Highly diastereoselective addition of a chiral ketene silyl acetal to nitrones: Asymmetric synthesis of β-amino acids and key intermediates of β- lactam antibiotics

Full text of DOI:10.1021/jo9902291

3790
J . Org. Chem. 1999, 64, 3790-3791
1a with chiral ketene silyl acetal 2 in the presence of a Lewis
acid catalyst gives a desired adduct quite efficiently. Actu-
ally, the reaction of (Z)-1a with 2 in the presence of zinc
iodide (20 mol %) and 4A molecular sieves at 0 °C gave 2-[(N-
ben zyl-N-h ydr oxya m in o)ph en ylm et h yl]-3-h ydr oxybu -
tanoate (3a ) in 89% yield after treatment with a 6 M HCl
solution. Inspection of 1H and 13C NMR spectra of the crude
product and those of purified 3a showed that only one
stereoisomer was formed among the possible four stereo-
isomers. N-Hydroxy-â-amino ester 3a was easily converted
to â-amino ester 4a upon treatment with zinc powder in
acetic acid in 88% yield. To determine the stereochemistry
of 3a , amino alcohol 4a was further transformed into the
corresponding cyclic urethane, (4R,5S,6R)-3-benzyl-6-meth-
yl-5-methoxycarbonyl-4-phenylperhydro-1,3-oxazin-2-one (5a)
(95%) upon treatment with carbonyl diimidazole. The ster-
eochemical assignment of 5a was made to be 4,5-anti-5,6-
High ly Dia ster eoselective Ad d ition of a
Ch ir a l Keten e Silyl Aceta l to Nitr on es:
Asym m etr ic Syn th esis of â-Am in o Acid s a n d
Key In ter m ed ia tes of â-La cta m An tibiotics
Hiroaki Ohtake,† Yasushi Imada, and
Shun-Ichi Murahashi*
Department of Chemistry, Graduate School of Engineering
Science, Osaka University, Machikaneyama 1-3,
Toyonaka, Osaka 560-8531, J apan
Received February 8, 1999
Addition of nucleophiles to nitrones is rapidly developing
as one of the most effective methods for the synthesis of
R-substituted amines and N-hydroxy derivatives,1 because
efficient catalytic methods for synthesis of nitrones from
secondary amines were explored recently.2 Syntheses of
optically active nitrogen-containing natural products3 from
chiral nitrones have been reported; however, a few attempts
have been made on asymmetric synthesis by addition of
chiral nucleophiles to prochiral nitrones4 with poor diaste-
reoselectivities except one example of double stereodiffer-
entiation with the matched set of chiral nucleophile and
chiral nitrone.4d We wish to report here highly diastereo-
selective zinc iodide-catalyzed reaction of nitrones 1 with
(Z)-(R)-1,3-bis(triethylsilyloxy)-1-methoxy-1-butene (2) de-
rived from methyl (R)-3-hydroxybutanoate, which is readily
available either by catalytic asymmetric hydrogenation5 or
by biological processes,6 as depicted in eq 1. The present
reaction has advantages over Mannich-like additions to
imines because nitrones are more stable than imines and
easily controlled.
3
anti on the basis of 1H NMR analysis (3J 4,5 ) 10.5 Hz, J 5,6
) 10.3 Hz). Thus, the absolute configuration of 3a was
established to be (RR,âS,γR), and hence the diastereoselec-
tive addition of 2 occurred with R,â-anti-â,γ-anti stereo-
chemistry.
The zinc iodide-catalyzed condensations have been carried
out for cyclic nitrones 1b-d , which have E-geometry with
carbon-nitrogen double bonds. 1-Pyrroline N-oxide (1b),
prepared by a single pot oxidation of pyrrolidine,2 smoothly
reacted with 2 to give N-hydroxy-â-amino ester 3b as a
single isomer with R,â-anti-â,γ-anti stereochemistry in 78%
yield. 2,3,4,5-Tetrahydropyridine N-oxide (1c) and 3,4-
dihydroisoquinoline N-oxide (1d ), prepared from piperidine
and 1,2,3,4-tetrahydroisoqunoline,2 underwent addition with
2 to give adducts 3c (72%) and 3d (71%), respectively. The
stereochemistries of 3b-d were also confirmed on the basis
The reaction of (Z)-N-benzylidenebenzylamine N-oxide
(1a ) (R1 ) Bn, R2 ) Ph) with dilithium enolate derived from
methyl (R)-3-hydroxybutanoate gave no adduct even under
a variety of reaction conditions. However, the reaction of (Z)-
† On leave from Basic Research Laboratory, Fujisawa Pharmaceutical
Co., Ltd. (Kashima, Osaka 532-0031, J apan).
(1) Risch, N.; Arend, M. In Stereoselective Synthesis, Helmchen, G.,
Hoffmann, R. W., Mulzer, J ., Schaumann, E., Eds.; Georg Thieme Verlag:
New York, 1996; E 21 Vol. 3, Chapter 1.4.1, 1.4.2, and 1.4.3, pp 1887-
1929.
(2) Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe, S. J .
Org. Chem. 1990, 55, 1736-1744. Murahashi, S.-I.; Shiota, T.; Imada, Y.
Org. Synth. 1992, 70, 265-271. Murahashi, S.-I.; Imada, Y.; Ohtake, H. J .
Org. Chem. 1994, 59, 6170-6172 and references therein.
(3) (a) L-Daunosamine (antitumor agent): Kita, Y.; Itoh, F.; Tamura, O.;
Ke, Y. Y.; Tamura, Y. Tetrahedron Lett. 1987, 28, 1431-1434. (b) (-)-
Anisomycin (antifungi agent): Ballini, R.; Marcantoni, E.; Petrini, M. J .
Org. Chem. 1992, 57, 1316-1318. (c) (+)- and (-)-zileuton (therapeutic
agents in asthma and ulcerative colitis): Basha, A.; Henry, R.; McLaughlin,
M. A.; Ratajczyk, J . D.; Wittenberger, S. J . J . Org. Chem. 1994, 59, 6103-
6106. (d) Amino sugars: Dondoni, A.; Franco, S.; J unquera, F.; Mercha´n,
F. L.; Merino, P.; Tejero, T.; Bertolasi, V. Chem. Eur. J . 1995, 1, 505-520.
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1
of H NMR analysis of the corresponding cyclic urethanes
5b-d . The hydroxylamines 3b-d thus obtained can be
easily converted into the corresponding amines 4b (81%),
4c (95%), and 4d (80%) by catalytic hydrogenation in acetic
acid. These â-amino acid derivatives 4b-d are enantiomeri-
cally pure and highly useful for the synthesis of a wide range
of pyrrolidine, piperidine, and isoquinoline alkaloids, re-
spectively.
These results reveal that the condensation of nitrones 1
with 2 exhibits extremely high R,â-anti-â,γ-anti diastereo-
facial selection, regardless of the geometry of nitrones 1. The
R,â-anti selectivity, which reflects the π-facial selectivity of
ketene silyl acetal 2, is best accounted for in terms of the
attack of nitrone from the less hindered top side (si-face) in
the preferred conformation (a)7 as shown in Figure 1. The
â,γ-anti stereoselectivity reflects the π-facial selectivity of
(6) Seebach, D.; Sutter, M. A.; Weber, R. H.; Zu¨ger, M. F. Org. Synth.
1985, 63, 1-9. Seebach, D.; Beck, A. K.; Breitschuh, R.; J ob, K. Org. Synth.
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10.1021/jo9902291 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/30/1999

