Enantiopure 4- and 5-Aminopiperidin-2-ones: Regiocontrolled Synthesis and Conformational Characterization as Bioactive β-Turn Mimetics

Article abstract of DOI:10.1021/jo000555c

Starting from aspartic acid, we synthesized lactam-bridged β- and γ-amino acid equivalents. Using the 1,4-bis-electrophile 1b as a central intermediate, the 4- and 5-aminopiperidin-2-ones 4 and 8, respectively, were approached by regioselective functional

Full text of DOI:10.1021/jo000555c

7406
J . Org. Chem. 2000, 65, 7406-7416
En a n tiop u r e 4- a n d 5-Am in op ip er id in -2-on es: Regiocon tr olled
Syn th esis a n d Con for m a tion a l Ch a r a cter iza tion a s Bioa ctive
â-Tu r n Mim etics
Klaus Weber, Ursula Ohnmacht, and Peter Gmeiner*
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University,
Schuhstraâe 19, D-91052 Erlangen, Germany
Gmeiner@pharmazie.uni-erlangen.de
Received April 12, 2000
Starting from aspartic acid, we synthesized lactam-bridged â- and γ-amino acid equivalents. Using
the 1,4-bis-electrophile 1b as a central intermediate, the 4- and 5-aminopiperidin-2-ones 4 and 8,
respectively, were approached by regioselective functionalization and subsequent lactamization.
Diastereoselective C-alkylation was performed after N-protection of the lactam functionality when
exclusive trans configuration resulting in the formation of 5a -f was observed in the 4-amino series.
On the other hand, cis selectivity was typical for the alkylations of the 5-amino lactams 5a ,b. To
investigate the ability of the lactam building blocks to induce reverse-turn structures by
intramolecular hydrogen bonding, the model peptidomimetics 12 and 14 representing Homo-
Freidinger lactams of type II and III were prepared from 4a and 8a , respectively. Conformational
analyses in dilute solution (1 mM) by IR and NMR spectroscopy at room temperature clearly
indicated that the 4-aminopiperidin-2-one derivative 12 predominantly adopts a reverse-turn
structure stabilized by a CO-HN hydrogen bond in an 11-membered ring. VT NMR experiments
showed a substantial temperature dependency of the terminal NH when ∆δNH/∆T ) -6.5 indicated
that the amount of intramolecular hydrogen bonding is higher at low temperature. An application
in the field of medicinal chemistry was demonstrated. Thus, starting from the Homo-Freidinger
lactam 11c and the enantiomer ent-11c, we synthesized the peptidomimetics 15c and 16c and
investigated them as lactam-bridged analogues of the dopamine receptor modulating peptide Pro-
Leu-Gly-NH2 (PLG). Both test compounds turned out to enhance significantly the agonist binding
of dopamine D2 receptors, when the isomer 15c revealed a potency comparable to the genuine
ligand PLG.
In tr od u ction
of using γ-amino-substituted lactams of type I (Freidinger
lactams),8 which have proven useful for the design of a
variety of medicinally relevant enzyme inhibitors,9 we
attempted to approach analogous â- and γ-amino acid-
derived congeners of type II and III, respectively, which
we call Homo-Freidinger lactams (Scheme 1).
We report here an ex-chiral pool approach to â-amino
acids10,11 and â- and γ-amino-substituted piperidin-2-
ones, including C-alkylation products. Furthermore, the
incorporation of the conformationally restricted building
blocks into tripeptide mimics and their conformational
properties, especially the ability to adopt â-turn-related
structures, are described. Application of the strategy led
to the PLG mimetics 15c and 16c, which induced an
increase in the affinity of dopamine D2 receptors.
One of the most challenging aspects of modern medici-
nal chemistry is the design of highly potent, target-
selective, and metabolically stable peptidomimetics.1 An
important step in the development of drug candidates of
this type is the employment of molecular scaffolds,
inducing conformational restraints.2 Within this field,
reverse-turn templates are of special interest because a
large number of small peptides having regulatory roles
in organisms adopt â- or γ-turn conformations.3
In conjunction with a program to design â-analogues4
of the dopamine D2 receptor modulating peptide Pro-Leu-
Gly-NH2 (PLG),5 we investigated the synthesis of lactam-
bridged amino acid derivatives by regioselective func-
tionalization of aspartic acid and asparagine.6,7 Instead
(6) For preliminary communication, see: Weber, K.; Gmeiner, P.
Synlett 1998, 885.
(7) Michel, D.; Waibel, R.; Gmeiner, P. Heterocycles 1999, 51, 365.
Lehmann, T.; Michel, D.; Gla¨nzel, M.; Waibel, R.; Gmeiner, P.
Heterocycles 1999, 51, 1389.
(8) Freidinger, R. M.; Schwenk Perlow, D.; Veber, D. F. J . Org.
Chem. 1982, 47, 104. Freidinger, R. M. J . Org. Chem. 1985, 50, 3631.
Wolf, J .-P.; Rapoport, H. J . Org. Chem. 1989, 54, 3164. Robl, J . A.;
Cimarusti, M. P.; Simpkins, L. M.; Weller, H. N.; Pan, Y. Y.; Malley,
M.; DiMarco, J . D. J . Am. Chem. Soc. 1994, 116, 2348.
(9) Wolfe, M. S.; Dutta, D.; Aube´, J . J . Org. Chem. 1997, 62, 654
and references therein.
(1) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32,
1244.
(2) Beck-Sickinger, A. G. In Methods in Molecular Biology, Neu-
ropeptide Protocols; Irvine, G. B., Williams, C. H., Eds.; Humana
Press: Totowa, NJ , 1997; p 61. Tamura, K.; Agrios, K. A.; Vander
Velde, D.; Aube´, J .; Borchardt, R. T. Bioorg. Med. Chem. 1997, 5, 1859.
(3) For examples, see: Vacca, J . P.; Condra, J . H. Drug Discovery
Today 1997, 2, 261. Blommaert, A. G. S.; Dhoˆtel, H.; Ducos, B.;
Durieux, C.; Goudreau, N.; Bado, A.; Garbay, C.; Roques, B. P. J . Med.
Chem. 1997, 40, 647. Hruby, V. J . Drug Discovery Today 1997, 2, 165.
(4) Thomas, C.; Ohnmacht, U.; Niger, M.; Gmeiner, P. Bioorg. Med.
Chem. Lett. 1998, 8, 2885.
(10) For review, see: J uaristi, E., Ed. Enantioselective Synthesis of
â-Amino Acids; Wiley-VCH: New York, 1997.
(11) Gmeiner, P. Tetrahedron Lett. 1990, 31, 5717. Weber, K.;
Kuklinkski, S.; Gmeiner, P. Org. Lett. 2000, 2, 647.
(5) Chiu, S.; Paulose, C. S.; Mishra, R. K. Science 1981, 214, 1261.
J ohnson, R. L.; Rajakumar, G.; Mishra, R. K. J . Med. Chem. 1986, 29,
2100.
10.1021/jo000555c CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/03/2000

Synthesis of 4- and 5-Aminopiperidin-2-ones
J . Org. Chem., Vol. 65, No. 22, 2000 7407
Sch em e 1
tion, it was necessary to employ a protected N-nucleo-
phile. Thus, we reacted 1b with 1 equiv of phthalimide-K
to afford the monosubstitution product 6a . Because
phthalimide-K reacted slower than LiCN and yielded
only 40% product, we increased the nucleophile concen-
tration. The best yield (61%, besides 16% of easily
separable diimide 6b) was observed when 4 equiv was
used. Upon treatment of the sulfonate 6b with LiCN,
formation of the displacement product 6c was observed.
Subsequent hydrazinolysis yielded the diamino nitrile 7
as a cyclization precursor. Finally, ring closure was
achieved under acidic conditions, resulting in formation
of the N,N-dibenzyl-protected 5-aminopiperidin-2-one 8a .
Whereas the 4-amino regioisomer 4a represents a
lactam-bridged â-alanine unit, the building block 8a can
be regarded as a γ-aminobutyric acid (GABA) analogue.18
We were intrigued by the question of whether deproto-
nation of the lactam R positions and subsequent trapping
with suitable electrophiles gave us the opportunity to
introduce residues representing amino acid side chains.
The C-alkylations should be performed after N-protec-
tion of the lactam functionality. Thus, we converted the
lactams 4a and 8a into the mixed imides 4b and 8b,
respectively, by treatment with Boc2O in the presence of
Et3N/DMAP.19 Alternatively, benzyl substituents were
attached by NaH-induced N-deprotonation and subse-
quent reaction with benzyl bromide. Starting from the
orthogonally protected 4-aminolactam 4b, our alkylation
studies were performed in THF, employing LDA as a base
and methyl iodide as an electrophile. C-Alkylation in high
yield and complete diastereoselection was observed when
2 equiv of base and 2.5 equiv of the electrophile turned
out to represent the optimal stoichiometry. Under these
conditions, the trans diastereomer 5a could be isolated
in 75% yield. Both diastereomeric purity and relative
configuration were determined by 1H NMR spectroscopic
investigation when no signal of any impurity of the crude
product exceeded the intensity of the 13C satellites of the
N-benzyl resonances (signal-to-noise ratio > 4:1), indicat-
ing a diastereoselectivity higher than 99%. The trans
configuration including an equatorial orientation of both
substituents was elucidated unambiguously by diagnostic
coupling constants and NOEs.20 Obviously, the si face of
an anionic reaction intermediate is effectively shielded
by the sterically demanding dibenzylamino substituent,
causing an exclusive attack of the electrophile from the
opposite side (re). Similar results were obtained when
employing benzyl bromide as an electrophile. Thus, the
lactam-bridged â-homophenylalanine derivative 5b could
be diastereoselectively synthesized from 4b in 85% yield.
Because fluoro-substituted amino acid analogues become
more and more important in bioorganic and medicinal
chemistry,21 we elaborated an electrophilic fluorination
Resu lts a n d Discu ssion
As a straightforward strategy for the synthesis of both
4- and 5-aminopiperidinones, representing lactam-bridged
â- and γ-amino acids, respectively, we chose a regiose-
lective functionalization of the 1,4-bis-electrophile 1b,
which is readily available from natural aspartic acid via
the aminobutanediol 1a (Scheme 2).12 According to previ-
ous experiments, attempts to isolate and store the
dimesylate 1b are generally not successful because
migration of the dibenzylamino function followed by
formation of enantiomerically pure N,N-dibenzyl-3-me-
syloxypyrrolidinium occurs.13,14 Thus, the bis-electrophile
1b should be employed as a freshly prepared solution in
THF. For the transformation to the target compounds,
we envisioned subsequent incorporation of amine and
carboxylate equivalents followed by cyclization. Because
of earlier observations on displacement reactions with
mono-O-protected derivatives, we anticipated a signifi-
cantly higher kinetic reactivity of position 1, which is
activated by an anchimeric participation of the dibenzyl-
amino group.12 In practice, treatment of the dimesylate
1b with LiCN at room temperature resulted in exclusive
formation of the â-amino nitrile 2. Conversion of the
mono-electrophile 2 into the â,δ-diamino nitrile 3a was
best accomplished when liquid ammonia was used as a
nucleophile, affording the cyclization precursor in 82%
yield based on 1a . Besides the function as an intermedi-
ate for the synthesis of Homo-Freidinger lactams, the
mesyloxynitrile 3a can also serve as a building block for
the preparation of â-amino acids when C,C-bond forma-
tion was facilitated by organocuprates.15,16 Thus, reaction
of 3a with Me2CuLi and Bu2CuLi gave the â-amino
nitriles 3b and 3c, which were converted into the
N-protected â-amino acids 3d and 3e by acidic hydrolysis.
On the other hand, treatment of the diamino nitrile 3a
with HCl in aqueous MeOH resulted in lactam formation.
Thus, the 4-aminopiperidinone 4a could be produced
efficiently in high overall yield (58% based on Asp).
As a complement of this route, we attempted to access
5-aminopiperidinones17 by changing the order of displace-
ment reactions. In this case, the bis-electrophile 1b has
to be reacted first with an NH2 equivalent in position 1
in the presence of the leaving group in position 4. To
prevent pyrrolidine formation by intramolecular alkyla-
(18) Krogsgaard-Larsen, P. J . Med. Chem. 1981, 24, 1377.
(19) Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H. Angew. Chem., Int. Ed.
Engl. 1978, 17, 569.
(12) Gmeiner, P.; Ka¨rtner, A.; J unge, D. Tetrahedron Lett. 1993, 34,
4325. Gmeiner, P.; J unge, D.; Ka¨rtner, A. J . Org. Chem. 1994, 59, 6766.
Gmeiner, P.; Ka¨rtner, A. Synthesis 1995, 83.
(20) Diagnostic NOEs for 5a :
(13) Gmeiner, P.; Orecher, F.; Thomas, C.; Weber, K. Tetrahedron
Lett. 1995, 36, 381.
(14) Thomas, C.; Orecher, F.; Gmeiner, P. Synthesis 1998, 1491.
(15) Posner, G. H. In Organic Reactions; Baldwin, J . E., Bittmann,
R., Dauben, W. G., Heck, R. F., Kende, A. S., Leimgruber, W., Marshall,
J . A., McKusick, B. C., Meinwald, J ., Trost, B. M., Weinstein, B., Eds.;
J ohn Wiley & Sons: New York, 1975; Vol. 22, p 253.
(16) Bajgrowicz, J . A.; El Hallaoui, A.; J acquier, R.; Pigie`re, C.;
Viallefont, P. Tetrahedon Lett. 1984, 25, 2759.
