Organic & Biomolecular Chemistry (v.17, #48)

Front cover (10111-10112).

Contents list (10113-10118).

Recent advances in cobalt-catalysed C–H functionalizations by Alessio Baccalini; Stefania Vergura; Pravas Dolui; Giuseppe Zanoni; Debabrata Maiti (10119-10141).
Ready availability, low cost and low toxicity of cobalt salts have redirected the attention of researchers away from noble metals, such as Pd, Rh, and Ir, towards Co in the field of C–H functionalization. In this context, the examples of Co-catalysed functionalization have exponentially grown over the last few decades. This present review focuses on the most recent developments on Co-catalysed C(sp2)–H and C(sp3)–H functionalizations. Included is also a comprehensive overview of enantioselective transformations.

Rhodium-catalyzed transfer hydrogenation of quinoxalines with water as a hydrogen source by Xia Zhang; Jingchao Chen; Ruhima Khan; Guoli Shen; Zhenxiu He; Yongyun Zhou; Baomin Fan (10142-10147).
Rhodium-catalyzed transfer hydrogenation of quinoxalines with water as a hydrogen source was reported. The reaction allowed the simple preparation of tetrahydroquinoxalines under mild conditions. The deuterium-labelling experiment confirmed that water is the sole hydrogen source in the transfer hydrogenation reaction.

Total chemical synthesis of murine ISG15 and an activity-based probe with physiological binding properties by Bo-Tao Xin; Jin Gan; Daniel J. Fernandez; Klaus-Peter Knobeloch; Paul P. Geurink; Huib Ovaa (10148-10152).
The linear synthesis of the N-terminal domain of mISG15 has been developed which enables the synthesis of full-length mISG15 and the activity-based probe Rho-mISG15-PA via native chemical ligation. Pilot experiments showed that the synthetic proteins were properly folded and recognized by endogenous enzymes. Our synthesis strategy allows the generation of other mISG15-based probes and reagents that can accelerate the research in this field.

An unprecedented direct C–C coupling reaction of unprotected primary amines with active methylene compounds is reported. The reaction involves a biomimetic deamination of amines which was achieved under conditions free of metallic reagents and strong oxidizing agents. A wide range of primary amines was reacted with different active methylene compounds to provide structurally diverse trisubstituted alkenes and dihydropyridines. A kinetic study revealed an activation barrier of 10.1 kcal mol−1 for the conversion of a key intermediate of the reaction.

Diastereoselective construction of 3-aryl-substituted indolines via annulation of in situ generated p-quinone methides by Junwei Wang; Xiang Pan; Lei Zhao; Lin Zhao; Jian Liu; Ying Zhi; Ai Wang; Kun Zhao; Lihong Hu (10158-10162).
A highly diastereoselective [4 + 1] annulation reaction of in situ generated p-quinone methides for the synthesis of 3-aryl-substituted indolines has been developed. Employing commercial manganese dioxide as the oxidant, a series of ortho-tosylaminophenyl-substituted p-QMs could be generated in situ. This new protocol is based on an unprecedented 1,6-conjugate addition/annulation cascade reaction, without the need for pre-synthesized p-QMs, and enables the easy preparation of a variety of 3-aryl-2,3-dihydroindoles in good to excellent yields.

Metal-free switchable ortho/ipso-cyclization of N-aryl alkynamides: divergent synthesis of 3-selenyl quinolin-2-ones and azaspiro[4,5]trienones by Harekrishna Sahoo; Gowri Sankar Grandhi; Isai Ramakrishna; Mahiuddin Baidya (10163-10166).
A selenium radical triggered switchable ortho/ipso-cyclization cascade of N-aryl alkynamides has been devised under metal-free conditions to access 3-selenyl quinolin-2-ones and 3-selenospiro[4,5]trienones in high yields (up to 98%). The simple protocol is scalable and the mechanistic studies suggest that the radical cascade proceeds through a spirocyclic intermediate which is formed via an intramolecular ipso-cyclization route.

Manganese-catalyzed cascade annulations of alkyne-tethered N-alkoxyamides: synthesis of polycyclic isoquinolin-1(2H)-ones by Gui-Xian Kong; Jiao-Na Han; Dandan Yang; Jun-Long Niu; Mao-Ping Song (10167-10171).
A strategy for the synthesis of isoxazolidine/1,2-oxazinane-fused isoquinolin-1(2H)-ones from alkyne-tethered N-alkoxyamides is described, in which cheap Mn(acac)2 is used as a catalyst to facilitate a radical cascade annulation. The method features mild conditions, additive-free reaction and broad substrate scope. It is the first example via manganese/air catalytic systems to construct isoquinolin-1(2H)-one heterocycles.

