Forty years ago the Richman-Atkins method for azamacrocycle synthesis represented a paradigm shift in the synthesis of important azamacrocycles such as tacn and cyclen.  Their method obviated high-dilution conditions, the need for metal templating, and greatly improved the yields compared to all alternative strategies.  The central advance of the Richman-Atkins synthesis, their use of the toluenesulfonyl moiety both as a protecting group and activating group, is also the greatest weakness of the synthesis by requiring dangerous conditions to remove (e.g., refluxing concentrated sulfuric acid at 100-170 degrees for many hours to a week).  Since protecting group chemistry has advanced significantly in the past four decades, we investigated several alternative protecting group strategies with the aim of enabling room-temperature reactions in less toxic solvents with high yields and greater atom economy and lower E factors (measures of how “green” a synthesis is).  Azamacrocycles were obtained in high yield using a completely new protecting group, trifluorotoluenesulfonyl, which can be removed using thiols at room temperature compared to prolonged refluxing in concentrated sulfuric acid for the Richman-Atkins toluenesulfonyl.  Azamacrocycles were also synthesized using tert-butyloxycarbonyl (boc), one of the greenest and mildest protecting groups to install, work with, and remove.  The Richman-Atkins synthesis also suffers from the high symmetry of the resulting macrocycles, meaning that orthogonally-substituted derivatives, such as the 3:1 substituted cyclens used as DOTA derivatives in the gadolinium(III) MRI contrast agents Gadavist and ProHance, need to incorporate secondary and even tertiary protecting groups in the synthesis.  Instead, we have developed a strategy to synthesize the parent macrocycle using protecting groups in the macrocyclization step that readily enable the eventual 3:1 substitution without the need for switching out protecting groups.

Updating Richman-Atkins for the 21<sup>st</sup> century: Simpler, faster, and greener azamacrocycle synthesis

249th National Meeting (2015)

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Updating Richman-Atkins for the 21st century: Simpler, faster, and greener azamacrocycle synthesis

Updating Richman-Atkins for the 21^st century: Simpler, faster, and greener azamacrocycle synthesis