Zinc(II) triflate-controlled 1,3-dipolar cycloadditions of C-(2-thiazolyl)nitrones: Application to the synthesis of a novel isoxazolidinyl analogue of tiazofurin

Article abstract of DOI:10.1021/jo051572a

The cycloaddition reaction between C-(2-thiazolyl) nitrones and allylic alcohol takes place with complete exo selectivity when the reactions are carried out in the presence of 1 equiv of zinc triflate. The rate of the reaction is increased enormously unde

Full text of DOI:10.1021/jo051572a

Zinc(II) Triflate-Controlled 1,3-Dipolar Cycloadditions of
C-(2-Thiazolyl)nitrones: Application to the Synthesis of a Novel
Isoxazolidinyl Analogue of Tiazofurin
Ugo Chiacchio,*,† Antonio Rescifina,† Maria G. Saita,† Daniela Iannazzo,‡ Giovanni Romeo,*,‡
Juan A. Mates,§ Tomas Tejero,§ and Pedro Merino*,§
Dipartimento di Scienze Chimiche, Universita` di Catania, Viale Andrea Doria 6, 95125 Catania, Italy,
Dipartimento Farmaco-Chimico, Universita` di Messina, Viale SS. Annunziata, 98168 Messina, Italy, and
Departamento de Quimica Organica, Facultad de Ciencias, ICMA, Universidad de Zaragoza, CSIC,
E-50009 Zaragoza, Aragon, Spain
pmerino@unizar.es
Received July 28, 2005
The cycloaddition reaction between C-(2-thiazolyl) nitrones and allylic alcohol takes place with
complete exo selectivity when the reactions are carried out in the presence of 1 equiv of zinc triflate.
The rate of the reaction is increased enormously under microwave irradiation. The use of a chiral
dipolarophile allowed application of the methodology to the synthesis of a hitherto unknown
enantiomerically pure isoxazolidinyl analogue of the C-nucleoside tiazofurin.
Introduction
pound.2 To improve its biological properties, several
analogues of 1 have also been prepared. Thus, modifica-
tions in the substitution on the carbohydrate moiety4 and
changes of the C-linked heterocycle, acting as a base,5
have been reported. In another class of nucleosides, the
natural ribose unit has been replaced with a different
heterocyclic moiety. In particular, Kini and co-workers6
reported the synthesis of aza tiazofurin 2, and Chu and
co-workers7 prepared the corresponding 1,3-dioxolanyl
derivative 3 (Chart 1).
Numerous naturally occurring and synthetic C-nucleo-
sides display potent antitumoral and/or antiviral activi-
ties.1 Among them, tiazofurin 1 has demonstrated potent
antitumor activity against several human cancers includ-
ing myeloid leukemia.2 From the first synthesis of 1
reported by Robins and co-workers in 1977,3 several
synthetic approaches have been reported for that com-
* To whom correspondence should be addressed. Tel.: +34 976
762075. Fax: +34 976 762075.
† Universita` di Catania.
(4) Popsavin, M.; Torovic, L.; Kojic, V.; Bogdanovic, G.; Spaic, S.;
Popsavin, V. Bioorg. Med. Chem. Lett. 2003, 13, 3167-3170.
(5) (a) Franchetti, P.; Marchetti, S.; Cappellacci, L.; Yalowitz, J. A.;
Jayaram, H. N.; Goldstein, B. M.; Grifantini, M. Bioorg. Med. Chem.
Lett. 2001, 11, 67-69. (b) Franchetti, P.; Cappellacci, L.; Marchetti,
S.; Martini, C.; Coa, B.; Varani, K.; Borea, P. A.; Grifantini, M. Bioorg.
Med. Chem. 2000, 8, 2367-2373. (c) Popsavin, M.; Torovic, L.; Spaic,
S.; Stankov, S.; Kapor, A.; Tomic, Z.; Popsavin, V. Tetrahedron 2002,
58, 569-580. (d) Navarre, J.-M.; Guianvarch, D.; Giorgio, A. F. D.;
Condom, R.; Behinda, R. Tetrahedron Lett. 2003, 44, 2199-2202.
(6) Kini, G. D.; Hennen, W. J.; Robins, R. K. J. Org. Chem. 1986,
51, 4436-4439.
‡ Universita` di Messina.
§ Universidad de Zaragoza.
(1) For reviews, see: (a) Postema, M. H. D. Tetrahedron 1992, 48,
8545-8599. (b) Hacksell, U.; Daves, G. D. Prog. Med. Chem. 1985, 22,
1-65. (c) Daves, G. D.; Cheng, C. C. Prog. Med. Chem. 1976, 13, 303-
349. (d) Watanabe, K. A. In The Chemistry of C-Nucleosides In
Chemistry of Nucleosides and Nucleotides; Townsend, L. B., Ed.;
Plenum Press: New York, 1994; Vol. 3, p 421.
(2) Ramasamy, K. S.; Bandaru, R.; Averett, D. J. Org. Chem. 2000,
65, 5849-5851 and references therein.
(3) Srivastava, P. C.; Pickering, M. V.; Allen, L. B.; Streeter, D. G.;
Campbell, M. T.; Witkowski, J. T.; Sidwell, R. W.; Robins, R. K. J.
Med. Chem. 1977, 20, 256-262.
(7) Xiang, Y.; Teng, Q.; Chu, C. K. Tetrahedron Lett. 1995, 36, 3781-
3784.
10.1021/jo051572a CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/06/2005
J. Org. Chem. 2005, 70, 8991-9001
8991

Chiacchio et al.
CHART 1. Tiazofurin and Its Analogues
SCHEME 1. Retrosynthetic Analysis of
Isoxazolidinyl Tiazofurin
SCHEME 2. Lewis Acid-Mediated Cycloaddition
The heterocyclic nucleosides8 have gained considerable
attention during the last years,9 and, among them, the
isoxazolidinyl analogues and related compounds show
great promise as drug candidates.10 For some years, our
groups have been investigating on the development of
efficient and flexible synthesis of isoxazolidinyl nucleo-
sides11 including psiconucleosides,12 amino acid nucleo-
sides,13 and C-nucleosides.14 Within the last context, we
have recently published the synthesis of isoxazolidinyl
pseudouridines.15
taining an isoxazolidine ring as a spacer between the
thiazole-4-carboxamide unit and the hydroxymethyl group.
According to our preliminary studies on the synthesis
of isoxazolidinyl-C-nucleosides14 and the retrosynthetic
analysis depicted in Scheme 1, we needed for the con-
struction of 4 the corresponding N-benzyl-C-(4-ethoxy-
carbonyl-2-thiazolyl) nitrone 5. Cycloaddition of this
nitrone with allylic alcohol under the appropriate condi-
tions should lead to an immediate precursor of the target
compound.
It has been well documented by previous work from
our14 and other16 laboratories that Lewis acids could be
used to control the endo/exo selectivity in cycloadditions
between allylic alcohol and nitrones bearing a coordinat-
ing group at the nitrone carbon atom (Scheme 2).
These nitrones include C-(ethoxycarbonyl) and C-
heteroaryl nitrones such as 2-pyridyl and 2-quinolyl. A
general transition state A as illustrated in Scheme 2
could explain the observed selectivities in favor of the
exo adducts. Also, the hydroxyl group of the allylic alcohol
is suitable of participating in complexation with the
catalyst.14
Following our interest in isoxazolidinyl nucleosides, we
report in this Article the synthesis of 4 (R ) Bn), the first
member of a new series of tiazofurin analogues con-
(8) The term heterocyclic nucleosides refers to nucleoside analogues
in which the furanose ring has been replaced by a different heterocyclic
ring. For a review on this topic, see ref 9a.
(9) (a) Merino P. Curr. Med. Chem.: Anti-Infect. Agents 2002, 1,
389-411. (b) Ichikawa, E.; Kato, K. Curr. Med. Chem. 2001, 8, 385-
423. (c) Mansour, T. S.; Storer, R. Curr. Pharm. Des. 1997, 3, 227-
264.
(10) (a) Chiacchio, U.; Balestrieri, E.; Macchi, B.; Iannazzo, D.;
Piperno, A.; Rescifina A.; Romeo, R.; Saglimbeni, M.; Sciortino, M. T.;
Valveri, V.; Mastino, A.; Romeo, G. J. Med. Chem. 2005, 48, 1389-
1394. (b) Coutouli-Argyropoulou, E.; Pilanidou, P. Tetrahedron Lett.
2003, 44, 3755-3758. (c) Lee, Y.-S.; Kim, B. H. Bioorg. Med. Chem.
Lett. 2002, 12, 1395-1397. (d) Colacino, E.; Converso, A.; Liguori, A.;
Napoli, A.; Siciliano, C.; Sindona, G. Tetrahedron 2001, 57, 8551-8557.
For a review, see: Pan, S.; Amankulor, N. M.; Zhao, K. Tetrahedron
1998, 54, 6587-6604.
