Resolution of terminal 1,2-diols via silyl transfer

Article abstract of DOI:10.1021/jo4012909

Through kinetic analysis and optimization, we report an improved resolution of terminal 1,2-diols via asymmetric silyl transfer. Because the reaction is a regiodivergent resolution, the monoprotected product could be isolated in excess of 95:5 er and 40% yield. The described method offers a means of chemically differentiating a terminal 1,2-diol with concomitant resolution of the enantiomers.

Full text of DOI:10.1021/jo4012909

Note
pubs.acs.org/joc
Resolution of Terminal 1,2-Diols via Silyl Transfer
Xixi Sun, Amanda D. Worthy, and Kian L. Tan*
Boston College, 2609 Beacon Street, Chestnut Hill, Massachusetts 02467-3860, United States
S
* Supporting Information
ABSTRACT: Through kinetic analysis and optimization, we
report an improved resolution of terminal 1,2-diols via
asymmetric silyl transfer. Because the reaction is a
regiodivergent resolution, the monoprotected product could
be isolated in excess of 95:5 er and 40% yield. The described
method offers a means of chemically differentiating a terminal
1,2-diol with concomitant resolution of the enantiomers.
Scheme 1. Regiodivergent kinetic resolution of terminal 1,2-
diol
erminal 1,2-diols have been shown to be practical building
Tblocks in the synthesis of biologically relevant com-
pounds.1,2 Based on the synthetic value of these compounds,
several metal-catalyzed methods have been explored for their
asymmetric synthesis including hydrolytic kinetic resolution of
epoxides,3−5 as well as diboration/oxidation6−8 and dihydrox-
ylation2,9 of terminal olefins. An alternative approach to the
synthesis of enantiopure terminal 1,2-diols is through kinetic
resolution via electrophile transfer.10−12 The robust nature and
chemical orthogonality of silyl protecting groups13−15 has made
asymmetric silyl transfer particularly synthetically valuable in
the resolution of alcohols. Early work by Ishikawa demon-
strated that chiral guanidine catalysts successfully promote the
resolution of indanol via silyl transfer.16 Subsequently, both
metal17−20 and nonmetal catalysts21−27 have been found to
effectively promote enantio- and stereoselective silyl transfer to
alcohols.
Recently, Hoveyda and Snapper disclosed the kinetic
resolution of 1,2-diols via silylation with an organic catalyst.22
The same groups23 and our group26 reported a highly effective
regiodivergent resolution of 1,2-diols. In a regiodivergent
resolution of a racemic mixture (RRM),28−31 the enantiomers
of the starting material are preferentially converted into
constitutionally isomeric products. The advantage of the
regiodivergent RRM over a traditional kinetic resolution is
that it is generally easier to obtain the products of the
transformation in both high yield and enantioselectivity. The
net effect is that in a single step the regiodivergent resolution
resolves the enantiomers and generates a synthetically more
valuable product. For example, using catalysts 4a and 4b, we
demonstrated that the regiodivergent resolution of terminal
1,2-diols is an efficient means of accessing enantiopure products
with the silyl-protected secondary hydroxyl (Scheme 1). In this
transformation, we resolve the enantiomers and simultaneously
chemically differentiate the primary and secondary hydroxyls.
A unique feature of catalysts 4a and 4b is their ability to
reversibly and covalently bond with organic molecules, which is
in part responsible for the protection of the inherently less
reactive secondary hydroxyl (Scheme 1). Organic catalysts and
metal-binding ligands that use reversible covalent bonding have
seen a resurgence over the past decade as a means of
controlling selectivity in a range of reactions.32−40 The majority
of this effort has focused on using reversible covalent bonding
to control site and regioselectivity, whereas less progress has
been made in the area of enantioselective catalysis.41−44 In this
article, we re-evaluate the reaction conditions of our original
divergent resolution in order to provide a practical method for
obtaining enantioenriched terminal 1,2-diols in which the
primary hydroxyl is silylated.
In our initial publication on the regiodivergent RRM, we
found using 15% of 4b that the secondary protected product 3a
formed in 40% yield and 99:1 er, while the primary protected
product 2a formed in a more modest 91:9 er (Scheme 1). In an
effort to improve the catalyst performance, we monitored the
conversion and selectivity of the reaction at a reduced catalyst
loading (10% 4b, Figure 1). To our surprise, the
enantioselectivity for both 2a and 3a increases with time
under these suboptimal conditions; moreover, the rate of
reaction appears to accelerate over time (Figure 1). A potential
explanation for the increasing enantioselectivity is that at low
conversion the catalyzed reaction could be limited by the rate
of the exchange between catalyst 4b and 1a, which allows for
unselective background silylation to be competitive. As the
Received: June 18, 2013
© XXXX American Chemical Society
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Note
Figure 1. Reaction time course at 0 °C with a single addition of TESCl.
Figure 2. Reaction time course at room temperature with a syringe pump addition of TESCl.
reaction progresses, the concentration of silyl chloride
decreases, slowing the silylation step; moreover, acid is
generated in the reaction, which catalyzes the exchange
reaction. To test this hypothesis, we monitored the reaction
while adding the silyl chloride at a rate such that conversion
and silyl chloride addition were matched, thus limiting the
amount of excess electrophile in solution (Figure 2). In
addition, we found that performing the reaction at room
temperature provided the optimal results. Under these
conditions, the formation of 2a proceeds in 97:3 er at low
conversion (10 min) with a small decrease in er (94.5:5.5) after
110 min. The conversion to 3a still shows a small increase in
enantioselectivity at the beginning of the reaction, but the effect
is considerably smaller and the final product is formed in high
enantioselectivity (96:4 er). Based on the time course, the
formation of 3a clearly accelerates as the reaction progresses. In
Figure 2, we have drawn a simplified version of the kinetics
model; notably, we have only shown the pathways for the major
products formed ((R)-2a and (S)-3a). Furthermore, we have
not included the equilibria for product bound to catalyst even
though these equilibria are present. The rapid formation of (R)-
2a is consistent with the primary alcohol being the inherently
more reactive alcohol and the substrate being stereochemically
matched to the catalyst. The accelerated formation of 3a as the
reaction progresses can be rationalized by considering that the
majority of 3a is the S enantiomer (er = 96:4). Therefore, any
catalyst bound to (R)-1a, through either the primary or
secondary alcohol, is lowering the concentration of catalyst
bound to (S)-1a, effectively inhibiting the formation of (S)-3a.