Double C–N bond cleavages of N-alkyl 4-oxopiperidinium salts: access to unsymmetrical tertiary sulfonamides by Ying Fu; Ming-Peng Li; Chun-Zhao Shi; Fang-Rong Li; Zhengyin Du; Congde Huo (10172-10177).
In this paper, regiospecific, double intraannular C–N bond cleavages of N-alkyl 4-oxopiperidinium salts are presented. The reaction sequence involves a charge-transfer complex, in situ formed between sulfonyl chloride and N-methylmorpholine, which induces S–Cl bond homolysis of sulfonyl chloride, yielding a reactive sulfonyl radical that further induces the double C–N bond cleavages of N-alkyl 4-oxopiperidinium salt. The secondary amine thus produced was trapped by sulfonyl chloride to yield the desired sulfonamide product. The key feature of this protocol is that two intraannular C–N bonds of the 4-oxopiperidine ring are cleaved in one step under metal- and oxidant-free conditions.

Transition-metal free C3-amidation of quinoxalin-2(1H)-ones using Selectfluor as a mild oxidant by Jin-Wei Yuan; Jun-Liang Zhu; Bing Li; Liang-Yu Yang; Pu Mao; Shou-Ren Zhang; Yan-Chun Li; Ling-Bo Qu (10178-10187).
A practical and efficient synthetic route to construct a variety of 3-amidated quinoxalin-2(1H)-ones was developed via transition-metal free direct oxidative amidation of quinoxalin-2(1H)-ones with amidates using Selectfluor reagent as a mild oxidant. This protocol features mild reaction conditions, operational simplicity, broad substrate scope, and good to excellent yields.

Synthesis and vitamin D receptor affinity of 16-oxa vitamin D3 analogues by Kouta Ibe; Takeshi Yamada; Sentaro Okamoto (10188-10200).
Two novel 16-oxa-vitamin D3 analogues were synthesized using a tandem Ti(ii)-mediated enyne cyclization/Cu-catalyzed allylation, Ru-catalyzed ring-closing metathesis reaction, and a low-valent titanium (LVT)-mediated stereoselective radical reduction of 8α,14α-epoxide as the key steps for the synthesis of the 16-oxa-C,D ring unit. The vitamin D receptor-binding affinity of the synthesized analogues, 16-oxa-1α,25-(OH)2VD3 and 16-oxa-19-nor-1α,25-(OH)2VD3, was evaluated by fluorescence polarization vitamin D receptor competitor assay and time-resolved fluorescence energy transfer vitamin D receptor co-activator assay.

The visible-light-triggered regioselective alkylation of quinoxalin-2(1H)-ones via decarboxylation coupling by Hongdou Zhang; Jun Xu; Min Zhou; Jianming Zhao; Pengfei Zhang; Wanmei Li (10201-10208).
An efficient protocol to synthesize 3-alkylated quinoxalin-2(1H)-ones through photocatalytic decarboxylation coupling reactions of quinoxalin-2(1H)-ones with N-hydroxyphthalimide ester was developed. The control experiment showed that a radical was involved in this transformation. This approach provides an alternative way to obtain various valuable corresponding products in moderate-to-good yields.

Electronic effects in tautomeric equilibria: the case of chiral imines from d-glucamine and 2-hydroxyacetophenones by Esther Matamoros; Pedro Cintas; Mark E. Light; Juan C. Palacios (10209-10222).
A one-pot procedure for preparing a series of chiral imines by direct condensation of d-glucamine with 2-hydroxyacetophenones is described. Under conventional acetylation an unexpected mixture of two different peracetylated molecules is obtained, one with an open enamine structure, and the other incorporating an N-acetyl-1,3-oxazolidine into the acyclic skeleton. Surprisingly, both molecules coexist within the crystal's unit cell, as inferred from single-crystal X-ray analysis of a 5-bromo-substituted aryl derivative. Moreover, the 1,3-oxazolidine ring exists as rotational conformers (E,Z) owing to the restricted rotation around the N-acetyl bond. The equilibrium involving imine and enamine structures has been assessed in detail, providing in addition linear free-energy relationships between the tautomerization constants (KT) and the electronic effect of the substituents.

