Diastereoselective synthesis and estimation of the conformational flexibility of 6-oxoperhydropyridazine-3-carboxylic acid derivatives

Article abstract of DOI:10.1021/jo0159800

α,β-Didehydroglutamates have been diastereoselectively transformed into 6-oxoperhydropyridazine-3-carboxylic acid derivatives (OPCAs), which constitute a new class of cyclic amino acid derivatives. Acylation at N-1 renders dipeptides which show considerable conformational rigidity. Semiempirical calculations suggest that OPCAs might force peptide turns with different amplitudes depending on the substitution pattern and relative stereochemistry of the substituents of the pyridazinone ring.

Full text of DOI:10.1021/jo0159800

J . Org. Chem. 2002, 67, 2789-2797
2789
Dia ster eoselective Syn th esis a n d Estim a tion of th e
Con for m a tion a l F lexibility of
6-Oxop er h yd r op yr id a zin e-3-ca r boxylic Acid Der iva tives
Carlos Alvarez-Ibarra,* Aurelio G. Csa´ky¨,* and Cristina Go´mez de la Oliva
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica, Universidad Complutense,
28040-Madrid, Spain
csaky@quim.ucm.es
Received J uly 30, 2001
R,â-Didehydroglutamates have been diastereoselectively transformed into 6-oxoperhydropyridazine-
3-carboxylic acid derivatives (OPCAs), which constitute a new class of cyclic amino acid derivatives.
Acylation at N-1 renders dipeptides which show considerable conformational rigidity. Semiempirical
calculations suggest that OPCAs might force peptide turns with different amplitudes depending
on the substitution pattern and relative stereochemistry of the substituents of the pyridazinone
ring.
In tr od u ction
homologue pipecolic acid (2-piperidinecarboxylic acid,
homoproline) (Pip) promotes significant changes in bio-
activity and leads to interesting model compounds for
studies on peptide conformations.5 More recently ꢀ-aza-
pipecolic acid (piperazic acid) (Piper) and 2,3,4,5-tetrahy-
dropyridazine-3-carboxylic acid derivatives (PCAs) have
attracted attention as highly rigid conformational ana-
logues of proline.6
We have considered the possibility of using the closely
related7 6-oxoperhydropyridazine-3-carboxylic acid de-
rivatives (OPCAs) as templates to control the geometry
(â-turn)8 of a peptide chain. In parallel with Piper
derivatives and PCAs, a trans conformation (ω ) 0°) of
the chain would be expected in OPCAs. Furthermore, the
stereochemically controlled introduction of different sub-
stituents at carbons C-4 and C-5 of the pyridazinone
skeleton of OPCAs may help stabilize different ring
conformations, which will enforce different dihedral
angles (φ) for the peptide chain (Figure 1).
Biological processes are mainly governed by the inter-
action of peptides with macromolecular receptors. For
these interactions to be successful, the three-dimensional
conformation of the peptide chain is of crucial importance.
There are considerable efforts to improve the pharma-
cological properties of natural peptides by structure
modifications of the amino acid constituents.1 However,
it is difficult to determine a priori the optimum confor-
mation of a peptide required to obtain the desired
biological response. Therefore, new procedures to enforce
conformational restrictions in peptides are welcome.
In this context, proline (Pro) occupies a special place
among the natural amino acids. The incorporation of
stereochemically constrained amino acids into peptides
can effectively reduce the populations of possible peptide
chain conformations. Accordingly, Pro derivatives have
been incorporated into bioactive peptides to study con-
formational effects.2 However, the imidic bond formed
with the preceding N-terminal amino acid is subject to
isomerization, and both cis and trans isomers occur in
solution (∆G° < 2 kcal/mol).3 Therefore, numerous Pro
mimetics have been developed to control the cis:trans
ratio.4 In particular, replacement of Pro for its higher
Resu lts a n d Discu ssion
The synthesis of the N-acyl OPCAs 9 and 10 was
accomplished starting from the readily obtainable R,â-
didehydroglutamates (DDGlu) 3 as common starting
materials as outlined in Scheme 1.
Enolization of 1 (KOtBu, THF, -78 °C) followed by
reaction with methylpropiolate (2a ) gave rise to (Z)-3a
(1) (a) Peptide Secondary Structure Mimetics, Tetrahedron; Kahn,
M., Ed.; Tetrahedron Symposia in Print No. 50; Elsevier: New York,
1993; Vol. 49, p 3433. (b) Giannis, A.; Kolter, T. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1244. (c) Giannis, A.; Ru¨bsam, F. Adv. Drug Res.
1997, 29, 1. (d) Kirshenbaum, K.; Zuckermann, R. N.; Dill, K. A. Curr.
Opin. Chem. Biol. 1999, 9, 530. (e) Stigers, K. D.; Soth, M. J .; Nowick,
J . S. Curr. Opin. Chem. Biol. 1999, 3, 714.
(2) See for example: (a) Hondrelis, J .; Lonergan, G.; Voliotis, S.;
Matsoukas, J . Tetrahedron 1990, 46, 565. (b) Karenewsky, D. S.; Badia,
M. C.; Cushman, D. W.; DeForrest, J . M.; Dejneka, T.; Lee, V. G.; Loots,
M. J .; Petrillo, E. W. J . Med. Chem. 1990, 33, 1459. (c) Shuman, R. T.;
Rothenberger, R. B.; Campbell, C. S.; Smith, G. F.; Giffordmoore, D.
S.; Paschal, J . W.; Gesellchen, P. D. J . Med. Chem. 1995, 38, 4446. (c)
Mierke, D. F.; Pattaroni, C.; Delaet, N.; Toy, A.; Goodman, M.;
Tancredi, T.; Motta, A.; Temussi, P. A.; Moroder, L.; Bovermann, G.;
Wunsch, E. Int. J . Pept. Protein Res. 1990, 36, 418. (d) J uvradi, P.;
Dooley, D. J .; Humblet, C. C.; Lu, G. H.; Lunney, E. A.; Panek, R. L.;
Skeean, R.; Marshall, G. R. Int. J . Pept. Protein Res. 1992, 40, 163. (e)
Soloshonok, V. A.; Cai, C.; Hruby, V. J .; Van Meervelt, L.; Mishenko,
N. Tetrahedron 1999, 55, 12031. (f) Soloshonok, V. A.; Cai, C.; Hruby,
V. J .; Van Meervelt, L. Tetrahedron 1999, 55, 12045.
(4) See: (a) Dummy, P.; Keller, M.; Ryan, D. E.; Rohwedder, B.;
Wo¨hr, T.; Mutter, M. J . Am. Chem. Soc. 1997, 119, 918. (b) Beausoleil,
R.; Sharma, R.; Michnick, S. W.; Lubell, W. D. J . Org. Chem. 1998,
63, 6572. (c) Beausoleil, E.; Lubell, W. D. J . Am. Chem. Soc. 1996,
118, 12902. (d) Chalmers, D. K.; Marshall, G. R. J . Am. Chem. Soc.
1995, 117, 5927 and references cited therein.
(5) (a) Toniolo, C. Int. J . Pept. Protein Res. 1990, 35, 287. (b) Genin,
M. J .; Gleason, W. B.; J ohnson, R. L. J . Org. Chem. 1993, 58, 860. (c)
Maison, W.; Lu¨tzen, A.; Kosten, M.; Schlemminger, I.; Westerhoff, O.;
Saak, W.; Martens, J . J . Chem. Soc., Perkin Trans. 1 2000, 1867.
(6) Xi, N.; Alemany, L. B.; Ciufolini, M. A. J . Am. Chem. Soc. 1998,
120, 80.
(7) Both PCAs and OPCAs are six-membered heterocycles with two
nitrogen atoms at positions 1 and 2, and C-6 is sp2 hybridized. The
nitrogen at position 1 is sp2 hybridized in PCAs, while the nitrogen at
position 1 is sp3 hybridized in OPCAs. See the calculations.
(8) (a) Giannis, A.; Kolter, A. Angew. Chem., Int. Ed. Engl. 1993,
32, 1244. (b) Gante, J . Angew. Chem., Int. Ed. Engl. 1994, 33, 1699.
(c) Kahn, M. Synthesis 1993, 821.
(3) Kern, D.; Schutkowski, M.; Drakenberg, T. J . Am. Chem. Soc.
1997, 119, 8403.
10.1021/jo0159800 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/06/2002

2790 J . Org. Chem., Vol. 67, No. 9, 2002
Alvarez-Ibarra et al.
Ta ble 2. Syn th esis of 4
no.
R1
R2
4 (%)a
(Z)-4:(E)-4b
1
2
3
4
5
6
H
H
CH3
CH3
Ph
CH3
Bn
CH3
Bn
CH3
Bn
4a (90)
4b (90)
4c (85)
4d (85)
4e (80)
4f (75)
100:0
100:0
65:35
85:15
0:100
0:100
Ph
a
b
Isolated yield Determined by integration of the 1H NMR
(CDCl3, 300 MHz) of the crude reaction products
Ta ble 3. Syn th esis of 5a -e a n d 4,5-cis-5f,g fr om 3 a n d 4
no.
R1
R2
5 (%)a
4,5-cis:4,5-transb
1
2
3
4
5
6
7
H
H
CH3
Ph
H
CH3
Bn
H
H
H
5a (85)
5b (85)
5c (80)
5d (75)
5e (85)
4,5-cis-5f (75)
4,5-cis-5g (75)
CH3
CH3
CH3
Bn
>99:<01
F igu r e 1.
70:30c
Isolated yield. Determined by integration of the 1H NMR
(CDCl3, 300 MHz) of the crude reaction products. c Separated by
silica gel chromatography (hexanes-EtOAc, 80:20).
a
b
Sch em e 1
Alkylation of compounds 3 under solid-liquid PTC
conditions took place exclusively at C-412,13 (R2X, NaOH,
(TEBA)Cl, acetonitrile), giving rise to compounds 4 as
Z:E mixtures (Table 2). However, it was found that
compounds 4 were obtained with the same Z:E ratio
irrespective of the double bond geometry of the starting
materials 3b, thus making unnecessary the separation
of isomers (Z)-3b,c and (E)-3b,c. The results are gathered
in Table 2.
Cyclization (NH2-NH2, EtOH) of compounds 3 or 4a ,b
(R1 ) H) and 4c,d (R1 ) CH3) afforded the 6-oxo-1,4,5,6-
tetrahydropyridazine-3-carboxylates 5. However, com-
pounds 4e,f (R1 ) Ph) did not cyclize under these reaction
conditions. In the case of compounds 4c,d , cyclization to
the corresponding 4,5-cis-5f,g took place in a diastereo-
selective fashion (Table 3).
This stereochemistry was evidenced by the value of the
3
3J H4-H5 coupling constant (4,5-cis-5f, J H4-H5 ) 7.0 Hz;
4,5-cis-5g, 3J H4-H5 ) 6.5 Hz), which is in agreement with
the dihedral angle value estimated for H4-C-C-H5 in
compound 4,5-cis-5f.14,15
PM3 calculations carried out for compound 4,5-cis-5f
(R1 ) CH3, R2 ) CH3) put forward two minimum-energy
conformations of similar energy (∆Hf(I) ) -112.6 kcal/
mol, ∆Hf(II) ) -113.0 kcal/mol, ∆∆Hf ) 0.4 kcal/mol)
where the CH3 groups can adopt either a pseudoaxial or
a pseudoequatorial disposition. Dihedral angles H4-C-
C-H5 of 44° and 46° were obtained for these conformers.
