Chiral tricyclic iminolactone derived from (1R)-(+)-camphor as a glycine equivalent for the asymmetric synthesis of α-amino acids

Article abstract of DOI:10.1021/jo011139a

The development of a highly efficient and stereoselective methodology for the preparation of α-amino acids is described. The chiral template, tricyclic iminolactone 7, was synthesized from (1R)-(+)-camphor in five steps in 50% overall yield. Alkylation of iminolactone 7 afforded the α-monosubstituted products in good yields (74-96%) and excellent diastereoselectivities (>98%). Hydrolysis of the alkylated iminolactones furnished the desired α-amino acids in good yields and enantioselectivities with nearly quantitative recovery of the chiral auxiliary 4.

Full text of DOI:10.1021/jo011139a

J . Org. Chem. 2002, 67, 2309-2314
2309
Ch ir a l Tr icyclic Im in ola cton e Der ived fr om (1R)-(+)-Ca m p h or a s a
Glycin e Equ iva len t for th e Asym m etr ic Syn th esis of
r-Am in o Acid s
Peng-Fei Xu,† Yuan-Shek Chen,‡ Shu-I Lin,‡ and Ta-J ung Lu*,‡
College of Chemistry and Chemical Engineering,
National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, PRC,
and Department of Chemistry, National Chung-Hsing University, Taichung, Taiwan 40227, ROC
tjlu@dragon.nchu.edu.tw
Received December 11, 2001
The development of a highly efficient and stereoselective methodology for the preparation of R-amino
acids is described. The chiral template, tricyclic iminolactone 7, was synthesized from (1R)-(+)-
camphor in five steps in 50% overall yield. Alkylation of iminolactone 7 afforded the R-monosub-
stituted products in good yields (74-96%) and excellent diastereoselectivities (>98%). Hydrolysis
of the alkylated iminolactones furnished the desired R-amino acids in good yields and enantiose-
lectivities with nearly quantitative recovery of the chiral auxiliary 4.
In tr od u ction
material in asymmetric synthesis,6 as chiral auxiliaries.
In developing an asymmetric glycine equivalent, we
focused our attention on the camphor-based tricyclic
iminolactone 7 for the following reasons: (1) A cyclic
system will allow for a more rigid transition state than
the corresponding acyclic one, which could enhance the
steric effect of the auxiliary in controlling the stereo-
chemistry of the reaction. (2) Unlike acyclic esters,
lactones give rise to only the Z-enolates, which in turn
will provide a single alkylated product if the electrophile
approaches specifically from one of the enolate reaction
faces. (3) The C12-methyl group of camphor could block
the top face of the alkylation step and thus result in good
stereoselectivity. (4) Both the imine and the lactone
functionalities can be hydrolyzed easily to form the amino
acids with the possibility of recovering the chiral auxil-
iary. (5) Camphor is inexpensive and readily available.
Therefore, iminolactone 7 is expected to form a rigid
transition state upon deprotonation and the electrophile
is expected to come in from the less hindered bottom side
of the lactone to produce the alkylated product in high
diastereomeric purity. We now report a practical and
highly stereoselective route to the synthesis of R-amino
acids via this tricyclic iminolactone derivative of camphor.
Nonproteinogenic amino acids have received tremen-
dous attention recently.1 They are widely used for
biological, biochemical, and pharmaceutical studies.2
They have also been utilized as chiral starting materials
in organic synthesis and for the preparation of chiral
auxiliaries.3 Rapid progress in the development of active
peptides requires the ready availability of a large number
of structurally diverse D-amino acids.4 Consequently, an
efficient and convenient general method for the prepara-
tion of optically pure enantiomers of R-substituted R-ami-
no acids would be of general interest.5
As part of our effort to develop synthetic procedures
for the preparation of optically active R-amino acids, we
have investigated the utility of compounds derived from
camphor, a versatile and inexpensive chiral starting
† Lanzhou University.
‡ National Chung-Hsing University.
(1) (a) Abella´n, T.; Chinchilla, R.; Galindo, N.; Na´jera, C.; Sansano,
J . M. J . Heterocycl. Chem. 2000, 37, 467. (b) Ishitani, H.; Komiyama,
S.; Hasegawa, Y.; Kobayashi, S. J . Am. Chem. Soc. 2000, 122, 762. (c)
Alonso, D. A.; Bertilsson, S. K.; J ohnsson, S. Y.; Nordin, S. J . M.;
So¨dergren, M. J .; Andersson, P. G. J . Org. Chem. 1999, 64, 2276. (d)
Bergmeier, S. C.; Stanchina, D. M. J . Org. Chem. 1999, 64, 2852. (e)
Chinchilla, R.; Galindo, N.; Na´jera, C. Tetrahedron: Asymmetry 1998,
9, 2769. (f) Beller, M.; Eckert, M.; Geissler, H.; Napierski, B.;
Rebenstock, H. P.; Holla, E. W. Chem. Eur. J . 1998, 4, 935. (g) Tanaka,
K.; Ahn, M.; Watanabe, Y.; Fuji, K. Tetrahedron: Asymmetry 1996, 7,
1771. (h) Ohfune, Y. Acc. Chem. Res. 1992, 25, 360.
(2) (a) Shibasaki, M. Yakugaku Zasshi-J . Pharm. Soc. J . 2000, 120,
76. (b) Bravo, P.; Bruche, L.; Crucianelli, M.; Viani, M.; Zanda, M. ACS.
Symp. Ser. 2000, 746, 98. (c) Bonner, G. G.; Davis, P.; Stropova, D.;
Edsall, S.; Yamamura, H. I.; Porreca, F.; Hruby, V. J . J . Med. Chem.
2000, 43, 569. (d) Lundquist, J . T.; Dix, T. A. J . Med. Chem. 1999, 42,
4914. (e) Zhang, D.; Miller, M. J . Curr. Pharm. Design 1999, 5, 73. (f)
Nishitani, H.; Sasaoka, A.; Tokumasu, M.; Ohkata, K. Heterocycles
1999, 50, 35. (g) Bommarius, A. S.; Schwarm, M.; Drauz, K. J . Mol.
Catal. B-Enzym. 1998, 5, 1. (h) Barrett, G. C. Chemistry and Biochem-
istry of the Amino Acids; Chapman and Hall: London, 1985.
(3) (a) Studer, A. Synthesis 1996, 793. (b) Reetz, M. T. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 1531. (c) Coppola, G. M.; Schuster, H. F.
Asymmetric Synthesis: Construction of Chiral Molecules Using Amino
Acid; Wiley: New York, 1987.
(5) For reviews on the asymmetric synthesis of R-amino acids, see:
(a) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000,
11, 645. (b) Williams, R. M. Methods Mol. Med. 1999, 23, 339. (c)
Palomo, C.; Aizpurua, J . M.; Ganboa, I.; Oiarbide, M. Amino Acids
1999, 16, 321. (d) Calmes, M.; Daunis, J . Amino Acids 1999, 16, 215.
