Chemoselective Michael reactions on pyroglutamates. Expeditious synthesis of spiro-bis-γ-lactams as β-turn peptidomimetics

Article abstract of DOI:10.1016/S0040-4020(02)00437-4

Starting from pyroglutamic acid, the synthesis of spiro-bis-γ-lactams, using as key step a chemoselective Michael reaction of pyroglutamates is reported. Thus, the reaction of N-BOC-L-methyl pyroglutamate with LiHMDS gives the enolates at C4 which react w

Full text of DOI:10.1016/S0040-4020(02)00437-4

TETRAHEDRON
Pergamon
Tetrahedron 58 ;2002) 4825±4836
Chemoselective Michael reactions on pyroglutamates.
Expeditious synthesis of spiro-bis-g-lactams
as b-turn peptidomimetics
a,p
Miguel F. BranÄa, Marõa Garranzo, Beatriz de Pascual-Teresa, Javier Perez-Castells
a
a
a
Â
Â
b
Â
and Marõa Rosario Torres
a
  Â
Departamento de Quõmica Organica y Farmaceutica, Facultad de CC, Experimentales y de la Salud, Universidad San Pablo-CEU,
Â
Urb. Monteprõncipe, Boadilla del Monte, 28668 Madrid, Spain
b
 Â
Laboratorio de Difraccion de Rayos-X, Facultad de Quõmica, Universidad Complutense de Madrid, Ciudad Universitaria,
28040 Madrid, Spain
Received 5February 2002; revised 5April 2002; accepted 22 April 2002
AbstractÐStarting from pyroglutamic acid, the synthesis of spiro-bis-g-lactams, using as key step a chemoselective Michael reaction of
pyroglutamates is reported. Thus, the reaction of N-BOC-l-methyl pyroglutamate with LiHMDS gives the enolates at C4 which react with
several Michael acceptors. On the other hand, N-benzyl-l-methyl pyroglutamate reacts under the same conditions, to give the ester enolate
which reacts with Michael acceptors leading to quaternized derivatives. The synthesis of the bicyclic spirolactams results from a reduction of
the nitro group present in these derivatives which directly gives the spiro compounds. These ®nal compounds may act as b-turn mimetics, as
they have torsion angles which are in the range of b-turns of type II and II0. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
turns are classi®ed according to their torsion angles C and F
;Fig. 1). The most common b-turns are type II in which the
ideal angles are 260, 120, 80 and 08 for F2, C2, F3, and C3,
respectively.7
Pyroglutamic acid is a useful starting material for the
synthesis of several natural products,1 and has also been
used as a chiral building block for the synthesis of proline
derivatives2 and glutamic acid analogs.3 Due to its function-
ality, pyroglutamic acid has been modi®ed many times to
avoid racemization at C-2, and to direct the reactivity to
either carbonyl group. Although many results have been
reported about aldol condensations and alkylations,4 we
have found few studies on this type of Michael reactions.5
We have previously reported that the nature of the nitrogen
protecting group determines the chemoselectivity of the
enolization.6 The Michael addition of a 3-;b-nitrovinyl)-
indole was used as a model system. In the present work,
we report our studies on the scope of this reaction with other
substrates. The results are used to effect an expeditious
synthesis of bis-spiro-g-lactams, which can be considered
as b-turn mimetics.
The synthesis of nonpeptidic mimetics of these secondary
structures of peptides has received much attention in the
past years.8 Thus, we summarize in Fig. 2 some examples
of structures described in the literature that share the char-
acteristic of being spirolactams based on the proline and
pyroglutamic rings. These spirocompounds are interesting
peptidomimetics, since they have ®xed angles that resemble
some naturally abundant b-turns.9 In addition, when they
are introduced into peptides, the conformational constraints
of these spirocyclic structures can lead to increased bio-
availability.10 In particular, compounds 1±3 are mimetics
of type II b-turns with increasing constraints.11 The
synthesis of these spirolactams was carried out using a
Mitsunobu reaction to close the spirocyclic system.12
Other examples of type II b-turn mimetics are compound
4,13 and the very recently described spirolactams 5 and 6.14
The development of new compounds designed to mimic the
main secondary structures of peptides is currently an impor-
tant approach for the study of the bioactive conformations of
a natural peptide. The b-turn is a secondary substructure
related in many peptides to their biological activity. These
Keywords: peptidomimetics; Michael reactions; aminoacids.
Corresponding author. Tel.: 134-91-372-4700; fax: 134-91-351-0475;
e-mail: mfbrana@ceu.es
p
Figure 1. Typical b-turn with its angles.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020;02)00437-4

4826
M. F. BranÄa et al. / Tetrahedron 58 52002) 4825±4836
Scheme 2.
The nitrogen protecting group directs the deprotonation to
each position of the pyroglutamic system due to electronic
and chelation effects. In all these reactions, no multiple
alkylation products were detected by NMR spectroscopy.
The cleavage of the pyroglutamic ring was neither observed.
Table 1 shows the results of these Michael reactions.
Functionalization of pyroglutamates at C4 by lithium
enolate chemistry is well established for alkylations and
for aldol reactions.4 While alkylations are described to
give exclusive formation of a products, aldol reactions are
only totally diastereoselective when using titanium
enolates.16 Our results show exclusive formation of a
products in Michael reactions. The relative stereochemistry
of the pyroglutamic ring was assigned by n.O.e experiments
and was trans in all cases.17 Since in most cases conversion
is not complete ;entries 2, 3 and 5, Table 1) it is possible to
recover unreacted starting materials. It is important to point
out that besides total facial diastereoselectivity, with trans
relative con®guration between C2 and C4, in one case ;entry
5, Table 1), only one product was obtained showing total
Figure 2. Some mimetics of b-turns.
Compound 5 was found to possess the same ability as PLG
;l-prolyl-l-leucyl-glycinamide) to enhance the binding of
[3H]ADTN to dopamine receptors.15
The conformational angles of these compounds depend on
the substitution patterns they have. We believe that the
introduction of different substituents in the spirolactam
system may ®x angles F and C. Thus, starting from pyro-
glutamic acid, we report here the synthesis, in few steps, of
spiro-bis-g-lactams, using as key step a chemoselective
Michael reaction of pyroglutamates ;Scheme 1).
Table 1. Michael reactions at C4 of compound 7
Entry
R
Z
Product
Ratioa
Yield
1
2
3
4
53-;
Ph
4-TBSOC6H4
3-;N-BOC-indolyl)
4-TBSOC6H4
N-Tos-indolyl)
NO2
NO2
NO2
CO2Me
CO2Me
8
9
10
11
12
85:15
80:20
60:40
80:20
.95:5d
40b
70:20c
60b
45b
50
a
Calculated by integration of H2 in the 1H NMR spectra of the crude
mixture.
In pure mixture of isomers. A small amount was separated by semi-
preparative HPLC for characterization.
Separated by column chromatography.
b
c
d
Only one reaction product is detected by NMR.
Scheme 1.
2. Results and discussion
We started this work with the study of the Michael
reactions of l-methyl pyroglutamate. As expected
from our previous experience for a similar system6
and other earlier works that reported the results for related
reactions,4c we found that the nature of the nitrogen protect-
ing group directed the enolization. Thus, the reaction of
N-BOC-l-methyl pyroglutamate, 7, with LiHMDS at
2788C, gave the enolates at C4 which reacted with
several Michael acceptors to give compounds 8±12 as
mixtures of only two diastereomers ;Scheme 2).
Scheme 3.

M. F. BranÄa et al. / Tetrahedron 58 52002) 4825±4836
Table 2. Michael reactions of compound 13 at C2
4827
conditions, gave the ester enolate which reacted with
Michael acceptors. The ®nal quenching with saturated
ammonium chloride gave mixtures of diastereomeric
racemic compounds, which were separated by column
chromatography, or by semipreparative HLPC ;Scheme 3,
Table 2).18 In this reaction, that involves the creation of a
quaternary center, yields go from moderate to good.19
Cleavage of the pyroglutamic ring or reaction at other
positions was not observed in any case. On the other
hand, Michael acceptors like cinnamonitrile and acrylo-
nitrile failed to give any addition products under all tested
conditions.
Entry
R
Z
Products
Ratioa
Yieldb
1
2
3
Ph
NO2
NO2
NO2
NO2
NO2
CO2Me
14a/14b
15a/15b
16a/16b
17a/17b
18a/18b
19a/19b
1.5:1
1:1
1.5:1
1:1.530/25
1:1
1:1
35/20
30/30
37/17
2-MeOC6H4
4-TBSOC6H4
3-;N-BOC-indolyl)
3C6H3
4
-;M53e,O4,)5
6
30/30
25/35
4-TBSOC6H4
a
Calculated by integration of the signal of the benzylic methylenes in the
1H NMR spectra of the crude mixture.
In pure products separated by column chromatography.
b
To identify each diastereomer, a single crystal of one of the
isomers 14 was submitted to X-ray diffraction analysis,
which showed that the relative stereochemistry corre-
sponded to 14a ;2Sp,10Rp).20 The identi®cation of the two
diastereomeric mixtures obtained in the reactions of entries
2±5in Table 2 was done by n.O.e. experiments carried out
for spirolactams derived from these compounds ;vide infra).
Nevertheless, as compounds 19a and 19b ;entry 6, Table 2)
were not to be cyclised, we identi®ed their stereochemistry
by analogy of their NMR spectra with those of the rest of the
series.
This procedure allows the preparation of glutamic
derivatives with quaternary carbons. This is a remarkable
feature, since the few examples reported in the
literature, dealing with the preparation of these amino acid
derivatives, usually involve the preparation of the pyro-
glutamic ring from previously a-substituted glutamic
acids.21
Scheme 4.
diastereoselectivity of the Michael process. In all other
cases, the two products obtained have opposite con®gura-
tion at the stereogenic center located outside the ring, with
one of them more abundant. This means that there must be
an important difference in stability between the two possible
transition states of the Michael reaction.
The synthesis of the bicyclic spirolactams was planned by a
reduction of the nitro group in compounds 14±18, followed
by aminolysis of the ester. Thus, compound 17a was
submitted to reduction with ammonium formate in the
presence of Pd;C). We were very pleased to observe the
direct cyclization of the intermediate to give two bicyclic
compounds that turned out to be compounds 23a and 27a
;Scheme 4).
On the other hand, N-benzyl-l-methyl pyroglutamate 13
was prepared from pyroglutamic acid following literature
procedures. The reaction with LiHMDS under the same
1
The H NMR spectra of these two compounds were very
Table 3. The reduction reactions of compounds 13±18
Method Aa
Ratioc
Method Bb
Product
Entry
R
Substrate
Products
Yieldd
Yieldd
1
2
3
Ph
Ph
2-MeOPh
2-MeOPh
14a
14b
15a
15b
16a
16b
17a
17b
18a
18b
20a/24a
20b/24b
21a/25a
21b/25b
22a/26a
22b/26b
23a/27a
23b/27b
±
19:1
3:1
6:1
3:1
6:1
3:1
4:1
3:1
±
70/0
24a
24b
±
72
70
±
65/10
55/20
60/25±
70/15
70/25
70/25
70/20
4
54-TBSOPh
6
7
8
±
26a
26b
27a
27b
28a
28b
80
90
50
50
75
70
4-TBSOPh
3-;N-BOC-indolyl)
3-;N-BOC-indolyl)
3,4,5-;MeO)3Ph
3,4,5-;MeO)3Ph
9
10
±
±
a
Ammonium formate/Pd;C) in MeOH.
Hydrogen/Ni Raney at 45psi in MeOH/THF.
b
c
d
Calculated by integration of two well resolved signals in the 1H NMR spectra of the crude mixture.
In pure product with correct spectroscopic and analytical data.