In a similar fashion, calculations carried out for the 4,5-
trans configuration of 5f rendered two minimum-energy
conformers (∆Hf(I) ) -114.7 kcal/mol, ∆Hf(II) ) -114.9
kcal/mol, ∆∆Hf ) 0.3 kcal/mol), both with dihedral angles
H4-C-C-H5 of 87°. This should correspond to a cou-
Ta ble 1. Syn th esis of 3
no.
R1
3 (%)a
(Z)-3:(E)-3b
1
2
3
H
3a (85)
3b (90)
3c (85)
100:0
65:35
30:70
CH3
Ph
a
b
Isolated yield. Determined by integration of the 1H NMR
(CDCl3, 300 MHz) of the crude reaction products.
in a thermodynamically driven process.9 On the other
hand, compounds 3b,c were best prepared10 by treatment
of 1 with alkynoates 2b,c (1 equiv) in the presence of KOt-
3
t
pling constant J H4-H5 smaller than those actually ob-
Bu (0.5 equiv), BuOH (0.5 equiv), and Ph3P (5 mol %).
served for compounds 4,5-cis-5f,g.
Compounds 3b,c were obtained as Z:E mixtures (Scheme
1, Table 1)11 which could be separated by silica gel
chromatography (hexane-Et2O, 80:20).
(12) Alvarez-Ibarra, C.; Csa´ky¨, A. G.; Mart´ın, M. E.; Quiroga, M. L.
Tetrahedron 1999, 55, 7319.
(13) Alvarez-Ibarra, C.; Csa´ky¨, A. B.; Go´mez de la Oliva, C.;
(9) Alvarez-Ibara, C.; Csa´ky¨, A. G.; Mart´ın, E.; de la Morena, M. J .;
Quiroga, M. L. Tetrahedron Lett. 1997, 38, 4501.
(10) Direct reaction of iminoglycinates 1 and related compounds with
alkynoates 2b,c requires the use of naked enolates. See ref 9.
(11) The assignment of the E or Z geometry of compounds 3b,c was
based on the comparison of their 1H and 13C NMR spectra with those
previously described for closely related compounds. See refs 9 and 12.
Rodr´ıguez, E. Tetrahedron Lett. 2001, 42, 2129.
(14) 3J H4-H5 and NOE correlations of 4,5-cis-5f are also to be
compared with those obtained for 4,5-trans-6f.
(15) Further confirmation of the cis stereochemical assignment came
from NOE experiments carried out on 4,5-cis-5f. Thus, irradiation of
H-5 in the 1H NMR spectrum (CDCl3, 300 MHz) (δ ) 2.68, q) gave
rise to a 4% NOE enhancement of the signal of H-4 (δ ) 3.16, q).

Synthesis and Conformational Flexibility of OPCAs
J . Org. Chem., Vol. 67, No. 9, 2002 2791
Sch em e 2
Sch em e 4
Sch em e 3
of the pyridazinone ring (Scheme 4). Thus, attack of the
hydride took place from the opposite side of the ring with
respect to R1, giving rise to high diastereoselectivities in
favor of the 3,4-cis isomers of compounds 8 and 9
irrespective of the 4,5-stereochemistry of the starting
materials. On the other hand, lower diastereoselectivities
were found in the reductions of compounds 6a ,b (R1 )
H). The results are gathered in Table 4. The stereochem-
istry of compounds 8 and 9 was assigned by comparison
of their NMR data with those of 3,4-cis-4,5-cis-8d , for
which NOE measurements were carried out.18
Finally, compounds 10 and 11 were synthesized by
acylation of N-1 of the OPCAs 8 and 9 (AcCl, K2CO3,
(TEBA)Cl, acetonitrile) (Scheme 4).
Compounds 12-16 were chosen as simplified models
for the conformational study19 of the OPCAs 10 and 11
(Figure 2).
Molecular mechanics (MM+ force field) calculations
were used as a rough estimate20 of the geometries of the
different conformers which were used as inputs for
semiempirical (PM3) calculations.21 Initial minimization
(MM+ force field) of compound 12 in an ω-trans confor-
mation (ω ) 0°) gave rise to a cyclohexanone-like ring,
where the substituents at N-1, N-2, and C-3 could adopt
either a pseudoequatorial or a pseudoaxial disposition
(eight conformers). Independent minimization (PM3) of
each of these eight conformers gave rise to three mini-
mum-energy conformations,22 ω-trans-12a -c (Table 5,
entries 1-3). These conformers showed different values
for the dihedral angle φ. However, the energy difference
(∆∆H°) found for conformers ω-trans-12a -c was less
than 2 kcal/mol. The same protocol was followed starting
from compound 12 in an ω-cis (ω ) 180°) conformation,
giving rise to conformers ω-cis-12a -c (Table 5, entries
4-6) whose energies (∆∆H°) also differed by less than 2
kcal/mol.
These calculations also put forward a higher stability
of 5f in a 4,5-trans configuration than in a 4,5-cis
configuration. Therefore, the obtention of compound 4,5-
cis-5f from the reaction with hydrazine of the didehy-
droglutamates 4c,d can be accounted for by the inter-
mediacy of the more stable anti open-chain hydrazone,
which affords the 4,5-cis products upon cyclization (Scheme
2). This also explains the failure in the cyclization of 4e,f
(R1 ) Ph), as a consequence of the steric hindrance.
Dihydropyridazinones 5 were transformed (Scheme
1) into compounds 6 and 7 by reaction with either
tbutylbromoacetate (6; LiHMDS, THF, -78 °C) or BnBr
(7; K2CO3, (TEBA)Cl, acetonitrile).
To access the 4,5-trans diastereomers of the final
compounds 10 and 11, an alternative strategy for the
introduction of the C-5 substituent was devised at this
stage (Scheme 3). Therefore, the C-5-unsubstituted di-
hydropyridazinones 7a ,b were enolized (LiHMDS, THF,
-78 °C) and reacted with electrophiles. These alkylations
took place anti with respect to R1 (CH3 or Ph), giving rise
to compounds 4,5-trans-7f-h . It is worth mentioning that
this strategy allowed for the synthesis of compound 7h
(R1 ) Ph, 4,5-trans), whereas the synthesis of the
corresponding 4,5-cis compound was not possible by
cyclization of 4e with NH2-NH2 (vide supra). The 4,5-
trans stereochemisty of compounds 4,5-trans-7f-h was
The previous conformers estimated for compound 12
by molecular mechanics calculations in either an ω-cis
3
evidenced by the value of the J H4-H5 coupling constant
(1.5 Hz) and NOE measurements.16,17
The OPCAs 8 (R3 ) CH2CO2 Bu) and 9 (R3 ) Bn) were
t
(18) Irradiation of H-3 in the 1H NMR spectrum of 8d (CDCl3, 300
MHz) (δ ) 3.66, d) gave rise to a 4% NOE enhancement of the signal
of H-4 (δ ) 4.11, ddd).
(19) All calculations were carried out with the Hyperchem 5.0
package, Hypercube, Inc., Ontario, Canada.
(20) Cyclic hydrazones of the type found in PCAs or OPCAs are not
parametrized in the MM+ method. The starting geometries calculated
by this procedure are approximate and only of qualitative value.
(21) Repulsive forces are not particularly strong in PM3. The
conformational energy differences calculated by this method represent
lower-end estimates.
(22) The minimum-energy conformation and those which did differ
by less than 2.5 kcal/mol were selected for all compounds 12-16. All
conformers showed pyramidalized nitrogen atoms for both N-1 and N-2.
prepared by reduction of the imino bond of compounds 6
and 7, which was carried out with NaCNBH3 (MeOH,
HCl). It was found that the diastereoselectivity of these
transformations was controlled by the substituent at C-4
(16) 3J H4-H5 and NOE correlations of 4,5-trans-6f are to be compared
with those obtained for 4,5-cis-5f.
(17) Irradiation of H-5 in the 1H NMR spectrum of 7d (CDCl3, 300
MHz) (δ ) 2.48, qd) gave rise to a 5% NOE enhancement of the signal
of CH3-C-4 (δ ) 1.09, d), and no NOE was observed with H-5 (δ )
2.90, qd).

2792 J . Org. Chem., Vol. 67, No. 9, 2002
Ta ble 4. Syn th esis of 8 a n d 9 fr om 6 a n d 7
Alvarez-Ibarra et al.
de (%)b
no.
R1
R2
R3
6, 7
8, 9 (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
H
H
CH3
Ph
H
CH3
CH3
CH3
Ph
CH3
Bn
H
H
H
CH3
Bn
H
H
H
CH2CO2tBu
CH2CO2tBu
CH2CO2tBu
CH2CO2tBu
CH2CO2tBu
CH2CO2tBu
CH2CO2tBu
Bn
Bn
Bn
Bn
Bn
6a
6b
6c
6d
6e
3,5-cis-8a (50)
3,5-cis-8b (45)
3,4-cis-8c (85)
3,4-cis-8d (80)
8e (90)
3,4-cis-4,5-cis-8f (80)
3,4-cis-4,5-cis-8g (80)
3,5-cis-9a (90)
3,5-cis-9b (85)
9c (95)
20
20
>98
>98
4,5-cis-6f
4,5-cis-6g
7a
7b
7c
4,5-trans-7d
4,5-trans-7e
4,5-trans-7f
>98
>98
>98
>98
H
CH3
CH3
Ph
CH3
Bn
CH3
3,4-cis-4,5-trans-9d (85)
3,4-cis-4,5-trans-9e (80)
3,4-cis-4,5-trans-9f (80)
>98
>98
>98
Bn
a
b
Isolated yield. Determined by integration of the 1H NMR (CDCl3, 300 MHz) of the crude reaction products. In entries 3-13 none of
the other isomers could be detected by 1H NMR. c Separated by silica gel chromatography (hexanes-Et2O, 80:20).
entries 7-10) instead of the three previously obtained
for 12 (Table 5, entries 1-6). However, the energy
difference (∆∆H°) was again less than 2 kcal/mol. On the
other hand, replacement of H-5 in 12 by methyl afforded
single minimum-energy conformations for ω-cis-14 and
ω-trans-14 (Table 5, entries 11 and 12).23 Furthermore,
the energy difference (∆∆H°) between the ω-cis and
ω-trans conformers of 14 was 2.97 kcal/mol, which
corresponds to a rotamer ratio24 of 99:1 in favor of
ω-trans-14. Replacement of both H-4 and H-5 in 12 gave
rise to 15 and 16. In the case of 15 (Table 5, entries 13-
18), the corresponding ω-trans conformations were fa-
vored over the ω-cis conformations, and conformer ω-trans-
15b (φ ) -95°) was favored over ω-trans-15a (conforma-
tion ratio 3:97 for ω-trans-15a :ω-trans-15b). In a similar
fashion, the ω-trans conformations were favored over the
ω-cis conformations for compound 16 (Table 5, entries
19-22). However, opposite to the case of 15, conformation
ω-trans-16a (φ ) -140°) was favored over ω-trans-16b
(conformation ratio 98:2 for ω-trans-16a :ω-trans-16b).25
These results qualitatively suggest that OPCAs 10 and
11 show a preference for the ω-trans geometry and might
force peptide turns with different amplitudes (φ angle)
as a function of the substitution pattern and relative
stereochemistry of the substituents of the pyridazinone
ring:26 φ ≈ 140-145° for the C-5-monosubstituted and
trans-C-4,5-disubstituted derivatives, and φ ≈ 95° for the
cis-C-4,5-disubstituted ones.
F igu r e 2.