(e) Seebach, D.; Hoffmann, M. Eur. J . Org. Chem. 1998, 1337. (f) Wirth,
T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225. (g) Meffre, P.; Le Goffic,
F. Amino Acids 1996, 11, 313. (h) North, M. Contemp. Org. Synth.
1996, 3, 323. (i) Duthaler, R. O. Tetrahedron 1994, 50, 1539. (j) Cintas,
P. Tetrahedron 1991, 47, 6079. (k) Lu, T.-J . Chemistry (The Chinese
Chem. Soc., Taiwan China) 1992, 50, 51. (l) Williams, R. M. Synthesis
of Optically Active Amino Acids; Pergamon Press: Oxford, 1989. (m)
El Achqar, A.; Boumzebra, M.; Roumestant, M.-L.; Viallefont, P.
Tetrahedron 1988, 44, 5319 and references cited therein.
(6) (a) Miyabe, H.; Konishi, C.; Naito, T. Org. Lett. 2000, 2, 1443.
(b) Yao, Z. J .; Gao, Y.; Burke, T. R. Tetrahedron: Asymmetry 1999, 10,
3727. (c) Verdaguer, X.; Marchueta, I.; Tormo, J .; Moyano, A.; Perica`s,
M. A.; Riera, A. Helv. Chim. Acta 1998, 81, 78. (d) Yeh, T.-L.; Liao,
C.-C.; Uang, B.-J . Tetrahedron 1997, 53, 11141. (e) Dondoni, A.;
Merchan, F. L.; Merino, P.; Rojo, I.; Tejero, T. Synthesis 1996, 641. (f)
Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241 and references therein.
(4) (a) Myers, A. G.; Gleason, J . L.; Yoon, T.; Kung, D. W. J . Am.
Chem. Soc. 1997, 119, 656. (b) Drauz, K., Kottenhahn, M.; Makryaleas,
K., Klenk, H.; Bernd, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 712
and references therein.
10.1021/jo011139a CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/09/2002

2310 J . Org. Chem., Vol. 67, No. 7, 2002
Xu et al.
Ta ble 1. Alk yla tion of th e Tr icyclic Im in ola cton e 7
Sch em e 1. Syn th esis of Im in ola cton e 7a
yielda
(%)
%
entry
solvent
base
E+
endo/exob de
1
2
3
THF/HMPA KOBut CH3I
71
81
58
3:1
>99:1
>99:1
50
>98
>98
a
THF/HMPA LDA
CH3I
Key: (a) SeO2/Ac2O, reflux, 17 h, 100%; (b) ethylene glycol,
THF/HMPA KOBut CH2dCH-
TsOH, benzene, 78%; (c) NaBH4, Et2O/CH3OH (1:1); (d) cold
H2SO4, 94%; (e) Z-GlyOH, DMAP, DCC, THF, rt, 16 h, 98%; (f)
H2 (1 atm), Pd/C, room temperature, 14 h.
CH2Br
4
THF/HMPA LDA
CH2dCH-
93
>99:1
>98
CH2Br
5
6
7
8
9
THF/HMPA KOBut C6H5CH2Br 85c
1.2:1.3
1:>99 >98
THF
KOBut C6H5CH2Br 58d
The synthesis of tricyclic iminolactone 7 from camphor
is outlined in Scheme 1. Thus, (1R)-(+)-camphor was first
treated with selenium dioxide to give (1R)-(+)-cam-
phorquinone (2) as a yellow solid in quantitative yield.7
Selective acetalization of the less hindered carbonyl group
was then accomplished using ethylene glycol and a
catalytic amount of p-toluenesulfonic acid in benzene
with azeotropic removal of water to afford the desired
monoacetal 3 in 78% yield.8,9 The remaining carbonyl
group was then reduced with sodium borohydride at ca.
0 °C followed by the removal of the acetal with aqueous
sulfuric acid to give the 2-exo-hydroxyepicamphor (4) as
the sole isomer in 94% isolated yield.10 Hydroxyketone 4
was then treated with N-Cbz-glycine, DCC, and DMAP
in dry THF to furnish ester 5 in quantitative yield after
column chromatography. The Cbz group was removed by
hydrogenolysis in absolute ethanol under a hydrogen
atmosphere (1 atm) using 5% palladium on carbon as
catalyst for 14 h. Concomitant cyclization to the imine
occurred simultaneously during hydrogenation to give
rise to the desired chiral template 7 in 76% isolated yield
over two steps.11,12
THF/HMPA n-BuLi C6H5CH2Br 51 (75)e >99:1
>98
>98
>98
THF
LDA
C6H5CH2Br 59 (81)e >99:1
C6H5CH2Br 83 (96)e >99:1
THF/HMPA LDA
a
The reported yields are isolated yields after column chroma-
b
tography. The ratios were estimated by NMR integrations of the
crude reaction mixtures on a Varian Mercury-400 NMR spectrom-
eter. c The yield is composed of endo, exo, and dialkylated products
d
in a ratio of 1.2:1.3:1. The yield is composed of exo and dialkyl-
ated products in a 1.4:1 ratio. e The yields in parentheses are based
on recovered starting material.
Hz) due to the lack of long-range coupling between it and
the C2-H. (b) The C5endo-H (3.88 ppm), on the other hand,
appeared as a doublet of doublets (J ) 18.0, 1.6 Hz). The
long-range coupling is possible for this proton since the
C-H bond is nearly parallel to the π-orbital of the imine
double bond, which in turn is almost parallel to the C2-H
bond. (c) The C2-H of compound 7 is a doublet (J ) 1.6
Hz) because it couples with the C5endo-H. The exception-
ally large difference (∆∆δ ) 0.66 ppm) between the
chemical shifts of the two C5-protons on the lactone ring
suggests that the chemical environments of the two
protons are considerably different.
The assignment of the C5endo-H and the C5exo-H of
compound 7 was based on the following observations: (a)
The C5exo-H (4.54 ppm) of the iminolactone 7 was a
doublet with a large geminal coupling constant (J ) 18.0
Alkylation of the tricyclic iminolactone 7 was carried
out at -78 °C using various combinations of different
bases, solvent systems, additives, and electrophiles. The
results of the alkylation reactions of the enolate of 7 were
strongly dependent on the reaction conditions employed.
The electrophile was injected slowly using a syringe
pump with the needle contacting the wall of the neck,
and thus, the reagent was dripped along the flask wall
to cool it to the reaction temperature before the electro-
phile reached the reaction mixture.13 The results in Table
1 clearly show that the combination of lithium diisopro-
pylamide (LDA) and HMPA gave the best yields. In every
case except one, extremely high diastereoselectivity was
realized.14
(7) Meyer, W. L.; Lobo, A. P.; McCarty, R. N. J . Org. Chem. 1967,
32, 1754.
(8) (a) Martin, K. E.; Bernard, T, G.; Antony, B. M.; William, P. W.
J . Chem. Soc., Perkin Trans. 1 1991, 747. (b) Fleming, I.; Woodward,
R. B. J . Chem. Soc. C 1968, 1289.
(9) Approximately 16% of the diacetal was also obtained in the
reaction, which can be hydrolyzed to regenerate camphorquinone. As
a result, the yield of the C3 carbonyl monoprotected camphorquinone
is 95% based on recovered camphorquinone. Under milder conditions,
the diacetal can be converted selectively to a monoacetal with the more
hindered carbonyl group being protected (2-acetal), which can be
utilized to prepare R-amino acids of the opposite configuration.
