Selective synthesis of either enantiomer of α-amino acids by switching the regiochemistry of the tricyclic iminolactones prepared from a single chiral source

Article abstract of DOI:10.1021/jo026285a

Preparation of L-α-amino acids was easily accomplished simply by exchanging the position of the lactone group of our recently reported chiral template I from C₂ to C₃. The new chiral template 7 was prepared in 54% overall yield over five steps from (1R)-(+)-camphor. Alkylation of iminolactone 7 afforded the α-monosubstituted products in good yields and excellent diastereoselectivities (>98%). Hydrolysis of the alkylated iminolactones furnished the desired L-α-amino acids in good yields and ee with nearly quantitative recovery of chiral auxiliary 4.

Full text of DOI:10.1021/jo026285a

SCHEME 1
Selective Syn th esis of Eith er En a n tiom er
of r-Am in o Acid s by Sw itch in g th e
Regioch em istr y of th e Tr icyclic
Im in ola cton es P r ep a r ed fr om a Sin gle
Ch ir a l Sou r ce
Peng-Fei Xu† and Ta-J ung Lu*,‡
Department of Chemistry, National Chung-Hsing
University, Taichung, Taiwan 40227, Republic of China,
and College of Chemistry and Chemical Engineering,
National Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou, Gansu 730000, PRC
SCHEME 2
tjlu@mail.nchu.edu.tw
Received August 5, 2002
Abstr a ct: Preparation of L-R-amino acids was easily ac-
complished simply by exchanging the position of the lactone
group of our recently reported chiral template 1 from C2 to
C3. The new chiral template 7 was prepared in 54% overall
yield over five steps from (1R)-(+)-camphor. Alkylation of
iminolactone 7 afforded the R-monosubstituted products in
good yields and excellent diastereoselectivities (>98%).
Hydrolysis of the alkylated iminolactones furnished the
desired L-R-amino acids in good yields and ee with nearly
quantitative recovery of chiral auxiliary 4.
Our laboratories have been interested in the design,
synthesis, and application of camphor-based chiral aux-
iliaries. We reported recently a highly stereocontrolled
asymmetric alkylation of a tricyclic glycinate 1 derived
from (1R)-(+)-camphor to provide D-R-amino acids in high
yields with excellent level of stereoselectivity, Scheme
1.1,2
In principle, the antipode of the R-amino acid can be
synthesized if the unnatural (1S)-(-)-camphor is utilized
through the same sequence. Unfortunately, the un-
natural camphor is much more expensive than the
natural d-camphor, making it an uneconomical route. We
have envisioned a more practical method that only
requires switching the position of the hydroxyl group of
the chiral auxiliary from C2 to C3. Namely, if the
C3-carbonyl group on (1R)-(+)-camphorquinone can be
selectively reduced to a hydroxyl group, the resulting
3-exo-hydroxycamphor (4) should provide the enantiomer
of the R-amino acid derived from 2-exo-hydroxyepicam-
phor. Thus, from the same cheap and easily accessible
chiral source both enantiomers of R-amino acids can be
produced. From a synthetic viewpoint, the fact that not
both enantiomers of a chiral auxiliary are always readily
available, a method which provides both enantiomers of
products by using chiral auxiliaries derived from a single
chiral source is most attractive and desirable.3 We now
would like to present our results on switching stereo-
selectivity by simply altering the position of the lactone
group on the chiral template that delivered L-R-amino
acids in high enantiomeric purity.
As depicted in Scheme 2, the required iminolactone 7
was prepared readily from camphorquinone. Regioselec-
tive reduction of the less hindered C3-carbonyl group on
(1R)-(+)-camphorquinone was accomplished by L-Selec-
tride reduction to afford the 3-exo-hydroxycamphor in
good yields but contaminated with side products.4 Alter-
natively, camphorquinone was transformed into com-
pound 4 through three highly efficient steps in 74%
overall yield. Thus, camphorquinone was first refluxed
with ethylene glycol in cyclohexane in the presence of
catalytic amount of p-toluenesulfonic acid for 4 days to
give a mixture of the diacetal 2 and two monoacetals (2-
† Lanzhou University.
