Asymmetric total synthesis of the indole alkaloid cyclopiazonic acid and first structure-activity data

The indole alkaloid α-cyclopiazonic acid (CPA) is one of the few known inhibitors of sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) besides the terpenoids thapsigargin and artemisinin. We report here the first asymmetric total synthesis of cyclopiazonic acid by a modification of the Knight synthesis, currently the most efficient route to CPA. First structure-activity data of CPA derivatives and stereoisomers are presented and will be discussed in connection with the published crystal structures of CPA-SERCA complexes.     

A total synthesis of (±)-α-cyclopiazonic acid using a cationic cascade as a key step

The indole alkaloid α-cyclopiazonic acid 1 has been synthesised by a route, which features at its core an acid-catalysed cationic cascade cyclisation terminated by a sulfonamide group.     

有机催化吲哚与环状酮亚胺膦酸酯的傅-克反应合成含手性季碳胺基膦酸衍生物

在有机合成中,季碳中心的构建始终是一项充满挑战的课题.含手性季碳中心的胺基膦酸化合物以其多样的生物活性,如酶抑制剂、抗真菌剂、抗菌剂和抗病毒剂等,受到了科研工作者的广泛关注.目前已有许多合成策略报道,其中亲核试剂与α-酮亚胺膦酸酯的不对称加成策略为含手性季碳中心胺基膦酸衍生物的合成提供了一条简洁有效的路径,但是却鲜有报道,已有的报道也仅局限于乙酰氰、丙酮、硝基甲烷和芳基硼酸作亲核试剂.为满足多样的手性胺基膦酸衍生物的合成需求,新的合成策略和亲核源仍有待进一步发展.值得一提的是,不对称傅-克反应是一种非常有效的构建碳-碳键的合成方法,并已有广泛报道.基于吲哚与亚胺底物的傅-克反应经验,我们研究组发展了一种有机催化吲哚与环状酮亚胺膦酸酯傅-克反应合成含手性季碳胺基膦酸衍生物的方法,使用的有机催化剂是手性磷酸.通过对溶剂、催化剂和温度的筛选发现,使用在3,3′-位引入吸电子的3,5-二三氟甲基苯基取代的H8-BINOL衍生的手性磷酸作催化剂,反应温度为30 oC,溶剂为均三甲苯时,最高能以98%对映选择性得到含手性季碳胺基膦酸酯化合物.该反应操作简单,条件温和,不仅适用于吲哚衍生物,对吡咯也能取得较好结果.总之,该方法提供了一条简洁有效的合成手性胺基膦酸衍生物的途径.     

Dynamic Kinetic Stereoselective Glycosylation via RhII and Chiral Phosphoric Acid-Cocatalyzed Carbenoid Insertion to the Anomeric OH Bond for the Synthesis of Glycoconjugates

Chemical synthesis of glycoconjugates is essential for studying the biological functions of carbohydrates. We herein report an efficient approach for the stereoselective synthesis of challenging α-linked glycoconjugates via a Rh^II/chiral phosphoric acid (CPA)-cocatalyzed dynamic kinetic anomeric O-alkylation of sugar-derived lactols via carbenoid insertion to the anomeric OH bond. Notably, we observed excellent anomeric selectivity, excellent diastereoselectivity, broad substrate scope, and high efficiency for this glycosylation reaction by exploring various parameters of the cocatalytic system. DFT calculations suggested that the anomeric selectivity was mainly determined by steric interactions between the C2-carbon of the carbohydrate and the phenyl group of the metal carbenoid, while π/π interactions with the C2−OBn substituent on the carbohydrate substrate play a significant role for diastereoselectivity at the newly generated stereogenic center.     

Seven-step total synthesis of α-cyclopiazonic acid

A seven-step total synthesis of α-cyclopiazonic acid is reported from a commercially available 4-bromoindole.Salient feature of the work is the rapid formation of tetracyclic skeleton via a bioinspired [3+2] annulation to form the C/D rings.     

