Supramolecular packing of alkyl substituted Janus face all-cis 2,3,4,5,6-pentafluorocyclohexyl motifs

This study uses X-ray crystallography, theory and Langmuir isotherm analysis to explore the conformations and molecular packing of alkyl all-cis 2,3,4,5,6-pentafluorocyclohexyl motifs, which are prepared by direct aryl hydrogenations from alkyl- or vinyl-pentafluoroaryl benzenes. Favoured conformations retain the more polar triaxial C–F bond arrangement of the all-cis 2,3,4,5,6-pentafluorocyclohexyl ring systems with the alkyl substituent adopting an equatorial orientation, and accommodating strong supramolecular interactions between rings. Langmuir isotherm analysis on a water subphase of a long chain fatty acid and alcohol carrying terminal all-cis 2,3,4,5,6-pentafluorocyclohexyl rings do not show any indication of monolayer assembly relative to their cyclohexane analogues, instead the molecules appear to aggregate and form higher molecular assemblies prior to compression. The study indicates the power and potential of this ring system as a motif for ordering supramolecular assembly.

Theory and Langmuir isotherm analysis was used to explore the conformations and molecular packing of alkyl all-cis 2,3,4,5,6-pentafluorocyclohexyl motifs, which are prepared by direct aryl hydrogenations from alkyl- or vinyl-pentafluoroaryl benzenes.     

The Emergence and Properties of Selectively Fluorinated ‘Janus’ Cyclohexanes

This account describes the evolution of a research programme that started by linking fluoromethylene (−CHF−) groups along aliphatic chains and then progressing to alicyclic rings with contiguous fluorine atoms. Different stereoisomers of aliphatic chains tend to adopt low polarity conformations. In order to force polar conformations, the programme began to address ring systems and in particular cyclohexanes, to restrain conformational freedom and co-aligned C−F bonds. The flagship molecule, all-cis-1,2,3,4,5,6-hexafluorocyclohexane 7 , emerged to be the most polar aliphatic compound recorded. The polarity arises because there are three co-aligned triaxial C−F bonds and the six fluorines occupy one face of the ring. Conversely the electropositive hydrogens occupy the other face. These have been termed Janus face cyclohexanes after the Roman god with two faces. The review outlines progress by our group and others in preparing derivatives of the parent cyclohexane 7 , in order to explore properties and potential applications of these Janus cyclohexanes.     

Janus Face All-cis 1,2,4,5-tetrakis(trifluoromethyl)- and All-cis 1,2,3,4,5,6-hexakis(trifluoromethyl)- Cyclohexanes

We report the synthesis of all-cis 1,2,4,5-tetrakis (trifluoromethyl)- and all-cis 1,2,3,4,5,6-hexakis (trifluoromethyl)- cyclohexanes by direct hydrogenation of precursor tetrakis- or hexakis- (trifluoromethyl)benzenes. The resultant cyclohexanes have a stereochemistry such that all the CF₃ groups are on the same face of the cyclohexyl ring. All-cis 1,2,3,4,5,6-hexakis(trifluoromethyl)cyclohexane is the most sterically demanding of the all-cis hexakis substituted cyclohexanes prepared to date, with a barrier (ΔG) to ring inversion calculated at 27 kcal mol⁻¹. The X-ray structure of all-cis 1,2,3,4,5,6-hexakis(trifluoromethyl)cyclohexane displays a flattened chair conformation and the electrostatic profile of this compound reveals a large diffuse negative density on the fluorine face and a focused positive density on the hydrogen face. The electropositive hydrogen face can co-ordinate chloride (K≈10³) and to a lesser extent fluoride and iodide ions. Dehydrofluorination promoted decomposition occurs with fluoride ion acting as a base.     

Accelerating Spirocyclic Polyketide Synthesis using Flow Chemistry

Over the past decade, the integration of synthetic chemistry with flow processing has resulted in a powerful platform for molecular assembly that is making an impact throughout the chemical community. Herein, we demonstrate the extension of these tools to encompass complex natural product synthesis. We have developed a number of novel flow‐through processes for reactions commonly encountered in natural product synthesis programs to achieve the first total synthesis of spirodienal A and the preparation of spirangien A methyl ester. Highlights of the synthetic route include an iridium‐catalyzed hydrogenation, iterative Roush crotylations, gold‐catalyzed spiroketalization and a late‐stage cis‐selective reduction.     

