Catalytic dissymmetrization of meso-2-imidazolidinones: Alternative route to chiral synthons for 1,2-diamines

Article abstract of DOI:10.1016/j.tetlet.2004.10.129

The chiral functionalization of a simple heterocycle, 1,3-dihydro-2- imidazolone, was achieved by the highly enantioselective monodeacylation of meso-1,3-diacetyl-2-imidazolidinones via an oxazaborolidine-catalyzed borane reduction. This kinetically controlled dissymmetrization is sufficiently effective to provide a synthetic route to either enantiomer of (4S, 5S)- or (4R, 5R)-4,5-dimethoxy-2-imidazolidinone derivatives, which serve as chiral synthons for threo-1,2-diamines.

Full text of DOI:10.1016/j.tetlet.2004.10.129

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9327–9330
Catalytic dissymmetrization of meso-2-imidazolidinones:
alternative route to chiral synthons for 1,2-diamines
Tadao Ishizuka,* Tomokazu Katahira, Ryushi Seo, Hirofumi Matsunaga and
Takehisa Kunieda
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe honmachi, Kumamoto 862-0973, Japan
Received 8 September 2004; revised 25 October 2004; accepted 25 October 2004
Available online 6 November 2004
Abstract—The chiral functionalization of a simple heterocycle, 1,3-dihydro-2-imidazolone, was achieved by the highly enantioselec-
tive monodeacylation of meso-1,3-diacetyl-2-imidazolidinones via an oxazaborolidine-catalyzed borane reduction. This kinetically
controlled dissymmetrization is sufficiently effective to provide a synthetic route to either enantiomer of (4S, 5S)- or (4R, 5R)-
4,5-dimethoxy-2-imidazolidinone derivatives, which serve as chiral synthons for threo-1,2-diamines.
Ó 2004 Elsevier Ltd. All rights reserved.
The simple heterocycle, 1,3-dihydro-2-imidazolone,1 has
proven to be a promising building block for 1,2-diamine
skeletons, which are found as structural units in bioac-
tive compounds of medicinal interest2 and chelating lig-
ands for metal catalysts.3 We recently reported on the
preparation of versatile chiral synthons for the 1,2-
diamines, (4S,5S)- and (4R,5R)-4,5-dimethoxy-2-imid-
alidinone (DMIm) derivatives, using 1,3-dihydro-2-
imidazolone as the starting material.4 Both methoxy
groups of the DMIm synthons can readily be replaced
with primary to tertiary alkyl groups and aryls with full
retention of configuration in a stepwise manner. Subse-
quent ring-opening provides a versatile route to opti-
cally active threo-1,2-diamines. The reported synthesis
of the chiral DMIm synthons involves an efficient, but
rather tedious step for optical resolution, in which stoi-
chiometric amounts of (1S,2R)-2-methoxy-1-apocam-
phanecarboxylic acid (MAC-acid) are used.5
A series of meso-4,5-dialkoxy-2-imidazolidinones (2a–e)
were conveniently prepared by treatment of (DL)-trans-
4,5-dimethoxy-2-imidazolidinone (1), which is easily
produced by the 4,5-dibromination of 1,3-diacetyl-2-
imidazolone with bromine followed by methanolysis,
with the meso-1,2-diols in the presence of BF3ÆOEt2 at
0°C to room temperature (Table 1). The cis–ꢀantiꢁ–cis
structures for the cyclized meso-products 2 shown here
are based on the X-ray crystal analysis of compound
6.7 This BF3-catalyzed procedure was equally applicable
to condensation reactions with meso-hydrobenzoin and
catechol, while ethylene glycol failed to give the cyclized
meso-products (2f), resulting in the formation of sub-
stantial amounts of polymeric adducts. meso-4,5-Ethyl-
enedioxy-2-imidazolidinone (2f) was synthesized by
alternate route involving treatment of 1,3-diacetyl-2-
imidazolone with NBS in 2-tert-butoxyethanol, followed
by cyclization in the presence of BF3ÆOEt2.8 The subse-
quent acetylation of compounds 2a–f thus obtained gave
meso-1,3-diacetyl-2-imidazolidinones (3a–f), which were
used in the kinetically controlled dissymmetrization
reactions.
In this paper, we describe a catalytic dissymmetrization
approach to the preparation of DMIm synthons, in
which the enantioselective N-monodeacetylation6 of
meso-1,3-diacetyl-2-imidazolidinones (3) by an oxaza-
borolidine-catalyzed borane reduction is a key step.
The reaction conditions for the deacetylation of meso-
1,3-diacetyl-2-imidazolidinone (3b) were examined, in
an attempt to optimize the oxazaborolidine-catalyzed
dissymmetrization (Table 2). The BH3–SMe2 complex
was the borane reagent of choice. Thus, the use of the
BH3–SMe2 complex (0.7equiv) in the presence of the
aminoalcohol 4 (0.2equiv) at 20 °C gave promising
results, while the THF complex resulted in a lower yield
Keywords: Diamine; Imidazolidinone; Synthon.
*
Corresponding author. Tel./fax: +81 96 371 4394; e-mail: tstone@
kumamoto-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.129