(10) The exo-stereochemistry of the hydroxyl group in compound 4
was verified by the absence of long-range coupling between the C2-H,
which exists as a singlet, and C6-H because the C2-H cannot form a
W-shaped conformer with the C6exo-H and is parallel to the C6endo-H.
Therefore, the C2-H and C6-H do not have a long-range coupling.
(11) Intermediate 6 was obtained as its hydrochloride salt by adding
a few drops of 2 N hydrochloric acid when the hydrogenation was
interrupted after 2 h. The structure of intermediate 6 was confirmed
by both NMR and MS spectra.
The stereochemistry of the two monomethylation prod-
ucts was revealed by the NMR coupling pattern of the
(13) This proved to be crucial in obtaining a high diastereoselectivity
since direct addition of the alkyl halide to the reaction resulted in a
significant loss of stereoselectivity.
(14) This served as a strong indication that the alkylation of the
enolate occurred exclusively from the bottom face. The NMR spectrum
of the crude methylation reaction was carefully examined and there
was no sign of the exo-methylated product within the NMR detection
limits.
(12) All new compounds gave satisfactory analytical and spectral
data. The elemental composition of all new compounds was established
by combustion or mass spectrometric analysis.

Asymmetric Synthesis of R-Amino Acids
J . Org. Chem., Vol. 67, No. 7, 2002 2311
Ta ble 2. Alk yla tion of Im in ola cton e 7a
T
yieldb
(%)
%
entry (°C)
E+
products endo/exoc de
1
2
3
4
5
6
7
8
9
-78 CH3I
81
8a + 9a
8b + 9b
8c + 9c
>99:1
>99:1
6:1
>99:1
>99:1
>99:1
>99:1
95:5
>98
>98
71
>98
>98
>98
>98
90
-78 CH2dCHCH2Br 93
-30 C6H5CH2Br
-78 C6H5CH2Br
-78 CH3CH2I
86
83 (96)d 8c + 9c
74
8d + 9d
-78 CH3(CH2)2I
-78 CH3(CH2)3I
-78 (CH3)2CdO
59 (88)d 8e + 9e
52 (84)d 8f + 9f
68
8g + 9g
8h + 9h
-78 CH2dCHCO2But 74
>99:1
>98
a
The reaction was carried out in THF/HMPA with LDA as the
b
base. The reported yields are isolated yields after column chro-
matograph. c The ratios were estimated by NMR integrations of
the crude reaction mixtures on
spectrometer. The yields in parentheses are based on recovered
starting material.
a Varian Mercury-400 NMR
d
F igu r e 1. X-ray structure of compound 7.
C
5exo-H and C5endo-H. The C5endo-H of the exo-methylated
product is a quartet of doublets (3.84 ppm, J ) 7.2, 1.2
Hz) while the C2-proton is a doublet (4.33 ppm, J ) 1.2
Hz). Long-range coupling between the C5endo proton and
C2-proton is allowed only when the two protons are
parallel to each other as well as to the π-orbital of the
imine double bond in this rigid ring system. Thus, the
existence of long-range coupling between these two
protons indicates that the methyl group is exo. On the
contrary, the C5exo-proton of the endo product appears as
a quartet (4.55 ppm, J ) 7.6 Hz) while the C2-proton
appears as a singlet (4.37 ppm). The absence of long-
range coupling supports the assignment of an endo-
methyl group.
Likewise, the stereochemistry of the two endo- and exo-
monobenzylated products also can be determined by the
NMR coupling pattern of the C5exo-H and C5endo-H. The
F igu r e 2. X-ray structure of compound 8g.
C
5endo-H of the exo product 9c is a doublet of doublets of
temperature seems to play an important role in deter-
mining the facial selectivity, as much lower diastereo-
meric ratio was obtained when the reaction was per-
formed at -30 °C (Table 2, entry 3). In addition, the aldol
reaction and Michael addition of the enolate also deliv-
ered the desired products smoothly with good facial
selectivities (Table 2, entries 8 and 9) demonstrating the
generality of the reaction.
X-ray crystallographic determination of single crystals
of compounds 7 and 8g, obtained by recrystallization from
a mixture of ethyl acetate and hexane, provided the
structures presented in Figure 1 and Figure 2.15 A salient
feature in the crystallographic structure in Figure 1 is
that the iminolactone ring fused with the rigid camphor
skeleton is in a boat conformation with the C2-proton and
the C5endo-proton being at the flagpole positions. The
aforementioned two hydrogens are both parallel to the
π-orbitals of the CdN double bond, which supports the
above assigned NMR coupling pattern. In addition, the
stereochemistry of the alkylated iminolactones is con-
firmed unequivocally by the fact that the hydroxypropyl
group of compound 8g is at the endo position in its X-ray
structure.
doublets (3.95 ppm, J ) 1.2, 4.4, 4.8 Hz) and the
C2-proton is a doublet (4.27 ppm, J ) 1.2 Hz). Further-
more, the chemical shift of the C2-proton is close to that
of the exo-methylated product (4.27 vs 4.33 ppm). On the
other hand, the C5exo-proton of the endo-benzylated
product appears as a doublet of doublets (4.84 ppm, J )
4.8, 5.4 Hz) while the C2-proton appears as a singlet (2.51
ppm). The chemical shift of the C2-proton is 1.76 ppm
higher field than that of the corresponding endo-methyl-
ated compound, presumably due to the shielding effect
of the phenyl group, which serves as a further evidence
for the endo stereochemistry of the benzyl group.
It is noteworthy that methylation of compound 7 using
KOBut as the base at -78 °C resulted in considerably
lower facial selectivity (8a /9a ) 3/1) compared to that
utilizing LDA (Table 1, entries 1 and 2). Similarly,
benzylation of iminolactone 7 with KOBut resulted in a
reversal of stereoselectivity but with a poor diastereo-
meric ratio (8c/9c ) 1.2/1.3) (Table 1, entry 5). Further-
more, complete reversal of stereochemistry of the ben-
zylated product was observed when the reaction was
performed in THF alone (Table 1, entry 6). On the
contrary, extremely high diastereoselectivity was achieved
in allylation regardless of the base used (Table 1, entries
3 and 4).
Hydrolysis of the alkylated iminolactones in 8 N HCl
solution at 87 °C for 2 h16 afforded the corresponding D-R-
amino acids in good yields and enantiomeric excesses
(Table 3). The R-configuration of the resulting amino
The alkylation was then conducted using the optimum
reaction conditions developed in Table 1. As summarized
in Table 2, the alkylation reaction generated the mono-
alkylated products in high yields with very high control
of the stereochemistry of the newly formed stereocenter
for a wide range of electrophiles. Moreover, the reaction
(15) Burnett, M. N.; J ohnson, C. K. ORTEP-III: Oak Ridge
Thermal Ellipsoid Plot Program for Crystal Structure Illustrations,
Oak Ridge National Laboratory Report ORNL-6895, 1996.
