Development of Asymmetric Protonation Reactions for the Synthesis of Indoline Alkaloids

Nitrogen-containing heterocycles, such as indolines and pyrroloindolines, are prevalent in a variety of diverse natural products, many of which exhibit remarkable biological activities. These frameworks have inspired innovative research aimed at discovering novel methods for their stereoselective preparation.

We have developed an enantioselective synthesis of pyrroloindolines based on a formal (3 + 2) cycloaddition of indoles and 2-amidoacrylates. This reaction is promoted by (R)-BINOL•SnCl₄; this complex is a Lewis acid-assisted Brønsted acid that effects a highly face-selective catalyst-controlled protonation of an enolate. Mechanistic studies also determined that the initial product of this reaction is an indolinium ion, which upon aqueous workup undergoes cyclization to the pyrroloindoline.

Based on this result, we investigated alternative nucleophiles to trap the indolinium ion. First, addition of sodium borohydride to the optimized reaction conditions yields indoline-containing amino acid derivatives.

Next, carbon nucleophiles were explored. Indole substrates incorporating a tethered alkene were exposed to the conditions for the formal (3 + 2) cycloaddition, resulting in a conjugate addition/asymmetric protonation/Prins cyclization cascade. In this transformation, the indolinium ion is attacked by the olefin, and the resulting carbocation is quenched by a chloride ion. Zirconium tetrachloride was found to be the optimal Lewis acid. Stoichiometric proton and chloride sources were also found to be crucial for reactivity.

The design and synthesis of a true, heterogeneous, asymmetric catalyst

This work describes the design and synthesis of a true, heterogeneous, asymmetric catalyst. The catalyst consists of a thin film that resides on a high-surface- area hydrophilic solid and is composed of a chiral, hydrophilic organometallic complex dissolved in ethylene glycol. Reactions of prochiral organic reactants take place predominantly at the ethylene glycol-bulk organic interface.

The synthesis of this new heterogeneous catalyst is accomplished in a series of designed steps. A novel, water-soluble, tetrasulfonated 2,2'-bis (diphenylphosphino)-1,1'-binaphthyl (BINAP-4S0_3Na) is synthesized by direct sulfonation of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP). The rhodium (I) complex of BINAP-4SO_3Na is prepared and is shown to be the first homogeneous catalyst to perform asymmetric reductions of prochiral 2-acetamidoacrylic acids in neat water with enantioselectivities as high as those obtained in non-aqueous solvents. The ruthenium (II) complex, [Ru(BINAP-4SO_3Na)(benzene)Cl]Cl is also synthesized and exhibits a broader substrate specificity as well as higher enantioselectivities for the homogeneous asymmetric reduction of prochiral 2-acylamino acid precursors in water. Aquation of the ruthenium-chloro bond in water is found to be detrimental to the enantioselectivity with some substrates. Replacement of water by ethylene glycol results in the same high e.e's as those found in neat methanol. The ruthenium complex is impregnated onto a controlled pore-size glass CPG-240 by the incipient wetness technique. Anhydrous ethylene glycol is used as the immobilizing agent in this heterogeneous catalyst, and a non-polar 1:1 mixture of chloroform and cyclohexane is employed as the organic phase.

Asymmetric reduction of 2-(6'-methoxy-2'-naphthyl)acrylic acid to the non-steroidal anti-inflammatory agent, naproxen, is accomplished with this heterogeneous catalyst at a third of the rate observed in homogeneous solution with an e.e. of 96% at a reaction temperature of 3°C and 1,400 psig of hydrogen. No leaching of the ruthenium complex into the bulk organic phase is found at a detection limit of 32 ppb. Recycling of the catalyst is possible without any loss in enantioselectivity. Long-term stability of this new heterogeneous catalyst is proven by a self-assembly test. That is, under the reaction conditions, the individual components of the present catalytic system self-assemble into the supported-catalyst configuration.

The strategies outlined here for the design and synthesis of this new heterogeneous catalyst are general, and can hopefully be applied to the development of other heterogeneous, asymmetric catalysts.

Palladium-catalyzed asymmetric allylic alkylation: insights, application toward cyclopentanoid and cycloheptanoid molecules, and the total synthesis of several daucane sesquiterpenes

The asymmetric construction of quaternary stereocenters is a topic of great interest in the organic chemistry community given their prevalence in natural products and biologically active molecules. Over the last decade, the Stoltz group has pursued the synthesis of this challenging motif via a palladium-catalyzed allylic alkylation using chiral phosphinooxazoline (PHOX) ligands. Recent results indicate that the alkylation of lactams and imides consistently proceeds with enantioselectivities substantially higher than any other substrate class previously examined in this system. This observation prompted exploration of the characteristics that distinguish these molecules as superior alkylation substrates, resulting in newfound insights and marked improvements in the allylic alkylation of carbocyclic compounds.

General routes to cyclopentanoid and cycloheptanoid core structures have been developed that incorporate the palladium-catalyzed allylic alkylation as a key transformation. The unique reactivity of α-quaternary vinylogous esters upon addition of hydride or organometallic reagents enables divergent access to γ-quaternary acylcyclopentenes or cycloheptenones through respective ring contraction or carbonyl transposition pathways. Derivatization of the resulting molecules provides a series of mono-, bi-, and tricyclic systems that can serve as valuable intermediates for the total synthesis of complex natural products.

The allylic alkylation and ring contraction methodology has been employed to prepare variably functionalized bicyclo[5.3.0]decane molecules and enables the enantioselective total syntheses of daucene, daucenal, epoxydaucenal B, and 14-p-anisoyloxydauc-4,8-diene. This route overcomes the challenge of accessing β-substituted acylcyclopentenes by employing a siloxyenone to effect the Grignard addition and ring opening in a single step. Subsequent ring-closing metathesis and aldol reactions form the hydroazulene core of these targets. Derivatization of a key enone intermediate allows access to either the daucane sesquiterpene or sphenobolane diterpene carbon skeletons, as well as other oxygenated scaffolds.

Enantioselective synthesis of pyrroloindolines and tryptophan derivatives by an asymmetric protonation reaction

Pyrroloindoline and unnatural tryptophan motifs are important targets for synthesis based on their incorporation into a diverse array of biologically active natural products. Both types of alkaloids have also found applications as chiral catalysts and tryptophan derivatives are commonly employed as biological probes. On account of their applications, these frameworks have inspired the development of numerous enantioselective, catalytic reactions. In particular, the past few years have witnessed an impressive number of novel approaches for pyrroloindoline formation.

The first project described herein involves our contribution to pyrroloindoline research. We have developed an (R)-BINOL•SnCl₄-catalyzed formal (3 + 2) cycloaddition reaction between 3-substituted indoles and 2-amidoacrylates that affords pyrroloindoline-2-carboxylates bearing an all-carbon quaternary center. Mechanistic studies have elucidated that the enantiodetermining step is a highly face-selective catalyst-controlled protonation reaction. The subsequent application of this asymmetric protonation strategy to the synthesis of a variety of enantioenriched tryptophan derivatives is also discussed.

Carbon-carbon bond forming reactions from bis(carbene)-platinum(II) complexes and olefin polymerization and oligomerization using group 4 post-metallocene complexes

A long-standing challenge in transition metal catalysis is selective C–C bond coupling of simple feedstocks, such as carbon monoxide, ethylene or propylene, to yield value-added products. This work describes efforts toward selective C–C bond formation using early- and late-transition metals, which may have important implications for the production of fuels and plastics, as well as many other commodity chemicals.

The industrial Fischer-Tropsch (F-T) process converts synthesis gas (syngas, a mixture of CO + H₂) into a complex mixture of hydrocarbons and oxygenates. Well-defined homogeneous catalysts for F-T may provide greater product selectivity for fuel-range liquid hydrocarbons compared to traditional heterogeneous catalysts. The first part of this work involved the preparation of late-transition metal complexes for use in syngas conversion. We investigated C–C bond forming reactions via carbene coupling using bis(carbene)platinum(II) compounds, which are models for putative metal–carbene intermediates in F-T chemistry. It was found that C–C bond formation could be induced by either (1) chemical reduction of or (2) exogenous phosphine coordination to the platinum(II) starting complexes. These two mild methods afforded different products, constitutional isomers, suggesting that at least two different mechanisms are possible for C–C bond formation from carbene intermediates. These results are encouraging for the development of a multicomponent homogeneous catalysis system for the generation of higher hydrocarbons.

A second avenue of research focused on the design and synthesis of post-metallocene catalysts for olefin polymerization. The polymerization chemistry of a new class of group 4 complexes supported by asymmetric anilide(pyridine)phenolate (NNO) pincer ligands was explored. Unlike typical early transition metal polymerization catalysts, NNO-ligated catalysts produce nearly regiorandom polypropylene, with as many as 30-40 mol % of insertions being 2,1-inserted (versus 1,2-inserted), compared to <1 mol % in most metallocene systems. A survey of model Ti polymerization catalysts suggests that catalyst modification pathways that could affect regioselectivity, such as C–H activation of the anilide ring, cleavage of the amine R-group, or monomer insertion into metal–ligand bonds are unlikely. A parallel investigation of a Ti–amido(pyridine)phenolate polymerization catalyst, which features a five- rather than a six-membered Ti–N chelate ring, but maintained a dianionic NNO motif, revealed that simply maintaining this motif was not enough to produce regioirregular polypropylene; in fact, these experiments seem to indicate that only an intact anilide(pyridine)phenolate ligated-complex will lead to regioirregular polypropylene. As yet, the underlying causes for the unique regioselectivity of anilide(pyridine)phenolate polymerization catalysts remains unknown. Further exploration of NNO-ligated polymerization catalysts could lead to the controlled synthesis of new types of polymer architectures.

Finally, we investigated the reactivity of a known Ti–phenoxy(imine) (Ti-FI) catalyst that has been shown to be very active for ethylene homotrimerization in an effort to upgrade simple feedstocks to liquid hydrocarbon fuels through co-oligomerization of heavy and light olefins. We demonstrated that the Ti-FI catalyst can homo-oligomerize 1-hexene to C₁₂ and C₁₈ alkenes through olefin dimerization and trimerization, respectively. Future work will include kinetic studies to determine monomer selectivity by investigating the relative rates of insertion of light olefins (e.g., ethylene) vs. higher α-olefins, as well as a more detailed mechanistic study of olefin trimerization. Our ultimate goal is to exploit this catalyst in a multi-catalyst system for conversion of simple alkenes into hydrocarbon fuels.

The development of an asymmetric palladium-catalyzed conjugate addition and its application toward the total syntheses of taiwaniaquinoid natural products

The asymmetric synthesis of quaternary stereocenters remains a challenging problem in organic synthesis. Past work from the Stoltz laboratory has resulted in methodology to install quaternary stereocenters α- or γ- to carbonyl compounds. Thus, the asymmetric synthesis of β-quaternary stereocenters was a desirable objective, and was accomplished by engineering the palladium-catalyzed addition of arylmetal organometallic reagents to α,β-unsaturated conjugate acceptors.

Herein, we described the rational design of a palladium-catalyzed conjugate addition reactions utilizing a catalyst derived from palladium(II) trifluoroacetate and pyridinooxazole ligands. This reaction is highly tolerant of protic solvents and oxygen atmosphere, making it a practical and operationally simple reaction. The mild conditions facilitate a remarkably high functional group tolerance, including carbonyls, halogens, and fluorinated functional groups. Furthermore, the reaction catalyzed conjugate additions with high enantioselectivity with conjugate acceptors of 5-, 6-, and 7-membered ring sizes. Extension of the methodology toward the asymmetric synthesis of flavanone products is presented, as well.

