Organic & Biomolecular Chemistry (v.15, #16)

Front cover (3355-3355).

Inside front cover (3356-3356).

Contents list (3357-3363).

New mechanistic interpretations for nitrone reactivity by Pedro Merino; Tomás Tejero; Ignacio Delso; Rosa Matute (3364-3375).
The reactivity of nitrones in cycloadditions and related reactions is revisited by introducing a topological perspective. In particular, the study of electron localization function (ELF) along a reaction pathway allows evaluating bond reorganization showing that in several cases the bonds are formed in a sequential way, the second one being formed once the first one is already formed. Both classical 1,3-dipolar cycloadditions and Mannich-type reactions revealed unexpected features often underestimated in classical mechanistic studies.

Thiopeptide antibiotics are a class of typical ribosomally synthesized and post-translationally modified peptides (RiPPs) with complex chemical structures that are difficult to construct via chemical synthesis. To date, more than 100 thiopeptides have been discovered, and most of these compounds exhibit remarkable biological activities, such as antibacterial, antitumor and immunosuppressive activities. Therefore, studies of the biosynthesis of thiopeptides can contribute to the development of new drug leads and facilitate the understanding of the complex post-translational modifications (PTMs) of peptides and/or proteins. Since the biosynthetic gene clusters of thiopeptides were first discovered in 2009, several research studies regarding the biochemistry and enzymology of thiopeptide biosyntheses have been reported, indicating that their characteristic framework is constructed via a cascade of common PTMs and that additional specific PTMs diversify the molecules. In this review, we primarily summarize recent advances in understanding the biosynthesis of thiopeptide antibiotics and propose some potential applications based on our insights into the biosynthetic logic and machinery.

JA-Ile-macrolactones uncouple growth and defense in wild tobacco by Guillermo H. Jimenez-Aleman; Ricardo A. R. Machado; Ian T. Baldwin; Wilhelm Boland (3391-3395).
Small molecules capable of uncoupling growth-defense in plants are currently not known. In this study, for the first time, semi-synthetic analogues of the phytohormone JA-Ile are employed to uncouple growth and defense responses in wild tobacco. The JA-Ile analogues are easily synthesized from inexpensive substrates via olefin metathesis.

Post-synthetic modification of tryptophan containing peptides via NIS mediation by Chen-Xue Gu; Qing-Wei Bi; Chu-Kun Gao; Jian Wen; Zhi-Gang Zhao; Zili Chen (3396-3400).
A new efficient method was developed to provide modified tryptophan peptides through NIS (N-iodosuccinimide) mediated N2-selective coupling of a Trp unit with 1,2,3-triazoles, of which, the preliminary spectral properties were also studied.

A useful enantioselective Friedel–Crafts reaction of 3,5-dimethoxylphenol with nitroolefins catalyzed by a bifunctional quinine derived thiourea catalyst 9 was developed. The Michael addition products could be obtained in good to high yields (68–92%) and with excellent enantioselectivities (89–98% ee). Such a reaction is exceptionally attractive in virtue of its simple protocol, ready availability of the starting materials, and practical applications of the products.

A concise and enantioselective synthesis of the tetracyclic indoles, including the naturally occurring compounds (+)-arborescidine C and (+)-arborescidine B, was achieved by the key step of Pictet–Spengler cyclization reaction with a Jacobsen-type thiourea organocatalyst. The synthetic process was further demonstrated in a pot-economy strategy and was achieved in a one-pot operation.

Oxadiazolones are first employed as the three-atom coupling partners in the Tf2NH-catalyzed cycloaddition with ynamides. This formal [3 + 2] cycloaddition allows a rapid synthesis of aminoimidazoles with a broad substrate scope. The approach also features a metal-free catalytic cycloaddition process, which may find applications in the synthesis of bioactive molecules. Besides, the resulting N-methyl products can further be readily converted to free N–H aminoimidazoles.

A transition-metal-free lithiation–borylation method has been developed to access a variety of 1,1-diboronate esters with a fully substituted benzylic center from readily available secondary benzylic N,N-diisopropyl carbamates. The method is applicable to scale-up synthesis of 1,1-diboron compounds. Furthermore, the current method is also applicable to synthesizing optically active 1,1-silylboronate esters.