(11) For selected references, see: (a) Chiacchio, U.; Corsaro, A.;
Iannazzo, D.; Piperno, A.; Pistara, V.; Rescifina, A.; Romeo, R.; Sindona,
G.; Romeo, G. Tetrahedron: Asymmetry 2003, 14, 2717-2723. (b)
Chiacchio, U.; Rescifina, A.; Corsaro, A.; Pistara, V.; Romeo, G.; Romeo,
R. Tetrahedron: Asymmetry 2000, 11, 2045-2048. (c). Chiacchio, U.;
Corsaro, A.; Gumina, G.; Iannazzo, D.; Rescifina, A.; Piperno, A.;
Romeo, R.; Romeo, G. J. Org. Chem. 1999, 64, 9321-9327. (d) Merino,
P.; Alamo, E. M.; Bona, M.; Franco, S.; Merchan, F. L.; Tejero, T.;
Vieceli, O. Tetrahedron Lett. 2000, 41, 9239-9243. (e) Merino, P.;
Alamo, E. M.; Franco, S.; Merchan, F. L.; Simon, A.; Tejero, T.
Tetrahedron: Asymmetry 2000, 11, 1543-1546. (f) Merino, P.; Franco,
S.; Garces, N.; Merchan, F. L.; Tejero, T. Chem. Commun. 1998, 493-
494. (g) Chiacchio, U.; Genovese, F.; Iannazzo, D.; Librando, V.; Merino,
P.; Rescifina, A.; Romeo, R.; Procopio, A.; Romeo, G. Tetrahedron 2004,
60, 441-448
In view of the above, we embarked on the search of
the best conditions for making cis-selective the cyclo-
addition between allylic alcohol and C-(2-thiazolyl) ni-
trone 5. We also describe synthetic approaches for the
preparation of enantiomerically pure 4 by introducing
chiral groups/auxiliaries at either the nitrone moiety or
the dipolarophile. Some mechanistic consideration based
on semiempirical calculations is reported, too.
Results and Discussion
(12) (a) Chiacchio, U.; Borrello, L.; Iannazzo, D.; Merino, P.; Piperno,
A.; Rescifina, A.; Richichi, B.; Romeo, G. Tetrahedron: Asymmetry
2003, 14, 2419-2425. (b) Chiacchio, U.; Corsaro, A.; Pistara, V.;
Rescifina, A.; Iannazzo, D.; Piperno, A.; Romeo, G.; Romeo, R.; Grassi,
G. Eur. J. Org. Chem. 2002, 1206-1212.
Nitrone 5 is easily obtained by condensation of the
corresponding aldehyde and N-benzylhydroxylamine. The
known17 aldehyde 10 was prepared by a classical
(13) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. J. Org. Chem.
2000, 65, 5575-5589.
(16) (a) Shimizu, T.; Ishizaki, M.; Nitada, N. Chem. Pharm. Bull.
2002, 50, 908-921. (b) Kanemasa, S. Synlett 2002, 1371-1387. (c)
Jones, A. D.; Knight, D. W.; Thornton, S. R. J. Chem. Soc., Perkin
Trans. 1 1999, 908-921.
(14) Merino, P.; Tejero, T.; Laguna, M.; Cerrada, E.; Moreno, A.;
Lopez, J. A. Org. Biomol. Chem. 2003, 1, 2336-2342.
(15) Chiacchio, U.; Corsaro, A.; Mates, J. A.; Merino, P.; Rescifina,
A.; Romeo, G.; Romeo, R.; Tejero, T. Tetrahedron 2003, 59, 4733-4738.
(17) Inami, K.; Shiba, T. Bull. Chem. Soc. Jpn. 1985, 58, 352-360.
8992 J. Org. Chem., Vol. 70, No. 22, 2005

1,3-Dipolar Cycloadditions of C-(2-Thiazolyl)nitrones
SCHEME 3. Synthesis of C-(2-Thiazolyl) Nitronesa
a Reagent and conditions: (i) P2S5, C6H6. (ii) EtOH, MS 4 Å. (iii) 1 M HCl, acetone, reflux. (iv) PhCH2NHOH, CH2Cl2, MgSO4. (v) NH3,
MeOH. (vi) PhCH2NHOH, CH2Cl2, MgSO4, reflux.
SCHEME 4. Cycloaddition Reaction of Nitrones
5a,b with Allylic Alcohola
Hantszch’s synthesis from diethoxyacetamide 7a and
ethyl 3-bromopyruvate 8, and further acidic treatment
(Scheme 3).
Condensation of 10 with N-benzylhydroxylamine18
afforded the hitherto unknown nitrone 5a in 90% yield.
Because the final nucleoside analogue should bear a
carboxamide group at the thiazole ring, we also consid-
ered the possibility of introducing such a group at an
earlier stage. Thus, intermediate 9 was transformed into
11 by the action of methanolic ammonia. Acidic hydroly-
sis of 11 gave aldehyde 12, which afforded nitrone 5b
after condensation with N-benzylhydroxylamine. To in-
troduce a chiral auxiliary at the nitrone moiety, D-
mannofuranosyl hydroxylamine 1319 was also condensed
with 10 leading to chiral nonracemic nitrone 5c. The
configuration of nitrones 5 was unambiguously estab-
lished by NOE experiments. The irradiation of the
azomethine proton led to 8-12% enhancements of the
signal corresponding to the benzyl (in 5a and 5b) or
anomeric (in 5c) protons, thus indicating a Z-configura-
tion in all cases.
The 1,3-dipolar cycloaddition reaction of nitrones 5a
and 5b with allylic alcohol (Scheme 4) was screened to
optimize the reaction. The results are collected in Table
1.
Condensation of 5a with 10 equiv of allylic alcohol in
a sealed tube at 60 °C using dichloromethane as a solvent
(entry 1) afforded after 25 days a 63:37 mixture of cis/
trans adducts 14 and 15. In the absence of solvent and
at 160 °C (entry 2), a similar ratio was obtained in a
considerable lower, but still long, reaction time (15 days).
An identical result was obtained with nitrone 5b (entry
7). It is well-known that microwave irradiation in cyclo-
addition reactions considerably reduces reaction times
a Reagent and conditions: (i) allylic alcohol (see Table 1). (ii)
NH3, MeOH.
and may affect product ratios and yields.20 Application
of this technique to the reaction shown in Scheme 4
resulted in a considerable acceleration of the process.
When the reaction was performed under solvent-free
conditions at 160 °C, the cycloaddition of nitrones 5a and
5b went to completion in 1 and 3 h, respectively (entries
3 and 8). However, also in this case a low cis/trans ratio
(60:40) was observed. The addition of MgBr2‚Et2O (entry
4), following the Kanemasa’s conditions,21 only afforded,
after 3 days, the nitrone 16 in which the ethyl ester
moiety had been transesterified with allylic alcohol.
Additional time of reaction did not lead to any cyclo-
(20) (a) Varma, R. S. Green Chem. 1999, 1, 43-55. (b) De la Hoz,
A.; Diaz-Ortiz, A.; Moreno, A.; Langa, F. Eur. J. Org. Chem. 2000,
3573-3659. (c) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250-
6284.
(21) Kanemasa, S.; Tsuruoka, T.; Yamamoto, H. Tetrahedron Lett.
1995, 36, 5019-5022.
(18) Borch, R. F.; Bernstein, M. D.; Durst, M. D. J. Am. Chem. Soc.
1971, 93, 2897-2904.
(19) Vasella, A. Helv. Chim. Acta 1977, 60, 1273-1285.
J. Org. Chem, Vol. 70, No. 22, 2005 8993

Chiacchio et al.
yield (%)d
TABLE 1. Cycloaddition between Nitrones 5a and 5b and Allylic Alcohola
entry
nitrone
solvent
Lewis acidb
temp (°C)
MW (watts)c
time
25 d
15 d
1 h
3 d
4 d
14:15
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5a
5a
5b
5b
5b
CH2Cl2
neat
none
60
160
120
80
63:37
60:40
60:40
70
68
80
none
neat
none
90
90
CH2Cl2
CH2Cl2
CH2Cl2
neat
neat
CH2Cl2
MgBr2
Zn(OTf)2
Zn(OTf)2
none
80
100:0
100:0
63:37
60:40
100:0
90e
90e
40
60
55
120
160
120
160
15 min
20 d
3 h
none
Zn(OTf)2
90
90
15 min
a All reactions were carried out in a sealed tube. b 1.0 equiv was used. c The reactions were carried out in a microwave reactor. d Isolated
yield. e Compounds 14 and 17 were obtained in 54% and 36% yields, respectively (corresponding to a 90% yield for the cycloaddition
reaction).
SCHEME 5. Cycloaddition Reaction of Nitrone 5c
with Allylic Alcohol
SCHEME 6. Cycloaddition Reaction of Nitrone 5a
with Homochiral Alkene 22
compound in 90% overall yield (two steps). The relative
stereochemistry of compounds (()-4, 14, and 15 were
deduced from detailed NMR studies including HMQC
13C-1H, COSY, and NOE.
