Understanding Internal Chirality Induction of Triarylsilyl Ethers Formed from Enantiopure Alcohols

Article abstract of DOI:10.1021/acs.joc.6b01137

Chirality transmission from point chirality to helical chirality was explored using triarylsilyl ethers. Circular dichroism (CD) spectroscopy was employed to show that the alcohol stereocenter of silylated, enantiopure secondary alcohols can transmit chirality to the aryl groups on the silicon resulting in a higher population of one helical conformation over another. Cotton effects characteristic of the aryl groups organized into one preferred conformation were observed for all of the compounds examined, which included both triphenyl- and trinaphthylsilyl groups. Alcohols with an R configuration typically induced a PMP helical twist, while an S configuration induced a MPM helical twist. Molecular modeling combined with solid-state structures also gave evidence signifying that point chirality adjacent to triphenylsilyl groups could bias the conformation of the phenyl groups. This work helps in our understanding of the origin of selectivity in our silylation-based kinetic resolutions and a role the phenyl groups play in that selectivity.

Full text of DOI:10.1021/acs.joc.6b01137

Article
pubs.acs.org/joc
Understanding Internal Chirality Induction of Triarylsilyl Ethers
Formed from Enantiopure Alcohols
Li Wang, Tian Zhang, Brandon K. Redden, Cody I. Sheppard, Robert W. Clark, Mark D. Smith,
and Sheryl L. Wiskur*
University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, United States
S
* Supporting Information
ABSTRACT: Chirality transmission from point chirality to helical chirality was explored using triarylsilyl ethers. Circular
dichroism (CD) spectroscopy was employed to show that the alcohol stereocenter of silylated, enantiopure secondary alcohols
can transmit chirality to the aryl groups on the silicon resulting in a higher population of one helical conformation over another.
Cotton effects characteristic of the aryl groups organized into one preferred conformation were observed for all of the
compounds examined, which included both triphenyl- and trinaphthylsilyl groups. Alcohols with an R configuration typically
induced a PMP helical twist, while an S configuration induced a MPM helical twist. Molecular modeling combined with solid-
state structures also gave evidence signifying that point chirality adjacent to triphenylsilyl groups could bias the conformation of
the phenyl groups. This work helps in our understanding of the origin of selectivity in our silylation-based kinetic resolutions and
a role the phenyl groups play in that selectivity.
carbon. Herein we explore this induction of chirality in
enantiopure alcohols protected as triarylsilyl ethers. The
circular dichroism (CD) spectrum shows a characteristic
Cotton effect indicating a helical twist formation, and the
helicity of the propeller is explored through crystal structures
and molecular modeling.
INTRODUCTION
■
The induction of chirality, either intra- or intermolecularly, is a
topic of current interest and is important in areas ranging from
asymmetric catalysis1−3 to sensing.4,5 Molecular propellers are
an interesting class of molecules that have been studied over
the years where a particular gearing in the propeller can be
induced by transmission or communication of chiral
information from a source of point chirality.6−12 Specifically,
we are interested in propellers or helical twists that are formed
from three aryl groups around a central atom and ways to
induce one propeller/helical twist form over another. We
wanted to know whether a molecule with point chirality could
induce helical chirality (M or P) in a triphenylsilyl group if the
two were covalently linked (Figure 1). Gearing of the phenyl
groups has been accomplished with a trityl group,7,8,13 but there
is a difference in size and bond lengths between silicon and
Our interest in the induction of chirality in a triphenylsilyl
group stems from the silylation-based kinetic resolution
methodology developed within our group (Scheme 1).14−16
A
kinetic resolution17−21 is a powerful method of separating
enantiomers by performing a reaction on one enantiomer and
leaving the other enantiomer unreacted. Our methodology
selectively silylates one alcohol enantiomer, resulting in the
enantiomeric enrichment of the unreacted alcohol enantiomer.
The reaction employs a chiral isothiourea catalyst (1 or 2)22
and triphenylsilyl chloride (3a) or derivatives thereof (3b),
where the phenyl groups on the silyl chloride have shown to be
important for selectivity. We theorize that the phenyl groups
aid in chirality transmission when the nucleophilic catalyst
reacts with the silyl chloride to form a reactive intermediate and
a helical twist in the triphenylsilyl group is induced by the chiral
catalyst attached to the silicon. This helical formation of
Figure 1. Helical formation of triphenyl groups induced by a chiral
ligand.
Received: May 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b01137
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formed a higher percentage of one helical twist.7 The lack of a
new signal in that region suggests that there is no preference for
one twist over the other, because equal ratios of two opposite
helical twists would not be CD active. Ultimately, the
preference for one helical twist and the presence of point
chirality means the molecule is a conformational diastereomer.
