Asymmetric synthesis of trisubstituted oxazolidinones by the thiourea-catalyzed aldol reaction of 2-isocyanatomalonate diester

Article abstract of DOI:10.1021/ol502198e

A new method has been developed for the synthesis of chiral 4-carboxyl oxazolidinones by the catalytic asymmetric aldol reaction of an isocyanatomalonate diester with an aldehyde in the presence of a thiourea catalyst. The resulting chiral 4-carboxyl oxazolidinones are the equivalent of β-hydroxy-α-amino acids bearing a tri- or tetrasubstituted carbon center at their α position. With this in mind, this procedure was successfully applied to the first total synthesis of mycestericin C, which was completed in 12 steps and represents one of the shortest reported sequences for the construction of natural products of this type.

Full text of DOI:10.1021/ol502198e

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of Trisubstituted Oxazolidinones by the
Thiourea-Catalyzed Aldol Reaction of 2‑Isocyanatomalonate Diester
Shota Sakamoto, Naoya Kazumi, Yusuke Kobayashi, Chihiro Tsukano, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
S
* Supporting Information
ABSTRACT: A new method has been developed for the
synthesis of chiral 4-carboxyl oxazolidinones by the catalytic
asymmetric aldol reaction of an isocyanatomalonate diester
with an aldehyde in the presence of a thiourea catalyst. The
resulting chiral 4-carboxyl oxazolidinones are the equivalent of
β-hydroxy-α-amino acids bearing a tri- or tetrasubstituted
carbon center at their α position. With this in mind, this
procedure was successfully applied to the first total synthesis of mycestericin C, which was completed in 12 steps and represents
one of the shortest reported sequences for the construction of natural products of this type.
xazolidinones are a fundamental structural class in organic
chemistry, where they have been used successfully as chiral
The direct catalytic asymmetric aldol reaction11 is a powerful
method for the construction of 4-carboxy oxazoline12 and
thiooxazolidinone13 scaffolds (Figure 2a and b). In 1986, Ito and
O
auxiliaries,1 and in medicinal chemistry (e.g., Linezolid, Figure
1).2 This structure bearing an ester moiety (i.e., 4-carboxyl
Figure 1. Biologically active compounds containing an oxazolidinone or
β-hydroxy-α-amino acid moiety.
oxazolidinones) is synthetically equivalent to β-hydroxy-α-amino
acids, which can be found in various biologically active
compounds, including peptides and β-lactams, as well as natural
products such as mycestericin C and polyoxin J.3 For this reason,
considerable research efforts have been directed toward the
development of synthetic methods for the enantioselective
construction of oxazolidinone systems.4 Oxazolidinones have
traditionally been synthesized from chiral β-hydroxy-α-amino
acids, and this particular method is generally both convenient
and robust when it is applied to natural amino acid substrates.
Several stepwise methods have also been developed for the
synthesis of chiral oxazolidinones, including catalytic asymmetric
reactions such as the Sharpless asymmetric aminohydroxylation5
and asymmetric aldol reaction.6 Chiral oxazolidinones can also
be accessed using dynamic kinetic resolution techniques.7−9
Although a variety of different methods have been reported for
the asymmetric synthesis of oxazolidinones, reports pertaining to
the direct asymmetric synthesis of 4-carboxyl oxazolidinone have
been scarce, with research in this area being focused
predominantly on the preparation of mono- and disubstituted
oxazolidinones.10
Figure 2. Synthetic strategy for 4-carboxyl oxazolidinone based on
catalytic asymmetric aldol reaction.
Hayashi12a reported their pioneering work toward the catalytic
asymmetric synthesis of oxazolines from isocyanoacetates using a
gold catalyst with a phenylphosphine ligand. In 2008, Seidel13a
developed a method for the catalytic enantioselective aldol
addition of α-isothiocyanato esters to aldehydes and ketones to
give the corresponding thiooxazolidinones using an organo-
catalyst. Furthermore, Shibasaki and Feng13b,c reported the
asymmetric aldol reactions of α-isothiocyanato esters and
aldehydes and ketones for the synthesis of tri- and tetrasub-
Received: July 25, 2014
Published: September 9, 2014
© 2014 American Chemical Society
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Letter
stituted thiooxazolidinones using Mg, Ag, and Ni catalysts.
