Chemoenzymatic synthesis of optically active phenolic 3,4-dihydropyridin-2-ones: A way to access enantioenriched 1,4-dihydropyridine and benzodiazepine derivatives

Article abstract of DOI:10.1039/c7ob01066d

A chemoenzymatic approach for the synthesis of optically active 4-(3-acetoxyphenyl)-5-(alkoxycarbonyl)-6-methyl-3,4-dihydropyridin-2-ones (3,4-DHP-2-ones) and their hydroxyphenyl derivatives has been developed, the key step being a Candida rugosa lipase (CRL)-catalyzed hydrolysis reaction. As a result, different optically active 3,4-DHP-2-ones have been prepared with very high enantiomeric excesses (ee = 94-99%) and good yields. The enantioenriched 3,4-DHP-2-ones have easily been converted into highly functionalized (R)- and (S)-1,4-dihydropyridines (1,4-DHPs) by means of a Vilsmeier-Haack reaction. Finally, the coupling of the 1,4-DHPs with benzene-1,2-diamine using TFA as an acid promoter provided us the corresponding optically active hybrid 1,5-benzodiazepine-1,4-dihydropyridine (BZD-DHP) derivatives. No racemization took place in these processes and all optically active compounds were obtained in excellent yields.

Full text of DOI:10.1039/c7ob01066d

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DOI: 10.1039/C7OB01066D
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Chemoenzymatic synthesis of optically active phenolic 3,4-
dihydropyridin-2-ones: a way to access enantioenriched 1,4-
dihydropyridine and benzodiazepine derivatives†‡
Susana Y. Torres,a,b Rosario Brievaa and Francisca Rebolledo*a
Received 00th January 20xx,
Accepted 00th January 20xx
A chemoenzymatic approach for the synthesis of optically active 4-(3-acetoxyphenyl)-5-(alkoxycarbonyl)-6-methyl-
3,4-dihydropyridin-2-ones (3,4-DHP-2-ones) and their hydroxyphenyl derivatives has been developed, the key step
being a Candida rugosa lipase (CRL)-catalyzed hydrolysis reaction. As a result, different optically active 3,4-DHP-2-ones
have been prepared with very high enantiomeric excesses (ee = 94-99%) and good yields. The enantioenriched 3,4-DHP-
2-ones have easily been converted into highly functionalized (R)- and (S)-1,4-dihydropyridines (1,4-DHPs) by means of a
Vilsmeier-Haack reaction. Finally, the coupling of the 1,4-DHPs with benzene-1,2-diamine using TFA as an acid promoter
provided us the corresponding optically active hybrid 1,5-benzodiazepine-1,4-dihydropyridine (BZD-DHP) derivatives. No
racemization took place in these processes and all optically active compounds were obtained in excellent yields.
DOI: 10.1039/x0xx00000x
www.rsc.org/
clinics for the treatment of cardiovascular and cerebrovascular
diseases7 and in the synthesis of natural products,8 while the
Introduction
hybrid BZD-DHP is
a multi-target-directed ligand whose
3,4-Dihydropyridin-2-ones (3,4-DHP-2-ones, Figure 1) are
components of natural products1 and essential structural units
in medicinal and synthetic chemistry. As an example, some
carboxamide derivatives exhibit activities as Rho kinase
inhibitors,2 selective 1a adrenergic receptor antagonists,3
P2X7 receptor antagonists4 or G protein-coupled kinase
receptor antagonists.5 In addition, these structures can be
easily converted into other valuable compounds such as 1,4-
dihydropyridines (1,4-DHPs) and 1H-1,5-benzodiazepine-1,4-
dihydropyridine derivatives (BZD-DHPs, Figure 1).6 1,4-DHPs
are recognized as privileged pharmacophores widely used in
potential as a neuroprotective agent is under study.9 The
concept of a single compound that may be able to hit multiple
targets is an emerging strategy for the treatment of complex
diseases like neurodegenerative syndromes.10
Despite the close relationship between biological activity
and stereochemistry, the preparation of optically pure 3,4-
DHP-2-ones and thus their derivatives have scarcely been
described. Besides the resolution of racemic mixtures by
preparative chiral HPLC,2a the asymmetric synthesis of a 5-
carboxy-4-(p-fluorophenyl)-3,4-DHP-2-one and its methyl ester
derivative have been described by desymmetrization of a meso
anhydride using an optically active thiourea as an
organocatalyst.3b,11 Also,
a
series of 4-substituted-5-
(alkoxycarbonyl or cyano)-3,4-DHP-2-ones has been
synthesized via an enantioselective NHC-catalyzed aza-Claisen
rearrangement.12
In a previous report, as a part of our research on the
chemoenzymatic preparation of optically active 3,4-DHP-2-
ones and hybrid BZD-DHPs, we described the enantioselective
hydrolysis of acyloxymethyl esters derived from 3,4-DHP-2-
ones (Figure 2) using the Lipase B from Candida antarctica.13
The acyloxymethyl ester derivatives were required as
substrates after checking the absence of reactivity of the alkyl
(methyl or ethyl) ester analogues due to both steric and
electronic factors.14 Still, poor enantioselectivities were
achieved in these processes and the enantiomeric excess of
the resulting products had to be improved by combining either
the enzymatic resolution with a selective crystallization
process, or by means of two consecutive kinetic resolutions.
Figure 1. Representative structures.
a.Departamento de Química Orgánica e Inorgánica and Instituto Universitario de
Biotecnología de Asturias, Universidad de Oviedo, 33006-Oviedo (Asturias), Spain.
E-mail: frv@uniovi.es; Tel: +34 985 102982
b.Laboratorio de Síntesis Orgánica, Facultad de Química, Universidad de La
Habana, 10400 La Habana, Cuba.
†Dedicated to Prof. Vicente Gotor on the occasion of his 70th birthday.
‡Electronic Supplementary Information (ESI) available: HPLC chromatograms, and
NMR spectra. See DOI: 10.1039/x0xx00000x
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Figure 2. Non-phenolic and phenolic 3,4-DHP-2-ones capable of being transformed by
lipases.
Here, we have focused on the synthesis and resolution of
new 3,4-DHP-2-one derivatives bearing a phenolic unit in their
structure (Figure 2). The presence of the phenolic hydroxyl
group as such or as ester derivative will allow to address the
resolution of these heterocycles from a different place in the
molecule, which could have a beneficial effect on the
enantioselectivity of the lipase. In addition, the presence of
these functional groups may facilitate a further derivatization
of the molecule. On the other hand, phenols and their ester
derivatives have been much less studied than alcohols as
substrates in lipase or esterase catalyzed processes, even
though, some resolutions of binaphthols,15 biphenols,16 and
other phenolic esters present in compounds with remote
hindered stereogenic centers17 or in chiral phosphines and
sulphoxides18 have been reported.
Scheme 1. Synthesis of substrates (±)-10a-d (meta), (±)-11a,c (para), and (±)-12a
(ortho).
this finding, we selected the unhindered meta-phenolic
derivative (±)-6a as a model substrate to test the enzymatic
acylation. Several commercially available lipases [Candida
antarctica (CAL-A and CAL-B), Burkholderia cepacia (PSL-IM),
and Candida rugose (CRL)] were tested as catalyst. The
processes were carried out in 2-methyltetrahydrofurane (2-
Me-THF) as the solvent and using 5.0 equiv of vinyl acetate, or
also using the vinyl acetate as the solvent. Selection of 2-Me-
THF was based on the high solubility of the substrate in this
solvent and also considering its advantages in terms of health
and environment.21 However, no satisfactory results were
found in any of the proposed experiments, and no traces of
the product were detected after a prolonged reaction time (up
to 3 days at 28 °C).
Results and discussion
Synthesis and enzymatic resolution of racemic 5-(alkoxycarbonyl)-
4-(hydroxyphenyl)-6-methyl-3,4-DHP-2-one derivatives
Several
racemic
5-(alkoxycarbonyl)-4-(hydroxyphenyl)-6-
, and (±)-9a were
multicomponent reaction using the
1), the corresponding hydroxybenzaldehyde
methyl-3,4-DHP-2-ones (±)-6a-c, (±)-7a
synthesized by
Meldrum’s acid (
,c
a
and the
-ketoester 5a-c, in the presence of ammonium
Taking these disappointing results into account, we
focused our study on the enzymatic hydrolytic processes. For
this, the acylated derivatives (±)-10a-d (meta), (±)-11a,c (para),
and (±)-12a (ortho) were synthesized by conventional chemical
methods (Scheme 1).
The initial experiments were designed to find the most
suitable lipase for catalysing the hydrolysis of the meta-acetyl
derivative (±)-10a as a model substrate. In a first set of
experiments, lipases CAL-B, PSL-IM, and CRL were checked as
catalysts (Table 1). Due to the low solubility of the substrate in
an aqueous medium, 2-Me-THF was again chosen as the
solvent and a little amount of water (1.0% v/v) was added as
the reagent.
acetate following the previously reported procedure (Scheme
1).13,19 In these conditions, the desired meta- and para-
substituted phenolic derivatives (±)-6a-c and (±)-7a,c,
respectively, were obtained in good or moderate yields, but
the method failed starting from the o-hydroxybenzaldehyde.
Nevertheless, the ortho derivative (±)-9a could be obtained in
54% overall yield using o-benzyloxybenzaldehyde (4) in the
multicomponent process, followed by a hydrogenation under
standard conditions.
Although the lipase-catalyzed acylation reaction had shown
scarce utility to carry out the resolution of phenols and related
compounds,15b-c,16 we decided to start our study testing the
activity of different lipases in the acylation of the phenolic 3,4-
DHP-ones using vinyl acetate as an acyl donor. Previous results
obtained in the regioselective acetylation of polyphenols with
vinyl acetate showed that the regioselectivity of lipases
