Lactam sulfoxide 4/? -Lactone

Cyclic sulfoxides, lactones, lactams, and other heterocycles as transdermal penetration enhancers 99CLY107. 

Hydrolysis Oxidation Photolysis Esters, lactones, amides, lactams, oximes, imides, and malonic ureas Amines, sulfides, disulfides, sulfoxides, phenol anions, thiols, nitriles, and catechols Aromatic hydrocarbons, aromatic heterocyclics, aldehydes, and ketones... 

The synthesis of unnatural (+)-mesembrine (387) through the asymmetric synthesis of methyl (i )-l-[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-enyl acetate (390) by cycloaddition of enantiomerically pure vinyl sulfoxide with dichloroketene has been performed 189) (Scheme 43). Vinyl sulfoxide 388 [prepared by conjugate addition of enantiopure acetylenic sulfoxide with (3,4-dimethoxy)phenylcopper] reacted with trichloroacetyl chloride in the presence of freshly prepared zinc-copper couple in THF at 0°C to produce a mixture of mono- and dichloro lactones 389. Reduction of 389 with zinc in acetic acid followed by cyclization and methylation afforded methyl IR-[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-enyl acetate (390), treatment of which with methylamine brought about amidation and concomitant intramolecular Michael addition to provide 2-oxo-mesembrine (391). Successively, 391 was transformed to (+)-mesembrine (387) in 79% yield (three steps ketalization of an oxo group, reduction of lactam, and deketali-zation)(/S9). 

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... 

An aldol mechanism was investigated by NMR monitoring. The sterically large TAS-enolate attacks the less-hindered face accounting for the observed diastereoselectivity. Some hindered TAS-enolates have shown basic properties that can cause dimerization of monosaccharide lactones. Cyclic enol ethers were also used to generate bicyclic lactams (eq 25) or /3-keto sulfoxides (eq 26). TASF appears to be a more potent source of fluoride than TBAF or BTAF, providing higher yields. 

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