Thomas R. Hoye

The hexadehydro-Diels–Alder reaction

Arynes (aromatic systems containing, formally, a carbon–carbon triple bond) are among the most versatile of all reactive intermediates in organic chemistry. They can be ‘trapped’ to give products that are used as pharmaceuticals, agrochemicals, dyes, polymers and other fine chemicals. Here we explore a strategy that unites the de novo generation of benzynes—through a hexadehydro-Diels–Alder reaction—with their in situ elaboration into structurally complex benzenoid products. In the hexadehydro-Diels–Alder reaction, a 1,3-diyne is engaged in a [4+2] cycloisomerization with a ‘diynophile’ to produce the highly reactive benzyne intermediate. The reaction conditions for this simple, thermal transformation are notable for being free of metals and reagents. The subsequent and highly efficient trapping reactions increase the power of the overall process. Finally, we provide examples of how this de novo benzyne generation approach allows new modes of intrinsic reactivity to be revealed.

A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts

This protocol is intended to provide chemists who discover or make new organic compounds with a valuable tool for validating the structural assignments of those new chemical entities. Experimental 1H and/or 13C NMR spectral data and its proper interpretation for the compound of interest is required as a starting point. The approach involves the following steps: (i) using molecular mechanics calculations (with, e.g., MacroModel) to generate a library of conformers; (ii) using density functional theory (DFT) calculations (with, e.g., Gaussian 09) to determine optimal geometry, free energies and chemical shifts for each conformer; (iii) determining Boltzmann-weighted proton and carbon chemical shifts; and (iv) comparing the computed chemical shifts for two or more candidate structures with experimental data to determine the best fit. For a typical structure assignment of a small organic molecule (e.g., fewer than ∼10 non-H atoms or up to ∼180 a.m.u. and ∼20 conformers), this protocol can be completed in ∼2 h of active effort over a 2-d period; for more complex molecules (e.g., fewer than ∼30 non-H atoms or up to ∼500 a.m.u. and ∼50 conformers), the protocol requires ∼3–6 h of active effort over a 2-week period. To demonstrate the method, we have chosen the analysis of the cis- versus the trans-diastereoisomers of 3-methylcyclohexanol (1-cis versus 1-trans). The protocol is written in a manner that makes the computation of chemical shifts tractable for chemists who may otherwise have only rudimentary computational experience.

Preparation of poly(ethylene glycol) protected nanoparticles with variable bioconjugate ligand density

Maleimide-functional poly(ethylene glycol)-b-poly(epsilon-caprolactone) nanoparticles (NPs) were prepared via the Flash NanoPrecipitation technique. Subsequent reaction with a model ligand, bovine serum albumin (BSA), was conducted using thiol-maleimide conjugation. Reaction of up to 22% of NP surface maleimide-PEG tethers was obtained, with the percent conversion being essentially independent of the ratio of maleimide-PEG to methyl-PEG over the range 30-100%, respectively. At the highest surface coverage, BSA is calculated to essentially cover the NP surface area. Reaction parameters (reaction order and docking constant) describing the extent of ligand conjugation were determined. The reaction order is applicable to the conjugation of ligands presenting free thiol functionalities, while the value of the docking constant is ligand-dependent and accounts for physical and dynamic properties of the ligand-PEG interaction. Jointly, the particle formation process, using block copolymer-directed kinetically controlled assembly and surface functionalization represent a versatile new platform for the preparation of bioconjugated NPs with accurate control of ligand density and minimal processing steps.

Hybrid Density Functional Methods Empirically Optimized for the Computation of 13 C and 1 H Chemical Shifts in Chloroform Solution

Two hybrid generalized-gradient approximation density functionals, WC04 and WP04, are optimized for the prediction of (13)C and (1)H chemical shifts, respectively, using a training set of 43 molecules in chloroform solution. Tests on molecules not included in the training set, namely six stereoisomeric methylcyclohexanols and a β-lactam antibiotic, indicate the models to be robust and moreover to provide results more accurate than those from equivalent B3LYP, PBE1, or mPW1PW91 calculations, particularly for the prediction of downfield resonances in nuclear magnetic resonance spectra. However, linear regression of the B3LYP, PBE1, and mPW1PW91 predicted values on the experimental data improves the accuracy of those models so that they are comparable to WC04 and WP04.

Alkane desaturation by concerted double hydrogen atom transfer to benzyne

The removal of two vicinal hydrogen atoms from an alkane to produce an alkene is a challenge for synthetic chemists. In nature, desaturases and acetylenases are adept at achieving this essential oxidative functionalization reaction, for example during the biosynthesis of unsaturated fatty acids, eicosanoids, gibberellins and carotenoids. Alkane-to-alkene conversion almost always involves one or more chemical intermediates in a multistep reaction pathway; these may be either isolable species (such as alcohols or alkyl halides) or reactive intermediates (such as carbocations, alkyl radicals, or σ-alkyl-metal species). Here we report a desaturation reaction of simple, unactivated alkanes that is mechanistically unique. We show that benzynes are capable of the concerted removal of two vicinal hydrogen atoms from a hydrocarbon. The discovery of this exothermic, net redox process was enabled by the simple thermal generation of reactive benzyne intermediates through the hexadehydro-Diels–Alder cycloisomerization reaction of triyne substrates. We are not aware of any single-step, bimolecular reaction in which two hydrogen atoms are simultaneously transferred from a saturated alkane. Computational studies indicate a preferred geometry with eclipsed vicinal C–H bonds in the alkane donor.

