Single-operation deracemization of 3H-indolines and tetrahydroquinolines enabled by phase separation

Article abstract of DOI:10.1021/ja4082827

The single-operation deracemization of 3H indolines and tetrahydroquinolines is described. An asymmetric redox approach was employed, in which a phosphoric acid catalyst, oxidant, and reductant are present in the reaction mixture. The simultaneous presence of both oxidant and reductant was enabled by phase separation and resulted in the isolation of highly enantioenriched starting materials in high yields.

Full text of DOI:10.1021/ja4082827

Communication
pubs.acs.org/JACS
Single-Operation Deracemization of 3H-Indolines and
Tetrahydroquinolines Enabled by Phase Separation
Aaron D. Lackner, Andrew V. Samant, and F. Dean Toste*
Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, United States
S
* Supporting Information
One archetypal approach to destroying and generating
stereocenters is through oxidation and reduction chemistry.
In order to test a redox method for deracemization, a reaction
platform must be identified in which a substrate reacts with an
oxidant, the subsequent oxidized intermediate reacts with a
reductant, and at least one of those steps is rendered
enantioselective by a chiral catalyst. As there exists an
abundance of effective catalytic methods for enantioselective
oxidation and enantioselective reduction of a wide variety of
substrates, many such combinations can be identified.
ABSTRACT: The single-operation deracemization of 3H
indolines and tetrahydroquinolines is described. An
asymmetric redox approach was employed, in which a
phosphoric acid catalyst, oxidant, and reductant are
present in the reaction mixture. The simultaneous
presence of both oxidant and reductant was enabled by
phase separation and resulted in the isolation of highly
enantioenriched starting materials in high yields.
Despite viable candidates for reaction development, accom-
plishment of a redox-driven deracemization as a single
operation is largely precluded by issues of chemoselectivity. A
single-operation procedure requires the simultaneous presence
of both an oxidant and reductant in the reaction medium, and
their direct reaction is likely to be the most kinetically favorable
process. Previously reported deracemization reactions have
avoided this reactivity issue either through separation into two
distinct operations,7 or through the use of enzymes with highly
specific reaction profiles to avoid reagent quenching.8 To the
best of our knowledge, nonenzymatic single-operation chemi-
cally induced deracemization has not been reported.9
imple and kinetic resolutions, in which one enantiomer of a
S
racemic mixture is selectively removed from the other,
remain important means for the isolation of enantioenriched
materials in an industrial setting.1 While attractive in its
simplicity, since one enantiomer is being removed, the
theoretical yield of the desired optically active material is
limited to 50% (eq 1). This restriction has been addressed
We considered that a single-operation deracemization might
be accomplished by nonenzymatic means if the relative
concentrations of both oxidant and reductant in bulk solution
were kept low enough compared to the substrate. This could
minimize their direct reaction and still allow for each reagent’s
reaction with the substrate. We have recently reported on the
use of chiral phosphate anions for phase-transfer catalysis, in
which undesired background reaction is minimized through the
use of poorly soluble cationic reagents.10 We hypothesized, in
the case of a redox-driven deracemization, that the undesired
reaction between oxidant and reductant might similarly be
suppressed through phase separation. Specifically, we envi-
sioned that if both an oxidant and a reductant with poor
solubility in nonpolar organic solvents were employed, their
direct reaction could be disfavored relative to reaction with the
substrate.
through dynamic kinetic processes.2 In such a process, both
enantiomers of a racemate proceed through a shared common
reactive species, which undergoes transformation to a new
optically active product (eq 2). However, if optically active
starting material is desired, (i.e., a resolution rather than a
transformation), this strategy requires additional steps to
convert the product back to starting material.3,4
In order to resolve a racemate in a dynamic sense, one
enantiomer of the starting material must be converted to the
other. In the case of the direct interconversion of enantiomers
proceeding through a single shared reaction pathway,
equilibrium is reached between the thermodynamically
equivalent starting material and product. The principle of
microscopic reversibility dictates that under such circumstances,
the racemate must be returned.5 Instead, to realize such a
deracemization,6 the forward and reverse reactions must follow
distinct mechanistic pathways; in other words, two sets of
reagents to drive opposing reactions are necessary. In analogy
to a dynamic kinetic transformation, deracemization can be
accomplished by proceeding through a shared, achiral
intermediate and reforming the stereocenter in an enantiose-
lective manner (eq 3).
