Chiral bronsted acid catalyzed enantioselective α- aminoxylation of enecarbamates

Article abstract of DOI:10.1002/anie.201002640

A practically simple, highly enantioselective Bronsted acid catalyzed α-aminoxylation of enecarbamates extends the substrate scope for the α-aminoxylation to linear and aromatic ketones, allowing convergent and stereoselective access to valuable α-hydroxy ketones, β-amino alcohols, and cis-oxazolidinones.

Full text of DOI:10.1002/anie.201002640

Communications
DOI: 10.1002/anie.201002640
Asymmetric Aminoxylation
Chiral Brønsted Acid Catalyzed Enantioselective
a-Aminoxylation of Enecarbamates**
Min Lu, Yunpeng Lu, Di Zhu, Xiaofei Zeng, Xinsheng Li, and Guofu Zhong*
Dedicated to Professor Pierre Vogel on the occasion of his 65th birthday
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Chemie
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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]
À
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
À
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
under http://dx.doi.org/10.1002/anie.201002640.
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Table 1: Screening of reaction conditions.[a]
Table 2: Substrate scope of the chiral phosphoric acid catalyzed
a-aminoxylation of enecarbamates.[a]
Entry
R
Ar
Yield [%][b] e.r.[c]
1
2
3
4
Ph (1a)
Ph (1a)
Ph (1a)
Ph (2a)
95 (4a)
95 (4b)
93 (4c)
44 (5)
97:3
98:2
98:2
p-ClC6H4 (2b)
p-BrC6H4 (2c)
p-Tol (2d)
Entry
Solvent
t [h]
O/N[b]
Yield [%][c]
e.r.[d]
Ph (1a)
97:3
1
2
3
CH2Cl2
toluene
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0.1
0.1
12
0.2
0.5
0.2
0.5
0.1
>95:5
94:6
88
85
-
90
85
95
90
-
90:10
88:12
–
92:8
90:10
97:3
96:4
–
5
6
7
8
Ph (1a)
Ph (1a)
Ph (1a)
m-ClC6H4 (2e)
o-ClC6H4 (2 f)
p-CO2MeC6H4 (2g) 98 (4 f)
p-ClC6H4 (2b)
p-ClC6H4 (2b)
p-ClC6H4 (2b)
p-ClC6H4 (2b)
p-ClC6H4 (2b)
p-ClC6H4 (2b)
p-ClC6H4 (2b)
91 (4d)
89 (4e)
98:2
96:4
97:3
98.5:1.5
96.5:3.5
97:3
96:4
96:4
<5:95
>95:5
>95:5
>95:5
>95:5
<5:95
4[e]
5[f]
6[e,g]
7[e,g,h]
8[e,g,i]
p-ClC6H4 (1b)
p-MeOC6H4 (1c)
p-Tol (1d)
m-Tol (1e)
o-Tol (1 f)
Me (1g)
96 (4g)
93 (4h)
95 (4i)
90 (4j)
89 (4k)
90 (4l)
92 (4m)
9
10
11
12
13[d]
14
[a] For screening details, see the Supporting Information. [b] Determined
by 1H NMR spectroscopy. [c] Yield of isolated product. [d] Determined by
HPLC on a chiral stationary phase. [e] Reaction conducted at 48C.
[f] Reaction conducted at À208C. [g] 5 ꢀM.S. were added. [h] 2 mol% of
3a was used. [i] (Z)-1a was used instead of (E)-1a. An=anthryl, Np=
naphthyl, THF=tetrahydrofuran.
90:10
98:2
Ph (1h)
[a] For detailed reaction conditions, see the Supporting Information.
[b] Yield of isolated product. [c] Determined by HPLC or GC analysis on a
chiral stationary phase. [d] 10 mol% of 3c was used.
Aromatic solvents delivered similar results (Table 1,
entry 2); however, when ethereal solvents were used, N-
addition was favored (Table 1, entry 3, O/N < 5:95). Notably,
although a prolonged reaction time was required at 48C, an
efficient catalytic performance with higher e.r. was observed
(Table 1, entry 4, e.r. 92:8); further lowering the temperature
to À208C gave rise to diminished enantiocontrol (Table 1,
entry 5). Remarkably, both the yields and optical purity were
improved in the presence of 5 ꢀ molecular sieves (Table 1,
entry 6; 95% yield, e.r. 97:3). Catalyst loadings as low as
2 mol% could be utilized without compromising the reac-
tivity and selectivity (Table 1, entry 7). It is also noteworthy
that when changing the enecarbamate geometry from E to Z,
a dramatic inversion in O/N selectivity was observed (Table 1,