The formation of (R)-3a is likely slow because of a mismatched
relationship between the catalyst and (R)-1a. Therefore, as (R)-
1a is converted to (R)-2a (where the primary hydroxyl is
silylated), this increases the concentration of catalyst bound to
(S)-1a, thereby accelerating the rate of formation of (S)-3a
(Scheme 2).
Analysis of the time course suggests that to obtain the
optimal yield and enantioselectivity of 2a approximately 0.7
equiv of TESCl is required. With this in mind, we examined the
substrate scope of the regiodivergent resolution with the aim of
obtaining 2a in high yield and enantioselectivity. To improve
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Note
case, the product with the secondary hydroxyl protected (3d)
was never observed even with excess silyl chloride. Even though
a regiodivergent kinetic resolution does not occur with 1d, a
traditional kinetic resolution provides 2d in 43% yield and
95.5:4.5 er (s = 44, Table 1, entry 4). The substrates with the
lowest enantioselectivities and yields were 2e and 2i, which
have the smallest R substituents (R = Me and vinyl, Table 1,
entries 5 and 9). A benzyl-protected glycerol derivative also
functions in the reaction, yielding the differentially protected
triol in 40% yield and 95:5 er (Table 1, entry 7). Under the
reaction conditions, halogen-containing substrates, both Cl and
Br, provide the highest stereoselectivities of the silylated
products while maintaining excellent yields (Table 1, entries 11
and 12). As further evidence of the practicality of the reaction,
we performed a larger scale reaction. Using 10 mmol of 1l (R =
CH2Cl), the resolution produced 2l in 45% yield and 97:3 er
(eq 1), consistent with the smaller scale reaction.
Scheme 2. Kinetic Model for Formation of (S)-3a
the operational practicality, we employed a portionwise
addition of the silyl chloride rather than a syringe pump
addition. Under these conditions, 2a was formed in 46% yield
and 96.5:3.5 er (Table 1, entry 1), matching the time course
Table 1. Kinetic Resolution of 1,2-Diols
Having explored the substrate scope of the resolution to
form the primary protected products, we next investigated the
range of silyl groups that could be transferred enantioselec-
tively. By employing more bulky silylating agents, it was
discovered that the product with the secondary hydroxyl
protected (3) does not form in appreciable quantities.
Consequently, reactions with the larger silylating agents
undergo traditional kinetic resolutions rather than the
regiodivergent RRMs. Using TBSCl in the resolution of 1,2-
hexanediol provides (R)-2 in 45% yield and 89:11 er (s = 15).
Increasing the steric bulk of the silyating reagent to TIPSCl
provides a significant increase in s factor to 45, allowing the
product to be isolated in 40% yield and 96:4 er, comparable to
the results with TESCl (eq 2).
g
entry
R
catalyst
yield 2 (%)
er 2 (%)
a
1
−CH2CH(CH3)2 (a)
−(CH2)3CH3 (b)
−Cy (c)
−t-Bu (d)
−CH3 (e)
−CH2Ph (f)
−CH2OBn (g)
−CH2OPh (h)
−CHCH2 (i)
−Ph (j)
10% 4b
10% 4a
10% 4b
15% 4b
15% 4b
10% 4b
15% 4a
15% 4a
15% 4b
15% 4b
10% 4b
10% 4b
46
44
47
43
37
41
40
36
41
39
40
41
96.5:3.5
96:4
b
2
3
96:4
c
4
95.5:4.5
94:6
d
5
a
6
96:4
b
7
95:5
e
8
94.5:5.5
89:11
a
9
f
10
95.5:4.5
97.5:2.5
97.5:2.5
a
11
−CH2Br (k)
−CH2Cl (l)
a
12
a
b
0.70 equiv of TESCl and 0.80 equiv of DIPEA were used. 0.60 equiv
of TESCl and 0.70 equiv of DIPEA were used. 0.60 equiv of TESCl
c
and 0.70 equiv of DIPEA were used; t-amyl-OH was used as solvent,
d
and reaction was run at 4 °C for 2 h. 0.80 equiv of TESCl and 0.90
e
equiv of DIPEA were used. 0.70 equiv of TESCl and 0.80 equiv of
f
DIPEA were used; reaction time was 2 h. 0.50 equiv of TESCl and
0.60 equiv of DIPEA were used; t-amyl-OH was used as solvent.
Isolated yields.
We have demonstrated that a catalyst that uses reversible
covalent bonding is effective at the resolution of 1,2-diols. By
monitoring the reaction kinetics, we were able to improve the
yield and selectivity of the reaction while also gaining insight
into the mechanism of the reaction. We believe the above
method will be a practical means of accessing enantiopure
terminal 1,2-diols in which the hydroxyls have been chemically
differentiated.
g
data. As a note of comparison, a traditional kinetic resolution
catalyst would need to operate with a selectivity factor (s) of 67
to obtain similar yield and enantioselectivity of 2a.
