ABSTRACT
Albeit notable endeavors in enantioselective carbene insertion into X-H bonds (X = C, O, N, S, Si, B), the catalytic asymmetric P-H insertion reactions still stand for a long-lasting challenge. By merging transition-metal catalysis with organocatalysis, we achieve a scalable enantioselective P-H insertion transformation between diazo pyrazoleamides and H-phosphine oxides that upon subsequent reduction delivers a wide variety of optically active ß-hydroxyl phosphine oxides in good yields with high enantioselectivity. The achiral copper catalyst fosters the carbenoid insertion into the P-H bond, while the chiral cinchona alkaloid-derived organocatalyst controls the subsequent enantioselective outcome. Density functional theory (DFT) calculations further reveal that the copper catalyst chelates to the organocatalyst, enhances its acidity, and accordingly promotes the enantioselective proton transfer. Our work showcases the potential of combining transition-metal catalysis with organocatalysis to realize elusive asymmetric reactions.
ABSTRACT
Catalytic selective hydroxylation of unactivated aliphatic (sp3 ) C-H bonds without a directing group represents a formidable task for synthetic chemists. Through directed evolution of P450BSß hydroxylase, we realize oxyfunctionalization of unactivated C-H bonds in a broad spectrum of aliphatic carboxylic acids with varied chain lengths, functional groups and (hetero-)aromatic moieties in a highly chemo-, regio- and enantioselective fashion (>30 examples, Cß/Cα>20 : 1, >99 % ee). The X-ray structure of the evolved variant, P450BSß -L78I/Q85H/G290I, in complex with palmitic acid well rationalizes the experimentally observed regio- and enantioselectivity, and also reveals a reduced catalytic pocket volume that accounts for the increased reactivity with smaller substrates. This work showcases the potential of employing a biocatalyst to enable a chemical transformation that is particularly challenging by chemical methods.
Subject(s)
Carboxylic Acids , Cytochrome P-450 Enzyme System , Biocatalysis , Cytochrome P-450 Enzyme System/metabolism , Hydroxylation , StereoisomerismABSTRACT
Herein, we report an engineered enzyme that can monooxygenate unprotected tryptophan into the corresponding 3a-hydroxyhexahydropyrrolo[2,3-b]indole-2-carboxylic acid (HPIC) in a single, scalable step with excellent turnover number and diastereoselectivity. Taking advantage of directed evolution, we analyzed the stepwise oxygen-insertion mechanism of tryptophan 2,3-dioxygenases, and transformed tryptophan 2,3-dioxygenase from Xanthomonas campestris into a monooxygenase for oxidative cyclization of tryptophans. It was revealed that residue F51 is vital in determining the product ratio of HPIC to N'-formylkynurenine. Our reactions and purification procedures use no organic solvents, resulting in an eco-friendly method to prepare HPICs for further applications.
Subject(s)
Mixed Function Oxygenases/chemistry , Tryptophan Oxygenase/chemistry , Tryptophan/chemistry , Humans , Oxidation-ReductionABSTRACT
A novel palladium-catalyzed Heck-type reaction of thiocarbamates has been designed to construct bridged seven-membered-ring systems that are otherwise challenging to prepare. Taking advantage of this newly developed method, enantioselective syntheses of lyconadinsâ A-E (1-5), lycopecurine (6), and dehydrolycopecurine (7) have been realized in a divergent fashion. Our synthetic strategy also features an intramolecular cyclization of a N-chloroamine to forge the C6-N bond, a transannular Mannich-type reaction of a cyclic nitrone to stitch the C4 and C13 together, and a cyclocondensation to deliver the (dihydro-)pyridone motif.
ABSTRACT
The C19-oxo-functionalized eburnane alkaloids display unique chemical structure and interesting biological activity. Herein, we report a divergent enantioselective strategy to access these alkaloids by use of a challenging palladium-catalyzed asymmetric allylic alkylation of an N-alkyl-α,ß-unsaturated lactam. 19-( S)-OH-Δ14-vincamone (phutdonginin), (-)-19-OH-eburnamine, (+)-19-oxoeburnamine, and (+)-19-OH-eburnamonine (1-4) have been concisely synthesized for the first time in 11 to 13 steps.