(16) Chinchilla, R.; Falvello, L. R.; Galindo, N.; Na´jera, C. Tetrahe-
dron: Asymmetry 1998, 9, 2223.

2312 J . Org. Chem., Vol. 67, No. 7, 2002
Xu et al.
Ta ble 3. Hyd r olysis of th e Alk yla ted Im in ola cton es 8
R-amino acids obtained from hydrolysis of the alkylated
iminolactones was determined by measuring the optical rota-
tion of the amino acids or by HPLC analysis on a Crownpak
CR(+) column. X-ray data were collected on a Bruker CCD
Smart-1000 diffractometer equipped with graphite-monochro-
mator Mo KR radiation (λ ) 0.710 73 Å).
Ca m p h or qu in on e (2).8a To a 250 mL flask were added
sequentially acetic anhydride (50 mL), (1R)-(+)-camphor (30.42
g, 200 mmol), and selenium dioxide (51.04 g, 460 mmol). The
mixture was heated to reflux (oil bath temperature ca. 170
°C) for 17 h. The reaction was then cooled to room temperature
and filtered to remove the black selenium precipitate. Addition
of cold water to the filtrate, cooled in an ice bath, resulted in
the precipitation of a yellow solid, and the mixture was stirred
for another 5 min. The yellow solids were filtered and washed
with cold water. The filtrate was neutralized with saturated
aqueous sodium hydroxide and then extracted with dichlo-
romethane. The organic layer was washed with brine, dried
(MgSO4), and filtered and solvent removed to afford cam-
phorquinone as a yellow solid that was combined with the
previous precipitate (33.1 g, 99.6%). The 1H NMR of the
camphorquinone indicated that the crude camphorquinone is
pure enough for the subsequent reactions and therefore was
amino
recovered
entry
R
acid (%) auxiliary (%) eea (%) [R]22
D
1
2
3
CH3
70
78
82
94
97
97
94
98
96
-9.0b
+36.4c
+33.7c
CH2dCHCH2
C6H5CH2
a
Ee values were determined by HPLC analysis utilizing a
b
Daicel Crownpak CR(+) column. The optical rotations were
measured in 2 N HCl solution on a Perkin-Elmer PE-241 pola-
rimeter. c The optical rotations were recorded in H2O solution.
acids, determined by comparing the optical rotation of
the products with literature values, is in accord with the
assigned stereochemistry of the alkylated iminolactones.
In addition, the chiral auxiliary 4 was also recovered in
excellent yield. The configuration of the R-amino acids
is in agreement with that assigned to the respective
precursors. The recovered chiral auxiliary 4 was recycled
to prepare the iminolactone 7, which exhibited the same
optical purity as that of the one derived from freshly
synthesized compound 4.
1
used without further purification: mp 197-198 °C; H NMR
(CDCl3) δ 2.64 (d, J ) 5.6 Hz, 1H), 2.08∼2.28 (m, 1H), 1.99-
1.82 (m, 1H), 1.71-1.56 (m, 2H), 1.11 (s, 3H), 1.07 (s, 3H), 0.94
(s, 3H); IR (NaCl, CHCl3) 3040 (m), 2980 (m), 1775 (m), 1760
(s) cm-1; HRMS m/z calcd for C10H14O2 M+ 166.0994, found
M+ 166.0987.
(1R,4S)-(-)-1,7,7-Tr im et h yl-3,3-et h ylen ed ioxyb icyclo-
[2.2.1]h ep ta n -2-on e (3).8b A solution of camphorquinone (8.32
g, 50 mmol), p-toluenesulfonic acid monohydrate (0.48 g, 2.5
mmol). and ethylene glycol (4 mL, 71.8 mmol) in benzene (60
mL) was heated under reflux using a Dean-Stark trap for 24
h. Benzene was removed, and the residue was dissolved in
EtOAc (40 mL). The solution was washed successively with
saturated aqueous NaHCO3 and water, dried (MgSO4), and
filtered and solvent removed. Column chromatography (EtOAc/
hexane ) 1:20) afforded the desired acetal (8.20 g, 78%) and
the over-protected diacetal (2.10 g, 16%). Acetal: mp 83-85
°C; 1H NMR (CDCl3) δ 4.34-4.28 (m, 1H), 4.21-4.15 (m, 1H),
4.06-3.95 (m, 2H), 2.03-1.94 (m, 1H), 1.96 (d, J ) 4.8 Hz,
1H), 1.87-1.76 (m, 1H), 1.72-1.53 (m, 2H), 1.02 (s, 3H), 0.98
(s, 3H), 0.91 (s, 3H); IR (NaCl, CHCl3) 2971 (s), 2899 (m), 1752
(s) cm-1; HRMS m/z calcd for C12H18O3 M+ 210.1250, found
M+ 210.1256. Diacetal: mp 59-60 °C; IR (NaCl, CHCl3) 2961
In summary, an efficient and practical method for the
preparation of R-amino acids starting from inexpensive
and readily available (1R)-(+)-camphor has been devel-
oped. Good chemical yields and excellent diastereoselec-
tivities were realized to produce the R-amino acids in high
optical purity. The fact that the chiral auxiliary can be
recycled without loss of optical integrity renders the
present method an economical method for the prepara-
tion of R-monosubstituted R-amino acids. The preparation
of R-amino acids of the opposite configuration can be
achieved by starting from the (1S)-(-)-camphor. Conse-
quently, our method is amenable to the synthesis of
R-amino acids of either stereochemistry.
Exp er im en ta l Section
(m), 2893 (m) cm-1 1H NMR (CDCl3) δ 3.98-3.75 (m, 8H),
;
1.99-1.92 (m, 1H), 1.83-1.77 (m, 1H), 1.69 (d, J ) 4.8 Hz,
1H), 1.59-1.52 (m, 1H), 1.39-1.32 (m, 1H), 1.18 (s, 3H), 0.87
(s, 3H), 0.80 (s, 3H); 13C NMR (CDCl3) δ 114.8, 113.8, 65.9,
65.0, 64.5, 64.2, 53.3, 52.7, 44.5, 29.3, 21.0, 20.9, 20.7, 9.8; MS
m/z 254 (M+, 23.5), 239 (10.5), 170 (15.9), 141 (56.0), 127 (55.8),
113 (100.0), 99 (96.3), 69 (49.3), 55 (55.3), 53 (16.0).
Gen er a l Meth od s. All alkylation reactions were conducted
in flame-dried round-bottom or modified long-neck flasks fitted
with rubber septa under an argon atmosphere unless other-
wise noted. Solvents and reagents were dried prior to use as
required. Diisopropylamine and hexamethylphosphoric tria-
mide (HMPA) were distilled from calcium hydride immediately
prior to use, THF was distilled from sodium benzophenone
ketyl, n-butylithium in hexane (nominally 1.6 M) was pur-
chased from Aldrich and titrated17 before each use. Thin-layer
chromatography plates visualized by exposure to ultraviolet
light and/or immersion in a staining solution (phosphomolybdic
acid) followed by heating on a hot plate. Flash chromatography
was carried out utilizing silica gel 60, 70-230 mesh ASTM.
