Synthesis of 4-amino derivatives of 5-oxoproline

Article abstract of DOI:10.1002/ejoc.200700346

The possibility of obtaining the stereoisomeric derivatives of 5-oxoproline and glutamic acid with a tertiary amino group at C-4, using the nucleophilic substitution of bromine in dimethyl (2S,4RS)-4-bromo-N-phthaloylglutamate with secondary amines follow

Full text of DOI:10.1002/ejoc.200700346

FULL PAPER
DOI: 10.1002/ejoc.200700346
Synthesis of 4-Amino Derivatives of 5-Oxoproline
Victor P. Krasnov,*[a] Alexey Yu. Vigorov,[a] Irina A. Nizova,[a] Tatyana V. Matveeva,[a]
Alexander N. Grishakov,[a] Iliya V. Bazhov,[a] Andrey A. Tumashov,[a] Marina A. Ezhikova,[a]
and Mikhail I. Kodess[a]
Keywords: Amino acids / Nucleophilic substitution / Hydrolysis / γ-Lactams / Diastereoselectivity
The possibility of obtaining the stereoisomeric derivatives of
5-oxoproline and glutamic acid with a tertiary amino group
at C-4, using the nucleophilic substitution of bromine in di-
methyl (2S,4RS)-4-bromo-N-phthaloylglutamate with sec-
ondary amines followed by resolution of diastereomers and
removal of protecting groups has been studied. We have
shown that the reaction with arylamines results in optically
pure 5-oxoproline derivatives in high yields. In the case of
more basic amines, the reaction is accompanied by racemiza-
tion, and the target products can be isolated only as dia-
stereomeric racemates.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
of less importance,[3a,4b,5e,6a,7] while communications con-
cerning the synthesis of 4-amino derivatives of 5-oxoproline
have described only the preparation of compounds with a
primary amino group in position 4 (in some cases an acyl-
ated one).
Previously, we have developed synthetic routes for 4-sub-
stituted derivatives of glutamic acid which are based on the
nucleophilic substitution of a halogen atom in (S or R)-4-
halogen-N-phthaloylglutamates[8] followed by the resolu-
tion of diastereomers and the removal of protecting groups.
According to the above methods we prepared glutamic acid
derivatives containing nitrogen,[9] oxygen,[10] sulfur,[11] and
phosphorus[12] atoms in position 4. When there is a func-
tional group (OH, SH, or NH2) in position 4 of glutamic
acid able to undergo ring formation, protecting groups re-
moval by acidic hydrolysis can be accompanied by heterocy-
clic ring closure (Scheme 1).[11,13] Moreover, any of the pro-
cess steps can be accompanied by racemisation.
Introduction
(S)-5-Oxoproline (pyroglutamic acid) plays an important
role in metabolic processes in living beings. 5-Oxoproline is
part of a number of neuropeptides and peptide hormones.[1]
Many 5-oxoproline derivatives exhibit biological activity
and have been used as probes for studying the action of
enzymes and cellular membrane receptors.[2] Consequently,
the conformationally restricted analogues of biologically
active peptides have been obtained.[2c,3] Stereoisomers of 5-
oxoproline derivatives have been used as convenient chiral
synthons and efficient chiral resolving agents.[4] The car-
bonyl group of the lactam cycle in substituted 5-oxoprolines
can be selectively reduced,[4b] which opens the way to the
corresponding optically pure substituted prolines. Deriva-
tives of 5-oxoproline possess significant synthetic potential
and are promising both for asymmetrical syntheses on their
basis, and for obtaining new physiologically active com-
pounds.
This discussion also applies to the 4-substituted deriva-
tives of proline. The electrophilic addition to lactam enol-
ates generated from 5-oxoproline,[5] or the transformation
of the hydroxy group in 4-hydroxyproline followed by oxi-
dation[6] have been applied for the synthesis of the stereoiso-
mers of 4-substituted 5-oxoprolines. Using these methods
4-substituted 5-oxoprolines containing C-4–C, C-4–O and
C-4–N bonds have been prepared. However, up to now a
limited number of 4-amino-substituted 5-oxoprolines have
been obtained using these methods as well as other methods
[a] I. Ya. Postovsky Institute of Organic Synthesis of RAS (Ural
Division),
22/20, S. Kovalevskoy/Akademicheskaya St., 620041 Ekaterin-
burg, Russian Federation
Fax: +7-343-3741189
E-mail: ca@ios.uran.ru
Scheme 1.
Eur. J. Org. Chem. 2007, 4257–4266
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4257

V. P. Krasnov et al.
FULL PAPER
For the purpose of obtaining the stereoisomers of
5-oxoproline and glutamic acid derivatives with tertiary
amino groups at C-4, we have studied and report herein the
possibility of applying the nucleophilic substitution of Br
in a 4-bromo derivative of glutamic acid with subsequent
resolution of diastereomers, deprotection of functional
groups, and then lactam ring closure.
Results and Discussion
The starting compound for the synthesis of 4-substituted
Figure 1. X-ray structure of glutamic acid derivative (2S,4S)-2.
5-oxoprolines
was
dimethyl
(2S,4RS)-4-bromo-N-
phthaloylglutamate [(2S,4RS)-1].[8a] Since the optical purity
of the starting compound was very essential in our study,
we have verified that starting compound (2S,4RS)-1 does
not contain detectable amounts of (2R) isomers by using
HPLC performed with a chiral column (Chiralcel OD-H).
The nucleophilic substitution of Br in (2S,4RS)-1 by sec-
ondary amines of different basicity such as N-methylaniline,
2-methylindoline, dibenzylamine, and piperidine, resulted in
diastereomers of dimethyl 4-amino-N-phthaloyl-substituted
glutamates (2–5, Scheme 2).
Compounds 3 and (2S,4S,2ЈS)-3 were obtained pre-
viously starting from (2S,4RS)-1 and 2-methylindoline.[9e]
Interest in preparing compounds combining fragments
of dibenzylamine and amino acids is caused by the fact that
the dibenzylamine fragment is incorporated into com-
pounds possessing neuroprotective activity, improving
memory and cognitive abilities in the experiments in ani-
mals.[14]
It has been found that interaction of (2S,4RS)-1 and di-
benzylamine results not only in the target product 4, but
also in the product of the γ-elimination of HBr, di-
methyl (Z)-1-phthalimidocyclopropane-1,2-dicarboxylate
(6, Scheme 3), similar to a previous report.[15]
Scheme 3.
Scheme 2.
To optimise the preparative method for 4, we studied the
effect of the reaction conditions on the product ratio. The
Product 2 was formed while refluxing (2S,4RS)-1 and N- reaction was carried out in refluxing benzene, dioxane,
methylaniline in CH3CN. It has been found that the interac- CH3CN, EtOH or MeOH for 10 h. The reaction mixtures
1
tion of derivative (2S,4RS)-1 and N-methylaniline proceeds were analysed by HPLC and H NMR spectroscopy.
diastereoselectively resulting in the predominant formation
It has been found that the degree of conversion of start-
of the threo diastereomer similar to the reaction of ing (2S,4RS)-1 increases with increasing solvent polarity,
(2S,4RS)-1 with primary aromatic amines.[9b–9d] The ratio but the yield of side product 6 also grows (Table 1). Com-
of (2S,4S)-2/(2S,4R)-2 in the reaction mixture was 83:17, pound 6 is practically not formed in benzene and dioxane;
1
according to H NMR and HPLC data. When the reaction in CH3CN, EtOH and MeOH the yield of 6 was 10%, 58%,
of (2S,4RS)-1 with N-methylaniline was carried out in and 81%, respectively. Moreover, the reaction in EtOH was
EtOH the yield (about 90%) and the diastereomeric com- accompanied by the partial transesterification (up to 30%,
position of product 2 were practically the same.
Stereoisomer (2S,4S)-2 (96% de) was isolated by twice interaction of (2S,4RS)-1 and arylamines.[9b,9c]
crystallizing it from MeOH. The configuration of (2S,4S)- Thus, the optimum conditions for the preparation of 4
according to 1H NMR), which was not observed during the
2 was determined by X-ray crystallography (Figure 1). Ac- are refluxing of (2S,4RS)-1 and dibenzylamine in benzene
cording to the X-ray data, (2S,4S)-2 crystallized in the for 20 h, to yield 94% of target product 4. The diastereomer
P212121 space group.
ratio of threo-/erythro-4 was 43:57.
4258
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4257–4266

Synthesis of 4-Amino Derivatives of 5-Oxoproline
Table 1. Composition of the reaction mixture after refluxing 1 and dibenzylamine[a] for 10 h according to H NMR spectroscopy.
FULL PAPER
1
Entry
Solvent
Temperature [°C]
Content of the compounds in the reaction mixture (molar ratio)
1
4 (threo-4/erythro-4)
6
1
2
3
4
5
benzene
dioxane
CH3CN
EtOH
80
101
82
78
65
22
25
14
–
78 (50:50)
75 (50:50)
76 (50:50)
42[b] (50:50)
19 (45:55)
–
–
10
58[c]
81
MeOH
–
[a] The starting molar ratio of 1/dibenzylamine was 1:2.8. [b] Overall content of 4 and products of its transesterification. [c] Overall
content of 6 and products of its transesterification.
threo-4 was isolated from the reaction mixture by re- isomeric racemates of 7 and 8 were isolated by flash
peated crystallization from MeOH. According to X-ray chromatography. Their structures were confirmed by com-
crystallographic data, this compound crystallized in the parison with the compounds obtained from the reaction of
centrosymmetrical P21/n space group (Figure 2), which sug- piperidine with 5 or 6. Heating of 7 in vacuo at 130 °C for
gests that threo-4 is a diastereomeric racemate. threo-4 was 4 h resulted in 5. The content of the compounds formed
optically inactive. Thus, it may be concluded that the syn- was determined by 1H NMR spectroscopy after the removal
thesis of 4 from (2S,4RS)-1 was accompanied by racemis- of excess piperidine and its hydrobromide from the reaction
ation.
mixture.
It has been found that the highest yield (78%) of 5 was
observed when the reaction was carried out in refluxing
benzene. When the reaction was carried out at room tem-
perature in benzene or MeOH, the ratio of 5/6/7/8 was
26:9:65:0 or 3:72:13:12, respectively. Thus, the γ-elimination
of HBr is dominant in the interaction of (2S,4RS)-1 with
dibenzylamine and piperidine in alcohols.
