Middle and Late Pleistocene Denisovan subsistence at Baishiya Karst Cave.

Genetic and fragmented palaeoanthropological data suggest that Denisovans were once widely distributed across eastern Eurasia1-3. Despite limited archaeological evidence, this indicates that Denisovans were capable of adapting to a highly diverse range of environments. Here we integrate zooarchaeological and proteomic analyses of the late Middle to Late Pleistocene faunal assemblage from Baishiya Karst Cave on the Tibetan Plateau, where a Denisovan mandible and Denisovan sedimentary mitochondrial DNA were found3,4. Using zooarchaeology by mass spectrometry, we identify a new hominin rib specimen that dates to approximately 48-32 thousand years ago (layer 3). Shotgun proteomic analysis taxonomically assigns this specimen to the Denisovan lineage, extending their presence at Baishiya Karst Cave well into the Late Pleistocene. Throughout the stratigraphic sequence, the faunal assemblage is dominated by Caprinae, together with megaherbivores, carnivores, small mammals and birds. The high proportion of anthropogenic modifications on the bone surfaces suggests that Denisovans were the primary agent of faunal accumulation. The chaîne opératoire of carcass processing indicates that animal taxa were exploited for their meat, marrow and hides, while bone was also used as raw material for the production of tools. Our results shed light on the behaviour of Denisovans and their adaptations to the diverse and fluctuating environments of the late Middle and Late Pleistocene of eastern Eurasia.

DFT Calculations Rationalize Unconventional Regioselectivity in PdII-Catalyzed Defluorinative Alkylation of gem-Difluorocyclopropanes with Hydrazones.

Density functional theory (DFT) calculations have been conducted to gain insight into the unique formation of the branched alkylation product in the PdII-catalyzed defluorinative alkylation of gem-difluorocyclopropanes with hydrazones. The reaction is established to occur in sequence through oxidative addition, ß-F elimination, η1-η3 isomerization, transmetalation, η3-η1 isomerization, 3,3'-reductive elimination, deprotonation/N2 extrusion, and proton abstraction. The rate-determining step of the reaction is identified as the ß-F elimination, featuring an energy barrier of 28.6 kcal/mol. The 3,3'-reductive elimination transition states are the regioselectivity-determining transition states. The favorable noncovalent π-π interaction between the naphthyl group of gem-difluorocyclopropane and the phenyl group of hydrazone is found to be mainly responsible for the observed regioselectivity.

Mechanism and Enantioselectivity in QUINOX-Catalyzed Asymmetric Allylations of Aromatic Aldehydes: Solvent and Substituent Effects.

Computational investigations were conducted on the QUINOX-catalyzed asymmetric allylation of aromatic aldehydes with allyltrichlorosilanes. Our calculations provide evidence that the catalytic allylation can follow distinct mechanisms, depending on the solvent employed. In toluene and CH2Cl2, the QUINOX-catalyzed allylation predominantly follows an associative pathway, while in CH3CN, a dissociative pathway becomes more favorable. Noncovalent interactions, such as π-stacking effects for the associative mechanism and CH/π interactions for the dissociative mechanism, play a pivotal role in enantiostereodifferentiation in the asymmetric QUINOX-catalyzed reactions of benzaldehyde. Furthermore, the study unveils how different aldehyde substituents exert differing influences on the catalytic allylation reaction. Specifically, the QUINOX-catalyzed allylation of 4-(trifloromethyl)benzaldehyde displays a strong preference for the associative pathway, yielding excellent results in both yield and enantioselectivity. Conversely, 4-methoxybenzaldehyde tends to favor a dissociative mechanism with reduced yields and enantioselectivity. The mechanistic basis for these remarkable substituent effects on the catalytic allylation reaction was also elucidated. In summary, this research enhances our understanding of the QUINOX-catalyzed asymmetric allylation, shedding light on the role of solvents and substituents in the reaction mechanism and enantioselectivity.

DFT Insight into a Strain-Release Mechanism in Bicyclo[1.1.0]butanes via Concerted Activation of Central and Lateral C-C Bonds with Rh(III) Catalysis.