Medium-pressure liquid chromatography was carried out using
Merck Lobar prepacked silica gel columns and a Fluid Meter-
(1S ,3S ,4R )-3-H yd r oxy-4,7,7-t r im e t h ylb icyclo[2.2.1]-
h ep ta n -2-on e (4).3 To a solution of acetal 3 (5.80 g 27.6 mmol)
in ether (30 mL) and methanol (30 mL), cooled in an ice bath,
was added sodium borohydride (1.26 g) in small batches over
10 min. The reaction mixture was stirred in an ice bath for
3.5 h. The reaction was washed with water, and the organic
layer was evaporated to leave an oil that was cooled to about
0 °C and was mixed with ice-cold concentrated sulfuric acid-
water (v/v ) 1:1, 60 mL). Ice (10 g) was added after 15 min,
and the mixture was extracted with ether. The ether layer was
washed with brine and water, dried (MgSO4), and filtered and
solvent evaporated while the bath temperature of the rotary
evaporator was kept under 30 °C to give the 2-exo-hydrox-
yepicamphor as a white powder (4.36 g, 94%): mp 218-220
1
ing, Inc., FMI Lab Pump. Melting points are uncorrected. H
NMR spectra were recorded at 400 or 600 MHz; 13C NMR
spectra were recorded at 100 or 150 MHz. Chloroform (δ )
7.27 ppm) or deuterium oxide (δ ) 4.63 ppm) was used as
internal standard in 1H NMR spectra. The center peak of
deuteriochloroform (δ ) 77.0 ppm) was used as internal
standard in 13C NMR spectra. Mass spectra (EI) were obtained
at 70 eV. The optical rotations were measured in CHCl3
solution with a cuvette of 1 dm length. The ee value of the
1
°C; IR (NaCl, CHCl3) 3444 (br), 2959 (m), 1746 (s) cm-1; H
NMR (CDCl3) δ 3.54 (d, J ) 2.8 Hz, 1H), 2.32 (d, J ) 2.8 Hz,
1H), 2.17 (d, J ) 4.4 Hz, 1H), 1.96-1.82 (m, 2H), 1.47-1.35
(m, 2H), 1.04 (s, 3H), 1.03 (s, 3H), 0.94 (s, 3H); 13C NMR
(CDCl3) δ 79.5, 58.6, 49.2, 46.5, 33.9, 21.1, 20.3, 18.8, 10.2;
MS m/z 168 (M+, 53.8), 153 (3.0), 140 (12.0), 125 (31.6), 107
(7.3), 100 (11.7), 83 (100.0), 69 (23.4), 55 (25.4), 53 (3.8).
(17) Winkle, M. R.; Lansinger, J . M.; Ronald, R. C. J . Chem. Soc.,
Chem. Commun. 1980, 87.

Asymmetric Synthesis of R-Amino Acids
J . Org. Chem., Vol. 67, No. 7, 2002 2313
(1R,2S,4S)-Ben zyloxyca r bon yla m in oa cetic Acid 1,7,7-
Tr im eth yl-3-oxobicyclo[2.2.1]h ep t-2-yl Ester (5). A solu-
tion of 2-exo-hydroxyepicamphor (5.09 g, 30.2 mmol), Cbz-
glycine (7.58 g, 36.3 mmol, 1.2 equiv), and 4-N,N-(dimeth-
ylamino)pyridine (DMAP, 1.85 g, 15.1 mmol, 0.5 equiv) in THF
(120 mL) in a 250 mL flask was stirred at 0 °C for 15 min,
and dicyclohexylcarbodiimide (DCC, 9.35 g, 45.4 mmol, 1.5
equiv) in THF (30 mL) was then added dropwise to the solution
via a syringe. The reaction was stirred at 0 °C for 2 h and
then at room temperature for 16 h. Precipitated 1,3-dicyclo-
hexylurea (DCU) was removed by filtration and the filtrate
concentrated under reduced pressure. Purification by flash
column chromatography (EtOAc/hexane ) 1:8) gave the ester
as a colorless viscous oil (10.73 g, 98.8%). The oil solidified
upon standing or evacuating with a vacuum pump: mp 72-
74 °C; IR (NaCl, CHCl3) 3360 (br), 2961 (m), 1758 (s), 1750 (s)
To the freshly prepared LDA solution, the same alkylation
procedures used above were followed to provide the desired
products.
(1R,2S,5R,8S)-1,5,11,11-Tetr am eth yl-3-oxa-6-azatr icyclo-
[6.2.1.02,7]u n d ec-6-en -4-on e (8a ): [R]22 -85.6 (c )1.09,
D
CHCl3); Rf 0.23 (hexane/EtOAc ) 2/1); mp 83-84 °C; IR (NaCl,
1
CHCl3) 2962 (ms), 1747 (s), 1695 (m) cm -1; H NMR (CDCl3)
δ 4.55 (q, J ) 7.6 Hz, 1H), 4.37 (s, 1H), 2.38 (d, J ) 4.4 Hz,
1H), 2.04-1.91 (m, 1H), 1.99-1.82 (m, 1H), 1.57-1.48 (m, 1H),
1.41-1.32 (m, 1H), 1.41 (d, J ) 7.6 Hz, 3H), 1.05 (s, 3H), 0.94
(s, 3H), 0.83 (s, 3H); 13C NMR (CDCl3) δ 179.3, 172.0, 80.4,
57.4, 53.6, 49.7, 48.2, 34.4, 21.3, 19.9, 19.3, 16.3, 9.7; HRMS
m/z calcd for C13H19NO2 M+ 221.1416, found M+ 221.1407.
Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N, 6.33; Found:
C, 70.52; H, 8.60; N, 6.35.
(1R,2S,5S,8S)-1,5,11,11-Tetr am eth yl-3-oxa-6-azatr icyclo-
[6.2.1.02,7]u n d ec-6-en -4-on e (9a ): [R]22 +291.9 (c )1.29,
cm-1; [R]22 ) -94.6 (c ) 2.04, CHCl3); 1H NMR (CDCl3) δ
D
D
CHCl3); mp 161-162 °C; IR (NaCl, CHCl3) 2953 (ms), 1744
7.36-7.35 (m, 5H), 5.24 (s, 1H), 5.12 (s, 2H), 4.90 (s, 1H), 4.15-
4.02 (m, 2H), 2.21-2.20 (d, J ) 4.0 Hz, 1H), 2.10-1.84 (m,
2H), 1.62-1.44 (m, 2H), 0.97 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H);
13C NMR (CDCl3) δ 212.4, 169.7, 156.5, 136.4, 128.8, 128.4,
79.4, 67.3, 58.9, 49.7, 46.8, 42.9, 33.7, 21.0, 20.6, 18.7, 10.6;
HRMS m/z calcd for C20H25NO5 M+ 359.1735, found M+
359.1733.
