One-pot synthesis of enantiopure 3,4-dihydroisocoumarins through dynamic reductive kinetic resolution processes

Article abstract of DOI:10.1021/ol401606x

A straightforward chemoenzymatic synthesis of enantiopure 4-alkyl-3-methyl-3,4-dihydroisocoumarins through a ketoreductase-catalyzed one-pot dynamic reductive kinetic resolution is reported. E. coli/ADH-A cells have shown outstanding diastereo- and enantioselectivity toward the bioreduction of a series of racemic ketones, with the use of anion exchange resins or triethylamine being compatible in the same aqueous reaction medium. The so-obtained enantiopure alcohols were subsequently cyclized in acid media affording the corresponding lactones in good to excellent conversions (72-96%) and excellent selectivities (dr ≥99:1 and ee >99%).

Full text of DOI:10.1021/ol401606x

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
One-Pot Synthesis of Enantiopure
3,4-Dihydroisocoumarins through Dynamic
Reductive Kinetic Resolution Processes
ꢀ
Juan Mangas-Sanchez, Eduardo Busto, Vicente Gotor, and Vicente Gotor-Fernandez*
ꢀ
ꢀ
Organic and Inorganic Chemistry Department, University of Oviedo, Avenida Julian
´
Claverıa s/n. Oviedo 33006, Spain
vicgotfer@uniovi.es
Received June 7, 2013
ABSTRACT
A straightforward chemoenzymatic synthesis of enantiopure 4-alkyl-3-methyl-3,4-dihydroisocoumarins through a ketoreductase-catalyzed one-
pot dynamic reductive kinetic resolution is reported. E. coli/ADH-A cells have shown outstanding diastereo- and enantioselectivity toward the
bioreduction of a series of racemic ketones, with the use of anion exchange resins or triethylamine being compatible in the same aqueous reaction
medium. The so-obtained enantiopure alcohols were subsequently cyclized in acid media affording the corresponding lactones in good to
excellent conversions (72ꢀ96%) and excellent selectivities (dr g99:1 and ee >99%).
Biocatalytic processes are well-established methodolo-
gies for the production of organic compounds under
environmentally friendly conditions.1 In fact, the potential
of biotransformations for sustainable manufacturing has
gained major attention because of the economic impact
of enzymes for industrial applications.2 From the group
of asymmetric biocatalytic transformations, enzymatic
kinetic resolutions (KRs) of racemic mixtures provide a
straightforward access to enantiopure compounds. Unfor-
tunately this approach is based on enantiomer separation
where the maximum yield is limited to 50%,3 although the
development of elegant enzymatic dynamic kinetic resolu-
tions (DKRs) has overcome this limitation. For instance
hydrolases in combination with metal catalysts have
allowed the synthesis of a wide variety of enantioenriched
compounds from racemic amine or alcohols.4 On the other
hand, BaeyerꢀVilliger monooxygenases have efficiently
catalyzed DKR processes for the formation ofenantiopure
esters.5 However, DKR processes have been scarcely ex-
plored using alcohol dehydrogenases (ADHs).6 Only some
examples have been reported in the bioreduction of
(4) See for instance recent bibliographic revisions: (a) Hoyos, P.;
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Pace, V.; Alcantara, A. R. Adv. Synth. Catal. 2012, 354, 2585. (b)
Pellisier, H. Tetrahedron 2011, 67, 3769–3802. (c) Lee, J. H.; Han, K.;
Kim, M.-J.; Park, J. Eur. J. Org. Chem. 2010, 999.
(5) de Gonzalo, G.; Mihovilovic, M.; Fraaije, M. W. ChemBioChem
2010, 11, 2208.
(6) Musa, M. M.; Phillips, R. S. Catal. Sci. Technol. 2011, 1, 1311.
€
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351, 253. (b) Ji, A.; Wolberg, M.; Hummel, W.; Wandrey, C.; Muller, M.
