Novel camphor-derived chiral auxiliaries: Significant solvent and additive effects on asymmetric reduction of chiral α-keto esters

Article abstract of DOI:10.1021/jo9902188

Stereoselective reduction of various α-keto esters 5a-d derived from exo-10,10-diphenyl-2,10-camphanediol 4a and exo-10,10-diphenyl-10-methoxy-2- camphanol 4b is described. High to excellent diastereomeric excess (99% de) with good chemical yields is obtained. The sense of stereoselectivity as a function of C10 modification is remarkable. Further, in the case of 5d, both diastereomers of α-hydroxyl esters can be obtained with excellent optical purity by the appropriate choice of reaction conditions. The influence of the solvents and additives on the reaction course has been investigated.

Full text of DOI:10.1021/jo9902188

J . Org. Chem. 1999, 64, 6993-6998
6993
Novel Ca m p h or -Der ived Ch ir a l Au xilia r ies: Sign ifica n t Solven t
a n d Ad d itive Effects on Asym m etr ic Red u ction of Ch ir a l r-Keto
Ester s
Ying-Yuan Chu,† Chia-Sheng Yu,† Chiou-J uy Chen,† Kung-Shuo Yang, J ung-Chaing Lain,
Chun-Hui Lin, and Kwunmin Chen*
Department of Chemistry, National Taiwan Normal University 88 Sec. 4 TingChow Road,
Taipei, Taiwan 116, ROC
Received February 4, 1999
Stereoselective reduction of various R-keto esters 5a -d derived from exo-10,10-diphenyl-2,10-
camphanediol 4a and exo-10,10-diphenyl-10-methoxy-2-camphanol 4b is described. High to excellent
diastereomeric excess (99% de) with good chemical yields is obtained. The sense of stereoselectivity
as a function of C10 modification is remarkable. Further, in the case of 5d , both diastereomers of
R-hydroxyl esters can be obtained with excellent optical purity by the appropriate choice of reaction
conditions. The influence of the solvents and additives on the reaction course has been investigated.
In tr od u ction
auxiliary. This represents a promising tool in asymmetric
synthesis.
The synthesis of homochiral R-hydroxyl acid deriva-
tives constitutes one of the most important tasks in
organic synthesis because many biologically active sub-
stances contain this functionality array.1 Among the
developed methods, the diastereoselective reduction of
chiral R-keto esters/R-keto amides that bear an appropri-
ate chiral auxiliary is a conventional strategy.2 The
asymmetric reduction of R-keto amides seems to be a
more promising approach owing to the well-known
planarity of the amide group and the lower number of
possible conformers in the transition state compared to
those of R-keto esters.2i-k However, asymmetric reduction
of R-keto esters with high to excellent diastereoselection
is possible if effective chiral auxiliaries can be developed.
In a previous publication, we described an efficient
method for the preparation of both diastereomers of
R-hydroxyl ester derived from a single enantiomer of
chiral auxiliary.3 Stereoselective reduction of R-keto ester
5a derived from exo-10,10-diphenyl-2,10-camphanediol
4a with various hydrides proceeded with high diastereo-
selectivities (g96% de) to afford the corresponding R-hy-
droxyl ester in excellent yield. In this article, we wish to
report more details of the stereoreduction of related
R-keto esters 5b-d . The methodology has been success-
fully utilized for achieving both diastereomers of R-hy-
droxyl esters without resorting to the enantiomeric
Resu lts a n d Discu ssion
The compounds exo-10,10-diphenyl-2,10-camphanediol
4a and exo-10,10-diphenyl-10-methoxy-2-camphanol 4b
can be easily prepared from ketopinic acid methyl ester
1.4 Treatment of 1 with 4.0 equiv of phenylmagnesium
bromide (THF, 0 °C) afforded hydroxyl ketone 2 in 89%
yield. LAH reduction of 2 (THF, -78 °C) provided the
desired exo alcohol 4a in 95% yield, together with a minor
1
endo product (exo:endo 95:5). The H NMR spectra of the
methine proton on C2 of 4a appeared at δ 4.26 ppm,
whereas the corresponding proton of the minor product
shifted downfield to δ 4.94 ppm. The tertiary hydroxyl
group in 2 may then be protected as its methyl ether
(NaH, MeI, THF, 0 °C) in 77% yield. Reduction of
compound 3 with LAH (THF, -78 °C) provided the exo
alcohol 4b as a sole product in 89% yield. Acylation of
4a with benzoformic acid chloride,5 generated in situ by
reaction of benzoformic acid with SOCl2 at 65 °C for 1 h,
in THF at 0 °C afforded 5a in almost quantitative yield.
Although similar conditions provided R-keto ester 5d
† Department of Applied Chemistry, Chaoyang University of Tech-
nology, 168 Gifeng E. Road, Wufeng, Taichung, Taiwan 413, ROC.
(1) Hanessian, S. Total Synthesis of Natural Products: The Chiron
Approach; Pergamon Press: New York, 1983; Chapter 2.
(2) For recent references, see: (a) Whitesell, J . K.; Deyo, D.;
Bhattacharya, A. J . Chem. Soc., Chem. Commun. 1983, 802. (b)
Solladie-Cavallo, A.; Bencheqroun, M. Tetrahedron: Asymmetry 1991,
2, 1165. (c) Akiyama, T.; Nishimoto, H.; Ozaki, S. Tetrahedron Lett.
1991, 32, 1335. (d) Xiang, Y. B.; Snow, K.; Belley, M. J . Org. Chem.
1993, 58, 993. (e) Maitra, U.; Mathivanan, P. Tetrahedron: Asymmetry
1994, 5, 1171. (f) Ghosh, A. K.; Chen, Y. Tetrahedron Lett. 1995, 36,
6811. (g) Akiyama, T.; Nishimoto, H.; Kuwata, T.; Ozaki, S. Bull. Chem.
