S-Alkyl dithioformates as 1,3-dipolarophiles. Generation of C(2)-unsubstituted penems

Article abstract of DOI:10.1021/ol048991z

S-Alkyl dithioformates, generated by a cycloreversion process, react as 1,3-dipolarophiles with β-lactam-based azomethine ylids to provide, after (net) elimination of MeSH, C(2)-unsubstituted penems. The overall cycloreversion/cycloaddition sequence was a

Full text of DOI:10.1021/ol048991z

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2781-2783
S-Alkyl Dithioformates as
1,3-Dipolarophiles. Generation of
C(2)-Unsubstituted Penems
,†
Sylvie Sanchez,† John H. Bateson,‡ Peter J. O’Hanlon,‡ and Timothy Gallagher*
School of Chemistry, UniVersity of Bristol, Bristol, BS8 1TS, UK, and
GlaxoSmithKline, New Frontiers Science Park, Harlow, CM19 5AW, UK
t.gallagher@bristol.ac.uk
Received June 1, 2004
ABSTRACT
S-Alkyl dithioformates, generated by a cycloreversion process, react as 1,3-dipolarophiles with â-lactam-based azomethine ylids to provide,
after (net) elimination of MeSH, C(2)-unsubstituted penems. The overall cycloreversion/cycloaddition sequence was accelerated by microwave
irradiation.
Penems represent a continuing area of interest within the
â-lactam area.1 In particular, 6-exoalkylidene variants such
as 12a and 22b have attracted attention because of their potent
activity against class A and class C â-lactamases and
bacterial signal peptidase, respectively, profiles that makes
this group of C(2)-unsubstituted penems attractive both for
clinical application and as biological probes for â-lactamase
structure and function.3
resulting from the generation of â-lactam-based azomethine
ylid reactivity.4
We have previously described a versatile entry to bicyclic
â-lactams, including C(2)-substituted penams and penems
Oxazolidinone 3 (PNB ) 4-nitrobenzyl) reacts (via a
sequential ring cleavage to give azomethine ylid 4 and then
cycloaddition followed by decarboxylation)4b,d with thioke-
tones to provide racemic penams 5 (R1 ) R2 ) alkyl, aryl).
Use of dithiocarboxylates and trithiocarbonates as 1,3-
dipolarophiles leads, after net loss of MeSH, to C(2)-
† University of Bristol.
‡ GlaxoSmithKline.
(1) Georg, G. I., Ed. Bioorg. Med. Chem. Lett. (Symposia-in-Print no.
8), 1993, 3, 2159-2313. The Organic Chemistry of â-Lactams; Georg, G.
I., Ed.; VCH: New York, 1992. Perrone, E.; Franceschi, G. In Recent Prog.
Chem. Synth. Antibiot. Lukacs, G., Ohno. M., Eds.; Springer: Berlin, 1990;
Vol. 1, pp 613-703.
(2) (a) Osborne, N. F.; Atkins, R. J.; Broom, N. J. P.; Coulton, S.;
Harbridge, J. B.; Harris, M. A.; Stirling-Franc¸ois, I.; Walker, G. J. Chem.
Soc., Perkin Trans. 1 1994, 179-188. (b) Allsop, A.; Brooks, G.; Edwards,
P. D.; Kaura, A. C.; Southgate, R. J. Antibiotics 1996, 49, 921-928. Allsop,
A. E.; Brooks, G.; Bruton, G.; Coulton, S.; Edwards, P. D.; Hatton, I. K.;
Kaura, A. C.; McLean, S. D.; Pearson, N. D.; Smale, T. C.; Southgate, R.
Bioorg. Med. Chem. Lett. 1995, 5, 443-448.
(3) For an example of the use of a novel 6-exoalkylidene variant related
to 1 as a probe for the â-lactamase structure and mechanism of action using
X-ray crystallography, see: Nukaga, M.; Abe, T.; Venkatesan, A. M.;
Mansour, T. S.; Bonomo, R. A.; Knox, J. R. Biochemistry 2003, 42, 13152-
13159.
(4) (a) 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.
(b) Martel, S. R.; Planchenault, D.; Wisedale, R.; Gallagher, T.; Hales, N.
J. J. Chem. Soc., Chem. Commun. 1997, 1897. (c) Gallagher, T. J.
Heterocycl. Chem. 1999, 36, 1365-1354. (d) Brown, D.; Brown, G. A.;
Martel, S. R.; Planchenault, D.; Turmes, E.; Walsh, K. E.; Wisedale, R.;
Hales, N. J.; Fishwick, C. W. G.; Gallagher, T. J. Chem. Soc., Perkin Trans.
1 2001, 1270-1280. (e) Brown, G. A.; Martel, S. R.; Wisedale, R.;
Charmant, J. P. H.; Hales, N. J.; Fishwick, C. W. G.; Gallagher, T. J. Chem.
Soc., Perkin Trans. 1 2001, 1281-1289.
10.1021/ol048991z CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/02/2004

Scheme 1. Azomethine Ylid Strategy for the Synthesis of
Scheme 3. Dithioformates as 1,3-Dipolarophilesa
Penams and Penems
a Thermal vs microwave conditions studied: (a) (thermal) 8a,
MeCN, 2 days, 80 °C (19%); (b) (microwave) screw cap pressure
vessel, 8a, PhMe, 55 W, 1 h (76%) or 8a, emimPF6 (10 mol %),
55 W, PhMe, 1 h (56%); (c) (microwave) open vessel, 8a, PhMe,
200 W, 5 h (62%) or 8a, emimPF6 (10 mol %), 55 W, PhMe, 4 h
(40%); (d) (microwave) open vessel, 8b, PhMe, 200 W, 4 h, (45%);
(e) (microwave) screw cap pressure vessel, 8c, PhMe, emimPF6
(10 mol %), 55 W, 1 h, (45%).
substituted penems 6 (R1 ) alkyl, aryl, S-alkyl) (Scheme
1).5 The extension of the azomethine ylid strategy to the
synthesis of the C(2)-unsubstituted penem moiety (i.e., 6,
R1 ) H) that is associated with 1 and 2 is the focus of this
paper.
Achieving this objective required access to dithioformates
7 and an evaluation of the ability of these units to function
as effective 1,3-dipolarophiles. Only a very limited range of
dithioformates have been reported to date,6,7 and various
approaches to S-alkyl dithioformates 7 were evaluated
(Scheme 2).
7b and 7c were best obtained by direct thionation of the
corresponding thioformates 99 and 109 using Lawesson’s
reagent.10 In both cases, the target dithioformates 7b and 7c
were not isolated but were trapped in situ with cyclopenta-
diene to give cycloadducts 8b and 8c, respectively, in
moderate yields for this two-step sequence.11,12
Scheme 2. Generation and Trapping of Dithioformates
Cycloadducts 8a-c were especially attractive for our
purposes, representing a potentially controlled supply of the
requisite dithioformate (via 4 + 2 cycloreversion); the retro
Diels-Alder reaction provides an in situ source of dipo-
larophile that is compatible with release of the key azome-
thine ylid intermediate 4 from oxazolidinone 3.13
This strategy was validated, and thermolysis of 8a in the
presence of oxazolidinone 3 provided the racemic cycload-
duct 11a as a 2.5:1 mixture of exo and endo isomers (Scheme
3). The structure of exo-11a was confirmed by X-ray
crystallography (see Supporting Information).
However, this thermal process (conditions a) did require
2 days to go to completion and this only achieved a very
S-Methyl dithioformate 7a is available by reduction of CS2
with LiBEt3H followed by S-methylation.7 We found it most
convenient (see below) to trap 7a with cyclopentadiene to
give the corresponding cycloadduct 8a as a 1.5:1 mixture of
exo and endo isomers in 35% yield.8 The S-benzyl variants
(9) Bax, P. C.; Holsboer, D. H.; Van der Veek, A. P. M. Recl. TraV.
Chim. Pays-Bas 1971, 90, 562-567.
(10) S-Benzyl dithioformate (PhCH2SC(S)H) could not be prepared using
the reduction/S-alkylation strategy associated with 7a but was obtained by
direct thionation of the corresponding thioformate (PhCH2SC(O)H) using
Lawesson’s reagent. NMR (CDCl3) for PhCH2SC(S)H: δH 11.28; δC 216.8).
However, we were unable to isolate this product in an efficient manner,
but this served as a model for the preparation of 7b and 7c.
(11) 8b and 8c were obtained as a 0.6:1 and 1.7:1 mixture of exo and
endo isomers, respectively.
(5) (a) Planchenault, D.; Wisedale, R.; Gallagher, T.; Hales, N. J. J. Org.
Chem. 1997, 62, 3438. (b) Highly reactive thioaldehydes have also been
generated and trapped in situ: Brown, G. A.; Anderson, K. M.; Large, J.
M.; Planchenault, D.; Urban, D.; Hales, N. J.; Gallagher, T. J. Chem. Soc.,
Perkin Trans. 1 2001, 1897-1900.
(6) Block, E.; Aslam, M. Tetrahedron Lett. 1985, 26, 2259-2262.
(7) (a) Seyferth, D.; Womack, G. B. Organometallics 1984, 3, 1891-
1897. (b) Gandhi, T.; Nethaji, M.; Jagirdar, B. R. Inorg. Chem. 2003, 42,
4798-4800. Jagirdar et al.7b were able to isolate 7a by distillation. Block6
and Seyferth7a did not isolate this volatile component but trapped it in situ
as a Diels Alder cycloadduct and as an Fe-based coordination complex,
respectively.
(8) Similar exo and endo cycloadducts based on thioaldehydes have been
characterized previously. Kirby, G. W.; Lochead, A. W. J. Chem. Soc.,
Chem. Commun. 1983, 1325-1327. Vedejs, E.; Stults, J. S.; Wilde, R. G.
J. Am. Chem. Soc. 1988, 110, 5452-5460.
(12) One of the issues contributing to the yields obtained for 8b/c was
purification of the desired product from the residues associated with the
thionation step. Ley (Ley, S. V.; Leach, A. G.; Storer, R. I. J. Chem. Soc.,
Perkin Trans. 1 2001, 358-361) has reported a solid-phase variant of
Lawesson’s reagent. In our hands, this reagent worked well for the thionation
of amides, but we were unsuccessful in our attempts to thionate S-benzyl
thioformate (PhCH2SC(O)H); see ref 10.
(13) Mechanistic studies provide evidence that oxazolidinone 3 is in
equilibrium with the carboxylated azomethine ylid 4. This pathway provides
an equilibrium concentration of 4, and we have exploited this to trap highly
reactive and short-lived 1,3-dipolarophiles.5b
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Org. Lett., Vol. 6, No. 16, 2004

Scheme 4. Generation of a C(2)-Unsubstituted Penem
Scheme 5. Extension to a C(6)-Substituted Varianta
modest 19% yield of cycloadduct 11a.14 This hurdle was
overcome by carrying out the fragmentation of 8a and
subsequent 1,3-dipolar cycloaddition step with microwave
irradiation (conditions b and c). Using toluene as a solvent,
a 76% yield of the target cycloadduct 11a was isolated
following irradiation of 3 and 8a.15 Cycloadduct 11a was
obtained in 56% yield when the same reaction was carried
out for 1 h using 10 mol % of an ionic liquid (emimPF6) as
an additive.16 This reaction was carried out using both sealed
and open vessel conditions. On the basis of other observa-
tions,14 microwave irradiation is expected to accelerate the
retro Diels-Alder reaction of 8a but may also promote the
1,3-dipolar cycloaddition step between 4 and 7a. Signifi-
cantly, we have observed considerable rate and yield
increases when 3 has been reacted with stable dipolarophiles,
e.g., N-phenyl maleimide, under the same microwave condi-
tions.
A similar cycloreversion/1,3-dipolar cycloaddition se-
quence was also achieved using cyclopentadiene adducts 8b
and 8c to provide the bicyclic â-lactams 11b and 11c
(Scheme 3).
Elaboration of 11a to the corresponding C(2)-unsubstituted
penem was carried out by S-oxidation followed by base
treatment to give the C(2)-unsubstituted penem 12 in 70%
yield (Scheme 4). The base-mediated elimination step was
also examined under microwave radiation conditions but
provided 12 in a lowered yield (40%).
a Microwave conditions employed: (a) screw cap pressure vessel,
8c, PhMe, 55 W, 1 h, 25%; (b) open vessel, 8c, PhMe, 200 W, 4
h, 25%.
the C(6)-O-silylated hydroxyethyl â-lactam-based oxazoli-
dinone 1317 reacted with 8c to give the corresponding dipolar
cycloadduct 14c in 25% yield. Subsequent oxidation and
elimination proceeded to give the C(2)-unsubstituted penem
15 in 40% yield (Scheme 5).18
In summary, simple S-alkyl dithioformates 7a-c are viable
1,3-dipolarophiles, which can be released in situ, reacting
with â-lactam-based oxazolidinones 3 and 13 to provide, after
oxidation and elimination, C(2)-unsubstituted penems, rep-
resented by 12 and 15. Importantly, the overall cyclorever-
sion/dipolar cycloaddition sequence (e.g., 3 + 8 f 11,
Scheme 3) was accelerated very significantly by microwave
irradiation.
Acknowledgment. We thank GSK for financial support
and Anob Kantacha for crystallographic analysis of exo-11a,
and we acknowledge the support provided by the EPSRC
Mass Spectrometry Service Centre at the University of
Swansea.
We were interested in extending the processes outlined in
Schemes 3 and 4 to a C(6)-substituted penem. In the event,
Supporting Information Available: Experimental and
characterization data for all new compounds and crystal-
lographic details for exo-11a. This material is available free
of charge via the Internet at http://pubs.acs.org.
(14) We tried to trap 7a (generated by reduction of CS2 and S-methylation
as outlined in Scheme 2) directly using oxazolidinone 3 and thereby avoiding
the need to prepare 8a. Crude 7a (in THF) was added to oxazolidinone 3
(MeCN, 80 °C) and cycloadduct 11a was isolated in 15% yield. However,
this yield was obtained after a reaction time of only 1 h, indicating the
high inherent reactivity of 7a as a 1,3-dipolarophile. This observation
suggests that cycloreversion of 8 is rate limiting.
OL048991Z
(15) We used the CEM Discover system as the microwave reactor.
Reactions were carried out on 0.25 mmol scale in a screw cap pressure
vessel in a PhMe solution in two stages. Stage 1: 150 W, 5 min, max temp
150 °C. Stage 2: 55 W, 60 min, max temp 200 °C. Attempts to accelerate
the direct reaction of 7a with 3 (see ref 14) under microwave conditions
led only to decomposition. For recent disclosures of microwave-assisted
1,3-dipolar cycloadditions, see: Cheng, Q.; Zhang, W.; Tagami, Y.; Oritani,
T. J. Chem. Soc., Perkin Trans. 1 2001, 452-456. Wilson, N. S.; Sarko,
C. R.; Roth, G. P. Tetrahedron Lett. 2001, 42, 8939-8941. Bashiardes,
G.; Safir, I.; Mohamed, A. S.; Barbot, F.; Laduranty, J. Org. Lett. 2003, 5,
4915-4918.
(17) See ref 4a and: Grabowski, E. J. J.; Reider, P. J. Eur. Pat. 78026;
Chem. Abstr. 1983, 99, 122171. Oxazolidinone 13 is not readily amenable
to purification. The yield of 14c observed then reflects the preparation of
13 as well as the cycloaddition step. We have noted4a that the presence of
the C(6)-substituent does reduce the efficiency of the cycloaddition reactions
as compared to reactions involving 3.
(18) Attempts to improve the yield of cycloadducts derived from 13 were
investigated. For example, cycloadduct 14a was generated in a one-pot
process. This involved carrying out the initial diazo insertion step under
microwave-assisted conditions, which were significantly faster (10 min vs
5 h) than without microwave irradiation, and 8a was added directly to crude
13 and subjected to our standard microwave cycloaddition conditions. This
provided 14a but in a low (17%) yield.
(16) Broadly similar yields and exo/endo ratios were observed when these
reactions were carried out (with and without ionic liquid) on a 1 mmol
scale under “open vessel” conditions (PhMe, 200 W, 4 h).
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