Synthesis of conformationally restricted glutamic acid analogs based on the spiro[3.3]heptane scaffold

Article abstract of DOI:10.1016/j.tetasy.2008.12.016

A library of isomeric glutamic acid analogs based on the spiro[3.3]heptane skeleton is designed. Two members of the library, (R)- and (S)-2-amino-spiro[3.3]heptane-2,6-dicarboxylic acid hydrochlorides, were synthesized. The stereochemistry of the synthesi

Full text of DOI:10.1016/j.tetasy.2008.12.016

Tetrahedron: Asymmetry 19 (2008) 2924–2930
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of conformationally restricted glutamic acid analogs based
on the spiro[3.3]heptane scaffold
Dmytro S. Radchenko a,b, Oleksandr O. Grygorenko a, Igor V. Komarov a,b,
*
a Department of Chemistry, Kyiv Taras Shevchenko University, Volodymyrska Street, 64, Kyiv 01033, Ukraine
b Enamine Ltd., Oleksandra Matrosova Street, 23, Kyiv 01103, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
A library of isomeric glutamic acid analogs based on the spiro[3.3]heptane skeleton is designed. Two
members of the library, (R)- and (S)-2-amino-spiro[3.3]heptane-2,6-dicarboxylic acid hydrochlorides,
were synthesized. The stereochemistry of the synthesized amino acids was determined using 1H–1H-
NOESY of their diastereomeric derivatives. The aminocarboxylate moiety and the carboxylic group in
the synthesized glutamic acid analogs are ‘fixed’ in space relative to each other due to the rigid spirocyclic
scaffold and therefore, they can be used to probe topologies of different glutamate receptors.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 16 December 2008
Accepted 17 December 2008
Available online 10 January 2009
1. Introduction
COOH
NH2
Design and synthesis of series of isomeric organic compounds
that possess functional groups mounted on a conformationally re-
stricted or rigid scaffold are of interest in medicinal chemistry for
structure–activity relationship (SAR) studies.1 Functional groups in
differentcompoundswithinsuchseries(libraries)havedifferentrig-
idly fixed dispositions in space. This can be used for mapping active
sites of biological targets, or in the search for the most efficient li-
gands for them. The rigidity of the scaffold might be beneficial for
the biological activity: if the fragments in a conformationally re-
stricted ligand are fixed in space exactly as needed for efficient inter-
action with a receptor or enzyme, the efficiency of the interaction
(due to decreasing of the entropy barrier) can be markedly higher
than that for the analogous conformationally flexible ligands.1
An example of such libraries is a set of spiro[2.2]pentane deriv-
atives ( )-1-( )-4 (Fig. 1).2 Compounds ( )-1-( )-4 are stereoiso-
mers; therefore, the whole set was called a ‘stereolibrary’. All the
compounds ( )-1-( )-4 mimic glutamic acid—an excitatory neuro-
transmitter in the central nervous system. The spiro[2.2]pentane
scaffold fixes the C–C bonds between the functional groups in dif-
ferent conformations; therefore, ( )-1-( )-4 were expected to
interact selectively with different types of glutamate receptors. In
fact, compounds ( )-1-( )-4 showed only modest or no activity at
ionotropic and metabotropic glutamate receptors, presumably, be-
cause the mutual orientation of the aminocarboxylate moiety and
the carboxylic group was unfavorable for the interaction with the
receptors.
HOOC
HOOC
NH2
( )-1
HOOC
HOOC
COOH
( )-2
NH2
COOH
COOH
NH2
( )-4
( )-3
Figure 1. ’Stereolibrary’ of glutamic acid analogs composed of spiro[2.2]pentane
derivatives (only one enantiomer is shown for each diastereomer).
modate functional groups at different mutual orientations. The
spiro[2.2]pentane skeleton allows only a limited number of spatial
arrangements of the functional groups, and as a consequence, com-
pounds with high biological activity are missing in the set.
A more diverse library, based on the norbornane skeleton, was
reported;3 the library is shown in Figure 2 (compounds ( )-5-( )-
12). Though all these compounds are less active than glutamic acid
at the glutamate receptor studied, the authors demonstrated that
some of the library members show receptor subtype selectivity.
Important conclusions regarding biologically active conformations
of the glutamic acid interacting with different subtypes of recep-
tors were drawn on the basis of this study.
This library illustrates the importance of scaffold in the design
of the libraries, in particular, the ability of the scaffold to accom-
2. Results and discussion
In designing a new library of glutamic acid analogs, we focused
our attention on the spiro[3.3]heptane skeleton, which allows one
* Corresponding author. Tel./fax: +38 044 239 33 15.
E-mail address: ik214@yahoo.com (I.V. Komarov).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.016

D. S. Radchenko et al. / Tetrahedron: Asymmetry 19 (2008) 2924–2930
2925
H
HOOC
H
COOH
NH2
COOH
NH2
HOOC
COOH
COOH
NH2
H
H
NH2
HOOC
HOOC
( )-5
( )-6
( )-7
( )-8
COOH
NH2
COOH
NH2
H
HOOC
HOOC
H
COOH
NH2
COOH
NH2
HOOC
H
HOOC
H
( )-12
( )-11
( )-10
( )-9
Figure 2. Norbornane-based library of glutamic acid analogs (one enantiomer is shown for each diastereomer).