1
(s), 1690 (m) cm -1; H NMR (CDCl3) δ 4.33 (d, J ) 1.2 Hz,
1H), 3.84 (qd, J ) 7.2, 1.2 Hz, 1H), 2.42 (d, J ) 4.4 Hz, 1H),
2.06-1.96 (m, 1H), 1.95∼1.87 (m, 1H), 1.67 (d, J ) 7.2 Hz,
3H), 1.59-1.52 (m, 1H), 1.44-1.34 (m, 1H), 1.10 (s, 3H), 0.97
(s, 3H), 0.84 (s, 3H); 13C NMR (CDCl3) δ 181.7, 171.5, 81.9,
56.7, 52.9, 49.3, 49.0, 33.9, 21.6, 20.0, 19.8, 17.2, 9.9; HRMS
m/z calcd for C13H19NO2 M+ 221.1416, found M+ 221.1406.
Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N, 6.33. Found:
C, 70.54; H, 8.61; N, 6.31.
(1R ,2S ,8S )-1,11,11-T r im e t h y l-3-o x a -6-a za t r ic y c lo -
[6.2.1.02,7]u n d ec-6-en -4-on e (7). A 100 mL two-necked flask
was charged with ester 5 (5.40 g, 15 mmol) and 5% palladium
on activated carbon (0.60 g). The flask was then evacuated
and filled with hydrogen three times. Dry ethanol (40 mL) was
added to the mixture followed by evacuation and filling with
hydrogen one more time. The mixture was stirred under
hydrogen atmosphere (1 atm) at room temperature (ca. 24 °C)
for 14 h. The catalyst was removed by filtration, and the
filtrate was concentrated to afford the crude product. Column
chromagraphy purification (EtOAc/hexane ) 1:4) furnished the
desired iminolactone as a colorless solid (2.36 g, 76%): mp 63-
64 °C; [R]22D -265.6 (c ) 2.34, CHCl3); 1H NMR (CDCl3) δ 4.52
(d, J ) 18 Hz, 1H), 4.32 (d, J ) 1.6 Hz, 1H), 3.90 (dd, J ) 1.6,
18 Hz, 1H), 2.45 (d, J ) 4.4 Hz, 1H), 2.05-1.98 (m, 1H), 1.95-
1.88 (m, 1H), 1.59-1.52 (m, 1H), 1.43-1.36 (m, 1H), 1.09 (s,
3H), 0.98 (s, 3H), 0.86 (s, 3H); 13C NMR (CDCl3) δ 181.8, 168.8,
81.7, 53.2, 52.5, 49.4, 48.9, 34.0, 21.6, 20.0, 19.3, 9.8; IR (NaCl,
CHCl3) 2962 (m), 1751 (s), 1695 (m) cm-1; HRMS m/z calcd
for C12H17NO2 M+ 207.1264, found M+ 207.1268. Anal. Calcd
for C12H17NO2: C, 69.48; H, 8.20; N, 6.75. Found: C, 69.44;
H, 8.25; N, 6.72.
Alk yla tion of Im in ola cton es. Gen er a l P r oced u r e A.
KOBut (1 M) in THF (1.54 mL, 1.54 mmol, 1.1 equiv) was
added to a dry 25 mL long-neck flask, immersed in a circulat-
ing cooler (FTS systems, Model MC 880A1) kept at -30 °C
under an argon atmosphere. Iminolactone 7 (0.29 g, 1.4 mmol)
in dry THF (10 mL) was added dropwise over a period of 10
min. The resulting mixture was stirred at -30 °C for 90 min
followed by the addition of HMPA (0.73 mL, 4.2 mmol, 3 equiv).
After the temperature of the cooler was lowered to -78 °C, a
solution of alkyl halide (2.1 mmol, 1.5 equiv) in dry THF (10
mL), precooled to 0 °C, was injected slowly using a syringe
pump over 15 min with the needle contacting the wall of the
neck allowing the reagent to cool to the reaction temperature
before it reached the reaction mixture by dripping along the
flask wall. The well-stirred reaction was then kept at -78 °C
for 10 h.
(1R ,2S ,5R ,8S )-5-Allyl-1,11,11-t r im e t h yl-3-oxa -6-a za -
tr icyclo[6.2.1.02,7]u n d ec-6-en -4-on e (8b): [R]22 -17.1 (c )
D
1.88, CHCl3); Rf 0.32 (hexane/EtOAc ) 2/1); 1H NMR (CDCl3)
δ 5.84 (ddt, J ) 17.2, 9.6, 7.2 Hz, 1H), 5.20 (dd, J ) 17.2, 1.6
Hz, 1H), 5.16 (dd, J ) 9.6, 1.6 Hz, 1H), 4.57 (t, J ) 7.2 Hz,
1H), 4.39 (s, 1H), 2.61-2.46 (m, 1H), 2.42 (d, J ) 4.4 Hz, 1H),
2.07-1.85 (m, 2H), 1.82-1.77 (m, 1H), 1.59-1.50 (m, 1H),
1.43-1.33 (m, 1H), 1.06 (s, 3H), 0.96 (s, 3H), 0.85 (s, 3H); 13
C
NMR (CDCl3) δ 180.0, 170.8, 132.8, 119.2, 81.1, 62.1, 53.9, 50.0,
48.4, 39.1, 34.7, 21.8, 20.2, 19.5, 10.0; HRMS m/z calcd for
C
C
15H21NO2 M+ 247.1572, found M+ 247.1578. Anal. Calcd for
15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C, 72.82; H,
8.49; N, 5.62.
(1R,2S,5R,8S)-5-Ben zyl-1,11,11-tr im eth yl-3-oxa -6-a za -
tr icyclo[6.2.1.02,7]u n d ec-6-en -4-on e (8c): [R]22 -11.4 (c )
D
2.07, CHCl3); Rf 0.27 (hexane/EtOAc ) 2/1); IR (NaCl, CHCl3)
1
3032 (s), 1734 (s), 1705 (m) cm -1; H NMR (CDCl3) δ 7.28-
7.15 (m, 5H), 4.83 (t, J ) 5.4 Hz, 1H), 3.44-3.38 (dd, J ) 5.4,
13.8 Hz, 1H), 3.16-3.11 (dd, J ) 5.4, 13.8 Hz, 1H), 2.51 (s,
1H), 2.34 (d, J ) 4.8 Hz, 1H), 1.89-1.82 (m, 1H), 1.68-1.60
(m, 1H), 1.40-1.33 (m, 1H), 0.87 (s, 3H), 0.84 (s, 3H), 0.77 (s,
3H), 0.72-0.68 (m, 1H); 13C NMR (CDCl3) δ 180.4, 171.4, 136.2,
130.1, 128.7, 127.4, 80.9, 62.7, 53.8, 49.0, 48.0, 38.0, 34.4, 21.2,
19.9, 19.1, 9.3; HRMS m/z calcd for C19H23NO2 M+ 297.1729,
found M+ 297.1728. Anal. Calcd for C19H23NO2: C, 76.73; H,
7.80; N, 4.71. Found: C, 76.80; H, 7.81; N, 4.67.
