Enantioselective michael reactions of β, β-disubstituted nitroalkenes: a new approach to β2,2-amino acids with hetero-quaternary stereocenters

Article abstract of DOI:10.1021/ol901572x

An atom-economic organocatalytic asymmetric Michael reaction of α,β,β-trisubstituted olefins has been successfully developed. The reaction exhibits excellent enantioselectivities under low loading of catalysts, and the conjugate addition products are valu

Full text of DOI:10.1021/ol901572x

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3946-3949
Enantioselective Michael Reactions of ꢀ,
ꢀ-Disubstituted Nitroalkenes: A New
Approach to ꢀ2,2-Amino Acids with
Hetero-Quaternary Stereocenters
Hai-Hua Lu, Fu-Gen Zhang, Xiang-Gao Meng, Shu-Wen Duan, and Wen-Jing Xiao*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry,
Central China Normal UniVersity, 152 Luoyu Road, Wuhan, Hubei 430079, China
wxiao@mail.ccnu.edu.cn
Received July 10, 2009
ABSTRACT
An atom-economic organocatalytic asymmetric Michael reaction of r,ꢀ,ꢀ-trisubstituted olefins has been successfully developed. The reaction
exhibits excellent enantioselectivities under low loading of catalysts, and the conjugate addition products are valuable for the synthesis of
novel ꢀ2,2-amino acids and ꢀ-peptides.
Recent advances in ꢀ-peptides1 and ꢀ-lactams2 have signifi-
cantly stimulated the development of catalytic asymmetric
synthesis of ꢀ-amino acids. The introduction of a diverse
array of functionalities to ꢀ-amino acids that is unprecedented
in nature through chemical methods is an important en-
deavor.3 In contrast to ꢀ3-amino acids, which can be easily
accessed by enantiospecific homologation of the natural
amino acids, the ꢀ2-analogues are much more difficult to
obtain.4 In particular, catalytic asymmetric synthesis of ꢀ2,2-
amino acids remains a challenge,5 especially the de novo
construction of the quaternary stereogenic center.6
The Michael addition has been established as a powerful
tool to generate quaternary stereogenic centers (Scheme 1).
(4) For an excellent review, see: (a) Seebach, D.; Beck, A. K.; Capone,
S.; Deniau, G.; Grosˇelj, U.; Zass, E. Synthesis 2009, 1. For representative
examples on catalytic asymmetric synthesis of ꢀ2-amino acids, see: (b)
Co´rdova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III. J. Am.
Chem. Soc. 2002, 124, 1866. (c) Davies, H. M. L.; Venkataramani, C.
Angew. Chem., Int. Ed. 2002, 41, 2197. (d) Sammis, G. M.; Jacobsen, E. N.
J. Am. Chem. Soc. 2003, 125, 4442. (e) Duursma, A.; Minnaard, A. J.;
Feringa, B. L. J. Am. Chem. Soc. 2003, 125, 3700. (f) Rimkus, A.; Sewald,
N. Org. Lett. 2003, 5, 79. (g) Sibi, M. P.; Patil, K. Angew. Chem., Int. Ed.
2004, 43, 1235. (h) Huang, H.; Liu, X.; Deng, J.; Qiu, M.; Zheng, Z. Org.
Lett. 2006, 8, 3359. (i) Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006,
128, 6804. (j) Chi, Y.; English, E. P.; Pomerantz, W. C.; Horne, W. S.;
Joyce, L. A.; Alexander, L. R.; Fleming, W. S.; Hopkins, E. A.; Gellman,
S. H. J. Am. Chem. Soc. 2007, 129, 6050. (k) Martin, N. J. A.; Cheng, X.;
List, B. J. Am. Chem. Soc. 2008, 130, 13862. (l) Lu, H.-H.; Wang, X.-F.;
Yao, C.-J.; Zhang, J.-M.; Wu, H.; Xiao, W.-J. Chem. Commun. 2009, 4251.
(1) (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001,
101, 3219. (b) Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008, 41, 1366.
(2) (a) Morin, R. B.; Gorman, M. Chemistry and Biology of ꢀ-Lactam
Antibiotics; Academic Press: New York, 1982; Vols. 1-3. (b) Alcaide, B.;
Almendros, P.; Aragoncillo, C. Chem. ReV. 2007, 107, 4437.
(3) (a) Juaristi, E.; Soloshonok, V. EnantioselectiVe Synthesis of ꢀ-Amino
Acids, 2nd ed.; Wiley-VCH: New York, 2005. (b) Abele, S.; Seebach, D.
Eur. J. Org. Chem. 2000, 1. (c) Yang, J. W.; Stadler, M.; List, B. Angew.
Chem., Int. Ed. 2007, 46, 609. (d) Yang, J. W.; Chandler, C.; Stadler, M.;
Kampen, D.; List, B. Nature 2008, 452, 453.
10.1021/ol901572x CCC: $40.75
Published on Web 08/04/2009
 2009 American Chemical Society

reocenters. In this paper, we describe an organocatalytic
Michael reaction of thiols with trisubstituted nitroacrylates
to afford enantioenriched R-sulfenylated ꢀ-nitro esters,
valuable precursors for the synthesis of R-thio-ꢀ2,2-amino
acids.5b,c Notably, this sulfa-Michael reaction10 proceeds
efficiently even in the presence of 0.3 mol % of catalyst
conferring excellent enantioselectivities on the products (up
to 98% ee).
Scheme 1
.
General Strategies to Quaternary Stereocenters via
Conjugate Additions
Initially, we examined the feasibility of the strategy by
reaction of p-thiocresol 1a with R-phenyl-ꢀ-nitroacrylate 2a
in the presence of various acid-base bifunctional organo-
catalysts.11,12 We were gratified to observe that the reaction
took place cleanly and effectively, affording the desired
product 3a in high yield (96%) and enantioselectivity (75%
ee), using the 9-thiourea cinchona alkaloid catalyst 4 (Table
1, entry 1).13 With this promising result in hand, we then
In this context, the conjugate addition of highly active
trisubstituted carbon nucleophiles by metallic or organic
catalysis has been well documented (Scheme 1, eq 1);5a,7
however, an alternative strategy, the addition to ꢀ,ꢀ-
disubstituted R,ꢀ-unsaturated systems (Scheme 1, eq 2), has
been largely unexplored.8 There are three main reasons that
have, perhaps, precluded intensive research in this transfor-
mation, which include: (1) the intrinsic steric constraint and
poor reactivity, (2) the difficulty in the stereocontrol, and
(3) the reaction reversibility, especially in the case of
heteronucleophiles.9 Yet, such tri- or tetrasubstituted Michael
acceptors constitute another kind of valuable synthon for the
construction of both all-carbon and hetero-quaternary ste-
Table 1. Conjugated Addition of p-Thiocresol 1a to
R-Phenyl-ꢀ-nitroacrylate 2a with Organocatalyst 4 under
Various Conditionsa
(5) (a) Liu, T.-Y.; Li, R.; Chai, Q.; Long, J.; Li, B.-J.; Wu, Y.; Ding,
L.-S.; Chen, Y.-C. Chem.sEur. J. 2006, 13, 319. For seminal reports using
chiral auxiliaries, see: (b) Avenoza, A.; Busto, J. H.; Jime´nez-Ose´s, G.;
Peregrina, J. M. J. Org. Chem. 2006, 71, 1692. (c) Avenoza, A.; Busto,
J. H.; Jime´nez-Ose´s, G.; Peregrina, J. M. Org. Lett. 2006, 8, 2855. (d)
Edmonds, M. K.; Graichen, F. H. M.; Gardiner, J.; Abell, A. D. Org. Lett.
