C-5′-substituted cinchona alkaloid derivatives catalyse the first highly enantioselective dynamic kinetic resolutions of azlactones by thiolysis

Article abstract of DOI:10.1002/ejoc.201300451

The highly enantioselective dynamic kinetic resolution (DKR) of azlactones by thiolysis has been achieved for the first time. Although both the parent alkaloid quinine and known C-5′-urea derivatives fail to promote the reaction effectively, a new class of C-5′-hydroxylated catalysts proved capable of catalysing the DKR of a range of azlactones derived from both unbranched- and, previously challenging, branched-chain amino acids in 84-92 % ee, including an example of the synthesis of an enantioenriched N-protected thioester derived from an extraterrestrial amino acid isolated from the Murchison meteorite. The highly enantioselective dynamic kinetic resolution (DKR) of azlactones by thiolysis has been achieved for the first time. Although both the parent alkaloid quinine and known C-5′-urea derivatives fail to promote the reaction effectively, a new class of C-5′-hydroxylated catalysts proved capable of catalysing the DKR of a range of azlactones in 84-92 % ee. Copyright

Full text of DOI:10.1002/ejoc.201300451

FULL PAPER
DOI: 10.1002/ejoc.201300451
C-5Ј-Substituted Cinchona Alkaloid Derivatives Catalyse the First Highly
Enantioselective Dynamic Kinetic Resolutions of Azlactones by Thiolysis
Carole Palacio[a] and Stephen J. Connon*[a]
Keywords: Organocatalysis / Kinetic resolution / Synthetic methods / Peptides / Heterocycles
The highly enantioselective dynamic kinetic resolution
(DKR) of azlactones by thiolysis has been achieved for the
first time. Although both the parent alkaloid quinine and
known C-5Ј-urea derivatives fail to promote the reaction ef-
fectively, a new class of C-5Ј-hydroxylated catalysts proved
capable of catalysing the DKR of a range of azlactones de-
rived from both unbranched- and, previously challenging,
branched-chain amino acids in 84–92% ee, including an ex-
ample of the synthesis of an enantioenriched N-protected
thioester derived from an extraterrestrial amino acid isolated
from the Murchison meteorite.
Introduction
The Dynamic Kinetic Resolution (DKR) of azlactones
by alcoholysis,[1,2,3] is now a mature technology involving
the catalytic addition of a primary alcohol to one enantio-
mer of the readily racemisable [pKa (H2O, 25 °C, ca. 9[4])]
racemic electrophile to generate a considerably more config-
urationally stable, orthogonally protected, α-amino acid
product. A successful catalyst must bring about a selective
kinetic resolution (i.e. kfast ϾϾ kslow), and it must also be
capable of catalysing the epimerization equilibrium of the
azlactone with an efficiency that ensures that racemization
occurs at a considerably faster rate than the addition of the
alcohol to the less preferred substrate enantiomer (i.e. krac
ϾϾ kslow, Figure 1).
Figure 1. DKR of azlactones by alcoholysis.
Several diverse catalytic strategies capable of delivering
high product yields and enantioselectivities have been em-
ployed, such as the use of enzymes,[5] Ti complexes,[6] cyclic
dipeptides,[7] nucleophilic organocatalysts,[8] bifunctional
organocatalysts[9] and chiral Brønsted acids.[10] Although
the practitioner now has several catalytic options to carry
out effective (Ͼ 90% ee) azlactone DKR by alcoholysis, the
corresponding reaction involving thiol nucleophiles remains
considerably more difficult. A selective variant of such a
reaction is an attractive catalytic target that would provide
direct access to enantioenriched thioesters potentially useful
in ligation[11] peptide coupling processes.[12,13,14]
focused on the corresponding alcoholysis reaction in
2008.[15] Although the alcoholysis reaction proceeded ef-
ficiently, under optimized conditions, it was found that cy-
clohexane thiol could be added to alanine-derived azlactone
1 in the presence of bifunctional urea-based cinchona alka-
loid catalyst 2 to give N-benzoyl amino acid thioester 3 in
excellent yield and moderate ee (Scheme 1, A).
C-2 symmetric squaramide catalyst 4 (developed by Song
et al.) is arguably the current benchmark system for the
catalysis of the analogous alcoholysis chemistry.[9f] How-
ever, in the thiol-based variant of this process (by using pri-
mary thiol nucleophile 5) catalysis was efficient but rela-
tively unselective (Scheme 1, B). Recently,[16] we reported
the synthesis of C-9 arylated cinchona alkaloid 7[17]
(Scheme 1, C), which proved capable of catalysing the thi-
olysis of furyl-substituted azlactone 8 with 73% product ee.
This catalyst could operate at room temperature and ac-
cepted a range of azlactone substrates derived from unhin-
dered amino acids, however both activity and selectivity
The state of the art in this area is summarized in
Scheme 1. We first reported this reaction as part of a study
[a] Centre for Synthesis and Chemical Biology, Trinity Biomedical
Sciences Institute, School of Chemistry, The University of
Dublin, Trinity College
Dublin 2, Ireland
Fax: +353-353-1-6712826
E-mail: connons@tcd.ie
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300451.
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Enantioselective Dynamic Kinetic Resolutions of Azlactones
Scheme 1. Previous reports of DKR of azlactones by thiolysis.
Figure 2. C-5Ј-substituted urea-based catalysts. Known catalytically competent examples and a proposed conformationally rigid analogue.
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Scheme 2. Synthesis of new rigid C-5Ј-substituted urea-based catalyst 14.
were markedly diminished in the presence of a valine-de- the known catalyst β-ICD (13),[19a,20,24] we prepared the
rived substrate. The use of reduced reaction temperatures new, rigid analogous C-5Ј-substituted urea-based catalyst
led to less selective catalysis.
14 as shown in Scheme 2.
Considerable scope for improvement remains, in particu-
lar from an enantioselectivity standpoint. Given that modi-
fication of the C-9 cinchona alkaloid substituent (i.e. cata-
lysts 2, 4 and 7, Scheme 1) has led to steady, yet ultimately
unsatisfactory, (from a synthetic utility perspective) pro-
gress, we postulated that the stereoelectronic demands of
this particular reaction cannot be satisfied (in an asymmet-
ric catalysis context) by the C-9-substituted catalyst’s two
bifunctional components (i.e. either their proximity to one
another or their relative orientation in space Ϫ in low en-
ergy conformations Ϫ is incompatible with efficient cataly-
sis of this transformation). In such a scenario, it is unlikely
that either major or minor alterations to the nature of the
C-9 substituent will lead to a successful outcome.
Results and Discussion
Catalyst Synthesis
Cyclized alkaloid derivative 16 was prepared from quin-
ine according to a procedure developed by Waldmann and
Kumar,[25] which avoids significant demethylation at C-6Ј
during the acid-mediated etherification reaction. Nitration
of this material proceeded regioselectively at C-5Ј to furnish
17 in excellent yield. Reduction of the nitro group through
Pd-catalysed hydrogenation afforded marginally stable 18,
which was treated with isocyanate 19 to give the required
C-5Ј-substituted urea.
Our search for a catalytic solution to this problem there-
fore turned towards C-5Ј-substituted[18] systems. We re-
cently introduced a class of quinine (10)-derived catalysts
characterized by the presence of a hydrogen-bond donating
urea moiety at C-5’ (two examples are shown in Figure 1),
Catalyst Evaluation
The next step was preliminary catalyst evaluation studies.
with the goal of offering the practitioner more variation in Three different azlactone substrates (1, 8b and 20) were sub-
the positioning of the catalyst’s bifunctional components jected to thiolysis by either 4-tert-butyl benzylmercaptan (5)
than is available from the widely employed C-9-[19] and C- or cyclohexane thiol in the presence of either quinine or
6Ј-substituted,[19a,20,21] analogues. Of these C-5Ј-substituted one of urea-based catalysts 11, 12 or 14 (Table 1). Beginning
systems, 11 and 12 (Figure 1) were shown to outperform with the azlactone derived from N-benzoyl alanine (i.e. 1)
C-9-substituted catalysts in highly enantioselective Henry and primary thiol 5 (which is considerably less malodorous
reactions involving trifluoromethyl-substituted ketones[22] than benzyl mercaptan), it was found that in the absence of
and conjugate additions of alkylthiols to nitro olefins,[23] catalyst no reaction occurs after 96 h (Table 1, Entry 1). In
respectively. We were curious as to the potential of these the presence of natural alkaloid quinine (10), quantitative
catalysts as promoters of the thiolytic DKR process. Before thiolysis to afford thioester 6 occurs with modest enantio-
commencing the investigation, we also attempted to aug- selectivity (Table 1, Entry 2). The C-5Ј-substituted urea-
ment the rigidity of these systems (Figure 2): inspired by based catalysts did not fare better than 10 in these pro-
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Enantioselective Dynamic Kinetic Resolutions of Azlactones
cesses. C-9-substituted carbamate 11 proved a relatively in-
On analysis of the data outlined in Table 1 it is clear that
active catalyst that furnished almost racemic product although the alkaloid-derivatives evaluated were highly
(Table 1, Entry 3), and although the corresponding C-9 active at low loadings, the urea substituent at C-5Ј does
TBDPS-protected analogue 12 promoted efficient thiolysis, nothing to augment the ability of the system to discriminate
product enantioselectivity was poor (Table 1, Entry 4). It is between the azlactone antipodes in the thiolysis process.
noteworthy however that the C-9 substituent (which is not
Based on an inspection of models and low level (MM2)
postulated to directly participate in catalysis) appears able calculations (e.g. a representation of 14 is shown in Fig-
to influence not only activity, but also the sense of enantio- ure 3), we speculated that this may be owing to, in part, the
discrimination in these reactions (Table 1, Entries 3 and 4). likely rather crowded nature of the catalyst’s active site; i.e.
Rigid analogue 14 also catalysed a clean reaction to give the catalyst conformations likely to facilitate synergistic ac-
6 in quantitative yield, however again with disappointing tion of the quinuclidine nitrogen atom and the urea func-
product ee (Table 1, Entry 5). Only marginal improvement tionality were characterized (by design) by a rather small
was observed on changing the azlactone substrate (but not pocket of space in which bifunctional catalysis must occur.
the thiol nucleophile) to valine-derived furyl species 8b If this were of insufficient volume to accommodate both the
(Table 1, Entries 6–9); with none of the urea-based catalysts large azlactone substrate and the thiol, then less selective
outperforming the parent alkaloid. More interestingly, al- monofunctional catalysis would result. It is interesting in
though C-9 O-tert-butylchlorodiphenylsilyl (TBDPS)-sub- this regard that the relatively unhindered quinine alkaloid
stituted catalyst promoted the addition of 5 to analogous proved the most able promoter of the enantioselective DKR
phenyl-substituted azlactone 20 with quantitative yield to of 1 in the study outlined in Table 1.
furnish 21 as a near racemate (Table 1, Entry 10), use of
new catalyst 14 resulted in considerably better (yet still
modest) enantioselectivity (Table 1, Entry 11). A similar
trend characterised the corresponding reactions involving
the secondary cyclohexane thiol, albeit with reduced cata-
lyst activity (i.e. 22; Table 1, Entries 12 and 13).
Table 1. The evaluation of C-5Ј urea-substituted cinchona alkaloid
catalysts in the thiolytic DKR of azlactones.
Figure 3. An energy minimised (MM2) representation of the likely
catalytically active conformation of 14.
Entry Cat. Azlactone Thiol Product Time [h] Yield [%][a] ee [%][b]
Attention therefore turned to C-5Ј-substituted analogues
with smaller steric requirements. Given the enormous suc-
cess of the C-6Ј-demethylated cupreine/cupreidine (and de-
rivatives, 23–24, Figure 4) class of catalysts[19a,20] and the
burgeoning utility of C-5Ј-urea-based systems (albeit not in
this particular process) we were surprised to learn that no
C-5Ј-hydroxylated analogues (such as 25, Figure 4) had
been previously evaluated as bifunctional organocatalysts.
An initial cause for concern was that we had previously
shown that unhindered phenols can be added to azlactones
in the presence of bifunctional organocatalysts (with low
levels of enantiocontrol),[9e] and thus we were concerned
that catalyst acylation would be problematic. However we
reasoned that this would be less of an issue by using hin-
dered, C-5Ј-hydroxylated systems (likely to be even more
1
2
3
4
5
6
7
8
–
1
1
1
1
5
5
5
5
5
5
5
5
6
6
6
6
6
9b
9b
9b
9b
21
21
22
22
96
96
96
96
96
44
44
44
44
96
96
96
96
0
100
10
100
100
100
100
95
–
17
2
–9
6
23
5
0
11
3
26
8
10
11
12
14
10
11
12
14
12
14
12
14
1
8b
8b
8b
8b
20
20
20
20
9
5
5
5
90
10
11
12
13
100
100
42
CySH
CySH
25
32
[a] Determined by 1H NMR spectroscopy by using styrene as an
internal standard. [b] Determined by CSP-HPLC, see Exp. Section
and the Supporting Information.
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C. Palacio, S. J. Connon
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hindered around the potentially nucleophilic phenolic that the introduction of a phenylazo group in the 8Ј posi-
group than catalyst 7) than with unhindered C-6 OH-sub- tion allowed facile hydrolysis of the 5Ј-amino group in
stituted catalysts.
acidic media without prior diazotization.[27]
Because the 8Ј-phenyldiazo appendage is located in a re-
gion of the molecule not likely to influence either binding
or catalysis in an deleterious fashion,[28] we prepared 5Ј-
hydroxy catalyst 26 from dihydroquinine (27) as described
by Jacobs and Heidelberger.[26] It is known from both pre-
vious studies on C-6Ј-hydroxy-cinchona alkaloids[19a,20] and
from our own work on the corresponding C-5Ј urea-based
systems (both this study and previous investigations[22,23]
)
that the bulk of the C-9 substituent can exert significant
influence over catalyst performance from both activity and
selectivity standpoints. Therefore, in addition to prototype
structure 26, new analogues incorporating the large
–OTBDPS and the considerably smaller –OMe moiety at
C-9 (i.e. 28 and 29, respectively) were also prepared as
shown in Scheme 3.
Figure 4. Cupreine, cupreidine and the proposed new class of C-
5Ј-hydroxylated catalysts 25.
The synthesis of materials of general type 25 proved
highly impractical: the key step in the synthesis is the con-
Treatment of 26 with 2 equiv. of tert-butyldiphenylsilyl
version of 5Ј-amino-dihydroquinine to the corresponding chloride in the presence of triethylamine and 4-(dimeth-
phenol. Conversion of the 5Ј-amino-dihydroquinine to the ylamino)pyridine (DMAP) led to the formation of C-9-pro-
corresponding diazonium salt followed by hydrolysis tected compound 28 after aqueous workup. Methoxy ana-
yielded multiple products, including 6Ј-demethylated com- logue 29 could not be conveniently accessed from 26, and
pounds. In 1920, Jacobs and Heidelberger[26] demonstrated was instead prepared from 27. Alkylation of the corre-
Scheme 3. Synthesis of C-5Ј-hydroxylated catalysts 26, 28 and 29.
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Enantioselective Dynamic Kinetic Resolutions of Azlactones
sponding potassium alkoxide with methyl iodide led to 30, Table 2. The evaluation of C-5Ј hydroxylated cinchona alkaloid cat-
alysts.
which was nitrated to yield 31 in good yield. Reduction of
the nitro moiety led to 32, which could be azo-coupled with
in situ generated benzene diazonium chloride. Heating the
crude material in aqueous acidic media leads to a remark-
able hydrolysis reaction that converts the aromatic amine
into corresponding phenol 29.
These catalysts were then evaluated as promoters of the
thiolytic DKR reaction (Table 2). An immediate improve-
ment in stereocontrol was observed. Relatively unhindered
(i.e. unsubstituted at C-9) catalyst 26 promoted the thiolysis
of alanine-derived azlactone 1 with considerably higher (al-
beit still modest) levels of enantioselectivity than was pre-
viously possible by using either quinine or the C-5Ј urea-
based systems (Table 1, Entry 1 relative to Entries 2–5).
More bulky analogue 28 participated in less selective cataly-
sis (Table 1, Entry 2). Gratifyingly, this trend was exagger-
ated in thiolysis reactions involving azlactones derived from
the more hindered N-furoyl and N-benzoyl valine (i.e. 8b
and 20, respectively; Table 1, Entries 3–6) in which levels
of product ee by using catalyst 26 comfortably exceed the
previous literature benchmark.
Noting that the azlactone aryl moiety appeared to influ-
ence both rate and selectivity, we investigated the DKR of
p-trifluoromethylbenzoyl- and p-nitrobenzoyl valine-de-
rived azlactones 33 and 34. Catalyst 26 promoted the ring
opening of 33 with a significant further improvement in
both rate and enantioselectivity (Table 1, Entry 7). Interest-
ingly, C-9-methylated catalyst 29 promoted the same reac-
tion with the formation of 36 as a near racemic mixture
Entry
Cat. Azlactone Product Time
[h]
Yield
[%][a]
ee [%][b]
1
2
3
4
5
6
7
8
9
26
28
26
28
26
28
26
29
26
1
6
96
96
44
44
96
96
20
44
48
80
52
75
51
100
60
92
100
28
31
14
34
7
40
5
1
6
8b
8b
20
20
33
33
34
9b
8b
21
21
35
35
36
57
2
n.d.[c]
[a] Determined by 1H NMR spectroscopy by using styrene as an
internal standard. [b] Determined by CSP-HPLC, see Exp. Section
and the Supporting Information. [c] Not determined.
Table 3. Optimization of the reaction conditions.
Entry
X [equiv.] Y [mol-%] Conc. [molL–1]
T [°C]
Time [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
1
1
1
1
2
2
4
2
2
2
2
2
2
4
8
5
10
20
10
5
10
10
10
10
10
10
20
20[c]
10
10
0.2
0.2
0.2
0.1
0.02
0.2
r.t.
–50
–50
–85
r.t.
–70
–70
–70
–70
–70
–70
–70
–70
–70
–70
68
44
44
68
68
20
20
20
44
92
92
92
92
92
92
50
52
69
15
13
42
52
38
39
21
11
36
27
51
63
58
72
72
86
60
84
75
87
91
91
88
85
88
87
80
0.2
0.07
0.05
0.03
0.01
0.03
0.03
0.03
0.03
9
10
11
12
13
14
15
1
[a] Determined by H NMR spectroscopy by using styrene as an internal standard. [b] Determined by CSP-HPLC, see Exp. Section and
the Supporting Information. [c] Added in 2 10 mol-% portions with the second portion at t = 44 h.
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(Table 1, Entry 8). Nitro-substituted substrate 34 proved Table 4. Evaluation of substrate scope.
markedly inferior to 33 and thus its use was not investigated
further (Table 1, Entry 9).
With the superior catalyst and substrates identified, we
next optimized the reaction conditions. Owing to the com-
plexity of the system (vide supra), exhaustive experimenta-
tion was required. A selection of data from this study is
presented in Table 3. The study began with an examination
of the influence of the thiol loading. Treatment of 33 with
one equivalent of thiol 5 in the presence of 26 under other-
wise identical conditions to those outlined in Table 2 led to
a small improvement in ee with an attendant drop in reac-
tion rate (Table 3, Entry 1). Attempts to improve selectivity
and simultaneously avoiding a deleterious reduction in rate
through increasing catalyst loading to 10 mol-% and reduc-
ing the reaction temperature to –50 °C proved a qualified
success. Compound 35 was formed in similar yield but with
improved ee (72%). As expected, increasing the catalyst
loading to 20 mol-% amplified the yield further (Table 3,
Entry 3). Although a reduction in concentration and reac-
tion temperature led to very good enantioselectivity, prod-
uct yield under these conditions was unacceptable (Table 3,
Entry 4). Returning to reaction at ambient temperature, we
next evaluated the influence of concentration. Dilution by
a factor of 2 (by using 2 equiv. of the thiol nucleophile) did
lead to a marginal improvement in selectivity (relative to
other reactions at room temp.) in a very slow process
(Table 3, Entry 5). Employment of a strategy involving care-
ful manipulation of both the concentration and the thiol
loading at –70 °C (Table 3, Entries 6–9) allowed the identifi-
cation of a set of conditions (Table 3, Entry 9) under which
35 could be formed in 39% yield and 91% ee at a reaction
concentration of 0.05 m. Further attempts to improve selec-
tivity through dilution produced only progressively slower
reactions (Table 3, Entries 10–12), however we found that it
was possible (at the cost of a small degree of enantio-
selectivity) to partially mitigate this through increases in
either catalyst or thiol loading (Table 3, Entries 12–15). It
is noteworthy that catalyst loading appeared to be less im-
portant than thiol loading. To investigate the possibility of
catalyst decomposition being significant in these reactions,
we analysed a reaction by using 20 mol-% catalyst to one
involving the same catalyst loading spread between two
portion-wise additions of 10 mol-% each. To our surprise
the portion-wise addition strategy proved inferior (Table 3,
Entries 12–13). In summary, this study produced two useful
sets of reaction conditions. The first allowed the DKR of
an azlactone by thiolysis to occur in Ͼ 90% ee (for the first
time) and 39% yield (Table 3, Entry 9), and the second in-
volved the use of a greater excess of thiol that produces the
product in slightly lower (yet still unprecedented) 87% ee
and 51% yield (Table 3, Entry 14).
Substrate Scope
[a] Data taken from ref.[16]. [b] Isolated yield after chromatography.
[c] Determined by CSP-HPLC, see Exp. Section and the Support-
ing Information. [d] 0.05 m, 5 (2 equiv.). [e] 0.05 m, 5 (4 equiv.), 26
Attention now focused on the issue of substrate scope
(Table 4). In our previous studies (Scheme 1), we failed to (20 mol-%).
