Total spontaneous resolution by deracemization of isoindolinones

Article abstract of DOI:10.1002/anie.201205097

Preferential crystallization is a powerful tool to obtain optically active materials from racemic mixtures without any chiral source, and has been utilized widely for optical resolution on large scales for example in industrial processes.[ 1] To resolve optically active materials by crystallization efficiently, dynamic preferential crystallization involving a racemization process, a so-called total spontaneous resolution, has been developed.[2] Many efforts have been invested in new variations of this method, and the racemization processes can be classified into three groups: 1) involving an intermediate enolate anion or enol at the a-position of a carbonyl group,[3] 2) involving atropisomerism of axially chiral materials,[4] and 3) involving an equilibrium reaction via an achiral intermediate.[5-7] We have now developed a new example of total spontaneous resolution of isoindolinones that involves a combination of an intramolecular equilibrium reaction via an achiral intermediate and preferential crystallization.

Full text of DOI:10.1002/anie.201205097

Angewandte
Chemie
DOI: 10.1002/anie.201205097
Chiral Resolution
Total Spontaneous Resolution by Deracemization of Isoindolinones**
Fumitoshi Yagishita, Hiroki Ishikawa, Tatsuo Onuki, Shoko Hachiya, Takashi Mino, and
Masami Sakamoto*
Preferential crystallization is a powerful tool to obtain
optically active materials from racemic mixtures without
any chiral source, and has been utilized widely for optical
resolution on large scales for example in industrial process-
es.[1] To resolve optically active materials by crystallization
efficiently, dynamic preferential crystallization involving
a racemization process, a so-called total spontaneous reso-
lution, has been developed.[2] Many efforts have been
invested in new variations of this method, and the racemiza-
tion processes can be classified into three groups: 1) involving
an intermediate enolate anion or enol at the a-position of
a carbonyl group,[3] 2) involving atropisomerism of axially
chiral materials,[4] and 3) involving an equilibrium reaction via
an achiral intermediate.[5–7] We have now developed a new
example of total spontaneous resolution of isoindolinones
that involves a combination of an intramolecular equilibrium
reaction via an achiral intermediate and preferential crystal-
lization.
Scheme 1. Racemization of 3-hydroxyisoindolinones under acidic or
basic conditions.
Table 1: Space groups of 3-hydroxy-3-phenylisoindolin-1-ones 1a–f.
Isoindolinone
R
Space group
1a
1b
1c
1d
1e
1 f
Me
Et
Pr
iPr
PhCH2
PhCH2CH2
C2/c
racemic
P212121
P212121
ꢀ
P1
P212121
Various heterocyclic compounds containing the isoindo-
linone skeleton have important biological activities, and many
of these have been prepared and examined as pharmaceutical
agents.[8] Much effort has also been focused on the asymmet-
ric synthesis of the isoindolinone structure,[9] which is widely
used as a building block for the synthesis of natural
products.[10] Therefore, development of a new methodology
to obtain optically active heterocycles such as isoindolinones
is eagerly anticipated.
zation of the other isoindolinones in a chloroform–hexane
solution afforded prismatic crystals except in the case of 1b.
These crystals were subjected to X-ray crystallographic
analysis to determine the crystal structure. Fortunately, X-
ray analyses indicated that isoindolin-1-ones 1d and 1 f also
crystallized in a chiral fashion with the orthorhombic chiral
space group P212121. Isoindolinones 1a and 1e crystallized in
ꢀ
the racemic space groups C2/c and P1, respectively. The space
We found that 3-hydroxy-3-phenylisoindolin-1-ones
1 afforded conglomerates by spontaneous crystallization and
were racemized under acidic or basic conditions (Scheme 1).
The dynamic preferential crystallization resulted in total
spontaneous resolution in high ee values.
