Gary A Molander
University Of Pennsylvania
Project start date: 1993-09-01
Project end date: 2014-01-31
Sponsored Links Excellgen http://Excellgen.com
Coupling Reactions-Methods Development And Applications
Gary A Molander, Professor
University Of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104
Grant 5R01GM035249-23 from National Institute Of General Medical Sciences IRG: MCHA
Abstract: Two broad areas of investigation are proposed. The first concentrates on the chemistry of samarium(ll) iodide and in particular its unique ability to mediate sequential processes that selectively transform simple starting materials to interesting products with considerable increase in molecular complexity. Unlike previous efforts in our group, we will devote substantial effort to the assembly of nitrogen heterocycles via synthetic pathways unique to this valuable reagent. Sequenced reactions to be explored include a conjugate addition/nucleophilic acyl substitution sequence, ketyl allene coupling/radical sequences, and sequences initiated by N-centered radicals. The second area of consideration is the application of organotrifluoroborates to organic synthesis. We have spent some time outlining the ways in which these useful reagents complement more commonly utilized classes of organoboron compounds in Suzuki-Miyaura cross-coupling reactions and certainly considerable advantages exist. In this proposal, however, we focus on the types of transformations that, for structural reasons, simply cannot be carried out with any other organoboron reagents. These include the synthesis of bimetallic reagents in which one of the metal centers is boron, and the development of unique reagents in which organic functionality has been oxidized in the presence of the trifluoroborate moiety. These types of transformations are anticipated to have broad generality and will thus prove valuable for the rapid, efficient, and unique assembly of complex organic molecules throughout the pharmaceutical industry and beyond.
Keywords: catalyst, chemical synthesis, method development, rare earth element, reducing agent, antibiotic, antihypertensive agent, boron, chemical substitution, cyclic compound, glycosylphosphatidylinositol, stereochemistry, terpene
Project start date: 1993-09-01
Project end date: 2008-07-31
5R01GM035249-23 (2007): $336507
5R01GM035249-22 (2006): $283296
5R01GM035249-21 (2005): $350961
INTRAMOLECULAR REDUCTIVE COUPLING REACTIONS
Gary A Molander, Professor
University Of Colorado At Boulder 572 Ucb Boulder, Co 80309
Grant 5R01GM035249-11 from National Institute Of General Medical Sciences IRG: MCHA
Abstract: The primary theme of this proposal is the further development of samarium(II) iodide (SmI2) and related reagents as highly selective reductive coupling agents for organic synthesis. Samarium(II) iodide promotes reactions with many functional groups of interest to synthetic organic chemists, and in this context this soluble one electron reductant has been found to be a.remarkably versatile reagent. The Sm(III) ion generated during the course of reductive coupling reactions is a highly oxophilic species. This Lewis acid can therefore be utilized as a template upon which to control stereochemistry. The combination of these features makes SmI2 highly complementary in many respects to other, perhaps more traditional, reductants such as Mg, Zn, Cr(II), and dissolving metal reductants. The unique combination of characteristics exhibited by SmI2 permits chemical transformations that are difficult, if not impossible, to achieve by other currently available means. The emphasis of our research will be in continuing the exploration of unconventional reactivity and selectivity patterns with SmI2, thereby facilitating the rapid and efficient synthesis of complex organic structures from relatively simple substrates. Several distinct areas have been targeted for study. An investigation of intramolecular nucleophilic acyl substitution reactions of halo- substituted carboxylic acid derivatives will be completed. Studies will be initiated to explore ketyl-olefin coupling reactions and subsequent transformations of the intermediates generated from them. Highlights of these studies will include the synthesis of eight-membered carbocycles, as well as an examination of five- through eight-membered oxygen and nitrogen heterocycle synthesis. One of the unique features of SmI2 is its ability to sustain sequential radical and carbanionic reactions in one-pot processes. Much of the proposal centers on this important feature of this versatile reductant. Over the past few years a tremendous database has been established which permits one to reliably predict relative reactivity of various organic functional groups with SmI2. This knowledge will be utilized to sequence organic reactions in polyfunctional organic substrates. This sequencing will permit formation of multiple carbon- carbon bonds in a single-pot process, in most instances with complete control of stereochemistry over several stereocenters. Finally, while past experience has demonstrated that SmI2 is an excellent reductant for many of the processes under study, development and employment of other SmX2 reducing agents that may exhibit enhanced reactivity or other desirable properties will also be undertaken. The types of studies outlined in this proposal are fundamental in nature, and yet may have direct application in the pharmaceutical industry for the efficient synthesis of pharmacologically active materials, analogues, metabolites, and other intermediates required for studies in drug developme .
