An Alkyne-Containing Isoprenoid Analogue Based on a Farnesyl Diphosphate Scaffold Is a Biologically Functional Universal Probe for Proteomic Analysis.

Prenylation consists of the modification of proteins with either farnesyl diphosphate (FPP) or geranylgeranyl diphosphate (GGPP) at a cysteine near the C-terminus of target proteins to generate thioether-linked lipidated proteins. In recent work, metabolic labeling with alkyne-containing isoprenoid analogues including C15AlkOPP has been used to identify prenylated proteins and track their levels in different diseases. Here, a systematic study of the impact of isoprenoid length on proteins labeled with these probes was performed.

The utility of Streptococcus mutans undecaprenol kinase for the chemoenzymatic synthesis of diverse non-natural isoprenoids.

Isoprene chemoenzymatic cascades (ICCs) overcome the complexity of natural pathways by leveraging a streamlined two-enzyme cascade, facilitating efficient synthesis of C5-isoprene diphosphate precursors from readily available alcohol derivatives. Despite the documented promiscuity of enzymes in ICCs, exploration of their potential for accessing novel compounds remains limited, and existing methods require additional enzymes for generating longer-chain diphosphates. In this study, we present the utility of Streptococcus mutans undecaprenol kinase (SmUdpK) for the chemoenzymatic synthesis of diverse non-natural isoprenoids.

Improved synthesis and application of an alkyne-functionalized isoprenoid analogue to study the prenylomes of motor neurons, astrocytes and their stem cell progenitors.

Protein prenylation is one example of a broad class of post-translational modifications where proteins are covalently linked to various hydrophobic moieties. To globally identify and monitor levels of all prenylated proteins in a cell simultaneously, our laboratory and others have developed chemical proteomic approaches that rely on the metabolic incorporation of isoprenoid analogues bearing bio-orthogonal functionality followed by enrichment and subsequent quantitative proteomic analysis. Here, several improvements in the synthesis of the alkyne-containing isoprenoid analogue C15AlkOPP are reported to improve synthetic efficiency.

Improved synthesis and application of an alkyne-functionalized isoprenoid analogue to study the prenylomes of motor neurons, astrocytes and their stem cell progenitors.

Protein prenylation is one example of a broad class of post-translational modifications where proteins are covalently linked to various hydrophobic moieties. To globally identify and monitor levels of all prenylated proteins in a cell simultaneously, our laboratory and others have developed chemical proteomic approaches that rely on the metabolic incorporation of isoprenoid analogues bearing bio-orthogonal functionality followed by enrichment and subsequent quantitative proteomic analysis. Here, several improvements in the synthesis of the alkyne-containing isoprenoid analogue C15AlkOPP are reported to improve synthetic efficiency.

Application of Chiral Transfer Reagents to Improve Stereoselectivity and Yields in the Synthesis of the Antituberculosis Drug Bedaquiline.

Bedaquiline (BDQ) is an important drug for treating multidrug-resistant tuberculosis (MDR-TB), a worldwide disease that causes more than 1.6 million deaths yearly. The current synthetic strategy adopted by the manufacturers to assemble this molecule relies on a nucleophilic addition reaction of a quinoline fragment to a ketone, but it suffers from low conversion and no stereoselectivity, which subsequently increases the cost of manufacturing BDQ.

Functional screening reveals prenylated proteins required for endocytic trafficking and rhoptry protein sorting.

In the apicomplexans, endocytosed cargos (e.g., hemoglobin) are trafficked to a specialized organelle for digestion.

Prenylomic Profiling in the Brain of a Transgenic Mouse Model of Alzheimer's Disease Reveals Increased Prenylation of a Key Set of Proteins.

Dysregulation of protein prenylation has been implicated in many diseases, including Alzheimer's disease (AD). Prenylomic analysis, the combination of metabolic incorporation of an isoprenoid analogue (C15AlkOPP) into prenylated proteins with a bottom-up proteomic analysis, has allowed the identification of prenylated proteins in various cellular models. Here, transgenic AD mice were administered with C15AlkOPP through intracerebroventricular (ICV) infusion over 13 days.

Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline.

Bedaquiline is a crucial medicine in the global fight against tuberculosis, yet its high price places it out of reach for many patients. Herein, we describe improvements to the key industrial lithiation-addition sequence that enable a higher yielding and therefore more economical synthesis of bedaquiline. Prioritization of mechanistic understanding and multi-lab reproducibility led to optimized reaction conditions that feature an unusual base-salt pairing and afford a doubling of the yield of racemic bedaquiline.

Enhanced Affinity for 3-Amino-Chromane-Derived σ Receptor Ligands.

The σ receptor is implicated in regulating a diverse range of physiology and is a target for developing therapies for cancer, pain management, neural degradation, and COVID-19. This report describes 36 phenethylamine-containing 3-amino-chromane ligands, which bind to σ with low nM affinities. The family consists of 18 distinct compounds and each enantiomer was independently assayed.

Primary Aminothiourea-Catalyzed Enantioselective Synthesis of Rauhut-Currier Adducts of 3-Arylcyclohexenone with a Tethered Enone on the Aryl Moiety at the Ortho-Position.

