Formal asymmetric enone aminohydroxylation: Organocatalytic one-pot synthesis of 4,5-disubstituted oxazolidinones

Article abstract of DOI:10.1039/c2cc32385k

A formal asymmetric organocatalytic aminohydroxylation reaction of enones has been achieved via an aziridination-double S_N2 sequence. As a part of the reaction design, the generated amino alcohol products are isolated as the corresponding oxazolidinones in good yields and excellent stereoselectivities.

Full text of DOI:10.1039/c2cc32385k

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COMMUNICATION
Formal asymmetric enone aminohydroxylation: organocatalytic one-pot
synthesis of 4,5-disubstituted oxazolidinonesw
David Cruz Cruz, Pedro A. Sanchez-Murcia and Karl Anker Jørgensen*
Received 2nd April 2012, Accepted 3rd May 2012
DOI: 10.1039/c2cc32385k
A formal asymmetric organocatalytic aminohydroxylation reaction
of enones has been achieved via an aziridination–double SN2
sequence. As a part of the reaction design, the generated amino
alcohol products are isolated as the corresponding oxazolidinones
in good yields and excellent stereoselectivities.
Optically active oxazolidinones represent a great source of
protected vicinal amino alcohols, which are robust and valuable
building blocks in asymmetric synthesis. Recently, oxazolidinones
were also found to have interesting biological activity e.g. as
broad-spectrum antibiotics and anticoagulants.1 Traditionally, the
oxazolidinones and their parent amino alcohols have been supplied
from natural sources; however, due to the increasing demand
for molecular diversity, new synthetic routes which may provide
greater structural variation are highly desirable. While anti-
configured amino alcohols are easily accessible by ring-opening
of epoxides using a nitrogen nucleophile,2 syn-selective synthetic
protocols are more limited. One of the most reliable processes
for this purpose is the Sharpless aminohydroxylation of olefins
(Scheme 1).3 While proving highly applicable for electron-poor
olefins such as a,b-unsaturated esters and surrogates, substrate
classes such as enones are more demanding. To the best of our
knowledge, there is only one successful report in the literature
on this matter.4 Alternatively, C–C bond forming reactions
between a-hydroxy ketones and aldimines can be applied.5
However, additional steps are necessary to transform the amino
alcohols into the requisite oxazolidinone scaffold. We envisioned
that a more direct access to enantioenriched oxazolidinones
could be realized by aminocatalyzed one-pot reactions.6 Herein,
we report the development of an efficient enone-aziridination–
iodide-mediated double SN2 reaction sequence for the formal
asymmetric aminohydroxylation of enones.
Scheme 1 Outline of current work.
It was further discovered that the nature of the chiral counterion
was crucial to achieve excellent selectivities. Boc-D-a-phenyl-
glycine was originally applied in combination with the
Cinchona alkaloid derived primary amine in 30 and 20 mol%,
respectively (Scheme 2). In our preliminary screening experiments, it
was discovered that the (R)-mandelic acid, a substitute more than
five times cheaper than the Boc-D-a-phenylglycine, serves as an
excellent chiral counterion in this reaction. By using the amine 2b in
combination with (R)-mandelic acid as drivers for the reaction,
aziridine 3a was formed in similar yield and diastereoselectivity
and slightly higher enantioselectivity when compared with the
initially published protocol. Moreover, it was discovered that
by fine-tuning the reaction setup and the concentration, the
loadings of the chiral catalyst and additive could be lowered to
10 and 15 mol%, respectively, without affecting the outcome of
the aziridination reaction.
To find the optimal reaction conditions, we started our
investigations on the synthesis of optically active oxazolidinones
by using (E)-oct-3-en-2-one 1a as a model substrate and performing
the envisaged sequence in two separate steps (Scheme 2). The enone
aziridination reaction7 was first developed by Melchiorre et al.
using the 9-epi-aminodihydroquinine 2a as catalyst (20 mol%).8
Subsequent treatment of the isolated optically active aziridine
3a with NaI in acetone at 60 1C first opened the aziridine at the
a-carbonyl center followed by an intramolecular O-alkylation
reaction, forming the desired trans-4,5-disubstituted oxazolidinone
4a in 86% yield, >20 : 1 dr and 98% ee (for screening details
Center for Catalysis, Aarhus University, Langelandsgade 140,
DK-8000 Aarhus C, Denmark. E-mail: kaj@chem.au.dk;
Fax: +45 8715 2068; Tel: +45 8715 5956
w Electronic supplementary information (ESI) available: Full experi-
mental details and NMR spectra. CCDC 872154. For crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2cc32385k
c
6112 Chem. Commun., 2012, 48, 6112–6114
