Stereospecific synthesis of pyrrolidines with varied configurations via 1,3-dipolar cycloadditions to sugar-derived enones

Article abstract of DOI:10.1021/jo500547y

Enantiomerically pure pyrrolidines have been obtained by 1,3-dipolar cycloaddition of stabilized azomethine ylides and sugar enones (dihydropyranones) derived from pentoses. Thus, the S-enone (menthyl 3,4-dideoxy-(1S)-pent-3-enopyranosid-2-ulose) was prepared from d-xylose, while the R analogue was obtained from l-arabinose. The dipoles were generated in situ from α-arylimino esters of common amino acids (glycine, alanine, or phenylalanine) and aromatic aldehydes (benzaldehyde, 3-formylpyridine and 4-methoxybenzaldehyde). Under optimized conditions, the cycloaddition reactions were highly diastereo- and regioselective to yield, in most of the cases, a very major adduct of the 16 theoretically possible. The diastereoselectivity relies on the strict stereocontrol exerted by the stereogenic center of the pyranone. Thus, the (S)-enone, derived from d-xylose, gave tetrasubstituted pyrrolidines having a defined stereochemistry for the four stereocenters of the ring, while they had the opposite configuration when starting from the (R)-dihydropyranone. Furthermore, some endo-cycloadducts underwent isomerization of the carbons vicinal to the nitrogen atom to afford pyrrolidines with a rather unusual stereochemistry for the direct dipolar cycloadditions.

Full text of DOI:10.1021/jo500547y

Article
pubs.acs.org/joc
Stereospecific Synthesis of Pyrrolidines with Varied Configurations
via 1,3-Dipolar Cycloadditions to Sugar-Derived Enones
Guillermo A. Oliveira Udry, Evangelina Repetto, and Oscar Varela*
CIHIDECAR-CONICET-UBA, Departamento de Química Organ
́
ica, Facultad de Ciencias Exactas y Naturales, Universidad de
Buenos Aires, Pabellon 2-Ciudad Universitaria, Buenos Aires 1428, Argentina
́
S
* Supporting Information
ABSTRACT: Enantiomerically pure pyrrolidines have been obtained by 1,3-
dipolar cycloaddition of stabilized azomethine ylides and sugar enones
(dihydropyranones) derived from pentoses. Thus, the S-enone (menthyl 3,4-
dideoxy-(1S)-pent-3-enopyranosid-2-ulose) was prepared from D-xylose, while the
R analogue was obtained from L-arabinose. The dipoles were generated in situ
from α-arylimino esters of common amino acids (glycine, alanine, or
phenylalanine) and aromatic aldehydes (benzaldehyde, 3-formylpyridine and 4-
methoxybenzaldehyde). Under optimized conditions, the cycloaddition reactions
were highly diastereo- and regioselective to yield, in most of the cases, a very
major adduct of the 16 theoretically possible. The diastereoselectivity relies on the strict stereocontrol exerted by the stereogenic
center of the pyranone. Thus, the (S)-enone, derived from D-xylose, gave tetrasubstituted pyrrolidines having a defined
stereochemistry for the four stereocenters of the ring, while they had the opposite configuration when starting from the (R)-
dihydropyranone. Furthermore, some endo-cycloadducts underwent isomerization of the carbons vicinal to the nitrogen atom to
afford pyrrolidines with a rather unusual stereochemistry for the direct dipolar cycloadditions.
azomethine ylides. This way, we succeeded in the synthesis of
tetrasubstituted pyrrolidine derivatives, obtained under the
strict stereocontrol exerted by the configuration of the
stereocenter of the starting sugar-derived dihydropyranone.
INTRODUCTION
■
The 1,3-dipolar cycloaddition reaction of azomethine ylides
with alkenes is a powerful and reliable strategy for the regio-
and stereocontrolled synthesis of substituted pyrrolidines.1−4
The pyrrolidine framework is found within a variety of natural
products,5 as well as a component of many biologically active
molecules and pharmaceuticals.6 In order to achieve stereo-
selective transformations, the versatile pyrrolidine scaffold has
been employed as a chiral auxiliary,7 as a chiral ligand,8 or as an
organocatalyst.9
Among the numerous strategies for the stereoselective
synthesis of pyrrolidines, the cycloaddition-based reactions
are attractive because of their ability to induce stereoselectivity
in a highly efficient process, which involves the construction of
multiple bonds in a single step.2−4,10 Varied molecules have
been used as stereodifferentiating auxiliaries in such cyclo-
additions, and carbohydrates have shown to be particularly
competent for these purposes.11 On the other hand,
enantiomerically pure carbohydrate derivatives have also been
used as chiral dipolarophiles in 1,3-dipolar cycloadditions with
achiral dipoles. The pioneering work of Wee12 exploited the
reaction of carbohydrate-derived dipolarophiles with non-
stabilized azomethine ylides. However, the use of carbohydrate
enones in 1,3-dipolar cycloadditions are scarce,13,14 compared
with their use as dienophiles in Diels−Alder reactions. For
example, we have reported the highly diastereoselective
cycloaddition of sugar enones with varied dienes to afford
enantiomerically pure carbocycles.15 Therefore, we decided to
explore the use of sugar enones (3-enopyranosid-2-uloses) as
the π-deficient counterparts in 1,3-dipolar cycloadditions with
RESULTS AND DISCUSSION
■
We have described a straightforward preparation of enantio-
merically pure sugar enones (3-enopyranosid-2-uloses or 2-
alkoxy-dihydropyran-3-ones) by the SnCl4-promoted glycosy-
lation of 2,3,4,6-tetra-O-acetylglycal derivatives of hexoses.16
However, this procedure applied to glycals derived from
pentoses afforded the corresponding dihydropyranones with
enantiomeric excesses (ee) lower than 90%.15a To overcome
this difficulty, the glycosylation was performed using chiral 2-
octanol to obtain the syrupy mixture of diasteroisomers, which
required a rather tedious separation by column chromatog-
raphy. Alternatively, an enantiospecific synthesis of dihydropyr-
anones from common pentoses was developed.17 In this case,
the several steps required for the generation of the α,β-
unsaturated system lowered the overall yield, compared with
the “one-pot” glycosylation of the glycal, which is obtained
from a pentose in a very good overall yield. Therefore, we
studied the glycosylation of the xylal derivative 1 using
(−)-menthol as chiral alcohol (Scheme 1). The dihydropyr-
anone 2 (configuration 1S) was obtained as a crystalline
product. As an additional advantage, the conditions for the
glycosylation were optimized using indium(III) chloride as
Received: March 10, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo500547y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
amine, in the presence of metal cations, leads to the in situ
formation of stabilized N-metalated azomethine ylides (6Aa−
6Cc) as reactive species for the cycloadditions.1−4
Scheme 1. Synthesis of Sugar Enones 2 and 4
In order to optimize the reaction conditions, we studied the
addition of the imino ester 5Aa to the enone 2. The reactions
were conducted at room temperature, and compound 2 showed
to be an excellent dipolarophile, as cycloadducts were formed
under varied conditions (Table 1). From the theoretically
possible 16 diastereoisomeric adducts only three have been
isolated. As described later, they have been identified as endo-7,
exo-8, and 9 (the C-4a epimer of 7). The data collected in
Table 1 show that the overall yield and the composition of the
diastereomeric mixtures was highly affected upon changes in
catalyst and catalyst load, solvent, and concentration of the base
(DBU).
Several metal cations such as Li(I),20 Cu(I)10e,21 and
Cu(II),22 Ag(I),10b,19,23 etc. have been employed to promote
these reactions, mainly as complexes for enantioselective
procedures. Therefore, in the first instance, we evaluated the
effect of the cation employed as catalyst (Table 1, entries 1−6).
Under identical conditions, silver acetate gave higher overall
yield and higher diastereoselectivity, in comparison with the
other salts employed, and it was selected for the following
experiments. The advantage of using triphenylphosphine to
facilitate the dissolution of the Ag+ catalyst has been
described.24 However, the addition of triphenylphosphine in
the Ag+-catalyzed reaction of 2 with 5Aa led to a lower yield
and loss of the selectivity (Table 1, entry 7).
A lowering in the concentration of AgOAc led to longer
times for completion of the reaction (Table 1, entries 8 and 9)
and poorer yields and diastereoselectivities, compared to those
of entry 6. However, under the same reaction conditions, a
longer reaction time has practically no effect on the product
distribution (Table 1, entries 10−12), which suggested that
compounds 7 and 8 are quite stable and they do not
interconvert when the concentration of the base remains low
(0.1 molar equiv). In contrast, an increase in the concentration
of DBU (to 1 molar equiv) resulted in a lower yield and loss of
selectivity (Table 1, entry 13), and in addition to 7 and 8, a
third diastereoisomer 9 was isolated and identified as the C-4a
epimer of 7. In contrast to the all-cis substitution pattern for the
pyrrolidine ring of 7, the ethyl ester group at C-4a of 9 is anti to
the other substituents of such a ring. An increased formation of
9 was observed when, maintaining the concentration of DBU
(1 molar equiv), the catalyst load was lowered to 0.1 molar
equiv (Table 1, entry 14). Adduct 9 was the major product if
the last reaction was conducted for a longer time (Table 1,
entry 15).
Lewis acid catalyst, instead of the hygroscopic and moisture
sensitive SnCl4, previously employed.15 The concentration of
the indium catalyst was lowered as much as to 5 mol %, and the
yield of the enone 2, for several large-scale preparations, was
higher than 80%. The slight contamination with the
diastereoisomer 4 (dr >10:1) was practically eliminated after
two successive recrystallizations (dr >98:2). The use of the
InCl3 to promote the Ferrier rearrangement of a glucal
derivative to afford 2,3-unsaturated glycosides has been
reported.18
The InCl3-catalyzed reactions between the L-arabino
derivative 3 and (−)-menthol afforded the (1R)-pent-3-
enopyranosid-2-ulose 4, having opposite configuration for the
anomeric center with respect to that of 2. This reaction seems
to follow the mechanism proposed for the SnCl4-promoted
Ferrier rearrangement of 1 or 3.15a Thus, the elimination of the
3-acetoxy group, assisted by the Lewis acid, gives a resonance-
stabilized carbocation which is attacked by the alcohol from the
face of the glycal opposite to that containing the acetoxy group
at C-4. The resulting 2-enopyranoside intermediate undergoes
a second allylic rearrangement to give 2 or 4.
The diastereomeric purity of enones 2 and 4 was readily
established on the basis of the NMR spectra, which showed
characteristic chemical shifts for the signals of H-1 (4.99 and
4.81 ppm, respectively) and C-1 (94.8 and 99.7 ppm,
respectively). The signal of the CH−O of the menthyl group
in 2 and 4 was also clearly differentiated.
The enones 2 and 4 were evaluated as dipolarophiles in the
1,3-dipolar cycloadditions with azomethine ylides. One of the
most simple and reliable procedures for the formation of
azomethine ylides consists in the preparation of α-aryliminio
esters (5Aa−5Cc) starting from common amino acids (Scheme
2).19 The reaction of 5Aa−5Cc with a base such as tertiary
Scheme 2. Synthesis of Carbohydrate-Derived Pyrrolidines 7−37
B
dx.doi.org/10.1021/jo500547y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 1. Reaction Conditions Employed for the Synthesis of Pyrrolidines 7−9
a
b
c
d
e
entry
catalyst (molar equiv)
DBU (molar equiv)
solvent
time (h)
yield (%)
ratio 7:8:9
1
LiBr (0.3)
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
1.0
1.0
1.0
0.1
0.1
0.1
0.1
0.1
0.1
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
hexane
toluene
Et2O
A
A
A
A
A
A
A
A
16
1
36
45
35
33
51
83
60
68
40:39:21
83:17:0
16:48:36
31:50:19
34:26:40
78:22:0
50:50:0
50:50:0
60:40:0
80:20:0
80:20:0
80:20:0
54:34:12
18:44:38
0:14:86
40:50:10
60:30:10
60:40:0
70:30:0
67:33:0
84:16:0
62:38:0
2
CuI (0.3)
3
CaCl2(0.3)
4
CuSO4 (0.3)
CeCl3·7H2O (0.3)
AgOAc (0.3)
AgOAc (0.3), Ph3P (0.6)
AgOAc (0.1)
AgOAc (0.05)
AgOAc (0.3)
AgOAc (0.3)
AgOAc (0.3)
AgOAc (0.3)
AgOAc (0.1)
AgOAc (0.1)
AgOAc (0.3)
AgOAc (0.3)
AgOAc (0.3)
AgOAc (0.3)
AgOAc (0.3)
AgOAc (0.3)
AgOAc (0.3)
5
6
7
8
9
61
f
10
11
12
13
14
15
16
17
18
19
20
21
22
f
f
3
16
A
A
16
A
A
A
A
A
A
A
58
52
46
60
48
60
58
53
52
47
THF
Me2CO
EtOAc
H2O
0.1
a
b
c
The reactions were conducted at room temperature. Except for entry 22, anhydrous solvents were used. A = The reaction time was 15−30 min.
d
e
f
Overall yields after isolation of the products by column chromatography. Relative ratio of isolated products. The ratio of products was estimated
from the H and 13C NMR spectra of the crude mixture.
1
The fact that in Ag+/acetonitrile cycloadditions the
formation of 9 increased in the presence of a higher
concentration of DBU suggested that the base could promote
the epimerization of 7 by enolization of the ester carboxylate at
C-4a. However, this hypothesis was ruled out as 7 did not
isomerize on treatment with DBU (1 molar equiv) in
acetonitrile. Therefore, the formation of 9 was attributed to
the isomerization of the ylide. Pyrrolidines like 7 and 8, that
bear a cis relationship for the substituent at C-3a and C-4a,
result from the cycloaddition of the W-shaped dipole (6Aa−
6Cc) to the dipolarophile 2, while the trans product involves an
S-shaped ylide (Scheme 3).3 A mixture of stereoisomers may be
formed as result of the isomerization of the ylide.20,25 The W or
S conformations of the ylide can be stabilized by metalation.26
The stability of the ylide and, hence, the stereoselectivity of the
cycloaddition reactions depend on the metal salt employed.27
The Ag+ cation in acetonitrile seems to stabilize, at low
concentration of DBU, the W arrangement to give, via the endo
(TS1) or exo (TS2) transition states, the respective adducts 7
and 8 (Table 1, entries 6−12). A higher concentration of DBU
could contribute to the stabilization of the metal through
chelation, with formation of the S ylide, the precursor of 9
(Table 1, entry 13). In line with this behavior, a lowering in the
catalyst load (Table 1, entry 14) at the same concentration of
DBU should shift the conformational equilibrium to the S ylide,
increasing the formation of 9, which became more important at
a longer reaction time (Table 1, entry 15); the absence of endo-
7 suggested its isomerization under these reaction conditions.
Scheme 3. Formation of Adducts 7−9 in the Presence of Ag+
and DBU
Therefore, compound 7 was treated with DBU/Ag+ as in entry
13 (Table 1). The gradual conversion of 7 into 8 was observed,
and after 16 h, isomer 8 was practically the only product
obtained. However, this adduct remained unchanged when
subjected to the same treatment. Similarly, adduct 9 was also
quite stable and did not isomerize under the reaction
conditions employed. In an additional experiment, the
concentration of Ag+ was lowered to 0.1 molar equiv and
compound 7 was increasingly converted into 8, but the
formation of 9 remained low during the process. All these
results seem to indicate that endo-7 is formed under kinetic
C
dx.doi.org/10.1021/jo500547y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 1. (a) Stereochemical assignment of isomers endo-7, exo-8, and 9, according to NOE correlations and selected NMR data (δ in ppm, J in Hz).
(b) Calculated low energy conformations for simplified model compounds analogues of endo-7 and exo-8.
control and isomerized to the thermodynamic product exo-8 in
the presence of Ag+ and a relatively high concentration of DBU
(1 molar equiv). As depicted in Scheme 3, the isomerization
seems to take place through the W ylide, which is released from
7. The approach of this ylide to the enone 2, via the TS2, leads
to 8. The adduct 9 is accumulated under reaction conditions
that favor the equilibrium between the W and S arrangements
of the ylide.
in hexane or toluene a low proportion of 9 was obtained,
probably via the S ylide.
