Organic & Biomolecular Chemistry (v.10, #20)

Front cover (3957-3957).

Inside front cover (3958-3958).

Contents list (3959-3968).

Asymmetric organocascades involving the formation of two C–heteroatom bonds from two distinct heteroatoms by Damien Bonne; Thierry Constantieux; Yoann Coquerel; Jean Rodriguez (3969-3973).
In the vast and expanding world of enantioselective organocascades, the ones in which two C–heteroatom bonds are created from two distinct heteroatoms are rare. These fascinating domino processes constitutes real synthetic challenges and allow very convenient syntheses of diverse optically active heterocycles and also highly functionalised acyclic derivatives.

Hybrids of amino acids and acetylenic DNA-photocleavers: optimising efficiency and selectivity for cancer phototherapy by Boris Breiner; Kemal Kaya; Saumya Roy; Wang-Yong Yang; Igor V. Alabugin (3974-3987).
Hybrid agents which combine potent DNA-photocleavers with tunable amino acids or small peptides were designed to improve selectivity of Nature's most potent class of antibiotics towards cancer cells. The ability of these compounds to photocleave DNA is controlled by their incorporation into hybrid architectures with functional elements derived from natural amino acids. These conjugates are highly effective at inducing double-strand DNA cleavage and, in some cases, rival or even surpass both naturally occurring DNA cleavers and anticancer agents that are currently in clinical use. The possibility of triggering their activity in a photochemical and pH-sensitive fashion allows for a high degree of selectivity over activation. The conjugates were shown to penetrate cell membranes and induce efficient intracellular DNA cleavage. Initial in vitro tests against a variety of cancer cell lines confirm the potential of these compounds as anticancer agents at low nanomolar concentrations.

A new enantioselective synthesis of the anti-influenza agent (−)-oseltamivir free base (7.1% overall yield; 98% ee) and (−)-methyl 3-epi-shikimate (16% overall yield; 98% ee) has been described from readily available raw materials. Sharpless asymmetric epoxidation and diastereoselective Barbier allylation of an aldehyde are the key reactions employed in the incorporation of chirality, while the cyclohexene carboxylic ester core was constructed through a ring closing metathesis reaction.

A zinc or indium-mediated Barbier-type allylation of aldehydes with 3-bromomethyl-5H-furan-2-one in aqueous solvents was developed to provide an efficient route to α-methylene-γ-butyrolactone, which is synthetically very useful. The desired products were obtained in moderate to high yields in aqueous solvents. Excellent drs were achieved, among which the best diastereomeric ratios of products were found when water was used in the indium-mediated reaction, and THF–NH4Cl (sat, aq) (2 : 1) mixture in the zinc-mediated reaction. Furthermore, the allylation can be induced by chiral centers, especially those in the α-position, as a substrate-controlled reaction to obtain the enantioselective homoallylation alcohols.

Aromatic capping surprisingly stabilizes furan moieties in peptides against acidic degradation by Kurt Hoogewijs; Annelies Deceuninck; Annemieke Madder (3999-4002).
We herein describe the synthesis of furan containing peptides for further post-synthetic derivatisation in solution through our recently developed furan-oxidation-labeling technology. Previously, it was reported by others that during acidic cleavage of furan-modified peptides, furan moieties can suffer from degradation. We demonstrate here that this degradation is position dependent and can be fully suppressed through introduction of proximate aromatic residues. Versatile introduction of 2-furylalanine at internal, C-terminal as well as the sensitive N-terminal positions has now been proven possible.

Highly selective binding of naphthyridine with a trifluoromethyl group to cytosine opposite an abasic site in DNA duplexes by Yusuke Sato; Yushuang Zhang; Takehiro Seino; Takashi Sugimoto; Seiichi Nishizawa; Norio Teramae (4003-4006).
We report on highly selective binding of a naphthyridine derivative with a trifluoromethyl group to cytosine opposite an abasic site in DNA duplexes; the binding-induced fluorescence quenching is applicable to the analysis of a C-related single-base mutation in DNAs amplified by PCR.