‡ National Chung-Hsing University.
(1) Xu, P.-F.; Chen, Y.-S.; Lin, S.-I.; Lu, T.-J . J . Org. Chem. 2002,
67, 2309.
(2) 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, 7. (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.
(3) Tanaka, K.; Uno, H.; Osuga, H.; Suzuki, H. Tetrahedron:
Asymmetry 1993, 4, 629.
(4) (a) Kouklovsky, C.; Pouilhes, A.; Langlois, Y. J . Am. Chem. Soc.
1990, 112, 6672. (b) Banks, M. R.; Blake, A. J .; Cadogan, J . I. G.; Doyle,
A. A.; Gosney, I.; Hodgson, P. K. G.; Thorburn, P. Tetrahedron 1996,
52, 4079. Reduction utilizing the procedures reported in these two
articles afforded the desired 3-exo-hydroxycamphor and the 2-exo-
hydroxyepicamphor in a 6:1 ratio in a combined yield of 90%. Morris
and Ryder also have pointed out that they and Professor G. Helmchen’s
laboratories were unable to reproduce Professor Langlois’s results
(Morris, D. G.; Ryder, K. S. Synthesis 1997, 620).
10.1021/jo026285a CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/31/2002
658
J . Org. Chem. 2003, 68, 658-661

TABLE 1. Alk yla tion of th e Tr icyclic Im in ola cton e 7
and 3-acetals) in 99% combined yield. The diacetal (62%)
can be easily separated from the mixture of monoacetals
(36%) by flash column chromatography.5,6 Conversion of
the mixture of monoacetals into the diacetal in 73% was
accomplished smoothly by subjecting the mixture to the
above reaction conditions. Therefore, the total yield of
the diacetal is 88% from camphorquinone over two steps.
The less hindered C3-dioxolane of the diacetal was then
selectively removed easily to furnish the 2-acetal 3 by
stirring it with an ice-cold aqueous sulfuric acid solution
at 0 °C for 30 min. Subsequent reduction of the C3-
carbonyl with NaBH4 gave intermediate 5, which was
hydrolyzed to provide the hydroxyketone 4. The 3-exo-
hydroxycamphor underwent coupling reaction with Cbz-
glycine under standard conditions to give rise to the ester
6 in 98% yield. Deprotection of the Cbz group and
cyclization occurred simultaneously during catalytic hy-
drogenation to generate the desired iminolactone 7 in
74% yield.
yielda
(%)
endo/
%
de
entry base
E+
product exob
1
2
3
4
5
6
7
8
9
LDA
CH3I
78 8a + 9a >99:1 >98
70 8a + 9a 5:3
KOBut CH3I
LDA
LDA
CH2dCHCH2Br
C6H5CH2Br
90 8b + 9b >99:1 >98
88 8c + 9c >99:1 >98
KOBut C6H5CH2Br
79 8c + 9c 1:5
67
LDA
LDA
LDA
LDA
CH3CH2I
68 (89)c 8d + 9d >99:1 >98
56 (85)c 8e + 9e >99:1 >98
59 (81)c 8f + 9f >99:1 >98
CH3(CH2)2I
CH3(CH2)3I
(CH3)2CdO
Like its regioisomer 1, iminolactone 7 showed a sig-
nificant behavior in its NMR spectra with respect to the
chemical shift and coupling pattern for the two hydrogens
at C-5. Some distinctive features are: (a) The C5exo-H
(4.57 ppm) is a doublet with a large geminal coupling
constant (J ) 18.0 Hz). (b) The C5endo-H (3.92 ppm) has
a long-range coupling with the C2-H and appears as a
doublet of doublets (J ) 18.0, 1.6 Hz). (c) The C2-H (4.49
64 (90)c 8g + 9g 7:1
75
a
The reported yields are isolated yields after column separation.
