Organic & Biomolecular Chemistry (v.15, #10)

Front cover (2125-2125).

Inside front cover (2126-2126).

Contents list (2127-2132).

A review of computational studies of the related biosyntheses of steroids and hopenes reported during the last two decades is presented. Computations in the gas phase and those that include the enzyme are covered. Based on the numerical results conclusions have been drawn about the biosynthetic mechansims of these all important biological reactions.

The consequences of spatial mismatch between a receptor and ligand on affinity and selectivity of supramolecular complexes are illustrated with several examples. Conformationally rigid complexes and shorter-range non-covalent forces are characterized by large affinity changes, in contrast to more flexible systems. In the most frequent complexes with several spaciously separated binding sites, the additivity of binding energies and the correlation between affinity and selectivity is often lost by partial mismatch. Complete changes of binding modes and preferences can be the consequence, as illustrated particularly with cyclodextrin complexes. Associations with biopolymers, which usually depend also on several interaction sites, rarely show affinity–selectivity correlations, particularly not for high-affinity drug–receptor interactions. The negative consequences of spatial mismatch can be reduced by the introduction of flexible linkers between one binding site which secures affinity and the other one responsible for selectivity.

Glycosyl thiols may be accessed from the corresponding reducing sugars in water without recourse to any sugar projecting groups by way of a DMC mediated reaction with thioacetic acid in the presence of base, and hydrolysis of the anomeric thioacetate. Glycosyl thiols produced by this method may be used to access glycoconjugates, such as glycopeptides by use of the thiol–ene click reaction.

Characterization of drug encapsulation and retention in archaea-inspired tetraether liposomes by Geoffray Leriche; Jessica L. Cifelli; Kevin C. Sibucao; Joseph P. Patterson; Takaoki Koyanagi; Nathan C. Gianneschi; Jerry Yang (2157-2162).
The passive leakage of small molecules across membranes is a major limitation of liposomal drug formulations. Here, we evaluate the leakage of 3 clinically used chemotherapeutic agents (cytarabine, methotrexate and vincristine) encapsulated in liposomes comprised of a synthetic, archaea-inspired, membrane-spanning tetraether lipid. Liposomes comprised of the pure tetraether lipid exhibited superior retention of both a neutrally and positively charged drug (up to an ∼9-fold decrease in the rate of drug leakage) compared to liposomes formed from a commercial diacyl lipid, while exhibiting a similar retention of a negatively charged drug that did not appreciably leak from either type of liposome. We also demonstrate that liposomes made of the archaea-inspired lipid can be used for the delivery of encapsulated small molecules into living cells.

The polycyclisation of polyenynes catalyzed by gold(i) has been extended for the first time to the simultaneous formation of up to four carbon–carbon bonds, leading to steroid-like molecules with high stereoselectivity in a single step with low catalyst loadings. In addition to terminal alkynes, bromoalkynes can also be used as initiators of polyene cyclisations, giving rise to synthetically useful cyclic bromoalkenes.

Copper-catalyzed C–O bond cleavage and cyclization: synthesis of indazolo[3,2-b]quinazolinones by Rui Qiao; Leping Ye; Kun Hu; Shuling Yu; Weiguang Yang; Miaochang Liu; Jiuxi Chen; Jinchang Ding; Huayue Wu (2168-2173).
The first example of a copper-catalyzed halogen-free protocol to construct indazolo[3,2-b]quinazolinones was developed through sequential inert C–O bond cleavage followed by intramolecular C–N bond formation. This protocol represents an efficient synthetic tool for accessing a more diverse range of functionalized indazolo[3,2-b]quinazolinones. The structure of the newly synthesized indazolo[3,2-b]quinazolinones was unambiguously confirmed by X-ray crystal diffraction analysis.

The evaluation of 5-amino- and 5-hydroxyuracil derivatives as potential quadruplex-forming agents by Gábor Paragi; Zoltán Kupihár; Gábor Endre; Célia Fonseca Guerra; Lajos Kovács (2174-2184).
5-Substituted uracils (NH2 or OH groups in position 5) have been examined theoretically and experimentally as potential building blocks in quadruplex structures. Our high level Density Functional Theory (DFT) calculations showed that the tetramer formation and stacking energies for 5-substituted uracils are similar to the energies of purine-based xanthine (X) or guanine (G) structures. As tetrads of 5-substituted uracils cover almost exactly the same area as purine tetrads, mixed tetrads or quadruplex structures based on X or G and 5-substituted uracil motifs are possible. According to the calculations, 5-hydroxyuracil-based structures are the best candidates for experimental implementation which was corroborated by the existence of higher complexes in the mass spectra of 1-benzyl-5-hydroxyuracil. These pyrimidine-based molecules can be used as efficient building blocks in different applications including aptamers, bio-sensors or – taking into account the larger cavity in the central region of 5-hydroxyuracil structures – as an artificial ion channel.

