Nonenzymatic dynamic kinetic resolution of secondary alcohols via enantioselective acylation: Synthetic and mechanistic studies

Article abstract of DOI:10.1021/ja307425g

Because of the ubiquity of the secondary carbinol subunit, the development of new methods for its enantioselective synthesis remains an important ongoing challenge. In this report, we describe the first nonenzymatic method for the dynamic kinetic resolution (DKR) of secondary alcohols (specifically, aryl alkyl carbinols) through enantioselective acylation, and we substantially expand the scope of this approach, vis-a-vis enzymatic reactions. Simply combining an effective process for the kinetic resolution of alcohols with an active catalyst for the racemization of alcohols did not lead to DKR, due to the incompatibility of the ruthenium-based racemization catalyst with the acylating agent (Ac₂O) used in the kinetic resolution. A mechanistic investigation revealed that the ruthenium catalyst is deactivated through the formation of a stable ruthenium-acetate complex; this deleterious pathway was circumvented through the appropriate choice of acylating agent (an acyl carbonate). Mechanistic studies of this new process point to reversible N-acylation of the nucleophilic catalyst, acyl transfer from the catalyst to the alcohol as the rate-determining step, and carbonate anion serving as the Bronsted base in that acyl-transfer step.

Full text of DOI:10.1021/ja307425g

Article
pubs.acs.org/JACS
Nonenzymatic Dynamic Kinetic Resolution of Secondary Alcohols via
Enantioselective Acylation: Synthetic and Mechanistic Studies
Sarah Yunmi Lee,†,‡ Jaclyn M. Murphy,† Atsushi Ukai,† and Gregory C. Fu*,†,‡
†Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
‡Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: Because of the ubiquity of the secondary
carbinol subunit, the development of new methods for its
enantioselective synthesis remains an important ongoing
challenge. In this report, we describe the first nonenzymatic
method for the dynamic kinetic resolution (DKR) of
secondary alcohols (specifically, aryl alkyl carbinols) through
enantioselective acylation, and we substantially expand the
̀
scope of this approach, vis-a-vis enzymatic reactions. Simply
combining an effective process for the kinetic resolution of alcohols with an active catalyst for the racemization of alcohols did
not lead to DKR, due to the incompatibility of the ruthenium-based racemization catalyst with the acylating agent (Ac2O) used in
the kinetic resolution. A mechanistic investigation revealed that the ruthenium catalyst is deactivated through the formation of a
stable ruthenium−acetate complex; this deleterious pathway was circumvented through the appropriate choice of acylating agent
(an acyl carbonate). Mechanistic studies of this new process point to reversible N-acylation of the nucleophilic catalyst, acyl
transfer from the catalyst to the alcohol as the rate-determining step, and carbonate anion serving as the Brønsted base in that
acyl-transfer step.
INTRODUCTION
■
Dynamic kinetic resolution (DKR) is a powerful strategy in
asymmetric synthesis, allowing the stereoconvergent trans-
formation of both enantiomers of a racemic substrate into a
single enantiomer of a target molecule.1 This approach
overcomes a limitation of simple kinetic resolutions, which
provide a maximum direct yield of 50% for a particular
enantiomer. For an efficient DKR, the reaction conditions for
kinetic resolution and for racemization of the substrate must be
compatible, and racemization must occur rapidly relative to
conversion of the slow-reacting enantiomer to product.
Because secondary carbinols are a common subunit in
bioactive compounds,2 a great deal of effort has been dedicated
to the development of efficient methods for their synthesis in
enantioenriched form.3 Enzymatic resolution, including DKR,
of racemic alcohols is one of the more widely used approaches,
especially in industry.4 With respect to enantioselective
acylation,5 although impressive progress has been described
for enzymatic DKR’s,6 as well as for nonenzymatic (and
nondynamic) kinetic resolutions,7 we are not aware of any
reports of useful nonenzymatic DKR’s.
In previous studies, we established that a planar-chiral DMAP
derivative serves as an effective catalyst for the kinetic
resolution of a variety of racemic aryl alkyl carbinols,8
propargylic alcohols,9 and allylic alcohols10 via acylation with
Ac2O, providing selectivity factors as high as ∼100 (eq 1). Our
early attempts to develop a dynamic variant were stymied either
by the incompatibility of the acylation and the racemization
processes, or else by the need for elevated temperature in order
to achieve racemization, which led to a substantial erosion in
enantioselectivity.
Recent discoveries of catalysts that rapidly racemize
secondary alcohols at room temperature11 provided fresh
impetus for us to revisit the unsolved challenge of developing
an effective method for the nonenzymatic DKR of alcohols via
enantioselective acylation. In this report, we describe the
achievement of this objective through the use of a planar-chiral
DMAP derivative (acylation catalyst) in combination with a
ruthenium complex (racemization catalyst) in the presence of
Received: July 27, 2012
Published: August 30, 2012
© 2012 American Chemical Society
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an acyl carbonate (eq 2), and we present mechanistic studies,
some of which were critical to the successful development of
this process.
RESULTS AND DISCUSSION
■
A variety of transition-metal complexes have been reported to
catalyze the racemization of secondary alcohols.11 We were
particularly drawn to the recent systematic studies of Backvall,
̈
who has established that (C5Ph5)Ru(CO)2(Ot-Bu) (RuOt‑Bu),
generated in situ from (C5Ph5)Ru(CO)2Cl (RuCl) and KOt-Bu,
is an active racemization catalyst at room temperature, and that
it can be applied to enzymatic DKR’s of secondary alcohols.12
butyl acetate and a ruthenium−acetate complex (RuOAc), and
indeed that has proved to be the case (eq 6). RuOAc is
sufficiently stable that it can be purified by column
chromatography and characterized by X-ray crystallography,
which reveals an η1-acetate ligand as part of an 18-electron
ruthenium complex.
Backvall generally employs toluene as the solvent when
̈
utilizing RuOt‑Bu as a racemization catalyst, whereas t-amyl
alcohol is the solvent of choice for kinetic resolutions catalyzed
by (C5Ph5)-DMAP* (eq 1). One could envision that use of an
alcohol as the solvent might inhibit racemization of a secondary
alcohol by RuOt‑Bu; we have, however, determined that
racemization of 1-phenylethanol proceeds smoothly in t-amyl
alcohol even at 0 °C (eq 3. We employ a small excess of RuCl in
As we had conjectured, RuOAc is not an active racemization
catalyst for 1-phenylethanol in t-amyl alcohol at 0 °C (eq 7; cf.
eq 3). Furthermore, we have confirmed that RuOAc forms
rapidly under the conditions that we had originally explored for
the DKR of 1-phenylethanol (eq 4).13
Thus, we needed to identify an acylating agent that would
not deactivate the ruthenium−alkoxide racemization catalyst
through the formation of a stable ruthenium carboxylate. Acyl
carbonates14 were among the array of candidates, since they are
less electrophilic than anhydrides and, if acylation of the
ruthenium alkoxide were to occur, the resulting ruthenium
carbonate might decarboxylate and thereby regenerate a
ruthenium alkoxide (eq 8).15,16
order to decrease the likelihood that adventitious KOt-Bu will
have a deleterious impact on our DKR’s, for example, by
facilitating a Brønsted base-mediated nonenantioselective
acylation). Furthermore, planar-chiral DMAP derivative
(C5Ph5)-DMAP* is compatible with the racemization process
(eq 3), and no interaction between RuOt‑Bu (or the ruthenium
alkoxide derived from 1-phenylethanol) and (C5Ph5)-DMAP*
1
can be detected in the H NMR spectrum of a mixture of the
two compounds in t-amyl alcohol/toluene.
Unfortunately, when we applied the conditions that we had
developed earlier for the kinetic resolution of secondary
alcohols (eq 1) to the DKR of 1-phenylethanol, it became
clear that the ruthenium racemization catalyst is not compatible
with the acylation process (eq 4). Thus, at partial conversion,
the unreacted alcohol was substantially enantiomerically
enriched (98% ee after 24 h; >99% ee after 48 h).