The final goal of this work was to develop a synthetic
route to unknown enantiomerically pure isoxazolidinyl
tiazofurin. For this, we applied this synthetic protocol to
enantiopure substrates. First, we checked the cyclo-
addition of 5c with allylic alcohol in the presence of 1.0
equiv of Zn(OTf)2 (Scheme 5). After 5 days of reaction,
no more starting nitrone was observed (TLC) and the
reaction was stopped. After a usual workup, a quite
complex crude mixture was obtained.
addition product. On the other hand, when the reaction
was conducted in the presence of 1.0 equiv of Zn(OTf)2
(entry 5), it went to completion in 4 days. A complete cis
selectivity was obtained, although the two adducts 14 and
17 were obtained in 54% and 36% isolated yields,
respectively. Even though the two adducts can be easily
separated by chromatographic methods, for synthetic
purposes it is preferable to treat the mixture with
methanolic ammonia to yield compound (()-4 in quan-
titative yield. Next, we considered taking advantage of
the two accelerating factors; thus, we carried out the
reaction both in the presence of Zn(OTf)2 and under
microwave irradiation (entries 6 and 9) using dichloro-
methane as a solvent. Under these conditions, a sub-
stantial improvement was finally achieved and the reac-
tion finished after only 15 min. Whereas the nitrone 5a
afforded the same mixture of cis adduct 14 and trans-
esterified product 17 that have been obtained without
microwave irradiation, the nitrone 5b afforded only (()-4
in 55% chemical yield. This lower chemical yield can be
explained by the lower solubility of nitrone 5b. From a
synthetic point of view, it is more advisable to carry out
the reaction with nitrone 5a and treat the obtained
mixture with methanolic ammonia to obtain the target
Assessment of cycloaddition diastereoselectivity was
1
difficult due to the complexities in the H NMR spectra
of N-sugar compounds. This was in part due to dynamic
properties associated with nitrogen inversion (in the
isoxazolidine) that was shown on the NMR time scale.
Semipreparative HPLC allowed the separation of four
peaks consisting of transesterified nitrones 18 and 19 and
two mixtures 20 and 21 that could not be separated. New
methylene signals for these mixtures appeared in the
range 2.0-3.6 ppm, which were only possible for 3,5-
1
disubstituted isoxazolidines. At a H NMR probe tem-
perature of 55 °C, the resonances in the isolated mixtures
20 and 21 were considerably sharpened and had baseline
separation, which allowed quantification of the diaster-
eomers. The presence of up to five different compounds
in each mixture indicated not only poor cis/trans and
diastereofacial selectivities but also epimerization at the
8994 J. Org. Chem., Vol. 70, No. 22, 2005

1,3-Dipolar Cycloadditions of C-(2-Thiazolyl)nitrones
SCHEME 7. Cycloaddition Reaction of Nitrone 5a with Homochiral Alkenes 25 and 26a
t
a Reagents and conditions: (i) BuMe2SiCl, imidazole, DMF. (ii) Bu4NF, THF.
TABLE 2. Cycloaddition between Nitrone 5a and
Alkenes 25 and 26a
chromatographic methods and fully characterized. Ad-
dition of Zn(OTf)2 to this reaction resulted in only
decomposition products, quite probably because of a
chelation between the diol and the Lewis acid as well as
the incompatibility of using Zn(OTf)2 in the presence of
ethanol.
To find conditions similar to those previously found for
allylic alcohol, the silylated compound 2622 was ulti-
mately considered to be the optimum compound. This was
prepared from diol 25 by selective silylation of the
primary hydroxyl group. Cycloaddition between nitrone
5a and 26 under microwave irradiation and in the
presence of Zn(OTf)2 afforded a 4:1 mixture of cis adducts
28a and 28b. Again, a complete cis selectivity was
observed in the reaction as evidenced by proton NMR and
NOE studies. The observed diastereofacial selectivity
(80% in favor of the (3R,5S)-isomer 28a) rendered the
process synthetically useful.
The absolute configuration of compounds 27 has been
assigned by NMR techniques and by circular dichroism.
We reported23 a sector rule for the circular dichroism of
the thiazole chromophore in a variety of 2-thiazolyl-
carbinamines. According to that sector rule, which matches
those proposed by us24 for similar furan derivatives and
by Smith and co-workers25 for phenylcarbinamines, the
observed Cotton effect in the range 210-230 nm for
adducts 27a and 27d is consistent with the (R)-configu-
ration at C-3 of the isoxazolidine ring (Figure 1).
The observed negative Cotton effect in the same range
for compounds 27b and 27c is consistent with the (S)-
configuration. These data were also in good agreement
with those reported by Holzapfel and co-workers for
compounds with a 4-carboxythiazole as a chromophore.26
Lewis
acidb
time
yield
entry alkene
solvent
CH2Cl2
CH2Cl2:EtOH none
CH2Cl2
CH2Cl2
(h) a:b:c:d (%)c
1
2
3
4
25
25
25
26
none
3
1
1
2
d
60
d
1:1:2:2
4:1:0:0
Zn(OTf)2
Zn(OTf)2
70
a All reactions were carried out in a sealed tube at 120 °C under
microwave irradiation (90 W). b 1.0 equiv was used. c Isolated
yield. d No reaction was observed.
anomeric center of the sugar moiety. Due to these
disappointing results, the N-sugar approach was defini-
tively discarded.
We therefore sought to explore the reactivity of nitrone
5a with chiral dipolarophiles. 1,3-Dipolar cycloaddition
of 5a with alkene 22 gave adducts 23 and 24 (Scheme
6).
The absolute configuration of compounds 23 and 24
was subsequently confirmed upon deacetalyzation and
comparison of the resulting diols with further assigned
identical compounds (see below). The reaction was ex-
tremely low, because after 12 days at 140 °C (sealed tube)
only 28% of conversion was observed. The diastereomeric
cis/trans ratio was only near 2:1 but the diastereofacial
induction was excellent; only anti adducts (with respect
to the stereogenic center of the dipolarophile) were
observed.
Unfortunately, the cis/trans selectivity of the reaction
was not affected by the presence of Lewis acids, identical
results being obtained when the reaction was carried out
in the presence of 1.0 equiv of Zn(OTf)2 or MgBr2‚Et2O.
These results further confirm the necessity of a hydroxyl
group at an allylic position to control the endo/exo
selectivity of the reaction.
The relative cis/trans configuration of the isoxazolidine
rings was determined by NOE experiments. The stereo-
chemical assignments for compounds 28a and 28b were
We next examined cycloaddition of 5a with com-
mercially available (2S)-1,2-dihydroxy-3-butene 25
(Scheme 7, Table 2). No reaction was observed under
microwave irradiation when dichloromethane was used
as a solvent either in the presence of or in the absence of
Zn(OTf)2 (entries 1 and 3). On the other hand, when a
1:1 CH2Cl2:EtOH mixture was used as a solvent (entry
2), the reaction went to completion in 30 min and a 1:1:
2:2 mixture of the four possible diastereomers 27 was
obtained. These compounds were easily separated by
(22) Bergmeier, S. C.; Stanchina, D. M. J. Org. Chem. 1999, 64,
2852-2859.
(23) Merchan, F. L.; Merino, P.; Rojo, I.; Tejero, T.; Dondoni, A.
Tetrahedron: Asymmetry 1995, 6, 2145-2148.
(24) Tejero, T.; Franco, S.; Junquera, F.; Lanaspa, A.; Merchan, F.
L.; Merino, P.; Rojo, I. Tetrahedron: Asymmetry 1996, 7, 1529-1534.
(25) (a) Colon, D. F.; Pickard, S. T.; Smith, H. E. J. Org. Chem. 1991,
56, 2322-2326. (b) Smith, H. E.; Fontana, L. P. J. Org. Chem. 1991,
56, 432-435.
(26) Bredenkamp, M. W.; Holzapfel, C. W.; Van Zyl, W. J. Synth.
Commun. 1990, 20, 2235-2249.
J. Org. Chem, Vol. 70, No. 22, 2005 8995

Chiacchio et al.
FIGURE 1. CD spectra of compounds 27.
SCHEME 8. Synthesis of Both Enantiomers of
Isoxazolidinyl Analogue of Tiazofurina
SCHEME 9. Proposed TS for the Reaction
between 5a and Allylic Alcohol
treatment of 27a with sodium periodate and in situ
reduction of the formed aldehyde.
The resulting alcohol (-)-14 was transformed into
isoxazolidinyl analogue of tiazofurin (-)-4 in quantitative
yield (Scheme 8). To further confirm the stereochemical
assignment, compound 27b was also obtained from
desilylation of the minor adduct 28b and transformed
into (+)-14 and then (+)-4 following the same reaction
sequence.
The above overall results suggested a confirmation of
our previous studies carried out with C-(2-pyridyl) ni-
trones.14 A free hydroxyl group is needed to achieve a
complete exo selectivity according to previously proposed
mechanisms through a transition state as outlined in
Scheme 2. A complete mechanism of the cycloaddition
between nitrone 5a and allylic alcohol promoted by
a Reagents and conditions: (i) NaIO4, MeOH-H2O then NaBH4,
MeOH. (ii) NH3, MeOH.
made by comparison of the corresponding desilylated
products with 27a and 27b, respectively. With the
(3R,5S)-isoxazolidine 27a efficiently in hand, its trans-
formation to the targeted enantiomerically pure isoxazo-
lidinyl analogue 4 only remained. This was achieved by
8996 J. Org. Chem., Vol. 70, No. 22, 2005

1,3-Dipolar Cycloadditions of C-(2-Thiazolyl)nitrones
FIGURE 2. NMR spectra of nitrone 5a before (up) and after (down) the addition of 1 equiv of zinc(II) triflate (NMR spectra
recorded in acetone-d6 at 25 °C).