According to the results in Table 1, the optimal experimental
conditions to carry out the cycloaddition reactions are those of
entry 6 (0.30 molar equiv of AgOAc, 0.10 equiv of DBU in
MeCN at room temperature). Under these conditions, a higher
selectivity in favor of endo-7 was observed (dr 7:8 = 77:23),
while the isomer 9 was a very minor product. However,
compound 9 was isolated in 34% yield when the cycloaddition
was conducted in the presence of a larger concentration of
DBU and for a longer time (16 h).
The absolute configuration of the stereocenters of adducts
7−9 were assigned using 1H NMR data (coupling constants (J)
and chemicals shift values) and NOE experiments (Figure 1). A
central issue for all these reactions is the remarkable facial
diastereoselectivity, which was also observed for Diels−Alder
cycloadditions and other additions to the double bond of 2.15,29
The stereocontrol was attributed to the axially oriented
anomeric menthoxy substituent (anomeric effect), which
induced the approach of the dipole from the less hindered α
face of the pyranone ring. The fact that some protons of the
menthoxy group showed NOE contacts with just one of the
methylene protons at C-5, allowed us to identify as H-5ax the
one involved in such a correlation (Figure 1a). Then, the
configuration of the new stereocenter at C-3, of both 7 and 8,
was established on the basis of the NOE contact between H-3
and H-5ax. Furthermore, H-3 showed an intense NOE with H-
4, as expected for vicinal syn-disposed protons and, in addition,
the small coupling constants for J4,5ax (4.6 Hz for 7, 3.2 Hz for
8) and J4,5eq (2.8 Hz for 7, 0 Hz for 8) are indicative that the C-
The formation of 9 observed for catalysts like Ca2+, Cu2+, or
Ce3+ (Table 1, entries 3−5) could be attributed to a less
effective stabilization of the W ylide by these cations, shifting
slightly the conformational equilibrium to the S ylide, the
precursor of 9, through the TS3. The stereochemical course of
the reaction is highly sensitive to the ligand employed for
chelation of the metal.10a For example, according to the
chelating agent, Cu+ ylides can lead to an exo-adduct10e or to a
cycloadduct with the same relative stereochemistry as
pyrrolidine 9.28 In the case of Ag+, the compact TS1, which
involves chelation of the oxygen atom of the electron-
withdrawing group of the dipolarophile,10d leads to the endo-
adduct as major product. Similar endo-selectivity has been
reported for Ag+-catalyzed reactions of azomethine ylides with
α-enones.10a,b,14
The reaction solvent plays also an important role in dipolar
cycloadditions, as they contribute to stabilize polar species.25a
The reaction of 2 with azomethine ylides was successfully
conducted with a variety of anhydrous organic solvents of
different polarity and even in water (Table 1, entry 22). The W
arrangement of the ylide seems to be stabilized in more polar,
oxygen-containing solvents25a (Table 1, entries 18−21), while
D
dx.doi.org/10.1021/jo500547y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 2. Pyrrolidines Obtained by Dipolar Cycloaddition of Dihydropyranones 2 and 4 with Imines 5Aa−5Cc
a
Yield of the isolated product after column chromatography.
4−H-4 bond bisects the angle formed by the vicinal methylene
group at C-5 and confirmed the configuration of C-4.
Another significant feature in the reaction of 2 with
the only isolated regioisomers result from the bonding of the
most nucleophilic carbon of the dipole to the most electrophilic
center of the enone system. Thus, the NOESY spectra of 7−9
exhibited NOE contacts between the aromatic protons with H-
azomethine ylides is the complete level of regioselectivity, as
E
dx.doi.org/10.1021/jo500547y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3 and H-3a, indicating the location of the phenyl group on C-
3a. In agreement with this result, H-4a showed the expected
NOE contacts with H-4 and with the protons of ethyl group of
the ester. The configuration of C-3a and C-4a of pyrrolidines
endo-7 and exo-8 was established by means of diagnostic NOE
contacts. Thus, in compound 7, H-3a showed cross peaks with
H-3, H-4, and H-4a, in agreement with the all cis disposition for
the protons of the pyrrolidine ring (endo configuration). In
contrast, in the isomer 8 the NOE contacts between H-1−H-
3a, H-1−H-4a, H-3a−H-4a and the observed cross peak
between H-4 and the aromatic protons indicated that we were
dealing with the exo-adduct.
7 (9.3 Hz). This could be explained because of the
conformational instability caused by the 1,3-anti disposition
for the substituents at C-3a and C-4a of the pyrrolidine, which
determines that one or the other should be quasiaxially oriented
0
in either the E or E0 forms.
To evaluate the scope of the 1,3-dipolar cycloaddition, a
representative set of α-imino esters of glycine (5Aa−5Ca),
alanine (5Ab−5Cb), and phenylalanine (5Ac−5Cc) were
prepared (Scheme 2) using aromatic aldehydes with varied
electronic properties, such as benzaldehyde (5Aa−5Ac), 3-
formylpyridine (5Ba−5Bc), and 4-anisaldehyde (5Ca−5Cc).
Reaction of the imino esters with the enone 2, under the
optimized conditions, led to cycloadducts in good to excellent
yields (Table 2). However, a different endo-selectivity was
observed for reactions performed on imino esters derived from
benzaldehyde (Table 2, entries 1−3). While the stereo-
selectivity remained modest for the glycine derivative 5Aa,
the endo adducts 10 and 11 were almost exclusively formed for
the alanine (5Ab) and phenylalanine (5Ac) derivatives,
respectively. This result suggests that the replacement of a
hydrogen atom by a bulkier Me or PhCH2 substituent at the α-
position of the imine destabilizes the competing exo transition
state. An example has been found in the literature14 that shows
a similar effect when a hydrogen atom at the carbon vicinal to
the ester of the imine was replaced by a bulkier group.
Dipole precursors 5Ba−5Bc have also been prepared and
used for the cycloadditions (Table 2, entries 4−6). They
possess a 3-pyridyl substituent as the electron-withdrawing
aromatic group. The reactivity and selectivity shown by
pyridylimines were very similar to those of phenylimines.
Thus, the increased endo-selectivity for the alanine (5Bb) and
phenylalanine (5Bc) derivatives led to adducts 14 and 15 in
excellent yields, while the glycine imine (5Ba) afforded 12
(62%) accompanied by the exo-13 (10%).
1
Comparison of the H NMR spectra of endo-7 and exo-8
showed two significant differences regarding the chemical shifts
of the signals of H-1 and H-3 and the values of J3,3a. The H-1
signal in endo-7 (4.05 ppm) is strongly shifted upfield, with
respect to the same signal in exo-8 (4.92 ppm), to a rather
unusual region of the spectra for an anomeric proton. In
contrast, the resonance of H-3 (3.58 ppm) in endo-7 is
deshielded compared to that of exo-8 (3.15 ppm). These effects
can be attributed to the relative orientation of the phenyl group
attached to C-3a. The phenyl and ethyl ester groups are syn
oriented, although in opposite faces, in the pyrrolidine ring of 7
and 8. Therefore, from the conformational point of view, this
ring for 7 is expected to populate the E0 region of the
pseudorotational cycle (with the N atom, numbered as 0, below
the plane defined by the contiguous carbon atoms C-3a, C-3,
C-4, and C-4a), while the pyrrolidine ring of 8 should prefer the
0
opposite E region. In the respective conformations, the bulky
substituents on C-3a and C-4a for 7 and 8 are quasiequatorially
oriented.
A preliminary theoretical calculation, using the semiempirical
AM1 method, was performed for the analogue of endo-7, in
which the menthyl group has been replaced by methyl to
facilitate the calculation (Figure 1b). The minimum energy
conformation for 7 shows a parallel disposition of the aromatic
ring with respect to H-1. Then, this proton is expected to be
shielded due to the anisotropy of the aryl group. In the adduct
exo-8 the orientation of the aromatic ring respect to H-1 is not
adequate for anisotropy shielding. Hence, the H-1 signal
appears in a δ value typical of anomeric protons of pyranosyd-
2-uloses.15,29 However, in exo-8 H-3 is located in the shielding
zone of the aromatic ring, and this proton signal is shifted
upfield compared with that of 7. The effect of the anisotropy of
the phenyl group on the chemical shift has been extensively
used to determine the absolute configuration of chiral alcohols
via Mosher esters.30 On the other hand, the larger J3,3a value
(9.3 Hz) for 7, compared with that of 8 (2.8 Hz) should be the
result of the respective 0E and E0 conformations adopted by the
pyrrolidine ring. Each J value matches with the dihedral angle
H-3−C-3−C-3a−H-3a measured from the low-energy con-
formation depicted in Figure 1b, which is close to 5° in the
former (H-3 and H-3a are nearly eclipsed) and 105° in the
latter.
Next, we explored the effect on the course of the dipolar
cycloaddition of the replacement of the phenyl or 3-pyridyl
substituent of the α-imino esters by the electron-donating p-
methoxyphenyl (PMP) group (Table 2, entry 7). Thus, the
glycine imine (5Ca) was allowed to react with enone 2 under
1
standard conditions. The crude H NMR spectrum of the
reaction mixture showed two main products, which were later
characterized as endo-16 and exo-17 (ratio 5:1). Column
chromatography of this mixture led first to exo-17, in a yield
(14%) that was in agreement with the proportion estimated by
NMR. Surprisingly, the isomer endo-16 was recovered from the
column in a very low yield (6%), and two other compounds,
not detected in the original mixture neither by TLC nor by
NMR, were obtained.
A detailed analysis of the NMR spectra of the minor
component isolated from the column indicated that compound
1
18 was the epimer at C-3a of endo-16. Examination of the H
NMR spectrum of the major product (40% yield) showed the
absence of the signals of H-3a and those corresponding to the
aromatic protons. Instead, a methylene group at C-3 was
detected, with one of the protons exhibiting a long-range
coupling (J ≈ 1 Hz) with H-5eq (the correlation was also
observed in the 2D-COSY spectrum), indicating the W
disposition of these two hydrogen atoms in a six-membered
ring. On the basis of this evidence, and taking into account the
molecular weight determined by HRMS, the structure of the
compound was assigned as the aminoacetal 19. In agreement
with this structure, the NOESY spectrum of 19 exhibited the
expected NOE contacts between H-3ax−H-5ax, H-3eq−H-4a,
The structure of the third diastereoisomer 9, isolated in some
cases, was determined on the basis of the NOE contacts
observed between the aromatic protons with H-1, H-3a, and H-
4a. Other diagnostic cross peaks were also detected between H-
3a with H-3 and H-4, as well as H-4a−H-5eq and H-3−H-5ax.
Furthermore, adduct 9 showed chemical shifts values for H-1
(4.25 ppm) and H-3 (3.42 ppm) similar to those of endo-7,
confirming the configuration of C-3a. However, the J3,3a value
(7.8 Hz) in 9 was somewhat smaller than the one measured for
F
dx.doi.org/10.1021/jo500547y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 4. Mechanism Proposed for the Acid-Promoted Isomerization
Scheme 5. Acetylation Reaction of Aminal 19
the methylene of the ethyl ester with H-4 and H-5eq, and H-1
The pyrrolidine ring-opening mechanism shown in Scheme
4, which explains the conversion of 16 into 18, justifies also the
formation of 21 and 23 as byproducts of the reaction of the
enone 2 with the p-methoxyphenyl imines 5Cb and 5Cc,
respectively. Similar to 18, compounds 21 and 23 could not be
detected in the original reaction mixtures (TLC and NMR).
However, after column chromatography, the isomeric products
21 and 23, respectively, together with the endo-adducts 20 and
22 were isolated. The structure of compounds 20−24 was
assigned, as already described for analogous pyrrolidine
derivatives, using extensive NMR experiments. Thus, the
structure of 21 was unambiguously established, mainly on the
basis of the NOESY spectrum, as the epimer of endo-20 at the
benzylic position (C-3a). Diagnostic NOE contacts were
detected between H-1 with H-3a, H-4 with aromatic protons
and with MeAla, H-5ax with H-3 and with H-Ment, and H-5eq
with MeAla. A similar analysis led to the determination of the
structure of 22 as the endo-adduct and the minor product 23 as
the epimer at C-3a of 22. Compounds 21 and 23 may be
formed according to the mechanism proposed in Scheme 4. In
these cases, the intermediate cation I (R = Me or R = PhCH2),
formed respectively from 20 or 22, may undergo ring closure
returning back to 20 or 22 or to produce the epimers 21 or 23,
depending on the face (Re or Si, respectively) of the benzylic
carbon of PMP attacked by the enol.
and H-5ax with protons of the menthyl group.
The fact that 18 and 19 were absent in the crude reaction
mixture suggested, and it was later confirmed, that they were
formed due to the acidity provided by the silica gel during the
purification. Therefore, the mechanism proposed for the
epimerization of 16 into 18, depicted in Scheme 4, consists
of the acid-catalyzed retro-Mannich reaction, which leads to an
iminium cation (I) stabilized by resonance due to electron
donation by the p-methoxyphenyl group. Ring closure by
Mannich-type attack of the α-face (Re) of the enol function
either to the Re or Si face of the PMP benzylic carbon leads,
respectively, back to 16 or to the isomer 18. Alternatively,
hydration of I by the water contained in the silica gel and O →
N proton transfer leads to the intermediate II, which undergoes
the releasing of anisaldehyde to produce III. The nucleophilic
attack of the amine of III to the carbonyl gives the aminoacetal
19.
Interestingly, when compound 19 was subjected to
acetylation with a 1:1 mixture of pyridine−Ac2O, instead of
the expected N- and O-diacetyl derivative 19a, an inseparable
mixture of the enol acetate 19b and the ketone 19c (ratio
19b:19c 4:1) was obtained (Scheme 5). This result suggests
that the cyclic aminal 19 becomes unstable upon N-acetylation
and undergoes elimination of H-3 with concomitant ring-
opening through a β-elimination process to afford 19b. The
formation of a small amount of 19c may be ascribed to
hydrolysis of the enol ester of 19b during column
chromatography.
In order to verify if other pyrrolidine derivatives are
susceptible to the acid-promoted isomerization, the crude
mixture of the reaction of 2 with imine 5Aa was treated with a
suspension of SiO2 in toluene. The isomer epi-7 was slowly
formed at room temperature. Sarotti et al.14 have observed a
G
dx.doi.org/10.1021/jo500547y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 3. Treatment of the Crude Mixture of the Cycloaddition Reaction with SiO2−Toluene at 80 °C for 2 h
similar low isomerization rate, and they found that conversion
was more efficient at higher temperatures, particularly under
microwave irradiation. Therefore, the crude mixture of reaction
of 2 with 5Aa was treated with SiO2 in toluene at 80 °C. The
progress of the reaction was followed by 13C NMR, which
showed increasing formation of epi-7 (δC‑1 = 95.3 ppm), while
the proportion of endo-7 (δC‑1 = 96.6 ppm) in the mixture was
decreasing. The relative proportion of exo-8 (δC‑1 = 95.7 ppm)
remained practically unchanged. After 2 h of heating at 80 °C,
epi-7 was isolated in 46% yield (Table 3). According to these
results, epi-7 seems to be formed by isomerization of endo-7.
This fact was experimentally verified since treatment of pure
endo-7 with hot SiO2−toluene led to epi-7 as the main product.
It should be highlighted that by adjusting the conditions of the
dipolar cycloaddition of 2 with 5Aa, or via isomerization, the
four stereoisomers at C-3a and C-4a (7, 8, 9 and epi-7) have
been obtained in moderate to good yields.
The cycloaddition protocol described for the dihydropyr-
anone 2 was applied, under identical reaction conditions, to the
enone 4 having opposite configuration for the stereogenic
center. As this center controls the stereochemical output of the
reaction with azomethine ylides, we were able to install the four
stereocenters of the resulting pyrrolidine rings in a predictable
way. Thus, the 1,3-dipolar cycloaddition of the same metal-
loazomethine ylides (6Aa−6Cc) to dipolarophile 4 afforded
tetrasubstituted pyrrolidine rings with the four stereocenters
having opposite configuration with respect to those of the
pyrrolidines obtained from 2 (Table 2), as illustrated in Scheme
6 for endo-adducts.
