The reaction of the acetonide of (R)-3,4-dihydroxybutanal (I) with the silylated 4-bromobenzyl alcohol (II) by means of n-BuLi in THF gives the corresponding carbinol (III), which is oxidized to the ethanone (IV) by means of tetrapropylammonium perruthenate (TPAP) and NMO in dichloromethane. The enantioselective reduction of the ketone (IV) by means of LiAlH4 and an excess of LiI in ethyl ether gives the (R,S)-enantiomer (V), which is mesylated with MsCl/TEA in dichloromethane and treated with NaN3 in hot DMF to yield the azide (VI). The reduction of (VI) with triphenylphosphine in THF/water affords the amine (VII), which is treated with allyl chloroformate and TEA in THF providing the carbamate (VIII). The desilylation of (VIII) with TBAF in THF gives the benzyl alcohol (IX), which is mesylated with MsCl and TEA in dichloromethane yielding the mesyl ester (X). The reaction of (X) with NaN3 in DMF affords the azide (XI), which is reduced as before to the benzylamine (XII). The reaction of (XII) with allyl chloroformate provides the bis carbamate (XIII).

Compound (XIII) is treated with TsOH in methanol to eliminate the acetonide group and yield the diol (XIV). The dimesylation of (XIV) with MsCl and TEA as before affords the dimesylate (XV). The cyclization of (XV) by means of t-BuOK in THF gives the pyrrolidine (XVI), which is treated with potassium thioacetate in hot DMF to yield the acetylsulfanyl derivative (XVII).The selective hydrolysis of (XVII) with NaOH in methanol affords the thiol (XVIII), which is condensed with the protected carbapenem (XIX) by means of DIEA in acetonitrile to furnish the protected target compound (XX). Finally, this compound is deprotected by a treatment with (PPh3)2PdCl2 and Bu3SnH in dichloromethane/water.

The protection of 4(R)-hydroxypyrrolidin-2-one (I) first with TBDMS-Cl and then with Boc2O gives the fully protected compound (II), which is condensed with the Grignard reagent of the 4-bromobenzaldehyde dimethyl acetal (III) yielding after working up the substituted benzaldehyde (IV). The reduction of (IV) with NaBH4 affords the benzyl alcohol (V), which is treated with methanesulfonyl chloride to give the corresponding mesylate (VI). The reaction of (VI) with methylamine, followed by protection with Boc2O yields the protected secondary amine (VII), which is desilylated with tetrabutylammonium fluoride to afford the pyrrolidinol (VIII). The reaction of (VIII) with MsCl gives the mesylate (IX), which is treated with potassium thioacetate to provide the acetylsulfanyl derivative (X). The hydrolysis and deprotection of (X) with HCl yields the pyrrolidinethiol (XI), which is condensed with the carbapenem phosphoric ester (XII) to afford the final 4-nitrobenzyl ester intermediate (XIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C.

(R)-4-hydroxy-2-pyrrolidinone (I) was protected as the tert-butyldimethylsilyl ether, and then converted to tert-butyl carbamate (II) by means of Boc2O. Subsequent condensation of (II) with Grignard reagent (III), followed by reduction with NaBH4, and acetal hydrolysis yielded the pyrrolidinyl benzaldehyde (IV). Horner-Emmons reaction of (IV) with phosphonate (V) produced the cinnamic acid derivative (VI), and further Michael addition of the chiral lithium amide (VII) furnished aminoester (VIII). After hydrogenolysis of both N-benzyl groups of (VIII), the resulting primary amine (IX) was protected with Boc2O, and the silyl ether was then cleaved by means of tetrabutylammonium fluoride to give the hydroxypyrrolidine derivative (X). This was converted to the required thiol (XI), which was then coupled with the carbapenem phosphate (XII). Finally, hydrogenolysis of the 4-nitrobenzyl ester of (XII) provided the title compound.

(R)-4-hydroxy-2-pyrrolidinone (I) was protected as the tert-butyldimethylsilyl ether, and then converted to tert-butyl carbamate (II) by means of Boc2O. Subsequent condensation of (II) with Grignard reagent (III), followed by reduction with NaBH4, and acetal hydrolysis yielded the pyrrolidinyl benzaldehyde (IV). Horner-Emmons reaction of (IV) with phosphonate (V) produced the cinnamic acid derivative (VI), and further Michael addition to (VI) of the chiral lithium amide (VII) furnished aminoester (VIII). After hydrogenolysis of both N-benzyl groups of (VIII), the resulting primary amine (IX) was protected with Boc2O, and the silyl ether was then cleaved by means of tetrabutylammonium fluoride to give the hydroxypyrrolidine derivative (X). This was converted to the required thiol (XI), which was then coupled with the carbapenem phosphate (XII). Finally, hydrogenolysis of the 4-nitrobenzyl ester of (XII) provided the title compound.

