Conjugate Addition of Nitroalkanes to an Acrylate Equivalent. Stereocontrol at C-α of the Nitro Group through Double Catalytic Activation

Article abstract of DOI:10.1021/ol901351k

Figur Presented An unprecedented highly selective direct conjugate addition of prochiral nitroalkanes (R ≠ H) to acrylate equivalents is described. The method employs a unique Lewis acid/Bronsted base/MS ternary catalytic system and affords products with

Full text of DOI:10.1021/ol901351k

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3826-3829
Conjugate Addition of Nitroalkanes to
an Acrylate Equivalent. Stereocontrol at
C-r of the Nitro Group through Double
Catalytic Activation
Jesu´s M. Garc´ıa,‡ Miguel A. Maestro,§ Mikel Oiarbide,† Jose´ M. Odriozola,‡
Jesu´s Razkin,‡ and Claudio Palomo*,†
Departamento de Qu´ımica Orga´nica I, Facultad de Qu´ımica, UniVersidad del Pa´ıs
Vasco, Apdo. 1072, 20080 San Sebastia´n, Spain, Departamento de Qu´ımica Aplicada,
UniVersidad Pu´blica de NaVarra, Campus de Arrosad´ıa 31006 Pamplona, Spain, and
Departamento de Qu´ımica Fundamental, Facultad de Ciencias, UniVersidade da
Corun˜a, Campus Zapateira s/n, 15071 A Corun˜a, Spain
claudio.palomo@ehu.es
Received June 16, 2009
ABSTRACT
An unprecedented highly selective direct conjugate addition of prochiral nitroalkanes (R * H) to acrylate equivalents is described. The method
employs a unique Lewis acid/Brønsted base/MS ternary catalytic system and affords products with dr up to 97/3. With ꢀ-substituted (R′ * H)
acceptors unprecedented levels of anti/syn selectivity (g96/4) are attained. Adducts can be transformed into enantioenriched γ-amino acids
and derivatives, including aldehydes, ketones, lactams, and peptides, through simple protocols with full recovery of camphor auxiliary, the
source of chiral information.
Conjugate addition of a nitroalkane to an electron-deficient
olefin is one of the most powerful C-C bond-forming
reactions and implies remote functionalization of a
substrate acceptor. Upon proper functional group manipu-
lation in the resulting adducts, a series of difunctional
compounds become rapidly accessible. In particular, if an
acrylate equivalent is used as the acceptor component,
reduction of the nitro group to the amine affords γ-amino
acid (γ-AA) derivatives, an important class of building
blocks in chemistry, biology, and materials sciences.1,2
To date considerable efforts have been devoted to the control
of the stereochemistry during the conjugate addition of nitro
compounds to Michael acceptors.3 However, while there is
a number of methods to control absolute configuration at
the resulting Cꢀ stereocenter (R′ * H, Scheme 1), most
known methods fail in controlling the configuration of the
Cγ stereocenter (R * H). Thus, virtually all reported catalytic
enantioselective conjugate additions4 of prochiral nitroalkanes
to unsaturated acyl equivalents5,6 deal with ꢀ-substituted
† Universidad del Pa´ıs Vasco.
§ Universidade da Corun˜a (X-ray analysis).
‡ Universidad Pu´blica de Navarra.
(1) For their relevance in peptide science, see: (a) Hanessian, S.; Luo,
X.; Schaum, R.; Michnick, S. J. Am. Chem. Soc. 1998, 120, 8569–8570.
(b) Hintermann, T.; Gademann, K.; Jaun, B.; Seebach, D. HelV. Chim. Acta
1998, 81, 983–1002. (c) Seebach, D.; Brenner, M.; Rueping, M.; Jaun, B.
Chem.sEur. J. 2002, 8, 573–584.
(2) For a review on the stereoselective synthesis of γ-AAs, see: Ordon˜ez,
M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18, 3–99
.
10.1021/ol901351k CCC: $40.75
Published on Web 08/10/2009
 2009 American Chemical Society

imparted by acrylate equivalent 1 in other transformations10
and stimulated by the simplicity of the approach, the present
investigation was initiated by studying the behavior of 1
during conjugate addition of nitroethane.
