Enantiomerically pure polyheterocyclic spiro-β-lactams from trans-4-hydroxy-l-proline

Article abstract of DOI:10.1021/jo100061s

"Chemical Equation Presented" The "Staudinger ketene-imine reaction" between ketenes generated from natural O,N-protected trans-4-hydroxy-L-prolines and the N-benzyl-N-benzylideneamine led to mixtures of diastereoisomeric, enantiomerically pure pyrrolidin

Full text of DOI:10.1021/jo100061s

pubs.acs.org/joc
Enantiomerically Pure Polyheterocyclic Spiro-β-lactams from
trans-4-Hydroxy-L-proline
Giuseppe Cremonesi,† Piero Dalla Croce,‡ Francesco Fontana,‡ and Concetta La Rosa*,†
, †DISMAB - Sezione di Chimica Organica “A. Marchesini”, and ‡Dipartimento di Chimica Organica e
Industriale, Universitaꢀ degli Studi di Milano, V. Venezian 21, I-20133 Milano, Italy
concetta.larosa@unimi.it
Received January 18, 2010
The “Staudinger ketene-imine reaction” between ketenes generated from natural O,N-protected
trans-4-hydroxy-L-prolines and the N-benzyl-N-benzylideneamine led to mixtures of diastereo-
isomeric, enantiomerically pure pyrrolidine-derived spiro-β-lactams with a relative cis configuration.
These were transformed into the corresponding pyrroline-spiro-β-lactams by means of treatment
with a base and the new CdC double bond was submitted to a number of different reactions
in order to evaluate its reactivity and obtain new polyheterocyclic enantiomerically pure spiro-β-
lactams.
Introduction
Their use as synthetic intermediates in organic chemistry
(the β-lactam synthon method)2 and recent discoveries of
their different biological activities3-8 have led to increasing
interest in them and their asymmetric synthesis, particularly
by means of a Staudinger ketene-imine reaction,9 which
makes it possible to obtain mono, di-, tri-, and even spiro-
cyclic β-lactams.
β-Lactam rings are key structures in the most widely used
antibiotics and of great interest to medicinal chemistry.1
(1) For reviews on antibiotic activity of β-lactams, see: (a) Morin, R. B.;
Gorman, M. Chemistry and Biology of β-Lactam Antibiotics; Academic Press:
New York, 1982; Vols. 2-3. (b) Page, M. I. The Chemistry of β-Lactams;
Chapman and Hall: London, 1992. (c) Coulton, S.; Hunt, E. In Recent Progress in
the Chemical Synthesis of Antibiotics and Related Microbial Products; Lukacs,
G., Ed.; Springer-Verlag: Berlin, 1993; Vol. 2, p 621.
(2) (a) Ojima, I. Acc. Chem. Res. 1995, 28, 383. (b) Palomo, C.; Aizpurua,
J. M.; Ganboa, I.; Oiarbide, M. Curr. Med. Chem. 2004, 11, 1837. (c) Juaristi,
E.; Soloshonok, V. In Synthesis of β-Amino Acids and Their Derivatives from
β-Lactams: An Update; Wiley: New York, 2005; p 477.
(6) For biological activity as anti-hyperglycemic agents, see: Goel, R. K.;
Mahajan, M. P.; Kulkarni, S. K. J. Pharm. Pharmaceut. Sci. 2004, 7, 80.
(7) For biological activity as anticancer agents, see: Kazi, A.; Hill, R.;
Long, T. E.; Kuhn, D. J.; Turos, E.; Dou, Q. P. Biochem. Pharmacol. 2004,
67, 365.
(3) For biological activity as thrombin inhibitors, see: Han, W. T.;
Trehan, A. K.; Wright, J. J. K.; Federici, M. E.; Seiler, S. M.; Meanwell,
N. A. Bioorg. Med. Chem. 1995, 3, 1123.
(8) For biological activity as leukocyte elastase inhibitors, see: Cainelli,
G.; Galletti, P.; Garbisa, S.; Giacomini, D.; Sartor, L.; Quintavalle, A.
Bioorg. Med. Chem. 2003, 11, 5391.
(4) For biological activity as cholesterol absorption inhibitors, see:
(a) Burnett, D. A.; Caplen, M. A.; Davis, H. R., Jr.; Burrier, R. E.; Clader,
J. W. J. Med. Chem. 1994, 37, 1733. (b) Vaccaro, W. D.; Sher, R.; Davis,
H. R., Jr. Bioorg. Med. Chem. Lett. 1998, 8, 35. (c) Vaccaro, W. D.; Davis,
H. R., Jr. Bioorg. Med. Chem. Lett. 1998, 8, 313.
(5) For biological activity as neuroprotection, see: Rothstein, J. D.; Patel,
S.; Regan, M. R.; Haenggelli, C.; Huang, Y. H.; Bergles, D. E.; Jin, L.;
Hoberg, M. D.; Vidensky, S.; Chung, D. S.; Toan, S. V.; Bruijn, L. I.; Su,
Z. Z.; Gupta, P.; Fisher, P. B. Nature 2005, 433, 73.
(9) (a) Isaacs, N. S. Chem. Soc. Rev. 1976, 5, 181. (b) Ghosez, L.; Marchand-
Brynaert, S. In Comprehensive Organic Synthesis; Trost, B., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 5, p 85. (c) Georg, G. I.; Ravikumar, V. T. In The
Organic Chemistry of β-Lactams; Georg, G. I., Ed.; Verlag Chemie: New York,
1993; p 295. (d) DeKimpe, N. In Comprehensive Heterocyclic Chemistry II;
Katrizky, A. R., Rees, C. W., Scriven, E. F. V., Padwa, A., Eds.; Pergamon: Oxford,
1996; Vol. 1B, p 507. (e) Miller, M. J., Ed. Recent Aspects of the Chemistry of β-
Lactams-II. Tetrahedron 2000, 56, 5553. (f) Singh, G. S. Tetrahedron 2003, 59,
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2010 J. Org. Chem. 2010, 75, 2010–2017
Published on Web 02/26/2010
DOI: 10.1021/jo100061s
r
2010 American Chemical Society

Cremonesi et al.
JOCArticle
Structures with a spiro-β-lactam skeleton have attracted
the attention of medicinal chemists because of their antiviral10a
and antibacterial properties,10b and because they inhibit
cholesterol absorption.10c In peptidomimetic chemistry,
spiro-β-lactams are used as β-turn mimetics11 and synthetic
precursors of cyclic R,R-disubstituted β-amino acids and
peptidomimetics,12 which is why their synthesis has aroused
particular interest.13
We have previously described our studies of the synth-
esis14 and reactivity15 of heterocyclic spiro-β-lactams. In
particular, we were interested in producing various substi-
tuted 4-spiro-β-lactams by means of a Staudinger reaction
between imines and nonsymmetrical cyclic ketenes generated
from cyclic N-acyl R-amino acids. At the same time, we also
realized the stereoselective synthesis of 4-spiro-β-lactams
using ketenes obtained from chiral, enantiomerically pure
N-acyl R-amino acids.15c,16
Achieving enantiopure β-lactams always arouses consid-
erable interest because of their various important biological
activities. With this in mind, and recalling our previous work
on the use of natural trans-4-hydroxy-L-proline as a cyclic N-
substituted R-amino acid,16a we decided to use this substrate
(conveniently N,O-protected) as a chiral synthon for the
stereoselective synthesis of spiro-β-lactams susceptible to
further transformation. We have already used this amino
acid as a profitable precursor for the stereoselective synthesis
of heterocyclic compounds, such as pyrrolidine-derived
spiro-β-lactams and condensed bicyclic imidazoles.16a More
recently, Thiruvazhi et al. have described the use of trans-4-
hydroxy-L-proline derivatives as precursors of the chiral
cyclic ketenes used in a Staudinger synthesis of enantiopure
pyrrolidine-derived spiro-β-lactams.17 In addition to allow-
ing asymmetric induction, we considered that the presence of
the conveniently protected hydroxyl group on the pyrroli-
dine ring could allow further modifications of the pyrrolidine
ring. In fact, carrying out a base-promoted elimination
reaction converting pyrrolidine-derived spiro-β-lactams into
pyrroline-derived spiro-β-lactams17 makes it possible to
introduce a versatile double bond that we have conceived
to test toward a series of olefin reactions, such as cycloaddi-
tion reactions and oxidation and cyclopropanation reac-
tions, thus leading to chemical diversity from the same
precursor. These transformations could afford new poly-
heterocyclic spiro-β-lactams, interesting compounds as such.