Under these modified conditions, the substrate scope was
examined, and in general, the primary protected products (2)
were isolated in synthetically practical levels of enantioselectiv-
ity (>95:5 er) and yields ≥40% (Table 1). In these cases,
groups both small (R = n-Bu, Table 1, entry 2) and large (R = t-
Bu, Table 1, entry 4) provide the desired products in high yield
and enantioselectivity. For Table 1, the majority of substrates
undergo a regiodivergent resolution; however, the conditions
are run such that only a minimal amount of 3 is formed during
the reaction. One substrate that did not undergo a
regiodivergent resolution was substrate 1d (R = t-Bu); in this
EXPERIMENTAL SECTION
■
General Considerations. Unless otherwise noted, all reagents
were obtained from commercial suppliers and used without further
purification. Lithium reagents were titrated against 2-pentanol using
1,10-phenanthroline as the indicator. All experiments were performed
in oven or flame-dried glassware under an atmosphere of nitrogen or
argon using standard syringe and cannula techniques, except where
otherwise noted. All reactions were run with dry, degassed solvents
dispensed from a glass contour solvent purification system. tert-Amyl
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alcohol and tert-butanol were distilled over CaH2 and stored over 3 Å
molecular sieves in a drybox under a nitrogen atmosphere. Deuterated
solvents were stored over 3 Å molecular sieves. C6D6 was degassed by
three successive freeze−pump−thaw cycles and stored over 3 Å
molecular sieves in a drybox under a nitrogen atmosphere. Column
chromatography was performed using and automatic purification
system prepacked columns. All NMR chemical shifts are reported in
ppm relative to residual solvent for 1H and 13C NMR. Coupling
constants are reported in Hz. All IR spectra values are reported in
cm−1. High-resolution mass spectra (HRMS) were taken using a TOF
analyzer.
96.5:3.5; run 2: 46%, er = 96:4): chiral GLC analysis (Beta Dex 120
(30 m × 0.15 mm × 0.25 mm film thickness), 95 °C for 90 min, 20
°C/min to 180 °C, 180 °C for 20 min, 15 psi, trminor = 74.4 min, trmajor
= 74.8 min); 1H NMR (CDCl3, 500 MHz) δ 3.71 (ddd, 1H, J = 16.4,
7.8, 3.2), 3.58 (dd, 1H, J = 9.8, 3.2), 3.33 (dd, 1H, J = 9.8, 7.8), 2.40
(d, 1H, J = 3.2), 1.74−1.82 (m, 1H), 1.36 (ddd, 1H, J = 14.2, 8.8, 5.9),
1.11 (ddd, 1H, J = 13.5, 8.5, 4.2), 0.95 (t, 9H, J = 7.8), 0.92 (d, 3H, J =
6.6), 0.90 (d, 3H, J = 6.6), 0.60 (q, 6H, J = 7.8); 13C NMR (CDCl3,
125 MHz) δ 70.3, 67.6, 42.0, 24.8, 23.6, 22.4, 6.9, 4.6; IR 2954, 2912,
2876, 1096, 1049, 1004, 789, 726 cm−1; HRMS (ESI+) calcd for
C12H28O2NaSi [M + Na]+ 255.1751, found 255.1763; [α]D20 = −1.9 (c
= 1.0, CH2Cl2, l = 50 mm).
The following compounds were made according to literature
procedure: 1-benzyloxy-2,3-propanediol,45 4-methylpentane-1,2-diol,26
1-cyclohexylethane-1,2-diol,26 3-phenylpropane-1,2-diol,26 4a,25 4b.26
Reaction Time Course at 0 °C with a Single Addition of
TESCl (Figure 1). In a drybox, a solution of diol 1a (24 mg, 0.20
mmol), catalyst 4b (6.2 mg, 0.02 mmol, 10 mol %), and N,N-
diisopropylethylamine hydrochloride (2.0 mg, 1.2 × 10−2 mmol, 6 mol
%) in anhydrous tert-butanol (3 mL) was prepared in an oven-dried
glass reaction vial. A solution of 1,3,5-trimethoxybenzene as internal
standard (50 μL, 2.0 × 10−2 mmol, 10 mol %, 0.40 M in CDCl3) was
added. The reaction was brought out of the drybox and was stirred at 4
°C for 15 min. N,N-Diisopropylethylamine (49 μL, 0.28 mmol, 1.4
equiv) was added, followed by addition of chlorotriethylsilane (44 μL,
0.26 mmol, 1.2 equiv). The reaction was stirred at room temperature
for 1 h. Aliquots (0.5 mL) were taken at every 10 min. Methanol (5
μL) was added to quench the aliquot. The solvent was removed under
reduced pressure. Chiral GLC analysis of the crude mixture afforded
the yield and selectivity. Chiral GLC Analysis (Beta Dex 120 (30 m ×
0.15 mm × 0.25 mm film thickness), 90 °C for 135 min, 20 °C/min to
160 °C, 160 °C for 20 min, 20 °C/min to 180 °C, 180 °C for 20 min,
(R)-1-((Triethylsilyl)oxy)hexan-2-ol (2b, Table 1, entry 2). The
general procedure was followed using 10 mol % of catalyst 4a, 0.70
equiv of N,N-diisopropylethylamine, and 0.60 equiv of chlorotriethyl-
silane to yield product as colorless oil (run 1: 101 mg, 43%, er = 96:4;
run 2: 44%, er = 95.5:4.5): chiral GLC analysis (Beta Dex 120 (30 m ×
0.15 mm × 0.25 mm film thickness), 95 °C for 120 min, 20 °C/min to
180 °C, 180 °C for 20 min, 15 psi, trminor = 102.5 min, trmajor = 103.4
1
min); H NMR (CDCl3, 500 MHz) δ 3.59−3.64 (m, 2H), 3.36 (dt,
1H, J = 2.0, 8.8), 2.44 (d, 1H, J = 3.2), 1.22−1.45 (m, 6H), 0.94 (t, 9H,
J = 7.8), 0.89 (t, 3H, J = 7.1), 0.60 (q, 6H, J = 7.8); 13C NMR (CDCl3,
125 MHz) δ 72.1, 67.2, 32.7, 28.0, 23.0, 14.2, 6.9, 4.6; IR 2955 cm−1;
HRMS (ESI+) calcd for C12H28O2NaSi [M + Na]+ 255.1751, found
20
255.1745; [α]D = −3.2 (c = 1.0, CH2Cl2, l = 50 mm).