Ta ble 5. Con for m a tion a l P r efer en ces in OP CAs 12-16
a
no.
conformation
∆Hf
φ (deg)
ω (deg)
1
2
3
4
5
6
7
8
9
10
11
12
13
16
17
18
19
20
21
22
ω-trans-12a
ω-trans-12b
ω-trans-12c
ω-cis-12a
ω-cis-12b
ω-cis-12c
ω-trans-13a
ω-trans-13b
ω-cis-13a
ω-cis-13b
ω-trans-14a
ω-cis-14a
144.0
142.2
143.6
141.4
140.7
142.9
148.7
147.1
146.3
144.8
148.1
145.1
148.8
150.9
146.2
148.7
153.3
150.9
151.3
148.3
140
153
109
143
158
136
140
95
143
111
141
147
136
95
137
109
140
94
142
105
21
12
30
179
171
131
20
8
179
147
15
165
20
Con clu sion s
The present study puts forward that OPCAs can be
prepared in a highly diastereoselective fashion using
readily available R,â-didehydroglutamates as starting
materials. This synthesis allows for the mono- or disub-
stitution of the pyridazinone moiety of OPCAs at carbons
C-4 and C-5, which can be obtained at will either in a
4,5-cis fashion or in a 4,5-trans fashion. Reduction of the
CdN bond took place with high diastereoselectivity in
favor of the 3,4-cis stereochemistry. These compounds can
ω-trans-15a
ω-trans-15b
ω-cis-15a
10
177
149
15
10
142
153
ω-cis-15b
ω-trans-16a
ω-trans-16b
ω-cis-16a
ω-cis-16b
aPM3 calculation, kcal/mol.
(ω ) 180°) or an ω-trans (ω ) 0°) disposition were used
as starting geometries to estimate the conformational
population of compounds 13-16 by replacing H-4 and/
or H-5 by methyl and running semiempirical (PM3)
calculations. The minimum-energy conformations22 and
geometries thus calculated are gathered in Table 5.
Inspection of these data reveals that replacement of H-4
by methyl afforded only two minimum-energy conforma-
tions for compounds ω-cis-13 and ω-trans-13 (Table 5,
(23) The complementary stereochemistry, i.e., 3,5-anti, was not
considered, as compounds 10a ,b and 11a ,b have only been obtained
as the corresponding 3,5-cis isomers.
(24) Estimated from ∆∆H° ≈ ∆∆G° ) -RT ln K at 25 °C.
(25) No significant qualitative modifications of these results with
respect to the φ or ω angles were observed upon replacement of the
methyl group at N-2 by PhCH2 or MeO2C-CH2 or by replacement of
the methyl groups at C-4 and C-5 by Ph and PhCH2, respectively.
(26) Bock, M. B.; Di Pardo, R. M.; Williams, P. D.; Pettibone, D. J .;
Clineschmidt, B. V.; Ball, R. G.; Veber, D. F.; Freidiger, R. M. J . Med.
Chem. 1990, 33, 2321.

Synthesis and Conformational Flexibility of OPCAs
J . Org. Chem., Vol. 67, No. 9, 2002 2793
Alk yla tion of Com p ou n d s 3. Gen er a l P r oced u r e. To a
solution of 3 (0.18 mmol) in acetonitrile (1 mL) were added
successively the corresponding alkylant R2X (0.2 mmol), NaOH
(0.18 mmol), and (TEBA)Cl (0.02 mmol). The reaction mixture
was stirred for 1 h. The resulting suspension was filtered
through Celite, and the remaining solid material was washed
with Et2O (3 × 1 mL). Evaporation of the solvent afforded an
oil that was purified by column chromatography (hexanes-
Et2O, 80:20).
be considered as new conformationally constricted amino
acids, where the amplitude of the φ dihedral angle can
be tuned with the substitution pattern of the pyridazi-
none ring, which may be of use for the design of new
peptides with controlled geometries. Although all prod-
ucts herein described are racemic, this procedure can be
adapted to the enantioselective preparation of OPCAs
making use of chiral auxiliaries.13
Da ta for (Z)-2-(Ben zh yd r ylid en ea m in o)-4-m eth ylp en t-
2-en ed ioic Acid 1-ter t-Bu tyl 5-Meth yl Ester , (Z)-4a : color-
Exp er im en ta l Section
1
less oil (90%); IR (CHCl3) ν 1879, 1721, 1635 cm-1; H NMR
(200 MHz, CDCl3) δ 7.71-7.35 (10H, m), 6.16 (1H, d, 3J ) 8.0
All starting materials were commercially available research-
grade chemicals and used without further purification. Toluene
was distilled after being refluxed over Na/benzophenone. Silica
gel 60 F254 was used for TLC, and the spots were detected with
UV. Flash column chromatography was carried out on silica
3
3
Hz), 4.01(1H, dc, J ) 8.0 Hz, J ) 7.0 Hz), 3.70 (3H, s), 1.27
(9H, s), 1.25 (3H, t, 3J ) 7 Hz) ppm; 13C NMR (200 MHz,
CDCl3) δ 173.6, 170.3, 162.6, 141.2, 139.4, 137.0, 130.5, 129.7,
129.0, 128.8, 127.9, 127.8, 122.5, 80.9, 51.7, 44.7, 27.8, 18.7
ppm. Anal. Calcd for C24H27NO4: C, 73.26; H, 6.92; N 3.56.
Found: C, 73.45; H, 7.94; N 3.72.
1
gel 60. IR spectra have been recorded as CHCl3 solutions. H
NMR spectra were recorded at 200 or 300 MHz and 13C NMR
NMR spectra at 50.5 or 75 MHz in CDCl3 solution with TMS
as internal reference. Glycine imine 1 was prepared from tert-
butyl glycinate following the literature procedure.27 Compound
(Z)-3a was prepared from 1 and 2a following the previously
described procedure.12
Da ta for (Z)-2-(Ben zh yd r ylid en ea m in o)-4-ben zylp en t-
2-en ed ioic Acid 1-ter t-Bu tyl 5-Meth yl Ester , (Z)-4b: color-
less oil (90%); IR (CHCl3) ν 1708, 1645 cm-1 1H NMR (300
;
MHz, CDCl3) δ 7.63-7.09 (15H, m), 6.00 (1H, d, 3J ) 10.0 Hz),
3
3
3
3.74 (1H, ddd, J ) 10.0 Hz, J ) 8.5 Hz, J ) 6.5 Hz), 3.70
(3H, s), 3.03 (1H, dd, 2J ) 13.5 Hz, 3J ) 8.5 Hz), 2.85 (1H, dd,
Ad d ition of Glycin e Im in e 1 to Alk yn oa tes 2b,c in th e
P r esen ce of tBu OH-KOtBu . Gen er a l P r oced u r e. To a
solution of PPh3 (5 mg, 17 µmol) in toluene (0.75 mL) were
3
2J ) 13.5 Hz, J ) 6.5 Hz), 1.18 (9H, s) ppm; 13C NMR (300
MHz, CDCl3) δ 173.2, 170.3, 162.2, 142.2, 139.1, 138.4, 136.8,
130.7, 129.5, 129.2, 128.9, 128.7, 128.0, 127.9, 126.5, 122.2,
81.1, 51.7, 45.8, 30.0, 27.7 ppm. Anal. Calcd for C30H31NO4:
C, 76.73; H, 6.65; N, 2.98. Found: C, 76.93; H, 6.55; N, 2.88.
Da ta for (Z)-2-(Ben zh yd r ylid en ea m in o)-3,4-d im eth yl-
p en t-2-en ed ioic Acid 1-ter t-Bu tyl 5-Eth yl Ester , (Z)-4c:
t
added KOtBu (18 mg, 0.17 mmol), BuOH (16 µL, 0.17 mmol),
the corresponding compounds 2b,c (0.34 mmol), and a solution
of the glycine imine 1 (100 mg, 0.34) in toluene (0.75 mL). The
mixture was heated at 80 °C for 24 h. The solution was filtered,
and the remaining solid material was washed with Et2O (3 ×
0.5 mL). The solvent was evaporated, and the residue was
separated by chromatography (hexane-Et2O, 80:20).
colorless oil (55%); IR (CHCl3) ν 1715, 1647 cm-1 1H NMR
;
(200 MHz, CDCl3) δ 7.71-7.40 (10H, m), 4.20-4.05 (3H, m),
1.99 (3H, s), 1.31-1.19 (6H, m), 1.15 (9H, s) ppm; 13C NMR
(200 MHz, CDCl3) δ 174.2, 168.5, 163.5, 140.1, 137.5, 137.0,
133.5, 130.3, 129.6, 129.4, 127.9, 80.8, 60.5, 42.6, 27.7, 14.5,
14.2, 13.8 ppm. Anal. Calcd for C26H31NO4: C, 74.08; H, 7.41;
N, 3.32. Found: C, 74.15; H, 7.40; N, 3.28.
Da ta for (Z)-2-(Ben zh yd r ylid en ea m in o)-3-m eth ylp en t-
2-en ed ioic Acid 1-ter t-Bu tyl 5-Eth yl Ester , (Z)-3b: white
solid (59%); mp 88-90 °C (hexane); IR (CHCl3) ν 1869, 1701,
1635 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.42-7.24 (10H, m),
3
4.11 (2H, c, J ) 7.0 Hz), 3.52 (2H, s), 1.88 (3H, s), 1.23 (3H,
Da ta for (E)-2-(Ben zh yd r ylid en ea m in o)-3,4-d im eth yl-
p en t-2-en ed ioic Acid 1-ter t-Bu tyl 5-Eth yl Ester , (E)-4c:
3
t, J ) 7.0 Hz), 1.19 (9H, s) ppm; 13C NMR (300 MHz, CDCl3)
δ 171.0, 169.4, 163.3, 129.4, 129.1, 128.0, 1127.9, 81.0, 60.4,
39.7, 27.7, 20.8, 14.2 ppm. Anal. Calcd for C27H33NO4: C, 74.45;
H, 7.64; N, 3.22. Found: C, 74.65; H, 7.64; N, 3.32.
colorless oil (30%); IR (CHCl3) ν 1710, 1637 cm-1
;
1H NMR
3
(200 MHz, CDCl3) δ 7.65-7.15 (10H, m), 4.48 (1H, c, J ) 7.0
3
Hz), 4.05 (2H, c, J ) 7.0 Hz), 1.60 (3H, s), 1.20 (9H, s), 1.18-
Da ta for (E)-2-(Ben zh yd r ylid en ea m in o)-3-m eth ylp en t-
2-en ed ioic Acid 1-ter t-Bu tyl 5-Eth yl Ester , (E)-3b: color-
1.07 (6H, m) ppm; 13C NMR (200 MHz, CDCl3) δ 174.2, 169.5,
163.0, 139.5, 130.5, 129.3, 128.6, 128.0, 127.9, 127.8, 81.1, 60.4,
41.1, 27.9, 15.3, 15.0, 14.3 ppm. Anal. Calcd for C26H31NO4:
C, 74.08; H, 7.41; N, 3.32. Found: C, 74.25; H, 7.30; N, 3.38.
Da t a for (Z)-2-(Ben zh yd r ylid en ea m in o)-4-b en zyl-3-
m eth ylp en t-2-en ed ioic Acid 1-ter t-Bu tyl 5-Eth yl Ester ,
1
less oil (32%); IR (CHCl3) ν 1899, 1716, 1635, cm-1; H NMR
3
(300 MHz, CDCl3) δ 7.74-7.57 (10H, m), 4.01 (2H, c, J ) 7.0
3
Hz), 3.73 (2H, s), 2.04 (3H, s), 1.10 (3H, t, J ) 7.0 Hz), 1.07
(9H, s) ppm; 13C NMR (300 MHz, CDCl3) δ 171.3, 169.4, 163.4,
132.4, 130.4, 130.1, 129.7, 128.3, 128.0, 80.8, 60.6, 40.9, 27.7,
19.4, 14.1 ppm. Anal. Calcd for C27H33NO4: C, 74.45; H, 7.64;
N, 3.22. Found: C, 74.72; H, 7.52; N, 3.45.
