Synthesis of cyclic constrained β-oxo-substituted α-amino acids

Article abstract of DOI:10.1081/SCC-120002404

Ru(II)-catalyzed RCM reaction with a 5,5-diene of (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine provided a spiroannulated cyclohexenone as substrate for conjugate additions of organocuprates. Acid hydrolysis gave β-oxo-substituted α-amino acids. Assignments of configurations are based on single crystal X-ray analyses.

Full text of DOI:10.1081/SCC-120002404

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SYNTHESIS OF CYCLIC CONSTRAINED β-OXO-
SUBSTITUTED α-AMINO ACIDS
Sonata Krikstolaityté a , Kristin Hammer a , Christian Rømming a & Kjell Undheim b
a Department of Chemistry , University of Oslo , Oslo, N-0315, Norway
b Department of Chemistry , University of Oslo , Oslo, N-0315, Norway
Published online: 16 Aug 2006.
To cite this article: Sonata Krikstolaityté , Kristin Hammer , Christian Rømming & Kjell Undheim (2002) SYNTHESIS OF
CYCLIC CONSTRAINED β-OXO-SUBSTITUTED α-AMINO ACIDS, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:4, 571-580, DOI: 10.1081/SCC-120002404
To link to this article: http://dx.doi.org/10.1081/SCC-120002404
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SYNTHETIC COMMUNICATIONS, 32(4), 571–580 (2002)
SYNTHESIS OF CYCLIC CONSTRAINED
b-OXO-SUBSTITUTED a-AMINO ACIDS
Sonata Krikstolaityte, Kristin Hammer,
Christian Rømming, and Kjell Undheim*
Department of Chemistry, University of Oslo,
N-0315 Oslo, Norway
ABSTRACT
Ru(II)-catalyzed RCM reaction with a 5,5-diene of (2R)-
a
2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine provided
spiroannulated cyclohexenone as substrate for conjugate
additions of organocuprates. Acid hydrolysis gave b-oxo-sub-
stituted a-amino acids. Assignments of configurations are
based on single crystal X-ray analyses.
INTRODUCTION
For some time we have been engaged in developing methodology for
the construction of exceptionally constrained a-amino acids which, when
incorporated into peptides, will constitute a powerful approach for generat-
ing structurally defined peptides as conformational probes and bioactive
agents.1 In particular, we have worked on the preparation of rigid
cyclic a-amino acids which have the a-carbon imbedded in a carbocyclic
*Corresponding author.
571
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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KRIKSTOLAITYTE ET AL.
structure.2–4 This report describes a method for the preparation of carbo-
substituted b-oxo derivatives. The carbon substituents in the target mol-
ecules were to be introduced by conjugate addition to an appropriately
constructed enone derived from the bislactim ether (2R)-2,5-dihydro-3,
6-dimethoxy-2-isopropylpyrazine as a chiral auxiliary. The cyclization rela-
tion of the geminal alkenyl derivative of the bislactim ether 2 as substrate
was to be effected by Grubbs methodology using a carbenoid ruthenium(II)
complex as the catalyst in the ring-closing metathesis (RCM) reactions.
Recent reviews highlight the importance and wide applicability of the
RCM methodology in the construction of cyclic structure.5–7
RESULTS AND DISCUSSION
A preliminary description of the preparation of the desired enone 3 in
Scheme 1 has been reported.8 The stereochemistry at the a-carbon in the
new amino acid is controlled by the configuration at C-2 in the bislactim
ether chiral auxiliary, or by the order of dialkylation of the bislactim ether
because the stereochemistry at the C-5 stereogenic centre in the bislactim
ether is determined by the second alkylation.2,3 Acrolein was used as
the second alkylation reagent for the lithiated monoalkylated bislactim
ether to yield substrate 1 by a 1,2-addition.2 The epimeric alcohols 1 can
Scheme 1.