SCHEME 10. Proposed TSs for the Reaction
between 5a and Alkene 26
Zn(OTf)2 is proposed in Scheme 9. In the case of nitrone
5a, a complex C1 was formed, in which the nitrone
oxygen is bound to the zinc atom forming a chelate with
the nitrogen thiazole atom.
Experimental evidence of this complex was provided
by comparison of NMR spectra of nitrone 5a in the
absence and in the presence of 1.0 equiv of zinc(II) triflate
(Figure 2).27 Thus, the formation of C1 was substantiated
by the observation of the signal due to the azomethine
proton, which is shifted downfield (∆δ ) 0.54 ppm) as
compared to that of the nonchelated nitrone and by the
same effect (∆δ ) 0.30 ppm) observed for the proton of
the thiazole ring. The observed downfield shifts are in
agreement with reported identical effects in other C-
hetaryl nitrones.28 In addition, from the 13C NMR spectra
of the free nitrone and complex C1, it can be seen that
the resonance of the CdO carbon of the ester moiety is
shifted downfield by ca. 5 ppm. This also provides
evidence that the ester moiety is also bound to the zinc
atom in solution. Such a coordination of the ester unit to
the metal atom can justify the observed transesterifica-
tion with allylic alcohol, which presumably occurs, in
some extent, after the cycloaddition process. According
to our previous findings14 with N-benzyl-C-(2-pyridyl)
nitrone, it is possible to propose an intramolecular exo
transition structure TSa leading to the cis adduct as the
only product of the reaction (Scheme 9).
tion states TSb and TSc are possible leading to the cis
isomers 28a and 28b, respectively (Scheme 10).
We also checked the validity of these hypothesis by
performing semiempirical calculations (PM3) of the whole
process.29 These calculations (PM3) point out the Si face
of the alkene as the less hindered one in a good agree-
ment with the observed experimental results.
The π-facial selectivity of the cycloaddition reactions
with homochiral 26 is controlled by the protected hy-
droxymethyl moiety. In this case, the transesterification
reaction could be disfavored due to steric interactions of
the siloxymethyl group, and this could be the reason no
transesterified products are found in the cycloaddition
with 26. Starting from complex C1, two possible transi-
Conclusions
In summary, the present study provides an insight into
the way in which C-(2-thiazolyl) nitrones undergo Lewis
acid-controlled cycloadditions with allylic alcohols. A
considerable acceleration of the process is achieved by
the use of both the Lewis acid and microwaves. The reac-
tion has been shown to be highly regio- and stereoselec-
(27) The sample was prepared by dissolving the nitrone in acetone-
d6 and adding 1.0 equiv of Zn(OTf)2 at ambient temperature under an
argon atmosphere. The resulting solution was stirred manually, and
the NMR was recorded at the same temperature immediately.
(28) (a) Das, P.; Boruah, M.; Kumari, N.; Sharma, A.; Konwar, D.;
Dutta, D. K. J. Mol. Cata. A: Chem. 2002, 178, 283-287. (b) Villamena,
F. A.; Dickman, M. H.; Crist, D. R. Inorg. Chem. 1998, 37, 1446-1453.
(c) Kahn, M. L.; Sutter, J.-P.; Golhen, S.; Guionneau, P.; Ouahab, L.;
Kahn, O.; Chasseau, D. J. Am. Chem. Soc. 2000, 122, 3413-3421.
(29) Semiempirical methods are intended for studying large and
complicated molecular systems of interest for which a complete
application of the ab initio methods is generally prohibitive in terms
of computational effort. Several studies have suggested semiempirical
methods as a good choice for studying cycloaddition processes and to
make general and qualitative estimation of the course of the reaction.
The complete calculations can be obtained from the authors.
J. Org. Chem, Vol. 70, No. 22, 2005 8997

Chiacchio et al.
for 1 h. The solution was then partially evaporated and treated
with EtOAc (30 mL). The organic layer was separated, and
the aqueous layer was extracted with EtOAc (2 × 50 mL). The
combined organic extracts were washed with saturated aq
NaHCO3 (3 × 25 mL) and brine (3 × 20 mL), dried over
MgSO4, and evaporated under reduced pressure. The obtained
crude aldehyde was used in the next step without purification.
δH (400 MHz, CDCl3) 1.38 (t, 3H, J ) 7.1 Hz), 4.42 (q, 2H, J )
7.1 Hz), 8.45 (s, 1H), 10.01 (s, 1H).
2-Formylthiazole-4-carboxamide 12. The same proce-
dure described above for the transformation of 9 into 10 was
applied to 11 (3.01 g, 13.1 mmol). The crude aldehyde 13 was
used in the next step without further purification. δH (400
MHz, DMSO-d6) 7.74 (bs, 1H), 7.96 (bs, 1H), 8.26 (s, 1H), 9.90
(s, 1H).
N-Benzyl-C-[4-(ethoxycarbonyl)-2-thiazolyl)] Nitrone
5a. A solution of 10 (obtained from 10.4 mmol of 9) in CH2Cl2
(30 mL) was treated sequentially with MgSO4 (1 g) and
N-benzylhydroxylamine (1.28 g, 10.4 mmol). The resulting
mixture was stirred at ambient temperature for 6 h, at which
time the reaction mixture was filtered and the residue was
washed with CH2Cl2 (5 × 20 mL). The combined filtrates were
evaporated under reduced pressure, and the residue was
purified by column chromatography (gradient hexane/EtOAC
60:40 to EtOAc 100%) to give nitrone 5a (2.17 g, 72% from 9)
as a white solid. Mp 164-166 °C. δH (400 MHz, CDCl3) 1.32
(t, 3H, J ) 7.0 Hz), 4.36 (q, 2H, J ) 7.0 Hz), 5.1 (s, 2H), 7.4 (s,
5H), 8.11 (s, 1H), 8.15 (s, 1H). δC (100 MHz, CDCl3) 14.3, 61.6,
69.6, 127.6, 129.3, 129.7, 130.0, 130.3, 131.2, 147.6, 157.0,
161.3. Anal. Calcd for C14H14N2O3S: C, 57.92; H, 4.86; N, 9.65.
Found: C, 58.13; H, 4.99; N, 9.42.
N-Benzyl-C-[4-(aminocarbonyl)-2-thiazolyl)] Nitrone
5b. The same procedure described above for the transformation
of 10 into 5a was applied to 12 (obtained from 13.1 mmol of
11). After purification by column chromatography (gradient
hexane/EtOAC 20:80 to EtOAc 100%), pure 5b (2.19 g, 64%
from 11) was obtained as a slightly yellow solid. Mp 198-200
°C (dec). δH (400 MHz, DMSO-d6) 5.32 (s, 2H), 7.38-7.45 (m,
3H), 7.49-7.55 (m, 2H), 7.65 (bs, 1Ha), 7.75 (bs, 1H), 8.26 (s,
1H), 8.84 (s, 1H). δC (100 MHz, DMSO-d6) 68.0, 123.9, 128.6,
128.7, 129.4, 129.9, 133.6, 150.9, 155.9, 162.3. Anal. Calcd for
C12H11N3O2S: C, 55.16; H, 4.24; N, 16.08. Found: C, 55.34;
H, 4.28; N, 15.86.
N-(2,3:5,6-Di-O-isopropylidene-r-D-mannofuranose-1-
yl)-C-[4-(ethoxycarbonyl)-2-thiazolyl)] Nitrone 5c. A solu-
tion of 10 (obtained from 10.4 mmol of 9) in CH2Cl2 (30 mL)
was treated sequentially with MgSO4 (1.0 g) and N-(2,3:5,6-
di-O-isopropylidene-R-D-mannofuranose-1-yl)hydroxylamine
(2.85 g, 4.7 mmol). The resulting mixture was heated at reflux
for 3 days, at which time the reaction mixture was filtered
and the residue was washed with CH2Cl2 (5 × 20 mL). The
combined filtrates were evaporated under reduced pressure,
and the residue was purified by column chromatography
(hexane/EtOAC 60:40) to give nitrone 5c (2.81 g, 61% from 9)
as a white solid. Mp 169-171 °C. [R]D +42 (c 0.88, CHCl3); δH
(400 MHz, CDCl3) 1.30 (s, 3H), 1.32 (s, 3H), 1.36 (t, 3H, J )
7.1 Hz), 1.39 (s, 3H), 1.47 (s, 3H3), 4.03-4.09 (m, 2H), 4.37
(ddd, 1H, J ) 0.8, 5.8, 6.8 Hz), 4.40 (q, 2H, J ) 7.1 Hz), 4.44
(dd, 1H, J ) 3.5, 6.8 Hz), 4.88 (dd, 1H, J ) 3.5, 5.8 Hz), 5.27
(d, 1H, J ) 5.8 Hz), 5.51 (s, 1H), 8.22 (s, 1H), 8.47 (s, 1H). δC
(100 MHz, CDCl3) 14.4, 24.4, 25.1, 26.0, 26.8, 61.8, 66.3, 73.0,
79.8, 84.5, 85.2, 102.5, 109.4, 113.7, 128.1, 128.6, 148.0, 156.0,
161.3. Anal. Calcd for C19H26N2O8S: C, 51.57; H, 5.92; N, 6.33.
Found: C, 51.76; H, 6.17; N, 6.14.
tive, providing a synthetically useful entry into racemic
and homochiral new nucleoside analogues of tiazofurin.