Dimethyl N-phthaloyl-4-(1-piperidyl)glutamate (5) was
isolated from the reaction mixture by crystallization from
MeOH or column chromatography in a 69% yield. erythro-5
(Ͼ99% de) was obtained by multiple crystallizations of the
diastereomeric mixture, and threo-5 (94% de) was obtained
by crystallization from the mother liquors with fast cooling.
The configuration of erythro-5 was confirmed by X-ray
crystallography (Figure 3). According to X-ray data,
erythro-5 crystallized in the P21/n space group, which sug-
gests that erythro-5 was a diastereomeric racemate. Com-
pounds erythro- and threo-5 were optically inactive. It fol-
lows that in this case the reaction is also accompanied by
racemisation.
Figure 2. X-ray structure of glutamic acid derivative threo-4.
The piperidine fragment is present in many biologically
active species, and this is responsible for the interest in com-
pounds containing this fragment. 4-(1-Piperidyl)glutamic
acid was obtained earlier;[16] its moderate radio-protective
activity was found,[9a] and inhibition towards glutamine
synthetase of Chlorella was studied.[17]
threo- and erythro-5 are readily epimerized, which is
To select the optimum conditions for obtaining 5, we likely due to the high basicity of the piperidine nitrogen
studied the interaction of (2S,4RS)-1 and piperidine at atom. Thus, the refluxing of a 3:97 mixture of threo-5/
room temperature in benzene and MeOH, and in refluxing erythro-5 in benzene for 10 h gave a 22:78 mixture of threo-
benzene (Table 2). The reaction of (2S,4RS)-1 and piperi- 5/erythro-5. Epimerization proceeds faster in MeOH; thus,
dine, which is more basic than dibenzylamine, led to the a 40:60 mixture of threo-/erythro-5 was formed after re-
product of the γ-elimination of HBr, 6, and 7 and 8 in ad- fluxing for 3 h. The ready epimerization of 5 makes it pos-
dition to the target product (Scheme 3). Compound 6 was sible to obtain the erythro isomer of 5 in an 85% yield with
isolated from the reaction mixture after washing with 3  a slow concentration of an MeOH solution of a 1:1 mixture
HCl followed by crystallization from MeOH. The diastereo- of diastereomers.
1
Table 2. Composition of the reaction mixture after interaction between 1 and piperidine[a] according to H NMR spectroscopy.
Entry
Reaction conditions
Temperature [°C]
Content of the compounds in the reaction mixture (molar ratio)
Solvent
Time [h]
1
5 (threo-5/erythro-5)
6
7
8
1
2
3
benzene
benzene
MeOH
20
80
20
48
1.5
48
–
3
–
26 (40:60)
78 (40:60)
3 (50:50)
9
9
72
65
10
13
–
–
12
[a] The starting molar ratio of 1/piperidine was 1:2.8.
Eur. J. Org. Chem. 2007, 4257–4266
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4259

V. P. Krasnov et al.
FULL PAPER
Figure 3. X-ray structure of glutamic acid derivative erythro-5.
Scheme 6.
The next step of our study was the removal of the pro-
tecting groups from 2–5 by acidic hydrolysis. Refluxing of
2–5 in 6  HCl resulted in mixtures of hydrochlorides of 4-
substituted glutamic acids 9–12 and their lactams, 4-substi-
tuted 5-oxoprolines 13–16 (Schemes 4, 5, and 6).
We carried out the acidic hydrolysis of (2S,4S)-2,
(2S,4S,2ЈS)-3, 4, threo-5 and erythro-5. It has been found
that partial racemisation takes place during the acidic hy-
drolysis of individual diastereomers. Thus, the hydrolysis of
erythro-5 (96% de) in 6  HCl for 8 h gave a 7:30:10:53
mixture of threo-/erythro-12/cis-/trans-16. That is, in the
course of the hydrolysis of erythro-5 the diastereomeric
products, threo-12 and cis-16 (in an overall 17% yield), were
formed in addition to erythro-12 and the product of its de-
hydration, trans-16. Partial epimerization during acidic hy-
drolysis of C-4-substituted glutamic acids has been pre-
viously observed for some derivatives of 2,4-diaminoglut-
aric acid,[13d] and 4-thio- and 4-mercaptoglutamic acids.[11]
The epimerization degree decreases with decreasing dura-
tion of acidic hydrolysis. Thus, when erythro-5 was hy-
drolyzed for 5 h, the overall yield of epimerization products
threo-12 and cis-16 was about 10%. The refluxing of 2–5 in
6  HCl for 5 h was chosen as the standard reaction condi-
tions.
The acidic hydrolysis of (2S,4S)-2 under the aforemen-
tioned conditions was also accompanied by epimerization.
A 32:6:52:10 mixture of the hydrochlorides of (2S,4S)-/
(2S,4R)-9/(2S,4S)-/(2S,4R)-13 was formed from (2S,4S)-2
(99% de), and the heating of this mixture in vacuo gave a
84:16 mixture of lactams (2S,4S)-/(2S,4R)-13 (Scheme 4).
We did not observe any epimerization during the dehy-
dration. Compound (2S,4S)-13 was obtained in a 61% yield
[taking into account the starting (2S,4S)-2] by crystalli-
zation from 40% EtOH in H2O. The configuration of
(2S,4S)-13 was confirmed by a 2D NOESY spectrum. Lac-
tam (2S,4R)-13 was isolated from a mixture of 9 and 13 by
preparative RP HPLC. Heating in vacuo and crystallization
of (2S,4S,2ЈS)-3 as described above gave lactam
(2S,4S,2ЈS)-14 in a 56% yield.
Scheme 4.
The optical purity (99% ee) of lactams (2S,4S)-13 and
(2S,4S,2ЈS)-14 was determined by HPLC and 1H NMR
spectroscopy after preliminary derivatization with [(S)-1-
phenylethyl]amine. The derivatization was carried out
through the acyl chlorides and gave optically pure 17 and
18 (Scheme 4).
We suppose that the isolation of optically pure lactams
Scheme 5.
4260
(2S,4S)-13 and (2S,4S,2ЈS)-14 from a mixture of stereoiso-
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4257–4266

Synthesis of 4-Amino Derivatives of 5-Oxoproline
FULL PAPER
mers is due to two reasons. The first is the enrichment of one being 9.0–9.5 Hz and that of another being 0–2.6 Hz.
the (2S,4S) diastereomer during crystallization, and the sec- The difference in chemical shifts of non-equivalent protons
ond is the fact that partial racemisation takes place at either of the 3-CH2 group of the 5-oxoproline ring (∆δAB = δ3A
of the chiral centres under conditions of acidic hydrolysis δ3B) is much larger for the cis diastereomers (∆δAB = 0.51–
of (2S,4S)-2 and (2S,4S,2ЈS)-3. 0.87 ppm) than for the trans diastereomers (∆δAB = 0.11–
The correctness of the above statement was confirmed by 0.21 ppm).
–
the following experiment. Heating of (2S,4S)-13 in 6  DCl
Similar rules have been pointed out previously[5d,19] for
in D2O for 8 h resulted in a mixture of (2S,4S)- and 1H NMR spectra of 5-oxoprolines containing C and O sub-
(2S,4R)-9, and (2S,4S)- and (2S,4R)-13, all compounds be- stituents at position 4.
ing partially deuterated at C-2 and C-4. Due to the partial
Thus, the parameters of the 1H NMR spectra [the differ-
overlapping of the CH signals, the integration was not quite ence in chemical shifts (∆δAB), and the coupling constants
accurate, but for (2S,4S)-9 and (2S,4S)-13 we observed pre- 3J2,3A and 3J2,3B] can serve as useful tools for distinguishing
dominant (about 25%) deuteration of the C-4 protons [4- between the relative configurations of 4-substituted 5-oxo-
CH–N(Me)Ph] while deuteration of the C-2 protons was prolines.
less than 5%.
Previously,[20] we reported a similar methodology for the
To obtain amino acids 11 and 15, we carried out the synthesis of 4-arylamino derivatives of glutamic acid, the
acidic hydrolysis of a diastereomeric mixture of 4 without acidic hydrolysis of which resulted in the spontaneous for-
the pre-resolution of diastereomers. The acidic hydrolysis mation of 5-oxoproline derivatives without any additional
resulted in a mixture of the hydrochlorides of dia- dehydration step, and we supposed that lactamisation pro-
stereomeric 4-(dibenzylamino)glutamic acids 11 and 4-(di- ceeded at the C-2 nitrogen atom. But the results of the pres-
benzylamino)-5-oxoprolines 15 (Scheme 5). The resolution ent study have forced us to revise these data. At present, we
of diastereomers of 11 and 15 was also performed by pre- are carefully re-checking the results obtained previously. We
parative RP HPLC.
will complete these studies and report the results in due
The configuration of cis-15 was confirmed by a 2D course.
NOESY spectrum, in which cross-peaks between 3A-H and
both 2-H and 4-H were observed.
Conclusions
To assign the configuration of threo-11 and erythro-11,
we used their ability to form lactams (Scheme 5). We have
shown that the heating of threo-11 at 120 °C in vacuo for
4 h leads to cis-15, and erythro-11 gives trans-15 under the
same conditions. That is, the formation of lactams proceeds
without epimerization in this case also.
The acidic hydrolysis of threo-5 and erythro-5 followed by
the removal of chloride ions using Ag2CO3 gave mixtures of
amino acids 12 and lactams 16 enriched with the starting
threo and erythro configurations (Scheme 6). threo-4-(1-pip-
eridyl)glutamic acid (threo-12, 96% de) was isolated from
the reaction mixture due to its low solubility in EtOH.
The complete conversion of 12 to lactams 16 took place
while heating of their mixture in vacuo at 120 °C for 4 h
or while refluxing in toluene for 4 h similar to a previous
report.[18] No epimerization was observed. cis-5-Oxo-4-(1-
piperidyl)proline cis-16 (99% de) was obtained in a 65%
yield by crystallization of a mixture of cis- and trans-16
from EtOH.
The results of the interaction of dimethyl (2S,4RS)-4-
bromo-N-phthaloylglutamate with secondary amines essen-
tially depend on the amine character and the reaction con-
ditions. The reaction with arylamines proceeds in high
yields without racemisation. It is accompanied by epimeri-
zation at C-4, but the configuration of C-2 remains un-
changed; as a result, mixtures of diastereomers of the (S)
series are formed. The reaction with more basic amines is
accompanied by the formation of side products, especially
in polar solvents and by racemisation at both chiral centres.