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Table 1 Reaction scopea
Yieldb
Product (%)
eed
(%)
Entry R0
R
drc
1
2
3
4
5
6
7
8
9
Me Bu
Me Me
Me i-Pr
Me CH2C6H11
Me (CH2)2NHCbz
Me (CH2)2Ph
Me (CH2)Ph-p-OMe
Me (CH2)2Ph-m-Cl
4a
4b
4c
4d
4e
4f
4g
4h
4i
64
78
51
81
56
73
93
53
57
>20 : 1 98
>20 : 1 99
>20 : 1 98
>20 : 1 97
>20 : 1 94
>20 : 1 98
>20 : 1 98
17 : 1
15 : 1
99
99
Et
Me
a
Performed on a 0.2 mmol scale (see ESI for experimental details).
c
Yield of isolated products. Determined by NMR spectroscopy of
b
d
the crude reaction mixture. Determined by chiral stationary phase
HPLC after derivatizations.
Scheme 2 Aziridination protocols and one-pot aminohydroxylation.
for the ring-opening, see ESIw). Moreover, it was discovered
that the intermediate purification process could be omitted
minimizing the manual efforts. By sequential additions of the
reagents, product 4a could be accessed in a one-pot fashion
from the simple enone 1a without affecting the overall yield
and selectivity of the reaction.
Fig. 1 X-Ray structure of compound 5b.
to R0-substitution, as an exchange of the methyl substituent with
ethyl provides the corresponding oxazolidinone in 15 : 1 dr and
99% ee (entry 9). The iodide-mediated ring-opening is believed to
proceed relatively fast, however, due to the restricted rotational
freedom the O-alkylation reaction is much more demanding and
product decomposition may occur as a competitive pathway.
The absolute configuration of product 4b was unambiguously
determined to be (4R,5S) by X-ray crystallography after
derivatization to compound 5b (Fig. 1, see ESIw for details).9
The remaining structures were assigned by analogy.
Having developed an optimized set of conditions for the
desired reaction sequence, the scope and limitation of the
one-pot process were evaluated. As illustrated in Table 1, a variety
of linear and branched R-substituents could be tolerated providing
oxazolidinones 4a–d in 51–81% yield, >20 : 1 dr and 97–99% ee
(entries 1–4). Furthermore, the reaction conditions proved to
be unbiased towards additional functional groups, such as
carbamate-protected amines (entry 5). Finally, alkyl functionalities
substituted with aryl groups having various electronic properties
could also be incorporated into the substrates with similar
good results (entries 6–8). Cyclic enones are poor substrates
for the described reaction sequence. The system is also tolerant
The proposed mechanism of the described one-pot reaction,
formal aminohydroxylation reaction, is outlined in Scheme 3.
Scheme 3 Proposed reaction mechanism.
c
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Condensation of the 9-epi-aminoquinine 2b and enone 1 in the
presence of an acidic additive leads to the formation of an
activated iminium-ion species, which is subjected to nucleophilic
attack of TsONHBoc at the b-position of the enone. Spontaneous
ring closure and hydrolysis yield the optically active aziridine 3
and the aminocatalyst is liberated. Next, the intermediate three-
membered ring is regioselectively opened by an iodide ion forming
an a-iodo-b-amino ketone species, which upon O-alkylation
provides the desired optically oxazolidinone 4. Noteworthily,
in the presence of other N-protective groups, such as acetates
or benzoates, the O-alkylative ring-closure is known to proceed
via an intermediate carbonimidate-ion leading to the formation
of oxazolines (Heine reaction).10 However, in this specific case it
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t
is believed that the Bu-group assists in the formation of a
carbamate-ion, which subsequently substitutes the iodide-ion
completing the overall transformation to product 4. Despite the
identical reaction conditions, no Heine products were detected
in the reaction mixture.
In summary, we have reported a formal asymmetric organo-
catalytic aminohydroxylation reaction of enones via an
aziridination–double SN2 sequence. As a part of the reaction
design, the generated amino alcohol products are protected as
the corresponding oxazolidinones, which were isolated in good
yields and stereoselectivities.
This research was made possible by Aarhus University,
Carlsberg Foundation and FNU. DCC thanks CONACYT
(Mexico) for the postdoctoral fellowship. PASM thanks
MICINN (Spain) for a FPI predoctoral fellowship. Thanks
to Dr H. Jiang for performing initial experiments and helpful
discussions.
6 For selected reviews on organocatalytic one-pot reactions, see:
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Ed., 2011, 50, 8492; (b) C. Vaxelaire, P. Winter and M. Christmann,
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Notes and references
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9 CCDC 872154w.
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c
6114 Chem. Commun., 2012, 48, 6112–6114
This journal is The Royal Society of Chemistry 2012