Synthesis of 3-Aminolactams as X-Gly Constrained Pseudodipeptides and Conformational Study of a Trp-Gly Surrogate

Article abstract of DOI:10.1021/jo035151+

3-Amino-δ-valerolactams trans-11a-c were synthesized through conjugate addition and Curtius rearrangement and converted into Fmoc-{Trp-Gly}, Fmoc-{Ile-Gly}, and Fmoc-{Phe-Gly} pseudodipeptides. Conformational analyses of tripeptide analogues Ac-{Trp-Gly}-

Full text of DOI:10.1021/jo035151+

Syn th esis of 3-Am in ola cta m s a s X-Gly Con str a in ed
P seu d od ip ep tid es a n d Con for m a tion a l Stu d y of a Tr p -Gly
Su r r oga te
Marta Ecija,† Anna Diez,†,‡ Mario Rubiralta,†,‡ and Nu´ria Casamitjana*,†
Laboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, Universitat de Barcelona, Av. J oan XXIII s/ n,
08028-Barcelona, Spain, and Parc Cient´ıfic de Barcelona, c/ J osep Samitier, 1-5, 08028-Barcelona, Spain
Marcelo J . Kogan§,‡ and Ernest Giralt§,‡
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica, Universitat de Barcelona, c/ Martı´ i Franque`s
1-11, 08028-Barcelona, Spain, and Parc Cient´ıfic de Barcelona, c/ J osep Samitier, 1-5, 08028-Barcelona,
Spain
ncasamitjana@ub.edu
Received August 5, 2003
3-Amino-δ-valerolactams trans-11a -c were synthesized through conjugate addition and Curtius
rearrangement and converted into Fmoc-{Trp-Gly}, Fmoc-{Ile-Gly}, and Fmoc-{Phe-Gly} pseudo-
dipeptides. Conformational analyses of tripeptide analogues Ac-{Trp-Gly}-Leu-NH2 17a and 17b
by NMR experiments and molecular modeling calculations showed that diastereomer 17a adopted
a γ-turn/distorted type II â-turn structure, whereas diastereomer 17b adopted mainly a γ-turn
structure.
In tr od u ction
In the context of our studies on the synthesis of
functionalized 3-aminolactams as constrained surrogates
of dipeptides,1 we established a new synthetic method
to obtain X-Gly pseudodipeptides based on the use of
3-benzyloxycarbonyl-5,6-dihydropyridin-2-one 1 as a start-
ing compound (Figure 1).2,3 This new methodology im-
plied introduction of a substituent in position C4 by
conjugate addition, and amination of C3 by subsequent
Curtius rearrangement.
F IGURE 1. Synthesis of X-Gly pseudopeptides.
In principle, this method would allow us to thermody-
namically control the relative stereochemistry of the ring
substituents (see Figure 2). Thus, conformational equili-
bration and epimerization on C3 would lead to the most
thermodynamically stable 3,4-trans isomers, and in this
way we would be able to obtain only two isomers out of
the four kinetic products.
Our interest in â- and γ-turn conformations1 and the
fact that Trp is usually not involved in turns,4 despite
its relevant biological role in nature,5 prompted us to
study whether the integration of the indole nucleus on
the piperidone backbone would still promote a turn.6
Since the lactam backbone provides the i+1 and i+2
residues of the tetrapeptide that forms the â- or γ-turns
(Figure 3), we chose to protect the N-terminus using an
acetyl group, extend the C-terminus by introducing
† Laboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, Univer-
sitat de Barcelona.
‡ Parc Cient´ıfic de Barcelona.
§ Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica, Univer-
sitat de Barcelona.
(1) (a) Ferna´ndez, M. M.; Diez, A.; Rubiralta, M.; Montenegro, E.;
Casamitjana, N.; Kogan, M. J .; Giralt, E. J . Org. Chem. 2002, 67,
7587-7599. (b) Estiarte, M. A.; Rubiralta, M.; Thormann, M.; Giralt,
E. J . Org. Chem. 2000, 65, 6992-6999.
(2) For previous applications of 5,6-dihydropyridin-2-ones in Diels-
Alder reactions, see: (a) Casamitjana, N.; Amat, M.; Llor, N.; Carreras,
M.; Pujol, X.; Ferna´ndez, M.; Lo´pez, V.; Molins, E.; Miravitlles, C.;
Bosch, J . Tetrahedron: Asymmetry 2003, 14, 2033-39. (b) Casamit-
jana, N.; Lo´pez, V.; J orge, A.; Bosch, J .; Molins, E.; Roig, A. Tetrahedron
2000, 56, 4027-4042. (c) Casamitjana, N.; J orge, A.; Pe´rez, C. G.;
Bosch, J .; Espinosa, E.; Molins, E. Tetrahedron Lett. 1997, 38, 2295-
2298.
(3) For the application of 5,6-dihydropyridin-2-ones in the synthesis
of indole alkaloids by conjugate addition, see: (a) Forns, P.; Ferna´ndez,
M. M.; Diez, A.; Rubiralta, M.; Cherrier, M.-P.; Bonin, M.; Quirion,
J .-C. Synthesis 1999, 258-263. (b) Forns, P.; Diez, A.; Rubiralta, M.;
Solans, X.; Font-Bardia, M.; Tetrahedron 1996, 52, 3563-3574. (c)
Micouin, L.; Diez, A.; Castells, J .; Lo´pez, D.; Rubiralta, M.; Quirion,
J .-C.; Husson, H.-P. Tetrahedron Lett. 1995, 36, 1693-1696. (d) Diez,
A.; Castells, J .; Forns, P.; Rubiralta, M.; Grierson, D. S.; Husson, H.-
P.; Solans, X.; Font-Bardia, M. Tetrahedron 1994, 50, 6585-6602.
(4) (a) Huang, F.; Nau, W. M. Angew. Chem., Int. Ed. 2003, 42,
2269-2272. (b) Griffiths-J ones, S. R.; Sharman, G. J .; Maynard, A. J .;
Searle, M. S. J . Mol. Biol. 1998, 284, 1597-1609.
(5) For biological relevance of Trp see: http://www.acdlabs.com/
publish/tryptophan/.
(6) It is well-known that Freidinger lactams induce turns: (a)
Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brooks, J . R.; Saperstein,
R. Science 1980, 210, 656-658. (b) Freidinger, R. M.; Perlow, D. S.;
Veber, D. F. J . Org. Chem. 1982, 47, 104-109.
10.1021/jo035151+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/18/2003
J . Org. Chem. 2003, 68, 9541-9553
9541

Ecija et al.
F IGURE 2. Thermodynamic control of the relative stereochemistry of C3 and C4 of 3,4-disubstituted piperidones 8.
F IGURE 3. Hydrogen bonds stabilizing â- and γ-turns in Ac-{Trp-Gly}-Leu-NH2 17a and 17b .
a Leu-NH2 residue, and study the conformational prefer-
ences of Ac-{Trp-Gly}-Leu-NH2 17a and 17b.
and phenylselanyl groups at position 3 was performed
in a one-pot procedure, using LHMDS as base and ClCO2-
Bn and PhSeCl as electrophiles. N-Deprotection of pi-
peridone 3 with 2,6-lutidine and TMSOTf9 to give disub-
stituted piperidone 610 followed by N-alkylation with tert-
butyl bromoacetate, K2CO3, and TBAB in CH3CN gave
trisubstituted piperidone 7 in good yield. Finally, elimi-
nation of the phenylselanyl group with m-CPBA as
oxidizing agent at 0 °C furnished dihydropyridone 1 in a
71% overall yield from compound 2. When the phenylse-
lanyl group elimination was performed prior to the
N-deprotection and alkylation steps, intermediate dihy-
dropyridone 4 was obtained as a crude product that was
subsequently treated with TFA to yield N-deprotected
dihydropyridone 5, but the last alkylation step to furnish
compound 1 was unsuccessful. Structure assignment of
dihydropyridone 1 was based on the presence of two
signals at δ 128.9 and 147.3 in the 13C NMR spectra for
the olephinic carbons and a multiplet at δ 7.25-7.45 in
Trp-Gly-Leu is the C-terminus of a synthetic peptide
corresponding to amino acids 400-429 of the gp21
envelope transmembrane glycoprotein.7 This synthetic
30-residue peptide (peptide 400-429) strongly inhibits
not only infection by cell-free Human T-Cell Leukemia
Virus Type 1 (HTLV-1) but also syncytium formation
induced by cocultivation with HTLV-1-producing cells.
According to J inno and co-workers, peptide 400-429
seems to be important for the envelope functions, not only
in cell-to-cell but also in virus-to-cell infection. In addi-
tion, they report that six residues, including the terminal
Leu, are necessary for the activity of gp21 peptide 400-
429.
Resu lts a n d Discu ssion
Syn th esis a n d Str u ctu r a l Assign m en t. The syn-
thesis of 3-benzyloxycarbonyl-5,6-dihydropyridin-2-one 1
was performed with our own methodology2 and N-tert-
butoxycarbonyl-2-piperidone (2)8 as the initial substrate
(Scheme 1). Thus, introduction of the benzyloxycarbonyl
1
the H NMR spectra for olephinic proton H-4.
(9) (a) Zhang, A. J .; Russell, D. H.; Zhu, J .; Burguess, K. Tetrahedron
Lett. 1998, 39, 7439-7442. (b) Sakaitani, M.; Ohfune, Y. J . Org. Chem.
1990, 55, 870-876. This reagent is compatible with the presence of
other functional groups, see: (c) Hamada, Y.; Shiori, T. J . Org. Chem.
1986, 51, 5489-5490.
(10) When N-deprotection was performed with TFA at 0 °C piperi-
done 6 was obtained in 63% yield accompanied by 3-(benzyloxycarbo-
nyl)piperidin-2-one (13%) as a byproduct, see Experimental Section.
(7) J inno, A.; Haraguchi, Y.; Shiraki, H.; Hoshino, H. J . Virol. 1999,
73, 9683-9689.
(8) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org. Chem. 1983, 48,
2424-2426.
9542 J . Org. Chem., Vol. 68, No. 25, 2003

Synthesis of 3-Aminolactams
SCHEME 1. Syn th esis of
SCHEME 2. Con ju ga te Ad d ition to
Dih yd r op yr id on e 1a
5,6-Dih yd r op yr id in -2(1H)-on e 1a
a
Reagents and conditions: (a) LHMDS, ClCO2Bn, PhSeCl, dry
a
THF, -78 °C, 93%; (b) m-CPBA, dry CH2Cl2, 0 °C to rt (not
Reagents and conditions: (a) indole, Montmorillonite KSF, dry
purified); (c) TFA, dry CH2Cl2, 0 °C (not purified); (d) TMSOTf,
CH2Cl2, rt, 80%; (b) EtMgBr, CuBr‚SMe2, dry THF, -78 °C to rt,
83%; (c) PhMgBr, CuBr‚SMe2, dry THF, -78 °C to rt, 77%; (d)
KCN, NH4Cl, DMF/H2O, 90 °C, 83%.
t
2,6-lutidine, dry CH2Cl2, rt, 80%; (e) BrCH2CO2 Bu, K2CO3, TBAB,
dry CH3CN, rt, 96% for 7.
Indole itself has been used in conjugate addition
reactions with R,â-unsaturated carbonylic compounds in
acidic media.11 Nevertheless, to overcome the problem of
acidity control when using acid catalysis, and to avoid
polymerization side reactions, the use of nonprotonic acid
catalysis by means of Montmorillonite clays has also been
described for the alkylation of indoles with R,â-unsatur-
ated ketones and esters.12 In our case, the presence of
the tert-butoxycarbonyl group made us choose this last
method to avoid ester hydrolysis. Following the described
procedure for conjugate additions with Montmorillonite
KSF13 as a catalyst, racemic 4-indolyl-2-piperidones cis-
and trans-8a (1:10) were prepared in 80% yield from
dihydropyridone 1 and indole in CH2Cl2 at room temper-
ature for 24 h12,14 (Scheme 2). As expected, the separation
of the cis and trans isomers was not possible, since during
the purification process the cis isomer was converted into
the trans isomer. To investigate the potential of 5,6-
dihydro-2(1H)-pyridones in conjugate addition reactions,
other nucleophiles, such as Grignard reagents and cya-
nide, were also studied.15 When using EtMgBr or Ph-
MgBr in the presence of the catalyst CuBr‚Me2S16 and
the solvent THF at -78 °C, 1,3,4-trisubstituted-2-pip-
eridones cis- and trans-8b (1:6) and cis- and trans-8c (1:
13) were obtained in 83% and 77% yield, respectively.
Finally, the addition of the cyano group, which can be
subsequently converted into other functions,17 on the
unsaturated pyridone 1 was achieved by reaction with
KCN and NH4Cl in DMF-H2O to yield 4-cyano-2-
piperidones cis- and trans-8d (1:5) in an 83% yield.
In all cases, the most favored diastereomer was trans,
although proportions varied according to the nucleophile
type. The most characteristic NMR data for 1,3,4-trisub-
stituted piperidones trans-8 are the δ values for carbons
C-3 and C-4, and the coupling constant between protons
3-H and 4-H (≈8-11 Hz).
As mentioned above, this method allowed us to ther-
modynamically control the relative stereochemistry of the
ring substituents (Figure 2). Thus, conformational equili-
bration and epimerization on C3 led mainly to the most
thermodynamically stable 3,4-trans isomers, and in this
way we obtained the two trans isomers as major products
out of the possible four kinetic products.
(11) (a) Sundberg, R. J. Indoles; Academic Press: London, UK, 1996;
pp 105-107. (b) Remers, W. A. Properties and Reactions of Indoles.
In Heterocyclic Compounds. Indoles. Part I; J ohn Wiley and Sons: New
York, 1972; pp 100-105. See also: (c) Dujardin, G.; Poirier, J .-M. Bull.
Soc. Chim. Fr. 1994, 131, 900-909. (d) Ranganathan, D.; Rao, C. B.;
Ranganathan, S.; Mehrotra, A. K.; Iyengar, R. J . Org. Chem. 1980,
45, 1185-1189. (e) Macor, J . E.; Blank, D. H.; Ryan, K.; Post, R. J .
Synthesis 1997, 443-449.
(12) Iqbal, Z.; J ackson, A. H.; Rao, K. R. N. Tetrahedron Lett. 1988,
29, 2577-2580.
(13) Paquette, L. A. Encyclopedia of Reagents for Organic Synthesis;
J ohn Wiley and Sons: Chichester, UK, 1995; Vol. 5, pp 3367-3671.
(14) Kawai, M.; Onaka, M.; Izumi, Y. Bull. Chem. Soc. J pn. 1988,
2157-2164.
To achieve Trp-Gly, Ile-Gly, and Phe-Gly dipeptide
analogues, 4-substituted 3-(benzyloxycarbonyl)piperi-
dones trans- and cis-8a -c were hydrogenated and the
resulting carboxylic acids were converted into carbamates
11a -c through a modified Curtius rearrangement,18,19
by treatment with Et3N and DPPA, followed by BnOH20
and dibutyltin dilaurate (Scheme 3).21 When 4-cyanopi-
(16) Lin, J .; Liao, S.; Han, Y.; Qiu, W.; Hruby, V. J . Tetrahedron:
Asymmetry 1997, 8, 3213-3221.
(15) (a) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon Press: Oxford, UK, 1992. (b) J ung, M. E.
Stabilized Nucleophiles with Electron Deficient Alkenes and Alkynes.
In Comprehensive Organic Synthesis; Pergamon Press: Oxford, UK,
1991; Vol. 4, pp 1-67. (c) Lee, V. J . Conjugate Additions of Reactive
Carbanions to Activated Alkenes and Alkynes. In Comprehensive
Organic Synthesis; Pergamon Press: Oxford, UK, 1991; Vol. 4, pp 70-
137.
(17) Nagata, W.; Yoshioka, M. Org. React. 1977, 25, 255-476.
(18) (a) Shiori, T.; Ninomiya, K.; Yamada, S. J . Am. Chem. Soc. 1972,
94, 6203-6205. (b) Yamada, S.; Ninomiya, K.; Shiori, T. Tetrahedron
Lett. 1973, 2343-2346. (c) Yamada, S.; Ninomiya, K.; Shiori, T.
Tetrahedron 1974, 30, 2151-2157.
(19) The classical Curtius rearrangement with NaN3 failed, see:
Fukazawa, T.; Shimoji, Y.; Hashimoto, T. Tetrahedron: Asymmetry
1996, 7, 1649-1658.
J . Org. Chem, Vol. 68, No. 25, 2003 9543

