Structurally Novel Bi- and Tricyclic β-Lactams via [2 + 2] Cycloaddition or Radical Reactions in 2-Azetidinone-Tethered Enallenes and Allenynes

Article abstract of DOI:10.1021/ol034995c

(Matrix presented) Thermolysis of β-lactam-tethered enallenyl alcohols gave tricyclic ring structures via a formal [2 + 2] cycloaddition of the alkene with the distal bond of the allene, while the tin-promoted radical cyclization in 2-azetidinone-tethered

Full text of DOI:10.1021/ol034995c

ORGANIC
LETTERS
2
003
Vol. 5, No. 21
795-3798
Structurally Novel Bi- and Tricyclic
â-Lactams via [2 + 2] Cycloaddition or
Radical Reactions in
3
2-Azetidinone-Tethered Enallenes and
Allenynes
,†
,‡
†
Benito Alcaide,* Pedro Almendros,* and Cristina Aragoncillo
Departamento de Qu ´ı mica Org a´ nica, Facultad de Qu ´ı mica, UniVersidad Complutense
de Madrid, 28040-Madrid, Spain, and Instituto de Qu ´ı mica Org a´ nica General, CSIC,
Juan de la CierVa 3, 28006-Madrid, Spain
alcaideb@quim.ucm.es; iqoa392@iqog.csic.es
Received June 4, 2003
ABSTRACT
Thermolysis of â-lactam-tethered enallenyl alcohols gave tricyclic ring structures via a formal [2 + 2] cycloaddition of the alkene with the
distal bond of the allene, while the tin-promoted radical cyclization in 2-azetidinone-tethered allenynes proceeded to provide bicyclic â-lactams
containing a medium-sized ring. The access to cyclization precursors was achieved by regio- and stereoselective metal-mediated carbonyl
allenylation of 4-oxoazetidine-2-carbaldehydes in an aqueous environment.
â-Lactam antibiotics have occupied a central role in the vigil
against bacterial infections over the past several decades.
rial agents featuring good resistance to â-lactamases and
dehydropeptidases. Besides, the ever-growing new applica-
1
3
The various families of â-lactam antibiotics differ in their
spectrum of antibacterial activity and in their susceptibility
to â-lactamase enzymes, which constitute the most common
tions of 2-azetidinones in fields ranging from enzyme
4
inhibition to the use of these products as starting materials
5
to develop new synthetic methodologies has triggered a
2
and growing form of antibacterial resistance. Bacterial
(2) â-Lactamase enzymes catalyze the hydrolysis of â-lactams to give
resistance to â-lactam antibiotics caused by their widespread
use over the past few decades has motivated a growing
interest in the preparation and biological evaluation of new
types of â-lactams that will overcome the defense mecha-
nisms of the bacteria. Tricyclic â-lactam antibiotics, generally
referred to as trinems, are a new class of synthetic antibacte-
ring-opened â-amino acids that are no longer effective as inhibitors against
their targets: bacterial membrane-bound transpeptidases enzymes. See, for
example: (a) Sandanayaka, V. P.; Prashad, A. S. Curr. Med. Chem. 2002,
9
, 1145. (b) Ritter, T. K.; Wong, C.-H. Angew. Chem., Int. Ed. 2001, 40,
3508. (c) D ´ı az, N.; Su a´ rez, D.; Merz, K. M. M., Jr. J. Am. Chem. Soc.
000, 122, 4197. (d) Page, M. I. Chem. Commun. 1998, 1609. (e) Niccolai,
2
D.; Tarsi, L.; Thomas, R. J. Chem. Commun. 1997, 2333. (f) Hook, V.
Chemistry in Britain 1997, 33, 34. (g) Spratt, B. G. Science 1994, 264,
3
88. (h) Davies, J. Science 1994, 264, 375.
(3) For selected references, see: (a) Kanno, O.; Kawamoto, I. Tetrahe-
†
Universidad Complutense de Madrid.
Instituto de Qu ´ı mica Org a´ nica General.
‡
dron 2000, 56, 5639. (b) Hanessian, S.; Reddy, B. Tetrahedron 1999, 55,
3427. (c) Biondi, S.; Pecunioso, A.; Busi, F.; Contini, S. A.; Donati, D.;
Maffeis, M.; Pizzi, D. A.; Rossi, L.; Rossi, T.; Sabbatine, F. M. Tetrahedron
2000, 56, 5649. (d) Ghiron, C.; Rossi, T. The Chemistry of Trinems in
Targets in Heterocyclic SystemssChemistry and Properties; Attanasi, O.
A., Spinelli, D., Eds.; Societa Chimica Italiana: Rome, 1997; Vol. 1, pp
161-186. (e) Ngo, J.; Casta n˜ er, J. Drugs Future 1996, 21, 1238.
(1) For selected reviews, see: (a) Setti, E. L.; Micetich, R. G. Curr.
Med. Chem. 1998, 5, 101. (b) The Organic Chemistry of â-Lactams; Georg,
G. I., Ed.; VCH: New York, 1993. (c) Neuhaus, F. C.; Georgeopapadakou,
N. H. In Emerging Targets in Antibacterial and Antifungal Chemotherapy;
Sutcliffe, J., Georgeopapadakou, N. H., Eds.; Chapman and Hall: New York,
1
992.
1
0.1021/ol034995c CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/24/2003

9
renewed interest in the building of new polycyclic â-lactam
from N,N-di-(p-methoxyphenyl)glyoxal diimine. R-Allenyl
systems in an attempt to move away from the classical
â-lactam antibiotic structures. On the other hand, allenes
alcohol (+)-2a was prepared by boron trifluoride diethyl
etherate-induced condensation of 4-oxoazetidine-2-carbal-
dehyde (+)-1a with propargyltrimethylsilane, while 2-aze-
tidinone-tethered allenes 2b-h were achieved via metal-
mediated Barbier-type carbonyl-allenylation reaction of
â-lactam aldehydes 1a-d in aqueous media using our
previously described methodologies (Scheme 1).8a
6
have most certainly reached the status of important and useful
functional groups in organic synthesis. Allenes can be
transformed into other functional groups, such as olefins,
alkynes, and R,â-unsaturated carbonyls and also participate
in a variety of cycloaddition and transition metal-catalyzed
7
cyclization reactions. During the course of our ongoing
project directed toward the synthesis of potentially bioactive
8
2
-azetidinones, we discovered a novel palladium-catalyzed
Scheme 1
8a
domino reaction in allenynes. In this contribution, we wish
to connect the chemistry of allenes with noncatalytic cy-
clization processes for the synthesis of enantiopure fused
polycyclic â-lactams of nonconventional structure.
The starting substrates, 4-oxoazetidine-2-carbaldehydes
1
a-d, were prepared both in the racemic form and in
optically pure form using standard methodology. Enantiopure
-azetidinones (+)-1a and (+)-1c were obtained as single
2
cis enantiomers from imines of (R)-2,3-O-isopropylidene-
glyceraldehyde, through Staudinger reaction with meth-
oxyacetyl chloride in the presence of Et N, followed by
3
sequential acidic acetonide hydrolysis and oxidative cleav-
8
age. Racemic compounds (()-1b and (()-1d were obtained
as single cis diastereoisomers following our one-pot method
(4) Some of the more notable advances concern the development of
mechanism-based serine protease inhibitors of elastase, cytomegalovirus,
protease, thrombin, and prostate-specific antigen. For selected examples,
see: (a) Page, M. I.; Laws, A. P. Tetrahedron 2000, 56, 5631. (b) Haley,
T. M.; Angier, S. J.; Borthwick, A. D.; Singh, R.; Micetich, R. G. Drugs
2
000, 3, 512. (c) Bonneau, P. R.; Hasani, F.; Plouffe, C.; Malenfant, E.;
LaPlante, S. R.; Guse, I.; Ogilvie, W. W.; Plante, R.; Davidson, W. C.;
Hopkins, J. L.; Morelock, M. M.; Cordingley, M. G.; Deziel, R. J. Am.
Chem. Soc. 1999, 121, 2965. (d) Ogilvie, W. W.; Yoakim, C.; Do, F.; Hache,
B.; Lagace, L.; Naud, J.; O’Meara, J. A.; Deziel, R. Bioorg. Med. Chem.
Lett. 1999, 9, 1521. (e) Vaccaro, W. D.; Davis, H. R., Jr. Bioorg. Med.
Chem. Lett. 1998, 8, 313. (f) Borthwick, A. D.; Weingarte, G.; Haley, T.
M.; Tomaszewski, M.; Wang, W.; Hu, Z.; Bedard, J.; Jin, H.; Yuen, L.;
Mansour, T. S. Bioorg. Med. Chem. Lett. 1998, 8, 365. (g) Han, W. T.;
Trehan, A. K.; Wright, J. J. K.; Federici, M. E.; Seiler, S. M.; Meanwell,
N. A. Bioorg. Med. Chem. 1995, 3, 1123.
The intermolecular [2 + 2] cycloaddition reaction has been
used to build tricyclic â-lactams bearing a four-membered
ring fused to a cephalosporin, by treatment of a â-lactam
enol triflate with different olefins, although in some cases a
large excess of alkene was required to obtain reasonable
yields. Although, in theory, an intramolecular cycloaddi-
tion of â-lactam-dienes could be used to prepare tricycles,
to our knowledge, there is no report involving intramolecular
1
0
(
5) For reviews, see: (a) Alcaide, B.; Almendros, P. Synlett 2002, 381.
(
b) Alcaide, B.; Almendros, P. Chem. Soc. ReV. 2001, 30, 226. (c) Alcaide,
B.; Almendros, P. Org. Prep. Proced. Int. 2001, 33, 315. (d) Palomo, C.;
Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Synlett 2001, 1813. (e) Palomo,
C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Amino Acids 1999, 16, 321.
[
2 + 2] cycloaddition reaction of 2-azetidinone-tethered
alkenes.
The inherent instability imparted by the cumulated double
(
f) Ojima, I.; Delaloge, F. Chem. Soc. ReV. 1997, 26, 377. (g) Ojima, I.
AdV. Asym. Synth. 1995, 1, 95. (h) Manhas, M. S.; Wagle, D. R.; Chiang,
J.; Bose, A. K. Heterocycles 1988, 27, 1755.
11
bond in allenes has been exploited by many research groups
taking advantage of the facility in which cycloaddition
reactions take place relative to that of an isolated double
bond. However, positional selectivity problems are sig-
nificant. Intramolecularization of the reactions, usually by
placing the group at distances such that five- or six-
membered rings are formed, automatically should solve the
(
6) For a recent review on bi- and tricyclic-â-lactams with nonclassical
structures, see: Alcaide, B.; Almendros, P. Curr. Org. Chem. 2002, 6, 245.
7) For general reviews, see: (a) Patai, S. In The Chemistry of Ketenes,
(
7
b
Allenes, and Related Compounds; Wiley: Chichester, 1980. (b) Schuster,
H. F.; Coppola, G. M. In Allenes in Organic Synthesis; Wiley: New York,
1
984. (c) Landor, S. R. The Chemistry of the Allenes; Academic Press:
New York, 1982. (d) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34,
35. For a review on transition metal-catalyzed reactions of allenes, see:
e) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2001, 39, 3590. For a review
5
(
on palladium-allene chemistry, see: (f) Zimmer, R.; Dinesh, C. U.;
Nandanan, E.; Khan, F. A. Chem. ReV. 2000, 100, 3067. For a review on
transition metal-based cyclization of allenes, see: (g) Bates, R. W.;
Satcharoen, V. Chem. Soc. ReV. 2002, 31, 12. For a selected recent paper
on the asymmetric synthesis of oxygenated heterocycles from allenes, see:
(9) (a) Alcaide, B.; Mart ´ı n-Cantalejo, Y.; Plumet, J.; Rodr ´ı guez-L o´ pez,
J.; Sierra, M. A. Tetrahedron Lett. 1991, 32, 803. (b) Alcaide, B.; Mart ´ı n-
Cantalejo, Y.; P e´ rez-Castells, J.; Rodr ´ı guez-L o´ pez, J.; Sierra, M. A.; Monge,
A.; P e´ rez-Garc ´ı a, V. J. Org. Chem. 1992, 57, 5921.
(10) Elliot, R. L.; Nicholson, N. H.; Peaker, F. E.; Takle, A. K.;
Richardson, C. M.; Tyler, J. W.; White, J.; Pearson, M. J.; Eggleston, D.
S.; Haltiwanger, R. C. J. Org. Chem. 1997, 62, 4998
(11) Allene moiety was originally thought to be very unstable (prior to
the 1970s, allenes were regarded as curiosities) and, in fact, upon undergoing
any addition reaction, experiences a relief in strain of about 10 kcal/mol:
Padwa, A.; Filipkowski, M. A.; Meske, M.; Murphree, S. S.; Watterson, S.
H.; Ni, Z. J. Org. Chem. 1994, 59, 591.
(
h) Xu, D.; Li, Z.; Ma, S. Chem. Eur. J. 2002, 8, 5012.
(8) See, for instance: (a) Alcaide, B.; Almendros, P.; Aragoncillo, C.
Chem. Eur. J. 2002, 8, 1719. (b) Alcaide, B.; Almendros, P.; Aragoncillo,
C.; Redondo, M. C. Chem. Commun. 2002, 1472. (c) Alcaide, B.;
Almendros, P.; Aragoncillo, C. Chem. Eur. J. 2002, 8, 3646. (d) Alcaide,
B.; Almendros, P.; Alonso, J. M.; Aly, M. F.; Pardo, C.; S a´ ez, E.; Torres,
M. R. J. Org. Chem. 2002, 67, 7004. (e) Alcaide, B.; Almendros, P.; Alonso,
J. M.; Redondo, M. C. J. Org. Chem. 2003, 68, 1426.
3796
Org. Lett., Vol. 5, No. 21, 2003