The concise synthesis of 2,3-dihydro-4H-benzo[e][1,3]oxazin-4-ones has been accomplished by copper-catalyzed tandem reactions of o-halobenzamides, LiOH and dichloromethane. The aryl–halogen bond hydroxylation and subsequent N,O-acetalization on CH2Cl2 are enabled under catalytic conditions which allows the generation of C(sp2)–O, C(sp3)–O and C(sp3)–N bonds to give the target products.

nBu4NI-Mediated oxidation of methyl ketones to α-ketoamides: using ammonium, primary and secondary amine-salt as an amine moiety by Dan Wang; Kuan Zhang; Luhan Jia; Danting Zhang; Yue Zhang; Yujia Cheng; Chang Lin; Bo Wang (3427-3434).
Presented here is the first example of synthesizing an array of primary-, secondary-, and tertiary-α-ketoamides with a non-metal catalyst nBu4NI from methyl ketones and inexpensive readily available amine/ammonium salts; the reactions proceeded smoothly under mild conditions, TBHP was used as an oxidant and the corresponding α-ketoamides were afforded in moderate to excellent yields.

Syntheses and kinetic studies of cyclisation-based self-immolative spacers by Steve Huvelle; Ahmed Alouane; Thomas Le Saux; Ludovic Jullien; Frédéric Schmidt (3435-3443).
Kinetic analysis of the disassembly of self-immolative spacers based on cyclisation processes was performed. Five compounds were synthesized belonging to two different series, and their kinetic constants were determined. Electron-donating substituents gave a slight acceleration but the main effect was steric, and the Thorpe–Ingold effect was indeed particularly effective. Comparison with the self-immolative spacers based on elimination processes showed that cyclisations gave comparable or lower rate, but the corresponding spacers are more difficult to modulate.

Semi-continuous multi-step synthesis of lamivudine by Devender Mandala; Sravanthi Chada; Paul Watts (3444-3454).
We report the first continuous flow synthesis of lamivudine, an antiretroviral drug used in the treatment of HIV/AIDS and hepatitis B. The key intermediate (5-acetoxy oxathiolane) was prepared by an integrated two step continuous flow process from l-menthyl glyoxalate hydrate in a single solvent, in 95% overall conversion. For the crucial glycosidation reaction, using pyridinium triflate as the novel catalyst, an improved conversion of 95% was obtained. The overall isolated yield of the desired isomer of lamivudine (40%) was improved in the flow synthesis compared to the batch process.

Rational design, synthesis, and biological evaluation of Pan-Raf inhibitors to overcome resistance by Lu Wang; Gaoyuan Zhu; Qing Zhang; Chunqi Duan; Yanmin Zhang; Zhimin Zhang; Yujun Zhou; Tao Lu; Weifang Tang (3455-3465).
Selective BRafV600E inhibitors with DFG-in conformation have been proven effective against a subset of melanoma. However, representative inhibitor vemurafenib rapidly acquires resistance in the BRafWT cells through a CRaf or BRafWT dependent manner. Simultaneous targeting of all subtypes of Raf proteins offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Herein, we describe the design and characterization of a series of compounds I-01–I-22, based on a pyrimidine scaffold with DFG-out conformation as Pan-Raf inhibitors. Among them, I-15 binds to all Raf protomers with IC50 values of 12.6 nM (BRafV600E), 30.1 nM (ARaf), 19.7 nM (BRafWT) and 17.5 nM (CRaf) and demonstrates cellular activity against BRafWT phenotypic melanoma and BRafV600E phenotypic colorectal cancer cells. The western blot results for the P-Erk inhibition in human melanoma SK-Mel-2 cell line showed that I-15 inhibited the proliferation of the SK-Mel-2 cell line at concentrations as low as 400 nM, without paradoxical activation of Erk as vemurafenib, which supported that I-15 may become a good candidate compound to overcome the resistance of melanoma induced by vemurafenib. I-15 also has a favorable pharmacokinetic profile in rats. Rational design, synthesis, SAR, lead selection and evaluation of the key compounds studied are described.

Acceptorless dehydrogenation and dehydrogenative coupling of alcohols catalysed by protic NHC ruthenium complexes by Weihong Chang; Xue Gong; Shuizhong Wang; Ling-Ping Xiao; Guoyong Song (3466-3471).
A new family of protic NHC Ru complexes ligated with a phosphine-tethered imidazole moiety were prepared, which can act as excellent catalysts for acceptorless dehydrogenation of secondary alcohols and dehydrogenative coupling of primary and secondary alcohols, thus leading to the formation of a variety of carbonyl compounds with release of H2.

A formal intermolecular [4 + 2] cycloaddition reaction of 1,3-disubstituted indoles and alkylquinones by Chao Lin; Hong-Jin Du; Hui Zhao; Ding-Fei Yan; Nai-Xin Liu; Hongbin Sun; Xiaoan Wen; Qing-Long Xu (3472-3478).
A formal [4 + 2] cycloaddition reaction of 1,3-disubstituted indoles and alkylquinones was realized to furnish polycyclic indolines in good yields. This protocol proceeded smoothly under basic conditions, with high atom-economy and broad substrate scope.

Mechanistic model for the firefly luciferin regeneration in biomimetic conditions: a model for the in vivo process? by Carla T. Salatino; Diêgo U. Melo; Ariane M. Yoshitake; Lucas S. Sgarbi; Paula Homem-de-Mello; Fernando H. Bartoloni; Luiz F. M. L. Ciscato (3479-3484).
The emission of light by fireflies involves the enzymatic oxidation of firefly luciferin and ends up in the formation of 2-cyano-6-hydroxybenzothiazole, and this is recycled back to luciferin by condensation with cysteine. In this work, we suggest a mechanism for this transformation that operates under mild conditions that are similar to in vivo environments (i.e. biomimetic); the rate-determining step consists of an intermolecular nucleophilic attack from the cysteine thiolate on the nitrile, catalysed by a specific base, followed by a complex sequence of intramolecular reactions which are highly dependent on the medium pH.

ZnBr2-Mediated oxidative spiro-bromocyclization of N-arylpropiolamide has been described herein for the synthesis of 3-bromo-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione with high efficiency. One equivalent of water was introduced into the final product. The reaction efficiently proceeded at room temperature, and an excellent tolerance of functional groups was demonstrated. Under standard conditions, 3-bromo-1-oxaspiro[4.5]deca-3,6,9-triene-2,8-dione and 3-bromo-1-azaspiro[4.5]deca-3,6,9-trien-8-one were synthesized.

An inexpensive Ru(ii) complex catalyzes the oxidative annulation reaction of disubstituted alkynes with benzamidines to provide highly valuable 1-aminoisoquinolines in high yields. The reaction also features excellent regioselectivity with some unsymmetrical alkynes.

Palladium-catalyzed C–H olefination of uracils and caffeines using molecular oxygen as the sole oxidant by Xinyu Zhang; Lv Su; Lin Qiu; Zhenwei Fan; Xiaofeng Zhang; Shen Lin; Qiufeng Huang (3499-3506).
The palladium-catalyzed oxidative C–H olefination of uracils or caffeines with alkenes using an atmospheric pressure of molecular oxygen as the sole oxidant has been disclosed. This novel strategy offers an efficient and environmentally friendly method to biologically important C5-alkene uracil derivatives or C8-alkene caffeine derivatives.

Amidation of unactivated ester derivatives mediated by trifluoroethanol by Christopher G. McPherson; Nicola Caldwell; Craig Jamieson; Iain Simpson; Allan J. B. Watson (3507-3518).
A catalytic amidation protocol mediated by 2,2,2-trifluoroethanol has been developed, facilitating the condensation of unactivated esters and amines, furnishing both secondary and tertiary amides. The complete scope and limitations of the method are described, along with modified conditions for challenging substrates such as acyclic secondary amines and chiral esters with retention of chiral integrity.

Synthesis and conformations of [2.n]metacyclophan-1-ene epoxides and their conversion to [n.1]metacyclophanes by Thamina Akther; Md. Monarul Islam; Shofiur Rahman; Paris E. Georghiou; Taisuke Matsumoto; Junji Tanaka; Carl Redshaw; Takehiko Yamato (3519-3527).
A series of syn- and anti-[2.n]metacyclophan-1-enes have been prepared in good yields by McMurry cyclizations of 1,n-bis(5-tert-butyl-3-formyl-2-methoxyphenyl)alkanes. Significantly, acid catalyzed rearrangements of [2.n]metacyclophan-1-enes afforded [n.1]metacyclophanes in good yield. The ratios of the products are strongly regulated by the number of methylene bridges present. The percentages of the rearrangement products increase with increasing length of the carbon bridges. Characterization and the conformational studies of these products are described. Single crystal X-ray analysis revealed the adoption of syn- and anti-conformations. DFT calculations were carried out to estimate the energy-minimized structures of the synthesized metacyclophanes.

Back cover (3529-3530).