Ecija et al.
SCHEME 4. Syn th esis of Tr ip ep tid es 17a ,ba
SCHEME 3. Syn th esis of X-Gly P seu d od ip ep tid esa
a
Reagents and conditions: (a) AcCl, pyridine, dry CH2Cl2, rt,
85%; (b) AcOH-iPrOH-H2O (2:1:1), 100 °C, quantitative; (c)
HCl‚L-Leu-NH2, Et3N, DCC, HOBt, dry DMF, rt, 41%.
a
Reagents and conditions: (a) H2, Pd-C 10%, MeOH or AcOEt,
Once pseudodipeptide analogues were obtained, we
proceeded to prepare tripeptides Ac-{Trp-Gly}-Leu-NH2
17a ,b to perform the corresponding structural studies.
The required N-acetylated dipeptide trans-16 was pre-
pared from 3-aminopiperidone trans-12a by N-acetylation
and hydrolysis of the resulting tert-butyl ester trans-15
(Scheme 4). The coupling of trans-16 with L-Leu-NH2‚
HCl, using standard conditions25 with Et3N, DCC, and
HOBt, yielded pseudotripeptides (2S,3′S,4′S)-17a and
(2S,3′R,4′R)-17b in 41% yield. Addition of the extra chiral
carbon of known configuration of the Leu residue on the
molecule converted the pair of trans enantiomers into two
diastereomers, so we should have been able to identify
the absolute configurations of compounds 17a and 17b
by X-ray crystallography and NMR. The two diastereo-
mers were separated by column chromatography, but
unfortunately, we could not suitably crystallize them.
Con for m a tion a l Stu d ies of Com p ou n d s 17a a n d
17b. To determine whether compounds 17a and 17b can
promote a â- or a γ-turn conformation, we performed
conformational studies using NMR experiments and
molecular modeling calculations. â- and γ-turns are
nonperiodic peptide segments that reverse the orientation
of the peptide chain.1a,26,27 The most general features of
a â-28,29 and a γ-turn30 are described in the literature. The
major types31 of â-turns show a characteristic hydrogen
rt, 9a , 9b, and 9c were not purified, 61% for 10d ; (b) Et3N, DPPA,
dry benzene, 50 °C; then dry BnOH, dibutyltin dilaurate, 80 °C,
53% for trans-11a , 65% for trans/ cis-11b, and 68% for trans-11c;
(c) H2, Pd-C 10%, MeOH or AcOEt, rt, trans-12a and trans-12c
were not purified, 63% for trans-12b; (d) Fmoc-OSu, NaHCO3,
acetone or acetone-H2O (4:1), rt, 63% for trans-13a , 61% for trans-
13b, and 30% for trans-13c from trans-11c; (e) for trans-14a ,
AcOH-iPrOH-H2O (2:1:1), 100 °C, 91%; for trans-14b,c, 10%
TFA-CH2Cl2, rt, 36% for trans-14b and quantitative for trans-
14c.
peridone 8d was hydrogenated in the same conditions,
3-decarboxylated piperidone 10d was the only product
obtained, together with unmodified starting material. In
the other cases, the decarboxylation products were also
obtained (traces for 10a and variable amounts for 10b
and 10c). However, the decarboxylation process could be
avoided, in all cases except for the cyano derivative, when
the products were not purified by chromatography with
use of silica gel and the solvent evaporated without
heating.22
Compounds trans-11a -c were derivatized to be used
as Trp-Gly, Ile-Gly, and Phe-Gly surrogates in peptide
synthesis. Thus, deprotection of the amino group by
hydrogenolysis afforded 3-aminopiperidones trans-12a -
c, and subsequent N-protection with Fmoc-OSu23 gave
Fmoc/OtBu derivatives trans-13a-c. Finally, N-Fmoc
protected carboxylic acids trans-14a -c were prepared by
mild acid hydrolysis24 of the tert-butyl ester function.
(25) Lloyd-Williams, P.; Albericio, F.; Giralt, E. Chemical Approaches
to the Synthesis of Peptides and Proteins; CRC Pres: Boca Raton, FL,
1997.
(20) To obtain the carbamate with the amino group protected with
Fmoc, (9-fluorenyl)methanol was used, instead of BnOH, but the
reaction failed, see: Evans, D. A.; Black, C. J . Am. Chem. Soc. 1993,
115, 4497-4513.
(26) (a) Nowick, J . S.; Smith, E. M.; Pairish, M. Chem. Soc. Rev.
1996, 25, 401-415. (b) Lippens, G.; Hallega, K.; Van Belle, D.; Wodak,
S. J .; Nirmala, N. R.; Hill, P.; Reussell, K. C.; Smith, D. D.; Hruby, V.
J . Biochemistry 1993, 32, 9423-9434.
(27) (a) Brickman, K.; Yuan, Z.; Sethon, I.; Somfai, P.; Kihlberg, J .
Chem. Eur. J . 1999, 5, 2241-2253. (b) Lindvall, M. K.; Rissanen, K.;
Hakala, J . M. L.; Koskinen, A. M. P. Tetrahedron. Lett. 1999, 40, 7427-
7430. (c) Belvisi, L.; Gennari, C.; Mielgo, A.; Potenza, D.; Scolastico,
C. Eur. J . Org. Chem. 1999, 389-400. (d) Belvisi, L.; Gennari, C.;
Madder, A.; Mielgo, A.; Potenza, D.; Scolastico, C. Eur. J . Org. Chem.
2000, 695-699. (e) Belvisi, L.; Bernardi, A.; Manzoni, L.; Potenza, D.;
Scolastico, C. Eur. J . Org. Chem. 2000, 2563-2569.
(21) Altmann, K.-H.; Kesselring, R.; Pieles, U. Tetrahedron 1996,
52, 12699-12722.
(22) The amount of decarboxylation product increased when the
resulting carboxylic acids 10a -c were stirred with SiO2 in AcOEt at
room temperature.
(23) Paquet, A. Can J . Chem. 1982, 60, 976-980.
(24) Gmeiner, P.; Feldman, P. L.; Chu-Moyer, M. Y.; Rapoport, H.
J . Org. Chem. 1990, 55, 3068-3074.
9544 J . Org. Chem., Vol. 68, No. 25, 2003

Synthesis of 3-Aminolactams
between NHc and the lactam carbonyl group would
stabilize a γ-turn.
2. Ch em ica l Sh ift, Ad d ition of a Com p etitive
Solven t, a n d Tem p er a tu r e Coefficien t. According to
Scolastico criteria,27c,34 which take into account NMR data
indicated in Table 1, results seemed more conclusive. For
diastereomer I, protons NHa and NHc were probably in
equilibrium between a hydrogen-bonded and a non-
hydrogen-bonded state whereas protons NHb and NHd
were non-hydrogen bonded. For diastereomer II, data
suggested that protons NHa and NHd were in equilib-
rium between a hydrogen-bonded and a non-hydrogen-
bonded state, proton NHb was exposed to the solvent,
and proton NHc was probably hydrogen bonded.
The overall NMR analysis suggested that proton NHa
of both diastereomers I and II was in equilibrium
between a hydrogen-bonded and a non-hydrogen-bonded
state, whereas proton NHb was clearly non-hydrogen
bonded. Concerning protons NHc and NHd, the results
suggested that in diastereomer I proton NHc was in
equilibrium between a hydrogen-bonded and a non-
hydrogen-bonded state and proton NHd was non-hydro-
gen bonded, whereas in diastereomer II, proton NHc was
clearly intramolecularly hydrogen-bonded and proton
NHd was in equilibrium between a hydrogen-bonded and
a non-hydrogen-bonded state. These results were not
conclusive and they were later evaluated together with
those from the molecular model calculations.
F IGURE 4. NOESY correlations in17a ,b.
bond between the oxygen atom of the carbonyl function
of the first amino acid (i) and the NH amide proton of
the fourth (i+3). If the distance between the oxygen and
the hydrogen atoms involved is less than 2.5 Å, a
hydrogen bond might be present,32 while if the distance
is between 2.5 and 4 Å,27c,33 there is a significant
interaction between them (see Figure 3).
Since at that moment absolute configuration of dia-
stereomers 17a and 17b was not known, in this study
we refer to them as tripeptides or diastereomers I and
II.
Molecu la r Mod elin g. 1. Mon te Ca r lo Ca lcu la -
tion s.35 To determine the conformational space available
to compounds 17a and 17b, we performed both Monte
Carlo and molecular dynamics with iterative simulated
annealing36 calculations. For the Monte Carlo protocol,
molecular models for compounds 17a and 17b were
initially constructed by using the model-building facility
implemented in Spartan 5.0. Coordinates for these
structures were used as input for the Monte Carlo
protocol.37 Rotation was allowed around the dihedral
angles, which constitute the main determinants of the
structure (Figure 5). A conformational search of 17a and
17b was carried out with Spartan version 5.0,1a,37 starting
from different extended conformations. Structures cor-
responding to the energy minima (as calculated with the
MMF94 force field38) within a 10-kcal/mol window above
the global minimum were analyzed on the basis of all
The first relevant observation was the splitting of some
of the signals in the 1H NMR spectra of each of the
tripeptides I and II due to the presence of two slow-
converting conformations in equilibrium in solution. The
affected signals were Ha, Hb, HR, Hâ, Hγ, and most of
the indole nucleus.
NMR Stu d ies. 1. NOESY. Different facts were ob-
served for each diastereomer. Correlations showing the
necessary approach to establish one of the two hydrogen
bonds that would stabilize a â- or γ-turn were not
observed in pseudotripeptide I. However, in its epimer
II correlations between protons NHc and H-R-Leu with
the acetyl methyl group protons and between protons
NHc and NHd were observed. These correlations allowed
us to establish a conformation in which the formation of
an intramolecular hydrogen bond32 would be possible, and
this, as indicated in Figure 4, could happen in both
diastereomers 17a and 17b. The formation of a hydrogen
bond between NHc and the acetyl carbonyl group would
stabilize a â-turn while the formation of a hydrogen bond
(33) Takeuchi, Y.; Marshall, G. R. J . Am. Chem. Soc. 1998, 120,
5363-5372.
(34) The temperature coefficients in DMSO, according to Kessler
criteria, suggested that in diastereomer I protons NHa and NHc (|∆δ/
∆T| < 3 ppb/K) were intramolecularly hydrogen bonded whereas
protons NHb and NHd (|∆δ/∆T| ∼ 4 ppb/K) were exposed to the solvent.
For diastereomer II, proton NHa (|∆δ/∆T| ) 2.5 ppb/K) was probably
intramolecularly hydrogen bonded whereas other NH protons were
exposed to the solvent (Table 1), see: Kessler, H. Angew. Chem., Int.
Ed. Engl. 1982, 21, 512-523.
(28) The most characteristic features of a â-turn are the distance R
(<7 Å) between the CRi and CRi+3 and the dihedral angle τ (-90° < τ
< 90°) formed by the four CR atoms belonging to the tetrapeptide,
see: Perczel, A.; McAllister, M. A.; Csaszar, P.; Csizmadia, I. G. J .
Am. Chem. Soc. 1993, 115, 4849-4858.
(29) The major â-turns are classified according to the torsion angles
of the second (φ1, ψ1: φ1 ) -60 ( 30° and ψ1 ) 120 ( 30°) and third
amino acids (φ2, ψ2: φ2 ) 80 ( 30° and ψ2 ) 0 ( 45°), see: (a) Rose, G.
D.; Gierash, L. M.; Smith, J . A. Adv. Protein Chem. 1985, 37, 1-109.
(b) Ball, J . B.; Hughes, R. A.; Alewood, P. F.; Andrews, P. R.
Tetrahedron 1993, 49, 3467-3478. (c) Liskamp, R. M. J . Recl. Trav.
Chim. Pays Bas 1994, 113, 1-63.
(30) The main features characterizing a classical γ-turn are the
torsion angles of the second amino acid (φ2, ψ2: φ2 ) 70°/85° and ψ2 )
-60°/-70°) and the distance between the carbonyl carbon atom of the
second amino acid (i+1) and the nitrogen atom of the amino group of
the third residue (i+3) with a preferential value of 3 Å, see ref 27a.
(31) Vencatachalam, C. M. Biopolymers 1968, 6, 1425-1436.
(32) Geffrey, G. A. Introduction to Hydrogen Bond; Oxford Univer-
sity Press: New York, 1997.
(35) The above results were confirmed performing a parallel con-
formational search, using molecular dynamics with Iterative Simulated
Annealing, see ref 36. This protocol was run five times, employing fully
extended starting structures of both compounds (17a and 17b) and
AMBER (implemented in DISCOVER 3) as force field. The profiles
for the main parameters characterizing γ- and â-turns were similar
to those found with the Monte Carlo protocol (data not shown).
(36) Corcho, F.; Filizola, M.; Peres J . J . Chem. Phys. Lett. 2000, 319,
65-70.
(37) Hehre, W. J .; Huang, W. W.; Klunzinger, P. E.; Deppmeier, B.
J .; Driessen, A. J . A Spartan Tutorial; Wavefunction, Inc.: Irvine, CA,
1997; pp 85-93.
(38) MMFF 94: Halgren, T. A. J . Comput. Chem. 1996, 17, 490-
519.
J . Org. Chem, Vol. 68, No. 25, 2003 9545

