Efficient synthesis of conformationally constrained peptidomimetics containing 2-oxopiperazines

Article abstract of DOI:10.1021/jo961398d

The enantioselective synthesis of a series of peptides containing the 3-substituted 2-oxopiperazine system is reported. The method involves a direct diastereoselective alkylation of the N-(hydroxyalkyl)-2-oxopiperazine 3, prepared in three steps from methyl L-leucinate in 38% yield, followed by oxidation of the hydroxyl function. Esterification of the resulting acids 11 and then deprotection and acylation of N-4 afforded tripeptide analogues 16 substituted by a large variety of alkyl side chains at the 3-position of the 2-oxopiperazine.

Full text of DOI:10.1021/jo961398d

1016
J . Org. Chem. 1997, 62, 1016-1022
Efficien t Syn th esis of Con for m a tion a lly Con str a in ed
P ep tid om im etics Con ta in in g 2-Oxop ip er a zin es1
Adriana Pohlmann,† Vincent Schanen, Dominique Guillaume, J ean-Charles Quirion,* and
Henri-Philippe Husson
Laboratoire de Chimie The´rapeutique associe´ au CNRS, Faculte´ des Sciences Pharmaceutiques et
Biologiques, Universite´ Rene´ Descartes, 4, Av. de l’Observatoire, 75270 Paris Cedex 06, France
Received J uly 23, 1996X
The enantioselective synthesis of a series of peptides containing the 3-substituted 2-oxopiperazine
system is reported. The method involves a direct diastereoselective alkylation of the N-(hydroxy-
alkyl)-2-oxopiperazine 3, prepared in three steps from methyl L-leucinate in 38% yield, followed by
oxidation of the hydroxyl function. Esterification of the resulting acids 11 and then deprotection
and acylation of N-4 afforded tripeptide analogues 16 substituted by a large variety of alkyl side
chains at the 3-position of the 2-oxopiperazine.
The determination of the bioactive conformation of
peptides, potentially highly flexible molecules, has often
been a key step leading to the synthesis of peptide
analogues with greater and more specific biological
activity. In addition to X-ray crystallography analysis,
the determination of peptide bioactive conformations is
most frequently achieved using either a combination of
computational and sophisticated spectroscopic methods2
or by the study of multiple selectively conformationally-
constrained (non)peptide analogues according to the
strategy particularly pioneered by Freidinger.3 To ex-
pand upon the latter approach, several building blocks
able to specifically stabilize some parts of the peptide side
chains or backbone have been designed.4 2-Oxopipera-
zines 1 constitute an interesting example of these build-
ing blocks in which the Ni and Ni+1 atoms of the peptide
backbone are linked by an ethylene bridge and conse-
quently in which the ωi, φi, and ψi torsion angles in
compounds 2b are restricted compared to the parent
peptide 2a (Figure 1).
F igu r e 1. Torsion angles frozen in a 2-oxopiperazine peptide
analogue.
F igu r e 2. General strategy for obtaining the 3-substituted
2-oxopiperazine containing peptides.
Although enkephalin analogues containing 3-substi-
tuted 2-oxopiperazine skeleton clearly display interesting
biological activities,5 very few methods have been avail-
able for the synthesis of these kind of conformationally
constrained compounds.6-9 Moreover, in these strategies,
2-oxopiperazines are built invariably by condensation of
two amino acids, the side chain of one becoming the C-3
substituent. Such an approach drastically narrows the
choice of the potential substituents at this position to the
side chains of readily available amino acids. This limita-
tion is severe since it is generally considered that side
chains are critical for specific peptide-receptor interac-
tions.
During the course of our studies on the asymmetric
synthesis of biologically interesting compounds, we de-
signed a general and highly enantioselective synthesis
of 3-substituted 2-oxopiperazines (Figure 2).10 This
method utilized a nonracemic R-substituted â-amino
alcohol, whose nitrogen atom is a part of the 2-oxopip-
erazine, as a chiral inductor. Stereoselective alkylation
of the 2-oxopiperazine C-3 atom was accomplished after
enolate formation by addition of electrophiles. The
observed diastereoselectivity has been explained by a
rigid intermediate.11,12 X-ray crystallography analysis
† On leave of absence from Instituto de Qu´ımica, Universidade
Federal do Rio Grande do Sul, Porto Alegre, Brazil.
X Abstract published in Advance ACS Abstracts, J anuary 15, 1997.
(1) Abbreviations used: DCC, dicyclohexylcarbodiimide; DMF, dim-
ethylformamide; HMPA, hexamethylphosphoramide; IBCF, isobutyl
chloroformate; NMM, N-methylmorpholine; THF, tetrahydrofuran;
TBDMSCl, tert-butyldimethylsilyl chloride.
(2) (a) Hruby, V.; Al-Obedi, F.; Kazmierski, W. Biochem. J . 1990,
268, 249. (b) Fesik, S. W. J . Med. Chem. 1991, 34, 2937. (c) Marshall,
G. R. Tetrahedron 1993, 49, 3547.
(3) Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brooke, J . R.;
Saperstein, R. Science 1980, 210, 656.
(4) Recent reviews: Toniolo, C. Int. J . Peptide Protein Res. 1990,
35, 287. Liskamp, R. M. J . Recl. Trav. Chim. Pays-Bas 1994, 113, 1.
Gante, J . Angew. Chem., Int. Ed. Engl. 1994, 33, 1699.
(5) Piercy, M. F.; Moon, M. W.; Blinn, J . R.; Dobry-Scheur, P. J . K.
Brain Res. 1986, 74, 385.
(6) DiMaio, J .; Belleau, B. J . Chem. Soc., Perkin Trans. 1 1989, 1687.
(7) Kojima, Y.; Yamashita, T.; Washizawa, M.; Ohsuka, A. Makro-
mol. Chem., Rapid Commun. 1989, 10, 1989.
(8) Yamashita, T.; Kojima, Y.; Hirotsu, K.; Ohsuka, A. Int. J . Peptide
Protein Res. 1989, 33, 110.
(9) Fobian, Y. M.; d’Avignon, D. A.; Moeller, K. D. Bioorg. Med.
Chem. Lett. 1996, 6, 315.
(10) (a) Schanen, V.; Riche, C.; Chiaroni, A.; Quirion, J .-C.; Husson,
H.-P. Tetrahedron Lett. 1994, 35, 2533. (b) Schanen, V.; Cherrier, M.
P.; de Melo, S. J .; Quirion, J .-C.; Husson, H.-P. Synthesis 1996, 833.
(11) Micouin, L.; J ullian, V.; Quirion, J .-C.; Husson, H.-P. Tetrahe-
dron: Asymmetry 1996, 7, 2839.
(12) Micouin, L.; Varea, T.; Riche, C.; Chiaroni, A.; Quirion, J .-C.;
Husson, H.-P. Tetrahedron Lett. 1994, 35, 2529.
S0022-3263(96)01398-9 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Peptidomimetics Containing 2-Oxopiperazines
J . Org. Chem., Vol. 62, No. 4, 1997 1017
Sch em e 1
Sch em e 2
sulfate, which we have found to be an efficient 1,2-
dielectrophile in this laboratory.14 Unfortunately, with
this compound we did not observe the formation of
expected product and recovered the starting material
completely. We became aware of a synthesis of 1,2,4-
triazinones15 involving a N,N-cyclization by use of eth-
ylene glycol bis-triflate.16 When we reacted ethylene
glycol bis-triflate with compound 5, oxopiperazine 9
was formed in 42% yield (Scheme 1). Compound 3
established that using a natural amino acid to prepare
2-oxopiperazine 3 allowed the creation of a dipeptide
analogue with the same C-3 configuration as its uncon-
strained parent.10
Furthermore, these substituted 2-oxopiperazines would
contain the two functions required to synthesize oli-
gopeptides since selective regeneration of the acidic
function by oxidation of the free hydroxyl and deprotec-
tion of N-4 should lead to derivatives suitable for
subsequent peptide chemistry (Figure 2).
