Dynamic kinetic resolution of 1,3-dihydro-2 h-isoindole-1-carboxylic acid methyl ester: Asymmetric transformations toward isoindoline carbamates

Article abstract of DOI:10.1021/ol300250h

Asymmetric syntheses of isoindoline carbamates have been successfully achieved through enzyme-mediated dynamic kinetic resolution processes and without requirement of metal or acid-base catalyst for the substrate racemization. Optically active carbamates

Full text of DOI:10.1021/ol300250h

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1696–1699
Dynamic Kinetic Resolution of
1,3-Dihydro-2H-isoindole-1-carboxylic Acid
Methyl Ester: Asymmetric Transformations
toward Isoindoline Carbamates
†
†
‡
ꢀ
ꢀ
Roberto Moran-Ramallal, Vicente Gotor-Fernandez, Pedro Laborda,
Francisco J. Sayago,‡ Carlos Cativiela,*,‡ and Vicente Gotor*,†
ꢀ
Departamento de Quımica Organica e Inorganica, Instituto Universitario de
Biotecnologıa de Asturias, Universidad de Oviedo, 33006 Oviedo, Spain, and
ꢀ
ꢀ
ꢀ
Departamento de Quımica Organica, Instituto de Sıntesis Quımica y Catalisis
ꢀ
Homogenea, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
cativiela@unizar.es; vgs@uniovi.es
Received January 31, 2012
ABSTRACT
Asymmetric syntheses of isoindoline carbamates have been successfully achieved through enzyme-mediated dynamic kinetic resolution
processes and without requirement of metal or acidꢀbase catalyst for the substrate racemization. Optically active carbamates were obtained in
good yields and an excellent degree of stereoselectivity when Pseudomonas cepacia lipase (PSL) was used as biocatalyst, with diallyl or dibenzyl
carbonates being both adequate reagents in alkoxycarbonylation reactions.
The isoindoline core is anattractivetarget in organic and
medicinal chemistry because of its presence in the structure
of some biologically active compounds.1 Among isoindo-
line derivatives, isoindoline-1-carboxylic acid has attracted
special attention due to its usefulness as scaffold in the
preparation of biologically active compounds.2 More con-
cretely, isoindoline-1-carboxylic acid is present in the
structure of diuretic agents2a or angiotensin converting en-
zyme inhibitors2b used in SAR studies. This proline analo-
gue is also included in the structure of organophosphorus
compounds showing antioxidant activity.2e Furthermore,
it constitutes the core skeleton of molecules with potential
use in the treatment of diabetes, obesity, dyslipidemia, and
atherosclerosis,2f the prevention of tissue damage in in-
flammatory diseases,2c or against cancer.2d
Even though there is potential interest in the preparation
of new drugs, only a few synthetic procedures have been
described in the literature (Scheme 1). Thus, isoindoline-1-
carboxylic acid or different esters have been synthesized by
the addition and further intramolecular cyclization of an
amine to alkyl 2-bromo-2-(o-bromomethyl)-acetates (path a)
and in turn were obtained from commercially available
o-tolylacetic acid after treatment with thionyl chloride and
subsequent bromination and esterification.2b,3 On the
other hand, as depicted in path b, protected isoindoline-
(1) (a) Bare, T. M.; Draper, C. W.; McLaren, C. D.; Pullan, L. M.;
Patel, J.; Patel, P. B. Bioorg. Med. Chem. Lett. 1993, 3, 55. (b) Kukkola,
P. J.; Bilci, N. A.; Ikler, T.; Savage, P.; Shetty, S. S.; DelGrande, D.;
Jeng, A. Y. Bioorg. Med. Chem. Lett. 2001, 11, 1737. (c) Van Goethem,
S.; Van der Veken, P.; Dubois, V.; Soroka, A.; Lambeir, A.-M.; Chen,
ꢀ
X.; Haemers, A.; Scharpe, S.; De Meester, I.; Agustyns, K. Bioorg. Med.
Chem. Lett. 2008, 18, 4159.
(2) (a) Cignarella, G.; Sanna, P. J. Med. Chem. 1981, 24, 1003. (b)
Klutchko, S.; Blankley, C. J.; Fleming, R. W.; Hinkley, J. M.; Werner,
A. E.; Nordin, I.; Holmes, A.; Hoefle, M. L.; Cohen, D. M.; Essenburg,
A. D.; Kaplan, H. R. J. Med. Chem. 1986, 29, 1953. (c) Chiba, J.;
Takayama, G.; Takashi, T.; Yokoyama, M.; Nakayama, A.; Baldwin,
J. J.; McDonald, E.; Moriarty, K. J.; Sarko, C. R.; Saionz, K. W.;
Swanson, R.; Hussain, Z.; Wong, A.; Machinaga, N. Bioorg. Med.
