Phosphoramidite-Cu(OTf)2 complexes as chiral catalysts for 1,3-dipolar cycloaddition of iminoesters and nitroalkenes

Article abstract of DOI:10.1021/ol4006618

Chiral complexes formed by phosphoramidites such as (S_a,R,R)-9 and Cu(OTf)₂ are excellent catalysts for the general 1,3-dipolar cycloaddition between azomethine ylides and nitroalkenes affording the corresponding tetrasubstituted pro

Full text of DOI:10.1021/ol4006618

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
PhosphoramiditeꢀCu(OTf)2 Complexes as
Chiral Catalysts for 1,3-Dipolar Cycloaddition
of Iminoesters and Nitroalkenes
†
Luis M. Castello, Carmen Najera, Jose M. Sansano,*
,†
ꢀ †
ꢀ
ꢀ
Olatz Larranaga, Abel de Cozar, and Fernando P. Cossıo
‡
‡,§
‡
~
ꢀ
´
´
Departamento de Quımica Organica e Instituto de Sıntesis Organica (ISO), Facultad de
Ciencias, Universidad de Alicante, 03080-Alicante, Spain, Departmento de Quımica
ꢀ
´
ꢀ
´
ꢀ
´
Organica I, Facultad de Quımica, Universidad del Paıs Vasco, P. K. 1072, E-20018 San
Sebastian, Spain, and IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
´
ꢀ
jmsansano@ua.es
Received March 14, 2013
ABSTRACT
Chiral complexes formed by phosphoramidites such as (Sa,R,R)-9 and Cu(OTf)2 are excellent catalysts for the general 1,3-dipolar cycloaddition
between azomethine ylides and nitroalkenes affording the corresponding tetrasubstituted proline esters mainly as exo-cycloadducts in high er at
room temperature. The exo-cycloadducts can be obtained in enantiomerically pure form just after simple recrystallization. DFT calculations
support the stereochemical results.
Substituted prolinates 1 (Figure 1), obtained from the
corresponding 1,3-dipolar cycloadditions (1,3-DC)1 between
glycine ester aldimines and nitroalkenes, are important
inhibitors of R4β1-integrin-mediated hepatic melanoma
metastasis.2 The most simple prolines exo-2 have been
recently used as chiral organocatalysts in aldol reactions.3
In particular, for the asymmetric 1,3-DC of nitroalkenes as
dipolarophiles, chiral copper(I) complexes, formed from
ferrocenyl-type phosphanes, have been mainly used as
catalysts.3,4 Copper(I) complexes 3,4a,c 4,4b,e and 5,3 gen-
erally afforded exo5-cycloadducts, whereas the corre-
sponding endo-diastereomers have been prepared using
complex 6.3 However, when copper(II) triflate and chiral
ligand PyBidine6 were combined the resulting catalyst
7 afforded mainly endo-cycloadducts. In the case of 1,3-
DC of glycinamides and nitrostyrene (R)-Segphos and
Cu(CH3CN)4PF6 as a catalytic mixture, exo-cycloadducts
were furnished in good yields (up to 76%) and up to
96:4 er.7 A 5-position epimer (called exo0-diastereoisomer)
was mainly obtained when a solid-phase imidazolidine-
aminophenol/Ni(OAc)2 was employed.8 Otherchiralmetal
† Universidad de Alicante.
‡ Universidad del País Vasco.
§ Basque Foundation for Science.
(1) For recent reviews of asymmetric 1,3-DC, see: (a) Pellissier, H.
ꢀ
Tetrahedron 2007, 63, 3235. (b) Najera, C.; Sansano, J. M. in Topics in
Heterocyclic Chemistry; Hassner, A., Ed.; Springer-Verlag: Berlin-Heidelberg,
2008; Vol. 12, p 117. (c) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108,
ꢀ
2887. (d) Alvarez-Corral, M.; Munoz-Dorado, M.; Rodrıguez-Garcıa, I.
´ ´
~
Chem. Rev. 2008, 108, 3174. (e) Naodovic, M.; Yamamoto, H. Chem. Rev.
ꢀ
2008, 108, 3132. (f) Najera, C.; Sansano, J. M.; Yus, M. J. Braz. Chem. Soc.
2010, 21, 377. (g) Kissane, M.; Maguire, A. R. Chem. Soc. Rev. 2010, 39,
845. (h) Adrio, J.; Carretero, J. C. Chem. Commun. 2011, 47, 678.
