Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Chloroform as a Carbon Monoxide Precursor: <i>In</i> or <i>Ex Situ</i> Generation of CO for Pd-Catalyzed Aminocarbonylations

Conditions for the rapid hydrolysis of chloroform to carbon monoxide (CO) using heterogeneous CsOH·H₂O are described. CO and ¹³CO can be generated cleanly and rapidly under mild conditions and can be captured either <i>in</i> or <i>ex situ</i> in palladium-catalyzed aminocarbonylation reactions. Utilizing only 1–3 equiv of CO allows for the aminocarbonylation of aryl, vinyl, and benzyl halides with a wide variety of primary and secondary amines giving amide products in good to excellent yields

Copper-Catalyzed Hydroarylation of Internal Alkynes: Highly Regio- and Diastereoselective Synthesis of 1,1-Diaryl, Trisubstituted Olefins

The copper-catalyzed hydroarylation of internal, unsymmeric alkynes is presented. Trisubstituted alkenes are obtained as single diastereomers in good to excellent yields and excellent regioselectivities. The scope of the reaction is presented with respect to alkyne and aryl iodide coupling partners. Initial mechanistic experiments indicate a hydrocupration event followed by a two-electron oxidative addition/reductive elimination pathway

Rhodium-Catalyzed Oxidative Amidation of Sterically Hindered Aldehydes and Alcohols

A rhodium-catalyzed oxidative amidation reaction has been developed with sterically hindered aldehydes and alcohols for the synthesis of amides containing a quaternary carbon at the α position. A variety of amine nucleophiles, both aliphatic and aromatic, are employed and afford the corresponding amides in good to excellent yields. Finally, mechanistic studies are performed to gain insight into both catalytic cycles

Rhodium-Catalyzed Regiodivergent Hydrothiolation of Allyl Amines and Imines

The regiodivergent Rh-catalyzed hydrothiolation of allyl amines and imines is presented. Bidentate phosphine ligands with larger natural bite angles (β_n ≥ 99°), for example, DPEphos, dpph, or <b>L1</b>, promote a Markovnikov-selective hydrothiolation in up to 88% yield and >20:1 regioselectivity. Conversely, when smaller bite angle ligands (β_n ≤ 86°), for example, dppbz or dppp, are employed, the anti-Markovnikov product is formed in up to 74% yield and >20:1 regioselectivity. Initial mechanistic investigations are performed and are consistent with an oxidative addition/olefin insertion/reductive elimination mechanism for each regioisomeric pathway. We hypothesize that the change in regioselectivity is an effect of diverging coordination spheres to favor either Rh–S or Rh–H insertion to form the branched or linear isomer, respectively

Cu-Catalyzed Three-Component Carboamination of Alkenes

Copper-catalyzed intermolecular carboamination of alkenes with α-halocarbonyls and amines is presented with 42 examples. Electron rich, electron poor, and internal styrenes, as well as α-olefins, are functionalized with α-halocarbonyls and aryl or aliphatic amines. Mechanistic investigations suggest the reaction is proceeding through addition of a carbon-centered radical across an olefin followed by oxidation to form a 5-membered oxocarbenium intermediate and subsequent nucleophilic ring opening to forge the C–N bond

Synthesis, Cycloaddition, and Cycloreversion Reactions of Mononuclear Titanocene–oxo Complexes

Titanocene–oxo complexes of the type Cp^x₂TiO­(L) (Cp^x = pentamethylcyclopentadienyl; tetramethylcyclopentadienyl; L = pyridine or derivatives) are synthesized from the corresponding titanocene–ethylene complexes via oxidation with pyridine <i>N</i>-oxides or styrene oxide. These oxo complexes react with alkynes, nitriles, and α,β-unsaturated carbonyls to form titanacycles, which undergo exchange reactions with organic substrates or react with 4-dimethylaminopyridine to regenerate the titanocene–oxo. Mechanistic experiments support a dissociative mechanism in which the first step is rate-determining retrocycloaddition followed by trapping of the reactive [Cp^x₂TiO] species. In the case of the retro-[4+2]-cycloaddition from dioxatitanacyclohexene complexes, a Hammett study gives ρ values of −1.18 and −1.04 for substituents on two different phenyl rings on the metallacycles, suggesting positive charge buildup and a slightly asynchronous cycloreversion in the rate-determining step

Synthesis and Reactivity of Dioxazirconacyclohexenes: Development of a Zirconium–Oxo-Mediated Alkyne–Aldehyde Coupling Reaction

The zirconium–oxo-mediated coupling of an alkyne and an aldehyde for the synthesis of α,β-unsaturated ketones is presented. Each intermediate along the reaction pathway has been fully characterized, and the scope of the alkynes and aldehydes has been explored

Facile C–H, C–F, C–Cl, and C–C Activation by Oxatitanacyclobutene Complexes

Aryl ketones react readily with oxatitanacyclobutenes bearing pentamethylcyclopentadienyl ligands to form unique titanocene complexes resulting from Cp* modification and C–H activation. An intermediate in this reaction is intercepted with various functional groups to form carbonyl insertion, C–F activation, and cyclopropane ring-opening products