1
5
7
COOH
HOOC
H
H2N
NH2
4
2
6
COOH
HOOC
3
H
13a
13b
COOH
H
H2N
COOH
H2N
COOH
H2N
COOH
COOH
H
H2N
HOOC
HOOC
H
H
COOH
14a,b
15a,b
COOH
16a,b
17a,b
H2N
COOH
COOH
H2N
COOH
COOH
H
H2N
H2N
COOH
H
H
COOH
COOH
H
18a,b
19a,b
20a,b
21a,b
Figure 3. Library of glutamic acid analogs composed of spiro[3.3]heptane derivatives. Only one enantiomer is shown for compounds 14–21.
to synthesize a larger library of isomeric glutamic acid analogs
than the known scaffolds. While the above described
spiro[2.2]pentane skeleton provides the possibility for synthesis
of eight isomeric glutamic acid analogs (four pairs of enantiomers),
the spiro[3.3]heptane scaffold, being still sufficiently conforma-
tionally restricted, gives rise to 18 isomers 13a,b–21a,b (nine pairs
of enantiomers, Fig. 3). Molecular models showed that spatial dis-
position of the aminocarboxylate moiety and the carboxylic group,
essential for the biological activity, is very diverse in the
spiro[3.3]heptane series. It should be noted that to the best of
our knowledge, the spiro[3.3]heptane scaffold has not been used
previously in construction of glutamic acid analogs.
Herein, we report both non-stereoselective and stereoselective
syntheses of the first two members of the library, namely,
compounds 13a and 13b, the molecules of which possess axial
dissymmetry. It is appropriate to note here that axially dissymmet-
ric spiro[3.3]heptane derivatives, for example, Fecht’s acid (spiro
[3.3lheptane-2,6-dicarboxylic acid), captured interest of chemists
long ago.4–6
ture,9 was transformed into its (bis)tosyl derivative 23, which, in
turn, was then used to alkylate the diisopropylmalonate in order
to form compound 24 possessing the spiro[3.3]heptane core. The
following ketal hydrolysis, hydantoine formation, decarboxylation,
and hydrolysis led to the target ( )-13. The overall yield of the syn-
thesis (calculated on the starting compound 29) is 8%.
The enantioselective synthesis of 13a and 13b was based on the
separation of diastereomeric derivatives, as shown in Scheme 2. It
commenced from the diester 24, which was used in the non-ster-
eoselective synthesis. Exhaustive hydrolysis gave the keto-dicar-
boxylic acid 30, which was then subjected to the decarboxylation
and esterification of the remaining carboxylic group. The resulting
keto-ester 32 smoothly underwent the asymmetric Strecker reac-
tion.10–13
Diastereoselectivity of the Strecker reaction was very low, but
the chiral auxiliary, (R)-a -phenylglycinol, allowed chromato-
graphic separation of the ꢀ1:1 mixture of diastereomers 33a and
33b on a silica gel column. Removal of the chiral auxiliary com-
pleted the synthesis.
In our syntheses, the construction of the cyclobutane rings was
based on malonate chemistry reported more than 100 years ago.7,8
Synthesis of the racemic mixture ( )-13 was performed first in
order to find optimal conditions for the formation of the
spiro[3.3]heptane scaffold and isolation of the target amino acid
(Scheme 1). Compound 22, which has been described in the litera-
The hydrolysis of the nitrile and ester groups in 33a and 33b
was carried out by prolonged reflux in 6 N HCl, which could cause
epimerization at the carbon atom bearing the distal carboxylic
group. We suspected this when measuring the specific rotation
of the final amino acids 13a.HCl and 13b.HCl: it turned out to be
surprisingly low for both enantiomers, ½a D20
¼ ꢂ2 and +2 corre-
ꢁ

2926
D. S. Radchenko et al. / Tetrahedron: Asymmetry 19 (2008) 2924–2930
MeO
Br
OMe
Br
MeO
MeO
MeO
MeO
OH
OH
COOiPr
COOiPr
CH2(COOiPr)2
LiAlH4
Et2O
NaH
53%
74%
22
TsCl
Py
29
80%
MeO
COOiPr
OTs
OTs
COOiPr
COOiPr
MeO
CH2(COOiPr)2
H3O+
92%
O
COOiPr
NaH
88%
MeO
MeO
23
24
25 (NH4)2CO3
77%
KCN
H
H
H
O
N
O
N
COOH
COOH
Pyridine
reflux
O
N
COOiPr
COOiPr
1. NaOH
COOH
2. H3O+
92%
HN
HN
HN
92%
O
O
1. NaOH
2. HCl
O
26
27
28
47%
( )-13·HCl
Scheme 1. Synthesis of racemic glutamate analog ( )-13.HCl.
Pyridine,
MeO
MeO
COOiPr
COOiPr
COOH
COOH
1) NaOH
COOH
reflux
O
O
2) H3O+
89%
H
86%
31
100%
30
24
CH2N2
H
COOMe
H
CN
HN
CN
HN
1) (R)-α-Phenyl-
glycinol
COOMe
H
+
COOMe
O
2) Me3SiCN
93%
Ph
Ph
33a
OH
OH
33b
32
1) Separation
2) Pb(OAc)4
80%
3) 6M HCl, reflux
13a.HCl and 13b.HCl
Scheme 2. Synthesis of individual enantiomers 13a.HCl and 13b.HCl.
spondingly (c 0.78, H2O). The literature data show that the optical
activity for similar compounds can be low indeed;14 nevertheless,
we decided to check the enantiomeric purity of 13a.HCl and
13b.HCl (non-crystallized). In order to do this, we transformed
the amino acids into the corresponding b-naphthylamide dimethyl
esters 34a,b under mild conditions (Scheme 3). Racemic ( )-34 was
synthesized from ( )-13.HCl to find optimal conditions for chiral
HPLC analysis of the derivatives 34a and 34b.
