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The diastereoselectivity of conventional polyene cyclization reactions is highly dependent on the configuration of the internal alkenes, where E-polyenes provide trans-decalins, while Z-polyenes of...

Previously, we developed a rhodium-catalyzed [5 + 2 + 1] cycloaddition of ene-vinylcyclopropanes (ene-VCPs) and carbon monoxide to synthesize eight-membered carbocycles. The efficiency of this reaction can be appreciated from its application in the synthesis of several natural products. Herein we report the results of a 15-year investigation into the mechanism of the [5 + 2 + 1] cycloaddition by applying visual kinetic analysis and high-level quantum chemical calculations at the DLPNO-CCSD(T)//BMK level. According to the kinetic measurements, the resting state of the catalyst possesses a dimeric structure (with two rhodium centers) whereas the active catalytic species is monomeric (with one rhodium center). The catalytic cycle consists of cyclopropane cleavage (the turnover-limiting step), alkene insertion, CO insertion, reductive elimination, and catalyst transfer steps. Other reaction pathways have also been considered but then have been ruled out. The steric origin of the diastereoselectivity (

We report here computational evidence for a metalla-Claisen rearrangement (MCR) in the case of gold-catalyzed [4 + 2] cycloaddition reaction of yne-dienes. The [4 + 2] reaction starts from exo cyclopropanation, followed by MCR and reductive elimination. The cyclopropane moiety formed in the first step is crucial for a low barrier of the MCR step. In addition, the importance of an appropriate combination of the tether group and the terminal substituent on alkyne in the yne-diene substrates was studied. The mechanism of rhodium-catalyzed [4 + 2] reaction of yne-dienes was also investigated to see whether an MCR mechanism is involved or not. The findings and new understanding hereby reported represent an important advance in the catalysis field.

Reported here is the Rh and Zn cocatalyzed [4 + 2] cycloaddition of newly designed yne-vinylcyclobutanones, which can generate 5/6 or 6/6 bicyclic products with an all-carbon quaternary bridgehead center. The reaction has a broad scope and can realize chirality transfer from enantioenriched substrates to the cycloadducts. The key to the success of this [4 + 2] reaction is the introduction of a vinyl group to cyclobutanones, which helps the C-C cleavage of vinylcyclobutanones via oxidative addition. This C-C cleavage step is synergistically aided by Zn coordination to the carbonyl group of vinylcyclobutanones. Of the same importance, visual kinetic analysis and computational studies have been carried out to support the dual activation in the rate-determining C-C cleavage, to derive the rate law of the [4 + 2] reaction, to understand another role of Zn in helping the in situ generation of the cationic Rh catalyst and preventing catalyst deactivation, and to analyze the key transition states and intermediates involved.

Nature produces many molecules (so-called natural products) containing compact scaffolds such as cis-anti-cis-configurated 5/5/5 and 5/6/4 tricycles. But other molecules with more strained structures, such as trans-anti-cis-configurated 5/5/5 tricycles have been rarely found in nature. Accessing all these natural and non-natural molecules will strengthen the power of organic synthesis and benefit many fields such as medicinal chemistry, chemical biology that are heavily dependent on the available quantity of new/important molecules. Herein, we report a new strategy to synthesize molecules with cis-anti-cis-configurated 5/5/5 tricycles, 5/6/4 tricycles and trans-anti-cis-configurated 5/5/5 tricyclic skeletons by [5+2+1]/epoxidation/transannular radical cyclization strategy, where challenging cis and trans 5/8 bicycles with both ene and carbonyl functional groups were accessed by Rh-catalyzed [5+2+1] reaction of ene-vinylcyclopropanes and carbon monoxide, followed by epoxidation of the double bond in the 5/8 bicycles, and Ti(III) mediated epoxide/carbonyl cyclization to build target skeletons. This strategy was further applied to the first total synthesis of (+)-antrodiellin B, the asymmetric total synthesis of (−)-hypnophilin and formal synthesis of (−)-coriolin with cis-anti-cis configurated 5/5/5 skeleton (both hypnophilin and coriolin are highly oxidized and have significant biological activities).