(17) For a previous synthesis of (S)-5-aminopiperidin-2-one, see:
Panday, S. K.; Langlois, N. Tetrahedron Lett. 1995, 36, 8205.

7408 J . Org. Chem., Vol. 65, No. 22, 2000
Weber et al.
Sch em e 2
of the building block 4b with NFSI (N-fluorobenzene
sulfonimide).22 Again, we observed a trans-selective
substitution, resulting in the formation of the R-fluoro
lactam 5c. In connection with structural variations of
benzamide-typed antipsychotics,23 N-benzylpiperidinone-
derived chiral building blocks are of special interest for
our SAR studies. Therefore, we envisioned to extend the
alkylation reactions described above for a stereoselective
synthesis of N-benzyllactams. In fact, the formal ex-
change of Boc by benzyl did not change the reactivity of
the systems toward C-alkylations when deprotonation of
4c and subsequent treatment with methyl iodide, benzyl
bromide, and NFSI gave the trans isomers 5d , 5e, and
5f, respectively. The products were formed in high yield
(38-72%) and highly diastereoselectively. Application of
the protocol elaborated for the synthesis of the 5-ami-
nopiperidinone surrogates turned out to be more difficult.
Starting from the N-Boc-protected lactam 8b, the at-
tempted methylation and benzylation initially failed.
Employing NFSI as an electrophile, we observed the
formation of a mono-C-alkylation product in 26% yield.
Careful NMR analysis indicated diastereomeric purity
and cis configuration. The stereoselective production of
10c was surprising to us because we assume a chairlike
transition state with an equatorially dispositioned diben-
zylamine substituent state, which should favor an axial
attack. This would preferably lead to the trans isomer
9c. However, the CH-acidic properties of the R-fluoro
imide structure are expected to facilitate equilibration
during the reaction. Thus, the formation of the bis-
equatorially substituted isomer 10c will be due to
thermodynamic control. When elaborating suitable reac-
tion conditions for the methylation and benzylation
reactions of the Boc-protected 5-aminopiperidinone 5b,
we found that addition of 4 equiv of the cosolvents HMPA
facilitated the methylation, giving access to the chro-
matographically separable diastereomers 9a and 10a in
a 3:4 ratio (yield 66%). The relative stereochemistry could
be clearly analyzed by diagnostic coupling patterns of the
1H NMR spectra. It is interesting to note that both
diastereomers revealed different conformational proper-
ties. In agreement with all of the lactams described
above, the cis isomer 10a predominantly exists in a half-
chair conformation. On the other hand, substantial NOEs
between the axially oriented protons in the positions 3
and 6 as well as 4 and 5 clearly indicate a boatlike
structure for the trans isomer 9a , making it possible that
both residues are positioned equatorially.24 In the pres-
ence of HMPA, benzylation and fluorination of 8b was
also accomplished, furnishing 1:9 and 1:20 mixtures of
the diastereomers 9b/10b and 9c/10c,25 respectively.
According to diagnostic 1H NMR coupling constants, both
diastereomers showed half-chair conformations. The
deprotonation of the N-benzyl lactam 8c, followed by
treatment with the electrophiles methyl iodide, benzyl
bromide, and NFSI gave smooth and effective conver-
sions, resulting in the formation of target compounds 9d /
10d , 9e/10e, and 10f, respectively. In accordance with
the observations made for the Boc-protected 5-amino
lactams, the methylation proceeded cis selective when a
3:10 ratio of the diastereomers 9d and 10d was deter-
mined. A 3:10 cis selectivity was also noticed for the
(24) Diagnostic NOEs for 9a :
(21) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1990. Selective Fluorination in Organic
and Bioorganic Chemistry; Welch, J . T., Ed.; ACS Symposium Series
456; American Chemical Society: Washington, DC, 1991. Imperiali, B.
Adv. Biotechnol. Processes 1988, 10, 97. Filler, R., Kobayashi, Y., Eds.
Biomedical Aspects of Fluorine Chemistry; Kodanasha Ltd., Elsevier
Biomedical Press: Tokyo, 1982. Chirakal, R.; Garnett, E. S.; Schro-
bilgen, G. J .; Nahmias, C.; Firnau, G. Chem. Br. 1991, 27, 47.
(22) Differding, E.; Duthaler, R. O.; Krieger, A.; Ru¨egg, G. M.;
Schmit, C. Synlett 1991, 395.
(23) For review, see: Ho¨gberg, T. Drugs Future 1991, 16, 333. For
a very recent example, see: Thomas, C.; Hu¨bner, H.; Gmeiner, P.
Bioorg. Med. Chem. Lett. 1999, 9, 841.
(25) The minor diastereomer 9c was not isolated but detected
unambiguously in the 1H NMR spectrum of crude 10c (diagnostic
signal: δ 5.02 (J ) 47.9, 6.8, 6.8, 1H, 3Heq)).

Synthesis of 4- and 5-Aminopiperidin-2-ones
J . Org. Chem., Vol. 65, No. 22, 2000 7409
Sch em e 3
Sch em e 4
F igu r e 1. NH stretch FT-IR data for 1 mM samples in
CH2Cl2 at room temperature after subtraction of the spectrum
of pure CH2Cl2.
benzylation reaction, whereas the fluorination of 8c gave
the cis diastereomer 10f exclusively.
We were intrigued by the question of whether the
Homo-Freidinger lactams II and III representing lac-
tam-bridged â- and γ-amino acid equivalents in peptido-
mimetics are able to induce stable reverse turns. Thus,
we observed the conformational behavior of the model
compounds 12 and 14 in dilute solution by IR (1 mM,
CH2Cl2) and 1H NMR spectroscopy (1 mM, CDCl3). Figure
1 shows the NH stretch regions of the IR spectra,
recorded at room temperature, of 12 and 14 compared
to N-methylacetamide and N-methyl-2-(2-oxopiperidin-
1-yl)acetamide (17). In accordance with the literature,27
N-methylacetamide displays a solvent-exposed NH band
at 3460 cm-1. Besides the extensive non-hydrogen-bonded
amide absorption at 3450 cm-1, the oxopiperidinylaceta-
mide 17 shows a small amount of intramolecular hydro-
gen bonding, indicated by a broad absorption at 3350
cm-1. Thus, formation of a seven-membered-ring hydro-
gen bond is not favored. On the other hand, the major
NH stretch band of the peptidomimetic 12 at 3350 cm-1
indicates strong internal hydrogen bonding. The combi-
nation of the data led us to conclude that this is the result
of an 11-membered-ring interaction. Obviously, the mo-
lecular scaffold 12 shows a substantial tendency for
reverse-turn formation. The amide 12 also displays a
minor absorption maximum at 3450 cm-1, which may be
assigned to a fully solvated NH. IR spectral data of the
amide 14 representing the Homo-Freidinger lactam III
display little intramolecular hydrogen bonding (major
band at 3450 cm-1 and minor absorption at 3350 cm-1).
To investigate the ability of the 4- and 5-amino lactams
to induce folded conformations, the synthesis of the model
tripeptide mimetics 12 and 14 was intended (Scheme 3).
Thus, deprotonation of the lactam 4a by KH and subse-
quent N-alkylation gave the protected dipeptide mimetic
11a. Subsequently, controlled N-debenzylation was elabo-
rated. Utilizing Pd(OH)2/C as a catalyst, we observed
complete hydrogenolysis after 15 h to give the primary
amine 11c. Terminating the reaction after 40 min and
repeating the procedure four times after the respective
product separations gave access to the mono-debenzyla-
tion product 11b. Alternatively, treatment of the tertiary
amine 11b with CAN26 gave a more convenient and
selective approach to 11b. The synthesis of the potential
reverse-turn mimetic 12 was completed by N-acylation,
yielding 11d , followed by aminolysis with MeNH2. Using
the same reaction sequence, the 5-aminopiperidone de-
rivative 14 was prepared from the building block 8a via
the intermediates 13a and 13c.
As an application in the field of dopamine receptor
modulating reagents, we tried to incorporate the Homo-
Freidinger lactam 11c and the optical antipode ent-11c,
readily available from (R)-aspartic acid, into the confor-
matively rigidized PLG mimetics 15c and 16c, respec-
tively (Scheme 4). In practice, DCC/HOBt coupling of 11c
and ent-11c with Cbz-Pro afforded the protected tri-
peptide mimetics 15a and 16a , respectively. Subsequent
treatment with liquid ammonia resulted in the formation
of the carboxamides 15b and 16b, which were depro-
tected by catalytic hydrogenation to give the PLG mi-
metics 15c and 16c, respectively.
(27) Dado, G. P.; Gellman, S. H. J . Am. Chem. Soc. 1993, 115, 4228.
Krautha¨user, S.; Christianson, L. A.; Powell, D. R.; Gellman, S. H. J .
Am. Chem. Soc. 1997, 119, 11719. Chung, Y. J .; Christianson, L. A.;
Stanger, H. E.; Powell, D. R.; Gellman, S. H. J . Am. Chem. Soc. 1998,
120, 10555.
(26) Hungerhoff, B.; Samanta, S. S.; Roels, J .; Metz, P. Synlett 2000,
77.

7410 J . Org. Chem., Vol. 65, No. 22, 2000
Weber et al.
Besides the IR-based analysis, 1H NMR investigations
of intermolecular hydrogen-bonding interactions of 12
including VT measurements were performed. The NMR
work was done in CDCl3 because protic dipolar solvents
such as D2O lead to a H/D exchange of the diagnostic
amide signals. D2O as an alternative solvent would be
more similar to biological liquids. However, we are
interested in model studies giving reference to putatively
bio-active conformations. When exerting its function, a
peptidomimetic is bound to a membrane receptor or an
enzyme. Then it is generally nonsolvated. In contrast to
the IR data, only one NH resonance (δ 6.6) was observed
by NMR because equilibrium among hydrogen-bonded
and non-hydrogen-bonded states is usually rapid on the
NMR time scale. Thus, the value represents a mixture
of both populations. By comparison, measurement of
N-methylacetamide under identical conditions displayed
a δNH at 5.45 ppm. VT NMR measurements showed a
significant chemical shift change for the NH proton with
temperature. J uxtaposition of the chemical shifts em-
F igu r e 2. Minimal energy conformation of 12 obtained by
molecular mechanics calculations.
ploying 10 °C steps between 230 and 320 K gave ∆δNH
/
∆T ) -6.5, indicating that the amount of intramolecular
hydrogen bonding is substantially higher at low temper-
ature.
After peak assignment utilizing H,H-COSY and C,H-
COSY experiments, careful analysis of the 1H NMR
spectrum of the peptidomimetic 12 and comparison to
that of the regioisomer 14 and the synthetic precursors
11d and 13c, respectively, supported the assumption of
a folded conformation for 12. According to coupling
patterns, the piperidinone ring of 12 predominantly
exists in a twisted conformation with a perpendicularly
orientated amine substituent (narrow signals for 3-H and
F igu r e 3. Stimulation of [3H]pramipexole binding to striatal
membranes by PLG, 15c, and 16c in concentrations of 10-9
M. Results are means ( SEM of three to five experiments each
carried out in triplicate; the data are significantly different
from the control value (p < 0.05).
1
4-H). This is in contrast to the H NMR data of the non-
hydrogen-bonded Homo-Freidinger lactams 11d , 13c,
and 14 when 3J values for antiperiplanar-positioned
protons (10.6-11.4 Hz) indicated half-chair conforma-
tions with equatorially positioned substituents. Obvi-
ously, this conformational change is caused by the
tendency of the molecule to form an internal hydrogen
bond, which is possible only when the aminoacyl group
is directed pseudoaxially. Systematic conformational
analysis based on force-field calculations showed that the
NH hydrogen donor and the CO hydrogen acceptor
cannot come closer than 4.6 Å when the aminoacyl group
is orientated equatorially. However, energetically favor-
able conformations allowing H bonding could be found
for the twisted system. Geometry optimization gave a
minimal energy conformation with an NH-OC distance
of 2.06 Å (Figure 2).
The PLG analogues 15c and 16c were tested for their
ability to increase the binding of the dopamine receptor
agonist [3H]pramipexole to dopamine D2 receptors pre-
pared from bovine striatal membranes.28 The results were
expressed as percentages in specific binding compared
to control membranes. Figure 3 shows the effects of PLG,
which is known as a genuine dopamine receptor modula-
tor probably exerting the effect in a type II â-bend
conformation, and the lactam-bridged analogues 15c and
16c. Significant enhancement of [3H]pramipexole binding
was observed for both test compounds when the diaste-
reomer 15c revealed an activity comparable to PLG.
Because dopamine receptor modulating agents are of
potential interest for the treatment of neurologic and
psychiatric disorders, further efforts in this field are in
progress.
Exp er im en ta l Section
Gen er a l. Solvents and reagents were purified and dried by
standard procedures. Unless otherwise noted, reactions were
conducted under dry N2. Evaporations of final product solu-
tions were done under vacuo with a rotatory evaporator. Flash
chromatography was carried out with 230-400 mesh silica gel.
If not otherwise stated, MS were run by EI ionization (70 eV)
with a solid inlet, and HRMS were obtained by employing peak
1
matching M/∆M ) 10 000. H NMR spectra were recorded on
250 MHz, 360 MHz, and 400 MHz spectrometers, if not
otherwise stated in CDCl3 relative to TMS (J values are in
hertz); 13C NMR spectra were recorded at 63 MHz in CDCl3.
Elemental analyses were performed by Beetz Microanalysis
Laboratory and by the Institute of Organic Chemistry (Ana-
lytical Departments) of the Friedrich-Alexander University
Erlangen-Nu¨rnberg.