A series of enantiopure secondary alcohols (D/L-menthol, (R/
S) chromanol, (R)-pantolactone, and (−)-borneol) were
silylated with triphenyl- and trinaphthylsilyl groups to test
this phenomenon. Trinaphthylsilyl groups were incorporated in
the study in an attempt to shift the Cotton effect originating
from the preferred gearing of the aryl groups to longer
wavelengths versus triphenylsilyl groups. The triphenylsilyl
ether compounds 4−7 were synthesized by protecting the
alcohols with triphenylsilyl chloride catalyzed by N-methyl-
imidazole (Scheme 2). The 2-substituted trinaphthylsilyl ethers
(8−10) were obtained by a tris(pentafluorophenyl)borane
catalyzed silylation37 using trinaphthylsilane (11) (Scheme 3).
Scheme 1. Previous Silylation-Based Kinetic Resolutions
Performed by Our Group
triphenyl groups would enhance the chiral space around the
catalyst aiding in selectivity. Because the catalyst complex is
highly reactive and thus far undetectable, we moved to an
analogue that can be easily handled and characterized to see if
attaching a compound with point chirality would induce
chirality in the triphenylsilyl group.
Scheme 2. Synthesis of Enantiopure Triphenylsilyl Ethers
Mislow and co-workers began work on propeller systems
stemming from three aryl groups around a tetrahedral core
atom 40 years ago.23−26 The aryl groups in these types of
systems have restricted rotation and display conformational
isomerism as two enantiomers, M and P (Figure 1). To form
the lowest energy species, the aryl groups all have the same
sense of twist when the molecule has true C3 symmetry (X =
́
Cl, H, etc.). More recently, Gawronski and co-workers
synthesized trityl ethers of chiral secondary alcohols, which
act as molecular bevel gears to transmit chirality from the
alcohol to the trityl group.7 The addition of enantiopure point
chirality results in the gearing of the trityl phenyl groups into
predominately one conformational isomer. With the lack of
true C3 symmetry (X = OR), they discovered one of the aryl
groups has a different twist than the other two, but the trityl
group still had stereoisomerism (either in a PMP or MPM
helicity). This could be detected via circular dichroism, showing
strong Cotton effect patterns from the helicity of the trityl
groups. While the triphenylsilyl group is found throughout the
literature due to its use as a protecting group,27 to our
knowledge induction of point chirality to the triarylsilane has
not been studied. Because silicon containing bonds are longer
compared to carbon (i.e., C−Si bond ∼1.9 Å versus C−C bond
∼1.5 Å) and silicon has a larger van der Waals radius than
carbon,28 there was a question of whether the components of a
triarylsilyl group were too far apart for the induction of one
helical structure over another via point chirality. Therefore, the
investigation of this phenomenon was needed to gain a better
understanding of the selectivity of our silylation methodology.
Scheme 3. Synthesis of Enantiopure Trinaphthylsilyl Ethers
RESULTS AND DISCUSSION
■
Circular dichroism (CD) spectroscopy is a powerful tool for
investigating the three-dimensional space of compounds.29−31
It is most commonly employed to study the structure of
proteins,32−34 but has also been employed to study the
configuration of smaller organic compounds.35,36 CD spectros-
copy relies on the principle that nonracemic chiral molecules
absorb left and right circularly polarized light differently. Thus,
we wanted to explore the conformational properties of a
triarylsilyl group covalently bonded to enantiopure alcohols by
this method. If the alcohol transmits chirality to the aryl groups,
a characteristic Cotton effect should be present in the 180−210
nm range of the spectrum indicating the three aryl groups
Circular Dichroism Analysis. Silyl ethers 4−10 were
investigated by CD spectroscopy, and a Cotton effect,
characteristic for the helical twist of triaryl groups, was
observed for all the compounds. The compounds were
dissolved in solutions of pentane in cyclohexane (1−10% v/
v) or 2-propanol in cyclohexane (3.5% v/v) at a concentration
of approximately 80 μM. These solvents were chosen to avoid a
background absorbance of the solvent in the same region of the
spectra where the phenyl groups on the silicon absorb.
Triphenylsilyl ethers (L)-4 and 7 (Table 1, entries 1 and 3)
were employed to provide a direct comparison to the CD
spectra of the trityl ether versions of these compounds from the
B
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comparisons to the triphenylsilyl ethers 4−6. The trinaph-
thylsilyl ethers all exhibited red shifts in the CD spectra of 20−
30 nm (Table 2) as would be expected with a change from
Table 1. Selected CD Data (Δε (nm)) for Chiral
Triphenylsilyl Ethers
triphenyl silyl
predicted
helicity
a
entry
ether
CD Δε (nm)
CD Δε (nm)
Table 2. Selected CD Data (Δε (nm)) for Chiral
1
2
3
(L)-4
(D)-4
7
6.7 (205)
−7.5 (204)
−17 (196)
23 (202)
−13.4 (192)
14 (190)
PMP
MPM
MPM
PMP
MPM
PMP
Trinaphthylsilyl Ethers
29 (186)
trinaphthyl silyl
ether
predicted
helicity
a
b
entry
CD Δε (nm)
CD Δε (nm)
4
(R)-5
(S)-5
(R)-6
−10 (190)
15 (191)
b
5
c
−23 (202)
1.9 (210)
1
2
(L)-8
(D)-8
(R)-9
10
4.9 (236)
−4.6 (236)
27 (229)
−5.3 (220)
4.8 (220)
PMP
MPM
PMP
PMP
6
−7.2 (199)
b
a
3
c
−23 (213)
−4.1 (214)
Data was collected at 80 μM (1% pentane in cyclohexane (v/v)) with
b
4
5.3 (232)
a 0.1 cm path length quartz cell. 10% pentane in cyclohexane (v/v).
