Silylation-based kinetic resolution of monofunctional secondary alcohols

Article abstract of DOI:10.1021/ol2012617

The nucleophilic small molecule catalyst (-)-tetramisole was found to catalyze the kinetic resolution of monofunctional secondary alcohols via enantioselective silylation. Optimization of this new methodology allows for selectivity factors up to 25 utilizing commercially available reagents and mild reaction conditions.

Full text of DOI:10.1021/ol2012617

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3794–3797
Silylation-Based Kinetic Resolution of
Monofunctional Secondary Alcohols
Cody I. Sheppard, Jessica L. Taylor, and Sheryl L. Wiskur*
Department of Chemistry and Biochemistry, University of South Carolina, 631 Sumter
Street, GSRC 109, Columbia, South Carolina 29208, United States
wiskur@chem.sc.edu
Received May 11, 2011
ABSTRACT
The nucleophilic small molecule catalyst (À)-tetramisole was found to catalyze the kinetic resolution of monofunctional secondary alcohols via
enantioselective silylation. Optimization of this new methodology allows for selectivity factors up to 25 utilizing commercially available reagents
and mild reaction conditions.
Nonenzymatic kinetic resolutions are a powerful technique1
for generating highly enantiomerically enriched chiral com-
pounds. The most common method for the kinetic resolution
of secondary alcohols is by acylation,2 but recently, silylation
based kinetic resolutions have become a new and active area of
research.3 Considerable attention has been given to this
methodology since silyl groups have a broad tolerance for
other functional groups and have many advantages over other
protecting groups (orthogonal deprotection to other protect-
ing groups, ease and high yields of protection and deprotec-
tion, and easily tunable reactivity).4 Of the substrates targeted
for silylation-based kinetic resolutions, a practical level of
selectivity for monofunctional, bicyclic secondary alcohols,
such as 1, has remained elusive and suprisingly difficult until
now. This alcohol class contains useful chiral building blocks
and important core structures in biologically active
compounds5 such as dopamine agonists, selective norepi-
nephrine reuptake inhibitors, and anti-HIV agents. Although
these compounds are most commonly synthesized by the
asymmetric reduction of prochiral carbonyl compounds,6
the work described herein is the first kinetic resolution of
monofunctional secondary alcohols via silylation achieving
useful levels of enantioselectivity. Our method employs mild
conditions and utilizes commercially available reagents, there-
by circumventing the need to synthesize catalysts or novel
chiral silylating agents.
Great progress hasbeen made inexistingsilylationbased
kinetic resolutions, but the substrates have been mostly
(1) For reviews on kinetic resolutions see: (a) Kagan, H. B.; Fiaud,
J. C. In Topics in Stereochemistry, Vol. 18; Eliel, E. L, Wilen, S. H, Eds.;
John Wiley & Sons, Inc.: New York, 1988; pp 249. (b) Keith, J. M.;
Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5.
(c) Robinson, D. E. J. E.; Bull, S. D. Tetrahedron: Asymm. 2003, 14,
1407. (d) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974.
(2) For representative examples see: (a) Oriyama, T.; Hori, Y.; Imai,
K.; Sasaki, R. Tetrahedron Lett. 1996, 37, 8543. (b) Ruble, J. C.;
Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794. (c) Copeland,
G. T.; Miller, S. J. J. Am. Chem. Soc. 2001, 123, 6496. (d) Vedejs, E.;
Daugulis, O. J. Am. Chem. Soc. 2003, 125, 4166. (e) MacKay, J. A.;
Vedejs, E. J. Org. Chem. 2004, 69, 6934. (f) Birman, V. B.; Li, X. Org.
Lett. 2006, 8, 1351. (g) Birman, V. B.; Li, X. Org. Lett. 2008, 10, 1115.
(h) Hu, B.; Meng, M.; Wang, Z.; Du, W.; Fossey, J. S.; Hu, X.; Deng,
W.-P. J. Am. Chem. Soc. 2010, 132, 17041.