(R)-1-Cyclohexyl-2-((triethylsilyl)oxy)ethanol (2c, Table 1, entry
3). The general procedure was followed using 10 mol % of catalyst 4b,
0.70 equiv of N,N-diisopropylethylamine, and 0.60 equiv of chloro-
triethylsilane to yield product as colorless oil (run 1: 123 mg, 48%, er =
95:5; run 2: 46%, er = 96.5:3.5). Chiral GC analysis (Gamma Dex 120
(30 m × 0.25 mm × 0.25 μm film thickness), 115 °C for 180 min, 20
°C/min to 180 °C, 180 °C for 20 min, 15 psi, trmajor = 172.2 min, trminor
15 psi, t(S)‑2a = 96.2 min, t(R)‑2a = 97.4 min, t(S)‑3a = 104.2 min, t(R)‑3a
=
1
= 169.5 min); H NMR (CDCl3, 500 MHz) δ 0.59 (q, 6H, J = 7.8),
110.9 min, tstandard = 143.7 min), response factors ((S)-2a = 0.59, (R)-
0.94 (t, 9H, J = 7.8), 0.98−1.06 (m, 2H), 1.10−1.25 (m, 3H), 1.33−
1.40 (m, 1H), 1.57−1.65 (m, 2H), 1.69−1.75 (m, 2H), 1.87−1.91 (m,
1H), 2.48 (d, 1H, J = 2.9), 3.34−3.38 (m, 1H), 3.44 (dd, 1H, J = 9.8,
8.3), 3.67 (dd, 1H, J = 9.8, 3.2); 13C NMR (CDCl3, 125 MHz) δ 4.6,
6.9, 26.3, 26.4, 26.7, 29.0, 29.1, 40.7, 65.2, 76.0; IR 2921, 2875, 2852,
1450, 1112, 1079, 1004, 817, 726 cm−1; HRMS (ESI+) calcd for
C14H30O2NaSi [M + Na]+ 281.1907, found 281.1915; [α]D20 = −7.4 (c
= 1.0, CH2Cl2, l = 50 mm).
2a = 0.59, (S)-3a = 0.66, (R)-3a = 0.66, standard = 1.0).
Reaction Time Course at Room Temperature with a Syringe
Pump Addition of TESCl (Figure 2). In a drybox, a solution of diol
1a (240 mg, 2.0 mmol), catalyst 4b (61 mg, 0.20 mmol, 10 mol %),
and N,N-diisopropylethylamine hydrochloride (20 mg, 0.12 mmol, 6
mol %) in anhydrous tert-butanol (30 mL) was prepared in an oven-
dried glass reaction vial. The solution brought out of the drybox, and a
solution of 1,3,5-trimethoxybenzene as internal standard (0.50 mL,
0.20 mmol, 10 mol %, 0.40 M in CDCl3) was added. The reaction was
stirred at room temperature for 15 min. N,N-Diisopropylethylamine
(490 μL, 2.8 mmol, 1.4 equiv) was added, followed by addition of
chlorotriethylsilane (440 μL, 2.6 mmol, 1.2 equiv) in 2 mL of THF via
syringe pump over 1.5 h. The reaction was stirred at room temperature
for 2 h. Aliquots (0.5 mL) were taken every at 10 min. Methanol (5
μL) was added to quench the aliquot. The solvent was removed under
reduced pressure. Chiral GLC analysis of the crude mixture afforded
the yield and selectivity.
(R)-3,3-Dimethyl-1-((triethylsilyl)oxy)butan-2-ol (2d, Table 1,
entry 4). The general procedure was followed using 15 mol % of
catalyst 4b, 0.70 equiv of N,N-diisopropylethylamine, 0.60 equiv of
chlorotriethylsilane, and t-amyl-OH as solvent. Reaction was run at 4
°C for 2 h to yield product as colorless oil (run 1: 104 mg, 45%, er =
96:4; run 2: 42%, er = 95.5:4.5): chiral GLC analysis (Gamma Dex
120 (30 m × 0.15 mm × 0.25 mm film thickness), 95 °C for 120 min,
20 °C/min to 180 °C, 180 °C for 20 min, 15 psi, trminor = 43.7 min,
1
trmajor = 45.0 min); H NMR (CDCl3, 500 MHz) δ 3.69 (dd, 1H, J =
9.8, 3.2), 3.43 (t, 1H, J = 9.3), 3.30 (ddd, 1H, J = 9.0, 3.2, 2.0), 2.65 (d,
1H, J = 2.2), 0.95 (t, 9H, J = 8.1), 0.90 (s, 9H), 0.60 (q, 6H, J = 8.1);
13C NMR (CDCl3, 125 MHz) δ 78.9, 63.5, 33.4, 26.2, 6.9, 4.6; IR
2954, 2912, 2877, 1460, 1108, 1067, 1003, 817, 726 cm−1; HRMS
(ESI+) calcd for C12H29O2Si: [M + H]+ 233.1937, found 233.1940;
General Procedure for Kinetic Resolution of Terminal 1,2-
Diols. In a drybox, a solution of diol substrate (1.0 mmol), catalyst 4b
(31 mg, 0.10 mmol, 10 mol %), and N,N-diisopropylethylamine
hydrochloride (10 mg, 6.0 × 10−2 mmol, 6 mol %) in anhydrous tert-
butanol (15 mL) was prepared in an oven-dried glass reaction vial. The
reaction was brought out of the drybox and was stirred at room
temperature for 15 min. N,N-Diisopropylethylamine (120 μL, 0.70
mmol, 0.70 equiv) was added, followed by addition of chlorotriethyl-
silane (100 μL, 0.60 mmol, 0.60 equiv) in four portions every 15 min
(dropwise addition was performed for each portion added). The
reaction was stirred at room temperature for 1 h (starting from the first
addition of chlorotriethylsilane). Methanol (150 μL) was added to
quench the reaction. The solvent was removed under reduced
pressure, and flash column chromatography (hexanes/EtOAc =
60:1) afforded pure product. Chiral GLC or HPLC analysis of the
product afforded the selectivity.