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b-OXO-SUBSTITUTED a-AMINO ACIDS
573
be separated by chromatography. In this work, however, the epimer mixture
was converted directly into the ketone substrate 2 by a Swern oxidation.
2 mol% of the ruthenium(II) complex, bis(tricyclohexylphosphine)-
benzylidene ruthenium dichloride [Ru(II)], was used as the catalyst precursor
for the RCM reaction which was effected in 1,2-dichloroethane (DCE). The
cyclohexenone spirane 3 was isolated in a 69% yield after running the reac-
tion at 40ꢀC for 4 h. Presumably the reaction is initiated by attack from the
carbenoid catalyst onto the more electron rich butene double bond rather
than onto the carbonyl deactivated double bond. Once the initial adduct has
been formed, the electronic state of the second double bond becomes less
important for the further intramolecular progress of the reaction.
Lithium dimethyl- and diphenylcuprates were used in the conjugate
addition reaction to the cyclohexenone 3. The addition reactions were run in
diethyl ether at ꢁ78ꢀC. The reactions proceeded well to give the adducts 4
and 5 in good yields. The stereoselectivities, however, were disappointingly
low. With the smallest reagent, the dimethyl cuprate, the epimeric ratio
4a : 4b was 1 : 1. For the diphenylcuprate the isomer ratio 5a : 5b was 4 : 1.
On the other hand, the diastereomers were readily separated by flash chro-
matography and could be hydrolyzed separately to their respective amino
acid esters (vide infra).
1
Characteristic differences in the H and 13C spectra for the isomer
pairs were not observed. Therefore single crystal X-ray analyses were used
for configurational assignments to the products. In Figure 1 the thermal-
ellipsoidal plot of the phenyl adduct 5a is shown. Ellipsoids are shown at
50% probability. The absolute configuration at C40 [C(12) in the plot] was
established to be S relative to the known chirality of C2(R) and C4(S) [C(2)
and C4 in the plot, respectively].
Figure 1. Thermal-ellipsoid plot of the X-ray structure of compound 5a.

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KRIKSTOLAITYTE ET AL.
In a similar way the structure of the methyl adducts 4a and 4b have
been determined.9
The major adduct isomer from the reaction with lithium diphenylcup-
rate was compound 5a. In this structure the phenyl group has a cis-facial
relationship to the 6-methoxy group in the pyrazine ring. The findings may
be rationalized by a preferential reaction of the substrate in a form where
the cyclohexenone assumes a boat-like conformation as indicated in struc-
ture A in Scheme 1. The overlying pyrazine methoxy group in the conformer
A exerts less shielding of the cis-facial plane of the double bond towards
attack by the organometallic reactant. The stereochemical course may also
in part be assisted by coordination forces between the methoxy oxygen
and the cuprate. Many ligands coordinate with copper(I) to form relatively
stable complexes. It is therefore conceivable that a group, appropriately
positioned within the substrate, may be able to coordinate with the cuprate
reagent and influence the overall stereoselectivity and reactivity.10
The cycloalkenone 3 was cleaved under mild acid conditions to form
a unique cyclohexenone a-amino acid ester 6. The saturated oxo-amino
acid esters 7–9 were available in the same manner. Acid hydrolysis next
to the spirocentre is slow, and the reaction had to be run at ambient
temperature for several days. In contrast to strongly acidic conditions,
Scheme 2.

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575
hydrolysis under weakly acidic conditions does not proceed via the corre-
sponding unwanted 2,5-diketopiperazine.11 Hydrolysis of the latter would
yield an amino acid and not the methyl ester product. Also, hydrolysis of
diketopiperazines requires more forcing conditions.12 Also, under relatively
vigorous conditions, dipeptide formation becomes important. The cyclic
hydrolytic products are exceptionally constrained a-amino acids.
In conclusion, we have shown that an electrophilic diene from an
a,b-unsaturated ketone readily undergoes Ru(II)-benzylidene initiated
RCM reaction to form six-membered ring spirane. The latter can either be
hydrolyzed to an amino acid or be further carbosubstituted and subse-
quently hydrolyzed to the title amino acid derivatives.