ABSTRACT
Vinylcyclopropanes (VCPs) are known to generate 1,3-dipoles with a palladium catalyst that initially serve as nucleophiles to undergo [3 + 2] cycloadditions with electron-deficient olefins. In this report, we reverse this reactivity and drive the 1,3-dipoles to serve as electrophiles by employing 3-alkylated indoles as nucleophiles. This represents the first use of VCPs for the completely atom-economic functionalization of 3-substituted 1 H-indoles and tryptophan derivatives via a Pd-catalyzed asymmetric allylic alkylation (Pd-AAA). Excellent yields and high chemo-, regio-, and enantioselectivities have been realized, providing various indolenine and indoline products. The method is amenable to gram scale and works efficiently with tryptophan derivatives that contain a diketopiperazine or diketomorpholine ring, allowing us to synthesize mollenine A in a rapid and ligand-controlled fashion. The obtained indolenine products bear an imine, an internal olefin, and a malonate motif, giving multiple sites with diverse reactivities for product diversification. Complicated polycyclic skeletons can be conveniently constructed by leveraging this unique juxtaposition of functional groups.
Subject(s)
Allyl Compounds/chemical synthesis , Cyclopropanes/chemistry , Indoles/chemistry , Palladium/chemistry , Tryptophan/chemistry , Alkylation , Allyl Compounds/chemistry , Catalysis , Cycloaddition Reaction , Molecular StructureABSTRACT
The synthesis of des-epoxy-amphidinolide N was achieved in 22 longest linear and 33 total steps. Three generations of synthetic endeavors are reported herein. During the first generation, our key stitching strategy that highlighted an intramolecular Ru-catalyzed alkene-alkyne (Ru AA) coupling and a late-stage epoxidation proved successful, but the installation of the α,α'-dihydroxyl ketone motif employing a dihydroxylation method was problematic. Our second generation of synthetic efforts addressed the scalability problem of the southern fragment synthesis and significantly improved the efficiency of the atom-economical Ru AA coupling, but suffered from several protecting group-based issues that proved insurmountable. Finally, relying on a judicious protecting group strategy together with concise fragment preparation, des-epoxy-amphidinolide N was achieved in a convergent fashion. Calculations disclose a hydrogen-bonding bridge within amphidinolide N. Comparisons of 13C NMR chemical shift differences using our synthetic des-epoxy-amphidinolide N suggest that amphidinolide N and carbenolide I are probably identical.
Subject(s)
Macrolides/chemical synthesis , Alkenes/chemistry , Alkynes/chemistry , Catalysis , Cyclization , Esterification , Hydrogen Bonding , Molecular Conformation , Oxidation-Reduction , Ruthenium/chemistry , StereoisomerismABSTRACT
Covering: 2012 to June 2017This review aims to show that complex natural product synthesis can be streamlined by taking advantage of molecular symmetry. Various strategies to construct molecules with either evident or hidden symmetry are illustrated. Insights regarding the origins and adjustments of these strategies as well as inspiring new methodological developments are deliberated. When a symmetric strategy fails, the corresponding reason is analysed and an alternative approach is briefly provided. Finally, the importance of exploiting molecular symmetry and future research directions are discussed.
Subject(s)
Biological Products/chemical synthesis , Biological Products/chemistry , Molecular StructureABSTRACT
CONSPECTUS: An ortho-quinone methide (o-QM) is a highly reactive chemical motif harnessed by nature for a variety of purposes. Given its extraordinary reactivity and biological importance, it is surprising how few applications within organic synthesis exist. We speculate that their widespread use has been slowed by the complications that surround the preparation of their precursors, the harsh generation methods, and the omission of this stratagem from computer databases due to its ephemeral nature. About a decade ago, we discovered a mild anionic triggering procedure to generate transitory o-QMs at low temperature from readily available salicylaldehydes, particularly OBoc derivatives. This novel reaction cascade included both the o-QM formation and the subsequent consumption reaction. The overall transformation was initiated by the addition of the organometallic reagent, usually a Grignard reagent, which resulted in the formation of a benzyloxy alkoxide. Boc migration from the neighboring phenol produced a magnesium phenoxide that we supposed underwent ß-elimination of the transferred Boc residue to form an o-QM for immediate further reactions. Moreover, the cascade proved controllable through careful manipulation of metallic and temperature levers so that it could be paused, stopped, or restarted at various intermediates and stages. This new level of domestication enabled us to deploy o-QMs for the first time in a range of applications including diastereocontrolled reactions. This sequence ultimately could be performed in either multipot or single pot processes. The subsequent reaction of the fleeting o-QM intermediates included the 1,4-conjugate additions that led to unbranched or branched ortho-alkyl substituted phenols and Diels-Alder reactions that provided 4-unsubstituted or 4-substituted benzopyrans and chroman ketals. The latter cycloadducts were obtained for the first time with outstanding diastereocontrol. In addition, the steric effects of the newly created stereocenters in subsequent reactions of chroman ketals and acetals were studied and proved predictable. Through the use of a chiral auxiliary, Diels-Alder products were deployed in numerous enantioselective reactions including several complex natural products syntheses. In this Account, we summarize our efforts, which we hope have contributed to the synthetic renaissance for this venerable species.
Subject(s)
Indolequinones/chemistry , Indolequinones/chemical synthesis , Molecular Structure , Phenols/chemistryABSTRACT
The total syntheses of medicarpin, sophoracarpanâ A, and kushecarpinâ A from a common intermediate are achieved by using ortho- and para-quinone methide chemistry. Additionally, the relative stereochemistry of sophoracarpanâ A and B have been reassigned.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Pterocarpans/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Pterocarpans/chemistry , StereoisomerismABSTRACT
The histidine kinase, CheA, couples environmental stimuli to changes in bacterial swimming behavior, converting a sensory signal to a chemical signal in the cytosol via autophosphorylation. The kinase activity is regulated in the platform of chemotaxis signaling complexes formed by CheW, chemoreceptors, and the regulatory domain of CheA. Our previous computational and mutational studies have revealed that two interdomain linkers play important roles in CheA's enzymatic activity. Of the two linkers, one that connects the dimerization and ATP binding domains is essential for both basal autophosphorylation and activation of the kinase. However, the mechanistic role of this linker remains unclear, given that it is far from the autophosphorylation reaction center (the ATP binding site). Here we investigate how this interdomain linker is coupled to CheA's enzymatic activity. Using modern nuclear magnetic resonance (NMR) techniques, we find that by interacting with the catalytic domain, the interdomain linker initiates long-range structural and dynamic changes directed toward the catalytic center of the autophosphorylation reaction. Subsequent biochemical assays define the functional relevance of these NMR-based observations. These findings extend our understanding of the chemotaxis signal transduction pathway.
Subject(s)
Bacterial Proteins/chemistry , Protein Kinases/chemistry , Thermotoga maritima/metabolism , Catalytic Domain , Enzyme Activation , Histidine Kinase , Models, Molecular , Phosphorylation , Protein MultimerizationABSTRACT
Exploring the scope of biocatalytic transformations in the absence of enzyme structures without extensive experimentation is a challenging task. To expand the limited substrate capacity of carrot-mediated bioreduction and hunt for new medicinally relevant ketones with minimum cost of labor and time, we deployed a practical method inspired by ligand-based drug design. Through analyzing collected literature data and building pharmacophore and reactivity prediction models, we screened a self-built virtual library of >8000 ketones bearing the most frequently used N,O,S-heterocycles and functional groups in drug discovery. Representative examples were validated, expanding the bioreduction substrate scope. The public availability of our models alongside the straightforward screening workflow makes it time-, labor-, and cost-saving to evaluate unknown bioreduction substrates for medicinal chemistry applications, especially for a large set of structurally differentiated ketones. Our studies also showcase the novelty of utilizing medicinal chemistry principles to solve a general biocatalysis problem.
Subject(s)
Drug Design , Ketones , Ligands , Ketones/chemistry , Ketones/metabolism , Oxidation-Reduction , Biocatalysis , Daucus carota/metabolism , Daucus carota/chemistryABSTRACT
We herein report an enantioselective bioreduction of ketones that bear the most frequently used nitrogen-heteroaromatics in FDA-approved drugs. Ten varieties of these nitrogen-containing heterocycles were systematically investigated. Eight categories were studied for the first time and seven types were tolerated, significantly expanding the substrate scope of plant-mediated reduction. By use of purple carrots in buffered aqueous media with a simplified reaction setup, this biocatalytic transformation was achieved within 48 h at ambient temperature, offering medicinal chemists a pragmatic and scalable tool to access a broad variety of nitrogen-heteroaryl-containing chiral alcohols. With multiple reactive sites, the structurally diverse set of chiral alcohols can be used for library compound preparation, early route-scouting activities, and synthesis of other pharmaceutical molecules, favorably accelerating medicinal chemistry campaigns.
ABSTRACT
A Cu-catalyzed diastereoselective [3 + 2] cycloaddition of 2-arylaziridines and cyclic silyl dienol ethers was developed to efficiently construct fused-[5,n] carbocyclic pyrrolidines, which are widespread in bioactive natural products. Mechanistic studies revealed that the high diastereoselectivity of this transformation arose from a sequential retro aza-Michael/epimerization/aza-Michael process. Taking advantage of this newly developed method, the first total syntheses of pancratinines B and C were concisely realized.