2008, 10, 885
.
entry
solvent
toluene
xylene
benzene
DCM
DCE
CHCl3
Et2O
CH3CN
DMF
time
yieldb (%)
eec (%)
(6) For selected reviews on catalytic asymmetric synthesis of quaternary
stereocenters: (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed.
1998, 37, 388. (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5363. (c) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(d) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007,
1
2
3
4
5
6
7
8
<1 min
<1 min
<1 min
<1 min
<1 min
<1 min
<1 min
<1 min
1 h
96
94
98
96
93
90
95
87
83
95
95
93
98
75
77
80
74
71
78
78
11
0
5969. (e) Bella, M.; Gasperi, T. Synthesis 2009, 1583
.
(7) For a review, see: (a) Christoffers, J.; Baro, A. Angew. Chem., Int.
Ed. 2003, 42, 1688. For selected examples, see: (b) Taylor, M. S.; Jacobsen,
E. N. J. Am. Chem. Soc. 2003, 125, 11204. (c) Bella, M.; Jørgensen, K. A.
J. Am. Chem. Soc. 2004, 126, 5672. (d) Li, H.; Wang, Y.; Tang, L.; Wu,
F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed.
2005, 44, 105. (e) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto,
Y. J. Am. Chem. Soc. 2005, 127, 119. (f) Terada, M.; Ube, M. H.; Yaguchi,
Y. J. Am. Chem. Soc. 2006, 128, 1454. (g) Liu, T.-Y.; Long, J.; Li, B.-J.;
Jiang, L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Org. Biomol. Chem.
2006, 4, 2097. (h) Jautze, S.; Peters, R. Angew. Chem., Int. Ed. 2008, 47,
9
10
11
12
13
benzene
benzene
benzene
benzene-Et2O
<5 min
20 min
5 h
88d
89e
88f
92e,g
9284
.
(8) Impressive progress in this endeavor has emerged very recently and
mainly focused on metal-catalyzed procedures with copper and rhodium
being the most prevalent, pioneered independently by the Hoveyda and
Alexakis groups; see the following. Copper-catalyzed asymmetric conjugate
addition of zinc reagents: (a) Wu, J.; Mampreian, D. M.; Hoveyda, A. H.
J. Am. Chem. Soc. 2005, 127, 4584. (b) Hird, A. W.; Hoveyda, A. H. J. Am.
Chem. Soc. 2005, 127, 14988. (c) Fillion, E.; Wilsily, A. J. Am. Chem.
Soc. 2006, 128, 2774. (d) Wilsily, A.; Fillion, E. Org. Lett. 2008, 10, 2801.
Copper-catalyzed asymmetric conjugate addition of Grignard reagents: (e)
Martin, D.; Kehrli, S.; d’Augustin, M.; Clavier, H.; Mauduit, M.; Alexakis,
A. J. Am. Chem. Soc. 2006, 128, 8416. Copper-catalyzed asymmetric
conjugate addition of aluminum reagents: (f) d’Augustin, M.; Palais, L.;
Alexakis, A. Angew. Chem., Int. Ed. 2005, 44, 1376. (g) d’Augustin, M.;
Alexakis, A. Chem.sEur. J. 2007, 13, 9647. (h) Hawner, C.; Li, K.; Cirriez,
V.; Alexakis, A. Angew. Chem., Int. Ed. 2008, 47, 8211. (i) May, T. L.;
Brown, M. K.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2008, 47, 7358.
Rhodium-catalyzed asymmetric conjugate addition of organoboronic acids:
(j) Mauleo´n, P.; Carretero, J. C. Chem. Commun. 2005, 4961. (k) Shintani,
R.; Duan, W.-L.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 5628. (l) For
an organocatalytic intramolecular Stetter reaction, see: Kerr, M. S.; Rovis,
T. J. Am. Chem. Soc. 2004, 126, 8876.
4 h
a Unless noted, reactions were carried out with 1a (0.22 mmol), 2a (0.20
mmol), and 4 (0.1-5 mol %) in 1.0 mL of solvent at 8 °C. b Isolated yield.
c Determined by chiral HPLC. d 0.5 mol % of 4. e 0.3 mol % of 4. f 0.1
mol % of 4. g Conducted at -25 °C.
undertook further optimization experiments, and the results
are summarized in Table 1. As shown, most common
solvents are compatible with this Michael reaction, and all
reactions proceed effectively in high yields (83-98%).