Ecija et al.
TABLE 1. Ch em ica l Sh ifts, ∆δ u p on Ad d ition of DMSO a n d Tem p er a tu r e Coefficien ts for Dia ster eom er s I a n d II
diastereomer I
diastereomer II
|∆δ/∆T| (ppb/K)
CDCl3 DMSO
∆δ/∆T| (ppb/K)
CDCl3
(ppm)
δDMSO
(ppm)
∆δ
(ppm)
δCDCl3
(ppm)
δDMSO
(ppm)
∆δ
(ppm)
CDCl3
DMSO
Ha
Hb
Hc
Hd
8.39
5.47
7.45
6.32
7.64
7.27
8.29
7.86
-0.75
1.8
0.84
1.54
3
2.5
4
2.6
4
2
8.51
5.54
7.69
6.89
7.63
7.27
8.43
7.89
-0.88
1.73
0.74
1
3.5
2.5
2.5
2.5
4
4
4.5
3.7
15.5
3.5
NHa‚‚‚COi+2 (see the Supporting Information) was present
in part of the population of conformers of both diaster-
1
eomers. This last result was in agreement with the H
NMR observation that in both diastereomers proton NHa
was in equilibrium between a hydrogen-bonded and non-
hydrogen-bonded state.
To determine the presence of cis and trans conformers
for the acetamide group, we analyzed the dihedral angles
ω0 and ω2 (Figure 5). Most of the conformers of both
diastereomers presented a trans disposition for the
CO-N bond whereas for conformer 17b a very low
percentage of the conformer population had a cis disposi-
tion for ω0 (Table 2).
F IGURE 5. Dihedral angles for structures 17.
A more detailed study of the conformers obtained in
the Monte Carlo search allowed us to classify the minima
energy conformers (with energies above 2.5 kcal/mol with
respect to the global minimum) of each diastereomer into
families (Table 3, Figure 6). Diastereomers 17a and 17b
yielded two and five families of conformers, respectively.
All conformers of both compounds met the general
criteria (R and τ) for a â-turn. On the other hand, only
conformers 17a 1 and 17b5 showed distances allowing a
hydrogen bond39 between NHc and COi. An analysis of
the dihedral angles Ψ1, Φ1, Ψ2, and Φ2 confirmed that
family 17a 1 was a â-II′ turn while 17b5 was a â-II turn.
In addition, these conformers presented a supplementary
TABLE 2. P er cen ta ges of Min im a En er gy Con for m er s
of th e P seu d op ep tid es Wh ich Exh ibit Differ en t F ea tu r es
of â-II a n d /or γ-Tu r n s (Mon te Ca r lo Con for m a tion a l
Sea r ch )
diastereomer
17a
49a
17b
R(CRi‚‚‚CRi+3) < 7 Å
-90° < τ > +90°
NHc‚‚‚OiC < 2.5 Å
+70° < Φ2 > +85°
-60° < Ψ2 > -70°
NHc‚‚‚Oi+1C < 2.5 Å
-90° < Φ1 > -30°
+90° < Ψ1 > +150°
+50° < Φ2 > +110°
-45° < Ψ2 > +45°
90° < Φ1 > 30°
40a
75a
16a
40b
33b
61b
63c
59c
60c
39c
70a
17a
61b
31b
64b
hydrogen bond between NHa and COi+1
.
Compound 17b showed distances allowing a hydrogen
bond39 between NHc and COi+1 for the families of
conformations 17b1, 17b2, 17b3, and 17b4 which cor-
responded to γ-turn conformations. A closer analysis of
the dihedral angles Ψ2 and Φ2 confirmed that these
families were γ-turn conformations. Conformers 17b1,
17b2, and 17b3 presented one supplementary hydrogen
bond between NHa and COi and, in addition, conformer
17b2 had another hydrogen bond between NHb and COi+2
(see Figure 6). Remarkably, conformer 17b4 (which is 1.8
kcal higher in energy than the global minima) presented
a cis disposition for the C-N bond belonging to the
acetamide group (ω0 ) 0) favoring the formation of an
extra hydrogen bond between NHd and COi+3. This last
result is in agreement with the observation in the 1H
NMR experiments that proton NHd in diasteromer II was
in equilibrium between a hydrogen-bonded and non-
hydrogen-bonded state.
31d
68d
-150° < Ψ1 > -90°
-45° < Φ2 > +45°
ω0 trans/cis
62d
69d
100/0
100/0
93/7
100/0
ω2 trans/cis
a
Percentage of conformers with expected values for canonical
b
â turns. Percentage of conformers with expected values for
canonical γ turns. c Percentage of conformers with expected values
d
for canonical â-II turns. Percentage of conformers with expected
values for canonical â-II′ turns.
the geometric turn parameters, which are diagnostic for
the presence of γ- and â-turns. The corresponding dis-
tribution profiles are summarized in Table 2 and the
Supporting Information.
A general analysis of the Monte Carlo results (Table
2) showed that two of the characteristic geometric
features of the â-turn (R and τ) were fulfilled by a
considerable percentage of the stable conformer popula-
tions of 17a and 17b while the distance COi‚‚‚NHc was
not fulfilled by the main part of the conformer population
of both diastereomers. On the other hand, in a consider-
able percentage of the population the distance between
NHc and COi+1 corresponded to that of a hydrogen bond,
and the angles φ2 and ψ2 agreed well with the values
expected for a γ-turn. Another hydrogen bond between
We measured the distance between the lactam ring
center (see the legend of Table 3) and the methine carbon
of the isobutyl group from the Leu side chain to evaluate
if the steric hindrance between this ring and the Leu side
chain could explain the relative stabilities of the families
of conformers. We observed that in the higher energy
(39) Toshima, H.; Maru, K.; Saito, M.; Ichihara, A. Tetrahedron
1999, 55, 5793-5808.
9546 J . Org. Chem., Vol. 68, No. 25, 2003

Synthesis of 3-Aminolactams
TABLE 3. Ch a r a cter istics of En er gy Min im a Con for m er s (Mon te Ca r lo) for Com p ou n d s 17
17a , families )
17b, families )
1
2
1
2
3
4
5
â-II′a
â-IIa
γa
∆E (kcal/mol)
NHc‚‚‚COi (Å)
NHc‚‚‚COi+1 (Å)
R(CRi‚‚‚CRi+3) (Å)
NHa‚‚‚COi (Å)
NHa‚‚‚COi+1 (Å)
τ (deg)
0
1.9
2.7
5.1
3.2
2.1
-11
62
1.9
2.8
2.2
6.1
1.8
3.3
-27
63
0
0.7
4.4
2.0
5.6
1.9
4.2
3.4
-74
151
75
1.2
3.5
2.1
6.3
1.9
2.9
14
-64
159
83
1.8
6.1
1.9
5.9
6.4
5.9
-31
164
88
2.0
2.0
2.7
5.2
3.1
2.1
13
-62
141
76
2.7
2.2
5.9
1.7
3.9
24
-63
154
87
e2.5 Å
e7 Å
e2.5 Å
e 7 Å
e2.5 Å
-90 e τ e 90
60 ( 30
-120 ( 30
-80 ( 30
0 ( 45
-90 e τ e 90
-60 ( 30
120 ( 30
80 ( 30
Φ1 (deg)
Ψ1 (deg)
-140
-77
5
-158
-87
46
Φ2 (deg)
81
-80
6.65
70/85
-60/-70
Ψ2 (deg)
-54
6.38
-95
7.21
-80
6.74
-4
5.58
0 ( 45
lactam-C(CH3)2 (Å)b
6.26
5.20
a
b
Expected values for canonical â-II, â-II′, and γ-turns. A pseudoatom was created in the mass center of the lactam ring. The distance
is between this pseudatom and the methine atom belonging to the isobutyl group from the side chain of the Leu residue.
F IGURE 6. Stick conformational representation of minimum energy conformers of diastereomers 17a ,b obtained after the Monte
Carlo conformational search.
conformers (approximately 2 kcal/mol above the global
minima) of diastereomers 17a 2 and 17b5 the distance was
shorter than that observed for the other conformers (5.20
and 5.58 Å compared to approximately 6.26-7.21 Å). It
is worth pointing out that the most energetic conforma-
tion for diastereomer 17a was the γ-turn conformation,
J . Org. Chem, Vol. 68, No. 25, 2003 9547

Ecija et al.
TABLE 4. P er cen ta ges of Con for m er s of th e
molecular dynamic simulations, and the distances found
for NHc‚‚‚OiC were not compatible with the presence of
a hydrogen bond. Nevertheless, the distance values
corresponding to NHc and COi+1 of this conformer
indicated that these atoms established a hydrogen bond
compatible with the presence of a γ-turn (100% of the
population). The supplementary hydrogen bond between
NHa and COi also maintained the distance during the
MD calculation in 85% of the population. The participa-
tion of proton NHc in an intramolecular hydrogen bond
was evidenced by the 1H NMR experiments (NOESY and
temperature coefficients in CDCl3 and in d6-DMSO).
Thus, this result would be in accordance with the fact
that proton NHc in diastereomer II was clearly intramo-
lecularly hydrogen bonded.
As was described above, the absolute configuration of
both diastereomers I and II has not been established so
far. Taking into account that 1H NMR experiments
(NOESY and temperature coefficients in CDCl3 and in
d6-DMSO) evidenced that NHc participated in an in-
tramolecular hydrogen bond in diastereomer II, but not
in I, our molecular modeling results would allow us to
assign the absolute configuration 17b to diastereomer II,
in which there is a hydrogen bond between NHc and
COi+1 stabilizing the formation of a γ-turn. In contrast,
absolute configuration 17a would be assigned to diaste-
reomer I, in which a hydrogen bond between NHc and
COi+1 was not observed.
P seu d op ep tid es Wh ich Exh ibit Differ en t F ea tu r es of â-II
a n d /or γ-Tu r n s fr om 1 n s, 300 K Molecu la r Dyn a m ics
conformer
17a 1
17b1
R(CR-CRi+3) < 7 Å
-90° < τ > +90°
NHc‚‚‚OiC < 2.5 Å
+70° < Φ2 > +85°
-60° < Ψ2 > -70°
NHc‚‚‚Oi+1C < 2.5 Å
NHa‚‚‚OiC < 2.5 Å
NHa‚‚‚Oi+1C < 2.5 Å
ω0 trans/cis
100a
100a
10a
0b
98a
100a
2a
91b
77b
100b
85
8b
1b
90
4
5
100/0
100/0
a
Percentage of conformers with expected values for canonical
b
â turns. Percentage of conformers with expected values for
canonical γ turns.
whereas the most energetic conformation for diastere-
omer 17b was the â-turn conformation. The shorter
distance (5.20 Å) between the center of the lactam ring
and the Leu side chain in 17a 2 could explain the lesser
stability of this γ-turn family with respect to the family
of conformer 17a 1, which defines a â-turn. For the other
diastereomer 17b, the shorter distance between the
center of the lactam ring and the Leu side chain was
observed in the 17b5 family of conformers. In this case,
this corresponded to a â-turn conformation and the γ-turn
conformation was more stable for this diastereomer.
In summary, our Monte Carlo calculations allowed us
to conclude that isomer 17a was a γ-turn/distorted type-
II â-turn structure, whereas isomer 17b was mainly a
γ-turn structure. Moreover, steric hindrance can explain
the different stabilities of both families of conformers.
2. Molecu la r Dyn a m ics Ca lcu la tion s. To study the
dynamic behavior of the most stable family of conforma-
tions of pseudopeptides 17a and 17b, the global minima
conformers of both compounds (17a 1 and 17b1) were
taken as the starting points for molecular dynamics
calculations. We analyzed the geometric â- and γ-turn
diagnosis parameters of the structures generated during
the molecular dynamics simulation for 1 ns at 300 K in
CDCl3 as an explicit solvent (Table 4).
Exp er im en ta l Section
3-(Ben zyloxyca r bon yl)-1-(ter t-bu toxyca r bon yl)-3-(p h e-
n ylsela n yl)p ip er id in -2-on e (3). A solution of LHMDS 1 M
in dry THF (100 mL) was added dropwise to a solution of
N-(tert-butoxycarbonyl)-2-piperidone 2 (8.7 g, 43.6 mmol) in
dry THF (100 mL) under inert atmosphere at -78 °C. The
resulting mixture was stirred at this temperature for 1 h,
benzyl chloroformate (7.9 mL, 52.3 mmol) was added dropwise,
and stirring was continued for 30 min. Next, a solution of
phenylselanyl chloride (10.8 g, 56.7 mmol) in dry THF (80 mL)
was added and stirring at -78 °C was continued for a further
30 min. The mixture was then allowed to warm to room
temperature for 2 h and, after addition of 1 N HCl (200 mL),
was extracted with AcOEt. The combined organic extracts were
washed with aqueous saturated NaHCO3 solution and brine,
dried, and concentrated to furnish a crude product, that after
purification by chromatography (hexane/AcOEt, 9/1) afforded
In the family of conformers 17a 1 all distances R
remained below 7 Å and no major dihedral angle τ
fluctuations with respect to those of the starting struc-
tures were observed for the molecular dynamic simula-
tions. The distances found for NHc‚‚‚OiC were not
compatible with the presence of a hydrogen bond (in-
volved in the formation of the â-turn), which was in
contrast with the starting structure. Although the initial
distances NHc‚‚‚COi and NHa‚‚‚COi+1 of conformer 17a 1
1
piperidone 3 (19.8 g, 93%): IR (NaCl) 1719 cm-1; H NMR δ
1.59 (s, 9 H), 1.65 (m, 1 H), 1.81 (dqn, J ) 14.3, 5.8 Hz, 1 H),
2.00 (ddd, J ) 13.9, 10.1, 5.7 Hz, 1 H), 2.24 (dt, J ) 13.7, 5.5
Hz, 1 H), 3.38 (dt, J ) 13.2, 6.2 Hz, 1 H), 3.60 (ddd, J ) 13.1,
8.2, 5.2 Hz, 1 H), 5.15 and 5.27 (2d, J ) 12.4 Hz, 1 H each),
7.20-7.60 (m, 10 H); 13C NMR δ 20.7, 27.8, 31.6, 45.2, 56.7,
67.6, 83.3, 126.3, 135.1, 127.9, 128.1, 128.3, 128.5, 128.6, 128.8,
129.1, 129.6, 131.3, 138.3, 152.6, 167.6, 169.2; EIMS m/z 489
(M+ + 1, 8), 389 (6), 157 (10), 91 (100), 57 (84); mp (AcOEt)
55-57 °C. Anal. Calcd for C24H27NO5Se: C, 59.02; H, 5.57; N,
2.87. Found: C, 59.28; H, 5.75; N, 2.91.
(Table 3, 1.9 Å for NHc‚‚‚COi and 2.1 Å for NHa‚‚‚COi+1
)
were appropriate for the formation of a hydrogen bond,
most of the conformers found during the MD calculation
did not establish a hydrogen bond while a new hydrogen
bond was established between NHa and COi (Table 4,
90% of the population). This was in agreement with the
3-(Ben zyloxyca r bon yl)-1-(ter t-bu toxyca r bon yl)-5,6-d i-
h yd r op yr id in -2(1H)-on e (4). To a stirred solution of piperi-
done 3 (6.0 g, 13.5 mmol) in dry CH2Cl2 (30 mL) at 0 °C was
added dropwise a solution of m-CPBA (3.7 g, 20.4 mmol, 95.5%)
in dry CH2Cl2 (80 mL). The resulting mixture was stirred at
0 °C for 15 min, then at room temperature for 1 h. The reaction
mixture was then quenched with aqueous saturated NaHCO3
solution (40 mL) and stirred for a further 10 min. The aqueous
layer was extracted several times with CH2Cl2, and the
combined organic extracts were washed with brine, dried, and
1
observation in the H NMR experiments that proton
NHa in both diastereomers was in equilibrium between
a hydrogen-bonded and non-hydrogen-bonded state.
Similarly, in the family of conformers of the other
diastereomer 17b1, all distances R remained below 7 Å,
no major dihedral angle τ fluctuations with respect to
those of the starting structures were shown for the
9548 J . Org. Chem., Vol. 68, No. 25, 2003

