Stereoselective intramolecular radical addition of polyhaloacyl pendant groups to the 1,3-dihydro-2-imidazolone moiety: The chiral synthesis of threo-diaminocarboxylic acids

Article abstract of DOI:10.1016/S0040-4039(01)01242-4

The intramolecular Ru(II)-catalyzed radical addition of trichloroacetyl and 2,2-dichloro-4-hexenoyl pendant groups to a 1,3-dihydro-2-imidazolone moiety provides a perfectly stereocontrolled approach to the preparation of 1,2-diamines which contain contig

Full text of DOI:10.1016/S0040-4039(01)01242-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6319–6322
Stereoselective intramolecular radical addition of polyhaloacyl
pendant groups to the 1,3-dihydro-2-imidazolone moiety:
the chiral synthesis of threo-diaminocarboxylic acids
Tomokazu Katahira, Tadao Ishizuka, Hirofumi Matsunaga and Takehisa Kunieda*
Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
Received 8 June 2001; revised 25 June 2001; accepted 6 July 2001
Abstract—The intramolecular Ru(II)-catalyzed radical addition of trichloroacetyl and 2,2-dichloro-4-hexenoyl pendant groups to
a 1,3-dihydro-2-imidazolone moiety provides a perfectly stereocontrolled approach to the preparation of 1,2-diamines which
contain contiguous multi-stereocenters. Typical examples for this approach are given by the chiral synthesis of vicinal-diaminocar-
boxylic acids, which are amino analogs of statine and MeBmt. © 2001 Elsevier Science Ltd. All rights reserved.
6
Diamines are, biologically, medicinally and syntheti-
cally, an important class of compounds.1 The 1,2-
diamine skeleton can be a structural unit found in a
number of bioactive compounds of medicinal interest
such as peptidic antibiotics, vitamin H, antitumor
agents and opioid receptor agonists1 and also functions
as a chelating ligand for metal catalysts in asymmetric
synthesis.2 The simple heterocycle, 1,3-dihydro-2-imida-
zolone,3 which is susceptible to various modes of addi-
tion reactions, represents a potential building block for
the synthesis of 1,2-diamines,4 as outlined in Scheme 1.
heated with RuCl2(PPh3)3 as the catalyst in benzene,
resulting in completely diastereocontrolled cyclization
to the 12-membered macrolides (2) with or without the
use of Lewis acid additives, such as rare metal triflates
or zinc chloride.7 As seen in Table 1, the addition of
catalytic amounts of La(OTf)3 and ZnCl2 as the addi-
tives was found to dramatically accelerate the rate of
intramolecular cyclization to near completion within 1
h, while the reaction was much more sluggish in the
absence of these additives. The use of La(OTf)3 in less
than equimolar amounts of the RuCl2(PPh3)3 catalyst
was found to be preferable.8
In this paper, we describe an alternative stereocon-
trolled approach to the preparation of chiral 1,2-
diamines with contiguous multi stereocenters, which
involves an intramolecular Ru(II)-catalyzed addition of
polyhaloacyl groups to the 2-imidazolone moiety as the
key step.
The cyclization product (2), which was obtained
diastereoselectively (99% de), was treated with boiling
methanol followed by N-tosylation to give the N-tosyl-
4-methoxy-cycloadduct (4) (Scheme 2). The stereostruc-
ture of 3 was unequivocally confirmed by X-ray crystal
analysis.9
Thus, the 1-apocamphanecarbonyl-2-imidazolones (1),5
containing
a trichloroacetyl pendant group, were
The apocamphanecarbonyl auxiliary was reductively
removed by treatment with LiBH4–MeOH (1:2)10 to
give the 4-methoxy-2-imidazolidinone (5), in which the
methoxy group could be substituted for a variety of
alkyl, alkenyl and aryl groups with full retention of
configuration, as has been previously pointed out.11
Thus, compound (5) would be expected to serve as a
versatile chiral synthon for the preparation of a wide
variety of 2,3-diamines. This versatility was demon-
strated by a facile conversion to the amino analog of
R1
R2
*
R1
R2
X
*
X
*
*
*
*
HN NH
O
HN NH
HN NH
H2N NH2
O
O
Scheme 1.