A computational and experimental investigation into the reaction mechanism provided a stereochemical model for enantioinduction, whereby the α-methylene protons adjacent the enone carbonyl clashes with the tert-butyl groups of the chiral ligand. Additionally, it was found that the addition of water and ammonium hexafluorophosphate significantly increases the reaction rate without sacrificing enantioselectivity. The synergistic effects of these additives allowed for the reaction to proceed at a lower temperature, and thus facilitated expansion of the substrate scope to sensitive functional groups such as protic amides and aryl bromides. Investigations into a scale-up synthesis of the chiral ligand (S)-tert-butylPyOx are also presented. This three-step synthetic route allowed for synthesis of the target compound of greater than 10 g scale.

Finally, the application of the newly developed conjugate addition reaction toward the synthesis of the taiwaniaquinoid class of terpenoid natural products is discussed. The conjugate addition reaction formed the key benzylic quaternary stereocenter in high enantioselectivity, joining together the majority of the carbons in the taiwaniaquinoid scaffold. Efforts toward the synthesis of the B-ring are presented.

Olefin cyclopropanation and carbon-hydrogen amination via carbene and nitrene transfers catalyzed by engineered cytochrome P450 enzymes

Synthetic biology promises to transform organic synthesis by enabling artificial catalysis in living cells. I start by reviewing the state of the art in this young field and recognizing that new approaches are required for designing enzymes that catalyze nonnatural reactions, in order to expand the scope of biocatalytic transformations. Carbene and nitrene transfers to C=C and C-H bonds are reactions of tremendous synthetic utility that lack biological counterparts. I show that various heme proteins, including cytochrome P450BM3, will catalyze promiscuous levels of olefin cyclopropanation when provided with the appropriate synthetic reagents (e.g., diazoesters and styrene). Only a few amino acid substitutions are required to install synthetically useful levels of stereoselective cyclopropanation activity in P450BM3. Understanding that the ferrous-heme is the active species for catalysis and that the artificial reagents are unable to induce a spin-shift-dependent increase in the redox potential of the ferric P450, I design a high-potential serine-heme ligated P450 (P411) that can efficiently catalyze cyclopropanation using NAD(P)H. Intact E. coli whole-cells expressing P411 are highly efficient asymmetric catalysts for olefin cyclopropanation. I also show that engineered P450s can catalyze intramolecular amination of benzylic C-H bonds from arylsulfonyl azides. Finally, I review other examples of where synthetic reagents have been used to drive the evolution of novel enzymatic activity in the environment and in the laboratory. I invoke preadaptation to explain these observations and propose that other man-invented reactions may also be transferrable to natural enzymes by using a mechanism-based approach for choosing the enzymes and the reagents. Overall, this work shows that existing enzymes can be readily adapted for catalysis of synthetically important reactions not previously observed in nature.

Reactions of small molecules facilitated by metal-acceptor interactions

The role of metal-acceptor interactions arising from M–BR3 and M–PR3 bonding is discussed with respect to reactions between first-row transition metals and N2, H2, and CO. Thermally robust, S = 1/2 (TPB)Co(H2) and (TPB)Co(N2) complexes (TPB = tris(2- (diisopropylphosphino)phenyl)borane) are described and the energetics of N2 and H2 binding are measured. The H2 and N2 ligands are bound more weakly in the (TPB)Co complexes than in related (SiP3)M(L) complexes (SiP3 = tris(2- (diisopropylphosphino)phenyl)silyl). Comparisons within and between these two ligand platforms allow for the factors that affect N2 (and H2) binding and activation to be delineated. The characterization and reactivity of (DPB)Fe complexes (DPB = bis(2- (diisopropylphosphino)phenyl)phenylborane) in the context of N2 functionalization and E–H bond addition (E = H, C, N, Si) are described. This platform allows for the one-pot transformation of free N2 to an Fe hydrazido(-) complex via an Fe aminoimide intermediate. The principles learned from the N2 chemistry using (DPB)Fe are applied to CO reduction on the same system. The preparation of (DPB)Fe(CO)2 is described as well as its reductive functionalization to generate an unprecedented Fe dicarbyne. The bonding in this highly covalent complex is discussed in detail. Initial studies of the reactivity of the Fe dicarbyne reveal that a CO-derived olefin is released upon hydrogenation. Alternative approaches to uncovering unusual reactivity using metal- acceptor interactions are described in Chapters 5 and 6, including initial studies on a new π-accepting tridentate diphosphinosulfinyl ligand and strategies for designing ligands that undergo site-selective metallation to generate heterobimetallic complexes.

