Organocatalysts promote enantioselective 1,3-dipolar cycloadditions of nitrones with 1-cycloalkene-1-carboxaldehydes

Article abstract of DOI:10.1002/ejoc.200300172

In the presence of enantiopure organocatalysts, 1-cycloalkene-1-carboxaldehydes and various nitrones furnished fused isoxazolidines. Thus, some chiral pyrrolidinium salts catalyzed the formation of such cycloadducts in high diastereoand enantioselectivity (up to 92% ee). The predominant diastereomer, the exo one, was mostly obtained in excellent diastereoselectivity (> 99:1 dr). Furthermore, after recrystallization of one of the cycloadducts, this was obtained enantiomerically pure (> 99% ee). The absolute configuration of one of the cycloadducts was determined. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300172

FULL PAPER
Organocatalysts Promote Enantioselective 1,3-Dipolar Cycloadditions of
Nitrones with 1-Cycloalkene-1-carboxaldehydes
Staffan Karlsson*[a] and Hans-Erik Högberg[a]
Keywords: Cycloaddition / Enantioselectivity / Catalysis / Nitrones / Azomethine ylides
In the presence of enantiopure organocatalysts, 1-cycloal-
kene-1-carboxaldehydes and various nitrones furnished
fused isoxazolidines. Thus, some chiral pyrrolidinium salts
catalyzed the formation of such cycloadducts in high diast-
ereo- and enantioselectivity (up to 92% ee). The predominant
diastereomer, the exo one, was mostly obtained in excellent
diastereoselectivity (Ͼ 99:1 dr). Furthermore, after recrystal-
lization of one of the cycloadducts, this was obtained enanti-
omerically pure (Ͼ 99% ee). The absolute configuration of
one of the cycloadducts was determined.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
liminary communication by us in which organocatalysts
are employed.[9]
Chiral nonracemic isoxazolidines are important building
blocks for the construction of biologically active com-
pounds.[1] One of the most efficient approaches for the
preparation of such isoxazolidines is the enantioselective
1,3-dipolar cycloaddition of nitrones with olefins, catalyzed
by various chiral metal-containing complexes.[2Ϫ4] Since the
early 1970s when proline was found to catalyze intramol-
ecular aldol reactions,[5] a range of other metal-free organic
compounds have been applied as catalysts in a variety of
organic reactions.[6] One example is the highly enantioselec-
tive 1,3-dipolar cycloaddition reaction of nitrones with α,β-
unsaturated aldehydes catalyzed by chiral imidazolidinone
salts.[7] The catalytic effect of these salts has been described
as being due to a reversible reaction between the catalyst
and the starting aldehyde leading to an activation of the
α,β-unsaturated aldehyde by iminium ion formation.[7] The
LUMO energy of the alkene moiety of this intermediate is
lower than that of the aldehyde. Therefore, interaction of
this with the unaffected HOMO of the nitrone is facilitated,
leading to an increased reaction rate.[7]
Figure 1. Organocatalysts for use in 1,3-dipolar cycloadditions of
nitrones 2aϪg with either aldehyde 1A or 1B
Here we report in full, our studies on the catalytic per-
formance of some chiral pyrrolidinium salts in the 1,3-di-
polar cycloaddition reaction of the 1-cycloalkene-1-carbox-
aldehydes 1A and 1B with various nitrones 2aϪg resulting
in highly enantio- and diastereoselective formation of fused
bicyclic isoxazolidines (Scheme 1).
In the reaction of α,β-unsaturated aldehydes with nitro-
nes, imidazolidinone salts such as 7 (Figure 1) have been
found to be excellent catalysts.[7] However, to the best of
our knowledge, there are only two examples in the literature
of enantioselective catalyzed 1,3-dipolar cycloadditions of
nitrones with 1-cycloalkene-1-carboxaldehydes, one of
which employ chiral Lewis acids as catalysts,[8] and one pre-
Results and Discussion
In the absence of a catalyst and at ambient temperature
in either DMF or CH3NO2, no reaction occurred between
aldehyde 1A and nitrone 2a (Scheme 1).
However, when catalyst 7[7] (HX ϭ HCl; Figure 1) was
added, reaction took place. After NaBH4 reduction of the
bicyclic diastereomeric aldehyde products, the major re-
duced cycloadduct 3a and the minor one 4a were obtained.
As described in our preliminary communication,[9] the im-
idazolidinone salt 7 was, however, not an efficient catalyst
[a]
Chemistry, Department of Natural and Environmental
Sciences, Mid Sweden University,
85170 Sundsvall, Sweden
E-mail: staffan.karlsson@mh.se
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
2782
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300172
Eur. J. Org. Chem. 2003, 2782Ϫ2791

Enantioselective 1,3-Dipolar Cycloadditions of Nitrones with 1-Cycloalkene-1-carboxaldehydes
FULL PAPER
Scheme 1. The organocatalyzed reaction of either aldehyde 1A or
1B with various nitrones 2aϪg
in this reaction. Thus, 3a was obtained as an approximately
racemic mixture in a low yield.
Although compound 7 is a documented efficient catalyst
for enantioselective 1,3-dipolar cycloaddition reactions of
nitrones with acyclic dipolarophiles,[7] this catalyst was ob-
viously not very efficient in reactions involving cyclic di-
polarophiles. Therefore, we wanted to investigate the cata-
lytic performance of some other chiral ammonium salts.
Scheme 2. Preparation of the potential organocatalysts 8Ϫ10; re-
agents and conditions: a) CH2Cl2, trifluoroacetic acid (cat.), 0 Ǟ
20 °C, 94%; b) (i) PhMgBr or p-MeOC6H4MgBr, THF, (ii) water,
62%; c) (i) 1-chloroethyl chloroformate, 1,8-bis(dimethylamino)-
naphthalene, ClCH2CH2Cl, reflux, (ii) MeOH, reflux, 65Ϫ96%
overall yield; d) (i) NaH, MeI, THF, (ii) water, 88%
First we wanted to test if increased rigidity and bulk in the
catalyst would lead to higher enantioselectivity.
We recently described some 1,3-dipolar cycloaddition re-
actions of chiral azomethine ylides with chiral di-
polarophiles containing a cyclic α,β-unsaturated alkenoic
moiety attached to camphorsultam.[10] Using this approach,
a facile method was established for the preparation of en-
antiopure highly functionalized bicyclic pyrrolidines. Such chosen for further reactions. The reason for this was, that
pyrrolidines should be very rigid and further transform- preliminary cycloaddition reactions of nitrone 2a with alde-
ation of the functional groups should lead to compounds hyde 1A catalyzed by 8 and its enantiomer ent-8 showed
containing bulky groups. Exploiting our recent results, we that the former provided a mixture of enantiomeric prod-
decided to prepare the rigid azabicyclo[3.3.0]octanes 8Ϫ10 ucts with suitable retention times (the minor enantiomer
(Scheme 2 and Figure 1) and to evaluate their potential as eluting prior to the major one) in the GC method used for
catalysts in the reaction depicted in Scheme 1. In the 1,3- the analysis of the enantiomeric purity. Therefore, the
dipolar cycloaddition reactions of chiral azomethine ylides minor diastereomer 19 was treated with the appropriate
with chiral cyclic dipolarophiles, the chirality of the azome- Grignard reagent to furnish either compound 20 or 21.
thine ylide is more important than that of the dipolarophile Etherification of 20 furnished the methyl ether 22. Initial
for obtaining high diastereoselectivity.[10] Thus, methyl 2,5- attempts to remove the phenylethyl groups of 20Ϫ22
dihydrothiophenecarboxylate (16 with S instead of SO2; through hydrogenation (H2 in the presence of Pd/C) were
Scheme 2) reacts with the ylide derived from ent-17 to give unsuccessful. Therefore, removal of the phenylethyl groups
a mixture of the major and the minor diastereomer ent-18 of these was accomplished using a dealkylation reagent.[11]
and ent-19 (both with S instead of SO2; 64:36 dr), respec- Thus, treatment of compounds 20Ϫ22 with 1-chloroethyl
tively.[10] After separation of the diastereomers, the major chloroformate, gave the desired ammonium salts 8Ϫ10.
one can be transformed to the potential catalysts 8Ϫ10
With the compounds 8Ϫ10 in hand, we explored their
through a few steps by oxidation of the sulfur moiety. How- ability to catalyze the diastereo- and enantioselective ad-
ever, in order to eliminate this oxidation step, we have dition of nitrone 2a to cyclopent-1-enecarboxaldehyde 1A
chosen to use the methyl sulfolenecarboxylate 16 as the (Scheme 1).[9] Although all these three catalysts gave a good
starting dipolarophile.