The configurations of compounds 24−37 were readily
established by comparison of their NMR spectra with those
of the pyrrolidines derived from 2 and also on the basis of the
NOESY contacts. It is worth mentioning that the PMP
derivative endo-33 seems to be more stable than the
In order to synthesize pyrrolidines with a stereochemistry
that is not achieved by the direct dipolar cycloaddition, the
crude mixture of reaction of 2 with 5Ab, 5Ba, 5Bb, 5Ca, and
5Cb was subjected to treatment with a suspension of SiO2 in
toluene at 80 °C for 2 h. As depicted in Table 3, in most of the
cases, the C-3a epimers of the respective endo-adducts were the
major products isolated, confirming the SiO2-promoted
isomerization. However, the crude mixtures of pyrrolidines
prepared from pyridylimines 5Ba or 5Bb remained unchanged
upon the SiO2 treatment. These results further support the
mechanism proposed (Scheme 4), as the isomerization does
not take place when the aromatic substituent vicinal to the
amine function of the pyrrolidine ring is an electron-
withdrawing group, which should destabilize the iminium
cation I, preventing the cleavage of the C-3−C-3a bond.
Scheme 6. Pyrrolidine Rings (Endo Isomers) Showed
Opposite Configuration for the Four Stereocenters,
According to the Starting Enone 2 or 4
H
dx.doi.org/10.1021/jo500547y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 7. Pyrrolidines Obtained from Enone 38
diastereomeric analogue endo-16 as, in contrast to this, it could
be isolated by column chromatography in good yield (68%). In
addition, Table 2 shows that the yields and dr of cycloadducts
obtained from 2 or 4 are quite different, suggesting that the
menthyl moiety influences the stereochemical course of the
respective cycloadditions acting as a chiral auxiliary. As a further
confirmation, the cycloaddition was conducted under the usual
conditions with the dihydropyranone 38 (Scheme 7), which
possesses a benzoyloxy group as an achiral counterpart of the
menthyl moiety of 2. Thus, the reaction of 38 with 5Aa was, as
observed in previous cycloadditions, highly diastereofacial
selective due to the influence of the stereocenter of the
dihydropyranone. However, a higher proportion of the exo
adduct (dr endo/exo 62.5:37.5) was formed in comparison with
those observed for the analogous reaction applied to 2 (dr
77:23) or 4 (dr 80:20). All these results indicate that the
anomeric substituent of the dyhydropyranone influences the
yield and stereochemistry of the resulting cycloadducts.
EXPERIMENTAL SECTION
■
Synthesis of Sugar Enones (Dihydropyranones) 2 and 4.
Glycal derivatives (2,3,4-tri-O-acetyl-1,5-anhydropent-1-enitols) 1 and
3 were prepared from D-xylose or L-arabinose, respectively, by the
procedure previously described.15a To a solution of each glycal (4.50 g,
17.4 mmol) and (1R,2S,5R)-(−)-menthol (2.72 g, 17.4 mmol) in
anhydrous CH2Cl2 (130 mL) was added InCl3 (192 mg, 0.87 mmol).
The solution was stirred at room temperature (rt) overnight, when
TLC (hexane/EtOAc, 7:3) showed a higher moving spot and
complete disappearance of the starting glycal. The organic solution
was washed with satd aq NaHCO3, water, and brine. Solvent
evaporation afforded a residue that was purified by column
chromatography (hexane/EtOAc, 40:1) to afford menthyl 3,4-
dideoxy-(1S)-pent-3-enopyranosid-2-ulose (2) or menthyl 3,4-di-
deoxy-(1R)-pent-3-enopyranosid-2-ulose (4).
Compound 2: white solid (3.80 g, 87%), purified after two
successive recrystallizations from ethanol/water (3.36 g, 77%); mp =
54 °C; [α]2D5 −200.8 (c 1.1, CHCl3); H NMR (CDCl3, 500 MHz) δ
1
7.04 (ddd, 1H, J3,4 = 10.5, J4,5 = 1.9, J4,5′ = 3.8 Hz, H-4), 6.13 (br dt,
1H, J3,4 = 10.5 Hz, H-3), 4.99 (s, 1H, H-1), 4.58 (br dt, 1H, J5,5′ = 19.2
Hz, H-5), 4.27 (ddd, 1H, J3,5′ = 1.9, J4,5′ = 3.8, J5,5′ = 19.2 Hz, H-5′),
3.56 (ddd, 1H, J = 4.1, J = 10.7 Hz, H-1 menthyl), 2.24−2.12 (m, 2H,
H menthyl), 1.65 (d, 2H, H menthyl), 1.41−1.26 (m, 2H, H menthyl),
1.00−0.75 (m, 12H, H menthyl); 13C NMR (CDCl3, 125.7 MHz) δ
189.3 (C-2), 148.0 (C-4), 125.0 (C-3), 94.8 (C-1), 77.4 (C-1
menthyl), 60.0 (C-5), 48.0, 40.2, 34.5, 31.6, 25.4, 23.1, 22.3, 21.2, 15.6
(C-menthyl); HRMS (ESI) m/z [M + Na]+ calcd for C15H24NaO3
275.1618, found 275.1627.
CONCLUSIONS
■
The 1,3-dipolar cycloaddition of azomethine ylides, derived
from common amino acids (glycine, alanine and phenyl-
alanine), with sugar enones afforded enantiomerically pure
tetrasubstituted pyrrolidines. Crystalline dihydropyranones,
having the S or R configuration for the anomeric center, were
readily prepared from D-xylose or L-arabinose via de InCl3-
promoted glycosylation with L-menthol followed by a double-
Ferrier rearrangement. The dipolar cycloadditions were highly
diastereo- and regioselective reactions, which led in many cases
to a very major pyrrolidine, from the 16 theoretically possible.
In particular, the strict stereocontrol exerted by the stereocenter
of the sugar dipolarophile allowed generation during the
cycloadditions of four asymmetric carbons of the pyrrolidine
ring with a configuration that depend on the starting (R) or
(S)-dihydropyranone. Thus, pairs of diastereomeric pyrroli-
dines with inverse configurations for the four stereocenters of
the ring were successfully obtained. This is a relevant result as
pyrrolidines have been used as chiral auxiliaries7 and as
organocatalysts.9,14
Compound 4: white solid (3.71 g, 85%), purified after two
successive recrystallizations from ethanol/water (3.27 g, 75%); mp =
75 °C; [α]2D5 +121.3 (c 1.0, CHCl3); H NMR (CDCl3, 500 MHz) δ
1
6.96 (ddd, 1H, J3,4 = 10.5, J4,5 = 1.9, J4,5′ = 3.8 Hz, H-4), 6.05 (br dt,
1H, J3,4 = 10.5 Hz, H-3), 4.84 (s, 1H, H-1), 4.55 (br dt, 1H, J5,5′ = 19.1
Hz, H-5), 4.20 (ddd, 1H, J5,5′ = 19.1 Hz, H-5′), 3.38 (ddd, 1H, J = 4.1,
J = 10.7, H-1 menthyl), 2.14−2.03 (m, 2H, H menthyl), 1.62−1.54 (d,
2H, H menthyl), 1.35 (m, 1H, H menthyl), 1.18 (m, 1H, H menthyl),
1.05−0.65 (m, 12H, H menthyl); 13C NMR (CDCl3, 125.7 MHz) δ
188.7 (C-2), 148.0 (C-4), 125.0 (C-3), 99.7 (C-1), 82.3 (C-1
menthyl), 60.0 (C-5), 48.6, 42.9, 34.3, 31.8, 25.4, 23.4, 22.4, 21.0, 16.2
(C-menthyl); HRMS (ESI) m/z [M + Na]+ calcd for C15H24NaO3
275.1618, found 275.1626.
General Procedures for the Synthesis of α-Imino esters. The
α-imino esters were prepared by a slight modification of the reported
procedures.19,24 A suspension of the methyl ester hydrochloride
derivative of the amino acid (glycine, alanine or phenylalanine, 1.10
mol) and anhydrous magnesium sulfate (2.00 mol) in anhydrous
CH2Cl2 and Et3N (1.10 mol) was stirred at rt for 1 h, and the
corresponding aldehyde (benzaldehyde, 3-formylpyridine or p-
methoxybenzaldehyde, 1.00 mol) was added. The mixture was stirred
at rt overnight, and then MgSO4 was filtered off. The organic solution
was washed with satd aq NaHCO3 and brine, dried (MgSO4), and
concentrated to afford the α-imino esters (5Aa−5Cc). The NMR
spectra of the crude imino esters showed that the compounds were
pure enough to be used for the cycloaddition reaction without further
purification.
In addition, depending on the substitution pattern, the endo
cycloadducts are prone to isomerize to afford pyrrolidines with
relative stereochemistries that are not accessible via the direct
1,3-dipolar cycloaddition. The adducts that contain a p-
methoxyphenyl group at C-3a of the pyrrolidine showed a
particular tendency to the acid-promoted isomerization or even
to the degradation with elimination of p-methoxybenzaldehyde
to give a cyclic aminal.
As continuation of the present studies, we are currently
performing chemical modifications of the cycloadducts, such as
removal of the menthyl group and degradation of the sugar-
derived dihydropyranone ring, to obtain polysubstituted
pyrrolidines and D- or L-prolines with different patterns of
substitution.
General Procedure for the [3 + 2] Cycloaddition Reactions.
The corresponding sugar enone 2 or 4 (1.00 mmol) and the α-imino
ester 5Aa−5Cc (1.50 mmol) were dissolved in the anhydrous solvent
(Table 1) to afford a final concentration of imino ester 0.5 M. In the
absence of light, the salt and DBU were added. The mixture was
stirred at rt, until TLC showed complete disappearance of the starting
I
dx.doi.org/10.1021/jo500547y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
enone. The reaction was diluted with CH2Cl2 and filtered through
Celite. Evaporation of the solvent afforded a residue which was
subjected to column chromatography with the solvent specified in
each individual case.
Synthesis of Pyrrolidine Derivative 10 from Imino Ester 5Ab.
According to the general procedure starting from enone 2 and imino
ester 5Ab (0.115 g, 0.60 mmol) at rt for 20 min. The reaction mixture
showed by TLC (hexane/EtOAc, 4:1) a main spot (Rf 0.17). After
column chromatography (hexane/EtOAc, 95:5 → 92.5:7.5), the
adduct 10 was isolated.
Synthesis of Pyrrolidine Derivatives 7−23 from Pyranone 2.
Synthesis of Pyrrolidine Derivatives 7−9 from Imino Ester 5Aa. The
general procedure described above was followed starting from 2 (0.10
g, 0.40 mmol) and the imino ester derived from glycine (5Aa, 0.115 g,
0.60 mmol) dissolved in anhydrous MeCN (1.2 mL). After addition of
AgOAc (20 mg, 0.12 mmol) and DBU (6 μL, 0.04 mmol) the mixture,
which immediately changed the color to a dark brown, was stirred at rt
for 15 min and then processed as indicated above. The residue showed
by TLC (hexane/EtOAc, 7:3) spots corresponding to 8 (Rf 0.67), 9
(Rf 0.45), and 7 (Rf 0.22). Under these conditions, only compounds 7
and 8 could be isolated by column chromatography (hexane/EtOAc,
92.5:7.5 → 85:15), while adduct 9 was a very minor component.
Compound 7: white solid, recrystallized from ethanol/water (113
Compound 10: syrup (160 mg, 90%); [α]2D5 −60.6 (c 1.0, CHCl3);
1H NMR (CDCl3, 500 MHz) δ 7.40−7.23 (5H, H-aromatic), 4.73 (d,
1H, J3,3a = 8.2 Hz, H-3a), 4.18 (dd, 1H, J4,5ax = 4.5, J5ax,5eq = 12.8 Hz,
H-5ax), 4.09 (s, 1H, H-1), 3.81 (s, 3H, OCH3), 3.75 (dd, 1H, J4,5eq
=
2.9, J5ax,5eq = 12.8 Hz, H-5eq), 3.68 (dd, 1H, J3,3a = 8.2, J3,4 = 7.7 Hz, H-
3), 3.29 (ddd, 1H, J = 4.1, J = 10.7 Hz, H-1 menthyl), 2.74 (ddd, 1H,
J3,4 = 7.7, J4,5ax = 4.5, J4,5eq = 2.9 Hz, H-4), 2.13 (m, 1H, H menthyl),
1.62−1.54 (m, 6H, H menthyl, CH3), 1.27−1.19 (m, 2H, H menthyl),
0.92−0.70 (m, 12H, H menthyl); 13C NMR (CDCl3, 125.7 MHz) δ
202.1 (C-2), 174.3 (OCOMe), 137.9−126.7 (C-aromatic), 96.5 (C-1),
76.7 (C-1 menthyl), 68.4 (C-4a), 62.3 (C-3a), 59.9 (C-5), 53.8 (C-3),
53.0 (C-4), 52.7 (OCH3), 47.6, 39.5, 34.3, 31.5 (C-menthyl), 25.5,
25.4 (C-menthyl, CH3), 22.9, 22.2, 21.1, 15.4 (C-menthyl); HRMS
(ESI) m/z [M + H]+ calcd for C26H38NO5 444.2744, found 444.2762.
Synthesis of Pyrrolidine Derivative 11 from Imino Ester 5Ac. The
general procedure starting from 2 (0.10 g, 0.40 mmol) and imino ester
5Ac (0.16 g, 0.60 mmol) at rt for 30 min afforded crude compound 11
(Rf 0.49, hexane/EtOAc, 4:1), which was purified by column
chromatography (hexane/EtOAc, 20:1).
Compound 11: white solid, recrystallized from methanol (131 mg,
63%); mp = 117 °C; [α]D25 −120.0 (c 1.0, CHCl3); 1H NMR (CDCl3,
500 MHz) δ 7.48−7.14 (10H, H-aromatic), 4.73 (d, 1H, J3,3a = 9.0 Hz,
H-3a), 4.15 (dd, 1H, J4,5ax = 5.1, J5ax,5eq = 12.5 Hz, H-5ax), 4.00 (s, 1H,
H-1), 3.83 (dd, 1H, J4,5eq = 4.5, J5ax,5eq = 12.5 Hz, H-5eq), 3.74 (s, 3H,
OCH3), 3.70 (dd, 1H, J3,3a = 9.0, J3,4 = 8.0 Hz, H-3), 3.25 (ddd, 1H, J =
4.1, J = 10.7 Hz, H-1 menthyl), 3.21, 2.98 (2d, 2H, J = 13.5 Hz,
CH2Ph), 2.87 (m, 1H, J3,4 = 8.0, J4,5ax = 5.1, J4,5eq = 4.5 Hz, H-4), 2.78
(br s, 1H, NH), 2.15 (m, 1H, H menthyl), 1.61−1.45 (m, 3H, H
menthyl), 1.26−1.16 (m, 2H, H menthyl), 0.90−0.68 (m, 12H, H
menthyl); 13C NMR (CDCl3, 125.7 MHz) δ 202.5 (C-2), 173.4
(OCOMe), 139.3−127.2 (C-aromatic), 97.0 (C-1), 76.8 (C-1
menthyl), 72.6 (C-4a), 61.5 (C-3a), 61.3 (C-5), 54.0 (C-3), 52.4
(OCH3), 50.8 (C-4), 47.5(C-menthyl), 43.1 (CH2Ph), 39.5, 34.4, 31.5,
25.4, 23.0, 22.2, 21.1, 15.5 (C-menthyl); HRMS (ESI) m/z [M + Na]+
calcd for C32H41NNaO5 542.2877, found 542.2886.
mg, 64%); mp = 149 °C; [α]2D5 −121.8 (c 1.0, CHCl3); H NMR
1
(CDCl3, 500 MHz) δ 7.39−7.23 (5H, H-aromatic), 4.63 (d, 1H, J3,3a
=
9.3 Hz, H-3a), 4.31 (m, 2H, OCH2CH3), 4.09 (d, 1H, J4,4a = 7.3 Hz,
H-4a), 4.06 (dd, 1H, J4,5ax = 4.6, J5ax,5eq = 12.6 Hz, H-5ax), 4.05 (s, 1H,
H-1), 3.77 (dd, 1H, J4,5eq = 2.8, J5ax,5eq = 12.6 Hz, H-5eq), 3.58 (dd,
1H, J3,3a = 9.3, J3,4 = 8.2 Hz, H-3), 3.28 (ddd, 1H, J = 4.1, J = 10.7, H-1
menthyl), 3.03 (m, 1H, J3,4 = 8.2, J4,4a = 7.3, J4,5ax= 4.6, J4,5eq = 2.8 Hz,
H-4), 2.12 (m, 1H, H menthyl), 1.61−1.53 (m, 3H, H menthyl), 1.34
(t, 3H, J = 7.1 Hz, OCH2CH3), 1.26−1.18 (m, 2H, H menthyl), 0.92−
0.63 (m, 12H, H menthyl); 13C NMR (CDCl3, 125.7 MHz) δ 203.7
(C-2), 171.2 (OCOEt), 138.1−126.7 (C-aromatic), 96.6 (C-1), 76.4
(C-1 menthyl), 64.3 (C-3a), 64.1 (C-4a), 61.5 (OCH2CH3), 60.6 (C-
5), 55.3 (C-3), 47.5 (C-menthyl), 44.6 (C-4), 39.4, 34.4, 31.5, 25.3,
23.0, 22.3, 21.1, 15.4 (C-menthyl), 14.4 (OCH2CH3); HRMS (ESI)
m/z [M + H]+ calcd for C26H38NO5 444.2744, found 444.2749.
