One-Step Synthesis of Chiral 9,10-Dihydrophenanthrenes via Ligand-Enabled Enantioselective Cascade ß,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 ß,γ-methylene C(sp3)-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(sp3)-H bonds and three C(sp2)-H bonds were activated, leading to the formation of four C-C bonds and three chiral centers in one pot. A plausible catalytic pathway starts with enantioselective ß,γ-dehydrogenation to form chiral ß,γ-cyclohexene. Intriguingly, this olefin serves as a norbornene-type reagent (presumably assisted by the carboxyl directing effect), relaying two successive Catellani arylation reactions and a C-H arylation reaction to furnish chiral 9,10-dihydrophenanthrenes along with meta-selective homocoupling products of iodoarene.

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. The sequential enantioselective editing of two methylene C-H bonds can be achieved by using chiral ligands with opposite configuration to construct carbocycles containing three chiral centers. Enantioselective remote δ-C-H (hetero)arylation is also realized to establish δ-stereocenters that are particularly challenging to access using classical methodologies.

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. The subsequent α-alkylation or arylation of the isolated arylated products proceeded with high diastereoselectivity to afford value-added disubstituted aminotetrahydropyrans.

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

α,ß-Dehydrogenation of aliphatic acids has been realized through both enolate and ß-C-H metalation pathways. However, the synthesis of isolated ß,γ-unsaturated aliphatic acids via dehydrogenation has not been achieved to date. Herein, we report the ligand-enabled ß,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. A variety of free aliphatic acids, including acyclic and cyclic systems with ring sizes from five-membered to macrocyclic, undergo efficient dehydrogenation. Notably, this protocol features good chemoselectivity in the presence of more accessible α-C-H bonds and excellent regioselectivity in fused bicyclic scaffolds. The utility of this protocol has been demonstrated by the late-stage functionalization of a series of bioactive terpene natural products at the γ-sites. Further functionalization of the ß,γ-double bond allows for the installation of covalent warheads, including epoxides, aziridines, and ß-lactones, into complex natural product scaffolds, which are valuable for targeted covalent drug discovery.

Transannular C-H functionalization of cycloalkane carboxylic acids.

Cyclic organic molecules are common among natural products and pharmaceuticals1,2. 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 candidates3-5. Consequently, new methods for the direct site and diastereoselective synthesis of functionalized carbocycles are highly desirable. In principle, molecular editing by C-H activation offers an ideal route to these compounds. However, the site-selective C-H functionalization of cycloalkanes remains challenging because of the strain encountered in transannular C-H palladation. Here we report that two classes of ligands-quinuclidine-pyridones (L1, L2) and sulfonamide-pyridones (L3)-enable transannular γ-methylene C-H arylation of small- to medium-sized cycloalkane carboxylic acids, with ring sizes ranging from cyclobutane to cyclooctane. Excellent γ-regioselectivity was observed in the presence of multiple ß-C-H bonds. This advance marks a major step towards achieving molecular editing of saturated carbocycles: a class of scaffolds that are important in synthetic and medicinal chemistry3-5. The utility of this protocol is demonstrated by two-step formal syntheses of a series of patented biologically active small molecules, prior syntheses of which required up to 11 steps6.

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

Zinc-mediated carboxylation of allylic halides under flow conditions delivered ß,γ-unsaturated carboxylic acids and subsequent bromolactonization provides a streamlined process for the synthesis of γ-bromo-ß-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 CO2 introduction led to improvements in conversion compared to a batch process and improved overall yields of ß-lactones. The described flow process was also applied to propargylic bromides for the synthesis of allenic and propargylic acids.

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

Herein, a novel switchable multipath cascade cyclization via 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).

Enantioselective Synthesis of Medium-Sized Lactams via Chiral α,ß-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,ß-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).