Exploiting Masked Alcohols to Guide Atom-Transfer Reactions

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This grant supports research to interrogate the hypothesis that “sulfamate esters will guide radical-mediated γ- functionalization reactions, and enable us to harness a ubiquitous functional group to replace a C–H bond at a site that is not generally accessible to direct functionalization.” The substrate tolerance of the developed technologies is being documented within the context of health-relevant complex small molecules so as to determine the extent to which these research advances complement available methods, are diastereoselective, and enable late-stage functionalization processes. For developed processes in which a catalyst appears directly involved in the radical trapping event, the potential for catalyst controlled enantioinduction should be evaluated. For the purposes of this equipment supplement abstract, the justification of need for a High Pressure Liquid Chromatograph (HPLC) that operates on analytical and semi-preparative scales will be described in the context of an ongoing project to develop a sulfamyl radical-directed photoredox-mediated Giese reaction. Nevertheless, the documented challenges are relevant to all of the Research Areas of 1R35GM128741. The development of a sulfamyl radical-directed photoredox-mediated Giese reaction is an early step to address the underexploration of nitrogen-centered radicals in synthetic chemistry. Nitrogen-centered radicals are an important and versatile class of chemical intermediates. Yet, nitrogen-centered radicals remain underutilized: most methods for their generation rely on harsh conditions to oxidize the nitrogen center to facilitate radical generation. Recently, photocatalytic strategies have been developed as mild processes to form nitrogen- centered radicals. Of neutral nitrogen-centered radicals accessed using photoredox catalysis without substrate pre-oxidation, only amidyl radicals are known to engage in C–H abstraction and subsequent functionalization. As a complement to amides, sulfamate esters may be non-intuitive. For sulfamate esters, experimental measurements that would inform a photoredox-mediated oxidation strategy have not been previously disclosed, and sulfamate esters are predicted to be significantly more acidic than similarly N-substituted amides. Nevertheless, sulfamate ester substrates are attractive because they derive from alcohols, which are ubiquitous in biologically active small molecules. Additionally, sulfamate esters are expected to guide functionalization to γ- C(sp3)–H bonds, which are not generally accessible to established directed processes. As such, a strategy to direct C–H functionalization using a sulfamyl radical could enable previously unrealized synthetic disconnections. We have developed the first photoredox-mediated process to access sulfamyl radicals, a method to guide γ-C– H functionalization as demonstrated in the reported Giese reactions (Schemes 1–3). One of the features of this Giese reaction is that many methylene centers engage in a single alkylation event, in preference to two sequential alkylation events, likely owing to steric encumbrance (Scheme 1). This is most readily evident with simple substrates, such as sulfamate esters 1a and 1b. These sulfamate esters engage in a single alkylation event to furnish Giese products 2a and 2b, respectively, which incorporate tertiary γ-C(sp3)– H bonds. These tertiary C–H centers are weaker than the secondary γ-C(sp3)–H centers in substrates 1a and 1b, and might thereby have been more susceptible to further alkylation to furnish fully-substituted 3a and 3b. To explain this selectivity, we hypothesized that the newly generated tertiary γ-C(sp3)–H bond may prove too sterically hindered to engage in further functionalization. Consistent with this hypothesis, bisalkylation seems to proceed only with a narrowly tailored subset of substrates that incorporate minimally sterically encumbered methylene centers, such as less sterically encumbered 1c, which undergoes initial monoalkylation with tert-butyl acrylate, followed by a second Giese reaction to generate fully-substituted 3c. Interrogation of the features that are required for bisalkylation has been limited by insufficient access to appropriate analytical and semi- preparative HPLC resources (see Scheme 2). Scheme 1. Sulfamate esters guide late-stage derivatization of bioactive small molecules.