An unusual enhancement of chiral induction by chiral 2-imidazolidinone auxiliaries

Article abstract of DOI:10.1016/S0040-4039(00)01547-1

Diastereoselectivity which is induced by the use of 2-imidazolidinone auxiliaries is greatly dependent on the N-substituents of the heterocycles, among which the bulky arenesulfonyl group is the moiety of choice. Reactions of this type afford an excellent level of diastereoselection in the methylation of N'-butyryl-2-imidazolidinones via the metal enolates. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01547-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8533–8537
An unusual enhancement of chiral induction by chiral
2-imidazolidinone auxiliaries
Alaa A.-M. Abdel-Aziz, Junko Okuno, Shinsuke Tanaka, Tadao Ishizuka,
Hirofumi Matsunaga and Takehisa Kunieda*
Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
Received 13 September 2000; accepted 14 September 2000
Abstract
Diastereoselectivity which is induced by the use of 2-imidazolidinone auxiliaries is greatly dependent on
the N-substituents of the heterocycles, among which the bulky arenesulfonyl group is the moiety of
choice. Reactions of this type afford an excellent level of diastereoselection in the methylation of
N%-butyryl-2-imidazolidinones via the metal enolates. © 2000 Published by Elsevier Science Ltd.
Methodology which involves the use of heterocyclic chiral auxiliaries for a wide range of
asymmetric transformations has been highly successful. Chiral 2-imidazolidinones,1 as well as
the widely used 2-oxazolidinone auxiliaries2 hold considerable promise as chiral auxiliaries for
use in diastereocontrolled reactions. Common methods for the preparation of 2-imidazolidi-
nones are based on the reactions of 1,2-diamines with diethyl carbonate, phosgen, triphosgen or
1,1%-carbonyldiimide.3 We recently reported an alternative route for the facile synthesis of
sterically constrained tricyclic 2-imidazolidin-ones (1–3),4 which served as versatile chiral auxil-
iaries. This approach involves the cycloaddition of 1,3-dihydro-2-imidazolone to the cyclic
dienes such as anthracene and cyclopentadiene derivatives (Scheme 1).
R1
R1
R1
HN
NH
R1
X
N
H
X
N
H
O
O
O
2
1
3: X=NR2 [HMCIm]
1: X=NR , R =H [DHAIm]
2
1
2: X=NR , R =Me [DMAIm]
Scheme 1.
* Corresponding author. Fax: +81-96-362-7692; e-mail: tkuni@kumamoto-u.ac.jp
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01547-1

