [M+Na+]; found: 427.1728.
threo (lower spot; 12cT): 1H NMR (300 MHz, CDCl3, 258C, TMS): d=
7.05–6.98 (m, 2H), 6.97–6.89 (m, 3H), 6.86 (dd, J=8.0, 1.6 Hz, 1H), 6.81
(d, J=8.0 Hz, 1H), 5.00 (dd, J=7.7, 2.7 Hz, 1H), 4.39 (d, J=7.7 Hz, 1H),
3.92 (d, J=2.7 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.86 (s, 3H), 1.25 ppm
(s, 9H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=168.3, 150.4, 149.1,
148.9, 147.5, 130.6, 123.7, 121.0, 120.2, 118.2, 112.2, 110.7, 110.4, 85.9,
82.1, 74.9, 55.9, 55.8 (2C), 27.7 ppm (3C); HRMS (ESI, 70 eV): m/z calcd
for C22H28O7 +K+: 443.1467 [M+K+]; found: 443.1468.
tert-Butyl (2-methoxyphenoxy)acetate (8d): The product was prepared
following the same procedure as for compound 8a, and the purification
was performed by flash chromatography (pentane/Et2O 2:1) yielding tert-
butyl (2-methoxyphenoxy)acetate as a white solid (93%, 22.13 g). M.p.
Representative procedure for the reductions of the b-hydroxy esters
erythro-1-(3,4-Dimethoxyphenyl)-2-(2-methoxyphenoxy)-l,3-propanediol
(5aE): A dry and argon flushed 250 mL three-necked flask equipped
with a magnetic stirrer, a reflux condenser, an argon inlet and an addition
funnel was charged with THF (25 mL) and LiAlH4 (0.95 g, 25 mmol,
2.5 equiv). The reaction mixture was cooled to 08C and a solution of
12cE (4.04 g, 10 mmol, 1 equiv) in THF (35 mL) was added dropwise in
15 min. The heterogeneous reaction mixture was then stirred at 608C for
3 h, and cooled to 08C. The reaction mixture was carefully quenched by
the dropwise and sequential addition of water (0.95 mL), aqueous NaOH
solution (15% w/w, 0.95 mL) and additional water (2.85 mL). The reac-
tion mixture was then stirred 30 min at ambient temperature, filtered
through a pad of celite, and the aluminium salts were washed with
CH2Cl2 (4ꢂ20 mL). The filtrate was dried over MgSO4 and evaporated
under reduced pressure. The crude residue was purified by flash chroma-
tography (CH2Cl2/MeOH 99:1!97:3). The resulting pure diol was dried
by azeotropic distillation with toluene (5ꢂ20 mL) under reduced pres-
sure, and then dried overnight under 10ꢀ2 mm Hg, yielding 5aE (3.01 g,
90%) as a white solid. M.p. 100–1018C; 1H NMR (400 MHz, CDCl3,
258C, TMS): d=7.06 (ddd, J=8.0 Hz, 7.2, 1.6 Hz, 1H), 6.99–6.88 (m,
5H), 6.83 (d, J=8.0 Hz, 1H), 4.98 (brt, J=4.7 Hz, 1H), 4.16 (ddd, J=
6.0, 4.7, 3.7 Hz, 1H), 3.95–3.89 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.87
(s, 3H), 3.66 (ddd, J=12.0, 7.2, 3.7 Hz, 1H), 3.55 (brs, 1H), 2.79 ppm
(brs, 1H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=151.6, 149.0,
148.5, 146.9, 132.4, 124.3, 121.7, 121.1, 118.4, 112.2, 111.0, 109.2, 87.5,
72.7, 60.7, 55.9 ppm (3C); HRMS (ESI, 70 eV): m/z calcd for C18H22O6 +
Na+: 357.1309 [M+Na +]; found: 357.1309.
1
62–638C; H NMR (400 MHz, CDCl3, 258C, TMS): d=6.89 (ddd, J=8.0,
7.2, 1.6 Hz, 1H), 6.86–6.77 (m, 2H), 6.74 (dd, J=8.0, 1.6 Hz, 1H), 4.51 (s,
2H), 3.81 (s, 3H), 1.40 ppm (s, 9H); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=167.9, 149.4, 147.3, 122.1, 120.6, 113.8, 112.1, 82.1, 66.6, 55.9,
28.1 ppm (3C); HRMS (ESI, 70 eV): m/z calcd for C13H18O4 +Na+:
261.1097 [M+Na+]; found: 261.1097.
Representative procedure for the syntheses of the aldol products 10
erythro-Ethyl 3-(3,4-dimethoxyphenyl)-3-hydroxy-2-(2-methoxyphenoxy)-
propanoate (10aE): A dry and argon flushed 250 mL three-necked flask
equipped with a magnetic stirrer, a low temperature thermometer, an
argon inlet, and an addition funnel was charged with diisopropylamine
(1.11 g, 11 mmol, 1.1 equiv) and THF (25 mL). The reaction mixture was
cooled to 08C and a solution of commercial nBuLi in hexanes (7.3 mL,
1.6m, 11.5 mmol, 1.15 equiv) was added dropwise in 15 min. After stirring
for 30 min at 08C the reaction mixture was cooled to ꢀ788C, and a solu-
tion of ethyl (2-methoxyphenoxy)acetate (2.10 g, 10 mmol, 1 equiv) in
THF (30 mL) was added dropwise over a period of 1 h. After stirring for
additional 10 min, a solution of 3,4-dimethoxybenzaldehyde (9a, 1.59 g,
10.5 mmol, 1.05 equiv) in THF (30 mL) was added in 30 min at ꢀ788C.
At the end of the addition, stirring was continued for 90 min at ꢀ788C,
and then distilled water (60 mL) was added. The aqueous phase was ex-
tracted with ethyl acetate (3ꢂ80 mL). The combined organic layers were
washed with a 1n aqueous HCl solution (80 mL), water (80 mL) and
brine (80 mL), then dried with MgSO4, filtered, and concentrated under
reduced pressure. The crude solid was recrystallized 3ꢂ in ethyl acetate
(2.5 mL of AcOEt for 4 g of crude material; diethyl ether was used to
wash the recrystallized solid) to obtain erythro-ethyl 3-(3,4-dimethoxy-
phenyl)-3-hydroxy-2-(2-methoxyphenoxy)propanoate (1.96 g, 52%, eryth-
ro/threo >98:2) as a white solid.
The product has also been obtained by reduction of the corresponding er-
ythro-ethyl b-hydroxy ester 10aE (3.07 g, 92%, white solid). In this case,
1.5 equiv of LiAlH4 have been used.
This procedure was also performed using ethyl (2-methoxyphenoxy)-ace-
tate 8a (8.4 g, 40 mmol, 1 equiv; all the amounts of products and volumes
of solvents were calculated proportionally to the procedure described
above). In that case, 7.81 g of the diastereostereomerically pure b-hy-
droxy ester 10aE were obtained (erythro/threo >98:2). M.p. 103–1048C;
Chem. Eur. J. 2011, 17, 13877 – 13882
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13881

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Acknowledgements
This research was supported by the Fonds der Chemischen Industrie and
by the Cluster of Excellence (Tailor-Made Fuels from Biomass) funded
by the Excellence Initiative of the German federal and state govern-
ments. J.M. thanks the NRW Graduate School BrenaRo for a doctoral
fellowship.
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1
nides, and H and 13C NMR analyses of these substrates allowed the
determination of the stereochemistry of the two diastereoisomers
(see the Supporting Information for more details).
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Received: May 23, 2011
Revised: August 31, 2011
Published online: November 10, 2011
13882
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 13877 – 13882