The acidic hydrolysis of the products of nucleophilic substi-
tution is also accompanied by partial racemisation and
leads to mixtures of 4-amino-5-oxoprolines and 4-amino-
glutamic acids. Diastereomers of the latter can be obtained
by preparative RP HPLC. Diastereomers of 4-amino-5-oxo-
proline derivatives were obtained after dehydration of the
aforementioned mixtures by heating in vacuo at 120–
130 °C, no racemisation being observed. (2S,4S)-4-[(Meth-
yl)(phenyl)amino]-5-oxoproline and (2S,4S)-4-[(2ЈS)-2-
methylindolin-1-yl]-5-oxoproline were obtained as individ-
ual stereoisomers.
By following the above procedure and starting from
erythro-5, we obtained trans-5-oxo-4-(1-piperidyl)proline
trans-16 (Ͼ99% de) in a 75% yield, and a mixture enriched
with erythro-(4-1-piperidyl)glutamic acid (erythro-12). Con-
figuration of trans-16 was confirmed by a 2D NOESY spec-
trum.
Thus, by using dimethyl (2S,4RS)-4-bromo-N-phthaloyl-
glutamate as the starting material one can manage to ob-
tain diastereomeric racemates of 4-amino-5-oxoproline and
4-aminoglutamic acid derivatives, although the preparation
of individual stereoisomers has some limitations.
1
Comparison of the H NMR spectra of the cis and trans
diastereomers of 4-substituted 5-oxoprolines 13–16 made it
possible to reveal the following common features. For the
cis diastereomers of 13–16, the values of the coupling con-
Experimental Section
3
3
stants J2,3A and J2,3B are close and fall within the range
of 7.9–9.2 Hz; for the trans diastereomers of 13, 15, 16 these
General:
Dimethyl
(2S,4RS)-4-bromo-N-phthaloylglutamate
constants are much different from each other, the value of [(2S,4RS)-1] was prepared according to a literature procedure.[8a]
Eur. J. Org. Chem. 2007, 4257–4266
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4261

V. P. Krasnov et al.
FULL PAPER
All other reagents were of commercial quality. Solvents were dried
and purified by standard methods. Routine monitoring of reaction
mixtures was carried out using Sorbfil UV 254 (Russia) TLC alu-
minium-plated silica gel. Silica gel 60 (230–400 mesh) was used for
flash chromatography. Analytical HPLC was performed with a
LiChrosorb Si-60 (4ϫ250 mm, 5 µm) column, with a flow rate of
1 mL/min, and by using a tuneable UV detector set at 230 nm.
Mixtures of hexane (solvent A), iPrOH (solvent B) and MeOH
(solvent C) were used as mobile phases. Analytical RP-HPLC was
performed with a LiChrosorb RP-18 (4.6ϫ250 mm, 5 µm) column,
with a flow rate of 0.7 mL/min, in a gradient mode, and by using
a tuneable UV detector set at 230 or 254 nm. Mixtures of MeOH
(solvent C) and 0.005  TFA in H2O (solvent D) or 0.01  KH2PO4
in H2O (solvent E) were used as mobile phases. Preparative RP-
HPLC was performed with a Reprosil-Pur C18 (20ϫ250 mm,
10 µm) column, with a flow rate of 8 mL/min, and by using a UV
detector at 254 nm. Mixtures of H2O (solvent F), MeOH (solvent
C), CH3CN (solvent G), and AcOH (solvent H) were used as mo-
bile phases. 1H NMR spectra were recorded at 400 MHz using
TMS or DSS as references. 13C NMR spectra were recorded at
100 MHz. MS data were obtained by using a quadrupole Shimadzu
LCMS-2010 system in positive mode with an APCI probe installed
with MeOH or CH3CN as the solvent. Quadrupole array and
curved desolvation line (CDL) were used in scan-mode according
to the parameters stored in the auto-tune file. The probe voltage
was set to 4.5 kV, and the APCI probe temperature was set to
400 °C. The CDL and block heater were set at 250 °C and 200 °C,
respectively. Optical rotations were measured with a Perkin–Elmer
M 341 polarimeter.
acetone, 99% de). 1H NMR (400 MHz, CDCl3): δ = 2.89 (ddd,
J3B,3A = 15.0, J3B,2 = 4.9, J3B,4 = 10.4 Hz, 1 H, 3B-H), 2.94 (s, 3
H, NMe), 3.01 (ddd, J3A,3B = 15.0, J3A,2 = 10.8, J3A,4 = 5.6 Hz, 1
H, 3A-H), 3.62 (s, 3 H, OMe), 3.74 (s, 3 H, OMe), 4.37 (dd, J4,3B
= 10.4, J4,3A = 5.6 Hz, 1 H, 4-H), 4.97, (dd, J2,3A = 10.8, J2,3B
=
4.9 Hz, 1 H, 2-H), 6.63–6.70 (m, 3 H, Ar), 7.02–7.09 (m, 2 H, Ar),
7.69–7.73 (m, 2 H, Ar-Phth), 7.75–7.80 (m, 2 H, Ar-Phth) ppm.
C22H22N2O6 (410.43): calcd. C 64.38, H 5.40, N 6.83; found C
64.32, H 5.38, N 6.64.
Dimethyl 4-(Dibenzylamino)-N-phthaloylglutamate (4): Dibenzyl-
amine (7.2 mL, 37.4 mmol) was added to a solution of (2S,4RS)-1
(5.0 g, 13.0 mmol) in benzene (50 mL). After 20 h of refluxing, the
precipitate was filtered off, the filtrate was concentrated under re-
duced pressure and treated with hexane, and the residue was dried
under reduced pressure to give 4 as an amorphous yellow solid
(6.15 g, 94% yield). threo-4/erythro-4, 43:57. HPLC [LiChrosorb Si-
60 (4ϫ250 mm, 5 µm), A/B = 160:1]: tR = 19.0 min (threo-4); tR
=
1
20.4 min (erythro-4). In the H NMR spectrum two sets of signals
corresponding to threo-4 and erythro-4 were observed. 1H NMR
(400 MHz, CDCl3): δ = 2.20 (ddd, J3B,3A = 14.3, J3B,4 = J3B,2
=
7.2 Hz, 1 H, 3B-H, 57%), 2.74 (ddd, J3B,3A = 15.3, J3B,4 = 11.7,
J3B,2 = 4.2 Hz, 1 H, 3B-H, 43%), 2.86 (ddd, J3A,3B = 14.3, J3A,2
J3A,4 = 7.2 Hz, 1 H, 3A-H, 57%), 2.95 (ddd, J3A,3B = 15.3, J3A,2
=
=
12.0, J3A,4 = 4.4 Hz, 1 H, 3A-H, 43%), 3.39 (dd, J4,3A = 11.7, J4,3B
= 4.4 Hz, 1 H, 4-H, 43%), 3.48 (dd, J4,3A = J4,3B = 7.2 Hz, 1 H, 4-
2
2
H, 57%), 3.50 (d, J = 13.5 Hz, 2 H, 2ϫCH-Ph, 43%), 3.53 (d, J
= 13.3 Hz, 2 H, 2ϫCH-Ph, 57%), 3.54 (s, 3 H, OMe, 57%), 3.66
(s, 3 H, OMe, 43%), 3.76 (s, 3 H, OMe, 43%), 3.80 (d, 2J = 13.3 Hz,
2 H, 2ϫCH-Ph, 57%), 3.83 (s, 3 H, OMe, 57%), 3.97 (d, 2J =
13.5 Hz, 2 H, 2ϫCH-Ph, 43%), 5.06 (dd, J2,3A = J2,3B = 7.2 Hz, 1
H, 2-H, 57%), 5.21 (dd, J2,3A = 12.0, J2,3B = 4.2 Hz, 1 H, 2-H,
43%), 6.96–7.01 (m, 2 H, Ar, 43%), 7.04–7.10 (m, 2 H, Ar, 57%),
7.12–7.17 (m, 4 H, Ar, 43%), 7.16–7.21 (m, 4 H, Ar, 57%), 7.31–
7.35 (m, 4 H, Ar, 100%, both isomers), 7.70–7.75 (m, 2 H, Ar-
Phth, 100%, both isomers), 7.76–7.80 (m, 2 H, Ar-Phth, 43%),
7.78–7.83 (m, 2 H, Ar-Phth, 57%) ppm. C29H28N2O6 (500.55):
calcd. C 69.59, H 5.64, N 5.60; found C 69.35, H 5.42, N 5.94.
Dimethyl (2S,4RS)-4-[(Methyl)(phenyl)amino]-N-phthaloylglutam-
ate (2): N-Methylaniline (8.5 mL, 78 mmol) was added to a solu-
tion of (2S,4RS)-1 (10.0 g, 26.0 mmol) in CH3CN (100 mL). After
90 h of refluxing, the precipitate was filtered off, the filtrate was
concentrated under reduced pressure, and the residue was dissolved
in EtOAc (100 mL). This solution was successively washed with 1 
HCl, H2O, 5% aq. NaHCO3, and H2O. The organic solution was
dried with Na2SO4, the solvent was evaporated to dryness, and the
residue was purified by flash chromatography with the use of ben-
zene as the eluent to obtain 2 as an amorphous brown solid (9.50 g,
89% yield). (2S,4S)-2/(2S,4R)-2, 83:17. HPLC [LiChrosorb Si-60
Dimethyl threo-4-(Dibenzylamino)-N-phthaloylglutamate (threo-4):
A mixture of threo-4 and erythro-4 (6.15 g) was crystallized three
times from MeOH to give threo-4 as a white solid (0.74 g, 12%
yield). M.p. 137–141 °C. 1H NMR (400 MHz, CDCl3): δ = 2.74
(ddd, J3B,3A = 15.3, J3B,4 = 11.7, J3B,2 = 4.2 Hz, 1 H, 3B-H), 2.95
(ddd, J3A,3B = 15.3, J3A,2 = 12.0, J3A,4 = 4.4 Hz, 1 H, 3A-H), 3.39
(4ϫ250 mm, 5 µm), A/B = 100:1]: tR = 16.5 min [(2S,4R)-2]; tR
=
1
17.2 min [(2S,4S)-2]. In the H NMR spectrum two sets of signals
corresponding to (2S,4S)-2 and (2S,4R)-2 were observed. 1H NMR
(400 MHz, CDCl3): δ = 2.44 (ddd, J3B,3A = 14.6, J3B,4 = 9.7, J3B,2
= 6.8 Hz, 1 H, 3B-H, 17%), 2.82 (s, 3 H, NMe, 17%), 2.89 (ddd,
J3B,3A = 15.0, J3B,4 = 10.4, J3B,2 = 4.9 Hz, 1 H, 3B-H, 83%), 2.94
2
(dd, J4,3A = 11.7, J4,3B = 4.4 Hz, 1 H, 4-H), 3.50 (d, J = 13.5 Hz,
2 H, 2ϫCH-Ph), 3.66 (s, 3 H, OMe), 3.76 (s, 3 H, OMe), 3.97 (d, 2J
= 13.5 Hz, 2 H, 2ϫCH-Ph), 5.21 (dd, J2,3A = 12.0, J2,3B = 4.2 Hz, 1
H, 2-H), 6.96–7.01 (m, 2 H, Ar), 7.12–7.17 (m, 4 H, Ar), 7.31–7.35
(m, 4 H, Ar), 7.70–7.75 (m, 2 H, Ar-Phth), 7.76–7.80 (m, 2 H, Ar-
Phth) ppm. C29H28N2O6 (500.55): calcd. C 69.59, H 5.64, N 5.60;
found C 69.66, H 5.40, N 5.62. 97% de. HPLC [LiChrosorb Si-60
(4ϫ250 mm, 5 µm), A/B = 160:1]: tR = 19.0 min.
