Stereoselective synthesis of (1R,2S)- and (1S,2R)-1-amino-cis-3- azabicyclo[4.4.0]decan-2,4-dione hydrochlorides: Bicyclic glutamic acid derivatives

Article abstract of DOI:10.1016/j.tet.2004.07.104

Asymmetric synthesis of (1R,2S)- and (1S,2R)-1-amino-cis-3-azabicyclo[4.4. 0]decan-2,4-diones has been achieved. The underlying second generation asymmetric synthesis proceeds via a Strecker reaction with commercially available (R)-1-phenylethylamine (1-PEA) as chiral auxiliary, TMSCN as cyanide source and racemic ethyl 2-(2-oxocyclohex-1-yl)ethanoate. A ring closure addition-elimination reaction between an amide nitrogen and the ester functionality leads to the 1-amino-3-azabicyclo[4.4.0]decan-2,4-diones. The absolute configurations of the title compounds have been assigned based on detailed NMR-spectroscopic analysis and X-ray data. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.07.104

Tetrahedron 60 (2004) 10541–10545
Stereoselective synthesis of (1R,2S)- and
(1S,2R)-1-amino-cis-3-azabicyclo[4.4.0]decan-2,4-dione
hydrochlorides: bicyclic glutamic acid derivatives
*
Philippe Bisel, Kamalesh P. Fondekar, Franz-Josef Volk and August W. Frahm
Department of Pharmaceutical Chemistry, Albert-Ludwigs-University, Albert-Straße 25, D-79104 Freiburg, Germany
Received 24 June 2004; accepted 28 July 2004
Available online 22 September 2004
Abstract—Asymmetric synthesis of (1R,2S)- and (1S,2R)-1-amino-cis-3-azabicyclo[4.4.0]decan-2,4-diones has been achieved. The
underlying second generation asymmetric synthesis proceeds via a Strecker reaction with commercially available (R)-1-phenylethylamine
(1-PEA) as chiral auxiliary, TMSCN as cyanide source and racemic ethyl 2-(2-oxocyclohex-1-yl)ethanoate. A ring closure addition–
elimination reaction between an amide nitrogen and the ester functionality leads to the 1-amino-3-azabicyclo[4.4.0]decan-2,4-diones. The
absolute configurations of the title compounds have been assigned based on detailed NMR-spectroscopic analysis and X-ray data.
q 2004 Published by Elsevier Ltd.
1. Introduction
The actual diastereoselectivity of the stereodetermining
step of this sequence, namely the cyanide addition,
was shown to yield enantiomeric excesses of around
30%.4
As early as 1850, the German chemist Adolf Strecker
described the one-pot synthesis of the amino acid alanine by
means of heating a mixture of acetaldehyde, ammonia and
hydrogen cyanide in the presence of hydrochloric acid.1,2a–k
This procedure, named after its originator and extended to a
variety of carbonyl substrates, is still the most common
method of preparing large amounts of a-amino acids.
Nevertheless and in contrast to his assumption, Strecker did
not prepare one single compound but a racemic mixture of
the enantiomeric D- and L-alanines. Since nowadays
enantiomeric purity is one of the major issues in a-amino
acid synthesis, tremendous efforts have been put into the
development of asymmetric versions of Strecker’s protocol.
In 1963, a ‘Nature’ paper of Harada et al.3 describes a
modified three-step asymmetric synthesis of L-alanine with
an enantiomeric excess (ee) of 90% and an overall
chemical yield of 17%. Starting from acetaldehyde, (S)-
(K)-phenylethylamine ((S)-1-PEA) and hydrogen
cyanide, the authors obtained the corresponding
secondary a-aminonitriles, which were subsequently
hydrolysed and hydrogenolysed to L-alanine. Nevertheless,
later investigations showed that the enantiomeric excess
was essentially due to fractional crystallisation of the
intermediate secondary a-amino acid hydrochlorides.
