Regio- and stereoselective synthesis of the enantiomers of monoterpene-based β-amino acid derivatives

Article abstract of DOI:10.1016/j.tetasy.2007.09.028

The regio- and stereospecific addition of chlorosulfonyl isocyanate to cis-δ-pinene enantiomers has furnished monoterpene-fused β-lactams. The observed regioselectivity can be explained by ab initio DFT modeling of transition state structures. In contrast with the less reactive α-pinane-fused β-lactam 4, the resulting β-lactams 5 and 13 containing an amino group connected to a secondary carbon possess similar reactivity to the cycloalkane-fused analogues and can be easily converted to the β-amino acid and its protected derivatives. The base-catalyzed isomerization of the cis-amino ester afforded the corresponding trans-amino ester in moderate yield.

Full text of DOI:10.1016/j.tetasy.2007.09.028

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2442–2447
Regio- and stereoselective synthesis of the enantiomers of
monoterpene-based b-amino acid derivatives
a
a
c
a,b,
*
´
Zsolt Szakonyi, Tamas A. Martinek, Reijo Sillanpaa and Ferenc Fulop
¨ ¨
¨ ¨
aInstitute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged Eo¨tvo¨s utca 6, Hungary
bResearch Group of Stereochemistry of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged Eo¨tvo¨s utca 6, Hungary
cDepartment of Chemistry, University of Jyva¨skyla¨, PO Box 35, 40351 Jyva¨skyla¨, Finland
Received 10 August 2007; accepted 27 September 2007
Available online 24 October 2007
Abstract—The regio- and stereospecific addition of chlorosulfonyl isocyanate to cis-d-pinene enantiomers has furnished monoterpene-
fused b-lactams. The observed regioselectivity can be explained by ab initio DFT modeling of transition state structures. In contrast with
the less reactive a-pinane-fused b-lactam 4, the resulting b-lactams 5 and 13 containing an amino group connected to a secondary carbon
possess similar reactivity to the cycloalkane-fused analogues and can be easily converted to the b-amino acid and its protected deriva-
tives. The base-catalyzed isomerization of the cis-amino ester afforded the corresponding trans-amino ester in moderate yield.
ꢀ 2007 Published by Elsevier Ltd.
1. Introduction
carboxylic acid (cispentacin).7 Icofungipen (PLD-118,
(1R,2S)-2-amino-4-methylenecyclopentanecarboxylic acid),
a b-amino acid, perturbs the biosynthesis of protein in Can-
dida albicans.8 b-Amino acids can also be used as building
blocks for the preparation of modified analogues of phar-
macologically active peptides. b-Amino acids and their
foldameric oligomers are currently at the focus of research
interest.9
The identification of new chiral building blocks and cata-
lysts for asymmetric syntheses is of increasing importance
in organic chemistry. Various powerful catalysts derived
from monoterpenes, such as (+)-pulegone,1 b-pinene,2
fenchone-camphor,3 and limonene,4 have been reported
to have been successfully used as chiral ligands in enantio-
selective syntheses.5
Herein we report the preparation and some transfor-
mations of a new family of monoterpene-based chiral
b-lactams and b-amino acid derivatives derived from (+)-
and (ꢀ)-d-pinenes 2 and 13.
We recently described the transformations of enantiomeri-
cally pure a-pinene and 3-carene to b-amino acid deriva-
tives, such as amino esters and amino alcohols, which
proved to be excellent building blocks for the syntheses
of monoterpene-fused saturated 1,3-heterocycles and were
also applied as chiral auxiliaries in the enantioselective
reactions of diethylzinc with aromatic aldehydes.6 These
results revealed that a tertiary carbon next to the amino
group dramatically decreases the reactivity of the synthons
relative to those containing a secondary carbon next to the
functional groups.6
2. Results and discussion
(+)- and (ꢀ)-cis-d-pinenes 2 and 13 were synthesized from
commercially available (ꢀ)- and (+)-isopinocampheols 1
and 12, by modification of the literature method.10 The tos-
ylate of isopinocampheol 1 was prepared according to the
Schmidt method.11 Decomposition of the tosylate of iso-
pinocampheol was carried out in DMF solution. This
smoothly running reaction yielded a ternary mixture
containing cis-d-pinene 2 (45%), a-pinene 3 (45%), and
unreacted starting material isopinocampheol 1 (10%). A
simple bulb to bulb distillation resulted in a 1:1 mixture
of alkenes 2 and 3. Instead of the cumbersome fractional
Besides the chemical importance of b-amino acids, some of
them exert significant pharmacological effects, for example,
the antifungal antibiotic (1R,2S)-2-aminocyclopentane-
*
Corresponding author. Tel.: +36 62 545564; fax: +36 62 545705; e-mail:
fulop@pharm.u-szeged.hu
0957-4166/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2007.09.028

Z. Szakonyi et al. / Tetrahedron: Asymmetry 18 (2007) 2442–2447
2443
distillation of 2 and 3,10 the separation of the isomers was
based on the different rates of the cycloaddition reaction of
chlorosulfonyl isocyanate (CSI) (Scheme 1).
