Angewandte
Chemie
a-Hydroxy carbonyl compounds are key motifs encountered
throughout natural products and pharmacueticals; thus, the
preparation of chiral a-hydroxy ketones has been of great
interest and has motivated a tremendous wealth of strategies
for their synthesis.[1] Catalytic asymmetric a-aminoxylation
reactions[2–6] are one of the most facile and conventional
synthetic methods towards chiral a-hydroxy ketones. How-
ever, despite considerable efforts in the area of a-amino-
xylation, so far the substrate scopes have been limited to
aldehydes,[4] cyclic ketones,[5] and b-dicarbonyl compounds.[6]
The use of linear ketones resulted in significant decrease in
both the reactivity and selectivity,[7] while no examples with
aromatic ketones have been documented, possibly because of
the severe steric hindrance which strongly inhibited the
covalent binding of the catalyst.
To address these challenges, enecarbamate 1 was chosen
as an activated ketone nucleophile (Figure 1);[8] we envi-
sioned that in the presence of an electron-withdrawing
carbamate group (TS), instead of an electron-donating
pyrrolidine moiety (used in proline catalysis, TS*), the
undesired N-addition pathway might be suppressed. The
fact that both the E and Z isomers of enecarbamates can be
conveniently prepared provides additional flexibility for this
approach.[9] Meanwhile, chiral Brønsted acids[10,11] would be
attractive alternatives for overcoming the limitations of
proline catalysis in a-aminoxylation reactions, as selective
protonation of the basic nitrogen of nitrosobenzene should be
realized by a judicious choice of stronger acid (TS).[12]
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However, no efficient C O bond formation of enecarbamates
has been reported, despite recent successes in the catalytic
asymmetric aza–ene reactions of enecarbamates with alde-
hydes[13] and imines.[14] In a continuation of our long standing
work in aminoxylation chemistry,[15] we recently discovered
that highly enantioselective a-hydroxylation of b-dicarbonyl
compounds can be achieved through activation of nitroso
compounds with binol-derived phosphoric acids.[6] To further
explore the extent of this novel activation mode, herein we
describe the first chiral-phosphoric-acid-catalyzed a-amino-
xylation of ene-carbamates, and its one-pot application
leading to direct access of optically pure a-hydroxy ketones,
b-amino alcohols, and oxazolidinones.
On the basis of our initial DFT calculations (Figure 2),[16]
it was found that with a stronger Brønsted acid, such as
Figure 2. DFT-calculated lowest-energy transition state for the O-
selective (TS-1) and N-selective (TS-2) pathways.[16]
Figure 1. Projected synthesis of chiral a-hydroxy ketones 5.
phosphoric acid, as the catalyst, the O-selective pathway (TS-
1) would be favored by 2.91 kcalmolÀ1; we proposed that the
utility of this activation mode would rely on the identification
of a phosphoric acid 3 with suitable R groups that could
[*] M. Lu, Dr. Y. Lu, D. Zhu, X. Zeng, Dr. X. Li, Prof. Dr. G. Zhong
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University
21 Nanyang Link, Singapore 637371 (Singapore)
Fax: (+65)6791-1961
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induce high levels of enantiocontrol in the C O bond-forming
step. To test this concept, we carried out the reaction using
1.1 equivalents of enecarbamate 1a and nitrosobenzene 2a
(Table 1).[16] As expected, 5 mol% of phosphoric acid (R)-3a
effectively promoted the reaction in dichloromethane at room
temperature within 5 minutes (Table 1, entry 1). The reaction
can be monitored easily by observation of its color change
from green to orange, and, after hydrolysis, furnished the
desired product 4a in 88% yield with almost complete O-
selectivity (O/N > 95:5), accompanied by promising enantio-
selectivity (90:10 e.r.).
E-mail: guofu@ntu.edu.sg
[**] Research support from the Ministry of Education in Singapore
(ARC12/07, no. T206B3225) and Nanyang Technological University
(URC, RG53/07 and SEP, RG140/06) is gratefully acknowledged.
Y.L. thanks the Division of Chemistry and Biological Chemistry at
Nanyang Technological University for providing the computational
resources.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2010, 49, 8588 –8592
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8589