However, in terms of enantioselectivity, less polar solvents
(71-80% ee, entries 1-7) are superior to polar solvents,
which caused a dramatic drop in enantiomeric excess (0 and
11% ee, entries 8 and 9). It is noteworthy that decreasing
the catalyst loading greatly improves the enantioselectivity
Org. Lett., Vol. 11, No. 17, 2009
3947

(entry 3 vs entries 10-12) with the best result obtained when
0.3 mol % of 4 was employed (89% ee, entry 11).
Importantly, the reaction works efficiently even with 0.1 mol
% of catalyst 4, though a slightly longer reaction time is
needed (88% ee, entry 12). Further improvement was
achieved when the reaction was performed at a lower
temperature using ether as the cosolvent (98% yield, 92%
ee, entry 13).
reaction. As revealed from entries 4-10, electron-rich (entries
4 and 5), electron-deficient (entries 6 and 7), and relatively
electron-neutral (entry 8) thiols, including disubstituted and
fused ones (entries 9 and 10), all reacted efficiently with
excellent results. Less active alkanethiols are also promising
substrates as long as a higher loading of catalyst is used. For
instance, 4-methoxybenzylmercaptan 1k reacted with R-phenyl
ethyl ꢀ-nitroacrylate 2a in the presence of 10 mol % of catalyst
4 to afford the corresponding product 3k in 90% yield and 87%
ee (entry 11).
Under optimal conditions, the Michael reactions of various
thiols were then investigated, and the results are presented in
Table 2. In the presence of 0.3 mol % of 4, all arenethiols,
Perhaps most importantly, this Michael reaction has
considerable versatility in the Michael acceptor component
as well, as illustrated in Table 3. R-Aryl-, heteroaryl-, and
Table 2. Asymmetric Addition of Thiols 1 to ꢀ-Phenyl Ethyl
Nitroacrylate 2a with Organocatalyst 4a
Table 3. Asymmetric Addition of 2-Thionaphthol 1j to Various
ꢀ-Nitroacrylates 2 with 0.3 mol % of Organocatalyst 4a
.
entry
R1
time (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
4-CH3C6H4 (1a)
2-CH3C6H4 (1b)
3-CH3C6H4 (1c)
4-CH3OC6H4 (1d)
4-t-BuC6H4 (1e)
4-FC6H4 (1f)
4-ClC6H4 (1g)
C6H5 (1h)
3,5-(CH3)2C6H3 (1i)
2-naphthyl (1j)
4-CH3OBn (1k)
4
2
2
2
3
2
2
3
4
3a
98
94
97
92
93
92
95
94
89
97
90
92
3b
3c
3d
3e
3f
3g
3h
3i
93d
88
90
92
90
88
92
91
9
10
11
4
96
3j
3k
93
87d,e
a Unless noted, reactions were carried out with 1 (0.22 mmol), 2a (0.20
mmol), and 4 (0.3 mol %) in 1.0 mL of benzene-Et2O (v/v ) 1/1) at -25
°C. b Isolated yield. c Determined by chiral HPLC. d Conducted in 1.0 mL
of toluene at -45 °C. e 3.0 equiv of thiol and 10 mol % of 4 were used.
a Method A: 1.0 mL of benzene-Et2O (v/v ) 1/1) at -25 °C. Method
B: 1.0 mL of toluene at -25 °C. Method C: 1.0 mL of toluene at -45 °C.
