1,3-Dipolar cycloaddition of furfuryl nitrones with acrylates. A convenient approach to protected 4-hydroxypyroglutamic acids

Full text of DOI:10.1021/jo991560n

1590
J . Org. Chem. 2000, 65, 1590-1596
synthesis of differentially protected derivatives of 3-hy-
droxy-2-pyrrolidine-5-carboxylic acid (4-hydroxypyro-
glutamic acid) 1.
1,3-Dip ola r Cycloa d d ition of F u r fu r yl
Nitr on es w ith Acr yla tes. A Con ven ien t
Ap p r oa ch to P r otected
4-Hyd r oxyp yr oglu ta m ic Acid s
Pedro Merino,* Sonia Anoro, Santiago Franco,
Francisco L. Merchan, Tomas Tejero,* and
Victoria Tun˜on
Departamento de Quimica Organica, ICMA, Facultad de
Ciencias, Universidad de Zaragoza, E-50009 Zaragoza,
Aragon, Spain
The different stereoisomers of 1 are valuable chiral
synthons of wide applicability whose potential has been
scarcely explored due to the few synthetic procedures
found in the literature. In this context, Lee and Kaneko6
reported a method for obtaining the four optical isomers
of γ-hydroxyglutamic acid (the open-chain form of 4-
hydroxypyroglutamic acid) that relied on fractional crys-
tallization of the corresponding brucine and/or strych-
nine salts. Koskinen et al.7 reported the asymmetric
synthesis of (4S)-4-hydroxy-L-glutamic acid via an asym-
metric 1,3-dipolar cycloaddition of a nitrone derived from
glyoxylic acid with acrylamide derived from Oppolzer’s
chiral sultam. Nozoe et al.8 have synthesized a protected
derivative of 1a by stereoselective hydroxylation of meth-
yl N-Boc-L-pyroglutamate. More recently, a concise syn-
thesis of racemic cis- and trans-4-hydroxypyroglutamic
acids has been reported.9
Received October 7, 1999
In tr od u ction
Enantiomerically pure highly functionalized pyrro-
lidines are basic building blocks for the synthesis of a
large variety of biologically interesting nitrogen-contain-
ing products.1 Several polyhydroxylated pyrrolidines also
show activity as inhibitors of various glycosidases2 and
other pyrrolidine alkaloids, like preussin and anisomycin,
are potent antifungal agents.3 These findings have
prompted significant interest in the synthesis of those
and related compounds.4 In particular, functionalized
derivatives of pyroglutamic acid are of current interest
because they have been employed as key intermediates
in numerous syntheses.5 Despite all of this activity in the
area, there still does not exist a practical stereoselective
Recent studies by us10 and others11 have shown that
nitrones are attractive starting materials for the syn-
thesis of 5-substituted 3-hydroxy-2-pyrrolidinones via
1,3-dipolar cycloadditions with acrylates and subse-
quent intramolecular cyclization after N-O bond reduc-
tion (eq 1).
* To whom correspondence should be addressed: Fax: +34 976
762075. E-mail: pmerino@posta.unizar.es.
(1) (a) Zhang, R.; Mamai, A.; Madalengoitia, J . S. J . Org. Chem.
1999, 64, 547-555. (b) Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron
1999, 55, 261-270. (c) Weir, C. A.; Taylor, C. M. J . Org. Chem. 1999,
64, 1554-1558. (d) Hart, B. P.; Rapoport, H. J . Org. Chem. 1999, 64,
2050-2056. (e) David, O.; Blot, J .; Bellec, C.; Fargeau-Bellassoued,
M. C.; Haviari, G.; Ce´le´rier, J .-P.; Lhommet, G.; Gramain, J .-C.;
Gardette, D. J . Org. Chem. 1999, 64, 3122-3131. (f) Yokoyama, M.;
Momotake, A. Synthesis 1999, 1541-1554. (g) de Koning, H.; Hiemstra,
H.; Moolenaar, M. J .; Speckamp, W. N. Eur. J . Org. Chem. 1998, 1729,
9-1737. (h) van der Deen, H.; Cuiper, A. D.; Hof, R. P.; van Oeveren,
A.; Feringa, B. L.; Kellogg, R. M. J . Am. Chem. Soc. 1996, 118, 3801-
3803. (i) Remuzon, P. Tetrahedron 1996, 52, 13803-13835.
(2) (a) Falb, E.; Bechor, Y.; Nudelman, A.; Hassner, A.; Albeck, A.;
Gottlieb, H. E. J . Org. Chem. 1999, 64, 498-506. (b) Shibano, M.;
Nakamura, S.; Motoya, N.; Kusano, G. Chem. Pharm. Bull. 1956, 4,
472-476. (c) Limbert, G.; Lundt, I.; Zavilla, J . Synthesis 1999, 178-
183. (d) Yoda, H.; Shimojo, T.; Takabe, K. Tetrahedron Lett. 1999, 40,
1335-1336. (e) Blanco, M. J .; Sardina, F. J . J . Org. Chem. 1998, 63,
3411-3416. (f) J ager, V.; Muller, R.; Leibold, T.; Hein, M.; Schwarz,
M.; Fengler, M.; J aroskova, L.; Patzel, M.; Leroy, P.-Y. Bull. Soc. Chim.
Belg. 1994, 103, 491-507.
(3) (a) Takebayashi, M.; Hiranuma, S.; Kanie, Y.; Kajimoto, T.;
Kanie, O.; Wong, C.-H. J . Org. Chem. 1999, 64, 5280-5291. (b) Delair,
P.; Brot, E.; Kanazawa, A.; Greene, A. E. J . Org. Chem. 1999, 64,
1383-1386. (c) Schwardt, O.; Veith, U.; Gaspard, C.; J ager, V.
Synthesis 1999, 1473-1490. (d) O’Hagan, D. Nat. Prod. Rep. 1997,
14, 637-651. (e) Plunkett, A. O. Nat. Prod. Rep. 1994, 11, 581-590.
(4) (a) Katritzky, A. R.; Cui, X. L.; Yang, B.; Steel, P. J . J . Org. Chem.
1999, 64, 1979-1985. (b) Serino, C.; Stehle, N.; Park, Y. S.; Florio, S.;
Beak, P. J . Org. Chem. 1999, 64, 1160-1165. (c) Schnell, B.; Bernar-
dinelli, G.; Kundig, E. P. Synlett 1999, 348-350. (d) Dudot, B.; Micouin,
L.; Baussane, I.; Royer, J . Synthesis 1999, 688-694. (e) Rassu, G.;
Zanardi, F.; Battistini, L.; Casiraghi, G. Synlett 1999, 1333-1350. (f)
Ma, D.; J iang, J . Tetrahedron: Asymmetry 1998, 9, 575-579. (g) Pichon,
M.; Frigadere, B. Tetrahedron: Asymmetry 1996, 7, 927-964. (h)
Sardina, F. J .; Rapoport, H. Chem. Rev. 1996, 96, 1825-1872. (i) Steele,
J . Contemp. Org. Synth. 1994, 1, 95-111. (j) Li, W.-R.; Han, S.-Y.;
J oullie, M. M. Heterocycles 1993, 36, 359-388. (k) Galeazzi, R.; Mobbili,
G.; Orena, M. In Targets in Heterocyclic Systems; Attanasi, O., Spinelli,
D., Eds.; Italian Chemical Society: Rome, 1997; Vol. 1, pp 355-400.
(5) Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245-
2303 and references therein.
With the goal of developing a simple route to protected
derivatives of 1, we envisioned that a similar synthetic
strategy using furfuryl nitrones 2 could be used to
construct the pyrrolidine ring. As we12 and others13 have
(6) Lee, Y. K.; Kaneko, T. Bull. Chem. Soc. J pn. 1973, 46, 3494-
3498.