4828
M. F. BranÄa et al. / Tetrahedron 58 52002) 4825±4836
similar, with the only remarkable difference of a signal at
10.38 ppm for compound 23a that did not appear in 27a.
The presence of an OH band in the IR spectrum prompted us
to propose the structure depicted in Scheme 1 for compound
23a. Mass spectra of compounds 23a and 27a also supported
this hypothesis. Compound 27a, with M1 at 459, shows a
loss of the BOC fragment leading to a M112100 peak
which is the base peak. For the N-hydroxylated compound
23a, the M1 peak could not be observed, but a peak corre-
sponding also to the same BOC fragmentation was clear and
indicated that the mass of this compound was 475, 16 amu
more than 27a. In order to con®rm the structure of these
compounds, we reduced 23a with TiCl3 in THF, following
the conditions described by Miller for the reduction of
N-hydroxy-b-lactams to NH-b-lactams.22 This reaction led
to 27a with 82% yield. We can assume that a N-hydroxy
intermediate is formed in the reduction of the nitro group
which attacks the ester to give the cyclic hydroxamic acid.
In order to effect the conformational study of these spiro-
compounds, we ®nally carried out the synthesis of two dia-
stereomeric N-deprotected bis-g-lactams, 32, following
Scheme 5. The PMB group was selected, since it was easier
to remove than the benzyl group. Thus, starting from methyl
N-;p-methoxybenzyl)pyroglutamate, 29, we obtained the
diastereomers 30a, b, which were separated and treated
with CAN before doing the reduction with hydrogen in
the presence of Raney±Nickel. The spirolactams 32 were
identi®ed by means of n.O.e. experiments. The reactions
proceeded with good yields in each step.
A Monte Carlo random variational conformational search
using amber force ®eld was performed on compounds 32 to
locate water-solvated low energy minima, using the solution
model GB/SA as implemented in Macromodel.23±25 The
lowest energy structures were subjected to a RHF/6-31Gp
geometry optimization using Gaussian 94.26 According to
these data, the torsion dihedral angles ®t reasonably well
with the ideal structural parameters of type-II b-turn. For
compound 32a, values of 237 and 1136 for angles F2 and
C2, respectively, were found. These values are within the
accepted interval ;^30) to classify this compound as a
b-turn type II mimetic. For compound 32b, values of 135
and 2106 for angles F2 and C2, respectively, were
obtained. These values lie within the interval to be con-
sidered as a type II0 b-turn mimetic. Optimized geometries
are represented in Fig. 5.
Table 3 shows the results for the reaction of compounds
14±18 with ammonium formate and Pd;C). The reaction
conditions were chosen to favor the formation of the
hydroxamic acids as the major reaction products. The direct
obtention of bis-g-lactams such as 24±28 as the only reduc-
tion products was achieved by hydrogenation of the starting
compounds 14±18 in the presence of Raney Nickel. The
results are also included in Table 3 and show the possibility
of the obtention of any of the two products just by changing
the reduction conditions.
In summary, Michael reactions of pyroglutamates can lead
The con®guration of these spirocompounds was assigned by
n.O.e. experiments. The methodology used exempli®ed for
compound 27 was as follows ;Fig. 3). Proton at C9 was
identi®ed by means of an HETCOR experiment and
irradiated observing a 6% n.O.e. effect in one of the protons
situated at C4 only for isomer 27b. The reverse n.O.e. effect
was of 5%. These effects were not observed for the other
diastereomer 27a, con®rming the relative stereochemistry
depicted in Fig. 3.
Figure 4. ORTEP drawing of compound 24a.
The con®guration of the rest of compounds shown in Table
3 was assigned the same way, resulting in a ;5Sp,9Rp)
con®guration for compounds 20±28a and compounds
;5Sp,9Sp) for 20±28b. These conclusions were later
con®rmed by an X-ray diffraction analysis of a single crystal
of compound 24a ;Fig. 4).
Figure 3. n.O.e. increments 27a, b.
Scheme 5. Synthesis of compounds 32a, b.

M. F. BranÄa et al. / Tetrahedron 58 52002) 4825±4836
4829
silica gel chromatography, using hexane/EtOAc mixtures as
eluent.
3.2.1. Methyl -2S,4S)-1--tert-butoxycarbonyl)-4-[10-
phenyl-20-nitroethyl]pyroglutamate, 8. This compound
was obtained as a 1/4 mixture of diastereoisomers
;440 mg, 40%). The isomers a and b were characterized
from a small fraction of this mixture after separation by
semipreparative HPLC. Isomer a: [a]Dˆ248.88 ;c 0.59,
CHCl3); IR ;CHCl3) 3010, 2980, 1790, 1745, 1735 cm21
;
1H NMR ;CDCl3) d 1.46 ;s, 9H), 1.96±2.16 ;m, 2H), 3.11±
3.19 ;m, 1H), 3.75±3.81 ;m, 1H), 3.75 ;s, 3H), 4.19 ;dd, 1H,
Jˆ9.3 and 2.7 Hz), 5.16 ;d, 2H, Jˆ7.7 Hz), 7.24±7.25;m,
2H), 7.30±7.35;m, 3H); 13C NMR ;CDCl3) d 172.8, 171.3,
149.1, 136.6, 129.2, 128.3, 127.9, 84.2, 77.9, 56.4, 52.7,
45.1, 43.2, 27.8, 27.4. Isomer b: [a]Dˆ271.48 ;c 0.07,
1H NMR ;CDCl3) d 1.50 ;s, 9H), 1.71±1.95 ;m, 2H), 2.92±
3.03 ;m, 1H), 3.65±3.66 ;m, 1H), 3.75 ;s, 3H), 4.47 ;dd, 1H,
Jˆ9.3 and 1.6 Hz), 4.74 ;dd, 1H, Jˆ12.6 and 10.4 Hz), 5.63
;dd, 1H, Jˆ12.6 and 5.0 Hz), 7.16±7.22 ;m, 2Hr), 7.29±
7.37 ;m, 3H); 13C NMR ;CDCl3) d 172.7, 171.4, 155.6,
149.1, 129.0, 128.9, 120.6, 84.2, 78.0, 56.4, 52.7, 44.3,
44.1, 27.8, 25.6.
Figure 5. Optimized geometries for compounds 32a, b.
to interesting compounds related to peptidomimetics. In the
case of C4 enolizations, two new stereocenters are formed.
Stereochemistry at C4 is exclusively a in all cases, showing
total diastereofacial selectivity for this reaction. In addition,
the stereogenic open chain carbon is formed with high
stereoselectivity. For C2 enolization, interesting quater-
nizated aminoacid derivatives are obtained, that can be
converted into spiro-bis-g-lactams in only one step with
good yields. These ®nal compounds may act as b-turn
mimetics, since they have torsion angles that are in the
range of b-turns of type II and II0.
CHCl3); IR ;CHCl3) 3010, 2960, 1780, 1745, 1730 cm21
;
3.2.2. Methyl -2S,4S)-1--tert-butoxycarbonyl)-4-{20-
nitro-10-[4--tert-butyldimethylsilanyloxy)phenyl]ethyl}-
pyro-glutamate, 9. This compound was obtained as a 4/1
mixture of diastereoisomers, which were separated by silica
gel chromatography. Isomer a: white solid ;350 mg, 71%);
mp 57±608C; [a]Dˆ15.78 ;c 0.70, CHCl3); IR ;KBr); 2950,
3. Experimental
3.1. General
1
1785, 1745, 1720 cm21; H NMR ;CDCl3) d 0.18 ;s, 6H),
0.96 ;s, 9H), 1.49 ;s, 9H), 1.75±1.95;m, 2H), 2.88±2.98 ;m,
1H), 3.62±3.70 ;m, 1), 3.75;s, 3H), 4.46 ;dd, 1H, Jˆ9.3 and
1.9 Hz), 4.69 ;dd, 1H, Jˆ13.2 and 10.4 Hz), 5.54 ;dd, 1H,
Jˆ13.2 and 5.0 Hz), 6.78 ;d, 2H, Jˆ8.8 Hz), 7.02 ;d, 2H,
Jˆ8.8 Hz); 13C NMR ;CDCl3) d 172.9, 171.4, 155.6, 149.1,
129.0, 128.9, 120.6, 84.2, 78.0, 56.4, 52.7, 44.3, 43.4, 27.8,
27.3, 25.6, 18.1, 24.5. Isomer b: white solid ;100 mg,
20%); mp 118±1218C; [a]Dˆ277.8 ;c 0.80, CHCl3); IR
1
Melting points are uncorrected. H and 13C NMR spectra
were recorded at 300 and 75.43 MHz, respectively. NMR
spectra were registered in CDCl3 and chemical shifts are
given in ppm relative to TMS ;1H, 0.00 ppm) or CDCl3
;13C, 77.00 ppm). Elemental analyses were preformed in
the UCM Microanalysis Service ;Facultad de Farmacia,
Universidad Complutense de Madrid, Spain). For puri®ca-
tion of crude reaction mixtures ¯ash chromatography was
applied in all cases. Silica gel ;230±400 mesh) was used as
the stationary phase. Analytical HPLC was with Hypersyl
BDS C18 column ;250£3 mm2), monitoring at 220 nm and
eluting with mixtures of CH3CN/H2O or MeOH/H2O. Semi-
preparative HPLC was performed with precolumn and
Zorbax ODS ;250£9.4 mm2) column.
1
;KBr); 3010, 1785, 1745, 1720 cm21; H NMR ;CDCl3) d
0.19 ;s, 6H, Me2Si), 0.96 ;s, 9H), 1.46 ;s, 9H), 1.97±2.15
;m, 2H), 3.07±3.14 ;m, 1H), 3.67±3.74 ;m, 1H), 3.74 ;s,
3H), 4.14 ;dd, 1H, Jˆ9.3 and 3.3 Hz), 5.12 ;d, 2H,
Jˆ8.2 Hz), 6.79 ;d, 2H, Jˆ8.8 Hz), 7.11 ;d, 2H,
Jˆ8.8 Hz); 13C NMR ;CDCl3) d 172.9, 171.3, 155.8,
148.8, 129.9, 127.7, 120.6, 83.9, 77.0, 57.0, 52.6, 44.3,
43.6, 27.8, 25.6, 25.5, 18.1, 24.4.
3.2.3. Methyl -2S,4S)-1--tert-butoxycarbonyl)-4-{10-[-1-
tert-butoxycarbonyl)indol-3-yl]-20-nitroethyl}pyro-gluta-
mate, 10. This compound was obtained as a 3/2 mixture of
diastereoisomers ;481 mg, 60%). The isomers were charac-
terized from a small fraction of this mixture separated by
semipreparative HPLC. Isomer a: oil; [a]Dˆ118.9 ;c 0.11,
3.2. Synthesis of 4-substituted pyroglutamates 8±12
General method. To a solution of ethyl ;2S)-1-;tert-butoxy-
carbonyl)pyroglutamate 7 ;1 mmol) in dry THF ;5ml)
stirred at 2788C under argon atmosphere was added a
1 M solution of lithium hexamethyldisilazide in THF
;1.2 ml, 1.2 mmol). The mixture was stirred at 2788C for
1 h.. The a,b-unsaturated compound ;1.3 mmol) dissolved
in dry THF ;2 ml) was added at 2788C, and the mixture was
then stirred for 3 h at this temperature. The reaction mixture
was quenched with saturated solution of ammonium
chloride at 2788C, and extracted with EtOAc. The
combined organic phases were dried over Na2SO4, ®ltered,
and evaporated to dryness. The products were puri®ed by
CHCl3); IR ;CHCl3) 2985, 1785, 1735, 1720 cm21 1H
;
NMR ;CDCl3) d 1.50 ;s, 9H), 1.68 ;s, 9H), 1.88±2.09 ;m,
2H), 3.11±3.21 ;m, 1H), 3.74 ;s, 3H), 3.97±4.05;m, 1H),
4.48 ;dd, 1H, Jˆ9.3 and 1.6 Hz), 4.89 ;dd, 1H, Jˆ12.6 and
10.46 Hz), 5.59 ;dd, 1H, Jˆ12.6 and 15.0 Hz), 7.24±7.37
;m, 2H), 7.49 ;s, 1H), 7.53 ;d, 1H, Jˆ7.7 Hz), 8.13 ;d, 1H,
Jˆ8.2 Hz); 13C NMR ;CDCl3) d 172.9, 171.3, 149.3, 149.1,
131.4, 125.1, 124.6, 124.5, 123.1, 118.7, 115.9, 115.7, 84.5,

