Synthesis of enantiomerically pure lignin dimer models for catalytic selectivity studies

Article abstract of DOI:10.1021/jo502685k

A series of highly enantioselective transformations, such as the Sharpless asymmetric epoxidation and Jacobsen hydrolytic kinetic resolution, were utilized to achieve the complete stereoselective synthesis of β-O-4 lignin dimer models containing the S, G, and H subunits with excellent ee (>99%) and moderate to high yields. This unprecedented synthetic method can be exploited for enzymatic, microbial, and chemical investigations into lignins degradation and depolymerization as related to its stereochemical constitution. Preliminary degradation studies using enantiopure Co(salen) catalysts are also reported.

Full text of DOI:10.1021/jo502685k

Article
pubs.acs.org/joc
Synthesis of Enantiomerically Pure Lignin Dimer Models for Catalytic
Selectivity Studies
Costyl N. Njiojob,†,‡ Jennifer L. Rhinehart,† Joseph J. Bozell,*,‡ and Brian K. Long*,†
†Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, United States
‡Center for Renewable Carbon, University of Tennessee, Knoxville, Tennessee 37917, United States
S
* Supporting Information
ABSTRACT: A series of highly enantioselective transforma-
tions, such as the Sharpless asymmetric epoxidation and
Jacobsen hydrolytic kinetic resolution, were utilized to achieve
the complete stereoselective synthesis of β-O-4 lignin dimer
models containing the S, G, and H subunits with excellent ee
(>99%) and moderate to high yields. This unprecedented
synthetic method can be exploited for enzymatic, microbial,
and chemical investigations into lignin’s degradation and
depolymerization as related to its stereochemical constitution. Preliminary degradation studies using enantiopure Co(salen)
catalysts are also reported.
INTRODUCTION
■
Lignin is the second most abundant biorenewable organic
polymer, exceeded only by cellulose, and constitutes over 40%
of the potential chemical energy stored in plants, trees, and
grasses.1 Unlike cellulose, which has been extensively studied
and is easily transformed into numerous monomeric and
polymeric products, little progress has been made toward the
selective, high yielding conversion of lignin into low molecular
weight value-added chemicals. A primary cause for this lack of
progress is due to the structural complexity encountered within
Figure 2. Representative structures of (a) β-O-4, (b) β-5, and (c) β−β
linkages found in lignin.
lignin, which originates from its biosynthesis in which p-
hydroxylphenyl (H), guiacyl (G), and syringyl (S) monolignol
units (Figure 1) are polymerized.2,3
various interunit linkages.6 This high concentration of β-O-4
linkages in crude lignin samples makes it an ideal target for
many fundamental synthetic transformations, depolymeriza-
tions, and degradations.1,7−13 Although it is known that lignin
as a macromolecule does not display optical activity,14−16 the
presence of multiple chiral centers within lignin’s interunit
linkages may ultimately confer varying physical and chemical
properties at localized sites within the structure. Therefore, it
can be surmised that these subtle stereochemical differences
could be exploited in depolymerization and degradation studies.
For example, Trametes versicolor employs a lignin peroxidase to
preferentially degrade the threo isomer in β-O-4 models.17
Recently, Ralph and co-workers examined glutathione S-
transferase enzymes which act as enantioselective β-aryl
etherases.18,19 Additionally, other studies have shown that
enzymes from Sphingobium sp. and other enzymatic systems
degrade lignin or lignin models in a stereospecific manner.20−23
Figure 1. Structures of H, G, and S monolignol units.
This biopolymerization results when H, G, and S
monolignols are enzymatically converted into delocalized
phenoxy radicals, which then undergo radical−radical coupling
at the sites of radical delocalization. This coupling produces a
plethora of interunit linkages, such as β-O-4, β-5, and β−β
linkages (Figure 2), which can be present in varying amounts
depending on the relative proportion of monolignols present in
the plant source and lignin isolation methods employed.3−5
The most common substructural unit of native lignin is the
β-O-4 linkage, which constitutes approximately 50−65% of the
Received: November 25, 2014
Published: January 13, 2015
© 2015 American Chemical Society
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The full impact that stereochemistry has on lignin
degradation and conversion represents a significant fundamen-
tal gap in the quest to use lignin as a chemical feedstock. As a
result, access to enantiomerically pure lignin models would
provide a useful probe by which the impact of relative and
absolute stereochemical differences may influence lignin
degradation. It should be noted that the synthesis of racemic,
yet diastereomerically enriched lignin dimer models has
previously been reported,24−28 and though enantiomerically
pure lignin dimers have also been reported, those enantiomeri-
cally enriched compounds were not selectively synthesized but
were isolated either via tedious resolution of a racemic mixture
or by separation of diastereomeric derivatives of each
enantiomer, both of which lead to very limited quantities of
material for subsequent studies.23,29,30
stereospecific techniques can be used to synthesize both
enantiomers of β-O-4 linked lignin dimers containing H, G, and
S subunits with very high ee.
Toward this goal, protection of the phenolic moiety of
commercially available aldehydes 1a−1c was accomplished
using benzyl chloride to provide intermediates 2a−2c (Scheme
2). The β- and γ-carbons were installed via Grignard reaction of
Scheme 2. Synthesis of Key Intermediates 4a−4c
To the best of our knowledge, and likely due to limited or no
access to meaningful quantities of enantiopure lignin models, a
systematic examination of the chemically catalyzed conversion
of enantiomerically pure β-O-4 type lignin linkages is absent
from the literature. To address this fundamental gap, we herein
report an efficient and highly selective synthesis of optically
pure lignin β-O-4 dimers and preliminary results toward their
catalytic decomposition (oxidative) using optically active Co-
Schiff base catalysts.
RESULTS AND DISCUSSION
■
It is important to note that though prior lignin literature
frequently uses stereochemical descriptors such as erythro and
threo, we will identify all isomers using standard Cahn-Ingold-
Prelog descriptors throughout to avoid any potential ambiguity.
For example, the erythro isomer of model compound 11 will be
stereochemically represented as (R,S) or (S,R), while the threo
isomer is stereochemically represented as (R,R) or (S,S).
Asymmetric Synthesis of β-O-4 Lignin Model Dimers.
A retrosynthetic analysis of enantiomerically enriched/
enantiopure lignin dimers is shown in Scheme 1 in which the
2a−2c with vinylmagnesium chloride, providing a racemic
mixture of secondary allylic alcohols 3a−3c. Those racemic
alcohols were then subjected to SAE conditions producing the
enantiomerically enriched epoxides 4a−4c in 37−47% yield
and in ∼91% ee (as determined from Mosher ester analysis).
Though only one enantiomer is shown in Scheme 2, both
enantiomers of allylic alcohols 3a−3c could be converted to
their corresponding enantiomerically enriched epoxides by
choice of either L-diethyltartrate (L-DET) or D-diethyltartrate
(D-DET) as a ligand.31 The unreacted enantiopure alcohols
5a−5c were separated via column chromatography and later
used to obtain the complementary enantiomers (see Exper-
imental Section).
Scheme 1. Retrosynthetic Analysis for the Asymmetric
Synthesis of Lignin Dimer Models
Epoxides 4a−4c were protected as t-butyldimethylsilyl
(TBS) ethers 6a−6c and hydrolyzed to compounds 7a−7c
using previously reported HKR techniques that utilize
enantiopure salen-Co(III)OAc catalysts (Scheme 3).32−34
Given that HKR is often used for the kinetic resolution of
racemic terminal epoxides,32,33 we envisioned that coupling this
step in series with SAE would facilitate enhancements in ee by
converting only the major epoxide enantiomer to the diol while
leaving the minor epoxide unreacted. By screening each
enantiomer of the Co(salen) catalyst, it was found that the
asymmetric epoxides 6a−6c were quantitatively converted to
the asymmetric diols 7a−7c when treated with (R,R) salen-
Co(III)OAc. Correspondingly, the (S,S) salen-Co(III)OAc
catalyst was used to quantitatively convert epoxides obtained
from SAE using D-DET as a ligand (see Supporting
Information). Overall, both enantiomers of diols 7a−7c were
obtained with ee’s ≥ 99%, as determined by Mosher ester
analysis. The primary alcohols of diols 7a−7c were selectively
protected as their TBS ethers to provide virtually enantiopure
key intermediates 8a−8c, representing each of the three
final β-O-4 linkage will be formed using a Mitsunobu reaction,
thereby establishing the final stereochemistry at the β-carbon.
Prior to the Mitsunobu reaction, the stereochemistry of the α-
and β-carbons will be established using two asymmetric
techniques, the Sharpless asymmetric epoxidation (SAE) and
the Jacobson hydrolytic kinetic resolution (HKR). By proper
choice of epoxidation ligands and catalysts, we can control the
absolute and relative stereochemistries of the α- and β-carbons.
We will demonstrate herein that the combination of these
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Scheme 3. Synthesis of (S,S)-Lignin Dimers 11a−11c
Figure 3. Chemical shift differences (ΔδS‑R) for the Mosher esters of
intermediates 12b and 13b.
(S) and (R) Mosher esters were determined as shown in Figure
3. The benzylic protons of 12b and 13b have a ΔδS‑R value of
−0.01 and −0.16, respectively, therefore indicating that the
absolute stereochemistry of the benzylic chiral carbon of this
intermediate is in an S-configuration. Also, the methine proton
at the β-carbon of intermediates 12b and 13b each have a ΔδS‑R
value of +0.04, confirming an R-configuration. Finally, the
methylene protons at the γ-carbon of intermediates 12b and
13b have a (ΔδS‑R) value of +0.05, +0.11 and +0.06, +0.09,
respectively. Obtaining the absolute configuration of these key
intermediates coupled with the well-established stereochemical
inversion of the Mitsunobu reaction enabled the overall
determination of the absolute stereochemistry of the final
dimers. Additionally, the stereochemistry was confirmed via X-
ray crystallographic analysis of compound 11b (see Supporting
Information), which was in perfect agreement with the results
obtained from the Mosher ester analysis.