(3S)-Meth a n esu lfon ic Acid 4-Cya n o-3-(N,N-d iben zyl-
a m in o)bu tyl Ester (2). To a solution of 1a 14 (5.76 g, 20.2
mmol) and Et3N (6.13 g, 60.6 mmol) in THF (100 mL) was
added methanesulfonyl chloride (4.74 g, 41.4 mmol) at -23
°C. After 30 min of stirring at room temperature, the mixture
was added to a precooled solution of LiCN (48 mL, 0.5 M in
DMF) at -30 °C. After 3 h at room temperature, saturated
aqueous NaHCO3 and Et2O were added. The organic layer was
washed with saturated aqueous NaHCO3, dried (MgSO4), and
evaporated. The residue (crude 2) could be purified by flash
(28) Ohnmacht, U.; Tra¨nkle, C.; Mohr, K.; Gmeiner, P. Pharmazie
1999, 54, 294.
(29) Sreenivasan, U.; Mishra, R. K.; J ohnson, R. L. J . Med. Chem.
1993, 36, 256. Subasinghe, N. L.; Bontems, R. J .; McIntee, E.; Mishra,
R. K.; J ohnson, R. L. J . Med. Chem. 1993, 36, 2356. Reed, L. L.;
J ohnson, P. L. J . Am. Chem. Soc. 1973, 95, 7523.

Synthesis of 4- and 5-Aminopiperidin-2-ones
J . Org. Chem., Vol. 65, No. 22, 2000 7411
chromatography (petroleum ether-EtOAc, 1:1) to give 2 (5.57
g, 74%) as a colorless oil. ent-2 was prepared under the same
reaction conditions, starting from ent-1a . 2: TLC Rf 0.38
(S)-3-(N,N-Diben zyla m in o)n on a n oic Acid (3e). A solu-
tion of 3c (57.5 mg, 0.17 mmol) in concentrated aqueous HCl
(5 mL) was reacted and worked up as described for 3d to give
pure 3e (36.5 mg, 61%) as a colorless oil: TLC Rf 0.48 (CH2-
(petroleum ether-EtOAc, 1:1); [R]23 -49.9° (c ) 1.2, CHCl3);
D
IR 3030, 2940, 2250, 1640, 1450 cm-1
;
1H NMR (360 MHz)
Cl2-MeOH, 95:5); [R]23 +53.3° (c ) 0.5, CHCl3); IR 3030,
D
1
δ 1.93 (dddd, J ) 14.6, 8.0, 5.9, 5.2, 1H), 2.16 (dddd, J )
14.6, 9.2, 5.7, 5.6, 1H), 2.46 (dd, J ) 16.8, 6.7, 1H), 2.60 (dd,
J ) 16.8, 6.3, 1H), 2.83 (s, 3H), 3.24 (dddd, J ) 9.2, 6.7, 6.3,
5.2, 1H), 3.51 (d, J ) 13.7, 2H), 3.80 (d, J ) 13.7, 2H), 4.25
(ddd, J ) 10.0, 8.0, 5.6, 1H), 4.34 (ddd, J ) 10.0, 5.9, 5.7, 1H),
7.20-7.42 (m, 10H); CIMS 373 (M + 1). Anal. Calcd for
2930, 1710, 1600, 1450 cm-1; H NMR (400 MHz) δ 0.90 (t, J
) 7.0, 3H), 1.28-1.41 (m, 9H), 1.79-1.89 (m, 1H), 2.33-2.57
(m, 2H), 2.98-3.12 (m, 1H), 3.40 (d, J ) 13.1, 2H), 3.99 (d, J
) 13.1), 7.24-7.40 (m, 10H); MS 171 (M - 182). Anal. Calcd
for C23H31NO2: C, 78.15; H, 8.84; N, 3.96. Found: C, 78.85;
H, 8.80; N, 3.29.
C
20H24N2O3S: C, 64.49; H, 6.49; N, 7.52. Found: C, 64.39; H,
(4S)-4-(N,N-Diben zyla m in o)p ip er id in -2-on e (4a ). A so-
lution of 3a (6.96 g, 23.7 mmol) in MeOH-H2O (200 mL, 99:
1) was saturated with HCl gas and, subsequently, stirred for
12 h at 60 °C. Then the mixture was adjusted to pH 8 by
addition of aqueous 2 N NaOH and NaHCO3. After addition
of Et2O, the organic layer was dried and evaporated, and the
residue was purified by flash chromatography (MeOH-CH2-
Cl2-N-ethyldimethylamine, 10:90:1) to give pure 4a (4.90 g,
70%) as a colorless solid. ent-4a was prepared under the same
reaction conditions, starting from ent-3a . 4a : TLC Rf 0.24
6.51; N, 7.60.
(3S)-5-Am in o-3-(N,N-diben zylam in o)pen tan en itr ile (3a).
To a solution of crude 2 in MeOH (200 mL) was added liquid
NH3 (50 mL) at -30 °C. After 4 days of stirring at room
temperature, saturated aqueous NaHCO3 and Et2O were
added. The organic layer was dried (MgSO4) and evaporated,
and the residue was purified by flash chromatography (petro-
leum ether-acetone, 1:4) to give pure 3a (4.86 g, 82%) as a
colorless oil. ent-3a was prepared under the same reaction
conditions, starting from ent-2. 3a : TLC Rf 0.10 (CH2Cl2-
MeOH, 95:5); [R]22 -31.3° (c ) 0.9, CHCl3). ent-3a : [R]20
(CH2Cl2-MeOH, 95:5); [R]23 -73.4° (c ) 1.0, CHCl3). ent-4a :
D
[R]25 +73.0° (c ) 1.0, CHCl3); mp 83-85 °C; IR 3200, 3020,
D
D
D
+32.1° (c ) 1.0, CHCl3); IR 3370, 3060, 2930, 2240, 1600, 1450
cm-1; 1H NMR (250 MHz) δ 1.46-1.63 (m, 1H), 1.83-2.01 (m,
1H), 2.41 (dd, J ) 16.8, 6.8, 1H), 2.58 (dd, J ) 16.8, 6.3, 1H),
2.74-2.81 (m, 2H), 3.07-3.20 (m, 1H), 3.47 (d, J ) 13.6,
2H), 3.77 (d, J ) 13.6, 2H), 7.24-7.38 (m, 10H); CIMS 294 (M
+ 1).
2920, 1650, 1450 cm-1; 1H NMR (360 MHz) δ 1.75 (dddd, J )
12.4, 12.3, 12.2, 5.5, 1H), 2.00-2.09 (m, 1H), 2.46 (dd, J ) 17.3,
11.5, 1H), 2.59 (ddd, J ) 17.3, 5.5, 2.0, 1H), 3.01 (ddd, J )
12.0, 5.5, 3.2, 1H), 3.12 (ddd, J ) 12.0, 12.2, 4.0, 1H), 3.28-
3.35 (m, 1H), 3.63 (d, J ) 14.2, 2H), 3.67 (d, J ) 14.2, 2H),
5.88 (s, 1H), 7.19-7.39 (m, 10H); CIMS 295 (M + 1). Anal.
Calcd for C19H22N2O: C, 77.51; H, 7.54; N, 9.52. Found: C,
77.56; H, 7.65; N, 9.36.
(S)-3-(N,N-Dib en zyla m in o)h exa n en it r ile (3b ). To a
stirred suspension of CuI (1.66 g, 8.69 mmol) in Et2O was
added MeLi (9.9 mL, 1.6 M in Et2O) at -50 °C. After 30 min,
3a (0.29 g, 0.79 mmol) dissolved in Et2O (10 mL) was added
dropwise, and the mixture was allowed to warm to -20 °C
over 3.5 h. Then the mixture was added to saturated aqueous
NaHCO3 and Et2O. The organic layer was dried, evaporated,
and purified by flash chromatography (petroleum ether-
EtOAc, 9:1) to give pure 3b (0.108 g, 47%) as a colorless oil:
(4S)-4-(N,N-Diben zyla m in o)-2-oxop ip er id in e-1-ca r box-
ylic Acid ter t-Bu tyl Ester (4b). To a solution of 4a (0.37 g,
1.25 mmol) in CH2Cl2 (20 mL) were added 4-dimethylami-
nopyridine (0.15 g, 1.25 mmol), NEt3 (174 µL, 1.25 mmol), and
di-tert-butyl dicarbonate (0.55 g, 2.5 mmol). After 15 h of
stirring at room temperature, the mixture was concentrated,
and the residue was purified by MPLC (petroleum ether-
EtOAc, 7:3) to give pure 4b (0.35 g, 71%) as slightly yellowish
crystals. ent-4b was prepared under the same reaction condi-
tions, starting from ent-4a . 4b: TLC Rf 0.27 (petroleum ether-
EtOAc, 8:2); [R]20 -45.4° (c ) 1.0, CHCl3). ent-4b: [R]20
TLC Rf 0.18 (petroleum ether-EtOAc, 9:1); [R]23 -15.7° (c )
D
0.6, CHCl3); IR 3030, 2960, 2230, 1450 cm-1
;
1H NMR (400
MHz) δ 0.84 (t, J ) 7.3, 3H), 1.22-1.34 (m, 1H), 1.39-1.51
(m, 2H), 1.70-1.81 (m, 1H), 2.37 (dd, J ) 16.9, 6.6, 1H), 2.51-
(dd, J ) 16.9, 6.6, 1H), 2.85-3.04 (m, 1H), 3.54 (d, J ) 13.2,
2H), 3.71 (d, J ) 13.9, 2H), 7.20-7.40 (m, 10H); CIMS 293 (M
+ 1). Anal. Calcd for C20H24N2: C, 82.15; H, 8.27; N, 9.58.
Found: C, 82.28; H, 8.15; N, 9.47.
D
D
+45.5° (c ) 1.0, CHCl3); mp 118-119 °C; IR 2980, 2930, 1770,
1
1720 cm-1; H NMR (360 MHz) δ 1.5 (s, 9H), 1.79 (dddd, J )
15.8, 11.1, 10.7, 4.8, 1H), 2.05-2.14 (m, 1H), 2.63 (dd, J ) 16.4,
9.8, 1H), 2.70 (ddd, J ) 16.4, 6.3, 1.3, 1H), 3.09-3.19 (m, 1H),
3.35 (ddd, J ) 13.0, 10.7, 4.3, 1H), 3.60 (d, J ) 13.8, 2H), 3.65
(d, J ) 13.8, 2H), 3.85 (ddd, J ) 13.0, 4.8, 4.3, 1H), 7.20-7.42
(m, 10H); CIMS 395 (M + 1). Anal. Calcd for C24H30N2O3: C,
73.07; H, 7.66; N, 7.10. Found: C, 73.03; H, 7.73; N, 6.99.
(4S)-1-Ben zyl-4-(N,N-d ib en zyla m in o)p ip er id in -2-on e
(4c). To a solution of 4a (0.66 g, 2.24 mmol) in THF (20 mL)
was added NaH (0.18 g, 4.48 mmol, 60% suspension in
paraffin). The mixture was stirred for 30 min at 0 °C and for
an additional 30 min at room temperature. After addition of
benzyl bromide (665 µL, 5.6 mmol), the mixture was stirred
for 15 h at room temperature. Then saturated aqueous
NaHCO3 and Et2O were added. The organic layer was dried
(MgSO4) and evaporated, and the residue was purified by
MPLC (petroleum ether-EtOAc, 6:4) to give pure 4c (0.61 g,
71%) as colorless crystals. ent-4c was prepared under the same
reaction conditions, starting from ent-4a . 4c: TLC Rf 0.33
(S)-3-(N,N-Diben zyla m in o)n on a n en itr ile (3c). CuI (1.40
g, 7.38 mmol) and n-BuLi (8.4 mL, 1.6 M in hexane) in Et2O
(40 mL) as well as 2 (0.25 g, 0.67 mmol) in Et2O (10 mL) were
reacted and worked up as described above for 3b to give 3c
(0.11 g, 48%) as a colorless oil: TLC Rf 0.21 (petroleum ether-
EtOAc, 95:5); [R]23 -12.0° (c ) 0.9, CHCl3); IR 3030, 2920,
D
2240, 1600, 1450 cm-1; 1H NMR (400 MHz) δ 0.86 (t, J ) 7.1,
3H), 1.20-1.29 (m, 7H), 1.35-1.46 (m, 2H), 1.70-1.81 (m, 1H),
2.38 (dd, J ) 16.8, 6.2, 1H), 2.51 (dd, J ) 16.8, 6.9, 1H),
2.96-3.03 (m, 1H), 3.53 (d, J ) 13.8, 2H), 3.70 (d, J ) 13.8,
2H), 7.21-7.39 (m, 10H); EIMS 334 (M+). Anal. Calcd for
C
23H30N2: C, 82.59; H, 9.04; N, 8.37. Found: C, 82.18; H, 8.99;
N, 8.35.
(S)-3-(N,N-Diben zyla m in o)h exa n oic Acid (3d ). A solu-
tion of 3b (81 mg, 0.28 mmol) in concentrated aqueous HCl (3
mL) was stirred at 80 °C for 2 h. Then the mixture was
concentrated, basified with 2 N aqueous NaOH, adjusted to
pH 6 by addition of 10% aqueous citric acid, and then extracted
with CH2Cl2. The organic layer was dried (MgSO4) and
evaporated. The residue was purified by flash chromatography
(CH2Cl2-MeOH, 9:1) to give 3d (68.6 mg, 79%) as a colorless
(petroleum ether-EtOAc, 6:4); [R]20 -56.5° (c ) 1.1, CHCl3).