(5) (a) Wu, K.; Pontillo, J.; Ching, B.; Hudson, S.; Gao, Y.; Fleck,
B. A.; Gogas, K.; Wade, W. S. Bioorg. Med. Chem. Lett. 2008, 18, 4224.
(b) Hudson, S.; Kiankarimi, M.; Eccles, W.; Mostofi, Y. S.; Genicot,
M. J.; Dwight, W.; Fleck, B. A.; Gogas, K.; Wade, W. S. Bioorg. Med.
Chem. Lett. 2008, 18, 4495. (c) Huang, L.; Kashiwada, Y.; Cosentino,
L. M.; Fan, S.; Chen, C.-H.; McPhail, A. T.; Fujioka, T.; Mihashi, K.;
Lee, K.-H. J. Med. Chem. 1994, 37, 3947. (d) DeWald, H. A.; Heffner,
T. G.; Jaen, J. C.; Lustgarten, D. M.; McPhail, A. T.; Meltzer, L. T.;
Pugsley, T. A.; Wise, L. D. J. Med. Chem. 1990, 33, 445.
(6) For reviews on asymmetric reductions see: (a) Modern Reduction
Methods; Wiley-VCH: Weinheim, 2008. (b) Brown, H. C.; Ramachandran,
P. V. Acc. Chem. Res. 1992, 25, 16. (c) Noyori, R.; Hashiguchi, S. Acc.
Chem. Res. 1997, 30, 97. (d) Corey, E. J.; Helal, C. J. Angew. Chem., Int.
Ed. 1998, 37, 1986.
(3) (a) Rendler, S.; Oestreich, M. Angew. Chem., Int. Ed. 2008, 47,
248. (b) Weickgenannt, A.; Mewald, M.; Oestreich, M. Org. Biomol.
Chem. 2010, 8, 1497.
(4) Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley-Interscience: New York, 1999.
(7) (a) Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L. Nature
2006, 443, 67. (b) Zhao, Y.; Mitra, A. W.; Hoveyda, A. H.; Snapper,
M. L. Angew. Chem., Int. Ed. 2007, 46, 8471.
r
10.1021/ol2012617
Published on Web 06/29/2011
2011 American Chemical Society

limited to compounds exhibiting multivalency such as syn-
diols,7 1,2,3- triols,8 pyridyl substituted alcohols,9 and
hydroxy ketones.10 Monofunctional alcohols have pro-
ven to be a difficult class of substrates because they
eliminate the possibility of two-point binding with
the catalyst, which is what the previous systems have
required to achieve good selectivity. The sole report of
an organocatalyzed silylation of monofunctional secondary
alcohols comes from the Ishikawa group but resulted in
low enantioselectivity.11
originally employed by Birman as an acylation catalyst,
gave the best selectivity factor12 of the catalysts studied,
whereas derivatives such as benzotetramisole (4)2f,13 and
(À)-p-bromotetramisole (5) showed less selectivity.14 In
the absence of catalyst, the background reaction was
minimal resulting in an 8% conversion after 45 h. By
comparison, the same substrate in the presence of 3 reaches
full conversion in less than an hour (Table 2, entry 1).
Nucleophilic tertiary amine catalysts such as cinchona
alkaloid based systems (6) or (À)-brucine (7) were not
found to be selective catalysts for this reaction.
Our choice of triphenylsilyl chloride proved important
in obtaining high selectivity and conversion in the kinetic
resolution. Alkyl substituted silyl groups such as triethyl-
silyl chloride (Table 1, entry 1) gave little selectivity
while the most sterically hindered silyl chlorides such as
t-butyldimethylsilyl chloride and triisopropylsilyl chloride
gave no observable conversion by 1H NMR (entries 5 and 6).
The silyl groups, which gave both practical conversion
and a higher selectivity factor, were those possessing
phenyl substituents (entries 2À4). We observed that the
selectivity increased when the silicon protecting group
contained more phenyl groups, with triphenylsilyl chloride
giving the highest selectivity factor of the silyl chlorides
screened.
