Stereoselective 1,3-dipolar cycloadditions of nitrones derived from amino acids. Asymmetric synthesis of N-(alkoxycarbonylmethyl)-3-hydroxypyrrolidin-2- ones Dedicated to Professor Giovanni Romeo on occasion of his 70th birthday

Article abstract of DOI:10.1016/j.tet.2013.08.084

Diastereoselective asymmetric 1,3-dipolar cycloadditions of N-(alkoxycarbonylmethyl) nitrones derived from glycine, alanine and phenylalanine have been studied both experimentally and theoretically. Asymmetric induction is evaluated by either introducing

Full text of DOI:10.1016/j.tet.2013.08.084

Accepted Manuscript
Stereoselective 1,3-Dipolar Cycloadditions of Nitrones derived from Amino Acids.
Asymmetric Synthesis of N-(Alkoxycarbonylmethyl)-3-Hydroxypyrrolidin-2-ones
Pedro Merino, Graziella Greco, Tomás Tejero, Ramon Hurtado-Guerrero, Rosa
Matute, Ugo Chiacchio, Antonino Corsaro, Venerando Pistarà, Roberto Romeo
PII:
S0040-4020(13)01406-3
10.1016/j.tet.2013.08.084
TET 24785
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 August 2013
Revised Date: 29 August 2013
Accepted Date: 30 August 2013
Please cite this article as: Merino P, Greco G, Tejero T, Hurtado-Guerrero R, Matute R, Chiacchio
U, Corsaro A, Pistarà V, Romeo R, Stereoselective 1,3-Dipolar Cycloadditions of Nitrones derived
from Amino Acids. Asymmetric Synthesis of N-(Alkoxycarbonylmethyl)-3-Hydroxypyrrolidin-2-ones,
Tetrahedron (2013), doi: 10.1016/j.tet.2013.08.084.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
2
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Stereoselective 1,3-Dipolar Cycloadditions of Nitrones derived
from Amino Acids. Asymmetric Synthesis of N-
Leave this area blank for abstract info.
(Alkoxycarbonylmethyl)-3-hydroxypyrrolidin-2-ones
Pedro Merino,*a Graziella Greco,a,b Tomás Tejero,a Ramon Hurtado-Guerrero,c,d Rosa Matute,e Ugo Chiacchio,b Antonino
Corsaro,b Venerando Pistarà,b Roberto Romeo.f
a
ISQCH. Universidad de Zaragoza. CSIC. Zaragoza. Spain. b Università di Catania, Catania, Italy. c BIFI, Universidad de Zaragoza. Zaragoza, Spain. d
ARAID. Zaragoza, Spain. e EINA. Universidad de Zaragoza. Zaragoza. Spain. f Università di Messina, Messina, Italy.

ACCEPTED MANUSCRIPT
3
Tetrahedron
journal homepage: www.elsevier.com
Stereoselective 1,3-Dipolar Cycloadditions of Nitrones derived from Amino Acids.
Asymmetric Synthesis of N-(Alkoxycarbonylmethyl)-3-Hydroxypyrrolidin-2-ones
Pedro Merino a Graziella Greco,a,b Tomás Tejero,a Ramon Hurtado-Guerrero,c,d Rosa Matute,e Ugo
Chiacchio,b Antonino Corsaro,b Venerando Pistarà,b Roberto Romeo.f
a
Laboratorio de Sintesis Asimetrica. Departamento de Sintesis y Estructura de Biomoléculas. Instituto de Sintesis Quimica y Catalisis Homgenea (ISQCH).
Universidad de Zaragoza. CSIC. 50009 Zaragoza. Spain.
b
Dipartimento di Scienze del Farmaco, Università di Catania, Viale Andrea Doria 6, Catania 95125, Italy.
Instituto de Biocomputación y Fisica de Sistemas complejos (BIFI), BIFI-IQFR (CSIC) Joint Unit, Universidad de Zaragoza. 50009 Zaragoza, Spain.
Fundación ARAID. Gobierno de Aragón, Zaragoza, Spain.
c
d
e Departamento de Ingenieria Química y Tecnologias del Medio Ambiente. EINA. Universidad de Zaragoza. 50009 Zaragoza, Spain
f
Dipartimento Farmaco-Chimico, Università di Messina, Via SS Anunziata, Messina 98168, Italy.
Dedicated to Prof. Giovanni Romeo on occasion of his 70th birthday
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Diastereoselective asymmetric 1,3-dipolar cycloadditions of N-(alkoxycarbonylmethyl) nitrones
derived from glycine, alanine and phenylalanine have been studied both experimental- and
theoretically. Asymmetric induction is evaluated by either introducing a chiral group at the
nitrone nitrogen atom or by using Oppolzer’s sultam acrylamide. In both cases the sense of the
asymmetric induction is the same, the (3R,5R)-isomer being preferentially obtained. The best
results were observed with the chiral dipolarophile which afforded an only isomer in all cases.
The obtained isoxazolidines are easily transformed into the corresponding 5-substituted-3-
hydroxypyrrolidin-2-ones. DFT studies are in a qualitative agreement with the observed
experimental results.
Available online
Keywords:
Nitrones
Isoxazolidines
Pyrrolidines
2009 Elsevier Ltd. All rights reserved.
1. Introduction
Even though the reaction performs with high chemical yields,
an inherent problem of the process is the induction of asymmetry
The 1,3-dipolar cycloaddition between a nitrone and an alkene
has been known for a long time as a powerful method for
accessing to a variety of nitrogenated compounds1 and the
reaction has been extensively studied and reviewed.2 The
isoxazolidines obtained in the reaction are useful intermediates in
organic synthesis.3 In particular, 5-alkoxycarbonyl isoxazolidines
obtained from the cycloaddition between nitrones and acrylates
are precursors of 5-substituted 3-hydroxypyrrolidin-2-ones of
synthetic interest (Scheme 1).4
when enantiomerically pure compounds are pursued. Catalytic
approaches have been widely studied and excellent results have
been obtained in several instances.5 However, in some cases and
depending on the required substrates, the catalytic approach,
usually based on the use of chiral Lewis acids,5,6 is not the best
option because only enriched mixtures of enantiomers, difficult
of being separated, are obtained. In such cases diastereoselective
approaches are
a good alternative providing homochiral
compounds with excellent selectivities.7 The asymmetric
induction can be exerted by incorporating chiral groups either at
the dipole or at the dipolarophile.8 There are numerous examples
of dipolar cycloadditions of nitrones bearing chiral groups at the
nitrone carbon,9 most of them derived from carbohydrates.10
Chiral groups at the nitrone nitrogen atom have also been utilized
and excellent results have been obtained when sugar moieties,
susceptible of being further eliminated, have been employed.11
Finally, the incorporation of chiral auxiliaries at the dipolarophile
Scheme 1. 1,3-Dipolar cycloadditions en route to 3-hydroxypyrrolin-2ones
———
Corresponding author. Tel.: +34-876-553783; fax: +34-976-509726; e-mail: pmerino@unizar.es

ACCEPTED MANUSCRIPT
4
(by forming chiral esters and amides) has been widely studied12
and among them the Oppolzer's sultam acrylamide has provided
the best results.13 In this context, we have recently reported a
preliminary communication on the cycloaddition reaction
between
a glycine-derived nitrone and Oppolzer’s sultam
acrylamide en route to pyrrolidinyl PNA monomers.14 Continuing
our work in this area, we now report our latest efforts at
expanding the scope of diastereoselective 1,3-dipolar
cycloadditions of N-(alkoxycarbonylmethyl) nitrones 1, which
are precursors of 5-substsituted-3-hydroxy-N-substituted
pyrrolidin-2-ones 4 through intermediate isoxazolidines 3. A
comparative study on the reactions between achiral nitrones 1
(Scheme 1, R1=H) and Oppolzer’s sultam acrylamide 2a, and
between chiral non-racemic nitrones 1 (Scheme 1, R1=Me, Bn)
and methyl acrylate 2b (Scheme 2, Z = Me) is presented. DFT
calculations are also discussed in order to rationalize the different
asymmetric inductions observed experimentally.
Scheme 3. Synthesis of N-(alkoxycarbonylmethyl) nitrones 1.
i)
H2NHOH·HCl, NaHCO3, 12 h, then BH3·Py. ii) Et3N, PhCHO, 12 h, then
MeReO3, UHP, MeOH, MgSO4. iii) H2NOH·HCl, MeOH (or HCl, H2O), iv)
MgSO4, CH2Cl2, 4 h. (For R1 and R2 see Table 1)
Table 1. Synthesis of N-(alkoxycarbonylmethyl) nitrones (Scheme 2).
R1
H
H
H
H
R2
iPr
Ph
aldehyde hydroxylamine nitrone yield (%)a
9a
9b
9c
9d
9e
9a
9b
9c
9d
9e
9a
9b
9c
9d
9e
5
5
1a
1b
1c
1d
1e
1f
60
60
2-furyl
BnOCH2
BocHNCH2
iPr
Ph
2-furyl
BnOCH2
5
80
5
5
90
H
----b
85
Me
Me
Me
Me
8a
8a
8a
8a
8a
8b
8b
8b
8b
8b
1g
1h
1i
1j
1k
78
89
70
Me BocHNCH2
----b
87
Bn
Bn
Bn
Bn
iPr
Ph
2-furyl
BnOCH2
1l
99
90
1m
1n
1o
83
----b
Scheme 2. Synthesis of 3-hydroxypyrrolidin-2-ones
2. Results and discussion
Bn BocHNCH2
a Isolated yield. b unstable; prepared in situ (see below)
The cycloaddition reactions were carried out in toluene as a
solvent in a sealed tube (Scheme 4). The results are collected in
Table 2. All the cycloadditions carried out utilizing N-acryloyl-
(2R)-bornane-10,2-sultam 2a as dipolarophile took place with
complete regio- (3,5), diastereo- (trans) and enantioselectivities
(3R,5R) and only one adduct was found in the crude isolated
reaction mixtures. The 5-(tert-butoxycarbonylaminomethyl)
adduct 3e was obtained by mixing aldehyde 9e, hydroxylamine 5
and 2a under the same reaction conditions.
2.1. Experimental study
N-(Alkoxycarbonylmethyl) nitrones
1
were prepared
following our previously reported procedure for achiral nitrones14
consisting of condensation of the corresponding hydroxylamines
and aldehydes (Scheme 3). The ethyl hydroxyglycinate 5a was
prepared from ethyl glyoxylate 4 by formation of the oxime and
further reduction with borane in pyridine. Condensation of
benzaldehyde with the corresponding α-aminoesters 6 afforded
intermediate imines which were oxidized in situ with
methyltrioxorhenium15 to afford the C-phenyl nitrones 7.
Liberation of the free hydroxylamines from 7 could be made by
acidic hydrolysis or transoximation with hydroxylamine
hydrochloride. Finally, nitrones 1 were obtained by condensation
of hydroxylamines 5 and 8 with the corresponding aldehydes 9 in
the presence of magnesium sulfate as a drying agent (Scheme 2,
Table 1). All the nitrones were obtained in good yields with the
exception of those derived from N-Boc-glycinal 9e, which
showed to be unstable. Since nitrones 1e, 1j and 1o could not be
isolated, the corresponding cycloadditions were made by forming
the nitrone in situ (see below).
Scheme 4. Cycloaddition between nitrones and alkenes. i) toluene, sealed
tube, 80 ºC, 16 h. (For R1 and R2 see see Table 2).