EXPERIMENTAL
1H NMR spectra were recorded in CDCl3 at 300 MHz with Bruker
DPX 300 unless otherwise specified. The 13C spectra were recorded in
CDCl3 at 75 MHz unless otherwise specified. Chemical shifts are reported
in ppm using residual CHCl3 (7.24 ppm) and CDCl3 (77 ppm) as references.
The mass spectra were recorded under electron impact conditions (EI)
to 70 eV ionizing potential. The spectra are presented as m/z (% rel. int.).
The optical rotations were measured at ambient temperature. Dry THF was
distilled from sodium and benzophenone under argon. Dry 1,2-dichlor-
oethane was distilled from calcium hydride under argon. Solvents
were degassed by bubbling argon through. Bis(tricyclohexylphosphine)
benzylidene ruthenium dichloride was purchased from Strem Chemicals
Inc., Newburyport, MA.
X-ray Crystallographic Analysis Data for Compound 5a
Crystal data for C20H26N2O3 (5a), M ¼ 243.43, Orthorhombic,
P2b2121, a ¼ 7.922 (1), b ¼ 12.149 (1), c ¼ 19.481 (1) A, V ¼ 1874.87 (5) A3,
Z ¼ 4, Db ¼ 1.213 Mg mꢁ3, ꢀ ¼ 0.082 mmꢁ1, F(000) ¼ 736, T ¼ 150 (2) K,
measured 23539 reflections in 2y range 4.0–66.3ꢀ, Rint ¼ 0.026. 330 par-
ameters refined against 7067F2, R ¼0.037 for I0>2ꢁ(I0) and 0.044 for all
data (residual Áꢂ <0.32 e Aꢁ3). X-ray data were collected on a Siemens
SMART CCD diffractometer13 using graphite monochromated MoKa
radiation (ꢃ ¼ 0.71073 A). Data collection method: o-scan, range 0.6ꢀ, crys-
tal to detector distance 5 cm. Data reduction and cell determination were
carried out with the SAINT and XPREP programs.13 Absorption correc-
tions were applied by the use of the SADABS program.14 The structure was

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KRIKSTOLAITYTE ET AL.
determined and refined using the SHELXTL program package.15 The non-
hydrogen atoms were refined with anisotropic thermal parameters; hydro-
gen positions were determined from different Fourier plots and refined with
isotropic thermal parameters.
Atomic coordinates, bond lengths and angles, and thermal parameters
have been deposited at the Cambridge Crystallographic Data Centre and
allocated the deposition number CCDC 160145.
(2R,5S )-5-(3-Butenyl)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-(1-oxo-
2-propenyl)pyrazine (2). DMSO (105 mg, 1.36 mmol) in CH2Cl2 (0.34 ml)
was added to a solution of oxalyl chloride (86 mg, 0.68 mmol) in CH2Cl2
(1.80 ml) under argon at ꢁ60ꢀC. The mixture was stirred for 2 min before
a
solution of (2R,5S,10S/R)-5-(3-butenyl)-2,5-dihydro-3,6-dimethoxy-5-
(1-hydroxy-2-propenyl)-2-isopropylpyrazine (1) (200 mg, 0.68 mmol) in
CH2Cl2 (1.5 ml) was added dropwise to the mixture. The resultant reaction
mixture was stirred at ꢁ10ꢀC for 15 min, cooled to ꢁ60ꢀC and triethylamine
(0.36 ml) added. The reaction mixture was stirred for another 5 min at this
temperature before warming to ambient temperature. The resultant solution
was evaporated almost to dryness and the product isolated by flash chro-
matography using hexane : EtOAc 9 : 1; yield 145 mg (73%) of a colourless
oil. Found: C, 65.75; H, 8.22, Calc. for C16H24N2O3: C, 65.92; H, 8.21%.
