Diastereoselective conjugate addition of 1-(α,β-unsaturated acyl)hydantoin with nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2005.07.116

A diastereomeric conjugate addition of dialkylaluminum chloride to 1-(α,β-unsaturated acyl)hydantoin provided the corresponding alkyl adduct with inducted chirality in the β-position. Treatment of 1-(α,β-unsaturated acyl)hydantoin with Gilman reagent in the presence of Lewis acid also gave the same product. In this reaction, diethylaluminum chloride was the most effective Lewis acid and the absolute configuration of the major adduct at the β-position of acyl group depended on the kinds of existing metals.

Full text of DOI:10.1016/j.tetlet.2005.07.116

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6411–6415
Diastereoselective conjugate addition of
1-(a,b-unsaturated acyl)hydantoin with nucleophiles
Jun-ichi Yamaguchi,* Masakazu Harada, Takao Narushima, Asumi Saitoh,
Kanako Nozaki and Takayuki Suyama*
Department of Applied Chemistry, Faculty of Engineering, Kanagawa Institute of Technology, Shimo-Ogino, Atsugi,
Kanagawa 243-0292, Japan
Received 6 June 2005; revised 22 July 2005; accepted 25 July 2005
Abstract—A diastereomeric conjugate addition of dialkylaluminum chloride to 1-(a,b-unsaturated acyl)hydantoin provided the cor-
responding alkyl adduct with inducted chirality in the b-position. Treatment of 1-(a,b-unsaturated acyl)hydantoin with Gilman
reagent in the presence of Lewis acid also gave the same product. In this reaction, diethylaluminum chloride was the most effective
Lewis acid and the absolute configuration of the major adduct at the b-position of acyl group depended on the kinds of existing
metals.
Ó 2005 Elsevier Ltd. All rights reserved.
A methodology for the synthesis of optically active
compounds has been developed based on the use of
chiral auxiliaries. Among them, five-membered hetero-
cycles containing a nitrogen atom such as 2-oxazolidi-
none1 or 2-imidazolidinone2 are the most widely used.
In many diastereoselective syntheses utilizing a chiral
auxiliary, although reactions inducing a chiral center
at the a- position of the acyl group gives the
corresponding chiral compounds in excellent diastereo-
selectivity (>98% de), it has been known that diastereo-
selectivities of compounds having a chiral center at the
b-position in the reaction of conjugate addition of
(a,b-unsaturated acyl)chiral auxiliary are relatively low
(ca. >75% de). Therefore, development of a new and
convenient chiral auxiliary is still required for synthesiz-
ing new optically active compounds at the b-position of
the acyl group utilizing a conjugate addition system, in
excellent diastereoselectivity. Recently, we reported a
facile preparation of optically active hydantoin from
amino acid amide without racemization.3 Hydantoin
resembles 2-oxazolidinone or 2-imidazolidinone, so that
it is expected that hydantoin will be utilized as a chiral
auxiliary (Fig. 1). In this letter, we wish to report that
conjugate addition of 1-(a,b-unsaturated acyl)hydan-
toin 1 with dialkylaluminum chloride or a Gilman
reagent–Lewis acid complex provides the corresponding
alkyl adduct 2 with induced chirality at the b-position
(Scheme 1).
O
O
O
O
Ph
Me
Ph
HN
N
HN
N
HN
N
HN
O
Me
1
1
1
O
R
Ph
R
R
hydantoin 2-imidazolidinone 2-imidazolidinone
from aminoalcohol
2-oxazolidinone
from aminoalcohol
from Ephedrine
Figure 1.
Keywords: Hydantoin; Chiral auxiliary; Conjugate addition; Alkylaluminum; Alkylcuprate; Asymmetric addition.