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Enantioselective Dynamic Kinetic Resolutions of Azlactones
achieve excellent levels of product enantiomeric excess with of the process and can be formed with excellent ee (41 and
any substrate;[15,16] with the problem particularly exacer- 42, respectively; Table 4, Entries 6 and 7).
bated by using azlactones derived from branched chain
Somewhat gratifyingly, catalyst 26 proved compatible
amino acids, such as valine. Consequently, we were pleased with azlactones prepared from the previously recalcitrant
to find that 26 could catalyse the thiolytic DKR of an ala- branched chain amino acids. Previously unobtainable tert-
nine-derived azlactone with 5 to furnish 37 in 55% yield leucine derived thioester 43 could be formed in 90% ee (al-
and 84% ee (Table 4, Entry 1). The enantioselectivity could beit with low isolated yield; Table 4, Entry 8) and unnatural
be improved slightly at lower loadings of thiol (Table 4, En- α-cyclohexyl-substituted variant 44 was generated with al-
try 2), at the expense of product yield. The corresponding most identical efficiency and enantioselectivity (Table 4,
phenylalanine-derived azlactone behaved in a similar man- Entry 9). Thioester 45 is derived from an extraterrestrial
ner affording thioester 38 in 84% ee and 41% yield (Table 4, amino acid isolated from the carbonaceous Murchison me-
Entry 3). Thioesters formally stemming from α-unbranched teorite[29] and was formed in relatively good yield and 90%
unnatural amino acids could also be synthesized by using ee (Table 4, Entry 10).
this methodology in high ee (39 and 40; Table 4, Entry 4
In every case in which a comparison was possible, the
and 5); while analogues based on the naturally occurring new methodology outlined above by using catalyst 26 pro-
isoleucine and methionine are also firmly within the orbit vided the thioester product with significantly higher levels
Scheme 4. Investigation into the source of catalyst deactivation.
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C. Palacio, S. J. Connon
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of enantiomeric excess than had been previously possible was due to unexpectedly rapid hydrolysis of the azlactone
(previous benchmark: 65–73% ee; this work: 84–92% ee, promoted by the catalyst. Attempts to ameliorate the results
Table 4).
through the use of molecular sieves were not successful.
An obvious limitation associated with the strategy is Most efficient catalyst 26 could promote the thiolytic DKR
lower product yields, which range from 24 to 60%. We also of azlactones with excellent enantioselectivity (84–92% ee)
observed that when the progress of these reactions was fol- for the first time, and surpassing the levels previously pos-
1
lowed by using H NMR spectroscopy, that the reaction sible for all substrates evaluated, including the hitherto re-
rate appeared to diminish rapidly after approximately 20– calcitrant azlactones derived from branched chain amino
40% conversion. In addition, several key resonances associ- acids.
ated with the catalyst shifted downfield during the reaction,
coinciding with the reduction in reaction rate. Because only
one new catalyst-derived compound is formed (as observed
by H NMR spectroscopy), we speculated that either cata-
Experimental Section
1
General Methods: Proton Nuclear Magnetic Resonance spectra
were recorded with a 400 MHz spectrometer in CDCl3 (unless
otherwise stated) referenced relative to residual CHCl3 (δ =
7.26 ppm). Carbon NMR spectra were recorded with the same in-
strument (100 MHz) with total proton decoupling. Fluorine NMR
spectra were recorded at 350 MHz. Mass spectra were recorded by
electron impact ionization, in ES positive or ES negative modes for
electron spray mass spectroscopy. Infrared spectra were recorded
with a Perkin–Elmer Spectrum 100 FT-IR spectrometer. All melt-
ing points were determined with a Stuart SMP3 apparatus. Flash
chromatography was carried out by using silica gel, particle size
0.04–0.063 mm. TLC analysis was performed on precoated 60F254
slides, and visualized by UV irradiation, and KMnO4 staining. Un-
less otherwise stated, all chemicals were commercially sourced and
used without purification. 4-tert-Butylbenzyl mercaptan was dis-
tilled under low pressure prior to use. All reactions were carried
out under a protective argon atmosphere. The azlactones were im-
mediately used after preparation owing to their instability. Di-
chloromethane was distilled from CaH2 under an Ar atmosphere.
The starting material used in the synthesis of cinchona alkaloid
derivative 26 was prepared according to the literature.[26]
lyst acylation (most likely at C-9, e.g. 46, Scheme 4, A) or
hydrolysis of the azlactone by adventitious water leading to
catalyst poisoning through protonation by the product N-
aroyl amino acid (i.e. 47) was responsible.
To distinguish between these two possibilities, we reacted
azlactone 33 with catalyst 26 in wet (i.e. not anhydrous)
CDCl3 (Scheme 4, B). Over a period of 4 days we observed
the conversion of 33 and 26 into a new product consistent
with ion pair structure 47. This result was confirmed by
independently mixing a 1:1 mixture of catalyst 26 and N-p-
trifluoromethylbenzoyl valine in CDCl3 and analysed the
resultant 1H NMR spectrum with that obtained from in
situ monitoring of the reaction outlined in Scheme 4 (B)[32]
.
Thus it is likely that adventitious water is the source of the
sub-optimal yields associated with the methodology.
This was quite a surprise, because we have significant
experience with this particular reaction and both related
azlactone DKR reactions[15,16,17] and other catalytic meth-
odologies involving thioester intermediates/products[30] and
had never encountered hydrolysis as a problem when stan-
dard precautions to eliminate adventitious water were
taken. In an attempt to circumvent this, we carried out the
reaction (under unoptimised conditions) in the presence
and absence of 3 Å molecular sieves. Unfortunately under
Synthesis of Catalyst 26: Hydrochloric acid (aq. 36.5–38%,
54.0 mL) was added to an open round-bottomed flask along with
freshly distilled aniline (1.8 mL, 19.86 mmol). The obtained mix-
ture was allowed to cool to 0 °C and a solution of NaNO2 (1.5 g,
21.6 mmol) in water (18.0 mL) was added dropwise. The mixture
these conditions the sieves appear to retard the reaction to was stirred at 0 °C for 30 min. Meanwhile, the cinchona derivative
5Ј-amino-dihydroquinine[26] (6.0 g, 17.4 mmol) was dissolved in a
solution of glacial acetic acid (36.0 mL) in water (360.0 mL). The
obtained solution was treated with a saturated solution of sodium
acetate (36.0 mL) and cooled to 0 °C. Then, the diazotizing mixture
was added to the solution containing the substrate, in a dropwise
manner, insuring that the reaction temperature remained below
0 °C. The resulting reaction was stirred at 0 °C for 30 min. Finally,
ammonia solution (300.0 mL) was added to the reaction mixture,
and the product extracted with CH2Cl2 (3ϫ 250.0 mL). The com-
bined organic extracts were dried with sodium sulfate and concen-
a considerable extent (Scheme 4, C).[31]
Conclusions
We evaluated the performance of C-5Ј-substituted cin-
chona alkaloid catalysts in the dynamic kinetic resolution
of azlactones by thiolysis. The recently developed C-5Ј urea-
based systems 11 and 12, which have been demonstrated to
serve as effective bifunctional catalysts in other transforma- trated under vacuum. The resulting crude material was purified by
column chromatography (from 9:1:0.4, EtOAc/methanol/triethyl-
amine to 10:3, EtOAc/methanol). The impure (degrades on silica)
amino intermediate was obtained as a deep red solid and was used
directly in the next step without further purification. The amino
derivative (2.1 g, 4.80 mmol) was then dissolved in ethanol
(12.0 mL) and a mixture of H2O/HCl (1:1, 12.0 mL) was added and
the solution heated to reflux overnight. The resulting solution was
allowed to cool and diluted with H2O (20.0 mL). A saturated solu-
tion of NaHCO3 was added until the pH of the solution reached
8. The product was then extracted with CH2Cl2 (3ϫ 40.0 mL), the
tions, both performed poorly in this challenging process
(from both enantioselectivity and activity standpoints) fail-
ing to catalyse the reaction more effectively than quinine
itself. New, ad hoc designed conformationally restricted
urea derivative 14 also performed poorly from an enantio-
selectivity perspective.
A new class of C-5Ј-hydroxylated cinchona alkaloid cata-
lysts were then developed that were capable of considerably
more effective catalysis. Product yields were low to moder-
ate, ranging from 26–60%. It was established that this result combined organic extracts were dried with MgSO4 and concen-
5406 Eur. J. Org. Chem. 2013, 5398–5413
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Enantioselective Dynamic Kinetic Resolutions of Azlactones
trated under vacuum. Finally, the compound was purified by selec-
tive precipitation with ether to afford the desired product as a deep
red solid (1.7 g, 24%), m.p. Ͼ 300 °C (ref.[26] m.p. 145–148 °C).
[α]2D0 = –91.1 (c = 0.06 in CHCl3). Note: The synthesis of this com-
pound has been described by Jacobs and Heidelberger[26] with
minimal spectroscopic characterization data. Accordingly we have
provided characterization data below: 1H NMR (400 MHz,
CDCl3): δ = 0.87 (app. t, 3 H), 1.29–1.44 (m, 2 H), 1.49–1.59 (m,
2 H), 1.67–1.80 (m, 2 H), 1.87 (app. br. s, 1 H), 2.03–2.09 (m, 1 H),
reaction vessel was charged with half of the obtained crude (8.30 g,
24.56 mmol) and methanol (40.0 mL). The reactor was flushed
with argon and palladium on charcoal (2.70 g, 2.54 mmol) was
carefully added in small portions. This mixture was reacted under
3 atm of hydrogen for 3 h. After removing the palladium by fil-
tration through Celite, the filtrate was concentrated in vacuo. The
crude residue was purified by column chromatography (10:2,
EtOAc/methanol) to give the desired alkylated compound (6.20 g,
74%) as a colourless oil. [α]2D0 = –67 (c = 0.4 in CHCl3). H NMR
1
2.47 (app. d, 1 H), 2.69 (app. t, 1 H), 3.08 (app. t, 1 H), 3.26–3.39 (400 MHz, CDCl3): δ = 0.79 (app. t, 3 H), 1.13–1.29 (m, 2 H),
(m, 1 H), 3.50 (dd, J = 7.5, 16.0 Hz, 1 H), 3.93 (s, 3 H), 5.40 (app. 1.30–1.51 (m, 3 H), 1.66–1.82 (m, 3 H), 2.32–2.37 (m, 1 H), 2.65–
br. s, 1 H), 7.02 (s, 1 H), 7.15 (t, J = 7.2 Hz, 1 H), 7.43 (app. t, 2 2.73 (m, 1 H), 3.00–3.12 (m, 2 H), 3.31 (s, 3 H), 3.49–3.39 (m, 1
H), 7.49 (d, J = 7.8 Hz, 2 H), 7.70 (d, J = 4.6 Hz, 1 H), 8.83 (d, J H), 3.96 (s, 3 H), 5.02 (d, J = 2.8 Hz, 1 H), 7.33 (d, J = 2.4 Hz, 1
= 4.6 Hz, 1 H), 15.73 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 12.0, 25.3, 27.6, 28.1, 29.6, 37.6, 42.4, 55.8, 57.7, 58.8, 77.1,
H), 7.40 (dd, J = 9.2, 2.4 Hz, 1 H), 7.45 (d, J = 4.4 Hz, 1 H), 8.06
(d, J = 9.2 Hz, 1 H), 8.77 (d, J = 4.4 Hz, 1 H) ppm. 13C NMR
115.4, 117.2, 123.5, 124.0 (q), 124.1, 128.7 (q), 129.5, 142.8 (q), (100 MHz, CDCl3): δ = 11.6, 21.1, 25.0, 27.2, 27.9, 37.1, 42.9, 55.4,
149.0 (q), 149.8, 150.9 (q), 155.5 (q), 179.0 (q) ppm. IR (neat): ν =
56.7, 58.3, 59.3, 82.8, 100.7, 118.2, 121.2 (q), 127.0, 131.3, 144.1
˜
3239, 1619, 1519, 1475, 1340, 1232, 1069, 983 cm–1. HRMS (ESI):
(q), 144.2 (q), 147.1, 157.3 ppm (q). IR (neat): ν = 2901, 1623,
˜
calcd. for C26H30N4O3 [M + H] 447.2396; found 447.2394.
