Switching Diastereoselectivity in Catalytic Enantioselective (3+2) Cycloadditions of Azomethine Ylides Promoted by Metal Salts and Privileged Segphos-Derived Ligands

Article abstract of DOI:10.1021/acs.joc.9b00267

Catalytic enantioselective 1,3-dipolar cycloaddition between imino esters and electrophilic alkenes, employing chiral metal complexes derived from copper(I) and silver(I) salts and (S)-DM-or (S)-DTBM-Segphos as ligands produces diastereodivergently exo-or

Full text of DOI:10.1021/acs.joc.9b00267

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Article
Switching Diastereoselectivity in Catalytic Enantioselective
(3 + 2) Cycloadditions of Azomethine Ylides Promoted
by Metal Salts and Privileged Segphos Derived Ligands
Guilherme S. Caleffi, Olatz Larrañaga, Marcos Ferrandiz Saperas, Paulo Roberto Ribeiro
Costa, Carmen Nájera, Abel de Cozar, Fernando P. Cossio, and José M. Sansano
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00267 • Publication Date (Web): 26 Jul 2019
Downloaded from pubs.acs.org on July 29, 2019
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Switching Diastereoselectivity in Catalytic Enantioselective (3 +
2) Cycloadditions of Azomethine Ylides Promoted by Metal
Salts and Privileged Segphos Derived Ligands
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Guilherme S. Caleffi,a Olatz Larrañaga,b,c Marcos Ferrándiz-Saperas,c,d,e Paulo
R. R. Costa,a Carmen Nájera,*c,d Abel de Cózar,b,c,f Fernando P. Cossío*b,c and
José M. Sansano,*c,d,e
Dedicated to the memory of Prof. Teruaki Mukaiyama
a Laboratório de Química Bioorgânica, Instituto de Pesquisas de Produtos Naturais. Universidade
Federal do Rio de Janeiro, Ilha do Fundão, CCS, Bloco H – Sala H27, 21941-902 Rio de Janeiro,
RJ, Brazil.
b Departamento de Química Orgánica I, Facultad de Química, Universidad del País Vasco/Euskal
Herriko Unibertsitatea UPV/EHU., P. K. 1072, E-20018 San Sebastián, Spain.
c Centro de Innovación en Química Avanzada (ORFEO-CINQA).
d Departamento de Química Orgánica. Universidad de Alicante. Ctra. Alicante-San Vicente s/n,
03080-Alicante, Spain.
e Institute of Organic Synthesis. Universidad de Alicante.
f IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain.
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ABSTRACT: The catalytic enantioselective 1,3-dipolar cycloaddition between imino
esters and electrophilic alkenes, employing chiral metal complexes derived from
copper(I) and silver(I) salts and (S)-DM- or (S)-DTBM-Segphos as ligands resulted
diasterodivergently giving either exo- or endo-cycloadducts, respectively. The effect of
the functional group of the dipolarophile and the fine tuning of the catalyst play an
important role promoting reverse diastereoselectivities. The origins of experimentally
observed enantioselectivity and diastereoselectivity data, as well as the origin of the
observed switched endo:exo ratios, are also explained by means of DFT calculations.
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INTRODUCTION
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The total control of the absolute configuration of the products in an
asymmetric process is highly desirable. Much more attractive results the
generation of different stereoisomers, starting from the same substrate, just
modulating the structure of the catalyst. This last concept, considered as
stereodivergence1 is extremely efficient although not so frequent in asymmetric
synthesis. However, the combination of different both homochiral ligands and
metallic salts and the modification of the functional group in the substrate allows
the design of catalytic reverse diastereoselective and or enantioselective
processes.
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Regarding catalytic enantioselective [3+2] 1,3-dipolar cycloadditions (1,3-
2
DCs)
involving azomethine ylides and electrophilic alkenes, several
enantiodivergent methodologies were based on switching primary/tertiary amine
in a chiral ferrocenyl ligand·AgOAc,3 or switching CuI/AgOAc in the presence of
4
brucine diol as common ligand. Besides, diastereodivergent processes
(switching endo↔exo cycloadducts) were achieved by: a) modification of part of
the structure of the same chiral ligand using a copper(II) salt,5 or a copper(I)
salt;6,7 b) the employment of the same chiral ligand with different metal salts.8,9,10
During our search of optimal chiral catalysts for enantioselective 1,3-DC,
employing privileged chiral ligands,11 for the synthesis of key intermediates in the
elaboration of natural or bioactive compounds, we found a weird behavior when
the family of Segphos ligands was assessed. Not only changes in the ligand
structure as well as the use of silver(I) or copper(I) salts but also the type of the
dipolarophile resulted to be crucial.
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It is known that chiral ligand Segphos 1 (Figure 1) has got a wide range of
scope for catalytic enantioselective 1,3-DCs involving azomethine ylides.2
Nevertheless, chiral ligands 2 and 3 (or their enantiomeric forms) have been
extensively employed. Thus, (S)-DM-Segphos ligand 2·Cu(OTf)2 was employed
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into the exo-selective 1,3-DC of imino esters and benzoisothiazole-2,2-dioxide-
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3-ylidenes,
whereas 2·AgOTf afforded endo-cycloadducts when α,β-
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unsaturated pyrazolamides were selected as dipolarophiles.
(S)-DTBM-
Segphos ligand 3·CuI complexes afforded exo-selectivity in the reactions of imino
esters14,15,16 with aryl alkenes,17 acyclic activated 1,3-dienes,18 (E)-tert-butyl 6-
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bromo-2-hexenoate,
3-sulfonylpropenoates,
β-sulfonyl
enones,7
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benzo[b]thiophene sulfones
and fullerenes.8c,d This analogous exo-
diastereoselection22 was found in 1,3-DC catalyzed by (S)-DTBM-Segphos
ligand 3·AgI complexes employing harsh reaction conditions,23 when imino esters
reacted with acrylic systems.23b,c,24
Figure 1. Privileged Segphos family ligands.
In this work, we describe the general scope of the 1,3-DC and study the
origin of the complete reversal diastereoselectivity observed in the experimental
results, involving chiral Segphos derived ligands 2 and 3 (Figure 1) with copper(I)
or silver(I) salts.25 We also try to rationalize these stereoselective outcomes by
means of DFT computational analyses.
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RESULTS AND DISCUSSION
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Initially, a brief evaluation of the copper(I) and copper(II) salts with chiral
ligands 2 and 3 was done choosing as benchmark reaction the 1,3-DC of imino
ester 4a (Ar = Ph) and methyl acrylate (see Table 1 in SI). Ligand 2 afforded
better results in combination with CuOTf·PhMe complex achieving compound 5a
with very high endo:exo ratio (4:96) and high ee (88%). However, the combination
of ligand 3·copper(I) salt was much more suitable, in terms of the chemical yield
achieved (87%), dr (2:98) and ee (98%) in the presence 5 mol% of triethylamine.8c
On the other hand, this reaction without base did not proceeded at all. The
absolute configuration of cycloadduct exo-5a was unambiguously assigned on
the basis of the X-ray diffraction analysis of the corresponding N-phenylsulfonyl
derivative NPS-exo-5a (see SI).26
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The influence of the aryl moiety of the imino ester 4 was next evaluated.
