Meetings by month
M. Ramu Yadav, Masahiro Nagaoka, Myuto Kashihara, Rong-Lin Zhong, Takanori Miyazaki, Shigeyoshi Sakaki , and Yoshiaki Nakao
Synthesis of biaryls via the Suzuki–Miyaura coupling (SMC) reaction using nitroarenes as an electrophilic coupling partners is described. Mechanistic studies have revealed that the catalytic cycle of this reaction is initiated by the cleavage of the aryl–nitro (Ar–NO2) bond by palladium, which represents an unprecedented elemental reaction.
Alex Swan's paper
Shilong Zheng , Shanchun Guo, Qiu Zhong, Changde Zhang, Jiawang Liu , Lin Yang†, Qiang Zhang, and Guangdi Wang*
Despite promising therapeutic utilities for treatment of hematological malignancies, histone deacetylase inhibitor (HDACi) drugs have not proven as effective in the treatment of solid tumors. To expand the clinical indications of HDACi drugs, we developed novel boron-containing prodrugs of belinostat (2), one of which efficiently releases active 2 through a cascade of reactions in cell culture and demonstrates activities comparable to 2 against a panel of cancer cell lines. Importantly, prodrug 7 is more efficacious than belinostat in vivo, not only inhibiting the growth of tumor but also reducing tumor volumes in an MCF-7 xenograft tumor model owing to its superior biocompatibility, which suggests its clinical potential in the treatment of solid tumors.
Baoli Dong , Xiuqi Kong, and Weiying Lin*
Nitroxyl (HNO) has been identified as an important signaling molecule in biological systems and plays critical roles in many physiological processes. Fluorescence imaging could provide a robust approach to explore the biological formation of HNO and its physiological functions. Herein, we summarize the organic reaction types for constructing HNO probes and specifically focus on review of the recent advances in the development of the reaction-based HNO probes and their imaging applications in living systems.
Lin Deng, Likun Jin, Prof. Dr. Guangbin Dong
The development of a catalytic intramolecular “cut-and-sew” transformation between cyclobutanones and alkynes to construct cyclohexenone-fused rings is described herein. The challenge arises from the need for selective coupling at the more sterically hindered proximal position, and can be addressed by using an electron-rich, but less bulky, phosphine ligand. The control experiment and 13C-labelling study suggest that the reaction may start with cleavage of the less hindered distal C−C bond of cyclobutanones, followed by decarbonylation and CO reinsertion to enable Rh insertion at the more hindered proximal position.
Alex Swan's paper
Jianming Kang†, Aaron J. Ferrell†, Wei Chen†, Difei Wang‡, and Ming Xian*†
The reactions of three model compounds (1–3) for cyclic acyl disulfides and cyclic acyl selenylsulfides are studied. These compounds were found to be effective precursors for persulfides (RSSH) and selenylsulfides (RSeSH) upon reacting with nucleophilic species. They could also act as H2S donors when interacting with cellular thiols. The most interesting discovery was the generation of RSeSH from compound 3 under mild conditions. Selenylsulfides (RSeSH) are expected to be important regulating molecules involved in Sec-related redox signaling. The method of producing RSeSH should allow researchers to better understand the chemical biology of RSeSH.
Dr. Shigeo Yasuda, Takuya Ishii, Shunsuke Takemoto, Hiroki Haruki, Prof. Dr. Hirohisa Ohmiya
Benzylation and allylation of aldehyde acyl anionswere enabled by the merger of athiazolium N-heterocycliccarbene (NHC) catalyst and apalladium/bisphosphine catalystin asynergistic manner.Owing to the mildness of the reactionconditions,various functional groups were tolerated in thesubstrates.
Zhe Huang†, Wen-Xiong Zhang† , and Zhenfeng Xi*†‡
Ring-contraction of 2,4,6,8-tetrasubstituted 1,5-diazacyclooctatetraenes was highly efficiently promoted by Lewis acid such as TiCl4, affording 2,4,6-trisubstituted pyridines in excellent yields, along with release of a nitrile. A reaction mechanism involving a 6π electrocyclic ring-closing followed by a retro [2 + 2] cyclization of an 1-azetine moiety was supported by both experimental observations and density functional theory calculation.
