Self-assembly of patterned monolayers with nanometer features: molecular selection based on dipole interactions and chain length

Patterned cocrystal monolayers self-assemble on HOPG in contact with solutions containing complementary pairs of 1,5-chain-substituted anthracene derivatives. Monolayer unit cells containing three or four molecules and spanning 9-11 nm are generated. The monolayers consist of alternating aromatic and aliphatic columns. The designs and dimensions of the cocrystal patterns (unit cells) are determined by (i) the preferred packing alignment of identical length side chains, (ii) the selectivity of each side chain for neighboring chains, (iii) the identities of the two side chains on each anthracene, and (iv) the 2D-chirality of 1,5-substituted anthracenes. The aliphatic columns form by interdigitation of identical length side chains arrayed in an antiparallel alignment, with the nth heavy atom of one side chain in registration with the (omega+2-n)th heavy atom of two adjacent chains ((omega <--> 2) packing). Adjacent side chains are attached, alternately, to anthracenes in one of the two flanking aromatic columns. The preference for (omega <--> 2) packing optimizes side-chain van der Waals interactions. The composition and fidelity of patterning in the cocrystal monolayers requires an additional source of "molecular recognition" in addition to side-chain length. Dipolar interactions, both attractive and repulsive, between ether groups in neighboring, (omega <--> 2) packed side chains, constitute a second recognition element needed for cocrystal self-assembly.     

Solid phase synthesis of two muramyl pentapeptide derivatives

Solid phase peptide synthesis (SPPS) of two selected muramyl pentapeptide derivatives is described. The simplicity of removing the protecting groups via one-step deprotection and cleavage from the resin is the biggest advantage of SPPS. Using this method, two muramyl pentapeptide derivatives, D-MurN₃-L-Ala-D-iGlu-L-Lys-D-Ala-D-Ser (5) and D-MurN₃-L-Ala-D-iGlu-L-Lys-D-Ala-D-Ala (6), were obtained. Their chemical structures were confirmed by high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR) spectroscopy. To determine the absolute configuration of the carbon atom in the side chain of the muramic acid derivative, single-crystal X-ray diffraction measurements were recorded.     

Cyclic homooligomers of furanoid sugar amino acids

Cyclic homooligomers of mannose-derived furanoid sugar amino acid 1 [H-Maa(Bn(2))-OH] were synthesized by using BOP reagent in the presence of DIPEA under dilute conditions that converted the sugar amino acid monomer directly into its cyclic homooligomers 3a and 4a. The glucose-based sugar amino acid 2 [H-Gaa(Bn(2))-OH] under the same reaction conditions gave a bicyclic lactam 5a as the major product. Cyclic homooligomers of 2 were prepared by cyclizing their linear precursors 6 and 7 leading to the formation of cyclic peptides 8a and 9a, respectively. Conformational analysis by NMR and constrained MD studies revealed that all the cyclic products, 3, 4, 8, and 9, had symmetrical structures. The deprotected cyclic trimer of Maa 3b displayed a conformation in which all the C=O and the N-H bonds of the molecule point in opposite directions. In the deprotected cyclic tetramer of Maa 4b, the COs and NHs were in the plane of the ring with the former pointing to outside and the latter inside the ring. The structure of the cyclic Gaa dimer 8b displayed an unusual six-membered intramolecular hydrogen bond between NH(i)() --> C3-O(i)()(-)(1) and a syn orientation between the C2-H and CO. In this molecule, the C2-hydrogens and the COs can be seen on one side of the ring while the NHs point to the other side. Addition of the bicyclic lactam 5b resulted in the influx of Na(+) ions across the lipid bilayer leading to the dissipation of valinomycin-mediated K(+) diffusion potential.     