4830
M. F. BranÄa et al. / Tetrahedron 58 52002) 4825±4836
84.2, 56.4, 52.7, 42.7, 36.9, 28.2, 27.9, 27.3. Isomer b:
[a]Dˆ258.4 ;c 0.15, CHCl3); IR ;CHCl3) 3010, 2980,
mixture was then stirred for 4 h. The reaction mixture was
quenched with saturated solution of ammonium chloride at
2258C, and the solution allowed to warm to room tempera-
ture. The solution was extracted with Et2O, and the
combined organic phases dried ;Na2SO4), and evaporated
to dryness. The products were separated and puri®ed by
silica gel chromatography, using hexane/EtOAc as
elluents.
1
1790, 1745, 1735 cm21; H NMR ;CDCl3) d 1.47 ;s, 9H),
1.67 ;s, 9H), 1.98±2.09 ;m, 2H), 2.11±2.22 ;m, 1H), 3.76 ;s,
3H), 4.15±4.20 ;m, 1H), 4.33 ;d, 1H, Jˆ8.2 Hz), 5.08 ;dd,
1H, Jˆ13.7 and 7.9 Hz), 5.26 ;dd, 1H, Jˆ13.7 and 7.2 Hz)
7.28±7.38 ;m, 2H), 7.52 ;d, 1H, Jˆ7.7 Hz), 7.56 ;s, 1H),
8.15;d, 1H, Jˆ8.2 Hz); 13C NMR ;CDCl3) d 172.7, 171.3,
149.2, 149.1, 130.5, 125.1, 124.5, 124.4, 123.1, 118.2,
115.5, 114.9, 84.3, 84.0, 56.7, 52.7, 43.8, 34.2, 28.2, 27.8,
25.9.
3.3.1. Methyl 1-benzyl-2--20-nitro-10-phenylethyl)pyro-
glutamate, 14. This compound was obtained as a 1.5:1
mixture of diastereoisomers. The isomers 14a and 14b
were separated by a second ¯ash chromatography, yielding
553 mg ;35%) of 14a and 316 mg ;20%) of 14b. 52Sp,10Rp)-
3.2.4. Methyl -2S,4S)-1--tert-butoxycarbonyl)-4-{10-[4-
-tert-butyldimethylsilanyloxy)phenyl]-20--methoxycar-
bonyl)ethyl}pyroglutamate, 11. This compound was
obtained as a 2/8 mixture of diastereoisomers ;256 mg,
45%). The isomers were characterized from a small fraction
of this mixture separated by semipreparative HPLC. Isomer
a: oil; [a]Dˆ228.68 ;c 0.07, CHCl3); IR ;CHCl3) 3010,
1
14a: oil; IR ;CHCl3); 3010, 2960, 1740, 1690 cm21; H
NMR ;CDCl3) d 1.50±1.61 ;m, 1H), 2.10±2.34 ;m, 2H),
2.57±2.68 ;m, 1H), 3.09 ;s, 3H), 4.27 ;d, 1H, Jˆ15.4 Hz),
4.54 ;dd, 1H, Jˆ10.4 and 3.8 Hz), 4.72 ;dd, 1H, Jˆ13.7 and
3.8 Hz), 4.93 ;dd, 1H, Jˆ13.7 and 10.4 Hz), 5.07 ;d, 1H,
Jˆ15.4 Hz), 7.17±7.36 ;m, 10H); 13C NMR ;CDCl3) d
175.3, 170.6, 136.1, 133.4, 129.2, 129.0, 128.5, 128.3,
127.5, 127.3, 75.4, 69.9, 52.6, 45.2, 44.6, 28.5, 23.6; MS
m/z ;%) 276 ;12), 233 ;15), 232 ;63), 91 ;100), 65 ;11).
1
1780, 1840, 1725cm 21; H NMR ;CDCl3) d 0.18 ;s, 6H),
0.97 ;s, 9H), 1.45;s, 9H), 1.97±2.13 ;m, 2H), 2.87 ;dd, 1H,
Jˆ15.9 and 8.2 Hz), 2.98±3.06 ;m, 1H), 3.12 ;dd, 1H,
Jˆ15.9 and 7.7 Hz), 3.45±3.51 ;m, 1H), 3.58 ;s, 3H), 3.72
;s, 3H), 4.11 ;dd, 1H, Jˆ9.1 and 1.4 Hz), 6.75;d, 2H,
Jˆ8.2 Hz), 7.08 ;d, 2H, Jˆ8.2 Hz); 13C NMR ;CDCl3) d
173.6, 172.5, 171.7, 155.6, 149.1, 132.3, 129.3, 120.1, 83.5,
56.8, 52.5, 51.6, 45.9, 41.3, 36.2, 27.9, 25.6, 25.4, 18.1,
24.4. Isomer b: oil; [a]Dˆ215.5 ;c 0.20, CHCl3); IR
52Sp,10Sp)-14b: IR ;CHCl3); 3020, 2940, 1740, 1690 cm21
;
1H NMR ;CDCl3) d 2.02±2.13 ;m, 1H), 2.38±2.46 ;m, 1H),
2.57±2.68 ;m, 2H), 3.33 ;s, 3H), 4.30 ;dd, 1H, Jˆ13.2 and
3.3 Hz), 4.42 ;dd, 1H, Jˆ11.6 and 3.3 Hz), 4.66 ;dd, 1H,
Jˆ13.2 and 11.6 Hz), 4.69 ;d, 1H, Jˆ15.4 Hz), 4.75 ;d, 1H,
Jˆ15.4 Hz), 7.21±7.38 ;m, 10H); 13C NMR ;CDCl3) d
176.1, 169.6, 137.0, 133.6, 129.2, 129.1, 128.8, 128.7,
127.9, 127.7, 75.3, 71.6, 52.3, 46.0, 44.9, 29.3, 25.4; MS
m/z ;%); 276 ;10), 233 ;12), 232 ;62), 91 ;100), 65;12).
1
;CHCl3) 3020, 1785, 1745, 1720 cm21; H NMR ;CDCl3)
d 0.18 ;s, 6H), 0.96 ;s, 9H), 1.47 ;s, 9H), 1.75±1.91 ;m, 2H),
2.68 ;dd, 1H, Jˆ15.9 and 9.3 Hz), 2.83±2.93 ;m, 1H), 3.31
;dd, 1H, Jˆ15.9 and 6.0 Hz), 3.45±3.52 ;m, 1H), 3.54 ;s,
3H), 3.74 ;s, 3H), 4.31 ;dd, 1H, Jˆ8.8 and 2.8 Hz), 6.75;d,
2H, Jˆ8.2 Hz), 7.03 ;d, 2H, Jˆ8.2 Hz); 13C NMR ;CDCl3)
d 173.6, 172.0, 171.7, 154.7, 149.2, 132.6, 129.1, 120.1,
83.6, 56.6, 52.5, 51.5, 45.7, 41.5, 38.5, 27.9, 26.3, 25.6,
18.1, 24.4.
3.3.2. Methyl 1-benzyl-2-[10--2-methoxyphenyl)-20-
nitroethyl]pyroglutamate, 15. These compounds were
obtained as a 1:1 mixture of diastereoisomers. The isomers
15a and 15b were separated by a second ¯ash chromato-
graphy, yielding 483 mg ;30%) of 15a and 483 mg ;30%) of
15b. 52Sp,10Rp)-15a: white solid ;MeOH/H2O); mp 125±
3.2.5. Methyl -2S,4S)-1--tert-butoxycarbonyl)-4-{20-
-methoxycarbonyl)-10-[1--toluene-4-sulfonyl)indol-3-
yl]ethyl}pyroglutamate, 12. This compound was obtained
as a single diastereoisomer ;360 mg, 50%); [a]Dˆ254.58 ;c
0.30, CHCl3); IR ;CHCl3) 3010, 1780, 1745, 1725 cm21; 1H
NMR ;CDCl3) d 1.50 ;s, 9H, tBu), 1.94±2.00 ;m, 2H), 2.32
;s, 3H), 2.90 ;dd, 1H, Jˆ15.9 and 8.8 Hz), 3.07±3.20 ;m,
2H), 3.53 ;s, 3H), 3.71 ;s, 3H), 3.88±3.94 ;m, 1H), 4.33 ;dd,
1H, Jˆ7.7 and 3.3 Hz), 7.18±7.35;m, 4H), 7.47 ;s, 1H),
7.51 ;d, 1H, Jˆ7.2 Hz), 7.69 ;d, 2H, Jˆ8.2 Hz), 7.96 ;d, 1H,
Jˆ8.2 Hz); 13C NMR ;CDCl3) d 173.0, 172.0, 171.4, 149.2,
144.9, 138.2, 134.9, 130.4, 129.8, 126.8, 125.1, 124.0,
123.5, 121.8, 119.2, 113.8, 83.8, 56.5, 52.6, 51.7, 44.9,
35.5, 31.6, 27.9, 25.1, 21.5.
1
1278C; IR ;KBr); 3000, 2960, 1720, 1685cm 21; H NMR
;CDCl3) d 1.67±1.79 ;m, 1H), 2.25±2.37 ;m, 2H), 2.55±
2.66 ;m, 1H), 3.10 ;s, 3H), 3.87 ;s, 3H), 4.34 ;d, 1H,
Jˆ15.9 Hz), 4.72 ;dd, 1H, Jˆ11.6 and 3.3 Hz), 4.91±5.00
;m, 3H), 6.88±6.97 ;m, 2H), 7.13±7.33 ;m, 7H); 13C NMR
;CDCl3) d 175.4, 170.7, 158.0, 136.7, 130.1, 128.7, 128.3,
127.3, 122.1, 121.7, 111.5, 75.9, 70.3, 55.6, 52.5, 44.6, 39.5,
28.8, 24.2; Anal. calcd for C22H24N2O6: C, 64.07; H, 5.87;
N, 6.79. Found: C, 64.14; H, 5.93; N, 7.01. 52Sp,10Sp)-15b:
1
oil; IR ;CHCl3); 3000, 2940, 1735, 1700 cm21; H NMR
;CDCl3) d 2.14±2.24 ;m, 1H), 2.28±2.38 ;m, 1H), 2.42±
2.53 ;m, 1H), 2.58±2.66 ;m, 1H), 3.31 ;s, 3H), 3.83 ;s, 3H),
4.36 ;dd, 1H, Jˆ13.2 and 3.3 Hz), 4.63 ;d, 1H, Jˆ15.4 Hz),
4.71 ;d, 1H, Jˆ15.4 Hz), 4.74 ;dd, 1H, Jˆ11.0 and 3.3 Hz),
4.91 ;dd, 1H, Jˆ13.2 and 11.0 Hz), 6.85±6.92 ;m, 2H),
3.3. General procedure for the synthesis of 2-substituted
pyroglutamates 14±19
7.13±7.16 ;m, 1H), 7.22±7.35;m, 6H);
13C NMR
;CDCl3) d 176.1, 170.5, 157.9, 137.4, 130.3, 129.9, 128.6,
127.9, 127.4, 122.3, 120.8, 111.4, 75.0, 72.2, 55.6, 52.2,
45.5, 41.6, 29.3, 27.1.
To a solution of HMDS ;1.1 mmol) in THF ;2 ml) under
argon atmosphere and at 2788C was added dropwise
n-BuLi ;1.05mmol of 1.6 M hexane solution). After
30 min, a solution of Methyl ;2S)-N-benzylpyroglutamate
13 ;1 mmol) in THF ;1 ml) was added at 2788C, and the
solution stirred for 1 h. The a,b-unsaturated compound
;1.2 ml) in THF ;2 ml) was added also at 2788C, and the
3.3.3. Methyl 1-benzyl-2-{10-[-4-tert-butyldimethyl-
silanyloxy)phenyl]-20-nitroethyl}pyroglutamate,
These compounds were obtained as a 1.5:1 mixture of
diastereoisomers. The isomers 16a and 16b were separated
16.