b
The ratios were estimated by NMR integrations of the crude
reaction mixtures. c The yields in the parentheses are the yields
based on recovered starting material.
is allowed only when the two protons are parallel to each
other as well as to the pi-orbital of the imine double bond
in this rigid ring system. Thus, the existence of long-
range coupling between these two protons clearly indi-
cates that the methyl group is exo. On the contrary, the
ppm) is a doublet (J ) 1.6 Hz) as it couples to the C5endo
-
H. (d) The chemical shifts of the two C5-protons display
a remarkably large difference (∆∆δ ) 0.65 ppm), indicat-
ing the chemical environments of the two protons are
considerably different.
C
5exo-proton of the endo product appears as a quartet
(4.63 ppm, J ) 7.6 Hz) while the C2-proton appears as a
singlet (4.59 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
NMR coupling pattern of the C5exo-H and C5endo-H. The
C5endo-H of the exo product 9c is a doublet of doublet of
doublet (3.94 ppm, J ) 4.8, 4.4, 1.2 Hz) and the C2-proton
is a doublet (4.43 ppm, J ) 1.2 Hz), indicating long-range
coupling between the C5endo-proton and C2-proton. Fur-
thermore, the chemical shift of the C2-proton is close to
that of the exo-methylated product (4.43 vs 4.51 ppm).
On the other hand, the C5exo-proton of the endo-benzy-
lated product appears as a doublet of doublet (4.87 ppm,
J ) 5.2, 4.8 Hz), while the C2-proton appears as a singlet
(2.63 ppm). The chemical shift of the C2-proton is 1.80
ppm higher field than that of the corresponding endo-
methylated, one presumably due to the shielding effect
of the phenyl group which serves as further evidence for
the endo stereochemistry of the benzyl group.
The nature of solvent, additives, and bases is known
to affect the facial selectivity in alkylation reactions.
Thus, treatment of compound 7 with 1.1 equiv of KOBut
or LDA at -30 °C for 30 min generated the corresponding
anions that reacted with a variety of different electro-
philes for 14 h.7 Depending on the base and quenching
electrophile, the alkylation afforded monosubstituted
iminolactones in good yields and different levels of
diastereoselectivity. The results in Table 1 clearly show
that lithium diisopropylamide (LDA) gave the best yields.
The diastereoselectivity realized in the alkylation reac-
tions are extremely high with compound 8 as the major
product.8 In addition, the aldol reaction of the enolate
also delivered the desired products smoothly with good
facial selectivities (entry 9, Table 1).
The stereochemistry of the two monomethylation prod-
ucts was revealed by NMR coupling pattern of the C5exo-H
and C5endo-H. The C5endo-H of the exo-methylated product
is a quartet of doublets (3.92 ppm, J ) 7.2, 1.2 Hz) and
the C2-proton is a doublet (4.51 ppm, J ) 1.2 Hz). Long-
range coupling between the C5endo proton and C2-proton
One thing noteworthy is that methylation of compound
7 using KOBut as the base at -78 °C gave considerably
lower stereoselectivity (8a /9a ) 5/3) as compared to that
of utilizing LDA (Table 1, entries 1 and 2). Similarly,
benzylation of iminolactone 7 with KOBut resulted in
reversed facial selectivity but poor diastereomeric ratio
(8c/9c ) 1/5) (Table 1, entries 4 and 5).9
(5) When camphorquinone was refluxed in toluene under similar
conditions for 10 h gave the diacetal (39%) and a mixture of two
monoacetals (60%).
(6) Verdaguer, X.; Marchueta, I.; Tormo, J .; Moyano, A.; Perica`s,
M. A.; Riera, A. Helv. Chim. Acta 1998, 81, 78.
(7) The optimum conditions for the alkylation of iminolactone
reported in ref 1 were used in this study.