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Chem. Commun. 2001, 57. (c) Wolberg, M.; Ji, A.; Hummel, W.; Muller,
M. Synthesis 2001, 937.
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9654.
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€
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(2) (a) Meyer, H.-P.; Eichhorn, E.; Hanlon, S.; Lutz, S.; Schurmann,
Lavandera, I.; de Gonzalo, G.; Kroutil, W.; Gotor, V. Adv. Synth. Catal.
2012, 354, 1743. (b) Padhi, S. K.; Kaluzna, I. A.; Buisson, D.; Azerad, R.;
Stewart, J. D. Tetrahedron: Asymmetry 2007, 18, 2133. (c) Kalaitzakis,
D.; Kambourakis, S.; Rozzell, J. D.; Smonou, I. Tetrahedron: Asym-
metry 2007, 18, 2418. (d) Zhu, D.; Mukherjee, C.; Rozzell, J. D.;
Kambourakis, S.; Hua, L. Tetrahedron 2006, 62, 901. (e) Kalaitzakis,
D.; Rozzell, J. D.; Kambourakis, S.; Smonou, I. Org. Lett. 2005, 7, 4799.
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Chem. Soc. 2004, 126, 12827. (g) Nakamura, N.; Miyai, T.; Ushio, K.;
Oka, S.; Ohno, A. Bull. Chem. Soc. Jpn. 1988, 61, 2089.
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2012, 7, 1138. (c) Bornscheuer, U. T.; Huisman, G. W.; Kazlauskas, R. J.;
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3011.
r
10.1021/ol401606x
XXXX American Chemical Society

diketones7 and racemic derivatives such as ketones,8
β-keto esters,9 or aldehydes.10 In spite of the enzyme
tridimensional structure, the generation in a single bio-
transformation of multiple stereogenic centers has been
scarcely reported and remains a challenging task.11 In this
context, it must be mentioned that DKR processes have
been also recently defined as dynamic reductive kinetic
resolution processes (DYRKR).12
experiments were independently conducted. As occurred
with prochiral 2-(2-oxopropyl)-benzonitriles,14 ADH-A
from Rhodococcus ruber overexpressed in E. coli cells
displayed outstanding activities in the bioreduction of
racemic 2a. For that reason this enzyme was chosen for
studying the KR experiments in depth (Table 1).
Chiral heterocyclic compounds are widely found in
biologically active natural products, and a great number
of synthetic pharmacologically active molecules contain at
least one heterocyclic ring. Therefore, the development of
novel synthetic asymmetric methods for the preparation
of enantiopure heterocyclic compounds is a highly appeal-
ing task for synthetic organic chemists. In particular, the
asymmetric chemical synthesis of enantioenriched 3,4-
dihydroisocoumarin derivatives has attracted much atten-
tion in recent years,13 due to its presence in many natural
products that display a vast range of biological activities such
as antibacterial, antifungal, antimalarial, or anticancer.14
Until now, different enzymatic transformations have
been described for the asymmetric synthesis of 3-alkyl-
3,4-dihydroisocoumarins, such as the oxidation of 2-alkyl-
1-indanones using BaeyerꢀVilliger monooxigenases15 or
the ADH-catalyzed bioreduction of 2-(2-oxopropyl)-
benzonitriles.16 However, as far as we know the chemoen-
zymatic synthesis of 3,4-dialkyl-3,4-dihydroisocumarines
remains unexplored. Herein, we report an effective, simple
one-pot synthesis of enantiopure 4-alkyl-3-methyl-3,4-
dihydroisocoumarins through DYRKR processes by a
combination of an alcohol dehydrogenase (ADH-A from
Rhodococcus ruber) and basic catalysis followed by intra-
molecular cyclization.