D
ent-4c: [R]20 +56.6° (c ) 1.0, CHCl3); mp 129-130 °C; IR
D
3060, 2930, 1640, 1450 cm-1; 1H NMR (360 MHz) δ 1.74 (dddd,
J ) 12.3, 12.3, 12.1, 5.6, 1H), 2.0-2.1 (m, 1H), 2.57 (dd, J )
17.1, 11.3, 1H), 2.73 (ddd, J ) 17.14, 5.5, 2.1, 1H), 3.00-3.10
(m, 1H), 3.05, (ddd, J ) 12.1, 12.1, 4.6, 1H), 3.21 (ddd, J )
12.1, 5.6, 2.5, 1H), 3.61 (d, J ) 14.1, 2H), 3.67 (d, J ) 14.1,
2H), 4.28 (d, J ) 14.6, 1H), 4.78 (d, J ) 14.6, 1H), 7.17-7.37
(m, 15H); EIMS 384 (M+). Anal. Calcd for C26H28N2O (+0.5
H2O): C, 79.97; H, 7.40; N, 7.17. Found: C, 79.68; H, 7.25; N,
7.04.
solid: TLC Rf 0.50 (CH2Cl2-MeOH, 9:1); [R]23 +54.3° (c )
D
1
1.4, CHCl3); IR 3030, 2960, 1720, 1600, 1460 cm-1; H NMR
(400 MHz) δ 0.97 (t, J ) 7.3, 3H), 1.14-1.38 (m, 2H), 1.39-
1.46 (m, 1H), 1.80-1.88 (m, 1H), 2.39-2.54 (m, 2H), 3.06-
3.14 (m, 1H), 3.43 (d, J ) 13.2, 2H), 4.00 (d, J ) 12.5, 2H),
7.26-7.38 (m, 10H); CIMS 312 (M + 1). Anal. Calcd for C20H25
-
NO2: C, 77.14; H, 8.09; N, 4.50. Found: C, 76.59; H, 8.30; N,
4.84.
(3R,4S)-4-(N,N-Diben zyla m in o)-3-m eth yl-2-oxop ip er i-
d in e-1-ca r boxylic Acid ter t-Bu tyl Ester (5a ). To a solution

7412 J . Org. Chem., Vol. 65, No. 22, 2000
Weber et al.
of 4b (108 mg, 0.27 mmol) in THF (20 mL) was added LDA
(3.1 mL, 0.175 M in THF) at -78 °C. After 1 h, methyl iodide
(42 µL, 0.68 mmol) was added and stirring was continued for
another 1 h at -78 °C. Then the mixture was allowed to warm
up to room temperature. After 12 h, saturated aqueous
NaHCO3 and Et2O were added. The organic layer was dried
(MgSO4) and evaporated, and the residue was purified by
MPLC (petroleum ether-EtOAc, 8:2) to give pure 5a (83 mg,
75%) as slightly yellowish crystals. ent-5a was prepared under
the same reaction conditions, starting from ent-4b. 4b: TLC
Rf 0.34 (petroleum ether-EtOAc, 8:2); [R]20 +35.6° (c ) 1.0,
D
CHCl3); IR 3060, 3030, 2930, 1630, 1450 cm-1; H NMR (360
1
MHz) δ 1.59 (dddd, J ) 12.1, 12.1, 12.1, 4.2, 1H), 2.00-2.05
(m, 1H), 2.56 (ddd, J ) 12.1, 12.0, 3.2, 1H), 2.90-3.01 (m, 4H),
3.32 (dd, J ) 12.7, 4.3, 1H), 3.39 (d, J ) 13.5, 2H), 3.84 (d, J
) 13.5, 2H), 4.37 (d, J ) 14.7, 1H), 4.56 (d, J ) 14.7, 1H),
6.57-6.62 (m, 2H), 6.93-7.00 (m, 2H), 7.18-7.38 (m, 10H);
EIMS 474 (M+). Anal. Calcd for C33H34N2O: C, 83.51; H, 7.22;
N, 5.90. Found: C, 83.49; H, 7.13; N, 5.92.
(3R,4S)-1-Ben zyl-4-(N,N-d ib en zyla m in o)-3-flu or op ip -
er id in -2-on e (5f). A solution of 4c (47 mg, 0.12 mmol) in THF
(10 mL), LDA (1 mL, 0.175 M in THF), and NFSI (94.6 mg,
0.30 mmol) in THF (5 mL) were reacted and worked up as
described for 5a to give pure 5f (47 mg, 38%) as a colorless
Rf 0.27 (petroleum ether-EtOAc, 8:2); [R]20 +37.1° (c ) 5.5,
D
CHCl3). ent-5a : [R]20 -36.9° (c ) 1.0, CHCl3); mp 111 °C; IR
D
2980, 2930, 1770, 1710 cm-1; 1H NMR (360 MHz) δ 1.31 (d, J
) 6.5, 3H), 1.50 (s, 9H), 1.82 (dddd, J ) 14.3, 9.6, 9.5, 4.8,
1H), 2.08 (m, 1H), 2.59 (m, 1H), 2.65 (m, 1H), 3.38 (d, J )
13.8, 2H), 3.53 (ddd, J ) 13.0, 9.6, 4.7, 1H), 3.72 (ddd, J )
13.0, 5.3, 4.8), 3.83 (d, J ) 13.8, 2H), 7.24-7.38 (m, 10H); CIMS
409 (M + 1). Anal. Calcd for C25H32N2O3: C, 73.50; H, 7.90;
N, 6.86. Found: C, 73.66; H, 7.99; N, 6.80.
oil: TLC Rf 0.19 (petroleum ether-EtOAc, 8:2); [R]20 -6.4°
D
(c ) 1.0, CHCl3); IR 3030, 2930, 1660, 1450 cm-1
;
1H NMR
(360 MHz) δ 1.81 (dddd, J ) 12.8, 12.1, 12.1, 5.8, 1H), 1.95-
2.04 (m, 1H), 3.05 (ddd, J ) 12.1, 12.0, 4.5, 1H), 3.12 (ddd, J
) 12.00, 5.8, 3.0, 1H), 3.25 (dddd, J ) 12.1, 12.1, 10.3, 3.9,
1H), 3.73 (d, J ) 13.8, 2H), 3.83 (d, J ) 13.8, 2H), 4.34 (d, J )
14.5, 1H), 4.68 (d, J ) 14.5, 1H), 5.09 (dd, J ) 48.6, 10.3, 1H),
(3R,4S)-3-Ben zyl-4-(N,N-d iben zyla m in o)-2-oxop ip er i-
d in e-1-ca r boxylic Acid ter t-Bu tyl Ester (5b). A solution
of 4b (100 mg, 0.25 mmol) in THF (20 mL), LDA (2.85 mL,
0.175 M in THF), and benzyl bromide (75 µL, 0.63 mmol) were
reacted and worked up as described for 5a to give pure 5b
(103 mg, 85%) as slightly yellowish crystals. ent-5b was
prepared under the same reaction conditions, starting from
7.15-7.45 (m, 15H); EIMS 384 (M+). HRMS calcd for C26H27
FN2O: 402.2108. Found: 402.2122.
-
(3S)-Meth an esu lfon ic Acid 4-P h th alim ido-3-(N,N-diben -
zyla m in o)bu tyl Ester (6a ) a n d (2S)-2-(N,N-Diben zyla m i-
n o)-1,4-d ip h th a lim id obu ta n e. To a solution of 1a 14 (11.04
g, 38.7 mmol) and Et3N (11.75 g, 116.1 mmol) was added
methansulfonyl chloride (9.09 g, 79.3 mmol) at -23 °C. After
30 min of stirring at room temperature, the mixture was added
to a precooled solution of phthalimide-K (7.17 g, 154.8 mmol
in 200 mL of THF) at -30 °C. After an additional 90 min at
room temperature, saturated aqueous NaHCO3 and Et2O were
added. The organic layer was dried (MgSO4) and evaporated.
The residue was purified by flash chromatography (petroleum
ether-EtOAc, 1:1) to give 6a (11.7 g, 61%) as a colorless solid
besides 6b (3.4 g, 16%). ent-6a was prepared under the same
reaction conditions, starting from ent-1a . 6a : TLC Rf 0.19
ent-4b. 5b: TLC Rf 0.43 (petroleum ether-EtOAc, 8:2); [R]20
D
-41.5° (c ) 1.0, CHCl3). ent-5b: [R]20D +42.0° (c ) 1.0, CHCl3);
mp 46-47 °C; IR 3060, 3030, 2980, 2930, 1770, 1710 cm-1; 1H
NMR (360 MHz, CD3OD) δ 1.46 (s, 9H), 1.63-1.75 (m, 1H),
2.06-2.14 (m, 1H), 2.70 (ddd, J ) 13.1, 10.0, 3.0, 1H), 2.84
(dd, J ) 13.1, 4.5, 1H), 2.88-2.98 (m, 2H), 3.15 (dd, J ) 13.1,
4.5, 1H), 3.42 (d, J ) 13.5, 2H), 3.72-3.79 (m, 1H), 3.80 (d, J
) 13.5, 2H), 6.53-6.58 (m, 2H), 6.98-7.09 (m, 3H), 7.20-7.40
(m, 10H); 13C NMR (61 MHz) δ 21.6, 28.0, 35.6, 42.9, 50.5,
53.9, 55.0, 82.7, 127.2, 127.9, 128.4, 128.9, 129.7, 138.6, 139,
151.8, 173.3; CIMS 485 (M + 1). HRMS calcd for C31H36N2O3
(M+): 484.2726. Found: 484.2725.
(petroleum ether-EtOAc, 7:3); [R]25 -12.7° (c ) 1.0, CHCl3).
D
(3R,4S)-4-(N,N-Dib en zyla m in o)-3-flu or o-2-oxop ip er i-
d in e-1-ca r boxylic Acid ter t-Bu tyl Ester (5c). A solution
of 4b (50 mg, 0.13 mmol) in THF (20 mL), LDA (1.48 mL, 0.175
M in THF), and NFSI (104 mg, 0.63 mmol) in THF (5 mL)
were reacted and worked up as described for 5a to give pure
5c (42 mg, 78%) as colorless crystals: TLC Rf 0.19 (petroleum
ent-6a : [R]20 +12.4° (c ) 1.0, CHCl3); mp 114 °C; IR 3200,
D
3060, 3030, 1770, 1750, 1710 cm-1; 1H NMR (360 MHz) δ 1.76
(dddd, J ) 14.4, 6.5, 6.3, 6.3, 1H), 2.17 (dddd, J ) 14.4, 6.8,
6.6, 6.5, 1H), 2.78 (s, 3H), 3.13 (dddd, J ) 6.8, 6.8, 6.7, 6.5,
1H), 3.55 (dd, J ) 13.6, 6.8, 1H), 3.61 (d, J ) 13.4, 2H), 3.75
(d, J ) 13.4, 2H), 4.09 (dd, J ) 13.6, 6.7, 1H), 4.21 (ddd, J )
9.8, 6.6, 6.3, 1H), 4.31 (ddd, J ) 9.8, 6.5, 6.3, 1H), 7.31-7.13
(m, 10H), 7.73-7.81 (m, 2H), 7.78-7.90 (m, 2H); EIMS 423
(M+). 6b: 1H NMR (360 MHz) δ 1.61-1.72 (m, 1H), 2.17 (dddd,
J ) 14.0, 9.5, 9.5, 5.0, 1H), 3.04 (m, 1H), 3.43 (ddd, J ) 13.8,
11.4, 4.7, 1H), 3.64 (dd, J ) 14.0, 7.0, 1H), 3.70 (s, 4H), 4.02
(ddd, J ) 13.8, 10.7, 5.0), 4.08 (dd, J ) 14.0, 6.4, 1H), 7.12-
7.30 (m, 10H), 7.70-7.75 (m, 4H), 7.80-7.85 (m, 4H); EIMS
543 (M+).
ether-EtOAc, 8:2); [R]20 +4.0° (c ) 1.0, CHCl3); mp 145 °C;
D
IR 3030, 2980, 2930, 1780, 1730 cm-1; H NMR (360 MHz) δ
1
1.49 (s, 9H), 1.89 (dddd, J ) 14.5, 9.9, 9.5, 5.1, 1H), 2.04-2.16
(m, 1H), 3.3 (dddd, J ) 11.9, 10.2, 9.9, 6.0, 1H), 3.52 (ddd, J )
13.3, 9.5, 4.3, 1H), 3.61 (ddd, J ) 13.3, 5.3, 5.1, 1H), 3.76 (d,
J ) 13.7, 2H), 3.82 (d, J ) 13.7, 2H), 5.11 (dd, J ) 48.7, 10.2,
1H), 7.19-7.40 (m, 10H); CIMS 413 (M + 1). Anal. Calcd for
C
24H29FN2O3: C, 69.88; H, 7.09; N, 6.79. Found: C, 69.88; H,
7.20; N, 6.53.