In order to confirm the possible use of 3 for the
synthesis of templates suitable for peptide chemistry and
widen the scope of our methodology, we describe herein
a general procedure and its limitations for the enantio-
merically pure synthesis of 3-substituted 2-oxopiperazine
derivatives. We also present the first examples of the
application of this strategy to the preparation of tripep-
tide analogues.
was obtained in optically pure [[R]20 -16.1 (c ) 0.11,
D
CHCl3)] form after reduction of the ester function in 9
by NaBH4 in the presence of LiCl.17 Hence, this new
pathway allowed the synthesis of 3 in the same yield
(40%) as in the first route but in only three steps from
Leu-OMe.
Dia ster eoselective Alk yla tion of Oxop ip er a zin e
3. In the stereoselective alkylation of C-3 in 3, amide
enolate was formed first in THF using t-BuLi (2 equiv)/
HMPA as a base (Scheme 2). This enolate was reacted
separately with nine different electrophiles, giving 10a -
i. Alkylation with methyl iodide furnished 10b in 90%
yield (de > 96% vide infra) together with 5% of the C-3
dimethylated derivative. Dialkylation occurred only in
this case. Compounds 10c,e,f were prepared in 75-80%
yield (de > 96%) using benzyl bromide, 2-bromobenzyl
bromide, and allyl bromide as electrophiles, respectively.
Consistent with previous observations on a closely related
compound,12 a significantly lower alkylation yield was
obtained when isobutyl bromide was used as the elec-
trophile and 10d was isolated in only 30% yield (de 99%).
It is noteworthy that while compounds 10b-d could have
been synthesized by condensation of natural amino acids,
compounds 10e,f could not, yet they were easily obtained
by our strategy.
Most of these electrophiles had been studied in the
phenylglycinol series;10,12 therefore, we decided to evalu-
ate more functionalized electrophiles and particularly
bromo ester derivatives. Only 10g and 10h could be
easily obtained by alkylation of 3 with tert-butyl bro-
moacetate and ethyl bromoacetate (67% and 66% yield,
78% and 75% de, respectively). The alkylation reaction
with 2-bromoethyl acetate afforded 10i in only 10% yield
together with several other compounds, two of which
were identified as 13 (20% yield) and the transesterified
Resu lts a n d Discu ssion
Syn th esis of Oxop ip er a zin e 3. In order to demon-
strate the generality of our method and its possible
application to peptidomimetic chemistry, we decided to
use a proteogenic amino acid as precursor of a chiral
inductor. For this reason, L-leucine was chosen instead
of D-phenylglycine, as used in all our previous studies.
2-Oxopiperazine 3 could be synthesized in six steps (35-
40% overall yield) starting from L-Leu-OMe (4) using our
established conditions10 (Scheme 1). This synthesis
involved the preparation of the known dipeptide 5.13
Selective reduction of amide and ester carbonyl groups
furnished 6, whose alcohol function was protected as the
silyl ether (7) before a two-step cyclization leading to 3
[[R]20 -16.5 (c ) 0.11, CHCl3)] after deprotection of the
D
hydroxyl group.
In order to make our strategy more attractive, we
decided to explore a shorter route for the synthesis of
2-oxopiperazine 3. We sought a method for the direct
formation of 3 from dipeptide 5. To the best of our
knowledge, there was no example of such a reaction
conducted on an amidocarbamate compound. Initially,
we attempted to condense dipeptide 5 with ethylene
(14) Guillaume, D.; Brum-Bousquet, M.; Aitken, D. J .; Husson, H.-
P. Bull. Soc. Chim. Fr. 1994, 131, 391.
(15) Gante, J .; Neunhoeffer, H.; Schmidt, A. J . Org. Chem. 1994,
59, 6487.
(16) Lindner, E.; von Au, G.; Eberle, H.-J . Chem. Ber. 1981, 114,
810.
(17) Hamada, Y.; Shibata, M.; Sugiura, T.; Kato, S.; Shioiri, T. J .
Org. Chem. 1987, 52, 1252.
(13) Sandrin, E.; Boissonnas, R. A. Helv. Chim. Acta 1963, 46, 1637.

1018 J . Org. Chem., Vol. 62, No. 4, 1997
Pohlmann et al.
Ta ble 1. Ch em ica l Sh ifts (δ, p p m ) of Leu r-CH of 10b-h
Sch em e 3
a n d Som e of Th eir C-3 Dia ster eoisom er s in CDCl3
products
10b
10c
10d
10e
10f
10g
10h
(S) C-3
(R) C-3
4.54
4.70
4.47
5.15
4.58
4.60
4.16
4.94
4.35
4.85
derivative 14 (10% yield). When methyl 3-bromopropi-
onate was used as the electrophile, 15 was obtained in
45% yield.
pounds 11, we only studied the reactivity of N-4 toward
acylation, its sterically hindered nature leading possibly
to lower reactivity. Activation of the carboxyl group of
Z-Ala by IBCF and coupling with 12a afforded 16a in
48% yield; analogous coupling with 12f furnished 16f in
only 27% (Scheme 3). Using more reactive coupling
intermediates led to improved yields. Formation of the
pentafluorophenol ester of Z-Ala (DCC, C6F5OH, CH2Cl2)
and condensation with 12a -c and 12f afforded 16a -c
and 16f, respectively, in 50-75% yield.
Oxidation of the primary alcohol function of 3 and
10b-f using J ones reagent afforded the corresponding
acids (11a -f) in 80-97% yield. Ester formation with
concomitant N-4 Boc removal (SOCl2/MeOH) furnished
amino esters 12a -f as hydrochloride salts in quantitative
yields.
Con clu sion
Deter m in a tion of th e Op tica l P u r ities of 10 a n d
12. The optical integrity of 10 and 12 was first studied
by 1H and 13C NMR spectroscopy. For compounds 10b-
f, only one diastereomer was observed in each NMR
spectrum, establishing the diastereomeric excesses of
these alcohols to be at least 96%. Compound 12d was a
known product whose former preparation required dras-
tic conditions.7 Despite promising NMR results with 12d ,
the optical rotation of 12d prepared by our method
In summary, the synthetic pathway described above
provides a general entry into a new series of interesting
peptidomimetics. Contrasting results have been ob-
served for alkylation reactions using bromo esters, but
analogues expected from these electrophiles should be
available from 11f. The ease of synthesis of enantio-
merically pure 2-oxopiperazines 11 combined with the
ability to vary the C-3 positions with a large number of
side chains should widen the use of this class of confor-
mationally constrained peptidomimetics in the determi-
nation of numerous structure-activity relationships.
Studies concerning the influence of the different substit-
uents (at N-4, C-3, or the C-terminal end) on the
conformation of the 2-oxopiperazine system are currently
in progress and will be reported in due time.
conflicted slightly with the literature [12d [R]20 -57 (c
D
) 0.1, EtOH) (lit.7 [R]20D -67 (c ) 0.97, EtOH))]. Accord-
ingly, we questioned the accuracy of our NMR measure-
ments. Thus, we prepared a partially C-3-epimerized
mixture of 10d (t-BuLi/THF, 4 h then H2O) and were able
to demonstrate by HPLC that the optical purity of the
previously obtained sample of 10d was at least 99%.
Because the transformations of 10d to 12d should not
promote racemization, we believe alkylated compounds
10b-f as well as 12b-f are formed with high degrees of
optical purity.
Exp er im en ta l Section
1H and 13C NMR spectra were recorded at 300.13 and 75.47
MHz. IR spectra were recorded on a 1600-FTIR instrument.
Mass spectra were obtained in chemical ionization mode by
direct insertion (ionizing gas NH3). Dichloromethane, ethanol,
and methanol were dried over CaH2 and distilled prior to use.
Et2O and THF were dried over sodium/benzophenone (then
lithium aluminum hydride in the case of THF) before distil-
lation. All alkylation and condensation reactions were carried
out under nitrogen atmosphere. Thin layer chromatography
was performed on precoated silica gel plates (60-F254, 0.2 mm)
and revealed by heating with phosphomolybdic acid. Silica
gel (grade 60, 230-400 mesh) was used for column chroma-
tography. Diastereomeric excesses (de) were determined by
HPLC using a NOVAPAK 18 mm column eluted with a MeOH/
H2O system. Elemental analyses were performed by Labora-
toire de microanalyse du CNRS, ICSN, Gif-sur-Yvette.
