Transition metal-free Suzuki type cross-coupling reaction for the synthesis of dissymmetric ketones

A simple, efficient and metal-free route for the synthesis of dissymmetric ketones through Suzuki type cross-coupling reaction has been established. This strategy signifies an attractive, cost-effective and operationally convenient tool for the synthesis of a wide range of dissymmetric ketones. Although conventional routes for the synthesis of ketones have been widely used, the potential challenge with these methods is functional group tolerance. The reported metal-free method represents a reaction with moderate functional group tolerance. The procedure is operationally convenient and shows broad substrate scope with good to excellent product yields.     

Total synthesis of the antitumor antibiotic (+/-)-fredericamycin A by a linear approach

A linear approach to the total synthesis of racemic fredericamycin A (1) through the oxidative intramolecular [4 + 2] cycloaddition of a (phenylthio)acetylene-cobalt complex is described, which is applicable for the asymmetric total synthesis of naturally occuring 1. The highlight of this work is the aromatic Pummerer-type reaction with 1-ethoxyvinyl chloroacetate, which effects the introduction of the oxygen functional group to the internal B-ring of the highly functionalized, congested polyaromatic ABC-ring moiety.     

Enantioselective total synthesis of (+)-largazole, a potent inhibitor of histone deacetylase

An enantioselective total synthesis of the cytotoxic natural product (+)-largazole (1) is described. It is a potent histone deacetylase inhibitor. Our synthesis is convergent and involves the assembly of thiazole 3-derived carboxylic acid with amino ester 4 followed by cycloamidation of the corresponding amino acid. The synthesis features an efficient cross-metathesis, an enzymatic kinetic resolution of a beta-hydroxy ester, a selective removal of a Boc-protecting group, a HATU/HOAt-promoted cycloamidation reaction, and synthetic manipulations to a sensitive thioester functional group.     

Copper‐Catalyzed 1,2‐Addition of α‐Carbonyl Iodides to Alkynes

β,γ‐Unsaturated ketones are an important class of organic molecules. Herein, copper catalysis has been developed for the synthesis of β‐γ‐unsaturated ketones through 1,2‐addition of α‐carbonyl iodides to alkynes. The reactions exhibit wide substrate scope and high functional group tolerance. The reaction products are versatile synthetic intermediates to complex small molecules. The method was applied for the formal synthesis of (±)‐trichostatin A, a histone deacetylase inhibitor.     

Optimization of a biomimetic transamination reaction

For a range of protein substrates, N-terminal transamination offers a convenient way to install a reactive ketone or aldehyde functional group at a single location. We report herein the effects of the identity of N-terminal residues on the product distribution generated upon reaction with pyridoxal 5'-phosphate (PLP). This study was accomplished through the combination of solid-phase peptide synthesis with detailed liquid chromatography-mass spectrometry analysis. Many N-terminal amino acids provided high yields of the desired transaminated products, but some residues (His, Trp, Lys, and Pro) generated adducts with PLP itself. N-terminal Cys and Ser residues were observed to undergo beta-elimination in addition to transamination, and the transamination product of N-terminal Gln was resistant to subsequent oxime formation attempts. The information generated through the screening of peptide substrates was successfully applied to a protein target, changing an initially unreactive terminus into one that could be modified in high (70%) yield. Thus, these studies have increased our predictive power for the reaction, both in terms of improving conversion and suppressing reaction byproducts. An initial set of guidelines that may be used to increase the applicability of this reaction to specific proteins of interest is provided.     

Metal-free synthesis of 3,3-disubstituted oxindoles via 1,2-alkylarylation of activated alkenes with alcohols

Metal-free synthesis of 3,3-disubstituted oxindoles utilizing N-arylacrylamides and simple alcohols is developed. It provides an efficient method for preparing a series of hydroxyl-containing oxindole derivatives. This reaction is proposed to proceed through oxidative radical cyclization mechanism. The remarkable features of the reaction are metal-free condition and excellent functional group tolerance.     

Total synthesis of spirotenuipesines A and B

Spirotenuipesines A and B, isolated from the entomopathogenic fungus Paecilomyces tenuipes by Oshima and co-workers, have been synthesized. The synthesis features the highly stereoselective construction of two vicinal all-carbon quaternary centers (C(5) and C(6)) via an intramolecular cyclopropanation/radical initiated fragmentation sequence and a diastereoselective intermolecular Diels-Alder reaction between alpha-methylenelactone dienophile 20 and synergistic diene 6a. Installation of the C(9) tertiary alcohol occurred via nucleophilic methylation. An RCM reaction to produce a tetrasubstituted double bond in the presence of free allylic alcohol and homoallylic oxygenated functional group is also described. This route shortened the synthesis of 11 from 9 steps to 3 steps. We have further developed a strategy to gain access to optically active spirotenuipesines A and B through the synthesis of enantioenriched 10 from commercially available R-(-)-epichlorohydrin.     