Soc. J pn. 1994, 67, 180. (h) Soai, K.; Isoda, T.; Hasegawa, H.; Ishizaki,
M. Chem. Lett. 1986, 1897. (i) Kawanami, Y.; Fujita, I.; Asahara, S.;
Kasuki, T.; Yamaguchi, M. Bull. Chem. Soc. J pn. 1989, 62, 3598. (j)
Kawanami, Y.; Fujita, I.; Taniguchi, Y.; Katsuki, T.; Yamaguchi, M.
Chem. Lett. 1987, 2021. (k) Solodin, I.; Goldberg, Y.; Zelcans, G.;
Lukevics, E. J . Chem. Soc., Chem. Commun. 1990, 1321.
(3) Chen, C.-J .; Chu, Y.-Y.; Liao, Y.-Y.; Tsai, Z.-H.; Wang, C.-C.;
Chen, K. Tetrahedron Lett. 1999, 40, 1141.
10.1021/jo9902188 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/25/1999

6994 J . Org. Chem., Vol. 64, No. 19, 1999
Chu et al.
F igu r e 1. X-ray ORTEP drawings of 5a and 5d .
without incident, the preparation of 5b and 5c under the
same conditions proved troublesome. After extensive
experimental investigation, the problem was resolved by
treatment of 4a with freshly prepared pyruvic acid chlor-
ide (pyruvic acid, DMF, oxalyl chloride) in CH2Cl2 at 0
°C to provide 5b in 57% yield. Chiral R-keto ester 5c was
obtained under the same conditions when 2-ketobutyric
acid was used. The structures of 5a and 5d were estab-
lished via 1H and 13C NMR spectroscopic analyses and
further confirmed by X-ray crystallographic analyses
(Figure 1).
obtained when 5d was reduced (Table 1, entries 6 and
7). We then investigated the solvent effect on this
reaction, and the results showed that the reaction is
highly dependent on the nature of the solvent. In general,
for cases of 5a -c, the use of a noncoordinating solvent
such as toluene led to appreciable decreases in diaste-
reoselectivity while the chemical yields remained (Table
1, entries 8-10). Quite surprisingly, in the case of 5d ,
the use of CH2Cl2 or toluene increases the stereoselec-
tivity significantly (Table 1, entries 11-14). Thus, treat-
ment of R-keto ester 5d with L-Selectride in either
CH2Cl2 or toluene resulted in a greater than 99% de for
7d . The absolute stereochemistry of 7d was assigned by
X-ray crystallographic analysis.
Another interesting and exciting observation is the
additive effect. There have been reports of other systems
in which the changeover of diastereofacial selectivity is
affected by the addition of Lewis acids9 or crown ethers.2f,g
The present study indicated that the addition of 18-
crown-6 or HMPA enhanced stereoselectivity in the cases
of 5a -c (Table 2, entries 1-3). However, the inclusion
of additive reversed diastereoselectivity to a significant
extent for chiral R-keto ester 5d (Table 2, entries 4-6).
High to excellent diastereoselectivity was attained with
S configuration dominating in all cases investigated.
Thus, treatment of 5c with K-Selectride in toluene at -78
°C in the presence of 1.0 equiv of 18-crown-6 improved
the selectivity to 99% de compared with 6% de in the
absence of this additive (Table 2, entry 3 and Table 1,
entry 10). Further, 84% de (S) was obtained when R-keto
ester 5d was treated with K-Selectride in CH2Cl2 in the
presence of 18-crown-6 (Table 2, entry 6 and Table 1,
entry 13). The reversal of diastereoselectivity is astonish-
ing and suggests that the cation(s) play a major role in
determining the transition state conformation.
With R-keto esters in hand, we turned our attention
to the asymmetric reduction. Our preliminary investiga-
tions failed to give good diastereoselectivity when 5a was
reduced with NaBH4 or BH3. For example, reduction of
R-keto ester 5a with NaBH4 gave two inseparable dia-
stereomers in 78% yield with a disappointingly low
diastereomeric ratio.3 However, reduction with a steri-
cally demanding reductant does afford practical levels of
diastereoselectivity. Thus, treatment of 5a with L-Selec-
tride (Aldrich) in THF at -78 °C affords R-hydroxyl ester
6a with a very high diastereoselectivity (Table 1, entry
1). Because of the inseparable nature of the products on
silica gel, the diastereomeric ratios were determined by
1
200 MHz H NMR analysis of relevant signals. Treat-
ment of 5b under the same reaction conditions provided
6b with high stereoselectivity (Table 1, entry 2). This
encouraged us to focus on Selectride as reducing agents.
A systematic investigation was then carried out, and the
chemical yields are generally moderate to excellent. The
absolute configurations of the newly generated stereo-
genic centers were assigned on the basis of the cleaved
R-hydroxyl acids 8a -c. Comparison of the sign of specific
rotations of the R-hydroxyl acids with literature values6-8
allows assignment of the absolute configurations (S).
In constrast to the 4a -derived R-keto esters, relatively
poor facial selectivity with opposite configuration was
From a practical synthetic point of view, the prepara-
tion of both stereoisomers with excellent optical purity
derived from the same chiral source is an attractive tool.10
Very recently, Duhamel and co-workers reported that
chiral auxiliaries containing a “switching center” allow
for the synthesis of enantiomerically pure (R)- and (S)-
(4) Bartlett, P. D.; Knox, L. H. Organic Syntheses; Wiley: New York,
1973; Collect. Vol. V, p 689.
(5) Padwa, A.; Koehler, K. F. J . Chem. Soc. Chem. Commun., 1986,
789.
(6) Mori, K.; Akao, H. Tetrahedron 1980, 36, 91.
(7) Byun, S.; Kim, Y. H. Synth. Commun. 1995, 25, 1963.