1589, 1507, 1449, 1430, 1372, 1227, 1133, 1112, 1086, 1028, 822,
717 cm–1. HRMS (ESI): calcd. for C21H28N2O2 [M + H] 341.2229;
found 341.2234.
Synthesis of Catalyst 28: Catalyst 26 (1.0 g, 2.24 mmol) was dis-
solved in freshly distilled CH2Cl2 (10.0 mL). DMAP (27.0 mg,
0.22 mmol) and triethylamine (1.6 mL, 11.20 mmol) were added. Synthesis of 31: Fuming nitric acid (22.0 mL) was added dropwise
The solution was cooled to 0 °C and tert-butylchlorodiphenylsilane into 250 mL round-bottomed flask containing 30 (5.40 g,
(1.30 mL, 4.87 mmol) was added dropwise through a syringe. The 15.89 mmol) at –10 °C ensuring the temperature remained below
a
reaction was then warmed to ambient temperature and stirred over-
night. The resulting solution was concentrated in vacuo and the
crude residue purified directly by column chromatography (100%
EtOAc to 7:3:0.5, EtOAc/methanol/triethylamine) to give the ex-
pected silyl protected derivative as a red solid (670 mg, 44%), m.p.
5 °C. The resulting solution was stirred at –10 °C for 30 min. Ice
water (340.0 mL), followed by NaOH (25% aq. solution, 84.0 mL)
were carefully added to the reaction in a dropwise manner. Finally,
a solution of NH3 (33% aq. solution, 104.0 mL) was poured onto
the obtained mixture. After extracting 31 from the reaction by
using CH2Cl2 (3ϫ 300.0 mL), the combined organic extracts were
washed with water (3ϫ 500.0 mL), dried with MgSO4 and concen-
trated in vacuo. The crude residue was purified by column
chromatography (10:0.5, EtOAc/methanol) to give the desired com-
pound (9.94 g, 86%) as a dark orange amorphous solid, m.p. 121–
123 °C. [α]2D0 = –162 (c = 0.1 in CHCl3). 1H NMR (400 MHz,
79–81 °C. [α]2D0 = –175.7 (c = 0.1 in CHCl3). H NMR (600 MHz,
1
CDCl3): δ = 0.91 (app. t, 3 H), 1.11 (s, 9 H), 1.25–1.51 (m, 4 H),
1.55–1.63 (m, 2 H), 1.77 (app. s, 1 H), 2.07 (app. t, 1 H), 2.24 (app.
d, 1 H), 2.41 (app. t, 1 H), 2.89 (dd, J = 9.6, 13.2 Hz, 1 H), 3.15
(app. dd, 1 H), 3.38 (m, 1 H), 3.88 (s, 3 H), 6.72 (s, 1 H), 7.00 (d,
J = 9.0 Hz, 1 H), 7.09 (t, J = 6.9 Hz, 1 H), 7.16–7.18 (m, 4 H),
7.22–7.26 (m, 2 H), 7.39–7.45 (m, 6 H), 7.50 (d, J = 7.2 Hz, 2 H), CDCl3): δ = 0.77 (app. t, 3 H), 1.12–1.41 (m, 5 H), 1.56–1.73 (m,
7.82 (d, J = 4.8 Hz, 1 H), 8.64 (d, J = 4.8 Hz, 1 H), 15.45 (s, 1
3 H), 2.39–2.47 (m, 1 H), 2.59–2.78 (m, 2 H), 3.04 (dd, J = 10.1,
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 12.2, 19.6 (q), 25.4, 3.2 Hz, 1 H), 3.25–3.41 (m, 4 H), 4.05 (s, 3 H), 4.76 (d, J = 2.4 Hz,
26.8, 27.2, 27.9, 28.7, 37.8, 43.0, 55.6, 58.2, 65.1, 71.5, 114.7, 115.1, 1 H), 7.58 (d, J = 9.4 Hz, 1 H), 7.76 (d, J = 4.5 Hz, 1 H), 8.29 (d,
122.4, 123.0, 123.5 (q), 127.1, 127.1, 128.7 (q), 129.3, 129.4, 129.4,
133.1 (q), 133.9 (q), 135.6, 135.9, 143.1 (q), 148.2 (q), 148.7, 150.6
J = 9.4 Hz, 1 H), 8.85 (d, J = 4.5 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 11.7, 20.7, 25.3, 27.3, 28.0, 37.1, 43.1, 56.5,
56.8, 58.2, 60.1, 80.5, 115.0, 118.8, 121.2 (q), 134.3 (q), 134.2, 143.0
(q), 158.7 (q), 178.5 (q) ppm. IR (neat): ν = 2928, 2858, 1631, 1517,
˜
1475, 1336, 1228, 1199, 1151, 1105, 1045, 861, 700 cm–1. HRMS
(q), 143.5 (q), 148.6, 149.3 (q) ppm. IR (neat): ν = 2969, 2906, 2862,
˜
(ESI): calcd. for C42H48N4O3Si [M + H] 685.3574; found 685.3566.
1622, 1580, 1526, 1509, 1458, 1443, 1343, 1100, 1085, 942, 903,
795, 787 cm–1. HRMS (ESI): calcd. for C21H27N3O4 [M + H]
386.2080; found 386.2087.
Synthesis of 30: Potassium hydride (3.96 g, 98.74 mmol) was
washed with hexane under a stream of argon and was suspended
in freshly distilled tetrahydrofuran (THF; 40.0 mL) in a 250 mL
round-bottomed flask fitted with a septum under an Ar atmo-
sphere (balloon). The suspension was cooled to 0 °C. In a second
250 mL round-bottomed flask fitted with a septum under an Ar
atmosphere was dissolved quinine (16.00 g, 49.32 mmol) in freshly
distilled THF (140.0 mL). This solution was added through a sy-
ringe at 0 °C to the stirred potassium hydride suspension. The re-
sulting mixture was stirred at 0 °C for 30 min and at 50 °C for an
additional 30 min. It was then cooled to room temperature and
methyl iodide (3.2 mL, 51.79 mmol) was added dropwise. After stir-
ring for 16 h, the reaction was cooled to 0 °C. Ice water (50.0 mL)
was cautiously added in a dropwise manner. The reaction was con-
centrated in vacuo and the residue was dissolved in ethyl acetate
(200.0 mL). The organic layer was washed with water (3ϫ
200.0 mL), dried with MgSO4 and concentrated in vacuo to give 9-
methoxy-quinine as a colourless oil. The crude residue was directly
used in the next step without further purification. A hydrogenation
Synthesis of 32: A hydrogenation reaction vessel was charged with
31 (7.05 g, 18.31 mmol) and methanol (20.0 mL). The reactor was
then flushed with argon and palladium on charcoal (2.54 g,
2.39 mmol) was carefully added portion wise. This mixture was re-
acted under 3 atm of hydrogen for 3 h. After removing the palla-
dium by filtration through Celite, the reaction was concentrated in
vacuo. The crude residue was purified by column chromatography
(10:0.2, EtOAc/methanol) to give the desired amino compound
(3.40 g, 53%) as an amorphous yellow solid, m.p. 56–62 °C. [α]2D0
= –188 (c = 0.1 in CHCl3). 1H NMR (400 MHz, [D6]DMSO, major
rotamer): δ = 0.72–0.85 (m, 3 H), 1.15–1.44 (m, 5 H), 1.56–1.73
(m, 2 H), 1.78–1.96 (m, 2 H), 2.24–2.36 (m, 1 H), 2.59–2.69 (m, 1
H), 2.94–3.12 (m, 1 H), 3.29 (s, 3 H), 3.75 (app. q, 1 H), 3.92 (s, 3
H), 4.50 (d, J = 6.8 Hz, 1 H), 5.97 (br. s, 2 H), 7.25–7.31 (m, 1 H),
7.34 (d, J = 9.1 Hz, 1 H), 7.49 (d, J = 9.1 Hz, 1 H), 8.51 (d, J =
4.1 Hz, 1 H) ppm. 1H NMR (400 MHz, [D6]DMSO, minor rot-
amer): δ = 0.72–0.85 (m, 3 H), 1.15–1.44 (m, 5 H), 1.56–1.73 (m,
Eur. J. Org. Chem. 2013, 5398–5413
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5407

C. Palacio, S. J. Connon
FULL PAPER
2 H), 1.78–1.96 (m, 1 H), 2.24–2.36 (m, 1 H), 2.59–2.69 (m, 1 H),
mixture was filtered and the filtrate was concentrated in vacuo.
2.94–3.12 (m, 3 H), 3.23 (s, 3 H), 3.92 (s, 3 H), 5.40 (br. s, 2 H), The remaining DCC by-product was precipitated with EtOAc and
5.55 (d, J = 2.0 Hz, 1 H), 7.25–7.31 (m, 1 H), 7.39 (d, J = 9.0 Hz, filtered. The obtained filtrate was concentrated under vacuum and
1 H), 7.47–7.55 (m, 1 H), 8.60 (d, J = 4.3 Hz, 1 H) ppm. 13C NMR
(100 MHz, [D6]DMSO, major rotamer): δ = 12.6, 25.4, 26.7, 27.8,
28.7, 37.5, 41.4, 56.4, 57.5, 58.0, 58.5, 89.3, 115.5, 116.9 (q), 117.9,
124.4, 132.7 (q), 143.0 (q), 144.2 (q), 146.0 (q), 147.4 ppm. 13C
NMR (100 MHz, [D6]DMSO, minor rotamer): δ = 12.4, 19.3, 25.5,
27.2, 28.1, 37.4, 42.6, 55.4, 56.4, 57.3, 60.9, 80.9, 115.9, 116.2, 117.8
(q), 119.0, 132.4 (q), 143.4 (q), 145.6 (q), 147.1 (q), 148.0 ppm. IR
was directly charged onto a short pad of silica gel for purification.
The desired azalactone was obtained pure as an oil that solidified
after drying under high vacuum (hygroscopic). This was used im-
mediately.
General Procedure by Using 1-Ethyl-3-(3-dimethylaminopropyl)-
carbodiimide (EDCI) for the Preparation of Azlactones: In a 50 mL
round-bottomed flask flushed with argon, fitted with a septum and
a magnetic stirring bar, was charged the appropriate N-protected
amino acid (1.08 mmol, 1 equiv.). Freshly distilled CH2Cl2
(10.0 mL) was added through a syringe, followed by a solution of
EDCI (1.19 mmol, 1.1 equiv.) in dry CH2Cl2 (5.0 mL). The reac-
tion was stirred at room temperature for 1 h. The resulting mixture
was washed with a saturated solution of NaHCO3 at 0 °C (2 ϫ
10.0 mL). The resulting organic layer was dried with MgSO4, con-
centrated under vacuum and directly charged onto a short pad of
silica gel for purification. The desired azalactone was obtained pure
as an oil that solidified after drying under high vacuum (hygro-
scopic). This was used immediately.
