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The ambi-valent character of the P-I bond in iodophosphonium complexes ensures that it can be electrophilic at either P or I. Herein, we use an ensemble of computational tools and methodologies to probe the nature of this ambi-valent bond. Geometric and atomic electron population analyses yielded strong trends between the electron donating ability of the phosphine and the strength and polarity of the P-I bond. Quasi-atomic orbital analysis demonstrated the near homo-polarity of the P-I bond, and energy decomposition analysis calculations demonstrated the ability to tune the polarization of the bond with only mild changes in secondary structural features. Finally, the ambi-valent nature of the P-I bond was demonstrated to follow hard-soft considerations in reactions with nucleophiles, with harder nucleophiles preferentially forming products of addition to P and softer nucleophiles to I.

A novel diastereoselective, Lewis acid catalyzed 1,6-difunctionalization of galactose and mannose derivatives has been developed in one pot, via sequential nucleophile additions. Our studies point to the formation of a 3,6-anhydrosugar intermediate as key to the 1,6-site-selectivity. Starting material-specific reactivity occurs when competitive ring-opening C-O cleavage is possible, owed to basicity and stereoelectronic stabilization differences. Lastly, Mayr nucleophilicity parameter values helped predict which reaction conditions would be most suitable for specific nucleophiles.

The condensative cyclization of sp

A variety of C-glycosides can be obtained from the fluoroarylborane (B(C6F5)3) or silylium (R3Si+) catalyzed functionalization of 1-MeO- and per-TMS-sugars with TMS-X reagents. A one-step functionalization with a change as simple as the addition order and/or Lewis acid and TMS-X enables one to afford chiral synthons that are common (C-pyranosides), have few viable synthetic methods (C-furanosides), or are virtually unknown (anhydro-C-pyranosides), which mechanistically arise from whether a direct substitution, isomerization/substitution, or substitution/isomerization occurs, respectively.

An experimental method of determining the electrophilicity of silicon in phosphinosilylium cations is reported and compared to Djukic’s DFT method of computing relative intrinsic silylicity, Π. We ...

The stoichiometric addition of aryl and alkyl nitriles to the silylpalladium cation [(PCy3)2Pd–SiMe2Et+]­[(C6F5)4B–] (1) resulted in the cleavage of the nitrile C–CN bond and the formation of palladium–aryl and palladium–alkyl cations. Low-temperature experiments support a mechanism where silylpalladium cation 1 transfers silylium to nitrile, generating a silylnitrilium cation and the reduced, zerovalent complex Pd­(PCy3)2. These two intermediates readily recombine at low temperatures to generate palladium–(N-silyl)­iminoacyl complexes, which upon warming can undergo aryl/alkyl group migration from the iminoacyl ligand to the metal. Additional experiments show that palladium–(N-silyl)­iminoacyl cations are potent sources of silylium, capable of cleaving the methyl C–O bond of an ether, while DFT calculations confirm the electrophilicity of the silyl moiety.

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The synthesis and characterization of the room-temperature and solution-stable silylpalladium cations (PCy3)2Pd–SiR3+(C6F5)4B– (SiR3 = SiMe2Et, SiHEt2) and (Xantphos)Pd–SiR3+(BArf4) (SiR3 = SiMe2Et...

The feedstocks from biomass are defined and limited by nature, but through the choice of catalyst, one may change the deoxygenation outcome. We report divergent but selective deoxygenation of sugar...

Site selective amide reductions of the cyclic undecapeptide, cyclosporine A, have been developed using the combination of a heteroleptic borane catalyst and a silane reductant. Tertiary silane Me(2)EtSiH provides two unique cyclosporine A derivatives, one of which can be readily diversified in subsequent reactions. The secondary silane Et(2)SiH(2) enables divergent reactivity that uses a free hydroxyl group to direct the reduction. The transient O-silyl hemiaminal intermediate of this reduction can additionally be trapped by reducing to the amine or by reductive cyanation.

