Kinetic resolution of β-substituted olefinic carboxylic acids by asymmetric bromolactonization

Article abstract of DOI:10.1021/ol401007u

A strategically novel kinetic resolution of β-substituted olefinic carboxylic acids is developed by asymmetric bromolactonization using an organocatalyst, 4-tBuPh-tris 1b. The cyclization stage, which provides δ-lactone, is proposed to be operative for discrimination of each enantiomer of carboxylic acids.

Full text of DOI:10.1021/ol401007u

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Kinetic Resolution of β‑Substituted
Olefinic Carboxylic Acids by Asymmetric
Bromolactonization
Kenichi Murai, Tomoyo Matsushita, Akira Nakamura, Norimichi Hyogo,
Junki Nakajima, and Hiromichi Fujioka*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka,
Suita, Osaka 565-0871, Japan
fujioka@phs.osaka-u.ac.jp
Received April 11, 2013
ABSTRACT
A strategically novel kinetic resolution of β-substituted olefinic carboxylic acids is developed by asymmetric bromolactonization using an
organocatalyst, 4-tBuPh-tris 1b. The cyclization stage, which provides δ-lactone, is proposed to be operative for discrimination of each
enantiomer of carboxylic acids.
Kinetic resolution of racemic carboxylic acids is one
of the useful ways to obtain both enantiomers of chiral
carboxylic acids.1 Consequently, a significant effort has
been devoted to the development of efficient chemical
methods by artificial molecules, as well as enzymatic
methods. Recently, a direct kinetic resolution of racemic
carboxylic acids, which is based on asymmetric esterifica-
tion reactions utilizing chiral acyl transfer catalysts, such
as L-histidine derivatized sulfonamide or benzotetramisole
(BTM) type catalysts, has been developed.2 In these meth-
ods, various R-substituted carboxylic acids are effectively
resolved (Scheme 1). In contrast, chemical methods for a
Scheme 1. Previous Reports: Kinetic Resolution of R-Substi-
tuted Carboxylic Acids by Esterification
kinetic resolution of β-substituted carboxylic acids have
been less explored to date.3 Although alternative strategies
for β-chiral carboxylic acid derivatives as represented by
asymmetric conjugate addition or the asymmetric hydro-
genation exist,4 it is important to develop a novel kinetic
resolution method. Herein, we wish to report a strategi-
cally novel approach for kinetic resolution of β-substituted
carboxylic acids, which features the utilization of an
organocatalytic asymmetric bromolactonization reaction.
In the case of β-substituted carboxylic acids, a stereo-
center to be discriminated is located far from the carbonyl
moiety. Therefore, we think that it would be difficult to
resolve β-substituted carboxylic acids by an asymmetric
esterification based approach. In fact, attempts at the
(1) Pellissier, H. Adv. Synth. Catal. 2011, 353, 1613.
(2) (a) Ishihara, K.; Kosugi, Y.; Umemura, S.; Sakakura, A. Org.
Lett. 2008, 10, 3191. (b) Sakakura, A.; Umemura, S.; Ishihara, K. Synlett
2009, 10, 1647. (c) Shiina, I.; Nakata, K.; Onda, Y. Eur. J. Org. Chem.
2008, 5887. (d) Nakata, K.; Onda, Y.; Ono, K.; Shiina, I. Tetrahedron
Lett. 2010, 51, 5666. (e) Shiina, I.; Nakata, K.; Ono, K.; Onda, Y.;
Itagaki, M. J. Am. Chem. Soc. 2010, 132, 11629. (f) Shiina, I.; Ono, K.;
Nakata, K. Catal. Sci. Technol. 2012, 2, 2200. (g) Yang, X.; Birman,
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Birman, V. B. Angew. Chem., Int. Ed. 2012, 51, 9638.
(3) Enzymatic kinetic resolution of β-substituted carboxylic esters
were reported. For examples, see: (a) Reis, J. S.; Andrade, L. H.
Tetrahedron: Asymmetry 2012, 23, 1294. (b) Brem, J.; Naghi, M.; Tosa,
M.-I.; Boros, Z.; Poppe, L.; Irimie, F.-D.; Paizs, C. Tetrahedron:
Asymmetry 2011, 22, 1672. (c) Felluga, F.; Pitacco, G.; Valentin, E.;
Venneri, C. D. Tetrahedron: Asymmetry 2008, 19, 945.
(4) For examples, see: (a) Khumsubdee, S.; Burgess, K. ACS Catal.
2013, 3, 237. (b) Chauhan, P.; Chimni, S. S. RSC Adv. 2012, 2, 6117.
r
10.1021/ol401007u
XXXX American Chemical Society

kinetic resolution of β-substituted carboxylic acids by using
chiral acyl transfer catalysts have not yet been described.
Instead, we envisioned that a process-including cyclization
reaction should be suitable for this purpose. In particular,
δ-lactone forming process should be promising because the
steric repulsion associated with 1,3-diaxial interactions in
6-membered transition states could expected to work for
distinction of stereoisomers.
Asymmetric halolactonization reactions are one of the
recent intensively developed areas of asymmetric reac-
tions.5 We have recently developed the asymmetric bro-
molactonization reaction catalyzed by trisimidazoline 1a
(Figure 1).6 This reaction efficiently produces δ-lactones
from 5-hexenoic acid derivatives. Accordingly, we hypo-
thesized that this bromolactonization reaction would be
applicable to a kinetic resolution of β-substituted olefinic
carboxylic acids. In the course of our studies probing this
proposal, Hamashima and Kan and Martin described
kinetic resolutions based on halolactonization reactions
of specific substrates, including 1,4-dihydronaphthalene-
1-carboxylic acids and 2-cyclopentene-1-acetic acid, as one
aspect of their work.7 These reports prompted us to describe
the results of our investigation of this methodology.
olefinic carboxylic acid 2a, which contains a methyl group
at the β-position. To our delight, we observed that, under
the bromolactonization conditions using trisimidazoline 1a
(10 mol %) and N-bromosuccinimide (NBS) (0.5 equiv),
2a is transformed to the corresponding bromolactone with a
moderate s factor (Table 1, entry 1, s = 7.4, calculated using
the reported equation8). To obtain insight into the reaction,
we further tested the two regioisomeric olefinic carboxylic
acids, R-isomer 2b and γ-isomer 2c, under the same condi-
tions. Interestingly, these isomer showed poor selectivity
compared to β-isomer 2a: s factors of 2b and 2c are 2.1
and 5.3, respectively. These observations suggest that the
substrate having substituent at the remote position both
from the carboxylic acid and the olefin (i.e., β-position) is
more efficient to be resolved by this bromolactonization
reaction.
It should be noted that the ee value of the product was
determined as the olefinic carboxylic acid (or correspond-
ing methyl ester). The olefinic carboxylic acids are regen-
erated by using reductive cleavage conditions with zinc
in the presence of NH4Cl in good yield (Scheme 2).9
This transformation of bromolactone which can readily
regenerate the starting carboxylic acids is an important
component of this resolution method.
Table 1. Effect of the Methyl Group Position on the Kinetic
Resolution of Olefinic Carboxylic Acid
Figure 1. Trisimidazoline catalysts.
In order to probe the feasibility of the use of halolactoniza-
tion reactions for the kinetic resolution of β-substituted
carboxylic acids, we initially examined the reaction of the
(5) (a) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B.
J. Am. Chem. Soc. 2010, 132, 3298. (b) Yousefi, R.; Whitehead, D. C.;
Mueller, J. M.; Staples, R. J.; Borhan, B. Org. Lett. 2011, 13, 608.
(c) Zhang, W.; Zheng, S.; Liu, N.; Werness, J. B.; Guzei, I. A.; Tang, W.
J. Am. Chem. Soc. 2010, 132, 3664. (d) Zhang, W.; Liu, N.; Schienebeck,
C. M.; Decloux, K.; Zheng, S.; Werness, J. B.; Tang, W. Chem.;Eur. J.
2012, 18, 7296. (e) Veitch, G. E.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2010, 49, 7332. (f) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung,
Y.-Y. J. Am. Chem. Soc. 2010, 132, 15474. (g) Tan, C. K.; Zhou, L.;
Yeung, Y.-Y. Org. Lett. 2011, 13, 2738. (h) Chen, J.; Zhou, L.; Tan,
C. K.; Yeung, Y.-Y. J. Org. Chem. 2012, 77, 999. (i) Tan, C. K.; Le, C.;
Yeung, Y.-Y. Chem. Commun. 2012, 48, 5793. (j) Jiang, X.; Tan, C. K.;
Zhou, L.; Yeung, Y.-Y. Angew. Chem., Int. Ed. 2012, 51, 7771.
(k) Dobish, M. C.; Johnston, J. N. J. Am. Chem. Soc. 2012, 134, 6068.
(l) Paull, D. H.; Fang, C.; Donald, J. R.; Pansick, A. D.; Martin, S. F.
J. Am. Chem. Soc. 2012, 134, 11128. (m) Tungen, J. E.; Nolsøe, J. M. J.;
Hansen, T. V. Org. Lett. 2012, 14, 5884.
a Ee was determined using HPLC analysis of the corresponding
methyl esters (see the Supporting Information). b Ee was determined
using HPLC analysis of the olefinic carboxylic acids (see the Supporting
Information).