Synthesis of 3-Aminolactams
concentrated to afford crude dihydropyridone 4 (4.3 g) that was
used in the next step without further purification: 1H NMR δ
1.52 (s, 9 H), 2.52 (td, J ) 6.3, 4.4 Hz, 2 H), 3.87 (t, J ) 6.2
Hz, 2 H), 5.27 (s, 2 H), 7.25-7.43 (m, 5 H), 7.52 (t, J ) 3.8 Hz,
1H).
for C25H29NO5Se: C, 59.76; H, 5.82; N, 2.79. Found: C, 59.29;
H, 5.89; N, 2.74.
3-(Ben zyloxycar bon yl)-1-[(ter t-bu toxycar bon yl)m eth yl]-
5,6-d ih yd r op yr id in -2(1H)-on e (1). To a solution of piperi-
done 7 (8.9 g, 17.7 mmol) in dry CH2Cl2 (100 mL) at 0 °C was
added dropwise a solution of m-CPBA (4.8 g, 26.6 mmol, 95.5%)
in dry CH2Cl2 (90 mL) under inert atmosphere. The resulting
mixture was stirred at 0 °C for 15 min and at room temper-
ature for 1 h. The reaction was then quenched with aqueous
saturated NaHCO3 solution (50 mL) and stirred for 10 min.
The organic layer was extracted several times with CH2Cl2,
washed with brine, and dried. After evaporation of the solvent,
the resulting crude dihydropyridone 1 (6.9 g) was used in the
next reaction without further purification: IR (NaCl) 1739,
3-(Ben zyloxyca r bon yl)-5,6-d ih yd r op yr id in -2(1H)-on e
(5). To a solution of dihydropyridone 4 (3.5 g, 10.6 mmol) in
dry CH2Cl2 (80 mL) at 0 °C was added dropwise a solution of
TFA (48.5 mL, 0.6 mol), and the resulting mixture was stirred
for 30 min. The reaction was quenched by addition of saturated
aqueous NaHCO3 solution (50 mL) and extracted with CH2-
Cl2. The organic extracts were dried and concentrated to afford
dihydropyridone 5 (2.25 g), which was used in the next step
without further purification: 1H NMR δ 2.50 (td, J ) 6.4, 4.8
Hz, 2 H), 3.43 (td, J ) 6.4, 2.6 Hz, 2 H), 5.27 (s, 2 H), 6.34 (br
s, 1 H), 7.25-7.41 (m, 5 H), 7.50 (t, J ) 4.8 Hz, 1 H).
3-(Ben zyloxyca r bon yl)-3-(p h en ylsela n yl)p ip er id in -2-
on e (6). Meth od A. To a solution of piperidone 3 (2.1 g, 4.1
mmol) in dry CH2Cl2 (10 mL) at 0 °C was added dropwise a
solution of TFA (9.4 mL, 0.12 mol), and the resulting mixture
was stirred for 30 min. The reaction was quenched by addition
of saturated aqueous NaHCO3 solution (7 mL) and extracted
with CH2Cl2. The organic extracts were dried and concentrated
to give a crude product, which was purified by chromatography
(hexane/ AcOEt 4/1) to afford piperidone 6 (1.01 g, 63%) and
3-(ben zyloxyca r bon yl)p ip er id in -2-on e (130 mg, 13%) as a
byproduct.
1
1661 cm-1; H NMR δ 1.47 (s, 9 H), 2.56 (td, J ) 6.8, 4.5 Hz,
2 H), 3.50 (t, J ) 6.9 Hz, 2 H), 4.13 (s, 2 H), 5.26 (s, 2 H),
7.25-7.45 (m, 6 H); 13C NMR δ 24.3, 28.0, 45.8, 48.8, 66.8,
82.0, 128.1, 128.3, 128.5, 128.9, 135.7, 147.3, 161.0, 163.9,
168.2; CIMS m/z 345 (M+, 2), 244 (24), 91 (100).
tr a n s/cis-3-(Ben zyloxyca r bon yl)-1-[(ter t-bu toxyca r bo-
n yl)m et h yl]-4-(3-in d olyl)p ip er id in -2-on e (tr a n s/cis-8a ).
Indole (1.79 g, 15.3 mmol) was added to a solution of dihydro-
pyridone 1 (5.3 g, 15.3 mmol) in dry CH2Cl2 (15 mL) and
Montmorillonite KSF (3.06 g) under inert atmosphere. The
resulting mixture was stirred at room temperature for 1 day.
The clay was then filtered through a Celite pad and the filtrate
was concentrated. The crude product was purified by chroma-
tography (hexane/AcOEt, 9/1) to yield a mixture of diastere-
omers trans/ cis-8a (10:1, 80%). The structure assignment was
made with enriched samples of both diastereomers. trans-8a :
IR (NaCl) 1739, 1733, 1650, 1640, 1634 cm-1; 1H NMR δ 1.46
(s, 9 H), 2.12 (m, 1 H), 2.30 (dq, J ) 13.5 and 4 Hz, 1 H), 3.38
(ddd, J ) 11.7, 5.5, and 4.0 Hz, 1 H), 3.57 (td, J ) 11.5 and
4.5 Hz, 1 H), 3.85 (m, 2 H), 3.86 and 4.26 (2 d, J ) 17.0 Hz, 1
H each), 5.02 and 5.08 (2 d, J ) 12.4 Hz, 1 H each), 6.97 (d, J
) 8.5 Hz, 2 H), 6.98 (d, J ) 2.0 Hz, 1 H), 7.15-7.20 (m, 3 H),
7.09 (t, J ) 8.0 Hz, 1 H), 7.18 (t, J ) 8.0 Hz, 1 H), 7.35 (d, J
) 8.0 Hz, 1 H), 7.57 (d, J ) 8.0 Hz, 1 H), 8.12 (br s, 1 H); 13C
NMR δ 28.0, 29.1, 34.2, 48.1, 49.4, 55.6, 66.7, 82.0, 111.4, 116.0,
118.6, 119.4, 121.2, 122.1, 125.9, 127.5, 127.6, 127.7, 128.0,
128.2, 135.4, 136.3, 166.5, 167.7, 170.1; EIMS m/z 462 (M+,
7), 389 (4), 327 (3), 91 (96), 57 (100). Anal. Calcd for C27H30N2O5‚
1/3H2O: C, 69.66; H, 6.02; N, 6.18. Found: C, 69.16; H, 6.64;
Meth od B. TMSOTf (10 mL, 55.2 mmol) was added drop-
wise to a solution of piperidone 3 (16.4 g, 36.8 mmol) in dry
CH2Cl2 (70 mL) and 2,6-lutidine (8.5 mL, 73.6 mmol) at room
temperature. The resulting mixture was stirred for 15 min and
the reaction was quenched by addition of aqueous saturated
NH4Cl solution (50 mL). The mixture was extracted several
times with Et2O, and the combined organic extracts were
washed with water and brine, dried, and concentrated. The
crude residue obtained was washed repeatedly with Et2O to
yield piperidone 6 as the unique product (10.4 g, 80%): IR
1
(NaCl) 1720, 1656 cm-1; H NMR δ 1.54 (m, 1 H), 1.78 (m, 1
H), 1.94 (ddd, J ) 13.7, 11.9, 3.4 Hz, 1 H), 2.16 (ddd, J ) 13.7,
4.8, 3.7 Hz, 1 H), 3.24 (m, 2 H), 5.23 (s, 2 H), 6.50 (br s, 1 H),
7.22-7.57 (m, 10 H); 13C NMR δ 20.1, 32.0, 41.9, 53.4, 67.4,
126.5, 135.4, 127.9, 128.1, 128.3, 128.6, 129.4, 138.2, 168.6,
170.4; EIMS m/z 389 (M++1, 16), 157 (2), 91 (100), 77 (16), 65
(19). Anal. Calcd for C19H19NO3Se: C, 58.77; H, 4.93; N, 3.61.
Found: C, 58.46; H, 4.97; N, 3.65. 3-(Ben zyloxyca r bon yl)-
p ip er id in -2-on e: IR (NaCl) 1736, 1669 cm-1; 1H NMR δ 1.73
(m, 1 H), 1.88 (m, 1 H), 2.08 (m, 2 H), 3.30 (m, 2 H), 3.43 (t, J
) 7.2 Hz, 1 H), 5.20 (s, 2 H), 7.35 (m, 6 H); 13C NMR δ 20.2,
24.7, 41.9, 48.5, 66.8, 127.9, 128.0, 128.3, 135.5, 167.9, 170.5;
EIMS m/z 233 (M+, 2), 142 (3), 99 (100), 91 (75). Anal. Calcd
for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 67.11;
H, 6.48; N, 6.10.
N, 6.21. cis-8a : IR (NaCl) 1739, 1733, 1650, 1640, 1634 cm-1
;
1H NMR δ 1.49 (s, 9 H), 2.12 (m, 1 H), 2.89 (qd, J ) 12.7 and
5.3 Hz, 1 H), 3.46 (ddd, J ) 11.7, 5.6, and 2.5 Hz, 1 H), 3.66
(td, J ) 11.5 and 5.0 Hz, 1 H), 3.76 and 4.48 (2d, J ) 17.1 Hz,
1 H each), 4.10 (dd, J ) 3.9 and 0.6 Hz, 1 H), 4.69 and 4.76
(2d, J ) 13 Hz, 1 H each), 6.65 (d, J ) 7.2 Hz, 2 H), 6.84 (d,
J ) 2.0 Hz, 1 H), 7.07-7.20 (m, 5 H), 7.57 (d, J ) 7.5 Hz, 1
H), 7.59 (d, J ) 8 Hz, 1 H), 8.02 (br s, 1 H);40 13C NMR δ 24.0,
28.1, 33.4, 48.6, 49.9, 53.4, 66.3, 82.0, 111.3, 114.8, 118.6, 119.6,
121.4, 122.2, 126.3, 127.6, 127.7, 128.0, 128.2, 135.2, 136.0,
166.1, 167.8, 169.5; EIMS m/z 462 (M+•, 7), 389 (4), 327 (3),
91 (96), 57 (100). Anal. Calcd for C27H30N2O5‚1/3H2O: C, 69.66;
H, 6.02; N, 6.18. Found: C, 69.16; H, 6.64; N, 6.21.
3-(Ben zyloxycar bon yl)-1-[(ter t-bu toxycar bon yl)m eth yl]-
3-(p h en ylsela n yl)p ip er id in -2-on e (7). To a solution of pi-
peridone 6 (13 g, 33.5 mmol) in dry CH3CN (150 mL) was
added TBAB (43.2 g, 134 mmol) and K2CO3 (46.3 g, 335 mmol)
at room temperature under inert atmosphere. Then, tert-
butylbromoacetate (7.4 mL, 50.2 mmol) was also added and
the resulting mixture was vigorously stirred for 24 h at the
same temperature. The mixture was filtered and the solvent
was evaporated. Chromatography of the resulting residue
(hexane/AcOEt, 9/1) furnished piperidone 7 (16.3 g, 96%): IR
tr a n s/cis-3-(Ben zyloxyca r bon yl)-1-[(ter t-bu toxyca r bo-
n yl)m eth yl]-4-eth ylp ip er id in -2-on e (tr a n s/cis-8b). A solu-
tion of dihydropyridone 1 (350 mg, 1.01 mmol) in dry THF (2
mL) was added dropwise to a mixture of EtMgBr (1.51 mL,
1.51 mmol) and CuBr‚Me2S (103 mg, 0.5 mmol) in dry THF
(1.5 mL) at -78 °C under inert atmosphere. The mixture was
stirred at this temperature during 15 min, then at 0 °C for 2
h, and finally at room temperature for 1 h. The reaction was
quenched with saturated aqueous NH4Cl solution (2 mL) and
extracted several times with Et2O. The organic extracts were
washed with brine and water, dried, and concentrated. The
resulting residue was purified by chromatography (hexane/
AcOEt, 3/2) to yield a mixture of diastereomers trans/ cis-8b
1
(NaCl) 1739, 1649 cm-1; H NMR δ 1.47 (s, 9 H), 1.63 (m, 1
H), 1.85 (dm, J ) 14 Hz, 1 H), 1.99 (ddd, J ) 13.4, 11.9, 3.6
Hz, 1 H), 2.15 (dt, J ) 13.8, 4.4 Hz, 1 H), 3.27 (ddd, J ) 11.6,
6.2, 4.0 Hz, 1 H), 3.33 (ddd, J ) 11.7, 9.9, 5.3 Hz, 1 H), 3.87
and 4.13 (2d, J ) 17.0 Hz, 1 H each), 5.22 (s, 2 H), 7.20-7.55
(m, 10 H); 13C NMR δ 20.8, 28.0, 32.6, 48.9, 49.9, 53.7, 67.4,
81.9, 127.0, 127.9, 128.0, 128.2, 128.3, 128.5, 129.3, 135.5,
138.3, 166.7, 167.5, 170.3; CIMS m/z 502 (M+, 6), 503 (M+
1, 37), 520 (M+ + 18, 6); mp (hexane) 83-85 °C. Anal. Calcd
+
(40) Proton 4-H could not be assigned because it is masked by
signals corresponding to the major isomer trans-9a .
J . Org. Chem, Vol. 68, No. 25, 2003 9549

Ecija et al.
(6:1, 83%). The structure assignment was made with an
enriched sample of diastereomer trans-8b: IR (NaCl) 1746,
1738, 1731, 1659, 1651, 1644 cm-1; 1H NMR δ 0.90 (t, J ) 7.5
Hz, 3 H), 1.31-1.57 (m, 2 H), 1.45 (s, 9 H), 1.57 (m, 1 H), 2.02
(ddd, J ) 13.5, 7.8, and 4.5 Hz, 1 H), 2.16 (m, 1 H), 3.23 (d, J
) 9.6 Hz, 1 H), 3.38 (m, 2 H), 3.77 and 4.24 (2 d, J ) 16.9 Hz,
1 H each), 5.20 (d, J ) 0.9 Hz, 2 H), 7.36 (m, 5 H); 13C NMR
δ 10.6, 25.8, 26.4, 27.9, 37.7, 47.5, 49.3, 55.2, 66.7, 81.8, 127.9,
128.0, 128.3, 135.6, 166.1, 167.6, 170.3; EIMS m/z 375 (M+,
2), 376 (M+ + 1, 2), 319 (51), 302 (26), 274 (41), 228 (53), 210
for C20H24N2O5: C, 64.50; H, 6.50; N, 7.52. Found: C, 64.13;
H, 6.89; N, 7.64.
tr a n s/cis-[1-[(ter t-Bu toxyca r bon yl)]m eth yl]-4-eth yl-2-
oxopiper idin e-3-car boxylic Acid (tr a n s/cis-9b) an d 1-[(ter t-
Bu t oxyca r b on yl)m et h yl]-4-et h ylp ip er id in -2-on e (10b ).
Operating as above for the preparation of 9a , a mixture of
esters trans/cis-8b (660 mg, 1.76 mmol) in AcOEt (25 mL)
containing 10% Pd-C (250 mg) was hydrogenated at room
temperature for 2 h to yield a diastereomeric mixture of acids
trans/cis-9b (2.8:1, 500 mg) that was used in the next step
without further purification. Piperidone 10b was obtained as
a byproduct when the evaporation of the solvent was done
while heating the water bath of the rotaevaporator. 1H and
13C NMR data were assigned from spectra of a crude sample
of the diastereomeric mixture: IR (NaCl) 3458, 1738, 1650,
1618 cm-1. trans-9b: 1H NMR δ 0.97 (t, J ) 7.2 Hz, 3 H), 1.35
(m, 1 H), 1.47 (s, 9 H), 1.67 (m, 1 H), 2.05 (m, 1 H), 2.29 (m, 1
H), 3.14 (d, J ) 7.8 Hz, 1 H), 3.40 (m, 2 H), 3.83 and 4.23 (2
d, J ) 17.1 Hz, 1 H each), 8.64 (br s, 1 H); 13C NMR δ 10.8,
25.4, 26.5, 27.9, 36.0, 47.4, 49.9, 52.9, 82.3, 167.1, 168.2, 170.8.
cis-9b: 1H NMR δ 0.98 (t, J ) 7.3 Hz, 3 H), 1.35 (m, 1 H),
1.47 (s, 9 H), 1.67 (m, 2 H), 2.05 (m, 1 H), 2.57 (m, 1 H), 3.40
(m, 2 H), 3.53 (td, J ) 12.0 and 5.7 Hz, 1 H), 3.83 and 4.18 (2
d, J ) 17.2 Hz, 1 H each), 8.64 (br s, 1 H); 13C NMR δ 11.5,
20.8, 23.9, 27.9, 35.0, 46.5, 49.7, 48.9, 82.6, 166.8, 169.6, 171.1;
EIMS m/z 270 (1), 185 (21), 140 (39), 112 (35), 57 (100). 10b:
(34), 184 (32), 166 (98), 91 (100), 57 (57). Anal. Calcd for C21H29
-
NO5: C, 67.18; H, 7.78; N, 3.73. Found: C, 67.21; H, 7.75; N,
3.69.
tr a n s/cis-3-(Ben zyloxyca r bon yl)-1-[(ter t-bu toxyca r bo-
n yl)m eth yl]-4-p h en ylp ip er id in -2-on e (tr a n s/cis-8c). Op-
erating as above for the preparation of 8b, from dihydropyri-
done 1 (1.05 g, 3.04 mmol) in dry THF (6 mL) and a mixture
of PhMgBr (3.04 mL, 3.04 mmol) and CuBr‚Me2S (312 mg, 1.52
mmol) in dry THF (4.5 mL), a diastereomeric mixture of trans/
cis-8c (13:1, 77%) was obtained after purification by chroma-
tography (hexane/AcOEt, 3/2). The structure assignment was
made with an enriched sample of diastereomer trans-8c: IR
(NaCl) 1740 and 1650 cm-1; 1H NMR δ 1.47 (s, 9 H), 2.11 (m,
2 H), 3.43 (ddd, J ) 11.8, 4.9, and 2.7 Hz, 1 H and td, J ) 11.5
and 3.7 Hz, 1 H), 3. 59 (td, J ) 11.4 and 5.4 Hz, 1 H), 3. 67 (d,
J ) 11.1 Hz, 1 H), 3.91 and 4.21 (2 d, J ) 17.1 Hz, 1 H each),
4.99 and 5.07 (2 d, J ) 12.4 Hz, 1 H each), 7.03-7.28 (m, 10
H); 13C NMR δ 28.0, 29.4, 42.6, 48.1, 49.1, 56.4, 66.5, 81.9,
126.7, 127.2, 127.6, 127.7, 128.1, 128.7, 135.4, 141.0, 166.0,
167.5, 169.3; EIMS m/z 423 (M+, 3), 367 (53), 322 (31), 276
1
IR (NaCl) 1742, 1651 cm-1; H NMR δ 0.93 (t, J ) 7.2 Hz, 3
H), 1.37 (qn, J ) 7.2 Hz, 2 H), 1.47 (s, 9 H), 1.55 (m, 1 H), 1.78
(m, 1 H), 1.93 (dm, J ) 12.9 Hz, 1 H), 2.03 (dd, J ) 17.4 and
10.8 Hz, 1 H), 2.56 (ddd, J ) 17.4, 4.9, and 1.8 Hz, 1 H), 3.31
(m, 1 H), 3.37 (qd, J ) 11.4 and 4.8 Hz, 1 H), 3.95 and 4.06 (2
d, J ) 17.1 Hz, 1 H each); 13C NMR δ 11.0, 28.0, 28.2, 28.6,
(63), 232 (38), 214 (86), 91 (100), 57 (59). Anal. Calcd for C25H29
-
NO5‚1/15H2O: C, 70.45; H, 6.93; N, 3.29. Found: C, 70.09; H,
6.87; N, 3.29.
34.6, 38.1, 48.1, 49.0, 81.7, 168.1, 170.2; EIMS m/z 242 (M+
+
1, 1), 185 (24), 168 (16), 140 (45), 112 (38), 57 (100).
tr a n s/cis-3-(Ben zyloxyca r bon yl)-1-[(ter t-bu toxyca r bo-
n yl)m eth yl]-4-cya n op ip er id in -2-on e (tr a n s/cis-8d ). NH4-
Cl (116 mg, 2.17 mmol) and a solution of KCN (189 mg, 2.9
mmol) in H2O (1.5 mL) were added to a solution of dihydro-
pyridone 1 (0.5 g, 1.45 mmol) in DMF (12 mL). The resulting
reaction mixture was stirred at 90 °C for 20 min. Then, H2O
(10 mL) was added and the aqueous phase was extracted
several times with AcOEt. The organic extracts were washed
with brine, dried, and concentrated to give a residue that after
purification by chromatography (hexane/AcOEt, 4/1) yielded
a diastereomeric mixture of trans/ cis-8d (5:1, 83%). The
structure assignment was made with an enriched sample of
diastereomer trans-8d : IR (NaCl) 2245, 1744, 1666, 1650, 1644
tr a n s-1-[(ter t-Bu t oxyca r b on yl)m et h yl]- 2-oxo-4-p h e-
n ylp ip er id in -3-ca r boxylic Acid (tr a n s-9c) a n d 1-[(ter t-
Bu toxyca r bon yl)m eth yl]-4-p h en ylp ip er id in -2-on e (10c).
Operating as above for the preparation of 9a , a mixture of
esters trans/cis-8c (831 mg, 1.96 mmol) in AcOEt (35 mL)
containing 10% Pd-C (300 mg) was hydrogenated at room
temperature for 4 h to yield acid trans-9c (570 mg) as the
unique diastereomer, which was used directly in the next step
without further purification. Piperidone 10c was obtained as
a byproduct when the evaporation of the solvent was done
while heating the water bath of the rotaevaporator. NMR
experiments were performed with a crude sample of trans-9c:
IR (KBr) 3432, 1740, 1604 cm-1; 1H NMR δ 1.49 (s, 9 H), 2.11
(m, 2 H), 3.39 (dt, J ) 12.6 and 4.8 Hz, 1 H), 3.52 (ddd, J )
12.1, 8.4, and 5.1 Hz, 1 H), 3.68 (m, 2 H), 3.96 and 4.22 (2 d,
J ) 16.8 Hz, 1 H each), 7.27-7.36 (m, 5 H), 7.34 (tt, J ) 7.5
and 1.2 Hz, 2 H); 13C NMR δ 27.9, 29.4, 41.1, 47.8, 49.8, 53.8,
82.4, 126.9, 127.1, 128.7, 141.6, 167.1, 167.8, 170.2; EIMS m/z
289 (1), 233 (33), 188 (29), 91 (20), 57 (100). 10c: IR (NaCl)
1740, 1650 cm-1; 1H NMR δ 1.48 (s, 9 H), 1.96-2.14 (m, 2 H),
2.52 (dd, J ) 17.4 and 11.4 Hz, 1 H), 2.75 (ddd, J ) 17.5, 5.1,
and 2.0 Hz, 1 H), 3.14 (m, 1 H), 3.36 (ddd, J ) 11.7, 5.1, and
3.3 Hz, 1 H), 3.53 (td, J ) 11.1 and 5.1 Hz, 1 H), 3.94 and 4.17
(2 d, J ) 17.1 Hz, 1 H each), 7.19-7.35 (m, 5 H); 13C NMR δ
27.9, 30.1, 38.6, 39.1, 48.1, 48.8, 81.7, 126.3, 126.6, 128.5, 143.2,
167.9, 169.5; EIMS m/z 289 (M+, 2), 233 (82), 188 (59), 91 (22),
57 (100).
1-[(ter t-Bu t oxyca r b on yl)m et h yl]-4-cya n op ip er id in -2-
on e (10d ). Operating as above for the preparation of 9a , a
mixture of esters trans/cis-8d (300 mg, 0.8 mmol) in AcOEt
(14 mL) containing 10% Pd-C (120 mg) was hydrogenated at
room temperature for 1 night to yield cyanopiperidine 10d (117
mg, 61%) after purification by chromatography (hexane/AcOEt,
4/1). Starting ester 8d (60 mg) was also recovered. 10d : IR
(NaCl) 2241, 1738, 1652 cm-1; 1H NMR δ 1.47 (s, 9 H), 2.09-
2.28 (m, 2 H), 2.70 (dd, J ) 17.5 and 7.8 Hz, 1 H), 2.76 (dd, J
) 17.4 and 6 Hz, 1 H), 3.14 (tdd, J ) 8.2, 6.0, and 3.6 Hz, 1
H), 3.41-3.57 (m, 2 H), 3.84 and 4.18 (2 d, J ) 17.2 Hz, 1 H
1
cm.-1; H NMR δ 1.46 (s, 9 H), 2.18 (m, 1 H), 2.35 (ddd, J )
14.1, 8.7, and 5.2 Hz, 1 H), 3.51 (m, 3 H), 3.72 (d, J ) 8.4 Hz,
1 H), 3.97 and 4.05 (2 d, J ) 17.1 Hz, 1 H each), 5.26 (s, 2 H),
7.31-7.40 (m, 5 H); 13C NMR δ 24.5, 27.7, 27.9, 46.4, 49.4,
50.9, 67.9, 82.4, 118.4, 128.0, 128.3, 128.5, 134.8, 162.5, 166.9,
167.3; EIMS m/z 299 (6), 271 (10), 181 (16), 91 (100), 57 (97);
mp (hexane/AcOEt 3/2) 114-115 °C. Anal. Calcd for C20H24
-
N2O5: C, 64.50; H, 6.50; N, 7.52. Found: C, 64.85; H, 6.54; N,
7.39.
tr a n s/cis-1-[(ter t-Bu toxycar bon yl)m eth yl]-4-(3-in dolyl)-
2-oxop ip er id in e-3-ca r boxylic Acid (tr a n s/cis-9a ). A mix-
ture of esters trans/cis-8a (10:1, 5.3 g, 11.5 mmol) in MeOH
(40 mL) containing 10% Pd-C (2 g) was hydrogenated at room
temperature for 36 h. The resulting crude product was filtered
through a Celite pad and the solvent was evaporated to furnish
quantitatively a diastereomeric mixture of acids trans/cis-9a ,
which was used directly in the next step without further
purification. An analytical sample of acids trans/cis-9a was
obtained by chromatography (hexane): IR (NaCl) 3357, 1737,
1
1636, 1631 cm-1; H NMR δ 1.47 (s, 18 H), 2.07-2.39 (m, 4
H), 3.37 (m, 4 H), 3.80-4.42 (m, 8 H), 7.10-7.81 (m, 10 H),
8.25 (br s, 4 H); 13C NMR δ 23.2 and 27.9, 27.9, 31.2 and 32.6,
47.5 and 47.7, 49.9, 47.8 and 57.7, 82.4 and 82.6, 111.6, 112.1
and 115.4, 118.4, 119.1, 119.2 and 121.1, 120.5 and 121.8, 125.8
and 126.1, 136.4, 166.9, 167.5, 168.1, 169.0 and 171.3; EIMS
m/z 328 (33), 272 (68), 156 (35), 84 (23), 57 (100). Anal. Calcd
9550 J . Org. Chem., Vol. 68, No. 25, 2003