Transition-metal-catalyzed, strain-release-driven transformations of "spring-loaded" bicyclo[1.1.0]butanes (BCBs) are considered potent tools in synthetic organic chemistry. Previously proposed strain-release mechanisms involve either the insertion of the central C-C bond of BCBs into a metal-carbon bond, followed by ß-C elimination, or the oxidative addition of the central or lateral C-C bond on the transition metal center, followed by reductive elimination. This study, employing DFT calculations on a Rh(III)-catalyzed model system in a three-component protocol involving oxime ether, BCB ester, and ethyl glyoxylate for constructing diastereoselective quaternary carbon centers, introduces an unusual strain-release mechanism for BCBs. In this mechanism, the catalytic reaction is initiated by the simultaneous cleavage of two C-C bonds (the central and lateral C-C bonds), resulting in the formation of a Rh-carbene intermediate. The new mechanism exhibits a barrier of 21.0 kcal/mol, making it energetically more favorable by 11.1 kcal/mol compared to the previously suggested most favorable pathway. This unusual reaction mode rationalizes experimental observation of the construction of quaternary carbon centers, including the excellent E-selectivity and diastereoselectivity. The newly proposed strain-release mechanism holds promise in advancing our understanding of transition-metal-catalyzed C-C bond activation mechanisms and facilitating the synthesis of transition metal carbene complexes.

Theoretical Insight into the Palladium-Catalyzed Prenylation and Geranylation of Oxindoles with Isoprene.

This work presents a comprehensive mechanistic study of the ligand-controlled palladium-catalyzed prenylation (with C5 added) and geranylation (with C10 added) reactions of oxindole with isoprene. The calculated results indicate that the prenylation with the bis-phosphine ligand and geranylation with the monophosphine ligand fundamentally share a common mechanism. This mechanism involves the formation of two crucial species: a η3-allyl-Pd(II) cation and an oxindole carbon anion. Furthermore, the reactions necessitate the assistance of a second oxindole molecule, which serves as a Brønsted acid, providing a proton to generate the oxindole nitrogen anion. The oxindole nitrogen anion then acts as a Brønsted base, abstracting a C-H proton from another oxindole molecule to form an oxindole carbon anion. These mechanistic details differ significantly from those proposed in the experimental work. The present calculations do not support the presence of the Pd-H species and the η3, η3-diallyl-Pd(II) intermediate, which were previously suggested in experiments. The theoretical results rationalize the experimental finding that the bis-phosphine ligand favors the prenylation of oxindole, while the monophosphine ligand enables the geranylation of oxindole.

Origin of Enantio- and Chemoselectivity in the Synthesis of Spirocycles via Palladium/Xu-Phos-Catalyzed Cascade Heck/Remote C(sp2)-H Alkylation: A Computational Mechanistic Study.

Density functional theory (DFT) calculations were performed to study the mechanism and factors affecting the enantio-, regio-, and chemoselectivities in the palladium/Xu-Phos-catalyzed cascade Heck/remote C(sp2)-H alkylation reaction. The active catalyst is found to be able to sustain coordination with P and S atoms and can adapt its coordination mode to accommodate the significant steric hindrance between the ligand and substrate, unlike previous findings that showed coordination with P and O atoms. The reaction is established to occur in sequence through the oxidative addition of the aryl iodide to Pd(0), intramolecular alkene insertion, C(sp2)-H bond activation, and C(sp2)-C(sp3) bond reductive elimination. The C(sp2)-C(sp3) bond reductive elimination is identified as the rate-determining step, and the intramolecular alkene insertion as the enantioselectivity-determining step. The high enantioselectivity originates from the stronger electronic interaction between the catalyst and substrate; the exclusive 5-exo-regioselectivity is due to the stronger nucleophilicity of the terminal alkene carbon atom, and the chemoselectivity of C-H activation over carboiodination is driven by thermodynamics.

New insights into the mechanism of synergetic photoredox/copper(i)-catalyzed carbocyanation of 1,3-dienes: a DFT study.

This work presents a DFT-based computational study to understand the mechanism, and regio- and enantioselectivities in the synergetic photoredox/copper(i)-catalyzed carbocyanation of 1,3-dienes with alkyl redox-active esters. The calculated results show an unprecedented copper catalytic mechanism, where the reaction follows a catalytic cycle involving CuI-only catalysis, instead of a Cu(i)/Cu(ii)/Cu(iii)/Cu(i) cycle as proposed in the experimental study. Moreover, it is found that the critical step involves the reaction of the cyanocopper(i) species with an allyl cation rather than the cyanocopper(ii) species reacting with an allyl radical as proposed in the experiment, and that the photocatalyst is regenerated via single electron transfer from the allyl radical to the oxidized photocatalyst. In the newly proposed photoredox/copper(i) catalysis, the reaction consists of four stages: (i) generation of the copper(i) active catalyst, (ii) formation of an allyl radical with oxidative quenching of the photoexcited species, (iii) generation of an allylcopper complex accompanied by the regeneration of the photocatalyst, and (iv) formation of the allyl cyanide product with the regeneration of the copper(i) active catalyst. The cyanation of the allyl cation is calculated to be the regio- and enantioselectivity-determining step. The excellent regio- and stereoselectivities are attributed to the favorable CH-π interaction between the substrate and catalyst as well as the small distortion of the substrate.

L-Shaped Heterobidentate Imidazo[1,5-a]pyridin-3-ylidene (N,C)-Ligands for Oxidant-Free AuI /AuIII Catalysis.

In the last decade, major advances have been made in homogeneous gold catalysis. However, AuI /AuIII catalytic cycle remains much less explored due to the reluctance of AuI to undergo oxidative addition and the stability of the AuIII intermediate. Herein, we report activation of aryl halides at gold(I) enabled by NHC (NHC=N-heterocyclic carbene) ligands through the development of a new class of L-shaped heterobidentate ImPy (ImPy=imidazo[1,5-a]pyridin-3-ylidene) N,C ligands that feature hemilabile character of the amino group in combination with strong σ-donation of the carbene center in a rigid conformation, imposed by the ligand architecture. Detailed characterization and control studies reveal key ligand features for AuI /AuIII redox cycle, wherein the hemilabile nitrogen is placed at the coordinating position of a rigid framework. Given the tremendous significance of homogeneous gold catalysis, we anticipate that this ligand platform will find widespread application.

Enantio- and Regioselective Ni-Catalyzed para-C-H Alkylation of Pyridines with Styrenes via Intermolecular Hydroarylation.

Direct asymmetric functionalization of the pyridyl C-H bond represents a longstanding challenge in organic chemistry. We herein describe the first enantioselective para-C-H activation of pyridines through the use of a Ni-Al bimetallic catalyst system and N-heterocyclic carbene (NHC) ligand for intermolecular hydroarylation of styrenes. The reaction procceds in high to excellent enantioselectivities (up to 98.5:1.5 er) and high site-selectivities for both styrene and pyridine components (up to >98:2). Consequently, a broad range of enantioenriched 1,1-diarylalkanes containing pyridine moieties could be prepared in a single step with 100% atom economy. Computational studies supported a mechanism involving a ligand-to-ligand H-transfer (LLHT) and reductive elimination sequence, with LLHT being the rate- and enantioselectivity-determining step. DFT studies indicate that the π-π stacking interaction between the NHC aryl fragment and trans-styrenes is critical for high reactivity and enantiocontrol.

Density Functional Theory Study of Gold-Catalyzed 1,2-Diarylation of Alkenes: π-Activation versus Migratory Insertion Mechanisms.

Density functional theory calculations are carried out to better understand the first gold-catalyzed 1,2-diarylation reactions of alkenes reported in the recent literature. The calculations on two representative reactions, aryl alkene/aryl iodide coupling pair (the aryl-I bond is located outside the aryl alkene) versus iodoaryl alkene/indole coupling pair (the aryl-I bond is located in the aryl alkene), confirm that the reaction involves a π-activation mechanism rather than the general migratory insertion mechanism in previously known metal catalysis by Pd, Ni, and Cu complexes. Theoretical results rationalize the regioselectivity of the reactions controlled by the aryl-I bond position (intermolecular or intramolecular) and also the ligand and substituent effects on the reactivity.

DFT Mechanistic Study of IrIII/NiII-Metallaphotoredox-Catalyzed Difluoromethylation of Aryl Bromides.

The work by MacMillan et al. ( Angew. Chem., Int. Ed. 2018, 57, 12543-12548) developed an IrIII/NiII-metallaphotoredox-catalyzed difluoromethylation strategy of aryl bromides using CHF2Br as the CHF2 reagent in the presence of tris(trimethylsilyl)silane. Here, we present a density functional theory (DFT)-based computational study to understand special dual catalysis promoting the C(sp2)-C(sp3) coupling. The calculated results show that the energetically more favorable pathway involves the reductive quenching of a photocatalyst (IrIII/*IrIII/IrII/IrIII) and a Ni0-initiated catalytic cycle (Ni0/NiI/NiIII/NiI/Ni0 or Ni0/NiII/NiIII/NiI/Ni0). The calculations reveal not only the mechanistic details delivering the difluoromethylarene product but also the molecular-level picture of the generation of Ni0 species from the NiII precatalyst. Moreover, the calculations also rationalize the observed stoichiometric effect of CHF2Br in the reactions of aryl bromides with different substituted groups.

Human population history at the crossroads of East and Southeast Asia since 11,000 years ago.

Past human genetic diversity and migration between southern China and Southeast Asia have not been well characterized, in part due to poor preservation of ancient DNA in hot and humid regions. We sequenced 31 ancient genomes from southern China (Guangxi and Fujian), including two ∼12,000- to 10,000-year-old individuals representing the oldest humans sequenced from southern China. We discovered a deeply diverged East Asian ancestry in the Guangxi region that persisted until at least 6,000 years ago. We found that ∼9,000- to 6,000-year-old Guangxi populations were a mixture of local ancestry, southern ancestry previously sampled in Fujian, and deep Asian ancestry related to Southeast Asian Hòabìnhian hunter-gatherers, showing broad admixture in the region predating the appearance of farming. Historical Guangxi populations dating to ∼1,500 to 500 years ago are closely related to Tai-Kadai and Hmong-Mien speakers. Our results show heavy interactions among three distinct ancestries at the crossroads of East and Southeast Asia.

Mechanistic insights into Ni-catalyzed hydrogen atom transfer (HAT)-triggered hydrodefluorination of CF3-substituted alkenes.

We report the first computational study on a nickel hydride HAT-initiated catalytic reaction, a novel hydrodefluorination of CF3-substituted aryl alkenes to afford gem-difluoroalkenes. This study provides detailed mechanistic insights into the reaction, including HAT from NiH to C[double bond, length as m-dash]C, a carbon radical rebound to nickel to facilitate chemoselective defluorination, and a two-state reactivity of Ni(ii) enabling σ-bond metathesis with PhSiH3 to regenerate the catalyst. The findings can have implications for developing new metal hydride HAT-initiated reactions.

Mechanistic Insights into Formation of All-Carbon Quaternary Centers via Scandium-Catalyzed C-H Alkylation of Imidazoles with 1,1-Disubstituted Alkenes.

This density functional theory (DFT) study reveals a detailed plausible mechanism for the Sc-catalyzed C-H cycloaddition of imidazoles to 1,1-disubstituted alkenes to form all-carbon quaternary stereocenters. The Sc complex binds the imidazole substrate to enable deprotonative C2-H bond activation by the Sc-bound α-carbon to afford the active species. This complex undergoes intramolecular cyclization (C═C into Sc-imidazolyl insertion) with exo-selectivity, generating a ß-all-carbon-substituted quaternary center in the polycyclic imidazole derivative. The Sc-bound α-carbon deprotonates the imidazole C2-H bond to deliver the product and regenerate the active catalyst, which is the rate-determining step. Calculations illuminate the electronic effect of the ancillary Cp ligand on the catalyst activity and reveal the steric bias caused by using a chiral catalyst that induce the enantioselectivity. The insights can have implications for advancing rare-earth metal-catalyzed C-H functionalization of imidazoles.

Earliest parietal art: hominin hand and foot traces from the middle Pleistocene of Tibet.

At Quesang on the Tibetan Plateau we report a series of hand and foot impressions that appear to have been intentionally placed on the surface of a unit of soft travertine. The travertine was deposited by water from a hot spring which is now inactive and as the travertine lithified it preserved the traces. On the basis of the sizes of the hand and foot traces, we suggest that two track-makers were involved and were likely children. We interpret this event as a deliberate artistic act that created a work of parietal art. The travertine unit on which the traces were imprinted dates to between ∼169 and 226 ka BP. This would make the site the earliest currently known example of parietal art in the world and would also provide the earliest evidence discovered to date for hominins on the High Tibetan Plateau (above 4000 m a.s.l.). This remarkable discovery adds to the body of research that identifies children as some of the earliest artists within the genus Homo.

Mechanistic Insight into Palladium-Catalyzed γ-C(sp3)-H Arylation of Alkylamines with 2-Iodobenzoic Acid: Role of the o-Carboxylate Group.

Density functional theory calculations were performed to understand the distinctly different reactivities of o-carboxylate-substituted aryl halides and pristine aryl halides toward the PdII-catalyzed γ-C(sp3)-H arylation of secondary alkylamines. It is found that, when 2-iodobenzoic acid (a representative of o-carboxylate-substituted aryl halides) is used as an aryl transfer agent, the arylation reaction is energetically favorable, while when the pristine aryl halide iodobenzene is used as the aryl transfer reagent, the reaction is kinetically difficult. Our calculations showed an operative PdII/PdIV/PdII redox cycle, which differs in the mechanistic details from the cycle proposed by the experimental authors. The improved mechanism emphasizes that (i) the intrinsic role of the o-carboxylate group is facilitating the C(sp3)-C(sp2) bond reductive elimination from PdIV rather than facilitating the oxidative addition of the aryl iodide on PdII, (ii) the decarboxylation occurs at the PdII species instead of the PdIV species, and (iii) the 1,2-arylpalladium migration proceeds via a stepwise mechanism where the reductive elimination occurs before decarboxylation, not via a concerted mechanism that merges the three processes decarboxylation, 1,2-arylpalladium migration, and C(sp3)-C(sp2) reductive elimination into one. The experimentally observed exclusive site selectivity of the reaction was also rationalized well.