Asymmetric aldol reactions involving the reaction of isocyanoa-
cetates with aldehydes or ketones in the presence of organo-
catalysts have also been developed by Dixon and Gong.12b,c
Although several methods have been reported in the literature for
the asymmetric synthesis of oxazoline and thiooxazolidinone
systems, there have, to the best of our knowledge, been no
reports concerning the use of a direct catalytic enantioselective
aldol reaction for the synthesis of 4-carboxyl oxazolidinones. For
this reason, di- and trisubstituted oxazolidinones have generally
been accessed by performing additional transformations with the
oxazoline and thiooxazolidinone systems described above. There
is therefore an urgent need for the development of new methods
allowing for the direct construction of oxazolidinones.
Table 1. Investigation of the Conditions for the Reaction of
the Aldehydes with the Isocyanates
It was envisaged that the coupling of an isocyanatomalonate
diester with an aldehyde in the presence of a thiourea catalyst
(TUC)14,15 would allow for the direct asymmetric construction
of the corresponding oxazolidinone (Figure 2c). To date,
isocyanatomalonate diesters bearing both nucleo- and electro-
philic groups have only been used as electrophiles for the
preparation of ureas,16 and the properties of these compounds
have never been reported in any great detail. Because the
isocyanate group is more reactive than the isothiocyanate group,
its application as a nucleophile in an aldol reaction would be
challenging. Compared with previously reported methods for the
direct catalytic synthesis of oxazolidinones, this method is at a
distinct advantage because trisubstituted oxazolidinones are
readily available. Furthermore, the resulting oxazolidinones
could be converted to syn-β-hydroxyl-α-amino acids derivatives
by decarboxylation, as well as anti-β-hydroxyl-α-amino acids
derivatives bearing a tetrasubstituted carbon center, which have
never before been synthesized from oxazolines and thioox-
azolidinones. Herein, we report the first catalytic asymmetric
aldol reaction of isocyanatomalonate diesters with aldehydes for
the synthesis of oxazolidinones, and the application of this
method to the total synthesis of mycestericin C, which contains
an anti-β-hydroxyl-α-amino acid structure with a tetrasubstituted
carbon center.
We initially investigated the aldol reaction of isocyanates 1a−d
with benzaldehyde (2a) in the presence of (R,R)-TUC 4a (Table
1). The aldol reaction of 1a proceeded smoothly in toluene at rt
to give oxazolidinone 3a in 87% yield with an enantiomeric
excess (ee) of 88%. This reaction also afforded a small amount of
the byproduct 3a′ (11%), resulting from the reaction of the
product 3a with 1a. It is noteworthy that higher ee values were
observed with the smaller ester groups (Table 1, entries 1−4).
Based on the ee values of the products, as well as the stabilities
and prices of the starting materials, diethyl 2-isocyanatomalonate
(1b) was selected for further investigation. The temperature of
the reaction was then examined, and it was found that the
formation of the byproduct could be suppressed at lower
temperatures. The use of a lower temperature also resulted in an
improved yield, although the reaction required 72 h to proceeded
to completion with the complete consumption of benzaldehyde
2a (Table 1, entries 5−8). The use of aliphatic aldehydes resulted
in lower ee values compared with aromatic aldehydes, and it was
therefore decided to optimize the TUC 4 using an aliphatic
aldehyde in the interest of developing a process with the broadest
possible substrate scope.17 The aldol reaction of 3-phenyl-
propanal (2b) with diethyl 2-isocyanatomalonate 1b in the
presence of 10 mol % of the TUC 4a at −60 °C gave
oxazolidinone 3e quantitatively with 65%ee (Table 1, entry 9).
