A New Highly Versatile Handle for Chemistry on a Solid Support: The Pipecolic Linker

The design, synthesis, and potential application of the pipecolic linker is presented. This new versatile handle can immobilize primary, secondary, and aromatic amines, as well as alcohols, phenols, and hydrazides, on a solid support. Compared with other linkers, the anchoring step is easy and efficient. The release of final products from the resin proceeds upon acidic treatment with high purities. The pipecolic linker offers the promise of being using in peptide chemistry to produce peptides modified at the N and C terminus, peptidomimetics, as well as small organic molecules.     

Synthesis of the DFGH ring system of Type B Physalins: Highly Oxygenated,Cage‐Shaped Molecules

Let the dominos fall : Synthesis of the complex DFGH ring system of the title compounds has been accomplished. The approach features simple treatment of the key intermediate with a Brønsted base to afford the tetracyclic cage‐shaped target in one pot through a four‐step domino transformation (see scheme; Mc= monochloromesylate, MOM=methoxymethyl).

     

Organocatalytic Domino Michael–Knoevenagel Condensation Reaction for the Synthesis of Optically Active 3‐Diethoxyphosphoryl‐2‐oxocyclohex‐3‐enecarboxylates

Versatile dominoes : A novel, organocatalytic, Michael–Knoevenagel condensation domino reaction of ethyl 4‐diethoxyphosphoryl‐3‐oxobutanoate with various aryl‐ and aliphatic‐substituted α,β‐unsaturated aldehydes catalyzed by a chiral diarylprolinol ether has been successfully performed. The reaction proceeds in a highly enantio‐ and diastereoselective manner giving access to optically active 6‐substituted‐3‐diethoxyphosphoryl‐2‐oxocyclohex‐3‐enecarboxylates (see scheme).

     

Cover Picture: Organocatalytic Domino Michael–Knoevenagel Condensation Reaction for the Synthesis of Optically Active 3‐Diethoxyphosphoryl‐2‐oxocyclohex‐3‐enecarboxylates (Chem. Eur. J. 13/2009)

In Buddhist imagery the gestures of the hand are very significant, which reflects the themes of asymmetry and chirality (derived from the word “hand”) found in the Full Paper by K. A. Jørgensen et al. on page 3093 ff. The professor is shown as a Buddha‐like image and is gesturing down with one hand and making the Buddhist gesture for “method and wisdom” with the other. Dice tumbling from his hand represent the organocatalytic Michael–Knoevenagel condensation domino reaction discussed in the paper, with the front die representing the cyclohexenone center of the molecule being formed. The two students standing by are making Buddhist gestures for “accomplishment” and “meditation”. Artwork by cartoonist Jorge Cham, http://www.phdcomics.com.

     

Solvent‐Enhanced Diastereo‐ and Regioselectivity in the PdII‐Catalyzed Synthesis of Six‐ and Eight‐Membered Heterocycles via cis‐Aminopalladation

The Pd^II‐catalyzed intramolecular oxidative cyclization of tosyl‐protected cis‐ and trans‐N‐allyl‐2‐aminocyclohexanecarboxamides was examined, and efficient syntheses of cyclohexane‐fused pyrimidin‐4‐ones and 1,5‐diazocin‐6‐ones were developed. In the course of the research, a marked solvent effect was observed on both the regio‐ and diastereoselectivity. Additionally, a novel Pd^II‐mediated domino oxidation, oxidative amination reaction was discovered. Our experimental and theoretical findings suggest that the reactions proceed via a cis‐aminopalladation mechanism.     

Facile Microwave‐Assisted Solid‐Phase Synthesis of Highly Fluorescent Nitrogen–Sulfur‐Codoped Carbon Quantum Dots for Cellular Imaging Applications

Carbon quantum dots (CQDs) have recently attracted significant attention for both their fundamental science and technological applications as a new class of fluorescent zero‐dimensional nanomaterials with a size below 10 nm. However, the reported methods of synthesis were generally less suitable for the large‐scale production of the CQDs with high‐fluorescent quantum yield (QY). In the paper, a novel one‐pot microwave‐assisted drying synthesis approach was presented to prepare CQDs with high QY of 61.3 % for the first time. The production yield of CQDs was 35±3 % in weight. The as‐prepared CQDs were characterized by various techniques such as TEM, AFM, XRD, XPS, FTIR spectroscopy, UV/Vis absorption spectroscopy, and fluorescence spectroscopy. The results showed that the high QY of CQDs was largely attributed to the dual doping of nitrogen and sulphur into CQDs. Such CQDs were then used as live‐cell imaging reagents due to their high QY, good water dispersibility, fine biocompatibility, high photostability, and low cytotoxicity.     

A One‐Pot Chemically Cleavable Bis‐Linker Tether Strategy for the Synthesis of Heterodimeric Peptides

Heterodimeric peptides linked by disulfide bonds are attractive drug targets. However, their chemical assembly can be tedious, time‐consuming, and low yielding. Inspired by the cellular synthesis of pro‐insulin in which the two constituent peptide chains are expressed as a single‐chain precursor separated by a connecting C‐peptide, we have developed a novel chemically cleavable bis‐linker tether which allows the convenient assembly of two peptide chains as a single “pro”‐peptide on the same solid support. Following the peptide cleavage and post‐synthetic modifications, this bis‐linker tether can be removed in one‐step by chemical means. This method was used to synthesize a drug delivery‐cargo conjugate, TAT‐PKCi peptide, and a two‐disulfide bridged heterodimeric peptide, thionin (7‐19)‐(24‐32R), a thionin analogue. To our knowledge, this is the first report of a one‐pot chemically cleavable bis‐linker strategy for the facile synthesis of cross‐bridged two‐chain peptides.     

A β‐Enaminone‐Initiated Multicomponent Domino Reaction for the Synthesis of Indoloquinolizines and Benzoquinolizines from Acyclic Precursors

The cerium(IV) ammonium nitrate (CAN)‐catalyzed sequential multicomponent reaction between tryptamine, α,β‐unsaturated aldehydes, and β‐dicarbonyl compounds affords highly substituted indolo[2,3‐a]quinolizines in a single synthetic operation. Two rings are generated through the creation of two C? C and two C? N bonds by a domino process comprising initial β‐enaminone formation, followed by individual Michael addition, 6‐exo‐trig cyclization, iminium formation, and Pictet–Spengler steps. Furthermore, the reaction is diastereoselective and affords exclusively compounds with a trans relationship between the H‐2 and H‐12b protons. The use of amines bearing a less nucleophilic side chain aromatic ring (5‐bromotryptamine, 3,4‐dimethoxyphenylethylamine) prevents the Pictet–Spengler final step and leads to N‐indolylethyl or N‐phenylethyl‐1,4‐dihydropyridines, which are cyclized to the corresponding indolo[2,3‐a]quinolizines or benzo[a]quinolizines in the presence of HCl in methanol/water. Treatment of the fused quinolizine derivatives with sodium triacetoxyborohydride led to the corresponding indolo[2,3‐a]quinolizidines or benzo[a]quinolizidines, possessing four stereogenic centers, as mixtures of two diastereomers.     

Synthesis of Nature‐Inspired Medium‐Sized Fused Heterocycles from Amino Acids

Herein, we describe the synthesis of molecular scaffolds consisting of medium‐sized fused heterocycles using amino acids, which are some of the most useful building blocks used by nature as well as chemists to create structural diversity. The acyclic precursors were assembled by using traditional Merrifield solid‐phase peptide synthesis, and cyclization was carried out through acid‐mediated tandem endocyclic N‐acyliminium ion formation, followed by nucleophilic addition with internal nucleophiles. The synthesis of molecular scaffolds consisting of seven‐, eight‐, and nine‐membered rings proceeded with full stereocontrol of the newly generated stereogenic center in most cases.     

Solid‐Phase Synthesis of Structurally Diverse Heterocycles by an Amide–Ketone Condensation/N‐Acyliminium Pictet–Spengler Sequence

An efficient approach for the solid‐phase synthesis of structurally diverse heterocyclic compounds is presented. Under acidic reaction conditions, peptidic levulinamides undergo intramolecular ketone–amide condensation reactions to form cyclic N‐acyliminium intermediates. In the presence of a tethered nucleophile, a second cyclization reaction results in the formation of a fused bicyclic ring system. The scope of the methodology was demonstrated by several combinations of substituted ketones and nucleophiles, the latter conveniently originating from amino acids with functionalized side chains, such as tryptophan, substituted phenylalanines, and cysteine. The cyclization sequence provides diastereomerically pure products in high yields. In one extension of the methodology, the resulting relative stereochemistry of the products enables the formation of bridged ring systems by a unique cyclative release mechanism.     

Solid‐phase Total Synthesis of (−)‐Apratoxin A and Its Analogues and Their Biological Evaluation

Two approaches for the solid‐phase total synthesis of apratoxin A and its derivatives were accomplished. In synthetic route A, the peptide was prepared by the sequential coupling of the corresponding amino acids on trityl chloride SynPhase Lanterns. After cleavage from the polymer‐support, macrolactamization of 10 , followed by thiazoline formation, provided apratoxin A. This approach, however, resulted in low yield because the chemoselectivity was not sufficient for the formation of the thiazoline ring though its analogue 33 was obtained. However, in synthetic route B, a cyclization precursor was prepared by solid‐phase peptide synthesis by using amino acids 13 – 15 and 18 . The final macrolactamization was performed in solution to provide apratoxin A in high overall yield. This method was then successfully applied to the synthesis of apratoxin analogues. The cytotoxic activity of the synthetic derivatives was then evaluated. The epimer 34 was as potent as apratoxin A, and O‐methyl tyrosine can be replaced by 7‐azidoheptyl tyrosine without loss of activity. The 1,3‐dipolar cycloaddition of 38 with phenylacetylene was performed in the presence of a copper catalyst without affecting the thiazoline ring.     

Selenium‐Containing Heterocycles from Isoselenocyanates: Use of Hydrazine for the Synthesis of 1,3,4‐Selenadiazine Derivatives

Aryl isoselenocyanates 1 react with different phenacyl halides 2 in the presence of hydrazine hydrate in a one‐pot reaction to give selenadiazines 3a – 3f in good‐to‐excellent yields.     

Convertible Fluorous Sulfonate Linker for the Synthesis of Diverse Library Scaffolds

Aryl perfluorooctanesulfonates (fluorous sulfonate) have been developed as triflates and nonaflates alternatives for Pd‐catalyzed coupling reactions to form C‐C, C‐N, C‐S, C‐H, and C‐CN bonds. They also serve as phase‐tags for fluorous solid‐phase extraction (F‐SPE) to facilitate product purifications. Other synthetic techniques such as microwave reactions and multicomponent reactions are combined with the fluorous linker strategy to further increase synthetic efficiency. The utility of fluorous sulfonate linkers in the synthesis of biologically interested library scaffolds is summarized in this short review article.     

Library‐directed Solution‐ and Solid‐phase Synthesis of 2,4‐Disubstituted Pyridines: One‐pot Approach through 6 π‐Azaelectrocyclization

An efficient one‐pot synthetic procedure for the synthesis of 2,4‐disubstituted pyridines has been successfully established. The method proceeds through a 6π‐azaelectrocyclization‐aromatization sequence. Using this method, a wide variety of pyridine structures substituted at the 2‐position have been rapidly constructed from vinyl stannanes, vinyl iodide, sulfonamide, and a palladium catalyst. The method was further applied to the solid‐phase synthesis wherein the use of a “traceless” sulfonamide linker enabled the rapid preparation of a small library of pyridines with high purity, without any chromatographic separation.