(7) Gefflaut, T.; Bauer, U.; Ariola, K.; Koskinen, A. M. P. Tetrahe-
dron: Asymmetry 1996, 7, 3099-3102.
(8) Ohta, T.; Hosoi, A.; Nozoe, S. Tetrahedron Lett. 1988, 29, 329-
332.
(9) Heinz, L. J .; Lunn, W. H. W.; Murff, R. E.; Paschal, J . W.;
Spangle, L. A. J . Org. Chem. 1996, 61, 4838-4841.
(10) Tejero, T.; Dondoni, A.; Rojo, I.; Merchan, F. L.; Merino, P.
Tetrahedron 1997, 53, 3301-3318.
(11) (a) Shimazaki, M.; Okazaki, F.; Nakasima, F.; Ishikawa, T.;
Ohta, A. Heterocycles 1993, 36, 1823-1836. (b) White, J . D.; Badger,
R. A.; Kezar, H. J ., III; Pallenberg, A. J .; Schieser, G. A. Tetrahedron
1989, 45, 6631-6644. (c) Burdisso, M.; Gamba, A.; Gandolfi, R.
Tetrahedron 1988, 44, 3735-3548. (d) Herczegh, P.; Kovacs, I.; Szilagyi,
L.; Varga, T.; Dinya, Z.; Sztaricskai, F. Tetrahedron Lett. 1993, 34,
1211-1214. (e) Coutouli-Argyropoulou, E.; Malamidou-Xenikaki, E.;
Stampelos, X. N.; Alexopoulou, I. N. Tetrahedron 1997, 53, 707-718.
(12) (a) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. J . Org.
Chem. 1998, 63, 5627-5630. (b) Dondoni, A.; J unquera, F.; Merchan,
F. L.; Merino, P.; Scherrmann, M.-C.; Tejero, T. J . Org. Chem. 1997,
62, 5484-5496. (c) Dondoni, A.; Franco, S.; J unquera, F.; Merchan, F.
L.; Merino, P.; Tejero, T. J . Org. Chem. 1997, 62, 5497-5507. (d)
Dondoni, A.; J unquera, F.; Merchan, F. L.; Merino, P.; Tejero, T.
Synthesis 1994, 1450-1454.
10.1021/jo991560n CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/17/2000

Notes
J . Org. Chem., Vol. 65, No. 5, 2000 1591
Ta ble 1. 1,3-Dip ola r Cycloa d d iton of Nitr on es 2 w ith
Alk en es 3
Sch em e 1
product ratioa
yieldb
entry
R
X
reaction conditions
neat/reflux/5 h
CH2Cl2/reflux/48 h 40 54
1,2-DCE/reflux/16 h 28 58 14
toluene/reflux/12 h 22 58 20
CHCl3/reflux/24 h
1,2-DCE/reflux/16 h 16 67 13
toluene/reflux/12 h 27 73
4
5
6
7
(%)
1
2
3
4
5
6
7
8
9
Bn
OMe
OMe
OMe
OMe
OMe
OEt
17 70 13
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
80
60
96
68
93
75
68
90
85
76
96
91
85
91
56
85
88
85
78
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
6
36 50 14
OEt
0
0
0
0
sultam CH2Cl2/reflux/48 h 15c 85c
sultam 1,2-DCE/reflux/24 h 16c 84c
sultam toluene/reflux/16 h 39c 61c
10 Bn
11 PMB OMe
12 PMB OMe
13 PMB OMe
14 PMB OMe
15 PMB OEt
16 PMB OEt
toluene/reflux/12 h 22 61 17
1,2-DCE/reflux/16 h 19 64 17
CH2Cl2/reflux/9 d
neat/reflux/5h
toluene/reflux/16 h 27 63 10
CH2Cl2/reflux/9 d 20 69 11
20 60 20
10 82
8
17 PMB sultam CH2Cl2/reflux/48 h 22c 78c
18 PMB sultam 1,2-DCE/reflux/24 h 25c 75c
19 PMB sultam toluene/reflux/16 h 45c 55c
0
0
0
previously demonstrated, the furan ring provides an
excellent template for the efficient introduction of a
masked carbonyl group. The presence of a surrogate of a
carboxylic acid is crucial for obtaining the target com-
pounds. It can be anticipated that a carboxyl group at
C-3 of the isoxazolidine ring (R1dCOOR2) could lead to
competitive cyclization with the emerging hydroxyl group
after the reduction of the N-O bond. Hence, it seems
more advisable to construct the pyrrolidine ring by in situ
cyclization rather than from γ-hydroxyglutamic acid.
a
Measured by integration of the corresponding signals in the
1H NMR spectra. Isolated yield of mixture of isomers. c Only one
diastereoisomer was observed at the limit of detection by NMR
spectroscopy (diastereofacial selectivity >25:1).
b
be explained qualitatively by the FMO method. Compar-
ing energy values (PM3) of nitrones with those of acry-
lates, the reaction results in controlled HOMOnitrone
LUMOalkene, the predominant interaction being derived
from the preferential combination between the atoms
with larger orbital coefficients. Addition of Lewis acids
such as MgBr2, Et2O, ZnBr2, or Et2AlCl only led to slow
reactions that did not show significant differences in
regio- and diastereoselectivities.
-
Resu lts a n d Discu ssion
Nitrones 2 were prepared according to our previously
reported procedure.14 The Z configuration of both nitrones
were ascertained by NOE experiments and, in the case
of N-benzyl nitrone 2a , confirmed by X-ray analysis.15
Our results in the cycloadditions of 2 with several
acrylates are illustrated in Scheme 1 and Table 1. We
initially investigated the reaction with achiral acrylates
under a variety of conditions, some of which appear in
Table 1 (entries 1-7 and 11-16). In all cases, mixtures
of racemic diastereomeric cycloadducts 4-6 were ob-
tained. The diastereoselectivities of these reactions were
Next, our attention turned to the use chiral auxiliaries
for the acryloyl moiety. Since we10 and others7,17 had
observed satisfactory results with Oppolzer’s chiral sul-
tam in similar reactions, we chose N-acryloyl-(2R)-
bornane-10,2-sultam 3c as the dipolarophile. Thus, ad-
dition of 3c to nitrones 2 gave the diastereomeric
isoxazolidines 4/5 in the cis/trans ratios indicated in
Table 1 (entries 8-10 and 17-19) and with a complete
stereoface discrimination at the limit of detection by
NMR (>95:5). This result is in marked contrast with our
previous findings on thiazolyl nitrones that presented a
complete control of regioselectivity and cis/trans diaste-
reoselectivity but a lower level of asymmetric induction.10
On the other hand, the result obtained with nitrones 2
is more consistent with previous 1,3-dipolar cycloaddi-
tions of dipolarophile 3c.7,18
1
measured by H NMR (300 MHz) on the crude reaction
products. The obtained cycloadducts were separated by
preparative, centrifugally accelerated, radial, thin-layer
chromatography with a Chromatotron. The regiochem-
istry of the adducts was evident from analysis of their
1H NMR spectra. The relative trans (endo) stereochem-
istry of 5 and 6 and the cis (exo) stereochemistry of 4
were readily deduced by means of NOE measurements.
The high 3,5-regioselectivity and preference for the endo
approach (leading to trans adducts) is comparable to that
obtained in similar reactions involving other heterocyclic
nitrones.10,11e,16 In fact, the observed regioselectivity can
Indeed, the observed difference in selectivity is well
reproduced by calculations of the transition states. We
attempted an explanation of the selectivity on the basis
of semiempirical calculations. These methods are more
practical and allow the treatment of molecular structures
of relevant size (such as sultam-containing adducts 4-7),
(13) (a) Marshall, J . A.; Luke, G. P. J . Org. Chem. 1993, 58, 6229-
6234. (b) Danishefsky, S. J .; Pearson, W. H.; Segmuller, B. E. J . Am.
