One-Step Synthesis of Chiral 9,10-Dihydrophenanthrenes via Ligand-Enabled Enantioselective Cascade β,γ-Diarylation of Acids.

Pd(II)-catalyzed enantioselective C-H activation has emerged as a versatile platform for constructing point, axial, and planar chirality. Herein, we present an unexpected discovery of a Pd-catalyzed enantioselective cascade β,γ-methylene C(sp)-H diarylation of free carboxylic acids using bidentate chiral mono-protected amino thioether ligands (MPAThio), enabling one-step synthesis of a complex chiral 9,10-dihydrophenanthrene scaffolds with high enantioselectivity. In this process, two methylene C(sp)-H bonds and three C(sp)-H bonds were activated, leading to the formation of four C-C bonds and three chiral centers in one pot.

Enantioselective remote methylene C-H (hetero)arylation of cycloalkane carboxylic acids.

Stereoselective construction of γ- and δ-stereocenters in carbonyl compounds is a pivotal objective in asymmetric synthesis. Here, we report chiral bifunctional oxazoline-pyridone ligands that enable enantioselective palladium-catalyzed remote γ-C-H (hetero)arylations of free cycloalkane carboxylic acids, which are essential carbocyclic building blocks in organic synthesis. The reaction establishes γ-tertiary and α-quaternary stereocenters simultaneously in up to >99% enantiomeric excess, providing access to a wide range of cyclic chiral synthons and bioactive molecules.

Synthesis of β,γ-Unsaturated Aliphatic Acids via Ligand-Enabled Dehydrogenation.

α,β-Dehydrogenation of aliphatic acids has been realized through both enolate and β-C-H metalation pathways. However, the synthesis of isolated β,γ-unsaturated aliphatic acids via dehydrogenation has not been achieved to date. Herein, we report the ligand-enabled β,γ-dehydrogenation of abundant and inexpensive free aliphatic acids, which provides a new synthetic disconnection as well as a versatile platform for the downstream functionalization of complex molecules at remote γ-sites.

Synthesis of Highly Substituted Aminotetrahydropyrans Enabled by Stereospecific Multivector C-H Functionalization.

Highly substituted aminotetrahydropyrans were synthesized via sequential C-H functionalizations. The process was initiated with a Pd(II)-catalyzed stereoselective γ-methylene C-H arylation of aminotetrahydropyran, followed by α-alkylation or arylation of the corresponding primary amine. The initial γ-C-H (hetero)arylation was compatible with a range of aryl iodides containing various substituents and provided the corresponding products in moderate to good yields.

Transannular C-H functionalization of cycloalkane carboxylic acids.

Cyclic organic molecules are common among natural products and pharmaceuticals. In fact, the overwhelming majority of small-molecule pharmaceuticals contain at least one ring system, as they provide control over molecular shape, often increasing oral bioavailability while providing enhanced control over the activity, specificity and physical properties of drug candidates. Consequently, new methods for the direct site and diastereoselective synthesis of functionalized carbocycles are highly desirable.

Switchable multipath cascade cyclization to synthesize bicyclic lactams and succinimides chemodivergent reaction.

Herein, a novel switchable multipath cascade cyclization chemodivergent reaction between readily available ketoamides and deconjugated butenolides was developed to efficiently synthesize γ-lactone fused γ-lactams and succinimide fused hemiketals. The Aldol/aza-Michael reaction and Aldol/imidation/hemiketalization reaction were enabled by catalytic amounts of two bases, namely tetramethyl guanidine and NaOAc. A wide range of substrate scope with diverse functional group compatibility was demonstrated to deliver the corresponding products with good yield and excellent diastereoselectivity (>60 examples).

Zinc-mediated carboxylations of allylic and propargylic halides in flow: synthesis of β-lactones subsequent bromolactonization.

Zinc-mediated carboxylation of allylic halides under flow conditions delivered β,γ-unsaturated carboxylic acids and subsequent bromolactonization provides a streamlined process for the synthesis of γ-bromo-β-lactones. The described process further demonstrates the utility of organozinc reagents prepared by passage of allylic halides through a metallic zinc column integrated into a flow process. Use of a tube-in-tube reactor for efficient CO introduction led to improvements in conversion compared to a batch process and improved overall yields of β-lactones.

Enantioselective Synthesis of Medium-Sized Lactams via Chiral α,β-Unsaturated Acylammonium Salts.

Medium-sized lactams are important structural motifs found in a variety of bioactive compounds and natural products but are challenging to prepare, especially in optically active form. A Michael addition/proton transfer/lactamization organocascade process is described that delivers medium-sized lactams, including azepanones, benzazepinones, azocanones, and benzazocinones, in high enantiopurity through the intermediacy of chiral α,β-unsaturated acylammonium salts. An unexpected indoline synthesis was also uncovered, and the benzazocinone skeleton was transformed into other complex heterocyclic derivatives, including spiroglutarimides, isoquinolinones, and δ-lactones.

Amino acid salts catalyzed asymmetric aldol reaction of tryptanthrin: a straightforward synthesis of phaitanthrin A and its derivatives.

The first asymmetric synthesis of (S)-Phaitanthrin A and its derivatives via a catalytic aldol reaction of Tryptanthrin and ketones is described, in which the cheap, easily prepared natural amino acid salts exhibited unique catalytic ability; importantly, this methodology tolerates a range of substrates with different substitution patterns. Moreover, the synthetic utility of this strategy was further illustrated by a gram-scale synthesis of Phaitanthrin A.

Regioselectivity-reversed asymmetric aldol reaction of 1,3-dicarbonyl compounds.

Reverse regioselectivity: The first catalytic asymmetric C-1 functionalization of 1,3-dicarbonyl compounds by an aldol reaction is described, which regioselectively affords 6-hydroxyhexane-2,4-dione derivatives as the only product with high optical purity of up to 93 % ee. Furthermore, this method provides a facile access to enantioenriched oxygen-containing spirooxindoles and spirobutyrolactones from simple commercial available starting materials (see scheme).