(Z)-4d : colorless oil (73%); IR (CHCl3) ν 1720, 1634 cm-1; H
NMR (200 MHz, CDCl3) δ 7.45-7.17 (15H, m), 4.48 (1H, dd,
1
3
3
3J ) 8.0 Hz, J ) 6.5 Hz), 4.10 (2H, c, J ) 7.0 Hz), 3.34 (1H,
Da ta for (Z)-2-(Ben zh yd r ylid en ea m in o)-3-p h en ylp en t-
2-en ed ioic Acid 1-ter t-Bu tyl 5-Eth yl Ester , (Z)-3c: color-
2
3
2
3
dd, J ) 14.0 Hz, J ) 8.0 Hz), 2.98 (1H, dd, J ) 14.0 Hz, J
3
) 6.5 Hz), 2.06 (3H, s), 1.21 (3H, t, J ) 7.0 Hz), 1.14 (9H, s)
1
less oil (26%); IR (CHCl3) ν 1798, 1657, 1600 cm-1; H NMR
ppm; 13C NMR (200 MHz, CDCl3) δ 173.0, 167.9, 163.5, 140.0,
139.5, 138.3, 136.8, 132.2, 130.2, 129.6, 129.2, 129.1, 128.1,
128.0, 127.8, 127.7, 126.0, 80.1, 60.5, 50.0, 35.2, 27.7, 14.9, 14.1
ppm. Anal. Calcd for C34H39NO4: C, 77.68; H, 7.48; N, 2.66.
Found: C, 77.77; H, 7.40; N, 2.63.
3
(200 MHz, CDCl3) δ 7.72-6.95 (15H, m), 3.99 (2H, c, J ) 7.0
Hz), 3.65 (2H, s), 1.30 (9H, s), 1.1 (3H, t, 3J ) 7.0 Hz) ppm;
13C NMR (200 MHz, CDCl3) δ 170.9, 169.1, 164.0, 140.6, 132.4,
130.3, 130.0, 129.3, 129.0, 128.7, 128.2, 127.8, 127.6, 126.8,
124.6, 81.7, 60.4, 39.7, 27.9, 14.1 ppm. Anal. Calcd for C32 H35
-
Da t a for (E)-2-(Ben zh yd r ylid en ea m in o)-4-b en zyl-3-
m eth ylp en t-2-en ed ioic Acid 1-ter t-Bu tyl 5-Eth yl Ester ,
(E)-4d : colorless oil (13%); IR (CHCl3) ν 1737, 1664 cm-1; 1H
NMR (200 MHz, CDCl3) δ 7.39-7.18 (15H, m), 5.00 (1H, dd,
NO4: C, 77.24; H, 7.09; N, 2.81. Found: C, 77.35; H, 7.29; N,
2.71.
Da ta for (E)-2-(Ben zh yd r ylid en ea m in o)-3-p h en ylp en t-
2-en ed ioic Acid 1-ter t-Bu tyl 5-Eth yl Ester , (E)-3c: white
solid (60%); mp 92-94 °C (hexane); IR (CHCl3) ν 1895, 1648,
1655 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.79-7.43 (15H, m),
4.03 (2H, c, 3J ) 7.0 Hz), 3.66 (2H, s), 1.10 (3H, t, 3J ) 7.0
Hz), 0.79 (9H, s) ppm; 13C NMR (200 MHz, CDCl3) δ 171.0,
170.2, 163.8, 141.3, 140.8, 139.5, 137.0, 130.6, 129.6, 129.5,
129.4, 128.2, 127.9, 127.7, 126.8, 80.7, 60.5, 40.6, 26.9, 13.9
ppm. Anal. Calcd for C32 H35NO4: C, 77.24; H, 7.09; N, 2.81.
Found: C, 77.55; H, 7.17; N, 2.75.
3
3
3J ) 8.0 Hz, J ) 7.0 Hz), 4.14 (2H, c, J ) 7.0 Hz), 3.22 (1H,
2
3
2
3
dd, J ) 14.0 Hz, J ) 8.0 Hz), 2.79 (1H, dd, J ) 14.0 Hz, J
3
) 7.0 Hz), 1.80 (3H, s), 1.28 (9H, s), 1.21 (3H, t, J ) 7.0 Hz)
ppm; 13C NMR (200 MHz, CDCl3) δ 172.8, 170.0, 163.0, 139.6,
137.9, 137.6, 136.5, 132.6, 130.4, 128.7, 81.0, 60.4, 47.8, 36.1,
27.8, 15.3, 14.1 ppm. Anal. Calcd for C34H39NO4: C, 77.68; H,
7.48; N, 2.66. Found: C, 77.67; H, 7.45; N, 2.69.
Da ta for (E)-2-(Ben zh yd r ylid en ea m in o)-4-m eth yl-3-
p h en ylp en t-2-en ed ioic Acid 1-ter t-Bu tyl 5-Eth yl Ester ,
1
(E)-4e: colorless oil (85%); IR (CHCl3) ν 1726, 1648 cm-1; H
3
(27) O’Donnell, M. J .; Polt, R. L. J . Org. Chem. 1982, 47, 2663.
NMR (300 MHz, CDCl3) δ 7.36-7.06 (15H, m), 4.19 (1H, c, J

2794 J . Org. Chem., Vol. 67, No. 9, 2002
Alvarez-Ibarra et al.
3
3
) 7.0 Hz), 4.01 (2H, c, J ) 7.0 Hz), 1.09 (3H, t, J ) 7.0 Hz),
1.08 (3H, d, 3J ) 7.0 Hz), 0.60 (9H, s) ppm; 13C NMR (300
MHz, CDCl3) δ 173.9, 169.7, 164.2, 139.9, 139.7, 138.8, 136.6,
135.2, 130.6, 129.8, 129.7, 128.5, 127.9, 127.6, 126.8, 80.5, 60.6,
42.7, 26.8, 14.5, 14.1 ppm. Anal. Calcd for C33H37NO4: C, 77.47;
H, 7.29; N, 2.74. Found: C, 77.57; H, 7.25; N, 2.76.
ppm. Anal. Calcd for C9H14N2O3: C, 54.53; H, 7.12; N, 14.13.
Found: C, 54.43; H, 7.15; N, 14.10.
Da ta for 4,5-cis-4,5-Dim eth yl-6-oxo-1,4,5,6-tetr a h yd r o-
p yr id a zin e-3-ca r boxylic Acid ter t-Bu tyl Ester , 4,5-cis-
5f: white solid (75%); mp 74-76 °C (hexanes-EtOAc); IR
(CHCl3) ν 3340, 1713, 1648 cm-1; 1H NMR (300 MHz, CDCl3)
δ 8.57 (1H, s), 3.16 (1H, q, 3J ) 7.0 Hz), 2.68 (1H, q, 3J )
Da t a for (E)-2-(Ben zh yd r ylid en ea m in o)-4-b en zyl-3-
p h en ylp en t-2-en ed ioic Acid 1-ter t-Bu tyl 5-Eth yl Ester ,
3
3
7.0 Hz), 1.57 (9H, s), 1.24 (3H, d, J ) 7.5 Hz), 1.04 (3H, d, J
) 7.0 Hz) ppm; 13C NMR (300 MHz, CDCl3) δ 170.5, 161.9,
149.3, 83.0, 34.9, 32.1, 28.0, 10.0, 9.5 ppm. Anal. Calcd for
(E)-4f: colorless oil (85%); IR (CHCl3) ν 1724, 1628 cm-1; H
1
NMR (200 MHz, CDCl3) δ 7.95-7.01 (20H, m), 4.69 (1H, dd,
3J ) 8.0 Hz, J ) 6.5 Hz), 4.03 (2H, c, J ) 7.0 Hz), 3.17 (1H,
C11H18N2O3: C, 58.39; H, 8.02; N, 12.38. Found: C, 58.35; H,
8.12; N, 12.34.
3
3
2
3
2
3
dd, J ) 14.0 Hz, J ) 8.0 Hz), 2.87 (1H, dd, J ) 14.0 Hz, J
) 6.5 Hz), 1.14 (3H, t, 3J ) 7.0 Hz), 0.67 (9H, s) ppm; 13C NMR
(200 MHz, CDCl3) δ 172.7, 170.4, 164.0, 134.0, 144.9, 140.9,
140.6, 139.7, 139.5, 139.4, 138.6, 136.9, 134.4, 129.1, 129.0,
128.8, 128.0, 127.9, 127.8, 127.6, 127.2, 80.5, 60.6, 49.7, 31.6,
26.8, 14.1 ppm. Anal. Calcd for C39H41NO4: C, 79.70; H, 7.03;
N, 2.38. Found: C, 79.78; H, 7.13; N, 2.28.
Da t a for 4,5-cis-4-Ben zyl-5-m et h yl-6-oxo-1,4,5,6-t et -
r a h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu tyl Ester ,
4,5-cis-5g: colorless oil (75%); IR (CHCl3) ν 3245, 1711, 1628
cm-1 1H NMR (200 MHz, CDCl3) δ 8.55 (1H, s), 7.59-7.47
;
2 3
(5H, m), 3.52 (1H, dd, J ) 14.0 Hz, J ) 4.0 Hz), 3.05 (1H, q,
3J ) 6.5), 2.84 (1H, ddd, 3J ) 10.5 Hz, 3J ) 6.5, 3J ) 4.0), 2.63
3
Cycliza tion of Com p ou n d s 3 a n d 4 w ith Hyd r a zin e.
Gen er a l P r oced u r e. To a solution of hydrazine hydrochloride
(72 mg, 1.08 mmol) in EtOH (7 mL) were added NaOAc (87
mg, 1.08 mmol) and a solution of compounds 3 and 4 (0.27
mmol) in EtOH (7 mL). The mixture was stirred at reflux
temperature for 24 h. At rt was added a saturated solution of
NaCl, and the organic layer was decanted. The aqueous layer
was extracted with EtOAc (3 × 7 mL), and the combined
organic extracts were dried over MgSO4. Evaporation under
reduced pressure afforded a residue which was purified by
chromatography (hexanes-EtOAc, 80:20).
(1H, dd, 2J ) 14.0 Hz, J ) 10.5 Hz), 1.02 (9H, s), 1.09 (3H, d,
3J ) 6.5 Hz) ppm; 13C NMR (200 MHz, CDCl3) δ 169.0, 161.8,
149.3, 138.3, 129.8, 129.1, 128.7, 128.6, 128.4, 126.6, 83.0, 46.2,
36.7, 31.0, 28.0, 9.6 ppm. Anal. Calcd for C17H22N2O3: C, 67.53;
H, 7.33; N, 9.26. Found: C, 67.50; H, 7.30; N, 9.29.
N-Alk yla tion of 5 w ith ter t-Bu tyl Br om oa ceta te. Gen -
er a l P r oced u r e. To a stirred solution of compounds 5 (0.47
mmol) in anhydrous THF (1 mL) at -78 °C was added
LiHMDS (1 M in THF, 0.94 mL, 0.94 mmol), and the solution
was stirred for 2 h. tert-Butyl bromoacetate (0.14 mL, 0.94
mmol) was added dropwise, the reaction mixture was stirred
for 20 h, and the temperature was slowly raised to rt. H2O (3
mL) was added, and the organic layer was decanted. The
aqueous layer was extracted with EtOAc (3 × 3 mL), and the
combined organic extracts were dried over MgSO4. Evaporation
under reduced pressure afforded a residue which was purified
by column chromatography (hexanes-EtOAc, 80:20).
