2-Azetidinones. with oxazolidinones

The diastereoselectivity of the zinc iodide catalyzed reaction of the azetidinone I with the trimethylsilyl enolate derivatives of the chiral 3-(l-oxopropyI)oxazolidinones 6 was considerably lower (about 60 40), although independent generation of the zinc enolate, via exchange of the lithium enolate with zinc bromide, afforded the /9-Iactam carboximide derivatives in a ratio (RIS) 80 20177. 

Further process optimization by Thiruvengadam and co-workers (Thimvengadam et al., 1999), led to a novel, stereoselective, scalable two-step process devoid of chromatography for chiral 2-azetidinone construction (Scheme 13.4). As above, the titanium-enolate of chiral oxazolidinone 11a was preformed, but now when reacted with well behaved imines of type 16, affords the unexpected anti-addition product. This surprising result was further supported by careful comparison to minor antiproducts obtained in the earlier aldol-addition methodology and determination that the major product was indeed 17a (undesired RSR series). Adjustment of the oxazolidinone absolute stereochemistry to the fortuitously less expensive 2S-series afforded the desired diastereo-mer 17b in 95% de and in 50-70% yield. Recrystallization improved the stereochemical purity to >99% de. 

Formation of a 3-amino azetidinone and its N-Boc protected form from oxazolidinone precursors shows that various reactions can be performed with good yields (67-95%) without affecting the 7V-[bis(trimethylsilyl)methyl] group... 

Schering-Plough Corp, has used an oxazolidinone in its synthesis of the cholesterol adsorption inhibitor (+)-SCH 54016 (24) (Scheme 7) [51], Condensation of an acid chloride intermediate with the (7 )-phenylglycine-derived Evans auxiliary followed by reaction of the titanium enolate with -(4-methoxybenzyh-dene)anihne gave the intermediate 25. This was silylated and treated with TBAF, resulting in removal of the auxiliary and cyclization to form the 2-azetidinone ring. The stereochemistry was exclusively trans. The azetidinone was then converted to the bromide, followed by intramolecular alkylation to form SCH 50416 in > 99% ee. 

Trifluoromethyl substituted aldimines react with a-benzyloxyacetyl chloride in the presence of triethylamine to give the CF3 substituted azetidinones in 50 % yields Also, A-o -(trimethylsilyl)methyl imines undergo cycloaddition with the oxazolidinone substituted ketene 269 to give the [2-1-2] cycloadducts 270 with excellent diastereomeric... 

Researehers at Schering-Plough have demonstrated the use of Evans ehiral oxazolidinone in their synthesis of the potent 2-azetidinone cholesterol inhibitor ezetimibe (Scheme 14.71). Reaetion of oxazolidinone 193 with imine 194 led to formation of the requisite antz-Evans-aldol product 196 in an impressive 95% de. Subsequent recrystallisation increased the de to 99%. Initial treatment of 193 with TiCU and DIPEA led to (Z)-enolate formation. It has been proposed that faeial seleetivity in the anfr-Evans aldol reaction is controlled through a boat transition state, ° and this may be facilitated by the ability of titanium to eoordinate to three heteroatoms. The combination of these two factors account for the high diastereoselectivity observed in this reaction. Silylation followed by fluoride eatalysed cyclisation afforded azetinone 197 in 85% yield whieh was subsequently transformed... 

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