Additionally, these spiro-β-lactams derivatives could be used
as potential scaffolds to construct β-turn mimetics. In fact,
proline-derived spirocyclic β-lactams have already been
shown to exhibit valuable conformational properties useful
for their utilization as efficient β-turn nucleators.11 The
modification of proline ring and in particular the introduc-
tion of a fused ring, could establish a further restriction of the
conformational freedom of the peptide chain, providing
structural stabilization when incorporated into a peptide.
Although many practical and theoretical studies have been
carried out since the Staudinger reaction was first described
more than 100 years ago,18 its rationalization (and, conse-
quently, its stereochemical course) is still debated.19 In
general, the stereochemistry of the products depends on the
nature of the substrates (stereoelectronic aspects) and the
experimental conditions. The use of different protecting
groups on the pyrrolidine nitrogen, besides influencing the
course of the Staudinger reaction, could also be opportune in
case the subsequent transformations may be unsuited to one
of them. As a consequence, we have designed a method to use
N-carbobenzyloxy- or N-tert-butoxycarbonyl-trans-4-hy-
droxy-L-proline derivatives as starting materials in the Stau-
dinger reaction.
Results and Discussion
Synthesis of Pyrroline-Spiro-β-lactams. First, we synthe-
sized (2S,4R)-4-methanesulfonyloxypyrrolidine-1,2-dicar-
boxylic acid 1-benzyl or 1-tert-butyl esters 1a and 1b as
convenient ketene precursors following known procedures
(Scheme 1). Compound 1a17 was quantitatively obtained
starting from commercially available N-Cbz-(4R)-hydroxy-
L-proline. Compound 1b was synthesized starting from
trans-4-hydroxy-L-proline, which was transformed into the
(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidine-
carboxylic acid20 and then O-protected using Schafer meth-
€
od21 with 34% total yield.
The geometry and electronic properties of imines also play
a key role in the Staudinger reaction. We have previously and
extensively used electron-rich (E)-N-benzylidene-1-phenyl-
methanamine 215b,16b as a convenient imine partner for
the Staudinger reaction, not least because of the gain in β-
lactam stability due to the N-benzyl substitution, and so
imine 2 was allowed to react with 4-hydroxy-L-proline
derivatives 1a,b.
(10) (a) Skiles, J. W.; McNeil, D. Tetrahedron Lett. 1990, 31, 7277.
(b) Sheehan, J. C.; Chacko, E.; Lo, Y. S.; Ponzi, D. R.; Sato, E. J. Org.
Chem. 1978, 43, 4856. (c) Wu, G.; Tormos, W. J. Org. Chem. 1997, 62, 6412 and
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Gonzalez, J. J. Org. Chem. 2001, 66, 6333. (b) Bittermann, H.; Gmeiner, P.
J. Org. Chem. 2006, 71, 97.
(12) Alonso, E.; del Pozo, C.; Gonzalez, J. Synlett 2002, 69.
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(b) Trabocchi, A.; Lalli, C.; Guarna, F.; Guarna, A. Eur. J. Org. Chem.
2007, 4594. (c) Chincholkar, P. M.; Puranik, V. G.; Rakeeb, A.; Deshmukh,
A. S. Synlett 2007, 2242. (d) Chincholkar, P. M.; Puranik, V. G.; Deshmukh,
(18) Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51.
(19) For an overview on the mechanism of the Staudinger reaction, see:
(a) Hegedus, L. S.; Montgomery, J.; Narukaua, Y.; Snustad, D. C. J. Am.
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Chem. Soc. 1991, 113, 5784. (b) Lopez, R.; Sordo, T. L.; Sordo, J. A.;
A. S. Tetrahedron 2007, 63, 9179. (e) Rojas-Lima, S.; Santillan-Sid, L.;
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Lopez-Ruiz, H.; Alvarez-Hernandez, A. Heterocycles 2007, 71, 531.
(14) (a) Dalla Croce, P.; Ferraccioli, R.; La Rosa, C. Tetrahedron 1995,
51, 9385. (b) Dalla Croce, P.; Ferraccioli, R.; La Rosa, C. Tetrahedron 1999,
55, 201. (c) Cremonesi, G.; Dalla Croce, P.; La Rosa, C. Tetrahedron 2004,
60, 93.
(15) (a) Dalla Croce, P.; La Rosa, C. Heterocycles 2000, 53, 2653.
(b) Cremonesi, G.; Dalla Croce, P.; La Rosa, C. Helv. Chim. Acta 2005,
88, 1580. (c) Cremonesi, G.; Dalla Croce, P.; Fontana, F.; La Rosa, C.
Tetrahedron: Asymmetry 2008, 19, 554.
(16) (a) Dalla Croce, P.; La Rosa, C. Tetrahedron: Asymmetry 1999, 10,
1193. (b) Cremonesi, G.; Dalla Croce, P.; Fontana, F.; Forni, A.; La Rosa, C.
Tetrahedron: Asymmetry 2005, 16, 3371.
(17) Khasanov, A. B.; Ramirez-Weinhouse, M. M.; Webb, T. R.;
Thiruvazhi, M. J. Org. Chem. 2004, 69, 5766.
Gonzalez, J. J. Org. Chem. 1993, 58, 7036. (c) Arrieta, A.; Cossio, F. P.;
Lecea, B.; Ugalde, J. M. J. Am. Chem. Soc. 1994, 116, 2085. (d) Arrieta, A.;
Lecea, B.; Cossio, F. P. J. Org. Chem. 1998, 63, 5869. (e) Alonso, E.; del Pozo,
C.; Gonzalez, J. J. Chem. Soc., Perkin Trans. 1 2002, 571. (f) Macias, A.;
Alonso, E.; del Pozo, C.; Venturini, A.; Gonzales, J. J. Org. Chem. 2004, 69,
7004. (g) Jiao, L.; Liang, Y.; Xu, J. J. Am. Chem. Soc. 2006, 128, 6060.
(h) Wang, Y.; Liang, Y.; Jiao, L.; Du, D. M.; Xu, J. J. Org. Chem. 2006, 71,
6983. (i) Weatherwax, A.; Abraham, C. J.; Lectka, T. Org. Lett. 2005, 7, 3461.
(j) Cossio, F. P.; Arrieta, A.; Sierra, M. A. Acc. Chem. Res. 2008, 41, 925.
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(20) Qiu, X.; Qing, F. J. Org. Chem. 2002, 67, 7162.
(21) (a) US 6,124,472, 2000. (b) Bernard, H.; B€ulow, G.; Lange, U. E. W.;
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Mack, H.; Pfeiffer, T.; Schafer, B.; Seitz, W.; Zierke, T. Synthesis 2004, 2367.