Such as shown in Scheme 1, methyl acrylate afforded excellent
enantioselectivities in cycloadducts 5, o-, m-, and p-substituted arenes and
heteroarenes furnished very high enantiomeric excesses of the almost pure exo-
diastereoisomer 5a, 5c-5j. In the same line, tert-butyl acrylate was an excellent
dipolarophile for this enantioselective process giving enantiomerically pure
cycloadduct exo-5b.
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Scheme 1. Scope of the 3·CuOTf·PhMe mediated 1,3-DC between acrylates and
methyl arylideneglycinates 4.
Maleimides also gave both excellent diastereo- and enantioselectivities for
cycloadducts 5k-5m derived from methyl benzylideneglycinate 4a (Scheme 2).
Alkenyl sulfones provided high optical purities in compounds exo-5n and exo-5o.
When both β-nitrostyrene and chalcone were independently tested, the results
obtained for molecules 5p and 5q in the presence of ligand 2 were better than
the obtained in the reaction performed with ligand 3. At this point, the individual
analysis of the absolute configuration of the cycloadducts 5 was confirmed on the
basis of already mentioned X-ray diffraction pattern, nOe analysis, specific optical
rotation and HPLC analysis using columns with chiral stationary phases,
comparing the data with the supplied ones in the literature for the same
molecules.27
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Surprisingly, a non-expected stereodivergency was found when N,N-
dimethylacrylamide was employed obtaining the corresponding endo-
diastereoisomer 5s with 99% ee. Cycloadditions involving acrylonitrile deserve a
special comment. The initial exo-control in compounds 5t-v (99% ee, Scheme 2)
was determined by comparison of the retention times of the known published data
of HPLC using chiral coated columns with the analogous isolated adducts (see
SI). The cycloadduct exo-5v underwent a very fast epimerization at C1,28 which
was detected two days after the isolation of the original exo-compounds during
the preparation of the sample for the X-ray diffraction analysis. Although this test
did not give appropriate diffraction patterns, nOe experiments and vibrational
circular dichroism (VCD) analysis confirmed the proposed structure of these new
exo’-cycloadduct 5v (see SI).29
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Scheme 2. Scope of the 3·copper(I)-mediated 1,3-DC between several
dipolarophiles and methyl benzylideneglycinate 4a.
Looking for the diastereodivergent 1,3-DCs based on the change of copper
by silver salts, the complex formed by 3 and different silver salts were tested for
the benchmark reaction (see, Table 2 in SI). Surprisingly, again the exo-product
5a was mainly obtained in 89% yield, 17:83 endo:exo ratio and 77% ee (in the
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presence of AgSbF6). However, the complex of ligand 2 with silver salts gave
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diastereodivergently
mainly
endo-5a,
AgSbF6
giving
the
best
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diastereoselectivities. Thus, the 1,3-DC of 4a with methyl acrylate, mediated by
2·AgSbF6 afforded 5a in 88:12 endo:exo ratio, 91% yield and 77% ee (Table 2 in
SI). The reactions without base gave very poor results and no improvements were
observed when chiral bases such as cinchonidine or cinchonine were added.30
With these optimal conditions in hands, the most representative
dipolarophiles were assayed obtaining endo-cycloadducts 5 as major or unique
diastereoisomer. In general, the enantioselectivities were good to excellent for
maleimides, chalcone and N-acryloyloxazolidine-2-one (Scheme 3).
Unfortunately, the enantioselective catalyzed reactions with phenyl vinyl sulfone,
1,2-bis(phenylsulfonyl)ethylene, N,N-dimethyl acrylamide and acrylonitrile
afforded racemic endo-cycloadducts (>90:10 endo:exo ratio in all cases).
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Scheme 3. Scope of the 2·AgSbF6–mediated 1,3-DCs between several
dipolarophiles and methyl benzylideneglycinate 4a.
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At this point, we decided to perform DFT calculations 31 on selected
reactions that capture the essentials of the factors that could be involved in the
stereodivergent results found in our experimental studies. In particular, our aim
was to unravel the endo:exo selectivities observed in the 1,3-DC of imino ester 4a
with
methyl
acrylate
and acrylonitrile (exo-preference)
or N,N-
dimethylacrylamide (endo-preference) despite of using the same catalytic system
[namely copper(I) salt in presence of chiral ligand 3]. In addition, the reaction of
imino ester 4a with methyl acrylate in presence of Ag·2 catalytic system was also
analyzed. In previous reported theoretical studies5b we have demonstrated that
the enantioselectivity observed in 1,3-DCs can be addressed to the effective
blockage of one of the prochiral faces by the chiral ligand in the reactive complex.
In addition, we have demonstrated that the endo:exo selectivities strongly depend
on the metal coordination pattern and the counterion. 32 Remarkably, in the
reaction presented here, the copper-induced diastereoselectivity is affected by
the dipolarophile (vide supra). Recently, another unusual dipolarophile selectivity-
biased (3 + 2) cycloaddition was reported. In this latter case the authors described
dipolarophile–ligand - interactions as the driving force for the reaction outcome.
[33]
Initial computational studies were performed analysing the possible initial
copper(I) and silver(I) reactive complexes. Due to the chelating character of both
2 and 3 chiral ligands, at the beginning of the reaction, the metal atom is
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coordinated to both phosphorus atoms of the ligand and to the nitrogen and the
oxygen atoms of the 1,3-dipole precursor 4a, thus fulfilling the preferred distorted
tetrahedral environment of Cu and Ag central atoms. Once the dipolarophile
approaches to the in situ formed metalated azomethine ylide, our initial
hypothesis was twofold: (a) the coordination sphere of the metal is not affected
by the interaction with the dipolarophile (INT1 in Figure 2B); or (b) one of the M–
P bonding interactions is replaced by a metal–oxygen interaction (INT1’ in Figure
2B), thus incorporating the dipolarophile to the coordination sphere of the metallic
centre. According to hypothesis a, since the coordination sphere of the metal is
fulfilled and therefore the cyano or carboxamido group occupies a distal
disposition with respect to the ester group of the azomethine ylide, exo–selectivity
is expected in the corresponding (3+2) cycloadduct.32 On the other hand, within
hypothesis b, the previously mentioned M–O/M–N bonding interaction will act as
the driving force towards preferential formation of endo-cycloadducts. Relative
energies and main geometrical features of the computed N-metalated complexes
are collected in Figure 2C.
