Concise Route Research Articles

Highly selective synthesis of d-amino acids from readily available l-amino acids by a one-pot biocatalytic stereoinversion cascade.

d-Amino acids are key intermediates required for the synthesis of important pharmaceuticals. However, establishing a universal enzymatic method for the general synthesis of d-amino acids from cheap and readily available precursors with few by-products is challenging. In this study, we constructed and optimized a cascade enzymatic route involving l-amino acid deaminase and d-amino acid dehydrogenase for the biocatalytic stereoinversions of l-amino acids into d-amino acids. Using l-phenylalanine (l-Phe) as a model substrate, this artificial biocatalytic cascade stereoinversion route first deaminates l-Phe to phenylpyruvic acid (PPA) through catalysis involving recombinant Escherichia coli cells that express l-amino acid deaminase from Proteus mirabilis (PmLAAD), followed by stereoselective reductive amination with recombinant meso-diaminopimelate dehydrogenase from Symbiobacterium thermophilum (StDAPDH) to produce d-phenylalanine (d-Phe). By incorporating a formate dehydrogenase-based NADPH-recycling system, d-Phe was obtained in quantitative yield with an enantiomeric excess greater than 99%. In addition, the cascade reaction system was also used to stereoinvert a variety of aromatic and aliphatic l-amino acids to the corresponding d-amino acids by combining the PmLAAD whole-cell biocatalyst with the StDAPDH variant. Hence, this method represents a concise and efficient route for the asymmetric synthesis of d-amino acids from the corresponding l-amino acids.

Total synthesis of (±)-antroquinonol.

We report the total synthesis of (±)-antroquinonol based on a concise and efficient route. Key features include two different strategies to install the required three contiguous stereogenic centers, which not only furnish the desired natural product but also provide natural product congeners for further biological studies.

Efficient two-step synthesis of structurally diverse indolo[2,3-b]quinoline derivatives.

A general and efficient synthesis of diverse tetracyclic indolo[2,3-b]quinoline derivatives was achieved through palladium-catalyzed domino carboannulation/cross-coupling and DDQ-mediated double cross-dehydrogenative C-N bond formation. This approach provides a straightforward, atom-economical and concise route to easily access a diverse range of tetracyclic indolo[2,3-b]quinolines and their analogues in excellent yields with good tolerance of functional groups.

A facile and concise route to (hydroxybenzoyl)pyrido[2,3-d]pyrimidine heterocycle derivatives: synthesis, and structural, spectral and computational exploration.

In this work, we report the efficient synthesis of novel (hydroxybenzoyl)pyrido[2,3-d]pyrimidine heterocycle derivatives: 6-(2-hydroxy-5-methylbenzoyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6a), 6-(5-fluoro-2-hydroxybenzoyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6b), 6-(5-ethyl-2-hydroxybenzoyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6c) and 6-(2-hydroxy-5-isopropylbenzoyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6d). The chemical structures of the title compounds were ascertained by spectral techniques including 1H, 13C NMR, UV-visible and FT-IR spectroscopy as well as single-crystal X-ray diffraction analysis. Additionally, density functional theory (DFT) and time-dependent (TD-DFT) computation were adopted to analyze the electronic structures of 6a–d. Compounds 6a–d were computed in the ground state for FT-IR spectroscopic and natural bond orbital (NBO) analysis by DFT/B3LYP with the 6-311+G(d,p) basis set. UV-vis spectroscopic and HOMO and LUMO energy values for 6a–d were determined via TD-DFT/B3LYP with the 6-311+G(d,p) basis set. The optimized geometric parameters, UV-vis findings, and vibrational frequencies indicate good consistency with the experimental data. NBO analysis was conducted to explore the interactions and charge transfer among different orbitals in the title compounds. The HOMO and LUMO band gap (ΔE) values for 6a–d were found to be 3.93, 3.91, 4.10 and 3.91 eV, respectively. Molecular electrostatic potential (MEP) analysis explored the reactivity of the title compounds by predicting their nucleophilic as well as electrophilic sites.