J. Org. Chem. Vol. 75, No. 6, 2010 2011

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SCHEME 1
We applied our usual method to activate the proline
carboxylic group and generate in situ the intermediate
ketene15c by heating a mixture of amino acids 1a,b, imine
2, and 2-chloro-1-methylpyridinium iodide, Mukaiyama’s
reagent, in the presence of TEA in refluxing dichloro-
methane for 24 h. In the case of 1a, the reaction with imine
2 afforded a diastereoisomeric mixture of the two spiro-β-
lactams (3R,4S,7R)-3a and (3S,4R,7R)-4a in a ratio of 1.7:1,
both of which have been shown to have a relative cis
configuration between N-Cbz and phenyl groups.17 In this
case, the stereochemical results and obtained ratio were
almost the same when the activator reagent of the amino
acid was changed (acyl chloride17 versus ester with Mukaiya-
ma’s reagent). A different course was observed when the N-
Boc-protected precursor 1b was used because only the
corresponding N-Boc-protected spiro-β-lactam 3b was ob-
tained, as shown by the 1H NMR spectra of the crude
reaction mixture. Compound 3b was obtained in 45% yield,
along with about 30% of unreacted 1b and a mixture of
unidentified products. This different result could be ascribed
to a minor reactivity of the ketene and/or zwitterionic
intermediates owing to a larger steric encumbrance gener-
ated by the contiguous N-Boc group. The 1H NMR spectra
of 3b (recorded at T = 55 °C to avoid the complication due to
the existence of rotamers about the carbamate bond) showed
a close relation with 3a, thus suggesting the analogous
structure (3R,4S,7R)-3b (Scheme 1). This assignment was
successively confirmed by means of chemical transformation
of 3b into a known compound (vide infra).
Having exhausted the role of the hydroxylated stereo-
center in the amino acid ring as a chiral auxiliary, subsequent
removal of methansulfonic acid makes it possible to intro-
duce the desired double bond in order to obtain the corre-
sponding pyrroline derivatives. The elimination reaction on
compounds 3a, 4a, and 3b was performed by means of basic
treatment, but once again, the behavior of the products was
different. Treatment of N-Cbz-protected 3a and 4a with
K2CO3 (in methanol at T = 65 °C for 8 h) led to the enantio-
meric pyrroline-spiro-β-lactams (3R,4S)-5a and (3S,4R)-50a
in high yields,17 but the same conditions were unsuccessful in
the case of the N-Boc derivative 3b as the reaction remained
incomplete even after prolonging the time, adding more
K2CO3, or using different bases. Finally, we found that
treatment with excess t-BuOK in tert-butyl alcohol at T =
75 °C for 3 h provided the desired enantiopure pyrroline
spiro-β-lactam (3R,4S)-5b in excellent yield (Scheme 1).
Like those of 5a (5.83 and 6.07 ppm), the alkene protons of
5b resonate at 5.90 and 6.09 ppm: these values and the
absence of any signals at about 7.0 ppm suggest that the
double bond is between C-7 and C-8 for both compounds,
thus denying the possibility of a C-6/C-7 double bond in the
isolated products.22 Furthermore, the chemical shift values
for protons H-6 (at 4.2-4.4 ppm for 5a and at 3.82-
4.17 ppm for 5b) confirmed their R-position in relation to
the pyrroline nitrogen atom.23
Compound 5b was used to confirm the (3R,4S) absolute
configurations of 3b: hydrogenation of the double bond
followed by elimination of the N-Boc group allowed to
obtain a compound having the same optical rotation than
the known compound (3R,4S)-2-benzyl-3-phenyl-2,5-diaza-
spiro[3.4]octan-1-one.17
At this point, taking into account the lower yields of
intermediates 1b and 3b and the useful availability of both
the enantiomeric pyrroline derivatives 5a,50a, we decided to
use these latter as the reference substrates in the following
series of olefin reactions.
Cycloaddition Reactions of Pyrroline-Spiro-β-lactams. The
regio- and stereochemical behavior of the double bond of
compound 5a was evaluated in relation to the [4 þ 2] and [3 þ
2] cycloaddition reactions, with the aim of obtaining new
functionalized tricyclic β-lactams. It was first submitted to
the Diels-Alder reaction using various electron-rich dienes
such as Danishefsky’s diene or reactive cyclic dienes such
as in situ depolymerized cyclopentadiene, cyclohexadiene,
and furan. Different reaction conditions, varying solvents
(toluene, CH2Cl2, DMF), reaction temperature (from 50 to
170 °C), or pressure (from 1 to 5 atm), using irradiation with
microwaves or ultrasound and even adding Lewis acids as
catalysts (Yb(OTf)3 or EtAlCl2), showed a complete lack of
reactivity of alkene 5a. Indeed, it was always recovered
unchanged from the reaction mixtures. We also tested an
electron-poor cyclic diene (methyl coumalate),24 but once
(22) Donohoe, T. J.; House, D. J. Org. Chem. 2002, 67, 5015.
(23) Oliveira, D. F.; Miranda, P. C. M. L.; Correia, C. R. D. J. Org. Chem.
1999, 64, 6646.
(24) Chen, C.; Liao, C. Org. Lett. 2000, 2, 2049.
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SCHEME 2
FIGURE 1
the corresponding value reported for the known compound
(Jcis = 9.5 Hz)28 allowed us to assign the hydrogens a trans
relationship. Despite the poor yield, the stereochemical
outcome of the reaction was excellent because, taking
into account a concerted mechanism, two possible regio-
isomers with three new stereocenters (i.e., a total of eight
stereoisomers) could theoretically be generated. As depicted
in Figure 1, the complete regio- and stereoselectivity ob-
served was explained by the endo approach of the E-nitrone
to the double bond from the less hindered side of the
pyrroline ring. The β-lactam ring is perpendicular to the
pyrroline ring as highlighted by X-ray analysis of very
similar compounds.16 Its presence, and in particular the
steric hindrance of the C-phenyl group, could direct the
nitrone attack from the less hindered side that is opposite
to the C-phenyl group.
again the alkene did not react. This complete lack of reacti-
vity to Diels-Alder cycloadditions is probably partially
attributable to the electronic condition of the starting alkene,
which seems to be neither electron poor nor electron rich, but
mainly to the steric encumbrance generated by the β-lactam
ring perpendicular to the pyrroline ring,16a,25 as examples of
Diels-Alder reactions of sterically less hindered pyrroline
derivative have been reported.26
On the basis of our previous experience in the field of the
1,3-dipolar cycloadditions,27 we treated 5a with different 1,3-
€
Alkene 5a was fully recovered when reacted with ethox-
ycarbonylnitrile oxide in situ generated from the correspond-
ing ethyl chlorooximinoacetate and Et3N,29 but the desired
isoxazolines were obtained using a recently proposed meth-
od.30 Heating a solution of 5a and ethyl nitroacetate in
CHCl3 in a sealed vessel at T=100 °C, in the presence of
catalytic amounts of DABCO, led to rather low yields of the
regioisomeric adducts 8 and 9 (Scheme 2). They were sepa-
rated by means of column chromatography, and their
structures were determined by means of suitable high-
temperature 1H NMR spectra and COSY and NOESY
experiments (DMSO-d6 at T = 120 °C). First, the 1H
NMR spectra allowed us to assign the regiochemistry: in
adduct 9, the proton at the lower chemical shift value of 5.75
δ (i.e., the proton near to the oxygen)31 showed only one
coupling (with H-3a0), whereas the proton at 5.42 δ in adduct
8 also showed a double doublet coupling with one H-60. This
was confirmed by COSY experiments, which made it possi-
ble to assign the chemical shifts to proton H-3a0 in both
compounds. The adducts’ stereochemistry was established
by means of NOESY data: the presence of a positive NOE
effect between H-3a0 and H-6a0 in both 8 and 9 confirmed the
cis junction between the condensed pyrrolidine, and isoxazo-
line rings suggested by their respective coupling constant
values of 9.1 and 8.9 Hz. Finally, the positive NOE effect
observed between H-4 and H-6a0 in 9 was not present
between H-4 and H-3a0 in 8, thus allowing us to assign the con-
figurations (3S,3a0R,4R,6a0S)-8 and (3R,3a0R,4R,6a0S)-9.