(neat): ν = 3430, 3318, 2929, 2862, 1621, 1569, 1521, 1457, 1344,
˜
1268, 1206, 1179, 1042, 1039, 810 cm–1. HRMS (ESI): calcd. for
C21H29N3O2 [M + H] 356.2338; found 356.2338.
Synthesis of Catalyst 29: Hydrochloric acid (aq. sol. 36.5–38%,
8.50 mL) was charged in an open round-bottomed flask and freshly
distilled aniline (0.26 mL, 2.87 mmol) was added. The obtained
mixture was allowed to cool to 0 °C and a solution of NaNO2
(220 mg, 3.17 mmol) in water (2.6 mL) was added dropwise. This
mixture was stirred at 0 °C for 30 min. Meanwhile, 32 (750 mg,
2.11 mmol) was dissolved in a solution of glacial acetic acid
(5.1 mL) in water (51.0 mL). The obtained solution was treated
with a saturated solution of sodium acetate (5.1 mL) and cooled to
0 °C. The diazotizing mixture was then added to the solution of
the substrate dropwise, keeping the reaction temperature at 0 °C.
The reaction was then stirred at 0 °C for 30 min. Ammonia solu-
tion (aq., 70.0 mL) was added and the product was extracted with
CH2Cl2 (3ϫ 50.0 mL). The combined organic extracts were dried
with NaSO4 and concentrated under vacuum. The resulting crude
was purified by column chromatography (100% CH2Cl2 to
10:0.5:0.5, CH2Cl2/methanol/triethylamine). The impure (degrades
on silica) amino derivative was obtained as a deep red solid and
was used in the second step without further purification. It was
dissolved in ethanol (6.0 mL) and a mixture of H2O/HCl (1:1,
12.0 mL) was added. The reaction was heated to reflux overnight.
The resulting solution was diluted in water (20.0 mL) and a satu-
rated solution of NaHCO3 was added until the pH of the solution
reached 8. The product was then extracted with CH2Cl2 (3ϫ
40.0 mL), the combined organic extracts were dried with MgSO4
and condensed under vacuum. Finally, the resulting crude material
was purified by column chromatography (10:0.2 to 10:0.6, EtOAc/
triethylamine) to give the desired compound as a deep red solid
(112 mg, 12%), m.p. 80–82 °C. [α]2D0 = –11.2 (c = 0.1 in CHCl3). 1H
NMR (600 MHz, CDCl3): δ = 0.86 (app. t, 3 H), 1.35–1.44 (m, 2
H), 1.60 (app. t, 1 H), 1.67–1.81 (m, 2 H), 1.90–2.05 (m, 3 H), 2.86
(app. d, 1 H), 3.15 (m, 1 H), 3.37 (s, 3 H), 3.43 (app. t, 1 H), 3.61
(m, 1 H), 3.82–3.96 (m, 4 H), 6.36 (d, J = 3.6 Hz, 1 H), 6.98 (s, 1
H), 7.13 (t, J = 7.5 Hz, 1 H), 7.42 (app. t, 2 H), 7.48 (d, J = 7.5 Hz,
2 H), 7.81 (d, J = 4.8 Hz, 1 H), 8.92 (d, J = 4.8 Hz, 1 H), 15.49 (s,
1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 11.7, 24.7, 26.0, 27.2,
36.1, 44.0, 53.3, 55.6, 56.8, 57.3, 59.8, 78.6, 115.1, 116.3, 120.7,
123.8, 123.9 (q), 128.2 (q), 129.4, 142.6 (q), 148.7 (q), 149.8, 150.7
N-p-Trifluoromethylbenzoyl Valine Azlactone Derivative (33): Pre-
pared according to the general procedure by using N-protected val-
ine (500 mg, 1.73 mmol) and DCC (371 mg, 1.80 mmol) in freshly
distilled CH2Cl2 (10.0 mL). After purification through a short pad
of silica gel (90:10, hexane/EtOAc), the desired substrate was ob-
tained as a white solid (406 mg, 87%), m.p. 40–42 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.05 (d, J = 6.8 Hz, 3 H), 1.19 (d, J =
6.8 Hz, 3 H), 2.44 (m, 1 H), 4.35 (d, J = 4.4 Hz, 1 H), 7.78 (d, J =
8.4 Hz, 2 H), 8.17 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 17.1, 18.3, 30.8, 70.4, 123.2 (q, J = 271.0 Hz), 125.4
(J = 3.7 Hz), 127.9, 128.8 (q), 133.7 (q, J = 32.0 Hz), 160.1 (q),
176.7 (q) ppm. 19F NMR (350 MHz, CDCl3): δ = –63.6 ppm. IR
(neat): ν = 2976, 2939, 1823, 1649, 1412, 1322, 1164, 1119, 1109,
˜
1036, 1005, 889, 840, 753, 699 cm–1. HRMS (ESI): calcd. for
C13H12NO2F3 [M – H] 270.0748; found 270.0742.
N-p-Trifluoromethylbenzoyl Alanine Azlactone Derivative: Prepared
according to the general procedure by using N-protected alanine
(400 mg, 1.53 mmol), DCC (272 mg, 1.32 mmol) in freshly distilled
CH2Cl2 (10.0 mL). After purification through a short pad of silica
gel (90:10, hexane/EtOAc) the desired substrate was obtained as a
white solid (276 mg, 74%), m.p. 38–39 °C. 1H NMR (400 MHz,
CDCl3): δ = 1.65 (d, J = 7.2 Hz, 3 H), 4.52 (q, J = 7.6 Hz, 1 H),
7.79 (d, J = 8.4 Hz, 2 H), 8.15 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 53.0, 60.7, 123.3 (q, J = 271.2 Hz), 125.3
(J = 3.7 Hz), 127.8, 128.7 (q), 133.8 (q, J = 32.7 Hz), 160.1 (q),
177.8 (q) ppm. 19F NMR (350 MHz, CDCl3): δ = –63.6 ppm. IR
(neat): ν = 2920, 1830, 1650, 1413, 1317, 1171, 1126, 1104, 1065,
˜
850, 684 cm–1. HRMS (ESI): calcd. for C11H8NO2F3 [M – H]
242.0429; found 242.0440.
(q), 152.2 (q), 178.2 (q) ppm. IR (neat): ν = 2956, 2916, 2849, 1620,
˜
N-p-Trifluoromethylbenzoyl Phenylalanine Azlactone Derivative:
Prepared according to the general procedure by using N-protected
phenylalanine (400 mg, 1.19 mmol) and DCC (257 mg, 1.25 mmol)
in freshly distilled CH2Cl2 (10.0 mL). After purification through a
short pad of silica gel (95:5, hexane/EtOAc), the desired substrate
was obtained as a white solid (223 mg, 59%). 1H NMR (400 MHz,
CDCl3): δ = 3.35 (d, J = 6.0 Hz, 2 H), 4.77 (app. s, 1 H), 7.06–7.54
(m, 5 H), 7.75 (app. s, 2 H), 8.07 (app. s, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 36.6, 66.2, 123.0 (q, J = 271.1 Hz), 125.3
(J = 3.7 Hz), 126.9, 127.8, 128.0, 128.6 (q), 129.1, 133.8 (q, J =
32.6 Hz), 134.5 (q), 160.2 (q), 176.5 (q) ppm. 19F NMR (350 MHz,
1518, 1473, 1463, 1366, 1221, 1230, 1158, 1103, 803, 730, 719 cm–1.
HRMS (ESI): calcd. for C27H32N4O3 [M – H] 459.2556; found
459.2570.
General Procedure by Using N,NЈ-Dicyclohexylcarbodiimide (DCC)
for the Preparation of Azlactones: In a 50 mL round-bottomed flask
flushed with argon, fitted with a septum and a magnetic stirring
bar, was charged the appropriate N-protected amino acid
(1.32 mmol, 1 equiv.). Freshly distilled CH2Cl2 (5.0 mL) was added
through a syringe, followed by a solution of 1,3-dicyclohexylcar-
bodiimide (1.26 mmol, 0.95 equiv.) in dry CH2Cl2 (5.0 mL). The
reaction was stirred at room temperature for 1–2 h. The resulting
CDCl ): δ = –63.7 ppm. IR (neat): ν = 2928, 1829, 1646, 1410,
˜
3
5408
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5398–5413

Enantioselective Dynamic Kinetic Resolutions of Azlactones
1320, 1298, 1124, 1107, 1062, 1048, 1015, 989, 895, 883, 692,
686 cm–1. HRMS (ESI): calcd. for C17H12NO2F3 [M – H] 318.0742;
found 318.0745.
1827, 1652, 1413, 1317, 1126, 1063, 1013, 880, 852, 693 cm–1.
HRMS (ESI): calcd. for C13H12NO2F3S [M – H] 302.0463; found
302.0464.
N-p-Trifluoromethylbenzoyl Butyric Acid Azlactone Derivative: Pre-
pared according to the general procedure by using N-protected but-
yric acid (406 mg, 1.48 mmol) and EDCI (367 mg, 1.92 mmol) in
freshly distilled CH2Cl2 (7.0 mL). After purification through a
short pad of silica gel (90:10, hexane/EtOAc), the desired substrate
was obtained as a white solid (148 mg, 39%), m.p. 24–26 °C. 1H
NMR (400 MHz, CDCl3): δ = 1.06 (t, J = 7.4 Hz, 3 H), 1.94–2.01
(m, 1 H), 2.05–2.14 (m, 1 H), 4.42 (t, J = 6.1 Hz, 1 H), 7.76 (d, J
= 8.1 Hz, 2 H), 8.13 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 9.5, 24.9, 66.6, 123.5 (q, J = 271.4 Hz),
125.8 (J = 3.7 Hz), 128.3, 129.2 (q), 134.3 (q, J = 31.7 Hz), 160.6
(q), 177.7 (q) ppm. 19F NMR (350 MHz, CDCl3): δ = –63.2 ppm.
N-p-Trifluoromethylbenzoyl tert-Leucine Azlactone Derivative: Pre-
pared according to the general procedure by using N-protected tert-
leucine (400 mg, 1.32 mmol) and DCC (259 mg, 1.26 mmol) in
freshly distilled CH2Cl2 (10.0 mL). After purification through a
short pad of silica gel (90:10, hexane/EtOAc), the desired substrate
was obtained as a white solid (138 mg, 37%), m.p. 51–53 °C. 1H
NMR (400 MHz, CDCl3): δ = 1.15 (s, 9 H), 4.11 (s, 1 H), 7.75 (d,
J = 8.2 Hz, 2 H), 8.14 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 26.1, 36.0 (q), 74.2, 123.6 (q, J = 271.1 Hz),
125.7 (J = 3.8 Hz), 128.3, 129.3 (q), 134.1 (q, J = 32.9 Hz), 160.2
(q), 176.3 (q) ppm. 19F NMR (350 MHz, CDCl3): δ = –63.2 ppm.
IR (neat): ν = 2928, 1830, 1650, 1413, 1317, 1171, 1104, 1065, 993,
˜
877, 850, 682 cm–1. HRMS (ESI): calcd. for C14H14NO2F3 [M –
IR (neat): ν = 2975, 2942, 1827, 1654, 1413, 1317, 1127, 1066, 1013,
˜
880, 853, 692 cm–1. HRMS (ESI): calcd. for C12H10NO2F3 [M –
H] 284.0898; found 284.0894.