A concise route for the one-pot multi-component synthesis of 4,6-disubstituted 2-aminopyridine-3-carbonitriles and pyranopyrazoles using cobalt (II) nitrate hexahydrate as catalyst

A concise route for the one-pot multi-component synthesis of 4,6-disubstituted 2-aminopyridine-3-carbonitriles and pyranopyrazoles using cobalt (II) nitrate hexahydrate as catalyst

Copper-Catalyzed Aerobic Oxidation Strategy: A Concise Route to Isatin

Copper-Catalyzed Aerobic Oxidation Strategy: A Concise Route to Isatin

Asymmetric One-Pot Construction of Three Stereogenic Elements: Chiral Carbon Center, Stereoisomeric Alkenes, and Chirality of Axial Styrenes.

An organocatalytic enantioselective method for the synthesis of multiple stereoisomers bearing E, Z configurations, stereogenic carbon centers, and axially chiral styrenes is reported. The method enabled the rapid construction of a series of stereochemical complexity products with excellent E, Z selectivity, diastereoselectivity (>20:1 dr), and enantioselectivity (up to 96% ee). This method provides an efficient and concise synthesis route of multiple stereoisomers with a wide range of potential applications in organic synthesis.

Enzymatic assembly of carbon-carbon bonds via iron-catalysed sp3 C-H functionalization.

Although abundant in organic molecules, carbon-hydrogen (C-H) bonds are typically considered unreactive and unavailable for chemical manipulation. Recent advances in C-H functionalization technology have begun to transform this logic, while emphasizing the importance of andchallenges associated with selective alkylation at a sp3 carbon1,2. Here we describe iron-based catalysts for the enantio-, regio- and chemoselective intermolecular alkylation of sp3 C-H bonds through carbene C-H insertion. The catalysts, derived from a cytochrome P450 enzyme in which the native cysteine axial ligand has been substituted for serine (cytochrome P411), are fully genetically encoded and produced in bacteria, where they can be tuned by directed evolution for activity and selectivity. That these proteins activate iron, the most abundant transition metal, to perform this chemistry provides a desirable alternative to noble-metal catalysts, which have dominated the field of C-H functionalization1,2. The laboratory-evolved enzymes functionalize diverse substrates containing benzylic, allylic or α-amino C-H bonds with high turnover and excellent selectivity. Furthermore, they have enabled the development of concise routes to several natural products. The use of the native iron-haem cofactor of these enzymes to mediate sp3 C-H alkylationsuggests thatdiverse haem proteins could serve as potential catalysts for this abiological transformation, and will facilitate the development of new enzymatic C-H functionalization reactions for applications in chemistry and synthetic biology.

Intramolecular Benzannulation of 3-Sulfonyl-2-benzylchromen-4-ones: Synthesis of Sulfonyl Dibenzooxabicyclo[3.3.1]nonanes.

In this work, a concise route for the synthesis of sulfonyl dibenzo-oxabicyclo[3.3.1]nonanes by a two-step route is described, including (i) NaBH4/LiCl-mediated reduction of 3-sulfonyl-2-benzylchromen-4-ones and (ii) sequential BF3·OEt2-mediated intramolecular annulation of the resulting 3-sulfonyl-2-benzylchroman-4-ols. A plausible mechanism is proposed and discussed herein. This protocol provides a highly effective stereocontrolled aryl-hydroxyl Friedel-Crafts-type cross-coupling to construct the tetra- or pentacyclic bridged framework. The use of various reaction conditions is investigated for an efficient transformation.

Synthesis of the C1–C12 Fragment of Calyculin C

Calyculins are a class of highly cytotoxic metabolites originally isolated from the marine sponge Discodermia calyx. To date, a total of twelve different calyculins (A–J) and calyculinamides (A, B and F) have been described, the most abundant (in D. calyx) being calyculins A and C. Herein, we demonstrate a concise route to access the C1–C12 tetraene fragment of calyculin C using transition-metal-catalyzed coupling reactions (Suzuki–Miyaura, Stille, Negishi and Heck) for the key connections. The synthesis starts from propionaldehyde and proceeds in 10 steps with 7.5% overall yield. We also describe an efficient route for the preparation of (Z)-3-iodobut-2-enenitrile in four steps and 68% yield.

