Silylation-based kinetic resolution of α-hydroxy lactones and lactams

Article abstract of DOI:10.1021/ol402982w

A silylation-based kinetic resolution has been developed for α-hydroxy lactones and lactams employing the chiral isothiourea catalyst (-)-benzotetramisole and triphenylsilyl chloride as the silyl source. The system is more selective for lactones than lactams, and selectivity factors up to 100 can be achieved utilizing commercially available reagents.

Full text of DOI:10.1021/ol402982w

ORGANIC
LETTERS
2013
Vol. 15, No. 24
6132–6135
Silylation-Based Kinetic Resolution of
r‑Hydroxy Lactones and Lactams
Robert W. Clark, T. Maxwell Deaton, Yan Zhang, Maggie I. Moore, and
Sheryl L. Wiskur*
The University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208,
United States
wiskur@mailbox.sc.edu
Received October 16, 2013
ABSTRACT
A silylation-based kinetic resolution has been developed for R-hydroxy lactones and lactams employing the chiral isothiourea catalyst (À)-
benzotetramisole and triphenylsilyl chloride as the silyl source. The system is more selective for lactones than lactams, and selectivity factors up
to 100 can be achieved utilizing commercially available reagents.
Enantiomerically pure R-hydroxy lactones and lactams
are highly desirable chiral building blocks for the synthesis
of biologically active compounds1 and natural products2
and have been used as chiral auxiliaries in a variety of
reactions.3 While a number of asymmetric synthetic meth-
ods3,4 have been developed to produce these compounds,
including enzymatic kinetic resolutions,5 until recently
there has been very little work with nonenzymatic kinetic
resolutions of these substrates. Currently, there are two
examples of nonenzymatic kinetic resolutions of lactones
which include a Cu-catalyzed carbamoylation6 and an
isothiourea-catalyzed acylation.7 However, to the best
of our knowledge, a successful nonenzymatic resolution
of R-hydroxy lactams remains unreported. Herein, we
describe the expansion of the substrates employed in
silylation-based kinetic resolutions to include R-hydroxy
lactones and lactams, as well as a few amides and esters.
The method employs commercially available reagents
to resolve a variety of synthetically useful substrates and
achieves selectivity factors8 up to 100.
The use of silicon in asymmetric reactions is an emerging
field. Until recently, the use of silicon based reagents
for the production of chiral secondary alcohols has been
limited to asymmetric hydrosilylation of a prochiral
ketone.9 An alternate and powerful method to produce en-
antioenriched secondary alcohols is the kinetic resolution
(1) (a) Winterbottom, R.; Clapp, J. W.; Miller, W. H.; English, J. P.;
Roblin, R. O. J. Am. Chem. Soc. 1947, 69, 1393. (b) King, T. E.; Stewart,
C. J.; Cheldelin, V. H. J. Am. Chem. Soc. 1953, 75, 1290. (c) Dolle, R. E.;
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Commun. 1992, 368.
(8) Selectivity factor (s) = (rate of the fast reacting enantiomer)/(rate
of slow reacting enantiomer).
(3) Camps, P.; Munoz-Terrero, D. Curr. Org. Chem. 2004, 8, 1339.
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O.; Mostefaı, N.; Courmarcel, J. Synthesis 2004, 2943. (c) Arena, C. G. Mini
Rev. Org. Chem. 2009, 6, 159.
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Chem. 2010, 8, 1497.
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hedron: Asymmetry 1995, 6, 985. (b) Baumann, M.; Hauer, B. H.;
Bornscheuer, U. T. Tetrahedron: Asymmetry 2000, 11, 4781.
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Tachikawa, H.; Ohkuma, T. Chem.;Asian J. 2008, 3, 1289.
