Copper-catalyzed Csp-S cross-coupling is known to form rare macrocyclic alkynyl sulfides. Computational study now suggests a mechanism for the reaction pathway. Upon formation of Cu-S species, subsequent a-addition/elimination at the ethynylic carbon affords the desired macrocycle

Energy-transfer processes involving copper complexes are rare. Using an optimized heteroleptic copper complex, Cu(bphen)(XantPhos)BF4, photosensitized E → Z isomerization of olefins is demonstrated. The XantPhos ligand afforded sensitizers with improved catalyst stability, while the bphen ligand lengthened the excited-state lifetime. A series of 25 di- and trisubstituted alkenes underwent photoisomerization, including macrocycles and 1,3-enynes. Cu(bphen)(XantPhos)BF4 could also be employed in a tandem ATRA/photoisomerization process employing arylsulfonyl chlorides, an example of photoisomerization with halide-substituted olefins

Flow science was implemented in the curriculum at UdeM though the NSERC CREATE grant in Continuous Flow Science. The training program involved both interpersonal and technical skills development. Examples include new practical laboratory experiments and traditional course material incorporated in the context of a course on Green Chemistry. A series of value-added training acitivities brought together students from various fields that intersect within flow chemistry, broadening horizons and providing a unique perspective on an emerging technology. As a whole, implementing flow chemistry in a chemistry curriculum benefits from a multipronged approach involving hands-on training, course work, and workshops.

The synthesis of rare macrocyclic alkynediyl sulfides via a new Cu-catalyzed Csp-S cross-coupling is presented. The catalytic protocol (Cu(MeCN)4PF6/dtbbpy) promotes macrocyclization of peptides, dipeptides and tripeptides at ambient temperature (14 examples, 23→73 % yields) via thiols and bromoalkynes, and is chemoselective with regards to terminal alkynes. Importantly, the underexplored alkynediyl sulfide functionality incorporates a rigidifying structural element and opens new opportunities for diversification of macrocyclic frameworks through S-oxidation, halide addition and azide-alkyne cycloaddition chemistries to integrate sulfones, halides or valuable fluorophores (7 examples, 37→92 % yields).

Copper-catalyzed cross-coupling of thiols and bromoalkynes affords a mild, rapid and selective Csp-S coupling with broad scope, enabling the use of aryl-, alkyl- and silyl-substituted alkynyl coupling partners (38 total examples, 50-99 % yields). Importantly, the method enables the preparation of difficult-to-access bis-heteroatom-functionalized (S,S-, S,P- and S,N-) alkynes.

The relative stability and predictable reactivity of alkynyl sulfides make them ideal synthons for the development of new transformations. Classic methods for forming alkynyl sulfides relied on dehydrohalogenation approaches. However more recent methods have focused on employing umpolung strategies, as well as nucleophilic and electrophilic thiol alkynylation. In addition, the recent syntheses of Csp-S bonds have trended towards exploiting catalysis and expanding the reaction scope of the methods. A survey of existing methods to form alkynyl sulfides is presented as well as an evaluation with regards to the scope of each method, to provide the reader with an overview of advantages and limitations of current technology.

A series of 12 new copper-based photocatalysts of the type Cu(N^N)(P^P)BF4 were synthesized bearing π-extended diimine ligands. The complexes have red shifted absorptions and larger extinction coefficients than complexes prepared with a parent diimine, dmp. The complexes were evaluated for their ability to promote three different photochemical transformations. While the complexes were inactive in a reductive PCET process, the complexes afforded good yields in both SET and ET processes. Interestingly, homoleptic copper-complexes derived from the π-extended diimines were significantly more active in SET processes than analogous complexes with simpler diimines.

Macrocycles can restrict the rotation of substituents through steric repulsions, locking in conformations that provide or enhance the activities of pharmaceuticals, agrochemicals, aroma chemicals, and materials. In many cases, the arrangement of substituents in the macrocycle imparts an element of planar chirality. The difficulty in predicting when planar chirality will arise, as well as the limited number of synthetic methods to impart selectivity, have led to planar chirality being regarded as an irritant. We report a strategy for enantio- and atroposelective biocatalytic synthesis of planar chiral macrocycles. The macrocycles can be formed with high enantioselectivity from simple building blocks and are decorated with functionality that allows one to further modify the macrocycles with diverse structural features.

