Efficient syntheses and ring-opening reactions of trans- and cis-Oxazoline-5-carboxylates

Article abstract of DOI:10.1021/ol005681h

cis- and trans-Oxazoline-5-carboxylates were synthesized effeciently from isopropyl trans-cinnamate utilizing the sharpless AA reaction. trans-Oxazoline was much more reactive than the cis-isomer toward ring opening reactions. From ab initio molecular calculation, the cis-isomer was predicted to be less reactive than the trans-isomer by 2.7 kcal/mol. Both syn and anti acetylthio ester and anti diamino ester were synthesized from these cis- and trans- oxazoline-5-carboxylates.

Full text of DOI:10.1021/ol005681h

ORGANIC
LETTERS
2000
Vol. 2, No. 9
1243-1246
Efficient Syntheses and Ring-Opening
Reactions of trans- and
cis-Oxazoline-5-carboxylates
,‡
,†
Sang-Hyeup Lee,† Juyoung Yoon,* Kensuke Nakamura,§ and Yoon-Sik Lee*
School of Chemical Engineering, Seoul National UniVersity, Seoul 151-742, Korea,
Department of New Materials Chemistry, Silla UniVersity, Pusan 617-736, Korea, and
Institute of Medicinal Molecular Design, Bunkyo-ku, Tokyo, 113-0033 Japan
yslee@snu.ac.kr
Received February 17, 2000
ABSTRACT
cis- and trans-Oxazoline-5-carboxylates were synthesized efficiently from isopropyl trans-cinnamate utilizing the Sharpless AA reaction. trans-
Oxazoline was much more reactive than the cis-isomer toward ring opening reactions. From ab initio molecular calculations, the cis-isomer
was predicted to be less reactive than the trans-isomer by 2.7 kcal/mol. Both syn and anti acetylthio esters and anti diamino esters were
synthesized from these cis- and trans-oxazoline-5-carboxylates.
Oxazolines are present in many biologically active natural
products,1 and chiral oxazolines are also widely applied as
powerful tools in asymmetric synthesis.2 Among them, the
enantioselective synthesis of oxazoline-4-carboxylates and
their ring-opening reactions are relatively well studied.3
Noteworthy was a paper reported by Laaziri4 and co-workers,
in which serine or threonine was exploited as a starting
material for the synthesis of oxazoline-4-carboxylate. The
ring opening of these oxazolines with a chloroformate or a
trimethylsilyl halide was used to prepare N,(N)-protected
â-halogeno R-amino esters. As Laaziri mentioned in his
paper, oxazoline-4-carboxylate can be considered as the
synthetic equivalent of a â-cation (Figure 1). Aziridine-2-
carboxylate is also known to be the synthetic equivalent of
either a â- or R-cation when R1 is an aliphatic substituent.
† Seoul National University.
‡ Silla University.
§ Institute of Medicinal Molecular Design.
(1) For recent leading references, see: (a) Davidson, B. S. Chem. ReV.
1993, 93, 1771. (b) Michael, J. P.; Pattenden, G. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1 and refs therein.
(2) (a) Frump, J. A. Chem. ReV. 1971, 71, 483. (b) Gant, T. G.; Meyers
A. I. Tetrahedron 1994, 50, 2297 and refs therein.
(3) (a) Wipf, P.; Miller, C. P.; Venkatraman, S.; Fritch, P. C. Tetrahedron
Lett. 1995, 36, 6395. (b) Wipf, P.; Venkatraman, S. Synlett 1997, 1 and
refs therein. (c) Suga, H.; Ikai, K.; Ibata, T. Tetrahedron Lett. 1998, 39,
869.
Figure 1. Oxazoline-4-carboxylate and aziridine-2-carboxylate as
the synthetic equivalent of a â-cation; oxazoline-5-carboxylate as
the synthetic equivalent of an R-cation.
(4) Laaziri, A.; Uziel, J.; Juge´, S. Tetrahedron: Asymmetry 1998, 9, 437.
10.1021/ol005681h CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/14/2000

In particular, when R1 is an aromatic substituent, a ring-
opening reaction occurs, mainly at the 3-position (benzylic
position) of the aziridine ring.5 On the other hand, oxazoline-
5-carboxylate can be a useful intermediate as the synthetic
equivalent of an R-cation for the preparation of R-substituted
â-amino esters. Unlike oxazoline-4-carboxylate, we found
that oxazoline-5-carboxylates were utilized by many groups,6
but mainly as an intermediate for N-benzoyl-(2R,3S)-3-
phenylisoserine, a taxol C-13 side chain. Herein, we report
an efficient synthesis of both cis- and trans-oxazoline-5-
carboxylates as well as their ring-opening reactions.
sulfonate 3 with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)
in refluxing chloroform for 1 h gave trans-oxazoline 5 with
net retention of configuration in 76% yield with a trace of
cis-oxazoline 4, which can be removed by column chroma-
tography. Epimerizations of cis-oxazoline-4-carboxylate or
cis-imidazoline to its thermodynamically more stable trans-
isomer using triethylamine were reported very recently.8,3c
However, in our case, we did not observe any epimerization
from cis-oxazoline to trans-oxazoline in refluxing chloroform
in the presence of DBU. We believe epimerization of 3 to
anti methanesulfonate occurred first, then trans-oxazoline
was obtained from this intermediate. The NMR spectra of
the cis-isomer 4 and the trans-isomer 5 showed a distinct
difference in the coupling constants. The coupling constant
between H-4 and H-5 for the cis-isomer 4 was 10.8 Hz and
that for the trans-isomer 5 was 6.8 Hz.
Commercially available isopropyl trans-cinnamate (1) was
the starting point of our synthesis (Scheme 1). Amino alcohol
Scheme 1
Ring-opening reactions of trans- and cis-oxazoline-5-
carboxylates are summarized in Table 1. When trimethylsilyl
Table 1. Ring-Opening Reaction of trans- and
cis-Oxazoline-5-carboxylates (5, 4)
2 was obtained in 81% yield following the reported Sharpless
AA reaction.7 Amino alcohol 2 was then converted to its
methanesulfonate 3, which was successfully transformed to
cis-oxazoline 4 with a clean inversion of configuration at
the R-center in 62% yield with potassium bicarbonate in
acetone-water. On the other hand, treatment of methane-
azide was used as an azide source for the synthesis of the
R,â-diamino acid derivative, we found that there were huge
differences in reactivity between the trans- and cis-oxazoline
compounds. Treatment of trans-oxazoline 5 with trimethyl-
silyl azide in methanol at 70-80 °C led to the trans-azide 6
in 90% yield. However, even at higher reaction temperature
or in the presence of additional Lewis acid such as boron
trifluoride diethyl etherate (Et2O‚BF3) or trimethylsilyl triflate
(TMSOTf), only unreacted cis-oxazoline 4 was recovered
in an attempt to open this oxazoline ring with trimethylsilyl
(5) (a) Papa, C.; Tomasini, C. Org. Lett. 1999, 1, 2153. (b) Tanner, D.
Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
(6) (a) Gou, D.-M.; Liu, Y.-C.; Chen, C.-S. J. Org. Chem. 1993, 58,
1287. (b) Kingston, D. G. I.; Chaudhary, A. G.; Gunatilaka, A. A. L.;
Middleton, M. L. Tetrahedron Lett. 1994, 35, 4483. (c) Bunnage, M. E.;
Davies, S. G.; Goodwin, C. J. J. Chem. Soc., Perkin Trans. 1 1993, 1375.
(d) Chen, S.-H.; Farina, V.; Vyas, D. M.; Doyle, T. W.; Long, B. H.;
Fairchild, C. J. Org. Chem. 1996, 61, 2065.
(7) Bruncko, M.; Schlingloff, G.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1483.
(8) Hayashi, T.; Kishi, E.; Soloshonok, V. A.; Uozumi, Y. Tetrahedron
Lett. 1996, 37, 4969.
1244
Org. Lett., Vol. 2, No. 9, 2000

