Bruce H. Lipshutz - US grants

The proposed research deals with the incorporation of highly functionalized heterocycles into a cyclophane network which, via one or more mild and efficient chemical events, is unmasked to afford the skeleton characteristic of the cyclo-peptide alkaloids. Each is discussed, therefore, as potential intermediates which are to function as latent diamide/dipeptide equivalents in these schemes. Preliminary work has demonstrated the viability of such an approach in two acyclic systems. The natural products show considerable promise as ionophoric agents, in addition to other biological activities.

The synthesis of complex natural products such as the antibiotics requires highly selective reactions. This work, which will provide new organometallic reagents derived from relatively simple starting materials, is supported in the Organic and Macromolecular Chemistry Program. Several new aspects of organocopper chemistry are to be studied including (1) a search for chiral induction using chiral higher order cuprates; (2) a study on the effect of gegenions on cuprates, including the generation of the first non-lithio and non-magnesio-containing agents; (3) a study on the role of Lewis acids in cuprate chemistry; (4) the first example of the exchange of ligands between a metal and copper, with subsequent cuprate chemistry; and (5)the utilization of these new reagents in the synthesis of the polyene macrolide antibiotic roflamycoin.

This research is being funded by the Organic Synthesis Program. Dr. Lipshutz will continue his very productive studies of organometallic reagents based upon complexes of copper. These have the potential for producing highly selective synthetic tools that can be used in the synthesis of the reactive molecules that are found in nature. This research describes, in part, a number of new synthetic methods which take advantage of the efficiency and mildness of higher order cuprate-based transmetalation processes of organotin compounds. Tolerance to a variety of functional groups within the stannane precursor itself will be studied, looking to form highly functionalized cuprates. Allylic reagents are to be examined with respect to substitutions at both tetrahedral and trigonal centers. Moreover, cyclic allylic stannanes are considered, as is the chemistry of allyl cuprates in the presence of carbon monoxide en route to direct 1,4-acylations of alpha,beta-unsaturated ketones. As part of a program in polyene construction, new lynchpins will be developed which will take advantage of site-selective transmetalations made possible by differences in relative rates between vinylstannanes. Applications to synthetic problems in the leukotriene and pheromone areas will be pointed out. The possibility of using oxidative "decomposition" of higher order cuprates, in a synthetic sense, to effect biaryl couplings will also be studied. The last portion of the research involves spectroscopic investigations of several species. One concerns the nature of the new reagent derived from CuI/LiCl/Bu3SnH, believed to be (X)HCuLi. Another will be an in-depth study of Yamamoto's reagent.

The broad, long term objectives of the proposed work are to provide short, rapid approaches to the construction of several polyene-containing natural products. Three unrelated types of polyene relationships are to be addressed: (1) all E, conjugated polyolefins; (2) skipped Z-polyenes; and (3) doubly skipped, polyprenoidal polyolefins. Specifically, the former classification will impact on polyene macrolide total synthesis. These large ring natural products are widely used as clinical agents for treatment of systemic infection. Skipped polyenes, with potential applications to e.g., pheromones and molecules derived from the arachidonic acid cascade (such as the slow reacting substances of anaphylaxis, SRSA's), the latter being especially prominent in their association with respiratory ailments. Coenzymes Qn, which make up a group of ubiquitous redox components intimately involved in the mitochondrial respiratory chain, are used clinically as well. The heart of the approach to these potent bimolecules lies in the further development of newly discovered organometallic methodology, with applications envisioned for effecting polyene construction via appropriately designed lynchpins. Taking advantage of either symmetry elements or differences in reactivity profiles between the termini of the novel lynchpins, 1-pot stitching via reagents preformed 'in-situ' with suitable electrophiles is to afford key components of the target molecules. Further extension of this new chemistry to the direct preparation of homochiral C-4-substituted (dideoxy) riboses is also envisioned.