(4S)-4-(N,N-Diben zyla m in o)-5-p h th a lim id op en ta n en i-
tr ile (6c). To a solution of LiCN (46.2 mL, 0.5 M in DMF)
was added 6a (3.8 g, 7.7 mmol). After 3 days of stirring at
room temperature, saturated aqueous NaHCO3 and Et2O were
added. The organic layer was washed with saturated aqueous
NaHCO3, dried (MgSO4), and evaporated. The residue was
purified by MPLC (petroleum ether-EtOAc, 7:3) to give 6c
(2.68 g, 82%) as colorless crystals. ent-6c was prepared under
the same reaction conditions, starting from ent-6a . 6c: TLC
(3R,4S)-1-Ben zyl-4-(N,N-d iben zyla m in o)-3-m eth ylp ip -
er id in -2-on e (5d ). A solution of 4c (1.35 g, 3.52 mmol) in THF
(50 mL), LDA (20.1 mL, 0.175 M in THF), and methyl iodide
(546 µL, 8.8 mmol) were reacted and worked up as described
for 5a to give pure 5d (738 mg, 53%) as colorless crystals. ent-
5d was prepared under the same reaction conditions, starting
from ent-4c. 5d : TLC Rf 0.16 (petroleum ether-EtOAc, 8:2);
[R]25 +30.0° (c ) 1.0, CHCl3). ent-5d : [R]25 -30.5° (c ) 1.0,
D
D
CHCl3); mp 107-108 °C; IR 3030, 2930, 16408, 1450 cm-1; 1H
NMR (360 MHz) δ 1.36 (d, J ) 6.5, 3H), 1.64 (dddd, J ) 12.3,
12.1, 11.6, 5.2, 1H, 5Hax), 2.06-2.15 (m, 1H), 2.54-2.63 (m,
1H), 2.65 (ddd, J ) 11.6, 11.1, 3.0, 1H), 3.02 (ddd, J ) 12.1,
12.1, 4.1, 1H), 3.24 (ddd, J ) 12.1, 5.2, 2.7, 1H), 3.36 (d, J )
13.5, 2H), 3.85 (d, J ) 13.5, 2H), 4.25 (d, J ) 14.6, 1H), 4.78
(d, J ) 14.6, 1H), 7.16-7.40 (m, 15H); EIMS 398 (M+). Anal.
Calcd for C27H30N2O: C, 81.37; H, 7.59; N, 7.30. Found: C,
81.40; H, 7.66; N, 7.04.
Rf 0.28 (petroleum ether-EtOAc, 7:3); [R]23 -35.4° (c ) 1.0,
D
CHCl3). ent-6c: [R]20 +36.6° (c ) 1.0, CHCl3); mp 126-128
D
°C; IR 3200, 3060, 2940, 1770, 1750, 1710 cm-1; 1H NMR (360
MHz) δ 1.69 (dddd, J ) 14.0, 9.1, 6.2, 4.8, 1H), 1.98 (dddd, J
) 14.0, 9.4, 9.4, 4.8, 1H), 2.08 (ddd, J ) 16.5, 9.4, 6.2, 1H),
2.52 (ddd, J ) 16.5, 9.1, 4.8, 1H), 2.94 (dddd, J ) 9.4, 8.2, 4.9,
4.8, 1H), 3.61 (dd, J ) 13.5, 8.2, 1H), 3.68 (d, J ) 13.3, 2H),
3.78 (d, J ) 13.3, 2H), 4.08 (dd, J ) 13.5, 4.9, 1H), 7.18-7.53
(m, 10H), 7.71-7.78 (m, 2H), 7.82-7.89 (m, 2H); EIMS 423
(M+). Anal. Calcd for C27H25N3O2: C, 76.57; H, 5.95; N, 9.92.
Found: C, 76.22; H, 5.71; N, 9.53.
(3R,4S)-1,3-Diben zyl-4-(N,N-d iben zyla m in o)p ip er id in -
2-on e (5e). A solution of 4c (51 mg, 0.13 mmol) in THF (10
mL), LDA (1.14 mL, 0.175 M in THF), and benzyl bromide
(39 µL, 0.33 mmol) were reacted and worked up as described
for 5a to give pure 5e (44.5 mg, 72%) as a colorless oil: TLC
(4S)-5-Am in o-4-(N,N-diben zylam in o)pen tan en itr ile (7).
To a solution of 6c (3.49 g, 8.24 mmol) in MeOH (100 mL) was
added hydrazinehydrate (5.2 g, 80 proz., 82.4 mmol). The

Synthesis of 4- and 5-Aminopiperidin-2-ones
J . Org. Chem., Vol. 65, No. 22, 2000 7413
solution was refluxed for 14 h. After evaporation, saturated
aqueous NaHCO3 and Et2O were added to the residue. The
organic layer was dried and evaporated to leave crude 7. For
analytical data, purification was performed by flash chroma-
tography (petroleum ether-acetone, 1:4). ent-7 was prepared
under the same reaction conditions, starting from ent-6c. 7:
CHCl3); IR 3030, 2980, 2930, 1770, 1720, 1450 cm-1; 1H NMR
(360 MHz) δ 1.16 (d, J ) 6.9, 3H), 1.49 (s, 9H), 1.66 (ddd, J )
14.0, 10.3, 8.7, 1H), 2.09 (ddd, J ) 14.0, 6.9, 6.8, 1H), 2.64
(dqd, J ) 10.3, 6.9, 6.9, 1H), 3.16 (dddd, J ) 11.1, 8.7, 6.8, 5.0,
1H), 3.42 (dd, J ) 12.9, 11.1, 1H), 3.66 (d, J ) 13.9, 2H), 3.70
(d, J ) 13.9, 2H), 4.23 (dd, J ) 12.9, 5.0, 1H), 7.21-7.39 (m,
10H); EIMS 408 (M+). Anal. Calcd for C25H32N2O3: C, 73.50;
H, 7.90; N, 6.86. Found: C, 73.48; H, 7.88; N, 6.77. 10a : TLC
TLC Rf 0.27 (petroleum ether-acetone, 2:8); [R]20 +7.5° (c )
D
1.0, MeOH). ent-7: [R]20D -7.7° (c ) 1.0, CHCl3); IR 3370, 3030,
2930, 2250, 1600, 1450 cm-1; 1H NMR (360 MHz) δ 1.74 (dddd,
J ) 14.1, 8.5, 6.5, 6.3, 1H), 1.84-1.96 (m, 1H), 2.24 (ddd, J )
16.9, 8.5, 6.5, 1H), 2.44 (ddd, J ) 16.9, 8.6, 6.3, 1H), 2.52-
2.64 (m, 2H), 2.91-3.08 (m, 1H), 3.62 (d, J ) 13.5, 2H), 3.65
(d, J ) 13.5, 1H), 7.22-7.35 (m, 10H); EIMS 293 (M+).
(5S)-5-(N,N-Diben zyla m in o)p ip er id in -2-on e (8a ). Crude
7, which was prepared as described above, was dissolved in
MeOH-H2O (200 mL, 99:1). After saturation of the solution
with HCl gas, the mixture was refluxed for 12 h. Then pH 8
was adjusted by addition of aqueous 2 N NaOH and NaHCO3.
After an additional 2 h of stirring, Et2O was added. The organic
layer was dried (MgSO4) and evaporated, and the residue was
purified by MPLC (petroleum ether-acetone, 2:8) to give pure
8a (2.01 g, 83%) as colorless crystals. ent-8a was prepared
under the same reaction conditions, starting from ent-7. 8a :
Rf 0.29 (petroleum ether-EtOAc, 8:2); [R]20 -41.2° (c ) 0.5,
D
CHCl3); IR 3030, 2980, 2930, 1770, 1710, 1450 cm-1; 1H NMR
(360 MHz) δ 1.20 (d, J ) 6.6, 3H), 1.52 (s, 9H), 1.62 (ddd, J )
13.0, 12.6, 10.3, 1H), 2.12 (ddd, J ) 13.0, 6.4, 6.2, 1H), 2.31
(dqd, J ) 12.6, 6.6, 6.4, 1H), 3.23 (dddd, J ) 10.3, 6.2, 6.1, 5.8,
1H), 3.50 (dd, J ) 13.7, 6.1, 1H), 3.56 (d, J ) 13.9, 2H), 3.70
(d, J ) 13.9, 2H), 4.10 (dd, J ) 13.7, 5.8, 1H), 7.22-7.35 (m,
10H); EIMS 408 (M+). Anal. Calcd for C25H32N2O3: C, 73.50;
H, 7.90; N, 6.86. Found: C, 73.54; H, 7.89; N, 6.84.
(3S,5S)-3-Ben zyl-5-(N,N-d ib en zyla m in o)-2-oxop ip er i-
d in e-1-ca r boxylic Acid ter t-Bu tyl Ester (9b) a n d (3R,5S)-
3-Ben zyl-5-(N,N-d iben zyla m in o)-2-oxop ip er id in e-1-ca r -
boxylic ter t-Bu tyl Ester (10b). A solution of 8b (106 mg,
0.27 mmol) in THF (15 mL), HMPA (189 µL, 1.08 mmol), LDA
(3.1 mL, 0.175 M in THF), and benzyl bromide (81 µL, 0.68
mmol) were reacted and worked up as described for 5a to give
9b (5.3 mg, 4%) and 10b (46 mg, 35%) as colorless oils. 9b:
TLC Rf 0.33 (petroleum ether-acetone, 2:8); [R]20 -8.3° (c )
D
1.0, CHCl3). ent-8a : [R]25 +8.7° (c ) 1.0, CHCl3); mp 60 °C;
D
IR 3210, 3030, 2940, 1670, 1450 cm-1; H NMR (360 MHz) δ
TLC Rf 0.28 (petroleum ether-EtOAc, 8:2); [R]20 +56.8° (c )
1
D
1
1.83 (dddd, J ) 12.2, 12.2, 12.1, 5.3, 1H), 2.00-2.10 (m, 1H),
2.25 (ddd, J ) 17.7, 12.1, 6.0, 1H), 2.49 (ddd, J ) 17.7, 5.3,
2.5, 1H), 3.00-3.10 (m, 1H), 3.26-3.76 (m, 2H), 3.62 (d, J )
14.0, 2H), 3.72 (d, J ) 14.0, 2H), 6.17 (s, 1H), 7.19-7.39 (m,
10H); EIMS 294 (M+). Anal. Calcd for C19H22N2O: C, 77.52;
H, 7.53; N, 9.52. Found: C, 77.05; H, 7.64; N, 9.59.
0.4, CHCl3); IR 3060, 3030, 2850, 1770, 1720, 1450 cm-1; H
NMR (360 MHz) δ 1.52 (s, 9H), 1.62 (ddd, J ) 14.6, 9.1, 6.7,
1H), 1.92 (ddd, J ) 14.6, 8.4, 7.2, 1H), 2.49 (dd, J ) 14.0, 9.9,
1H), 2.80 (dddd, J ) 9.9, 8.4, 6.7, 4.3, 1H), 3.18 (dddd, J )
9.1, 9.0, 7.2, 5.3, 1H), 3.29 (dd, J ) 14.0, 4.3, 1H), 3.43 (dd, J
) 12.9, 9.0, 1H), 3.49 (d, J ) 14.1, 2H), 3.61 (d, J ) 14.1, 2H),
4.12 (dd, J ) 12.9, 5.3, 1H), 7.08-7.37 (m, 15H); EIMS 484
(M+). HRMS calcd for C31H36N2O3: 484.2726. Found: 484.2725.
10b: TLC Rf 0.31 (petroleum ether-EtOAc, 8:2); [R]20D -67.1°
(5S)-5-(N,N-Diben zyla m in o)-2-oxop ip er id in e-1-ca r box-
ylic Acid ter t-Bu tyl Ester (8b). To a solution of 8a (3.18 g,
10.8 mmol) in CH2Cl2 (100 mL) were added 4-dimethylami-
nopyridine (2.64 g, 21.6 mmol), NEt3 (2.3 mL, 16.2 mmol), and
di-tert-butyl dicarbonate (7.07 g, 32.4 mmol). After 4 h of
refluxing, the mixture was concentrated, and the residue was
purified by MPLC (petroleum ether-EtOAc, 6:4) to give pure
8b (2.83 g, 66%) as slightly yellowish crystals: TLC Rf 0.26
(c ) 1.0, CHCl3); IR 3060, 3030, 1770, 1710, 1450 cm-1 1H
;
NMR (360 MHz) δ 1.49 (ddd, J ) 13.7, 12.0, 9.4, 1H), 1.54 (s,
9H), 2.02 (ddd, J ) 13.7, 6.2, 5.5, 1H), 2.45 (dddd, J ) 12.0,
8.9, 5.5, 4.3, 1H), 2.59 (dd, J ) 13.9, 8.9, 1H), 3.10 (dddd, J )
10.5, 6.2, 5.9, 5.9, 1H), 3.40 (dd, J ) 13.9, 4.3, 1H), 3.47 (dd,
J ) 13.7, 5.9, 1H), 3.52 (d, J ) 14.1, 2H), 3.66 (d, J ) 14.1,
2H), 4.04 (dd, J ) 13.7, 5.9, 1H), 7.14-7.32 (m, 15H); EIMS
484 (M+). HRMS calcd for C31H36N2O3: 484.2726. Found:
484.2729.
(petroleum ether-EtOAc, 7:3); [R]20 -47.0° (c ) 1.0, CHCl3);
D
mp 71-73 °C; IR 3030, 2980, 2930, 1770, 1720 cm-1; 1H NMR
(360 MHz) δ.51 (s, 9H), 1.85 (dddd, J ) 12.8, 11.0, 9.9, 5.5,
1H), 2.05 (dddd, J ) 12.8, 6.8, 6.2, 4.7, 1H), 2.33 (ddd, J )
16.8, 11.0, 6.2, 1H), 2.58 (ddd, J ) 16.8, 5.5, 4.7, 1H), 3.12
(dddd, J ) 9.9, 6.8, 6.6, 6.6, 1H), 3.64 (d, J ) 14.0, 2H), 3.69
(d, J ) 14.0, 2H), 3.74 (d, J ) 6.6, 2H), 7.20-7.37 (m, 10H);
CIMS 395 (M + 1). Anal. Calcd for C24H30N2O3: C, 73.07; H,
7.66; N, 7.10. Found: C, 72.50; H, 7.80; N, 6.81.