Keywords: chemical synthesis, rare earth element, reducing agent, chemical substitution, cyclic compound, stereochemistry
Project start date: 1993-09-01
Project end date: 1997-08-31
5R01GM035249-11 (1995): $218819
5R01GM035249-10 (1994): $210431
5R01GM035249-19 (2003): $237799
5R01GM035249-18 (2002): $237799
5R01GM035249-17 (2001): $299715
5R01GM035249-14 (1998): $194764
Sponsored Links Excellgen http://Excellgen.com
5R01GM035249-08 (1992): $209490
5R01GM035249-12 (1996): $229260
Grants awarded to Gary A Molander
Coupling Reactions-Methods Development And Applications
Gary A Molander, Professor
University Of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104
Grant 2R01GM035249-20 from National Institute Of General Medical Sciences IRG: MCHA
Abstract: Two broad areas of investigation are proposed. The first concentrates on the chemistry of samarium(ll) iodide and in particular its unique ability to mediate sequential processes that selectively transform simple starting materials to interesting products with considerable increase in molecular complexity. Unlike previous efforts in our group, we will devote substantial effort to the assembly of nitrogen heterocycles via synthetic pathways unique to this valuable reagent. Sequenced reactions to be explored include a conjugate addition/nucleophilic acyl substitution sequence, ketyl allene coupling/radical sequences, and sequences initiated by N-centered radicals. The second area of consideration is the application of organotrifluoroborates to organic synthesis. We have spent some time outlining the ways in which these useful reagents complement more commonly utilized classes of organoboron compounds in Suzuki-Miyaura cross-coupling reactions and certainly considerable advantages exist. In this proposal, however, we focus on the types of transformations that, for structural reasons, simply cannot be carried out with any other organoboron reagents. These include the synthesis of bimetallic reagents in which one of the metal centers is boron, and the development of unique reagents in which organic functionality has been oxidized in the presence of the trifluoroborate moiety. These types of transformations are anticipated to have broad generality and will thus prove valuable for the rapid, efficient, and unique assembly of complex organic molecules throughout the pharmaceutical industry and beyond.
Keywords: catalyst, chemical synthesis, method development, rare earth element, reducing agent, antibiotic, antihypertensive agent, boron, chemical substitution, cyclic compound, glycosylphosphatidylinositol, stereochemistry, terpene
Project start date: 1993-09-01
Project end date: 2008-07-31
2R01GM035249-20 (2004): $300872
ORGANOTRIFLUOROBORATES IN SELECTIVE ORGANIC SYNTHESIS
Gary A Molander, Hirschmann-makineni Professor Of Chemist
University Of Pennsylvania, 3451 Walnut Street, Philadelphia, Pa 19104
Grant 2R01GM035249-24A2 from National Institute Of General Medical Sciences
Abstract: The Suzuki-Miyaura coupling reaction is widely recognized as one of the most powerful and broadly utilized synthetic methods developed over the past thirty years. Thousands of papers employing the reaction have been published during that time, and many of these have been devoted to improvements on the original procedure. Among the latter contributions, the vast majority of these studies have dealt with improving the transformation by optimizing important characteristics of the reaction such as the catalyst/ligand complex, the electrophile (aryl, heteroaryl, alkenyl, alkynyl, alkyl), the nucleofuge (chlorides, sulfonates, phosphates), the solvent (e.g., water, ionic liquids), the bases required, and the conditions of the reaction (e.g., by using sonication or microwaves). Curiously, little effort has been expended to expand the scope of the reaction by altering the essential organoboron reagent, which is clearly a key ingredient. To provide more versatile, easily functionalized organoborons that would create more structurally diverse reagents for cross-coupling, we initiated a program on the development of organotrifluoroborates, which have the potential to transform the implementation of Suzuki coupling in a very powerful way. The aim of the currently proposed research is to build on this foundation in a demonstration of the breadth of complementarity and, in some cases, orthogonal reactivity between organotrifluoroborates and boronic acids and their derivatives. In the current investigations we will build and couple novel and unique organoboron reagents (e.g., 2-homoenolates, oxiranyltrifluoroborates, aziridinyltrifluoroborates, and