Da ta for 5-Meth yl-6-oxo-1,4,5,6-tetr a h yd r op yr id a zin e-
3-ca r boxylic Acid ter t-Bu tyl Ester , 5a : white solid (85%);
mp 146-148 °C (hexanes-EtOAc); IR (CHCl3) ν 3355, 1753,
1628 cm-1; 1H NMR (200 MHz, CDCl3) δ 8.85 (1H, s), 3.07 (1H,
2
3
dd, J ) 15.0 Hz, J ) 4.5 Hz), 2.59-2.42 (2H, m), 1.57 (9H,
s), 1.27 (3H, d, J ) 7.0 Hz) ppm; 13C NMR (200 MHz, CDCl3)
3
δ 170.6, 162.2, 144.5, 83.1, 30.5, 28.7, 28.0, 14.9 ppm. Anal.
Calcd for C10H16N2O3: C, 56.59; H, 7.60; N, 13.20. Found: C,
56.49; H, 7.69; N, 13.21.
Da ta for 1-ter t-Bu toxyca r bon ylm eth yl-5-m eth yl-6-oxo-
1,4,5,6-tetr a h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu -
tyl Ester , 6a : white solid (90%); mp 120-122 °C (hexane);
1
Da ta for 5-Ben zyl-6-oxo-1,4,5,6-tetr a h yd r op yr id a zin e-
3-ca r boxylic Acid ter t-Bu tyl Ester , 5b: white solid (85%);
mp 128-130 °C (hexanes-EtOAc); IR (CHCl3) ν 3340, 1715,
IR (CHCl3) ν 1712, 1621 cm-1; H NMR (200 MHz, CDCl3) δ
2
3
4.46 (2H, s), 3.02 (1H, dd, J ) 15.0 Hz, J ) 4.5 Hz), 2.64-
3
2.41 (2H, m), 1.54 (9H, s), 1.46 (9H, s), 1.26 (3H, d, J ) 6.5
1
1615 cm-1; H NMR (300 MHz, CDCl3) δ 8.79 (1H, s), 7.24-
Hz) ppm; 13C NMR (200 MHz, CDCl3) δ 169.6, 167.3, 161.9,
144.1, 82.8, 82.1, 51.8, 30.9, 29.3, 28.1, 28.0, 15.2 ppm. Anal.
Calcd for C16H26N2O5: C, 58.88; H, 8.03; N, 8.58. Found: C,
58.96; H, 8.11; N, 8.40.
7.09 (5H, m), 3.18 (1H, dd, 2J ) 18.0 Hz, 3J ) 8.5 Hz), 2.79
2
3
(1H, dd, J ) 17.0 Hz, J ) 6.0 Hz), 2.68-2.60 (2H, m), 2.41
(1H, dd, 2J ) 17.0 Hz, 3J ) 9.5 Hz) 1.53 (9H, s) ppm; 13C NMR
(300 MHz, CDCl3) δ 169.3, 162.0, 144.5, 137.3, 129.2, 128.7,
126.9, 83.0, 37.3, 35.3, 27.9, 25.3 ppm. Anal. Calcd for
Da ta for 5-Ben zyl-1-ter t-bu toxyca r bon ylm eth yl-6-oxo-
1,4,5,6-tetr a h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu -
tyl Ester , 6b: white solid (90%); mp 95-97 °C (hexane); IR
(CHCl3) ν 1709, 1641 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.23-
7.08 (5H, m), 4.42 (2H, s), 3.17 (1H, dd, 2J ) 13.0 Hz, 3J ) 2.5
Hz), 2.73-2.46 (4H, m), 1.44 (9H, s), 1.40 (9H, s) ppm; 13C
NMR (300 MHz, CDCl3) δ 168.5, 167.3, 161.8, 144.0, 137.6,
129.2, 128.6, 126.8, 82.8, 82.2, 51.9, 37.7, 35.3, 28.0, 27.9, 25.7
ppm. Anal. Calcd for C22H30N2O5: C, 65.65; H, 7.51; N, 6.96.
Found: C, 65.69; H, 7.55; N, 6.90.
C
16H20N2O3: C, 66.65; H, 6.99; N, 9.72. Found: C, 66.68; H,
6.96; N, 9.75.
Da ta for 4-Meth yl-6-oxo-1,4,5,6-tetr a h yd r op yr id a zin e-
3-ca r boxylic Acid ter t-Bu tyl Ester , 5c: white solid (80%);
mp 100-102 °C (hexanes-EtOAc); IR (CHCl3) ν 3413, 1710,
1631 cm-1; 1H NMR (300 MHz, CDCl3) δ 9.26 (1H, s), 3.25 (1H,
qd, 3J ) 7.5 Hz, 3J ) 1.5 Hz), 2.62 (1H, dd, 2J ) 17.5 Hz, 3J )
2
3
7.5 Hz), 2.39 (1H, dd, J ) 17.5 Hz, J ) 1.5 Hz), 1.54 (9H, s),
1.15 (3H, d, J ) 7.5 Hz) ppm; 13C NMR (300 MHz, CDCl3) δ
Da ta for 1-ter t-Bu toxyca r bon ylm eth yl-4-m eth yl-6-oxo-
1,4,5,6-tetr a h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu -
tyl Ester , 6c: white solid (90%); mp 98-100 °C (hexane); IR
(CHCl3) ν 1733, 1695 cm-1; 1H NMR (200 MHz, CDCl3) δ 4.57
(1H, d, 2J ) 17.0 Hz), 4.35 (1H, d, 2J ) 17.0 Hz), 3.22 (1H, qd,
3
166.7, 161.8, 147.9, 83.0, 33.4, 27.9, 27.2, 16.0 ppm. Anal. Calcd
for C10H16N2O3: C, 56.59; H, 7.60; N, 13.20. Found: C, 56.49;
H, 7.70; N, 13.21.
Da ta for 6-Oxo-4-p h en yl-1,4,5,6-tetr a h yd r op yr id a zin e-
3-ca r boxylic Acid ter t-Bu tyl Ester , 5d : white solid (75%);
mp 143-145 °C (hexanes-EtOAc); IR (CHCl3) ν 3260, 1701,
3
2
3
3J ) 7.0 Hz, J ) 2.0 Hz), 2.69 (1H, dd, J ) 17.0 Hz, J ) 7.0
Hz), 2.43 (1H, dd, 2J ) 17.0 Hz, 3J ) 2.0 Hz), 1.53 (9H, s),
1.45 (9H,s), 1.21 (3H, d, 3J ) 7.0 Hz) ppm; 13C NMR (200 MHz,
CDCl3) δ 167.2, 165.4, 161.5, 147.9, 82.7, 82.0, 51.5, 33.5, 28.0,
27.9, 27.8, 16.0 ppm. Anal. Calcd for C16H26N2O5: C, 58.88;
H, 8.03; N, 8.58. Found: C, 58.80; H, 8.06; N, 24.61.
1
1640 cm-1; H NMR (300 MHz, CDCl3) δ 8.91 (1H, s), 7.25-
7.09 (5H, m), 4.42 (1H, dd, 3J ) 8.5 Hz, 3J ) 2.5 Hz), 2.86
(1H, dd, 2J ) 17.5 Hz, 3J ) 8.5 Hz), 2.71 (1H, dd, 2J ) 17.5
Hz, 3J ) 2.5 Hz), 1.40 (9H, s) ppm; 13C NMR (300 MHz, CDCl3)
δ 165.9, 161.8, 145.4, 137.9, 129.2, 127.8, 126.8, 83.2, 38.0, 33.9,
27.9 ppm. Anal. Calcd for C15H18N2O3: C, 65.68; H, 6.61; N,
10.21. Found: C, 65.65; H, 6.60; N, 10.24.
Da ta for 1-ter t-Bu toxyca r bon ylm eth yl-5-p h en yl-6-oxo-
1,4,5,6-tetr a h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu -
tyl Ester , 6d : colorless oil (90%); IR (CHCl3) ν 1732, 1697 cm-1
;
Da ta for 6-Oxo-1,4,5,6-tetr a h yd r op yr id a zin e-3-ca r box-
ylic Acid ter t-Bu tyl Ester , 5e: white solid (85%); mp 146-
1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (5H, m), 4.59 (1H, d,
2 3
2J ) 17.0 Hz), 4.47 (1H, d, J ) 17.0 Hz), 4.39 (1H, dd, J )
148 °C (hexanes-EtOAc); IR (CHCl3) ν 3410, 1695, 1624 cm-1
;
9.0 Hz, J ) 3.0 Hz), 2.99 (1H, dd, J ) 17.5 Hz, J ) 9.0 Hz),
2.80 (1H, dd, 2J ) 17.5 Hz, 3J ) 3.0 Hz), 1.48 (9H, s), 1.41
(9H, s) ppm; 13C NMR (300 MHz, CDCl3) δ 167.1, 165.0, 161.5,
144.8, 138.4, 129.2, 127.7, 127.1, 82.9, 82.3, 51.9, 39.2, 34.4,
3
2
3
1H NMR (200 MHz, CDCl3) δ 9.10 (1H, s), 2.86 (2H, t, 3J )
3
7.5 Hz), 2.54 (2H, t, J ) 7.5 Hz), 1.55 (9H, s) ppm; 13C NMR
(200 MHz, CDCl3) δ 167.1, 162.1, 144.4, 83.1, 28.0, 26.0, 21.0

Synthesis and Conformational Flexibility of OPCAs
J . Org. Chem., Vol. 67, No. 9, 2002 2795
28.1, 27.8 ppm. Anal. Calcd for C21H28N2O5: C, 64.94; H, 7.27;
N, 7.21. Found: C, 64.84; H, 7.29; N, 7.26.
Alk yla tion of Com p ou n d s 7a -c. Gen er a l P r oced u r e.
To a stirred solution of compounds 7a -c (0.33 mmol) in
anhydrous THF (1 mL) at -78 °C was added LiHMDS (1 M
in THF, 0.66 mL, 0.66 mmol), and the solution was stirred for
2 h. The corresponding alkylant R3X (0.66 mmol) was added
dropwise, the reaction mixture was stirred for 20 h, and the
temperature was slowly raised to rt. H2O (3 mL) was added,
and the organic layer was decanted. The aqueous layer was
extracted with EtOAc (3 × 3 mL), and the combined organic
extracts were dried over MgSO4. Evaporation under reduced
pressure afforded a residue which was purified by column
chromatography (hexanes-EtOAc, 80:20).
Da ta for 1-ter t-Bu toxyca r bon ylm eth yl-6-oxo-1,4,5,6-
tetr a h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu tyl Es-
ter , 6e: white solid (90%); mp 95-97 °C (hexane); IR (CHCl3)
ν 1733, 1683 cm-1; 1H NMR (200 MHz, CDCl3) δ 4.47 (2H, s),
3
3
2.87 (2H, t, J ) 8.0 Hz), 2.57 (2H, t, J ) 8.0 Hz), 1.54 (9H,
s), 1.46 (1H, s) ppm; 13C NMR (200 MHz, CDCl3) δ 167.3, 166.0,
161.7, 144.3, 82.8, 81.2, 51.7, 28.0, 27.9, 26.2, 21.8 ppm. Anal.
Calcd for C15H24N2O5: C, 57.68; H, 7.74; N, 8.97. Found: C,
57.60; H, 7.79; N, 8.95.