(3R,5S)-5-(N,N-Dib en zyla m in o)-3-flu or o-2-oxop ip er i-
d in e-1-ca r boxylic Acid ter t-Bu tyl Ester (10c). A solution
of 8b (75 mg, 0.13 mmol) in THF (20 mL), LDA (2.2 mL, 0.175
M in THF), and NFSI (150 mg, 0.48 mmol) were reacted and
worked up as described for 5a to give pure 10c (20 mg, 26%)
as a colorless oil. In the presence of HMPA (4 equiv), a 96:4
diastereomeric mixture of 10c and 9c was obtained in 22%
(5S)-1-Ben zyl-5-(N,N-d ib en zyla m in o)p ip er id in -2-on e
(8c). A solution of 8a (0.27 g, 0.92 mmol) in THF (20 mL) was
reacted with NaH (73.6 mg, 1.84 mmol, 60 proz. suspension
in paraffin) and benzyl bromide (393 µL, 2.3 mmol) and worked
up as described for 4c to give 8c (0.34 g, 97%) as a colorless
oil. ent-8c was prepared under the same reaction conditions,
starting from ent-8a . 8c: TLC Rf 0.16 (petroleum ether-
EtOAc, 6:4); [R]20 -43.0° (c ) 1.0, CHCl3). ent-8c: [R]20
yield. 10c: TLC Rf 0.26 (petroleum ether-EtOAc, 8:2); [R]20
D
-6.4° (c ) 0.5, CHCl3); IR 3030, 2980, 2930, 1780, 1730 cm-1
;
1H NMR (360 MHz) δ 1.52 (s, 9H), 2.13 (dddd, J ) 12.8, 12.6,
10.9, 10.7, 1H), 2.55 (dddd, J ) 12.6, 10.4, 6.0, 5.8, 1H), 3.2
(dddd, J ) 10.7, 8.0, 5.8, 5.5, 1H), 3.64 (d, J ) 14.1, 2H), 3.67
(dd, J ) 13.5, 5.5, 1H), 3.68 (d, J ) 14.1, 2H), 3.88 (dd, J )
13.5, 8.0, 1H), 4.79 (ddd, J ) 47.7, 10.9, 6.0, 1H), 7.19-7.40
(m, 10H); CIMS 413 (M + 1). Anal. Calcd for C24H29FN2O3:
C, 69.88; H, 7.09; N, 6.79. Found: C, 69.97; H, 7.03; N, 6.51.
(3S,5S)-1-Ben zyl-5-(N,N-d iben zyla m in o)-3-m eth ylp ip -
er id in -2-on e (9d ) a n d (3R,5S)-1-Ben zyl-5-(N,N-d iben zyl-
a m in o)-3-m eth ylp ip er id in -2-on e (10d ). A solution of 8c
(173 mg, 0.45 mmol) in THF (20 mL), HMPA (314 µL, 1.8
mmol), LDA (3 mL, 0.3 M in THF), and methyl iodide (70 µL,
1.13 mmol) were reacted and worked up as described for 5a
to give pure 9d (34 mg, 19%) and 10d (88 mg, 49%) as colorless
oils. ent-9d and ent-10d were prepared under the same
reaction conditions, starting from ent-8c. 9d : TLC Rf 0.20
D
D
1
+42.5° (c ) 1.0, CHCl3); IR 3030, 2930, 1640, 1450 cm-1; H
NMR (360 MHz) δ 1.84 (dddd, J ) 12.2, 11.9, 11.8, 5.5, 1H),
1.99-2.07 (m, 1H), 2.34 (ddd, J ) 17.6, 11.9, 6.2, 1H), 2.62
(ddd, J ) 17.6, 5.5, 3.0, 1H), 3.03 (dddd, J ) 11.8, 8.2, 7.2,
4.0, 1H), 3.21 (dd, J ) 12.0, 8.2, 1H), 3.24 (dd, J ) 12.0, 7.2,
1H), 3.58 (d, J ) 13.8, 2H), 3.64 (d, J ) 13.8, 2H), 4.40 (d, J )
14.7, 1H), 4.59 (d, J ) 14.7, 1H), 7.15-7.40 (m, 15H); EIMS
384 (M+). Anal. Calcd for C26H28N2O: C, 77.58; H, 7.51; N,
6.91. Found: C, 77.84; H, 7.12; N, 6.91.
(3S,5S)-5-(N,N-Diben zyla m in o)-3-m eth yl-2-oxop ip er i-
d in e-1-ca r boxylic Acid ter t-Bu tyl Ester (9a ) a n d (3R,5S)-
5-(N,N-Diben zyla m in o)-3-m eth yl-2-oxop ip er id in e-1-ca r -
boxylic ter t-Bu tyl Ester (10a ). A solution of 8b (57 mg, 0.14
mmol) in THF (15 mL), HMPA (98 µL, 0.56 mmol), LDA (1.6
mL, 0.175 M in THF), and methyl iodide (22 µL, 0.35 mmol)
were reacted and worked up as described for 5a to give 9a (16
mg, 28%) and 10a (22 mg, 38%) as colorless oils. 9a : TLC Rf
(petroleum ether-EtOAc, 6:4); [R]20 -10.2° (c ) 0.9, CHCl3).
D
ent-9d : [R]25D +9.7° (c ) 1.0, CHCl3); IR 3060, 2930, 1640, 1450
1
cm-1; H NMR (360 MHz) δ 1.20 (d, J ) 6.9, 3H), 1.70-1.79
(m, 1H), 2.05 (ddd, J ) 13.4, 9.6, 6.6, 1H), 2.72 (qdd, J ) 6.9,
6.6, 6.4, 1H), 3.12 (dddd, J ) 9.9, 9.6, 5.3, 4.8, 1H), 3.17 (dd,
J ) 12.0, 5.3, 1H), 3.25 (dd, J ) 12.0, 9.9, 1H), 3.55 (d, J )
0.24 (petroleum ether-EtOAc, 8:2); [R]20 +26.4° (c ) 0.5,
D

7414 J . Org. Chem., Vol. 65, No. 22, 2000
Weber et al.
14.1, 2H), 3.64 (d, J ) 14.1, 2H), 4.31 (d, J ) 14.7, 1H), 4.56
(d, J ) 14.7, 1H), 7.11-7.37 (m, 15H); EIMS 398 (M+). Anal.
Calcd for C27H30N2O: C, 81.37; H, 7.59; N, 7.03. Found: C,
81.34; H, 7.56; N, 7.04. 10d : TLC Rf 0.33 (petroleum ether-
EtOAc, 6:4); [R]20 -25.4° (c ) 1.0, CHCl3). ent-10d : [R]25
left as a colorless oil. B: To a solution of 11a (125 mg, 0.33
mmol) in acetonitrile (4 mL) was added CAN (383.8 mg, 0.7
mmol) in H2O (1 mL) at 0 °C. After 30 min of stirring at 0 °C,
saturated aqueous NaSO3 and Et2O were added. The organic
layer was washed with saturated aqueous NaCl, dried (Mg-
SO4), and evaporated. The residue was purified by flash
chromatography (MeOH-CH2Cl2, 5:95) to give pure 11b (57
mg, 60%) as a colorless oil: TLC Rf 0.43 (CH2Cl2-MeOH, 95:
D
D
+25.5° (c ) 1.0, CHCl3); IR 3060, 2930, 1640, 1450 cm-1; H
NMR (360 MHz) δ 1.28 (d, J ) 6.7, 3H), 1.60 (ddd, J ) 12.4,
12.3, 12.0, 1H), 2.15-2.30 (m, 1H), 2.31 (dqd, J ) 12.4, 6.7,
6.2, 1H), 3.08 (dddd, J ) 12.0, 8.7, 7.0, 3.5, 1H), 3.22 (dd, J )
12, 8.7, 1H), 3.27 (ddd, J ) 12.0, 7.0, 1.1, 1H), 3.56 (d, J )
13.8, 2H), 3.60 (d, J ) 13.8, 2H), 4.44 (d, J ) 14.6, 1H), 4.62
(d, J ) 14.6, 1H), 7.16-7.40 (m, 15H); EIMS 398 (M+). Anal.
Calcd for C27H30N2O: C, 81.37; H, 7.59; N, 7.03. Found: C,
81.39; H, 7.52; N, 7.10.
1
5); [R]20 -25.1° (c ) 1.0, CHCl3); IR 3300, 2930, 2870, 1750,
D
1640, 1450 cm-1; H NMR (360 MHz) δ 1.26 (t, J ) 7.1, 3H),
1
1.79 (dddd, J ) 13.5, 8.8, 8.8, 5.4, 1H), 2.02-2.12 (m, 1H), 2.32
(dd, J ) 17.1, 8.4, 1H), 2.72 (ddd, J ) 17.1, 5.1, 1.6, 1H), 3.11
(dddd, J ) 8.6, 8.4, 5.1, 3.3, 1H), 3.35 (ddd, J ) 11.6, 8.8, 4.9,
1H), 3.43 (ddd, J ) 11.6, 5.7, 5.4, 1H), 3.81 (d, J ) 13.5, 1H),
3.85 (d, J ) 13.5, 1H), 4.00 (d, J ) 17.4, 1H), 4.18 (q, J ) 7.1,
2H), 4.20 (d, J ) 17.4, 1H), 7.25-7.35 (m, 5H); EIMS 290 (M+).
Anal. Calcd for C16H22N2O3: C, 66.18; H, 7.64; N, 9.65.
Found: C, 66.12; H, 7.57; N, 9.66.
(3R,5S)-1,3-Dib en zyl-5-(N,N-d ib en zyla m in o)-3-m et h -
ylp ip er id in -2-on e (10e). A solution of 8c (51 mg, 0.13 mmol)
in THF (20 mL), HMPA (91 µL, 0.52 mmol), LDA (1.51 mL,
0.175 M in THF), and benzyl bromide (40 µL, 0.33 mmol) were
reacted and worked up as described for 5a to give pure 10e
(4S)-(4-Am in o-2-oxop ip er id in -1-yl)a cetic Acid Eth yl
Ester (11c). A mixture of 11a (218 mg, 1.40 mmol) and Pd-
(OH)2/C (107 mg) in MeOH (10 mL) was stirred under a balloon
of H2 for 15 h at room temperature. The mixture was filtered
through Celite, and the filtrate was evaporated. The residue
was purified by flash chromatography (MeOH-CH2Cl2-N-
ethyldimethylamine, 20:80:1) to give pure 11c (269 mg, 70%)
as a colorless oil. ent-11c was prepared under the same
reaction conditions, starting from ent-11a . 11c: TLC Rf 0.1-
1
(33 mg, 54%) as a colorless solid. H NMR spectroscopy of the
crude product mixture indicated a mixture of the diastere-
omeres 9e and 10e in
a 1:14 ratio. 10e: TLC Rf 0.18
(petroleum ether-EtOAc, 8:2); [R]20 -28.9° (c ) 1.0, CHCl3);
D
IR 3060, 3030, 1640, 1450 cm-1; H NMR (360 MHz) δ 1.52
1
(ddd, J ) 12.3, 12.3, 12.3, 1H), 1.88-1.97 (m, 1H), 2.52 (dddd,
J ) 12.3, 9.1, 5.4, 3.7, 1H), 2.79 (dd, J ) 13.7, 9.1, 1H), 2.99
(dddd, J ) 12.3, 9.6, 6.0, 3.3, 1H), 3.15 (dd, J ) 11.7, 9.6,
1H), 3.22 (ddd, J ) 11.7, 6.0, 1.6, 1H), 3.41 (dd, J ) 13.7, 3.7,
1H), 3.41 (s, 4H), 4.53 (d, J ) 14.9, 1H), 4.58 (d, J ) 14.9,
1H), 7.12-7.38 (m, 20H); EIMS 474 (M+). HRMS calcd for
0.3 (CH2Cl2-MeOH, 9:1); [R]20 -33.3° (c ) 1.0, MeOH). ent-
D
11c: [R]20D +33.1° (c ) 1.0, MeOH); IR 3430, 2980, 1740, 1630
1
cm-1; H NMR (360 MHz) δ 1.08 (t, J ) 7.2, 3H), 2.51 (dddd,
C
33H34N2O: 474.2671. Found: 474.2683.
J ) 13.0, 11.5, 10.7, 5.9, 1H), 2.66-2.73 (m, 1H), 3.26 (dd, J
) 17.0, 11.0, 1H), 3.35 (ddd, J ) 17.0, 5.6, 1.5, 1H), 3.52 (dddd,
J ) 11.5, 11.0, 5.5, 3.8, 1H), 3.55-3.64 (m, 2H), 4.08 (d, J )
17.6, 1H), 4.09 (q, J ) 7.2, 2H), 4.48 (d, J ) 17.6, 1H); EIMS
200 (M+).
(3R,5S)-1-Ben zyl-5-(N,N-d ib en zyla m in o)-3-flu or op ip -
er id in -2-on e (10f). A solution of 8c (74 mg, 0.19 mmol) in
THF (15 mL), HMPA (132 µL, 0.76 mmol), LDA (2.2 mL, 0.175
M in THF), and NFSI (151 mg, 0.48 mmol) in THF (2 mL)
were reacted and worked up as described for 5a to give pure
10f (25 mg, 32%) as a colorless oil. 10f: TLC Rf 0.34 (petroleum
ether-EtOAc, 6:4); [R]20D +9.5° (c ) 1.0, CHCl3); IR 3060, 3030,
2920, 1670, 1450 cm-1; 1H NMR (360 MHz) δ 2.09 (dddd, J )
12.4, 12.2, 12.1, 11.4, 1H), 2.51-2.61 (m, 1H), 3.06-3.17 (m,
1H), 3.20 (ddd, J ) 11.7, 5.5, 1.4, 1H), 3.27 (dd, J ) 11.7, 10.5,
1H), 3.56 (d, J ) 14.0, 2H), 3.62 (d, J ) 14.0, 2H), 4.50 (d, J )
14.6, 1H), 4.57 (d, J ) 14.6, 1H), 4.80 (ddd, J ) 47.5, 11.4,
6.1, 1H), 7.25-7.40 (m, 15H); EIMS 402 (M+). HRMS calcd
for C26H27FN2O: 402.2107. Found: 402.2106.