Enantioselective De Novo Synthesis of α,α-Diaryl Ketones from Alkynes

Chiral α,α-diaryl ketones are structural motifs commonly present in bioactive molecules, and they are also valuable building blocks in synthetic organic chemistry. However, catalytic asymmetric synthesis of α,α-diaryl ketones bearing a tertiary stereogenic center remains largely unsolved. Herein, we report a catalytic de novo enantioselective synthesis of α,α-diaryl ketones from simple alkynes via chiral phosphoric acid (CPA) catalysis. A broad range of enolizable α,α-diaryl ketones are prepared in good yields and with excellent enantioselectivities. The described protocol also serves as an efficient deuteration method for the preparation of enantiomerically enriched deuterated α,α-diaryl ketones. Using the methodology reported, bioactive molecules, including one of the best-selling anti-breast cancer drugs, tamoxifen, are readily synthesized.     

Synthetic Studies on Sialoglycoconjugates 50: Total Synthesis of Ganglioside GD2

Abstract

As more and more biological functions^1-10 of gangliosides are being revealed, their facile, stereocontrolled synthesis is strongly required. We have developed^11-l4 an α-stereoselective glycosylation of sialic acids, α-sialyl-(2→8)-sialic acid and α-sialyl-(2→8)-α-sialyl-(2→8)-sialic acid, by using their 2-thioglycosides as the glycosyl donor and suitably protected acceptors, and dimethyl(methy1thio)sulfonium triflate (DMTST) or N-iodosuccinimide (NIS)-trifluoromethanesufonic acid (or TMS triflate) as the glycosyl promoter in acetonitrile. In this way, we have synthesized a variety of gangliosides¹⁵ and their analogs.¹⁶ Previously,¹³ we synthesized Ganglioside GD3 containing α-sialyl-(2-8)-sialic acid residue in the molecule, in connection with a novel approach for systematic synthesis of polysialo-glycoconjugates. As a part of our continuing studies on the synthesis and elucidation of the functions of gangliosides, we describe here a facile, stereocontrolled, total synthesis of ganglioside GD2. Ganglioside GD2, which was first isolated from human brain by R. Kuhn et al.,¹⁷ is well known as a human melanoma associated antigen.¹⁸     

Biomimetic synthesis of α-amino acids from α-keto acids

Protonated α-imino acids, RC(=NH₂⁺)COOH, were easily reduced to α-amino acids by an acid-stable NADH analogue, 1-benzyl-3-carbamoyl-1,4-dihydroquinoline. This is the first model reaction of NADH-mediated α-amino acid synthesis from α-keto acids.     

B(C6F5)3/Chiral Phosphoric Acid Catalyzed Ketimine–Ene Reaction of 2-Aryl-3H-indol-3-ones and α-Methylstyrenes

The enantioselective ketimine–ene reaction is one of the most challenging stereocontrolled reaction types in organic synthesis. In this work, catalytic enantioselective ketimine–ene reactions of 2-aryl-3H-indol-3-ones with α-methylstyrenes were achieved by utilizing a B(C₆F₅)₃/chiral phosphoric acid (CPA) catalyst. These ketimine–ene reactions proceed well with low catalyst loading (B(C₆F₅)₃/CPA=2 mol %/2 mol %) under mild conditions, providing rapid and facile access to a series of functionalized 2-allyl-indolin-3-ones with very good reactivity (up to 99 % yield) and excellent enantioselectivity (up to 99 % ee). Theoretical calculations reveal that enhancement of the acidity of the chiral phosphoric acid by B(C₆F₅)₃ significantly reduces the activation free energy barrier. Furthermore, collective favorable hydrogen-bonding interactions, especially the enhanced N−H⋅⋅⋅O hydrogen-bonding interaction, differentiates the free energy of the transition states of CPA and B(C₆F₅)₃/CPA, thereby inducing the improvement of stereoselectivity.     

A novel general method for preparation of α-fluoro-α-arylcarboxylic acid. Direct fluorination of silyl ketene acetals with Selectfluor

The reaction of an α-arylcarboxylic acid with TBSCl and LiHMDS in THF yielded bis-silyl ketene acetal, which was directly fluorinated with inexpensive Selectfluor^® to produce the corresponding α-fluoro-α-arylcarboxylic acid in high yield. Application of the methodology to the synthesis of α-fluorocarboxylic ester from the corresponding carboxylic ester is also described.     

A Convenient Synthesis of β-Amino Acid

We have reported the reductive cleavage of azlactones¹ and phenylhydrazones² of carbonyl compounds in the presence of a suitable catalyst. In this paper a general method involving a one step synthesis of β-amino acid^3,4, in good yield, through catalytic reduction of oximes of α-β-unsaturated acid is reported. This method involves the reaction of α, β-unsaturated acid with hydroxylamine hydrochloride in the presence of sodium acetate. Markovnikov's rule is followed in the synthesis of oximes of α, β-unsaturated acids.     

Communication: Synthetic Studies on Sialoglycoconjugates 25: Reactivity of Glycosyl Promoters in α-Glycosylation of N-Acetyl-Neuraminic Acid with the Primary and Secondary Hydroxyl Groups in the Suitably Protected Galactose and Lactose Derivatives

Development of an efficient α-glycoside synthesis of sialic acids is critically significant for the syntheses of sialoglycoconjugates, especially gangliosides which carry important biological functions¹ in biological systems. Previously, we demonstrated² a new α-glycosylation of sialic acids by use of dimethyl(methylthio)sulfonium triflate (DMTST)³ as the glycosyl promoter, the suitably protected glycosyl acceptors and the methyl 2-thioglycoside 1 of N-acetylneuraminic acid (Neu5Ac) as the donor in acetonitrile under kinetically controlled conditions, and accomplished⁴ the syntheses of a variety of gangliosides and their analogs.     

An examination of chlorpromazine hydrochloride as indicator and spectrophotometric reagent for the determination of molybdenum(V)

Chlorpromazine hydrochloride (CPA) has been tested as indicator in the titration of molybdenurn(V) with cerium(IV)sulphate at room temperature in sulphuric acid medium. It gives a sharp, reversible colour change from colourless to dark-red at the equivalence point. Chlorpromazine hydrochloride also reacts in acidic media with thiocyanatomolybdenum(V) complexes forming an orange compound with the formula (CPA · H) [MoO(SCN)₄]. This reaction provides a sensitive method for spectrophotometric determination of molybdenum(V). Molybdenum(VI) is reduced with ascorbic acid in hydrochloric acid solution, and complexed with thiocyanate, and the complex formed is extracted with chlorpromazine hydrochloride in chloroform. The molar absorptivity is 1.6 × 10⁴ l mol^-1 cm^-1 at 465 nm. Beer's law is obeyed in the range 0.5–5.0 μg Mo ml^-1.     

Electrocatalytic Synthesis of Essential Amino Acids from Nitric Oxide Using Atomically Dispersed Fe on N-doped Carbon

How to transfer industrial exhaust gases of nitrogen oxides into high-values product is significantly important and challenging. Herein, we demonstrate an innovative method for artificial synthesis of essential α-amino acids from nitric oxide (NO) by reacting with α-keto acids through electrocatalytic process with atomically dispersed Fe supported on N-doped carbon matrix (AD-Fe/NC) as the catalyst. A yield of valine with 32.1 μmol mg_cat⁻¹ is delivered at −0.6 V vs. reversible hydrogen electrode, corresponding a selectivity of 11.3 %. In situ X-ray absorption fine structure and synchrotron radiation infrared spectroscopy analyses show that NO as nitrogen source converted to hydroxylamine that promptly nucleophilic attacked on the electrophilic carbon center of α-keto acid to form oxime and subsequent reductive hydrogenation occurred on the way to amino acid. Over 6 kinds of α-amino acids have been successfully synthesized and gaseous nitrogen source can be also replaced by liquid nitrogen source (NO₃⁻). Our findings not only provide a creative method for converting nitrogen oxides into high-valued products, which is of epoch-making significance towards artificial synthesis of amino acids, but also benefit in deploying near-zero-emission technologies for global environmental and economic development.     

Glycosylation Using Methylthioglycosides of N-Acetylneuraminic Acid and Dimethyl(Methylthio)Sulfonium Triflate

Abstract

Recently, great interest has been focussed on the synthesis of oligosaccharides containing N-acetylneuraminic acid (Neu5Ac) because of its important roles in a variety of biological recognitions.² However, many difficulties in the synthesis of naturally occurring α-glycosides still remained.³ We have recently reported the stereo-selective synthesis of a series of α- and β-2-thio-neuraminyl glycosides.^1-4

In the meantime, the utility of thioglycosides in oligosaccharide synthesis has been widely developed.⁵ Particularly noteworthy is the dimethyl(methylthio)sulfonium triflate (DMTST) promoted glyco-sylation method^5k.1 because excellent yields are achieved due to the high thiophilicity of this reagent.     

Synthesis of novel β2,2-amino acid from D-mannose and attempted synthesis of peptides from the amino acid

The study describes the synthesis of new α,α-disubstituted β-amino acid (β^2,2-Caa) and attempts the synthesis of peptides from it. The β^2,2-Caa was prepared from D-(+)-mannose, using crossed aldol and Cannizzaro reactions.     

Sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) reduces the migratory capacity of CCL21-treated monocyte-derived dendritic cells

The migration of dendritic cells (DCs) to secondary lymphoid organs depends on chemoattraction through the interaction of the chemokine receptors with chemokines. However, the mechanism of how lymphoid chemokines attract DCs to lymphoid organs remains unclear. Here, we demonstrate the mechanism of DC migration in response to the lymphoid chemokine CCL21. CCL21-mediated DC migration is controlled by the regulation of sarcoplasmic reticulum Ca²⁺ ATPase 2 (SERCA2) expression rather than through the activation of mitogen-activated protein kinases CCL21-exposed mature DCs (mDCs) exhibited decreased SERCA2 expression but not decreased phospholamban (PLB) or Hax-1 expression, which are known to be SERCA2-interacting proteins. In addition, CCL21 did not affect the mRNA levels of SERCA2 or its interacting protein Hax-1. Interestingly, SERCA2 expression was inversely related to DC migration in response to chemokine stimulation. The migratory capacity of CCL21-treated mDCs was decreased by the phospholipase C inhibitor {"type":"entrez-nucleotide","attrs":{"text":"U73122","term_id":"4098075","term_text":"U73122"}}U73122 and by the protein kinase C inhibitor BAPTA-AM. The migratory capacities of mDCs were increased in response to SERCA2 siRNA expression but were decreased by SERCA2 overexpression. In addition, DCs treated with a SERCA2-specific inhibitor (cyclopiazonic acid) had significantly increased migratory capacities as mDCs regardless of SERCA2 expression. Moreover, SERCA2 expression was dependent on DC maturation induced by cytokines or Toll-like receptor agonists. Therefore, the migratory capacities differed in differentially matured DCs. Taken together, these results suggest that SERCA2 contributes to the migration of CCL21-activated DCs as an important feature of the adaptive immune response and provide novel insights regarding the role of SERCA2 in DC functions.     

α-Methoxythioanisole. Further Uses as an Umpolung Reagent

The facile lithiation of thioacetals has led to their extensive development as Umpolung reagents of great utility in general organic synthesis.¹ In contrast, the corresponding monothioacetals, such as α-alkoxysulfides, have received little attention for similar synthetic purposes. The most investigated reagent of this class has been the α-lithio derivative (2) of α-methoxy-thioanisole (methoxymethylphenylthioether, 1), which we will henceforth refer to as LMT. The first reported use of LMT was in 1975 by Trost, who showed that it added cleanly to the carbonyl of several bicyclic lactones.² Subsequent studies of LMT have been limited to one example of its addition to a lithiated tosylhydrazone to give eventually an enol ether,³ and several cases of its addition to ketone carbonyls as the first step of an unsaturated aldehyde synthesis.^4,5 We now report a new, convenient and non-hazardous synthesis of α-methoxythioanisole (1), as well as a broad overview of the reactions of its lithio derivative LMT (2) with some representative alkyl halides, epoxides, aldehydes, nitriles, amides, and an ester and an acid chloride.     

Aminomethylation of Enals through Carbene and Acid Cooperative Catalysis: Concise Access to β2‐Amino Acids

A convergent, organocatalytic asymmetric aminomethylation of α,β‐unsaturated aldehydes by N‐heterocyclic carbene (NHC) and (in situ generated) Brønsted acid cooperative catalysis is disclosed. The catalytically generated conjugated acid from the base plays dual roles in promoting the formation of azolium enolate intermediate, formaldehyde‐derived iminium ion (as an electrophilic reactant), and methanol (as a nucleophilic reactant). This redox‐neutral strategy is suitable for the scalable synthesis of enantiomerically enriched β²‐amino acids bearing various substituents.