Indeed, we have determined that, with acetyl isopropyl
carbonate17 as the acylating agent in a mixture of the preferred
solvents for (C5Ph5)-DMAP*-catalyzed acylation (t-amyl
alcohol) and RuOt‑Bu-catalyzed racemization (toluene), the
DKR of 1-phenylethanol proceeds with good ee and in
An additional control experiment revealed that RuOt‑Bu is
deactivated by Ac2O (eq 5 vs eq 3). We hypothesized that the
ruthenium alkoxide might be acylated by Ac2O to generate t-
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excellent yield (eq 9). We observe lower enantioselectivity and
yield when other acyl carbonates are employed as the acylating
agent.
three isomers of a diol are subjected to our DKR conditions,
the C2-symmetric bis(acetate) can be isolated in excellent ee
(eq 10).
The rate law for the DKR of 1-phenylethanol is first order in
1-phenylethanol, first order in the acylation catalyst ((C5Ph5)-
DMAP*), “fractional” (first order at low concentration,
approaching zeroth order at higher concentration) order in
acetyl isopropyl carbonate, and zeroth order in the racemization
catalyst. According to an NMR spectroscopic study, the resting
state of the planar-chiral DMAP derivative during a DKR is a
mixture of the free catalyst and the N-acylated catalyst,19 which
accounts for the “fractional” dependence of rate on the
concentration of acetyl isopropyl carbonate. Acyl transfer from
the catalyst to the alcohol is likely the rate-determining step of
the DKR (Figure 1).
This method achieves the DKR of an array of aryl alkyl
carbinols with ∼90% ee and in high yield (Table 1, entries 1−
Table 1. Nonenzymatic Dynamic Kinetic Resolution of
Secondary Alcohols (for the Reaction Conditions, See eq
a
2)
Figure 1. Outline of a mechanism for the nonenzymatic dynamic
kinetic resolution of a secondary alcohol catalyzed by (+)-(C5Ph5)-
DMAP* and RuOt‑Bu
.
When (C5Ph5)-DMAP* is treated with 2 equiv of acetyl
isopropyl carbonate at −20 °C, the acylpyridinium salt is
generated almost quantitatively, according to 1H NMR
spectroscopy (eq 11).20 The salt is stable for at least 6 h at
this temperature.
a
All data are the average of two experiments. The predominant
b
product is the S enantiomer. The yield was determined by GC
analysis with the aid of a calibrated internal standard. The yield of
purified product is provided in parentheses.
9).18 The scope of the process is relatively broad: for example,
the alkyl substituent of the carbinol can range in size from Me
to isopropyl. In contrast, corresponding enzymatic DKR’s of aryl
alkyl carbinols are only effective when the alkyl group is not
branched (in the α, β, or even the γ position).6
Effective DKR is observed when the aromatic ring of the aryl
alkyl carbinol is electron-poor or electron-rich (Table 1, entries
5 and 6), para-, meta-, or ortho-substituted (entries 5−8), or an
extended π system (entry 9). Furthermore, the nonenzymatic
DKR of an allylic alcohol can be achieved with useful
enantioselectivity and yield (entry 10).
This combination of planar-chiral DMAP derivative (C5Ph5)-
DMAP* and a ruthenium racemization catalyst can also be
applied to the stereoconvergent acylation of a diol. Thus, when
We hypothesize that ion pair A, rather than B, is the species
that reacts with the secondary alcohol in the rate-determining
acyl-transfer step of the reaction (Figure 1). Consistent with
this suggestion, the decarboxylation of acetyl isopropyl
carbonate in the presence of (C5Ph5)-DMAP* proceeds
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significantly more slowly (eq 12; 5% after 3 h) than the
acylation of 1-phenylethanol under DKR conditions (37%
conversion after 3 h).
REFERENCES
■
(1) (a) Pellissier, H. Chirality from Dynamic Kinetic Resolution; Royal
Society of Chemistry: Cambridge, 2011. (b) Pellissier, H. Tetrahedron
2011, 67, 3769−3802.
(2) For an example, see: Atorvastatin in the Management of
Cardiovascular Risk: From Pharmacology to Clinical Evidence; Grundy,
S., Ed.; Kluwer: Auckland, New Zealand, 2007.
(3) For example, see: Science of Synthesis, Stereoselective Synthesis;
Molander, G. A., Ed.; Thieme: New York, 2011; Vol. 2.
(4) For leading references, see: (a) Fischer, T.; Pietruszka, J. Top.
Curr. Chem. 2010, 297, 1−43. (b) Asymmetric Catalysis on Industrial
Scale; Blaser, H.-U., Federsel, H.-J., Eds.; Wiley−VCH: New York,
2010. (c) Pollard, D.; Kosjek, B. In Organic Synthesis with Enzymes in
Non-aqueous Media; Carrea, G., Riva, S., Eds.; Wiley−VCH: New York,
2008; pp 169−188.
CONCLUSIONS
■
Dynamic kinetic resolution is a powerful approach to the
enantioselective synthesis of secondary alcohols, an important
family of bioactive compounds. We have developed the first
nonenzymatic method for the DKR of alcohols through
enantioselective acylation, and we have established that this
process is effective for a variety of aryl alkyl carbinols (including
a diol); this study complements corresponding enzymatic
DKR’s, which are not useful when the alkyl substituent is
branched. We were not able to address this challenge simply by
combining an effective method for the kinetic resolution of
alcohols with an active catalyst for the racemization of
alcoholsthe two processes proved to be incompatible,
specifically, the ruthenium-based racemization catalyst was
poisoned by the acylating agent (Ac2O) employed in the kinetic
resolution. Nevertheless, we determined the pathway for
deactivation (formation of a stable, inactive ruthenium−acetate
adduct) and developed a method that circumvents this
problem. Mechanistic studies (reactivity, kinetics, and spectro-
scopic) of this new process for the DKR of aryl alkyl carbinols
indicate that N-acylation of the nucleophilic catalyst is
reversible, acyl transfer from the catalyst to the alcohol is the
rate-determining step, and a carbonate anion serves as the
Brønsted base in that acyl-transfer step. The development of
additional applications of planar-chiral DMAP derivatives in
asymmetric catalysis is underway.
(5) For some leading references, see: (a) Oriyama, T. In Science of
Synthesis, Stereoselective Synthesis; De Vries, J. G., Molander, G. A.,
Evans, P. A., Eds.; Thieme: New York, 2011; Vol. 3., pp 829−849.
(b) Muller, C. E.; Schreiner, P. R. Angew. Chem., Int. Ed. 2011, 50,
̈
6012−6042. (c) Spivey, A. C.; Arseniyadis, S. Top. Curr. Chem. 2010,
291, 233−280.
(6) For reviews and leading references, see: (a) Martín-Matute, B.;
Backvall, J. E. Asymmetric Organic Synthesis with Enzymes; Gotor, B.,
̈
Alfonso, I., Garcia-Urdiales, E., Eds.; Wiley−VCH: New York, 2008;
pp 89−113. (b) Lee, J. H.; Han, K.; Kim, M.-J.; Park, J. Eur. J. Org.
Chem. 2010, 999−1015.
(7) For a review, see: Pellissier, H. Adv. Synth. Catal. 2011, 353,
1613−1666.
(8) (a) Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997,
119, 1492−1493. (b) Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem.
1998, 63, 2794−2795. (c) For an application of this method, see:
Chen, Y.-H.; McDonald, F. E. J. Am. Chem. Soc. 2006, 128, 4568−
4569.
(9) Tao, B.; Ruble, J. C.; Hoic, D. A.; Fu, G. C. J. Am. Chem. Soc.
1999, 121, 5091−5092.
(10) Bellemin-Laponnaz, S.; Tweddell, J.; Ruble, J. C.; Breitling, F.
M.; Fu, G. C. Chem. Commun. 2000, 1009−1010. For a recent
application of this method, see: Francais, A.; Leyva, A.; Etxebarria-
Jardi, G.; Ley, S. V. Org. Lett. 2010, 12, 340−343.