As medicinal chemists we were particularly interested in
stereomerically pure and conformationally restricted
analogues of naturally occuring a-amino acids. In order to
get access to compounds bearing such structural features we
have developed and extensively studied the asymmetric
Strecker procedure starting from racemic 2-substituted
cycloaliphatic ketones. Depending on the reaction con-
ditions (temperature and nature of the solvent), the
established reaction sequence has proven to be a powerful
tool for the diastereoselective synthesis of all four feasible
stereomers of a series of carbocyclic a-amino acids with
vicinal stereocentres.5,6a–c
Carbocyclic a-amino acids as representatives of the a,a-
disubstituted a-amino acid family are widely used in the
isosteric replacement of proteinogenic amino acids resulting
in specific backbone conformations and increased stability
towards chemical and enzymatic degradations.7a–c More-
over, conformationally restricted analogues of glutamic
acid such as 1-aminoindanedicarboxylic acid (AIDA) or
1-aminocyclopentane-1,3-dicarboxylic acids (ACPD) have
been described as agonists and/or antagonists at both the
ionotropic (iGluRs) and the metabotropic glutamate
receptors (mGluRs). Recently, they have been used in
the characterisation and the subtype classification of
mGluRs.8a,b
Keywords: Asymmetric Strecker synthesis; 3-Azabicyclo[4.4.0]decan-2,4-
dione; Diastereoselectivity; X-ray analysis; Glutamic acid derivatives.
* Corresponding author. Tel.: C49-761-203-6334; fax: C49-761-203-
6351; e-mail: august.wilhelm.frahm@pharmazie-uni-freiburg.de
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.07.104

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P. Bisel et al. / Tetrahedron 60 (2004) 10541–10545
standard Stork-enamine procedure from cyclohexanone,
was reacted with enantiomerically pure (R)-1-phenylethyl-
amine under acidic catalysis and azeotropic removal of
water in benzene to yield a diastereomeric mixture of only
the two (E)-imines 2. It is noticable that, if the imine
condensation is run in higher boiling solvents, some
aminolysis of the ester could be observed.
Figure 1. 1-Amino-cis-3-azabicyclo[4.4.0]decan-2,4-diones.
The imine mixture was subsequently subjected to a Lewis
acid (ZnCl2) catalysed cyanide addition using trimethy-
silylcyanide (TMSCN) affording the four feasible dia-
stereomeric a-aminonitriles 3. Indeed, since the cyanide
addition to the prochiral imine carbon atom provides a new
stereocentre, the a-aminonitriles exhibit two adjacent
asymmetrically substituted carbon atoms. The stereo-
chemical outcome of this stereodetermining step depends
upon the reaction conditions, that is, the nature of the
solvent and the reaction temperature which allows the
reaction to be carried out either under kinetic (aprotic
solvents and low temperatures) or under thermodynamic
(protic solvents and higher temperatures) conditions.5,6a,b
For the purposes of developing a straight-forward synthesis
of the bicyclic amino imides 6a,b presented here, the
Herein, we wish to report on the synthesis of the bicyclic
imides 6a,b (Fig. 1) as conformationally restricted
templates, which mimic folded conformations of
glutamic acid, with a focus on the elucidation of the
relative and the absolute stereochemistry of the intermediate
a-aminonitriles.
2. Results and discussion
The synthetic route is exemplified using (R)-1-phenylethyl-
amine as the chiral auxiliary. Racemic ethyl 2-(2-oxo-
cyclohex-1-yl)ethanoate (1), prepared according to the
Scheme 1. Reagents and conditions: (i) (R)-1-PEA, p-TsOH, benzene, reflux, 16 h; (ii) TMSCN, ZnCl2 anhyd, MeOH, 0 8C to rt, overnight; (iii) H2SO4 concd
CH2Cl2, K20 8C, 3 days; (iv) CC on SiO2, cyclohexane/EtOAc 3:2; (v) for 4a–c, ether–HCl; (vi) extraction of the base with EtOAc, then stirring with SiO2,
,
cyclohexane/EtOAc 3:2, rt, 5 days; (vii) NHC4 HCO2K, Pd/C (10%), EtOH, reflux, 2 h.