Polar Organofluorine Substituents: Multivicinal Fluorines on Alkyl Chains and Alicyclic Rings

This Review outlines the progression, primarily of our own work, but with important contributions from other labs, on the synthesis and properties of multiple vicinally fluorinated alkyl chains and rings. Chain conformations of individual diastereoisomers with -CHF- at adjacent carbons are influenced by stereoelectronic factors associated with the polar C−F bond and the polarised geminal hydrogens. Generally, the chain will prefer a conformation which acts to minimise overall molecular polarity, and where the C−F bonds orient away from each other. However, when vicinal fluorine atoms are positioned on a ring then conformations are more constrained. The ring will adopt optimal conformations such as a chair in cyclohexane and then C−F bonds can be introduced with a stereochemistry that forces parallel (axial) orientations. In the case of cyclohexane, 1,3-diaxial arrangements of C−F bonds impart considerable polarity to the ring, resulting in an electronegative ‘fluorine face’ and an electropositive ‘hydrogen face’. For all-syn 1,2,3,4,5,6-hexafluorocyclohexane, this arrangement generates an unusually polar aliphatic ring system. Most recently the concept has been extended to the preparation of all-syn 1,2,3-trifluorocyclopropanes, a rigid ring system with fluorine atoms on one face and hydrogens on the other. Lipophilicity Log P values of such compounds indicate that they are significantly more polar than their parent alicyclic hydrocarbons and give some positive indication for a future role of such substituents in medicinal chemistry. Expanding to such a role will require access to improved synthesis methods to these motifs and consequently access to a broader a range of building blocks, however some exciting new methods have emerged recently and these are briefly reviewed.     

Synthesis and Elaboration of All‐cis‐1,2,4,5‐Tetrafluoro‐3‐Phenylcyclohexane: A Polar Cyclohexane Motif

A stereocontrolled synthesis of all‐cis‐1,2,4,5‐ tetrafluoro‐3‐phenylcyclohexane is developed as the first functionalised example of this polar cyclohexane motif. The dipolar nature of the ring, arising due to two 1,3‐diaxial C?F bonds, is revealed in the solid‐state (X‐ray) structure. The orthogonal conformation of the aryl and cyclohexyl rings in all‐cis‐1,2,4,5‐tetrafluoro‐3‐phenylcyclohexane, and in an ortho‐nitro derivative, result in intramolecular ^1hJ_HF and ^2hJ_CF NMR couplings relayed through hydrogen bonding. The aryl group of all‐cis‐1,2,4,5‐tetrafluoro‐3‐phenylcyclohexane is elaborated in different ways to demonstrate the versatility of this compound for delivering the motif to a range of molecular building blocks.     

Thiolated Janus Silsesquioxane Tetrapod: New Precursors for Functional Materials

Herein, we report synthetic strategies for the development of a bifunctional Janus T₄ tetrapod (Janus ring), in which the orthogonal silsesquioxane and organic faces are independently functionalized. An all-cis T₄ tetrasilanolate was functionalized to introduce thiol moieties on the silsesquioxane face and naphthyl groups on the organic face to introduce luminescent and self-organization properties. The stepwise synthesis conditions required to prepare such perfectly defined oligomers via a suite of well-defined intermediates and to avoid polymerization or reactions over all eight positions of the tetrapod are explored via ²⁹Si, ¹³C and ¹H NMR, FTIR and TOF-ESI mass spectroscopy. To the best of our knowledge, this is one of the few reports of Janus T₄ tetrapods, with different functional groups located on both faces of the molecule, thus expanding the potential range of applications for these versatile precursors.     

Total Synthesis of (−)-Lepadin F based on a Stereoselective Diels–Alder Reaction Controlled by a Ketolactone-type Dienophile

An efficient approach to the type III lepadin alkaloids (lepadins F and G) has been developed through a key Diels–Alder reaction, in which a novel ketolactone-type dienophile with chiral diol unit is employed to generate the desirable all-cis-trisubstituted cyclohexene with excellent regio- and stereoselectivity control. The subsequent selective sulfonylation of the diol unit followed by S_N2 cyclization under hydrogenation conditions could construct the substituted piperidine ring. By using this approach, (−)-lepadin F is synthesized from ethyl l -lactate for the first time.     

Determining the Diastereoselectivity of the Formation of Dipeptidonucleotides by NMR Spectroscopy

Proteins are composed of l -amino acids, but nucleic acids and most oligosaccharides contain d -sugars as building blocks. It is interesting to ask whether this is a coincidence or a consequence of the functional interplay of these biomolecules. One reaction that provides an opportunity to study this interplay is the formation of phosphoramidate-linked peptido RNA from amino acids and ribonucleotides in aqueous condensation buffer. Here we report how the diastereoselectivity of the first peptide coupling of the peptido RNA pathway can be determined in situ by NMR spectroscopy. When a racemic mixture of an amino acid ester was allowed to react with an 5′-aminoacidyl nucleotide, diastereomeric ratios of up to 72 : 28 of the resulting dipeptido nucleotides were found by integration of ³¹P- or ¹H-NMR peaks. The highest diastereomeric excess was found for the homochiral coupling product d -Ser-d -Trp, phosphoramidate-linked to adenosine 5′-monophosphate with its d -ribose ring. When control reactions with an N-acetyl amino acid and valine methyl ester were run in organic solvent, the diastereoselectivity was found to be lower, with diastereomeric ratios≤62 : 38. The results from the exploratory study thus indicate that the ribonucleotide residue not only facilitates the coupling of lipophilic amino acids in aqueous medium but also the formation of a homochiral dipeptide. The methodology described here may be used to search for other stereoselective reactions that shed light on the origin of homochirality.     

Controlling thermomechanical behavior of semicrystalline hydrogenated polynorbornene through the cis- to trans-cyclopentylene ratio

Though polynorbornene synthesized by ring-opening metathesis polymerization has an intrinsically all-cis configuration of the cyclopentylene backbone rings, a fraction of these rings can be epimerized to the trans configuration during hydrogenation over suitable catalysts. By varying the method of hydrogenation, semicrystalline hydrogenated polynorbornenes (hPNs) with trans levels between 0 and 36% were obtained. With increasing trans content, the glass transition temperature, melting point, and enthalpy of melting decrease modestly. By contrast, the temperature at which the hPN crystal transitions into a rotationally disordered polymorph varies strongly with trans content, ranging from 126 °C (all-cis) to 71 °C at 27% trans; at trans contents of 34% and above, no rotationally-ordered phase is observed at any temperature. The room-temperature Young's modulus shows no dependence on trans content, while the yield stress drops by 20% at 1% trans content and slowly decreases further with additional epimerization. The temperature dependence of the Young's modulus differs for trans-containing versus all-cis polymers, while the temperature dependence of the yield stress is set by the polymorph type (rotationally ordered vs. disordered).     

Synthesen der Nonactinsäure

Two stereoselective syntheses of nonactic acid I, the building block of the macrotetrolide antibiotic nonactin are described. The characteristic cis-configuration of the 2,5-substituents on the tetrahydrofuran ring of I is obtained in the first synthesis by catalytic hydrogenation of the furan derivative X. This key intermediate possesses the carbon skeleton and correct distribution of oxygen functions for conversin into nonactic acid. It is synthesized by an electrophilic substitution of 2-acetonylfuran (VI) with the N-cyclohexyl-N-propenyl nitrosonium ion (V) generated from the corresponding α-chloronitrone (VII) and silver fluoroborate, followed by hydrolysis and oxidation of the aldehyde group. The second synthesis starts with a diol already having the correct configuration of the side chain that contains the hydroxyl group. For this purpose threo-1-octen-5,7-diol (XV) is synthesized from acetylacetone in two steps. Oxidative cleavage of the terminal double bond of this threo-diol yields an aldehyde which is converted by a Wittig reaction, with the carbanion, obtained from diethyl α-methoxycarbonylethyl phosphonate, into the open chain intermediate, 2-methyl-6,8-dihydroxy-2-nonenoic acid methylester (XVIII). Base-catalyzed cyclisation of this α,β-unsaturated dihydroxy ester yields the methyl ester of nonactic acid (I) as the main product.     