dipoles, such as nitrones, nitriloxides, munchnones, and
diazomethane, but the double bond showed very little re-
activity because only the reaction with the C-p-nitrophenyl-
N-phenylnitrone 6 and the ethyl nitroacetate, in the presence
of catalytic amounts of DABCO, afforded new heteropoly-
cyclic-derived spiro-β-lactams. Heating a solution of 5a and
an equimolar amount of C-phenyl-N-methylnitrone in re-
fluxing toluene for 95 h did not afford any product; the
reagents were recovered unchanged. On the contrary, the
reaction of 5a with the more activated and stable C-p-
nitrophenyl-N-phenylnitrone 6 conducted in refluxing to-
luene for 100 h led, in 40% yield, only to the diastereoisomer
1
(3S,30R,3a0R,4R,6a0R)-7 as shown by the H NMR spectra
of the crude reaction mixture (Scheme 2), and unreacted 5a
was recovered in 50% yield. This result was achieved using a
20% molar excess of nitrone 6, but no improvement of the
yield was observed increasing the excess of the nitrone until
2-fold.
The exact stereochemistry of compound 7 was assigned by
comparison with the 1H NMR data of a known similar
compound28 whose absolute stereochemistry had been es-
tablished by X-ray analysis and was confirmed by COSY and
NOESY experiments. In particular, the positive NOE effect
between H-3a0/H-4 and H-3a0/H-6a0observed in 7 made it
possible to assign the shown configurations to the carbons C-
4, C-3a0, and C-6a0. Moreover, the absence of NOE effect
between H-30 and H-3a0 and comparison of the measured
value of the H-30/H-3a0 coupling constant (J = 5.1 Hz) with
(25) Forni, A. Acta Crystallogr. 1998, C54, 1320.
(29) Caldirola, P.; De Amici, M.; De Micheli, C. Tetrahedron 1986, 42,
5267.
(30) (a) Cecchi, L.; De Sarlo, F.; Machetti, F. Tetrahedron Lett. 2005, 46,
7877. (b) Machetti, F.; Cecchi, L.; Trogu, E.; De Sarlo, F. Eur. J. Org. Chem.
2007, 4352.
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Bente, F.; Nielsen, B.; Thomsen, C.; Ebert, B.; De Micheli, C. Eur. J. Org.
Chem. 2006, 5533.
(26) (a) Pandey, S. K.; Orellana, A.; Greene, A. E.; Poisson, J. F. Org.
Lett. 2006, 8, 5665. (b) Arakawa, Y.; Ohnishi, M.; Yoshimura, N.; Yoshifuji,
S. Chem. Pharm. Bull. 2003, 51, 1015.
(27) Dalla Croce, P.; Ferraccioli, R.; La Rosa, C.; Pilati, T. J. Chem. Soc.,
Perkin Trans. 2 1993, 1511 and references cited therein.
(28) Muzychenko, G. F.; Kul’nevich, V. G.; Zharkikh, L. N.; Zavodnik,
V. E.; Motalkin, V. V. Chem. Heterocycl. Compd. 1990, 26, 1392.
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SCHEME 3
SCHEME 4
Analogously to the approach reported in Figure 1, the
formation of the isomer 8 could be ascribe to the concerted
attack of the proposed intermediate30b from the more hin-
dered side of the alkene with the same regiochemistry as that
observed in7. Onthe contrary, 9 may derive fromanattack on
the less hindered side of the alkene, with the opposite regio-
chemistry. The above cycloaddition reactions were also con-
ducted using the enantiomer alkene 50a, which lead to the
enantiomeric cycloadducts 70, 80, and 90.
Cyclopropanation Reaction of Pyrroline-Spiro-β-lactams.
We then approached the reaction of alkene 5a with the
carbene generated by the metal-catalyzed decomposition
of ethyl diazoacetate (EDA).32 This reaction should lead
to the formation of particularly interesting tricyclic spiro-β-
lactams because of their similarity to previously reported
pharmacologically active compounds such as glutamate
agonists.33 Various experimental conditions were tested,
and the best results were obtained using a (CuOTf)2-
benzene complex as catalyst and a large excess of EDA. This
reaction led to the formation of the enantiopure adduct
(1R,2S,40R,5S,6R)-10 in good yield (Scheme 3).
As three new stereocenters were generated, the reaction
once again proceeded with total diastereoselectivity. The
stereochemistry was attributed by means of 1H NMR spectra
and NOESY experiments at high temperature (120 °C,
DMSO-d6) considering the molecular models of all four
possible diastereoisomers. A positive NOE effect was ob-
served between the singlet at 4.89 δ (H-40) and the proton at
2.50 δ. The latter also showed a positive NOE effect with the
proton at δ 2.16, but neither had a positive effect with the
third cyclopropane proton at δ 1.82. Furthermore, the
proton at δ 2.16 showed a positive NOE effect with one of
the two H-4 protons. On the basis of all this spectroscopic
evidence, we were able to assign the signals at δ 2.50, 2.16,
and 1.82 to H-1, H-5, and H-6 protons and the absolute
configurations shown in Scheme 3 to the corresponding
carbons. Also in this case the high degree of stereoselectivity
could be explained as a consequence of the selective attack of
the carbenoid species on the less hindered face of the pyrro-
line ring, opposite the C-40 of the lactam ring.
to the tricyclic derivative (10R,20R,4R,50S)-11 (Scheme 4).34
Once again, the 1H NMR spectra of the crude reaction
mixture confirmed the formation of only one diastereo-
isomer in good yield, whose stereochemical features were
attributed by means of NOESY and 1H NMR experiments at
high temperature (120 °C, DMSO-d6). As in the case of the
assignment mentioned above, the presence of a positive NOE
effect between H-4 (4.91 δ) and the doublet at 4.22 δ (H-10)
suggested the attributed configurations.
syn-Dihydroxylation. We then subjected alkene 5a to syn-
dihydroxylation: various reagents were tried, but the best
results were obtained using catalytic amounts of OsO4 and
N-methylmorpholine N-oxide (NMO) as co-oxidant.35 Un-
fortunately, the reaction led to an inseparable mixture of two
diastereoisomeric diols 12 in 85% yield and a ratio of 83:17,
as detected by 1H NMR analysis (Scheme 4).
Double-Bond Oxidative Cleavage. In order to further
oxidize these diols to the corresponding dialdehyde, the
mixture was treated with a number of oxidizing reagents,36,37
but without any positive result. We therefore decided to
perform the direct oxidative cleavage of the enantiomeric
alkenes 5a and 50a and did so using catalytic OsO4 in the
presence of an excess of NaIO4 either as a co-oxidant and as a
reagent for the following oxidation.38 The desired dialde-
hydes, (3R,4R)-13 and its enantiomer (3S,4S)-130, were ob-
tained in very good yields (Scheme 4).
At this point, we considered the possible transformations
of these versatile products and were particularly attracted by
the possibility of generating spiranic hetereocycles to give
access to new categories of spiro-β-lactams. A preliminary
experiment using hydrazine to obtain the corresponding
triazepine derivative completely failed, but reductive amina-
tion of the dialdehyde led to good results as the treatment of
both enantiomers 13 and 130 with Na(AcO)3BH in the
presence of p-methoxybenzylamine (PMB-NH2) furnished
Oxidation Reactions of Pyrroline-Spiro-β-lactams. The
reactivity of the double bond to oxidation was also consid-
ered. These reactions would produce polyfunctionalized β-
lactams by preserving (epoxidation, syn-dihydroxylation) or
opening the five-membered ring (double-bond oxidative
cleavage).