(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic
acid
* Corresponding author. Tel.: +81-96-371-4680; fax: +81-96-362-7692;
e-mail: tkuni@gpo.kumamoto-u.ac.jp
(statine), a key structural component of amastatine.12
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01242-4

6320
T. Katahira et al. / Tetrahedron Letters 42 (2001) 6319–6322
Table 1. Diastereoselective Ru(II)-catalyzed intramolecular additions of the trichloroacetyl pendant groupa
O
O
CCl3
NR
O
Cl O
O
Cl
Cl
O
Ru(II)
N
N
R
O
N
O
CCl3
N
N
O
O
R
O
O
O
O
O
2
1
Entry
R
RuCl2(PPh3)3 (equiv.)
Additive (equiv.)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
Ac
Ac
Ac
Ac
Ac
Ac
0.1
0.1
0.05
0.1
0.1
0.1
0.1
–
93
1
7
1
1
48
76
72
57
82
85
92
La(OTf)3 (0.05)
La(OTf)3 (0.025)
La(OTf)3 (0.1)
ZnCl2 (0.05)
ZnCl2 (0.1)
1
1
PhCO
La(OTf)3 (0.05)
a The reaction was performed in refluxing benzene under an argon atmosphere.
b Isolated yield.
O
N
O
N
Cl
O
OMe
O
X
Cl
Cl
Cl
Cl
Cl
O
HO
O
OMe
c
d
b
90%
77%
N
N
78%
N
NH
Tos
R
Tos
O
O
O
O
O
2: R=Ac, Bz; X=Cl
3: R=H; X=OMe
4
5
a
97%
Cl
Cl
Cl
Cl
TBDMSO
MeOOC
Tos
f
e
MeOOC
Tos
N
NH
N
NH
62%
79%
Tos
NH HN
Boc
O
O
6
7
8
Scheme 2. (a) MeOH; reflux, 1 h; (b) Tos-Cl, Et3N, DMAP/CH2Cl2; rt; (c) (1) LiBH4 (6 equiv.), MeOH (12 equiv.)/THF; rt; (d)
(1) imidazol, TBDMS-Cl/DMF; rt, (2) iso-BuCuCNMgBr, LiCl, BF3·OEt2; −78°C, 4 h; (e) (1) TBAF/CH2Cl2; rt, (2) PCC,
NaOAc/CH2Cl2; rt, (3) CH2N2; (f) (1) Bu3SnH, AIBN/benzene; reflux, 1 h, (2) Ba(OH)·8H2O/EtOH–H2O; reflux, 24 h, (3)
(Boc)2O, Et3N/CH2Cl2; rt, (4) CH2N2.
Thus, the protection of hydroxy group as the tert-
butyldimetylsilyl ether followed by treatment with
isobutylcuprates in the presence of BF3·OEt2 gave the
trans-4-isobutyl derivative (6) with complete retention of
configuration. The removal of the silyl group followed
by oxidation with pyridinium chlorochromate (PCC) and
subsequent esterification gave 7 in moderate yield. Reduc-
tive dechlorination with tributyltin hydride followed by
ring-opening smoothly gave the reasonable yield of the
optically pure 3,4-diamino carboxylic acid derivative
(8),13 an amino analog of statine, in which each of the
amino groups was derivatized by a different protecting
group.
This methodology was applied to the chiral synthesis of
the diaminocarboxylic acid with three contiguous stereo-
genic centers, which is the amino analog of
(2S,3R,4R,6E)-3-hydroxy-4-methyl-2-(methylamino)-6-
octenoic acid (Me–Bmt), an unusual and key amino acid
component of cyclosporin.14 When compound 9 was
subjected to the intramolecular Ru(II)-catalyzed reaction,
the addition of the 2,2-dichloro-(4E)-hexenoyl pendant
group to the 2-imidazolone moiety proceeded much more
sluggishly than that for the trichloroacetyl function
described above and the effect of additives, La(OTf)3 and
ZnCl2, on accelerating the cyclization was quite limited
and not as effective, as seen in Table 2. The cyclization

T. Katahira et al. / Tetrahedron Letters 42 (2001) 6319–6322
6321
Table 2. Ru(II)-catalyzed intramolecular additions of the 2,2-dichloro-(4E)-hexenoyl pendant groupa
O
O
Cl O
N
N
Cl
Cl Cl
O
Ac
O
N
N
O
O
O
Ac
O
O
9
1
Entry
RuCl2(PPh3)3 (equiv.)
