Solid supported chiral auxiliaries in asymmetric synthesis. Part 2: Catalysis of 1,3-dipolar cycloadditions by Mg(II) cation

Article abstract of DOI:10.1016/S0040-4020(01)00769-4

1,3-Dipolar cycloadditions of supported Evans' chiral auxiliary with nitrile oxides and nitrones in the presence of Mg(II) cation as catalyst were evaluated. The presence of acetonitrile as co-solvent was found to be fundamental for the Lewis acid catalysis on solid-phase. The regio- and stereochemical outcome of nitrile oxide cycloadditions is influenced by nearly stoichiometric quantities of the cation, whilst catalytic amounts of Mg(II) influence both the reactivity and the stereoselectivity of the nitrone cycloadditions. The results obtained support a reaction mechanism involving the coordination of the Mg(II) to the dicarbonyl fragment of the chiral auxiliary.

Full text of DOI:10.1016/S0040-4020(01)00769-4

TETRAHEDRON
Pergamon
Tetrahedron 57 ,2001) 8313±8322
Solid supported chiral auxiliaries in asymmetric synthesis.
Part 2: Catalysis of 1,3-dipolar cycloadditions
by Mg II) cationq
Giuseppe Faita,a,p Alfredo Paio,b Paolo Quadrelli,a,p Fabio Rancatia and Pierfausto Senecic
a
Á
Dipartimento di Chimica Organica dell'Universita degli Studi di Pavia, Viale Taramelli 10, I-27100 Pavia, Italy
bGSK GroupGlaxo Wellcome Medicines Research Centre, Via Fleming 4, I-37135 Verona, Italy
cNucleotide Analog Design, Landsbergerstrasse 50, D-80339 Munich, Germany
Received 7 May 2001; revised 21 June 2001; accepted 19 July 2001
AbstractÐ1,3-Dipolar cycloadditions of supported Evans' chiral auxiliary with nitrile oxides and nitrones in the presence of Mg,II) cation
as catalyst were evaluated. The presence of acetonitrile as co-solvent was found to be fundamental for the Lewis acid catalysis on solid-
phase. The regio- and stereochemical outcome of nitrile oxide cycloadditions is in¯uenced by nearly stoichiometric quantities of the cation,
whilst catalytic amounts of Mg,II) in¯uence both the reactivity and the stereoselectivity of the nitrone cycloadditions. The results obtained
support a reaction mechanism involving the coordination of the Mg,II) to the dicarbonyl fragment of the chiral auxiliary. q 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
phase approach allows some practical advantages, since the
chiral information could be easily recycled for further
processes.1,7
A useful approach to asymmetric synthesis is offered by the
use of temporary linked chiral information. Among the
examples in the literature, one of the most useful chiral
auxiliaries has been developed by Evans,2 ®nding wide
applications in several C±C bond forming reactions3 and,
in particular, in the ®eld of cycloadditions.2±4
Despite the increasing relevance of solid phase synthesis in
contemporary organic chemistry, only few examples of
cycloadditions involving solid supported dienophiles or
dipolarophiles have been reported,1,7d,8,9 and even fewer
are the reports investigating catalysed supported cyclo-
additions.7d,9a,10 To the best of our knowledge, the only
paper referring to the catalysis of cycloadditions involving
a supported chiral oxazolidin-2-one derivative is related to a
Diels±Alder reaction of the solid supported N-crotonyl
oxazolidone with cyclopentadiene.7d The cycloaddition
was ef®ciently catalysed by Et2AlCl ,1.4±2.8 equiv.),
giving results very similar to those observed under classic
solution conditions ,endo/exo ratio, 21:1; ee endo-adduct,
86%), when Merri®eld resin was used. The Wang-resin
supported dienophile was unstable in the presence of
Al,III) and the catalysed cycloaddition did not yield any
of the desired reaction products.
The extensive use of chiral oxazolidinones in asymmetric
synthesis is due to their ful®lment of several requirements:
easy preparation, high induced selectivities, and ability to
interact with several metal cations. The latter feature is
particularly relevant since catalysed reactions usually
yield increased reactivities and selectivities; the suitable
choice of the catalytic system can lead to the selective
formation of only one of the possible diastereoisomers.
Chiral oxazolidin-2-ones are easily prepared either starting
from natural amino acids or by using a modi®ed sharpless
asymmetric aminohydroxylation strategy.5 When the oxa-
zolidin-2-one is synthesised starting from tyrosine, it can be
grafted to a polymer through the phenolic group.6 A solid-
In a previous communication, we reported the synthesis and
the reactivity of polymer grafted chiral oxazolidin-2-ones
derived from tyrosine in 1,3-dipolar cycloadditions.1 1,3-
Dipolar cycloaddition reactions of 1a,b with either
mesitonitrile oxide 3 ,Scheme 2) or diphenyl nitrone 4
,Scheme 3) evidenced good reactivities and selectivities,
but the cycloadditions were not in¯uenced by the
presence of Lewis acids such as Mg,II) or Sc,III) cations.
This behaviour strongly argued with classical solution
q See Ref. 1.
Keywords: asymmetric induction; 1,3-dipolar cycloaddition; catalysis;
solid-phase synthesis.
Corresponding author. Tel.:139-0382-507-866; fax:139-0382-507-323;
e-mail: faita@chi®s.unipv.it
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,01)00769-4

8314
G. Faita et al. / Tetrahedron 57 72001) 8313±8322
Scheme 1.
conditions, where both stereo- and enantioselectivity were
deeply in¯uenced by the presence of Lewis acids.4c
mesitonitrile oxide 3 to give the corresponding cyclo-
adducts, which can be cleaved by reduction with NaBH4
and analysed by chiral HPLC ,Scheme 2). When the
cycloadditions were run in the presence of Mg,ClO4)2 or
Sc,OTf)3 in dichloromethane the strong catalytic in¯uence
observed in solution was not detected.1 The bis-coordinant-
ing ability of the oxazolidinone moiety, usually observed in
solution, was most likely prevented by its grafting on the
solid support. Hence, we reasoned that more appropriate
reaction conditions could help the interaction of the
dicarbonyl fragment with the metal cation and the following
optimisation protocol was tested.
2. Results
,4S)-p-Hydroxybenzyl-1,3-oxazolidin-2-one was obtained
starting from commercial l-tyrosine by optimising a general
protocol described for similar compounds ,40% overall
yields, see Section 5 for details).11 The chiral auxuliary
was attached directly onto both Wang resin ,XˆOH)
under Mitsunobu conditions and Merri®eld resin ,XˆCl)
by nucleophilic substitution ,NaH in DMF).12,13 Resin-
bound oxazolidinones 1a,b were then mildly acylated by
reaction with trans-crotonic anhydride in THF in the
presence of catalytic DMAP and triethylamine under re¯ux
for 72 h ,Scheme 1).
Resins 2a,b were suspended in DCM and increasing
amounts of 1 M magnesium perchlorate±CH3CN solution
were added. Mesitonitrile oxide was then added portionwise
and after 7 days the resins were ®ltered, washed with DCM,
methanol, THF, and dried under vacuum. The ®ltered resins
were suspended in THF and then a solution of NaBH4 in
H2O was added. The mixtures were shaken at room
temperature for 15 h, the resins were ®ltered and washed
with THF and DCM. The ®ltered solvents were evaporated
2.1. Reactions of resin-bound chiral oxazolidinones 2a,b
with mesitonitrile oxide
As previously reported, substrates 2a,b reacted with both
Scheme 2.

G. Faita et al. / Tetrahedron 57 72001) 8313±8322
8315
Table 1. Reaction conditions, yields, and product distribution of the 1,3-DC of 2a,b and 7 with 3 at rt in DCM with increasing amounts of 1 M MP±CH3CN
solution
n
Dipolarophile
Equiv. of catalyst
Time ,days)/yield
5:6
%ee 5
%ee 6
1
2
3
4
5
6
7a
±
4/quant.
4/quant.
4/quant.
4/quant.
4/quant.
4/quant.
71:29
55:45
46:54
42:58
45:55
43:57
63
18
222
230
270
286
n.r.
5
7
11
13
25
0.1
0.2
0.3
0.5
2.0
7
8
9
10
11
2a
2b
±
4/54%
7/48%
7/53%
7/49%
7/47%
67:33
70:30
59:41
36:64
26:74
60
56
38
241
255
n.r.
n.r.
7
18
20
0.2
0.5
1.0
2.0
12
13
14
15
16
17
18
±
4/55%
7/51%
7/49%
7/53%
7/43%
7/41%
7/44%
72:28
60:40
54:46
41:59
29:71
23:77
20:80
60
48
41
7
224
241
244
n.r.
6
7
7
8
0.1
0.2
0.3
0.5
1.0
2.0
17
16
a
The data related to the 1,3-DC involving 7 are referred to products 5a and 6a and the values in the last two columns are de.
to dryness, and the residue was analysed by HPLC ,see
Section 5 for details). The obtained results are reported in
Table 1.
,solution conditions), even if the regioselectivity drift was
lower ,Table 1, entries 2±6). Enantioselectivity was also
in¯uenced by the presence of the cation, providing an inver-
sion in the enantioselective formation of 5. In the case of 6
the increase in the ee values was only moderate ,Table 1,
entries 3±6, 10, 11, 16±18).
In order to compare these results with those obtained in
solution, the cycloaddition of ,4S)-benzyl-N-crotonyl-
oxazolidin-2-one ,7) with 3 was run under analougous
conditions ,Scheme 2). The diastereomeric cycloadducts
5,6a were directly submitted to HPLC analysis without
any further puri®cation ,see Table 1 for results).
Wang-supported dipolarophile 2b seems to be more
sensitive to the cation concentration. In fact, 0.3±
0.5 equiv. of Mg,II) were enough to invert both regio- and
enantioselectivity of the cycloaddition, whereas in the case
of the Merri®eld resin 2a higher salt concentrations
[1.0 equiv. of Mg,II)] were required to observe similar
effects. Data in Table 1 seem to rank dipolarophiles
as 7.2b.2a in terms of their response to cation
concentration.
The results in Table 1 indicate some interesting features.
Reactivity was not affected by the presence of the Mg,II)
cation, whilst cycloaddition regioselectivity changed in
favour of cycloadduct 6 ,Table 1, entries 10, 11, 16±18).
A similar trend was also observed in the cycloaddition of 7
Scheme 3.

8316
G. Faita et al. / Tetrahedron 57 72001) 8313±8322
Table 2. Reaction conditions, yields, and product distribution of the 1,3-DC of 2a,b and 7 with 4 at rt in DCM with increasing amounts of 1M MP±CH3CN
solution
n
Dipolarophile
Equiv. of catalyst
Time ,days)/yield
8:9
%ee 8
%ee 9
1a
2
7a
±
0.1
15/quant.
2.5/quant.