Chem. 2006, 14, 2725. (d) Kung, P.-P.; Huang, B.; Zhang, G.; Zhou,
J. Z.; Wang, J.; Digits, J. A.; Skaptason, J.; Yamazaki, S.; Neul, D.;
Zientek, M.; Elleraas, J.; Mehta, P.; Yin, M.-J.; Hickey, M. J.; Gajiwala,
K. S.; Rodgers, C.; Davies, J. F., II; Gehring, M. R. J. Med. Chem. 2010,
53, 499. (e) Reddy, M. V. N.; Krishna, A. B.; Reddy, C. S. Eur. J. Med.
Chem. 2010, 45, 1828. (f) Luckhurst, C. A.; Stein, L. A.; Furber, M.;
Webb, N.; Ratcliffe, M. J.; Allenby, G.; Botterell, S.; Tomlinson, W.;
Martin, B.; Walding, A. Bioorg. Med. Chem. Lett. 2011, 21, 492.
r
10.1021/ol300250h
Published on Web 03/14/2012
2012 American Chemical Society

Scheme 1. Synthetic Methods Described in the Literature for the
Preparation of Isoindoline-1-carboxylic Acid Derivatives
Scheme 2. Synthesis of R-Amino Acid Hydrochloride Salt 5
active coumpounds in aqueous medium but also in organic
or neoteric solvents.7 In particular, amino acid derivatives
are extremely versatile substrates because of their intrinsic
bifunctionality.8 Within this context, we have focused on
the study of biocatalytic methods for the enzymatic resolu-
tion of suitably protected isoindoline-1-carboxylic acid
derivatives. With that aim, the use of hydrolases9 has been
deeply analyzed because of their excellent properties in the
asymmetric synthesis of N-heterocyclic compounds.10
Different experiments were planned, looking for chemo-
selectively controlled reactivity of the ester moiety or the
amino group. The results have been summarized depend-
ing on the moiety part susceptible to be transformed:
hydrolysis or transesterification reactions were considered
when modifying the ester, while alkoxycarbonylation pro-
cesses were studied when the free amino group was altered.
1-carboxylic acid derivatives can also be prepared via
metalation and acylation of the formamidinio derivative
of isoindoline4 (Meyers’ methodology). Recently, the
synthesis of many isoindoline-1-carboxylic acid derivatives
has been achieved by Pd(0)-catalyzed enolate arylation of
aryl halides derived from glycine (path c).5 Herein, we have
synthesized racemic isoindoline-1-carboxylic acid in a high
yield starting from phthalimide (path d), which provided
the suitable N-acyl lactam 1 following the procedure
previously reported by our research group.6 The N-Boc
protected isoindolin-1-one (1) was converted into nitrile 4
byathree-stepprocedurethatinvolvedthereduction ofthe
lactam carbonyl group with diisobutylaluminium hydride
to obtain an intermediate hemiaminal, which was imme-
diately transformed into the corresponding methoxyam-
inal. Subsequent addition of trimethylsilyl cyanide in the
presence of boron trifluoride etherate yielded compound 4
in 78% yield. Hydrolysis of nitrile 4 furnished the isoindo-
line-1-carboxylic acid (5) as a hydrochloride salt (Scheme 2).
Interestingly, and despite the importance of using en-
antiomerically pure compounds in biological tests, to the
best of our knowledge all reported synthetic procedures
onlyprovideisoindoline derivatives inracemic form;there-
fore, the development of methodologies that provide en-
antiomerically pure isoindoline-1-carboxylic acid deriva-
tives is an outstanding research field. Biocatalysis provides
a wide toolbox for the asymmetric synthesis of optically
Scheme 3. Synthesis of Compounds for Use in Lipase-Catalyzed
Hydrolysis, Esterification, or Alkoxycarbonylation Reactions
(3) (a) Cignarella, G.; Cerri, R.; Grella, G.; Sanna, P. Gazz. Chim.
Ital. 1976, 106, 65. (b) New, J. S.; Yevich, J. P. J. Heterocyclic Chem.
1984, 21, 1355. (c) Bankley, C. J.; Kaltenbronn, J. S.; DeJhon, D. E.;
Werner, A.; Benett, L. R.; Bobowski, G.; Krolls, U.; Johnson, D. R.;
Pearlman, W. M.; Hoefle, M. L.; Essenburg, A. D.; Cohen, D. M.;
Kaplan, H. R. J. Med. Chem. 1987, 30, 992.