towards phenolic hydroxyls usually paralleled their chemical
reactivity, favouring the less hindered positions.20 Based on
Hydrolysis reactions of (±)-10a were carried out at 28 °C,
on a 5 mg (screening) or up to 100 mg (preparative) scale
amount. The processes were allowed to react until the
conversion was near 50% (TLC monitoring) or when hardly
further progress was observed. The obtained results have
2 | Org. Biomol. Chem, 2017, 00, 1-3
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Table 1. Lipase-catalyzed hydrolysis of (±)-10a, (±)-11a, and ()-12a in 2-Me-THF.
yields and high enantiomeric excesses, by simplyVaienw AardticeleqOunalitnee
control of the extent of the conversion.DTOhIu: 1s0,.1b0o3t9h/C(7RO)-B60a10a6n6Dd
(S)-10a were isolated with 94% ee after 5.5 and 7 h of
incubation, respectively (Table 1, entries 3 and 4). Moreover, it
can be noted that the resulting enantioenriched compounds
were recovered without significant loss of material after a
flash chromatography column (see experimental section).
All enzymes shown the same stereochemical preference
except PSL-IM (Table 1, entry 2). The assignment of the
absolute configuration of the enantioenriched products and
the remaining substrates is described later on this text.
Once the efficacy of the CRL lipase in the resolution of
substrate (±)-10a was demonstrated, the same reaction
conditions were applied to the resolution of the isomeric (±)-
11a (para) and (±)-12a (ortho) but, for both substrates, the
reaction proceeded with a E value near to 1 (Table 1, entries 5
and 6). Regarding the reactivity, the same trend described in
the regioselective hydrolysis of polyphenolic esters20 was
Substrate[a] Lipase[b]
t
(h)
ees
(%)[c]
12
eep
c
E[d]
Entry
(%)[c] (%)[d]
1
2
3
4
5
6
(±)-10a
(±)-10a
(±)-10a
(±)-10a
(±)-11a
(±)-12a
CAL-B
PSL-IM
CRL
CRL
CRL
9.0
5.5
5.5
7.0
0.25
432
32
27
52
41
51
57
44
2
4
64
67
1
1
45(R) 42(S)
66
94
16
8
94
90
12
10
observed in the processes with 10a-12a, the reaction rate
decreasing in the order para>meta>>ortho.
CRL
To check the influence of the substrate structure on the
enantioselectivity of the enzymatic hydrolysis, some structural
changes were incorporated in the model compound 10a. All
results achieved with the new substrates are summarized in
Table 2 and, for an easier comparison among them, those
obtained with (±)-10a have been included again (entry 1).
Firstly, the isobutyryl derivative (±)-10d with a higher steric
demand in the phenolic ester was prepared (Scheme 1) and
examined in the enzymatic hydrolysis. In this case, the reaction
was very slow and the enantioselectivity of the process
decreased considerably (E = 4, Table 2, entry 2). This result
discouraged us to try the same structural modification with the
para and ortho isomers.
a Reactions were carried out using 5 mg (entries 1, 2, 5, and 6), 77 mg (entry 3) or
86 mg (entry 4); 100 L of solvent/mg of substrate and H2O (1.0% v/v) were used.
b
c
Weight ratio enzyme/substrate 1:1. Enantiomeric excess of remaining
substrates 10a-12a (ees) and products 6a, 7a, and 9a (eep) were determined by
chiral HPLC; all enzymes showed the stereochemical preference indicated in the
scheme, except PSL-IM. d Conversion, c = ees/(ees + eep), and enantiomeric ratio,
E = ln[(1 – c)(1 – ees)]/ln [(1 – c)((1 + ees)] as indicated in ref. 22.
been summarized in Table 1 (entries 1-3). The reaction rate
was considerably fast in the processes catalyzed by PSL-IM and
CRL, and moderate in the case of CAL-B, but only CRL showed
simultaneously a high enantiomeric ratio22 (E = 64, entry 3).
This E value is high enough to allow us to obtain either the
remaining substrate (S)-10a and the product (R)-6a in good
Table 2. CRL-catalyzed hydrolysis of substrates (±)-10a-d and (±)-11c in 2-Me-THF.
Substrate[a]
R1
R2
t (h) Remaining ees (%)[c] Yield (%)[d] Product eep (%)[c] Yieldp(%)[d] c (%)[e] E[e]
Entry
Substrate
1
2
3
4
5
6
(±)-10a
(±)-10d
(±)-10b
(±)-10c
(±)-10c
(±)-11c
Me
Me
t-Bu Me
Bn
Bn
Bn
Me
7.0
(S)-10a
94
41
58
63
99
15
45
--
38
55
43
--
(R)-6a
(R)-6a
(R)-6b
(R)-6c
(R)-6c
(R)-7c
90
43
88
96
89
17
45
--
11
37
50
--
51
49
40
40
53
47
67
4
28
93
89
2
i-Pr 103 (S)-10d
8.3
15
44
(S)-10b
(S)-10c
(S)-10c
(S)-11c
Me
Me
Me
2.0
a Reactions were carried out at 77-150 mg scale amount, except in entries 2 and 6 (5 mg). b Weight ratio enzyme/substrate 1:1. c Determined by chiral HPLC.
d Isolated yield. e Conversion (c) and enantiomeric ratio (E) determined as in Table 1.
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DOI: 10.1039/C7OB01066D
Next, we planned to change the methyl ester at the 5-position
of the pyridone ring by the t-butyl or benzyl ester, [(±)-10b and
(±)-10c, respectively]. This modification could improve the
enantioselectivity of the enzyme due to the increased size of
one of the substituents of the chiral center. Furthermore, it
has the additional attractiveness of the greater synthetic
versatility of the new esters. As it was demonstrated in a
previous paper,13 whereas the hydrolysis of the methyl ester in
both conventional basic and enzymatic hydrolyses are
ineffective, the t-butyl or benzyl ester can be easily converted
into the carboxylic acids because this transformation does not
imply a nucleophilic attack to the carbonyl group.
Once synthesized esters (±)-10b and (±)-10c (Scheme 1),
their enzymatic hydrolyses were investigated in the already
described reaction conditions, using 2-Me-THF as the solvent
and CRL as catalyst. No satisfactory results were found in the
hydrolysis of the t-butyl ester (±)-10b. The reaction rate was
slightly lower than that of the methyl ester (±)-10a, and the
enantioselectivity decreased (E = 28, Table 2, entry 3). Another
drawback to this reaction was the poor performance of the
chromatographic separation of the resulting mixture (R)-6b
and (S)-10b, which led to a loss of yield as can be appreciated
in the data shown in Table 2. On the contrary, a considerable
enhancement of enantioselectivity (E = 93) was observed in
the CRL-catalyzed hydrolysis of the benzyl analogue (±)-10c
Scheme 2. Assignment of the absolute configuration to the enzymatically produced
compounds. a Its chiral-HPLC chromatogram was compared with a known sample.
established by chemical correlation. Thus, the hydrogenolysis
of the benzylic ester of the product ()-6c (see Table 2, entry
4) and the subsequent esterification of the resulting carboxylic
acid with diazomethane gave 6a (Scheme 2), which showed
the same chiral-HPLC chromatogram as (R)-6a. Taking into
account the (R)-enantiopreference of the CRL towards the
esters (±)-10a and (±)-10c, we have tentatively assigned the R
configuration to the enantioenriched product 6b and the S
configuration for the remaining ester 10b, both compounds
isolated in the CRL-catalyzed hydrolysis of (±)-10b (Table 2,
entry 3).
(Table 2, entry 4), which allowed us to isolate the product (R)
-
6c with very high ee (96%) and high yield after 15 h of
incubation. After a larger reaction time, a slightly higher 50%
conversion was reached and the remaining substrate (S)-10c
was isolated with 99% ee (Table 2, entry 5).
In view of the results obtained using the benzyl ester (±)-
10c, the analogue para-substituted (±)-11c was also prepared
(Scheme 1) and tested in the same conditions but, in this case,
no improvement in the enantioselectivity of the process was
observed (Table 2, entry 6). The preparation of the analogue
benzyl ortho derivative was discarded in the light of the
observed decreasing of the reaction rate with both 10c and
11c. This fact would have a dramatical consequence on the
hydrolysis process considering the extremely slow hydrolysis of
the methyl ortho derivative 12a (Table 1, entry 6).
Synthesis of optically active 6-chloro-5-formyl-1,4-DHP derivatives
and their hybrids 1,5-BZD-1,4-DHPs.
In order to address the synthesis of optically active hybrid BZD-
DHPs with potential therapeutic interest,9 the transformation
of the optically active 3,4-DHP-2-ones into the highly
functionalized 6-chloro-5-formyl-1,4-DHP derivatives is
required. To this aim, the enantioenriched 3,4-DHP-2-ones (R)-
6a,c and (S)-10a,c (ee 94%) were submitted to a Vilsmeier-
Haack (V-H) reaction (Scheme 3).23 When the acetylated
compounds (S)-10a,c were used as starting materials, the
corresponding 1,4-DHP derivatives (S)-14a,c were isolated in
excellent yields (86-92%). However, when the V-H reaction
was applied to (R)-6a,c, which contain the free hydroxyl group,
the reactions resulted in low yields due to the partial
formylation of this group. To avoid this undesired reaction,
previously to the V-H reaction, compounds (R)-6a,c were
converted into the corresponding acetates (R)-10a,c by a
conventional acetylation and then, transformed into the 1,4-
DHP (R)-14a,c. No racemization was observed in any of the
involved synthetic steps, as it was proven by chiral-HPLC
analysis.
Assignment of the absolute configuration of the
compounds isolated from the lipase catalyzed hydrolyses, and
thus the enantiopreference shown by the lipases in these
processes, was determined as follows: product ()-6a (94%
ee), which was obtained from the CRL-catalyzed hydrolysis of
(±)-10a (see Table 1, entry 3), was treated with KOH in DMF,
followed by methyl iodide, affording the methoxy derivative
(
)-13 (Scheme 2). The R configuration for this compound was
established after comparison of its chiral-HPLC chromatogram
with that one reported for (R)-13 13
configuration was also assigned to the preceding (
.
Therefore, the
R