(R)-4-hydroxy-2-pyrrolidinone (I) was protected as the tert-butyldimethylsilyl ether, and then converted to tert-butyl carbamate (II) by means of Boc2O. Subsequent condensation of (II) with Grignard reagent (III), followed by reduction with NaBH4, and acetal hydrolysis yielded the pyrrolidinyl benzaldehyde (IV). Horner-Emmons reaction of (IV) with phosphonate (V) produced the cinnamic acid derivative (VI), and further Michael addition of the chiral lithium amide (VII) furnished aminoester (VIII). After hydrogenolysis of both N-benzyl groups of (VIII), the resulting primary amine (IX) was protected with Boc2O, and the silyl ether was then cleaved by means of tetrabutylammonium fluoride to give the hydroxypyrrolidine derivative (X). This was converted to the required thiol (XI), which was then coupled with the carbapenem phosphate (XII). Finally, hydrogenolysis of the 4-nitrobenzyl ester of (XII) provided the title compound.

In an alternative procedure, aldehyde (IV) was condensed with ethyl acetate in the presence of lithium hexamethyldisilazide to give hydroxyester (XIII). This was esterified with chloroacetyl chloride to provide (XIV) as a diastereomeric mixture. Kinetic resolution of (XIV) employing lipase selectively hydrolyzed the required isomer to furnish hydroxyester (XVI), which was separated from the undesired chloroacetate (XV). Alcohol (XVI) was converted to mesylate (XVII). Subsequent displacement in (XVII) by NaN3 afforded the corresponding azide, which was reduced to amine (IX) by hydrogenation over Pd/C. This was finallyconverted to the title compound by the same sequence as above.

(R)-4-hydroxy-2-pyrrolidinone (I) was protected as the tert-butyldimethylsilyl ether, and then converted to tert-butyl carbamate (II) by means of Boc2O. Subsequent condensation of (II) with Grignard reagent (III), followed by reduction with NaBH4, and acetal hydrolysis yielded the pyrrolidinyl benzaldehyde (IV). Horner-Emmons reaction of (IV) with phosphonate (V) produced the cinnamic acid derivative (VI), and further Michael addition to (VI) of the chiral lithium amide (VII) furnished aminoester (VIII). After hydrogenolysis of both N-benzyl groups of (VIII), the resulting primary amine (IX) was protected with Boc2O, and the silyl ether was then cleaved by means of tetrabutylammonium fluoride to give the hydroxypyrrolidine derivative (X). This was converted to the required thiol (XI), which was then coupled with the carbapenem phosphate (XII). Finally, hydrogenolysis of the 4-nitrobenzyl ester of (XII) provided the title compound.

In an alternative procedure, aldehyde (IV) was condensed with ethyl acetate in the presence of lithium hexamethyldisilazide to give hydroxyester (XIII). This was esterified with chloroacetyl chloride to provide (XIV) as a diastereomeric mixture. Kinetic resolution of (XIV) employing lipase selectively hydrolyzed the undesired isomer to furnish hydroxyester (XV), which was separated from the required chloroacetate (XVI). After hydrolysis of the chloracetyl ester (XVI) by means of ammonium hydroxide, the resulting alcohol was converted to mesylate (XVII). Subsequent displacement in (XVII) by NaN3 afforded the corresponding azide, which was reduced to amine (IX) by hydrogenation over Pd/C. This was converted to the title compound by the same sequence as above.

The protection of 4(R)-hydroxypyrrolidin-2-one (I) first with TBDMS-Cl and then with Boc2O gives the fully protected compound (II), which is condensed with the Grignard reagent of the 4-bromobenzaldehyde dimethyl acetal (III) yielding after working up the substituted benzaldehyde (IV). The reduction of (IV) with NaBH4 affords the benzyl alcohol (V), which is treated with methanesulfonyl chloride to give the corresponding mesylate (VI). The reaction of (VI) with methylamine, followed by protection with Boc2O yields the protected secondary amine (VII), which is desilylated with tetrabutylammonium fluoride to afford the pyrrolidinol (VIII). The reaction of (VIII) with MsCl gives the mesylate (IX), which is treated with potassium thioacetate to provide the acetylsulfanyl derivative (X). The hydrolysis and deprotection of (X) with HCl yields the pyrrolidinethiol (XI), which is condensed with the carbapenem phosphoric ester (XII) to afford the final 4-nitrobenzyl ester intermediate (XIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C.

