Organic & Biomolecular Chemistry (v.10, #1)

Front cover (1-1).

Contents list (3-14).

Towards the systematic exploration of chemical space by Mark Dow; Martin Fisher; Thomas James; Francesco Marchetti; Adam Nelson (17-28).
The discovery of biologically active small molecules is shaped, in large part, by their synthetic (or biosynthetic accessibility). However, chemists' historical exploration of chemical space has been highly uneven and unsystematic. This article describes synthetic strategies that have emerged that may allow chemical space to be explored more systematically. Particular emphasis is placed on approaches that allow the scaffolds of small molecules to be varied combinatorially. In addition, some examples of bioactive small molecules that have been discovered by screening diverse small molecule libraries are highlighted. The authors comment on the likely scope of each of the strategies to deliver skeletally-diverse libraries. In addition, the authors highlight some key challenges for the future: the extension to libraries based on hundreds of distinct scaffolds; and the development of approaches that focus overtly on drug-relevant chemical space.

A concise asymmetric synthesis of (−)-rasfonin by Yange Huang; Adriaan J. Minnaard; Ben L. Feringa (29-31).
A very efficient total synthesis of the apoptosis inducer (−)-rasfonin has been developed using CuBr/JosiPhos catalyzed iterative asymmetric conjugate addition of MeMgBr and Feringa's butenolide.

Rhodium-catalysed enantioselective synthesis of 4-arylchroman-2-ones by Joseph C. Allen; Gabriele Kociok-Köhn; Christopher G. Frost (32-35).
The rhodium-catalysed enantioselective 1,4-addition of organoboron reagents to arylidene Meldrum's acids as acceptors, allows convenient access to 4-arylchroman-2-ones with good to excellent levels of enantioselectivity. The use of silyl-protected dioxaborinanes as donors was found to be advantageous to achieving good yields of product under anhydrous conditions.

Expeditious diastereoselective construction of a thiochroman skeleton via a cinchona alkaloid-derived catalyst by Zhiyun Du; Chenggang Zhou; Yaojun Gao; Qiao Ren; Kun Zhang; Hansong Cheng; Wei Wang; Jian Wang (36-39).
An example of diastereoselective and enantioselective synthesis of thiochroman derivatives through a sulfa-Michael–Michael cascade sequence is disclosed. This is a significant complement of the quinine-thiourea catalyzed sulfa-Michael–Michael cascade reaction. The densely functionalized target thiochromans were obtained in high diastereoselectivities, and with high to excellent enantioselectivities.

Anion mediated activation of guanidine rich small molecules by Abhigyan Som; Yongjiang Xu; Richard W. Scott; Gregory N. Tew (40-42).
Cell penetrating peptides (CPPs) and their synthetic analogs are of widespread interest. Here we report that guanidine rich small molecules can be potential membrane transporters in the presence of hydrophobic counteranion activators. To our knowledge, this is the first example of small molecules that mimic the anion-activated transport function of CPP.

Ruthenium-catalyzed highly selective codimerization of N-acetyl α-arylenamines with ethyl acrylates is reported. This codimerization reaction provides a new efficient method for the synthesis of α,β-unsaturated γ-amino esters with a quaternary center.

Metal-mediated DNA assembly using the ethynyl linked terpyridine ligand by Thomas Ehrenschwender; Anna Barth; Holger Puchta; Hans-Achim Wagenknecht (46-48).
The terpyridine ligand directly attached to the 5-position of a uridine allows metal-mediated DNA assembly towards potentially electronically coupled DNA conjugates.

Modified nucleoside mono- (dARMPs and dCRMPs) and triphosphates (dARTPs and dCRTPs) bearing bipyridine or terpyridine ligands attached via acetylene linker were prepared by single-step aqueous-phase Sonogashira cross-coupling of 7-iodo-7-deaza-dAMP or -dATP, and 5-iodo-dCMP or -dCTP with the corresponding bipyridine- or terpyridine-linked acetylenes. The modified dNRTPs were successfully incorporated into the oligonucleotides by primer extension experiment (PEX) using different DNA polymerases and the PEX products were used for post-synthetic complexation with Fe2+.

A general method for the synthesis of β-substituted and unsubstituted cycloheptenones bearing enantioenriched all-carbon γ-quaternary stereocenters is reported. Hydride or organometallic addition to a seven-membered ring vinylogous ester followed by finely tuned quenching parameters achieves elimination to the corresponding cycloheptenone. The resulting enones are elaborated to bi- and tricyclic compounds with potential for the preparation of non-natural analogs and whose structures are embedded in a number of cycloheptanoid natural products.

Dynamic combinatorial libraries for the recognition of heavy metal ions by Jörg M. Klein; Vittorio Saggiomo; Lisa Reck; Ulrich Lüning; Jeremy K. M. Sanders (60-66).
We present the use of hydrazone dynamic combinatorial libraries (DCLs) to identify macrocyclic receptors that are selective for alkaline earth metal ions over alkali metal ions. In particular, the toxic heavy metal ions Sr2+ and Ba2+ induce characteristic changes in the DCLs. Four macrocycles were isolated and characterised by LCMS, HRMS, NMR and X-ray crystallography; binding studies by UV-Vis spectroscopy confirm the selectivity observed in the DCLs.