(1R,2S,5S,8S)-5-Ben zyl-1,11,11-t r im et h yl-3-oxa -6-a za -
tr icyclo[6.2.1.02,7]u n d ec-6-en -4-on e (9c): [R]22 -223.5 (c
D
)1.01, CHCl3); Rf 0.42 (hexane/EtOAc ) 2/1); mp 68-69 °C;
IR (NaCl, CHCl3) 2961 (m), 1746 (s), 1693 (m) cm -1; 1H NMR
(CDCl3) δ 7.38-7.22 (m, 5H), 4.27 (d, J ) 1.2 Hz, 1H), 3.97-
3.93 (m, 1H), 3.58-3.53 (dd, J ) 4.8, 14.4 Hz, 1H), 3.26-3.20
(dd, J ) 8.4, 14.4 Hz, 1H), 2.43 (d, J ) 4.4 Hz, 1H), 2.00-1.84
(m, 2H), 1.56-1.49 (m, 1H), 1.38-1.31 (m, 1H), 1.08 (s, 3H),
0.95 (s, 3H), 0.80 (m, 3H); 13C NMR (CDCl3) δ 181.5, 170.5,
138.7, 129.6, 128.3, 126.4, 81.7, 62.6, 53.0, 49.3, 48.9, 37.2, 33.9,
21.6, 20.0, 19.3, 9.9; MS m/z 297 (M+, 58.9), 269 (6.5), 253 (8.2),
238 (6.3), 206 (13.7), 178 (22.6), 162 (100.0), 148 (36.6), 131
(32.7), 91 (80.4), 83 (12.0), 77 (11.6), 55 (11.2); HRMS m/z calcd
for C19H23NO2 M+ 297.1729, found M+ 297.1729. Anal. Calcd
for C19H23NO2: C, 76.73; H, 7.80; N, 4.71. Found: C, 76.77;
H, 7.81; N, 4.66.
Aqueous acetic acid solution (2 M, 2 mL) was added to the
mixture to quench the reaction. The reaction was allowed to
warm to room temperature and then was washed with
saturated LiCl solution, dried (MgSO4), concentrated, and
purified by column chromatography to yield the desired
compounds.
Gen er a l P r oced u r e B. Diisopropylamine (216 µL, 1.54
mmol, 1.1 equiv) was added to a 25 mL long-neck flask,
immersed in a circulating cooler kept at -30 °C under an argon
atmosphere, containing a solution of dry THF (1.2 mL) and
n-BuLi (1.6 M, 962 µL, 1.54 mmol, 1.1 equiv), and the mixture
was stirred for 30 min at -30 °C.
(1R,2S,5R,8S)-5-E t h yl-1,11,11-t r im et h yl-3-oxa -6-a za -
tr icyclo[6.2.1.02,7]u n d ec-6-en -4-on e (8d ): [R]22 -46.7 (c )
D
2.17, CHCl3); Rf 0.30 (hexane/EtOAc ) 2/1); IR (NaCl, CHCl3)
1
1742 (s), 1604 (s) cm -1; H NMR (CDCl3) δ 4.40 (t, J ) 8 Hz,
1H), 4.38 (s, 1H), 2.41 (d, J ) 4.4 Hz, 1H), 2.06-1.97 (m, 1H),
1.93-1.86 (m, 1H), 1.82-1.74 (m, 2H), 1.59-1.52 (m, 1H),

2314 J . Org. Chem., Vol. 67, No. 7, 2002
Xu et al.
1.41-1.34 (m, 1H), 1.11 (t, J ) 7.6 Hz, 3H), 1.07 (s, 3H), 0.97
(s, 3H), 0.85 (s, 3H); 13C NMR (CDCl3) δ 179.2, 171.0, 80.5,
63.7, 53.6, 49.6, 48.1, 34.4, 24.9, 21.4, 19.9, 19.3, 11.1, 9.7;
HRMS m/z calcd for C14H21NO2 M+ 235.1572, found M+
235.1574. Anal. Calcd for C14H21NO2: C, 71.46; H, 8.99; N,
5.95; Found: C, 71.50; H, 8.97; N, 6.01.
ester (8h ): [R]22 -41.2 (c ) 2.78, CHCl3); IR (NaCl, CHCl3)
D
2983 (ms), 1742 (s), 1604 (m) cm -1; H NMR (CDCl3) δ 4.46
1
(s, 1H), 4.43 (t, J ) 7.6 Hz, 1H), 2.47 (t, J ) 7.2 Hz, 2H), 2.39
(d, J ) 4.4 Hz, 1H), 2.07-1.98 (m, 2H), 2.05-1.86 (m, 2H),
1.66-1.53 (m, 1H), 1.48-1.36 (m, 1H), 1.45 (s, 9H), 1.07 (s,
3H), 0.97 (s, 3H), 0.84 (s, 3H); 13C NMR (CDCl3) δ 180.3, 171.8,
170.7, 80.8, 80.4, 61.7, 53.7, 49.6, 48.1, 34.3, 31.9, 28.0, 26.1,
19.9, 19.2, 9.7; MS: m/z 335 (M+, 5.6), 279 (66), 262 (29), 251
(12), 220 (100); HRMS m/z calcd for C19H29NO4 M+ 335.2097,
found M+ 335.2107. Anal. Calcd for C19H29NO4: C, 68.03; H,
8.71; N, 4.18. Found: C, 68.00; H, 8.75; N, 4.14.
(1R,2S,5R,8S)-1,11,11-Tr im eth yl-5-p r op yl-3-oxa -6-a za -
tr icyclo[6.2.1.02,7]u n d ec-6-en -4-on e (8e): [R]22 -40.2 (c )
D
1.39, CHCl3); Rf 0.40 (hexane/EtOAc ) 2/1); IR (NaCl, CHCl3)
1
2960 (ms), 1747 (s), 1697 (m) cm -1; H NMR (CDCl3) δ 4.49
(t, J ) 7.2 Hz, 1H), 4.40 (s, 1H), 2.41 (d, J ) 4.4 Hz, 1H), 2.08-
1.86 (m, 2H), 1.72-1.70 (m, 2H), 1.58-1.53 (m, 3H), 1.42-
1.38 (m, 1H), 1.07 (s, 3H), 0.99 (t, J ) 7.2 Hz, 3H), 0.97 (s,
3H) 0.85 (s, 3H); 13C NMR (CDCl3) δ 179.0, 171.1, 80.5, 61.9,
53.6, 49.6, 48.0, 34.3, 33.4, 21.4, 19.9, 19.6, 19.2, 13.5, 9.7; MS
m/z 249 (M+, 22.8), 221 (10.1), 205 (42.6), 190 (74.4), 176
(100.0), 162 (51.0), 148 (11.9), 110 (10.1), 91 (12.4), 71 (42.6),
55 (20.0); HRMS m/z calcd for C15H23NO2 M+ 249.1729, found
M+ 249.1732. Anal. Calcd for C15H23NO2: C, 72.25; H, 9.30;
N, 5.62. Found: C, 72.30; H, 9.33; N, 5.58.
Gen er a l P r oced u r e for th e Hyd r olysis of Alk yla ted
Im in ola cton es. Compound 8 (0.4 mmol) was dissolved in 8
N HCl (2 mL) in a sealed tube with a Teflon screw cap and
heated at 87 °C for 2 h. After the mixture was cooled to room
temperature, water (2 mL) was added, and the mixture was
extracted with diethyl ether. The chiral auxiliary 4 was
recovered from the ether layer after the removal of solvent.
