Procedure-controlled enantioselectivity switch in organocatalytic 2-oxazolidinone synthesis

Article abstract of DOI:10.1021/ja407027e

In a novel organocatalytic formal [3 + 2] cycloaddition to afford chiral 2-oxazolidinones, an enantioselectivity switch could be induced by changing the manner of addition of the reactants, even when the reaction components (cinchona-alkaloid-derived aminothiourea catalyst, substrates, and solvent) were the same.

Full text of DOI:10.1021/ja407027e

Communication
pubs.acs.org/JACS
Procedure-Controlled Enantioselectivity Switch in Organocatalytic
2‑Oxazolidinone Synthesis
Yukihiro Fukata, 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
Scheme 1. Formal [3 + 2] Cycloaddition via Asymmetric
Intramolecular Hetero-Michael Addition by Aminothiourea
Catalysts
ABSTRACT: In a novel organocatalytic formal [3 + 2]
cycloaddition to afford chiral 2-oxazolidinones, an
enantioselectivity switch could be induced by changing
the manner of addition of the reactants, even when the
reaction components (cinchona-alkaloid-derived amino-
thiourea catalyst, substrates, and solvent) were the same.
rotein function can be altered by post-translational
Pmodification or by genetic mutation as a result of chemical
damage or ionizing radiation. Post-translational modification of
biological catalysts, such as phosphorylation of enzymes like
Smurf11a or MEK,1b can dramatically alter the selectivity of the
enzyme and downstream biological events. In chemical
synthesis, asymmetric catalysts, especially biomimetic organo-
catalysts, may undergo similar functional switches in response
to environmental changes.2 For example, reversal of enantio-
selectivity by using a single chiral source has been accomplished
in several reactions simply by changing an achiral component
(e.g., the solvent) or using additional achiral additives.3,4
Chiral 2-oxazolidinones are important frameworks found in a
wide range of bioactive compounds5 and chiral auxiliaries for
asymmetric synthesis.6 We recently reported asymmetric formal
[3 + 2] cycloaddition reactions via intermediates generated in
situ from γ-hydroxy-α,β-unsaturated carbonyls with aldehydes
or imines (Scheme 1).7a−c In the presence of cinchona-alkaloid-
based aminothiourea catalysts (Figure 1),8 those intermediates
underwent intramolecular hetero-Michael addition with high
enantioselectivity to afford a diastereomeric mixture.7 Thus
inspired, we envisioned that reactions of an isocyanate with γ-
hydroxy-α,β-unsaturated carbonyl compounds could also be
carried out enantioselectively to furnish chiral 2-oxazolidinones
(Scheme 1).9 Moreover, the use of a heterocumulene as a
nitrogen source would circumvent the generation of diaster-
eomers, thereby allowing more effective enantioselective
amination of the β-carbon.
Figure 1. Cinchona-alkaloid-derived aminothiourea catalysts.
We initially carried out the cycloaddition of (E)-4-hydroxy-1-
phenylbut-2-en-1-one (1a) and 4-methylbenzenesulfonyl iso-
cyanate (2) using 5 mol % cinchonidine-derived catalyst 4a
(Scheme 2). The reaction was effected by mixing the starting
Scheme 2. Effect of the Amount of Isocyanate 2 in the
Formal [3 + 2] Cycloaddition of 1a with 2
In the present study, we found that a slight change in the
reaction procedure led to a reversal of the enantioselectivity,
even when the chiral catalyst, substrates, and solvent used were
unaltered. Herein we present a novel asymmetric reaction to
afford 2-oxazolidinones in which a procedure-controlled
enantioselectivity switch was observed when using a single
cinchona-alkaloid-derived organocatalyst. To the best of our
knowledge, there has been no previous report of such an
inversion behavior that requires no change in the reaction
components.
Received: April 5, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja407027e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
materials and the catalyst in one portion in toluene at 0 °C. The
addition of 1.0 equiv of 2 resulted in the formation of the (R)-
2-oxazolidinone (R)-3a in an enantiomeric ratio (er) of 70:30,
while the use of 1.5 equiv of 2 afforded (S)-3a with an er of
26:74.
the addition of 1.01 equiv of 1a (Scheme 3, procedure B), the
opposite enantiomer, (S)-3a, was obtained selectively.14 We
carried out the aforementioned reaction protocols in the
presence of catalysts derived from other readily available
cinchona alkaloids (Table 1)15 and found that all of them led to
reversal of the enantioselectivity.
To gain insight into the unusual effect of an excess amount of
the isocyanate on the stereoselectivity, spectroscopic studies
were carried out. 1H NMR analysis of a solution of 2 and 4a in
toluene-d8 indicated that the signals associated with the protons
adjacent to the quinuclidine nitrogen of 4a were shifted
downfield in the presence of 2 [Figure S1 in the Supporting
Information (SI)]. In addition, 13C NMR analysis of the
solution revealed the disappearance of the sp carbon of 2 in the
presence of 4a (Figure S2). Furthermore, high-resolution mass
spectrometry analysis of a solution of 2 and 4a (20:1 mixture)