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Our results show that the binding affinity of the oxygen atom of methyl
acrylate and the nitrogen atom of acrylonitrile are not strong enough to displace
the phosphorus atom outside of the copper coordination sphere. Therefore,
chelated species INT1A and INT1C are more stable than their open counterparts
INT1’A and INT1’C. In the case of the interaction of 3·AgI with methyl acrylate both
reactive complexes are energetically closer to each other, with an energy
difference for INT1’D of 2 kcal·mol-1 with respect to INT1D. On the other hand, the
oxygen atom of N,N-dimethylacrylamide can displace one of the phosphorus
atoms of 3, being complexes INT1’B the most stable ones in these cases. All
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attempts to isolate species in which the nitrogen atom of N,N-dimethylacrylamide
interacts with the metallic centre lead to uncoordinated species in few
optimization steps (see Supporting Information for further details about other
reactive complexes not included in Figure 2). This difference in the metal binding
affinity can be addressed to a stronger metal–oxygen Coulombic interaction as a
consequence of the higher charge of the oxygen atom in N,N-
dimethylacrylamide[natural bond orbital (NBO) charge of -0.64 e vs -0.57 e in
methyl acrylate. Remarkably, in all cases the chiral ligands 2 and 3 efficiently
block the (2Re,5Si) prochiral face.
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X
Ar
Y
A
C
Y
M
N
L
X
O
INT2
OMe
Cu-O
TS1
interaction
Cu
Ar
N
CO2Me
TS2
5
Cu
4a
Ar
2
L
M
N
5
+
M+
2
X
O
OMe
Ar
N
Y
3
3
INT1
+
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L
X
Y
O
INT3
OMe
4a
Ar
Blockage of
(2Re,5Si)-face
CO2Me
N
H
INT1’B
INT1A
5
B
endo
exo
X
X
Ph
Ph
N
P
P
M
N
M
Cu
5
2
O
O
Ag
OMe
5
L
L
OMe
2
3
2
P
P
INT1'A (+6.1)
INT1'B (- 7.4)
INT1'C (+ 8.9)
INT1’D (+2.0)
INT1A (0.0)
INT1B (0.0)
INT1C (0.0)
INT1D (0.0)
A: M=Cu; X=COOMe; L=3
B: M=Cu; X=CONMe2; L=3
C: M=Ag; X=CN; L=3
Blockage of
(2Re,5Si)-face
INT1D
INT1C
D: M=Ag; X=COOMe; L=2
Figure 2. (A) Generally accepted stepwise mechanism of the metal catalyzed
[3+2] cycloaddition. (B) Relative Gibbs free energies (in kcal·mol-1) of reactive
complexes associated with the 1,3-DC reaction of 4a with methyl acrylate, N,N-
dimethylacrylamide or acrylonitrile catalyzed by 3·Cu(I) catalytic systems,
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computed at B3LYP-D3/6-31G*&LANL2DZ/ONIOM(B3LYP/LANL2DZ:PM6)
level of theory or 2·Ag(I) catalytic system for the 1,3-DC of methyl acrylate and
4a computed at B3LYP-D3/6-31G*&LANL2DZ level. Atoms capable to coordinate
to the metal center are highlighted in red. (C) Main geometrical features of the
most stable reactive complexes.
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According to the widely accepted catalytic cycle associated with metal
catalyzed 13-DCs, the reaction corresponds to a Michael addition–intramolecular
Mannich stepwise mechanism, in which the stereochemical outcome of the whole
reaction is determined in the first step (Figure 2A).5b,17 ,30 The main geometrical
features and the relative Gibbs free energies of the least energetic transition
structures, corresponding to the first step of the reaction paths gathered in Figure
2, are collected in Figure 3 (see Supporting Information for the complete energetic
profiles associated with the corresponding catalytic cycles).
Our calculations show that in the two least energetic transition structures
associated with the 1,3-DC of imino ester 4a with methyl acrylate catalyzed by
3·CuI (TS1A-exo and TS1A-exo’ in Figure 3) the dipolarophile approaches the
azomethine ylide according to the exo-mode. This is a consequence of the
absence of a copper vacant coordination site that would allow the stabilizing
interaction between the oxygen atom and the metallic centre (hypothesis a).
Indeed, the calculated enantioselectivity towards formation of exo-5a is eecalc
=
99, which is in excellent agreement with the experimental evidence (Scheme 2).
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The opposite scenario is observed for N,N-dimethylacrylamide as
dipolarophile. In this case, the existence of a strong Cu–O=C-NMe2 interaction
that displaces one of the P atoms of the ligand favours the endo-approach of the
dipolarophile (hypothesis b). As in the previous case, the effective blockage of
the (2Re,5Si) face, due to the chiral ligand, promotes an energetic difference of
3.4 kcal·mol-1 between TS1B-endo and TS1B-endo’ due to the higher deformation
energy required in the latter to reach the required TS geometry. In this case, the
theoretical enantioselectivity towards endo-5s is eecalc = 99, which also
corresponds to a perfect match with experimental evidence (Scheme 1).
As far as acrylonitrile dipolarophile is concerned, our calculations show the
preferential formation of exo-cycloaddutcs (TS1C-exo in Figure 3). As in the imino
ester 4a case, the least energetic transition state shows a fulfilled metallic center
coordination sphere, thus promoting the exo–conformation. However, the
nitrogen atom of the CN group is also capable to displace a P catalytic atom
(TS1C-endo in Figure 3). Therefore, formation of exo-5t is computationally
predicted, with high enantioselectivity (eecalc = 99) and low diastereoselectivity
(12:88 exo:endo), in nice agreement with the experimental evidences.
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When 2·AgI was analyzed as catalyst in the 1,3-DC of imino ester 4a with
methyl acrylate, preferential formation of endo-cycloadducts was not expected
since methyl acrylate is, in principle, not able to shift the stronger Ag–P bond34 in
the most stable intermediate reactive complex INT1D (vide supra). However, in
the first TS of the stepwise cycloaddition the silver(I) centre is able to adopt a
distorted bipyramidal geometry that permits the interaction of the metallic centre
with the 1,3-dipole, the oxygen atom of the dipolarophile and both P atoms of the
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chiral ligand 2. Within this geometry, one of the Ag–P bonds is elongated, but still
kept, thus allowing the interaction with the incoming dipolarophile. In this case,
the energy difference between TS1D-endo and TS1D-endo’ is rather small (0.7
kcal·mol-1), therefore a lower enantioselectivity towards endo-5a is theoretically
computed (eecalc = 55). In addition, since there is no complete cleavage of Ag–P
bonding interactions in silver(I) systems, the ligand remains doubly coordinated
to the metallic centre. As a consequence, the use of catalytic system 3·Ag(I)
would not favour endo adducts formation (Table 2 in the Supporting Information)
because of the hindrance of dipolarophile-metal interaction hampered by the
bulky But groups that hindered any dipolarophile–metal interaction (see
Supporting Information for further details about DFT calculations of this reaction).