(8) Chenault, H. K.; Kim, M.-J .; Akiyama, A.; Miyazawa, T.; Simon,
E. S.; Whitesides, G. M. J . Org. Chem. 1987, 52, 2608.
(9) Solladie´, G.; Demailly, G.; Greck, C. Tetrahedron Lett. 1985, 26,
435.

Novel Camphor-Derived Chiral Auxiliaries
J . Org. Chem., Vol. 64, No. 19, 1999 6995
Ta ble 1. Asym m etr ic Red u ction of r-Keto Ester s 5 w ith Meta l Hyd r id esa
entry
ester
hydride
equiv
solvent
yield (%)b
6/7c
configd
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5a
5b
5b
5c
5c
5d
5d
5a
5b
5c
5d
5d
5d
5d
L-Selectride
L-Selectride
K-Selectride
L-Selectride
K-Selectride
L-Selectride
K-Selectride
L-Selectride
K-Selectride
K-Selectride
L-Selectride
L-Selectride
K-Selectride
K-Selectride
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.2
1.2
1.2
1.2
THF
THF
THF
THF
THF
THF
THF
toluene
toluene
toluene
CH2Cl2
toluene
CH2Cl2
toluene
92
92
85
92
94
87
70
77
92
86
95
98
80
75
6a /7a (97.5/2.5)
6b/7b (95.0/5.0)
6b/7b (93.0/7.0)
6c/7c (99.0/1.0)
6c/7c (94.0/6.0)
6d /7d (31.0/69.0)
6d /7d (18.0/82.0)
6a /7a (69.0/31.0)
6b/7b (47.0/53.0)
6c/7c (53.0/47.0)
6d /7d (0.5/99.5)
6d /7d (0.5/99.5)
6d /7d (0.5/99.5)
6d /7d (0.5/99.5)
S
S
S
S
S
R
R
S
R
S
R
R
R
R
a
b
All reactions were carried out at -78 °C. Isolated yield. c Ratios determined by 200 MHz 1H NMR analysis of relevant signals.
d
The absolute stereochemistry was determined either by comparison of the sign of optical rotation of the cleaved acids, (S)-(+)-mandelic
acid (8a ), (S)-(+)-lactic acid (8b), and (S)-(+)-2-hydroxybutyric acid (8c), or by X-ray crystallographic analysis (7d ).
Ta ble 2. Ad d itive Effect of Asym m etr ic Red u ction of r-Keto Ester s 5a
entry
ester
hydride
additiveb
solvent
yield (%)c
6/7d
config
1
2
3
4
5
6
5a
5b
5c
5d
5d
5d
L-Selectride
L-Selectride
K-Selectride
L-Selectride
K-Selectride
K-Selectride
HMPA
toluene
CH2Cl2
toluene
THF
THF
CH2Cl2
58
95
89
75
60
60
6a /7a (99.5/0.5)
6b/7b (99.0/1.0)
6c/7c (99.5/0.5)
6d /7d (99.0/1.0)
6d /7d (99.5/0.5)
6d /7d (92.0/8.0)
S
S
S
S
S
S
18-crown-6
18-crown-6
HMPA
18-crown-6
18-crown-6
a
b
d
All reactions were carried out at -78 °C with 1.0 equiv of Selectride. One equivalent of additive was added. c Isolated yield. Ratios
determined by 200 MHz 1H NMR analysis of relevant signals.
R-amino acids.10c In our system, the sense of stereose-
lectivity as a function of C10 modification is remarkable.
Further, the dramatic change of diastereoselectivity in
5d by the appropriate choice of reaction conditions
deserves special attention. Although a detailed mecha-
nistic explanation of the present study remained to be
answered, the stereochemical outcomes may be rational-
ized as follows. In the cases of 5a -c, the more extended
s-trans conformation is energetically favored over s-cis
under either chelation or nonchelation conditions. This
may be due primarily to the presence of the C10 hydroxyl
functionality toward the direction of the carbonyl groups
(Figure 1). Thus, the metal cation chelates more strongly
to the C10 hydroxyl group and carbonyl groups than
R-dicarbonyl groups. The X-ray data of 5a indicates that
there exists an intramolecular hydrogen-bonding interac-
tion at O(1)H‚‚‚O(2). The intramolecular distance of
O(1)H‚‚‚O(2) is 2.115 Å. The complex hydride then
attacks from the re-face, resulting in an (S)-configuration
of the newly generated stereogenic center. In contrast,
the s-cis conformation predominates for 5d , especially in
the presence of strongly coordinating metal cation(s).2d,2g
However, the s-trans conformation prevails in the pres-
ence of additives. This may be due to the avoidance of
steric hindrance between the C10 phenyl groups and side
chain moiety in a congested area. As a consequence, the
reduction proceeded through either cisoid or transoid
conformation depending on the reaction conditions and
led to the reversal of stereoselection. The different
ligating ability of the solvent used affects the transition
state conformation to a certain degree. In all the cases,
the C10 phenyl and/or C8 methyl group of the chiral
auxiliary shields one face of the R-carbonyl sp2 carbon
center, leading to the desired configuration.
(10) (a) Kobayashi, S.; Horibe, M. Tetrahedron 1996, 52, 7277. (b)
Alvarez-Ibarra, C.; Csa´ky¨, A. G.; Maroto, R.; Quiroga, M. L. J . Org.
Chem. 1995, 60, 7934. (c) Meyer, L.; Poirier, J .-M.; Duhamel, P.;
Duhamel, L. J . Org. Chem. 1998, 63, 8094. (d) Solladie, G.; Greck, C.;
Demailly, G.; Solladie-Cavallo, A. Tetrahedron Lett. 1982, 23, 5047.
(e) Kobayashi, S.; Hayashi, T. J . Org. Chem. 1995, 60, 1098. (f)
Kobayashi, S.; Horibe, M.; Saito, Y. Tetrahedron 1994, 50, 9629. (g)
Kobayashi, S.; Horibe, M. J . Am. Chem. Soc. 1994, 116, 9805. (h) Sibi,
M.; Shay, J . J .; Liu, M.; J asperse, C. P. J . Am. Chem. Soc. 1998, 120,
6615.