Mg(OMe)2 promoted allylic isomerization of γ-hydroxy-α,β-alkenoic esters to synthesize γ-ketone esters by Luhao Lai; A-Ni Li; Jiawei Zhou; Yarong Guo; Li Lin; Wei Chen; Rui Wang (2185-2190).
This work concerns the Mg(OMe)2 promoted allylic isomerization of γ-hydroxy-α,β-alkenoic esters with TMEDA as an additive. The isomerization proceeded under mild conditions and afforded γ-keto esters in high yield (up to 96%) within 2 h. Both (Z)- and (E)-γ-hydroxy-α,β-alkenoic esters were tolerated under the reaction conditions. This transformation involves the in situ formation of a dienolate intermediate from the easily accessible γ-hydroxy-α,β-alkenoic ester. The in situ generated dienolate can react with benzaldehyde and undergo a practical, useful tandem allylic isomerization-Aldol reaction to afford more functionalized compounds.

A photo-degradable supramolecular hydrogel for selective delivery of microRNA into 3D-cultured cells by Zhengquan Zhou; Qikun Yi; Tingting Xia; Wencui Yin; Adnan A. Kadi; Jinbo Li; Yan Zhang (2191-2198).
Multi-functional supramolecular hydrogels have emerged as smart biomaterials for diverse biomedical applications. Here we report a multi-functional supramolecular hydrogel formed by the conjugate of the bioactive GRGDS peptide with biaryltetrazole that is the substrate of photo-click reaction. The hydrogel was used as a biocompatible matrix to encapsulate live cells for 3D culture. The presence of the RGD epitope in the hydrogelator enhanced the interaction of the nanofiber with integrin over-expressing cells, which resulted in the selective enhancement in the miRNA delivery into the encapsulated U87 cells. The intramolecular photo-click reaction of the biaryltetrazole moiety in the hydrogelator leads to a sensitive photo-response of the hydrogel, which allowed photo-degradation of the hydrogel for release of the encapsulated live cells for further bio-assay of the intracellular species.

Intramolecular Minisci acylation under silver-free neutral conditions for the synthesis of azafluorenones and fluorenones by Joydev K. Laha; Ketul V. Patel; Gurudutt Dubey; Krupal P. Jethava (2199-2210).
Despite its synthetic potential, intramolecular acylation by the Minisci reaction remains unexplored. The development of a new intramolecular Minisci acylation under silver-free neutral conditions providing access to azafluorenones and fluorenones is described. Distinct from the current literature known approaches for Minisci acylation, the report described herein features a method that: (a) avoids the use of silver that is invariably used in Minisci acylation, (b) does not require any acidic conditions for the activation of pyridines, and (c) shows tolerance to functional groups under neutral conditions.

A 4,5-quinolimide-based fluorescent sensor for the turn-on detection of Cd2+ with live-cell imaging by Yu Zhang; Xiangfeng Guo; Mengmeng Zheng; Rui Yang; Hongming Yang; Lihua Jia; Mengmeng Yang (2211-2216).
A 4,5-quinolimide derivative, BNA, bearing the amide-DPA receptor, was synthesized as a turn-on fluorescent sensor for Cd2+. Under physiological conditions, BNA could distinguish Cd2+ from Zn2+, showing turn-on fluorescence behaviour and an increased fluorescence lifetime. BNA and Cd2+ formed a 1 : 1 stoichiometric complex, and the detection limit was measured to be as low as 11 nM. Furthermore, BNA was utilized for fluorescence imaging of Cd2+ in live cells. To the best of our knowledge, it is the first 4,5-quinolimide-based sensor for the detection of metal ions.