c
a
3.5% 2-propanol in cyclohexane (v/v).
Data was collected at 80 μM (1% pentane in cyclohexane (v/v)) with
b
a 0.1 cm path length quartz cell. 10% pentane in cyclohexane (v/v).
c
literature. These silyl ethers display the same Cotton effects as
the trityl versions of these compounds,7 indicating that an
induction of chirality is indeed taking place from the
enantiopure alcohols to the triphenylsilyl groups, presumably
resulting in the same helical twist as the trityl compounds.
Compound (L)-4 has a positive Cotton effect,38 which can
tentatively be assigned as the PMP helical twist based on the
3.5% 2-propanol in cyclohexane (v/v).
phenyl to naphthyl groups.39 All the compounds exhibited the
same Cotton effects as their phenyl counterparts (i.e., (L)-8
(Table 2, entry 1) has the same positive Cotton effect as (L)-4
(Table 1, entry 1)), and the pair of enantiomers still displayed
opposite Cotton effects ((L)-8 and (D)-8, Table 2, entries 1 and
2). Again, the CD spectra for silyl ethers 9 and 10 overlapped
with the spectra of the basic core structure of the alcohol.
Therefore, the CD spectra of the free alcohols were subtracted
from the CD spectra of the trinaphthylsilyl ether compounds to
get the data in entries 3 and 4, Table 2. All of these results show
that point chirality can still induce a helical twist in the
trinaphthylsilyl group, and the orientation of these aryl groups
matches the results from the phenylsilyl ether equivalents.
Crystal Structure Analysis. Crystal structures were
obtained of the triphenylsilyl ethers (R)-5, (S)-5, and 7,
showing the orientation of the phenyl groups on the silicon in
the solid phase. See Supporting Information for additional
views. (For other examples of crystal structures of triphenylsilyl
compounds see reports in the literature40−42). Both enan-
tiomers of 5 were crystallized independently, and the resulting
structures showed the phenyl groups on the silicon oriented in
the same but opposite pattern for the two enantiomers (Figure
3). To quantitatively assign each phenyl group as M or P, a
dihedral angle (ω) was measured between the O−Si bond and
the closest Cipso−Cortho bond, for each phenyl group. Looking
down the Cipso−Si bond, if the turn from the Cipso−Cortho bond
to the Si−O bond is clockwise, ω is positive and the phenyl is
assigned M; if the turn is counterclockwise, ω is negative and
the phenyl is assigned P.
The measured dihedral angles and resulting phenyl group
helicity assignments are shown in Table 3 for (R)-5, (S)-5, and
7. Enantiomers (R)- and (S)-5 have opposite helical twists of
the triphenylsilyl groups as one would expect, with very similar
angles but different signs. The solid-phase structures matched
the predicted conformations from the CD data, resulting in a
PMP helical twist for (R)-5 and a MPM helical twist for (S)-5
(Table 1, entries 4 and 5 vs Table 3, entries 1 and 2). The
pattern of one phenyl group being geared opposite the other
two comes from the lack of C3 symmetry discussed previously.7
These structures also show that the silicon−oxygen bond
lengths (1.64 Å) and silicon−carbon bond lengths (1.86−1.87
Å) in the crystal structures are similar to literature values,28
again signifying that helical twist formations are possible even
with these extended bond lengths versus a trityl group.
model developed by Gawron
́
ski (Figure 2a).7 The model
Figure 2. Model of the correlation between the position of the large
subsituent7 (L) or π system to the resultant Cotton effect and helical
twist.
depends on the size of the substituents around the stereocenter,
not the absolute configuration, which was correlated to the
Cotton effect obtained and the helical twist expected. Its
enantiomer (D)-4 (Table 1, entry 2) as well as 7 display an
opposite Cotton effect (negative), suggesting an MPM helical
twist (Figure 2b).7 The results from (L)-4 and (D)-4 indicate
that the opposite point chirality induces the opposite helical
twist.
Silyl ethers 5 and 6 were a little more complicated. The
alcohols used to synthesize 5 and 6 are also CD active at low
wavelengths, causing an overlap of signals.38 To more clearly
discern the Cotton effect resulting from the helical twist of the
triphenylsilyl group, the CD spectrum of the free alcohols was
subtracted from the CD spectrum of the silyl ether compounds.