selectivity, compound 10 was the most efficient one. In the
Thus, the chiral azomethine ylide produced from the (R)- presence of this catalyst, the reaction of nitrone 2a with
phenylethylamine derivative 17 and the methyl sulfolenecar- aldehyde 1A furnished the reduced cycloadduct 3a in a
boxylate 16 reacted to give the diastereomeric cycloadducts reasonable yield in up to 76% ee along with the separable
18 and 19 (60:40 dr), which were separated by chromatogra- diastereomer 4a.[9] In terms of enantioselectivity, the sol-
phy. Although, the major diastereomer 18 could be trans- vent of choice appeared to be wet DMF. The sulfone moiety
formed into compounds ent-8Ϫ10, the minor one, 19, was present in catalysts 8Ϫ10 had a major influence on the en-
Eur. J. Org. Chem. 2003, 2782Ϫ2791
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2783

S. Karlsson, H.-E. Högberg
FULL PAPER
antioselectivity. Thus, exchange of this moiety with a sulfur
Proline and other enantiopure synthetic derivatives of
atom or a methylene group resulted in catalysts showing this amino acid are known to activate the α-position of ali-
reduced enantioselectivity.
phatic aldehydes[12] and ketones[13] in Michael reactions
Although the catalysts studied so far yielded products in with nitroolefins. Such organocatalysts also facilitate the
both fair yields and selectivity, we decided to try to search Michael reactions of nitroalkanes with α,β-unsaturated cyc-
for ways to further improve the enantioselectivity in the re- lic[14] and acyclic ketones,[15] the reactions of α,β-unsatu-
actions depicted in Scheme 1.
rated aldehydes with dienes in asymmetric DielsϪAlder re-
Table 1. 1,3-Dipolar cycloaddition of aldehyde 1A or 1B (100 mol %) with various nitrones 2aϪg (100 mol %) in wet DMF catalyzed by
15 (·2HCl salt; 10 mol %)
[a]
The nitrone (3.7 mmol) and the catalyst (0.37 mmol) were added to a solution of the aldehyde (3.7 mmol) in DMF (15 mL) and water
(86 µL); after the specified time and when a satisfactory conversion had been obtained, water and EtOAc were added; extraction with
EtOAc, drying (Na2SO4), filtration, and concentration gave a residue, which was subjected to chromatography (silica gel, EtOAc/cyclohex-
ane as eluent); All fractions containing the desired products were collected and subjected to NaBH4 reduction in MeOH; after a standard
workup, the reduced diastereomeric exo/endo-cycloadducts were separated (silica gel, EtOAc/cyclohexane as eluent); no regioisomers
could be detected in any instance [b] Combined overall yield of the exo/endo diastereomers. [c] Determined by GC analyses. [d] Determined
by GC analyses on a chiral β-dex 325 column of the corresponding trifluoroacetate of 3aϪ3e and 5d. [e] 10:1:8 ratio of aldehyde/catalyst/
[f]
[g]
[h]
nitrone. No water added. One recrystallization from EtOAc/heptane furnished 3b in Ͼ 99% ee.
The nitrone, dissolved in DMF
(10 mL), was slowly added (36 h) to a solution containing the aldehyde and the catalyst in DMF (5 mL) and water (86 µL). [i] Determined
1
through H NMR integration after esterification of 3f using (S)-α-methoxy-α-(trifluoromethyl)phenylacetic chloride (MTPA-Cl).
2784
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2782Ϫ2791

Enantioselective 1,3-Dipolar Cycloadditions of Nitrones with 1-Cycloalkene-1-carboxaldehydes
FULL PAPER
actions[16] and the newly discovered nucleophilic addition
The reactions described so far have been performed on a
reactions of nitrones to ketones.[17] Hence, we turned our small scale using 10Ϫ13 mol % of the catalyst. In order to
attention to the catalytic performance of some pyrrolidin- demonstrate the synthetic utility of these reactions, the
ium salts derived from proline.
cyclopentenylnitrone 2b and the aldehyde 1A were chosen
as reagent and substrate, respectively, in an experiment on
a large scale using a low catalyst loading. Thus, when a
stoichiometric amount of these were used on a 90 mmol
scale in the presence of 5 mol % of catalyst 15 (·2HCl salt)
while the reaction was allowed to go to completion at Ϫ8
°C, a diastereomeric mixture (94:6) of the reduced cycload-
ducts 3b (85% ee) and 4b in 80% overall yield after 11 d
was obtained. One single recrystallization of the crude mix-
ture from EtOAc/heptane improved the ee and dr of the
major product 3b to over 99% and Ͼ 99:1, respectively
(56% overall yield). Thus, this result is similar to that ob-
tained when the reaction was performed on a smaller scale
using a higher catalyst loading (Table 1, Entry 6). However,
the yield in the large-scale experiment was improved.
The significant difference in enantioselectivity observed,
when the aldehyde 1A reacts with various nitrones 2aϪf, is
difficult to explain based only on steric factors. In some
experiments we have noticed that a longer reaction time re-
sults in a lower enantioselectivity (compare Entries 13 and
14, Table 1). We have also found that if the concentration
of the nitrone is kept at a minimum, we are able to improve
the enantioselectivity (compare Entries 4 and 5, Table 1).
These observations indicate that a competing reaction is
taking place, which leads to racemic cycloadducts. Of co-
urse, this reaction can be the uncatalyzed reaction of the
nitrones with the aldehydes. However, as mentioned above,
at ambient temperature and in the absence of a catalyst, the
aldehyde 1A does not react with the nitrone 2a. Moreover,
the presence of a catalyst in the reaction of nitrone 2c with
the aldehyde 1A at Ϫ25 °C (Entry 7, Table 1) is a prerequi-
site to obtain any conversion. Thus, another competing re-
action is probably taking place.
When testing the prolinols 11[18] and 12[19] we found that
they were inefficient as catalysts in the reaction of 1A with
nitrone 2a (Scheme 1). However, the methyl ether 13[20] did
catalyze this reaction and after reduction of the formyl
group of the corresponding cycloadduct, we obtained the
isoxazolidine 3a in high enantioselectivity (68% ee), albeit
in a low yield.[9] A probable explanation for the lack of
catalytic activity observed for the salts 11 and 12, was that
these became trapped as unreactive protonated cyclic N,O-
acetals.[9] Probably due to their rigid structures, this side
reaction did not seem to occur with catalysts 8Ϫ10.
When we tested various mono- and diammonium salts of
14[21] and 15[21] (Figure 1) as catalysts in the reaction of
aldehyde 1A with nitrone 2a (Scheme 1), we were pleased
to find that the isoxazolidine 3a was obtained in both a
very high diastereoselectivity and enantioselectivity.[9] For
example, in the presence of catalyst 15 (·2HCl salt), the
major reduced cycloadduct 3a was obtained in a reasonable
yield in 97:3 dr and 92% ee (Table 1, Entry 1).[9] The best
results were obtained when catalyst 15 (·2HCl salt) was used
and therefore, further studies were performed using the lat-
ter. We wanted to investigate the effect of added water to
the reaction mixture at both low and high temperatures.
Hence, when the initial addition of water to the reaction
mixture was excluded (Entry 2), both the enantioselectivity
and diastereoselectivity decreased and under these dry con-
ditions, the diastereoselectivity was to our surprise reversed
in one reaction run at a low temperature (Ϫ25 °C; Entry 3).
Having established that the organocatalyst 15 (·2HCl salt)
(Figure 1) efficiently promoted the diastereo- and enanti-
oselective addition of nitrone 2a to cyclopentenecarboxal-
dehyde 1A, we studied its catalytic efficiency in reactions
involving other nitrones and aldehydes (Table 1, Entries
4Ϫ14). The nitrones were derived from both aliphatic and
aromatic aldehydes. Although the diastereoselectivity re-
mained high in the reactions of both aldehydes with nearly
all of the nitrones, a considerable variation in enantioselec-
tivity was observed. Thus, whereas the reduced cycloadduct
3b was obtained in a high enantioselectivity (90% ee; Entry
6), that of 3d was low (41% ee; Entries 8 and 9).
When treating the aldehyde 1A with the nitrone 2g, we
obtained the known[8] diastereomeric cycloadducts 3g and
4g as an inseparable mixture after reduction in low dia-
stereoselectivity (Entry 12; yield and ee not determined).
The structure of the aldehyde was found to be important
for achieving a successful reaction. Thus, the reaction of the
sterically more demanding dimethylcyclopentenecarboxal-
dehyde 1B with the nitrone 2a gave only trace amount of
the corresponding major cycloadduct, albeit in high enanti-
oselectivity (70% ee). However, the aldehyde 1B did react
with nitrone 2d to give a low yield of the reduced cycload-
duct 5d in high diastereoselectivity and moderate enantiose-
lectivity (Entry 13).
Scheme 3. Proposed competing reactions furnishing either nonra-
cemic 3b as a by-product or one of the cycloadducts 3aϪe as a race-
mate
Eur. J. Org. Chem. 2003, 2782Ϫ2791
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2785

S. Karlsson, H.-E. Högberg
FULL PAPER
Such a competing reaction can involve nitrone 2b acting
Assignments of relative and absolute configurations of
as a spontaneously reacting dipolarophile (Scheme 3). The the major cycloadducts obtained from the reactions de-
nitrone 2b is indeed detected in many of the reactions in- scribed above (Scheme 1, Table 1) were based on NMR
volving the various nitrones 2 and aldehyde 1A and is spectroscopic data and chemical transformations.
formed through hydrolysis of the original nitrone followed
The relative configuration of the major diastereomer 3a
by condensation of the resulting hydroxylamine with alde- and the minor one 4a was determined through 1D NOE
hyde 1A (Scheme 3). The nitrone 2b can, of course, react experiments (Figure 2). Thus, the minor diastereomer 4a
with the aldehyde 1A in the presence of catalyst 15 to give displayed a 2% NOE between the two methine protons
after reduction, nonracemic diastereomeric cycloadducts shown. This NOE was absent in the major diastereomer 3a.