ACCEPTED MANUSCRIPT
5
Table 2. Cycloadditions between nitrones 1 and dipolarophiles 2 (Scheme 4).
R1
H
H
H
H
R2
iPr
Ph
nitrone alkene isoxazolidine
d.r.a yield (%)b
1a
1b
1c
1d
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
3a
3b
3c
3d
3e
3f
>98:2:0:0d
50
61
80
80
75
55
83
77
68
45
64
82
81
54
52
>98:2:0:0d
>98:2:0:0d
>98:2:0:0d
>98:2:0:0d
72:10:9:9
82:10:8:0
80:15:5:0
70:20:10:0
80:10:10:0
78:8:8:6
2-furyl
BnOCH2
H
BocHNCH2 1ec
Me
Me
Me
Me
iPr
Ph
1f
1g
1h
1i
3g
3h
3i
2-furyl
BnOCH2
Me BocHNCH2 1jc
3j
Bn
Bn
Bn
Bn
iPr
Ph
2-furyl
BnOCH2
1k
1l
3k
3l
89:6:5:0
85:9:6:0
85:9:6:0
88:6:6:0
1m
1n
3m
3n
3o
Scheme 6. Synthesis of pyrrolidin-2-ones. i) H2, Pd(OH)2-C, 2000 psi, 48 h
Bn BocHNCH2 1oc
a
Determined by NMR on the crude mixture b Isolated yield. c prepared in
The relative configuration of compounds 3 was assigned by
conventional 1D and 2D NMR techniques. The absolute
configurations were determined by preparing the corresponding
Mosher esters of pyrrolidines 10. In order to apply successfully
the Kakisawa’s rule16 we prepared Mosher esters 11 and 12
derived from (R)- and (S)-Mosher acids, respectively (Scheme 6)
and the 1H NMR spectra were recorded to calculate differences in
the chemical shift between the values corresponding to a pair of
isomers.
situ. d only one diastereomer was observed
When nitrones 1f-o, bearing a chiral group at the nitrone
nitrogen were used as dipoles in the cycloaddition reaction with
methyl acrylate 2b, lower diastereomeric ratios were found with
respect to the use of the chiral dipolarophile 2a. The (3R,5R)-
isomer was also the preferred one but minor isomers were
detected by NMR of the crude mixtures. After chromatographic
purification the major isomer was isolated and characterized.
Similarly to the obtention of isoxazolidine 3e, the corresponding
adducts 3j and 3o were obtained by mixing aldehyde 9e and 2b
with hydroxylamines 8a and 8b, respectively, under the same
reaction conditions. In general, nitrones bearing a benzyl group
(1k-1o) gave better diastereomeric rations than those bearing a
methyl group (1f-1j).
The reaction can also be carried out in a one-pot procedure as
in the case of nitrones derived from N-Boc-glycinal 9e. However,
when we check such
a protocol for the synthesis of
isoxazolidines 3f,g and 3k,l (Scheme 5) considerably lower
yields (25-40%) were observed; the diastereoselectivity was not
affected so, it can be considered intrinsic of the cycloaddition
reactions. Consequently, the multicomponent reaction in this case
cannot be considered as an advantageous approach.
Scheme 7. Mosher esters of compounds 10.
According to Kakisawa’s rule16 the methylene group (H4a and
H4b) is selectively shielded by the phenyl group when the two
groups are located on the same side of the plane containing H3
and the carbonyl group (compounds 11). By defining ∆δ as
indicated in Scheme 7 (δS and δR refers to chemical shifts of
(S)- and (R)-MTPA esters, respectively) positive values
indicate a 3R configuration, whereas negative values indicate
a 3S configuration. According to the values illustrated in
Scheme 6 it was confirmed a 3R configuration for compounds
10a-c. This confirmation served to ascertain the absolute
configuration of the major product of the cycloaddition,
compounds 3 as (3R,5R).
Scheme 5. Multicomponent synthesis of isoxazolidines. i) toluene, sealed
tube, 60 ºC, 16 h. (For R1 and R2 see see Tables 1 and 2)
The synthetic utility of the isoxazolidines was demonstrated
through the efficient conversion to the corresponding 3-
hydroxypyrrolidin-2-ones
10
(Scheme
6).
Catalytic
hydrogenation of isoxazolidines 3f and 3k afforded in a
quantitative yield pyrrolidin-2-ones 10a and 10b, respectively.
The transformation of isoxazolidine 3e into 10c has been reported
in our previous communication.14
2.2. Theoretical study
In order to rationalize the stereochemical course of the studied
reactions we carried out theoretical studies of all the possible
paths of reaction. All calculations were performed with the
GAUSSIAN 09 package.17 The hybrid density functional theory
B3LYP18 with the 6-31G(d) basis set19 was employed for

ACCEPTED MANUSCRIPT
6
geometry optimizations. This method has been successfully used
in theoretical investigations of reactions involving dipolar
cycloadditions of nitrones.14
transition state leads to the (3R,5S)-adduct, whereas the obtained
adduct is that with (3S,5R) configuration in the model (actually,
(3R,5R) in the real adduct.22 In addition, energy differences
between TSs lower than 1.0 kcal/mol do not justify the excellent
diastereoselectivity observed in the reaction. Because of these
reasons (failure in prediction) we decided to move to Thrular’s
functional M06-2X for performing more accurate calculations. It
has been reported that B3LYP functionals, adequate for
determining geometries, are not so precise in energy calculations
and Thrular’s functionals should provide more accurate energy
values more in agreement with the experimental findings.23
To evaluate inclusion of diffuse functions and different
functionals with a higher level basis set, single point calculations
were carried out on the optimized structures using both B3LYP18
and M06-2X20 functionals with triple Z basis set 6-311+G(d).
Geometry optimizations and vibrational analyses were performed
without any constraint and all transition structures were
characterized by analysis of the normal mode corresponding to its
unique imaginary frequency. All the located transition states were
confirmed to connect to reactants and products by intrinsic
reaction coordinate (IRC) calculations.21 Regarding the
computational costs, the only changes made in the model is the
use of C-methyl nitrones and methyl esters. The rest of the
molecule has been preserved. Two model reactions have been
studied (Scheme 8) corresponding to the cycloaddition with
Oppolzer’s sultam acrylamide and nitrones bearing chiral groups
at the nitrogen atom. In both cases the four possible transition
states corresponding to the obtention of 3,5-adducts through endo
and exo attacks by the Re and Si faces have been considered.
We located (B3LYP/6-31G(d)) four transition states for the
cycloaddition between nitrone 13 and 2a (Figure 1) and four
transition states for the reaction between nitrone 14 and 2b
(Figure 2). The energy values are given in Tables 3 and 4. All the
transition states are concerted asynchronous as expected for a
typical normal-demand 1,3-dipolar cycloaddition. The C-O
forming bonds are in the range of 2.28-2.39 Ǻ and the C-C
forming bonds in the range of 2.04-2.11 Ǻ. The geometry of the
transition structures is rather similar independently of the
position of the chiral auxiliary, with shorter C-O forming bonds
for exo approaches. On the opposite, the shorter C-C forming
bonds correspond to the endo approaches.
TS1
TS2
(2.80)
(2.75)
TS3
TS4
(1.80)
(0.00)
Figure 1. Transition structures (B3LYP/6-31G(d)) corresponding to the
reaction between 13 and 2a. TS1, TS2, TS3 and TS4 correspond to Si exo, Re
exo, Si endo and Re endo approaches leading to (3R,5R)-, (3S,5S)-, (3R,5S)-
and (3S,5R)-isomers. Relative energy values between TSs are calculated at
M06-2X/6-311+G(d,p)//B3LYP/6-31G(d) level on theory and given in
kcal/mol. Bond distances are given in Ǻ.
Scheme 8. Model reactions studied at DFT level
In our previous communication, preliminary calculations at
B3LYP/6-311G+(d,p)//B3LYP/6-31G(d) level predicted in the
case of cycloaddition with 2a, a preferred Si-endo attack with
very small energy differences (within the experimental error)
with respect to the other transition states. However, such a

ACCEPTED MANUSCRIPT
7
Table 4. Calculated (M06-2X/6-311+G(d,p)//B3LYP/6-31G(d) and
B3LYP/6-311+G(d,p)//B3LYP/6-31G(d)) free (ꢀG, hartrees) and relative
energies (ꢀꢀG, kcal·mol-1) of the transition structures corresponding to the
reaction of nitrone 14 with 2b (see Scheme 8).a
B3LYP/6-311G(d,p)
//B3LYP/6-31G(d)
M06-2X/6-311G(d,p)
//B3LYP/6-31G(d)
ꢀG
ꢀꢀGb
ꢀG
ꢀꢀGb
2b
-306.475408
-515.627400
-822.065070
-822.067509
-822.067220
-822.069269
-822.108544
-822.111340
-822.109955
-822.111883
14
TS5
TS6
TS7
TS8
16a
16b
16c
16d
23.68
22.15
22.33
21.05
-3.60
-5.35
-4.48
-5.69
-821.713674
-821.715380
-821.716713
-821.719235
-821.772882
-821.775567
-821.775804
-821.777319
15.48
14.40
13.57
11.99
-21.68
-23.36
-23.51
-24.46
TS5
(3.49)
TS6
(2.42)
a
TS5 corresponds to Si exo approach leading to (3R,5R)-16a; TS6
corresponds to Re exo approach leading to (3S,5S)-16b; TS7 corresponds to
Si endo approach leading to (3R,5S)-16c; TS8 corresponds to Re endo
approach leading to (3S,5R)-16d. bReferred to starting materials (2b+14 =
-822.102808 and -821.738335 hartree for B3LYP and M06-2X single point
calculations, respectively).
TS7
TS8
The energy values were calculated through single point
calculations using B3LYP and M06-2X functionals and triple Z
basis sets including diffuse functions. As mentioned above, while
the use of B3LYP functional does not predict correctly the
stereochemical course of the reaction, the use of M06-2X
functional indicated the lower transition states those
corresponding to a Re-endo attack in both cases (TS4 and TS8)
leading to the corresponding (3S,5R)-isomers 15d and 16d. The
barrier for the cycloaddition between 2a and 13 is 14.75 kcal/mol
and the barrier for the cycloaddition between 2b and 14 is 11.99
kcal/mol. These results are in good agreement with the
experimental observations. Moreover, the energy differences
between transition states are sufficient to justify a good
selectivity, even though it is not possible to evaluate in a
quantitative way the observed diastereoselectivity.
(1.58)
(0.00)
Figure 2. Transition structures (B3LYP/6-31G(d)) corresponding to the
reaction between 14 and 2b. TS5, TS6, TS7 and TS8 correspond to Si exo,
Re exo, Si endo and Re endo approaches leading to (3R,5R)-, (3S,5S)-,
(3R,5S)- and (3S,5R)-isomers. Relative energy values between TSs are
calculated at M06-2X/6-311+G(d,p)//B3LYP/6-31G(d) level on theory and
given in kcal/mol. Bond distances are given in Ǻ.
Table 3. Calculated (M06-2X/6-311+G(d,p)//B3LYP/6-31G(d) and
B3LYP/6-311+G(d,p)//B3LYP/6-31G(d)) free (ꢀG, hartrees) and relative
energies (ꢀꢀG, kcal·mol-1) of the stationery points corresponding to the
reaction of nitrone 13 with 2a (see Scheme 8).a
B3LYP/6-311G(d,p)
//B3LYP/6-31G(d)
M06-2X/6-311G(d,p)
//B3LYP/6-31G(d)
ꢀG
ꢀꢀGb
ꢀG
ꢀꢀGb
2a
-1106.712249
-476.328878
-1583.002915
-1583.001658
-1583.003196
-1583.002396
-1583.049313
-1583.047860
-1583.048858
-1583.050002
-1106.397708
-476.120257
-1582.489996
-1582.490071
-1582.491584
-1582.494459
-1582.558545
-1582.550269
-1582.555084
-1582.556095
3. Conclusions
13
Diastereoselective 1,3-dipolar cycloadditions of achiral N-
(alkoxycarbonylmethyl) nitrones with Oppolzer’s sultam
acrylamide has been compared with the corresponding
cycloadditions between N-(alkoxycarbonylmethyl) nitrones
bearing a chiral group at the nitrone nitrogen and methyl acrylate.
In all cases the regio- and diastereoselectvity is complete towards
3,5-trans-disubstituted isoxazolidines. Also, the asymmetric
induction is the same leading to (3R,5R)-isomers; however
whereas inclusion of chirality at the nitrogen atom in the nitrone
moiety affords mixtures of isomers, the use of the Oppolzer’s
sultam acrylamide as dipolarophile furnishes only one isomer. In
conclusion, and according to previously reported dipolar
cycloadditions with such a dipolarophile13 the Oppolzer’s sultam
is confirmed to be an excellent chiral auxiliary. For this sort of
1,3-dipolar cycloadditions it is more advisable to include the
chiral group at the dipolarophile rather than at the nitrone
nitrogen atom. Whereras DFT calculations at B3LYP/6-
311G+(d,p)//B3LYP/6-31G(d) level of theory are not capable of
predicting correctly the stereochemical course of the reaction, the
use of Thrular’s functional ((M06-2X/6-311G+(d,p)//B3LYP/6-
TS1
TS2
TS3
TS4
15a
15b
15c
15d
23.98
24.77
23.80
24.30
-5.14
-4.23
-4.85
-5.57
17.55
17.50
16.55
14.75
-25.46
-20.27
-23.29
-23.93
a TS1 corresponds to Si exo approach leading to (3R,5R)-15a; TS2
corresponds to Re exo approach leading to (3S,5S)-15b; TS3 corresponds to
Si endo approach leading to (3R,5S)-15c; TS4 corresponds to Re endo
approach leading to (3S,5R)-15d. bReferred to starting materials (2a+13 =
-1583.041127 and -1582.517965 hartree for B3LYP and M06-2X single point
calculations, respectively).