Experimental Section
General. The reaction flasks and other glass equipment
were heated in an oven at 130 °C overnight and assembled in
a stream of Ar. All reactions were monitored by TLC on silica
gel 60 F254; the position of the spots was detected with 254
nm UV light or by spraying with one of the following staining
systems: 50% methanolic sulfuric acid, 5% ethanolic phos-
phomolybdic acid, and iodine. Preparative centrifugally ac-
celerated radial thin-layer chromatography (radial chroma-
tography) was performed with solvents that were distilled prior
to use; the rotors (1 or 2 mm layer thickness) were coated with
silica gel, TLC grade, with binder and fluorescence indicator,
and the eluting solvents were delivered by the pump at a flow-
rate of 0.5-1.5 mL min-1. Column chromatography was
carried out in a MPLC system using silica gel 5-60 µm.
Melting points were uncorrected. 1H and 13C NMR spectra
were recorded on a 400 MHz instrument in CDCl3. Chemical
shifts are reported in ppm (δ) relative to CHCl3 (δ ) 7.26) in
CDCl3. Optical rotations were taken at 25 °C.
Diethoxythioacetamide 7b. To a solution of diethoxy-
acetamide 7a (16 g, 0.108 mmol) in dry benzene (200 mL) was
added P2S5 (8 g, 36 mmol) portionwise with stirring during a
period of 10 min. After the mixture was stirred at ambient
temperature for an additional 10 min (color changed from
yellow to violet), an insoluble material was removed by
decantation. The solution was washed with saturated aq
NaHCO3 (2 × 605 mL) and brine (2 × 60 mL). The organic
layer was separated, dried over MgSO4, and evaporated. A red
solid was remaining. The residue was recrystallized from
benzene/hexane (1:1) to give 10.4 g (59%) of pure 7 as red
needles. Mp 54-56 °C. δH (400 MHz, CDCl3) 1.25 (t, 6H, J )
7.0 Hz), 3.65 (q, 4H, J ) 7.0 Hz), 5.05 (s, 1H), 7.55 (s, 1H),
7.85 (s, 1H). δC (100 MHz, CDCl3) 14.9, 62.9, 103.1, 201.9. Anal.
Calcd for C6H13NO2S: C, 44.15; H, 8.03. Found: C, 44.52; H,
7.88.
Ethyl-2-(diethoxymethyl)thiazole-4-carboxylate 9. A
solution of 7 (7.8 g, 23.5 mmol) in absolute ethanol (200 mL)
was treated with ethyl-3-bromopyruvate 8 (8.85 g, 48.9 mmol)
and activated 4 Å molecular sieves (8.0 g). The resulting
mixture was refluxed for 90 min and then filtered and
concentrated in a vacuum. The residue was partitioned
between EtOAc (100 mL) and saturated aq NaHCO3 (50 mL).
The organic layer was separated and washed with brine (2 ×
50 mL), dried over MgSO4, and evaporated under reduced
pressure. The crude product was purified by column chroma-
tography (gradient hexane/EtOAc 80:20 to 100% EtOAc) to
give pure 9 (4.87 g, 80%) as a yellow oil. δH (400 MHz, CDCl3)
1.19 (t, 6H, J ) 7.1 Hz), 1.33 (t, 3H, J ) 7.1 Hz), 3.60 (q, 2H,
J ) 7.1 Hz), 3.60 (q, 2H, J ) 7.1 Hz), 3.67 (q, 2H, J ) 7.1 Hz),
4.35 (q, 2H, J ) 7.1 Hz), 5.64 (s, 1H), 8.14 (s, 1H). δC (100
MHz, CDCl3) 14.4, 15.0 (2C), 61.4, 62.7 (2C), 98.8, 128.4, 147.0,
161.4, 170.2. Anal. Calcd for C11H17NO4S: C, 50.95; H, 6.61.
Found: C, 50.78; H, 6.72.
2-(Diethoxymethyl)thiazole-4-carboxamide 11. A solu-
tion of 9 (6 g, 23.2 mmol) in methanol (60 mL) was saturated
with ammonia (ca. 7% p/v). The resulting solution was stirred
at ambient temperature for 24 h. The solvent was then
evaporated under reduced pressure. The crude product was
purified by column chromatography (hexane/EtOAc, 50:50) to
give pure 11 (3.05 g, 57%) as a white solid. Mp 112-114 °C.
δH (400 MHz, DMSO-d6) 1.16 (t, 6H, J ) 7.1 Hz), 3.65 (bq,
4H, J ) 7.1 Hz), 5.71 (s, 1H), 7.59 (bs, 1H), 7.70 (bs, 1H), 8.28
(s, 1H). δC (100 MHz, DMSO-d6) 15.1, 61.8, 97.7, 125.0, 150.5,
162.1, 168.7. Anal. Calcd for C9H14N2O3S: C, 46.94; H, 6.13.
Found: C, 47.11; H, 6.27.
Cycloaddition Reactions between Nitrones 5 and
Allylic Alcohol. In the Absence of a Lewis Acid. A solution
of the corresponding nitrone 5 (3.4 mmol) in CH2Cl2 (100 mL)
was treated with allylic alcohol (12 mL, 176 mmol) at ambient
temperature. The reaction mixture was heated at 70 °C in a
sealed tube until no more starting material was observed
(TLC). After being cooled at ambient temperature, the reaction
mixture was treated with brine (100 mL). The organic layer
Ethyl-2-formylthiazole-4-carboxylate 10. To a solution
of 2.70 g of 9 (10.4 mmol) in acetone (100 mL) was added 1 M
hydrochloric acid (10 mL). The resulting solution was refluxed
8998 J. Org. Chem., Vol. 70, No. 22, 2005

1,3-Dipolar Cycloadditions of C-(2-Thiazolyl)nitrones
was separated, washed with brine (50 mL), dried over MgSO4,
and evaporated under reduced pressure to afford the crude
product, which was purified by column chromatography (hex-
ane/EtOAc, 60:40).
1.3, 17.2 Hz), 6.02 (tdd, 1H, J ) 6.1, 10.2, 17.2 Hz), 7.23-7.41
(m, 5H), 8.13 (s, 1H). δC (100 MHz, CDCl3) 37.5, 60.4, 63.9,
65.5, 66.7, 78.5, 118.1, 128.3, 128.5, 128.6, 129.2, 132.6, 137.3,
147.5, 160.9, 173.8. Anal. Calcd for C18H20N2O4S: C, 59.98;
H, 5.59; N, 7.77. Found: C, 59.71; H, 5.47; N, 7.52.
In the Presence of a Lewis Acid. A solution of the
corresponding nitrone 5 (3.4 mmol) in CH2Cl2 (100 mL) was
treated with 1.0 equiv of Lewis acid (3.4 mmol) at ambient
temperature, and the resulting mixture was stirred for 15 min,
at which time allylic alcohol (12 mL, 176 mmol) was added.
The reaction mixture was heated at 70 °C in a sealed tube
until no more starting material was observed (TLC). After
being cooled at ambient temperature, the reaction mixture was
treated with a saturated aq solution of EDTA (100 mL). The
organic layer was separated, washed with brine (2 × 50 mL),
dried over MgSO4, and evaporated under reduced pressure to
afford the crude product, which is purified by column chro-
matography (hexane/EtOAc, 80:20).
Under Microwave Irradiation and in the Presence of
Lewis Acids (Only for Nitrone 5a). To a pressure tube
containing 2 mL of anhydrous CH2Cl2 were added 0.1 g (0.34
mmol) of nitrone 5a and 0.12 g (0.34 mmol) of Zn(OTf)2. The
resulting suspension was stirred for 15 min, then 1.2 mL (1.76
mmol) of allylic alcohol was added, and the mixture was
inserted into the cavity of a microwave apparatus and heated
at 90 W for 15 min (internal temperature 120 °C). After being
cooled at room temperature, the reaction mixture was treated
with a saturated aqueous solution of Na-EDTA (10 mL). The
organic layer was separated, washed with brine (2 × 5 mL),
dried over MgSO4, and evaporated under reduced pressure to
afford the crude product, which is purified by flash chroma-
tography (hexane/EtOAc 80:20) to give 14 (64 mg, 54%) and
17 (44 mg, 36%) as the only products of the reaction (see Table
1, entry 6).