)-6a. This
indicates that CRL shows preference towards the R-
enantiomer of the substrate (±)-10a, and that the isolated
optically active remaining 10a has the S configuration. The (R)-
preference of CRL towards the benzyl analogue 10c was also
Considering that the racemic 1,4-DHP phenolic acetates
(±)-14a-c are also susceptible to be hydrolysed by lipases,
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Absolute configuration of the enzymatically produced 1,4-
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DOI: 10.1039/C7OB01066D
DHPs (Table 3) and thereby, the opposite enantiopreference of
both employed lipases, was established by comparison of the
chiral-HPLC chromatogram of each sample with that of the
optically active 1,4-DHPs (S)-14a and (S)-14c previously
synthesized (Scheme 3).
Finally, the last objective of this work was the
transformation of the enantioenriched 1,4-DHPs (R)- and (S)-
14a,c (ee 94%) into the corresponding hybrids BZD-DHPs. The
coupling reaction between (R)- and (S)-14a,c and benzene-1,2-
diamine was carried out using trifluoroacetic acid (TFA) as an
acid promoter (Scheme 4), following our previously developed
method.6b In this way, the corresponding hybrids (R)- and (S)-
16a,c were isolated in almost quantitative yield (95-97%) as an
approximately 2:1 mixture of hydrochloride and trifluoroacetic
salts. Quantification of the presence of the counterion in the
structure of each BZD-DHP was carried out by 1H- and 19F-RMN
analyses using 1-chloro-3-fluoropropan-2-ol as an internal
reference.6b As it can be expected, taking the mild reaction
conditions and the non-involvement of the chiral centre in the
coupling reaction into account, the chiral-HPLC analyses
confirmed that no racemization took place in the process.
Scheme 3. Synthesis of optically active 4-(3-acetoxyphenyl)-1,4-DHPs 14a,c. The
priority order of the substituents of the chiral C-4 according to Cahn-Ingold-Prelog rule
is given (a>b>c).
these 1,4-DHPs were prepared from the racemic 3,4-DHP-2-
ones (±)-10a-c and evaluated as substrates. The lipases CAL-B,
PSL-IM, and CRL were tested as catalysts and the hydrolysis
processes conducted in the conditions described above for (±)-
10a-c. The most representative results obtained in these
reactions are summarized in Table 3.
When CRL was used as the catalyst, the reaction rates and
enantioselectivities were lower than for the corresponding 3,4-
DHP-2-ones (±)-10a-c (entries 1,3,5). On the contrary, the PSL-
IM-catalyzed hydrolysis of substrate (±)-14c showed better
enantioselectivity (E = 17, Table 3, entry 6) than that obtained
in the analogous hydrolysis of its precursor (±)-10c (E = 3, this
value is not shown in tables). Nevertheless, this result did not
improve what was obtained in the resolution of (±)-10c with
CRL (E = 93, Table 2, entry 4). Thus, although a further
optimization of the enzymatic resolution of the 1,4-DHP
derivatives can be performed, from the study carried out so
far, it can be concluded that the best approach to the
preparation of optically active 1,4-DHPs is the resolution at the
3,4-DHP-2-one stage.
Scheme 4. Synthesis of optically active phenolic BZD-DHP derivatives.
Table 3. Lipase-catalyzed hydrolysis of (±)-14a-c in 2-Me-THF.
Substrate[a]
(±)-14a
(±)-14a
(±)-14b
(±)-14b
(±)-14c
R
Lipase[b]
CRL
PSL-IM
CRL
PSL-IM
CRL
PSL-IM
t (h)
98
127
144
144
72
ees (%)[c]
Configuration
eep (%)[c]
Configuration
c (%)[d]
34
13
<5
E[d]
16
1
-
6
Entry
1
2
3
4
5
6
Me
Me
t-Bu
t-Bu
Bn
43
3
-
18
15
47
S
R
-
R
S
R
83
20
-
67
79
83
R
S
-
S
R
S
21
16
36
10
17
(±)-14c
Bn
7.5
a Reactions were carried out using 5 mg scale amount. b Weight ratio enzyme/substrate 1:1. c Determined by chiral HPLC. d Conversion, c = ees/(ees + eep),
enantiomeric ratio, E = ln[(1 – c)(1 – ees)]/ln [(1 – c)((1 + ees)].22
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Organic & Biomolecular Chemistry
CHIRALPAK IA column (4.6 × 250 mm), CHIRALCEVLieOwDArticcolelOunmlinne
(4.6 × 250 mm), and CHIRALPAK AD-H coDluOmI:n10(.410.639×/C275O0B0m10m66).D
In Figure 3 we show the numbering used in the assignation of
the NMR signals in the different structures.
General procedure for the synthesis of racemic 4-
(hydroxyphenyl)-3,4-DHP-2-ones (±)-6a-c, (±)-7a,c, and (±)-8a.
Conclusions
An efficient chemoenzymatic procedure to obtain valuable
optically active phenolic 3,4-DHP-2-ones, highly functionalized
1,4-DHPs, and their hybrids BZD-DHPs has been developed. In
this strategy the key step was an enantioselective hydrolysis of
the 3,4-DHP-2-one acetyl derivatives catalyzed by the
commercially available Candida rugose lipase. The mild
reaction conditions of the subsequent transformations
required to access to the 1,4-DHP and BZD-DHP derivatives
ensures the maintenance of the optical purity of the products,
which have been obtained in excellent yields.
Several aspects are noteworthy in this procedure. Firstly,
the high value of the synthesized optically active compounds,
whose biological activities are currently under study. Secondly,
the involvement of a biocatalytic step in the synthetic strategy
which improves the scalability of the process and affords
additional benefits from the sustainability point of view; this
feature was taken into account for the selection of 2-Me-THF
as the solvent of that step. Finally, focusing on the enzymatic
catalysis, the results presented here highlight the efficacy of
using the transformation of a phenolic ester to address the
resolution of a remote and sterically hindered stereogenic
centre.
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione
32.8 mmol) in acetic acid (9.5 mL), the aromatic aldehyde
or (32.8 mmol), the -ketoester 5a-c (32.8 mmol), and
1 (4.73 g,
2, 3
4