Several di-n-alkyl amines were then introduced to the TUC
a
entry
1a−d
2a−b
cat.
temp, time
yield (%)
ee (%)
b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1b
1b
1b
1b
2a
2a
2a
2a
2a
2a
2a
2a
4a
4a
4a
4a
4a
4a
4a
4a
rt, 24 h
87
88
83
61
78
87
88
87
87
rt, 24 h
82
88
80
84
88
85
90
rt, 24 h
rt, 24 h
0 °C, 24 h
−20 °C, 24 h
−40 °C, 24 h
−60 °C, 72 h
9
1b
1b
1b
1b
1b
1b
1b
2b
2b
2b
2b
2b
2b
2b
4a
4b
4c
4d
4e
4f
−60 °C, 72 h
−60 °C, 72 h
−60 °C, 72 h
−60 °C, 72 h
−60 °C, 72 h
−60 °C, 72 h
−60 °C, 72 h
quant
66
65
78
77
71
54
54
19
10
11
12
13
14
15
72
60
36
62
4g
76
a
b
1
Isolated yield. The yield was estimated by H NMR.
instead of the dimethylamine moiety. In the case of the TUCs
containing di-n-pentyl- and di-n-hexylamine groups (4a and 4b),
the enantioselectivity was improved to 78%ee, although further
increases in the length of the alkyl side chain were ineffective
(Table 1, entries 10−13). Based on these results, steric factors
appeared to be particularly important to the outcome of this
reaction. However, TUCs 4f and 4g did not give satisfactory
results (Table 1, entries 14−15), and catalyst 4b bearing a
dipentylamine side chain was selected as the optimum TUC for
the reaction.
With the optimized conditions in hand, we proceeded to
investigate the scope of the reaction using TUC 4a or 4b as the
catalyst with a broad range of aryl aldehydes 2f−p. All of the
reactions were conducted with isocyanate 1b (10 mol %) in
toluene at −60 °C and proceeded smoothly to give the
corresponding oxazolidinones 3f−p in high yields with good
enantioselectivities (Scheme 1). Various aldehydes reacted
successfully under the optimized conditions, including elec-
tron-rich and -deficient aryl aldehydes, as well as heteroaromatic
aldehydes. The use of catalyst 4b instead of 4a led to
improvements in the ee in some cases (89−92%ee for 3g−i, k,
l), whereas 4a gave satisfactory ee values in other cases (87−95%
ee for 3f, j, m−p). The reactions of α-branched aliphatic
aldehydes including isopropyl aldehyde (2q) and cyclohexane-
carboxaldehyde (2r) gave the corresponding oxazolidinones 3q
and 3r in moderate yields with high ee values. In contrast, the
reactions of trans-cinnamaldehyde, n-heptaldehyde, and isobutyl
aldehyde resulted in moderate ee values (65−82%ee, 3s−u),
even when catalyst 4b was used. Furthermore, the use of a bulky
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Letter
a
enantioselective aldol reaction could be used to construct an
oxazolidinone, which could be converted to a β-hydroxy-α-
amino acid bearing a tetrasubstituted carbon center for a concise
synthesis of mycestericin C.
Scheme 1. Scope and Limitations
The commercially available α,β-unsaturated aldehyde 6 was
subjected to an aldol reaction with diethyl isocyanatomalonate
1b under the optimized conditions using (R,R)-TUC 4a to give
oxazolidinone 7 in 91% yield with high enantioselectivity (88%
ee, Scheme 3).21 Treatment of 7 with aqueous KOH gave
Scheme 3. Total Synthesis of Mycestericin C
a
b
Isolated yield. Racemic catalyst was used.