Synthesis of 3-Aminolactams
each); 13C NMR δ 24.3, 25.9, 27.9, 34.1, 46.2, 48.9, 82.1, 119.7,
165.7, 167.4; EIMS m/z 182 (11), 165 (1), 137 (34), 109 (21),
57 (100).
obtained as the unique product after purification by chroma-
tography (hexane/AcOEt, 4/1): IR (NaCl) 3318, 1733, 1652
cm-1; 1H NMR δ 1.48 (s, 9 H), 2.14 (m, 1 H), 2.25 (qd, J ) 11.7
and 5.7 Hz, 1 H), 3.27 (br t, J ) 11.7 Hz, 1 H), 3.39 (m, 1 H),
3.58 (m, 1 H), 4.04 (s, 2 H), 4.29 (t, J ) 10.3 Hz, 1 H), 4.99 (s,
2 H), 5.17 (d, J ) 8.4 Hz, 1 H), 7.18-7.30 (m, 10 H); 13C NMR
δ 28.0, 30.0, 44.5, 47.9, 49.4, 57.2, 66.5, 82.0, 127.0, 127.2,
127.6, 127.7, 128.2, 128.5, 136.4, 141.2, 156.3, 167.9, 169.3;
EIMS m/z 382 (2), 337 (2), 247 (7), 91 (100), 57 (74). Anal. Calcd
for C25H30N2O5‚1/5H2O: C, 67.92; H, 6.93; N, 6.34. Found: C,
67.44; H, 6.87; N, 6.65.
tr a n s-3-[(Ben zyloxyca r b on yl)a m in o]-1-[(ter t-b u t oxy-
ca r b on yl)m et h yl]-4-(3-in d olyl)p ip er id in -2-on e (tr a n s-
11a ). To a solution of trans/cis-9a (1 g, 2.7 mmol) in dry
benzene (15 mL) at room temperature was added Et3N (0.94
mL, 6.7 mmol) and DPPA (1.48 mL, 6.7 mmol), and the
mixture was stirred for 3.5 h at 50 °C. After the mixture was
cooled to room temperature, dry BnOH (0.7 mL, 6.7 mmol)
and dibutyltin dilaurate (0.16 mL, 0.26 mmol) were added and
stirring at 80 °C was continued for 4 h. The reaction was then
cooled to room temperature and diluted with Et2O (70 mL).
The resulting solution was washed with water and brine, and
the organic layer was dried and concentrated. The crude
residue was washed several times with Et2O to yield trans-
11a (678 mg, 53%) as the unique diastereomer: IR (NaCl)
3401, 1735, 1725, 1648 cm-1; 1H NMR δ 1.49 (s, 9 H), 2.22 (m,
2 H), 3.33 (dt, J ) 14.3 and 4.8 Hz, 1 H), 3.58 (m, 2 H), 4.07
(s, 2 H), 4.37 (dd, J ) 11.1 and 9.0 Hz, 1 H), 4.86 and 4.95 (2
d, J ) 12 4 Hz, 1 H each), 5.28 (d, J ) 8.4 Hz, 1 H), 7.00 (s, 1
H), 7.05 (t, J ) 7.8 Hz, 1 H), 7.11 (m, 2 H), 7.16 (t, J ) 6.9 Hz,
1 H), 7.23 (m, 3 H), 7.34 (d, J ) 7.8 Hz, 1 H), 7.51 (d, J ) 7.8
Hz, 1 H), 8.55 (br s, 1 H); 13C NMR δ 28.1, 29.9, 36.1, 48.0,
49.6, 57.2, 66.6, 82.1, 111.4, 116.3, 118.4, 119.3, 121.1, 121.8,
126.6, 127.7, 128.2, 136.1 136.3, 156.6, 168.1, 169.5; CIMS m/z
478 (M+ + 1, 30), 495 (M+ + 18, 3). Anal. Calcd for
tr a n s-3-Am in o-1-[(ter t-b u t oxyca r b on yl)m et h yl]-4-(3-
in d olyl)p ip er id in -2-on e (tr a n s-12a ). A solution of carbam-
ate trans-11a (2.2 g, 1.13 mmol) in MeOH (100 mL) containing
10% Pd-C (0.8 g) was hydrogenated at room temperature
overnight. The resulting mixture was then filtered through a
Celite pad and the solvent was evaporated. The crude product
was dissolved in CH2Cl2, washed with an aqueous saturated
solution of NaHCO3, and extracted several times with CH2-
Cl2. The organic layer was dried and concentrated to yield
3-aminopiperidone trans-12a (1.4 g). An analytical sample was
obtained by crystallization from dry Et2O: IR (NaCl) 3303,
1
1739, 1650 cm-1; H NMR δ 1.49 (s, 9 H), 2.17 (m, 3 H), 2.29
(qd, J ) 13.8 and 5.7 Hz, 1 H), 3.24 (td, J ) 11.4 and 2.8 Hz,
1 H), 3.37 (ddd, J ) 11.8, 5.7, and 2.5 Hz, 1 H), 3.57 (td, J )
11.4 and 4.5 Hz, 1 H), 3.76 (d, J ) 10.8 Hz, 1 H), 3.97 and
4.15 (2 d, J ) 17.1 Hz, 1 H each), 6.99 (s, 1 H), 7.08 (t, J ) 7.3
Hz, 1 H), 7.17 (t, J ) 7.3 Hz, 1 H), 7.37 (d, J ) 8.1 Hz, 1 H),
7.63 (d, J ) 7.8 Hz, 1 H), 8.98 (br s, 1 H); 13C NMR δ 27.9,
28.7, 38.6, 48.4, 49.3, 56.8, 81.9, 111.6, 115.9, 118.6, 118.9,
121.5, 121.7, 125.9, 136.4, 167.9, 171.9; CIMS m/z 343 (M+,
5), 344 (M+ + 1, 16), 372 (M+ + 29, 2); HRMS calcd for
C
27H31N3O5: C, 67.91; H, 6.54; N, 8.8. Found: C, 67.68; H,
6.57; N, 9.1.
tr a n s/cis-3-[(Ben zyloxyca r b on yl)a m in o]-1-[(ter t-b u -
toxyca r bon yl)m eth yl]-4-eth ylp ip er id in -2-on e (tr a n s/cis-
11b). Operating as above for the preparation of 11a , from acids
trans/cis-9b (450 mg, 1.6 mmol) in dry benzene (14 mL), Et3N
(0.5 mL, 3.9 mmol), DPPA (0.88 mL, 3.9 mmol), dry BnOH
(0.41 mL, 3.9 mmol), and dibutyltin dilaurate (0.10 mL, 0.16
mmol) compounds trans- and cis-11b (321 mg and 82 mg
respectively, 65%) were obtained after purification by chro-
matography (hexane/AcOEt, 4/1). trans-11b: IR (NaCl) 3304,
1728, 1662, 1650 cm-1; 1H NMR (500 MHz) δ 0.93 (t, 3 H, J )
7.3 Hz), 1.26 (qnd, 1 H, J ) 6.5 and 1.5 Hz), 1.43 (s, 9 H),
1.61-1.76 (m, 3 H), 2.05 (m, 1 H), 3.31 (ddd, J ) 11.7, 5.5,
and 3.5 Hz, 1 H), 3.37 (m, 1 H), 3.96 (t, J ) 10.0 Hz, 1 H), 3.79
and 4.11, and 3.83 and 4.09 (4 d, J ) 17.0 Hz, 1 H each two
d),41 5.1 (s, 2 H), 5.15 and 5.52 (d, J ) 8.2 Hz; 1 H), 7.23-7.33
(m, 5 H); 13C NMR41 δ 10.2 and 10.3, 24.9, 25.9 and 26.0, 27.8,
39.3 and 39.8, 47.3, 49.2, 56.1 and 56.3, 66.5, 81.6 and 81.7,
127.6 and 128.1, 136.2, 156.8 and 156.9, 167.6 and 167.7, 168.8
and 169.6; EIMS m/z 390 (M+, 1), 334 (8), 289 (8), 199 (21), 91
(100), 57 (50). Anal. Calcd for C21H30N2O5: C, 67.91; H, 6.54;
N, 8.8. Found: C, 67.68; H, 6.57; N, 9.1. cis-11b: IR (NaCl)
C
19H25N3O3 343.1896, found 343.1898.
tr a n s-3-Am in o-1-[(ter t-bu toxyca r bon yl)m eth yl]-4-eth -
ylp ip er id in -2-on e (tr a n s-12b). Operating as above for the
preparation of trans-12a , a solution of carbamate trans-11b
(216 mg, 0.55 mmol) in AcOEt (25 mL) containing 10% Pd-C
(86 mg) was hydrogenated at room temperature for 4 h. The
resulting crude product was purified by washing with hexane
and dry Et2O to yield 3-aminopiperidone trans-12b (90 mg,
1
63%): IR (NaCl) 3301, 1740, 1649 cm-1; H NMR δ 0.95 (t, 3
H, J ) 7.2 Hz), 1.25 (m, 1 H), 1.46 (s, 9 H), 1.61 (m, 2 H), 1.86
(m, 1 H), 1.99 (m, 1 H), 2.10 (br s, 2 H, NH2), 3.07 (d, J ) 9.9
Hz, 1 H), 3.30 (ddd, J ) 11.5, 5.4 ,and 3.0 Hz, 1 H), 3.38 (td,
J ) 11.1 and 4.8 Hz, 1 H), 3.98 (s, 2 H); 13C NMR δ 10.4, 25.4,
25.7, 28.0, 41.4, 47.9, 49.4, 56.3, 81.8, 167.9, 172.8; EIMS m/z
256 (M+, 1), 239 (8), 211 (1), 183 (7), 155 (5), 127 (9), 111 (16),
97 (34), 57 (100).
tr a n s-3-Am in o-1-[(ter t-bu toxyca r bon yl)m eth yl]-4-p h e-
n ylp ip er id in -2-on e (tr a n s-12c). Operating as above for the
preparation of trans-12a , a solution of carbamate trans-12c
(438 mg, 0.99 mmol) in AcOEt (40 mL) containing 10% Pd-C
(175 mg) was hydrogenated at room temperature overnight
to yield trans-12c (227 mg). The resulting product was used
directly in the next step without further purification. An
analytical sample was obtained when the crude product was
treated with 1 N HCl and extracted with CH2Cl2. Then the
aqueous layer was quenched with solid NaHCO3 and extracted
with CH2Cl2, and the combined organic extracts were dried
and concentrated to furnish pure trans-12c: IR (NaCl) 3380,
3317, 1739, 1650 cm-1; 1H NMR δ 1.49 (s, 9 H), 1.84 (m, 2 H),
2.06 (m, 1 H), 2.23 (qd, J ) 13.4 and 4.8 Hz, 1 H), 2.93 (br t,
J ) 10.5 Hz, 1 H), 3.39 (ddd, J ) 11.8, 5.7, and 1.8 Hz, 1 H),
3.59 (td, J ) 11.7 and 4.8 Hz, 1 H), 3.59 (d, J ) 11.7 Hz, 1 H),
3.97 and 4.11 (2 d, J ) 17.1 Hz, 1 H each), 7.25-7.38 (m, 5
H); 13C NMR δ 28.1, 29.2, 47.0, 48.4, 49.3, 57.1, 81.9, 127.0,
128.8, 142.2, 167.9, 171.8; EIMS m/z 304 (M+, 6), 287 (5), 231
(20), 203 (8), 91 (24), 77 (8), 57 (100). Anal. Calcd for
1
3397, 1728, 1662, 1650 cm-1; H NMR (500 MHz) δ 0.91 (t, J
) 7.5 Hz, 3 H), 1.25 (m, 1 H), 1.43 (s, 9 H), 1.56 (m, 1 H), 1.93
(m, 1 H), 2.03 (m, 1 H), 2.41 (m, 1 H), 3.24 (ddd, J ) 12.0, 6.5,
and 3.5 Hz, 1 H), 3.41 (td, J ) 11.1 and 6.0 Hz, 1 H), 3.59 and
4.22 (2d, J ) 17.2 Hz, 1 H each), 4.30 (t, J ) 5.0 Hz, 1 H), 5.06
and 5.09 (2 d, J ) 12.2 Hz, 1 H each), 5.80 (d, J ) 4.0 Hz, 1
H), 7.27-7.34 (m, 5 H); 13C NMR δ 11.5, 18.6, 23.5, 28.1, 36.3,
45.3, 49.6, 55.8, 66.6, 82.0, 127.8, 127.9, 128.4, 136.4, 156.0,
167.6, 169.1; EIMS m/z 390 (M+, 3), 334 (24), 317 (9), 289 (18),
243 (11), 227 (8), 199 (36), 91 (100), 57 (60); HRMS calcd for
C
21H30N2O5 390.2155, found 390.2138.
tr a n s-3-[(Ben zyloxyca r b on yl)a m in o]-1-[(ter t-b u t oxy-
ca r bon yl)m eth yl]-4-p h en ylp ip er id in -2-on e (tr a n s-11c).
Operating as above for the preparation of trans-11a , from acids
trans/cis-9c (570 mg, 1.71 mmol) in dry benzene (18 mL), Et3N
(0.59 mL, 4.27 mmol), DPPA (0.95 mL, 4.27 mmol), and then
dry BnOH (0.44 mL, 4.27 mmol) and dibutyltin dilaurate (0.10
mL, 0.16 mmol) piperidone trans-11c (560 mg, 68%) was
C
17H24N2O3‚1/10H2O: C, 66.69; H, 7.97; N, 9.15. Found: C,
66.34; H, 7.92; N, 9.00.
(41) Splitting of this signal and of the majority of signals in the 13C
NMR spectra indicated the presence of rotamers. This fact was not
observed for the cis isomer.
tr a n s-1-[(ter t-Bu toxycar bon yl)m eth yl]-3-{[(9-flu or en yl)-
m et h oxyca r b on yl]a m in o}-4-(3-in d olyl)p ip er id in -2-on e
J . Org. Chem, Vol. 68, No. 25, 2003 9551