ACCEPTED MANUSCRIPT
8
31G(d)) provides energy values that are in good qualitative
agreement with the observed asymmetric induction.
7.1 Hz), 4.75 (q, 1H, J = 7.0 Hz), 7.41-7.44 (m, 3H), 7.87-7.89
(m, 1H), 8.23-8.27 (m, 2H).
4.2.2. (S,Z)-N-(1-ethoxy-1-oxo-3-phenylpropan-2-yl)-1-
4. Experimental Section
phenylmethanimine oxide 7b
1
The reaction flasks and other glass equipment were heated in
an oven at 130 °C overnight and assembled in a stream of Ar. All
reactions were monitored by TLC on silica gel 60 F254; the
position of the spots were detected with 254 nm UV light or by
spraying with either 5% ethanolic phosphomolybdic acid or
Mostain solution. Column chromatography was carried out in a
Buchi 800 MPLC system or a Combiflash apparatus, using silica
gel 60 microns and with solvents distilled prior to use. Melting
points were uncorrected. 1H and 13C NMR spectra were recorded
on Bruker Avance 400 or 500 instruments in the stated solvent.
Chemical shifts are reported in ppm (δ) relative to CHCl3 (δ =
7.26) in CDCl3. Optical rotations were taken on a JASCO DIP-
370 polarimeter. Elemental analysis were performed on a Perkin
(4.14 g, 93%); white foam. H NMR (CDCl3, 400 MHz) δ
1.30 (t, 3H, J = 7.1 Hz), 3.41 (dd, 1H, J = 14.2, 4.6 Hz), 3.72 (dd,
1H, J = 14.2, 10.1 Hz), 4.31 (q, 2H, J = 7.1 Hz), 4.70 (dd, 1H, J =
10.1, 4.6 Hz), 7.14 (s, 1H), 7.22-7.29 (m, 5H), 7.41-7.43 (m, 3H),
8.16-8.19 (m, 2H)
4.3. General Procedure for the Synthesis of Hydroxylamines 8
To a cooled (0 °C) solution of hydroxylamine hydrochloride
(3.16 g, 45.5 mmol) in MeOH (50 ml), NaOH (1.82 g, 45.4
mmol) and acetic acid (2.73 g, 2.7 mL, 45.4 mmol) were added
sequentially. The resulting solution was stirred for 15 min at
which time the corresponding nitrone (16 mmol) was added. The
reaction mixture was heated under reflux for 16 h. After
concentration under reduced pressure a 6N solution of KOH
saturated with NaCl was added until pH = 7. The resulting
mixture was extracted with EtOAc (3 x 60 ml). The combined
organic extracts were dried (MgSO4), filtered and evaporated
under reduced pressure. The crude product was used in the next
step without further purification
Elmer 240B microanalyzer or with
instrument.
a Perkin-Elmer 2400
4.1. Ethyl hydroxyglycinate 5
A solution of ethyl glyoxylate 4 (8.5 mL of a 50% solution in
toluene, 43.2 mmol) in toluene (75 mL) was treated with
hydroxylamine hydrochloride (3 g, 43.1 mmol) and sodium
bicarbonate (7 g, 86.4 mmol) and the resulting mixture was
stirred at room temperature for 12 h. The reaction mixture was
filtered and the filtrate evaporated under reduced pressure. The
crude product was taken up in dichloromethane and washed with
brine. The organic layer was separated, dried (MgSO4) and
evaporated under reduced pressure to give the crude oxime (3.53
g, 70%; 1H NMR (CDCl3, 400 MHz) δ 1.34 (t, 3H), 4.33 (q, 2H),
7.56 (s, 1H), 9.10 (bs, 1H)) which was dissolved in ethanol (60
mL), cooled to 0 °C and treated sequentially with borane in
pyridine (18.7 mL, 149.6 mmol) and 7N HCl in EtOH. After
stirring for 2 h at 0 °C the solvent is evaporated under reduced
pressure and the residue is taken up in dichloromethane. Solid
sodium carbonate is added and stirred for 15 min. The mixture is
filtered and the filtrate evaporated to give the crude
4.3.1. Ethyl N-hydroxy-L-alaninate 8a
1
(1.11 g, 52%). H NMR (CDCl3, 400 MHz) δ 1.26-1.31 (m,
6H), 3.72 (q, 1H), 4.23 (q, 2H), 5.48 (bs, 1H).
4.3.2. Ethyl N-hydroxy-L-phenylalaninate 8b
1
(1.67 g, 50%). H NMR (CDCl3, 400 MHz) d 1.12 (t, 3H, J =
7.1 Hz), 2.79 (dd, 1H, J = 13.8, 8.2 Hz), 2.88 (dd, 1H, J = 13.8,
6.2 Hz), 3.77 (dd, 1H, J = 8.2, 6.2 Hz), 4.08 (q, 2H, J = 7.1 Hz),
7.08-7.22 (m, 5H).
4.4. General Procedure for the Synthesis of Nitrones 1.
A solution of the corresponding aldehyde (5 mmol) and
hydroxylamine (5 mmol) in dichlorometane (25 mL) was treated
with magnesium sulfate (1 g, 13.3 mmol). The resulting mixture
was stirred at ambient temperature for 4 h, filtrated and the
filtrate evaporated to give the crude nitrone, which was purified
by column chromatography.
1
hydroxylamine (1.9 g, 55%; H NMR (CDCl3, 400 MHz) δ 1.30
(t, 3H), 3.67 (s, 2H), 4.25 (q, 2H), 5.37 (br, 2H)), which is used
in the next step without further purification.
4.4.1. (Z)-N-(2-Ethoxy-2-oxoethyl)-2-methylpropan-1-imine
4.2. General Procedure for the Synthesis of Nitrones 7
oxide 1a
1
A suspension of the corresponding ester hydrochloride (15
mmol) in dichloromethane (25 mL) was treated with
triethylamine (15 mmol); the resulting mixture was stirred
vigorously for 2 h at ambient temperature under an argon
atmosphere. Benzaldehyde (15 mmol) was added and stiring was
maintained for additional 24 h at room temperature. The reaction
mixture was filtered through a pad of Celite® and the filtrate was
evaporated under reduced pressure to give crude imine, which
was taken up in MeOH (20 mL) and treated sequentially with
MgSO4 (1.80 g, 15 mmol), methyl trioxorhenium (0.08 g, 0.28
mmol) and urea-hydrogen peroxide complex (4.25 g, 45 mmol).
The resulting mixture was stirred for 7 h at ambient temperature,
filtered and evaporated under reduced pressure to give the crude
nitrones, which were used in the next step without further
purification.
Eluent: EtOAc. (0.520 g, 60 %); oil; H NMR (CDCl3, 400
MHz) δ 1.15 (d, 6H, J = 6.9 Hz) 1.30 (t, 3H, J = 7.2 Hz) 3.21
(ddd, 1H, J = 6.9, 7.3 Hz), 4.27 (q, 1H, J = 7.2 Hz), 4.50 (s,
2H),6.58 (d, 1H, J = 7.3 Hz); 13C NMR (CDCl3, 100 MHz) δ 18.7
19.2, 20.2, 26.7, 52.8, 66.5, 147.8, 165.9. Anal. Calcd for
C8H15NO3: C, 55.47; H, 8.73; N, 8.09. Found: C, 55.47; H, 8.61;
N, 8.22.
4.4.2. (Z)-N-(2-Ethoxy-2-oxoethyl)-1-phenylmethanimine oxide
1b
Eluent: hexane/EtOAc, 1:1. (0.622 g, 60 %); oil; 1H NMR
(CDCl3, 400 MHz) δ 1.32 (t, 3H), 4.30 (q, 2H), 4.73 (s, 2H),
7.43-7.45 (m, 4H), 8.24-8.27 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ 26.9, 53.0, 67.9, 128.5, 128.9, 130.1, 131.1, 137.4,
166.2. Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76.
Found: C, 63.88; H, 6.48; N, 6.53.
4.2.1. (S,Z)-N-(1-ethoxy-1-oxopropan-2-yl)-1-phenylmethanimine
4.4.3. (Z)-N-(2-Ethoxy-2-oxoethyl)-1-(furan-2-yl)methanimine
oxide 7a
1
oxide 1c
(3.15 g, 95%); white foam. H NMR (CDCl3, 400 MHz) d
Eluent: hexane/EtOAc, 1:1. (0.789 g, 80 %); oil; 1H NMR
1.34 (t, 3H, J = 7.1 Hz), 1.78 (d, 3H, J = 7.0 Hz), 4.29 (q, 2H, J =
(CDCl3, 400 MHz) δ 1.31 (t, 3H), 4.29 (q, 2H), 4.67 (s, 2H), 6.58

ACCEPTED MANUSCRIPT
9
(bs, 1H), 7.51(s, 1H), 7.60 (s, 1H), 7.84 (d, 1H; 13C NMR
(CDCl3, 100 MHz) δ, 14.1, 62.4, 66.4, 112.5, 116.5, 127.8, 144.3,
146.3, 165.4. Anal. Calcd for C9H11NO4: C, 54.82; H, 5.62; N,
7.10. Found: C, 54.91; H, 5.50; N, 6.89.
C15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C, 68.58; H, 8.21;
N, 5.49.
4.4.10. (S,Z)-N-(1-Ethoxy-1-oxo-3-phenylpropan-2-yl)-1-
phenylmethanimine oxide 1l
25
4.4.4. (Z)-2-(Benzyloxy)-N-(2-ethoxy-2-oxoethyl)ethan-1-imine
oxide 1d
Eluent: hexane/EtOAc, 1:1. (1.47 g, 99 %); oil; [α]D -35 (c
1
1.0 CHCl3); H NMR (CDCl3, 400 MHz) δ 1.30 (t, 3H, J = 7.1
Eluent: hexane/EtOAc, 1:1. (1.13 g, 90 %); oil; 1H NMR
(CDCl3, 400 MHz) δ 1.22 (t, 3H, J = 7.14 Hz), 4.18 (q, 2H, J =
7.14 Hz), 4.42-4.44 (m, 4H), 4.49 (s, 2H), 6.90 (t, 1H), 7.22-7.28
(m, 5H); 13C NMR (CDCl3, 100 MHz) δ 13.9, 62.3, 65.6, 65.8,
73.6, 127.8, 127.9, 128.4, 137.1, 140.6, 165.0. Anal. Calcd for
C13H17NO4: C, 62.14; H, 6.82; N, 5.57. Found: C, 62.23; H, 6.73;
N, 5.42.
Hz), 3.41 (dd, 1H, J = 14.2, 4.6 Hz), 3.72 (dd, 1H, J = 14.2, 10.1
Hz), 4.31 (q, 2H, J = 7.1 Hz), 4.70 (dd, 1H, J = 10.1, 4.6 Hz),7.14
(s, 1H), 7.22-7.29 (m, 5H), 7.40-7.44 (m, 3H), 8.16-8.19 (m, 2H);
13C NMR (CDCl3, 100 MHz) δ 25.7, 34.6, 62.2, 78.0, 127.0,
128.5, 128.6, 128.9, 129.1, 130.3, 135.4, 136.3, 146.9, 166.8.
Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C,
72.58; H, 6.63; N, 4.90.
4.4.5. (S,Z)-N-(1-Ethoxy-1-oxopropan-2-yl)-2-methylpropan-1-
imine oxide 1f
25
Eluent: hexane/EtOAc, 1:1. (0.796 g, 85 %); oil; [α]D -27 (c
0.5 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 1.14 (dd, 6H, J = 9.9,
6.9 Hz), 1.28 (t, 3H, J = 7.2 Hz), 1.67 (d, 3H, J = 7.0 Hz), 3.21
(qd, 1H, J = 13.9, 6.9 Hz), 4.24 (q, 2H, J = 7.2 Hz), 4.52 (q, 1H, J
= 7.0 Hz), 6.61 (d, 1H, J = 7.3 Hz); 13C NMR (CDCl3, 100 MHz)
δ 13.9, 15.2, 18.5, 18.8, 25.9, 62.1, 71.6, 145.3, 168.0. Anal.
Calcd for C9H17NO3: C, 57.73; H, 9.15; N, 7.48. Found: C, 57.81;
H, 9.32; N, 7.19.
4.4.6. (S,Z)-N-(1-Ethoxy-1-oxopropan-2-yl)-1-
phenylmethanimine oxide 1g
4.4.12. (S,Z)-2-(Benzyloxy)-N-(1-ethoxy-1-oxo-3-phenylpropan-
25
2-yl)ethan-1-imine oxide 1n
Eluent: hexane/EtOAc, 7:3. (0.863 g, 78 %); oil; [α]D -23 (c
1
25
0.9 CHCl3); H NMR (CDCl3, 400 MHz) δ 1.30 (t, 3H), 1.78 (d,
Eluent: hexane/EtOAc, 7:3. (1.42 g, 83 %); oil; [α]D -39 (c
3H, J = 7.0 Hz) 4.23-4.30 (m, 2H), 4.74 (q, 1H, J = 7.0 Hz), 7.43-
7.44 (m, 3H),7.47 (s, 1H), 8.25-8.27 (m, 2H).; 13C NMR (CDCl3,
100 MHz) δ 14.1, 15.6, 62.3, 73.3, 128.6, 128.9, 130.2, 130.7,
135.0, 168.0 Anal. Calcd for C12H15NO3: C, 65.14; H, 6.83; N,
6.33. Found: C, 64.90; H, 6.93; N, 6.17.
1.0 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 1.21 (t, 3H), 3.22 (dd,
1H, J = 14.2, 4.8 Hz),3.48 (dd, 1H, J = 14.2, 10.6 Hz),4.14-4.24
(m, 2H), 4.27-4.38 (m, 4H), 4.44 (ddd, 1H, J = 10.6, 4.8 Hz),
6.59 (t, 1H), 7.13-7.28 (m, 10H); 13C NMR (CDCl3, 100 MHz) δ
13.9, 34.7, 62.4, 65.5, 73.4, 77.7, 127.2, 1279, 128.4, 128.7,
128.9, 135.9, 137.1, 139.9, 166.3. Anal. Calcd for C20H23NO4: C,
70.36; H, 6.79; N, 4.10. Found: C, 70.19; H, 6.54; N, 4.41.
4.4.7. (S,Z)-N-(1-Ethoxy-1-oxopropan-2-yl)-1-(furan-2-
yl)methanimine oxide 1h
25
4.5. General Procedure for the Cycloaddition Reactions
Eluent: hexane/EtOAc, 7:3. (0.940 g, 89 %); oil; [α]D -36 (c
1
1.0 CHCl3); H NMR (CDCl3, 400 MHz) δ 1.28 (t, 3H, J = 7.2
A solution of nitrone 1 (1 mmol) and the corresponding alkene
(1 mmol) in toluene (15 mL) is place in a sealed tube and heated
at 80 °C for 16 h at which time the solvent was evaporated and
the crude product was purified by column chromatography.
Hz), 1.77 (d, 3H, J = 7.0 Hz), 4.26 (q, 2H, ), 4.72(q, 1H, J = 7.0
Hz), 6.57 (s, 1H,), 7.51 (s, 1H), 7.65 (s, 1H), 7.81 (d, 1H).; 13C
NMR (CDCl3, 100 MHz) δ 13.9, 15.5, 62.3, 71.7, 112.4, 116.2,
125.7, 144.0, 144.1, 146.5, 167.8. Anal. Calcd for C10H13NO4: C,
56.87; H, 6.20; N, 6.63. Found: C, 56.65; H, 6.37; N, 6.85.
4.5.1. Ethyl 2-((3R,5R)-5-((6R,7aR)-8,8-dimethyl-2,2-
dioxidohexahydro-3H-3a,6-methanobenzo[c]isothiazole-1-
carbonyl)-3-isopropylisoxazolidin-2-yl)acetate 3a
4.4.8. (S,Z)-2-(Benzyloxy)-N-(1-ethoxy-1-oxopropan-2-yl)ethan-
1-imine oxide 1i
25
Eluent: hexane/EtOAc, 4:1. (0.221 g, 50%); oil; [α]D -25 (c
25
Eluent: hexane/EtOAc, 1:1. (0.929 g, 70 %); oil; [α]D -8 (c
1
1.0 CHCl3); H NMR (CDCl3, 400 MHz) δ 0.93 (s, 6H), 0.95 (s,
0.65 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 1.21 (t, 3H, J = 7.14
3H), 1.12 (s, 3H), 1.30 (t, 3H), 1.42-1.48 (m, 1H), 1.70-1.78 (m,
1H), 1.79-1.95 (m, 6H), 2.05-2.18 (m, 1H), 2.52 (t, 1H), 2.97 (q,
1H), 3.11 (d, 2H), 3.57 (d, 1H), 3.87-3.98 (m, 2H), 4.18-4.21 (m,
2H), 5.03 (t, 1H; 13C NMR (CDCl3, 100 MHz) δ 13.7, 19.4, 19.9,
20.1, 20.4, 26.3, 29.9, 31.4, 35.6, 37.9, 44.2, 49.9, 52.5, 60.3,
Hz), 1.58 (d, 3H, J = 7.06 Hz), 4.17 (q, 2H, J = 7.14 Hz), 4.44
(dd, 2H), 4.49-4.51 (m, 3H), 6.94 (t, 1H), 7.22-7.30 (m, 5H); 13
C
NMR (CDCl3, 100 MHz) δ 13-9, 15.3, 62.3, 65.8, 71.4, 73.7,
127.9, 128.0, 128.5, 137.1, 137.9, 167.5. Anal. Calcd for
C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.06; H, 7.46;
N, 5.07.
62.4, 64.9, 71.1, 76.5, 168.9, 171.1.
Anal. Calcd for
C21H34N2O6S: C, 56.99; H, 7.74; N, 6.33; S, 7.24. Found: C,
56.84; H, 7.68; N, 6.51; S, 7.45.
4.4.9. (S,Z)-N-(1-Ethoxy-1-oxo-3-phenylpropan-2-yl)-2-
methylpropan-1-imine oxide 1k
4.5.2. Ethyl 2-((3R,5R)-5-((6R,7aR)-8,8-dimethyl-2,2-
dioxidohexahydro-3H-3a,6-methanobenzo[c]isothiazole-1-
carbonyl)-3-phenylisoxazolidin-2-yl)acetate 3b
25
Eluent: hexane/EtOAc, 2:1. (1.15 g, 87 %); oil; [α]D -66 (c
1
0.5 CHCl3); H NMR (CDCl3, 400 MHz) δ 0.86 (d, 3H, J = 6.9
Hz), 1.03 (d, 3H, J= 6.9 Hz), 1.29 (t, 3H, J = 7.1 Hz), 3.08 (qd,
1H, J = 13.9, 6.9 Hz), 3.25 (dd, 1H, J = 14.2, 4.2 Hz), 3.59 (dd,
1H, J = 14.2, 10.8 Hz), 4.26 (q, 2H, J = 7.1 Hz), 4.40 (dd, 1H, J =
10.8, 4.2 Hz), 6.20 (d, 1H, J = 7.3 Hz), 7.21-7.30 (m, 5H); 13C
NMR (CDCl3, 100 MHz) δ 13.9, 18.5, 18.7, 25.7, 34.6, 62.2,
78.0, 127.0, 128.6, 129.1, 136.3, 146.9, 166.8. Anal. Calcd for
25
Eluent: hexane/EtOAc, 9:1. (0.291g, 61%); oil; [α]D -35 (c
0.75 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 0.97 (s, 3H), 1.15 (s,
3H), 1.22 (t, 3H, J = 7.1 Hz), 1.36-1.44 (m, 2H), 1.89-1.93 (m,
3H), 2.10 (dd, 1H, J = 13.8, 7.9 Hz), 2.18-2.24 (m, 1H), 2.80-
2.84 (m, 2H), 3.45 (q, 2H, J = 13.8 Hz), 3.56 (d, 1H, J = 16.5

ACCEPTED MANUSCRIPT
10
Hz), 3.78 (d, 1H, J = 16.5 Hz), 3.92 (dd, 1H, J = 7.9, 5.0 Hz),
4.08-4.18 (m, 3H), 5.31 (t, 1H), 7.28-7.43 (m, 5H); 13C NMR
(CDCl3, 100 MHz) δ 14-1, 19.9, 20.8, 26.4, 32.9, 38.4, 44.6,
47.8, 49.0, 532.9, 57.9, 60.8, 65.6, 69.2, 75.9, 127.8, 128.2,
128.7, 136.9, 169.1, 170.8. Anal. Calcd for C24H32N2O6S: C,
60.48; H, 6.77; N, 5.88; S, 6.73. Found: C, 60.52; H, 6.84; N,
5.72; S, 6.90.
C13H23NO5: C, 57.13; H, 8.48; N, 5.12;. Found: C, 57.28; H,
8.36; N, 5.27.
4.5.7. Methyl (3R,5R)-2-((S)-1-ethoxy-1-oxopropan-2-yl)-3-
phenylisoxazolidine-5-carboxylate 3g
25
Eluent: hexane/EtOAc, 9:1. (0.209 g, 68%); oil; [α]D +11 (c
1
1.0 CHCl3); H NMR (CDCl3, 400 MHz) δ 1.09 (t, 3H), 1.34 (d,
3H, J = 6.7 Hz), 2.63 (ddd, 1H, J = 12.7, 8.9, 7.0 Hz), 2.74 (ddd,
1H, J = 12.7, 7.2, 5.6 Hz), 3.63 (q, 1H, J = 6.7 Hz), 3.71 (s, 3H),
3.82-3.91 (m, 2H), 4.25 (t, 1H, J = 7.1 Hz), 4.61 (dd, 1H, J = 8.9,
5.6 Hz), 7.21-7.27 (m, 3H), 7.32-7.34 (m, 2H); 13C NMR (CDCl3,
100 MHz) δ 13.9, 14.4, 42.5, 52.4, 60.8, 63.1, 66.4, 75.2, 127.6,
127.9, 128.6, 138.9, 171.7, 172.1. Anal. Calcd for C16H21NO5: C,
62.53; H, 6.89; N, 4.56. Found: C, 62.47; H, 6.79; N, 4.63.
4.5.3. Ethyl 2-((3R,5R)-5-((6R,7aR)-8,8-dimethyl-2,2-
dioxidohexahydro-3H-3a,6-methanobenzo[c]isothiazole-1-
carbonyl)-3-(furan-2-yl)isoxazolidin-2-yl)acetate 3c
25
Eluent: hexane/EtOAc, 9:1. (0.373 g, 80%); oil; [α]D -31 (c
1
1.0 CHCl3); H NMR (CDCl3, 400 MHz) δ 0.97 (s, 3H), 1.15 (s,
3H), 1.25 (t, 3H, J = 7.1 Hz), 1.33-1.42 (m, 2H), 1.85-1.97 (m,
3H), 2.04-2.11 (m, 1H,), 2.15-2.21 (m, 1H), 2.73-2.83 (m, 1H),
2.97-3.05 (m, 1H), 3.47 (q, 2H, J = 13.7 Hz), 3.68- 3.77 (m, 1H),
3.91 (dd, 1H, J = 7.7, 5.0 Hz), 4.17 (q, 1H, J = 7.1 Hz), 4.32-4.36
(m, 1H), 5.29 (dd, 1H, J = 8.7, 4.8 Hz), 6.31-6.34 (m, 2H), 7.38-
7.39 (m, 1H).; 13C NMR (CDCl3, 100 MHz) δ 14.2, 19.9, 20.8,
26.5, 29.7, 32.9, 38.3, 44.7, 47.9, 48.9, 53.0, 60.9, 65.5, 76.0,
108.8, 110.4, 142.8, 149.9, 168.7, 170.7. Anal. Calcd for
C22H30N2O7S: C, 56.64; H, 6.48; N, 6.00; S, 6.87. Found: C,
56.73; H, 6.52; N, 5.84; S, 6.99.
4.5.8. Methyl (3R,5R)-2-((S)-1-ethoxy-1-oxopropan-2-yl)-3-
(furan-2-yl)isoxazolidine-5-carboxylate 3h
25
Eluent: hexane/EtOAc, 9:1. (0.184 g, 62%); oil; [α]D -2 (c
1
0.5 CHCl3); H NMR (CDCl3, 400 MHz) δ 1.24 (t, 3H), 1.44 (d,
3H, J = 6.7 Hz), 2.74-2.80 (m, 2H), 2.89 (ddd, 1H, J = 13.5, 8.8,
4.8 Hz), 3.57-3.60 (m, 1H), 3.78 (s, 3H), 4.11 (q, 2H), 4.50 (dd,
1H, J = 7.4, 4.9 Hz), 4.74 (dd, 1H, J = 8.6, 6.8 Hz), 6.28 (d, 1H),
6.32-6.33 (m, 1H), 7.38-7.39 (m, 1H); 13C NMR (CDCl3, 100
MHz) δ 14.1, 15.3, 38.7, 51.9, 52.4, 60.9, 74.8, 75.1, 108.5,
110.3, 142.5, 151.2, 171.8, 171.9.. Anal. Calcd for C14H19NO6:
C, 56.56; H, 6.44; N, 4.71. Found: C, 56.72; H, 6.39; N, 4.90.
4.5.4. Ethyl 2-((3R,5R)-3-((benzyloxy)methyl)-5-((6R,7aR)-8,8-
dimethyl-2,2-dioxidohexahydro-3H-3a,6-methanobenzo-
[c]isothiazole-1-carbonyl)isoxazolidin-2-yl)acetate 3d
25
4.5.9. Methyl (3R,5R)-3-((benzyloxy)methyl)-2-((S)-1-ethoxy-1-
Eluent: hexane/EtOAc, 7:3. (0.417 g, 80%); oil; [α]D -52 (c
oxopropan-2-yl)isoxazolidine-5-carboxylate 3i
1
1.0 CHCl3); H NMR (CDCl3, 400 MHz) δ 0.96 (s, 3H), 1.13 (s,
25
Eluent: hexane/EtOAc, 5:1. (0.169 g, 48%); oil; [α]D -23 (c
3H), 1.26 (t, 3H, J = 7.1 Hz), 1.34-1.43 (m, 2H), 1.87-1.92 (m,
3H), 1.98-2.09 (m, 1H), 2.13-2.19 (m, 1H), 2.54-2.58 (m, 2H),
3.39-3.51 (m, 3H), 3.53-3.63 (m, 2H), 3.85-3.97 (m, 3H), 4.20 (q,
2H, J = 7.1 Hz), 4.52 (q, 2H), 5.10 (t, 1H), 7.26-7.36 (m, 5H0;
13C NMR (CDCl3, 100 MHz) δ 14.2, 19.8, 20.8, 26.4, 32.9, 36.4,
38.3, 44.6, 47.8, 48.9, 52.9, 59.9, 60.7, 64.7, 65.4, 70.8, 73.3,
76.2, 127.6, 127.7, 128.4, 137.8, 169.3, 171.0. Anal. Calcd for
C26H36N2O7S: C, 59.98; H, 6.97; N, 5.38; S, 6.16. Found: C,
60.12; H, 6.77; N, 5.48; S, 6.33.
1
1.0 CHCl3); H NMR (CDCl3, 400 MHz) δ 1.25 (t, 3H), 1.48 (d,
3H, J= 6.7 Hz), 2.51 (ddd, 1H, J = 12.4, 7.5 Hz), 2.62 (ddd, 1H, J
= 12.4, 8.6 Hz), 3.39 (dd, 1H, J= 9.0, 7.2 Hz), 3.58-3.66 (m, 2H),
3.73-3.76(m, 4H), 4.12-4.24 (m, 2H), 4.49-4.56 (m, 3H), 7.28-
7.37 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 14.0, 16.4, 35.6,
52.2, 60.6, 61.0, 63.7, 71.2, 73.3, 75.9, 127.6, 128.3, 128.7,
130.7, 137.7, 171.5, 172.1. Anal. Calcd for C18H25NO6: C, 61.52;
H, 7.17; N, 3.99. Found: C, 61.48; H, 6.95; N, 4.13.
4.5.10. Methyl (3R,5R)-3-(((tert-butoxycarbonyl)amino)methyl)-
4.5.5. Ethyl 2-((3R,5R)-3-(((tert-butoxycarbonyl)amino)methyl)-
5-((6R,7aR)-8,8-dimethyl-2,2-dioxidohexahydro-3H-3a,6-meth-
anobenzo[c]isothiazole-1-carbonyl)isoxazolidin-2-yl)acetate 3e
2-((S)-1-ethoxy-1-oxopropan-2-yl)isoxazolidine-5-carboxylate 3j
Eluent: hexane/EtOAc, 95:5. (0.130 g, 36%); oil; [α]D25 -21 (c
1
25
1.0 CHCl3); H NMR (CDCl3, 400 MHz) δ 1.27 (t, 3H, J = 7.1
Eluent: hexane/EtOAc, 3:2. (0.444 g, 75%); oil; [α]D -73 (c
1
Hz), 1.41 (s, 9H), 1.49 (d, 3H, J = 6.6 Hz), 2.34 (ddd, 1H, J =
13.1, 8.9 Hz), 2.58 (ddd, 1H, J = 13.1, 7.8 Hz), 2.97-3.03 (m, 1H)
3.18-3.24 (m, 1H), 3.43-3.49 (m, 1H), 3.60 (q, 1H, J = 6.6 Hz),
3.74 (s, 3H) 4.18 (q, 2H, J = 7.1 Hz), 4.52 (t, 1H, J = 8.5 Hz) 5.23
(bs, 1H).; 13C NMR (CDCl3, 100 MHz) δ 14.1, 16.6, 28.4, 29.7,
35-0, 43.0, 52.4, 61.1, 63.9, 64.3, 77.3, 81.5, 158.2, 172.1, 172.5.
Anal. Calcd for C16H28N2O7: C, 53.32; H, 7.83; N, 7.77. Found:
C, 53.48; H, 7.91; N, 7.85.
1.0 CHCl3); H NMR (CDCl3, 400 MHz) δ 0.96 (s, 3H), 1.13 (s,
3H),1.27 (t, 3H, J = 6.9 Hz), 1.33-1.40 (m, 2H), 1.42 (s, 9H),
1.87-1.92 (m, 3H), 2.02-2.12 (m, 2H), 2.43-2.49 (m, 1H), 2.65
(dt, 1H, J = 7.1, 13.7 Hz), 3.08-3.15 (m, 1H), 3.19-3.25 (m, 1H),
3.41 (d, 1H, J = 13.8 Hz), 3.44-3.47 (m, 1H), 3.50 (d, 1H, J =
13.8 Hz) 3.56 (d, 1H, J = 16.5 Hz), 3.88 (dd, 1H), 3.96 (d, 1H, J
= 16.5 Hz), 4.20 (q, 2H, J = 6.9 Hz), 5.05 (dd, 1H, J = 7.1, 8.0
Hz), 5.20 (bs, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.1, 19.9,
20.9, 26.4, 28.4, 32.9, 38.2, 40.1, 42.2, 44.7, 47.8, 48.9, 52.9,
59.5, 60.9, 71.5, 77.5, 79.4, 85.5, 156.6, 168.9, 171.1. Anal.
Calcd for C24H39N3O8S: C, 54.43; H, 7.42; N, 7.93; S, 6.05.
Found: C, 54.49; H, 7.52; N, 7.96; S, 6.19.
4.5.11. Methyl (3R,5R)-2-((S)-1-ethoxy-1-oxo-3-phenylpropan-2-
yl)-3-isopropylisoxazolidine-5-carboxylate 3k
25
Eluent: hexane/EtOAc, 4:1. (0.175 g, 50%); oil; [α]D -15 (c
1
0.75 CHCl3); H NMR (CDCl3, 400 MHz) δ 0.92 (d, 3H, J = 6.7
Hz), 0.98 (d, 3H, J = 6.7 Hz) 1.06 (t, 3H, J = 7.1Hz), 1.68 (dt,
1H, J = 13.6, 6.8 Hz), 2.49-2.56 (m, 2H), 2.98-3.02 (m, 1H), 3.08
(dd, 1H, J = 13.1, 10.6 Hz), 3.58 (dd, 1H, J = 13.1, 4.3 Hz), 3.80
(s, 3H), 3.85 (q, 1H, J = 10.6, 4.3 Hz), 3.98 (q, 1H, J = 7.1 Hz),
4.56 (t, 1H, J = 8.4 Hz), 7.16-7.26 (m, 5H); 13C NMR (CDCl3,
100 MHz) δ 13.7, 18.9, 19.8, 30.5, 34.0, 36.9, 52.2, 60.5, 70.4,
71.9, 77.4, 126.2, 128.1, 129.2, 137.2, 170.4, 172.9. Anal. Calcd
for C19H27NO5: C, 65.31; H, 7.79; N, 4.01. Found: C, 65.22; H,
7.68; N, 4.26.
4.5.6. Methyl (3R,5R)-2-((S)-1-ethoxy-1-oxopropan-2-yl)-3-
isopropylisoxazolidine-5-carboxylate 3f
25
Eluent: hexane/EtOAc, 9:1. (0.109 g, 40%); oil; [α]D -21 (c
1
0.5 CHCl3); H NMR (CDCl3, 400 MHz) δ 0.92 (d, 3H, J = 6.8
Hz), 0.98 (d, 3H, J = 6.7 Hz) 1.27 (t, 3H, J = 7.1 Hz), 1.48 (d, 3H,
J = 6.6 Hz), 1.70 (qd, 1H, J = 13.7, 6.8 Hz), 2.47 (ddd, 2H, J =
8.5, 4.7 Hz), 3.05 (ddd, 1H, J = 7.2, 6.8 Hz), 3.61 (q, 1H, J = 6.6
Hz), 3.65 (s, 3H), 4.17 (q, 2H, J = 7.1Hz), 4.48 (t, 1H, J = 8.5
Hz);; 13C NMR (CDCl3, 100 MHz) δ 14.1, 16.0, 18.7, 20.1, 30.8,
33.9, 52.2, 60.8, 64.5, 70.1, 77.2, 172.3, 172.9. Anal. Calcd for

