Squeezing fragments into cycles

Today is dedicated to the efforts of Chris White, my PhD student who is soon leaving us for Zurich, where he will work as a postdoctoral associate at the ETH in the laboratory of Professor Jeff Bode. Over the past 3 years, Chris has been painstakingly perfecting a reaction that amounts to insertion of amino acid fragments into cyclic peptides. While there is no precedent for integrative operations in the realm of synthetic chemistry, nature is known to do it. One particularly well-known process in biology involves integration of DNA fragments into host chromosomes. This function-driven insertion of “foreign” fragments into existing biological entities has far-reaching consequences. When we think about synthetic challenges in our lab, we often draw inspiration from nature. Several years ago we asked a question: if the retroviral enzyme integrase can do it by binding both termini of viral DNA, can we think of a reductionist approach to this process? How about instead of DNA and enzymes we teach some new tricks to lithium hydroxide and simple coupling reagents? Chris has capitalized on the susceptibility of N-acyl aziridines to amide hydrolysis –  their “Achilles’ heel” – and developed a tool to site-selectively incorporate molecular fragments into cyclic peptides. We think that this method should be readily adaptable to solid phase synthesis, be extended to split and pool protocols using molecular fragments of varying diversity, and help create non-amide bond forming approaches to fragment integration. Our lab will now actively work in these directions. Thanks Chris for your trailblazing efforts!

ccc 7.46.16 PM

http://pubs.acs.org/doi/abs/10.1021/ja412256f

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