https://cen.acs.org/synthesis/catalysis/Enzyme-smooths-path-planar-chiral/98/i8

https://nouvelles.umontreal.ca/article/2020/02/21/faconner-les-molecules/

A bifunctional copper-based photocatalyst has been prepared that employs a novel pyrazole-pyridine ligand incorporating a sulfonamide moiety that functions as an intramolecular hydrogen-bond donor for a photochemical PCET process. In typical reductive PCET processes, the photocatalyst and H-bond donor must have an appropriate redox potential and pKa respectively to promote the PCET. When working in concert in a bifunctional catalyst such as Cu(pypzs)(BINAP)BF4, the pKa of the H-bond donor can have an acidity that is orders of magnitude less and still efficiently promote the PCET process. A reductive pinacol-type coupling can be performed using a base-metal derived photocatalyst to afford valuable diols in good to excellent yields (24 examples, 46-99 % yield), from readily available aldehydes and ketones.

A photochemical hydroalkynylation is reported employing a metallaphotoredox approach using cobalt catalysis and an organic dye, 4CzIPN. The protocol enables catalysis without the need for stoichiometric metal reductants, normally needed to convert higher oxidation state cobalt complexes to their more active lower oxidation states. The hydroalkynylation provides 1,3-enynes in good to high yields and E-selectivity (25-99% yield, 17→>99:1 E:Z, 27 examples). Importantly, “cross-dimerizations” of terminal alkynes that are typically rare are also possible and occur with unusually high levels of stereoselection. In addition, macrocyclic hydroalkynylations are reported in good to high yields, affording macrocyclic enyne motifs which are found in numerous bioactive natural products.

The renewable macrocyclic musk 3-methylcyclohexadec-6-enone was prepared via macrocyclic olefin metathesis on gram scale using two different protocols: a room temperature batch process which afforded a 57 % yield of the desired macrocycle, but required long reaction times (5 d). In contrast, a continuous flow strategy provided a lower yield of 32% of macrocycle, although the short reaction times (150 °C, 5 min) improve throughput (1 gram/4.8 h). Batch and continuous flow protocols were also tested on other macrocyclizations involving substrates bearing tri-substituted olefins.

A copper-based photocatalyst, Cu(tmp)(BINAP)BF4, was found to be active in a photoredox Appel-type conversion of alcohol to bromides. The catalyst was identified from a screening of 50 complexes and promoted the transformation of primary and secondary alcohols to their corresponding bromides and carboxylic acids to their anhydrides. The protocol was also amendable and optimized under continuous flow conditions.

The synthesis and derivatization of carbazoles based upon the natural product clausine C has been accomplished using two different two-step continuous processes. The resulting carbazoles (9 examples, 33-74 % yield) were prepared via a continuous flow set-up integrating a UV-mediated transformation employing a purple LED reactor (394 nm) as the first step in the multi-step sequence. The second derivatization step involved cross-coupling through Pd-catalyzed Suzuki cross-coupling or Ni-catalyzed metallophotoredox cross-coupling with potassium trifluoroborate salts. The latter represents the first example of using sequential photochemical reactors, at different wavelengths, in a continuous flow process.

An undergraduate teaching laboratory experiment involving a continuous flow, photocatalytic thiol-ene reaction using visible light irradiation is described that allows students to explore concepts of green chemistry, photochemistry, photocatalysis, and continuous flow chemistry.

A library of 50 copper-based complexes derived from bisphosphines and diamines was prepared and evaluated in three mechanistically distinct photocatalytic reactions. In all cases, a copper-based catalyst was identified to afford high yields, where new heteroleptic complexes derived from the bisphosphine BINAP displayed high efficiency across all reaction types. Importantly, the evaluation of the library of copper-complexes revealed that even when photophysical data is available, it is not always possible to predict which catalyst structure will be efficient or inefficient in a given process, emphasizing the advantages for catalyst structures with high modularity and structural variability.

Traditional macrocyclization reactions often use batch reactors and/or apparatus for slow addition protocols. However, an emerging alternative exists in performing macrocyclizations in continuous flow. Continuous processing can offer several advantages, including higher yields and shorter reaction times due to improved mass and energy transfer. To date, continuous flow macrocyclization has impacted well-known reactions for macrocyclization, such as the olefin metathesis, the Glaser-Hay coupling and CuAAC reactions, been applied to ring expansions, as well as opening the door to exploring new photochemical macrocyclizations.