1
[a]D-21.4 (c ¼ 0.90, CHCl3). H NMR (200 MHz): d 0.67 (3H, d, J 7 Hz,
CH3), 1.05 (3H, d, J 7 Hz, CH3), 1.82–2.12 (4H, m, 2 Â CH2), 2.33 (1H,
m, CH), 3.63 (3H, s, CH3O), 3.68 (3H, s, CH3O), 3.92 (1H, d, J 3 Hz, CH),
4.88 (2H, m, CH2¼), 5.61–5.67 (2H, m, CH2¼), 6.27–6.62 (2H, m,
2 Â CH¼). 13C NMR (50 MHz): d 17.62 (CH3), 20.18 (CH3), 29.02 (CH2),
31.25 (CH), 34.66 (CH2), 53.44 (CH3O), 53.51 (CH3O), 61.35 (C-2), 70.84
(C-5), 115.11 (CH2¼), 130.32 (CH2¼), 131.31 (CH¼), 138.94 (CH¼), 160.76
(C), 165.16 (C), 193.88 (C¼O). MS (EI): 292 (0.5, Mþ), 237 (55), 195 (100),
153 (34), 123 (10), 55 (22).
(2 R,5S ) - 2,5- Dihydro- 3,6- dimethoxy- 2-isopropylpyrazine-5-spiro-
(3-cyclohexen-2-one) (3). A solution of bis(tricyclohexylphosphine)benzyli-
dene ruthenium dichloride (130 mg, 0.16 mmol, 2 mol%) in dry degassed
1,2-dichloroethane (10 ml) was added to a solution of (2R,5S)-5-(3-bute-
nyl)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-(1-oxo-2-propenyl)pyrazine
(2) (2.26 g, 7.73 mmol) in dry degassed 1,2-dichloroethane (80 ml). The reac-
tion mixture was stirred at 40ꢀC for 4 h. The solvent was evaporated and the
product was purified by flash chromatography using hexane : EtOAc 19 : 1,
and then 9 : 1; yield 1.55 g of a colourless oil (76%). Found: C, 63.88; H,
7.70. Calc. For C14H20N2O3: C, 63.64; H, 7.58%. [a]D-21.7 (c ¼ 0.70,
1
CHCl3). H NMR (200 MHz): d 0.62 (3H, d, J 7 Hz, CH3), 1.05 (3H, d,
J 7 Hz, CH3), 1.90–2.63 (5H, m, 2 Â CH2, CH), 3.60 (3H, s, CH3O), 3.67
(3H, s, CH3), 4.30 (1H, d, J 3 Hz, CH), 5.90 (1H, m, CH ¼), 6.99–7.06

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577
(1H, m, CH¼). 13C NMR (50 MHz): d 16.61 (CH3), 19.30 (CH3), 22.40
(CH2), 30.57 (CH), 34.20 (CH2), 52.47 (CH3O), 52.55 (CH3O), 60.70
(C-2), 65.01 (C-5), 127.56 (CH¼), 151.41 (CH¼), 161.06 (C), 164.47 (C),
193.63 (C¼O). MS(EI): 264 (8, Mþ), 221 (100), 193 (17), 153 (35), 80 (29).
(2R,5S,40S )-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine-5-spiro-
(4-methylcyclohexan-2-one) (4a) and (2R,5S,40R)-2,5-dihydro-3,6-dimethoxy-
2-isopropylpyrazine-5-spiro(4-methylcyclohexan-2-one) (4b). The reagent was
prepared by addition of an etheral MeLi solution (0.86 ml, 1.25 mmol,
1.45 M) with stirring to a mixture of dry CuI(109 mg, 0.57 mmol) and
dry degassed diethyl ether (8 ml) under argon at 0ꢀC. A clear solution
was formed which was stirred at 0ꢀC for 10 min prior to use. A solution
of (2R,5S )-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine-5-spiro(3-cyclo-
hexen-2-one) (3) (150 mg, 0.57 mmol) in dry diethyl ether (2 ml) was added
with stirring to the cuprate solution at ꢁ78ꢀC and the stirring continued for
45 min at ꢁ78ꢀC. The reaction was quenched by injection of saturated
NH4Cl : conc. aq. NH3 solution (25 ml) (ratio 25 : 4) and the stirring con-
tinued until a deep blue colour had developed and all the solid had dissolved.