*
Corresponding authors. Tel.: +86 46 291 3179; fax: +86 46 242 8760; e-mail: yamagu@chem.kanagawa-it.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.116

6412
J. Yamaguchi et al. / Tetrahedron Letters 46 (2005) 6411–6415
3
O
O
O
O
R
O
3
3
R
AlCl or R CuM-Et AlCl
2 2
2
Ph
2
Ph
Ph
2
N
1
N
R
N
N
R
O
1
O
R
R
1
2
1
O
Phe: R =PhCH
Val: =i-Pr
Trp: =3-indolylCH
2
2
N
N
R
2
1
O
R
3
Scheme 1. Diastereomeric conjugate addition of some nucleophiles to 1.
The starting material 1 was prepared by the reaction of
hydantoin with carboxylic acid anhydride in the pres-
ence of triethylamine and 4-(N,N-dimethylamino)pyri-
dine (DMAP) in DMF at room temperature. Initially,
we examined the treatment of 1-Phe (R2 = Ph) with ethyl-
aluminum in CH2Cl2, and the results are shown in
Table 1. Among the attempts with three types of ethyl-
aluminum, diethylaluminum chloride gave the best
result in ethyl addition to 1-Phe (Run 2). Other hydan-
toins derived from valine and tryptophan were also
examined. In the present reaction systems, the R1 group
was not a significant factor in determination of diastereo-
selectivity of 2 (Runs 2, 4 and 5).
molar amounts of dimethyl- or diisobutylaluminum
chloride were necessary to complete consumption of 1
(Runs 3–6). The rate of addition of an isobutyl group
to 1-(4-chlorocinnamoyl)hydantoin was slow, so that
the reduced compound 3 was mainly isolated (Run 6).
Concerning the first report on conjugate addition of
organoaluminum to a,b-unsaturated carboxylic acid
derivatives, Kunz and co-workers reported asymmetric
conjugate addition of dialkylaluminum chloride to 3-
(a,b-unsaturated acyl)-oxazolidinone.4 However, 4 equi-
molar amounts of dialkylaluminum chloride such as
ethyl, methyl and isobutyl were used in all reactions.
Further, addition of an equimolar amount of dimethyl-
aluminum chloride is necessary for isobutyl addition
using isobutylaluminum chloride, and methyl addition
using dimethylaluminum chloride proceeds under irradi-
ation only. In contrast, the present reaction smoothly
proceeded without an additive and irradiation to give
2 to completion.
Next, alkyl addition of various 1-Phe using some
dialkylaluminum chlorides, which were commercially
available, was performed (Table 2). Generally, ethyl
addition of an equimolar amount of diethylaluminum
chloride smoothly proceeded to form the corresponding
ethyl adduct 2 (Runs 1 and 2). In contrast, 2–3 equi-
Table 1. Effect of ethylaluminums on ethyl addition of 1-Phe (R2 = Ph)
(S):(R)b
a
Run
1
EtmAlCln
Temp./°C
Time/h
Yield/%
1
2
3
4
5
Phe
Phe
Phe
Val
Trp
EtAlCl2
Et2AlCl
Et3Alc
Et2AlCl
Et2AlCl
À40 to À20
À50 to À20
À40 to À20
À50 to 0
24
3
20
5
8
97
85:15
94:6
Complicated
97
78
90:10
88:12
À50 to À40
19
a Ethylaluminum (1.1 equiv) was used except for Run 3.
b Product ratios were determined by integration of diastereomeric a-methine signals of hydantoin in 1H NMR spectra.
c Et3Al (2.2 equiv) was used.
Table 2. Diastereoselective conjugate addition of dialkylaluminum chloride to 1-Phe (R1 = PhCH2)
Run
R2
R3 (equiv)
Temp./°C
Time/h
Yield/%
(S):(Ra)
1
2
3
4
5
6
4-ClC6H4
Me
Ph
4-ClC6H4
Ph
4-ClC6H4
Et (1.2)
Et (1.2)
Me (3.0)
Me (2.2)
i-Bu (2.5)
i-Bu (2.5)
À40 to À10
À50 to À15
À40 to À15
À40 to À20
À50 to À40
À40 to À20
20
0.5
14
18
19
24
83
91
79
85
78
16c
91:9
—
76:24
77:23
88:12
89:11
b
a Product ratios were determined by integration of diastereomeric a-methine signals of hydantoin in 1H NMR spectra.
b Determination of diastereomeric ratio was impossible by 1H NMR spectra and HPLC analysis.
c The reduced compound 3 was isolated in 71% yield.