H] 256.0585; found 256.0589.
N-p-Trifluoromethylbenzoyl 2-Cyclohexyl Glycine Azlactone Deriva-
tive: Prepared according to the general procedure by using N-pro-
tected 2-cyclohexyl glycine (500 mg, 1.52 mmol) and EDCI
(319 mg, 1.67 mmol) in freshly distilled CH2Cl2 (10.0 mL). After
purification through a short pad of silica gel (95:5, hexane/EtOAc),
the desired substrate was obtained as a cream solid (322 mg, 68%),
N-p-Trifluoromethylbenzoyl Norleucine Azlactone Derivative: Pre-
pared according to the general procedure by using N-protected nor-
leucine (328 mg, 1.08 mmol) and EDCI (228 mg, 1.19 mmol) in
freshly distilled CH2Cl2 (10.0 mL). After purification through a
short pad of silica gel (95:5, hexane/EtOAc), the desired substrate
was obtained as a white solid (234 mg, 76%), m.p. 42–44 °C. 1H
NMR (400 MHz, CDCl3): δ = 0.93 (t, J = 7.2 Hz, 3 H), 1.34–1.55
(m, 4 H), 1.81–1.94 (m, 1 H), 1.98–2.1 (m, 1 H), 4.44 (dd, J = 5.8,
7.0 Hz, 1 H), 7.76 (d, J = 8.3 Hz, 2 H), 8.13 (d, J = 8.3 Hz, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.7, 22.2, 27.3, 31.2,
65.5, 123.7 (q, J = 271.1 Hz), 125.7 (J = 3.9 Hz), 128.2, 129.2 (q),
134.2 (q, J = 32.7 Hz), 160.5 (q), 177.8 (q) ppm. 19F NMR
1
m.p. 39–40 °C. H NMR (400 MHz, CDCl3): δ = 1.11–1.49 (m, 5
H), 1.63–1.96 (m, 5 H), 2.10 (m, 1 H), 4.33 (d, J = 4.4 Hz, 1 H),
7.78 (d, J = 8.1 Hz, 2 H), 8.16 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 25.3, 25.4, 25.5, 27.3, 28.7, 40.2, 70.0, 123.1
(q, J = 271.2 Hz), 125.3 (J = 3.6 Hz), 127.8, 128.8 (q), 133.5 (q, J
= 32.6 Hz), 160.0 (q), 176.7 (q) ppm. 19F NMR (350 MHz, CDCl3):
δ = –63.7 ppm. IR (neat): ν = 2934, 2859, 1820, 1651, 1454, 1412,
˜
(350 MHz, CDCl ): δ = –63.3 ppm. IR (neat): ν = 2959, 2864, 1818,
˜
3
1320, 1297, 1166, 1110, 1064, 1013, 928, 879, 859, 843, 688,
685 cm–1. HRMS (ESI): calcd. for C16H16NO2F3 [M – H] 310.1055;
found 310.1052.
1655, 1412, 1320, 1167, 1126, 1107, 1068, 879, 852, 689 cm–1.
HRMS (ESI): calcd. for C14H14NO2F3 [M – H] 284.0898; found
284.0892.
N-p-Trifluoromethylbenzoyl 2-Amino-3-Ethylpentanoic Acid Azlact-
one Derivative: Prepared according to the general procedure by
using N-protected 2-amino-3-ethylpentanoic acid (400 mg,
1.26 mmol) and EDCI (266 mg, 1.39 mmol) in freshly distilled
CH2Cl2 (7.0 mL). After purification through a short pad of silica
gel (90:10, hexane/EtOAc), the desired substrate was obtained as a
cream solid (297 mg, 79%), m.p. 23–25 °C. 1H NMR (400 MHz,
CDCl3): δ = 0.93 (t, J = 7.4 Hz, 3 H), 1.02 (t, J = 7.4 Hz, 3 H),
1.37 (m, 2 H), 1.55 (m, 2 H), 1.89–2.01 (m, 1 H), 4.52 (d, J =
3.9 Hz, 1 H), 7.75 (d, J = 8.2 Hz, 2 H), 8.13 (d, J = 8.2 Hz, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.6 (2 C), 22.5, 23.1,
44.4, 67.6, 123.6 (q, J = 271.2 Hz), 125.7 (J = 3.8 Hz), 128.2, 129.3
(q), 134.1 (q, J = 32.7 Hz), 160.4 (q), 178.0 (q) ppm. 19F NMR
N-p-Trifluoromethylbenzoyl Isoleucine Azlactone Derivative: Pre-
pared according to the general procedure by using N-protected iso-
leucine (400 mg, 1.32 mmol) and DCC (259 mg, 1.25 mmol) in
freshly distilled CH2Cl2 (10.0 mL). After purification through a
short pad of silica gel (90:10, hexane/EtOAc), the desired substrate
was obtained as a white solid (291 mg, 77%), m.p. 25–27 °C. 1H
NMR (400 MHz, CDCl3): δ = 1.02 (d, J = 6.7 Hz, 3 H), 1.04 (d,
J = 6.7 Hz, 3 H), 1.69 (m, 1 H), 1.86 (m, 1 H), 2.02–2.12 (m, 1 H),
4.44 (dd, J = 5.6, 9.0 Hz, 1 H), 7.75 (d, J = 8.3 Hz, 2 H), 8.12 (d,
J = 8.3 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.0,
22.7, 25.3, 40.7, 64.1, 123.5 (q, J = 271.2 Hz), 125.8 (J = 3.8 Hz),
128.3, 129.4 (q), 134.2 (q, J = 33.2 Hz), 160.3 (q), 178.3 (q) ppm.
19F NMR (350 MHz, CDCl ): δ = –63.2 ppm. IR (neat): ν = 2962,
˜
3
(350 MHz, CDCl ): δ = –62.8 ppm. IR (neat): ν = 2940, 2877, 1823,
˜
3
2874, 1829, 1655, 1414, 1320, 1171, 1132, 1066, 1042, 1017, 882,
854, 694 cm–1. HRMS (ESI): calcd. for C14H14NO2F3 [M – H]
284.0898; found 284.0890.
1651, 1412, 1317, 1124, 1067, 941, 882, 847, 695 cm–1. HRMS
(ESI): calcd. for C15H16NO2F3 [M – H] 298.1055; found 298.1046.
N-p-Trifluoromethylbenzoyl Methionine Azlactone Derivative: Pre-
pared according to the general procedure by using N-protected
General Procedure for the Dynamic Kinetic Resolution of Azlact-
ones: A reaction vessel containing a stirring bar was flushed with
methionine (350 mg, 1.09 mmol) and EDCI (271 mg, 1.42 mmol) argon, charged with the quinine-based cinchona alkaloid catalyst
in freshly distilled CH2Cl2 (10.0 mL). After purification through a
short pad of silica gel (95:5, hexane/EtOAc), the desired substrate
was obtained as a white solid (54 mg, 16%), m.p. 47–48 °C. 1H
NMR (400 MHz, CDCl3): δ = 2.11–2.22 (m, 4 H), 2.29–2.39 (m, 1
H), 2.74 (app. t, 2 H), 4.65 (app. t, 1 H), 7.76 (d, J = 8.2 Hz, 2 H),
(0.010 equiv. or 0.020 equiv. as appropriate) and azlactone
(1 equiv.), before being closed with a suitable capp. Freshly distilled
CH2Cl2 (0.05 m or 0.03 m as appropriate) was injected through a
syringe. The vial was then introduced in the cooling machine set
up at –70 °C and the reaction mixture was let stir for 10 min to
8.13 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = reach this temperature. Finally, tert-butylbenzylmercaptan (2 equiv.
15.1, 30.1, 30.3, 63.8, 123.5 (q, J = 271.1 Hz), 125.8 (J = 3.7 Hz), or 4 equiv. as appropriate) was added dropwise to the reaction me-
128.3, 129.2 (q), 134.3 (q, J = 32.7 Hz), 161.0 (q), 177.8 (q) ppm. dia through a syringe. The resulting solution was stirred at –70 °C
1
19F NMR (350 MHz, CDCl ): δ = –63.2 ppm. IR (neat): ν = 2921,
for 3–4 d. The obtained solution was analysed by H NMR spec-
˜
3
Eur. J. Org. Chem. 2013, 5398–5413
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5409

C. Palacio, S. J. Connon
FULL PAPER
troscopy. The product was directly purified by flash chromatog-
raphy.
H), 7.10 (d, J = 3.6 Hz, 2 H), 7.20–7.31 (m, 5 H), 7.36 (d, J =
7.6 Hz, 2 H), 7.70 (d, J = 7.6 Hz, 2 H), 7.80 (d, J = 7.6 Hz, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 30.9, 32.6, 34.1 (q),
37.9, 59.2, 123.1 (q, J = 270.9 Hz), 125.2, 125.3 (J = 3.7 Hz), 127.0,
127.0, 128.2, 128.3, 129.0, 133.1 (q), 133.2 (q, J = 33.1 Hz), 134.6
(q), 136.5 (q), 150.1 (q), 165.2 (q), 198.5 (q) ppm. 19F NMR
N-p-Trifluoromethylbenzoyl Valine, 4-tert-Butylbenzyl Thioester
(35): Prepared according to the general procedure by using the val-
ine azlactone derivative (21.03 mg, 0.08 mmol), tert-butylbenz-
ylmercaptan (29 μL, 0.016 mmol) and the quinine-based cinchona
alkaloid catalyst (3.47 mg, 0.008 mmol) in freshly distilled CH2Cl2
(1.6 mL, 0.05 m). After purification of the crude material by flash
chromatography (90:10, hexane/EtOAc), the product was obtained
as a colourless oil (13.9 mg, 39%). The enantiomeric excess was
determined by chiral stationary phase (CSP)-HPLC analysis with a
Chiralcel OD-H column (4.6 mm ϫ 25 cm), n-hexane/IPA (90:10),
1.0 mL/min, λ = 220 nm. tR (major) = 6.40 min, tR (minor) =
7.53 min. 91% ee. [α]2D0 = –22.7 (c = 0.2 in CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 0.97 (d, J = 6.9 Hz, 3 H), 1.07 (d, J =
6.9 Hz, 3 H), 1.32 (s, 9 H), 2.37–2.51 (m, 1 H), 4.18 (app. s, 2 H),
4.95 (m, 1 H), 6.64 (d, J = 8.9 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 2 H),
(350 MHz, CDCl ): δ = –63.1 ppm. IR (neat): ν = 3291, 2963, 1647,
˜
3
1536, 1324, 1169, 1129, 1066, 1017, 909, 836, 731, 698 cm–1. HRMS
(ESI): calcd. for C28H28NO2F3S [M + Na] 522.1691; found
522.1684.