This reaction scheme would constitute a triphasic system,11
in which the substrate is dissolved in organic reaction solvent,
and the oxidant and the reductant exist mainly as solids out of
solution (solid−organic−solid phase separation). Alternatively,
if either of the reagents has high water solubility (e.g., if it is a
salt), it could be partitioned into an aqueous phase,
representing an aqueous−organic−solid phase separation. By
Received: August 9, 2013
Published: September 11, 2013
© 2013 American Chemical Society
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Communication
Scheme 1. Identification of a Reaction System
Figure 1. Schematic representation of a phase-separation enabled
deracemization.
limiting the majority of reagent interaction to the phase
interfaces, direct quenching of oxidant and reductant could be
minimized while still allowing for their individual reactions with
the solubilized substrate, thus permitting the possibility of
deracemization.
Chiral phosphate anions have been shown to promote the
reaction of insoluble cationic electrophiles with soluble
substrates in nonpolar solvents,10 and their conjugate acids
are well-known catalysts for the enantioselective reduction of
imines through activation toward hydride delivery.12,13 By
selecting appropriate reagents (a cationic oxidant and a
reductant with minimal solubility in reaction solvent), we
initially hoped to show that a single chiral catalyst could
mediate not just distinct but actually opposing processes
(Figure 1).
3H-indoline 1a was identified as a test substrate, as it met the
aforementioned criteria for deracemization: it is readily oxidized
to 3H indole 2a by oxopiperidinium salt 314 in toluene under
anionic phase-transfer conditions (addition of the chiral
phosphoric acid TCYP, 5a, and inorganic base to generate
the anionic phosphate); and the enantioselective reduction of
2a by a hydride source, Hantzsch ester 4a, in the presence of
chiral phosphoric acid catalysts is precedented.15 We were able
to reproduce these results using the conjugate acid of the
phase-transfer catalyst, 5a.
Though the enantioselectivity of the oxidation step was low
under the listed conditions, (s < 1.1), the high selectivity of the
reductive second step still permitted the possibility of an
effective deracemization. While this feature would allow for this
methodology to be performed as two distinct operations, it was
our goal to show that by choosing appropriate conditions, an
equally effective single-operation deracemization could be
developed. The observation that both oxopiperidinium 3 and
Hantzsch ester 4a have low solubility in toluene allowed us to
evaluate our hypothesis (7.8 and 2.0 mM, respectively)
(Scheme 1).
In order to interpret the one-pot deracemization reaction
outcome in a more useful manner, deuterated 3H indoline 1a-
D, was used, and deuterium erosion (which occurs by oxidation
and subsequent hydride delivery from the Hantzsch ester) was
monitored as an indicator of conversion. Given the high
enantioselectivity of the reduction, we were confident that
conversion of the deuterated substrate and enantiomeric excess
would track closely. To evaluate the feasibility of solid−
organic−solid phase separation, 2 equiv of reductant and
oxidant were added to substrate in the presence of 10 mol % 5a
in toluene under phase-transfer (basic) conditions. The
Table 1. Development of Reaction Conditions for the Single-
Operation Deracemization of 3H Indolines
Hantzsh ester
additive
(equiv)
% D
%
a
entry
1
(equiv)
solvent
PhCH3
erosion
ee
4a (2.0)
Na2CO3
(2.0)
0
0
2
3
4
4a (2.0)
4a (2.0)
4a (2.0)
PhCH3
−
−
−
0
5
0
4
1:1 PhCH3/H2O
9:1:10 Hex/
Et2O/H2O
68
67
5
6
4a (2.0)
4a (2.0)
4b (2.0)
4c (2.0)
4c (1.5)
4d (1.5)
4d (1.5)
4d (1.5)
9:1:10 Hex/
Et2O/H2O
Na2CO3
(2.0)
57
84
56
97
94
96
98
97
42
81
56
92
91
92
94
94
9:1:10 Hex/
Et2O/H2O
HCl (1.0)
HCl (1.0)
HCl (1.0)
HCl (1.0)
HCl (1.0)
HCl (1.0)
7
9:1:10 Hex/
Et2O/H2O
8
9:1:10 Hex/
Et2O/H2O
9
9:1:10 Hex/
Et2O/H2O
10
9:1:10 Hex/
Et2O/H2O
b
11
9:1:10 Hex/
Et2O/H2O
b,c
12
9:1:10 Hex/
Et2O/H2O
HCl (1.0)
a
b
Equimolar amount of oxopiperidinium used. (S)-TRIP, 5b, used as
c
catalyst instead of (S)-TCYP. Reaction run in stepwise fashion.
indoline was reisolated as the racemate with no detectable
deuterium erosion (Table 1, entry 1). The consumption of
oxidant, which could be followed qualititatively by the
dissipation of its bright-yellow color, appeared faster than in
the presence of substrate alone, and it is most likely that the
oxidant was consumed completely by reaction with reductant
rather than substrate. Since basic conditions may impede the
enantioselective reduction of any oxidized intermediate, we also
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ran the reaction under nonbasic conditions (entry 2), though
again no deuterium erosion was observed.
