Diastereoselective and Enantioselective Silylation of 2-Arylcyclohexanols

Article abstract of DOI:10.1021/acs.orglett.5b00919

The silylation-based kinetic resolution of trans 2-arylcyclohexanols was accomplished by employing a triaryl silyl chloride as the derivatizing reagent with a commercially available isothiourea catalyst. The methodology is selective for the trans diastereomer over the cis, which provides an opportunity to selectively derivatize one stereoisomer out of a mixture of four. By employing this technology, a facile, convenient method to form a highly enantiomerically enriched silylated alcohol was accomplished through a one-pot reduction-silylation sequence that started with a 2-aryl-substituted ketone.

Full text of DOI:10.1021/acs.orglett.5b00919

Letter
pubs.acs.org/OrgLett
Diastereoselective and Enantioselective Silylation of
2‑Arylcyclohexanols
Li Wang, Ravish K. Akhani, and Sheryl L. Wiskur*
The University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, United States
S
* Supporting Information
ABSTRACT: The silylation-based kinetic resolution of trans 2-arylcyclohexanols was accomplished by employing a triaryl silyl
chloride as the derivatizing reagent with a commercially available isothiourea catalyst. The methodology is selective for the trans
diastereomer over the cis, which provides an opportunity to selectively derivatize one stereoisomer out of a mixture of four. By
employing this technology, a facile, convenient method to form a highly enantiomerically enriched silylated alcohol was
accomplished through a one-pot reduction−silylation sequence that started with a 2-aryl-substituted ketone.
Scheme 1. Previous Silylation-Based Kinetic Resolutions
Performed by Our Group
he formation of enantiopure secondary alcohols is an
important endeavor due to their prevalence in the synthetic
T
community as building blocks. Specifically, enantiomerically pure
2-arylcyclohexanols are widely used as chiral auxiliaries in a
variety of asymmetric reactions.1 While these compounds can be
synthesized asymmetrically,2 a viable economical approach is to
enrich them through kinetic resolutions:3 enzymatically4 or
nonenzymatically.5 The nonenzymatic, small molecule approach
usually offers the advantage of facile access to both enantiomers
of the resolution catalyst. Even though a number of these
methods are highly selective toward resolving 2-arylcyclohex-
anols, many of them are selective for or react with both
diastereomers of the alcohol, cis and trans.5a,d,g,k−m Two common
methods to form these alcohols are through nucleophilic opening
of epoxides and reduction of 2-arylcyclohexanones.6 While trans-
substituted 2-arylcyclohexanols are selectively formed from the
epoxide opening, the ketone reduction generates a mixture of
diastereomers. When the reduction method is used, this means
additional purification steps are needed to separate the
diastereomers before the kinetic resolution can be performed.
Herein we report the selective silylation-based kinetic resolution
of trans-2-arylcyclohexanols, with selectivity factors up to the 50s
employing a commercially available catalyst. The method is
selective for the trans compound over the cis and can selectively
resolve the trans-substituted compound out of a mixture of
diastereomers (cis and trans) in order to isolate the silylated
product in excellent enantiomeric ratios.
isothiourea catalyst tetramisole (1) or benzotetramisole (2) first
reported by Birman12 and triphenylsilyl chloride (3a) as the silyl
source for the selective silylation of one enantiomer over another.
The kinetic resolution of trans 2-phenylcyclohexanol (4) was
attempted using conditions similar to those in Scheme 1. When
catalyst 1 was employed, very little selectivity was obtained
(Table 1, entry 1), but changing the catalyst to 2 improved the
selectivity factor to 6 (Table 1, entry 2). We have previously
noted that the choice of silyl group can dramatically affect the
selectivity of the kinetic resolution, with three phenyl groups on
silicon being particularly important.10 Most recently, we
discovered that electron-donating alkyl groups in the para
position of the phenyl groups on triphenylsilyl chloride resulted
in improved selectivity.13 When tris(4-isopropylphenyl)silyl
chloride (3b) was investigated, an improvement in selectivity
was again observed (Table 1, entry 3) with an increase in silyl
chloride equivalents and reaction time to improve conversion.