An Enantioconvergent and Concise Synthesis of Lasonolide A.

Efficient access to medicinally significant natural products is an essential basis for the development of pharmaceuticals. The limited availability of marine natural products impedes broad biological evaluation. Despite several elegant syntheses of (-)-lasonolide A having been reported, a practical synthesis of this potent anticancer polyketide remains elusive. Based on the application of borane as a traceless protecting group and the development of an unprecedented bissulfone reagent for Julia olefination, (-)-lasonolide A was assembled in an enantioconvergent manner through the application of stereoselective hydroboration, allylation, and oxidation. This concise route may provide a realistic solution for accessing derivatives and analogues.

An Enantioconvergent and Concise Synthesis of Lasonolide A

AbstractEfficient access to medicinally significant natural products is an essential basis for the development of pharmaceuticals. The limited availability of marine natural products impedes broad biological evaluation. Despite several elegant syntheses of (−)‐lasonolide A having been reported, a practical synthesis of this potent anticancer polyketide remains elusive. Based on the application of borane as a traceless protecting group and the development of an unprecedented bissulfone reagent for Julia olefination, (−)‐lasonolide A was assembled in an enantioconvergent manner through the application of stereoselective hydroboration, allylation, and oxidation. This concise route may provide a realistic solution for accessing derivatives and analogues.

Alkyne-Tagged Analogue of Jaspine B: New Tool for Identifying Jaspine B Mode of Action.

The first biologically relevant clickable probe related to the antitumor marine lipid jaspine B is reported. The concise synthetic route to both enantiomers relied on the supercritical fluid chromatography (SFC) enantiomeric resolution of racemic materials. The eutomeric dextrogyre derivative represents the first jaspine B analogue with enhanced cytotoxicity with IC50 down to 30 nm. These enantiomeric probes revealed a chiralitydependent cytoplasmic imaging of U2OS cancer cells by in situ click labeling.

Asymmetric Synthesis of Netarsudil: A New Therapeutic for Open-Angle Glaucoma

The asymmetric synthesis of a Rho kinase/norepinephrine transport inhibitor, netarsudil, the active component in the recently FDA-approved product Rhopressa™, is described herein. This concise six-step synthetic route utilizes the 2,4-dimethylbenzoate ester of a phenylacetic acid as the backbone of the β-amino acid’s framework. A chiral enolate of the Evans auxiliary, (R)-4-benzyloxazolidin-2-one, is used to direct the formation of the (S)-stereocenter by incorporating the N-Boc-protected β-amino methyl arm with high diastereoselectivity (96:4 dr) using N-Boc-1-aminomethylbenzotriazole as the electrophile. Uniquely, 2,2,2-trichloro-1,1-dimethylethyl chloroformate is used as a non-racemizing activating agent for the coupling reaction between the chiral (S)-N-Boc-protected 2,4-dimethylbenzoyloxymethyl phenyl propanoic acid and 6-aminoisoquinoline to provide N-Boc-protected netarsudil in good yield and excellent enantiomeric purity (63%, 98% ee). Final acidic deprotection and recrystallization provides netarsudil (>99% ee), an ophthalmic agent used for the treatment of patients with open-angle glaucoma.

Total Synthesis of (±)-Prostratin

Summary Prostratin, a highly complex diterpene natural product, is a pre-clinical candidate in developing a cure for HIV-1 infection and also a potent and selective inhibitor of several tumors. Despite nearly 40 years of progress, prostratin and related natural products still present formidable challenges for synthetic chemists. Here, we report a total synthesis of (±)-prostratin that proceeds in 23 steps from cyclopentadiene. The synthetic strategy includes rapid assembly of the tricyclic core and highly controlled establishment of the densely functionalized C ring, featuring an array of stereoselective transformations including alkoxide-guided 1,4-additions and cyclopropane formation. This work should enable further explorations of chemical and biological spaces based on prostratin and related natural products.

