The efficiency and selectivity of hydrogen atom transfer from organic molecules are often difficult to control in the presence of multiple potential hydrogen atom donors and acceptors. Here, we describe the mechanistic evaluation of a mode of catalytic activation that accomplishes the highly selective photoredox α-alkylation/lactonization of alcohols with methyl acrylate via a hydrogen atom transfer mechanism. Our studies indicate a particular role of tetra-n-butylammonium phosphate in enhancing the selectivity for α C–H bonds in alcohols in the presence of allylic, benzylic, α-C=O, and α-ether C–H bonds.

A direct β-coupling of cyclic ketones with imines has been accomplished via the synergistic combination of photoredox catalysis and organocatalysis. Transient β-enaminyl radicals derived from ketones via enamine and oxidative photoredox catalysis readily combine with persistent α-amino radicals in a highly selective hetero radical–radical coupling. This novel pathway to γ-aminoketones is predicated upon the use of DABCO as both a base and an electron transfer agent. This protocol also formally allows for the direct synthesis of β-Mannich products via a chemoselective three-component coupling of aryl aldehydes, amines, and ketones.

Increasing interest in C(sp 3 )-H bond functionalization has led to a multitude of recent advances in intramolecular C(sp 3 )-H amination. Direct, intramolecular C(sp 3 )-N bond-forming processes provide expedient access to a range of azacycles without the need for prefunctionalized amine precursors such as aminoaldehydes, aminoalkyl halides or aminoalkenes. Some of these methods have been successfully applied to the synthesis of complex natural products. This Perspective provides a historical context for these methods and describes recent contributions, as well as the remaining challenges to intramolecular C(sp 3 )-H amination. Scheme 1 A hypothetical direct C(sp 3 )-H amination. Jenna was born and raised in Eugene, OR. She received her B.S. from the University of Oregon in 2008, where she conducted research as a Barry M. Goldwater Scholar in the laboratory of Prof. Michael Haley. Jenna began her doctoral studies in 2008 with Prof. Richmond Sarpong at the University of California, Berkeley, where she worked on the synthesis of dimeric resveratrol-derived natural products and direct C-H functionalizations for the synthesis of nitrogen heterocycles. Jenna is the recipient of a National Science Foundation Graduate Research Fellowship (2009-2011). Aer receiving her PhD in 2013, she moved to Princeton University to pursue postdoctoral studies on photoredox organocatalysis with Prof.

A Pd-catalyzed Larock annulation provides expedient access to a subset of resveratrol-derived natural products. The reported approach resulted in the structural revision of an intermediate en route to the natural product pauciflorol F, the total synthesis of which proceeded in two steps from the requisite pentannulation product.Polyphenolic natural products such as resveratrol and its derivatives (Figure 1) 1 have emerged as important synthetic targets due to their diverse architectures and their potential medicinal utility. Many of these compounds are produced by various plants in response to infection or stress. 2 Recent reports have demonstrated that resveratrol inhibits cancer growth in vitro 3 and extends the lifespan of living organisms, including fruit flies and the turquoise killifish. 4 To date, the specific mechanism of action of resveratrol in humans remains elusive due to its rapid metabolism and relatively low bioavailability. 5 Several dimeric resveratrol metabolites (e.g., 2-5 , Figure 1), which presumably arise from radical dimerizations of 1, have shown biological activities comparable to or greater than their parent monomer. 6 For example, a mixture of resveratrol dimers and oligostilbenes isolated from Caragana sinica exhibited in vitro stimulation of osteoblast proliferation at concentrations as low as 100 pg/mL. 6d However, most biological studies of resveratrol and its congeners have concentrated on plant models. Consequently, relatively little is known about the potential benefits of these molecules to human health. A more thorough exploration of the properties, mechanism of action and biochemical significance of resveratrol and its derivatives requires efficient and versatile syntheses of these molecules and their unnatural analogs.Several research groups have recently reported syntheses of resveratrol-derived compounds. In 2006, Li et al. employed the biomimetic dimerization of a resveratrol derivative for the total synthesis of quadrangularin A (2a, Figure 1). 7a In the same year, She, Pan and coworkers reported the total synthesis of pauciflorol F by employing a Pd-catalyzed 5-endo Heck cyclization strategy. 7b Snyder et al. subsequently reported the syntheses of several polyphenolic natural products, including 2a, 3, and 5. 7c,d As a part of a program to develop concise synthetic routes to resveratrol-derived compounds, we recently reported a domino Heck cyclization/pentannulation process, which provided the scaffold of a subset of dimeric resveratrol-derived compounds (Scheme 1). We envisioned that compounds such as pauciflorol F (5, Scheme 2) could arise from a 2,3-disubstituted indenone precursor (e.g., 10a) using a related carbocyclization strategy.Encouraged by the wide substrate scope of Larock's Pd-catalyzed annulation of alkynes to form 2,3-disubstituted-1-indenones, 9 we imagined obtaining 10a from o-bromobenzaldehyde 11 10 and tolane 7. 8 When a mixture of 11 and 7 was subjected to Larock's original annulation conditions, 9 a 1:1 mixture of indenone regioisomers...

Extracellular adenosine (ADO), present in high concentrations in the tumor microenvironment (TME), suppresses immune function via inhibition of T cell and NK cell activation. Intratumoral generation of ADO depends on the sequential catabolism of ATP by two ecto-nucleotidases, CD39 (ATP → AMP) and CD73 (AMP → ADO). Inhibition of CD73 eliminates a major pathway of ADO production in the TME and can reverse ADO-mediated immune suppression. Extensive interrogation of structure−activity relationships (SARs), structure-based drug design, and optimization of pharmacokinetic properties culminated in the discovery of AB680, a highly potent (K i = 5 pM), reversible, and selective inhibitor of CD73. AB680 is further characterized by very low clearance and long half-lives across preclinical species, resulting in a PK profile suitable for long-acting parenteral administration. AB680 is currently being evaluated in phase 1 clinical trials. Initial data show AB680 is well tolerated and exhibits a pharmacokinetic profile suitable for biweekly (Q2W) iv-administration in human.