N-Alkylated 3-hydroxy-3-phenylisoindolin-1-ones 1a–f
were synthesized from 2-benzoylbenzoic acid and the corre-
sponding primary amines (Table 1).[11] To perform preferen-
tial crystallization, it is a requirement that the materials
crystallize as a conglomerate. The crystal structure of 1c was
reported with the chiral space group P212121.[12] Recrystalli-
group of 1b could not be determined; however, a racemic
crystal system was suggested from the results of dynamic
preferential crystallization described below.
Racemization must proceed much faster than crystalliza-
tion to achieve total resolution by dynamic preferential
crystallization. All 3-hydroxy-3-phenylisoindolin-1-ones
1 were not easily racemized under neutral conditions or in
the solid state; however, they were racemized in solution
under both acidic and basic conditions. The rates of race-
mization using trifluoroacetic acid (TFA) as an acid and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) as a base were mea-
sured according to the change of optical rotation at 208C, and
the activation free energy and the half-life were calculated
(Table 2).
[*] F. Yagishita, H. Ishikawa, T. Onuki, S. Hachiya, Prof. T. Mino,
Prof. M. Sakamoto
Department of Applied Chemistry and Biotechnology
Graduate School of Engineering, Chiba University
Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
E-mail: sakamotom@faculty.chiba-u.jp
When optically active isoindolinone 1c was dissolved in
a chloroform solution (2.0 ꢀ 10À2 molLÀ1) containing TFA
(1.0 ꢀ 10À2 molLÀ1), the half-life of racemization was 478 min
and the DG° value was 23.8 kcalmolÀ1. DBU was more
effective than TFA; the half-life of racemization was 347 min
and the DG° value was 23.6 kcalmolÀ1, even if diluted DBU
(1.0 ꢀ 10À4 molLÀ1) was used as a catalyst. The same tendency
was observed in the cases of 1d and 1 f. Therefore, we selected
DBU as a catalyst for racemization to perform total sponta-
[**] This work was supported by Grants-in-Aid for Scientific Research
(Nos. 21350024, 22655012) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) of the Japanese Govern-
ment.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205097.
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13023

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Communications
Table 2: Kinetic parameters for racemization of 3-hydroxy-3-phenyl-
isoindolin-1-ones 1c, 1d, 1 f.[a]
loss by decomposition or side reactions, and obtained in
optically active form at 15% ee (Table 3, entry 1). Optically
active 1c was obtained from all crystallizations with random
signs of optical rotation. However, enantiomerically pure 1c
could not be obtained by using this method, because
racemization did not proceed faster than crystallization.
Thus, the crystallization temperature and the DBU concen-
tration were increased to obtain better ee values by accel-
erating the rate of racemization (Table 3, method B). The use
of toluene as a solvent and crystallization at 1008C gave 97%
ee as expected (Table 3, entry 2). In both methods A and B
given in Table 3, the compounds were dissolved in solution
and then the solvent was allowed to evaporate to achieve
supersaturation and slow crystallization.
Isoindolinone
Catalyst
t1/2 [min]
DG° [kcalmolÀ1
]
1c
1c
1d
1d
1 f
1 f
TFA[b]
DBU[c]
TFA[b]
DBU[c]
TFA[b]
DBU[c]
478
347
146
15
2066
228
23.8
23.6
23.1
21.7
24.6
23.3
[a] Measurement conditions: 2.0ꢀ10À2 molLÀ1 of each isoindolinone in
CHCl3 at 208C. [b] 1.0ꢀ10À2 molLÀ1. [c] 1.0ꢀ10À4 molLÀ1
.
neous resolution of 1 by dynamic preferential crystallization
(Scheme 2).