Synthesis of C6′′-modified α-C-GalCer analogues as mouse and human iNKT cell agonists by Joren Guillaume; Toshiyuki Seki; Tine Decruy; Koen Venken; Dirk Elewaut; Moriya Tsuji; Serge Van Calenbergh (2217-2225).
α-GalCer analogues that combine known Th1 polarizing C6′′-modifications with a C-glycosidic linkage were synthesized. We employed a protecting group strategy that allowed the preparation of both saturated and unsaturated derivatives with variable C6′′-substituents. Selected analogues demonstrate promising activity in mice. Interestingly, the introduction of a 6′′-O-pyridinylcarbamoyl substituent to α-C-GalCer restores its antigenicity in human iNKT cells.

Atropisomeric biaryl disulfoxides contain two independent chiral elements. Previously, the (M,S,S)-diastereomer showed very high catalytic activity and selectivity in the Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to α,β-enones whereas the (M,R,R) counterpart – none. Herein, DFT computations on the key transmetallation (turnover-determining) and carborhodation (enantioselectivity-determining) steps of the catalytic cycle show that the (M,S,S)-ligand gives rise to lower reaction barriers for these elementary steps. However, the barriers for the (M,R,R)-ligand are not sufficiently high to explain the lack of reactivity. Hence, this phenomenon is most likely due to the failure of catalyst formation from the ligand and the dimeric Rh precatalyst complex. The hitherto unknown (M,S,R)-ligand shows predicted enantioselectivity similar to the (M,S,S)-ligand as a consequence of lower reaction barriers associated with those isomers whose key features resemble the (M,S,S)-ligand.

N-Acyl sulfonimidamides were synthesized via a Cu-catalyzed double C–H/N–H activation protocol. The imino end of sulfonimidamides was acylated using aldehyde as the acylating agent and t-butyl hydrogen peroxide (TBHP) as the oxidant in acetonitrile (MeCN) at 82 °C. The mild reaction conditions afforded low-to-moderate yields of N-acyl sulfonimidamides with high structural diversity.

Zwitterionic indenylammonium with carbon-centred reactivity towards reversible CO2 binding and catalytic reduction by Yanxin Yang; Linfan Yan; Qinyu Xie; Qiuming Liang; Datong Song (2240-2245).
We report the synthesis and characterization of a zwitterionic indenylammonium compound and its carbon-centred reactivity towards reversible CO2 binding at ambient temperature through its formal insertion into a C–H bond as well as the catalytic hydroboration of CO2 to methanol derivatives.

Thermolysis and radiofluorination of diaryliodonium salts derived from anilines by Ethan J. Linstad; Amy L. Vāvere; Bao Hu; Jayson J. Kempinger; Scott E. Snyder; Stephen G. DiMagno (2246-2252).
Aniline-derived diaryliodonium salts were synthesized and functionalized in good to excellent yields by judicious utilization of electron-withdrawing protecting groups. This simple approach opens another route to radiolabeling amino arenes in relatively complex molecules, such as flutemetamol.

Divergent synthesis from reactions of 2-trifluoromethyl-1,3-conjugated enynes with N-acetylated 2-aminomalonates by Jieru Yang; Xiaofan Zhou; Yu Zeng; Chaoqian Huang; Yuanjing Xiao; Junliang Zhang (2253-2258).
A simple base mediated reaction of 2-trifluoromethyl-1,3-conjugated enynes with N-acetylated 2-aminomalonates was developed, which could deliver two distinct types of products depending on substrates, i.e. 4-trifluoromethyl pyrrolidine derivatives, or gem-difluoro-1,3-conjugated enyne derivatives. Various functionalized 4-(difluoromethylene)-1,2,3,4-tetrahydropyridines could be obtained in good yields via the gold(i)-catalysed 6-endo-dig cyclization of the corresponding gem-difluoro-1,3-conjugated enynes under mild conditions.

Copper-catalyzed aerobic oxidative coupling of o-phenylenediamines with 2-aryl/heteroarylethylamines: direct access to construct quinoxalines by Kovuru Gopalaiah; Anupama Saini; Sankala Naga Chandrudu; Devarapalli Chenna Rao; Harsh Yadav; Binay Kumar (2259-2268).
A copper-catalyzed oxidative coupling reaction of o-phenylenediamines with 2-aryl/heteroarylethylamines using molecular oxygen as an oxidant has been developed. This approach provides a practical and direct access to construct quinoxalines in excellent yields at room temperature. The reaction has a broad substrate scope and exhibits excellent functional-group tolerance. This method could be easily scaled up and applied to the synthesis of biologically active molecules bearing a quinoxaline structural scaffold.

Back cover (2269-2270).