Oxazolopiperidin-2-ones as type II' β-turn mimetics: Synthesis and conformational analysis

Article abstract of DOI:10.1021/jo000416v

We describe a straightforward synthesis of 9-substituted 3-aminooxazolidinopiperidin-2-ones 4. Some derivatives were prepared for use in peptide synthesis as rigidified surrogates of the Ala-Pro dipeptide. Analysis of the amide derivatives 14 by NMR experiments and molecular mechanics/dynamics calculations shows that the major isomer 14a has a stronger propensity than the minor isomer 14b to adopt β-turn conformations, and the calculations indicate that in water 14a adopts a stable βII' turn conformation.

Full text of DOI:10.1021/jo000416v

6992
J . Org. Chem. 2000, 65, 6992-6999
Oxa zolop ip er id in -2-on es a s Typ e II′ â-Tu r n Mim etics: Syn th esis
a n d Con for m a tion a l An a lysis
M. Angels Estiarte, Mario Rubiralta, and Anna Diez*
Laboratori de Quı´mica Orga`nica, Facultat de Farma`cia, Universitat de Barcelona, Av. J oan XXIII,
08028-Barcelona, Spain
Michael Thormann and Ernest Giralt
Departament de Quı´mica Orga`nica, Facultat de Quı´mica, Universitat de Barcelona, c/ Martı´ i Franque`s,
08028-Barcelona, Spain
adiez@farmacia.far.ub.es
Received March 21, 2000
We describe a straightforward synthesis of 9-substituted 3-aminooxazolidinopiperidin-2-ones 4. Some
derivatives were prepared for use in peptide synthesis as rigidified surrogates of the Ala-Pro
dipeptide. Analysis of the amide derivatives 14 by NMR experiments and molecular mechanics/
dynamics calculations shows that the major isomer 14a has a stronger propensity than the minor
isomer 14b to adopt â-turn conformations, and the calculations indicate that in water 14a adopts
a stable âII′ turn conformation.
In tr od u ction
A large number of bicyclic systems have been reported
as â-turn mimetics, including the 6,5-bicyclic systems
type 1-3 (Figure 1).1 In particular, thiazolopiperidones
1, first introduced as â-turn mimetics by Nagai and co-
workers,2 have been extensively used to study numerous
bioactive peptides.3-9 However, we have found that
oxazolopiperidones 4 have not been studied as con-
strained pseudopeptides.
Despite the fact that 1a induces a âII′ turn conforma-
tion in collaboration with the adjacent residues, this
* To whom correspondence should be addressed. Phone: 34-93-
4024540. Fax: 34-93-4024539.
(1) For
a review, see: Hanessian, S.; McNaughton-Smith, G.;
Lombart H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789-12854.
(2) Nagai, U.; Sato, K. Tetrahedron Lett. 1985, 26, 647-650.
(3) For the use of 1a in studies on gramicidin S, see: (a) Sato, K.;
Nagai, U. J . Chem. Soc., Perkin Trans. 1 1986, 1231-1234. (b) Bach,
A. C., II.; Markwalder, J . A.; Ripka, W. C. Int. J . Peptide Protein Res.
1991, 38, 314-323. (c) Andreu, D.; Ruiz, S.; Carrero, C.; Alsina, J .;
Albericio, F.; J ime´nez, M. A.; de la Figuera, N.; Herranz, R.; Garc´ıa-
Lo´pez, M. T.; Gonza´lez-Mun˜iz, R. J . Am. Chem. Soc. 1997, 119, 10579-
10586.
(4) For studies on cyclosporin A, see: Belshaw, P. J .; Meyer, S. D.;
J ohnson, D. D.; Romo, D.; Ikeda, Y.; Andrus, M.; Alberg, D. G.; Schultz,
W. L.; Clardy, J .; Schreiber, S. L. Synth. Lett. 1994, 381-392.
(5) For studies on RGD peptides, see: Haubner, R.; Schmitt, W.;
Hˆlzemann, G.; Goodman, S. L.; J onczyk, A.; Kessler, H. J . Am. Chem.
Soc. 1996, 118, 7881-7891.
(6) For studies on Tendamistat, see: Etzkorn, F. A.; Guo, T.; Lipton,
M. A.; Goldberg, S. D.; Bartlett, P. A. J . Am. Chem. Soc. 1994, 116,
10412-10425.
F igu r e 1.
â-turn dipeptide seems not to be very useful for improving
the activity of small peptides, where the â-turn position
itself plays some role in interaction with the receptor
site.10 Interestingly, recent molecular modeling calcula-
tions on the tetrapeptide Ac-Ala-{1a }-Ala-NHMe indicate
that the geometry of a turn induced by thiazolopiperidone
1a differs significantly from that of an ideal â-turn.11 In
addition, the incorporation of each epimer 1a or 1b in a
bioactive peptide has been shown to provoke distinct
changes in its bioactivity.8a
We thought that the isosteric substitution of the sulfur
in 7-position by an oxygen atom (Figure 1) might improve
the binding properties of the â-turn dipeptide, since
oxygen could act as a better hydrogen bond acceptor on
the “external part” of the turn. With the aim of establish-
ing the possible usefulness of oxazolopiperidones 4 as
â-turn mimetics, we have prepared these bicyclic lactams
(7) FOr studies on thrombin inhibitors, see: (a) Wagner, J .; Kallen,
J .; Ehrhardt, C.; Evenou, J .-P.; Wagner, D. J . Med. Chem. 1998, 41,
3664-3674. (b) Bachand, B.; DiMaio, J .; Siddiqui, M. A. Bioorg. Med.
Chem. Lett. 1999, 9, 913-918.
(8) For studies on dopamine receptor activity modulators, see: (a)
Subasinghe, N. L.; Bontems, R. J .; McIntee, E.; Mishra, R. K.; J ohnson,
R. L. J . Med. Chem. 1993, 36, 2356-2361. For the use of a spiro
derivative of 1a in the study of dopamine receptor modulators, see:
(b) Khalil, E. M.; Ojala, W. H.; Pradhan, A.; Nair, V. D.; Gleason, W.
B.; Mishra, R. K.; J ohnson, R. L. J . Med. Chem. 1999, 42, 628-637.
(9) For studies on a zinc finger incorporating 1a as an artificial
â-turn, see: Viles, J . H.; Patel, S. U.; Mitchell, J . B. O.; Moody, C. M.;
J ustice, D. E.; Uppenbrink, J .; Doyle, P. M.; Harris, C. J .; Sadler, P.
J .; Thornton, J . M. J . Mol. Biol. 1998, 279, 973-986. For more
examples, see ref 10.
(10) Nagai, U.; Sato, K.; Nakamura, R.; Kato, R. Tetrahedron 1993,
49, 3577-3592.