A variety of

Poly(methylhydrosiloxane) (PMHS) has been examined for its ability to reduce and subsequently cyclize carbohydrate substrates using catalytic tris(pentafluorophenyl)borane (BCF). The work herein is the first reported example of the direct conversion of monosaccharides to 1,4-anhydro and 2,5-anhydro products utilizing a hydrosiloxane reducing agent. PMHS is produced from waste products of the silicone industry, making it a green alternative to traditional hydrosilane reducing agents. This work thus contributes to the goal of utilizing renewable feedstocks in the production of fine-chemicals.

Catalytic sp3 C–O bond cleavage using B(C6F5)3/HBcat is reported. This method is first demonstrated on simple ethers and silyl protected alcohols, which exhibit reactivity parallel to the known B(C6F5)3/HSiR3 system. In more complex carbohydrate derivatives, however, unique selectivities that are not possible with hydrosilane reductants have been achieved, including regioselective cyclizations. Preliminary computational studies suggest that diboryl oxonium ions are disfavored and that four-coordinate boronium ions may contribute to selectivity.

The silylium (Me2EtSi+) catalyzed condensative cyclization of persilylated linear or cyclic sugars has been examined as a selective route to monoanhydro sugars. The silylium could be generated either from the sequential addition of [Ph3C+][B(C6F5)4–] and R3SiH (where Si is the silyl protecting group (either trimethylsilyl (TMS) or Me2EtSi)) or by abstracting a primary silyl ether with the Lewis acid catalyst B(C6F5)3. This latter method forms [R3SiO–B(C6F5)3–] and a silylium-coordinated product. This reactive pair eventually converts to L–B(C6F5)3 (L = THF-like product) and the condensate (R3Si)2O. The L–B(C6F5)3 is a much less potent form of the catalyst. Under the silylium catalyzed conditions, linear sugars (CnOn, n = 5, 6) and biomass-derived tetraols (C6O4) afford a diverse collection of diastereomerically pure THFs in good to excellent yields (50–99%). Persilylated 1,6-anhydrogalactofuranose is provided in a single step from persilylated galactose (85% isolation yield after silyl deprotection) and t...

The transition from petroleum to biorenewable sources of carbon to meet our energy and chemical feedstock needs is difficult, in part because these sources are so different, with petroleum being under-functionalized and biomass being over-functionalized relative to commercial chemicals. However, target lists such as the US Department of Energy’s Top 10 have converged efforts to develop the technologies needed to manufacture the most important feedstocks accessible from biorenewables. Less well defined but equally important to the economic viability of an integrated biorefinery are low-volume, high-value product streams, which would help offset the capital costs of a biorefinery. In this Review, we attempt to bring together some of the advances that could fill these niche areas, with a focus on the conversion of cellulosics into chemicals using homogeneous catalysis. The products range from high-value jet fuels to monomers for high-performance polymers and materials to pharmaceutical intermediates and cover a broad range of structural complexities. A move away from fossil fuels as an energy source will also require a move to new sources for important chemical feedstocks. This Review considers the use of homogeneous catalysis to convert cellulosics into low-volume, high-value chemicals that are currently derived from crude oil.

We report a computational study of the transfer of silylium from phosphine to heteroatom containing Lewis bases including ethers, phosphines, and amines. The relative free energies of these compounds are compared to develop a thermodynamic scale of stabilities that can help to interpret the chemoselectivity observed with complex natural products and biomass-derived sugars. Both the choice of silane and the phosphine Lewis base impact the thermodynamics of this transfer.

The catalytic partial deoxygenation of the per-silylated gluco-disaccharides maltose, cellobiose, trehalose, and isomaltose by Me2EtSiH and the Lewis acid catalyst B(C6F5)3 have been examined to determine which C–O bonds are favorably removed. In the case of maltose, cellobiose and trehalose, the linking anomeric center is the kinetically preferred site of reduction and cleavage of the disaccharide occurs to yield 1-deoxyglucose and glucose as the primary products. Although 1-deoxyglucose is kinetically inert, glucose continues to reduce by ring opening to sorbitol and is eventually 1,6-deoxygenated to the corresponding tetraol. Isomaltose differs from the other disaccharides in that it has a α-(1´→6) linkage, which is more resistant to cleavage and thus directs reactivity to a ring opening of the reducing sugar and the generation of isomaltitol.