(s, 3 H, NMe, 83%), 3.01 (ddd, J3A,3B = 15.0, J3A,2 = 10.8, J3A,4
=
5.6 Hz, 1 H, 3A-H, 83%), 3.02–3.10 (m, 1 H, 3A-H, 17%), 3.62 (s,
3 H, OMe, 83%), 3.69 (s, 3 H, OMe, 17%), 3.72 (s, 3 H, OMe,
17%), 3.74 (s, 3 H, OMe, 83%), 4.37 (dd, J4,3B = 10.4, J4,3A
=
5.6 Hz, 1 H, 4-H, 83%), 4.80 (dd, J4,3B = 9.7, J4,3A = 5.3 Hz, 1 H,
4-H, 17%), 4.97 (dd, J2,3A = 10.8, J2,3B = 4.9 Hz, 1 H, 2-H, 83%),
5.04 (dd, J2,3A = 7.3, J2,3B = 6.8 Hz, 1 H, 2-H, 17%), 6.63–6.70 (m,
3 H, Ar, 83%), 6.68–6.74 (m, 3 H, Ar, 17%), 7.02–7.09 (m, 2 H,
Ar, 83%), 7.08–7.14 (m, 2 H, Ar, 17%), 7.69–7.73 (m, 2 H, Ar-
Phth, 100%, both isomers), 7.75–7.80 (m, 2 H, Ar-Phth, 83%),
7.77–7.82 (m, 2 H, Ar-Phth, 17%) ppm. C22H22N2O6 (410.43):
calcd. C 64.38, H 5.40, N 6.83; found C 64.68, H 5.20, N 6.67.
Dimethyl N-Phthaloyl-4-(1-piperidyl)glutamate (5): Piperidine
(2.7 mL, 27.6 mmol) was added to a solution of (2S,4RS)-1 (3.84 g,
10.0 mmol) in benzene (35 mL). After 2 h of refluxing, the precipi-
tate was filtered off, the filtrate was washed with H2O to neutral
pH, dried with Na2SO4, and the solvent was evaporated to dryness.
The residue was dissolved in MeOH (5 mL), and the solution was
Dimethyl (2S,4S)-4-[(Methyl)(phenyl)amino]-N-phthaloylglutamate stored at –10 °C for 24 h. The filtration of the precipitate gave a
[(2S,4S)-2]: A mixture of (2S,4S)-2 and (2S,4R)-2 (9.18 g) was twice
crystallized from MeOH to give (2S,4S)-2 as a yellow solid (5.05 g,
55% yield, 96% de). An additional crystallization from MeOH gave
(2S,4S)-2 in Ͼ99% de. M.p. 109–111 °C. [α]2D0 = –85.8 (c = 1.0,
mixture of threo-5 and erythro-5 as a yellow solid (0.84 g). The
mother liquor was concentrated to dryness; the residue was dis-
solved in EtOAc (40 mL) and extracted with HCl (3 , 2ϫ15 mL).
The combined acidic extracts were adjusted with Na2CO3 to pH =
4262
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4257–4266

Synthesis of 4-Amino Derivatives of 5-Oxoproline
FULL PAPER
9 and extracted with EtOAc (3ϫ15 mL). The combined organic
layers were washed with water to neutral pH, dried with Na2SO4
and the solvents were evaporated to dryness. The residue (2.41 g)
was dissolved in MeOH (2.6 mL) under heating, a seed of the first
precipitate was added, and the solution was stored at –10 °C for
24 h. The filtration of the precipitate gave an additional 1.42 g of
a threo-5/erythro-5 mixture. An additional amount of the threo-
5/erythro-5 mixture was isolated from the mother liquor by flash
chromatography (hexane/iBuOH from 20:1 to 4:1). Overall yield
2.67 g (69%). threo-5/erythro-5, 1:1. HPLC [LiChrosorb Si-60
(4ϫ250 mm, 5 µm), A/B/C = 80:0.7:0.3]: tR = 15.9 min (threo-5);
tR = 17.6 min (erythro-5). C20H24N2O6 (388.42): calcd. C 61.85, H
6.23, N 7.21; found C 61.94, H 6.28, N 6.83.
a solution of threo-5 (0.10 g, 0.257 mmol) in benzene (0.5 mL). The
reaction mixture was kept at room temperature for 4 d and then
diluted with benzene (5.5 mL), washed with H2O to neutral pH,
and dried with Na2SO4. The solvent was evaporated to dryness
under reduced pressure to yield a 81:19 mixture of threo-7/erythro-
7 as an amorphous white solid (0.102 g, 77% yield). 1H NMR
(400 MHz, [D6]DMSO): δ = 1.31–1.61 (m, 12 H, piperidyl), 1.89
(m, 1 H, C3HB), 2.13 (ddd, J = 14.4, 11.2, 3.4 Hz, 1 H, C3HA),
2.32 (m, 2 H, piperidyl), 2.63 (m, 2 H, piperidyl), 3.06 (m, 2 H,
piperidyl), 3.29 (dd, J = 11.3, 3.7 Hz, 1 H, C4H), 3.49 (m, 2 H,
piperidyl), 3.63 (s, 3 H, OMe), 3.66 (s, 3 H, OMe), 4.72 (m, 1 H,
C2H), 7.26 (dd, J = 7.3, 1.3 Hz, 1 H, Ar), 7.48 (td, J = 7.4, 1.5 Hz,
1 H, Ar), 7.53 (td, J = 7.4, 1.4 Hz, 1 H, Ar), 7.61–7.66 (m, 1 H,
Ar), 8.64 (d, 1 H, NH, J = 8.1 Hz) ppm. MS (in CH3CN, Q-array
scan): m/z (%) = 474 (100) [M + H]+. MS (in CH3CN, Q-array
voltage 80 V): m/z (%) = 474 (24) [M + H]+, 389 (100) [M –
C5H10N]+, 329 (8) [M – C5H10NH – CO2CH3]+, 304 (6) [M – 2
C5H10N – H]+, 242 (8) [M – C5H10NH – PhthN]+, 216 (31)
[OCC6H4 – CO – NC5H10]+, 182 (8) [M – C5H10NH – PhthNH –
Dimethyl threo-N-Phthaloyl-4-(1-piperidyl)glutamate (threo-5): A
1:1 mixture of threo-5/erythro-5 (2.20 g) was dissolved in MeOH
(30 mL). After slow evaporation of 25 mL of MeOH at 20 °C in an
open vial, the precipitate was filtered off to give erythro-5 (1.4 g,
64% yield). After 2 h of cooling of the mother liquor at –10 °C,
the precipitate was filtered off to give threo-5 as a white solid
CO2CH3]+, 156 (6) [M
C25H35N3O6·0.5C6H6 (512.63): calcd. C 65.60, H 7.47, N 8.20;
found 65.47, 7.64, 8.24. HPLC [LiChrosorb Si-60
–
2
C5H10NH
–
PhthNH]+.
1
(0.55 g, 25% yield). M.p. 91–96 °C. H NMR (400 MHz, CDCl3):
δ = 1.43 (m, 2 H, piperidyl), 1.53 (m, 2 H, piperidyl), 1.60 (m, 2
C
H
N
H, piperidyl), 2.27 (m, 2 H, piperidyl), 2.58 (ddd, J = 15.1, J3B,2
=
(4ϫ250 mm, 5 µm), A/B/C = 10:0.5:0.5]: tR = 14.2 min.
10.9, J3B,4 = 4.8 Hz, 1 H, 3B-H), 2.63–2.77 (m, 3 H, 3A-H, piperi-
dyl), 3.01 (dd, J = 11.2, J4,3B = 4.9 Hz, 1 H, 4-H), 3.62 (s, 3 H,
OMe), 3.74 (s, 3 H, OMe), 5.31 (dd, J2,3B = 11.0, J = 3.8 Hz, 1 H,
2-H), 7.75 (m, 2 H, Ar-Phth), 7.88 (m, 2 H, Ar-Phth) ppm. 13C
NMR (100 MHz, CDCl3): δ = 24.47, 26.33, 27.82, 49.13, 50.50,
50.86, 52.68, 64.08, 123.39, 131.71, 134.12, 167.46, 170.11, 171.20
ppm. C20H24N2O6 (388.42): calcd. C 61.85, H 6.23, N 7.21; found
C 61.84, H 6.33, N 7.06. 94% de. HPLC [LiChrosorb Si-60
(4ϫ250 mm, 5 µm), A/B/C = 80:0.7:0.3]: tR = 15.9 min.
Dimethyl erythro-4-(1-Piperidyl)-N-[2-(1-piperidylcarbonyl)benzoyl]-
glutamate (erythro-7): According to the above procedure and start-
ing from erythro-5, a 19:81 mixture of threo-7/erythro-7 as an
amorphous white solid (0.107 g, 81% yield) was obtained. 1H
NMR (400 MHz, [D6]DMSO): δ = 1.30–1.61 (m, 12 H, piperidyl),
2.00 (ddd, J = 14.4, 7.3, 7.3 Hz, 1 H, C3HB), 2.18 (ddd, J = 13.9,
7.2, 6.3 Hz, 1 H, C3HA), 2.32 (m, 2 H, piperidyl), 2.59 (m, 2 H,
piperidyl), 3.04 (m, 2 H, piperidyl), 3.39 (dd, J = 7.4, 7.3 Hz, 1 H,
C4H), 3.51 (m, 2 H, piperidyl), 3.63 (s, 3 H, OMe), 3.65 (s, 3 H,
OMe), 4.48 (q, J = 7.1 Hz, 1 H, C2H), 7.26 (dd, J = 7.4, 1.4 Hz, 1
H, Ar), 7.48 (td, J = 7.5, 1.4 Hz, 1 H, Ar), 7.54 (td, J = 7.4, 1.3 Hz,
1 H, Ar), 7.68 (d, J = 7.3 Hz, 1 H, Ar), 8.72 (d, J = 7.6 Hz, 1 H,
NH) ppm. MS (in CH3CN, Q-array scan): m/z = 474 (100) [M +
H]+. MS (in CH3CN, Q-array voltage 80 V): m/z (%) = 474 (28)
[M + H]+, 389 (100) [M – C5H10N]+, 329 (8) [M – C5H10NH –
CO2CH3]+, 304 (8) [M – 2 C5H10N – H]+, 242 (9) [M – C5H10NH –
PhthN]+, 216 (33) [OCC6H4 – CO – NC5H10]+, 182 (7) [M –
C5H10NH – PhthNH – CO2CH3]+, 156 (6) [M – 2 C5H10NH –
PhthNH]+. HPLC [LiChrosorb Si-60 (4ϫ250 mm, 5 µm), A/B/C =
10:0.5:0.5]: tR = 18.4 min.
