Enantioselective desymmetrization of meso-cyclic anhydrides catalyzed by hexahydro-1H-pyrrolo[1,2-c]imidazolones

Article abstract of DOI:10.1016/S0040-4039(00)01972-9

Asymmetric methanolysis of meso cyclic carboxylic anhydrides including hexahydrophthalic anhydride proceeded in toluene in the presence of (6R,7aS)-(2-aryl-6-hydroxy)hexahydro-1H-pyrrolo[1,2-c]imidazol-1-one to give the corresponding desymmetrized mono ester acids (e.g. (1S,2R)-2-(methoxycarbonyl)cyclohexane-1-carboxylic acid) with enantiomeric excesses of up to 89%.

Full text of DOI:10.1016/S0040-4039(00)01972-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 411–414
Enantioselective desymmetrization of meso-cyclic anhydrides
catalyzed by hexahydro-1H-pyrrolo[1,2-c]imidazolones
Yasuhiro Uozumi,a,* Kayo Yasoshima,b Takamasa Miyachib and Shin-ichi Nagaib
aInstitute for Molecular Science, Myodaiji, Okazaki 444-8585, Japan
bFaculty of Pharmaceutical Sciences, Nagoya City University, Mizuho, Nagoya 467-8603, Japan
Received 18 September 2000; revised 27 October 2000; accepted 2 November 2000
Abstract—Asymmetric methanolysis of meso cyclic carboxylic anhydrides including hexahydrophthalic anhydride proceeded in
toluene in the presence of (6R,7aS)-(2-aryl-6-hydroxy)hexahydro-1H-pyrrolo[1,2-c]imidazol-1-one to give the corresponding
desymmetrized mono ester acids (e.g. (1S,2R)-2-(methoxycarbonyl)cyclohexane-1-carboxylic acid) with enantiomeric excesses of
up to 89%. © 2001 Elsevier Science Ltd. All rights reserved.
Enantioselective desymmetrization of meso compounds
is a powerful synthetic means of preparing enantiomer-
ically enriched products where plural stereogenic car-
bon centers are generated in one-step.1 Enantioselective
ring opening of meso cyclic anhydrides is one of the
cases.2,3 Although much work has appeared on enan-
tioselective nonenzymatic alcoholysis,3 high enantiose-
lectivity has been achieved only by use of stoichiometric
amounts of unrecyclable chiral agents4 and/or in highly
toxic halogenated solvent systems,5,6 which renders
them impractical. Development of chiral nucleophilic
catalysts for enantioselective acyl transfer has seen very
rapid growth,7 however, surprisingly, little attention has
been paid to the use of catalysts for the enantioselective
alcoholysis of meso cyclic anhydrides. As part of our
effort to develop highly stereoselective and useful asym-
metric processes, the catalytic asymmetric methanolysis
of meso cyclic anhydrides was examined. We report
herein the asymmetric methanolysis of hydrophthalic
anhydride derivatives which is catalyzed by a new N-
chiral bicyclic amine (6R,7aS)-(2-aryl-6-hydroxy)-
hexahydro-1H-pyrrolo[1,2-c]imidazol-1-one (3) in tolu-
ene to give the corresponding optically active mono
ester acids with enantiomeric excesses of up to 89%
(Scheme 1).
Various chiral tertiary amines including quinine,
quinidine, sparteine, and pyrrolo[1,2-c]imidazolones (3)
were examined for the enantioselective methanolysis of
hexahydrophthalic anhydride 1. The optically active
amines
3
having the hexahydro-1H-pyrrolo[1,2-
c]imidazol-1-one framework have been identified as
effective chiral agents from the library of N-chiral
bicyclic tertiary amines.8 The chiral amine library was
designed and prepared with a view to using it for
screening asymmetric catalysts where the target reac-
tion is promoted by Lewis bases or nucleophiles. The
bicyclic amines 3a–e were readily prepared in high
yields starting with anilines, prolines, and aldehydes by
two sets of one-pot reactions shown in Scheme 2.
Reaction of hexahydrophthalic anhydride (1) with
methanol (2 equiv.) was performed at −25°C in toluene
Scheme 1.
Keywords: enantioselective desymmetrization; nucleophilic catalyst; pyrrolo[1,2-c]imidazolone.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01972-9