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Figure 3. Relative Gibbs free energies (in kcal·mol-1) of the least energetic
transition structures associated with the reaction of 4a with methyl acrylate, N,N-
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dimethylacrylamide or acrylonitrile catalyzed by 3·Cu(I) catalytic system
computed at B3LYP-D3/6-31G*&LANL2DZ/ONIOM(B3LYP/LANL2DZ:PM6) or
catalyzed by 2·Ag(I) for the 1,3-DC of methyl acrylate and 4a computed at
B3LYP-D3/6-31G*&LANL2DZ level. In ONIOM calculations, Ball&stick and wire
models correspond to the high and low level layers, respectively. Distances are
in Å.
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CONCLUSION
The (S)-DTBM-Segphos·CuOTf·PhMe complex promoted efficiently the
exo-enantioselective 1,3-DC of stabilized azomethine ylides derived from imino
esters and electrophilic alkenes different from N,N-dimethylacrylamide. However,
with these last alkene a total enantioselective endo-approach was observed. In
both approaches the final ee’s were excellent. In some cases, the employment of
(S)-DM-Segphos·CuOTf·PhMe was crucial for the increment of the
enantioselectivity. A switch of the diastereoselectivity was achieved when (S)-
DM-Segphos·AgSbF6 was used as catalyst. These results demonstrate the
strong influence of the ligand structure in the diastereoselectivity in the (3 + 2)
cycloadditions mediated by (S)-DM-Segphos·AgSbF6 versus the observed one
in the reaction run with (S)-DTBM-Segphos·AgSbF6. In addition, an unexpected
substrate-dependent reverse diastereoselectivity was demonstrated with the (S)-
DTBM-Segphos·CuOTf·PhMe complex using N,N-dimethyl acrylamide. DFT
analysis of the corresponding transition structures permitted to identify the origins
of the exo to endo switching of diasteroselectivity in the case of these
dipolarophiles with an amido group. The most important feature of this shift is the
alteration of the coordination of the copper(I) sphere, which changes from a
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bidentate to a monodentate mode of the bisphosphane-copper complex, thus
allowing the coordination of the dipolarophile in an endo-mode . On the other
hand, the change from exo- to endo-diasteroselectivity promoted by (S)-DM-
Segphos·AgSbF6 is due to a stronger bidentate coordination between the
diphosphine ligand and the silver cation in a distorted bipyramidal geometry that
permits the interaction of the metallic center with the 1,3-dipole. Exo’-
cycloadducts bearing a nitrile group at 3-position, formed through epimerization
in the C1 of the original exo-cycloadducts (stable around 1.5 days at rt), are more
stable stereoisomers.
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EXPERIMENTAL SECTION
1. General
All commercially available reagents and solvents were used without further
purification, only aldehydes were also distilled prior to use. Analytical TLC was
performed on Schleicher & Schuell F1400/LS 254 silica gel plates, and the spots
were visualised under UV light (λ = 254 nm). Flash chromatography was carried
out on hand packed columns of Merck silica gel 60 (0.040-0.063 mm). Melting
points were determined with a Reichert Thermovar hot plate apparatus and are
uncorrected. Optical rotations were measured on a Perkin Elmer 341 polarimeter
with a thermally jacketted 5 cm cell at approximately 25˚C and concentrations (c)
are given in g/100 mL. The structurally most important peaks of the IR spectra
(recorded using a Nicolet 510 P-FT) are listed and wavenumbers are given in cm-
1. NMR spectra were obtained using a Bruker AC-300 or AC-400 and were
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recorded at 300 or 400 MHz for H NMR and 75 or 100 MHz for C{1H} NMR,
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using CDCl3 as the solvent and TMS as internal standard (0.00 ppm) unless
otherwise stated. The following abbreviations are used to describe peak patterns
where appropriate: s = singlet, d = doublet, t = triplet q = quartet, m = multiplet or
unresolved and br s = broad signal. All coupling constants (J) are given in Hz and
chemical shifts in ppm. 13C{1H} NMR spectra were referenced to CDCl3 at 77.16
ppm. 2D-COSY experiments were performed for the NMR peak assignments for
compounds exo-5r and endo-5r (in CDCl3 and C6D6). 2D-NOESY experiments of
exo-5h, exo-5i, exo-5o, and simple nOe of exo-5t, exo-5r, endo-5r, endo-5s and
exo’-5v were crucial to control the relative configuration of all series of the
reaction products. Low-resolution electron impact (EI) mass spectra were
obtained at 70 eV using a Shimadzu QP-5000 by injection or DIP; fragment ions
in m/z are given with relative intensities (%) in parentheses. High-resolution mass
spectra (HRMS) were measured on an instrument using a quadrupole time-of-
flight mass spectrometer (QTOF) and also through the electron impact mode (EI)
at 70 eV using a Finnigan VG Platform or a Finnigan MAT 95S. Enantiomeric
excesses were determined by using a JASCO-2000 series equipped with a chiral
column using mixtures of n-hexane/isopropyl alcohol as the mobile phase at 25
˚C.
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Computational methods: All the computational mechanistic studies were
carried out with the Gaussian0935 suite of programs. Density functional Theory
(DFT) geometry optimizations and harmonic analysis were performed with the
B3LYP36 functional. Relative energies were computed by means of single-point
calculations on the optimized geometries with the M06-2X37 functional.
This latter functional was chosen because it is well suited for the treatment
of nonbonding interactions and dispersion forces in densely substituted
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interacting systems38 and produce similar geometries to B3LYP, 39 although it
tends to slightly overestimate the barriers of hetero Diels Alder reactions. 40
The 6-31G* basis set was used. Solvent effects were computed with the
PCM method using toluene as solvent. 41 All the stationary points were
characterized by harmonic analysis. Reactants, intermediates and products
showed positive definite Hessian values. Transition structures (TSs) showed one
and only one imaginary frequency associated with nuclear motion along the
chemical transformation. Activation and reaction (Gibbs) energies were
calculated at 298.15 K. Figures including optimized structures were made with
Maestro42 and CYL-view43 programs. Orbital diagrams were prepared by using
the Gauss-view interface. 44
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2. Conventional Procedure for the Synthesis of known α-Imino Esters.
The amino ester (1.1 mmol) was dissolved in DCM (2 mL) and aldehyde
(1 mmol) and Et3N (1.1 mmol) were added. The mixture was then stirred for 16 h
at room temperature. The reaction was quenched with (sat. aq.) NaCl, extracted
with DCM (3x10 mL) and dried over MgSO4.
Methyl (E)-2-(benzylideneamino)acetate (4a): (154 mg, 87%). All spectra were
in agreement with reported data;45 1H NMR (300 MHz, CDCl3): δ = 3.78 (s, 3H),
4.42 (s, 2H), 7.40-7.48 (m, 3H), 7.78 (d, J = 8.0 Hz, 2H), 8.29 (s, 1H).
Methyl (E)-2-[(2-methylbenzylidene)amino]acetate (4c): (172 mg, 90%). All
spectra were in agreement with reported data;46 1H NMR (300 MHz, CDCl3): δ =
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2.52 (s, 3H), 3.78 (s, 3H), 4.44 (s, 2H), 7.09-7.37 (m, 3H), 7.93 (dd, J = 7.7, 1.6
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Hz, 1H), 8.60 (s, 1H).