Silylation-based kinetic resolutions have been growing in
interest over the last 10 years,7 with a variety of substrates being
resolved through either nucleophilic activation of silyl chlorides8
or dehydrogenative silylation.9 Regarding the silyl chloride
activation method, our group has developed a silylation-based
kinetic resolution for the enrichment of cyclic secondary
alcohols10 and α-hydroxy lactones and lactams11 with selectivity
factors up to 100 (Scheme 1). The method employs either the
Received: March 30, 2015
Published: May 7, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00919
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Organic Letters
Letter
Table 1. Optimization of Catalyst and Silyl Chloride for the
Silylation-Based Kinetic Resolution of 2-Phenylcyclohexanol
Table 2. Substrate Scope of the Silylation-Based Kinetic
Resolution of trans-2-Arylcyclohexanols
b
R3SiCl
(equiv)
time
(h)
conv
(%)
a
b
entry catalyst
3, R
3a, Ph
s
1
2
3
4
1
2
2
2
0.6
24
24
48
72
52
59
51
2
6
3a, Ph
0.6
3b, p-i-Pr-Ph
3c, p-t-Bu-Ph
0.65
0.65
10
d
c
<5
a
Reactions were run at a concentration of 0.42 M with respect to
b
c
alcohol. See ref 15. Conversion was determined by 1H NMR.
d
Reactions were run at a concentration of 0.28 M with respect to
alcohol.
Interestingly, the previously more selective, sterically hindered
tris(4-tert-butylphenyl)silyl chloride (3c) was unreactive under
the reaction conditions (Table 1, entry 4), even with increased
reaction time relative to that used for entry 3 in Table 1. In the
absence of catalyst there is no background reaction after 24 h,
even when the less sterically hindered silyl chloride 3a is used.
With this information in hand, kinetic resolutions were
performed on a number of trans-2-arylcyclohexanol substrates
employing the more selective isopropyl-substituted silyl chloride
(Table 2). When the aryl group of the alcohol was substituted
with a methoxy, the selectivity generally improved compared to
just a phenyl (Table 2, entry 2−4 vs entry 1), but the selectivity
was dependent on the position of the methoxy on the aryl group
(ortho, meta, or para). The ortho-substituted compound (Table
2, entry 2) had a lower conversion probably due to the increased
steric effect, with a modest selectivity factor of 13. The m- (6) and
p-methoxy-substituted compounds (Table 2, entries 3 and 4)
had excellent selectivity factors of 53 and 28, respectively. The m-
fluoro-substituted aryl compound had significantly higher
selectivity over just a phenyl group (Table 2, entry 5 vs entry
1), but when an electron-donating m-methyl-substituted aryl
group was employed, it was only modestly more selective than a
phenyl group (Table 2, entry 6, s = 14). The aryl π system proved
to be important for selectivity, as shown by the very small
selectivity factor of the saturated cyclohexyl-substituted substrate
(Table 2, entry 7). The increased π surface area of a 1-naphthyl
aryl group proved too bulky, with only modest conversion (11%)
and selectivity (Table 2, entry 8). Cyclohexanol rings are needed
for selectivity, as shown by the inability of the method to resolve
2-phenylcyclopentanol (Table 2, entry 9). The importance of the
isopropyl-substituted silyl chloride for maintaining high
selectivity was demonstrated when the m-methoxy-substituted
compound 6 was resolved with triphenylsilyl chloride (3a),
resulting in a much lower selectivity factor (s = 13, conv = 45%)
as compared to entry 3 in Table 2 (s = 53). Finally, the
methodology can be scaled up to gram scale without any loss in
selectivity,14 and the silyl ether product 5b was efficiently
desilylated with fluoride to obtain the alcohol in 86% yield.
As for cis 2-arylcyclohexanols, those substrates failed to even
silylate under the kinetic resolution reaction conditions. Both the
phenyl and m-methoxyphenyl cis-substituted compounds (7 and
8, respectively) were employed, but no conversion was observed
(Scheme 2). This is likely attributed to the position of the alcohol
in the cyclohexane chair conformation, axial versus equatorial.
a
Reactions were run for 48 h at a concentration of 0.42 M with respect
b
to alcohol on a 0.4 mmol scale. See ref 15.