Stereoselective bromination-suzuki cross-coupling of dehydroamino acids to form novel reverse-turn peptidomimetics: substituted unsaturated and saturated indolizidinone amino acids

A general and efficient methodology has been developed to prepare the C4-substituted dipeptide reverse-turn mimetics unsaturated (9a, 10a) and saturated (11a) azabicyclo[4.3.0] alkane amino acid derivatives. The side chain was introduced by bromination of dehydroamino acid intermediates followed by Suzuki coupling. Hydrogenation of the bicyclic dehydroamino acid 9a afforded saturated bicyclic lactam 11a. This approach can be further explored for the synthesis of a variety of such beta-turn mimetics with aryl and alkyl side chain functionalities. [reaction: see text]     

Pseudoamide-type pyrrolidine and pyrrolizidine glycomimetics and their inhibitory activities against glycosidases

Coupling reaction of (2R,3R,4R,5R)-2,5-hydroxymethyl-3,4-dihydroxypyrrolidine (DMDP) with isothiocyanates afforded the corresponding thiourea adducts, which were transformed into isourea-type bicyclic oxapyrrolizidine glycomimetics by mercury(II) oxide-assisted intramolecular sulfur displacement. Cyclic carbamate and thiocarbamate analogues were also prepared by direct carbonylation or thiocarbonylation of DMDP. Evaluation of the glycosidase inhibitory properties demonstrated that remarkable specificities in enzyme inhibition can be achieved upon modifications on the pseudoaglyconic side chain and on the nature of the sp(2)-hybridized endocyclic ring nitrogen.     

Complexes of iron(II) with cysteine-containing peptides in the gas phase

Gas-phase interactions of peptides that contain cysteine with iron(II) atoms were examined by using fast-atom bombardment and tandem mass spectrometry. Specific and strong interactions of iron and sulfur from the thiol group of the cysteine side chain occur in the gas phase and are the basis for highly specific fragmentation to give abundant [a _n ?⁺ ions. For peptides that contain two cysteines, an internal ion, which results from the interaction of Fe and both thiol groups, is formed upon collisional activation. The mechanism for the formation of [a _n ?2H+Fe]⁺ fragment ions requires the metal to be coordinated at sulfur in close proximity to the site of reaction. Iron-bis(pentapeptide) complexes, which form under the same conditions, decompose predominantly to lose a pentapeptide molecule and, to a lesser extent, to give [a _a ?2H+Fe]⁺ ions.     

Obtusallene I,a new halogenated allene from Laurencia Obtusa

Obtusallene, a new halogenated bicyclic ether with an allenic side chain, has been isolated from the red form of the alga Laurencia obtusa, and identified by spectroscopic methods and X-ray crystallography.     

Effects of solute-solvent proton exchange on polypeptide chain dynamics: a constant-pH molecular dynamics study

A method for performing implicit-solvent molecular dynamics simulations at constant pH was applied to a pentapeptide acetyl-Ala-Asp-Ala-Lys-Ala-amide at pH 4. As a reference, molecular dynamics simulations were done for the same peptide with two variants of its fixed protonation patterns expected to dominate at pH 4, i.e., with a protonated and a deprotonated side chain of the Asp residue and the protonated Lys residue in both cases. The dynamic trajectories of the peptide were used to discuss the problem of the significance of the solute-solvent proton exchange phenomena for the dynamics and structural distributions of the polypeptide chain. The Asp-Lys distance was used as a probe of the overall molecular structure of the investigated pentapeptide. To characterize the dynamics, distributions of the "waiting" times for a transition from a "short" distance conformation to a "long" distance conformation were constructed, based on the generated molecular dynamics trajectories. We show that the relaxation time for the transitions, derived from the constant-pH simulations, is very close to the relaxation time characterizing a permanently protonated molecule, although the average protonation probability of the short-distance conformation is close to zero. However, the distribution of the Asp-Lys distances obtained from constant-pH simulations cannot be reproduced as a linear combination of the distributions resulting from the simulations with fixed protonation states.     

