Publication Date:
2015-08-27
Description:
Redox processes and radical intermediates are found in many biochemical processes, including deoxyribonucleotide synthesis and oxidative DNA damage. One of the core principles underlying DNA biosynthesis is the radical-mediated elimination of H2O to deoxygenate ribonucleotides, an example of 'spin-centre shift', during which an alcohol C-O bond is cleaved, resulting in a carbon-centred radical intermediate. Although spin-centre shift is a well-understood biochemical process, it is underused by the synthetic organic chemistry community. We wondered whether it would be possible to take advantage of this naturally occurring process to accomplish mild, non-traditional alkylation reactions using alcohols as radical precursors. Because conventional radical-based alkylation methods require the use of stoichiometric oxidants, increased temperatures or peroxides, a mild protocol using simple and abundant alkylating agents would have considerable use in the synthesis of diversely functionalized pharmacophores. Here we describe the development of a dual catalytic alkylation of heteroarenes, using alcohols as mild alkylating reagents. This method represents the first, to our knowledge, broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox and hydrogen atom transfer catalysis. The value of this multi-catalytic protocol has been demonstrated through the late-stage functionalization of the medicinal agents, fasudil and milrinone.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560617/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560617/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jin, Jian -- MacMillan, David W C -- R01 GM103558/GM/NIGMS NIH HHS/ -- R01 GM103558-03/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Sep 3;525(7567):87-90. doi: 10.1038/nature14885. Epub 2015 Aug 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26308895" target="_blank"〉PubMed〈/a〉
Keywords:
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives/chemistry
;
Alcohols/*chemistry
;
Alkylating Agents/*chemistry
;
Alkylation
;
Carbon/*chemistry
;
Catalysis
;
Hydrogen/*chemistry
;
Milrinone/chemistry
;
Oxidation-Reduction
;
Oxygen/chemistry
;
Photochemical Processes
;
Substrate Specificity
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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