Dimethyl erythro-N-Phthaloyl-4-(1-piperidyl)glutamate (erythro-5):
A 1:1 mixture of threo-5/erythro-5 (2.67 g) was dissolved in MeOH
(30 mL). The solvent was slowly evaporated to dryness, and the
residue was crystallized from MeOH to give eryhtro-5 as a yellow
solid (2.27 g, 85% yield). M.p. 124–126 °C. 1H NMR (400 MHz,
CDCl3): δ = 1.27 (m, 6 H, piperidyl), 2.26 (m, 2 H, piperidyl), 2.41
(ddd, J3B,3A = 14.8, J3B,4 = 9.8, J3B,2 = 8.4 Hz, 1 H, 3B-H), 2.60
(m, 2 H, piperidyl), 2.62 (ddd, J3A,3B = 14.8, J3A,2 = 6.0, J3A,4
=
5.3 Hz, 1 H, 3A-H), 3.42 (dd, J4,3B = 9.8, J4,3A = 5.3 Hz, 1 H, 4-
H), 3.70 (s, 3 H, OMe), 3.74 (s, 3 H, OMe), 5.14 (dd, J2,3B = 8.4,
J2,3A = 6.0 Hz, 1 H, 2-H); 7.75 (m, 2 H, Ar-Phth), 7.87 (m, 2 H,
Ar-Phth) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.25, 26.08,
27.87, 49.38, 50.60, 50.95, 52.67, 65.60, 123.40, 132.01, 134.06,
167.35, 169.60, 171.11 ppm. C20H24N2O6 (388.42): calcd. C 61.85,
H 6.23, N 7.21; found C 61.90, H 6.55, N 7.00. 99% de. HPLC
Dimethyl (Z)-1-{[2-(1-Piperidylcarbonyl)benzoyl]amino}cycloprop-
ane-1,2-dicarboxylate (8): A solution of dimethyl (Z)-1-(phthal-
imido)cyclopropane-1,2-dicarboxylate (6, 0.30 g, 1.0 mmol) and pip-
eridine (0.67 mL, 6.84 mmol) in benzene (4 mL) was kept at 5 °C
for 5 d, washed with H2O to neutral pH, and dried with Na2SO4.
The solvent was evaporated to dryness under reduced pressure; the
residue was purified by flash chromatography (hexane/acetone
from 50:1 to 4:1) to give 8 as a white solid (192 mg, 49% yield).
M.p. 155–157 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 1.21–1.68
(m, 6 H, piperidyl), 1.76 (m, 2 H, CH2), 2.64 (dd, J = 8.6, 7.8 Hz,
1 H, CH), 3.02 (m, 2 H, piperidyl), 3.19 (m, 1 H, piperidyl), 3.56
(br. s, 3 H, OMe), 3.65 (s, 3 H, OMe), 3.81 (m, 1 H, piperidyl),
7.24 (dd, J = 7.4, 1.2 Hz, 1 H, Ar), 7.47 (td, J = 7.5, 1.3 Hz, 1 H,
Ar), 7.54 (td, J = 7.5, 1.3 Hz, 1 H, Ar), 7.66 (dd, J = 7.4, 0.9 Hz,
1 H, Ar), 9.11 (s, 1 H, NH) ppm. C20H24N2O6 (388.42): calcd.
C 61.85, H 6.23, N 7.21; found C 62.10, H 6.42, N 6.99. HPLC
[LiChrosorb Si-60 (4ϫ250 mm, 5 µm), A/B/C = 80:0.7:0.3]: tR
=
17.6 min.
Dimethyl (Z)-1-(Phthalimido)cyclopropane-1,2-dicarboxylate (6):
The organic layers obtained after the extraction of an EtOAc solu-
tion with 3  HCl (see the above procedure for 5) was washed with
H2O to neutral pH and dried with Na2SO4. The solvent was evapo-
rated to dryness under reduced pressure; the residue was dissolved
in MeOH (1 mL) and kept at –10 °C for 24 h. The precipitate was
filtered off to give cyclopropane 6 as a white solid [0.16 g, 5% yield
taking into account the starting (2S,4RS)-1]. M.p. 98–100 °C
1
(MeOH) [ref.[15] m.p. 83.5–85.5 °C (heptane/sBuOH, 4:1)]. The H
NMR spectrum is identical to the literature data.[15] HPLC
[LiChrosorb Si-60 (4ϫ250 mm, 5 µm), A/B/C = 80:0.7:0.3]: tR
=
[LiChrosorb Si-60 (4ϫ250 mm, 5 µm), A/B/C = 10:0.8:0.2]: tR
17.2 min.
=
15.9 min. C15H13NO6 (303.27): calcd. C 59.41, H 4.32, N 4.62;
found C 59.37, H 4.50, N 4.68.
Dimethyl threo-4-(1-Piperidyl)-N-[2-(1-piperidylcarbonyl)benzoyl]-
glutamate (threo-7): Piperidine (0.10 mL, 1.02 mmol) was added to
threo-4-(Dibenzylamino)glutamic Acid (threo-11), erythro-4-(Di-
benzylamino)glutamic Acid (erythro-11), cis-4-(Dibenzylamino)-
Eur. J. Org. Chem. 2007, 4257–4266
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4263

V. P. Krasnov et al.
FULL PAPER
5-oxoproline (cis-15), and trans-4-(Dibenzylamino)-5-oxoproline
(trans-15): Compound 4 (1.24 g, 2.48 mmol) was refluxed in HCl
(6 , 12 mL) for 5 h. After cooling the mixture to room tempera-
ture, the precipitate of phthalic acid was filtered off, and the filtrate
was concentrated to dryness under reduced pressure to give a mix-
ture of the hydrochlorides of threo- and erythro-11, and cis- and
trans-15 (1.0 g). The mixture (120 mg) was separated by using pre-
parative RP HPLC [Reprosil-Pur C18 (20ϫ250 mm, 10 µm)] in a
gradient mode (F/C/G/H from 90:5:5:0.5 to 30:35:35:0.5) to give
threo-11 (13 mg, 11% yield), erythro-11 (15 mg, 12% yield), cis-15
(20 mg, 17% yield), and trans-15 (25 mg, 21% yield) as amorphous
solids.
HPLC [LiChrosorb RP-18 (4.6ϫ250 mm, 5 µm), C/E from 10:90
to 80:20]: tR = 30.4 min.
threo-4-(1-Piperidyl)glutamic Acid (threo-12): Compound threo-5
(1.16 g, 2.99 mmol) was refluxed in HCl (20%, 12 mL) for 5 h. Af-
ter cooling the mixture to room temperature, the precipitate of
phthalic acid was filtered off, the filtrate was concentrated to dry-
ness under reduced pressure, and the residue was dried with P2O5
and KOH under reduced pressure at room temperature to give a
39:6:46:10 mixture of the hydrochlorides (0.85 g) of threo-/erythro-
12/cis-/trans-16. Ag2CO3 (0.69 g, 2.5 mmol) was added to a solu-
tion of the above mixture in H2O (2 mL). The reaction mixture was
stirred at room temperature for 30 min, the precipitate was filtered
off, the filtrate was treated with H2S, the precipitate was filtered
off, and the filtrate was concentrated to dryness under reduced
pressure. The residue (0.67 g) was crystallized from EtOH to give
threo-12 as a white solid (0.19 g, 28% yield). M.p. 234–239 °C (de-
threo-4-(Dibenzylamino)glutamic Acid (threo-11): 1H NMR
(400 MHz, D2O, NaOD): δ = 1.52 (ddd, J3B,3A = 14.3, J = 10.7,
4.6 Hz, 1 H, 3B-H), 2.18 (ddd, J3A,3B = 14.3, J = 11.3, 3.3 Hz, 1
H, 3A-H), 3.19 [dd, J = 11.4, 4.3 Hz, 1 H, 2(4)-H], 3.50 [dd, J =
10.8, 3.3 Hz, 1 H, 4(2)-H], 3.59 (d, 2J = 13.7 Hz, 2 H, CH-Ph), 3.89 comp.). 96% de according to 1H NMR spectroscopy. 1H NMR
2
(d, J = 13.7 Hz, 2 H, CH-Ph), 7.29–7.47 (m, 10 H, Ar) ppm. MS (400 MHz, D2O, NaOD): δ = 1.43 (m, 2 H, piperidyl), 1.54 (m, 4
(in CH3CN, Q-array scan): m/z (%) = 343 (100) [M + H]+. MS (in H, piperidyl), 1.82 (ddd, J = 13.4, 9.4, 6.7 Hz, 1 H, 3B-H), 1.89
CH3CN, Q-array voltage 60 V): m/z (%) = 343 (100) [M + H]+, 325
(ddd, J = 13.4, 7.2, 4.7 Hz, 1 H, 3A-H), 2.53 (m, 4 H, piperidyl),
(41) [M + H – H2O]+, 299 (31) [M + H – CO2]+, 251 (18) [M + 2.98 [dd, J = 9.4, 4.7 Hz, 1 H, 2(4)-H], 3.15 [dd, J = 7.1, 7.0 Hz, 1
H – CH2Ph]+, 224 (28) [M – 2 CO2 – CH2NH2]+, 132 (42) [M – 2
CO2 – CH2NH2 – CH2Ph]+, 91 (31) [CH2Ph]+. RP HPLC
[LiChrosorb RP-18 (4.6ϫ250 mm, 5 µm), C/E from 10:90 to
80:20]: tR = 23.6 min.
