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.

Mechanistic study of enantioselective Pd-catalyzed C(sp3)-H activation of thioethers involving two distinct stereomodels.

Enantioselective C(sp3)-H activation has gained considerable attention from the synthetic chemistry community. Despite the intense interest in these reactions, the mechanisms responsible for enantioselection are still vague. In the course of the development of aryl thioether-directed C(sp3)-H arylation, we noticed extreme variation in sensitivity of two substrate classes to substituent effects of ligands and directing groups: whereas 3-pentyl sulfides (prochiral α-center) responded positively to substitution on ligands and directing groups, isobutyl sulfides (prochiral ß-center) were entirely insensitive. Quantitative structure selectivity relationship (QSSR) analyses of directing group and ligand substitution and the development of a new class of mono-N-acetyl protected amino anilamide (MPAAn) ligands led to high enantiomeric ratios (up to 99:1) for thioether-directed C(sp3)-H arylation. Key to the realization of this method was the exploitation of transient chirality at sulfur, which relays stereochemical information from the ligand backbone to enantiotopic carbons of the substrate in a rate- and enantio-determining cyclometallation deprotonation. The absolute stereochemistry of the products for these two substrates were revealed to be opposite. DFT evaluation of all possible diastereomeric transition states confirmed initial premises that guided rational ligand and directing group design. The implications of this study will assist in the further development of enantioselective C(sp3)-H activation, namely by highlighting the non-innocence of directing groups, distal steric influences, and the delicate interplay between steric Pauli repulsion and London dispersion in enantioinduction.

Design and Identification of a Novel, Functionally Subtype Selective GABAA Positive Allosteric Modulator (PF-06372865).

The design, optimization, and evaluation of a series of novel imidazopyridazine-based subtype-selective positive allosteric modulators (PAMs) for the GABAA ligand-gated ion channel are described. From a set of initial hits multiple subseries were designed and evaluated based on binding affinity and functional activity. As designing in the desired level of functional selectivity proved difficult, a probability-based assessment was performed to focus the project's efforts on a single subseries that had the greatest odds of delivering the target profile. These efforts ultimately led to the identification of two precandidates from this subseries, which were advanced to preclinical safety studies and subsequently to the identification of the clinical candidate PF-06372865.

One-Pot Synthesis of α-Branched N-Acylamines via Titanium-Mediated Condensation of Amides, Aldehydes, and Organometallics.

A three-component, titanium-mediated synthesis of α-branched N-acylamines from commercial or readily accessible amides, aldehydes, and organometallic reagents is reported. The transformation proceeds under mild reaction conditions and tolerates a variety of functional groups (including nitrile, carbamate, olefin, basic amine, furan, and other sensitive heteroaromatics) to generate a large umbrella of α-branched N-acylamine products in high yields. The operationally practical procedure enables the use of this method in parallel chemical synthesis, a valuable feature that can facilitate the screening of bioactive molecules by medicinal chemists.

Stereoselectivity in nucleophilic additions to 3-azidoalkanals.

The stereoselectivity of nucleophilic additions to 3-azidoalkanals was investigated. Non-chelating, BF(3)·OEt(2)-mediated Sakurai addition to 3-azidoalkanals afforded 1,3-anti products, whereas use of a chelating Lewis acid, TiCl(4), resulted in 1,3-syn products with moderate selectivity. A boat-like chelation structure of the 3-azidoalkanal with the Lewis acid is proposed to be consistent with the 1,3-syn selectivity of the reactions. Mukaiyama aldol addition to 3-azidohexanal generated 1,3-anti products regardless of the chelating ability of the Lewis acid.

One-pot synthesis of lactams using domino reactions: combination of Schmidt reaction with Sakurai and aldol reactions.

A series of domino reactions in which the intramolecular Schmidt reaction is combined with either a Sakurai reaction, an aldol reaction, or both is reported. The Sakurai reaction of an allylsilane with an azido-containing enone under Lewis acidic conditions followed by protonation of the resulting titanium enolate species allowed for a subsequent intramolecular Schmidt reaction. Alternatively, the intermediate titanium enolate could undergo an aldol reaction followed by the intramolecular Schmidt reaction to form lactam products with multiple stereogenic centers. The stereochemical features of the titanium enolate aldol reaction with several 3-azidoaldehyde substrates during this domino process is discussed.

Highly stereoselective and modular syntheses of 10-hydroxytrilobacin and three diastereomers via stereodivergent [3 + 2]-annulation reactions.

A convergent synthesis of the annonaceous acetogenin, 10-hydroxytrilobacin ( 4a), was accomplished by using the [3 + 2]-annulation reaction of tetrahydrofuranyl carboxaldehyde 2a and allylsilane 3. The stereodivergency of the [3 + 2]-annulation reaction made it possible to achieve modular, highly stereoselective syntheses of three 10-hydroxytrilobacin diastereomers from the same precursors by using simple modifications of reaction conditions.

Concerning the selective protection of (Z)-1,5-syn-ene-diols and (E)-1,5-anti-ene-diols as allylic triethylsilyl ethers.

Treatment of unsaturated 1,5-diols 2 with TES-Cl (1.1 equiv), imidazole, and catalytic DMAP in 1:1 CH2Cl2-DMF at -78 degrees C effects selective silylation of the allylic alcohol with >95:5 chemoselectivity when the allylic and homoallylic alcohols are in similar steric environments.