Epoxidation. We first considered the epoxidation reaction
of 5a, which was easily converted under classical conditions
(34) (a) Chapman, T. M.; Courtney, S.; Hay, P. Chem.;Eur. J. 2003, 9,
3397. (b) Garcia, A. L. L.; Correia, C. R. D. Tetrahedron Lett. 2003, 44, 1553.
(35) Murruzzu, C.; Riera, A. Tetrahedron: Asymmetry 2007, 18, 149.
(36) Giersch, W.; Ohloff, G. Angew. Chem., Int. Ed. 1973, 12, 401.
(37) Quenau, Y.; Krol, W. J.; Bornmann, W. G.; Danishefsky, S. J.
J. Org. Chem. 1992, 57, 4043.
(32) For a recent review on cyclopropanation reactions, see: Pellissier, H.
Tetrahedron 2008, 64, 7041.
(33) Marinozzi, M.; Natalini, B.; Ni, M. H.; Costantino, G.; Pellicciari,
N. Il Farm. 1995, 50, 327.
(38) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478.
2014 J. Org. Chem. Vol. 75, No. 6, 2010

Cremonesi et al.
JOCArticle
the corresponding piperazine-derived spiro-β-lactams (3R,4S)-
14 and (3S,4R)-140, respectively (Scheme 4).39
NMR shows the presence of two rotamers: δ 27.7, 28.0 ((CH3)3C);
45.3, 45.8 (CH2Ph); 54.7, 54.9 (C-6); 66.9, 67.5 (C-3); 79.9, 81.3
((CH3)3C); 84.3, 84.9 (C-4); 126.3-128.9 (Ph); 134.7-138.1 (Ph,
C-7, C-8); 152.4, 153.0 (COO-t-Bu); 168.1, 168.3 (C-1). IR (Nujol):
1692 (νCO, NCOO-t-Bu), 1763 (νCO, N-CO). MS-FABþ (m/z): 391
[MH]þ. Anal. Calcd for C24H26N2O3: C, 73.82; H, 6.71; N, 7.17.
Found: C, 73.79; H 6.72; N, 7.09.
Conclusions
Our studies of the reactivity of the pyrroline-derived spiro-
β-lactams 5a and 50a allowed us to synthesize several new
enantiomerically pure polyfunctionalized β-lactams, some of
which were also susceptible to subsequent transformations,
thus leading to greater chemical diversity. Alkenes 5a and 50a
were generally little reactive against cycloaddition reactions,
but all of the other reactions led to good yields. The
stereochemical outcomes were largely excellent as only one
diastereoisomer was generally obtained. These results can be
attributed to the presence of the β-lactam ring which, by
promoting the attack of the reactant from the less hin-
dered side of the alkene, increases diastereoselectivity. To
the best of our knowledge, the reported compounds are
the first examples of new polyheterocyclic spiro-condensed
β-lactams.
(3S,30R,3a0R,4R,6a0R)-1-Benzyl-30-(4-nitrophenyl)-2-oxo-20,4-
diphenyltetrahydrospiro[azetidine-3,40-pyrrolo[3,4-d]isoxazole]-
50(20H)-carboxylic Acid Benzyl Ester (7). (E)-C-p-Nitrophenyl-
N-phenylnitrone 6 (0.21 g, 0.86 mmol) was added to a solution
of 5a (0.30 g, 0.72 mmol) in toluene (10 mL). The mixture was
heated at reflux temperature for 100 h. The solvent was evapo-
rated under reduced pressure. The residue was treated with hot
MeOH (10 mL) and filtered to afford a colorless crystalline solid
(0.19 g, 40%). Mp: 220-21 °C. [R]20D = þ54.2 (c 0.63, CH2Cl2).
1H NMR (DMSO-d6, T = 120 °C): δ 3.03 (dd, J = 12.8, 6.0, 1H,
H-60); 3.61 (dd, J = 12.8, 1.5, 1H, H-60); 3.89 (dd, J = 7.1, 5.1,
1H, H-3a0); 4.04 (d, J = 15.2, 1H, CH2Ph); 4.68 (s, 1H, H-4);
4.76 (d, J = 15.2, 1H, CH2Ph); 4.78 (d, J = 12.7, 1H, CH2Ph-
(Cbz)); 4.89 (d, J = 12.7, 1H, CH2Ph(Cbz)); 5.27 (dd, J = 5.9,
1.5, 1H, H-6a0); 5.46 (d, J = 5.1, 1H, H-30); 6.89-7.37 (m, 20H,
Ph); 7.70 (d, J = 8.7, 2H, 4-NO2Ph); 8.20 (d, J = 8.7, 2H, 4-
NO2Ph). 13C NMR shows the presence of two rotamers: δ 44.8,
45.0 (C-60); 51.3, 51.7 (CH2Ph); 65.6, 67.0 (C-3a0); 67.5, 68.4
(CH2Ph(Cbz)); 68.9, 69.9 (C-4); 70.6 (C-30); 79.5, 79.7 (C-6a0);
118.5-147.9 (Ph); 153.8, 154.1 (COOCH2Ph); 165.2, 164.5 (C-
2). IR (Nujol): 1710 (νCO, NCOOCH2Ph), 1759 (νCO, N-CO).
MS-FABþ (m/z): 667 [M þ H]þ. Anal. Calcd for C40H34N4O6:
C, 72.06; H, 5.14; N, 8.40. Found: C, 72.00; H 5.02; N, 8.29.
(3R,30S,3a0S,4S,6a0S)-1-Benzyl-30-(4-nitrophenyl)-2-oxo-20,4-
diphenyltetrahydrospiro[azetidine-3,40-pyrrolo[3,4-d]isoxazole]-
50(20H)-carboxylic Acid Benzyl Ester (70). From 50a and (E)-C-p-
nitrophenyl-N-phenylnitrone 6 (45%). [R]20D = -50.1 (c 0.54,
CH2Cl2).
Reaction of 5a with Ethyl R-Nitroacetate. A solution of 5a
(0.29 g, 0.68 mmol), ethyl R-nitroacetate (0.15 mL, 1.37 mmol),
and DABCO (20 mol %, 15 mg, 0.14 mmol) in CHCl3 (10 mL)
was heated in a sealed tube at 100 °C for 65 h. The solvent was
removed under reduced pressure. The products were purified by
means of column chromatography (SiO2, toluene/AcOEt =
98:2).
(3S,3a0R,4R,6a0S)-1-Benzyl-2-oxo-4-phenyl-60,6a0-dihydrosp-
iro[azetidine-3,40-pyrrolo[3,4-d]isoxazole]-30,50(3a0H)-dicarboxylic
Acid 50-Benzyl 30-Ethyl Ester (8). Colorless solid (15%). Mp:
155-6 °C (i-PrOH). [R]20D = -195.9 (c 0.90, CH2Cl2). 1H
NMR (DMSO-d6, T = 120 °C): δ 1.34 (t, J = 7.1, 3H,
COOCH2CH3); 3.11 (dd, J = 13.2, 4.5, 1H, H-60); 3.89 (d,
J = 13.2, 1H, H-60); 4.27 (d, J = 14.8, 1H, CH2Ph); 4.28 (q, J =
7.2, 1H, COOCH2CH3); 4.37 (q, J = 7.1, 1H, COOCH2CH3);
4.67 (d, J = 14.8, 1H, CH2Ph); 4.81 (d, J = 9.1,1H, H-3a0); 4.83
(d, J = 12.5, 1H, CH2Ph(Cbz)); 4.93 (d, J = 12.5, 1H, CH2Ph-
(Cbz)); 5.42 (dd, J = 9.1, 4.5, 1H, H-6a0); 5.65 (s, 1H, H-4);
7.22-7.38 (m, 15H, Ph). 13C NMR shows the presence of two
Experimental Section
General Procedure for the Reactions of 1a,b with 2 and
Mukaiyama’s Reagent. A mixture of 1a or 1b (1.1 mmol), imine
2 (1.0 mmol), 2-chloro-N-methylpyridium iodide (1.2 mmol),
and Et3N (3.0 mmol) in dry CH2Cl2 (15 mL) was heated at reflux
temperature for 16-24 h under a nitrogen atmosphere. After
cooling, the solution was washed with 5% aq HCl, 5% aq
NaHCO3, and then with H2O. The organic layer was dried
(Na2SO4), and the solvent was removed under reduced pressure.