(4S)-[4-(N,N-Acetylben zyla m in o)-2-oxop ip er id in -1-yl]-
a cetic Acid Eth yl Ester (11d ). To a solution of 11c (57 mg,
0.2 mmol) in pyridine (2 mL) was added acidic anhydride (1
mL). After 15 h of stirring at room temperature, CH2Cl2 and
H2O were added. The organic layer was dried (MgSO4) and
evaporated, and the residue was purified by flash chromatog-
raphy (CH2Cl2-MeOH, 95:5) to give pure 11d (64 mg, 96%)
as a colorless oil: TLC Rf 0.15 (CH2Cl2-MeOH, 95:5); [R]20
D
-15.3° (c ) 1.0, CHCl3); IR 2980, 2940, 1750, 1640 cm-1; H
1
NMR (360 MHz) δ 1.26 (t, J ) 7.2, 3H), 1.88-1.97 (m,
1H), 2.06 (dddd, J ) 11.9, 11.7, 11.4, 5.3, 1H), 2.11 (s, 3H),
2.55 (dd, J ) 17.2, 10.9, 1H), 2.63 (ddd, J ) 17.2, 6.3, 1.5, 1H),
3.27 (ddd, J ) 11.7, 5.3, 2.8, 1H), 3.43 (ddd, J ) 11.7, 11.7,
4.3, 1H), 4.02 (d, J ) 17.0, 1H), 4.12 (d, J ) 17.0, 1H), 4.18 (q,
J ) 7.2, 2H), 4.55 (s, 2H), 4.81 (dddd, J ) 11.4, 10.9, 6.3, 3.7,
1H), 7.13-7.40 (m, 5H); EIMS 332 (M+). Anal. Calcd for
(4S)-4-(N,N-Dib en zyla m in o-2-oxop ip er id in -1-yl)a ce-
tic Acid Eth yl Ester (11a ). To a solution of 4a (600 mg, 2.05
mmol) in THF (20 mL) was added KH (470 mg, 35% solution
in paraffin) at 0 °C. After 30 min of stirring, ethyl bromoac-
etate (450 µL, 4.1 mmol) was added and stirring was continued
for another 4 h at 4 °C and 19 h at room temperature. Then
EtOAc and a saturated aqueous NaCl solution were added.
The organic layer was dried (MgSO4) and evaporated, and the
residue was purified by flash chromatography (petroleum
ether-EtOAc, 2:8) to give pure 11a (750 mg, 96%) as a
colorless oil. ent-11a was prepared under the same reaction
conditions, starting from ent-4a . 11a : TLC Rf 0.48 (petroleum
C
18H24N2O4: C, 65.04; H, 7.28; N, 8.43. Found: C, 65.01; H,
7.26; N, 8.32.
(4S)-[4-(N,N-Acetylben zyla m in o)-2-oxop ip er id in -1-yl]-
N-m eth yla ceta m id e (12). A solution of 11c (12 mg, 0.04
mmol) in ethanolic methylamine solution (5 mL, 8.03 M in
EtOH) was stirred for 15 h at room temperature. After
evaporation, the residue was purified by flash chromatography
(CH2Cl2-MeOH, 95:5) to give pure 12 (11.4 mg, 100%) as a
colorless oil: TLC Rf 0.11 (CH2Cl2-MeOH, 95:5); [R]20D -29.7°
(c ) 1.0, CHCl3); IR 3310, 2930, 1630 cm-1; 1H NMR (360 MHz)
δ 1.88-1.96 (m, 1H), 2.00-2.10 (m, 1H), 2.13 (s, 3H), 2.62 (d,
J ) 7.9, 2H), 2.77 (d, J ) 4.8, 3H), 3.37-4.43 (m, 2H), 3.72 (d,
J ) 15.2, 1H), 4.12 (d, J ) 15.2, 1H), 4.47-4.51 (m, 1H), 4.49
(d, J ) 17.8, 1H), 4.56 (d, J ) 17.8, 1H), 6.60 (s, 1H), 7.17-
7.41 (m, 5H); 13C NMR (63 MHz) δ 22.6, 26.1, 27.3, 35.8, 47.1,
49.6, 50.2, 51.5, 125.8, 127.8, 129.1, 136.9, 169.0, 169.4, 171.7;
EIMS 317 (M+). Anal. Calcd for C17H23N3O3: C, 64.33; H, 7.30;
N, 13.24. Found: C, 63.78; H, 7.25; N, 13.20.
ether-EtOAc, 2:8); [R]24 -43.5° (c ) 1.0, CHCl3). ent-11a :
D
[R]25D +41.0° (c ) 1.0, CHCl3); IR 3020, 2920, 1740, 1650, 1450
1
cm-1; H NMR (360 MHz) δ 1.23 (t, J ) 7.1, 3H), 1.89 (dddd,
J ) 12.3, 12.3, 9.9, 7.5, 1H), 2.02-2.14 (m, 1H), 2.53 (dd, J )
17.1, 11.3, 1H), 2.68 (ddd, J ) 17.1, 5.5, 2.1, 1H), 3.07-3.15
(m, 1H), 3.23-3.33 (m, 2H), 3.63 (d, J ) 14.2, 2H), 3.67 (d, J
) 14.2, 2H), 4.00 (d, J ) 17.1, 1H), 4.10 (d, J ) 17.1, 1H), 4.15
(q, J ) 7.1, 2H), 7.16-7.41 (m, 10H); EIMS 380 (M+). Anal.
Calcd for C23H28N2O3 (+0.6 H2O): C, 70.60; H, 7.52; N, 7.16.
Found: C, 70.40; H, 7.27; N, 7.05.
(4S)-4-(N-Ben zyla m in o-2-oxop ip er id in -1-yl)a cetic Acid
Eth yl Ester (11b). A: A mixture of 11a (218 mg, 0.45 mmol)
and Pd(OH)2/C (20 mg) in MeOH (10 mL) was stirred under a
balloon of H2 for 40 min. The mixture was filtered through
Celite, and the filtrate was evaporated. The residue was
purified by flash chromatography (MeOH-CH2Cl2, 5:95) to
give 11b and recovered 11a . After repeating the procedure
with the recovered 11a nine times, 108 mg (83%) of 11b was
(5S)-5-(N,N-Dib en zyla m in o-2-oxop ip er id in -1-yl)a ce-
tic Acid Eth yl Ester (13a ). To a solution of 8a (580 mg, 1.97
mmol) in THF (20 mL) was added KH (157.6 mg, 60% solution
in paraffin, 3.94 mmol) at 0 °C. After 30 min of stirring, ethyl
bromoacetate (547 µL, 4.93 mmol) was added, and stirring was
continued for an additional 4 h at 4 °C and 19 h at room

Synthesis of 4- and 5-Aminopiperidin-2-ones
J . Org. Chem., Vol. 65, No. 22, 2000 7415
temperature. Then EtOAc (10 mL) and a saturated aqueous
NaCl solution (10 mL) were added. After extraction with
EtOAc, the organic layer was dried (MgSO4) and evaporated,
and the residue was purified by flash chromatography (petro-
leum ether-EtOAc, 1:4) to give pure 13a (273 mg, 36.4%) as
a yellow oil, in addition to recovered 8a (352 mg, 1.19 mmol):
(CHCl3-MeOH, 95:5); [R]20D -24.7° (c ) 1.0, CHCl3); IR 3300,
3070, 2940, 1750, 1700, 1650, 1640 cm-1; 1H NMR (DMSO-d6,
360 MHz) δ 1.20 (t, J ) 7.1, 3H), 1.59 (dddd, J ) 12.9, 9.1,
9.1, 6.5, 1H), 1.69-1.97 (m, 4H), 2.03-2.18 (m, 1H), 2.23 (dd,
J ) 16.7, 9.1, 1H), 2.44 (dd, J ) 16.7, 5.0, 1H), 3.17-3.25 (m,
1H), 3.28-3.51 (m, 3H), 3.88-4.00 (m, 1H), 3.90/3.95 (d, J )
17.2/17.0, 1H), 4.07-4.18 (m, 1H), 4.10 (q, J ) 7.1, 2H), 4.12/
4.14 (d, J ) 17.2/17.0, 1H), 4.96/5.04 (d, J ) 13.0/12.8, 1H),
5.08/5.09 (d, J ) 13.0/12.8, 1H), 7.26-7.42 (m, 5H), 8.00/8.06
(d, J ) 7.4/7.1, 1H); EIMS 431 (M+).
(2S,4S)-4-[[[1-Ben zyloxyca r b on yl-2-p yr r olid in yl]ca r -
bon yl]a m in o](2-oxop ip er id in -1-yl)a ceta m id e (15b). To a
solution of MeOH (10 mL) saturated with NH3 at -30 °C was
added 15a (153 mg, 0.35 mmol). The mixture was stirred for
10 h at room temperature. After evaporation, the residue was
purified by flash chromatography (CH2Cl2-MeOH, 9:1) to give
pure 15b (120 mg, 85%) as a colorless oil: TLC Rf 0.32 (CH2-
Cl2-MeOH, 9:1); [R]20D -34.5° (c ) 1.0, CHCl3); IR 3300, 3070,
2950, 1700, 1680, 1630 cm-1; 1H NMR (DMSO-d6, 360 MHz) δ
1.53-1.53 (m, 5H), 2.03-2.15 (m, 1H, 5Hb), 2.18 (dd, J ) 16.4,
8.3, 1H), 2.41 (dd, J ) 16.4, 5.0, 1H), 3.14 (ddd, J ) 17.7, 11.9,
6.0, 1H), 3.24-3.51 (m, 3H), 3.73/3.74 (d, J ) 16.3/16.3, 1H),
3.87/3.90 (d, J ) 16.3/16.3, 1H), 3.94-4.07 (m, 1H), 4.09-4.18
(m, 1H), 4.95/5.03 (d, J ) 12.8/12.8, 1H), 5.08/5.09 (d, J ) 12.8/
12.8, 1H), 7.06 (s, 1H), 7.25-7.40 (m, 6H), 8.02/8.04 (d, J )
7.5/7.5, 1H); EIMS 402 (M+). Anal. Calcd for C20H26N4O5 (+0.5
H2O): C, 58.38; H, 6.61; N, 13.62. Found: C, 58.71; H, 6.66;
N, 13.53.
TLC Rf 0.39 (petroleum ether-EtOAc, 2:8); [R]20 -26.0° (c )
D
1.0, CHCl3); IR 3030, 1750, 1650 cm-1; H NMR (360 MHz) δ
1
1.23 (t, J ) 7.2, 3H), 1.91 (dddd, J ) 12.2, 12.0, 11.7, 5.1, 1H),
2.05-2.12 (m, 1H), 2.29 (ddd, J ) 17.5, 12.0, 5.7, 1H), 2.59
(ddd, J ) 17.5, 5.1, 3.1, 1H), 3.15 (dddd, J ) 11.7, 10.3, 5.7,
3.9, 1H), 3.31 (ddd, J ) 11.3, 5.7, 1.3, 1H), 3.45 (dd, J ) 11.3,
10.3, 1H), 3.61 (d, J ) 14.0, 2H), 3.76 (d, J ) 14.0, 2H), 3.86
(d, J ) 17.3, 1H), 4.11 (d, J ) 17.1, 1H), 4.16 (q, J ) 7.2, 2H),
7.18-7.39 (m, 10H); EIMS 380 (M+). Anal. Calcd for C23H28N2O3
(+0.6 H2O): C, 70.60; H, 7.52; N, 7.16. Found: C, 70.27; H,
7.93; N, 7.24.
(5S)-5-(N-Ben zyla m in o-2-oxop ip er id in -1-yl)a cetic Acid
Eth yl Ester (13b). A mixture of 13a (270 mg, 0.72 mmol) and
Pd(OH)2/C (25 mg) in MeOH (10 mL) was reacted and worked
up as described for 11b to give 13b (175 mg, 84%) as a colorless
oil: TLC Rf 0.39 (CH2Cl2-MeOH, 95:5); [R]20D -28.0° (c ) 0.5,
1
CHCl3); IR 3310, 2930, 1740, 1640 cm-1; H NMR (360 MHz)
δ 1.27 (t, J ) 7.2, 3H), 1.81 (dddd, J ) 13.1, 8.7, 8.2, 6.1, 1H),
2.05 (ddddd, J ) 13.1, 6.4, 6.2, 3.5, 0.6, 1H), 2.41 (ddd, J )
17.8, 8.7, 6.4, 1H), 2.59 (ddd, J ) 17.8, 6.2, 6.1, 1H), 3.14 (dddd,
J ) 8.2, 7.5, 4.1, 3.5, 1H), 3.23 (dd, J ) 11.4, 7.5, 1H), 3.50
(ddd, J ) 11.4, 4.1, 0.6, 1H), 3.82 (d, J ) 13.1, 1H), 3.87 (d, J
) 13.1, 1H), 4.07 (s, 2H), 4.19 (q, J ) 7.2, 2H), 7.22-7.38 (m,
5H); EIMS 290 (M+). HRMS calcd for C22H16N2O3: 290.1630.