ammonium acetate (3.78 g, 49.1 mmol) were added. The
resulting mixture was stirred for 22-24 h at 80 ᵒC. Then, 15 mL
of water were added and the resulting mixture was extracted
with ethyl acetate (3 x 15 mL). The organic layer was
successively washed with aq saturated NaHCO3 (10 mL), water
(2 x 10 mL), and brine (10 mL), dried with Na2SO4, and
evaporated under reduced pressure to give the corresponding
4-(hydroxyphenyl)-3,4-DHP-2-one, which was purified by flash
chromatography (hexane:EtOAc mixtures).
(±)-4-(3-Hydroxyphenyl)-5-(methoxycarbonyl)-6-methyl-3,4-
dihydro-2(1H)-pyridone [(±)-6a]. Reaction time: 22 h. White
solid; mp 189-191 ᵒC; yield 82%; max(KBr) 3274, 1685, 1657,
1
1627, 1525 cm-1; H-NMR (CD3OD, 300.13 MHz):
 2.40 (d, 3H,
5J 0.7 Hz, CH3), 2.53 (dd, 1H, J 1.8, |2J| 16.3 Hz, HH-3), 2.94
3
(dd, 1H, J 8.0, |2J| 16.3 Hz, HH-3), 3.63 (s, 3H, OCH3), 4.16 (br
3
3
d, 1H, J 7.5 Hz, H-4), 6.75-6.51 (m, 3H, H-2’, H-4’, H-6’), 7.14-
7.03 (m, 1H, H-5’); 13C-NMR (CD3OD, 75.5 MHz): δ 18.6 (CH3),
39.1 (C-4), 39.4 (C-3), 51.7 (OCH3), 107.6 (C-5), 114.5
(CH),114.7 (CH), 118.9 (C-6’), 130.7 (C-5’), 145.1 (C-1’), 149.1
(C-6), 158.8 (C-3’), 169.1 (CO), 172.7 (C-2); HRMS-ESI+ calcd. for
[C14H15NNaO4]+ (MNa)+ 284.0893 m/z, found 284.0900.
Experimental Protocols
General. Enzymatic reactions were carried out in a
Gallenkamp incubatory orbital shaker. Immobilized Candida
antarctica lipase B, CAL-B (Novozym 435, 7300 PLU/g), was a
gift from Novo Nordisk co., immobilized CAL-A (lipase
IMMCALA-T2-150, 3000 U/g) from Chiralvision, C. rugosa
lipase was purchased from Sigma-Aldrich (CRL type VII, 700
U/mg), and immobilized Burkholderia cepacia (PSL-IM, 783
U/g) is commercialized by Amano Pharmaceutical Co. Chemical
reagents were supplied by Aldrich, Merck, ACROS organics or
Alfa Aesar. Solvents were distilled over an appropriate
desiccant under nitrogen. Flash chromatography was
performed using Merck silica gel 60 (230-400 mesh). Optical
rotations were measured using a Perkin-Elmer 343 polarimeter
and are quoted in units of 10-1 deg cm2 g-1. For the protonated
BZD a low concentration was used due to the intense color of
the solution. So, solutions of c = 1.0 (g/100 mL) were prepared
and they were successively diluted until to obtain a good
measurement of the optical deviation. 1H-NMR, 13C-NMR,
DEPT, and 19F-NMR spectra were recorded in a Bruker AC-300
or DPX-300 (1H, 300.13, 13C, 75.5, and 19F, 254.99 MHz)
(±)-5-(tert-Butoxycarbonyl)-4-(3-hydroxyphenyl)-6-methyl-
3,4-dihydro-2(1H)-pyridone [(±)-6b]. Reaction time: 22 h.
White solid; mp 187-188 ᵒC; yield 81%; max(KBr) 3406, 1617,
1
1599, 1481 cm-1; H-NMR (CD3OD, 300.13 MHz):
 1.35 (s, 9H,
5
3
But), 2.34 (d, 3H, J 0.9 Hz, CH3), 2.51 (dd, 1H, J 2.5, |2J| 16.3
Hz, HH-3), 2.91 (dd, 1H, J 8.2, |2J| 16.3 Hz, HH-3), 4.16-4.03
3
(m, 1H, H-4), 6.70-6.55 (m, 3H, H-2’, H-4’, H-6’), 7.13-7.02 (m,
1H, H-5’); 13C-NMR (CD3OD, 75.5 MHz): δ 18.4 (CH3), 28.4
[(CH3)3C], 39.4 (C-3), 39.8 (C-4), 81.4 [C(CH3)3], 109.6 (C-5),
114.6 (CH), 114.7 (CH), 119.0 (C-6’), 130.7 (C-5’), 145.8 (C-1’),
147.3 (C-6), 158.7 (C-3’), 168.1 (CO), 172.7 (C-2); HRMS-ESI+
calcd. for [C17H21NNaO4]+ (MNa)+ 326.1363 m/z, found
326.1358.
spectrometers using the
 scale (ppm) for chemical shifts.
Calibration was made on the signal of the solvent (13C: CDCl3,
77.16; CD3OD, 49.00; DMSO-d6, 39.52 ppm), the residual
solvent partially or non-deuterated (1H: CHCl3, 7.26; CHD2OD,
3.31; DMSO-d5, 2.50 ppm), or an externalreference (19F:
CF3COOH, –
76.55 ppm). HRMS were measured in ESI+ mode
with a Bruker micrOTOF spectrometer. IR spectra were
recorded in a FT-IR Rayleigh (WQF-510). The enantiomeric
excesses were determined by chiral HPLC analysis on a
Hewlett-Packard 1100, LC liquid chromatograph, using a
Figure 3. Numbering used in the assignation of the NMR signals.
6 | Org. Biomol. Chem, 2017, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
(±)-5-(Bencyloxycarbonyl)-4-(3-hydroxyphenyl)-6-methyl-3,4- 107.0 (C-5), 116.2 (C-3’), 120.3 (C-5’), 127.5 (C-4’), 128.1 (C-1’),
View Article Online
DOI: 10.1039/C7OB01066D
dihydro-2(1H)-pyridone [(±)-6c]. Reaction time: 23 h. White 128.9 (C-6’), 149.7 (C-6), 156.0 (C-2’), 169.2 (CO), 173.4 (C-2);
solid; mp 130-132 ᵒC; yield 84%; 
max(KBr) 3310, 1709, 1676, HRMS-ESI+ calcd. for [C14H16NO4]+ (M+H)+ 262.1074 m/z, found
1
1634, 1598 cm-1; H-NMR (CD3OD, 300.13 MHz):
 2.40 (s, 3H, 262.1069.
CH3), 2.53 (dd, 1H, J 1.7, |2J| 16.2 Hz, HH-3), 2.96 (dd, 1H, J General procedure for the acylation of 4-(hydroxyphenyl)-
3
3
8.2, |2J| 16.3 Hz, HH-3), 4.20 (br d, 1H, 3J 7.9 Hz, H-4), AB 3,4-DHP-2-ones. To a solution of the corresponding phenolic
system (
Ar), 7.17-7.01 (m, 3H, Ar), 7.31-7.17 (m, 3H, Ar); 13C-NMR (94 mg, 0.77 mmol) and acetic anhydride (109
(CD3OD, 75.5 MHz): δ 18.6 (CH3), 39.3 (C-4), 39.4 (C-3), 66.7 or 2-methylpropanoyl chloride (123 L, 1.16 mmol), were
A 5.04, 
B 5.11, |2JA,B| 12.7 Hz, CH2), 6.69-6.57 (m, 3H, (±)-6a-c, (±)-7a,c, or (±)-9a (0.77 mmol) in THF (5 mL), DMAP
L, 1.16 mmol)

