Optically Active Axially Chiral Anilide and Maleimide Derivatives as New Chiral Reagents: Synthesis and Application to Asymmetric Diels-Alder Reaction

Article abstract of DOI:10.1021/jo9721711

New axially chiral N-acryl-N-allyl-o-tert-butylanilide and N-(o-tert-butylphenyl)-2-methylmaleimide with high optical purity and definite absolute configurations were prepared from o-tert-butylaniline and (S)-O-acetyl lactic acid or (R)-2-methylsuccinic acid, respectively. Iodine- or Lewis acid-mediated asymmetric Diels-Alder reaction of these axially chiral compounds with various dienes proceeded with high endo and diastereofacial selectivity.

Full text of DOI:10.1021/jo9721711

2634
J . Org. Chem. 1998, 63, 2634-2640
Op tica lly Active Axia lly Ch ir a l An ilid e a n d Ma leim id e Der iva tives
a s New Ch ir a l Rea gen ts: Syn th esis a n d Ap p lica tion to
Asym m etr ic Diels-Ald er Rea ction
Osamu Kitagawa, Hirotaka Izawa, Kiyonobu Sato, Akira Dobashi, and Takeo Taguchi*
Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-03, J apan
Motoo Shiro
Rigaku Corporation, 3-9-12 Matsubara-cho, Akishima, Tokyo 196, J apan
Received December 1, 1997
New axially chiral N-acryl-N-allyl-o-tert-butylanilide and N-(o-tert-butylphenyl)-2-methylmaleimide
with high optical purity and definite absolute configurations were prepared from o-tert-butylaniline
and (S)-O-acetyl lactic acid or (R)-2-methylsuccinic acid, respectively. Iodine- or Lewis acid-mediated
asymmetric Diels-Alder reaction of these axially chiral compounds with various dienes proceeded
with high endo and diastereofacial selectivity.
Sch em e 1
In tr od u ction
In contrast to axially chiral biaryl compounds such as
binaphthyl and biphenyl derivatives which are widely
used as chiral ligands or chiral auxiliaries,1 the applica-
tion of nonbiaryl axially chiral compounds to asymmetric
reactions has not been reported so far except for a few
examples.2 On the other hand, stereoselective reactions
using axially chiral amides or axially twisted imide
derivatives of their racemic or achiral forms have been
recently reported by several groups.3,4 In particular,
highly diastereoselective reactions with axially chiral
N-acryl-o-tert-butylanilide and axially twisted N-(o-tert-
butylphenyl)-maleimide, which were disclosed by Curran,4a
Kishikawa,4b and Simpkins,4c should be noted as a new
method for stereocontrol (Scheme 1). Curran termed
such transfer of axial chirality into the newly constructed
chiral center as “atropselective reaction”.4a However, in
these reactions, the racemic axially chiral anilides and
σ-symmetrical maleimides which cannot be applied to an
asymmetric reaction were used. Although Shimpkins et
al. attempted to prepare an optical active anilide through
the kinetic resolution of racemic N-propionyl-o-tert-
butylanilide by a chiral lithium amide, the chiral anilide
with insufficient optical purity (88% ee) was obtained in
poor yield at the stage of about 90% conversion.4c In
addition, there has been no report regarding determina-
tion of the absolute configuration of this anilide.
In this paper, we report a synthesis of chiral N-acryl-
N-allyl-o-tert-butylanilide 1 and N-(o-tert-butylphenyl)-
2-methylmaleimide 2 with high optical purity (96% ee)
and definite absolute configuration.5 Furthermore, as an
application to asymmetric reaction, the iodine- or Lewis
acid-mediated Diels-Alder reaction of the axially chiral
compounds which proceeds with high endo and diaste-
reofacial selectivity is also described.
* FAX and Tel: 81-426-76-3257, e-mail: kitagawa@ps.toyaku.ac.jp.
(1) (a) Rosini, C.; Franzini, L.; Raffaelli, A.; Salvatori, P. Synthesis
1992, 503. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994. (c) Fuji, K.; Yang, X.; Tanaka, K., Asakawa,
N.; Hao, X. Tetrahedron Lett. 1996, 37, 7373 and references therein.
(2) (a) Kawabata, T.; Yahiro, K.; Fuji, K. J . Am. Chem. Soc. 1991,
113, 9694. (b) Kawamoto, T.; Taga, T.; Bessho, K.; Yoneda, F. Hayami,
J . Tetrahedron Lett. 1994, 35, 8631. (c) Ohno, A.; Kunimoto, J .; Kawai,
Y.; Kawamoto, T.; Tomishima, M.; Yoneda, F. J . Org. Chem. 1996, 61,
9344.
(3) (a) Bowles, P.; Clayden, J .; Tomkinson, M. Tetrahadron Lett.
1995, 36, 9219. (b) Thayumanavan, S.; Beak, P.; Curran, D. P.
Tetrahedron Lett. 1996, 37, 2899. (c) Clayden, J .; Pink, J . H. Tetra-
hedron Lett. 1997, 38, 2561. (d) Clayden, J . Angew. Chem., Int. Ed.
Engl. 1997, 36, 949 and references therein.
(4) (a) Curran, D. P.; Qi, H.; Geib, S. J .; DeMello, N. C. J . Am. Chem.
Soc. 1994, 116, 3131. (b) Kishikawa, K.; Tsuru, I.; Kohomoto, S.;
Yamamoto, M.; Yamada, K. Chem. Lett. 1994, 1605. (c) Hughes, A.
D.; Price, D. A.; Shishkin, O.; Shimpkins, N. S. Tetrahadron Lett. 1996,
37, 7607.
(5) Preliminary communication of this work: Kitagawa, O.; Izawa,
H.; Taguchi, T.; Shiro, M. Tetrahedron Lett. 1997, 38, 4447.