Da ta for 4,5-cis-1-ter t-Bu toxyca r bon ylm eth yl-4,5-d im -
eth yl-6-oxo-1,4,5,6-tetr ah ydr opyr idazin e-3-car boxylic Acid
ter t-Bu tyl Ester , 4,5-cis-6f: colorless oil (90%); IR (CHCl3)
Da ta for 4,5-tr a n s-1-Ben zyl-4,5-d im eth yl-6-oxo-1,4,5,6-
tetr a h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu tyl Es-
ter , 4,5-tr a n s-7d : colorless oil (95%); IR (CHCl3) ν 1689, 1629
1
ν 1738, 1672 cm-1; H NMR (300 MHz, CDCl3) δ 4.58 (1H, d,
1
2J ) 17.0 Hz), 4.35 (1H, d, 2J ) 17.0 Hz), 3.11 (1H, q, 3J ) 6.5
Hz), 2.73 (1H, q, 3J ) 6.5 Hz), 1.56 (9H, s), 1.47 (9H, s),
cm-1; H NMR (300 MHz, CDCl3) δ 7.37-7.25 (5H, m), 5.08
2
2
(1H, d, J ) 14.0 Hz), 4.92 (1H, d, J ) 14.0 Hz), 2.90 (1H, cd,
1.24 (3H, d, J ) 6.5 Hz), 1.09 (3H, d, J ) 6.5 Hz) ppm; 13C
NMR (300 MHz, CDCl3) δ 169.5, 167.4, 161.7, 148.8, 82.7, 82.1,
51.7, 35.2, 32.9, 28.1, 28.0, 10.4, 9.6 ppm. Anal. Calcd for
3J ) 7.5 Hz, J ) 1.5 Hz), 2.48 (1H, cd, J ) 7.5 Hz, J ) 1.5
3
3
3
3
3
3
3
Hz), 1.56 (9H, s), 1.09 (3H, d, J ) 7.5 Hz), 1.06 (3H, d, J )
7.5 Hz) ppm; 13C NMR (300 MHz, CDCl3) δ 168.8, 164.3, 153.0,
130.2, 128.4, 128.2, 127.5, 82.3, 53.0, 35.2, 30.0, 28.0, 16.4, 16.1
ppm. Anal. Calcd for C18H24N2O3: C, 68.33; H, 7.65; N, 8.85.
Found: C, 68.39; H, 7.55; N, 8.84.
C
17H28N2O5: C, 59.98; H, 8.29; N, 8.23. Found: C, 59.98; H,
8.29; N, 8.23.
Da ta for 4,5-cis-5-Ben zyl-1-ter t-bu toxyca r bon ylm eth yl-
4-m eth yl-6-oxoper h ydr opyr idazin e-3-car boxylic Acid ter t-
Bu tyl Ester , 4,5-cis-6g: colorless oil (90%); IR (CHCl3) ν 1728,
Da ta for 4,5-tr a n s-1,5-Diben zyl-4-m eth yl-6-oxo-1,4,5,6-
tetr a h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu tyl Es-
ter , 4,5-tr a n s-7e: colorless oil (90%); IR (CHDCl3) ν 1698,
1620 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.38-6.97 (10H, m),
1
1687 cm-1; H NMR (300 MHz, CDCl3) δ 7.38-7.05 (5H, m),
4.62 (1H, d, 2J ) 18.0 Hz), 4.36 (1H, d, 2J ) 18.0 Hz), 3.50
(1H, dd, 2J ) 15.0 Hz, 3J ) 6.0 Hz), 3.01-259 (3H, m), 1.50
2
2
5.11 (1H, d, J ) 14.5 Hz), 4.96 (1H, d, J ) 14.5 Hz), 2.97-
3
2
(9H, s), 1.48 (9H, s), 1.36 (3H, d, J ) 7.0 Hz) ppm; 13C NMR
2.85 (2H, m), 2.62-2.57 (1H, m), 2.44 (1H, dd, J ) 13.0 Hz,
3
(300 MHz, CDCl3) δ 168.5, 168.0, 161.6, 149.0, 138.9, 134.5,
129.1, 128.6, 82.7, 81.7, 51.7, 46.5, 36.2, 30.5, 28.1, 27.9, 9.7
ppm. Anal. Calcd for C23H32N2O5: C, 66.32; H, 7.74; N, 6.73.
Found: C, 66.42; H, 7.70; N, 6.70.
3J ) 11.0 Hz), 1.55 (9H, s), 0.97 (3H, d, J ) 7.5 Hz) ppm; 13
C
NMR (200 MHz, CDCl3) δ 167.3, 161.7, 146.9, 137.1, 129.1,
128.6, 128.4, 127.5, 126.9, 82.5, 53.1, 46.7, 36.3, 31.1, 28.0, 15.8
ppm. Anal. Calcd for C18H24N2O3: C, 68.33; H, 7.65; N, 8.85.
Found: C, 68.39; H, 7.55; N, 8.84.
N-Alk yla tion of 5 w ith Ben zyl Br om id e. Gen er a l P r o-
ced u r e. To a stirred solution of compounds 5 (0.47 mmol) in
acetonitrile (10 mL) were added K2CO3 (260 mg, 1.88 mmol)
and (TEBA)Cl (43 mg, 0.19 mmol), and the solution was stirred
for 10 min. Benzyl bromide (15 µmL, 0.19 mmol) was added,
and the reaction mixture was stirred at reflux temperature
for 5 h. The resulting suspension was filtered through Celite,
and the remaining solid material was washed with EtOAc (3
× 2 mL). The solvent was evaporated, and the residue was
purified by column chromatography (hexanes-EtOAc, 80:20).
Da ta for 1-Ben zyl-4-m eth yl-6-oxo-1,4,5,6-tetr a h yd r o-
p yr id a zin e-3-ca r boxylic Acid ter t-Bu tyl Ester , 7a : white
solid (95%); mp 81-83 °C (hexane); IR (CHCl3) ν 1685, 1604
Da ta for 4,5-tr a n s-1-Ben zyl-5-m eth yl-4-p h en yl-6-oxo-
1,4,5,6-tetr a h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu -
tyl Ester , 4,5-tr a n s-7f: colorless oil (90%); IR (CHCl3) ν 1708,
1685 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.39-7.18 (10H, m),
5.16 (1H, d, 2J ) 14.0 Hz), 4.94 (1H, d, 2J ) 14.0 Hz), 4.00
(1H, d, 3J ) 4 Hz), 2.78 (1H, cd, 3J ) 7.5 Hz, 3J ) 4.0 Hz),
1.41 (9H, s), 1.25 (3H, d, 3J ) 7.5 Hz) ppm; 13C NMR (200
MHz, CDCl3) δ 168.1, 162,1, 144.4, 137.7, 136.7, 129.0, 128.7,
128.4, 128.2, 127.7, 127.6, 127.0, 82.7, 53.1, 46.7, 40.2, 27.8,
16.9 ppm. Anal. Calcd for for C23H26N2O3: C, 72.99; H, 6.92;
N, 7.40. Found: C, 72.97; H, 6.90; N, 7.41.
Red u ction of Com p ou n d s 6 a n d 7 w ith Na CNBH3.
Gen er a l P r oced u r e. To a solution of compounds 6 and 7 (0.32
mmol) in MeOH (1 mL) was added 2 N HCl to pH 2. NaCNBH3
(9.6 mmol) was added in three portions with an interval of 5
min. The acid mixture was stirred for 24 h. The solvent was
evaporated, and the aqueous solution was alkalanized with 3
M KOH to pH 12. The mixture was extracted with EtOAc (3
× 3 mL) and the combined extract dried on MgSO4. The solvent
was evaporated, and the residue was purified by chromatog-
raphy (hexanes-EtOAc, 70:30).
1
cm-1; H NMR (200 MHz, CDCl3) δ 7.34-7.27 (5H, m), 5.09
(1H, d, 2J ) 14.5 Hz), 4.91 (1H, d, 2J ) 14.5 Hz), 3.19 (1H, qd,
3
2
3
3J ) 7.0 Hz, J ) 2 Hz), 2.62 (1H, dd, J ) 17.0 Hz, J ) 7.0
Hz), 2.42 (1H, dd, 2J ) 17.0 Hz, 3J ) 2.0 Hz), 1.55 (9H, s),
3
1.08 (3H, d, J ) 7.0 Hz) ppm; 13C NMR (200 MHz, CDCl3) δ
165.0, 161.7, 147.6, 137.0, 129.0, 128.4, 128.3, 127.5, 126.9,
82.6, 52.8, 34.2, 27.9, 27.7, 16.1 ppm. Anal. Calcd for
C
17H22N2O3: C, 67.53; H, 7.33; N, 9.26. Found:: C, 67.50; H,
7.30; N, 9.36.
Da ta for 1-Ben zyl-4-p h en yl-6-oxo-1,4,5,6-tetr a h yd r o-
p yr id a zin e-3-ca r boxylic Acid ter t-Bu tyl Ester , 7b: color-
Da ta for 3,5-cis-1-ter t-Bu toxyca r bon ylm eth yl-5-m eth -
yl-6-oxop er h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu tyl
Ester , 3,5-cis-8a : colorless oil (50%); IR (CHCl3) ν 3275, 1730,
1645 cm-1; 1H NMR (200 MHz, CDCl3) δ 4.88 (1H, s), 4.49 (1H,
less oil (95%); IR (CHCl3) ν 1709, 1604 cm-1 1H NMR (300
;
MHz, CDCl3) δ 7.12-6.87 (10H, m), 5.09 (1H, d, 2J ) 14.0 Hz),
2
3
3
2
2
3
4.84 (1H, d, J ) 14.0 Hz), 4.27 (1H, dd, J ) 8.5 Hz, J ) 3.0
d, J ) 17.0 Hz), 4.43 (1H, d, J ) 17.0 Hz), 3.75 (1H, t, J )
7.5 Hz), 2.65-2.52 (3H, m), 1.48 (9H, s), 1.47 (9H, s), 1.27 (3H,
d, 3J ) 7.0 Hz) ppm; 13C NMR (200 MHz, CDCl3) δ 170.7, 168.0,
167.7, 83.4, 83.2, 60.4, 55.0, 35.7, 32.7, 28.1, 28.0, 15.2 ppm;
Anal. Calcd for C16H28N2O5: C, 58.52; H, 8.59; N, 8.53.
Found: C, 58.47; H, 8.62; N, 8.62.
2
3
2
Hz), 2.83 (1H, dd, J ) 17.0 Hz, J ) 8.5 Hz), 2.70 (1H, dd, J
) 17.0 Hz, 3J ) 3.0 Hz), 1.36 (9H, s) ppm; 13C NMR (300 MHz,
CDCl3) δ 164.3, 161.6, 145.1, 137.7, 136.6, 129.0, 128.7, 128.5,
128.4, 127.6, 126.8, 82.8, 52.6, 38.6, 34.8, 27.8 ppm. Anal. Calcd
for C22H24N2O3: C, 72.50; H, 6.64; N, 7.69. Found: C, 72.54;
H, 6.61; N, 7.60.
Da ta for 3,5-cis-5-Ben zyl-1-ter t-bu toxyca r bon ylm eth yl-
6-oxop er h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu t yl
Ester , 3,5-cis-8b: colorless oil (45%); IR (CHCl3) ν 3401, 1728,
1655 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.69 (1H, d, 2J ) 14.5
Hz), 4.66 (1H, d, 2J ) 14.5 Hz), 4.48 (1H, d, 3J ) 10.5 Hz),
3.42-3.36 (2H, m), 2.78-2.68 (2H, m), 2.08-1.85 (2H, m), 1.48
(9H, s), 1.47 (9H, s) ppm; 13C NMR (200 MHz, CDCl3) δ 170.2,
167.5, 167.2, 139.0, 128.5, 128.3, 128.2, 82.9, 82.7, 60.0, 56.5,
35.2, 32.2, 30.4, 27.6, 27.5 ppm. Anal. Calcd for C22H32N2O5:
C, 65.32; H, 7.97; N, 6.93. C, 65.42; H, 7.89; N, 7.01.
