Molecules with restricted rotation around a single bond or atropisomers are found in a wide number of natural products and bioactive molecules as well as in chiral ligands for asymmetric catalysis and smart materials. Although most of these compounds are biaryls and heterobiaryls displaying a CÀ C stereogenic axis, there is a growing interest in less common and more challenging axially chiral CÀ N atropisomers. This review offers an overview of the various methodologies available for their asymmetric synthesis. A brief introduction is initially given to contextualize these axially chiral skeletons, including a historical background and examples of natural products containing axially chiral CÀ N axes. The preparation of different families of CÀ N based atropisomers is then presented from anilides to chiral fiveand six-membered ring heterocycles. Special emphasis has been given to modern catalytic asymmetric strategies over the past decade for the synthesis of these chiral scaffolds. Applications of these methods to the preparation of natural products and biologically active molecules will be highlighted along the text.
We report first Fe-catalyzed hydroborylative cyclization reaction. The process provides one C-C and one C-B bond in a single operation and shows a wide scope, allowing the formation of carbo- and heterocycles containing a homoallylic boryl unit that can be further functionalized. The reaction takes place in smooth conditions, with inexpensive catalytic system and full atom economy since HBpin is the borylation agent, in contrast to our previously reported Pd-catalyzed reaction. Both aryl and alkyl substituted alkynes are reactive, revealing a wide reaction scope. Mechanistic studies suggest the intermediacy of Fe -hydride active catalyst capable to react with the alkyne group prior to alkene insertion, and computational studies suggest the occurrence of barrierless σ-bond metathesis involving HBpin and Fe-C bonds along the catalytic cycle.
A highly enantioselective biocatalytic dynamic kinetic
resolution
(DKR) of configurationally labile N-arylindole aldehydes
is described. The DKR proceeds by atroposelective bioreduction of
the carbonyl group catalyzed by commercial ketoreductases (KREDs),
thus affording the corresponding axially chiral N-arylindole aminoalcohols, with excellent conversions and optical
purities. The strategy relies on the racemization of the stereogenic
axis that takes place thanks to a transient Lewis pair interaction
between the NMe2 and the aldehyde groups. This protocol
features a broad substrate scope under very mild conditions.
An atroposelective Ir‐catalyzed dynamic kinetic resolution (DKR) of 2‐(quinolin‐8‐yl)benzaldehydes/1‐naphthaldehydes by transfer hydrogenative coupling of allyl acetate is disclosed. The allylation reaction takes place with simultaneous installation of central and axial chirality, reaching high diastereoselectivities and excellent enantiomeric excesses when ortho‐cyclometalated iridium‐DM‐BINAP is used as the catalyst. The racemization of the substrates occurs through a designed transient Lewis acid‐base interaction between the quinoline nitrogen atom and the aldehyde carbonyl group.
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