P. Bisel et al. / Tetrahedron 60 (2004) 10541–10545
10543
cyanide addition was carried out under thermodynamic
control leading preferentially to the required trans amino
nitriles. Thus, at room temperature in methanol the four
feasible a-aminonitriles were obtained in a 44:30:18:8 ratio
as determined by 13C NMR-analysis of selected significant
carbon atoms.5
The subsequent hydrolysis of the nitriles to the correspond-
ing stable secondary a-amino amidoesters 4 proved
troublesome. Indeed, the hydrolysis of the sterically
hindered cyano group of the a,a-disubstituted aminonitriles
needs drastic reaction conditions and the aminonitriles are
prone to undergo a ‘retro-Strecker-reaction’ even in acidic
milieu under such conditions. Finally, the hydrolysis was
achieved in 73% yield with concd H2SO4 at K20 8C over a
period of 3 days avoiding any cleavage of the chiral
auxiliary. It could be shown by means of 13C NMR
spectroscopy that the stereochemical distribution of the four
stereoisomers was not altered during this specific type of
mild hydrolysis. Thus, we reasoned that the assignment of
the configuration of the different stereoisomeric secondary
aminonitriles 3 should be deducible from the corresponding
derived secondary amino amides 4. For this purpose, the
amino amidoesters 4 were separated by means of column
chromatography (CC) on silica gel eluted with cyclohexane/
ethyl acetate 3:2. Surprisingly, the CC did not lead to the
expected four compounds but to five different structures.
Three of the structures could be identified as the amino
amidoesters 4a–c, and two of them, which lack the ethyl
ester moiety, as the amino imides 5a,b by means of 1D- and
2D NMR techniques. We reasoned that the imides are the
desired follow-up products of the trans-amino amidoesters
and arise from a ring closure addition–elimination reaction
between the amide nitrogen and the ester functionality. In
this case, the low nucleophilicity of the amide nitrogen is
compensated by the geometric proximity of the electrophilic
reaction partner and finally by the extreme thermodynamic
stability of the bicyclic imides. We could show that ester 4a,
by far the major compound, is converted to 5a if stirred with
silica gel under exactly the conditions of the CC. The same
occurs with 4b, the second major ester, which is converted
to 5b. The third ester 4c, with cis configuration, did not yield
a bicyclic analogue under those reaction conditions. Indeed,
neither a bicyclic imide nor the theoretically feasible
bicyclic lactam rising from a nucleophilic displacement of
the ethyl ester moiety by the secondary amine nitrogen were
observed. Note, that neither the fourth diastereomeric ester
nor any of the possible follow-up compounds could be
traced after column chromatography (Scheme 1).
Figure 2. (a) (top) NOE-effect between H-a and H-2 in compound 5a and
(b) (bottom) X-ray structure of 5a.
compared to 6a. Thus, the enantiomeric 1S,2R configuration
could be assigned to the parent compounds 4b and 5b. Since
4a and 4b represent the two feasible trans configured esters,
the third ester 4c has to exhibit a cis configuration. In this
case, the relative stereochemistry cannot be unambiguously
confirmed by a NMR analysis since earlier investigations
from our group have shown that the exclusively accessible
3J C–H coupling constants are not a reliable parameter in
assessing the relative stereochemistry of 1,1-disubstituted-
2-substituted cyclohexane derivatives.9
Interestingly, the major ester 4a features 1R-configuration
which is the configuration of the chiral auxiliary. This
means that the diastereoselective cyanide addition occurs
with like-induction at C1 which is in accordance with all our
previous observations.4,5a–c The two feasible cis-amino-
nitriles represent 18 and 8% of the crude aminonitrile
mixture, repectively. Since the amino amidoester 4c is
isolated in more than 8%, it has to arise from the major cis
aminonitrile formed during the cyanide addition and as we
observe like-induction at C1, 4c must be 1R,2R configured.
The enantiomeric cis amino amidoester with 1S,2S
configuration would be accessible by the same pathway,
using (S)-1-phenylethylamine as chiral auxiliary. The final
bicyclic imides 6a and 6b are obtained in an approximate
ratio of 3:1 from a reaction sequence carried out with the
chiral auxiliary (R)-1-PEA. The same sequence run with the
enantiomeric auxiliary would lead to the same final products
with the opposite ratio.
The relative stereochemistry of 5a was deduced from a
positive NOE effect between Ha and H2 indicating a cis-
fusion of the rings (Fig. 2a).
The absolute configuration of 5a was finally derived from a
single crystal X-ray structure analysis and established as
aR,1R,2S (Fig. 2b). Thus, the absolute configuration of the
parent 4a could be deduced as trans-aR,1R,2S. Subsequent
hydrogenolysis of 5a under transfer catalysis conditions
with ammonium formate and Pd on charcoal affords the
primary amino imide 6a with 1R,2S configuration, whereas
hydrogenolysis of 5b yields the corresponding primary
amino imide 6b with the opposite optical rotation as
3. Conclusions
The application of the asymmetric Strecker protocol
followed by a ring closure reaction led to the synthesis of
the previously unknown 1R,2S- and 1S,2R-1-amino-cis-3-
azabicyclo[4.4.0]decan-2,4-dione hydrochlorides.

