Process for the preparation of penems

An efficient, multistep process for the synthesis of 6-(1-hydroxyethyl) 2-thio-substituted penem antibiotics from 2-[4R-(triphenylmethy lthio)-3S-(1S-(dimethyl-t-butylsilyloxy)ethyl)-2-azetidon-1-yl]acetic acid esters.

BACKGROUND OF THE INVENTION 
The present invention is directed to an efficient multistep process for the 
preparation of compounds of the formula (6), as shown in Scheme 3 below; 
and to certain of the intermediates, specified by the general formula (8) 
below, which find special value in this multistep process. The compounds 
of the formula (6) are useful as precursors of the various penem 
antibiotics specified by the formula (7), also shown in Scheme 3 below. 
Heretofore, a number of processes have been reported for the preparation of 
penem antibiotics substituted at the 2-position with a thioether group, 
--SR.sup.2, as found in the formulas (6) and (7) below. Two of the more 
general of these processes are illustrated in Schemes 1 and 2. In Scheme 
1, an alternative intermediate to the silver salt of the mercaptan is the 
mercaptan itself, reportedly obtained by Zn/H.sup.+ reduction of the 
tritylated thiol (Girijavallabhan et al., J. Antibiotics 39, 1182 (1986); 
U.S. Pat. No. 4,584,133). 
##STR1## 
References: 
Girijavallabhan et al., J. Antibotics 39, 1182 (1986); U.S. Pat. No. 
4,584,133, wherein 
##STR2## 
R.sup.e =--CH.sub.2 CH.dbd.CH.sub.2, R.sup.f .dbd.beta-naphthyl, R.sup.g 
.dbd.C.sub.2 H.sub.5, 
##STR3## 
etc., X.sup.a .dbd.leaving group. 
DiNinno et al., U.S. Pat. No. 4,610,823 (1986); Leanza et al., Tetrahedron 
39, 2505 (1983), wherein 
##STR4## 
R.sup.e =--CH.sub.2 CH.dbd.CH.sub.2 or --CH.sub.2 .phi.NO.sub.2,R.sup.f 
.dbd.C.sub.6 H.sub.5, R.sup.g =alkyl, aralkyl, etc., Xk.sup.a =leaving 
group. 
See also Girijavallabhan et al., U.S. Pat. Nos. 4,443,373 and 4,530,793 for 
an altermative synthesis of the components (E), wherein R.sup.d is 
CH.sub.3 CHOH-- and R.sup.e is CH.sub.2 CH.dbd.CH.sub.2 or CH.sub.2 
CH.sub.2 OSi(CH.sub.3).sub.3, from the compound (A). 
##STR5## 
Reference 
DiNinnio et al., Tetrahedon Letters 23, 3535 (1982), wherein: 
##STR6## 
R.sup.b =--CH.sub.2 CH.dbd.CH.sub.2, R.sup.c =--CH(CH.sub.3).sub.2, 
--CH.sub.2 CH.sub.2 OH, etc. 
*These steps assumed on the basis of the footnote reference to U.K. 
2,042,514. 
See also Ganguly et al., J. Antimicrob. Chemo. 9, Suppl. Cl, (1982) using 
several similar steps in a different sequence. 
Ghosez et al., Tetrahedron Letters 39, 2493 (1983) have described the 
synthesis of 2-oxopenams from penicillin G and the conversion of same to 
2-alkoxypenem derivatives of penicillin G. Japanese Kokai 84-115,788 
(Chem. Abst. 96:34979y, Derwent Abst. 78700D) similarly describes 
conversion of hydroxy and carboxy protected 6-(1-hydroxyethyl)-2-oxopenams 
to the corresponding alkoxy analogs. 
Additional, alternative methods for the synthesis of penems include those 
described by Dextraze et al., U.S. Pat. No. 4,769,451; Pirie et al., U.S. 
Pat. No. 4,751,297; Volkmann et al., U.S. Pat. No. 4,739,047; Brighty, 
U.S. Pat. No. 4,695,626; and Brighty et al., U.S. Pat. No. 4,782,145. 
There have been numerous reports in the literature concerning the 
conversion of 2-oxo-carbapenams and 3-oxocephams to 
2-(alkylthio)-2-carbapenems and 3-alkylthio-3-cephems via enolic esters: 
##STR7## 
where R.sup.h is a conventional carboxy protecting group, R.sup.i is, for 
example, diphenyl- or diethylphosphoryl, tosyl, mesyl, or 
trifluoromethanesulfonyl. See for example Sletzinger et al., Tetrahedron 
Letters 21, 4221 (1980); Andrus et al., J. Am. Chem. Soc. 106, 1808 
(1984); Evans et al., Tetrahedron Letters 26, 3787 (1985), and 27, 3119 
(1986) and U.S. Pat. No. 4,073,737; Ratcliffe et al., 21, 31 (1980); ibid. 
1979, 4947; Salzmann et al., ibid. 21, 1193 (1980); Melillo et al., ibid. 
21, 2783 (1980); Iimori et al., and J. Am. Chem. Soc. 105, 1659 (1983). 
However, the chemistry observed with these carbapenem ketone groups has 
been generally inapplicable to the thiolactone carbonyl group of 
2-oxopenems. For example, the reaction of mesyl chloride or mesyl 
anhydride with a compound of the type (4) below produces a compound of the 
type 
##STR8## 
while either tosyl chloride or triflyl chloride and a compound of the type 
(4) produces a compound of the type: 
##STR9## 
More recently it was specifically reported in published European patent 
application No. 257,419 that a compound of the type (4) below was reacted 
with diphenylphosphoryl chloride to form the diphenylphosphoryl ester in 
situ, which was in turn reacted with a phenol to form a compound of the 
type 
##STR10## 
in very low yield. This application offers no specific support for the 
asserted broader use of other potential enol ester forming reagents such 
as triflyl chloride, which is in fact a known chlorinating agent, not a 
triflate ester forming reagent (vide supra; and Hakimelahi et al., 
Tetrahedron Letters, 1979, pp. 3643-3644). 
SUMMARY OF THE INVENTION 
We have now discovered an efficient multistep process for the synthesis of 
penem antibiotics, as summarized in Scheme 3. In particular, the present 
invention is directed to the processes of combined chemical steps: 
##STR11## 
In Scheme 3, the various variable symbols are defined as follows: 
EQU R is --CH.sub.2 CX.dbd.CH.sub.2,--CH.sub.2 CH.sub.2 Si(CH.sub.3).sub.3 
p-nitrobenzyl, 
or a conventional radical forming an ester which is hydrolyzed under 
physiological conditions; 
X is H or Cl; and 
R.sup.1 is a conventional silyl protecting group; and 
R.sup.2 is a pharmaceutically acceptable radical. 
##STR12## 
Conventional radicals which form esters which are hydrolyzed under 
physiological conditions have become as common in the beta-lactam art as 
pharmaceutically-acceptable salts. As in the case of numerous other 
beta-lactam antibiotics, such "pro-drug" esters are generally used orally 
to enhance gastrointestinal absorption. Once absorbed, they are hydrolyzed 
in vivo to form the corresponding penem acid. Preferred ester radicals are 
--CHR.sup.2 OCOR.sup.3 or --CHR.sup.2 OCO.sub.2 R.sup.3, where R.sup.2 is 
hydrogen or methyl and R.sup.3 is (C.sub.1-C.sub.8) alkyl, most 
particularly pivaloyloxymethyl and 1-(ethoxycarbonyloxy)ethyl. 
Among the conventional silyl protecting groups are trimethylsilyl and 
dimethyl-t-butylsilyl. The latter is most preferred for its ease of 
introduction and removal, while at the same time possessing excellent 
stability as a protecting group during the various other process steps of 
the present invention. 
Pharmaceutically acceptable radicals R.sup.2 have been extensively defined 
in the prior art, as will be evident from the following prior art 
references: 
(a) Hamanaka, U.S. Pat. No. 4,614,737; 
(b) Girijavallabhan et al., U.S. Pat. No. 4,614,738; 
(c) Hamanaka, U.S. Pat. No. 4,619,924; 
(d) Girijavallabhan et al., U.S. Pat. No. 4,443,463; 
(e) Girijavallabhan et al., U.S. Pat. No. 4,530,793; 
(f) Girijavallabhan et al., U.S. Pat. No. 4,584,133; 
(g) Ganguly et al., U.S. Pat. No. 4,690,922; 
(h) McCombie, European published application No. 61,205; 
(i) Hamanaka, European published application No. 132,101; 
(j) Hamanaka, European published application No. 138,539; 
(k) Perrone et al., European published application No. 199,490; 
(1) Takemura et al., European published application No. 210,883; 
(m) Kirkup et al., European published application No. 238,285; 
(n) Sunegawa et al., European published application No. 243,686; 
(o) McCombie et al., European published application No. 257,602; and 
(p) DiNinno et al., Tetrahedron Letters 3535 (1982). 
Preferred values of R.sup.2 found in the prior art (as noted by lower case 
letter from the list of references immediately above) are as follows: 
(C.sub.1 -C.sub.4)alkyl (b, e, h, p), (1,3-dioxacyclopent-4-yl)methyl (a), 
(1,3-dioxacyclopent-2-yl)methyl (a), (2-oxo-1,3-dioxacyclopent-4-yl)methyl 
(a), (1-methyl-2-imidazolyl)methyl (i), piperidinomethyl (k), 
2-hydroxyethyl (b, e, h), 2-(p-nitrobenzyloxycarbonylamino)ethyl (e, h), 
2-(piperidino)ethyl (b), 2-(pyrrolidino)ethyl (b), 2-(morpholino)ethyl 
(b), 2-(4-(allyloxycarbonyl)piperazino)ethyl (b), 1-oxo-3-thiolanyl (cis 
and/or trans) (c), 1,1-dioxo-3-thiolanyl (c), 1-oxo-3-thianyl (cis and/or 
trans) (c), 1,1-dioxo-3-thianyl (c), 1-oxo-4-thianyl (cis and/or trans) 
(c), 1,1-dioxo-4-thianyl (c), 4-hydroxy-3-thiolanyl (m), 
4-hydroxy-1-oxo-3thiolanyl (cis and/or trans) (m), 
4-hydroxy-1,1-dioxo-3-thiolanyl (m), 4-hydroxy-3-furyl (m), 
1,3-dioxacyclohex-5-yl (a), 2-oxo-1,3-dioxacyclohex-5-yl (a), 
1-(p-nitrobenzyloxycarbonyl)-3-pyrrolidinyl (e, f), 2-oxo-3-pyrrolidinyl 
(j, o), 1-methyl-5-(dimethylaminocarbonyl)-3-pyrrolidinyl (n), 
1-methyl-5-(2-(dimethylaminocarbonyl)ethyl-3-pyrrolidinyl (n), and 
trans-4-hydroxy-1-(benzyloxycarbonyl)-3-pyrrolidinyl (m). 
The most highly preferred values of R.sup.2 in the present process are 
--C.sub.2 H.sub.5, --CH.sub.2 CH(CH.sub.3).sub.2, --CH.sub.2 CH.sub.2 OH, 
##STR13## 
In addition to the processes noted above, the present invention is also 
specifically directed to novel intermediates of the formulas (3) and (5), 
shown in combined form by the formula 
##STR14## 
wherein R and R.sup.1 are as defined above; and 
z, X.sup.1 and X.sup.2 are taken together and are 
##STR15## 
Z, X.sup.1 and X.sup.2 are taken separately, X.sup.1 and X.sup.2 are each 
hydrogen, and Z is p-nitrophenyloxycarbonyl. 