La(OTf)3 (equiv.)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
0.1
0.3
0.3
0.3
0.3
0.05
0.05
0.05
–
Benzene
Benzene
Toluene
Toluene
Toluene
48
188
24
24
48
16 (61)
55 (0)
34 (36)
29 (44)
64 (0)
0.05
a The reaction was carried out in refluxing benzene or toluene under an argon atmosphere.
b Recovery yield in parentheses.
proceeded with excellent diastereoselectivity in excess of
99% de, although a higher temperature and prolonged
reaction time were required to give moderate yields.
followed by attack of the bulky reductant to the less
hindered side of the radicals generated in situ. Reductive
removal of the chiral auxiliary with LiBH4–MeOH (1:2)8
gave the 2-imidazolidinone derivative (13), of which the
hydroxymethyl group was converted to a methyl group
by conventional procedures. N-Methylation of 14, fol-
lowed by 4-cyanation gave a mixture of trans and
cis-cyanides, which, after treatment of the isomeric
mixture with K2CO3 in MeOH, gave the trans-methyl
ester (15) in good yield. Hydrolytic ring-opening with
Ba(OH)2 furnished the 2,3-diamino carboxylic acid with
completely controlled (2R,3R,4R)-stereocenters (16),16
the amino analog of MeBmt.
Methanolysis of the cycloadduct (10), followed by N-
tosylation and diastereoselective dechlorination with
(Me3Si)3SiH in the presence of an initiator, Et3B,
resulted in the smooth formation of the macrolide (12)
in excess of 99% de15 (Scheme 3).
The excellent chiral functionalization observed can be
rationalized by assuming a stereocontrolled intramolec-
ular radical-based addition to the 2-imidazolone moiety,
O
O
O
Hb
Hb
O
Cl O
O
OMe
O
O
O
a
b
Ha
OMe
Cl
Cl
H
71%
92%
N
N
N
N
O
N
N
Ac
Tos
Tos
O
O
O
O
O
10
11
12
HO
OMe
NH
14
OMe
NH
c
d
e
H
H
N
83%
86%
N
63%
Tos
Tos
O
O
13
COOMe
COOMe
NH HN
f
H
H
N
N
71%
Me
Tos
Tos
Me
O
15
16
Scheme 3. (a) (1) MeOH, (2) Tos-Cl, n-BuLi/THF; (b) Et3B, (TMS)3SiH/toluene; −78°C; (c) LiBH4 (6 equiv.), MeOH (12
equiv.)/THF; (d) (1) MsCl, Et3N/CH2Cl2, (2) NaI/DME; reflux, (3) Bu3SnH, Et3B/THF; −78°C; (e) (1) MeI, NaH/THF; rt, (2)
TMSCN, BF3·OEt2/CH2Cl2; 0°C, (3) K2CO3/MeOH; rt, (4) 2N HCl; rt; (f) (1) Ba(OH)2·8H2O/EtOH–H2O, reflux, 24 h, (2)
CH2N2.

6322
T. Katahira et al. / Tetrahedron Letters 42 (2001) 6319–6322
In conclusion, a highly enantioselective synthetic route
to 1,2-diamines with two and three contiguous stereo-
genic centers such as the amino-analogs of statine and
MeBmt, has been developed via the perfect chiral func-
tionalization of a simple 1,3-dihydro-2-imidazolone
skeleton with the aid of intramolecular Ru(II)-catalyzed
radical cyclization.
9. Crystal date for 3 (mp 227°C): orthorhombic, P212121,
,
,
,
a=15.314(2) A, b=20.569(1) A, c=12.623(1) A, V=
3
,
3976.1(6) A , Z=4. The structure was refined to the
R-value of 0.181%. We are much indebted to the
Fukuoka Research Laboratories, Welfide Corporation
for the X-ray crystallographic analysis.
10. (a) Matsunaga, H.; Kimura, K.; Ishizuka, T.; Kunieda,
T. Tetrahedron Lett. 1991, 32, 7751–7754; (b) Matsunaga,
H.; Ishizuka, T.; Marubayashi, N.; Kunieda, T. Chem.
Pham. Bull. 1992, 40, 1077–1079.
References
11. Ishizuka, T.; Ishibuchi, S.; Kunieda, T. Tetrahedron 1993,
49, 1841–1852.
12. (a) Umezawa, H.; Aoyagi, T.; Morishima, H.; Matsuzaki,
M.; Hamada, M.; Takeuchi, T. J. Antibiot. 1970, 23,
259–262; (b) Workman, R. J.; Burkitt, D. S. Arch.
Biochem. Biophys. 1977, 194, 157–165.
13. Compound 8: mp 44–45°C. [h]D −45.5° (c 1.00, CHCl3).
1H NMR (500 MHz, CDCl3): l 0.65 (d, 3H, J=6.1 Hz),
0.68 (d, 3H, J=6.1 Hz), 0.81 (m, 1H), 1.41 (s, 9H), (m,
2H), 1.32–1.44 (m, 2H), 1.70 (s, 3H), 2.49 (m, 1H), 2.71
(m, 1H), 3.47 (m, 1H), 3.69 (s, 3H), 4.06 (m, 1H), 4.85 (br
s, 1H), 4.91 (br s, 1H), 7.30 (d, 2H, J=7.9 Hz), 7.73 (d,
2H, J=7.9 Hz).
14. (a) Dreyfuss, M.; Harri, E.; Hofmann, H.; Kobel, H.;
Pache, W.; Tscherter, H. Eur. J. Appl. Microbiol. 1976, 3,
125–132; (b) Wengar, R. M. In Cyclosporin A; White, D.
J. G., Ed.; Elsevier, Biomedical: Amsterdam, 1982; pp.
19–34.
1. For a review, see: Denis, L.; Thierry Le, G.; Charles, M.
Angew. Chem., Int. Ed. 1998, 37, 2580–2627.
2. 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.
3. Wang, P. C. Heterocycles 1985, 23, 3041–3042.
4. Seo, R.; Ishizuka, T.; Abdel-Aziz, A. A.-M.; Kunieda, T.
Tetrahedron Lett. 2001, 42, 6353–6355.
5. Compounds 1 and 9 were obtained in 70–80% overall
yields by condensation of N-monoacetyl-2-imidazolone
with the corresponding 2-(2-acyloxyethoxy)-1-apocam-
phanecarboxylic acid.
6. Matsumoto, H.; Nikaido, T.; Nagai, Y. J. Org. Chem.
1976, 41, 396–398; (cf.) Yamamoto, T.; Ishibuchi, S.;
Ishizuka, T.; Haratake, M.; Kunieda, T. J. Org. Chem.
1993, 58, 1997–1998.
7. Exclusive cyclization to the 12-membered macrolide(2)
may be rationalized by assuming that the pendant chain
length would be adjusted to form the less strained ring-
structure based on an intramolecular steric and electro-
static interaction, although the details are not clear.
8. It seems likely that coordination of the Lewis acids to
carbonyl groups would be responsible for the enormous
acceleration observed, but we have no direct evidence for
this at present.
15. The configurational assignment was made on the basis of
a positive NOE effect between Ha and Hb. Use of
Bu3SnH in the place of (Me3Si)3SiH resulted in lower
selectivity of 80% de.
16. Compound 16: [h]D +30.4° (c 1.00, CHCl3). 1H NMR
(500 MHz, CDCl3): l 0.92 (d, 3H, J=6.7 Hz), 1.54 (d,
3H, J=6.1 Hz), 2.01 (m, 2H), 2.11 (m, 1H), 2.51 (s, 3H),
2.97 (s, 3H), 3.78 (m, 1H), 3.85 (s, 3H), 4.22 (m, 1H), 4.80
(br s, 1H), 4.95 (br s, 1H), 5.41 (m, 2H), 7.29 (d, 2H,
J=7.9 Hz), 7.75 (d, 2H, J=7.9 Hz).
.