Organic & Biomolecular Chemistry (v.11, #22)

Front cover (3575-3575).

Inside front cover (3576-3576).

Contents list (3577-3582).

Transition metal-catalyzed functionalization of pyrazines by Nicolai I. Nikishkin; Jurriaan Huskens; Willem Verboom (3583-3602).
Transition metal-catalyzed reactions are generally used for carbon–carbon bond formation on pyrazines and include, but are not limited to, classical palladium-catalyzed reactions like Sonogashira, Heck, Suzuki, and Stille reactions. Also a few examples of carbon–heteroatom bond formation in pyrazines are known. This perspective reviews recent progress in the field of transition metal-catalyzed cross-coupling reactions on pyrazine systems. It deals with the most important C–C- and C–X-bond formation methodologies.

A novel domino strategy for forming poly-substituted quaternary imidazoles through a Cs2CO3-promoted aryl migration process by Hai-Wei Xu; Wei Fan; Meng-Yuan Li; Bo Jiang; Shu-Liang Wang; Shu-Jiang Tu (3603-3607).
A new domino strategy for the synthesis of highly functionalized quaternary imidazole derivatives via [3 + 2] heterocyclization, involving aryl migration and ring-opening of oxirane, has been developed. This domino reaction enables the successful assembly of three new sigma bonds including two C–N bonds in a simple operation. Features of this strategy include the mild conditions, convenient operation, and short reaction periods (15–20 min).

A new sequential organocatalytic method for the synthesis of chiral 3-substituted (X = OH, NH2) tetrahydroquinoline derivatives (THQs) [ee up to 99%, yield up to 87%] based on α-aminooxylation or -amination followed by reductive cyclization of o-nitrohydrocinnamaldehydes has been described. This methodology has been efficiently demonstrated in the synthesis of two important bioactive molecules namely (−)-sumanirole (96% ee) and 1-[(S)-3-(dimethylamino)-3,4-dihydro-6,7-dimethoxy-quinolin-1(2H)-yl]propanone (92% ee).

Catalyst-controlled switchable phosphination of α-diazoesters by Honglai Jiang; Hongming Jin; Ablimit Abdukader; Aijun Lin; Yixiang Cheng; Chengjian Zhu (3612-3615).
Organocatalyst and metal provide different products: a catalyst-controlled switchable phosphination of α-diazoesters has been developed by using DBU and copper as catalysts. It provided an efficient synthetic method for the construction of various phosphorus compounds via the formation of N–P and C–P bonds.

Reaction of known meso-tetraarylporpholactone free bases 3, made from the corresponding porphyrins, with hydrazine produces three products: It converts the lactone functional group into an N-aminolactam moiety, generating porphyrin-like N-aminoporpholactams 8. It also reduces regioselectively the β,β′-double bond of the pyrrolic moiety opposite to the imidazolone in both the starting material and the N-aminoporpholactam, thus forming the chlorin-like chlorolactones 7 and N-aminochlorolactams 9. An equivalent set of reaction products is also derived from the reaction of porpholactones 3 with tosylhydrazide. Reductive N–N cleavage of the N-aminoporpholactams 8 generated the parent porpholactams 10. The molecular structures of all key compounds were shown by single crystal X-ray diffraction to be essentially planar. Porpholactam 10a can be converted in two steps (enolization and halogenation α to the imine, followed by reductive removal of the halogen) to known imidazoloporphyrin 5a, thus constituting the third independent pathway to replace a β-carbon of a tetraphenylporphyrin by a nitrogen. All these transformations show the flexibility of our ‘porphyrin breaking and mending’ strategy toward the synthesis of novel porphyrin and chlorin analogues incorporating non-pyrrolic heterocycles that carry functionalities at their periphery.

Highly stereoselective directed reactions and an efficient synthesis of azafuranoses from a chiral aziridine by Hogyu Lee; Jun Hee Kim; Won Koo Lee; Jaeheung Cho; Wonwoo Nam; Jaedeok Lee; Hyun-Joon Ha (3629-3634).
Polyhydroxylated pyrrolidines, such as biologically important azafuranoses represented by the natural product (+)-2,5-imino-2,5,6-trideoxy-gulo-heptitol and its C(3)-epimer, were elaborated from a commercially available enantiomerically pure (2R)-hydroxymethylaziridine by highly stereoselective directed reactions in more than 61% overall yield. At first, the nucleophile 2-trimethylsilyloxyfuran was directed to (2R)-aziridine-2-carboxaldehyde by ZnBr2 to yield the unusual anti-addition product as a single isomer via the chelation-controlled transition. The ring opening of aziridine was followed by conjugate addition to give a cis-fused bicycle, which was converted to the target molecule after the required reductive operations.

CAL-B catalyzed desymmetrization of 3-alkylglutarate: “olefin effect” and asymmetric synthesis of pregabalin by Jae-Hoon Jung; Doo-Ha Yoon; Philjun Kang; Won Koo Lee; Heesung Eum; Hyun-Joon Ha (3635-3641).
CAL-B catalyzed desymmetrization of prochiral 3-alkylglutaric acid diesters was performed to prepare optically active 3-alkylglutaric acid monoesters bearing various alkyl substituents, including methyl, ethyl, propyl and allyl groups. Allyl esters showed far better stereoselectivity among the alkyl esters, suggesting possible π–π interactions between the olefin of the substrate and the Trp104 or His224 side chains at the enzyme active site. Based on this reaction, the synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (pregabalin) was achieved with a 70% overall yield.

One-shot preparation of an inherently chiral trifunctional calix[4]arene from an easily available cone-triformylcalix[4]arene by Maria Ciaccia; Irene Tosi; Roberta Cacciapaglia; Alessandro Casnati; Laura Baldini; Stefano Di Stefano (3642-3648).
Via selective 1,3-distal intramolecular Cannizzaro disproportionation of an easily available cone-triformylcalix[4]arene, an inherently chiral trifunctional cone-calix[4]arene derivative has been prepared. The presence of three different functional groups (–CH2OH, –CHO and –COOH) at the upper rim of the calixarene scaffold makes this compound a versatile intermediate for the development of multifunctional devices. Interesting chiral discrimination of serine derivatives has been observed, presumably thanks to a multipoint-interaction involving the reversible imine bond formation and the hydrogen bonding of the hydroxyl group of the amino acid side-chain with the upper rim functional groups. Consistently, chiral discrimination was not observed with alanine and valine derivatives, lacking hydrogen bonding groups on the side-chain.

A novel approach towards the synthesis of α-ketoamides using tertiary amines as nitrogen group sources via C–N bond cleavage has been developed. In the presence of Ag2CO3 and K2S2O8, α-keto acids reacted with tertiary amines to afford the corresponding α-ketoamides in good yields.

A new green protocol for the efficient synthesis of pharmacologically relevant 4-amidyl-2-methyl-1,2,3,4-tetrahydroquinolines (THQs) through the domino type ABB′ imino Diels–Alder reaction in acidified water in the presence of sodium dodecyl sulphate (SDS) surfactant was developed for the first time. The influence of the SDS micelles and their different concentrations (5.0, 8.2 and 12.0 mM) on reactivity of the imino Diels–Alder reaction was studied. It was found that the best THQ yields (70–99%) are achieved above the critical micellar concentration (12 mM) using pH 1.0–2.5. This procedure resulted in a general and clean environmentally benign protocol to obtain the privileged diastereospecific cis 2,4-disubstituted THQ molecules of highest biological interest.

An efficient coupling of N-tosylhydrazones with 2-halopyridines: synthesis of 2-α-styrylpyridines endowed with antitumor activity by Marie Lawson; Abdallah Hamze; Jean-François Peyrat; Jérôme Bignon; Joelle Dubois; Jean-Daniel Brion; Mouad Alami (3664-3673).
The synthesis of 2-α-styrylpyridines has been carried out by using the coupling of polyoxygenated N-tosylhydrazones with various 2-halopyridines. We demonstrated that the use of a catalytic amount of PdCl2(MeCN)2 in combination with a bidentate ferrocene DPPF or a monodentate alkyl phosphine tBu2MeP-HBF4 constitutes an efficient protocol for this coupling, providing 2-α-styrylpyridines 2 in satisfactory to good yields. Among several polyoxygenated derivatives 2 evaluated, compound 2aa was found to exhibit excellent antiproliferative and antimitotic activities comparable to that of the reference compound isoCA-4.

4-Phenol diazonium salts undergo Pd-catalyzed Heck reactions with various styrenes to 4′-hydroxy stilbenes. In almost all cases higher yields and fewer side products were observed, compared to the analogous 4-methoxy benzene diazonium salts. In contrast, the reaction fails completely with 2- and 3-phenol diazonium salts. For these substitution patterns the methoxy-substituted derivatives are superior.

Four-component assembly in the crystalline state driven by amidinium–carboxylate salt bridge formation from an aqueous solution by Takahiro Kusukawa; Kazuya Matsumoto; Hajime Nakamura; Wataru Iizuka; Keisuke Toyama; Shota Takeshita (3692-3698).
A series of diamidine dihydrochlorides was prepared utilizing a spacer unit to control the distance between the two amidinium groups. The introduction of two amidinium groups to the 1,8-position of each spacer unit (i.e., 9,10-dihydroanthracene, anthracene, biphenylene) can control the direction of formation of a self-assembled structure. The fine-tuning of the distances between the two amidinium groups in the spacer units can help control the stabilizing interactions of two carboxylic acid units (intermolecular attraction) after the four-component assembly (see Scheme 1). Based on this concept, we succeeded in the formation of a four-component box-like assembled structure using amidinium–carboxylate salt bridge formation in the crystalline state from aqueous solutions.

Regioselective di- and tetra-functionalisation of γ-cyclodextrin using capping methodology by Matthieu Jouffroy; Dominique Armspach; Dominique Matt; Loïc Toupet (3699-3705).
Alkylation of γ-cyclodextrin with 3 equiv. of 1,3-bis[bis(4-tert-butylphenyl)chloromethyl]benzene, followed by permethylation afforded selectively a singly capped (A,B), as well as two doubly capped (A,B:D,E and A,B:E,F) methylated γ-CDs. Deprotection with HBF4 gave quantitatively the corresponding diols and tetrols, which constitute valuable starting compounds for further functionalisation.

Structural modifications of (Z)-3-(2-aminoethyl)-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione that improve selectivity for inhibiting the proliferation of melanoma cells containing active ERK signaling by Kwan-Young Jung; Ramin Samadani; Jay Chauhan; Kerrick Nevels; Jeremy L. Yap; Jun Zhang; Shilpa Worlikar; Maryanna E. Lanning; Lijia Chen; Mary Ensey; Sagar Shukla; Rosene Salmo; Geoffrey Heinzl; Caryn Gordon; Troy Dukes; Alexander D. MacKerell, Jr.; Paul Shapiro; Steven Fletcher (3706-3732).
We herein report on the pharmacophore determination of the ERK docking domain inhibitor (Z)-3-(2-aminoethyl)-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione, which has led to the discovery of compounds with greater selectivities for inhibiting the proliferation of melanoma cells containing active ERK signaling.

Theoretical investigation of the Diels–Alder reactions of unsaturated boronates by Nicolás Grimblat; Silvina C. Pellegrinet (3733-3741).
The Diels–Alder reactions of simple unsaturated boronates have been investigated using computational methods and the results were compared with those for the analogue dihalo- and dialkylboranes. Our results indicate that the activating effect of the boronate moiety is small. All the studied reactions are concerted normal electron-demand Diels–Alder reactions with asynchronous transition structures and weak [4 + 3] C–B secondary orbital interactions, which explains the low experimental reactivity. Both electronic and steric effects contribute to give the observed low stereo- and regioselectivities.

Design and synthesis of tryptophan containing dipeptide derivatives as formyl peptide receptor 1 antagonist by Tsong-Long Hwang; Chih-Hao Hung; Ching-Yun Hsu; Yin-Ting Huang; Yu-Chi Tsai; Pei-Wen Hsieh (3742-3755).
Our previous studies identified an Fmoc-(S,R)-tryptophan-containing dipeptide derivative, 1, which selectively inhibited neutrophil elastase release induced by formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP) in human neutrophils. In an attempt to improve pharmacological activity, a series of tryptophan-containing dipeptides were synthesized and their pharmacological activities were investigated in human neutrophils. Of these, five compounds 3, 6, 19a, 24a, and 24b exhibited potent and dual inhibitory effects on FMLP-induced superoxide anion (O2˙) generation and neutrophil elastase release in neutrophils with IC50 values of 0.23/0.60, 1.88/2.47, 1.87/3.60, 0.12/0.37, and 1.32/1.03 μM, respectively. Further studies indicated that inhibition of superoxide production in human neutrophils by these dipeptides was associated with the selective inhibition of formyl peptide receptor 1 (FPR1). Furthermore, the results of structure–activity relationship studies concluded that the fragment N-benzoyl-Trp-Phe-OMe (3) was most suitable as a core structure for interaction with FPR1, and may be approved as a lead for the development of new drugs in the treatment of neutrophilic inflammatory diseases. As some of the synthesized compounds exhibited separable conformational isomers, and showed diverse bioactivities, the conformation analysis of these compounds is also discussed herein.

The syntheses and physicochemical properties for a series of 2,6-disubstituted-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dyes are reported. The use of chromophores or redox active species as π-spacers, such as BODIPY, requires the inclusion of a sufficiently conjugated donor in order to achieve appropriate charge separation upon photoexcitation. The information derived from this study offers guiding principles for incorporating strongly absorbing, non-innocentπ-spacers in organic dye design.

Back cover (3761-3762).