donating substituent. For 3, the attached methyl substitu-
ent can exert this stabilization effect, which rationalizes
both the faster reaction toward 4 and the regiospecificity
of the reaction.
1. 1.2 equiv. TsCl,
pyridine, 48 h,
cat. DMAP, rt
It is more difficult to account for the regiospecificity of CSI
addition to 2. DFT calculations at the level of B3LYP/6-
31+g(d,p) were performed to model the transition states
A and B as shown in Figure 2.
OH
+
2. DMF, 110 ˚C
3 h, 60%
3
2
1
1. 0.5 equiv. CSI,
Et2O, 1 h, rt
2. Na2SO3, KOH
3. column chrom.
92% for 2
Cl
A
B
O
S
N
O
O
O
Cl
H
N
δ-
S
1. 1.05 equiv. CSI,
CH2Cl2, 96 h
reflux
O
O
N
O
O
δ+
δ-
NH
δ+
2. Na2SO3, KOH
59%
2
4
5
Scheme 1. Synthesis of azetidinone 5.
Figure 2. Possible transition states in CSI cycloaddition to 2.
When the progress of the cycloaddition of 0.5 equiv of CSI
to the mixture of 2 and 3 was monitored, a marked differ-
ence in the reactivity of 2 and 3 was observed. In a dry
ether solution at room temperature, the CSI addition to
a-pinene 3 was completed within 1 h,6a whereas the addi-
tion to cis-d-pinene 2 was negligible. After the usual
work-up, cis-d-pinene 2 and b-lactam 4 were easily sepa-
rated by simple crystallization of the resulting azetidinone
4. CSI addition to 2 was then successfully accomplished
by refluxing the mixture in CH2Cl2 for 96 h. The NMR
and GC studies on the crude product proved that the cyclo-
addition took place with high regio- and stereoselectivity
(ee >99%), resulting in only b-lactam 5 (Scheme 1).12
The transition state-searching algorithm implemented in
Gaussian03 converged to stable saddle points for both
models with single imaginary frequencies corresponding
to the cycloaddition step. The single point energies were
ꢀ1567.49232521 a.u. and ꢀ1567.48939210 a.u. for A and
B, respectively, which means that transition state A is
favored by 1.84 kcal/mol stabilization energy. Under the
reaction conditions applied, this energy difference can
explain the 20-fold higher reaction rate via transition state
A, which is in good agreement with the experimental find-
ings. To gain insight into the stereoelectronic features
explaining the difference, NBO14 calculations were per-
formed (Fig. 3). The results revealed that the cycloaddition
through A is less asynchronous, because the nN3–nꢁC2 over-
lap occurs in the transition state, while B does not exhibit
such an interaction. The synchronicity contributes to the
increased stability of the transition state. Interestingly,
an additional stabilizing nO–rꢁC6–H6 orbital overlap can be
observed in A, while such an interaction does not build
up in B. This partial electron donation from the oxygen
lone pair to the antibonding orbital of the C–H single
bond can be interpreted as an irregular C–H–O hydro-
gen-bond, which has been thoroughly studied in biological
systems and has been shown to have significant stabilizing
effect.15
The structure of azetidinone 5 was determined by X-ray
crystallography (Fig. 1), while the relative stereochemistry
was established by NOESY.
Figure 1. X-ray structure of azetidinone 5.
The considerable difference in the rates of CSI addition to 2
and 3 can be explained on the basis of the ab initio theoret-
ical results of Cossio et al.13 CSI addition proceeds via
[2+2] cycloaddition, where the transition state is partially
asynchronous and has a zwitterionic nature. The partial
positive charge that develops on the sp2 carbon attacked
by the nitrogen is significantly stabilized by any electron-
Figure 3. NBO analysis of DFT transition state models in CSI cycload-
dition to 2.