The auxiliary can be easily removed by treatment of
the reduction product with LiOH in THF/H2O at room
temperature (Table 3). No significative racemization of
reduced products was observed.

6996 J . Org. Chem., Vol. 64, No. 19, 1999
Ta ble 3. Hyd r olysis of r-Hyd r oxyl Ester s 6
Chu et al.
entry
R-hydroxyl ester
acid (%)
[R]D
% ee
4a (%)
1
2
3
6a (95% de)
6b (98% de)
6c (99% de)
8a (84)
8b (80)
8c (85)
+145.0° (c 2.8, H2O)a
-13.1° (c 1.5 1.5 N NaOH)b
+7.1° (c 3.0, CHCl3)c
95
97
99
97d
90
91
a
b
d
Lit.6 [R]D +153.0° (c 0.153, H2O). Lit.7 [R]D -13.5° (c 2.5, 1.5 N NaOH). c Lit.8 [R]D +7.15° (c 8.13, CHCl3). Recovered 4a : [R]D
+164.8° (c 1.0, CHCl3); original compound 4a : [R]D +166.1° (c 1.0, CHCl3).3
mL). The combined extracts were washed (brine), dried (Na2-
Con clu sion s
SO4), filtered, and concentrated in vacuo. The crude product
was purified by flash column chromatography, using hexane/
ethyl acetate (10:1) as eluent, to give 0.8 g (77%) of 3 as a
yellow oil: 1H NMR (CDCl3, 200 MHz) δ 7.61-7.52 (m, 4H),
7.37-7.25 (m, 6H), 3.14-3.01 (m, 1H), 2.91 (s, 3H), 2.37-2.26
(m, 1H), 2.14-1.97 (m, 2H), 1.69-1.67 (m, 2H), 1.29-1.23 (m,
1H), 0.91 (s, 3H), 0.13 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ
214.56, 140.25, 130.39, 129.89, 127.06, 126.93, 126.89, 126.86,
85.75, 70.32, 52.79, 49.80, 45.37, 44.06, 27.36, 26.08, 21.80,
21.50; IR (film) 3055, 2938, 1738 cm-1; HRMS m/z 334.1925
(calcd for C23H26O2 334.1933). Anal. Calcd for C23H26O2: C,
82.60; H, 7.84. Found: C, 82.29; H, 7.60.
exo-10,10-Dip h en yl-10-h yd r oxym et h yl-7,7-d im et h yl-
bicyclo[2.2.1]h ep ta n e-2-ol (4a ). To a suspension of LAH
(1.77 g, 46.64 mmol) in THF (50 mL) was added a solution of
2 (5.0 g, 15.61 mmol) in THF (100 mL) at -78 °C under N2
atmosphere. This was allowed to stir at -78 °C for 30 min
and quenched with H2O. The aqueous layer was extracted with
ethyl acetate (2 × 50 mL). The combined extracts were washed
(brine), dried (Na2SO4), filtered, and concentrated in vacuo.
The crude product was purified by flash column chromatog-
raphy, using hexane/ethyl acetate (16:1) as eluent, to give 4.8
g (95%) of 4a as a white solid: 1H NMR (CDCl3, 200 MHz) δ
7.86 (dd, 2Η, J ) 7.7, 1.5 Hz), 7.64 (dd, 2H, J ) 7.7, 1.5 Hz),
7.33-7.11 (m, 6H), 5.05 (br, 1H), 4.23 (dd, 1H, J ) 8.2, 3.7
Hz), 2.31 (ddd, 1H, 12.4, 12.3, 4.2 Hz), 2.10 (br, 1H), 1.91-
1.44 (m, 4H), 1.50 (s, 3H), 1.42 (t, 1H, J ) 4.4 Hz), 0.99 (ddd,
1H, J ) 9.5, 6.2, 3.8 Hz), 0.48 (s, 3H); 13C NMR (CDCl3, 50
MHz) δ 150.25, 144.30, 128.47, 128.20, 127.03, 126.59, 126.04,
81.70, 79.95, 59.51, 50.67, 47.53, 40.12, 30.46, 27.38, 24.77,
22.98; IR (film) 3426, 2930, 748 cm-1; HRMS m/z 322.1935
(calcd for C22H26O2 322.1933). Anal. Calcd for C22H26O2: C,
81.95; H, 8.13. Found: C, 81.80; H, 8.06.
In summary, exo-10,10-diphenyl-2,10-camphanediol 4a
and exo-10,10-diphenyl-10-methoxy-2-camphanol 4b have
proved to be effective chiral auxiliaries for the asym-
metric reduction of R-keto esters. Our procedure repre-
sents a simple and effective alternative for the highly
diastereoselective synthesis of R-hydroxyl esters through
the reduction of the corresponding R-keto esters. More-
over, both diastereomers of R-hydroxyl esters (6d and 7d )
can be prepared with excellent optical purity from a
single chiral auxiliary (5d ) by means of the proper choice
of reaction conditions. Further investigations of these
novel chiral auxiliaries in asymmetric synthesis are in
progress.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out in flame-
or oven-dried glassware under a positive pressure of nitrogen.
Air- and moisture-sensitive compounds were introduced by the
use of a gastight syringe or cannula through a rubber septum.
Most reagents were commercially available and of synthetic
grade. Tetrahydrofuran was distilled from sodium/benzophe-
none ketyl. Dichloromethane and toluene were dried over CaH2
and distilled before use. Analytical thin-layer chromatography
was performed with E. Merck silica gel 60F glass plates, and
flash column chromatography performed by the use of E.
