Versatile chiral synthons for 1,2-diamines: (4S,5S)- and (4R,5R)-4,5-dimethoxy-2-imidazolidinones

Article abstract of DOI:10.1016/S0040-4039(01)01279-5

(4S,5S)- and (4R,5R)-1-Acyl-4,5-dimethoxy-2-imidazolidinone derivatives, which are readily accessible from simple 1,3-dihydro-2-imidazolone heterocycles, represent good candidates for a new class of chiral synthons for use in the preparation of optically active threo-diamines such as 2S,3R- and 3S,4S-diamino carboxylic acids.

Full text of DOI:10.1016/S0040-4039(01)01279-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6353–6355
Versatile chiral synthons for 1,2-diamines: (4S,5S)- and
(4R,5R)-4,5-dimethoxy-2-imidazolidinones
Ryushi Seo, Tadao Ishizuka, Alaa A.-M. Abdel-Aziz and Takehisa Kunieda*
Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
Received 30 May 2001; accepted 13 July 2001
Abstract—(4S,5S)- and (4R,5R)-1-Acyl-4,5-dimethoxy-2-imidazolidinone derivatives, which are readily accessible from simple
1,3-dihydro-2-imidazolone heterocycles, represent good candidates for a new class of chiral synthons for use in the preparation
of optically active threo-diamines such as 2S,3R- and 3S,4S-diamino carboxylic acids. © 2001 Elsevier Science Ltd. All rights
reserved.
The vicinal diamine skeleton is a structural unit found
in a substantial number of compounds of biological
and medicinal interest,1 and functions as a chelating
ligand for transition metals as well as main group metal
complexes.2 Thus, the use of 1,2-diamines as reliable
building blocks in organic synthesis has increased con-
siderably, particularly in the field of catalytic asymmet-
ric synthesis.1,2 Hence, a versatile route for the chiral
synthesis of both unsymmetric and C2-symmetric 1,2-
diamines from simple, unexpensive starting materials
would be highly desirable.3
is fully stereocontrolled by a vicinal group, followed by
ring opening to give the threo-1,2-diamines 5, as out-
lined in Scheme 1. It should be noted that the 4-
methoxy group is preferentially replaced with organo
metals in the presence of Lewis acids, due to the higher
stability of acyliminium cation intermediate, which is
generated in situ.
Synthesis of (4S,5S)- and (4R,5R)-4,5-dimethoxy-2-imi-
dazolidinones (Scheme 2)
The simple heterocycle, 1,3-dihydro-2-imidazolone 1,4
which contains vicinal amino groups masked with a
carbonyl group and an enamine moiety and would be
susceptible to various modes of addition reactions,
suggests its synthetic potential as a building block for
the preparation of 1,2-diamines. In this paper we wish
to report on a promising route for an efficient synthesis
of optically active 1,2-diamines through the key inter-
mediates, (4S,5S)- and (4R,5R)-4,5-dimethoxy-2-imida-
zolidinones, which are readily accessible from the
2-imidazolone. Both the 4- and 5-methoxy groups on
the 2-imidazolidinones 2 may undergo a stepwise and
regioselective substitution with organo cuprates, which
The 1,3-diacetyl-2-imidazolone 64 underwent a smooth
electrophilic addition of bromine in methylene chloride
to give trans-4,5-dibromo-2-imidazolidinone 7, which
was methanolyzed to the dimethoxy derivatives in the
presence of a tertiary amine. The imidazolidone rac-8
was N-acylated with (1S,2R)-2-methoxy-1-apocam-
phanecarbonyl chloride (MAC-Cl)5 followed by
deacetylation with Cs2CO3 to give the diastereomeric
mixture of 9a and 9b, of which chromatographic sepa-
ration on silica gel was unsuccessful. Thus, they were
converted to the diastereomeric 1-MAC-4-benzyloxy-5-
methoxy derivatives, 10a and 10b, by treatment with
Scheme 1.
* Corresponding author. Tel.: +81-96-371-4680; fax: +81-96-362-7692; e-mail: tkuni@kumamoto-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01279-5