Good separation of enantiomers of the racemic mixture ( )-34
was achieved on a ChiralPack IBÒ column. Analysis of the 34a
and 34b under the same conditions showed that they are not race-
mic. Moreover, the enantiomeric purity of each compound (ꢀ86
ee) was essentially the same as the de of the aminonitriles 33a
and 33b (determined by the analysis of their 1H NMR spectra).
Thus, racemization did not occur at all under the drastic conditions
of the last steps of the 13a.HCl and 13b.HCl synthesis.
mers based on the correlation patterns in their H,H-NOESY spectra
(assignment of the signals in the 1H NMR spectra of 35a,b was done
using DQF-COSY, Long-Range COSY, and HSQC experiments).
For one of the diastereomers, 35a, there is a continuous path of
strong NOE correlations from H(8) to H(2) signals as shown in Fig-
ure 4, which proves the configuration shown. Another convincing
proof of the stereochemistry of 35a is the NOE correlation peak
H(2)–H(5a) (marked by a red arrow in Fig. 4), possible only for this
diastereomer. For the other compound, 35b, the strong NOE corre-
lation paths from H(8) and from H(2) are not convergent. These
facts allow the conclusion that the amino acid 13a possesses the
(aS)-configuration, and 13b—(aR). Of course, for the above hypoth-
eses on the stereochemistry of 35a,b and 13a,b to be correct, one
should be sure that the six-membered rings in 35a and 35b are
in the (flattened) chair conformations, in which the phenyl substi-
tuent adopts equatorial position. This assumption is verified by the
vicinal coupling constants between H(8) and H(9) in both the 35a
and 35b 1H NMR spectra. The constants are markedly different
(10.5 and 3.5 Hz in 35a; 10.5 and 2.5 Hz in 35b) and are character-
istic for axial-axial and axial-equatorial couplings, which should be
expected for the conformation shown in Figure 4.
To address the question of absolute stereochemistry, we synthe-
sized cyclic derivatives 35a and 35b (Scheme 4) and analyzed them
by NMR spectroscopy. As the absolute configuration of the stereo-
genic carbon center bearing phenyl substituent (C(8)) is known
(we used (R)-a-phenylglycinol), it was possible to assign stereoiso-

D. S. Radchenko et al. / Tetrahedron: Asymmetry 19 (2008) 2924–2930
2927
H
MeOOC
HN
COOMe
O
34a
or
1. SOCl2, MeOH
-10oC
COOMe
H
13a·
13b·
HCl
HCl or
MeOOC
HN
or ( )-13
2. NEt3
2-NpCOOH
DCC
HOBt
O
34b
or ( )-34
Scheme 3.
O
O
H
CN
HN
O
H
Ph
Ph
COOMe
N
COOMe
H
Ph
1. HCl (gas), MeOH
2. NaHCO3
3. Toluene, reflux
OH
33a
35a
or
or
70%
O
COOMe
H
COOMe
H
CN
HN
N
H
Ph
OH
35b
33b
Scheme 4.
added to a suspension of LiAlH4 (13.6 g, 358.4 mmol) in diethyl
ether (1000 ml) under stirring. After the addition, the mixture
was refluxed for 2 h. The excess of the lithium alanate was slowly
quenched by water (26.3 ml) (CAUTION! Exothermic reaction, use
external cooling). The precipitate was filtered off, washed by ether,
the filtrate was dried by MgSO4 and evaporated. The resulting diol
22 (23 g, 74%) was sufficiently pure (HPLC-MS analysis) for the
next step. 1H NMR (CDCl3), d: 1.94 (s, 4H, CCH2C), 3.12 (s, 6H,
OCH3), 3.29 (s, 2H, OH), 3.70 (s, 4H, CH2OH). 13C NMR (CDCl3), d:
34.15 ((CH2)2C(CH2OH)2), 36.51 (C(CH2)2C), 48.23 (OCH3), 69.06
(CH2OH), 99.41 (C(OCH3)2).
3. Experimental
General: Solvents were purified according to the standard pro-
cedures.15 Compound 29 has been synthesized from acetone fol-
lowing the procedure described in the literature.16 All other
materials were purchased from Acros, Merck, and Fluka. Melting
points are uncorrected. Analytical TLC was performed using Poly-
chrom SI F254 plates. Column chromatography was performed
using Kieselgel Merck 60 (230-400 mesh) as the stationary phase.
1H-, 13C NMR, and all 2D NMR spectra were recorded on a Bruker
Avance 500 spectrometer (at 499.9 MHz for protons, 124.9 MHz
for carbon-13). Chemical shifts are reported in ppm downfield from
TMS (1H, 13C) as an internal standard. HPLC-MS analyses were done
on an Agilent 1100 LCMSD SL instrument (chemical ionization (CI)).
Elemental analysis: Analytical Laboratory of Institute of Organic
Chemistry of NAS, Ukraine. Optical rotation values were measured
on a PerkinElmer 341 Polarimeter. Chiral HPLC analysis was done
at 20 °C on an Agilent 1100 instrument equipped with CHIRALPAK
IBÒ column (4.6*250 mm, 5 mkm), using UV detection (215 nm);
eluent—hexane/2-propanol 80:20, flow rate—1.3 mL/min.
3.2. (1-Hydroxymethyl-3,3-dimethoxycyclobutyl)methanol bis-
p-toluenesulfonate 23
The diol 22 (21.4 g, 121.4 mmol) was dissolved in dry pyridine
(200 ml) and cooled by an ice bath. p-Toluenesulfonyl chloride
(69.2 g, 364.2 mmol) was added in small portions to the cooled
solution under stirring in a dry atmosphere. The mixture was left
standing overnight. The precipitate was filtered off, the filtrate
was carefully poured into water (1000 ml), and the product was
extracted with CH2Cl2. The extract was washed with 3 N HCl and
water, dried by K2CO3/MgSO4, and was evaporated to dryness.