Merck silica gel 60 (230-400 mesh). HRMS values were
measured by a J EOL J MS-SX or J EOL J MS-SX 102A spec-
trometer. Elemental analyses were performed by a Heraeus
CHN-OS rapid instrument. IR spectra were recorded on
1
J ASCO FT/IR-300E. H and 13C NMR spectra were recorded
exo-10,10-Dip h en yl-10-m et h oxym et h yl-7,7-d im et h yl-
bicyclo[2.2.1]h ep ta n e-2-ol (4b). To a suspension of LAH
(0.23 g, 6.06 mmol) in THF (10 mL) was added a solution of 3
(1.0 g, 3.0 mmol) in THF (20 mL) at -78 °C under N2
atmosphere. This was allowed to stir at -78 °C for 30 min
and warm to room temperature over a period of 1 h. The
mixture was cooled to 0 °C and quenched with H2O. The
aqueous layer was extracted with ethyl acetate (2 × 30 mL).
The combined extracts were washed (brine), dried (Na2SO4),
filtered, and concentrated in vacuo. The product was recrystal-
lized from hexane/ethyl acetate (4:1) to give 0.9 g (89%) of 4b
as a colorless crystal: 1H NMR (CDCl3, 200 MHz) δ 7.88 (dd,
2H, J ) 8.4, 1.6 Hz), 7.64 (dd, 2H, J ) 8.4, 1.6 Hz), 7.46-7.31
(m, 6H), 6.98 (s, 1H), 4.65 (dd, 1H, J ) 8.2, 3.4 Hz), 2.86 (s,
3H), 2.02-1.96 (m, 2H), 1.74 (dd, 1H, J ) 12.4, 8.0 Hz), 1.50-
1.44 (m, 1H), 1.39-1.32 (m, 1H), 1.31 (s, 3H), 0.89-0.79 (m,
2H), -0.22 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ 139.06, 137.81,
130.41, 130.28, 128.28, 127.94, 127.74, 127.44, 127.33, 92.65,
80.14, 58.45, 52.49, 48.70, 47.96, 40.70, 29.66, 26.97, 21.65,
21.29; IR (film) 3402, 2937, 1040, 747 cm-1; HRMS m/z
routinely in CDCl3 on a Varian Gemini 2000 spectrometer.
exo-10,10-Dip h en yl-10-h yd r oxym et h yl-7,7-d im et h yl-
bicyclo[2.2.1]h ep ta n e-2-on e (2). To a solution of ketopinic
acid methyl ester 1 (10.0 g, 50.96 mmol) in THF (100 mL) was
added PhMgBr (203.84 mmol, 1.0 M solution in THF, 203.84
mL) dropwise at 0 °C under N2 atmosphere. The resulting
mixture was allowed to stir for 30 min and quenched with H2O/
ethyl acetate dropwise at 0 °C. The layers were separated, and
the aqueous layer was extracted with ethyl acetate (3 × 200
mL). The combined extracts were washed (brine), dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was
recrystallized from hexane/ethyl acetate (4:1) to give 14.5 g
(89%) of 2 as a colorless crystal: 1H NMR (CDCl3, 200
MHz) δ 7.45-7.19 (m, 10H), 3.84 (br, 1H), 2.55-2.48 (m,
1H), 2.45 (d, 1H, J ) 6.3 Hz), 2.29 (ddd, 1H, J ) 13.9, 9.3, 4.8
Hz), 1.96-1.87 (m, 2H), 1.77 (t, 1H, J ) 4.8 Hz), 1.41 (ddd,
1H, J ) 11.9, 9.3, 4.0 Hz), 1.06 (s, 3H), 0.26 (s, 3H); 13C NMR
(CDCl3, 50 MHz) δ 220.19, 147.25, 144.61, 129.23, 128.39,
127.39, 127.28, 126.99, 126.90, 79.98, 68.25, 50.37, 44.69,
43.69, 27.14, 25.76, 22.88, 21.88; IR (film) 3500, 2965, 1715
cm-1; HRMS m/z 320.1773 (calcd for C22H24O2 320.1776). Anal.
Calcd for C22H24O2: C, 82.46; H, 7.55. Found: C, 82.16; H,
7.58.
336.2097 (calcd for
23H28O2: C, 82.10; H, 8.39. Found: C, 82.14; H, 8.31.
Gen er a l P r oced u r e for th e P r ep a r a tion of R-Keto
C23H28O2 336.2089). Anal. Calcd for
C
exo-10,10-Dip h en yl-10-m et h oxym et h yl-7,7-d im et h yl-
bicyclo[2.2.1]h ep ta n e-2-on e (3). To a suspension of NaH
(0.22 g, 9.17 mmol) in THF (10 mL) was added a solution of
ketone 2 (1.0 g, 3.10 mmol) in THF (15 mL) dropwise at 0 °C.
This was followed by the addition of MeI (0.23 mL, 3.70 mmol)
dropwise. The resulting mixture was allowed to warm to room
temperature over a period of 30 min and quenched with H2O.