The focus of this research is to exploit organozirconium reagents, resulting from standard zirconations of various alkynes, for ligand exchange reactions with Cu(I) reagents, particularly higher order cyanocuprates. Vinyl zirconocenes generated from a number of compounds including acetylenic stannanes and acetylenic ethers afford reagents for multiple C-C bond constructions. The transmetalation protocol will also be extended to Ti and a study of titanacyclobutenes will be initiated. NMR will be used to probe the aggregation states of a number of interesting cuprates. %%% With this renewal award, the Synthetic Organic Program is supporting the research of Dr. Bruce H. Lipshutz of the Department of Chemistry at the University of California, Santa Barbara. Professor Lipshutz will focus his work on developing new syntetic methods that rely on the transmetalations of selected organometallic intermediates composed of Group 4 metals with Cu(I) reagents. The research will lead to the facile preparation of efficient reagents for C-C bond making.

With this award, the Synthetic Organic Program is supporting student attendance at a meeting entitled "Organometallic Chemistry Directed Towards Organic Synthesis "(OMCOS-8). The award will help subsidize 33 graduate students and postdoctorals at the meeting, which has environmental concerns as a salient theme.

During the past two years we have initiated a program in polyene chemistry, which has been directly supported by NIH grant GM 40287. The accent associated with the work described is on the development of new methodology, based in large measure on vinylic organometallics, since coupling reactions of sp2 carbon centers bearing a metal tend to retain their stereochemical integrity. A number of polyene types were identified, including (1) conjugated, all E polyenes, containing between four and seven olefins, typified by the polyene macrolides. These natural products are potent, clinically useful antifungals; (2) doubly skipped polyenes, characteristic of the ubiquinones (CoQn). These coenzymes are valuable in vivo antioxidants. A third type of polyene, distinct from those above, is the biaryl nucleus. With each of these specific functional groups, novel reagents and/or technologies were envisioned which rely on either cuprate mediated transmetalations between vinylic stannanes or zirconocenes, or 'kinetic' higher order cuprate oxidations toward unsymmetrical biaryls. Lastly, new methodology for rapid construction of the prostanoid skeleton has been developed, the scope of which is to be examined. As an outgrowth of these projects, the discoveries made have expanded our involvement in organometallics to include (beyond Cu, Sn, and Zr) organozinc, palladium and nickel chemistry as they relate to polyenes as well. Thus, this renewal application will highlight our accomplishments relating to GM 40287, point out the important discoveries made along the way, and then focus attention, in large measure, on the new directions planned which rely on a variety of organometallic intermediates.

This project is purchasing a network of six graphics workstations that, together with existing Macintosh and DEC computers, serves as the basis for new course developments in the area of computational chemistry within the undergraduate curriculum in the chemistry department and the Pharmacology Program of the biological sciences department. The new computers are being used in courses in Freshman chemistry, organic and advanced organic chemistry, biochemistry, polymer chemistry, computational chemistry, and upper-division pharmacology courses and are being used to support undergraduate research projects in the academic year and the summers. The capabilities of this new instrumentation makes it possible to communicate to students the reality and excitement of modern developments in chemistry and to involve these students in exercises and projects that will give them "hands-on" access to these computational techniques as an integral part of our undergraduate curriculum. Thus far, experimental courses in this area have been very enthusiastically accepted by students and give students a set of skills that serve them in graduate and professional schools and careers in the bulk chemical and pharmaceutical industries.

Naturally occurring compounds consisting of multiple olefinic sites occupy a special niche among physiologically active agents. Included in this polyene group are (1) the polyene macrolide antibiotics, clinically valued as anti-fungals. The ion channel-forming materials usually contain between four and seven E-olefins in a conjugated array. The use of conjunctive reagents for rapidly preparing oxo tetra- to heptaene subsections in stereochemically homogeneous form is to be pursued; (2) new routes to biaryls bearing axial chirality, in particular the biaryl portions of vancomycin and michellamine B, will be studied. The former is one of the world's last lines of defense against certain bacterial infections, and the latter is an especially effective anti-AIDS compound. Both targets will derive from an intra-molecular biaryl coupling strategy via organometallic intermediates. Stereoinduction will be controlled by the nature of the tether joining the individual aryl components. Thus, this application discusses not only considerable published progress made during the currant grant period, but extensive unpublished data in support of both the continuing and especially, the new directions in our polyene program, outlined herein. In amines, and (b) nickel-on-charcoal as an effective, inexpensive and environmentally benign catalyst for effecting C-C band formations which should assist us in reaching our goals, and provide general utility as well to the synthetic community.