Facile entry to substituted decahydroquinoline alkaloids. Total synthesis of lepadins A-E and H

Condensation of a L-alanine derived delta-bromo-beta-silyloxy-propylamine with 1,3-cyclohexadione followed by alkylative cyclization produces a bicyclic enone. Diastereoselective Pt/C-catalyzed hydrogenation of this enone in HOAc provides a 5-oxo-cis-fused decahydroquinoline. Wittig olefination of this decahydroquinoline and subsequent epimerization of the resulting 5-formyl intermediate gives rise to a 5-beta-formyl decahydroquinoline exclusively. In a parallel procedure, Peterson reaction of this decahydroquinoline and subsequent hydrogenation of the generated 5-exo-olefin provides a decahydroquinoline with a 5-alpha-substituent predominantly. For these two diastereoselective processes, using the intermediates without N-protection as the substrates is essential because the corresponding N-Boc intermediates give poor diastereoselectivity. The intermediate with beta-form side chain is further converted into lepadins A-C via carbon chain elongation, while the intermediate with alpha-form side chain is transformed into lepadins D, E, and H and corresponding 5'-epimers via connection with two sulfones generated from two Sharpless epoxidation products. By comparison of the rotations and NMR data, the stereochemistry of lepadins D, E, and H is assigned as 2S,3R,4aS,5S,8aR,5'R.     

Intramolecular carboxylic acid trapping of pyran-4-one derived zwitterions: A novel synthesis of fused bicyclic lactones

Pyran-4-ones bearing carboxylic acid side chains were prepared either by direct carboxylation with carbon dioxide or through oxidative cleavage of side chain olefins. Irradiation in a non-nucleophilic solvent yielded fused bicyclic lactones. The efficiency of the reaction was not dependent on ring substitution.     

Bicyclic homodetic peptide libraries: comparison of synthetic strategies for their solid-phase synthesis

Preliminary studies and synthesis development for the preparation of a bicyclic homodetic peptide library have been carried out using orthogonal protection schemes. The best results have been obtained using two Fmoc/tBu-based strategies, in which the first cycle is carried out in the solid phase through side chain functional groups previously protected with Aloc/Al groups. The second cycle is performed either in the solid phase, which requires side chain anchoring of a trifunctional amino acid and Dmb protection for the C-terminus carboxyl group, or in solution, which requires the use of highly labile resins, such as the 2-chlorotrityl (Barlos) resin. Only when the cycles are formed in a ziplike manner, that is, first the small cycle and then the larger ring, is the desired final product obtained.     

Modelling the interaction of several bisphosphonates with hydroxyapatite using the generalised AMBER force field