An undergraduate teaching laboratory experiment involving a continuous flow, bleach-mediated oxidation of aldehydes under biphasic conditions was developed that allowed students to explore concepts of mixing or mass transport, solvent sustainability, biphasic reactions, phase transfer catalysis, and continuous flow chemistry.

Polycyclic heterocycles can be formed in good to excellent yields via photochemical conversion of the corresponding substituted aryl azides under irradiation with purple LEDs in a continuous flow reactor. The experimental set-up is tolerant to UV-sensitive functional groups while affording diverse carbazoles, as well as an indole and pyrrole framework, in short reaction times. The photochemical method is presumed to progress through a mechanism differing from the other methods of azide activation involving transition metal catalysis.

A photochemical dual-catalytic cross-coupling to form alkynyl sulfides via C(sp)-S bond formation is described. The cross-coupling of thiols and bromoalkynes is promoted by a soluble organic carbazole-based photocatalyst using continuous flow techniques. Synthesis of alkynyl sulfides bearing a wide range of electronically and sterically diverse aromatic alkynes and thiols can be achieved in good to excellent yields (50-96%). The simple continuous flow setup also allows for short reaction times (30 min) and high reproducibility on gram scale. In addition, we report the first application of photoredox/nickel dual catalysis towards macrocyclization, as well as the first example of the incorporation of an alkynyl sulfide functional group into a macrocyclic scaffold.

A phase separation/continuous flow strategy employing an oxidative Glaser–Hay coupling of alkynes has been applied toward the synthesis of the macrocyclic core of complex pharmaceutical vaniprevir. The phase separation/continuous flow strategy afforded similar yields at 100–500 times the concentration and at shorter reaction times than common slow addition/high dilution techniques. In addition, dendritic PEG cosolvents were employed in the phase separation strategy for the first time and shown to allow productive macrocyclization at concentrations up to 200 mM.

A synthesis of neomarchantin A has been achieved wherein key bond constructions involving C–O or C–C bond formations were augmented via continuous flow techniques. Of note, the synthesis of neomarchantin A represents the first demonstration of catalytic macrocyclic olefin metathesis as a key step for the synthesis of a macrocyclic bisbibenzyl natural product.

An increasingly sustainable photochemical synthesis of carbazoles was developed using a catalytic system of Fe(phen)3(NTf2)2/O2 under continuous flow conditions and was demonstrated on gram-scale using a numbering-up strategy. Photocyclization of triaryl and diarylamines into the corresponding carbazoles occurs in general in higher yields than with previously developed photocatalysts.

A formal total synthesis of ivorenolide A has been accomplished employing a Z-selective olefin cross metathesis and a macrocyclic Glaser-Hay coupling as key steps. The macrocyclization protocol employed a phase separation/continuous flow manifold whose advantages include catalysis, fast reaction times, high concentrations and facile scale-up.

Photochemistry is an important tool in organic synthesis that has largely been underdeveloped in comparison to thermal activation. Recent advances in technology have ushered in a new era in synthetic photochemistry. The emergence of photocatalysis, which exploits sensitizers for the absorption of visible light, has provided organic chemists with a new route to the generation of radical intermediates for synthesis. Of particular interest is the development of Cu-based complexes for photocatalysis, which possess variable photophysical properties and can display complementary reactivity with common photocatalysts based on heavier transition metals such as Ru or Ir.  Heteroleptic Cu-based sensitizers incorporating the presence of both a bisphosphine and diamine ligand bound to the copper center are a promising class of photocatalysts. Their synthesis is a single step, often involving only precipitation for purification.  In addition, it was shown that the sensitizers could be formed in situ in the reaction mixture, simplifying the experimental set-up.  The heteroleptic nature of the Cu-complexes also affords opportunities to fine tune properties. For example, structurally rigidified bisphosphones reinforce geometries about the metal center to extend the excited state lifetime. Variation of the diamine ligand can influence the excited state oxidation/reduction potentials and optical absorbances. The heteroleptic complex Cu(XantPhos)(neo)BF4 has demonstrated utility in the synthesis of helical polyaromatic carbocycles. The synthesis of [5]helicene, a  relatively simple member of the helicene family, was improved from the existing UV-light mediated method, by eliminating the formation of unwanted by-products. In addition, the Cu-based sensitizers also promoted the formation of novel pyrene/helicene hydrids for materials science application. The synthetic methods that were developed were augmented when combined with continuous flow technology. The irradiation of reaction mixtures as they are pumped through small diameter tubing provides a more homogeneous and increased photon flux when compared to irradiation in round-bottom flasks or other batch reactors.  The value of continuous flow methods is also evident when examining UV-light photochemistry, where the simple and safe experimental set-ups allow for further exploration of high energy light for synthetic purposes. The synthesis of functionalized complex carbazoles was also studied using both a visible light method exploiting a heteroleptic copper-based sensitizer, as well as a UV-light mediated method. It was demonstrated that both the photocatalysis methods and UV light photochemistries were rendered more user friendly, safe, and reproducible when using continuous flow methods.  Interestingly, the two photochemical methods often afford contrasting selectivities as a result of their inherently different mechanisms. It can be expected that the complementarity of the various photochemical methods will be an asset to synthetic chemists as the field continues to evolve.