The crude products were purified by flash chromatography
(SiO2, n-exane/AcOEt = 50:50). Spectroscopic data of com-
pounds 3a and 4a were identical to those previously reported.17
(3R,4S,7R)-2-Benzyl-7-methanesulfonyloxy-1-oxo-3-phenyl-
2,5-diazaspiro[3.4]octane-5-carboxylic Acid tert-Butyl Ester
(3b). Colorless solid. Yield: 45%. Mp: 139-141 °C (i-PrOH/
i-Pr2O). [R]20D =-66.4 (c=0.53inCHCl3).1HNMR(T=50°C):
δ = 1.33 (s, 9H, (CH3)3C); 2.59 (dd, J = 13.2, 6.5, 1H, H-8); 2.77
(dd, J = 13.2, 8.5, 1H, H-8); 3.08 (s, 3H, SO2CH3); 3.47 (dd, J =
12.2, 7.2, 1H, H-6); 3.68 (m, 1H, H-6); 4.14 (d, J = 14.7, 1H,
CH2Ph); 4.34 (s, 1H, H-3); 5.10 (d, J = 14.7, 1H, CH2Ph); 5.23
(quintet, 1H, H-7); 7.22-7.35 (m, 10H, Ph). 13C NMR shows the
presence of two rotamers: δ = 27.8, 28.0 ((CH3)3C); 38.7
(CH3SO2); 39.4, 40.6 (C-8); 45.1, 45.4 (CH2Ph); 51.4, 51.6 (C-
6); 68.9, 69.2 (C-3); 73.5, 73.8 (C-7); 80.7 ((CH3)3C); 82.2 (C-4);
126.8-129.0 (Ph); 133.9, 135.4 (Ph), 153.2 (COO-t-Bu); 166.8
(C-1). IR (Nujol): 1703 (νCO, NCOO-t-Bu), 1751 (νCO, N-CO).
MS-FABþ (m/z): 487 [MH]þ. Anal. Calcd for C25H30N2O6S: C,
61.71; H, 6.21; N, 5.76. Found: C, 61.62; H 6.15; N, 5.71.
(3R,4S)-2-Benzyl-1-oxo-3-phenyl-2,5-diazaspiro[3.4]oct-7-ene-
5-carboxylic Acid tert-Butyl Ester (5b). t-BuOK (0.47 g, 4.2 mmol)
was added to a solution of 3b (0.34 g, 0.7 mmol) in t-BuOH
(15 mL). The mixture was heated at 75 °C for 3 h. The solvent was
removed under reduced pressure, and the residue was taken up
with water (20 mL) and extracted with CH2Cl2 (4 ꢀ 10 mL). The
organic layer was dried (Na2SO4), and the solvent was removed
under reduced pressure. The crude product was recrystallized from
i-Pr2O to afford a colorless solid (0.256 g, 94%). Mp: 78-80 °C.
rotamers:
δ
14.1 (COOCH2CH3); 45.0 (C-60); 53.4, 53.9
(CH2Ph); 58.0, 59.2 (C-3a0); 62.4 (COOCH2CH3); 67.3, 68.1
(CH2Ph(Cbz)); 70.0 (C-4); 81.2, (C-3); 84.8, 85.4 (C-6a0);
126.4-134.4 (Ph); 150.3, 153.1 (COOCH2Ph, COOCH2CH3);
160.8 (C-2). IR (Nujol): 1639 (νCO, COOCH2CH3); 1712 (νCO
,
NCOOCH2Ph), 1766 (νCO, N-CO). MS-FABþ (m/z): 540 [M þ
H]þ. Anal. Calcd for C31H29N3O6: C, 69.00; H, 5.42; N, 7.79.
Found: C, 68.92; H 5.37; N, 7.65.
1
[R]20 = -196.9 (c 0.55, CH2Cl2). H NMR (DMSO-d6, T =
120 °DC): δ 1.19 (s, 9H, (CH3)3C); 3.82 (dt, J = 16.2, 2.0, 1H, H-6);
4.17 (d, J = 16.2, 1H, H-6); 4.37 (d, J = 15.1, 1H, CH2Ph); 4.53 (s,
1H, H-3); 4.83 (d, J = 15.1, 1H, CH2Ph); 5.90 (dt, J = 6.2, 2.1, 1H,
H-7); 6.09 (d, J = 6.2, 1H, H-8); 7.11-7.33 (m, 10H, Ph). 13C
(3R,3a0R,4R,6a0S)-1-Benzyl-2-oxo-4-phenyl-3a0,6a0-dihydro-
spiro[azetidine-3,60-pyrrolo[3,4-d]isoxazole]-30,50(40H)-dicarboxylic
Acid 50-Benzyl 30-Ethyl Ester (9). Amorphous solid (12%).
[R]20 = þ42.7 (c 0.15, CH2Cl2). H NMR (DMSO-d6, T =
1
D
120 °C): δ 1.29 (t, J = 7.0, 3H, COOCH2CH3); 3.01 (dd, J =
11.9, 8.5, 1H, H-40); 3.71 (dd, J = 11.9, 2.5, 1H, H-40); 4.24
(39) Gelmi, M. L.; Cattaneo, C.; Pellegrino, S.; Clerici, F.; Montali, M.;
Martini, C. J. Org. Chem. 2007, 72, 9811.
J. Org. Chem. Vol. 75, No. 6, 2010 2015

Cremonesi et al.
JOCArticle
(d, J = 15.2, 1H, CH2Ph); 4.29 (q, J = 7.0, 2H, COOCH2CH3);
4.31 (m, 1H, H-3a0); 4.77 (d, J = 15.2, 1H, CH2Ph); 4.81 (s, 1H,
H-4); 4.81 (d, J = 12.6, 1H, CH2Ph(Cbz)); 4.91 (d, J = 12.6, 1H,
CH2Ph(Cbz)); 5.75 (d, J = 8.9, 1H, H-6a0); 7.22-7.38 (m, 15H,
Ph). 13C NMR (DMSO-d6) shows the presence of two rotamers:
δ 13.8 (COOCH2CH3); 44.5 (CH2Ph); 47.8, 48.8 (C-3a0);
49.5, 50.2 (CH2Ph); 61.7 (COOCH2CH3); 65.9, 66.1 (C-4);
66.8 (CH2Ph(Cbz)); 82.1 (C-3); 91.9, 93.2 (C-6a0); 126.1-
135.7 (Ph); 152.5, 152.9 (COOCH2Ph, COOCH2CH3); 159.4
7.10-7.37 (m, 15H, Ph). 13C NMR shows the presence of two
rotamers: δ 45.0, 45.7 (C-40); 49.6, 50.1 (CH2Ph); 57.0, 57.4 (C-
4); 60.4, 61.3 (C-50); 63.3, 63.6 (C-10); 66.8, 67.7 (CH2Ph(Cbz));
77.8, 78.5 (C-3); 126.5-136.0 (Ph); 153.8 (COOCH2Ph), 168.4
(C-2). IR (neat): 1716 (νCO, NCOOCH2Ph), 1763 (νCO, NCO).