(2) Zubia, A.; Mendoza, L.; Vivanco, S.; Aldaba, E.; Carrascal, T.;
Lecea, B.; Arrieta, A.; Zimmerman, T.; Vidal-Vanaclocha, F.; Cossı
F. P. Angew. Chem., Int. Ed. 2005, 44, 2903.
´
o,
ꢀ
ꢀ
(3) Conde, E.; Bello, D.; de Cozar, A.; Sanchez, M.; Vazquez, M. A.;
ꢀ
Cossıo, F. P. Chem. Sci. 2012, 3, 1486.
´
ꢀ
ꢀ
(4) (a) Cabrera, S.; Gomez-Arrayas, R.; Carretero, J. C. J. Am. Chem.
Soc. 2005, 127, 16394. (b) Yan, X.-X.; Peng, Q.; Zhang, K.; Hong, W.; Hou,
X.-L.; Wu, Y.-D. Angew. Chem., Int. Ed. 2006, 45, 1979. (c) Cabrera, S.;
(5) The endo/exo descriptor refers to the approach of the electron-
withdrawing group to the metallodipole before the cycloaddition.
(6) Arai, T.; Mishiro, A.; Yokoyama, N.; Suzuki, K.; Sato, H. J. Am.
Chem. Soc. 2010, 132, 5338.
ꢀ
ꢀ
Gomez-Arrayas, R.; Martın-Matute, B.; Cossıo, F. P.; Carretero, J. C.
´ ´
Tetrahedron 2007, 63, 6587. (d) Padilla, S.; Tejero, R.; Adrio, J.; Carretero,
J. C. Org. Lett. 2010, 12, 5608. (e) Kim, H.-Y.; Li, J.-Y.; Kim, S.; Oh, K.
J. Am. Chem. Soc. 2011, 133, 20750. (f) Li, Q.; Ding, C.-H.; Li, X.-H.;
Weissensteiner, W.; Hou, X.-L. Synthesis 2012, 44, 265.
ꢀ
(7) Gonzalez-Esguevillas, M.; Adrio, J.; Carretero, J. C. Chem.
Commun. 2012, 48, 2149.
r
10.1021/ol4006618
XXXX American Chemical Society

complexes such as [BinapAuTFA]2 afforded modest results
for the cycloaddition of methyl benzylideneglycinate and
nitrostyrene (up to 80:20 dr and 85:15 er).9 On the other
hand, benzophenone-derived N-(diphenylmethylene) glyci-
nates have also been employed as azomethine ylide precur-
sors in the presence of chiral silver catalysts10 and organo-
catalysts.11 In general, only glycinate derived imino esters
have been employed as azomethine ylide precursors except
in the case of the ligand 7 and Cu(OTf)2 which catalyzed the
1,3-DC with the corresponding alaninate. In many of these
examples the elucidation of the reaction pathways has been
studied by both DFT calculations12 and experimental results.4e
Initially, we selected (Sa)-Monophos 8 and (Sa,R,R)-9
(Figure 2) as chiral phosphoramidites for the preliminary
catalyzed 1,3-DC between methyl N-benzylideneglycinate
10a and β-nitrostyrene 11a, in toluene as solvent, at rt for
17 h (25 °C, Table 1). When (Sa)-Monophos 8 Cu(OTf)2
3
was used as the catalyst mainly racemic endo-2a was
obtained (Table 1, entry 1). However, in the case of
(Sa,R,R)-9 Cu(OTf)2, 88/11 dr and excellent enantioselec-
3
tion >99:1 were obtained for the exo-diastereoisomer 2a
(Table 1, entry 2). When using the enantiomeric ligand
(Ra,S,S)-9 the corresponding enantiomer exo-2a was
mainly isolated (Table 1, entry 3). By contrast, the complex
formed by phosphoramidite (Sa,S,S)-9 and Cu(OTf)2
demonstrated to be a mismatched combination because
the reaction gave the opposite diastereoselection with no
enantioselection (Table 1, entry 4). Cu(OTf)2 was the most
appropriate copper(II) salt rather than Cu(OAc)2 in terms of
both diastereo- and enantioselection (Table 1, compare
entries 2 and 5). Copper(I) bromide did not afford the
expected results, while Cu(OTf) C6H6 showed the same
3
result that was obtained in the reaction run with Cu(OTf)2
(Table 1, entries 6 and 7). We selected the catalyst formed by
Cu(OTf)2 because reactions involving copper(I) usually re-
quire an inert atmosphere and degassed solvents in order to
avoid dismutation. The presence of an external base is crucial
for the reaction success, triethylamine being more adequate
than DIPEA and DABCO (Table 1, compare entry 2 with
entries 8ꢀ10). The solvent effect was also dramatic because
almost racemic mixtures of the product 2a were isolated
when Et2O, MeCN, or DCM was employed, although in
the last example the diastereomeric exo/endo ratio was the
highest achieved in this transformation and in very good
yields (Table 1, entries 11ꢀ14). Unexpectedly, in all the cases,
cycloadduct endo-2a was obtained in racemic form.