(8) 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 examined very carefully and
there was no sign of the exo-methylated product as far as the NMR
detection limit can tell.
X-ray crystallographic determination of single crystals
of compounds 7 and 8d ,f obtained by recrystallization
(9) Similar trend also was observed in the alkylation of iminolactone
1, see ref 1.
J . Org. Chem, Vol. 68, No. 2, 2003 659

TABLE 2. Hyd r olysis of th e Alk yla ted Im in ola cton es
amino
recovered
entry
R
acid (%) auxiliary (%) eea (%) [R]22
D
1
2
CH2dCHCH2
C6H5CH2
70
74
96
94
94
96
-33.4b
-32.9b
a
ee (%) values are determined by HPLC analysis utilizing a
b
Dicel Crownpak CR(+) column. The optical rotations were
measured in H2O solution.
F IGURE 1. X-ray structure of compound 7.
acids were obtained in good yields and enantiomeric
excesses. In addition, the chiral auxiliary 4 was also
recovered in nearly quantitative yield. The configuration
of the R-amino acids is in agreement with that assigned
to the respective precursors. The recovered chiral aux-
iliary 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.
In summary, we have developed an efficient and
practical method for the preparation of natural R-amino
acids starting from inexpensive and readily available
(1R)-(+)-camphor. Good chemical yields and excellent
diastereoselectivity 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 preparation of R-monosubstituted R-amino acids.
Simple switching the regiochemistry of the chiral auxil-
iary, derived from the same starting material, allow the
preparation of R-amino acids of the opposite configura-
tion. Consequently, our method is amenable to the
synthesis of R-amino acids of either stereochemistry.
F IGURE 2. X-ray structure of compound 8d .
Exp er im en ta l Section
(1R,4S)-2,2,3,3-Bis(eth ylen edioxy)-1,7,7-tr im eth ylbicyclo-
[2.2.1]h ep ta n e (2).6 A stirred solution of camphorquinone (9.96
g, 60 mmol), p-toluenesulfonic acid (0.571 g, 3.0 mmol), and
ethylene glycol (16.2 mL, 300 mmol) in cyclohexane (80 mL) was
heated under reflux using a Dean-Stark trap and was moni-
tored by TLC. Additional quantities of ethylene glycol (5 mL after
15 h and 2.5 mL after 40 h) and TsOH (150 mg after 60 h) were
added to the mixture. After 4 days, the reaction mixture was
washed with 10% aqueous sodium hydroxide and brine, dried
(MgSO4), and filtered, and the cyclohexane was removed under
reduced pressure. The crude product was separated by flash
column (EtOAc/hexane ) 1:20) to provide the desired diacetal
(9.45 g, 62%) and a mixture of two monoprotected acetals (4.54
g, 36%). The mixture of monoacetals was resubmitted to the
above reaction conditions to afford the diacetal (4.01 g, 73%) and
recovered some monoacetal starting material (0.9 g, 20%).
Diacetal 2: Rf 0.19 (hexane/EtOAc ) 4/1), mp 59-60 °C; 1H
NMR 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 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
F IGURE 3. X-ray structure of compound 8f.
from a mixture of ethyl acetate and hexane provided the
structures presented in Figures 1-3.10 A significant
feature in the crystallographic structure among three
compounds 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 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 are con-
firmed unequivocally by the fact that the hydroxypropyl
group of compounds 8d and 8f are at the endo position
in their X-ray structures (Table 2).
Upon hydrolysis of the alkylated iminolactones in 8 N
(16.0); IR (NaCl, CHCl3) 2961 (m), 2893 (m), cm-1
.