Chem. Soc. 1985, 107, 1280-1285. (c) Danishefsky, S. J .; DeNinno,
M. P.; Chen, S. J . Am. Chem. Soc. 1988, 110, 3929-3940. (d) Kang, S.
H.; Lee, S. B. Tetrahedron Lett. 1993, 34, 7579-7582. (e) Mukaiyama,
T.; Tsuzuki, R.; Kato, S. Chem. Lett. 1985, 837-840.
(14) Dondoni, A.; Franco, S.; J unquera, F.; Merchan, F. L.; Merino,
P.; Tejero, T. Synth. Commun. 1994, 24, 2537-2550.
(15) The authors have deposited atomic coordinates for the structure
of 2a with the Cambridge Crystallographic Data Centre. The coordi-
nates can be obtained, on request, from the director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.
(16) Malamidou-Xenikaki, E.; Stampelos, X. N.; Coutouli-Argy-
ropoulou, E.; Cardin, C. J .; Teixeira, S.; Kavounis, C. A. J . Chem. Soc.,
Perkin Trans. 1 1997, 949-957.
(17) (a) Kim, B. H.; Lee, J .-Y. Tetrahedron: Asymmetry 1991, 2,
1359-1370. (b) Kanemasa, S.; Onimura, K.; Wada, E.; Tanaka, J .
Tetrahedron: Asymmetry 1991, 2, 1185-1188. (c) Curran, D. P.; Kim,
B. H.; Daugherty, J .; Heffner, T. A. Tetrahedron Lett. 1988, 29, 3555-
3558.
(18) Oppolzer, W.; Poli, G.; Starkemann, C.; Bernardinelli, G.
Tetrahedron Lett. 1988, 29, 3559-3562.

1592 J . Org. Chem., Vol. 65, No. 5, 2000
Notes
Ta ble 2. Sem iem p ir ica l a n d a b In itio En er gies of
which precludes the use of high-level ab initio methods.19
For comparison, all optimized structures were calculated
at both AM1 and PM3 levels.20 Single-point energy
calculations were also carried out at the RHF/6-31G* and
B3LYP/6-31G* levels using PM3 geometries.21
Gr ou n d Sta tes, Tr a n sition Str u ctu r es, a n d Ad d u cts for
Cycloa d d ition s of 2a w ith 3ca
AM1
(kcal
PM3
(kcal
mol-1
RHF/
B3LYP/
6-31G*c,d
(hartrees)
6-31G* c,d
(hartrees)
structure
mol-1
)
)
The optimized geometries of the nitrone 2a and alkene
3c showed the expected bond lengths and angles. In fact,
rather similar structural data were obtained when the
optimized geometry of 2a was compared with its X-ray
structure. In a similar way, the optimized geometry of
alkene 3c was in good agreement with previously pro-
posed conformations for that compound.17c The TSs for
the four different approaches of 3c to 2a were located by
the calculation of a reaction path profile starting from
optimized geometries of the corresponding final adducts,
followed by an optimization of the TS with respect of all
structural variables. The TSs were characterized through
the calculation of the force constant matrix by ensuring
that they had one and only one imaginary harmonic
vibrational frequency corresponding to the formation of
new bonds. Both sides of the reaction path were also
investigated starting from each transition state by using
the internal reaction coordinate procedure. In all cases,
it could be verified that the TSs proceed from the reac-
tants and give rise to the products. The results are sum-
marized in Table 2 and the TSs illustrated in Figure 1.
As expected for 1,3-dipolar cycloadditions, all TSs were
asynchronous, the newly created C-O bond being formed
to a greater extent than the C-C bond. Interestingly,
whereas PM3, RHF/6-31G*, and B3LYP/6-31G* calcula-
tions correctly identify the favored products correspond-
ing to approach of nitrone by the Re face of dipolarophile
3c, AM1 does not predict correctly the observed selectiv-
ity. For this reason, AM1 values will not be considered
further in this work. The transition states TSRe/en d o and
TSRe/exo for Re attack are clearly more stable than attack
from the opposite Si face, thus explaining the excellent
diastereofacial selectivity observed for the reaction. The
calculated TS energies for endo (TSRe/en d o) and exo
(TSRe/exo) approaches indicate that the reaction should
lead to the formation of cis/trans mixtures of cycload-
ducts.
nitrone 2a b
alkene 3c
27.460
9.049 -435.316 150 3 -437.948 927 6
-73.408 -92.631 -1179.773 702 3 -1185.333 677 6
TS exo/Re -21.438 -47.748 -1615.033 071 7 -1623.256 391 8
(24.51) (35.83) (35.63) (16.45)
-19.542 -41.547 -1615.010 269 1 -1623.237 849 4
(26.41) (42.04) (49.94) (28.08)
TS endo/Re -23.563 -49.563 -1615.035 656 7 -1623.258 832 0
(22.39) (34.02) (34.00) (14.89)
TS endo/Si -21.893 -44.585 -1615.011 421 2 -1623.240 147 4
TS exo/Si
(24.06)
(39.00)
(49.22)
(26.64)
(3S,5R)-4e -72.657 -111.248 -1615.125 300 3 -1623.302 079 4
(3R,5S)-4f -72.096 -106.662 -1615.122 071 6 -1623.298 255 2
(3R,5R)-5g -74.624 -111.876 -1615.126 896 7 -1623.303 061 6
(3S,5S)-5h -74.476 -106.054 -1615.124 792 1 -1623.300 314 5
a
For TSs, potential energy barriers are given in parentheses.
b
For simplicity, the N-benzyl group of the nitrone was replaced
by a methyl group. c Single-point calculations using PM3 geom-
etries. Energy barriers given in kcal mol-1
.
e From TS exo/Re.
d
f From TS exo/Si. From TS endo/Re. From TS endo/Si.
g
h
and accounts for both the cis/trans and diastereofacial
selectivity of the reaction.
Returning to the synthetic methodology, inseparable
mixtures of 4/5 were obtained in cycloaddition reactions
of both 2a and 2b.22 The isoxazolidine ring of cycloadducts
4 and 5 was subsequently transformed into a pyrrolidin-
2-one ring by reduction (Zn/AcOH) of the N-O bond
followed by in situ lactamization (Scheme 2). From this
reaction, pyrrolidin-2-ones 8 and 9 could be easily
separated by column chromatography, and the chiral
auxiliarysthe Oppolzer’s sultamswas recovered in high
yield (ca. 92%). Since better results in the cycloaddition
reaction were obtained with N-benzyl nitrone 2a , we
chose the corresponding pyrrolidines 8a and 9a for
further transformations.
The relative cis/trans stereochemistry of chiral isox-
azolidines 4c,f and 5c,f were assigned by comparing the
optically pure pyrrolidin-2-ones 8/9 with the same com-
pounds obtained previously in a racemic form. The
absolute configuration and stereochemical integrity of the
compounds 8 and 9 were determined by preparation of
corresponding Mosher esters. Analysis of the 300 MHz
NMR spectra of these esters showed the presence of only
one diastereoisomer in each case, at the limit of detection,
indicating enantiomeric purity >98%. Racemic products
obtained from methyl/ethyl acrylate cycloaddition and
further cyclization were used as reference materials.23
The absolute configuration of 8 and 9 was ascertained
by employing the Kakisawa method24 on the Mosher
esters derived from both racemic and optically pure
compounds.23
The lowest calculated TS energy is for the endo
approach of the nitrone to the Re face of the alkene, thus
predicting the formation of (3R,5R) isomer preferentially.
These results are in agreement with the experimental
data observed for cycloadditions of nitrones 2a and 2b
(19) Several comparative studies have suggested semiempirical
methods as a good choice for studying cycloaddition processes involving
chiral substrates. See: (a) Sbai, A.; Branchadell, V.; Ortun˜o, R. M.;
Oliva, A. J . Org. Chem. 1997, 62, 3049-3054. (b) Annunziata, R.;
Benaglia, M.; Cinquini, M.; Cozzi, F.; Raimondi, L. J . Org. Chem. 1995,
60, 4697-4706.