Smaller amounts of a catalyst loading (3 mol %) in the
reaction gave a lower yield (55%) and an enantioselectivity
similar of that of 2a (not included in Table 1). The absolute
configuration of exo-cycloadduct 2a was established ac-
cording to the retention times in HPLC using chiral
columns and comparison with the data obtained for the
same known product.4c,9
Figure 1. Useful nitro-substituted prolines 1 and 2 and pre-
viously reported chiral catalysts for the enantioselective 1,3-
DC of imino esters and nitroalkenes.
We envisaged that the use of chiral phosphoramidites 8
and 9,13 as monodentate privileged ligands,14 could be a
good alternative to the described sophisticated ligands for
copper salts15 to be used as chiral catalysts in the general
asymmetric 1,3-DC of azomethine ylides, derived from
R-amino acids, and nitroalkenes.
The reaction of nitrostyrene 11a and imino ester 10a was
studied at lower temperatures. At ꢀ80 °C a 1:1 mixture of
the corresponding exo-cycloadduct-2a and the syn-imino
ester 12a was obtained. After acidic treatment at ꢀ80 °C
and simple extractive workup, the corresponding syn-
amino ester 13a and exo-2a hydrochloride were isolated
(Scheme 1). Diastereomeric ratios of 13a and enantiomeric
ratios of both exo/endo-2a and syn-13a were independent
of the working temperature.16
Figure 2. Employed chiral phosphoramidites.
(8) Arai, T.; Yokoyama, N.; Mishiro, A.; Sato, H. Angew. Chem., Int.
Ed. 2010, 49, 7895.
ꢀ ꢀ
(9) Martı
´
n-Rodrıguez, M.; Najera, C.; Sansano, J. M.; de Cozar, A.;
´
Cossıo, F. P. Chem.;Eur. J. 2011, 17, 14224.
´
(10) Imae, K.; Konno, T.; Ogata, K.; Fukuzawa, S.-I. Org. Lett.
2012, 14, 4410.
(11) (a) Xie, J.; Yoshida, K.; Takasu, K.; Takemoto, Y. Tetrahedron
Lett. 2008, 49, 6910. (b) Xue, M.-X.; Zhang, X.-M.; Gong, L.-Z. Synlett
2008, 691.
(14) The versatility and efficiency of the chiral phosphoramidite
ꢀ
Retamosa, M. G.; Sansano, J. M. Angew. Chem., Int. Ed. 2008, 47, 6055.
9ꢀAgClO4 complex was described first by our group: (a) Najera, C.;
ꢀ
(b) Najera, C.; Retamosa, M. G.; Martı
´
n-Rodrı
ꢀ
´
J. M.; de Cozar, A.; Cossıo, F. P. Eur. J. Org. Chem. 2009, 5622.
´
guez, M.; Sansano,
ꢀ
(12) For a review, see: de Cozar, A.; Cossı
2011, 13, 10858.
(13) (a) Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed. 2010, 49,
2486. (b) Privileged Chiral Ligands and Catalysts; Zhou, Q.-L., Ed.; Wiley-
VCH: New York, 2011.
´
o, F. P. Phys. Chem. Chem.
(15) Chiral phosphoramidite 9ꢀCuOTf has been isolated and char-
acterized (IR, 1H NMR, 13C NMR, 31P NMR, 19F NMR, and HRMS)
by: Maksymowicz, R. M.; Roth, P. M. C.; Fletcher, S. P. Nat. Chem.
2012, 4, 649.
(16) See Supporting Information for more details.
B
Org. Lett., Vol. XX, No. XX, XXXX

o-position decreased both the diastereo- and enantiomeric
ratios in 2e (Table 2, entry 5). The m- and p-substitution
increased these two parameters up to an exo/endo ratio of
89/11 with higher enantioselections 90:10 and 94:6 er for
compounds 2f and 2g, respectively (Table 2, entries 6
and 7). Other p-halogen-substituted imino esters gave very
good results, especially the fluoroaryl derivative 2i, which
was obtained with a 99:1 er (Table 2, entries 8 and 9). The
2-naphthyl derivative also gave a similar diastereoselection
(86/14) although the er of product 2j was sensibly lower
(85:15) (Table 2, entry 10).