We present here a rhodium-catalyzed asymmetric N-H insertion reaction, which is a concerted process revealed by DFT calculations, for the synthesis of novel axially chiral

Ring-closing metathesis (RCM) represents an ideal and atom-economical way to construct cyclic compounds. The precedented reaction systems for endo-selective enyne RCM mainly rely on precious transition metal carbene complexes or activated substrates. Here we report the utility of group 13 metal halides, such as InBr3 and InI3, as simple and efficient catalysts for endo-selective RCM of nitrogen-tethered 1,6-enynes under mild conditions. Conventionally, these substrates underwent cycloisomerization to generate 6,3-fused bicycles under transition metal catalysis. The reaction mechanism and nature of the catalytic species have been revealed by kinetic experiments and density functional theory calculations.

Achieving transition metal-catalyzed reactions of diene-enes/diene-ynes and carbon monoxide (CO) to deliver [4+2+1] cycloadducts, rather than the kinetically favored [2+2+1] products, is challenging. Here, we report that this can be solved by adding a cyclopropyl (CP) cap to the diene moiety of the original substrates. The resulting cyclopropyl-capped diene-ynes/diene-enes can react with CO under Rh catalysis to give [4+2+1] cycloadducts exclusively without forming [2+2+1] products. This reaction has a broad scope and can be used to synthesize useful 5/7 bicycles with CP moiety. Of the same importance, the CP moiety in the [4+2+1] cycloadducts can act as the intermediate group for further transformations so that other challenging bicyclic 5/7 and tricyclic 5/7/5 and 5/7/6, 5/7/7 skeletons, which are widely found in natural products, can be obtained. The mechanism of this [4+2+1] reaction has been investigated by quantum chemistry calculations, and the role of the CP group in avoiding the possible side reaction of [2+2+1] reaction have been identified, showing that the [4+2+1] is controlled by releasing the ring strain in the methlenecyclopropyl (MCP) group (about 7 kcal/mol) in the CP-capped dienes.

A bimetallic protocol has been developed to construct (Z)-γ-alkylidenebutenolide compounds from readily available propargyl α-ketoesters. It involves a gold-catalyzed 1,3-acyloxy migration of propargyl α-ketoesters and a carbonyl-ene cyclization of in situ generated allenyl esters. DFT calculations suggest that the copper salt might play dual roles as both chloride abstractor facilitating the generation of highly active gold catalyst and Lewis acid promoting the stepwise intramolecular carbonyl-ene reaction.

Developing new transition metal-catalyzed asymmetric cycloadditions for the synthesis of five-membered carbocycles (FMCs) is a research frontier in reaction development due to the ubiquitous presence of chiral FMCs in various functional molecules. Reported here is our discovery of a highly enantioselective intramolecular [3+2] cycloaddition of yne-alkylidenecyclopropanes (yne-ACPs) to bicyclo[3.3.0]octadiene and bicyclo[4.3.0]nonadiene molecules using a cheap Co catalyst and commercially available chiral ligand (S)-Xyl-BINAP. This reaction avoids the use of precious Pd and Rh catalysts, which are usually the choices for [3+2] reactions with ACPs. The enantiomeric excess in the present reaction can be up to 92 %. Cationic cobalt(I) species was suggested by experiments as the catalytic species. DFT calculations showed that this [3+2] reaction starts with oxidative cyclometallation of alkyne and ACP, followed by ring opening of the cyclopropyl (CP) group and reductive elimination to form the cycloadduct. This mechanism is different from previous [3+2] reactions of ACPs, which usually start from CP cleavage, not from oxidative cyclization.

Here we report the total synthesis of clovan-2,9-dione via Rh-catalyzed [3 + 2 + 1] cycloaddition/hydroformylation/aldol reaction. The [3 + 2 + 1] reaction of 1-yne-vinylcyclopropane and CO was used for the generation of a 5/6 bicyclic skeleton with a bridgehead vinyl group. The hydroformylation reaction converted the congested olefin of the [3 + 2 + 1] cycloadduct to a one-carbon elongated aldehyde, which underwent in situ aldol reaction, with the carbonyl group in the [3 + 2 + 1] cycloadduct, to generate the tricyclic bridged-ring skeleton of the target molecule.

Reported here is the room-temperature metal-free iodoarene-catalyzed oxyamination of unactivated alkenes. In this process, the alkenes are difunctionalized by the oxygen atom of the amide group and the nitrogen in an exogenous HNTs

We report the first Rh2(II)-catalyzed asymmetric cycloisomerization of activated enynes to provide cyclopropane-fused tetrahydropyridines in good yields and excellent enantioselectivities under mild conditions. The activated group, CHZ (Z is electron-withdrawing group (EWG)), in the enyne substrates exerts two synergetic roles, one is to activate alkyne for the cyclopropanation reaction; the other is to introduce the C–H···O interaction between substrate and catalyst (reducing the energy barrier of the reaction). This double-mode activation was supported by both density functional theory (DFT) calculations and experimental tests. This strategy was also extended to other CH2Z (Z can be OH, OMe, F) as activating groups that made the CH2 more acidic so that the substrates could also form increased C–H···O interaction with the catalyst.

In the presence of accessible β-C–H bonds, γ-C–H activation of saturated aliphatic carboxamides remains unresolved because β-C–H activation is kinetically favored. This is almost a dogma in the dev...

Lewis base-catalyzed transformations of allenes have received much attention over the last decades. However, this type of reaction has so far been limited to activated allenes bearing an electron-w...

A six-step total synthesis of isohirsut-4-ene with a 5/5/5 tricyclic core has been achieved. The synthesis features a Rh(I)-catalyzed [5+2+1] cycloaddition, a Corey-Chaykovsky reaction, and a transannular epoxide-alkene cyclization that afford the skeleton of the target molecule. This three-step strategy was further utilized to synthesize more 5/5/5 tricyclic analogues with one or two bridgehead quaternary centers.

Report here is the development of a [5 + 2 + 1]/ene strategy for the synthesis of molecules with linear tricyclic 5/5/5 and 6/5/5 skeletons widely found in natural products. The first step of this strategy is applying a Rh-catalyzed [5 + 2 + 1] reaction of ene-vinylcyclopropanes and CO to synthesize 5/8 and 6/8 bicyclic compounds, which can then be transformed to the final target molecules by an InCl3-catalyzed ene reaction.

Previously, we developed a gold-catalyzed cycloisomerization of dienediynes to synthesize the fused 6,7,5-tricyclic compounds. This reaction involves aliphatic C-H functionalization under mild conditions with high regio- and diastereoselectivities. Herein, we present a combined density functional theory (DFT) and experimental study to understand its mechanism. The reaction starts with a 6-endo-dig cyclization to generate a cis-1-alkynyl-2-alkenylcyclopropane. Then, a Cope rearrangement takes place to give a seven-membered-ring allene intermediate, whose central carbon atom possesses vinyl cation character and thus is highly reactive toward aliphatic C-H insertion. After the C-H insertion, two successive [1,2]-hydride shifts then occur to give the tricyclic product and to complete the catalytic cycle. Notably, steric effect induced by the bulky ligand is found to be important for the diastereocontrol in the C-H insertion step. DFT calculations suggested that the malonate-tethered substrate utilized in our previous work may undergo an undesired 5-exo-dig cyclization under gold catalysis, which could be the reason why the desired fused 6,7,5-tricarbocyclic product was not generated. These mechanistic insights then guided us to design substrates with a shortened carbon tether in the present work to inhibit the exo-dig cyclization so that the tandem cyclopropanation/Cope rearrangement/C-H functionalization could occur to construct polycarbocycles containing a seven-membered ring. This prediction was supported by new experiments, providing a new strategy to access fused 5,7,5-tricyclic and 5,7,6,6-tetracyclic carbocycles. In addition, how the substituents affect the chemoselectivity was also investigated.

