Chiral Arrangement of N-Ethyl-N-isopropylphenylglyoxylamide Molecule in Its Own Crystal and in an Inclusion Crystal with a Host Compound and Their Photoreactions in the Solid State That Give Optically Active β-Lactam Derivatives. X-ray Analytical and CD Spectral Studies

Article abstract of DOI:10.1021/jo971584z

N-Ethyl-N-isopropylphenylglyoxylamide (3c) forms chiral crystal in which its achiral molecules are arranged in a chiral form, and the chirality in the crystal was identified by measurement of the CD spectrum in Nujol mull. Generation of the chirality occurs by twisting of the CO-CO bond of 3c in the crystal. Photoirradiation of the chiral crystal of 3c in the solid state gave optically active β-lactam derivative (4c) of 80% ee. By X-ray analysis, absolute configurations of the chiral crystal and 4c were elucidated. The achiral molecules of 3c are also arranged in chiral forms in inclusion complexes with chiral hosts such as (R,R)-(-)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspiro[4,4]nonane (5a), (R,R)-(-)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspiro[5.4]-decane (5b), and their (S,S)-(+)-enantiomers, 6a and 6b, respectively. The crystal structure of a 1:1 inclusion complex of 3c with 5b (7b) was analyzed. Photoirradiation of 7b in the solid state gave (R)-(+)-4c of 85% ee. Photochemical conversions of some other derivatives of 3c to the corresponding β-lactams were also studied. Interestingly, however, irradiation of the 1:1 inclusion complex of N,N-dimethylglyoxylamide (3a) with 5a, which had been prepared by mixing both components in the absence of solvent, gave (R)-(+)-β-lactam (9a) of 45% ee, although the 1:1 complex that had been prepared by recrystallization of the components from toluene gave (S)-(-)-9a of 100% ee. Mixing of powdered chiral (-)-3c crystal with a 2:1 inclusion complex of 5b and MeOH gave a new 1:1 complex of 5b and chiral (+)-3c. The inversion of the chirality of 3c in the solid state was studied by continuous measurements of CD spectra in Nujol mulls.

Full text of DOI:10.1021/jo971584z

J . Org. Chem. 1997, 62, 9261-9266
9261
Ch ir a l Ar r a n gem en t of N-Eth yl-N-isop r op ylp h en ylglyoxyla m id e
Molecu le in Its Ow n Cr ysta l a n d in a n In clu sion Cr ysta l w ith a
Host Com p ou n d a n d Th eir P h otor ea ction s in th e Solid Sta te Th a t
Give Op tica lly Active â-La cta m Der iva tives. X-r a y An a lytica l a n d
CD Sp ectr a l Stu d ies
Fumio Toda,*,† Hisakazu Miyamoto,† Hideko Koshima,‡ and Zofia Urbanczyk-Lipkowska§
Department of Applied Chemistry, Faculty of Engineering, Ehime University,
Matsuyama, Ehime 790, J apan, Department of Material Sciences, Faculty of Science and Engineering,
Ryukoku University, Seta, Otsu 520-21, J apan, and Institute of Organic Chemistry, Polish Academy of
Sciences, Warsaw, Poland
Received August 25, 1997X
N-Ethyl-N-isopropylphenylglyoxylamide (3c) forms chiral crystal in which its achiral molecules
are arranged in a chiral form, and the chirality in the crystal was identified by measurement of
the CD spectrum in Nujol mull. Generation of the chirality occurs by twisting of the CO-CO bond
of 3c in the crystal. Photoirradiation of the chiral crystal of 3c in the solid state gave optically
active â-lactam derivative (4c) of 80% ee. By X-ray analysis, absolute configurations of the chiral
crystal and 4c were elucidated. The achiral molecules of 3c are also arranged in chiral forms in
inclusion complexes with chiral hosts such as (R,R)-(-)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4-
dioxaspiro[4.4]nonane (5a ), (R,R)-(-)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspiro[5.4]-
decane (5b), and their (S,S)-(+)-enantiomers, 6a and 6b, respectively. The crystal structure of a
1:1 inclusion complex of 3c with 5b (7b) was analyzed. Photoirradiation of 7b in the solid state
gave (R)-(+)-4c of 85% ee. Photochemical conversions of some other derivatives of 3c to the
corresponding â-lactams were also studied. Interestingly, however, irradiation of the 1:1 inclusion
complex of N,N-dimethylglyoxylamide (3a ) with 5a , which had been prepared by mixing both
components in the absence of solvent, gave (R)-(+)-â-lactam (9a ) of 45% ee, although the 1:1 complex
that had been prepared by recrystallization of the components from toluene gave (S)-(-)-9a of 100%
ee. Mixing of powdered chiral (-)-3c crystal with a 2:1 inclusion complex of 5b and MeOH gave
a new 1:1 complex of 5b and chiral (+)-3c. The inversion of the chirality of 3c in the solid state
was studied by continuous measurements of CD spectra in Nujol mulls.
In tr od u ction
intramolecular photocyclization reactions. However, re-
cently chiral synthesis by photoreaction between two
different molecules that are arranged in a chiral form in
a crystal has also been reported.8
Various kinds of achiral compounds form chiral crys-
tals in which the achiral molecules are arranged in a
chiral form. Freezing of the chirality in the crystal by
chemical reaction is a goal of absolute chiral synthesis.
It would be very beneficial to be able to carry out chiral
synthesis without using any chiral auxiliary and is
interesting in relation to the origin of optically active
compounds on the earth.1 In view of these points, some
research groups have been searching for appropriate
methods to achieve chiral synthesis in the crystalline
state, and several successful syntheses of optically active
compounds by photoreactions of chiral crystals have been
reported. For example, â-lactam derivatives have been
formed from oxoamide,2a-d amide,3a,b and thioamide,4
oxetane from amide,5 γ-butyrolactone from diketone,6 and
cyclopropane derivatives from olefins.7a-c These are all
We report here formation of a chiral crystal of the title
oxoamide (3c) and photochemical conversion of the chiral
crystal to optically active â-lactam (4c). We also report
that the chiral configuration of 3c in its own chiral crystal
is easily converted to the other configuration in the solid
state in the presence of a chiral host compound, and their
new inclusion complex is constructed. These dynamic
molecular behaviors in the solid state were detected by
continuous measurment of CD spectra in Nujol mull.
Absolute configurations of the chirally ordered molecule
of 3c in the chiral crystal and of the â-lactam 4c were
determined by X-ray analysis.
Resu lts a n d Discu ssion
† Ehime University.
The phenylglyoxylamide 3c was prepared as colorless
crystals, mp 62-64 °C, from benzoylformyl chloride (1)
‡ Ryukoku University.
§ Polish Academy of Sciences.
X Abstract published in Advance ACS Abstracts, December 1, 1997.
(1) Addadi, L.; Lahav, M. Origin of Optical Activity in Nature;
Walker, D. C., Ed.; Elsevier: New York, 1979; Chapter 14.
(2) (a) Toda, F.; Yagi, M.; Soda, S. J . Chem. Soc., Chem. Commun.
1987, 1413. (b) Sekine, A.; Hori, K.; Ohashi, Y.; Yagi, M.; Toda, F. J .
Am. Chem. Soc. 1989, 111, 697. (c) Toda, F.; Miyamoto, H. Chem. Lett.
1995, 809. (d) Sakamoto, M.; Takahashi, M.; Fujita, T.; Nishio, T.; Iida,
I.; Watanabe, S. J . Org. Chem. 1995, 60, 4682.
(3) (a) Sakamoto, N.; Hokari, N.; Takahashi, M.; Fujita, T.; Wa-
tanabe, S.; Iida, I.; Nishio, T. J . Am. Chem. Soc. 1993, 115, 618. (b)
Sakamoto, M.; Takahashi, M.; Shimizu, M.; Fujita, T.; Nishio, T.; Iida,
I.; Yamaguchi, K.; Watanabe, S. J . Org. Chem. 1995, 60, 7088.
(4) Sakamoto, M.; Takahashi, M.; Kamiya, K.; Yamaguchi, K.;
Fujita, T.; Watanabe, S. J . Am. Chem. Soc. 1996, 118, 10664.
(5) Sakamoto, M.; Takahashi, M.; Fujita, T.; Watanabe, S.; Iida, I.;
Nishio, T.; Aoyama, H. J . Org. Chem. 1993, 58, 3476.
(6) Sakamoto, M.; Takahashi, M.; Morizumi, S.; Yamaguchi, K.;
Fujita, T.; Watanabe, S. J . Am. Chem. Soc. 1996, 118, 8138.
(7) (a) Evans, S. V.; Garicia-Garibay, M.; Omkaram, N.; Scheffer,
J . R.; Trotter, J .; Wirenko, F. J . Am. Chem. Soc. 1986, 108, 5648. (b)
Garcia-Garibay, M.; Scheffer, J . R.; Trotter, J .; Wirenko, F. J . Am.
Chem. Soc. 1989, 111, 4985. (c) Fu, T. Y.; Liu, Z.; Scheffer, J . R.;
Trotter, J . J . Am. Chem. Soc. 1993, 115, 12202. (d) Roughton, A. L.;
Muneer, M.; Klopp, I.; Kruger, C.; Demuth, M. J . Am. Chem. Soc. 1993,
115, 2085.
(8) Koshima, H.; Ding, K.; Chisaka, Y.; Matsuura, T. J . Am. Chem.
Soc. 1996, 118, 12059.
S0022-3263(97)01584-3 CCC: $14.00 © 1997 American Chemical Society

9262 J . Org. Chem., Vol. 62, No. 26, 1997
Toda et al.
F igu r e 2. X-ray structure of (R)-(+)-3c crystal, which gives
(R-)-(+)-4c upon irradiation.
F igu r e 1. CD spectra in Nujol mulls of (S)-(-)- (A) and (R)-
(+)-3c crystal (B).
F igu r e 3. X-ray structure of (R)-(+)-4c.
(R)-(+)-3c was carried out. As shown in Figure 2, the
molecule of 3c becomes chiral by twisting around the
single bond C7-C8 between the two CO groups, and the
isopropyl group is located in a position near the benzoyl
carbonyl, C7dO1. The analysis also revealed that due
to conformational restriction introduced by bicarbonyl
unit, the central carbon atom of the isopropyl group and
the carbon atom from benzoyl group are in close proxim-
ity (3.51 Å), permitting easy â-lactam ring closure.
Moreover, inspection of the Cambridge Crystallographic
Database showed that among 23 molecules containing
the NCOCOC unit, the distance between terminal C and
N atoms is shorter than 3.55 Å in 14 cases. Conforma-
tional restriction was manifested in that case by the value
of the N-C-C-C-C tortion angle limited to the range
+80-120°.
The steric course of the photocyclization of 3c to 4c
was studied by X-ray structure analysis of 4c (Figure 3).
The absolute configuration and steric course of the
photocyclization of the (R)-(+)-3c was further confirmed
by an internal reference method using a 1:1 inclusion
complex (7b) of (R)-(+)-3c with (R,R)-(-)-trans-2,3-bis-
(hydroxydiphenylmethyl)-1,4-dioxaspiro[5.4]decane (5b)10a
(Figure 4). The molecule of (R)-(+)-3c is included by
forming an intermolecular hydrogen bond between the
and N-ethyl-N-isopropylamine (2c). The chirality of each
crystal of 3c was easily detected by measurement of their
CD spectra in Nujol mulls9 as shown in Figure 1. The
chiral crystals that give (S)-(-)-4c and (R)-(+)-4c by
photoirradiation are tentatively termed as (S)-(-)-3c and
(R)-(+)-3c crystals, respectively. When one piece of (S)-
(-)-3c crystal was added as a seed crystal during the
recrystallization of 3c from ether, a large quantity of (S)-
(-)-3c crystal was obtained easily. Of course, recrystal-
lization of the (S)-(-)-3c crystal from ether by adding one
piece of (R)-(+)-3c crystal as a seed crystal gave (R)-(+)-
3c crystal in large quantitity. Irradiation of powdered
(S)-(-)- and (R)-(+)-3c crystal gave (S)-(-)- and (R)-(+)-
4c of 80% ee, respectively, in 55% yield. In the photo-
reaction, only the isopropyl group of 3c reacted and no
other compound produced by photoreaction of the ethyl
group was detected.
In order to know why only the isopropyl group reacts
and how the molecules of 3c are arranged in a chiral form
in their own crystal, X-ray crystal structure analysis
followed by determination of absolute configuration of
(9) (a) Toda, F.; Miyamoto, Kikuchi, S.; H.; Kuroda, R; Nagami, F.
J . Am. Chem. Soc. 1996, 118, 11315. (b) Toda, F.; Miyamo,H.;
Kanemoto, K. J . Org. Chem. 1996, 61, 6490.
(10) (a) Seebach, D.; Beck, A. K.; Imwinkelried, R.; Roggo, S.;
Wonnacott, A. Helv. Chim. Acta 1987, 70, 954. (b) Toda, F.; Tanaka,
K. Tetrahedron Lett. 1988, 29, 551.

N-Ethyl-N-isopropylphenylglyoxylamide Molecule
J . Org. Chem., Vol. 62, No. 26, 1997 9263
F igu r e 4. X-ray structure of a 1:1 inclusion complex (7b) of
(R)-(+)-3c with 5b.
C35dO5 carbonyl group of 3c and the O4-H2 hydroxyl
group of 5b with an O5---O4 distance of 2.72 Å. The
other remaining O3-H1 hydroxyl group of 5b also forms
an intramolecular hydrogen bond with the O4-H2 hy-
droxyl oxygen, and the distance between O3 and O4 is
2.67 Å. The absolute configuration of (R)-(+)-3c included
in 7b (Figure 4), assigned by the (R,R) absolute config-
uration of the host 5b as the internal reference, was
consistent with that of the host-free (R)-(+)-3c (Figure
2), giving further confirmation of the absolute configu-
ration. In crystals of both (R)-(+)-3c and its inclusion
complex 7b with 5b, the chirality of the molecules of 3c
is generated by a similar chiral conformation due to the
twisting around the single bond of CO-CO. Irradiation
of 7b in the solid state gave (R)-(+)-4c of 85% ee in 37%
yield as the sole product. The reaction mechanism can
be explained as follows. The O6 carbonyl oxygen of (R)-
(+)-3c excited by the irradiation abstracts the nearest
H3 hydrogen atom of the isopropyl group over the
O6---H3 distance of 2.74 Å to form a hydroxyl group.
Next, a radical coupling occurs between the C36 and C45
radicals due to the short distance of 2.84 Å, resulting in
the formation of (R)-(+)-4c. Similarly, irradiation of a
1:1 inclusion complex (7a ) of (R)-(+)-3c with (R,R)-(-)-
trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspiro[4.4]-
nonane (5a )10a,b afforded (R)-(+)-4c of 87% ee in 31%
yield.
F igu r e 5. CD specta of (S)-(-)- (A) and (R)-(+)-3e (B).
structure analysis of the complex showed that the achiral
glyoxylamide molecule is arranged in a chiral form due
to a similar twisitng of the CO-CO bond.12
As mentioned above, the chiral arrangement of achiral
molecule in a crystal can easily be detected by CD
spectral measurement in Nujol mull, and (S)-(-)- and (R)-
(+)-3c crystals showed CD spectra of a mirror-imaged
relation (Figure 1). Similarly, (S)-(-)- and (R)-(+)-chiral
crystals of 3e showed the CD spectra of similar mirror-
imaged relation (Figure 5). Since â-lactams 4 and 9 have
no benzoyl chromophore any more, their characteristic
bands become weaker as the photoconversion of 3 to the
â-lactam proceeds. The photoconversion of the m-bro-
mophenyl derivative of 3e (10), which shows relatively
strong CD absorptions to the corresponding â-lactam
(11),13 was followed by the CD spectral measurement. As
shown in Figure 6, CD spectra of the chiral crystal of 10
in Nujol mull turn to the weak absorptions of 11 as the
photoreaction proceeds. It is also very interesting that
the solid-state photoreaction proceeds efficiently in Nujol
mull. This is not a solution reaction in liquid paraffin
because the achiral molecules of 3c, 3e, and 10 can exist
in a chiral form only in the crystalline state but not in
solution. Photoreactions of 3c, 3e, and 10 in solution give
rac-products.
By a similar inclusion complexation with chiral host
compound, achiral oxoamide molecules are arranged in
a chiral form and irradiation of the inclusion complex
gives optically active â-lactam derivative. For example,
irradiation of a 1:1 inclusion complex of oily N,N-
dimethylphenylglyoxylamide (3a ) with (S,S)-(-)-1,6-di-
(o-chlorophenyl)-1,6-diphenylhexa-1,4-diyne-1,6-diol (8)11
gives (S)-(-)-9a of 100% ee in quantitative yield.12 X-ray
(11) Toda, F.; Tanaka, K.; Omata, T.; Nakamura, K.; Oshima, T. J .
Am. Chem. Soc. 1983, 105, 5151.
(12) Kaftory, M.; Yagi, M.; Tanaka, K.; Toda, F. J . Org. Chem. 1988,
53, 4391.
(13) Toda, F.; Miyamoto, H. J . Chem. Soc., Perkin Trans. 1 1993,
1129.

9264 J . Org. Chem., Vol. 62, No. 26, 1997
Toda et al.
87% ee (45%) or (-)-9c of 93% ee (39%), respectively, in
the yields indicated.
Very interestingly, irradiation of the 1:1 inclusion
complex (13) of 3a with 5b, which had been prepared by
mixing both components in the absence of solvent, gave
(+)-9a of 45% ee in 42% yield, although the same
irradiation of the complex (14) prepared by recrystalli-
zation of 3a and 5b from toluene gave the other enanti-
omer (-)-9a of 100% ee in 40% yield. The type of chiral
arrangement of 3a molecules varies depending on the
conditions of the inclusion complexation experiment. The
chiral arrangement of 3a in 13 and 14 in an opposite type
was detected by measurement of their CD spectra in
Nujol mull (Figure 8). Nevertheless, both the inclusion
complexations of 3a with 5a by the mixing and recrys-
tallization methods gave the same 1:1 complex, which
gives (-)-9a .
Chiral arrangement of 3a in an inclusion crystal with
8 also depends on the conditions of the inclusion com-
plexation experiment. As described above, irradiation of
the 1:1 inclusion complex that had been prepared by
recrystallization of the component from ether gave
(-)-9a of 100% ee in quantitative yield.12 X-ray struc-
tural study of the inclusion crystal showed that 3a
molecules are arranged in the chiral form, which gives
(-)-9a by the photoreaction. On the other hand, irradia-
tion of the inclusion crystal prepared by mixing 3a and
5a gave rac-9a . However, both inclusion crystals are
thermally interconvertible. After melting (mp 126-127
°C), the former is solidified by cooling to give the latter,
but the latter is converted to the former by heating
gradually and melts again at 126-127 °C.
F igu r e 6. Photoconversion of (+)- and (-)-chiral crystals of
10 to (+)- (A) and (-)-11(B), respectively, by continuous
measurements of CD spectra in Nujol mulls, after (a) 0 min,
(b) 2 min, (c) 4 min, and (d) 6 min of irradiation.
Easy conversion of (S)-(-)-3c to (R)-(+)-3c in the solid
state was observed during an inclusion complexation
experiment of the former with 5b. By mixing powdered
2:1 inclusion complex of 5b with MeOH (12) with twice
the molar amount of powdered (S)-(-)-3c for 4 h at room
temperature, a new 1:1 inclusion complex of (R)-(+)-3c
with 5b was formed (Scheme 1). Irradiation of the newly
formed complex gave (R)-(+)-4c instead of (S)-(-)-4c,
although irradiation of (S)-(-)-3c gives (S)-(-)-4c. This
result shows that the configuration of (S)-(-)-3c was
converted to (R)-(+)-3c during the inclusion complexation
with 5b by mixing in the solid state. This conversion
would occur due to the following reasons: (a) the system
becomes thermodynamically more stable by the inclusion
complex formation of (R)-(+)-3c with 5b, and (b) since
5b includes (R)-(+)-3c but not (S)-(-)-3c, the latter
should be converted to the former before the inclusion
complexation. It has also been well established that
inclusion complexation occurs efficiently in the solid
state.14 The conversion of (S)-(-)-3c into (R)-(+)-3c
during the complexation in the solid state was observed
by continuous measurement of CD spectra in Nujol mull
(Figure 7). As the complexation proceeds, strong CD
spectra of the (-)-Cotton effect due to (S)-(-)-3c are
gradually converted to the spectra of the (+)-Cotton effect
of (R)-(+)-3c. These spectra are attributed to the chiral-
ity of 3c because 5b does not show a clear CD spectrum.