N-p-Trifluoromethylbenzoyl 4-tert-Butylbenzyl Thio-2-aminobut-
yrate (39): Prepared according to the general procedure by using
the aminobutyric acid azlactone derivative (32.40 mg, 0.13 mmol),
tert-butylbenzylmercaptan (48 μL, 0.26 mmol) and the quinine-
based cinchona alkaloid catalyst (5.76 mg, 0.01 mmol) in freshly
distilled CH2Cl2 (2.6 mL, 0.05 m). After purification of the crude
material by flash chromatography (95:5, hexane/EtOAc), the prod-
7.35 (d, J = 8.4 Hz, 2 H), 7.75 (d, J = 7.7 Hz, 2 H), 7.95 (d, J = uct was obtained as a colourless oil (18.30 mg, 47%). The enantio-
7.7 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.6, 19.1,
30.8, 31.3, 32.6, 34.1 (q), 63.5, 123.6 (q, J = 270.8 Hz), 125.2, 125.3
(J = 3.7 Hz), 127.5, 128.1, 133.0 (q), 133.3 (q, J = 32.6 Hz), 136.8
(q), 150.1 (q), 165.7 (q), 198.8 (q) ppm. 19F NMR (350 MHz,
meric excess was determined by CSP-HPLC analysis with a Chi-
ralcel OD-H column (4.6 mm ϫ 25 cm), n-hexane/IPA (90:10),
1.0 mL/min, λ = 220 nm. tR (major) = 7.92 min, tR (minor) =
10.30 min. 85% ee. [α]2D0 = +11.3 (c = 0.2 in CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 0.97 (t, J = 7.4 Hz, 3 H), 1.28 (s, 9 H),
1.74–1.89 (m, 1 H), 2.04–2.18 (m, 1 H), 4.14 (app. s, 2 H), 4.91
(ddd, J = 5.1, 7.9, 12.8 Hz, 1 H), 6.62 (d, J = 7.9 Hz, 1 H), 7.19
(d, J = 8.3 Hz, 2 H), 7.30 (d, J = 8.3 Hz, 2 H), 7.70 (d, J = 8.2 Hz,
2 H), 7.90 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 9.5, 26.4, 31.3, 33.0, 34.5 (q), 60.5, 123.5 (q, J = 271.2 Hz),
125.6, 125.7 (J = 3.8 Hz), 127.6, 128.5, 133.5 (q), 133.6 (q, J =
32.7 Hz) 137.1 (q), 150.5 (q), 165.8 (q), 199.4 (q) ppm. 19F NMR
CDCl ): δ = –63.5 ppm. IR (neat): ν = 3313, 2967, 1742, 1647,
˜
3
1535, 1323, 1161, 1126, 1065, 1017, 858, 733 cm–1. HRMS (ESI):
calcd. for C24H28NO2F3S [M + Na] 474.1691; found 474.1698.
N-p-Trifluoromethylbenzoyl Alanine, 4-tert-Butylbenzyl Thioester
(37): Prepared according to the general procedure by using the
alanine azlactone derivative (18.31 mg, 0.08 mmol), tert-butylbenz-
ylmercaptan (28 μL, 0.016 mmol) and the quinine-based cinchona
alkaloid catalyst (3.37 mg, 0.008 mmol) in freshly distilled CH2Cl2
(1.5 mL, 0.05 m). After purification of the crude material by flash
chromatography (95:5, hexane/EtOAc), the product was obtained
as a white solid (11.24 mg, 35%). The enantiomeric excess was de-
termined by CSP-HPLC analysis with a Chiralcel AS column
(4.6 mm ϫ 25 cm), n-hexane/IPA (90:10), 1.0 mL/min, λ = 220 nm.
(350 MHz, CDCl ): δ = –63.0 ppm. IR (neat): ν = 3326, 2960, 1676,
˜
3
1650, 1525, 1506, 1327, 1170, 1123, 1065, 1018, 855, 777, 706,
687 cm–1. HRMS (ESI): calcd. for C23H26NO2F3S [M + Na]
460.1534; found 460.1554.
N-p-Trifluoromethylbenzoyl Norleucine, 4-tert-Butylbenzyl Thio-
tR (major) = 8.00 min, tR (minor) = 10.64 min. 86% ee, m.p. 103– ester (40): Prepared according to the general procedure by using
105 °C. [α]2D0 = –2.9 (c = 0.1 in CHCl3). 1H NMR (400 MHz,
the norleucine azlactone derivative (38.21 mg, 0.13 mmol), tert-but-
CDCl3): δ = 1.32 (s, 9 H), 1.58 (d, J = 7.1 Hz, 3 H), 4.18 (app. t, ylbenzylmercaptan (100 μL, 0.52 mmol) and the quinine-based cin-
2 H), 4.95–5.08 (m, 1 H), 6.75 (d, J = 7.5 Hz, 1 H), 7.24 (d, J = chona alkaloid catalyst (5.98 mg, 0.013 mmol) in freshly distilled
8.2 Hz, 2 H), 7.35 (d, J = 8.2 Hz, 2 H), 7.74 (d, J = 8.1 Hz, 2 H), CH2Cl2 (4.5 mL, 0.03 m). After purification of the crude material
7.94 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = by flash chromatography (95:5, hexane/EtOAc), the product was
19.2, 31.3, 33.0, 34.5 (q), 55.4, 123.4 (q, J = 271.0 Hz), 125.7, 125.8
(J = 3.7 Hz), 127.6, 128.6, 133.4 (q, J = 32.7 Hz), 133.8 (q), 137.0
(q), 150.6 (q), 165.6 (q), 200.2 (q) ppm. 19F NMR (350 MHz,
obtained as a colourless oil (18.02 mg, 32%). The enantiomeric ex-
cess was determined by CSP-HPLC analysis with a Chiralcel AD-
H column (4.6 mm ϫ 25 cm), n-hexane/IPA (90:10), 1 mL/min, λ
CDCl ): δ = –63.0 ppm. IR (neat): ν = 3312, 2959, 1684, 1645,
= 220 nm. tR (major) = 15.74 min, tR (minor) = 16.89 min. 88%
˜
3
1534, 1505, 1323, 1167, 1110, 1064, 1017, 862, 840, 774, 694 cm–1. ee. [α]2D0 = –8.0 (c = 0.2 in CHCl3). H NMR (400 MHz, CDCl3):
1
HRMS (ESI): calcd. for C22H24NO2F3S [M + Na] 446.1385; found δ = 0.87 (t, J = 6.9 Hz, 3 H), 1.17–1.42 (s, 13 H), 1.64–1.81 (m, 1
446.1378.
H), 1.94–2.11 (m, 1 H), 4.13 (app. s, 2 H), 4.94 (ddd, J = 5.0, 8.2,
13.1 Hz, 1 H), 6.63 (d, J = 8.2 Hz, 1 H), 7.19 (d, J = 8.3 Hz, 2 H),
7.30 (d, J = 8.3 Hz, 2 H), 7.69 (d, J = 8.1 Hz, 2 H), 7.89 (d, J =
8.1 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.8, 22.3,
27.3, 31.2, 32.9, 33.0, 34.5 (q), 59.5, 123.6 (q, J = 271.2 Hz), 125.6,
125.7 (J = 3.7 Hz), 127.6, 128.5, 133.5 (q), 133.6 (q, J = 32.6 Hz),
137.1 (q), 150.5 (q), 165.8 (q), 199.7 (q) ppm. 19F NMR (350 MHz,
N-p-Trifluoromethylbenzoyl Phenylalanine, 4-tert-Butylbenzyl Thio-
ester (38): Prepared according to the general procedure by using
the phenylalanine azlactone derivative (24.13 mg, 0.076 mmol),
tert-butylbenzylmercaptan (56 μL, 0.30 mmol) and the quinine-
based cinchona alkaloid catalyst (3.37 mg, 0.008 mmol) in freshly
distilled CH2Cl2 (2.5 mL, 0.03 m). After purification of the crude
material by flash chromatography (95:5 to 85:15, hexane/EtOAc),
the product was obtained as a white solid (15.09 mg, 40%). The
enantiomeric excess was determined by CSP-HPLC analysis with a
Chiralcel AD-H column (4.6 mm ϫ 25 cm), n-hexane/IPA (90:10),
1.0 mL/min, λ = 220 nm. tR (major) = 15.91 min, tR (minor) =
18.96 min. 84% ee, m.p. 34–36 °C. [α]2D0 = +24.9 (c = 0.1 in CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.34 (s, 9 H), 3.30 (d, J = 5.6 Hz,
CDCl ): δ = –63.0 ppm. IR (neat): ν = 3284, 2961, 1646, 1535,
˜
3
1324, 1167, 1129, 1086, 1017, 909, 857, 732 cm–1. HRMS (ESI):
calcd. for C25H30NO2F3S [M + Na] 488.1847; found 488.1834.
N-p-Trifluoromethylbenzoyl Leucine, 4-tert-Butylbenzyl Thioester
(41): Prepared according to the general procedure by using the leu-
cine azlactone derivative (20.48 mg, 0.072 mmol), tert-butylbenz-
ylmercaptan (54 μL, 0.29 mmol) and the quinine-based cinchona
2 H), 4.16 (app. s, 2 H), 5.25 (app. dd, 1 H), 6.64 (d, J = 8.4 Hz, 1 alkaloid catalyst (3.21 mg, 0.007 mmol) in freshly distilled CH2Cl2
5410
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5398–5413

Enantioselective Dynamic Kinetic Resolutions of Azlactones
(2.4 mL, 0.03 m). After purification of the crude material by flash
chromatography (95:5, hexane/EtOAc), the product was obtained
as a colourless oil (19.30 mg, 60%). The enantiomeric excess was
determined by CSP-HPLC analysis with a Chiralcel AD-H column
(4.6 mm ϫ 25 cm), n-hexane/IPA (90:10), 1.0 mL/min, λ = 220 nm.
tR (major) = 6.61 min, tR (minor) = 8.40 min. 89% ee. [α]2D0 = +24.9
1168, 1129, 1066, 1017, 909, 856, 732 cm–1. HRMS (ESI): calcd.
for C25H30NO2F3S [M + Na] 488.1847; found 488.1852.