Encouraged by the promising results obtained by the
preliminary study shown in Table 1, we carried out an
optimization study of the kinetic resolution of β-substituted
olefinic carboxylic acid (Scheme 3). The β-phenyl-substituted
(6) (a) Murai, K.; Matsushita, T.; Nakamura, A.; Fukushima, S.;
Shimura, M.; Fujioka, H. Angew. Chem., Int. Ed. 2010, 49, 9174.
(b) Murai, K.; Nakamura, A.; Matsushita, T.; Shimura, M.; Fujioka,
H. Chem.;Eur. J. 2012, 18, 8448.
(8) S = ln[(1 ꢀ c){1 ꢀ ee(s)}]/ln[(1 ꢀ c){1 þ ee(s)}], c = ee(s)/{ee(s) þ
ee(p)} (ee(s) = ee of recovered carboxylic acid; ee(p) = ee of regenerated
carboxylic acid); see: Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988,
18, 249.
(7) (a) Ikeuchi, K.; Ido, S.; Yoshimura, S.; Asakawa, T.; Inai, M.;
Hamashima, Y.; Kan, T. Org. Lett. 2012, 14, 6016. (b) Fang, C.; Paull,
D. H.; Hethcox, J. C.; Shugrue, C. R.; Martin, S. F. Org. Lett. 2012, 14,
6290.
(9) Examples for the zinc-mediated reductive cleavage of bromolac-
tones: (a) Yoshino, T.; Nagata, Y.; Itoh, E.; Hashimoto, M.; Katoh, T.;
Terashima, S. Tetrahedron 1997, 53, 10239. (b) Doi, T.; Yanagisawa, A.;
Yamamoto, K.; Takahashi, T. Chem. Lett. 1996, 25, 1085.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Generalitya
Scheme 2. Regeneration of the Olefinic Carboxylic Acids
Scheme 3. Optimization Study
a Reaction was carried out using 1b (5 mol %) and DBDMH (0.3
equiv) in toluene (0.1 M) at ꢀ60 °C. Reaction time: 24 h. b Ee was
determined using HPLC analysis of the olefinic carboxylic acids (see the
Supporting Information). c Ee was determined using HPLC analysis of
the corresponding methyl esters (see the Supporting Information).
a Ee of 3d was determined as the regenerated carboxylic acid 2d.
carboxylic acid 2d was employed in this effort in place of 2a
because analysis of its optical purity by HPLC is more easily
carried out.10 Under the same conditions used for the reaction
of 2a (Table 1), 2d was also resolved with a moderate s factor
(s = 6.0). The results of studies in which the reaction
conditions were varied showed that a good s factor (s =
14.3) was obtained under the reaction conditions using 1,3-
dibromodimethylhydantoin (DBDMH, 0.3 equiv) as bro-
mine source with 5 mol % of catalyst 1a in toluene (0.1 M) at
ꢀ60 °C. Furthermore, more bulky catalyst 1b containing a
4-tert-butylphenyl group (4-tBuPh-tris) was found to be an
effective catalyst to give sufficient selectivity (s = 20.8).11
Having established optimized reaction conditions and
the ideal catalyst 1b, the scope of the kinetic resolution
reaction was investigated (Table 2). β-Aryl-substituted
olefinic carboxylic acids were observed to serve as good
substrates for this process, as reflected in the finding that
the 4-chloro-, 4-bromo-, 4-methoxyphenyl-substituted
carboxylic acids 2e, 2f, and 2g all are resolved with
moderate to good levels of selectivity (entries 2ꢀ4). In
particular, bromolactonization reaction of 2e takes place
with the highest level of selectivity in the series (entry 2, s =
24.7), while 4-bromobenzene substituted carboxylic acid 2f
reacts with a lower selectivity (entry 3, s = 6.4), a finding
that might be associated with lower solubility of 2f under
the reaction conditions. β-Alkyl-substituted olefinic car-
boxylic acids also serve as good substrates for this kinetic
resolution process (entries 5ꢀ7). The β-methyl 2a as well as
isopropyl 2h substituted acids react with good selectivity
(s = 15.6 and 15.7). Surprisingly, carboxylic acids posses-
sing a more bulky β-alkyl group, such as tert-butyl, do
not serve as good substrates (entry 7, s = 8.4). In addition,
alkyl substituents (e.g., cyclohexyl) rather than phenyl
on the olefin moiety unfortunately promote decreased
levels of selectivity (entry 8, s = 6.1). It should be noted
that in previously studied asymmetric bromolactonization
reactions using trisimidazoline 1a, substrates containing
aromatic groups on the olefin moiety react with higher
levels enantioselectivity than those possessing alkyl groups.5
Thus, it appears that the current kinetic resolution process
follows trends that have been observed earlier for the related
enantioselective bromolactonization reaction.