Some other N,N-dialkylphenylglyoxylamides also form
inclusion complexes on mixing with 5 or 6, and the
achiral molecules of these glyoxylamides are arranged
in a chiral form in the inclusion crystal. Mixing of oily
3a with an equimolar amount of powdered 5a or 6a for
30 min followed by irradiation in the solid state with
occasional mixing for 30 h gave (-)-9a of 78% ee (54%)
or (+)-9a of 65% ee (50%), respectively, in the yields
indicated. Similar treatment of oily 3b with 5a or of oily
3d with 5b followed by photoirradiation gave (-)-9b of
Con clu sion s
It was established that glyoxylamide 3c forms a chiral
crystal in which achiral molecules of 3c are arranged in
a chiral form, and its irradiation in the solid state gave
optically active â-lactam 4c. The achiral molecules of 3c
are also arranged in a chiral form in its inclusion complex
crystal with a chiral host such as 5a or 5b, and irradia-
tion of the complex gave optically active â-lactam. The
chiral arrangement of 3c in the chiral crystal and in the
inclusion crystal were also proven by X-ray analysis.
Absolute configuration of the chirally arranged 3c and
the â-lactam 4c, which was derived from 3c, was deter-
mined by X-ray analysis. It was also found that the
chiral order of the achiral molecule of 3c can be easily
detected by measurement of CD spectrum of powdered
crystal in Nujol mull. By mixing (S)-(-)-3c crystal and
a 2:1 inclusion complex crystal of 5b and MeOH, a new
1:1 inclusion complex of (R)-(+)-3c and 5b was formed
and irradiation of the complex gave (R)-(+)-4c. During
the mixing, (S)-(-)-3c is converted to (R)-(+)-3c and is
included with 5b to give a new 1:1 inclusion complex with
5b. The conversion of the chirality of (S)-(-)-3c to the
opposite one (R)-(+)-3c in the solid state can be followed
by continuous measurement of the CD spectra in Nujol
mull. These data suggest that molecules easily move
enantioselectively and order selectively in the solid state.
Interestingly, chirality of 3a in the inclusion complex
with 5b, which had been prepared by recrystallization
of the components from toluene, was found to be just
opposite to that in the complex that had been prepared
by mixing of both components in the solid state. These
opposite chiralities were measured by CD spectroscopy.
(14) Toda, F.; Tanaka, K.; Sekikawa, A. J . Chem. Soc., Chem.
Commun. 1987, 279.

N-Ethyl-N-isopropylphenylglyoxylamide Molecule
J . Org. Chem., Vol. 62, No. 26, 1997 9265
Sch em e 1
F igu r e 7. CD spectra of a mixture of (S)-(-)-3c crystal (1 mg),
a 2:1 inclusion complex of 5b with MeOH (12) (3 mg), and
liquid paraffin (10 mg) after (a) 0 min, (b) 30 min, (c) 60 min,
and (d) 180 min in the preparation of the Nujol paste sample.
F igu r e 8. CD spectra of 1:1 inclusion complexes of 3a with
5b that were prepared by mixing in the absence of solvent (A)
and recrystallization from toluene (B) of both components.
colorless needles (0.22 g, 55% yield, mp 139-141 °C, [R]D -40°
(c 1.9, MeOH). By recrystallization from ether, (S)-(-)- and
(R)-(+)-4c of 100% ee were obtained easily: IR 3215 (OH) and
Exp er im en ta l Section
1
1735 cm-1 (CdO); H NMR δ 0.97 (s, 3H, CH3), 1.26 (t, J ) 7
P r ep a r a tion of 3c. To an ice-cooled solution of N-ethyl-
N-isopropylamine (6 g, 60 mmol) and triethylamine (30 mL)
in dry ether (60 mL) was added a solution of benzoylformyl
chloride14 (10 g, 60 mmol) in dry ether (10 mL), and the
mixture was stirred for 3 h in an ice bath. After filtration of
triethylammonium hydrochloride, the filtrate was washed with
dilute HCl and aqueous NaHCO3 and dried over MgSO4. The
crude product obtained by evaporation of the solvent was
chromatographed on silica gel using toluene-AcOEt (4:1) and
recrystallized from ether to give 3c as colorless prisms (4.2 g,
Hz, 3H, CH2CH3), 1.50 (s, 3H, CH3), 3.23 (s, 1H, OH), 3.22-
3.31 (m, 2H, CH2CH3), 7.31-7.41 (m, 5H, Ph). Anal. Calcd
for C13H17O2N: C, 71.21; H, 7.81; N, 6.39. Found: C, 71.38;
H, 8.15; N, 6.34.