(2S)-6-(ter t-Bu toxycar bon yl)-2-isobu tyl-3,6-diazah exan -
1-ol (6). To an ice-cooled solution of dipeptide 5 (16.4 g, 54.3
mmol) in dry Et2O (300 mL) was added LiAlH4 (2.05 g, 54.0
mmol). The mixture was stirred for 1 h at rt, and then
additional LiAlH4 (5.39 g, 142.0 mmol) was added to the
reaction. Stirring was continued for 30 h, and then a 15%
aqueous solution of NaOH (2.4 mL) was added dropwise to
the reaction cooled at -10 °C. One hour later, water (6 mL)
was added, and the suspension was stirred overnight at rt.
The white precipitate was filtered and then washed with CH2-
Cl2. The filtrate was dried over MgSO4, evaporated, and
X-ray crystallographic analysis of 10b18 confirmed the
expected S-absolute configuration of both asymmetric
centers. We used the chemical shift of R-Leu CH as a
diagnostic tool to determine the absolute configuration
of the 3-position of 10c-h . Hence, in deuteriochloroform,
this signal was constantly observed at 4.2 < δ < 4.7 when
the stereochemistry of C-3 was S and at 4.8 < δ < 5.2 in
the case of the C-3 R configuration (Table 1). Conse-
quently, the C-3 S configuration is assigned for 10c-h .
Finally, these results also confirmed the importance of
the chiral inductor configuration over its side chain
nature, since similar diastereomeric excesses are ob-
served with D-phenylglycinol or L-leucine derivatives.
P r ep a r a tion of Tr ip ep tid e An a logu es 16. Because
of the great number of diastereomerically pure C-3-
substituted 2-oxopiperazine derivatives accessible by this
method, we were eager to demonstrate the possible
incorporation of our building block into a peptide. Be-
cause elongation of the peptide chain from the C-terminal
end should be classically realized starting from com-
(18) Chiaroni, A.; Riche, C.; Pohlmann, A.; Guillaume, D.; Quirion,
J .-C.; Husson, H.-P. Acta Crystallogr. To be published.

Synthesis of Peptidomimetics Containing 2-Oxopiperazines
J . Org. Chem., Vol. 62, No. 4, 1997 1019
dissolved in Et2O. The insoluble material was discarded and
the solution concentrated yielding, in 75% yield, 6 as a viscous
oil that was rapidly used for the next step. The hydrochloride
and then a second portion of a 55% oily suspension of NaH
(0.21 g, 5.7 mmol) was added. The reaction was stirred for 1
h at 0 °C and 15 h at rt and then poured onto a 1 N HCl
solution (15 mL)/ice. The phases were separated, the aqueous
phase was extracted with Et2O (1 × 100 mL), and the organic
phases were dried and concentrated. The oily residue purified
by silica gel column chromatography [EtOAc/C6H12 (1:2)]
yielded an oil in 42% yield that crystallized from cyclohex-
salt was isolated as a white hygroscopic solid: [R]19 +13.3
D
(c ) 0.15, MeOH, HCl salt); 1H NMR (free base) δ (CDCl3)
5.25 (bs, 1H), 3.52 (dd, 1H, J ) 10.8, 3.5 Hz), 3.19 (dd, 1H,
J ) 10.8, 6.6 Hz), 3.12 (m, 2H), 2.78 (m, 1H), 2.68 (m, 2H),
2.10 (m, 2H, OH, NH), 1.60 (m, 1H), 1.41 (s), 1.31 (m, 1H),
1.20 (m, 1H), 0.87 (d, 6H, J ) 6.5 Hz); 13C NMR (free base)
δ (CDCl3) 156.5, 79.7, 63.2, 56.6, 46.3, 40.8, 28.2, 24.8, 22.9,
22.5; IR (free base) (film) 3333, 1711, 1173 cm-1; MS m/ z
261 (MH+, 100), 205 (79), 175 (80), 118 (26). Anal. Calcd for
C13H28N2O3‚H2O: C, 56.11; H, 10.79; N, 10.07. Found: C,
56.57; H, 10.49; N, 8.81.
ane: mp 80-81 °C (cyclohexane); [R]20 -31.3 (c ) 0.08,
D
CHCl3); 1H NMR δ (CDCl3) 5.28 (dd, 1H, J ) 9.8, 6.2 Hz), 4.05
(AB syst., 2H), 3.66 (m, 1H), 3.63 (s, 3H), 3.46 (m, 1H), 3.31
(m, 2H), 1.65 (m, 2H), 1.40 (m, 1H), 1.39 (s, 9H), 0.88 (d, 3H,
J ) 6.4 Hz), 0.86 (d, 3H, J ) 6.4 Hz); 13C NMR δ (CDCl3) 171.7,
166.3, 153.7, 80.6, 53.4, 52.1, 47.7, 42.3, 40.1, 36.7, 28.2, 24.8,
23.0, 21.1; IR (film) 1743, 1698, 1660, 1170 cm-1; MS m/ z 329
(MH+, 58), 273 (100). Anal. Calcd for C16H28N2O5: C, 58.54;
H, 8.54; N, 8.54. Found: C, 58.14; H, 8.64; N, 8.05.
(2S )-6-(t er t -Bu t oxyca r b on yl)-2-isob u t yl-1-[(t er t -b u -
t yld im et h ylsilyl)oxy]-3,6-d ia za h exa n e (7). To an ice-
cooled solution of 6 (2.53 g, 9.73 mmol) were added imidazole
(1.32 g, 19.4 mmol) in DMF (8 mL) and a solution of tert-
butyldimethylsilyl chloride (1.760 g, 11.7 mmol) in DMF (5
mL). The solution was stirred for 3 h at 0 °C. The reaction
was quenched by addition of H2O (15 mL) and then made
alkaline by addition of a saturated aqueous solution of Na2-
CO3 (60 mL). The aqueous phase was extracted with Et2O (2
× 100 mL), which was further washed with H2O (3 × 50 mL),
dried over MgSO4, and concentrated. The viscous oil (98%
yield) could be used in such a state or the hydrochloride salt
(70% yield) could be crystallized from Et2O: mp 187 °C (Et2O);
(1′S)-4-(ter t-Bu toxyca r bon yl)-1-(1′-isobu tyl-2′-h yd r oxy-
eth yl)-2-oxop ip er a zin e (3). F r om Com p ou n d 8. To a cold
solution (0 °C) of compound 8 (0.42 g, 1 mmol) in THF (13
mL) was added 1.84 mL of a 1.0 M solution of Bu4NF in THF.
The reaction was stirred for 2 h at rt, and then H2O (20 mL)
was added. The two phases were separated, and the aqueous
phase was extracted with CH2Cl2 (2 × 30 mL). The combined
organic phases were washed with H2O (4 × 30 mL), dried, and
concentrated, affording after silica gel column chromatography
(eluting with a gradient of MeOH in CH2Cl2) 3 as a white solid
crystallized from EtOAc (yield: 92%).
[R]19 +3.9 (c ) 0.13, MeOH, HCl salt); 1H NMR (free base) δ
D
(CDCl3) 5.16 (bs, 1H), 3.56 (dd, 1H, J ) 10.1, 4.0 Hz), 3.37
(dd, 1H, J ) 10.1, 6.3 Hz), 3.30 (bs, 1H), 3.16 (m, 2H), 2.69
(m, 2H), 2.58 (m, 1H), 1.58 (m, 1H), 1.37 (s), 1.18 (m, 2H), 0.84
(m, 15H), 0.00 (s, 6H); 13C NMR (free base) δ (CDCl3) 156.1,
79.0, 64.5, 56.7, 45.9, 40.4, 40.4, 28.3, 25.8, 24.9, 23.0, 22.7,
18.2, 1.0; IR (free base) (film) 3333, 1708, 1253, 1173, 1096
cm-1; MS m/ z 375 (MH+, 100), 319 (24), 244 (6), 173 (7). Anal.
Calcd for C19H42N2O3Si‚HCl: C, 55.54; H, 10.47; N, 6.21.
Found: C, 55.69; H, 10.71; N, 6.49.
F r om Com p ou n d 9. A solution of compound 9 (0.33 g, 1
mmol) in THF (7 mL) was cooled at 0 °C. Then LiCl (0.08 g,
2 mmol), NaBH4 (0.08 g, 2 mmol), and absolute EtOH (14 mL)
were consecutively added. The reaction was allowed to warm
at rt and stirred for 10 h, and then the reaction was adjusted
to pH 4 by addition of a 10% aqueous solution of citric acid.