acyltrifluoroborates). We will continue to take advantage of the ability to operate on other functional groups within the organoboron reagent itself as a means to build molecular complexity into the organotrifluoroborates while retaining the valuable carbon-boron bond for further transformations (i.e., using the trifluoroborate as a protected boronic acid). We will also examine challenging, paradigm-changing strategies for C-C bond formation (reactions of chiral secondary alkyltrifluroborate, synthesis of dibora compounds and bidirectional synthesis) as well as novel reactivity patterns (intramolecular reactions with activated electrophiles). Success in the efforts proposed will provide enabling technologies for new drug discovery, and will also result in the development of robust synthetic transformations for the synthesis of complex target structures required for pharmaceutical process research and development, pilot plant technologies, and drug manufacturing. In this way, new drug entities can be delivered to the public more rapidly and efficiently at lower cost
Keywords: Acids; Alkanesulfonates; Alkyl Sulfonates; Alkylsulfonate Compound; B element; Biological Factors; Boron; Boronic Acids; C element; Carbon; Characteristics; Chemistry; Chemistry, Pharmaceutical; Chloride; Chloride Ion; Chlorides; Cl- element; Complex; Coupling; Development; Development and Research; Drugs; Electromagnetic, Microwave; Esters; Factor, Biologic; Foundations; Hydrogen Oxide; Investigation; Investigators; Ligands; Liquid substance; Medication; Medicinal Chemistry; Methods; Microwaves; Molecular; NIH; National Institutes of Health; National Institutes of Health (U.S.); Natural Products; Organic Synthesis; Oxidants; Oxidizing Agents; Paper; Pattern; Pharmaceutic Chemistry; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phosphates; Plants; Plants, General; Principal Investigator; Procedures; Process; Programs (PT); Programs [Publication Type]; Protocol; Protocols documentation; Publishing; R & D; R&D; Reaction; Reagent; Research; Research Personnel; Researchers; Role; Salts; Science of Chemistry; Solvents; Sonication; Structure; Technology; Time; United States National Institutes of Health; Water; base; catalyst; cost; drug discovery; drug/agent; electron acceptor; fluid; functional group; improved; infancy; infantile; inorganic phosphate; liquid; microwave electromagnetic radiation; microwave radiation; new technology; novel; programs; public health relevance; research and development; social role; success; sulfonate
Relevance: Success in the efforts proposed will provide enabling technologies for new drug discovery, and will also result in the development of robust synthetic transformations for the synthesis of complex target structures required for pharmaceutical process research and development, pilot plant technologies, and drug manufacturing. In this way, new drug entities can be delivered to the public more rapidly and efficiently at lower cost
Project start date: 1993-09-01
Project end date: 2014-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
PFA/PA: PA-07-070
2R01GM035249-24A2 (2010): $339238
3R01GM035249-24A2S1 (2010): $42365
NOVEL BORONIC ACIDS FOR PILOT-SCALE SCREENING
Gary A Molander, Hirschmann-makineni Professor Of Chemist
University Of Pennsylvania, 3451 Walnut Street, Philadelphia, Pa 19104
Grant 5P41GM086209-03 from Office Of The Director, National Institutes Of Health
Abstract: The principal goal of this new research program is to design, synthesize, and deliver a series of Pilot-Scale Libraries composed of structurally diverse and unique boronic acids and their derivatives to the NIH Molecular Libraries Small-Molecule Repository (MLSMR). While boronic acids have been reported to act as enzyme inhibitors through mimicking transition states, their use as probes of biological systems has been limited. The recent introduction of the boronic acid Velcade as a proteasome inhibitor approved for treatment of certain cancers has renewed interest in using this unconventional functional group in probe and drug development efforts. Toward this end, the PI has assembled an experienced interdisciplinary team of collaborators, including synthetic, medicinal, and computational chemists to assure these novel compounds possess "lead-like" or "drug-like" properties and cover broad areas of structural space not currently represented in the NIH MLSMR, while at the same time possessing the requisite physicochemical and pharmacokinetic properties to be of value as probes for the exploration of biological systems at the molecular level. The specific