For that reason, a series of racemic amino acid deriva-
tives were prepared from readily available isoindoline-1-
carboxylic acid (5): R-amino ester 6 for alkoxycarbonyla-
tion processes, N-Cbz methyl amino ester 7 withhydrolytic
purposes and N-Cbz protected amino acid 8 for esterifica-
tion reactions (Scheme 3). Then, 5 was esterified with
thionyl chloride (SOCl2) in MeOH forming the racemic
(4) Beeley, L. J.; Rockell, C. J. M. Tetrahedron Lett. 1990, 31, 417.
(5) (a) Gaertzen, O.; Buchwald, S. L. J. Org. Chem. 2002, 67, 465. (b)
ꢀ
Sole, D.; Serrano, O. J. Org. Chem. 2010, 75, 6267.
ꢀ
ꢀ~
(6) Arizpe, A.; Sayago, F. J.; Jimenez, A. I.; Ordonez, M.; Cativiela,
C. Eur. J. Org. Chem. 2011, 6732.
(8) (a) Liljeblad, A.; Kanerva, L. T. Tetrahedron 2006, 62, 5831–5854.
(b) Gotor-Fernandez, V.; Gotor, V. Curr. Opin. Drug Discov. Dev. 2009,
12, 784.
(9) Hydrolases in Organic Synthesis: Regio- and Stereoselective
Transformations, 2nd ed.; Bornscheuer, U. T., Kazlauskas, R. J., Eds.;
Wiley-VCH: Weinheim, Germany, 2006.
(7) (a) Asymmetric Organic Synthesis with Enzymes; Gotor, V.,
Alfonso, I., Garcıa-Urdiales, E., Eds.; Wiley-VCH: Weinheim, Germany,
2008. (b) Organic Synthesis with Enzymes in Non-Aqueous Medium;
Carrea, G., Riva, S., Eds.; Wiley-VCH: Weinheim, Germany, 2008. (c)
Modern Biocatalysis. Stereoselective and Environmentally Friendly Re-
actions; Fessner, W.-D. Anthonsen, T., Eds.; Wiley-VCH: Weinheim,
Germany, 2009. (d) Hudlicky, T.; Reed, J. W. Chem. Soc. Rev. 2009, 38,
3117.
ꢀ
ꢀ
(10) Busto, E.; Gotor-Fernandez, V.; Gotor, V. Chem. Rev. 2011,
111, 3998.
Org. Lett., Vol. 14, No. 7, 2012
1697

amino ester 6 in high yield (Scheme 2), and then conve-
niently protected as the N-Cbz methyl amino ester 7 with
benzyloxycarbonyl chloride (CbzCl) in the presence of (N,
N)-diisopropylethylamine (DIPEA). Before carrying out
the hydrolase-catalyzed hydrolysis reactions, N-Cbz pro-
tected amino acid 8 was prepared by saponification of 7 in
quantitative yield.
Enzymatic hydrolysis reactions of the methyl ester 7 in
either aqueous medium (phosphate buffer) or organic
solvent (THF) using a 20-fold excess of water were un-
successful, recovering the starting material in all cases
when Candida antarctica lipase type A (CAL-A), Candida
antarctica lipase type B (CAL-B), or Pseudomonas cepacia
lipase (also known as Burkholderia cepacia lipase, PSL-C I)
were used at 28 °C and 200 rpm.
a metal or an oxidation agent, which is typical in DKR
processes, and gives an added value to this methodology.15
Coming back to the description of the enzymatic alkox-
ycarbonylation, it is worth noting that the reaction with
3-methoxyphenyl allyl carbonate (9a) released 3-methox-
yphenol to the reaction medium, making monitoring the
enzymatic processes difficult. Therefore, we decided to
attempt the stereoselective alkoxycarbonylation of race-
mic 6 using the commercially available diallyl carbonate
(9b) that produced volatile allylic alcohol as byproduct.
Initial assays using THF as solvent and variable tempera-
tures and amounts of carbonate led us to fix 10 equiv of 9b
and 50 °C as optimal values to start the process optimiza-
tion. In these conditions, a 72% conversion was achieved,
recovering the carbamate (R)-10 with very high selectivity
and substrate with low enantiomeric excess (entry 1, Table 1).
Esterification processes with the racemic amino acid 8
were attempted in a similar manner to that described
by Pietruszka and co-workers in structurally related
compounds;11 however, neither of the lipases tested displayed
activity using 5 equiv of MeOH or BuOH in dry THF, or
alternatively a biphasic toluene/phosphate buffer system.