M. F. BranÄa et al. / Tetrahedron 58 52002) 4825±4836
4831
by a second ¯ash chromatography, yielding 790 mg ;37%)
of 16a and 362 mg ;17%) of 16b. 52Sp,10Rp.)-16a: solid
;MeOH/H2O); mp 102±1048C; IR ;KBr); 3020, 2940, 1730,
1680 cm21; 1H NMR ;CDCl3) d 0.19 ;s, 6H), 0.97 ;s, 9H),
1.50±1.61 ;m, 1H), 2.04±2.14 ;m, 1H), 2.24±2.34 ;m, 1H),
2.56±2.67 ;m, 1H), 3.08 ;s, 3H), 4.20 ;d, 1H, Jˆ15.4 Hz),
4.47 ;dd, 1H, Jˆ10.4 and 3.8 Hz), 4.68 ;dd, 1H, Jˆ13.2 and
3.8 Hz), 4.87 ;dd, 1H, Jˆ13.2 and 10.4 Hz), 5.07 ;d, 1H,
Jˆ15.4 Hz), 6.81 ;d, 2H, Jˆ8.2 Hz), 7.10 ;d, 2H,
Jˆ8.2 Hz), 7.17±7.31 ;m, 5H); 13C NMR ;CDCl3) d
175.3, 170.6, 156.2, 136.2, 129.5, 128.3, 127.4, 127.3,
125.5, 120.7, 75.5, 69.9, 52.6, 44.6, 44.5, 29.3, 25.5, 23.5,
18.1, 24.5; Anal. calcd for C27H36N2O6Si: C, 64.48; H,
5.99; N, 8.06. Found: C, 64.13; H, 5.74; N, 8.09.
52Sp,10Sp)-16b: solid ;MeOH/H2O); mp 110±1128C; IR
obtained as a 1:1 mixture of diastereoisomers. This mixture
was separated by a second ¯ash chromatography yielding
590 mg ;30%) of 18a and 595 mg ;30%) of 18b. 52Sp,10Rp)-
18a: solid; mp 72±758C; IR ;KBr); 3000, 2980, 1730,
1690 cm21 1H NMR ;CDCl3) d 1.57±1.69 ;m, 1H),
;
2.05±2.14 ;m, 1H), 2.29±2.39 ;m, 1H), 2.56±2.67 ;m,
1H), 3.13 ;s, 3H), 3.84 ;s, 9H), 4.28 ;d, 1H, Jˆ15.4 Hz),
4.42 ;dd, 1H, Jˆ11.0 and 3.8 Hz), 4.73 ;dd, 1H, Jˆ13.2 and
3.8 Hz), 4.89 ;dd, 1H, Jˆ13.2 and 11.0 Hz), 5.09 ;d, 1H,
Jˆ15.4 Hz), 6.41 ;s, 2H), 7.18±7.33 ;m, 5H); 13C NMR
;CDCl3) d 175.5, 170.6, 153.5, 138.6, 136.0, 128.6, 128.4,
127.4, 127.3, 105.0, 75.5, 69.9, 61.0, 56.4, 52.7, 45.4, 44.7,
28.6, 24.2. Anal. calcd for C24H28N2O8: C, 61.01; H, 5.97;
N, 5.93. Found: C, 58.01; H, 5.62; N, 5.73. 52Sp,10Sp)-18b:
solid; mp 141.1438C; IR ;KBr); 3000, 2980, 1725,
;KBr); 3020, 2940, 1740, 1690, 1600, 1550, 1510 cm21
1H NMR ;CDCl3) d 0.17 ;s, 6H), 0.95;s, 9H), 1.97±2.05
;
1680 cm21 1H NMR ;CDCl3) d 2.00±2.10 ;m, 1H),
;
2.39±2.51 ;m, 2H), 2.54±2.64 ;m, 1H), 3.43 ;s, 3H), 3.78
;s, 6H), 3.80 ;s, 3H), 4.29±4.37 ;m, 2H), 4.56±4.74 ;m, 3H),
6.38 ;s, 2H), 7.25±7.33 ;m, 5H); 13C NMR ;CDCl3) d 176.2,
170.0, 153.2, 138.2, 137.0, 128.9, 128.0, 127.7, 127.6,
106.3, 74.6, 71.7, 60.8, 56.2, 52.5, 46.8, 45.1, 29.2, 26.3;
Anal. calcd for C24H28N2O8: C, 61.01; H, 5.97; N, 5.93.
Found: C, 61.26; H, 5.76; N, 6.00.
;m, 1H), 2.38±2.46 ;m, 1H), 2.53±2.62 ;m, 2H), 3.35 ;s,
3H), 4.26 ;dd, 1H, Jˆ13.2 and 3.3 Hz), 4.35;dd, 1H,
Jˆ11.5and 3.3 Hz), 4.50 ;dd, 1H, Jˆ13.2 and 11.5Hz),
4.69 ;d, 1H, Jˆ15.4 Hz), 4.73 ;d, 1H, Jˆ15.4 Hz), 6.73
;d, 1H, Jˆ8.2 Hz), 7.07 ;d, 1H, Jˆ8.2 Hz), 7.24±7.37 ;m,
5H); 13C NMR ;CDCl3) d 176.1, 169.7, 155.9, 137.1, 130.3,
128.8, 128.0, 127.7, 125.8, 120.3, 75,5, 71.7, 52.3, 45.4,
44.9, 29.3, 25.6, 25.5, 18.1, 24.4; Anal. calcd for
C27H36N2O6Si: C, 64.48; H, 5.99; N, 8.06. Found: C,
64.39; H, 5.63; N, 7.95.
3.3.6. Methyl 1-benzyl-2-{10-[4--tert-butyldimethyl-
silanyloxy)phenyl]-20-methoxycarbonylethyl}pyrogluta-
mate, 19. This compound was obtained as a 1:1 mixture of
diastereoisomers. This mixture was separated by a second
¯ash chromatography, yielding 280 mg, ;25%) of 19a and
393 mg, ;35%) of 19b. 52Sp,10Rp)-19a: oil; IR ;CHCl3);
3.3.4. Methyl 1-benzyl-2-{10-[-1-tert-butoxycarbonyl)-
indol-3-yl]-2-nitroethyl}pyroglutamate, 17. This com-
pound was obtained as a 1:1.5mixture of diastereoisomers.
This mixture was separated by a second ¯ash chromato-
graphy, yielded 887 mg ;25%) of 17a and 1.06 g, ;30%) of
17b. 52Sp,10Rp)-17a: solid, mp 110±1128C ;cyclohexane); IR
1
3010, 1740, 1690 cm21; H NMR ;CDCl3) d 0.16 ;s, 6H),
0.95;s, 9H), 2.08±2.16 ;m, 1H), 2.32 ;dd, 1H, Jˆ15.9 and
2.8 Hz), 2.39±2.66 ;m, 4H), 3.23 ;s, 3H), 3.43 ;s, 3H), 4.04
;dd, 1H, Jˆ11.0 and 2.8 Hz), 4.62 ;d, 1H, Jˆ15.9 Hz), 4.79
;d, 1H, Jˆ15.9 Hz), 6.71 ;d, 2H, Jˆ8.2 Hz), 7.08 ;d, 2H,
Jˆ8.2 Hz), 7.20±7.35;m, 5H); 13C NMR ;CDCl3) d 175.6,
171.4, 170.8, 155.4, 136.8, 129.5, 128.2, 127.7, 128.0,
126.8, 120.2, 71.4, 52.3, 51.8, 44.5, 42.0, 34.6, 28.6, 25.6,
22.5, 18.1, 24.5. 52Rp,10Rp)-19b: oil; IR ;CHCl3); 3010,
1
;KBr); 3100±2990, 1730, 1680 cm21; H NMR ;CDCl3) d
1.69 ;s, 9H), 2.31±2.47 ;m, 2H), 2.52±2.70 ;m, 2H), 3.19 ;s,
3H), 4.01 ;d, 1H, Jˆ15.4 Hz), 4.74 ;d, 1H, Jˆ15.4 Hz),
4.74±4.99 ;m, 3H), 7.17±7.37 ;m, 7H), 7.56 ;s, 1H), 7.71±
7.74 ;m, 1H), 8.06 ;d, 1H, Jˆ6.6 Hz); 13C NMR ;CDCl3) d
175.4 ;C), 171.2 ;C), 149.5;C), 136.5;C), 134.7 ;C), 128.5
;C), 128.3 ;CH), 128.0 ;CH), 127.6 ;CH), 125.2 ;CH), 123.6
;CH), 123.2 ;CH), 118.4 ;CH), 115.6 ;CH), 114.2 ;C), 84.6
;C), 77.4 ;CH2), 69.7 ;C), 52.6 ;CH3), 44.8 ;CH2), 37.6 ;CH),
29.0 ;CH2), 28.2 ;CH3), 25.6 ;CH2); MS m/z ;%); 375;2), 315
;2), 301 ;6), 232 ;45), 188 ;10), 174 ;11), 143 ;10), 130 ;11),
115;6), 91 ;100), 57 ;28); Anal. calcd for C 28H31N3O7: C,
64.48; H, 5.99; N, 8.06. Found: C, 64.23; H, 5.69; N, 7.94.
52Sp,10Sp)-17b: solid mp 143±1458C ;Tol/Hex); IR ;KBr);
1
2980, 1740, 1690 cm21; H NMR ;CDCl3) d 0.18 ;s, 6H),
0.97 ;s, 9H), 1.24±1.41 ;m, 1H), 2.05±2.26 ;m, 2H), 2.48
;dd, 1H, Jˆ15.9 and 3.8 Hz), 2.69 ;m, 1H), 2.84 ;dd, 1H,
Jˆ15.9 and 11.0 Hz), 3.06 ;s, 3H), 3.54 ;s, 3H), 4.11 ;dd,
1H, Jˆ11.0 and 3.8 Hz), 4.34 ;d, 1H, Jˆ15.9 Hz), 5.10 ;d,
1H, Jˆ15.9 Hz), 6.79 ;d, 2H, Jˆ8.8 Hz), 7.08 ;d, 2H,
Jˆ8.8 Hz), 7.13±7.23 ;m, 5H); 13C NMR ;CDCl3) d
175.6, 171.4, 170.8, 155.4, 136.8, 129.5, 128.2, 127.4,
127.3, 126.8, 120.2, 71.4, 52.3, 51.8, 44.5, 42.0, 34.6,
28.6, 25.6, 22.5, 18.1, 24.5.
1
3100±2990, 1730, 1680 cm21; H NMR ;CDCl3) d 1.67 ;s,
9H), 2.15±2.18 ;m, 1H), 2.52±2.61 ;m, 1H), 2.65±2.85 ;m,
2H), 3.14 ;s, 3H), 4.35;dd, 1H, Jˆ13.2 and 11.0 Hz), 4.55
;dd, 1H, Jˆ11.0 and 3.3 Hz), 4.80 ;s, 2H), 4.83 ;dd, 1H,
Jˆ11.0 and 3.3 Hz), 7.20±7.38 ;m, 7H), 7.52 ;s, 1H), 7.66
;m, 1H), 8.02 ;d, 1H, Jˆ6.6 Hz); 13C NMR ;CDCl3) d 176.1,
169.7, 149.3, 136.7, 134.5, 129.7, 128.9, 128.0, 127.9, 125.0,
123.9, 122.9, 119.3, 115.1, 114.7, 84.6, 76.5, 71.0, 52.4, 44.7,
36.5, 29.4, 28.1, 25.4;; MS m/z ;%); 375;1), 315;1), 301 ;4),
232 ;43), 188 ;6), 174 ;8), 143 ;6), 130 ;7), 115;6), 91 ;100),
57 ;27); Anal. calcd for C28H31N3O7: C, 64.48; H, 5 .99; N,
8.06. Found: C, 64.32; H, 6.02; N, 8.00.
3.4. General procedure for reduction of nitroethylpyro-
glutamates
Method A. To a stirred suspension of the nitrocompound
14±18 ;1 mmol) and 10% Pd±C ;150 mg) in dry methanol
;20 ml), anhydrous ammonium formate ;20 mmol) was
added in a single portion. The resulting reaction mixture
was stirred at room temperature for 10±30 min under
argon. The catalyst was removed by ®ltration through a
celite pad and washed with methanol. The ®ltrated was
evaporated under reduced pressure and the resulting
residue was triturated with water and extracted with
CHCl3. The organic layer was dried over Na2SO4, ®ltered,
3.3.5. Methyl 1-benzyl-2-[20-nitro-10--3,4,5-trimethoxy-
phenyl)ethyl]pyroglutamate, 18. This compound was