Compound 8: white solid, recrystallized from ethanol (34 mg,
19%), mp = 88 °C; [α]2D5 −128.0 (c 0.8, CHCl3); H NMR (CDCl3,
1
500 MHz) δ 7.47−7.25 (5H, H-aromatic), 5.01 (d, 1H, J3,3a = 2.8 Hz,
H-3a), 4.92 (s, 1H, H-1), 4.36 (dd, 1H, J4,5ax = 3.2, J5,5eq = 12.5 Hz, H-
5ax), 4.26 (m, 2H, OCH2CH3), 3.98 (d, 1H, J4,4a = 10.4 Hz, H-4a),
3.90 (d, 1H, J5ax,5eq = 12.5 Hz, H-5eq), 3.54 (ddd, 1H, J = 4.1, J = 10.7
Hz, H-1 menthyl), 3.15 (dd, 1H, J3,3a = 2.8, J3,4 = 8.2 Hz, H-3), 2.82
(ddd, 1H, J3,4 = 8.2, J4,4a = 10.4, J4,5ax = 3.2 Hz, H-4), 2.21 (m, 1H, H
menthyl), 2.08 (d, 1H, H menthyl), 1.65 (d, 2H, H menthyl), 1.39−
1.25 (m, 2H, H menthyl), 1.31 (t, 3H, J = 7.1 Hz, OCH2CH3), 0.98−
0.72 (m, 12H, H menthyl); 13C NMR (CDCl3, 125.7 MHz) δ 201.4
(C-2), 172.9 (OCOEt), 143.4−126.6 (C-aromatic), 95.7 (C-1), 77.0
(C-1 menthyl), 61.5 (OCH2CH3), 60.9 (C-4a), 60.3 (C-3a), 57.6 (C-
5), 56.3 (C-3), 47.9 (C-menthyl), 44.3 (C-4), 40.0, 34.4, 31.5, 25.4,
22.9, 22.3, 21.2, 15.4 (C-menthyl), 14.4 (OCH2CH3); HRMS (ESI)
m/z [M + H]+ calcd for C26H38NO5 444.2744, found 444.2744.
Synthesis of Adduct 9. The cycloaddition reaction between 2 (0.10
g, 0.40 mmol) and 5Aa (0.115 g, 0.60 mmol) was repeated using
AgOAc (3 mg, 0.02 mmol) and DBU (60 μL, 0.40 mmol). The
mixture was stirred at rt overnight. After the same workup and column
chromatography (hexane/EtOAc, 19:1), the following products were
obtained: 7 (10 mg, 6%) and 9 (60 mg, 34%).
Synthesis of Pyrrolidine Derivatives 12 and 13 from Imino Ester
5Ba. According to the general procedure starting from 2 (0.10 g, 0.40
mmol) and imino ester 5Ba (0.115 g, 0.60 mmol) at rt for 15 min. The
reaction mixture showed by TLC (EtOAc) two main spots
corresponding to 13 (Rf 0.61) and 12 (Rf 0.20). The mixture was
separated by column chromatography (hexane/EtOAc, 1:1 → 3:7).
Compound 12: white solid, recrystallized from ethanol/water (110
mg, 62%); mp = 147 °C dec; [α]2D5 −119.0 (c 0.8, CHCl3); H NMR
1
(CDCl3, 500 MHz) δ 8.61 (d, 1H, J = 1.8 Hz, H-2′Py), 8.48 (dd, 1H, J
= 1.3, 4.7 Hz, H-6′Py), 7.71 (dt, 1H, J = 1.5, 7.9 Hz, H-4′Py), 7.24
(dd, 1H, J = 4.7, 7.9 Hz, H-5′Py), 4.47 (d, 1H, J3,3a = 7.7 Hz, H-3a),
4.26 (m, 2H, OCH2CH3), 4.23 (s, 1H, H-1), 4.22 (dd, 1H, J4,5ax = 4.2,
J5ax,5eq = 12.7 Hz, H-5ax), 4.04 (d, 1H, J4,4a = 8.3 Hz, H-4a), 3.86 (d,
1H, J4,5eq= 2.0, J5ax,5eq = 12.7 Hz, H-5eq), 3.53 (dd, 1H, J3,3a = 7.7, J3,4
=
Compound 9: white solid, recrystallized from hexane; mp = 145
°C; [α]2D5 −80.3 (c 0.9, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.37−
7.20 (5H, H-aromatic), 4.78 (d, 1H, J3,3a = 7.8 Hz, H-3a), 4.25 (m, 4H,
H-1, 5ax, OCH2CH3), 4.16 (d, 1H, J4,4a = 5.5 Hz, H-4a), 3.90 (d, 1H,
J4,5eq = 2.1, J5,5eq = 12.2 Hz, H-5eq), 3.42 (t, 1H, J3,3a = 7.8, J3,4 = 8.7
Hz, H-3), 3.36 (ddd, 1H, J = 4.1, J = 10.7 Hz, H-1 menthyl), 2.95
(dddd, 1H, J3,4 = 8.7, J4,4a = 5.5, J4,5ax = 3.4, J4,5eq= 2.1 Hz, H-4), 2.18
(m, 1H, H menthyl), 1.73 (d, 1H, H menthyl), 1.60 (d, 2H, H
menthyl), 1.31 (t, 3H, J = 7.1 Hz, OCH2CH3), 1.25 (m, 2H, H
menthyl), 0.96−0.72 (m, 12H, H menthyl); 13C NMR (CDCl3, 125.7
MHz) δ 202.8 (C-2), 174.5 (OCOEt), 139.8−126.9 (C-aromatic),
96.6 (C-1), 77.0 (C-1 menthyl), 65.3 (C-3a), 63.1 (C-4a), 61.9 (C-5),
61.5 (OCH2CH3), 53.4 (C-3), 47.6 (C-menthyl), 45.5 (C-4), 39.7,
34.4, 31.5, 25.4, 22.9, 22.2, 21.1, 15.4 (C-menthyl), 14.4 (OCH2CH3);
HRMS (ESI) m/z [M + H]+ calcd for C26H38NO5 444.2744, found
444.2731.
7.8 Hz, H-3), 3.34 (ddd, 1H, J = 4.1, J = 10.7, H-1 menthyl), 3.08
(dddd, 1H, J3,4 = 7.8, J4,4a = 8.3, J4,5ax = 4.2, J4,5eq = 2.0 Hz, H-4), 2.85
(br s, 1H, NH), 2.15 (m, 1H, H menthyl), 1.73 (m, 1H, H menthyl),
1.62−1.55 (m, 2H, H menthyl), 1.31 (t, 3H, J = 7.1 Hz, OCH2CH3),
1.26−1.19 (m, 2H, H menthyl), 0.92−0.70 (m, 12H, H menthyl); 13C
NMR (CDCl3, 125.7 MHz) δ 201.9 (C-2), 171.7 (OCOEt), 148.7−
123.1 (C-aromatic), 96.2 (C-1), 76.7 (C-1 menthyl), 62.3 (C-4a), 62.1
(C-3a), 61.7 (OCH2CH3), 58.9 (C-5), 52.7 (C-3), 47.7 (C-menthyl),
44.7 (C-4), 39.6, 34.2, 31.4, 25.4, 22.9, 22.2, 21.1, 15.4 (C-menthyl),
14.3 (OCH2CH3); HRMS (ESI) m/z [M + Na]+ calcd for
C25H36N2NaO5 467.2516, found 467.2522.
Compound 13: syrup (18 mg, 10%); [α]2D5 −107.5 (c 1.1, CHCl3);
1H NMR (CDCl3, 500 MHz) δ 8.63 (d, 1H, J = 2.0 Hz, H-2′Py), 8.47
(dd, 1H, J = 1.6, 4.8 Hz, H-6′Py), 7.86 (dt, 1H, J = 1.8, 7.9 Hz, H-
4′Py), 7.24 (dd, 1H, J = 4.8, 7.9 Hz, H-5′Py), 5.06 (d, 1H, J3,3a = 2.4
J
dx.doi.org/10.1021/jo500547y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Hz, H-3a), 4.91 (s, 1H, H-1), 4.38 (dd, 1H, J4,5ax = 3.0, J5ax,5eq = 12.5
Hz, H-5ax), 4.25 (m, 2H, OCH2CH3), 3.96 (d, 1H, J4,4a = 10.5 Hz, H-
4a), 3.88 (d, 1H, J5ax,5eq = 12.5 Hz, H-5eq), 3.53 (ddd, 1H, J = 4.1, J =
10.7, H-1 menthyl), 3.13 (dd, 1H, J3,3a = 2.4, J3,4 = 8.1 Hz, H-3), 2.79
(m, 1H, J3,4 = 8.1, J4,4a = 10.5, J4,5ax = 3.0 Hz, H-4), 2.44 (br s, 1H,
NH), 2.20 (m, 1H, H menthyl), 2.07 (m, 1H, H menthyl), 1.67−1.61
(m, 2H, H menthyl), 1.36−1.21 (m, 2H, H menthyl), 1.31 (t, 3H, J =
7.1 Hz, OCH2CH3), 0.94−0.75 (m, 12H, H menthyl); 13C NMR
(CDCl3, 125.7 MHz) δ 201.0 (C-2), 173.0 (OCOEt), 148.6−123.4
(C-aromatic), 95.7 (C-1), 77.2 (C-1 menthyl), 61.5 (OCH2CH3), 60.6
(C-4a), 57.5 (C-3a), 57.3 (C-5), 56.1 (C-3), 47.9 (C-menthyl), 44.3
(C-4), 40.0, 34.3, 31.6, 25.5, 22.9, 22.3, 21.2, 15.4 (C-menthyl), 14.4
(OCH2CH3); HRMS (ESI) m/z [M + H]+ calcd for C25H37N2O5
445.2697, found 445.2717.
Hz, H-5eq), 3.52 (dd, 1H, J3,3a = 9.4, J3,4 = 8.4 Hz, H-3), 3.29 (ddd,
1H, J = 4.1, J = 10.7, H-1 menthyl), 3.01 (m, 1H, J3,4 = 8.4, J4,4a = 6.8,
J4,5ax = 4.7, J4,5eq = 3.0 Hz, H-4), 2.12 (m, 1H, H menthyl), 1.61−1.56
(m, 2H, H menthyl), 1.34 (t, 3H, J = 7.1 Hz, OCH2CH3), 1.30−1.20
(m, 3H, H menthyl), 0.89−0.68 (m, 12H, H menthyl); 13C NMR
(CDCl3, 125.7 MHz) δ 204.2 (C-2), 171.2 (OCOEt), 159.0−113.9
(C-aromatic), 96.6 (C-1), 76.4 (C-1 menthyl), 64.2 (C-4a), 63.9 (C-
3a), 61.5 (OCH2CH3), 60.8 (C-5), 55.5 (C-3), 55.3 (OCH3), 47.5 (C-
menthyl), 44.4 (C-4), 39.5, 34.4, 31.5, 25.3, 22.9, 22.3, 21.1, 15.4 (C-
menthyl), 14.4 (OCH2CH3); HRMS (ESI) m/z [M + Na]+ calcd for
C27H39NNaO6 496.2670, found 496.2650.
Compound 17: white solid, recrystallized from ethanol/water (26
mg, 14%); mp = 107 °C; [α]2D5 −88.5 (c 1.0, CHCl3); 1H NMR
(CDCl3, 500 MHz) δ 7.40, 6.86 (2d, 2H each, J = 8.8 Hz, H-
aromatic), 4.92 (s, 1H, H-1), 4.90 (d, 1H, J3,3a = 3.2 Hz, H-3a), 4.36
(dd, 1H, J4,5ax = 3.3, J5ax,5eq = 12.4 Hz, H-5ax), 4.26 (m, 2H,
Synthesis of Pyrrolidine Derivative 14 from Imino Ester 5Bb.
According to the general procedure, starting from 2 (0.10 g, 0.40
mmol) and imino ester 5Bb (0.115 g, 0.60 mmol) at rt for 15 min.
The product (Rf 0.15, EtOAc) was purified by column chromatog-
raphy (EtOAc/hexane 1.5:1).
OCH2CH3), 3.94 (d, 1H, J4,4a = 10.2 Hz, H-4a), 3.89 (d, 1H, J5ax,5eq
=
12.4 Hz, H-5eq), 3.79 (s, 3H, OCH3), 3.53 (ddd, 1H, J = 4.1, J = 10.7,
H-1 menthyl), 3.09 (dd, 1H, J3,3a = 3.2, J3,4 = 8.4 Hz, H-3), 2.78 (m,
1H, J3,4 = 8.4, J4,4a = 10.2, J4,5ax = 3.3 Hz, H-4), 2.22 (m, 1H, H
menthyl), 2.09 (m, 1H, H menthyl), 1.69−1.62 (m, 2H, H menthyl),
1.36 (m, 1H, H menthyl), 1.32 (t, 3H, J = 7.1 Hz, OCH2CH3), 1.27
(m, 1H, H menthyl), 0.98−0.75 (m, 12H, H menthyl); 13C NMR
(CDCl3, 125.7 MHz) δ 201.9 (C-2), 173.2 (OCOEt), 158.9−114.0
(C-aromatic), 95.7 (C-1), 77.0 (C-1 menthyl), 61.4 (OCH2CH3), 61.2
(C-4a), 60.2 (C-3a), 58.0 (C-5), 56.7 (C-3), 55.4 (OCH3), 47.9 (C-
menthyl), 44.6 (C-4), 40.0, 34.4, 31.6, 25.5, 23.0, 22.3, 21.2, 15.4 (C-
menthyl), 14.4 (OCH2CH3); HRMS (ESI) m/z [M + H]+ calcd for
C27H40NO6 474.2850, found 474.2830.