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2013, 15, 1170.
r
10.1021/ol402982w
Published on Web 12/03/2013
2013 American Chemical Society

of racemic alcohols,10 but relatively few examples of
silylation-based kinetic resolutions have been explored,11
despite the many synthetic advantages (tunable reactivity,
ease of protection, and selective deprotection).12 The
substrates that have been targeted with enantioselective
silylation thus far include diols,13 1,2,3-triols,14 pyridyl
substituted alcohols,15 simple alcohols,16 and β-hydroxy
esters.17 Recently, we reported a synthetically useful silyla-
tion-based kinetic resolution of secondary cyclic alcohols
(Scheme 1).18 This methodology utilizes the chiral iso-
thiourea (À)-tetramisole (1) as a chiral Lewis base to acti-
vate triphenylsilyl chloride.19 Moderate to high selectivity
factors (s up to 25) were obtained for a variety of mono-
functional, cyclic, secondary alcohols. Unfortunately,
when acyclic secondary alcohols, such as 1-phenylethanol,
were attempted nearly all selectivity was lost.
€
diisopropyl-3-pentyl amine to Hunig’s base because of the
limited availability of the former. When catalysts 1 and
(À)-benzotetramisole 227 were tested, little to no conver-
sion was observed (Table 1, entries 1 and 2). When the
reaction was warmed from À78 to À40 °C using 2 as the
catalyst, only minor amounts of product formed, but some
selectivity was achieved (Table 1, entry 3). Utilizing cata-
lyst 2, the concentration was almost tripled which led to an
increase in conversion to ∼40% and an impressive selec-
tivity factor of 28 (Table 1, entry 4). In an attempt to
increase the conversion further, the catalyst loading was
increased to 25 mol %, resulting in a slight increase in
conversion to 52% and a selectivity factor of 36 (Table 1,
entry 6). When catalyst 1 was applied under the exact same
conditions there was little conversion (Table 1, entry 5);
thus, catalyst 2 was chosen for subsequent studies.
An investigation into the effect of different silyl groups,
solvents, and bases revealedthat the previously determined
conditions were still the optimum choice (triphenylsilyl
Scheme 1. Reaction Conditions for Silylation-Based
Resolutions of Cyclic 2° Benzylic Alcohols
21
€
chloride, THF, and Hunig’s base). As was seen in our
previous paper, the phenyl groups on the silyl chloride play
a critical role in affecting the selectivity of the reaction.
When silyl chlorides were employed that contained fewer
or no phenyl groups, the selectivity of the reaction dra-
matically decreased. Solvents such as dichloromethane,
toluene, or DME provided high conversions, but selectiv-
ity factors were significantly decreased (s = 7, 10, and 5,
respectively). Other bases that were investigated, such as
triethylamine, triisobutylamine, and tribenzylamine, re-
sulted in a decrease in product formation as well as a
slight decrease in selectivity. Employing the optimal con-
ditions on a preparative scale kinetic resolution of 3
showed similar results to the smaller scale runs.22
In order to expand the substrate scope of our silylation-
based kinetic resolution, we concluded that a successful
substrate class would possess many of the same topologies
as cyclic benzylic alcohols (Scheme 1): a relatively planar
substrate with a π-system adjacent to the alcohol. We
hypothesized R-hydroxy lactones or lactams could be
amenable to resolution based on the position of the
carbonyl and inherent conformational rigidity.
Table 1. Reaction Optimization Conditions for Pantolactone
Initially, reaction conditions were developed using
commercially available pantolactone 3 as the model sub-
strate. Conditions similar to our previous work were em-
ployed, with the exception of a change in the base from
entry
catalyst (equiv)
concn [M]a
% convb
sb
(12) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, USA, 1999.
(13) (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. (c) Sun, X.;
Worthy, A. D.; Tan, K. L. Angew. Chem., Int. Ed. 2011, 50, 8167.
(14) You, Z.; Hoveyda, A. H.; Snapper, M. L. Angew. Chem., Int. Ed.
2009, 48, 547.
1
2
3c
4
5
6
1 (0.2)
2 (0.2)
2 (0.2)
2 (0.2)
1 (0.25)
2 (0.25)
0.16
0.16
0.16
0.42
0.42
0.42
<5%
<5%
9%
À
À
18
28
À
41%
6%
52%
36
(15) (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.;
a Concentration with respect to substrate. b See ref 20. c Reaction was
run at À40 °C for 19 h.