Aqueous ring-opening metathesis polymerizations

Past workers in this group as well as in others have made considerable progress in the understanding and development of the ring-opening metathesis polymerization (ROMP) technique. Through these efforts, ROMP chemistry has become something of an organometallic success story. Extensive work was devoted to trying to identify the catalytically active species in classical reaction mixtures of early metal halides and alkyl aluminum compounds. Through this work, a mechanism involving the interconversion of metal carbenes and metallacyclobutanes was proposed. This preliminary work finally led to the isolation and characterization of stable metal carbene and metallacyclobutane complexes. As anticipated, these well-characterized complexes were shown to be active catalysts. In a select number of cases, these catalysts have been shown to catalyze the living polymerization of strained rings such as norbornene. The synthetic control offered by these living systems places them in a unique category of metal catalyzed reactions. To take full advantage of these new catalysts, two approaches should be explored. The first takes advantage of the unusual fact that all of the unsaturation present in the monomer is conserved in the polymer product. This makes ROMP techniques ideal for the synthesis of highly unsaturated, and fully conjugated polymers, which find uses in a variety of applications. This area is currently under intense investigation. The second aspect, which should lend itself to fruitful investigations, is expanding the utility of these catalysts through the living polymerization of monomers containing interesting functional groups. Polymer properties can be dramatically altered by the incorporation of functional groups. It is this latter aspect which will be addressed in this work.

After a general introduction to both the ring-opening metathesis reaction (Chapter 1) and the polymerization of fuctionalized monomers by transition metal catalysts (Chapter 2), the limits of the existing living ROMP catalysts with functionalized monomers are examined in Chapter 3. Because of the stringent limitations of these early metal catalysts, efforts were focused on catalysts based on ruthenium complexes. Although not living, and displaying unusually long induction periods, these catalysts show high promise for future investigations directed at the development of catalysts for the living polymerization of functionalized monomers. In an attempt to develop useful catalysts based on these ruthenium complexes, efforts to increase their initiation rates are presented in Chapter 4. This work eventually led to the discovery that these catalysts are highly active in aqueous solution, providing the opportunity to develop aqueous emulsion ROMP systems. Recycling the aqueous catalysts led to the discovery that the ruthenium complexes become more activated with use. Investigations of these recycled solutions uncovered new ruthenium-olefin complexes, which are implicated in the activation process. Although our original goal of developing living ROMP catalysts for the polymerization of fuctionalized monomers is yet to be realized, it is hoped that this work provides a foundation from which future investigations can be launched.

In the last chapter, the ionophoric properties of the poly(7-oxanobornene) materials is briefly discussed. Their limited use as acyclic host polymers led to investigations into the fabrication of ion-permeable membranes fashioned from these materials.

Signal transduction with hybridization chain reactions

Some of the most exciting developments in the field of nucleic acid engineering include the utilization of synthetic nucleic acid molecular devices as gene regulators, as disease marker detectors, and most recently, as therapeutic agents. The common thread between these technologies is their reliance on the detection of specific nucleic acid input markers to generate some desirable output, such as a change in the copy number of an mRNA (for gene regulation), a change in the emitted light intensity (for some diagnostics), and a change in cell state within an organism (for therapeutics). The research presented in this thesis likewise focuses on engineering molecular tools that detect specific nucleic acid inputs, and respond with useful outputs.