MS-FABþ (m/z) 463 [M þ Na]þ, 441 [M þ H]þ. Anal. Calcd for
C27H24N2O4: C, 73.62; H, 5.49; N, 6.36. Found: C, 73.51; H
5.60; N, 6.39.
(3R,4R)-2-Benzyl-7,8-dihydroxy-1-oxo-3-phenyl-2,5-diazasp-
iro[3.4]octane-5-carboxylic Acid Benzyl Ester (12). 4-Methyl-
morpholine N-oxide (NMO) (0.11 g, 0.94 mmol) and OsO4
(2.5% w/w solution in t-BuOH, 20 mol %, 1.58 mL, 0.13 mmol)
were added to a solution of 5a (0.27 g, 0.68 mmol) in an acetone/
water 10:1 mixture (20 mL). The mixture was stirred at room
temperature for 40 h. The solvent was removed under reduced
pressure, and the residue was taken up with AcOEt (10 mL) and
washed with 5% aq HCl and saturated Na2S2O3 solution. The
organic layer was dried (Na2SO4), and the solvent was removed
under reduced pressure. The crude products were purified by
column chromatography (SiO2, n-hexane/AcOEt = 25:75) to
afford a colorless oil (0.26 g, 85%, inseparable mixture of two
diastereoisomers with a ratio = 83:17 determined by NMR). 1H
NMR (DMSO-d6, T = 120 °C): major diastereoisomer δ 3.22
(dd, J = 10.3, 6.9, 1H, H-6); 3.32 (dd, J = 10.3, 7.2, 1H, H-6);
4.20 (d, J = 15.4, 1H, CH2Ph); 4.22 (m, 1H, H-7); 4.35 (t, J =
4.2, 1H, H-8); 4.46 (m, 2H, OH); 4.55 (s, 1H, H-3); 4.75 (d, J =
15.4, 1H, CH2Ph); 4.77 (d, J = 12.4, 1H, CH2Ph(Cbz)); 4.92 (d,
J = 12.4, 1H, CH2Ph(Cbz)); 7.16-7.34 (m, 15H, Ph); minor
diastereoisomer δ 5.07 (s, 1H, H-3).13C NMR shows the pre-
sence of two rotamers: major diastereoisomer δ 45.5, 45.6 (C-6);
51.6, 52.2 (CH2Ph); 66.4, 66.9 (C-3); 67.3, 68.3 (CH2Ph(Cbz));
69.5, 70.1 (C-7); 76.9, 78.1 (C-8); 81.0 (C-4); 127.2-136.8
(Ph); 154.8 (COOCH2Ph); 167.4 (C-1); minor diastereoisomer
δ 45.8 (C-6); 52.9, 53.2 (CH2Ph); 62.5, 63.8 (C-3); 67.1, 68.1
(CH2Ph(Cbz)); 69.0, 69.9 (C-7); 73.6, 74.6 (C-8); 80.4 (C-4);
127.2-136.8 (Ph). IR (Nujol): 1707 (νCO, NCOOCH2Ph), 1750
(νCO, NCO). MS-ESI (m/z): 481 [M þ Na]þ. Anal. Calcd for
C27H26N2O5: C, 70.73; H, 5.72; N, 6.11. Found: C, 70.60; H
5.66; N, 6.25.
(3R,4R)-1-Benzyl-3-formyl-2-oxo-4-phenylazetidin-3-yl(2-oxo-
ethyl)carbamic Acid Benzyl Ester (13). NaIO4 (0.16 g, 0.77
mmol) and OsO4 (2.5% w/w solution in t-BuOH, 5 mol %,
188 μL, 0.015 mmol) were added to a solution of 5a (0.13 g,
0.31 mmol) in an acetone/water 5:1 mixture (6 mL). The mixture
was stirred at room temperature for 46 h. The solvent was
removed under reduced pressure, and the residue was taken
up with CH2Cl2 (10 mL). The organic layer was washed with
brine and dried (Na2SO4), and the solvent was removed under
reduced pressure to afford a colorless amorphous solid (0.14 g,
98%). [R]20D = þ35.1 (c 1.41, CHCl3). 1H NMR (C6D6) shows
the presence of two rotamers: δ major rotamer 3.57 (d, J =
15.0, 1H, CH2CHO); 3.91 (d, J = 18.6, 1H, CH2Ph); 4.32 (d, J =
18.6, 1H, CH2Ph); 4.44 (d, J = 12.2, 1H, CH2Ph(Cbz)); 4.56 (d,
J = 15.0, 1H, CH2CHO); 4.68 (d, J = 12.2, 1H, CH2Ph(Cbz));
5.29 (s, 1H, H-4); 6.60-7.05 (m, 15H, Ph); 8.96 (s, 1H, CHO);
9.90 (s, 1H, CHO); minor rotamer 3.47 (d, J = 15.0, 1H,
CH2CHO); 3.83 (d, J = 18.2, 1H, CH2Ph); 4.40 (d, J = 18.2,
1H, CH2Ph); 4.50 (d, J = 12.1, 1H, CH2Ph(Cbz)); 4.58 (d, J =
15.0, 1H, CH2CHO); 4.60 (d, J = 12.1, 1H, CH2Ph(Cbz)); 4.96
(s, 1H, H-4); 6.60-7.05 (m, 15H, Ph); 9.41 (s, 1H, CHO); 9.93
(s, 1H, CHO). 13C NMR shows the presence of two rotamers:
δ 44.9, 45.2 (CH2Ph); 56.5, 56.8 (CH2CHO); 62.2, 62.7 (C-4);
68.2, 68.7 (CH2Ph(Cbz)); 84.5 (C-3); 127.8-129.3, (Ph); 155.0
(COOCH2Ph); 161.4 (C-2); 193.5, 194.6 (CHO); 195.9, 196.1
(C-2). IR (Nujol): 1654 (νCO, COOCH2CH3); 1714 (νCO
,
NCOOCH2Ph), 1764 (νCO, NCO). MS-FABþ (m/z): 540 [M þ
H]þ. Anal. Calcd for C31H29N3O6: C, 69.00; H, 5.42; N, 7.79.
Found: C, 68.90; H 5.39; N, 7.68.
(3R,3a0S,4S,6a0R)-1-Benzyl-2-oxo-4-phenyl-60,6a0-dihydrosp-
iro[azetidine-3,40-pyrrolo[3,4-d]isoxazole]-30,50(3a0H)-dicarboxylic
Acid 50-Benzyl 30-Ethyl Ester (80). From 50a and ethyl R-nitro-
acetate (17%). [R]20D = þ187.3 (c 0.65, CH2Cl2).
(3S,3a0S,4S,6a0R)-1-Benzyl-2-oxo-4-phenyl-3a0,6a0-dihydros-
piro[azetidine-3,60-pyrrolo[3,4-d]isoxazole]-30,50(40H)-dicarboxylic
Acid 50-Benzyl 30-Ethyl Ester (90). From 50a and ethyl R-nitro-
acetate (12%). [R]20D = -38.1 (c 0.74, CH2Cl2).
(1R,2S,40R,5S,6R)-10-Benzyl-20-oxo-40-phenyl-3H-spiro[3-aza-
bicyclo[3.1.0]hexane]-2,30-azetidine]-3,6-dicarboxylic Acid 3-Benzyl
6-Ethyl Ester (10). (CuOTf)2C6H6 (5.8 mg, 0.011 mmol) was
added to a solution of 5a (0.10 g, 0.23 mmol) in dry CH2Cl2
(1.5 mL) under nitrogen atmosphere. The mixture was heated at
40 °C, and then ethyl diazoacetate (EDA) (0.11 mL, 0.92 mmol)
was dropped in during 7 h. After 24 h, other (CuOTf)2C6H6
(5.8 mg, 0.011 mmol) was added, and a second amount of ethyl
diazoacetate (EDA) (0.11 mL, 0.92 mmol) was dropped in
during 3 h. The mixture was heated at reflux for a total of
48 h. The solvent was then removed under reduced pressure, and
the crude product was purified by means of column chro-
matography (SiO2, toluene/AcOEt = 90/10). The product was
recrystallized from i-Pr2O/n-hexane to afford a colorless solid
(0.09 g, 79%): mp 126-9 °C; [R]20D = -84.5 (c 1.025, CHCl3).