H, 4(2)-H] ppm. C10H18N2O4 (230.26): calcd. C 52.16, H 7.88, N
12.17; found C 52.09, H 7.94, N 11.98.
erythro-4-(1-Piperidyl)glutamic Acid (erythro-12): According to the
above procedure and starting from a 4:37:7:52 mixture (2.57 g) of
erythro-4-(Dibenzylamino)glutamic Acid (erythro-11): 1H NMR threo-/erythro-12/cis-/trans-16, a 17:78:5 mixture (0.41 g, 16% yield)
(400 MHz, D2O, NaOD): δ = 1.74 (ddd, J3B,3A = 13.6, J = 9.5,
6.5 Hz, 1 H, 3B-H), 2.18 (ddd, J3A,3B = 13.6, J = 8.7, 4.4 Hz, 1 H,
3A-H), 3.18 [dd, J = 9.4, 3.8 Hz, 1 H, 2(4)-H], 3.33 [dd, J = 8.4,
of threo-/erythro-12/trans-16 was obtained. erythro-12: 1H NMR
(400 MHz, D2O, NaOD): δ = 1.43 (m, 2 H, piperidyl), 1.47–1.62
(m, 4 H, piperidyl), 1.56 (ddd, J = 13.3, 10.8, 3.4 Hz, 1 H, 3B-H),
2.15 (ddd, J = 13.3, 11.5, 2.8 Hz, 1 H, 3A-H), 2.49–2.61 (m, 4 H,
2
6.4 Hz, 1 H, 4(2)-H], 3.60 (d, J = 13.8 Hz, 2 H, CH-Ph), 3.92 (d,
2J = 13.8 Hz, 2 H, CH-Ph), 7.27–7.41 (m, 10 H, Ar) ppm. MS (in piperidyl), 3.08 [dd, J = 11.5, 3.4 Hz, 1 H, 2(4)-H], 3.11 [dd, J =
CH3CN, Q-array scan): m/z (%) = 343 (100) [M + H]+. MS (in
CH3CN, Q-array voltage 60 V): m/z (%) = 343 (100) [M + H]+, 325
(38) [M + H – H2O]+, 299 (30) [M + H – CO2]+, 251 (17) [M +
H – CH2Ph]+, 224 (31) [M – 2 CO2 – CH2NH2]+, 132 (42) [M – 2
CO2 – CH2NH2 – CH2Ph]+, 91 (33) [CH2Ph]+. RP HPLC
[LiChrosorb RP-18 (4.6ϫ250 mm, 5 µm), C/E from 10:90 to
80:20]: tR = 23.8 min.
10.9, 2.8 Hz, 1 H, 4(2)-H] ppm.
(2S,4S)-4-[(Methyl)(phenyl)amino]-5-oxoproline [(2S,4S)-13]: Com-
pound (2S,4S)-2 (2.14 g, 5.21 mmol) was refluxed in HCl (6 ,
25 mL) for 5 h. After cooling the mixture to room temperature, the
precipitate of phthalic acid was filtered off, and the filtrate was
concentrated to dryness under reduced pressure to give a 32:6:52:10
mixture of the hydrochlorides of threo-/erythro-9/(2S,4S)-/(2S,4R)-
13 (1H NMR). The mixture was heated under reduced pressure at
130 °C for 4 h, and then crystallized from 40% EtOH in H2O to
give amino acid (2S,4S)-13 as a white solid (0.75 g, 61% yield).
M.p. 215–220 °C (decomp.). [α]2D0 = 152.5 (c = 0.5, MeOH). 1H
NMR (400 MHz, [D6]DMSO): δ = 1.81 (ddd, J3B,3A = 12.7, J3B,4
cis-4-(Dibenzylamino)-5-oxoproline (cis-15): 1H NMR (400 MHz,
[D6]DMSO): δ = 1.87 (ddd, J3B,3A = 12.4, J3B,4 = 9.1, J3B,2
7.9 Hz, 1 H, 3B-H), 2.44 (ddd, J3A,3B = 12.4, J3A,4 = 9.1, J3A,2
=
=
7.9 Hz, 1 H, 3A-H), 3.43 (t, J4,3A = J4,3B = 9.1 Hz, 1 H, 4-H), 3.52
(d, 2J = 13.9 Hz, 2 H, CH-Ph), 3.72 (d, 2J = 13.9 Hz, 2 H, CH-
Ph), 3.91 (t, J2,3A = J2,3B = 7.9 Hz, 1 H, 2-H), 7.22 (m, 2 H, Ar),
7.31 (m, 4 H, Ar), 7.39 (m, 4 H, Ar), 8.01 (s, 1 H, NH) ppm. MS
= 9.1, J3B,2 = 8.2 Hz, 1 H, 3B-H), 2.68 (ddd, J3A,3B = 12.7, J3A,4
9.1, J3A,2 = 8.2 Hz, 1 H, 3A-H), 2.69 (s, 3 H, NMe), 4.09 (t, J2,3A
=
(in CH3CN, Q-array scan): m/z (%) = 325 (100) [M + H]+. MS (in = J2,3B = 8.2 Hz, 1 H, 2-H), 4.68, (t, J4,3A = J4,3B = 9.1 Hz, 1 H,
CH3CN, Q-array voltage 60 V): m/z (%) = 325 (25.7) [M + H]+,
233 (97.6) [M – CH2Ph]+, 222 (23.8) [M – CO2 – CONHCH2]+,
4-H), 6.66 (t, J = 7.2 Hz, 1 H, para-Ar), 6.79 (d, J = 8.1 Hz, 2 H,
ortho-Ar), 7.16 (m, 2 H, meta-Ar), 8.27 (s, 1 H, NH), 12.92 (br. s,
181 (45.9), 132 (40.2) [M – CH2Ph – CO2 – CONHCH2]+, 91 (100) 1 H, CO2H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 27.47
[CH2Ph]+. RP HPLC [LiChrosorb RP-18 (4.6ϫ250 mm, 5 µm), C/
E from 10:90 to 80:20]: tR = 31.5 min.
(C3H2), 33.22 (CH3N), 51.37 (CH), 59.32 (CH), 112.80 (ortho-Ar),
116.69 (para-Ar), 128.98 (meta-Ar), 149.54 (ipso-Ar), 173.48 (CO),
173.58 (CO) ppm. C12H14N2O3 (234.26): calcd. C 61.53, H 6.02, N
11.96; found C 61.48, H 6.16, N 11.89. 99% de. RP HPLC [LiChro-
sorb RP-18 (4.6ϫ250 mm, 5 µm), C/D from 5:95 to 80:20]: tR
30.7 min.
trans-4-(Dibenzylamino)-5-oxoproline
(trans-15):
1H
NMR
(400 MHz, [D6]DMSO): δ = 2.11 (dd, J3B,3A = 12.8, J3B,4 = 9.2 Hz,
1 H, 3B-H), 2.32 (ddd, J3A,3B = 12.8, J3A,2 = 9.7, J3A,4 = 9.2 Hz, 1
=
2
H, 3A-H), 3.41 (t, J4,3A = J4,3B = 9.2 Hz, 1 H, 4-H), 3.55 (d, J =
13.9 Hz, 2 H, CH-Ph), 3.72 (d, 2J = 13.9 Hz, 2 H, CH-Ph), 3.96
(d, J4,3A = 9.7 Hz, 1 H, 2-H), 7.22 (m, 2 H, Ar), 7.31 (m, 4 H, Ar),
(2S,4R)-4-[(Methyl)(phenyl)amino]-5-oxoproline [(2S,4R)-13]: Ac-
cording to the above procedure and starting from a 64:36 mixture
7.39 (m, 4 H, Ar), 8.10 (s, 1 H, NH) ppm. MS (in CH3CN, Q-array of (2S,4S)-2/(2S,4R)-2 (2.29 g, 5.58 mmol), a 23:16:35:26 mixture
scan): m/z (%) = 325 (100) [M + H]+. MS (in CH3CN, Q-array
voltage 60 V): m/z (%) = 325 (25.7) [M + H]+, 233 (95.7) [M –
CH2Ph]+, 222 (16.4) [M – CO2 – CONHCH2]+, 181 (38.6), 132
of the hydrochlorides of threo-/erythro-9/(2S,4S)-/(2S,4R)-13 (1H
NMR) was obtained. Amino acid (2S,4R)-13 (22 mg, 18% yield)
was isolated from the above mixture (120 mg) as an amorphous
(52.8) [M – CH2Ph – CO2 – CONHCH2]+, 91 (100) [CH2Ph]+. RP solid by using preparative RP HPLC [Reprosil-Pur C18
4264
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4257–4266

Synthesis of 4-Amino Derivatives of 5-Oxoproline
(20ϫ250 mm, 10 µm)] in gradient mode (F/C/G/H from
FULL PAPER
piperidyl), 26.66 (C3H2), 49.52 (2 CH2N piperidyl), 52.65 (CH),
a
1
90:5:5:0.5 to 60:20:20:0.5). H NMR (400 MHz, [D6]DMSO): δ = 62.81 (CH), 174.11 (CO), 174.62 (CO) ppm. MS (in MeOH, Q-
2.26 (ddd, J3B,3A = 13.3, J3B,2 = J3B–4 = 9.2 Hz, 1 H, 3B-H), 2.37
(dd, J3A,3B = 13.3, J3A,4 = 9.2 Hz, 1 H, 3A-H), 2.70 (s, 3 H, NMe),
array scan): m/z (%) = 245 (16) [M + H + MeOH]+, 213 (100)
[M + H]+. MS (in MeOH, Q-array voltage 80 V): m/z (%) = 245
4.06 (d, J2,3B = 9.2 Hz, 1 H, 2-H), 4.54, (dd, J4,3A = J4,3B = 9.2 Hz, (9) [M + H + MeOH]+, 213 (100) [M + H]+, 185 (26) [M + H –
1 H, 4-H), 6.66 (t, J = 7.2 Hz, 1 H, para-Ar), 6.76 (d, J = 8.0 Hz,
2 H, ortho-Ar), 7.16 (m, 2 H, meta-Ar), 8.28 (s, 1 H, NH) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 27.39 (C3H2), 33.11
(CH3N), 52.03 (CH), 58.59 (CH), 112.95 (ortho-Ar), 116.73 (para-
Ar), 128.96 (meta-Ar), 149.61 (ipso-Ar), 173.95 (CO), 174.42 (CO)
ppm. MS (in CH3CN, Q-array scan): m/z (%) = 276 (13) [M + H
+ CH3CN]+, 235 (100) [M + H]+. MS (in CH3CN, Q-array voltage
70 V): m/z (%) = 276 (8) [M + H + CH3CN]+, 235 (55) [M + H]+,
190 (28) [M – CO2]+, 175 (29) [M – CO2 – NH]+, 148 (100) [M +
H – CO2 – CONH]+, 134 (74) [M + H – CO2 – CONHCH2]+,
107 (75) [PhNCH3]+. 99% de. RP HPLC [LiChrosorb RP-18
(4.6ϫ250 mm, 5 µm), C/D from 5:95 to 80:20]: tR = 31.4 min.