20
[α]D = −21.2 (c = 1.0, CH2Cl2, l = 50 mm).
(R)-1-((Triethylsilyl)oxy)propan-2-ol (2e, Table 1, entry 5). The
general procedure was followed using 15 mol % of catalyst 4b, 0.90
equiv of N,N-diisopropylethylamine, and 0.80 equiv of chlorotriethyl-
silane to yield product as colorless oil (run 1: 72 mg, 36%, er =
94.5:5.5; run 2: 38%, er = 93.5:6.5): chiral GLC analysis (Beta Dex
120 (30 m × 0.15 mm × 0.25 mm film thickness), 80 °C for 45 min,
20 °C/min to 180 °C, 180 °C for 20 min, 15 psi, trminor = 35.4 min,
1
trmajor = 36.5 min); H NMR (CDCl3, 500 MHz) δ 3.77−3.84 (m,
1H), 3.57 (dd, 1H, J = 9.8, 3.4), 3.32 (dd, 1H, J = 9.8, 7.8), 2.48 (d,
1H, 3.0), 1.10 (d, 3H, J = 6.4), 0.94 (t, 9H, J = 7.8), 0.60 (q, 6H, J =
7.8); 13C NMR (CDCl3, 125 MHz) δ 68.4, 68.2, 18.4, 6.9, 4.6; IR
2955, 2911, 2877, 1459, 1239, 1087, 1006, 801, 724 cm−1; HRMS
(ESI+) calcd for C9H22O2NaSi [M + Na]+ 213.1281, found 213,1271;
(R)-4-Methyl-1-((triethylsilyl)oxy)pentan-2-ol (2a, Table 1, entry
1). The general procedure was followed using 10 mol % of catalyst 4b,
0.80 equiv of N,N-diisopropylethylamine, and 0.70 equiv of chloro-
triethylsilane to yield product as colorless oil (run 1: 108 mg, 46%, er =
20
[α]D = −11.2 (c = 1.0, CH2Cl2, l = 50 mm).
D
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Note
(R)-1-Phenyl-3-((triethylsilyl)oxy)propan-2-ol (2f, Table 1, entry
6). The general procedure was followed using 10 mol % of catalyst 4b,
0.80 equiv of N,N-diisopropylethylamine, and 0.70 equiv of chloro-
triethylsilane to yield product as a colorless oil (run 1: 107 mg, 41%, er
= 96:4; run 2: 40%, er = 96:4): chiral HPLC analysis (OD-H, hexanes/
125 MHz) δ 104.5, 128.5, 128.0, 126.4, 74.6, 68.8, 6.9, 4.6; IR 2954,
2911, 2876, 1454, 1103, 1062, 1004, 727, 698, 532 cm−1; HRMS (ESI
20
+) calcd for C14H23OSi [M − OH]+ 235.1518, found 235.1523; [α]D
= −26.2 (c = 1.0, CH2Cl2, l = 50 mm).
(S)-1-Bromo-3-((triethylsilyl)oxy)propan-2-ol (2k, Table 1, entry
11). The general procedure was followed using 10 mol % of catalyst
4b, 0.80 equiv of N,N-diisopropylethylamine, and 0.70 equiv of
chlorotriethylsilane to yield product as colorless oil (run 1: 110 mg,
41%, er = 97.5:2.5; run 2: 40%, er = 97.5:2.5): chiral GLC analysis
(Gamma Dex 120 (30 m × 0.15 mm × 0.25 mm film thickness), 110
°C for 160 min, 20 °C/min to 180 °C, 180 °C for 20 min, 15 psi,
iPrOH = 98/2, 1.0 mL/min, 220 nm, trmajor = 5.51 min and trminor
=
6.12 min); 1H NMR (CDCl3, 500 MHz) δ 7.27−7.30 (m, 2H), 7.18−
7.22 (m, 3H), 3.85−3.90 (m, 1H), 3.60 (dd, 1H, J = 10.0, 3.7), 3.46
(dd, 1H, J = 9.8, 6.8), 2.78 (dd, 1H, J = 13.7, 7.1), 2.74 (dd, 1H, J =
13.7, 6.4), 2.42 (d, 1H, J = 3.9), 0.94 (t, 9H, J = 7.8), 0.59 (q, 6H, J =
7.8); 13C NMR (CDCl3, 125 MHz) δ 138.5, 129.5, 128.6, 126.5, 73.0,
66.2, 39.8, 6.9, 4.6; IR 2953, 2911, 2876, 1239, 1111, 1031, 792, 727,
698 cm−1; HRMS (ESI+) calcd for C15H26O2NaSi [M + Na]+
1
trminor = 73.6 min, trmajor = 74.8 min); H NMR (CDCl3, 500 MHz) δ
3.83 (ddd, 1H, J = 16.4, 6.1, 4.9), 3.72 (dd, 1H, J = 10.0, 4.6), 3.68 (dd,
1H, J = 10.0, 4.9), 3.41−3.49 (m, 2H), 2.56 (d, 1H, J = 6.4), 0.93−0.96
(m, 9H), 0.61 (q, 6H, J = 7.8); 13C NMR (CDCl3, 125 MHz) δ 71.3,
64.0, 34.7, 6.9, 4.5; IR 2955, 2876, 1459, 1240, 1108, 1006, 799, 727,
671 cm−1; HRMS (ESI+) calcd for C9H22BrO2Si [M + H]+ 269.0572,
20
289.1594, found 289.1600; [α]D = +3.2 (c = 1.0, CH2Cl2, l = 50
mm).
