A direct and convergent approach to penams and penems

Full text of DOI:10.1021/jo962367l

3438
J . Org. Chem. 1997, 62, 3438-3439
Sch em e 1
A Dir ect a n d Con ver gen t Ap p r oa ch to
P en a m s a n d P en em s
Denis Planchenault,† Richard Wisedale,†
Timothy Gallagher,*,† and Neil J . Hales*,‡
School of Chemistry, University of Bristol, Bristol BS8 1TS,
U.K., and Zeneca Pharmaceuticals, Mereside, Alderley Park,
Macclesfield SK10 4TG, U.K.
Received December 18, 1996
The sulfur-containing bicyclic â-lactams,1 the naturally-
occuring penams and the penems, a group of synthetic
variants first described by Woodward,2 have attracted a
very substantial level of interest both for their potential
as antibiotics and, more recently, as inhibitors of serine
proteases.3 Variation of both the structure and pattern
of substitution associated with the five-membered ring
plays an important role in defining biological profile, and
penams 1, together with penems 2 and thiaclavams 3 (the
exocyclic penem isomer), are important target systems.
Ta ble 1
In this paper, we present concise and flexible routes
to all three subgroups 1-3 of bicyclic sulfur-based
â-lactams. The central feature of the chemistry described
revolves around application of a versatile range of thio-
carbonyl derivatives as 1,3-dipolarophiles4 toward â-lac-
tam-based azomethine ylides, which allows the penam/
penem skeleton to be assembled in a single step.
a
The readily available oxazolidinone 45 provides a
convenient source of reactivity that is, in essence, equiva-
lent to the stabilized azomethine ylide 5.6 Thermolysis
of 4 (MeCN, 80 °C, 80 h) in the presence of the appropri-
ate thioketone provided the 2,2-dialkyl and 2,2-diaryl
penams 6a and 6b directly. Using dimethyl trithiocar-
bonate and dithiocarboxylates as the dipolarophile com-
All products shown are racemic. Isolated as a 4:1 mixture of
diastereoisomers.
ponent gave, under similar reaction conditions (48-72
h), cycloadducts 7a -d (Scheme 1). The range of products
available, which are all racemic, are presented in Table
1, and in all cases, only the regioisomer shown was
detected.7
Conversion of the more highly functionalized cycload-
ducts 7a -d , each carrying a potential leaving group at
C(2), to the corresponding penem was straightforward
(Scheme 2). Oxidation of 7a gave a diastereomeric
mixture of sulfoxides that underwent facile elimination
on warming to room temperature to give the 2-(meth-
ylthio) penem 8a .8 Under similar conditions, cycload-
ducts 7b-d provided the 2-phenyl,2b 2-methy,l2bc,9 and
2-ethyl10 penems 8b-d , respectively. However, in these
latter cases a base (Et3N) was required to complete a two-
step elimination sequence, the overall yields of which
have not yet been optimized.
† University of Bristol.
‡ Zeneca Pharmaceuticals.
(1) Chemistry and Biology of â-Lactam Antibiotics; Morin, R. B.,
Gorman, M., Eds.; Academic Press: New York, 1982; Vols. 1-3.
Du¨rchheimer, W.; Blumbach, J .; Lattrell, R.; Scheunemann, K. H.
Angew. Chem., Int. Ed. Engl. 1985, 24, 180. Recent Advances in the
Chemistry and Biology of â-Lactams and â-Lactam Antibiotics; Georg,
G. I., Ed.; VCH: New York, 1993.
(2) (a) Ernest, I.; Gosteli, J .; Greengrass, C. W.; Holick, W.; J ackman,
D. E.; Pfaendler, H. P.; Woodward, R. B. J . Am. Chem. Soc. 1978, 100,
8214. (b) Lang, M.; Prasad, K.; Holick, W.; Gosteli, J .; Ernest, I.;
Woodward, R. B. J . Am. Chem. Soc. 1979, 101, 6296. (c) Ernest, I.;
Gosteli, J .; Woodward, R. B. J . Am. Chem. Soc. 1979, 101, 6301. (d)
Pfaendler, H. R.; Gosteli, J .; Woodward, R. B. J . Am. Chem. Soc. 1979,
101, 6306.