CO]+, 168 (53) [M + H – CO2]+, 113 (92) [C5H10NCO]+.
{(2S,4S)-4-[(Methyl)(phenyl)amino]-5-oxoprolyl}[(1S)-1-phenylethyl]-
amine (17): Oxalyl chloride (0.35 mL, 4.0 mmol) and DMF (5 µL)
were added to a solution of cis-13 (206 mg, 0.88 mmol) in CHCl3
(10 mL) whilst stirring and cooling (to 0 °C). After complete dissol-
ution, the reaction mixture was concentrated to dryness under re-
duced pressure. The residue was suspended in dry benzene (10 mL),
and [(S)-1-phenylethyl]amine (0.5 mL, 3.91 mmol) was added
whilst stirring and cooling. The reaction mixture was stirred at
room temperature for 3 h, and the precipitate was filtered off. The
filtrate was washed successively with 5% aq. citric acid, H2O, 5 %
aq. NaHCO3, and then dried with Na2SO4. Evaporation of the
solvent under reduced pressure to dryness gave 17 as an amorphous
yellow solid (148 mg, 50% yield). Ͼ99% de. HPLC [LiChrosorb Si-
60 (4ϫ250 mm, 5 µm), A/B/C = 5:0.5:0.5]: tR = 11.0 min. Crystalli-
zation from EtOAc gave 17 as a yellow solid (74 mg, 25% yield).
M.p. 174–177 °C. [α]2D0 = 71.2 (c = 0.64, acetone). 1H NMR
(400 MHz, CDCl3): δ = 1.46 (d, JMe,CH = 7.1 Hz, 3 H, Me), 2.03
(ddd, J3B,3A = 13.2, J3B,H = 9.4, J3B,H = 8.4 Hz, 1 H, 3B-H), 2.72
(ddd, J3A,3B = 13.2, J3A,H = 9.4, J3A,H = 8.4 Hz, 1 H, 3A-H), 2.82
(s, 3 H, NMe), 4.00 [t, JH,3A = JH,3B = 8.4 Hz, 1 H, 2(4)-H], 4.54
[t, JH,3A = JH,3B = 9.4 Hz, 1 H, 4(2)-H], 5.09, (dq, JCH,NH = 7.8,
JCH,Me = 7.1 Hz, 1 H, CH-Phe), 6.64 (d, JNH,CH = 7.8 Hz, 1 H,
NH), 6.81–6.76 (m, 3 H, Ar), 7.06 (s, 1 H, NH-lactam), 7.29–7.20
(m, 7 H, Ar) ppm. C20H23N3O2 (337.42): calcd. C 71.19, H 6.87,
N 12.45; found C 70.83, H 6.90, N 12.36.
(2S,4S)-4-[(2ЈS)-2-Methylindolin-1-yl]-5-oxoproline
[(2S,4S,2ЈS)-
14]: According to the procedure described for amino acid (2S,4S)-
13 and starting from (2S,4S,2ЈS)-3,[9e] lactam (2S,4S,2ЈS)-14 was
obtained in a 56% yield as a white solid. M.p. 222–226 °C (de-
comp.). [α]2D0 (578 nm) = 141.1 (c = 0.5, MeOH). 1H NMR
(400 MHz, [D6]DMSO): δ = 1.25 (d, JMe,2Ј = 6.5 Hz, 3 H, Me),
1.88 (ddd, J3B,3A = 12.2, J3B,4 = 9.8, J3B,2 = 9.2 Hz, 1 H, 3B-H),
2.50 (dd, J3ЈB,3ЈA = 15.5, J3ЈB,2Ј = 9.3 Hz, 1 H, 3ЈB-H), 2.56 (ddd,
J3A,3B = 12.2, J3A,4 = 9.0, J3A,2 = 8.6 Hz, 1 H, 3A-H), 3.09 (dd,
J3ЈA,3ЈB = 15.5, J3ЈA,2Ј = 8.7 Hz, 1 H, 3ЈA-H), 3.72 (ddq, J2Ј,3ЈB
=
9.3, J2Ј,3ЈA = 8.7, J2Ј,Me = 6.5 Hz, 1 H, 2Ј-H), 4.10 (dd, J2,3B = 9.2,
J2,3A = 8.6 Hz, 1 H, 2-H), 4.20 (dd, J4,3B = 9.8, J4,3A = 9.0 Hz, 1
H, 4-H), 6.26 (d, J7Ј,6Ј = 7.7 Hz, 1 H, 7Ј-H), 6.54 (dd, J5Ј,6Ј = 7.3,
J5Ј,4Ј = 7.0 Hz, 1 H, 5Ј-H), 6.89 (dd, J6Ј,7Ј = 7.7, J6Ј,5Ј = 7.3 Hz, 1
H, 6Ј-H), 6.98 (d, J4Ј,5Ј = 7.0 Hz, 1 H, 4Ј-H), 8.28 (s, 1 H, NH),
12.89 (br. s, 1 H, CO2H) ppm. C14H16N2O3 (260.29): calcd. C
64.60, H 6.20, N 10.76; found C 64.61, H 6.20, N 10.64.
{(2S,4S)-4-[(2S)-2-Methylindolin-1-yl]-5-oxoprolyl}[(1S)-1-phenyl-
ethyl]amine (18): According to the above procedure and starting
from amino acid cis-14, derivative 18 was obtained in 54% yield.
M.p. 106–110 °C. [α]2D0 = 82.1 (c = 1.0, CHCl3). Ͼ99% de; HPLC
cis-5-Oxo-4-(1-piperidyl)proline (cis-16): Compound threo-5 (1.16 g,
2.99 mmol) was refluxed in HCl (6 , 12 mL) for 5 h. Then accord-
ing to the procedure described for amino acid (2S,4S)-13, a
39:6:46:10 mixture of hydrochlorides of threo-/erythro-12/cis-/trans-
16 (0.85 g) was obtained. Ag2CO3 (0.69 g, 2.5 mmol) was added to
a solution of the above mixture in H2O (2 mL). The reaction mix-
ture was stirred at room temperature for 30 min, the precipitate
was filtered off, the filtrate was treated with H2S, the precipitate
was filtered off, and the filtrate was concentrated to dryness under
reduced pressure. The residue (0.67 g) was heated under reduced
pressure at 120–130 °C over P2O5 for 4 h. Crystallization from
EtOH gave cis-16 as a white solid (0.41 g, 65% yield, 99% de). M.p.
204–211 °C (decomp.). 1H NMR (400 MHz, [D6]DMSO): δ = 1.37
(m, 2 H, H-piperidyl), 1.47 (m, 4 H, H-piperidyl), 1.87 (ddd, J =
13.0, 8.0, 8.0 Hz, 1 H, 3B-H), 2.38 (ddd, J = 13.3, 8.7, 8.7 Hz, 1
H, 3A-H), 2.42 (m, 2 H, H-piperidyl), 2.65 (m, 2 H, H-piperidyl),
3.36 (dd, J = 8.7, 8.6 Hz, 1 H, 4-H), 3.96 (dd, J = 7.9, 7.9 Hz, 1
H, 2-H), 8.09 (s, 1 H, NH) ppm. C10H16N2O3 (212.25): calcd. C
56.59, H 7.60, N 13.20; found C 56.53, H 7.79, N 13.18.
[LiChrosorb Si-60 (4ϫ250 mm, 5 µm), A/B/C = 5:0.7:0.3]: tR
=
=
15.6 min. 1H NMR (400 MHz, CDCl3): δ = 1.34 (d, JMe,CH
7.2 Hz, 3 H, Me), 1.38 (d, J = 6.1 Hz, 3 H, Me-Ind), 2.23 (ddd,
J3B,3A = 12.9, J = 10.5, 9.2 Hz, 1 H, 3B-H), 2.62 (ddd, J3A,3B
12.9, J = 9.2, 8.4 Hz, 1 H, 3A-H), 2.66 (dd, J3ЈB,3ЈA = 15.5, J =
10.1 Hz, 1 H, 3ЈB-H), 3.13 (dd, J3ЈA,3ЈB = 15.5, J = 8.6 Hz, 1 H,
3ЈA-H), 3.72 (m, 1 H, 2Ј-H), 4.05 [dd, J = 9.2, 8.4 Hz, 1 H, 2(4)-
=
H], 4.10 [dd, J = 10.5, 9.2 Hz, 1 H, 4(2)-H], 5.02 (dq, JCH,NH
=
8.2, JCH,Me = 7.2 Hz, 1 H, CH-Phe), 6.39 (d, J7Ј,6Ј = 7.8 Hz, 1 H,
7Ј-H), 6.70 (dd, J5Ј,6Ј = 7.5, J5Ј,4Ј = 7.2 Hz, 1 H, 5Ј-H), 6.79 (d,
JNH,CH = 8.2 Hz, 1 H, NH), 6.90 (s, 1 H, NH-lactam), 7.00 (dd,
J6Ј,7Ј = 7.8, J6Ј,5Ј = 7.5 Hz, 1 H, 6Ј-H), 7.05 (d, J4Ј,5Ј = 7.2 Hz, 1 H,
4Ј-H), 7.32–7.20 (m, 5 H, Ph) ppm. C22H25N3O2 (363.46): calcd. C
72.70, H 6.93, N 11.56; found C 72.61, H 6.99, N 11.42.