Da ta for 1-Ben zyl-6-oxo-1,4,5,6-tetr a h yd r op yr id a zin e-
3-ca r boxylic a cid ter t-Bu tyl Ester , 7c: white solid (95%);
mp 72-74 °C (hexane); IR (CHCl3) ν 1683, 1637 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.26-7.17 (5H, m), 4.88 (2H, s), 2.67 (2H,
3
t, 3J ) 8.0 Hz), 2.38 (2H, t, J ) 8.0 Hz), 1.44 (9H, s) ppm; 13
C
NMR (300 MHz, CDCl3) δ 165.5, 161.9, 144.0, 137.0, 128.5,
128.4, 127.6, 126.9, 82.6, 52.6, 27.9, 26.6, 21.7 ppm. Anal. Calcd
for C16H20N2O3: C, 66.65; H, 6.99; N, 9.72. Found: C, 66.75;
H, 6.90; N, 9.73.

2796 J . Org. Chem., Vol. 67, No. 9, 2002
Alvarez-Ibarra et al.
δ 7.17-6.91 (10H, m), 5.05 (1H, d, J ) 14.0 Hz), 4.39 (1H, d,
2
Da ta for 3,4-cis-1-ter t-Bu toxyca r bon ylm eth yl-4-m eth -
yl-6-oxop er h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu tyl
Ester , 3,4-cis-8c: white solid (85%); mp 67-69 °C (hexanes-
2J ) 14.0 Hz), 4.33 (1H, d, J ) 12.0 Hz), 3.96 (1H, dd, J )
3
3
3
3
12.0 Hz, J ) 5.5 Hz), 3.56 (1H, c, J ) 5.5 Hz), 2.86 (1H, dd,
EtOAc); IR (CHCl3) ν 3421, 1732, 1651 cm-1
;
1H NMR (300
2J ) 17.0 Hz, J ) 5.5 Hz), 2.75 (1H, dd, J ) 17.0 Hz, J )
5.5 Hz), 1.15 (9H, s) ppm; 13C NMR (300 MHz, CDCl3) δ 168.6,
168.1, 138.0, 136.5, 128.6, 127.9, 127.7, 82.5, 60.6, 51.9, 42.6,
35.9, 27.8 ppm. Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15;
N, 7.64. Found: C, 72.18; H, 7.17; N, 7.60.
3
2
3
3
MHz, CDCl3) δ 5.00 (1H, d, J ) 12.0 Hz), 4.55 (1H, d, 2J )
17.0 Hz), 3.96 (2H, m), 2.68 (1H, dd, 2J ) 17.0 Hz, 3J ) 6.5
Hz), 2.52 (1H, m), 2.33 (1H, dd, 2J ) 17.0 Hz, 3J ) 4.5 Hz),
3
1.49 (9H, s), 1.47 (9H, s), 1.06 (3H, d, J ) 7.0 Hz) ppm; 13C
NMR (300 MHz, CDCl3) δ 169.3, 168.9, 168.2, 82.5, 82.2, 59.8,
Da ta for 1-Ben zyl-6-oxop er h yd r op yr id a zin e-3-ca r box-
ylic Acid ter t-Bu tyl Ester , 9c: white solid (95%); mp 110-
50.5, 37.4, 31.1, 28.1, 28.0, 14.7 ppm. Anal. Calcd for
112 °C (hexanes-EtOAc); IR (CHCl3) ν 3288, 1726, 1655 cm-1
;
C
16H28N2O5: C, 58.52; H, 8.59; N, 8.53. Found: C, 58.58; H,
1H NMR (300 MHz, CDCl3) δ 7.65-7.28 (5H, m), 4.69 (2H, s),
8.55; N, 8.53.
4.37 (1H, d, 3J ) 10.0 Hz), 3.66 (1H, dd, 3J ) 10.0 Hz, 3J ) 7.0
Da ta for 3,4-cis-1-ter t-Bu toxyca r bon ylm eth yl-4-p h en -
yl-6-oxop er h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu tyl
Ester , 3,4-cis-8d : colorless oil (80%); IR (CHCl3) ν 3385, 1722,
3
2
3
Hz), 2.53 (2H, t, J ) 7.0 Hz), 2.23 (1H, q, J ) 7.0 Hz, J )
7.0 Hz), 2.05 (1H, q, 2J ) 7.0 Hz, 3J ) 7.0 Hz), 1.46 (9H, s)
ppm; 13C NMR (300 MHz, CDCl3) δ 170.9, 170.7, 137.1, 128.5,
128.4, 127.5, 82.3, 56.4, 51.7, 29.4, 27.9, 27.4 ppm. Anal. Calcd
for C16H22N2O3: C, 66.18; H, 7.64; N, 9.65. Found: C, 66.24;
H, 7.60; N, 9.65.
1
1648 cm-1; H NMR (300 MHz, CDCl3) δ 7.29-7.16 (5H, m),
4.90 (1H, d, 3J ) 12.0 Hz), 4.55 (1H, d, 2J ) 17.0 Hz), 4.11
(1H, dd, 3J ) 12.0 Hz, 3J ) 5.0 Hz), 4.03 (1H, d, 2J ) 17.0 Hz),
3.66 (1H, td, 3J ) 7.0 Hz, 3J ) 5.0 Hz), 2.87 (1H, dd, 2J ) 17.5
Hz, 3J ) 7.0 Hz), 2.75 (1H, dd, 2J ) 17.5 Hz, 3J ) 5.0 Hz),
1.42 (9H, s), 1.19 (9H, s) ppm; 13C NMR (300 MHz, CDCl3) δ
170.5, 169.5, 168.2, 138.3, 128.8, 128.2, 127.8, 82.2, 82.2, 60.6,
51.0, 42.8, 35.6, 28.1, 27.8 ppm. Anal. Calcd for C21H30N2O5:
C, 64.59; H, 7.74; N, 7.17. Found: C, 64.55; H, 7.70; N, 7.16.
Da ta for 1-ter t-Bu toxyca r bon ylm eth yl-6-oxop er h yd r o-
p yr id a zin e-3-ca r boxylic Acid ter t-Bu tyl Ester , 8e: white
solid (90%); mp 81-83 °C (hexanes-EtOAc); IR (CHCl3) ν
3417, 1736, 1666 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.70 (1H,
Da ta for 3,4-cis-4,5-tr a n s-1-Ben zyl-4,5-d im eth yl-6-oxo-
p er h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu tyl Ester ,
3,4-cis-4,5-tr a n s-9d : colorless oil (85%); IR (CHCl3) ν 3308,
1711, 1665 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.34-7.30 (5H,
m), 5.05 (1H, 2J ) 14.0 Hz), 4.98 (1H, 2J ) 14.0 Hz), 3.73 (1H,
3
3
3
d, J ) 7.5 Hz), 3.68 (1H, s), 3.08 (1H, cd, J ) 7.5 Hz, J )
3
3
1.5 Hz), 2.56 (1H, qd, J ) 7.5 Hz, J ) 1.5 Hz), 1.25 (9H, s),
1.22 (3H, d, J ) 7.5 Hz), 1.10 (3H, d, J ) 7.5 Hz) ppm; 13C
NMR (200 MHz, CDCl3) δ 169.8, 168.9, 136.3, 128.8, 128.0,
127.9, 82.2, 64.1, 52.6, 39.4, 33.9, 28.7, 16.7, 16.1 ppm. Anal.
Calcd for C18H26N2O3: C, 67.90; H, 8.23; N, 8.80. Found: C,
67.98; H, 8.20; N, 8.84.
3
3
3
3
3
d, J ) 10.0 Hz), 4.14 (2H, s), 3.78 (1H, dt, J ) 10.0 Hz, J )
3
2
3
7.0 Hz), 2.46 (2H, t, J ) 7.0 Hz), 2.26 (1H, q, J ) 7.0 Hz, J
2
3
) 7.0 Hz), 2.00 (1H, q, J ) 7.0 Hz, J ) 7.0 Hz), 1.41 (9H, s),
1.39 (9H, s) ppm; 13C NMR (300 MHz, CDCl3) δ 171.6, 170.9,
168.3, 82.3, 82.1, 56.3, 50.6, 29.1, 28.1, 28.0, 27.5 ppm. Anal.
Calcd for C15H26N2O5: C, 57.31; H, 8.34; N, 8.91. Found: C,
57.38; H, 8.30; N, 8.81.
Da ta for 3,4-cis-4,5-tr a n s-1,5-Diben zyl-4-m eth yl-6-oxo-
p er h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu tyl Ester ,
3,4-cis-4,5-tr a n s-9e: colorless oil (85%); IR (CHCl3) ν 3299,
1724, 1645 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.29-6.94 (10H,
m), 5.31 (1H, d, 3J ) 10.0 Hz), 5.02 (1H, d, 2J ) 14.5 Hz), 4.82
Da ta for 3,4-cis-4,5-cis-1-ter t-Bu toxyca r bon ylm eth yl-
4,5-dim eth yl-6-oxoper h ydr opyr idazin e-3-car boxylic Acid
ter t-Bu tyl Ester , 3,4-cis-4,5-cis-8f: colorless oil (80%); IR
(CHCl3) ν 3402, 1726, 1659 cm-1; 1H NMR (200 MHz, CDCl3)
δ 4.69 (1H, d, 2J ) 17 Hz), 4.17 (1H, d, 3J ) 4.0 Hz), 3.97 (1H,
s), 3.83 (1H, d, 2J ) 17 Hz), 2.79 (1H, q, 3J ) 7.0 Hz), 2.39
2
3
3
(1H, d, J ) 14.5 Hz), 4.04 (1H, dd, J ) 10 Hz, J ) 4.5 Hz),
2.86-2.47 (4H, m), 1.47 (9H, s), 0.88 (3H, d, 3J ) 7.5 Hz) ppm.
13C NMR (200 MHz, CDCl3) δ 171.1, 170.1, 137.0, 129.1, 128.5,
127.6, 82.3, 60.4, 53.0, 46.7, 36.3, 31.1, 28.0, 15.8 ppm. Anal.
Calcd for C24H30N2O3: C, 73.07; H, 7.66; N, 10.00. Found: C,
73.15; H, 7.66; N, 10.06.
3
(1H, m), 1.45 (9H, s), 1.48 (9H, s), 1.24 (3H, d, J ) 7.0 Hz),
3
0.97 (3H, d, J ) 7.0 Hz) ppm; 13C NMR (200 MHz, CDCl3) δ
Da ta for 3,4-cis-4,5-tr a n s-1-Ben zyl-5-m eth yl-4-p h en yl-
6-oxop er h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu t yl
Ester , 3,4-cis-4,5-tr a n s-9f: colorless oil (85%); IR (CHCl3) ν
171.2. 169.4, 168.4, 82.3, 82.2, 60.9, 50.5, 38.8, 35.4, 28.1, 28.0,
13.0, 8.8 ppm; Anal. Calcd for C17H30N2O5: C, 59.63; H, 8.83;
N, 8.18. Found: C, 59.69; H, 8.80; N, 8.18.
1
3287, 1720, 1653 cm-1; H NMR (200 MHz, CDCl3) δ 7.44-
Da ta for 3,4-cis-4,5-cis-5-Ben zyl-1-ter t-bu toxyca r bon -
ylm eth yl-4-m eth yl-6-oxop er h yd r op yr id a zin e-3-ca r boxy-
lic Acid ter t-Bu tyl Ester , 3,4-cis-4,5-cis-8g: colorless oil
(80%); IR (CHCl3) ν 3428, 1728, 1678 cm-1; 1H NMR (300 MHz,
7.32 (10H, m), 5.0 (1H, s), 4.84 (1H, d, 2J ) 14.0 Hz), 4.49
2
3
3
(1H, d, J ) 14.0 Hz), 4.22 (1H, dd, J ) 6.0 Hz, J ) 1.5 Hz),
3
3
3.98 (1H, d, J ) 6.0 Hz), 2.94 (1H, m), 1.22 (3H, d, J ) 7.5
Hz), 1.05 (9H, s) ppm; 13C NMR (200 MHz, CDCl3) δ 172.4,
170.6, 136.6, 130.8, 128.7, 128.6, 128.5, 84.0, 66.7, 53.6, 49.9,
36.5, 27.6, 14.2 ppm. Anal. Calcd for C23H28N2O3: C, 72.60;
H, 7.42; N, 7.36. Found: C, 72.48; H, 7.36; N, 7.49.
