Direct asymmetric hydroxyamination reaction catalyzed by an axially chiral secondary amine catalyst

Article abstract of DOI:10.1021/ja0604515

A direct asymmetric hydroxyamination reaction of aldehydes with nitrosobenzene was found to be catalyzed by the novel axially chiral secondary amine catalyst (S)-1d. The resulting optically enriched hydroxyamination products were readily converted to β-am

Full text of DOI:10.1021/ja0604515

Published on Web 04/18/2006
Direct Asymmetric Hydroxyamination Reaction Catalyzed by an Axially Chiral
Secondary Amine Catalyst
Taichi Kano, Mitsuhiro Ueda, Jun Takai, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received January 28, 2006; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Table 1. Enantioselective Hydroxyamination of Propanal with
Nitrosobenzene Catalyzed by (S)-1-2a
Nitroso compounds are frequently utilized as a nitrogen and/or
an oxygen source in synthetic organic chemistry,1 and various
catalytic asymmetric reactions, such as aminoxylation,2-5 hydroxy-
amination,4-6 and nitroso Diels-Alder reaction,7 have recently been
developed by exploiting their unique properties. In this area, the
reactions between nitrosobenzene and activated carbonyl com-
pounds including enolates and enamines were known to provide
aminoxylation or hydroxyamination products, depending on the
catalyst used, and the reaction course and enantioselectivity were
successfully controlled in both metal- and organocatalytic ap-
proaches.2,4,5 Furthermore, highly enantioselective aminoxylation
reactions using simple aldehydes and ketones were also realized
by proline and the related catalysts through the in situ generation
of the reactive enamine (Scheme 1).3 In marked contrast, however,
the opposite chemoselectivity, i.e., the direct enantioselective
hydroxyamination of aldehydes has not been realized to a syntheti-
cally useful level despite the potential application of the resulting
R-amino aldehydes in organic synthesis.6 Thus far, a highly
enantioselective hydroxyamination of enamines instead of simple
aldehydes has been developed by selective activation of nitroso
compounds with chiral tertiary alcohols such as TADDOL.4 In this
context, we have been interested in the possibility of designing a
sterically and electrically tunable organocatalyst, which may
simultaneously activate both aldehydes and nitrosobenzene. Herein,
we report a highly efficient organocatalytic asymmetric hy-
droxyamination reaction of aldehydes with nitroso compounds by
using a binaphthyl-modified catalyst with dual functions.
entry
catalyst
3/4
% yieldb
% eec
configd
1
(S)-1a
(S)-1a
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1d
(S)-1d
(S)-1e
(S)-2a
(S)-2b
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
22
37
36
55
78
90
87
36
28
23
9
29
13
21
77
95
99
98
62
83
5
S
S
S
S
S
S
S
S
S
R
R
2e
3e
4
5
6
7f
8g
9
10h
11h
23
a The reaction of propanal (3 equiv) with nitrosobenzene was carried
out in THF in the presence of catalyst (S)-1-2 at 0 °C. b Isolated yield.
c Determined by HPLC analysis using chiral column (Chiralpak AD-H,
Daicel Chemical Industries, Ltd.). d The absolute configuration was deter-
mined by comparison of the sign of optical rotation with reported values.
See Supporting Information. e In the presence of 1 equiv of MeOH (entry
2) or t-BuOH (entry 3). f 5 mol % of (S)-1d. g 1 mol % of (S)-1d. h Reaction
was conducted for 24 h.
Scheme 1
Due to the ease of modification of the binaphthyl backbone, we
first attempted to use (S)-1a as a catalyst for the direct asymmetric
hydroxyamination reaction. Thus, treatment of propanal with
nitrosobenzene in the presence of 10 mol % of (S)-1a in THF at 0
°C and subsequent reduction with NaBH4 in THF/MeOH furnished
the corresponding N-hydroxy-â-amino alcohol 3 in low yield and
enantioselectivity (Table 1, entry 1). We then examined the effect
of an alcohol with the expectation that the hydroxyamination
reaction would be facilitated by modest activation of nitrosobenzene
through hydrogen bonding with alcohols. Indeed, addition of 1 equiv
of either MeOH or t-BuOH was found to enhance the reaction rate
(entries 2 and 3). These results prompted us to design new amine
catalysts of type (S)-1b-d having hydroxyl groups at the appropri-
ate positions to improve both reactivity and enantioselectivity. When
(S)-1b having hydroxylmethyl groups at 3,3′-positions was used