Scheme 1. Conjugate Addition of Nitroalkanes to Michael
Acceptors As a Route to Remote Functionalization
Compound 1 is readily accessible in gram quantities from
camphor, one of the cheapest chiral raw materials available
in bulk, and has been shown to be activated by added acid,
either Brønsted acid,10a Lewis acid,10b or combined Lewis
acid-molecular sieves (MS).10c However, none of these
conditions was effective for the target reaction (Table 1,
acceptors and usually provide mixtures of syn/anti isomers
in nearly 1:1 ratio, epimeric at Cγ.5,7 On the other hand, the
alternative approach, which relies on chiral acryloyl systems
covalently bound to the corresponding auxiliary, tends to
provide unsatisfactory levels of stereocontrol as a conse-
quence of the distance (4 chemical bonds away) between
the chiral inductor and the newly formed stereocenter.8,9
Here we describe the first realization of highly stereose-
lective conjugate addition of unmodified prochiral nitroal-
kanes to acrylate systems based on an intriguing double
catalytic activation of substrates.
Table 1. Catalyst Screening for the 1,4-Addition of Nitroethane
(2a, R ) CH3) to 1a
entry
acid
TfOH
Cu(OTf)2
Cu(OTf)2
Mg(OTf)2
base
additive t (h)
dr
conv. (%)
1
2
24
24
0
0
It was argued that in order to get satisfactory levels of
remote stereocontrol in the approach depicted in Scheme 2,
3
4
4 Å MS
4 Å MS
24
18
0b
0
5
6
7
8
i-Pr2NEt
NMP
24 59/41
24 52/48
24 55/45
98
>99b
50
Cu(OTf)2 i-Pr2NEt
Cu(OTf)2 i-Pr2NEt 4 Å MS
Cu(OTf)2 Et3N
Cu(OTf)2 NMP
Cu(OTf)2 NMP
NMP
4
1
1
1
80/20
88/12
97/3
>99
>99
>99
>99b
90b
>99b
Scheme 2. Challenging Remote Stereocontrol in Conjugate
9
4 Å MS
4 Å MS
4 Å MS
Addition of Nitroalkanes to Chiral Acrylates
10
11
12
13
90/10
4 Å MS 120 60/40
Cu(OTf)2 NMP
18 50/50
a Ratio of 1/2a/acid/base ) 1:5:0.2:0.4 as applicable; loading of
powdered 4 Å MS ) 100 mg/mmol of 1. b Reaction run at rt. NMP )
N-methylpiperidine.
auxiliary groups (Xc) displaying strong steric shielding would
be required. Given the high level of asymmetric induction
entries 1-4). It was then found that base-promoted activation
of the pronucleophilic nitroalkane was effective, although
the reaction to afford 3a was totally unselective with all
tertiary amines tested (entries 5 and 6). These results suggest
once again that for full realization of the stereodiscriminating
power of reagent 1, conformational restriction of the ketol
(3) For a review on conjugate additions of nitrocompounds, see: Ballini,
R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. ReV. 2005, 105,
933–971
.
(4) For reviews on asymmetric conjugate additions covering metal
catalysis, see: (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033–
8061. Covering organocatalysis: (b) Tsogoeva, S. B. Eur. J. Org. Chem.
2007, 1701–1716. (c) Almasi, D.; Alonso, D. A.; Na´jera, C. Tetrahedron
Asymmetry 2007, 18, 299–365. (d) Vicario, J. L.; Bad´ıa, D.; Carrillo, L.
Synthesis 2007, 2065–2092.
(6) Conjugate additions of prochiral nitroalkanes to non-carbonyl
Michael acceptors promoted by bifunctional thiourea organocatalysts. To
nitroalkenes: (a) Rabalakos, C.; Wulff, W. J. Am. Chem. Soc. 2008, 130,
13524–13525. (b) Dong, X.-Q.; Teng, H.-L.; Wang, C.-J. Org. Lett. 2009,
11, 1265–1268. To vinyl sulfones: (c) Zhu, Q.; Lu, Y. Org. Lett. 2009, 11,
1721–1724.