The solution was concentrated, and the residue was dissolved
in H2O (60 mL) and extracted with CH2Cl2 (3 × 40 mL). The
organic phases were combined, dried over MgSO4, and con-
centrated, and compound 3 was obtained in 95% yield after
silica gel column chromatography (EtOAc, C6H12) and crystal-
lization from EtOAc: mp 108-112 °C (EtOAc); [R]19D -16.5 (c
) 0.1, CHCl3); 1H NMR δ (CDCl3) 4.61 (m, 1H), 4.05 (AB syst,
2H), 3.65 (dd, 1H, J ) 11.7, 4.1 Hz), 3.56 (m, 3H), 3.24 (m,
2H), 1.86 (bs, 1H), 1.44 (m, 2H), 1.43 (s, 9H), 1.22 (m, 1H),
0.89 (d, 6H, J ) 6.4 Hz); 13C NMR δ (CDCl3) 167.1, 153.7, 80.6,
63.1, 53.9, 47.8, 41.3, 40.3, 36.3, 28.3, 24.9, 23.2, 22.1; IR
(Nujol) 3324, 1697, 1639, 1186 cm-1; MS m/ z 301 (MH+, 100),
245 (59), 225 (4), 214 (6), 201 (9), 152 (7). Anal. Calcd for
(1′S)-4-(ter t-Bu toxyca r bon yl)-1-[1′-isobu tyl-2′-[(ter t-bu -
tyld im eth ylsilyl)oxy]eth yl]-2-oxop ip er a zin e (8). A solu-
tion of bromoacetic acid (5.64 g, 40.6 mmol) and DCC (4.04 g,
19.6 mmol) in CH2Cl2 (30 mL) was stirred at rt for 45 min.
The white precipitate was removed and the filtrate poured into
a solution of 7 (3.58 g, 9.58 mmol) and NMM (3 mL, 27.3 mmol)
in CH2Cl2 (15 mL) cooled at -15 °C. The reaction was stirred
for 2.5 h and then diluted with CH2Cl2 (100 mL) and quenched
by addition of H2O (125 mL). The organic phase was collected
at rt and the aqueous phase extracted with CH2Cl2 (3 × 50
mL). The combined organic phases were washed with H2O (3
× 100 mL), dried over MgSO4, and concentrated to afford a
viscous oil that was purified by silica gel chromatography (CH2-
Cl2) (yield 73%). To this oil (3.46 g, 7 mmol), dissolved in 80
mL of THF/DMF (1:1) and cooled at 0 °C, was added NaH (0.50
g, 21 mmol). The mixture was stirred for 4 h at rt and then
quenched by careful addition of H2O (400 mL). The solution
was extracted with EtOAc (3 × 100 mL), combined organic
phases were washed with H2O (4 × 100 mL), and 8 was
directly isolated by crystallization from EtOH 80% (70% yield)
or column chromatography (MeOH, CH2Cl2) (90% yield): mp
C
15H28N2O4‚1/4H2O: C, 59.11; H, 9.36; N, 9.19. Found: C,
59.23; H, 9.23; N, 9.05.
Gen er a l P r oced u r es. P r ep a r a tion of Alk yla ted Com -
p ou n d s 10b-i. A solution of piperazin-2-one 3 (0.3 mmol) in
THF (4 mL) and HMPA (1 mmol) was cooled at -78 °C under
nitrogen atmosphere. A pentane solution of t-BuLi (0.6 mmol)
was carefully added, the flow of nitrogen removed, and the
reaction stirred 10 min. The electrophile (1 mmol) was then
slowly added and the reaction stirred at -78 °C for 2-7 h. At
the end of this period, a saturated aqueous solution of
ammonium chloride (10 mL) was poured and the reaction
mixture allowed to warm to rt. The two phases were separated
and the aqueous phase extracted by CH2Cl2 (3 × 5 mL). The
organic phases were combined, dried over MgSO4, and con-
centrated under reduced pressure. Purification of the alky-
lated compounds was achieved by silica gel column chroma-
tography (EtOAc, cyclohexane).
110-112 °C (EtOH); [R]19 -23.1 (c ) 0.1, CHCl3); 1H NMR δ
D
(CDCl3) 4.60 (m, 1H), 4.01 (s, 2H), 3.58 (m, 2H), 3.50 (m, 2H),
3.33 (m, 1H), 3.22 (m, 1H), 1.46 (m, 2H), 1.41 (s, 9H), 1.21 (m,
1H), 0.87 (d, 6H, J ) 6.4 Hz), 0.81 (s, 9H), 0.02 (s, 6H); 13C
NMR δ (CDCl3) 166.0, 153.8, 80.5, 63.9, 52.4, 47.9, 41.7, 40.4,
36.4, 28.3, 25.7, 24.9, 23.2, 22.2, 18.0, 1.41, 1.30; IR (Nujol)
1693, 1651, 1252, 1179, 1100 cm-1; MS m/ z 415 (MH+, 100),
359 (24), 301 (36), 245 (14), 225 (7). Anal. Calcd for C21H42N2O4-
Si: C, 60.87; H, 10.14; N, 6.76. Found: C, 61.14; H, 9.86; N,
6.91.
P r ep a r a tion of Acid s 11. To a solution of alcohol (0.3
mmol) in acetone (1.5 mL) cooled at 0 °C was added J ones
reagent (0.45 mL). The solution was stirred for 30 min at rt
and then cooled at 0 °C, and 2-propanol (6 mL) was added.
The solution was stirred for 30 min more at rt. The solvent
was removed in vacuo, and then H2O (10 mL) was added and
the aqueous phase was extracted with EtOAc (3 × 5 mL). The
organic phase was washed with water (3 × 8 mL), dried over
MgSO4, and concentrated under reduced pressure. The acids
obtained in 80-97% yield were used in the next step without
purification.
Met h yl (2S)-2-Isob u t yl-2-[4′-(ter t-b u t oxyca r b on yl)-2′-
oxop ip er a zin -1′-yl]a ceta te (9). To a solution of 5 (1.00 g,
3.3 mmol) in Et2O (200 mL) was added a 55% oily suspension
of NaH (0.15 g, 4.0 mmol) in mineral oil at 0 °C. The
suspension was stirred for 15 min, and then a solution of
ethylene glycol ditriflate (1.30 g, 4.0 mmol) in Et2O (15 mL)
was slowly added. The mixture was stirred for 1 h at 0 °C,

1020 J . Org. Chem., Vol. 62, No. 4, 1997
Pohlmann et al.
P r ep a r a tion of N-Dep r otected Ester s 12. A solution of
acid 11 (1 mmol) in MeOH (5 mL) was cooled in an ice bath.
SOCl2 (0.4 mL, 5.5 mmol) was carefully added, and the reaction
was stirred overnight at rt. The solution was evaporated and
the excess of HCl eliminated by successive addition/evapora-
tion of MeOH. Compounds 12 were obtained in quantitative
yield.
3.63 (m, 1H), 3.48 (m, 2H), 3.30 (m, 2H), 3.04 (m, 2H), 2.94
(bs, 1H), 1.45-1.22 (m, 3H), 1.10 (s, 9H), 0.89 (m, 6H); 13C
NMR δ (CDCl3) 168.8, 153.4, 137.4, 132.7, 131.9, 128.3, 127.3,
125.3, 80.5, 63.2, 57.7, 54.5, 41.7, 37.7, 37.1, 36.3, 28.2, 24.8,
23.2, 22.1; IR (film) 3447, 1695, 1637, 1166 cm-1; MS m/ z 471
(MH+, 98), 469 (MH+, 100), 415 (66), 413 (67), 389 (12), 299
(5), 199 (52). Anal. Calcd for C22H33N2O4Br‚1/3H2O: C, 55.58;
H, 6.95; N, 5.89. Found: C, 55.28; H, 6.88; N, 5.87.