Table 2. Substrate Scope for Substituted 3H Indolines
Given the high water solubility of the oxammonium salt
(∼70 mM),14a we rationalized that aqueous−organic−solid
phase separation might more effectively partition oxidant and
reductant. Indeed, when the oxidant was added as an aqueous
solution,16 5% deuterium erosion was observed, along with 4%
ee (entry 3), indicating that a small fraction of the substrate had
been oxidized and subsequently reduced enantioselectively.
Switching the organic phase to a 9:1 hexanes/diethyl ether
mixture resulted in a significant improvement in both
conversion and enantioenrichment (entry 4). This result is in
line with our phase-separation hypothesis, as both oxopiper-
idinium 3 (0.07 mM) and Hantzsch ester 4a (0.4 mM) have
lower solubility in the less-polar organic solvent mixture. Under
the analogous basic conditions, though comparable conversion
was observed, the indoline was isolated in a significantly
deteriorated enantioenrichment (entry 5). Conversely, we
found that addition of 1 equiv of strong acid led to improved
results in the presence of an aqueous phase (entry 6).17,18
By altering the solubility properties of the Hantzsch ester
reductant, we hoped to further eliminate reagent quenching
and thus improve enantioenrichment of the isolated product.
While benzyl Hantzsch ester 4b gave worse results compared to
the ethyl analog (entry 7), use of 4-Cl-Bn Hantzsch ester 4c
improved conversion of deuterated substrate, also reflected in
the product enantioenrichment (entries 8). Furthermore,
oxidant and reductant stoichiometry could be lowered from
2.0 to 1.5 equiv without compromising enantioselectivity (entry
9). 2,6-Cl2-Bn Hantzsch ester 4d (which has a measured
solubility of 0.08 mM in 9:1 hexanes/diethyl ether) gave
slightly improved conversion (entry 10), and its highly
crystalline nature makes it easier to handle than 4c. Use of
the chiral phosphoric acid TRIP (5b) in place of TCYP as
catalyst led to a further increase in enantioselectivity (entry 11).
Under these conditions, the enantioenrichment matched that of
a stepwise oxidation−reduction sequence (entry 12), indicating
that the starting racemate had been fully converted under
reaction conditions. Absolute stereochemistry of the product
was confirmed through X-ray crystallography of the hydro-
chloride salt and is in agreement with the literature assign-
ment.15
a
Enantioenrichment of stepwise reaction listed in parentheses; 1.75
b
equiv oxopiperidinium, 1.80 equiv Hantzsch ester 4. (S)-TCYP used
as catalyst.
Scheme 2. Substrate Scope for Substituted
Tetrahydroquinoilnes
The isotopologue 1a was deracemized to the same degree as
1a-D (Table 2, 1a), and 3H indolines of various substitution
patterns were then subjected to the same single-operation
deracemization conditions (a slight excess of reductant was
used to ensure full reduction) and compared to their stepwise
oxidation−reduction to determine efficacy. Spirocyclic products
were obtained in good yields and high enantiomeric excesses
(1b and 1c). Substitution around the indoline arene was well
tolerated, as in the cases of benzoindoline 1d and 5-
bromoindoline 1e. Substrates with 2-aryl functionality were
subjected to reaction conditions and isolated in good to high
enantiomeric excess, including para- (1f, 1j, 1k), meta- (1g, 1h,
1i), and ortho- (1h) substituted 2-arylindolines. Electron-rich
arenes (1f, 1g) were suitable substrates, though in the case of
1f, the enantioselectivity of the reduction (rather than degree of
deracemization) was slightly diminished. Electron-poor sub-
strates (1e, 1h−k) were also isolated in high enantiomeric
excess, however in these cases a higher loading of oxidant (1.75
equiv) and reductant (1.80 equiv) was needed for full
deracemization.19
Under similar reaction conditions, substituted tetrahydroqui-
noline substrates were similarly effectively deracemized
(Scheme 2).15b In these instances, 3 or more equiv of oxidant
and reductant were required since a second oxidation of the
intermediate dihydroquinoline to quinoline occurred rapidly.
Additionally, highly enantioenriched starting material was
converted to the opposite enantiomer under the same reaction
conditions as were used for racemic starting material. When
(S)-1a (93% ee) was submitted to reaction conditions, the
antipode (R)-1a was isolated in excellent yield and enantio-
meric excess (eq 4).