An evaluation of both a visible-light and UV-light mediated synthesis of carbazoles from various triarylamines with differing electronic properties under continuous flow conditions has been conducted. In general, triarylamines bearing electron-rich groups tend to produce higher yields than triarylamines possessing electron-withdrawing groups. The incorporation of nitrogen-based heterocycles, as well as halogen-containing arenes in carbazole skeletons was well tolerated, and often synthetically useful complementarity was observed between the UV-light and visible-light (photoredox) methods.

Efficient direct synthesis of macrodiolides via catalysis using Hf(OTf)4 is possible in high yields, forming water as the sole by-product. The first protocol for the direct synthesis of macrodiolides from equimolar mixtures of diols and dicarboxylic acids was developed (58-96 %).  In addition, modification of the reaction concentration allows for the synthesis of head-to-tail macrodiolides from the corresponding seco acids. The catalytic preparation of the macrodiolides using a commercially available catalyst without the need for slow addition or azeotropic condition provides an operationally simple alternative to protocols which employ toxic tin catalysts or stoechiometric activation strategies.

The continuous flow synthesis of a series of 11- to 26-membered macrocycles via copper-catalyzed azide–alkyne cycloaddition is reported.  The approach employs homogeneous catalysis to promote formation of triazole-containing macrocycles in good to excellent yields (65- 90 %) at relatively high concentration (30-50 mM) using a phase separation strategy.

Efficient direct macrolactonization of seco acids can be catalyzed by Hf(OTf)4 in high yields forming water as the sole by-product. The Hf(OTf)4 catalyst possesses unique reactivity characteristics relative to other Lewis acids as it promotes macrolactonization over hydrolysis even in the presence of excess water.  In addition to forming a variety of macrolactones and benzolactones (55-90 %), intermolecular direct esterifications of carboxylic acids and alcohols were also possible and demonstrated compatibility with common carbamate, silyl ether, alkoxymethyl ether and acetal protecting groups. All of the macrolactonization and esterification processes developed are operationally simple, “one-pot” reactions that exploit a commercially available catalyst without the need for slow addition or azeotropic techniques.

A continuous flow UV light reactor has been constructed using commercially available equipment and its efficiency was demonstrated by performing a photocyclodehydrogenation reaction to prepare carbazole derivatives of the drug carprofen.

A macrocyclic Cu-catalyzed Sonogashira-type cross-coupling reaction has been developed that employs an operationally simple CuCl/phen/Cs2CO3 catalyst system.  Macrocyclizations can be performed at relatively high concentrations without the need for slow addition techniques and form macrocycles with various ring sizes and functional groups.  The optimized protocol was employed in the synthesis of (S)-zearalane, demonstrating applicability towards the synthesis of a macrocycle with known biological activity.

Macrocyclic olefin metathesis has seen advances in the areas of stereochemistry, chemoselectivity and catalyst stability, but strategies aimed at controlling dilution effects in macrocyclizations are rare.  Herein, a protocol to promote macrocyclic olefin metathesis, one of the most common synthetic tools used to prepare macrocycles, at relatively high concentrations (up to 60 mM) is described via exploitation of a phase separation strategy. A variety of macrocyclic skeletons could be prepared having either different alkyl, aryl or amino acids spacers.