(CH2), 107.5 (C-5), 114.6 (CH), 114.8 (CH), 119.1 (C-6’), 128.6 (2 added under an inert atmosphere. The mixture was stirred at
x CH), 128.8 (CH), 129.4 (2 x CH), 130.8 (CH), 137.8 (C-1”), room temperature for 4 h. Then, EtOAc (20 mL) was added and
145.4 (C-1’), 149.6 (C-6), 158.8 (C-3’), 168.3 (CO), 172.6 (C-2); the solution was successively washed with aq 1N HCl (15 mL),
HRMS-ESI+ calcd. for [C20H20NO4]+ (M+H)+ 338.1387 m/z, found water (2 x 15 mL) and brine (15 mL). The organic phase was
338.1371.
dried over Na2SO4 and the solvent was removed under
reduced pressure. No further purification was necessary.
(±)-4-(4-Hydroxyphenyl)-5-(methoxycarbonyl)-6-methyl-3,4-
dihydro-2(1H)-pyridone [(±)-7a]. Reaction time: 24 h. White (±)-4-(3-Acetoxyphenyl)-5-(methoxycarbonyl)-6-methyl-3,4-
solid; mp 195-197 ᵒC; yield 64%; max(KBr) 3341, 1749, 1638, dihydro-2(1H)-pyridone [(±)-10a]. White solid; mp 196-197 ᵒC;
1
1598, 1481 cm-1; H-NMR (CD3OD, 300.13 MHz):
 2.38 (d, 3H, yield 88%; 
max(KBr) 3217, 3123, 1768, 1705, 1689, 1636 cm-1;
5J 0.6 Hz, CH3), 2.50 (dd, 1H, J 1.9, |2J| 16.2 Hz, HH-3), 2.91 1H-NMR (CDCl3, 300.13 MHz):
 2.27 (s, 3H, CH3), 2.40 (s, 3H,
3
(dd, 1H, J 7.8, |2J| 16.2 Hz, HH-3), 3.63 (s, 3H, OCH3), 4.14 (br CH3COO), 2.71 (dd, 1H, 3J 1.2, |2J| 16.6 Hz, HH-3), 2.92 (dd, 1H,
3
d, 1H, 3J 7.8 Hz, H-4), 6.68 (d, 2H, 3J 8.6, H-3’, H-5’), 6.97 (d, 2H, 3J 8.0, |2J| 16.6 Hz, HH-3), 3.66 (s, 3H, OCH3), 4.26 (br d, 1H, J
3
3J 8.5, H-2’, H-6’); 13C-NMR (CD3OD, 75.5 MHz): δ 18.5 (CH3), 7.2 Hz, H-4), 6.89 (t, 1H, J 2.0 Hz, Ar), 6.96 (ddd, 1H, J 0.9, 4J
4
5
3
3
3
38.4 (C-4), 39.7 (C-3), 51.7 (CH3), 108.2 (C-5), 116.4 (C-3’ and C- 2.2, J 8.0 Hz, Ar), 7.05 (br d, 1H, J 7.8 Hz, Ar), 7.28 (t, 1H, J
5’), 128.7 (C-2’ and C-6’), 134.2 (C-1’), 148.8 (C-6), 157.3 (C-4’), 7.9 Hz, Ar), 7.91 (br s, 1H, NH); 13C-NMR (CDCl3, 75.5 MHz): δ
169.2 (CO), 172.9 (C-2); HRMS-ESI+ calcd. for [C14H15NNaO4]+ 19.5 (CH3), 21.3 (CH3COO), 37.7 (C-4), 38.0 (C-3), 51.7 (OCH3),
(MNa)+ 284.0893 m/z, found 284.0897.
106.7 (C-5), 120.0 (CH), 120.4 (CH), 124.2 (C-6’), 129.8 (C-5’),
(±)-5-(Bencyloxycarbonyl)-4-(4-hydroxyphenyl)-6-methyl-3,4- 143.8 (C-1’), 146.7 (C-6), 151.1 (C-3’), 167.3 (CO), 169.4
dihydro-2(1H)-pyridone [(±)-7c]. Reaction time: 24 h. White (CH3COO), 170.4 (C-2); HRMS-ESI+ calcd. for [C16H17NNaO5]+
solid; mp 166-167 ᵒC; yield 54%; 
max(KBr) 3367, 3235, 2949, (MNa)+ 326.0999 m/z, found 326.1007.
1
1694, 1628 cm-1; H-NMR (CD3OD, 300.13 MHz):
 2.39 (s, 3H, (±)-4-(3-Acetoxyphenyl)-5-(tert-butoxycarbonyl)-6-methyl-
CH3), 2.50 (dd, 1H, J 1.9, |2J| 16.3 Hz, HH-3), 2.93 (dd, 1H, J 3,4-dihydro-2(1H)-pyridone [(±)-10b] White solid; mp 133-134
3
3
8.0, |2J| 16.3 Hz, HH-3), 4.18 (br d, 1H, 3J 7.5 Hz, H-4), AB ᵒC; yield 82%; max(KBr) 3222, 3125, 1767, 1703, 1632 cm-1; 1H-

system (

A 5.02,

B 5.13, |2JA,B| 12.7 Hz, CH2), 6.68 (d, 2H, 3J 8.6 NMR (CDCl3, 300.13 MHz):