synthetic tactics to be employed have their foundation in exciting chemistry being developed in our laboratory concerning the utilization of organotrifluoroborates as protected forms of boronic acids. Organotrifluoroborates have been demonstrated to be resistant to oxidation, acids, bases, nucleophiles, and iminium ion chemistry to which boronic acids have various susceptibilities. This flexibility allows processing of ancillary functional groups incorporated within the organotrifluoroborates, while retaining the valuable boron carbon bonds. In this manner, small, readily available organotrifluoroborates can be elaborated in a highly efficient manner, increasing molecular complexity and diversity in a manner that is incompatible with the boronic acid moiety. Subsequently, the key boronic acid functional group can be unveiled through a simple deprotection protocol of the trifluoroborate. This will facilitate the construction and assembly of carefully designed libraries that have absolutely no precedent in the NIH MLSMR, thus significantly expanding the diversity of small molecules with the potential to be valuable probes for the exploration of biological systems at the molecular level
Project start date: 2008-09-05
Project end date: 2011-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: RFA-RM-08-003
5P41GM086209-03 (2010): $363898
5P41GM086209-02 (2009): $366721
1P41GM086209-01 (2008): $368664
INTRAMOLECULAR REDUCTIVE COUPLING REACTIONS
Gary A Molander, Professor
University Of Colorado At Boulder 572 Ucb Boulder, Co 80309
Grant 2R01GM035249-09 from National Institute Of General Medical Sciences IRG: MCHA
Abstract: The primary theme of this proposal is the further development of samarium(II) iodide (SmI2) and related reagents as highly selective reductive coupling agents for organic synthesis. Samarium(II) iodide promotes reactions with many functional groups of interest to synthetic organic chemists, and in this context this soluble one electron reductant has been found to be a.remarkably versatile reagent. The Sm(III) ion generated during the course of reductive coupling reactions is a highly oxophilic species. This Lewis acid can therefore be utilized as a template upon which to control stereochemistry. The combination of these features makes SmI2 highly complementary in many respects to other, perhaps more traditional, reductants such as Mg, Zn, Cr(II), and dissolving metal reductants. The unique combination of characteristics exhibited by SmI2 permits chemical transformations that are difficult, if not impossible, to achieve by other currently available means. The emphasis of our research will be in continuing the exploration of unconventional reactivity and selectivity patterns with SmI2, thereby facilitating the rapid and efficient synthesis of complex organic structures from relatively simple substrates. Several distinct areas have been targeted for study. An investigation of intramolecular nucleophilic acyl substitution reactions of halo- substituted carboxylic acid derivatives will be completed. Studies will be initiated to explore ketyl-olefin coupling reactions and subsequent transformations of the intermediates generated from them. Highlights of these studies will include the synthesis of eight-membered carbocycles, as well as an examination of five- through eight-membered oxygen and nitrogen heterocycle synthesis. One of the unique features of SmI2 is its ability to sustain sequential radical and carbanionic reactions in one-pot processes. Much of the proposal centers on this important feature of this versatile reductant. Over the past few years a tremendous database has been established which permits one to reliably predict relative reactivity of various organic functional groups with SmI2. This knowledge will be utilized to sequence organic reactions in polyfunctional organic substrates. This sequencing will permit formation of multiple carbon- carbon bonds in a single-pot process, in most instances with complete control of stereochemistry over several stereocenters. Finally, while past experience has demonstrated that SmI2 is an excellent reductant for many of the processes under study, development and employment of other SmX2 reducing agents that may exhibit enhanced reactivity or other desirable properties will also be undertaken. The types of studies outlined in this proposal are fundamental in nature, and yet may have direct application in the pharmaceutical industry for the efficient synthesis of pharmacologically active materials, analogues, metabolites, and other intermediates required for studies in drug developme .