HCl solution at 87 °C for 2 h,11 the corresponding R-amino
(1S,4S)-3,3-Eth ylen ed ioxy-4,7,7-tr im eth ylbicyclo[2.2.1]-
h ep ta n -2-on e (3). To a flask containing a solution of diacetal 2
(10) Michael N. Burnett and Carroll K. J ohnson, ORTEP-III: Oak
Ridge Thermal Ellipsoid Plot Program for Crystal Structure Illustra-
tions, Oak Ridge National Laboratory Report ORNL-6895, 1996.
(11) Chinchilla, R.; Falvello, L. R.; Galindo, N.; Na´jera, C. Tetrahe-
dron: Asymmetry 1998, 9, 2223.
660 J . Org. Chem., Vol. 68, No. 2, 2003

(5.09 g 20.0 mmol), cooled in an ice bath, was added an ice-cold
solution of concentrated sulfuric acid-water (v/v ) 1:1, 40 mL)
with stirring. After 5 min. ethanol (5 mL) was added, and the
reaction was stirred at 0 °C for 30 min. The reaction was
extracted with diethyl ether. The combined ether layer was
washed with brine and water, dried (MgSO4), and filtered, and
solvent was evaporated to give the title compound as a white
tography (EtOAc/hexane ) 1:8) gave the ester as a colorless oil
(10.04 g, 98%): [R]23 ) +45.6 (c ) 1.94, CHCl3); IR (NaCl,
D
CHCl3) 3366 (br), 3033 (m), 1754 (s), 1746 (s) cm-1; H NMR δ
1
7.36-7.34 (m, 5H), 5.24 (b, 1H), 5.12 (s, 2H), 4.84 (s, 1H), 4.02
(d, J ) 5.6 Hz, 2H), 2.13 (d, J ) 4.4 Hz, 1H), 1.79-1.62 (m, 2H),
1.58-1.43 (m, 2H), 0.95 (s, 6H), 0.92 (s, 3H); 13C NMR δ 213.6,
169.3, 156.2, 136.1, 128.4, 128.3, 128.1, 128.0, 67.0, 57.2, 48.2,
46.5, 42.7, 28.4, 24.7, 20.6, 19.5, 9.0; MS m/z 359 (M+, 23.1), 316
(1.2), 258 (2.8), 224 (6.6), 192 (15.2), 152 (32.3), 139 (66.2), 108
powder (3.83 g, 91%). 2-Acetal 3: mp 42-44 °C; [R]23 ) +45.3
D
(c ) 1.96, CHCl3); IR (NaCl, CHCl3) 2962 (s), 2896 (m), 1758 (s)
1
cm-1; H NMR δ 4.31-4.25 (m, 1H), 4.19-4.12 (m, 1H), 4.02-
(52.0), 91 (100.0), 83 (25.4), 55 (20.2); HRMS m/e calcd for C20H25
-
-
3.91 (m, 2H), 2.17 (d, J ) 5.6 Hz, 1H), 2.09-2.02 (m, 1H), 1.97-
1.88 (m, 1H), 1.62-1.51 (m, 2H), 1.04 (s, 3H), 0.95 (s, 3H), 0.90
(s, 3H); 13C NMR δ 216.5, 107.3, 66.3, 64.8, 59.2, 51.3, 43.7, 29.2,
22.7, 21.5, 18.2, 8.7; MS m/z 210 (M+, 7.8), 182 (68.7), 165 (8.3),
113 (100.0), 99 (63.7), 95 (12.4), 69 (56.7), 67 (16.1), 55 (14.3).
Anal. Calcd for C12H18O3: C, 68.54; H, 8.63. Found: C, 68.56;
H, 8.61.
NO5 M+ 359.1738, found M+ 359.1733. Anal. Calcd for C20H25
NO5: C, 66.83; H, 7.01; N, 3.90. Found: C, 66.85; H, 6.98; N,
3.92.