Table 1. Effect of the Substituents on the Silyl Groupa
Figure 1. Catalyst screening for the silylation based kinetic
resolution of 1.15 Reactions were carried out at a substrate
concentration of 0.3 M on a 0.3 mmol scale.16 aReaction was
run with 0.6 equiv of Ph3SiÀCl, 0.6 equiv of iPr2EtN, and 25 mol
% 3 on a 0.5 mmol scale.
entry
“silyl”
conv (%)b
sb
1
Et3SiÀ
48
50
46
59
<5
<5
4.0
3.4
5.2
8.6
2
Me2PhSiÀ
Ph2MeSiÀ
Ph3SiÀ
3
4c
5d
6d
Our approach in silylation based kinetic resolutions of
alcohols employs a nucleophilic chiral catalyst to selec-
tively silylate one enantiomer over another. We investi-
gated a number of catalysts with different structural motifs
to see how this affected reactivity and selectivity (Figure 1).
The silylation reactions were run with 1-indanol (1) and
triphenylsilyl chloride (Ph3SiÀCl) to give enriched alcohol
and silylated product 2. It was discovered that the com-
mercially available chiral isothiourea (À)-tetramisole (3),2f
tBuMe2SiÀ
iPr3SiÀ
a Reactions were carried out at a substrate concentration of 0.3 M on
a 0.3 mmol scale. b See refs 15 and 16. c Reaction was run with 0.6 equiv
of Ph3SiÀCl, 0.6 equiv of iPr2EtN, and 25 mol % 3 on a 0.5 mmol scale.
d Conversion for this entry was determined via recovered starting
material after 48 h.
We also showed that solvent polarity plays a role in
reaction selectivity. Polar, coordinating solvents such as
THF gave the highest selectivity factor, while other sol-
vents such as dichloromethane and toluene resulted in
lower selectivity factors (s = 2.8 to 3.6). Diethyl ether
inhibited the formation of product, presumably through
(8) You, Z.; Hoveyda, A. H.; Snapper, M. L. Angew. Chem., Int. Ed.
2009, 48, 547.
(9) (a) Rendler, S.; Auer, G.; Oestreich, M. Angew. Chem., Int. Ed.
2005, 44, 7620. (b) Klare, H. F. T.; Oestreich, M. Angew. Chem., Int. Ed.
2007, 46, 9335. (c) Rendler, S.; Plefka, O.; Karatas, B.; Auer, G.;
€
€
Frohlich, R.; Muck-Lichtenfeld, C.; Grimme, S.; Oestreich, M.
Chem.;Eur. J. 2008, 14, 11512. (d) Karatas, B.; Rendler, S.; Frohlich,
R.; Oestreich, M. Org. Biomol. Chem. 2008, 6, 1435. (e) Weickgenannt,
A.; Mewald, M.; Muesmann, T. W. T.; Oestreich, M. Angew. Chem., Int.
Ed. 2010, 49, 2223.
(12) Selectivity factor (s) = (rate of fast reacting enantiomer)/(rate of
slow reacting enantiomer).
(10) Patel, S. G.; Wiskur, S. L. Tetrahedron Lett. 2009, 50, 1164.
(11) Isobe, T.; Fukuda, K.; Araki, Y.; Ishikawa, T. Chem. Commun.
2001, 243.
(13) Birman, V. B.; Guo, L. Org. Lett. 2006, 8, 4859.
(14) Molecular sieves were added to prevent the hydrolysis of
Ph3SiÀCl and help with reproducibility.
Org. Lett., Vol. 13, No. 15, 2011
3795

precipitation of the catalyst/Ph3SiÀCl intermediate. Selec-
tivity was achieved in DMF (s = 6.9 at À40 °C), which is
known to activate silicon for alcohol protection.4 The
origin of this selectivity is still under investigation.