In the case of 1d, the rate of racemization was much
greater than in that of 1c (Table 2), and an optical resolution
of 71% ee was obtained by crystallization at room temper-
ature (Table 3, entry 3). Seeding with the powdered single
crystal obtained by the normal recrystallization method from
a CHCl3–hexane solution gave a better ee value of 84%
(Table 3, entry 4). In this case, crystals with the same chirality
as the seed crystal were obtained as a matter of course.[4]
Crystallization at 1008C using toluene instead of hexane gave
excellent results of 97% ee (Table 3, entry 5).[13]
In the case of 1 f, crystallization from a mixture of CHCl3
and hexane at room temperature resulted in the low
resolution of 13% ee (Table 3, entry 6); however, crystalliza-
tion at 1008C from toluene using 50 mol% of DBU gave an
excellent ee value of 94% (Table 3,entry 7). All crystalliza-
tions at high temperatures using increased amounts of DBU
(Table 3, entries 2, 5, 7) resulted in high ee values with good
reproducibility. Deracemization could be controlled by the
use of seed crystals during crystallization.
Scheme 2. Total spontaneous resolution by dynamic preferential crys-
tallization involving an intramolecular equilibrium reaction.
From the X-ray results, 1c, 1d, and 1 f afforded conglom-
erates and have the possibility for total resolution by
crystallization. When a mixed solution of chloroform and
hexane containing 1c and DBU (0.5 mol%) in a test tube was
stirred at room temperature until all the solvent evaporated
completely, crystals of 1c were generated at the bottom of the
test tube (Table 3, method A). After DBU was removed
through a short silica gel column using ethyl acetate as an
eluent, the enantiomeric excess of 1c was analyzed by HPLC
using a chiral stationary phase (Daicel Ind. CHIRALPAK
AD-H). As a result, 1c was recovered quantitatively without
The stereogenic center of 1 did not racemize under neutral
conditions; therefore, optically pure materials were easily
obtained by recrystallization from a THF–hexane solution of
the solid obtained by dynamic crystallization (Table 3,
entries 2, 5, 7).
Recently, attrition-enhanced deracemization and resolu-
tion of chiral conglomerate solids were performed.[5] We also
tried the attrition-enhanced deracemization using glass
beads; unfortunately, the deracemization could not be
achieved with our substrates.[14]
In conclusion, we succeeded in the total spontaneous
resolution of three 3-hydroxy-3-phenylisoindolin-1-ones by
dynamic preferential crystallization. Each compound was
efficiently racemized in the presence of DBU, and the
enantiomer was obtained in quantitative recovery rates and
with excellent ee values. Three of the six 3-hydroxy-3-
phenylisoindolin-1-ones yielded conglomerate crystals by
spontaneous crystallization. An incidence of 50% conglom-
erates is striking, because the typical incidence is only around
20%.[15] We are continuing to explore the high incidence by
synthesizing many derivatives by changing the phenyl group.
This research provided not only a new example of the total
spontaneous resolution process involving racemization
through ring-opening and ring-closing reactions, but also
a fine preparative method of optically active heterocycles
without an external chiral source.
Table 3: Dynamic preferential crystallization of racemic isoindolinones.
Entry
1
Method
T [8C]
Recovered 1 [%]
ee [%][a]
1
2
3
4
5
6
7
1c
1c
1d
1d
1d
1 f
1 f
A[b]
B[c]
A[b]
A[b,d]
B[c]
A[b]
B[c]
RT
100
RT
RT
100
RT
99
96
98
100
100
91
15
97
71
84
97
13
94
100
100
[a] Determined by HPLC using a chiral stationary phase (Daicel Ind.
CHIRALPAK AD-H). [b] Method A: CHCl3/hexane as a solvent, DBU
(0.50 mol%) as a base, room temperature. [c] Method B: CHCl3/toluene
as a solvent, DBU (50 mol%) as a base, 1008C. [d] Seeding.
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[5] For intermolecular reaction, see a) W. L. Noorduin, A. A. C.
Experimental Section
Bode, M. van der Meiden, H. Meekes, A. F. van Etteger, W. J. P.
van Enckevort, P. C. M. Christianen, B. Kaptein, R. M. Kellogg,
T. Rasing, E. Vlieg, Nat. Chem. 2009, 1, 729732; b) W. L.
Noorduin, P. Van DerAsdonk, H. Meekes, W. J. P. van Enck-
evort, B. Kaptein, M. Leeman, R. M. Kellogg, E. Vlieg, Angew.