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Methyl (E)-2-[(3-methylbenzylidene)amino]acetate (4d): (174 mg, 91%). All
spectra were in agreement with reported data;45 1H NMR (300 MHz, CDCl3): δ =
2.39 (s, 3H), 3.78 (s, 3H), 4.42 (s, 2H), 7.21-7.78 (m, 4H), 8.26 (s, 1H).
Methyl (E)-2-[(4-methylbenzylidene)amino]acetate (4e): (180 mg, 94%). All
spectra were in agreement with reported data;45 1H NMR (300 MHz, CDCl3): δ =
2.39 (s, 3H), 3.77 (s, 3H), 4.40 (s, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.67 (d, J = 8.1
Hz, 2H), 8.25 (s, 1H).
Methyl (E)-2-[(2-bromobenzylidene)amino]acetate (4f): (210 mg, 82%). All
spectra were in agreement with reported data;46 1H NMR (300 MHz, CDCl3): δ =
3.79 (s, 3H), 4.47 (s, 2H), 7.27-7.34 (m, 2H), 7.56-7.62 (m, 1H), 8.09 (d, J = 7.6
Hz, 1H), 8.67 (s, 1H).
Methyl (E)-2-[(3-bromobenzylidene)amino]acetate (4g): (223 mg, 87%). All
spectra were in agreement with reported data;47 1H NMR (300 MHz, CDCl3): δ =
3.79 (s, 3H), 4.42 (s, 2H), 7.27-7.34 (m, 1H), 7.54-7.62 (m, 1H), 7.66 (d, J = 7.7
Hz, 1H), 7.98 (s, 1H), 8.23 (s, 1H).
Methyl (E)-2-[(4-bromobenzylidene)amino]acetate (4h): (228 mg, 89%). All
spectra were in agreement with reported data;47 1H NMR (300 MHz, CDCl3): δ =
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3.78 (s, 3H), 4.41 (s, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 8.24
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(s, 1H).
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Methyl (E)-2-[(thiophen-2-ylmethylene)amino]acetate (4j): (156 mg, 85%). All
spectra were in agreement with reported data;46 1H NMR (300 MHz, CDCl3): δ =
3.77 (s, 3H), 4.38 (s, 2H), 7.07-7.11 (m, 1H), 7.36-7.40 (m, 1H), 7.45 (dd, J = 5.0,
1.1 Hz, 1H), 8.39 (s, 1H).
Methyl (E)-2-[(pyridin-2-ylmethylene)amino]acetate (4l): (142 mg, 80%). All
spectra were in agreement with reported data;48 1H NMR (300 MHz, CDCl3): δ =
3.79 (s, 3H), 4.46 (s, 2H), 7.33-7.48 (m, 1H), 8.19 (d, J = 7.9 Hz, 1H), 8.35 (s,
1H), 8.65-8.75 (m, 1H), 8.90 (s, 1H).
Methyl (E)-2-[(naphthalen-2-ylmethylene)amino]acetate (4m): (204, 90%). All
spectra were in agreement with reported data;45 1H NMR (300 MHz, CDCl3): δ =
3.79 (s, 3H), 4.46 (s, 2H), 7.45-8.12 (m, 7H), 8.42 (s, 1H).
3. General Experimental Procedure for the 1,3 Dipolar Cycloaddition of α-
Imino Esters and Dipolarophiles.
Method A: In a flask was added CuOTf·PhMe (2.59 mg, 0.05 mmol), and (S)-
DTBM-Segphos 3 (11.80 mg, 0.05 mmol) and toluene (1 mL), the resulting
mixture was stirred for 1 h. Then, was added a solution of α-imino ester (0.2
mmol), dipolarophile (0.2 mmol) in toluene (1 mL). To the resulting suspension
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trimethylamine (1.39 µL, 0.05 mmol) was added and the mixture stirred at room
temperature (20 – 35 ˚C) for 16 – 24 h. The crude reaction mixture was filtered
through a small Celite path and the residue was purified by flash chromatography
yielding pure exo-cycloadducts or endo-cycloadducts, respectively.
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Method B: In a covered flask by aluminium foil was added AgSbF6 (3.34 mg, 0.05
mmol), and (S)-DM-Segphos 2 (7.22 mg, 0.05 mmol) and mixture of xylenes (1
mL), the resulting mixture was stirred for 1 h. Then, was added a solution of α-
imino ester (0.2 mmol), dipolarophile (0.2 mmol) in mixture of xylenes (1 mL). To
the resulting suspension trimethylamine (1.39 µL, 0.05 mmol) was added and the
mixture stirred at room temperature (20 - 35 ˚ C) for 16 – 24 h. The crude reaction
mixture was filtered through a small Celite path and the residue was purified by
flash chromatography yielding pure endo-cycloadducts.
Dimethyl (2S,4R,5R)-5-phenylpyrrolidine-2,4-dicarboxylate (exo-5a): All
spectra were in agreement with reported data.8c, 49 Purification by flash
chromatography (n-Hexane-EtOAc 8:2). Pale yellow liquid (46 mg 87 % yield);
Enantiomeric excess (98 % ee) was determined by HPLC. Chiralcel OD-H n-
hexane/isopropyl alcohol = 90/10, 1.0 mL/min, tRmaj: 11.1 min, tRmin: 26.8 min,
220.5 nm. [α]2퐷8 = +45.6 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): δ = 2.35-2.54
(m, 2H, CH2), 2.74 (br s, 1H, NH), 2.94 (q, J = 8.6 Hz, 1H, PhCHCH), 3.64 (s, 3H,
OCH3), 3.78 (s, 3H, OCH3), 4.06 (dd, J = 8.8, 5.5 Hz, 1H, NHCHCH2), 4.44 (d, J
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= 8.6 Hz, 1H, PhCH), 7.25-7.37 (m, 3H, ArH), 7.43-7.46 (m, 2H, ArH). C{1H}
NMR (101 MHz, CDCl3): δ = 34.4 (CH2), 51.0 (CH2CHCO), 52.1, 52.6 (2xOCH3),
59.3 (NHCHCO), 66.6 (PhCHNH), 127.1, 128.1, 128.8, 140.4 (ArC), 173.5, 174.2
(2xC=O).
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4-(tert-Butyl) 2-methyl (2S,4R,5R)-5-phenylpyrrolidine-2,4-dicarboxylate
(exo-5b): All spectra were in agreement with reported data.49,50 Purification by
flash chromatography (n-Hexane-EtOAc 6:4). Pale yellow liquid (48 mg, 78 %
yield); Enantiomeric excess (>99 % ee) was determined by HPLC. Chiralpak AS-
H n-hexane/isopropyl alcohol = 95/5, 1.0 mL/min, tRmaj: 7.9 min, tRmin: 9.7 min,
220.5 nm. [α]2퐷8 = -38.7 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): δ = 1.35 [s, 9H,
CH(CH3)3], 2.30-2.56 (m, 2H, CH2), 2.82 (br s, 1H, NH), 2.80-2.90 (m, 1H,
PhCHCH), 3.78 (s, 3H, OCH3), 4.04 (dd, J = 9.0, 5.3 Hz, 1H, NHCHCH2), 4.35
(d, J = 8.7 Hz, 1H, PhCH), 7.25-7.37 (m, 3H, ArH), 7.42-7.47 (m, 2H, ArH).