(20) Semiempirical geometry optimizations for all systems were
carried out at the AM1 and PM3 levels of theory as implemented in
WINMOPAC 2.0. Fujitsu Limited. 1998. For simplicity, the N-benzyl
group of the nitrone 2a was replaced with a methyl group.
(21) Ab initio single point energy calculations were performed using
Gaussian 98, Revision A.3: Frisch, M. J .; Trucks, G. W.; Schlegel, H.
B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.;
Montgomery J r., J . A.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.;
Millam, J . M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.;
Tomasi, J .; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli,
C.; Adamo, C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P.
Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu,
G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R.
L.; Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara,
A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B.; Chen,
W.; Wong, M. W.; Andres, J . L.; Gonzalez, C.; Head-Gordon, M.;
Replogle, E. S.; Pople, J . A. Gaussian, Inc., Pittsburgh, PA, 1998.
To further illustrate the utility of compounds 8a and
9a as precursors of versatile building blocks, we under-
took the preparation of differentially protected deriva-
tives of 4-hydroxy pyroglutamic acids. The cyclization
products 8a and 9a formed in the reduction of cycload-
(22) After tedious chromatographic separations enriched mixtures
of diastereomers could be obtained in order to identify selected signals
from the NMR spectra (see the Experimental Section). Nevertheless,
subsequent reduction-cyclization to diastereomeric pyrrolidin-2-ones
afforded separable mixtures of isomers.
(23) See the Supporting Information for the detailed discussion.
(24) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092-4096.

Notes
J . Org. Chem., Vol. 65, No. 5, 2000 1593
F igu r e 1. Transition-state structures for 1,3-dipolar cycloaddition of 2a and 3c.
Sch em e 2
Sch em e 4
Sch em e 3
Sch em e 5
ducts 4c and 5c, respectively, were acetylated in es-
sentially quantitative yield. Subjection of the correspond-
ing acetylated compounds 10 to ruthenium-mediated
oxidation (RuO2-NaIO4) followed by esterification of the
resulting carboxylic acid with diazomethane delivered the
protected 4-hydroxypyroglutamic acid derivatives 11
(Scheme 3).
Debenzylation of compounds 8a and 9a was achieved,
without affecting the furan ring, by using lithium in
liquid ammonia. Attempted introduction of a tert-butoxy-
carbonyl group at the nitrogen atom with Boc2O under a
variety of conditions in compounds 12 returned only
starting material. Other less common N-Boc protection
conditions examined without success included Boc-ON,
tert-butylchloroformate, and BocONH2.25 However, treat-
ment of 12 with TBSCl in the presence of imidazole
yielded silylated compounds 13, which were amenable
to protection with Boc2O to provide 14 in good chemical
yield. Oxidation of the furan ring as described above
proceeded smoothly for both isomers to provide after
esterification the protected derivatives 15 (Scheme 4).
Furthermore, additional confirmation of the absolute
configuration of pyrrolidin-2-ones synthesized was
achieved by reducing (BH3-DMS)26 and desilylating com-
pounds 15a and 15b to give protected cis-4-hydroxy-D-
proline 16a and trans-4-hydroxy-L-proline 16b, respec-
tively (Scheme 5). Comparison of the spectroscopic data
(1H and 13C NMR) and optical rotation data with the
reported literature values for 16a 27 and 16b28 verified the
previously assigned absolute configuration. In addition,
and given the complexity of NMR spectra (due to the
presence of rotamers), compounds 16a and 16b were also
prepared from commercial cis-4-hydroxy-D-proline and
trans-4-hydroxy-L-proline, respectively.
(26) Langlois, N.; Andriamialisoa, R. Z. Tetrahedron Lett. 1991, 32,
3057-3058.
(27) Peterson, M. L.; Vince, R. J . Med. Chem. 1991, 34, 2787-2797.
(28) Schumaker, K. K.; J iang, J .; J oullie, M. M. Tetrahedron:
Asymmetry 1998, 9, 47-53.
(25) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons: New York, 1991.

1594 J . Org. Chem., Vol. 65, No. 5, 2000
Notes
(bs, 2H), 3.75 (s, 3H), 3.90 (dd, 1H, J ) 5.8, 7.1 Hz), 3.94 and
4.08 (2d, 2H, J ) 13.8), 4.19 (t, 1H, J ) 7.3), 5.28 (dd, 1H, J )
5.6, 9.1 Hz), 6.30 (m, 2H), 6.82 (m, 2H), 7.31 (m, 2H), 7.37 (dd,
1H, J ) 0.9, 1.7 Hz).
Su m m a r y
In summary, an asymmetric 1,3-dipolar cycloaddition
with furfuryl nitrones has been used to synthesize
protected derivatives of cis- and trans-4-hydroxy pyro-
glutamic acids by short and efficient sequences. These
derivatives would appear to be particularly attractive for
preparing a variety of nitrogenated compounds endowed
with similar structures. Moreover, the sense of induction
could be reversed by employing the antipodal dipolaro-
phile in the cycloaddition step, thus being accessible all
stereoisomers. The utilization of this chemistry in the
context of natural products and related compounds
synthesis is being explored in our laboratory.
5f (selected signals): 1H NMR (CDCl3, 55 °C) δ 0.92 and 1.10
(2s, 6H), 1.71-1.86 (m, 4H), 1.90-2.02 (m, 2H), 2.08-2.12 (m,
1H), 2.82 (ddd, 1H, J ) 6.9, 7.9, 12.7 Hz), 2.92 (dt, 1H, J ) 6.9,
12.7 Hz) 3.25 and 3.31 (2d, 2H, J ) 13.6 Hz), 3.72 (s, 3H), 3.83
(dd, 1H, J ) 5.2, 7.2 Hz), 3.92 and 4.00 (2d, 2H, J ) 13.8), 4.28
(t, 1H, J ) 6.9), 5.11 (dd, 1H, J ) 6.9, 7.9 Hz), 6.27 (m, 2H),
6.79 (m, 2H), 7.25 (m, 2H), 7.35 (bs, 1H).
(3R ,5R )-1-Be n zyl-5-(2-fu r yl)-3-h yd r oxyp yr r olid in -2-
on e (8a ) a n d (3R,5S)-1-Ben zyl-5-(2-fu r yl)-3-h yd r oxyp yr r o-
lid in -2-on e (9a ). To a solution of a mixture of cycloadducts 4c
and 5c (0.471 g, 1 mmol) in THF (10 mL) were added AcOH (20
mL) and H2O (10 mL). The resulting solution was treated with
Zn dust (0.4 g, 6.1 mmol) and heated at 60 °C for 5 h. The reac-
tion mixture was allowed to cool to room temperature and fil-
tered; the filtrate was treated with saturated aqueous Na2SO4,
and the resulting mixture was extracted with CH2Cl2. The com-
bined organic extracts were dried (MgSO4) and evaporated under
reduced pressure. Column chromatography on silica gel (Et2O/
EtOAc, 95:5) of the residue gave the pure pyrrolidin-2-ones. Elu-
ted first was recovered (2R)-bornane-10,2-sultam (0.198 g, 92%).
Eluted second (9a ): 0.033 g, 13%; white solid; mp 91-93 °C;
[R]D +10.7 (c 1.10, CHCl3); 1H NMR (CDCl3) δ 2.22 (dt, 1H, J )
8.8, 13.0 Hz), 2.54 (ddd, 1H, J ) 2.1, 8.8, 13.0 Hz), 3.66 and
4.97 (2d, 2H, J ) 14.7 Hz), 4.30 (bs, 1H, ex. D2O), 4.48 (dd, 1H,
J ) 2.1, 8.8 Hz), 4.80 (t, 1H, J ) 8.8 Hz), 6.16 (dd, 1H, J ) 0.8,
3.3 Hz), 6.30 (dd, 1H, J ) 1.8, 3.3 Hz), 7.30-7.18 (m, 5H), 7.39
(dd, 1H, J ) 0.8, 1.8 Hz); 13C NMR (CDCl3) δ 33.8, 44.8, 51,5,
69.1, 108.5, 110.3, 127.7, 128.3, 128.7, 135.5, 143.0, 151.8, 175.1.
Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found:
C, 70.28; H, 5.59; N, 5.27.
Exp er im en ta l Section
Gen er a l Meth od s. For general experimental information see
ref 29. Furfuryl nitrones 214 and N-acryloyl-(2R)-bornane-10,2-
sultam 3c17a were prepared as described.
Gen er a l P r otocol for th e Cycloa d d ition of Nitr on es (2)
w ith Acr yla tes (3). To a solution of the appropriate nitrone 2
(1 mmol) in CH2Cl2 (10 mL) was added the corresponding
acrylate 3 (5 mmol), and the resulting mixture was heated at
reflux under Ar atmosphere for 48 h. The solvent was evapo-
rated, and the product ratio was established by 1H NMR
analysis. The residue was purified by preparative, centrifugally
accelerated, radial, thin-layer chromatography (Chromatotron).
Spectroscopic and analytical data for racemic compounds are
given in the Supporting Information.
N-[[(3S,5R)-2-Ben zyl-3-(2-fu r yl)-5-isoxa zolid in yl]ca r bo-
n yl]-(2R)-bor n a n e-10,2-su lta m (4c) a n d N-[[(3R,5R)-2-Ben -
zyl-3-(2-fu r yl)-5-isoxa zolid in yl]ca r b on yl]-(2R)-b or n a n e-
10,2-su lta m (5c). Nitrone 2a (0.2 g, 1 mmol) and N-acryloyl-
(2R)-bornane-10,2-sultam 3c (1.35 g, 5 mmol) were allowed to
react according to the general protocol detailed above. The
residue was purified by column chromatography on silica gel
(hexane/EtOAc, 30:70) to separate the excess of dipolarophile
and to afford 0.425 g (90%) of a 15:85 mixture of two diastere-
omers. Purification of this mixture with a Chromatotron using
hexane/EtOAc, 20:80 as eluent gave an almost pure sample of
5c (eluted first) and a mixed fraction of 4c and 5c. 4c (selected
signals): 1H NMR (CDCl3, 55 °C) δ 0.85 and 1.05 (2s, 6H), 1.85-
1.94 (m, 4H), 2.00-2.08 (m, 2H), 2.11-2.15 (m, 1H), 2.83 (dt,
1H, J ) 8.6, 12.6 Hz), 3.14 (ddd, 1H, J ) 5.2, 8.6, 12.6 Hz) 3.28
and 3.45 (2d, 2H, J ) 13.7 Hz), 3.75 (dd, 1H, J ) 5.5, 7.5 Hz),
3.94 and 4.02 (2d, 2H, J ) 13.8), 4.34 (t, 1H, J ) 8.6), 5.00 (dd,
1H, J ) 5.2, 8.6 Hz), 6.27 (m, 2H), 7.20-7.40 (m, 6H).
Eluted third (8a ): 0.188 g, 73%; white solid; mp 134-136 °C;
1
[R]D -7.6 (c 0.42, CHCl3); H NMR (CDCl3) δ 2.23 (dt, 1H, J )
8.6, 12.9 Hz), 2.67 (ddd, 1H, J ) 6.8, 8.6, 12.9 Hz), 3.32 (bs, 1H,
ex. D2O), 3.61 and 4.89 (2d, 2H, J ) 14.7 Hz), 4.41 (t, 1H, J )
8.6 Hz), 4.43 (dd, 1H, J ) 6.8, 8.6 Hz), 6.25 (dd, 1H, J ) 0.7, 3.2
Hz), 6.34 (dd, 1H, J ) 1.8, 3.2 Hz), 7.11-7.30 (m, 5H), 7.39 (dd,
1H, J ) 0.7, 1.8 Hz); 13C NMR (CDCl3) δ 33.8, 44.8, 51.3, 69.4,
110.1, 110.4, 127.6, 128.3, 128.6, 136.0, 143.3, 150.6, 174.1. Anal.
Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.16;
H, 5.70; N, 5.61.
(3R,5R)-1-(p-Meth oxyben zyl)-5-(2-fu r yl)-3-h yd r oxyp yr -
r olid in -2-on e (8b) a n d (3R,5S)-1-(p-Meth oxyben zyl)-5-(2-
fu r yl)-3-h yd r oxyp yr r olid in -2-on e (9b). The same procedure
described above for the conversion of a mixture of 4c and 5c to
8a and 9a was applied to a mixture of cycloadducts 4f and 5f
(0.500, 1 mmol). After column chromatography on silica gel
(Et2O/EtOAc, 90:10) of the crude product, the pure pyrrolidin-
2-ones 8b and 9b were obtained. Eluted first was recovered (2R)-
bornane-10,2-sultam (0.194 g, 90%).
Eluted second (9b): 0.055 g, 19%; sticky foam; [R]D +23.4 (c
1.26, CHCl3); 1H NMR (CDCl3) δ 2.17 (dt, 1H, J ) 8.3, 13.1 Hz),
2.50 (ddd, 1H, J ) 2.1, 8.3, 13.1 Hz), 3.12 (bs, 1H, ex. D2O), 3.57
and 4.90 (2d, 2H, J ) 14.6 Hz), 3.75 (s, 3H), 4.46 (dd, 1H, J )
2.1, 8.3 Hz), 4.75 (t, 1H, J ) 8.3 Hz), 6.20 (dd, 1H, J ) 0.9, 3.2
Hz), 6.31 (dd, 1H, J ) 1.7, 3.2 Hz), 6.80 (m, 2H), 7.1 (m, 2H),
7.40 (dd, 1H, J ) 0.9, 1.7 Hz); 13C NMR (CDCl3) δ 33.8, 44.1,
50.9, 55.1, 69.2, 108.4, 110.3, 114.0, 128.4, 129.5, 142.9, 151.8,
159.1, 174.8. Anal. Calcd for C16H17NO4: C, 66.89; H, 5.96; N,
4.88. Found: C, 66.74; H, 5.78; N, 4.95.
Eluted third (8b): 0.198 g, 69%; white solid; mp 91-93 °C;
[R]D -10.1 (c 1.01, CHCl3); 1H NMR (CDCl3) δ 2.20 (dt, 1H, J )
8.8, 12.8 Hz), 2.65 (ddd, 1H, J ) 6.8, 8.1, 12.8 Hz), 3.06 (bs, 1H,
ex. D2O), 3.54 and 4.84 (2d, 2H, J ) 14.5 Hz), 3.76 (s, 3H), 4.39
(dd, 1H, J ) 8.1, 8.8 Hz), 4.40 (dd, 1H, J ) 6.8, 8.8 Hz), 6.24
(dd, 1H, J ) 0.7, 3.2 Hz), 6.35 (dd, 1H, J ) 1.8, 3.2 Hz), 6.80 (m,
2H), 7.05 (m, 2H), 7.40 (dd, 1H, J ) 0.7, 1.8 Hz); 13C NMR
(CDCl3) δ 33.8, 44.1, 51.2, 55.2, 69.4, 109.9, 110.4, 113.9, 128.1,
129.7, 143.2, 150.8, 159.0, 174.2. Anal. Calcd for C16H17NO4: C,
66.89; H, 5.96; N, 4.88. Found: C, 66.95; H, 6.03; N, 4.97.