These results are given in Table 1, entries 4−6. A positive
Cotton effect is obtained for compounds (R)-5 and (R)-6,
indicating a PMP helicity (entries 4 and 6). The π system
adjacent to the stereocenter now plays a more dominate role in
directing the helical twist of the triphenylsilyl group (Figure
2a). The S enantiomer of 5 again generates the opposite result,
with a predicted MPM helicity for the negative Cotton effect
(entry 5). These results show that even with the longer silicon
bond lengths, one helical twist is predominately formed over
another due to the point chirality of the alcohols.
By extending the conjugation of the aromatic rings on silicon
via changing the phenyls to naphthyls, the CD spectra
associated with the helical twist is shifted to longer wavelengths,
therefore eliminating solvent interference and improving
accuracy. Trinaphthylsilyl ethers 8−10 were employed as direct
However, when the bicyclic compound 7 was crystallized,
two independent conformational stereoisomers crystallized in
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Figure 3. Independent molecular structures of (S)- and (R)-5 as viewed down the oxygen−silicon bond. The alcohol portion of the molecule is
drawn in wireframe, and the hydrogens are removed for clarity. The crystals of (S)-5 and (R)-5 were grown independently and are enantiomerically
pure; all molecules in the crystals are identical. C1 was determined by the X-ray data to have the “S” configuration for (S)-5 and the “R” configuration
for (R)-5.
within 2 kcal/mol of the lowest energy conformation were
selected, and geometry optimization was performed using
density functional theory (DFT), specifically B3LYP43,44 and 6-
311++G** basis set.45 Three types of triphenylsilyl conformers
resulted from the modeling of (S)-5, with the predominant one
having an MPM helical twist (92%) and only small percentages
of the less thermodynamically stable conformers MMM (6%)
and PMP (2%) (Table 4, entry 1 to 4). This result (MPM
Table 3. Dihedral Angles and Helicity Types of (R)-5, (S)-5,
and 7
entry
alcohol
ω1
ω2
75
ω3
helicity type
1
(R)-5
(S)-5
7
−34
32
−16
17
PMP
MPM
PPP
2
−76
−50
61
3a
3b
−45
31
−37
40
7
MMM
the asymmetric unit cell of the crystal (Figure 4). Even though
the CD spectra suggested one helical twist was preferred in
Table 4. Population of Helicity Types and Calculated
Dihedral Angles of (S)-5 and 7
silyl
conformer
helicity
type
entry ether
distribution (%)
ω1
24
ω2
ω3
87
MPM:MMM:PMP = 92:6:2
1
2
3
4
(S)-5
23
69
6
−7
−88
28
MPM
MPM
MMM
PMP
1
83
15
28
2
−69
9
−18
MMM:PPP = 85:15
5
6
7
85
15
79
31
32
MMM
PPP
−35
−29
−78
preference) is consistent with the predicted helicity from the
CD experiments (Table 1, entry 5) as well as the conformation
in the crystal structure of (S)-5 (Table 3, entry 2).
Figure 4. Structure of two independent, chemically identical but
conformationally distinct molecules of 7 as viewed down the oxygen−
silicon bond. The alcohol portion of the molecule is drawn in
wireframe, and the hydrogens are removed for clarity.
The CD spectroscopy of 7 indicated a higher population of
the conformation with an MPM configuration, while the solid-
state structure indicated the presence of two stereoisomers
(MMM and PPP). A Monte Carlo search resulted in two low
energy triphenylsilyl conformations, the MMM and PPP
stereoisomers (Table 4, entries 5 and 6), consistent with the
solid-state structure. After DFT geometry optimization, the
structures were shown to have an energy difference of 1.1 kcal/
mol with a preference for the MMM helical twist, leading to a
ratio of 85 to 15 of the MMM to PPP helicity, respectively. This
preference for the MMM helical twist would result in a negative
Cotton effect curve in the CD spectra, which is consistent with
our observed experimental outcome (Table 1, entry 3). The
tied-back nature of bicyclic 7 offers less steric hindrance
compared to the other substrates studied, resulting in a smaller
energy difference between the two conformations, leading to an
increased presence of the higher energy conformation. This
bicyclic structure ultimately affects the resulting helical twist,
allowing for a true propeller formation.
solution (Table 1, entry 3), in the solid phase two helical twists
formed from the (−)-borneol triphenylsilyl ether. The two
conformational diastereomers resulted in helical twists of
MMM and PPP which are true propeller formations. (Table
3, entry 3a,b). The presence of these two stereoisomers does
not necessarily suggest that the two conformational diaster-
eomers are present in equal amounts but that two successfully
pack well in the solid state. Molecular modeling (below)
provided additional support toward our CD findings that there
is a preference for one stereoisomer in solution over two solid-
state structures.
