Enantioselective nitroaldol reaction of α-ketoesters catalyzed by cinchona alkaloids

Article abstract of DOI:10.1021/ja057237l

The development of highly enantioselective and general catalytic nitroaldol (Henry) reactions with ketones is a challenging yet desirable task in organic synthesis. In this communication, we report an asymmetric nitroaldol reaction with α-ketoesters catalyzed by a new C6′-OH cinchona alkaloid catalyst. This is the first highly efficient organocatalytic asymmetric Henry reaction with ketones. This reaction is operationally simple and affords high enantioselectivity as well as good to excellent yield for a broad range of α-ketoesters. . Copyright

Full text of DOI:10.1021/ja057237l

Published on Web 12/22/2005
Enantioselective Nitroaldol Reaction of r-Ketoesters Catalyzed by Cinchona
Alkaloids
Hongming Li, Baomin Wang, and Li Deng*
Department of Chemistry, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
Received October 24, 2005; E-mail: deng@brandeis.edu
Scheme 1. A General Approach to Optically Active Tertiary
Carbinols
The nitroaldol reaction or Henry reaction constitutes an important
class of C-C bond forming reactions that provide straightforward
access to important synthetic intermediates from readily accessible
nitroalkanes and carbonyl compounds.1 Due to its significance in
organic synthesis, considerable efforts have been devoted to the
development of efficient catalytic asymmetric nitroaldol reactions.2
Consequently, several chiral metal complexes and chiral phase
transfer catalysts have been identified to be highly efficient catalysts
for enantioselective nitroaldol reactions with aldehydes.3
In contrast to the substantial progress made with aldehydes, the
development of enantioselective nitroaldol reaction with ketones
has met with limited success.4 To date, only one catalyst system,
consisting of a Cu-bisoxazoline complex and triethylamine, has
been identified to afford synthetically useful enantioselectivity for
the addition of nitromethane to R-ketoesters 2.4a,b However, in
addition to requiring a catalyst loading of 20 mol % and the use of
anhydrous conditions, both the yield and enantioselectivity of the
reaction display a dependence on the structure of 2. For example,
the enantioselectivity was high for reactions with aryl R-ketoesters
bearing an electron-withdrawing group on the aromatic ring, and
it became moderate when the electron-withdrawing group was
replaced with an electron-donating substituent. Depending on the
steric bulk of the alkyl R-ketoesters, the enantioselectivity could
be either high or modest. For R-ketoesters bearing an alkenyl group,
synthetically useful enantioselectivity was not attainable.
On the other hand, it is especially desirable to realize a catalytic
asymmetric nitroaldol reaction that affords high enantioselectivity
for a wide rang of R-ketoesters 2. Such a reaction, in combination
with the synthetic versatility of the ester and the nitro groups, will
provide enantioselective access to a broad range of optically active
tertiary carbinols (Scheme 1). In this communication, we wish to
report a significant progress toward achieving this goal.
Figure 1. C6′-OH cinchona alkaloid derivatives.
Table 1. Enantioselective Nitroaldol Addition of Nitromethane to
R-Ketoester 2aa
c
entry
catalystb
conv. (%)c
3a/3a
′
ee (%)d
1
2
Et3N
QD
>95
91
80/20
>95/5
>95/5
>95/5
>95/5
>95/5
>95/5
>95/5
>95/5
>95/5
-17
59
40
61
86
70
93
97
-97
3
4
5
6
DHQD-PHN
(DHQD)2AQN
â-ICD
74
>95
>95
>95
93
QD-1a
7
QD-1b
8
QD-1c
93
9
10
QD-1d
Q-1d
>95
>95
a Unless noted, reactions were carried out with 0.1 mmol of 2a, 1 mmol
of CH3NO2 in 0.1 mL of CH2Cl2 with 10 mol % catalyst at -20 °C for 12
h. b See Supporting Information for the structure of the catalysts. c Deter-
1
Although effective chiral organic catalysts have been reported
for enantioselective aza-Henry reactions,5,6 no broadly effective
chiral organic catalyst has been developed for the direct asymmetric
Henry reaction. We recently reported C6′-OH cinchona alkaloids
1a-c (Figure 1) as efficient catalysts for various enantioselective
conjugate additions.7 Mechanistic studies from our laboratories
indicated that catalysts 1 could serve as acid-base bifunctional
catalysts via hydrogen bonding interactions with the Michael donor
and acceptor through the quinuclidine nitrogen and the C6′-OH,
respectively. In light of the wide range of nucleophiles and
electrophiles that could engage in hydrogen bonding interactions,
we envisaged that catalysts 1 might be able to effectively stabilize
and organize transition states involving nucleophiles and electro-
philes other than Michael donors and acceptors, thereby allowing
1 to function as efficient enantioselective catalysts for reactions
that are mechanistically distinct from conjugate additions. Guided
by these considerations, we began to investigate 1 as catalysts for
enantioselective nitroaldol reaction with R-ketoesters 2.
mined by H NMR analysis. d Determined by HPLC analysis.
achieved for nitroaldol reactions of this important class of R-ke-
toesters. Furthermore, alkenyl R-ketoesters could engage in 1,2-
as well as 1,4-additions with a nitroalkane, thus presenting a
particularly challenging class of substrates for nitroaldol reactions.