J. Yamaguchi et al. / Tetrahedron Letters 46 (2005) 6411–6415
6413
O
Ph
Et
O
1) H O , LiOH, THF
2
2
HN
N
2-Phe
+
Ph
OH
2) Na SO
2
2
3
R =Ph
O
3
R =Et
Ph
4
5
%
98
97%
Scheme 2. Removal of hydantoin.
We examined the removal of the chiral auxiliary and
determination of the absolute configuration at the b-po-
sition of the acyl group of 2. Since separation of each
diastereomer of the ethyl or isobutyl adduct was possi-
ble by preparative TLC, the major diastereomer of the
ethyl adduct was isolated. Scheme 2 gives the result of
removal of the chiral auxiliary by the use of lithium
hydroperoxide as a cleavage agent. The corresponding
carboxylic acid 4 was separated from chiral auxiliary
5, which was recovered in excellent yield. The value of
the specific rotation of the synthesized 4 was the same
as that of the reported value.5 Thus, its absolute config-
uration at the b-position was determined to be (S)-form.
be obtained in high yield. It is well known that a com-
plex composed of the Gilman reagent and a Lewis acid
such as BF3 etherate or AlCl3 had high potential as a
Michael donor,7 and the use of Lewis acid would
decrease the basicity of the reaction system. BF3 etherate
was a powerful additive for suppressing decomposition
of 1 and the butyl adduct was isolated in moderate yield
and diastereoselectivity (Run 3). After several attempts,
conjugate addition of the Gilman reagent to 1-Val
derived from valine in the presence of Et2AlCl
gave the best yield and diastereoselectivity (Run 6).
Although the reaction of 1-Trp derived from tryptophan
afforded the butyl adduct in moderate yield, its stereo-
selectivity showed to be the highest of all (Run 7).
From the above results, it was found that hydantoin has
a capacity as a chiral auxiliary. The next aim was conju-
gate addition of another nucleophile to 1-(a,b-unsatu-
rated acyl)hydantoin. For example, diastereo-selective
conjugate addition of an alkylmetal compound to N-
(a,b-unsaturated acyl)chiral pyrrolidone in the presence
of additive has been reported.6 Among many nucleo-
philes, organocopper reagents are the most versatile re-
agents available for conjugate addition reactions, so that
we examined treatment of 1 with the Gilman reagent
prepared from 2 equimolar amounts of butyllithium
and copper(I) iodide. Unfortunately, the reaction was
complicated and none of the corresponding butyl ad-
ducts were given (Table 3, Run 1). Since hydantoin
was generally unstable under basic conditions, it was
suspected that the basicity of the Gilman reagent would
decompose the hydantoin moiety of 1. When the reac-
tion system using the Gilman reagent is performed un-
der neutral or acidic conditions, decomposition of 1
will be suppressed and the corresponding adduct 3 can
Bergdahl and co-workers reported a similar examination
when 2-oxazolidinone was used as a chiral auxiliary.8 In
conjugate additions employing the BuLi–CuI–Me3SiI
(TMSI) system, the absolute configuration of the major
product was (S)-form. The absolute configuration of 2
synthesized from the present reaction at the b-position
was determined by HPLC analysis of the benzyl ester
obtained after removal of hydantoin using lithium benz-
yloxide, and the major absolute configuration of benzyl
3-methylheptanate prepared by the present reaction sys-
tem was (R)-form.9
Further conjugate addition was also performed under
different reaction conditions (Table 4). Interestingly, the
