A [4+4] 2-pyridone approach to taxol. 3. Stereocontrol during elaboration of the cyclooctane

Intramolecular photocycloaddition of 8-pyridones connected through a four-c arbon tether (6-[4-(1,2-dihydro- 1,methyl-2-oxo-3-pyridinyl)-4-[[( 1,1-dime thylethyl)dimethylsilyl]oxy]butyl]-4-methoxy-1,3-dimethyl-2(1H)-pyridinone) yields a single tetracyclic product with four new stereogenic centers. The diastereoselectivity of this [4 + 4] reaction is fully controlled by a ste reogenic carbon of the tether. Treatment of the photoproduct with osmium te traoxide transforms the alkene to a diol and the enol ether to an ol-hydrox y ketone, with stereocontrol dictated by nearby lactams that block one face of each alkene. Allylmagnesium bromide addition to the ketone also yields a single diastereomer, but unexpectedly this product results from approach of the nucleophile to the most-hindered face of the ketone. Study of this r eaction in a model system has found the allylic nucleophile to be unique, w ith nonallylic reagents approaching along the expected, least-hindered path . This contrasteric addition likely results from coordination of the allyli c nucleophile to the nearby amide. The amide can therefore act either as a steric shield or as a directing group. The three steps of photocycloadditio n, cis-hydroxylation, and nucleophilic addition constructs both quaternary carbons of the cyclooctane and four of the five stereogenic centers found i n the eight-membered ring of Taxol.