The two layers were separated, the aqueous layer extracted with diethyl
ether (3 Â 10 ml), the etheral solutions dried (MgSO4) and the ether distilled
off. The isomer ratio in the product was 1 : 1. The isomers were separated by
flash chromatography using hexane : EtOAc 9 : 1, 4a was eluted first.
(2R,5S,40S )-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine-5-spiro(4-
methylcyclohexan-2-one) (4a): yield 55 mg (35%) of a white crystalline solid,
mp 73ꢀC (crude). Found: C, 64.23; H, 8.64. Calc. for C15H24N2O3: C, 64.29;
1
H, 8.60%. [a]D þ28.9 (c ¼ 0.88, CHCl3). H NMR: d 0.63 (3H, d, J 7 Hz,
CH3), 1.01 (3H, d, J 7 Hz, CH3), 1.03 (3H, d, J 7 Hz, CH3), 1.74 (2H, m,
CH2), 2.12–2.27 (4H, m, 2 Â CH2), 2.45 (1H, m, CH), 2.79–2.86 (1H,
dd, CH), 3.63 (3H, s, CH3O), 3.66 (3H, s, CH3O), 3.88 (1H, d, J 3 Hz,
CH). 13C NMR: d 16.58 (CH3), 19.34 (CH3), 20.09 (CH3), 27.42 (CH2),
30.44 (CH), 31.29 (CH), 35.11 (CH2), 45.55 (CH2), 52.55 (CH3O), 52.61
(CH3O), 60.37 (C-2), 67.74 (C-5), 160.99 (C), 163.67 (C), 206.09 (C¼O).
MS (EI): 280 (2, Mþ), 237 (100), 209 (28), 153 (17).
The assigned structure has been verified by a single crystal X-ray
analysis.9
(2R,5S,40R-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine-5-spiro(4-
methylcyclohexan-2-one) (4b): yield 56 mg (35%) of a white crystalline solid,
mp 78ꢀC (crude). Found: C, 64.35; H, 8.95. Calc. for C15H24N2O3: C, 64.29;
H, 8.60%. HRMS: M 280.1784. Calc. for C15H24N2O3: 280.1786. [a]D þ56.1
1
(c ¼ 0.72, CHCl3). H NMR: d 0.62 (3H, d, J 7 Hz, CH3), 1.03 (6H, m,
2 Â CH3), 1.61–1.73 (2H, m, CH2), 1.92–1.95 (2H, m, CH2), 2.17–2.55
(4H, m, 2 Â CH, CH2), 3.63 (3H, s, CH3O), 3.68 (3H, s, CH3O), 3.90
(1H, d, J 3 Hz, CH). 13C NMR: d 16.45 (CH3), 19.24 (CH3), 22.39 (CH3),

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KRIKSTOLAITYTE ET AL.
28.32 (CH2), 30.49 (CH), 34.03 (CH), 37.02 (CH2), 45.69 (CH2), 52.49
(2 Â CH3O), 60.26 (C-2), 67.45 (C-5), 161.25 (C), 163.31 (C), 205.99
(C¼O). MS (EI): 280 (3, Mþ), 237 (100), 209 (27), 153 (16).
(2R,5S,40S-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine-5-spiro(4-
phenylcyclohexan-2-one) (5a) and (2R,5S,40R-2,5-dihydro-3,6-dimethoxy-
2-isopropylpyrazine-5-spiro(4-phenylcyclohexan-2-one) (5b) were prepared
as above from (2R,5S )-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine-
5-spiro(3-cyclohexen-2-one) (3) (204 mg, 0.77 mmol) and lithium diphenyl-
cuprate. The isomer ratio 5a : 5b in the crude product was 4 : 1. The isomers
were separated by flash chromatography using hexane : EtOAc 4 : 1, 5b was
eluted first.