As reported previously,4b nitromethane reacted with 2a in the
presence of Et3N to give products 3a and 3a′ in 4:1 ratio (entry 1,
Table 1).
Promoted by various cinchona alkaloids, the addition of ni-
tromethane to 2a in methylene chloride proceeded in a highly
chemoselective fashion to cleanly afford the nitroaldol product 3a
(Table 1). The enantioselectivity of the C6′-OH cinchona alkaloids
1a-c was found to be considerably higher than that displayed by
C6′-OMe cinchona alkaloids (entries 6-8 vs 2-4, Table 1).
Furthermore, the significant impact of the C9 substituent (OR) on
the enantioselectivity of 1 raised the possibility of finding a more
effective and practical C6′-OH cinchona alkaloid for the nitroaldol
reaction by modifications of this substituent. Further studies
following this hypothesis led to the discovery that C6′-OH
We first focused on the addition of nitromethane to alkenyl
R-ketoester 2a because high enantioselectivity had not yet been
9
732
J. AM. CHEM. SOC. 2006, 128, 732-733
10.1021/ja057237l CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Nitroaldol Addition of Nitromethane to
R-Ketoester 2 Catalyzed by QD-1d and Q-1d (in parentheses)a
aziridines 7 are valuable intermediates for the synthesis of optically
active R,R-disubstituted R-amino acids. It should be noted that
R-methylcysteine (8j) was the key intermediate in the total syntheses
of mirabazoles and thiangazole.11 The ability of 1d to promote
highly enantioselective nitroaldol reaction for a wide range of
R-ketoesters 2 should facilitate the preparations of analogues of
these antitumor and anti-HIV natural products.
In conclusion, we have developed the first efficient organocata-
lytic enantioselective nitroaldol reaction with ketones using a new
C6′-OH cinchona alkaloid 1d. Employing a relatively low loading
of an easily accessible and recyclable chiral catalyst and affording
high enantioselectivity for a wide range of R-ketoesters 2, the
reaction should provide a broadly useful approach for the asym-
metric synthesis of chiral compounds containing tetrasubstituted
carbon stereocenters. The current study also reveals for the first
time that the C6′-OH cinchona alkaloids 1 are highly efficient
catalysts for enantioselective 1,2-additions to carbonyls.
Acknowledgment. We are grateful for the generous financial
support from National Institutes of Health (GM-61591).
Supporting Information Available: Experimental procedures and
characterization of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Unless noted, reactions were run with 0.5 mmol of 2, 5 mmol of
CH3NO2 in 0.5 mL of CH2Cl2 with 5 mol % QD-1d; the results in
parentheses were obtained with Q-1d to give opposite enantiomer; see
Supporting Information for details. b Isolated yield. c Determined by HPLC
analysis. d The absolute configuration is determined to be S; see Supporting
Information for details.
References
(1) For reviews, see: (a) Luzio, F. A. Tetrahedron 2001, 57, 915-945. (b)
Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York,
2001. (c) Seebach, D.; Beck, A. K.; Mukhopadhyay, T.; Thomas, E. HelV.
Chim. Acta 1982, 65, 1101-1133.
(2) For a recent review of catalytic asymmetric nitroaldol reactions, see:
Palomo, C.; Oiarbide, M.; Mielgo, A. Angew. Chem., Int. Ed. 2004, 43,
5442-5444.
Scheme 2. Asymmetric Synthesis of â-Lactam, Aziridine, and
R-Methylcysteine Derivatives (see Supporting Information for
details)a
(3) (a) Sasai, H.; Suzuki, T.; Arai, S.; Shibasaki, M. J. Am. Chem. Soc. 1992,
114, 4418-4420. (b) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002,
102, 2187-2209. (c) Trost, B.; Yeh, V. S. C. Angew. Chem., Int. Ed.
2002, 41, 861-863. (d) Trost, B.; Yeh, V. S. C.; Ito, H.; Bremeyer, N.
Org. Lett. 2002, 4, 2621-2623. (e) Evans, D. A.; Seidel, D.; Rueping,
M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2003,
125, 12692-12693. (f) Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem.,
Int. Ed. 2005, 44, 3881-3884. (g) Corey, E. J.; Zhang, F.-Y. Angew.
Chem., Int. Ed. 1999, 38, 1931-1934. (h) Ooi, T.; Doda, K.; Maruoka,
K. J. Am. Chem. Soc. 2003, 125, 2054-2055.
(4) (a) Christensen, C.; Juhl, K.; Jørgensen, K. A. Chem. Commun. 2001,
2222-2223. (b) Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K.