1.36 (s, 9H, But), 2.27 (s, 3H, CH3),
Hz, Ar), 6.96 (d, 2H, J 8.6 Hz, Ar), 7.20-7.10 (m, 2H, Ph), 7.31- 2.35 (s, 3H, CH3COO), 2.66 (dd, 1H, J 2.6, |2J| 16.7 Hz, HH-3),
7.22 (m, 3H, Ph); 13C-NMR (CD3OD, 75.5 MHz): δ 18.6 (CH3), 2.91 (dd, 1H, 3J 8.2, |2J| 16.7 Hz, HH-3), 4.18 (dd, 1H, 3J 2.6 Hz,
3
3
38.5 (C-4), 39.6 (C-3), 66.7 (CH2), 108.0 (C-5), 116.4 (2 x CH), 3J 8.5 Hz, H-4), 6.89 (t, 1H, J 1.9 Hz, Ar), 6.94 (ddd, 1H, J 0.9
128.6 (2 x CH), 128.81 (C-6’), 128.84 (2 x CH), 129.3 (2 x CH), Hz, 4J 2.2, 3J 8.0 Hz, Ar), 7.05 (d, 1H, 3J 7.8 Hz, Ar), 7.28 (t, 1H, 3J
134.5 (C), 137.8 (C), 149.1 (C-6), 157.3 (C), 168.3 (CO), 172.8 7.9 Hz, Ar), 7.59 (br s, 1H, NH); 13C-NMR (CDCl3, 75.5 MHz): δ
(C-2); HRMS-ESI+ calcd. for [C20H19NNaO4]+ (M+Na)+ 360.1220 18.9 (CH3), 21.3 (CH3COO), 28.2 [(CH3)3C], 37.9 (C-3), 38.3 (C-
3
5
m/z, found 360.1204.
(±)-4-(2-Hydroxyphenyl)-5-(methoxycarbonyl)-6-methyl-3,4-
4), 80.7 [C(CH3)3], 108.4 (C-5), 120.0 (CH), 120.2 (CH), 124.1 (C-
6’), 129.7 (C-5’), 144.5 (C-1’), 145.3 (C-6), 151.0 (C-3’), 166.1
dihydro-2(1H)-pyridone [(±)-9a]. Once the pyridone (±)-8a was (CO), 169.3 (CH3COO), 171.1 (C-2); HRMS-ESI+ calcd. for
obtained after a reaction time of 23 h and purification by flash [C19H23NNaO5]+ (MNa)+ 368.1468 m/z, found 368.1488.
chromatography (hexane:EtOAc 3:1), this compound (351 mg, (±)-4-(3-Acetoxyphenyl)-5-(bencyloxycarbonyl)-6-methyl-3,4-
1.0 mmol) was dissolved in methanol (69 mL) and 10% Pd-C dihydro-2(1H)-pyridone [(±)-10c]. White solid; mp 128-130 ᵒC;
1
(96 mg) was added. The mixture was stirred at room yield 94%;

max(KBr) 3216, 3117, 1763, 1692, 1632 cm-1; H-
temperature for 4 days. After this time, the catalyst was NMR (CDCl3, 300.13 MHz):
 2.25 (s, 3H, CH3), 2.40 (s, 3H,
filtered through a pad of Celite

and washed with methanol. CH3COO), 2.68 (dd, 1H, 3J 1.3, |2J| 16.6 Hz, HH-3), 2.92 (dd, 1H,
The solvents were evaporated giving (±)-9a as a white solid; 3J 8.2, |2J| 16.7 Hz, HH-3), 4.27 (br d, 1H, J 7.6 Hz, H-4), AB
3
mp 191-192 ᵒC; overall yield 54%; max(KBr) 3250, 1684, 1583, system (A 5.08, 
B 5.10, |2JA,B| 12.6 Hz, CH2), 6.87 (t, 1H, 4J 1.9
1
5
4
3
1431, 1343 cm-1; H-NMR (CD3OD, 300.13 MHz):
 2.38 (d, 3H, Hz, Ar), 6.97 (ddd, 1H, J 0.8 Hz, J 2.3, J 8.0 Hz, Ar), 7.02 (d,
3
3
5J 0.5 Hz, CH3), 2.67 (dd, 1H, J 2.1, |2J| 16.3 Hz, HH-3), 2.77 1H, J 7.8 Hz, Ar), 7.19-7.09 (m, 2H, Ar), 7.33-7.21 (m, 4H, Ar),
3
(dd, 1H, J 7.7, |2J| 16.3 Hz, HH-3), 3.55 (s, 3H, OCH3), 4.51 (br 8.67 (br s, 1H, NH); 13C-NMR (CDCl3, 75.5 MHz): δ 19.2 (CH3),
3
4
3
d, 1H, J 6.9 Hz, H-4), 6.65 (td, 1H, J (d) 1.2, J (t) 7.5 Hz, Ar), 21.3 (CH3COO), 37.7 (C-4), 37.9 (C-3), 66.1 (CH2), 106.4 (C-5),
6.74 (dd, 1H, 4J 1.2, 3J 8.0 Hz, Ar), 6.81 (dd, 1H, 4J 1.8, 3J 7.7 Hz, 120.0 (CH), 120.4 (CH), 124.2 (CH), 127.9 (CH), 128.0 (CH),
4
3
Ar), 6.98 (td, 1H, J (d) 1.7, J (t) 7.9 Hz, Ar); 13C-NMR (CD3OD, 128.5 (CH), 129.8 (CH), 136.2 (C-1”), 144.0 (C-1’), 147.4 (C-6),
75.5 MHz): δ 18.5 (CH3), 33.4 (C-4), 37.3 (C-3), 51.7 (OCH3), 151.1 (C-3’), 166.5 (CO), 169.3 (CH3COO), 171.1 (C-2); HRMS-
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Page 8 of 11
ARTICLE
Organic & Biomolecular Chemistry
ESI+ calcd. for [C22H21NNaO5]+ (MNa)+ 402.1312 m/z, found 2); HRMS-ESI+ calcd. for [C16H17NNaO5]+ (MNa)+ 32Vi6ew.0A9rt9ic9le Omnl/inze,
DOI: 10.1039/C7OB01066D
402.1325.
found 326.1003.
(±)-5-(Methoxycarbonyl)-6-methyl-4-[3-(2-
methylpropanoyloxy)phenyl)]-3,4-dihydro-2(1H)-pyridone
General procedure for the enzymatic hydrolysis. At the
screening processes scale, the reaction mixture containing the
[(±)-10d]. White solid; mp 178-180 ᵒC; yield 89%; max(KBr) corresponding acylated substrate (5.0 mg), the lipase (5.0 mg),
3431, 3224, 1754, 1693, 1639 cm-1; 1H-NMR (CDCl3, 300.13 H2O (5.0

L, 1% v/v) in 2-Me-THF (0.50 mL) was shaken at 28
5
MHz):