as a catalyst, both reactivity and enantioselectivity were significantly
improved (entry 4). To our delight the reaction using (S)-1c, which
has sterically congested tert-alcohol moieties at 3,3′-positions,
proceeded smoothly under similar conditions to give the desired
hydroxyamination product in good yield with excellent regio- and
enantioselectivity (entry 5). Further improvement in both reactivity
and enantioselectivity was achieved by using (S)-1d with hydroxy-
diphenylmethyl groups at 3,3′-positions (entry 6). The marked effect
of hydroxyl groups in (S)-1d on the reaction rate is apparent by
comparison with des-hydroxyl catalyst (S)-1e, which affords 3 in
low yield with high enantioselectivity (entry 9). The catalyst loading
in (S)-1d could be reduced to 5 mol % (entry 7), while the use of
1 mol % of (S)-1d resulted in a considerable decrease in both yield
and enantioselectivity (entry 8). In contrast, attempted use of the
proline-derived catalysts (S)-2a and (S)-2b resulted in a significant
loss of reactivity and enantioselectivity, probably due to the catalyst
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J. AM. CHEM. SOC. 2006, 128, 6046-6047
10.1021/ja0604515 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Hydroxyamination of Various Aldehydes
with Nitrosobenzene and Catalyzed by (S)-1da
Figure 1. Possible transition state for the direct asymmetric hydroxyami-
nation reaction catalyzed by (S)-1d.
the hydroxydiphenylmethyl groups on the catalyst (S)-1d might play
a different role in the present reaction. After formation of the
enamine intermediate from aldehydes and the catalyst (S)-1d, one
hydroxydiphenylmethyl group shields the re face of the enamine
effectively, and another directs and activates the nitrosobenzene
by hydrogen bonding. Hence, the obtained hydroxyamination
products have the S configuration.
In summary, we have developed a direct asymmetric hy-
droxyamination reaction of aldehydes with nitrosobenzene catalyzed
by the novel axially chiral secondary amine catalyst (S)-1d. The
resulting optically enriched hydroxyamination products are readily
converted to the corresponding â-amino alcohol or 1,2-diamine in
one pot. We are currently applying this and related methodologies
toward the preparation of a variety of nitrogen-containing chiral
building blocks.
a The reaction of an aldehyde (3 equiv) with nitrosobenzene was carried
out in THF in the presence of catalyst (S)-1d at 0 °C. b Isolated yield. c No
aminoxylation product was detected. d Determined by HPLC analysis using
chiral column. Details are given in Supporting Information.
deactivation through the undesired oxazolidine formation from
catalysts and propanal (entries 10 and 11).
With the axially chiral secondary amine catalyst (S)-1d in hand,
the direct asymmetric hydroxyamination reaction of several other
aldehydes with nitrosobenzene was executed, and the results are
shown in Table 2. In general, these direct asymmetric hydroxyami-
nation reactions proceeded smoothly, and the subsequent reduction
with NaBH4 gave the corresponding N-hydroxy-â-amino alcohols
in good isolated yields with excellent levels of enantioselectivity.
To enhance the synthetic utility of this methodology, p-
methoxynitrosobenzene was employed instead of nitrosobenzene,
and by using the resulting hydroxyamination product, one-pot
procedures to prepare the â-amino alcohol or the 1,2-diamine were
also developed (Scheme 2). Thus, under similar conditions, the
reaction of 3-cyclohexylpropanal with p-methoxynitrosobenzene
was carried out, and the hydroxyamination product was treated with
LiAlH4 in the same pot to give the (S)-â-amino alcohol 5 protected
with a cleavable p-methoxyphenyl group with excellent enantiose-
lectivity. Moreover, the hydroxyamination product could be con-
verted to the fully protected (S)-1,2-diamine 6 without loss of
enantiopurity by the one-pot procedure including O-benzyloxime
formation, reduction of the NdC double bond and reductive
cleavage of two N-O bonds with LiAlH4, and Boc protection.
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Experimental details and
characterization data for new compounds including the preparation of
catalysts. This material is available free of charge via the Internet at
http://pubs.acs.org.
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Scheme 2. One-Pot Synthesis of â-Amino Alcohol and
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