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P. Bisel et al. / Tetrahedron 60 (2004) 10541–10545
4. Experimental
residue. 3 g of the above residue were separated by means of
silica gel column chromatography eluting with cyclo-
hexane/EtOAc 3:2 yielding four fractions A, B, C, and D.
Fraction D consisted of pure 4a (1.04 g, 31%). Fraction A
consisted of pure 5a (292 mg, 10%). Fraction B was
rechromatographed on silica gel eluting with cyclohexane/
EtOAc 2:1 yielding 5b (170 mg, 6%) and 4c (328 mg, 10%).
Fraction C was rechromatographed on silica gel eluting with
cyclohexane/EtOAc 2:1 yielding 4b (295 mg, 9%).
4.1. General methods
Melting points were determined with a Mel-Temp II
apparatus (Devices Laboratory USA) and are uncorrected.
1H and 13C NMR spectra were recorded at 300 and
75.4 MHz, respectively, on a Varian Unity 300 spectrometer
with chloroform-d and methanol-d4, respectively, as
internal standards. The chemical shifts are reported as d
values using the solvent peaks as reference. Optical
rotations were measured on a Perkin–Elmer 241 polari-
meter. Column chromatography was carried out with Merck
silica gel Si60 (0.2–0.063 mm). TLC was performed on
Si60 F254 TLC plates from Merck. Drying of organic
extracts during the workup of reactions was performed over
anhydrous Na2SO4 with subsequent filtration. Evaporation
of the solvents was accomplished under reduced pressure
with a rotatory evaporator. HRMS (EI, 70 eV) was
performed on a Finnigan MAT 8200 spectrometer at the
Department of Biochemistry and Organic Chemistry,
University of Freiburg.
The amine bases 4a–c were each taken up in ether and
treated with ether–HCl to yield the corresponding hydro-
chlorides in quantitative yields (4a$HCl can be precipitated
directly from the crude oily residue upon treatment with
acetone and ether–HCl).
4.2.1. trans-Ethyl-2-[2(S)-carbamoyl-(2(S)-(1(R)-phenyl-
ethyl)amino)cyclohex-1(R)-yl]ethanoate hydrochloride
(4a$HCl). White solid, mp 200 8C; [a]2D5ZC1.85 (EtOH,
c 1.03); 1H NMR (CD3OD) d 1.22 (t, JZ7.0 Hz, 3H), 1.1–
1.3 (m, 3H), 1.3–1.6 (m, 3H), 1.74 (d, JZ6.7 Hz, 3H), 1.7–
1.8 (m, 1H), 1.9–2.1 (m, 1H), 2.4–2.6 (m, 2H), 2.7–2.80 (m,
1H), 4.13 (q, JZ7.0 Hz, 2H), 4.51 (q, JZ6.7 Hz, 1H), 7.4–
7.5 (m, 3H), 7.6–7.7 (m, 2H); 13C NMR (CD3OD) d 14.5,
20.8, 21.5, 22.4, 25.8, 26.0, 35.7, 38.9, 60.1, 62.1, 71.7,
129.0, 130.4, 130.9, 138.8, 172.4, 173.4; MS (CI, NH3,
45 eV): m/z (%) 333 (100) [MCHC]; HRMS (EI, 70 eV)
calcd for C18H26NO2 [MKCONH2] 288.1963. Found
288.1968.
4.1.1. (RS)-Ethyl 2-(2-oxocyclohex-1-yl)ethanoate (1).
Prepared from cyclohexanone by classical ‘Stork-enamine’
synthesis in a 0.1 M batch (30% yield). For NMR data see
Ref. 10.
4.1.2. E-Ethyl-2-[(2-(1(R)-phenylethyl)imino)cyclohex-
1(RS)-yl]ethanoate (2). A solution of 1 (5.5 g, 30 mmol),
p-toluenesulfonic acid (15 mg) and (R)-1-phenylethylamine
(4.5 g, 37 mmol) in dry benzene was refluxed using a Dean–
Stark apparatus for 16 h. The solvent was removed under
reduced pressure and the residue was dried under high
vacuum to yield the crude ketimine mixture which was used
without further purification in the cyanide addition step. 13C
NMR (CDCl3) d 14.0/14.1, 25.4/25.5, 25.5/25.7, 26.9/27.6,
28.7/28.9, 33.9/34.1, 36.6/36.8, 43.8/44.0, 57.4/57.5, 59.6/
59.7, 125.9/126.0, 126.3/126.3, 127.8/128.0, 146.5/147.0,
169.2/169.9, 173.2/173.4.