Resu lts a n d Discu ssion
Syn th esis of Op tica lly Active Axia lly Ch ir a l N-
Acr yl-N-a llyl-o-ter t-bu tyla n ilid e a n d N-o-ter t-Bu -
tylp h en yl 2-Meth ylm a leim id e. To prepare axially
chiral compounds with high optical purity and definite
S0022-3263(97)02171-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/28/1998

Optically Active Axially Chiral Anilide and Maleimide Derivatives
J . Org. Chem., Vol. 63, No. 8, 1998 2635
Sch em e 2
F igu r e 1. Chem 3D drawing of 3b obtained by X-ray analysis.
Hydrogen atoms have been omitted for clarity.
Sch em e 3
absolute configuration, the optical resolution based on
the formation of diastereomeric derivatives with certain
optically active compounds was investigated. After a
survey of various optically active compounds, the resolu-
tion through the formation of a carboxamide 3 from
N-allyl-o-tert-butylaniline and (S)-O-acetyl lactic acid6
was found to be the most effective. These diastereomeric
anilides 3a and 3b on the basis of the axial chirality of
the o-tert-butylanilide moeity and the chiral R-carbon of
lactic acid can be easily separated by column chroma-
tography [TLC (SiO2), ∆Rf ) 0.13, hexane/AcOEt ) 3],
readily affording a diastereomerically pure anilide (Scheme
2). In this condensation reaction, although various
methods such as the use of DCC, (EtO)2P(O)CN, (PhO)2P-
(O)N3, and mixed anhydride were attempted, anilide 3
could not be obtained in good yield (e20%) because of
the low reactivity of the aniline having a bulky tert-butyl
group at the ortho position.7 On the other hand, it was
found that the use of 2 equiv of lactic acid and 3-ethyl-
1-(3-(dimethylamino)propyl)carbodiimide hydrochloride
(EDC) as a condensation reagent and a highly concen-
trated solution (1.5 M) were required to get products 3
in good yield. Under these conditions, 3a and 3b were
obtained in 74% yield in a ratio of 3:1.
Anilides 3a and 3b were converted to the correspond-
ing N-acryl anilides (+)-1 and (-)-1 in good yields in
accordance with Scheme 2, respectively. The physical
data of (+)-1 completely coincided with those of (-)-1
except for the sign of [R]D. The ee of (+)-1 having [R]D )
+185 (CHCl3) was estimated to be 97% by HPLC analysis
using a CHIRALPAK AS column.
Axially twisted N-(o-tert-butylphenyl)-maleimides re-
ported by Curran and Kishikawa are achiral compounds
with a symmetrical plane;4a,b therefore, we tried to
prepare a chiral R-monosubstituted N-(o-tert-butylphen-
yl)-maleimide in optically active form.
The condensation reaction of (R)-2-methylsuccinic acid8
with o-tert-butylaniline proceeded to give a good yield
(75%) of diastereomer mixture of succinimides in a ratio
of 5a :5b ) 1.3:1 (Scheme 3). Similar to the case of anilide
3, the use of EDC as a condensation reagent and a highly
concentrated solution (3 M) were required to get good
yield of product 5. These diastereomeric imides 5a
(crystal) and 5b (oil) can be easily separated by column
chromatography [TLC (SiO2), ∆Rf ) 0.04, hexane/AcOEt
) 3] to give diastereomerically pure imides. However,
the ee of the separated imides 5a and 5b was estimated
to be 89% and 90%, respectively, by HPLC analysis using
a CHIRALPAK OJ column (5a : 30% i-PrOH in hexane,
The stereochemistries of these anilides 3a and 3b were
determined on the basis of X-ray crystallography of 3b.
The X-ray crystal structure indicates that the planes of
the amide and aryl group are twisted by 83° (Figure 1).
(6) (S)-O-Acetyl lactic acid was purchased from Kanto Chemicals
Co.
(7) Although anilides 3a and 3b were obtained in quantitative yield
from N-allyl-o-tert-butyl aniline and (S)-acetoxypropionyl chloride
(commercially available), the preparation through this method gave 1
with lower optical purity (82% ee).
(8) (R)-2-Methylsuccinic acid was purchased from Azmax Co. Ltd.

2636 J . Org. Chem., Vol. 63, No. 8, 1998
Kitagawa et al.
Ta ble 1. Iod in e-Med ia ted Asym m etr ic Diels-Ald er
Rea ction of (+)-1a
F igu r e 2. Chem 3D drawing of 5a obtained by X-ray analysis.
Hydrogen atoms have been omitted for clarity.
Sch em e 4
5b: 30% i-PrOH in hexane); thus, this condensation
reaction was accompanied with partial epimerization.
The optical purity of 5a could be improved by recrystal-
lization from hexane-AcOEt (10:1); that is, 5a of 96%
ee was obtained in 44% yield.
The stereochemistries of these imides 5a and 5b were
determined on the basis of X-ray crystallography of 5a .
The X-ray crystal structure indicates that the plane of
the aryl group is almost perpendicular to the plane of
the cyclic imide moiety (85°, Figure 2). As shown in
Scheme 3, 5a could be converted to maleimide 2 in 42%
We have recently found that in the presence of I2, the
Diels-Alder reaction of N-allylic enamide proceeds in
good yield through an activating process involving the
formation of a cationic iodocyclization intermediate.10,11
The application of the iodine-mediated activating method
to the asymmetric Diels-Alder reaction12 of anilide (+)-1
resulted in remarkable improvement in the reactivity and
the selectivity (Table 1). The reaction of anilide (+)-1
with cyclopentadiene in the presence of I2 proceeded in
good yield (92%) even at below room temperature to give
the adduct 6 with high endo and diastereofacial selectiv-
ity (29:1:1, entry 1). The reaction with cyclohexadiene
also gave the adduct 7 in good yield (84%) with almost
complete endo selectivity and high diastereofacial selec-
tivity (14:1, entry 2). In the reaction of an unreactive
diene such as isoprene, the adduct 8 was also obtained
in good yield (87%) with high diastereoselectivity (20:1,
entry 3).
yield without racemization. The ee of (+)-2 having [R]28
D
) +1.3 was estimated to be 96% by HPLC analysis using
a CHIRALPAK AD column.