Table 2. Substrate Scope of Silylation-Based Kinetic Resolution
(Reactions were carried out at a substrate concentration of
0.3 M on a 0.5 mmol scale)
Both chiral and achiral amine bases were examined to
determine the dependence of the selectivity of the reaction
upon the base. From these experiments, we determined
that non-nucleophilic, sterically hindered bases such as N,
N-diisopropyl-3-pentylamine (iPr2NCHEt2) gave the best
€
selectivity factors. Hunig’s base (iPr2EtN) offered little
difference in selectivity when used with substrate 1, but it
did give inferior results for several other substrates; there-
fore, the more sterically hindered iPr2NCHEt2 was used
for subsequent studies.
Our kinetic resolution of 1 is an impressive achieve-
ment, since 1 is historically one of the most challenging
alcohols to enrich via kinetic resolutions. While enzy-
matic processes (mainly lipases) have been successful
at resolving the two enantiomers of 1 with high
selectivity,17 chemists have had a more difficult time
achieving only moderate selectivities with small mole-
cule catalysts. The literature reports selectivity factors
for nonenzymatic acylation based kinetic resolutions
ranging between 2.5 and 6.18 To the best of our knowl-
edge, our selectivity factor of 8.6 with the triphenylsilyl
chloride reagent is the highest for the organocatalyzed
kinetic resolution of 1. Even under preparative scale
conditions, 1 was enriched with only a minor reduction
in the selectivity factor.19
The reaction conditions developed for the enantiose-
lective silylation of 1 also proved efficient at resolving
several other secondary bicyclic benzylic alcohols.20
There was an increase in selectivity when the substrate’s
alkyl side was expanded to a six member ring as in the
case of 1-tetralol (Table 2, entry 2), however when this
ring was further expanded to a seven member ring (entry 3),
a decrease in selectivity was observed. Expanding the
pi-system in entry 4 decreased the selectivity as well,
likely due to the five membered ring in the substrate
(15) Conversions and selectivity factors were calculated from the ee
of the product and the ee of the left over starting material. See ref 1a.
(16) Selectivity factors are an average of two runs. Conversion and er
correspond to a single run.
(17) (a) Bouzemi, N.; Debbeche, H.; Aribi-Zouioueche, L.; Fiaud,
J.-C. Tetrahedron Lett. 2004, 45, 627. (b) Bouzemi, N.; Aribi-Zouioueche,
L.; Fiaud, J.-C. Tetrahedron: Asymmetry 2006, 17, 797. (c) Wu, X.-M.; Xin,
J.-Y.; Sun, W.; Xia, C.-G. Chem. Biodiv. 2007, 4, 183. (d) Ou, L.; Ludwig,
D.; Pan, J.; Xu, J. H. Org. Process Res. Dev. 2008, 12, 192.
(18) (a) Clapham, B.; Cho, C.-W.; Janda, K. D. J. Org. Chem. 2001,
66, 868. (b) Spivey, A. C.; Leese, D. P.; Zhu, F.; Davey, S. G.; Jarvest,
R. L. Tetrahedron 2004, 60, 4513–455. (c) Shiigi, H.; Mori, H.; Tanaka,
T.; Demizu, Y.; Onomura, O. Tetrahedron Lett. 2008, 49, 5247.
(19) Kinetic resolution of 1.5 g of 1: s = 6.8 with 52% conversion and
recovered alcohol er was 81:19.
(20) Typical procedure: To an oven-dried 1-dram vial fitted with a
˚
stir bar and 4 A sieves were added, alcohol substrate (0.5 mmol), 3 (0.125
mmol) and dry THF (1.6 mL). The solution was then treated with
iPr2NCHEt2 (0.3 mmol) and stirred at À78 °C for 30À45 min. Once
cooled, Ph3SiÀCl (0.3 mmol, 0.357 M in THF) was added via syringe
and the resulting solution was left to stir at À78 °C. The reaction was
quenched with 250 μL MeOH, poured into saturated NH4Cl and
extracted with diethyl ether. The combined ethereal layers were dried
over silica gel, filtered, evaporated, and purified by column chromato-
graphy (1:1 hexanes:CH2Cl2 to 2% MeOH in CH2Cl2) to provide the
product and unreacted starting material.
a See ref 15 and 16. b Reaction performed with iPr2EtN. c Reaction
performed with 30 mol % catalyst.