entry 8).[17]
enough steric bulkiness when subjected to the chiral environ-
ment created by catalyst 3c, and the product 4l was isolated in
90% yield with 90:10 e.r. (Table 2, entry 13). Furthermore,
the more-challenging enecarbamates derived from indanones
and tetralones could also successfully undergo a-aminoxyla-
tion to give a-oxygenated products in good yields and ee
values [Eq. (1)], although specific catalyst was needed for
Experiments that probed the scope of this novel trans-
formation under optimized conditions are summarized in
Table 2. A broad spectrum of nitrosoarenes could be
employed in the reaction to afford the desired products in
excellent yields and high enantioselectivities (Table 2,
entries 1–7), with the exception of 4-nitrosotoluene (Table 2,
each substrate. The absolute configuration of 4a, 7a, and 7d
were determined to be S after catalytic hydrogenation to
convert them to the corresponding a-hydroxy ketones[16] and
comparing the optical rotation with literature.[18] The stereo-
chemistry of other products was tentatively assumed by
analogy.
To highlight the synthetic utility of this procedure, we
present preliminary results for the one-pot synthesis of
orthogonally protected b-amino alcohols and a straightfor-
ward access to cis-oxazolidinones. The b-amino alcohol
moiety is found in a wide range of biologically active natural
products,[19] and is also well-recognized in asymmetric syn-
thesis, as many chiral auxiliaries and ligands contain this
À
entry 4) in which N O bond heterolysis was observed after
the initial aminoxylation.[6] Enecarbamates derived from
aromatic ketones that have substituents with various elec-
tronic and steric properties were also found to efficiently react
with 4-chloronitrosobenzene (2b), and the products were
obtained in high enantioselectivities (Table 2, entries 8–12).
For aliphatic-ketone-derived enecarbamate, the use of an
ethyl carbamate group resulted in poor enantioselectivity
(70:30 e.r.); nevertheless, following systematic modification
of the carbamate group as well as fine tuning of the catalyst,[16]
wer found that the mesitylmethyl group was able to provide
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substructure.[20] Specifically, after the a-aminoxylation of 1a
had been completed, reduction of the crude product with
DIBAL (diisobutylaluminium hydride) at À788C efficiently
furnished the protected b-amino alcohol 10 in 88% yield and
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À
12.5:1 d.r. (Scheme 1). After a SmI2-promoted N O bond
heterolysis, cis-oxazolidinone was obtained using a reported
procedure.[21]
À
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In conclusion, we have reported a facile, practically
appealing, highly enantioselective Brønsted acid-catalyzed
a-aminoxylation of enecarbamates. This procedure consider-
ably extend the substrate scope for the a-aminoxylation
reaction to linear and aromatic ketones, allowing convergent
and stereoselective access to valuable a-hydroxy ketones, b-
amino alcohols, and cis-oxazolidinones in their enantiopure
form. This discovery also provides mechanistic insights into
the N/O selectivity of a-aminoxylation. Further applications
of this activation mode to other enantioselective reactions are
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Received: May 2, 2010
Published online: July 26, 2010
Keywords: a-hydroxy ketones · aminoxylation ·
.
asymmetric catalysis · Brønsted acid catalysis ·
nitroso compounds
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