(R)-1-(Benzyloxy)-3-((triethylsilyl)oxy)propan-2-ol (2g, Table 1,
entry 7). The general procedure was followed using 15 mol % of
catalyst 4a, 0.70 equiv of N,N-diisopropylethylamine, and 0.60 equiv of
chlorotriethylsilane to yield product as colorless oil (run 1: 122 mg,
41%, er = 95:5; run 2: 40%, er = 95:5): chiral HPLC analysis (OD-H,
hexanes/iPrOH = 95/5, 1.0 mL/min, 220 nm, trminor = 7.12 min and
20
found 269.0576; [α]D = −1.0 (c = 1.0, CH2Cl2, l = 50 mm).
(S)-1-Chloro-3-((triethylsilyl)oxy)propan-2-ol (2l, Table 1, entry
12). The general procedure was followed using 10 mol % of catalyst
4b, 0.80 equiv of N,N-diisopropylethylamine, and 0.70 equiv of
chlorotriethylsilane to yield product as colorless oil (run 1: 94 mg,
42%, er = 97.5:2.5; run 2: 40%, er = 97.5:2.5): chiral GLC analysis
(Gamma Dex 120 (30 m × 0.15 mm × 0.25 mm film thickness), 110
°C for 50 min, 20 °C/min to 180 °C, 180 °C for 20 min, 15 psi, trminor
= 44.3 min, trmajor = 45.0 min); 1H NMR (CDCl3, 500 MHz) δ 3.80−
3.86 (m, 1H), 3.66−3.72 (m, 2H), 3.54−3.61 (m, 2H), 2.54 (d, 1H, J
= 6.4), 0.93−0.96 (m, 9H), 0.61 (q, 6H, J = 8.1); 13C NMR (CDCl3,
125 MHz) δ 71.6, 63.3, 45.6, 6.9, 4.5; IR 3425, 2955, 2877, 1459,
1240, 1111, 1006, 804, 740 cm−1; HRMS (ESI+) calcd for
1
trmajor = 8.19 min); H NMR (CDCl3, 500 MHz) δ 7.26−7.35 (m,
5H), 4.54 (s, 2H), 3.82−3.87 (m, 1H), 3.66 (dd, 1H, J = 10.0, 4.9),
3.62 (dd, 1H, J = 10.0, 5.9), 3.53 (dd, 1H, J = 9.5, 4.9), 3.49 (dd, 1H, J
= 9.5, 5.9), 2.48 (d, 1H, J = 4.9), 0.94 (t, 9H, J = 7.8), 0.59 (q, 6H, J =
7.8); 13C NMR (CDCl3, 125 MHz) δ 138.4, 128.6, 128.0, 127.9, 73.7,
71.3, 71.0, 64.0, 6.9, 4.6; IR 2953, 2910, 2875. 1089, 1004, 804, 728,
696 cm−1; HRMS (ESI+) calcd for C16H28O3NaSi [M + Na]+
20
319.1700, found 319.1697; [α]D = −1.1 (c = 1.0, CH2Cl2, l = 50
mm).
(R)-1-Phenoxy-3-((triethylsilyl)oxy)propan-2-ol (2h, Table 1, entry
8). The general procedure was followed using 15 mol % of catalyst 4a,
0.80 equiv of N,N-diisopropylethylamine, and 0.70 equiv of chloro-
triethylsilane. The reaction was stirred for 2 h to yield product as
colorless oil (run 1: 98 mg, 35%, er = 95:5; run 2: 37%, er = 94:6):
chiral HPLC analysis (OD-H, hexanes/iPrOH = 90/10, 1.0 mL/min,
220 nm, trminor = 5.11 min and trmajor = 10.66 min); 1H NMR (CDCl3,
500 MHz) δ 7.25−7.28 (m, 2H), 6.92−6.96 (m, 1H), 6.89−6.91 (m,
2H), 3.99−4.05 (m, 3H), 3.78 (dd, 1H, J = 10.3, 4.6), 3.74 (dd, 1H, J
= 10.3, 5.1), 2.55 (d, 1H, J = 5.1), 0.94 (t, 9H, J = 7.8), 0.61 (q, 6H, J =
7.8); 13C NMR (CDCl3, 125 MHz) δ 158.9, 129.7, 121.2, 114.8, 70.5,
68.7, 63.7, 6.9, 4.6; IR 2953, 2876, 1599, 1495, 1458, 1242, 1079, 1043,
1005, 802, 745, 727, 689 cm−1; HRMS (ESI+) calcd for
20
C9H22ClO2Si [M + H]+ 225.1070, found 225.1078; [α]D = −2.5
(c = 1.1, CH2Cl2, l = 50 mm).
Large Scale Experiment (eq 1). In a drybox, a solution of 3-
chloropropane-1,2-diol (1.1 g, 10 mmol), catalyst 4b (310 mg, 1.0
mmol, 10 mol %), and N,N-diisopropylethylamine hydrochloride (99
mg, 0.60 mmol, 6 mol %) in anhydrous tert-butanol (150 mL) was
prepared in an oven-dried 250 mL round-bottom flask. The reaction
was brought out of the drybox and was stirred at room temperature for
45 min. N,N-Diisopropylethylamine (1.4 mL, 8.0 mmol) was added,
followed by addition of chlorotriethylsilane (1.2 mL, 7.0 mmol) in four
portions every 15 min (dropwise addition was performed for each
portion added). The reaction was stirred at room temperature for 1 h
(starting from the first addition of chlorotriethylsilane). Methanol (1.5
mL) was added to quench the reaction. The solvent was removed
under reduced pressure, and flash column chromatography (hexanes/
EtOAc = 60:1) afforded pure product as colorless oil (940 mg, 45%, er
= 97:3).
20
C15H26O3NaSi [M + Na]+ 305.1543, found 305.1552; [α]D = +1.2
(c = 1.0, CH2Cl2, l = 50 mm).
