Coupling reactions of cephalosporin sulfones: A stable 3-stannylated cephem

Article abstract of DOI:10.1021/ol016142v

matrix presented The first stable 3-metalated cephalosporin is reported and shown to be an excellent synthetic precursor to a number of prospective β-lactamase inhibitors.

Full text of DOI:10.1021/ol016142v

ORGANIC
LETTERS
2001
Vol. 3, No. 19
2953-2956
Coupling Reactions of Cephalosporin
Sulfones: A Stable 3-Stannylated
Cephem
John D. Buynak,* Lakshminarayana Vogeti, and Hansong Chen
Department of Chemistry, Southern Methodist UniVersity, Dallas, Texas 75275-0314
jbuynak@mail.smu.edu
Received May 20, 2001
ABSTRACT
The first stable 3-metalated cephalosporin is reported and shown to be an excellent synthetic precursor to a number of prospective â-lactamase
inhibitors.
One highly effective method for countering antibiotic-
resistant microorganisms is the co-administration of an
antibiotic and a â-lactamase inhibitor.1 â-Lactamase repre-
sents a collection of bacterial enzymes (classes A, B, C, and
D) that effectively hydrolyze â-lactam antibiotics. Histori-
cally, the most clinically important of these were the plasmid-
mediated class A enzymes.2 However, in recent years,
bacterial resistance mediated by class B, C, and D enzymes
has become increasingly significant.3 Current commercial
inhibitors target only class A â-lactamases.1 Our group has
recently described classes of compounds that simultaneously
inhibit both class A and class C â-lactamases.4 We have
designed new inhibitors both of the penicillin and of the
cephalosporin skeleton. Unlike the corresponding penicillin
and cephalosporin antibiotics, however, these new com-
pounds have the sulfur in the sulfone oxidation state and
have an alkylidene side chain in place of the more common
acylamido side chain at C6 (penam) or C7 (cephem). Some
examples are shown in Figure 1.
(1) Maiti, S. N.; Phillips, O. A.; Micetich, R. G.; Livermore, D. M. Curr.
Med. Chem. 1998, 5, 441-456.
(2) Bush, K.; Mobashery, S. Resolving the Antibiotic Paradox. AdV. Exp.
Med. Biol. 1998, 456, 71-98.
Figure 1. Representative â-lactamase inhibitors containing an
R-alkylidene-â-lactam substructure.
(3) Medeiros, A. A. Clin. Infect. Dis. 1997, 24 (Suppl. 1), S19-S45.
(4) a) Buynak, J. D.; Wu, K.; Bachmann, B.; Khasnis, D.; Hua, L.;
Nguyen, H. K.; Carver, C. L. J. Med. Chem. 1995, 38, 1022-1034. (b)
Buynak, J. D.; Rao, A. S.; Doppalapudi, V. R.; Adam, G.; Nidamarthy, S.
D. Bioorg. Med. Chem. Lett. 1999, 9, 1997-2002. (c) Buynak, J. D.;
Doppalapudi, V. R.; Rao, A. S.; Nidamarthy, S. D.; Adam, G. Bioorg. Med.
Chem. Lett. 2000, 10, 847-851. (d) Buynak, J. D.; Doppalapudi, V. R.;
Adam, G. Bioorg. Med. Chem. Lett. 2000, 10, 853-857.
We have recently reported crystallographic evidence that
these altered structural features are mechanistically important
to the inhibition, leading to the production of a stabilized
10.1021/ol016142v CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/30/2001

acyl-enzyme after reaction with the active site serine hy-
droxyl as shown in Scheme 1.5
cephalosporin. The commercially available7 3-hydroxy-
cephem 6 seemed a promising precursor for the generation
of such materials. Reasoning that it was probably not possible
to subject a reactive C3 triflate to the reaction conditions
needed to prepare the appropriate C7 alkylidene analogues,
we initially attempted to use O-protected derivatives. How-
ever, we found that such intermediates were prone to double
bond isomerization (i.e., migration of the double bond from
the ∆-3,4 position to the ∆-2,3 position), and we settled on
the 3-halocephalosporin sulfones as potential alternatives.
Our synthesis of key precursors 11 and 12 is shown in
Scheme 3.
Scheme 1. Mechanistic Pathway Leading to a Stabilized Acyl
Enzyme Intermediate
Scheme 3. New Synthetic Route Employing
3-Halo-7-alkylidenecephem Sulfonesa
In the process of preparing these new inhibitors, it became
necessary for us to devise methodology for the synthesis of
C3 functionalized cephalosporins. In particular, we desired
a method for the preparation of a structurally diverse
collection of side chains from an appropriate late-stage C3-
substituted synthetic precursor. As shown in Scheme 2, we
a Reagents: (i) Tf2O, DIPEA, DCM -78 °C, 85%; (ii) LiBr or
LiI (2.5 equiv), THF, rt 36 h, 88% or 72%; (iii) PCl5, py, DCM/
MeOH, 0 °C, 74%; (iv) i-prONO, cat. TFA, EtOAc; (v) propylene
oxide, cat. Rh2(OOct)4, C6H6; (vi) R-py-CH2-PPh3Cl, KO-t-Bu,
THF/DCM (30% overall for steps iv, v, and vi); (vii) MCPBA (2.5
equiv), DCM, rt, 30 min, 90%; (viii) R′3SnR, cat. Pd2(dba)3, DMF
or THF (see Table 1).
Scheme 2. Previous Route to 3-Substituted
7-Alkylidenecephem Sulfones
Thus the enol 6 was readily converted to the corresponding
triflate using triflic anhydride in the presence of Hunig’s base.
Subsequent treatment of the triflate with anhydrous LiX in
dry THF produced the corresponding vinyl halides in good
yield. Removal of the phenylacetyl group using PCl5
produced the corresponding amines 7 and 8, which were then
converted to the 7-oxocephalosporins 9 and 10, respectively,
using our reported procedure.8 These ketones were then used
directly in the following Wittig reaction, and the alkylidene
products were selectively oxidized to the corresponding
sulfones 11 and 12.
As demonstrated in Table 1, the vinyl iodide 12, in
particular, was an excellent precursor to a number of
(previously unavailable) C3-functionalized 7-(Z-pyridyl-
methylidene)cephalosporin sulfones, 13. As shown by entry
4, we were able to prepare the benzhydryl ester of the 3′Z
stereoisomer of our highly potent inhibitor 2 from the 3Z-
had earlier reported a route to such compounds employing
aldehyde 5.4d However, the suitability of this earlier route
to the preparation of libraries of inhibitors is limited by both
the unexpectedly low reactivity of aldehyde 5 and the need
for the use of a separate Wittig reagent in the preparation of
each new inhibitor.
Farina had earlier reported the synthesis of substituted
cephalosporins through a versatile Stille-coupling of the
3-position cephalosporin triflates with organostannanes.6
Effective utilization of such a catalytic coupling in the
generation of new â-lactamase inhibitors in this series of
molecules would require an appropriately C3 functionalized
(5) a) Crichlow, G. V.; Nukaga, M.; Buynak, J. D.; Knox, J. R.
Biochemistry 2001, 40, 6233-6239. (b) Strynadka, N.; Buynak, J. D.
Unpublished results.
(7) Otsuka Chemical Co.
(6) Farina, V.; Baker, S.; Sapino, C. Tetrahedron Lett. 1988, 29, 6043-
6046. (b) Farina, V.; Baker, S. R.; Hauck, S. I. J. Org. Chem. 1989, 54,
4962-4966.
(8) Buynak, J. D.; Rao, A. S.; Nidamarthy, S. D. Tetrahedron Lett. 1998,
39, 4945-4946. Ketones 9 and 10 are not purified because of their
instability.
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Org. Lett., Vol. 3, No. 19, 2001

trialkyltin esters may be of use in transfer of alkyl groups to
other vinylic halides.
Table 1. Coupling Reactions of 11 and 12 with
Most importantly, coupling of iodide 12 with hexameth-
yldistannane produced trimethylstannane 13e as shown in
entry 6; 13e represents the first stable C3 metalated cephem.11
As shown in Table 2, this stannane is a versatile precursor
Organostannanes
Table 2. Coupling Reactions of Stannane 13e with
Organohalides
to a number of new cephalosporins. Unlike the vinyl iodide
12 and the C3 cephalosporin triflates, which both must be
coupled with organostannanes, the cephalosporin stannane
13e is suitable for the preparation of a library of prospective
inhibitors through coupling with the large number of com-
mercially available vinyl- and arylhalides.
As shown in Scheme 5, an initial attempt to reduce iodide
12 with tributyltin hydride unexpectely resulted in formation
of dimer 16. We believe that this product was produced
(trimethylstanyl)propenamide 15, which is itself prepared
from 3Z-iodopropenamide9 as shown in Scheme 4.
Scheme 5. Reaction of 12 with Tributyltin Hydride
Scheme 4. Synthesis of 3Z-(Trimethylstannyl)-propenamide
(15)a
a Reagents: (i) LiI, CH3COOH, 90 °C, 8 h, 85%; (ii) (Me3Sn)2,
10 mol % Pd2(dba)3, DMF, rt, 1 h, 59%.
Second, as shown in entry 7, attempted transfer of oxygen
from tributyltin acetate instead resulted in the unusually facile
transfer of a butyl group from tin to carbon. This result
contrasts with a recent report that tributyltin acetate can be
an effective reagent for the transfer of acetate to aryl
halides.10 Given the relative ease of migration of the alkyl
group in the present case, our results indicate that such
(9) Ma, S.; Lu, X.; Li, Z. J. Org. Chem. 1992, 57, 709-713.
Org. Lett., Vol. 3, No. 19, 2001
2955

through the intermediacy of the 3-(tributylstanylated)cephem
17, which itself was likely produced as a result of conversion
of the tributyltin hydride to hexabutyldistannane under the
influence of the catalyst as shown.12 In confirmation of this
mechanism, we observed that the dimer 16 could also be
synthesized through direct coupling of iodide 12 and 3-(tri-
methylstannanyl)cephem 13e.
tion of 3-fluoro cephems has previously been possible only
in extremely low (<5%) yield.15
In summary, we have employed organotin reagents to
facilitate the preparation of new cephalosporins. In the
process, we have described a number of novel and potentially
useful synthetic transformations. These include the prepara-
tion of Z-vinylstannane 15 and its coupling with 12 to
stereospecifically produce 13d, the rapid transfer of the butyl
group from tributyltin acetate, and the preparation of the first
3-stannylcephem, 13e. This stannylcephem, in turn, was
extremely useful in preparing other, previously unavailable,
cephalosporins, including cephalosporin dimer 16 and
3-fluorinated cephalosporin 13j. Stannylcephem 13e appears
well suited to the preparation of cephalosporin-derived
â-lactamase inhibitor libraries.
Stannane 13e also proved to be synthetically useful in the
preparation of the 3-fluorocephem 13j as shown in Scheme
6. Using conditions previously described by Tius in the
Scheme 6. Fluorination of 13e
Acknowledgment. We thank the Robert A. Welch
Foundation, the Texas Higher Education Coordinating Board,
and the Petroleum Research Fund, administered by the
American Chemical Society, for support of this research. We
also thank Otsuka Chemical Co. for a generous gift of
compound 6.
Supporting Information Available: Experimental pro-
cedures for the preparation of 13d and 13e and spectral data
for compounds 12, 13b-h, 13j, 13k, and 16. This material
is available free of charge via the Internet at http://pubs.acs.org.
preparation of unrelated vinyl fluorides,13 treatment of 13e
with XeF2 in the presence of silver triflate afforded fluoride
13j (42%) and reduced compound 13k (28%).14 The prepara-
OL016142V
(10) Forngren, T.; Andersson, Y.; Lamm, B.; Langstrom, B. Acta Chem.
Scand. 1998, 52, 475-479.
(13) a) Tius, M.; Kawakami, J. K. Synlett 1993, 207-208. (b) Tius, M.
A.; Kawakami, J. K. Tetrahedron 1995, 3997-4010.
(14) The production of 13k is presumably caused by adventitious amounts
of HF in the reaction.
(15) Muller, B.; Peter, H.; Schneider, P.; Bickel, H. HelV. Chim. Acta
1975, 58, 2469-2473.
(11) A very recent report has described a C3-metalated cephem as a
hypothetical intermediate in a catalytic process: Tanaka, H.; Zhao, J.;
Kumase, H. J. Org. Chem. 2001, 66, 570-577.
(12) Al-Allaf, T. A. K.; Kobs, U.; Neumann, W. P. J. Organomet. Chem.
1989, 373, 29-35.
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Org. Lett., Vol. 3, No. 19, 2001