(3R,5R)-3-Acet oxy-1-b en zyl-5-(2-fu r yl)p yr r olid in -2-on e
(10a ). A solution of 8a (0.257 g, 1 mmol) in pyridine (2 mL) was
treated with Ac2O (2 mL) and DMAP (2.4 mg, 0.02 mmol). The
resulting mixture was stirred at room temperature for 10 h, and
5c (selected signals): 1H NMR (CDCl3, 55 °C) δ 0.85 and 1.05
(2s, 6H), 1.78-1.92 (m, 4H), 2.02-2.06 (m, 2H), 2.10-2.14 (m,
1H), 2.88-2.95 (m, 2H), 3.26 and 3.35 (2d, 2H, J ) 13.5 Hz),
3.85 (dd, 1H, J ) 5.3, 7.3 Hz), 4.00 and 4.08 (2d, 2H, J ) 13.9),
4.38 (t, 1H, J ) 7.1), 5.15 (dd, 1H, J ) 5.8, 8.0 Hz), 6.34 (m,
2H), 7.18-7.40 (m, 6H); 13C NMR (CDCl3, 55 °C) δ 18.8, 19.4,
26.5, 28.3, 32.5, 35.8, 44.5, 49.0, 49.4, 52.7, 60.7, 62.3, 65.2, 75.8,
108.3, 110.4, 127.8, 128.2, 128.9, 137.4, 142.6, 150.9, 170.4.
N-[[(3S,5R)-2-(p -Met h oxyb en zyl)-3-(2-fu r yl)-5-isoxa zo-
lidinyl]carbonyl]-(2R)-bornane-10,2-sultam (4f)and N-[[(3R,5R)-
2-(p-m eth oxyben zyl)-3-(2-fu r yl)-5-isoxazolidin yl]car bon yl]-
(2R)-bor n a n e-10,2-su lta m (5f). Nitrone 2b (0.231 g, 1 mmol)
and N-acryloyl-(2R)-bornane-10,2-sultam 3c (1.35 g, 5 mmol)
were allowed to react according to the general protocol detailed
above. The residue was purified by column chromatography on
silica gel (hexane/EtOAc, 30:70) to separate the excess of
dipolarophile and to afford 0.440 g (88%) of a 22:78 mixture of
two diastereomers. Purification of this mixture with a Chroma-
totron using hexane/EtOAc, 25:75, as eluent afforded mixed
fractions of 4f and 5f.
4f (selected signals): 1H NMR (CDCl3, 55 °C) δ 0.97 and 1.13
(2s, 6H), 1.72-1.90 (m, 4H), 2.00-2.12 (m, 3H), 2.60 (ddd, 1H,
J ) 5.6, 7.2, 12.8 Hz), 3.04 (ddd, 1H, J ) 7.4, 9.1, 12.8 Hz) 3.35
(29) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. J . Org.
Chem. 1996, 61, 9028-9032.

Notes
J . Org. Chem., Vol. 65, No. 5, 2000 1595
then CH2Cl2 (20 mL) and H2O (15 mL) were added. The organic
layer was washed sequentially with saturated aqueous CuSO4
and brine, dried (MgSO4), and evaporated under reduced pres-
sure to give the crude product. Purification by column chroma-
tography on silica gel (hexane/Et2O, 40:60) gave 10a (0.300 g,
100%) as a sticky oil; [R]D -33.0 (c 0.98, CHCl3); 1H NMR (CDCl3)
δ 2.05 (s, 3H), 2.10 (dt, 1H, J ) 8.4, 13.2 Hz), 2.66 (ddd, 1H, J
) 7.1, 8.4, 13.2 Hz), 3.56 and 4.79 (2d, 2H, J ) 14.7 Hz), 4.36
(dd, 1H, J ) 7.1, 8.4 Hz), 5.32 (t, 1H, J ) 8.4 Hz), 6.23 (dd, 1H,
J ) 0.8, 3.2 Hz), 6.34 (dd, 1H, J ) 1.8, 3.2 Hz), 6.98-7.25 (m,
5H), 7.30 (dd, 1H, J ) 0.8, 1.8 Hz); 13C NMR (CDCl3) δ 22.6,
31.7, 44.7, 51.2, 70.0, 110.0, 110.3, 127.5, 128.3, 128.4, 135.6,
143.2, 150.2, 169.6, 170.1. Anal. Calcd for C17H17NO4: C, 68.21;
H, 5.72; N, 4.68. Found: C, 68.44; H, 5.61; N, 4.80.
was added, and the ammonia was allowed to evaporate. The
mixture was concentrated, and the residue was purified by
column chromatography on silica gel (EtOAc) to afford 12a
(0.154 g, 95%) as a white powder: mp 130-132 °C; [R]D -7.6 (c
1
0.11, CHCl3); H NMR (CDCl3) δ 2.02-2.10 (m, 1H), 2.74 (ddd,
1H, J ) 6.5, 8.0, 12.6 Hz), 3.55 (bs, 1H, ex. D2O), 4.30 (dd, 1H,
J ) 8.0, 9.5 Hz), 4.68 (dd, 1H, J ) 6.5, 9.2 Hz), 5.65 (bs, 1H),
6.28-6.38 (m, 2H), 7.28 (m, 1H); 13C NMR (CDCl3) δ 37.3, 47.9,
69.8, 107.4, 111.2, 143.4, 155.2, 176.9. Anal. Calcd for C8H9-
NO3: C, 57.48; H, 5.43; N, 8.38. Found: C, 57.33; H, 5.21; N,
8.12.
(3R,5S)-5-(2-F u r yl)-3-h yd r oxyp yr r olid in -2-on e (12b). The
same procedure described above for the conversion of 8a to 12a
was applied to compound 9a (0.1 g, 0.39 mmol). After column
chromatography on silica gel (EtOAc) of the crude product, pure
12b (0.061 g, 94%) was obtained as white solid: mp 68-70 °C;
[R]D -10.5 (c 0.15, CHCl3); 1H NMR (CDCl3) δ 2.32 (dt, 1H, J )
8.3, 13.2 Hz), 2.49 (ddd, 1H, J ) 2.2, 8.2, 13.2 Hz), 3.46 (bs, 1H,
ex. D2O), 4.54 (t, 1H, J ) 8.2 Hz), 4.73 (dd, 1H, J ) 2.2, 8.4 Hz),
5.65 (bs, 1H), 6.18 (bd, 1H, J ) 3.3 Hz), 6.22 (dd, J ) 1.8, 3.3
Hz), 7.27 (bd, 1H, J ) 1.8 Hz); 13C NMR (CDCl3) δ 35.3, 48.6,
68.3, 106.3, 110.2, 142.4, 153.7, 178.6. Anal. Calcd for C8H9-
NO3: C, 57.48; H, 5.43; N, 8.38. Found: C, 57.39; H, 5.55; N,
8.24.
(3R,5S)-3-Acet oxy-1-b en zyl-5-(2-fu r yl)p yr r olid in -2-on e
(10b). The same procedure described above for the conversion
of 8a to 10a was applied to compound 9a (0.077 g, 0.3 mmol).
After column chromatography on silica gel (hexane/Et2O, 40:
60) of the crude product, pure 10b (0.090 g, 100%) was obtained
1
as a sticky oil: [R]D -12.8 (c 0.52, CHCl3); H NMR (CDCl3) δ
2.13 (s, 3H), 2.17 (dt, 1H, J ) 8.8, 13.3 Hz), 2.63 (ddd, 1H, J )
2.2, 8.8, 13.3 Hz), 3.60 and 5.01 (2d, 2H, J ) 14.7 Hz), 4.47 (dd,
1H, J ) 2.2, 8.8 Hz), 5.64 (t, 1H, J ) 8.8 Hz), 6.17 (dd, 1H, J )
0.7, 3.2 Hz), 6.29 (dd, 1H, J ) 1.8, 3.2 Hz), 7.15-7.35 (m, 6H);
13C NMR (CDCl3) δ 20.9, 32.1, 44.8, 51.4, 70.6, 109.4, 110.9,
127.9, 128.4, 128.7, 135.4, 144.0, 152.0, 170.0, 171.2. Anal. Calcd
for C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found: C, 68.00; H,
5.69; N, 4.76.