Molecular Modeling Analysis. To further investigate the
structure of the low energy conformations in these
triphenylsilyl ethers, molecular modeling using a Monte Carlo
search was employed for (S)-5 and 7. All of the conformers
D
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temperature, and the crude reaction was concentrated under vacuum.
The residue was then purified via silica gel chromatography (2%
EtOAc to 5% EtOAc in hexane).
CONCLUSIONS
■
We successfully showed that point chirality can induce helical
chirality in triarylsilyl groups by derivatizing enantiopure
alcohols with triphenylsilyl and trinaphthylsilyl groups and
exploring the conformations of the triarylsilyl groups through
CD spectroscopy, solid-state structures, and molecular
modeling. CD spectroscopy of the compounds all displayed a
Cotton effect that was characteristic for a helical twist
formation, with R configuration alcohols generally exhibiting
positive Cotton effects indicating a PMP helical twist, and S
configuration alcohols exhibiting negative Cotton effects
indicating a MPM helical twist. The crystal structures for (R)-
and (S)-5 each crystallized as one conformation, with the
gearing of the phenyl groups consistent with the proposed
helicity determined from CD spectroscopy. Molecular model-
ing of (S)-5 was performed through a Monte Carlo search
predicting the same conformation as was determined
experimentally. Even though compound 7 crystallized as two
conformational diastereomers, molecular modeling resulted in
the MMM helical twist as the low energy conformation which
would give the same negative CD signal that was obtained
experimentally. Ultimately, the understanding of chirality
transmission between the alcohol and the triarylsilyl group
can be extrapolated to explain the importance of phenyl groups
in silylation-based kinetic resolutions through potential gearing
of the phenyl groups when a chiral, nucleophilic catalyst attacks
a triphenylsilyl chloride. This gearing through point chirality
transmission could also be exploited as a derivatizing reagent
for determining the enantiomeric excess of alcohols through
CD spectroscopy. Future studies will be focused on continuing
to elucidate the mechanism of asymmetric silylation.
Preparation of Tri(naphthalen-2-yl)silane (11).48 A 250 mL
round-bottom flask was fitted with a stir bar and septa and purged with
argon. The flask was charged with 20 mL of ether, and the solution
was allowed to cool to 0 °C in an ice bath. N-Butyllithium (10.25
mmol, 8.1 mL of 1.26 M in hexane) was added via syringe with
stirring. A solution of 1-iodonaphthalene (10 mmol, 1.46 mL in 20 mL
ether) was prepared and added to the reaction vessel slowly via
syringe. The mixture was then allowed to warm to room temperature
for 1 h. The mixture was then cooled to −40 °C in a dry ice/MeCN
bath. A solution of trichlorosilane Cl3SiH (3.0 mmol, 303 μL in 7.5 mL
of ether) was prepared and added to the reaction slowly via syringe.
The reaction was left to stir at −40 °C for 2 h and then quenched with
water. A significant quantity of solid formed. The solid was filtered and
washed with cold acetone to reveal a white solid, 0.99 g, 80% yield.
1H NMR (400 MHz, CDCl3): δ ppm 8.16 (s, 3H), 7.89−7.83 (m,
6H), 7.80 (d, J = 7.9 Hz, 3H), 7.71 (d, J = 8.2 Hz, 3H), 7.56−7.44 (m,
6H), 5.85 (s, 1H). 13C NMR (101 MHz, CDCl3) δ ppm 137.3, 134.2,
133.1, 131.5, 130.8, 128.3, 127.8, 127.5, 126.9, 126.1
General Procedures for the Preparation of Trinaphthylsilyl
Ether Derivatives (GP2). Synthesis of trinaphthylsilyl ether
derivatives followed a procedure similar to that reported in the
literature.37 To a 4-dram vial that was oven-dried with a stir bar were
added enantiopure alcohol (1 equiv) and trinaphthylsilane (0.9 equiv)
under N2. Commercially available tris(pentafluorophenyl)borane
(B(C6F5)3) (0.02 equiv) was added to the mixture in a glovebox.
Enough toluene was then added to make a concentration of 0.5 M
with respect to alcohol. The reaction was then stirred at room
1
temperature and was monitored through H NMR. Full conversion
was achieved after 1 h. The crude mixture was concentrated under
vacuum, and the residue was purified via silica gel chromatography
(2% EtOAc to 5% EtOAc in hexane).
Characterization Triarylsilyl Ether Derivatives. (((1R,2S,5R)-2-
Isopropyl-5-methylcyclohexyl)oxy)triphenylsilane ((L)-4):49 Synthe-
sized according to GP1 with 48 mg of L-menthol and 76 mg of
EXPERIMENTAL SECTION
■
1
triphenylsilyl chloride which yielded a white solid 120 mg, 90%; H
General Information. Trinaphthylsilane and all the triarylsilyl
ethers were obtained through the general procedures below. Reactions
were carried out under a nitrogen atmosphere using oven-dried
glassware. Tetrahydrofuran (THF), toluene, and diethyl ether were
degassed and passed through a column of activated alumina prior to
use. Unless otherwise stated, all the other chemicals, including the
enantiopure starting alcohols, were obtained from major commercial
sources and used without further purification. High resolution mass
spectrometry (HRMS) was obtained either using an orthogonal
quadrupole time-of-flight instrument or an orbitrap instrument.