2444
Z. Szakonyi et al. / Tetrahedron: Asymmetry 18 (2007) 2442–2447
H
Boc
N
NH2
N
THF, TEA (2 equiv.)
Boc2O (1.3 equiv.)
O
O
1. 10% HCl/EtOH
rt, 1 h
CO2Et
cat. DMAP
rt, 12 h, 61%
2. NaHCO3
86%
5
7
8
NaOEt
EtOH
rt, 48 h
30%
LiOH/H2O
THF, rt, 7 h
91%
o
15% HCl
rt, 1 h, 91%
NH2
NHBoc
CO2H
NH2 . HCl
CO2H
NH2 . HCl
CO2H
H2O/dioxane
pH = 8
CO2Et
acidic or
Boc2O (1.1 equiv.)
94%
alkaline
hydrolysis
9
10
11
6
Scheme 2. Ring opening of 5 to b-amino acid derivatives.
Treatment of azetidinone 5 with hydrochloric acid resulted
in amino acid 6 with excellent yield. Similarly, amino ester
7 was prepared by acid-catalyzed ethanolysis of 5 (Scheme
2). Our results suggest that a change in the position of the
double bond of monoterpene, shifting the methyl group
from the neighborhood of the functional groups, yields
compounds with normal reactivity, similar to those with
a cyclopentane or cyclohexane skeleton. These results differ
significantly from those observed on a-pinene-based lactam
4, where acidic hydrolysis was unsuccessful.
OH
13
12
H
NH2 . X
N
O
CO2R
The N-Boc b-amino acid was prepared via two alternative
pathways. Treatment of b-lactam 5 with di-tert-butyl dicar-
bonate resulted in the N-Boc b-lactam 8, which was readily
opened under mild conditions. The reaction of 8 with aque-
ous LiOH in THF gave N-Boc b-amino acid 9 in excellent
yield (94%). Compound 9 was also prepared directly from
amino acid 6 by Boc protection (Scheme 2).
14
15: X = HCl, R = H
16: X = HCl, R = Et
Scheme 3. Synthesis of enantiomeric b-amino acid 15.
of the crude products after the transformations, the high
enantiomeric purity of the compounds prepared can be
regarded as proven.
Under strongly alkaline conditions, the cis-amino ester 7
underwent partial isomerization at the carboxylic function,
resulting in a cis- and trans-amino ester mixture, from
which 10 was isolated in low yield by chromatography.
3. Conclusion
Heating the reaction mixture or applying a stronger base
than sodium ethoxide (e.g., potassium tert-butoxide) led
to the decomposition of 7. The acidic or alkaline hydrolysis
of amino ester 10 to the corresponding amino acid 11 failed
completely. When highly acidic (5 M hydrochloric acid
solution) or alkaline (5 M sodium hydroxide solution)
was applied, only the decomposition of ester 10 was
observed (Scheme 2).
In conclusion, the highly regio- and stereospecific addition
of CSI to cis-d-pinene enantiomers resulted in b-lactam
enantiomers. b-Lactams 5 and 14 and the corresponding
b-amino acids 6 and 15 have similar reactivities to those
of cyclopentane and cyclohexane. The lactams and b-
amino acids prepared are highly valuable building
blocks for the synthesis of bioactive compounds, combina-
torial libraries and foldamers with exotic b-amino acid
units.
Since (+)-enantiomer 12 of isopinocampheol 1 is commer-
cially available, we prepared the enantiomeric (ꢀ)-cis-
d-pinene 13, b-lactam 14, amino acid 15, and amino
ester 16 successfully by the methods presented in Schemes
1–3.
4. Experimental
4.1. General experimental procedures
The enantiomeric purities of 2, 5, 7, and 14 were measured
by GC on a chiral column. Since there was no sign of the
presence of any other diastereomer in the NMR spectra
1H and 13C NMR spectra were recorded on a Bruker
Avance DRX 400 spectrometer (400 and 68 MHz) in an

Z. Szakonyi et al. / Tetrahedron: Asymmetry 18 (2007) 2442–2447
2445
appropriate solvent. Chemical shifts are expressed in ppm
(d) relative to TMS as the internal reference. J values are
given in Hz. FT-IR spectra were recorded on an AVATAR
330 FT-IR spectrometer (Thermo Nicolet, USA). Micro-
analyses were determined on a Perkin–Elmer 2400 elemental
analyzer.
(1R,4R,5S)-Enantiomer 13 was prepared as described
above, starting from a 1:1 mixture of (1R,4R,5S)-d-pinene
20
13 and (ꢀ)-(1S,5S)-a-pinene; ½aꢂD ¼ ꢀ58:0 (c 1.0, MeOH)
ee = 90% [similar to the ee of the commercial (+)-iso-
pinocampheol]; all the spectroscopic data were similar to
those for 2.
GC measurements were performed on a Perkin–Elmer
Autosystem XL GC, consisting of a flame ionization detec-
tor and a Turbochrom Workstation data system (Perkin–
Elmer Corporation, Norwalk, USA). The direct separation
of enantiomers was carried out on a CHIRASIL-DEX CB
column (2500 · 0.25 mm ID) at 60 ꢁC (1 mL/min flow rate)
for 2 and 13 and at 140 ꢁC (1 mL/min flow rate) for 5 and
14. Optical rotations were measured on a Perkin–Elmer
341 polarimeter. Melting points were determined on a
Kofler apparatus and are uncorrected. Chlorosulfonyl iso-
cyanate (CSI) and (ꢀ)- and (+)-isopinocampheols 1 and 12
were purchased from Aldrich. Diethyl ether was dried over
sodium wire, pyridine was dried over molecular sieve, and
dichloromethane was distilled over phosphorus pentoxide
before use. All the other solvents and reagents were used
as received from commercial sources.
4.3. (1R,2R,5S,6R,7R)-6,8,8-Trimethyl-3-azatricyclo-
[5.1.1.02,5]nonan-4-one 5
A mixture of (1S,4S,5R)-d-pinene 2 (5.0 g, 37 mmol) and
CSI (5.24 g, 37 mmol) was stirred and refluxed in 100 mL
of anhydrous dichloromethane for 96 h. Anhydrous
sodium sulfite (10.2 g, 81 mmol) in 70 mL of water was
then cautiously added dropwise to the cooled solution.
The pH was held at 7–8 by the addition of 20% aqueous
potassium hydroxide. After 2 h stirring at the appropriate
pH, the organic phase was separated and the aqueous layer
extracted with dichloromethane (2 · 50 mL). The com-
bined organic layer was dried over Na2SO4 and evapo-
rated. The crude product obtained was purified by flash
chromatography on a silica gel column (n-hexane/ethyl
acetate = 1:1), resulting in a white crystalline product 5.
X-ray data for 5 have been deposited in Cambridge Crys-
tallographic Data Centre (CCDC 658251).
Isolated compound 5: 3.9 g (59%); mp: 115–117 ꢁC (n-hex-
20
1
ane); ½aꢂD ¼ ꢀ85:0 (c 0.25, EtOH); ee = 99%; H NMR
(CDCl3, 400 MHz):
d 0.99 (3H, s); 1.12 (3H, d,
J = 7.5 Hz); 1.31 (3H, s); 1.35 (1H, d, J = 10.3 Hz); 1.83–
1.91 (1H, m); 2.12–2.23 (2H, m); 2.45–2.55 (1H, m); 3.05
(1H, dd, J = 2.7, 4.9 Hz); 4.02 (1H, t, J = 4.1 Hz); 5.50
(1H, br s). 13C NMR (CDCl3, 68 MHz): d 21.8, 21.9,
25.2, 27.8, 33.7, 40.5, 43.0, 48.4, 51.9, 52.8, 173.1. IR
(KBr, cmꢀ1): 3287, 2952, 2360, 1734, 1698, 1474, 1342.
Anal. Calcd for C11H17NO (179.26): C, 73.70; H, 9.56; N,
7.81. Found: C, 73.95; H, 9.34; N, 7.99.
4.2. (1S,4S,5R)-4,6,6-Trimethylbicyclo[3.1.1]hept-2-ene
((1S,4S,5R)-d-pinene) 2
A 1:1 mixture of (1S,4S,5R)-d-pinene 2 and (+)-(1R,5R)-a-
pinene 3 (13.6 g, 100.0 mmol), prepared as described by
Rykowski et al.,10 and 7.15 g (50.51 mmol) of CSI was stir-
red in 300 mL of anhydrous diethyl ether for 1 h. Then
10.2 g of sodium sulfite in 70 mL of water was cautiously
added dropwise to the solution. The pH was held at 7–8
by the addition of 20% aqueous potassium hydroxide.
After the separation of the organic phase, the aqueous
layer was extracted with diethyl ether (2 · 100 mL). The
combined organic layer was dried over Na2SO4 and evap-
orated at 228 mmHg and 45 ꢁC. Crystalline compound 4
was isolated by simple filtration, washing of the crystals
with n-hexane, and by recrystallization from isopropyl
ether. All the physical and analytical data on the resulting
azetidinone 4 matched exactly those reported in the litera-
ture.6 The mother liquor containing the crude unreacted
(1S,4S,5R)-d-pinene 2 in n-hexane solution was filtered
through a plug of silica gel, followed by distillation at
760 mmHg, resulting in a colorless oily product 2. Isolated
compound 2: 6.23 g (92%, calculated for 50% d-pinene con-
(1S,2S,5R,6S,7S)-Enantiomer 14 was prepared as described
20
above, starting from (1R,4R,5S)-d-pinene 13; ½aꢂD ¼ þ76:0
(c 0.25, EtOH; ee = 90%); the spectroscopic data and mp
were similar to those for 5. Analysis found: C, 73.98; H,
9.79; N, 7.59.
4.4. (1R,2R,3S,4R,5R)-2-Amino-4,6,6-trimethylbicyclo-
[3.1.1]heptane-3-carboxylic acid hydrochloride 6
Azetidinone 5 (0.70 g, 3.9 mmol) was stirred in a solution
of 15 mL of 15% hydrochloric acid at room temperature.
When the mixture became clear (approximately 1 h), the
solution was evaporated to dryness and the resulting white
crystalline product 6 was filtered off and washed with ace-
tone. Isolated compound 6: 0.83 (91%); mp: 185–187 ꢁC;
tent of the starting mixture); bp: 156–158 ꢁC (760 mmHg;
20
20
1
lit.:10 59–60 ꢁC, 22 mmHg); ½aꢂD ¼ þ66:0 (c 1.0, MeOH)
½aꢂD ¼ ꢀ23:0 (c 0.25, EtOH); H NMR (D2O 400 MHz):
d 0.99 (3H, s); 1.07 (3H, d, J = 7.1 Hz); 1.24 (3H, s); 1.28
(1H, d, J = 10.1 Hz); 1.82 (3H, t, J = 5.0 Hz); 2.18–2.30
(3H, m); 3.05 (1H, t, J = 9.1 Hz); 3.82 (1H, d,
J = 9.1 Hz); 8.05 (1H, br s), 12.94 (1H, br s). 13C NMR
(D2O, 68 MHz): d 21.1, 22.1, 27.5, 27.6, 38.5, 38.8, 43.8,
44.5, 46.1, 49.1, 174.2. IR (KBr, cmꢀ1): 3216, 2915, 1705,
1519, 1373, 1197; Anal. Calcd for C11H20ClNO2 (233.74):
C, 56.52; H, 8.62; N, 5.99. Found: C, 56.79; H, 8.91; N,
5.67.
ee = 95% (lit.10 = +48.6, neat); 1H NMR ðCDCl3,
400 MHz): d 1.00 (3H, s); 1.08 (3H, d, J = 7.6 Hz); 1.29
(3H, s); 1.30 (1H, d, J = 8.4 Hz); 2.00–2.11 (2H, m); 2.45
(1H, dt, J = 5.7, 8.5 Hz); 2.59–2.68 (1H, m); 5.53 (1H, d,
J = 8.7 Hz); 6.06–6.13 (1H, m). 13C NMR ðCDCl3,
68 MHz): d 18.4, 23.8, 27.4, 35.2, 37.9, 40.3, 42.1, 48.3,
129.7, 134.4. IR (KBr, cmꢀ1): 3363, 2940, 2360, 1366,
1250, 726. Anal. Calcd for C10H16 (136.23): C, 88.16; H,
11.84. Found: C, 88.31; H, 11.69.

2446
Z. Szakonyi et al. / Tetrahedron: Asymmetry 18 (2007) 2442–2447
(1S,2S,3R,4S,5S)-Enantiomer 15 was prepared as de-
4.7. (1R,2R,3S,4R,5R)-2-tert-Butoxycarbonylamino-4,6,6-
trimethylbicyclo[3.1.1]heptane-3-carboxylic acid 9
scribed above, starting from (1S,2S,5R,6S,7S)-lactam 14;
20
½aꢂD ¼ þ18:0 (c 0.25, EtOH); the spectroscopic data and
mp were similar to those for 6. Analysis found: C, 56.81;
Method A: Amino acid hydrochloride 6 (0.30 g, 1.3 mmol)
was dissolved in distilled water (5 mL) at 0 ꢁC and the pH
of the solution was adjusted to 8 with 3% sodium hydrox-
ide solution in the presence of bromothymol blue indicator.
Dioxane (5 mL) and di-tert-butyl dicarbonate (0.31 g,
1.4 mmol) were then added to the mixture. The reaction
mixture was stirred at room temperature, with pH 8 being
maintained with 3% sodium hydroxide solution. After stir-
ring for 6 h at room temperature, the solution was cooled
to 0 ꢁC and acidified with 5% aqueous hydrochloric acid
to pH 5, and the solution was then extracted with chloro-
form (3 · 30 mL). The combined organic layer was dried
ðNa2SO4Þ and evaporated, and the oily product obtained
was purified by flash chromatography on a silica gel col-
umn (n-hexane/ethyl acetate = 4:1), resulting in compound
9. In CDCl3, 1H NMR and NOESY measurements showed
H, 8.53; N, 6.24.
4.5. Ethyl (1R,2R,3S,4R,5R)-2-amino-4,6,6-trimethyl-
bicyclo[3.1.1]heptane-3-carboxylate 7
Azetidinone 5 (1.20 g, 6.7 mmol) was dissolved in 80 mL of
ethanol containing 10% dry hydrogen chloride. After stir-
ring for 1 h at room temperature, the mixture was evapo-
rated to dryness in vacuo. The residue was dissolved in
water (30 mL), basified with cold saturated sodium hydro-
gencarbonate and extracted with chloroform (3 · 50 mL).
The combined organic phase was dried over Na2SO4,
filtered and evaporated. The oily residue obtained was
purified by flash chromatography on a silica gel column
(toluene/ethanol = 9:1). Isolated compound 7: 1.30 g
the presence of two rotamers in a ratio of 73:27. Isolated
20
1
(86%) oil; ½aꢂ ¼ ꢀ30 (c 0.25, EtOH); H NMR ðCDCl3,
400 MHz): dD0.99 (3H, d, J = 8.1 Hz); 1.02 (3H, s); 1.16
(1H, d, J = 10.1 Hz); 1.26 (3H, s); 3.31 (3H, t,
J = 7.1 Hz); 1.43 (2H, br s); 1.82 (1H, t, J = 6.0 Hz); 2.21
(1H, dt, J = 6.0, 10.1 Hz); 2.49–2.59 (1H, m), 2.96 (1H, t,
J = 8.5 Hz); 3.62–3.70 (1H, m); 4.21 (2H, dd, J = 7.1,
14.1 Hz). 13C NMR ðCDCl3, 68 MHz): d 14.4, 21.7, 22.2,
28.1, 28.2, 37.2, 39.4, 47.0, 49.7, 49.9, 50.6, 60.2, 174.9.
IR (KBr, cmꢀ1): 2904, 1732, 1470, 1375, 1181, 1037. Anal.
Calcd for C13H23NO2 (225.33): C, 69.29; H, 10.29; N, 6.22.
Found: C, 69.51; H, 10.15; N, 6.53.
20
compound 9: 0.38 g (94%); mp: 121–123 ꢁC; ½aꢂD ¼ ꢀ7 (c
1
0.25, EtOH); H NMR ðCDCl3, 400 MHz): d 0.98 (3H,
d, J = 7.2 Hz, major + minor rotamers); 1.03 (3H, s,
major + minor rotamers); 1.25 (3H, s, major + minor rota-
mers); 1.28 (1H, d, J = 10.6 Hz, major + minor rotamers);
1.42 (9H, s, minor); 1.45 (9H, s, major); 1.78–1.88 (1H, m,
major + minor rotamers); 1.95–2.08 (1H, m, major + mi-
nor rotamers); 2.22–2.32 (1H, m, major + minor rotamers);
2.46–2.51 (1H, m, minor); 2.61–2.72 (1H, m, major); 2.98
(1H, dd, J = 7.5, 10.1 Hz, major); 3.10–3.19 (1H, m,
minor); 4.45 (1H, t, J = 10.0 Hz, major); 4.58 (1H, t,
J = 8.4 Hz, minor); 5.30 (1H, br s, minor), 7.23 (1H, br s,
major). 13C NMR ðCDCl3, 68 MHz): d 21.6, 22.4, 27.7,
28.1, 28.3, 28.4, 29.7, 36.0, 38.9, 46.2, 46.4, 47.0, 47.3,
47.8, 48.9, 50.5, 80.8, 157.7, 177.5. IR (KBr, cmꢀ1): 3313,
2915, 1713, 1659, 1405, 1174, 1051. Anal. Calcd for
C16H27NO4 (297.39): C, 64.62; H, 9.15; N, 4.71. Found:
C, 64.79; H, 9.37; N, 4.49.
(1S,2S,3R,4S,5S)-Enantiomer 16 was prepared as described
20
above, starting from (1S,2S,5R,6S,7S)-lactam 14; ½aꢂD
¼
þ22:0 (c 0.25, EtOH); the spectroscopic data and mp were
similar to those for 7. Analysis found: C, 69.30; H, 10.03;
N, 6.41.
4.6. (1R,2R,5S,6R,7R)-N-tert-Butoxycarbonyl-6,8,8-tri-
methyl-3-azatricyclo[5.1.1.02,5]nonan-4-one 8
Method B: N-Boc lactam 8 (0.30 g, 1.3 mmol) was dissolved
in THF (8 mL) and treated with LiOH (0.18 g in 3 mL of
water) at room temperature. The mixture was stirred at
room temperature for 7 h. The THF was removed in
vacuo, water (10 mL) was added, and the solution was
acidified to pH 3.5–4.0 with acetic acid and extracted with
ethyl acetate (3 · 30 mL). The combined organic phase was
dried over Na2SO4, and evaporated to give a colorless vis-
cous oil, which was purified by flash chromatography on a
silica gel column (n-hexane/ethyl acetate = 4:1), resulting
in compound 9, 0.37 g (91%).
To a stirred solution of azetidinone 5 (0.50 g, 2.8 mmol)
and dry THF (14 mL), triethylamine (0.56 g, 5.5 mmol),
di-tert-butyl dicarbonate (0.79 g, 3.6 mmol) and 10 mg of
4-dimethylaminopyridine were added. After stirring for
12 h at room temperature (the reaction was monitored by
means of TLC), the mixture was evaporated to dryness.
The oily residue obtained was purified by flash chromato-
graphy on a silica gel column (n-hexane/ethyl acetate = 4:1),
resulting in a white crystalline product 8. Isolated com-
20
pound 8: 0.48 g (61%): mp: 75–77 ꢁC (n-hexane); ½aꢂD
¼
1
ꢀ83 (c 0.25, EtOH); H NMR ðCDCl3, 400 MHz): d 0.99
(3H, s); 1.13 (3H, d, J = 7.5 Hz); 1.21 (1H, d,
J = 11.4 Hz); 1.31 (3H, s); 1.50 (9H, s); 1.51–1.55 (1H,
m); 1.86–1.91 (1H, m); 2.20–2.28 (1H, m); 2.47–2.55 (2H,
m); 3.05 (1H, dd, J = 2.7, 6.0 Hz); 4.29 (1H, dd, J = 3.8,
5.6 Hz). 13C NMR ðCDCl3, 68 MHz): d 21.7, 22.1, 25.6,
27.6, 28.1, 34.2, 39.7, 41.3, 48.2, 51.4, 55.2, 82.7, 148.0,
169.3; IR (KBr, cmꢀ1): 3310, 2925, 1743, 1665, 1407,
1181, 1055. Anal. Calcd for C13H23NO2 (279.37): C,
69.29; H, 10.29; N, 6.22. Found: C, 69.45; H, 10.15; N,
6.51.
4.8. Ethyl (1R,2R,3R,4R,5R)-2-amino-4,6,6-trimethyl-
bicyclo[3.1.1]heptane-3-carboxylate 10
To a solution of sodium (0.23 g, 10 mmol) in 30 mL of dry
ethanol, (1R,2R,3S,4R,5R)-aminoester 7 (1.13 g, 5 mmol)
was added in one portion. The solution was stirred at room
temperature for 3 days (the isomerization process was
monitored by means of TLC and GC). The solution was
next evaporated to approximately 5 mL, diluted with ice-
cold water (50 mL) and extracted with ethyl acetate
(3 · 50 mL). The combined organic layer was dried over

Z. Szakonyi et al. / Tetrahedron: Asymmetry 18 (2007) 2442–2447
2447
Szakonyi, Z.; Fulo¨p, F. Tetrahedron: Asymmetry 2003, 14,
¨
Na2SO4 and evaporated. The oily residue obtained was
purified by flash chromatography on a silica gel column
(toluene/ethanol = 9:1). Isolated compound 10: 0.38 g
´
´
3965–3972; (d) Szakonyi, Z.; Balazs, A.; Martinek, T. A.;
Fulo¨p, F. Tetrahedron: Asymmetry 2006, 17, 199–204.