Chem. 2009, 121, 3328 – 3330; Angew. Chem. Int. Ed. 2009, 48,
3278 – 3280; c) W. L. Noorduin, B. Kaptein, H. Meekes, W. J. P.
van Enckevort, R. M. Kellogg, E. Vlieg, Angew. Chem. 2009,
121, 4651 – 4653; Angew. Chem. Int. Ed. 2009, 48, 4581 – 4583.
[6] Catalytic asymmetric synthesis coupled with in situ deracemiza-
tion. S. B. Tsogoeva, S. Wei, M. Freund, M. Mauksch, Angew.
Chem. 2009, 121, 598 – 602; Angew. Chem. Int. Ed. 2009, 48, 590 –
594.
Dynamic preferential crystallization (method A): A mixed solution of
chloroform and hexane containing
1 (5–50 mg) and DBU
(0.50 mol%) was stirred in a test tube or a vial at room temperature
until all solvent evaporated. After DBU was removed through a short
silica gel column using ethyl acetate as an eluent, the enantiomeric
excess of 1 was analyzed by HPLC using a chiral stationary phase
(Daicel Ind. CHIRALPAK AD-H).
Dynamic preferential crystallization (method B):
A mixed
solution of chloroform and toluene containing 1 (5–50 mg) and
DBU (50 mol%) was stirred in a test tube at 1008C until all solvent
evaporated. After DBU was removed through a short silica gel
column using ethyl acetate as an eluent, the enantiomeric excess of
1 was analyzed by HPLC using a chiral stationary phase.
[7] Intramolecular equilibrium reaction is very rare. J. Siegwarth, J.
Bornhoft, C. Nather, R. Herges, Org. Lett. 2009, 11, 3450 – 3452.
[8] a) K. Smith, G. A. Ei-Hiti, A. S. Hegazy, B. Kariuki, Beilstein J.
Org. Chem. 2011, 7, 1219 – 1227; b) P. Pigeon, B. Decroix,
Tetrahedron Lett. 1997, 38, 2985 – 2988; c) I. Osante, E. Lete, N.
Sotomayor, Tetrahedron Lett. 2004, 45, 1253 – 1256; d) R. A.
Abramovitch, I. Shinkai, B. J. Mavunkel, K. M. More, S.
OꢁConnor, G. H. Ooi, W. T. Pennington, P. C. Srinivason, J. R.
Stowers, Tetrahedron 1996, 52, 3339 – 3354; e) J.-M. Ferland,
C. A. Demerson, L. G. Humber, Can. J. Chem. 1985, 63, 361 –
365; f) Z.-P. Zhuang, M.-P. Kung, M. Mu, H. F. Kung, J. Med.
Chem. 1998, 41, 157 – 166.
[9] a) S. Yamada, K. Yamashita, Tetrahedron Lett. 2008, 49, 32 – 35;
b) V. Agouridas, F. Capet, A. Couture, E. Deniau, P. Grand-
claudon, Tetrahedron: Asymmetry 2011, 22, 1441 – 1447; c) V.
More, R. Rohlmann, O. G. Mancheno, C. Petronzi, L. Palombi,
A. D. Rosa, A. D. Mola, A. Massa, RSC Adv. 2012, 2, 3592 –
3595.
Determination of activation free energy and half-life: The time
course of optical rotation of a solution of optically active 1 (4.0 ꢀ
10À2 molLÀ1) containing trifluoroacetic acid (1.0 ꢀ 10À3 molLÀ1) or
DBU (1.0 ꢀ 10À4 molLÀ1) was measured by using a DIP 370 polar-
imeter (JASCO) at 208C.
Received: June 29, 2012
Revised: October 29, 2012
Published online: November 13, 2012
Keywords: chirality · chiral resolution · deracemization ·
.
heterocycles · preferential crystallization
[1] a) J. Jacques, A. Collet, S. H. Wilen in Enantiomers, Racemates
and Resolutions, Wiley, New York, 1981; b) K. M. J. Brands, A. J.