(R)-4-hydroxy-2-pyrrolidinone (I) was protected as the tert-butyldimethylsilyl ether, and then converted to tert-butyl carbamate (II) by means of Boc2O. Subsequent condensation of (II) with Grignard reagent (III), followed by reduction with NaBH4, and acetal hydrolysis yielded the pyrrolidinyl benzaldehyde (IV). Horner-Emmons reaction of (IV) with phosphonate (V) produced the cinnamic acid derivative (VI), and further Michael addition of the chiral lithium amide (VII) furnished aminoester (VIII). After hydrogenolysis of both N-benzyl groups of (VIII), the resulting primary amine (IX) was protected with Boc2O, and the silyl ether was then cleaved by means of tetrabutylammonium fluoride to give the hydroxypyrrolidine derivative (X). This was converted to the required thiol (XI), which was then coupled with the carbapenem phosphate (XII). Finally, hydrogenolysis of the 4-nitrobenzyl ester of (XII) provided the title compound.

(R)-4-hydroxy-2-pyrrolidinone (I) was protected as the tert-butyldimethylsilyl ether, and then converted to tert-butyl carbamate (II) by means of Boc2O. Subsequent condensation of (II) with Grignard reagent (III), followed by reduction with NaBH4, and acetal hydrolysis yielded the pyrrolidinyl benzaldehyde (IV). Horner-Emmons reaction of (IV) with phosphonate (V) produced the cinnamic acid derivative (VI), and further Michael addition to (VI) of the chiral lithium amide (VII) furnished aminoester (VIII). After hydrogenolysis of both N-benzyl groups of (VIII), the resulting primary amine (IX) was protected with Boc2O, and the silyl ether was then cleaved by means of tetrabutylammonium fluoride to give the hydroxypyrrolidine derivative (X). This was converted to the required thiol (XI), which was then coupled with the carbapenem phosphate (XII). Finally, hydrogenolysis of the 4-nitrobenzyl ester of (XII) provided the title compound.

The protection of 4(R)-hydroxypyrrolidin-2-one (I) first with TBDMS-Cl and then with Boc2O gives the fully protected compound (II), which is condensed with the Grignard reagent of the 4-bromobenzaldehyde dimethyl acetal (III) yielding after working up the substituted benzaldehyde (IV). The reduction of (IV) with NaBH4 affords the benzyl alcohol (V), which is treated with methanesulfonyl chloride to give the corresponding mesylate (VI). The reaction of (VI) with methylamine, followed by protection with Boc2O yields the protected secondary amine (VII), which is desilylated with tetrabutylammonium fluoride to afford the pyrrolidinol (VIII). The reaction of (VIII) with MsCl gives the mesylate (IX), which is treated with potassium thioacetate to provide the acetylsulfanyl derivative (X). The hydrolysis and deprotection of (X) with HCl yields the pyrrolidinethiol (XI), which is condensed with the carbapenem phosphoric ester (XII) to afford the final 4-nitrobenzyl ester intermediate (XIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C.

(R)-4-hydroxy-2-pyrrolidinone (I) was protected as the tert-butyldimethylsilyl ether, and then converted to tert-butyl carbamate (II) by means of Boc2O. Subsequent condensation of (II) with Grignard reagent (III), followed by reduction with NaBH4, and acetal hydrolysis yielded the pyrrolidinyl benzaldehyde (IV). Horner-Emmons reaction of (IV) with phosphonate (V) produced the cinnamic acid derivative (VI), and further Michael addition of the chiral lithium amide (VII) furnished aminoester (VIII). After hydrogenolysis of both N-benzyl groups of (VIII), the resulting primary amine (IX) was protected with Boc2O, and the silyl ether was then cleaved by means of tetrabutylammonium fluoride to give the hydroxypyrrolidine derivative (X). This was converted to the required thiol (XI), which was then coupled with the carbapenem phosphate (XII). Finally, hydrogenolysis of the 4-nitrobenzyl ester of (XII) provided the title compound.

(R)-4-hydroxy-2-pyrrolidinone (I) was protected as the tert-butyldimethylsilyl ether, and then converted to tert-butyl carbamate (II) by means of Boc2O. Subsequent condensation of (II) with Grignard reagent (III), followed by reduction with NaBH4, and acetal hydrolysis yielded the pyrrolidinyl benzaldehyde (IV). Horner-Emmons reaction of (IV) with phosphonate (V) produced the cinnamic acid derivative (VI), and further Michael addition to (VI) of the chiral lithium amide (VII) furnished aminoester (VIII). After hydrogenolysis of both N-benzyl groups of (VIII), the resulting primary amine (IX) was protected with Boc2O, and the silyl ether was then cleaved by means of tetrabutylammonium fluoride to give the hydroxypyrrolidine derivative (X). This was converted to the required thiol (XI), which was then coupled with the carbapenem phosphate (XII). Finally, hydrogenolysis of the 4-nitrobenzyl ester of (XII) provided the title compound.