The aqueous layer was extracted with ethyl acetate (2 × 30
Ester s 5a a n d 5d . To a freshly prepared benzoylformic acid
chloride [benzoylformic acid (0.5 g, 3.33 mmol) and thionyl
chloride (20 mL) reacted at 65 °C for 1 h; excess thionyl
chloride removed in vacuo and the residue dried under a high
vacuum pump line for 10 min] in THF (15 mL) was added a
solution of 4a (0.3 g, 0.93 mmol) in THF (15 mL) dropwise at
0 °C under N2 atmosphere. The resulting mixture was stirred
for 4 h at 0 °C. This was quenched with saturated NaHSO3

Novel Camphor-Derived Chiral Auxiliaries
J . Org. Chem., Vol. 64, No. 19, 1999 6997
and extracted with ethyl acetate (1 × 30 mL). The organic layer
was washed (brine), dried (Na2SO4), filtered, and concentrated
in vacuo. The crude product was purified by flash column
chromatography, using hexane/ethyl acetate (10:1) as eluent,
to give 0.42 g (99%) of 5a as a white solid: 1H NMR (CDCl3,
200 MHz) δ 7.76-7.42 (m, 7H), 7.4 (d, 2H, J ) 7.5 Hz), 7.23-
7.06 (m, 6H), 5.49 (dd, 1H, J ) 7.3, 4.2 Hz), 3.83 (s, 1H), 2.38
(td, 1H, J ) 12.1, 4.2 Hz), 2.08-1.90 (m, 3H), 1.66-1.62 (m,
1H), 1.56 (s, 3H), 1.56 (buried, 1H), 1.21(ddd, 1H, J ) 11.9,
9.5, 4.2 Hz), 0.65 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ 184.72,
160.24, 149.14, 143.57, 134.98, 132.30, 130.49, 128.88, 128.72,
128.28, 126.99, 126.73, 126.44, 126.38, 83.46, 81.33, 59.44,
51.75, 47.95, 38.45, 31.26, 27.26, 24.68, 22.81; IR (film) 3596,
2932, 1734, 1681, 1198 cm-1; HRMS m/z 454.2134 (calcd for
C30H30O4 454.2144). Anal. Calcd for C30H30O4: C, 79.27; H,
6.65. Found: C, 79.59; H, 6.79. Crystal data for 5a at 22 °C:
Gen er a l P r oced u r e for th e Asym m etr ic Red u ction of
r-Keto Ester s 5. To a solution of 5a (0.12 g, 0.26 mmol) in
THF (2.0 mL) was added a solution of L-Selectride (0.26 mmol,
1.0 M in THF, 0.26 mL) dropwise at -78 °C under N2
atmosphere. The resulting mixture was stirred for 30 min and
quenched with H2O. The aqueous layer was extracted with
ethyl acetate (2 × 20 mL). The combined extracts were washed
(brine), dried (Na2SO4), filtered, and concentrated in vacuo.
The crude product was purified by flash column chromatog-
raphy, using hexane/ethyl acetate (16:1) as eluent, to give 0.11
g (92%) of 6a as a white solid: 1H NMR (CDCl3, 200 MHz) δ
7.81 (d, 2H, J ) 8.6 Hz), 7.55 (d, 2H, J ) 8.6 Hz), 7.42-7.07
(m, 11H), 5.15 (dd, 1H, J ) 8.1, 3.3 Hz), 4.57 (d, 1H, J ) 3.3
Hz), 3.26 (s, 1H), 3.13 (d, 1H, J ) 3.5 Hz), 2.23 (td, 1H, J )
12.3, 4.2 Hz), 2.04-1.80 (m, 2H), 1.60-1.40 (m, 2H), 1.36 (t,
1H, J ) 4.4 Hz), 1.13 (ddd, 1H, J ) 9.3, 8.1, 4.4 Hz), 0.90 (s,
3H), 0.56 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ 171.72, 149.41,
143.24, 137.96, 129.24, 129.02, 128.61, 128.36, 127.04, 126.99,
126.94, 126.44, 126.05, 83.85, 81.44, 73.11, 59.24, 51.55, 47.79,
38.37, 31.39, 27.08, 23.73, 22.65; IR (film) 3580, 2952, 1737,
1183, 749 cm-1; HRMS m/z 456.2296 (calcd for C30H32O4
406.2144). Anal. Calcd for C30H32O4: C 79.09; H 6.86. Found:
C 78.97; H 6.99.
C
30H30O4, M 454.54, monoclinic, P21, a )6.8806(1) Å, b
)14.0735(1) Å, c )12.8483(2) Å, V )1198.83 Å3, Z ) 2, λ )
0.71073 Å, F(000) ) 484, Dc ) 1.259 Mg/m3, µ ) 0.082 mm-1
8878 reflections, 308 parameters, R ) 0.0376, Rw ) 0.0890 for
all data.
,
5d : 1H NMR (CDCl3, 200 MHz) δ 7.78-7.60 (m, 7H), 7.47
(d, 2H, J ) 7.7 Hz), 7.26-7.21 (m, 6H), 5.12 (dd, 1H, J )
8.0, 3.6 Hz), 3.14 (td, 1H, J ) 16.7, 4.0 Hz), 2.72 (s, 3H),
2.02 (dd, 1H, J ) 13.2, 8.0 Hz), 1.77-1.68 (m, 3H), 1.49 (t,
1H, J ) 4.0 Hz), 1.15-1.09 (m, 1H), 0.99 (s, 3H), 0.26 (s, 3H);
13C NMR (CDCl3, 50 MHz) δ 185.99, 162.24, 140.46, 137.78,
134.60, 132.33, 131.79, 130.01, 129.75, 128.68, 127.55, 127.18,
126.73, 126.64, 86.66, 83.27, 61.65, 52.54, 49.26, 49.16, 39.24,
31.11, 25.93, 22.40, 21.54; IR (film) 3056, 2936, 1730, 1687,
1197, 703 cm-1; HRMS m/z 468.2303 (calcd for C31H32O4
468.2301). Anal. Calcd for C31H32O4: C, 79.46; H, 6.88.
Found: C, 79.63; H, 6.83. Crystal data for 5d at 22 °C:
6b: 1H NMR (CDCl3, 200 MHz) δ 7.73 (d, 2H, J ) 7.9 Hz),
7.59 (d, 2H, J ) 7.9 Hz), 7.31-7.09 (m, 6H), 5.26 (dd, 1H, J )
8.0, 3.6 Hz), 3.85 (q, 1H, J ) 7.0 Hz), 3.65 (br, 1H), 2.58 (br,
1H), 2.29 (td, 1H, J ) 12.3, 4.3 Hz), 2.03-1.95 (m, 2H), 1.82-
1.67 (m, 2H), 1.54-1.40 (m, 1H), 1.50 (s, 3H), 1.23 (d, 3H, J )
7.0 Hz), 1.23-1.20 (m, 1H), 0.65 (s, 3H); 13C NMR (CDCl3, 50
MHz) δ 173.02, 149.15, 143.13, 128.39, 128.29, 128.04, 126.83,
126.63, 126.24, 125.91, 82.80, 81.32, 66.30, 59.20, 51.46, 47.70,
38.40, 31.13, 26.93, 24.51, 22.50, 19.81; IR (film) 3520, 2989,
2939, 1738 cm-1; HRMS m/z 394.2148 (calcd for C25H30O4
394.2144). Anal. Calcd for C25H30O4: C, 76.11; H, 7.66.
