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Catalytic selective hydroxylation of unactivated aliphatic (sp

Inspired by the catalytic mechanism of cytochrome P450 enzymes, we have evolved a fatty acid hydroxylase, P450BSβ, into a decarboxylase after four rounds of saturation mutagenesis that now predomin...

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.

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.

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 lyconadins 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.

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.

An efficient catalytic asymmetric hydrophosphination of ortho-quinone methides with H-phosphine oxides is established. A chiral bifunctional squaramide is superior to catalyze this enantioselective carbon-phosphorus bond formation, delivering optically active α-arylmethyl phosphine oxides in high yields with high enantioselectivities (up to 94% yield, 99:1 er). Additionally, employing in situ-generated o-QMs for this hydrophosphination step economically provides the corresponding phosphine oxides with comparable yield and enantioselectivity.

Fusing the decarboxylase OleTJE and the reductase domain of P450BM3 creates a self-sufficient protein, OleT-BM3R, which is able to efficiently catalyze oxidative decarboxylation of carboxylic acids into linear α-olefins (LAOs) under mild aqueous conditions using O2 as the oxidant and NADPH as the electron donor. The compatible electron transfer system installed in the fusion protein not only eliminates the need for auxiliary redox partners, but also results in boosted decarboxylation reactivity and broad substrate scope. Coupled with the phosphite dehydrogenase-based NADPH regeneration system, this enzymatic reaction proceeds with improved product titers of up to 2.51 g L–1 and volumetric productivities of up to 209.2 mg L–1 h–1 at low catalyst loadings (∼0.02 mol %). With its stability and scalability, this self-sufficient biocatalyst offers a nature-friendly approach to deliver LAOs.

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,β-unsaturated lactam. 19-( S)-OH-Δ

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 usin...

The total syntheses of medicarpin, sophoracarpan A, and kushecarpin A from a common intermediate are achieved by using ortho- and para-quinone methide chemistry. Additionally, the relative stereochemistry of sophoracarpan A and B have been reassigned.

A catalytic diastereoselective aldol reaction has been developed for N1-arylated/C2-O-silylated/C3-methylated and brominated/C4-O-methylated pyrroles in its reactions with various aldehydes. Syn adducts emerge with regard to the vicinal nitrogen and oxygen heteroatom substituents. The N1-aryl residue undergoes oxidative cleavage, and the C3-bromine atom undergoes palladium-mediated coupling reactions, both without disturbing the newly created stereocenters.

A highly efficient enantioselective synthe- sis of chiral b-aryloxy alcohols by the {RuCl2((S)- SDP)AR,R)-DPEN)} ((Sa,R,R)-1a ;S DP= 7,7'-bis- A)-1,1'-spirobiindane; DPEN = trans-1,2-diphenylethylenediamine) complex-cata- lyzed asymmetric hydrogenation of racemic a- aryloxydiA ketones via dynamic kinetic resolu- tion (DKR) has been developed. Enantioselectivi- ties of up to 99% ee with good to high cis/anti-selec- tivities (up to > 99:1) were achieved.

The asymmetric hydrogenation of the conformationally flexible racemic α-substituted acyclic dialkyl ketones via dynamic kinetic resolution (DKR) has been developed by using Ru-SDPs/diamine catalysts. Chiral alcohols were produced in high yields with good to excellent enantioselectivities (85%–97% ee) and diastereoselectivities (up to 97:3). This hydrogenation reaction provided a new approach to the synthesis of the key intermediate of J-104118.

The title process proceeds with good to excellent syn selectivity to provide the corresponding aldol products.

A highly efficient asymmetric hydrogenation of racemic acyclic α-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.

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.