Our present study unveils a new and efficient N-heterocyclic carbene (NHC)-boryl radical-catalyzed cycloisomerization of N-(2-ethynylaryl)arylamides. This catalytic process is triggered by the addi...

Photoredox-catalyzed aminoarylation and thioamination of unactivated alkenes have been developed, providing novel synthetic routes to access synthetically challenging quaternary carbon-centered ben...

An originally designed Rh-catalyzed [4 + 2] cycloaddition reaction of nitrogen-tethered 1,7-ene-dienes turned out to be a cycloisomerization reaction, which involves allylic C–H activation/alkene i...

Ring expansion of in situ generated cyclopropylmethyl cations via Wagner-Meerwein rearrangement to cyclobutanes is widely used in synthesis. However, the cyclopropylmethyl cations generated are planar, which would lead to loss of chiral information in the case of chiral precursors, making an asymmetric version of such ring expansion difficult. In the present work, a gold(I)-catalyzed asymmetric cyclopropanation/C-C cleavage/Wagner-Meerwein rearrangement of easily affordable yne-methylenecyclopropanes (1,6-yne-MCPs) has been developed to synthesize 3-azabicyclo[5.2.0]nonadiene, a bicyclic 7/4 ring (azepine fused with cyclobutane) with a bridgehead aryl substituent. This reaction overcomes the challenging loss of chirality from the Wagner-Meerwein rearrangement. Density functional theory calculations indicate that the chirality of the final product comes from the first cyclopropanation step in this reaction. The chirality in the resultant cyclopropane is lost in the following C-C cleavage step, generating rigid, planar cyclopropylmethyl carbocation intermediate. Then, only one carbon of the cyclopropyl group in the cyclopropylmethyl carbocation intermediate can migrate via ring expansion in the Wagner-Meerwein rearrangement process, and consequently, the chirality in the cyclopropane generated in the first step is transferred to the final product.

1,3-Azaprotio transfer of propargylic α-ketocarboxylate oximes, a new type of alkynyl oximes featuring an ester tether, has been explored by taking advantage of gold catalysis. The incorporation of an oxygen atom to the chain of alkynyl oximes led to the formation of two different oxa-cyclic nitrones. It was found that internal alkynyl oximes with an E-configuration deliver five-membered nitrones, whereas terminal alkynyl oximes with an E-configuration afford six-membered nitrones. DFT calculations on four possible pathways supported a stepwise formation of C-N and C-H bonds, in which a 1,3-acyloxy-migration competes with the 1,3-azaprotio-transfer, especially in the case of internal alkynyl oximes. The relative nucleophilic properties of oxygen in the carbonyl group and the nitrogen in the oxime, the electronic effects of alkynes, and the influence of the ring system have been investigated computationally.

Summary Herein, we describe the protecting-group-free total synthesis of two structurally diverse Isodon diterpenoids, (+)-ent-kauradienone (3) and (−)-jungermannenone C (4), in 12 and 14 steps respectively, through sequential applications of three radical-based reactions, including the photoinduced skeletal rearrangements of bicyclo[3.2.1]octene ring systems. Further investigations of this photochemical radical rearrangement on a series of diverse terpenoids demonstrated both the unparalleled functional-group tolerance and the broad applicability of such late-stage photochemical rearrangements for the synthesis of structurally diverse and complex small molecules. Overall, the mild nature of late-stage photoinduced skeletal rearrangements might suggest that they are possible in a biological setting in unappreciated complimentary biosynthetic pathways.

The study of new C-H silylation reagents and reactions remains an important topic. We reported that under Rh catalysis, silacyclobutanes (SCBs) for the first time were able to react with C(sp2)-H and C(sp3)-H bonds, however the underlying reasons for such a new reactivity were not understood. Through this combined computational and experimental study on C-H silylation with SCBs, we not only depict a reaction pathway that fully accounts for the reactivity and all the experimental findings but also streamline a more efficient catalyst that significantly improves the reaction rates and yields. Our key findings include: (1) the active catalytic species is a [Rh]-H as opposed to the previously proposed [Rh]-Cl; (2) the [Rh]-H is generated via a reductive elimination/β-hydride (β-H) elimination sequence, as opposed to previously proposed endocyclic β-H elimination; (3) the regio- and enantio-determining steps are identified; (4) and of the same importance, the discretely synthesized [Rh]-H is shown to be a more efficient catalyst. This work suggests that the [Rh]-H/diphosphine system should find further applications in C-H silylations involving SCBs.

The mechanisms of [8 + 2] cycloaddition reactions between dienylfurans/dienylisobenzofurans and the activated alkyne, DMAD (dimethyl acetylenedicarboxylate), have been investigated by DFT calculations. The former [8 + 2] reaction is stepwise, starting from attack of the diene substituent on furan, not the furyl moiety in dienylfurans, to DMAD to give a diradical intermediate, which then undergoes ring closure to form the second bond between DMAD and the furan moiety, generating the final [8 + 2] cycloadducts. In contrast, the latter [8 + 2] reaction starts from [4 + 2] cycloaddition of the diene in the furan ring of dienylisobenzofurans toward DMAD, followed by the rate-determining stepwise [1,5]-vinyl shift, forming the [8 + 2] products. The different mechanisms of [8 + 2] reactions are attributed to the facts that for dienylfurans, the reactive diene part is the diene substituent on furan, but in the case of dienylisobenzofurans, it is the diene in the furan ring (its reaction with DMAD to generate an aromatic benzene ring is the driving force for this regiochemistry). Consequently, the [8 + 2] reactions begin with the reaction of the most reactive part of tetraene (either the diene substituent on furan for dienylfurans or the diene in the furan ring for dienylisobenzofurans) with DMAD. FMO analysis and kinetic study have been carried out to gain more information of the reaction mechanisms. Two [8 + 2] reactions of dienylisobenzofurans with different substituents toward DMAD have also been further analyzed by DFT calculations in this paper.

The traditional medicinal plant, and endangered species Aristolochia delavayi (Aristolochiaceae) is an endemic species in China and occurs in the warm and dry areas along the Jinsha river. It is also a specific host of the larvae of Byasa daemonius, a vulnerable butterfly. In this study, 15 pairs of polymorphic microsatellite primers of A. delavayi were designed and screened based on the Simple Sequence Repeats (SSR) loci found by using the results of genome skimming. Based on these 15 SSR markers, the genetic diversity and structure of 193 individuals from ten natural populations were analyzed in detail. In comparison to other endemic and endangered plants in the region, the population of A. delavayi possess a relatively high genetic diversity (He = 0.550, I = 1.112). AMOVA analysis showed that 68.4% of the total genetic diversity was within populations and 31.6% of the variation occurred among populations. There was a significant genetic differentiation among natural populations of A. delavayi detectable, with low gene flow (Nm = 0.591). This might be attributed to geographical barriers and limited seed dispersal. To test the isolation by distance (IBD), we performed Mantel test, which showed a significant correlation between the geographic and genetic distances. In order to cope with the possible biases caused by IBD, we additionally performed Bayesian genetic cluster analyses and principal coordinate analysis (PCoA). The final cluster analysis revealed three groups with distinct geographical distribution. Habitat fragmentation and limited gene flow between these populations may be the main reasons for the current genetic structure. For conservation of this species, we suggest to divide its populations into three protection management units, with subsequent focus on the Yongsheng and Luquan populations which experienced a genetic bottleneck event in the past.