2
CDCl3) δ 7.33-7.24 (5H, m), 4.65 (1H, d, J ) 17.0 Hz), 3.96
2
3
(1H, d, J ) 17.0 Hz), 3.87 (1H, d, J ) 3.5 Hz), 3.58 (1H, dd,
2J ) 14.5 Hz, J ) 4.5 Hz), 2.96 (1H, dt, J ) 9.0 Hz, J ) 4.5
3
3
3
2
3
Hz), 2.60 (1H, dd, J ) 14.5 Hz, J ) 9.0 Hz), 2.29-2.24 (1H,
3
Ad d ition of Acetyl Ch lor id e to 8 a n d 9. Gen er a l
P r oced u r e. To a stirred solution of compounds 8 and 9 (0.33
mmol) in acetonitrile (4 mL) were added K2CO3 (182 mg, 1.32
mmol) and (TEBA)Cl (29 mg, 0.13 mmol), and the solution was
stirred for 10 min. Acetyl chloride (94 µmL, 1.32 mmol) was
added, and the reaction mixture was stirred at refluxed
temperature for 5 h. The resulting suspension was filtered
through Celite, and the remaining solid material was washed
with EtOAc (3 × 2 mL). The solvent was evaporated, and the
residue was purified by column chromatography (hexanes-
EtOAc, 80:20).
m), 1.49 (9H, s), 1.44 (9H, s), 1.01 (3H, d, J ) 7.0 Hz) ppm;
13C NMR (300 MHz, CDCl3) δ 171.5, 169.3, 168.4, 139.4, 128.7,
128.6, 126.3, 82.4, 82.3, 61.0, 50.5, 46.5, 32.5, 31.9, 28.1, 28.0,
9.1 ppm. Anal. Calcd for C23H34N2O5: C, 66.00; H, 8.19; N,
6.69. Found: C, 66.09; H, 8.14; N, 6.67.
Da ta for 3,4-cis-1-Ben zyl-4-m eth yl-6-oxop er h yd r op y-
r id a zin e-3-ca r boxylic Acid ter t-Bu tyl Ester , 3,4-cis-9a :
white solid (90%); mp 83-85 °C (hexanes-EtOAc); IR (CHCl3)
1
ν 3428, 1726, 1629 cm-1; H NMR (300 MHz, CDCl3) δ 7.28-
7.26 (5H, m), 4.87 (1H, d, 2J ) 14.5 Hz), 4.43 (1H, d, 2J ) 14.5
3
3
3
Hz), 4.34 (1H, d, J ) 10.5 Hz), 3.71 (1H, dd, J ) 10.5 Hz, J
) 4.5 Hz), 2.60 (1H, dd, 2J ) 16.5 Hz, 3J ) 6.0 Hz), 2.43-2.33
(1H, m), 2.27 (1H, dd, 2J ) 16.5 Hz, 3J ) 5.0 Hz), 1.38 (9H, s),
Da ta for 3,4-cis-2-Acetyl-1-ter t-Bu toxyca r bon ylm eth yl-
4-m eth yl-6-oxoper h ydr opyr idazin e-3-car boxylic Acid ter t-
Bu tyl Ester , 3,4-cis-10a : colorless oil (85%); IR (CHCl3) ν
3
0.88 (3H, d, J ) 7.0 Hz) ppm; 13C NMR (300 MHz, CDCl3) δ
3
169.3, 168.4, 136.7, 128.6, 128.2, 127.5, 82.5, 59.8, 51.6, 37.6,
31.0, 28.0, 14.8 ppm. Anal. Calcd for C17H24N2O3: C, 67.08;
H, 7.95; N, 9.20. Found: C, 67.00; H, 7.85; N, 9.29.
1740, 1680 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.46 (1H, d, J
2
2
) 9.5 Hz), 4.30 (1H, d, J ) 17.0 Hz), 4.18 (1H, d, J ) 17.0
Hz), 3.00 (1H, m), 2.39-2.15 (5H, m), 1.50 (9H, s), 1.49 (9H,
3
Da ta for 3,4-cis-1-Ben zyl-4-p h en yl-6-oxop er h yd r op y-
r id a zin e-3-ca r boxylic Acid ter t-Bu tyl Ester , 3,4-cis-9b:
white solid (85%); mp 142-144 °C (hexanes-EtOAc); IR
(CHCl3) ν 3415, 1730, 1676 cm-1; 1H NMR (300 MHz, CDCl3)
s), 1.12 (3H, d, J ) 7.5 Hz) ppm; 13C NMR (300 MHz, CDCl3)
δ 172.9, 172.9, 168.6, 166.1, 82.7, 82.1, 58.3, 54.7, 36.6, 30.8,
28.1, 28.0, 20.8, 16.0 ppm. Anal. Calcd for C18H30N2O6: C,
58.36; H, 8.16; N, 7.56. Found: C, 58.42; H, 8.19; N, 7.50.

Synthesis and Conformational Flexibility of OPCAs
J . Org. Chem., Vol. 67, No. 9, 2002 2797
Da ta for 2-Acetyl-1-ter t-Bu toxyca r bon ylm eth yl-6-oxo-
p er h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu tyl Ester ,
10b: colorless oil (85%); IR (CHCl3) ν 1731, 1670 cm-1; 1H NMR
(200 MHz, CDCl3) δ 5.66 (1H, dd, J ) 9.5 Hz, J ) 7.0 Hz),
5.03 (1H, d, 2J ) 17.5 Hz), 3.87 (1H, d, 2J ) 17.5 Hz), 3.01
(2H, t, 3J ) 8.0 Hz), 2.72-2.63 (2H, m), 2.19 (3H, s), 1.49 (9H,
s), 1.48 (9H, s), ppm; 13C NMR (200 MHz, CDCl3) δ 174.0,
173.3, 169.7, 167.2, 83.4, 83.2, 56.8, 54.5, 32.9, 28.7, 28.7, 25.0,
20.3 ppm. Anal. Calcd for C17H28N2O6: C, 57.29; H, 7.92; N,
7.86. Found: C, 57.19; H, 7.98; N, 7.82.
C19H26N2O4: C, 65.87; H, 7.56; N, 8.09. Found: C, 65.95; H,
7.44; N, 8.13.
Da ta for 2-Acetyl-1-ben zyl-6-oxop er h yd r op yr id a zin e-
3-ca r boxylic Acid ter t-Bu tyl Ester , 11b: colorless oil (85%);
3
3
1
IR (CHCl3) ν 1736, 1681 cm-1; H NMR (300 MHz, CDCl3) δ
3
2
7.47-7.32 (5H, m), 5.52 (1H, t, J ) 8.5 Hz), 5.18 (1H, d, J )
14.5 Hz), 4.61 (1H, d, 2J ) 14.5 Hz), 2.59-2.45 (2H, m), 2.17-
2.03 (2H, m), 1.56 (3H, s), 1.48 (9H, s) ppm; 13C NMR (300
MHz, CDCl3) δ 174.8, 174.6, 169.7, 136.2, 129.7, 128.7, 128.1,
82.6, 55.6, 54.6, 31.2, 28.0, 25.0, 20.3 ppm. Anal. Calcd for
Da ta for 3,4-cis-4,5-cis-2-Acetyl-1-ter t-Bu toxyca r bon -
ylm eth yl-4,5-d im eth yl-6-oxop er h yd r op yr id a zin e-3- ca r -
boxylic Acid ter t-Bu tyl Ester , 3,4-cis-4,5-cis-10c: colorless
C18H24N2O4: C, 65.04; H, 7.28; N, 8.43. Found: C, 65.14; H,
7.20; N, 8.45.
Data for 3,4-cis-4,5-tr a n s-2-Acetyl-1-ben zyl-4,5-dim eth yl-
6-oxop er h yd r op yr id a zin e-3-ca r b oxylic Acid ter t-Bu t yl
Ester , 3,4-cis-4,5-tr a n s-11c: colorless oil (75%); IR (CHCl3)
ν 1735, 1693 cm-1; 1H NMR δ 7.37-7.25 (5H, m), 5.35 (1H, d,
3J ) 6.0 Hz), 5.05 (1H, d, 2J ) 14.5 Hz), 4.95 (1H, d, 2J ) 14.5
1
oil (75%); IR (CHCl3) ν 1735, 1691 cm-1; H NMR (300 MHz,
3
2
CDCl3) δ 5.14 (1H, d, J ) 9.0 Hz), 5.34 (1H, d, J ) 14.5 Hz),
4.86 (1H, d, 2J ) 14.5 Hz), 2.82-2.77 (1H, m), 2.66-2.54 (1H,
m), 2.19 (3H, s), 1.51 (9H, s), 1.50 (9H, s), 1.16 (3H, d, 3J )
3
3
3
7.0 Hz), 0.98 (3H, d, J ) 7.0 Hz) ppm; 13C NMR (200 MHz,
Hz), 2.58 (1H, cd, J ) 7.5 Hz, J ) 1.0 Hz), 2.35-2.28 (1H,
3
CDCl3) δ 173.4, 172.9, 172.3, 168.2, 82.5, 82.1, 60.2, 50.6, 41.2,
m), 1.54 (3H, s), 1.25 (9H, s), 1.11 (3H, d, J ) 7.5 Hz), 1.10
36.5, 28.0, 27.9, 22.0, 12.2, 11.5 ppm. Anal. Calcd for
(3H, d, 3J ) 7.5 Hz) ppm; 13C NMR δ 171.3, 169.8, 165.0, 136.7,
130.1, 129.2, 128.4, 128.3, 82.1, 64.0, 53.0, 39.8, 33.2, 29.3, 17.1,
16.5 ppm. Anal. Calcd for C, 65.87; H, 7.56; N, 8.09. Found:
C, 65.75; H, 7.54; N, 8.18.
C
19H32N2O6: C, 59.36; H, 8.39; N, 7.29. Found: C, 59.25; H,
8.47; N, 7.32.
Da ta for 3,4-cis- 2-Acetyl-1-ben zyl-4-m eth yl-6-oxop er -
h yd r op yr id a zin e-3-ca r boxylic Acid ter t-Bu tyl Ester , 3,4-
cis-11a : colorless oil (80%); IR (CHCl3) ν 1736, 1696 cm-1; 1H
NMR δ 7.56-7.31 (5H, m), 5.42 (1H, d, 3J ) 9.0 Hz), 5.32 (1H,
d, 2J ) 14.5 Hz), 4.64 (1H, d, 2J ) 14.5 Hz), 2.61-2.34 (3H,
Ack n ow led gm en t. DGCYT (Project PB96-0009) is
gratefully acknowledged for financial support. We also
thank UCM (MS, RMN, and Elemental Analysis
services).
3
m), 1.51 (3H, s), 1.45 (9H, s), 0.99 (3H, d, J ) 7.0 Hz) ppm;
13C NMR δ 172.6, 169.9, 164.7, 139.4, 132.7, 130.2, 128.6, 82.9,
63.8, 55.4, 39.9, 32.7, 28.1, 22.7, 14.1 ppm. Anal. Calcd for
J O0159800