We report studies delineating the speciation, kinetics, and deoxygenation catalysis of phosphine-modified mixtures of B(C6F5)3 (BCF) and R3SiH. Combinations of BCF, a tertiary silane, and PAr3 generate the [H–B(C6F5)3–][R3Si–PAr3+] ion pair with conversions that depend on the silane and the phosphine. Smaller silanes enhance the ionization of the Si–H, as judged by heteronuclear NMR spectroscopy. Kinetic studies indicate that from BCF·PPh2(p-tol), formation of the borohydride/silyl phosphonium ion pair is α [Et3SiH]1[PPh2(p-tol)]0. DFT calculations confirmed the intermediacy of the weakly coordinated BCF···H–SiEt3 adduct en route to the silyl phosphonium. For the catalytic deoxygenation of anisole with Et3SiH, phosphine additives slow the reaction relative to phosphine-free conditions. In situ monitoring confirmed the presence of [H–B(C6F5)3–][Et3Si–PAr3+] at early times, but this slowly converts to [H–B(C6F5)3–][H3C–PAr3+], which is catalytically inactive. These data are reconciled by invoking a competit...

The selective (and controllable) modification of complex molecules with disparate functional groups (for example, natural products) is a long-standing challenge that has been addressed using catalysts tuned to perform singular transformations (for example, C-H hydroxylation). A method whereby reactions with diverse functional groups within a single natural product are feasible depending on which catalyst or reagent is chosen would widen the possible structures one could obtain. Fluoroarylborane catalysts can heterolytically split Si-H bonds to yield an oxophilic silylium (R3Si+) equivalent along with a reducing (H-) equivalent. Together, these reactive intermediates enable the reduction of multiple functional groups. Exogenous phosphine Lewis bases further modify the catalyst speciation and attenuate aggressive silylium ions for the selective modification of complex natural products. Manipulation of the catalyst, silane reagent and the reaction conditions provides experimental control over which site is modified (and how). Applying this catalytic method to complex bioactive compounds (natural products or drugs) provides a powerful tool for studying structure-activity relationships.

Silylium ions (formally [R3Si]+) have long been the subject of investigations and significant debate in both theoretical and experimental chemistry, but few catalytic, synthetic applications have been reported due to the exceptionally high reactivity and Lewis acidity of these elusive species. Results to be discussed include the application of easily accessible silylium ion catalysts to the stereoselective synthesis of various N-heterocyclic pyrrolidine and piperidine scaffolds. The tested substrates are derived from the chiral pool and can be obtained in three high-yielding steps from amino alcohols; subsequent stereoselective silylium ion catalyzed Prins cyclization and trapping with R3Si–Nu nucleophiles (e.g., Nu = H, allyl, azide, and enol ethers) results in novel nitrogen-containing polycyclic scaffolds with potential medicinal chemistry applications.

A set of B(C6F5)3-catalyzed methods for diversification of unsaturated carbohydrate derived substrates is disclosed. Lewis acid cyclization, allylic alcohol hydrosilylation, and selective silyl group exchange is achieved with this single versatile catalyst. Allylic polyols and highly enriched (Z)-triols are obtained in high yields under a single-step protocol.

This paper reports the binding properties of tetrameric pseudo-peptide receptors for protonated cytidines. The receptors, which were isolated from a dynamic combinatorial chemistry (DCC) experiment, bind the analytes with affinities that depend on the presence or absence of excess acid, and with a stoichiometry that is both concentration and temperature dependent.

A diastereoselective, gold-catalyzed cascading cycloisomerization of alkylidene cyclopropane bearing 1,5-enynes that terminates in a cyclo-addition of aldehydes has been developed. This diastereoselective reaction provides convergent access to novel polycyclic molecular structures (18 examples), and tolerates a diverse scope of aldehydes. Mechanistic studies reveal that the catalytic cycle rests at a digold off-cycle intermediate, one of which was isolated.

