β-Lactam-based azomethine ylide reactivity. Expedient synthesis of carbapenams and carbapenems

Full text of DOI:10.1021/ja9637560

J. Am. Chem. Soc. 1997, 119, 2309-2310
2309
Scheme 1a
â-Lactam-Based Azomethine Ylide Reactivity.
Expedient Synthesis of Carbapenams and
Carbapenems
Sarah R. Martel,† Richard Wisedale,† Timothy Gallagher,*,†
Lee D. Hall,‡ Mary F. Mahon,§ Robert H. Bradbury, and
Neil J. Hales*,
a Reagents: (a) PNBBr or BnBr, then O3; (b) MeCN, 80-100 °C,
1,3-dipolarophile (Tables 1 and 2).
School of Chemistry, UniVersity of Bristol
Bristol BS8 1TS, U.K.
and benzyl (Bn) esters 3a and 3b, respectively, are prepared
from lithium clavulanate using an established two-step proce-
dure5 (Scheme 1).
X-ray Crystallographic Unit, School of Chemistry
UniVersity of Bristol, Bristol, BS8 1TS, U.K.
X-ray Crystallographic Unit, School of Chemistry
UniVersity of Bath, Bath, BA2 7AY, U.K.
Zeneca Pharmaceuticals, Mereside, Alderley Park
Macclesfield SK10 4TG, U.K.
Cycloaddition reactions were achieved by thermolysis of
either 3a or 3b in acetonitrile (at reflux or in a sealed tube at
100 °C) in the presence of a dipolarophile: alkenyl dipolaro-
philes gave carbapenams 4a-f, and alkynes produced the
corresponding ∆1-carbapenems 5a-d directly. These products,
which are racemic, are shown in Tables 1 and 2 with examples
chosen to highlight the key features of this versatile cyclo-
addition process.
Several aspects merit specific comment. In the alkenyl series
(Table 1), endo cycloadducts predominate and the cycloaddition
step, which exhibits a high degree of regioselectivity for
unsymmetrical 1,3-dipolarophiles, is also stereospecific.6 Cy-
cloalkenones provide access to the basic trinem7 skeleton, as
present in 4d,8 and use of benzoquinone gave the tricyclic adduct
4e which has aromatized after cycloaddition.9 A variety of other
substitution patterns are tolerated, including heteroatoms (see
4f and 4g) to provide an important and effective level of
functionality at C(2).10 In the alkynyl series (Table 2), good
regioselectivity was again observed and cycloaddition to sulfur-
substituted dipolarophiles allows access to 2-(arylthio)- and
2-(alkylthio)-∆1-carbapenems 5c and 5d, respectively.
ReceiVed October 28, 1996
Carbapenems and carbapenams comprise a structurally di-
verse and clinically important class of â-lactam antibiotics that
have been the focus of a sustained synthetic effort over the past
20 years.1 While a variety of substitution patterns are known,
for example at C(1), C(2), and C(6), the carbapenem skeleton
1 constitutes a modified pyrroline moiety fused to a â-lactam
nucleus. As a consequence, synthesis of the carbapenem
framework should be suited to a strategy based on 1,3-dipolar
cycloaddition chemistry which would offer a direct method for
assembling this strained and reactive bicycle. Such an approach
does, however, require access to a stabilized azomethine ylide
2 (eq 1), and generating a species of this type represents a
significant challenge.2
Base-mediated isomerization of ∆1-carbapenems to the
biologically more relevant ∆2-carbapenem isomer, though
achievable, is inefficient,11 and we have sought to harness the
1,3-dipolar cycloaddition strategy to provide a direct entry to
∆2-carbapenems. Thermolysis of 3a (1,2-dichlorobenzene,
reflux, 5 min) in the presence of phenyl vinyl selenide gave
the endo adduct 4g which, on oxidation (H2O2, -20 °C), gave
the (()-∆2-carbapenem 612 in 45% overall yield (Scheme 2).
In this communication we disclose a method that expresses,
for the first time, the reactivity of azomethine ylides that are
equivalent to 2. We also describe the synthesis of a representa-
tive series of carbapenams and carbapenems to exemplify the
potential offered by the 1,3-dipolar cycloaddition strategy
outlined in eq 1.
(5) (a) Brown, A. G.; Corbett, D. F.; Goodacre, J.; Harbidge, J. B.;
Howarth, T. T.; Ponsford, R. J.; Stirling, I.; King, T. J. J. Chem. Soc., Perkin
Trans. 1 1984, 635. (b) Howarth, T. T.; Stirling, I. Ger. Offen. 2,655,675;
Chem. Abstr. 1977, 87, 102313. Also Campbell, M. M.; Jasys, V. J.
Heterocycles 1981, 16, 1487.
(6) See the Supporting Information for experimental procedures. The
regio- and stereochemical features of the cycloadducts described in Tables
1 and 2 were elucidated by NMR (2D and NOE). Structures of 4b and 4f
were established by X-ray crystallographic analysis. Stereospecific reactions
were observed using 3b with (i) dimethyl maleate and (ii) dimethyl fumarate.
(7) Tamburini, B.; Perboni, A.; Rossi, T.; Donati, D.; Gaviraghi, G.;
Tarzia, G. In Recent AdVances in the Chemistry of Anti-InfectiVe Agents;
Bentley, P. H., Ponsford, R., Eds.; Royal Society of Chemistry: Cambridge,
1992; p 21. Camerini, R.; Panunzio, M.; Bonanomi, G.; Donati, D.; Perboni,
A. Tetrahedron Lett. 1996, 37, 2467.
We have found that the requisite azomethine ylide reactivity3
is available in a reaction involving decarboxylation4 of a
â-lactam-based oxazolidinone, 3. Both the p-nitrobenzyl (PNB)
† School of Chemistry, University of Bristol.
‡ X-ray Crystallographic Unit, School of Chemistry, University of Bristol.
§ X-ray Crystallographic Unit, School of Chemistry, University of Bath.
Zeneca Pharmaceuticals.
(1) (a) Du¨rchheimer, W.; Blumbach, J.; Lattrell, R.; Scheunemann, K.
H. Angew. Chem., Int. Ed. Engl. 1985, 24, 180. (b) Recent AdVances in the
Chemistry and Biology of â-Lactams and â-Lactam Antibiotics; Georg, G.
I., Ed. Bioorg. Med. Chem. Lett. 1993, 3, (Symposia-in-Print No. 8), 2159-
2313. The penam/carbapenam numbering scheme (see eq 1) is used in this
paper.
(2) (a) Lown, J. W. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984; Vol. 1, p 653. (b) Grigg, R. Chem. Soc.
ReV. 1987, 16, 89. (c) Pearson, W. H. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1988; Vol. 1. (d)
Tsuge, O.; Kanemasa, S. In AdVances in Heterocyclic Chemistry; Katritsky,
A. R., Ed.; Academic Press, Inc.: San Diego, 1989; Vol. 45, p 231.
(3) An azomethine ylide related to 2 has been implicated in the base-
mediated racemization of desoxyclavulanic acid. Newall, C. E. In Recent
AdVances in the Chemistry of â-Lactam Antibiotics; Gregory, G. I., Ed.;
Royal Society of Chemistry: London, 1981; Chapter 13, p 151.
(4) Simple oxazolidin-5-ones undergo thermal decarboxylation (1,3-
dipolar cycloreversion) to give nonstabilized azomethine ylides. (a) Grigg,
R.; Idle, J.; McMeekin, P.; Surendrakumar, S.; Vipond, D. J. Chem. Soc.,
Perkin Trans. 1 1988, 2703. (b) Kanesawa, S.; Sakamoto, K.; Tsuge, O.
Bull. Chem. Soc. Jpn. 1989, 62, 1960. See also: Burger, K.; Meffert, A.;
Bauer, S. J. Fluorine Chem. 1977, 10, 57. Eschenmoser, A. Chem. Soc.
ReV. 1976, 5, 377.
(8) Reaction of 3a with 2-cyclopentenone gave a major product (in 26%
yield) corresponding to an endo-adduct but with the opposite regiochemistry
to that shown for 4d (see the Supporting Information).
(9) Aryl-based tricyclic carbapenems analogous to 4e have been de-
scribed. Heck, J. V.; Christensen, B. G. Tetrahedron Lett. 1981, 22, 5027.
Heck, J. V.; Szymonifka, M. J.; Christensen, B. G. Tetrahedron Lett. 1982,
23, 1519.
(10) Bateson, J. H.; Roberts, P. M.; Smale, T. C.; Southgate, R. J. Chem.
Soc., Perkin Trans. 1 1990, 1541.
(11) Bateson, J. H.; Hickling, R. I.; Smale, T. C.; Southgate, R. J. Chem.
Soc., Perkin Trans. 1 1990, 1793. Schmitt, S. M.; Johnston, D. B. R.;
Christensen, B. G. J. Org. Chem. 1980, 45, 1135. Bateson, J. H.; Hickling,
R. I.; Roberts, P. M.; Smale, T. C.; Southgate, R. J. Chem. Soc., Chem.
Commun. 1980, 1084. Ona, H.; Uyeo, S.; Motakowa, K.; Yoshida, T. Chem.
Pharm. Bull. 1985, 33, 4346.
(12) Parker, W. L.; Rathnum, M. L.; Wells, J. S.; Trejo, W. H.; Principe,
P. A.; Sykes, R. B. J. Antibiot. 1982, 35, 653.
S0002-7863(96)03756-0 CCC: $14.00 © 1997 American Chemical Society

2310 J. Am. Chem. Soc., Vol. 119, No. 9, 1997
Communications to the Editor
Table 1. Carbapenam Cycloadducts Derived from Alkenes
Scheme 2
Scheme 3
requisite azomethine ylide precursor, oxazolidinone 7, is avail-
able in enantiomerically pure form.14 Exposure of 7 to
N-phenylmaleimide (MeCN, 100 °C) gave the endo-cycloadduct
8 in 25% yield, but unlike cycloadducts derived from 3a/b,
adduct 8 is produced in enantiomerically pure form; the C(6)
substituent serves both to maintain enantiomeric purity and to
control facial selectivity in the cycloaddition step (Scheme 3).
We have, however, observed that reactions involving 7 are less
efficient than those based on 3a/b which is attributed to the
sterically demanding silyl ether moiety.
In summary, we have realized a new strategy for the synthesis
of carbapenams and carbapenems founded on the generation
and exploitation of novel azomethine ylide reactivity.16 This
provides bicyclic â-lactams in a direct and convergent manner,
with the dipolar reactivity also offering potential in the
construction of other classes of â-lactam antibiotics. New
opportunities for exploiting this methodology to provide efficient
chemical and structural diversity are also now under evaluation.
a Determined by X-ray crystallographic analysis. b exo-Adduct pre-
dominates.8
Acknowledgment. We thank Dr. R. Galt for advice and EPSRC
and Zeneca Pharmaceuticals for financial support and acknowledge use
of the EPSRC’s Chemical Database Service at Daresbury.17
Table 2. ∆1-Carbapenem Cycloadducts Derived from Alkynes
Supporting Information Available: Spectroscopic and analytical
data for cycloadducts 4a-g, 5a-d, and 8 and ORTEP views and related
structural details of 4b and 4f (26 pages). See any current masthead
page for ordering and Internet access instructions.
JA9637560
(14) Synthesis of 7 was carried out by treatment of 4-chloroazetidinone
i (Endo, M. Can. J. Chem. 1987, 65, 2140) with potassium benzyl
diazomalonate followed by Rh(II)-mediated cyclization as described for a
closely related derivative.15
(15) Grabowski, E. J. J.; Reider, P. J. Eur. Pat. 78 026; Chem. Abstr.
1983, 99, 122171.
(16) While cycloadducts 4 and 5 are formally derived from azomethine
ylide 2, the nature of the 1,3-dipole has not been established. Concerted
decarboxylation to give an azomethine ylide (as with simple oxazolidinones5a)
may occur. However, given the strain associated with 3a/b, a pathway
involving initial ring opening (to give an N-acyliminium species) followed
by a proton transfer to provide the carboxylated variant ii of 2 cannot be
excluded.3 Cycloaddition may precede the decarboxylation event.
a Plus 10% of the regioisomer. b Plus 14% of the regioisomer.
Substituents at C(6) play a critical role in defining the
biological profile of carbapenems.13 Of these, the (R)-R-
hydroxyethyl unit (as in thienamycin) is important, and the
(13) Leanza, W. J.; Wildonger, K. L.; Hannah, J.; Shih, D. H.; Ratcliffe,
R. W.; Barash, L.; Walton, E.; Firestone, R. A.; Patel, G. F.; Kahan, F. M.;
Kahan, J. S.; Christensen, B. G. In Recent AdVances in the Chemistry of
â-Lactam Antibiotics; Gregory, G. I., Ed.; Royal Society of Chemistry:
London, 1981; Chapter 20, p 240. Christensen, B. G. J. Am. Chem. Soc.
1978, 100, 8004.
(17) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. J. Chem. Inf.
Comput. Sci. 1996, 36, 746.