4832
M. F. BranÄa et al. / Tetrahedron 58 52002) 4825±4836
1
and evaporated to dryness. The products were puri®ed by
¯ash chromatography ;CHCl3/MeOH mixtures).
;KBr) 3400, 1710, 1650 cm21; H NMR ;CDCl3) d 1.64±
1.73 ;m, 1H), 1.79±1.90 ;m, 1H), 1.97±2.07 ;m, 1H), 2.31±
2.41 ;m, 1H), 3.66±3.81 ;m, 3H), 3.75;s, 3H), 4.13 ;d, 1H,
Jˆ15.4 Hz), 4.74 ;d, 1H, Jˆ15.4 Hz), 6.77±6.89 ;m, 3H),
7.23±7.42 ;m, 6H); 13C NMR ;CDCl3) d 175.8, 167.4,
157.4, 137.3, 134.0, 128.9, 128.8, 128.3, 128.2, 128.0,
127.9, 71.5, 55.3, 50.6, 44.7, 38.2, 29.1, 25.3.
Method B. A solution of the nitrocompound 14±18
;1 mmol) in 10 ml of a mixture MeOH/THF ;2:1) was
hydrogenated over 500 mg of Raney-Ni at 45 psi on a
shaker at room temperature for 4 h. The catalyst was
removed by ®ltration through a celite pad and washed
with methanol. The ®ltrated was evaporated under reduced
pressure. The resulting residue was triturated with water and
extracted with CHCl3. The organic layer was dried over
Na2SO4, evaporated to dryness and the product was puri®ed
by crystallization.
3.4.4. -5Sp,9Sp)-1-Benzyl-9--2-methoxyphenyl)-1,7-diaza-
spiro[4.4]nonane-2,6-dione, 21b and -5Sp,9Sp)-1-benzyl-
7-hydroxy-9--2-methoxyphenyl)-1,7-diaza-spiro[4.4]no-
nane-2,6-dione 25b. Following the method A, reduction of
15b yielded, after puri®cation by ¯ash chromathography
;CH2Cl2/MeOH, 100:1), 20 mg ;24%) of 21b as a white
solid ;Et2O), and 50 mg ;57%) of 25b as a white solid
;CH2Cl2/Et2O). Compound 21b: mp 234±2378C; IR ;KBr)
3360, 1710, 1680 cm21. 1H NMR ;CDCl3) d 2.27±2.32 ;m,
1H), 2.37±2.52 ;m, 3H), 3.42 ;d, 1H, Jˆ15.4 Hz), 3.59±
3.69 ;m, 2H), 3.80 ;d, 1H, Jˆ15.4 Hz), 3.82 ;s, 3H), 4.21
;dd, 1H, Jˆ7.1 and 4.4 Hz), 6.80 ;sa, 1H), 6.87±6.97 ;m,
2H), 7.17±7.33 ;m, 7H); 13C NMR ;CDCl3) d 175.8, 172.3,
157.5, 137.2, 129.2, 127.8, 127.7, 127.4, 126.6, 125.3,
120.7, 110.5, 72.7, 55.3, 46.7, 43.7, 41.8, 30.8, 29.5.
Compound 25: mp 220±2238C; IR ;KBr) 3250, 2720,
3.4.1. -5Sp,9Rp)-1-Benzyl-7-hydroxy-9-phenyl-1,7-diaza-
spiro[4.4]nonane-2,6-dione, 20a. Following method A
and after puri®cation by ¯ash chromathography ;CHCl3/
MeOH, 100:1), 59 mg, ;70%) were obtained as a white
1
solid: mp 158±1608C ;CH2Cl2/Et2O). H NMR ;CDCl3) d
1.56±1.62 ;m, 1H), 1.80±1.98 ;m, 2H), 2.19±2.29 ;m, 1H),
3.57 ;t, 1H, Jˆ8.8 Hz), 3.77 ;dd, 1H, Jˆ9.3 and 8.3 Hz),
3.94 ;dd, 1H, Jˆ9.9 and 8.3 Hz), 3.99 ;d, 1H, Jˆ14.8 Hz),
5.11 ;d, 1H, Jˆ14.8 Hz), 6.72±6.75;m, 2H), 7.22±7.26 ;m,
3H), 7.31±7.40 ;m, 3H), 7.47±7.49 ;m, 2H); 13C NMR
;CDCl3) d 176.2, 168.0, 137.7, 134.0, 128.9, 128.8, 128.3,
128.2, 128.0, 127.9, 71.8, 49.5, 45.3, 43.1, 30.8, 28.6; IR
;KBr) 3400, 2880, 1710, 1650 cm21; EM m/z ;%) 320
;M1216, 26), 319 ;17), 215;59), 174 ;8), 138 ;8), 119
;12), 106 ;13), 91 ;100), 65;18), 55;18), 104 ;9); Anal.
calcd for C20H20N2O3.H2O: C, 67.89; H, 6.26; N, 7.90.
Found: C, 67.57; H, 6.03; N, 7.91.
1690, 1675cm 21; H NMR ;CDCl3) d 2.00±2.06 ;m, 1H),
1
2.19±2.40 ;m, 2H), 2.48±2.59 ;m, 1H), 3.21 ;d, 1H;
Jˆ15.4 Hz), 3.50 ;d, 1H; Jˆ15.4 Hz), 3.69±3.75 ;m, 1H),
3.80 ;s, 3H), 3.86±3.92 ;m, 1H), 4.00±4.03 ;m, 1H), 6.86±
6.91 ;m, 2H), 7.18±7.30 ;m, 7H); 13C NMR ;CDCl3) d
175.5, 167.7, 157.5, 137.0, 129.4, 127.8, 127.7, 127.4,
126.7, 124.7, 120.7, 110.5, 72.0, 55.2, 50.6, 46.7, 38.6,
30.8, 29.2.
3.4.2. -5Sp,9Sp)-1-Benzyl-7-hydroxy-9-phenyl-1,7-diaza-
spiro[4.4]nonane-2,6-dione, 20b. Following method A
and after puri®cation by ¯ash chromathography ;CHCl3/
MeOH, 100:1), 52 mg, ;65%) were obtained as a white
solid: mp 152±1558C ;CH2Cl2/Et2O), together with 16 mg
3.4.5.
-5Sp,9Rp)-1-Benzyl-7-hydroxy-9-[4--tert-butyl-
dimethylsilanyloxy)phenyl]-1,7-diaza-spiro[4.4]nonane-
2,6-dione, 22a. Following method A and after puri®cation
by ¯ash chromathography ;CHCl3/MeOH, 75:1), 70 mg,
;70%) were obtained as a white solid: mp 186±1888C
;CH2Cl2/Et2O), together with 14 mg ;15%) of 26a. IR
1
;10%) of 24b. IR ;KBr) 3250, 2720, 1690, 1675 cm21; H
NMR ;CDCl3) d 2.14±2.18 ;m, 1H), 2.34±2.61 ;m, 3H),
3.54±3.59 ;m, 2H), 3.84±3.90 ;m, 1H), 3.96±4.07 ;m, 2H),
7.17±7.21 ;m, 7H), 7.33±7.34 ;m, 3H); 13C NMR ;CDCl3)
d 175.7, 166.4, 136.1, 134.9, 129.0, 128.2, 127.9, 127.8,
127.7, 127.0, 71.1, 50.9, 46.7, 46.6, 30.2, 29.0; Anal.
calcd for C20H20N203.H2O: C, 67.89; H, 6.26; N, 7.90.
Found: C, 68.09; H, 5.76; N, 7.88.
;CHCl3) 3500±3300, 1700 cm21 1H NMR ;CDCl3) d
;
0.16 ;s, 6H), 0.95 ;s, 9H), 1.55±1.66 ;m, 1H), 1.85±1.93
;m, 2H), 2.17±2.27 ;m, 1H), 3.49 ;t, 1H, Jˆ8.8 Hz), 3.72±
3.78 ;m, 1H), 3.82±3.88 ;m, 1H), 3.96 ;d, 1H, Jˆ15.4 Hz),
5.10 ;d, 1H, Jˆ14.8 Hz), 6.58 ;d, 2H, Jˆ8.2 Hz), 6.69 ;d,
2H, Jˆ8.2 Hz), 7.30±7.39 ;m, 3H), 7.46±7.48 ;m, 2H); 13C
NMR ;CDCl3) d 176.1, 168.2, 155.6, 137.8, 132.0, 129.3,
129.0, 128.8, 128.0, 126.2, 120.3, 72.0, 49.7, 45.4, 42.5,
29.7, 28.6, 25.6, 24.8, 18.1, 24.5; EM m/z ;%)450 ;47),
393 ;30), 345 ;50), 314 ;13), 288 ;15), 234 ;10), 201 ;10),
177 ;23), 174 ;27), 151 ;7), 119 ;11), 91 ;100), 73 ;32), 65
;8), 55 ;10). Anal. calcd for C26H34N2O4Si´H2O: C, 64.43;
H, 7.49; N, 5.78. Found: C, 64.80; H, 7.16; N, 5.46.
3.4.3. -5Sp,9Rp)-1-Benzyl-9--2-methoxyphenyl)-1,7-diaza-
spiro[4.4]nonane-2,6-dione 21a and -5Sp,9Rp)-1-benzyl-
7-hydroxy-9--2-methoxyphenyl)-1,7-diaza-spiro[4.4]no-
nane-2,6-dione 25a. Following the method A, reduction of
15a yielded, after puri®cation by ¯ash chromatography
;CH2Cl2/MeOH, 100:1), 17 mg ;21%) of 21a as an oil,
and 49 mg ;56%)of 25a as a white solid ;CH2Cl2/Et2O).
Compound 21a: IR ;CHCl3) 3200, 1720, 1710,
3.4.6.
-5Sp,9Sp)-1-Benzyl-7-hydroxy-9-[4--tert-butyl-
1650 cm21
;
1H NMR ;CDCl3) d 1.72±1.89 ;m, 2H),
dimethylsilanyloxy)phenyl]-1,7-diazaspiro[4.4]nonane-
2,6-dione, 22b. Following method A and after puri®cation
by ¯ash chromathography ;CHCl3/MeOH, 19:1), 65mg,
;70%) were obtained as a white solid: mp 192±1958C
;CH2Cl2/Et2O), together with 22 mg ;25%) of 26b. IR
2.00±2.09 ;m, 1H), 2.31±2.40 ;m, 1H), 3.46 ;dd, 1H,
Jˆ9.4 and 8.2 Hz), 3.64 ;dd, 1H, Jˆ9.4 and 8.2), 3.79 ;s,
3H), 4.16 ;t, 1H, Jˆ8.2 Hz), 4.51 ;d, 1H, Jˆ15.4 Hz), 4.64
;d, 1H, Jˆ15.4 Hz), 6.53 ;sa, 1H), 6.86±6.96 ;m, 3H),
1
7.24±7.35;m, 4H), 7.43±7.45;m, 2H);
13C NMR
;KBr) 3500±3300, 1700 cm21; H NMR ;CDCl3) d 0.20
;CDCl3) d 176.1, 175.7, 157.6, 137.5, 129.1, 129.0, 128.3,
128.2, 127.2, 125.1, 120.7, 110.7, 71.7, 55.3, 44.8, 43.0,
40.3, 29.1, 25.4. Compound 25a: mp 164±1678C; IR
;s, 6H), 0.98 ;s, 9H), 1.89±1.94 ;m, 1H), 2.35±2.41 ;m,
3H), 3.30 ;t, 1H, Jˆ7.2 Hz), 3.55 ;d, 1H, Jˆ15.4 Hz),
3.72±3.80 ;m, 1H), 3.93±3.98 ;m, 1H), 4.07 ;d, 1H,