Found: 290.1627.
(2S,4S)-4-[(2-P yr r olid in ylca r bon yl)a m in o](2-oxop ip e-
r id in -1-yl)a ceta m id e (15c). A solution of 15b (177 mg, 0.44
mmol) and NEt3 (61 µL, 0.44 mmol) in MeOH (10 mL) was
hydrogenated (15 h, 50 bar H2) at room temperature using
Pd/C (44 mg) as a catalyst. The mixture was filtered through
Celite and evaporated to give 15c (118 mg, 100%) as a colorless
(5S)-[5-(N,N-Acetylben zyla m in o)-2-oxop ip er id in -1-yl]-
a cetic Acid Eth yl Ester (13c). A mixture of 13b (73 mg, 0.25
mmol) in pyridine (2 mL) and acidic anhydride (1 mL) was
reacted and worked up as described for 11c. After flash
chromatography (petroleum ether-acetone, 1:1), pure 13c (67
mg, 81%) was obtained: TLC Rf 0.31 (petroleum ether-
solid: TLC Rf 0.29 (CH2Cl2-MeOH, 8:2); [R]21 -26.7° (c )
D
1
1.0, MeOH); IR 3310, 3200, 2980, 1680, 1640 cm-1; H NMR
(C5D5N, 360 MHz) δ 1.53 (dddd, J ) 12.8, 12.8, 12.8, 6.5, 1H),
1.64 (dddd, J ) 12.8, 7.0, 7.0, 7.0, 1H), 1.88-2.10 (m, 5H), 2.63
(dd, J ) 17.2, 8.3, 1H), 2.83-2.96 (m, 2H), 3.32-3.55 (m, 3H),
4.22/4.30 (d, J ) 16.2/16.2, 1H), 4.54/4.57 (d, J ) 16.2/16.2,
1H), 4.45-4.55 (m, 1H), 8.06 (s, 1H), 8.25 (s, 1H), 8.39 (d,
J ) 7.5, 1H); EIMS 268 (M+). HRMS calcd for C12H20N4O3:
268.1535. Found: 268.1534.
(2S,4R)-4-[[[1-Ben zyloxyca r bon ylp yr r olid in e-2-ca r bo-
n yl]a m in o]p ip er id in -1-yl]a cetic Acid Eth yl Ester (16a ).
To a solution of Cbz-L-proline (365.5 mg, 1.43 mmol) in THF
(5 mL) at -7 °C were added HOBt (193 mg, 1.43 mmol), DCC
(310 mg, 1.50 mmol), and ent-11c (286 mg, 1.43 mmol)
dissolved in THF (10 mL). The reaction mixture was reacted
and worked up as described for 15a to give pure 16a (187 mg,
30%) as a colorless oil: TLC Rf 0.40 (hexane-acetone, 1:4);
[R]20D -71.0° (c ) 1.0, CHCl3); IR 3300, 3070, 2980, 1740, 1700,
1650, 1640 cm-1; 1H NMR (DMSO-d6, 360 MHz) δ 1.20 (t, J )
7.1, 3H), 1.61-1.97 (m, 5H), 2.08-2.19 (m, 1H), 2.22 (dd, J )
17.4, 9.1, 1H), 2.40 (dd, J ) 17.4, 5.5, 1H), 3.24-3.93 (m, 4H),
3.89-4.03 (m, 1H), 3.94/3.96 (d, J ) 17.1/17.0, 1H), 4.10 (q, J
) 7.1, 2H), 4.12 (d, J ) 17.0, 1H), 4.12-4.20 (m, 1H), 4.96/
5.04 (d, J ) 13.0/13.1, 1H), 5.08/5.09 (d, J ) 13.0/13.1, 1H),
7.22-7.40 (m, 5H), 8.00/8.05 (d, J ) 7.5/7.5, 1H); EIMS 431
(M+).
acetone, 1:1); [R]20 -37.9° (c ) 1.0, CHCl3); IR 3030, 2980,
D
1
1750, 1650 cm-1; H NMR (360 MHz) δ 1.25 (t, J ) 7.1, 3H),
1.82-1.95 (m, 1H), 2.04 (dddd, J ) 12.0, 11.7, 11.6, 6.0, 1H),
2.10 (s, 3H), 2.44 (ddd, J ) 17.6, 11.7, 6.2, 1H), 2.53 (ddd, J )
17.6, 6.0, 2.9, 1H), 3.33 (ddd, J ) 10.8, 5.6, 0.9, 1H), 3.43 (dd,
J ) 10.8, 10.5, 1H), 3.72 (d, J ) 17.4, 1H), 3.90 (d, J ) 17.4,
1H), 4.16 (q, J ) 7.1, 2H), 4.54 (d, J ) 17.8, 1H), 4.59 (d, J )
17.8, 1H), 4.88 (dddd, J ) 11.6, 10.5, 5.6, 4.8, 1H), 7.13-7.40
(m, 5H); EIMS 332 (M+). Anal. Calcd for C18H24N2O4 (+0.75
H2O): C, 62.50; H, 7.43; N, 8.10. Found: C, 62.68; H, 7.44; N,
8.03.
(5S)-[5-(N,N-Acetylben zyla m in o)-2-oxop ip er id in -1-yl]-
N-m eth yla ceta m id e (14). A solution of 13c (47 mg, 0.14
mmol) in ethanolic methylamine solution (5 mL, 8.03 M in
EtOH) was reacted and worked up as described for 12 to give
pure 14 (44 mg, 99%) as a colorless oil: TLC Rf 0.11 (CH2-
Cl2-MeOH, 95:5); [R]20 -31.9° (c ) 1.0, CHCl3); IR 3310,
D
2940, 1640 cm-1
;
1H NMR (360 MHz) δ 1.78-1.95 (m, 1H),
2.05 (dddd, J ) 12.2, 12.0, 11.8, 6.0, 1H), 2.10 (s, 3H), 2.43
(ddd, J ) 17.7, 11.8, 6.1, 1H), 2.53 (ddd, J ) 17.7, 6.0, 3.1,
1H), 2.77 (d, J ) 5.0, 3H), 3.42 (dd, J ) 11.4, 6.6, 1H), 3.47
(ddd, J ) 11.4, 10.6, 1H), 3.79 (d, J ) 15.3, 1H), 3.99 (d, J )
15.3, 1H), 4.52 (d, J ) 17.9, 1H), 4.58 (d, J ) 17.9, 1H), 4.76
(dddd, J ) 12.0, 10.6, 6.6, 4.0, 1H), 6.45 (s, 1H), 7.12-7.43
(m, 5H); EIMS 317 (M+). HRMS calcd for C17H23N3O3: 317.1739.
Found: 317.1739.
(2S,4R)-4-[[[1-Ben zyloxyca r b on yl-2-p yr r olid in yl]ca r -
bon yl]a m in o](2-oxop ip er id in -1-yl)a ceta m id e (16b). To a
solution of MeOH (10 mL) saturated with NH3 at -30 °C was
added 16a (260 mg, 0.60 mmol). The mixture was stirred for
10 h at room temperature. After evaporation, the residue was
purified by crystalisation (MeOH-Et2O) to give pure 16b
(193.5 mg, 80%) as a colorless crystals: TLC Rf 0.28 (CH2Cl2-
(2S,4S)-4-[[[1-Ben zyloxyca r bon ylp yr r olid in e-2-ca r bo-
n yl]a m in o]p ip er id in -1-yl]a cetic Acid Eth yl Ester (15a ).
To a solution of Cbz-L-proline (183 mg, 0.73 mmol) in THF (5
mL) at -7 °C were added HOBt (99 mg, 0.73 mmol), DCC (159
mg, 0.77 mmol), and 11c (147 mg, 0.73 mmol) dissolved in THF
(10 mL). The reaction mixture was stirred for 3 h at 0 °C and
19 h at room temperature. The mixture was filtrated and
diluted with EtOAc (10 mL). The solution was washed
consecutively with brine, 0.5 N KHSO4, brine, 5% NaHCO3,
and then brine; dried (MgSO4); and evaporated. The residue
was purified by flash chromatography (CHCl3-MeOH, 95:5)
to give pure 15a (193 mg, 61%) as a colorless oil: TLC Rf 0.30
MeOH, 9:1); [R]20 -29.4° (c ) 0.67, CHCl3-MeOH, 1:2); mp
D
218-219 °C; IR 3320, 2960, 1704, 1680, 1630 cm-1; H NMR
1
(DMSO-d6, 360 MHz) δ 1.63-1.93 (m, 5H), 2.04-2.15 (m, 1H),
2.19 (dd, J ) 17.3, 8.3, 1H), 2.41 (dd, J ) 17.3, 5.7, 1H), 3.15-
3.52 (m, 4H), 3.75/3.90 (d, J ) 16.3/16.3, 1H), 3.90/3.91 (d, J
) 16.3/16.3, 1H), 3.97-4.06 (m, 1H), 4.08-4.19 (m, 1H), 4.96/
5.04 (d, J ) 12.8/12.8, 1H), 5.07/5.09 (d, J ) 12.8/12.8, 1H),
7.05 (s, 1H), 7.26-7.39 (m, 6H), 8.02/8.06 (d, J ) 7.5/7.5, 1H);

7416 J . Org. Chem., Vol. 65, No. 22, 2000
Weber et al.
EIMS 402 (M+). Anal. Calcd for C20H26N4O5(+0.5 H2O): C,
58.38; H, 6.61; N, 13.62. Found: C, 58.39; H, 6.62; N, 13.32.
(2S,4R)-4-[(2-P yr r olid in ylca r bon yl)a m in o](2-oxop ip e-
r id in -1-yl)a ceta m id e (16c). A mixture of 16b (54.5 mg, 0.14
mmol), NEt3 (20 µl, 0.14 mmol), and Pd/C (11 mg) as a catalyst
in MeOH (10 mL) was reacted and worked up as described
for 15c to give pure 16c (36.5 mg, 100%) as a colorless solid:
and CH2CO single bonds in 60° steps. Employing a conjugate
gradient-type algorithm, we performed geometry optimization
on the basis of the starting conformations.
Dop a m in e Recep tor Bin d in g. Bovine striatal membranes
were homogenized in 20 vol % sucrose (0.32 M).28 The suspen-
sion was centrifuged at 1000g for 15 min. Subsequently, the
supernatant was then centrifuged for 1 h at 100000g. The
resultant pellet was resuspended in Tris-EDTA buffer (50 mM
Tris, 1 mM EDTA, pH 7.4) and stored at -80 °C in small
aliquots. On the day of use, the membrane preparations were
thawed; diluted with Tris-EDTA buffer containing 5 mM
MgCl2, 0.1 mM dithiothreitol, 100 µg/mL bacitracin, and 5 µg/
mL soybean trypsin inhibitor as an incubation buffer; and used
for binding assays.
TLC Rf 0.30 (CH2Cl2-MeOH, 8:2); [R]21 -24.2° (c ) 1.0,
D
MeOH); IR 3310, 3200, 2980, 1680, 1640 cm-1
;
1H NMR
(DMSO-d6, 360 MHz) δ 1.55-1.84 (m, 5H), 1.84-2.05 (m, 3H),
3.19-4.00 (m, 4H), 3.79-3.93 (m, 1H), 3.82/3.85 (d, J ) 16.1/
16.1, 1H), 3.87/3.89 (d, J ) 16.1/16.1, 1H), 3.96-4.10 (m, 1H),
7.05 (s, 1H), 7.34 (s, 1H), 7.87/7.98 (d, J ) 7.6, 1H); EIMS 268
(M+).
NMR Exp er im en ts. The variable-temperature NMR ex-
periments were performed with a 1 nM solution of the amide
12 (analytical-grade purity) in degassed CDCl3 of highest
quality. NOEs were ascertained by nuclear Overhauser dif-
ference spectroscopy, using multiple selective irradiation. For
presaturation, each signal was irradiated for 4 s altogether,
with the decoupler attenuated to 78 dB. The samples were
degassed by five freeze-pump-thaw cycles and sealed under
Ar. H,H-COSY and H,C-COSY (HMBQ) were performed in
phase-sensitive mode, using company-provided standard pulse
sequences. 1K data points were used in F2, zero-filled to 1K
(H,H-COSY) and 512 (HMBQ) in F1. Adopted Gaussian
windows were applied in both dimensions.
Com p u ta tion a l Stu d ies. The Tripos force field choosing
Gasteiger-Marsili charges, included in the program package
Sybyl 6.5.1, was employed. Starting from two conformations
of 12 including equatorially and axially dispositioned amino
substituents, respectively, we performed a systematic confor-
mational search. The conformational space was investigated
by systematically varying the torsional angles of the CN bond
in position 4 of the piperidinone as well as the exocyclic NCH2
For the binding assays, ∼300 µg membrane proteins and
0.5 nM [3H]pramipexole were incubated without (control) or
with the modulating agents PLG, 15c or 16c, employed as 10-9
M solutions in an incubation buffer, for 2 h at 23 °C.
Nonspecific binding was determined in the presence of 1 µM
(+)-butaclamol. Incubation was terminated by rapid filtration.
The filters were rinsed with ice-cold Tris-EDTA buffer (3 ×
5 mL), and the radioactivity was determined in a scintillation
counter (LS 6500). The results were expressed as percent of
specific binding compared to control membranes (100%). The
statistical significance of the data was performed using a t test.
Values of p < 0.05 were considered to be significantly different
from those of the control.
Ack n ow led gm en t. This work was supported by the
Deutsche Forschungsgemeinschaft (DFG) and the Fonds
der Chemischen Industrie. Dr. R. Waibel is acknowl-
edged for NMR and HRMS measurements.
J O000555C