(11) Takeuchi, Y.; Marshall, G. R. J . Am. Chem. Soc. 1998, 120,
5363-5372.
10.1021/jo000416v CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/21/2000

Oxazolopiperidin-2-ones as Type II′ â-Turn Mimetics
J . Org. Chem., Vol. 65, No. 21, 2000 6993
F igu r e 2.
F igu r e 5.
F igu r e 3. NOESY correlations and stereochemical assign-
ment of oxazolopiperidones Cbz-4a -OMe and Cbz-4b-OMe.
F igu r e 6.
Resu lts a n d Discu ssion
Syn th esis a n d Str u ctu r a l Assign m en t. Oxazolopi-
peridones Cbz-4-OMe were prepared by condensation of
aldehyde 5 and Ser-OMe in a “one pot” process. Aldehyde
5 was obtained from Cbz-(S)-glutamic acid in three steps,
following Fukuyama’s procedure.13,14 The condensation
reaction of aldehyde 5 with Ser-OMe was assayed in a
number of experimental conditions, summarized in Table
1. We observed that the yields and the number of
stereoisomers varied according to the reaction conditions.
When the reaction was carried out at room temperature
in pyridine, followed by evaporation of the base and
subsequent treatment with K2CO3 in MeOH (entry 7),
the reaction yielded oxazolopiperidone Cbz-4a -OMe as
the sole product. In the other conditions assayed we
obtained mixtures of the three Cbz/OMe stereoisomers
4a , 4b, and 4c.
F igu r e 4.
and their derivatives 14 (Figure 6). The conformational
analysis of 14, both by NMR experiments and by molec-
ular modeling calculations, indicates that oxazolopiperi-
done 14a mimics a âII′ turn and that 14b adopts a â-turn
conformation that does not correspond to the classified
types.12
Compounds Cbz-4-OMe were identified from their
analytical data. Thus, the most characteristic signals of
(12) (a) Perczel, A.; McAllister, M. A.; Csa´sza´r, P.; Csizmadia, I. G.
J . Am. Chem. Soc. 1993, 115, 4849-4858. (b) Richardson, J . Adv. Prot.
Chem. 1981, 34, 167-339. (c) Rose, G. D.; Gierasch, L. M.; Smith, J .
A. Adv. Prot. Chem. 1985, 37, 1-109. (d) Chou, P. Y.; Fasman, G. D.
J . Mol. Biol. 1977, 115, 135-175. (e) Venkatachalam, C. M. Biopoly-
mers 1968, 6, 1425-1436.
(13) Fukuyama, T.; Liu, G.; Linton, S. D.; Lin, S.-C.; Nishino, H.
Tetrahedron Lett. 1993, 34, 2577-2580.
(14) Fukuyama, T.; Lin, S.-C.; Li, L. J . Am. Chem. Soc. 1990, 112,
7050-7051.

6994 J . Org. Chem., Vol. 65, No. 21, 2000
Ta ble 1. Con d en sa tion Con d ition s Assa yed to Obta in Oxa zolop ip er id on es Cbz-4-OMe
Estiarte et al.
entry
ref
reagents
solvent
conditions
Cbz-4-OMe (a :b:c)
yield (%)
8
1
2
15
8a
Et3N, Na2SO4
(1) NaHCO3
(2) DMF
TFA
Et3N
pyridine
(1) pyridine
(2) K2CO3
Et2O
0 °C - rt, 24 h
EtOH, H2O
DMF
1,2-dichloroethane
toluene
pyridine
pyridine
rt, 16 h
10:5.5:1
42 °C, 24 h
reflux, 48 h
reflux, Dean-Stark, 48 h
reflux, 18 h
rt, 6 d
3
5
6
7
16
10:5.7:1
10:5.7:1
10:5:1
45
58
40
54
17
6
1:0:0
MeOH
rt, 4 h
1
the oxazolopiperidone backbone in the H NMR spectra
are as follows: an AMX system consisting of two double
doublets (J ) 9, 7 Hz) and a triplet (J ) 9 Hz), that
correspond to the C8- and C9-protons, and the signals of
the protons H-3 and H-6, at δ ∼4.1 and ∼4.9. In the 13C
NMR spectra, the bicyclic system typically shows the
methine signals at δ ∼87 and δ ∼51, corresponding to
C6 and C3, respectively. In isomer Cbz-4a -OMe, H-6
resonated at δ 4.91 as a double doublet (J ) 9 and 4 Hz),
and H-3 appeared as a double triplet (J ) 11 and 5 Hz)
at δ 4.16. These multiplicities indicated that both H-3
and H-6 adopt a pseudoaxial disposition (Figure 3). In
compound Cbz-4b-OMe, H-3 also appears as a double
triplet (J ) 11, 5 Hz, δ 4.10), and is therefore in an axial
disposition; however, H-6 appeared here as a broad signal
at δ 4.83, proving that Cbz-4b-OMe is the C6-epimer of
Cbz-4a -OMe. In contrast, the third isomer Cbz-4c-OMe
was identified as the C3-epimer of compound Cbz-4a -
OMe: the H-3 proton resonated as a triplet (J ) 5 Hz)
at δ 4.02, whereas H-6 was a double doublet (J ) 8, 6
Hz) at 4.90 ppm. The fact that Cbz-4c-OMe was detected
when the condensation was performed at temperatures
above 40 °C (Table 1) meant that once Cbz-4a -OMe was
formed, it underwent a limited degree of epimerization
on C3 in these conditions.18
hyde function of compound 5 to form imine 6, the alcohol
group can then attack either side of the intermediate
imine, resulting in an epimeric mixture of oxazolidines
7 (pathway A). Subsequent lactamization would yield the
epimeric mixture of oxazolopiperidones 4a and 4b. This
mechanism explains why the a :b ratios obtained were
always similar (about 10:6). However, it does not explain
how a single isomer can be obtained at room temperature.
Alternatively, if the closure of the oxazolidine ring
took place on the acyliminium salt 8,20 the approach of
the alcohol group on C6 could be stereocontrolled (path-
way B).21
Treatment of pure Cbz-4a -OMe with TFA in dry 1,2-
dichloroethane for 2.5 days at room temperature yielded
a C6 epimeric mixture of isomers a :b of Cbz-4-OMe in a
9:1 proportion (NMR), which increased up to 2:1 when
the mixture was refluxed for 3 days (Table 1, entry 3).22
This indicates that in the acid medium, an equilibrium
with the intermediate acyliminium salt 8 is established
by protonation on the O7 oxigen atom, and that the ring
closure is not fully stereoselective in the acid medium.