€
€
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.
(16) Isobe, T.; Fukuda, K.; Araki, Y.; Ishikawa, T. Chem. Commun.
(20) (a) Conversions and selectivity factors are based on the ee of the
recovered starting materials and products. See ref 10a. (b) Selectivity
factors are an average of two runs. Conversions are from a single run.
(21) See Supporting Information.
2001, 243.
(17) Patel, S. G.; Wiskur, S. L. Tetrahedron Lett. 2009, 50, 1164.
(18) Sheppard, C. I.; Taylor, J. L.; Wiskur, S. L. Org. Lett. 2011, 13,
3794.
(22) (a) Molecular sieves were added to prevent hydrolysis of Ph3SiCl
and aid in reproducibility. (b) Kinetic resolution of 1.04 g of 3: s = 28
with 50% conversion and recovered alcohol with an er of 92:8.
(19) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1560.
Org. Lett., Vol. 15, No. 24, 2013
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Table 2. Substrate Scope of the Silylation-Based Kinetic
Resolution of R-Hydroxy Lactones
Table 3. Scope of the Silylation-Based Kinetic Resolution
of R-Hydroxy Lactams
a See ref 20. b Conversion determined by 1H NMR. c Reaction
performed with 0.75 equiv of Ph3SiCl and iPr2NEt.
a See ref 20. b Conversion determined by 1H NMR.
With the optimized reaction conditions obtained from
the resolution of 3, the substrate scope was explored. When
R-hydroxy-γ-butyrolactone (Table 2, entry 1) was re-
solved, a decrease in selectivity was observed presumably
due to a decrease in steric bulk at the β-position. Inorder to
test this hypothesis, a variety of lactones possessing steri-
cally hindered groups in the β-position were synthesized.23
As predicted, changing the β,β-dimethyl group in 3 to a
β,β-diethyl group resulted in a dramatic increase in selec-
tivity to an s of 100 (Table 2, entry 3). This result is the
highest selectivity factor obtained to date for the triphenyl
silylation-based kinetic resolution of secondary alcohols.18
Spiro cyclic lactones (Table 2, entries 4 and 5) were also
resolved with a high degree of selectivity. The cyclohexane
substituted spiro lactone (Table 2, entry 5) was more
selective than the cyclopentane substituted one (Table 2,
entry 4), presumably due to the increased sterics of the
six-membered ring. A fused bicyclic lactone was also ex-
plored with moderate selectivity (Table 2, entry 6). Inter-
estingly, when the lactone was substituted in the γ-position
with sterically large phenyl groups (Table 2, entry 7) nearly
all selectivity was lost. Finally, when the β,β-disubstituted
lactone ring was expanded from a five- to a six-membered
ring (Table 2, entry 8), the substrate became too sterically
hindered and no conversion was obtained. Unfortunately,
the corresponding unsubstituted six-membered ring lac-
tone decomposed under the reaction conditions and there-
fore could not be examined.
Next, R-hydroxy lactams were examined. These N-aryl
substituted lactams were prepared in one step from the
corresponding lactone and an aryl amine.24 The lactams
were universally less selective than their lactone counter-
parts. Unfortunately, complete loss of enantioselectivity
was observed for the N-phenyl lactam with no substituents
~
(24) Barrios, I.; Camps, P.; Comes-Franchini, M.; Munoz-Torrero,
(23) Hata, H.; Morishita, T.; Akutsu, S.; Kawamura, M. Synthesis
1991, 289.
ꢀ
D.; Ricci, A.; Sanchez, L. Tetrahedron 2003, 59, 1971.
6134
Org. Lett., Vol. 15, No. 24, 2013

Substituents in the β-position are advantageous to selec-
tivity, whereas sterics in the γ-position are detrimental.