The Coordination Chemistry of the N-Donor-Substituted Phosphazanes

Phosph(III)azanes, featuring the heterocyclobutane P₂N₂ ring, have now been established as building blocks in main-group coordination and supramolecular compounds. Previous studies have largely involved their use as neutral P-donor ligands or as anionic N-donor ligands, derived from deprotonation of amido-phosphazanes [RNHP(μ-NR)]₂. The use of neutral amido-phosphazanes themselves as chelating, H-bond donors in anion receptors has also been an area of recent interest because of the ease by which the proton acidity and anion binding constants can be modulated, by the incorporation of electron-withdrawing exo- and endo-cyclic groups (R) and by the coordination of transition metals to the ring P atoms. We observed recently that the effect of P,N-chelation of metal atoms to the P atoms of cis-[(2-py)NHP(μ-N^tBu)]₂ (2-py=2-pyridyl) not only pre-organises the N−H functionality for optimum H-bonding to anions but also results in a large increase in anion binding constants, well above those for traditional organic receptors like squaramides and ureas. Here, we report a broader investigation of ligand chemistry of [(2-py)NHP(μ-^tNBu)]₂ (and of the new quinolyl derivative [(8-Qu)NHP(μ-N^tBu)]₂ (8-Qu=8-quinolyl). The additional N-donor functionality of the heterocyclic substituents and its position has a marked effect on the anion and metal coordination chemistry of both species, leading to novel structural behaviour and reactivity compared to unfunctionalized counterparts.     

The Configuration of Tricyclo [7.1.1.02,7]undecanes and the Stereochemistry of the Reduction of Tricyclone

A full discussion of the configuration of tricyclo [7.1.1.0^2,7]undecanes related to cis-10, 10-dimethyltricyclo [7.1.1.0^2,7]undec-2-en-4-one (2) , the Robinson annelation product from norpinone 1 and 3-buten-2-one is given, based on 360-MHz-NMR. spectra. Nuclear Overhauser effects confirm the cis configuration of 2 , and show that the saturated ketone 10 , obtained by catalytic hydrogenation, is also all-cis with the cyclohexanone ring in the boat conformation. The parent hydrocarbon, cis-10, 10-dimethyltricyclo[7.1.1.0^2,7]undecane is compared with one of the corresponding trans isomers prepared from pinocarvone (14) . The stereochemistry of metal hydride reduction and Grignard reaction of 2 is examined.     

Diastereoselective synthesis of linear‐fused tricyclic nitrogen heterocycles by a tandem reduction‐reductive amination reaction

A two‐step diastereoselective synthesis of linear‐fused tricyclic nitrogen heterocycles has been developed from cyclic β‐ketoesters. The cyclization substrates are readily prepared by alkylation of the methyl 2‐oxo‐cycloalkanecarboxylates with 2‐nitrobenzyl bromide. Hydrogenation of these substrates initiates a reaction sequence involving (1) reduction of the aromatic nitro group, (2) condensation of the resulting hydroxyl‐amine or aniline nitrogen with the cycloalkanone and (3) reduction of the imine. The products are isolated in high yield as single diastereomers having the trans‐fused ring junction. The observed selectivity is rationalized in terms of a steric effect imposed by the ester group in the final reductive amination step which directs the incoming hydrogen to the opposite face of the molecule. By comparison, reductive cyclizations of substrates lacking the stereodirecting ester group give mixtures of cis and trans products with a preference for the cis‐fused heterocycle.     

Synthesis,characterization, and solution properties of 5-ethyl-substituted poly(L-prolines). Synthesis of cis- and trans-5-ethyl-L-proline and optically active poly(cis-5-ethyl-D-proline)

This article reports a continuation of our work on the substituent effects on the preferred helical conformations and the mutarotation of substituted poly(L -prolines). The size of the substituent has been increased from a methyl group to an ethyl group in the 5 position. The purpose is twofold: (i) according to our theoretical conformational energy calculations, an ethyl group in the 5 position can exert a greater steric effect than can a methyl group; and (ii) the rotation-isomerization of the ethyl group introduces a new intriguing fact to the problem. The cis isomer of 5-ethylproline was synthesized by catalytic hydrogenation of Δ′-2-ethylpyrroline-5-carboxylic acid, whereas for trans-5-ethylproline, a chemical separation method involving p-toluenesulfonyl chloride was used. The resolution of cis-5-ethylproline and the assignment of absolute configurations have been carried out by fractional crystallization and circular dichroism spectroscopic techniques, respectively. Poly(cis-5-ethyl-D -proline) was obtained from its corresponding N-carboxyanhydrides via a ring opening polymerization.     