Scheme 1. Chemical Synthesis and Kinetic Resolution of
Ketone 2a Using E. coli/ADH-A Cells
Preliminary results showed that, after 24 h, E. coli/ADH-A
was able to reduce 2a with 38% of conversion and high
enantioselectivity (entry 1). The remaining ketone 2a was
recovered in high ee (60%), showing that the enzyme reacts
exclusively with the (S)-enantiomer. Different experiments
were performed in order to obtain higher conversions. First,
the influence of the enzyme loading was analyzed finding a
slight improvement when using 15 mg (entry 2); unfortu-
nately the use of higher amounts of the enzyme (25 mg,
entry 3) did not provide better results. Interestingly, when
the enzyme was added in portions, slightly better results
were attained (entry 4) suggesting problems associated with
the reversibility of the reaction or a possible inhibition effect
by the product. To verify the correct hypotheses, additional
2-propanol and a hydrophobic solvent as hexane were used
(entries 5 and 6). Any improvement of the conversion could
be detected with higher amounts of 2-propanol discarding
the problem of reversibility (entry 5). To our delight, the best
conditions were obtained when using 5% of hexane as
cosolvent (56% conversion, entry 6).
The addition of a hydrophobic cosolvent improved the
process since the organic phase acts as a reservoir for the
product and substrate, reducing its presencein the aqueous
phase where the bioreduction takes place. To our surprise,
conversion values and substrate ee did not fit with a classic
KR model since 3a was found in enantiopure form at
conversion values higher than 50%. This unexpected
behavior could be easily explained considering a partial
racemization of the ketone caused by the acidity of the
R-hydrogen to the carbonyl group. Encouraged by this
result, the racemization step has been deeply studied to
develop an efficient DKR process.
2-(3-Oxobutan-2-yl)benzonitrile (2a) was chosen as a
model substrate because of its easy access through methyl-
ation of 2-(2-oxopropyl)benzonitrile (1a) with methyl
iodide and sodium hydroxide under phase transfer catal-
ysis conditions (Scheme 1). Trying to find suitable condi-
tions for the dynamic process, KR and racemization
(10) (a) Giacomini, D.; Galletti, P.; Quintavalla, A.; Gucciardo, G.;
Paradisi, F. Chem. Commun. 2007, 4038. (b) Galletti, P.; Emer, E.;
Gucciardo, G.; Quintavalla, A.; Pori, M.; Giacomini, D. Org. Biomol.
Chem. 2010, 8, 4117.
€
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(11) Muller, C. R.; Perez-Sanchez, M.; Domınguez de Marıa, P. Org.
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Biomol. Chem. 2013, 11, 2000.
(12) (a) Applegate, G. A.; Cheloha, R. W.; Nelson, D. L.; Berkowitz,
D. B. Chem. Commun. 2011, 47, 2420. (b) Friest, J. A.; Maezato, Y.;
Broussy, S.; Nelson, D. L.; Berkowitz, D. B. J. Am. Chem. Soc. 2010,
132, 5930.
(13) (a) Babu, D. C.; Rao, C. B.; Ramesh, D.; Swamy, S. R.;
Venkateswarlu, Y. Tetrahedron Lett. 2012, 53, 3633. (b) Chen, J.; Zhou,
L.; Tan, C. K.; Yeung, Y.-Y. J. Org. Chem. 2012, 77, 999. (c) Sharma,
A. K.; Maheshwary, Y.; Singh, P.; Singh, K. N. Arkivoc 2010, ix, 54. (d)
Uchida, K.; Fukuda, T.; Iwao, M. Tetrahedron 2007, 63, 7178. (e)
Kurosaki, Y.; Fukuda, T.; Iwao, M. Tetrahedron 2005, 61, 3289.
(14) (a) Jiao, P.; Gloer, J. B.; Campbell, J.; Shearer, C. A. J. Nat.
Prod. 2006, 69, 612. (b) Zidorn, C.; Lohwasser, U.; Pschorr, S.;
€
Salvenmoser, D.; Ongania, K.-H.; Ellmerer, E. P.; Borner, A.; Stuppner,
Relative and absolute configurations were determined
by NMR experiments (see Supporting Information (SI)).