Compound 14: syrup (156 mg, 88%); [α]2D5 −108.0 (c 1.0, CHCl3);
1H NMR (CDCl3, 500 MHz) δ 8.58 (br s, 1H, Hz, H-2′Py), 8.45 (dd,
1H, J = 1.3, 4.8 Hz, H-6′Py), 7.75 (br d, 1H, J = 7.9 Hz, H-4′Py), 7.24
(dd, 1H, J = 4.8, 7.9 Hz, H-5′Py), 4.47 (d, 1H, J3,3a = 6.5 Hz, H-3a),
4.32 (dd, 1H, J4,5ax = 3.9, J5ax,5eq = 12.7 Hz, H-5ax), 4.28 (s, 1H, H-1),
3.85 (dd, 1H, J4,5eq= 1.9, J5ax,5eq = 12.7 Hz, H-5eq), 3.74 (s, 3H,
OCH3), 3.57 (dd, 1H, J3,3a = 6.5, J3,4 = 7.3 Hz, H-3), 3.35 (ddd, 1H, J =
4.1, J = 10.7 Hz, H-1 menthyl), 2.68 (ddd, 1H, J3,4 = 7.3, J4,5ax = 3.9,
J4,5eq = 1.9 Hz, H-4), 2.17 (m, 1H, H menthyl), 2.00 (s, 1H, H
menthyl), 1.77 (m, 1H, H menthyl), 1.61−1.55 (m, 2H, H menthyl)
1.50 (s, 3H, CH3), 1.24−1.20 (m, 1H, H menthyl), 0.92−0.72 (m,
12H, H menthyl); 13C NMR (CDCl3, 125.7 MHz) δ 200.5 (C-2),
174.9 (OCOMe), 148.3−123.0 (C-aromatic), 96.0 (C-1), 76.7 (C-1
menthyl), 66.4 (C-4a), 60.4 (C-3a), 58.0 (C-5), 53.8 (C-4), 52.9
(OCH3), 52.3 (C-3), 47.7, 39.7, 34.3, 31.4 (C-menthyl), 26.4 (CH3),
25.5, 22.9, 22.1, 21.1, 15.4 (C-menthyl); HRMS (ESI) m/z [M + H]+
calcd for C25H37N2O5 445.2697, found 445.2702.
Compound 18: syrup (4 mg, 4%); Rf 0.52; [α]2D5 −91.7 (c 1.1,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.34, 6.86 (2d, 2H each, J =
8.8 Hz, H-aromatic), 5.26 (br s, 1H, J3,3a < 1 Hz, H-3a), 4.75 (s, 1H,
H-1), 4.36 (dd, 1H, J4,5ax = 2.9, J5ax,5eq = 12.5 Hz, H-5ax), 4.17 (q, 2H,
OCH2CH3), 4.01 (d, 1H, J4,4a = 7.9 Hz, H-4a), 3.97 (d, 1H, J5ax,5eq
=
12.5 Hz, H-5eq), 3.79 (s, 3H, OCH3), 3.48 (ddd, 1H, J = 4.1, J = 10.7,
H-1 menthyl), 2.99 (m, 1H, J3,4 = 9.0, J4,4a = 7.9, J4,5ax = 2.9 Hz, H-4),
2.97 (dd, 1H, J3,3a < 1, J3,4 = 9.0 Hz, H-3), 2.20 (m, 1H, H menthyl),
2.07 (m, 1H, H menthyl), 1.67−1.62 (m, 2H, H menthyl), 1.32−1.25
(m, 2H, H menthyl), 1.28 (t, 3H, J = 7.1 Hz, OCH2CH3), 0.92−0.76
(m, 12H, H menthyl); 13C NMR (CDCl3, 125.7 MHz) δ 200.7 (C-2),
174.6 (OCOEt), 158.7−113.9 (C-aromatic), 95.3 (C-1), 76.8 (C-1
menthyl), 61.8 (C-4a), 61.7 (OCH2CH3), 59.8 (C-3a), 56.3 (C-5),
55.5 (OCH3), 55.1 (C-3), 48.0 (C-menthyl), 43.0 (C-4), 40.0, 34.4,
31.6, 25.4, 22.9, 22.3, 21.2, 15.4 (C-menthyl), 14.4 (OCH2CH3);
HRMS (ESI) m/z [M + H]+ calcd for C27H40NO6 474.2850, found
474.2848.
Synthesis of Pyrrolidine Derivative 15 from Imino Ester 5Bc.
According to the general procedure, starting from 2 (0.10 g, 0.40
mmol) and imino ester 5Bc (0.16 g, 0.60 mmol) at rt for 1 h. The
product of Rf 0.35 (hexane/EtOAc, 1:1) was purified by column
chromatography (hexane/EtOAc, 85:15).
Compound 15: syrup (185 mg, 89%); [α]2D5 −75.7 (c 1.0, CHCl3);
1H NMR (CDCl3, 500 MHz) δ 8.63−7.21 (9H, H-aromatic), 4.34 (d,
1H, J3,3a = 7.2 Hz, H-3a) 4.33 (dd, 1H, J4,5ax = 4.2, J5ax,5eq = 12.6 Hz, H-
5ax), 4.26 (s, 1H, H-1), 3.96 (dd, 1H, J4,5eq= 2.8, J5ax,5eq = 12.6 Hz, H-
5eq), 3.71 (s, 3H, OCH3), 3.60 (t, 1H, J3,3a = J3,4 = 7.2 Hz, H-3), 3.36
(ddd, 1H, J = 4.1, J = 10.7, H-1 menthyl), 3.23, 2.97 (2d, 2H, J = 13.5
Hz, CH2Ph), 2.87 (m, 1H, J3,4 = 7.2, J4,5ax = 4.2, J4,5eq = 2.8 Hz, H-4),
2.20 (m, 1H, H menthyl), 1.74 (d, 1H, H menthyl), 1.64−1.58 (m,
2H, H-menthyl), 1.25−1.21 (m, 2H, H menthyl), 0.92−0.75 (m, 12H,
H menthyl); 13C NMR (CDCl3, 125.7 MHz) δ 201.0 (C-2), 173.7
(OCOMe), 148.7−123.0 (C-aromatic), 96.3 (C-1), 76.8 (C-1
menthyl), 70.8 (C-4a), 59.9 (C-3a), 58.8 (C-5), 52.7 (OCH3), 52.1
(C-3), 51.5 (C-4), 47.7 (C-menthyl), 43.6 (CH2Ph), 39.7, 34.3, 31.5,
25.5, 22.9, 22.2, 21.2, 15.5 (C-menthyl); HRMS (ESI) m/z [M + H]+
calcd for C31H41N2O5 521.3010, found 521.3001.
Compound 19: syrup (57 mg, 40%); [α]2D5 −142.8 (c 0.9, CHCl3);
1H NMR (CDCl3, 500 MHz) δ 4.63 (s, 1H, H-1), 4.24 (m, 2H,
OCH2CH3), 4.06 (d, 1H, J4,4a = 5.2 Hz, H-4a), 3.75 (d, 1H, J5ax,5eq
=
11.3 Hz, H-5ax), 3.54 (dt, 1H, J3eq,5eq ∼ J4,5eq ∼ 1.0, J5ax,5eq = 11.3 Hz,
H-5eq), 3.48 (ddd, 1H, J = 4.1, J = 10.7, H-1 menthyl), 2.56 (br m,
1H, H-4), 2.40 (d, 1H, J3ax,3eq = 10.9 Hz, H-3ax), 2.26 (m, 1H, H
menthyl), 2.09 (m, 1H, H menthyl), 1.94 (br dd, 1H, J3ax,3eq = 10.9,
J3eq,4 = 3.5, J3eq,5eq ∼ 1 Hz, H-3eq), 1.65−1.60 (m, 2H, H menthyl),
1.29 (t, 3H, J = 7.1 Hz, OCH2CH3), 0.92−0.74 (m, 12H, H menthyl);
13C NMR (CDCl3, 125.7 MHz) δ 172.2 (OCOEt), 98.9 (C-1), 75.2
Synthesis of Pyrrolidine Derivatives 16−19 from Imino Ester 5Ca.
The general procedure was followed starting from 2 (0.10 g, 0.40
mmol) and imino ester 5Ca (0.13 g, 0.60 mmol) at rt for 15 min.
Monitoring by TLC (hexane/EtOAc, 7:3) showed two main spots
corresponding to compounds 17 (Rf 0.55) and 16 (Rf 0.24). However,
after column chromatography (hexane/EtOAc, 19:1 → 4:1) of the
crude mixture, two new compounds were isolated. One of them
(compound 19, Rf 0.10) turned out to be the major product.
Compound 16: white solid recrystallized from ethanol/water (11
mg, 6%); [α]2D5 −54.9 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz) δ
(C-1 menthyl), 63.9 (C-5), 61.4 (OCH2CH3), 59.5 (C-4a), 47.8 (C-
menthyl), 40.5 (C-4), 39.7 (C-menthyl), 37.8 (C-3), 34.6, 31.6, 25.5,
23.0, 22.4, 21.2, 15.4 (C-menthyl), 14.4 (OCH2CH3); HRMS (ESI)
m/z [M + H]+ calcd for C19H34NO5 356.2431, found 356.2438.
Synthesis of Pyrrolidine Derivatives 20 and 21 from Imino Ester
5Cb. According to the general procedure, starting from 2 (0.10 g, 0.40
mmol) and imino ester 5Cb (0.13 g, 0.60 mmol) at rt for 1 h. The
residue showed by TLC (hexane/EtOAc, 4:1) spots corresponding to
20 (Rf 0.10) and 21 (Rf 0.35). The mixture was purified by column
chromatography (hexane/EtOAc, 9:1).
Compound 20: syrup (85 mg, 45%); [α]2D5 −80.9 (c 1.1, CHCl3);
7.29, 6.86 (2d, 2H each, J = 8.8 Hz, H-aromatic), 4.60 (d, 1H, J3,3a
=
1H NMR (CDCl3, 500 MHz) δ 7.29, 6.86 (2d, 2H each, J = 8.5 Hz, H-
aromatic), 4.67 (d, 1H, J3,3a = 8.6 Hz, H-3a), 4.12 (dd, 1H, J4,5ax = 4.8,
J5ax,5eq = 12.7 Hz, H-5ax), 4.04 (s, 1H, H-1), 3.81, 3.78 (2s, 3H each, 2
9.4 Hz, H-3a), 4.31 (q, 2H, OCH2CH3), 4.08 (s, 1H, H-1), 4.07 (d,
1H, J4,4a = 6.8 Hz, H-4a), 4.04 (dd, 1H, J4,5ax = 4.7, J5ax,5eq = 12.7 Hz,
H-5ax), 3.78 (s, 3H, OCH3), 3.75 (dd, 1H, J4,5eq = 3.0, J5ax,5eq = 12.7
K
dx.doi.org/10.1021/jo500547y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
OCH3), 3.71 (dd, 1H, J4,5eq= 3.2, J5ax,5eq = 12.7 Hz, H-5eq), 3.60 (dd,
1H, J3,3a = 8.6, J3,4 = 7.8 Hz, H-3), 3.28 (ddd, 1H, J = 4.1, J = 10.7 Hz,
H-1 menthyl), 2.68 (m, 1H, J3,4 = 7.8, J4,5ax = 4.8, J4,5eq = 3.2 Hz, H-4),
2.13 (m, 1H, H menthyl), 1.62−1.56 (m, 3H, H menthyl), 1.51 (s, 3H,
CH3), 1.26−1.18 (m, 2H, H menthyl), 0.92−0.69 (m, 12H, H
menthyl); 13C NMR (CDCl3, 125.7 MHz) δ 203.0 (C-2), 174.6
(OCOMe), 158.9−113.8 (C-aromatic), 96.6 (C-1), 76.6 (C-1
menthyl), 68.6 (C-4a), 62.0 (C-3a), 60.7 (C-5), 55.3, 52.7 (2
OCH3), 54.4 (C-3), 52.1 (C-4), 47.6, 39.6, 34.4, 31.5 (C-menthyl),
25.6 (CH3), 25.4, 23.0, 22.2, 21.1, 15.4 (C-menthyl); HRMS (ESI) m/
z [M + H]+ calcd for C27H40NO6 474.2850, found 474.2863.
removed by filtration, and the solution was concentrated and
chromatographed on silica gel. The results are shown in Table 3.
The new compounds have been isolated and characterized as follows.
Compound epi-7: white solid, recrystallized from ethanol/water
(41 mg, 46%); mp = 82 °C; Rf 0.61, hexane/EtOAc, 7:3; [α]2D5 −97.3
1
(c 1.0, CHCl3); H NMR (CDCl3, 500 MHz) δ 7.43−7.23 (5H, H-
aromatic), 5.33 (br s, 1H, H-3a), 4.76 (s, 1H, H-1), 4.34 (dd, 1H, J4,5ax
= 3.0, J5ax,5eq = 12.5 Hz, H-5ax), 4.18 (m, 2H, OCH2CH3), 4.03 (d, 1H,
J4,4a = 8.0 Hz, H-4a), 3.98 (d, 1H, J5ax,5eq = 12.5 Hz, H-5eq), 3.48 (ddd,
1H, J = 4.1, J = 10.7, H-1 menthyl), 3.00 (m, 2H, H-3, H-4), 2.19 (m,
1H, H menthyl), 2.08 (m, 1H, H menthyl), 1.66−1.61 (m, 2H, H
menthyl), 1.29 (t, 3H, J = 7.1 Hz, OCH2CH3), 1.32−1.25 (m, 2H, H
menthyl), 0.93−0.65 (m, 12H, H menthyl); 13C NMR (CDCl3, 125.7
MHz) δ 200.5 (C-2), 174.6 (OCOEt), 144.9−126.3 (C-aromatic),
95.3 (C-1), 76.8 (C-1 menthyl), 61.8 (C-4a), 61.7 (OCH2CH3), 60.2
(C-3a), 56.2 (C-5), 55.1, 43.0 (C-3, C-4), 48.0 (C-menthyl), 40.0,
34.4, 31.6, 25.4, 22.9, 22.3, 21.2, 15.4 (C-menthyl), 14.2 (OCH2CH3);
HRMS (ESI) m/z [M + Na]+ calcd for C26H37NNaO5 466.2564,
found 466.2559.
Compound 21: syrup (40 mg, 21%); [α]2D5 −88.1 (c 0.9, CHCl3);
1H NMR (CDCl3, 500 MHz) δ 7.41, 6.86 (2d, 2H each, J = 8.6 Hz, H-
aromatic), 5.20 (d, 1H, J3,3a = 3.1 Hz, H-3a), 4.74 (s, 1H, H-1), 4.33
(dd, 1H, J4,5ax = 4.1, J5ax,5eq = 12.7 Hz, H-5ax), 3.86 (d, 1H, J5ax,5eq
=
12.7 Hz, H-5eq), 3.79, 3.64 (2s, 3H each, 2 OCH3), 3.48 (ddd, 1H, J =
4.1, J = 10.1 Hz, H-1 menthyl), 2.96 (dd, 1H, J3,3a = 3.1, J3,4 = 9.3 Hz,
H-3), 2.51 (dd, 1H, J3,4 = 9.3, J4,5ax = 4.1 Hz, H-4), 2.18 (m, 1H, H
menthyl), 2.08 (m, 1H, H menthyl), 1.65−1.60 (m, 2H, H menthyl),
1.54 (s, 3H, CH3), 1.36−1.21 (m, 2H, H menthyl), 0.93−0.75 (m,
12H, H menthyl); 13C NMR (CDCl3, 125.7 MHz) δ 200.5 (C-2),
176.8 (OCOMe), 158.7−113.9 (C-aromatic), 95.1 (C-1), 76.9 (C-1
menthyl), 66.7 (C-4a), 59.9 (C-3a), 55.5 ( × 2), 55.4 (C-3, C-5,
OCH3), 52.3 (OCH3), 50.0 (C-4), 48.0, 40.0, 34.4, 31.6, 25.4 (C-
menthyl), 25.2 (CH3), 23.0, 22.3, 21.2, 15.5 (C-menthyl); HRMS
(ESI) m/z [M + H]+ calcd for C27H40NO6 474.2850, found 474.2845.
Synthesis of Pyrrolidine Derivatives 22 and 23 from Imino Ester
5Cc. According to the general procedure starting from 2 (0.10 g, 0.40
mmol) and imino ester 5Cc (0.18 g, 0.60 mmol) at rt for 1 h. The
reaction mixture showed by TLC (hexane/EtOAc, 4:1) spots
corresponding to 22 (Rf 0.38) and 23 (Rf 0.44). The products were
separated by column chromatography (hexane/EtOAc, 20:1).