1H NMR (DMSO-d6, T = 120 °C): δ 1.22 (t, J = 7.0, 3H,
COOCH2CH3); 1.82 (t, J = 3.1, 1H, H-6); 2.16 (m, 1H, H-5);
2.50 (dd, J = 7.1, 3.0, 1H, H-1); 3.20 (dd, J = 11.1, 4.0, 1H,
H-4); 3.63 (d, J = 11.1, 1H, H-4); 4.15 (q, J = 7.0, 2H,
COOCH2CH3); 4.32 (d, J = 15.1, 1H, CH2Ph); 4.70 (d, J =
15.1, 1H, CH2Ph); 4.72 (d, J = 12.6, 1H, CH2Ph(Cbz)); 4.87 (d,
J = 12.6, 1H, CH2Ph(Cbz)); 4.89 (s, 1H, H-40); 7.16-7.37 (m,
15H, Ph). 13C NMR shows the presence of two rotamers: δ 14.0
(C-6); 22.0, 22.7 (COOCH2CH3); 30.9, 32.2 (C-5); 45.1
(CH2Ph); 48.9, 49.4 (C-4); 60.5 (COOCH2CH3); 65.7,66.5
(CH2Ph(Cbz)); 68.1, 68.4 (C-40); 78.2, 78.9 (C-2); 126.5-135.9
(Ph); 151.7, 152.8 (COOCH2Ph, COOCH2CH3); 170.9 (C-20).
IR (Nujol): 1717 (νCO, NCOOCH2Ph), 1766 (νCO, NCO). MS-
FABþ (m/z): 533 [M þ Na]þ, 511 [M þ H]þ. Anal. Calcd for
C31H30N2O5: C, 72.92; H, 5.92; N, 5.49. Found: C, 72.76; H
5.92; N, 5.39.
(10R,20R,4R,50S)-1-Benzyl-2-oxo-4-phenyl-30H-spiro[azetidine-
3,20-[6]oxa[3]azabicyclo[3.1.0]hexane]-30-carboxylic Acid Benzyl
Ester (11). A solution of m-chloroperbenzoic acid (m-CPBA)
(0.14 g, 1.06 mmol, purity e77%) in dry CH2Cl2 (4 mL) was
dropped into a solution of 5a (0.15 g, 0.35 mmol) in dry CH2Cl2
(1.5 mL) heated at 40 °C during 4 h under nitrogen atmosphere
for 24 h. The mixture was cooled and washed with 5% aq
NaHCO3. The organic layer was dried (Na2SO4), and the solvent
was removed under reduced pressure. The crude product was
purified by column chromatography (SiO2, toluene/AcOEt =
90:10) to afford a colorless oil (0.12 g, 75%). [R]20D = -166.7 (c
0.72, CHCl3). 1H NMR (DMSO-d6, T = 120 °C): δ 3.50 (d, J =
12.7, 1H, H-40); 3.72 (dd, J = 12.7, 2.4, 1H, H-40); 4.09 (m, 1H,
H-50); 4.22 (d, J = 3.1, 1H, H-10); 4.41 (d, J = 15.1, 1H, CH2Ph);
4.84 (d, J = 15.1, 1H, CH2Ph); 4.84 (d, J = 12.8, 1H, CH2Ph-
(Cbz)); 4.85 (d, J = 12.8, 1H, CH2Ph(Cbz)); 4.91 (s, 1H, H-4);
(CHO). IR (nujol): 1726 (νCO, NCOOCH2Ph), 1769 (νCO
,
NCO). MS-EIþ (m/z): 456 (Mþ). Anal. Calcd for C27H24-
N2O5: C, 71.04; H, 5.30; N, 6.14. Found: C, 71.10; H 5.22; N,
6.24.
2016 J. Org. Chem. Vol. 75, No. 6, 2010

Cremonesi et al.
JOCArticle
(3S,4S)-1-Benzyl-3-formyl-2-oxo-4-phenylazetidin-3-yl(2-oxo-
ethyl)carbamic Acid Benzyl Ester (130). From 50a and NaIO4-
OsO4 (98%): [R]20D = -44.6 (c 0.87, CHCl3).
3.40 (d, J = 13.0, 1H, CH2PMP); 3.54 (m, 1H, H-6/7); 3.62
(d, J = 13.0, 1H, CH2PMP); 3.83 (s, 3H, OCH3); 3.98 (d, J =
15.0, 1H, CH2Ph); 4.44 (s, 1H, H-3); 4.61 (d, J = 15.0, 1H,
(3R,4S)-2-Benzyl-8-(4-methoxybenzyl)-1-oxo-3-phenyl-2,5,8-
triazaspiro[3.5]nonane-5-carboxylic Acid Benzyl Ester (14). p-
Methoxybenzylamine (41 μL, 0.32 mmol), sodium triacetoxy-
boronhydride (0.16 g, 0.73 mmol, 95% purity), and acetic acid
(10 mol %, 22 mg, 0.003 mmol) were added to a solution of 13
(0.13 g, 0.29 mmol) in dry CH2Cl2 (6 mL). The mixture was
stirred at room temperature for 4 h. The reaction was treated
with 5% NaHCO3 aq solution. The organic layer was washed
with brine and dried (Na2SO4), and the solvent was removed
under reduced pressure. The crude product was purified by
column chromatography (SiO2, toluene/AcOEt = 80:20) to
CH2Ph); 4.97 (s, 2H, CH2Ph(Cbz)); 6.88-7.38 (m, 19H, Ph). 13
C
NMR: δ 42.1 (C-6/7); 44.3 (CH2Ph); 52.1 (C-6/7); 55.2 (OCH3);
57.7 (C-9); 61.8 (CH2PMP); 61.9 (CH2Ph(Cbz)); 67.3 (C-3); 82.5
(C-3); 113.8-133.7 (Ph); 158.9 (COOCH2Ph); 167.4 (C-1). IR
(Nujol): 1706 (νCO, NCOOCH2Ph), 1761 (νCO, NCO). MS-EIþ
(m/z): 561 [M]þ. Anal. Calcd for C35H35N3O4: C, 74.84; H, 6.28;
N, 7.48. Found: C, 74.75; H 6.32; N, 7.41.
(3S,4R)-2-Benzyl-8-(4-methoxybenzyl)-1-oxo-3-phenyl-2,5,8-
triazaspiro[3.5]nonane-5-carboxylic Acid Benzyl Ester (140). From
130 and p-methoxybenzylamine, sodium triacetoxyboronhydride,
and acetic acid (58%). [R]20D = þ92.5 (c 2.35, CHCl3).
afford a colorless oil (98 mg, 60%). [R]20 = -82.4 (c 0.98,
D
CHCl3). 1H NMR (DMSO-d6, T = 120 °C): δ 2.10 (dt, J = 11.8,
3.6, 1H, H-6/7); 2.44 (dt, J = 11.8, 3.6, 1H, H-6/7); 2.77 (m, 1H,
H-6/7); 2.83 (d, J = 11.5, 1H, H-9); 2.84 (d, J = 11.5, 1H, H-9);
Supporting Information Available: Compounds 1H and 13
C
NMR spectra and NOESY experiments. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 6, 2010 2017