Rhodium-Catalyzed Highly Regio- and Enantioselective Hydrogenation of Tetrasubstituted Allenyl Sulfones: An Efficient Access to Chiral Allylic Sulfones.

A highly regio- and enantioselective hydrogenation of challenging tetrasubstituted allenyl sulfones has been developed, affording chiral allylic sulfones in good yields with excellent regio- and enantioselectivities (up to 99 % yield and 99 % ee). This method provides an efficient and concise route to chiral allylic sulfones, thus offering an atom-economic process with a wide range of potential applications in organic synthesis and medicinal chemistry.

Rhodium‐Catalyzed Highly Regio‐ and Enantioselective Hydrogenation of Tetrasubstituted Allenyl Sulfones: An Efficient Access to Chiral Allylic Sulfones

AbstractA highly regio‐ and enantioselective hydrogenation of challenging tetrasubstituted allenyl sulfones has been developed, affording chiral allylic sulfones in good yields with excellent regio‐ and enantioselectivities (up to 99 % yield and 99 % ee). This method provides an efficient and concise route to chiral allylic sulfones, thus offering an atom‐economic process with a wide range of potential applications in organic synthesis and medicinal chemistry.

Diversity‐Oriented Synthetic Endeavors of Newly Designed Ferrier and Ferrier‐Nicholas Systems Derived from 1‐C‐Alkynyl‐2‐deoxy‐2‐C‐Methylene Pyranosides

Novel pyranose derivatives that display Ferrier‐ and Ferrier‐Nicholas‐like reactivity have been designed. These systems: 1‐C‐alkynyl‐2‐deoxy‐2‐C‐methylene pyranosides (Ferrier), and their corresponding dicobalthexacarbonyl alkenyl derivatives (Ferrier‐Nicholas), which can be accessed by a concise synthetic route from commercially available tri‐O‐acetyl‐d‐glucal, allow the incorporation of two nucleophiles (at positions C‐3 and C‐2′) in the pyranose ring. The study of these systems has resulted in the discovery of novel reaction patterns that allow, among others, access to open‐chain derivatives, branched pyranosides, 1,6‐anhydro derivatives and, when reacting with indole, access to a new family of tetracyclic indole‐containing carbohydrate derivatives, namely, cyclohepta[b]indole‐fused glycals. The latter are, most likely, formed by a bis Ferrier‐type rearrangement followed by an unusual intramolecular 7‐endo‐dig Friedel–Crafts alkenylation of one of the indole moieties by the C‐1 alkyne.

Stereocontrolled Construction of 1-Vinylindanes via Intramolecular Cyclization of o-Cinnamyl Chalcones.

In this paper, a concise route for the synthesis of 1-vinylindanes is described, including (i) NaBH4-mediated reduction of o-cinnamyl chalcones and (ii) sequential BF3·OEt2-mediated intramolecular annulation of the resulting alkenols. The plausible mechanism is proposed and discussed herein. This protocol provides highly effective stereocontrolled cinnamyl-enone cross-coupling to construct three contiguous trans- trans stereocenters and one ( E)-configured alkenyl or styryl group.

Myoglobin‐Catalyzed C−H Functionalization of Unprotected Indoles

AbstractFunctionalized indoles are recurrent motifs in bioactive natural products and pharmaceuticals. While transition metal‐catalyzed carbene transfer has provided an attractive route to afford C3‐functionalized indoles, these protocols are viable only in the presence of N‐protected indoles, owing to competition from the more facile N−H insertion reaction. Herein, a biocatalytic strategy for enabling the direct C−H functionalization of unprotected indoles is reported. Engineered variants of myoglobin provide efficient biocatalysts for this reaction, which has no precedents in the biological world, enabling the transformation of a broad range of indoles in the presence of ethyl α‐diazoacetate to give the corresponding C3‐functionalized derivatives in high conversion yields and excellent chemoselectivity. This strategy could be exploited to develop a concise chemoenzymatic route to afford the nonsteroidal anti‐inflammatory drug indomethacin.