13C{1H} NMR (101 MHz, CDCl3): δ = 28.0 [(CH3)3], 34.4 (CH2), 51.1
(CH2CHCOOCH3), 52.5 (OCH3), 59.3 (NHCHCO), 66.7 (PhCHNH), 81.1
[OCH(CH3)3], 127.0, 128.0, 128.7, 140.8 (ArC), 172.5, 173.7 (2xC=O).
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Dimethyl (2S,4R,5R)-5-(2-methylphenyl)pyrrolidine-2,4-dicarboxylate (exo-
5c): Purification by flash chromatography (n-Hexane-EtOAc 6:4). Pale yellow
liquid (43 mg, 78 % yield). Enantiomeric excess (>99 % ee) was determined by
HPLC. Chiralpak AS-H n-hexane/isopropyl alcohol = 90/10, 1.0 mL/min, tRmaj: 8.9
min, tRmin: 12.2 min, 220.5 nm. IR (neat) υmax: 2954, 2362, 2342, 1437, 1362,
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1266, 1117, 1011, 703 cm-1. [α]퐷 = + 55.3 (c 1.3, CHCl3); H NMR (300 MHz,
CDCl3): δ = 2.33-2.40 (m, 1H, CH2), 2.38 (s, 3H, CH3), 2.54 (ddd, J = 13.1, 8.7,
7.9 Hz, 1H, CH2), 2.90 (br s, 1H, NH), 2.98 (q, J = 8.1 Hz, 1H, PhCHCH), 3.64 (s,
3H, OCH3), 3.79 (s, 3H, OCH3), 4.10 (dd, J = 8.7, 6.0 Hz, 1H, NHCHCH2), 4.71
(d, J = 8.0 Hz, 1H, PhCH), 7.15-7.27 (m, 3H, ArH), 7.58 (dd, J = 7.5, 1.4 Hz, 1H,
ArH). 13C{1H} NMR (101 MHz, CDCl3): δ = 19.5 (CH3), 34.4 (CH2), 50.4
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(CH2CHCO), 52.2, 52.7 (2xOCH3), 59.4 (NHCHCO), 62.3 (PhCHNH), 126.0,
126.7, 127.9, 130.7, 136.8, 138.2 (ArC), 173.5, 174.1 (2xC=O). MS (EI) m/z: 277
(M+, 9%), 219 (14), 218 (100), 191 (47), 186 (27), 160 (17), 158 (53), 143 (17),
131 (54), 130 (24), 118 (16), 115 (20), 91 (16). HRMS (EI) m/z: [M]+ Calcd for
C15H19NO4 277.1314; Found 277.1317.
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Dimethyl (2S,4R,5R)-5-(3-methylphenyl)pyrrolidine-2,4-dicarboxylate (exo-
5d): Purification by flash chromatography (n-Hexane-EtOAc 6:4). Pale yellow
liquid (45 mg, 82 % yield). Enantiomeric excess (95 % ee) was determined by
HPLC. Chiralcel OD-H n-hexane/isopropyl alcohol = 90/10, 1.0 mL/min, tRmaj
:
12.4 min, tRmin: 42.2 min, 220.5 nm. IR (neat) υmax: 2954, 1734, 1608, 1436, 1363,
1266, 1116, 1011, 940, 886, 734 cm-1. [α]퐷28 = + 47.1 (c 1, CHCl3); 1H NMR (300
MHz, CDCl3): δ = 2.35 (s, 3H, CH3), 2.36-2.44 (m, 1H, CH2), 2.46-2.55 (m, 1H,
CH2), 2.96 (br s, 1H, NH), 2.88-2.99 (m, 1H, PhCHCH), 3.64 (s, 3H, OCH3), 3.78
(s, 3H, OCH3), 4.06 (dd, J = 8.8, 5.6 Hz, 1H, NHCHCH2), 4.40 (d, J = 8.7 Hz, 1H,
PhCH), 7.08-7.11 (m, 1H, ArH), 7.22-7.27 (m, 3H, ArH). 13C{1H} NMR (101 MHz,
CDCl3): δ =21.6 (CH3), 34.5 (CH2), 50.9 (CH2CHCO), 52.1, 52.6 (2xOCH3), 59.3
(NHCHCO), 66.7 (PhCHNH), 124.1, 127.8, 128.7, 128.9, 138.5, 140.0 (ArC),
173.5, 174.1 (2xC=O). MS (EI) m/z: 277 (M+, 11%), 219 (16), 218 (100), 191 (12),
191 (60), 186 (33), 160 (19), 158 (74), 143 (20), 131 (51), 130 (18), 115 (17), 91
(17). HRMS (EI) m/z: [M]+ Calcd for C15H19NO4 277.1314; Found 277.1308.
Dimethyl (2S,4R,5R)-5-(4-methylphenyl)pyrrolidine-2,4-dicarboxylate (exo-
5e): Purification by flash chromatography (n-Hexane-EtOAc 6:4). Pale yellow
liquid (50 mg, 91 % yield); Enantiomeric excess (98 % ee) was determined by
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HPLC. Chiralcel OD-H n-hexane/isopropyl alcohol = 90/10, 1.0 mL/min, tRmaj: 9.7
min, tRmin: 30.4 min, 220.5 nm. IR (neat) υmax: 2954, 2361, 2341, 1734, 1435,
1363, 1200, 1169, 1115, 1020, 1011, 702, 651 cm-1. [α]퐷28 = + 46.1 (c 1, CHCl3);
1H NMR (300 MHz, CDCl3): δ = 2.33 (s, 3H, CH3), 2.37-2.58 (m, 2H, CH2), 2.93
(br s, 1H, NH), 2.86-2.95 (m, 1H, PhCHCH), 3.63 (s, 3H, OCH3), 3.78 (s, 3H,
OCH3), 4.05 (dd, J = 8.9, 5.4 Hz, 1H, NHCHCH2), 4.39 (d, J = 8.8 Hz, 1H, PhCH),
7.15 (d, J = 7.5 Hz, 2H, ArH), 7.33 (d, J = 8.1 Hz, 2H, ArH). 13C{1H} NMR (101
MHz, CDCl3): δ = 21.2 (CH3), 34.5 (CH2), 50.9 (CH2CHCO), 52.1, 52.6 (2xOCH3),
59.2 (NHCHCO), 66.5 (PhCHNH), 127.0, 129.5, 137.2, 137.8 (ArC), 173.5, 174.2
(2xC=O). MS (EI) m/z: 277 (M+, 7%), 276 (10), 246 (12), 219 (14), 218 (100), 191
(93), 186 (43), 160 (20), 158 (86), 143 (25), 131 (69), 130 (18), 128 (13), 115
(19), 91 (18). HRMS (EI) m/z: [M]+ Calcd for C15H19NO4 277.1314; Found
277.1310.
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Dimethyl (2S,4R,5R)-5-(2-bromophenyl)pyrrolidine-2,4-dicarboxylate (exo-
5f): Purification by flash chromatography (n-Hexane-EtOAc 6:4). Brown liquid (46
mg, 67 % yield); Enantiomeric excess (>99 % ee) was determined by HPLC.
Chiralpak AS-H n-hexane/isopropyl alcohol = 90/10, 1.0 mL/min, tRmaj: 12.4 min,
tRmin: 14.6 min, 220.5 nm. IR (neat) υmax: 2954, 1734, 1436, 1200, 1265, 1169,
1022, 757, 735, 702 cm-1. [α]퐷29 = - 44.8 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3):
δ = 2.31 (ddd, J = 13.1, 8.4, 7.3 Hz, 1H, CH2), 2.51 (ddd, J = 13.1, 8.1, 6.1 Hz,
1H, CH2), 2.96 (br s, 1H, NH), 2.94-3.01 (m, 1H, PhCHCH), 3.69 (s, 3H, OCH3),
3.79 (s, 3H, OCH3), 4.13-4.18 (m, 1H, NHCHCH2), 4.93 (d, J = 6.4 Hz, 1H, PhCH),
7.13 (ddd, J = 8.0, 7.3, 1.7 Hz, 1H, ArH), 7.34 (m, 1H, ArH), 7.52 (dd, J = 8.0, 1.2
Hz, 1H, ArH), 7.81 (dd, J = 7.8, 1.8 Hz, 1H, ArH). 13C{1H} NMR (101 MHz,
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CDCl3): δ = 33.1 (CH2), 50.5 (CH2CHCO), 52.4, 52.6 (2xOCH3), 59.3 (NHCHCO),
64.3 (PhCHNH), 123.7, 128.0, 128.9, 129.3, 132.9, 140.4 (ArC), 173.4, 174.0
(2xC=O). MS (EI) m/z: 343 (M+, 4%), 341 (4), 285 (13), 284 (96), 283 (15), 282
(100), 257 (19), 255 (20), 224 (37), 222 (36), 197 (18), 195 (18). HRMS (EI) m/z:
[M-Br]+ Calcd for C14H16NO4 262.1079; Found 262.1084.
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Dimethyl (2S,4R,5R)-5-(3-bromophenyl)pyrrolidine-2,4-dicarboxylate (exo-
5g): Purification by flash chromatography (n-Hexane-EtOAc 6:4). Brown liquid
(53 mg, 78 % yield); Enantiomeric excess (96 % ee) was determined by HPLC.
Chiralcel OD-H n-hexane/isopropyl alcohol = 90/10, 1.0 mL/min, tRmaj: 11.3 min,
tRmin: 20.9 min, 220.5 nm. IR (neat) υmax: 2953, 1734, 1436, 1199, 1264, 1012,
786, 735, 697 cm-1. [α]퐷29 = -46.7 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3): δ =
2.37-2.54 (m, 2H, CH2), 2.92 (br s, 1H, NH), 2.87-2.96 (m, 1H, PhCHCH), 3.66
(s, 3H, OCH3), 3.79 (s, 3H, OCH3), 4.07 (dd, J = 8.6, 5.7 Hz, 1H, NHCHCH2),
4.43 (d, J = 8.3 Hz, 1H, PhCH), 7.20 (t, J = 7.8 Hz,1H, ArH), 7.40 (m, 2H, ArH),
7.64 (t, J = 1.8 Hz, 1H, ArH). 13C{1H} NMR (101 MHz, CDCl3): δ = 33.8 (CH2),
50.9 (CH2CHCO), 52.3, 52.6 (2xOCH3), 59.1 (NHCHCO), 65.6 (PhCHNH), 122.8,
125.9, 130.3, 131.2, 143.0 (ArC), 173.2, 173.9 (2xC=O). MS (EI) m/z: 343 (M+,
6%), 341 (6), 285 (13), 284 (96), 283 (14), 282 (100), 257 (32), 255 (33), 252
(11), 250 (13), 225 (9), 224 (44), 223 (11), 222 (39), 197 (18), 195 (17). HRMS
(EI) m/z: [M-Br]+ Calcd for C14H16NO4 262.1079; Found 262.1079.
Dimethyl (2S,4R,5R)-5-(4-bromophenyl)pyrrolidine-2,4-dicarboxylate (exo-
5h): Purification by flash chromatography (n-Hexane-EtOAc 6:4). Brown liquid
(61 mg, 90 % yield); Enantiomeric excess (>99 % ee) was determined by HPLC.
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Chiralcel OD-H n-hexane/isopropyl alcohol = 90/10, 1.0 mL/min, tRmaj: 10.4 min,
tRmin: 17.7 min, 220.5 nm. IR (neat) υmax: 2953, 1734, 1436, 1201,1170, 1011,
822, 734, 703 cm-1. [α]퐷29 = - 45.3 (c 1, CHCl3); 1H NMR (300 MHz, CHCl3): δ =
2.34-2.55 (m, 2H, CH2), 2.88 (q, J = 8.6 Hz, 1H, PhCHCH), 2.92 (br s, 1H, NH),
3.64 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 4.06 (dd, J = 8.8, 5.4 Hz, 1H, NHCHCH2),
4.41 (d, J = 8.6 Hz, 1H, PhCH), 7.35 (d, J = 8.3 Hz, 2H, ArH), 7.46 (d, J = 8.5 Hz,
2H, ArH). 13C{1H} NMR (75 MHz, CDCl3): δ = 34.1 (CH2), 51.0 (CH2CHCO), 52.2,
52.6 (2xOCH3), 59.1 (NHCHCO), 65.8 (PhCHNH), 122.0, 129.0, 131.8, 139.6
(ArC), 173.2, 174.0 (2xC=O). MS (EI) m/z: 343 (M+, 4%), 341 (5), 312 (7), 310
(8), 285 (12), 284 (97), 283 (16), 282 (100), 257 (63), 255 (64), 252 (18), 250
(21), 224 (49), 223 (17), 222 (41), 197 (30), 195 (26). HRMS (EI) m/z: [M]+ Calcd
for C14H16NO4 262.1079; Found 262.1072.
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Dimethyl (2S,4R,5R)-5-(pyridin-3-yl)pyrrolidine-2,4-dicarboxylate (exo-5i):
Purification by flash chromatography (n-Hexane-EtOAc 5:5). Pale yellow solid (26
mg, 48 % yield); Enantiomeric excess (>99 % ee) was determined by HPLC.