detected their 1:1 adduct (found, m/z 762.2000; calcd for [M +
H]+, 762.2002) but not oligomeric n:1 adducts (n > 1) (see
Scheme S1 in the SI for details). These results strongly
suggested that 4a was mutated by 2 to form a zwitterionic 1:1
adduct by addition of the quinuclidine nitrogen of 4a to 2
(Figure 2),10 which had a significant influence on the
Table 1. Investigation of the Enantioselectivity Switch with
a
Cinchona-Alkaloid-Based Catalysts 4
procedure A
procedure B
b
b
entry catalyst yield (%)
er
yield (%)
er
1
2
3
4
4a
4b
4c
4d
47
75
53
61
88.5:11.5 (R)
79:21 (R)
69
57
50
46
13:87 (S)
20:80 (S)
83:17 (R)
82:18 (R)
26:74 (S)
20.5:79.5 (S)
a
Reactions were run using 1a (0.253 mmol), 2 (0.25 mmol), and the
b
catalyst (0.0125 mmol) in toluene. Isolated yields.
With the established procedures and conditions using 4a as a
single catalyst, we next explored the substrate scope (Table
2).16 Reversal of enantioselectivity was observed in all of the
reactions with γ-hydroxy-α,β-unsaturated ketones 1a−h (Table
2, entries 1−16). Both electron-rich and electron-deficient
substrates were tolerated under the employed reaction
conditions (entries 3−6). A substrate bearing a p-bromo
group also selectively afforded both enantiomers of the 2-
oxazolidinone product (entries 7 and 8). In addition, enones
bearing bulky biphenyl and naphthyl groups yielded the
corresponding products with high enantioselectivity (entries
9−12), and a heterocycle-substituted substrate also allowed for
the enantiodivergent synthesis (entries 13 and 14). An aliphatic
ketone could also be used in the reaction (entries 15 and 16),
although the enantioselectivity with procedure A (entry 15)
was modest in comparison with that in other cases. However, in
the reaction using a γ-hydroxy-α,β-unsaturated ester, the same
2-oxazolidinone enantiomer was obtained as the major product
in both procedures, and higher enantioselectivity was observed
with procedure B (Table 2, entries 17 and 18).
Figure 2. Proposed structure of the catalyst mutated by 2.
stereoselectivity. Thus, we modified the reaction procedure as
follows: 1a (1.01 equiv) was first treated with 2 (1.0 equiv)
until the latter was completely consumed, generating the
carbamate intermediate; subsequently, 4a (5 mol %) was added
(Scheme 3, procedure A).11,12 This sequential protocol yielded
(R)-3a with improved enantioselectivity.13 In contrast, when 4a
(5 mol %) was mutated by treatment with 2 (1.0 equiv) before
Scheme 3. Enantioselectivity Switch in the Formal [3 + 2]
Cycloaddition Using Sequential Protocols
To demonstrate the utility of the products as valuable
synthetic intermediates, transformations of (R)-3a with high
optical purity obtained after one-time recrystallization were
carried out. The tosyl group of 3a could be removed by
treatment with sodium naphthalenide to afford 5 without
significant loss of optical purity (Scheme 4). In addition,
treatment of (R)-3a with lithium hydroxide and hydrogen
peroxide gave optically active 1,2-amino alcohol 6 (Scheme 5).
Thus, the proposed 2-oxazolidinone synthesis protocol and
transformation methods would constitute a facile, practical
enantiodivergent route to optically active 2-oxazolidinones and
chiral 1,2-amino alcohols. The absolute configuration of 5 was
B
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Journal of the American Chemical Society
Communication
a
configurations of the products were controlled only by the
employed reaction procedure. The proposed reaction protocols
are particularly valuable for catalysts derived from chiral natural
products, including cinchona alkaloids, since these compounds
are available in only one enantiomeric form. Studies to clarify
the enantioselectivity switch in further detail and the
application of this methodology to other asymmetric reactions
are currently underway in our laboratory, and the results will be
reported in due course.
Table 2. Substrate Scope
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, including spectroscopic and analytical
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
b
entry
R (3)
Ph (3a)
procedure yield (%)
er
AUTHOR INFORMATION
Corresponding Author
asano.keisuke.5w@kyoto-u.ac.jp; matsubara.seijiro.2e@kyoto-u.
ac.jp
■
1
2
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
47
69
67
49
79
71
95
74
27
19
66
49
53
53
83
73
73
30
88.5:11.5 (R)
13:87 (S)
c
3
4-CH3OC6H4 (3b)
4-CF3C6H4 (3c)
4-BrC6H4 (3d)
4-PhC6H4 (3e)
2-naphthyl (3f)
2-thienyl (3g)
PhCH2CH2 (3h)
PhO (3i)
73:27 (R)
c
4
25.5:74.5 (S)
80.5:19.5 (R)
6.5:93.5 (S)
81:19 (R)
c
Notes
5
c
The authors declare no competing financial interest.
6
7
8
ACKNOWLEDGMENTS
This work was supported financially by the Japanese Ministry of
Education, Culture, Sports, Science and Technology.
■
14:86 (S)
9
89.5:10.5 (R)
15.5:84.5 (S)
91:9 (R)
10
11
12
13
14
15
16
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18:82 (S)
■
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Journal of the American Chemical Society
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1
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