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the obtained product differs from the starting material only in that it is
enantioenriched; relevant discussions: (a) Turner, N. J. Curr. Opin.
Chem. Biol. 2010, 2, 115. (b) Gruber, C. C.; Lavandera, I.; Faber, K.;
Kroutil, W. Adv. Synth. Catal. 2006, 348, 1789.
(7) (a) Shimada, Y.; Miyake, Y.; Matsuzawa, H.; Nishibayashi, Y.
Chem. Asian J. 2007, 2, 393. (b) Adair, G. R. A.; Williams, J. M. J.
Chem. Commun. 2007, 2608.
(8) (a) Soda, K.; Oikawa, T.; Yokoigawa, K. J. Mol. Catal. B: Enzym.
2001, 11, 149. (b) Carr, R.; Alexeeva, M.; Enright, E.; Eve, T. S. C.;
Dawson, M. J.; Turner, N. J. Angew. Chem. Int. 2003, 42, 4807.
(c) Dunsmore, C. J.; Carr, R.; Fleming, T.; Turner, N. J. J. Am. Chem.
Soc. 2006, 128, 2224. (d) Carr, R.; Alexeeva, M.; Dawson, M. J.;
The development of a single-operation deracemization
enabled by a three-phase system indicates the ability of phase
separation to suppress undesired reactivity: it has allowed us to
develop a class of transformation for which there was no purely
chemical protocol; that it has been used to enable what would
be a minor or fully inaccessible reaction pathway under more
typical reaction conditions (cf. Table 1, entries 1, 2)
demonstrates its efficacy. Future studies aimed at applying
phase separation to develop reaction sequences of incompatible
transformations are ongoing.
Gotor-Fernan
2005, 6, 637. (e) Voss, C. V.; Gruber, C. C.; Faber, K.; Knaus, T.;
Macheroux, P.; Kroutil, W. J. Am. Chem. Soc. 2008, 130, 13969.
́
dez, V.; Humphrey, C. E.; Turner, N. J. ChemBioChem
A
review see: (f) Hall, M.; Bommarius, A. S. Chem. Rev. 2011, 111, 4088.
(9) Enantioenrichment of a racemate based on the physical process
of selective crystallization from solution is known for compounds
which crystallize as enantiopure conglomerates: (a) Kuenburg, B.;
̈
Czollner, L.; Frohlich, J.; Jordis, U. Org. Process Res. Dev. 1999, 3, 425.
(b) Yagishita, F.; Ishikawa, H.; Onuki, T.; Hachiya, S.; Mino, T.;
Sakamoto, M. Ang. Chem. Int. Ed. 2012, 51, 13023.
ASSOCIATED CONTENT
* Supporting Information
Procedures, spectral and X-ray crystallographic data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
(10) (a) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D.
Science 2011, 334, 1681. (b) Phipps, R. J.; Hiramatsu, K.; Toste, F. D.
J. Am. Chem. Soc. 2012, 134, 8376. (c) Wang, Y.-M.; Wu, J.; Hoong,
C.; Rauniyar, V.; Toste, F. D. J. Am. Chem. Soc. 2012, 134, 12928.
(d) Honjo, T.; Phipps, R. J.; Rauniyar, V.; Toste, F. D. Angew. Chem.,
Int. Ed. 2012, 51, 9684. (e) Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc.
S
AUTHOR INFORMATION
Corresponding Author
fdtoste@berkeley.edu
■
2013, 135, 1268. (f) Shunatona, H. P.; Fruh, N.; Wang, Y.-M.;
̈
Rauniyar, V.; Toste, F. D. Angew. Chem., Int. Ed. 2013, 52, 7724.
Reviews: (g) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nature Chem.
2012, 4, 603. (h) Brak, K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2013,
52, 534. (i) Mahlau, M.; List, B. Angew. Chem., Int. Ed. 2013, 52, 518.
(11) (a) Cohen, B. J.; Kraus, M. A.; Patchornik, A. J. Am. Chem. Soc.
1977, 99, 4165. (b) Davies, I. W.; Matty, L.; Hughes, D. L.; Reider, P.
J. J. Am. Chem. Soc. 2001, 123, 10139.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge NIHGMS (RO1 GM104534) for
financial support. A.D.L. was supported by a Dauben
Fellowship from UCB Department of Chemistry. We would
like to thank Dr. Gregory L. Hamilton for helpful discussions,
William J. Wolf for obtaining crystallographic data, and Dr.
Joerg P. Hehn and Ji Lee for experimental assistance.
(12) (a) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed.
2005, 44, 7424. (b) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2006, 128, 84. (c) Li, G.; Liang, Y.; Antilla, J.