(5) Iminium ion mediated additions to enals: (a) Zu, L.; Xie, H.; Li, H.;
Wang, J.; Wang, W. AdV. Synth. Catal. 2007, 349, 2660–2664. (b) Gotoh,
H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5397–5309. (c) Hojabri,
L.; Hartikka, A.; Moghaddam, F. M.; Arvidsson, P. I. AdV. Synth. Catal.
2007, 349, 740–748. (d) Wang, Y.; Li, P.; Liang, X.; Zhang, T. Y.; Ye, J.
Chem. Commun. 2008, 1232–1234. Bifunctional thiourea-catalyzed additions
to unsaturated N-acyl pyrroles: (e) Vakulya, B.; Varga, S.; Soo´s, T. J. Org.
Chem. 2008, 73, 3475–3480. Diphenylprolinol-catalyzed cross-conjugate
additions between nitroalkenes and enals: (f) Zhong, C.; Chen, Y.; Petersen,
J. L.; Akhmedov, N. G.; Shi, X. Angew. Chem., Int. Ed 2009, 48, 1279–
1282. Iminium ion mediated additions to enones: (g) Dong, L.-t.; Lu, R.-j.;
Du, Q.-s.; Zhang, J.-m.; Liu, S.-p.; Xuan, Y.-n.; Yan, M. Tetrahedron 2009,
65, 4124–4129. For methods involving ꢀ-unsubstituted vinyl ketones that
provide from poor to moderate ee, see the following. Al-catalyzed addition
of nitroesters: (h) Keller, E.; Veldman, N.; Spek, A. L.; Feringa, B. L.
Tetrahedron: Asymmetry 1997, 8, 3403–3413. Peptide-catalyzed additions
of R-nitroketones: (i) Linton, B. R.; Reutershand, R. H.; Aderman, C. M.;
Richardson, E. A.; Brownell, K. R.; Ashley, C. W.; Evans, C. A.; Miller,
S. J. Tetrahedron Lett. 2007, 48, 1993–1997.
(7) For exceptions using preformed silyl nitronates, see: (a) Ooi, T.;
Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 9022–9023. (b) Ooi,
T.; Fujioka, S.; Maruoka, K. J. Am. Chem. Soc. 2004, 126, 11790–11791.
(8) For a review on remote stereocontrol, see: Mikami, K.; Shimizu,
M.; Zhang, H.-C.; Maryanoff, B. E. Tetrahedron 2001, 57, 2917–2951.
(9) For conjugate addition of prochiral nitroalkanes (R * H) to selected
chiral acrylate systems, leading to 70:30 or lower dr, see: Ballini, R.; Fiorini,
D.; Palmieri, A.; Petrini, M. Lett. Org. Chem. 2004, 1, 335–339.
(10) (a) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M.; Gonza´lez, A.;
Lecumberri, A.; Linden, A. J. Am. Chem. Soc. 2002, 124, 10288–10289.
(b) Palomo, C.; Oiarbide, M.; Arceo, E.; Garc´ıa, J. M.; Lo´pez, R.; Gonza´lez,
A.; Linden, A. Angew. Chem., Int. Ed. 2005, 44, 6187–6190. (c) Palomo,
C.; Oiarbide, M.; Garc´ıa, J. M.; Ban˜uelos, P.; Odriozola, J. M.; Razkin, J.;
Linden, A. Org. Lett. 2008, 10, 2637–2640.