X-ray Analysis: Data for (2S,4S)-2 and threo-4 were collected with
an XCALIBUR-3 diffractometer, and that for erythro-5 was col-
lected with a Bruker P4 diffractometer with graphite-monochro-
mated Mo-Kα radiation. The structures were solved by direct meth-
ods and expanded using Fourier techniques. The non-hydrogen
atoms were refined anisotropically. The hydrogen atoms involved
in hydrogen bonding were located in electron-density maps. The
remainder of the hydrogen atoms were placed in idealised positions
and allowed to ride on the C atoms to which they are bonded.
trans-5-Oxo-4-(1-piperidyl)proline (trans-16): According to the
above procedure and starting from erythro-5, lactams trans-16 were
obtained in a 75% yield (99% de). M.p. 133–136 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 1.37 (m, 2 H, piperidyl), 1.46 (m, 4 H,
piperidyl), 2.07 (ddd, J = 13.2, 8.9, 2.7 Hz, 1 H, 3B-H), 2.27 (ddd,
J = 13.2, 9.2, 9.2 Hz, 1 H, 3A-H), 2.38 (m, 2 H, piperidyl), 2.70
(m, 2 H, piperidyl), 3.31 (dd, J = 8.9, 8.6 Hz, 1 H, 4-H), 3.97 (ddd,
Crystal Data for (2S,4S)-2: Mr = 410.42; 0.50ϫ0.43ϫ0.23 mm;
yellow prism; T = 295 K; orthorhombic; space group P212121; a =
J = 9.5, 2.6, 1.0 Hz, 1 H, 2-H), 8.07 (s, 1 H, NH) ppm. 13C NMR 10.1205(4) Å, b = 11.3428(4) Å, c = 17.8131(7) Å; β = 90.00°; V =
(100 MHz, [D6]DMSO): δ = 23.61 (CH2 piperidyl), 25.20 (2 CH2
2044.85(13) Å3; ρcalcd. = 1.333 gcm–3; θmax = 26.37°; R1 = 3.76%.
Eur. J. Org. Chem. 2007, 4257–4266
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4265

V. P. Krasnov et al.
FULL PAPER
[6]
[7]
[8]
a) K.-i. Tanaka, H. Sawanishi, Tetrahedron: Asymmetry 2000,
11, 3837–3843; b) M. Hudlicky, J. S. Merola, Tetrahedron Lett.
1990, 31, 7403–7406.
a) I. Funaki, L. Thijs, B. Zwanenburg, Tetrahedron 1996, 52,
9909–9924; b) A. Javidan, K. Schafer, S. G. Pyne, Synlett 1997,
100–102.
CCDC-643957 contains the supplementary crystallographic data
for this compound.
Crystal Data for threo-4: Mr = 500.53; 0.48ϫ0.37ϫ0.22 mm;
colourless plate; T = 295 K; monoclinic; space group P21/n; a =
17.3292(10) Å, b = 9.6538(5) Å, c = 31.7835(18) Å; β = 100.055(5)°;
V = 5235.5(5) Å3; ρcalcd. = 1.270 gcm–3; θmax = 26.00; R1 = 5.90%.
CCDC-643956 contains the supplementary crystallographic data
for this compound.
a) V. P. Krasnov, I. M. Bukrina, E. A. Zhdanova, M. I. Kodess,
M. A. Korolyova, Synthesis 1994, 961–964; b) I. M. Bukrina,
V. P. Krasnov, V. Kh. Kravtsov, V. N. Biyushkin, L. V.
Alexeeva, Izv. Akad. Nauk SSSR, Ser. Khim. 1989, 2077–2081
(Chem. Abstr. 1990, 112, 235791).
a) G. G. Vatulina, T. N. Tuzhilkova, T. V. Matveeva, V. P. Kras-
nov, N. L. Burde, L. V. Alexeeva, Khim.-Pharm. Zh. 1986, 20,
1078–1083 (Chem. Abstr. 1987, 106, 15186); b) I. A. Nizova,
V. P. Krasnov, O. V. Korotovskich, L. V. Alekseeva, Izv. Akad.
Nauk SSSR, Ser. Khim. 1989, 2781–2785 (Chem. Abstr. 1990,
113, 78906); c) V. P. Krasnov, M. A. Koroleva, Russ. Chem.
Bull. 1995, 44, 631–634; d) V. P. Krasnov, M. A. Koroleva,
N. G. Evstigneeva, I. A. Nizova, Russ. Chem. Bull. 1995, 44,
635–638; e) V. P. Krasnov, A. Yu. Vigorov, I. A. Nizova, A. N.
Grishakov, N. G. Evstigneeva, M. I. Kodess, Russ. Chem. Bull.
2004, 53, 1327–1330.
V. P. Krasnov, L. V. Alekseeva, N. A. Firsova, I. K. Kodess,
N. L. Burde, Khim.-Pharm. Zh. 1984, 18, 655–659 (Chem.
Abstr. 1984, 101, 192417).
a) V. P. Krasnov, I. M. Bukrina, M. A. Korolyova, V. Kh.
Kravtsov, Russ. J. Org. Chem. 1998, 34, 333–339; b) V. P. Kras-
nov, E. A. Zhdanova, V. N. Biyushkin, V. Kh. Kravtsov, Russ.
J. Org. Chem. 1999, 35, 572–577.
Crystal Data for erythro-5: Mr = 388.41; 1.10ϫ0.46ϫ0.24 mm;
colourless prism; T = 298 K; monoclinic; space group P21/n; a =
9.3423(8) Å, b = 9.3345(10) Å, c = 23.018(2) Å; β = 96.249(7)°; V
= 1995.3(3) Å3; ρcalcd. = 1.293 gcm–3; θmax = 26.00; R1 = 4.47%.
CCDC-617321 contains the supplementary crystallographic data
for this compound.
[9]
These data can be obtained free of charge from The Cambridge
Crystallographic
data_request.cif.
Data
Centre
via
www.ccdc.cam.ac.uk/
Acknowledgments
[10]
[11]
This work was financially supported by the Russian Foundation
for Basic Research (grant no. 06-03-32791), and the State Program
for Supporting of Leading Scientific Schools of the Russian Feder-
ation (grant NSh 9178.2006.3). The authors thank Dr. Ilya Ganeb-
nykh for recording mass spectra, and Dr. Pavel Slepukhin for per-
forming X-ray crystallography analyses.
[12]
[13]
R. R. Khristoforov, B. S. Sukhareva, H. B. F. Dixon, M. J.
Sparks, V. P. Krasnov, I. M. Bukrina, A. N. Grishakov, Bio-
chemistry (Moscow) 1996, 61, 343–348.
[1] a) H.-D. Jakubke, H. Jeschkeit, Aminosäuren, Peptide, Proteine,
Eine Einführung, Akademie-Verlag, Berlin, 1982; b) F. Hucho,
Neurochemistry, Fundamentals and Concepts, VCH, Weinheim,
1986.
[2] a) M. M. Moloney, Nat. Prod. Rep. 1998, 15, 205–219; b)
M. M. Moloney, Nat. Prod. Rep. 1999, 16, 485–498; c) D. So-
bolewski, W. Kowalczyk, I. Derdowska, J. Slaninova, K.
Kaczmarek, J. Zabrocki, B. Lammek, Pol. J. Chem. 2005, 79,
731–737.
a) Y. K. Lee, T. Kaneko, Bull. Chem. Soc. Jpn. 1973, 46, 3494–
3498; b) T. Kusumi, H. Kakisawa, S. Suzuki, K. Harada, C.
Kashima, Bull. Chem. Soc. Jpn. 1978, 51, 1261–1262; c) Yu. N.
Belokon’, N. I. Chernoglazova, A. S. Batsanov, N. S. Garbalin-
skaya, V. I. Bakhmutov, Yu. T. Struchkov, V. M. Belikov, Izv.
Akad. Nauk SSSR, Ser. Khim. 1987, 852–857; d) A. Avenoza,
C. Cativiela, J. M. Peregrina, M. M. Zurbano, Tetrahedron:
Asymmetry 1997, 8, 863–871; e) F. A. Luzzio, D. Y. Duveau,
E. R. Lepper, W. D. Figg, J. Org. Chem. 2005, 70, 10117–10120.
[3] a) K. Kaczmarek, M. Kaleta, N. N. Chung, P. W. Schiller, J.
Zabrocki, Acta Biochim. Pol. 2001, 48, 1159–1163; b) L. M.
Beal, B. Liu, W. Chu, K. D. Moeller, Tetrahedron 2000, 56,
10113–10125.
[4] a) G. M. Coppola, H. F. Schuster, Asymmetric Synthesis, Con-
struction of Chiral Moleculs Using Amino Acids, Wiley-Intersci-
ence, New York, Chichester, Brisbane, Toronto, Singapore,
1987; b) C. Nájera, M. Yus, Tetrahedron: Asymmetry 1999, 10,
2245–2303.
[14] S. Bachurin, S. Tkachenko, I. Baskin, N. Lermontova, T. Mu-
khina, L. Petrova, A. Ustinov, A. Proshin, V. Grigoriev, N. Lu-
koyanov, V. Palyulin, N. Zefirov, Ann. N. Y. Acad. Sci. 2001,
939, 219–236.
[15] V. P. Krasnov, M. A. Koroleva, T. V. Matveeva, E. A.
Zhdanova, A. N. Grishakov, N. A. Klyuev, Russ. Chem. Bull.
2001, 50, 644–648.
[16] L. V. Alekseeva, N. L. Burde, G. V. Bilim, Zh. Org. Khim. 1971,
7, 645–647 (Chem. Abstrs. 1971, 75, 36611).
[5] a) S. Danishefsky, E. Berman, L. A. Clizbe, M. Hirama, J. Am.
Chem. Soc. 1979, 101, 4385–4386; b) N. E. Allen, D. B. Boyd,
J. B. Campbell, J. B. Deeter, T. K. Elzey, B. J. Foster, L. D. Hat-
fied, J. N. Hobbs, W. J. Hornback, D. C. Hunden, N. D. Jones,
M. D. Kinnick, J. M. Morin, J. E. Munroe, J. K. Swartzend-
ruber, D. G. Vogt, Tetrahedron 1989, 45, 1905–1928; c) J. E.
Baldwin, T. Miranda, M. G. Moloney, T. Hokelek, Tetrahedron
1989, 45, 7459–7468; d) J. Ezquerra, C. Pedregal, A. Rubio, B.
Yruretagoyena, A. Escribano, F. Sánchez-Ferrando, Tetrahe-
dron 1993, 49, 8665–8678; e) R. Goswami, M. G. Moloney,
Chem. Commun. 1999, 2333–2334.
[17] N. A. Firsova, L. V. Alekseeva, K. M. Selivanova, Z. G. Evstig-
neeva, Biokhimiya 1986, 51, 980–984.
[18] A. Bladé-Font, Tetrahedron Lett. 1980, 21, 2443–2446.
[19] L. J. Heinz, W. H. W. Lunn, R. E. Murff, J. W. Paschal, L. A.
Spangle, J. Org. Chem. 1996, 61, 4838–4841.
[20] a) V. P. Krasnov, I. A. Nizova, T. A. Sinitsyna, N. V. Avdyu-
kova, Russ. Chem. Bull. 1993, 42, 2001–2004; b) I. A. Nizova,
V. P. Krasnov, G. L. Levit, M. I. Kodess, Amino Acids 2002, 22,
179–186.
Received: April 19, 2007
Published Online: July 10, 2007
4266
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4257–4266