A simple method removing 2-oxazolidinone and 2-hydroxyethylamine auxiliaries in methoxide-carbonate systems for synthesis of planar-chiral nicotinate

Article abstract of DOI:10.1016/S0040-4039(03)00698-1

A facile and practical removal of 2-oxazolidinone and 2-hydroxyethylamine auxiliaries was accomplished by treating the corresponding N-acyl-2-oxazolidinone and N-(2-hydroxyethyl)amide derivatives in simple methoxide-carbonate systems. The presence of excess DMC (dimethyl carbonate) accelerates the N-acyl bond cleavage for those substrates under mild reaction conditions, and the present method was found to be useful especially for the synthesis of planar-chiral nicotinate.

Full text of DOI:10.1016/S0040-4039(03)00698-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3599–3603
A simple method removing 2-oxazolidinone and
2-hydroxyethylamine auxiliaries in methoxide–carbonate systems
for synthesis of planar-chiral nicotinate
Nobuhiro Kanomata,a,b,* Satoshi Maruyama,a Katsuhito Tomonoa and Shinnosuke Anadaa
aDepartment of Industrial Chemistry, Meiji University, Tama-ku, Kawasaki 214-8571, Japan
bPRESTO, Japan Science and Technology Corporation, Japan
Received 15 February 2003; revised 15 March 2003; accepted 17 March 2003
Abstract—A facile and practical removal of 2-oxazolidinone and 2-hydroxyethylamine auxiliaries was accomplished by treating
the corresponding N-acyl-2-oxazolidinone and N-(2-hydroxyethyl)amide derivatives in simple methoxide–carbonate systems. The
presence of excess DMC (dimethyl carbonate) accelerates the N-acyl bond cleavage for those substrates under mild reaction
conditions, and the present method was found to be useful especially for the synthesis of planar-chiral nicotinate. © 2003 Elsevier
Science Ltd. All rights reserved.
2-Oxazolidinone derivatives have been widely used as
chiral auxiliaries for a number of asymmetric reactions
and for resolution in synthetic organic chemistry.1 Sev-
eral useful methods have been reported on non-destruc-
tive removal of those auxiliaries by cleaving their
N-acyl bonds with hydrolytic reagents such as alkox-
ides,2 thiolate,3 amine,4 hydroxide,2c,5 hydroperoxide,6
etc., or with hydride reagents7 for reductive removal.
Among them, the methoxide ion is obviously one of the
most convenient reagents in terms of its commercial
availability and technical simplicity in that the corre-
sponding esters produced are easily separable from the
co-produced 2-oxazolidinone derivatives. However,
exo-carbonyl selectivity leading to the desired N-acyl
bond cleavage depends on the steric and electronic
properties surrounding the carbonyl group, and unde-
sired endo-carbonyl alcoholysis often takes place to give
ring-opening 2-hydroxyethylamide as by-products.6a,8,9
We have been studying, on the other hand, the syn-
thetic utility of the 2-hydroxyethylamide derivatives
and have recently reported that chiral N-(2-hydroxy-
ethyl)carbamoyl groups play an important role in the
stereocontrol of planar-chiral nicotinamides,10,11 which
are key synthetic intermediates of chiral bridged
NADH models effecting biomimetic reduction with
high enantioselectivity.12 We report here a simple
method removing 2-oxazolidinone and its related 2-
hydroxyethylamine auxiliaries in common methoxide–
carbonate systems from the corresponding N-acyl-2-
oxazolidinones and N-(2-hydroxyethyl)amides, respec-
tively. We also describe its application to the synthesis
of enantiomerically pure bridged nicotinate with
single planar-chirality.
Our method simply runs the removal of those chiral
auxiliaries in methoxide–carbonate systems instead of
methoxide alone, where an excess amount of DMC
(dimethyl carbonate) remarkably accelerates the reac-
tions to improve the yields of ester products. Scheme 1
depicts the reaction pathways for the formation of the
desired esters 2 and undesired amides 4, the latter of
which is initiated by methoxide attack onto the endo-
cyclic carbonyl of N-acyl-2-oxazolidinones 1. These
unfavorable reactions causing the formation of the
Scheme 1. Reaction pathways for the reaction of 1 with
methoxide.
* Corresponding author. Tel.: +81-44-934-7228; fax: +81-44-934-7906;
e-mail: kanomata@isc.meiji.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00698-1