The product 23 (47 g, 80%) was sufficiently pure (HPLC-MS analy-
sis) for the next step. Mp 110 °C. 1H NMR (CDCl3, d): 1.92 (s, 4H,
3.1. (1-Hydroxymethyl-3,3-dimethoxycyclobutyl)methanol 22
A solution of diisopropyl 3,3-dimethoxycyclobutane-1,1-dicar-
boxy-late9 (51 g, 176.9 mmol) in diethyl ether (500 ml) was slowly

2928
D. S. Radchenko et al. / Tetrahedron: Asymmetry 19 (2008) 2924–2930
Ha
O
8
Ha
H
Hb
9
O
7
O
8
Ha
H
Ha
Hb
9
O
7
3
5
4
Hb
3
COOMe
2
strong NOE
weak NOE
5
Hb
Ph
H
Ha
4
6
Ph
Ha
6
2
N
H
12
H
N
H
1
12
1
COOMe
Hb
Ha
Hb
Hb
Ha
Hb
35b
35a
H(1a)
H(3a,b)
A
B
H(3a,1a)
H(12a)
H(5a)
H(5b)
H(12a)
H(1b)H(5a)
H(8)
H(12b)
H(5b)
H(8)
H(1b)
H(3b)
H(12b)
H(2)
H(2)
H(2)-H(5a)
H(8)
H(8)
Figure 4. Determination of absolute stereochemistry of 35a and 35b by H,H-NOESY experiments, A for 35a and B for 35b.
CH2), 2.46 (s, 6H, Ar-CH3), 3.01 (s, 6H, OCH3), 3.99 (s, 4H, CH2OTs),
7.35 (d, J = 8 Hz, 4H, CH), 7.74 (d, J = 8 Hz, 4H, CH). 13C NMR
(CDCl3), d: 21.67 (Ar-CH3), 32.42 (C(CH2)4), 36.53 (cyclic-CH2),
48.28 (OCH3), 71.45 (CH2OTs), 98.31 ((CH2)2C(OMe)2), 127.93,
129.99, 132.50 (CH2OSO2C), 145.09 (CCH3).
NMR (CDCl3), d: 21.55 (CH(CH)3), 28.06 (CH(CH3)2), 40.31, 48.62,
59.49, 69.10 (CH(CH3)2), 170.82 (COOCH(CH3)2), 206.11 (C@O).
3.5. 8,10-Dioxo-7,9-diaza-dispiro[3.1.4.1]undecane-2,2-
dicarboxylic acid diisopropyl ester 26
3.3. 6,6-Dimethoxy-spiro[3.3]heptane-2,2-dicarboxylic acid
diisopropyl ester 24
Keto-ester 25 (5 g, 17.7 mmol) was dissolved in a mixture of
ethanol (50 ml) and water (20 ml). Potassium cyanide (1.72 g,
26.4 mmol mmol) and ammonium carbonate (7.08 g, 86.3 mmol)
were added to the solution. The resulting mixture was stirred at
60 °C for 20 h. Then, pH of the mixture was adjusted to 3 by 3 N
HCl. The precipitate of 26 formed was filtered, washed with
water, and dried. White powder, 4.82 g (77%). 1H NMR (CDCl3), d:
1.22 (d, J = 6 Hz, 12H, OCH(CH3)2), 2.38 (d, J = 13.5 Hz, 2H,
NH(CO)C(CHH)2), 2.59 (s, 2H, (CH2)(CH2)C(COOi-Pr)2), 2.72 (d,
J = 13.5 Hz, 2H, NH(CO)C(CHH)2), 2.78 (s, 2H, (CH2)(CH2)C(COOi-
Pr)2), 5.03 (septet, J = 6 Hz, 2H, OCH(CH3)2), 6.48 (s, 1H,
(CH2)2CNHCO), 8.45 (s, 1H, CONHCO). 13C NMR (CDCl3), d: 21.55
(CH(CH3)2), 30.64, 40.83, 40.99, 45.04, 48.22, 58.67, 68.96, 156.15
(NH–CO–NH), 171.15 (CCOOH), 176.98 (10-C).
Diisopropylmalonate (19.34 g, 103 mmol) was slowly added
to a suspension of NaH (60% suspension in mineral oil) (4.94 g,
113 mmol) in dry DMF (120 ml) under stirring at such a rate
that the temperature was maintained below 70 °C. The ditosylate
23 (24.9 g, 51 mmol) and KI (0.86 g, 5.1 mmol) were added to
the mixture in one portion. The mixture was then stirred at
140 °C for 12 h. Then, it was cooled, poured into saturated aque-
ous solution of NH4Cl, and the products were extracted with
hexanes. The extract was dried with MgSO4 and evaporated.
The residue was distilled in vacuum. The unreacted diisopropyl-
malonate was distilled off first (64 °C/2 mm), followed by 24 as a
colorless oil (125–127 °C/2 mm). The yield was 14.91 g (88%). 1H
NMR (CDCl3, d): 1.22 (d, J = 6.5 Hz, 12H, CH(CH3)2), 2.20 (s, 4H),
2.57 (s, 4H), 3.11 (s, 6H, OCH3), 5.04 (septet, J = 6.5 Hz, 2H,
CH(CH3)2). 13C NMR (CDCl3), d: 21.51 (CH(CH3)2), 28.94
(C(CH2)4), 41.13, 44.72, 48.51, 48.97, 68.64 (CH(CH3)2), 99.57
(C(OMe)2), 171.22 (COOCH(CH3)2).