Catalytic proficiency of ubiquitin conjugation enzymes: balancing pK(a) suppression, entropy, and electrostatics

Biological organisms orchestrate coordinated responses to external stimuli through temporal fluctuations in protein-protein interaction networks using molecular mechanisms such as the synthesis and recognition of polyubiquitin (polyUb) chains on signaling adaptor proteins. One of the pivotal chemical steps in ubiquitination involves reaction of a lysine amino group with a thioester group on an activated E2, or ubiquitin conjugation enzyme, to form an amide bond between Ub and a target protein. In this study, we demonstrate a nominal 14-fold range for the rate of the chemical step, k(cat), catalyzed by different E2 enzymes using non-steady-state, single-turnover assays. However, the observed range for k(cat) is as large as ～100-fold for steady-state, single-turnover assays. Biochemical assays were used in combination with measurement of the underlying protein-protein interaction kinetics using NMR line-shape and ZZ-exchange analyses to determine the rate of polyUb chain synthesis catalyzed by the heterodimeric E2 enzyme Ubc13-Mms2. Modest variations in substrate affinity and k(cat) can achieve functional diversity in E2 mechanism, thereby influencing the biological outcomes of polyubiquitination. E2 enzymes achieve reaction rate enhancements through electrostatic effects such as suppression of substrate lysine pK(a) and stabilization of transition states by the preorganized, polar enzyme active site as well as the entropic effects of binding. Importantly, modestly proficient enzymes such as E2s maintain the ability to tune reaction rates; this may confer a biological advantage for achieving specificity in the diverse cellular roles for which these enzymes are involved.     

Synthesis of 2-(phenoxymethyl)oxirane derivatives through unexpected rearrangement of oxiran-2-ylmethyl benzenesulfonates

The synthesis of 2-(phenoxymethyl)oxirane derivatives from oxiran-2-ylmethyl benzenesulfonates was developed through a base promoted rearrangement. A new C-O bond was formed along with the unexpected cleavage of C-S bond via this process. This unusual reaction was characterized with mild reaction conditions, high efficiency, and excellent functional group tolerance. A plausible reaction mechanism was proposed on the basis of experimental results and control experiments.     

A modified approach to the phomoidrides: synthesis of a late-stage intermediate containing a key carbon quaternary stereocenter

A previously developed approach to the synthesis of the phomoidrides has been modified to incorporate all necessary carbon atoms prior to the key tandem carbonylation/Cope rearrangement reaction. This modification necessitated the synthesis of a challenging all-carbon quaternary stereocenter, which in turn rendered ineffective several reactions from the original synthesis. An oxidative radical cleavage of a spirocyclopropane ring system was developed that accomplishes the synthesis of the quaternary center, and a regioselective double hydroboration reaction was devised that provides an alternate approach to a key sequence of functional group interconversions, where the originally developed route was found to be ineffective.     

Cu-mediated 1,3-dipolar cycloaddition of azomethine ylides with dipolarophiles: a faster access to spirooxindoles of potential pharmacological interest

CuI facilitated three-component reaction of isatin derivatives, l-proline and terminal alkynes containing an amide or ester functional group. The multi-component reaction (MCR) afforded a faster and practical synthesis of spirooxindole derivatives. A range of novel spirooxindoles were synthesized by using this straightforward and one-pot efficient methodology. A representative compound showed significant inhibition of PDE4B enzyme in vitro and good interactions with this protein in silico.     

Synthesis of functionalized 1H-indenes via copper-catalyzed arylative cyclization of arylalkynes with aromatic sulfonyl chlorides

A variety of polysubstituted 1H-indenes can be prepared through the copper-catalyzed arylative cyclization of simple arylalkynes with commercially available aromatic sulfonyl chlorides that function as an aryl group donor. The reaction tolerates a broad range of functional groups, including bromide and iodide, nitrile, ketone, and nitro groups. The reaction allowed the synthesis of polycyclic aromatic hydrocarbons, such as a bis(indene), indacene, and fused polyarene derivatives, some of them showing strong fluorescence in solution and the solid state.     

TESOTf-induced rearrangement of quinols. Efficient construction of the fully functionalized carbon skeleton of the griseusins by a divergent-reconvergent approach

[reaction: see text] The "reverse polarity" or "umpolung" strategy for the total synthesis of aryl C-glycosides was developed in the context of the antibiotic (-)-griseusin B. Although a key reaction in a model sequence for the total synthesis produced two structurally divergent products, both were converted to the same advanced model intermediate that contains the complete carbon skeleton and (except for the extraneous oxygen substituent in the model series) the functional group pattern of the griseusins.     

Organocatalytic Atroposelective Arylation of 2‐Naphthylamines as a Practical Approach to Axially Chiral Biaryl Amino Alcohols

The first phosphoric acid catalyzed direct arylation of 2‐naphthylamines with iminoquinones for the atroposelective synthesis of axially chiral biaryl amino alcohols has been developed. This reaction constitutes a highly functional‐group‐tolerant route for the rapid construction of enantioenriched axially chiral biaryl amino alcohols, and is a rare example of 2‐naphthylamines acting as nucleophiles in an organocatalytic enantioselective transformation. Furthermore, the products, which feature various halogen atoms, provide access to structurally diverse axially chiral amino alcohols through further transformations.     

A Unified Approach for the Assembly of Atisine‐ and Hetidine‐type Diterpenoid Alkaloids: Total Syntheses of Azitine and the Proposed Structure of Navirine C

A tetracyclic dinitrile was synthesized in twelve steps from cyclohex‐2‐en‐1‐one by using a chelation‐triggered conjugate addition to a γ‐hydroxy‐substituted α,β‐unsaturated nitrile and an oxidative dearomatization/Diels–Alder cycloaddition cascade as the key steps. The first total synthesis of azitine (in 17 steps) was achieved through a simple reductive cyclization of this intermediate and subsequent transformations while the total synthesis of the proposed structure of navirine C (in 19 steps) was accomplished by a hydrogen‐atom‐transfer reaction of the tetracyclic dinitrile, Pd/C‐catalyzed reductive cyclization, and subsequent functional group manipulation.     

Generation of 4-iodoisocoumarins through a TBAI-mediated oxidative cyclization of 2-alkynoates

A tetra-butylammonium iodide (TBAI)-mediated oxidative iodocyclization of 2-alkynoates for the synthesis of various 4-iodoisocoumarin is described herein, and the reaction is highly efficient and shows broad functional group tolerance. This newly developed reaction uses a mixture of water and DCE as co-solvent, and avoids the use of iodine as iodine source for the electrophilic halocyclization.     

Synthesis of a chemically bonded weak cation exchange material by conversion of an allyl phase

Summary The allyl bonded phase is used as an intermediate in the synthesis of a weak cation exchange material. The double bond is first converted to an aldehyde by an ozonation reaction and then subsequent oxidation to the carboxylate group is accomplished with dichromate. Diffuse reflectance Fourier transform infrared spectroscopy (DRIFT) is used to monitor the conversion process. The presence of the aldehyde functional group is confirmed by reaction with 2,4-dinitrophenylhydrazine. ESCA spectra reveal no residual chromium on the silica surface. The product is tested chromatographically by the retention of alkylarylketones, the ion-exchange behavior of both monovalent and divalent cations, the retention of nucleosides and bases, and the separation of a mixture of hemoglobins.     

Copper-Catalyzed Enantioselective Formation of C−CF3 Centers from β-CF3-Substituted Acrylates and Acrylonitriles

The catalytic asymmetric synthesis of β-trifluoromethylated esters or nitriles is reported. The use of an in situ formed chiral Cu−H complex allowed the enantioselective reduction of β-trifluoromethylated acrylates or acrylonitriles. The reaction proceeds smoothly affording the corresponding enantioenriched products in good to excellent yields and outstanding enantioselectivities (up to 98 % ee). The mechanism of the reaction was studied, and a plausible reaction pathway was suggested accordingly. Finally, the versatility of the products was highlighted through functional group manipulations.     

Copper(I)‐Catalyzed Interrupted Click/Sulfenylation Cascade: One‐Pot Synthesis of Sulfur Cycle Fused 1,2,3‐Triazoles

Herein, we report a practical protocol for the synthesis of sulfur cycle fused 1,2,3‐triazoles through a copper(I)‐catalyzed tandem click/intramolecular sulfenylation reaction. The reaction proceeded via a copper‐catalyzed alkyne azide cycloaddition, followed by interception of the in situ formed cuprate‐triazole intermediate with p‐toluenesulfonothioate. This reaction shows broad substrate scope, complete regioselectivity, and excellent functional group tolerance under mild reaction conditions.     

“Design of Experiments” as a Method to Optimize Dynamic Disulfide Assemblies: Cages and Functionalizable Macrocycles

Cyclophanes are a venerable class of macrocyclic and cage compounds that often contain unusual conformations, high strain, and unusual properties. However, synthesis of complex, functional derivatives remains difficult due to low functional group tolerance, high dilution, extreme reaction conditions, and sometimes low yields using traditional stepwise synthetic methods. “Design of experiments” (DOE) is a method employed for the optimization of reaction conditions, and we showcase this approach to generate a dramatic increase in the yield of specific targets from two different self-assembling systems. These examples demonstrate that DOE provides an additional tool in tuning self-assembling, dynamic covalent systems.