Ecija et al.
(tr a n s-13a ). To a mixture of 3-aminopiperidone trans-12a (300
mg, 0.87 mmol) and NaHCO3 (109 mg, 1.3 mmol) in acetone
(12 mL) was added Fmoc-OSu (438 mg, 1.3 mmol). The
resulting mixture was stirred overnight at room temperature.
Then the solvent was evaporated and the residue was dissolved
in CH2Cl2. The organic layer was washed with aqueous 0.1 N
HCl solution and water, dried, and concentrated to yield
piperidone trans-13a (312 mg, 63%) after purification by
chromatography (hexane/AcOEt, 7/3): IR (NaCl) 3415, 1747,
1725, 1618 cm-1; 1H NMR (500 MHz) δ 1.49 (s, 9 H), 2.18 (m,
1 H), 2.26 (m, 1 H), 3.40 (m, 1 H), 3.63 (m, 2 H), 3.97 and 4.57
(2 d, J ) 17.0 Hz, 1 H each), 4.03-4.15 (m, 3 H), 4.41 (t, J )
9.5 Hz, 1 H), 5.23 (d, J ) 7.5 Hz, 1 H), 7.01 (t, J ) 7.5 Hz, 1
H), 7.04 (s, 1 H), 7.09 (d, J ) 8.0 Hz, 1 H), 7.11 (d, J ) 8.0 Hz,
2 H), 7.26 (d, J ) 7.0 Hz, 2 H), 7.27 (d, J ) 8.0 Hz, 1 H), 7.33
(d, J ) 8.0 Hz, 1 H), 7.37 (d, J ) 7.5 Hz, 1 H), 7.52 (d, J ) 7.0
Hz, 1 H), 7.63 (d, J ) 7.5 Hz, 2 H), 8.15 (br s, 1 H); 13C NMR
δ 27.9, 29.7, 35.9, 46.8, 47.9, 49.5, 57.2, 66.8, 81.9, 111.5, 116.0,
118.3, 119.1, 119.6, 121.1, 121.7, 125.1, 126.5, 126.8, 127.3,
136.1, 140.9, 143.7, 143.8, 156.6, 168.1, 169.5; EIMS m/z 179
(100). Anal. Calcd for C34H35N3O5‚1/5H2O: C, 71.74; H, 6.27;
N, 7.38. Found: C, 71.44; H, 6.50; N, 7.66.
tr a n s-1-[(ter t-Bu t oxyca r b on yl)m et h yl]-4-et h yl-3-{[(9-
fluorenyl)methoxycarbonyl]amino}-piperidin-2-one (tra ns-
13b). Operating as above for the preparation of trans-13a , from
aminopiperidone trans-12b (90 mg, 0.35 mmol) and NaHCO3
(44 mg, 0.52 mmol) in acetone:H2O (5 mL, 4:1), and then Fmoc-
OSu (175 mg, 0.52 mmol), piperidone trans-13b (103 mg, 61%)
was obtained after purification by chromatography (hexane/
AcOEt, 4/1): IR (NaCl) 3316, 1727, 1654 cm-1; 1H NMR δ 0.91
(m, 3 H), 1.25 (m, 1 H), 1.46 (s, 9 H), 1.67-1.87 (m, 3 H), 2.06
(m, 1 H), 3.37 (m, 2 H), 3.98 (t, J ) 9.9 Hz, 1 H), 3.85 and 4.13
(2 d, J ) 17.1 Hz, 1 H each), 4.24 (t, J ) 7.2 Hz, 1 H), 4.38
(dd, J ) 7.5 and 2.4 Hz, 2 H), 5.24 and 5.32 (2 d, J ) 9.3 and
8.4 Hz, 1 H), 7.30 (td, J ) 7.3 and 1.0 Hz, 2 H), 7.39 (d, J )
7.2 Hz, 2 H), 7.62 (t, J ) 6.7 Hz, 2 H), 7.75 (d, J ) 7.5 Hz, 2
H); 13C NMR δ 10.5, 25.0, 26.1, 27.9, 40.1, 47.0, 47.4, 49.4,
56.4, 66.8, 81.8, 119.6, 125.0, 126.8, 127.4, 127.7, 128.2, 141.0,
143.6, 143.9, 157.0, 167.8, 169.7; EIMS m/z 256 (5), 239 (9),
200 (4), 178 (100), 152 (22), 127 (42), 98 (61), 84 (47), 57 (83);
HRMS calcd for C28H34N2O5 478.2468, found 478.2482.
for C30H27N3O5‚1/2H2O: C, 69.49; H, 5.44; N, 8.10. Found: C,
69.10; H, 5.71; N, 8.06.
tr a n s-3-{[(9-Flu or en yl)m eth oxycar bon yl]am in o}-4-eth -
yl-2-oxop ip er id in e-1-a cetic Acid (tr a n s-14b). A solution of
piperidone trans-13b (50 mg, 0.1 mmol) in TFA-CH2Cl2 (10%,
2 mL) was stirred at room temperature overnight. The solvent
was then evaporated and the resulting residue was dissolved
in CH2Cl2. The organic solution was washed with 5% NaHCO3,
acidified with 1 N HCl, and extracted with CH2Cl2. The
combined organic extracts were dried and concentrated to yield
acid trans-14b (16 mg, 36%): IR (NaCl) 3319, 1723, 1650 cm-1
;
1H NMR δ 0.94 (t, J ) 6.9 Hz, 3 H), 1.25 (m, 1 H), 1.63-1.85
(m, 3 H), 2.08 (m, 1 H), 3.36 (m, 1 H), 3.57 (m, 1 H), 3.70 and
4.37 (2 d, J ) 17.8 Hz, 1 H each), 4.05 (t, J ) 10.2 Hz, 1 H),
4.24 (t, J ) 7.0 Hz, 1 H), 4.36 (d, J ) 7.8 Hz, 2 H), 6.12 (d, J
) 9.6 Hz, 1 H), 7.29 (td, J ) 7.2 and 0.9 Hz, 2 H), 7.39 (t, J )
6.9 Hz, 1 H), 7.62 (t, J ) 6.9 Hz, 2 H), 7.75 (d, J ) 7.5 Hz, 2
H); 13C NMR δ 10.5, 25.0, 26.2, 39.8, 47.1, 48.8, 50.2, 56.4,
67.0, 119.8, 125.2, 126.9, 127.5, 141.1, 143.8, 143.9, 157.4,
171.3, 172.0; EIMS m/z 196 (17), 178 (100), 165 (56). Anal.
Calcd for C24H26N2O5‚1/5TFA: C, 65.82; H, 5.93; N, 6.29.
Found: C, 65.35; H, 6.28; N, 6.12.
t r a n s-3-{[(9-F lu or e n yl)m e t h oxyca r b on yl]a m in o}-4-
p h en yl-2-oxop ip er id in e-1-a cetic Acid (tr a n s-14c). Operat-
ing as above for the preparation of trans-14b, from piperidone
trans-13c (50 mg, 0.09 mmol) and TFA-CH2Cl2 (10%, 2 mL)
carboxylic acid trans-14c (45 mg, quantitative) was obtained:
IR (NaCl) 3323, 1722, 1643 cm-1 1H NMR δ 2.13 (m, 1 H),
;
2.24 (m, 1 H), 3.27 (m, 1 H), 3.66 (m, 1 H), 3.78 (m, 1 H), 3.92
and 4.24 (2 d, J ) 17.1 Hz, 1 H each), 4.27-4.38 (m, 2 H),
4.98 (s, 2 H), 5.69 and 5.83 (2 d, J ) 8.7 Hz, 1 H),42 7.17-7.31
(m, 12 H), 7.72 (d, J ) 7.8 Hz, 1 H); 13C NMR δ 29.7, 44.3,
47.1, 48.2, 48.3, 56.9, 66.4, 119.6, 125.0, 127.0, 127.1, 127.4,
127.6, 128.2, 128.5, 136.3, 141.7, 143.7, 156.5, 170.1; EIMS
m/z 248 (2), 196 (18), 178 (100), 165 (63), 57 (16).
tr a n s-3-Aceta m id o-1-[(ter t-bu toxyca r bon yl)m eth yl]-4-
(3-in d olyl)p ip er id in -2-on e (tr a n s-15). To a solution of ami-
nopiperidone trans-12a (200 mg, 0.58 mmol) in dry CH2Cl2 (0.4
mL), under inert atmosphere at room temperature, was added
pyridine (62 µL, 0.87 mmol) and AcCl (93 µL, 1.16 mmol). The
resulting mixture was stirred for 3 h and 0.1 N HCl was then
added. The organic layer was washed with aqueous saturated
NaHCO3 solution and brine, dried, and concentrated to yield
3-acetamidopiperidone trans-15 (190 mg, 85%): IR (KBr) 3448,
tr a n s-1-[(ter t-Bu toxycar bon yl)m eth yl]-3-{[(9-flu or en yl)-
m eth oxycar bon yl]am in o}-4-ph en ylpiper idin -2-on e (tr a n s-
13c). Operating as above for the preparation of trans-13a , from
aminopiperidone trans-12c (227 mg, 0.74 mmol) and NaHCO3
(93 mg, 1.11 mmol) in acetone:H2O (5 mL, 4:1), and then Fmoc-
OSu (374 mg, 1.11 mmol), trans-13c (157 mg, 30% from trans-
11c) was obtained after purification by chromatography
1
3289, 1741, 1640 cm-1; H NMR δ 1.49 (s, 9 H), 1.77 (s, 3 H),
2.16 (qd, J ) 11.4 and 5.6 Hz, 1 H), 2.34 (dm, J ) 10.5 Hz, 1
H), 3.37 (ddd, J ) 11.7, 5.4, and 2.7 Hz, 1 H), 3.60 (td, J )
11.5 and 3.6 Hz, 1 H), 3.66 (td, J ) 11.7 and 3.8 Hz, 1 H), 3.97
and 4.16 (2 d, J ) 17.1 Hz, 1 H each), 4.71 (dd, J ) 11.4 and
9.0 Hz, 1 H), 6.01 (d, J ) 9.3 Hz, 1 H), 7.09 (t, J ) 7.5 Hz, 1
H), 7.15 (s, 1 H), 7.18 (t, J ) 6.9 Hz, 1 H), 7.37 (d, J ) 8.1 Hz,
1 H), 7.53 (d, J ) 7.8 Hz, 1 H), 8.62 (br s, 1 H); 13C NMR δ
22.9, 28.1, 30.2, 36.0, 48.0, 49.6, 55.2, 82.1, 111.6, 116.2, 118.2,
119.2, 121.1, 121.8, 126.6, 136.2, 168.2, 169.6, 170.9; CIMS
m/z 385 (M+, 100), 386 (M+ + 1, 25), 403 (M+ + 18, 1). Anal.
Calcd for C21H27N3O4: C, 65.44; H, 7.06; N, 10.90. Found: C,
65.11; H, 7.10; N, 10.85.
(hexane/AcOEt, 4/1): IR (NaCl) 3321, 1734, 1655 cm-1 1H
;
NMR δ 1.48 (s, 9 H), 2.16 (m, 1 H), 2.27 (m, 1 H), 3.32 (m, 1
H), 3.39 (m, 1 H), 3.62 (m, 1 H), 4.06 (s, 2 H), 4.15 (d, J ) 6.9
Hz, 1 H), 4.22-4.28 (m, 3 H), 5.25 (d, J ) 6.9 Hz, 1 H), 7.22-
7.29 (m, 7 H), 7.36 (t, J ) 7.2 Hz, 2 H), 7.47 (t, J ) 7.9 Hz, 2
H), 7.72 (d, J ) 7.8 Hz, 2 H); 13C NMR δ 26.0, 29.8, 44.4, 46.9,
47.9, 49.4, 57.3, 66.8, 82.0, 119.7, 125.1, 126.8, 127.0, 127.2,
127.4, 128.5, 141.0, 141.3, 143.8, 156.2, 167.9, 169.3; EIMS
m/z 196 (6), 178 (100), 57 (33).
tr a n s-3-Aceta m id o-4-(3-in d olyl)-2-oxop ip er id in e-1-a ce-
tic Acid (tr a n s-16). A solution of acetamidopiperidone trans-
15 (429 mg, 1.11 mmol) in AcOH:iPrOH:H2O (2:1:1, 60 mL)
was stirred for 24 h at 100 °C. The solvent was then evaporated
and crude acid trans-16 (358 mg, quantitative) was obtained.
An analytical sample was purified by chromatography (CH2-
Cl2/MeOH, 94/6): IR (NaCl) 3359, 1648 cm-1; 1H NMR (MeOH)
δ 1.74 (s, 3 H), 2.23 (m, 2 H), 3.38 (m, 1 H), 3.61 (m, 3 H, 6-H),
4.12 (s, 2 H), 4.59 (d, J ) 11.4 Hz, 1 H), 6.99 (td, J ) 7.2 and
1.0 Hz, 1 H), 7.07 (td, J ) 7.5 and 1.2 Hz, 1 H), 7.11 (s, 1 H),
7.32 (d, J ) 8.1 Hz, 1 H), 7.57 (d, J ) 7.5 Hz, 1 H); 13C NMR
(MeOH) δ 22.5, 30.6, 37.1, 49.0, 49.6, 56.9, 112.3, 117.0, 119.3,
119.7, 122.2, 122.3, 128.0, 137.9, 171.5, 172.5, 173.2; CIMS
m/z 329 (M+, 2), 330 (M+ + 1, 100), 347 (M+ + 18, 1).
tr a n s-3-{[(9-F lu or en yl)m eth oxyca r bon yl]a m in o}-4-(3-
in d olyl)-2-oxop ip er id in e-1-a cetic Acid (tr a n s-14a ). A so-
lution of piperidone trans-13a (266 mg, 0.47 mmol) in PrOH:
i
H2O:AcOH (1:1:2, 15 mL) was stirred for 72 h at 100 °C. The
solvent was then evaporated and carboxylic acid trans-14a
(219 mg, 91%) was obtained. An analytical sample was purified
by chromatography (hexane): IR (KBr) 3400, 1712, 1640, 1246
1
cm-1; H NMR δ 2.13 (m, 2 H), 3.41 (m, 1 H), 3.61 (m, 2 H),
4.08-4.38 (m, 5 H), 4.42 (br t, J ) 8.1 Hz, 1 H), 5.96 (d, J )
9.3 Hz, 1 H), 7.10 (br s, 1 H), 7.17 (t, J ) 7.5 Hz, 1 H), 7.36
(m, 7 H), 7.60 (d, J ) 7.2 Hz, 2 H), 7.70 (d, J ) 7.2 Hz, 2 H),
8.25 (br s, 1 H); 13C NMR δ 29.3, 35.7, 46.8, 48.2, 49.6, 56.8,
66.8, 111.4, 115.7, 118.2, 119.0, 119.6, 120.9, 121.1, 121.6,
125.0, 126.5, 126.8, 127.3, 135.9, 136.1, 140.8, 143.5, 143.6,
156.8, 170.4, 171.1; EIMS m/z 287 (4), 178 (100). Anal. Calcd
(42) Rotamers were observed.
9552 J . Org. Chem., Vol. 68, No. 25, 2003