Site- and Enantiodifferentiating C(sp3)-H Oxidation Enables Asymmetric Access to Structurally and Stereochemically Diverse Saturated Cyclic Ethers.

A manganese-catalyzed site- and enantiodifferentiating oxidation of C(sp3)-H bonds in saturated cyclic ethers has been described. The mild and practical method is applicable to a range of tetrahydrofurans, tetrahydropyrans, and medium-sized cyclic ethers with multiple stereocenters and diverse substituent patterns in high efficiency with extremely efficient site- and enantiodiscrimination. Late-stage application in complex biological active molecules was further demonstrated. Mechanistic studies by combined experiments and computations elucidated the reaction mechanism and origins of stereoselectivity. The ability to employ ether substrates as the limiting reagent, together with a broad substrate scope, and a high level of chiral recognition, represent a valuable demonstration of the utility of asymmetric C(sp3)-H oxidation in complex molecule synthesis.

Denisovan DNA in Late Pleistocene sediments from Baishiya Karst Cave on the Tibetan Plateau.

A late Middle Pleistocene mandible from Baishiya Karst Cave (BKC) on the Tibetan Plateau has been inferred to be from a Denisovan, an Asian hominin related to Neanderthals, on the basis of an amino acid substitution in its collagen. Here we describe the stratigraphy, chronology, and mitochondrial DNA extracted from the sediments in BKC. We recover Denisovan mitochondrial DNA from sediments deposited ~100 thousand and ~60 thousand years ago (ka) and possibly as recently as ~45 ka. The long-term occupation of BKC by Denisovans suggests that they may have adapted to life at high altitudes and may have contributed such adaptations to modern humans on the Tibetan Plateau.

Mechanism and Origins of Enantio- and Regioselectivities in Catalytic Asymmetric Minisci-Type Addition to Heteroarenes.

This work presents a density functional theory (DFT) study on the mechanism and origins of enantio- and regioselectivities in dual photoredox/chiral Brønsted acid-catalyzed asymmetric Minisci-type addition of carbon-centered radicals to N-heteroarenes [Science, 2018, 360, 419-422]. The previously proposed mechanism has been partially revised. First, photoexcited *[IrIII] is reductively quenched by TRIP anion rather than the experimentally proposed neutral radical generated from the chiral Brønsted acid cycle. Second, final product formation involves a hydrogen-atom transfer (HAT) from a neutral radical intermediate to the TRIP radical, instead of single-electron transfer (SET) to *[IrIII]. The TRIP catalyst has been shown to play a triple role by reductively quenching *[IrIII] with its anion form, activating the substrate, and inducing asymmetry. The calculated results rationalize the experimentally observed enantio- and regioselectivities and reveal that the enantioselectivity of the reaction originates from the hydrogen-bond interaction between TRIP and the N-H group of the carbon-centered radical, and the regioselectivity arises from the electron-withdrawing inductive effect from the protonated N-atom and the intramolecular hydrogen-bond interaction between the acetylamino group and the protonated pyridine ring. We also provide explanations for the experimentally observed a dramatic decrease in enantioselectivity when changing substrate or radical precursor and rationalize the solvent-controlled switch of regioselectivity.

Computational Study on Why and How of Nonconventional meta-C-H Arylation of Electron-Rich Arenes via Pd/Quinoxaline-Based Ligand/Norbornene Cooperative Catalysis.

By performing density functional theory (DFT) calculation, this work aims at understanding the nonconventional meta-C-H arylation reaction of electronic-rich arenes with aryl iodide via a Pd/quinoxaline-based ligand/norbornene cooperative catalysis. The reaction is indicated to be initiated either from the ortho-C-H carbopalladation to give the meta-monoarylation product via a sequence of subsequent steps, including norbornene insertion, meta-C-H activation, oxidative addition, and reductive elimination via the Pd(II)/Pd(IV)/Pd(II) redox cycle, norbornene extrusion, and protodepalladation, or from the para-C-H carbopalladation to form the meta-diarylation product via two sequential arylation processes following similar mechanisms. The initial carbopalladation process promoted by the ligand is characterized as the rate-determining step of the reaction. The calculated mechanism shows the distinct role of the norbornene as a transient mediator that enables the final C-H arylation at the same meta-position wherever the initial carbopalladation occurs at either ortho- or para-position. The Pd/ligand/norbornene cooperative catalysis is essential for achieving the exclusive meta-selectivity of the C-H arylation of electron-rich arenes.