The proposed research involves the development of new synthetic methods involving organocopper intermediates used at catalytic concentrations. Reactions will include 1) Fleming's silyl cuprate chemistry, 2)the use of lanthanide and other rare earth cocatalysts, 3) alkylations of functionalized Zn and Zr reagents with vinyl and aryl triflates, and 4)1,4-reductions of alpha,beta-unsaturated carbonyl compounds using copper hydride complexes. Raman and IR spectroscopy, and electrospray mass spectrometry, will be used to determine organocuprate compositions and structures in solution. With this renewal award, the Organic and Macromolecular Chemistry Program provides continuing support for the research of Dr. Bruce Lipshutz of the Department of Chemistry at the University of California at Santa Barbara. The research involves the developmentof synthetic methods for preparing organic compounds under mild conditions and with high selectivities. The work will provide valuable training to graduate students and post-doctoral fellows in organic synthesis and the spectroscopic identification of reaction intermediates.

DESCRIPTION: (applicant's abstract) In the field of asymmetric synthesis, one of the most powerful approaches involves use of BINOL and BINAP ligands as catalysts. These binaphthylic species are among the most extensively utilized systems for inducing chirality into a vast array of intermediates of value en route to physiologically active compounds. Their involvement in such targets as naproxen (anti-inflammatory), morphine (narcotic), and dextromethorphan (cough suppressant) only begin to touch upon their importance to the pharmaceutical arena, where most new drugs must now be "chiral" (i.e., single enantiomer). Remarkably, however, there are very few substituted BINOLs known, and no substituted BINAPs, where any of the remaining positions on the naphthalene rings bear groups that might significantly improve enantioselectivity of numerous reactions which rely on one of these ligands. This proposal, therefore, seeks to address this fundamental problem; that is, of supplying methodology for arriving at substituted BINOLs and BINAPs. In particular, substitution at the 3- and 3,3'-positions will be addressed, as these sites can play a pivotal role in enhancing nonracemic binaphthyl-induced stereoinduction via steric factors and/or chelation properties. The key to providing such new ligands rests upon the attachment of the individual naphythylic components to a nonracemic tether, with subsequent intramolecular oxidative biaryl coupling to the corresponding, optically pure, substituted cyclo-BINOL array. From ligands of this type come further options, such as opportunities for polymer mounting, and potentially of greatest attention, conversion to substituted cyclo BINAPs.

The main theme of this work is the use of copper (I) complexes to catalyze a variety of asymmetric organic reactions. Most of the proposed chemistry involves the catalytic use of asymmetrically ligated copper hydride or alkyl complexes. The copper hydrides will be used for asymmetric hydrosilylation of ketones and a 1,4-reducation-transmetallation protocol for converting alpha, beta unsaturated ketones into Z-boron enolates. The copper alkyl complexes will be used primarily for asymmetric 1,2 additions to aldehydes and to effect alkylative kinetic resolution of racemic epoxides.

With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. Bruce H. Lipshutz of the Department of Chemistry at the University of California at Santa Barbara. Dr. Lipshutz will work on the development of copper complexes capable of catalyzing a number of chemical reactions. Most of these copper catalyzed carbon-hydrogen and carbon-carbon bond forming reactions produce molecules which are chiral (have two nonsuperimposable mirror images) and make only one of the two possible forms (a single enantiomer). Development of this family of reactions is one of the most important problems facing the pharmaceutical industry today. These transformations which are catalytic in copper may be amenable to large scale production of fine chemicals and pharmaceuticals. Students trained during the course of this work will gain skills needed by the pharmaceutical and speciality chemicals industries which now produce a number of single enantiomer compounds.