ACCEPTED MANUSCRIPT
11
4.5.12. Methyl (3R,5R)-2-((S)-1-ethoxy-1-oxo-3-phenylpropan-2-
yl)-3-phenylisoxazolidine-5-carboxylate 3l
4.6.1. ethyl 2-((3R,5R)-5-(((tert-butoxycarbonyl)amino)methyl)-
3-hydroxy-2-oxopyrrolidin-1-yl)acetate 10a
25
25
Eluent: hexane/EtOAc, 9:1. (0.280 g, 73%); oil; [α]D +36 (c
Eluent: EtOAc. (0.220 g, 93%); oil; [α]D +59 (c 0.9 CHCl3);
1H NMR (CDCl3, 400 MHz) δ 1.27 (t, 3H, J = 7.0 Hz), 1.42 (s,
9H),1.77 (dt, 1H, J = 7.2, 13.4 Hz), 2.52 (ddd, 1H, J = 7.2, 8.5,
13.4 Hz), 3.30-3.41 (m, 2H), 3.77-3.83 (m, 1H), 3.98 (m, 1H),
4.16-4.22 (m, 2H), 4.37 (q, 2H, J = 7.0 Hz), 5.27 (bs, 2H, ex.
D2O); 13C NMR (CDCl3, 100 MHz) δ 13.9, 28.4, 30.8, 41.1, 42.6,
55.2, 61.7, 68.9, 79.8, 156.2, 168.8, 175.9 Anal. Calcd for
C14H24N2O6: C, 53.15; H, 7.65; N, 8.86. Found: C, 53.09; H,
7.51; N, 8.96.
1
0.9 CHCl3); H NMR (CDCl3, 400 MHz) δ 0.96 (t, 3H), 2.73
(ddd, 1H, J = 13.0, 8.7, 6.5 Hz), 2.85 (ddd, 1H, J = 13.0, 7.2, 5.9
Hz), 3.05 (dd, 1H, J = 13.3, 10.5 Hz), 3.37 (dd, 1H, J = 13.3, 4.3
Hz), 3.74-3.78 (m, 2H), 3.82 (s, 3H), 3.92 (dd, 1H, J = 10.5, 4.3
Hz), 4.40 (t, 1H), 4.70 (dd, 1H, J = 8.7, 5.9 Hz), 7.13-7.41 (m,
10H); 13C NMR (CDCl3, 100 MHz) δ 13.8, 36.2, 42.6, 52.4, 60.6,
66.6, 70.9, 75.9, 126.5, 127.5, 127.8, 128.3, 128.5, 129.3, 137.2,
138.9, 170.2, 172.1. Anal. Calcd for C22H25NO5: C, 68.91; H,
6.57; N, 3.65. Found: C, 69.02; H, 6.47; N, 3.56.
4.6.2. Ethyl (S)-2-((3R,5R)-3-hydroxy-5-isopropyl-2-
oxopyrrolidin-1-yl)-3-phenylpropanoate 10b
4.5.13. Methyl (3R,5R)-2-((S)-1-ethoxy-1-oxo-3-phenylpropan-2-
25
yl)-3-(furan-2-yl)isoxazolidine-5-carboxylate 3m
Eluent: hexane/EtOAc, 4:1. (0.228 g, 95%); oil; [α]D +10 (c
25
1
Eluent: hexane/EtOAc, 9:1. (0.258 g, 69%); oil; [α]D +2 (c
1.0 CHCl3); H NMR (CDCl3, 400 MHz) δ 0.89 (d, 3H, J = 6.8
1
1.0 CH2Cl2); H NMR (CDCl3, 400 MHz) δ 1.01 (t, 3H, J = 7.1
Hz), 0.96 (d, 3H, J = 6.7 Hz), 1.27 (t, 3H, J = 7.2 Hz), 1.33 (d,
3H, J=7.0 Hz), 1.75-1.89 (m, 3H), 2.51 (ddd, 1H, J = 7.4, 6.1
Hz), 3.45 (q, 1H, J = 7.0 Hz), 4.18 (q, 1H, J = 7.2 Hz), 4.53 (dd,
1H, J = 7.4, 3.5 Hz); 13C NMR (CDCl3, 100 MHz) δ 14.1, 17.0,
19.5, 19.9, 29.0, 30.9, 54.2, 60.9, 61.0, 70.2, 174.8, 175.2. Anal.
Calcd for C18H25NO4: C, 67.69; H, 7.89; N, 4.39. Found: C,
67.49; H, 7.74; N, 4.50.
Hz), 2.80 (ddd, 1H, J =13.1, 7.5, 7.0 Hz), 2.91 (ddd, 1H, J = 13.1,
8.7, 4.6 Hz), 3.05 (dd, 1H, J = 13.1, 10.8 Hz), 3.34 (dd, 1H, J =
13.1, 4.2 Hz), 3.73-3.76 (m, 1H), 3.81 (s, 3H), 3.93 (q, 1H, J =
7.1 Hz), 4.58 (dd, 1H, J = 7.5, 4.6 Hz), 4.77 (dd, 1H, J = 8.7, 7.0
Hz), 6.29 (d, 1H, J = 3.2 Hz), 6.34 (dd, 1H, J = 1.9 Hz, J = 3.2
Hz), 7.13-7.24 (m, 5H), 7.41-7.42 (m, 1H); 13C NMR (CDCl3,
100 MHz) δ 13.7, 36.6, 38.2, 52.4, 60.1, 60.7, 70.3, 75.9, 108.6,
110.5, 126.5, 128.2, 129.1, 136.9, 142.8, 151.3, 170.5, 172.0.
Anal. Calcd for C20H23NO6: C, 64.33; H, 6.21; N, 3.75. Found: C,
64.29; H, 6.18; N, 3.90.
4.6.3. Ethyl (S)-2-((3R,5R)-3-hydroxy-5-isopropyl-2-
oxopyrrolidin-1-yl)propanoate 10c
25
Eluent: hexane/EtOAc, 4:1. (0.173 g, 95%); oil; [α]D -2 (c
1
0.5 CHCl3); H NMR (CDCl3, 400 MHz) δ 0.85 (d, 3H, J = 6.8
4.5.14. Methyl (3R,5R)-3-((benzyloxy)methyl)-2-((S)-1-ethoxy-1-
Hz), 0.88 (d, 3H, J = 6.7 Hz), 1.11 (t, 3H, J = 7.1 Hz), 1.69-1.83
(m, 3H), 2.48 (ddd, 1H, J = 7.4, 6.1, 3.0 Hz), 2.89 (dd, 1H, J =
13.4, 7.7 Hz), 3.02 (dd, 1H, J = 13.4, 6.0 Hz), 3.61 (dd, 1H, J =
7.7, 6.0 Hz), 4.04 (q, 2H, J = 7.1 Hz), 4.43 (dd, 1H, J = 8.0, 3.4
Hz), 7.14-7.29 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 13.9,
17.0, 19.8, 29.5, 31.4, 40.6, 60.8, 61.1, 61.4, 69.7, 126.7, 128.3,
129.2, 136.6, 174.5, 174.9. Anal. Calcd for C12H21NO4: C, 59.24;
H, 8.70; N, 5.76. Found: C, 59.37; H, 8.58; N, 5.83
oxo-3-phenylpropan-2-yl)isoxazolidine-5-carboxylate 3n
25
Eluent: hexane/EtOAc, 7:3. (0.197 g, 46%); oil; [α]D +9 (c
1
1.0 CHCl3); H NMR (CDCl3, 400 MHz) δ 0.94 (t, 3H), 2.49
(ddd, 1H, J = 12.8, 7.7 Hz), 2.61 (ddd, 1H, J = 12.8, 8.7 Hz), 2.99
(dd, 1H, J = 13.2, 10.5 Hz), 3.31 (dd, 1H, J = 9.4, 7.8 Hz),3.45
(dd, 1H, J = 13.2, 4.3 Hz), 3.51 (dd, 1H, J = 9.4, 5.5 Hz) 3.59
(ddd, 1H, J = 7.8, 5.5 Hz), 3.73 (s, 3H), 3.83-3.94 (m, 3H), 4.46
(d, 2H), 4.51 (t, 1H), 7.10, 7.29 (m, 10H); 13C NMR (CDCl3, 100
MHz) δ 13.9, 34.9, 36.8, 52.4, 60.8, 63.3, 70.8, 71.1, 73.4, 76.7,
126.5, 127.7, 128.2, 128.4, 129.4, 137.1, 137.9, 170.6, 172.6.
Anal. Calcd for C24H29NO6: C, 67.43; H, 6.84; N, 3.28. Found: C,
67.36; H, 6.94; N, 3.11.
4.7. General Procedure for the Synthesis of Mosher Esters 11
and 12
To a solution of the pyrrolidin-2-one (0.5 mmol) in anhydrous
dichloromethane (15 mL), the corresponding Mosher acid (1.24
mmol), DCC (0.309 g, 1.5 mmol) and DMAP (12 mg, 0.1 mmol)
are sequentially added. The resulting mixture is stirred at ambient
temperature for 12 h at which time the solvent is eliminated
under reduced pressure. The crude product is purified by column
chromatography to provide the pure Mosher ester.
4.5.15. Methyl (3R,5R)-3-(((tert-butoxycarbonyl)amino)methyl)-
2-((S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl)isoxazolidine-5-
carboxylate 3o
25
Eluent: hexane/EtOAc, 9:1. (0.201 g, 46%); oil; [α]D -7 (c
1
0.25 CHCl3); H NMR (CDCl3, 400 MHz) δ 1.05 (t, 3H, J = 7.1
Hz), 1.43 (s, 9H), 2.42 (ddd, 1H, J = 13.2, 9.0 Hz), 2.64 (ddd, 1H,
J = 13.2, 7.8 Hz), 2.96-3.02 (m, 1H), 3.07 (dd, 1H, J = 13.3 10.3
Hz), 3.23-3.29 (m, 1H), 3.45-3.49 (m, 1H), 3.57 (dd, 1H, J =
13.3, 4.3 Hz), 3.81 (s, 3H), 3.83 (dd, 1H, J = 10.3, 4.3 Hz), 3.97
(q, 2H, J = 7.1 Hz), 4.61 (t, 1H, J = 8.5 Hz), 5.15 (bs, 1H), 7.18-
7.26 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 13.6, 28.1, 37.1,
42.6, 52.3, 60.6, 64.1, 71.0, 77.3, 78.6, 126.3, 128.0, 129.1,
136.7, 155.5, 170.1, 172.8. Anal. Calcd for C22H32N2O7: C,
60.54; H, 7.39; N, 6.42. Found: C, 60.67; H, 7.26; N, 6.51.
4.7.1. (3R,5R)-5-(((tert-butoxycarbonyl)amino)methyl)-1-(2-
ethoxy-2-oxoethyl)-2-oxopyrrolidin-3-yl (R)-3,3,3-trifluoro-2-
methoxy-2-phenylpropanoate 11a
25
Eluent: hexane/EtOAc, 7:3. (0.186 g, 70%); oil; [α]D +22 (c
1
0.5 CHCl3); H NMR (CDCl3, 400 MHz) δ 1.27 (t, 3H), 1.38 (s
,9H), 2.33-2.36 (m, 1H), 2.63 (ddd, 1H, J= 13.8, 8.8, 7.3 Hz),
3.15-3.19 (m, 1H), 3.30-3.35 (m, 1H), 3.64 (s, 3H), 3.82-3.87 (m,
1H), 4.04 (d, 1H), 4.17 (d, 1H), 4.18-4.23 (m, 2H), 4.82 (bs, 1H),
5.66 (dd, 1H, J = 8.8, 7.2 Hz), 7.40-7.42 (m, 3H), 7.59-7.61 (m,
2H).; 13C NMR (CDCl3, 100 MHz) δ 14.2, 28.0, 28.4, 29.8, 41.5,
43.3, 55.4, 55.9, 61.9, 71.2, 80.2, 83.2, 121.6, 124.5, 127.3,
128.7, 129.7, 131.4, 156.3, 165.9, 168.6, 170.2. Anal. Calcd for
C24H31F3N2O8: C, 54.13; H, 5.87; F, 10.70; N, 5.26. Found: C,
54.34; H, 5.69; N, 5.36.
4.6. General Procedure for the Synthesis of 3-hydroxypyrrolidin-
2-ones 10
A solution of cycloadduct (0.75 mmol) in ethanol (12 mL) is
treated with Pd(OH)2-C (28 mg, 0.19 mmol) and stirred at
ambient temperature for 48 h under a pressure of 100 atm of
hydrogen. The reaction mixture is filtered and the solvent
evaporated to afford the crude product which was purified by
column chromatography.
4.7.2. (3R,5R)-1-((S)-1-ethoxy-1-oxopropan-2-yl)-5-isopropyl-2-
oxopyrrolidin-3-yl (R)-3,3,3-trifluoro-2-methoxy-2-
phenylpropanoate 11b