Compound epi-10: syrup (26 mg, 30%); Rf 0.63, hexane/EtOAc,
7:3; [α]2D5 −74.9 (c 0.7, CHCl3); H NMR (CDCl3, 500 MHz) δ
1
7.52−7.20 (5H, H-aromatic), 5.27 (d, 1H, J3,3a = 3.0 Hz, H-3a), 4.75
(s, 1H, H-1), 4.34 (dd, 1H, J4,5ax = 4.1, J5ax,5eq = 12.7 Hz, H-5ax), 3.87
(d, 1H, J5ax,5eq = 12.7 Hz, H-5eq), 3.65 (s, 3H, OCH3), 3.48 (ddd, 1H,
J = 4.1, J = 10.1 Hz, H-1 menthyl), 2.99 (dd, 1H, J3,3a = 3.0, J3,4 = 9.3
Hz, H-3), 2.52 (dd, 1H, J3,4 = 9.3, J4,5ax = 4.1, J4,5eq = 0 Hz, H-4), 2.18
(m, 1H, H menthyl), 2.08 (m, 1H, H menthyl), 1.66−1.61 (m, 2H, H
menthyl), 1.56 (s, 3H, CH3), 1.36−1.20 (m, 2H, H menthyl), 0.92−
0.76 (m, 12H, H menthyl); 13C NMR (CDCl3, 125.7 MHz) δ 200.3
(C-2), 176.8 (OCOMe), 146.0−126.5 (C-aromatic), 95.1 (C-1), 76.9
(C-1 menthyl), 66.8 (C-4a), 60.2 (C-3a), 55.5, 55.4 (C-3, C-5), 52.3
(OCH3), 49.9 (C-4), 48.0, 40.0, 34.4, 31.6, 25.4 (C- menthyl), 25.2
(CH3), 23.0, 22.3, 21.2, 15.5 (C-menthyl); HRMS (ESI) m/z [M +
Na]+ calcd for C26H37NNaO5 466.2564, found 466.2576.
Compound 22: syrup (64 mg, 29%); [α]2D5 −69.5 (c 0.9, CHCl3);
1H NMR (CDCl3, 500 MHz) δ 7.38−6.84 (9H, H-aromatic), 4.75 (d,
1H, J3,3a = 9.3 Hz, H-3a), 4.13 (dd, 1H, J4,5ax = 5.2, J5ax,5eq = 12.5 Hz,
H-5ax), 4.00 (s, 1H, H-1), 3.81 (dd, 1H, J4,5eq = 4.9, J5ax,5eq = 12.5 Hz,
H-5eq), 3.78, 3.73 (2s, 3H each, 2 OCH3), 3.66 (dd, 1H, J3,3a = 9.3, J3,4
= 8.2 Hz, H-3), 3.26 (ddd, 1H, J = 4.1, J = 10.7 Hz, H-1 menthyl),
Isomerization of endo-7 to epi-7 with SiO2−Toluene. Compound
epi-7 was obtained upon treatment of pure endo-7 (50 mg, 1.13 mmol)
with SiO2 (100 mg) in toluene (2 mL). The suspension was heated at
80 °C for 2 h, filtered, and concentrated. Column chromatography
(hexane/EtOAc, 12:1) of the resulting syrup gave epi-7 (20 mg, 40%),
and starting endo-7 (9 mg) was also recovered.
3.21, 2.97 (2d, 2H, J = 13.5 Hz, CH2Ph), 2.86 (m, 1H, J3,4 = 8.2, J4,5ax
=
5.2, J4,5eq = 4.9 Hz, H-4), 2.14 (m, 1H, H menthyl), 1.61−1.56 (m, 2H,
H menthyl), 1.50 (m, 1H, H-menthyl), 1.28−1.20 (m, 2H, H-
menthyl), 0.86−0.69 (m, 12H, H menthyl); 13C NMR (CDCl3, 125.7
MHz) δ 202.8 (C-2), 173.3 (OCOMe), 159.0−113.8 (C-aromatic),
97.1 (C-1), 76.8 (C-1 menthyl), 72.8 (C-4a), 61.7 (C-5), 61.0 (C-3a),
55.3 (OCH3), 54.1 (C-3), 52.3 (OCH3), 50.4 (C-4), 47.5 (C-
menthyl), 43.0 (CH2Ph), 39.5, 34.4, 31.5, 25.3, 23.0, 22.2, 21.1, 15.5
(C-menthyl); HRMS (ESI) m/z [M + Na]+ calcd for C33H43NNaO6
572.2983, found 572.2991.
Synthesis of Pyrrolidine Derivatives 24−37 from Dihydro-
pyranone 4. The dipolar cycloaddition reactions of azomethine ylides
(6Aa−6Cc) to the pyranone 4 have been conducted using the general
procedures and the particular methodologies applied for the
preparation of the analogous adducts from 2. The following
pyrrolidines derived from the sugar pyranone 4 have been obtained.
Synthesis of Pyrrolidine Derivatives 24 and 25 from Imino Ester
5Aa. Compound 24: white crystals obtained upon slow evaporation of
MeCN; mp = 139 °C; Rf 0.18, 76 mg, 43%; [α]2D5 +32.4 (c 1.0,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.36−7.20 (5H, H-aromatic),
4.62 (d, 1H, J3,3a = 9.3 Hz, H-3a), 4.30 (m, 2H, OCH2CH3), 4.08 (dd,
1H, J4,5ax = 4.7, J5ax,5eq = 12.8 Hz, H-5ax), 4.06 (d, 1H, J4,4a = 6.9 Hz, H-
4a), 3.94 (s, 1H, H-1), 3.76 (dd, 1H, J4,5eq = 2.9, J5ax,5eq = 12.8 Hz, H-
5eq), 3.56 (dd, 1H, J3,3a = 9.3, J3,4 = 8.4 Hz, H-3), 3.08 (ddd, 1H, J =
4.1, J = 10.7 Hz H-1 menthyl), 3.00 (m, 1H, J3,4 = 8.4, J4,4a = 6.9, J4,5ax
= 4.7, J4,5eq = 2.9 Hz, H-4), 1.95−1.88 (m, 2H, H menthyl), 1.59−1.51
(m, 2H, H menthyl), 1.34 (t, 3H, J = 7.1 Hz, OCH2CH3), 1.30−1.40
(m, 2H, H menthyl), 0.86−0.45 (m, 12H, H menthyl); 13C NMR
(CDCl3, 125.7 MHz) δ 202.8 (C-2), 171.3 (OCOEt), 138.1−126.7
(C-aromatic), 101.2 (C-1), 81.0 (C-1 menthyl), 64.1 ( × 2) (C-3a,
4a), 61.5 (OCH2CH3), 60.2 (C-5), 55.0 (C-3), 48.7 (C-menthyl), 44.7
(C-4), 42.9, 34.3, 31.8, 25.0, 23.2, 22.3, 21.1, 16.0 (C-menthyl), 14.4
(OCH2CH3); HRMS (ESI) m/z [M + H]+ calcd for C26H38NO5
444.2744, found 444.2763.
Compound 23: syrup (11 mg 5%); [α]2D5 −105.5 (c 0.7, CHCl3);
1H NMR (CDCl3, 500 MHz) δ 8.35−6.82 (9H, H-aromatic), 5.14 (d,
1H, J3,3a = 3.4 Hz, H-3a), 4.76 (s, 1H, H-1), 4.37 (dd, 1H, J4,5ax = 4.1,
J5ax,5eq = 12.7 Hz, H-5ax), 4.05 (dd, 1H, J5ax,5eq = 12.7 Hz, H-5eq), 3.79,
3.63 (2s, 3H each, 2 OCH3), 3.48 (m, 2H, CHPh, H-1 menthyl), 2.91
(dd, 1H, J3,3a = 3.4, J3,4 = 9.4 Hz, H-3), 2.89 (d, 1H, J = 13.5 Hz,
CHPh), 2.64 (m, 1H, J3,4 = 9.4, J4,5ax = 4.1 Hz, H-4), 2.20 (m, 1H, H
menthyl), 2.07 (m, 1H, H menthyl), 1.67−1.60 (m, 3H, NH, H-
menthyl), 1.33 (m, 1H, H-menthyl), 1.24 (m, 1H, H menthyl), 0.92−
0.78 (m, 12H, H menthyl); 13C NMR (CDCl3, 125.7 MHz) δ 200.6
(C-2), 175.6 (OCOMe), 158.6−113.8 (C-aromatic), 95.2 (C-1), 76.9
(C-1 menthyl), 70.6 (C-4a), 59.2 (C-3a), 55.7 (C-5), 55.5 (OCH3),
55.2 (C-3), 52.2 (OCH3), 48.3 (C-4), 48.0 (C-menthyl), 43.8
(CH2Ph), 40.0, 34.4, 31.6, 25.5, 23.0, 22.3, 21.2, 15.5 (C-menthyl);
HRMS (ESI) m/z [M + H]+ calcd for C33H44NO6 550.3163, found
550.3140.
Compound 25: syrup; Rf 0.60, 19 mg, 11%; [α]2D5 +70.1 (c 1.0,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.46−7.22 (5H, H-aromatic),
5.01 (d, 1H, J3,3a = 2.5 Hz, H-3a), 4.82 (s, 1H, H-1), 4.44 (dd, 1H, J4,5ax
= 3.3, J5ax,5eq = 12.4 Hz, H-5ax), 4.27 (q, 2H, J = 7.1 Hz, OCH2CH3),
3.93 (d, 1H, J4,4a = 10.5 Hz, H-4a), 3.92 (d, 1H, J5ax,5eq = 12.4 Hz, H-
5eq), 3.42 (ddd, 1H, J = 4.1, J = 10.7, H-1 menthyl), 3.15 (dd, 1H, J3,3a
Isomerization of Pyrrolidines with SiO2−Toluene. The general
procedure for the cycloaddition reaction was followed starting from 2
(50 mg, 0.20 mmol) and the corresponding α-imino ester. After the
usual workup and filtration through Celite, the solvent was evaporated,
the residue was dissolved in toluene (5 mL), and SiO2 (200 mg) was
added. The mixture was heated at 80 °C for 2 h. The SiO2 was
L
dx.doi.org/10.1021/jo500547y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
= 2.5, J3,4 = 8.2 Hz, H-3), 2.78 (m, 1H, J3,4 = 8.2, J4,4a = 10.5, J4,5ax = 3.3
Hz, H-4), 2.17 (m, 1H, H menthyl), 2.04 (m, 1H, H menthyl), 1.67−
1.59 (m, 2H, H menthyl), 1.40 (m, 1H, H menthyl), 1.32 (t, 3H, J =
7.1 Hz, OCH2CH3), 1.29−1.25(m, 1H, H menthyl), 0.94−0.73 (m,
12H, H menthyl); 13C NMR (CDCl3, 125.7 MHz) δ 200.7 (C-2),
173.3 (OCOEt), 144.0−126.5 (C-aromatic), 100.8 (C-1), 82.5 (C-1
menthyl), 61.4 (OCH2CH3), 61.0 (C-4a), 60.1 (C-3a), 57.5 (C-5),
56.3 (C-3), 48.6 (C-menthyl), 44.6 (C-4), 43.1, 34.3, 31.8, 25.5, 23.3,
22.3, 21.1, 16.2 (C-menthyl), 14.4 (OCH2CH3); HRMS (ESI) m/z
[M + H]+ calcd for C26H38NO5 444.2744, found 444.2756.
Hz, H-4a), 3.90 (d, 1H, J5ax,5eq = 12.4 Hz, H-5eq), 3.42 (ddd, 1H, J =
4.1, J = 10.7, H-1 menthyl), 3.15 (dd, 1H, J3,3a = 1.9, J3,4 = 8.0 Hz, H-
3), 2.78 (m, 1H, J3,4 = 8.0, J4,4a = 10.6, J4,5ax = 3.3 Hz, H-4), 2.59 (br s,
1H, NH), 2.16 (m, 1H, H menthyl), 2.02 (m, 1H, H menthyl), 1.67−
1.59 (m, 2H, H menthyl), 1.40 (m, 1H, H menthyl), 1.32 (t, 3H, J =
7.1 Hz, OCH2CH3), 1.24 (m, 1H, H menthyl), 0.92−0.73 (m, 12H, H
menthyl); 13C NMR (CDCl3, 125.7 MHz) δ 200.1 (C-2), 173.1
(OCOEt), 148.5−123.5 (C-aromatic), 100.8 (C-1), 82.7 (C-1
menthyl), 61.5 (OCH2CH3), 60.6 (C-4a), 57.3 (C-3a), 57.2 (C-5),
55.9 (C-3), 48.6 (C-menthyl), 44.5 (C-4), 43.1, 34.3, 31.8, 25.6, 23.3,
22.3, 21.1, 16.2 (C-menthyl), 14.4 (OCH2CH3); HRMS (ESI) m/z
[M + H]+ calcd for C25H37N2O5 445.2697, found 445.2696.
Synthesis of Pyrrolidine Derivative 26 from Imino Ester 5Ab.
Compound 26: white crystals obtained upon slow evaporation of
MeCN; mp = 116 °C; Rf 0.17, 120 mg, 68%; [α]2D5 +36.5 (c 0.9,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.37−7.20 (5H, H-aromatic),
Synthesis of Pyrrolidine Derivatives 30 and 31 from Imino Ester
5Bb. Compound 30: syrup; Rf 0.18, 95 mg, 53%; [α]2D5 +27.4 (c 0.7,
1
4.66 (d, 1H, J3,3a = 8.4 Hz, H-3a), 4.16 (dd, 1H, J4,5ax = 4.6, J5ax,5eq
=
CHCl3); H NMR (CDCl3, 500 MHz) δ 8.59 (d, 1H, J = 1.3 Hz, H-
12.8 Hz, H-5ax), 3.93 (s, 1H, H-1), 3.81 (s, 3H, OCH3), 3.72 (dd, 1H,
J4,5eq = 2.9, J5ax,5eq = 12.8 Hz, H-5eq), 3.63 (dd, 1H, J3,3a = 8.4, J3,4 = 7.7
Hz, H-3), 3.09 (ddd, 1H, J = 4.1, J = 10.7 Hz, H-1 menthyl), 2.66
(ddd, 1H, J3,4 = 7.7, J4,5ax = 4.6, J4,5eq = 2.9 Hz, H-4), 1.96−1.86 (m,
2H, H menthyl), 1.60−1.49 (m, 5H, H menthyl, CH3), 1.34−1.13 (m,
2H, H menthyl), 0.88−0.48 (m, 12H, H menthyl); 13C NMR (CDCl3,
125.7 MHz) δ 201.8 (C-2), 174.5 (OCOMe), 138.4−126.7 (C-
aromatic), 101.1 (C-1), 81.0 (C-1 menthyl), 68.5 (C-4a), 62.2 (C-3a),
60.0 (C-5), 54.1 (C-3), 52.7 (OCH3), 52.4 (C-4), 48.6, 42.9, 34.2, 31.7
(C-menthyl), 25.6 (CH3), 25.0, 23.2, 22.2, 21.1, 16.1 (C-menthyl);
HRMS (ESI) m/z [M + H]+ calcd for C26H38NO5 444.2744, found
444.2755.
2′Py), 8.48 (dd, 1H, J = 1.3, 4.8 Hz, H-6′Py), 7.77 (dt, 1H, J = 1.4, 7.9
Hz, H-4′Py), 7.27 (dd, 1H, J = 4.8, 7.9 Hz, H-5′Py), 4.48 (d, 1H, J3,3a
= 6.4 Hz, H-3a), 4.39 (dd, 1H, J4,5ax = 4.0, J5ax,5eq = 12.6 Hz, H-5ax),
4.22 (s, 1H, H-1), 3.86 (dd, 1H, J4,5eq= 2.0, J5ax,5eq = 12.6 Hz, H-5eq),
3.77 (s, 3H, OCH3), 3.59 (dd, 1H, J3,3a = 6.4, J3,4 = 7.4 Hz, H-3), 3.22
(ddd, 1H, J = 4.1, J = 10.7 Hz, H-1 menthyl), 2.68 (ddd, 1H, J3,4 = 7.4,
J4,5ax = 4.0, J4,5eq = 2.0 Hz, H-4), 2.03 (m, 1H, H menthyl), 1.90 (m,
1H, H menthyl), 1.62−1.55 (m, 2H, H menthyl), 1.52 (s, 3H, CH3),
1.34 (m, 1H, H menthyl), 1.18 (m, 1H, H menthyl), 0.92−0.57 (m,
12H, H menthyl); 13C NMR (CDCl3, 125.7 MHz) δ 199.7 (C-2),
175.0 (OCOMe), 148.5−123.1 (C-aromatic), 101.0 (C-1), 81.8 (C-1
menthyl), 66.5 (C-4a), 60.3 (C-3a), 58.0 (C-5), 54.0 (C-4), 53.0
(OCH3), 52.2 (C-3), 48.7, 43.0, 34.3, 31.8 (C-menthyl), 26.5 (CH3),
25.3, 23.2, 22.3, 21.0, 16.1 (C-menthyl); HRMS (ESI) m/z [M + H]+
calcd for C25H37N2O5 445.2697, found 445.2689.