Ethyl 2-((3S*,5R*)-2-Benzyl-5-(hydroxymethyl)isox-
azolidin-3-yl)thiazole-4-carboxylate 14. Oil. δH (400 MHz,
CDCl3) 1.38 (t, 3H, J ) 7.0 Hz), 2.22 (bs, 1H), 2.49 (td, 1H, J
) 5.4, 13.1 Hz), 2.97 (td, 1H, J ) 8.6, 13.1 Hz), 3.55 (dd, 1H,
J ) 5.5, 11.8 Hz), 3.66 (dd, 1H, J ) 2.2, 11.8 Hz), 4.00 (d, 1H,
J ) 13.4 Hz), 4.08 (d, 1H, J ) 13.4 Hz), 4.39 (q, 2H, J ) 7.0
Hz), 4.47 (dtd, 1H, J ) 2.9, 5.5, 8.5 Hz), 4.53 (dd, 1H, J ) 5.4,
8.6 Hz), 7.23-7.40 (m, 5H), 8.10 (s, 1H). δC (100 MHz, CDCl3)
14.3, 37.6, 60.4, 61.0, 64.0, 66.8, 78.6, 127.9, 128.1, 128.6, 129.2,
137.3, 147.9, 161.4, 173.7. Anal. Calcd for C17H20N4O4S: C,
58.60; H, 5.79; N, 8.04. Found: C, 58.49; H, 5.90; N, 8.24.
Ethyl 2-((3S*,5S*)-2-Benzyl-5-(hydroxymethyl)isoxazo-
lidin-3-yl)thiazole-4-carboxylate 17. Oil. δH (400 MHz,
CDCl3) 1.38 (t, 3H, J ) 7.1 Hz), 2.26 (bs, 1H), 2.56 (ddd, 1H,
J ) 4.4, 7.4, 12.5 Hz), 2.72 (td, 1H, J ) 8.1, 12.5 Hz), 3.59 (dd,
1H, J ) 4.4, 12.1 Hz), 3.80 (dd, 1H, J ) 2.9, 12.1 Hz), 4.01 (d,
1H, J ) 13.6 Hz), 4.08 (d, 1H, J ) 13.6 Hz), 4.22 (ddt, 1H, J
) 2.9, 4.4, 7.7 Hz), 4.40 (q, 2H, J ) 7.1 Hz), 4.52 (dd, 1H, J )
4.4, 8.1 Hz), 7.24-7.40 (m, 5H), 8.12 (s, 1H). δC (100 MHz,
CDCl3) 14.3, 37.8, 61.3, 61.5, 62.8, 66.5, 78.5, 127.6, 128.3,
128.4, 128.8, 136.3, 147.2, 161.3, 173.1. Anal. Calcd for
C17H20N4O4S: C, 58.60; H, 5.79; N, 8.04. Found: C, 58.83; H,
5.95; N, 7.88.
N-(2,3:5,6-Di-O-isopropylidene-r-D-mannofuranose-1-
yl)-C-[4-(allyloxycarbonyl)-2-thiazolyl)] Nitrone 18. Mp
146-148 °C; [R]D +27 (c 0.70, CHCl3). δH (400 MHz, CDCl3)
1.34 (s, 3H), 1.36 (s, 3H), 1.44 (s, 3H), 1.51 (s, 3H), 4.07-4.13
(m, 2H), 4.41 (ddd, 1H, J ) 4.4, 5.5, 7.0 Hz), 4.48 (dd, 1H, J )
3.7, 7.0 Hz), 4.87 (ddd, 2H, J ) 1.1, 1.5, 5.9 Hz), 4.92 (dd, 1H,
J ) 3.7, 5.9 Hz), 5.29 (tdd, 1H, J ) 1.1, 1.5, 10.3 Hz), 5.31 (d,
1H, J ) 5.9 Hz), 5.40 (qd, 1H, J ) 1.5, 17.3 Hz), 5.56 (s, 1H),
6.03 (tdd, 1H, J ) 5.9, 10.3, 17.3 Hz), 8.28 (s, 1H), 8.51 (s,
1H). δC (100 MHz, CDCl3) 24.3, 25.0, 25.9, 26.7, 66.2(×2), 73.0,
79.8, 84.4, 85.2, 102.5, 109.3, 113.7, 119.2, 128.3, 128.5, 131.6,
147.6, 156.0, 160.1. Anal. Calcd for C20H26N2O8S: C, 52.85;
H, 5.77; N, 6.16. Found: C, 52.64; H, 5.55; N, 6.01.
N-(2,3-O-Isopropylidene-r-D-mannofuranose-1-yl)-C-
[4-(allyloxycarbonyl)-2-thiazolyl)] Nitrone 19. Mp 150-
152 °C; [R]D +31 (c 0.70, CHCl3). δH (400 MHz, CDCl3) 1.36 (s,
3H3), 1.53 (s, 3H), 2.98 (bs, 2H), 3.81 (dd, 1H, J ) 5.1, 11.4
Hz), 3.90 (dd, 1H, J ) 3.3, 11.4 Hz), 4.00-4.11 (m, 1H), 4.47
(dd, 1H, J ) 4.0, 8.5 Hz), 4.86 (ddd, 2H, J ) 1.1, 1.5, 5.9 Hz),
5.01 (dd, 1H, J ) 4.0, 5.9 Hz), 5.30 (tdd, 1H, J ) 1.1, 1.5, 10.3
Hz), 5.31 (d, 1H, J ) 5.9 Hz), 5.40 (qd, 1H, J ) 1.5, 17.0 Hz),
5.58 (s, 1H), 6.02 (tdd, 1H, J ) 5.9, 10.3, 17.0 Hz), 8.27 (s,
1H), 8.56 (s, 1H). δC (100 MHz, CDCl3) 24.7, 26.1, 63.7, 66.3,
70.1, 80.4, 83.9, 84.4, 102.4, 113.8, 119.3, 128.4, 128.5, 131.6,
147.5, 156.2, 160.9. Anal. Calcd for C17H27N2O8S: C, 49.27;
H, 5.35; N, 6.76. Found: C, 49.47; H, 5.16; N, 6.96.
Ethyl 2-[2-(2,3:5,6-Di-O-isopropylidene-r-D-mannofura-
nose-1-yl)-5-(hydroxymethyl)isoxazolidin-3-yl]thiazole-
4-carboxylate 21. (Selected signals) δH (400 MHz, CDCl3) 1.30
(s, 3H), 1.32 (s, 3H), 1.34 (s, 6H), 1.35 (t, 3H, J ) 7.0 Hz), 1.45
(s, 1H), 2.70 (ddd, 1H, J ) 3.7, 6.6, 13.2 Hz), 2.83 (td, 1H, J )
8.8, 13.2 Hz), 3.46 (dd, 1H, J ) 5.1, 12.5 Hz), 3.66 (dd, 1H, J
) 2.9, 12.5 Hz), 3.77 (dd, 1H, J ) 4.4, 8.5 Hz), 3.98 (dd, 1H, J
) 6.2, 8.5 Hz), 4.09 (dd, 1H, J ) 3.7, 7.0 Hz), 4.28-4.41 (m,
1H), 4.36 (q, 2H, J ) 7.0 Hz), 4.44-4.53 (m, 1H), 4.56 (s, 1H),
4.83 (dd, 1H, J ) 3.7, 5.9 Hz), 4.89 (dd, 1H, J ) 3.7, 8.8 Hz),
5.02 (d, 1H, J ) 5.9 Hz), 8.05 (s, 1H). δC (100 MHz, CDCl3)
14.3, 24.5, 25.1, 26.0, 26.8, 35.9, 61.5, 63.0, 63.2, 66.6, 73.0,
80.0, 80.2, 82.8, 83.9, 96.6, 109.2, 112.8, 127.9, 147.4, 161.3,
174.2.
Ethyl 2-{(3S,5R)-2-Benzyl-5-[(4R)-2,2-dimethyl-1,3-di-
oxolan-4-yl]isoxazolidin-3-yl}thiazole-4-carboxylate 23
and Ethyl 2-{(3R,5R)-2-Benzyl-5-[(4R)-(2,2-dimethyl-1,3-
dioxolan-4-yl]isoxazolidin-3-yl}thiazole-4-carboxylate 24.
A solution of nitrone 5a (1.46 g, 5 mmol) in toluene (100 mL)
was treated with vinyl dioxolane (1.3 g, 10 mmol) at ambient
temperature. The resulting solution was heated at 140 °C for
12 days in a sealed tube and under an argon atmosphere. The
solvent was evaporated under reduced pressure, and the
residue was purified by radial chromatography (hexane/EtOAc,
80:20) to afford recovered starting nitrone 5a (0.88 g, 60%)
and pure 23 and 24.
N-Benzyl-C-[4-(allyloxycarbonyl)-2-thiazolyl)] Nitrone
16. White solid. Mp 136-138 °C. δH (400 MHz, CDCl3) 4.81
(ddd, 2H, J ) 1.1, 1.5, 5.9 Hz), 5.12 (s, 2H), 5.25 (td, 1H, J )
1.3, 10.3 Hz), 5.35 (dq, 1H, J ) 1.5, 17.3 Hz), 5.98 (tdd, 1H, J
) 5.9, 10.3, 17.3 Hz), 7.40 (s, 5H), 8.12 (s, 1H), 8.20 (s, 1H). δC
(100 MHz, CDCl3) 66.1, 69.6, 119.1, 127.8, 129.3, 129.7, 129.9,
130.3, 131.1, 131.6, 147.2, 157.0, 161.0. Anal. Calcd for
C15H14N2O3S: C, 59.59; H, 4.67; N, 9.27. Found: C, 59.43; H,
4.51; N, 9.66.