Employing A values, it is simple to figure out the lowest energy
conformation of cis- and trans-2-phenylcyclohexanols 4 and 7
and the percentage of each compound found at that
conformation. Due to the larger A value of a phenyl substituent
over an alcohol (2.8 and 0.95 kcal/mol, respectively),16 the
phenyl group controls the overall conformation of 4 and 7 by
placing the phenyl group in the lower energy equatorial position
(Scheme 2). This results in >99% of 4 in the conformation where
the alcohol is equatorial and 99% of 7 where the alcohol is axial at
−78 °C. The position of the alcohol, axial versus equatorial,
seems to dictate the reactivity of the alcohol toward silylation in
this methodology. This is further validated by employing cis- and
trans-4-tert-butylcyclohexanols (Scheme 2). These compounds
lack any substituents in the 2-position, eliminating any effect the
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Organic Letters
Letter
Scheme 2. Substrate Reactivity toward Silylation Based on the
OH Conformation (Axial vs Equatorial) and the Population
of That Conformation at −78 °C
Scheme 3. One-Pot, Chromatography-Free Reduction
Followed by a Kinetic Resolution To Selectively Silylate One
Stereoisomer out of a Mixture of Four
further purification. In order to obtain the product with a high
enantiomeric ratio, the reaction needed to be stopped before full
conversion was achieved, which was accomplished through
limiting the amount of silyl chloride added (0.45 equiv). The
resulting one-pot process maintained the selectivity of previous
kinetic resolution runs (s = 50), and the resulting silylated
product (−)-11 was obtained with a high enantiomeric ratio of
97:3. This provides a valuable tool for the facile formation and
separation of 2-substituted cyclohexanol diastereomers from the
starting ketone by eliminating the need for a workup or
chromatography between reactions.
In conclusion, we have developed a procedure to effectively
resolve trans-2-arylcyclohexanols via a kinetic resolution employ-
ing a silylation methodology. The system obtains high selectivity
when the aryl group is derivatized with a fluoro or a methoxy
substituent. Compared to other methods, ours has the advantage
of selectively resolving the trans enantiomer from a mixture of the
cis/trans diastereomers. This affords the opportunity to
selectively remove one compound from a mixture of four
stereoisomers. Because of this cis/trans selectivity, we were able
to determine that the alcohol needs to be in the equatorial
position to be silylated, with alcohols locked in the axial position
being completely unreactive. We are currently performing
studies to help elucidate the mechanism of this reaction.
a
1
Conversion determined via H NMR.
phenyl group of cis-2-phenylcyclohexanol may have played. Since
the A value of a tert-butyl group is 4.7 kcal/mol,16 at low
temperatures these compounds have a nearly quantitative bias
toward one conformation (>99.99%) with the hydroxyl group in
either the axial (cis) or equatorial (trans) position. This reduces
the possibility of the Curtin−Hammett principle playing a role by
eliminating the presence of one conformation. When the
compound was subjected to the same reaction conditions as
above, again the hydroxyl group in the equatorial position
becomes silylated and the hydroxyl group in the axial position is
unreactive toward silylation.
The reactivity of other cis-2-substituted cyclohexanols toward
silylation can be determined by again employing A values to
calculate the population of the two main chair conformations.
Substituents with small A values result in the presence of both
conformations, with the alcohol in both the axial and the more
reactive equatorial position. The methyl group has an A value of
1.74 kcal/mol, resulting in cis-2-methylcyclohexanol (9) having
approximately a 12% population of the conformation with the
alcohol equatorial and 88% of the methyl axial (at −78 °C)
(Scheme 2). As expected, there was significant conversion (54%)
of 9 to the silylated ether due to the increased concentration of
the more reactive conformation. Even though the substrate could
be silylated, the methodology was not selective for this substrate
(s = 1.4).