Combining two-directional synthesis and tandem reactions: a short formal synthesis of halichlorine by Camille Gignoux; Annabella F. Newton; Alexandre Barthelme; William Lewis; Marie-Lyne Alcaraz; Robert A. Stockman (67-69).
A short and efficient synthesis of an advanced intermediate (1) in the Clive route to halichlorine has been achieved in 12 steps and 13.2% yield by a combined two-directional synthesis/tandem reaction strategy.

Indolizinones are under-explored N-heterocycles that react with exquisite chemo- and stereoselectivity. An exploration of the fundamental reactivity of these azabicycles demonstrates the potential to relay stereochemical information from the ring-fusion to newly formed stereocenters on the bicyclic core. The indolizinone diene undergoes selective hydrogenation and readily participates in Diels–Alder cycloadditions as well as ene reactions. The vinylogous amide embedded in the five-membered ring is resistant to reaction when the diene is in place. However, removal of the diene allows for diastereoselective hydrogenation of, and 1,4-additions to, the vinylogous amide. These fundamental reactions with indolizinones have provided a structurally diverse array of products that hold promise in the context of natural product synthesis.

Synthesis of novel 2,8-disubstituted indolo[3,2-b]carbazoles by Sven Van Snick; Wim Dehaen (79-82).
A new synthetic pathway towards 2,8-difunctionalised indolo[3,2-b]carbazoles was investigated. The presented method offers a short and high yielding route towards 2,8-dibromo-5,11-dihexyl-6,12-diphenyl-indolo[3,2-b]carbazole. It is demonstrated that the latter compound is a versatile building block, enabling the synthesis of a number of previously unreported 5,11-dialkyl-6,12-diphenyl-indolo[3,2-b]carbazoles in moderate to good yields, using Suzuki and Sonogashira cross-coupling reaction. Furthermore it is shown that 2,8-dibromo-5,11-dihexyl-6,12-diphenyl-indolo[3,2-b]carbazole can be easily formylated, giving rise to the 2,8-diformyl-5,11-dihexyl-6,12-diphenyl-indolo-[3,2-b]carbazole. The latter compound was successfully subjected to condensation reactions.

Asymmetric cyanation of nitroalkenes catalyzed by a salen–titanium catalyst by Li Lin; Wen Yin; Xu Fu; Jinlong Zhang; Xiaojuan Ma; Rui Wang (83-89).
The salen–Ti complex catalyzed cyanation of nitroolefins was accomplished via the silyl nitronate intermediate for the synthesis of chiral β-nitronitriles with e.r. up to 92 : 8 and high yields (up to 90%). The catalyst also kept a high turnover frequency at room temperature. The yield and enantioselectivity of the protocol were slightly affected even in a 10 mmol scale.

We report that a polyhedral oligomeric silsesquioxane (POSS) core in a dendrimer can enhance the affinity of the molecular recognition via hydrogen bonds between 1,8-naphthyridine and guanosine nucleotides. The complexation of the naphthyridine ligands with a series of guanosine nucleotides was investigated, and it is shown that the POSS core should play a significant role in the stabilization of the complexes via hydrogen bonds. Finally, we demonstrate that the 1,8-naphthyridine ligand can selectively recognize guanosine triphosphate by assisting with the POSS-core dendrimer.

In this study, we used solid phase synthesis to prepare three kinds of peptides and then formulated their peptide–siRNA complexes and peptide–siRNA conjugates. Both the complexation and conjugation systems were nontoxic and allowed the delivery of siRNA into the cytoplasm without the need for any transfection agents and with subsequent inhibition of gene expression.

Barton radical reactions of 2-C-branched carbohydrates by Tukaram M. Pimpalpalle; Jian Yin; Torsten Linker (103-109).
Barton esters have been introduced into the side chain of carbohydrates with high yields in only a few steps from easily available glycals. Their radical reactions afford 2-C-methyl and 2-C-bromomethyl hexoses, pentoses and disaccharides in good yields in analytically pure form. Since the Barton esters have been synthesized by an oxidative radical addition and their transformations by reductive radical processes, our results demonstrate the power of such reactions in carbohydrate chemistry.

Mono thiomalonates (MTMs) are introduced as thioester enolate equivalents. Asymmetric organocatalyzed conjugate addition reactions to nitroolefins proceed under mild conditions to afford synthetically useful γ-nitrothioesters with excellent yields and enantioselectivities.

1,3-Dipolar cycloadditions afforded fast access to isoxazolidines bearing N-alkyl or N-benzyl substituents. The electronic properties of the substituents in the nitrones define the activity of the dipoles and modulate diastereoselectivity in the non-catalyzed reactions. Using a chiral one-point binding ruthenium Lewis acid catalyst, products were obtained in good yields and with excellent regio-, diastereo-, and enantioselectivity.

During in vitro selection for DNA-catalyzed lysine reactivity, we identified a deoxyribozyme that instead catalyzes nucleophilic attack of a phosphoramidate functional group at a 5′-triphosphate-RNA, forming an unusual pyrophosphoramidate (N–PV–O–PV) linkage. This finding highlights the relatively poor nucleophilicity of nitrogen using nucleic acid catalysts, indicating a major challenge for future experimental investigation.

The investigation into the luminescence properties of a lanthanide-binding peptide, derived from the Ca-binding loop of the parvalbumin, and modified by incorporating a 1,8-naphthalimide (Naph) chromophore at the N-terminus is described. Here, the Naph is used as a sensitising antenna, which can be excited at lower energy than classical aromatic amino acids, such as tryptophan (the dodecapeptide of which was also synthesised and studied herein). The syntheses of the Naph antenna, its solid phase incorporation into the dodecapeptide, and the NMR investigation into the formation of the corresponding lanthanide complexes in solution is presented. We also show that this Naph antenna can be successfully employed to sensitize the excited states of both europium and terbium ions, the results of which was used to determined the stability constants of their formation complexes, and we demonstrated that our peptide ‘loop’ can selectively bind these lanthanide ions over Ca(ii).

The preparation of a range of asymmetric iron and ruthenium-cyclone complexes, and their application to the asymmetric reduction of a ketone, are described. The enantioselectivity of ketone reduction is influenced by a single chiral centre in the catalyst, as well as by the planar chirality in the catalyst. This represents the first example of asymmetric ketone reduction using an iron cyclone catalyst.

Synthesis and in vitro enzymatic and antiviral evaluation of phosphoramidate d4T derivatives as chain terminators by Shiqiong Yang; Christophe Pannecouque; Eveline Lescrinier; Anne Giraut; Piet Herdewijn (146-153).
The anti-HIV activity of nucleoside analogues is highly related to their substrate specificity for cellular and viral kinase and, as triphosphate, for HIV-RT. A series of phosphoramidate d4T derivatives have been synthesized and evaluated as substrates for HIV-1 RT, and also tested for their in vitro anti-HIV activity. Compounds 2 and 4 are able to inhibit HIV-1 replication to the same extent as d4T and d4TMP in MT-4 cells as well as in CEM/0 cells and CEM/TK cells. The data suggests that these phosphoramidates are hydrolysed to d4T before exerting their antiviral activity.

3,4′-Linked bis(piperidines) related to the haliclonacyclamine class of marine alkaloids: synthesis using crossed-aldol chemistry and preliminary biological evaluations by Martin G. Banwell; Mark J. Coster; Natasha L. Hungerford; Mary J. Garson; Stephen Su; Andrew C. Kotze; Murray H. G. Munro (154-161).
Compounds 2–5, incorporating various elements of the 3,4′-bis(piperidine) core associated with the sponge-derived alkaloid haliclonacyclamine A (HA, 1), have been prepared through, inter alia, aldol-type reactions of N-substituted piperidin-4-ones and certain derivatives. Screening of these compounds in various assays, including an ecological one, reveals that compound 5 exhibits allelochemical properties similar to those associated with HA itself.

Four-component reactions between amino alcohols, aldehydes, isocyanides and thiols proceed rapidly under microwave or conventional heating at 60 °C in methanol. The reaction is successful with a wide range of components and gives access to potentially drug-like products containing amine, amide and thioether functionality in moderate to excellent yield. The reaction conditions are also applicable to the synthesis of a range of 8–10 membered medium ring lactones via three-component reactions of amino alcohols, isocyanides and acid-aldehydes. Incorporation of l-prolinol as the amino alcohol component in each case gives access to multicomponent products with moderate to high diastereoselectivity.

Highly efficient DABCO-catalyzed [4 + 2] cycloaddition of β,γ-unsaturated α-ketophosphonates or β,γ-unsaturated α-ketoesters with allenic esters gives the corresponding highly functionalized tetrahydropyran and dihydropyran derivatives in good to excellent yields and moderate to good regioselectivities under mild conditions.

Discovery of a potent and highly β1 specific proteasome inhibitor from a focused library of urea-containing peptide vinyl sulfones and peptide epoxyketones by Wouter A. van der Linden; Lianne I. Willems; Tamer B. Shabaneh; Nan Li; Mark Ruben; Bogdan I. Florea; Gijs A. van der Marel; Markus Kaiser; Alexei F. Kisselev; Herman S. Overkleeft (181-194).
Syringolins, a class of natural products, potently and selectively inhibit the proteasome and show promising antitumour activity. To gain insight in the mode of action of syringolins, the ureido structural element present in syringolins is incorporated in oligopeptide vinyl sulfones and peptide epoxyketones yielding a focused library of potent new proteasome inhibitors. The distance of the ureido linkage with respect to the electrophilic trap strongly influences subunit selectivity within the proteasome. Compounds 13 and 15 are β5 selective and their potency exceeds that of syringolin A. In contrast, 5 may well be the most potent β1 selective compound active in living cells reported to date.

Back cover (195-196).