Infrared spectroscopy (IR) was conducted using an FT-IR ATR
spectrophotometer, νmax in cm−1. NMR spectra were recorded with a
NMR (400 MHz, CDCl3): δ ppm 7.62 (dd, J = 7.9, 1.5 Hz, 6H),
7.46−7.32 (m, 9H), 3.54 (td, J = 10.1, 4.3 Hz, 1H), 2.38 (dtd, J = 13.9,
6.9, 2.4 Hz, 1H), 1.93−1.82 (m, 1H), 1.62−1.47 (m, 2H), 1.39−1.07
(m, 3H), 0.88 (d, J = 7.1 Hz, 3H), 0.84−0.80 (m, 2H), 0.79 (d, J = 6.0
Hz, 3H), 0.39 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
ppm 135.6, 135.2, 129.8, 127.7, 73.9, 50.2, 45.3, 34.5, 31.6, 25.3, 22.6,
22.3, 21.4, 15.3. Optical rotation [α]25D: −40.0 (c = 0.022) in CHCl3.
(((1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl)oxy)triphenylsilane
((D)-4):49 Synthesized according to GP1 with 48 mg of D-menthol and
76 mg of triphenylsilyl chloride which yielded a white solid 120 mg,
1
90%; H NMR (400 MHz, CDCl3): δ ppm 7.62 (dd, J = 7.9, 1.5 Hz,
400 MHz instrument for H and a 101 MHz instrument for 13C with
1
6H), 7.49−7.31 (m, 9H), 3.54 (td, J = 10.1, 4.3 Hz, 1H), 2.38 (dtd, J =
13.9, 6.9, 2.4 Hz, 1H), 1.94−1.83 (m, 1H), 1.63−1.50 (m, 2H), 1.39−
1.09 (m, 3H), 0.88 (d, J = 7.1 Hz, 3H), 0.85−0.80 (m, 2H), 0.79 (d, J
= 6.0 Hz, 3H), 0.38 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ ppm 135.6, 135.2, 129.8, 127.7, 73.9, 50.2, 45.3, 34.5, 31.6, 25.3,
22.6, 22.3, 21.4, 15.3. Optical rotation [α]25D: +39.0 (c = 0.02) in
CHCl3.
complete proton decoupling. Chemical shifts were reported in ppm
with TMS or chloroform as an internal standard (TMS 0.00 ppm or
1
CHCl3 7.26 ppm for H and 77.16 for 13C). Optical rotations were
obtained utilizing a polarimeter. Circular dichroism (CD) spectra were
taken at concentrations of approximately 8 × 10−5 M, aiming to reach
a maximum absorbance without oversaturating the detector.46 The
samples were analyzed in a 1 mm path length, strain free, quartz cell to
have a better observed Cotton effect while minimizing noise. All
reported spectra were processed by using 15-point Sacitzy-Golay
smoothing.47 Structure determinations were performed using standard
single-crystal X-ray diffraction techniques. See Supporting Information
for full experimental and structure refinement details.
General Procedure for the Preparation of Triphenylsilyl
Ether Derivatives (GP1). To a 4-dram vial with a stir bar were added
the enantiopure alcohol (1 equiv), N,N-diisopropylethylamine (0.9
equiv), and N-methylimidazole (0.25 equiv). Dry THF was then added
to obtain a concentration of 0.3 M with respect to alcohol. The
solution was stirred at room temperature for 5 min followed by the
addition of triphenylsilyl chloride in a THF solution (0.6 M, 0.9
equiv). The reaction was allowed to react for 24 h at room
Triphenyl(((1S,2R,4S)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl)-
oxy)silane (7):50 Synthesized according to GP1 with 18 mg of
(−)-borneol and 24 mg of triphenylsilyl chloride which yielded a white
1
solid 40 mg, 95%; H NMR (400 MHz, CDCl3): δ ppm 7.66−7.57
(m, 6H), 7.46−7.33 (m, 9H), 4.18 (d, J = 9.4 Hz, 1H), 2.39−2.27 (m,
1H), 1.98−1.87 (m, 1H), 1.77−1.64 (m, 1H), 1.34−1.18 (m, 3H),
1.01 (dd, J = 13.2, 3.2 Hz, 1H), 0.81 (s, 3H), 0.70 (d, J = 6.6 Hz, 6H).