(3) Recent work in this area of â-lactam chemistry has been
presented: Bioorg. Med. Chem. Lett. (Symposia-in-Print No. 8) 1993,
3, 2159-2313. The penam numbering scheme, see 1, is used through-
out this paper.
(4) (a) Campaigne, E. In The Chemistry of the Carbonyl Group; Patai,
S., Ed.; Wiley: New York, 1966; p 918. (b) Schaumann, E. In The
Chemistry of Double-Bonded Functional Groups; Patai, S., Ed.;
Wiley: New York, 1989; Vol. 2, p 1270. (c) Huisgen, R.; Langhals, E.
Tetrahedron Lett. 1989, 30, 5369.
(5) Oxazolidinone 4 is most readily obtained from clavulanic acid,
a component of Augmentin (SB Pharmaceuticals): (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, 102 313. For other approaches to the synthesis of oxazolidinone 4
see: Bentley, P. H.; Berry, P. D.; Brooks, G.; Gilpin, M. L.; Hunt, E.;
Zomaya, I. I. J . Chem. Soc., Chem. Commun. 1977, 748. Campbell, M.
M.; J asys, V. J . Heterocycles 1981, 16, 1487.
With the 2-alkyl variants 7c and 7d , the elimination
process has a regiochemical option that can be exercised
(6) For the application of azomethine ylide reactivity to the synthesis
of carbapenams and carbapenems, see: Martel, S. R.; Wisedale, R.;
Gallagher, T.; Hall, L. D.; Mahon, M. F.; Bradbury, R. H.; Hales, N. J .
J . Am. Chem. Soc. 1997, 119, 2309. While the precise nature of the
1,3-dipolar species involved in Scheme 1 has not been determined,
azomethine ylide 5 offers a convenient way to rationalize the products
available.
(7) The relative (and thermodynamically more stable) configuration
between C(3) and C(5) of adducts 6a ,b, 7a -d , and 11 (penicillin
stereochemistry) is based on chemical shift comparisons to those
observed in the diastereomeric series and on the absence of a long-
range coupling (1-1.5 Hz) between H(3) and H(6â). Smale, T. C.;
Southgate, R. J . Chem. Soc., Perkin Trans. 1 1985, 2235. Wolfe, S.;
Sterzycki, R. Z. Can. J . Chem. 1987, 65, 26. Barrett, A. G. M.;
Sakadarat, S. J . Org. Chem. 1990, 55, 5110.
S0022-3263(96)02367-5 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 11, 1997 3439
Sch em e 2a
Sch em e 4
(MeCN, 110 °C, sealed tube, 24 h) of the enantiomerically
pure oxazolidinone 106 in the presence of dimethyl
trithiocarbonate gave cycloadduct 11 in 20% isolated
yield (Scheme 4); the presence of a bulky residue at C(6)
does reduce the efficiency of the cycloaddition step, and
this problem is being addressed. However, it is impor-
tant to recognize that the C(6) substituent present in 10
serves not only to deliver enantiomeric integrity to adduct
11 but also controls facial selectivity in the cycloaddition
step.
a
Key: 7a , (a) m-CPBA, CH2Cl2, 0 °C to rt; 7b-d , (b) (i) m-CPBA,
CH2Cl2, 0 °C to rt, (ii) Et3N, CH2Cl2, reflux.
Sch em e 3a
In summary, the azomethine ylide strategy for as-
sembling bicyclic â-lactams constitutes a simple, versa-
tile, and above all, direct synthesis of penams and
penems. This chemistry permits access to a range of
targets, some of which are difficult to prepare by con-
ventional methods, and we are currently exploring ways
of increasing the efficiency and diversity associated with
the processes outlined in this paper.
a
Key: (a) m-CPBA, CH2Cl2, 0 °C to rt; (b) MeCN, 80 °C.
(Scheme 3).11 Oxidation of 7c and 7d (m-CPBA) followed
by thermolysis (MeCN, 80 °C) of the resulting mixture
of diastereomeric sulfoxides gave the thiaclavams 9c and
9d , respectively; in the case of 9d only the (Z)-isomer was
observed.12 In addition, isomerization (Et3N, CH2Cl2) of
the exo-isomer 9c to the thermodynamically more stable
penem 8c has also been accomplished in 95% yield.13,14
Penems incorporating the (R)-R-hydroxyethyl substitu-
ent at C(6) are also important targets,3 and thermolysis
Ack n ow led gm en t. We thank The Royal Society,
The Swiss National Science Foundation, EPSRC, and
Zeneca Pharmaceuticals for financial support.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
procedures and spectroscopic and physical data are available
for 6a ,b, 7a -d , 8a -d , 9c,d , and 11 (5 pages).
(8) (a) Oida, S.; Yoshida, A.; Hayashi, T.; Takeda, N.; Ohki, E. Chem.
Pharm. Bull. 1980, 28, 3232. (b) Oida, S.; Yoshida, A.; Hayashi, T.;
Nakayama, E.; Sato, S.; Ohki, E. Tetrahedron Lett. 1980, 619.
(9) (a) Beels, C. M. D.; Abu-Rabie, M. S.; Murray-Rust, P.; Murray-
Rust, J . J . Chem. Soc., Chem. Commun. 1979, 665. (b) Henderson, A.;
J ohnson, G.; Moore, K. W.; Ross, B. C. J . Chem. Soc., Chem. Commun.
1982, 809. (c) Yoshida, A.; Hayashi, T.; Takeda, N.; Oida, S.; Ohki, E.
Chem. Pharm. Bull. 1983, 31, 768.
J O962367L
(13) In reactions of 7a -d , no evidence for oxidation of the endocyclic
sulfur atom, which is presumably less reactive for both steric and
electronic reasons, has been detected. For relatived observations:
Hanessian, S.; Bedeschi, A.; Battistini, C.; Mongelli, N. J . Am. Chem.
Soc. 1985, 107, 1438. Fahey, J . L.; Lange, B. C.; Van der Veen, J . M.;
Young, G. R.; Bose, A. K. J . Chem. Soc., Perkin Trans. 1 1977, 1117.
Chemoselective oxidation of 2-thio-substituted penems has also been
reported: Girijavallabhan, V. M.; McCombie, S. W.; Pinto, P.; Lin, S.-
I.; Versace, R. J . Chem. Soc., Chem. Commun. 1987, 691. Krahmwer-
Seifert, U.; Emmer, G. Heterocycles 1984, 22, 375.
(14) The relative configuration between C(3) and C(5) of thiaclavams
9c and 9d (penicillin stereochemistry) is based on comparison with
data available in the literature.11 Assignment of (Z)-geometry of 9d is
based on NOE experiments involving the alkenyl proton and H(3) and
isomerization of 9d to the endo isomer 8d took place under basic
conditions. However, this is a slower and less efficient reaction than
was observed for the formation of 8c from 9c.
(10) Cherry, P. C.; Newall, C. E.; Watson, N. S. J . Chem. Soc., Chem.
Commun. 1979, 663.
(11) For alternative syntheses of thiaclavams (exocyclic penems),
see: (a) Cherry, P. C.; Evans, D. N.; Watson, N. S.; Murray-Rust, P.;
Murray-Rust, J . Tetrahedron Lett. 1980, 561. (b) Baldwin, J . E.;
Forrest, A. K.; Ko, S.; Sheppard, L. N. J . Chem. Soc., Chem. Commun.
1987, 81. (c) Tanaka, H.; Kameyama, Y.; Kosaka, A.; Yamauchi, T.;
Torii, S. Tetrahedron Lett. 1991, 32, 7445. (d) Tanaka, H.; Kameyama,
Y.; Yamauchi, T.; Torii, S. J . Chem. Soc., Chem. Commun. 1992, 1793.
(e) Tanaka, H.; Sumida, S.; Sorajo, K.; Torii, S. J . Chem. Soc., Chem.
Commun. 1994, 1461.
(12) Isomerization of penems to thiaclavams and structural
assignment: Douglas, J . L.; Martel, A.; Caron, G.; Me´nard, M.; Silveira,
L.; Clardy, J . Can. J . Chem. 1984, 62, 2282. See also ref 11b.