Kenichi Murai, Hiromichi Fujioka et al.
Results and Discussion
As part of a study designed to develop a method for asym-
metric bromolactonization reactions of b-branched symmet-
ric compounds of type 2 and 3 (Scheme 2), we initially ex-
plored the reaction of diene-carboxylic acid 2a. As expect-
ed, treatment of compound 2a under standard asymmetric
bromolactonization conditions developed in our earlier ef-
forts (i.e. Ph-tris 1a (10 mol%), 1,3-dibromo-5,5-dimethyl-
hydantoin (DBDMH, 1.0 equiv), toluene, À408C) led to the
generation of bromolactone 4 in 99% yield and 87% ee
(Scheme 3).[13,14]
Scheme 2. Two types of b-branched symmetrical compounds.
contained an olefin moiety as the R’ group, whereas dicar-
boxylic acid 3 contained a carboxylic acid moiety as the R’
group (Scheme 2).
Several reports describing the asymmetric desymmetriza-
tion of diene- and dialkyne-carboxylic acids that utilized hal-
olactonization methods have been reported.[8] For example,
Hamashima, Kan, and co-workers demonstrated that asym-
metric bromolactonization reactions of 1,4-cyclohexadienyl
carboxylic acids produced synthetically useful b- and g-lac-
tones in a highly enantioselective manner with bis-cinchona
alkaloid catalysts, such as (DHQD)2PHAL.[9] In addition,
asymmetric bromolactonization reactions of dialkyne-car-
boxylic acids that utilize the same catalyst have very recent-
ly been described by Hennecke and co-workers.[10] Several
successful examples of the desymmetrizing haloetherifica-
tion of ene-diol substrates have also been reported. The first
desymmetrizing iodolactonization reaction of diols, such as
alk-4-ene-1,8-diols, was reported by Hennecke and co-work-
ers, which proceeded through the desymmetrization of in-
situ-generated meso-halonium ions.[3u,11] Very recently,
Yeung and co-workers reported the bromoetherification of
olefinic or diolefinic 1,3-diols.[12] On the other hand, the de-
symmetrization of dicarboxylic acid substrates has been less
explored. For example, an attempt using Hennecke’s meso-
halonium-ion strategy for dicarboxylic acid substrates was
reported to result in poor enantioselectivities, which con-
trasted with the high levels of stereocontrol for related idoe-
therification reactions of ene-diols.[3u]
Scheme 3. Asymmetric bromolactonization of diene-carboxylic acid 2a.
Guided by the positive results arising from our brief study
with compound 2a, our attention turned the desymmetriza-
tion reaction of ene-dicarboxylic acid 3a. Our synthetic
route to this substrate is shown in Scheme 4. Thus, the 1,4-
Scheme 4. Preparation of ene-dicarboxylic acid 3a.
In the design of conditions/catalysts that could promote
the bromolactonization of substrates that contained two car-
boxylic acids, we envisaged that the interactions between
the carboxylic acid groups and an organocatalyst with an
amino functionality—which are often used for asymmetric
halolactonization reactions—could be complicated, which
might lead to poor efficiencies and low enantioselectivities.
Herein, we report our investigations into asymmetric desym-
metrization through a bromolactonization reaction with a tri-
simidazoline catalyst. In particular, our study on the reac-
tions with dicarboxylic acids was mainly performed owing to
our interest in the properties of the trisimidazoline catalyst,
which could form ion pairs with carboxylic acids, and the
fact that their reactivity has been less well-explored.
addition of b-ketoester 5a to the known 1,5-diethyl 2-pente-
nedioate[15] afforded triester 6a. Then, compound 6a was
subjected to Krapcho decarboxylation with NaCl in DMF
and water,[16] followed by Wittig olefination with the ylide of
CH3PPh3Br to produce olefinic diester 8a. Hydrolysis of the
diester groups in compound 8a with LiOH gave dicarboxylic
acid 3a. A series of ene-dicarboxylic acids (3b–3j, Table 3)
was also prepared in a similar manner.
Next, dicarboxylic acid 3a was subjected to the bromolac-
tonization conditions. To our delight, it underwent the enan-
tioselective desymmetrizing bromolactonization reaction
with moderate enantioselectivity (38% ee, Scheme 5). In
this study, the reaction product was isolated as its corre-
sponding methyl ester (10a), owing to the ease of purifica-
tion with column chromatography on silica gel, and to the
ease of determination of enantioselectivity by HPLC analy-
sis compared to carboxylic acid 9a.[14,17] Methyl ester 10a
Chem. Asian J. 2014, 9, 3511 – 3517
3512
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim