Asymmetric synthesis of β-amino acids by addition of chiral enolates to N-Acyloxyiminium ions and application for synthesis of optically active 5-substituted 8-methylindolizidines

Article abstract of DOI:10.1021/ol9905755

(Equation Presented) N-Acyloxyiminium species generated from nitrones with acyl halides are highly reactive and can undergo reaction with soft nucleophiles such as enolates. Optically active β-amino acid derivatives can be prepared using chiral enolates bearing chiral auxiliary. The usefulness of the present method is demonstrated by the enantioselective synthesis of (5R,8R,8aS)-5-cyano-8-methylindolizidine ((-)-7), which is a common key intermediate for 5-substituted 8-methylindolizidines.

Full text of DOI:10.1021/ol9905755

ORGANIC
LETTERS
1999
Vol. 1, No. 1
107-110
Asymmetric Synthesis of â-Amino Acids
by Addition of Chiral Enolates to
N-Acyloxyiminium Ions and Application
for Synthesis of Optically Active
5-Substituted 8-Methylindolizidines
Toru Kawakami,† Hiroaki Ohtake,‡ Hiroaki Arakawa, Takahiro Okachi,
Yasushi Imada, and Shun-Ichi Murahashi*
Department of Chemistry, Graduate School of Engineering Science, Osaka UniVersity,
Machikaneyama 1-3, Toyonaka, Osaka 560-8531, Japan
mura@chem.es.osaka-u.ac.jp
Received April 10, 1999
ABSTRACT
N-Acyloxyiminium species generated from nitrones with acyl halides are highly reactive and can undergo reaction with soft nucleophiles such
as enolates. Optically active â-amino acid derivatives can be prepared using chiral enolates bearing chiral auxiliary. The usefulness of the
present method is demonstrated by the enantioselective synthesis of (5R,8R,8aS)-5-cyano-8-methylindolizidine ((−)-7), which is a common key
intermediate for 5-substituted 8-methylindolizidines.
Nitrones are highly valuable intermediates for synthesis of
various nitrogen-containing biologically active compounds.1
Various hard carbon nucleophiles can be introduced at the
position R to the nitrogen of nitrones to give R-substituted
hydroxylamines;2,3 however, soft nucleophiles such as eno-
lates cannot be introduced because of low reactivity of
nitrones toward soft nucleophiles. To raise the reactivity, we
examined the generation of N-acyloxyiminium species 2
which are known to be formed by the reaction of nitrones 1
with acylating reagents and undergo rearrangement to give
† Present address: Institute for Protein Research, Osaka University,
Yamadaoka 3-2, Suita, Osaka 565-0871, Japan.
‡ On leave from Basic Research Laboratory, Fujisawa Pharmaceutical
Co., Ltd., Kashima, Osaka 532-0031, Japan.
(1) Recent reports for asymmetric synthesis of nitrogen-containing
biologically active compounds utilizing diastereoselective addition of
nucleophiles to chiral nitrones are given in the following. (a) (+)-Zileuton:
Basha, A.; Henry, R.; McLaughlin, M. A.; Ratajczyk, J. D.; Wittenberger,
S. J. J. Org. Chem. 1994, 59, 6103-6106. (b) Amino sugars: Dondoni,
A.; Franco, S.; Junquera, F.; Mercha´n, F. L.; Merino, P.; Tejero, T.;
Bertolasi, V. Chem. Eur. J. 1995, 1, 505-520. (c) (+)-Lentiginosine:
Giovannini, R.; Marcantoni, E.; Petrini, M. J. Org. Chem. 1995, 60, 5706-
5707. (d) (+)-Polyoxin J: Dondoni, A.; Franco, S.; Junquera, F.; Mercha´n,
F. L.; Merino, P.; Tejero, T. J. Org. Chem. 1997, 62, 5497-5507.
(2) (a) Breuer, E. In The Chemistry of Amino, Nitroso and Nitro
Compounds and Their DeriVatiVes, Part 1; Patai, S., Ed.; Wiley: New York,
1982; pp 459-564. (b) Torsell, K. B. G. Nitrile Oxides, Nitrones, and
Nitronates in Organic Synthesis; VCH: Weinheim, 1988.
(3) (a) Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe, S.
J. Org. Chem. 1990, 55, 1736-1744. (b) Murahashi, S.-I.; Shiota, T.; Imada,
Y. Org. Synth. 1992, 70, 265-271. (c) Murahashi, S.-I.; Shiota, T.
Tetrahedron Lett. 1987, 28, 2383-2386. (d) Murahashi, S.-I.; Imada, Y.;
Ohtake, H. J. Org. Chem. 1994, 59, 6170-6172.
10.1021/ol9905755 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/24/1999