(R)-1-((Triethylsilyl)oxy)but-3-en-2-ol (2i, Table 1, entry 9). The
general procedure was followed using 15 mol % of catalyst 4b, 0.80
equiv of N,N-diisopropylethylamine, and 0.70 equiv of chlorotriethyl-
silane to yield product as colorless oil (run 1: 84 mg, 42%, er = 89:11;
run 2: 40%, er = 89:11): chiral GLC analysis (Beta Dex 120 (30 m ×
0.15 mm × 0.25 mm film thickness), 90 °C for 50 min, 20 °C/min to
180 °C, 180 °C for 20 min, 15 psi, trminor = 42.9 min, trmajor = 44.6
Kinetic Resolution Using tert-Butyldimethylsilyl Chloride (eq
2). In a drybox, a solution of hexane-1,2-diol (120 mg, 1.0 mmol),
catalyst 4a (42 mg, 0.15 mmol, 15 mol %), and N,N-diisopropyl-
ethylamine hydrochloride (10 mg, 0.060 mmol, 6 mol %) in anhydrous
tert-butanol (15 mL) was prepared in an oven-dried glass reaction vial.
The reaction was brought out of the drybox and was stirred at room
temperature for 45 min. N,N-Diisopropylethylamine (140 μL, 0.80
mmol) was added, followed by addition of tert-butyldimethylsilyl
chloride (110 mg, 0.70 mmol). The reaction was stirred at 4 °C for 24
h. Methanol (150 μL) was added to quench the reaction. The solvent
was removed under reduced pressure, and flash column chromatog-
raphy (hexanes/EtOAc = 60:1) afforded pure product as colorless oil
(run 1: 106 mg, 46%, er = 89:11; run 2: 101 mg, 43%, er = 89:11):
chiral GLC analysis (Beta Dex 120 (30 m × 0.15 mm × 0.25 mm film
thickness), 95 °C for 80 min, 20 °C/min to 180 °C, 180 °C for 20
min, 15 psi, trminor = 56.9 min, trmajor = 57.8 min).
1
min); H NMR (CDCl3, 500 MHz) δ 5.80 (ddd, 1H, J = 17.1, 10.5,
5.6), 5.33 (dt, 1H, J = 17.4, 1.5), 5.17 (dt, 1H, 10.5, 1.5), 4.13−4.18
(m, 1H), 3.64 (dd, 1H, J = 10.0, 3.7), 3.42 (dd, 1H, J = 10.0, 7.8), 2.57
(d, 1H, 3.4), 0.95 (t, 9H, J = 7.8), 0.60 (q, 6H, J = 7.8); 13C NMR
(CDCl3, 125 MHz) δ 136.8, 116.7, 73.3, 66.9, 6.9, 4.6; IR 2955, 2912,
2877, 1238, 1102, 1004, 923, 795, 725 cm−1; HRMS (ESI+) calcd for
C10H22O2NaSi [M + Na]+ 225.1281, found 225.1285; [α]D20 = +0.3 (c
= 1.0, CH2Cl2, l = 50 mm).
(R)-1-Phenyl-2-((triethylsilyl)oxy)ethanol (2j, Table 1, entry 10).
The general procedure was followed using 15 mol % of catalyst 4b,
0.60 equiv of N,N-diisopropylethylamine, 0.50 equiv of chloro-
triethylsilane, and t-amyl-OH as solvent to yield product as colorless
oil (run 1: 96 mg, 38%, er = 96:4; run 2: 39%, er = 95:5): chiral HPLC
analysis (OD-H, hexanes/iPrOH = 95/5, 1.0 mL/min, 220 nm, trminor
(R)-1-((tert-Butyldimethylsilyl)oxy)hexan-2-ol (2ba): 1H NMR
(CDCl3, 500 MHz) δ 3.59−3.63 (m, 2H), 3.37 (dd, 1H, J = 10.5,
8.3), 2.38 (d, 1H, J = 3.4), 1.24−1.43 (m, 6H), 0.86−0.90 (m, 12H),
0.05 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ 72.1, 67.5, 32.7, 28.0,
26.1, 23.0, 18.5, 14.2, −5.1, −5.2; IR 2955, 2929, 2858, 1463, 1254,
1098, 835, 775 cm−1; HRMS (ESI+) calcd for C12H29O2Si [M + H]+
1
= 4.84 min and trmajor = 5.56 min); H NMR (CDCl3, 500 MHz) δ
7.31−7.37 (m, 4H), 7.25−7.28 (m, 1H), 4.74 (dt, 1H, J = 8.3, 3.2),
3.75 (dd, 1H, J = 10.3, 3.7), 3.52 (dd, 1H, J = 10.0, 9.0), 2.97 (d, 1H, J
= 2.2), 0.95 (t, 9H, J = 8.1), 0.61 (q, 6H, J = 8.1); 13C NMR (CDCl3,
E
dx.doi.org/10.1021/jo4012909 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
20
233.1937, found 233.1938; [α]D = −4.6 (c = 1.0, CH2Cl2, l = 50
(12) Voituriez, A.; Panossian, A.; Fleury-Bregeot, N.; Retailleau, P.;
Marinetti, A. Adv. Synth. Catal. 2009, 351, 1968.
(13) Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic
Synthesis, 4th ed.; Wiley-Interscience: New York, 2007.
(14) Kocienski, P. Protecting Groups, 3rd ed.; Thieme: Stuttgart, 2005.
(15) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031.
(16) Isobe, T.; Fukuda, K.; Araki, Y.; Ishikawa, T. Chem. Commun.
2001, 243.
(17) Rendler, S.; Auer, G.; Oestreich, M. Angew. Chem., Int. Ed. 2005,
44, 7620.
(18) Weickgenannt, A.; Mewald, M.; Muesmann, T. W. T.;
Oestreich, M. Angew. Chem., Int. Ed. 2010, 49, 2223.