Keywords: chemical synthesis, rare earth element, reducing agent, chemical substitution, cyclic compound, stereochemistry
Project start date: 1993-09-01
Project end date: 1997-08-31
2R01GM035249-09 (1993): $202573
2R01GM035249-16A1 (2000): $258121
3R01GM035249-16A1S1 (2000): $45085
2R01GM035249-13 (1997): $197319
Sponsored Links Excellgen http://Excellgen.com
STEREOCONTROLLED [M+N] ANNULATION REACTIONS
Gary A Molander, Professor
Chemistryuniversity Of Pennsylvania
3451 Walnut Street
philadelphia, Pa 19104
Grant 5R01GM038066-11 from National Institute Of General Medical Sciences IRG: ZRG3
Abstract: The primary goal of research outlined in this proposal is the development of general, stereocontrolled annulation approaches to highly functionalized seven- and eight-membered rings. Readily accessible synthons have been designed to allow conversion to carbocycles and heterocycles bearing different substitution patterns and stereochemistries. Control of stereochemistry and regiochemistry is established by a novel mechanistic pathway which has high predictability and reliability. This permits unprecedented control in conversion of acyclic synthons to important carbocycles and heterocycles. In terms of new synthetic methods development, several areas will be explored. Procedures for fragmenting the bicyclic ether subunit initially generated in the annulation process will be investigated. Extension of the method to the synthesis of bicyclic amines will also be examined. If successful, the method would have implications in the synthesis of tropane alkaloids as well alkaloids containing five- and six-membered ring nitrogen heterocycles. Other fundamental studies are described which may lead to significant new areas for study. A natural evolution of this program is the application of these new synthetic methods to the synthesis of complex organic molecules. Challenging target structures have been put forward which will be constructed in order to demonstrate the value of these synthetic methods. Included are approaches to the eunicellin/cladiellin/asbestinin class of diterpenes, which possess particular importance in health related fields. It is suggested that the eunicellin ring system may be accessed by the annulation strategy outlined in this proposal, leading to a synthesis of sclerophytin B. Finally, an approach to the "in-out" bridged bicyclic skeleton of ingenol pharmacophores is proposed
Keywords: chemical synthesis, cyclization, stereochemistry bicyclic compound, carbopolycyclic compound, chemical substitution, diterpene, heterocyclic polycyclic compound, tropane
Project start date: 1987-04-01
Project end date: 2001-03-31
5R01GM038066-11 (2000): $163824
5R01GM038066-08 (1998): $145359
STEREOCONTROLLED (M + N) ANNULATION REACTIONS
Gary A Molander, Professor
Chemistry And Biochemistryuniversity Of Colorado At Boulder
572 Ucb
boulder, Co 80309
Grant 5R01GM038066-06 from National Institute Of General Medical Sciences IRG: MCHA
Abstract: The primary goal of research outlined in this proposal is the continued development of general, stereocontrolled annulation approaches to highly functionalized seven- and eight-membered rings. Readily accessible synthons have been designed to allow conversion to carbocycles and heterocycles bearing different substitution patterns and stereochemistries. Control of stereochemistry and regiochemistry is proposed to be established by a novel mechanistic pathway which has high predictability and reliability. This permits unprecedented control in conversion of acyclic synthons to important carbocycles and heterocycles. A natural evolution of this program is the application of these exciting and important new synthetic methods to the total synthesis of complex organic molecules. Several challenging target structures have been put forward which will be constructed in order to demonstrate the value of these synthetic methods. Included are approaches to dactylol, furanether B, and the eunicellin/cladiellin class of diterpenes. The latter possess particular importance in health related fields. Many unique, highly oxygenated cembranoids have recently been isolated and fully characterized. Much less common are bicyclic cembranoids in which a transannular C-C bond is formed across the cembrane skeleton. Of this group, the eunicellin class of gorgonian and alcyonarian metabolites are the best represented. The eunicellin skeleton is present in several known natural products, including eunicellin, cladiellin, the asbestinins, and the sclerophytins. The latter materials have exhibited promising cytotoxic activity against a variety of cancerous cell lines. No efforts directed towards the total synthesis of these novel compounds have been reported. It is suggested that the eunicellin ring system may be accessed by the annulation strategy outlined in this proposal, leading to enantioselective syntheses of cladiellin and sclerophytin B. Finally, an approach to a skeletal substructure of the antineoplastic compound taxol is also outlined