H. Phytochemistry 2005, 66, 1691. (c) Umehara, K.; Matsumoto, M.;
Nakamura, M.; Miyase, T.; Kuroyanagi, M.; Noguchi, H. Chem.
Pharm. Bull. 2000, 48, 566.
~
(15) Rioz-Martı
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nez, A.; de Gonzalo, G.; Torres-Pazmino, D. E.;
Fraaije, M. W.; Gotor, V. J. Org. Chem. 2010, 75, 2073.
(17) Rodrıguez, C.; de Gonzalo, G.; Rioz-Martınez, A.; Torres-
´ ´
~
ꢀ
ꢀ
(16) Mangas-Sanchez, J.; Busto, E.; Gotor-Fernandez, V.; Gotor, V.
Pazmino, D. E.; Fraaije, M. W.; Gotor, V. Org. Biomol. Chem. 2010,
8, 1121.
Catal. Sci. Technol. 2012, 2, 1590.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Kinetic Resolution of (()-Ketone 2a (20 mM)
Catalyzed by ADH-A Using 2-Propanol as Cosubstrate
(5% v/v), NADH as Cofactor in TRIS-HCl pH 7.5 Buffer at
250 rpm for 24 h
Table 2. Racemization of (R)-2a (20 mM) Using Different
Additives, 2-Propanol as Cosubstrate (5% v/v) in TRIS-HCl pH
7.5 Buffer for 24 h at 30 °C and 250 rpm
initial ee final ee
entry
additive
2a (%)a
2a (%)a
ADH-A
(mg)
conv
(%)a
ee 2a
(%)a
ee 3a
(%)b
dr 3a
(%)b
entry
1
2
3
4
5% hexane (5% v/v)
60
66
57
63
54
6
DOWEX MWA-1b
1
2
3
4
5
6
10
38
41
41
44
44
56
56
59
59
64
64
90
>99
>99
>99
>99
>99
>99
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
hexane (5% v/v) þ DOWEX MWA-1b
5
15
25
hexane (5% v/v) þ Et3N (1% v/v)
0
10 þ 10c
15d
15e
a Enantiomeric excesses determined by chiral GC. b 12 mg of
DOWEX MWA-1 were used.
a Conversions and enantiomeric excesses determined by chiral GC.
b Enantiomeric excesses and diastereomeric ratio determined by chiral
HPLC after derivatization to the 3,4-dihydroisocoumarin 4a using an
aq HCl concd solution. c Additional 10 mg were added after 12 h.
d 2-Propanol was used for a total concentration of 10% v/v. e Biphasic
media with 5% of hexane.
diastereomer and in enantiopure form. However, substrate
2awas obtainedin45% eeand longerreaction times do not
improve the process significantly (entry 2). These results
suggest that the racemization system is not completely
effective for a total conversion into (S,S)-3a. Unfortu-
nately, higher quantities of triethylamine led to enzyme
inactivation (entries 3 and 4).
For the relative configuration, 1H NMR NOESY experi-
ments were performed showing space correlation between
the two methyl groups in (þ)-4a, confirming the syn
disposition of the substituents. This correlates with the
favored addition of the hydride by NADH to the carbonyl
group through the less hindered face, disposing both
groups on the same side. The absolute configuration was
assigned preparing the Mosher’s ester derivative, conclud-
ing that the absolute configuration was S,S (see SI for
further details).
Table 3. Dynamic Reductive Kinetic Resolution of Ketone 2a
(20 mM) Using Different Racemization Systems
Racemization of the ketone was then investigated using
enantioenriched alcohol (R)-2a obtained during KR stud-
ies (Table 2). First, KR conditions were attempted using
TRIS-HCl buffer, 5% of 2-propanol as the cosubstrate,
and 5% of hexane, with a slight loss of the optical purity
(entry 1). Nevertheless, this racemization is not enough to
perform a proper DKR where, at least, racemization has to
be 10 times faster than the conversion of the slow-reacting
enantiomer in the kinetic resolution. On the other hand,
thisslight decrease of ee may explainresults observed in the
KR optimization. Then, different additives were assayed
to improve the kinetic of the racemization (entries 2ꢀ4).