Several derivatives of oxazolopiperidone 4a were pre-
pared for further application in peptide synthesis (Figure
5). Selective hydrogenolysis of the N-Cbz protecting group
in the presence of Boc2O yielded the N-Boc/OMe deriva-
tive 9. When the hydrogenolysis was done in the absence
of Boc2O, pseudodipeptide 10 was obtained quantita-
tively, and compound 10 was transformed to the N-Fmoc/
OMe 11. Selective cleavage of the ester was performed
on Cbz-4a -OMe and on 11 to yield 12 (Cbz/OH) and 13
(Fmoc/OH). The stability of the bicyclic system in acid/
base conditions that are common in peptide synthesis was
also checked. Thus, compound 12 was recovered unal-
tered after treatment with a 20% solution of piperidine
in CH2Cl2 at room temperature; and compound 13 was
unaltered in a 30% solution of TFA in DMF. Most
importantly, no epimerization was observed during these
experiments.
The absolute configuration of oxazolopiperidones 4a
and 4b was determined from the NOESY experiments
(Figure 3). Thus, in oxazolopiperidone Cbz-4a -OMe, H-6
was correlated with H-4 and H-8, whereas H-3 was
correlated with H-5. Since the S configuration of C3 was
fixed, Cbz-4a -OMe could be identified as the (3S,6S,9S)
isomer. In compound Cbz-4b-OMe, protons H-6, H-3, and
H-5 were correlated, and this isomer was thus identified
as (3S,6R,9S).
When we tried to rationalize the synthetic outcome of
the condensation reaction, we observed that the only
relevant difference in the experimental conditions used
was the temperature (Table 1). When the reaction was
carried out at 0 °C no reaction was observed, at room
temperature only Cbz-4a -OMe was obtained, and when
we heated to temperatures over 40 °C, the epimeric mix-
tures were formed. These results can be explained if we
consider that there are two mechanisms that can lead to
the formation of the oxazolopiperidone bicyclic system
(Figure 4). Thus, if Ser-OMe reacts first with the alde-
Finally, we prepared the Cbz/NHMe compounds 14a
and 14b that we needed for the conformational analysis
by NMR experiments by treatment of Cbz-4a -OMe and
Cbz-4b-OMe with MeNH2 (Figure 6).
Con for m a tion a l Stu d ies. To determine whether the
oxazolopiperidone system can promote a â-turn forma-
tion, we performed conformational studies by NMR and
(15) Amat, M.; Llor, N.; Hidalgo, J .; Bosch, J . Tetrahedron: Asym-
metry 1997, 13, 2237-2240.
(19) Lloyd-Williams, P.; Albericio, F.; Giralt, E. Chemical Approaches
to the Synthesis of Peptides and Proteins; CRC Press: Boca Raton, FL,
1997; pp 116-119.
(20) The acyliminium salt 8 could be formed either from imine 6
through an imine-enamine tautomeric equilibrium in the basic me-
dium, or by reaction of 5 on the oxazolidone carbonyl group, via an
amide intermediate.
(21) The stereocontrolled cyclization of chiral oxazolopiperidones is
well documented. See, for instance: (a) Romo, D.; Meyers, A. I.
Tetrahedron 1991, 47, 9503-9569, and references therein. (b) Husson,
H.-P.; Royer, J . Chem. Soc. Rev. 1999, 6, 383-394. (c) See also ref 15.
(22) No epimerization was observed when treating pure Cbz-4a -OMe
with TFA in CH2Cl2 at room temperature for 30 min.
(16) Siddiqui, M. A.; Pre´ville, P.; Tarazi, M.; Warder, S. E.; Eby, P.;
Gorseth, E.; Puumala, K.; DiMaio, J . Tetrahedron Lett. 1997, 38, 8807-
8810.
(17) Baldwin, J . E.; Lee, E. Tetrahedron 1986, 42, 6551-6554.
(18) Compound 4c was always isolated together with 4a . The C3
epimerization in the basic medium probably occurs through the
formation of a 4H-oxazolo-5-one, rather than through a keto-enol
tautomeric equilibrium.19 This would explain why the epimerization
is not observed in the reaction at room temperature, in which the
protecting N-hydroxymethyl chain is lost only during the K2CO3
treatment.

Oxazolopiperidin-2-ones as Type II′ â-Turn Mimetics
J . Org. Chem., Vol. 65, No. 21, 2000 6995
Ta ble 2. Sta n d a r d Tor sion An gles in th e Ma jor â-Tu r n
to evaluate the strength of this hydrogen bond, we carried
out a second experiment which consisted of running the
1H NMR spectrum in a gradient of DMSO in CDCl3.23
Thus, at low concentrations of DMSO, protons that are
non-hydrogen-bonded or intermolecularly hydrogen-
bonded will immediately establish a bond with the
DMSO, and will therefore quickly shift downfield. How-
ever, intramolecularly bonded protons are less accessible
to DMSO, and will not shift until the intramolecular
hydrogen bond is broken. Figure 7 summarizes the
spectral evidence that NHi shifted immediately, but that
the NHi+3 proton needed a 20% solution of DMSO in
CDCl3 to start shifting. This result demonstrated that
in compound 14a the NHi+3 is intramolecularly hydrogen-
bonded, and that this hydrogen bond is stable until the
concentration of the competitive solvent reaches 20%.
NMR Stu d ies. 2. Tem p er a tu r e Coefficien t. The
Typ es12
a
a
a
a
turn
φ2
ψ2
φ3
ψ3
âI
-60
60
-60
60
-60
60
-30
30
120
-120
-30
30
-90
90
0
0
0
0
âI′
âII
80
âII′
âIII
âIII′
-80
-60
60
-30
30
a
All angles are given in degrees.
1
temperature dependence of the H NMR chemical shift
of peptide NH protons also reflects their hydrogen-
bonding state. In this regard, several interpretations of
the temperature coefficient (∆δ/∆T) values have been
suggested.24 The most meaningful results are usually
obtained in DMSO: coefficients above -4 ppb/K (in
absolute value) indicate an external orientation of the
NH amide proton, whereas coefficients below -3 ppb/K
(in absolute value) indicate shielding from the solvent.
However, in our case the intramolecular hydrogen bond
that NHi+3 establishes was cleaved in DMSO, and a high-
temperature coefficient value would be expected in
DMSO. In accordance with this expectation, we observed
∆δ/∆Τ (NHi+3) ) -5.4 ppb/K.
F igu r e 7. 1H NMR chemical shift of the NH protons of
pseudopeptide 14a at different proportions of DMSO-d6 in
CDCl3 (25 °C).
by molecular modeling. â-Turns are nonperiodic tet-
rapeptide segments which reverse the orientation of the
peptide chain.12 The most general â turn features are the
distance R (R e 7 Å) between the CR atoms of the first
and the fourth amino acids, and the dihedral angle
τ(-90° e τ e +90°) formed by the four CR atoms. Many
conformers fulfill these requirements.12a The major types12e
show a characteristic hydrogen bond between the carbo-
nyl function of the first amino acid and the amide group
of the fourth. The major â turns (Table 2, Figure 8a) are
classified according to the torsion angles of the second
amino acid (φ2, ψ2) and of the third (φ3, ψ3). We shall
maintain this classification for the â turn mimetics of the
oxazolopiperidone type 14a and 14b.