DETAILED DESCRIPTION OF THE INVENTION 
The present invention provides an efficient process for penem antibiotics 
having the formula (7) which is readily carried out. 
In the first step of this process, a triphenylmethylthio compound of the 
formula (1), in the presence of two or more molar equivalents of a weakly 
basic amine such as pyridine and in the dark, is reacted with silver 
nitrate (at least one molar equivalent, usually in excess, e.g., 1.5-2 
molar equivalents) to produce the silver salt of the corresponding 
mercaptan. This reaction is generally carried out in a reaction inert 
solvent, such as methanol. Temperature is not critical, but lower 
temperatures, e.g., -25.degree. to 25.degree. C. are generally preferred, 
with 0.degree.-5.degree. C. particularly convenient and satisfactory. 
Generally without isolation the intermediate silver salt is converted 
directly with excess hydrogen sulfide gas to the mercaptan. Silver is 
recovered as the sulfide by filtration and the mercaptan (2) recovered 
from the mother liquor by conventional methods such as extraction and 
solvent evaporation. 
As used herein, the expression "reaction inert solvent" refers to a solvent 
which does not interact with starting materials, reagents, intermediates 
or products in a manner which adversely affects the yield of the desired 
product. 
In the second step, the mercaptan (2) is reacted with substantially one 
molar equivalent of 4-nitrophenyl chloroformate to form the intermediate 
compound of the formula (3). This step is carried out in the presence of 
substantially one molar equivalent of a tertiary amine, preferably 
diisopropylethylamine and/or dimethylaminopyridine, usually in a reaction 
inert solvent such As tetrahydrofuran, and is preferably carried out at 
lower temperatures, e.g., -25.degree. to 25.degree. C., conveniently at 
0.degree.-5.degree. C. If desired, the intermediate (3) is isolated and 
characterized by conventional methods. However, it is preferred to simply 
employ the initially obtained solution of the compound of formula (3) 
directly in the next step. 
In the third step, the intermediate (3) is cyclized in the presence of a 
strong base to form the desired 2-oxopenem of the formula (4), a known 
compound, for example, when R is allyl. Preferably, this step is carried 
out on a solution of the compound of the formula (3) in a reaction inert 
solvent such as tetrahydrofuran. The preferred strong base is lithium 
hexamethyldisilylamide in the same reaction inert solvent, generally used 
in a large molar excess (e.g., 3-5 molar equivalents). This base, 
conveniently purchased as a 1M solution in tetrahydrofuran, is generally 
diluted (e.g., to about 0.1 to 0.2M) with tetrahydrofuran and cooled to 
low temperature (e.g., -50.degree. to -100.degree. C., conveniently 
-78.degree. C., the temperature of an acetone-dry ice bath. A solution of 
the compound of the formula (3) in the same solvent is added portionwise, 
maintaining the same low temperature. The reaction, which is substantially 
complete upon completion of the addition, is conveniently quenched with 
excess acetic acid and the 2-oxopenem ( 4) isolated by conventional 
methods of concentration and extraction. 
In the next step the 2-oxopenem (4) is reacted with freshly distilled 
triflic anhydride, generally in slight molar excess, at reduced 
temperature (0.degree. to -90.degree. C., conveniently -78.degree. C.) in 
a reaction inert solvent such as methylene chloride in the presence of a 
molar excess (generally 4-6 molar equivalents) of a tertiary amine, 
preferably diisopropyl ethyl amine. If desired, the resulting enolic 
triflate ester of the formula (5) is isolated by chromatography of the 
reaction mixture on silica gel and characterized. However, this is 
unnecessary, the reaction solution being well-suited for direct reaction 
with a mercaptan R.sup.2 SH in the next step. 
In the fifth step of the present sequence, in its preferred embodiment, a 
solution of the appropriate mercaptan, R.sup.2 SH, conveniently dissolved 
in the same reaction inert solvent such as methylene chloride, is added 
portionwise to the cold solution of the triflate ester (5), generally 
allowing the temperature to rise no more than about 10.degree.-40.degree. 
C. from its initial value, i.e., a temperature in the range of about 
0.degree. to -90.degree. C. Upon completion of the reaction, the desired 
penem intermediate of the formula (6) is isolated by conventional methods, 
as exemplified below. 
When R is a conventional radical forming an ester which is hydrolyzed under 
physiological conditions, and absent an amino protecting group in the 
radical R.sup.2, the penem antibiotic is obtained by conventional removal 
of the silyl protecting group, e.g., by methods specifically exemplified 
below. When R is --CH.sub.2 CX.dbd.CH.sub.2, --CH.sub.2 CH.sub.2 
Si(CH.sub.3).sub.3 or p-nitrobenzyl, an additional conventional chemical 
step is required to form the acidic penem antibiotic of the formula (8), 
or its pharmaceutically acceptable salt. 
When R is --CH.sub.2 CX.dbd.CH.sub.2, the group is best removed by the 
action of at least one molar equivalent of an alkali metal salt of an acid 
such as 2-ethylhexanoic acid in a reaction inert solvent such as ethyl 
acetate, in the presence of catalytic amounts of triphenylphosphine and 
tetrakis(triphenylphosphine)palladium, directly forming the alkali metal 
salt of the penem antibiotic. When R.sup.2 contains nitrogen protected by 
an allyloxycarbonyl group, said group is removed by the same method. 
When R is --CH.sub.2 CH.sub.2 Si(CH.sub.3).sub.3, the group is best 
concurrently removed with the dimethyl-t-butylsilyl protecting group, 
preferably using a molar excess of tetrabutylammonium fluoride in a 
reaction inert solvent such as tetrahydrofuran. 
When R is p-nitrobenzyl, the group is generally removed by conventional 
hydrogenolysis over a noble metal catalyst, preferably palladium, for 
example palladium-on-carbon. When R.sup.2 contains a nitrogen protecting 
group such as benzyloxycarbonyl, said group is removed by the same method. 
The mercaptans required for the present reaction sequence are generally 
known or available by conventional methods. A preferred method for the 
synthesis of 3S-mercaptothiolane 1R-oxide is specifically described below. 
The penem antibiotics of the formula (7), as well as their pharmaceutically 
acceptable salts and esters, are employed in medicine according to methods 
described in references cited above. 
It will be specifically noted that the compounds the of the formula (6) 
wherein R.sup.2 is 
##STR16## 
are used to prepare the corresponding product of Hamanaka, U.S. Pat. No. 
4,619,924, i.e., the compound of the above formula (7), or an ester with 
R.sup.2 of the same value. These products are a mixture of 
diasteroisomers, one having R.sup.2 as 1R-oxo-3S-thiolanyl and the other 
R.sup.2 as 1S-oxo-3R-thiolanyl. Of these, the 1R,3S-isomer of the formula 
##STR17## 
and its pharmaceutically acceptable salts and esters are preferred. This 
is not only because these compounds, and their several immediate 
precursors, are single, homogeneous compounds, such that the quality of 
the final products is much better controlled relative to the previously 
reported diastereomeric mixture (an important factor in clinical use), but 
because they show clinical advantages over Hamanaka's diastereomeric 
mixture. 
The pure diasteromeric, antibacterial compound of the formula (9), its 
salts and its esters are tested, formulated and used according to methods 
detailed in above cited Hamanaka, U.S. Pat. No. 4,619,924, hereby 
incorporated by reference. Within the human dosage ranges there disclosed, 
the more preferred dosage range for these compounds is about 10-80 
mg/kg/day, both orally and parenterally. These figures are illustrative 
only, since in some circumstances the attending physician will find it 
more beneficial to employ dosages outside of these ranges. In vivo 
hydrolyzable esters, particularly the pivaloyloxymethyl and 
1-(ethoxycarbonyloxy)ethyl esters, are preferred in oral use, while the 
sodium or potassium salts are particularly preferred for parenteral use.

The following examples are given by way of illustration and are not to be 
construed as limitations of this invention, many variations of which are 
possible within the scope and spirit thereof. 
EXAMPLE 1 
Allyl 2-[4R-Mercapto-3S-(1S-(dimethyl-t-butyl 
silyloxy)ethyl)-2-azetidinon-1-yl]acetate 
A solution of 20 g (33.2 mmol) of allyl 
2-[4R-(tri-phenylmethylthio)-3S-(1S-(dimethyl-t-butylsilyloxy)-ethyl)-2-az 
etidinon-1-yl]acetate (Jeff et al., Tetrahedron, vol. 39, 2505-2513, 1983; 
U.S. Pat. No. 4,610,823) in 600 ml of methanol was cooled to 0.degree. C. 
and was treated with 5.94 ml (73 mmol) of pyridine. The following portion 
of the reaction sequence was conducted with the reaction flask protected 
from light. To the solution was added solid silver nitrate (10.2 g, 60 
mmol) and the reaction mixture was allowed to stir for 1.5 hours while 
maintained at 0.degree. C. Once this reaction was complete, hydrogen 
sulfide gas was slowly introduced with constant stirring. The dark mixture 
was then filtered through celite with recovery of silver sulfide and the 
filtrate was concentrated. The organic residue was partitioned between 
ethyl acetate and brine. The layers were separated and the aqueous phase 
was reextracted with fresh ethyl acetate. The combined organic layers were 
dried over sodium sulfate and were then evaporated to yield title product 
which was used directly in the next step. 
EXAMPLE 2 
Allyl 
2-[4R-=(4-Nitrophenyloxycarbonylthio)-3S-(1S-(dimethyl-t-butylsilyloxy)eth 
yl)-2-azetidrnon-1-yl]acetate 
A solution of 4.06 g (33.2 mmol) of dimethylaminopyridine and 6.69 g (33.2 
mmol) of 4-nitrophenylchloroformate was prepared in 700 ml of THF. The 
solution was cooled to 0.degree. C. and was treated simultaneously with a 
solution of the entire batch of title product from the preceding Example 
in 60 ml of THF, and a separate solution of 5.78 ml (33.2 mmol) of 
diisopropylethylamine in 60 ml of THF. The addition required 0.5 hours and 
formed a white precipitate. After stirring the mixture for 5 minutes, the 
reaction mixture was filtered with exclusion of atmospheric moisture and 
the filtered solution of present title product placed in a constant 
addition funnel and immediately used in the next step. 
A portion of this solution, following filtration through a small portion of 
silica gel using CDCl.sub.3 as eluant was characterized by means of .sup.1 
H-NMR (300 MHz) which showed delta: 8.22 (2H, d, J=8 Hz), 7.29 (2H, d, J=8 
Hz), 5.74-5.89 (1H, ddd, J=18 Hz, 12 Hz, J=6 Hz), 5.46 (1H, d, J=2 Hz), 
5.25 (1H, d, J=18 Hz), 5.17 (1H, d, J=12 Hz), 4.57 (2H, d, J=6 Hz), 4.25 
(1H, dq, J=6 Hz, J=5 Hz), 4.10 (1H, d, J=19 Hz), 3.90 (1H, d, J=19 Hz), 
3.27 (1H, dd, J=5 Hz, J=2 Hz), 1.26 (3H, d, J=6 Hz), 0.84 (9H, s), 0.06 
(3H, s), 0.04 (3H, s). 
EXAMPLE 3 
Allyl 5R,6S-2-Oxo-6-[1R-(dimethyl-t-butyl 
silyloxy)ethyl]penam-3-carboxylate 
The entire solution of the product of the preceding Example was added to 
133 ml (133 mmol) of 1.0M lithium hexamethyldisilylamide (in THF) which 
was previously diluted with 1000 ml of THF and cooled to -78.degree. C. 
The addition required 0.5 hours and the solution turned bright yellow. 
Acetic acid (38 ml, 664 mmol) was added and the reaction mixture was 
stirred for 10 minutes. Approximately 1/2 of the solvent was removed 
through concentration and the remainder was diluted with diethyl ether to 
a volume of 2.7 liters. The ether solution was washed with saturated 
bicarbonate solution, saturated brine solution and then dried over sodium 
sulfate. The organic phase was concentrated and the residue was filtered 
through a pad of silica gel eluting with 15% ethyl acetate in hexane. 
There was obtained 6.98 g (56%) present title product as a waxy solid; 
m.p. 45.degree.-48.degree. C.; .sup.1 H-NMR(CDCl.sub.3, 300 MHz)delta: 
5.78-5.94 (1H, ddd, J=18 Hz, J=11 Hz, J=7 Hz), 5.51 (1H, d, J=2 Hz), 5.32 
(1H, d, J=18 Hz), 5.25 (1H, d, J=11 Hz), 5.00 (1H, s), 4.65 (2H, d, J=7 
Hz), 4.32 (1H, dt, J=7 Hz, J=4 Hz), 3.54 (1H, dd, J=4 Hz, J=2 Hz), 1.28 
(3H, d, J=7 Hz), 0.86 (9H, s), 0.07 (3H, s), 0.05 (3H, s); C.sup.13 
--NMR(CDCl.sub.3, 75.43 MHz)delta: 199.0, 169.0, 163.4, 130.4, 119.6, 
71.7, 67.1, 66.1, 64.6, 62.4, 25.6, 22.5, 17.9, -4.2, -5.1; m/e calculated 
for C.sub.13 H.sub.18 NO.sub.5 SSi[P-tBu]: 328.0675, found: 328.0615. 
EXAMPLE 4 
Allyl 
5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)ethyl]-2-(trifluoromethanesulfonylox 
y)penem-3-carboxylate 
A solution of 100 mg (0.260 mmol) of title product of the preceding Example 
in 5 ml of methylene chloride was treated with 0.180 ml (1.03 mmol) 
diisopropylethyl amine. This clear solution was then cooled to -78.degree. 
C. in a dry ice-acetone bath. Freshly distilled triflic anhydride (0.045 
ml, 0.270 mmol) was added and the clear solution was stirred for 1 hour at 
-78.degree. C. to form a cold solution of present title product, which was 
used directly in the next step. 
A small portion of this solution was purified by chromatography on silica 
gel followed by low temperature (-78.degree. C.) crystallization from 
pentane; m.p. 40.degree. C.; .sup.1 H-NMR(CDCl.sub.3, 300 MHz)delta: 
5.84-5.98 (1H, ddd, J=18 Hz, J=12 Hz, J=6 Hz), 5.73 (1H, d, J=2 Hz), 5.37 
(1H, dd, J=18 Hz, J=1 Hz), 5.25 (1H, dd, J=12 Hz, J=1 Hz), 4.73 (2H, dd, 
J=6 Hz, J-1 Hz), 4.25 (1H, dq, J=6 Hz, J=4 Hz), 3.86 (1H, dd, J=4 Hz, J=2 
Hz), 1.24 (3H, d, J=6 Hz), 0.87 (9H, s), 0.08 (6H, s); m/e calculated for 
C.sub.14 H.sub.17 NO.sub.7 S.sub.2 SiF.sub.3 [ p-tBu]460,0168, found: 
460.0246. 
EXAMPLE 5 
Allyl 
5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)ethyl]-2-[(1R-oxo-3S-thiolanyl)thio] 
penem-3-carboxylate 
A solution of 69 mg (0.388 mmol) of 3S-(acetylthio)thiolane-1R-oxide in 5 
ml of methylene chloride was treated with 5 ml of water and was cooled to 
0.degree. C. The stirred mixture was charged with 0.78 ml (1.56 mmol) of 
2.0M sodium hydroxide and was allowed to stand for 0.5 hours. The reaction 
mixture was quenched with 0.089 ml (1.56 mmol) acetic acid and was 
extracted with 5.times.10 ml of methylene chloride. The organic phase was 
dried with sodium sulfate, filtered and was then treated with 0.135 ml 
(0.780 mmol) of diisopropylethyl amine. This solution of 
3S-mercaptthiolane-1R-oxide was allowed to stand while the operation of 
the preceding Example was completed. It was then added to the entire cold 
solution of the preceding Example over 0.5 hour while maintaining the 
temperature below -65.degree. C. at all times. After 18 hours at 
-78.degree. C. the reaction mixture was treated with 10 ml of water and 
was allowed to warm to room temperature. The product was extracted with 
methylene chloride and the organic phase was washed with brine and then 
dried and evaporated. After filtration through silica gel, there was 
obtained 129 mg (98%) of present title product; m.p. 
131.degree.-134.degree. C.; .sup.1 --NMR(CDCl.sub.3, 300 MHz)delta: 
5.80-5.96 (1H, ddd, J=18 Hz, J=12 Hz, J=6 Hz), 5.62 (1H, d, J=2 Hz), 5.35 
(1H, dq, J=18 Hz, J=2 Hz), 5.19 (1H, dq, J=12 Hz, J=2 Hz), 4.66 (2H, m), 
4.21 (1H, dq, J=7 Hz, J=3 Hz), 3.93 (1H, dd, J=14, J=7 Hz), 3.67 (1H, dd, 
J=3, J=2 Hz), 3.56-3.72 (1H, m), 3.09 (1H, m), 2.54-2.84 (4H, m), 1.23 
(3H, d, J=7 Hz), 0.85 (9H, s), 0.05 (6H, s); C.sup.13 --NMR(CDCl.sub.3, 
75.43 MHz)delta: 171.9, 159.4, 150.8, 131.7, 118.7, 118.5, 71.8, 65.7, 
65.2, 64.1, 61.7, 52.7, 46.7, 33.2, 25.7, 22.5, 17.9; m/e calculated for 
C.sub.17 H.sub.24 NO.sub.5 S.sub.3 Si[P-tBu]: 446.0587, found: 446.0597. 
EXAMPLE 6 
Allyl 
5R,6S-6-(1R-Hydroxyethyl)-2-[(1R-oxo-3S-thiolanyl)thio]penem-3-carboxylate 
A solution of 100 mg (0.198 mmol) of the title product of the preceding 
Example in 2 ml of dry THF and 0.114 ml of acetic acid was treated with 
0.594 ml (0.594 mmol) 1M tetrabutylammonium fluoride and the solution was 
allowed to stir at room temperature for 18 hours. The reaction mixture was 
poured into a mixture of 50 ml ethyl acetate and 10 ml of water. The 
solution pH was adjusted to 6.4 by the addition of 20% potassium acetate 
in water. The organic phase was removed and the aqueous layer was washed 
twice more with 20 ml of ethyl acetate. The combined organic layers were 
dried over sodium sulfate and then evaporated. The residue was 
chromatographed on silica gel (32-63 microns) with 15% methanol in ethyl 
acetate. There was obtained 70.6 mg (92%) of present title product as a 
solid; m.p. 151.degree.-155.degree. C.; .sup.1 --NMR(DMSO-d-6, 300 
MHz)delta: 596 (1 H, m), 5.82 (1H, d, J=3 Hz), 5.45 (1H, dd, J=18 Hz, J=3 
Hz), 5.31 (1H, s), 5.29 (1H, dd, J=12 Hz, J=3 Hz), 5.78 (1H, dd, J=18 Hz, 
J=6 Hz), 5.65 (1H, dd, J=18 Hz, J=6 Hz), 3.77-4.12 (4H, m), 3.08 (1H, m), 
2.67-2.98 (3H, m), 2.49 (1H, m), 1.23 (3H, d, J=7 Hz); C.sup.13 
-NMR(DMSO-d-6, 75.43 MHz)delta: 173.5, 158.9, 153.6, 132.4, 117.6, 116.2, 
71.3, 71.2, 64.6, 63.8, 60.4, 52.2, 46.3, 33.4, 21.4. 
EXAMPLE 7 
Sodium 5R,6S-6-(1R-Hydroxyethyl)-2-[(1R-oxo-3S-thiolanyl) 
thio]penem-3-carboxylate 
A solution of the title product of the preceding Example (30 mg, 0.077 
mmol) in 1 ml of methylene chloride was treated with 0.058 ml (0.081 mmol) 
of sodium ethylhexanoate in ethyl acetate solution (1.39 mmol/ml). The 
reaction mixture was treated with 6 mg (0.0223 mmol) triphenylphosphine 
and 6 mg (0.005 mmol) tetrakis(triphenylphosphine) palladium in 0.5 ml of 
methylene chloride. The mixture was allowed to stir for 1 hour at room 
temperature. Ethyl acetate (30 ml) was added and the mixture filtered to 
yield crude product. The latter was taken up in distilled water and 
treated with a small amount of activated carbon, filtered and the filtrate 
lyophilized to yield present title product, 10.5 mg; .sup.1 
H-NMR(DMSO-d-6, 300 MHz)delta: 5.52 (1H, d, J=3 Hz), 5.24 (1H, brs), 
3.74-3.96 (2H, m), 3.50-3.66 (2H, m), 2.88-2.98 (1H, m), 2.70-2.86 (1 H, 
m), 2.44-2.60 (2H, obscured), 2.2-2.36 (1H, m), 1.14 (3H, d, J=7 Hz). 
EXAMPLE 8 
Allyl 5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)ethyl]-2-[(1,1-dioxo-3R- and 
3S-thiolanyl)thio]penem-3-carboxylate 
A solution of 50 mg (0.129 mmol) of the title product of Example 3 at 
0.degree. C. in 4 ml of methylene chloride was treated with 0.089 ml (0.51 
mmol) diisopropylethyl amine. This clear solution was then cooled to 
-78.degree. C. in a dry ice-acetone bath. Freshly distilled 
trifluoromethanesulfonic anhydride (0.024 ml, 0.142 mmol) was added and 
the clear solution that resulted was stirred for 1 hour at -78.degree. C. 
The resulting cold solution of Example 4 title product was treated with a 
solution of 19.6 mg (0.129 mmol) of racemic 3-mercaptothiolane-1,1-dioxide 
(Bezmenova et al., Khim. Geterotsikl. Soedin. 1975, 188, 2; Chem. Abstr. 
1975, 170558) and 0.022 ml (0.129 mmol) diisopropylethyl amine in 1 ml of 
methylene chloride. Addition required 0.5 minutes and the solution 
temperature was kept below -b 70.degree. C. at all times. After 2 hours at 
-78.degree. C. the reaction mixture was allowed to warm to room 
temperature and was stirred overnight. The solution was then treated with 
10 ml of water and was extracted with ethyl acetate. The organic phase was 
washed with brine and then dried and evaporated. After filtration through 
silica gel (3:2 hexane:ethyl acetate), there was obtained 66.7 mg (100%) 
present title product as a mixture of diastereomers. These diastereomers 
were separated by chromatography on silica gel by eluting with a solution 
of 6:3:1 hexane:ethyl acetate:benzene. The more polar diastereomer had the 
following properties: m.p. 180.degree.-181.degree. C., [alpha].sub. D 
=+57.14.degree.(c=0.49 g/100 ml); HRMS calculated for C.sub.17 H.sub.24 
NO.sub.6 S.sub.3 Si: 462.0536 (P-tBu), found: 462.0473. The less polar 
diastereomer had the following properties: m.p. 169.degree.-170.degree. C. 