Davies, Chem. Rev. 2006, 106, 2711 – 2733.
[2] a) L. Addadi, Z. Berkovitch-Yellin, N. Domb, E. Gati, M. Lahav,
L. Leiserowitz, Nature 1982, 296, 21 – 26; b) L. Addadi, S.
Weinstein, E. Gati, I. Weissbuch, M. Lahav, J. Am. Chem. Soc.
1982, 104, 4610 – 4617; c) C. Viedma, Phys. Rev. Lett. 2005, 94,
065504; d) C. Viedma, Cryst. Growth Des. 2007, 7, 553 – 556;
e) G. Coquerel, Top. Curr. Chem. 2007, 269, 1 – 51; f) R.
Yoshioka, Top. Curr. Chem. 2007, 269, 83 – 132.
[3] a) W. J. Boyle, Jr., S. Sifniades, J. F. Van Peppen, J. Org. Chem.
1979, 44, 4841 – 4847; b) S. Yamada, C. Hongo, R. Yoshioka, I.
Chibata, J. Org. Chem. 1983, 48, 843 – 846; c) B. Kaptein, W. L.
Noorduin, H. Meekes, W. J. P. van Enckevort, R. M. Kellogg, E.
Vlieg, Angew. Chem. 2008, 120, 7336 – 7339; Angew. Chem. Int.
Ed. 2008, 47, 7226 – 7229.
[4] a) R. E. Pincock, R. R. Perkins, A. S. Ma, K. R. Wilson, Science
1971, 174, 1018 – 1020; b) D. K. Kondepudi, J. Laudadio, K.
Asakura, J. Am. Chem. Soc. 1999, 121, 1448 – 1451; c) M.
Sakamoto, N. Utsumi, M. Ando, M. Saeki, T. Mino, T. Fujita,
A. Katoh, T. Nishio, C. Kashima, Angew. Chem. 2003, 115, 4496 –
4499; Angew. Chem. Int. Ed. 2003, 42, 4360 – 4363; d) M.
Sakamoto, F. Yaghishita, M. Ando, Y. Sasahara, N. Kamataki,
M. Ohta, T. Mino, Y. Kasashima, T. Fujtia, Org. Biomol. Chem.
2010, 8, 5418 – 5422.
[10] a) D. L. Comins, S. Schilling, Y. Zhang, Org. Lett. 2005, 7, 95 – 98;
b) H. Heaney, K. F. Shuhaibar, Synlett 1995, 47 – 48; c) D. L.
Boger, J. K. Lee, J. Goldberg, Q. Jin, J. Org. Chem. 2000, 65,
1467 – 1474.
[11] K. Bowden, S. P. Hiscocks, A. Perjꢂssy, J. Chem. Soc. Perkin
Trans. 2 1998, 291 – 295.
[12] E. J. Valente, S. B. Martin, L. D. Sullivan, Acta. Crystallogr. Sect.
B 1998, 54, 264 – 276.
[13] Gram scale crystallization was also examined.
A toluene
solution (50 mL) containing 1c (5.0 g) and DBU (20 mol%)
was stirred in a flask at 1008C until 1c was gradually crystallized
and all solvent evaporated. After DBU was removed, the
enantiomeric excess of 1c was analyzed by HPLC, and was
shown to be 93% ee. It was revealed that the total spontaneous
resolution could be applied for large scale crystallization.
[14] Optically active solid of 1d (10% ee or 20% ee, 0.50 g,
1.98 mmol) was suspended in hexane (10.0 mL) with 1.0 g of
glass beads (2 mm) and was stirred in the presence of DBU
(0.06 g, 0.40 mmol) for 12 h. The enantiomeric excess of the
crystalline solid was measured and found to be racemic in both
cases.
[15] M. Sakamoto, J. Photochem. Photobiol. C 2007, 7, 183 – 196.
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