The ability of the Generalised AMBER Force Field (GAFF) of Kollman and co-workers to model the structures of bisphosphonate ligands, C(R₁)(R₂)(PO₃²⁻)₂, important compounds in the treatment of bone cancer, by molecular mechanics methods is evaluated. The structure of 50 bisphosphonates and nine bisphosphonate esters were predicted and compared to their crystal structures. Partial charges were assigned from a RHF/6-31G¹ single point calculation at the geometry of the crystal structure. Additional parameters required for GAFF were determined using the methods of the force field’s developers. The structures were found to be well replicated with virtually all bond lengths reproduced to within 0.015 Å, or within 1.2σ of the crystallographic mean. Bond angles were reproduced to within 1.9° (0.8σ). The observed gauche or anti conformation of the molecules was reproduced, although in several instances gauche conformations observed in the solid state energy-minimised into anti conformations, and vice versa. The interaction of MDP (R₁ = R₂ = H), HEDP (R₁ = OH, R₂ = CH₃), APD (R₁ = OH, R₂ =  (CH₂)₂NH₃⁺), alendronate (R₁ = OH, R₂ = (CH₂)₃NH₃⁺) and neridronate (R₁ = OH, R₂ = (CH₂)₅NH₃⁺) with the (001), (010) and (100) faces of hydroxyapaptite was examined by energy-minimising 20 random orientations of each ligand 20 Å from the mineral (where there is no interaction), and then at about 8 Å from the surface whereupon the ligand relaxes onto the surface. The difference in energy between the two systems is the interaction energy. In all cases interaction with hydroxyapatite caused a decrease in energy. When modelled with a dielectric constant of 78ε_o, non-bonded interactions dominate; electrostatic interactions become important when the dielectric constant is <10ε_o. Irrespective of the value of the dielectric constant used, the structure of the ligands on the hydroxyapatite surface is very similar. On the (001) face, both phosphonate groups interact near a surface Ca²⁺ ion. The magnitude of the exothermic interaction energy varies with molecular volume (MDP<HEDP<APD<alendronate) except for neridronate which interacts less effectively than alendronate because the long amino side chain folds in on itself and does not align with the surface of the mineral. The bisphosphonates adopt two conformations on the (010) face. In the first of these, found for MDP and 40% of the alendronate structures, both phosphonates interact with the surface and the side chain points away from the surface. Hence, the interaction energy is similar for both species. In the second conformation, adopted by the majority of ligands, one phosphonate and the Cα side chain interact with the surface. The interaction energy, the magnitude of which is very similar to that on the (001) face, increases with the molecular volume of the ligand, again with the exception of neridronate. Two conformations also occur on the (100) face. In the first conformation, only one of the phosphonate groups points towards the surface and the Cα side chain interacts with the surface; in the second conformation the Cα side chain interacts strongly with the surface and both phosphonate groups point away from the surface towards the solution. The first conformation, which is the more common, is energetically more favourable. Its magnitude is virtually insensitive to the nature of the side chain and is similar to the magnitude of the interaction energy on the other two faces. The magnitude of the second conformation increases with the size of the Cα side chain.     

Total synthesis of batzelladine D

[structure: see text] Stereoselective total synthesis of batzelladine D was accomplished in 15 steps. This synthesis features (i) successive 1,3-dipolar cycloaddition reactions to form the 2,5-disubstituted pyrrolidine ring system, (ii) esterification of the side chain to the bicyclic guanidine carboxylate, a common synthetic intermediate of batzelladine alkaloids, and (iii) tricyclic guanidine formation under the Mitsunobu reaction conditions.     

Intramolecular conjugate displacement: a general route to hexahydroquinolizines, hexahydroindolizines, and related [m,n,0]-bicyclic structures with nitrogen at a bridgehead

N-Protected amino aldehydes can be converted into allylic alcohols by the classical Morita-Baylis-Hillman reaction (cf. 2 --> 3) or by condensation with selenium-stabilized carbanions, followed by oxidation (cf. 2 --> 8 --> 3). The derived acetates undergo cyclization when the nitrogen protecting group is removed, affording [m,n,0]-bicyclic structures with nitrogen at a bridgehead (cf. 4 --> 5 --> 6). Formation of bicyclic structures via the reactions of Schemes 1 and 2 is general, and the stereochemistry of the starting amino aldehyde is preserved.     

Model Studies towards the Synthesis of the Right‐Hand Part of Pederin

Bicyclic acetal derivatives of the type 3 were prepared based either on a dihydroxyaldehyde 5 or an oxiranebutanal 6 (cf. Scheme 2). Lewis acid catalyzed reaction of the bicyclic acetal with allyltrimethylsilane introduces the side chain (as yet unfunctionalized) and sets the stereogenic centers at the tetrahydro‐2H‐pyran ring of the pederin moiety.     