Michaela Bauer, Wei Wang, Dr. Mélanie M. Lorion, Chuan Dong, Prof. Dr. Lutz Ackermann
Secondary C(sp3)@Harylations were accomplishedby palladium catalysis with triazoles as peptide bond isosteres.The unique power of this approachishighlighted by thepossibility of achieving secondary C(sp3)@Hfunctionalizationson terminal peptides as well as the unprecedented positional-selective C(sp3)@Hfunctionalization of internal peptide posi-tions,setting the stage for modular peptide late-stage diversi-fication.
Lu Wang*†‡ , Hai Xiao‡ , Tao Cheng‡ , Youyong Li*† , and William A. Goddard III*‡
We report here the reaction mechanism for explicit aqueous solvent quantum mechanics (QM) studies determining the energetics and reaction barriers for the photocatalytic hydrogen evolution reaction (HER) on CH3NH3PbI3 surface. We find that both the lead (Pb) atoms and the surface organic molecules play essential roles, leading to a two-step Pb-activated amine-assisted (PbAAA) reaction mechanism involving an intermediate lead hydride state. Both H of H2 product are extracted from surface organic molecules, while two protons from the solution migrate along water chains via the Grotthuss mechanism to replace the H in organic molecule. We obtain a reaction barrier of 1.08 eV for photochemical generation of H2 on CH3NH3PbI3 compared to 2.61 eV for the dark reaction. We expect this HER mechanism can also apply to the other organic perovskites, but the energy barriers and reaction rates may depend on the basicity of electrolyte and intrinsic structures of perovskites.
Zhaofeng Wang, Ana G. Herraiz, Ana M. del Hoyo & Marcos G. Suero
Carbon has the unique ability to bind four atoms and form stable tetravalent structures that are prevalent in nature. The lack of one or two valences leads to a set of species—carbocations, carbanions, radicals and carbenes—that is fundamental to our understanding of chemical reactivity1. In contrast, the carbyne—a monovalent carbon with three non-bonded electrons—is a relatively unexplored reactive intermediate2,3,4,5,6; the design of reactions involving a carbyne is limited by challenges associated with controlling its extreme reactivity and the lack of efficient sources7,8,9. Given the innate ability of carbynes to form three new covalent bonds sequentially, we anticipated that a catalytic method of generating carbynes or related stabilized species would allow what we term an ‘assembly point’ disconnection approach for the construction of chiral centres. Here we describe a catalytic strategy that generates diazomethyl radicals as direct equivalents of carbyne species using visible-light photoredox catalysis. The ability of these carbyne equivalents to induce site-selective carbon–hydrogen bond cleavage in aromatic rings enables a useful diazomethylation reaction, which underpins sequencing control for the late-stage assembly-point functionalization of medically relevant agents. Our strategy provides an efficient route to libraries of potentially bioactive molecules through the installation of tailored chiral centres at carbon–hydrogen bonds, while complementing current translational late-stage functionalization processes10. Furthermore, we exploit the dual radical and carbene character of the generated carbyne equivalent in the direct transformation of abundant chemical feedstocks into valuable chiral molecules.
Chris's paper 2
Ming Chen, Feipeng Liu, Guangbin Dong
A direct and catalytic method is reported here for -arylation of N-protected lactams with simple aryl iodides. The transformation is enabled by merging soft enolization of lactams, Pd-catalyzed desaturation, Ar−X bond activation and aryl conjugate addition. The reaction is operated under mild conditions, scalable and chemoselective. Application of this method to concise syntheses of pharmaceutically relevant compounds is demonstrated.
Alex Swan's paper
Dominik Marx† and María Isabel Menéndez*‡
The Staudinger reaction yielding β-lactam rings via [2 + 2] cycloaddition is a torquoselective reaction where the stereochemistry of the product can be steered by suitable substituents. Although the mechanochemical ring-opening of β-lactams has been investigated recently, the force-assisted synthesis of this important functional four-ring motif remains unexplored. As it will be computationally demonstrated, mechanochemical activation greatly reduces the barrier of the rate-limiting ring-closure step while, at the same time, preserves its torquoselectivity. This finding strongly suggests that strained four-membered rings can be readily incorporated in chain molecules using sonication techniques that greatly enhance reactivity while conserving selectivity.
Julien Caillé,a Fatma Boukattaya,ab Fabien Boeda,a Morwenna S. M. Pearson-Long,a Houcine Ammarb and Philippe Bertus*a
The successive addition of two different Grignard reagents to acyl cyanohydrins was performed with success by taking advantage of the low reactivity of alkynyl Grignard reagents. The experimental conditions were adjusted so that they were not reactive during the first addition step, but reactive only in the second one. The synthetic utility of the prepared compounds was validated by the preparation of chiral quaternary α-amino acids.
Alex Swan's paper
Valeria Dantignana†‡, Michela Milan†‡, Olaf Cussó†, Anna Company*†, Massimo Bietti*§ , and Miquel Costas*†
Methods for selective oxidation of aliphatic C–H bonds are called on to revolutionize organic synthesis by providing novel and more efficient paths. Realization of this goal requires the discovery of mechanisms that can alter in a predictable manner the innate reactivity of these bonds. Ideally, these mechanisms need to make oxidation of aliphatic C–H bonds, which are recognized as relatively inert, compatible with the presence of electron rich functional groups that are highly susceptible to oxidation. Furthermore, predictable modification of the relative reactivity of different C–H bonds within a molecule would enable rapid diversification of the resulting oxidation products. Herein we show that by engaging in hydrogen bonding, fluorinated alcohols exert a polarity reversal on electron rich functional groups, directing iron and manganese catalyzed oxidation toward a priori stronger and unactivated C–H bonds. As a result, selective hydroxylation of methylenic sites in hydrocarbons and remote aliphatic C–H oxidation of otherwise sensitive alcohol, ether, amide, and amine substrates is achieved employing aqueous hydrogen peroxide as oxidant. Oxidations occur in a predictable manner, with outstanding levels of product chemoselectivity, preserving the first-formed hydroxylation product, thus representing an extremely valuable tool for synthetic planning and development.
Hiromichi Egami, Tomoki Niwa, Hitomi Sato, Ryo Hotta, Daiki Rouno, Yuji Kawato, and Yoshitaka Hamashima*
Inspired by the dicationic nature of the electrophilic fluorinating reagent, Selectfluor (1), we rationally designed a series of dicarboxylic acid precatalysts (2), which, when deprotonated, act as anionic phase-transfer catalysts for asymmetric fluorination of alkenes. Among them, 2a having the shortest linker moiety efficiently catalyzed unprecedented 6-endo-fluoro-cyclization of various allylic amides, affording fluorinated dihydrooxazine compounds with high enantioselectivity (up to 99% ee). In addition to cyclic substrates, acyclic trisubstituted alkenes underwent the reaction with good diastereoselectivity, whereas low diastereoselectivity was observed for linear disubstituted alkenes. Results suggest that the reaction proceeds via a fluoro-carbocation intermediate.
Feng Yan†‡, Zhichao Zhu†, Xiaobiao Dong†‡, Chao Wang†‡, Xiaohui Meng†, Yue Xie†, Guanxin Zhang† , and Dong Qiu*†‡
Polymer adsorption and desorption are fundamental in many industrial and biomedical applications. Here, we introduce a new method to monitor the polymer desorption kinetics in situ based on the behavior of aggregation-induced emission. Poly(ethylene oxide) and colloidal silica (SiO2) were used as a model system. It was found that the aggregation-induced emission method could be successfully used to determine the polymer desorption kinetics, and the polymer desorption followed the first-order kinetics. It was also found that the polymer desorption rate constant decreased with the increasing molecular weight, which could be described by a power law function kd ≈ M–0.28, close to that of the adsorption rate constant.
Masao Ohashi, Fang Liu, Yang Hai, Mengbin Chen, Man-cheng Tang, Zhongyue Yang, Michio Sato, Kenji Watanabe, K. N. Houk & Yi Tang
Pericyclic reactions—which proceed in a concerted fashion through a cyclic transition state—are among the most powerful synthetic transformations used to make multiple regioselective and stereoselective carbon–carbon bonds1. They have been widely applied to the synthesis of biologically active complex natural products containing contiguous stereogenic carbon centres2–6. Despite the prominence of pericyclic reactions in total synthesis, only three naturally existing enzymatic examples (the intramolecular Diels–Alder reaction7 , and the Cope8 and the Claisen rearrangements9 ) have been characterized. Here we report a versatile S-adenosyl-l-methionine (SAM)-dependent enzyme, LepI, that can catalyse stereoselective dehydration followed by three pericyclic transformations: intramolecular Diels–Alder and hetero-Diels–Alder reactions via a single ambimodal transition state, and a retro-Claisen rearrangement. Together, these transformations lead to the formation of the dihydropyran core of the fungal natural product, leporin10. Combined in vitro enzymatic characterization and computational studies provide insight into how LepI regulates these bifurcating biosynthetic reaction pathways by using SAM as the cofactor. These pathways converge to the desired biosynthetic end product via the (SAM-dependent) retro-Claisen rearrangement catalysed by LepI. We expect that more pericyclic biosynthetic enzymatic transformations remain to be discovered in naturally occurring enzyme ‘toolboxes’11. The new role of the versatile cofactor SAM is likely to be found in other examples of enzyme catalysis.
Zhongyue Yang†∥ , Xiaofei Dong†∥, Yanmin Yu†‡, Peiyuan Yu†§ , Yingzi Li†, Cooper Jamieson†, and K. N. Houk*†
Ambimodal reactions involve a single transition state leading to multiple products. In such reactions, transition state theory gives no information about the ratio of products that are formed, and molecular dynamics must be performed to predict this ratio. Understanding the relationship between the transition structure and the product ratio is a long-standing problem in molecular dynamics. We have studied 15 ambimodal pericyclic reactions and investigated the relationship between the TS bond lengths in the saddle points and the product ratios from trajectory simulations. A linear correlation, ln(B:A) = −9.4(Bond 3 – Bond 2), is found with R2 = 0.92, where A and B refer to the products formed upon formation of bonds 2 and 3, respectively. The correlation shows that the ratio of products formed after the bifurcation is related to the partial bond lengths, and corresponding bond orders, in the transition state.
Gang Liao, Qi-Jun Yao, Zhuo-Zhuo Zhang, Yong-Jie Wu, Dan-Ying Huang, Prof. Dr. Bing-Feng Shi
Dibenzocyclooctadiene lignans are an interestingclass of molecules because of their unique structure based onan axially chiral biaryl moiety as well as their significantbiological activity. Herein, we describe the development ofa palladium-catalyzed atroposelective CH alkynylation andits application in gram-scale, stereocontrolled formal synthesesof (+)-isoschizandrin and (+)-steganone. tert-Leucine wasidentified as an efficient, catalytic transient chiral auxiliary. Awide range of enantiomerically enriched biaryl compoundswere prepared by this approach in good yields (up to 99 %)with excellent enantioselectivity (up to > 99 % ee).
Hao-jui Hsu†, Helena Palka-Hamblin‡, Gaurang P. Bhide‡, Ja-Hye Myung†, Michael Cheong†, Karen J. Colley*‡ , and Seungpyo Hong*†§∥
Enumeration of circulating tumor cells (CTCs) of small-cell lung cancer (SCLC) patients has been shown to predict the disease progress and long-term survival. Most CTC detection methods rely on epithelial surface markers, such as epithelial cell adhesion molecule (EpCAM). However, this marker in SCLC is reported to be often downregulated after a variety of phenotypic changes, which impairs the reliability of EpCAM-based CTC detections. In this regard, the development of an alternative CTC detection method involving different CTC surface markers is in demand. In this study, we evaluated, for the first time to our knowledge, the feasibility of detecting SCLC CTCs using a noncatalytic endosialidase (EndoN Trap, EndoNt). This noncatalytic enzyme was chosen due to its high affinity to polysialic acid (polySia), a cell-surface glycan, that is highly expressed by SCLC tissue. Furthermore, this enzyme-based system was integrated into our dendrimer-mediated CTC capture platform to further enhance the capture efficiency via multivalent binding. We found that the EndoNt-immobilized surfaces could specifically capture polySia-positive SCLC cells and the binding between SCLC cells and EndoNt surfaces was further stabilized by dendrimer-mediated multivalent binding. When compared to the EpCAM-based capture, EndoNt significantly improved the capture efficiency of polySia-positive SCLC cells under flow due to its higher binding affinity (lower dissociation rate constants). These findings suggest that this enzyme-based CTC capture strategy has the potential to be used as a superior alternative to the commonly used EpCAM-based methods, particularly for those types of cancer that overexpress polySia.