N-p-Trifluoromethylbenzoyl 2-Cyclohexylglycine, 4-tert-Butylbenzyl
Thioester (44): Prepared according to the general procedure by
using the 2-cyclohexylglycine azlactone derivative (34.69 mg,
0.11 mmol), tert-butylbenzylmercaptan (83 μL, 0.44 mmol) and the
quinine-based cinchona alkaloid catalyst (4.98 mg, 0.011 mmol) in
freshly distilled CH2Cl2 (3.7 mL, 0.03 m). After purification of the
crude material by flash chromatography (95:5, hexane/EtOAc), the
product was obtained as a white solid (14.3 mg, 26%). The enantio-
meric excess was determined by CSP-HPLC analysis with a Chi-
ralcel ODH column (4.6 mm ϫ 25 cm), n-hexane/IPA (90:10),
1.0 mL/min, λ = 220 nm. tR (major) = 5.31 min, tR (minor) =
6.59 min. 89% ee, m.p. 113–114 °C. [α]2D0 = –20.0 (c = 0.1 in
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.99–1.24 (m, 5 H), 1.27
(s, 9 H), 1.58–1.80 (m, 5 H), 1.97–2.08 (m, 1 H) 4.13 (app. s, 2 H),
4.88 (dd, J = 5.1, 9.1 Hz, 1 H), 6.59 (d, J = 9.1 Hz, 1 H), 7.19 (d,
J = 8.4 Hz, 2 H), 7.30 (d, J = 8.4 Hz, 2 H), 7.70 (d, J = 8.2 Hz, 2
H), 7.90 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 25.9, 25.9, 25.9, 27.7, 29.9, 31.3, 33.1, 34.5 (q), 41.5, 63.7, 123.6
(q, J = 271.2 Hz), 125.6, 125.7 (J = 3.8 Hz), 127.6, 128.5, 133.4 (q),
133.5 (q, J = 32.6 Hz), 137.2 (q), 150.5 (q), 165.9 (q), 199.2
(q) ppm. 19F NMR (350 MHz, CDCl3): δ = –63.0 ppm. IR (neat):
1
(c = 0.1 in CHCl3). H NMR (400 MHz, CDCl3): δ = 1.01 (t, J =
6.2 Hz, 6 H), 1.32 (s, 9 H), 1.63–1.82 (m, 2 H), 1.83–1.93 (m, 1 H),
4.16 (app. s, 2 H), 5.02 (ddd, J = 4.5, 9.1, 13.7 Hz, 1 H), 6.49 (d, J
= 9.1 Hz, 1 H), 7.23 (d, J = 8.3 Hz, 2 H), 7.35 (d, J = 8.3 Hz, 2
H), 7.75 (d, J = 8.1 Hz, 2 H), 7.95 (d, J = 8.1 Hz, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 21.7, 23.6, 25.0, 31.3, 33.0, 34.5 (q),
42.1, 58.1, 123.6 (q, J = 271.1 Hz), 125.6, 125.7 (J = 3.7 Hz), 127.6,
128.5, 133.4 (q), 133.6 (q, J = 30.4 Hz), 137.1 (q), 150.5 (q), 165.9
(q), 200.1 (q) ppm. 19F NMR (350 MHz, CDCl3): δ = –63.0 ppm.
IR (neat): ν = 3312, 2962, 1646, 1535, 1325, 1262, 1169, 1131, 1066,
˜
1017, 907. 802, 730 cm–1. HRMS (ESI): calcd. for C25H30NO2F3S
[M + Na] 488.1847; found 488.1870.
N-p-Trifluoromethylbenzoyl Methionine, 4-tert-Butylbenzyl Thio-
ester (42): Prepared according to the general procedure by using
the methionine azlactone derivative (26.30 mg, 0.085 mmol), tert-
butylbenzylmercaptan (32 μL, 0.17 mmol) and the quinine-based
cinchona alkaloid catalyst (3.87 mg, 0.009 mmol) in freshly distilled
CH2Cl2 (1.7 mL, 0.05 m). After purification of the crude material
by flash chromatography (98:2 to 95:5, hexane/EtOAc), the product
was obtained as a colourless oil (10.11 mg, 24%). The enantiomeric
excess was determined by CSP-HPLC analysis with a Chiralcel AS
column (4.6 mm ϫ 25 cm), n-hexane/IPA (95:5), 1.0 mL/min, λ =
220 nm. tR (major) = 16.35 min, tR (minor) = 21.66 min. 92% ee.
ν = 3400, 2931, 1672, 1655, 1521, 1485, 1323, 1269, 1164, 1128,
˜
1066, 1017, 856, 772, 700 cm–1. HRMS (ESI): calcd. for
C27H32NO2F3S [M + Na] 514.2004; found 514.1995.
N-p-Trifluoromethylbenzoyl 3-Pentylglycine, 4-tert-Butylbenzyl Thio-
ester (45): Prepared according to the general procedure by using
the 3-pentylglycine azlactone derivative (33.13 mg, 0.11 mmol),
tert-butylbenzylmercaptan (83 μL, 0.44 mmol) and the quinine-
based cinchona alkaloid catalyst (9.89 mg, 0.022 mmol) in freshly
distilled CH2Cl2 (2.2 mL, 0.05 m). After purification of the crude
material by flash chromatography (95:5, hexane/EtOAc), the prod-
uct was obtained as a white solid (27.7 mg, 51%). The enantiomeric
excess was determined by CSP-HPLC analysis with a Chiralcel
ADH column (4.6 mm ϫ 25 cm), n-hexane/IPA (90:10), 1.0 mL/
min, λ = 220 nm. tR (major) = 7.49 min, tR (minor) = 9.36 min.
90% ee, m.p. 60–62 °C. [α]2D0 = –6.11 (c = 0.2 in CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 0.92 (t, J = 7.4 Hz, 3 H), 1.00 (t, J =
7.4 Hz, 3 H), 1.18–1.32 (m, 11 H), 1.37–1.55 (m, 2 H) 1.91–2.03
(m, 1 H), 4.13 (app. s, 2 H), 5.12 (dd, J = 3.8, 9.4 Hz, 1 H), 6.49
(d, J = 9.4 Hz, 1 H), 7.19 (d, J = 8.3 Hz, 2 H), 7.30 (d, J = 8.3 Hz,
2 H), 7.71 (d, J = 8.2 Hz, 2 H), 7.90 (d, J = 8.2 Hz, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 11.8, 11.9, 22.4, 23.0, 31.3, 33.1,
34.5 (q), 45.0, 61.0, 123.6 (q, J = 271.9 Hz), 125.6, 125.8 (J =
3.7 Hz), 127.6, 128.5, 133.5 (q), 133.6 (q, J = 34.0 Hz), 137.3 (q),
150.5 (q), 166.1 (q), 200.1 (q) ppm. 19F NMR (350 MHz, CDCl3):
[α]2D0 = +19 (c = 0.1 in CHCl3). H NMR (400 MHz, CDCl3): δ =
1
1.28 (s, 9 H), 2.02–2.21 (m, 4 H), 2.24–2.35 (m, 1 H), 2.53–2.63 (m,
2 H), 4.14 (app. s, 2 H), 5.09 (ddd, J = 4.6, 7.7, 12.4 Hz, 1 H),
7.16–7.24 (m, 3 H), 7.31 (d, J = 8.3 Hz, 2 H), 7.72 (d, J = 8.2 Hz,
2 H), 7.93 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 15.5, 30.1, 31.2, 31.4, 33.1, 34.5 (q), 59.1, 123.6 (q, J =
271.1 Hz), 125.6, 125.7 (J = 3.7 Hz), 127.7, 128.5, 133.4 (q), 133.7
(q, J = 32.6 Hz), 136.8 (q), 150.6 (q), 165.9 (q), 199.3 (q) ppm. 19F
NMR (350 MHz, CDCl ): δ = –63.1 ppm. IR (neat): ν = 3271,
˜
3
2922, 1682, 1537, 1327, 1261, 1170, 1130, 1071, 1018, 854, 799,
705 cm–1. HRMS (ESI): calcd. for C24H28NO2F3S2 [M + Na]
506.1411; found 506.1419.
N-p-Trifluoromethylbenzoyl tert-Leucine, 4-tert-Butylbenzyl Thio-
ester (43): Prepared according to the general procedure by using
the tert-leucine azlactone derivative (35.57 mg, 0.125 mmol), tert-
butylbenzylmercaptan (93 μL, 0.50 mmol) and the quinine-based
cinchona alkaloid catalyst (5.57 mg, 0.012 mmol) in freshly distilled
CH2Cl2 (4.2 mL, 0.03 m). After purification of the crude material
by flash chromatography (98:2 to 95:5, hexane/EtOAc), the product
was obtained as a colourless oil (15.30 mg, 26%). [α]2D2 = +8.6 (c =
0.1, CHCl3). The enantiomeric excess was determined by CSP-
HPLC analysis with a Chiralcel ADH column (4.6 mm ϫ 25 cm),
n-hexane/IPA (90:10), 1.0 mL/min, λ = 220 nm. tR (major) =
7.91 min, tR (minor) = 8.73 min. 90% ee. [α]2D0 = +8.6 (c = 0.1 in
δ = –63.0 ppm. IR (neat): ν = 3284, 2965, 1676, 1641, 1535, 1322,
˜
1166, 1130, 1066, 1017, 857, 839, 770, 697 cm–1. HRMS (ESI):
calcd. for C26H32NO2F3S [M + Na] 502.2004; found 502.1999.
Supporting Information (see footnote on the first page of this arti-
cle): The synthesis of cinchona alkaloid 14, the determination of
the absolute configuration of (R)-35, NMR spectroscopic data, and
HPLC conditions and chromatograms are presented in the Sup-
porting Information.
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 1.08 (s, 9 H), 1.29 (s, 9
H), 4.14 (dd, J = 13.7, 23.2 Hz, 2 H), 4.79 (d, J = 9.4 Hz, 1 H),
6.66 (d, J = 9.4 Hz, 1 H), 7.20 (d, J = 8.2 Hz, 2 H), 7.31 (d, J =
8.2 Hz, 2 H), 7.72 (d, J = 8.2 Hz, 2 H), 7.90 (d, J = 8.2 Hz, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.3, 28.7, 30.8, 31.9
(q), 32.7 (q), 63.8, 121.1 (q, J = 271.2 Hz), 123.0, 123.2 (J =
3.8 Hz), 125.0, 125.9, 130.8 (q), 130.9 (q), 130.7 (q, J = 32.0 Hz),
Acknowledgments
147.9 (q), 163.1 (q), 195.8 (q) ppm. 19F NMR (350 MHz, CDCl3): Financial Support from the Irish Research Council is gratefully
δ = –63.0 ppm. IR (neat): ν = 3301, 2965, 1647, 1527, 1500, 1323, acknowledged.
˜
Eur. J. Org. Chem. 2013, 5398–5413
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5411

C. Palacio, S. J. Connon
FULL PAPER
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[26]
[27]
Presumably conjugation with the azo group allows tautomeri-
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hydrazone at C-8Ј. Hydrolysis of this imine-like tautomer in
the presence of acid, followed by tautomerisation to the phenol
may account for the facile incorporation of the hydroxy group
in these azo compounds.
We readily acknowledge that the pKa of the phenol moiety is
likely to be influenced by the presence of the 8Ј-azo group.
However we anticipated that the likely effect would be to in-
crease the acidity of the phenol and hence improve the poten-
tial hydrogen-bond donating prowess of the catalyst. For exam-
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[28]
[29]
[30]
5412
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5398–5413

Enantioselective Dynamic Kinetic Resolutions of Azlactones
2011, iv, 115; d) C. J. O’ Connor, F. Manoni, S. P. Curran, S. J.
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high propensity for hydrolysis despite considerable precautions
to avoid the introduction of moisture into the system. See: A.
Nakano, S. Kawahara, S. Akamatsu, K. Morokuma, M. Naka-
tani, Y. Iwabuchi, K. Takahashi, J. Ishihar, S. Hatakeyama,
Tetrahedron 2006, 62, 381.
1
[32] We carried out a preliminary H NMR spectroscopic study on
[31] While this manuscript was being prepared, we became aware
that Hatakeyama had reported that β-ICD (13; when recrys-
tallized from MeOH/H2O) contains a bound water molecule in
its crystalline form. Thus it is tempting (by analogy) to suggest
that 26 (which is also a demethylated cinchona alkaloid) may
be particularly hygroscopic, which would in part, explain the
the solution conformations of catalysts 26, 28 and 29. Their
conformational preferences are broadly in line with those of
the parent alkaloid, quinine. For details, see the Supplementary
Information.
Received: March 26, 2013
Published Online: July 4, 2013
Eur. J. Org. Chem. 2013, 5398–5413
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5413