(1S,2R,8R)-8,11,11-Tr im eth yl-3-oxa-6-azatr icyclo[6.2.1.02,7]-
u n d ec-6-en -4-on e (7). To a 100 mL two-necked flask was
charged with ester 6 (7.19 g, 20 mmol) and 5% palladium on
activated carbon (0.90 g). The flask was then evacuated and filled
with hydrogen three times. Freshly dried ethanol (60 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 rt for 14 h. The catalyst was
removed by filtration and the filtrate was concentrated to afford
the crude product. The residue was purified by column chro-
magraphy (EtOAc/hexane ) 1:4) to furnish the desired imino-
(1R,3R,4S)-1,7,7-Tr im eth yl-2,2-eth ylen edioxybicyclo[2.2.1]-
h ep ta n -3-ol (5). To a solution of 2-acetal 3 (6.31 g, 30.0 mmol)
in ether (30 mL) and methanol (30 mL), cooled in an ice bath,
was added sodium borohydride (1.36 g, 36 mmol, 1.2 equiv) in
small batches over 10 min. The reaction mixture was stirred in
an ice bath for 3 h. The reaction was washed with water, dried
(MgSO4), and filtered, and the organic layer was concentrated
lactone as a colorless solid (3.07 g, 74%): mp 103-104 °C; [R]22
to leave an oil (6.16 g, 97%): [R]23 ) -26.0 (c ) 1.11, CHCl3);
D
D
IR (NaCl, CHCl3) 3473 (br), 2952 (s), 2885 (m) cm-1; 1H NMR δ
4.07-4.03 (m, 1H), 3.99-3.95 (m, 1H), 3.87-3.82 (m, 1H), 3.77-
3.71 (m, 1H), 3.43 (d, J ) 5.2 Hz, 1H), 2.54 (d, J ) 5.2 Hz, 1H),
1.83-1.65 (m, 3H), 1.36-1.30 (m, 1H), 1.16-1.10 (m, 1H), 1.07
(s, 3H), 0.81 (s, 3H), 0.80 (s, 3H); MS m/z 212 (M+, 16.8), 197
(6.4), 155 (54.5), 141 (74.3), 127 (15.4), 113 (24.5), 95 (20.4), 73
(100.0), 69 (45.9), 55 (23.8). Anal. Calcd for C12H20O3: C, 67.89;
H, 9.50. Found: C, 67.93; H, 9.49.
) +266.3 (c ) 1.35, CHCl3); IR (NaCl, CHCl3) 2972 (m), 1758
1
(s), 1685 (m) cm-1; H NMR δ 4.57 (d, J ) 18 Hz, 1H), 4.49 (d,
J ) 1.6 Hz, 1H), 3.95-3.90 (dd, J ) 18 Hz, 1.6 Hz, 1H), 2.28 (d,
J ) 4.8 Hz, 1H), 2.13-2.06 (m, 1H), 1.83-1.75 (m, 1H), 1.62-
1.55 (m, 1H), 1.41-1.34 (m, 1H), 1.07 (s, 3H), 0.98 (s, 3H), 0.81
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 184.0, 169.2, 79.9, 52.9,
49.3, 47.7, 29.7, 25.6, 20.2, 19.9, 10.1; MS m/z 207 (M+, 64.0),
192 (5.1), 179 (100.0), 164 (13.7), 150 (32.0), 136 (31.9), 111
(51.2), 110 (22.7), 82 (44.0), 69 (54.7), 55 (15.4), 53 (10.7); HRMS
m/e calcd for C12H17NO2 M+ 207.1268, found M+ 207.1259. Anal.
Calcd for C12H17NO2: C, 69.48; H, 8.27; N, 6.75. Found: C, 69.54;
H, 8.26; N, 6.44.
Alk yla tion of Im in ola cton e. Gen er a l P r oced u r e. Diiso-
propylamine (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,3R,4S)-3-Hydr oxy-1,7,7-tr im eth ylbicyclo[2.2.1]h eptan -
2-on e (4).3 Meth od A. To a flask containing crude compound 5
(6.37 g, 30 mmol), cooled to about 0 °C, and was added an ice-
cold solution of concentrated sulfuric acid-water (v/v ) 1:1, 40
mL). Ice (10 g) was added after 15 min, and the mixture was
extracted with ether. The combined ether layer was washed with
brine and water, dried (MgSO4), and filtered, and solvent was
evaporated to give the 3-exo-hydroxycamphor as a white solid
(4.84 g, 93%): mp 166-168 °C; IR (NaCl, CHCl3) 3442 (br), 2957
1
(s), 1744 (s) cm-1; H NMR δ 3.74 (s, 1H), 2.10 (d, J ) 4.4 Hz,
Iminolactone (292 mg, 1.4 mmol) in dry THF (8 mL) was
added dropwise over a period of 10 min into the above fleshly
prepared LDA solution at -30 °C, and the resulting solution
was stirred at -30 °C for 90 min. Hexamethylphosphoric
triamide (HMPA) (distilled from CaH2, 0.73 mL, 4.2 mmol, 3
equiv) was then added to the reaction mixture, which was
subsequently cooled to -78 °C. While the reaction mixture was
kept at -78 °C, a solution of alkyl halides (4.2 mmol, 3 equiv)
in dry THF (8 mL), precooled to 0 °C, was slowly added to the
reaction with the needle contacting the wall of the flask over 10
min.1 The well-stirred reaction was kept at -78 °C for another
14 h.
A solution of aqueous acetic acid (2 M, 2 mL) was added to
the mixture to quench the reaction. The reaction was warmed
to rt, washed with saturated aqueous LiCl, dried (MgSO4), and
concentrated to give the crude product. The crude product was
purified by column chromatography to yield desired compounds.
1H), 2.06-1.97 (m, 1H), 1.70-1.63 (m, 1H), 1.49-1.35 (m, 2H),
0.99 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H); 13C NMR δ 220.2, 77.4,
57.0, 49.3, 46.8, 28.6, 25.2, 21.0, 20.1, 9.0; 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).
Meth od B. L-Selectride (25 mL of a 1.0 M solution, 25 mmol,
1.1 equiv) was added to a solution of camphorquinone (3.69 g,
22.2 mmol) in dry THF (80 mL) at -78 °C under argon. The
reaction mixture was allowed to stir at -78 °C for 3.5 h,
quenched by the addition of a 3 M solution of hydrochloric acid
in methanol (40 mL), and stirred at the same temperature for
another 20 min. The THF was then removed by a rotavapor,
and the resulting aqueous layer was extracted into dichloro-
methane. Drying (MgSO4), filtration, and evaporation in vacuo
of the combined dichloromethane extract gave an unpleasant
smelling yellow liquid. The liquid was purified by flash chro-
matography (hexane/ether ) 9:1-3:1) to give a clear colorless
oil (3.36 g, 90%) as an inseparable 6:1 mixture of hydroxycam-
phor 4 and 2-exo-hydroxyepicamphor.
(1S,3R,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 (6). A solution
of 3-exo-hydroxycamphor 4 (4.80 g, 28.53 mmol), Cbz-glycine
(6.58 g, 31.48 mmol, 1.1 equiv), and N,N-(dimethylamino)-
pyridine (DMAP, 1.74 g, 14.26 mmol, 0.5 equiv) in THF (100
mL) in a 250 mL round-bottomed flask was stirred at 0 °C for
15 min, and dicyclohexylcarbodiimide (DCC, 8.83 g, 42.80 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 rt for 16 h. Precipitated 1,3-dicyclohexylurea was
removed by filtration and the filtrate concentrated under reduced
pressure. Purification of the residue by flash column chroma-
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.
Xu by the NSFC (QT program) is also acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Spectral and ana-
lytical data for compounds 8a -g and 9a ,c,g; general procedure
and reaction yields for hydrolysis of alkylated iminolactones;
and X-ray data of compounds 7 and 8d ,f. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O026285A
J . Org. Chem, Vol. 68, No. 2, 2003 661