412
Y. Uozumi et al. / Tetrahedron Letters 42 (2001) 411–414
without further purification. The results are summa-
rized in Table 1. Among the tertiary amines, the (6R,
7aS)-(2-aryl-6-hydroxy)hexahydro-1H-pyrrolo[1,2-c]-
imidazol-1-one (3b or 3e) turned out to be the best
catalyst giving the mono methyl ester (1S,2R)-2 with
high enantioselectivity. Thus, the asymmetric methanoly-
sis catalyzed by 3b afforded 65% ee of the ester acid
(1S,2R)-2 in 40% yield. It was found that Cinchona
alkaloids, quinine and quinidine, catalyzed the
methanolysis with low stereoselectivities to give
(1S,2R)-2 (27% ee) and (1R,2S)-2 (27% ee), respec-
tively, although it has been reported that the stoichio-
metric use of the Cinchona alkaloids in CCl4 promotes
desymmetrization of related meso anhydrides with high
enantioselectivity.5 Sparteine showed little enantioselec-
tivity under the same reaction conditions. It is notewor-
thy that the stereochemical outcome of the
methanolysis is strongly affected by the substituent at
the C6 position of the amine 3. The reaction using the
amine 3a, which lacks the C6 hydroxy group, was much
less enantioselective giving <3% ee of the mono ester 2.
The amine 3c having a sterically bulky silyloxy group at
the C6 position gave (1R,2S)-2,which is the antipode of
that obtained using 3b. The pyrrolo[1,2-c]imidazolone
3d having a C3-phenyl substituent showed little cata-
lytic activity under the same reaction conditions. The
phenyl substituent at the C3 position in 3d is in close
proximity to the reactive lone pair of the bridgehead
nitrogen atom thereby disturbing the nucleophilic at-
tack on the anhydride 1 (Table 1).
Scheme 2.
Table 1. Asymmetric methanolysis of 1 catalyzed by vari-
ous chiral tertiary aminesa
Catalyst
Yield % of 2b
% ee of 2c
Absolute
configurationc
Quinine
Quinidine
Sparteine
3a
3b
3c
49
61
69
26
40
11
B3
33
27
27
B3
B3
65
34
–
65
89
(1S,2R)
(1R,2S)
–
–
(1S,2R)
(1R,2S)
–
(1S,2R)
(1S,2R)
3d
3e
The highest enantioselectivity was observed when 1
equiv. of 1 to 1 equiv. of methanol and 1 equiv. of the
catalyst 3e were used. Thus, the reaction of 1 with
methanol in toluene at −25°C for 20 h in the presence
of 3e (1.0 equiv.) gave 72% of (1S,2R)-2 with 89% ee.
Tetrahydrophthalic anhydride (5) and norbornenedicar-
boxylic anhydride (7) gave 6 and 8 with 85% ee and
82% ee, respectively, under the same reaction condi-
tions (Scheme 3). A practical procedure is given for the
methanolysis of 1 with 1 equiv. of 3e: A toluene solu-
tion of hexahydrophthalic anhydride 1 (0.1 M soln), 1.0
equiv. of methanol, and 1.0 equiv. of 3e was stirred at
−25°C for 7 days. The reaction mixture was extracted
with dil. HCl and sat. NaHCO3, successively to sepa-
rate the remaining 1, 3e, and the ester acid 2. The
catalyst 3e was recovered from the acidic layer quanti-
tatively. The aqueous basic layer was acidified with dil.
3ed
72
a All reactions were carried out in toluene (0.1 M of 1) at −25°C for
20 h. 1/MeOH/cat=1.0/2.0/0.1.
b Without chromatographical purification.
c Determined by HPLC (see text).
d 1/MeOH/cat=1.0/1.0/1.0.
for 20 h in the presence of 10 mol% of the chiral
tertiary amine catalyst. The desired methyl ester 2 was
isolated by acid–base extraction. The resulting crude
ester acid 2 was converted into the anilide 4 which was
taken on to HPLC analysis with a chiral stationary
phase column (Chiralcel OJ, hexane/i-PrOH=4/1)
Scheme 3.

Y. Uozumi et al. / Tetrahedron Letters 42 (2001) 411–414
413
Scheme 4.
HCl and extracted with toluene to give the crude 2. The
crude methyl ester acid 2 was dissolved in ether/hexane
(1:15) and the insoluble materials were filtered off. The
filtrate was concentrated and chromatographed on sil-
ica gel to give 2 in 72% yield. The enantiomeric purity
of 2 was determined by HPLC analysis of the anilide 4
to be 89% ee. The absolute configuration of 2 was
assigned to be (1S,2R) by comparison of the order of
retention time in the HPLC analysis of the anilide 4 to
that of an authentic sample prepared from (1S,2R)-6.5
1984, 779–781. (d) Hiratake, J.; Inagaki, M.; Yamamoto,
Y.; Oda, J. J. Chem. Soc., Perkin Trans. 1 1987, 1053–
1058. (e) Hiratake, J.; Yamamoto, Y.; Oda, J. J. Chem.
Soc., Chem. Commun. 1985, 1717–1719. (f) Theisen, P. D.;
Heathcock, C. H. J. Org. Chem. 1993, 58, 142–146. (g)
Suda, Y.; Yago, S.; Shiro, M.; Taguchi, T. Chem. Lett.
1992, 389–392. (h) Das, J.; Haslanger, M. F.; Gougoutas,
J. Z.; Malley, M. F. Synthesis 1987, 1100–1103. (i) Albers,
T.; Biagini, S. C. G.; Hibbs, D. E.; Hursthouse, M. B.;
Malik, K. M. A.; North, M.; Uriarte, E.; Zagotto, G.
Synthesis 1996, 393–398. (j) Ward, R. S.; Pelter, A.;
Edwards, M. I.; Gilmore, J. Tetrahedron: Asymmetry 1995,
6, 843–844. (k) Shimizu, M.; Matsukawa, K.; Fujisawa, T.
Bull. Chem. Soc. Jpn. 1993, 66, 2128–2130. (l) Seebach,
D.; Jaeschke, G.; Wang, Y. M. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2395–2396. (m) Seebach, D.; Jaeschke, G.;
Gottwald, K.; Matsuda, K.; Formisano, R.; Chaplin, D.
A.; Breuning, M.; Bringmann, G. Tetrahedron 1997, 53,
7539–7556.
The mono ester acid 11, which is a synthetic intermedi-
ate for (−)-PGE1,9 and 12 were readily obtained in their
enantiomerically enriched form via asymmetric
methanolysis of (3-methyl)tetrahydrophthalic anhy-
dride 10. A racemic mixture of 10 (rac-10) was sub-
jected to the methanolysis catalyzed by 3e to give 80%
ee of (1R,2S,3S)-11 in 12% yield and 71% ee of
(1S,2R,3R)-12 in 29% yield. A Curtius rearrangement
of the methyl ester acids 11 and 12 gave the corre-
sponding N-protected b-amino acids (Scheme 4).
4. Recently, a highly enantioselective catalytic ring opening
of norbornenedicarboxylic anhydride using Ti-TADDO-
Late/Al(OiPr) system has been reported: Jaeschke, G.;
Seebach, D. J. Org. Chem. 1998, 63, 1190–1197.
Acknowledgements
5. It has been reported that Cinchona alkaloids promote
methanolysis of meso cyclic anhydrides with high enan-
tioselectivity of up to 98% ee in CCl4: Bolm, C.; Gerlach,
A.; Dinter, C. L. Synlett 1999, 195–196.
6. Risk data of carbon tetrachloride are given on the web
data base of IRIS, see: http://www.epa.gov/ngispgm3/iris/
subst/0020.htm? and references cited therein. Selected risk
data of carbon tetrachloride are as follows: RfDo(mg/kg/
d)=0.0007; CpSo (kg d/mg)=0.13; CpSi(kg d/mg)=
0.0525; Tap Water (mg/l: carcinogenic effects)=0.16;
Ambient Air (mg/m3: carcinogenic effects)=0.12.
This work was supported by a Grant-in-Aid for Scien-
tific Research, the Ministry of Education, Japan. Y.U.
thanks the Kowa Foundation for Life Science and
Technology and the Naito Foundation for partial
financial support of this work.
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