P r ep a r a tion of P ep tid e An a logu es 16. To a solution of
Z-Ala (0.580 g, 2.6 mmol) in CH2Cl2 (10 mL) was added DCC
(0.268 g, 1.3 mmol). The solution was stirred for 30 min and
the white precipitate filtered off the reaction. The filtrate was
poured, at 0 °C, into a solution of pentafluorophenol (0.24 g,
1.3 mmol) and DMAP (cat.) in CH2Cl2 (3 mL). The reaction
was stirred for 1.5 h at 0 °C and then diluted with CH2Cl2 (20
mL) and successively washed with 1 N HCl (2 × 10 mL) and
saturated Na2CO3 (2 × 15 mL). The dried organic phase was
concentrated and the white precipitate recrystallized from
Et2O in 85% yield. The crystals (0.09 g, 2.45 mmol) were
dissolved in DMF (1 mL) and poured into a solution of 12 (2.04
mmol) and NMM (6.0 mmol) in DMF (3 mL). The reaction
was stirred for 15-35 h at 35 °C and then diluted with CH2-
Cl2 (3 mL) and quenched by addition of 1 N HCl (7.5 mL). The
organic phase was collected, the aqueous phase was re-
extracted with CH2Cl2 (2 × 3 mL), the combined organic
phases were washed with a 1 N HCl solution (3 × 4 mL), dried,
and concentrated, and compound 16 was purified by silica gel
column chromatography [EtOAc/C6H12 (2:1)].
(1′S,3S)-3-Allyl-4-(ter t-bu toxyca r bon yl)-1-(1′-isobu tyl-
2′-h yd r oxyeth yl)-2-oxop ip er a zin e (10f) was prepared ac-
cording to the general procedure in 80% yield: mp 85 °C
(cyclohexane); [R]20D +64.0 (c ) 0.1, CHCl3); 1H NMR δ (CDCl3)
5.73 (m, 1H), 5.02 (d, 1H, J ) 15.6 Hz), 4.98 (d, 1H, J ) 8.5
Hz), 4.60 (m, 1H), 4.52 (m, 1H), 4.02 (m, 1H), 3.61 (m, 1H),
3.50 (m, 1H), 3.28 (m, 1H), 3.18 (m, 1H), 3.09 (m, 1H), 2.90
(bs, 1H), 2.57 (m, 2H), 1.40 (m, 2H), 1.40 (s, 9H), 1.19 (m, 1H),
0.87 (d, 6H, J ) 5.0 Hz); 13C NMR δ (CDCl3) 169.1, 153.7,
133.9, 118.0, 80.6, 63.2, 57.0, 54.0, 41.3, 37.9, 37.4, 36.3, 28.2,
24.8, 23.2, 21.9; IR (film) 3444, 1695, 1644, 1171 cm-1; MS
m/ z 358 (MNH4+, 7), 341 (MH+, 100), 285 (38), 241 (6), 229
(9). Anal. Calcd for C18H32N2O4‚1/6H2O: C, 62.97; H, 9.32;
N, 8.16. Found: C, 63.06; H, 8.84; N, 8.02.
ter t-Bu tyl 2-[(1′S,3S)-4-(ter t-Bu toxycar bon yl)-1-(1′-isobu -
tyl-2′-h ydr oxyeth yl)-2-oxopiper azin -3-yl]acetate (10g) was
prepared as an oil according to the general procedure in 67%
yield: de 78% (HPLC): 1H NMR of the major diastereomer δ
(CD3OD, 55 °C) 4.51 (m, 1H), 4.42 (m, 1H), 3.85 (m, 1H), 3.37
(d, 2H, J ) 6.9 Hz), 3.16 (m, 3H), 2.65 (dd, 1H, J ) 15.3, 5.9
Hz), 2.57 (dd, 1H, J ) 15.3, 5.6 Hz), 1.50-0.95 (m, 3H), 1.28
(s, 9H), 1.25 (s, 9H), 0.74 (d, 6H, J ) 6.5 Hz); 13C NMR δ (CD3-
OD, 55 °C) 171.4, 169.8, 154.4, 82.2, 63.3, 55.8, 55.6, 42.5, 40.4,
39.6, 37.9, 28.6, 28.4, 25.9, 23.6, 22.6; IR (film) 3418, 1728,
1699, 1652, 1152 cm-1; MS m/ z 415 (MH+, 78), 359 (100), 303
(41), 271 (9), 180 (25). Anal. Calcd for C21H38N2O6: C, 60.87;
H, 9.18; N, 6.76. Found: C, 60.78; H, 9.18; N, 6.57.
(1′S,3S)-4-(ter t-Bu t oxyca r b on yl)-1-(1′-isob u t yl-2′-h y-
d r oxyeth yl)-3-m eth yl-2-oxop ip er a zin e (10b) was prepared
according to the general procedure in 90% yield: mp 124 °C
(cyclohexane); [R]20 +61.6 (c ) 0.13, CHCl3); 1H NMR δ
D
(CDCl3) 4.54 (m, 2H), 3.95 (m, 1H), 3.64 (dd, 1H, J ) 11.6, 4.0
Hz), 3.54 (m, 1H), 3.30 (m, 1H), 3.21-3.08 (m, 2H), 2.74 (bs,
1H), 1.58-1.16 (m, 3H), 1.42 (s, 9H), 1.37 (d, 3H, J ) 6.9 Hz),
0.88 (d, 6H, J ) 5.7 Hz); 13C NMR δ (CDCl3) 170.4, 153.5, 80.4,
63.0, 53.8, 53.2, 41.4, 37.3, 36.3, 28.3, 24.9, 23.2, 22.0, 17.8;
IR (Nujol) 3334, 1695, 1634, 1170 cm-1; MS m/ z 315 (MH+,
2), 283 (6), 259 (18), 241 (5), 227 (100), 213 (24), 183 (5), 171
(2), 158 (18), 155 (19), 139 (7), 113 (7). Anal. Calcd for
Eth yl 2-[(1′S,3S)-4-(ter t-Bu toxyca r bon yl)-1-(1′-isobu tyl-
2′-h yd r oxyeth yl)-2-oxop ip er a zin -3-yl]a ceta te (10h ) was
prepared as an oil according to the general procedure in 66%
yield: de 75% (NMR): 1H NMR of the major diastereomer δ
(CDCl3, 55 °C) 4.66 (t, 1H, J ) 5.1 Hz), 4.28 (m, 1H), 4.11 (q,
2H, J ) 7.1 Hz), 4.09 (m, 1H), 3.72 (dd, 1H, J ) 11.6, 8.6 Hz),
3.62 (dd, 1H, J ) 11.6, 4.5 Hz), 3.41 (m, 2H), 3.27 (m, 1H),
3.04 (dd, 1H, J ) 15.7, 5.2 Hz), 2.85 (dd, 1H, J ) 15.7, 5.1
Hz), 1.63 (m, 2H), 1.46 (s, 9H), 1.30 (m, 1H), 1.23 (t, 3H, J )
C
16H30N2O4: C, 61.15; H, 9.55; N, 8.92. Found: C, 60.98; H,
9.28; N, 8.81.
(1′S,3S)-4-(ter t-Bu t oxyca r b on yl)-1-(1′-isob u t yl-2′-h y-
d r oxyeth yl)-3-(p h en ylm eth yl)-2-oxop ip er a zin e (10c) was
prepared according to the general procedure in 76% yield: mp
115 °C (cyclohexane); [R]20 +48.8 (c ) 0.21, CHCl3); 1H NMR
7.2 Hz), 0.92 (d, 3H, J ) 6.4 Hz), 0.91 (d, 3H, J ) 6.4 Hz); 13
C
D
δ (CDCl3) 7.3-7.1 (m, 5H), 4.70 (m, 2H), 3.98 (m, 1H), 3.65
(m, 1H), 3.52 (m, 1H), 3.22 (bs., 2H), 2.99 (dd, 1H, J ) 7.4 4.0
Hz), 2.87 (m, 1H), 2.55 (m, 1H), 2.15 (bs, 1H), 1.41-1.18 (m,
3H), 1.34 (s, 9H), 0.97 (d, 3H, J ) 6.1 Hz), 0.89 (d, 3H, J ) 6.1
Hz); 13C NMR δ (CDCl3) 168.9, 153.6, 137.4, 129.8, 128.3,
126.6, 80.5, 63.3, 58.7, 54.2, 41.2, 37.9, 37.9, 36.2, 28.1, 24.6,
23.3, 22.0; IR (Nujol) 3384, 1700, 1615, 1168 cm-1; MS m/ z
391 (MH+, 100), 335 (15), 299 (13), 199 (41). Anal. Calcd for
C22H34N2O4: C, 67.69; H, 8.72; N, 7.18. Found: C, 67.27; H,
8.35; N, 7.14.
NMR δ (CDCl3) 172.2, 168.0, 153.5, 80.9, 63.0, 60.7, 57.1, 53.9,
43.9, 38.9, 37.5, 36.5, 28.2, 24.7, 23.2, 22.0, 14.0; IR (film) 3443,
1731, 1696, 1651, 1170 cm-1; MS m/ z 387 (MH+, 59), 331 (100),
287 (26). Anal. Calcd for C19H34N2O6: C, 59.07; H, 8.81; N,
7.25. Found: C, 59.23; H, 8.56; N, 7.08.
(2S)-2-Isobu tyl-2-[4′-(ter t-bu toxyca r bon yl)-2′-oxop ip er -
a zin -1′-yl]a cetic a cid (11a ) was prepared in 80% yield
according to the general procedure: [R]20 -39.8 (c ) 0.09,
D
1
CHCl3); H NMR δ (CDCl3) 7.10 (bs, 1H), 5.24 (m, 1H), 4.10
(AB syst., 2H), 3.72 (m, 1H), 3.58-3.28 (m, 3H), 1.72 (m, 2H),
1.42 (s, 9H), 1.42 (m, 1H), 0.90 (m, 6H); 13C NMR δ (CDCl3)
174.7, 167.0, 153.8, 80.9, 54.1, 47.7, 42.8, 41.0, 36.7, 28.4, 24.9,
23.1, 21.2; IR (Nujol) 2900, 1740, 1694, 1613, 1166 cm-1; MS
m/ z 332 (MNH4+, 100), 315 (MH+, 85), 276 (30), 271 (15), 259
(70). Anal. Calcd for C15H26N2O5: C, 57.32; H, 8.28; N, 8.92.
Found: C, 57.24; H, 8.18; N, 8.74.
(1′S,3S)-4-(ter t-Bu toxyca r bon yl)-3-isobu tyl-1-(1′-isobu -
tyl-2′-h yd r oxyeth yl)-2-oxop ip er a zin e (10d ) was prepared
according to the general procedure in 30% yield: mp 120 °C
(cyclohexane); [R]20 +29.3 (c ) 0.08, CHCl3); 1H NMR δ
D
(CDCl3) 4.47 (m, 2H), 4.02 (m, 1H), 3.61 (m, 2H), 3.34 (m, 1H),
3.21 (m, 1H), 3.11 (dt, 1H, J ) 11.7, 3.2 Hz), 2.47 (bs, 1H),
1.60 (m, 4H), 1.43 (s, 9H), 1.28 (m, 2H), 0.91 (m, 12H); 13C
NMR δ (CDCl3) 170.5, 154.0, 80.7, 63.3, 56.1, 54.2, 41.8, 41.4,
37.3, 36.3, 28.3, 24.9, 24.8, 23.2, 23.0, 22.2, 22.0; IR (Nujol)
3464, 1672, 1642, 1166 cm-1; MS m/ z 357 (MH+, 2), 300 (29),
283 (7), 269 (100), 255 (23), 244 (95), 227 (6), 213 (13), 201
(45), 199 (28), 197 (48), 181 (8), 113 (7), 99 (8). Anal. Calcd
for C19H36N2O4‚1/4H2O: C, 63.24; H, 10.12; N, 7.77. Found:
C, 63.18; H, 9.64; N, 7.84.
(2S,3′S)-2-Isobu tyl-2-[4′-(ter t-bu toxyca r bon yl)-3′-m eth -
yl-2′-oxop ip er a zin -1′-yl]a cetic a cid (11b) was prepared in
87% yield according to the general procedure: mp 139 °C
(EtOAc); [R]20 +29.8 (c ) 0.13, CHCl3); 1H NMR δ (CDCl3)
D
5.14 (m, 1H), 4.53 (d, 1H, J ) 6.6 Hz), 3.91 (d, 1H, J ) 12.3
Hz), 3.42 (m, 1H), 3.22 (m, 2H), 1.71 (m, 2H), 1.60 (m, 1H)
1.41 (s, 9H), 1.36 (d, 3H, J ) 6.7 Hz), 0.89 (m, 6H); 13C NMR
δ (CDCl3) 174.5, 170.4, 153.7, 80.7, 54.3, 53.3, 42.4, 38.1,
36.7, 28.3, 25.0, 23.1, 21.2 18.0; IR (Nujol) 3000, 1740, 1702,
1596, 1173 cm-1; MS m/ z 329 (MNH4+, 1), 328 (MH+, 1), 273
(21), 272 (19), 128 (21), 127 (89), 198 (14), 183 (16), 181 (26),
172 (32), 155 (30), 139 (36), 113 (100). Anal. Calcd for
(1′S,3S)-3-[(2-Br om op h en yl)m eth yl]-4-(ter t-bu toxyca r -
b on yl)-1-(1′-isob u t yl-2′-h yd r oxyet h yl)-2-oxop ip er a zin e
(10e) was prepared according to the general procedure in 75%
yield: mp 138 °C (cyclohexane); [R]20 -2.1 (c ) 0.09, CHCl3);
D
1H NMR δ (CDCl3) 7.47 (d, 1H, J ) 7.8 Hz), 7.14 (m, 2H), 7.05
C
16H28N2O5: C, 58.54; H, 8.54; N, 8.53. Found: C, 58.41; H,
(m, 1H), 4.82 (d, 1H, J ) 7.3 Hz), 4.58 (m, 1H), 4.16 (m, 1H),
8.38; N, 8.58.

Synthesis of Peptidomimetics Containing 2-Oxopiperazines
J . Org. Chem., Vol. 62, No. 4, 1997 1021
(2S,3′S)-2-Isobu tyl-2-[4′-(ter t-bu toxyca r bon yl)-3′-(p h e-
n ylm eth yl)-2′-oxop ip er a zin -1′-yl]a cetic a cid (11c) was
Meth yl (2S,3′S)-2-isobu tyl-2-[3′-(p h en ylm eth yl)-2′-ox-
op ip er a zin -1′-yl]a ceta te, h yd r och lor id e (12c): [R]20D -84.3
1
prepared in 89% yield according to the general procedure:
(c ) 0.07, EtOH abs); H NMR δ (CDCl3) 7.30 (m, 5H), 5.30
1
[R]20 +34.7 (c ) 0.07, CHCl3); H NMR δ (CDCl3) 7.19-7.09
(m, 1H), 4.30-2.80 (m, 10H), 1.70 (m, 2H), 1.40 (m, 1H), 0.90
(m, 6H); 13C NMR δ (CDCl3) 171.3, 164.3, 134.4, 130.1, 129.1,
127.8, 58.1, 54.2, 52.9, 40.6, 36.7, 36.4, 24.7, 23.3, 21.2; IR (CH2-
Cl2) 2700, 1738, 1660 cm-1; MS m/ z 336 (MNH4+, 2), 319
(MH+, 100). Anal. Calcd for C18H27N2O3Cl‚H2O: C, 57.99; H,
7.78; N, 7.51. Found: C, 58.24; H, 7.19; N, 7.26.
D
(m, 5H), 5.24 (dd, 1H, J ) 10.6, 5.2 Hz), 4.74 (m, 1H), 4.15
(bs, 1H), 3.98 (m, 1H), 3.29 (m, 1H), 3.20 (bs, 2H), 2.85 (m,
1H), 2.63 (m, 1H), 1.70-1.19 (m, 3H), 1.33 (s, 9H), 0.93 (d,
3H, J ) 6.5 Hz), 0.88 (d, 3H, J ) 6.5 Hz); 13C NMR δ (CDCl3)
174.2, 169.0, 153.8, 137.5, 129.8, 128.3, 126.7, 80.8, 58.7, 54.3,
42.1, 37.7, 36.4, 28.1, 24.6, 23.1, 21.3; IR (Nujol) 3060, 1738,
1658, 1643 cm-1; MS m/ z 422 (MNH4+, 15), 405 (MH+, 100),
361 (14), 349 (78), 313 (13), 291 (18), 269 (4), 257 (3), 213 (52).
Anal. Calcd for C22H32N2O5‚1/4H2O: C, 64.63; H, 7.95; N, 6.85.
Found: C, 64.74; H, 7.88; N, 6.75.