DESCRIPTION (provided by applicant): Biaryls represent a major area of natural and unnatural products chemistry. Given the widespread occurrence of physiologically active compounds in Nature that contain a biaryl axis, many of which due to hindered rotation possess an element of axial chirality, methodology is needed to respond to these special synthetic challenges. Representative targets which highlight existing limitations yet which provide opportunities for significant advances in this area include the clinically essential antibiotic vancomycin, and the potent anti-AIDS biaryls, the michellamines. Using a judiciously placed internal phosphine ligand in an aryl halide coupling partner, the directionality associated with our key Suzuki-biaryl coupling-based approach to the vancomycin biaryl and the subunits of the michellamines will be controlled. Alternatively, a conceptually new entry to stereocontrolled biaryls, as applied to vancomycin, will be pursued using a Bergman cyclization of a substituted nonracemic endiyne. The chemistry of biaryl constructions, which is usually effected in solution using Pd(0) catalysis, is to be pursued via an alternative metal system: nickel. Proposed herein are new methods for heterogeneous catalysis based on Ni/C, to be examined under microwave conditions, and the next generation species nickel-on-graphite ("Ni/Cg"), which appears to offer a different reactivity profile. Finally, a new series of nonracemic ligands based on the binaphthyl core, in particular of NOBIN, will be constructed. The approach presented will provide entry to unprecedented substitution patterns on this ligand system, as well as opportunities for their mounting on a solid support for use, and re-use, under heterogeneous conditions. A particular, albeit representative, application of a novel substituted cyclo-NOBIN will be studied for selected asymmetric aldol reactions.

This project is focused on the theme of catalysis, specifically involving copper(I) hydrido complexes that are mainly ligated by nonracemic bis-phosphines ((L*)CuH). The action of catalytic (L*)CuH on aryl ketone intermediates will form products useful for the synthesis of known pharmaceuticals. Catalytic (L*)CuH will be used in new contexts that will afford valued nonracemic intermediates for synthesis, extending the limits of this CuH chemistry. A newly designed ligand will be synthesized to test the factors that may control both reaction rates and enantioselectivities. Experiments aimed at investigating the nature of the species (L*)CuH are planned, supporting the goal of providing a practical source of (L*)CuH; i.e., effectively CuH in a Bottle. Using boranes as the stoichiometric source of hydride, new inroads to boron enolates will be developed and used to synthetic advantage based on transmetalations. Finally, copper-in-charcoal (Cu/C) will be explored as a potential new approach to asymmetric (heterogeneous) organocopper chemistry.

With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. Bruce H. Lipshutz of the Department of Chemistry and Biochemistry at the University of California at Santa Barbara. Catalysis represents a powerful tool in the development of more economical and environmentally friendly technologies. Professor Lipshutz and his students are exploring new ways to catalyze organic chemical transformations using copper compounds. These copper compounds are significantly less expensive than the more commonly used precious metal catalysts and offer unique chemical reactivity as well. By developing these new catalysts, Professor Lipshutz is developing methodologies that may be generally and broadly applicable in the synthesis of complex organic molecules and pharmaceuticals.

A nanomicelle-forming amphiphile "PTS" has been identified that allows for several Pd- and Ru-catalyzed cross-couplings to take place in water as the only solvent, and at room temperature, in high isolated yields. The new processes include Heck, Suzuki, Sonogashira, and olefin cross-metathesis reactions, where product isolation is especially facile. Several additional studies are planned based on the "micellar effect." The notion of "designer" surfactants applied to organometallic catalysis is advanced in this proposal, and represents a variable essentially overlooked by the synthetic community. This technology also is to be applied to other important cross-couplings, such as aminations and asymmetric additions of hydride to Michael acceptors, all in water at room temperature.

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5). This project will initiate work on the development of methods for two unprecedented reactions: (1) in situ Grignard formation and use in cross-coupling reactions in water, and (2) formation of unstabilized ylides for Wittig-like olefinations, also in water. These will take advantage of micellar catalysis, where the reactive species to be generated either on the surface of the metal, or within a micelle, are protected from their aqueous surroundings by the hydrophobic interior of these nanoparticles. For these studies, many variables will need to be screened, including the nature of the amphiphile that is to supply a dry reaction medium, in water.

With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Professor Bruce H. Lipshutz of the Department of Chemistry at the University of California, Santa Barbara. Professor Bruce Lipshutz's research efforts revolve around the development of new synthetic methods for the formation of C-C, C-H, C-O, and C-N bonds. Such chemistry will contribute to environmentally benign methods for chemical synthesis, as these new processes will be developed in the absence of organic solvents. Successful development of the methodology will have an impact on synthesis in the pharmaceutical, fine chemicals, and agricultural industries.