Org. Lett., Vol. 11, No. 17, 2009
3827

unit through 1,4-metal or 1,4-proton binding in the transition
state is crucial. Guided by this idea, a concurrent activation
of the nucleophile and the electrophile components by
combined Lewis acid-Brønsted base system was pursued.11
Experiments were carried out in both the presence and
absence of molecular sieves (MS), which demonstrated that
sieves are an important additive for the reaction to proceed
efficiently. Thus, while no improvement was observed in the
absence of MS (entry 7), in their presence the reaction
proceeded to afford 3a with increasing level of diasterose-
lectivity (entries 8-10). Of the amines studied, N-methyl
piperidine was the most effective12 and after 1 h of reaction
at 0 °C gave a remarkable 97/3 dr value. The reaction
temperature was important, since the same reaction run at rt
led to 90/10 dr.13 As data from entries 12 and 13 show,
reactions carried out in the absence of either the Lewis acid
or the MS were completely unselective. To the best of our
knowledge, the present system represents one of the most
intriguing demonstrations of MS-dependent reaction stereo-
selectivity.14 Subsequently, we observed that lowering the
reaction temperature from 0 to -20 °C did not lead to better
results, while changing the solvent from CH2Cl2 to Et2O led
to higher isolated yields.
ketones, or ethers were well tolerated, with the alcohol group
in 2m being the one exception due to the competing oxa-
Michael reaction (15% of isolated product). Of practical
interest, reactions could be run at 10 mmol scale without
compromising selectivity or yield.
The potential of the present methodology is illustrated by
elaboration of adduct 3 into the corresponding γ-nitro
carboxylic acids, aldehydes, and ketones using simple
protocols that tolerate the nitro group. For instance, Scheme
3, treatment of adducts 3a,h,l with periodic acid afforded
Scheme 3
.
Removal of the Auxiliary Leading to Carboxylic
Acids, Aldehydes, and Ketones
The scope of the method is shown in Table 2. In general,
reactions proceeded with diastereoselectivities from very
acids 6 in high yields. Similarly, reduction or, alternatively,
nucleophilic alkylation of the carbonyl prior to the oxidation
step yielded the corresponding aldehyde, 4, or ketone, 5. Of
special interest, the method can be integrated with a peptide
coupling step (3a f 7 f 8, Scheme 4) wherein camphor,
the source of chiral information that is easy to recover and
recycle, also functions as an efficient protecting group of
the carboxy terminus.15
Table 2. Scope of the Catalytic Addition of Nitroalkanes 2 to 1a
compd
R
drb (3)
yield (%)c (3)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
CH3
CH3CH2
CH3(CH2)2
CH3(CH2)3
CH3(CH2)4
(CH3)2CH
(CH3)2CHCH2
CH2dCH(CH2)2
PhCH2
2-Me-Furyl-CH2
MeO2C(CH2)2
MeCO(CH2)2
HOCH2(CH2)2
BnOCH2(CH2)2
97/3
97/3
97/3
97/3
97/3
97/3
97/3
96/4
93/7
92/8
96/4
96/4
96/4
94/6
79d
74
74
To further assess the generality of the method, the same
catalytic conditions were applied to ꢀ-substituted enoyl
77
(12) Other cyclic amines led to comparable results (N-methyl pyrrolidine,
dr ) 97/3; N-methyl morpholine, dr ) 95/5).
79
62e
75
(13) Because of the acid character of the CH positioned R to the nitro
group, base-promoted epimerization of the product nitroalkane may be of
concern. We carried out control experiments by stirring solutions of product
3b (dr ) 97/3) in Et2O in the presence of 20 mol % of various amine
77
79
bases. With i-Pr2NEt, epimeration was bellow the limit of detection of 13
C
57d
89
NMR spectroscopy (50 MHz) after 24 h at rt. Under the same conditions
but with NMP as base, dr diminished to 93/7. Finally, with DBU complete
epimerization was observed after 24 h even at 0 °C. Therefore, and in
agreement with the high dr values observed under our reaction conditions,
we can conclude that epimerization of products would be a problem in the
presence of strong bases (DBU) only, or eventually when weaker bases
(NMP, i-Pr2NEt) are employed at temperatures above 0 °C.
(14) (a) Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem.
1998, 63, 5483–5488. (b) Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2005, 44, 466–468. (c) Steinhoff, B. A.; King, A. E.; Stahl, S. S. J.
Org. Chem. 2006, 71, 1861–1868. (d) Itoh, J.; Fuchibe, K.; Akiyama, T.
Angew. Chem., Int. Ed. 2008, 47, 4016–4018. (e) Hasegawa, M.; Ono, F.;
Kanemasa, S. Tetrahedron Lett. 2008, 49, 5220–5223.