3b and 4b. In fact, when performed at a low temperature However, a strong NOE was observed for this isomer be-
(Ϫ10 °C), we do obtain the adduct 3b in Ͼ 90% ee as a tween the phenyl protons and the CH2OH protons. The as-
major by-product in the reaction of nitrone 2a with alde- signment of relative configuration of the major and minor
hyde 1A.[9]
diastereomer was also supported by the strong shielding ef-
Another possible competing reaction can occur if the π- fect of the phenyl group resulting in an upfield shift of the
bond of the cyclopentenyl moiety of nitrone 2b is suffic- CH2OH signals (δ ϭ 3.27Ϫ3.42 ppm) of the major dia-
iently activated for attack of the original nitrone. This will, stereomer 3a relative to those of the minor diastereomer 4a
after hydrolysis in situ and reduction with NaBH4, result (δ ϭ 3.56Ϫ3.75 ppm).
in a racemic cycloadduct 3 along with the corresponding
hydroxylamine (Scheme 3). Thus, such a hypothetical com-
peting reaction furnishing racemic cycloadducts can explain
why longer reaction times and high concentrations of the
original nitrones result in lower enantioselectivity.
To test the hypothesis of the nitrone 2b acting as a spon-
taneously reacting dipolarophile, this nitrone was dissolved
in dry DMF and stirred at ambient temperature. After five
weeks, hydrolysis and reduction (NaBH4) of the reaction
mixture, furnished a considerably amount (ca. 30% yield)
of the expected racemic product 3b. Furthermore, when a
diammonium salt (i.e. TMEDA·2HCl salt) not able to form
a catalytically active iminium species was added, the reac-
tion rate slightly increased. Thus, these observations
strongly support that the competing reaction furnishing ra-
cemic cycloadducts (Scheme 3) is taking place. Although
the main reason for the low ee values obtained in some of
the reactions of the aldehydes 1A and 1B with the nitrones 2
is probably due to the catalyst used, the competing reaction
furnishing racemic cycloadducts may also have a negative
impact on the enantioselectivity.
In addition to the competing reaction furnishing racemic
cycloadducts caused by the in situ production of the nitrone
2b, its formation in the reactions depicted in Scheme 1 also
leads to reduced yields. Thus, after workup and reduction,
the major product is accompanied by the nonracemic by-
product 3b (Scheme 3). Reducing the amount of water ad-
ded to the reaction mixture will lead to a decrease of the
rate of formation of the unwanted nitrone 2b from the orig-
inal nitrone and thus the two competing reactions depicted
in Scheme 3 will be suppressed. However, because the pres-
ence of water is a prerequisite for obtaining high diastereo-
as well as enantioselectivity (Table 1, Entries 2 and 3) an-
other method, which will suppress the formation of 2b is
desirable. We have attempted to solve this problem by the
addition of a large excess of the aldehyde corresponding
to the original nitrone, in order to trap any hydroxylamine
liberated. However, when we use butanal as an additive (10
equiv.) in the reaction of the corresponding nitrone 2c with
aldehyde 1A, the yield of 3c drops dramatically, while leav-
ing the enantioselectivity unaffected.
Figure 2. NOE observed in the major and minor diastereomer 3a
and 4a, respectively
Assuming that all of the major cycloadducts 3 and 5 have
the same relative configuration as that of 3a, the R3 sub-
stituents of those are in closer proximity to the hydroxy-
methyl moiety than they are in the minor cycloadducts 4
and 6 (Scheme 1). Thus, in the adduct 3b, the alkene and
the hydroxymethyl moieties will be located close enough for
an iodoetherification reaction to take place. In contrast,
such a reaction will not be possible for the minor dia-
stereomer 4b.
Indeed, when a diastereomeric mixture of 3b and 4b was
subjected to I2 in the presence of a base (NaHCO3) in
CH3CN, only the major diastereomer 3b undergoes iodo-
etherification (Scheme 4). Based on the results from the
GC-MS and NMR analyses performed, a single tetracyclic
adduct is formed (position of the iodine atom not deter-
mined).
Scheme 4. Iodoetherification of a mixture of the reduced major
cycloadduct 3b and the minor one 4b
The 1H NMR spectroscopic data of the known com-
pound 4g[8] allowed us to assign the same relative configu-
2786
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2782Ϫ2791

Enantioselective 1,3-Dipolar Cycloadditions of Nitrones with 1-Cycloalkene-1-carboxaldehydes
FULL PAPER
ration for the major cycloadduct 3g obtained from the reac-
tion of the aldehyde 1A with the nitrone 2g. Albeit the dia-
stereoselectivity was low in this case (see Entry 12, Table 1),
we were thus able to establish that this reaction also pro-
ceeded with exo selectivity.
The general exo selectivity observed in this work is op-
posite to that obtained when chiral Lewis acid catalysts are
used in the reaction of aldehyde 1A with C,N-diaryl nitro-
nes.[8]
The exo selectivity can originate either from an exo at-
tack of the (Z) forms of the nitrones 2aϪg or from an endo
attack of the (E) forms of those (Figure 3).
Scheme 5. Preparation of diol 24 and the enantiomer ent-24 from
compound 3a and 25, respectively; reagents and conditions: a)
Pd(OH)2, HCl, MeOH, H2; b) AcCl, pyridine, CH2Cl2; c) (i) Li-
AlH4, THF, (ii) water; d) Pd/C, H2, MeOH
duced using LiAlH4 to give ent-24 {[α]2D5 ϭ ϩ6.4 (c ϭ 1.35,
MeOH)} as the major product.
Thus, on the basis of the reasoning given above, the
major reduced cycloadduct obtained from aldehyde 1A and
the nitrone 2a is the stereoisomer 3a. Although not certain,
Figure 3. Origin of diastereoselectivity in the reactions of the nitro-
nes 2aϪg with the reactive intermediate from cyclopentenecarbox-
aldehyde 1A and catalyst 15; the definition of exo and endo attack
is related to the α,β-unsaturated system
Some aliphatic aldonitrones have previously been as- it is reasonable to assume that all the major cycloadducts
signed the (Z) configuration, and acyclic nitrones in general obtained from the reactions of the nitrones 2bϪg with
exist almost exclusively in their (Z) forms with a large bar- either the aldehyde 1A or 1B have related configurations.
rier of interconversion into the (E) form.[22] However, this
The sense of enantioselectivity observed in these reac-
barrier varies depending on the reaction conditions used. It tions may be due to steric factors in the reactive iminium
has for example been demonstrated that traces of benzoic ion intermediate. Considering only these factors, the sense
acid markedly reduce the barrier to isomerization.[23] Thus, of π-facial selectivity observed, when the nitrones 2aϪg re-
a more reactive (E) isomer of the nitrone can be present acted with aldehyde 1A in the presence of catalyst 15 (·2HCl
due to such an isomerization. However, because it has been salt), can be explained through the models depicted in Fig-
reported that some aldonitrones react in their (Z) forms ure 4. Thus, either (Z)- or (E)-iminium ion formation from
with α,β-unsaturated aldehydes under similar conditions to the catalyst and the aldehyde can occur. The π-moiety from
those used in this work,[7] it is reasonable to believe that the the aldehyde can adopt either an s-cis or an s-trans confor-
major attack of the nitrones 2aϪg to aldehydes 1A and 1B mation. This results in the four possible intermediates AϪD
proceeds in an exo mode with the nitrones adopting the (Z) (Figure 4). Out of these, A and D are unlikely to be the
configuration (Figure 3).
major reactive ones, because in order to explain the path-
The absolute configuration of one of the major reduced way leading to the major enantiomers of the cycloadducts,
cycloadducts, 3a, could after transformation to the diol 24 attack of the nitrones have to occur from the sterically hin-
be assigned by comparision of the sign of optical rotation dered side of the π-bond. However, attack on either the in-
of the latter with that of an independently prepared termediate B or C by the nitrones from the sterically least
sample (Scheme 5).
hindered side will yield the major enantiomers obtained in
We first tried to prepare the diol 24 directly from the this work.
reduced cycloadduct 3a by hydrogenation in one single step.
Out of the two isomers B and C, the latter has one of
However, only NϪO cleavage was observed. As demon- the π-faces efficiently shielded by the piperidinium ring and
strated by others, similar difficulties were encountered in should therefore best explain the observed enantioselectiv-
attempts to simultaneously reduce both NϪO and NϪBn ity. In isomer B, due to the long distance between the piperi-
bonds of isoxazolidines.[24] Therefore, an alternative ap- dinium moiety of the catalyst and the reacting π-bond of
proach was chosen. Hydrogenolysis of the NϪO bond of the aldehyde moiety, such an efficient shielding cannot be
3a (91% ee) was followed by acetylation to give compound obtained and thus attack of the nitrones are expected to
23. Reduction of the ester groups and the N-Ac moiety of occur with low enantioselectivity. Using a simple molecular
23 using LiAlH4 gave an amino diol which, after catalytic modeling program (CS Chem3D ProTM 4.0), we have calcu-
hydrogenation, furnished the desired diol 24 {[α]2D5 ϭ Ϫ20.5 lated the relative energies of simplified models of the inter-
(c ϭ 0.62, MeOH)}. An authentic sample of 38% ee of com- mediates B and C in which the piperidinium moiety has
pound 25[25] with known absolute configuration was re- been replaced by a trimethylammonium one. The variation
Eur. J. Org. Chem. 2003, 2782Ϫ2791
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2787

S. Karlsson, H.-E. Högberg
FULL PAPER
instrument, coupled to a Varian 3800 GC instrument. The nitrones
2aϪg were used without further purification and were generated
from the corresponding hydroxylamine and aldehyde.[26] Aldehydes
1A[27] and 1B[28] and catalysts 7,[16] 11,[18] 12,[19] 13,[20] 14[21] and
15[21] were prepared according to literature procedures.
Methyl
(3aR,6aS)-5-[(1R)-1-Phenylethyl]tetrahydro-1H-thieno-
[3,4-c]pyrrole-3a(3H)-carboxylate 2,2-Dioxide (18) and Methyl
(3aS,6aR)-5-[(1R)-1-Phenylethyl]tetrahydro-1H-thieno[3,4-c]-
pyrrole-3a(3H)-carboxylate 2,2-Dioxide (19): To a solution of
methyl 2,5-dihydrothiophene-3-carboxylate 1,1-dioxide (16)[29]
(6.73 g, 38.2 mmol) in TFA/CH2Cl2 (5 m; 50 mL) at 0 °C, N-[(R)-
1-phenylethyl]-N-(methoxymethyl)-N-(trimethylsilylmethyl)amine
(17)[30] (10.0 g, 39.8 mmol) was added slowly (0.5 h). The reaction
mixture was warmed to room temperature and after 0.5 h,
NaHCO3 (aq. satd.; 100 mL) was added. The aqueous phase was
extracted with EtOAc (3 ϫ 50 mL) and the pooled organic phases
Figure 4. Potential reactive iminium ion intermediates AϪD from
catalyst 15 and aldehyde 1A; as described by the arrows, α-Si,β-Re
attack on the α,β-unsaturated iminium ion derivative gives the
major enantiomer of the product obtained; filled arrows indicate
attack from the front, and the unfilled ones attack from the back
in energies for the low-energy conformations of these inter- were dried (MgSO4) and concentrated. 1H NMR analysis of the
crude product indicated a diastereomeric ratio of 60:40 (18/19). The
residue was subjected to column chromatography [SiO2; EtOAc/
cyclohexane (10 Ǟ 60%)] to yield 18 (6.59 g, 53%), a mixture of
the diastereomers 18 and 19 (0.70 g, 6%), and 19 (4.29 g, 35%).
According to their NMR spectra, both diastereomers, which were
obtained as highly viscous oils, were diastereomerically pure. 18
(Major): [α]2D5 ϭ ϩ43.1 (c ϭ 1.33, CHCl3). 1H NMR (CDCl3): δ ϭ
1.37 (d, J ϭ 6.6 Hz, 3 H), 2.39 (d, J ϭ 9.7 Hz, 1 H), 2.64 (d, J ϭ
9.3 Hz, 1 H), 2.66 (d, J ϭ 9.3 Hz, 1 H), 2.95Ϫ3.11 (m, 3 H),
3.28Ϫ3.53 (m, 3 H), 3.74 (s, 3 H), 3.74Ϫ3.82 (m, 1 H), 7.22Ϫ7.36
(m, 5 H) ppm. 13C NMR (CDCl3): δ ϭ 22.9, 40.9, 53.1, 54.0, 54.8,
55.9, 57.3, 62.9, 63.3, 126.7, 127.4, 128.6, 144.3, 172.9 ppm. MS
(EI): m/z (%) ϭ 324 (8) [M ϩ H]ϩ, 308 (100), 292 (3), 245 (9), 218
(7) 105 (25). C16H21NO4S (323.41): calcd. C 59.4, H 6.5, N 4.3;
found C 59.3, H 6.7, N 4.2. 19 (Minor): [α]2D5 ϭ ϩ8.5 (c ϭ 1.18,
CHCl3). 1H NMR (CDCl3): δ ϭ 1.35 (d, J ϭ 6.6 Hz, 3 H),
2.48Ϫ2.60 (m, 2 H), 2.61 (d, J ϭ 9.4 Hz, 1 H), 2.90 (dd, J ϭ 8.6,
13.1 Hz, 1 H,), 3.09 (d, J ϭ 9.4 Hz, 1 H), 3.15Ϫ3.42 (m, 4 H), 3.79
(s, 3 H), 3.89 (dd, J ϭ 2.6, 13.8 Hz, 1 H), 7.21Ϫ7.36 (m, 5 H) ppm.
13C NMR (CDCl3): δ ϭ 22.8, 40.8, 53.2, 54.1, 54.4, 56.2, 57.9,
62.2, 63.2, 126.7, 127.4, 128.6, 144.3, 173.0 ppm. MS (EI): m/z
(%) ϭ 324 (11) [M ϩ H]ϩ, 308 (100), 292 (2), 245 (10), 218 (2), 105
(19). C16H21NO4S (323.41): calcd. C 59.4, H 6.5, N 4.3; found C
mediates all lie within 1 kcal/mol. According to the Ham-
met-Curtin principle, the reaction does not have to proceed
via the most stable intermediate. Moreover, the charges in
the dication intermediate as well as their counterions may
also play a major role here in directing the approach of the
incoming nitrone. Thus, although the dication intermediate
C best seems to explain the observed enantioselectivity, in-
termediate B cannot be ruled out as the major reactive in-
termediate.
Conclusion
In summary, when catalyzed by various pyrrolidinium
salts, nitrones undergo 1,3-dipolar cycloaddition reactions
with 1-cycloalkene-1-carboxaldehydes, furnishing reason-
able yields of fused exo-bicyclic isoxazolidines in both high
diastereoselectivities and enantioselectivities. One of the
cycloadducts could be obtained enantiomerically pure (Ͼ
99% ee) after recrystallization. The low loading of both the
catalyst and the substrate aldehyde that can be employed
for achieving a reasonable yield of the cycloadducts, should 59.7, H 6.6, N 4.4.
make this procedure useful for preparing enantiopure fused
[(3aS,6aR)-2,2-Dioxido-5-[(1R)-1-phenylethyl]tetrahydro-1H-thieno-
bicyclic isoxazolidines.
[3,4-c]pyrrol-3a(3H)-yl]bis(4-methoxyphenyl)methanol (21): To
a
solution of the minor diastereomer 19 (2.30 g, 7.1 mmol) from
above in THF (75 mL), p-MeOC6H4MgBr (0.5  in diethyl ether;
57 mL, 28 mmol) was added over a period of 2 h. After an ad-
ditional 5 h, water (200 mL) and EtOAc (200 mL) were added. The
aqueous phase was extracted with EtOAc (2 ϫ 100 mL) and the
pooled organic phases were dried (Na2SO4) and concentrated to
Experimental Section
General Remarks: All chemicals were used as received. THF (K,
benzophenone), CH2Cl2, ClCH2CH2Cl (both CaH2) were distilled
from the indicated drying agents. Diethyl ether, ethyl acetate give a residue, which was subjected to column chromatography
1
(EtOAc) and cyclohexane were distilled prior to use. The H and
[SiO2; EtOAC/cyclohexane (5 Ǟ 100%)] followed by recrystalliza-
tion from EtOAc/heptane. This afforded compound 21 (2.23 g,
13C NMR spectra were recorded with a Bruker DMX 250
(250 MHz 1H and 62.9 MHz 13C) instrument. Preparative liquid 62%) as colorless crystals in Ͼ 98% purity (GC). M.p. 205Ϫ206
1
chromatography was performed on straight phase silica gel 60
°C. [α]2D5 ϭ ϩ10.6 (c ϭ 0.42, CHCl3). H NMR (CDCl3): δ ϭ 1.40
(Merck, 230Ϫ400 mesh). GC analyses were carried out using either
(d, J ϭ 6.1 Hz, 3 H), 2.45Ϫ3.10 (m, 6 H), 3.25Ϫ3.35 (m, 1 H),
a capillary column EC-5, 30 m, 0.32 mm i.d., df ϭ 0.25 µm, carrier 3.53Ϫ3.80 (m, 3 H), 3.73 (s, 3 H), 3.77 (s, 3 H), 6.68 (d, J ϭ 8.5 Hz,
gas N2 or a chiral capillary column β-Dex 325, 30 m, 0.25 mm i.d., 2 H), 6.83 (d, J ϭ 8.9 Hz, 2 H), 6.94 (s, OH), 7.08Ϫ7.39 (m, 9 H)
df ϭ 0.25 µm, carrier gas He. The elemental analyses (C, H, N) ppm. 13C NMR (CDCl3): δ ϭ 21.6, 38.4, 52.7, 55.0, 55.1, 55.2,
were performed by Mikro Kemi AB, 75228 Uppsala, Sweden. Boil-
ing points are uncorrected and given as air bath temperatures (bath
56.3, 57.0, 61.6, 63.5, 82.5, 113.0, 113.4, 126.6, 127.4, 128.4, 128.5,
128.7, 135.4, 137.9, 143.3, 158.2, 158.6 ppm. MS (EI): m/z (%) ϭ
temp./mbar) in a bulb-to-bulb (Büchi GKR-51) apparatus. Optical 508 (4) [M ϩ H]ϩ , 492 (26), 264 (10), 243 (37), 201 (67), 135 (100),
rotations were measured with a PerkinϪElmer 241 MC polarimeter
105 (65). C29H33NO5S (507.64): calcd. C 68.6, H 6.6, N 2.8; found
in a 1-dm cell. Mass spectra were recorded with a Saturn 2000 C 68.3, H 6.5, N 2.7.