(3R,5R)-3-(ter t-Bu tyld im eth ylsiloxy)-5-(2-fu r yl)p yr r oli-
d in -2-on e (13a ). To a warmed (70 °C), stirred solution of 12a
(0.150 g, 0.90 mmol) and imidazole (0.368 g, 5.4 mmol) in
anhydrous DMF (4 mL) was added tert-butyldimethylsilyl
chloride (0.407 g, 2.7 mmol). The mixture was stirred at 70 °C
for 18 h and then cooled to ambient temperature, treated with
MeOH (1 mL), stirred for additional 15 min, diluted with H2O,
and extracted with EtOAc. The combined organic extracts were
dried (MgSO4) and evaporated under reduced pressure. Purifica-
tion of the crude product by column chromatography on silica
gel (hexane/EtOAc, 60:40) gave 13a (0.223 g, 88%) as a white
solid: mp 72-74 °C; [R]D +1.8 (c 0.23, CHCl3); 1H NMR (CDCl3)
δ 0.09 and 0.11 (2s, 6H), 0.86 (s, 9H), 2.11 (dt, 1H, J ) 8.8, 12.6
Hz), 2.66 (ddd, 1H, J ) 6.7, 7.7, 12.6 Hz), 4.33 (dd, 1H, J ) 7.7,
8.8 Hz), 4.56 (dd, 1H, J ) 6.7, 8.8 Hz), 6.23 (bd, 1H, J ) 3.2
Hz), 6.26 (dd, J ) 1.8, 3.2 Hz), 7.20 (bs, 1H), 7.30 (bd, 1H, J )
1.8 Hz); 13C NMR (CDCl3) δ -5.1, -4.4, 18.3, 25.8, 37.5, 47.7,
(3R,5R)-3-Acetoxy-1-ben zyl-5-(m eth oxyca r bon yl)p yr r o-
lid in -2-on e (11a ). To a well-stirred mixture of CH3CN, (9.5 mL),
CCl4 (6.3 mL), and H2O (9.5 mL) were added sequentially NaIO4
(0.98 g, 4.6 mmol) and RuO2‚H2O (12.2 mg, 0.092 mmol). The
mixture was stirred vigorously at room temperature. After 30
min, NaHCO3 (1.9 g, 23 mmol) was added in one portion followed
by 4.6 mL of H2O. After 15 min, the resulting mixture was
treated with a solution of 10a (0.275 g, 0.92 mmol) in CH3CN
(0.7 mL). The solution turned black, and after 5 min enough
NaIO4 (ca. 0.250 g) was added in small portions to turn the color
light green. The mixture was diluted with water (10 mL) and
extracted with AcOEt (3 × 15 mL). The aqueous layer was
acidified with 1 N HCl to pH ) 2-3 and reextracted with AcOEt
(3 × 20 mL). The combined organic extracts were washed
sequentially with 20% aqueous NaHSO3 until colorless and then
with brine and dried (MgSO4), and the solvent was evaporated
under reduced pressure. The crude acid was dissolved in Et2O
(20 mL), and the solution was cooled to 0 °C and treated with
an ethereal solution of diazomethane until a slight yellow color
persisted. The excess of diazomethane was eliminated by
quenching with acetic acid. The resulting solution was concen-
trated under reduced pressure, and the crude ester was purified
by column chromatography on silica gel (hexane/Et2O, 50:50)
to give 11a (0.236 g, 88%) as an oil: [R]D -16.2 (c 0.55, CHCl3);
1H NMR (CDCl3) δ 2.00 (dt, 1H, J ) 6.4, 13.9 Hz), 2.07 (s, 3H),
2.77 (dt, 1H, J ) 8.5, 13.9 Hz), 3.65 (s, 3H), 3.92 (dd, 1H, J )
6.4, 8.5 Hz), 4.13 and 5.13 (2d, 2H, J ) 14.9 Hz), 5.29 (dd, 1H,
J ) 6.4, 8.5), 7.10-7.30 (m, 5H); 13C NMR (CDCl3) δ 20.6, 29.9,
45.8, 52.5, 55.4, 69.5, 128.0, 128.4, 128.7, 134.8, 170.0, 170.1,
170.8. Anal. Calcd for C15H17NO5: C, 61.85; H, 5.88; N, 4.81.
Found: C, 61.93; H, 6.01; N, 4.72.
(3R,5S)-3-Acetoxy-1-ben zyl-5-(m eth oxyca r bon yl)p yr r o-
lid in -2-on e (11b). The same procedure described above for the
conversion of 10a to 11a was applied to compound 10b (0.075
g, 0.25 mmol). After column chromatography on silica gel
(hexane/Et2O, 50:50) of the crude product, pure 11b (0.063 g,
87%) was obtained as an oil: [R]D -6.7 (c 0.52, CHCl3); 1H NMR
(CDCl3) δ 2.15 (dt, 1H, J ) 8.9, 13.4 Hz), 2.15 (s, 3H), 2.64 (ddd,
1H, J ) 1.5, 8.9, 13.4 Hz), 3.67 (s, 3H), 4.00 (dd, 1H, J ) 1.5,
8.9 Hz), 4.06 and 4.98 (2d, 2H, J ) 14.8 Hz), 5.46 (t, 1H, J )
8.9), 7.20-7.40 (m, 5H); 13C NMR (CDCl3) δ 20.8, 30.6, 46.2, 52.7,
55.9, 69.7, 128.1, 128.7, 128.8, 134.7, 170.2, 170.5, 171.3. Anal.
Calcd for C15H17NO5: C, 61.85; H, 5.88; N, 4.81. Found: C, 61.77;
H, 5.72; N, 4.90.
70.4, 106.4, 110.4, 142.4, 154.0, 175.7. Anal. Calcd for C14H23
-
NO3Si: C, 59.75; H, 8.24; N, 4.98. Found: C, 59.69; H, 8.11; N,
5.05.
(3R,5S)-3-(ter t-Bu tyld im eth ylsiloxy)-5-(2-fu r yl)p yr r oli-
d in -2-on e (13b). The same procedure described above for the
conversion of 12a to 13a was applied to compound 12b (0.060
g, 0.36 mmol). After column chromatography on silica gel
(hexane/EtOAc, 60:40) of the crude product, pure 13b (0.094 g,
93%) was obtained as an oil: [R]D -3.6 (c 0.17, CHCl3); 1H NMR
(CDCl3) δ 0.14 and 0.16 (2s, 6H), 0.91 (s, 9H), 2.33 (ddd, 1H, J
) 6.4, 7.9, 13.0 Hz), 2.47 (ddd, 1H, J ) 4.0, 7.4, 13.0 Hz), 4.43
(dd, 1H, J ) 6.4, 7.4 Hz), 4.76 (dd, 1H, J ) 4.0, 7.9 Hz), 5.80
(bs, 1H), 6.17 (dd, 1H, J ) 0.8, 3.2 Hz), 6.29 (dd, J ) 1.8, 3.2
Hz), 7.34 (dd, 1H, J ) 0.8, 1.8 Hz); 13C NMR (CDCl3) δ -5.1,
-4.5, 18.3, 25.8, 37.4, 48.4, 69.5, 106.1, 110.3, 142.6, 154.4, 175.6.
Anal. Calcd for C14H23NO3Si: C, 59.75; H, 8.24; N, 4.98. Found:
C, 59.86; H, 8.38; N, 4.90.