8534
This paper describes a new synthetic route to optically active 4-tert-butyl and 4-(1-
adamantyl)-2-imidazolidinones, which serve as highly potent chiral auxiliaries, from the parent
2-imidazolidinone heterocycle as well as a surprisingly strong chiral control effect by the
N-substituents of such 2-imidazolidinone auxiliaries on diastereoselective enolate alkylations.
The method involves the conversion of functionalized 4-methoxy and 4-phenylthio-2-imidazo-
lidinones with organo cuprates to give the 4-alkyl- and 4-aryl-derivatives, followed by a facile
optical resolution through either a stoichiometric or catalytic process.
Thus, electrolytic oxidation5 of N-acetyl-2-imidazolidinone (4) in methanol resulted in the
exclusive formation of 4-methoxy-imidazolidinone (5), of which the methoxy groups were
readily displaced with a variety of alkyl and aryl groups by using cuprate complexes in the
presence of BF3·OEt2. The 4-methoxy group was readily converted into the phenylthio group on
treatment with benzenethiol/TFA. The latter nucleophilic substitution proceeded with or
without the Lewis acid. Using this versatile procedure, 4-substituted 2-imidazolidinones (6)
including bulky 4-tert-butyl and 4-(1-adamantyl) compounds were prepared in good yields
(65–89%).6 An optical resolution was performed with the aid of (1S,2R)-2-methoxy-1-apocam-
phanecarboxylic acid ((+)-Mac acid)7 to give the diastereomeric N-Mac derivatives 7a and b,
which were readily separable by chromatography on silica gel (Scheme 2). The N%-protection
with a series of arenesulfonyl chlorides with different degrees of bulkiness and methyl iodide,
followed by removal of the Mac moieties either by reductive deacylation with LiBH4/MeOH or
by thiolysis with PhCH2SLi gave the enantiomerically pure 4-substituted-2-imidazolidinones 9a
and b.
R1CuCNLi
LiCl
BF3•OEt 2
MeO
HN
R1
R1=Ph: 65%
R1=t-Bu: 89%
R1=1-adamantyl: 84%
Electrolysis
MeOH
HN
N-Ac
N-Ac
HN
N-Ac
THF; -30 °C
O
O
O
5
6
4
R1
R1
R1
LiBH4-MeOH (1:2)
NaH
[Mac-Cl]
Mac-N
NH
Mac-N
NR2
HN NR2
Cl
i)
R2X, THF
THF
, NaH
OMe
THF; r.t, 3h
O
O
9a
O
7a
O
8a
PhCH2SLi (1.5 eq.)
or
LiBH4-MeOH (1:2)
ii) Cs2CO3, MeOH
r.t., 15 min
R1
R1
R1
NaH
Mac-N
NR2
HN NR2
Mac-N
NH
THF
R2X, THF
O
O
O
7b
9b
8b
Scheme 2.
The absolute configurations of the chiral 4-phenyl and 4-tert-butyl-2-imidazolidinones (9b)
were determined by X-ray crystallographic analysis8 of the N-Mac-isomers (7b).
An alternative means for optical resolution of the 2-imidazolidinones was provided by the
dynamic kinetic resolution with enantioselective deacylation of the N-acetyl-derivatives via a
catalytic process.9 Thus, the N-acetyl-derivative 10 smoothly underwent an enantioselective
partial deacetylation on treatment with borane (2 equiv.) in the presence of aminoalcohol (+)-11
(0.1 equiv.) to give a quantitative yield of (4R)-12 and (4S)-13, which were readily purified by
a single recrystallization (Scheme 3).

8535
OH
NH2
(+)-11
Ac
N
N S
O2
Ac
N
N S
O2
+
HN
N S
O2
BH3•THF
(2 eq.)
O
O
O
10
12
51% (83% ee)
13
48% (91% ee)
Scheme 3.
The chiral 2-imidazolidinone auxiliaries thus obtained could be conveniently evaluated by the
sterically undemanding probe reaction, involving a-methylation of the butyryl derivatives (14),
which is generally difficult to control with a high level of diastereoselection.10 The diastereoselec-
tive methylations of the N-alkyl and N-arenesulfonyl-N%-butyryl-2-imidazolidinones (14) pro-
ceeded smoothly to give moderate to excellent diastereoselectivity when the reaction was
performed with methyl iodide in the presence of lithium or sodium hexamethyldisilazanide
(LHMDS or NHMDS) as well as lithium diisopropylamide (LDA).
As can be seen in Table 1, the chiral induction by the 2-imidazolidinone auxiliaries is greatly
dependent on both the 4-substituent groups of the 2-imidazolidinones and the N-substituents
which are located at a considerable distance from the site of the reaction. Apparently, a small
structural variation in the chiral auxiliary may induce a tremendous effect on asymmetric
control. It is noteworthy that the observed diastereoselectivity of the reaction was highly
dependent on the bulkiness of the N-arenesulfonyl substituents on the 2-imidazolidinone
auxiliaries, in which ortho-disubstituents played an important role in achieving an excellent level
of diastereocontrol. The 2,4,6-triisopropylbenzenesulfonyl (Tps) and 2-mesitylenesulfonyl (Mes)
groups represent the N-substituents of choice for the 2-imidazolidinone auxiliaries in regard to
chiral induction and efficiency. Nevertheless, excellent diastereoselectivity was obtained with
chiral 4-(1-adamantyl)-3-methyl-2-imidazolidinones as the auxiliary, providing, to our know-
ledge, the highest selectivity observed thus far. Such a positive effect by N-substituents was not
apparent in the cases of 4-phenyl-2-imidazolidinones with considerably less steric hindrance. It
is unlikely that the N%-substituents and metal species could significantly affect the E/Z ratio of
enolates and the chelate structures which might play a crucial role in high level of chiral
induction,11 although we have no evidence at the present.
The N-substituent effect leading to a dramatic enhancement in chiral induction was also
observed when sterically congested 2-imidazolidinone auxiliaries such as DHAIm (1), DMAIm
(2) and HMCIm (3) were used in the diastereoselective methylation of N%-butyryl derivatives 15
using LHMDS as a base (Table 2). Our findings clearly show that the bulky N-sulfonyl
substituents were much superior to alkyl groups, such as methyl and 2,4,6-trimethylbenzyl
groups.
The present chiral auxiliaries are highly crystalline and could be recovered easily with
LiOH/H2O2 in quantitative yields. In conclusion, this study demonstrates the remarkable
diastereocontrolling effects of the N-substituents of 2-imidazolidinone auxiliaries, leading to
excellent chiral auxiliaries, namely bulky N-(ortho-disubstituted benzenesulfonyl)-2-imidazolidi-
nones. The mechanistic details for this reaction remain under investigation.

