A highly enantioselective intramolecular arylative dearomatization of indoles via palladium-catalyzed reductive Heck reactions was developed. The new strategy led to a series of optically active indolines bearing C2-quaternary stereocenters in modest to good yields with excellent enantioselectivities (up to 99% ee).
Enantioselective
intramolecular dearomative Heck reactions have
been developed by Pd-catalyzed cross-coupling of aryl halides or aryl
triflates with the internal CC bond of indoles, benzofurans,
pyrroles, and furans. A variety of structurally unique spiroheterocycles
and benzofused heterocycles having N/O-substituted quaternary carbon
stereocenters, and exocyclic olefin moieties were afforded in moderate
to excellent yields with good to excellent enantioselectivities, showing
a broad scope of the present protocol. A series of new BINOL- and
H8-BINOL-based phosphoramidite ligands were synthesized and proved
to be efficient chiral ligands in the reactions of C2-tethered substrates
to form spiroheterocycles. (S)-SEGPHOS turned out
to be a good ligand for the reaction delivering benzofused indolines
and pyrrolines. Synthetic applications based on transformations of
the exocyclic double bonds were realized without loss of enantiopurities,
including hydrogenation, hydroborylation, and stereospecific ring-expanding
rearrangement.
NÀ N Atropisomers are a common motif in natural products and represent a significant dimension for exploration in modern pharmaceutical and medicinal chemistry. However, the catalytic atroposelective synthesis of such molecules remains challenging, hampering meaningful development. In particular, an enantioselective synthesis of NÀ N bisindole atropisomers is unprecedented. Herein, the first enantioselective synthesis of NÀ N bisindole atropisomers via the palladium-catalyzed de novo construction of one indole skeleton is presented. A wide variety of NÀ N axially chiral bisindoles were generated in good yields with excellent enantioselectivities via a cascade condensation/N-arylation reaction. Structurally diverse indole-pyrrole, indolecarbazole, and non-biaryl-indole atropisomers possessing a chiral NÀ N axis were accessed using this protocol. Moreover, investigations using density functional theory (DFT) calculations provided insight into the reaction mechanism and enantiocontrol.
Palladium-catalyzed enantioselective dearomative arylalkynylation of N-substituted indoles, through a Heck/Sonogashira sequence, was established using a new BINOL-based phosphoramidite as the chiral ligand. A wide range of 2,3-disubstituted indolines, bearing vicinal quaternary and tertiary stereocenters, were efficiently constructed in one step with excellent enantioselectivities (up to 97 % ee) and diastereoselectivities (>20:1).
Nitrogen–nitrogen bonds containing
motifs are ubiquitous
in natural products and bioactive compounds. However, the atropisomerism
arising from a restricted rotation around an N–N bond is largely
overlooked. Here, we describe a method to access the first enantioselective
synthesis of N–N biaryl atropisomers via a Cu-bisoxazoline-catalyzed
Friedel–Crafts alkylation reaction. A wide range of axially
chiral N–N bisazaheterocycle compounds were efficiently prepared
in high yields with excellent enantioselectivities via desymmetrization
and kinetic resolution. Heating experiments showed that the axially
chiral bisazaheterocycle products have high rotational barriers.
A highly enantioselective palladium/l-proline-catalyzed α-arylative desymmetrization of cyclohexanones was developed. The new strategy for α-arylation reaction led to a series of optically active morphan derivatives bearing α-carbonyl tertiary stereocenters in good yields with excellent enantioselectivities (up to 99% ee).
A palladium-catalyzed dearomative arylborylation of indoles is reported, which provides straightforward access to structurally diverse indolines bearing vicinal tetrasubstituted and borylated trisubstituted stereocenters in moderate to good yields with excellent diastereoselectivities.
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