Allyl 2-((3S*,5R*)-2-Benzyl-5-(hydroxymethyl)isoxazo-
lidin-3-yl)thiazole-4-carboxylate 17. Oil. δH (400 MHz,
CDCl3) 2.16 (bs, 1H), 2.50 (td, 1H, J ) 5.1, 12.8 Hz), 2.98 (td,
1H, J ) 8.6, 12.8 Hz), 3.52-3.71 (m, 2H), 4.01 (d, 1H, J )
13.4 Hz), 4.10 (d, 1H, J ) 13.4 Hz), 4.45-4.51 (m, 1H), 4.53
(dd, 1H, J ) 5.1, 8.6 Hz), 4.83 (ddd, 2H, J ) 1.0, 1.3, 6.1 Hz),
5.28 (tdd, 1H, J ) 1.0, 1.3, 10.2 Hz), 5.39 (tdd, 1H, J ) 1.0,
23. (0.316 g, 18%). Oil; [R]D +66 (c 0.70, CHCl3). δH (400
MHz, CDCl3) 1.28 (s, 3H, CH3), 1.33 (s, 3H), 1.39 (t, 3H, J )
7.1 Hz), 2.67 (ddd, 1H, J ) 5.0, 5.3, 13.4 Hz), 3.05 (td, 1H, J
) 8.3, 13.4 Hz), 3.76 (m, 1H), 3.95-4.02 (m, 3H), 4.12 (d, 1H,
J ) 13.4 Hz), 4.30 (m, 1H), 4.40 (q, 2H, J ) 7.1 Hz), 4.55 (dd,
1H, J ) 5.0, 8.6 Hz), 7.24-7.39 (m, 5H), 8.10 (s, 1H). δC (100
MHz, CDCl3) 14.4, 25.2, 26.7, 39.4, 60.6, 61.4, 66.4, 67.3, 76.9,
78.7, 109.5, 127.7, 128.2, 128.5, 128.9, 136.3, 147.2, 161.4,
174.1. Anal. Calcd for C21H26N2O5S: C, 60.27; H, 6.26; N, 6.69.
Found: C, 60.14; H, 6.00; N, 6.83.
24. (0.209 g, 10%). Oil; [R]D -46 (c 0.70, CHCl3). δH (400
MHz, CDCl3) 1.36 (s, 3H), 1.40 (t, 3H, J ) 7.1 Hz), 1.41 (s,
3H), 2.72 (ddd, 1H, J ) 4.8, 7.3, 12.9 Hz), 2.78 (td, 1H, J )
7.8, 12.9 Hz), 3.75 (dd, 1H, J ) 5.8, 8.6 Hz), 3.98 (d, 1H, J )
13.4 Hz), 4.03-4.08 (m, 2H), 4.11 (d, 1H, J ) 13.0 Hz), 4.15
J. Org. Chem, Vol. 70, No. 22, 2005 8999

Chiacchio et al.
(dd, 1H, J ) 6.3, 12.4 Hz), 4.42 (q, 2H, J ) 7.1 Hz), 4.56 (dd,
1H, J ) 4.8, 7.8 Hz), 7.23-7.38 (m, 5H), 8.13 (s, 1H). δC (100
MHz, CDCl3) 14.4, 25.2, 26.5, 38.7, 53.4, 61.5, 68.4, 67.3, 76.8,
79.1, 109.8, 127.7, 128.4, 128.5, 129.0, 136.4, 147.2, 161.4,
173.2. Anal. Calcd for C21H26N2O5S: C, 60.27; H, 6.26; N, 6.69.
Found: C, 60.39; H, 6.17; N, 6.54.
Cycloaddition Reaction between Nitrone 5a and (2S)-
1,2-Dihydroxy-1-butene 25. To a pressure tube containing
4 mL of 1:1 CH2Cl2:EtOH was added 0.2 g (0.68 mmol) of
nitrone 5a. The resulting solution was treated with 0.182 g
(2.06 mmol) of (2S)-1,2-hydroxybutene 25, and the resulting
mixture was inserted into the cavity of a microwave apparatus
and heated at 90 W for 1 h (internal temperature 120 °C). After
being cooled at room temperature, the reaction mixture was
treated with brine (5 mL). The organic layer was separated,
washed with brine (5 mL), dried over MgSO4, and evaporated
under reduced pressure to afford the crude product, which was
purified by flash chromatography (hexane/EtOAc 70:30) to give
the pure compounds 27 (see Table 2, entry 2) in 60% total yield.
Ethyl 2-{(3R,5S)-2-Benzyl-5-[(2R)-1,2-dihydroxy-2-eth-
yl]isoxazolidin-3-yl}thiazole-4-carboxylate 27a. (30 mg,
10%). Oil; [R]D -86 (c 0.56, CHCl3). δH (400 MHz, CDCl3) 1.34
(t, 3H, J ) 7.1 Hz), 2.18 (bs, 2H), 2.50 (dt, 1H, J ) 5.6, 12.2
Hz), 2.91 (dt, 1H, J ) 8.6, 12.2 Hz), 3.50 (dd, 1H, J ) 6.6, 12.4
Hz), 3.55-3.60 (m, 2H), 3.95 (s, 2H), 4.34 (q, 2H, J ) 7.1 Hz),
4.37 (m, 1H), 4.47 (dd, 1H, J ) 5.8, 8.4 Hz), 7.22-7.31 (m,
5H), 8.06 (s, 1H). δC (100 MHz, CDCl3) 14.4, 38.8, 60.6, 61.5,
63.8, 66.8, 73.2, 78.2, 127.8, 128.2, 128.6, 128.8, 136.2, 147.2,
161.2, 172.6. Anal. Calcd for C18H22N2O5S: C, 57.13; H, 5.86;
N, 7.40. Found: C, 57.32; H, 5.74; N, 7.28.
Ethyl 2-{(3S,5R)-2-Benzyl-5-[(2R)-1,2-dihydroxy-2-eth-
yl]isoxazolidin-3-yl}thiazole-4-carboxylate 27b. (30 mg,
10%). Oil; [R]D +52 (c 0.38, CHCl3). δH (400 MHz, CDCl3) 1.32
(t, 3H, J ) 7.1 Hz), 2.40 (bs, 2H), 2.70 (dt, 1H, J ) 5.6, 13.2
Hz), 2.90 (dt, 1H, J ) 8.6, 13.2 Hz), 3.49 (dd, 1H, J ) 5.8, 11.6
Hz), 3.58 (dd, 1H, J ) 3.5, 11.6 Hz), 3.66 (q, 1H, J ) 5.1 Hz),
3.90 (d, 1H, J ) 13.2 Hz), 4.01 (d, 1H, J ) 13.2 Hz), 4.32 (q,
2H, J ) 7.1 Hz), 4.36 (m, 1H), 4.46 (dd, 1H, J ) 4.8, 8.4 Hz),
7.20-7.31 (m, 5H), 8.03 (s, 1H). δC (100 MHz, CDCl3) 14.4,
37.0, 60.5, 61.4, 63.6, 67.6, 72.2, 79.1, 127.8, 128.2, 128.7, 129.0,
136.1, 147.2, 161.2, 171.3. Anal. Calcd for C18H22N2O5S: C,
57.13; H, 5.86; N, 7.40. Found: C, 57.04; H, 5.79; N, 7.60.
Ethyl 2-{(3S,5S)-2-Benzyl-5-[(2R)-1,2-dihydroxy-2-eth-
yl]isoxazolidin-3-yl}thiazole-4-carboxylate 27c. (60 mg,
20%). Oil; [R]D -70 (c 0.32, CHCl3). δH (400 MHz, CDCl3) 1.33
(t, 3H, J ) 7.3 Hz), 2.00 (bs, 2H), 2.55 (ddd, 1H, J ) 4.5, 7.0,
12.3 Hz), 2.75 (dt, 1H, J ) 8.6, 12.3 Hz), 3.49 (dd, 1H, J ) 6.6,
11.6 Hz), 3.62 (dd, 1H, J ) 3.3, 11.6 Hz), 3.81 (m, 1H), 3.94
(d, 1H, J ) 13.4 Hz), 4.00 (d, 1H, J ) 13.4 Hz), 4.02 (m, 1H),
4.34 (q, 2H, J ) 7.3 Hz), 4.46 (m, 1H), 7.20-7.32 (m, 5H), 8.06
(s, 1H). δC (100 MHz, CDCl3) 14.4, 37.4, 60.8, 61.4, 63.7, 66.5,
72.0, 78.9, 127.7, 128.0, 128.6, 129.0, 136.2, 147.0, 161.3, 172.5.
Anal. Calcd for C18H22N2O5S: C, 57.13; H, 5.86; N, 7.40.
Found: C, 57.35; H, 5.93; N, 7.58.
