Kinetic resolution of racemic carboxylic acids through asymmetric protolactonization promoted by chiral phosphonous acid diester

Article abstract of DOI:10.1021/ol401313d

Chiral phosphonium salts induce the kinetic resolution of racemic α-substituted unsaturated carboxylic acids through asymmetric protolactonization. Both the lactones and the recovered carboxylic acids are obtained with high enantioselectivities and high S

Full text of DOI:10.1021/ol401313d

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Kinetic Resolution of Racemic
Carboxylic Acids through Asymmetric
Protolactonization Promoted by
Chiral Phosphonous Acid Diester
Masayuki Sakuma,† Akira Sakakura,*,‡ and Kazuaki Ishihara*,†,§
Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku,
Nagoya 464-8603, Japan, Graduate School of Natural Science and Technology,
Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530,
Japan, and JST, CREST, Japan
ishihara@cc.nagoya-u.ac.jp; sakakura@okayama-u.ac.jp
Received April 25, 2013
ABSTRACT
Chiral phosphonium salts induce the kinetic resolution of racemic R-substituted unsaturated carboxylic acids through asymmetric protolactonization. Both
the lactones and the recovered carboxylic acids are obtained with high enantioselectivities and high S (= kfast/kslow) values. Asymmetric protolactonization
also leads to the desymmetrization of achiral carboxylic acids. Notably, chiral phosphonous acid diester not only induced the enantioselectivity but also
promoted protolactonization.
The synthesis of optically active carboxylic acids and
lactones is an important subject in the field of medicinal
and pharmaceutical chemistry. Intramolecular cyclization
of unsaturated carboxylic acids is a useful method for the
direct synthesis of lactones. However, the conventional
methods, which use electrophilic reagents (EX) such as
halonium compounds, organochalcogens, and transition
metal complexes,1,2 have the drawback that they require
an additional step to remove the substituents (E) of the
products. Although the proton-induced lactonization
(protolactonization) of unsaturated carboxylic acids using
a Brønsted acid is also well-known, it most often occurs with
more than a stoichiometric amount of a Brønsted acid.3 On
the other hand, it has been reported that trifluoromethane-
sulfonic acid (TfOH) catalyzes the cyclization of unsatu-
rated carboxylic acids to give a variety of R- or β-substituted
γ- and δ-lactones in excellent yields.4 However, it would
be very difficult to apply this method to an asymmetric
version, since these reactions require harsh conditions.
(2) For selected recent reports on enantioselective halolactonizations,
see: (a) Fang, C.; Paull, D. H.; Hethcox, J. C.; Shugrue, C. R.; Martin, S. F.
Org. Lett. 2012, 14, 6290. (b) Tungen, J. E.; Nolsøe, J. M. J.; Hansen, T. V.
Org. Lett. 2012, 14, 5884. (c) Dobish, M. C.; Johnston, J. N. J. Am. Chem.
Soc. 2012, 134, 6068. (d) Jiang, X.; Tan, C. K.; Zhou, L.; Yeung, Y.-Y.
Angew. Chem., Int. Ed. 2012, 51, 7771. (e) Murai, K.; Nakamura, A.;
Matsushita, T.; Shimura, M.; Fujioka, H. Chem.;Eur. J. 2012, 18, 8448. (f)
Zhang, W.; Liu, N.; Schienebeck, C. M.; Decloux, K.; Zheng, S.; Werness,
J. B.; Tang, W. Chem.;Eur. J. 2012, 18, 7296. (g) Tan, C. K.; Le, C.;
Yeung, Y.-Y. Chem. Commun. 2012, 48, 5793. (h) Paull, D. H.; Fang, C.;
Donald, J. R.; Pansick, A. D.; Martin, S. F. J. Am. Chem. Soc. 2012, 134,
11128. (i) Ikeuchi, K.; Ido, S.; Yoshimura, S.; Asakawa, T.; Inai, M.;
Hamashima, Y.; Kan, T. Org. Lett. 2012, 14, 6016.
† Nagoya University.
‡ Okayama University.
§ JST.
(1) (a) Ohfune, Y.; Kurokawa, N. Tetrahedron Lett. 1985, 26, 5307.
(b) Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298.
(c) Kang, S. H.; Lee, J. H.; Lee, S. B. Tetrahedron Lett. 1998, 39, 59.
(d) Jonasson, C.; Horvath, A.; Backvall, J. E. J. Am. Chem. Soc. 2000,
122, 9600. (e) Chavan, S. P.; Sharma, A. K. Tetrahedron Lett. 2001, 42,
4923. (f) Tiecco, M.; Testaferri, L.; Temperini, A.; Bagnoli, L.; Marini,
F.; Santi, C. Synlett 2001, 1767. (g) Gruttadauria, M.; Aprile, C.; Noto,
R. Tetrahedron Lett. 2002, 43, 1669. (h) Curini, M.; Epifano, F.;
Marcotullio, M. C; Montanari, F. Synlett 2004, 368.