diastereoselectivity of the butyl adduct 2 depended on
the existing metals in the reaction mixture. Although
the conjugate addition using the butyllithium-derived
reagent resulted in (S)-adduct as the main product
(Table 4, Run 1),10 a similar addition using a Grignard re-
agent instead of organolithium gave the opposite major
diastereomer, namely, (R)-form, predominantly (Table
4, Run 2). Concerning conjugate addition using N-(a,b-
unsaturated acyl)-oxazolidinone in the LiRCuI–TMSI
Table 3. Conjugate addition of 1 using Gilman reagent–Lewis acid
complex
Runa
1
Lewis acid
Temp./°C Yield/%b (S):(R)c
e
1d
2
3
4
5
6
7
Phe None
Phe SnCl4
À50 to rt
À78
—
—
—
Table 4. Conjugate addition of some R3M to 1-Val (R2 = Me)
Trace
85
74
86
88
Phe BF3 etherate À78
32:68
20:80
8:92
9:91
3:97
Run
R3M
Solvent
Yield/%
(S):(R)a
Phe EtAlCl2
Phe Et2AlCl
À78
À78
À78
À78
1
2
3
4
5b
BuLi
BuMgBr
BuLi
BuMgBr
BuLi
THF
THF
Et2O
Et2O
THF
93
76
88
84
26c
95:5
14:86
92:8
46:54
12:88
Val
Et2AlCl
Trp Et2AlCl
65
a All reactions were performed for 3 h.
b Isolated yield.
a Product ratios were determined by integration of diastereomeric
a-methylene signals of acyl group in 1H NMR spectra.
b The reaction was performed in the BuLi–CuI–TMSI system.8
c The starting material was recovered in 65% yield.
c Product ratios were determined by integration of diastereomeric
a-methylene signals of acyl group in 1H NMR spectra.
d The reaction was performed for 16 h.
e The reaction was complicated.

6414
J. Yamaguchi et al. / Tetrahedron Letters 46 (2005) 6411–6415
O
Bu
O
LiOCH2Ph, THF, 1 h
Ph
Bu
O
Me
Me
N
N
Me
Me
O
Ph
Ph
O
Ph
(R)-form
O
O
1) BuLi-CuI-TMSI7
Bu
O
N
O
O
2) LiOCH2Ph, THF, 1 h
Ph
(S)-form
Scheme 3. Conversion of butyl adducts to benzyl 3-methylheptanate.
Re-face
Cu R3
R3
R3
Al
O
R3
O
R3
R2
O
Ph
R2
N
N
O
N
N
R1
O
Ph
R1
O
A
(S)-2
Si-face
Et
Cu R3
Mg
R3
R2
R3
O
O
Et
Cl
Al
Ph
R2
N
N
O
O
N
O
N
R1
O
Ph
R1
(R)-2
B
Scheme 4. Proposed reaction pathway.
system, the absolute configuration of the adduct at the
b-position depended on not only the presence or absence
of a magnesium ion but also the solvent. Contrarily, the
absolute configuration of 2 at the b-position was indepen-
dent of the solvent in the present reaction system (Runs 2
and 4) (Scheme 3).
on new reactions, new cleavage methods, and unique
utilization by taking advantage of the characteristics of
hydantoin are now in progress.
References and notes
Scheme 4 shows the proposed reaction pathway. In
the conjugate addition using R3 AlCl or R3 CuLi–
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therein.
2
2
Et2AlCl system, since 1 will be fixed conformationally
upon complexation with the dialkylaluminum chloride,
addition or migration of the alkyl group should occur
from the Re-face of intermediate A, leading to (S)-form
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the present reaction is crucial for giving the (R)-form
adduct via attack of the alkyl group from the Si-face
of intermediate B.
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J. Yamaguchi et al. / Tetrahedron Letters 46 (2005) 6411–6415
6415
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suspension of copper(I) iodide was added 2 equimolar
amounts of butyllithium in hexane or butylmagnesium
bromide in THF at À78 °C and the reaction mixture was
stirred for 20 min at À20 °C. An equimolar amount of
Et2AlCl in hexane was added to the reaction mixture at
À78 °C.