Table 1. Optimization of the 1,3-DC between 10a and 11a
Several β-arylnitroalkenes were allowed to undergo
this 1,3-DC employing imino ester 10a (Table 2, entries
11ꢀ17). The o-substituted aryl group afforded very good
enantioselection with a lower endo/exo ratio in 2k than
the corresponding m- and p-substituted alkenes as, for
example, 2l and 2m (Table 2, entries 11ꢀ13). Again, the
p-substitution (Table2, entries13ꢀ17) resultedinbeingthe
most favorable for this transformation, as it was exempli-
fied by molecules 2o and 2p (Table 2, entries 15 and 16).
Again, the presence of the isopropyl ester afforded the
same results obtained when methyl ester was used (Table 2,
compare entries 13 and 14). The same enantioselection was
achieved with both esters, but better diastereoselection was
obtained using the methyl substituent. Heteroaryl substi-
tuents anchored to the imino ester did not afford any
profitable result except the 2-furyl substituent in the
dipolarophile skeleton generated product 2r in moderate
yield and good diastereo- and enantiomeric ratio (Table 2,
entry 18). The reaction performed with an aliphatic ni-
troalkene (R4 = cyclohexyl) afforded the corresponding
endo-2 derivative as a racemic mixure in moderate yield
and impurified with other diastereoisomers (not included
in Table 2).
Cu
solvent/
base
yield
(%)a
drb
erexo
c
salt
ligand
(Sa)-8
1
2
3
4
5
6
7
8
9
Cu(OTf)2 PhMe/Et3N
Cu(OTf)2 PhMe/Et3N
Cu(OTf)2 PhMe/Et3N
Cu(OTf)2 PhMe/Et3N
Cu(OAc)2 PhMe/Et3N
78
79
79
16
41
nd
78
16
13
79
50
70
40
82
24/76 50:50
89/11 >99:1
89/11 <1:99
20/80 50:50
68/32 94:6
(Sa,R,R)-9
(Ra,S,S)-9
(Sa,S,S)-9
(Sa,R,R)-9
(Sa,R,R)-9
(Sa,R,R)-9
(Sa,R,R)-9
CuBr
PhMe/Et3N
nd
nd
Cu(OTf)d PhMe/Et3N
Cu(OTf)2 PhMe/none
89/11 >99:1
20/80 50:50
66/34 70:30
84/16 50:50
78/22 58:42
84/16 55:45
64/36 55:45
Cu(OTf)2 PhMe/DIPEA (Sa,R,R)-9
10 Cu(OTf)2 PhMe/DABCO (Sa,R,R)-9
11 Cu(OTf)2 Et2O/Et3N
12 Cu(OTf)2 THF/Et3N
13 Cu(OTf)2 MeCN/Et3N
14 Cu(OTf)2 DCM/Et3N
(Sa,R,R)-9
(Sa,R,R)-9
(Sa,R,R)-9
(Sa,R,R)-9
93/4
50:50
a Isolated yield of the exo-cycloadduct after flash chromatography.
b Exo/endo ratio from the crude product, determined by 1H NMR. Other
stereoisomers were detected in low proportions. c For the major stereo-
isomer. d Benzene complex.
Scheme 1. Reaction at Low Temperature
Table 2 also shows chemical yields and enantiomeric ratios
of recrystallized solid compounds previously purified by flash
chromatography. In all these examples the diastereoselec-
tivity was excellent affording exclusively the exo-derivative
2. The enantiomeric ratio was notably increased after
recrystallization of purified adducts 2 obtaining almost
enantiopure samples (Table 2, entries 7ꢀ13 and 15ꢀ17).
An exception was the example performed with o-methyl
substituted imino ester 10 whose er could not be improved
(Table 2, entry 5).
The scope of the reaction was surveyed by modifying the
structure of the 1,3-dipole precursor and then varying
the nitroalkene aromatic substituent (Table 2). The pre-
sence of an isopropyl group in the ester moiety improved
the exo/endo ratio of the result obtained for the methyl ester
derivative keeping the same enantioselection, but the reac-
tion of the isopropyl ester afforded larger amounts of other
steresoisomers (ca. 20%) (Table 2, entries 1 and 2). When R-
substituted amino acids, such as leucine and phenylalanine,
were employed in the elaboration of imino esters 10,
moderate yields of enantiomerically enriched exo-cycload-
ducts 2c and 2d were isolated (Table 2, entries 3 and 4).