13C NMR (101 MHz, CDCl3) δ ppm 135.6, 135.2, 129.8, 127.7, 78.6,
50.2, 47.3, 45.2, 39.4, 28.4, 26.5, 20.2, 18.8, 13.6. Optical rotation
[α]25D: +24.1 (c = 0.02) in CHCl3.
(R)-(Chroman-4-yloxy)triphenylsilane ((R)-5):14 Synthesized ac-
cording to GP1 with 23 mg of (R)-chromanol and 36 mg of
1
triphenylsilyl chloride which yielded a white solid 50 mg, 81%; H
NMR (400 MHz, CDCl3): δ ppm 7.66 (d, J = 6.5 Hz, 6H), 7.48−7.37
E
DOI: 10.1021/acs.joc.6b01137
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
(m, 9H), 7.18−7.14 (m, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.83−6.76 (m,
2H), 4.97 (t, J = 4.0 Hz, 1H), 4.51−4.45 (m, 1H), 4.24−4.19 (m, 1H),
2.02−1.96 (m, 2H); 13C NMR (101 MHz, CDCl3) δ ppm 154.5,
135.5, 134.3, 130.1, 130.0, 129.2, 127.8, 124.2, 120.0, 116.7, 65.0, 62.2,
31.4. Optical rotation [α]25D: +53.4 (c = 0.031) in CHCl3.
solid 110 mg, 95%; mp range = 70−71 °C; H NMR (400 MHz,
CDCl3): δ 8.24 (s, 3H), 7.91 (t, J = 7.3 Hz, 6H), 7.85 (d, J = 8.0 Hz,
3H), 7.78 (dd, J = 8.2, 1.0 Hz, 3H), 7.60−7.49 (m, 6H), 4.25 (dd, J =
5.1, 3.3 Hz, 1H), 3.86−3.80 (m, 2H), 1.23 (s, 3H), 0.94 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ ppm 137.1, 134.3, 132.9, 131.7, 131.0,
128.5, 127.8, 127.4, 127.1, 126.2, 80.5, 78.7, 75.0, 43.3, 24.8, 19.6.
Optical rotation [α]25D: +17.6 (c = 0.031) CHCl3 HRMS: (ESI)
calculated for (C36H30O3Si+) (M+): 538.1964, observed: 538.1965. IR
(neat, cm−1) 3051, 2959, 2928, 1733, 1590, 1464, 1272, 1087, 1021,
951, 853, 818, 741
(S)-(Chroman-4-yloxy)triphenylsilane ((S)-5):14 Synthesized ac-
cording to GP1 with 23 mg of (S)-chromanol and 36 mg of
1
triphenylsilyl chloride which yielded a white solid 43 mg, 70%; H
NMR (400 MHz, CDCl3): δ ppm 7.62 (t, J = 12.8 Hz, 6H), 7.41 (dt, J
= 24.3, 7.2 Hz, 9H), 7.14 (t, J = 7.7 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H),
6.78 (dd, J = 17.2, 8.0 Hz, 2H), 4.96 (t, J = 4.0 Hz, 1H), 4.46 (td, J =
10.4, 3.1 Hz, 1H), 4.24−4.15 (m, 2H); 13C NMR (101 MHz, CDCl3)
δ ppm 154.6, 135.6, 134.5, 130.2, 130.1, 129.3, 128.0, 124.3, 120.1,
116.8, 65.1, 62.2, 31.5. Optical rotation [α]25D: −49.0 (c = 0.031)
CHCl3
Molecular Modeling Information. Conformer searches were
carried out using the Monte Carlo for Complex Chemical System
(MCCCS) Towhee51 plug-in built into the Scienomics Materials
Processes and Simulations (MAPS) platform.52 The conformers with
energies within 2 kcal/mol relative to the lowest energy conformer
were selected, and the structures were optimized using DFT (B3LYP)