Eric D. Nacsa and David W. C. MacMillan*
Nature routinely engages alcohols as leaving groups, as DNA biosynthesis relies on the removal of water from ribonucleoside diphosphates by a radical-mediated “spin-center shift” (SCS) mechanism. Alcohols, however, remain underused as alkylating agents in synthetic chemistry due to their low reactivity in two-electron pathways. We report herein an enantioselective α-benzylation of aldehydes using alcohols as alkylating agents based on the mechanistic principle of spin-center shift. This strategy harnesses the dual activation modes of photoredox and organocatalysis, engaging the alcohol by SCS and capturing the resulting benzylic radical with a catalytically generated enamine. Mechanistic studies provide evidence for SCS as a key elementary step, identify the origins of competing reactions, and enable improvements in chemoselectivity by rational photocatalyst design.
Tomasz Klucznik, Barbara Mikulak-Klucznik, Michael P. McCormack, ..., Milan Mrksich, Sarah L.J. Trice, Bartosz A. Grzybowski
Although computers have demonstrated the ability to challenge humans in various games of strategy, their use in the automated planning of organic syntheses remains unprecedented. As a result of the impact that such a tool could have on the synthetic community, the past half century has seen numerous attempts to create in silico chemical intelligence. However, there has not been a successful demonstration of a synthetic route designed by machine and then executed in the laboratory. Here, we describe an experiment where the software program Chematica designed syntheses leading to eight commercially valuable and/or medicinally relevant targets; in each case tested, Chematica significantly improved on previous approaches or identified efficient routes to targets for which previous synthetic attempts had failed. These results indicate that now and in the future, chemists can finally benefit from having an “in silico colleague” that constantly learns, never forgets, and will never retire.
Abstract: Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is an innovative molecular imaging technique in which contrast agents are labeled by saturating their exchangeable protons spins by radio frequency irradiation. Salicylic acid and its analogues are a promising class of highly sensitive, diamagnetic CEST agents. We synthesized polymeric agents grafted with salicylic acid moieties and a known high-affinity ligand targeting prostate-specific membrane antigen (PSMA) in a ~10:1 molar ratio to provide sufficient MRI sensitivity and receptor specificity. We report here the proton exchange properties of the contrast agent in solution and in an experimental murine model to demonstrate the feasibility of receptor-targeted CEST MRI of prostate cancer. Furthermore, we have validated the CEST imaging data with 111In-labeled analog of the agent by in vivo SPECT imaging and tissue biodistribution studies.
Xi Xu, Raoling Gea, Lei Li, Jubo Wang, Xiaoyu Lu, Siqi Xue, Xijing Chen, Zhiyu Lia, Jinlei Biana
Prostate cancer (PC) is a major cause of cancer-related male death in worldwide and the identification of new and improved potent anti-PC molecules is constantly required. A novel scaffold of tetrahydroisoquinoline thiohydantoin was rationally designed based on the enzalutamide structures and our pre-work, leading to the discovery of a series of new antiproliferative compounds. Several new analogues displayed improved androgen receptor (AR) antagonistic activity, while maintaining the higher selective toxicity toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient) compared to enzalutamide. In fact, compound 55 exhibited promising in vitro antitumor activity by impairing AR unclear translocation. More importantly, 55 showed better pharmacokinetic properties compared to the compound 1 reported in our pre-work. These results demonstrate a step towards the development of novel and improved AR antagonists.