Chiralpak AS-H n-hexane/isopropyl alcohol = 90/10, 1.0 mL/min, tRmaj: 26.0 min,
tRmin: 29.7 min, 210.0 nm. IR (neat) υmax: 2953, 1733, 1435, 1200, 1171, 1026,
809, 714 cm-1. [α]퐷25 = -23.9 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3): δ 2.38-
2.58 (m, 2H, CH2), 2.92-3.00 (m, 1H, PhCHCH), 2.93 (br s, 1H, NH), 3.67 (s, 3H,
OCH3), 3.79 (s, 3H, OCH3), 4.10 (dd, J = 8.7, 5.4 Hz, 1H, NHCHCH2), 4.50 (d, J
= 8.5 Hz, 1H, PhCH), 7.32 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H, ArH), 7.93 (td, J = 7.9,
1.9 Hz, 1H, ArH), 8.54 (dd, J = 4.9, 1.6 Hz, 1H, ArH), 8.65 (d, J = 2.3 Hz, 1H,
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ArH). C{1H} NMR (75 MHz, CDCl3): δ = 34.0 (CH2), 51.0 (CH2CHCO), 52.3,
52.6 (2xOCH3), 59.1 (NHCHCO), 63.6 (PhCHNH), 124.12, 136.1, 137.6, 148.0,
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148.2 (ArC), 173.0, 174.1 (2xC=O). MS (EI) m/z: 264 (M+, 3%), 233 (5), 206 (12),
205 (100), 178 (33), 173 (15), 146 (10), 145 (56), 118 (28). HRMS (EI) m/z: [M]+
Calcd for C13H16N2O4 264.1110; Found 264.1105.
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Dimethyl (2S,4R,5R)-5-(thiophen-2-yl)pyrrolidine-2,4-dicarboxylate (exo-5j):
Purification by flash chromatography (n-Hexane-EtOAc 6:4). Pale red liquid (48
mg, 90 % yield); Enantiomeric excess (94 % ee) was determined by HPLC.
Chiralpak AS-H n-hexane/isopropyl alcohol = 90/10, 1.0 mL/min, tRmin: 14.0 min,
tRmaj: 15.4 min, 220.5 nm. IR (neat) υmax: 2953, 1734, 1437, 1266, 1200, 1171,
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1030, 936, 734, 701 cm-1. [α]퐷 = +46.2 (c 0.96, CHCl3); H NMR (300 MHz,
CDCl3): δ 2.37-2.56 (m, 2H, CH2), 2.98-3.03 (m, 1H, PhCHCH), 2.98 (br s, 1H,
NH), 3.69 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 4.05 (dd, J = 8.6, 5.9 Hz, 1H,
NHCHCH2), 4.73 (dd, J = 8.3, 0.8 Hz, 1H, PhCH), 6.95 (dd, J = 5.1, 3.5 Hz, 1H,
ArH), 7.06 (ddd, J = 3.5, 1.2, 0.8 Hz, 1H, ArH), 7.23 (dd, J = 5.1, 1.2Hz, 1H, ArH).
13C{1H} NMR (101 MHz, CDCl3): δ = 34.2 (CH2), 51.5 (CH2CHCO), 52.3, 52.6
(2xOCH3), 59.2 (NHCHCO), 61.9 (PhCHNH), 125.1, 125.2, 127.0, 144.0 (ArC),
173.1, 173.6 (2xC=O). MS (EI) m/z: 270 (M+, 6%), 269 (25), 238 (21), 210 (77),
184 (11), 183 (100), 178 (84), 152 (18), 151 (50), 150 (97), 149 (18), 123 (75),
117 (21), 96 (25). HRMS (EI) m/z: [M]+ Calcd for C12H15NO4S 269.0722; Found
269.0723.
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c]pyrrole-1-carboxylate (exo-5k): All spectra were in agreement with reported
data;25a Purification by column chromatography (n-Hexane-EtOAc 6:4). White
solid (32 mg, 56 % yield); Enantiomeric excess (>99 % ee) was determined by
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32.5 min, tRmaj: 44.4 min, 210.0 nm; [α]퐷 = -9.9 (c 0.5, CHCl3); H NMR (300
MHz, CDCl3): δ = 3.03 (s, 3H, OCH3), 3.50 (dd, J = 8.9, 5.3 Hz, 1H, PhCHCH),
3.62 (s, 3H, OCH3), 3.90 (dd, J = 8.9, 4.5 Hz, 1H, CHCHCOOMe), 4.09 (d, J =
4.6 Hz, 1H, CHCOOMe), 4.52 (d, J = 5.3 Hz, 1H, PhCH), 7.27-7.43 (m, 5H, ArH).
13C{1H} NMR (101 MHz, CDCl3): δ = 25.4 (NCH3), 49.2, 52.0 (2xCHCO), 52.8
(CH3), 62.3 (CHCOO), 65.3 (PhCHNH), 126.7, 128.1, 128.8, 140.4, (ArC), 171.9,
177.0, 177.1 (3xC=O).
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Methyl (1S,3R,3aR,6aS)-5-benzyl-4,6-dioxo-3-phenyloctahydropyrrolo[3,4-
c]pyrrole-1-carboxylate (exo-5l): Purification by column chromatography (n-
Hexane-EtOAc 6:4). White solid (64 mg, 87 % yield); Enantiomeric excess (>99
% ee) was determined by HPLC. Chiralpak AS-H n-hexane/isopropyl alcohol =
65/35, 0.5 mL/min, tRmin: 37.5 min, tRmaj: 47.1 min, 210.0 nm. IR (neat) υmax: 2953,
1736, 1432, 1394, 1343, 1266, 1223, 1168, 1029, 920, 730 cm-1. mp: 145-150
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ºC; [α]퐷 = - 43.6 (c 1, CHCl3); H NMR (300 MHz, CDCl3): δ = 2.76 (br s, 1H,
NH), 3.44 (dd, J = 8.9, 5.6 Hz, 1H, PhCHCH), 3.62 (s, 3H, OCH3), 3.84 (dd, J =
8.9, 4.8 Hz, 1H, CHCHCOOMe), 4.04 (d, J = 4.8 Hz, 1H, CHCOOMe), 4.42 (d, J
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= 5.6 Hz, 1H, PhCH), 4.67 (s, 2H, NCH2Ph), 7.24-7.40 (m, 10H, ArH). C{1H}
NMR (101 MHz, CDCl3): δ = 42.9 (CH2), 48.8, 51.5 (2xCHCO), 53.0 (CH3), 62.0
(CHCOO), 65.2 (PhCHNH), 127.1, 128.2, 128.4, 128.7, 128.8, 128.6, 135.6
(ArC), 171.0, 176.1, 176.0 (3xC=O). MS (EI) m/z: 364 (M+, 6%), 306 (21), 305
(100), 177 (13), 144 (45), 117 (20), 91 (23). HRMS (EI) m/z: [M]+ Calcd for
C21H20N2O4 364.1423; Found 364.1423.
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