Enantioselective addition of ketene silyl acetals to nitrones catalyzed by chiral titanium complexes. Synthesis of optically active β-amino acids

Article abstract of DOI:10.1021/ja0176649

A chiral titanium complex, Ti(O-i-Pr)₄/BINOL/tert-butylcatechol, catalyzes enantioselective addition reaction of ketene silyl acetals to nitrones to give optically active β-amino acid derivatives which are biologically active compounds and useful synthetic intermediates of natural products and pharmaceuticals such as β-lactam antibiotics. The combined process of catalytic oxidation of secondary amines and enantioselective carbon-carbon bond formation of nitrones thus obtained with ketene silyl acetals provides a useful two-step method for the synthesis of optically active β-amino acid derivatives and related nitrogen compounds. Copyright

Full text of DOI:10.1021/ja0176649

Published on Web 02/27/2002
Enantioselective Addition of Ketene Silyl Acetals to Nitrones Catalyzed by
Chiral Titanium Complexes. Synthesis of Optically Active â-Amino Acids
Shun-Ichi Murahashi,* Yasushi Imada, Toru Kawakami, Kazuhito Harada, Yoshiharu Yonemushi, and
Naomi Tomita
Department of Chemistry, Graduate School of Engineering Science, Osaka UniVersity, 1-3, Machikaneyama,
Toyonaka, Osaka 560-8531, Japan, and Department of Chemistry, Faculty of Engineering,
Okayama UniVersity of Science, 1-1, Ridaicho, Okayama 700-0005, Japan
Received December 2, 2001
The synthesis of enantiomerically pure â-amino acids and their
derivatives has attracted increasing attention in view of their
pharmacological activities,1 structural properties,2 and usefulness
as precursors of biologically active compounds such as â-lactam
antibiotics.3 Various methods for diastereoselective synthesis of
â-amino acids have been reported;4 however, the number of catalytic
) Ph) was obtained with Ti(Oi-Pr)4 catalyst. However, the adduct
and enantioselective methods is small and limited to hydrogenation
of aminoacrylates,5 aminohydroxylation of olefins,6 addition of
aminonucleophiles to acrylates,7 and Mannich-type reaction of
aldimines with silyl enolates.8 We report the first catalytic,
enantioselective synthesis of optically active N-hydroxyl-â-amino
acid derivatives 3, which are related to natural products of biological
significance,9 and â-amino acids 4, from nitrones 1 (eq 1). This is
a rare case of a catalytic, enantioselective carbon-carbon bond
formation reaction.10
7a was obtained in 85% isolated yield, when the reaction was
carried out in the presence of Ti(OPh)4 catalyst. Apparently, the
phenoxy ligand is suitable for the carbon-carbon bond formation
with an increase in the Lewis acidity of titanium. Next, we examined
the enantioselectivity of the reaction of 5a with 6 in the presence
of various titanium(IV)-BINOL catalysts 8 (20 mol %) in toluene
at -78 °C. The representative results are summarized in Table 1.
In the presence of chiral titanium catalyst 8a prepared from Ti(Oi-
Pr)4 and (S)-BINOL (1:1),14 the adduct (R)-7a was obtained in 99%
yield with 18% ee (entry 1). Additional ligands affect the enantio-
selectivity of the reaction dramatically.15 The catalysts Ti-(S)-
BINOL-2ArOH 8b,c and Ti-(S)-BINOL-Ar(OH)2 8d,e were pre-
pared in situ by the reaction of Ti(Oi-Pr)4 with 2 equiv of phenols
or 1 equiv of catechols, respectively, in toluene at room temperature
in the presence of MS 4A, followed by treatment with 1 equiv of
(S)-BINOL. In the presence of the titanium catalyst 8b, the adduct
(R)-7a was obtained in 99% yield with 34% ee (entry 2). With use
of sterically bulky phenols, such as 1-naphthol (55% ee) (entry 3),
2,6-dimethylphenol (50% ee), and 2-phenylphenol (49% ee), (R)-
7a was obtained with higher enantioselectivities. Interestingly, the
adduct (S)-7a with inverse absolute configuration was obtained
when catechols were used as additional ligands. Thus, the reaction
in the presence of the titanium catalyst 8d gave the (S)-â-amino
acid derivative 7a in 73% ee (entry 4). Furthermore, when 4-tert-
butylcatechol was used, the adduct (S)-7a was obtained in 99%
yield with 92% ee (entry 5). The cleavage of the nitrogen-oxygen
bond of the (S)-7a with Zn/H2SO4 and recrystallization of the oxalic
acid salt of the product gave optically pure N-benzyl-â-phenyl-
alanine methyl ester. With use of the (R)-BINOL catalyst, the (R)-
enantiomer was obtained in pure form.
Nitrones 1 have become highly valuable intermediates for the
synthesis of nitrogen-containing biologically active compounds,
because they are prepared readily by catalytic oxidation of
11a-g
secondary amines with H2O2
as well as condensation of
carbonyl compounds with N-hydroxylamines,11h which can be
obtained by hydrolysis of the corresponding nitrones.12 Diastereo-
selective additions of chiral enolates to nitrones have been
performed with excellent selectivity, giving optically active â-amino
acids and their derivatives.12,13 This method is very useful for the
synthesis of biologically active compounds, such as â-lactams and
indolizidine alkaloids.12,13b Catalytic, enantioselective addition of
ketene silyl acetals 2 to nitrones 1 is a very attractive proposition
for the synthesis of â-amino acid derivatives 3, and is comparable,
or in some cases superior, to the asymmetric Mannich-type addition
to imines8 because of the configurational stability of nitrones, ease
of handling, and readiness of preparation.
The enantioselective addition of ketene silyl acetal 6 to nitrones
5a-e catalyzed by chiral titanium complex 8e gave â-amino acid
derivatives 7a-e in high yields as shown in Table 2.
Various catalysts were evaluated for the reaction of N-benzyl-
idenebenzylamine N-oxide (5a, R ) Ph), which was prepared by
the Na2WO4-catalyzed oxidation of dibenzylamine with H2O2,11a
with 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (6) (1.2 equiv)
in CH2Cl2 at -78 °C (eq 2). In the absence of a catalyst the reaction
did not occur, and only a small amount of methyl 3-(N-tert-
butyldimethylsilyloxy-N-benzylamino)-3-phenylpropanoate (7a, R
R-2-Naphthyl and R-p-tolyl substituted nitrones 5b,c underwent
reaction with 6 smoothly to give the desired adducts with 88% ee
each (entries 2 and 3). The â-amino-â-arylpropanoic acid derivatives
7b,c thus obtained can be readily converted into the corresponding
esters of â-amino acids upon treatment with Zn/H2SO4 and
hydrogenation over palladium on charcoal catalyst. The adduct 7e
can be converted to ethyl 3-amino-3-[5-(benzo-1,3-dioxole)]pro-
panoate, which is an important precursor of the aspartic acid
* Address correspondence to this author. E-mail: mura@chem.es.osaka-u.ac.jp.
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2888 VOL. 124, NO. 12, 2002 J. AM. CHEM. SOC.
10.1021/ja0176649 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Asymmetric Reactions of Nitrone 5a with Ketene Silyl
Acetal 6 in the Presence of Ti-(S)-BINOL-2ArOH (or Ar(OH)2) 8 To
Give N-Hydroxyl-â-amino Acid Derivative 7a
catechol ligands remains unclear. Experiments are underway to
examine the mechanism.
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 Research, the Ministry
of Education, Science, Sports and Culture of Japan.
yield of
7a/%
ee of
config.
of 7a
entry
ArOH or Ar(OH)2 of 8
7aa/%
1
2
3
4
5
none
8a
8b
8c
8d
8e
99
99
99
95
99
18
34
55
73
92
(R)
(R)
(R)
(S)
(S)
phenol
1-naphthol
catechol
Supporting Information Available: Experimental procedures and
spectroscopic data for compounds 7 and 10 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
4-tert-butylcatechol
a Determined by HPLC analysis using CHIRALCEL OD-H after
conversion to the corresponding â-amino acid ester with Zn/H2SO4.