Four contributions to the field of nucleic acid engineering are presented: (1) the construction of a single nucleotide polymorphism (SNP) detector based on the mechanism of hybridization chain reaction (HCR); (2) the utilization of a single-stranded oligonucleotide molecular Scavenger as a means of enhancing HCR selectivity; (3) the implementation of Quenched HCR, a technique that facilitates transduction of a nucleic acid chemical input into an optical (light) output, and (4) the engineering of conditional probes that function as sequence transducers, receiving target signal as input and providing a sequence of choice as output. These programmable molecular systems are conceptually well-suited for performing wash-free, highly selective rapid genotyping and expression profiling in vitro, in situ, and potentially in living cells.

Advances in organic catalysis: the design of a novel asymmetric, organocatalytic intramolecular Diels Alder reaction

No abstract.

Progress towards the total synthesis of a spermine-conjugated dynemicin analog

Progress towards the synthesis of the spermine-conjugated Dynemicin analog 4 is described. The synthetic route starts with the Michael addition of menthyl acetoacetate to trans-ethyl crotonate followed by a Dieckman condensation to form the cyclohexanedione 14 which, through a series of chemical reactions, is transformed into the quinone imine 6. Key features in the route include the Suzuki coupling reaction of the aryl boronic acid 11 and the enol triflate 12, thermal deprotection/internal amidation of the biaryl 19, cis addition of the (Z)-enediyne 33 to the quinoline 25, intramolecular acetylide addition to a carbonyl within the ketone 29, and an addition/elimination of the cyanophthalide to the quinone imine 6 to form the anthraquinone 36 utilizing the Kraus and Sugimoto methodology.

Studies of molecular bonding, interactions and decomposition reactions on the (001) surface of ruthenium

The interactions of N₂, formic acid and acetone on the Ru(001) surface are studied using thermal desorption mass spectrometry (TDMS), electron energy loss spectroscopy (EELS), and computer modeling.

Low energy electron diffraction (LEED), EELS and TDMS were used to study chemisorption of N₂ on Ru(001). Adsorption at 75 K produces two desorption states. Adsorption at 95 K fills only the higher energy desorption state and produces a (√3 x √3)R30° LEED pattern. EEL spectra indicate both desorption states are populated by N₂ molecules bonded "on-top" of Ru atoms.

Monte Carlo simulation results are presented on Ru(001) using a kinetic lattice gas model with precursor mediated adsorption, desorption and migration. The model gives good agreement with experimental data. The island growth rate was computed using the same model and is well fit by R(t)^m - R(t₀)^m = At, with m approximately 8. The island size was determined from the width of the superlattice diffraction feature.

The techniques, algorithms and computer programs used for simulations are documented. Coordinate schemes for indexing sites on a 2-D hexagonal lattice, programs for simulation of adsorption and desorption, techniques for analysis of ordering, and computer graphics routines are discussed.

The adsorption of formic acid on Ru(001) has been studied by EELS and TDMS. Large exposures produce a molecular multilayer species. A monodentate formate, bidentate formate, and a hydroxyl species are stable intermediates in formic acid decomposition. The monodentate formate species is converted to the bidentate species by heating. Formic acid decomposition products are CO₂, CO, H₂, H₂O and oxygen adatoms. The ratio of desorbed CO with respect to CO₂ increases both with slower heating rates and with lower coverages.

The existence of two different forms of adsorbed acetone, side-on, bonded through the oxygen and acyl carbon, and end-on, bonded through the oxygen, have been verified by EELS. On Pt(111), only the end-on species is observed. On dean Ru(001) and p(2 x 2)O precovered Ru(001), both forms coexist. The side-on species is dominant on clean Ru(001), while O stabilizes the end-on form. The end-on form desorbs molecularly. Bonding geometry stability is explained by surface Lewis acidity and by comparison to organometallic coordination complexes.