Theoretical study of the reaction from 7-alkylidenecephalosporin sulfone to bicyclic intermediates in inhibiting β-lactamase

Density functional theory (DFT) calculations have been performed on the 7-alkylidenecephalosporin sulfone in order to study the mechanism of producing the bicyclic intermediate. The solvent effect was considered via polarizable continuum model (PCM) computations. The results show that in the acyl-enzyme intermediate, the side chain pyridine nitrogen atom attacks the C6 atom, which is followed by cleavage of the C6–S1 bond. The unsaturated C7 is attacked by the leaving sulfinate, and a tricyclic structure yields. This structure is unstable, and the proton is transferred from C6 to the sulfone to yield the bicyclic end product. Besides, the reactant can undergo enamine–imine tautomerism. This suggests the end products have two forms, viz. imine and enamine. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Free radical 5-exo-dig cyclization as the key step in the synthesis of bis-butyrolactone natural products: experimental and theoretical studies

Radical cyclization reactions were performed by 5-exo-dig mode to yield cis-fused bicyclic systems, leading to the synthesis of bis-butyrolactone class of natural products. The study was aimed at understanding the impact of alkyl side chains of furanoside ring systems in L-ara configuration on the radical cyclization. It was amply demonstrated by experimental studies that the increase in the length of the alkyl side chain has an effect on the cyclization: while efficient cyclization reactions could be realized with methyl and ethyl side chains, the yields were significantly reduced in the case of n-pentyl side chain. Theoretical studies using DFT and (RO)MP2 methods were carried out to analyze the influence of the substitution pattern on the cyclization barriers.     

Step-wise and pre-organization induced synthesis of a crossed alkene-bridged nisin Z DE-ring mimic by ring-closing metathesis

This paper describes two approaches for the synthesis of a crossed alkene-bridged mimic of the thioether ring system of the nisin Z DE-fragment. The first approach comprised the stepwise total synthesis featuring a cross metathesis and a macrolactamization on a solid support followed by a ring-closing metathesis in solution. Via this route the title compound was obtained in an overall yield of 7% (85% on average for 16 reaction steps). In the second approach, the linear precursor peptide was subjected to ring-closing metathesis and the bicyclic peptide with the correct side chain connectivity pattern was obtained in yields up to 95%. The preferred formation of the bicyclic crossed alkene-bridged mimic of the DE-ring suggests a favorable pre-organization of the linear precursor peptide.     

Efficient stereoselective alkenylation through a homolytic domino reaction involving a 1,5 sulfur-to-carbon translocation

An effective method for cis-stereoselective attachment of functionalized alkenyl appendages to sp3 carbon is reported. This method is based on a free-radical process, involving a sequence of addition-elimination steps, resulting in alkenyl group transposition from divalent sulfur to a prochiral carbon radical. Absolute stereoselectivity is secured since the new carbon-carbon bond is formed in a ring-closure reaction leading to a bridged bicyclic carbon-centered radical intermediate. The latter undergoes beta-scission of the C-S bond, leaving the alkenyl side chain in its predetermined position while releasing a thiyl radical. This thiyl radical is trapped by tri-n-butylstyryltin, affording a (styrylsulfanyl)methyl side chain and a tri-n-butyltin radical that continues the chain. When 2-(alkenylsulfanyl)methyl-4-bromo(or iodo)pyrrolidines were used as starting materials 2,4-cis-disubstituted 4-alkenyl-2-(styrylsulfanyl)methylpyrrolidines were obtained as products (70-90% yield). Tri-n-butylstyryltin was used rather then the more common n-Bu3SnH as tin radicals sources because the latter led predominantly to bridged bicyclic 3-thia-6-azabicyclo[3.2.1]octanes (up to 77% yield). An additional advantage of using tri-n-butylstyryltin derives from the discovery that the resulting styrylsulfide functionality is an excellent synthetic equivalent to the formyl group. Thus, using a Pummerer-type oxidative desulfurization, 4-cis-alkenyl-proline aldehydes were obtained.     

α-Carbonyl Radicals for Total Synthesis of Natural Products

Intramolecular cyclization of α-carbonyl radicals to the trimethylsilylacetylenic side chain gives bicyclic vinylsilane ketones and enones. Application of this cyclization to total synthesis of (±)-modhephene is described.