References
(1) For review: (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. (c)
Bewley, C. A.; Faulkner, D. J. Angew. Chem., Int. Ed. Engl. 1998, 37,
2162-2178.
Table 2. Asymmetric Reactions of Nitrones 5a-e with Ketene
Silyl Acetal 6 in the Presence of Titanium Catalyst 8e To Give
7a-ea
yield of
ee of
config.
(2) (a) Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015-2022. (b)
Gellman, S. H. Acc. Chem. Res. 1998, 31, 173-180.
entry
R of 5
7/%
7/%
of 7
(3) For review: Berks, A. H. Tetrahedron 1996, 52, 331-375.
(4) For review: EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E.,
Ed.; Wiley-VCH: New York, 1997.
1
2
3
4
5
phenyl
2-naphthyl
p-MeC6H4
3-pyridyl
5a
5b
5c
5d
5e
99
94
66
90
74
92a
88b
88a
80c
80a
(S)
(-)
(-)
(+)
(S)
(5) Lubell, W. D.; Kitamura, M.; Noyori, R. Tetrahedron: Asymmetry 1991,
2, 543-554.
(6) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996,
35, 451-453
3,4-(OCH2O)C6H3
(7) (a) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc.
1998, 120, 6615-6616. (b) Myers, J. K.; Jacobsen, E. N. J. Am. Chem.
Soc. 1999, 121, 8959-8960.
a Determined by HPLC analysis using CHIRALCEL OD-H after
conversion to the corresponding â-amino acid esters with Zn/H2SO4.
b Determined by HPLC analysis using CHIRALPAK AD after conversion
to the corresponding â-amino acid ester with Zn/H2SO4. c Determined by
HPLC analysis using CHIRALCEL OD-H.
(8) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997, 119, 7153-
7154.
(9) Ottenheijm, H. C. J.; Herscheid, J. D. M. Chem. ReV. 1986, 86, 697-
707.
(10) For review: (a) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999; Vols. 1-3.
Enantioselective addition of carbon nucleophiles to nitrones. Et2Zn: (b)
Ukaji, Y.; Kenmoku, Y.; Inomata, K. Tetrahedron: Asymmetry 1996, 7,
53-56. RMgX: (c) Merchan, F. L.; Merino, P.; Rojo, I.; Tejero, T.;
Dondoni, A. Tetrahedron: Asymmetry 1996, 7, 667-670. Zinc acetyl-
ides: (d) Frantz, D. E.; Fassler, R.; Tomooka, C. S.; Carreira, E. M. Acc.
Chem. Res. 2000, 33, 373-381.
mimetic of the RDG (Arg-Gly-Asp) peptide mimetic fibrinogen
receptor antagonist, anti-platelet aggregation agent.16
A variety of cyclic nitrones were found to undergo the chiral
titanium catalyzed reaction with 6. The addition of 6 to 6,7-
dimethoxy-3,4-dihydroisoquinoline N-oxide (9a), derived by the
catalytic oxidation of the corresponding 1,2,3,4-tetrahydroisoquino-
line, in the presence of the titanium catalyst 8e gave 1,2,3,4-
tetrahydro-1-isoquinolineacetic acid derivative 10a in 84% yield
with 83% ee (eq 3).
(11) Oxidative transformation of secondary amines to nitrones. Na2WO4
catalyst: (a) Mitsui, H.; Zenki, S.; Shiota, T.; Murahashi, S.-I. J. Chem.
Soc., Chem. Commun. 1984, 874-875. (b) Murahashi, S.-I.; Mitsui, H.;
Shiota, T.; Tsuda, T.; Watanabe, S. J. Org. Chem. 1990, 55, 1736-1744.
(c) Murahashi, S.-I.; Shiota, T.; Imada, Y. Org. Synth. 1991, 70, 265-
271. SeO2 catalyst: (d) Murahashi, S.-I.; Shiota, T. Tetrahedron Lett. 1987,
28, 2383-2386. Flavin catalyst: (e) Murahashi, S.-I.; Oda, T.; Masui, Y.
J. Am. Chem. Soc. 1989, 111, 5002-5003. MeReO3 catalyst: (f) Murray,
R. W.; Iyanar, K.; Chen, J.; Wearing, J. T. J. Org. Chem. 1996, 61, 8099-
8102. (g) Goti, A.; Nannelli, L. Tetrahedron Lett. 1996, 37, 6025-6028.
Other methods: (h) Torssell, K. B. G. In Nitrile Oxides, Nitrones, and
Nitronates in Organic Synthesis; VCH: Weinheim, 1988; pp 75-94.
(12) Kawakami, T.; Ohtake, H.; Arakawa, H.; Okachi, T.; Imada, Y.;
Murahashi, S.-I. Bull. Chem. Soc. Jpn. 2000, 73, 2423-2444.
(13) Additon of chiral ketete silyl acetals to nitrones: (a) Ohtake, H.; Imada,
Y.; Murahashi, S.-I. J. Org. Chem., 1999, 64, 3790-3791. Additon of
chiral enolates to nitrones via N-acyloxyiminium ions: (b) Kawakami,
T.; Ohtake, H.; Arakawa, H.; Okachi, T.; Imada, Y.; Murahashi, S.-I. Org.
Lett. 1999, 1, 107-110. (c) Kawakami, T.; Ohtake, H.; Arakawa, H.;
Okachi, T.; Imada, Y.; Murahashi, S.-I. Chem. Lett. 1999, 795-796.
(14) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,
115, 8467-8468. (b) Kitamoto, D.; Imma, H.; Nakai, T. Tetrahedron Lett.
1995, 36, 1861-1864. (c) Matsukawa, S.; Mikami, K. Tetrahedron:
Asymmetry 1995, 6, 2571-2574.
(15) Kawakami, T.; Harada, K.; Imada, Y.; Murahashi, S.-I. Abstracts of
Papers, 69th Annual Meeting of the Chemical Society of Japan, Kyoto,
Japan; The Chemical Society of Japan: Tokyo, Japan, 1995; Abstract
2H105. See also the ref 14c.
(16) Zablocki, J. A.; Rico, J. G.; Garland, R. B.; Rogers, T. E.; Williams, K.;
Schretzman, L. A.; Rao, S. A.; Bovy, P. R.; Tjoeng, F. S.; Lindmark, R.
J.; Toth, M. V.; Zupec, M. E.; McMackins, D. E.; Adams, S. P.; Miyano,
M.; Markos, C. S.; Milton, M. N.; Paulson, S.; Herin, M.; Jacqmin, P.;
Nicholson, N. S.; Panzer-Knodle, S. G.; Haas, N. F.; Page, J. D.; Szalony,
J. A.; Taite, B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen,
L. P. J. Med. Chem. 1995, 38, 2378-2394.
Recrystallization of the adduct thus obtained from 2-propanol
gave optically pure 10a. Treatment of 10a with Zn/H2SO4 gave
methyl 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolineacetate, which
is an important precursor of isoquinoline alkaloids. Similarly, the
corresponding adduct 10b was obtained in 88% yield with 90%
ee. Optically active N-hydroxyl-â-amino acids or â-amino acids
can be prepared in large scale from the corresponding secondary
amines by two catalytic processes in combination with the catalytic
synthesis of nitrones from secondary amines.
The reactions exhibit a positive nonlinear relationship between
the enantiomeric purities of the chiral titanium catalyst 8e and the
products 7a and 10a, indicating that binaphtholato-bridged dimeric
complex seems to be involved as the active species in these
reactions. The origin of the reversed sense of stereoinduction using
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