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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...

Catalytic selective hydroxylation of unactivated aliphatic (sp

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.

The tetrapetalones were pursued for well over a decade by numerous research groups. Herein, we detail our motivations and findings, which we imagine are very different from the many others who tackled this extremely challenging problem. In this chapter, we explain how our many failures caused us to revise our strategy eight times. Although we failed to reach the genuine natural product, we hope the reader will conclude that we nevertheless developed several valuable methods and that we gained important strategic insights from our trials and tribulations. At the very least, we can emphatically state that we developed a great appreciation of the wonderful ways in which our chemistry community is interconnected, and the great benefit we all enjoy from one another's achievements.

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 sp

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.

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.

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

Nonreducing, pH-neutral conditions for the selective cleavage of the 2,2,2-trichloroethoxycarbonyl (Troc) protecting group are reported. Using trimethyltin hydroxide in 1,2-dichloroethane, Troc-protected alcohols, thiols, and amines can be selectively unmasked in the presence of various functionalities that are incompatible with the reducing conditions traditionally used to remove the Troc group. This mild deprotection protocol tolerates a variety of other hydrolytically sensitive and acid/base-sensitive moieties as well.

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...

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.

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.

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 β-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.

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.

Synthetic access to regiodifferentiated meta-amino phenols is described. The strategy relies upon distinct deprotonation conditions to afford regioisomeric thermodynamic and kinetic dienes that undergo a tandem Diels–Alder and retro-Diels–Alder sequence with assorted acetylenic dienophiles to afford a range of aromatic products.

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.

Stereodivergent total syntheses of ent-heliespirone A and C were both completed in 11 vessels and ∼24% 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.

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.

ConspectusAn 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 m...

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

Reaction of amino acid derivatives with SmI2/ HMPA provides a general approach to optically active title compounds.

A general method to construct 3-methyl-4-O-methylated tetramic acids displaying a C-5 stereocenter is presented. The synthetic sequence employs a SmI(2)-mediated cyclization, whereby the chirality of the emerging tetramic acid core is retained from the starting chiral amino acid. Application to palau'imide is discussed.

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.