4.2.2. trans-Ethyl-2-[2(R)-carbamoyl-(2(R)-(1(R)-phenyl-
ethyl)amino)cyclohex-1(S)-yl] ethanoate hydrochloride
(4b$HCl). White solid, mp 195 8C; [a]2D5ZK22.04 (EtOH,
c 1.00); 1H NMR (CD3OD) d 1.1 (t, JZ7.1 Hz, 3H), 1.4–1.6
(m, 3H), 1.6–1.8 (m, 2H), 1.78 (d, JZ6.8 Hz, 3H), 1.9–2.2 (m,
2H), 2.2–2.4 (m, 1H), 2.45(dd, JZ16.9, 10.7 Hz, 1H), 2.5–2.7
(m, 2H),4.12(q, JZ7.1 Hz, 2H),4.50(q, JZ6.8 Hz, 1H),7.3–
7.4 (m, 3H), 7.4–7.6 (m, 2H);13C NMR(CD3OD) d 14.5, 22.0,
22.5,22.6,27.3,27.5,36.1,39.4,58.8, 62.0, 70.7, 129.6,129.9,
130.5, 138.2, 171.6, 173.7; MS (CI, NH3, 45 eV): m/z (%) 333
(100) [MCHC]; HRMS (EI, 70 eV) calcd for C18H26NO2
[MKCONH2] 288.1963. Found 288.1972.
4.1.3. Ethyl-2-[2(RS)-cyano-(2(RS)-(1(R)-phenylethyl)-
amino)cyclohex-1(RS)-yl]ethanoate (3). To a solution of
the ketimine mixture 2 (8.5 g, 29.6 mmol) and anhydrous
ZnCl2 (200 mg) in MeOH (100 mL), TMSCN (4.4 mL,
35 mmol) was added at 0 8C over a period of 30 min. The
reaction mixture was allowed to warm up to room
temperature and stirred over night. The solids were filtered
off, the solvent was evaporated and the residue was dried to
yield a mixture of the a-amino nitrile mixture 3 (8.9 g, 96%)
which was further reacted without purification.
4.2.3. cis-Ethyl-2-[2(R)-carbamoyl-(2(R)-(1(R)-phenyl-
ethyl)amino)cyclohex-1(R)-yl]ethanoate hydrochloride
(4c$HCl). White solid, mp 210 8C; [a]2D5ZC10.8 (EtOH,
c 1.12); 1H NMR (CD3OD) d 1.12 (t, JZ7.0 Hz, 3H), 1.4–
1.9 (m, 11H with 1.77 (d, JZ6.7 Hz, 3H)), 2.2–2.4 (m, 3H),
4.12 (q, JZ7.0 Hz, 2H), 4.47 (q, JZ6.7 Hz, 1H), 7.3–7.4
(m, 3H), 7.5–7.6 (m, 2H); 13C NMR (CD3OD) d 13.3, 20.8,
21.4, 23.0, 26.2, 28.4, 34.3, 39.0, 58.6, 61.0, 70.9, 128.1,
128.8, 129.2, 138.4, 171.0, 172.6; MS (CI, NH3, 45 eV): m/z
(%) 333 (100) [MCHC]; HRMS (EI, 70 eV) calcd for
C18H26NO2 [MKCONH2] 288.1963. Found 288.1967.
4.2. Hydrolysis of the nitrile mixture 3
A solution of the nitrile mixture 3 (5 g, 16 mmol) in CH2Cl2
(3 mL) was added dropwise to concd H2SO4 (50 mL) at
K20 8C. Stirring was maintained for a period of 3 days. The
reaction mixture was poured onto ice (600 mL) and the
solids filtered off. The filtrate was adjusted to pH 8 with
concd ammonia and extracted with EtOAc (3!150 mL).