Regarding the racemization of these axially chiral
compounds, at 80 °C, the half-lives of 1 and 2 were
estimated to be 33 and 15 h, respectively. The optical
purity of anilide 1 did not change after standing for more
than one month at room temperature, while imide 2
racemized slowly at room temperature. For example, the
optical purity of 2 (96% ee) dropped to 82% ee after 4
weeks at room temperature. The racemization of 2 could
be prevented by storing in a freezer; that is, no racem-
ization of 2 was observed after 8 weeks at -20 °C. Thus,
use of 1 and 2 as chiral reagents for asymmetric reactions
should be possible.
Ap p lica tion to Asym m etr ic Diels-Ald er Rea c-
tion . For the investigation of the efficacy of anilide 1
and imide 2 as chiral reagents, asymmetric Diels-Alder
reactions using 1 and 2 were examined. It has been
pointed out that enamide derivatives compared to enals
and enoates sometime work less well with a diene even
in the presence of Lewis acid.9,10 Indeed, the reaction of
anilide (+)-1 with cyclopentadiene at room temperature
for 2 d afforded Diels-Alder adduct 6 in low yield (<10%,
Scheme 4). In addition, in this case, diastereomer
mixtures which may correspond to endo- or exo-isomers
were obtained in a ratio of 2:1.
The relative and absolute configurations of major
products endo-6 and endo-7 were determined based on
1
the comparison of the H NMR and the [R]D values after
conversion to the known alcohols 913 and 1014 by LiAlH4
reduction,15 respectively, while that of 8 was determined
(11) We have also found R-iodination reaction of unsaturated
carboxamides and N-allylic enamides derivatives through a similar
iodine-mediated activating process. (a) Kitagawa, O.; Hanano, T.;
Hirata, T.; Inoue, T.; Taguchi, T. Tetrahadron Lett. 1992, 33, 1299.
(b) Kitagawa, O.; Kikuchi, N.; Hanano, T.; Aoki, K.; Yamazaki, T.;
Okada, M.; Taguchi, T. J . Org. Chem. 1995, 60, 7161.
(12) Reviews in relation to asymmetric Diels-Alder reactions using
a chiral auxiliary; (a) Paquette, L. A. Asymmetric Synthesis; Morrison,
J . D., Ed.; Academic Press: New York, 1984; Vol. 3, p 455. (b)
Helmchen, G.; Karge, R.; Weetman, J . Modern Synthetic Methods;
Scheffold, R., Ed.; Springer-Verlag: New York, 1986; Vol. 4, p 262. (c)
Oppolzer, W. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press, Inc.: New York, 1991; Vol. 5, p
315. (d) Ishizuka, T.; Kunieda, T. Rev. Heteroat. Chem. 1996, 15, 227.
(9) (a) J ung, M.; Vaccaro, W.; Buszek, K. Tetrahedron Lett. 1989,
30, 1893. (b) Nakagawa, M.; Lai, Z.; Torisawa, Y.; Hino, T. Heterocycles
1990, 31, 999.
(10) Kitagawa, O.; Aoki, K.; Inoue, T.; Taguchi, T. Tetrahadron Lett.
1995, 36, 593.

Optically Active Axially Chiral Anilide and Maleimide Derivatives
J . Org. Chem., Vol. 63, No. 8, 1998 2637
Sch em e 5
F igu r e 3. The most stable confomer of trans-1A (s-trans)
estimated by MM and MD calculation.
by X-ray crystallography. In all cases shown in Table 1,
it was found by HPLC analysis of products using a chiral
column that the reactions proceed without loss of the
optically purity.
Sch em e 6
The observed high reactivity and diastereoselectivity
can be rationalized based on the structure of cationic
iodocyclization intermediate 1A (Scheme 6). 1H NMR
spectrum data of 1A obtained by reaction of 1 with I2 in
CDCl3 indicated marked downfield shifts of olefinic
hydrogens, demonstrating significant decrease in electron
density of the olefinic moeity as compared with 1. In this
spectrum, two sets of signals which may be due to the
diastereomer on the basis of axial chirality and the newly
constructed asymmetric center were observed in a ratio
of 2.9:1. On the other hand, although the conformation
between the olefin and the iminium moeity (s-trans or
s-cis) could not be determined by NOE experiment, it was
tentatively assigned to be s-trans based on the chemical
shifts of olefinic protons (Ha, Hb) in intermediates 1A and
previously reported 11A10 derived from N-allyl N-benzyl
acrylamide, and the s-trans structure of the latter 11A
was determined by NOE experiment. That is, because
of anisotropy effect by a Ph group perpendicular to an
imidate plane in s-trans conformer of 1A, the R-hydrogen
Ha may appear at a more upfield site than that in 11A,
while in s-cis confomer of 1A, the chemical shift of
â-hydrogen Hb should considerably differ from that of Hb
1
in 11A. In H NMR of 1A observed, Ha appeared at an
upfield site (6.13 ppm) in comparison with that (6.93
ppm) of 11A, while the chemical shift of Hb is similar to
that of Hb in 11A. Thus, the diene should preferentially
attack from the opposite side of the tert-Bu group in
s-trans intermediate 1A to give products with high
diastereoselectivity.
group but not by the iodomethyl group. In addition, the
s-trans confomer having the lowest energy level was also
found to be more stable than the corresponding s-cis
conformer by 2.1 kcal/mol by PM3 calculation (Figure 4).