Synthesis of 3-Aminolactams
(2S)-2-{2-[(3SR, 4SR)-3-Aceta m id o-4-(3-in d olyl)-2-oxo-
1-p ip er id in yl]a cet a m id o}-4-m et h ylp en t a n a m id e (Tr i-
p ep tid es I a n d II or 17a a n d 17b). To a solution of carboxylic
acid trans-16 (108 mg, 0.34 mmol) in dry DMF (2 mL) at 0 °C
was added DCC (85 mg, 0.41 mmol) and HOBt (63 mg, 0.41
mmol). The resulting mixture was stirred for 10 min at room
temperature and HCl‚L-Leu-NH2 (62 mg, 0.37 mmol) and Et3N
(71 µL, 0.51 mmol) were added. Stirring was continued
overnight at room temperature. The solvent was then evapo-
rated and the residue was dissolved in toluene and washed
several times with brine. The organic layer was dried and
concentrated to afford a mixture of diastereomers I and II (17a
and 17b, 60 mg, 41%) after purification by chromatography
(AcOEt/MeOH, 98/2). Tr ip ep tid e I (17a ): IR (NaCl) 3286,
here (see Figure 5). Each run included 3000 steps. The
structures obtained were clustered by conformation and
energy. The resulting lowest energy conformations were the
starting points for molecular dynamics studies.
Molecu la r Dyn a m ics. The resulting lowest energy con-
formers of compounds 17a 1 and 17b1 (resulting from the Monte
Carlo search and Iterative simulated annealing) constituted
the starting points for molecular dynamics studies with a
distance dependent dielectric (4r) constant and an explicit
solvent model in chloroform. NVT calculations at 300 K were
performed by using cubic boxes of 48 Å side length and 433
chloroform molecules. Periodical bounded conditions were
applied. After adequate heating and equilibration of the system
for 50 ps, evolution times were 1 ns. One thousand structures
were saved periodically from each profile distribution for
further analyses. Profile distributions were analyzed for
conformational preferences measuring the γ- and/or â-turn
descriptors. For the â-turn, these are the distance R (R < 7 Å)
between the CRi and the CRi+1, the dihedral angle τ (-90 < τ
< 90) formed by the four CR atoms, and the distance between
the carbonyl function of the first amino acid (i) and the amide
group of the fourth (i+3). The major â-turns are classified
according to the torsion angles of the second (φ1, ψ1: φ1 ) -60
( 30° and ψ1 ) 120 ( 30°) and the third amino acids (φ2, ψ2:
φ1 ) 80 ( 30° and ψ1 ) 0 ( 45°). For the γ-turn, they are the
distance between the carbonyl function of the second amino
acid (i+1) and the amide group of the fourth amino acid (i+3)
and the torsion angles of the second amino acid (φ2, ψ2: φ1 )
70°/85° and ψ1 ) -60°/-70°).
1
1632 cm-1; H NMR (600 MHz) δ 0.95 and 0.98 (2 d, J ) 6.6
Hz, 3 H each), 1.58-1.68 (m, 3 H), 1.92 (s, 3 H), 2.20 (dq, J )
13.8 and 2.5 Hz, 1 H), 2.31 (qd, J ) 13.3 and 4.4 Hz, 1 H),
3.42 (m, 1 H), 3.77 (ddd, J ) 12.7, 10.5, and 3.4 Hz, 1 H), 3.82
(td, J ) 12.0 and 3.6 Hz, 1 H), 3.87 (dd, J ) 10.6 and 6.8 Hz,
1H), 4.51 (m, 1 H), 3.34 and 5.06 (2 d, 1 H each, J ) 16.0 Hz),
5.47 (br s, 1 H), 6.32 (d, J ) 6.8 Hz, 1 H), 7.06 (d, J ) 2.2 Hz,
1 H), 7.11 (td, J ) 7.0 and 0.9 Hz, 1 H), 7.21 (td, J ) 8.1 and
0.9 Hz, 1 H), 7.39 (d, J ) 8.1 Hz, 1 H), 7.45 (d, J ) 8.1 Hz, 1
H), 7.52 (d, J ) 7.9 Hz, 1 H), 8.15 (br s, 1 H), 8.38 (br s, 1 H).
Some of the signals corresponding to a minor rotamer could
be assigned: 0.90 and 0.92 (2 d, J ) 6.1 Hz, 3 H each), 4.62
(m, 1 H), 5.33 (br s, 1 H), 6.78 (br s, 1 H). 13C NMR δ 21.6,
22.2, 22.7, 23.0, 23.3, 24.5, 24.6, 32.9, 36.2, 40.1, 49.2, 52.1,
52.5, 52.7, 55.1, 111.6, 116.5, 118.6, 119.7, 121.0, 122.4, 126.2,
136.1, 168.5, 168.9, 170.9, 174.1, 175.1; EIMS m/z 319 (12),
276 (22), 194 (18), 156 (39), 98 (17), 55 (30). Tr ip ep tid e II
(17b): IR (NaCl) 3294, 1641 cm-1; 1H NMR (600 MHz) δ 0.88
and 0.92 (2 d, J ) 6.4 Hz, 3 H each), 1.20-1.85 (m, 3-H), 1.85
(s, 3 H), 2.23 (m, 1 H), 2.32 (m, 1 H), 3.42 (dm, J ) 12.0 Hz,
1 H), 3.76 (dd, J ) 10.2 and 6.7 Hz, 1 H), 3.85 (ddd, J ) 13.3,
10.2, and 3.0 Hz, 1 H), 3.92 (td, J ) 12.0 and 5.4 Hz), 4.51 (m,
1 H), 3.48 and 4.76 (2 d, J ) 16.7 Hz, 1 H each), 5.54 (br s, 1
H), 6.89 (br s, 1 H), 7.05 (d, J ) 2.2 Hz, 1 H), 7.11 (t, J ) 7.1
Hz, 1 H), 7.21 (t, J ) 7.5 Hz, 1 H), 7.39 (d, J ) 8.2 Hz, 1 H),
7.51 (d, J ) 7.9 Hz, 1 H), 7.69 (d, J ) 8.8 Hz, 1 H), 8.20 (br s,
1 H), 8.51 (br s, 1 H). Some of the signals corresponding to a
minor rotamer could be assigned: 0.92 and 0.99 (2 d, J ) 6.1
Hz, 3 H each), 5.77 (br s, 1 H), 6.89 (br s, 1 H), 7.27 (t, J ) 6.6
Hz, 1 H), 7.27 (t, J ) 6.6 Hz, 1 H), 7.59 (d, J ) 8.0 Hz, 1 H),
7.75 (d, J ) 8.0 Hz, 1 H). 13C NMR δ 21.1, 21.8, 22.6, 23.3,
24.3, 24.5, 24.9, 25.1, 32.8, 35.5, 39.1, 48.5, 50.3, 51.9, 52.3,
53.9, 110.8, 111.5, 116.7, 118.0, 118.4, 119.5, 120.8, 122.2,
124.3, 125.0, 126.3, 127.9, 136.2, 168.2, 171.0, 171.5, 174.8,
176.2; EIMS m/z 319 (7), 276 (15), 194 (17), 156 (36), 98 (53),
55 (100).
Iter a tive Sim u la ted An n ea lin g. The calculations were
carried out within the molecular mechanics with use of the
AMBER force field implemented in DISCOVER v 97. They
were conducted under vacuum with
a distant-dependent
dielectric constant (4r) and a cutoff of 13 Å. Starting from
extended structures of the diastereomers, the structure is
minimized and subsequently heated to 900 K in a very short
period of time. The structure is then cooled slowly to 100 K
and minimized. In our case the heating was carried out in
steps. At each step, the temperature was raised by 100 K in
0.1 ps, and then the system was allowed to stay 1 ps at the
new temperature. The system was allowed to stand for 10 ps
at 1000 K and then cooled in steps. At each step, the
temperature was lowered by 100 K in 0.1 ps, and after cooling,
the system was allowed to stay 10 ps at the new temperature.
This structure is the starting conformation for another cycle,
creating a library of conformations that are rank ordered by
energy every 150 cycles. The procedure is repeated until no
new conformations appear after a predetermined number of
cycles (in our case 5 times) within a 5-kcal/mol energy range
with respect to the lowest energy structure already found.
Heating has to be carried out rapidly to make the molecule
jump to a different region in the space. In contrast, cooling is
slow to obtain the lowest energy minimum of the region. This
protocol was run five times, employing fully extended starting
structures of both diastereomers 17a and 17b.
Molecu la r Mod elin g Stu d ies: Con for m a tion a l Sea r ch .
All calculations were run on a SGI workstation (R4000, 128
MB RAM, 19 GB hard disk) under an Irix 5.3 operating
system. Molecular mechanics calculations were carried out
with Spartan v 5.0 and Insight II discover 3.0 v1997.
Op tim ized Mon te Ca r lo Sea r ch a n d En er gy Min im iza -
tion . In this paper, we used the MMFF94 force field imple-
mented in Spartan v 5.0. By default, atomic partial charges
were calculated from data in the chosen molecular mechanics
force field. The conformational search of diastereomers 17a
and 17b was carried out with an optimized Monte Carlo
method employing the MMFF94 force field as implemented
in Spartan 5.0. Energy minimization used a conjugated
gradient method, with a final gradient of 0.0001 kcal/Å mol
as the convergence criteria. All conformers within a 10-kcal/
mol window above the global minimum were used to determine
the profiles. To determine the conformer families, atoms
belonging to the lactam skeleton and peptide backbones were
considered. We employed a similar protocol for the conforma-
tional search of compounds 17a and 17b starting from
extended structures. Eight degrees of freedom were considered
Ack n ow led gm en t. Support for this research has
been provided by the CIRIT (Generalitat de Catalunya)
through grants QFN95-4703, 1995SGR-000429, 1997-
SGR-00075, and 1999SGR-00077, and by the DGYCIT
(Ministerio de Educacio´n y Cultura, Spain) through
grants PB97-0976 and 2FD97-0293. We also thank the
Universitat de Barcelona (Divisio´ de Cie`ncies de la
Salut) for a fellowship given to M.E.Q.
Su p p or tin g In for m a tion Ava ila ble: Distribution profiles
for Monte Carlo and molecular dynamics calculations of
compounds 17a and 17b . This material is available free of
charge via the Internet at http://pubs.acs.org.
J O035151+
J . Org. Chem, Vol. 68, No. 25, 2003 9553