Co-Catalyzed Oxidation of Optically Active Lignin
Models. We have previously reported that racemic Co-Schiff
base catalysts are effective for converting lignin-like phenols
into their corresponding para-benzoquinones,28,39 and as a
preliminary demonstration of the potential utility of these
essentially enantiopure lignin dimer models, we examined their
catalytic oxidation using both enantiomers of commercially
available Co-based Jacobsen catalysts. The reaction is
postulated to proceed via formation of an intermediate Co-
superoxo complex 14oxo in which the catalysts stereoselectivity
may be influenced by the stereochemistry of the enantiopure
lignin dimers 11a−11c due to its suggested coordination to the
active metal site via a “top-on” trajectory (Figure 4).
To probe the potential effects of substrate stereochemistry
on Co-catalyzed lignin oxidation/degradation, we examined the
enantiopure β-O-4 model 11c and its enantiomeric (R,R)
analogue (Table 1). Oxidation of the (R,R)-lignin dimer model
provided an average yield of 74.39% dimethoxybenzoquinone
(DMBQ) after four individual experiments as compared to an
average of 70.10% DMBQ isolated when using the (S,S)-lignin
dimer model (11c). This difference in average isolated yield of
DMBQ is quite small, and given the potential for error
associated with isolation of such degradation compounds (as
noted in Table 1), it is considered to fall within the error of our
measurements. Though it has been suggested that the sterics of
related Mnoxo catalysts can restrict the substrate approach to a
path that passes over the ligand’s cyclohexyl group,40 in our
system, we postulate that the stereochemical information
contained within the β-O-4 linkage may be too far removed
from the active Co-superoxo complex, hence resulting in only a
very small difference in reactivity. In light of this hypothesis and
inspired by our recently published work on related Co-catalysts
primary lignin substructural units (H, G, and S). Overall, each
reaction presented in Schemes 2 and 3 proceeded in similar
yields regardless of the subunit (H, G, or S) involved; however,
the SAE of compounds 3a−3c to 4a−4c did proceed in slightly
lower yield when the more highly substituted compound S
model 3c was used.
Intermediates 8a−8c were then coupled with 4-hydroxy-3-
methoxybenzaldehyde using specific Mitsunobu reaction
conditions to yield protected (S,S) dimers 9a−9c with
complete inversion of configuration at the β-carbon. Under
traditional Mitsunobu conditions in which the phosphine,
secondary alcohol, and nucleophile were dissolved in organic
solvent followed by the dropwise addition of azodicarboxylate,
low yields were obtained (∼20%).35,36 However, it was found
that if the phosphine and azodicarboxylate were premixed to
form the proposed zwitterionic species first,37 followed by the
dropwise addition of 4-hydroxy-3-methoxybenzaldehyde (nu-
cleophile) and intermediate 8, a dramatic improvement in the
yield (65%) could be realized. The TBS-ethers of compounds
9a−9c were then deprotected using tetra-n-butylammonium
fluoride (TBAF) to provide diols 10a−10c. Lastly, the benzyl
protecting groups were cleaved via hydrogenolysis using Pd/C
in EtOH to provide the final enantiomerically enriched
compounds 11a−11c in which the aldehyde functionality was
also reduced.
Assignment of Absolute Stereochemistry. To confirm
the stereochemistry of final compounds 11a−11c, intermedi-
ates 4a and 8b were converted to their corresponding Mosher
esters by reacting each intermediate with either (R) or (S)-
(+)-α-methoxy-α-trifluoro-methylphenylacetyl chloride
(MPTA-Cl), respectively, following a well-established proto-
col.38 The difference in the chemical shifts (ΔδS‑R) between the
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on a column, or by an automated chromatography system using high
performance silica gel. The eluents employed are reported as volume/
volume percentages. Melting points were recorded using a melting
point apparatus and are uncorrected. Specific rotations were obtained
using a polarimeter. 1H and 13C NMR spectra were measured in
CDCl3 and CD3OD using a 500 MHz instrument, and chemical shifts
are reported relative to tetramethylsilane or residual solvent resonance
and reported in parts per million. Infrared spectra were obtained on an
Fourier transform-infrared (FT-IR) spectrometer at 4 cm−1 resolution
and are reported in cm−1. High-resolution mass spectra (HRMS) are
reported as m/e (relative ratio), and accurate masses are reported for
the molecular ion (M + H)+ or a suitable fragment ion and are
reported with an error <5 ppm. Oxidation reactions were carried out in
thick-walled glass reactors under the oxygen pressure indicated in the
text. Detailed synthetic procedures, including the complete character-
ization [nuclear magnetic resonance (NMR), HRMS, IR, and specific
rotations] for each intermediate, are reported for the (S,S) enantiomer.
The corresponding (R,R) enantiomer has identical NMR, MS and IR
data, but displays an opposite specific rotation value that is also
reported. X-ray diffraction measurements were performed on single
crystals coated with Paratone oil, mounted on a loop, and frozen under
a stream of N2 while data were collected on a diffractometer.
Reflections were merged and corrected for Lorenz and polarization
effects, scan speed, and background. The structure was solved by direct
methods with the aid of successive difference Fourier maps and were
refined against all data. All of the solvent molecules were squeezed.
General Procedure for the Oxidation of Enantiomerically
Pure Lignin Dimer Models to Benzoquinones. The synthesized
enantiopure lignin dimer model (0.30 mmol) and enantiomerically
pure Jacobsen catalyst (0.03 mmol) were combined in 15 mL of
methanol in a Fisher-Porter bottle. The bottle was flushed with oxygen
three times and then pressurized with oxygen to 55 psi. Each reaction
was run for 16 h, after which the reaction mixture was concentrated
under vacuum and the crude material purified via flash chromatog-
raphy using EtOAc/CH2Cl2 (5:95) as an eluent to provide the product
2,6-dimethoxybenzoquinone as a bright yellow solid. The data
obtained satisfactorily matched all previously reported data.42
Figure 4. Mechanism of radical formation during phenol oxidation by
Co-Schiff base complexes.
Table 1. Oxidative Degradation of (S, S)-Lignin Model
Dimer 11c and Its (R,R) Analogue Using Enantiopure
a
Jacobsen Catalysts.
b
entry
substrate
catalyst
t (h)
% DMBQ
1
2
3
4
(R,R)
(R,R)
(S,S)
(S,S)
(R,R)
(S,S)
(R,R)
(S,S)
16
16
16
16
74.05% ( 3.9)
74.73% ( 6.7)
69.55% ( 7.1)
70.65% ( 4.0)
a
b
[Catalyst] = 10 mol %, 55 psi O2. Isolated yields, reported as an
average over four trials one standard deviation.
that bear sterically bulky Lewis bases pendant to the
ethylenediamine bridge of the Schiff-base ligand,41 our future
efforts will be to examine if precisely positioned, optically active
groups pendant to the Schiff-base ligand may influence
substrate approach and overall oxidative enantioselectivity.
In conclusion, we have reported an efficient method for the
preparation of enantiomerically pure β-O-4-linked lignin dimer
model compounds with moderate-to-high yields, and in
excellent ee via the application of successive asymmetric
transformations. Ready access to such enantiopure lignin
models provides a platform by which researchers may
ultimately ascertain the extent to which enzymatic and
organometallic catalyst systems may be influenced by native
lignin stereochemical differences. Our initial investigations into
the oxidative degradation of enantiopure lignin models using
chiral Jacobsen catalysts showed little to no differentiation
based on substrate stereochemistry, and future studies will be
conducted to determine if targeted ligand modifications may
impact overall substrate selectivity. These studies hold promise
to pave the way for intelligent catalyst design that not only
focuses on functional group reactivity but also considers the
role that lignin stereochemistry may play in the catalytic
conversion of lignin into useful, value-added chemical feed-
stocks.
4-(Benzyloxy)-3-methoxybenzaldehyde (2a). To a stirred solution
of vanillin (10.0 g, 65.7 mmol) in anhydrous DMF was added K2CO3
(13.7 g, 99.1 mmol) and benzyl chloride (9.08 mL, 78.9 mmol) under
N2 followed by a catalytic amount of 4-dimethylaminopyridine
(DMAP). The resulting solution was stirred overnight at rt. After
consumption of the starting material as confirmed by TLC, the
reaction was quenched by addition of saturated ammonium chloride.
The resulting suspension was extracted with CH2Cl2 (3 × 100 mL).
The combined organic extracts were dried over MgSO4 and
concentrated in vacuo. The crude material was purified by
recrystallization in hexane/ethanol (1:4) to provide 15.0 g of phenol
2a (94%) as a cream white solid. Mp: 53−55 °C. IR (neat): 2937.89,
2833.93, 1679.33, 1584.26, 15, 1506.45, 1463.89, 1261.1, 1194.7,
730.21 cm−1. 1H NMR (500 MHz, CDCl3): δ 9.73 (s, 1H), 7.35−7.31
(m, 3H), 7.30−7.25 (m, 3H), 7.22 (t, J = 7.3 Hz, 1H), 6.88 (d, J = 8.2
Hz, 1H), 5.13 (s, 2H), 3.83 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
190.8, 153.6, 136.01, 150.1, 130.3, 128.7, 128.2, 127.2, 126.5, 112.4,
+
109.4, 70.8, 56.0; HRMS (DART-TOF): calcd for C15H15O3 (M +
H)+, 243.10157; found, 243.10160.