This project will explore several synthetic methods that rely on copper as the metal that effects catalysis. A number of the transformations are on copper hydride chemistry, which includes new uses of nonracemically ligated CuH for syntheses. The potential to realize unprecedented ligand-accelerated catalysis with CuH in pure water at room temperature will be pursued, along with the potential to deliver water-sensitive carbon-based residues via conjugate addition chemistry, with both approaches based on micellar catalysis in water. Heterogeneous processes that take advantage of both readily accessed valence states of copper [Cu(I) and Cu(II)] impregnated into the pores of inexpensive charcoal matrices will also be developed. A high substrate-to-ligand ratio and tandem processes that can be carried out in a single reaction vessel will be studied.

With this award, the Chemical Synthesis Program is supporting the research of Professor Bruce H. Lipshutz of the Department of Chemistry at the University of California, Santa Barbara. Professor Lipshutz's research efforts revolve around the development of organocopper-based asymmetric catalysis leading to new methods for the formation of C-C and C-H bonds. Such chemistry will contribute to environmentally benign methods for chemical synthesis as most of these new technologies will be developed in the absence of organic solvents, where water serves as the macroscopic medium. Successful applications of the methodology will have an impact on synthesis in the pharmaceutical, fine chemical, and agricultural industries.

DESCRIPTION (provided by applicant): A new paradigm for Pd-catalyzed cross-couplings between alkyl and aryl halides in water at room temperature will be further developed. Reactive, highly water-sensitive sp3-based organozinc reagents can be generated in situ and used as coupling partners, protected from their aqueous surroundings by a micellar environment. A study on the use of alkyl bromides as a less costly alternative to iodides will be undertaken. This new micellar nanotechnology will be applied to related cross-couplings of stereo-defined alkenyl halides. Such couplings would be an especially attractive alternative to Suzuki-Miyaura couplings that normally require prior formation of boronic acids or the equivalent. The stereochemistry of the products resulting from these couplings in water relative to that seen in organic solvents will also be compared. Related couplings applied to heteroaromatic halides will be studied, given the importance of heterocycles to the pharmaceutical industry. Novel transition metal-catalyzed tandem processes will be developed, both reactions of in this sequence to be conducted in water at room temperature. Stille couplings involving organostannane intermediates will also be investigated as coupling partners in micellar media. The first cases of couplings using nickel catalysis will also be further investigated in reactions of alkenyl halides with in situ-generated organozinc halides. A newly designed, inexpensive yet healthy surfactant has been identified and will be developed that enables room temperature couplings for several name reactions to be done in water. Higher levels of conversion relative to those seen in previous studies can be achieved, and hence, better yields of cross-coupling products are to be expected. The secret to this success is based on proper engineering of particle size, which better accommodates the intended chemistry.

The Chemical Catalysis Program in the Chemistry Division supports this Grant Opportunity for Academic Liaison with Industry (GOALI) award to Professor Bruce Lipshutz. Professor Lipshutz is a faculty member at the University of California, Santa Barbara (UCSB). The project is a collaboration between UCSB and Novartis, a pharmaceutical company. The research undertaken at UCSB focuses on developing new catalysts for valuable organic reactions, where the amount of precious metal, palladium, is only needed in parts per million, rather than the greater levels normally used in palladium-catalyzed reactions. These new reactions reduce the environmental footprint associated with industrial uses of palladium as the reactions are done in water, avoiding use of toxic, flammable, and costly organic solvents. The reagents and experiments under development are of general synthetic utility, and thus may have an impact in academic settings. Students in these research groups learn to couple industrial manufacturing with sustainable chemistry.

New nanoparticles (NPs) are formed by treatment of inexpensive iron(III) trichloride (containing ca. 350 ppm palladium) and a phosphine ligand, with methyl Grignard at room temperature. The new iron nanoparticles (NPs) containing trace palladium metal (Pd) catalyze Suzuki-Miyaura cross-couplings reactions. Synthesis of the Novartis drug valsartan, which contains biaryl residue, is under development using this technology. These NPs are being investigated as catalysts for other important Pd-catalyzed reactions, such as Sonogashira couplings. The reactions are performed in water, thereby eliminating organic solvents as the reaction medium. The NPs can be recycled, effectively reducing not only the amount of Pd needed, but also the levels of residual metal found in the products. In addition, it has been found that these same iron nanoparticles, in the absence of ligand, are effective catalysts for the reduction of aromatic and heteroaromatic nitro groups in water. The reduction leads to the corresponding amine, which is a valuable transformation in the pharmaceutical industry. These new technologies are developed by graduate students, who receive their training both in synthetic organic chemistry and in green chemistry. The students involved in the project are develop the know how to minimize organic and metal waste in reaction development and scale-up.