ꢀ
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10.1021/ol401313d
XXXX American Chemical Society

While the number of chiral Brønsted acid catalysts is
increasing, the chiral protolactonization of unsaturated
carboxylic acids remains rare, mainly due to the difficulty
of controlling the Brønsted acidities of catalysts and the
low nucleophilicity of the carboxyl group toward unacti-
vated alkenes.5
(5 mol %) at ꢀ30 °C also gave 3a in high enantioselectivity
(95% ee) although the conversion was low (17%, entry 3).
Next, other achiral Brønsted acids (HX) were investi-
gated under these conditions. The use of FSO3H gave
almost the same result as with the use of TfOH (95% ee,
12% conv, entry 4), although FSO3H was the optimal
Brønsted acid in the cyclization of 2-geranylphenols. On
the other hand, the use of ClSO3H improved the conver-
sion of 3a without a significant loss of enantioselectivity
(92% ee, 41% conv, entry 5). To our delight, when the
Recently, we developed chiral phosphonium salts (1 HX),
3
which were prepared from chiral phosphonous acid diester 1
with achiral Brønsted acids (HX), as new chiral Brønsted
acid catalysts for the enantioselective polyene cyclization
of 2-geranylphenols (Scheme 1).6 With regard to asymmetric
protocyclization reactions, we envisioned that the chiral
phosphonium salt-promoted method could be applied to
the kinetic resolution of racemic unsaturated carboxylic acids
through asymmetric protolactonization. This reaction sys-
tem may lead to a novel and straightforward approach for
providing optically active carboxylic acids and lactones with-
out byproduct generation derived from activating reagents.
Here, we report the kinetic resolution of racemic R-substi-
1 ClSO3H-catalyzed protolactonization was conducted
3
at ꢀ40 °C, the enantioselectivity was increased to 94% ee
without any decrease in the conversion, which gave the
highest selectivity factor (S = 62, entry 6). Additionally,
when the reaction was conducted at ꢀ20 °C, the recovered
carboxylic acid was obtained with 95% ee (entry 7). These
results suggested that simple control of the reaction tem-
perature could allow easy access to optically active car-
boxylic acids and lactones with high enantioselectivities.
Meanwhile, when the reaction was conducted in the
absence of 1 at ꢀ20 °C, racemic lactone 3a was obtained
in 8% yield (entry 8). These results indicated that the use of
Brønsted base 1 controlled not only the stereoselectivity but
also the reactivity.
tuted carboxylic acids catalyzed by chiral 1 HX through
3
asymmetric protolactonization.
Scheme 1. Chiral Phosphonium Salts (1 HX)
3
Table 1. Kinetic Resolution of (()-2a Catalyzed by Chiral 1 HX
3
Initially, racemic carboxylic acid (()-2a was chosen as a
model substrate for the chiral Brønsted acid catalyzed
kinetic resolution (Table 1). Based on our previous study,
temp
ee of
ee of
conv
(%)b
entry
HX
(°C)
3a (%)a
4a (%)a
Sc
we envisioned that the use of chiral 1 HX would be
3
1d
2d
3
TfOH
ꢀ40
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ40
ꢀ20
ꢀ20
95
76
95
95
92
94
82
;
33
98
20
13
65
63
95
;
26
56
17
12
41
40
54
8f
54
29
47
44
46
62
40
;
important for the enantioface selection of the isoprenyl
group of (()-2a. First, the 6-endo-protolactonization of
(()-2a was conducted under the same conditions as those
for the enantioselective cyclization of 2-geranylphenol
[in the presence of 1 (40 mol %) and TfOH (10 mol %)
in CHCl3 at ꢀ40 °C].6 As a result, the reaction gave the
corresponding lactone3awith95% ee (26% conv, entry1).
The unreacted carboxylic acid 2a was recovered after the
transformation to the methyl ester 4a (33% ee) using
TMSCHN2. Therefore, these results gave a selectivity factor
(S = kfast/kslow) of 54 (entry 1). When the reaction was
conducted at ꢀ30 °C, the carboxylic acid was recovered
with 98% ee (entry 2). The use of 1 (20 mol %) and TfOH
TfOH
TfOH
4
FSO3H
ClSO3H
ClSO3H
ClSO3H
ClSO3H
5
6
7
8e
a Determined by chiral HPLC analysis. b Conversion was calculated
as C = ee(4a)/(ee(3a) þ ee(4a)). c The selectivity factor was calculated as
S = ln[1 ꢀ C(1 þ ee(3a))]/ln[1 ꢀ C(1 ꢀ ee(3a))]. d Reaction was
conducted in the presence of 1 (40 mol %) and TfOH (10 mol %).
e Reaction was conducted in the absence of 1. f Isolated yield.
With the optimized reaction conditions in hand, we next
examined the kinetic resolution of racemic carboxylic acids
(()-2 bearing various R-substituents (Table 2). The reac-
tion of(()-2 was conducted in the presence of 1 (20 mol %)
and ClSO3H (5 mol %) in CHCl3 at ꢀ40 to ꢀ20 °C for
1 day. The introduction of several aromatic rings at the
R-position of carboxylic acids gave good to excellent
selectivities (S = 26ꢀ62, entries 1ꢀ4). The absolute con-
figuration of lactone 3b was assigned to be (S) based on
the results of an X-ray single crystallographic analysis.7,8
(3) (a) Anscll, M. F.; Palmer, M. H. Quart. Rev.(London) 1964, 18,
211. (b) Tiecco, M.; Testaferri, L.; Tingoli, M. Tetrahedron 1993, 49,
5351. (c) Mali, R. S.; Babu, K. N. Helv. Chim. Acta 2002, 85, 3525.
(e) Miura, K.; Hayashida, J.; Takahashi, T.; Nishikori, H.; Hosomi, A.
J. Organomet. Chem. 2003, 686, 242. (f) Zhou, Y.; Woo, L. K.; Angelici,
R. J. Appl. Catal. A: General 2007, 333, 238.
~
(4) Coulombel, L.; Dunach, E. Synth. Commun. 2005, 35, 153.
(5) For a report on the chiral LBA-induced polyene cyclization of
unsaturated carboxylic acids, see: Upar, K. B.; Mishra, S. J.; Nalawade,
S. P.; Singh, S. A.; Khandare, R. P.; Bhat, S. V. Tetrahedron: Asymmetry
2009, 20, 1637.
(6) Sakakura, A.; Sakuma, M.; Ishihara, K. Org. Lett. 2011, 13, 3130.
B
Org. Lett., Vol. XX, No. XX, XXXX

at ꢀ40 °C gave the recovered carboxylic acid in 43% yield
with 94% ee (S = 26, entry 5). Substrate 2f bearing an
isopropyl group also gave good selectivity (S = 37, entry 6).
On the other hand, this method was not effective for benzyl-
substituted substrate 2g due to the lower steric hindrance of
the primary alkyl substituent (S = 4, entry 7). The kinetic
resolution of racemic tertiary carboxylic acid 2h did not give
a satisfactory level of enantioselectivity (S = 6, entry 8).
Oxidative cleavage of the isoprenyl group of recovered
chiral ester 4a gave 2-phenylsuccinate 5a9 without a signifi-
cant loss of optical purity (Scheme 2).10 Chiral 2-substituted
succinates 5 are important chiral building blocks for the syn-
thesis of various bioactive compounds and natural prod-
ucts.11 Since (R)-5a was obtained from recovered 4a, the
absolute configuration of 4a was determined to be (R),
which was consistent with the fact that the absolute config-
uration of lactone 3b was (S).
Table 2. Substrate Scope for the Kinetic Resolution of (()-2
Scheme 2. Synthesis of Chiral 2-Substituted Succinate 5a
To explore the substrate scope of the reaction, we
examined the kinetic resolution of racemic 4-methyl-4-
pentenoic acids 6 bearing an R-substituent (Table 3). Since
the protonation of 1,1-disubstituted alkenes 6 would gen-
erate carbocation intermediates similar to those in the
reaction of 2, a high level of enantioselectivity is expected
to be induced. The asymmetric protolactonization of (()-
6a in the presence of 1 (20 mol %) and ClSO3H (10 mol %)
at ꢀ40 °C showed good selectivity (S = 21, entry 1).
This reaction proceeded through 5-exo-cyclization to give
the corresponding five-membered lactone 7a with 83% ee.
The absolute configuration of recovered ester 8a was
assigned to be (R).7 The introduction of 2-bromophenyl
and 1-naphthyl groups at the R-position of 4-methyl-4-
pentenoic acids also gave the corresponding lactones 7
with good S values (entries 2 and 3).
Based on the kinetic resolution of racemic R-substituted
carboxylic acids, we envisioned that the chiral 1 ClSO3H-
3
catalyzed system could be applied to the desymmetrization
of achiral unsaturated carboxylic acids 9 and 11 (Scheme 3).