2788
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2782Ϫ2791

Enantioselective 1,3-Dipolar Cycloadditions of Nitrones with 1-Cycloalkene-1-carboxaldehydes
FULL PAPER
[(3aS,6aR)-2,2-Dioxido-5-[(1R)-1-phenylethyl]tetrahydro-1H-thieno- crystals, Ͼ 99% purity (GC; free base), m.p. 298Ϫ299 °C (dec).
[3,4-c]pyrrol-3a(3H)-yl]diphenylmethanol (20): The title compound
was prepared from compound 19 and phenylmagnesium bromide
according to the same procedure as that for the preparation of 21
with the following exception. The crude product was chromato-
graphed with diethyl ether/cyclohexane as eluent. No further purifi-
cation was necessary. Yield 62%, colorless crystals, Ͼ 99% purity
[α]2D5 ϭ Ϫ29.7 (c ϭ 0.67, MeOH). 1H NMR [(CD3)2SO]: δ ϭ
1.30Ϫ1.55 (m, 1 H), 3.03 (s, 3 H), 3.04Ϫ3.62 (m, 5 H), 3.68 (d, J ϭ
12.3 Hz, 1 H), 4.12 (d, J ϭ 14.9 Hz, 1 H), 4.15Ϫ4.31 (m, 1 H),
7.12Ϫ7.51 (m, 10 H), 8.70 (s, NH), 10.00 (s, NH) ppm. 13C NMR
[(CD3)2SO]: δ ϭ 41.1, 47.4, 50.4, 52.6, 55.0, 56.4, 56.5, 89.5, 128.1,
128.2, 128.4, 128.7, 129.3, 131.2, 136.2, 137.9 ppm. MS (EI; free
(GC), m.p. 201Ϫ202 °C. [α]2D5 ϭ ϩ37.3 (c ϭ 0.94, CHCl3). 1H base): m/z (%) ϭ 358 (100) [M ϩ H]ϩ, 326 (8), 197 (82), 105 (68).
NMR (CDCl3): δ ϭ 1.40 (d, J ϭ 6.4 Hz, 3 H), 2.45Ϫ3.11 (m, 6 C20H23NO3S·HCl (393.93): calcd. C 61.0, H 6.1, N 3.6; found C
H), 3.25Ϫ3.35 (m, 1 H), 3.60Ϫ3.75 (m, 3 H), 7.11Ϫ7.46 (m, 16 H) 60.8, H 6.2, N 3.6.
ppm. 13C NMR (CDCl3): δ ϭ 21.6, 38.4, 52.8, 54.7, 56.2, 57.0,
[(3aS,6aR)-2,2-Dioxidotetrahydro-1H-thieno[3,4-c]pyrrol-3a(3H)-
61.6, 63.5, 82.9, 126.5, 127.0, 127.3, 127.4, 127.5, 127.8, 128.2,
128.5, 143.0, 143.2, 145.5 ppm. MS (EI): m/z (%) ϭ 448 (24) [M ϩ
H]ϩ, 432 (65), 264 (55), 184 (20), 105 (100). C27H29NO3S (447.59):
calcd. C 72.5, H 6.5, N 3.1; found C 72.8, H 6.6, N 3.2.
yl]diphenylmethanol Hydrochloride (8): The title compound was
prepared from compound 20 according to the same procedure as
that described for the preparation of compound 10. Yield 65%,
colorless crystals, Ͼ 99% purity (GC; free base). M.p. 292Ϫ293 °C
(dec). [α]2D5 ϭ Ϫ40.7 (c ϭ 0.61, MeOH). 1H NMR [(CD3)2SO]: δ ϭ
1.51Ϫ1.97 (m, 1 H), 3.08Ϫ4.43 (m, 8 H), 6.75 (s, OH), 7.22Ϫ7.41
(m, 10 H), 9.20 (s, 2 H, NH2) ppm. 13C NMR [(CD3)2SO]: δ ϭ
40.1, 48.5, 50.8, 54.5, 55.7, 56.9, 82.9, 127.5, 127.7, 127.8, 128.2 (2
C), 128.5, 143.2, 144.3 ppm. MS (EI; free base): m/z (%) ϭ 344
(3aS,6aR)-3a-[(Methoxy)diphenylmethyl]-5-[(1R)-1-phenylethyl]-
hexahydro-1H-thieno[3,4-c]pyrrole 2,2-Dioxide (22): To a cold (0
°C) solution of compound 20 (1.43 g, 3.2 mmol) in THF (50 mL)
was added NaH (400 mg, 16.7 mmol), followed by the addition of
MeI (1.5 g, 10.6 mmol). After standing overnight, water (50 mL)
and EtOAc (50 mL) were added, followed by extraction of the
aqueous phase with EtOAc (2 ϫ 50 mL). The pooled organic
phases were dried (Na2SO4), concentrated and the residue was
purified by flash chromatography [SiO2; EtOAc/cyclohexane (0 Ǟ
40%)] to afford 22 (1.30 g, 88%) as colorless crystals in purity Ͼ
(25) [M
ϩ
H]ϩ, 325 (12), 183 (22), 160 (25), 105 (100).
C19H21NO3S·HCl (379.90): calcd. C 60.1, H 5.8, N 3.7; found C
60.3, H 5.9, N 3.8.
General Method for the 1,3-Dipolar Cycloaddition Reactions: The
reactions were performed as described above (footnote [a], Table 1).
When performed on a larger scale, a slightly modified procedure
was used. To a cold (Ϫ8 °C) solution of nitrone 2b (11.3 g,
90.3 mmol) in dimethylformamide (DMF; 150 mL) and water
(0.75 mL), the aldehyde 1A (8.68 g, 90.3 mmol) and the catalyst 15
(·2HCl salt; 1.08 g, 4.5 mmol) were added. The reaction mixture
was stirred at Ϫ8 °C for 264 h, followed by the addition of water
(100 mL) and EtOAc (100 mL). The aqueous phase was extracted
with EtOAc (5 ϫ 50 mL) and the pooled organic phases were dried
(MgSO4) and concentrated. To the crude product mixture at 0 °C,
MeOH (100 mL) and NaBH4 (3.8 g, 100 mmol) were added. After
stirring at ambient temperature for 30 min, the reaction was
quenched by the addition of water (100 mL) and NH4Cl (aq. satd.;
50 mL), followed by addition of EtOAc (100 mL). The aqueous
phase was extracted with EtOAc (6 ϫ 50 mL). The pooled organic
phases were dried (MgSO4) and concentrated. The resulting mix-
ture of 3b (94:6 dr, 85% ee; GC) and 4b was placed on a short pad
of silica gel and eluted with EtOAc/cyclohexane (20 Ǟ 100%). This
1
99% (GC). M.p. 75Ϫ77 °C. [α]2D5 ϭ ϩ34.7 (c ϭ 0.38, CHCl3). H
NMR (C6D6): δ ϭ 1.15 (d, J ϭ 6.5 Hz, 3 H), 2.31Ϫ2.68 (m, 5 H),
2.80 (s, 3 H), 2.98Ϫ3.35 (m, 4 H), 3.75Ϫ3.82 (m, 1 H), 7.00Ϫ7.25
(m, 15 H) ppm. 13C NMR (CDCl3): δ ϭ 23.3, 42.4, 53.2, 54.1,
55.6, 58.8, 62.8, 64.3, 64.8, 90.0, 126.8, 127.6, 127.9, 128.0, 128.1,
128.2, 130.3, 130.5, 138.9, 139.2, 145.0 ppm. MS (EI): m/z (%) ϭ
462 (4) [M ϩ H]ϩ, 446 (35), 431 (50), 264 (15), 197 (57), 105 (100).
C28H31NO3S (461.62): calcd. C 72.8, H 6.8, N 3.0; found C 72.9,
H 6.9, N 3.0.