with 6-311++** basis set in Spartan.45 For all optimized structures,
frequency calculations were carried out at the same level of theory to
confirm that the conformers were stable. A Boltzmann distribution of
the selected conformers was calculated on the basis of ΔG and T =
298 K.
(R)-4,4-Dimethyl-3-((triphenylsilyl)oxy)dihydrofuran-2(3H)-one
((R)-6):15 Synthesized according to GP1 with 6 mg of (R)-
pantolactone and 10 mg of triphenylsilyl chloride which yielded a
1
white solid 12 mg, 70%; H NMR (400 MHz, CDCl3): δ 7.72 (d, J =
6.6 Hz, 6H), 7.48−7.37 (m, 9H), 4.15 (s, 1H), 3.94 (d, J = 8.9 Hz,
1H), 3.76 (d, J = 8.9 Hz, 1 H), 1.18 (s, 3H), 0.86 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ ppm 175.2, 135.7, 133.4, 130.4, 127.9, 75.5, 41.1,
22.6, 19.7. Optical rotation [α]25D: +8.2 (c = 0.84) CHCl3
ASSOCIATED CONTENT
* Supporting Information
■
(((1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl)oxy)tri(naphthalen-
2-yl)silane ((L)-8). Synthesized according to GP2 with 51 mg of L-
menthol and 125 mg of trinaphthylsilane which yielded a white solid
180 mg, 97%; mp range = 102−105 °C; 1H NMR (400 MHz, CDCl3):
δ 8.22 (s, 3H), 7.80 (ddd, J = 14.8, 9.2, 4.5 Hz, 12H), 7.50 (dtd, J =
14.7, 6.9, 1.3 Hz, 6H), 3.68 (td, J = 10.3, 4.3 Hz, 1H), 2.56 (dtd, J =
13.9, 6.9, 2.4 Hz, 1H), 2.03 (d, J = 11.9 Hz, 1H), 1.60−1.54 (m, 2H),
1.51−1.12 (m, 3H), 0.93 (d, J = 7.1 Hz, 3H), 0.85 (dd, J = 19.6, 10.9
Hz, 2H), 0.78 (d, J = 6.4 Hz, 3H), 0.41 (d, J = 6.9 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ ppm 137.1, 134.2, 132.9, 132.7, 131.4, 128.5,
127.8, 127.1, 126.9, 126.0, 74.3, 50.3, 45.5, 34.5, 31.6, 25.5, 22.6, 22.3,
21.4, 15.6. Optical rotation [α]25D: −24.9 (c = 0.03) CHCl3 HRMS:
(ESI) calculated for (C40H40OSi+) (M+): 564.2848, observed:
564.2850. IR (neat, cm−1) 3049, 2953, 2921, 1589, 1250, 1456,
1272, 1083, 853, 816, 740.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01137.
CD spectra, crystal structure data, molecular modeling
information, and NMR spectra (PDF)
CIF data for (S)-5, (R)-5, and 7 (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: wiskur@mailbox.sc.edu.
Notes
■
The authors declare no competing financial interest.
(((1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl)oxy)tri(naphthalen-
2-yl)silane ((D)-8). Synthesized according to GP2 with 51 mg of D-
menthol and 125 mg of trinaphthylsilane which yielded a white solid
183 mg, 97%; mp range = 102−105 °C; 1H NMR (400 MHz, CDCl3):
δ 8.22 (s, 3H), 7.80 (ddd, J = 14.8, 9.2, 4.5 Hz, 12H), 7.50 (dtd, J =
14.7, 6.9, 1.3 Hz, 6H), 3.68 (td, J = 10.3, 4.3 Hz, 1H), 2.56 (dtd, J =
13.9, 6.9, 2.4 Hz, 1H), 2.03 (d, J = 11.9 Hz, 1H), 1.60−1.54 (m, 2H),
1.51−1.12 (m, 3H), 0.93 (d, J = 7.1 Hz, 3H), 0.85 (dd, J = 19.6, 10.9
Hz, 2H), 0.78 (d, J = 6.4 Hz, 3H), 0.41 (d, J = 6.9 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ ppm 137.1, 134.2, 132.9, 132.7, 131.4, 128.5,
127.8, 127.1, 126.9, 126.0, 74.3, 50.3, 45.5, 34.5, 31.6, 25.5, 22.6, 22.3,
21.4, 15.6. Optical rotation [α]25D: +24.0 (c = 0.03) CHCl3; HRMS:
(ESI) calculated for (C40H40OSi+) (M+): 564.2848, observed:
564.2851. IR (neat, cm−1) 3050, 2952, 2918, 1589, 1456, 1272,
1082, 852, 815, 739.
(R)-(Chroman-4-yloxy)tri(naphthalen-2-yl)silane ((R)-9). Synthe-
sized according to GP2 with 36 mg of (R)-chromanol and 85 mg of
trinaphthylsilane which yielded a white solid 125 mg, 96%; mp range =
110−112 °C; 1H NMR (400 MHz, CDCl3): δ ppm 8.22 (s, 3H), 8.22
(s, 6H), 7.79 (dd, J = 7.5, 4.8 Hz, 6H), 7.51 (ddd, J = 14.9, 13.6, 6.8
Hz, 6H), 7.21−7.14 (m, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 8.1
Hz, 1H), 6.77 (t, J = 7.4 Hz, 1H), 5.11 (t, J = 4.0 Hz, 1H), 4.58 (td, J =
10.7, 2.7 Hz, 1H), 4.25 (dt, J = 8.5, 4.1 Hz, 1H), 2.16−1.94 (m, 2H);
13C NMR (101 MHz, CDCl3) δ ppm 154.7, 137.2, 134.3, 132.9, 131.9,
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the University of
South Carolina ASPIRE and the National Science Foundation
CAREER Award CHE-1055616. We also appreciate the use of
the modeling software from Prof. Linda Shimizu, and helpful
discussions with Prof. Sophya Garashchuk, Prof. Tom Makris,
Sahan Salpage, Baillie Dehaven, and Bing Gu from the
Chemistry Department.
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