M. F. BranÄa et al. / Tetrahedron 58 52002) 4825±4836
4833
Jˆ15.4 Hz), 6.76 ;d, 2H, Jˆ8.2 Hz), 6.92 ;d, 2H,
Jˆ8.2 Hz), 7.16±7.26 ;m, 5H); 13C NMR ;CDCl3) d
175.4, 166.6, 155.7, 136.5, 129.0, 128.1, 127.9, 127.2,
127.0, 120.6, 70.9, 51.3, 46.6, 46.3, 30.1, 29.0, 25.6, 18.2,
24.4; Anal. calcd for C26H34N2O4Si´H2O: C, 64.43; H, 7.49;
N, 5.7. Found: C, 64.17; H, 7.19; N, 5.42.
174 ;10), 138 ;10), 119 ;10), 106 ;13), 91 ;100), 65;18), 55
;11), 104 ;9); Anal. calcd for C20H20N2O2: C, 74.98; H, 6.29;
N, 8.79. Found: C, 74.70; H, 6.28; N, 8.58.
3.4.10. -5Sp,9Sp)-1-Benzyl-9-phenyl-1,7-diaza-spiro[4.4]
nonane-2,6-dione, 24b. Following method B, 58 mg,
;70%) were obtained as a white solid: mp 162±1648C
3.4.7. -5Sp,9Rp)-1-Benzyl-7-hydroxy-9-[1--tert-butoxy-
carbonyl)indol-3-yl]-1,7-diazaspiro[4.4]nonane-2,6-dione,
23a. Following method A and after puri®cation by ¯ash
chromathography ;CHCl3/MeOH, 19:1), 55 mg, ;70%)
were obtained as a white solid: mp 124±1268C ;CH2Cl2/
Et2O), together with 47 mg ;25%) of 27a. IR ;KBr) 3400,
;CH2Cl2/Et2O). IR ;KBr) 3380, 1700, 1675cm 21 1H
.
NMR ;CDCl3) d 2.20±2.28 ;m, 1H), 2.32±2.45;m, 1H),
2.50±2.59 ;m, 1H), 2.62±2.73 ;m, 1H), 3.65±3.81 ;m, 4H),
4.40 ;d, 1H, Jˆ15.9 Hz), 6.69 ;sa, 1H), 7.21±7.25 ;m, 7H),
7.35±7.38 ;m, 3H); 13C NMR ;CDCl3) d 175.6, 175.0,
136.4, 135.4, 129.0, 128.1, 127.9, 127.8, 127.7, 126.9,
70.9, 50.6, 46.4, 44.3, 30.0, 29.2; Anal. calcd for
C20H20N2O2 C, 74.98; H, 6.29; N, 8.79. Found C, 74.75;
H, 6.49; N, 8.78.
1
1740, 1700 cm21; H NMR ;CDCl3) d 1.66 ;s, 9H), 1.84±
1.94 ;m, 1H), 1.98±2.12 ;m, 2H), 2.31±2.39 ;m, 1H), 3.76±
3.89 ;m, 2H), 3.96±4.03 ;m, 1H), 4.06 ;d, 1H, Jˆ15.4 Hz),
5.10 ;d, 1H, Jˆ15.4 Hz), 6.98 ;d, 1H, Jˆ7.7 Hz),7.09±7.14
;m, 2H), 7.29±7.40 ;m, 4H), 7.49±7.51 ;m, 2H), 8.10 ;d,
1H, Jˆ8.2 Hz). 13C NMR ;CDCl3) d 175.3 ;C), 168.1 ;C),
149.1 ;C), 137.4 ;C), 135.0 ;C), 129.0 ;CH), 128.9 ;CH),
128.7 ;CH), 128.0 ;CH), 125.1 ;CH), 124.8 ;CH), 123.2
;CH), 119.2 ;CH), 115.5 ;CH), 114.9 ;C), 84.4 ;C), 71.8
;C), 49.9 ;CH2), 45.3 ;CH2), 35.9 ;CH), 29.7 ;CH2), 28.1
;CH3), 26.0 ;CH2); EM m/z ;%) 375 ;5), 359 ;73), 357 ;12),
302 ;9), 254 ;18), 174 ;26), 158 ;27), 143 ;39), 130 ;23), 117
;11), 115 ;12), 91 ;100), 65 ;15), 56 ;16); Anal. calcd for
C27H29N3O5´H2O: C, 65.71; H, 6.33; N, 8.51. Found: C,
65.56; H, 6.25; N, 8.31.
3.4.11. -5Sp,9Rp)-1-Benzyl-9-[4--tert-butyldimethylsilanyl-
oxy)phenyl]-1,7-diaza-spiro[4.4]nonane-2,6-dione, 26a.
Following method B, 70 mg, ;80%) were obtained as a
white solid: mp 99±1028C ;CH2Cl2/Et2O). IR ;CHCl3)
1
3420, 1735, 1700 cm21; H NMR ;CDCl3) d 0.16 ;s, 6H),
0.96 ;s, 9H), 1.57±1.68 ;m, 1H), 1.93±1.98 ;m, 2H), 2.18±
2.29 ;m, 1H), 3.48±3.59 ;m, 3H), 4.08 ;d, 1H, Jˆ14.8 Hz),
5.15 ;d, 1H, Jˆ14.8 Hz), 6.57 ;d, 2H, Jˆ8.8 Hz), 6.79 ;d,
2H, Jˆ8.8 Hz), 6.92 ;s, 1H), 7.32±7.40 ;m, 3H), 7.50±7.52
;m, 2H); 13C NMR ;CDCl3) d 176.4, 176.0, 155.3, 138.2,
129.4, 129.2, 128.8, 127.1, 120.2, 72.3, 45.8, 45.4, 42.2,
28.6, 25.6, 24.7, 18.1, 24.5; EM m/z ;%) 450 ;M1,50),
393 ;27), 345;53), 314 ;13), 288 ;16), 234 ;10), 201 ;9),
177 ;25), 174 ;30), 119 ;11), 91 ;100), 73 ;32), 65 ;10), 55
;10); Anal. calcd for C26H34N2O3Si: C, 69.30; H, 7.60; N,
6.22. Found: C, 69.05; H, 7.59; N, 6.29.
3.4.8. -5Sp,9Sp)-1-Benzyl-7-hydroxy-9-[1--tert-buthoxy-
carbonyl)indol-3-yl]-1,7-diazaspiro[4.4]nonane-2,6-dione,
23b. Following method A and after puri®cation by ¯ash
chromathography ;CHCl3/MeOH, 19:1), 57 mg, ;70%)
were obtained as a white solid: mp 143±1468C ;CH2Cl2/
Et2O), together with 15mg ;20%) of 27b. IR ;KBr) 3440,
3.4.12. -5Sp,9Sp)-1-Benzyl-9-[4--tert-butyldimethylsilanyl-
oxy)phenyl]-1,7-diaza-spiro[4.4]nonane-2,6-dione, 26b.
Following method B, 90 mg, ;90%) were obtained as a
white solid: mp 162±1648C ;CH2Cl2/Et2O). IR ;KBr)
1
1720, 1700 cm21; H NMR ;CDCl3) d 1.69 ;s, 9H), 1.87±
1.97 ;m, 1H), 2.11±2.23 ;m, 1H), 2.29±2.38 ;m, 1H), 2.49±
2.60 ;m, 1H), 3.72 ;t, 1H, Jˆ8.9 Hz), 3.88±4.04 ;m, 3H),
4.58 ;d, 1H, Jˆ15.4 Hz), 7.20±7.38 ;m, 7H), 7.44±7.46 ;m,
2H), 8.08 ;d, 1H, Jˆ8.2 Hz); 13C NMR ;CDCl3) d 175.2
;C), 166.3 ;C), 149.2 ;C), 136.4 ;C), 135.1 ;C), 129.8 ;C),
128.1 ;CH), 127.8 ;CH), 127.4 ;CH), 125.2 ;CH), 124.1
;CH), 123.1 ;CH), 117.9 ;CH), 115.8 ;CH), 113.5 ;C),
84.6 ;C), 70.4 ;C), 51.9 ;CH2), 46.6 ;CH2), 39.4 ;CH),
30.0 ;CH2), 29.0 ;CH2), 28.2 ;CH3); IR ;KBr) 3440, 1720,
1700 cm21; EM m/z ;%) 459 ;1), 402 ;3), 375 ;5), 359 ;69),
3.57 ;10), 302 ;6), 268 ;3), 254 ;13), 174 ;19), 158 ;17), 143
;27), 130 ;17), 117 ;8), 115 ;10), 91 ;100), 65 ;17), 56 ;51);
Anal. calcd for C27H29N3O5´H2O: C, 65.71; H, 6.33; N, 8.51.
Found: C, 65.60; H, 6.28; N, 8.21.
1
3450±3150, 1710, 1680 cm21; H NMR ;CDCl3) d 0.21
;s, 6H), 0.99 ;s, 9H), 2.14±2.21 ;m, 1H), 2.23±2.68 ;m,
3H), 3.55±3.69 ;m, 4H), 4.35 ;d, 1H, Jˆ15.9 Hz), 6.59 ;s,
1H), 6.82 ;d, 2H, Jˆ8.8 Hz), 7.05;d, 2H, Jˆ8.8 Hz), 7.19±
7.22 ;m, 5H); 13C NMR ;CDCl3) d 175.6, 174.8, 155.6,
136.5, 128.8, 128.1, 128.0, 127.8, 127.1, 120.7, 70.6, 49.8,
46.5, 44.4, 30.1, 29.3, 25.6, 18.2, 24.4; Anal. calcd for
C26H34N2O3Si: C, 69.30; H, 7.60; N, 6.22. Found: C,
68.92; H, 7.49; N, 6.18.
3.4.13. -5Sp,9Rp)-1-Benzyl-9-[1--tert-buthoxycarbonyl)-
indol-3-yl]-1,7-diaza-spiro[4.4]nonane-2,6-dione,
27a.
Following method B, 64 mg, ;50%) were obtained as a
white solid: mp 113±1168C ;CH2Cl2/Et2O). IR ;KBr)
3.4.9. -5Sp,9Rp)-1-Benzyl-9-phenyl-1,7-diaza-spiro[4.4]
nonane-2,6-dione, 24a. Following method B, 60 mg,
;72%) were obtained as a white solid: mp 167±1698C
1
3400, 3250, 1720 cm21; H NMR ;CDCl3) d 1.67 ;s, 9H),
1.89±1.94 ;m, 1H), 2.09±2.2.14 ;m, 2H), 2.31±2.42 ;m,
1H), 3.60 ;dd, 1H, Jˆ9.9 and 8.8 Hz), 3.71±3.69 ;dd, 1H,
Jˆ9.9 and 9.3 Hz), 3.91 ;dd, 1H, Jˆ9.3 and 8.8 Hz), 4.22
;d, 1H, Jˆ15.4 Hz), 5.09 ;d, 1H, Jˆ15.4 Hz), 6.95 ;d, 1H,
Jˆ7.7 Hz), 7.08±7.13 ;m, 2H), 7.26±7.41 ;m, 4H),
7.52±7.54 ;m, 2H), 7.63 ;s, 1H), 8.09 ;d, 1H, Jˆ8.2 Hz).
13C NMR ;CDCl3) d 176.3 ;C), 176.0 ;C), 149.4 ;C), 137.8
;C), 134.9 ;C), 129.4 ;C), 129.0 ;C), 128.7 ;CH), 127.8
;CH), 124.9 ;CH), 124.6 ;CH), 122.9 ;CH), 119.4 ;CH),
115.6 ;C), 115.4 ;CH), 84.3 ;C), 72.1 ;C), 45.5 ;CH2),
;CH2Cl2/Et2O). IR ;KBr) 3200, 1720, 1710, 1650 cm21
;
1H NMR ;CDCl3) d 1.58±1.69 ;m, 1H), 1.94±1.99 ;m,
2H), 2.20±2.31 ;m, 1H), 3.48±3.57 ;m, 1H), 3.62±3.71
;m, 2H), 4.10 ;d, 1H, Jˆ15.4 Hz), 5.17 ;d, 1H,
Jˆ15.4 Hz), 6.69±6.72 ;m, 2H), 7.16±7.23 ;m, 3H),
7.32±7.40 ;m, 3H), 7.52±7.54 ;m, 2H), 7.93 ;s, 1H); 13C
NMR ;CDCl3) d 176.6, 176.3, 138.1, 134.6, 130.2, 129.2,
128.6, 128.5, 128.1, 127.7, 127.6, 72.4, 46.3, 45.4, 42.2,
28.6, 24.6; MS m/z ;%) 320 ;M1, 27), 216 ;12), 215;70),