The selectivity of trans compounds being reactive and cis
compounds being completely unreactive provides the oppor-
tunity to selectively resolve trans enantiomers in the presence of
cis enantiomers. This allows for one compound to be silylated
selectively over the three other stereoisomers (Scheme 3).
Additionally, we wanted to start with a ketone in a one-pot
reduction−silylation procedure. The reduction can be accom-
plished through an ammonia−borane ketone reduction in
methanol.17 This reduction is essentially traceless after the
removal of solvents, due to the volatility of the B(OMe)3
byproduct. Therefore, after the reduction of 2-(3-methoxy-
phenyl)cyclohexanone, the solvent was removed, and the
mixture of trans and cis alcohols 6 and 8 (dr = 2.5:1) was
subjected to the kinetic resolution without chromatography or
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, NMR spectra,
and HPLC traces. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b00919.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wiskur@mailbox.sc.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the University of South
Carolina and the National Science Foundation CAREER Award
CHE-1055616.
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Letter
(12) (a) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351. (b) Birman has
demonstrated recoverability and stability of 2: Bumbu, V. D.; Birman, V.
B. J. Am. Chem. Soc. 2011, 133, 13902.
(13) Akhani, R. K.; Moore, M. I.; Pribyl, J. G.; Wiskur, S. L. J. Org.
Chem. 2014, 79, 2384.
(14) Kinetic resolution of 998 mg of the compound in Table 2, entry 1:
s = 10 with 52% conversion and recovered alcohol with an er of 85:15.
(15) (a) Conversions and selectivity factors are based on the ee of the
recovered starting materials and products. Percent conversion = ees/(ees
+ eep) × 100% and s = ln[(1 − C)(1 − ees)]/ln[(1 − C)(1 + ees)], where
ees = ee of recovered starting material and eep = ee of product. See ref 3a..
(b) Selectivity factors are an average of two runs. Conversions are from
a single run.
REFERENCES
■
(1) (a) Brown, H. C.; Cho, B. T.; Park, W. S. J. Org. Chem. 1988, 53,
1231. (b) Whitesell, J. K. Chem. Rev. 1992, 92, 953.
(2) For representative examples, see: (a) Brown, H. C.; Vara Prasad, J.
V. N.; Gupta, A. K.; Bakshi, R. K. J. Org. Chem. 1987, 52, 310.
(b) Gonzalez, J.; Aurigemma, C.; Truesdale, L. Org. Synth. 2002, 79, 93.
(c) Alexakis, A.; Tomassini, A.; Leconte, S. Tetrahedron 2004, 60, 9479.
(d) Vrancken, E.; Alexakis, A.; Mangeney, P. Eur. J. Org. Chem. 2005,
1354. (e) Cho, B. T.; Shin, S. H. Bull. Korean Chem. Soc. 2006, 27, 1283.
(3) (a) Kagan, H. B.; Fiaud, J. C. In Topics in Stereochemistry; Ernest, L.,
Wilen, S. H., Eds.; John Wiley and Sons: New York, 1988; Vol. 18, p 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: Asymmetry
2003, 14, 1407. (d) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44,
3974. (e) Pellissier, H. Adv. Synth. Catal. 2011, 353, 1613.
(16) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
John Wiley & Sons, Inc.: New York, 1994.
(17) Yang, X.; Fox, T.; Berke, H. Tetrahedron 2011, 67, 7121.
(4) (a) Whitesell, J. K.; Chen, H.-H.; Lawrence, R. M. J. Org. Chem.
1985, 50, 4663. (b) Laumen, K.; Seemayer, R.; Schneider, M. P. J. Chem.
Soc., Chem. Commun. 1990, 49. (c) Schwartz, A.; Madan, P.; Whitesell, J.
K.; Lawrence, R. M. Org. Synth. 1990, 69, 1. (d) Basavaiah, D.; Rao, P. D.
Tetrahedron: Asymmetry 1994, 5, 223.
(5) (a) Oriyama, T.; Hori, Y.; lmai, K.; Sasaki, R. Tetrahedron Lett.
1996, 37, 8543. (b) Sano, T.; Imai, K.; Ohashi, K.; Oriyama, T. Chem.