aldehyde such as pivalaldehyde (2v) resulted in no reaction
under the optimized conditions. These results indicated that the
stereoselectivity of the reaction resulted from the recognition of
the α position of the aldehyde by the catalyst. The trisubstituted
oxazolidinone 3 could be converted to a disubstituted
oxazolidinone by decarboxylation. For example, a hydrolysis of
compound 3b followed by treatment of the resulting acid with
DBU gave the trans-disubstituted oxazolidinone 5, which is a
precursor for the synthesis of syn-β-hydroxyl-α-amino acid
(Scheme 2).10c,17 The absolute stereochemistry of the newly
formed chiral center in 5 was confirmed to be the R configuration
by comparing its optical rotation with the literature data.8b
carboxylic acid 8 as a single product following the nucleophilic
attack of the hydroxide anion at the least hindered ester. The
subsequent formation of an acid chloride followed by reduction
with Zn(BH4)4 gave alcohol 9 in 96% yield, which was protected
with TBSCl to give the corresponding silyl ether. The carbon−
carbon double bond was cleaved by ozonolysis, followed by
reduction with NaBH4 to give lactone 10 as a 4:1 mixture of
diastereomers. Oxidation of 10 followed by a Wittig reaction
gave 11, which was coupled with compound 1221 using Grubbs
first generation catalyst.20c,22,23 Subsequent hydrogenation and
removal of the TBS group gave the protected mycestericin C 13,
and the minor isomer was removed by silica gel column
chromatography at this stage. The treatment of 13 with aq.
NaOH completed the first total synthesis of mycestericin C. This
material was treated with Ac2O to give the corresponding
triacetylated mycestericin C, which was subjected to spectro-
scopic analysis and found to be identical to the reported
material.17,18 The longest liner sequence in this synthesis was 12
steps from the commercially available aldehyde 6, which
demonstrates that this protocol is preferable to the other
synthetic methods currently available for mycestericins.
Scheme 2. Derivatization to a Disubstituted Oxazolidinone
To demonstrate of the synthetic utility of our newly developed
asymmetric aldol reaction, it was applied to the total synthesis of
mycestericin C. Mycestericins are potent immunosuppressant
agents that were originally isolated from the culture broth of
Mycelia sterilia by Fujita et al. in 1994 (Figure 1).18 Although
there have been no reports in the literature concerning the total
synthesis of mycestericin C, several related synthetic studies have
revealed that the construction of the β-hydroxy-α-amino acid
moiety requires several challenging manipulations, including the
diastereo- and enantioselective synthesis of a tetrasubstituted
carbon center.19,20 It was envisaged that our newly developed
In summary, we have developed a catalytic asymmetric aldol
reaction for the synthesis of 4-carboxyl oxazolidinone. This
reaction represents the first reported example of the use of
isocyanatomalonate diester in an aldol reaction, which is critical
to the success of this transformation. By tuning the TUC, we
have enhanced the scope of this reaction so that it can be applied
to a broad range of aldehydes, including aryl and branched alkyl
aldehydes. The resulting oxazolidinones are equivalent to β-
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Letter
(10) (a) Fukata, Y.; Asano, K.; Matsubara, S. J. Am. Chem. Soc. 2013,
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hydroxy-α-amino acids, and this process was therefore
successfully applied to the total synthesis of mycestericin C.
This synthesis not only represents the first reported total
synthesis of mycestericin C but also is one of the shortest
reported sequences for the synthesis of related natural products.
We believe that this method could be used for the preparation of
chiral 4-carboxyl oxazolidinones, and further studies toward the
application of this transformation are currently underway in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedure, spectroscopic data, 1H, 13C NMR
spectra were described. This material is available free of charge
via the Internet at http://pubs.acs.org.
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(16) (a) Cesa, M. C.; Rinz, J. E.; Kopp, T. T. U.S. patent, 1987, US
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(17) Further details have been provided in the Supporting
Information.
(18) Sasaki, S.; Hashimoto, R.; Kikuchi, M.; Inoue, K.; Ikumoto, T.;
Hirose, R.; Chiba, K.; Hoshino, Y.; Okumoto, T.; Fujita, T. J. Antibiot.
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■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: takemoto@pharm.kyoto-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysts” from The Ministry of Education,
Culture, Sports, Science and Technology, Japan.
(19) For a review, see: Byun, H.-S.; Lu, X.; Bittman, R. Synthesis 2006,
38, 2447.
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