The combined organic extracts were washed with water,
brine, dried with MgSO4, filtered, concentrated and finally
dried in high vacuum to yield 4.77 g (89%) of an oily
4.2.4. (1R,2S)-1-((1(R)-Phenylethyl)amino)-cis-3-azabi-
cyclo[4.4.0]decan-2,4-dione (5a). White solid, mp
170 8C; [a]2D5ZC12.5 (EtOH, c 1.00); H NMR (CDCl3)
1
d 1.0–1.4 (m, 7H with 1.28 (d, JZ6.7 Hz, 3H)), 1.4–1.5 (m,
1H), 1.6–1.8 (m, 2H), 1.8–2.0 (m, 1H), 2.18 (dd, JZ18.0,
2.8 Hz, 1H), 2.3–2.4 (m, 1H), 2.97 (dd, JZ17.9, 5.5 Hz,
1H), 4.0 (q, JZ6.7 Hz, 2H) 7.2–7.4 (m, 5H), 7.6 (s br, 1H);
13C NMR (CD3OD) d 23.0, 24.5, 26.6, 30.0, 32.1, 35.2,

P. Bisel et al. / Tetrahedron 60 (2004) 10541–10545
10545
37.7, 51.9, 61.1, 126.3, 126.83, 128.48, 147.52, 171.90,
173.65; MS (CI, NH3, 45 eV): m/z (%) 287 (100) [MCHC];
HRMS (EI, 70 eV) calcd for C17H22N2O2 286.1681. Found
286.1674.
Germany) for providing us with the X-ray structure of
compound 5a (CCDC No. 239246), E. Breitling for technical
assistance and V. Brecht for skilful NMR measurements.
4.2.5. (1S,2R)-1-((1(R)-Phenylethyl)amino)-cis-3-azabi-
cyclo[4.4.0]decan-2,4-dione (5b). White solid, mp
156 8C; [a]2D5ZK8.5 (EtOH, c 1.00); H NMR (CDCl3) d
1
References and notes
0.9–1.1 (m, 1H), 1.1–1.5 (m, 6H, with 1.32 (d, JZ6.72 Hz,
3H)), 1.5–1.8 (m, 3H), 1.8–1.9 (m, 1H), 1.9–2.0 (m, 1H),
2.2–2.4 (m, 1H), 2.49 (dd, JZ17.7, 7.0 Hz, 1H), 2.9–3.0 (m,
1H), 3.82 (q, JZ6.6 Hz, 1H), 7.1–7.4 (m, 5H), 8.1 (s br,
1H); 13C NMR (CDCl3) d 21.8, 22.4, 27.1, 27.3, 32.5, 34.8,
35.6, 53.15, 61.19, 126.3, 126.6, 128.1, 146.9, 172.3, 175.4;
MS (CI, NH3, 45 eV): m/z (%) 287 (100) [MCHC]; HRMS
(EI, 70 eV) calcd for C17H21NO2 286.1681. Found
286.1688.
1. Strecker, A. Liebigs Ann. Chem. 1850, 75, 27–45.
2. For reviews on asymmetric Strecker synthesis see the
following: (a) Wirth, T. Angew. Chem., Int. Ed. Engl. 1997,
36, 225–227. (b) Duthaler, R. O. Tetrahedron 1994, 50,
1539–1650. (c) Williams, R. M. Synthesis of Optically Active
a-Amino Acids; Baldwin, J. E., Magnus, P. D., Eds.; Organic
Chemistry Series: Pergamon: Oxford, 1989; Vol. 7, Chapter 5,
pp 208–229. For recent work on asymmetric Strecker synthesis
see: (d) Byrne, J.; Chavarot, M.; Chavant, P.; Vallee, Y.
Tetrahedron Lett. 2000, 41, 873–876. (e) Ishitani, H.;
Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem.
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Tetrahedron Lett. 1999, 40, 9385. (g) Ma, D.; Guozhi, T.; Zou,
G. Tetrahedron Lett. 1999, 40, 5753–5756. (h) Corey,
E. J.; Grogan, M. Org. Lett. 1999, 1, 157–160. (i) Ma, D.;
Tian, H.; Zou, G. J. Org. Chem. 1999, 64, 120–124. (j)
Dominguez, C.; Ezquerra, J.; Baker, S. R.; Borrelly, S.; Prieto,
L.; Espada, M.; Pedregal, C. Tetrahedron Lett. 1998, 39,
9305–9307. (k) Vergne, C.; Bouillon, J.-P.; Chastanet, J.;
Bois-Choussy, M.; Zhu, J. Tetrahedron: Asymmetry 1998, 9,
3095–3103.