(2R,5S,40S )-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine-5-spiro(4-
phenylcyclohexan-2-one) (5a): yield 145 mg (56%) of a crystalline solid, mp
82ꢀC (crude). Found: C, 69.70; H, 7.54. Calc. for C20H26N2O3: C, 70.10; H,
7.60%. HRMS: M 342.1931. Calc. for C20H26N2O3: 342.1943. [a]D þ 10.7
1
(c ¼ 0.98, CHCl3). H NMR: d 0.70 (3H, d, J 7 Hz, CH3), 1.11 (3H, d, J
7 Hz, CH3), 1.88–2.40 (7H, m, 3 Â CH2, CH), 2.82–3.02 (1H, m, CH), 3.75
(6H, s, 2 Â CH3O), 3.99 (1H, d, J 3 Hz, CH), 7.26–7.38 (5H, m, C6H5).
13C NMR: d 16.69 (CH3), 19.39 (CH3), 28.42 (CH2), 30.49 (CH), 36.16
(CH2), 41.80 (CH), 44.48 (CH2), 52.76 (CH3O), 52.84 (CH3O), 60.53
(C-2), 67.45 (C-5), 126.44 (CH), 126.57 (CH), 127.53 (CH), 128.53 (CH),
129.07 (CH), 144.43 (C), 160.64 (C), 164.09 (C), 205.52 (C¼O). MS (EI): 342
(12, Mþ), 299 (100), 257 (22), 153, (22).
The assigned structure has been verified by a single crystal X-ray
analysis.
(2R,5S,40R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine-5-spiro(4-
phenylcyclohexan-2-one) (5b): yield 35 mg (14%) of a crystalline solid,
mp 73ꢀC (crude). HRMS: M 342.1927. Calc. for C20H26N2O3: 342.1943.
1H NMR: d 0.71 (3H, d, J 7 Hz, CH3), 1.14 (3H, d, J 7 Hz, CH3),
1.88–1.91 (2H, m, CH2), 2.31–2.59 (4H, m, CH2, 2 Â CH), 3.13 (2H, d, J
9 Hz, CH2), 3.72 (3H, s, CH3O), 3.81 (3H, s, CH3O), 4.02 (1H, d, J 3 Hz,
CH), 7.25–7.47 (5H, m, C6H5). 13C NMR: d 16.57 (CH3), 19.29 (CH3), 27.42
(CH2), 30.57 (CH), 37.14 (CH2), 44.52 (CH), 44.68 (CH2), 52.62
(2 Â CH3O), 60.39 (C-2), 67.49 (C-5), 126.57 (CH), 126.67 (CH), 127.15
(CH), 128.67 (CH), 128.74 (CH), 144.57 (C), 161.06 (C), 163.7 (C), 205.40
(C¼O). MS (EI): 342 (5, Mþ), 299 (100), 257 (21), 153 (23).
Hydrolytic formation of cyclic a-amino acid esters (6–9). General pro-
cedure: The (2R,5S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine-5-
spirane (3, 4a, 4b, 5a) (0.70 mmol) was stirred with trifluoroacetic acid
(38 ml, 7.50 mmol, 0.2 M) and acetonitrile (38 ml) at ambient temperature
for 5 d. The solution was evaporated almost to dryness at reduced pressure,
water (15 ml) and dichloromethane (30 ml) were added and the aqueous

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b-OXO-SUBSTITUTED a-AMINO ACIDS
579
layer made alkaline (pH 10) by addition of conc. aq. ammonia. The mixture
was extracted with dichloromethane (2 Â 30 ml), the combined organic
layers dried (MgSO4), evaporated and the product isolated by flash chro-
matography using 3% methanol in dichloromethane.