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R. Seo et al. / Tetrahedron Letters 42 (2001) 6353–6355
i
Scheme 2. (a) Br2, CH2Cl2; (b) Pr2NEt, MeOH; (c) MAC-Cl, NaH, THF; (d) Cs2CO3, MeOH, (e) BnOH, BF3·OEt2, CH2Cl2
(43% for 10a and 36% for 10b); (f) H2, Pd-black, MeOH; (g) LiBH4, MeOH (87–96%); (h) AcCl, Et3N, DMAP (82–84%); (i) Br2,
MeC(OMe)3.
Ph2CH2OH/BF3·OEt2. The benzyloxy derivatives thus
obtained were readily separated by chromatography on
silica gel, resulting in the clear-cut separation into the
diastereomers 10a and 10b,6 which were reductively
debenzylated with H2/Pd-black in methanol to give
quantitative yields of (4S,5S)- and (4R,5R)-1-MAC-4,5-
dimethoxy-2-imidazolidinones 9a7 and 9b,7 respectively.
On the other hand, treatment of 1-acetyl-3-MAC-2-imi-
dazolone 11 with bromine in trimethyl orthoacetate8
followed by methanolysis resulted in the diastereoselec-
tive formation of 9a with a moderate selectivity of 72%
de. The absolute configuration of diastereomer 9b was
determined by chemical correlation with the authentic
(1R,1R)-1,2-diphenylethylenediamine via its conversion
to (4R,5R)-3-MAC-1-tosyl-4,5-diphenyl-2-imidazolidi-
none.9 Subsequent removal of the MAC auxiliary with
LiBH4–MeOH, followed by N-mono-acetylation,
resulted in the smooth formation of 1-acetyl-4,5-
dimethoxy-2-imidazolidinones, (4S,5S)-810 and (4R,5R)-
8,10 which represent promising chiral synthons for the
1,2-diamines.
Theversatilityofthe(4S,5S)-and(4R,5R)-4,5-dimethoxy
derivatives (8 and 9) thus obtained was demonstrated by
the chiral synthesis of 2,3-diamino and 3,4-diamino
carboxylic acids, 17 and 19, which can be regarded as the
diamino analogs of the biologically important amino
hydroxy acids, statine11 and the key component of amas-
tatine,12 3-amino-2-hydroxy-5-methylhexanoic acid.
Synthesis of 2,3-and 3,4-diamino acids (Schemes 3 and 4)
The (4S,5S)-1-MAC-4,5-dimethoxy-2-imidazolidinone
i
9a was treated with BuCu(CN)MgBr/LiCl in the pres-
Scheme 3. (a) (CH3)2CHCH2MgBr, CuCN, LiCl, BF3·OEt2, THF; (b) TsCl, BuLi, THF; (c) PhCH2SH, BuLi, THF, (Cs2CO3,
MeOH for 13); (d) allylTMS, BF3·OEt2, CH2Cl2; (e) Ba(OH)2·8H2O, EtOH, H2O; (f) (Boc)2O, Et3N, CH2Cl2; (g) KMnO4, NaIO4,
(CH3)2CO, H2O; (h) CH2N2.
Scheme 4. (a) TMSCN, BF3·OEt2, CH2Cl2; (b) HCl, MeOH; (c) Ba(OH)2·8H2O, EtOH, H2O; (d) (Boc)2O, Et3N, CH2Cl2; (e)
CH2N2.