¨
20
1
7. (a) Fulo¨p, F. Chem. Rev. 2001, 101, 2181–2204, and
¨
(30%) oil; ½aꢂ ¼ ꢀ17 (c 0.25, EtOH); H NMR ðCDCl3,
400 MHz): dD0.99 (3H, d, J = 8.1 Hz); 1.02 (3H, s); 1.22
(3H, s); 1.25–1.29 (1H, m); 1.30 (3H, t, J = 7.1 Hz); 1.49
(2H, br s); 1.80 (1H, t, J = 5.0 Hz); 1.92–1.99 (1H, m);
2.13–2.20 (1H, m); 2.57–2.67 (1H, m); 2.76 (1H, dd,
J = 7.1, 11.1 Hz); 3.73–3.77 (1H, m); 4.20 (2H, dd,
J = 7.1, 14.1 Hz). 13C NMR ðCDCl3, 68 MHz): d 14.2,
16.7, 22.0, 25.4, 28.0, 29.5, 34.6, 48.0, 48.5, 49.3, 50.8,
60.1, 174.5. IR (KBr, cmꢀ1): 2925, 1732, 1470, 1375,
1253, 1181; Anal. Calcd for C13H23NO2 (225.33): C,
69.29; H, 10.29; N, 6.22. Found: C, 69.56; H, 10.01; N,
6.65.
´
references cited therein; (b) Kuhl, A.; Hahn, M. G.; Dumic,
M.; Mittendorf, J. Amino Acids 2005, 29, 89–100.
8. (a) Hasenoehrl, A.; Galic, T.; Ergovic, G.; Marsic, N.;
Skerlev, M.; Mittendorf, J.; Geschke, U.; Schmidt, A.;
Schoenfeld, W. Antimicrob. Agents Chemother. 2006, 50,
ˇ
´
´
3011–3018; (b) Hamersˇak, Z.; Roje, M.; Avdagic, A.; Sunjic,
V. Tetrahedron: Asymmetry 2007, 18, 635–644.
9. (a) Enantioselective Synthesis of b-Amino Acids; Juaristi, E.,
Soloshonok, V. A., Eds.; Wiley-Interscience: New York,
2005; (b) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahe-
dron: Asymmetry 2005, 16, 2833–2891; (c) Davies, S. G.;
Mulvaney, A. W.; Russell, A. J.; Smith, A. D. Tetrahedron:
Asymmetry 2007, 18, 1554–1566; (d) Fulo¨p, F.; Martinek, T.
¨
´
A.; Toth, G. K. Chem. Soc. Rev. 2006, 35, 323–334, and
references cited therein; (e) Horne, W. S.; Price, J. L.; Keck, J.
L.; Gellman, S. H. J. Am. Chem. Soc. 2007, 129, 4178–4180;
(f) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev.
Acknowledgments
We are grateful to the Hungarian Research Foundation
(OTKA Nos. NF69316 and T049407) and the National
Research and Development Office, Hungary (GVOP-311-
2004-05-0255/3.0) for financial support.
´
2001, 101, 3219–3232; (g) Martinek, T. A.; Mandity, I. M.;
´
´
´
Fulo¨p, L.; Toth, G. K.; Vass, E.; Hollosi, M.; Forro, E.;
¨
Fulo¨p, F. J. Am. Chem. Soc. 2006, 128, 13539–13544; (h)
¨
´
´
Martinek, T. A.; Hetenyi, A.; Fulo¨p, L.; Mandity, I. M.;
¨
´
´ ´
Toth, G. K.; Dekany, I.; Fulo¨p, F. Angew. Chem., Int. Ed.
¨
2006, 45, 2396–2400; (i) Seebach, D.; Hook, D. F.; Glattli, A.
Biopolymers 2006, 84, 23–37.
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