The impact of the macrodipole of peptide helices on catalysis was examined using density functional theory calculations. Transition state structures for histidine-containing polyalanine nucleophilic catalysts adding to carbonyls were computed, and the impact of both global and local noncovalent interactions was assessed. Although the peptide macrodipole appears to influence energy barriers, local interactions dominate.

Claisen rearrangements of allyl aryl ethers to generate enones bearing all carbon quaternary centers are accelerated by Ph3PAuNTf2 under mild conditions in good yields. Multiple C–C bond containing variants of the allyl fragment are viable, including alkylidenecyclopropanes, allenes, and alkynes, which generate all-carbon stereogenic centers substituted with vinyl cyclopropanes, 1,3-butadienyl, and allenyl substituents, respectively, for subsequent synthetic manipulation. With allyl phenyl ethers, the product of the [3,3] rearrangements can be trapped by a tandem [4 + 2] cycloaddition to generate complex molecular scaffolds from readily available, achiral starting materials.

Results of kinetic experiments and quantum chemical computations on a series of platinum-promoted polycyclization reactions are described. Analyses of these results reveal a reactivity model that reaches beyond the energetics of the cascade itself, incorporating an ensemble of pre-cyclization conformations of the platinum-alkene reactant complex, only a subset of which are productive for bi- (or larger) cyclization and lead to products. Similarities and differences between this scenario, including reaction coordinates for polycyclization, for platinum- and enzyme-promoted polycyclization reactions are highlighted.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive enzyme defect of purine metabolism that usually manifests as 2,8-dihydroxyadenine (2,8-DHA) nephrolithiasis and more rarely chronic kidney disease. The disease is most often misdiagnosed and can recur in the renal allograft. We analyzed nine patients with recurrent 2,8-DHA crystalline nephropathy, in all of whom the diagnosis had been missed prior to renal transplantation. The diagnosis was established at a median of 5 (range 1.5-312) weeks following the transplant procedure. Patients had delayed graft function (n=2), acute-on-chronic (n=5) or acute (n=1) allograft dysfunction, whereas one patient had normal graft function at the time of diagnosis. Analysis of allograft biopsies showed birefringent 2,8-DHA crystals in renal tubular lumens, within tubular epithelial cells and interstitium. Fourier transformed infrared microscopy confirmed the diagnosis in all cases, which was further supported by 2,8-DHA crystalluria, undetectable erythrocyte APRT enzyme activity, and genetic testing. With allopurinol therapy, the allograft function improved (n=7), remained stable (n=1) or worsened (n=1). At last follow-up, two patients had experienced allograft loss and five had persistent chronic allograft dysfunction. 2,8-DHA nephropathy is a rare but underdiagnosed and preventable disorder that can recur in the renal allograft and may lead to allograft loss.

Reaction of a complex Pt organometallic species with electrophilic halogen sources in the presence of X– ligands changes the mechanism of reductive elimination from a concerted reductive coupling type to an SN2 type reductive elimination. In the absence of the added X– ligand the reductive elimination is stereoretentive; in its presence, the process is stereoinvertive. This selectivity hinges on the reactivity of a key five-coordinate Pt(IV) intermediate with the X– ligand.