Methyl (S)-1-amino-2-oxo-3-cyclohexene-1-carboxylate (6): yield 73%
of a colourless oil. HRMS: M 169.0745. Calc. for C8H11NO3: 169.0739.
[a]D-59.0 (c ¼ 0.30, CHCl3). 1H NMR: d 1.88–2.34 (6H, m, 2 Â CH2,
NH2), 3.68 (3H, s, CH3O), 6.06 (1H, m, CH¼), 6.95 (1H, m, CH¼).
13C NMR: d 23.70 (CH2), 33.69 (CH2), 52.73 (CH3O), 64.23 (C-1), 127.39
(CH¼), 150.27 (CH¼), 172.48 (C¼O), 194.77 (C¼O). MS (EI): 169 (10,
Mþ), 110 (100), 101 (63), 82 (37), 68 (33).
Methyl (1S,4S)-1-amino-4-methyl-2-oxocyclohexane-1-carboxylate (7):
yield 41% of a colourless oil. HRMS: M 185.1035. Calc. for C9H15NO3:
1
185.1051. [a]D-125.15 (c ¼ 0.33, CHCl3). H NMR: d 0.99 (3H, d, J 7 Hz,
CH3), 1.38–1.50 (2H, m, CH2), 1.74–1.90 (4H, m, CH2, NH2), 2.20 (1H, m,
CH), 2.48–2.57 (2H, m, CH2), 3.72 (3H, s, CH3O). 13C NMR: d 22.02 (CH3),
30.94 (CH2), 34.77 (CH), 37.84 (CH2), 47.92 (CH2), 52.73 (CH3O), 67.02
(C-1), 172.15 (C¼O), 206.67 (C¼O). MS (EI): 185 (7, Mþ), 126 (43), 98
(100), 81 (18), 54 (14).
Methyl (1S,4S )-1-amino-4-phenyl-2-oxocyclohexane-1-carboxylate (8):
yield 50% of a colourless oil. HRMS: M 247.1212. Calc. for C14H17NO3:
1
247.1208. [a]D-105 (c ¼ 0.4, CHCl3). H NMR: d 1.70–2.14 (5H, m, CH2,
NH2, CH), 2.69–3.07 (4H, m, 2 Â CH2), 3.84 (3H, s, CH3O), 7.22–7.40 (5H,
m, C6H5). 13C NMR: d 30.17 (CH2), 37.94 (CH2), 44.94 (CH), 47.02 (CH2),
52.88 (CH3O), 67.26 (C-1), 126.44 (CH, CH), 126.67 (CH), 126.88 (CH),
128.67 (CH), 143.37 (C) 172.02 (C¼O), 205.95 (C¼O). MS (EI): 247 (17,
Mþ), 188 (30), 160 (100), 114 (28).
Methyl (1S,4R)-1-amino-4-methyl-2-oxocyclohexane-1-carboxylate (9):
yield 48% of a colourless oil. HRMS: M 185.1042. Calc. for C9H15NO3:
185.1051. [a]D þ 6.3 (c ¼ 0.3, CHCl3). 1H NMR: d 0.99 (3H, d, J 7 Hz, CH3),
1.58–1.82 (5H, m, 2 Â CH2, CH), 2.11–2.52 (4H, m, CH2, NH2), 3.74 (3H, s,
CH3O). 13C NMR: d 20.06 (CH3), 28.35 (CH2), 33.14 (CH), 34.74 (CH2),
45.46 (CH2), 52.63 (CH3O), 67.35 (C-1), 173.37 (C¼O), 207.86 (C¼O).
MS (EI): 185 (5, Mþ), 126 (40), 98 (100), 81 (18), 54 (14).
REFERENCES
1. Goodman, M.; Shao, H. Pure Appl. Chem. 1996, 68, 1303 and
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ORDER
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Received in the UK January 30, 2001

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