Organic Chemistry of Drug Synthesis. Volume 7

thiadiazole carboxylic acid ( 214 ). The hydroxyl group in the product ( 216 )
is then oxidized with manganese dioxide to afford the corresponding
aldehyde ( 217 ). This product is condensed with the bis(pyrrolidyl phos-
phonium) salt ( 218 ), itself protected with the complex carbonate ( 219 ).
Removal of the several protecting groups then affords the highly modified
cephalosporin 220.^32

S N

H 2 N N O

N

O

OSi(CH 3 ) 3

P(OC 2 H 5 ) 2

S N

S

O

H 2 N

OH

CO 2 CHPh 2

N

S

O OH

CO 2 CHPh 2

S N

H 2 N N

N

O

OSi(CH 3 ) 3

MnO 2

N

S

O CH=O

CO 2 CHPh 2

SN

H 2 N N

N

O

OSi(CH 3 ) 3

N NH

O

N

S

O

CO 2 H

SN

H 2 N N

N

O

OH

N N

Ph 3 P O

+

R

O

O O

O

214

+

215 216

217

218

(^220) R =
219
NH NH
HN
Yet another recent beta-lactam active against multidrug resistant
organisms is based on the “unnatural” carbapenem nucleus first used
for the antibiotic imipenem. The preparation of the side chain starts
with the protection of the nitrogen in hydroxyproline ( 221 ) as its diiso-
propyl phosphoryl derivative ( 222 ). The carboxyl is then activated as the
mixed anhydride ( 223 ) by reaction with diphenylphosphinic anhydride.
The ring hydroxyl is next converted to its mesylate ( 224 ) by reaction
with methanesulfonyl chloride. Treatment of 224 with sodium sulfide
serves to replace phosphorus on the carboxyl group by sulfur ( 225 ).
Under somewhat basic reaction conditions, the sulfide anion slowly dis-
places the transannular mesylate group to form a bridged thiolactone
ring. The stereochemistry at the new carbon sulfur bond is inverted in
the process ( 226 ). This intermediate is then treated with 3-aminobenzoic
acid. The thiolactone now opens to form amide 228 thus completing the
side-chain. The requisite beta-lactam intermediate 229 is perhaps surpris-
ingly available commercially. Reaction of that with the side-chain
intermediate ( 228 ) leads to replacement of phosphorus by the side-
chain thiol function. Removal of the protecting groups then affords the
carbapenemertapenem( 230 ).^33
214 BICYCLIC FUSED HETEROCYCLES