1.30 [d, 6H, (CH3)2CH], 2.41 (d, 3H, J 0.5 Hz, CH3), oC and 250 rpm in an orbital shaker. The progress of the
3
2.86-2.67 [m, 2H, HH-3 and CH(CH3)2], 2.91 (dd, 1H, J 8.0, |2J| reaction was monitored by TLC and chiral HPLC until the
3
16.6 Hz, HH-3), 3.66 (s, 3H, CH3O), 4.26 (br d, 1H, J 7.9 Hz, H- achievement of the required conversion. The same ratio of
4), 6.89 (t, 1H, J 1.9 Hz, Ar), 6.95 (ddd, 1H, J 1.0, 4J 2.2, 3J 8.0 substrate, enzyme, and solvent was employed in the
Hz, Ar), 7.02 (br d, 1H, 3J 7.8 Hz, Ar), 7.31-7.23 (m, 2H, Ar preparative scale processes. The reaction was carried out in
overlapped with CHCl3), 7.49 (br s, 1H, NH); 13C-NMR (CDCl3, the same conditions until the required conversion was
75.5 MHz): δ 19.0 [(CH3)2CH], 19.2 (CH3), 34.3 [(CH3)2CH], 37.6 achieved. Then, the enzyme was removed by filtration and
(C-4), 38.0 (C-3), 51.6 (OCH3), 106.6 (C-5), 120.0 (CH), 120.3 washed with MeOH. The crude residue was purified by flash
(CH), 123.8 (C-6’), 129.8 (C-5’), 143.7 (C-1’), 147.0 (C-6), 151.3 chromatography on silica gel (hexane:EtOAc 3:1 as the eluent).
4
5
(C-3’), 167.3 (CO), 171.0 (CH3COO), 175.5 (C-2); HRMS-ESI+ (R)-4-(3-Hydroxyphenyl)-5-(methoxycarbonyl)-6-methyl-3,4-
calcd. for [C18H21NNaO5]+ (MNa)+ 354.1312 m/z, found dihydro-2(1H)-pyridone [(R)-6a]. Yield 45%; D
92.5 (c
20
354.1308.
0.57, MeOH), ee 94%.
(S)-4-(3-Acetoxyphenyl)-5-(methoxycarbonyl)-6-methyl-3,4-
(±)-4-(4-Acetoxyphenyl)-5-(methoxycarbonyl)-6-methyl-3,4-
20
dihydro-2(1H)-pyridone [(±)-11a]. White solid; mp 178-180 ᵒC; dihydro-2(1H)-pyridone [(S)-10a]. Yield 45%; D +84.1 (c
yield 71%; 
max(KBr) 3213, 1765, 1685, 1631, 1430 cm-1; H- 0.64, CHCl3), ee 94%.
1
NMR (CDCl3, 300.13 MHz):
 2.28 (s, 3H, CH3), 2.40 (s, 3H, (R)-5-(tert-Butoxycarbonyl)-4-(3-hydroxyphenyl)-6-methyl-
20
CH3COO), 2.69 (dd, 1H, 3J 1.3, |2J| 16.5 Hz, HH-3), 2.92 (dd, 1H, 3,4-dihydro-2(1H)-pyridone [(R)-6b]. Yield 11%; D
162.8
3J 7.9, |2J| 16.6 Hz, HH-3), 3.65 (s, 3H, CH3O), 4.25 (br d, 1H, J (c 0.44, MeOH), ee 88%.
3
7.4 Hz, H-4), 6.99 (d, 2H, H-3’, H-5’), 7.18 (d, 2H, H-2’, H-6’), (S)-4-(3-Acetoxyphenyl)-5-(tert-butoxycarbonyl)-6-methyl-
20
8.15 (br s, 1H, NH); 13C-NMR (CDCl3, 75.5 MHz): δ 19.4 (CH3), 3,4-dihydro-2(1H)-pyridone [(S)-10b]. Yield 38%; D +66.0
21.3 (CH3COO), 37.3 (C-4), 38.1 (C-3), 51.6 (OCH3), 107.1 (C-5), (c 0.75, CHCl3), ee 58%.
121.9 (C-3’, C-5’), 127.9 (C-2’, C-6’), 139.5 (C-1’), 146.6 (C-6), (R)-5-(Bencyloxycarbonyl)-4-(3-hydroxyphenyl)-6-methyl-3,4-
20
149.7 (C-4’), 167.3 (CO), 169.6 (CH3COO), 170.8 (C-2); HRMS- dihydro-2(1H)-pyridone [(R)-6c]. Yield 37%; D
74.5 (c
ESI+ calcd. for [C16H17NNaO5]+ (MNa)+ 326.0999 m/z, found 0.72, MeOH), ee 96%.
326.0996.
(S)-4-(3-Acetoxyphenyl)-5-(bencyloxycarbonyl)-6-methyl-3,4-
dihydro-2(1H)-pyridone [(S)-10c]. Colourless oil. Yield 43%;
(±)-4-(4-Acetoxyphenyl)-5-(bencyloxycarbonyl)-6-methyl-3,4-
dihydro-2(1H)-pyridone [(±)-11c]. White solid; mp 163-164 ᵒC; D20 +81.1 (c 0.68, CHCl3), ee >99%.
yield 91%; 
max(KBr) 3221, 3112, 2974, 1759, 1693, 1633 cm-1; Acetylation of optically active 4-(hydroxyphenyl)-3,4-DHP-2-
1H-NMR (CDCl3, 300.13 MHz):
 2.29 (s, 3H, CH3), 2.41 (s, 3H, ones. The optically active 4-(hydroxyphenyl)-3,4-DHP-2-ones
CH3COO), 2.67 (dd, 1H, 3J 1.1, |2J| 16.6 Hz, HH-3), 2.93 (dd, 1H, (R)-6a and (R)-6c were acetylated in the same conditions used
3J 8.2, |2J| 16.6 Hz, HH-3), 4.28 (br d, 1H, J 7.7 Hz, H-4), AB for the racemic samples, thus affording the corresponding (R)-
3
20
system (

A 5.07,

B 5.11, |2JA,B| 12.6 Hz, CH2), 6.98 (d, 2H, 3J 8.6 10a (yield 85%; D
81.1 (c 1.41, CHCl3), ee 94%) and (R)-
Hz, Ar), 7.22-7.08 (m, 4H, Ar), 7.35-7.25 (m, 3H, Ar), 8.41 (br s, 10c (yield 90%; D20 77.4 (c 0.66, CHCl3), ee 96%).
1H, NH); 13C-NMR (CDCl3, 75.5 MHz): δ 19.3 (CH3), 21.3 Synthesis of optically active 1,4-DHPs 14a and 14c. (R)-14a
,
(CH3COO), 37.5 (C-4), 38.1 (C-3), 66.1 (CH2), 106.8 (C-5), 121.9 (S)-14a
, (R)-14c, and (S)-14c were prepared from the
(2 x CH), 127.9 (2 x CH), 128.0 (2 x CH), 128.1 (C), 128.6 (2 x corresponding optically active 3,4-DHP-2-ones (R)-10a, (S)-10a
,
CH), 136.2 (C), 139.7 (C), 147.2 (C-6), 149.7 (C), 166.5 (CO), (R)-10c, and (S)-10c, respectively, following the procedure
169.6 (CH3COO), 170.9 (C-2); HRMS-ESI+ calcd. for described in Ref. 13. Purification of the products was carried
[C22H21NNaO5]+ (MNa)+ 402.1312 m/z, found 402.1315.
(±)-4-(2-Acetoxyphenyl)-5-(methoxycarbonyl)-6-methyl-3,4-
out by flash chromatography (hexane:EtOAc 3:1 as the eluent).
Methyl (S)-4-(3-acetoxyphenyl)-6-chloro-5-methanoyl-2-
dihydro-2(1H)-pyridone [(±)-12a]. White solid; mp 167-169 ᵒC; methyl-1,4-dihydropyridine-3-carboxylate [(S)-14a]. Yellow
1
20
yield 88%;  3.4 (c 1.37, CHCl3), ee 94%. max(KBr)
max(KBr) 3210, 1723, 1710, 1628, 1548 cm-1; H- solid; yield 86 %; D
NMR (CDCl3, 300.13 MHz):

2.35 (s, 3H, CH3), 2.42 (s, 3H, 3407, 3259, 1763, 1661, 1492 cm-1; 1H-NMR (CDCl3, 300.13
CH3COO), 2.62 (dd, 1H, 3J 1.3, |2J| 16.6 Hz, HH-3), 2.87 (dd, 1H, MHz):
 2.27 (s, 3H, CH3), 2.42 (s, 3H, CH3COO), 3.63 (s, 3H,
3J 8.6, |2J| 16.7 Hz, HH-3), 3.57 (s, 3H, OCH3), 4.39 (br d, 1H, J CH3O), 5.16 (s, 1H, H-4), 6.51 (br s, 1H, NH), 6.92 (d, 1H, J 8.0
3
3
3
3
7.9 Hz, H-4), 7.17-6.98 (m, 3H, Ar), 7.34-7.18 (m, 1H, H-3’), 8.54 Hz, Ar), 6.99 (s, 1H, H-2’), 7.13 (d, 1H, J 7.8 Hz, Ar), 7.24 (t, J
(br s, 1H, NH). 13C-NMR (CDCl3, 75.5 MHz): δ 19.1 (CH3), 21.2 7.9 Hz, H-5’ overlapped with CHCl3), 9.78 (s, 1H, HC=O). 13C-
(CH3COO), 32.2 (C-4), 36.9 (C-3), 51.6 (OCH3), 105.9 (C-5), NMR (CDCl3, 75.5 MHz): δ 18.9 (CH3), 21.4 (CH3COO), 38.1 (C-
123.1 (C-3’), 126.5 (CH), 127.3 (CH), 128.3 (CH), 133.4 (C-1’), 4), 51.6 (OCH3), 105.8 (C-5), 112.6 (C-3) 120.1 (C-4’), 120.9 (C-
147.4 (C-6), 148.1 (C-2’), 167.1 (CO), 169.2 (CH3COO), 170.8 (C- 2’), 125.3 (C-6’), 129.2 (C-5’), 142.3 (C-1’), 144.6 (C-2), 146.7 (C-
6), 150.7 (C-3’), 167.1 (CO), 169.7 (CH3COO), 187.6 (CHO).
8 | Org. Biomol. Chem, 2017, 00, 1-3
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ARTICLE
HRMS-ESI+ calcd. for [C17H16ClNNaO5]+ (MNa)+ 372.0609 m/z, chloride/trifluoroacetate (5:2) mixed salt [(R)-16Vicew].ARrtieclaecOtniloinne
20
DOI: 10.1039/C7OB01066D
found 372.0608.
time 7.0 h; yield 97 %; D
36.7 (c 0.03, MeOH), ee >99%.
(R)-14a. Yield 84 %; D20 3.1 (c 1.32, CHCl3), ee 93%.