Once we explored the unsuccessful modification of the
carboxylic group, we decided to study the lipase-catalyzed
alkoxycarbonylation reaction of racemic methyl 1,3-dihy-
dro-2H-isoindole-1-carboxylate (6).12 Initially 3-methox-
yphenyl allyl carbonate (9a) was selected as alkoxy-
carbonylating agent because of the good results shown in
the lipase mediated kinetic resolution of indoline13 or
isoquinoline derivatives.14 Unfortunately CAL-A, CAL-
B, or Candida cycindracea lipase (CCL) did not display any
activity with 2.5 equiv of carbonate (Scheme 4). On the
other hand, PSL-C I allowed the formation of the desired
enantioenriched allyl carbamate 10 in 28% conversion
after 19 h, although surprisingly the starting amino ester
was recovered in racemic form, which means that racemi-
zation is occurring during the process. Therefore we
propose that the racemization equilibrium consists in a
deprotonationꢀprotonation process through an achiral
intermediate, a stabilized enolate. Amino ester racemiza-
tion occurs without the addition of an acidꢀbase catalyst,
Table 1. DKR of Racemic 6 (0.1 M) Using Diallyl Carbonate
and PSL-C I at 50 °C during 48 h at 250 rpm
entry
solvent
carbonate 9b c (%)a eeP (%)b eeS (%)b
1
2
3
4
5
6
THF
10 equiv
72
29
0
96
15
8
1,4-dioxane 10 equiv
>99
MeCN
toluene
TBME
9b
10 equiv
10 equiv
10 equiv
0.1 M
83
87
85
95
94
91
65
78
ndc
a Conversion values determined by 1H NMR of the reaction crude.
b Enantiomeric excesses determined by HPLC. c Not determined.
In order to increase the conversion values, different
solvents were tested, finding a remarkable influence de-
pending on the reaction medium, yielding enantiopure (R)-
10 and the remaining substrate in very low enantiomeric
excess with 1,4-dioxane (entry 2, Table 1), while a more
polar solvent such as acetonitrile provokes the inactivation
of the enzyme (entry 3, Table 1). Solvents with a lower
polaritiy such as tert-butyl methyl ether (TBME) or to-
luene led to higher conversions (83ꢀ87%), yielding (R)-10
with high stereoselectivities (94ꢀ95% ee, entries 4 and 5,
Table 1), while racemizationfailedatlongerreaction times.
The use of diallyl carbonate as both solvent and alkoxycarbo-
nylating agent did not improve the results previously obtained.
Additionally, other PSL preparations were also employed, but
while no conversion was found for PSL-SD (supported on
diatomite mainly active only in aqueous systems), lower
conversions and similar selectivities were found for PSL-IM
(crude preparation stabilized with cyclodextrins).
Scheme 4. Lipase-Catalyzed Alkoxycarbonylation of Racemic 6
Using Allyl Carbonates 9aꢀb in Dynamic Kinetic Resolutions
Biocatalytic reactions were finally examined in terms of
enzyme loading and temperature by adding double the
amount of enzyme in weight or heating at 60 °C (Table 2);
however, in all cases doubling the amount of enzyme led to
similar results as the ones previously obtained (entries 3
(11) Pietruszka, J.; Simon, R. C.; Kruska, F.; Braun, M. Eur. J. Org.
Chem. 2009, 6217.
(12) Amino ester 6 was highly unstable, leading to the corresponding
aromatic heterocycle in short reaction times. Therefore, it was used
immediately after its preparation or stored as a dichloromethane stock
solution previously to be enzymatically reacted with allyl carbonates.
ꢀ
€
(15) (a) Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247. (b)
€
Martın-Matute, B.; Backvall, J.-E. Curr. Opin. Chem. Biol. 2007, 11, 226.
ꢀ
ꢀ
(13) Gotor-Fernandez, V.; Fernandez-Torres, P.; Gotor, V. Tetra-
(c) Ahn, Y.; Ko, S.-B.; Kim, M.-J.; Park, J. Coord. Chem. Rev. 2008, 252,
647. (d) Lee, J. H.; Han, K.; Kim, M.-J.; Park, J. Eur. J. Org. Chem. 2010,
999. (e) Pellisier, H. Tetrahedron 2011, 67, 3769.
hedron: Asymmetry 2006, 17, 2558.
(14) Breen, G. F. Tetrahedron: Asymmetry 2004, 15, 1427–1430.