3796
Org. Lett., Vol. 13, No. 15, 2011

having a more planar structure. However, when oxygen
or sulfur was included in the saturated ring (entries 5À6),
the reaction proceeded in a highly selective fashion.
When we changed the electronics of the aryl ring on tetralol
with either a methoxy or fluoro substituent (entry 7a and b)
only minor adjustments in the selectivity factor were
observed. The absolute stereochemistry of entry 7b was
confirmed by comparison of specific rotation of literature
versus experimental.21
large difference between their reactivities and selectivities is
seen. This suggests the presence of a narrow reaction pocket
that only unhindered cyclic alcohols can enter.
This work demonstrates that the silylation method is
amenable to difficult and biologically important sub-
strate targets. The results presented herein show pre-
viously unachieved levels of selectivity for monofunc-
tional bicyclic alcohols via silylation based kinetic
resolutions. Along with achieving selectivity factors of up
to 25, the reactions were carried out under mild conditions,
with a commercially available, low molecular weight cata-
lyst (3) and triphenylsilyl chloride, resulting in high conver-
sion with reaction times as short as one hour. We are
currently working to elucidate the mechanism of how our
chiral system distinguishes between the enantiomers. The
enantioselectivity in this reaction is currently believed to
originate from the known chiral propeller conformation of
triphenyl substituted silyl groups.22 Future endeavors will
involve the determination of the mechanism as well as
expanding the scope of substrates that can be resolved.
The reaction’s sensitivity to steric hindrance on the
saturated ring is shown in entries 8 and 9 when 4-chro-
manol was substituted with methyl groups in the 2 and 3
positions respectively. When the methyl groups are in
the 2 position (Table 2, entry 8), a lower selectivity factor
was achieved, while the methyl groups adjacent to the
alcohol prevent the reaction from proceeding at all (entry 9).
Overall, the alcohols discussed thus far required longer reac-
tion times respective to 1to achieve similarly high conversions,
however, the transformations requiring the longest reaction
times reached near total conversion in less than one day.
While the success with cyclic alcohols is impressive,
acyclic secondary alcohols have proven to be more diffi-
cult, resulting in poor selectivity and reaction times requir-
ing up to two days for complete conversion. Low to
moderate selectivity factors were obtained with 1-phenyl-
ethanol and 2-methyl-1-phenylpropanol (Table 2, entry 10
and 11) and even after 48 h, full conversion had not been
reached. Entry 12 (2,2-dimethyl-1-phenylpropanol) proved
to be too sterically hindered to react resulting in no obser-
vable conversion. These as well as the above examples show
the sensitivity of the system to the steric environment adja-
cent to the alcohol. The major structural difference between
1-phenylethanol and 1 is the ability of the phenyl group to
rotate, and presumably because of the large entropic cost, a
Acknowledgment. We gratefully acknowledge support
from the University of South Carolina and the National
Science Foundation CAREER Award CHE-1055616.
This paper is dedicated to the memory of Dr. Marc S.
Maynor (University of Texas at Austin).
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of 1H and 13C
NMR, and HPLC traces. This material is available free
of charge via the Internet at http://pubs.acs.org.
(22) (a) Aroney, M. J.; Le Fevre, R. J. W.; Ritchie, G. L. D.; Ross, V.
J. Chem. Soc. B 1966, 188. (b) Gust, D.; Mislow, K. J. Am. Chem. Soc.
1973, 95, 1535. (c) Mislow, K. Acc. Chem. Res. 1976, 9, 26. (d) Barbieri,
G. J. Organomet. Chem. 1979, 172, 285. (e) Allen, G. W.; Aroney, M. J.;
Hambley, T. W. J. Mol. Struct. 1990, 216, 227. (f) Shankar, R.; Joshi, A.;
Upreti, S. Polyhedron 2006, 25, 2183.
(21) Ohkuma, T.; Hattori, T.; Ooka, H.; Inoue, T.; Noyori, R. Org.
Lett. 2004, 6, 2681.
Org. Lett., Vol. 13, No. 15, 2011
3797