amides 34 or R-acyloxyimines.5 The active intermediates 2
thus formed have never been used as the precursors for
synthesis of R-substituted nitrogen compounds. Therefore,
we examine the possibility of trapping the highly reactive
N-acyloxyiminium species 2 with soft nucleophiles before
the rearrangement. Actually we succeeded in trapping 2 with
enolates 4 to give R-substituted hydroxylamine derivatives
5. Since nitrones 1 can be prepared conveniently by catalytic
oxidation of secondary amines with H2O2,3 the present
reaction provides a highly useful method for the synthesis
of R-substituted amine derivatives 6 from secondary amines
(Scheme 1).
at room temperature. However, treatment of nitrone 9 with
benzoyl chloride in CH2Cl2 at -78 °C to give N-benzoyl-
oxyiminium ion 10 and subsequent addition of the titanium
enolate 11 and warming up to room temperature gave 3-(N-
benzoyloxybenzylamino)-2-methyl-3-phenylpropiophenone
(12) (79%, (2R*,3R*)-12/(2R*,3S*)-12 ) 64:36) (Scheme
3). Apparently, the reactivity of the nitrone improved
significantly by converting it to the corresponding N-
acyloxyiminium ion.
Scheme 3
Scheme 1
This method can be applied to the diastereoselective
addition of chiral enolates to nitrones. Thus, the reaction of
N-acyloxyiminium ion 10 with chiral titanium enolate 13a,
prepared upon treatment of (4R,5S)-4-methyl-5-phenyl-3-
propanoyloxazolidinone11 with (i-PrO)TiCl3 and i-Pr2NEt,10
gave R-methyl-â-phenylalanine derivative 14 in 65% isolated
yield (Scheme 4). Only two diastereomers (2′S,3′S)-14 and
Scheme 4
We wish to report a highly convenient method for
synthesis of optically active â-amino acids,6 which are of
interest in view of pharmacological activity7 and useful
precursors for synthesis of nitrogen-containing biologically
active compounds such as â-lactam antibiotics,8 by addition
of chiral enolates to N-acyloxyiminium ions thus formed.
Further, we wish to show the usefulness of the present
method by demonstrating enantioselective synthesis of
(5R,8R,8aS)-5-cyano-8-methylindolizidine (7),9 which is a
common key intermediate for the synthesis of indolizidine
alkaloids such as 205A (8a) and 235B (8b), from pyrrolidine
(Scheme 2).
(2′S,3′R)-14 were obtained in a ratio of 85:15 among the
possible four stereoisomers. A major diastereomer (2′S,3′S)-
Scheme 2
(4) Heine, H. W.; Zibuck. R.; VandenHeuvel, W. J. A. J. Am. Chem.
Soc. 1982, 104, 3691-3694 and references therein.
(5) Coates, R. M.; Cummins, C. H. J. Org. Chem. 1986, 51, 1383-
1389.
(6) For a review, see: EnantioselectiVe Synthesis of â-Amino Acids;
Juaristi, E., Ed.; Wiley-VCH: New York, 1996.
(7) For reviews, see: (a) Drey, C. N. C. In Chemistry and Biochemistry
of the Amino Acids; Barrett, G. C., Ed.; Chapman and Hall: London, 1985;
pp 25-54. (b) Griffith, O. W. Annu. ReV. Biochem. 1986, 55, 855-878.
(8) For a review, see: Berks, A. H. Tetrahedron 1996, 52, 331-375.
(9) Polniaszek, R. P.; Belmont, S. E. J. Org. Chem. 1991, 56, 4868-
4874.
The reaction of (Z)-N-benzylidenebenzylamine N-oxide
(9)3b with the titanium enolate 11, generated from propiophe-
none, TiCl4, and i-Pr2NEt in CH2Cl2,10 did not occur even
(10) Evans, D. A.; Urp´ı, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T.
J. Am. Chem. Soc. 1990, 112, 8215-8216.
108
Org. Lett., Vol. 1, No. 1, 1999

14 ([R]24.5 +73.4° (c 1.02, CHCl3)) was isolated in 50%
yield by column chromatography on silica gel. The com-
pound (2′S,3′S)-14 was converted to (2S,3S)-3-(N-benzyl-
D
Scheme 5a
oxycarbonylamino)-2-methyl-3-phenylpropanonic
acid
((-)-15) (mp 169.0-171.0 °C, [R]31 -36.7° (c 1.10,
D
MeOH)) along with the recovered chiral auxiliary upon
hydrolysis, catalytic hydrogenation, and N-protection.
The stereochemistry obtained can be rationalized by
assuming the chelation model shown schematically in Figure
1. The stereochemistry at the C-2′ position of 14 arises from
a diastereofacial selection of chelated (Z)-enolate 13a induced
by its bulky substituents. Thus, the N-benzoyloxyiminium
ion 10 approaches from the opposite side of the methyl and
phenyl groups (re face) of 13a to give 14 with 2′S-
configuration. The stereochemistry at the C-3′ position of
14 reflects the enantiofacial selection of (Z)-N-benzoyloxy-
iminium ion 10. Coordination of the carbonyl group of 10
to the titanium of 13a as the sixth coordinating ligand would
give the most favorable transition state with si face selection
as shown in Figure 1, which has the lowest steric repulsion,
affording the major isomer (2′S,3′S)-14.
a Reagents: (a) PhCH(OAc)COCl; (b) 13b; (c) Zn, HCl; (d)
CbzCl, K2CO3; (e) NaBH4; (f) PPh3, CBr4; (g) NaCH(CO2Et)2; (h)
NaCl, DMSO; (i) DIBALH; (j) MeOH, TsOH; (k) H2, Pd/C; (l)
KCN, HCl.
acetylmandelyl chloride. Further, to avoid the decomposition
of the less stable N-acyloxyiminium ion 17, we used weaker
Lewis acidic titanium enolate 13b, prepared by the reaction
of (4R,5S)-4-methyl-5-phenyl-3-propanoyloxazolidinone with
TiCl4 and i-Pr2NEt,10 and subsequent treatment with PhCO2H
and i-Pr2NEt. Addition of the titanium enolate 13b to the
N-acyloxyiminium ion 17 at -78 °C gave the adduct 18 in
84% yield in extremely high diastereoselectivity ((2′S,2′′S)-
18/(2′S,2′′R)-18 ) 98:2). Reductive cleavage of the NsO
bond of 18 upon treatment with Zn/HCl followed by
N-protection with benzyloxycarbonyl chloride (CbzCl) gave
N-protected â-amino acid derivative. Further, reduction with
NaBH4 and column chromatography on silica gel gave
(2S,2′S)-γ-amino alcohol 19 ([R]23D -37.3° (c 1.43, MeOH))
in 77% yield as a single diastereomer along with the
recovered chiral auxiliary. The carbon chain elongation was
accomplished by bromination of 19, treatment with sodi-
omalonate, and dealkoxycarbonylation, giving amino ester
(4R,2′S)-20 ([R]25D -26.9° (c 1.05, CHCl3)) in 65% isolated
yield. Reduction of 20 with diisobutylaluminum hydride
(DIBALH), p-toluenesulfonic acid-catalyzed acetalization,
and subsequent removal of N-protection afforded the amino
Figure 1. A proposed chelation model for the reaction of
N-benzyloxyiminium ion 10 with titanium enolate 13a.
The stereoselective synthesis of N-hydroxy-â-amino acids
can be applied to the synthesis of optically active R-substi-
tuted pyrrolidines, which are hardly accessible. Thus, this
method was used for the enantioselective synthesis of
(5R,8R,8aS)-5-cyano-8-methylindolizidine ((-)-7),9 which is
a common key intermediate of a series of 5-substituted
8-methylindolizidines such as (-)-205A (8a) and (-)-235B
(8b). These are the skin alkaloids of neotropical arrow-poison
frogs and are noncompetitive inhibitors of the acetylcholine
receptor complexes.12
Our strategy for the synthesis of (-)-7 is illustrated in
Scheme 5. The stereocontrol at the R-position of pyrrolidines
is extremely difficult because of its five-membered planar
structure. We used the bulky N-(acetylmandelyloxy)iminium
ion 17 derived from 1-pyrroline N-oxide (16)3c and (()-
acetal (4R,2′S)-21 ([R]23D +7.8° (c 1.12, CH2Cl2), lit.9 [R]23
D
+7.4° (c 1.1, CH2Cl2)) (55%). Treatment of amino acetal
21 with a solution of KCN and then a solution of HCl gave
(-)-7 (98%).9,13 The transformation of (-)-7 into (5R,8R,8aS)-
5-substituted 8-methylindolizidines 8a and 8b has been
performed readily by the literature procedures.9
(11) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127-2129.
(12) Examples for the asymmetric synthesis of 5-substituted 8-meth-
ylindolizidines: (a) Holmes, A. B.; Smith, A. L.; Williams, S. F.; Hughes,
L. R.; Lidert, Z.; Swithendank, C. J. Org. Chem. 1991, 56, 1393-1405.
(b) Gnecco, D.; Marazano, C.; Das, B. C. J. Chem. Soc., Chem. Commun.
1991, 625-626. (c) Shishido, Y.; Kibayashi, C. J. Org. Chem. 1992, 57,
2876-2883. (d) Momose, T.; Toyooka, N. J. Org. Chem. 1994, 59, 943-
945. (e) Comins, D. L.; LaMunyon, D. H.; Chen X. J. Org. Chem. 1997,
62, 8182-8187. (f) Bardou, A.; Ce´le´rier, J.-P.; Lhommet, G. Tetrahedron
Lett. 1998, 39, 5189-5192.
(13) The cyclization was carried out according to the reported procedure9
to give R-amino nitrile 7, which contains the epimer at C-5 (7% by 1H
NMR).
Org. Lett., Vol. 1, No. 1, 1999
109

Further investigations to apply to the present method for
synthesis of biologically active nitrogen-containing com-
pounds are now in progress.
Research, the Ministry of Education, Science, Sports and
Culture of Japan.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 7, 12, 14, 15,
and 18-21. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the
Research for the Future program, the Japan Society for the
Promotion of Science, and a Grant-in-Aid for Scientific
OL9905755
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