The energy difference between s-trans and s-cis conform-
ers corresponds to a population ratio of 97:3 at 300 K.
The conclusions regarding the conformation of inter-
mediate 1A on the basis of the 1H NMR analysis and the
MO calculation cannot be extrapolated to analysis of the
reactive rotamer in transition-state rationalizations of
the asymmetric Diels-Alder reaction according to the
The conformation of 1A assumed from 1H NMR was
also supported by MM and semiempirical PM3 calucu-
lations; that is, in the most stable conformer of trans-1A
having s-trans orientation estimated by calculation, the
plane of the aryl group is almost perpendicular to that
of the iminium part (93°), and the conformation between
the olefin and the iminium part is antiperiplanar (158°,
Figure 3).16 In this conformer, the iodine atom of the
iodomethyl group is located outside of the five-membered
ring remote from the olefin part; thus, the diastereofacial
selectivity may be considerably controlled by the tert-Bu
(16) The conformation of 1A was preexamined through MM and MD
calculations using MM2 force field as implemented in MacroModel 4.5
(Department of Chemistry, Columbia University, New York). Molecular
dynamics calculation in vacuo at 300 K was carried out with a path
length of 100 ps and followed by minimizing random structures
sampled after multiple 1 ps intervals. Final full geometry was then
optimized by semiempirical PM3 calculation as implemented in
SPARTAN 4.0 (Wave function Inc., California).
(13) J anssen, A. J . M.; Klunder, A. J . H.; Zwanenburg, B. Tetrahe-
dron 1991, 47, 5513.
(14) Arai, Y.; Takadoi, M.; Koizumi, T. Chem. Pharm. Bull. 1988,
36, 4162.
(15) Curran, D. P.; Yu, H.; Liu, H. Tetrahedron 1994, 50, 7343.

2638 J . Org. Chem., Vol. 63, No. 8, 1998
Kitagawa et al.
pressure liquid chromatography (MPLC) was performed on a
30 × 4 cm i.d. prepacked column (silica gel, 50 µm) with a UV
detector.
(S)-N-Allyl-N-(2-ter t-bu tylp h en yl)-2-a cetoxyp r op ion a -
m id e (3a a n d 3b). To a solution of (S)-O-acetyl lactic acid (4
g, 30 mmol) and N-allyl-o-tert-butylaniline (2.8 g, 15 mmol)
in CH2Cl2 (8 mL) was added 1-(3-(dimethylamino)propyl)-3-
ethylcarbodiimide hydrochloride (EDC) (5.8 g, 30 mmol) at
room temperature. After being stirred for 15 h, the mixture
was poured into water and extracted with Et2O. The Et2O
extracts were washed with brine, dried over MgSO4, and
evaporated to dryness. Purification of the residue by column
chromatography (hexane/AcOEt ) 9) gave 3a (less polar, 2.58
g, 56%) and 3b (more polar, 0.82 g, 18%). 3a : colorless solid;
mp 44 °C; [R]25D ) +55.0 (c ) 1.0, CHCl3); IR (KBr) 2971, 1745,
F igu r e 4. Standard heats of formation of 1A estimated by
PM3 calculation.
Sch em e 7
1
1665 cm-1; H NMR (CDCl3) δ 1.29 (3H, d, J ) 6.4 Hz), 1.38
(s, 9H), 1.98 (3H, s), 3.36 (1H, dd, J ) 8.1, 14.1 Hz), 4.95 (1H,
tdd, J ) 1.5, 4.9, 14.1 Hz), 5.02 (1H, q, J ) 6.4 Hz), 5.11 (1H,
md, J ) 17.0 Hz), 5.18 (1H, dd, J ) 0.8, 10.2 Hz), 5.99 (1H,
dddd, J ) 4.9, 8.1, 10.2, 17.0 Hz), 7.06 (1H, dd, J ) 1.6, 7.8
Hz), 7.15 (1H, dt, J ) 1.5, 7.8 Hz), 7.32 (1H, ddd, J ) 1.5, 7.2,
7.8 Hz), 7.56 (1H, dd, J ) 1.6, 7.2 Hz); 13C NMR (CDCl3) δ:
15.7, 20.8, 32.2, 36.1, 54.7, 67.6, 118.9, 126.3, 128.9, 130.1,
131.9, 137.9, 146.0, 169.2, 169.4; MS (m/z) 304 (M+ + 1), 288.
Anal. Calcd for C18H25NO3: C, 71.26; H, 8.31; N, 4.62.
Found: C, 71.35; H, 8.30; N, 4.56. 3b: colorless crystals; mp
94-95 °C; [R]25D ) -99.0 (c ) 1.0, CHCl3); IR (KBr) 2967, 1738,
Curtin-Hammett principle.17 Neverthless, these results
are in agreement with the diastereoselectivities which
were observed in the present reaction. On the other
hand, although the stereochemistries of diastereomers
of 1A observed in 1H NMR are not clear, the observed
ratio (2.9:1) was quite close to that (3.1:1) estimated from
standard heats of formation of trans- and cis-1A (Figure
4).
1
1660 cm-1; H NMR (CDCl3) δ 1.30 (3H, d, J ) 6.5 Hz), 1.35
(s, 9H), 2.02 (3H, s), 3.34 (1H, dd, J ) 8.2, 14.1 Hz), 4.95 (1H,
tdd, J ) 1.3, 5.0, 14.1 Hz), 5.08 (1H, q, J ) 6.5 Hz), 5.09 (1H,
md, J ) 17.1 Hz), 5.18 (1H, d, J ) 10.4 Hz), 5.98 (1H, m), 6.92
(1H, dd, J ) 1.5, 7.8 Hz), 7.19 (1H, dt, J ) 1.4, 7.4 Hz), 7.34
(1H, dt, J ) 1.5, 7.4 Hz), 7.58 (1H, dd, J ) 1.5, 8.2 Hz); 13C
NMR (CDCl3) δ: 17.8, 20.9, 31.9, 36.1, 54.4, 67.7, 119.1, 126.5,
128.9, 130.4, 131.5, 131.9, 137.8, 146.4, 169.7, 169.8; MS (m/
z) 304 (M+ + 1), 288. Anal. Calcd for C18H25NO3: C, 71.26;
H, 8.31; N, 4.62. Found: C, 71.25; H, 8.30; N, 4.42. In 1H
and 13C NMR spectra of 3a and 3b, the minor signals which
may be due to the existence of the amide C-N rotamers were
also observed in a ratio of 20:1 and 10:1, respectively.