Silicon tethered ring-closing metathesis reactions for self- and cross-coupling of alkenols

Abstract The title process can be used to couple allylic, homoallylic, and bishomoallylic alkenols. Cyclic silaketals with ring sizes from 7–11 members can all be formed. This constitutes a general and versatile strategy for approximately doubling the molecular complexity of readily available alkenol precursors.

Flash nanoprecipitation: particle structure and stability.

Flash nanoprecipitation (FNP) is a process that, through rapid mixing, stabilizes an insoluble low molecular weight compound in a nanosized, polymer-stabilized delivery vehicle. The polymeric components are typically amphiphilic diblock copolymers (BCPs). In order to fully exploit the potential of FNP, factors affecting particle structure, size, and stability must be understood. Here we show that polymer type, hydrophobicity and crystallinity of the small molecule, and small molecule loading levels all affect particle size and stability. Of the four block copolymers (BCP) that we have studied here, poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (PEG-b-PLGA) was most suitable for potential drug delivery applications due to its ability to give rise to stable nanoparticles, its biocompatibility, and its degradability. We found little difference in particle size when using PLGA block sizes over the range of 5 to 15 kDa. The choice of hydrophobic small molecule was important, as molecules with a calculated water-octanol partition coefficient (clogP) below 6 gave rise to particles that were unstable and underwent rapid Ostwald ripening. Studies probing the internal structure of nanoparticles were also performed. Analysis of differential scanning calorimetry (DSC), cryogenic transmission electron microscopy (cryo-TEM), and (1)H NMR experiments support a three-layer core-shell-corona nanoparticle structure.

Controlled polymerization of a cyclic diene prepared from the ring-closing metathesis of a naturally occurring monoterpene.

The diene 3-methylenecyclopentene (2) was synthesized from the naturally occurring monoterpene myrcene (1) by ring-closing metathesis using Grubbs second generation catalyst. Radical, anionic, and cationic polymerizations of 2 were investigated. The anionic polymerization of 2 with sec-butyllithium (s-BuLi) in cyclohexane gave poly-2 in quantitative yield, with a narrow molecular weight distribution and predictable molecular weight based on the molar ratio of 2 and s-BuLi. Radical polymerization of 2 was also successful using AIBN as the initiator. Samples of poly-2 obtained from the anionic and radical polymerization of 2 possessed mixed regiochemistry (i.e., 4,3 and 1,4 addition). The cationic polymerization of 2 proceeded smoothly to afford regiopure 1,4-poly-2. For example, the i-BuOCH(Cl)Me/ZnCl(2)/Et(2)O initiating system afforded 1,4-poly-2 with controlled molecular weight and narrow molecular weight distribution. Samples of 1,4-poly-2 were semicrystalline as determined by differential scanning calorimetry.

Synthesis of (-)-bullatacin: The enantiomer of a potent, antitumor, 4-hydroxylated, Annonaceous acetogenin

Abstract Synthesis of the title compound represents the first construction of any of these potent, antitumor Annonaceous acetogenins with the entire relative stereochemistry in place. Palladium(0)-mediated crossed diyne coupling and the use of three, natural, α-hydroxy acids as the origin of all absolute stereochemistry highlight this flexible approach that sets the stage for access to structural analogs for further study.

Effects of block copolymer properties on nanocarrier protection from in vivo clearance

Drug nanocarrier clearance by the immune system must be minimized to achieve targeted delivery to pathological tissues. There is considerable interest in finding in vitro tests that can predict in vivo clearance outcomes. In this work, we produce nanocarriers with dense PEG layers resulting from block copolymer-directed assembly during rapid precipitation. Nanocarriers are formed using block copolymers with hydrophobic blocks of polystyrene (PS), poly-ε-caprolactone (PCL), poly-D,L-lactide (PLA), or poly-lactide-co-glycolide (PLGA), and hydrophilic blocks of polyethylene glycol (PEG) with molecular weights from 1 kg/mol to 9 kg/mol. Nanocarriers with paclitaxel prodrugs are evaluated in vivo in Foxn1(nu) mice to determine relative rates of clearance. The amount of nanocarrier in circulation after 4h varies from 10% to 85% of initial dose, depending on the block copolymer. In vitro complement activation assays are conducted to correlate in vivo circulation to the protection of the nanocarrier surface from complement binding and activation. Guidelines for optimizing block copolymer structure to maximize circulation of nanocarriers formed by rapid precipitation and directed assembly are proposed, relating to the relative sizes of the hydrophilic and hydrophobic blocks, the hydrophobicity of the anchoring block, the absolute size of the PEG block, and polymer crystallinity. The in vitro results distinguish between the poorly circulating PEG(5k)-PCL(9 k) and the better circulating nanocarriers, but could not rank the better circulating nanocarriers in order of circulation time. Analysis of PEG surface packing on monodisperse 200 nm latex spheres indicates that the size of the hydrophobic PCL, PS, and PLA blocks are correlated with the PEG blob size. Suggestions for next steps for in vitro measurements are made.