Intramolecular nucleophilic dealkylation

Racemic hydroxy ester 225 was converted, via a Sharpless kinetic resolution, to the enantiomerically pure epoxide 226. This epoxide was then converted to the diol "/-lactone by intramolecular attack of the ester, assisted by nucleophilic dealkylation with iodide ion. Deprotonation and methylation anti to the alkoxide followed by acetonide formation afforded 227 in 56% yield. Dibal reduction, protection of the resulting aldehyde as the terminal olefin, silylation of the tertiary alcohol, and liberation of the aldehyde via ozonolysis provided a 45% yield of the C-9 to C-15 fragment 228. 

In mammalian liver microsomes, cytochrome P-450 is not specific and catalyzes a wide variety of oxidative transformations, such as (i) aliphatic C—H hydroxylation occurring at the most nucleophilic C—H bonds (tertiary > secondary > primary) (ii) aromatic hydroxylation at the most nucleophilic positions with a characteristic intramolecular migration and retention of substituents of the aromatic ring, called an NIH shift,74 which indicates the intermediate formation of arene oxides (iii) epoxidation of alkenes and (iv) dealkylation (O, N, S) or oxidation (N, S) of heteroatoms. In mammalian liver these processes are of considerable importance in the elimination of xenobiotics and the metabolism of drugs, and also in the transformation of innocuous molecules into toxic or carcinogenic substances.75 77... 

The reverse process, the nucleophile-induced dealkylations of methyl-Co(III)-corrins, has been less studied due to the impediment of the intramolecular coordination of the nucleotide base [134,137]. Indeed, thiolates demethylate methylcobinamide (45) to cob(l)inamide (43) approximately 1000 times faster than MeCbl (3) to B s (40") [137], reflecting the strong stabilizing effect of the coordinated nucleotide in 3 [86,134]. This is of relevance for enzymatic methyl group transfer reactions involving protein bound Co(l)- and methyl-Co(lll)-corrins, where considerable axial base effects are expected [125,138]. 

A survey of the many examples of Lewis acid-promoted Passerini-type reactions, finds that most are characterized by one of four distinct processes a) nucleophilic attack of an additional equivalent(s) of isonitrile to form oligomeric products " (17) b) nitrogen dealkylation to give cyanohydrin-type products (18) c) intramolecular capture of tethered-nucleophiles to form cyclic products (19) and d) intermolecular capture of other weakly-basic nucleophiles such as dissociable counterions of the Lewis acid (20) such as the chloride ion for TiCk. 

Chloroadenallene 45 gave, after refluxing with triethylphosphite for 30 min, g-2 -phosphonate 47 in 30% yield (Scheme 7). A routine dealkylation afforded phosphonic acid 48 (60%). Thus, the usual reaction at the reactive allylic terminal was suppressed in favor of a nucleophilic attack at the sp carbon atom. The mechanism may include an intramolecular dealkylation as indicated in formula 49, although an intermolecular reaction is also possible. 

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