Met h yl (2S,3′S)-2-isob u t yl-2-(3′-isobu t yl-2′-oxop ip er -
a zin -1′-yl)a ceta te, h yd r och lor id e (12d ): [R]20 -56.9 (c )
D
1
0.1, EtOH abs); H NMR δ (CDCl3) 10.68 (bs, 1H), 10.27 (bs,
1H), 5.25 (m, 1H), 3.88 (m, 2H), 3.68 (s, 3H), 3.68 (m, 1H),
3.52 (m, 1H), 3.28 (m, 1H), 1.98, (m, 3H), 1.68 (m, 2H), 1.55
(m, 1H), 0.98 (m, 6H), 0.92 (d, 3H, J ) 6.0 Hz), 0.87 (d, 3H, J
) 7.4 Hz); 13C NMR δ (CDCl3) 171.6, 165.3, 55.5, 54.3, 52.5,
40.8, 39.9, 39.9, 36.7, 24.9, 24.4, 23.1, 22.8, 21.2, 21.0; IR (film)
2630, 1739, 1660 cm-1; MS m/ z 285 (MH+, 100). Anal. Calcd
for C15H29N2O3Cl‚3/2H2O: C, 51.79; H, 9.20; N, 8.06. Found:
C, 52.26; H, 8.65; N, 7.54.
(2S,3′S)-2-Isobu tyl-2-[4′-(ter t-bu toxyca r bon yl)-3′-isobu -
tyl-2′-oxop ip er a zin -1′-yl]a cetic a cid (11d ) was prepared in
89% yield according to the general procedure: [R]20 +15.0 (c
D
1
) 0.08, CHCl3); H NMR δ (CDCl3) 5.09 (dd, 1H, J ) 9.5, 6.2
Hz), 4.59 (m, 1H), 4.01 (m, 1H), 3.39 (m, 1H), 3.20 (m, 2H),
1.68, (m, 4H), 1.45 (m, 2H), 1.44 (s, 9H), 0.88 (m, 12H); 13C
NMR δ (CDCl3) 174.8, 170.5, 154.3, 81.3, 56.2, 54.9, 42.7, 41.9,
37.7, 36.8, 28.4, 25.1, 24.7, 23.2, 23.0, 22.4, 21.4; IR (Nujol)
3100, 1740, 1666, 1644, 1180 cm-1; MS m/ z 388 (MNH4+, 68),
371 (MH+, 100), 327 (60), 315 (44), 274 (26), 271 (16), 257 (25),
229 (7), 201 (7), 152 (10). Anal. Calcd for C19H34N2O5: C,
61.62; H, 9.19; N, 7.56. Found: C, 61.74; H, 9.05; N, 7.42.
Met h yl (2S,3′S)-2-isobu t yl-2-(3′-a llyl-2′-oxop ip er a zin -
1′-yl)a ceta te, h yd r och lor id e (12f): [R]20 -56.6 (c ) 0.07,
D
EtOH abs); 1H NMR δ (CDCl3) 10.85 (bs, 1H), 10.10 (bs, 1H),
5.92 (m, 1H), 5.30 (m, 3H), 4.00-3.30 (m, 5H), 3.67 (s, 3H),
2.89 (m, 2H), 1.67, (m, 2H), 1.52 (m, 1H), 0.91 (d, 3H, J ) 5.9
Hz), 0.85 (d, 3H, J ) 5.1 Hz); 13C NMR δ (CDCl3) 171.5, 164.0,
130.5, 122.0, 56.8, 54.1, 52.5, 40.9, 39.8, 36.6, 34.7, 24.7, 23.1,
20.9; IR (CH2Cl2) 2743, 1740, 1654 cm-1; MS m/ z 269 (MH+,
100). Anal. Calcd for C14H25N2O3Cl‚H2O: C, 52.09; H, 8.37;
N, 8.68. Found: C, 51.54; H, 8.29; N, 8.20.
(2S,3′S)-2-Isob u t yl-2-[4′-(ter t-b u t oxyca r b on yl)-3′-[(2-
br om op h en yl)m eth yl]-2′-oxop ip er a zin -1′-yl]a cetic a cid
(11e) was prepared in 88% yield according to the general
procedure: [R]20 -20.6 (c ) 0.09, CHCl3); 1H NMR δ (CDCl3)
D
Meth yl (2S)-2-isobu tyl-2-[4′-(Z-Ala )-2′-oxop ip er a zin -1′-
yl]a ceta te (16a ) was prepared according to the general
procedure in 76% yield: [R]20D -26.6 (c ) 0.9, CHCl3); 1H NMR
δ (CDCl3, 55 °C) 7.30 (m, 5H), 5.66 (bs, 1H), 5.30 (m, 1H), 5.05
(s, 2H), 4.60 (m, 1H), 4.25 (m, 2H), 3.87 (m, 1H), 3.66 (s, 3H),
3.66 (m, 1H), 3.38 (m, 1H), 3.28 (m, 1H), 1.70 (m, 2H), 1.45
(m, 1H), 1.29 (d, 3H, J ) 6.8 Hz), 0.90 (d, 3H, J ) 6.6 Hz),
0.89 (d, 3H, J ) 6.5 Hz); 13C NMR δ (CDCl3, 55 °C) 171.9,
171.2, 165.8, 155.6, 136.2, 128.5, 128.2, 128.0, 66.9, 53.9, 52.2,
7.48 (d, 1H, J ) 7.4 Hz), 7.14 (m, 2H), 7.05 (m, 1H), 6.50 (bs,
1H), 5.13 (m, 1H), 4.87 (m, 1H), 4.16 (m, 1H), 3.46 (m, 2H),
3.12 (m, 3H), 1.72 (m, 2H), 1.31 (m, 1H), 1.10 (s, 9H), 0.91 (d,
6H, J ) 6.3 Hz); 13C NMR δ (CDCl3) 174.1, 168.6, 153.6, 137.2,
132.7, 131.9, 128.4, 127.3, 125.3, 80.7, 57.7, 54.8, 42.6, 37.7,
37.4, 36.7, 27.8, 24.9, 23.1, 21.5; IR (CH2Cl2) 3000, 1731-1630
cm-1; MS m/ z 502 (MNH4+, 15), 500 (MNH4+, 15), 485 (MH+,
40), 485 (MH+, 40), 471 (10), 469 (10), 429 (27), 427 (27), 385
(57), 383 (58), 332 (20), 303 (22), 276 (26), 230 (18), 213 (61),
187 (20) 167 (17), 102 (100). Anal. Calcd for C22H31N2O5Br:
C, 54.66; H, 6.42; N, 5.79. Found: C, 54.54; H, 6.62; N, 5.58.
46.9, 46.6, 42.5, 42.2, 37.1, 25.2, 23.0, 21.4, 18.9; IR (CH2Cl2)
+
3318, 1734, 1713, 1652, 1177 cm-1; MS m/ z 451 (MNH4
,
65), 434 (MH+, 41), 300 (100), 229 (19). Anal. Calcd for
C22H31N3O6: C, 60.97; H, 7.16; N, 9.70. Found: C, 60.92; H,
7.18; N, 9.65.
(2S,3′S)-2-Isobu tyl-2-[4′-(ter t-bu toxyca r bon yl)-3′-a llyl-
2′-oxop ip er a zin -1′-yl]a cetic a cid (11f) was prepared in 97%
yield according to the general procedure: [R]20 +37.7 (c )
D
Meth yl (2S)-2-isobu tyl-2-[4′-(Z-Ala)-3′-m eth yl-2′-oxopip-
er a zin -1′-yl]a ceta te (16b) was prepared according to the
general procedure in 63% yield: [R]20D +30.0 (c ) 0.14, CHCl3);
1H NMR δ (CDCl3) 7.30 (s, 5H), 5.78 (d, 1H, J ) 7.6 Hz, 1H),
5.30 (dd, 1H, J ) 10.0, 5.4 Hz), 5.05 (s, 2H), 4.84 (q, 1H, J )
7.0 Hz), 4.60 (m, 1H), 3.80 (m, 1H), 3.66 (s, 3H), 3.66 (m, 1H),
3.49 (m, 1H), 3.30 (m, 1H), 1.70 (m, 2H), 1.38 (m, 1H), 1.38 (d,
3H, J ) 7.0 Hz), 1.30 (d, 3H, J ) 6.7 Hz), 0.92 (d, 3H, J ) 6.8
Hz), 0.91 (d, 3H, J ) 6.7 Hz); 13C NMR δ (CDCl3) 171.8, 170.4,
169.4, 155.5, 136.2, 128.4, 128.0, 127.9, 66.7, 53.4, 52.8, 52.3,
46.9, 41.7, 40.7, 37.0, 25.0, 23.1, 21.1, 19.0, 17.5; IR (film) 3295,
1736, 1716, 1652 cm-1; MS m/ z 465 (MNH4+, 41), 448 (MH+,
100), 314 (33). Anal. Calcd for C23H33N3O6: C, 61.74; H, 7.38;
N, 9.39. Found: C, 61.19; H, 7.46; N, 9.11.