max(KBr) 3413; 3220; 1767; 1714; 1646; 1616 cm-1; H-NMR
1
Benzyl
methyl-1,4-dihydropyridine-3-carboxylate [(S)-14c]. Yellow CH3COO), 4.51 (s, 1H, H-4), AB system (A 5.00, B 5.13, |2JA,B
solid; yield 92 %; D20 14.9 (c 1.02, CHCl3), ee >99%; mp 75- 12.9 Hz, CH2), 6.65-6.47 (m, 2H, H-7, H-10), 7.31-6.80 (m, 11H,
(S)-4-(3-Acetoxyphenyl)-6-chloro-5-methanoyl-2- (DMSO-d6, 300.13 MHz): δ 2.25 (s, 3H, CH3), 2.37 (s, 3H,
|
3
3
77 ᵒC;
max(KBr) 3441, 3240, 3219, 1767, 1705, 1634, 1595, Ar and H-5), 7.35 (t, 1H, J 7.9 Hz, H-5’), 10.14 (br d, 2H, J 7.5
1
1489 cm-1; H-NMR (CDCl3, 300.13 MHz):

2.27 (s, 3H, CH3), Hz, H-6, NH), 11.04 (br s, 1H, NH). 13C-NMR (DMSO-d6, 75.5
2.42 (s, 3H, CH3COO), AB system (A 5.03, B 5.09, |2JA,B| 12.5 MHz): δ 17.9 (CH3), 20.9 (CH3COO), 41.2 (C-4), 65.6 (CH2), 94.6
Hz, CH2), 5.17 (s, 1H, H-4), 6.40 (br s, 1H, NH), 6.99-6.89 (m, (C-4a), 107.5 (C-3), 119.4 (C-4’), 120.5 (C-2’), 122.3 and 122.9
3
2H, Ar), 7.17-7.06 (m, 3H, Ar), 7.21 (t, 1H, J 7.8 Hz, Ar), 7.31- (C-7, C-10), 123.5 (C-6’), 127.4 (C-3”, C-5”), 127.7, 127.8 and
7.26 (m, 3H, Ar), 9.76 (s, 1H, HC=O). 13C-NMR (CDCl3, 75.5 128.0 (C-4”, C-8, C-9), 128.3 (C-2”, C-6”), 130.1 (C-5’), 131.8 (C-
MHz): δ 19.3 (CH3), 21.4 (CH3COO), 38.3 (C-4), 66.3 (CH2), 10a), 135.8 (C-6a), 136.0 (C-1”), 142.8 (C-2), 147.3 (C-1’), 150.9
105.9 (C-5), 113.0 (C-3) 120.2 (C-4’), 121.1 (C-2’), 125.63 (C-6’), (C-3’), 159.6 (C-11a), 160.3 (C-5), 165.2 (CO), 169.1 (CH3COO).
128.1 (C-3”, C-4”, C-5”), 128.6 (C-2”, C-6”), 129.2 (C-5’), 136.0 19F-NMR (DMSO-d6, 254.99 MHz): δ 74.05. HRMS-ESI+ calcd.

(C-1”), 141.4 (C-1’), 144.6 (C-2), 146.6 (C-6), 150.8 (C-3’), 166.2 For [C29H26N3O4]+ (M)+ 480.1918 m/z, found 480.1916 (the
(CO), 169.5 (CH3COO), 187.4 (CHO). HRMS-ESI+ calcd. for symbol M has been used for the no protonated molecule).
[C23H20ClNNaO5]+ (MNa)+ 448.0922 m/z, found 448.0913.
(R)-14c. Yield 84 %; D20 13.1 (c 1.14, CHCl3), ee 96%.
Synthesis of optically active hybrid BZD-DHPs 16a and 16c.
Following an analogous procedure to that described in Ref. 6b,
(S)-16a, (R)-16a, (S)-16c, and (R)-16c were prepared from the
(S)-16c. Reaction time 7.5 h; yield 96 %; D  (c 0.05,
20
MeOH), ee 96%.
Acknowledgements
optically active (R)-14a
, (S)-14a, (R)-14c, and (S)-14c,
This work was supported by the Ministerio de Ciencia e
Innovation of Spain (Project CTQ 2014-55015) and Principado
de Asturias (FC-15-GRUPIN14-002). S. Y. T. thanks to the
Spanish MAEC for a grant (MAEC-AECID program).
respectively (notice the change of the priority order of the
substituents of the chiral C-4 according to Cahn-Ingold-Prelog
rule, see Scheme 4): To a solution of the corresponding 1,4-
DHP 14 (0.10 mmol) in anhydrous THF (1.4 mL), bencene-1,2-
diamine (12 mg, 0.11 mmol) and TFA (7.7 L, 0.10 mmol) were
added. The resulting solution was stirred at r.t. for 7–8 h. The
specific reaction time is indicated in each case. All
benzodiazepines were isolated by filtration or by previous
removing of the solvent. The resulting solid was finally washed
with a hexane-diethyl ether mixture to yield the salt derivative
16 as dark red solids.
Notes and references
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20
time 8.0 h; Yield 97 %; D


50.0 (c 0.03, MeOH), ee 94%.
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3
4
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
2.25 (s, 3H, CH3), 2.35 (s, 3H,
CH3COO), 3.57 (s, 3H, CH3O), 4.48 (s, 1H, H-4), 6.64-6.46 (m,
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3J 7.8 Hz, Ar), 7.36 (t, 1H, 3J 7.8 Hz, H-5’), 10.14 (br d, 2H, 3J 8.1
Hz, H-6, NH), 11.01 (br s, 1H, NH). 13C-NMR (DMSO-d6, 75.5
MHz): δ 17.9 (CH3), 20.9 (CH3COO), 41.1 (C-4), 51.6 (CH3O),
94.5 (C-4a), 107.7 (C-3), 119.3 (C-4’), 120.5 (C-2’), 122.4 and
122.8 (C-7, C-10), 123.4 (C-6’), 127.7 and 128.0 (C-8, C-9),
130.1 (C-5’), 131.7 (C-10a), 135.8 (C-6a), 142.2 (C-2), 147.1 (C-
1’), 150.9 (C-3’), 159.6 (C-11a), 160.1 (C-5), 165.9 (CO), 169.2
5
6
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74.51. HRMS-
ESI+ calcd. for [C23H22N3O4]+ (MH)+ 404.1605 m/z, found
404.1606 (the symbol M has been used for the no protonated
molecule).
7
20
(S)-16a. Reaction time 8.0 h; yield 95 %; D  (c 0.03,
MeOH), ee 93%.
(R)-4-(3-Acetoxyphenyl)-3-(benzyloxycarbonyl)-2-methyl-
4,11-dihydro-1H-benzo[b]pyrido[2,3-e][1,4]diazepin-6-ium
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ARTICLE
Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB01066D
Table of contents information
Kinetic resolution of 3,4-DHP-2-ones with Candida rugose lipase (CRL) has been possible due to
the presence of a reactive phenolic ester in a remote position.
OAc
OAc
OAc
A-
H
OAc
N
CO2R
OHC
Cl
CO2R
CO2R
O
N
H
N
H
N
N
H
H
CO2R
CRL, H2O
up to 93)
(S)-1,4-DHP
(R)-BZD-DHP
O
N
H
(
E
OH
ee = 93 - >99%
rac-3,4-DHP-2-one
CO2R
(R)-1,4-DHP
(S)-BZD-DHP
O
N
H