Asymmetric Oxy-Michael Addition to γ-Hydroxy-α,β-Unsaturated Carbonyls Using Formaldehyde as an Oxygen-Centered Nucleophile

Article abstract of DOI:10.1021/ol503104b

Formaldehyde was utilized as an oxygen-centered nucleophile in an asymmetric oxy-Michael addition to γ-hydroxy-α,β-unsaturated carbonyl compounds using bifunctional organocatalysts through hemiacetal intermediates. The cyclic acetal product could be further transformed into β-hydroxycarbonyl compounds, useful synthetic intermediates leading to various important target molecules. As such, this method is an example of a novel formal asymmetric hydration of α,β-unsaturated carbonyl compounds.

Full text of DOI:10.1021/ol503104b

Letter
pubs.acs.org/OrgLett
Asymmetric Oxy-Michael Addition to γ‑Hydroxy-α,β-Unsaturated
Carbonyls Using Formaldehyde as an Oxygen-Centered Nucleophile
Naoki Yoneda, Ayano Hotta, Keisuke Asano,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto
615-8510, Japan
S
* Supporting Information
ABSTRACT: Formaldehyde was utilized as an oxygen-centered nucleophile in an asymmetric oxy-Michael addition to γ-
hydroxy-α,β-unsaturated carbonyl compounds using bifunctional organocatalysts through hemiacetal intermediates. The cyclic
acetal product could be further transformed into β-hydroxycarbonyl compounds, useful synthetic intermediates leading to various
important target molecules. As such, this method is an example of a novel formal asymmetric hydration of α,β-unsaturated
carbonyl compounds.
he asymmetric hydration of α,β-unsaturated carbonyl
compounds via oxy-Michael additions represents an
We also recently reported enantioselective oxy-Michael
addition reactions to γ-hydroxy-α,β-unsaturated carbonyl
compounds, which go through hemiacetal intermediates to
give 1,3-dioxolanes, which contain an easily removable acetal
functionality (Scheme 2).6 Although this reaction proceeded
T
attractive route toward chiral β-hydroxycarbonyl compounds,
which are important synthetic intermediates and exist as
structural motifs in a variety of natural products.1 However, the
Michael addition of water is challenging because of the low
nucleophilicity of water, frequent reaction reversibility, and
difficulties concerning stereochemical control.2 Thus, a
promising alternative is formal hydration utilizing the Michael
addition of water surrogates, which are oxygen-centered
nucleophiles bearing an easily removable group (Scheme 1).
Scheme 2. Asymmetric Oxy-Michael Addition Using
Formaldehyde as Oxygen-Centered Nucleophile
Scheme 1. Formal Hydration of α,β-Unsaturated Carbonyl
Compounds
Among the oxygen-centered nucleophiles investigated thus far,
oximes3a−c and hydrogen peroxide3d are advantageous because
of their high nucleophilicity. On the other hand, intra-
molecularization4 by a cleavable tether is also an efficient
strategy to achieve high reactivity of oxy-Michael additions.5
Received: October 23, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
with high enantioselectivity, the products consisted of a mixture
of diastereomers in a modest ratio. However, fortunately, the β-
positions of the carbonyl groups in both diastereomers proved
to have the same absolute configuration, indicating that the step
comprising the intramolecular oxy-Michael addition from the
hemiacetal intermediates can proceed enantioselectively,
regardless of the stereochemistry of the hemiacetal.7 Thus, in
order to avoid the generation of diastereomers, we attempted to
use formaldehyde as an oxygen-centered nucleophile that could
provide an achiral hemiacetal intermediate (Scheme 2). Here,
we present an asymmetric oxy-Michael addition to γ-hydroxy-
α,β-unsaturated carbonyl compounds using formaldehyde as an
oxygen source and demonstrate further transformations of the
product.
We initially investigated the reaction between (E)-4-hydroxy-
1-phenylbut-2-en-1-one (1a) and formaldehyde (2) with 10
mol % of quinidine-derived bifunctional aminothiourea catalyst
4a in various solvents at 25 °C (Table 1, entries 1−9).8,9 The
enantioselectivity was superior in aromatic hydrocarbon-based
solvents (Table 1, entries 1 and 5−8); mesitylene gave the best
enantioselectivity (Table 1, entry 8). The presence of water did
not affect the enantioselectivity of the reaction in mesitylene
(Table 1, entries 8 and 9). Other catalysts were also
investigated,10,11 and the quinidine-derived catalyst 4a led to
higher enantioselectivity, among the cinchona-derived thiourea
catalysts and Takemoto catalyst (Table 1, entries 8 and 10−
13). In addition, the bifunctionality of the catalyst, including the
thiourea moiety, proved to be significant for enantioselectivity
(Table 1, entries 8, 14, and 15).
Other substrates were also investigated by using 4a as the
catalyst in mesitylene at 25 °C (Table 2). An electron-rich
enone resulted in slightly higher stereoselectivity, although an
electron-poor substrate was also tolerated (Table 2, entries 2
and 3). In addition, a substrate bearing a p-bromophenyl
moiety afforded the corresponding product in comparable yield
and enantioselectivity (Table 2, entry 4). Unfortunately, the
stereoselectivity was sensitive to ortho-substituents on the aryl
a
Table 2. Substrate Scope
a
Table 1. Optimization of Conditions
b
entry
1
catalyst
solvent
yield (%)
ee (%)
c
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
CPME
91
54
76
94
65
82
84
92
51
92
76
89
76
75
84
62
72
d
c
2
CPME
3
4
5
6
7
8
CH2Cl2
61
hexane
43
benzene
69
toluene
72
xylene
73
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
75
d
9
75
10
11
12
13
14
15
73
−57
−58
57
71
4g
4
a
Reactions were run using 1a (0.15 mmol), 2 (37% aqueous solution,
0.18 mmol), and the catalyst (0.015 mmol) in the solvent (0.3 mL).
b
c
d
Isolated yields. CPME = cyclopentyl methyl ether. Reaction was
run using paraformaldehyde (0.18 mmol).
a
Reactions were run using 1 (0.15 mmol), 2 (37% aqueous solution,
b
0.18 mmol), and 4a (0.015 mmol) in mesitylene (0.3 mL). Isolated
yields.
B
dx.doi.org/10.1021/ol503104b | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
groups of the α,β-unsaturated ketones (Table 2, entries 5 and
6). Substrates with heterocyclic and aliphatic substituents also
gave the corresponding products in moderate enantioselectivity
(Table 2, entries 7 and 8).
In addition, α,β-unsaturated carboxylic acid derivatives
proved to be useful substrates in this reaction (Scheme 3).
including natural products are currently underway in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures including spectroscopic and analytical
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 3. Reactions from α,β-Unsaturated Thioester and
a
Ester
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: asano.keisuke.5w@kyoto-u.ac.jp.
*E-mail: matsubara.seijiro.2e@kyoto-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported financially by the Japanese Ministry of
Education, Culture, Sports, Science and Technology. K.A. also
acknowledges the Asahi Glass Foundation.
a
REFERENCES
Reactions were run using 1 (0.15 mmol), 2 (37% aqueous solution,
■
b
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An α,β-unsaturated thioester, which is amenable to further
transformations, gave the product 3i in high yield and
enantioselectivity. Furthermore, the reaction of 1i was scalable;
the reaction with 5.0 mmol of 1i gave 3i in similar, good
enantioselectivity. Moreover, even though α,β-unsaturated
esters rarely serve as viable substrates for oxy-Michael
additions,3 α,β-unsaturated ester 1j gave the corresponding
product in comparable enantioselectivity.
To demonstrate the utility of the developed reaction as a
formal hydration method, we carried out the deacetalization of
3i. The treatment of 3i with titanium tetrachloride afforded free
β-hydroxy thioester 5, in which the γ-hydroxy group was
protected by a methoxymethyl group (Scheme 4). The absolute
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Scheme 4. Deacetalization of the Product
configuration of 5 was assigned as (S) after further trans-
formations to a known compound, (S)-4-(benzyloxy)butane-
1,2-diol, by comparing the optical rotation with the literature
value12 (see the Supporting Information (SI) for details). The
configurations of all other products were assigned analogously.
In summary, we have demonstrated the utility of form-
aldehyde as an oxygen-centered nucleophile for the formal
hydration of γ-hydroxy-α,β-unsaturated carbonyl compounds.
The reaction proceeded in high yield and acceptable
enantioselectivity, and the subsequent deacetalization yielded
a valuable chiral β-hydroxycarbonyl compound. Further studies
regarding expanding the scope of substrates to other α,β-
unsaturated carbonyls and the application of this methodology
to the asymmetric syntheses of various chiral molecules
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(9) Results of further solvent screening are described in the SI (Table
S1).
(10) Results of further catalyst screening are described in the SI
(Table S2).
(11) Further details on screening of reaction conditions are described
in the SI (Table S3).
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dx.doi.org/10.1021/ol503104b | Org. Lett. XXXX, XXX, XXX−XXX