In the Diels-Alder reaction of maleimide (+)-2 with
cyclopentadiene, although prolonged reaction time (3
days) was required at room temperature, the reaction
proceeded in good yield (83%) even in the absence of
activating reagents (Scheme 7). In the presence of Et2-
AlCl, the reaction was completed within 20 min at room
temperature to give the adduct 12 in a quantitative
yield.18 In these reactions, almost complete endo and
diastereofacial selectivities were observed as determined
N-Acr yl-N-a llyl-2-ter t-bu tyla n ilid e [(+)-1]. To a mixture
of 1 N NaOH (5 mL) and EtOH (2 mL) was added 3a (1.15 g,
3.8 mmol), and the mixture was stirred for 30 min at room
temperature. The mixture was poured into water and ex-
tracted with Et2O. The Et2O extracts were washed with brine,
dried over MgSO4, and evaporated to dryness. Purification of
the residue by column chromatography (hexane/AcOEt ) 4)
gave 4a (993 mg, quantitative, see Supporting Information).
To a solution of 4a (993 mg, 3.8 mmol) and Et3N (0.68 mL, 4.9
mmol) in THF (8 mL) was added methanesulfonyl chloride
(0.38 mL, 4.9 mmol) at 0 °C. After being stirred for 30 min at
room temperature, the mixture was poured into aqueous NH4-
Cl solution and extracted with Et2O. The Et2O extracts were
washed with brine, dried over MgSO4, and evaporated to
dryness. Purification of the residue by column chromatogra-
phy (hexane/AcOEt ) 7) gave the mesylate. To a solution of
PhSeSePh (890 mg, 2.85 mmol) in EtOH (2 mL) was added
NaBH4 (216 mg, 5.7 mmol) at 0 °C, and the mixture was
stirred for 1 h at room temperature. To this was added the
mesylate in EtOH (5 mL) at 0 °C, the whole was stirred for 4
h at room temperature, and then THF (2 mL) and 30% H2O2
(5 mL) were added to the mixture. After being stirred for 20
h at 0 °C to room temperature, the mixture was poured into
aqueous Na2S2O3 solution and extracted with Et2O. The Et2O
extracts were washed with brine, dried over MgSO4, and
evaporated to dryness. Purification of the residue by column
chromatography (hexane/AcOEt ) 20) gave (+)-1 (754 mg, 3.1
mmol). The ee of (+)-1 (97% ee) was determined by HPLC
analysis using a CHIRALPAK AS column [25 cm × 0.46 cm
i.d.; solvent, 0.1% i-PrOH in hexane; flow rate, 1.0 mL/min;
(+)-1; tR ) 20.6 min, (-)-1; tR ) 15.5 min]. (+)-1: colorless
1
by 300 MHz H NMR. The structure of the adduct 12
confirmed by X-ray analysis indicates that the attack of
the diene to 2 occurs in an endo-mode from the opposite
side of the tert-Bu group (see Supporting Information).
In conclusion, we have succeeded in the synthesis of
chiral N-acryl-N-allyl-o-tert-butylanilide and N-(o-tert-
butylphenyl)-2-methylmaleimide with high optical purity
and definite absolute configuration. In addition to the
stability of these axially chiral compounds which can be
stored without racemization at an appropriate temper-
ature, the above highly diastereoselective Diels-Alder
reaction should indicate the usefulness of these com-
pounds as chiral reagents.
Exp er im en ta l Section
Melting points are uncorrected. 1H and 13C NMR spectra
were recorded on a 400- and 300-MHz spectrometer. In 1H
and 13C NMR spectra, chemical shifts were expressed in δ
(ppm) downfield from CHCl3 (7.26 ppm) and CDCl3 (77.0 ppm),
respectively. Mass spectra were recorded by electron impact
or chemical ionization. Column chromatography was per-
formed on silica gel, Wakogel C-200 (75-150 µm). Medium-
solid; mp 41-42 °C; [R]28 ) +185.0 (97% ee, c ) 1.1, CHCl3);
D
IR (KBr) 2965, 1660 cm-1
;
1H NMR (CDCl3) δ 1.38 (9H, s),
(17) Seeman, J . I. Chem. Rev. 1983, 83, 83.
(18) In the presence of Et2AlCl, the reaction of (+)-2 with cyclo-
hexadiene gave a complex mixture together with recovery of (+)-2.
3.41 (1H, dd, J ) 8.1, 14.1 Hz), 5.00 (1H, tdd, J ) 1.3, 5.1,
14.1 Hz), 5.10 (1H, md, J ) 17.1 Hz), 5.17 (1H, d, J ) 9.9 Hz),

Optically Active Axially Chiral Anilide and Maleimide Derivatives
J . Org. Chem., Vol. 63, No. 8, 1998 2639
5.47 (1H, dd, J ) 2.1, 10.3 Hz), 5.90 (1H, dd, J ) 10.3, 16.8
Hz), 6.03 (1H, dddd, J ) 5.1, 8.1, 9.9, 17.1 Hz), 6.37 (1H, dd,
J ) 2.1, 16.8 Hz), 6.94 (1H, dd, J ) 1.5, 7.8 Hz), 7.18 (1H, dt,
J ) 1.5, 7.4 Hz), 7.33 (1H, dt, J ) 1.5, 7.3 Hz), 7.57 (1H, dd,
J ) 1.5, 8.1 Hz); 13C NMR (CDCl3) δ: 31.9, 35.7, 54.0, 118.5,
126.6, 127.2, 128.4, 128.7, 129.4, 131.9, 132.2, 139.0, 146.5,
165.3; MS (m/z) 243 (M+), 228. Anal. Calcd for C16H21NO:
C, 78.97; H, 8.70; N, 5.76. Found: C, 79.06; H, 8.55; N, 5.61.