First, anion exchange resins were tested since they are
efficient catalysts for the racemization of 1-aryl-1-
alkylacetones.17 Satisfyingly, DOWEX MWA-1 afforded
the ketone 2a in almost racemic form after 24 h in both
aqueous and biphasic systems (entries 2 and 3). Bearing in
mind the biphasic media where KR was optimized, we
envisaged a plausible racemization in the hydrophobic
phase so an organic base, triethylamine (Et3N), was tested,
affording total racemization after 24 h (entry 4).
racemization
system
ee 2a conv ee 3a dr 3a
entry
t (h)
(%)a
(%)a
(%)b
(%)b
1
2
3
4
5
6
Et3N (1% v/v)
Et3N (1% v/v)
Et3N (2% v/v)
Et3N (3% v/v)
DOWEX MWA-1
DOWEX MWA-1
44
72
70
70
24
92
45
45
0
81
85
77
45
63
86
>99
>99
>99
>99
>99
>99
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
0
81
13
a Enantiomeric excesses and conversions determined by chiral GC.
b Enantiomeric excesses and diastereomeric ratio determined by chiral
HPLC after derivatization to the corresponding 3,4-dihydroisocoumar-
ins 4a using an aq HCl concd solution.
Because of the good results previously obtained with the
DOWEX MWA-1 anion exchange resin toward the race-
mization of ketone 2a (entries 2 and 3, Table 2), this system
was subjected to study. After 24 h, 63% conversion of
enantiopure alcohol (S,S)-3a was reached, obtaining 2a in
81% ee (entry 5). Satisfyingly, both the biocatalyst and
racemization system remained active after long reaction
times, leading to an efficient DYRKR with 86% conver-
sion after 92 h (entry 6).
With the optimized conditions for the model substrate
(()-2a, the scope of the methodology was then examined.
Ketones (()-2bꢀg were prepared by alkylation of different
1-arylacetones 1bꢀg in moderate to good yields.18 In all
cases, goodtoexcellent conversionswere reached after 72h
(Table 4), obtaining the enantiopure alcohols (S,S)-3b-g
Once both KR and racemization were independently
optimized, theywerecombinedina wholedynamic process
(Table 3). First, the best conditions of both were brought
together, using lyophilized E. coli/ADH-A cells, 5% of
hexane, 2-propanol as the cosubstrate (5% v/v), triethyl-
amine as the racemization system, and NADH as the
cofactor in TRIS-HCl pH 7.5 buffer. After 44 h, 81%
conversion was reached, obtaining (S,S)-3a as single
Org. Lett., Vol. XX, No. XX, XXXX
C

with a perfect diastereomeric ratio. The presence of differ-
ent substituents in the aromatic ring (R1) or in the chiral
center (R2) does not affect the enzyme selectivity, demon-
strating the scope of the methodology; albeit differences in
conversions may be explained by the influence they have in
the racemization rate.
Scheme 2. One-Pot Synthesis of 4-Alkyl-3-methyl-3,4-
dihydroisocoumarins (S,S)-4aꢀg in Enantiopure Form
Table 4. Dynamic Reductive Kinetic Resolution of Racemic
Ketones 2aꢀg (20 mM) Using E. coli/ADH-A Cells as
Biocatalysts
performed using 15 mg of substrate and both racemization
systems. At this scale, the Et3N system showed excellent
reliability compared to the anion exchange resin where
many phases are involved. Therefore, scale-ups (0.3 mmol)
were performed using the Et3N-catalyzed racemization
system at 30 °C and 250 rpm for 72 h.19 Then, concd
HCl was added and reactions were shaken for an addi-
tional 24 h, affording in all cases enantio- and diastereo-
merically pure 4-alkyl-3-methyl-3,4-dihydroisocoumarins
(S,S)-4aꢀg (24ꢀ86% overall isolated yields). The case of
(S,S)-4e(R = 4-F) isnoteworthywherethe isolated yield is
very low in comparison with the rest of substrates. In this
case, the formation of the corresponding carboxylic acid is
preferred, obtaining (S,S)-4e in poor yield (24%).