The reaction of the acetonide of (R)-3,4-dihydroxybutanal (I) with the silylated 4-bromobenzyl alcohol (II) by means of n-BuLi in THF gives the corresponding carbinol (III), which is oxidized to the ethanone (IV) by means of tetrapropylammonium perruthenate (TPAP) and NMO in dichloromethane. The enantioselective reduction of the ketone (IV) by means of LiAlH4 and an excess of LiI in ethyl ether gives the (R,S)-enantiomer (V), which is mesylated with MsCl/TEA in dichloromethane and treated with NaN3 in hot DMF to yield the azide (VI). The reduction of (VI) with triphenylphosphine in THF/water affords the amine (VII), which is treated with allyl chloroformate and TEA in THF providing the carbamate (VIII). The desilylation of (VIII) with TBAF in THF gives the benzyl alcohol (IX), which is mesylated with MsCl and TEA in dichloromethane yielding the mesyl ester (X). The reaction of (X) with NaN3 in DMF affords the azide (XI), which is reduced as before to the benzylamine (XII). The reaction of (XII) with allyl chloroformate provides the bis carbamate (XIII).

Compound (XIII) is treated with TsOH in methanol to eliminate the acetonide group and yield the diol (XIV). The dimesylation of (XIV) with MsCl and TEA as before affords the dimesylate (XV). The cyclization of (XV) by means of t-BuOK in THF gives the pyrrolidine (XVI), which is treated with potassium thioacetate in hot DMF to yield the acetylsulfanyl derivative (XVII).The selective hydrolysis of (XVII) with NaOH in methanol affords the thiol (XVIII), which is condensed with the protected carbapenem (XIX) by means of DIEA in acetonitrile to furnish the protected target compound (XX). Finally, this compound is deprotected by a treatment with (PPh3)2PdCl2 and Bu3SnH in dichloromethane/water.

The protection of 4(R)-hydroxypyrrolidin-2-one (I) first with TBDMS-Cl and then with Boc2O gives the fully protected compound (II), which is condensed with the Grignard reagent of the 4-bromobenzaldehyde dimethyl acetal (III) yielding after working up the substituted benzaldehyde (IV). The reduction of (IV) with NaBH4 affords the benzyl alcohol (V), which is treated with methanesulfonyl chloride to give the corresponding mesylate (VI). The reaction of (VI) with methylamine, followed by protection with Boc2O yields the protected secondary amine (VII), which is desilylated with tetrabutylammonium fluoride to afford the pyrrolidinol (VIII). The reaction of (VIII) with MsCl gives the mesylate (IX), which is treated with potassium thioacetate to provide the acetylsulfanyl derivative (X). The hydrolysis and deprotection of (X) with HCl yields the pyrrolidinethiol (XI), which is condensed with the carbapenem phosphoric ester (XII) to afford the final 4-nitrobenzyl ester intermediate (XIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C.

(R)-4-hydroxy-2-pyrrolidinone (I) was protected as the tert-butyldimethylsilyl ether, and then converted to tert-butyl carbamate (II) by means of Boc2O. Subsequent condensation of (II) with Grignard reagent (III), followed by reduction with NaBH4, and acetal hydrolysis yielded the pyrrolidinyl benzaldehyde (IV). Horner-Emmons reaction of (IV) with phosphonate (V) produced the cinnamic acid derivative (VI), and further Michael addition of the chiral lithium amide (VII) furnished aminoester (VIII). After hydrogenolysis of both N-benzyl groups of (VIII), the resulting primary amine (IX) was protected with Boc2O, and the silyl ether was then cleaved by means of tetrabutylammonium fluoride to give the hydroxypyrrolidine derivative (X). This was converted to the required thiol (XI), which was then coupled with the carbapenem phosphate (XII). Finally, hydrogenolysis of the 4-nitrobenzyl ester of (XII) provided the title compound.

(R)-4-hydroxy-2-pyrrolidinone (I) was protected as the tert-butyldimethylsilyl ether, and then converted to tert-butyl carbamate (II) by means of Boc2O. Subsequent condensation of (II) with Grignard reagent (III), followed by reduction with NaBH4, and acetal hydrolysis yielded the pyrrolidinyl benzaldehyde (IV). Horner-Emmons reaction of (IV) with phosphonate (V) produced the cinnamic acid derivative (VI), and further Michael addition to (VI) of the chiral lithium amide (VII) furnished aminoester (VIII). After hydrogenolysis of both N-benzyl groups of (VIII), the resulting primary amine (IX) was protected with Boc2O, and the silyl ether was then cleaved by means of tetrabutylammonium fluoride to give the hydroxypyrrolidine derivative (X). This was converted to the required thiol (XI), which was then coupled with the carbapenem phosphate (XII). Finally, hydrogenolysis of the 4-nitrobenzyl ester of (XII) provided the title compound.