Organic & Biomolecular Chemistry (v.15, #14)

Front cover (2859-2860).

Contents list (2861-2868).

The enzymatic polycyclization reactions catalyzed by oxidosqualene (OXSQ) cyclases (OSCs) proceed with complete regio- and stereospecificity, leading to the formation of new C–C bonds and chiral centers and to the generation of diverse polycyclic sterols and triterpenoids. The diverse structural array is remarkable, and approximately 150 different carbon frameworks have been found. Detailed investigations on squalene-hopene cyclase (SHC) and lanosterol synthase (LaS) have been reported, but progress in the study of β-amyrin synthase, which is ubiquitously found in plants, has lagged in comparison. In the past several years, remarkable advances in β-amyrin biosynthetic studies have been made. In this review, the catalytic mechanism and substrate recognition of β-amyrin synthase, as revealed by site-directed mutagenesis and substrate analog experiments, are outlined and compared with those of LaS and SHC to highlight the features of β-amyrin synthase.

A dramatic synergistic effect of a flexible achiral linker on a rigid chiral cis-1,2-diamine bifunctional organocatalyst by Hirofumi Matsunaga; Daisuke Tajima; Tetsuro Kawauchi; Takuro Yasuyama; Shin Ando; Tadao Ishizuka (2892-2896).
The combination of a “rigid” chiral bicyclic cis-1,2-diamine skeleton with steric bulkiness and a “flexible” achiral linker was newly designed as a bifunctional organocatalyst framework and it showed excellent catalytic activity of up to 0.05 mol%, accompanied by the reversal of enantioselection depending on the position of the linker, in an amine-thiourea organocatalyzed asymmetric Michael reaction.

Manganese(iii) acetate catalyzed oxidative amination of benzylic C(sp3)–H bonds with nitriles by Yaxing Zhang; Jianyu Dong; Lixin Liu; Long Liu; Yongbo Zhou; Shuang-Feng Yin (2897-2901).
Mn-Catalyzed oxidative amination of benzylic C(sp3)–H bonds with nitriles is disclosed, which enables the synthesis of a broad range of secondary amides in moderate to excellent yields under mild conditions. The interaction between Mn(iii) and DDQ facilitates the oxidation and makes it highly efficient and selective.

Diazo compounds play an important role as a coupling partner in the synthesis of unique π-conjugated 7-azaindole derivatives via rhodium(iii)-catalyzed double C–H activation/cyclization.

Structurally diverse arene-fused ten-membered lactams accessed via hydrolytic imidazoline ring expansion by Alexander Sapegin; Angelina Osipyan; Mikhail Krasavin (2906-2909).
Imidazoline-fused [1,4]oxazepines (prepared in two simple steps from methyl 2-hydroxyaroates, ethylene diamine and bis-electrophilic aromatics) undergo a facile, good-yielding hydrolytic imidazoline ring expansion (HIRE) upon N-alkylation and treatment with aqueous K2CO3. The resulting arene-fused ten-membered lactams significantly add to the contemporary arsenal of small-molecule scaffolds where medium-sized ring systems are severely underrepresented.

Pd(t-Bu3P)2 has been successfully identified as an efficient catalyst for the hydroaminocarbonylation of aromatic alkenes to branched amides under relatively mild reaction conditions. With hydroxylamine hydrochloride as an additive, both aliphatic and aromatic amines could be used as coupling partners for the present reaction, leading to production of branched amides in high yields with excellent regioselectivities.

Direct palladium-mediated on-resin disulfide formation from Allocam protected peptides by Thilini D. Kondasinghe; Hasina Y. Saraha; Samantha B. Odeesho; Jennifer L. Stockdill (2914-2918).
The synthesis of disulfide-containing polypeptides represents a long-standing challenge in peptide chemistry, and broadly applicable methods for the construction of disulfides are in constant demand. Few strategies exist for on-resin formation of disulfides directly from their protected counterparts. We present herein a novel strategy for the on-resin construction of disulfides directly from Allocam-protected cysteines. Our palladium-mediated approach is mild and uses readily available reagents, requiring no special equipment. No reduced peptide intermediates or S-allylated products are observed, and no residual palladium can be detected in the final products. The utility of this method is demonstrated through the synthesis of the C-carboxy analog of oxytocin.

Metabolism of 2,3-dihydroxypropane-1-sulfonate by marine bacteria by Ersin Celik; Michael Maczka; Nils Bergen; Thorsten Brinkhoff; Stefan Schulz; Jeroen S. Dickschat (2919-2922).
Both enantiomers of the sulfoquinovose breakdown product 2,3-dihydroxypropane-1-sulfonate, an important sulfur metabolite produced by marine algae, were synthesised in a 34S-labelled form and used in feeding experiments with marine bacteria. The labelling was efficiently incorporated into the sulfur-containing antibiotic tropodithietic acid and sulfur volatiles by the algal symbiont Phaeobacter inhibens, but not into sulfur volatiles released by marine bacteria associated with crustaceans. The ecological implications and the relevance of these findings for the global sulfur cycle are discussed.

An attractive and novel methodology involving Pd/Cu-catalyzed tandem head-to-tail dimerization/cycloisomerization of terminal ynamides for the synthesis of 3,5-disubstituted oxazolones was developed. Under Pd(PPh3)2Cl2/CuI cooperative catalyzed reaction conditions, it provided efficient access to 5-vinyloxazolones with exceptional functional group tolerance and good chemoselectivity. The control experiments demonstrated that Pd(PPh3)2Cl2 serves a key role in the dimerization of terminal ynamides and shows low catalytic activity in the intramolecular cyclization. Moreover, the hetero-Diels–Alder reaction of product 5-vinyloxazolones was also described, which provided polycyclic oxazolones in good yield.

A dual removable activating group enabled the Povarov reaction of N-arylalanine esters: synthesis of quinoline-4-carboxylate esters by Xiaodong Jia; Shiwei Lü; Yu Yuan; Xuewen Zhang; Liang Zhang; Liangliang Luo (2931-2937).
A dual removable activating group enabled Povarov reaction of N-arylalanine esters was reported. N-Arylalanine ester was utilized as the sole carbon source to generate N-arylimine and its tautomer, enamine, in situ by aerobic oxidation of sp3 C–H bonds, and then the consecutive reaction delivered the desired quinoline-4-carboxylate esters in high yields.

Ruthenium-catalyzed regioselective allylic amination of 2,3,3-trifluoroallylic carbonates by Shin-ichi Isobe; Shou Terasaki; Taisyun Hanakawa; Shota Mizuno; Motoi Kawatsura (2938-2946).
We demonstrated the ruthenium-catalyzed allylic amination of 2,3,3-trifluoroallylic carbonates with several types of amines. The reactions proceeded with several types of amines, and succeeded in obtaining polyfluorinated terminal alkenes possessing branched allylic amines as a single regioisomer.

Optimisation of the dibromomaleimide (DBM) platform for native antibody conjugation by accelerated post-conjugation hydrolysis by Maurício Morais; João P. M. Nunes; Kersti Karu; Nafsika Forte; Irene Benni; Mark E. B. Smith; Stephen Caddick; Vijay Chudasama; James R. Baker (2947-2952).
Disulfide bridging offers a convenient approach to generate site-selective antibody conjugates from native antibodies. To optimise the reagents available to achieve this strategy, we describe here the use of dibromomaleimides designed to undergo accelerated post-conjugation hydrolysis. Conjugation and hydrolysis, which serve to ‘lock’ the conjugates as robustly stable maleamic acids, is achieved in just over 1 h. This dramatic acceleration is also shown to infer significant improvements in homogeneity, as demonstrated by mass spectrometry analysis.

Enantioselective synthesis of an octahydroindolizine (indolizidine) alcohol using an enzymatic resolution by Jing Zhang; Rao Kolluri; Salvador G. Alvarez; Mark M. Irving; Rajinder Singh; Matthew A. J. Duncton (2953-2961).
A homo-chiral synthesis of (7R,8aS)-octahydro-5,5-dimethylindolizin-7-amine 8 and (7S, 8aS)-octahydro-5,5-dimethylindolizin-7-ol 9, amine building blocks which have found applications within the pharmaceutical industry, is presented. The approach uses a Novozym 435-mediated kinetic resolution of racemic octahydroindolizine (indolizidine) alcohol 13 as a key step (up to 100 g scale).

Cyclic peptide unguisin A is an anion receptor with high affinity for phosphate and pyrophosphate by A. Daryl Ariawan; James E. A. Webb; Ethan N. W. Howe; Philip A. Gale; Pall Thordarson; Luke Hunter (2962-2967).
Unguisin A (1) is a marine-derived, GABA-containing cyclic heptapeptide. The biological function of this flexible macrocycle is obscure. Here we show that compound 1 lacks any detectable activity in antimicrobial growth inhibition assays, a result that runs contrary to a previous report. However, we find that 1 functions as a promiscuous host molecule in a variety of anion-binding interactions, with high affinity particularly for phosphate and pyrophosphate. We also show that a series of rigidified, backbone-fluorinated analogues of 1 displays altered affinity for chloride ions.

Betti's base for crystallization-induced deracemization of substituted aldehydes: synthesis of enantiopure amorolfine and fenpropimorph by Andrea Carella; Gabriel Ramos Ferronatto; Emanuela Marotta; Andrea Mazzanti; Paolo Righi; Claudio Paolucci (2968-2978).
The acid-promoted crystallization-induced diastereoisomer transformation (CIDT) of naphthoxazines derived from racemic O-protected 2-substituted 4-hydroxybutyraldehydes and enantiopure Betti's base allows the deracemization of the starting aldehydes with ee up to 96%. As an alternative, reduction with lithium aluminum hydride of the diastereoisomerically enriched naphthoxazines leads to enantioenriched primary amines. The utility of the latter strategy was demonstrated by applying it to the synthesis of enantioenriched fenpropimorph and to the first synthesis of enantiopure amorolfine, with ee up to 99.5%.

The design and synthesis of an α-Gal trisaccharide epitope that provides a highly specific anti-Gal immune response by Kensaku Anraku; Shun Sato; Nicholas T. Jacob; Lisa M. Eubanks; Beverly A. Ellis; Kim D. Janda (2979-2992).
Carbohydrate antigens displaying Galα(1,3)Gal epitopes are recognized by naturally occurring antibodies in humans. These anti-Gal antibodies comprise up to 1% of serum IgG and have been viewed as detrimental as they are responsible for hyperacute organ rejections. In order to model this condition, α(1,3)galactosyltransferase-knockout mice are inoculated against the Galα(1,3)Gal epitope. In our study, two α-Gal trisaccharide epitopes composed of either Galα(1,3)Galβ(1,4)GlcNAc or Galα(1,3)Galβ(1,4)Glc linked to a squaric acid ester moiety were examined for their ability to elicit immune responses in KO mice. Both target epitopes were synthesized using a two-component enzymatic system using modified disaccharide substrates containing a linker moiety for coupling. While both glycoconjugate vaccines induced the required high anti-Gal IgG antibody titers, it was found that this response had exquisite specificity for the Galα(1,3)Galβ(1,4)GlcNAc hapten used, with little cross reactivity with the Galα(1,3)Galβ(1,4)Glc hapten. Our findings indicate that while homogenous glycoconjugate vaccines provide high IgG titers, the carrier and adjuvanting factors can deviate the specificity to an antigenic determinant outside the purview of interest.

Asymmetric organocatalytic synthesis of tertiary azomethyl alcohols: key intermediates towards azoxy compounds and α-hydroxy-β-amino esters by José A. Carmona; Gonzalo de Gonzalo; Inmaculada Serrano; Ana M. Crespo-Peña; Michal Šimek; David Monge; Rosario Fernández; José M. Lassaletta (2993-3005).
A series of peracylated glycosamine-derived thioureas have been synthesized and their behavior as bifunctional organocatalysts has been tested in the enantioselective nucleophilic addition of formaldehyde tert-butyl hydrazone to aliphatic α-keto esters for the synthesis of tertiary azomethyl alcohols. Using the 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-β-d-glucosamine derived 3,5-bis-(trifluoromethyl)phenyl thiourea the reaction could be accomplished with high yields (75–98%) and moderate enantioselectivities (50–64% ee). Subsequent high-yielding and racemization-free tranformations of both aromatic- and aliphatic-substituted diazene products in a one pot fashion provide a direct entry to valuable azoxy compounds and α-hydroxy-β-amino esters.

Synthesis of chiral cyclic amines via Ir-catalyzed enantioselective hydrogenation of cyclic imines by Ying Zhang; Duanyang Kong; Rui Wang; Guohua Hou (3006-3012).
A highly enantioselective hydrogenation of cyclic imines for synthesis of chiral cyclic amines has been realized. With the complex of iridium and (R,R)-f-spiroPhos as the catalyst, a range of cyclic 2-aryl imines were smoothly hydrogenated under mild conditions without any additive to provide the corresponding chiral cyclic amines with excellent enantioselectivities of up to 98% ee. Moreover, this method could be successfully applied to the synthesis of (+)-(6S,10bR)-McN-4612-Z.

Novel fluorescent anthracene–bodipy dyads displaying sensitivity to pH and turn-on behaviour towards Cu(ii) ions by A. Vanessa Saura; M. Isabel Burguete; Francisco Galindo; Santiago V. Luis (3013-3024).
Three bichromophoric compounds containing anthracene and bodipy moieties connected by different spacers have been synthesized and fully characterized. The set of spacers comprises a variety of bridges (short and flexible 1,2-diaminoethane in compound 1a, long and flexible 1,8-diaminooctane in compound 1b and short and rigid piperazine in compound 1c). The new compounds show interchromophoric communication via Electronic Energy Transfer (EET). When anthracene is excited, the energy is efficiently transferred to the bodipy moiety. The emission of the acceptor is partially quenched in dyad 1a but remarkably not in 1b and 1c. In an aqueous environment, the fluorescence of the new compounds display sensitivity to pH (emissive at acidic values and non-emissive at neutral ones), a typical behaviour of photoinduced electron-transfer (PET) probes, but with remarkable differences in the pKa of each compound, attributable to the nature of the linker. Additionally, the behaviour in the presence of several metallic cations (Cu2+, Ni2+, Cd2+, Zn2+) has been studied, and a turn-on response towards Cu2+ in water at neutral pH has been found.

Thiyl radical-mediated cyclization of ω-alkynyl O-tert-butyldiphenylsilyloximes by Nina Shibata; Takahisa Tsuchiya; Yoshimitsu Hashimoto; Nobuyoshi Morita; Shintaro Ban; Osamu Tamura (3025-3034).
ω-Alkynyl O-tert-butyldiphenylsilyloximes, upon treatment with odorless 4-tert-butylbenzenethiol in the presence of azobisisobutyronitrile (AIBN) in refluxing benzene, underwent addition of a thiyl radical to the alkynyl group followed by radical cyclization of the corresponding vinyl radical onto the O-silyloxime moiety to give cyclic O-silylhydroxylamines in good yields. The reactivity of O-silyloximes in radical cyclization was similar to or even higher than that of O-benzyloximes. Facile removal of the silyl group of the cyclization products leading to hydroxylamines and nitrone formation of the hydroxylamines were also demonstrated.

The amino substituted bicyclo[4.3.0]nonane is a molecular scaffold found in a wide range of natural products and medicinal agents. Despite this, synthetic methods for the general preparation of this structural motif are sparse. Here we evaluate a diastereoselective approach for the preparation of vinylsilyl derived aminobicyclo[4.3.0]nonanes using a one-pot multi-bond forming process involving a Pd(ii)-catalysed Overman rearrangement, a Ru(ii)-catalysed ring closing enyne metathesis reaction, followed by a hydrogen bonding directed Diels–Alder reaction. We show that a benzyldimethylsilyl-substituted alkene analogue is amenable to further functionalisation and the late stage generation of diverse sp3-rich, drug-like aminobicyclo[4.3.0]nonane scaffolds with up to six stereogenic centres.

Small molecule Hedgehog pathway antagonists by Trieu N. Trinh; Eileen A. McLaughlin; Christopher P. Gordon; Ilana R. Bernstein; Victoria J. Pye; Kate A. Redgrove; Adam McCluskey (3046-3059).
Leveraging our quinolone-1-(2H)-one based Hedgehog signalling pathway (HSP) inhibitors we have developed two new classes of HSP inhibitors based on: l-tryptophan and benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amine. Synthesis of focused compound libraries identified six l-tryptophan based inhibitors, and two stimulators, of Gli at 10 μM compound concentration. 2,4-Dichloro-13 and indole 16 suppressed mRNA expression of Ptch1 in Shh LIGHT2 cells, with 13 suppressing and 16 stimulating Gli2 mRNA expression. Focused library development of the benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amine scaffold afforded two sub-micro molar potent inhibitors of Gli expression with 5-methoxy-1H-indole-2-carboxylic acid benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amide 29 and 5-chloro-1H-indole-2-carboxylic acid benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amide 30 returning IC50 values of 0.5 and 0.24 μM, respectively. Neither 29 nor 30 acted directly on Smo with our data supporting inhibition of the HSP downstream of Smo.

Metal-free oxidative ring contraction of benzodiazepinones: an entry to quinoxalinones by Hasan Mtiraoui; Kevin Renault; Morgane Sanselme; Moncef Msaddek; Pierre-Yves Renard; Cyrille Sabot (3060-3068).
A novel and practical synthesis of 3-benzoylquinoxalin-2(1H)-ones from benzodiazepin-2-ones in two steps from commercially available starting materials is reported. The reaction was achieved in the presence of N-bromosuccinimide in DMSO which served both as a solvent and an oxidant. Significantly, the yet unknown ketone to alcohol fluorescence turn-on of benzoylquinoxalinones was unveiled through the preparation of a fluorescently labelled cholesterol conjugate.

The choice of protein scaffolds is an important element in the design of artificial metalloenzymes. Herein, we introduce Multidrug Resistance Regulators (MDRs) from the TetR family as a viable class of protein scaffolds for artificial metalloenzyme design. In vivo incorporation of the metal binding amino acid (2,2-bipyridin-5yl)alanine (BpyA) by stop codon suppression methods was used to create artificial metalloenzymes from three members of the TetR family of MDRs: QacR, CgmR and RamR. Excellent results were achieved with QacR Y123BpyA in the Cu2+ catalyzed enantioselective vinylogous Friedel–Crafts alkylation reaction with ee's up to 94% of the opposite enantiomer that was achieved with other mutants and the previously reported LmrR-based artificial metalloenzymes.

Substantial research has suggested that the configuration and the total number of functional groups on flavones influence their bioactivity. To investigate the changes in the biological activities of selenoflavones in relationship to structural changes, the development of a generally applicable synthetic method was a key. Until now, an efficient pathway for palladium-catalyzed direct arylation with the selenocyclic enone systems is not known in the literature. We herein introduce a simple direct C–H arylation of two difficult coupling partners, selenochromones and electron-rich aryl bromide, affording diverse polymethoxyselenoflavones with great efficiency and high selectivity.

Back cover (3085-3086).