[alpha].sub.D =+111.78.degree. (c=0.73 g/100 ml); HRMS calculated for 
C.sub.17 H.sub.24 NO.sub.6 S.sub.3 Si: 462.0536 (P-tBu), found: 462.0506. 
The blocking groups are removed from these compounds according to the 
methods of Examples 6 and 7 to yield the known products of Hamanaka, U.S. 
Pat. No. 4,619,924. 
EXAMPLE 9 
Allyl 
5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)ethyl]-2-(ethylthio)penem-3-carboxyl 
ate 
Title product of Example 3 (100 mg, 0.262 mmol) was converted to a cold 
solution of title product of Example 4 according to the method of Example 
4. This solution, at -78.degree. C., was treated with a solution of 0.096 
ml (1.3 mmol) ethanethiol and 0.226 ml (1.3 mmol) diisopropylethylamine in 
1 ml of acetonitrile. Addition required 0.5 minutes and the solution 
temperature was kept below -70.degree. C. during this time. After 5 
minutes at -78.degree. C. the reaction mixture was allowed to warm to 
0.degree. C. and was stirred for 2 hours. The solution was then treated 
with 10 ml of water and was extracted with ethyl acetate. The organic 
phase was washed with brine and then dried and evaporated. After 
filtration through silica gel (4:1 hexane:ethyl acetate) there was 
obtained 110 mg of present title product; m.p. 83.degree.-84.degree. C.; 
HRMS calculated for C.sub.19 H.sub. 31 NO.sub.4 S.sub.2 Si: 429.1464, 
found: 429.1026; a compound earlier reported in racemic form by Leanza et 
al. Tetrahedron, vol. 39, 2505-2513 (1983). 
Present title compound is deblocked according to Examples 6 and 7 to form 
the corresponding known penem antibiotic previously reported by Gangaly et 
al., J. Antimicrobiol. Chemotherapy, vol. 9, pp. C1-C5 (1982). 
EXAMPLE 10 
Allyl 
5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)ethyl]-2-(isopropylthio)penem-3-carb 
oxylate 
By the methods of the preceding Example, title product of Example 3 (105.3 
mg, 0.274 mmol) and isopropyl mercaptan (0.239 ml, 1.37 mmol) were 
converted to present title product, purified by chromatography on silica 
gel using 19:1 hexane:ethyl acetate as eluant, 60 mg, m.p. 
104.degree.-106.degree. C.; previously known in racemic form, Leanza et 
al., loc. cit.; deblocked by the methods of Examples 6 and 7 to yield the 
corresponding, known penem antibiotic, Ganguly et al., loc. cit. 
EXAMPLE 11 
Allyl 
5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)ethyl-2-[(hydroxyethyl)thio]penem-3- 
carboxylate 
By the methods of Example 8, the title product of Example 3 (61 mg, 0.158 
mmol) and 2-mercaptoethanol (0.012 ml, 0.174 mmol) were converted to 
present title product, purified by chromatography on silica gel using 3:2 
hexane:ethyl acetate as eluant, 60 mg; m.p. 80.degree. C.; [alpha].sub.D 
=+160.4.degree. (c=2.22 g/100 ml); HRMS calculated for C.sub.19 H.sub.31 
NO.sub.5 S.sub.2 Si: 445.1412, found: 445.1420. 
EXAMPLE 12 
Allyl 
5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)ethyl]-2-[2-(4-nitrobenzyloxycarbony 
lamino)ethylthio]penem-3-carboxylate 
By the methods of the preceding Example, the title product of Example 3 
(49.5 mg, 0.129 mmol) and 2-[(4-nitrobenzyloxycarbonyl)amino]ethyl 
mercaptan (33 mg, 0.129 mmol; Shinkai et al., Synthesis 1980, 924) were 
converted to present, chromatographed title product, 71 mg; m.p. 
103.degree.-105.degree. C.; [alpha].sub.D =+88.34.degree. (c=3.26 g/100 
ml); HRMS calculated for C.sub.23 H.sub.28 N.sub.3 O.sub.8 S.sub.2 Si: 
566.1088 (P-tBu), found: 566.1119. 
EXAMPLE 13 
Allyl 
5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)ethyl]-2-[1-(4-nitrobenzyloxycarbony 
l)-3S-pyrrolidinylthio]penem-3-carboxylate 
By the methods of Example 8, the title product of Example 3 (101.7 mg, 
0.264 mmol) and 3S-mercapto-1-(p-nitrobenzyloxycarbonyl) pyrrolidine 
(0.050 ml 0.289 mmol; Sigimura et al., Heterocycles 24,1331, 1986) were 
converted to present title product which, following extraction into ethyl 
acetate, was purified by chromatography on silica gel using 2:1 
hexane:ethyl acetate as eluant, 147 mg; m.p. 105.degree.-106.degree. C.; 
[alpha].sub.D =+260.degree. (c=0.84, CHCl.sub.3). 
EXAMPLE 14 
2-(Trimethylsilyl)ethyl 
5R,6S-2-Oxo-6-[1R-(Dimethyl-t-butylsilyloxy)ethyl]penem-3-carboxylate 
By the methods of Examples 1-3 above, 2-(trimethylsilylethyl 
2-[4R-(triphenylmethylthio)-3S-(1S-(dimethyl-t-butylsilyloxy)ethyl)-2-azet 
idinon-1-yl]acetate was converted to present title product; .sup.1 
H-NMR(CDCl.sub.3, 300 MHz)delta: 5.52 (1H, d, J=3 Hz), 4.96 (1H, s), 4.35 
(1H, q, J=8 Hz, J=5 Hz), 4.26 (2H, dt, J=12 Hz), 3.56 (1H, dd, J=5 Hz, J=3 
Hz), 1.30 (3H, d, J=8 Hz), 1.06 (2H, dt, J=12 Hz), 0.89 (9H, s), 0.1 (3H, 
s), 0.08 (3H, s), 0.05 (9H, s); C.sup.3 
13-NMR (CDCl , 62.89 MHz)delta: 199.3, 169.2, 163.9, 71.8, 66.4, 65.5, 
64.7, 62.5, 25.7, 22.5, 17.9, 17.4, -1.5, -4.2, -5.1; m/e calculated for 
C.sub.15 H.sub.26 NO.sub.5 SSi.sub.2 [P-t-Bu]388.1179, found: 388.1125. 
According to the sequential steps and methods of Examples 4-6, the product 
is further converted, via key intermediate 2-(trimethylsilyl)ethyl 
5R,6S-6-[1R-(di-methyl-t-butylsilyloxy)ethyl]-2-(trifluoromethanesulfonylo 
xy)penem-3-carboxylate, to 2-(trimethylsilyl)ethyl 
5R,6S-6-[1R-(dimethyl-t-butylsilyloxy)ethyl]-2-[(1R-oxo-3S-thiolanyl)thio] 
penem-3-carboxylate. The dimethyl-t-butylsilyl and trimethylsilylethyl 
protecting groups are removed by the action of tetrabutylammonium fluoride 
in THF at room temperature according to the method described in Example 8, 
above and Girijavallabhan et al., U.S. Pat. No. 4,443,373. 
EXAMPLE 15 
Pivaloyloxymethyl 
5R,6S-6-(1R-Hydroxyethyl)-2-[(1R-oxo-3S-thiolanyl)thio]penem-3-carboxylate 
By the sequential steps and methods of Examples 1-6, pivaloyloxymethyl 
2-[4R-(triphenylmethylthio)-3S-(1S-(dimethyl-t-butylsilyloxy)ethyl)-2-azet 
idinon-1-yl]acetate is converted to present title product. The 
corresponding 1-(ethoxycarbonyloxy)ethyl ester is prepared in like manner. 
PREPRATION 1 
(R)-3-Thiolanyl p-Toluenesulfonate 
(R)-4-(methylthio)1,2-butanediol (1.0 , 7.35 mmol) and p-toluenesulfonyl 
chloride (3.0 g, 15.8 mmol) were combined in 10 ml of pyridine at 
0.5.degree. C., then stirred at room temperature, at which time tlc (3:1 
hexane:ethyl acetate) indicated no diol (Rf 0.1), appreciable of th ediol 
ditosylate (Rf 0.53), some intermediate thiolanium salt (Rf 0.03) and a 
trace of title product (Rf 0.72). The reaction mixture was then heated at 
60.degree. C. for 8 hours, at which time tlc (5:1 hexane:ethyl acetate) 
indicated an appreciable amount of the desired title product (Rf 0.45 ), 
only a trace of the ditosylate (Rf 0.22), some probable thiolanium salt 
(Rf 0.0), and other, generally less polar impurities. The cooled reaction 
mixture was diluted with an equal volume of water and two volumes of ethyl 
acetate. The organic layer was separated, washed with saturated NaCl, 
dired (MgSO.sub.4), stripped and the residue chromatographed on silica gel 
using 10:1 g less polar impurities (stench-) and 0.25 g of present, 
purified title product; tlc Rf 0.55 (4:1 hexane:ethylacetate); 
[alpha].sub.D =+15.87 (c=0.6, CH.sub.3 OH). 
PREATION 2 
3R-(p-Toluenesulfonyloxy)thiolane 1R-Oxide 
A solution of 46.30 g (0.179 mol) title product of the preceding 
Preparation in 600 ml acetone, under nitrogen was cooled to 0.degree. C. 
In a separate flask 61.73 g (0.100 mol) potassium peroxymonosulfate was 
stirred in 500 ml distilled water until clear. This was added to the 
acetone solution at 0.degree. C. and the mixture allowed to warm to room 
temperature. After 25 minutes 75 ml of 10% (w/v) aqueous sodium sulfite 
was added, the acetone was evaporated, 300 ml ethyl acetate added and the 
aqueous layer was extracted with ethyl acetate (3.times.100 ml). The 
combined extracts were dried (MgSO.sub.4) and concentrated to dryness to 
yield 48.57 g of crude product. The latter was purified by silica gel 
chromatography using 10:10:1 ethyl acetate:CH.sub.2 C.sub.12 CH.sub.30 H 
as eluant to afford purified title product, 34.67 g (71%); [alpha].sub.D 
=+4.26.degree. (c=3.0, CHCl.sub.3). 
PREATION 3 
3S-(Acetylthio)thiolane 1R-Oxide 
In a flame-dried flask under nitrogen, 31.67 g (0.1156 mol) title product 
of the preceding Preparation was dissolved in 300 ml acetone and 19.81 g 
(0.1734 mol) potassium thioacetate was added. The mixture was heated at 
reflux for 3.5 hours and allowed to stir at room temperature overnight. 
The mixture was filtered, rinsed and washed with 500 ml acetone and the 
filtrate and washings were evaporated in vacuo to obtain 23.96 g of the 
desired product as an oil. The oil was purified by flash chromatography on 
a 120 mm.times.25 cm silica gel column eluting with 19:1 ethyl 
acetate:methanol collecting 125 ml fractions. Fractions 42-64 were 
combined and stripped to yield purified title product as an oil which 
crystallized on standing, 16.46 g; (80%); m.p. 51.degree.-52.degree. C.; 
[alpha].sub.D =-83.41.degree. (c=0.86, CHCl.sub.3). 
Analysis calculated for C.sub.6 H.sub.10 S.sub.2 O.sub.2 : C, 40.4; H, 
5.6%. 
Found: C, 40.15; H, 5.53%.