3.6. 8,10-Dioxo-7,9-diaza-dispiro[3.1.4.1]undecane-2,2-
dicarboxylic acid 27
The hydantoine 26 (4,59 g, 13 mmol mmol) was dissolved in
2 M aqueous NaOH (52 ml) and the resulting solution was main-
tained at ambient temperature overnight. The solution was then
acidified by 3 N HCl to pH 3 and was left at ꢀ5 °C for several hours
to allow the dicarboxylic acid 27 to precipitate completely. The
precipitate was filtered, washed with 1 N HCl, and dried. White
needles, 3.18 g (92%). 1H NMR (CD3OD), d: 2.39 (dd, J = 11 Hz and
J = 3 Hz, 2H, 5-CHH and 11-CHH), 2.59 (s, 2H, 1-CH2), 2.61 (dd,
J = 11 and 3 Hz, 2H, 5-CHH and 11-CHH), 2.76 (s, 2H, 3-CH2). 13C
NMR (CD3OD), d: 30.07 (C(CH2)4), 41.09 (1-CH2), 41.33 (3-CH2),
44.33 (5-CH2 and 11-CH2), 47.91 ((CH2)2C(COOH)2), 58.09 (6-C),
3.4. 6-Oxo-spiro[3.3]heptane-2,2-dicarboxylic acid diiso-propyl
ester 25
Compound 24 (6.32 g, 19.2 mmol) was stirred in 3 M aqueous
HCl (63 ml) for 8 h. The precipitate formed was filtered to yield
5 g (92%) of white crystals. Mp 72 °C. 1H NMR (CDCl3, d): 1.24 (d,
J = 6.4 Hz, 12H, CH(CH3)2), 2.78 (s, 4H, 1-CH2 and 3-CH2), 3.14 (s,
4H, 5-CH2 and 7-CH2), 5.07 (septet, J = 6.4 Hz, 2H, CH(CH3)2). 13C

D. S. Radchenko et al. / Tetrahedron: Asymmetry 19 (2008) 2924–2930
2929
157.24 (NH–CO–NH), 173.81 (CCOOH), 179.09 (10-C). Anal. Calcd
for C11H12N2O6: C, 49.26; H, 4.51; N, 10.44. Found: C, 49.22; H,
4.56; N, 10.40.
tained below 5 °C. The yellow solution of the diazomethane
formed was decanted. The ketoacid 31 (1 g, 6.5 mmol) was added
to the solution under stirring, the ice bath was removed, and the
stirring continued for 8 h. The solution was evaporated to yield yel-
low oil, 1.1 g (100% yield). 1H NMR (CDCl3), d: 2.45 (dt, J = 9 and
2 Hz, 2H), 2.57 (m, 2H), 3.09 (m, 2H, CH2), 3.15 (m, 3H, CH2 and
CHCOOMe), 3.70 (s, 3H, CH3). 13C NMR (CDCl3), d: 29.87
((CH2)4C), 32.97, 36.95, 51.87 (CH3), 58.81 (COCH2), 59.24 (COCH2),
175.24 (COOMe), 206.62 (C@O).
3.7. 8,10-Dioxo-7,9-diaza-dispiro[3.1.4.1]undecane-2-carboxylic
acid 28
The dicarboxylic acid 27 (2.78 g, 10.4 mmol) was dissolved in
pyridine (20 ml), and the solution was refluxed for 20 h. The mix-
ture was then evaporated, the residue triturated by concd HCl.
White crystals of the acid 28 were filtered, washed with cold water,
and dried. White crystals, 2.14 g (92% yield). 1H NMR (CD3OD, d):
2.75 (s, 2H), 2.96 (quintet, J = 8.8 Hz, 1H), 2,65 (dd, J = 8.8 Hz and
3 Hz, 1H), 2,52 (m, 2H), 2.2–2.4 (m, 5H). 13C NMR (CD3OD), d:
179.59, 177.33, 159.66, 66.10, 40.05, 37.79, 33.78, 32.99.
3.12.
spiro[3.3]heptane-2-carboxylic acid methyl ester 33a
3.13. (aR)-6-Cyano-6-((1R)-2-hydroxy-1-phenyl-ethylamino)-
(aS)-6-Cyano-6-((1R)-2-hydroxy-1-phenyl-ethylamino)-
spiro[3.3]heptane-2-carboxylic acid methyl ester 33b
(R)-phenylglycinol (0.9 g, 6.5 mmol) was added to the solution
of 32 (1 g, 6 mmol) in benzene (15 ml), and the resulting mix-
ture was stirred for 2 h. Benzene was evaporated; the residue
was dissolved in MeOH (15 ml). Trimethylsilylcyanide (1.5 ml,
12 mmol) was added to this solution at 0 °C. The solution was
stirred overnight at ambient temperature and evaporated to give
a crude mixture of two diastereomers at 1:1 ratio. Both isomers
were obtained in pure form by column chromatography on silica
gel (Hexane/EtOAc, 3:2 was used as an eluent). The chromato-
graphic separation yielded 300 mg (16%) of (aS,1R)-isomer 33a
(eluted first) and 340 mg (18%) of (aR,1R)-isomer 33b as well
as 1.1 g (59%) of mixed fractions, which can be subjected for fur-
ther separation. Yellow viscous oil. Spectral data for 33a:
3.8. 2-Amino-spiro[3.3]heptane-2,6-dicarboxylic acid
hydrochloride ( )-13.HCl
The hydantoine 28 (1 g, 4.5 mmol) and NaOH (1.8 g, 45 mmol)
were dissolved in water, and were heated in an autoclave at
150 °C for 20 h. The solution was evaporated in order to remove
ammonia, acidified with 3 M HCl, evaporated, and dried in vacuum.