An enantioselective synthesis of Rauhut-Currier (RC) adducts from 3-aryl cyclohexenone with a tethered enone moiety at the ortho-position on the aryl group is accomplished. This method provides a wide range of valuable synthetic building blocks having a unique [6-5-6] all-carbon-fused tricyclic skeleton. A primary amine-containing thiourea, a bifunctional organocatalyst, was found to be an efficient catalyst for this transformation.

Switchable Chemoselectivity for Organocatalytic, Asymmetric Malononitrile Addition to ortho-Formyl Chalcones.

Chemoselective 1,2- and 1,4-addition of malononitriles to ortho-formyl chalcones using cinchona alkaloid based bifunctional chiral organocatalysts has been shown by tuning the electronic nature of the malononitriles. Alkyl (hard) malononitriles undergo an asymmetric 1,2-addition followed by oxa-Michael reaction cascade to afford 1,3-disubstituted isobenzofurans with high enantio- and diastereoselectivity. Aryl (soft) malononitriles proceed through 1,4-addition followed by an aldol reaction cascade to provide indanols, having three consecutive stereocenters, in good yields and with good to excellent enantio- and diastereoselectivites.

Dynamic Kinetic Spiroketalization/Oxa-Michael Addition Cascade of Alkoxyboronates and Peroxyacetals: Enantio- and Diastereoselective Synthesis of Benzannulated Spiroketals.

A unified dynamic kinetic spiroketalization/enantioselective oxa-Michael addition cascade of an aromatic ketone tethered to an alkoxyboronate and an enone moiety has been developed using cinchona alkaloid based amino-thiourea/squaramide organocatalysts to provide isobenzofuran-based benzannulated spiroketals with high diastereoselectivities and excellent enantioselectivities. Further, a dynamic kinetic peroxy-hemiacetalization/dynamic kinetic spiroketalization/enantioselective oxa-Michael addition cascade of the above substrates provides the corresponding exo-peroxy-benzannulated spiroketals with outstanding enantio- and diastereoselectivities.

Organocatalytic, enantioselective synthesis of benzoxaboroles Wittig/oxa-Michael reaction Cascade of α-formyl boronic acids.

An unprecedented enantioselective synthesis of 3-substituted benzoxaboroles has been developed. An generated -boronic acid containing chalcone provides the chiral benzoxaboroles an asymmetric oxa-Michael addition of hydroxyl group attached to the boronic acid triggered by the cinchona alkaloid based chiral amino-squaramide catalysts. In general, good yields with good to excellent enantioselectivities (up to 99%) were obtained.

Catalytic Asymmetric Conjugate Addition of Carboxylic Acids via Oxa-Michael Reaction of Peroxy Hemiacetals followed by Kornblum DeLaMare Fragmentation.

Disclosed herein an overall methodology constitutes an equivalent to the long sought after enantioselective intramolecular oxa-Michael (IOM) reaction of carboxylic acids. An organocatalyzed IOM reaction of in situ formed peroxy hemiacetals followed by a Kornblum DeLaMare type rearrangement cascade provides a broad class of chiral lactones in good yields and with excellent enatioselectvities. Remarkably, the pure chiral lactones are obtained without any silica gel column chromatography, and in many cases, the enantioselectivity is further increased by a simple hexane wash of the isolated solid products.

Transition-Metal-Free Synthesis of Homo- and Hetero-1,2,4-Triaryl Benzenes by an Unexpected Base-Promoted Dearylative Pathway.

An unprecedented approach for the synthesis of homo- and hetero-1,2,4-triaryl benzenes has been developed using a simple base-mediated reaction of either α-aryl cinnamyl alcohols or α,γ-di-aryl propanones. The salient feature of this strategy involves the sequential hydride transfer, regiospecific condensation, regiospecific dearylation, and aromatization under metal-free reaction conditions. The synthesis of unsymmetrically substituted triphenylenes by oxidative coupling of the synthesized 1,2,4-triaryl benzenes has also been demonstrated.

Enantio- and Diastereoselective Synthesis of exo-Peroxyacetals: An Organocatalyzed Peroxyhemiacetalization/oxa-Michael Addition Cascade.

An unprecedented enantioselective peroxyhemiacetalization/oxa-Michael addition cascade of ortho-formyl homochalcones has been developed using cinchona-alkaloid-based chiral bifunctional organocatalysts to provide cis-configured exo-peroxyacetals, a new class of organic peroxide, in good yields with excellent enantio- and diastereoselectivities. The resulting cis-configured exo-peroxyacetals were converted into the corresponding trans-configured peroxyacetals without affecting the enantioselectivity. Furthermore, the displacement of the peroxide moiety of exo-peroxyacetals with various nucleophiles has been demonstrated to afford 1,3-disubstituted isochromans with high diastereoselectivities and excellent enantioselectivities.

Organocatalytic, Enantioselective Synthesis of 1- and 3-Substituted Isochromans via Intramolecular Oxa-Michael Reaction of Alkoxyboronate: Synthesis of (+)-Sonepiprazole.

The enantioselective oxa-Michael reaction of alkoxyboronate strategy was demonstrated to provide a new and practical route to enantioriched 1- and 3-substituted isochromans using a chiral bifunctional organocatalyst. Furthermore, this methodology was extended to the enantioselective synthesis of (+)-sonepiprazole, a dopamine receptor antagonist.