Transformation of phospholipid membranes by thiyl radicals via cis–trans isomerization of fatty acid residues

Thiyl radical-mediated transformation of unsaturated fatty acid residues are reported. Beside the initiation of lipid peroxidation, thiyl radicals can efficiently cause isomerization of fatty acid residues in a catalytic manner. The latter process is observed in homogeneous solutions as well as in organized assemblies, leading to a denaturation of the natural all-cis-isomers of fatty acid residues of lipid bilayers. The degree of denaturation goes parallel with an increase in the number of double bonds and in the hydrophobicity of thiols. For arachidonic acid methyl ester, a decay of the all-cis-isomer to approximately 30% after a gamma irradiation dose of 1.8 kGy in micelles is observed. The reversibility of the isomerization reaction is demonstrated in liposomes by the fact that the cis/trans-equilibrium is independent of configuration of the starting compound.     

Hydrogenation of Borylated Arenes

A cis‐selective hydrogenation of abundant aryl boronic acids and their derivatives catalyzed by rhodium cyclic (alkyl)(amino)carbene (Rh–CAAC) is reported. The reaction tolerates a variety of boron‐protecting groups and provides direct access to a broad scope of saturated, borylated carbo‐ and heterocycles with various functional groups. The transformation is strategically important because the versatile saturated boronate products are difficult to prepare by other methods. The utility of the saturated cyclic building blocks was demonstrated by post‐functionalization of the boron group.     

Room‐Temperature,Ligand‐ and Base‐Free Heck Reactions of Aryl Diazonium Salts at Low Palladium Loading: Sustainable Preparation of Substituted Stilbene Derivatives

The Pd(OAc)₂‐catalyzed Heck reaction of aryl diazonium salts with 2‐arylacrylates led to cis‐stilbenes with good to excellent stereoselectivity. The environmentally friendly protocol developed in this work features low palladium loading in technical‐grade methanol at room temperature under base‐, additive‐, and ligand‐free conditions. The same protocol applied to simple Heck coupling of aryl diazonium salts with methyl acrylate allows astonishingly low palladium loading, down to 0.005 mol %. The stereoselectivity experimentally observed for the synthesis of cis‐stilbenes has been rationalized by DFT calculations. Moreover, the role of methanol in promoting the reaction has been clarified by a computational study.     

Three-membered ring formation reaction—III : Mechanism of the reaction of α-halogenoacrylic ester with organozinc compounds

The stereochemistry of ring formation in the reaction of α-halogenoacrylic ester with organozinc compounds was studied using β-deuterated α-halogenoacrylic ester. A quantitative study was made on the steric course of every step of the reactions involved in the synthesis of methyl β-deuterio-α-bromoacrylate-cis-d₁ starting from methyl propiolate. The mode of the CC double bond opening of methyl β-deuterio-α-bromoacrylate-cis-_d1 to form dimethyl 1 -bromo-2-propyl-cis-1,2- cyclopropanedicarboxylate-d₂ was confirmed to be cis and trans in a 50 to 50 ratio. Asymmetric syntheses for the cyclopropanedicarboxylic ester were possible, especially under the influence of chiral organozinc alkoxide system. A stepwise mechanism was postulated for the ring formation reaction.     

Convenient synthesis of 1-aryl-9H-β-carboline-3-carbaldehydes and their transformation into dihydropyrimidinone derivatives by Biginelli reaction

In the present work, a practical synthesis of 1-aryl-β-carboline-3-carbaldehydes as versatile building blocks and their application in Biginelli reaction is reported. The starting material of the four-step synthesis is racemic tryptophan methyl ester. The procedure involves a Pictet–Spengler cyclization, a dehydrogenation, an ester reduction, and an alcohol oxidation step. The β-carboline-3-carbaldehydes were further transformed using a Biginelli reaction into derivatives containing a pharmacologically significant dihydropyrimidine ring at position-3.