Compounds 14a and 14b were used as the models
because they possess the minimum structural elements
required to form a â turn. NMR experiments allowed us
to search for the characteristic intramolecular hydrogen
bond that would prove that oxazolopiperidones 14 form
â turns. The molecular mechanics/dynamics (MM/MD)
calculations were performed to provide further insight
into the static and dynamic conformational properties of
the two derivatives.
NMR Stu d ies. 1. Ch em ica l Sh ift a n d Ad d ition of
a Com p etitive Solven t. In solvents such as CDCl3, NH
amide protons that are involved in hydrogen bonding
resonate around δ 7-8. In the 1H NMR spectrum of
compound 14a in CDCl3, the carbamate NH (NHi)
resonates at δ 5.72, and the amide NH (NHi+3) at δ 7.23.
This suggests that in CDCl3 the NHi proton is free, while
the NHi+3 proton is involved in a hydrogen bond. How-
ever, in DMSO both the NHi and the NHi+3 protons
undergo a downfield shift (∆δ ) +1.99 ppm and ∆δ )
+0.45, respectively), which proves that in DMSO both
are accessible to the solvent, i.e., that NHi+3 is no longer
hydrogen-bonded in the presence of a competitive solvent.
To prove that NHi+3 establishes an intramolecular
hydrogen bond rather than an intermolecular one, and
Scolastico and co-workers have recently described the
hydrogen-bonding states of amide protons in CDCl3,
1
taking into account all their H NMR parameters.24a They
distinguish three different states: (a) strongly bonded
amide protons: low-temperature coefficient, high chemi-
cal shift value (δ ) 7.0), and small ∆δ upon addition of
competitive solvent (∆δ e 0.2 ppm); (b) non-hydrogen-
bonded amide protons: low-temperature coefficient (∆δ/
∆Τ ) -2.6 ppb/K), low chemical shift (δ ) 7), and high
∆δ upon addition of competitive solvent (∆δ g 0.2 ppm);
and (c) amide protons in equilibrium between hydrogen-
bonded and non-hydrogen-bonded states: large temper-
ature coefficient (∆δ/∆Τ > -2.6 ppb/K).
According to this classification, our results indicate
that the amide NH proton is weakly hydrogen bonded,
in equilibrium with a non-hydrogen-bonded state (∆δ/
∆Τ(NHi+3) ) -3.4 ppb/K), whereas the carbamate proton
is non-hydrogen-bonded (∆δ/∆Τ (NHi) ) -4.6 ppb/K).
Similar results were obtained for isomer 14b by NMR
experiments. The chemical shifts in CDCl3 and addition
of competitive solvent experiments showed that the NHi
carbamate proton is non-hydrogen-bonded and that the
NHi+3 amide proton is intramolecularly hydrogen-bonded,
although weakly, i.e., the hydrogen bond breaks at a 20%
concentration of DMSO in CDCl3, and the temperature
coefficient in CDCl3 is ∆δ/∆Τ (NHi+3) ) -3.3 ppb/K
(CDCl3) (see Supporting Information).
Molecu la r Mod elin g Ca lcu la tion s. According to the
simulated annealing calculations (see the Experimental
(23) Andre´, F.; Vicherat, A.; Boussard, G.; Aubry, A.; Marraud, M.
J . Peptide Res. 1997, 50, 372-381.
(24) (a) Belvisi, L.; Gennari, C.; Mielgo, A.; Potenza, D.; Scolastico,
C. Eur. J . Org. Chem. 1999, 389-400 and references therein. (b)
Kessler, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 512-523 and
references therein.

6996 J . Org. Chem., Vol. 65, No. 21, 2000
Estiarte et al.
F igu r e 8. (a) Minimum energy conformation of compound 14a resulting from simulated annealing calculations (Table 3), in
continuum. Used â turn descriptors are also indicated. (b) Stereoview of (a). (c) Snapshot of compound 14a after 500 ps simulation
time in DMSO.

Oxazolopiperidin-2-ones as Type II′ â-Turn Mimetics
J . Org. Chem., Vol. 65, No. 21, 2000 6997
Ta ble 3. P op u la tion of Secon d a r y Str u ctu r es of
Com p ou n d s 14, As Obta in ed by Sim u la ted An n ea lin g
Con clu sion
We have established a straightforward synthesis of the
epimeric oxazolopiperidin-2-one systems (3S,6S,9S)-Cbz-
4a -OMe and (3S,6R,9S)-Cbz-4b-OMe. Experimental and
theoretical conformation studies by NMR and by MM/
MD have been performed on the N-methyl derivatives
14a and 14b. These demonstrate that 14a is an excellent
âII′ turn mimetic, whereas 14b is more flexible and
adopts either unusual â-turns or L-shaped conformations.
The bicyclic system (3S,6S,9S)-4a is therefore a new
dipeptide scaffold for the synthesis of âII′ turn mimetics,
which might have its application in bioactive peptide-
based rational drug design.
compd
φ2
52.1 -123.4 -68.4
-169.0 -141.7 -64.3 114.9 -56.5 L-shaped
58.8 -130.2 -63.1 -8.7 -60.8 âII′
-167.3 -166.3 -38.5 115.9 -56.6 L-shaped
Energies in kcal/mol.
ψ2
φ3
ψ3
Ea
conformer
14a
-6.0 -61.9 âII′
14b
a
Ta ble 4. â-Tu r n P r op en sities of Com p ou n d s 14 As
Der ived fr om MD Ca lcu la tion s in Differ en t Med ia
a,b
compd
medium
âT
âIa âI′a âIIa âII′a âIIIa âIII′a
continuum
DMSO
H2O
continuum
DMSO
H2O
98.1 0.1 0.0 0.0 93.3 0.0
100.0 0.0 0.0 0.0 0.0 0.0
99.1 0.1 0.0 0.0 83.8 0.1
67.7 0.0 0.0 0.0 42.9 0.0
0.0
0.0
0.0
0.0
0.0
0.0
14a
Exp er im en ta l Section 26
14b
89.5 0.0 0.0 0.0
18.7 0.0 0.0 0.0
0.0 0.0
3.0 0.0
Meth yl (3S,6RS,9S)-3-Ben zyloxyca r bon yla m in o-2-oxo-
7,1-oxa za b icyclo[4.3.0]n on a n e-9-ca r b oxyla t es (Cb z-4a -
OMe a n d Cbz-4b-OMe). Meth od A (Ta ble 1, En tr y 7). A
solution of aldehyde 527 (12.8 g, 46.2 mmol) and the hydro-
chloride of (S)-Ser-OMe (7.93 g, 50.9 mmol) in dry pyridine
(462 mL) was stirred at room temperature for 10 d. The
reaction mixture was filtered and the solvent evaporated. The
residue was dissolved in dry CH3OH (380 mL), and solid
K2CO3 (4.4 g, 32.3 mmol) was added until the starting
substrate disappeared (TLC control, 3-5 h). The reaction
mixture was filtered, the solvent was evaporated, and the
resulting oil was chromatographed (hexane/AcOEt, 7:3) to yield
oxazolopiperidone (3S,6S,9S)-Cbz-4a -OMe (8.7 g, 54%) as a
a
b
In percent. Based on the general â-turn criteria R and τ.