Communications
J . Org. Chem., Vol. 64, No. 11, 1999 3791
subsequent treatment with acetic acid gave N-hydroxy-â-
amino ester 9 ([R]25 -23.5 (c 1.43, CHCl3)) in 75% yield as
D
a single stereoisomer. Hydrogenation of 9 over Pd/C catalyst
followed by treatment with a dilute HCl solution gave
â-amino ester hydrochloride 10 ([R]27D -7.2 (c 0.85, MeOH))
in 98% yield. The â-lactam 12 (mp 60.2-61.7 °C; [R]21D -74.0
nitrones 1 activated by the coordination of a weak Lewis
acid of zinc iodide to the oxygen atom. This is understand-
able as a result of the favorable antiperiplanar open transi-
tion state (b)8 in Figure 1, where the R2 group in the
nitrone-Lewis acid complex occupies a less hindered posi-
tion between H and the methoxy group in 2 to avoid
unfavorable steric interactions.
(c 1.10, CHCl3); g99% ee (lit. [R]22 -74.4 (c 1.05, CHCl3))12
D
was obtained from 10 by ring closure and subsequent
silylation of 11 (73%). Since oxidative transformation of 12
to 6 can be carried out readily by ruthenium-catalyzed
reaction with peracetic acid (99%)13 or a combination of
acetaldehyde and O2 (91%),14 we can obtain the useful key
intermediate 6 highly diastereoselectively.
F igu r e 1. Proposed diastereoselection model for the addition of
2 to nitrones 1 (a) and its Newman projection (b).
This diastereoselective condensation is highly useful for
synthesis of (2R,3S)-2-acetoxy-3-[(1R)-1-(tert-butyldimeth-
ylsilyloxy)ethyl]azetidin-2-one (6),9 which is a key intermedi-
ate of â-lactam antibiotics.10 Thus, the zinc iodide-catalyzed
reaction of N-methoxycarbonylmethylidenebenzylamine N-
oxide (1e) with 2 and subsequent treatment with zinc
powder in acetic acid gave pentanolide 7 (mp 90.5-91.5 °C;
[R]27D -28.1 (c 1.23, CHCl3)) as a single isomer in 60% yield
via cyclization of γ-hydroxypentanoate followed by concomi-
tant epimerization at the C-2 position. The stereochemistry
of 7 was assigned on the basis of the nuclear Overhauser
effects between H(2) and H(4) and between H(3) and Me(4).
The pentanolide 7 was easily transformed to the known 811
Further work is currently in progress on the extension of
the highly diastereoselective reaction to other systems and
application to the synthesis of nitrogen-containing biologi-
cally active compounds.
Ack n ow led gm en t. This work was supported by Re-
search for the Future program, the J apan Society for the
Promotion of Science, and a Grant-in-Aid for Scientific
Research, the Ministry of Education, Science, Sports and
Culture of J apan.
(mp 107.5-108.7 °C; [R]24 -41.7 (2.9% MeOH)) by hydro-
D
genation and subsequent acylation (95%). Further conver-
sion of 8 to â-lactam 6 was achieved by the known method.11
An alternative approach to â-lactam 6 was performed
starting from N-methylidenebenzylamine N-oxide (1f). Thus,
the reaction of 2 with nitrone 1f, prepared in situ by the
reaction of N-benzylhydroxylamine with formaldehyde, and
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and spectroscopic data for compounds 3a -d , 4a -d , 5a -d ,
and 7-12. This material is available free of charge via the Internet
at http://pubs.acs.org.
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J O9902291
(9) For a review, see: Berks, A. H. Tetrahedron 1996, 52, 331-375.
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(11) Ciba-Geigy, Eur. Pat. 1988, Appl 279781.