Lactam formation from keto-acid

Preparative Methods the chiral bicyclic lactams are easily procured via condensation of commercially available (15, 25)-(+)-2-amino-l-phenyl-1,3-propanediol and the appropriate 5-keto acid (eq 1). - Similar bicyclic lactams have been prepared from other amino alcohols and have been extensively utilized in the stereocontrolled formation of quaternary carbon-carbon bonds. ... 

More complex products are obtained from cyclizations in which the oxidizable functionality and the alkene are present in the same molecule. y9-Keto esters have been used extensively for Mn(III)-based oxidative cyclizations and react with Mn(OAc)3 at room temperature or slightly above [4, 10, 11, 15], They may be cyclic or acyclic and may be a-unsubstituted or may contain an a-alkyl or chloro substituent. Cycloalkanones are formed if the unsaturated chain is attached to the ketone. y-Lactones are formed from allylic acetoacetates [10, 11]. Less acidic /3-keto amides have recently been used for the formation of lactams or cycloalkanones [37]. Malonic esters have also been widely used and form radicals at 60-80 °C. Cycloalkanes are formed if an unsaturated chain is attached to the a-position. y-Lactones are formed from allylic malonates [10, 11]. yff-Diketones have been used with some success for cyclizations to both alkenes and aromatic rings [10, 11]. Other acidic carbonyl compounds such as fi-keto acids, /3-keto sulfoxides, j8-keto sulfones, and P-nitro ketones have seen limited use [10, 11]. We have recently found that oxidative cyclizations of unsaturated ketones can be carried out in high yield in acetic acid at 80 °C if the ketone selectively enolizes to one side and the product cannot enolize... 

The ready formation of esters of P amino acids by reduction of the correspond ing imines/enamines (Table 4.6, entries 12 14), which in turn can be prepared from the readily available P keto esters, allowed an expedient synthesis of SCH48461 (56), a potent, orally active inhibitor of cholesterol absorption [22]. Enamine 36n (Scheme 4.6) was reduced (via imine lOn) with ChSiH in the presence of Sigamide (35) to afford the P amino ester ISn (80% isolated yield, 88% ee), whose treatment with methylmagnesium bromide (acting as a base) produced p lactam 55 (92%). Enolization of the latter derivative with LDA followed by alkylation with cinnamyl bromide and catalytic hydrogenation afforded 56 in 77% overall yield for the last two steps (S. Stoncius, A.V. Malkov, and P. Kocovsky, unpublished results). 

The keto ester XXVI has been derived in a different sequence beginning with lactam VIII which, from its mode of formation, must have the partial structure shown in Scheme 6. From VIII it was possible to derive the epimeric hydroxy acids XXVII and XXVIII and their corresponding esters. The ester XXIX was unstable relative to XXX. 

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