An advanced strategy for efficient macrocyclic Cu(I)-catalyzed cycloaddition is described. The key features include: employing azide-iodoalkyne cycloadditions (CuAiAC), low catalyst loadings, relatively high concentrations (30 mM→300 mM) and application to continuous flow. The remarkably efficient new tool affords a variety of macrocyclic skeletons having either different alkyl, aryl or amino acid spacers in high yields, (70-97 %).  The macrocyclic CuAiAC process affords macrocycles having an iodotriazole moiety that can be further functionalized using standard Pd-catalyzed cross-couplings.

Synthesis of novel helically chiral aromatics resulting from fusion of pyrene and [4]- or [5]helicene has been accomplished using Cu-based photoredox catalysis in batch and in continuous flow. The solid state structure, UV-Vis absorption and fluorescence spectroscopy of the pyrene/helicene hybrids compared to that of the parent [5].

An efficient, mild, photosynthetic protocol for the preparation of N-aryl and N-alkyl carbazoles has been achieved utilizing visible light under continuous flow conditions while employing a Cu-based sensitizer, [Cu(Xantphos)(dmp)]BF4. The method allows for the straightforward synthesis of different carbazole skeletons including various substituents, heteroatoms and incorporation of complex carbon architectures.

Novel chiral C1-symmetric NHC ligands can be prepared via di-alkylation of chiral imidazoline scaffolds. Asymmetry in the ligand/metal complexes results from a chiral relay effect. The C1-symmetric nature of the NHC ligand was proposed to allow for improved reactivity versus other achiral and chiral NHC complexes. The benefit of such ligands was demonstrated in Cu-catalyzed oxidative coupling reactions.

A phase separation/continuous flow macrocyclization protocol eliminates the need for high-dilution conditions and can be used to prepare gram quantities of biologically relevant macrocyclic lipid structures. The method presents several green advantages towards macrocycle synthesis: 1) the prevention of unwanted oligomers and waste, 2) a reduction in the large quantities of toxic, volatile organic solvents and 3) the use of PEG as an environmentally benign reaction media. Macrocycles could be synthesized in high yields (up to 99%) in short reaction times (1.5 h) and on gram scales without the need to alter the reaction conditions.

The first evaluation of the structural effects of 6 different PEG-derived polymers in MeOH mixtures on their aggregation abilities, ability to control dilution effects and catalysis has been performed through examining surface tension measurements and the isolated yields of a model Glaser-Hay macrocyclization reaction of diyne 3. Three different structural effects were studied involving: 1) the presence of capping groups on the terminal hydroxyl functionalities of the polymers, 2) the length of the polymer chain and 3) the effects of branching alkyl groups in the polymer backbone. The data obtained provides important guidelines for conducting macrocyclizations using PEG/solvent mixtures, suggesting that macrocyclizations are most efficient at high ratios of PEG/MeOH and when employing medium-length lipophilic branched PPG polymers. In particular, the use of PPG bearing terminal uncapped hydroxyl groups allows for a significant reduction in the catalyst loading. The macrocyclization studies reinforce that the aggregation characteristics of PEG-derived solvents can be harnessed in catalysis, particularly in reactions where control of concentration effects is important.

The reactivity of a Cu catalyst for oxidative coupling is modulated by a small molecule additive, diethyl malonate, that slows over-oxidation of 2-naphthols. Efficient heterocoupling between electron-rich and electron-poor 2-naphthols/2-naphthylamines affords C1-symmetric BINOLs with yields ranging from 35-98%.

Macrocyclization via Glaser-Hay coupling can be conducted at high concentrations by exploiting solvent mixtures containing PEG400/MeOH. The origin of the selectivity has been studied using surface tension measurements, UV spectroscopy and chemical "tagging" and demonstrate the dependence of the yield and selectivity on the aggregation of PEG400 and its ability to preferentially solubilize organic substrates, resulting in a phase separation from the catalyst system.

A photochemical synthesis of [5]helicene employing a copper-based sensitizer 7 has been developed that avoids the disadvantages associated with the traditional UV light mediated method. The visible light mediated synthesis uses common glassware and a simple household light bulb without the competing formation of [2+2] cycloadducts, regioisomers or the overoxidation product benzo[ghi]perylene 3. Preliminary results show that the reaction time can be significantly reduced through the use of a continuous flow strategy.