Section), epimers 14a and 14b present two distinct
conformers (Table 3). In both cases, the most stable
conformer corresponds to a type II′ â-turn (Figure 8), and
the second conformer adopts an L-shaped structure25 due
to the more extended conformation of the i + 1 residue
in the pseudodipeptide moiety. The âII′ turns are about
4-5 kcal/mol more stable than the corresponding L-
shaped conformations, and the âII′ turn of compound 14a
is about 1 kcal/mol more stable than that of compound
14b. The distance of the O-H hydrogen bond (d ) 1.92
Å) of the âII′ turns is the same in both isomers, but the
hydrogen bond angle OHN is 162.0° for 14a and 149.8°
for 14b. This leads to a weaker hydrogen bond in 14b,
which might account for its slightly lower stabilization.
In a next step, the âII′ conformers of both compounds
were taken as the starting points for MD calculations in
order to get some insight into their dynamic behavior in
different media. The results are summarized in Table 4.
The âII′ turn conformation of compound 14a shows no
major dihedral angle fluctuations, and remains very
stable in the continuum during 10 ns. In water, the
preferred conformation is also a âII′ turn. In DMSO,
despite the fact that 14a shows a tendency to adopt
â-turn conformations and not L-shaped ones, these turns
do not correspond to any of the major â-turn types. In
DMSO the intramolecular hydrogen bond is broken,
allowing the amide proton to point outward and form a
hydrogen bond with the solvent. This behavior is consis-
tent with the experimental NMR data.
In contrast, pseudopeptide 14b flips to the L-shaped
form after 2 ns and flips back to the âII′ turn conforma-
tion after 5.5 ns. In DMSO, the competitive solvent again
breaks the intramolecular hydrogen bond, as observed
by NMR. More interestingly, the proportion of â-confor-
mations in water is extremely low (less than 20%), and
the analysis of the trajectory shows that isomer 14b
adopts the L-shaped form after about 50 ps and main-
tains it to the end of the evolution time.
These conformational studies indicate that pseudopep-
tide 14a (6H-â) is a good âII′ turn mimetic in water. In
contrast, 14b (6H-R) exhibits a pronounced ψ2 flexibility
in the bicyclic framework, which leads to a preference
for an L-shaped conformation in water.
single isomer: [R]22 ) -100.1 (c 1, CHCl3); IR (NaCl) 3390,
D
1721, 1667 cm-1; H NMR 1.61-1.87 (m, 2H), 2.32-2.38 (m,
1
1H), 2.52 (br s, 1H), 3.77 (s, 3H), 3.84 (dd, J ) 9, 7 Hz, 1H),
4.16 (dt, J ) 11, 5 Hz, 1H), 4.44 (d, J ) 9 Hz, 1H), 4.68 (dd, J
) 9, 7 Hz, 1H), 4.91 (dd, J ) 9, 4 Hz, 1H), 5.12 (s, 2H), 5.61 (d,
J ) 5 Hz, 1H), 7.34 (s, 5H); 13C NMR 24.9, 26.6, 52.0, 52.6,
55.8, 66.8, 68.4, 87.9, 127.9, 128.4, 136.2, 156.4, 166.7, 170.1.
Meth od B (Ta ble 1, En tr y 5). To a solution of the
hydrochloride of (S)-Ser-OMe (1.3 g, 8.4 mmol) and Et3N (1.17
mL, 8.4 mmol) in dry toluene (10 mL), cooled at 0 °C and under
N2 atmosphere, was added via cannula a solution of aldehyde
5 (2.54 g, 8.4 mmol) in dry toluene (32 mL). The reaction
mixture was refluxed for 24 h in a Dean-Stark trap. More
Et3N (1.17 mL, 8.4 mmol) was added, and after 24 h at reflux,
the reaction mixture was filtered and the solvent was evapo-
rated to give an oil which was chromatographed (hexane/
AcOEt, 3:7) to yield oxazolopiperidone (3S,6R,9S)-Cbz-4b-OMe
(555 mg, 19%) as an orange oil, and a yellow foam identified
as a 10:1 diastereomeric mixture of compound (3S,6S,9S)-Cbz-
4a -OMe and a third isomer (3R,6S,9S)-Cbz-4c-OMe (1.14 g,
39%). Oxa zolop ip er id on e (3S,6R,9S)-Cbz-4b-OMe (higher
Rf): [R]22 ) +98.5 (c 1, CHCl3); IR (NaCl) 3380, 1742, 1721,
D
and 1667 cm-1; 1H NMR 1.61 (dtd, J ) 13, 11 and 5.5 Hz, 1H),
1.99 (ddd, J ) 14.5, 8.5, 5 Hz, 1H), 2.13-2.20 (m, 1H), 2.24-
2.28 (m, 1H), 3.69 (s, 3H), 3.74 (dd, J ) 9, 7 Hz, 1H), 4.10 (dt,
J ) 11, 5 Hz, 1H), 4.24 (t, J ) 9 Hz, 1H), 4.83 (br s, 1H), 4.85
(dd, J ) 9, 7 Hz, 1H), 5.04 (s, 2H), 5.72 (br s, 1H), 7.35 (s, 5H);
13C NMR 23.9, 24.5, 51.2, 52.7, 56.1, 66.8, 67.0, 86.8, 128.0,
128.1, 128.4, 136.2, 155.9, 168.7, 170.1. EIMS m/z 348 (M+,
5), 257 (5), 241 (9), 197 (12), 130 (13), 91 (100). Anal. Calcd
for C17H20N2O6: C, 58.61; H, 5.79; N, 8.04. Found: C, 58.58;
H, 5.99; N, 7.77. Oxa zolop ip er id on e Cbz-4c-OMe (from a
10:1 mixture of 4a and 4c, lower Rf): 1H NMR 1.69-1.77 (m,
2H), 1.82-1.89 (m, 1H), 2.18-2.32 (m, 2H), 3.69 (s, 6H), 3.74
(dd, J ) 9, 7 Hz, 2H), 4.02 (t, J ) 5 Hz, 1H), 4.19 (d, J ) 10
Hz, 1H), 4.42 (d, J ) 7 Hz, 1H), 4.90 (dd, J ) 8, 6 Hz, 1H),
5.04 (s, 4H), 5.74 (d, J ) 5 Hz, 1H), 7.27 (s, 10H); 13C NMR
24.1, 24.4, 49.3, 52.5, 56.1, 66.7, 69.9, 86.2, 127.8, 128.3, 136.2,
156.3, 166.7, 170.0.