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N. Kanomata et al. / Tetrahedron Letters 44 (2003) 3599–3603
amides 4 usually become more problematic for such
substrates where R1 is an aromatic or sterically
demanding alkyl group making their exocyclic carbonyl
groups less reactive. We then focused on the side-reac-
tion pathway simultaneously releasing an equimolecular
amount of DMC after the second methoxide substitu-
tion. Therefore, further addition of DMC should shift
the equilibrium toward the starting oxazolidinone 1 to
improve the yield of the desired ester 2. Based on this
simple strategy, we treated various N-acyl-2-oxazolidi-
nones 1 with NaOMe in the presence of excess DMC.
MeOH (entries 1–3). On the contrary, compound 1a
readily reacted with NaOMe in the presence of DMC
to form both 2a and 4a in 76% and 10% yields,
respectively (entry 4), and the further conversion of 4a
to 2a was complete within an additional hour to result
in the formation of 2a in 98% yield (entry 5). Similarly,
DMC affected the reaction of a benzoate derivative
having an electron-donating amino group on its aro-
matic moiety. The reaction of 1b gave the desired 2b in
97% yield within 4 h, although the reaction with
methoxide alone co-produced the 2-hydroxyethylamide
4b in 8–34% yields (entries 6–9). Compounds 1c,d with
alkenyl and phenethyl groups readily reacted to afford
the corresponding esters 2c,d in high yields (entries 10,
11). The reaction of 1e,f14 and 1g,h having another
alkyl group on the a-position was also readily complete
within 2.5–5 h to give optically active esters 2e–h in
93–96% yields (entries 12–15). Though the esters (S)-2e,
(R)-2f and (S)-(+)-2g15 were obtained without signifi-
Table 1 summarizes the results of transesterfication of
N-acyl-2-oxazolidinones 1.13 Initially, we investigated
the reactions of benzoate derivative 1a in the absence or
presence of DMC at room temperature. The reactions
of 1a with NaOMe alone afforded significant amounts
of undesired 4a in 8–30% yields as well as the desired
ester 2a even in the standard solvents such as THF and
Table 1. Transesterification of 2-oxazolidinones 1 in methoxide–carbonate systemsa

N. Kanomata et al. / Tetrahedron Letters 44 (2003) 3599–3603
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simple secondary amide, is completely inert in the
cant racemization (entries 12–14), a decrease of enan-
tiomeric purity was observed in case of (R)-(−)-2h15
(entry 15). This problem was overcome efficiently by
running the reaction in large excess DMC as solvent to
give (R)-(−)-2h with 98% selectivity (entry 16). On the
other hand, conversion of compound 1i incorporating a
more sterically demanding dimethyl group required
much higher temperature and longer reaction times for
its completion (entries 17–19). However, the DMC
effect is still evident in these reactions so that removal
of the oxazolidinone moiety proceeded in DMC at
50°C to increase the yield of 2i to 87% (entry 19). In
each reaction, oxazolidinone 3 was isolated in almost
identical yields as those for the esters obtained, which is
compatible with the proposed reaction mechanism
depicted in Scheme 1.
methoxide–carbonate systems.
An efficient transesterification of compounds 416 pro-
ceeds also in methoxide–carbonate systems to remove
chiral hydroxyethylamine auxiliaries with a clean N-
acyl bond cleavage (Table 2). The transesterification of
4d underwent in excellent yields with 3–5 equiv. of
NaOMe though the less amount of methoxide required
longer reaction times (entries 1–3). Aprotic solvents are
compatible with this system (entries 4–6), but no reac-
tion took place in methanol, a common solvent with
methoxide for the conventional method removing 2-
oxazolidinone auxiliaries (entry 7). Reaction of
diastereomerically pure compounds 4e–h also pro-
ceeded smoothly to give the corresponding chiral esters
2e–h in excellent yields (entries 8–12). For compound 4i
with fully substituted quaternary carbon as R, N-acyl
cleavage was less efficient and the ester 2i was obtained
in modest yields (entries 13 and 14). The formation of
the oxazolidinone intermediate is apparently less favor-
able due to steric repulsion between the substituents on
R and the isopropyl group on the 2-oxazolidinone
moiety, and the relatively acidic protons generating
methanol in situ also decrease the reactivity of methox-
ide toward 4i (see entry 7).
The postulated reaction pathways were further rational-
ized by the following results: (1) the N-(2-hydroxy-
ethyl)amide derivatives 4 also afforded the correspond-
ing ester 2 in excellent yields under similar reaction
conditions as those employed for N-acyl-2-oxazolidi-
nones 1 (vide infra), (2) methoxide alone did not cleave
the N-acyl bond of the compounds 4 without addition
of DMC, and (3) N-propyl phenethylcarboxamide, a
Table 2. Transesterification of N-hydroxyethylamides 4 in methoxide–carbonate systemsa

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N. Kanomata et al. / Tetrahedron Letters 44 (2003) 3599–3603
Table 3. Transesterification of 5 having a chiral oxazolidinone auxiliary
which might face a risk of isomerization at higher
temperatures. Further synthetic application of planar-
chiral pyridines is now under way.
Acknowledgements
Scheme 2. Synthesis of bridged nicotinate (S)-6 with single
planar-chirality.
We thank JSPS for financial support with Grant-in-Aid
for Scientific Research (C) (12650838).
These efficient transesterification developed here was
best applied to the synthesis of the enantiomerically
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