(R)-N-(2-ter t-Bu tylph en yl)-2-m eth ylsu ccin im ide (5a an d
5b). To a solution of (R)-methylsuccinic acid (1.59 g, 12 mmol)
and o-tert-butylaniline (1.56 mL, 10 mmol) in CH2Cl2 (4 mL)
was added 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide
hydrochloride (EDC) (2.3 g, 12 mmol) under argon atmosphere
at room temperature. After being stirred for 15 h, the mixture
was poured into 2% HCl and extracted with Et2O. The Et2O
extracts were washed with brine, dried over MgSO4, and
evaporated to dryness. Purification of the residue by column
chromatography (hexane/AcOEt ) 7) gave 5b (less polar, 810
mg, 33%) and 5a (more polar, 1.03 g, 42%). The optical purity
of 5a (89% ee, 1.03 g) was improved to 96% ee (0.453 g, 44%
yield) by recrystallization from hexane-AcOEt (30 mL-3 mL).
solution and extracted with AcOEt. The AcOEt extracts were
washed with 2% HCl and brine, dried over MgSO4, and
evaporated to dryness. The residue was purified by column
chromatography (hexane/AcOEt ) 20) to give a mixture of
major-endo-6, minor-endo-6, and exo-6 (285 mg, 92%, major-
endo-6/minor-endo-6/exo-6 ) 29/1/1). Further purification by
MPLC (hexane/AcOEt ) 12) gave major-endo-6 (263 mg, 85%),
minor-endo-6 (3 mg, 1%), and exo-6 (2 mg, 0.7%).
(3R,4R,6R), (3R,4S,6R), a n d (3S,4S,6S)-N-Allyl-N-(2-
ter t-b u t ylp h en yl)b icyclo[2.2.1]h ep t en e-4-ca r b oxa m id e
[en d o-6 (m a jor ), exo-6, en d o-6 (m in or )]. Major-endo-6:
colorless solid; mp 65-66 °C; [R]22D ) +243.9 (96% ee, c ) 1.0,
CHCl3); IR (KBr) 2980, 1646 cm-1 1H NMR (CDCl3) δ 0.94
;
(1H, d, J ) 8.1 Hz), 1.21 (1H, ddd, J ) 1.9, 4.3, 8.1 Hz), 1.36
(9H, s), 1.48 (1H, ddd, J ) 2.5, 4.7, 11.3 Hz), 1.56-1.65 (1H,
m), 2.61 (1H, ddd, J ) 3.5, 4.7, 8.2 Hz), 2.77 (1H, brs), 2.83
(1H, brs), 3.26 (1H, dd, J ) 8.2, 14.2 Hz), 4.90 (1H, tdd, J )
1.4, 4.8, 14.2 Hz), 5.06 (1H, qd, J ) 1.1, 17.1 Hz), 5.14 (1H, d,
J ) 9.6 Hz), 5.89 (1H, dd, J ) 3.0, 5.5 Hz), 5.97 (1H, dddd, J
) 4.8, 8.2, 9.6, 17.1 Hz), 6.28 (1H, dd, J ) 3.0, 5.5 Hz), 7.12
(1H, dd, J ) 1.6, 7.7 Hz), 7.23 (1H, dt, J ) 1.6, 7.2 Hz), 7.34
(1H, dt, J ) 1.6, 7.2 Hz), 7.57 (1H, dd, J ) 1.6, 8.1 Hz); 13C
NMR (CDCl3) δ: 30.2, 32.2, 36.0, 42.0, 43.0, 46.8, 50.3, 54.2,
117.9, 126.4, 128.4, 129.6, 130.7, 132.1, 133.2, 137.2, 140.0,
5a : colorless solid; mp 103-106 °C; [R]26 ) +9.9 (96% ee, c
D
1
) 1.0, CHCl3); IR (KBr) 2968, 1710 cm-1; H NMR (CDCl3) δ
1.31 (9H, s), 1.47 (3H, d, J ) 7.2 Hz), 2.50 (1H, dd, J ) 4.2,
17.3 Hz), 3.02 (1H, m), 3.09 (1H, dd, J ) 9.2, 17.3 Hz), 6.84
(1H, dd, J ) 1.5, 7.8 Hz), 7.29 (1H, dt, J ) 1.4, 7.6 Hz), 7.39
(1H, dt, J ) 1.5, 7.9 Hz), 7.58 (1H, dd, J ) 1.4, 8.0 Hz); 13C
NMR (CDCl3) δ: 16.6, 31.6, 35.2, 35.6, 37.0, 127.3, 128.7, 129.6,
130.5, 130.6, 147.9, 176.7, 180.3; MS (m/z) 245 (M+), 230. Anal.
Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C,
146.2, 174.1; MS (m/z) 309 (M+), 294. Anal. Calcd for C21H27
-
NO: C, 81.51; H, 8.79; N, 4.53. Found: C, 81.41; H, 8.75; N,
4.41. Minor-endo-6: colorless oil; 1H NMR (CDCl3) δ 0.95 (1H,
d, J ) 8.2 Hz), 1.04 (1H, ddd, J ) 2.4, 5.7, 11.2 Hz), 1.27 (1H,
m), 1.41 (9H, s), 1.56 (1H, m), 2.59 (1H, ddd, J ) 3.0, 5.6, 9.2
Hz), 2.71 (1H, brs), 2.92 (1H, brs), 3.27 (1H, dd, J ) 8.2, 14.2
Hz), 4.91 (1H, tdd, J ) 1.3, 5.0, 14.2 Hz), 5.01 (1H, dd, J )
1.1, 17.2 Hz), 5.09 (1H, d, J ) 10.1 Hz), 5.92 (1H, dddd, J )
5.0, 8.2, 10.1, 17.2 Hz), 6.14 (1H, dd, J ) 3.0, 5.5 Hz), 6.36
(1H, dd, J ) 3.0, 5.5 Hz), 6.86 (1H, dd, J ) 1.6, 7.6 Hz), 7.17
(1H, dt, J ) 1.6, 7.6 Hz), 7.32 (1H, dt, J ) 1.6, 7.2 Hz), 7.58
(1H, dd, J ) 1.6, 7.2 Hz); MS (m/z) 309 (M+), 294. exo-6:
73.64; H, 7.76; N, 5.56. 5b: colorless oil; [R]26 ) +5.3 (90%
D
ee, c ) 1.05, CHCl3); IR (KBr) 2986, 1713 cm-1
;
1H NMR
(CDCl3) δ 1.30 (9H, s), 1.46 (3H, d, J ) 7.1 Hz), 2.51 (1H, dd,
J ) 4.3, 17.7 Hz), 3.02 (1H, m), 3.11 (1H, dd, J ) 9.3, 17.7
Hz), 6.83 (1H, dd, J ) 1.5, 7.8 Hz), 7.28 (1H, dt, J ) 1.5, 7.6
Hz), 7.38 (1H, dt, J ) 1.5, 7.6 Hz), 7.58 (1H, dd, J ) 1.4, 8.1
Hz); 13C NMR (CDCl3) δ: 16.5, 31.5, 35.1, 35.5, 36.9, 127.3,
128.7, 129.7, 130.3, 130.6, 147.9, 176.5, 180.6; MS (m/z) 245
(M+), 230. Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N,
5.71. Found: C, 73.50; H, 7.79; N, 5.47.
1
colorless oil; H NMR (CDCl3) δ 1.01 (1H, ddd, J ) 2.3, 8.3,
11.0 Hz), 1.24 (1H, d, J ) 8.0 Hz), 1.33 (9H, s), 1.89 (1H, ddd,
J ) 1.0, 4.4, 8.1 Hz), 1.98-2.06 (2H, m), 2.74 (1H, brs), 2.89
(1H, brs), 3.34 (1H, dd, J ) 8.2, 14.2 Hz), 4.96 (1H, tdd, J )
1.4, 4.8, 14.2 Hz), 5.08 (1H, qd, J ) 1.6, 17.1 Hz), 5.16 (1H, d,
J ) 10.2 Hz), 5.70 (1H, dd, J ) 3.0, 5.6 Hz), 5.96 (1H, dd, J )
3.0, 5.6 Hz), 6.03 (1H, dddd, J ) 4.8, 8.2, 10.2, 17.1 Hz), 7.07
(1H, dd, J ) 1.7, 7.6 Hz), 7.21 (1H, dt, J ) 1.6, 7.6 Hz), 7.30
(1H, dt, J ) 1.6, 7.2 Hz), 7.53 (1H, dd, J ) 1.6, 7.2 Hz); MS
(m/z) 309 (M+), 294.
N-(2-ter t-Bu t ylp h en yl)-2-m et h ylm a lein im id e [(+)-2].
To a solution of 5a (313 mg, 1.28 mmol) in toluene (13 mL)
was added TMS2NNa (1 M THF solution, 1.28 mL, 1.28 mmol)
at -78 °C. After being stirred for 10 min at -78 °C, PhSeCl
(245 mg, 1.28 mmol) was added to the reaction mixture, and
then the mixture was stirred for 1.5 h at -78 °C. The mixture
was poured into 2% HCl and extracted with AcOEt. The
AcOEt extracts were washed with brine, dried over MgSO4,
and evaporated to dryness. To the residue were added THF
(5 mL) and 30% H2O2 (2 mL) at 0 °C, and then the mixture
was stirred for 1.5 h at room temperature. The mixture was
poured into aqueous Na2S2O3 solution and extracted with
AcOEt. The AcOEt extracts were washed with brine, dried
over MgSO4, and evaporated to dryness. Purification of the
residue by column chromatography (hexane/AcOEt ) 12) gave
(+)-2 (133 mg, 43%). The ee of (+)-2 (96% ee) was determined
by HPLC analysis using a CHIRALPAK AD column [25 cm ×
0.46 cm i.d.; 1% i-PrOH in hexane; flow rate, 1.0 mL/min; (-)-
2; tR ) 10.5 min, (+)-2; tR ) 11.9 min]. (+)-2: colorless oil;
(4R)-Bicyclo[2.2.1]h ep ten e-4-m eth a n ol (9). To a solu-
tion of endo-6 (257 mg, 0.83 mmol) in THF (5 mL) was added
LiAlH4 (31.5 mg, 0.83 mmol) at 0 °C. After being stirred for
5 h at room temperature, the mixture was successively treated
with AcOEt, H2O, and 2% HCl and then extracted with Et2O.