1
0.09, CHCl3); H NMR δ (CDCl3) 8.10 (bs, 1H), 5.73 (m, 1H),
5.19 (m, 1H), 5.03 (d, 1H, J ) 12.9 Hz), 4.98 (d, 1H, J ) 9.7
Hz), 4.58 (m, 1H), 3.98 (m, 1H), 3.42 (m, 1H), 3.20 (m, 2H),
2.57 (m, 2H), 1.70, (m, 2H), 1.45 (m, 1H), 1.41 (s, 9H), 0.98 (d,
3H, J ) 6.6 Hz), 0.88 (d, 3H, J ) 6.4 Hz); 13C NMR δ (CDCl3)
174.8, 169.1, 153.9, 133.5, 118.2, 80.9, 57.0, 54.3, 42.3, 37.4,
36.5, 28.2, 24.8, 23.2, 21.1; IR (Nujol) 3000, 1725, 1694, 1641,
1604, 1173 cm-1; MS m/ z 372 (MNH4+, 50), 355 (MH+, 100),
311 (47), 299 (48), 255 (11), 241 (20), 213 (7). Anal. Calcd for
C18H30N2O5‚1/5H2O: C, 60.40; H, 8.38; N, 7.82. Found: C,
60.42; H, 8.49; N, 7.66.
Meth yl (2S)-2-isobu tyl-2-(2′-oxop ip er a zin -1′-yl)a ceta te,
1
h yd r och lor id e (12a ): [R]20 -23.2 (c ) 0.18, EtOH abs); H
D
NMR (free base) δ (CDCl3) 5.28 (t, 1H, J ) 7.7 Hz), 3.63 (s,
3H), 3.52 (s, 2H), 3.22 (m, 2H), 3.03 (t, 2H, J ) 5.3 Hz), 2.06
(bs, 1H), 1.65 (t, 2H, J ) 7.0 Hz), 1.45 (m, 1H), 0.88 (d, 3H, J
) 6.4 Hz), 0.86 (d, 3H, J ) 6.3 Hz); 13C NMR (free base) δ
(CDCl3) 171.8, 168.1, 53.1, 52.0, 50.0, 43.8, 42.9, 36.3, 24.6,
23.0, 21.1; IR (salt, CH2Cl2) 2950, 1740, 1666 cm-1; MS m/ z
246 (MNH4+, 17), 229 (MH+, 100), 96 (8). Anal. Calcd for
C11H21N2O3Cl‚3/2H2O: C, 47.80; H, 8.15; N, 10.11. Found: C,
47.64; H, 7.86; N, 10.06.
Meth yl (2S)-2-isobu tyl-2-[4′-(Z-Ala )-3′-(p h en ylm eth yl)-
2′-oxop ip er a zin -1′-yl]a ceta te (16c) was prepared according
to the general procedure in 50% yield: [R]20 +66.7 (c ) 0.12,
D
CHCl3); 1H NMR δ (CDCl3) 7.35-7.05 (m, 10H), 5.67 (d, 1H, J
) 8.4 Hz, 1H), 5.39 (dd, 1H, J ) 11.0, 5.0 Hz), 5.11 (s, 2H),
5.04 (m, 1H), 4.57 (m, 1H), 3.65 (s, 3H), 3.59 (m, 1H), 3.40
(dd, 1H, J ) 13.6, 3.7 Hz), 3.28 (m, 1H), 3.22 (dd, 1H, J )
13.6, 5.8 Hz), 2.79 (m, 1H), 2.57 (m, 1H), 1.59 (m, 3H), 1.28
(d, 3H, J ) 6.8 Hz), 0.98 (d, 3H, J ) 6.4 Hz), 0.87 (d, 3H, J )
6.6 Hz); 13C NMR δ (CDCl3) 171.6, 170.5, 167.7, 155.4, 136.7,
129.7, 128.7, 128.3, 128.2, 128.0, 127.8, 128.8, 66.7, 57.7, 53.3,
52.1, 46.7, 41.5, 41.3, 36.5, 36.4, 24.4, 23.1, 21.2, 18.7, 17.5;
IR (CH2Cl2) 3307, 1736, 1718, 1654 cm-1; MS m/ z 541
(MNH4+, 67), 524 (MH+, 100). Anal. Calcd for C29H37N3O6:
C, 66.54; H, 7.07; N, 8.03. Found: C, 66.13; H, 7.13; N, 8.12.
Meth yl (2S)-2-isobu tyl-2-[4′-(Z-Ala )-3′-a llyl-2′-oxop ip -
er a zin -1′-yl]a ceta te (16f) was prepared according to the
general procedure in 60% yield: [R]20D +36.3 (c ) 0.10, CHCl3);
Meth yl (2S,3′S)-2-isobu tyl-2-(3′-m eth yl-2′-oxopiper azin -
1′-yl)a ceta te, h yd r och lor id e (12b): [R]20 -43.4 (c ) 0.08,
D
1
EtOH abs); H NMR δ (CDCl3) 10.50 (bs, 2H), 5.27 (m, 1H),
4.00-3.30 (m, 5H), 3.70 (s, 3H), 1.70 (m, 6H), 0.92 (d, 3H, J )
5.5 Hz), 0.88 (d, 3H, J ) 5.4 Hz); 13C NMR δ (CDCl3) 171.4,
165.3, 54.1, 53.2, 52.5, 40.3, 39.8, 36.6, 24.7, 23.0, 21.1, 16.0;
IR (CH2Cl2) 2732, 1734, 1654 cm-1; MS m/ z 260 (MNH4+, 15),
243 (MH+, 100). Anal. Calcd for C12H23N2O3Cl‚3/2H2O: C,
47.13; H, 8.51; N, 9.16. Found: C, 47.22; H, 8.11; N, 8.96.

1022 J . Org. Chem., Vol. 62, No. 4, 1997
Pohlmann et al.
1H NMR δ (CDCl3) 7.32 (m, 5H), 5.71 (m, 1H), 5.65 (m, 1H),
5.32 (m, 1H), 5.07 (s, 2H), 5.02 (d, 1H, J ) 8.9 Hz), 5.01 (d,
1H, J ) 11.8 Hz), 4.92 (m, 1H), 4.62 (m, 1H), 3.84 (m, 1H),
3.67 (s, 3H), 3.67 (m, 1H), 3.47 (m, 1H), 3.31 (m, 1H), 2.65 (m,
2H), 1.69 (m, 2H), 1.39 (m, 1H), 1.31 (d, 3H, J ) 6.8 Hz), 0.94
(d, 3H, J ) 6.6 Hz), 0.90 (d, 3H, J ) 6.5 Hz); 13C NMR δ
(CDCl3) 171.8, 170.0, 168.0, 155.6, 137.6, 133.2, 128.5, 128.2,
127.9, 118.5, 66.9, 56.3, 53.5, 52.3, 46.9, 41.8, 41.5, 36.9, 25.0,
23.3, 21.1, 19.0; IR (film) 3318, 1742, 1712, 1653, 1635, 1174
cm-1; MS m/ z 491 (MNH4+, 7), 474 (MH+, 12), 340 (50), 327
(100), 237 (24), 211 (7), 181 (12), 108 (9). Anal. Calcd for
C25H35N3O6‚H2O: C, 61.10; H, 7.53; N, 8.55. Found: C, 61.44;
H, 7.24; N, 8.25.
Ack n ow led gm en t. We are grateful to M. T. Adeline,
ICSN, CNRS, Gif-sur-Yvette, for performing the HPLC
analysis. This work was supported by a CAPES/
COFECUB grant award to A.P.
J O961398D