A discontinuity exists between the importance of the cation–olefin reaction as the principal C–C bond forming reaction in terpene biosynthesis and the synthetic tools for mimicking this reaction under catalyst control; that is, having the product identity, stereochemistry, and functionality under the control of a catalyst. The main reason for this deficiency is that the cation–olefin reaction starts with a reactive intermediate (a carbocation) that reacts exothermically with an alkene to reform the reactive intermediate; not to mention that reactive intermediates can also react in nonproductive fashions. In this Account, we detail our efforts to realize catalyst control over this most fundamental of reactions and thereby access steroid like compounds. Our story is organized around our progress in each component of the cascade reaction: the metal controlled electrophilic initiation, the propagation and termination of the cyclization (the cyclase phase), and the turnover deplatinating events. Electrophilic Pt(II) complexes efficiently initiate the cation–olefin reaction by first coordinating to the alkene with selection rules that favor less substituted alkenes over more substituted alkenes. In complex substrates with multiple alkenes, this preference ensures that the least substituted alkene is always the better ligand for the Pt(II) initiator, and consequently the site at which all electrophilic chemistry is initiated. This control element is invariant. With a suitably electron deficient ligand set, the catalyst then activates the coordinated alkene to intramolecular addition by a second alkene, which initiates the cation–olefin reaction cascade and generates an organometallic Pt(II)-alkyl. Deplatination by a range of mechanisms (β-H elimination, single electron oxidation, two-electron oxidation, etc.) provides an additional level of control that ultimately enables A-ring functionalizations that are orthogonal to the cyclase cascade. We particularly focus on reactions that combine an initiated cyclization reaction with a turnover defining β-hydride elimination, fluorination, and oxygenation. These latter demetalation schemes lead to new compounds functionalized at the C3 carbon of the A-ring (steroid numbering convention) and thus provide access to interesting potentially bioactive targets. Progress toward efficient and diverse polycyclization reactions has been achieved by investing in both synthetic challenges and fundamental organometallic reactivity. In addition to an interest in the entrance and exit of the metal catalyst from this reaction scheme, we have been intrigued by the role of neighboring group participation in the cyclase phase. Computational studies have served to provide nuance and clarity on several key aspects, including the role (and consequences) of neighboring group participation in cation generation and stabilization. For example, these calculations have demonstrated that traversing carbonium ion transition states significantly impacts the kinetics of competitive 6-endo and 5-exo A-ring forming reactions. The resulting nonclassical transition states then become subject to a portion of the strain energy inherent to bicyclic structures, with the net result being that the 6-endo pathway becomes kinetically favored for alkene nucleophiles, in contrast to heteroatom nucleophiles which progress through classical transition states and preferentially follow 5-exo pathways. These vignettes articulate our approach to achieving the desired catalyst control.

An enantioselective ring-expanding cycloisomerization of 1,5-enynes bearing a cyclopropylidene moiety has been developed. This methodology provides a new approach to bicyclo[4.2.0]octanes, a structural motif present in many biologically active natural products.

Reductive late-stage functionalization of gibberellic acid is reported using three fluoroarylborane Lewis acids; (B(C(6)F(5))(3), B(3,5-C(6)H(3)(CF(3))(2)), and B(2,4,6-C(6)H(2)F(3))(3)) in combination with a tertiary silane and a borane (HBCat) reductant. In each case, C–O bond activation occurs, and different products are obtained depending on the reductant and catalyst employed.

In situ generated benzyne reacts at room temperature with (triphos)Pt–CH3+ to form a five-coordinate π-complex (2) that is isolable and stable in solution. Thermolysis of 2 at 60 °C generates (triphos)Pt(o-tolyl)+ (3), which is the product of formal migratory insertion of CH3– onto the coordinated benzyne. The reaction of 2 with the acid Ph2NH2+ yields toluene at room temperature over the course of 8 h, while the same reaction with 3 only proceeds to 40% conversion over 2 days. These data indicate that the protonolysis of 2 does not proceed by CH3 migration onto benzyne to form 3 followed by protodemetalation. Instead, the data suggest either that protonation of 2 is first and is followed by H migration to yield a PtIVPh(Me) dication or that this latter species is generated by direct protonolysis of coordinated benzyne prior to reductive elimination of toluene.

Application of a tridentate NHC containing pincer ligand to Pt catalyzed cascade cyclization reactions has allowed for the catalytic, diastereoselective cycloisomerization of biogenic alkene terminated substrates to the their polycyclic counterparts.

The combination of the N-based pincer ligand PyBOX with Pt2+ leads to new catalysts for the enantioselective cycloisomerization of dienyl- and trienyl-ols. The mechanistic combination of electrophilic cyclization followed by rapid protodemetalation is surprising and leads to a powerful construct for developing new reactions.

