Gold(I)-Catalyzed Coupling Reactions for the Synthesis of Diverse Small Molecules Using the Build/Couple/Pair Strategy

The build/couple/pair strategy has yielded small molecules with stereochemical and skeletal diversity by using short reaction sequences. Subsequent screening has shown that these compounds can achieve biological tasks considered challenging if not impossible (‘undruggable’) for small molecules. We have developed gold(I)-catalyzed cascade reactions of easily prepared propargyl propiolates as a means to achieve effective intermolecular coupling reactions for this strategy. Sequential alkyne activation of propargyl propiolates by a cationic gold(I) catalyst yields an oxocarbenium ion that we previously showed is trapped by C-based nucleophiles at an extrannular site to yield α-pyrones. Here, we report O-based nucleophiles react by ring opening to afford a novel polyfunctional product. In addition, by coupling suitable building blocks, we subsequently performed intramolecular pairing reactions that yield diverse and complex skeletons. These pairing reactions include one based on a novel aza-Wittig-6π-electrocyclization sequence and others based on ring-closing metathesis reactions

Skeletally Diverse Small Molecules Using a Build/Couple/Pair Strategy

Intermolecular couplings of simple building blocks using catalytic, stereoselective cross-Mannich reactions followed by intramolecular functional group-pairing reactions of easily accessed variants of the Mannich products are explored as a route to skeletally diverse small molecules. The synthetic pathway yields products having 12 different skeletons using only three steps and has the potential to enable substantial stereochemical diversification in the future

Divergent Synthesis and Real-Time Biological Annotation of Optically Active Tetrahydrocyclopenta[<i>c</i>]pyranone Derivatives

Sp³-rich compounds are underrepresented in libraries for probe- and drug-discovery, despite their promise of extending the range of accessible molecular shapes beyond planar geometries. With this in mind, a collection of single-enantiomer bicyclic, fused cyclopentenones underpinned by a complexity-generating Pauson–Khand cyclization was synthesized. A fingerprint of biological actions of these compounds was determined immediately after synthesis using real-time annotation−a process relying on multiplexed measurements of alterations in cell morphological features

Stereochemical and Skeletal Diversity Arising from Amino Propargylic Alcohols

An efficient synthetic pathway to the possible stereoisomers of skeletally diverse heterocyclic small molecules is presented. The change in shape brought about by different intramolecular cyclizations of diastereoisomeric amino propargylic alcohols is quantified using principal moment-of-inertia (PMI) shape analysis

Syntheses of α-Pyrones Using Gold-Catalyzed Coupling Reactions

Sequential alkyne activation of terminal alkynes and propiolic acids by gold(I) catalysts yields compounds having α-pyrone skeletons. Novel cascade reactions involving propiolic acids are reported that give rise to α-pyrones with different substitution patterns

Synthesis of Oxazocenones via Gold(I)-Catalyzed 8-<i>Endo</i>-Dig Hydroalkoxylation of Alkynamides

Several benzoxazocenones have been found to exhibit novel cellular activities. In the present study, we report a gold­(I)-catalyzed 8-<i>endo</i>-dig hydroalkoxylation reaction of alkynamides to access analogous oxazocenone scaffolds. This methodology provided an advanced intermediate, which was elaborated to a des-benzo analog of a bioactive benzoxazocenone

Gene Expression-Based Screen for Parkinson’s Disease Identifies GW8510 as a Neuroprotective Agent

We carried out a gene expression-based <i>in silico</i> screen in order to identify small molecules with gene-expression profiles that are anticorrelated with a gene-expression profile for Parkinson’s disease (PD). We identified the cyclin-dependent kinase 2/5 (CDK2/5) inhibitor GW8510 as our most significant hit and characterized its effects in rodent MN9D cells and in human neuronal cells derived from induced pluripotent stem cells. GW8510 demonstrated neuroprotective ability in MN9D cells in the presence of 1-methyl-4-phenylpyridium (MPP⁺), a widely used neurotoxin model for Parkinson’s disease. In order to delineate the nature and extent of GW8510’s neuroprotective properties, we studied GW8510 in human neuronal cells in the context of various mechanisms of cellular stress. We found that GW8510 was protective against small-molecule mitochondrial and endoplasmic reticulum stressors. Our findings illustrate an approach to using small-molecule gene expression libraries to identify compounds with therapeutic potential in human diseases

Synthesis of Oxazocenones via Gold(I)-Catalyzed 8-<i>Endo</i>-Dig Hydroalkoxylation of Alkynamides

Several benzoxazocenones have been found to exhibit novel cellular activities. In the present study, we report a gold­(I)-catalyzed 8-<i>endo</i>-dig hydroalkoxylation reaction of alkynamides to access analogous oxazocenone scaffolds. This methodology provided an advanced intermediate, which was elaborated to a des-benzo analog of a bioactive benzoxazocenone

Synthesis of Oxazocenones via Gold(I)-Catalyzed 8-<i>Endo</i>-Dig Hydroalkoxylation of Alkynamides

Several benzoxazocenones have been found to exhibit novel cellular activities. In the present study, we report a gold­(I)-catalyzed 8-<i>endo</i>-dig hydroalkoxylation reaction of alkynamides to access analogous oxazocenone scaffolds. This methodology provided an advanced intermediate, which was elaborated to a des-benzo analog of a bioactive benzoxazocenone

Stereospecific Palladium-Catalyzed C–H Arylation of Pyroglutamic Acid Derivatives at the C3 Position Enabled by 8‑Aminoquinoline as a Directing Group

An efficient and stereospecific Pd-catalyzed protocol for the C–H arylation of pyroglutamic acid derivatives that uses 8-aminoquinoline as a directing group is described. The reaction was shown to proceed efficiently with a variety of aryl and heteroaryl iodides bearing different functional groups, giving C3-arylated <i>cis</i> products in good to high yields. Removal of the 8-aminoquinoline unit from these C–H arylation products enables access to synthetically useful <i>cis</i> and <i>trans</i> pyroglutamic acid-based building blocks