Simultaneous Arming and Structure/Activity Studies of Natural Products Employing O−H Insertions: An Expedient and Versatile Strategy for Natural Products-Based Chemical Genetics

The identification of “druggable” targets is an immediate opportunity and challenge in the post-genomic era. Natural products are enduring tools for basic cellular studies and leads for identifying medically
relevant protein targets. However, their use for these studies is often hampered by limited quantities and
a lack of selective and mild monofunctionalization reactions. The development of selective methods that
could simultaneously equip the natural product with a reactive group for subsequent conjugation to reporter
tags and provide important structure−activity relationship (SAR) information, requiring only a knowledge
of functional groups present in the natural product, could significantly decrease the time between bioactive
natural product isolation and target identification. Herein, we report such a strategy that enables simultaneous
arming and SAR studies of alcohol-containing natural products involving both chemo- and site-selective
(“chemosite” selective) and site-nonselective O−H insertion reactions with rhodium carbenoids derived
from alkynyl diazo acetates. This strategy was applied to a diverse set of natural products, and general
guidelines for predicting chemosite selectivity were formulated. A subsequent Sharpless−Hüisgen [3 + 2]
cycloaddition reaction with the appended alkyne allows for attachment of a variety of reporter tags. Using
this strategy, we synthesized a novel FK506−biotin conjugate that enabled pull-down of the entire
“immunosuppressive complex” including FKBP12, calcineurins A and B, and calmodulin. In addition, the
potential for a chemoselective but site-nonselective process was shown with both gibberellic acid methyl
ester and brefeldin A using only achiral rhodium catalysts.