C. J. Am. Chem. Soc. 2007, 129, 5830. Relevant recent reviews:
(a) Rueping, M.; Sugiono, E.; Schoepke, F. R. Synlett 2010, 852.
(b) Kampen, D.; Reisinger, C. M.; List, B. Top. Curr. Chem. 2010, 291,
395. (c) Wang, Z.; Jiang, Z. Asian J. Chem. 2010, 22, 4141.
(13) During the preparation of this manuscript, a report using a chiral
phosphoric acid catalyst and racemic indoline as a reductant led to
highly enantioselective reduction of N-arylimines and concomitant
oxidative kinetic resolution of the indoline: Saito, K.; Shibata, Y.;
Yamanaka, M.; Akiyama, T. J. Am. Chem. Soc. 2013, 135, 11740.
(14) (a) Bobbitt, J. M. J. Org. Chem. 1998, 63, 9367. (b) Qiu, J. C.;
Pradhan, P. P.; Blanck, N. B.; Bobbitt, J. M.; Bailey, W. F. Org. Lett.
2012, 14, 350.
REFERENCES
■
(1) (a) Pellissier, H. Adv. Synth. Catal. 2011, 353, 1613. (a) Fogassy,
E.; Nog
́
rad
́
i, M.; Kozma, D.; Egri, G.; Pal
́
ovics, E.; Kiss, V. Org. Biol.
Chem. 2006, 4, 3011. (b) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N.
Adv. Synth. Catal. 2001, 343, 5.
(2) (a) Wolf, C. Dynamic Stereochemistry of Chiral Compounds:
Principles and Application; RSC: London, 2007. (b) Faber, K. Chem.−
Eur. J. 2001, 7, 5004. (c) Steinreiber, J.; Faber, K.; Griengl, H. Chem.−
Eur. J. 2008, 14, 8060.
(3) Dynamic kinetic transformations of secondary alcohols to their
ester-protected forms have been reported chemo-enzymatically:
(15) (a) Rueping, M.; Brinkmann, C.; Antonchick, A. P.; Atodiresei,
I. Org. Lett. 2010, 12, 4604. (b) Rueping, M.; Antonchick, A. P.;
Thiessmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683.
(16) (a) Rueping, M.; Thiessmann, T. Chem. Sci. 2010, 1, 473.
(a) Persson, B. A.; Larsson, A. L. E.; Le Ray, M.; Backvall, J.-E. J.
̈
(b) Scroggins, S. T.; Chi, Y.; Frec
2010, 49, 2393.
́
het, J. M. J. Angew. Chem., Int. Ed.
Am. Chem. Soc. 1999, 121, 1645. (b) Pamies, O.; Backvall, J.-E. Trends
̈
Biotechnol. 2004, 22, 130. (c) Martín-Matute, B.; Backvall, J.-E. In
̈
(17) (a) Li, G.; Antilla, J. C. Org. Lett. 2009, 11, 1075. (b) Rueping,
M.; Azap, C. Angew. Chem., Int. Ed. 2006, 45, 7832.
Organic Synthesis with Enzymes in Non-Aqueous Media; Carrea, G., Riva,
S., Eds.; Wiley-VCH: Weinheim, 2008, pp 113−144. More recently, a
purely chemical variant was reported: (c) Lee, S. Y.; Murphy, J. M.;
Ukai, A.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 15149.
(18) Observation that the reaction is faster under acidic conditions
implies that the catalyst may not act as an anionic phase-transfer
catalyst. Preliminary investigations indicate that the oxidation does
proceed more rapidly in the presence of the phosphoric acid, and
further investigations on mechanism are ongoing. Reviews of
phosphoric acid catalysis: (a) Akiyama, T. Chem. Rev. 2007, 107,
5744. (b) Terada, M. Synthesis 2010, 1929.
(4) Chemoenzymatic dynamic kinetic transformations of amines:
(a) Reetz, M. T.; Schimossek, K. Chimia 1996, 50, 668. (b) Paetzold,
J.; Backvall, J.-E. J. Am. Chem. Soc. 2005, 127, 17620. A review:
̈
(c) Kim, Y.; Park, J.; Kim, M.-J. ChemCatChem 2011, 3, 271.
(5) (a) Blackmond, D. G.; Matar, O. K. J. Phys. Chem. B 2008, 112,
5098. (b) Blackmond, D. G. Angew. Chem., Int. Ed. 2009, 48, 2648.
(6) While other definitions exist (for example, see refs 2b, c),
deracemization is used in this context in its strict sense, indicating that
(19) See ref 14b for a discussion of relative rate of oxidation using
oxopiperidinium salts.
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