Table 1
The 1,4-disubstituent effect of 2-imidazolidinone auxiliaries on diastereocontrolled methylation
R1
N
R1
N
R1
N
i) Base (1 eq.); 30min
ii) MeI (3 eq.)
Me
Me
N R2
N R2 +
N R2
THF; 3 h
Temp
O
O
O
O
O
O
14
A
B
R1
Ph
R2a
Base
Temp. (°C)
Yield (%)b
86 (88)
75 (95)
89 (90)
90 (98)
65 (89)
73 (82)
79 (100)
15 (21)d
A:Bc
R1
t-Bu
1-Adamantyl
R2a
Base
Temp. (°C)
Yield (%)b
A:Bc
32:1
37:1
38:1
179:1
284:1
39:1
\500:1
\500:1
Tos
Tps
Me
Tos
Mes
Tps
Tps
Tps
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LDA
0
0
0
3.9:1
5.7:1
5.2:1
32:1
190:1
490:1
420:1
17:1
Me
Me
Tos
Mes
Tps
Me
Me
Me
LHMDS
LDA
−30
−30
−30
−10
−10
−30
−30
−30
79 (91)
86 (99)
54 (92)
66 (71)
72 (72)
79 (92)
86 (86)
85 (85)
LHMDS
LHMDS
LHMDS
LHMDS
LDA
t-Bu
−30
−10
−10
−30
−30
NaHMDS
NaHMDS
a Tos: p-toluenesulfonyl; Mes: 2-mesitylenesulfonyl; Tps: 2,4,6-triisopropylbenzenesulfonyl.
b Determined by HPLC. Corrected yields in parentheses based on unchanged starting material.
c Determined by HPLC.
1
d Determined by H NMR (500 MHz).

8537
Table 2
The N-substituent effect of 2-imidazolidinone auxiliaries on diastereocontrolled methylation
Me
Me
*
LHMDS, MeI (10 eq.)
NX
*
*
NX
NX
+
THF; -30 °C, 3h
O
O
O
A
B
15
NX*H R2
LHMDS Yield (%)a A:Bb NX*H R2
LHMDS Yield (%)a A:Bb
(equiv.)
(equiv.)
1
1
1
1
N-Me
2
2
2
2
97
97
82
91
1.8:1
4:1
1
2
3
N SO2
N SO2
2
84
31:
1
2
82c,d
>500:1
>500:1
N CH2
N SO2
9:1
5e
71d
N SO2
N SO2
OMe
9:1
a Isolated yields.
b Determined by HPLC.
c For 10 h.
1
d Determined by H NMR (500 MHz) spectra.
e 31% yield was obtained by using 2 equiv. of LHMDS.
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