Stereoselective Synthesis of 3-Substituted
4-(Formyloxy)-2-azetidinones by the Unusual Baeyer-Villiger
Reaction of -Lactam Aldehydes. Scope and Synthetic
Applications
Benito Alcaide,* Moustafa F. Aly,
†
and Miguel A. Sierra
Departamento de Quı ´mica Orga ´ nica I, Facultad de Quı ´mica, Universidad Complutense,
28040 Madrid, Spain
Received September 4, 1996
X
The Baeyer-Villiger oxidation of 4-formyl--lactams 1 with m-CPBA gave 4-(formyloxy) -lactams
2 in a simple, efficient, and totally stereoselective process. This reaction is one of the scarce examples
of the preferred migration of a carbon moiety in an aliphatic aldehyde. The influence of the
substituents at N1 and C3 of the four-membered ring in the Baeyer-Villiger rearrangement has
been studied. Thus, alkyl, alkenyl, aryl, and alkyloxy 3-substituted-1-(p-anisyl)-2-azetidinones 1
form exclusively 4-(formyloxy) -lactams 2. Amide or acetoxy substituents at C3 of the four-
membered ring produce mixtures of 4-(formyloxy) -lactams 2 and 4-carboxy -lactams 5. The
exclusive formation of carboxy derivatives is observed sometimes for 1-alkyl-substituted-2-
azetidinones 1. 4-(Formyloxy) -lactams 2 are suitable starting materials to prepare different
4-unsubstituted -lactams 9 using -hydroxy amides 8 as isolable intermediates. The overall
transformation 4-formyl-2-azetidinone to 4-unsubstituted -lactam is an easy and convenient
stereoselective route to these interesting types of compounds.
Introduction
One of the well established principles in the oxidation
of aldehydes with peracids is the formation of carboxylic
acids due to the preferential migration of hydrogen over
the carbon moiety.
2
Formates, formed by migration of
the carbon group, are the alternative reaction products,
but this rearrangement seldom occurs. In fact, to the
best of our knowledge, electron-rich aromatic
3
and het-
eroaromatic
4
aldehydes and R-oxygen-substituted alde-
hydes
5
are the main exceptions to the general rule and
are converted to formate esters upon peroxy acid treat-
ment. The bizarre behavior of the 2-azetidinone ring,
exemplified by different unique transformations,
6
pro-
vides a new example of preferential carbon migration on
the Baeyer-Villiger rearrangement of aldehydes. We
recently reported
1
that -lactam aldehydes 1 (Chart 1)
exclusively yield 4-(formyloxy) -lactams 2 after Baeyer-
Villiger oxidation. This transformation represents one
of the scarce examples of the preferred migration of a
carbon group in an aliphatic aldehyde.
3-5
Total synthesis of mono- and bicyclic -lactam antibiot-
ics often rests on the modification of monocyclic 2-azeti-
dinones having acyloxy substituents at the C4 of the four-
membered ring.
7
Elimination of the ester group promotes
the nucleophilic substitution through acyliminium inter-
mediates,
8
and different functionalized nucleophiles are
thus attached to the -lactam ring. Among others,
4-acetoxy-2-azetidinones 3 are recognized as universal
key intermediates
7
to obtain biologically active -lactams.
Compounds 3 have been prepared by the classical isocy-
anate-olefin cycloaddition
9
using chlorosulfonyl isocy-
anate and different vinyl acetates. However, this ap-
proach is often a low yielding, unselective step,
incompatible with different functional groups needed for
further synthetic steps.
10
Alternative entries to 4-ac-
etoxy-2-azetidinones have been developed, for example,
by oxidation of 2-azetidinones lacking substituents at
†
Permanent address: Chemistry Department, Faculty of Science
at Qena, South Valley University, Qena-Egypt.
X
Abstract published in Advance ACS Abstracts, November 15, 1996.
(1) For a preliminary communication of part of this work see:
Alcaide, B.; Aly, M. F.; Sierra, M. A. Tetrahedron Lett. 1995, 36, 3401-
4.
(2) For recent reviews of Baeyer-Villiger reaction, see: (a) Krow,
G. R. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon
Press: New York, 1991; Vol. 7, p 671. (b) Krow, G. R. Organic
Reactions; Paquette, L. A., Ed.; John Willey and Sons: New York, 1993;
Vol. 43, p 251. (c) Krow, G. R. Tetrahedron 1981, 37, 2697. For recent
papers, see: (a) Kaneda, K.; Ueno, S.; Imanaka, T.; Shimotsuma, E.;
Nishiyama, Y.; Ishii, Y. J. Org. Chem. 1994, 59, 2915. (b) Chida, N.;
Tobe, T.; Ogawa, S. Tetrahedron Lett. 1994, 35, 7249.
(3) See, for example: (a) Grosby, D. G. J. Org. Chem. 1961, 26, 1215.
(b) Ogata, Y.; Sawaki, Y. J. Org. Chem. 1969, 34, 3985. (c) Godfrey, I.
M.; Sargent, M. V.; Elix, J. A. J. Chem. Soc., Perkin Trans. 1 1974,
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1983, 48, 3863. (f) Nelson, W. L.; Burke, T. R. J. Med. Chem. 1979,
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(4) See, for example: (a) Masman, J.-A. H.; Pensar, K. G. Synthesis
1985, 786. (b) Langendoen, A.; Koomen, G.-J.; Pandit, U. K. Hetero-
cycles 1987, 26, 91. (c) Jefford, C. W.; Jaggi, D.; Boukouvalas, J.
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(b) Manhas, M. S.; Wagle, D. R.; Chiang, J.; Bose, A. K. Heterocycles
1988, 27, 1755. (c) Alcaide, B.; Miranda, M.; Pe ´ rez-Castells, J.; Sierra,
M. A. J. Org. Chem. 1993, 58, 297. (d) Alcaide, B.; Martı ´n-Cantalejo,
Y.; Rodrı ´guez-Lo ´pez, J.; Sierra, M. A. J. Org. Chem. 1993, 58, 4767.
(e) Alcaide, B.; Pe ´rez-Castells, J.; Polanco, C.; Sierra, M. A. J. Org.
Chem., 1995, 60, 6012.
(7) For comprehensive reviews, see: (a) Kametani, T.; Fukumoto,
K.; Ihara, M. Heterocycles 1982, 17, 463. (b) Nagahara, T.; Kametani,
T. Heterocycles 1987, 25, 729. (c) Davies, D. E.; Storr, R. C. In
Comprehensive Heterocyclic Chemistry; Lwowski, W., Ed.; Pergamon:
New York, 1984; Vol. 7, p 237. (d) Wild, H. In The Organic Chemistry
of -Lactams; Georg, G. I., Ed.; VCH Publishers, Inc.: New York, 1993;
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(8) Gavin ˜ a, F.; Costero, A. M.; Andreu, M. R. J. Org. Chem. 1990,
55, 434 and references cited therein.
(9) Klaus, K.; Grimm, D.; Prossel, G. Liebigs Ann. Chem. 1974, 539.
Chart 1
8819 J. Org. Chem. 1996, 61, 8819-8825
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