Project start date: 1987-04-01
Project end date: 1996-06-30
5R01GM038066-06 (1994): $134600
2R01GM038066-04A1 (1992): $139223
STEREOCONTROLLED [M+N] ANNULATION REACTIONS
Gary A Molander, Professor
University Of Colorado At Boulder 572 Ucb Boulder, Co 80309
Grant 2R01GM038066-07A1 from National Institute Of General Medical Sciences IRG: ZRG3
Abstract: The primary goal of research outlined in this proposal is the development of general, stereocontrolled annulation approaches to highly functionalized seven- and eight-membered rings. Readily accessible synthons have been designed to allow conversion to carbocycles and heterocycles bearing different substitution patterns and stereochemistries. Control of stereochemistry and regiochemistry is established by a novel mechanistic pathway which has high predictability and reliability. This permits unprecedented control in conversion of acyclic synthons to important carbocycles and heterocycles. In terms of new synthetic methods development, several areas will be explored. Procedures for fragmenting the bicyclic ether subunit initially generated in the annulation process will be investigated. Extension of the method to the synthesis of bicyclic amines will also be examined. If successful, the method would have implications in the synthesis of tropane alkaloids as well alkaloids containing five- and six-membered ring nitrogen heterocycles. Other fundamental studies are described which may lead to significant new areas for study. A natural evolution of this program is the application of these new synthetic methods to the synthesis of complex organic molecules. Challenging target structures have been put forward which will be constructed in order to demonstrate the value of these synthetic methods. Included are approaches to the eunicellin/cladiellin/asbestinin class of diterpenes, which possess particular importance in health related fields. It is suggested that the eunicellin ring system may be accessed by the annulation strategy outlined in this proposal, leading to a synthesis of sclerophytin B. Finally, an approach to the "in-out" bridged bicyclic skeleton of ingenol pharmacophores is proposed.
Keywords: chemical synthesis, cyclization, stereochemistry, bicyclic compound, carbopolycyclic compound, chemical substitution, diterpene, heterocyclic polycyclic compound, tropane
Project start date: 1987-04-01
Project end date: 2001-03-31
2R01GM038066-07A1 (1997): $152742
5R01GM038066-09 (1999): $149187
DEVELOPMENT OF HETEROSUBSTITUTED ORGANOTRIFLUOROBORATES
Gary A Molander, Hirschmann-makineni Professor Of Chemist
University Of Pennsylvania, 3451 Walnut Street, Philadelphia, Pa 19104
Grant 5R01GM081376-04 from National Institute Of General Medical Sciences
Abstract: Studies will be carried out on the synthesis of alkoxymethyltrifluoroborates and their utility in transition metal catalyzed coupling reactions. Both intermolecular and intramolecular versions of these reactions will be explored. Through such studies, we will gain an understanding and appreciation of these unusual reagents for the introduction of alkoxymethyl subunits into complex organic molecules, thus providing a new paradigm for the installation of this functional unit into acyclic molecules. Additionally, suitably functionalized substrates provide the opportunity for a distinctive route to oxygen heterocycles via intramolecular reactions. In a similar manner, aminomethyl- and aminoethyltrifluoroborates will be prepared, and the scope and limitations of these reagents in selective organic synthesis will be explored. Of notable interest in this particular line of research will be the development of enantiomerically pure alanine b-anion equivalents. Cyclization of appropriately ornamented analogues provides an unprecedented entry to nitrogen heterocycles that is applicable to myriad structures of biological significance. Again, the development of these reagents affords a unique approach to the construction of diverse classes of organic molecules, and the cultivation of this chemistry will thus be aggressively pursued. As a means to demonstrate the value of the developed reagents and their viability in demanding systems, several natural products have been targeted for synthesis. These include zoapatanol, alkaloid 