( )-13.HCl was extracted from the residue by methanol. White
crystals, 0.49 g (47%). Mp > 240 °C (decomp.). 1HNMR (CD3OD), d:
2.28–2.60 (m, 6H), 2.71 (dd, J = 13.2 Hz and 2.4 Hz, 1H), 2.81 (dd,
J = 13.6 Hz and 3.2 Hz, 1H), 3.05 (quintet, J = 8 Hz, 1H, CHCOOH).
13C NMR (CD3OD), d: 33.89, 34.57, 39.16, 39.61, 43.46, 43.82,
54.17 (2-C), 173.76 (2-CCOOH), 177.74 (6-CHCOOH). Anal. Calcd
for C9H14ClNO4: C, 45.87; H, 5.99; N, 5.94. Found: C, 45.88; H,
5.95; N, 5.91.
½
a 2D0
ꢁ
¼ ꢂ42 (c 0.13, MeOH). 1H NMR (CDCl3), d: 1.81 (d,
J = 11.5 Hz, 1H), 2.08 (dd, J = 12 and 4 Hz, 1H), 2.16 (m, 2H),
2.26 (d, J = 12.5 Hz, 1H), 2.32 (m, 2H), 2.39 (d, J = 8 Hz, 1H),
2.62 (dd, J = 12 and 4 Hz, 2H), 2.90 (quintet, J = 8.5 Hz, 1H,
CHCOOMe), 3.57–3.75 (m, 6H), 3.97 (dd, J = 8.5 and 4 Hz, 1H,
CHHOH), 7.36 (m, 5H, C6H5). 13C NMR (CDCl3), d: 175.45
(C@O), 139.68, 128.62, 128.22, 128.01, 122.24 (CN), 66.66
(CH2OH), 62.35 (CHNH), 51.76, 49.63, 46.66, 46.26, 37.76,
3.9. 6-Oxo-spiro[3.3]heptane-2,2-dicarboxylic acid 30
Compound 24 (13.5 g, 41.1 mmol) was refluxed in a solution of
NaOH (9.1 g, 0.225 mol) in ethanol (150 ml) for 3 h. The solvent
was evaporated, the residue was triturated by 6 M aqueous HCl
(100 ml), stirred for 30 min. Then, the solution was evaporated,
dissolved in water, and evaporated again. This procedure was re-
peated three times in order to remove the residual HCl. The keto-
dicarboxylic acid 30 was extracted from the dried residue by
ethanol. The extract was evaporated. White crystals, 7.6 g (89%
yield), 1H NMR (DMSO-D6), d: 2.66 (s, 4H, CH2), 3.08 (s, 4H, CH2).
13C NMR (DMSO-D6), d: 27.84, 40.04, 48.35, 59.34 (COCH2),
173.16 (COOH), 207.41 (C@O).
37.40, 34.93, 33.05. 33b: ½a D20
ꢁ
¼ ꢂ68 (c 0.72, MeOH). 1H NMR
(CDCl3), d: 1.76 (d, J = 12.5 Hz, 1H), 2.04 (dd, J = 12.5 and 3 Hz,
1H), 2.25 (d, J = 8 Hz, 2H), 2.30–2.45 (m, 4H), 2.70 (dd,
J = 12.5 Hz and 3.5 Hz, 1H), 3.00 (quintet, J = 8 Hz, 1H,
CHCOOMe), 3.65 (m, 4H), 3.74 (dd, J = 4 and 11 Hz, 1H), 3.96
(dd, J = 8 and 4 Hz, 1H, CHHOH), 7.36 (m, 5H, C6H5); 13C NMR
(CDCl3), d: 175.31 (C@O), 139.62, 128.63, 128.23, 127.91,
122.23 (CN), 66.67 (CH2OH), 62.30 (CHNH), 49.63, 46.67, 46.13,
37.76, 37.54, 34.93, 33.06.
The aminonitriles 33a and 33b underwent retro-Shtrecker reac-
tion on standing: their NMR spectra showed appearance of ketone
32 upon storage at ambient temperature in several hours. There-
fore, the chromatographic separation and deprotection should be
performed immediately after obtaining the 33a and 33b.
3.10. 6-Oxo-spiro[3.3]heptane-2-carboxylic acid 31
The dicarboxylic acid 30 (7.6 g, 38.3 mmol) was dissolved in
pyridine (300 ml), and the resulting solution was refluxed for 5 h.
Pyridine was distilled off on a rotary evaporator; the residue was
combined with 6 N aqueous HCl, and was evaporated again. Com-
pound 31 was extracted from the residue by diethyl ether
(10 ꢃ 20 ml), the extract was dried over MgSO4, evaporated. White
solid, 5.1 g (86%). 1H NMR (CDCl3), d: 3.15 (m 3H), 3.01 (m, 2H).
2.55 (m, 2H), 2.42 (m, 2H). 13C NMR (CDCl3), d: 29.69 ((CH2)4C),
35.49, 36.87, 58.83 (COCH2), 59.19 (COCH2), 181.57 (COOH),
206.11 (C@O).
