Studies on the synthesis of ammonificin A: New synthesis of trans-4-arylchroman-3-ols via intramolecular dehydrative Friedel–Crafts alkylation of 3-aryloxy-1-arylpropane-1,2-diols

Abstract

A synthesis route which passes through a trans-4-arylchroman-3-ol intermediate en route to the total synthesis of the marine natural product ammonificin A was designed and pursued. Initial model studies were focused on the development of suitable method for constructing trans-4-arylchroman-3-ol core and then its conversion into cis-3-aryloxy-4-arylchromane scaffold. In this context, a new strategy has been developed to prepare trans-4-arylchroman-3-ols bearing ortho/para-EDG in the C-4 aryl group via intramolecular dehydrative Friedel–Crafts alkylation of 3-aryloxy-1-arylpropane-1,2-diols. A number of attempts to convert trans-4-arylchroman-3-ols into cis-3-aryloxy-4-arylchromans failed. This problem was successfully overcome using diphenyliodonium tetrafluoroborate for the O-arylation of a cis-4-arylchroman-3-ol intermediate. Notwithstanding these noteworthy accomplishments, the first total synthesis of ammonificin A remained elusive as the planned applications of these two newly developed methodologies for the total synthesis was disastrous because commonly used reaction conditions unexpectedly thwarted the deprotection of an acetonide moiety of early-stage intermediates.