The N-aryl group25 seems to alter the selectivity of the
reaction resulting in a decrease in enantio-discrimination
as compared to the lactone counterparts. Presumably, this
is the result of a change in sterics on the substrates due
to the phenyl group rotating out of the lactam plane to
form a carbonylÀπ interaction.25b The interaction would
be more pronounced with the bromo substituted phenyl
group, resulting in the low selectivity observed.
Table 4. Scope of the Silylation Kinetic Resolution of Amides
and Esters
Acyclic esters and amides were also explored employing
the standard reaction conditions developed (Table 4). Pre-
viously, acyclic substrates, such as 1-phenylethanol, were
slow to silylate and displayed no enantio-discrimination.18
The N-phenyl amides and O-phenyl and O-benzyl ester in
Table 4 did show a small amount of selectivity with decent
conversions. The small improvement of the amides over
previous acyclic substrates is presumably due to the high
energy barrier of rotation around the NÀC bond provid-
ing some degree of planarity.26 The amides showed no
sensitivity to substituents next to the alcohol (Table 4,
entries 1À3), but wereslightly moreselectivethantheesters
(Table 4, entries 4 and 5). This is probably the result of the
increased barrier of rotation for the amides vs the esters.
In conclusion, silylation-based kinetic resolutions have
beenexpandedtoinclude synthetically valuable R-hydroxy
carbonyl compounds employing an isothiourea catalyst
and commercially available reagents. This is one of the few
nonenzymatic kinetic resolutions of R-hydroxy lactones
and the first nonenzymatic kinetic resolution of R-hydroxy
lactams. Selectivity factors up to 100 were obtained by
including sterics adjacent to the alcohol, and spiro contain-
ing lactones and lactams were efficiently resolved under
these conditions. It was discovered that sterics elsewhere
on the ring proved detrimental, and acyclic amides and
esters were tolerated in this system with limited selectivity.
Further studies to elucidate the mechanism, including a
linear free energy relationship and computational studies,
are currently underway in our laboratory.
a See ref 20.
in the β-position (Table 3, entry 1). Even though amides
are known to catalyze silylation reactions,12 no product
was detected when the reaction was run with the same
unsubstituted substrate in the absence of catalyst 2. This
shows that the lack of selectivity is not due to an uncon-
trolled background reaction.
Similar to the lactones, increasing sterics in the β-position
of the lactams increased the selectivity. As the substituents
werechanged from methyltoethyltoa six-memberedspiro
ring (Table 3, entries 2, 6, and 7), the selectivity factors
increased from 14 to 20 to 24 respectively. However, the
reactions became sluggish as the sterics increased in the
β-position; therefore, more equivalents of silyl chloride
and base were employed to force higher conversions
(Table 3, entry 7). The effect of electronics on the N-aryl
group was investigated by substituting electron-donating
(methyl, methoxy) and an electron-withdrawing group
(bromo) in the para position (Table 3, entries 3À5). Sur-
prisingly, a decrease in selectivity was observed for both
electron-withdrawing and -donating substituents. The se-
lectivity factor for electron-donating groups dropped by a
factor of 2, while electron-withdrawing groups decreased
the selectivity factor even further (s = 7.1, 6.8, and 3.3,
respectively).
Acknowledgment. We gratefully acknowledge support
from the University of South Carolina and the National
Science Foundation CAREER Award CHE-1055616. We
would also like to thank Oakwood Chemicals for supply-
ing some compounds.
Note Added after ASAP Publication. Reference 27 was
added December 12, 2013.
Supporting Information Available. Experimental pro-
cedures, characterization data, NMR spectra, and HPLC
traces. This material is available free of charge via the
Internet at http://pubs.acs.org.
As shown in Table 2 (entry 3 vs 7), the reaction
is sensitive to the position of sterics on the substrates.
(25) (a) Manhas, M. S.; Jeng, S.; Bose, A. K. Tetrahedron 1968, 24,
1237. (b) Gautrot, J. E.; Hodge, P.; Cupertino, D.; Helliwell, M. New J.
Chem. 2006, 30, 1801.
(27) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351.
(26) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic
Chemistry; University Science Books: Sausalito, CA, 2006.
The authors declare no competing financial interest.
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