2-[(3aS,6aR)-2,2-Dioxidotetrahydro-1H-thieno[3,4-c]pyrrol-3a(3H)-
yl]bis-(4-methoxyphenyl)methanol Hydrochloride (10): 1-Chloroe-
thyl chloroformate (2.5 g, 17 mmol) was added to a solution of 21
(2.23 g, 4.39 mmol) and 1,8-bis(dimethylamino)naphthalene
(1.88 g, 8.8 mmol) in ClCH2CH2Cl (40 mL). After 0.5 h at room
temperature, the reaction mixture was refluxed for 8 h. After cool-
ing, water (10 mL) and EtOAc (150 mL) were added, followed by
the addition of HCl (aq. 2 ; 50 mL). The organic phase was ex-
tracted with HCl (aq. 2 ; 50 mL), NaHCO3 (aq. satd.; 50 mL),
dried (Na2SO4) and concentrated. The residue was purified by col-
umn chromatography [SiO2; EtOAc/cyclohexane (5 Ǟ 80%)]. The
resulting carbamate intermediate was dissolved in MeOH (5 mL)
and refluxed for 0.5 h. Concentration afforded 10 (1.55 g, 80%) in
Ͼ 99% purity (GC; free base). Recrystallization from 2-propanol/
MeOH gave colorless needles of 10 (1.25 g, 65%). M.p. 188Ϫ190
furnished
a diastereomeric mixture of 3b and 4b (16.1 g,
72.1 mmol; 80%) in 95% chemical purity (GC). One recrystalliza-
tion from EtOAc/heptane furnished 3b (11.2 g, 50.2 mmol; 56%) as
colorless crystals in Ͼ 99% chemical purity and in Ͼ 99:1 dr and
Ͼ 99% ee.
[(3R,3aR,6aR)-2-Methyl-3-phenylhexahydro-3aH-cyclopenta[d]-
isoxazol-3a-yl]methanol (3a): 93% ee. M.p. 68Ϫ70 °C. [α]2D5 ϭ Ϫ153
(c ϭ 0.80, CHCl3). 1H NMR (CDCl3): δ ϭ 1.26Ϫ1.32 (m, OH),
1.46Ϫ1.65 (m, 2 H), 1.76Ϫ2.06 (m, 4 H), 2.57 (s, 3 H), 3.23 (s, 1
H), 3.31 (dd, J ϭ 6.7, 11.2 Hz, 1 H), 3.39 (dd, J ϭ 4.9, 11.2 Hz, 1
H), 4.30 (d, J ϭ 5.1 Hz, 1 H), 7.28Ϫ7.38 (m, 5 H) ppm. 13C NMR
(CDCl3): δ ϭ 24.0, 32.0, 33.6, 42.8, 64.0, 65.5, 81.2, 86.1, 127.3,
128.0, 128.8, 136.1 ppm. MS (EI): m/z (%) ϭ 233 (57) [Mϩ], 216
(2), 134 (100). C14H19NO2 (233.31): calcd. C 72.1, H 8.2, N 6.0;
found C 72.2, H 8.3, N 6.0.
1
°C (dec). [α]2D5 ϭ Ϫ53.4 (c ϭ 1.1, MeOH). H NMR [(CD3)2SO]:
δ ϭ 1.78Ϫ1.98 (m, 1 H), 3.12Ϫ3.75 (m, 6 H), 3.78 (s, 3 H), 3.79
(s, 3 H), 3.93Ϫ4.25 (m, 2 H), 6.58 (s, ϪOH), 6.84Ϫ6.96 (m, 4 H),
7.19Ϫ7.30 (m, 4 H), 8.80 (s, NH), 9.90 (s, NH) ppm. 13C NMR
(CD3OD): δ ϭ 41.1, 50.5, 51.8, 55.8 (2 C), 56.4, 57.1, 57.7, 84.0,
114.5, 114.8, 130.9 (2 C), 136.2, 137.4, 160.6, 160.8 ppm. MS (EI;
free base): m/z (%) ϭ 404 (23) [M ϩ H]ϩ, 386 (12), 243 (14), 135
(100). C21H25NO5S·HCl (439.95): calcd. C 57.3, H 6.0, N 3.2;
found C 57.4, H 6.0, N 3.2.
(3aS,6aR)-3a-[(Methoxy)diphenylmethyl]hexahydro-1H-thieno- [(3S,3aR,6aR)-2-Methyl-3-phenylhexahydro-3aH-cyclopenta[d]-
[3,4-c]pyrrole 2,2-Dioxide Hydrochloride (9): The title compound
was prepared from 22 according to the same procedure as that
described for the preparation of compound 10. Yield 96%, colorless
isoxazol-3a-yl]methanol (4a): ee not determined. M.p. 68Ϫ71 °C.
1H NMR (CDCl3): δ ϭ 0.90Ϫ1.02 (m, 1 H), 1.42Ϫ1.60 (m, 2 H),
1.75Ϫ2.01 (m, 4 H), 2.60 (s, 3 H), 3.60 (d, J ϭ 10.9 Hz, 1 H), 3.63
Eur. J. Org. Chem. 2003, 2782Ϫ2791
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2789

S. Karlsson, H.-E. Högberg
FULL PAPER
(s, 1 H), 3.71 (d, J ϭ 10.9 Hz, 1 H), 4.47Ϫ4.52 (m, 1 H), 7.25Ϫ7.40
(31), 91 (100). C15H21NO2 (247.33): calcd. C 72.8, H 8.6, N 5.7;
(m, 5 H) ppm. 13C NMR (CDCl3): δ ϭ 25.4, 30.6, 35.1, 43.8, 64.1, found C 72.8, H 8.6, N 5.8.
66.2, 77.7, 85.1, 127.4, 128.1, 128.3, 137.5 ppm. MS (EI): m/z (%) ϭ
233 (63) [Mϩ], 216 (2), 134 (100). C14H19NO2 (233.31): calcd. C
72.1, H 8.2, N 6.0; found C 72.3, H 8.1, N 5.9.
[(3R,3aR,6aR)-3-Cyclopropyl-2,5,5-trimethylhexahydro-3aH-cyclo-
penta[d]isoxazol-3a-yl]methanol (5d): 48% ee. M.p. 41Ϫ42 °C.
[α]2D5 ϭ Ϫ55.0 (c ϭ 0.96, CHCl3). 1H NMR (CDCl3): δ ϭ
0.16Ϫ0.34 (m, 2 H), 0.51Ϫ0.71 (m, 2 H), 0.80Ϫ0.95 (m, 1 H), 1.03
(s, 3 H), 1.15 (s, 3 H), 1.40 (d, J ϭ 13.6 Hz, 1 H), 1.48 (d, J ϭ
13.6 Hz, 1 H), 1.64 (dd, J ϭ 4.5, 13.6 Hz, 1 H), 1.72 (d, J ϭ 8.3 Hz,
1 H), 1.78 (dd, J ϭ 6.3, 13.6 Hz, 1 H), 2.72 (s, 3 H), 3.52 (s, OH),
3.63 (d, J ϭ 10.5 Hz, 1 H), 3.98 (d, J ϭ 10.5 Hz, 1 H), 4.58 (dd,
J ϭ 4.5, 6.3 Hz, 1 H) ppm. 13C NMR (CDCl3): δ ϭ Ϫ0.4, 4.1, 7.0,
30.1, 30.5, 42.1, 43.5, 46.2, 47.7, 63.0, 66.8, 84.1, 86.1 ppm. MS
(EI): m/z (%) ϭ 225 (34) [Mϩ], 184 (10), 100 (100), 84 (82).
C13H23NO2 (225.33): calcd. C 69.3, H 10.3, N 6.2; found C 69.1,
H 10.2, N 6.1.
[(3R,3aR,6aR)-3-(Cyclopent-1-en-1-yl)-2-methylhexahydro-3aH-
cyclopenta[d]isoxazol-3a-yl]methanol (3b): Ͼ 99% ee. M.p. 123Ϫ125
°C. [α]2D0 ϭ Ϫ155 (c ϭ 0.51, CHCl3) 1H NMR (CDCl3): δ ϭ
1.35Ϫ1.99 (m, 8 H), 2.23Ϫ2.48 (m, 5 H), 2.58 (s, 3 H), 2.74 (s, 1
H), 3.43 (dd, J ϭ 6.1, 11.0 Hz, 1 H), 3.60 (dd, J ϭ 3.5, 11.0 Hz, 1
H), 4.40 (d, J ϭ 5.4 Hz, 1 H), 5.66Ϫ5.70 (m, 1 H) ppm. 13C NMR
(CDCl3): δ ϭ 23.0, 24.0, 31.8, 32.4, 33.6, 34.8, 43.3, 63.1, 65.7,
78.1, 85.3, 127.6, 139.1 ppm. MS (EI): m/z (%) ϭ 223 (40) [Mϩ],
125 (50), 68 (100). C13H21NO2 (223.31): calcd. C 69.9, H 9.5, N
6.3; found C 69.8, H 9.6, N 6.2.
[(3S,3aR,6aR)-3-(Cyclopent-1-en-1-yl)-2-methylhexahydro-3aH-
cyclopenta[d]isoxazol-3a-yl]methanol (4b): ee not determined. 1H
NMR (CDCl3): δ ϭ 1.23Ϫ1.93 (m, 9 H), 2.13Ϫ2.41 (m, 4 H), 2.60
(s, 3 H), 3.00 (s, 1 H), 3.60 (d, J ϭ 10.8 Hz, 1 H), 3.69 (d, J ϭ
10.8 Hz, 1 H), 4.37 (t, J ϭ 4.6 Hz, 1 H), 5.60Ϫ5.66 (m, 1 H) ppm.
13C NMR (CDCl3): δ ϭ 23.3, 25.6, 30.7, 32.3, 34.7, 34.8, 44.3,
63.4, 67.0, 75.3, 85.2, 127.9, 139.7 ppm. MS (EI): m/z (%) ϭ 223
(55) [Mϩ], 125 (42), 68 (100).
[(1R,2R)-2-Acetoxy-1-{(R)-[acetyl(methyl)amino](phenyl)-
methyl}cyclopentyl]methyl Acetate (23): Compound 3a (434 mg,
1.86 mmol; 91% ee, Ͼ 98% de), 20% Pd(OH)2/C (100 mg) and HCl
(37% aq.; 0.3 mL) in MeOH (10 mL) were stirred under hydrogen
at ambient pressure and room temperature overnight. The suspen-
sion was filtered, rinsed with MeOH, followed by concentration.
To the resulting amino diol were added pyridine (1.5 g) and CH2Cl2
(25 mL), followed by dropwise addition of AcCl (1.5 g). After 1 h,
HCl (2 ; 30 mL) and EtOAc (50 mL) were added. The organic
phase was extracted with NaHCO3 (aq. satd.; 30 mL), dried
(Na2SO4) and concentrated. The residue was purified by flash chro-
matography [SiO2; EtOAc/cyclohexane (0 Ǟ 100%)] to give the title
compound (612 mg, 1.69 mmol) as an oil in 98% purity (GC).
[(3R,3aR,6aR)-2-Methyl-3-propylhexahydro-3aH-cyclopenta[d]-
isoxazol-3a-yl]methanol (3c): 57% ee. B.p. 120 °C/0.9 mbar. [α]D25
ϭ
Ϫ58.3 (c ϭ 0.82, CHCl3). 1H NMR (CDCl3): δ ϭ 0.98 (t, J ϭ
7.0 Hz, 3 H), 1.22Ϫ1.91 (m, 10 H), 2.11Ϫ2.18 (m, 1 H), 2.59 (s, 3
H), 3.21 (s, OH), 3.45 (d, J ϭ 10.6 Hz, 1 H), 3.85 (d, J ϭ 10.6 Hz,
1 H), 4.43 (d, J ϭ 5.7 Hz, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 14.6,
20.4, 24.2, 28.7, 31.7, 33.1, 42.9, 61.7, 65.2, 76.0, 85.3 ppm. MS
(EI): m/z (%) ϭ 199 (14) [Mϩ], 156 (100), 102 (39). C11H21NO2
(199.29): calcd. C 66.3, H 10.6, N 7.0; found C 66.2, H 10.7, N 6.9.
1
[α]2D5 ϭ Ϫ75.2 (c ϭ 0.39, CHCl3). H NMR [(CD3)2SO; * denotes
peaks arising from a minor rotamer]: δ ϭ 1.35Ϫ2.18 (m, 7.8 H),
1.76 (s, 2.4 H), 1.93 (s, 2.4 H), 1.98 (s, 2.4 H), 2.93 (s, 3 H), 3.84
(d, J ϭ 12.0 Hz, 1 H), 4.02* (d, J ϭ 11.9 Hz, 0.2 H), 4.10 (d, J ϭ
12.0 Hz, 0.8 H), 5.12Ϫ5.19 (m, 1 H), 5.25* (s, 0.2 H), 6.05 (s, 0.8
H), 7.21Ϫ7.50 (m, 5 H) ppm. 13C NMR (CDCl3; * denotes peaks
arising from a minor rotamer]: δ ϭ 20.8*, 20.9, 21.1, 21.2, 22.0*,
22.4, 30.9, 31.0*, 31.7, 34.1, 52.6*, 52.9, 57.4, 62.9*, 65.7, 67.0*,
79.1, 79.7*, 127.1, 127.6*, 128.2, 128.5*, 128.6*, 129.4, 138.8*,
139.2, 169.8*, 170.3*, 170.4, 170.8, 171.1, 171.4* ppm. MS (EI):
m/z (%) ϭ 361 (8) [Mϩ], 302 (10), 162 (70), 120 (100). C20H27NO5
(361.43): calcd. C 66.5, H 7.5, N 3.9; found C 66.7, H 7.6, N 3.9.
[(3R,3aR,6aR)-3-Cyclopropyl-2-methylhexahydro-3aH-cyclo-
penta[d]isoxazol-3a-yl]methanol (3d): 41% ee. M.p. 83Ϫ85 °C.
[α]2D5 ϭ Ϫ41.4 (c ϭ 0.86, CHCl3). 1H NMR (CDCl3): δ ϭ
0.15Ϫ0.24 (m, 1 H), 0.29Ϫ0.38 (m, 1 H), 0.53Ϫ0.70 (m, 2 H),
0.86Ϫ1.00 (m, 1 H), 1.27Ϫ1.84 (m, 7 H), 2.67 (s, 3 H), 2.83 (s,
OH), 3.60 (d, J ϭ 10.5 Hz, 1 H), 3.96 (d, J ϭ 10.5 Hz, 1 H), 4.40
(d, J ϭ 5.5 Hz, 1 H) ppm. 13C NMR (CDCl3): δ ϭ Ϫ0.2, 3.9, 7.2,
23.9, 31.7, 33.5, 43.2, 62.5, 66.1, 81.7, 85.1 ppm. MS (EI): m/z
(%) ϭ 197 (33) [Mϩ], 156 (20), 100 (87), 84 (100). C11H19NO2
(197.27): calcd. C 67.0, H 9.7, N 7.1; found C 67.0, H 9.6, N 7.1.
(1R,2R)-2-Benzyl-2-(hydroxymethyl)cyclopentanol (24) by Re-
duction of 23: To a cold (0 °C) suspension of LiAlH4 (0.48 g,
12.7 mmol) in dry THF (10 mL), compound 23 (460 mg,
1.27 mmol; 91% ee, Ͼ 98% de) was added, dissolved in dry THF
(10 mL). The reaction mixture was then allowed to reach room
temperature. After 0.5 h, water (0.53 mL) and NaOH (aq. 15%,
0.53 mL) were added, followed by the addition of water (1.6 mL).
The resulting suspension was filtered, the solid rinsed with EtOAc
and the filtrate concentrated. The resulting amino diol was dis-
solved in MeOH (5 mL). 10% Pd/C (100 mg) was added, followed
by stirring under hydrogen at ambient pressure and room tempera-
ture overnight. Filtration, followed by concentration furnished the
crude diol 24. Flash chromatography [SiO2; EtOAc/cyclohexane (0
Ǟ 100%)] gave the title compound as colorless crystals in Ͼ 99%
(3S,3aR,6aR)-3a-(Hydroxymethyl)-2-methylhexahydro-2H-cyclo-
penta[d]isoxazole-3-carbaldehyde (3e): 53% ee. M.p. 86Ϫ88 °C.
[α]2D5 ϭ Ϫ93.5 (c ϭ 0.51, CHCl3). 1H NMR (CDCl3): δ ϭ 1.35Ϫ2.05
(m, 7 H), 2.60 (s, 3 H), 3.36 (s, 1 H), 3.47 (d, J ϭ 11.4 Hz, 1 H),
3.52 (d, J ϭ 11.4 Hz, 1 H), 4.49 (d, J ϭ 5.4 Hz, 1 H), 6.37Ϫ6.43
(m, 2 H), 7.44Ϫ7.47 (m, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 23.8,
31.8, 33.4, 43.2, 63.8, 65.6, 75.8, 85.8, 108.6, 110.6, 142.7, 149.6
ppm. MS (EI): m/z (%) ϭ 223 (25) [Mϩ], 125 (100). C12H17NO3
(223.27): calcd. C 64.6, H 7.7, N 6.3; found C 64.5, H 7.8, N 6.2.
[(3R,3aR,6aR)-2-Benzyl-3-methylhexahydro-3aH-cyclopenta[d]-
isoxazol-3a-yl]methanol (3f): 70% ee. [α]2D5 ϭ Ϫ93.7 (c ϭ 0.83,
CHCl3). H NMR (CDCl3): δ ϭ 1.12Ϫ1.25 (m, 1 H), 1.25 (d, J ϭ purity (GC). M.p. 116Ϫ118 °C. [α]2D5 ϭ Ϫ20.5 (c ϭ 0.62, MeOH).
6.7 Hz, 3 H), 1.45Ϫ1.88 (m, 5 H), 2.50 (q, J ϭ 6.7 Hz, 1 H), 3.00 1H NMR (CDCl3): δ ϭ 0.93Ϫ1.09 (m, 1 H), 1.50Ϫ2.16 (m, 5 H),
(s, OH), 3.44 (d, J ϭ 10.6 Hz, 1 H), 3.62 (d, J ϭ 14.4 Hz, 1 H), 2.23Ϫ2.31 (m, OH), 2.51 (d, J ϭ 13.4 Hz, 1 H), 2.60Ϫ2.65 (m,
3.83 (d, J ϭ 10.6 Hz, 1 H), 4.09 (d, J ϭ 14.4 Hz, 1 H), 4.45 (d, J ϭ OH), 3.10 (d, J ϭ 13.4 Hz, 1 H), 3.27 (dd, J ϭ 3.0, 10.4 Hz, 1 H),
1
5.7 Hz, 1 H), 7.21Ϫ7.40 (m, 5 H) ppm. 13C NMR (CDCl3): δ ϭ
11.3, 23.8, 32.0, 32.3, 59.1, 61.7, 65.6, 68.9, 84.9, 127.2, 128.2, 7.15Ϫ7.35 (m, 5 H) ppm. 13C NMR (CDCl3): δ ϭ 19.2, 29.2, 31.6,
128.6, 137.0 ppm. MS (EI): m/z (%) ϭ 247 (59) [Mϩ], 232 (37), 150
33.0, 49.6, 68.1, 80.1, 125.9, 128.0, 130.5, 139.0 ppm. MS (EI):
3.55 (dd, J ϭ 5.1, 10.4 Hz, 1 H), 4.18 (dt, J ϭ 3.3, 7.4 Hz, 1 H),
2790
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2782Ϫ2791

Enantioselective 1,3-Dipolar Cycloadditions of Nitrones with 1-Cycloalkene-1-carboxaldehydes
FULL PAPER
m/z (%) ϭ 207 (5) [M ϩ H]ϩ, 188 (22), 171 (100), 115 (22), 91 (27).
C13H18O2 (206.28): calcd. C 75.7, H 8.8; found C 75.7, H 8.8.
Int. Ed. Engl. 1971, 10, 496Ϫ497; U. Eder, G. Sauer, R. Wiech-
ert, Angew. Chem. 1971, 83, 492Ϫ493.
P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2001, 40,
3726Ϫ3748.
W. S. Jen, J. J. M. Wiener, D. W. C. MacMillan, J. Am. Chem.
Soc. 2000, 122, 9874Ϫ9875.
T. Mita, N. Ohtsuki, T. Ikeno, T. Yamada, Org. Lett. 2002,
4, 2457Ϫ2460.
S. Karlsson, H.-E. Högberg, Tetrahedron: Asymmetry 2002,
13, 923Ϫ926.
S. Karlsson, H.-E. Högberg, J. Chem. Soc., Perkin Trans. 1
2002, 1076Ϫ1082.
[6]
[7]
(1S,2S)-2-Benzyl-2-(hydroxymethyl)cyclopentanol (ent-24) by Re-
duction of Oxo Ester 25: To a suspension of LiAlH4 (200 mg,
5.2 mmol) in dry THF (2 mL) at 0 °C was added 25[25] (83 mg,
0.3 mmol; 38% ee), dissolved in dry THF (2 mL). The reaction mix-
ture was then allowed to reach room temperature. After 12 h, water
(10 mL) and HCl (2 ; 30 mL) were added, followed by dilution
with EtOAc (30 mL). The aqueous phase was extracted with
EtOAc (2 ϫ 30 mL). The pooled organic phases were dried
(Na2SO4) and concentrated. GC-MS analysis indicated a dia-
stereomeric ratio of 8:1 of the crude diol. The major and the minor
diastereomer were separated by column chromatography [SiO2;
EtOAc/cyclohexane (0 Ǟ 100%)]. This furnished the title com-
pound (34 mg; 55%) in Ͼ 98:2 diastereomeric ratio and in purity
Ͼ 99% (GC). [α]2D5 ϭ ϩ6.4 (c ϭ 1.35, MeOH). Other data are
identical with those for the enantiomer 24 described above.
[8]
[9]
[10]
[11]
[12]
R. A. Olofson, J. T. Martz, J.-P. Senet, M. Piteau, T. Malfroot,
J. Org. Chem. 1984, 49, 2081Ϫ2082.
J. M. Betancort, C. F. Barbas, III, Org. Lett. 2001, 3,
3737Ϫ3740.
[13] [13a]
B. List, P. Pojarliev, H. J. Martin, Org. Lett. 2001, 3,
[13b]
2423Ϫ2425.
D. Enders, A. Seki, Synlett 2002, 26Ϫ28.
[14]
S. Hanessian, V. Pham, Org. Lett. 2000, 2, 2975Ϫ2978.
N. Halland, R. G. Hazell, K. A. Jørgensen, J. Org. Chem. 2002,
67, 8331Ϫ8338.
K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am.
Chem. Soc. 2000, 122, 4243Ϫ4244.
A. Bøgevig, K. V. Gothelf, K. A. Jørgensen, Chem. Eur. J.
2002, 8, 5652Ϫ5661.
G.-Q. Lin, M. Hjalmarsson, H.-E. Högberg, K. Jernstedt, T.
Norin, Acta Chem. Scand., Ser. B 1984, 38, 795Ϫ801.
E. J. Corey, S. Shibata, R. K. Bakshi, J. Org. Chem. 1988, 53,
2861Ϫ2863.
[15]
[16]
[17]
[18]
[19]
[20]
[21]
Supporting Information: Copies of the 1H and 13C NMR spectra
for the cycloadducts 3aϪf, 4aϪb and 5d (see also footnote on the
first page of this article).
Acknowledgments
Financial support by the Swedish Research Council (VR formerly
NFR) and the Mid Sweden University is gratefully acknowledged.
We are grateful to Dr. Kei Manabe for his generous gift of an auth-
entic sample of compound 25.
C. B. Bucher, A. Linden, H. Heimgartner, Helv. Chim. Acta
1995, 78, 935Ϫ946.
S. K. Hendrie, J. Leonard, Tetrahedron 1987, 43, 3289Ϫ3294.
[22] [22a] P. Deshong, Jr., S. W. Lander, J. M. Leginus, C. M. Dicken,
in Advances in Cycloaddition (Ed.: D. P. Curran), JAI Press,
London, 1988, p. 89Ϫ93. [22b]K. V. Gothelf, R. G. Hazell, K.
A. Jørgensen, Acta Chem. Scand. 1997, 51, 1234Ϫ1235.
[1]
M. Frederickson, Tetrahedron 1997, 53, 403Ϫ425.
[2]
S. Karlsson, H.-E. Högberg, Org. Prep. Proced. Int. 2001, 33,
103Ϫ172.
[23]
[3] [3a]
J. Björgo, D. R. Boyd, D. C. Neill, J. Chem. Soc., Chem. Com-
mun. 1974, 478Ϫ479.
G. Broggini, F. Folcio, N. Sardone, M. Sonzogni, G. Zecchi,
K. V. Gothelf, K. B. Jensen, K. A. Jørgensen, Sci. Prog.
[3b]
1999, 82, 327Ϫ350.
K. V. Gothelf, K. A. Jørgensen, Chem.
[24]
[3c]
Rev. 1998, 98, 863Ϫ909.
Chem. Commun. 2000, 1449Ϫ1458.
K. V. Gothelf, K. A. Jørgensen,
[3d]
Tetrahedron: Asymmetry 1996, 7, 797Ϫ806.
K. V. Gothelf, K. A.
[25]
K. Manabe, Tetrahedron 1998, 54, 14465Ϫ14476.
Jørgensen, in Synthetic Applications of 1,3-Dipolar Cycload-
dition Chemistry Toward Heterocycles and Natural Products
(Eds.: A. Padwa, W. Pearson), Wiley-VCH, Weinheim, 2002,
vol. 59, p. 864Ϫ882.
[26] [26a]
K. S. Chan, M. L. Yeung, W.-K. Chan, R.-J. Wang, T. C.
[26b]
W. Mak, J. Org. Chem. 1995, 60, 1741Ϫ1747.
K. Torssell,
O. Zeuthen, Acta Chem. Scand., Ser. B 1978, B32, 118Ϫ124.
[26c] C. M. Tice, B. Ganem, J. Org. Chem. 1983, 48, 5048Ϫ5050.
J. B. Brown, H. B. Henbest, E. R. H. Jones, J. Chem. Soc.
1950, 3634Ϫ3641.
L. A. Paquette, A. L. Bay, J. Am. Chem. Soc. 1983, 105,
7352Ϫ7358.
J. Leonard, A. B. Hague, M. F. Jones, R. A. Ward, Synthesis
1999, 507Ϫ509.
A. H. Fray, A. I. Meyers, J. Org. Chem. 1996, 61, 3362Ϫ3374.
Received March 13, 2003
[4]
For some very recent publications, see e.g.: [4a] S. Iwasa, S. Tsu-
shima, T. Shimada, H. Nishiyama, Tetrahedron 2002, 58,
227Ϫ232. [4b] S. Iwasa, H. Maeda, K. Nishiyama, S. Tsushima,
Y. Tsukamoto, H. Nishiyama, Tetrahedron 2002, 58,
[27]
[28]
[29]
[30]
8281Ϫ8287. [4c] F. Viton, G. Bernardinelli, E. P. Kündig, J. Am.
[4d]
Chem. Soc. 2002, 124, 4968Ϫ4969.
X. Ding, Y. Ukaji, S.
Fujinami, K. Inomata, Chem. Lett. 2002, 302Ϫ303.
[5] [5a]
Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39,
[5b]
1615Ϫ1621.
U. Eder, G. Sauer, R. Wiechert, Angew. Chem.
Eur. J. Org. Chem. 2003, 2782Ϫ2791
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2791