(11) For a review of racemization catalysts for the DKR of alcohols
and amines, see: Ahn, Y.; Ko, S.-B.; Kim, M.-J.; Park, J. Coord. Chem.
Rev. 2008, 252, 647−658.
́
(12) Martín-Matute, B.; Edin, M; Bogar, K.; Kaynak, F. B.; Backvall,
̈
J.-E. J. Am. Chem. Soc. 2005, 127, 8817−8825.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
(13) Notes: (a) RuOt‑Bu reacts with AcOH within 10 min at room
temperature (in t-amyl alcohol/toluene (1:1)) to generate RuOAc and
t-BuOH. (b) In the presence of propionic acid and 1-phenylethanol,
RuOAc does not react to form a ruthenium-propionate adduct after 20
h at room temperature (in t-amyl alcohol/toluene (1:1)).
(14) For an example of the use of an acyl carbonate in an enzymatic
kinetic resolution of an alcohol, see: Guibe-Jampel, E.; Chalecki, Z.;
Bassir, M.; Gelo-Pujic, M. Tetrahedron 1996, 52, 4397−4402.
(15) We subsequently determined that RuOt‑Bu does not react with
acetyl isopropyl carbonate after 20 h at room temperature, in the
absence or in the presence of 1-phenylethanol (in t-amyl alcohol/
toluene (1:1)).
S
AUTHOR INFORMATION
Corresponding Author
gcfu@caltech.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(16) Kim has reported that DMAP catalyzes the decarboxylation of
acyl carbonates to form esters: Kim, S.; Lee, J. I.; Kim, Y. C. J. Org.
Chem. 1985, 50, 560−565.
■
Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences: R01−
GM057034 for G.C.F. and F32 GM087889 for J.M.M.) and
by the Global COE in Chemistry, Nagoya University
(fellowship to A.U.). We thank Dr. Jeffrey H. Simpson
(Department of Chemistry Instrumentation Facility) for
(17) Notes: (a) Acetyl isopropyl carbonate can be synthesized in one
step from acetic acid and isopropyl chloroformate. After five days at
room temperature under nitrogen, there is no detectable decom-
position. (b) We are not aware of previous reports of the use of this
acyl carbonate as an acylating agent for alcohols. (c) Whereas
acylations of alcohols by Ac2O generally include a stoichiometric
Brønsted base as an additive (to capture AcOH), when acetyl
isopropyl carbonate is used as the acylating agent, isopropyl alcohol is
produced, and no added base is required.
assistance with NMR spectroscopy, Dr. Peter Muller for
̈
assistance with X-ray crystallography (and NSF grant CHE-
0946721 for the purchase of an X-ray diffractomer), and Dr.
Gerald B. Rowland for preliminary studies.
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(18) Notes: (a) On a gram scale, the DKR illustrated in entry 8 of
Table 1 proceeded in 92% ee and >99% yield (1.25 g of product;
catalyst recovery for C5Ph5-DMAP*: 74%). (b) During the course of
the DKR of 1-phenylethanol (Table 1, entry 1), the ee of the product
was constant, and the ee of the unreacted starting material was less
than 15%. (c) Under the conditions described in eq 2, a simple kinetic
resolution (i.e., without RuCl and KOt-Bu) of 1-phenylethanol
proceeded with a selectivity factor of 14, a value consistent with the
87% ee that we observe for the DKR of 1-phenylethanol (Table 1,
entry 1). (d) Under our standard conditions, DKR’s of phenyl t-butyl
carbinol and of phenyl chloromethyl carbinol were not effective. (e)
Both enantiomers of C5Ph5-DMAP* are available from Strem
Chemicals.
(19) Notes: (a) For spectroscopic characterization and X-ray
structural analysis of N-acetylated C5Ph5-DMAP*, see ref 9. (b)
This DKR was conducted with 3.6% (C5Ph5)-DMAP*, in order to
1
facilitate analysis by H NMR spectroscopy.
(20) For the reaction of acetyl isopropyl carbonate with (C5Ph5)-
DMAP*, lower temperature favors N-acylation.
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