The Et2O extracts were washed with brine, dried over MgSO4,
and evaporated to dryness. Purification of the residue by
column chromatography (pentane/Et2O ) 5) gave 9 (53 mg,
51%). 9: [R]24D ) +79.3 (c ) 0.86, 95% EtOH) [lit. [R]D ) +61.9
1
(68% ee, c ) 0.6, 95% EtOH)]; H NMR data coincided with
that reported in the literature.13
Ca tion ic Iod ocycliza tion In ter m ed ia te (1A). To a solu-
tion of the anilide 1 (52 mg, 0.21 mmol) in CDCl3 (8 mL) was
added I2 (161 mg, 0.63 mmol) at room temperature. After
being stirred for 2 h, the 1H NMR spectrum of the reaction
[R]D ) +1.3 (96% ee, c) 1.1, CHCl3); IR (KBr) 2960, 1703 cm-1
;
1H NMR (CDCl3) δ 1.29 (9H, s), 2.18 (3H, d, J ) 1.9 Hz), 6.51
(1H, q, J ) 1.9 Hz), 6.89 (1H, dd, J ) 1.4, 7.7 Hz), 7.26 (1H,
dt, J ) 1.4, 7.7 Hz), 7.38 (1H, dt, J ) 1.6, 8.1 Hz), 7.57 (1H,
dd, J ) 1.6, 8.1 Hz); 13C NMR (CDCl3) δ: 11.1, 31.5, 35.3, 127.1,
128.2, 128.4, 129.6, 129.7, 131.3, 146.6, 149.4, 170.8, 171.8;
MS (m/z) 243 (M+), 228. Anal. Calcd for C15H17NO2: C, 74.05;
H, 7.04; N, 5.76. Found: C, 74.21; H, 6.89; N, 5.87.
1
mixture was measured. In H NMR of 1A, two sets of signals
which may be due to the diastereomer on the basis of axial
chirality and newly constructed asymmetric center were
observed in a ratio of 2.9:1. Major-1A: 1H NMR (CDCl3) δ
1.48 (9H, s), 4.02 (1H, dd, J ) 3.0, 11.9 Hz), 4.11 (1H, dd, J )
4.9, 11.9 Hz), 4.48 (1H, dd, J ) 9.1, 12.8 Hz), 5.14 (1H, dd, J
) 9.8, 12.8 Hz), 5.84 (1H, m), 6.13 (1H, dd, J ) 11.0, 17.2 Hz),
6.73 (1H, d, J ) 11.0 Hz), 7.19 (1H, d, J ) 17.2 Hz), 7.50-
7.87 (4H, m). Minor-1A: 1H NMR (CDCl3) δ 1.48 (9H, s), 3.81
(1H, dd, J ) 6.4, 11.7 Hz), 3.86 (1H, dd, J ) 4.6, 11.7 Hz),
4.58 (1H, dd, J ) 8.2, 12.6 Hz), 5.03 (1H, dd, J ) 10.5, 12.6
Hz), 5.84 (1H, m), 6.04-6.17 (2H, m), 6.73 (1H, d, J ) 11.0
Hz), 7.19 (1H, d, J ) 17.2 Hz), 7.50-7.87 (4H, m).
Gen er a l P r oced u r e of Iod in e-Med ia ted Diels-Ald er
Rea ction . To a solution of (+)-1 (96% ee, 243 mg, 1 mmol) in
AcOEt (5 mL) was added I2 (508 mg, 2 mmol) at room
temperature. After being stirred for 30 min, cyclopentadiene
(0.16 mL, 2 mmol) was added, and then the reaction mixture
was stirred for 15 h at -78 °C to room temperature. n-Bu4NI
(739 mg, 2 mmol) was added to the mixture, and after being
stirred for 2 h, the mixture was poured into aqueous Na2S2O3

2640 J . Org. Chem., Vol. 63, No. 8, 1998
Kitagawa et al.
(1S,2S,6R,7S)-4-(2-ter t-Bu t ylp h en yl)-2-m et h yl-4-a za -
tr icyclo[5.2.1.02,6]d ec-8-en e-3,5-d ion e (12). To a solution
of (+)-2 (96% ee, 61 mg, 0.25 mmol) in CH2Cl2 (2.5 mL) was
added Et2AlCl (0.95 M in hexane, 0.26 mL, 0.25 mmol) at room
temperature. After being stirred for 10 min, cyclopentadiene
(0.1 mL, 1.25 mmol) was added, and then the reaction mixture
was stirred for 20 min at room temperature. The mixture was
poured into 2% HCl solution and extracted with Et2O. The
Et2O extracts were dried over MgSO4 and evaporated to
dryness. The residue was purified by column chromatography
(hexane/AcOEt ) 12) to give 12 (77 mg, quantitative) as a
7.22 (1H, dt, J ) 1.5, 7.4 Hz), 7.36 (1H, dt, J ) 1.6, 7.2 Hz),
7.52 (1H, dd, J ) 1.5, 8.1 Hz); 13C NMR (CDCl3) δ: 21.3, 31.5,
35.5, 45.9, 50.3, 51.0, 51.6, 53.1, 127.2, 128.4, 129.5, 130.6,
131.1, 134.7, 136.8, 147.9, 177.9, 181.0; MS (m/z) 309 (M+),
294. Anal. Calcd for C20H23NO2: C, 77.64; H, 7.49; N, 4.53.
Found: C, 77.40; H, 7.44; N, 4.57.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data and experimental procedures of 4a , 4b, endo-7, and 8,
and X-ray crystal data of 3b, 5a , 8, and 12 (95 pages). This
material is contained in libraries on microfiche, immediately
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.
single isomer. 12: colorless solid; mp 162-164 °C; [R]26
)
D
-35.0 (96% ee, c ) 1.24, CHCl3); IR (KBr) 2969, 1706 cm-1
;
1H NMR (CDCl3) δ 1.29 (9H, s), 1.62 (3H, s), 1.81 (1H, td, J )
1.7, 9.2 Hz), 1.85 (1H, td, J ) 1.5, 9.2 Hz), 2.98 (1H, d, J ) 4.5
Hz), 3.03 (1H, m), 3.46 (1H, m), 6.30 (1H, dd, J ) 3.0, 5.5 Hz),
6.39 (1H, dd, J ) 3.0, 5.5 Hz), 6.72 (1H, dd, J ) 1.5, 7.7 Hz),
J O9721711