1698
Org. Lett., Vol. 14, No. 7, 2012

Scheme 6. Synthesis of Mosher Derivative for 1H NMR Analysis in the Assignment of Carbamates (R)-7 and (R)-10 Absolute Configurations
and 4, Table 2). On the otherhand, higher temperaturesled
to a significant increase in the conversion value from 83 to
90% with toluene, yielding the desired carbamate in 94%
ee (entry 5, Table 2).
processes, hydrochloride and hydrobromide salts were
prepared, but unfortunately none of them were suitable
for X-ray diffraction analysis. For that reason, the corre-
sponding Mosher derivative was synthesized from the
already obtained carbamates 7 and 10 through DKR
processes. For allyl carbamate 10, the allyloxycarbonyl
group was deprotected by reaction with 1,3-dimethylbar-
bituric acid (DMBA), palladium(II) acetate, and triphe-
nylphosphine, while for 7, cleavage of the benzylox-
ycarbonyl rest was achieved through conventional palla-
dium-catalyzed hydrogenation. Then, subsequent protec-
tion of the free amino ester acid 6 using (S)-(þ)-R-
methoxy-R-trifluoromethylphenylacetic acid chloride
(MTPA-Cl) in the presence of triethylamine led to the
formation of the Mosher amide (1R,20R)-12 in good yields
(Scheme 6).17 This relative stereochemistry defines the R
configuration for the chiral center C-1, and then a (1R,20R)
for the Mosher derivative. It must be noticed that partial
epimerization was observed after the deprotectionꢀprotection
sequence, highlighting the lability of this type of compound
(see Figure S1, Supporting Information). This aspect is not
surprising because the intermediate of the transformation is
the free amino ester 6, which has a high tendency to racemize.
In summary, we have developed for the first time a
chemoenzymatic access to isoindoline carbamates in high
optical purity by means of an efficient dynamic kinetic
resolution strategy without using metal, acid, or basic
catalyst for the racemization of the slow reacting amine
enantiomer, yielding carbamates in very high optical pu-
rities and good yields. The scope of the reaction has been
expanded using not only diallyl carbonate but also diben-
zyl carbonate, in order to selectively modify the N-protec-
tion of amino acid derivatives with synthetic purposes.
Table 2. DKR of Racemic 6 (0.1 M) Using 9b during 48 h at 250
rpm and Different Amounts of PSL-C I
entry solvent t (°C) PSL-C Ia c (%)b eeP (%)c eeS (%)c
1
2
3
4
5
toluene
TBME
toluene
TBME
toluene
50
50
50
50
60
1:1
1:1
2:1
2:1
2:1
83
87
85
87
90
95 (66)
94 (68)
92 (71)
90 (70)
94 (72)
65
78
82
81
72
a Ratio (enzyme:substrate) in weight. b Conversion values deter-
mined by 1H NMR of the reaction crude. Isolated yields of carbamate
10 in parentheses. c Enantiomeric excesses determined by HPLC.
Probing the flexibility of our system and although
dibenzyl carbonate (11) is traditionally considered as a
poor reactive reagent,14,16 the introduction of the Cbz
group was possible, gratifyingly yielding the N-Cbz ami-
noester (R)-7 in 85% conversion (63% isolated yield and
98% ee, Scheme 5) when using identical conditions as the
ones employed with diallyl carbonate (entry 5 in Table 2).
Introduction of different N-protective groups is a highly
demanding task because of the versatility of selective
functionalization in peptide coupling.
Scheme 5. Use of Dibenzyl Carbonate (11) in PSL-C I catalyzed
DKR Process of Racemic Amino Ester 6
Acknowledgment. This work has been supported by the
Spanish Ministry of Science and Innovation (MICINN,
CTQ2007-61126 and CTQ2010-17436 research projects)
ꢀ
and Gobierno de Aragon (research group E40). V.G.-F.
thanks also MICINN for personal funding inside the
ꢀ
Ramon y Cajal Program.
To confirm the absolute configurations for enantioen-
riched products obtained by means of lipase-catalyzed
Supporting Information Available. General methods,
experimental procedures, characterization data for new
(16) Takayama, S.; Lee, S. T.; Hung, S.-C.; Wong, C.-H. Chem.
Commun. 1999, 127.
1
compounds, and copies of H, 13C, and DEPT NMR
(17) After registering the 1H NMR spectra for both racemic (1RS, 20R)
and optically active (1R, 20R)-12, we compared their H-1 signal, hydrogen
atom in R to the carboxylic rest (5.75ꢀ5.90 ppm), observing that the proton
corresponding to the major diastereoisomer appears at higher fields and
therefore is in the opposite side to the Ph group bearing the MTPA rest (it is
not affected by ring anisotropy of the Ph group).
experiments. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
1699