4-(Benzyloxy)benzaldehyde (2b). Following the general procedure
outlined above for compound 2a, 4-hydroxybenzaldehyde (1b) (10.0
g, 81.9 mmol) was converted to yield 17.0 g of compound 2b (98%)
which was isolated as a white solid. Mp: 68−70 °C. IR (neat): 1738.88,
1604.53, 1507.18, 1451.91, 1266.02, 1061.29, 708.27, 617.29 cm−1. 1H
NMR (500 MHz, CDCl3): δ 9.77 (s, 1H), 7.72 (d, J = 8.7 Hz, 2H),
7.35−7.22 (m, 5H), 6.97 (d, J = 8.7 Hz, 2H), 5.03 (s, 2H). 13C NMR
(125 MHz, CDCl3): δ 190.8, 163.7, 136.0, 132.0, 130.1, 128.7, 128.3,
EXPERIMENTAL SECTION
■
General Methods and Materials. All reactions were carried out
under an atmosphere of nitrogen unless otherwise specified. All
reagents and solvents were purchased from commercial sources and
were used as received. Analytical thin layer chromatography (TLC)
was performed using glass-backed precoated silica gel plates with an
extra hard layer of 60 Ao mesh, 250 μm thick silica. Flash column
chromatography was performed using either 230−400 mesh silica gel
+
127.5, 115.1, 70.2; HRMS (DART-TOF): calcd for C14H13O2 (M +
H)+, 213.09101; found, 213.09100.
4-(Benzyloxy)-3,5-dimethoxybenzaldehyde (2c). Following the
general procedure outlined above for compound 2a, 4-(hydroxy)-
3,5-dimethoxybenzaldehyde (1c) (10.0 g, 54.9 mmol) was converted
to yield 14.5 g of protected phenol 2c (97%) as a cream white solid.
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Mp: 56−58 °C. IR (neat): 3062.99, 2883.02, 2848.38, 1683.65,
1587.39, 1323.13, 1221.24, 727.22, 614.58 cm−1. 1H NMR (500 MHz,
CDCl3): δ 9.77 (s, 1H), 7.38 (d, J = 7.1 Hz, 2H), 7.22 (dq, J = 23.0,
8.6, 7.8 Hz, 3H), 7.02 (s, 2H), 5.04 (s, 2H), 3.81 (s, 6H). 13C NMR
(125 MHz, CDCl3): δ 191.1, 154.0, 142.4, 137.2, 131.9, 128.4, 128.2,
2H), 7.30 (t, J = 7.3 Hz, 1H), 6.95 (d, J = 1.4 Hz, 1H), 6.89−6.84 (m,
2H), 5.15 (s, 2H), 4.88−4.78 (m, 1H), 3.90 (s, 3H), 3.20 (q, J = 3.0
Hz, 1H), 2.94 (dd, J = 5.0, 2.7 Hz, 1H), 2.77 (dd, J = 4.9, 4.1 Hz, 1H),
2.34 (d, J = 2.2 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 149.8,
148.1, 137.0, 132.6, 128.5, 127.8, 127.2, 118.7, 113.9, 110.1, 71.0, 70.7,
+
+
128.1, 106.7, 75.0, 56.2. HRMS (DART-TOF): calcd for C16H17O4
56.0, 55.0, 43.7. HRMS (DART-TOF): calcd for C17H17O3 (M −
(M + H)+, 273.11214; found, 273.11138.
25
OH)+, 269.11722; found, 269.11592. [α]D +48.3 (c 1.00, CHCl3).
1-(4-(Benzyloxy)-3-methoxyphenyl)prop-2-en-1-ol (3a). Vinyl
magnesium bromide (49 mL, 49 mmol) was added to a stirred
solution of aldehyde 2a (10 g, 41.3 mmol) in anhydrous THF at 0 °C.
The resulting solution was warmed to rt and stirred for 3 h. After
complete consumption of the starting material, as monitored by TLC,
the reaction was quenched by addition of saturated ammonium
chloride. The resulting suspension was extracted with CH2Cl2 (3 ×
100 mL). The combined organic extracts were dried over MgSO4 and
concentrated in vacuo. The crude compound was purified by column
chromatography using hexane/EtOAc (7:3) to afford 10.5 g of vinyl
alcohol 2a (94.1%) as a light yellow oil. IR (neat): 3416.26, 2933.67,
1592.81, 1510.57, 1259.82, 1222, 746.92, 696.65 cm−1. 1H NMR (500
MHz, CDCl3): δ 7.33 (d, J = 7.7 Hz, 2H), 7.25 (t, J = 7.5 Hz, 2H),
7.18 (t, J = 7.3 Hz, 1H), 6.82 (s, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.69 (d,
J = 8.2 Hz, 1H), 5.91 (d, J = 36.0 Hz, 1H), 5.21 (dd, J = 17.1, 3.6 Hz,
1H), 5.06 (dd, J = 10.3, 3.1 Hz, 1H), 5.02 (s, 2H), 4.98 (s, 1H), 3.76
(s, 3H). 13C NMR (125 MHz, CDCl3): δ 149.7, 147.7, 140.3, 137.4,
135.9, 128.5, 127.8, 127.3, 118.6, 114.8, 113.9, 110.1, 75.00, 71.0, 56.0.
The opposite enantiomer, (R)-(4-(benzyloxy)-3-methoxyphenyl)-
((S)-oxiran-2-yl)methanol, provides a specific rotation of [α]D25 −48.3
(c 1.00, CHCl3).
(S)-(4-(Benzyloxy)phenyl)((R)-oxiran-2-yl)methanol (4b). Follow-
ing the general procedure outlined above for compound 4a, 1-(4-
(benzyloxy)phenyl)prop-2-en-1-ol (3b) (8.0 g, 33.3 mmol) was
converted to yield 4.0 g of the asymmetric epoxide 4b (47%) as a
light yellow solid. Mp: 50−52 °C. IR (neat): 3433.21, 1610.91,
1511.93, 1241.98, 1024.59, 698.37 cm−1. 1H NMR (500 MHz,
CDCl3): δ 7.30 (d, J = 7.4 Hz, 2H), 7.26 (t, J = 7.4 Hz, 2H), 7.19 (dd,
J = 16.3, 7.9 Hz, 3H), 6.85 (d, J = 8.7 Hz, 2H), 4.93 (s, 2H), 4.66 (s,
1H), 3.03 (q, J = 3.2 Hz, 1H), 2.79 (dd, J = 5.1, 2.8 Hz, 1H), 2.62−
2.59 (m, 1H), 2.56 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 158.8,
136.9, 128.6, 128.0, 127.8, 127.4, 115.0, 70.5, 70.0, 55.0, 43.6. HRMS
+
(DART-TOF): calcd for C16H15O2 (M − OH)+, 239.10666; found,
25
239.10641. [α]D +64.0 (c 1.00, CHCl3).
The opposite enantiomer, (R)-(4-(benzyloxy) phenyl)((S)-oxiran-
25
2-yl)methanol, provides a specific rotation of [α]D −62.3 (c 1.00,
+
HRMS (DART-TOF): calcd for C17H17O2 (M − OH)+, 253.12317;
CHCl3).
found, 253.12231.
(S)-(4-(Benzyloxy)-3,5-dimethoxyphenyl)((R)-oxiran-2-yl)-
methanol (4c). Following the general procedure outlined above for
compound 4a, 1-(4-(benzyloxy)-3,5-dimethoxyphenyl)prop-2-en-1-ol
(3c)(10.0 g, 33.32 mmol) was converted to yield 3.8 g of the
asymmetric epoxide 4c (36.1%) as a colorless oil. IR (neat): 3441.27,
2938.9, 1591.6, 1505.65, 1328.53, 1125, 783.04, 697.42 cm−1. 1H
NMR (500 MHz, CDCl3): δ 7.50 (d, J = 7.0 Hz, 2H), 7.34 (t, J = 7.3
Hz, 2H), 7.29 (t, J = 7.3 Hz, 1H), 6.62 (s, 2H), 5.00 (s, 2H), 4.85 (d, J
= 3.0 Hz, 1H), 3.24 (q, J = 3.2 Hz, 1H), 2.96 (dd, J = 5.0, 2.7 Hz, 1H),
2.82−2.78 (m, 1H), 2.20 (s, 1H). 13C NMR (125 MHz, CDCl3): δ
153.7, 137.8, 136.8, 135.3, 128.4, 128.1, 127.8, 103.4, 75.0, 71.2, 56.1,
1-(4-(Benzyloxy)phenyl)prop-2-en-1-ol (3b). Following the general
procedure outlined above for compound 3a, 4-(benzyloxy)-
benzaldehyde (2b) (10.0 g, 47.15 mmol) was converted to yield
10.5 g of protected phenol 3b (92.7%) as a cream white solid. Mp:
57−59 °C. IR (neat) 3402.98, 2936.55, 1744.43, 1592.85, 1510.56,
1
1259.54, 1221.6, 779.29 cm−1. H NMR (500 MHz, CDCl3): δ 7.33
(d, J = 7.2 Hz, 2H), 7.28 (t, J = 7.4 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H),
7.18 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.99−5.88 (m, 1H),
5.22 (dt, J = 17.1, 1.4 Hz, 1H), 5.08 (dt, J = 10.3, 1.3 Hz, 1H), 5.03 (s,
1H), 4.95 (s, 2H). 13C NMR (125 MHz, CDCl3): δ 158.4, 140.4,
137.0, 135.2, 128.6, 128.0, 127.7, 127.5, 114.9, 114.8, 74.8, 70.0.
HRMS (DART-TOF): calcd for C16H15O+ (M − OH)+, 223.11174;
found, 223.11197.
+
55.0, 43.8. HRMS (DART-TOF): calcd for C18H21O5 (M + H)+,
25
317.13835; found, 317.13809. [α]D +18.5 (c 1.00, CHCl3).
The opposite enantiomer, (R)-(4-(benzyloxy)-3,5-dimethoxy-
1-(4-(Benzyloxy)-3,5-dimethoxyphenyl)prop-2-en-1-ol (3c). Fol-
lowing the general procedure outlined above for compound 3a, 4-
(benzyloxy)-3,5-dimethoxybenzaldehyde (2c) (10.0 g, 36.75 mmol)
was converted to yield 10.5 g of protected phenol 3c (95.2%) as a
viscous oil. IR (neat): 3435.92, 2938.3, 2838.26, 1591.64, 1417.56,
phenyl)((S)-oxiran-2-yl)methanol, provides a specific rotation of
[α]D −15.9 (c 1.00, CHCl3).
25
((S)-(4-(Benzyloxy)-3-methoxyphenyl)((R)-oxiran-2-yl)methoxy)-
(tert-butyl)-dimethylsilane (6a). To a stirred solution of the
asymmetric epoxy alcohol 4a (3.5 g, 12.23 mmol) dissolved in dry
CH2Cl2, was added TBSCl (5.53 g, 36.7 mmol), imidazole (5.0 g, 73.4
mmol), and a catalytic amount of DMAP. The resulting solution was
stirred for 3 h at rt. After complete consumption of the starting
material, as monitored by TLC, the reaction was quenched by addition
of saturated NH4Cl solution and extracted with CH2Cl2 (2 × 100 mL).
The combined organic extracts were dried over MgSO4 and
concentrated in vacuo. The crude compound was purified by column
chromatography using hexane/EtOAc (9:1) to afford the protected
asymmetric epoxide 6a (5.0 g, 12.0 mmol, 98.1%) as a light yellow oil.
IR (neat) 2953.61, 2856.75, 1683.03, 1593.11, 1513.29, 1226.43,
1079.82, 696.05 cm−1. 1H NMR (500 MHz, CDCl3): δ 7.49−7.43 (m,
2H), 7.38 (td, J = 6.7, 6.3, 1.6 Hz, 2H), 7.34−7.28 (m, 1H), 6.99 (d, J
= 1.8 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.85 (dd, J = 8.2, 1.8 Hz, 1H),
5.16 (s, 2H), 4.67 (d, J = 3.7 Hz, 1H), 3.91 (s, 3H), 3.05 (td, J = 3.8,
2.6 Hz, 1H), 2.84 (dd, J = 5.6, 2.6 Hz, 1H), 2.71 (dd, J = 5.6, 3.9 Hz,
1H), 0.92 (s, 9H), 0.10 (s, 3H), 0.00 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 149.6, 147.7, 137.2, 134.7, 128.5, 127.8, 127.3, 118.3, 113.7,
109.8, 72.9, 71.1, 55.9, 44.3, 25.7, 18.3, −4.9. HRMS (DART-TOF):
1
1230.57, 1123.58, 922.14 cm−1. H NMR (500 MHz, CDCl3): δ 7.41
(d, J = 7.2 Hz, 2H), 7.26 (t, J = 7.3 Hz, 2H), 7.20 (t, J = 7.3 Hz, 1H),
6.50 (s, 2H), 5.95 (ddd, J = 17.0, 10.3, 6.0 Hz, 1H), 5.27 (dt, J = 17.1,
1.4 Hz, 1H), 5.12 (dt, J = 10.3, 1.3 Hz, 1H), 5.03 (d, J = 5.7 Hz, 1H),
4.91 (s, 2H), 3.74 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 153.6,
140.0, 138.4, 137.8, 136.4, 128.4, 128.1, 127.8, 115.2, 103.3, 75.4, 75.0,
+
56.1. HRMS (DART-TOF): calcd for C18H19O3 (M − OH)+,
283.13287; found, 283.13234.
(S)-(4-(Benzyloxy)-3-methoxyphenyl)((R)-oxiran-2-yl)methanol
(4a). To a stirred suspension of 4 Å molecular sieves in dry CH2Cl2
(20 mL) was added racemic allylic alcohol 3a (7.0 g, 26 mmol) and
Ti(OiPr)4 (1.55 mmol, 0.46 mL) under N2 atmosphere. The reaction
mixture was cooled to −5 °C, and L-DET (2.07 mmol, 0.36 mL) was
added dropwise. The resulting mixture was stirred at −5 °C for 30
min, before a solution of t-butyl hydroperoxide in hexanes (5.5 M, 26
mmol, 4.73 mL) was added dropwise over 30 min at 0 °C and stirred
for 8 h. The reaction was quenched with a 10% aqueous solution of
tartaric acid, and the resulting suspension was extracted with CH2Cl2
(3 × 100 mL) and filtered. The combined organic extracts were dried
over MgSO4 and concentrated in vacuo. The crude compound was
purified via column chromatography using hexane/EtOAc (7:3) to
afford asymmetric epoxide 4a (3.0 g, 11.1 mmol, 42.7%) as a cream
white solid. Mp: 59−61 °C. IR (neat) 3441.08, 2933.96, 1743.91,
+
calcd for C17H17O3 (M − OTBS)+, 269.11722; found, 269.11594.
25
[α]D +41.9 (c 1.00, CHCl3).
The opposite enantiomer (R)-(4-(benzyloxy)-3-methoxyphenyl)-
((S)-oxiran-2-yl)methoxy)(tert-butyl)dimethylsilane, provides a specif-
25
ic rotation of [α]D −38.0 (c 1.00, CHCl3).
1
1743.91, 1512.7, 1261.03, 1137.48, 1024.87, 697.04 cm−1. H NMR
((S)-(4-(Benzyloxy)phenyl)((R)-oxiran-2-yl)methoxy)(tert-butyl)-
(500 MHz, CDCl3): δ 7.43 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.4 Hz,
dimethylsilane (6b). Following the general procedure outlined above
1775
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The Journal of Organic Chemistry
Article
for compound 6a, (S)-(4-(benzyloxy)phenyl)((R)-oxiran-2-yl)-
methanol (4b)(3.7 g, 14.44 mmol) was converted to yield 5.0 g of
the protected asymmetric epoxy alcohol 6b (93.5%) as a light yellow
oil. IR (neat) 2954.85, 2856.55, 1761.13, 1611.07, 1510.55, 1249.89,
1002.58, 696.21 cm−1. 1H NMR (500 MHz, CDCl3): δ 7.48 (d, J = 8.8
Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.33 (d, J =
8.5 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 5.09 (s, 2H), 4.72 (d, J = 3.5 Hz,
1H), 3.09−3.04 (m, 1H), 2.87 (dd, J = 5.6, 2.6 Hz, 1H), 2.73 (dd, J =
5.6, 3.9 Hz, 1H), 0.92 (s, 10H), 0.11 (s, 3H), −0.00 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ 158.4, 137.0, 133.9, 128.6, 128.0, 127.51,
127.47, 114.6, 72.7, 70.0, 56.0, 44.1, 25.8, 18.3, −4.9. HRMS (DART-
yl)methoxy)(tert-butyl)dimethylsilane (6b) (4.1 g, 11.07 mmol) was
converted to yield 3.85 g of the asymmetric diol 7b (89.6%) as a light
yellow oil. IR (neat): 3420.43, 2953.5, 2928.59, 1511.17, 1258.05,
1
1077.5, 1033.85, 695.72 cm−1. H NMR (500 MHz, CDCl3): δ 7.58
(d, J = 7.1 Hz, 2H), 7.53 (t, J = 7.4 Hz, 2H), 7.48 (t, J = 7.2 Hz, 1H),
7.39 (d, J = 7.4 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 5.20 (s, 2H), 4.85
(d, J = 5.2 Hz, 1H), 3.82 (d, J = 22.0 Hz, 3H), 2.49 (d, J = 34.7 Hz,
2H), 1.04 (s, 9H), 0.21 (s, 3H), −0.00 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 158.5, 128.6, 128.0, 127.8, 127.5, 114.7, 75.5, 70.0, 63.0,
25.8, 18.1, −4.7, −5.2. HRMS (DART-TOF): calcd for C16H17O3+ (M
25
− OTBS)+, 257.11722; found, 257.11606. [α]D +54.3 (c 1.00,
+
TOF): calcd for C16H15O2 (M − OTBS)+, 239.10666; found,
CHCl3).
25
239.10706. [α]D +56.2 (c 1.00, CHCl3).
The opposite enantiomer, (2S,3R)-3-(4-(benzyloxy)phenyl)-3-
The opposite enantiomer, ((R)-(4-(benzyloxy)phenyl)((S)-oxiran-
((tert-butyldimethylsilyl)oxy)propane-1,2-diol, provides a specific
rotation of [α]D −56.9 (c 1.00, CHCl3).
25
2-yl)methoxy)(tert-butyl) dimethylsilane, provides a specific rotation
25
of [α]D −53.5 (c 1.00, CHCl3).
(2R,3S)-3-(4-(Benzyloxy)-3,5-dimethoxyphenyl)-3-((tert-butyldi-
methylsilyl)oxy) propane-1,2-diol (7c). Following the general
procedure outlined above for compound 7a, ((R)-(4-(benzyloxy)-
3,5-dimethoxyphenyl)((S)-oxiran-2-yl)methoxy)(tert-butyl)dimethyl-
silane (6c) (1.5 g, 3.5 mmol) was converted to yield 1.4 g of the
asymmetric diol 7c (88.6%) as a yellow oil. IR (neat): 3434.72,
((R)-(4-(Benzyloxy)-3,5-dimethoxyphenyl)((S)-oxiran-2-yl)-
methoxy)(tertbutyl) dimethylsilane (6c). Following the general
procedure outlined above for compound 6a, (S)-(4-(benzyloxy)-3,5-
dimethoxyphenyl)((R)-oxiran-2-yl)methanol (4c) (1.4 g, 4.43 mmol)
was converted to yield 1.85 g of the protected asymmetric epoxy
alcohol 6c (97%) as a light yellow oil. IR (neat): 2953.92, 2856.12,
1
2929.08, 2856.9, 1592.71, 1461.43, 1234.31, 1080.5, 696.35 cm−1. H
1
1592.19, 1461.66, 1251.02, 862.87, 697.38, 670.95 cm−1. H NMR
NMR (500 MHz, CDCl3): δ 7.57 (d, J = 6.9 Hz, 2H), 7.43 (dt, J =
14.8, 7.0 Hz, 3H), 6.66 (s, 2H), 5.13 (s, 2H), 4.79 (s, 1H), 3.92 (s,
6H), 3.82 (d, J = 32.8 Hz, 3H), 2.40 (s, 2H), 1.03 (s, 10H), 0.20 (s,
3H), −0.00 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 153.5, 137.7,
136.9, 136.0, 128.5, 128.0, 127.8, 103.4, 75.4, 74.9, 62.9, 56.0, 25.7,
(500 MHz, CDCl3): δ 7.45 (d, J = 6.9 Hz, 2H), 7.30 (t, J = 7.2 Hz,
2H), 7.25 (d, J = 7.2 Hz, 1H), 6.57 (s, 2H), 4.97 (s, 2H), 4.56 (d, J =
3.9 Hz, 1H), 3.78 (s, 6H), 3.05−2.99 (m, 1H), 2.79 (dd, J = 5.5, 2.6
Hz, 1H), 2.69 (dd, J = 5.5, 3.8 Hz, 1H), 0.87 (s, 9H), 0.04 (s, 3H),
−0.05 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 153.4, 137.9, 137.4,
136.2, 128.4, 128.1, 127.7, 103.0, 75.0, 73.4, 56.1, 44.4, 25.7, 18.3,
−3.6, −4.9, −5.0. HRMS (DART-TOF): calcd for C24H35O5Si+ (M +
+
18.1, −4.7, −5.2. HRMS (DART-TOF): calcd for C18H21O5 (M −
OTBS)+, 317.13835; found, 317.13692. [α]D25 +55.3 (c 1.00, CHCl3).
The opposite enantiomer, (2S,3R)-3-(4-(benzyloxy)-3,5-dimethoxy-
phenyl)-3-((tert-butyldimethyl silyl)oxy)propane-1,2-diol, provides a
25
H)+, 431.22438; found, 431.22608. [α]D +47.3 (c 1.00, CHCl3).
25
The opposite enantiomer, ((S)-(4-(benzyloxy)-3,5-dimethoxy-
specific rotation of [α]D −58.4 (c 1.00, CHCl3).
phenyl)((R)-oxiran-2-yl)methoxy)(tert-butyl)dimethylsilane, provides
(5S,6R)-5-(4-(Benzyloxy)-3-methoxyphenyl)-2,2,3,3,9,9,10,10-
octamethyl-4,8-dioxa-3,9-disilaundecan-6-ol (8a). To a stirred
solution of asymmetric diol 7a (3.0 g, 7.1 mmol) in dry CH2Cl2
was added TBSCl (1.2 g, 7.9 mmol), imidazole (0.58 g, 8.6 mmol),
and a catalytic amount of DMAP. The resulting solution was stirred at
rt for 2 h. After complete consumption of the starting material, as
monitored on TLC, the reaction was quenched by addition of
saturated NH4Cl solution and extracted with CH2Cl2 (3 × 100 mL).
The combined organic extracts were dried over MgSO4 and
concentrated in vacuo. The crude compound was purified by column
chromatography using hexane/EtOAc (9:1) to afford the protected
asymmetric alcohol 8a (3.41 g, 6.8 mmol, 96%) as a colorless oil. IR
(neat): 3389.2, 2953.74, 2928.47, 2884.07, 1593.59, 1511.49, 1463.32,
1254.58, 1077.1, 834.85, 695.85 cm−1. 1H NMR (500 MHz, CDCl3): δ
7.48−7.41 (m, 2H), 7.40−7.33 (m, 2H), 7.33−7.27 (m, 1H), 6.95 (d, J
= 1.8 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.80 (dd, J = 8.2, 1.8 Hz, 1H),
5.14 (s, 2H), 4.58 (d, J = 5.7 Hz, 1H), 3.88 (s, 3H), 3.76−3.63 (m,
3H), 2.34−2.30 (m, 1H), 0.91 (s, 8H), 0.88 (s, 8H), 0.07 (d, J = 4.2
Hz, 5H), 0.04 (s, 3H), −0.16 (s, 3H). 13C NMR (125 MHz, CDCl3):
δ 149.4, 147.6, 137.2, 134.9, 128.5, 127.8, 127.3, 119.4, 113.5, 110.4,
76.0, 75.1, 71.1, 63.7, 55.9, 25.9, 18.3, −4.6, −5.1, −5.4. HRMS
(DART-TOF): calcd for C23H33O4Si+ (M − OTBS)+, 401.21426;
25
a specific rotation of [α]D −43.5 (c 1.00, CHCl3).
(2R,3S)-3-(4-(Benzyloxy)-3-methoxyphenyl)-3-((tert-butyldimeth-
ylsilyl)oxy)propane-1,2-diol (7a). Commercially available (R,R)-
(−)-N,N′-Bis(3,5-ditert-butylsalicylidene)-1,2-cyclohexane-diamino-
cobalt(II) (1g, 1.66 mmol) was dissolved in toluene and cooled to 0
°C. To this solution, AcOH (1.9 mL, 33 mmol) was added dropwise
and the resulting suspension was stirred at rt in open air for 45 min.
The color of the solution changed from red to brown, indicating
complete conversion of the catalyst from Co(II) to the active Co(III)
complex. The solvent was evaporated under vacuum to provide the
(R,R)-salen-Co(III)OAc as a brown solid that was used in the next
step without further purification. To a stirred solution of ((S)-(4-
(benzyloxy)-3-methoxyphenyl)((R)-oxiran-2-yl)methoxy)(tert-butyl)-
dimethylsilane (6a) (3.0 g, 7.5 mmol) dissolved in THF at 0 °C was
added (R,R)-salen-Co(III)OAc (0.15 g, 0.23 mmol) followed by the
dropwise addition of water (0.2 mL, 11.25 mmol). The reaction was
warmed to rt and stirred for 24 h. After consumption of the starting
material, as monitored on TLC, the organic phase was washed with
water (2 × 50 mL), dried over MgSO4, and concentrated in vacuo.
The crude compound was purified via column chromatography using
hexane/EtOAc (7:3) to afford the asymmetric diol 7a (2.84 g, 6.78
mmol, 90.5%) as a yellow oil. IR (neat): 3406.3, 2929.04, 2856.23,
25
found, 401.21422. [α]D +30.0 (c 1.00, CHCl3).
1
1511.79, 1258.96, 1137.9, 836.93, 696.08 cm−1. H NMR (500 MHz,
The opposite enantiomer, (5R,6S)-5-(4-(benzyloxy)-3-methoxy-
CDCl3): δ 7.53 (d, J = 7.3 Hz, 2H), 7.44 (t, J = 7.2 Hz, 2H), 7.38 (t, J
= 7.1 Hz, 1H), 7.08 (s, 1H), 6.99−6.85 (m, 2H), 5.18 (s, 2H), 4.72 (d,
J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.87−3.75 (m, 3H), 3.31 (s, 1H), 3.11
(s, 1H), 1.04 (s, 9H), 0.20 (s, 3H), −0.00 (s, 3H). 13C NMR (125
MHz, CDCl3): δ 149.7, 147.8, 137.2, 135.0, 128.5, 127.9, 127.5, 119.3,
113.8, 110.6, 76.4, 76.1, 71.1, 63.2, 56.0, 25.9, 18.2, −4.5, −5.0. HRMS
(DART-TOF): calcd for C17H19O4+ (M − OTBS)+, 287.12779; found,
phenyl)-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-ol,
provides a specific rotation of [α]D −28.5 (c 1.00, CHCl3).
25
(5S,6R)-5-(4-(Benzyloxy)phenyl)-2,2,3,3,9,9,10,10-octamethyl-4,8-
dioxa-3,9-disilaundecan-6-ol (8b). Following the general procedure
outlined above for compound 8a, (2R,3S)-3-(4-(benzyloxy)phenyl)-3-
((tert-butyl-dimethylsilyl)oxy)propane-1,2-diol (7b) (4.3 g, 11.07
mmol) was converted to yield 5.74 g of the protected asymmetric
alcohol 8b (97.5%) as a colorless oil. IR (neat): 3361.91, 2928.59,
2856.66, 1610.56, 1510.61, 1249.83, 1102.25, 833.79, 621.71 cm−1. 1H
NMR (500 MHz, CDCl3): δ 7.61 (d, J = 7.3 Hz, 2H), 7.55 (t, J = 7.6
Hz, 2H), 7.49 (t, J = 7.2 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.12 (d, J =
8.6 Hz, 2H), 5.22 (s, 2H), 4.77 (d, J = 5.5 Hz, 1H), 3.86 (s, 3H), 2.51
(d, J = 3.3 Hz, 1H), 1.08 (s, 9H), 1.05 (s, 9H), 0.24 (d, J = 4.2 Hz,
6H), 0.21 (s, 3H), −0.00 (s, 3H). 13C NMR (125 MHz, CDCl3): δ
25
287.12785. [α]D +55.0 (c 1.00, CHCl3).
The opposite enantiomer, (2S,3R)-3-(4-(benzyloxy)-3-methoxy-
phenyl)-3-((tert-butyldimethylsilyl)oxy) propane-1,2-diol, provides a
25
specific rotation of [α]D −58.0 (c 1.00, CHCl3).
(2R,3S)-3-(4-(Benzyloxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-
propane-1,2-diol (7b). Following the general procedure outlined
above for compound 7a, ((S)-(4-(benzyloxy)phenyl)((R)-oxiran-2-
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The Journal of Organic Chemistry
Article
158.3, 137.1, 134.1, 128.5, 128.2, 127.9, 127.5, 127.5, 114.4, 76.1, 74.9,
70.0, 63.7, 25.9, 25.8, 18.3, 18.1, −4.6, −5.1, −5.3. HRMS (DART-
TOF): calcd for C22H31O3Si+ (M − OTBS)+, 371.20370; found,
114.5, 113.9, 109.7, 84.8, 74.4, 70.0, 62.5, 55.7, 25.7, 25.6, 18.13, 18.05,
−5.0, −5.2, −5.6. HRMS (DART-TOF): calcd for C36H53O6Si2+ (M +
25
H)+, 637.33752; found, 637.33654. [α]D +18.8 (c 1.00, CHCl3).
25
371.20343. [α]D +31.2 (c 1.00, CHCl3).
The opposite enantiomer, 4-(((5R,6R)-5-(4-(benzyloxy)phenyl)-
The opposite enantiomer, (5R,6S)-5-(4-(benzyloxy)phenyl)-
2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)oxy)-3-
methoxybenzaldehyde, provides a specific rotation of [α]D −17.4 (c
1.00, CHCl3).
25
2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-ol, provides
25
a specific rotation of [α]D −30.7 (c 1.00, CHCl3).
(5S,6R)-5-(4-(Benzyloxy)-3,5-dimethoxyphenyl)-2,2,3,3,9,9,10,10-
octamethyl-4,8-dioxa-3,9-disilaundecan-6-ol (8c). Following the
general procedure outlined above for compound 8a, (2R,3S)-3-(4-
(benzyloxy)-3,5-dimethoxyphenyl)-3-((tert-butyldimethylsilyl)oxy)-
propane-1,2-diol (7c) (1.4 g, 3.1 mmol) was converted to yield 1.68 g
of the protected asymmetric alcohol 8c (96.7%) as a colorless oil. IR
(neat): 3517.93, 2953.75, 2928.51, 2856.42, 1462.2, 1251.07, 834.83,
671.17 cm−1. 1H NMR (500 MHz, CDCl3): δ 7.61 (d, J = 6.8 Hz, 2H),
7.47 (t, J = 7.2 Hz, 2H), 7.44−7.40 (m, 1H), 6.72 (s, 2H), 5.16 (s,
2H), 4.71 (d, J = 5.5 Hz, 1H), 3.95 (s, 6H), 3.88−3.79 (m, 3H), 1.06
(s, 9H), 1.03 (s, 9H), 0.22 (d, J = 3.9 Hz, 6H), 0.19 (s, 3H), −0.00 (s,
3H). 13C NMR (125 MHz, CDCl3): δ 153.2, 137.9, 137.5, 135.9,
128.5, 128.0, 127.7, 103.9, 76.0, 75.4, 74.9, 63.6, 56.0, 25.9, 18.2, −4.7,
−5.1, −5.3. HRMS (DART-TOF): calcd for C24H35O5Si+ (M −
OTBS)+, 431.22483; found, 431.22634. [α]D25 +25.7 (c 1.00, CHCl3).
The opposite enantiomer, (5R,6S)-5-(4-(benzyloxy)-3,5-dimethoxy-
phenyl)-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-ol,
4-(((5S,6S)-5-(4-(Benzyloxy)-3,5-dimethoxyphenyl)-
2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)oxy)-
3-methoxybenzaldehyde (9c). Following the general procedure
outlined above for compound 9a, (5S,6R)-5-(4-(benzyloxy)-3,5-
dimethoxyphenyl)-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disila-un-
decan-6-ol (8c) (1.3 g, 2.3 mmol) was converted to yield 1.04 g of the
intermediate 9c (65%) as a light yellow oil. IR (neat): 2952.25,
2929.26, 2855.95, 1684.02, 1505.49, 1463.28, 1268.19, 697.2 cm−1. 1H
NMR (500 MHz, CDCl3): δ 9.92 (s, 1H), 7.54 (d, J = 6.7 Hz, 2H),
7.49−7.46 (m, 2H), 7.43−7.35 (m, 3H), 7.21 (d, J = 7.9 Hz, 1H), 6.77
(s, 2H), 5.11 (s, 2H), 5.01 (d, J = 6.4 Hz, 1H), 4.58−4.55 (m, 1H),
3.97 (s, 3H), 3.89 (s, 6H), 3.85−3.82 (m, 1H), 3.61 (dd, J = 11.4, 5.6
Hz, 1H), 0.90 (d, J = 16.0 Hz, 20H), 0.06 (d, J = 10.1 Hz, 6H), 0.00
(d, J = 3.6 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 190.9, 154.5,
153.2, 150.2, 137.7, 136.7, 136.0, 129.8, 128.5, 128.0, 127.7, 126.4,
113.5, 109.6, 104.0, 84.2, 74.8, 74.4, 62.3, 56.0, 55.6, 25.7, 25.6, 18.2,
18.1, −5.0, −5.2, −5.58, −5.61. HRMS (DART-TOF): calcd for
25
C32H41O7Si+ (M − OTBS)+, 565.26161; found, 565.26184. [α]D
25
provides a specific rotation of [α]D −26.8 (c 1.00, CHCl3).
+29.5 (c 1.00, CHCl3).
4-(((5S,6S)-5-(4-(Benzyloxy)-3-methoxyphenyl)-2,2,3,3,9,9,10,10-
octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)oxy)-3-methoxyben-
zaldehyde (9a). To a solution of THF containing PPh3 (2.8 g, 10.8
mmol) was added diisopropylazodicarboxylate (2.2 mL, 10.8 mmol),
and the mixture was stirred for 30 min. This was followed by the
simultaneous addition of 4-hydroxy-3-methoxybenzaldehyde (1.6 g,
10.8 mmol) and the alcohol intermediate 8a (2.3 g, 4.3 mmol). The
reaction mixture was stirred at rt for 1 h before being refluxed for a
further 3 h. After complete consumption of the starting material, as
monitored by TLC, the organic phase was washed with water (2 × 100
mL), dried over MgSO4, and concentrated in vacuo. The crude
compound was purified by column chromatography using hexane/
acetone (9:1) to afford the intermediate 9a (1.9 g, 2.8 mmol, 65%) as a
light yellow oil. IR (neat): 2953.02, 2928.77, 2855.95, 1683.97,
The opposite enantiomer, 4-(((5R,6R)-5-(4-(benzyloxy)-3,5-dime-
thoxyphenyl)-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-
6-yl)oxy)-3-methoxybenzaldehyde, provides a specific rotation of
25
[α]D −32.7 (c 1.00, CHCl3).
4-(((1S,2S)-1-(4-(Benzyloxy)-3-methoxyphenyl)-1,3-dihydroxypro-
pan-2-yl)oxy)-3-methoxybenzaldehyde (10a). To a 100 mL round-
bottom flask was added the TBS-protected intermediate 9a (1.4 g, 2.1
mmol) and dissolved in anhydrous THF. The flask was cooled to 0 °C,
and t-butylammonium fluoride (TBAF) (5.3 mL, 5.3 mmol) was
added to the reaction mixture. The resulting solution was warmed to rt
and stirred for 2 h. After complete consumption of the starting
material, as monitored on TLC, the reaction was quenched by the
addition of saturated NH4Cl. The organic phase was extracted with
EtOAc (3 × 100 mL), dried over MgSO4, and concentrated in vacuo.
The crude compound was purified by column chromatography using
DCM/EtOAc (3:2) to afford the asymmetric diol intermediate 10a
(0.78 g, 1.78 mmol, 85.0%) as a white solid. Mp: 117−118 °C. IR
(neat): 3435.15, 2935.72, 2835.93, 1677.69, 1593.32, 1504.38,
1262.33, 1134.84, 652.27 cm−1. 1H NMR (500 MHz, CDCl3): δ
9.78 (s, 1H), 7.34 (dd, J = 7.8, 5.7 Hz, 4H), 7.28 (t, J = 7.4 Hz, 2H),
7.22 (t, J = 7.2 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 1.4 Hz,
1H), 6.82−6.76 (m, 2H), 5.06 (s, 2H), 4.89 (d, J = 7.3 Hz, 1H), 4.23
(dt, J = 7.8, 4.4 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.61 (dd, J = 12.3,
3.2 Hz, 1H), 3.53 (dd, J = 12.3, 4.6 Hz, 1H), 3.28 (s, 1H), 2.40 (s,
1H). 13C NMR (125 MHz, CDCl3): δ 190.8, 153.4, 151.2, 149.9,
148.2, 137.0, 132.4, 131.8, 128.5, 127.9, 127.2, 126.3, 119.3, 118.0,
113.9, 110.3, 110.1, 87.8, 73.8, 71.0, 61.5, 56.0. HRMS (DART-TOF):
1
1584.92, 1259.2, 1035.52, 835.42, 696.52 cm−1. H NMR (500 MHz,
CDCl3): δ 9.83 (s, 1H), 7.44 (d, J = 7.3 Hz, 2H), 7.40−7.34 (m, 4H),
7.30 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 1.4 Hz,
1H), 6.89−6.83 (m, 2H), 5.14 (s, 2H), 4.92 (d, J = 6.5 Hz, 1H), 4.48
(td, J = 6.1, 2.9 Hz, 1H), 3.88 (s, 6H), 3.70 (dd, J = 11.3, 2.9 Hz, 1H),
3.51 (dd, J = 11.3, 5.8 Hz, 1H), 0.81 (s, 9H), 0.77 (s, 9H), −0.05 (d, J
= 8.4 Hz, 6H), −0.11 (d, J = 4.5 Hz, 6H). 13C NMR (125 MHz,
CDCl3): δ 190.9, 154.7, 150.2, 149.4, 147.7, 137.1, 134.2, 129.7, 128.5,
127.8, 127.3, 126.4, 119.1, 113.7, 113.5, 110.7, 109.6, 84.5, 74.3, 71.1,
62.4, 55.9, 55.6, 25.7, 25.6, 18.13, 18.08, −5.0, −5.2, −5.60, −5.62.
+
HRMS (DART-TOF): calcd for C37H55O7Si2 (M + H)+, 667.34808;
25
found, 667.34567. [α]D +37.8 (c 1.00, CHCl3).
The opposite enantiomer, 4-(((5R,6R)-5-(4-(benzyloxy)-3-methox-
yphenyl)-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-
+
25
calcd for C25H27O7 (M + H)+, 439.17513; found, 439.17461. [α]D
25
yl)oxy)-3-methoxybenzaldehyde, provides a specific rotation of [α]D
+88.8 (c 1.00, CHCl3).
The opposite enantiomer, 4-(((1R,2R)-1-(4-(benzyloxy)-3-
−38.6 (c 1.00, CHCl3).
4-(((5S,6S)-5-(4-(Benzyloxy)phenyl)-2,2,3,3,9,9,10,10-octamethyl-
4,8-dioxa-3,9-disilaundecan-6-yl)oxy)-3-methoxybenzaldehyde
(9b). Following the general procedure outlined above for compound
9a, (5S,6R)-5-(4-(benzyloxy)phenyl)-2,2,3,3,9,9,10,10-octamethyl-4,8-
dioxa-3,9-disilaundecan-6-ol (8b) (2.6 g, 5.2 mmol) was converted to
yield 2.1 g of the intermediate 9b (65%) as a light yellow oil. IR
(neat): 2953.25, 2928.28, 2855.97, 1683.92, 1584.61, 2505.51,
methoxyphenyl)-1,3-dihydroxypropan-2-yl)oxy)-3-methoxybenzalde-
25
hyde, provides a specific rotation of [α]D −85.2 (c 1.00, CHCl3).
4-(((1S,2S)-1-(4-(Benzyloxy)phenyl)-1,3-dihydroxypropan-2-yl)-
oxy)-3-methoxy-benzaldehyde (10b). Following the general proce-
dure outlined above for compound 10a, 4-(((5S,6S)-5-(4-(benzyloxy)-
phenyl)-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)-
oxy)-3-methoxybenzaldehyde (9b) (1.7 g, 2.7 mmol) was converted to
yield 0.98 g of the intermediate 10b (89%) as a colorless oil which
solidifies under vacuum. IR (neat): 3431.3, 2928.17, 1682.84, 1585.12,
1
1236.11, 1035.11, 864.3 cm−1. H NMR (500 MHz, CDCl3): δ 9.82
(s, 1H), 7.43 (d, J = 7.3 Hz, 2H), 7.41−7.35 (m, 4H), 7.33 (d, J = 8.6
Hz, 3H), 7.15 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 5.05 (s,
2H), 4.92 (d, J = 6.9 Hz, 1H), 4.50 (td, J = 6.4, 2.8 Hz, 1H), 3.88 (s,
3H), 3.67 (dd, J = 11.3, 2.8 Hz, 1H), 3.50 (dd, J = 11.3, 5.9 Hz, 1H),
0.79 (s, 9H), 0.74 (s, 9H), −0.05 (s, 3H), −0.08 (s, 3H), −0.11 (s,
3H), −0.14 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 191.0, 158.4,
155.0, 150.3, 137.0, 133.5, 129.7, 128.6, 128.2, 128.0, 127.5, 126.4,
1
1267.3, 1135.35, 1025, 794.92 cm−1. H NMR (500 MHz, CDCl3): δ
9.78 (s, 1H), 7.34 (dd, J = 8.3, 3.3 Hz, 4H), 7.30 (t, J = 7.4 Hz, 2H),
7.28−7.23 (m, 3H), 7.14 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H),
4.98 (s, 2H), 4.91 (d, J = 7.6 Hz, 1H), 4.26−4.22 (m, 1H), 3.85 (s,
3H), 3.60 (dd, J = 12.3, 3.1 Hz, 1H), 3.51 (dd, J = 12.3, 4.5 Hz, 1H),
1777
DOI: 10.1021/jo502685k
J. Org. Chem. 2015, 80, 1771−1780

The Journal of Organic Chemistry
Article
Scheme 4. Mosher Ester Analysis of Compound 4a
3.25 (s, 1H), 2.40 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 190.9,
158.8, 153.5, 151.1, 136.8, 131.8, 131.6, 128.6, 128.2, 128.00, 127.4,
126.3, 117.8, 115.0, 110.1, 87.6, 73.5, 70.0, 61.4, 56.0. HRMS (DART-
(d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.1 Hz, 1H), 6.70 (s, 1H), 6.65 (d, J =
6.9 Hz, 2H), 6.56 (d, J = 10.0 Hz, 1H), 4.76 (d, J = 6.6 Hz, 1H), 4.05−
4.00 (m, 1H), 3.56 (dd, J = 12.0, 3.8 Hz, 1H), 3.29 (dd, J = 12.0, 5.1
Hz, 1H), 2.16 (s, 3H). 13C NMR (125 MHz, CD3OD): δ 156.8, 150.3,
145.9, 132.5, 131.6, 128.0, 121.2, 118.7, 114.6, 113.1, 86.8, 72.8, 70.9,
+
TOF): calcd for C24H25O6 (M + H)+, 409.16456; found, 409.16543.
25
[α]D +68.8 (c 1.00, CHCl3).
+
The opposite enantiomer, 4-(((1R,2R)-1-(4-(benzyloxy)phenyl)-
60.4, 55.1, 19.7. HRMS (DART-TOF): calcd for C17H19O4 (M −
25
1,3-dihydroxypropan-2-yl)oxy)-3-methoxybenzaldehyde, provides a
OH)+, 287.12779; found, 287.12796. [α]D +64.1 (c 1.00, MeOH).
25
specific rotation of [α]D −69.7 (c 1.00, CHCl3).
The opposite enantiomer, (1R,2R)-1-(4-hydroxyphenyl)-2-(2-me-
4-(((1S,2S)-1-(4-(Benzyloxy)-3,5-dimethoxyphenyl)-1,3-dihydrox-
ypropan-2-yl)oxy)-3-methoxybenzaldehyde (10c). Following the
general procedure outlined above for compound 10a, 4-(((5S,6S)-5-
(4-(benzyloxy)-3,5-dimethoxyphenyl)-2,2,3,3,9,9,10,10-octa-methyl-
4,8-dioxa-3,9-disilaundecan-6-yl)oxy)-3-methoxybenzaldehyde (9c)
(1.0 g, 1.43 mmol) was converted to yield 0.57 g of the intermediate
10c (85%) as a viscous oil. IR (neat): 3443.02, 2939.57, 2310.98,
1678.07, 1504.02, 1265.95, 735.42, 698.97 cm−1. 1H NMR (500 MHz,
CDCl3): δ 9.78 (s, 1H), 7.41−7.32 (m, 4H), 7.25 (t, J = 7.2 Hz, 2H),
7.22−7.18 (m, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.57 (s, 2H), 4.91 (s,
2H), 4.89 (d, J = 7.1 Hz, 1H), 4.24 (dd, J = 7.1, 3.7 Hz, 1H), 3.86 (s,
3H), 3.73 (s, 6H), 3.65 (dd, J = 12.4, 3.6 Hz, 1H), 3.56 (dd, J = 12.4,
4.7 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 190.8, 153.7, 153.3,
151.2, 137.7, 136.8, 135.1, 131.8, 128.5, 128.1, 127.8, 126.3, 118.0,
110.1, 103.9, 87.6, 75.0, 74.1, 61.5, 56.2, 56.1. HRMS (DART-TOF):
thoxy-4-methylphenoxy)propane-1,3-diol, provides a specific rotation
25
of [α]D −65.6 (c 1.00, MeOH).
(1S,2S)-1-(4-Hydroxy-3,5-dimethoxyphenyl)-2-(2-methoxy-4-
methylphenoxy) propane-1,3-diol (11c). Following the general
procedure outlined above for compound 11a, 4-(((1S,2S)-1-(4-
(benzyloxy)-3,5-dimethoxyphenyl)-1,3-dihydroxypropan-2-yl)oxy)-3-
methoxybenzaldehyde (10c) (0.4 g, 0.85 mmol) was converted to
yield 0.25 g of the intermediate 11c (80%) as a viscous colorless oil. IR
(neat): 3424.66, 2936.19, 2324.72, 1612.8, 1508.35, 1217.2, 1113.05,
1
650.55 cm−1. H NMR (500 MHz, CD3OD): δ 6.81 (d, J = 8.2 Hz,
1H), 6.66 (d, J = 1.7 Hz, 1H), 6.60 (s, 2H), 6.55−6.50 (m, 1H), 4.76
(d, J = 5.7 Hz, 1H), 4.09 (q, J = 5.4 Hz, 1H), 3.68 (s, 3H), 3.67 (s,
6H), 3.61 (dd, J = 11.9, 4.1 Hz, 1H), 3.35 (dd, J = 11.9, 5.3 Hz, 1H),
2.13 (s, 3H). 13C NMR (125 MHz, CD3OD): δ 150.1, 147.6, 145.8,
134.6, 132.3, 131.6, 121.2, 118.0, 113.0, 104.1, 103.9, 86.1, 72.8, 60.5,
+
25
+
calcd for C26H29O8 (M + H)+, 469.18569; found, 469.18556. [α]D
55.3, 55.1, 19.8. HRMS (DART-TOF): calcd for C19H23O6 (M −
25
+80.8 (c 1.00, CHCl3).
OH)+, 347.14891; found, 347.14947. [α]D +74.2 (c 1.00, CHCl3).
The opposite enantiomer, 4-(((1R,2R)-1-(4-(benzyloxy)-3,5-dime-
The opposite enantiomer, (1R,2R)-1-(4-hydroxy-3,5-dimethoxy-
thoxyphenyl)-1,3-dihydroxy-propan-2-yl)oxy)-3-methoxybenzalde-
hyde, provides a specific rotation of [α]D −78.3 (c 1.00, CHCl3).
phenyl)-2-(2-methoxy-4-methyl phenoxy)propane-1,3-diol, provides a
specific rotation of [α]D −74.5 (c 1.00, CHCl3).
25
25
(1S,2S)-1-(4-Hydroxy-3-methoxyphenyl)-2-(2-methoxy-4-methyl-
phenoxy)propane-1,3-diol (11a). To a 100 mL round-bottom flask
containing an asymmetric diol intermediate 10a (0.7 g, 1.6 mmol) was
added ethanol and 150 mg of Pd/C. Hydrogen gas was added via
balloon, allowing slow diffusion into the solution while stirring gently
for 3 h. After complete consumption of the starting material, as
monitored by TLC, the reaction mixture was filtered through Celite to
remove the Pd/C. The filtrate was concentrated under vacuum to
provide the crude lignin model dimer that was purified by column
chromatography using DCM/acetone (7:3) to afford the enantiomeri-
cally pure lignin model dimer 11a as a clear viscous oil (0.5 g, 1.5
mmol, 94%). IR (neat): 3414.05, 1509.07, 1463.99, 1267.63, 1029.43,
815.53, 612.73 cm−1. 1H NMR (500 MHz, CD3OD): δ 6.88 (d, J = 1.6
Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.71 (dd, J = 8.1, 1.6 Hz, 1H),
6.66−6.60 (m, 2H), 6.51−6.46 (m, 1H), 4.75 (d, J = 6.2 Hz, 1H), 4.04
(q, J = 5.1 Hz, 1H), 3.63 (d, J = 6.0 Hz, 6H), 3.57 (dd, J = 12.0, 3.9
Hz, 1H), 3.31 (dd, J = 12.0, 5.1 Hz, 1H), 2.09 (s, 3H). 13C NMR (125
MHz, CD3OD): δ 150.2, 147.4, 145.8, 145.8, 132.5, 132.3, 121.3,
119.5, 118.3, 114.6, 113.1, 110.4, 86.5, 72.9, 60.5, 55.2, 55.0, 19.9.
(S)-(4-(Benzyloxy)-3-methoxyphenyl)((R)-oxiran-2-yl)methyl(R)-
3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (12a). A stirred
solution of asymmetric epoxy alcohol 4a (0.026 g, 0.09 mmol) in
dry DCM was charged into a round-bottom flask containing a stir bar.
To this, TEA (0.02 mL, 0.14 mmol) and (S)-3,3,3-trifluoro-2-
methoxy-2-phenylpropanoyl chloride (0.025 g, 0.10 mmol) were
added sequentially (see Scheme 4). A catalytic amount of DMAP was
added, and the resulting solution was stirred for 3 h. After complete
consumption of the starting material, as monitored by TLC, the
reaction was quenched by addition of saturated NH4Cl and extracted
with CH2Cl2 (3 × 100 mL). The combined organic extracts were dried
over MgSO4 and concentrated in vacuo. The crude compound was
purified by column chromatography using hexane/EtOAc (7:3) to
afford the ester 12a (0.035 g, 0.07 mmol, 78%) as a colorless oil. IR
(neat): 2948.99, 1750.35, 1593.76, 1515.79, 1263.13, 1121.84, 716.72,
640.75 cm−1. 1H NMR (500 MHz, CDCl3): δ 7.44 (dd, J = 7.4, 3.4 Hz,
4H), 7.41−7.36 (m, 3H), 7.33 (t, J = 7.5 Hz, 3H), 6.94−6.88 (m, 3H),
6.07 (d, J = 3.7 Hz, 1H), 5.17 (s, 2H), 3.86 (s, 3H), 3.47 (s, 3H),
3.26−3.23 (m, 1H), 2.74 (dd, J = 5.1, 4.0 Hz, 1H), 2.66 (dd, J = 5.1,
2.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 165.5, 149.7, 148.8,
136.8, 132.1, 129.6, 128.6, 128.3, 127.9, 127.8, 127.4, 127.38, 127.2,
120.2, 113.7, 111.0, 75.3, 71.0, 56.0, 55.4, 52.5, 44.3. HRMS (DART-
+
HRMS (DART-TOF): calcd for C18H21O5 (M − OH)+, 317.13835;
25
found, 317.13864. [α]D +70.5 (c 1.00, MeOH).
The opposite enantiomer, (1R,2R)-1-(4-hydroxy-3-methoxyphen-
+
yl)-2-(2-methoxy-4-methylphenoxy)propane-1,3-diol, provides a spe-
TOF): calcd for C27H26F3O6 (M + H)+, 503.16760; found,
25
25
cific rotation of [α]D −68.6 (c 1.00, MeOH).
503.16844. [α]D +18.0 (c 1.00, CHCl3).
(1S,2S)-1-(4-Hydroxyphenyl)-2-(2-methoxy-4-methylphenoxy)-
propane-1,3-diol (11b). Following the general procedure outlined
above for compound 11a, 4-(((1S,2S)-1-(4-(benzyloxy)phenyl)-1,3-
dihydroxy-propan-2-yl)oxy)-3-methoxybenzaldehyde (10b) (0.83 g,
2.03 mmol) was converted to yield 0.56 g of the intermediate 11b
(90%) as a white solid. Mp: 127−130 °C. IR (neat): 3421.3, 2924.85,
1260.05, 1026.45, 800.05 cm−1. 1H NMR (500 MHz, CD3OD): δ 7.13
(S)-(4-(Benzyloxy)-3-methoxyphenyl)((R)-oxiran-2-yl)methyl-(S)-
3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (12b). Following the
general procedure outlined above for compound 12a, (S)-(4-
(benzyloxy)-3-methoxyphenyl)((R)-oxiran-2-yl)methanol (4a) (0.04
g, 0.14 mmol) was converted to yield 0.053 g of the ester 12b (75%)
as a colorless oil. IR (neat) 2948.99, 1750.35, 1593.76, 1515.79,
1263.13, 1121.84, 716.72, 640.75 cm−1. 1H NMR (500 MHz, CDCl3):
1778
DOI: 10.1021/jo502685k
J. Org. Chem. 2015, 80, 1771−1780

The Journal of Organic Chemistry
Article
Scheme 5. Mosher Ester Analysis of Compound 8b
δ 7.42 (t, J = 7.6 Hz, 4H), 7.37 (t, J = 7.3 Hz, 3H), 7.34−7.29 (m, 3H),
6.84−6.76 (m, 3H), 6.06 (d, J = 3.4 Hz, 1H), 5.15 (s, 2H), 3.76 (s,
3H), 3.55 (s, 3H), 3.30−3.26 (m, 1H), 2.79 (dd, J = 5.1, 4.0 Hz, 1H),
2.76 (dd, J = 5.2, 2.6 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 165.3,
149.6, 148.7, 136.8, 132.0, 129.6, 128.6, 128.3, 127.9, 127.7, 127.3,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
25
127.2, 119.9, 113.5, 110.6, 75.2, 70.9, 55.8, 55.6, 52.6, 44.2. [α]D
The authors would like to thank UTK’s Institute for a Secure
and Sustainable Environment (ISSE) for their financial support
of this work. This work was also supported as part of the
Center for Direct Catalytic Conversion of Biomass to Biofuels
(C3Bio), an Energy Frontier Research Center funded by the
U.S. Department of Energy, Office of Science, Office of Basic
Energy Sciences under Award Number DESC0000997.
+
+16.1 (c 1.00, CHCl3). HRMS (DART-TOF): calcd for C27H26F3O6
(M + H)+, 503.16760; found, 503.16826.
(5S,6R)-5-(4-(Benzyloxy)phenyl)-2,2,3,3,9,9,10,10-octamethyl-4,8-
dioxa-3,9-disilaundecan-6-yl-(R)-3,3,3-trifluoro-2-methoxy-2-phe-
nylpropanoate (13a). Following the general procedure outlined
above for compound 12a, (5S,6R)-5-(4-(benzyloxy)phenyl)-
2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-ol (8b)
(0.08 g, 0.16 mmol) was converted to yield 0.09 g of the ester 13a
(75%) as a viscous and colorless oil (see Scheme 5). IR (neat):
1
2954.09, 2929.43, 2857.61, 1610.9, 1251.21, 836.25, 696.16 cm−1. H
REFERENCES
■
NMR (500 MHz, CDCl3): δ 7.42 (d, J = 7.1 Hz, 2H), 7.37 (t, J = 7.4
Hz, 2H), 7.30 (dd, J = 16.9, 7.3 Hz, 2H), 7.23 (dt, J = 7.1, 3.2 Hz, 4H),
7.16 (d, J = 7.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.33−5.29 (m, 1H),
5.02 (s, 2H), 4.84 (d, J = 6.9 Hz, 1H), 3.80 (dd, J = 6.5, 4.8 Hz, 2H),
3.32 (s, 3H), 0.87 (s, 10H), 0.84 (s, 10H), 0.01 (s, 6H), −0.01 (s, 3H),
−0.24 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 166.0, 158.6, 136.9,
132.7, 132.3, 129.2, 129.0, 128.6, 128.1, 128.0, 127.6, 127.5, 114.4,
80.1, 72.5, 70.0, 61.4, 55.1, 25.8, 25.7, 18.2, 18.1, −4.6, −5.2, −5.6,
−5.7. HRMS (DART-TOF): calcd for C32H38F3O5Si+ (M − OTBS)+,
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587.24351; found, 587.24371. [α]D +19.2 (c 1.00, CHCl3).
(5S,6R)-5-(4-(Benzyloxy)phenyl)-2,2,3,3,9,9,10,10-octamethyl-4,8-
dioxa-3,9-disilaundecan-6-yl-(S)-3,3,3-trifluoro-2-methoxy-2-phe-
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2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-ol (8b)
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(70%) as a viscous colorless oil. IR (neat): 2954.09, 2929.43, 2857.61,
1610.9, 1251.21, 836.25, 696.16 cm−1. 1H NMR (500 MHz,CDCl3): δ
7.43 (d, J = 8.4 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.35−7.27 (m, 4H),
7.26−7.24 (m, 2H), 7.10 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H),
5.34 (td, J = 6.7, 3.3 Hz, 1H), 5.01 (s, 2H), 4.68 (d, J = 6.7 Hz, 1H),
3.91 (dd, J = 11.3, 3.3 Hz, 1H), 3.84 (dd, J = 11.3, 6.8 Hz, 1H), 3.36
(s, 3H), 0.88 (s, 9H), 0.82 (s, 9H), 0.04 (d, J = 4.8 Hz, 6H), −0.07 (s,
3H), −0.31 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 165.8, 158.4,
136.9, 132.6, 132.3, 129.1, 128.6, 128.6, 128.1, 128.0, 127.5, 127.2,
114.3, 80.1, 73.0, 69.9, 61.8, 55.4, 25.8, 25.6, 18.2, 18.0, −4.7, −5.4,
−5.5, −5.6. HRMS (DART-TOF): calcd for C32H38F3O5Si+ (M −
OTBS)+, 587.24351; found, 587.24628. [α]D25 +17.1 (c 1.00, CHCl3).
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ASSOCIATED CONTENT
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* Supporting Information
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: jbozell@utk.edu.
*E-mail: Long@utk.edu.
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DOI: 10.1021/jo502685k
J. Org. Chem. 2015, 80, 1771−1780

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