ACCEPTED MANUSCRIPT
12
25
Eluent: hexane/EtOAc, 7:3. (0.156 g, 68%); oil; [α]D +32 (c
1H, J = 13.7, 7.0 Hz), 1.89 (dtd, 1H, J = 6.9, 6.7, 3.4 Hz), 2.11
(ddd, 1H, J = 13.7,9.3 Hz), 2.37 (ddd, 1H, J = 7.0, 3.4 Hz), 3.31-
3.41 (m, 2H), 3.52 (s, 3H), 3.98 (dd, 1H, J = 9.7, 6.3 Hz), 4.12-
4.24 (m, 2H), 5.49 (dd, 1H, J = 9.3, 7.0 Hz), 7.17-7.19 (m, 2H),
7.27-7.33 (m, 3H), 7.40-7.41 (m, 3H), 7.58- 7.61 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ 13.9, 18.6, 25.2, 27.7, 34.2, 55.4,
57.4, 61.4, 61.6, 71.4, 127.0, 127.8, 128.4, 128.7, 129.0, 129.6,
131.4, 137.7, 165.9, 168.9, 169.1. Anal. Calcd for C28H32F3NO6:
C, 62.80; H, 6.02; F, 10.64; N, 2.62. Found: C, 62.97; H, 5.95; N,
2.69.
1
1.0 CHCl3); H NMR (CDCl3, 400 MHz) δ 0.69 (d, 3H, J = 6.7
Hz), 0.86 (d, 3H, J = 6.9 Hz), 1.21 (t, 3H, J = 7.1 Hz), 1.43 (d,
3H, J = 7.2 Hz), 1.67 (ddd, 1H, J = 13.9, 6.4 Hz), 2.05 (dtd, 1H, J
= 6.9, 6.7, 3.4 Hz), 2.44 (ddd, 1H, J = 13.9, 9.4, 7.6 Hz), 3.62 (s,
3H), 3.66 (ddd, 1H, J = 7.6, 6.4, 3.4 Hz), 4.16- 4.27 (m, 3H), 5.59
(dd, 1H, J = 9.4, 6.4 Hz), 7.39-7.41 (m, 3H), 7.58-7.61 (m, 2H).;
13C NMR (CDCl3, 100 MHz) δ 13.6, 13.9, 14.6, 18.7, 24.8, 28.2,
50.9, 55.7, 59.9, 61.5, 71.1, 124.6, 127.3, 128.4, 129.6, 132.0,
165.9, 169.4, 170.0. Anal. Calcd for C22H28F3NO6: C, 57.51; H,
6.14; F, 12.40; N, 3.05. Found: C, 57.78; H, 5.95; N, 3.19.
Acknowledgments
4.7.3. (3R,5R)-1-((S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl)-5-
isopropyl-2-oxopyrrolidin-3-yl (R)-3,3,3-trifluoro-2-methoxy-2-
phenylpropanoate 11c
This study was supported by the Ministerio de Ciencia e
Innovación (MICINN) and FEDER Program (Madrid, Spain,
projects CTQ2010-19606 and BFU2010-19504) and the
Gobierno de Aragón (Zaragoza, Spain. Bioorganic Chemistry
Group. E-10). We thank MIUR (Italy) and CNMPS (Italy) for
their financial support. G.C. thanks MICINN for a contract and
University of Palermo for a pre-doctoral grant. We also
acknowledge the Institute of Biocomputation and Physics of
Complex Systems (BIFI) at the University of Zaragoza for
computer time (Terminus, Memento and CesAr clusters).
25
Eluent: hexane/EtOAc, 7:3. (0.193 g, 72%); oil; [α]D -36 (c
1
0.6 CHCl3); H NMR (CDCl3, 400 MHz) δ 0.62 (d, 3H, J = 6.9
Hz), 0.66 (d, 3H, J= 6.7 Hz), 1.20 (t, 3H, J = 7.1 Hz), 1.50 (ddd,
1H, J = 13.7, 6.4 Hz), 1.83 (dtd, 1H, J = 6.8, 6.7, 3.5 Hz), 2.04
(ddd, 1H, J = 13.7, 9.2, 7.5 Hz), 2.36 (ddd, 1H, J = 7.5, 6.4, 3.5
Hz), 3.33-3.42 (m, 2H), 3.63 (s, 3H),3.97 (dd, 1H, J = 10.1, 5.8
Hz), 4.15-4.26 (m, 2H), 5.49 (dd, 1H, J = 9.2, 6.4 Hz), 7.17-7.19
(m, 2H), 7.27-7.33 (m, 3H), 7.38-7.40 (m, 3H), 7.58- 7.61 (m,
2H).; 13C NMR (CDCl3, 100 MHz) δ 13.7, 13.9, 18.6, 25.1, 27.7,
34.2, 55.7, 57.5, 61.6, 61.8, 71.0, 127.0, 127.3, 128.4, 128.7,
129.0, 129.6, 132.0, 137.7, 166.0, 168.9, 169.1. Anal. Calcd for
C28H32F3NO6: C, 62.80; H, 6.02; F, 10.64; N, 2.62. Found: C,
62.99; H, 5.92; N, 2.75.
5. References
1. Martin, J. N.; Jones, R. C. F. In Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry toward Heterocycles and
Natural Products; Padwa, A., Pearson, W. H., Eds.; Wiley:
Chichester, 2002. pp. 1-81
4.7.4. (3R,5R)-5-(((tert-butoxycarbonyl)amino)methyl)-1-(2-
ethoxy-2-oxoethyl)-2-oxopyrrolidin-3-yl (S)-3,3,3-trifluoro-2-
methoxy-2-phenylpropanoate 12a
2. (a) Merino, P. In Science of Synthesis, Knowldedge Updates
Schaumann, E. (Ed.), George Thieme, Stuttgart, 2011, vol.
2010/4, pp. 325-403. (b) Merino, P. In Science of Synthesis
Bellus, D.; Padwa, A. (Eds.), George Thieme, Stuttgart, 2004, vol.
27, pp. 511-580. (c) Bokach, N. A.; Kuznetsov, M. L.; Kukushkin,
V. Y. Coord. Chem. Rev. 2011, 255, 2946-2967. (d) De March, P.;
Figueredo, M.; Font, J. Heterocycles 1999, 50, 1213-1226. (e)
Confalone, P. N.; Huie, E. M. Org. React. (N.Y.) 1988, 36, 1-136.
3. (a) Frederickson, M. Tetrahedron 1997, 53, 403-425. (b) Hay, M.
B.; Wolfe, J. P. Angew. Chem. Int. Ed. 2007, 46, 6492-6494. (c)
Pellisier, H. Tetrahedron 2007, 63, 3235-3285.
4. (a) Merino, P.; Anoro, S.; Franco, S.; Merchan, F. L.; Tejero, T.;
Tuñon, V. J. Org. Chem. 2000, 65, 1590-1596. (b) Merino, P.;
Anoro, S.; Merchan, F.; Tejero, T. Heterocycles 2000, 53, 861-
875. (d) Merino, P.; Franco, S.; Merchan, F. L.; Romero, P.;
Tejero, T.; Uriel, S. Tetrahedron: Asymmetry 2003, 14, 3731-
3743.
5. (a) Gothelf, K. V.; Jorgensen, K. A. J. Chem. Soc., Chem.
Commun. 2000, 1449-1458. (b) Gothelf, K. V.; Jorgensen, K. A.
Chem. Rev. 1998, 98, 863-909.
6. (a) Kanemasa, S. Synlett 2002, 1371-1387. (b) Carmona, D.;
Lamata, M. P.; Viguri, F.; Rodriguez, R.; Oro, L. A.; Lahoz, F. J.;
Balana, A. I.; Tejero, T.; Merino, P. J. Am. Chem. Soc. 2005, 127,
13386-13398. (c) Carmona, D.; Lamata, M. P.; Viguri, F.;
Rodriguez, R.; Oro, L. A.; Balana, A. I.; Lahoz, F. J.; Tejero, T.;
Merino, P.; Franco, S.; Montesa, I. J. Am. Chem. Soc. 2004, 126,
2716-2717.
25
Eluent: hexane/EtOAc, 7:3. (0.186 g, 70%); oil; [α]D +24 (c
1
0.5 CHCl3); H NMR (CDCl3, 400 MHz) δ 1.27 (t, 3H), 1.42 (s,
9H), 1.94 (ddd, 1H, J = 13.8, 7.7 Hz), 2.67 (ddd, 1H, J= 13.6, 9.0,
7.3 Hz), 3.25-3.29 (m, 1H), 3.42-3.48 (m, 1H), 3.54 (s, 3H),
3.84-3.89 (m, 1H), 4.02 (d, 1H), 4.12-4.23 (m, 3H), 5.10 (bs,
1H), 5.56 (dd, 1H, J = 9.0, 8.2 Hz), 7.40-7.42 (m, 3H), 7.58-7.60
(m, 2H); 13C NMR (CDCl3, 100 MHz) δ 14.0, 28.0, 28.2, 29.7,
41.2, 43.1, 55.1, 55.5, 61.8, 71.6, 80.0, 121.6, 124.5, 127.7,
128.4, 129.7, 131.4, 156.3, 165.9, 168.6, 170.2. Anal. Calcd for
C24H31F3N2O8: C, 54.13; H, 5.87; F, 10.70; N, 5.26. Found: C,
54.35; H, 5.96; N, 5.07.
4.7.5. (3R,5R)-1-((S)-1-ethoxy-1-oxopropan-2-yl)-5-isopropyl-2-
oxopyrrolidin-3-yl (S)-3,3,3-trifluoro-2-methoxy-2-
phenylpropanoate 12b
25
Eluent: hexane/EtOAc, 7:3. (0.159 g, 69%); oil; [α]D -4 (c
1
0.8 CHCl3); H NMR (CDCl3, 400 MHz) δ 0.88 (d, 3H, J = 6.7
Hz), 0.93 (d, 3H, J = 6.9 Hz),1.20 (t, 3H, J = 7.1 Hz), 1.43 (d, 3H,
J = 7.1 Hz), 1.86 (ddd, 1H, J = 13.8, 7.0 Hz), 2.12 (dtd, 1H, J =
6.9, 6.7, 3.4 Hz), 2.49 (ddd, 1H, J = 13.8, 9.4 Hz), 3.52 (s, 3H),
3.69 (ddd, 1H, J = 7.1, 3.5 Hz), 4.17 (q, 2H, J = 7.1 Hz), 4.26 (q,
1H, J = 7.1 Hz), 5.53 (dd, 1H, J = 9.4, 7.0 Hz), 7.39-7.41 (m,
3H), 7.58-7.61 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 13.8,
13.9, 14.6, 18.7, 24.9, 28.2, 50.9, 55.4, 59.7, 61.5, 71.4, 124.5,
127.8, 128.4, 129.7, 131.4, 165.8, 169.4, 170.0. Anal. Calcd for
C22H28F3NO6: C, 57.51; H, 6.14; F, 12.40; N, 3.05. Found: C,
57.69; H, 5.98; N, 3.16.
7. (a) Rück-Braun, K.; Kunz, H. Chiral Auxiliaries in
Cycloadditions.; Wiley: New York, 1999. pp. 113-143. (b)
Revuelta, J.; Cicchi, S.; Goti, A.; Brandi, A. Synthesis 2007, 485-
504. (c) Ishikawa, T.; Tajima, Y.; Fukui, M.; Saito, S. Angew.
Chem. Int. Ed. 2003, 35, 1863-1864. For overviews of the use of
chiral auxiliaries in organic synthesis and cycloadditions see: (c)
Gnas, Y.; Glorius, F. Synthesis 2006, 1899-1930. (d) Evans, D. A.;
4.7.6. (3R,5R)-1-((S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl)-5-
isopropyl-2-oxopyrrolidin-3-yl (S)-3,3,3-trifluoro-2-methoxy-2-
phenylpropanoate 12c
Helmchen, G.; Rüping, M. In Asymmetric Synthesis
Essentials; Christmann, M., Bräse, S., Eds.; Wiley-VCH:
Weinheim, 2006, p 3-9.
- The
25
8. Karlsson, S.; Hogberg, H. E. Org. Prep. Proced. Int. 2001, 33,
105-172.
9. (a) DeShong, P.; Lander, S. W., Jr.; Leginug, J. M.; Dickson, C.
M. In Advances in Cycloaddition; Curran, D. P., Ed.; Jai Press,
Eluent: hexane/EtOAc, 7:3. (0.193 g, 72%); oil; [α]D -74 (c
1
0.6 CHCl3); H NMR (CDCl3, 400 MHz) δ 0.68 (d, 3H, J = 6.9
Hz),0.82 (d, 3H, J= 6.7 Hz), 1.18 (t, 3H, J = 7.2 Hz), 1.68 (ddd,