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T. Ishizuka et al. / Tetrahedron Letters 45 (2004) 9327–9330
Table 1. Preparation of meso-1,3-diacetyl-4,5-dialkoxy-2-imidazolidin
R
R
MeO
OMe
O
N
diols
O
O
N
O
Et3N
BF3•OEt2
DMAP
HN NH
HN NH
O
CH2Cl2
Ac
Ac
Ac2O
O
O
1
2 a-f
3 a-f
Entry
1
Diols
R
2a (%)
3 (%)
OH
OH
–(CH2)3–
(a)
74 (14)
85
OH
OH
OH
2
3
–(CH2)4–
–(CH2)6–
(b)
(c)
75 (8)
91
88
61
OH
OH
Ph
Ph
4
Ph, Ph
(d)
60 (15)
70
80
OH
OH
5
6
o-Phenylene
H, H
(e)
(f)
22 (58)
0 (88)b
OH
OH
OH
a The reaction was performed by the dropwise addition of BF3ÆOEt2 in CH2Cl2 into a stirred equimolecular mixture of 2-imidazolidinone (1) and
meso-diol in CH2Cl2 at room temperature. Recovery yields were in parentheses.
b See Ref. 8.
Table 2. Enantioselective monodeacetylation by aminoalcohol-catalyzed borane reduction
NH2
O
O
N
O
O
4
OH
a
BH3-complex
N
HN
N
Ac
Ac
Ac
5b
THF
O
O
3b
Entry
BH3-complex (equiv)
–THF (0.7)
(0.5)
Temp (°C)
Time (h)
Yieldb (%)
Eec (%)
1
2–SMe
20
20
2
34
94
93
93
93
98
93
—
70
72
1
47 (6)
60 (9)
60 (6)
55
2
3
4
5
6
7
8
9e
–SMe2 (0.7)
–SMe2 (1.2)
–SMe2 (1.7)
–SMe2 (0.7)d
–Et3N (0.7)
20
20
1
1
0
20
0.5
5
68 (11)
0 (100)
47 (22)
39 (15)
20–40
20
20
3
Thexylborane (0.7)
–SMe2 (0.7)
1
5
a
To a stirred solution of 4 (0.2equiv) and BH3-complex (0.2equiv) in THF was added a mixture of 3b and another portion of BH3-complex.
b Recovery yield in parentheses.
c Determined by HPLC as the N-Cbz derivatives.
d Borane-complex was added portionwise.
e (1S,2R)-1-Amino-2-indanol was employed instead of 4.
and the Et3N complex was completely unreactive (en-
tries 1 and 7). Lower amount (0.1equiv) of aminoalco-
hol 4 gave slightly low yield (51%) and selectivity (89%
ee). A reaction with BH3–SMe2 complex (1.7equiv) at