The conversion of readily available cellulosic biomass to valuable feedstocks and fuels is an attrative goal but a challenging transformation that requires the cleavage of multiple nonactivated CO bonds. Herein, the Lewis acid trispentafluorophenylborane (B(C6 F5 )3 ) is shown to catalyze the metal-free hydrosilylative reduction of monosaccharides and polysaccharides to give hydrocarbons with reduced oxygen content. The choice of the silane reductant influences the degree of deoxygenation, with diethylsilane effecting the complete reduction to produce hexanes while tertiary silanes give partially deoxygenated tetraol and triol products.

A method for the selective transamidation of the 3-oxo sub-family of N-acyl homoserine lactones (3-oxo-AHLs) under physiologically relevant conditions has been developed. The reaction has the potential to serve as a strategy for selective knockdown of key autoinducers in a multicellular environment.

A reactive tagging methodology was used to select the species most reactive to an acylation reagent from a solid phase library of beta hairpin peptides. Hits bearing an electron-rich aromatic residue across strand from a reactive histidine were found to competitively become N-acylated. In addition to displaying rapid N-acylation rates the hit peptide was additionally deacylated in the presence of a nucleophile, thus closing a putative catalytic cycle. Variants of the hit peptide were studied to elucidate both the magnitude (up to 18,000-fold over background, kcat/kuncat = 94,000,000, or 45-fold over Boc-histidine methyl ester) and mechanism of acyl transfer catalysis. A combination of CH-π, cation-π and HisH(+)-O interactions in the cationic imidazole transition state is implicated in the rate acceleration, in addition to the fidelity of the beta hairpin fold. Moreover, NMR structural data on key intermediates or models thereof suggest that a key feature of this catalyst is the ability to access several different stabilizing conformations along the catalysis reaction coordinate.

Herein we describe the screening and subsequent optimization of peptide catalysts for ester activation. A combinatorial methodology using dye-tagged substrate analogs is described for determining which components of a His-containing helical library display acyl transfer activity. We found that helical peptides display high activity, and amino acids that reinforce this propensity are advantaged. Through this approach two new structural motifs have been discovered that are capable of activating esters in organic solvents. Unlike most acyl transfer catalysts functioning in organic solvents, these catalysts are histidine- rather than N-alkyl histidine-based. Longer peptides with localization of reactive groups on the C-terminal end of the peptide were found to further enhance catalytic activity up to ∼2800-fold over background.

Oxidatively induced halogenation and oxygenation reactions of complex Pt(II) organometallic complexes provide a route to a catalytic cation–olefin cyclization/oxygenation sequence. The evidence suggests the involvement of a Pt(III) intermediate, which reacts homolytically to generate an organic free radical that can be intercepted by O2 followed by the Russell breakdown of the resulting alkyl peroxy radicals or by CuX2 (X = Br, Cl) to yield the X–R product.

Selective carbocyclizations of unsaturated carbohydrates yield cyclopentanes and cyclopropanes via sila-THF cations as key intermediates.

This book chapter discusses the effects of aurophilicity on gold catalysis. First, a brief historic account of aurophilicity in organogold chemistry is given, focusing on the pioneering results which set the stage for its association with catalytic intermediates (gold vinyl and gold aryl complexes); this is followed by an introduction to cationic gold(I) as an electrophilic catalyst, and the first isolation of organogold intermediates from catalysis. In the main section, the growing number of reports observing aurophilic interactions in catalysis or illustrative model systems is reviewed in a non-comprehensive tutorial way. The effects of aurophilicity are discussed in the following structures: (1) the geminal diauration of C(sp²)-atoms; (2) geminal diauration of other atoms; (3) σ-π-diauration of terminal alkynes. It is apparent that in most cases efficient catalysis is hindered by aurophilic effects as less active aggregates tend to be formed from more active species [LAu]⁺, but there are a growing number of reports using aurophilicity as a driving force to access new reactivity and selectivity.

A B(C6F5)3-catalyzed method for the selective conversion of unsaturated carbohydrates to cyclopentanes and cyclopropanes is disclosed. Catalyst activation of tertiary silanes generates the ion pair [(C6F5)3B–H][ROSi2] whose components synergistically activate C–O bonds for diastereoselective C–C bond formation. Sila-THF cations are invoked as key intermediates facilitating carbocyclizations. Complex chiral synthons are thereby obtained in a single pot.