4.3. Hydrogenolytic cleavage of the chiral auxiliary
Ammonium formate (150 mg) was added to a solution of 5a
and 5b, respectively, (100 mg, 0.35 mmol) and Pd/C (10%)
(80 mg) in ethanol (10 mL). The reaction mixture was
refluxed for 2 h, cooled, filtered through a pad of celite,
washed with methanol, concentrated and dried in high
vacuum yielding 6a (49 mg, 76%) and 6b (52 mg, 81%),
respectively. Each of the residues were treated with ether–
HCl to yield 6a$HCl and 6b$HCl, respectively, in
quantitative yields.
4.3.1. (1R,2S)-1-Amino-cis-3-azabicyclo[4.4.0]decan-2,4-
dione hydrochloride (6a$HCl). White solid, mp O250 8C
3. Harada, K. Nature 1963, 200, 1201–1202.
1
(dec); [a]2D5ZC13.1 (EtOH, c 1.00); H NMR (CD3OD) d
4. Harada, K.; Okawara, T. J. Org. Chem. 1973, 38, 707–710.
5. Volk, F. J.; Frahm, A. W. Liebigs Ann. 1996, 1893–1903.
6. (a) Fondekar, K. P. F.; Volk, F. J.; Khaliq-zu-Zaman,
S. M.; Bisel, P.; Frahm, A. W. Tetrahedron: Asymmetry
2002, 13, 2241–2249. (b) Pai Fondekar, K. P.; Volk, F. J.;
Frahm, A. W. Tetrahedron: Asymmetry 1999, 10, 727–735.
(c) Wede, J.; Volk, F. J.; Frahm, A. W. Tetrahedron: Asymmetry
2000, 11, 3231–3252.
1.5–2.0 (m, 7H), 2.1–2.4 (m, 1H), 2.4–2.6 (m, 1H), 2.70 (dd,
JZ18.0, 5.3 Hz, 1H), 3.00 (dd, JZ18.2, 10.8 Hz, 1H); 13C
NMR (CD3OD) d 20.29, 21.01, 25.90, 29.32, 33.98, 34.38,
59.65, 172.67, 172.99; MS (CI, NH3, 45 eV): m/z (%) 183
(100) [MCHC]; HRMS (EI, 70 eV) calcd for C9H14N2O2
182.1055. Found 182.1051.
4.3.2. (1S,2R)-1-Amino-cis-3-azabicyclo[4.4.0]decan-2,4-
dione hydrochloride (6b$HCl). White solid, mp O250 8C
7. (a) Kaul, R.; Balaram, B. Bioorg. Med. Chem. Lett. 1999, 7,
105–117. (b) Ohfune, Y.; Nanba, K.; Takada, I.; Kann, T.
Chirality 1997, 9, 459–462. (c) Horikawa, M.; Shigeni, Y.;
Yumato, N.; Yoshikawa, S.; Nakajima, T.; Ohfune, Y. Bioorg.
Med. Chem. Lett. 1998, 8, 2027–2032.
1
(dec); [a]2D5ZK14.1 (EtOH, c 0.9); H NMR (CD3OD) d
1.5–2.0 (m, 7H), 2.1–2.4 (m, 1H), 2.4–2.6 (m, 1H), 2.70 (dd,
JZ18.0, 5.3 Hz, 1H), 3.00 (dd, JZ18.2, 10.8 Hz, 1H); 13C
NMR (CD3OD) d 20.29, 21.01, 25.90, 29.32, 33.98, 34.38,
59.65, 172.67, 172.99; MS (CI, NH3, 45 eV): m/z (%) 183
(100) [MCHC]; HRMS (EI, 70 eV) calcd for C9H14N2O2
182.1055. Found 182.1053.
8. (a) Trist, D. G. Pharm. Acta Helv. 2000, 74, 221–229.
(b) Karcz-Kubicha, M.; Wedzony, K.; Zajaczkowski, W.;
Danysz, W. J. Neural Transm. 1999, 105, 1189–1204.
9. Frahm, A. W. Unpublished results.
10. Molander, G. A.; Harris, C. R. J. Am. Chem. Soc. 1995, 117,
3705–3716.
Acknowledgements
We wish to thank Prof. Dr. E. Weckert (Hasylab, Hamburg,