The stereochemical course or the reaction was also in-
fluenced by the aryl substituent of the imino ester (Table 2,
entries 5ꢀ10). Thus, a methyl group bonded at the
In our hands, the (Sa,R,R)-9 Cu(OTf)2 complex could
3
not be successfully recrystallized. However, 31P NMR
spectra revealed a signal at 57.14 ppm and a monomeric
structure can be postulated as the catalytic species accord-
ing to electrospray ionization-MS (Mþ, 602)16 and the lack
of nonlinear effects (NLE).14
DFT calculations on the (Sa,R,R)-9 Cu(OTf)2 cata-
3
lyzed reaction to obtain 2a showed that the coordina-
tion sphere of the Cu(II) atom is saturated by an OTf
moiety. The most stable transition structures located are
depicted in Figure 3. (S,S)-exo-TS1ꢀ2a was found to be
about 1.5 kcal molꢀ1 more stable than its enantiomeric
counterpart. These calculations support a computed erexo
of about 92%, in good agreement with the experimental
results.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Scope of the 1,3-DC between Iminoesters and Nitroalkenes Catalyzed by the (Sa,R,R)-9 Cu(OTf)2 Complex
3
R1
R2
R3
R4
2
yield (%)a
exo/endob
erexo
yield (%)c
erexo
d
entry
1
Ph
Ph
Ph
Ph
H
H
Bui
PhCH2
H
Me
Pri
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Pri
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2f
79
69e
60
65
51
61
59
76
70
70
56
61
70
72
48
68
73
41
89/11
99/1
>99:1
>99:1
>99:1
>99:1
75:25
90:10
94:6
68
60
47
51
37
>99:1
>99:1
>99:1
>99:1
77:23
2
3
92/8
4
75/25
59/41
79/21
79/21
89/11
87/13
86/14
73/27
90/10
86/14
80/20
82/18
72/28
82/12
77/23
5
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-BrC6H4
4-FC6H4
2-Naphthyl
Ph
f
f
6
H
ꢀ
ꢀ
7
H
2g
2h
2i
46
69
62
59
48
52
64
99:1
99:1
>99:1
94:6
98:2
98:2
99:1
8
H
95:5
9
H
99:1
10
11
12
13
14
15
16
17
18
H
2j
85:15
96:4
H
2-BrC6H4
3-BrC6H4
4-BrC6H4
4-BrC6H4
4-MeC6H4
4-(MeO)C6H4
4-FC6H4
2k
2l
Ph
H
94:6
Ph
H
2m
2n
2o
2p
2q
2r
95:5
f
f
Ph
H
95:5
ꢀ
ꢀ
Ph
H
99:1
40
63
70
99:1
99:1
99:1
Ph
H
98:2
Ph
H
96:4
f
f
Ph
H
2-Furyl
91:9
ꢀ
ꢀ
a Isolated yield of the major cycloadduct after flash chromatography (SiO2). b From the crude product, determined by 1H NMR. Other stereoisomers
were detected in low proportions. c Isolated yield after recrystallization for the exo-adduct based on the starting compound 10. d After recrystallization.
e 20% of the other stereoisomers were also obtained. f Oily products.
both components of the reaction are suitable. These simple
reaction conditions allow the preparation of a variety of
prolines 2, useful candidates for organocatalyzed asymmetric
aldol reactions.3 A notable increment of the enantiomeric
ratio occurred by recrystallization of the purified exo-
products. The isolation of Michael-type addition com-
pounds at lower temperatures supported the existence
of a stepwise mechanism. The experimentally obtained
diastereo- and enantioselectivities were supported by
DFT calculations.
Acknowledgment. This work has been supported by
the Spanish Ministerio de Economıa y Competitividad
´
(MINECO) (Consolider INGENIO 2010 CSD2007-
00006, CTQ2010-20387), FEDER, Generalitat Valenciana
(PROMETEO/2009/039), and the University of Alicante.
L.M.C. thanks the MINECO for an FPI fellowship. The
DIPC and the SGI/IZO-SGIker UPV/EHU (European
Social Fund) are gratefully acknowledged for generous
allocation of computational resources.
Figure 3. Main geometric features and relative energies
(in kcal molꢀ1) of the computed transition structures associated with
the first step of the reaction between 11a and (Sa,R,R)-9 CuOTf-II
3
with 10a computed at the M06/LANL2DZ//ONIOM (B3LYP/
LANL2DZ:UFF) þ ΔZPCE level of theory. Bond lengths are
given in A. The chiral ligand and OTf moiety are highligted in
green and blue, respectively.
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data for all new compounds,
and computational data. This material is available free of
charge via the Internet at http://pubs.acs.org.
In summary, we can conclude that chiral phosphorami-
dites can be used as very good privileged ligands in the
copper(II)-catalyzed 1,3-DC of azomethine ylides with
β-nitrostyrenes at rt. In general, aromatic substituents in
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX