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.
Chiral 1,5-diaza-cis-decalins have been examined as ligands in the enantioselective oxidative biaryl coupling of substituted 2-naphthol derivatives. Under the optimal conditions employing 2.5-10 mol % of a 1,5-diaza-cis-decalin copper(II) catalyst with oxygen as the oxidant, enantioselective couplings (44-96% ee) could be achieved for a range of 3-substituted 2-naphthols including the ester, ketone, phosphonyl, and sulfonyl derivatives. The relationship between the substitution of the naphthalene starting materials and reactivity/selectivity is determined by several factors which act in concert: (1) the effect of substituents on the oxidation potential of the substrate, (2) the ability of the substrate to participate in a chelated copper complex which depends on (a) the inherent coordinating ability of the 3-substituent and (b) substituent steric interactions that affect chelation between the 2-hydroxyl and 3-substituent, (3) the effect of substituents on dissociation of the product from the copper catalyst.
Simple
catalysts that use atom-economical oxygen as the terminal
oxidant to accomplish selective ortho–ortho, ortho–para, or para–para homo-couplings
of phenols are described. In addition, chromium salen catalysts have
been discovered as uniquely effective in the cross-coupling of different
phenols with high chemo- and regioselectivity.
The C
2-symmetric (S,S)-tert-butyl-bis(oxazolinyl)Cu(OTf)2 complex (1a) has been shown to catalyze
the enantioselective aldol reaction between α-keto esters and silylketene acetals or enolsilanes with
enantioselectivities ranging from 93 to 99%. With substituted silylketene acetals, syn reaction diastereoselection
ranging from 90:10 to 98:2 and enantioselectivities ranging from 93 to 98% are observed. High levels of
carbonyl regioselectivity (98:2), diastereoselectivity (93:7), and enantioselectivity (97% ee) are also observed
in the aldol addition to 2,3-pentanedione. In all instances, the aldol adducts are generated in high yield and in
excellent enantiomeric excess using as little as 1 mol % of the chiral complex 1a. Mechanistic insight into the
pyruvate aldol reaction has also been gained. Silyl crossover experiments demonstrate that the silyl-transfer
step is intermolecular. Based upon these results, TMSOTf has been identified as an addend to accelerate these
reactions. Furthermore, solvent was shown to have a dramatic impact on the rates of addition and catalyst
turnover in the pyruvate aldol reaction. Crystallographic structures and semiempirical calculations provide
insight into the mode of asymmetric induction, allowing the construction of a model in which chelation of the
pyruvate ester through a square planar Cu(II) complex accounts for the observed sense of asymmetric induction.
Two other Cu(II) complexes, [Cu((S,S-i-Pr-pybox)](SbF6)2 and bis(imine) complex 26, have also been evaluated
as enantioselective catalysts for the pyruvate aldol reaction; however, the scope of the process with these
systems is more limited.
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