Method D: 1.0 mL of toluene at -60 °C. b Isolated yield. c Determined by
chiral HPLC. d Absolute configuration of 3o was assigned by X-ray analysis.
regardless of their steric or electronic properties, underwent
efficient reactions affording R-sulfenylated ꢀ-nitro esters con-
taining quaternary stereocenters in excellent yields (89-98%)
with high enantioselectivities (88-93% ee). For example,
thiocresols bearing a methyl group at the para, ortho, and meta
positions all provided the corresponding products in great yields
and enantioselectivities (entries 1-3). Moreover, electronic
variations of arenethiols also have minimal impact on the
alkyl-substituted ꢀ-nitroacrylates all reacted efficiently to
provide the corresponding chiral R-sulfenylated ꢀ-nitro esters
containing quaternary stereocenters in excellent yields
(90-100%) with excellent enantioselectivities (90-98% ee)
(9) (a) March, J. AdVanced Organic Chemistry, 4th ed.; Wiley: New
York, 1992; p 796. (b) Node, M.; Nishide, K.; Shigeta, Y.; Shiraki, H.;
Obata, K. J. Am. Chem. Soc. 2000, 122, 1927. (c) Marigo, M.; Schulte, T.;
Franze´n, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 15710. (d)
Palomo, C.; Oiarbide, M.; Dias, F.; Lo´pez, R.; Linden, A. Angew. Chem.,
Int. Ed. 2004, 43, 3307, and references therein.
(11) For reviews on acid-base bifunctional organocatalysis, see: (a)
Marcelli, T.; Maarseveen, J. H. V.; Hiemstra, H. Angew. Chem., Int. Ed.
2006, 45, 7496. (b) Connon, S. J. Chem. Commun. 2008, 2499. For selected
recent examples, see: (c) Liu, T.-Y.; Cui, H.-L.; Long, J.; Li, B.-J.; Wu,
Y.; Ding, L.-S.; Chen, Y.-C. J. Am. Chem. Soc. 2007, 129, 1878. (d) Alema´n,
J.; Milelli, A.; Cabrera, S.; Reyes, E.; Jørgensen, K. A. Chem.sEur. J.
2008, 14, 10958. (e) Guo, C.; Xue, M.-X.; Zhu, M.-K.; Gong, L.-Z. Angew.
Chem., Int. Ed. 2008, 47, 3414. (f) Bui, T.; Syed, S.; Barbas, C. F., III.
J. Am. Chem. Soc. 2009, 131, 8758. (g) Yu, Z.-P.; Liu, X.-H.; Zhou, L.;
Lin, L.-L.; Feng, X.-M. Angew. Chem., Int. Ed. 2009, 48, 5195.
(12) See the Supporting Information for details.
(13) (a) Vakulya, B.; Varga, S.; Csa´mpai, A.; Soo´s, T. Org. Lett. 2005,
7, 1967. (b) Li, B.; Jiang, L.; Liu, M.; Chen, Y.; Ding, L.; Wu, Y. Synlett
2005, 603. (c) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005,
44, 6367. (d) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005,
4481.
(10) For an excellent review, see: (a) Enders, D.; Luttgen, K.; Narine,
A. Synthesis 2007, 959. For selected examples, see: (b) McDaid, P.; Chen,
Y.; Deng, L. Angew. Chem., Int. Ed. 2002, 41, 338. (c) Zu, L.; Wang, J.;
Li, H.; Xie, H.; Jiang, W.; Wang, W. J. Am. Chem. Soc. 2007, 129, 1036.