(3R,5R)-1-(ter t-Bu t oxyca r b on yl)-3-(ter t-b u t yld im et h yl-
siloxy)-5-(2-fu r yl)p yr r olid in -2-on e (14a ). To a solution of 13a
(0.200 g, 0.71 mmol) in dry CH2Cl2 (25 mL) at 0 °C were added
Et3N (0.108 g, 1.06 mmol) and DMAP (13 mg, 0.11 mmol) with
magnetic stirring. After 30 min, a solution of Boc2O (0.186 g,
0.85 mmol) in dry CH2Cl2 (10 mL) was added dropwise. The
resulting reaction mixture was then allowed to warm to ambient
temperature and stirred for additional 18 h. The mixture was
then treated with 1 N aqueous KHSO4 (10 mL). The organic
layer was separated and washed with 1 N aqueous KHSO4,
saturated aqueous NaHCO3, and brine, dried (MgSO4), and
evaporated under reduced pressure. Purification of the residue
by column chromatography on silica gel (hexane/Et2O, 80:20)
afforded 14a (0.244 g, 90%) as a white solid: mp 90-92 °C; [R]D
1
(3R,5R)-5-(2-F u r yl)-3-h yd r oxyp yr r olid in -2-on e (12a ). To
cold (-35 °C) stirred liquid ammonia (35 mL) were added a
solution of 8a (0.250 g, 0.97 mmol) in anhydrous THF (20 mL)
and lithium (0.48 g, 69 mmol). The deep blue solution was stirred
at -35 °C for 2 h while the blue color persisted. Ethanol (3 mL)
+12.2 (c 0.35, CHCl3); H NMR (CDCl3, 55 °C) δ 0.11 and 0.17
(2s, 6H), 0.88 (s, 9H), 1.37 (s, 9H), 2.06 (dt, 1H, J ) 7.4, 13.1
Hz), 2.56 (dt, 1H, J ) 7.4, 13.1 Hz), 4.32 (t, 1H, J ) 7.4 Hz),
4.97 (t, 1H, J ) 7.4 Hz), 6.23 (dd, 1H, J ) 1.1, 3.2 Hz), 6.31 (dd,
J ) 1.8, 3.2 Hz), 7.31 (dd, 1H, J ) 1.1, 1.8 Hz); 13C NMR (CDCl3,

1596 J . Org. Chem., Vol. 65, No. 5, 2000
Notes
55 °C) δ -5.4, -4.6, 18.1, 25.6, 29.7, 34.8, 52.0, 70.7, 83.0, 106.5,
110.4, 141.4, 154.0, 154.5, 172.2. Anal. Calcd for C19H31NO5Si:
C, 59.81; H, 8.19; N, 3.67. Found: C, 59.73; H, 8.24; N, 3.77.
(3R,5S)-1-(ter t-Bu toxyca r bon yl)-3-(ter t-bu tyld im eth ylsi-
loxy)-5-(2-fu r yl)p yr r olid in -2-on e (14b). The same procedure
described above for the conversion of 13a to 14a was applied to
compound 13b (0.090 g, 0.32 mmol). After column chromatog-
raphy on silica gel (Hexane/Et2O, 80:20) of the crude product,
pure 14b (0.112 g, 92%) was obtained as an oil: [R]D -3.0 (c
procedure described above for the conversion of 10a to 11a was
applied to compound 14b (0.100 g, 0.26 mmol). After column
chromatography on silica gel (hexane/Et2O, 80:20) of the crude
product, pure 15b (0.082 g, 84%) was obtained as an oil: [R]D
1
+27.6 (c 0.27, CHCl3); H NMR (CDCl3, 55 °C) δ 0.10 and 0.15
(2s, 6H), 0.87 (s, 9H), 1.48 (s, 9H), 2.18 (ddd, 1H, J ) 9.7, 10.2,
13.2 Hz), 2.23 (ddd, 1H, J ) 1.7, 8.3, 13.2 Hz), 3.76 (s, 3H), 4.39
(t, 1H, J ) 8.3, 10.2 Hz), 4.55 (dd, 1H, J ) 1.7, 9.7 Hz); 13C NMR
(CDCl3, 55 °C) δ -5.3, -4.4, 18.2, 25.7, 27.9, 31.9, 52.7, 55.0,
76.6, 83.9, 149.5, 171.8, 172.0. Anal. Calcd for C17H31NO6Si: C,
54.66; H, 8.37; N, 3.75. Found: C, 54.89; H, 8.24; N, 3.87.
1
1.00, CHCl3); H NMR (CDCl3, 55 °C) δ 0.12 and 0.17 (2s, 6H),
0.89 (s, 9H), 1.43 (s, 9H), 2.25 (ddd, 1H, J ) 9.3, 10.5, 12.8 Hz),
2.46 (dt, 1H, J ) 7.9, 12.8 Hz), 4.70 (dd, 1H, J ) 7.9, 10.5 Hz),
5.16 (dd, 1H, J ) 7.9, 9.3 Hz), 6.19 (dd, 1H, J ) 1.0, 3.2 Hz),
6.29 (dd, J ) 1.7, 3.2 Hz), 7.32 (dd, 1H, J ) 1.0, 1.7 Hz); 13C
NMR (CDCl3, 55 °C) δ -5.2, -4.4, 18.3, 25.8, 28.0, 34.8, 50.9,
70.4, 83.2, 107.0, 110.4, 142.1, 153.5, 154.7, 172.4. Anal. Calcd
for C19H31NO5Si: C, 59.81; H, 8.19; N, 3.67. Found: C, 59.73;
H, 8.24; N, 3.77.
Ack n ow led gm en t. We thank the MEC (Madrid,
Spain) for financial support (DGES, Project PB97-1014)
and for a predoctoral fellowship to one of us (V.T.).
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data,
1H NMR assignments, and NOE data for 4a ,b,d ,e, 5a ,b,d ,e,
and 6a ,b,d ,e. Experimental details for the preparation of 16a
and 16b and characterization data of these compounds. Details
on the determination of the absolute configuration and enan-
tiomeric purity of pyrrolidin-2-ones 8a and 9a by 1H NMR
analysis and characterization data of the corresponding Mosh-
er esters. ORTEP drawing and CIF file of the X-ray structure
(3R,5R)-1-(ter t-Bu t oxyca r b on yl)-3-(ter t-b u t yld im et h yl-
siloxy)-5-(m et h oxyca r b on yl)p yr r olid in -2-on e (15a ). The
same procedure described above for the conversion of 10a to 11a
was applied to compound 14a (0.220 g, 0.58 mmol). After column
chromatography on silica gel (hexane/Et2O, 80:20) of the crude
product, pure 15a (0.184 g, 85%) was obtained as an oil: [R]D
1
+24.4 (c 0.37, CHCl3); H NMR (CDCl3, 55 °C) δ 0.07 and 0.13
(2s, 6H), 0.85 (s, 9H), 1.46 (s, 9H), 1.94 (dt, 1H, J ) 7.1, 12.9
Hz), 2.54 (dt, 1H, J ) 7.7, 12.9 Hz), 3.73 (s, 3H), 4.24 (t, 1H, J
) 7.4 Hz), 4.43 (t, 1H, J ) 7.6 Hz); 13C NMR (CDCl3, 55 °C) δ
-5.4, -4.6, 18.1, 25.6, 27.9, 32.3, 52.5, 55.6, 70.6, 83.8, 149.4,
171.0, 171.4. Anal. Calcd for C17H31NO6Si: C, 54.66; H, 8.37;
N, 3.75. Found: C, 54.47; H, 8.31; N, 3.69.
of 2a . Cartesian coordinates of the transition states TSRe/en d o
,
TSR e/exo, TSSi/en d o, and TSSi/en d o at the PM3 level of theory.
Copies of 1H and 13C NMR spectra of final products 11a ,b and
15a ,b. This material is available free of charge via the Internet
at http;//pubs.acs.org.
(3R,5S)-1-(ter t-Bu toxyca r bon yl)-3-(ter t-bu tyld im eth ylsi-
loxy)-5-(m eth oxyca r bon yl)p yr r olid in -2-on e (15b). The same
J O991560N