Diastereoselective Manipulations of Bicyclo[m.1.0]alkane Derivatives. 4. Reactions of Nucleophiles with Bicyclo[m.1.0]alk-3-en-2-ones

Abstract

Enantiomerically enriched bicyclo[m.1.0]alk-3-en-2-ones possessing 8-, 12-, and 15-membered rings were prepared and subjected to additions of nucleophiles. 1,2-Additions of n-butyllithium were highly diastereoselective for all cyclopropyl enones examined. Reactions of (Z)-bicyclo[6.1.0]non-3-en-2-one and (E)-bicyclo[13.1.0]hexadec-3-en-2-one with dimethyloxosulfonium methylide were highly diastereoselective, while reaction of (E)-bicyclo[10.1.0]tridec-3-en-2-one with this reagent was not diastereoselective. In contrast, 1,4-additions of lithium diorganocuprates were highly diastereoselective for the 8- and 12-membered enones but were not diastereoselective for the 15-membered enone. All reactions were chemically efficient. The diastereoselectivities observed for 1,2-additions, which are thought to involve early transition states, can be rationalized by consideration of the low-energy conformations of each cyclopropyl enone. The diastereoselectivities observed for 1,4-additions, which may involve late transition states, do not correlate simply with the lowest energy conformations of these enones.

Total Synthesis of Acaulide and Acaulone A

“…Generally, the late stage Michael addition of a nucleophile to a macrocyclic compound, as in the plausible biosynthetic pathways of 1 , is challenging because controlling regio- and stereoselectivity is difficult. Therefore, stereogenic centers, which can be constituted by Michael addition, are commonly introduced by using asymmetric catalysts, bicyclic scaffolds of medium- and large-sized carbocycles to fix their conformations, or prior to macrocyclization with chiral building blocks …”