The catalytic resolution of racemic cyclic amines has been achieved by an enantioselective amidation reaction featuring an achiral N-heterocyclic carbene catalyst and a new chiral hydroxamic acid cocatalyst working in concert. The reactions proceed at room temperature, do not generate nonvolatile byproducts, and provide enantioenriched amines by aqueous extraction.
Silicon amine protocol (SLAP) reagents for photocatalytic cross-coupling with aldehydes and ketones to form N-unprotected piperazines have been developed. This blue light promoted process tolerates a wide range of heteroaromatic, aromatic, and aliphatic aldehydes and structurally and stereochemically complex SLAP reagents. It provides a tin-free alternative to SnAP (tin amine protocol) reagents for the synthesis of substituted piperazines.
Studying the relationship between
catalyst conformational dynamics
and selectivity in an asymmetric reaction is a challenge. In this
study, cyclic peptides were computationally designed to stabilize
different ground state conformations of a highly effective, flexible
tetrapeptide catalyst for the atroposelective bromination of N-aryl quinazolinones. Through a combination of computational
and experimental techniques, we have determined that dynamic movement
of the lead catalyst plays a crucial role in achieving high enantioselectivity
in the reaction of study. This approach may also serve as a valuable
method for investigating the mechanism of other peptide-catalyzed
transformations.
The
N-heterocyclic carbene and hydroxamic acid cocatalyzed kinetic
resolution of cyclic amines generates enantioenriched amines and amides
with selectivity factors up to 127. In this report, a quantum mechanical
study of the reaction mechanism indicates that the selectivity-determining
aminolysis step occurs via a novel concerted pathway in which the
hydroxamic acid plays a key role in directing proton transfer from
the incoming amine. This modality was found to be general in amide
bond formation from a number of activated esters including those generated
from HOBt and HOAt, reagents that are broadly used in peptide coupling.
For the kinetic resolution, the proposed model accurately predicts
the faster reacting enantiomer. A breakdown of the steric and electronic
control elements shows that a gearing effect in the transition state
is responsible for the observed selectivity.
The catalytic, enantioselective N-oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high levels of asymmetric induction are provided by aspartic-acid-containing peptides as the aspartyl side chain shuttles between free acid and peracid forms. Desymmetrizations of bis(pyridine) substrates bearing a remote pro-stereogenic center substituted with a group capable of hydrogen bonding to the catalyst are demonstrated. Our approach presents a new entry into chiral pyridine frameworks in a heterocycle-rich molecular environment. Representative functionalizations of the enantioenriched pyridine N-oxides further document the utility of this approach. Demonstration of the asymmetric N-oxidation in two venerable drug-like scaffolds, Loratadine and Varenicline, show the likely generality of the method for highly variable and distinct chiral environments, while also revealing that the approach is applicable to both pyridines and 1,4-pyrazines.
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