An analysis of the bromolactones 3d obtained from
kinetic resolution of the carboxylic acid 2d provides inter-
esting insight into the origin of stereoselectivity in the
process. As depicted in Scheme 4, the four stereoisomers
of bromolactone (i (4R,6S), ii (4S,6R), iii (4S,6R), and iv
(4S,6S)) can possibly form by cyclization of 2d. In the
bromolactonization reaction (Table 2), four stereoisomers
of lactone 3d i: ii: iii: iv are actually produced in a respective
i:ii:iii:iv ratio of approximately 90.7:6.8:0.1:2.4, as estimated
by analysis of HPLC peak area %. Among the two di-
astereomers, the one having the trans relationship between
the two phenyl groups (i.e., i and ii) is preferably produced
according to the nature of substrate.12 These observations
(10) Ee of 2a was not determined as the carboxylic acid, and
preparation of the methyl ester was necessary.
(11) For optimization study and screening of catalysts, see the
Supporting Information.
(12) This selectivity trend was confirmed by exploring the reaction of
2d with NBS and NaHCO3 in CH3CN at rt which showed that the trans
isomer is produced with a 6.2: 1 diastereoselectivity.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Analysis of Produced Bromolactone
Figure 2. Proposed TS1ꢀ3.
carbon center. On the other hand, TS1 may have little
such disadvantages. Therefore, the observation that the
R isomers of β-substituted olefinic carboxylic acids react
faster than the S isomers seems reasonable.
In conclusion, we have demonstrated a new approach
for the kinetic resolution of β-substituted carboxylic acids
that is based on asymmetric bromolactonization reactions.
The cyclization stage is proposed to be important for the
discrimination of stereoisomers. The reductive cleavage
process is also shown to be useful for ready regeneration of
the starting olefinic carboxylic acids from the bromolac-
tones. Although the substrate scope of the bromolactoni-
zation reaction is limited to olefinic carboxylic acids,
the olefin moiety is useful because it can be employed
to various transformations. We believe that the present
study provides a novel strategy for kinetic resolution of
β-substituted carboxylic acids and it can be further applic-
able to other enantioselective halocyclization reactions of
various olefinic substrates.13
suggest the following reactivity of each enantiomer of
olefinic carboxylic acids under the asymmetric bromolac-
tonization conditions: (1) For the matched carboxylic acid
(R-isomer), the diastereoselectivity (i vs iii) is very high. An
interesting aspect of this finding is that double-asymmetric
induction occurs in highly selective manner. (2) For the
mismatched carboxylic acid (S-isomer), the bromolactone
isomer ii is formed in preference to isomer iv. Since our
previous results indicate reactions promoted by catalysts
1 prefer to form a new lactone stereo center with S
configuration,6 this observation suggested that the stereo
chemical control by catalyst 1 was not over the substrate
control.
Although a detailed transition-state analysis including
interactions between the catalyst and substrate has not
been clear at this stage, the source of stereochemical
control in the kinetic resolution reactions of β-substituted
olefinic carboxylic acids is presumed to be associated with
the cyclization step in the process (Figure 2). On the basis
of the analysis of the structures displayed in Scheme 4, the
matched carboxylic acid (R isomer) would produce cor-
responding bromolactone through 6-membered ring TS1
predominantly. On the other hand, cyclization of the
mismatched carboxylic acid (S isomer) could take place
through TS2 (giving isomer iv) or TS3 (giving isomer ii).
TS2 or TS3 probably have disadvantages owing to the
1,3-diaxial interaction between the two phenyl groups
or the repulsive interaction with catalyst due to the mis-
match stereochemistry of the generating tetrasubstituted
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research on Innovative
Areas “Advanced Molecular Transformations by Organo-
catalysts” from MEXT.
Supporting Information Available. Experimental details
and detailed spectroscopic data of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Recently, asymmetric halocyclizations have been extensively
developed as well as halolactonizations. For recent reviews, see: (a)
Hennecke, U. Chem. Asian. J. 2012, 7, 456. (b) Denmark, S. E.; Kuester,
W. E.; Burk, M. T. Angew. Chem., Int. Ed. 2012, 51, 10938. (c) Murai, K.;
Fujioka, H. Heterocycles 2013, 4, 763.
The authors declare no competing financial interest.
D
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