The cationic gold phosphine complex [{PCy2 (o-biphenyl)}Au(NCMe)](+) SbF6 (-) (Cy=cyclohexyl) catalyzes the intermolecular, anti-Markovnikov hydroamination reaction of monosubstituted and cis- and trans-disubstituted alkylidenecyclopropanes (ACPs) with imidazolidin-2-ones and other nucleophiles. This reaction forms 1-cyclopropyl alkylamine derivatives in high yield and with high regio- and diastereoselectivity. NMR spectroscopic analysis of gold π-ACP complexes and control experiments point to the sp hybridization of the ACP internal alkene carbon atom as controlling the regiochemistry of the ACP hydroamination reaction.
Optimization of the catalyst structure to simultaneously improve multiple reaction objectives (e.g., yield, enantioselectivity, and regioselectivity) remains a formidable challenge. Herein, we describe a machine learning workflow for the multi-objective optimization of catalytic reactions that employ chiral bisphosphine ligands. This was demonstrated through the optimization of two sequential reactions required in the asymmetric synthesis of an active pharmaceutical ingredient. To accomplish this, a density functional theory-derived database of >550 bisphosphine ligands was constructed, and a designer chemical space mapping technique was established. The protocol used classification methods to identify active catalysts, followed by linear regression to model reaction selectivity. This led to the prediction and validation of significantly improved ligands for all reaction outputs, suggesting a general strategy that can be readily implemented for reaction optimizations where performance is controlled by bisphosphine ligands.
An efficient asymmetric synthesis of a potent KRAS G12C
covalent
inhibitor, GDC-6036 (1), is reported. The synthesis features
a highly atroposelective Negishi coupling to construct the key C–C
bond between two highly functionalized pyridine and quinazoline moieties
by employing a Pd/Walphos catalytic system. Statistical modeling by
comparing computational descriptors of a range of Walphos chiral bisphosphine
ligands to a training set of experimental results was used to inform
the selection of the best ligand, W057-2, which afforded
the desired Negishi coupling product (
R
a
)-3 in excellent selectivity.
A subsequent telescoped reaction sequence of alkoxylation, global
deprotection, and acrylamide formation, followed by a final adipate
salt formation, furnished GDC-6036 (1) in 40% overall
yield from starting materials pyridine 5 and quinazoline 6.
SummaryA series of polycyclic frameworks with fluorinated syn-facial quinoxaline sidewalls has been prepared as potential molecular tweezers for electron-rich guest compounds. Our synthetic route to the cyclooctadiene-derived scaffolds 16a–d takes advantage of the facile isolation of a novel spirocyclic precursor 9b with the crucial syn-orientation of its two alkene moieties. The crystal structure of 16c displays two features typical of a molecular tweezer: inclusion of a solvent molecule in the molecular cleft and self-association of the self-complementary scaffolds. Furthermore, host–guest NMR studies of compound 16c in solution show chemical exchange between the unbound and bound electron-rich guest, N,N,N′,N′-tetramethyl-p-phenylenediamine.
The atropselective iodination of 2-amino-6-arylpyridines catalyzed by chiral disulfonimides (DSIs) is described. Key to the development of this transformation was the use of a chemoinformatically guided workflow for the curation of a structurally diverse training set of DSI catalysts. Utilization of this catalyst training set in the atropselective iodination across a variety 2-aminopyridine substrates allowed for the recommendation of statistically higher-performing DSIs for this reaction. Data Fusion techniques were implemented to successfully predict the performance of catalysts when classical linear regression analysis failed to provide suitable models. This effort identified a privileged class of 3,3′alkynyl-DSI catalysts which were effective in catalyzing the iodination of a variety of 2-amino-6-arylpyridines with high stereoselectivity and generality. Subsequent preparative-scale demonstrations highlighted the utility of this reaction by providing iodinated pyridines >90:10 er and in good chemical yield.
The total syntheses
of caesalpinnone A (1) and its
putative biosynthetic precursor caesalpinflavan B (3)
are described. Herein, we describe the evolution of a synthetic strategy
toward 1 and 3, which entails a convergent
Barluenga coupling that quickly delivers a heavily functionalized
benzopyran containing the core carbon framework and exploration of
two distinct synthetic routes for forging the flavanoid C-ring by
reducing a sterically encumbered embedded alkene: one via a stepwise
approach and a second, more direct and atom-economical, enabled by
a Shenvi-HAT hydrogenation. The latter strategy allowed access to
caesalpinflavan B in 6 steps after Pd-mediated deallylation. A late-stage
dearomative phenolic oxidation and deallylation/oxa-Michael cascade
was implemented to access caesalpinnone A (1) in 7 steps.
We also describe an enantioselective total synthesis and stereochemical
revision of (−)-caesalpinflavan B, as well as a formal enantioselective
synthesis of (−)-caesalpinnone A, by implementing an enantioselective
Pd-catalyzed conjugate addition developed by Stoltz.
The mechanism of the intermolecular hydroamination of 3-methylbuta-1,2-diene (1) with N-methylaniline (2) catalyzed by (IPr)AuOTf has been studied by employing a combination of kinetic analysis, deuterium labelling studies, and in situ spectral analysis of catalytically active mixtures. The results of these and additional experiments are consistent with a mechanism for hydroamination involving reversible, endergonic displacement of N-methylaniline from [(IPr) Au(NHMePh)] + (4) by allene to form the cationic gold π-C1,C2-allene complex [(IPr)Au(η 2 -H 2 C=C=CMe 2 )] + (I), which is in rapid, endergonic equilibrium with the regioisomeric π-C2,C3-allene complex [(IPr)Au(η 2 -Me 2 C=C=CH 2 )] + (I'). Rapid and reversible outer-sphere addition of 2 to the terminal allene carbon atom of I' to form gold vinyl complex (IPr) Au[C(=CH 2 )CMe 2 NMePh] (II) is superimposed on the slower addition of 2 to the terminal allene carbon atom of I to form gold vinyl complex (IPr)Au[C(=CMe 2 )CH 2 NMePh] (III). Selective protodeauration of III releases N-methyl-N-(3-methylbut-2-en-1-yl)aniline (3 a) with regeneration of 4. At high conversion, gold vinyl complex II is competitively trapped by an (IPr)Au + fragment to form the cationic bis(gold) vinyl complex {[(IPr) Au] 2 [C(=CH 2 )CMe 2 NMePh]} + (6).
Cationic gold complexes containing an N-heterocyclic carbene ligand catalyze the intermolecular anti-Markovnikov hydroarylation of monosubstituted and cis- and trans-disubstituted methylenecyclopropanes (MCPs) with N-alkyl and 1,2-dialkyl indoles to form the corresponding 3-(cyclopropylmethyl)indoles in high regio- and diastereoselectivity and in good to excellent chemical yield.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.