Efficient macrocyclization can be conducted at high concentrations employing microwave irradiation and a phase separation strategy. The rate of the Glaser-Hay macrocyclization is accelerated using microwave irradiation and reaction times decreased from 48 h to 1-6 h, depending on the nature of the substrate. Macrocyclization concentrations could be increased up to 0.1M compared to traditional concentrations (0.2mM).

Macrocycles are abundant in numerous chemical applications, however the traditional strategy for the preparation of these compounds remains cumbersome and environmentally damaging; involving tedious reaction set-ups and extremely dilute reaction media. The development of a macrocyclization strategy conducted at high concentrations is described which exploits phase separation of the catalyst and substrate, as a strategy to control dilution effects. Sequestering a copper catalyst in a highly polar and/or hydrophilic phase can be achieved using a hydrophilic ligand, T-PEG1900, a PEGylated TMEDA derivative. Similarly, phase separation is possible when suitable copper complexes are soluble in PEG400, a green and efficient solvent which can be utilized in biphasic mixtures for promoting macrocyclization at high concentrations. The latter phase separation technique can be exploited for the synthesis of a wide range of industrially relevant macrocycles with varying ring sizes and functional groups.

Zwitterionic carboxylates can be thermally decarboxylated in the presence of copper salts to form NHC-copper complexes. The selective formation of either mono- or bis-NHC complexes is possible through simple control of the molar equivalents of the copper salt. A variety of different NHC ligands with either saturated or unsaturated backbones or bearing N-aryl or N-alkyl substituents can be complexed to copper.

lign: justify;" class="font_8">Quinolinium salt 3 is an effective additive that acts as a conformation control element (CCE) to promote macrocyclization to form rigid cyclophanes via olefin metathesis or Glaser-Hay coupling, which do not cyclize in the absence of the additive. The additives are easily synthesized and highly modifiable and have solubility profiles which allow for simple recovery via filtration.

Dimerization of a hydroxycarbazole produces an axially chiral biaryl, BICOL (2). One enantiomer (R)-2, is capable of enantioselective binding to different polymorphs of DNA. The biaryl (R)-2 was shown by fluorescence and circular dichroism to induce a shift of Z-DNA to B-DNA. The opposite enantiomer (S)-2 shows no specific binding. The significant difference in behaviour between the two enantiomers (S)-2 and (R)-2is in line with molecular modelling studies which show two very different binding geometries between the enantiomers with each polymorph of DNA.

Highly reactive chiral Ru-based catalysts possessing C1-symmetric N-heterocyclic carbene ligands adorned with one N-alkyl group and one N-aryl group, were evaluated in asymmetric desymmetrizations to form cyclic products possessing a tetrasubstituted olefin.

The axially chiral 1,1'-binaphthalene-2,2'-diol (BINOL) structure is a privileged structure in catalysis. Many synthetic methods exist to prepare C2-symmetric BINOLs, but methods for the direct syntheses of C1-symmetric BINOLs from mixed oxidative couplings remains underdeveloped. Consequently, bis-N-heterocyclic carbene (NHC) Cu complexes can be used for both homo- and hetero-oxidative coupling of 2-naphthols. Product yields of homocouplings are highest when using electron deficient 2-naphthols. Investigations into the mixed coupling of electron-poor and electron-rich 2-naphthols suggest that bis-NHC-Cu complexes perform the oxidative coupling via a radical-addition type mechanism. Mixed couplings between electron rich and electron poor 2-naphthols can be conducted to give good yields of the mixed products.

Four new Ru-based olefin metathesis catalysts that possess an N-heterocyclic carbene (NHC) ligand with Bn or n-Pr N-alkyl groups have been prepared. The synthetic routes developed for the synthesis of the required dihydroimidazolium salts are general. Catalysts bearing larger NHC ligands with larger N-alkyl groups displayed improved thermal and solution state stability up to 80 °C. The reactivity of the new catalysts in ring closing metathesis is directly related to the increased steric bulk of the NHC ligand. The new catalysts have been evaluated in desymmetrization reactions and the nature of the N-alkyl group of the NHC ligands has been shown to have an important effect on the observed enantioselectivities.

Functionalized heterohelicenes were prepared using sequential olefin metathesis and direct arylation reactions. Functionalization via C-H activation always occurs at the least hindered position of the [5]helicene carbon skeleton. Attempts at blocking the least hindered positions to force arylation at the interior of the helicene skeleton result in decomposition of the starting material. Installation of larger aromatic groups via arylation can form helicenes albeit with limited solubility in common organic solvents.