83:17
85:15
83
293
.99
.99
3
4
5
6
7
8
9
2a
±
40/12%
7/20%
7/29%
7/30%
7/24%
7/26%
7/26%
53:47
58:42
28:72
23:77
20:80
20:80
16:84
88
90
22
27
78
78
80
80
75
0.1
0.2
0.3
0.5
1.0
2.0
285
285
280
280
284
10
11
12
13
14
15
16
2b
±
40/12%
7/19%
7/20%
7/18%
7/18%
7/19%
7/19%
46:54
29:71
23:77
18:82
10:90
13:87
15:85
86
9
0.1
0.2
0.3
0.5
1.0
2.0
286
285
285
287
275
270
80
74
77
77
77
78
a
The data related to the 1,3-DC involving 7 are referred to products 8a and 9a and the values in the last two columns are de and are taken from Ref. 4c.
2.2. Reaction of resin-bound chiral oxazolidinones 2a,b
with diphenyl nitrones
2.3. Reusability of resin-bound chiral oxazolidinones
2a,b
The encouraging results obtained using 3 prompted us to test
the same solid phase protocol in the 1,3-dipolar cycloaddi-
tions of 2a,b with diphenylnitrone 4 ,Scheme 3). The
obtained results, together with those previously reported
for the reaction of 7 with 4,4c are collected in Table 2.
Next we addressed the key issue of polymer reusability. In
our preliminary communication,1 the resins 1a,b recovered
after a 1,3-dipolar cycloaddition reactions were charac-
terised by gel-phase 13C NMR spectroscopy,14 transformed
again into 2a,b, and re-used in a further 1,3-dipolar cyclo-
addition reaction with 3. The recycled Merri®eld resins 2a
gave comparable reaction yields and selectivities, while
the recycled Wang resin 2b yielded an increased regio-
selectivity, but the enantioselectivity diminished up to
14% ee.
The reactions involving nitrone
4
exhibit more
evident catalytic effects than the ones involving nitrile
oxides. The presence of #0.2 equiv. of Mg,II) gave rise
to an increase in reactivity ,higher yields in shorter
reaction times), in stereo- and in enantioselectivity. The
endo adduct 9 became the favoured product ,endo/exo
ratio with up to 90:10), and was obtained with ees ranging
from 75 to 80%.
Recycling of the supported chiral auxiliary was checked on
a semi-preparative scale under catalytic conditions. Resins
2a,b ,1 g) were allowed to react with both 3 and 4 under the
previously described protocol [1.0 equiv. of Mg,II)]. After
reductive cleavage, 1a,b were again converted into 2a,b and
allowed to react with either 3 or 4. This sequence was
repeated and the results of the three cycloadditions are listed
in Table 3.
By analogy with the results shown in Table 1, the Wang-
supported dipolarophile 2b was more sensitive to the salt
concentration, since 0.1 equiv. of Mg,II) showed signi®cant
catalytic effects ,Table 2, entry 11), whereas in the case of
the Merri®eld-supported derivative 2a a higher salt concen-
tration was required ,Table 2, entry 5).
The ®rst run of each reaction set reproduced with acceptable
Table 3. Reaction conditions, yields, and product distribution of the 1,3-DC of recovered 2a,b with 3 ,entries 1±6) and 4 ,entries 7±12) at rt in DCM with
1.0 equiv. of MP±CH3CN solution
n
Dipolarophile
Equiv. of catalyst
Time ,days)/yield
5:6
%ee 5
%ee 6
1
2
3
2a
1st recycle
2nd recycle
1.0
1.0
1.0
7/42%
7/43%
7/40%
29:71
29:71
34:66
268
255
245
22
20
18
4
5
6
2b
1st recycle
2nd recycle
1.0
1.0
1.0
7/40%
7/41%
7/43%
23:77
25:75
40:60
8:9
243
240
217
%ee 8
12
16
8
%ee 9
7
8
9
2a
1st recycle
2nd recycle
1.0
1.0
1.0
7/32%
7/33%
7/30%
14:86
6:94
36:64
281
270
267
80
80
73
10
11
12
2b
1st recycle
2nd recycle
1.0
1.0
1.0
7/28%
7/30%
7/25%
5:95
5:95
7:93
280
270
255
78
73
73

G. Faita et al. / Tetrahedron 57 72001) 8313±8322
8317
accuracy the data reported in Tables 1 and 2 for smaller
scale experiments. Only a few runs showed a small increase
in regio-, stereo-, and enantioselectivity ,Table 3, entries 1
and 10). When the recycled resins 2a,b were used in a ®rst
recycling run, the observed reactivities and selectivities
were substantially con®rmed. However, a measurable drop
in regio-, stereo-, and enantioselectivity was generally
observed in the second recycling run ,Table 3).
control since, in the 1,3-dipolar cycloaddition of crotonoate
derivatives, mixtures of 4- and 5-acyl isoxazolines are
generally obtained in ratios close to 50:50.15 In the case of
crotonamides regioselective formation of both 4- and 5-acyl
isoxazolines can be observed, depending on several factors
such as nitrogen substituents.16 Data available in the
literature on regio- and stereoselectivities obtained in 1,3-
dipolar cycloadditions involving b-substituted chiral
dipolarophiles are summarised in Chart 1. 1,3-Dipolar
cycloadditions with bornyl17 and Sultan18 crotonoates did
not allow the regioselective formation of cycloadducts,
obtained with negligible to good diastereomeric excesses
,de). In the case of Rebeck benzoxazole19 the excellent dia-
stereoselectivity was not associated with a good level of
regioselectivity. The use of chiral imidazoline20 was highly
ef®cient both in terms of regio- and diastereoselectivity, and
depended on the nitrogen atom substituent.