(26) Estiarte, M. A.; de Souza, M. V. N.; Del R´ıo, X.; Dodd, R. H.;
Rubiralta, M.; Diez, A. Tetrahedron 1999, 55, 10173-10186.
(27) Aldehyde 5: [R]22 ) +92 (c ) 1, CH3CN) [lit.14 [R]22 ) +89 (c
(25) For an example of an L-shaped conformation of the Ala-Pro
moiety in a cyclic peptide, see: Brown, J . N.; Teller, R. G. J . Am. Chem.
Soc. 1976, 98, 7565-7569.
D
D
) 1.4, MeCN)].

6998 J . Org. Chem., Vol. 65, No. 21, 2000
Estiarte et al.
Meth yl (3S,6S,9S)-3-ter t-Bu toxyca r bon yla m in o-2-oxo-
7,1-oxa za bicyclo[4.3.0]n on a n e-9-ca r boxyla te (9). A solu-
tion of oxazolopiperidone Cbz-4a -OMe (200 mg, 0.28 mmol),
(Boc)2O (163 mg, 0.74 mmol), and 10% Pd/C in CH3OH (5 mL)
was hydrogenated at Patm for 2 h at room temperature. An
AcOH/NaOAc buffer solution (pH ) 3, 2 mL) was added, and
the mixture was stirred for 3 h at room temperature. The
reaction mixture was filtered through Celite, and the resulting
oil was chromatographed (hexane/AcOEt, 2:8) to yield the Boc-
156.6, 168.7, 170.9; EIMS m/z 334 (M+, 7), 290 (1), 227 (12),
178 (48), 108 (47), 91 (100). Anal. Calcd for C16H18N2O6: C,
55.64; H, 5.61; N, 8.11. Found: C, 55.64; H, 5.38; N, 8.22.
(3S,6S,9S)-3-[9-(F lu or en yl)m eth oxyca r bon yla m in o]-2-
oxo-7,1-oxazabicyclo[4.3.0]n on an e-9-car boxylic Acid (13).
To a solution of oxazolopiperidone 11 (60 mg, 0.13 mmol) in
THF (2 mL), cooled at 0 °C, was added aqueous 1 N NaOH
(0.3 mL, 0.3 mmol), and the mixture was stirred at 0 °C for 1
h. The reaction was quenched by addition of 1 N HCl, until
pH ) 1, at 0 °C. The CH3OH was evaporated, and the remains
were partitioned in AcOEt-H2O. The organic layer was
washed with brine, dried, and evaporated to yield acid 13 (45
oxazolopiperidone 9 (112 mg, 72%) as a white foam: [R]22
)
D
-102.3 (c 1, CHCl3); IR (NaCl) 3320, 1749, 1714, 1671 cm-1
;
1H NMR 1.45 (s, 9H), 1.61-1.82 (m, 2H), 2.31-2.38 (m, 1H),
2.48 (br s, 1H), 3.77 (s, 3H), 3.84 (dd, J ) 9, 7 Hz, 1H), 4.17
(br s, 1H), 4.44 (t, J ) 9 Hz, 1H), 4.68 (dd, J ) 9, 7 Hz, 1H),
4.92 (dd, J ) 9, 4 Hz, 1H), 5.23 (br d, J ) 6 Hz, 1H); 13C NMR
25.0, 26.6, 28.1, 51.6, 52.5, 55.8, 68.3, 79.7, 87.9, 155.8, 167.1,
170.1; EIMS m/z 258 (M+ - C(CH3)3, 2), 197 (10), 130 (18), 57
(100). Anal. Calcd for C14H22N2O6: C, 53.50; H, 7.05; N, 8.91.
Found: C, 53.32; H, 7.38; N, 8.72.
mg, 77%) as a white solid: mp 200-202 °C (AcOEt); [R]22
)
D
-114.7 (c 0.5, CHCl3); IR (NaCl) 3417, 3010, 1726, 1694 cm-1
;
1H NMR 1.68-1.85 (m, 2H), 2.35 (br s, 1H), 2.59 (br s, 1H),
3.84 (t, J ) 9 Hz, 1H), 4.19 (br s, 1H), 4.22 (t, J ) 7 Hz, 1H),
4.39 (br d, J ) 6.5 Hz, 2H), 4.45 (t, J ) 9 Hz, 1H), 4.69 (dd, J
) 9, 7 Hz, 1H), 4.92 (br s, 1H), 5.49 (br s, 1H), 7.31 (td, J )
7.5, 1 Hz, 2H), 7.40 (t, J ) 7.5 Hz, 2H), 7.60 (dd, J ) 7, 3 Hz,
2H), 7.76 (t, J ) 7.5 Hz, 2H); 13C NMR (CDCl3/CD3OD) 24.8,
25.5, 47.0, 51.6, 56.0, 66.9, 68.2, 87.9, 119.8, 125.0, 127.0, 127.6,
141.1, 143.5 and 143.8, 156.6, 167.7, 171.1; EIMS m/z 244 (M+
- Fmoc, 0.1), 196 (13), 178 (100), 165 (48), 57 (15). Anal. Calcd
for C23H22N2O6: C, 65.39; H, 5.25; N, 6.63. Found: C, 65.39;
H, 5.45; N, 6.37.