3.14. (aS)-2-Amino-spiro[3.3]heptane-2,6-dicarboxylic acid
hydrochloride 13aꢄHCl
3.15. (aR)-2-Amino-spiro[3.3]heptane-2,6-dicarboxylic acid
hydrochloride 13bꢄHCl
Compound 33a (150 mg, 0.5 mmol) was dissolved in 1:1 mixture
of CH2Cl2–MeOH (30 ml). The resulting solution was cooled to 0 °C,
and Pb(OAc)4 was added rapidly. After 5 min at 0 °C, a saturated
solution of NaHCO3 (7 ml) was added. The precipitate was filtered
andwashedbyCH2Cl2 (15 ml). Theaqueouslayerwasextractedwith
CH2Cl2 (2 ꢃ 20 ml). The combined organic extracts were dried over
MgSO4 and evaporated. The residue was dissolved in 5 N aqueous
HCl (30 ml) and refluxed for 2 h, then washed with Et2O
(3 ꢃ 15 ml) and evaporated to give 90 mg (80%) of 13a.
3.11. 6-Oxo-spiro[3.3]heptane-2-carboxylic acid methyl ester
32
A mixture of diethyl ether (20 ml) and 40% aqueous KOH solu-
tion (4.5 ml) was cooled in an ice bath. N-nitroso-N-methylurea
(1.46 g, 14.2 mmol) was added carefully to the cooled mixture un-
der stirring. The temperature of the reaction mixture was main-
Mp > 250 °C (decomp.). ½a D20
ꢁ
¼ ꢂ2 (c 0.78, H2O). 1H NMR (CD3OD),

2930
D. S. Radchenko et al. / Tetrahedron: Asymmetry 19 (2008) 2924–2930
d: 2.28–2.60 (m, 6H), 2.71 (dd, J = 13.2 and 2.4 Hz, 1H), 2.81 (dd,
J = 13.6 and 3.2 Hz, 1H), 3.05 (quintet, 1H, CHCOOH). 13C NMR
(CD3OD), d: 33.89, 34.57, 39.16, 39.61, 43.46, 43.82, 54.17 (2-C),
173.76 (2-CCOOH), 177.74 (6-CHCOOH). Anal. Calcd for C9H14ClNO4:
C, 45.87; H, 5.99; N, 5.94. Found: C, 45.83; H, 5.97; N, 5.90.
vent was evaporated, the residue was dissolved in toluene and re-
fluxed for 12 h. The mixture was evaporated, and the solid residue
recrystallized from a mixture of hexane-ethyl acetate to give
150 mg (70%) of 35a. ½a D20
ꢁ
¼ ꢂ23 (c 0.75, MeOH). Mp 115 °C. 1H
NMR (CDCl3), d: 1.92 (br s, 1H, NH), 2.12 (d, J = 12 Hz, 1H, 12a-
H), 2.16 (d, J = 12 Hz, 1H, 5a-H), 2.25 (pt, J = 8 Hz, 1H, 1a-H), 2.40
(dd, J = 8 and 10 Hz, 1b-H), 2.45 (two d, J = 8 Hz, 2H, 3a,b-H), 2.86
(d, J = 12 Hz, 1H, 12b-H), 2.88 (d, J = 12 Hz, 1H, 5b-H), 3.00 (quintet,
J = 8 Hz, 1H, 2-H), 3.67 (s, 3H, OCH3), 4.18 (pt, J = 10.5 Hz, 1H, 9-H),
4.26 (dd, J = 3.5 and 10.5 Hz, 1H, 8-H), 4.31 (dd, J = 3.5 and 10.5 Hz,
1H, 9-H),7.25–7.35 (m, 5H, arom.). 13C NMR (CDCl3), d: 32.83 (CH),
33.46 (C), 38.14 (CH2), 38.78 (CH2), 45.90 (CH2), 48.46 (CH2), 51.71
(CH3), 54.26 (CH), 56.45 (C), 73.65 (OCH2), 127.00 (CH), 128.56
(CH), 128.92 (CH), 138.23 (C), 172.59 (C@O), 175.55 (C@O).
Compound 35b was obtained analogously from 33b:
Compound 13b.HCl was obtained analogously to 13a.HCl from
33b. Mp > 250
a
°C (decomp.). ½a D20
¼ þ2 (c 0.78, H2O). The NMR
ꢁ
spectral data were identical to that for 13a.HCl.
3.16. (aS)-dimethyl 2-(1-naphthoylamino)spiro[3.3]hepta-ne-
2,6-dicarboxylate 34a
3.17. (aR)-dimethyl 2-(1-naphthoylamino)spiro[3.3]hepta-ne-
2,6-dicarboxylate 34b
Compound ( )-13ꢄHCl, 13aꢄHCl, or 13bꢄHCl (200 mg, 0.85 mmol)
was dissolved in dry methanol (5 ml), the solution was cooled to
ꢂ10 °C. Thionyl chloride (107 mg, 0.9 mmol) was added to the stir-
red solution; the stirring continued for 5 h, then the reaction mix-
ture was refluxed for 1 h. The solvent was distilled off, the residue
was dissolved in methanol again, and evaporated to dryness. The
dimethyl ester of 13 thus obtained was sufficiently pure for the
next synthetic operation. It was suspended in CH2Cl2 (200 mg,
½
a 2D0
ꢁ
¼ ꢂ72 (c 0.6, MeOH). Mp 136 °C. 1H NMR (CDCl3), d:1.91 (br
s, 1H, NH), 2.12 (d, J = 13 Hz, 1H, 5a-H), 2.16 (d, J = 13 Hz, 1H,
12a-H), 2.28 (pt, J = 8 Hz, 1H, 1b-H), 2.36 (pt, J = 13 Hz, 1H, 1a-H),
2.38 (pt, J = 13 Hz, 1H, 3a-H), 2.54 (pt, J = 8 Hz, 1H, 3b-H), 2.80 (d,
J = 12 Hz, 1H, 5b-H), 2.97 (d, J = 12 Hz, 1H, 12b-H), 3.03 (quintet,
J = 8 Hz, 1H, 2-H), 3.67 (s, 3H, OCH3), 4.20 (pt, J = 10.5 Hz, 1H, 9-
H), 4.24 (dd, J = 10.5 and 2.5 Hz, 1H, 8-H), 4.31 (dd, J = 10.5 and
2.5 Hz, 1H, 9-H), 7.30–7.50 (m, 5H, arom.). 13C NMR (CDCl3), d:
32.90 (CH), 33.51 (C), 38.35 (CH2), 38.95 (CH2), 46.26 (CH2),
48.22 (CH2), 51.71 (CH3), 54.14 (CH), 56.39 (C), 74.19 (OCH2),
127.04 (CH), 128.58 (CH), 128.92 (CH), 138.10 (C), 172.10 (C@O),
175.70 (C@O).