ACCEPTED MANUSCRIPT
13
Inc.: Greenwich, CT, 1988; Vol. 1, pp. 87-128 (b) Brandi, A.;
Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Eur. J.
2009, 15, 7808-7821.
change of the substituents when a methyl group is used instead an
alkyl chain. Consequently, for the theoretical study we should
consider as the preferred adducts those corresponding to an endo
attack by the Re face (see Scheme 8).
10. (a) Fisera, L.; Altimari, U. A. R.; Ertl, P. In Cycloaddition
Reactions in Carbohydrate Chemistry; Giuliano, R. M., Ed.; Amer
Chemical Soc: Washington, DC, 1992, p 158-171. (b) Holmes, A.
B.; Bourdin, B.; Collins, I.; Davison, E. C.; Rudge, A. J.; Stork, T.
C.; Warner, J. A. Pure Appl. Chem. 1997, 69, 531-536. (c)
Broggini, G.; Zecchi, G. Synthesis 1999, 905-917. (d) Osborn, H.
M. I.; Gemmell, N.; Harwood, L. M. J. Chem. Soc., Perkin Trans.
1 2002, 2419-2438. (e) Koumbis, A. E.; Gallos, J. K. Curr. Org.
Chem. 2003, 7, 585-628.
23. Wheeler, S. E.; Moran, A.; Pieniazek, S. N.; Houk, K. N. J. Phys.
Chem. 2009, 113, 10376-10384.
11. (a) Merino, P.; Revuelta, J.; Tejero, T.; Chiacchio, U.; Rescifina,
A.; Piperno, A.; Romeo, G. Tetrahedron: Asymmetry 2002, 13,
167-172. (b) Chiacchio, U.; Corsaro, A.; Gumina, G.; rescifina,
A.; Iannazzo, D.; Piperno, A.; Romeo, G.; Romeo, R. J. Org.
Chem. 1999, 64, 9321-9327. (c) Chiacchio, U.; Rescifina, A.;
Saita, M. G.; Iannazzo, D.; Romeo, G.; Mates, J. A:; Tejero, T.;
Merino, P. J. Org. Chem. 2005, 70, 8991-9001.
12. (a) Ito, M.; Kibayashi, C. Tetrahedron Lett. 1990, 31, 5065-5069.
(b) Ina, H.; Ito, M.; Kibayashi, C: J. Org. Chem. 1996, 61, 1023-
1029. (c) Garcia-Ruano, J. L.; Fraile, A.; Martin-Castro, A. M.;
Martin, M. R. J. Org. Chem. 2005, 70, 8825-8834. (d) Raimondi,
L. Gazz. Chim. Ital. 1997, 127, 167-175. (e) Olsson, T.; Stern, K.;
Westman, G.; Sundell, S: Tetrahedron 1990, 46, 2473-2482.
13. (a) Merino, P.; Mates, J. A.; Revuelta, J.; Tejero, T.; Chiacchio,
U.; Romeo, G.; Iannazzo, D.; Romeo, R. Tetrahedron: Asymmetry
2002, 13, 173-190. (b) Gefflaunt, T.; Bauer, U.; Airola, K.;
Koskinen, M. P. Tetrahedron: Asymmetry 1996, 7, 3099-3102. (c)
Tejero, T.; Dondoni, A.; Rojo, I.; Merchan, F. L.; Merino, P.
Tetrahedron 1997, 53, 3301-3318. (d) Tamura, O.; Kanoh, A:;
Yamashita, M.; Ishibashi, H. Tetrahedron 2004, 60, 9997-10003.
For a review on chiral cycloadditions with acrylamides see: (e)
Kissane, M.; Maguire, A. R. Chem. Soc. Rev. 2010, 39, 845-883.
14. Merino, P.; Greco, G. Tejero, T.; Chiacchio, U.; Corsaro, A.;
Pistara, V.; Romeo, G. Tetrahedron Lett. 2011, 52, 6003-6006.
15. (a) Soldani, G.; Cardona, F.; Goti, A. Org. Lett. 2007, 9, 473-476.
(b) Goti, A.; Cardona, F.; Soldani, G. Org. Synth. 2005, 81, 204.
16. (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092-4096. (b) Kusumi, T.; Fukushima, T.;
Ohtani, I.; Kakisawa, H. Tetrahedron Lett. 1991, 32, 2939-2942.
17. Gaussian 09, Revision A.1, Frisch, M. J.; Trucks, G. W.; Schlegel,
H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani,
G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.;
Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.; Peralta,
J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.;
Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.; Knox,
J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian,
Inc., Wallingford CT, 2009.
18. (a) Becke, A. D: J. Chem. Phys 1993, 98, 5648-5652. (b) Lee, C.;
Yang, W.; Parr, R. G. Phys. Rev. B 1998, 37, 785-789. (c)
Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett.
1989, 157, 200-205.
19. (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys 1971,
54, 724-728. (b) Hehre, W.. J.; Ditchfield, R.; Pople, J. A. J.
Chem. Phys 1972, 56, 2257-2261. (c) Hariharan, P. C.; Pople, J.
A. Mol. Phys. 1974, 27, 209-214. (d) Gordon, M. S: Chem. Phys.
Lett. 1980, 76, 163-168. (e) Franci, M. M.; Pietro, W. J.; Hehre,
W. J.; Binkley, J. S.; DeFrees, D. J.; Pople, J. A.; Gordon, M. S. J.
Chem. Phys 1982, 77, 3654-3655. (f) Rassolow, V. A.; Pople, J.
A:; Ratner, M. A:; Windus, T. L. J. Chem. Phys 1998, 109, 1223-
1229.
20. Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157-167.
21. Fukui, K. Acc. Chem. Res. 1981, 14 363-368.
22. While the adduct obtained preferentially has
a (3R,5R)
configuration, the same adduct considered in the theoretical study
has a (3S,5R) configuration as a consequence of the priority