ABSTRACT
B3GNT2 is responsible for elongation of cell surface long-chain polylactosamine, which influences the regulation of the immune response, making it an attractive target for immunomodulation. In the development of amide containing B3GNT2 inhibitors guided by structure-based drug design, imidazolones were found to successfully serve as amide bioisosteres. This novel imidazolone isosteric strategy alleviated torsional strain of the amide bond on binding to B3GNT2 and improved potency, isoform selectivity, as well as certain physicochemical and pharmacokinetic properties. Herein, we present the synthesis, SAR, X-ray cocrystal structures, and in vivo PK properties of imidazol-4-ones in the context of B3GNT2 inhibition.
Subject(s)
Amides , N-Acetylglucosaminyltransferases , Amides/pharmacology , Amides/chemistry , N-Acetylglucosaminyltransferases/metabolism , Drug Design , Structure-Activity RelationshipABSTRACT
Stereodivergent total syntheses of ent-heliespirone A and C were both completed in 11 vessels and â¼24% combined overall yield (A + C). These syntheses employed an identical inverse demand Diels-Alder reaction between a surrogate for an extendedly conjugated γ-δ unsaturated ortho-quinone methide and L-lactic-acid-derived exocyclic enol ether. Novel reactions of special note include a diastereoselective reduction of a chroman spiroketal by combination of borontrifluoride etherate and triethyl silane, along with oxidative rupture of a chroman etherial ring into the corresponding p-quinone by argentic oxide (AgO). In addition, an unusual intramolecular etherification of a 3° alcohol caused by cerium ammonium nitrate was observed.
Subject(s)
Benzoquinones/chemical synthesis , Chromans/chemistry , Indolequinones/chemistry , Quinones/chemistry , Sesquiterpenes/chemical synthesis , Silanes/chemistry , Cyclization , Molecular Structure , Oxidation-Reduction , StereoisomerismABSTRACT
Polyketide natural products are an important class of biologically active compounds. Although substantial progress has been made on the synthesis of repetitive polyketide motifs through the iterative application of a single reaction type, synthetic access to more diverse motifs that require more than one type of carbon-carbon bond connection remains a challenge. Here we describe a catalytic, multicomponent method for the synthesis of the privileged polyketide 1,3-dienyl-6-oxy motif. The method allows for the formation of two new carbon-carbon bonds and two stereodefined olefins. It generates products that contain up to three contiguous sp3 stereocentres with a high stereoselectivity in a single operation and can be used to generate chiral products. The successful development of this methodology relies on the remarkable efficiency of the ruthenium-catalysed alkene-alkyne coupling reaction between readily available vinyl boronic acids and alkynes to provide unsymmetrical 3-boryl-1,4-diene reagents. In the presence of carbonyl compounds, these reagents undergo highly diastereoselective allylations to afford the desired 1,3-dienyl-6-oxy motif and enable complex polyketide synthesis in a rapid and asymmetric fashion.
ABSTRACT
A highly efficient asymmetric hydrogenation of racemic acyclic alpha-amino aliphatic ketones via dynamic kinetic resolution has been realized, providing chiral amino alcohols in excellent enantioselectivities and diastereoselectivities. A hydrogen-bonding transition state mode was proposed for explaining the high diastereoselectivity and enantioselectivity of the reaction.
ABSTRACT
A nickel-catalyzed coupling of N-sulfonyl-1,2,3-triazole with various H-phosphine oxides for the construction of C(sp2)-P bonds is established. This unexpected reaction proceeds through a formal nickel-bound ketenimine pathway, representing a previously unknown 1,2-reactivity type of an azavinyl carbene. The method provides an efficient approach to the stereoselective and site-selective synthesis of α-aminovinylphosphoryl derivatives with moderate to good yield. A plausible mechanism is proposed based on experimental and theoretical studies.
ABSTRACT
A strategy toward tetrapetalones was explored including a site-selective ethylenation of the silyl enol ether A to afford a quaternary stereocenter that serves in a stereogenic capacity. Regio- and diastereoselective reactions were observed in conjunction with the oxidative formation of cation B, which included subsequent selective formation of either carbon-oxygen or carbon-carbon bonds at the δ or ζ position on the seven-membered ring. The fourth ring was formed using a Stetter reaction.