positional selectivity problems because larger rings are
unfavored. Because allenes can react as 2π-electron donors
in [2 + 2] cycloadditions, 2-azetidinone-tethered enallenyl
alcohols 2 would be an ideal cyclization partner for the
generation of a diverse array of tricyclic â-lactams containing
a cyclobutane ring.12 Equipped with an efficient synthesis
of functionalized 2-azetidinone-tethered enallenes 2, we
attempted the thermolysis and succeeded in isolating tricyclic
â-lactams 3 containing a cyclobutane ring. Substitution
patterns on enallenes (+)-2a-c were selected in order to
direct the regiochemical outcome of the cycloaddition to the
six-membered central ring formation. However, we found
that the thermal reaction produced tricycles 3 bearing a
central seven-membered ring. No traces of the exocyclic
methylene regioisomer 4 could be detected (Scheme 2).
regioselectivity from their study of intramolecular [2 + 2]
cycloaddition reactions on (phenylsulfonyl)enallenes on
1
4
preparing bicyclo[4.2.0]octene systems, related to com-
pounds 5. However, these authors were not able to prepare
bicyclo[5.2.0]nonenes, related to compounds 3, obtaining
14
instead monocyclic-substituted cyclooctenes.
Recently, the use of radical cyclization for carbon-carbon
bond-forming reactions has become widespread in organic
chemistry for the construction of carbocycles and hetero-
1
5
cycles. The majority of commonly employed methods
utilize tributyltin hydride to induce homolysis of an organic
halide or alcohol derivative in forming the reactive carbon
radical species. The addition of a free radical to two carbon-
carbon double bonds, one double bond and one triple bond,
or two triple bonds, constitutes an alternative approach that
has the advantage of incorporating some useful additional
functional groups into the cyclized products. Although the
utility of this methodology using dienes, enynes, and diynes
has been demonstrated, the radical reaction of allenic
Scheme 2
16
derivatives has received little attention, because the addition
reaction to allenes will be complicated in terms of chemo-,
regio-, and stereoselectivity. The radical-induced cyclization
of 2-azetidinone-tethered allenynes is appealing because
useful functionality is introduced in one simple step in which
new carbon-carbon bond formation occurs to afford bicyclic
The tricyclic ring structures 3 arise from a formal [2 + 2]
cycloaddition of the alkene with the distal bond of the allene,
most likely via a diradical intermediate. Similar behavior
patterns were observed on heating enallenes (()-2d and
6
â-lactams of nonconventional structure. The resulting cyclic
compounds would be particularly useful to allow further
synthetic transformations. This cyclization proceeded el-
egantly in enynes 2f-h to provide the desired fused bicycles
bearing a medium-sized ring 6a-c as single isomers in fair
(()-2e to give fused tricycles 5. Compounds 3 and 5 were
obtained in moderate yields as single isomers. Selected
examples are shown below in Scheme 3. An unsubstituted
17
yields (Scheme 4). It is presumed that the addition of
stannyl radical to the terminal position of the triple bond
gives the vinylic radical intermediates in the propagation step,
followed by cyclization toward the central carbon bond of
Scheme 3
Scheme 4
allene results in a somewhat slower rate of reaction but with
similar regiochemical preference. Our observed regiochem-
istry for the [2 + 2] cycloaddition is remarkable, because it
is in sharp contrast with previously reported related examples
in which the 2π-component was the internal double bond of
13
the allene moiety; only Padwa et al. have reported a similar
Org. Lett., Vol. 5, No. 21, 2003
3797

the allene moiety to give bicycles 6 in a totally regio- and
stereoselective fashion.
ceeded to provide bicyclic â-lactams in a totally regio- and
stereoselective fashion. This opens up new prospects for the
use of enallenes and allenynes as precursors of optically pure
fused heterocycles without recourse to transition metal
chemistry.
In conclusion, a novel entry to enantiopure nonconven-
tional fused bi- and tricyclic â-lactams has been developed
by using intramolecular [2 + 2] cycloaddition or radical
reactions in monocyclic enallenes and allenynes. The ther-
molisis of â-lactam-tethered enallenyl alcohols gave tri-
cyclic ring structures via a [2 + 2] cycloaddition of the alkene
with the distal bond of the allene, while the tin-promoted
radical cyclization in 2-azetidinone-tethered allenynes pro-
Acknowledgment. Support for this work by the DGI-
MCYT (Project BQU2000-0645) is gratefully acknowledged.
C. Aragoncillo thanks the Comunidad Aut o´ noma de Madrid
for a fellowship.
Supporting Information Available: Spectroscopic and
analytical data for compounds (+)-3b, (+)-3c, (()-5a,
(-)-6a, and (()-6c, as well as general experimental proce-
dures for compounds 3, 5, and 6. This material is available
free of charge via the Internet at http://pubs.acs.org.
(
12) Methodology of the asymmetric formation of cyclobutane derivatives
is limited in preparative organic chemistry. For example, see: Methods of
Organic Chemistry (Houben-Weyl); De Meijere, A., Ed.; Thieme: Stuttgart,
1
997; Vol. E17e.
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(
(
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(
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