P r ep a r a tion of In clu sion Com p lex of (R)-(+)-3c w ith
5a a n d 5b. When a solution of 3c (1.5 g, 6.8 mmol) and 5a
(3.37 g, 6.8 mmol) in ether (10 mL) was kept at room
temperature for 12 h, a 1:1 inclusion complex (7a ) of (R)-(+)-
3c with 5a was obtained as colorless needles (4.66 g, 96% yield,
mp 97-99 °C): IR 3365 and 3240 (OH), 1680 and 1625
cm-1(CdO). Anal. Calcd for C46H49O6N: C, 77.61; H, 6.94;
N, 1.97. Found: C, 77.50; H, 7.02; N, 1.98.
When a solution of 3c (1.5 g, 6.8 mmol) and 5b (3.47 g, 6.8
mmol) in ether (10 mL) was kept at room temperature for 12
h, a 1:1 inclusion complex (7b) of (R)-(+)-3c with 5b was
obtained as colorless needles (3.67 g, 74% yield, mp 132-135
°C): IR 3365 and 3240 (OH), 1680 and 1625 cm-1 (CdO).
Anal. Calcd for C47H51O6N: C, 77.77; H, 7.08; N, 1.93.
Found: C, 77.86; H, 7.08; N, 2.00.
1
32% yield, mp 62-64 °C): IR 1675 and 1630 cm-1 (CdO); H
NMR δ 1.20 (d, J ) 7 Hz, 6H, CH(CH3)2), 1.36 (t, J ) 7 Hz,
3H, CH2CH3), 3.46 (q, J ) 7 Hz, 2H, CH2CH3), 3.70-3.83 (m,
1H, CH(CH3)2), 7.49-7.95 (m, 5H, Ph). Anal. Calcd for
C13H17O2N: C, 71.21; H, 7.81; N, 6.39. Found: C, 71.10; H,
8.05; N, 6.33.
P r ep a r a tion of Ch ir a l Cr ysta ls of (-)- a n d (+)-3c. The
chirality of each crystal of 3c can be determined by CD spectral
measurement in Nujol mull (Figure 1). When one piece of (S)-
(-)-3c or (R)-(+)-3c crystal was added during the recrystalli-
zation of 3c from ether, (S)-(-)-3c or (R)-(+)-3c, respectively,
was obtained in large quantity.
Ir r a d ia tion of (S)-(-)- a n d (R)-(+)-3c Cr ysta ls in th e
Solid St a t e. After irradiation of powdered (S)-(-)- or (R)-
(+)-3c (0.4 g) for 50 h, crude product was purified by column
chromatography on silica gel using toluene-AcOEt (4:1) as
eluent to give (S)-(-)- or (R)-(+)-4c of 80% ee, respectively, as
P h otor ea ction of 7a a n d 7b in th e Solid Sta te. After
irradiation of powdered 7a (4.66 g) for 75 h, the reaction
mixture was extracted with ether and chromatographed on
silica gel using toluene-AcOEt (4:1) as an eluent to give (R)-
(+)-4c of 87% ee as colorless needles (0.445 g ,31% yield, mp
143-145 °C, [R]D +88° (c 4.5 MeOH)).
After irradiation of powdered 7b (3.67 g) for 53 h, the
reaction mixture was extracted with ether and chromato-

9266 J . Org. Chem., Vol. 62, No. 26, 1997
Toda et al.
graphed by the same method as described above to give (+)-
4c of 85% ee as colorless needles (0.41 g, 37% yield, mp 141-
144 °C, [R]D +88° (c 4.0, MeOH)).