Palladium-catalysed aminosulfonylation of aryl-, alkenyl- and heteroaryl halides: scope of the three-component synthesis of N-aminosulfonamides by Edward J. Emmett; Charlotte S. Richards-Taylor; Bao Nguyen; Alfonso Garcia-Rubia; Barry R. Hayter; Michael C. Willis (4007-4014).
By using DABCO·(SO2)2, DABSO, as a solid bench-stable SO2-equivalent, the palladium-catalysed aminosulfonylation of aryl-, alkenyl- and heteroaryl halides has been achieved. N,N-Dialkylhydrazines are employed as the N-nucleophiles and provide N-aminosulfonamides as the products in good to excellent yields. The reactions are operationally simple to perform, requiring only a slight excess of SO2 (1.2–2.2 equiv.), and tolerate a variety of substituents on the halide coupling partner. Variation of the hydrazine component is also demonstrated. The use of N,N-dibenzylhydrazine as the N-nucleophile delivers N-aminosulfonamide products that can be converted into the corresponding primary sulfonamides using a high-yielding, telescoped, deprotection sequence. The ability to employ hydrazine·SO2 complexes as both the N-nucleophile and SO2 source is also illustrated.

Design and synthesis of screening libraries based on the muurolane natural product scaffold by Emma C. Barnes; Vanida Choomuenwai; Katherine T. Andrews; Ronald J. Quinn; Rohan A. Davis (4015-4023).
The plant-derived natural product 14-hydroxy-6,12-muuroloadien-15-oic acid (1) was identified as a unique scaffold that could be chemically elaborated to generate novel lead- or drug-like screening libraries. Prior to synthesis a virtual library was generated and prioritised based on drug-like physicochemical parameters such as log P, log D5.5, hydrogen bond donors/acceptors, and molecular weight. The natural product scaffold (1) was isolated from the endemic Australian plant Eremophila mitchellii and then utilised in the parallel solution-phase generation of two series of analogues. The first library consisted of six semi-synthetic amide derivatives, whilst the second contained six carbamate analogues. These libraries have been evaluated for antimalarial activity using a chloroquine-sensitive Plasmodium falciparum line (3D7) and several compounds displayed low to moderate activity with IC50 values ranging from 14 to 33 μM.

New coumarin-based chiral thiourea sensor 1 was found to be an enantioselective fluorescent chemosensor for N-Boc-protected proline. The chiral sensor shows lower background fluorescence, and higher fluorescence enhancement with 18 nm blue shifts. Job plot analysis result indicates that sensor 1 can form a 1 : 1 stoichiometric complex and it could be used as a fluorescence sensor for the determination of enantiomer composition of N-Boc-protected proline.

Enantioselective direct aldol reaction of α-keto esters catalyzed by (Sa)-binam-d-prolinamide under quasi solvent-free conditions by Santiago F. Viózquez; Abraham Bañón-Caballero; Gabriela Guillena; Carmen Nájera; Enrique Gómez-Bengoa (4029-4035).
(Sa)-Binam-d-prolinamide (20 mol%), instead of (Sa)-binam-l-prolinamide, in combination with chloroacetic acid (100 mol%) is an efficient organocatalyst for the direct aldol reaction between α-keto esters as electrophiles and alkyl and α-functionalised ketones, under quasi solvent-free conditions, providing access to highly functionalised chiral quaternary γ-keto α-hydroxyesters with up to 92% ee.

Another side of the oxazaphospholidine oxide chiral ortho-directing group by Nelson Martins; Nuno Mateus; Daniele Vinci; Ourida Saidi; Amadeu Brigas; John Bacsa; Jianliang Xiao (4036-4042).
A new ferrocenyl oxazaphospholidine oxide 3 was synthesized together with its P-epimer 2 in the reaction of ferrocene lithium with phosphoramidite chloride 1. 3 was successfully derivatized into planar chiral 1,2-ferrocenes, including phosphine ligands, via highly diastereoselective ortho-lithiation and subsequent functionalization; these compounds display opposite planar chirality to those obtained from 2. Some of these 1,2-ferrocenes were further lithiated, allowing for the introduction of a free phosphine group at the oxazaphospholidine ring. The X-ray structures of the compounds 2 and 3 as well as those of the new 1,2-ferrocenes 4 and 7 have been determined.

Triazole phosphohistidine analogues compatible with the Fmoc-strategy by Tom E. M<sup>c</sup>Allister; Michael E. Webb (4043-4049).
Phosphorylation of histidine is essential for bacterial two-component signalling; its importance to modulation of eukaryotic protein function remains undefined. Until recently, no immunochemical probes of this post-translational modification existed, however triazole phosphonate analogues of this modified amino acid have now been applied to the generation of site-specific antibodies. The protecting group strategy used in the original report is incompatible with standard protocols for Fmoc-solid phase peptide synthesis. In this paper, we report the application of P(iii) chemistry to generate the complementary dibenzyl and di-tert-butyl phosphonate esters. These forms of the triazole analogue are fully compatible with standard Fmoc-SPPS and are therefore ideal for wider application by the chemical and biochemical community.

Searching for new cell-penetrating agents: hybrid cyclobutane–proline γ,γ-peptides by Esther Gorrea; Daniel Carbajo; Raquel Gutiérrez-Abad; Ona Illa; Vicenç Branchadell; Miriam Royo; Rosa M. Ortuño (4050-4057).
Two generations of hybrid γ,γ-peptides containing cyclobutane amino acids and cis-γ-amino-l-proline joined in alternation have been synthesized and their capacity to cross the eukaryotic cell membrane has been evaluated. The first generation consists of di-, tetra- and hexapeptides, and their properties have been analyzed as well as the influence of peptide length and chirality of the cyclobutane residues. Results have shown that the absolute configuration of the cyclobutane amino acid does not have a relevant influence. The second generation consists of hybrid γ,γ-hexapeptides with a common backbone and distinct side chains introduced with different linkage types through the α-amino group (Nα) of the proline monomers. These peptides have been shown to be non-toxic towards HeLa cells and to internalize them effectively, the best results being obtained for the peptides with a spacer of five carbons between the Nα atom and the guanidinium group. The introduction of cyclobutane residues inside the sequence affords a good balance between charge and hydrophobicity, reducing the number of positive charges. This results in lower toxicity and similar cell-uptake properties when compared to previously described peptide agents.

o-Benzenedisulfonimide (OBS) has efficiently catalysed the one-pot three-component reaction of ketones and aromatic amines with trimethylsilyl cyanide (TMSCN) giving the corresponding α-amino nitriles in excellent yields (23 examples; average yield 85%). Reaction conditions were very simple, green and efficient. Theoretical calculations have allowed us to explain the mechanism of this reaction which has been found to take place in two phases; the first consists of the nucleophilic addition of the aniline to the ketone and the subsequent dehydration to an imine; the second one consists of the formal addition of cyanide anion to the protonated imine. OBS acts in all steps of this mechanism. Without an acid catalyst, the reaction mechanism is more simple but barriers are sensibly higher. A chiral derivative of OBS was also used and gave fairly good results.

Solar irradiation of the seed germination stimulant karrikinolide produces two novel head-to-head cage dimers by Adrian Scaffidi; Mark T. Waters; Brian W. Skelton; Charles S. Bond; Alexandre N. Sobolev; Rohan Bythell-Douglas; Allan J. McKinley; Kingsley W. Dixon; Emilio L. Ghisalberti; Steven M. Smith; Gavin R. Flematti (4069-4073).
Karrikinolide is a naturally derived potent seed germination stimulant that is responsible for triggering the germination of numerous plant species from various habitats around the world. We now report that solar irradiation of karrikinolide yields two novel head-to-head cage photodimers with the formation, stability and bioactivity of both presented herein.

Mycobacterial cell wall galactan, composed of alternating β-(1→5) and β-(1→6) galactofuranosyl residues, is assembled by the action of two bifunctional galactofuranosyltransferases, GlfT1 and GlfT2, which use UDP-galactofuranose (UDP-Galf) as the donor substrate. Kinetic analysis of synthetic UDP-Galf analogs identified critical interactions involved in donor substrate recognition by GlfT2, a processive polymerizing glycosyltransferase. Testing of methylated UDP-Galf analogs showed the donor substrate-binding pocket is sterically crowded. Evaluation of deoxy UDP-Galf analogs revealed that the C-6 hydroxyl group is not essential for substrate activity, and that interactions with the UDP-Galf C-3 hydroxyl group orient the substrate for turnover but appears to play no role in substrate recognition, making the 3-deoxy-analog a moderate competitive inhibitor of the enzyme. Moreover, the addition of a Galf residue deoxygenated at C-5 or C-6, or an l-arabinofuranose residue, to the growing galactan chain resulted in “dead end” reaction products, which no longer act as an acceptor for the enzyme. This finding shows dual recognition of both the terminal C-5 and C-6 hydroxyl groups of the acceptor substrate are required for GlfT2 activity, which is consistent with a recent model developed based upon a crystal structure of the enzyme. These observations provide insight into specific protein–carbohydrate interactions in the GlfT2 active site and may facilitate the design of future inhibitors.

The NHC-catalyzed reactions of ortho electron-deficient vinyl substituted arylaldehydes with nitrosoarenes were studied. The reactions produced multifunctional 2,3-benzoxazin-4-ones in good to excellent yields via a cascade aza-benzoin reaction between aldehyde and nitroso groups followed by an intramolecular oxo-Michael addition. The resulting 1-acetate substituted 2,3-benzoxazinones were transformed into a new type of β-hydroxycarboxylate derivatives or 3-oxo-1-isobenzofuranacetates, respectively, under different reductive conditions. This work not only provides a simple and efficient method for the construction of multifunctional 2,3-benzoxazin-4-ones of potential pharmacological interest, but also expands the application of NHC-catalyzed cascade reactions in the formation of carbon–heteroatom and heteroatom–heteroatom bonds.

Construction of the biaryl-part of vancomycin aglycon via atropo-diastereoselective Suzuki–Miyaura coupling by Timo Leermann; Pierre-Emmanuel Broutin; Frédéric R. Leroux; Françoise Colobert (4095-4102).
An atropo-diastereoselective synthesis with dr up to 98/2 towards the biaryl subunit of vancomycin based on the use of enantiopure β-hydroxysulfoxide derivatives as novel chiral auxiliary is reported.

Stereoselective total synthesis of the acetylenic carotenoids alloxanthin and triophaxanthin by Yumiko Yamano; Mahankhali Venu Chary; Akimori Wada (4103-4108).
Stereoselective total synthesis of the C40-diacetylenic carotenoid alloxanthin (1) and the C31-acetylenic apocarotenoid triophaxanthin (2) was accomplished by Wittig condensation of C10-dialdehyde 20 or C16-keto aldehyde 19, respectively, with C15-acetylenic tri-n-butylphosphonium salt 12.

Continuous flow synthesis and scale-up of glycine- and taurine-conjugated bile salts by Francesco Venturoni; Antimo Gioiello; Roccaldo Sardella; Benedetto Natalini; Roberto Pellicciari (4109-4115).
A multi-gram scale protocol for the N-acyl amidation of bile acids with glycine and taurine has been successfully developed under continuous flow processing conditions. Selecting ursodeoxycholic acid (UDCA) as the model compound and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) as the condensing agent, a modular mesoreactor assisted flow set-up was employed to significantly speed up the optimization of the reaction conditions and the flow scale-up synthesis. The results in terms of yield, in line purification, analysis, and implemented flow set-up for the reaction optimization and large scale production are reported and discussed.

A chiral sulfonamide primary amine-organocatalysed, highly enantioselective Michael addition of malonates to enones has been developed. This reaction afforded the corresponding products in excellent yields (up to 99%) and excellent enantioselectivity (up to 99% ee).

Synthesis of the unique angular tricyclic chromone structure proposed for aspergillitine, and its relationship with alkaloid TMC-120B by Sebastián O. Simonetti; Enrique L. Larghi; Andrea B. J. Bracca; Teodoro S. Kaufman (4124-4134).
The synthesis of the tricyclic angular chromone structure originally assigned to aspergillitine is reported. The synthesis was achieved in 11 steps and 15% overall yield from 2,4-dihydroxypropiophenone, through the intermediacy of 2,3-dimethyl-7-hydroxychromen-4-one. Construction of the nitrogen-bearing heterocyclic ring entailed a Stille cross-coupling reaction with n-Bu3SnCH2CHCH2, followed by double bond isomerization, oximation of the chromone carbonyl, and a final microwave-assisted electrocyclization of the thus formed 6π-electron aza-triene system.

Back cover (4135-4136).