The aqueous layer was evaporated under reduced pressure (40
mmHg) and the residue was dissolved in EtOH (2 mL). Propyl-
ene oxide (1.5 mL) was then added, and the mixture was
stirred at room temperature for 30 min during which time
white solids precipitated. The precipitate was collected by
filtration, washed successively with cold EtOH and Et2O, and
air-dried to afford the desired R-amino acid.
(1R,2S,5R,8S)-5-Bu t yl-1,11,11-t r im et h yl-3-oxa -6-a za -
tr icyclo[6.2.1.02,7]u n d ec-6-en -4-on e (8f): [R]22 -43.8 (c )
D
1.43, CHCl3); Rf 0.46 (hexane/EtOAc ) 2/1); IR (NaCl, CHCl3)
1
2958 (s), 1747 (s), 1697 (m) cm -1; H NMR (CDCl3) δ 4.46 (t,
J ) 8 Hz, 1H), 4.39 (s, 1H), 2.40 (d, J ) 4.4 Hz, 1H), 2.08-
1.84 (m, 2H), 1.72-1.68 (m, 2H), 1.59-1.38 (m, 6H), 1.07 (s,
D-Ala n in e (10a ): 25 mg, 70%;[R]22D -9.0 (c ) 1.15, 2 N HCl);
lit.18 1H NMR (D2O) δ 3.64-3.58 (q, J ) 7.2 Hz, 1H), 1.31 (d,
J ) 7.2 Hz, 3H), recovered 4 (63 mg, 94%).
3H), 0.97 (s, 3H), 0.94-0.90 (t, J ) 8 Hz, 3H), 0.85 (s, 3H); 13
C
NMR (CDCl3) δ 179.0, 171.1, 80.4, 62.1, 53.5, 49.6, 48.0, 34.3,
31.0, 28.4, 22.1, 21.3, 19.8, 19.2, 13.6, 9.6; MS m/z 263 (M+,
15.2), 235 (8.7), 204 (44.9), 176 (100.0), 162 (44.8), 149 (24.4),
134 (13.5), 95 (14.3), 91 (26.0), 67 (29.8), 55 (45.3), 54 (26.6);
HRMS m/z calcd for C16H25NO2 M+ 263.1885, found M+
263.1879. Anal. Calcd for C16H25NO2: C, 72.96; H, 9.57; N,
5.32. Found: C, 72.99; H, 9.61; N, 5.29.
D-R-Allylglycin e (10b): 35 mg, 78%; [R]22 ) +36.4° (c )
D
1.34, H2O); lit.19 1H NMR (D2O) δ 5.65-5.47 (m, 1H), 5.12-
5.03 (m, 2H), 3.63-3.57 (dd, J ) 5.6, 6.8 Hz, 1H), 3.01-2.96
(m, 2H); recovered 4 (65 mg, 97%).
D-P h en yla la n in e (10c): 64 mg, 82%; [R]22 ) +33.7 (c )
D
2.67, H2O); 1H NMR (D2O) δ 7.31 (lit.20 7.18) (m, 5H), 3.81 (lit.20
3.75) (dd, J ) 4.4, 8.0 Hz, 1H), 3.15 (lit.203.11) (dd, J ) 4.4,
14.0 Hz, 1H), 2.96 (lit.20 2.85) (dd, J ) 8.0, 14.0 Hz, 1H);
recovered 4 (65 mg, 97%).
(1R,2S,5R,8S)-5-(1-Hyd r oxy-1-m eth yleth yl)-1,11,11-tr i-
m eth yl-3-oxa-6-azatr icyclo[6.2.1.02,7]u n dec-6-en -4-on e (8g):
[R]22 -15.6 (c ) 1.06, CHCl3); mp 159-160 °C; Rf 0.52
D
(hexane/EtOAc ) 2/1); IR (NaCl, CHCl3) 3400 (br), 1752 (s)
1
cm-1; H NMR (CDCl3) δ 4.67 (s, 1H), 4.41 (s, 1H), 2.44 (d, J
Ack n ow led gm en t. Financial support by the Na-
tional Science Council of the Republic of China and the
collection and processing of the X-ray data by Dr. Bao-
Tsan Ko are gratefully acknowledged. Support of P.-F.X.
by the NSFC (QT program) is also acknowledged.
) 4.4 Hz, 1H), 2.05-1.98 (m, 1H), 1.91-1.84 (m, 1H), 1.65-
1.58 (m, 1H), 1.51 (s, 3H), 1.42-1.36 (m, 1H), 1.40 (s, 3H), 1.05
(s, 3H), 0.97 (s, 3H), 0.85 (s, 3H); 13C NMR (CDCl3) δ 181.6,
169.6, 82.2, 75.3, 70.3, 54.1, 49.5, 48.2, 34.6, 28.8, 28.1, 21.6,
20.0, 19.3, 9.7; HRMS m/z calcd for C15H23NO3 M+ 265.1678,
found M+ 265.1670.
(1R,2S,5S,8S)-5-(1-Hyd r oxy-1-m eth yleth yl)-1,11,11-tr i-
m eth yl-3-oxa-6-azatr icyclo[6.2.1.02,7]u n dec-6-en -4-on e (9g):
[R]22D -198.0 (c ) 0.96, CHCl3); mp 73-74 °C; Rf 0.28 (hexane/
EtOAc ) 2/1); 1H NMR (CDCl3) δ 4.26 (d, J ) 1.6 Hz, 1H),
3.93 (s, 1H, OH), 3.56 (d, J ) 1.6 Hz, 1H), 2.44 (d, J ) 4.8 Hz,
1H), 2.06-1.85 (m, 2H), 1.64-1.56 (m, 1H), 1.41-1.35 (m, 1H),
1.40 (s, 3H), 1.39 (s, 3H), 1.08 (s, 3H), 0.96 (s, 3H), 0.80 (s,
3H); 13C NMR (CDCl3) δ 181.1, 170.5, 81.9, 71.9, 68.0, 53.1,
49.3, 48.9, 33.8, 26.5, 24.5, 21.5, 19.9, 19.3, 9.9; HRMS m/z
calcd for C15H23NO3 M+ 265.1678, found M+ 265.1667.
3-[(1R,2S,8S)-1,11,11-Tr im et h yl-4-oxo-3-oxa -6-a za t r i-
cyclo[6.2.1.02,7]u n d ec-6-en -5-yl]p r op ion ic a cid ter t-bu tyl
Su p p or tin g In for m a tion Ava ila ble: X-ray data of com-
pounds 7 and 8g. The material is available free of charge via
the Internet at http://pubs.acs.org.
J O011139A
(18) [R]22 ) -14.1 (c ) 0.9, 1 N HCl): Walsh, C. T. J . Biol. Chem.
D
1989, 264, 2393.
(19) [R]24 ) -37.1 (c ) 4, H2O): Black, S.; Wright, N. G. J . Biol.
D
Chem. 1955, 213, 39.
(20) [R]23D ) -34.7 (c ) 2, H2O):, Bull, S. D.; Davies, S. G.; Epstein,
S. W.; Ouzman, J . V. A. Tetrahedron: Asymmetry 1998, 9, 2795.