T. Ishizuka et al. / Tetrahedron Letters 45 (2004) 9327–9330
9329
0°C gave the highest enantioselectivity of 98% ee (entry
5) but lower yield. The portionwise addition of the bor-
ane reagent at 30–60min intervals further improved the
efficiency of the reaction (entry 6). A conventional ami-
noalcohol, such as (1S,2R)-1-amino-2-indanol, was not
as effective as a catalyst resulting in an enantioselectivity
as low as 72% ee (entry 9). As summarized in Table 3,
when meso-1,3-diacetyl-2-imidazolidinone derivatives
3a–f were treated with BH3–SMe2 complexes (0.7equiv)
in the presence of (À)-aminoalcohol 4 (0.2equiv), the
enantioselective monodeacetylation proceeded smoothly
at 20°C to give monoacetyl derivatives in excellent enan-
tioselectivity, except for compound 3f which resulted in
a much poorer enantioselectivity and yield. Compound
3e, produced using catechol in place of the meso-diols
served equally well, providing a selectivity in excess of
90% ee. The absolute configurations of the products
were determined on the basis of X-ray crystal analyses
of the N-(1S,2R)-MAC derivatives 6. From the yield
and selectivity, we accepted 3b as the meso-2-imidazo-
lidinone of choice and examined further conversions.
Unfortunately, 5b failed to react with organocuprate as
we had reported for 4,5-dimethoxy-2-imidazolidinones,4
we tried to convert the acetal moiety of 5b to O-methyl
acetals. Both enantiomers of the 4,5-dimethoxy-2-imi-
dazolidinone derivatives (9 and ent-9) were synthesized
by the straightforward manipulation of the kinetically
discriminated product 5b, including stepwise methanoly-
sis of acetal moieties catalyzed by cationic ion-exchange
resin, AmberlystÒ 15.
Thus, the AmberlystÒ-catalyzed methanolysis of 5b,
which were readily obtained in an optical pure form
by single recrystallization, proceeded smoothly only in
part to give an equilibrium mixture of compounds 5b
(41%) and 7 (46%). This is also the case for deacetylated
compound of 10 (45%) and compound 11 (37%).
Table 3. Enantioselective monodeacetylation of meso-1,3-diacetyl-2-imidazolidinones
R
R
NH2
O
O
O
O
OH
4
a
BH3-SMe2 (0.7 equiv.)
N
N
HN
N
Ac
Ac
Ac
THF
O
3
O
5
Entry
Compound
Time (h)
Product
Yieldb (%)
Eec (%)
1
2
3
4
5
6
3a
3b
3c
3d
3d
3f
2
5
5
5
5
5
5a
5b
5c
5d
5e
5f
50 (14)
60 (9)
60 (5)
53 (18)
63 (8)
42(32)
93
93
92
89
90
34
a
To a stirred solution of 4 (0.2equiv) and BH3–SMe2 (0.2equiv) in THF was added a mixture of 3 and another portion of BH3–SMe2 at 20°C.
b Recovery yield in parentheses.
c Determined by HPLC as the N-Cbz derivatives except for 5d and 5e, which were directly determined.
HO
O
HO
O
MeO
MeO
OMe
NH
MeO
HN
MeO
MeO
c
d
N
N
N
N
Ac
Ac
b
O
O
O
O
O
7
8
9
O
O
O
O
a
HN
N
N
NH
OH
Ac
O
5b
O
MeO
O
OMe
OMe
N OMe
MeO
HN
O
O
O
e
6
f
g
N
NH
N
N
Ac
10
Cbz
Cbz
O
O
ent -9
O
O
11
Scheme 1. Reagents and conditions: (a) (i) MAC-Cl, Et3N, CH2Cl2, 80%, (ii) Cs2CO3, MeOH, 91%; (b) Amberlyst 15, MeOH,50°C, 41%; (c)
ClCO2Me, Et3N, CH2Cl2, 98%; (d) Amberlyst 15, MeOH, reflux, 72%; (e) Cbz-Cl, Et3N, CH2Cl2, 96%; (f) Amberlyst 15, MeOH, reflux, 45%; (g) (i)
ClCO2Me, Et3N, CH2Cl2, 97%, (ii) Pd–C, Amberlyst 15 MeOH, H2, rt.

9330
T. Ishizuka et al. / Tetrahedron Letters 45 (2004) 9327–9330
3. For examples, see: (a) Kobayashi, S.; Uchino, H.; Fujishita,
Y.; Shiina, I.; Mukaiyama, T. J. Am. Chem. Soc. 1991, 113,
4247–4252; (b) Mukaiyama, T.; Iwasawa, N.; Stevens, R.
W.; Haga, T. Tetrahedron 1984, 40, 1381–1392, and
references cited therein.
4. Seo, R.; Ishizuka, T.; Abdel-Aziz, A. A.-M.; Kunieda, T.
Tetrahedron Lett. 2001, 42, 6353–6355.
5. (a) Ishizuka, T.; Kimura, K.; Ishibuchi, S.; Kunieda, T.
Chem. Pharm. Bull. 1990, 38, 1717–1718; (b) Ishizuka, T.;
Kimura, K.; Ishibuchi, S.; Kunieda, T. Chem. Lett. 1992,
991–994.
6. (a) Hashimoto, N.; Ishizuka, T.; Kunieda, T. Tetrahedron
Lett. 1998, 39, 6317–6319; (b) Yokoyama, K.; Ishizuka, T.;
Kunieda, T. Tetrahedron Lett. 1999, 40, 6285–6288(c) N-
Monodeacetylation of 1,3-diacetyl-4,5-dimethoxy-2-imid-
azolidinone showed poor results.
Methanolysis occurred exclusively at 4-position, the
unprotected NH-side of 2-imidazolidinone heterocycles,
in perfect regio and trans selectivity.
Methoxycarbonylated compound 8 underwent deacetyl-
ation and methanolysis to give (4R,5R)-N-methoxycar-
bonyl-4,5-dimethoxy-2-imidazolidinone 9 under reflux
condition with AmberlystÒ 15.
On the other hand, N-Cbz derivative 10 underwent
deacetylation and methanolysis to give the equilibrium
mixture of deacetylated compound of 10 and compound
11. After protection of the NH moiety by methoxycar-
bonylation, hydrogenolysis on Pd–C in the presence of
AmberlystÒ 15 yielded the (4S,5S)-dimethoxy com-
pound ent-9.
7. Crystal data for 6 (mp 227°C): monoclinic, P21, a =
14.028(1) A, b = 13.029(1) A, c = 10.012(2) A,
˚
˚
˚
3
V = 1966.1(4) A , Z = 2. The structure was refined to the
˚
These mono-protected dimethoxy-2-imidazolidinones 9
and ent-9 can be used as chiral synthons for 1,2-diam-
ines similar to the N-methoxyapocamphancarbonyl-
4,5-demethoxy derivatives (MAC-derivatives).4
R value of 0.037. We are much indebted to the Yoshitomi
Research Laboratories, Yoshitomi Pharmaceutical Ind.
Ltd (Fukuoka, Japan) for this X-ray crystallographic
analysis.
8. Compound 3f was readily synthesized via 4,5-dialkoxy-2-
imidazolidinone 13 derived from 1,3-diacetyl-2-imidazolone
(12) and NBS in the presence of ethylene glycol mono tert-
butyl ether.
In summary, we reported on the development of a cata-
lytic process for the efficient discrimination between two
enantiotropic acyl groups of meso-1,3-diacetyl-2-imi-
dazolidinones, thus providing a facile synthetic route
to chiral synthons for threo-1,2-diamines (Scheme 1).
OtBu
O
O
O
N
MeO
a
b
N
N
Ac
Ac
N
N
N
References and notes
Ac
Ac
3f
O
Ac
Ac
O
12
O
13
1. Wang, P. C. Heterocycles 1985, 23, 3041–3042.
2. For a review, see: Denis, L.; Thierry Le, G.; Charles, M.
Angew. Chem., Int. Ed. 1998, 37, 2580–2627.
a: (i) HOCH2CH2OtBu, NBS, dioxane, 77%, (ii) Et3N, Cs2CO3, MeOH, 81%
b: (i) BF3•OEt2, CH2Cl2, 65%, (ii) Et3N, DMAP, Ac2O, 88%