azide. To explain the poor reactivity of cis-oxazoline, we
carried out ab initio molecular orbital calculations (Figure
2).9 The cis-oxazoline 4-Me10 was found to be less stable
Scheme 2
Figure 2. Ab initio molecular orbital calculations.
than the trans-oxazoline 5-Me by 1.2 kcal/mol at the RHF/
6-31G* level. This is due to the steric repulsion between
the phenyl and ester groups in close contact. However, the
relative instability of the reactant does not explain the lower
reactivity of the cis-isomer. At the transition state for ring
opening upon azide attack, the cis-isomer is found to be less
stable by 3.9 kcal/mol at the same level of theory. Therefore,
the cis-oxazoline is less reactive than the trans-oxazoline
by 2.7 kcal/mol. The difference in activation energy is worth
more than 100-fold difference in the reaction rate at room
temperature. The reason that the energy difference between
the cis- and trans-isomers is larger in the transition state than
in the ground state can be seen from the structures. At the
transition state, the ester group is in a perpendicular
orientation to the forming and breaking bonds, to maximize
the resonance between the p-orbitals of the carbonyl and the
reaction center carbons. This makes steric repulsion between
the phenyl and ester groups in the cis-orientation more severe.
We observed similar results when thiophenol was used as
a reagent. Phenylthioether 7 was obtained in 96% yield,
whereas cis-oxazoline was unreactive under the same condi-
tions. However, when thiolacetic acid was used, both the
anti and syn acetylthio esters (8, 9) were isolated in 78%
and 53% yields, respectively. This result may be due to the
better reactivity of thiolacetic acid toward the ring opening
reactions than the other reagents. Either amino alcohol 2 or
methanesulfonate 3 can be considered as candidates for the
synthetic equivalent of an R-cation. However, we could not
obtain the desired acetylthio ester from 2 using the Mitsunobu
reaction conditions (DEAD, PPh3, thiolacetic acid). An
attempt to displace the methanesulfonate group in 3 by the
acetylthio group using triethylamine and thiolacetic acid also
failed.
(9) Gaussian 94, Revision B.3, M. J. Frisch, G. W. Trucks, H. B.
Schlegel, P. M. W. Gill, B. G. Johnson, M. A. Robb, J. R. Cheeseman, T.
Keith, G. A. Petersson, J. A. Montgomery, K. Raghavachari, M. A. Al-
Laham, V. G. Zakrzewski, J. V. Ortiz, J. B. Foresman, C. Y. Peng, P. Y.
Ayala, W. Chen, M. W. Wong, J. L. Andres, E. S. Replogle, R. Gomperts,
R. L. Martin, D. J. Fox, J. S. Binkley, D. J. Defrees, J. Baker, J. P. Stewart,
M. Head-Gordon, C. Gonzalez, and J. A. Pople, Gaussian, Inc., Pittsburgh,
PA, 1995.
To show the possible utility of these oxazoline-5-carbox-
ylates, 2′-sulfur analogues and nitrogen analogues of the taxol
C-13 side chain were prepared. To change the N-protecting
group from an acetyl group to a benzoyl group, amino
alcohol 2 was refluxed in 0.5 M methanolic HCl for 10 h
(10) For computational simplification, the isopropyl group of 4 and 5
was replaced with a methyl group to provide 4-Me and 5-Me, respectively.
Org. Lett., Vol. 2, No. 9, 2000
1245

(twice) followed by benzoyl protection using benzoyl
chloride (BzCl) and triethylamine (Scheme 2). In this step,
transesterification of the isopropyl ester to the methyl ester
also occurred. Treatment of 10 with triflic anhydride (Tf2O)
afforded cis-oxazoline 11 in 84% yield.11 When this cis-
oxazoline 11 was reacted with neat thiolacetic acid, syn
acetylthio ester 12 (2R,3S) was obtained in 67% yield after
heating for 12 h at 70 °C and additional heating for 1 day at
80 °C. This reaction needed a much longer reaction time
because cis-oxazoline is much less reactive toward the ring
opening reaction than is trans-oxazoline. On the other hand,
treatment of methanesulfonate 13 with DBU afforded both
trans- and cis-oxazolines (14, 11) in a ratio of 25 to 1. Unlike
2-methyl oxazoline, we failed to isolate 2-phenyl trans-
oxazoline by column chromatography. However, from this
mixture, we could obtain the diastereomerically pure anti
acetylthio ester 15 (2S,3S) in 72% yield under rather mild
conditions (70 °C, 12 h) with thiolacetic acid/tetrahydrofuran
(1:1) after chromatography.
Scheme 3
The selectively protected anti isomer of methyl 2-amino-
3-(benzoylamino)-3-phenylpropionate (17a) and methyl
2-amino-3-(tert-butoxycarbonylamino)-3-phenylpropionate
(17b) were synthesized from azide 6 (Scheme 3). After
sequential hydrolysis, esterification, and appropriate N-
protection, either the benzoyl or the Boc-protected anti azide
methyl ester (16a, 16b) were obtained. Catalytic hydrogena-
tion of the azide group gave the anti diamino esters 17a
(>98% de) and 17b (>97% de) in 69% and 70% yields,
respectively. Less than 2% epimers were detected in both
products by 1H NMR. They were probably produced during
the heating (90 °C) in acidic solution.
ring-opening reactions. In addition, we have shown that
oxazoline-5-carboxylate can be a powerful intermediate as
a synthetic equivalent of an R-cation for the preparation of
R-substituted â-amino esters.
Acknowledgment. We thank Professor Hyunsoo Han,
Kim D. Janda, and Dr. Jae Uk Jeong for their valuable
information and helpful discussions. Financial supports from
Silla University (1998) and the Brain Korea 21 Program are
gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterization data for the compounds de-
scribed in this paper. This material is available free of charge
via the Internet at http://pubs.acs.org.
In conclusion, we have shown an efficient stereoselective
synthesis of cis- and trans-oxazoline-5-carboxylates and their
(11) Cabri, W.; Curini, M.; Marcotullio, M. C.; Rosati, O. Tetrahedron
Lett. 1996, 37, 4785.
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