4834
M. F. BranÄa et al. / Tetrahedron 58 52002) 4825±4836
42.9 ;CH2), 39.3 ;CH), 29.1 ;CH2), 28.2 ;CH3), 26.0 ;CH2);
EM m/z ;%); 459 ;1), 359 ;80), 302 ;6), 268 ;3), 254 ;21),
174 ;32), 158 ;29), 143 ;42), 130 ;21), 117 ;10), 115 ;11), 91
;100), 65;13), 56 ;14); Anal. calcd for C 27H29N3O4: C,
70.57; H, 6.36; N, 9.14. Found: C, 70.56; H, 6.75; N, 9.46.
51.0, 42.3, 30.4, 26.2; IR ;KBr) 3320, 3200, 1720,
1680 cm21; Anal. calcd for C13H14N2O2: C, 67.81; H,
6.13; N, 12.17. Found: C, 68.02; H, 6.19; N, 11.94.
3.4.18. -5Sp,9Sp)-9-Phenyl-1,7-diaza-spiro[4.4]nonane-
2,6-dione, 32b. Following method B, 45mg, ;75%) were
obtained as a white solid: mp .2308C ;dec) ;CH2Cl2/
3.4.14. -5Sp,9Sp)-1-Benzyl-9-[1--tert-buthoxycarbonyl)-
indol-3-yl]-1,7-diaza-spiro[4.4]nonane-2,6-dione, 27b.
Following method B, 52 mg, ;50%) were obtained as a
white solid: mp 110±1138C ;CH2Cl2/Et2O). IR ;KBr)
1
MeOH). IR ;KBr) 3220, 3100, 1710, 1690 cm21; H NMR
;MeOD-d4) d 1.92±2.04 ;m, 1H), 2.11±2.20 ;m, 1H), 2.25±
2.35;m, 1H), 2.45±2.55;m, 1H), 3.53±3.71 ;m, 3H), 7.32±
7.36 ;m, 5H); 13C NMR ;MeOD-d4) d 180.6, 178.0, 137.3,
130.2, 129.7, 128.9, 68.4, 52.2, 45.6, 30.7, 29.6; Anal. calcd
for C13H14N2O2 C, 67.81; H, 6.13; N, 12.17. Found: C,
67.42; H, 6.29; N, 11.94.
1
3220, 2970, 1725, 1710, 1680 cm21; H NMR ;CDCl3) d
1.70 ;s, 9H), 2.16±2.29 ;m, 2H), 2.35±2.46 ;m, 1H), 2.69±
2.80 ;m, 1H), 3.53 ;dd, 1H, Jˆ9.9 and 8.3 Hz), 3.66 ;dd, 1H,
Jˆ9.9 and 8.8 Hz), 3.86 ;dd, 1H, Jˆ8.8 and 8.3 Hz), 3.97
;d, 1H, Jˆ15.4 Hz), 4.66 ;d, 1H, Jˆ15.4 Hz), 7.16±7.20 ;m,
5H), 7.28±7.38 ;m, 2H), 7.43 ;s, 1H), 7.53 ;d, 1H,
Jˆ7.2 Hz), 7.67 ;s, 1H), 8.08 ;d, 1H, Jˆ7.9 Hz); 13C
NMR ;CDCl3) d 175.8 ;C), 174.9 ;C), 149.3 ;C), 136.2
;C), 135.0 ;C), 130.0 ;C), 127.9 ;CH), 127.4 ;CH), 127.0
;CH), 125.0 ;CH), 123.8 ;CH), 123.0 ;CH), 117.9 ;CH),
115.6 ;CH), 114.6 ;C), 84.4 ;C), 70.4 ;C), 46.4 ;CH2),
45.3 ;CH2), 42.7 ;CH), 29.9 ;CH2), 29.1 ;CH2), 28.1
;CH3); EM m/z ;%) 459 ;M1, 3), 403 ;3), 359 ;80), 302
;4), 268 ;3), 254 ;16), 174 ;23), 158 ;21), 143 ;27), 130
;17), 117 ;8), 115;9), 91 ;100), 65;17), 57 ;28); Anal.
calcd for C27H29N3O4: C, 70.57; H, 6.36; N, 9.14. Found:
C, 70.17; H, 6.46; N, 8.67.
3.4.19.
Methyl
1--4-methoxybenzyl)-2--20-nitro-10-
phenylethyl)pyroglutamate 30. Following the general
method for Michael reactions at C2, this compound was
prepared from methyl ;2S)-1-;4-methoxibenzyl)pyrogluta-
mate and trans-b-nitrostyrene, and obtained as a 1.5:1
mixture of diastereomers. Upon separation by ¯ash column
chromatography using Hex/AcOEt 2:1, 284 mg ;39%) of
30a and 210 mg ;29%) of 30b were obtained. 52Sp,10Rp)-
1
30a: IR ;CHCl3); 3010, 2980, 1740, 1700 cm21; H NMR
;CDCl3) d 2.00±2.09 ;m, 1H), 2.35±2.43 ;m, 1H), 2.50±
2.62 ;m, 2H), 3.38 ;s, 3H), 3.76 ;s, 3H), 4.29 ;dd, 1H,
Jˆ13.2 Hz, Jˆ2.8 Hz), 4.43 ;dd, 1H, Jˆ11.6 and 2.8 Hz),
4.61 ;d, 1H, Jˆ15.4 Hz), 4.66 ;dd, 1H, Jˆ13.2 and
11.6 Hz), 4.71 ;d, 1H, Jˆ15.4 Hz), 6.83 ;d, 2H,
Jˆ8.2 Hz), 7.22±7.29 ;m, 5H), 7.33 ;d, 2H, Jˆ8.2 Hz);
13C NMR ;CDCl3) d 176.0, 169.6, 159.0, 133.5, 129.4,
129.1, 129.0, 128.6, 128.5, 114.0, 75.2, 71.5, 55.1, 52.2,
45.8, 44.1, 29.2, 25.2. 52Sp,10Sp-30b: IR ;CHCl3); 3010,
3.4.15. -5Sp,9Rp)-1-Benzyl-9--3,4,5-trimethoxyphenyl)-
1,7-diaza-spiro[4.4]nonane-2,6-dione, 28a. Following
method B, 62 mg, ;75%) were obtained as a white solid:
mp 216±2188C ;CH2Cl2/Et2O). IR ;KBr) 3410, 3250,
1
1710, 1675cm 21; H NMR ;CDCl3) d 1.64±1.75;m, 1H),
1
1.95±2.00 ;m, 2H), 2.21±2.31 ;m, 1H), 3.55±3.72 ;m, 2H),
3.68 ;s, 6H), 3.78 ;s, 3H), 3.78±3.86 ;m, 1H), 4.02 ;d, 1H,
Jˆ15.4 Hz), 5.21 ;d, 1H, Jˆ15.4 Hz), 5.99 ;s, 2H), 7.28±
7.89 ;m, 3H), 7.49 ;s, 1H), 7.59 ;m, 2H); 13C NMR ;CDCl3)
d 176.6, 176.1, 153.2, 138.2, 137.6, 130.4, 129.6, 128.8,
127.8, 105.1, 72.4, 60.8, 56.3, 46.4, 45.7, 41.9, 28.8, 24.8;
Anal. calcd for C23H26N2O5: C, 67.30; H, 6.38; N, 6.82.
Found: C, 67.45; H, 6.53; N, 6.72.
2980, 1740, 1700 cm21; H NMR ;CDCl3) d 1.52±1.64
;m, 1H), 2.11±2.34 ;m, 2H), 2.54±2.64 ;m, 1H), 3.16 ;s,
3H), 3.68 ;s, 3H), 4.13 ;d, 1H, Jˆ14.8 Hz), 4.54 ;dd, 1H,
Jˆ10.4 and 3.8 Hz), 4.76 ;dd, 1H, Jˆ13.2 and 3.8 Hz), 4.92
;dd, 1H, Jˆ13.2 and 10.4 Hz), 4.99 ;d, 1H, Jˆ14.8 Hz),
6.82 ;d, 2H, Jˆ8.8 Hz), 7.14 ;d, 2H, Jˆ8.8 Hz), 7.24±
7.27 ;m, 3H), 7.34±7.39 ;m, 2H); 13C NMR ;CDCl3) d
175.3, 170.8, 158.8, 133.4, 129.2, 129.1, 129.0, 128.5,
128.2, 113.8, 75.5, 69.8, 55.2, 52.8, 45.2, 44.0, 28.6, 23.7.
3.4.16. -5Sp,9Sp)-1-Benzyl-9--3,4,5-trimethoxyphenyl)-
1,7-diaza-spiro[4.4]nonane-2,6-dione, 28b. Following
method B, 59 mg, ;70%) were obtained as a white solid:
3.4.20. Methyl -2Sp,10Rp)-2--20-nitro-10-phenylethyl)-
pyroglutamate, 31a. A solution of CAN ;303 mg,
0.55 mmol) in H2O ;3 ml) was added to a solution of 30a
;73 mg, 0.18 mmol) in CH3CN ;2 ml) at 258C. After the
reaction mixture was stirred at 08C for 25min, the reaction
mixture was diluted with H2O, and extracted with EtOAc
;2£20 ml). The combined organic phases were washed with
5% NaHCO3 and brine, dried ;Na2SO4), and concentrated.
The product was puri®ed by ¯ash chromatography using
CH2Cl2 as elluent, obtaining 32 mg ;60%) of 31a as a
white solid, mp 201±2048C ;CH2Cl2/MeOH); IR ;KBr);
1
mp 172±1748C ;CH2Cl2/Et2O). H NMR ;CDCl3) d 2.16±
2.24 ;m, 1H), 2.38 ;m, 3H), 3.51±3.56 ;m, 1H), 3.78±3.86
;m, 2H), 3.75;d, 1H, Jˆ15.4 Hz), 3.81 ;s, 6H), 3.85 ;s, 3H),
4.35;d, 1H, Jˆ15.4 Hz), 6.38 ;s, 2H), 7.16±7.19 ;m, 5H),
7.46 ;s, 1H); 13C NMR ;CDCl3) d 175.5, 174.9, 153.4,
137.8, 136.3, 131.2, 127.8, 127.4, 126.8, 105.1, 70.8, 60.9,
56.2, 50.4, 46.4, 44.6, 30.0, 29.2; IR ;KBr); 3400, 3200,
3080, 1710, 1680 cm21; Anal. calcd for C23H26N2O5: C,
67.30; H, 6.38; N, 6.82. Found: C, 66.98; H, 6.28; N, 6.67.
1
3400, 3180, 1725, 1680 cm21; H NMR ;CDCl3) d 1.66±
3.4.17. -5Sp,9Rp)-9-Phenyl-1,7-diaza-spiro[4.4]nonane-
2,6-dione, 32a. Following method B, 42 mg, ;70%) were
obtained as a white solid: mp .2268C ;dec) ;CH2Cl2/
1.77 ;m, 1H), 2.12±2.32 ;m, 2H), 2.36±2.48 ;m, 1H), 3.80
;s, 3H), 3.96 ;dd, 1H, Jˆ10.4 and 4.4 Hz), 4.75;dd, 1H,
Jˆ13.2 and 4.4 Hz), 4.98 ;dd, 1H, Jˆ13.2 and 10.4 Hz),
6.85;s, 1H), 7.25±7.26 ;m, 3H), 7.37±7.39 ;m, 2H); 13C
NMR ;CDCl3) d 174.0, 169.2, 133.6, 129.2, 129.1, 128.9,
75.9, 67.3, 53.3, 51.2, 30.2, 29.3; Anal. calcd for
C14H16N2O5: C, 57.43; H, 5.52, N, 9.58. Found: C, 57.49;
H, 5.72, N, 9.48.
1
MeOH). IR ;KBr) 3320, 3200, 1720, 1680 cm21; H NMR
;MeOD-d4) d 1.28±1.43 ;m, 1H), 1.86±2.02 ;m, 2H), 2.04±
2.17 ;m, 1H), 3.55 ;dd, 1H, Jˆ9.2 and 7.3 Hz), 3.64±3.70
;m, 1H), 3.77±3.84 ;m, 1H), 7.33±7.39 ;m, 5H); 13C NMR
;MeOD-d4) d 181.2, 178.9, 136.7, 129.8, 129.4, 129.0, 69.0,