In summary, a straightforward method has been de-
scribed for the transformation of a series of racemic
ketones into benzofused lactones as single diastereomers
and in enantiopure form. Remarkably, two new stereo-
genic centers were created starting from a prochiral ketone
in a one-pot transformation by means of dynamic kinetic
reductiveresolutionprocesses catalyzed by E. coli/ADH-A
followed by an intramolecular cyclization reaction.
conv ee 3aꢀg dr 3aꢀg
entry substrate
R1
R2
(%)a
(%)b
(%)b
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
H
Me
Me
Me
93
72
77
93
95
87
96
>99
>99
>99
>99
>99
>99
>99
>99:1
>99:1
>99:1
99:1
5-Me
4-Me
5-OMe Me
4-F
H
Me
Et
99:1
>99:1
99:1
2g
H
allyl
a Conversion values determined by chiral GC. b Enantiomeric excesses
determined by chiral HPLC after derivatization to the corresponding 3,4-
dihydroisocoumarins 4aꢀg using an aq HCl concd solution.
Finally, once the dynamic process was studied and
optimized, we focused on the development of a one-pot
methodology for the preparation of the target molecules in
enantiopure form (Scheme 2). Reactions were initially
(18) General procedure for the synthesis of racemic ketones 2aꢀg: Fry,
A. J.; Bajanauskas, J. P. J. Org. Chem. 1978, 43, 3157. To a solution of
the corresponding ketone 1aꢀg (1 mmol) in a biphasic mixture of
CH2Cl2 (500 μL, 2 M) and NaOH (500 μL, 2 M), tetrabutylammonium
bisulfate (340 mg, 1 mmol) and the corresponding alkyl iodide (1.2
mmol) were added. The reaction mixture was stirred at 40 °C for 2 h until
no starting material was detected by TLC analysis. The mixture was
extracted afterwards with CH2Cl2 (3 ꢁ 10 mL); the organic layers were
collected, dried over Na2SO4, and filtered; and the solvent was evapo-
rated under reduced pressure. The crude was then purified by flash
chromatography (50% Et2O/Hexane), affording the corresponding
alkyl ketones 2aꢀg in moderate to good yields (57ꢀ78%).
Acknowledgment. We thank Prof. Wolfgang Kroutil
(University of Graz, Austria) for providing us ADH-A
overexpressed in E. coli cells. Financial support of this
ꢀ
work by the Spanish Ministerio de Ciencia e Innovacion
(19) General procedure for the one-pot synthesis of 4-alkyl-3-methyl-
isochroman-1-ones 4aꢀg. To a solution containing rehydrated E. coli/
ADH-A cells (425 mg/mmol, 128 mg) in TRIS-HCl 50 mM pH 7.5 buffer
(0.02 M, 13.35 mL), isopropyl alcohol (5% v/v, 750 μL), hexane (5% v/v,
750 μL), Et3N (1% v/v, 150 μL), NADH (1 mM, 10.5 mg), and the
corresponding ketone 2aꢀg (0.3 mmol) were succesively added. The
reaction was shaken for 72 h and at 250 rpm, and then hydrochloric acid
was added (37%, 0.02 M, 15 mL) and the mixture was shaken overnight
at 30 °C. The reaction was centrifuged and extracted with EtOAc (3 ꢁ
25 mL); organic layers were collected, dried over Na2SO4, and filtered;
the solvent was evaporated under reduced pressure; and the crude was
purified by flash chromatography (50% Et2O/Hexane) to afford the
corresponding enantiopure lactones 4aꢀg in low to high isolated yields
(24ꢀ86%).
(MICINN) through CTQ 2012-24237 project is gratefully
acknowledged. J.M.-S. thanks MICINN for a predoctoral
fellowship (FPU Program).
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds
are included. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX