Organic & Biomolecular Chemistry (v.17, #37)

Front cover (8459-8460).

Contents list (8461-8466).

α-Halogenoacetamides: versatile and efficient tools for the synthesis of complex aza-heterocycles by Abderrahman El Bouakher; Arnaud Martel; Sébastien Comesse (8467-8485).
This review provides an overview of the applications of α-halogenoacetamides in domino and cycloaddition reactions. α-Halogenoacetamides are versatile building blocks that can lead to a wide variety of complex aza-heterocycles of biological interest when engaged in domino and/or cycloaddition reactions. The reactivity and the reaction conditions involved for these species (solvent, base, etc.) are closely related to the substituent onto the nitrogen atom of the amide: N-alkyl α-halogenoacetamides usually act as formal 1,3-dipoles in domino processes whereas N-alkoxy derivatives often react as real 1,3-dipoles via the formation of aza-oxyallyl cation species. This important modulation of the reactivity of these compounds opens the way to a large panel of reactions and therefore to a large diversity of aza-heterocycles.

Azines: synthesis, structure, electronic structure and their applications by Sumit S. Chourasiya; Deepika Kathuria; Aabid Abdullah Wani; Prasad V. Bharatam (8486-8521).
Azines are organic molecules which bear the CN–NC functional unit. In the recent past, azines have received increased attention due to the recognition of their biological, chemical and materials properties. Azines have been conventionally synthesised by the condensation of hydrazine with ketones and aldehydes, and many alternate routes are also available. Azines have been extensively studied to investigate the presence or absence of conjugation with the help of computational studies and crystal structure analysis owing to their importance in nonlinear optics. The tautomerism in azines is a topic of contemporary interest. Herein, we present a review of recent advances in the structure and electronic structure properties of azines along with information on the modern methods of their synthesis and application as precursors in generating heterocycles in organic synthesis and in medicinal chemistry. A few applications of azines in the field of materials chemistry in developing metal–organic frameworks (MOFs), covalent organic frameworks (COFs), energetic materials and chemosensors are also included.

Gold(i)-catalyzed Nicholas reaction with aromatic molecules utilizing a bifunctional propargyl dicobalt hexacarbonyl complex by Toshitaka Okamura; Shogo Fujiki; Yoshiharu Iwabuchi; Naoki Kanoh (8522-8526).
A benchtop-stable reagent for the catalytic Nicholas reaction was developed. By combining a propargyl dicobalt hexacarbonyl cluster with an ortho-alkynylbenzoate unit and a fluorous tag, introduction of a propargyl hexacarbonyl complex on various aromatic compounds having acid- or base-sensitive functional groups becomes possible by using a gold(i) catalyst. In addition, the presence of a fluorous tag facilitates convenient separation of the target products from byproducts.

Described is a silver-promoted decarboxylative radical addition/annulation of oxamic acids with gem-difluoroalkenes. This reaction proceeded under mild reaction conditions with broad functional group compatibility, enabling the convenient synthesis of various structurally diverse CF2-containing 3,4-dihydroquinolin-2-ones that might find applications in medical chemistry.

Facile synthesis of stable selenocystine peptides and their solution state NMR studies by Ram P. Gokula; Kirti Patel; Shakti K. Maurya; Harkesh B. Singh (8533-8536).
A facile general route for the synthesis of various selenocystine tripeptides containing acidic, basic and neutral side chain amino acids is reported. Here, TFA labile side chain protected selenocysteine has been used as a precursor for the synthesis of selenopeptides. The peptides are highly stable in dimethyl sulphoxide, thus enabling detailed NMR studies by solution phase 1- and 2-dimensional NMR spectroscopy.

Catalytically active chiral π-conjugated polymers (poly-1(NO)r) bearing pyridine N-oxide pendants were synthesized by ternary copolymerization of a d-glucose-bound diethynyl compound with two types of thieno[3,4-b]thiophene comonomer, one of which contained a pyridine N-oxide group. When the pyridine N-oxide content in the copolymer was 10 mol% (poly-1(NO)0.10), the polymer backbone formed a one-handed helical structure in acetonitrile. Pyridine N-oxide pendants arranged inside the helical cavity of poly-1(NO)0.10 exhibited catalytic activity for the asymmetric allylation of benzaldehydes, producing the corresponding allyl alcohols with up to 43% ee.

A three-component difluoroalkylamination of alkenes with BrCF2CO2Et and amines mediated by visible-light photoredox and iron cooperative catalysis is described. Electron rich, electron poor, and internal styrenes are all tolerated giving the desired products in good yields. The Csp3–Csp3 and Csp3–N bonds are simultaneously formed under mild conditions. A radical pathway is proposed by experimental studies.