The Chemical Synthesis Program of the Chemistry Division supports the project by Professor Lipshutz. Professor Lipshutz is a faculty member in the Department of Chemistry at the University of California at Santa Barbara. The project features several new synthetic methods highlighting copper, and to a lesser degree, nickel, as the metals catalyzing the chemistry. The objectives include developing a method to make carbon-carbon bonds using readily available copper as a catalyst rather than palladium, a scarce precious metal. Another objective is the oxidation and cleavage of carbon-carbon double bonds to form carbon-oxygen double bonds using copper catalysis. Each transformation provides a solution to important problems in pharmaceutical development. These processes, in particular those developed to be conducted in water, should encourage process chemists in the fine chemicals and pharmaceuticals areas to consider running their reactions under these sustainable and green chemistry conditions. These projects are well suited for the education of scientists at all levels. Development of undergraduate laboratory experiments using green chemistry principles is a component of this project.

Studies conducted under this NSF award focus on the development of new technologies in organocopper chemistry, to be used under green chemistry conditions. These new methods feature use of water as the reaction medium, with the chemistry to be enabled using designer surfactants that provide nanoreactors in which these reactions take place. The methodologies to be studied include (1) a copper-catalyzed Suzuki-Miyaura cross-coupling done with the exclusion of palladium; (2) development of a copper-catalyzed alternative to ozonolysis; and (3) examination of the use of asymmetrically ligated copper(I) for intermolecular hydroaminations of allenes, leading to nonracemic allylic amines. Development of undergraduate laboratory experiments using green chemistry principles is a component of this project.

This award is supported by the Major Research Instrumentation and the Chemistry Research Instrumentation Programs. Professor Liming Zhang from the University of California Santa Barbara (UCSB) and colleagues Bruce Lipshutz, Trevor Hayton and Javier Read de Alaniz have acquired a 500 MHz NMR spectrometer equipped with a liquid-nitrogen cooled probe and a probe with multinuclear capabilities. This spectrometer allows research in a variety of fields such as those that accelerate chemical reactions of significant economic importance, as well as those that facilitate studies of biologically relevant species. In general, Nuclear Magnetic Resonance (NMR) spectroscopy is one of the most powerful tools available to chemists to describe the structure of molecules. NMR is used to identify unknown substances, to characterize specific arrangements of atoms within molecules, and to study the dynamics of interactions between molecules in solution or in the solid state. Access to state-of-the-art NMR spectrometers is essential to chemists who are carrying out frontier research. The cryogenic probe provides a significant increase in sensitivity relative to standard NMR probes while the multinuclear probe allows study of a wide range of elements above and beyond the common hydrogen and carbon atoms. The NMR studies improve understanding of synthetic organic/inorganic chemistry, materials chemistry and biochemistry. This instrument is an integral part of teaching as well as research. This broadly accessible instrumentation strengthens the regional instrumentation infrastructure and helps advance the scientific careers of about 200 regular undergraduate and graduate researchers, postdocs and visiting scholars in more than 18 research groups. The spectrometer enriches the education and training experience of underrepresented undergraduate students in several NSF-supported science, technology, engineering and mathematics (STEM) programs and several hundred undergraduate students in chemistry and biochemistry laboratory classes at UCSB and from Santa Barbara Community College. This NMR instrumentation also facilitates research and development (R&D) efforts of several local startup companies specializing in clean energy and food preservation.

The award of the NMR spectrometer with a cryoprobe is aimed at enhancing research and education at all levels. This acquisition especially benefits the development of a thermochemical model for nanocluster formation and the exploration of actinide electronic structures. The instrumentation also serves researchers studying fluorinated functional polymers and those using boron-11 isotopes in boron-catalyzed peptide bond formation. Finally, the spectrometer benefits the syntheses and characterization of complex bioactive natural products.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.