A. J. Org. Chem. 2002, 67, 4875-4881. (c) Misumi, Y.; Bulman, R. A.;
Matsumoto, K. Heterocycles 2002, 56, 599-606. (d) Lu, S. F.; Du, D.
M.; Zhang, S. W.; Xu, J. X. Tetrahedron: Asymmetry 2004, 15, 119-
126. (e) Du. D. M.; Lu, S. F.; Fang, T.; Xu, J. X. J. Org. Chem. 2005, 70,
3712-3715.
a Conditions: (a) Raney Ni, H2 (1 atm); (b) i-PrMgCl, 38% yield over
two steps; (c) TfN3, CuSO4(cat.), for 6c, 84% yield over two steps; for 6j,
63% yield over two steps; (d) PPh3, CH3CN, for 7c, 80% yield; for 7j,
71% yield; (e) BF3‚Et2O, p-methoxybenzyl mercaptan, 56% yield.
(5) For a recent review on catalytic asymmetric aza-Henry reactions, see:
Westermann, B. Angew. Chem., Int. Ed. 2003, 42,151-153.
(6) For recent examples of catalytic asymmetric aza-Henry reactions with
organic catalysts see: (a) Yoon, T. P.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2005, 44, 466-468. (b) Nugent, B. M.; Yoder, R. A.; Johnston,
J. N. J. Am. Chem. Soc. 2004, 126, 3418-3419. (c) Okino, T.; Nakamura,
S.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625-627.
(7) (a) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126,
9906-9907. (b) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.;
Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105-108. (c)
Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7, 167-169. (d) Li, H.; Song,
J.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2005, 127, 8948-8949.
(8) For preparations of Q-1d and QD-1d, see Supporting Information.
(9) Under the same condition, the addition of nitroethane to 2c with Q-1d
afforded the 1,2-adducts in 4/1 dr and in 75% ee/88% ee, respectively;
acetophenone was found to be inactive for the 1-catalyzed nitroaldol
reaction with nitromethane.
cinchona alkaloid bearing a C9-OBz group (QD-1d) is even more
effective than 1a-c. The addition of nitromethane to 2a with either
QD-1d or Q-1d occurred in 97% ee (entries 9 and 10, Table 1). It
is noteworthy that the preparation of 1d employs significantly
cheaper reagents than those required for the preparation of 1c.8
With 5.0 mol % of 1d, excellent enantioselectivity and high yield
could be attained not only for alkenyl R-ketoesters 2a,b but also
for a broad range of aryl and alkyl R-ketoesters 2c-m (Table 2).9
Thus, the enantioselectivity of 1d is insensitive to either the steric
or the electronic properties of 2. The unprecedented excellent
enantioselectivity obtained with R-ketoestes 2 bearing alkenyl,
electron-rich aryl and sterically bulky alkyl groups is noteworthy.
Among them 2a, 2d, and 2l were previously reported to react with
nitromethane in 57-77% ee with existing catalyst systems, and
enantioselective nitroaldol reaction was not documented for 2b, 2e,
and 2m.4a,b,e
(10) (a) Greenlee, W. J.; Springer, J. P.; Patchett, A. A. J. Med. Chem. 1989,
32, 165-170. (b) Kiyota, H.; Takai, T.; Saitoh, M.; Nakayama, O.; Oritani,
T.; Kuwahara, S. Tetrahedron Lett. 2004, 45, 8191-8194.
(11) (a) Pattenden, G.; Thom, S. M. Synlett 1992, 533-534. (b) Mulqueen, G.
C.; Pattenden, G.; Whiting, D. A. Tetrahedron 1993, 49, 5359-5364. (c)
Boyce, R. J.; Pattenden, G. Synlett 1994, 587-588. (d) Boyce, R. J.;
Mulqueen, G. C.; Pattenden, G. Tetrahedron Lett. 1994, 35, 5705-5708.
(e) Parsons, R. L.; Heathcock, C. H. Tetrahedron Lett. 1994, 35, 1379-
1382. (f) Parsons, R. L.; Heathcock, C. H. Tetrahedron Lett. 1994, 35,
1383-1384. (g) Parsons, R. L.; Heathcock, C. H. J. Org. Chem. 1994,
59, 4733-4734. (h) Shao, H.; Zhu, Q.; Goodman, M. J. Org. Chem. 1995,
60, 790-791.
We have applied the 1d-catalyzed nitroaldol reaction to develop
new and concise asymmetric syntheses of synthetically important
chiral intermediates, such as aziridines 7 and â-lactams 5 (Scheme
2).10 As shown by the conversion of 7j to 8j, optically active
JA057237L
9
J. AM. CHEM. SOC. VOL. 128, NO. 3, 2006 733