86
50d, f
60d
a Reactions carried out at 1 mmol scale in Et2O (4 mL) in the presence
of 4 Å MS (100 mg) at 0 °C. Molar ratio of 1:2:Cu(OTf)2/N-methylpip-
eridine ) 1:5:0.1:0.3. b Determined by 1H NMR. c Isolated yields after
chromatography. d 20 mol % of Cu(OTf)2 and 40 mol % of N-methylpip-
eridine employed. e Reaction run at room temperature. f 15% of O-addition
product was obtained.
(15) Usual carboxy-protecting groups fail with γ-amino acids because
of their high tendency to lactamize spontaneously. See, for instance: (a)
Pettit, G. R.; Singh, S. B.; Hogan, F.; Lloyd-Williams, P.; Herald, D. L.;
Burkett, D. D.; Clewlow, P. J. J. Am. Chem. Soc. 1989, 111, 5463–5465.
(b) O’Connell, C. E.; Salvato, K. A.; Meng, Z.; Littlefield, B. A.; Schwartz,
C. E. Bioorg. Med. Chem. Lett. 1999, 9, 1541–1546.
good to almost perfect for simple saturated and unsaturated
nitroalkanes. In addition, functional groups such as esters,
(11) For the concept of, and inherent problems associated with, double
activation of substrates in the context of enantioselective catalysis, see: Itoh,
K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394–13395.
(16) In the case of ꢀ-substituted enones 9, the reaction with nitroethane
did not proceed at all in the absence of Cu(OTf)2 (2 equiv of N-
methylpiperidine, rt, 24 h, 0% conversion).
3828
Org. Lett., Vol. 11, No. 17, 2009

Scheme 4. Auxiliary Camphor-Derived Ketol Working As
Carboxy Protecting Group in Peptide Coupling
Figure 1. Stereomodels with both the acceptor hydroxy enone and
donor nitronate coordinated to Cu displaying a (A) re and (B) si
approach of nitronate.
derivatives 9. Gratifyingly, Scheme 5, the addition reaction
of nitroalkanes to 9 also proceeded satisfactorily and ster-
eoisomer anti-10 was obtained as the major product out of
the four possible isomers. As shown in Scheme 5, anti/syn
ratios of up to 97: 3 were obtained, which is the highest
selectivity so far reported for this type of conjugate addition.5
hydroxy enone would be a key activation16 and organiza-
tional element, and the camphor skeleton would sterically
favor a re-re approach of the two prochiral carbon atoms.
In conclusion, we have developed a highly stereoselective
direct conjugate addition of prochiral nitroalkanes to ꢀ-un-
substituted Michael acceptors. The method, which requires
a unique ternary Lewis acid/Brønsted base/MS catalytic
system, also tolerates ꢀ-substituted enoyl acceptors with
unprecedented levels (g96:4) of anti/syn selectivity. Simple
elaboration of adducts affords enantiopure difunctional
building blocks, such as γ-AA and derivatives, camphor, the
source of chiral information, being easy to recycle. Although
the precise role played by each catalyst component is still
unclear, the bases are set for the development of an
enantioselective version, which is currently under study.
Scheme 5
.
anti-Selective 1,4-Addition of Nitroalkanes to
ꢀ-Substituted Enones 9
Acknowledgment. This work was financially supported
by Universidad del Pa´ıs Vasco, Gobierno Vasco, and by
Ministerio de Educacio´n y Ciencia (Spain).
Supporting Information Available: Experimental pro-
cedures and characterization data of compounds 1 and 3-10,
including NMR spectra and HPLC chromatograms. This
material is available free of charge via the Internet at
http://pubs.acs.org.
While the precise role played at the molecular level by
MS on the course of the present catalytic reactions is yet far
from being understood, simplified stereomodels A and B
might account for the preferable re-face attack of the
evolving nitronate species. Accordingly, metal centered
preassociation of both the in situ generated nitronate and
OL901351K
Org. Lett., Vol. 11, No. 17, 2009
3829