A further experiment was set up in order to verify the
stability of the chiral auxiliary through all the reaction
sequences. The Wang-supported dipolarophile 2b ,1 g)
was reacted with 3 in the presence of 1 equiv. of magnesium
perchlorate in CH3CN. After reductive cleavage ,no
changes in reaction yield and selectivities were observed),
the chiral oxazolidinone was recovered by treatment of 1b
with CF3COOH/DCM, puri®ed by column chromatography
and recrystallised from methanol. The optical rotation of
the recovered chiral auxiliary was in full accordance with
the literature value, con®rming that no racemisation of the
chiral auxiliary occurred ,see Section 5). The same reaction
sequence was repeated after the second recycling run and
the chiral auxiliary was again recovered with unaffected
optical purity.
The only substrate able to achieve complete regio- and dia-
stereoselectivity was a b-borane derivative of Sultan
crotonoate21 and this strategy was usefully applied in the
synthesis of optically active 4-hydroxy-D2-isoxazolines.
None of the previously reported 1,3-dipolar cycloaddition
reactions was tested in the presence of a catalyst; a single
example is found in the 1,3-dipolar cycloadditions involving
chiral 1,3-dithiane-1-oxide.22 The cycloaddition was
completely regioselective and the low diastereoselectivity
was depending on both the solvent and the catalyst. Use of
Mg,II) and Zn,II) allowed reversal of diastereoselectivity.
Other attempts to catalyse analogous 1,3-dipolar cyclo-
addition reactions were reported by Kanemasa,23 but both
regio- and diastereoselectivity were not improved in the
presence of metal cations such as Zn,II) and Ti,IV).
3. Discussion
3.1. Nitrile oxide cycloadditions
In order to achieve selective nitrile oxide cycloadditions to
chiral b-substituted a,b-unsaturated carbonyl derivatives
two distinct levels of control have to be satis®ed: regio-
and stereoselectivity. The ®rst one is the more dif®cult to
Chart 1.

8318
G. Faita et al. / Tetrahedron 57 72001) 8313±8322
The low number of papers on metal assisted 1,3-dipolar
cycloadditions of nitrile oxides is probably the consequence
of the dif®culty to control their stereoselectivity. This
derives from two distinct problems. First, 1,3-dipoles are
usually generated in situ in the presence of a base, condi-
tions that are not compatible with a catalyst. Furthermore,
nitrile oxides are low-lying FMOs species and therefore
attempts to use cations to activate a,b-unsaturated carbonyl
compounds are ineffective.4a
Data reported in Table 1 demonstrate that the catalysis of
these cycloadditions ,Scheme 2) can in¯uence the observed
selectivities on solid phase as well as in solution. In nitrile
oxide cycloadditions, a stronger effect was observed on
chemoselectivity, since an inversion of regiochemistry
was clearly evidenced by the presence of the Mg,II) cation.
The cycloaddition in solution involving 7 was only
moderately affected by the presence of the salt, and a
value of about 60% was obtained with 0.3 or more equiv.
of salt. Solid phase catalysed cycloadditions involving 2a,b
showed a stronger regiochemistry drift, and 6 became the
largely predominant product. Thus, the lower reactivity
associated to solid phase synthesis with respect to classical
solution chemistry allowed to emphasise the catalytic
effects.
Scheme 5.
nitrile oxide approached the dipolarophile from the opposite
Re-face to give 5 after reductive cleavage.
When the Mg,II) cation coordinated the oxygen carbonyl
atoms, the carbonyl groups in the reacting substrate
assumed a s-cis conformation, and nitrile oxide approached
the double bond from the less hindered Si-face to yield
enant-5.
The regiochemistry shift in response to low salt concentra-
tions observed with Wang resin 2b was similar to that
observed in solution, but the increase in the yield of 6 is
observed with an amount of Mg,II) up to 1 equiv. The
Merri®eld resin was less sensitive to the catalyst concentra-
tion than the Wang resin since higher Mg,II) concentrations
were required in the reaction of 2a to obtain high yields of 6.
The same reversion in enantioselectivity was not observed
in the case of regioisomer 6 that, moreover, did not show
signi®cant levels of enantioselectivity in all the tested
conditions. The latter result was the consequence of the
loss of the steric interaction between the mesityl group
and the chiral information on the oxazolidinone ring, inter-
action that is discriminant in determining the stereochemical
outcome.
The change in regiochemistry was consistent with a
mechanism analogous to that proposed by Kanemasa23 in
the catalysed 1,3-dipolar cycloadditions between nitrile
oxides and allylic alcohols. The Mg,II) cation coordinated
both carbonyl oxygen atoms of the chiral oxazolidinone and
the oxygen atom of the nitrile oxide to give complex 10,
which favoured the formation of the 5-acyl-substituted
isoxazoline that, after the reductive cleavage, led to 6
,Scheme 4).
As a matter of fact, the Mg,II) cation drove regioselectivity
to the formation of the C5-acyl substituted isoxazoline, but
the latter product was obtained with a low control of the
enantioselectivity, being less sensitive to steric information.
This intrinsic disadvantage was overcome in the cyclo-
addition involving a nitrone dipole.
Complex 10 rationalises the inversion in the enantio-
selectivity observed in the formation of the 4-substituted
oxazoline 5 ,Scheme 5). In the uncatalysed cycloaddition,
the preferred conformation of the reacting dipolarophile had
the two carbonyls in the s-trans disposition. The chiral
information on the C4 of the oxazolidinone ring hindered
the C-a Si-face of the CC double bond and, therefore, the
3.2. Nitrone cycloadditions
Several examples of syntheses involving either ,chiral
substrate±achiral catalyst) or ,achiral substrate±chiral
catalyst) combinations have been proposed in the literature
for nitrone cycloadditions.4a Cycloaddition involving
dipolarophile bearing the Evans chiral auxiliary are
catalysed by Mg,II) and Sc,III) cations and, with an
appropriate choice of the catalytic system, exo and endo
cycloadducts can be selectively obtained with good to
excellent control of the diastereoselectivity.4c,24
Data reported in Table 2 clearly evidence that both
reactivity and selectivity are in¯uenced by the presence of
the Mg,II) cation.
Reactivity. The coordination of the metal cation, acting as a
Lewis acid, to the conjugated carbonyl lowered the LUMO
energy of the alkene with respect to the uncoordinated
Scheme 4.

G. Faita et al. / Tetrahedron 57 72001) 8313±8322
8319
ole®n. The increase in reaction yields observed within
shorter reaction times is fully consistent with such a
mechanism.
An important factor in both catalysis and solid phase
synthesis is the reaction solvent. Chlorinated media such
as chloroform and DCM are frequently used because of
their low coordinating abilities and good swelling proper-
ties. Nevertheless, the same reactions were tested in a more
coordinating solvent ,THF) by adding either increasing
volumes of magnesium perchlorate±acetonitrile solution
or directly the solid salt. Quite surprisingly, such conditions
optimised the stereochemical outcome: with 0.5±1.0 equiv.
of Mg,II) cation the endo/exo ratio was 98:2, and the ee of
the endo adduct was 90%.
Stereoselectivity. The stereochemical outcome of the
cycloaddition was in¯uenced by:
a. the polymer grafted to the reacting dipolarophile;
b. the coordination of the Mg,II) cation.
A tentative rationale of point ,a) involves a change in the
steric demand of the reacting ole®n from solution to solid
phase chemistry, since a decrease in the exo preference was
observed going from solution ,reaction of 7) to solid phase
chemistry ,reactions of 2a,b).
3.3. Polymer reusability
Polymer reusability was tested by performing three sequen-
tial cycloadditions between 2a,b and either 3 or 4. The ®rst
recycling of the supported chiral oxazolidinone gave, in
general, acceptable results in terms of regio-, stereo-, and
enantioselectivities ,Table 3, entries 2, 5, 8, and 11), but the
second recycle gave disappointing results. Nitrile oxide
cycloadditions evidenced a decrease in both regio- and
enantioselectivity ,Table 3, entries 3, 6), as did the nitrone
cycloaddition of the Merri®eld-supported dipolarophile 2a
,decrease in both stereo and enantioselectivity). Only the
Wang support gave reproducible results, at least in terms
of both stereoselectivity and enantioselectivity of the major
endo adduct. Since the recovered chiral auxiliary did not
show any drop in optical purity, a possible explanation
may involve the presence of traces of moisture able to
modify the catalyst activity. Further studies are required to
better understand this phenomenon.
Under classical solution conditions, catalysis with mag-
nesium perchlorate did not in¯uence the stereoselectivity
and the exo cycloadduct was again obtained as major
product.4c endo Selectivity was observed only when the
salt was used with molecular sieves. In the case of solid
supported dipolarophiles 2a,b, the addition of increasing
amounts of Mg,II), without molecular sieves, drove stereo-
selectivity towards the formation of the endo cycloadduct
,endo/exo with up to a ratio of 9:1). The Wang support
showed an higher sensitivity to salt concentrations than
the Merri®eld resin, and also exhibited higher levels of
selectivity.
Enantioselectivity. The uncatalysed cycloaddition of
diphenylnitrone and 2a,b showed good enantioselectivity
only in the formation of the exo adduct. However, when it
was performed in the presence of Mg,II) the favoured
product became the endo adduct, which was obtained with
up to 80% ee. These results strongly paralleled those
observed under standard solution conditions. The inversion
in the exo enantioselectivity, as well as the increase in the
endo one, was observed with 0.1 ,Wang support) or
0.2 equiv. of cation ,Merri®eld support). This result is a
further evidence that 2b has a more solution-like behaviour
than 2a, pointing out the relevance of the distance between
reaction sites and resin bulk in determining the substrate
ability to interact with the metal cation.
4. Conclusion
A carrier of the cation is needed in solid phase chemistry to
allow the Lewis acid to interact with grafted bis-coordinat-
ing dipolarophile and to simulate classical catalysis
conditions in solution. The transfer of Mg,II) from the
swelling solution to the bead reacting sites can be achieved
by using small volumes of Mg,II)-acetonitrile solution
added to DCM ,a solvent with good swelling properties).
Under these conditions, the 1,3-dipolar cycloaddition
reactions involving solid supported chiral dipolarophiles
are effectively catalysed by the Mg,II) cation.
The absolute stereochemistry of the adducts 8 and 9 were
determined by correlation with compounds 8a and 9a of
known con®guration, and con®rmed a mechanism involving
10 as the reacting complex, since both endo and exo
cycloadducts derived from the approach of nitrone to the
less hindered Si-face of the dipolarophile ,Scheme 6).
Even if nitrile oxide cycloadditions are less sensitive to
cation catalysis than those involving nitrones, stoichio-
metric amounts of salt in¯uence both regioselectivity
,shift toward the formation of the 5-acyl-substituted
isoxazoline) and stereoselectivity ,reversion in the enantio-
selectivity of the 4-acyl-substituted isoxazoline). In the case
of nitrone cycloadditions catalytic amounts of Mg,II) are
suf®cient to strongly in¯uence both reactivity and
selectivity, which are increased in the presence of 0.1±
0.2 equiv. of Mg,II). In particular, stereoselectivity is
enhanced and the endo adduct becomes the largely
predominant one with ee higher than 90%.
All results are consistent with a reaction mechanism involv-
ing a reacting complex with the dicarbonyl fragment of
the chiral oxazolidinone coordinated by the Mg,II)
cation. Such a coordination deeply in¯uences the selectivity
Scheme 6.

8320
G. Faita et al. / Tetrahedron 57 72001) 8313±8322
,regio- stereo- and enantioselectivity) of 1,3-dipolar
cycloadditions and, at least in the case of nitrone cyclo-
additions, also the reactivity is signi®cantly increased.
5.1.2.
S)-2-Amino-N-ethoxycarbonyl-3- 4-hydroxy-
phenyl)-propionic acid methyl ester 13). The ester hydro-
chloride 12 ,23.7 g, 0.10 mol) was dissolved in water
,50 mL) and K2CO3 ,13.8 g, 0.10 mol) was added portion-
wise. DCM ,100 mL) was added to the obtained suspension,
and ethyl chloroformate ,10.0 mL, 0.105 mol) was then
added dropwise under vigorous stirring. After 10 min, satu-
rated solution of NaHCO3 ,50 mL) was added and the
mixture was stirred for 2 h. The aqueous phase was sepa-
rated and extracted with DCM ,150 mL), and the organic
layers, dried over MgSO4, were concentrated under vacuo to
give 13 ,26.7 g, quantitative yield) as a pale yellow oil, that
was used in the next step without any further puri®cation. 1H
NMR ,CDCl3): 6.96 ,d, 2H, Jˆ7.5 Hz, Ar), 6.72 ,d, 2H,
Jˆ7.5 Hz, Ar), 5,78 ,s, 1H), 5.15 ,d, 1H, Jˆ8 Hz, NH),
4.6 ,m, 1H, CH±CO), 4.10 ,q, 2H, Jˆ6.5 Hz, OCO±CH2),
3.23 ,s, 3H, COO±CH3), 3.02 ,m, 2H, CH2±Ar), 1.23 ,t, 3H,
Jˆ6.5 Hz, CH3).
5. Experimental
All melting points are uncorrected. Elemental analyses were
1
done on a Carlo Erba 1106 elemental analyser. H and 13C
NMR spectra were recorded on a Bruker AVANCE 300
spectrometer ,solvents speci®ed). Chemical shifts are
expressed in ppm from internal tetramethylsilane ,d) and
coupling constants are in Hertz ,Hz): b, broad; s, singlet; bs,
broad singlet; d, doublet; t, triplet; q, quartet; qi, quintet; m,
multiplet. IR spectra ,nujol mulls for standard compounds,
and diffuse re¯ectanceÐDRÐfor resins) were recorded on
an FT-IR Perkin±Elmer Paragon 1000 spectrophotometer
and absorbtions ,n) are in cm21. The optical rotations
were determined on a Perkin±Elmer 241 polarimeter.
Column chromatography and TLC: silica gel H60 and
GF254 ,Merck), respectively. The cycloadduct ratios were
determined by HPLC on either a Chiralcel OD or a
Chiralpack AD.
5.1.3.
2S)-2-Amino-N-ethoxycarbonyl-3- 4-hydroxy-
phenyl)-propanol 14). Product 13 ,26.7 g, 0.10 mol) was
dissolved in THF ,200 mL) and NaBH4 ,15 g, 0.40 mol)
was added portionwise. The suspension was stirred for 1 h
at room temperature and then re¯uxed overnight. The
mixture was cooled at 08C and 10% HCl ,50 mL) was
added with caution. The solid was ®ltered and treated
with acetone. Aqueous and organic layers were collected
and concentrated under vacuum. The residue was extracted
with DCM ,150 mL), the organic layers were washed with
brine, dried on MgSO4 and concentrated to give a pale
yellow oil, which was ®ltered through a silica plug ,25 g
of silica gel, ethyl acetate as eluant). Compound 14 ,19.1 g,
82% yield) was obtained as a colourless viscous oil, which
5.1. Synthesis of the chiral auxiliary
The synthesis of the chiral oxazolidinone was optimised on
the basis of a protocol described for analogous derivatives11
following the procedure depicted in Scheme 7. The
synthetic method reported in literature25 for the synthesis
of 15 gave less satisfactory results.
1
5.1.1. 2S)-2-Amino-3- 4-hydroxyphenyl)-propionic acid
methyl ester hydrochloride 12). Thionyl chloride ,39.3 g,
0.33 mol) was added dropwise to ice cooled methanol
,300 mL) over 20 min, keeping the temperature below
2108C. l-Tyrosine ,50 g, 0.28 mol) was added and the solu-
tion was stirred at room temperature for 2 days. The solvent
was removed by evaporation and the residue was twice
triturated with methanol and concentrated, dissolved in
hot methanol, diluted with ether and left to crystallise.
Compound 12 was obtained in quantitative yield as white
was directly used in the next reaction. H NMR ,CDCl3):
8.15 ,s, 1H, OH), 7.06 ,d, 2H, Jˆ7.5 Hz, Ar), 6.74 ,d, 2H,
Jˆ7.5 Hz, Ar), 5.90 ,d, 1H, Jˆ7 Hz, NH), 4.00 ,q, 2H,
Jˆ7.5 Hz, OCOCH2), 3.75 ,m, 1H, CH), 3.52 ,t, 2H,
Jˆ6 Hz, CH2±O), 2.9±2.6 ,m, 2H, CH2±Ar), 1.12 ,t, 3H,
Jˆ7.5 Hz, CH3).
5.1.4. 4S)- 4-Hydroxybenzyl)-1,3-oxazolidin-2-one 15).
The previously obtained product 14 ,19.1 g, 0.082 mol) was
dissolved in toluene ,100 mL) and K2CO3 ,2.0 g, 0.015 mol)
was added. The mixture was re¯uxed in a Dean±Stark appa-
ratus for 4 h. Toluene was removed and ethanol was added
to the sticky residue. After 1 h, the insoluble material was
crystals: mp 190±1918C ,lit.26 189±1918C); [a]D ˆ170.9
20
,c 1.1, pyridine) [opposite enantiomer, lit.26 [a]D ˆ268.0
20
,c 1.0, pyridine)].
Scheme 7.

G. Faita et al. / Tetrahedron 57 72001) 8313±8322
8321
®ltered off and the ®ltrate concentrated leaving a viscous oil
which solidi®ed by treatment with 5 mL of 1:1 EtOH/HCl
conc. The white solid was recrystallised from methanol to
give 7.7 g of 15 ,50% yield, total yield of the three steps,
water ,0.3 mL), were added.26 The suspension was shaken
overnight at room temperature. The solvent was recovered
by ®ltration and the resin washed with THF and DCM. The
combined organic layers were washed with water ,15 mL),
dried over anhydrous magnesium sulphate and the residue
obtained was analysed by HPLC.
20
40%). Mp 178±1798C ,lit.25 175±1788C). [a]D ˆ111.8 ,c
0.5, ethanol) [lit.25 18.6 ,c 0.5, ethanol)].
5.2. Preparation of the supported chiral auxiliary
5.3. Nitrile oxide cycloadducts 5,6
5.2.1. Merri®eld resin. The chiral auxiliary 15 ,7.5 g,
38 mmol) was dissolved in dry DMF ,10 mL) and Merri®eld
resin ,10 g, 12 mmol) was added to the solution. The
suspension was cooled at 08C and NaH ,1.9 g, 38 mmol)
was added portionwise under gentle stirring. After three
days of vigorous shaking at room temperature the suspen-
sion was ®ltered. Resin 1a was washed with DMF, with
methanol and THF, and then with DCM before drying
under vacuum. FT-IR ,DR), n: 3278, 1772 cm21. Gel-
phase 13C NMR spectrum, d ,CDCl3): 159.5, 158.2, 115.2,
69.5, and 53.9.
They were analysed on a Chiralpak AD Column; eluant:
n-hexane/i-propanolˆ96:4; ¯ow, 1 mL min21. Retention
times: 5, 40.0 and 49.3 min; 6, 35.7 and 56.8 min.
5.3.1. trans-5-Methyl-3-mesityl-2-isoxazoline-4-metha-
nol 5). The product was obtained as colourless oil. IR
1
,neat) 3405 and 1612 cm21. H NMR ,CDCl3) d 1.50 ,3H,
d, Jˆ6.3 Hz, ±Me), 1.76 ,1H, bs, ±OH), 2.26 ,6H, s,
±CH3Mes), 2.30 ,3H, s, ±CH3Mes), 3.30±3.37 ,1H, m,
H-4), 3.63 ,2H, AB syst., ±CH2OH), 4.72 ,1H, dq, Jˆ7.0,
6.3 Hz, H-5), 6.88 ,2H, s, ±Arom.); 13C NMR ,CDCl3) d
20.0, 20.7, 21.0, 60.6, 61.3, 80.2, 125.4, 128.7, 136.8, 138.7,
157.8. Elem. Anal.: found C, 72.0; H, 8.2; N, 6.0.
C14H19NO2 requires C, 72.07; H, 8.21; N, 6.00.
5.2.2. Wang resin. The chiral auxiliary 15 ,5.95 g,
30.9 mmol) and triphenylphosphine ,7.98 g, 30.9 mmol)
were dissolved in dry THF ,100 mL); 10 g of Wang resin
,1.03 mmol g21, 10.3 mmol) were then added to the solu-
tion. The suspension was cooled at 08C and DEAD ,4.8 mL,
30.9 mmol) in dry THF ,10 mL) was added dropwise under
gentle stirring, in such a rate to maintain the solution colour-
less. After three days of vigorous shaking at room tempera-
ture the suspension was ®ltered. Resin 1b was washed
several times with methanol and THF, and then with
DCM before drying under vacuum. FT-IR ,DR), n:
1754 cm21. Gel-phase 13C NMR spectrum, d ,CDCl3):
67.8 and 55.3.
5.3.2. trans-4-Methyl-3-mesityl-2-isoxazoline-5-metha-
nol 6). The product was obtained as colourless oil. IR
1
,neat) 3406 and 1612 cm21. H NMR ,CDCl3) d 1.13 ,3H,
d, Jˆ7.3 Hz, ±Me), 2.25 ,6H, s, ±CH3Mes), 2.29 ,3H, s,
±CH3Mes), 2.76 ,1H, bs, ±OH), 3.55 ,1H, qi, Jˆ7.3 Hz,
H-4), 3.72 ,1H, dd, Jˆ12.2, 4.4 Hz, ±CH2OH), 3.89 ,1H,
ddd, Jˆ12.2, 4.4, 1.5 Hz, ±CH2OH), 4.36 ,1H, m, H-5),
6.88 ,2H, s, Arom.); 13C NMR ,CDCl3) d 15.6, 20.0, 20.8,
47.3, 62.6, 87.8, 125.1, 128.5, 136.9, 138.5, 162.0. Elem.
Anal.: found C, 72.1; H, 8.1; N, 5.9. C14H19NO2 requires C,
72.07; H, 8.21; N, 6.00.
5.2.3. Functionalisation of resins 1a,b. General pro-
cedure. Resin portions corresponding to 1.2 mmol of chiral
auxiliary ,1.0 g for 1a and 1.35 g for 1b) were swollen in dry
THF ,10.0 mL for 1a, 13.5 mL for 1b). DMAP ,0.3 g,
2.4 mmol) and TEA ,0.8 mL, 6 mmol) were added to the
suspension that was then cooled in an ice bath. Trans-
crotonic anhydride ,0.7 mL, 4.8 mmol) was added dropwise
and, after 1 h of gentle stirring, the ice bath was removed
and the mixture re¯uxed for three days. The solvent was
®ltered, and the resin was washed several times with THF
and methanol, until the washing phase was colourless, and
then with DCM before drying under vacuum. 2a: FT-IR
,DR), n: 1718.2 cm21. Gel-phase 13C NMR spectrum, d
,CDCl3): 164.8, 66.1, 55.3 and 18.6. 2b: FT-IR ,DR), n:
1778 and 1730 cm21. Gel-phase 13C NMR spectrum, d
,CDCl3): 164.9, 146.9, 121.8, 66.0, 55.2, and 18.5.
5.4. Nitrone cycloadducts 8,9
They were analysed on a Chiralcel OD Column; eluant:
n-hexane/i-propanolˆ90:10; ¯ow, 1 mL min21. Retention
times: 8, 10.4 ,3S,4R,5R) and 14.9 min ,3R,4S,5S); 9, 12.3
,3S,4S,5S) and 18.1 min ,3R,4R,5R).
5.4.1. 3R,4S,5S) 3S,4R,5R)-5-Methyl-2,3-diphenyl-
isoxazolidine-4-methanol 8). The product was obtained
as colourless oil. IR ,neat) 3420, 1596 cm21. H NMR
1
,CDCl3) d 1.44 ,3H, d, Jˆ6.2 Hz, ±Me), 2.61±2.71 ,1H,
m, H-4), 3.38 ,2H, AB syst., ±CH2OH), 4.30 ,1H, qi,
Jˆ6.2 Hz, H-5), 4.76 ,1H, d, Jˆ8.9 Hz, H-3), 7.53 ,2H,
m, o-Ph±N), 6.8±7.6 ,10H, m, Arom.); 13C NMR ,CDCl3)
d 18.7, 55.6, 61.2, 71.1, 76.4, 115.3, 121.5, 127.5, 127.7,
128.4, 128.7, 138.2, 150.9. Elem. Anal.: found C, 75.7; H,
7.0; N, 5.3. C17H19NO2 requires C, 75.81; H, 7.11; N, 5.20.
5.2.4. Standard protocol for the 1,3-dipolar cyclo-
addition. A measured volume of 1 M solution of
magnesium perchlorate in acetonitrile ,from 15 to
300 mL) was added to 200 mg of 2a,b swollen in
10 mL g21 of dry DCM, and the suspension shaken for
15 min. Then 1.1 equiv. of the 1,3-dipole were added ,for
2a: 37 mg of 3 and 45 mg of 4; for 2b: 33 mg of 3, 37 mg of
4). The reaction was shaken at room temperature for seven
days. The solvent was ®ltered off and the resin was washed
with DCM, methanol and THF. The obtained resins were
swollen in THF ,2 mL) and 30 mg of NaBH4, dissolved in
5.4.2. 3R,4R,5R) 3S,4S,5S)-5-Methyl-2,3-diphenyl-
isoxazolidine-4-methanol 9). The product was obtained
as colourless oil. IR ,neat) 3422, 1597 cm21. H NMR
1
,CDCl3) d 1.47 ,3H, d, Jˆ6.2 Hz, ±Me), 2.47±2.38 ,1H,
m, H-4), 3.78±3.65 ,2H, AB system, ±CH2OH), 4.17 ,1H,
dq, Jˆ8.6, 6.2 Hz, H-5), 4.53 ,1H, d, Jˆ8.6 Hz, H-3), 6.7±
7.6 ,10H, m, Arom.); 13C NMR ,CDCl3) d 17.6, 61.1, 63.1,
73.4, 77.2, 113.9, 121.1, 126.5, 127.4, 127.5, 128.8, 142.5,

8322
G. Faita et al. / Tetrahedron 57 72001) 8313±8322
Lett. 2000, 41, 967. ,d) Park, K.-H.; Kurth, M. J. Chem.
Commun. 2000, 1835.
152.2. Elem. Anal.: found C, 75.9; H, 7.0; N, 5.2.
C17H19NO2 requires C, 75.81; H, 7.11; N, 5.20.
9. For applications of solid supported dienophiles see:
,a) Zhang, W.; Xie, W.; Fang, J.; Wang, P. G. Tetrahedron
Lett. 1999, 40, 7929. ,b) Burkett, B. A.; Chai, C. L. L.
Tetrahedron Lett. 1999, 40, 7035. ,c) Kuster, G. J.; Scheeren,
H. W. Tetrahedron Lett. 2000, 41, 515. ,d) Winkler, J. D.;
Kwak, Y.-S. J. Org. Chem. 1998, 63, 8634. ,e) Sun, S.;
Murray, W. V. J. Org. Chem. 1999, 64, 5941.
Acknowledgements
Financial support for this work was provided by the
Á
Ministero dell'Universita e della Ricerca Scienti®ca e
Tecnologica ,MURSTÐPRIN 2000) and by the University
of Pavia ,FAR 2000).
10. ,a) Kiselyov, A. S.; Smith II, L.; Armstrong, R. W.
Tetrahedron 1998, 54, 5089. ,b) Leconte, S.; Dujardin, G.;
Brown, E. Eur. J. Org. Chem. 2000, 639.
11. Lewis, N.; McKillop, A.; Taylor, R. J. K.; Watson, R. J. Synth.
Commun. 1995, 25, 561.
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