0.76 mmol in 5 ml) and combined with triethylamine (116
1.52 mmol), 2-hydroxybenzotriazole (112 mg, 0.82 mmol),
1-naphthoic acid (130 mg, 0.76 mmol), and then—N-[3-(dimethyl-
amino)propyl]-N0-ethylcarbodiimide
hydrochloride (160 mg,
lL,
0.83 mmol). The mixture was left stirring for 18 h. Dichlorometh-
ane (50 ml) was added, the solution was washed with saturated
aqueous NaHCO3 solution, then with water, dried over MgSO4,
and evaporated. The product obtained was subjected to chiral
HPLC analysis without recrystallization. 1H NMR (CDCl3), d: 8.28
(d, J = 8 Hz, 1H), 7.85 (d, J = 8 Hz, 1H), 7.81 (d, J = 8 Hz, 1H), 7.54
(d, J = 8 Hz, 1H), 7.48 (m, 2H), 7.36 (t, J = 8 Hz, 1H), 6.88 (s, 1H),
3.75 (s, 3H), 3.64 (s, 3H), 2.97 (quintet, J = 9 Hz, 1H), 2.83 (d,
J = 13 Hz, 1H), 2.71 (d, J = 13 Hz, 1H), 2.51 (d, J = 13 Hz, 1H), 2.42
(d, J = 13 Hz, 1H), 2.36 (m, 4H). 13C NMR (CDCl3), d: 175.75,
173.68, 169.45, 133.75, 133.59, 130.69, 130.23, 128.23, 127.11,
126.40, 125.40, 125.17, 124.60, 54.95, 52.68, 51.73, 44.09, 43.69,
38.58, 37.88, 34.52, 32.82.
References
1. Patrick, G. L.. In An Introduction to Medicinal Chemistry; Oxford University Press:
New York, 2005; pp 1–741.
2. de Meijere, A.; Ernst, K.; Zuck, B.; Brandl, M.; Kozhushkov, S. I.; Tamm,
M.; Yufit, D. S.; Howard, J. A. K.; Labahn, T. Eur. J. Org. Chem. 1999, 3105–
3115.
3. Tellier, F.; Acher, F.; Brabet, I.; Pin, J.-P.; Azerad, R. Bioorg. Med. Chem. 1998, 6,
195–208.
4. Fecht, H. Ber. 1907, 40, 3883–3888.
5. Backer, H. J.; Schurink, H. B. J. Proc. Acad. Wetenschoppen (Amsterdam) 1928, 31,
370.
6. Rice, L. M.; Grogan, C. H. J. Org. Chem. 1961, 26, 54–58.
7. Perkin, W. H. Ber. Dtsch. Chem. Ges. 1883, 16, 1787–1790.
8. Perkin, W. H. Ber. Dtsch. Chem. Ges. 1884, 17, 54–58.
9. Wang, G. Tetrahedron Lett. 2000, 41, 7139–7143.
10. Chakraborty, T. K.; Reddy, G. V.; Azhar Hussain, K. Tetrahedron Lett. 1991, 32,
7597–7600.
3.18. (aS,8R)-11-Oxo-8-phenyl-10-oxa-7-aza-dispiro[3.1.5.1]-
dodecane-2-carboxylic acid methyl ester 35a
11. Inaba, T.; Kozono, I.; Fujita, M.; Ogura, K. Bull. Chem. Soc. Jpn. 1992, 65, 2359–
2365.
12. Chakraborty, T. K.; Azhar Hussain, K.; Reddy, G. V. Tetrahedron 1995, 51, 9179–
9190.
13. Dave, R. H.; Hosangadi, B. D. Tetrahedron 1999, 55, 11295–11308.
14. Wynberg, H.; Houbiers, J. P. M. J. Org. Chem. 1971, 36, 834–842.
15. Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chemicals; Elsevier:
Oxford, 2003.
Compound 33a (215 mg, 0.7 mmol) was dissolved in CH2Cl2
(20 ml) and saturated with gaseous HCl for 15 min at 0 °C. MeOH
(5 ml) was added, and the resulting mixture was saturated with
HCl for another 15 min. The reaction mixture was stirred overnight
at ambient temperature, and then evaporated. The residue was
treated by CH2Cl2 (20 ml). The resulting solution was washed with
saturated aqueous NaHCO3 and dried over Na2SO4 Then, the sol-
16. Rynpod, U. G. Becnybr Rbedcrouo yybdepcbnena. Xbvbz 1990, 31, 37–39.