Efficient macrocyclic olefin and en-yne metathesis can be conducted employing benzyl ester auxiliaries that engage in quadrupolar interactions. The use of amide linkers in place of esters results in higher overall yields. Computational studies suggest that amide auxiliaries stabilize conformers conducive to macrocyclization over 22 times more efficiently than an ester linkage. Molecular modelling studies also suggest a preference for engaging in quadrupolar interaction for the amide auxiliaries, in contrast to the lp-π interactions predicted for ester based auxiliaries.

The asymmetric synthesis of [7]helicene was accomplished in good ee (80%) using a kinetic resolution via asymmetric olefin metathesis. Three key factors contributed to the success of the kinetic resolution: the use of new Ru-based olefin metathesis catalysts bearing C1-symmetric N-heterocyclic carbene ligands, the use of simple olefins as additives to control the nature of the propagating alkylidene and the use of hexafluorobenzene as a solvent.

2,3,4,5,6-Pentafluorobenzyl and 3,5-bistrifluoromethylbenzyl ester auxiliaries can enable difficult macrocyclizations to afford rigid all-carbon paracyclophanes. The effectiveness of these auxiliaries has been demonstrated in preparing the carbon skeleton of the macrocyclic natural product longithorone C.

In asymmetric olefin metathesis reactions, the addition of halide additives is often required to augment enantioselectivities, despite the fact that the additives result in catalysts with diminished reactivities. Exploiting previously reported mechanistic studies, the preparation of new chiral Ru-based catalysts was accomplished that possess a high level of reactivity and successfully induces high levels of asymmetry in desymmetrization reactions without the use of halide additives.

Efficient direct en-yne metathesis of strained macrocyclic systems is possible using highly active Grubbs-Hoveyda 2nd generation catalyst and when exploiting fluoroarene-arene gearing interactions. These interactions are effective even under high reaction temperatures and in the presence of a competitive π-rich solvent such as toluene. These results suggest that efficient π-π stacking, or π-lp interactions between auxiliaries containing pentafluorophenyl and 3,5-bis(trifluoromethyl)phenyl groups are responsible for the good yields of macrocyclization products. The 3,5-bis(trifluoromethyl)benzyl gearing elements provide higher yields and greater E-selectivity in the macrocyclic en-yne metathesis to form model paracyclophanes that could be applied towards the preparation of members of the longithorone family of natural products.

A chiral Ru-based olefin metathesis catalyst bearing a chiral NHC ligand that is both C1-symmetric and monodentate is described. The catalyst possesses a NHC ligand with an unprecedented geometry whereby the N-alkyl group of the ligand is syn to the carbene. The catalyst shows increased reactivity when compared to existing chiral Ru-based catalysts that possess a C2-symmetric NHC and successfully induces asymmetry in desymmetrization reactions.

Efficient direct en-yne metathesis of strained macrocyclic systems is possible using highly active Grubbs-Hoveyda 2nd generation catalyst and when exploiting fluoroarene-arene gearing interactions. These interactions are effective even under high reaction temperatures and in the presence of a competitive π-rich solvent such as toluene. These results suggest that efficient π-π stacking, or π-lp interactions between auxiliaries containing pentafluorophenyl and 3,5-bis(trifluoromethyl)phenyl groups are responsible for the good yields of macrocyclization products. The 3,5-bis(trifluoromethyl)benzyl gearing elements provide higher yields and greater E-selectivity in the macrocyclic en-yne metathesis to form model paracyclophanes that could be applied towards the preparation of members of the longithorone family of natural products.

The possibility of combining the electronic properties of oligothiophenes with potential chiroptical properties has fueled research in the area of thiaheterohelicenes. Recent reports that these molecules also exhibit fascinating interactions with biologically important macromolecules place further emphasis on the need for new synthetic methods to access thiaheterohelicenes. This review highlights the synthetic methods currently being used to prepare thiaheterohelicenes and dicusses the role that chemical synthesis plays in the exploration of the properies of these helically chiral molecules.

