24 peroxide [Cu I (pyr)(tpb)] 10 mol % TBHP, 1 atm O 2 , 1:2 AcOH/pyr, rt, 24 h ∼2.5 26 74 g 35 25 n-hexane aldehyde CuCl 2 , 18-crown-6 1 atm O 2 , MeCHO, CH 2 Cl 2 , 70 °C, 24 h 2.4 91 h 9 34a 26 n-decane aldehyde Cu II Cl 16 Pc-AM(PS) 3 equiv of PhCHO, MeCN, 1 atm O 2 , 50 °C 15.4 100 i 61 a See Chart 2 for ligand structures. b Also 28% cyclohexene. c Also 26% cyclohexene. d Mixture of alcohol and hydroperoxide. e Remainder of product is cyclohexene. f Approximately 93:7 of 1-adamantol/2-adamantol. g Approximately 98:2 of 1-adamantol/2-adamantol. h Afforded oxidation products in an approximately 1:1 ratio at the 2-and 3-positions. i Mixture of decanones.

The cross-coupling of sp3-hybridized organoboron reagents via photoredox/nickel dual catalysis represents a new paradigm of reactivity for engaging alkylmetallic reagents in transition-metal-catalyzed processes. Reported here is an investigation into the mechanistic details of this important transformation using density functional theory. Calculations bring to light a new reaction pathway involving an alkylnickel(I) complex generated by addition of an alkyl radical to Ni(0) that is likely to operate simultaneously with the previously proposed mechanism. Analysis of the enantioselective variant of the transformation reveals an unexpected manifold for stereoinduction involving dynamic kinetic resolution (DKR) of a Ni(III) intermediate wherein the stereodetermining step is reductive elimination. Furthermore, calculations suggest that the DKR-based stereoinduction manifold may be responsible for stereoselectivity observed in numerous other stereoconvergent Ni-catalyzed cross-couplings and reductive couplings.

The replacement of a carboxylic acid with a surrogate structure, or (bio)-isostere, is a classical strategy in medicinal chemistry. The general underlying principle is that by maintaining the features of the carboxylic acid critical for biological activity, but appropriately modifying the physicochemical properties, improved analogs may result. In this context, a systematic assessment of the physicochemical properties of carboxylic acid isosteres would be desirable to enable more informed decisions of potential replacements to be used for analog design. Herein we report the structure-property relationships (SPR) of 35 phenylpropionic acid derivatives, in which the carboxylic acid moiety is replaced with a series of known isosteres. The dataset generated provides an assessment of the relative impact on the physicochemical properties that these replacements may have compared to the carboxylic acid analog. As such, this study presents a framework for how to rationally apply isosteric replacements of the carboxylic acid functional group.

This tutorial review highlights the use of catalytic asymmetric 2-naphthol couplings in total synthesis. The types of chirality, chiral biaryl natural products, prior approaches to chiral biaryl natural products, and other catalytic asymmetric biaryl couplings are outlined. The three main categories of chiral catalysts for 2-naphthol coupling (Cu, V, Fe) are described with discussion of their limitations and advantages. Applications of the copper catalyzed couplings in biomimetic syntheses are discussed including nigerone, hypocrellin, calphostin D, phleichrome, and cercosporin.

C 2-Symmetric bis(oxazolinyl)pyridine (pybox)−Cu(II) complexes have been shown to catalyze enantioselective Mukaiyama aldol reactions between (benzyloxy)acetaldehyde and a variety of silylketene acetals. The aldol products are generated in high yields and in 92−99% enantiomeric excess using as little as 0.5 mol % of chiral catalyst [Cu((S,S)-Ph-pybox)](SbF6)2. With substituted silylketene acetals, syn reaction diastereoselection ranging from 95:5 to 97:3 and enantioselectivities ≥95% are observed. Investigation into the reaction mechanism utilizing doubly labeled silylketene acetals indicates that the silyl-transfer step is intermolecular. Further mechanistic studies revealed a significant positive nonlinear effect, proposed to arise from the selective formation of the [Cu((S,S)-Ph-pybox)((R,R)-Ph-pybox)](SbF6)2 2:1 ligand:metal complex. A stereochemical model is presented in which chelation of (benzyloxy)acetaldehyde to the metal center to form a square pyramidal copper intermediate accounts for the observed sense of induction. Support for this proposal has been obtained from double stereodifferentiating reactions, EPR spectroscopy, ESI spectrometry, and, ultimately, the X-ray crystal structure of the aldehyde bound to the catalyst. The C 2-symmetric bis(oxazolinyl)−Cu(II) complex [Cu((S,S)-tert-Bu-box)](OTf)2 is also an efficient catalyst for the aldol reaction, but the scope with this system is not as broad.