Cr ysta l d a ta for 7b: C47H51NO6, M )725.92, space group
P21, a ) 10.279(5) Å, b )9.586(6) Å, c ) 20.754(4) Å, â ) 95.69-
(3)°, Z ) 2, Dc ) 1.185 g cm-3. Data were collected on a Rigaku
AFC7R automatic four-circle X-ray diffractometer equipped
with graphite-monochromated Mo KR (λ ) 0.710 69 Å) radia-
tion and a rotating anode. Absorption correction was applied.
No degradation of the crystal by X-ray was ascertained by
repeated monitoring of the three representative reflections
every 150 reflections. The structure was solved by direct
methods (MITHRIL8417) and refined with full-matrix least-
squares methods to R ) 0.050 and Rw ) 0.071 for 2575
independent observed reflections [I > 3.00σ(I)] of 3828 unique
reflections with 2θ < 50.0°. GOF ) 1.26. All the calculations
were carried out on teXsan crystallographic software package,
Molecular Structure Corporation.18
Con ver sion of (S)-(-)-3c to (R)-(+)-3c by Mixin g w ith
12 a n d th e F or m a tion of 7b Wh ich Up on Ir r a d ia tion
Gives (+)-4c. A mixture of (-)-3c (0.11 g, 0.5 mmol) and 12
(0.26 g, 0.25 mmol) was ground for 4 h by using mortar and
pestle to give the inclusion complex of (R)-(+)-3c with 5b (7b).
7b was irradiated for 5 h and chromatographed on silica gel
using toluene-AcOEt (4:1) as eluent to give (R)-(+)-4c of 76%
ee (38% yield).
Cr ysta l d a ta for 3c: C13H17NO2, M ) 219.28, space group
P21P21P21, a ) 7.5905(5) Å, b ) 12.3453(5) Å, c ) 13.3201(7)
Å, Z ) 4, Dc ) 1.167 g cm-3. Data were collected on an Enraf-
Nonius CAD4 diffractometer with graphite-monochromated Cu
KR radiation and corrected for Lorenz and polarization factors
only. The structure was solved by direct methods with the
use of SHELXS8615 and refined against F2 using SHELXL9316
with full-matrix least-squares methods to R ) 0.0327 and Rw
) 0.0863 for 2341 independent, observed reflections [I > 2σ-
(I)] with 4.88 < θ < 67.79°. All H-atoms were placed in ideal
positions and refined with the riding model and fixed isotropic
displacement parameters.
Ack n ow led gm en t. We thank the Ministry of Edu-
cation, Science and Culture, J apan, for a Grant-in-Aid
for Scientific Research on Priority Areas, No. 0624105.
We also thank Mr. Yasuo Oki for his technical as-
sistance with the preparative procedure.
Cr ysta l d a ta for 4c: C13H17NO2, M ) 219.28, space group
Su p p or tin g In for m a tion Ava ila ble: Tables of data and
details of crystal structure determinations, bond lengths and
angles, and anisotropic displacement parameters (42 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
P21, a ) 8.247(2) Å, b ) 6.762(1) Å, c ) 22.782(5) Å, â ) 97.84-
(3)°, Z ) 4, Dc ) 1.157 g/cm-3
. Data collection and the
structure analysis were carried out by the same method
applied to 3c. The structure refinement was also carried out
by the same method applied to 3c with full-matrix least-
squares methods to R ) 0.0479 and Rw ) 0.1219 for 1740
independent, observed reflections [I > 2σ(I)] with 3.92 < θ <
58.26°. All H-atoms were placed in ideal positions and refined
with the riding model and fixed isotropic displacement pa-
rameters.
J O971584Z
(17) Gilmore, C. J . MITHRIL84-an integrated direct methods com-
puter program, University of Glasgow, Scotland. J . Appl. Crystallogr.
1984, 17, 42.
(18) teXAN: Crystal Structure Analkysis Package, Molecular Struc-
ture Corporation, 1985, 1992.
(15) Sheldrick, G. M. SHELXS86, Program for Crystal Structure
Solution, University of Gottingen, Germany, 1985.
(16) Sheldrick, G. M. SHELXL93, Program for Crystal Structures
Refinement, University of Gottingen, Germany, 1993.