Metathesis with a twist! A ring-closing metathesis strategy has been developed for the preparation of various substituted [5]-helicene motifs and [6]- and [7]-helicene. The two optimized protocols include a method utilizing Grubbs 2nd generation catalyst under microwave irradiation and a second employs a modified Grubbs-Hoveyda catalyst at 40 °C in a sealed reaction vessel.

The formation of various macrocyclic cyclophanes via ring closing olefin metathesis is possible through the use of a pendant pentafluorobenzyl ester group. A quadrupolar interaction between the cyclophane core and the auxiliary is proposed to act as a gearing element facilitating cyclization. The development of these non-covalent interactions as gearing elements as well as the investigation of the effect of the site of metathesis upon the macrocyclization process is described.

Exploiting solution phase quadrupolar interactions between arenes and pentafluoroarenes reverses the tendency to form dimeric products during macrocyclizations to form cyclophanes. The preparation of various macrocyclic paracyclophanes possessing multiple ring sizes and diverse functionality via olefin metathesis is made possible due to the interaction between the cyclophane core and a pendant pentafluoroarene.

Marine natural products that feature polycyclic guanidine motifs, such as crambescidins and batzelladines, are known to have antiviral activities toward some viruses including HSV and HIV. In this study we evaluated a synthetic library containing 28 batzelladine analogues, the structures of which encompass and surpass variations seen in natural batzelladines, for their ability to inhibit HIV-1 envelope-mediated cell-cell fusion. Clear structure-activity relationships were revealed and indicated that the best inhibitors of fusion were most similar in structure to natural batzelladine F, with IC50 values ranging from 0.8 to 3.0 μM. Proceeding from the earlier finding that some batzelladines block gp120-CD4 binding, modeling studies of inhibitors binding to the CD4 binding site on gp120 were carried out. The lowest energy models suggest a preferred orientation for inhibitor binding that is consistent with the observed structure-activity relationships.

The oxidation of two tethered Biginelli adducts was examined as a potential key step in total syntheses of highly oxidized batzelladine and crambescidin alkaloids. Although angular hydroxyl substitution could not be introduced, dehydrogenation was readily accomplished. This latter conversion is a key step in the first total synthesis of dehydrobatzelladine C.

Double tethered Biginelli condensations furnish linked polycyclic bisguanidines or bisureas. Alteration of the bis­ketoester component allows bispolycyclic guanidine motifs to be constructed that resemble natural batzelladine alkaloids or have novel linkages.

The syntheses of two distinct families of phenylyne helical cyclophanes with potential for organic materials are described. The meta-bonded atropisomers afford interesting bowtie-like and butterfly-like conformers from a palladium(0), copper-mediated coupling sequence. Molecular modeling revealed the contrasting stereochemistry in these systems from differential molecular folding pathways during cyclization. The interplanar separation of the superimposed aromatic rings is ~3.5 Å.

Copper-mediated oxidative coupling of 3 afforded the strained product 4 from intramolecular cyclization rather than the triply bridged cyclophane 5 from dimerization. X-ray analysis of the bromo derivative 15 confirmed the distorted nature of the butadiyne bridge (bond angles 164.1 and 153.4). The distortion in the strained triple bond is reflected in its cycloaddition reactivity. Cyclopentadiene and 1,3-cyclohexandiene afforded the new adduct macrocycles 16 and 17, respectively

An efficient method for the in situ desilylation/oxidative dimerization of (trialkylsilyl)acetylenes is described. This protocol avoids the complications encountered with sensitive diynes by eliminating the deprotection and isolation steps. Various aromatic and alkyl diynes and tetraynes can be synthesized in a straightforward manner in good yields (82-99%) from TIPS-protected acetylenes. This method facilitates the efficient synthesis of novel tetrayne-bridged acetylenic cyclophanes 6 and 7 in a direct manner.

The synthesis of a series of novel acetylenic cyclophanes is described. X-ray crystallographic analysis of the core structure revealed a twisted conformation with helical chirality. Preliminary results suggest that these cyclophanes, with appropriate functionality, have the potential to act as unique liquid crystalline materials.

Relieve strain with a twist! Synthesis of the paracyclophane 1 and its dimer 2 employed a sequence of metal-mediated couplings. The X-ray analysis of 2 revealed a helical twist inherent in this structure, which created extended arms, that trapped a molecule of solvent. A carboxylic acid derivative of 1 was also prepared, and its structure indicated the diyne rod moiety of 1 is distorted more than in analogous compounds.