It could also be a useful approach to the synthesis of optically
active lactones. When the reaction of 9 was conducted in the
presence of 1(40mol%) andClSO3H(10mol%) atꢀ30 °C,
the desired lactone 10 was obtained in 82% yield with
79% ee. For substrate 11 bearing 1,1-disubstituted alkenes,
a Determined by chiral HPLC or GC analysis. b Isolated yield.
c Conversion was calculated as C = ee(4)/(ee(3) þ ee(4)). d The selectivity
factor was calculated as S = ln[1 ꢀ C(1 þ ee(3))]/ln[1 ꢀ C(1 ꢀ ee(3))].
e After recrystallization. f Reaction was conducted in the presence of 1
(20 mol %) and ClSO3H (10 mol %). g Reaction was conducted in the
presence of 1 (40 mol %) and ClSO3H (10 mol %).
Furthermore, substrate 2e bearing a 3-benzofuranyl group
was also tolerated, and the use of ClSO3H (10 mol %)
(9) Chung, Y.-C.; Janmanchi, D.; Wu, H.-L. Org. Lett. 2012, 14,
2766.
(10) LaLonde, R. L.; Wang, Z. J.; Mba, M.; Lackner, A. D.; Toste,
F. D. Angew. Chem., Int. Ed. 2010, 49, 598.
(7) See Supporting Information for details.
€
(11) (a) Schottner, M.; Spiteller, G.; Gansser, D. J. Nat. Prod. 1998,
(8) The supplementary crystallographic data for this paper can be
found as CCDC 934314 (3b) and CCDC 934315 (1). These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
61, 119. (b) Ayres, D. C.; Loike, J. D. In Lignans, Chemical, Biological,
and Clinical Properties; Cambridge University: Cambridge, 1990; Chapters
3 and 4 and references therein. (c) Ward, R. S. Chem. Soc. Rev. 1982, 11, 75.
(d) Ward, R. S. Tetrahedron 1990, 46, 5029.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Kinetic Resolution of (()-6 through Asymmetric
5-exo-Protolactonization
ee (%)a [yield (%)]b
conv
entry
6 (R)
6a (Ph)
7
8
(%)c
Sd
1
2
3
83 [nd]
78 [nd]
82 [nd]
64 [50]
30 [57]
53 [54]
44
28
39
21
11
17
6b (2-BrC6H4)
6c (1-naphthyl)
a Determined by chiral HPLC analysis. b Isolated yield. c Conversion
was calculated as C = ee(8)/(ee(7) þ ee(8)). d The selectivity factor was
calculated as S = ln[1 ꢀ C(1 þ ee(7))]/ln[1 ꢀ C(1 ꢀ ee(7))].
the five-membered lactone 12 was obtained with 76% ee.
These reactions gave the corresponding lactones 10 and 12
with good enantioselectivities, although the selectivity of the
kinetic resolution of racemic carboxylic acid 2g bearing a
primary alkyl substituent at the R-position was low.
Figure 1. Proposed explanation for the absolute stereoprefer-
ence observed in 1 ClSO3H-catalyzed kinetic resolution.
3
of R-substituent R with a triphenylsilyl group. Thus, (R)-
carboxylic acid 2 is selectively recovered after the reaction.
In conclusion, we have achieved the kinetic resolu-
tion of racemic R-substituted carboxylic acids 2 and 6
through asymmetric protolactonization catalyzed by a
Scheme 3. Desymmetrization of Achiral R-Substituted
Carboxylic Acids 9 and 11
chiral Brønsted acid, 1 ClSO3H. This reaction system
3
may represent a novel and straightforward approach for
obtaining optically active carboxylic acids and lactones.
In addition, the desymmetrization reactions of achiral
carboxylic acids 9 and 11 were also accomplished via the
chiral 1 ClSO3H-catalyzed protolactonization. To the
3
best of our knowledge, these are the first successful exam-
ples of reactions that give δ-lactones with high enantios-
electivities through the chiral Brønsted acid catalyzed
asymmetric protolactonization of unsaturated carboxylic
acids.
Figure 1 shows a proposed explanation for the absolute
stereopreference we observed. Structure A is the Newman
projection of the chiral phosphonium salt 1 ClSO3H viewed
along the HꢀP bond. Based on our previous study6 and
3
Acknowledgment. This project was support in part by
JSPS.KAKENHI (23350039) and the Program for Lead-
ing Graduate Schools “Integrative Graduate Education
and Research in Green Natural Sciences,” MEXT, Japan.
the X-ray single crystallographic structure of 1,7,8 1 ClSO3H
3
selectively reacts with the Re-face of the terminal iso-
prenyl group of 2, the dimethyl group of which is placed
at the least-hindered side in the transition-state assem-
bly. (S)-Carboxylic acid 2 immediately undergoes pro-
tolactonization through transition state B to give the
corresponding (S)-lactone 3. On the other hand, the reaction
of (R)-carboxylic acid 2 through transition state C is
much slower than that of B due to the steric repulsion
Supporting Information Available. Experimental pro-
cedure and full characterization of new compounds.
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