Found: C, 76.01; H, 7.58.
C
31H32O4, M 468.57, orthorhombic, P212121, a ) 10.3404(1) Å,
b ) 14.8728(2) Å, c ) 16.7626(1) Å, V ) 2577.93 Å3, Z ) 4, λ
) 0.71073 Å, F(000) ) 1000, Dc ) 1.207 Mg/m3, µ ) 0.079
6c: 1H NMR (CDCl3, 200 MHz) δ 7.76 (d, 2H, J ) 7.5 Hz),
7.59 (d, 2H, J ) 7.5 Hz), 7.36-7.11 (m, 6H), 5.26 (dd, 1H, J )
7.9, 3.5 Hz), 3.71 (td, 1H, J ) 6.6, 4.5 Hz), 3.60 (s, 1H), 2.24
(td, 2H, J ) 12.0, 4.2 Hz), 1.97 (q, 2H, J ) 7.2 Hz), 1.82-1.52
(m, 4H), 1.49 (s, 3H), 1.52-1.43 (m, 1H), 1.25-1.16 (m, 1H),
0.86 (t, 3H, J ) 7.2 Hz), 0.65 (s, 3H); 13C NMR (CDCl3, 50
MHz) δ 172.67, 149.04, 143.08, 128.37, 128.08, 126.84, 126.65,
126.25, 125.85, 82.89, 81.32, 70.77, 59.18, 51.43, 47.70, 38.42,
31.12, 26.92, 26.84, 24.46, 22.51, 8.59; IR (film) 3541, 2968,
2880, 1730, 750 cm-1. Anal. Calcd for C26H32O4: C, 76.44; H,
7.90. Found: C, 76.44; H, 7.87.
mm-1, 14780 reflections, 317 parameters, R ) 0.0613, Rw
)
0.1045 for all data.
Gen er a l P r oced u r e for th e P r ep a r a tion of R-Keto
Ester s 5b a n d 5c. To a solution of oxalyl chloride (7.8 g, 61.60
mmol) in CH2Cl2 (200 mL) was added a solution of pyruvic
acid (5.5 g, 62.12 mmol) in DMF (0.01 mL) dropwise at 0 °C.
This was allowed to stir for 5 min at 0 °C, and the solvent
was removed in vacuo and under high vacuum pump line for
10 min. CH2Cl2 (50 mL) was added to the residue, and
transferred into a solution of 4a (2.0 g, 6.21 mmol) and Et3N
(6.27 g, 61.96 mmol) in CH2Cl2 (100 mL) dropwise at 0 °C.
The resulting mixture was stirred for 30 min and quenched
with H2O. The aqueous layer was extracted with ethyl acetate
(2 × 30 mL). The combined extracts were washed (brine), dried
(Na2SO4), filtered, and concentrated in vacuo. The crude
product was purified by flash column chromatography, using
hexane/ethyl acetate (10:1) as eluent, to give 1.4 g (57%) of 5b
as a colorless oil: 1H NMR (CDCl3, 200 MHz) δ 7.74-7.63 (m,
4H), 7.26-7.09 (m, 6H), 5.24 (dd, 1H, J ) 7.4, 4.2 Hz), 3.92 (s,
1H), 2.32 (td, 1H, J ) 11.5, 5.0 Hz), 2.18 (s, 3H), 2.04-2.02
(m, 1H), 1.92-1.88 (m, 1H), 1.86-1.78 (m, 2H), 1.54 (s, 3H),
1.54 (buried, 1H), 1.54-1.17 (m, 1H), 0.68 (s, 3H); 13C NMR
(CDCl3, 50 MHz) δ 190.55, 157.05, 148.18, 142.53, 128.50,
127.94, 127.39, 126.30, 126.01, 125.66, 82.66, 80.45, 58.92,
50.93, 47.23, 37.19, 30.50, 26.46, 25.20, 23.96, 21.96; IR (film)
3555, 2941, 1731, 1135, 749 cm-1; HRMS m/z 392.1983 (calcd
for C25H28O4 392.1988; Anal. Calcd for C25H28O4: C, 76.50; H,
7.19. Found: C, 76.70; H, 7.40.
7d : 1H NMR (CDCl3, 200 MHz) δ 7.53-7.51 (m, 2H), 7.48-
7.36 (m, 2H), 7.35-7.12 (m, 11H), 4.87 (s, 1H), 4.78 (dd, 1H, J
) 7.8, 2.8 Hz), 2.73-2.63 (m, 1H), 2.61 (s, 3H), 1.78 (dd, 1H,
J ) 13.2, 7.8 Hz), 1.62-1.47 (m, 2H), 1.38-1.33 (m, 1H), 1.05-
0.94 (m, 1H), 0.90 (s, 3H), 0.85-0.78 (m, 1H), 0.66 (s, 3H); 13
C
NMR (CDCl3, 50 MHz) δ 171.50, 139.40, 139.11, 131.15,
129.80, 128.71, 128.55, 127.36, 127.04, 126.96, 126.81, 87.93,
83.30, 74.15, 60.99, 52.57, 49.72, 49.09, 39.42, 31.24, 25.70,
22.89, 22.83; IR (film) 3502, 2937, 1727, 1054, 744 cm-1; HRMS
m/z 470.2455 (calcd for C31H34O4 470.2457). Crystal data for
7d at 23 °C: C31H34O4, M 470.58, orthorhombic, P212121, a )
11.3199(2) Å, b ) 13.16400(10) Å, c ) 17.2638(3) Å, V )
2572.57 Å3, Z ) 4, λ ) 0.71073 Å, F(000) ) 1008, Dc ) 1.215
Mg/m3, µ ) 0.079 mm-1, 10668 reflections, 316 parameters, R
) 0.1121, Rw ) 0.1998 for all data.