Synthesis of Pyrrolidine Derivative 27 from Imino Ester 5Ac.
Compound 27: syrup; Rf 0.56, 160 mg, 77%; [α]2D5 +15.4 (c 1.0,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.44−7.16 (5H, H-aromatic),
Compound 31: syrup; Rf 0.38, 25 mg, 14%; [α]2D5 +27.3 (c 1.0,
4.73 (d, 1H, J3,3a = 9.1 Hz, H-3a), 4.17 (dd, 1H, J4,5ax = 5.1, J5ax,5eq
12.6 Hz, H-5ax), 3.90 (s, 1H, H-1), 3.82 (dd, 1H, J4,5eq = 4.4, J5ax,5eq
12.6 Hz, H-5eq), 3.74 (s, 3H, OCH3), 3.69 (dd, 1H, J3,3a = 9.1, J3,4
=
=
=
1
CHCl3); H NMR (CDCl3, 500 MHz) δ 8.85 (d, 1H, J = 2.0 Hz, H-
2′Py), 8.49 (dd, 1H, J = 1.6, 4.8 Hz, H-6′Py), 8.00 (dt, 1H, J = 1.8, 7.9
7.9 Hz, H-3), 3.22, 2.97 (2d, 2H, J = 13.5 Hz, CH2Ph), 3.07 (ddd, 1H,
J = 4.1, J = 10.7 Hz, H-1 menthyl), 2.85 (ddd, 1H, J3,4 = 7.9, J4,5ax = 5.1,
J4,5eq = 4.4 Hz, H-4), 1.96−1.86 (m, 2H, H menthyl), 1.59−1.52 (m,
2H, H menthyl), 1.28−1.16 (m, 2H, H menthyl), 0.90−0.46 (m, 12H,
H menthyl); 13C NMR (CDCl3, 125.7 MHz) δ 201.7 (C-2), 173.3
(OCOMe), 139.3−127.1 (C-aromatic), 101.2 (C-1), 80.9 (C-1
menthyl), 72.7 (C-4a), 61.3 (C-3a), 60.9 (C-5), 53.7 (C-3), 52.3
(OCH3), 50.6 (C-4), 48.5 (C-menthyl), 42.9, 42.8 (CH2Ph, C-
menthyl), 34.2, 31.7, 25.0, 23.1, 22.2, 21.0, 16.0 (C-menthyl); HRMS
(ESI) m/z [M + Na]+ calcd for C32H41NNaO5 542.2877, found
542.2877.
Hz, H-4′Py), 7.24 (dd, 1H, J = 4.8, 7.9 Hz, H-5′Py), 4.73 (s, 1H, H-1),
4.60 (d, 1H, J3,3a = 9.4 Hz, H-3a), 4.21 (dd, 1H, J4,5ax = 6.9, J5ax,5eq
=
10.7 Hz, H-5ax), 3.80 (s, 3H, OCH3), 3.74 (dd, 1H, J4,5eq= 10.6, J5ax,5eq
= 10.7 Hz, H-5eq), 3.37 (ddd, 1H, J = 4.1, J = 10.7 Hz, H-1 menthyl),
3.26 (dd, 1H, J3,3a = 9.4, J3,4 = 14.4 Hz, H-3), 2.68 (ddd, 1H, J3,4 = 14.4,
J4,5ax = 6.9, J4,5eq = 10.6 Hz, H-4), 2.23 (m, 1H, H menthyl), 2.13 (m,
1H, H menthyl), 1.65−1.61 (m, 2H, H menthyl), 1.56 (s, 3H, CH3),
1.39 (m, 1H, H menthyl), 1.28 (m, 1H, H menthyl), 0.92−0.72 (m,
12H, H menthyl); 13C NMR (CDCl3, 125.7 MHz) δ 201.7 (C-2),
175.2 (OCOMe), 149.4−123.4 (C-aromatic), 100.3 (C-1), 82.7 (C-1
menthyl), 65.6 (C-4a), 62.9 (C-5), 57.7 (C-3a), 57.5 (C-3), 52.5
(OCH3), 51.4 (C-4), 48.7, 43.0, 34.3, 31.9 (C-menthyl), 25.6 (CH3),
25.3, 23.3, 22.4, 21.1, 16.2 (C-menthyl); HRMS (ESI) m/z [M + H]+
calcd for C25H37N2O5 445.2697, found 445.2679.
Synthesis of Pyrrolidine Derivatives 28 and 29 from Imino Ester
5Ba. Compound 28: white solid, recrystallized from ethanol/water;
mp = 75 °C; Rf 0.18, 105 mg, 59%; [α]2D5 +30.3 (c 0.9, CHCl3); H
1
NMR (CDCl3, 500 MHz) δ 8.60 (d, 1H, J = 2.2 Hz, H-2′Py), 8.49
(dd, 1H, J = 1.5, 4.8 Hz, H-6′Py), 7.74 (m, 1H, H-4′Py), 7.26 (dd, 1H,
J = 4.8, 7.9 Hz, H-5′Py), 4.46 (d, 1H, J3,3a = 7.5 Hz, H-3a), 4.30 (dd,
1H, J4,5ax = 4.3, J5ax,5eq = 12.4 Hz, H-5ax), 4.26 (m, 2H, OCH2CH3),
4.16 (s, 1H, H-1), 4.04 (d, 1H, J4,4a = 8.3 Hz, H-4a), 3.87 (d, 1H,
J4,5eq= 2.4, J5ax,5eq = 12.4 Hz, H-5eq), 3.53 (t, 1H, J3,3a = J3,4 = 7.5 Hz,
H-3), 3.19 (ddd, 1H, J = 4.1, J = 10.7, H-1 menthyl), 3.08 (m, 1H, J3,4
= 7.5, J4,4a = 8.3, J4,5ax = 4.3, J4,5eq = 2.4 Hz, H-4), 2.70 (br s, 1H, NH),
2.01 (m, 1H, H menthyl), 1.92 (m, 1H, H menthyl), 1.62−1.53 (m,
2H, H menthyl), 1.32 (t, 3H, J = 7.1 Hz, OCH2CH3), 1.27−1.14 (m,
2H, H menthyl), 0.97−0.53 (m, 12H, H menthyl); 13C NMR (CDCl3,
125.7 MHz) δ 200.8 (C-2), 171.8 (OCOEt), 148.6−123.2 (C-
aromatic), 101.1 (C-1), 81.7 (C-1 menthyl), 62.1 (C-4a), 61.9 (C-3a),
61.8 (OCH2CH3), 58.6 (C-5), 52.2 (C-3), 48.7 (C-menthyl), 45.1 (C-
4), 42.9, 34.3, 31.8, 25.4, 23.2, 22.3, 21.0, 16.1 (C-menthyl), 14.3
(OCH2CH3); HRMS (ESI) m/z [M + H]+ calcd for C25H37N2O5
445.2697, found 445.2677
Synthesis of Pyrrolidine Derivative 32 from Imino Ester 5Bc.
Compound 32: syrup; Rf 0.30, 152 mg, 73%; [α]2D5 +14.8 (c 1.2,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 8.61−7.23 (9H, H-aromatic),
4.39 (dd, 1H, J4,5ax = 4.3, J5ax,5eq = 12.5 Hz, H-5ax), 4.33 (d, 1H, J3,3a
7.0 Hz, H-3a), 4.17 (s, 1H, H-1), 3.95 (dd, 1H, J4,5eq = 2.9, J5ax,5eq
12.5 Hz, H-5eq), 3.71 (s, 3H, OCH3), 3.60 (dd, 1H, J3,3a = 7.0, J3,4
=
=
=
7.4 Hz, H-3), 3.22, 2.96 (2d, 2H, J = 13.5 Hz, CH2Ph), 3.21 (ddd, 1H,
J = 4.1, J = 10.7, H-1 menthyl), 2.86 (m, 1H, J3,4 = 7.4, J4,5ax = 4.3, J4,5eq
= 2.9 Hz, H-4), 2.04 (m, 1H, H menthyl), 1.90 (m, 1H, H menthyl),
1.63−1.54 (m, 2H, H-menthyl), 1.33 (m, 1H, H menthyl), 1.18 (m,
1H, H menthyl), 0.90−0.56 (m, 12H, H menthyl); 13C NMR (CDCl3,
125.7 MHz) δ 200.0 (C-2), 173.8 (OCOMe), 148.7−123.1 (C-
aromatic), 101.1 (C-1), 81.7 (C-1 menthyl), 70.8 (C-4a), 59.8 (C-3a),
58.7 (C-5), 52.7 (OCH3), 51.8 (C-3), 51.6 (C-4), 48.6 (C-menthyl),
43.6 (CH2Ph), 43.0, 34.3, 31.8, 25.3, 23.3, 22.3, 21.0, 16.1 (C-
menthyl); HRMS (ESI) m/z [M + H]+ calcd for C31H41N2O5
521.3010, found 521.2992.
Compound 29: syrup; Rf 0.62, 20 mg, 11%; [α]2D5 +38.5 (c 1.0,
Synthesis of Pyrrolidine Derivatives 33 and 34 from Imino Ester
1
CHCl3); H NMR (CDCl3, 500 MHz) δ 8.65 (d, 1H, J = 2.0 Hz, H-
5Ca. Compound 33: white solid, recrystallized from hexane; mp =
1
2′Py), 8.48 (dd, 1H, J = 1.3, 4.8 Hz, H-6′Py), 7.89 (dt, 1H, J = 1.7, 7.9
145 °C; Rf 0.16, 130 mg, 68%; [α]2D5 +37.4 (c 0.6, CHCl3); H NMR
Hz, H-4′Py), 7.27 (dd, 1H, J = 4.8, 7.9 Hz, H-5′Py), 5.08 (d, 1H, J3,3a
(CDCl3, 500 MHz) δ 7.28, 6.86 (2d, 2H each, J = 8.8 Hz, H-
aromatic), 4.60 (d, 1H, J3,3a = 9.5 Hz, H-3a), 4.31 (m, 2H,
OCH2CH3), 4.09−4.03 (m, 2H, H-4a, H-5ax), 3.96 (s, 1H, H-1),
= 1.9 Hz, H-3a), 4.83 (s, 1H, H-1), 4.45 (dd, 1H, J4,5ax = 3.3, J5ax,5eq
=
12.4 Hz, H-5ax), 4.25 (m, 2H, OCH2CH3), 3.95 (d, 1H, J4,4a = 10.6
M
dx.doi.org/10.1021/jo500547y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3.77 (s, 3H, OCH3), 3.75 (dd, 1H, J4,5eq= 3.1, J5ax,5eq = 12.8 Hz, H-
5eq), 3.52 (dd, 1H, J3,3a = 9.5, J3,4 = 8.3 Hz, H-3), 3.11 (ddd, 1H, J =
3.08 (ddd, 1H, J = 4.1, J = 10.7 Hz, H-1 menthyl), 2.85 (m, 1H, J3,4 =
7.9, J4,5ax = 5.3, J4,5eq = 4.8 Hz, H-4), 1.98−1.88 (m, 2H, H menthyl),
1.60−1.52 (m, 2H, H menthyl), 1.30 (m, 1H, H-menthyl), 1.20 (m,
1H, H-menthyl), 0.90−0.48 (m, 12H, H menthyl); 13C NMR (CDCl3,
125.7 MHz) δ 202.1 (C-2), 173.3 (OCOMe), 159.0−113.7 (C-
aromatic), 101.4 (C-1), 81.0 (C-1 menthyl), 72.9 (C-4a), 61.3 (C-5),
60.9 (C-3a), 55.3 (OCH3), 53.9 (C-3), 52.3 (OCH3), 50.3 (C-4), 48.8
(C-menthyl), 42.9, 42.8 (CH2Ph, C-menthyl), 34.3, 31.8, 25.1, 23.2,
22.3, 21.1, 16.0 (C-menthyl); HRMS (ESI) m/z [M + H]+ calcd for
C33H44NO6 550.3163, found 550.3153.
4.1, J = 10.7, H-1 menthyl), 3.00 (m, 1H, J3,4 = 8.3, J4,4a = 6.9, J4,5ax
=
4.8, J4,5eq = 3.1 Hz, H-4), 1.98−1.90 (m, 2H, H menthyl), 1.61−1.52
(m, 3H, H menthyl), 1.34 (t, 3H, J = 7.1 Hz, OCH2CH3), 1.19 (m,
1H, H menthyl), 0.95−0.50 (m, 12H, H menthyl); 13C NMR (CDCl3,
125.7 MHz) δ 203.2 (C-2), 171.3 (OCOEt), 159.0−113.9 (C-
aromatic), 101.2 (C-1), 81.0 (C-1 menthyl), 64.3 (C-4a), 63.7 (C-3a),
61.5 (OCH2CH3), 60.4 (C-5), 55.3 (OCH3), 55.2 (C-3), 48.7 (C-
menthyl), 44.6 (C-4), 42.9, 34.3, 31.8, 25.0, 23.2, 22.3, 21.1, 16.0 (C-
menthyl), 14.4 (OCH2CH3); HRMS (ESI) m/z [M + H]+ calcd for
C27H40NO6 474.2850, found 474.2831.
Synthesis of Pyrrolidine Derivatives 39 and 40 from Dihydropyr-
anone 38. The general procedure for the dipolar cycloaddition was
followed starting from enone 38 (0.082 g, 0.40 mmol) and the imino
ester derived from glycine (5Aa, 0.115 g, 0.60 mmol), which were
dissolved in anhydrous MeCN (1.2 mL). After addition of AgOAc (20
mg, 0.12 mmol) and DBU (6 μL, 0.04 mmol), the mixture was stirred
at rt for 15 min. The reaction mixture showed by TLC (hexane/
EtOAc, 7:3) spots corresponding to 40 (Rf 0.46) and 39 (Rf 0.10),
which were separated by column chromatography (hexane/EtOAc,
93:7).
Compound 34: syrup; Rf 0.52, 22 mg, 12%; [α]2D5 +48.2 (c 0.9,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.39, 6.86 (2d, 2H each, J =
8.8 Hz, H-aromatic), 4.91 (d, 1H, J3,3a = 2.9 Hz, H-3a), 4.81 (s, 1H, H-
1), 4.42 (dd, 1H, J4,5ax = 3.3, J5ax,5eq = 12.4 Hz, H-5ax), 4.26 (m, 2H,
OCH2CH3), 3.91 (d, 1H, J4,4a = 10.3 Hz, H-4a), 3.90 (d, 1H, J5ax,5eq
=
12.4 Hz, H-5eq), 3.78 (s, 3H, OCH3), 3.41 (ddd, 1H, J = 4.1, J = 10.7,
H-1 menthyl), 3.10 (dd, 1H, J3,3a = 2.9, J3,4 = 8.3 Hz, H-3), 2.76 (m,
1H, J3,4 = 8.3, J4,4a = 10.3, J4,5ax = 3.3 Hz, H-4), 2.16 (m, 1H, H
menthyl), 2.05 (m, 1H, H menthyl), 1.66−1.59 (m, 2H, H menthyl),
1.40 (m, 1H, H menthyl), 1.32 (t, 3H, J = 7.1 Hz, OCH2CH3), 1.23
(m, 1H, H menthyl), 0.95−0.72 (m, 12H, H menthyl); 13C NMR
(CDCl3, 125.7 MHz) δ 200.9 (C-2), 173.3 (OCOEt), 158.9−114.0
(C-aromatic), 100.7 (C-1), 82.5 (C-1 menthyl), 61.4 (OCH2CH3),
61.2 (C-4a), 60.0 (C-3a), 57.6 (C-5), 56.3 (C-3), 55.4 (OCH3), 48.7
(C-menthyl), 44.7 (C-4), 43.1, 34.3, 31.8, 25.5, 23.3, 22.3, 21.1, 16.2
(C-menthyl), 14.4 (OCH2CH3); HRMS (ESI) m/z [M + H]+ calcd
for C27H40NO6 474.2850, found 474.2859.