R. Seo et al. / Tetrahedron Letters 42 (2001) 6353–6355
6355
References
a recent review, see: Lueet, D.; Gall, T. L.;
Mioskowski, C. Angew. Chem. Int., Ed. Engl. 1998, 37,
2580–2627.
ence of BF3·OEt2 at −30°C, resulting in the regioselec-
tive replacement of the 4-methoxy group with an
isobutyl group with complete retention of configura-
tion. The attack of cuprate toward the acyliminium
ion intermediate might be effectively controlled by the
vicinal methoxy group. Subsequent N-sulfonylation
with p-toluenesulfonyl chloride (Ts-Cl) followed by the
removal of the MAC auxiliary with PhCH2SLi yielded
the N-Ts derivative (4S,5S)-14. This derivative could
also be obtained from compound (4S,5S)-8 in yields
as given in parenthesis (Scheme 3) by virtually the
same procedure as above. Smooth allylation was
achieved by treatment with allyltrimethylsilane in the
presence of BF3·OEt2 to give (4S,5S)-4-allyl-5-
isobutyl-1-tosyl-2-imidazolidinone 15. The hydrolytic
ring-opening with Ba(OH)2·8H2O followed by N-BOC
protection yielded the N-protected diamine 16. Oxida-
tive cleavage of the allyl group followed by esterifica-
1. For
2. For a review, see: Bennai, Y. L.; Hanessian, S. Chem. Rev.
1997, 97, 3161–3195.
3. For recent examples: (a) Imagawa, K.; Hata, E.; Yamada,
T.; Mukaiyama, T. Chem. Lett. 1996, 291–294; (b)
Bruncko, M.; Khuong, T.-A. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 454–456.
4. Wang, P. C. Heterocycles 1985, 23, 3041–3042.
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. The ratio of Rf values for diastereomers 10a and 10b on
0.2 mm silica gel plates (Merck, Kieselgel 60F254) with the
mixture of dichloromethane and ethyl acatate (4:1) as a
developing solvent is 1.2.
tion
with
diazomethane
afforded
(3S,4S)-3-
7. Compound 9a: mp 84.5–85.0°C (from hexane); [h]2D8 −64.8°
(c 1.00, CHCl3). Compound 9b: mp 113.5–114.0°C (from
hexane); [h]3D1 +33.0° (c 1.00, CHCl3).
aminodeoxystatine methyl ester 17,13 in which the two
amino functions were protected with different types of
groups.
8. Ishizuka, T.; Ishibuchi, S.; Kunieda, T. Tetrahedron Lett.
1989, 26, 3449–3452.
9. 1H NMR (500 MHz, CDCl3): l 7.55 (d, 2H, J=8.6 Hz),
7.37–7.38 (m, 3H), 7.26–7.29 (m, 5H), 7.15–7.17 (m, 4H),
5.19 (d, 1H, J=1.8 Hz), 5.05 (d, 1H, J=1.8 Hz), 4.68 (dd,
1H, J= 4.0, 7.6 Hz), 3.12 (s, 3H), 2.41 (s, 3H), 2.27–2.38
(m, 1H), 1.59–1.82 (m, 5H), 1.10–1.16 (m, 1H), 1.10 (s, 3H),
0.97 (s, 3H).
The (4R,5R)-2-imidazolidinones, 9b and (4R,5R)-8,
were also successfully employed for the chiral synthesis
of (2S,3R)-2,3-diamino-5-methylhexanoic acid, which
represents an amino analog of the key amino acid
component of amastatine.
10. Compound (4S,5S)-8: mp 61–62°C (from hexane); [h]D25
−68.0° (c 1.0, CHCl3). Compound (4R,5R)-8: mp 61–62°C
(from hexane); [h]2D5 +68.0° (c 1.0, CHCl3).
Thus, (4R,5R)-14 was converted to (4S,5R)-4-cyano-5-
isobutyl-1-tosyl-2-imidazolidinone 18 by treatment
with trimethylsilyl cyanide/BF3·OEt2. Straightforward
manipulation including hydrolytic ring-opening and
protection gave (2S,3R)-2,3-diamino-5-methylhexanoic
acid 1914 in a fully protected form.
11. Umezawa, H.; Aoyagi, T.; Morishima, H.; Matsuzaki, M.;
Hamada, M.; Takeuchi, T. J. Antibiot. 1970, 23, 259–262.
12. Aoyagi, T.; Tobe, H.; Kojima, F.; Hamada, M.; Takeuchi,
T.; Umezawa, H. J. Antibiot. 1978, 31, 636–638.
13. Compound 17: mp 41.5–42.0°C (from hexane); [h]2D8 −40.0°
1
The diamino carboxylic acids 17 and 19 thus obtained
were thoroughly free from contamination by erythro-
isomers, as evidenced by spectrographic data. The
methodology presented here has applicability to the
chiral synthesis of C2-symmetric 2-imidazolidinone
auxiliaries and the 1,2-diamine ligands.
(c 0.70, CHCl3); H NMR (500 MHz, CDCl3): l 7.73 (d,
2H, J=7.9 Hz), 7.30 (d, 2H, J=7.9 Hz), 4.91 (br d, 1H),
4.85 (br d, 1H), 4.06 (m, 1H), 3.69 (s, 3H), 3.48–3.46 (m,
1H), 2.72–2.70 (m, 1H,), 2.55–2.43 (m, 1H), 1.70 (s, 3H),
1.56–1.32 (m, 2H), 1.41 (s, 9H), 0.84–0.78 (m, 1H), 0.69 (d,
3H, J=6.1 Hz), 0.65 (d, 3H, J=6.1 Hz).
14. Compound 19: [h]D25 +62.0° (c 1.00, CHCl3); 1H NMR (500
MHz, CDCl3): l 7.75 (d, 2H, J=7.9 Hz), 7.30 (d, 2H,
J=7.9 Hz), 5.31 (d, 1H, J=8.5 Hz), 4.63 (br, 1H), 4.31 (br,
1H), 3.79–3.78 (m, 1H), 3.71 (s, 3H), 2.43 (s, 3H,),
1.55–1.54 (m, 1H), 1.43 (s, 9H), 1.36–1.31 (m, 1H),
1.02–0.99 (m, 1H), 0.77 (d, 3H, J=6.7 Hz), 0.68 (d, 3H,
J=6.7 Hz).
In conclusion, the (4S,5S)- and (4R,5R)-1-acyl-4,5-
dimethoxy-2-imidazolidinones, which are readily acces-
sible in stable, crystalline forms from the simple
heterocycle, 1,3-dihydro-2-imidazolone, represent good
candidates for chiral synthons for use in the chiral
preparation of synthetically, biologically and medici-
nally important 1,2-diamines as well as 2-imidazolidi-
none auxiliaries.15
15. Facile conversion of the chiral synthons 8 and 9 into
C2-4,5-disubstituted 2-imidazolidinones and C2-1,2-
diamines will be the subject of a separate paper.
.