CO2 activation by electrogenerated divalent samarium for aryl halide carboxylation by Sakna Bazzi; Gaëtan Le Duc; Emmanuelle Schulz; Corinne Gosmini; Mohamed Mellah (8546-8550).
The reductive carboxylation of aryl halides has been investigated using a samarium electrode as a sacrificial anode to yield the corresponding benzoic acids, providing a smooth strategy for CO2 activation. Carboxylation occurred after an efficient reduction of carbon dioxide mediated by an electrogenerated Sm(ii)-complex acting as a strong monoelectronic reductive reagent.

Hyperconjomer stereocontrol of cationic polyene cyclisations by Robert T. Rodger; Marlowe S. Graham; Christopher S. P. McErlean (8551-8560).
Polyene cyclisations are a powerful method for the direct generation of molecular complexity. This paper describes the use of computational methods to investigate the stereoselectivity of cationic polyene cyclisations of geranylbenzene derivatives. The outcomes highlight the different reactivity of hyperconjomers during the key Friedel–Crafts alkylation step, and informed a successful strategy for the synthesis of (±)-taiwaniaquinone G with improved levels of stereoselectivity.

A base-promoted cascade reaction of α,β-unsaturated N-tosylhydrazones with o-hydroxybenzyl alcohols: highly regioselective synthesis of N-sec-alkylpyrazoles by Lian-Mei Chen; Juan Zhao; An-Jie Xia; Xiao-Qiang Guo; Ya Gan; Chuang Zhou; Zai-Jun Yang; Jun Yang; Tai-Ran Kang (8561-8570).
An efficient method for the synthesis of N-sec-alkylpyrazoles through a base-promoted cascade cyclization/Michael addition reaction of α,β-unsaturated N-tosylhydrazones with ortho-hydroxybenzyl alcohols has been developed. The desired products containing di- or triaryl groups at the same carbon atom were afforded in good to excellent yields with excellent regioselectivities (>20 : 1). Moreover, a three-component reaction of ortho-hydroxybenzyl alcohols, α,β-unsaturated N-tosylhydrazones and saturated N-tosylhydrazones also took place to afford pyrazoles in good yields. This reaction offers a new route to triarylmethanes with a simple operation and is applicable for large-scale synthesis.

Ketoreductase from growing cells of Klebsiella pneumoniae (NBRC 3319) acts as an efficient reagent for converting racemic α-benzyl/cinnamyl substituted-β-ketoesters to the corresponding β-hydroxy esters with excellent yields and stereoselectivities (ee and de >99 %). The reactions described herein followed a biocatalytic dynamic kinetic reductive resolution (DKRR) pathway, which is reported for the first time with such substrates. It was found that the enzyme system can accept substituted mono-aryl rings with different electronic natures. In addition, it also accepts a substituted naphthyl ring and heteroaryl ring in the α-position of the parent β-ketoester. The synthesized enantiopure β-hydroxy esters were then synthetically manipulated to valuable tetrahydropyran building blocks.

Rhodium(iii)-catalysed cascade [3 + 2] annulation of N-aryloxyacetamides with 3-(hetero)arylpropiolic acids: synthesis of benzofuran-2(3H)-ones by Jin-Long Pan; Tuan-Qing Liu; Chao Chen; Quan-Zhe Li; Wei Jiang; Tong-Mei Ding; Zhi-Qiang Yan; Guo-Dong Zhu (8589-8600).
Herein, a cascade [3 + 2] annulation of N-aryloxyacetamides with 3-(hetero)arylpropiolic acids affording benzofuran-2(3H)-ones via rhodium(iii)-catalyzed redox-neutral C–H functionalization/isomerization/lactonization using an internal oxidative directing group O–NHAc was achieved. This catalytic system provides a regio- and stereoselective approach to synthesize (Z)-3-(amino(aryl)methylene)benzofuran-2(3H)-ones with exclusive Z configuration selectivity, acceptable yields and good functional group tolerance. Preliminary investigations on ultraviolet–visible and fluorescence behaviors reveal that the annulation products may be applied as a promising fluorescent probe for sensing metal cations, especially for cerium (Ce3+).

Side-chain deuterated cholesterol as a molecular probe to determine membrane order and cholesterol partitioning by Shinya Hanashima; Yuki Ibata; Hirofumi Watanabe; Tomokazu Yasuda; Hiroshi Tsuchikawa; Michio Murata (8601-8610).
Cholesterol is an essential and ubiquitous component in mammalian cell membranes. However, its distributions and interactions with phospholipids are often elusive, partly because chemical modifications for preparing cholesterol probes often cause significant perturbations in its membrane behavior. To overcome these problems, a 2H-labeled probe (24-d-cholesterol), which perfectly retained the original membrane properties, was synthesized by a stereoselective introduction of 2H into the side chain of cholesterol. A deuterium label at the side-chain more sensitively reflects membrane fluidity than the conventional labeling at the 3 position of a sterol core (3-d-cholesterol), thus providing 24-d-cholesterol with desirable properties to report membrane ordering. Solid state 2H NMR of 24-d-cholesterol with sphingomyelins (SM) and unsaturated phosphatidylcholine in the bilayer membranes clearly revealed the partitioning ratio of cholesterol in the raft-like liquid ordered (Lo) phase and the liquid disordered phase based on cholesterol interactions with surrounding lipids in each phase. This probe turned out to be superior to the widely used 3-d-cholesterol; e.g., 24-d-cholesterol clearly revealed a 10 mol% difference in the Lo distribution ratios of cholesterol between palmitoyl-SM and stearoyl-SM. The comprehensive use of 24-d-cholesterol in solid state 2H NMR will disclose the cholesterol–lipid interactions, distribution ratio of cholesterol, and membrane ordering in model bilayers as well as more complicated biological membranes.

Molecular imprinting is a facile method to create guest-complementary binding sites in a cross-linked polymeric network. When performed within cross-linked micelles, the resulting molecularly imprinted nanoparticles (MINPs) exhibited an extraordinary ability to distinguish subtle structural changes in the guest, including the shift of a hydrophilic or hydrophobic group by 1 carbon and addition of a single methylene/methyl group. A high surface-cross-linking density prior to core-cross-linking was key to the high-fidelity imprinting, enhancing both the binding affinity of the imprinted micelle for the template and selectivity among structural analogues. Whereas the imprinted site closely complemented the hydrophilic surface anchoring group and rigid hydrophobic aromatic core, it was expanded significantly for a conformationally mobile small group (i.e., methoxy).

Substrate-product analogue inhibitors of isoleucine 2-epimerase from Lactobacillus buchneri by rational design by Noa T. Sorbara; Joshua W. M. MacMillan; Gregory D. McCluskey; Stephen L. Bearne (8618-8627).
A rational approach that may be applied to a broad class of enzyme-catalyzed reactions to design enzyme inhibitors affords a powerful strategy, facilitating the development of drugs and/or molecular probes of enzyme mechanisms. A strategy for the development of substrate-product analogues (SPAs) as inhibitors of racemases and epimerases is elaborated using isoleucine 2-epimerase from Lactobacillus buchneri (LbIleE) as a model enzyme. LbIleE catalyzes the PLP-dependent, reversible, racemization or epimerization of nonpolar amino acids at the C-2 position. The enzyme plays an important role in the biosynthesis of branched-chain d-amino acids and is a potential target for the development of antimicrobial agents. 3-Ethyl-3-methyl-l-norvaline (Ki = 2.9 ± 0.2 mM) and 3-ethyl-3-methyl-d-norvaline (Ki = 1.5 ± 0.2 mM) were designed as SPAs based on the movement of the sec-butyl side chain of the substrate l-Ile during catalysis, and were competitive inhibitors with binding affinities exceeding that of l-Ile by 1.3- and 2.5-fold, respectively. Surprisingly, these compounds were not substrates, but the corresponding compounds lacking the 3-methyl group were substrates. Unlike serine, glutamate, and proline racemases, which exhibit stringent steric requirements at their active sites, the active site of LbIleE was amenable to binding bulky SPAs. Moreover, LbIleE bound the SPA 2,2-di-n-butylglycine (Ki = 11.0 ± 0.2 mM) as a competitive inhibitor, indicating that the hydrophobic binding pocket at the active site was sufficiently plastic to tolerate gem-dialkyl substitution at the α-carbon of an amino acid. Overall, these results reveal that amino acid racemases/epimerases are amenable to inhibition by SPAs provided that they possess a capacious active site.

Nucleophilic ring opening of cyclohexene oxides is known to proceed preferentially through the trans-diaxial pathway (the Fürst–Plattner rule). This preference, however, is not absolute, and can be affected by substituents on the cyclohexene oxide ring, as illustrated by LiAlH4 ring-opening of the cis- and trans-isomers of 4-t-butyl- and 3-methylcyclohexene oxide (cis- and trans-1, cis- and trans-2). We performed B3LYP/6-31+G*(PCM) geometry optimizations to locate the chair-like and twist-boat-like transition structures for the hydride attacks on the pseudoaxial and pseudoequatorial conformers of these epoxides. Our calculations are consistent with the experimental observation of effective Fürst–Plattner control of AlH4-opening of cis-1, trans-1, and cis-2, but low selectivity in ring-opening of trans-2. Our data at B3LYP/6-31+G*(PCM) suggests this reduction in selectivity is due to a diminished pseudoequatorial preference of the 3-methyl group in trans-2 relative to that in cis-2. The two calculated chair-like transition structures for hydride opening of trans-2 differ in activation energy free energy (ΔΔG) by only 0.4 kcal mol−1. Thus, these calculations account for the reduced regioselectivity of ring opening seen for trans-2 by AlH4 and other nucleophiles.

Back cover (8637-8638).