(19) Weickgenannt, A.; Mewald, M.; Oestreich, M. Org. Biomol.
Chem. 2010, 8, 1497.
mm).
Kinetic Resolution Using Triisopropylsilyl Chloride (eq 2). In
a drybox, a solution of hexane-1,2-diol (120 mg, 1.0 mmol), catalyst 4a
(42 mg, 0.15 mmol, 15 mol %), and N,N-diisopropylethylamine
hydrochloride (10 mg, 0.060 mmol, 6 mol %) in anhydrous tert-
butanol (15 mL) was prepared in an oven-dried glass reaction vial. The
reaction was brought out of the drybox and was stirred at room
temperature for 45 min. N,N-Diisopropylethylamine (140 μL, 0.80
mmol) was added, followed by addition of triisopropylsilyl chloride
(150 μL, 0.70 mmol). The reaction was stirred at 4 °C for 48 h.
Methanol (150 μL) was added to quench the reaction. The solvent
was removed under reduced pressure, Flash column chromatography
(hexanes/EtOAc = 60:1) afforded pure product as colorless oil (run 1:
115 mg, 42%, er = 95:5; run 2: 105 mg, 38%, er = 97:3): chiral GLC
analysis (Gamma Dex 120 (30 m × 0.15 mm × 0.25 mm film
thickness), 110 °C for 150 min, 20 °C/min to 180 °C, 180 °C for 20
min, 15 psi, trminor = 137.4 min, trmajor = 140.7 min).
(20) Takeichi, T.; Kuriyama, M.; Onomura, O. Tetrahedron Lett.
2011, 52, 6646.
(21) Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L. Nature
2006, 443, 67.
1
(R)-1-((Triisopropylsilyl)oxy)hexan-2-ol (2bb): H NMR (CDCl3,
(22) Zhao, Y.; Mitra, A. W.; Hoveyda, A. H.; Snapper, M. L. Angew.
500 MHz) δ 3.64 (dd, 1H, J = 9.5, 3.2), 3.56−3.61 (m, 1H), 3.40 (dd,
1H, J = 9.5, 7.6), 2.47 (d, 1H, 3.2), 1.25−1.39 (m, 6H), 0.95−1.07 (m,
21H), 0.84 (m, 3H); 13C NMR (CDCl3, 125 MHz) δ 72.2, 67.8, 32.7,
28.0, 23.0, 18.2, 14.2, 12.1; IR 2940, 2865, 1463, 1103, 882, 797, 681,
660 cm−1; HRMS (ESI+) calcd for C15H35O2Si [M + H]+ 275.2406,
Chem., Int. Ed. 2007, 46, 8471.
(23) Rodrigo, J. M.; Zhao, Y.; Hoveyda, A. H.; Snapper, M. L. Org.
Lett. 2011, 13, 3778.
(24) Sheppard, C. I.; Taylor, J. L.; Wiskur, S. L. Org. Lett. 2011, 13,
3794.
(25) Sun, X. X.; Worthy, A. D.; Tan, K. L. Angew. Chem., Int. Ed.
2011, 50, 8167.
(26) Worthy, A. D.; Sun, X. X.; Tan, K. L. J. Am. Chem. Soc. 2012,
134, 7321.
(27) You, Z.; Hoveyda, A. H.; Snapper, M. L. Angew. Chem., Int. Ed.
20
found 275.2415; [α]D = −4.2 (c = 1.0, CH2Cl2, l = 50 mm).
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
2009, 48, 547.
(28) Miller, L. C.; Sarpong, R. Chem. Soc. Rev. 2011, 40, 4550.
(29) Kumar, R. R.; Kagan, H. B. Adv. Synth. Catal. 2010, 352, 231.
(30) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974.
(31) Wu, B.; Parquette, J. R.; RajanBabu, T. V. Science 2009, 326,
1662.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kian.tan@novartis.com.
■
(32) Tan, K. L. ACS Catal. 2011, 1, 877.
Notes
(33) Rousseau, G.; Breit, B. Angew. Chem., Int. Ed. 2011, 50, 2450.
(34) Park, Y. J.; Park, J. W.; Jun, C. H. Acc. Chem. Res. 2008, 41, 222.
(35) Taylor, M. S.; Beale, T. M. Org. Lett. 2013, 15, 1358.
(36) Lee, D.; Williamson, C. L.; Chan, L. N.; Taylor, M. S. J. Am.
Chem. Soc. 2012, 134, 8260.
(37) Chan, L. N.; Taylor, M. S. Org. Lett. 2011, 13, 3090.
(38) Gouliaras, C.; Lee, D.; Chan, L. N.; Taylor, M. S. J. Am. Chem.
Soc. 2011, 133, 13926.
(39) Lee, D.; Taylor, M. S. J. Am. Chem. Soc. 2011, 133, 3724.
(40) Lee, D.; Taylor, M. S. Synthesis 2012, 44, 3421.
(41) Worthy, A. D.; Joe, C. L.; Lightburn, T. E.; Tan, K. L. J. Am.
Chem. Soc. 2010, 132, 14757.
(42) MacDonald, M. J.; Hesp, C. R.; Schipper, D. J.; Pesant, M.;
Beauchemin, A. M. Chem.Eur. J. 2013, 19, 2597.
(43) Guimond, N.; MacDonald, M. J.; Lemieux, V.; Beauchemin, A.
M. J. Am. Chem. Soc. 2012, 134, 16571.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Alfred P. Sloan Foundation (K.L.T.), LaMattina
Fellowship (X.S. and A.D.W.), NSF (CHE-1150393), and
NIGMS (RO1GM087581) for funding of this project. Mass
spectrometry instrumentation at Boston College is supported
by funding from the NSF (DBI-0619576).
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dx.doi.org/10.1021/jo4012909 | J. Org. Chem. XXXX, XXX, XXX−XXX