Lett. 1999, 265. (c) Sekar, G.; Nishiyama, H. J. Am. Chem. Soc. 2001, 123,
3603. (d) Miyake, Y.; Iwata, T.; Chung, K.-G.; Nishibayashi, Y.; Uemura,
S. Chem. Commun. 2001, 2584. (e) Copeland, G. T.; Miller, S. J. J. Am.
Chem. Soc. 2001, 123, 6496. (f) Jeong, K.-S.; Kim, S.-H.; Park, H.-J.;
Chang, K.-J.; Kim, K. S. Chem. Lett. 2002, 1114. (g) Matsugi, M.;
Hagimoto, Y.; Nojima, M.; Kita, Y. Org. Process Res. Dev. 2003, 7, 583.
(h) Spivey, A. C.; Zhu, F.; Mitchell, M. B.; Davey, S. G.; Jarvest, R. L. J.
́
́
Org. Chem. 2003, 68, 7379. (i) Dalaigh, C. O.; Hynes, S. J.; O’Brien, J. E.;
McCabe, T.; Maher, D. J.; Watsonb, G. W.; Connon, S. J. Org. Biomol.
Chem. 2006, 4. (j) Ebner, D. C.; Trend, R. M.; Genet, C.; McGrath, M.
J.; O’Brien, P.; Stoltz, B. M. Angew. Chem., Int. Ed. 2008, 47, 6367.
(k) Birman, V. B.; Li, X. Org. Lett. 2008, 10, 1115. (l) Tomizawa, M.;
Shibuya, M.; Iwabuchi, Y. Org. Lett. 2009, 11, 1829. (m) Harada, S.;
Kuwano, S.; Yamaoka, Y.; Yamada, K.-i.; Takasu, K. Angew. Chem., Int.
Ed. 2013, 52, 10227.
(6) (a) Huynh, C.; Derguini-Boumechal, F.; Linstrumelle, G.
Tetrahedron Lett. 1979, 20, 1503. (b) Schwartz, A.; Madan, P.;
Whitesell, J. K.; Lawrence, R. M. Org. Synth. 1990, 69, 1. (c) Cho, B.
T.; Kang, S. K.; Kim, M. S.; Ryub, S. R.; An, D. K. Tetrahedron 2006, 62,
8164.
(7) (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.
(8) (a) Isobe, T.; Fukuda, K.; Araki, Y.; Ishikawa, T. Chem. Commun.
2001, 243. (b) Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L.
Nature 2006, 443, 67. (c) Zhao, Y.; Mitra, A. W.; Hoveyda, A. H.;
Snapper, M. L. Angew. Chem., Int. Ed. 2007, 46, 8471. (d) You, Z.;
Hoveyda, A. H.; Snapper, M. L. Angew. Chem., Int. Ed. 2009, 48, 547.
(e) Rodrigo, J. M.; Zhao, Y.; Hoveyda, A. H.; Snapper, M. L. Org. Lett.
2011, 13, 3778. (f) Sun, X.; Worthy, A. D.; Tan, K. L. Angew. Chem., Int.
Ed. 2011, 50, 8167. (g) Worthy, A. D.; Sun, X.; Tan, K. L. J. Am. Chem.
Soc. 2012, 134, 7321. (h) Giustra, Z. X.; Tan, K. L. Chem. Commun.
2013, 49, 4370. (i) Manville, N.; Alite, H.; Haeffner, F.; Hoveyda, A. H.;
Snapper, M. L. Nat. Chem. 2013, 5, 768. (j) Sun, X.; Worthy, A. D.; Tan,
K. L. J. Org. Chem. 2013, 78, 10494.
(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) Weickgenannt, A.; Mewald, M.; Muesmann, T. W. T.;
Oestreich, M. Angew. Chem., Int. Ed. 2010, 49, 2223.
(10) Sheppard, C. I.; Taylor, J. L.; Wiskur, S. L. Org. Lett. 2011, 13,
3794.
(11) Clark, R. W.; Deaton, T. M.; Zhang, Y.; Moore, M. I.; Wiskur, S. L.
Org. Lett. 2013, 15, 6132.
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