Meth yl (3S,6S,9S)-3-Am in o-2-oxo-7,1-oxazabicyclo[4.3.0]-
n on a n e-9-ca r boxyla te (10). To a solution of oxazolopiperi-
done Cbz-4a -OMe (2 g, 5.74 mmol) in CH3OH (57.4 mL) was
added 10% Pd/C (10 mg), and the mixture was hydrogenated
at Patm for 2 h, at room temperature. The reaction mixture
was filtered through Celite, and the solvent was evaporated
(3S,6S,9S)-3-Ben zyloxycar bon ylam in o-2-oxo-7,1-oxaza-
bicyclo[4.3.0]n on a n e-9-m eth ylca r boxa m id e (14a ). To a
saturated solution of CH3NH2 in CH3OH (28 mL), cooled at
-40 °C, was added oxazolopiperidone Cbz-4a -OMe (200 mg,
0.57 mmol), and the tube was sealed. The reaction mixture
was stirred at room temperature for 12 h. More CH3NH2 was
bubbled into the mixture, and the reaction was continued for
48 h. The mixture was filtered, and the solvent was evaporated
to give an oil that was chromatographed (AcOEt/CH3OH, 98:
2) to yield amide 14a (97 mg, 50%): [R]22D ) -87.4 (c 1, CHCl3);
IR (NaCl) 3350, 1702, 1663 cm-1; 1H NMR (CDCl3) 1.54 (ddd,
J ) 13, 10, 3 Hz, 1H), 1.98-2.06 (m, 1H), 2.13-2.23 (m, 1H),
2.33 (ddd, J ) 13, 7, 3 Hz, 1H), 2.68 (d, J ) 5 Hz, 3H), 3.70
(dt, J ) 11, 6 Hz, 1H), 4.03 (t, J ) 8 Hz, 1H), 4.34 (t, J ) 9 Hz,
1H), 4.65 (t, J ) 8 Hz, 1H), 4.77 (dd, J ) 9, 4 Hz, 1H), 5.02 (s,
2H), 5.67 (br s, 1H), 7.22 (br s, 1H), 7.29-7.35 (m, 5H); 1H
NMR (C6D6) 0.74-0.81 (m, 1H), 1.20-1.25 (m, 1H), 1.30-1.36
(m, 2H), 2.39 (d, J ) 4 Hz, 3H), 3.16 (br s, 1H), 3.85 (t, J ) 8.5
Hz, 2H), 4.14 (dd, J ) 9.5, 4 Hz, 1H), 4.35 (ta, J ) 7 Hz, 1H),
4.66 and 4.74 (2d, J ) 12.5 Hz, 1H each), 6.73 (d, J ) 7 Hz,
1H), 6.75-6.85 (m, 5H), 7.05 (s, 1H); 1H NMR (DMSO-d6)
1.52-1.60 (m, 1H), 1.75-1.82 (m, 1H), 1.94-1.98 (m, 1H),
2.18-2.23 (m, 1H), 2.57 (d, J ) 4, 5 Hz, 3H), 3.67 (t, J ) 8 Hz,
1H), 3.94 (dt, J ) 10, 7 Hz, 1H), 4.33 (t, J ) 9 Hz, 1H), 4.43 (t,
J ) 8 Hz, 1H), 4.81 (dd, J ) 9, 4 Hz, 1H), 5.03 (s, 2H), 7.29-
7.35 (m, 5H), 7.68 (d, J ) 4 Hz, 1H), 7.71 (d, J ) 8.5 Hz, 1H);
13C NMR (CDCl3) 24.1, 26.1, 26.7, 52.1, 56.9, 67.1, 68.3, 87.4,
127.7, 128.2 and 128.5, 135.9, 156.5, 167.7, 169.4; EIMS m/z
347 (M+, 1), 289 (3), 181 (11), 153 (15), 108 (43), 91 (100). Anal.
Calcd for C23H22N2O6‚2/3H2O: C, 56.97; H, 6.25; N, 11.72.
Found: C, 56.97; H, 6.03; N, 11.47.
(3S,6R,9S)-3-Ben zyloxycar bon ylam in o-2-oxo-7,1-oxaza-
bicyclo[4.3.0]n on a n e-9-m eth ylca r boxa m id e (14b). Oper-
ating as above, from oxazolopiperidone Cbz-4b-OMe (200 mg,
0.57 mmol) and a saturated solution of CH3NH2 in CH3OH
(28 mL), amide 14b (99 mg, 51%) was obtained: [R]22D ) +79.7
(c 1, CHCl3); 1H NMR (CDCl3) 1.49 (tdd, J ) 13, 9.5 and 3 Hz,
1H), 1.98 (q, J ) 13 Hz, 1H), 2.14 (dddd, J ) 13, 7, 4 and 3
Hz, 1H), 2.28 (ddd, J ) 13, 7 and 4 Hz, 1H), 2.67 (d, J ) 5 Hz,
3H), 3.70 (t, J ) 4 Hz, 1H), 4.03 (t, J ) 8 Hz, 1H), 4.34 (t, J )
9 Hz, 1H), 4.65 (t, J ) 8 Hz, 1H), 4.77 (dd, J ) 9, 4 Hz, 1H),
5.03 (s, 2H), 5.67 (br s, 1H), 7.22 (br s, 1H), 7.29-7.35 (m, 5H);
1H NMR (DMSO-d6) 1.56 (tdd, J ) 13, 9.5, 3 Hz, 1H), 1.79 (q,
J ) 13 Hz, 1H), 1.94-1.99 (m, 1H), 2.19-2.22 (m, 1H), 2.58
(d, J ) 4.5 Hz, 3H), 3.68 (dd, J ) 8, 7 Hz, 1H), 3.93 (dt, J )
10, 7 Hz, 1H), 4.32 (t, J ) 9 Hz, 1H), 4.43 (t, J ) 8 Hz, 1H),
4.81 (dd, J ) 9, 4 Hz, 1H), 5.04 (s, 2H), 7.29-7.35 (m, 5H),
7.68 (d, J ) 4 Hz, 1H), 7.70 (d, J ) 8.5 Hz, 1H); 13C NMR
(CDCl3) 24.2, 26.2, 26.8, 52.2, 56.9, 67.2, 68.2, 87.3, 127.8, 128.3
and 128.6, 135.8, 156.5, 167.7, 169.3.
to yield amine 10 (1.22 g, 99%) as pale yellow oil: [R]22
)
D
-157.3 (c 1, CHCl3); IR (NaCl) 3410, 1741, 1658 cm-1; 1H NMR
1.54-1.74 (m, 2H), 1.96 (br s, 2H), 2.24-2.38 (m, 2H), 3.34
(dd, J ) 11, 5 Hz, 1H), 3.78 (s, 3H), 3.85 (dd, J ) 9, 7 Hz, 1H),
4.44 (t, J ) 9 Hz, 1H), 4.70 (t, J ) 9 Hz, 1H), 4.92 (dd, J ) 9,
4 Hz, 1H); 13C NMR 26.1, 26.8, 51.8, 52.5, 55.5, 68.2, 88.1,
170.1, 170.5. EIMS m/z 214 (M+, 2), 197 (36), 149 (50), 130
(88), 57 (100). Anal. Calcd for C9H14N2O4: C, 50.46; H, 6.59;
N, 13.08. Found: C, 50.72; H, 6.47; N, 13.27.