Ethyl 2-{(3S,5R)-2-Benzyl-5-[(2R)-1,2-dihydroxy-2-eth-
yl]isoxazolidin-3-yl}thiazole-4 carboxylate 27d. (60 mg,
20%). Oil; [R]D +59 (c 0.496, CHCl3). δH (400 MHz, CDCl3) 1.33
(t, 3H, J ) 7.1 Hz), 2.15 (bs, 2H), 2.64 (ddd, 1H, J ) 3.8, 6.6,
12.2 Hz), 2.75 (dt, 1H, J ) 8.4, 12.2 Hz), 3.55-365 (m, 3H),
3.95 (d, 1H, J ) 13.2 Hz), 3.97 (m, 1H), 4.05 (d, 1H, J ) 13.2
Hz), 4.35 (q, 2H, J ) 7.1 Hz), 4.51 (m, 1H), 7.20-7.32 (m, 5H),
8.06 (s, 1H). δC (100 MHz, CDCl3) 14.5, 37.9, 61.6 (2C), 64.5,
66.2, 72.9, 79.7, 127.8, 128.5, 128.6, 128.9, 136.2, 147.3, 161.5,
171.4. Anal. Calcd for C18H22N2O5S: C, 57.13; H, 5.86; N, 7.40.
Found: C, 56.93; H, 5.96; N, 7.21.
suspension was stirred for 15 min, then 0.34 g (1.03 mmol) of
(2S)-1-O-(tert-butyldiphenylsylyl)-3-butene-1,2-diol 2622 was
added, and the mixture was inserted into the cavity of a
microwave apparatus and heated at 90 W for 2 h (internal
temperature 120 °C). After being cooled at room temperature,
the reaction mixture was treated with a saturated aqueous
solution of Na-EDTA (10 mL). The organic layer was sepa-
rated, washed with brine (2 × 5 mL), dried over MgSO4, and
evaporated under reduced pressure to afford the crude product,
which was purified by flash chromatography (hexane/EtOAc
80:20) to give pure 28a and 28b.
28a. (0.117 g, 56%). Oil; [R]D -53 (c 0.29, CHCl3). δH (500
MHz, CDCl3) 0.96 (9H, s), 1.32 (t, 3H, J ) 7.0 Hz), 2.45 (dt,
1H, J ) 6.0, 12.5 Hz), 2.63 (bs, 1H), 2.90 (dt, 1H, J ) 5.0, 12.5
Hz), 3.59 (m, 3H), 3.92 (d, 1H, J ) 13.5 Hz), 3.97 (d, 1H, J )
13.5 Hz), 4.33 (q, 2H, J ) 7.0 Hz), 4.44 (dd, 1H, J ) 6.0, 8.5
Hz), 4.49 (dd, 1H, J ) 5.0, 9.0 Hz), 7.17-7.35 (m, 10H), 7.54-
7.59 (m, 4H), 8.02 (s, 1H). δc (200 MHz, CDCl3) 14.3, 19.2, 26.8,
38.9, 60.4, 61,4, 64.6, 66.8, 73.3, 77.3, 127.7, 128.1, 128.4, 128.7,
129.7, 133.1, 135.5, 136.2, 147.08, 161.2, 172.8. Anal. Calcd
for C34H40N2O5SSi: C, 66.20; H, 6.54; N, 4.54. Found: C, 66.47;
H, 6.20; N, 4.80.
28b. (30 mg, 14%). Oil; [R]D +22 (c 0.3, CHCl3). δH (500 MHz,
CDCl3) 0.97 (s, 9H), 1.32 (t, 3H, J ) 7.5 Hz), 1.59 (bs, 1H),
2.61 (dt, 1H, J ) 12.0, 5.5 Hz), 2.85 (dt, 1H, J ) 12.0, 8.0 Hz),
3.57 (dd, 1H, J ) 5.0, 10.0 Hz), 3.62 (dd, 1H, J ) 8.0, 10.0
Hz), 3.69 (m, 1H), 3.90 (d, 1H, J ) 13.0 Hz), 3.96 (d, 1H, J )
13.0 Hz), 4.33 (q, 2H, J ) 7.5 Hz), 4.37 (ddd, 1H, J ) 3.5, 5.5,
8.5 Hz), 4.44 (dd, 1H, J ) 5.5, 9.0 Hz), 7.15-7.36 (m, 10H),
7.53-7.56 (m, 4H), 8.07 (s, 1H). Anal. Calcd for C34H40N2O5-
SSi: C, 66.20; H, 6.54; N, 4.54. Found: C, 66.27; H, 6.48; N,
4.54.
Desilylation of 28a and 28b. A solution of 28a (0.1 g, 0.162
mmol) in THF (20 mL) was treated with anhydrous Bu4NF in
THF (2 mL of a 1.0 M solution, 2 mmol). The resulting solution
was stirred at ambient temperature for 3 h, at which time the
reaction mixture was partitioned between brine (20 mL) and
EtOAc (20 mL). The organic layer was separated, and the
aqueous layer was extracted with EtOAc (20 mL). The
combined organic extracts were washed with brine (25 mL),
dried over MgSO4, and evaporated under reduced pressure.
The residue was purified by column chromatography (hexane/
EtOAc, 50:50) to afford pure 27a (55 mg, 90%).
The same procedure was applied to 28b (0.1 g, 0.162 mmol).
After purification, pure 27b was obtained (54 mg, 88%).
These compounds showed physical and spectroscopic prop-
erties identical to those obtained from the cycloaddition
between 5a and 24.
2-[(3S,5R)-2-Benzyl-5-(hydroxymethyl)isoxazolidin-3-
yl]thiazole-4-carboxamide 4 (Isoxazolidine Analogue of
Tiazofurin). From 14 (Synthesis of (()-4). A solution of
14 (0.4 g, 1.14 mmol) in methanol (30 mL) was saturated with
ammonia (ca 7% p/v). The resulting solution was stirred at
ambient temperature for 24 h. The solvent was then evapo-
rated under reduced pressure. The crude product was purified
by column chromatography (EtOAc) to give pure (()-4 (0.37
g, quant.) as a sticky foam.
From 27a (Synthesis of (-)-4). A cooled (to 0 °C) solution
of 27a (76 mg, 0.2 mmol) in a 1:1 mixture of MeOH:H2O (10
mL) was treated with NaIO4 (42 mg, 0.2 mmol). The resulting
suspension was stirred at 0 °C for 1 h, filtered, and rotatory
evaporated. The residue was taken up in aqueous methanol
(8 mL), cooled to 0 °C, and treated with NaBH4 (24 mg, 0.6
mmol). After being stirred at the same temperature for 2 h,
the reaction mixture was concentrated under reduced pressure.
The residue was purified by column chromatography (hexane/
EtOAc, 80:20) on silica gel to give pure (-)-14 (56 mg, 80%;
[R]D -54 (c 0.38, CHCl3)). The same procedure described above
was then applied to 14. After purification by radial chroma-
tography (EtOAc), enantiomerically pure 4 (52 mg, 80% from
27a) was obtained.
Ethyl 2-{(3R,5S)-2-Benzyl-5-[(2R)-1-(tert-butyldiphenyl-
siloxy)-2-ethyl]isoxazolidin-3-yl}thiazole-4-carboxylate
28a and Ethyl 2-{(3S,5R)-2-Benzyl-5-[(2R)-1-(tert-butyl-
diphenylsiloxy)-2-hydroxy-2-ethyl]isoxazolidin-3-yl}-
thiazole-4-carboxylate 28b. To a pressure tube containing
2 mL of anhydrous CH2Cl2 were added 0.1 g (0.34 mmol) of
nitrone 5a and 0.12 g (0.34 mmol) of Zn(OTf)2. The resulting
9000 J. Org. Chem., Vol. 70, No. 22, 2005

1,3-Dipolar Cycloadditions of C-(2-Thiazolyl)nitrones
(-)-4. Oil; [R]D -73 (c 0.45, CHCl3). δH (400 MHz, CDCl3)
2.49 (ddd, 1H, J ) 5.0, 5.6, 12.6 Hz), 2.73 (bs, 1H), 2.84 (ddd,
1H, J ) 8.3, 8.6, 12.6 Hz), 3.49 (dd, 1H, J ) 5.6, 11.9 Hz),
3.58 (dd, 1H, J ) 2.8, 11.9 Hz), 3.93 (d, 1H, J ) 13.4 Hz), 4.05
(d, 1H, J ) 13.4 Hz), 4.35 (dd, 1H, J ) 4.5, 8.6 Hz), 4.44 (m,
1H), 6.28 (bs, 1H), 7.02 (bs, 1H), 7.17-7.34 (m, 5H), 7.97 (s,
1H). δC (100 MHz, CDCl3) 37.3, 60.6, 63.6, 66.2, 78.5, 125.3,
127.8, 128.6, 128.9, 136.3, 149.5, 163.3, 173.1. Anal. Calcd for
C15H17N3O3S: C, 56.41; H, 5.37; N, 13.16. Found: C, 56.21;
H, 5.48; N, 13.34.
Acknowledgment. This work was partially sup-
ported by M.U.R.S.T. and Italian C.N.R. We also thank
the Spanish Ministry of Science and Technology (MCYT)
and FEDER Program (Project BQU2004-00421) for their
support. Mrs. Stefanie Sparka is gratefully acknowl-
edged for technical assistance. The Government of
Aragon in Spain is also acknowledged for financial
support and for a grant to J.A.M.
JO051572A
J. Org. Chem, Vol. 70, No. 22, 2005 9001