M. F. BranÄa et al. / Tetrahedron 58 52002) 4825±4836
4835
3.4.21. Methyl -2Sp,10Sp)-2--20-nitro-10-phenylethyl)-
pyroglutamate, 31b. Following the same previous method,
38 mg, ;65%) of 31b were obtained as a white solid: mp
.2268C ;dec) ;CH2Cl2/MeOH). ;71 mg, 55%): mp 212±
4. ;a) Beard, M. J.; Bailey, J. H.; Cherry, D. T.; Moloney, M. G.;
Shim, S. B.; Stathom, K. A. Tetrahedron 1996, 52, 3719±
3740. ;b) Griffart-Brunet, D.; Langlois, N. Tetrahedron Lett.
1994, 35, 119±122. ;c) Ezquerra, J.; Pedregal, C.; Rubio, A.;
1
2158C; IR ;KBr); 3400, 3200, 1730, 1675cm 21; H NMR
Â
Vaquero, J. J.; Matõa, M. P. J. Org. Chem. 1994, 59, 4327±
4331. ;d) Dikshit, D. K.; Panday, S. K. J. Org. Chem. 1992, 57,
1920±1924. ;e) Baldwin, J. E.; Miranda, T.; Moloney, M.;
Hokelek, T. Tetrahedron 1989, 45, 7459±7468.
;CDCl3) d 2.25±2.39 ;m, 3H), 2.50±2.59 ;m, 1H), 3.63 ;s,
3H), 4.02 ;dd, 1H, Jˆ9.9 and 4.9 Hz), 4.84±4.99 ;m, 2H),
7.16±7.20 ;m, 3H), 7.23 ;s, 1H), 7.32±7.34 ;m, 2H); 13C
NMR ;CDCl3) d 177.3, 171.9, 134.1, 129.1, 128.9, 128.3,
75.4, 67.9, 52.9, 50.6, 29.5, 28.6; Anal. calcd for
C14H16N2O5: C, 57.43; H, 5.52, N, 9.58. Found: C, 57.37;
H, 5.48, N, 9.28.
5. One Michael reaction has been reported with a N-benzyl thio-
pyroglutamate enolate: Dikshit, D. K.; Panday, S. K. Ind. J.
Chem. 1992, 31b, 123±124.
Â
6. BranÄa, M. F.; Garranzo, M.; Perez-Castells, J. Tetrahedron
Lett. 1998, 39, 6569±6572.
7. ;a) Ball, J. B.; Hughes, R. A.; Alewood, P. F.; Andrews, P. R.
Tetrahedron 1993, 49, 3467±3478. ;b) Rose, G. D.; Gierash,
L. M.; Smith, J. A. Adv. Protein Chem. 1985, 37, 1±109.
8. For recent reviews see: ;a) Westermann, B.; Diedrichs, N.;
Gedrath, I.; Walter, A. Bioorg. Chem. 1999, 185±192.
;b) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-J.;
Lubell, W. D. Tetrahedron 1997, 53, 12789±12854.
;c) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl.
1993, 32, 1244±1267.
3.5. Molecular modeling
Conformational searches and energy minimizations were
performed using Macromodel version 5.5.23 The Macro-
model implementation of the amber all atom force ®eld
was used ;denoted AMBERp). All calculations were
performed using the implicit water GB/SA solvation
model of Still et al.24 Conformational searches were
performed using the Monte Carlo method of Goodman
and Still.25 For each search 1000 starting structures were
generated and minimized to an energy convergence of
9. Very recently the real nature of many `so called' b-turn
mimics was questioned in view of molecular modeling data,
but spirolactams of these type were found to have a high
potential for turn induction: Muller, G.; Hessler, G.; Decornez,
H. Y. Angew. Chem., Int. Ed. Engl. 2000, 39, 894±895.
10. Burgess, K.; Ho, K.-K.; Pettit, B. M. J. Am. Chem. Soc. 1995,
117, 5 4.
Ê
0.05;kJ/mol)/A using the Polak±Ribiere conjugate gradient
minimization method implemented in Macromodel.23
Duplicated structures and those greater than 50 kJ/mol
above the global minimum were discarded. The lowest
energy structures were subjected to a RHF/6-31Gp geometry
optimization using Gaussian 94.26 The full geometries and
energies of the ab initio optimized structures are given in the
Supporting Information.
11. Ward, P.; Ewan, G. B.; Jordan, C. C.; Ireland, S. J.; Hagan,
R. M.; Brown, J. R. J. Med. Chem. 1990, 33, 1848±1851.
12. Hinds, M. G.; Welsh, J. H.; Brennend, D. M.; Fischer, J.;
Glennie, M. J.; Richards, N. G. J.; Turner, D. L.; Robinson,
J. A. J. Med. Chem. 1991, 34, 1777±1789.
3.6. Supplementary material
13. Genin, M. J.; Gleason, W. B.; Johnson, R. L. J. Org. Chem.
1993, 58, 860±866.
ORTEP drawing for compound 14a. Full geometries and
energies for the optimized structures of 32a and 32b.
14. Khalil, E. M.; Ojala, W. H.; Pradhan, A.; Nair, V. D.; Gleason,
W. B.; Mishra, R. K.; Johnson, R. L. J. Med. Chem. 1999, 42,
628±637.
15. ;a) Genin, M. J.; Mishra, R. K.; Johnson, R. L. J. Med. Chem.
1993, 36, 3481±3483. ;b) Genin, M. J.; Johnson, R. L. J. Am.
Chem. Soc. 1992, 114, 8778±8783.
Acknowledgements
The authors are grateful to the DGICYT ;MEC Spain,
SAF96-0045) and the Universidad San Pablo-CEU for
®nancial support. Predoctoral research grant from the
Universidad San Pablo-CEU ;M. G.) is gratefully acknowl-
edged. We thank the CEIMAT ;Spain) for computer time
and facilities.
16. Dikshit, D. K.; Bajpai, S. N. Tetrahedron Lett. 1995, 36,
3231±3233.
17. In all cases a n.O.e. increment was observed between H2 and
H3a ;6±8%) and between H3b and H4 ;4±6%). No n.O.e.
were observed between H2 and H4. Ezquerra has observed a
pattern for the coupling constants of H3a and H3b in 4-substi-
tuted pyroglutamates which can be used to con®rm the relative
con®gurationn of C2 and C4. Following these method we also
con®rmed the assignement being trans in all cases. See:
Ezquerra, J.; Pedregal, C.; Rubio, A.; Yruretagoyena, B.;
Escribano, A.; Sanchez-Ferrando, F. Tetrahedron 1993, 49,
8665±8678.
References
1. ;a) Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10,
2245±2303. ;b) Collado, I.; Ezquerra, J.; Mateo, A. I.;
Rubio, A. J. Org. Chem. 1998, 63, 1995±2001. ;c) Ikota, N.
Tetrahedron Lett. 1992, 33, 2553±2556. ;d) Rosset, S.;
18. Semipreparative high performance liquid chromatography
was performed using Zorbax ODS column ;9.4 mm
ID£25cm) and MeOH/H2O 85:15as eluent.
 Â
Celerier, J. P.; Lhommet, G. Tetrahedron Lett. 1991, 51,
7521±7524. ;e) Langlois, N.; Adriamialisoa, R. Z.
Tetrahedron Lett. 1991, 32, 3057±3060.
19. Uno, H.; Baldwin, J. E.; Churcher, I.; Russell, A. T. Synlett
1997, 390±392.
2. ;a) Li, H.; Sakamoto, T.; Kikugawa, Y. Tetrahedron Lett.
1997, 38, 6677. ;b) Skamoto, T.; Li, H.; Kikugawa, Y.
J. Org. Chem. 1996, 61, 8496±8499.
20. Atomic coordinates for compounds 14a and 24b have been
deposited in the Cambridge Crystallographic Data Centre and
allocated the deposition numbers CCDC 164582 and 164583,
respectively.
3. Sakamoto, T.; Li, H.; Kikugawa, Y. J. Org. Chem. 1996, 61,
8496±8499.

4836
M. F. BranÄa et al. / Tetrahedron 58 52002) 4825±4836
Â
Á
Â
21. Alvarez-Ibarra, C.; CsakyÈ, A. G.; Lopez de Silanes, I.;
Quiroga, M. L. J. Org. Chem. 1997, 62, 479±484 and
references cited therein.
24. Still, W. C.; Temczyk, A.; Hawely, R. C.; Hendrickson, T.
J. Am. Chem. Soc. 1990, 112, 6127±6129.
25. Goodman, J. M.; Still, W. C. J. Comput. Chem. 1991, 12,
1110±1117.
22. ;a) Miller, M. J.; Biseas, A.; Krook, M. A. Tetrahedron 1983,
39, 2571. ;b) Mattingly, P.; Miller, M. J. J. Org. Chem. 1980,
45, 411.
26. Pople, J. A., et al.; Gaussian94, rev. C3; Gaussian Inc.:
Pittsburg, PA, 1995.
23. Macromodel version 5.5; MacroModel Interactive Modeling
System; Department of Chemistry, Columbia University: New
York, NY, 1996.