Met h yl (3S,6S,9S)-3-[9-(F lu or en yl)m et h oxyca r b on yl-
a m in o]-2-oxo-7,1-oxa za b icyclo[4.3.0]n on a n e-9-ca r b ox-
yla te (11). To a solution of amine 10 (500 mg, 2.34 mmol) in
a mixture of CH3CN-H2O (15 mL, 1:1) was added Fmoc-OSu
(800 mg, 2.34 mmol). Et3N was added until pH ) 8 (10 drops),
and the solution was stirred at room temperature for 5 h. The
CH3CN was evaporated, and the remains were partitioned in
CH2Cl2 and H2O. The mixture was acidified by careful addition
of 1 N aqueous HCl. The layers were separated, and the
aqueous phase was washed with CH2Cl2. The organic extracts,
dried and evaporated, gave a white solid, which was chro-
matographed (hexane/AcOEt, 1:9) to yield the Fmoc-oxazol-
opiperidone 11 (836 mg, 82%): mp 160-161 °C (AcOEt); [R]22
D
) -74.1 (c 0.5, CHCl3); IR (NaCl) 3417, 1736, 1720, 1669 cm-1
;
1H NMR 1.68-1.85 (m, 2H), 2.35 (br s, 1H), 2.59 (br s, 1H),
3.78 (s, 3H), 3.84 (t, J ) 9 Hz, 1H), 4.19 (br s, 1H), 4.22 (t, J
) 7 Hz, 1H), 4.39 (br d, J ) 6.5 Hz, 2H), 4.45 (t, J ) 9 Hz,
1H), 4.69 (dd, J ) 9, 7 Hz, 1H), 4.92 (br s, 1H), 5.49 (br s, 1H),
7.31 (td, J ) 7.5, 1 Hz, 2H), 7.40 (t, J ) 7.5 Hz, 2H), 7.60 (dd,
J ) 7, 3 Hz, 2H), 7.76 (t, J ) 7.5 Hz, 2H); 13C NMR 24.8, 26.5,
47.0, 52.0, 52.6, 55.7, 66.8, 68.3, 87.9, 119.8, 125.0, 126.9, 127.5,
141.1, 143.8, 156.3, 166.6, 170.0. EIMS m/z 259 (M+ - Fmoc,
0.1), 196 (22), 178 (100), 165 (97), 130 (16), 57 (40). Anal. Calcd
for C24H24N2O6: C, 66.05; H, 5.54; N, 6.42. Found: C, 66.73;
H, 5.34; N, 6.42.
(3S,6S,9S)-3-Ben zyloxycar bon ylam in o-2-oxo-7,1-oxaza-
bicyclo[4.3.0]n on a n e-9-ca r boxylic Acid (12). To a solution
of oxazolopiperidone Cbz-4a -OMe (820 mg, 2.35 mmol) in CH3-
OH (5.5 mL) cooled at 0 °C was added aqueous 1 N NaOH
(5,18 mL, 5,18 mmol), and the mixture was stirred for 1 h.
The reaction was quenched by addition of 1 N HCl at 0 °C,
until pH ) 1. The CH3OH was evaporated, the residue was
partitioned with AcOEt-H2O, and the organic layer was
washed with brine. The organic phase, dried and evaporated,
yielded acid 12 (744 mg, 95%) as a white foam: IR (NaCl) 3380,
1
3200, 1720, 1666 cm-1; H NMR 1.63-1.95 (m, 2H), 2.46 (br
s, 2H), 4.04 (t, J ) 8 Hz, 1H), 4.13-4.19 (m, 1H), 4.42 (t, J )
9 Hz, 1H), 4.64 (t, J ) 8 Hz, 1H), 4.84 (br d, J ) 5 Hz, 1H),
5.11 (s, 2H), 5.72 (br s, 1H), 5.98 (br s, 1H), 7.35 (s, 5H); 13C
NMR 24.7, 26.6, 51.7, 56.2, 67.0, 68.0, 87.9, 128.0, 128.4, 136.1,

Oxazolopiperidin-2-ones as Type II′ â-Turn Mimetics
J . Org. Chem., Vol. 65, No. 21, 2000 6999
Molecu la r Mod elin g Stu d ies. Theoretical conformational
analyses of compounds 14a and 14b were performed using the
CHARMM24b2 program package28 and the CHARMm 23.1
force field.29 To get insight on the possible conformations of
these compounds, a simulated annealing approach was used
to sample their conformational space. One hundred structures
were obtained by subsequent cycles of heating (20 ps from 0
to 1000 K), cooling (20 ps from 1000 to 0 K), and energy
minimization (100 steps steepest descend and 10000 steps
adopted basis Newton-Raphson) and were clustered by con-
formation and energy. The resulting lowest energy conforma-
tions were the starting points for molecular dynamics studies
using an implicit solvent description (ꢀ ) 80) and two different
explicit solvent models for H2O and DMSO. NVT calculations
at 300 K were performed using cubic boxes of 30 Å side length
and 1000 TIP3P water molecules,30 and of 31 Å side length
and 216 DMSO molecules,31 respectively. Periodic boundary
conditions were applied. After adequate heating and equilibra-
tion of the system, evolution times were of 10 ns for the implicit
water model and of 1 ns for both explicit models. 6000
structures were saved periodically from each trajectory for
further analyses.
Trajectories were analyzed for conformational preferences
measuring the dihedral angles ψ2,φ2, ψ3, φ3, and the â-turn
descriptors R and τ (Figure 8). A conformation was accepted
as a general â-turn if R < 7 Å and -90° < τ < 90°, and
classified as one of the main â-turn types if none of the four
dihedral angles differed by more than 30° from the standard
torsion angle values as given in Table 2.
Ack n ow led gm en t. Support for this research has
been provided by the CIRIT (Generalitat de Catalunya)
through grants QFN95-4703, 1997SGR-00075, and
1999SGR-00077, and by the DGICYT (Ministerio de
Educacio´n y Cultura, Spain) through grants PB97-0976
and 2FD97-0293. We also thank the MEC for a fellow-
ship given to M.A.E. and CESCA for computing facilities
and financial support to M.T.
Su p p or tin g In for m a tion Ava ila ble: Graphic representa-
tion of the 1H NMR chemical shift of the NH protons of
pseudodipeptide 14b at different proportions of DMSO-d6 in
CDCl3, 1H NMR spectra of compounds 14a and 14b at different
proportions of DMSO-d6 in CDCl3, calculated trajectories of
compounds 14a and 14b in continuum, in water, and in
DMSO, and snapshots of compound 14b in water (L-shaped)
and in DMSO (unusual â-turn). This material is available free
of charge via the Internet at http://pubs.acs.org.
(28) Brooks, B. R.; Bruccoleri, R. E., Olafson, B. D., States, D. J .;
Swaminathan, S.; Karplus, M. J . Comput. Chem. 1983, 4, 187-217.
(29) Momany, F. A.; Rone, R. J . Comput. Chem. 1992, 13, 888-900.
b. Momany, F. A.; Rone, R.; Kunz, H.; Frey, R. F., Newton, S. Q.;
Sha¨fer, L. THEOCHEM 1993, 286, 1-18.
(30) J orgensen, W. L.; Chandrasekhar, J .; Madura, J . D.; Impey, R.
W.; Klein, M. L. J . Chem. Phys. 1983, 79, 926-935.
(31) Liu, H.; Mu¨ller-Plathe, F.; van Gunsteren, W. F. J . Am. Chem.
Soc. 1995, 117, 4363-4365.
J O000416V