(d) Ricci, P.; Carlone, A.; Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorre,
P. AdV. Synth. Catal. 2008, 350, 49. (e) Leow, D.; Lin, S.; Chittimlla, S. K.;
Fu, X.; Tan, C.-H. Angew. Chem., Int. Ed. 2008, 47, 5641. (f) Enders, D.;
Hoffman, K. Eur. J. Org. Chem. 2009, 1665. (g) Liu, Y.; Sun, B.; Wang,
B.; Wakem, M.; Deng, L. J. Am. Chem. Soc. 2009, 131, 418. During the
manuscript preparation, Ellman and co-workers reported the addition of
thioacetic acid to nitroalkenes: (h) Kimmel, K. L.; Robak, M. T.; Ellman,
J. A. J. Am. Chem. Soc. 2009, 131, 8754.
3948
Org. Lett., Vol. 11, No. 17, 2009

in the presence of 0.3 mol % of catalyst 4. Furthermore, the
absolute configuration of the newly formed S-quaternary
stereocenter in product 3o was unambiguously determined
to be S by X-ray crystallographic analysis.14 Upon this and
previous reported bifunctional aspects of Cinchona alkaloid
based thiourea catalysts, we proposed a plausible working
model (TS1) in which the synergistic cooperative activation
of the nucleophilic thiol 1 and electrophilic nitroacrylate 2
should be essential for the observed high enantioselective
discrimination in the present catalytic system (Figure 1).
of p-thiocresol 1a and R-phenyl-ꢀ-nitroacrylate 2a in 96% yield
with 94% ee (Scheme 2).
Scheme 2.
Synthesis of R-Thiol-ꢀ2,2-amino Acid 5
In addition, the ꢀ2,2-amino acids would be valuable
precursors for the synthesis of novel ꢀ or mixed ꢀ/R-peptides
as illustrated in the synthesis of dipeptide 8 (eq 3). In the
presence of peptide-coupling reagent 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and
N,N-diisopropylethylamine (DIPEA), R-thio-ꢀ2,2-amino acid
6 reacted with L-Phe-OMe·HCl 7 cleanly to provide dipeptide
8 in 87% yield after 12 h.
Figure 1. X-ray structure of 3o and proposed transition state (TS) of
the Michael reaction. Key: C, gray; H, white; N, blue; O, red; S, yellow.
In conclusion, we have developed a highly efficient and
enantioselective organocatalytic Michael reaction with R,ꢀ,ꢀ-
disubstituted Michael acceptors, which opened a new way
to construction of a heteroquaternary stereocenter, and
synthesis of ꢀ2,2-amino acid and ꢀ-peptides. The reaction
itself features simple experimental procedures under benign
conditions and is completely atom-economic in character.
The significance of the current protocol was then demon-
strated in the expedient synthesis of R-thio-ꢀ2,2-amino acids from
the conjugate addition products. As a representative example,
the (S)-3-acetamido-2-phenyl-2-(p-tolylthio)propanoic acid 6
was obtained in an overall yield of 65% with retention of optical
purity after a straightforward three-step sequence (nitro-reduc-
tion/amine acylation/ester hydrolysis) from the Michael adduct
3a, which was conveniently prepared in a gram-scale reaction
Acknowledgment. We are grateful to the National Science
Foundation of China (20872043) and the Program for New
Century Excellent Talents in University (NCET-05-0672) for
support of this research.
(14) Crystal data of 3o: C27H23NO4S, Mr ) 457.52, monoclinic, space
group P2(1), a ) 12.7746(9) Å, b ) 5.8697(4) Å, c ) 16.0370(11) Å,
R ) 90°, ꢀ ) 102.412(4)°, γ ) 90°, V ) 1174.40(14) Å3, Dcalc ) 1.294
Mg/m3, T ) 298(2) K, Z ) 2, 12749 reflections collected, 4770 independent
(Rint ) 0.0239), final R indices [I > 2σ(I)]: R1 ) 0.0473, wR2 ) 0.1188, R
indices (all data): R1 ) 0.0563, wR2 ) 0.1243, absolute structure parameter:
0.02(8), GOF(F2) ) 1.051. CCDC 735278 contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Supporting Information Available: Experimental pro-
cedures and compound characterization data including X-ray
crystal data (CIF) for 3o. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL901572X
Org. Lett., Vol. 11, No. 17, 2009
3949