Synthesis of Pyrrolidine Derivatives 35 and 36 from Imino Ester
5Cb. Compound 35: syrup; Rf 0.13, 114 mg, 60%; [α]2D5 +29.3 (c 1.0,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.26, 6.86 (2d, 2H each, J =
8.8 Hz, H-aromatic), 4.65 (d, 1H, J3,3a = 8.7 Hz, H-3a), 4.12 (dd, 1H,
J4,5ax = 4.8, J5ax,5eq = 12.8 Hz, H-5ax), 3.91 (s, 1H, H-1), 3.80, 3.75 (2s,
3H each, 2 OCH3), 3.68 (dd, 1H, J4,5eq= 3.1, J5ax,5eq = 12.8 Hz, H-5eq),
3.58 (dd, 1H, J3,3a = 8.7, J3,4 = 7.9 Hz, H-3), 3.09 (ddd, 1H, J = 4.1, J =
10.7 Hz, H-1 menthyl), 2.64 (m, 1H, J3,4 = 7.9, J4,5ax = 4.8, J4,5eq = 3.1
Hz, H-4), 1.95−1.86 (m, 2H, H menthyl), 1.59−1.51 (m, 2H, H
menthyl), 1.48 (s, 3H, CH3), 1.29 (m, 1H, H menthyl), 1.16 (m, 1H,
H menthyl), 0.86−0.47 (m, 12H, H menthyl); 13C NMR (CDCl3,
125.7 MHz) δ 202.3 (C-2), 174.5 (OCOMe), 158.8−113.7 (C-
aromatic), 101.1 (C-1), 80.9 (C-1 menthyl), 68.7 (C-4a), 61.8 (C-3a),
60.4 (C-5), 55.2 (OCH3), 54.3 (C-3), 52.7 (OCH3), 51.9 (C-4), 48.6,
42.9, 34.2, 31.7 (C-menthyl), 25.4 (CH3), 25.0, 23.1, 22.2, 21.0, 15.9
(C-menthyl); HRMS (ESI) m/z [M + H]+ calcd for C27H40NO6
474.2850, found 474.2833.
Compound endo-39: syrup (58 mg, 30%); [α]2D5 −44.1 (c 1.0,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.35−7.20 (10H, H-
aromatic), 4.62, 4.41 (2d, 2H, J = 11.8 Hz, CH2Ph), 4.59 (d, 1H, J3,3a
=
9.3 Hz, H-3a), 4.31 (m, 2H, OCH2CH3), 4.08 (d, 1H, J4,4a = 7.2 Hz,
H-4a), 4.07 (dd, 1H, J4,5ax = 4.6, J5ax,5eq = 12.8 Hz, H-5ax), 4.04 (s, 1H,
H-1), 3.82 (dd, 1H, J4,5eq = 2.4, J5ax,5eq = 12.8 Hz, H-5eq), 3.58 (dd,
1H, J3,3a = 9.3, J3,4 = 8.0 Hz, H-3), 3.03 (m, 1H, J3,4 = 8.0, J4,4a = 7.3,
J4,5ax= 4.6, J4,5eq = 2.4 Hz, H-4), 1.35 (t, 3H, J = 7.2 Hz, OCH2CH3);
13C NMR (CDCl3, 125.7 MHz) δ 202.9 (C-2), 171.2 (OCOEt),
137.7−126.6 (C-aromatic), 98.5 (C-1), 69.8 (CH2Ph), 64.4 (C-3a),
64.0 (C-4a), 61.6 (OCH2CH3), 60.3 (C-5), 55.0 (C-3), 44.5 (C-4),
14.4 (OCH2CH3); HRMS (ESI) m/z [M + Na]+ calcd for
C23H25NNaO5 418.1625, found 418.1624.
Compound exo-40: syrup (34 mg, 18%); [α]2D5 −66.5 (c 0.9,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.44−7.20 (10H, H-
aromatic), 5.00 (d, 1H, J3,3a = 2.6 Hz, H-3a), 4.85 (s, 1H, H-1), 4.80,
4.61 (2d, 2H, J = 11.6 Hz, CH2Ph), 4.36 (dd, 1H, J4,5ax = 3.3, J5,5eq
=
12.4 Hz, H-5ax), 4.27 (m, 2H, OCH2CH3), 3.96 (br d, 2H, J = 10.8
Hz, H-4a, H-5eq), 3.18 (dd, 1H, J3,3a = 2.6, J3,4 = 8.2 Hz, H-3), 2.81
(ddd, 1H, J3,4 = 8.2, J4,4a ∼ 10.0, J4,5ax = 3.3 Hz, H-4), 1.32 (t, 3H, J =
7.1 Hz, OCH2CH3); 13C NMR (CDCl3, 125.7 MHz) δ 200.9 (C-2),
173.1 (OCOEt), 143.7−126.5 (C-aromatic), 98.1 (C-1), 70.0
(CH2Ph), 61.4 (OCH2CH3), 60.9 (C-4a), 60.0 (C-3a), 57.6 (C-5),
56.4 (C-3), 44.6 (C-4), 14.4 (OCH2CH3); HRMS (ESI) m/z [M +
Na]+ calcd for C23H25NNaO5 418.1625, found 418.1626.
Compound 36: syrup; Rf 0.41, 20 mg, 11%; [α]2D5 +20.1 (c 0.9,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.41, 6.86 (2d, 2H each, J =
8.8 Hz, H-aromatic), 5.18 (d, 1H, J3,3a = 3.0 Hz, H-3a), 4.64 (s, 1H, H-
1), 4.41 (dd, 1H, J4,5ax = 4.1, J5ax,5eq = 12.7 Hz, H-5ax), 3.86 (d, 1H,
J5ax,5eq = 12.7 Hz, H-5eq), 3.79, 3.64 (2s, 3H each, 2 OCH3), 3.36
(ddd, 1H, J = 4.1, J = 10.1 Hz, H-1 menthyl), 2.98 (dd, 1H, J3,3a = 3.0,
J3,4 = 9.4 Hz, H-3), 2.50 (dd, 1H, J3,4 = 9.4, J4,5ax = 4.1, J4,5eq = 0 Hz, H-
4), 2.14 (m, 1H, H menthyl), 2.02 (m, 1H, H menthyl), 1.65−1.59
(m, 2H, H menthyl), 1.53 (s, 3H, CH3), 1.43−1.33 (m, 2H, H
menthyl), 0.91−0.70 (m, 12H, H menthyl); 13C NMR (CDCl3, 125.7
MHz) δ 199.5 (C-2), 176.7 (OCOMe), 158.7−114.0 (C-aromatic),
100.4 (C-1), 82.6 (C-1 menthyl), 66.8 (C-4a), 60.0 (C-3a), 55.5 ( ×
2) (C-5, OCH3), 55.2 (C-3), 52.3 (OCH3), 50.2 (C-4), 48.7, 43.1,
34.3, 31.8, 25.4 (C-menthyl), 25.1 (CH3), 23.2, 22.3, 21.1, 16.1 (C-
menthyl); HRMS (ESI) m/z [M + H]+ calcd for C27H40NO6
474.2850, found 474.2835.
ASSOCIATED CONTENT
■
S
* Supporting Information
Details on general experimental methods; copies of 1H and 13
C
NMR and NOESY spectra for compounds 2, 4, 7, epi-7, 8−10,
epi-10, 11−37, 39, and 40. A table with relevant 1H NMR data
for configurational assignments is also included. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*CFax: +5411-4576-3352. E-mail: varela@qo.fcen.uba.ar.
Notes
The authors declare no competing financial interest.
Synthesis of Pyrrolidine Derivative 37 from Imino Ester 5Cc.
Compound 37: white crystals obtained upon slow evaporation of
MeCN; mp = 158 °C; Rf 0.42, 95 mg, 43%; [α]2D5 +43.4 (c 1.1,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.37−6.84 (9H, H-aromatic),
ACKNOWLEDGMENTS
■
Support of this work by the University of Buenos Aires (Project
200 201001 00536), the National Research Council of
Argentina (CONICET, Project PIP 0064), and the National
Agency for Promotion of Science and Technology (ANPCyT,
PICT 2007-00291) is gratefully acknowledged. O.V. and E.R.
4.75 (d, 1H, J3,3a = 9.4 Hz, H-3a), 4.16 (dd, 1H, J4,5ax = 5.3, J5ax,5eq
12.6 Hz, H-5ax), 3.91 (s, 1H, H-1), 3.80 (dd, 1H, J4,5eq = 4.8, J5ax,5eq
=
=
12.6 Hz, H-5eq), 3.77, 3.75 (2s, 3H each, 2 OCH3), 3.65 (dd, 1H, J3,3a
= 9.4, J3,4 = 7.9 Hz, H-3), 3.21, 2.97 (2d, 2H, J = 13.5 Hz, CH2Ph),
N
dx.doi.org/10.1021/jo500547y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(24) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002,
124, 13400−13401.
(25) (a) Garcia Ruano, J. L.; Tito, A.; Peromingo, M. T. J. Org. Chem.
are Research Members from CONICET, and G.A.O.U. is a
fellow from the same institution.
2002, 67, 981−987. (b) Casa, J.; Grigg, R.; Naj
́
era, C.; Sansano, J. M.
REFERENCES
■
Eur. J. Org. Chem. 2001, 1971−1982.
(1) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887−2902.
(2) Pellissier, H. Tetrahedron 2007, 63, 3235−3285.
(26) Kanemasa, S. Synlett 2002, 9, 1371−1378.
(27) Chaulagain, M. R.; Aron, Z. D. J. Org. Chem. 2010, 75, 8271−
8274.
(28) Galliford, C. V.; Martenson, J. S.; Stern, C.; Scheidt, K. A. Chem.
Commun. 2007, 631−633.
(29) (a) Manzano, V. E.; Uhrig, M. L.; Varela, O. J. Org. Chem. 2008,
77, 7224−7235. (b) Repetto, E.; Manzano, V. E.; Uhrig, M. L.; Varela,
O. J. Org. Chem. 2012, 77, 253−265. (c) Uhrig, M. L.; Manzano, V. E.;
Varela, O. Eur. J. Org. Chem. 2006, 162−168.
(30) (a) Dale, J. S.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512−
519. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092−4096.
(3) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106,
4484−4517.
(4) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765−2810.
(5) (a) Lewis, J. R. Nat. Prod. Rep. 2001, 18, 95−128. (b) O’Hagan,
D. Nat. Prod. Rep. 2000, 17, 435−446.
(6) (a) Fish, P. V.; Andrews, M. D.; Fray, M. J.; Stobie, A.;
Wakenhut, F.; Whitlock, G. A. Bioorg. Med. Chem. Lett. 2009, 19,
2829−2834. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed.
2007, 46, 8748−8758. (c) Bellina, F.; Rossi, R. Tetrahedron 2006, 62,
7213−7256. (d) Moloney, M. G.; Trippier, P. C.; Yaqoob, M.; Wang,
Z. Curr. Drug Discovery Technol. 2004, 1, 181−199. (e) Hussaini, S. R.;
Moloney, M. G. Org. Biomol. Chem. 2003, 1, 1838−1841. (f) Royles,
B. J. L. Chem. Rev. 1995, 95, 1981−2001.
(7) (a) Enders, D.; Klatt, M. Synthesis 1996, 1403−1418.
(b) Whitesell, J. K. Chem. Rev. 1989, 89, 1581−1590.
(8) (a) Caputo, C. A.; Jones, N. D. Dalton Trans. 2007, 4627−4640.
(b) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev.
2000, 100, 2159−2232.
(9) (a) Brazier, J. B.; Tomkinson, N. C. O. Top. Curr. Chem. 2010,
291, 281−347. (b) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev.
̈
2007, 107, 5416−5470. (c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.;
List, B. Chem. Rev. 2007, 107, 5471−5569. (d) Lelais, G.; MacMillan,
D. W. C. Aldrichimica Acta 2006, 39, 79−87. (e) Notz, W.; Tanaka, F.;
Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580−591.
(10) (a) Adrio, J.; Carretero, J. C. Chem. Commun. 2011, 47, 6784−
6794. (b) Oura, I.; Shimizu, K.; Ogata, K.; Fukuzawa, S. Org. Lett.
2010, 12, 1752−1755. (c) Kumar, A.; Gupta, G.; Srivastava, S. J. Comb.
́
Chem. 2010, 12, 458−462. (d) Najera, C.; Sansano, J. M. Angew.
Chem., Int. Ed. 2005, 44, 6272−6276. (e) Gao, W.; Zhang, X.;
Raghunath, M. Org. Lett. 2005, 7, 4241−4244.
(11) (a) Cai, S.; Gorityala, B. K.; Ma, J.; Leow, M. L.; Liu, X.-W. Org.
Lett. 2011, 13, 1072−1075. (b) Boysen, M. K. Chem.Eur. J. 2007,
13, 8648−8659. (c) Totani, K.; Takao, K.; Tadano, K. Synlett 2004, 12,
2066−2080. (d) Vasella, A. Helv. Chim. Acta 1977, 60, 1273−1295.
(e) Kunz, H.; Muller, B.; Schanzenbach, D. Angew. Chem., Int. Ed.
1987, 26, 267−269.
(12) Wee, A. G. H. J. Chem. Soc., Perkin Trans. 1 1989, 1363−1364.
́
(13) Bashiardes, G.; Cano, C.; Mauze, B. Synlett 2005, 4, 587−590.
(14) Sarotti, A. M.; Spanevello, R. A.; Suar
Piro, O. E. Org. Lett. 2012, 14, 2556−2559.
́
ez, A. G.; Echeverría, G. A.;
(15) (a) Iriarte Capaccio, C. A.; Varela, O. J. Org. Chem. 2001, 66,
8859−8866. (b) Iriarte Capaccio, C. A.; Varela, O. J. Org. Chem. 2002,
67, 7839−7846. (c) Iriarte Capaccio, C. A.; Varela, O. Tetrahedron
Lett. 2003, 44, 4023−4026. (d) Iriarte Capaccio, C. A.; Varela, O.
Tetrahedrom: Asymmetry 2004, 15, 3023−3028.
(16) Manzano, V. E.; Repetto, E.; Uhrig, M. L.; Barat
Proven Methods Carbohydr. Chem. 2011, 1, 291−297.
́
h, M.; Varela, O.
(17) Uhrig, M. L.; Varela, O. Synthesis 2005, 6, 893−898.
(18) Boga, S. B.; Balasubramanian, K. K. ARKIVOC 2004, 7, 87−102.
(19) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125,
10174−10175.
(20) Tsuge, O.; Kanemasa, S.; Yoshioka, M. J. Org. Chem. 1988, 53,
1384−1391.
(21) (a) Llamas, R.; Gomez Arrayas, R.; Carretero, J. C. Org. Lett.
2006, 8, 1795−1798. (b) Cabrera, S.; Gomez Arrayas, R.; Carretero, J.
C. J. Am. Chem. Soc. 2005, 127, 16394−16395. (c) Gao, W.; Zhang, X.;
Raghunath, M. Org. Lett. 2005, 7, 4241−4244.
(22) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.; Minakata,
S.; Komatsu, M. Org. Lett. 2003, 5, 5043−5046.
(23) (a) Zeng, W.; Zhou, Y.-G. Org. Lett. 2005, 7, 5055−5058.
(b) Stohler, R.; Wahl, F.; Pfaltz, A. Synthesis 2005, 1431−1436.
(c) Knopfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;
Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971−5973.
O
dx.doi.org/10.1021/jo500547y | J. Org. Chem. XXXX, XXX, XXX−XXX