Reactions of oxygen containing ligands in the coordination sphere of permethylhafnocene and permethyltantalocene

A series of terl-butylperoxide complexes of hafnium, Cp*₂Hf(R)(OOCMe₃) (Cp* = ((η⁵-C₅Me₅); R = Cl, H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CH₂CH₂CH₃, CH₂CHMe₂, CH=CHCMe₃, C₆H₅, meta-C₆H₃(CH₂)2) and Cp*(η⁵-C₅(CH₃)₄CH₂CH₂CH₂)Hf(OOCMe₃), has been synthesized. One example has been structurally characterized, Cp*₂Hf(OOCMe₃)CH₂CH₃ crystallizes in space group P2₁/c, with a = 19.890(7)Å, b = 8.746(4)Å, c = 17.532(6)Å, β = 124.987(24)°, V = 2498(2)ų, Z = 4 and R_F = 0.054 (2222 reflections, I > 0). Despite the coordinative unsaturation of the hafnium center, the terl-butylperoxide ligand is coordinated in a mono-dentate ligand. The mode of decomposition of these species is highly dependent on the substituent R. For R = H, CH₂CH₃, CH₂CH₂CH₃, CH₂CH₂CH₂CH₃, CH₂CHMe₂ a clean first order conversion to Cp*₂Hf(OCMe₃)(OR) is observed (for R CH₂CH₃, ΔHǂ = 19.6 kcal•mol^-1, ΔSǂ = -13 e.u.). These results are discussed in terms of a two step mechanism involving η²-coordination of the terl-butylperoxide ligand. Homolytic O-O bond cleavage is observed upon heating of Cp*₂Hf(OOCMe₃) R (R = C₆H₆, meta-C₆H₃(CH₃)₂). In the presence of excess 9,10-dihydroanthracene thermolysis of Cp*₂Hf(OOCMe₃)C₆H₆ cleanly affords Cp*₂Hf(C₆H₆)OH and HOCMe₃ (ΔHǂ = 22.6 kcal•mol^-1, ΔSǂ = -9 e.u.). The O-O bond strength in these complexes is thus estimated to be 22 kcal•mol^-1.

Cp*₂Ta(CH₂)H, Cp*₂Ta(CHC₆H₅)H, Cp*₂Ta(C₆H₄)H, Cp*₂Ta(CH₂=CH₂)H and Cp*₂Ta(CH₂=CHMe)H react, presumably through Cp*₂Ta-R intermediates, with H₂O to give Cp*₂Ta(O)H and alkane. Cp*₂Ta(O)H was structurally characterized: space group P2₁/n, a= 13.073(3)Å, b = 19.337(4)Å, c = 16.002(3)Å, β = 108.66(2)°, V = 3832(1)ų, Z = 8 and R_F = 0.0672 (6730 reflections). Reaction of terlbutylhydroperoxide with these same starting materials ultimately yields Cp*₂Ta(O)R and HOCMe₃. Cp*₂Ta(CH₂=CHR)OH species are proposed as intermediates in the olefin hydride reactions. Cp*₂Ta(O₂)R species can be generated from the reaction of the same starting materials and O₂. Lewis acids have been shown to promote oxygen insertion in these complexes.

Use of pseudoephedrine as a practical chiral auxiliary for asymmetric synthesis

The use of pseudoephedrine as a practical chiral auxiliary for asymmetric synthesis is describe. Both enantiomers of pseudoephedrine are inexpensive commodity chemicals and can be N-acylated in high yields to form tertiary amides. In the presence of lithium chloride, the enolates of the corresponding pseudoephedrine amides undergo highly diastereoselective a1kylations with a wide range of alkyl halides to afford α-substituted products in high yields. These products can then be transformed in a single operation into highly enantiomerically enriched carboxylic acids, alcohols, and aldehydes. Lithium amidotrihydroborate (LAB) is shown to be a powerful reductant for the selective reduction of tertiary amides in general and pseudoephedrine amides in particular to form primary alcohols.