Gen er a l P r oced u r e for th e Asym m etr ic Red u ction of
R-Keto Ester s 5 in th e P r esen ce of Ad d itive. To a solution
of 5d (0.20 g, 0.43 mmol) and HMPA (0.09 mL, 0.51 mmol) in
THF (5 mL) was added a solution of L-Selectride (0.43 mmol,
1.0 M in THF, 0.43 mL) dropwise at -78 °C under N2
atmosphere. This was allowed to stir for 3 h and quenched
with H2O. The aqueous layer was extracted with ethyl acetate
(2 × 20 mL). The combined extracts were washed (brine), dried
(Na2SO4), filtered, and concentrated in vacuo. The crude
product was purified by flash column chromatography, using
hexane/ethyl acetate (10:1) as eluent, to give 0.15 g (75%) of
6d as a white solid: 1H NMR (CDCl3, 200 MHz) δ 7.77-7.74
(m, 2H), 7.52 (d, 2H, J ) 7.0 Hz), 7.42-7.37 (m, 6H), 7.28-
7.26 (m, 3H), 7.04-6.99 (m, 2H), 4.81 (dd, 1H, J ) 7.9, 3.3
5c: 1H NMR (CDCl3, 200 MHz) δ 7.73-7.68 (m, 4H), 7.27-
7.10 (m, 10 H), 5.25 (dd, 1H, J ) 7.6, 4.2 Hz), 3.94 (s, 1H),
2.57-2.45 (m, 2H), 2.31 (td, 1H, J ) 12.3, 4.2 Hz), 2.04-1.82
(m, 3H), 1.72-1.62 (m, 2H), 1.54 (s, 3H), 1.21-1.15 (m, 1H),
0.99 (t, 3H, J ) 7.2 Hz), 0.67 (s, 3H); 13C NMR (CDCl3, 50
MHz) δ 194.03, 157.69, 148.78, 143.12, 129.59, 128.47, 128.04,
127.84, 126.81, 126.49, 126.19, 83.02, 80.95, 59.42, 51.48,
47.76, 37.78, 31.83, 31.03, 26.66, 24.49, 23.00, 6.63; IR (film)
3558, 2940, 1731, 749 cm-1; HRMS m/z 406.2140 (calcd for
C
26H30O4 406.2144). Anal. Calcd for C26H30O4: C, 76.82; H,
7.44. Found: C, 76.69; H, 7.57.

6998 J . Org. Chem., Vol. 64, No. 19, 1999
Chu et al.
Hz), 4.68 (s, 1H), 3.43 (br, 1H), 2.80 (s, 3H), 2.67 (t, 1H, J )
10.9 Hz), 1.65-1.47 (m, 2H), 1.28-1.12 (m, 2H), 1.09 (s, 3H),
0.88-0.81 (m, 2H), 0.34 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ
172.49, 139.88, 138.94, 137.79, 131.48, 129.42, 128.37, 128.30,
127.49, 127.11, 127.04, 126.86, 126.73, 87.70, 82.59, 72.61,
60.83, 52.67, 50.09, 48.73, 38.49, 31.40, 25.12, 22.94, 22.87;
IR (film) 3508, 2934, 1727, 1184, 742 cm-1; HRMS m/z
(brine), dried (Na2SO4), filtered, and concentrated in vacuo.
The crude product was purifed by flash column chromatogra-
phy, using hexane/ethyl acetate (4:1) as eluent, to give 39.3
mg (84%) of 8a : [R]D +145.0° (c 2.8, H2O).
Ack n ow led gm en t. Financial support by the Na-
tional Science Council of the Republic of China and
collection and processing of X-ray data by Taipei In-
strumentation Center, College of Science (National
Taiwan University) are gratefully acknowledged. The
(1S)-(+)-10-camphorsulfonic acid was provided by the
China Camphor Co.
470.2456 (calcd for
31H34O4: C, 79.12; H, 7.28. Found: C, 79.04; H, 7.39.
Gen er a l P r oced u r e for th e Hyd r olysis of r-Hyd r oxyl
C31H34O4 470.2457). Anal. Calcd for
C
Ester s 6a -c. To a solution of 6a (0.14 g, 0.31 mmol) in THF/
H2O (10 mL, 1:1) was added LiOH (50.3 mg, 1.20 mmol)
portionwise at room temperature. The resulting mixture was
stirred for 2 h. The organic solvent was removed in vacuo, and
the residue was extracted with ethyl acetate (2 × 20 mL). The
combined extracts were washed (brine), dried (Na2SO4), fil-
tered, and concentrated in vacuo. The crude product was
purified by flash column chromatography, using hexane/ethyl
acetate (10:1) as eluent, to give 98 mg (97%) of 4a as a white
foam (recovered 4a : [R]D +164.8° (c 1.0, CHCl3); original
compound 4a : [R]D +166.1° (c 1.0, CHCl3)).3 The aqueous layer
was acidified (pH ) 1) with 2 N HCl and extracted with ethyl
acetate (3 × 20 mL). The combined extracts were washed
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 2, 3, 4a , 4b, 5a -d , 6a -d , and 7d and
X-ray crystallographic data (table of atomic coordinates,
hydrogen coordinates, bond lengths and angles and ORTEP
diagrams) for structures 5a , 5d , and 7d . This material is
available free of charge via the Internet at http://pubs.acs.org.
J O9902188