Absolute asymmetric synthesis by nucleophilic carbonyl addition using chiral crystals of achiral amides

Article abstract of DOI:10.1039/b315729f

Reaction of the chiral crystals of the achiral amides with n-butyllithium in toluene at -80°C gave optically active alcohols in 17-84% ee.

Full text of DOI:10.1039/b315729f

Absolute asymmetric synthesis by nucleophilic carbonyl addition using
chiral crystals of achiral amides†
Masami Sakamoto,* Shuichiro Kobaru, Takashi Mino and Tsutomu Fujita
Department of Materials Technology, Faculty of Engineering, Chiba University, Yayoi-cho, Chiba 263-8522,
Japan. E-mail: sakamotom@faculty.chiba-u.jp; Fax: 81 43 290 3401; Tel: 81 43 290 3387
Received (in Cambridge, UK) 3rd December 2003, Accepted 19th February 2004
First published as an Advance Article on the web 19th March 2004
Reaction of the chiral crystals of the achiral amides with n-
butyllithium in toluene at 280 °C gave optically active alcohols
in 17–84% ee.
To achieve the proposed absolute asymmetric synthesis, it was
requisite that the achiral materials crystallize in a chiral space
group. Whereas 1d forms racemic crystals (space group: Pbca),
1
fortunately the other three amides 1a–c afforded a chiral crystal
Spontaneous crystallization is a most attractive phenomenon
because achiral molecules are doped in molecular chirality or chiral
arrangement in the crystals without any outside chiral source. A
number of apparent achiral organic compounds have been obtained
as chiral crystals, and many successful absolute asymmetric
1 1 1
system P2 2 2 , and the constituent molecules adopted a chiral and
helical conformation in the crystal lattice. Each single crystal is
chiral, and all molecules in one crystal are optically active, offering
the same chiral configuration. Generally, the selection of either
enantiomorphic form of molecular configuration is equally proba-
ble. Once enantiomorphic crystals are formed, a large amount of
chiral crystals with the same optical rotation can be selectively
prepared through recrystallization by seeding the desired crystals.
The X-ray structural analysis also revealed that all amides tend to
have almost the same molecular conformation. The twist angle
defined by the benzoyl and the amide groups against the central
phenyl ring may be the most important factor for the formation of
the helical and chiral structure. Remarkably, both carbonyl groups
are considerably inclined to opposite sides of each other, and the
twist angle formed by the amide group (55.8–82.1°) is relatively
bigger than that of the benzoyl group (31.8–43.0°). The asymmet-
rically substituted amide 1c exists as a mixture of syn- and anti-
isomers (anti/syn = 1.13) in solution; however, in the crystal, it
takes on anti-form. The X-ray analyses did not establish the
absolute stereochemistry of the compounds 1a,1b, and 1c.
1
syntheses have been achieved using the chiral crystals. Most of
them were limited to photochemical reactions. Exceptionally, a few
fine examples are reported for gas–solid heterogeneous reactions;
2
however, regretfully, the ee values were not so high. Now, we are
able to achieve absolute asymmetric synthesis via nucleophilic
carbonyl addition using n-butyllithium with chiral crystals of
3
achiral amides in high optical yields.
The rotational barrier of N,N-disubstituted aromatic amides has
considerably high activation energy for Ar–(CNO) bond rotation,
which corresponds to the enantiomerization of the atropisomerism
4
(
Fig. 1). Clayden et al. reported that some axially chiral amides
with bulky substituents on its ortho-position have been isolated in
optically active form, and used to further asymmetric synthesis.5
Here we studied the chiral crystallization of achiral aromatic
amide with one substituent on the ortho-position and further
application to asymmetric synthesis without any outside chiral
source.
Can the amides 1a–c retain the molecular chirality after
dissolving the crystals into a cold solution? Activation free energies
2
-Benzoylbenzamides 1a–d were conveniently prepared by a
for racemization of 1b were studied by the use of VT NMR
spectroscopy,1
0,11
and the barrier to interconversion of the
condensation reaction from commercially available amine and
benzoylbenzoic acid (Fig. 2). Recrystallization of these amides
from a chloroform–hexane solution afforded colorless prisms in all
cases. All crystals were subjected to X-ray crystallographic
analysis to obtain details of the molecular conformation and the
1
enantiomers in toluene-d
6
was found to be 42.6 kJ mol2
,
corresponding to a half-life for racemization of 0.002 s at 260 °C.
If the subsequent chemical reaction can occur on the surface of the
crystals or proceed faster than the enantiomerization, chiral
conformation in the chiral crystal will be transferred effectively to
optically active products.
6
–9
architecture in the crystals.
Nucleophilic addition with n-butyllithium was examined to
achieve absolute asymmetric synthesis. The powdered crystals of 1
(
0.5 mmol) were added to a toluene solution (10 ml) containing n-
butyllithium (commercially available hexane solution 2.5 mmol) at
80 °C. After the mixture was stirred for 2.0 h at the same
temperature, aq. NH Cl was added to quench the reaction, and was
2
4
followed by the usual work-up. The products were separated by
chromatography on silica gel. When chiral crystals of N,N-dimethyl
derivatives 1a were used, nucleophic addition to the benzoyl
carbonyl group occurred effectively and the adduct 2a was
obtained; however, 2a was not stable and gradually changed to
phthalide 3a. Then, the crude reaction mixture in toluene was
heated at 80 °C for 2 h in the presence of AcOH. Phthalide 3a was
isolated in 82% yield, which showed optical activity of 17% ee,
determined by HPLC using a chiral cel OD column (Table 1, entry
Fig. 1 Enantiomerization of aryl amides.
1
). The cyclization to 3 from 2 should involve substitution reaction
at CNO.
In the case of N,N-diethyl derivative 1b, the corresponding
alcohol 2b was obtained in 82% yield, surprisingly in the highly
optically active form of 84% ee (entry 2). The reaction with chiral
crystals of 1c also gave alcohol 2c which was also unstable and then
changed to phthalide 3 as in the case of the reaction of 1a. Phthalide
3c also showed optical activity of 80% ee (entry 3). The reaction
with racemic crystals of 1d gave the corresponding phthalide 3d in
Fig. 2
†
1
Electronic supplementary information (ESI) available: crystal data for
a–1d; determination of ee. See http://www.rsc.org/suppdata/cc/b3/
b315729f/
1
002
C h e m . C o m m u n . , 2 0 0 4 , 1 0 0 2 – 1 0 0 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

8
7%, and naturally in racemic form (entry 4). Whereas the optical
amides. The absolute configuration of the starting amides in chiral
crystals and the products has not been determined yet. Whereas a
mechanistic approach for the asymmetric synthesis can not be
determined without correlation of the absolute configuration of
both the starting amides 1 and the products 2, we believe that this
methodology can be applied to the development of new absolute
asymmetric syntheses.
This work was supported by a Grant-in-Aid for Scientific
Research on Priority Area (417) from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) of the Japanese
Government.
rotations of the products were dependent on the configuration of the
starting amides, they were inconsistent in the case of auto-seeding.
However, the desired crystals could be easily prepared by the
seeding method.
Table 2 shows the results of the reaction of the chiral crystals of
1
b with n-butyllithium under various conditions. When a hexane
solution of n-butyllithium was added to a toluene solution of 1b at
80 °C, which was prepared by dissolving the crystals in toluene
2
at room temperature and cooling to 280 °C, racemic 2b was
obtained. As a matter of course, the molecules immediately lost
chirality on dissolving the chiral crystals in a solvent at room
temperature (entry 1). As the reaction temperature was raised, the
ee’s of the product decreased (entries 2–6); however, it is
noteworthy that optically active products were isolated from the
reaction even at 0 °C (entry 6).
Notes and references
1
(a) B. S. Green, M. Lahav and D. Rabinovich, Acc. Chem. Res., 1979,
9, 191–197; (b) M. Vaida, R. Popovitz-Biro, L. Leiserowitz and M.
6
Addition of TMEDA or THF, both of which are effective in
coordination to the lithium ion, resulted in low enantioselectivity
Lahav, Photochemistry in Organized and Constrined Media, V.
Ramamurthy, ed., VCH, New York, 1991, ch. 6; (c) M. Sakamoto,
Chem. Eur. J., 1997, 3, 684–689; (d) S. V. Evans, M. Garcia-Garibay,
N. Omkaram, J. R. Scheffer, J. Trotter and F. Wireko, J. Am. Chem.
Soc., 1986, 108, 5648–5650; (e) A. Sekine, K. Hori, Y. Ohashi, M. Yagi
and F. Toda, J. Am. Chem. Soc., 1989, 111, 697–699; (f) B. L. Feringa
and R. A. van Delden, Angew. Chem., Int. Ed., 1999, 38, 3418–3438; (g)
K. Venkatesan and V. Ramamurthy, Photochemistry in Organized and
Constrained Media, V. Ramamurthy, ed., VCH, New York, 1991, ch. 4;
(entries 7 and 8). When hexane was used as a solvent, the crystals
did not dissolve at the early stage; however, the crystals dissolved
according to the progress of the reaction and gave 64% chemical
and 74% optical yields (entry 9). It is concluded that toluene is the
most appropriate solvent for this asymmetric nucleophilic reac-
tion.
In conclusion, we have provided a new example of absolute
asymmetric synthesis via nucleophilic reaction by the use of
molecular chirality generated by chiral crystallization of achiral
(
h) M. Sakamoto, N. Sekine, H. Miyoshi, T. Mino and T. Fujita, J. Am.
Chem., Soc., 2000, 122, 10210–10211.
2 (a) K. Penzein and G. M. J. Schmidt, Angew. Chem., 1969, 8, 608–609;
b) B. S. Green and L. Heller, Science, 1974, 185, 525–527; (c) R.
Gerdil, L. Huiyou and B. Gerald, Helv. Chim. Acta, 1999, 82,
18–434.
(
Table 1 Absolute asymmetric synthesis via nucleophilic reaction using
chiral crystals
4
3
Recently we reported an absolute asymmetric synthesis using the frozen
chirality memorized by chiral crystallization of an achiral imide. M.
Sakamoto, T. Iwamoto, N. Nono, M. Ando, W. Arai, T. Mino and T.
Fujita, J. Org. Chem., 2003, 68, 942–946.
4
5
P. Bowles, J. Clayden, M. Helliwell, C. McCarthy, M. Tomkinson and
N. Westlund, J. Chem. Soc., Perkin Trans. 1, 1997, 2607–1616.
(a) J. Clayden, Angew. Chem., Int. Ed. Engl., 1997, 35, 949–951; (b) D.
P. Curran, H. Qi, S. J. Geib and N. C. DeMello, J. Am. Chem. Soc., 1994,
Yield (%)
of 2 or 3
1
3
3
16, 3131–3132; (c) J. Clayden and J. H. Pink, Tetrahedron Lett., 1997,
8, 2561–2564; (d) R. A. Bragg and J. Clayden, Org. Lett., 2000, 2,
351–3354; (e) J. Clayden, J. H. Pink, N. Westlund and C. S. Frampton,
Entry
Amide
ee (%)b
1
2
3
4
1a
1b
1c
1d
82a
82
17c
84
J. Chem. Soc., Perkin Trans. 1, 2002, 901–917.
Crystal data of 1a: C16
6
H15NO
2
, M = 253.301, orthorhombic, a =
a
c
83
80
3
1
0.420(2) Å, b = 17.208(4) Å, c = 7.519(2) Å, U = 1348.3(6) Å , T
a
c
87
0
=
293 K, space group P2
2 2
1 1 1
(no. 19), Z = 4, m(Cu-Ka) = 0.66
a
21
These alcohols 2 were unstable, and then the reaction mixture was heated
mm , 1511 reflections measured, 1326 unique (Rint = 0.046) which
were used in all calculations. The final wR(F ) was 0.151 (all data).
CCDC 215658.
b
2
in toluene in the presence of acetic acid leading to phthalide 3. Directions
of optical rotations were dependent on the configuration of the starting
amides in the chiral crystals, and were inconsistent in the case of auto-
7 Crystal data of 1b: C18
10.937(5) Å, b = 13.987(5) Å, c = 9.896(4) Å, U = 1513.8(10) Å , T
1 1 1
293 K, space group P2 2 2 (no. 19), Z = 4, m(Cu-Ka) = 0.64
2
H19NO , M = 281.355, orthorhombic, a =
c
3
seeding. Enantiomeric yields of phthalide 3.
=
21
mm , 1655 reflections measured, 1616 unique (Rint = 0.059) which
were used in all calculations. The final wR(F ) was 0.346 (all data).
2
Table 2 Asymmetric synthesis using chiral crystals of 1b with n-
butyllithium in various conditions
CCDC 215659.
8
Crystal data of 1c: C23
14.384(4) Å, b = 16.234(5) Å, c = 8.049(4) Å, U = 1879.6(12) Å , T
1 1 1
293 K, space group P2 2 2 (no. 19), Z = 4, m(Cu-Ka) = 0.61
2
H21NO , M = 343.426, orthorhombic, a =
3
Entry
Solvent
T/°C
Yield (%)
ee (%)
=
a
21
1
toluene
toluene
toluene
toluene
toluene
toluene
toluene, TMEDA
THF
hexane
280
280
260
240
220
0
280
280
280
82
82
60
58
55
55
77
83
64
0
84
70
59
35
16
18
17
74
mm , 2086 reflections measured, 1810 unique (Rint = 0.037) which
b
2
2
were used in all calculations. The final wR(F ) was 0.094 (all data).
b
3
CCDC 215660.
b
4
9 Crystal data of 1d: C28
19.753(5) Å, b = 22.214(7) Å, c = 9.936(3) Å, U = 1513.8(10) Å , T
1 1 1
= 293 K, space group P2 2 2 (no. 61), Z = 8, m(Cu-Ka) = 0.61
2
H23NO , M = 405.497, orthorhombic, a =
b
3
5
b
6
c
21
7
mm , 4437 reflections measured, 2926 unique (Rint = 0.050) which
b
2
8
were used in all calculations. The final wR(F ) was 0.217 (all data).
b
9
CCDC 215661. See http://www.rsc.org/suppdata/cc/b3/b315729f/ for
crystallographic data in CIF or other electronic format.
0 J. Sandström Dynamic NMR Spectroscopy, Academic Press, London,
1982.
1 (a) A. Ahmed, R. A. Bragg, J. Clayden, L. W. Lai, C. McCarthy, J. H.
Pink, N. Westlund and S. A. Yasin, Tetrahedron, 1998, 54,
a
A commercially available hexane solution of n-butyllithium (2.5 mmol)
was added to a toluene solution (10 ml) of 1b (0.5 mmol) at 280 °C, which
was prepared by dissolving 1b at room temperature. Powdered crystals of
1
1
b
1
b were added to a cooled solution of n-butyllithium and cited solvent.
Powdered crystals (0.5 mmol) were added to a cooled toluene solution
c
1
3277–13294; (b) P. Beak, A. Tse, J. Hawkins, C.-W. Chen and S.
including n-butyllithium (2.5 mmol) and TMEDA (2.5 mmol).
Milles, Tetrahedron, 1983, 39, 1983–1989.
C h e m . C o m m u n . , 2 0 0 4 , 1 0 0 2 – 1 0 0 3
1003