Ultrasound accelerated synthesis of O-alkylated hydroximides under solvent- and metal-free conditions by Hongmei Jiang; Xiaoyue Tang; Sihan Liu; Lian Wang; Haicheng Shen; Jiankui Yang; Huixian Wang; Qing-Wen Gui (10223-10227).
A novel, sustainable, environmentally friendly, high substrate scope, efficient, solvent-free and metal catalyst-free method for the cross-dehydrogenative coupling (CDC) reaction between N-hydroxyphthalimide (NHPI) and benzyl/ether compounds is described. This coupling reaction proceeds through ultrasound acceleration. Compared to conventional heating conditions, the use of ultrasound techniques not only improves the reaction efficiency and enhances the reaction rate but also minimizes the side reactions.

A trimethyllysine-containing trityl tag for solubilizing hydrophobic peptides by Shun Masuda; Shugo Tsuda; Taku Yoshiya (10228-10236).
Hydrophobic membrane peptides/proteins having low water solubility are often difficult to prepare. To overcome this issue, temporal introduction of solubilizing tags has been demonstrated to be beneficial. Following our recent work on the solubilization of a difficult target by using a hydrophilic oligo-Lys tag bearing a trityl linker (Trt-K method), this paper describes a comparative study of the solubilizing abilities of several peptidic trityl tags containing Lys, Arg, Glu, Asn, Nε-tri-Me-Lys or Cys-sulfonate using two hydrophobic model peptides. Among the tags evaluated, that containing Nε-tri-Me-Lys exhibits superior solubilizing ability.

Chemical synthesis of Shiga toxin subunit B using a next-generation traceless “helping hand” solubilizing tag by James M. Fulcher; Mark E. Petersen; Riley J. Giesler; Zachary S. Cruz; Debra M. Eckert; J. Nicholas Francis; Eric M. Kawamoto; Michael T. Jacobsen; Michael S. Kay (10237-10244).
The application of solid-phase peptide synthesis and native chemical ligation in chemical protein synthesis (CPS) has enabled access to synthetic proteins that cannot be produced recombinantly, such as site-specific post-translationally modified or mirror-image proteins (D-proteins). However, CPS is commonly hampered by aggregation and insolubility of peptide segments and assembly intermediates. Installation of a solubilizing tag consisting of basic Lys or Arg amino acids can overcome these issues. Through the introduction of a traceless cleavable linker, the solubilizing tag can be selectively removed to generate native peptide. Here we describe the synthesis of a next-generation amine-reactive linker N-Fmoc-2-(7-amino-1-hydroxyheptylidene)-5,5-dimethylcyclohexane-1,3-dione (Fmoc-Ddap-OH) that can be used to selectively introduce semi-permanent solubilizing tags (“helping hands”) onto Lys side chains of difficult peptides. This linker has improved stability compared to its predecessor, a property that can increase yields for multi-step syntheses with longer handling times. We also introduce a new linker cleavage protocol using hydroxylamine that greatly accelerates removal of the linker. The utility of this linker in CPS was demonstrated by the preparation of the synthetically challenging Shiga toxin subunit B (StxB) protein. This robust and easy-to-use linker is a valuable addition to the CPS toolbox for the production of challenging synthetic proteins.

An atom-economical and regioselective metal-free C-5 chalcogenation of 8-aminoquinolines under mild conditions by Vipin Kumar; Klaus Banert; Devalina Ray; Biswajit Saha (10245-10250).
A general and simple metal-free protocol for expedient C–H functionalization leading to the regioselective generation of C-5 chalcogenated 8-aminoquinoline analogues in up to 90% yield at room temperature (25 °C) has been established. This methodology is an eco-friendly approach to the atom-economical utilization of diaryl/dialkyl chalcogenides for direct access to chalcogenated quinolines and is scalable to the gram scale without considerable decrease in the yield of the product. It represents a practical alternative to the existing metal-catalyzed functionalization of 8-aminoquinoline derivatives with broad functional group tolerance. The controlled experiments suggest that the reaction possibly proceeds through an ionic pathway at room temperature. Furthermore, the potentiality for the functionalization of free amines in chalcogenated-8-aminoquinolines provides an attractive perspective for further elaboration of the amine substituent through chemical manipulations. The applicability of the standardized method has been augmented through late-stage antimalarial drug diversification of primaquine analogues.

Back cover (10251-10252).