233F, nakadomarin A, and halicyclamine A. The discovery of new Pharmaceuticals in a cost and time efficient manner requires the development of new and improved methods for their chemical synthesis. The research proposed herein addresses one aspect of this requirement. The basic science to be explored would make available several protocols that could be immediately incorporated into the pharmaceutical discovery process as well as industrial scale synthesis . Additionally, syntheses of two compounds (halicyclamine A and nakadomarin A) that exhibit selective cytoxicity against several different cell lines in preliminary tests are proposed, and these molecules could serve as lead compounds for the treatment of cancer and perhaps other afflictions
Keywords: Address; Alanine; Alanine, L-Isomer; Alkaloids; Anions; Area; Basic Research; Basic Science; Biological; Biological Factors; Cancer Treatment; Cell Line; Cell Lines, Strains; CellLine; Chemistry; Complex; Coupling; Cyclization; Development; Exhibits; Factor, Biologic; Family; Funding; Goals; Investigation; L-Alanine; Lead; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Methods; N element; N2 element; Natural Products; Nitrogen; O element; O2 element; Organic Synthesis; Oxygen; Pathway interactions; Pb element; Pharmaceutical Agent; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Procedures; Process; Programs (PT); Programs [Publication Type]; Protocol; Protocols documentation; Reaction; Reagent; Research; Route; Science of Chemistry; Site; Structure; System; System, LOINC Axis 4; Testing; Time; Transition Elements; analog; anticancer therapy; cancer therapy; chemical synthesis; cost; cultured cell line; halicyclamine A; heavy metal Pb; heavy metal lead; improved; interest; nakadomarin A; novel; pathway; programs; transition metal; zoapatanol
Project start date: 2007-09-07
Project end date: 2011-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
5R01GM081376-04 (2010): $302291
5R01GM081376-03 (2009): $298357
5R01GM081376-02 (2008): $291568
1R01GM081376-01 (2007): $295893
Sponsored Links Excellgen http://Excellgen.com
NEW CATALYTIC PROCESSES FOR SELECTIVE ORGANIC SYNTHESIS
Gary A Molander, Professor
University Of Colorado At Boulder 572 Ucb Boulder, Co 80309
Grant 3R01GM048580-03S1 from National Institute Of General Medical Sciences IRG: MCHA
Abstract: New catalytic processes for selective organic synthesis are described. Organolanthanides and group 3 organometallics will be utilized as catalysts in a wide range of processes for the construction of complex organic molecules from rather simple, readily available precursors. Although at this point the chemistry described is focused on the more fundamental aspects of the new synthetic methods, ready access to compounds generated by these methods (many of which may be synthesized in chiral, nonracemic form) will provide more efficient and economic means to biologically active materials of vital interest to the pharmaceutical industry. Processes to be developed are expected to exhibit a high degree of regioselectivity and diastereoselectivity. Asymmetric synthesis utilizing chiral, nonracemic organometallic catalysts will also be explored. Five specific areas have been targeted for study. These include 1) Catalytic hydrogenation reactions. 2) Stoichiometric intermolecular carbometalation reactions. 3) Selective catalytic hydrosilylation and hydroboration reactions. 4) Olefin amination reactions. 5) Catalytic cyclooligomerization reactions of dienes, enynes, and polyunsaturated organics. Initial goals will be to synthesize organometallic complexes exhibiting significant reactivity and catalytic turnover in the processes outlined above. This may require substantial "tuning" of both the metal and the ligand in the targeted systems. Secondly, we will examine diastereoselectivity in reaction of suitable catalysts with chiral substrates. A long-term, very challenging objective will be to develop chiral, nonracemic catalysts for use in asymmetric synthesis of organic molecules.
Keywords: catalyst, chemical synthesis, organometallic compound, stereochemistry, alkene, amination, cyclization, protonation, rare earth element
Project start date: 1993-08-01
Project end date: 1997-11-30
3R01GM048580-03S1 (1997): $45189
5R01GM048580-02 (1994): $145189
Catalytic Processes For Selective Organic Synthesis
Gary A Molander, Professor
University Of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104
Grant 5R01GM048580-12 from National Institute Of General Medical Sciences IRG: MCHA
Abstract: Catalytic processes for selective organic synthesis are described. Organolanthanides and group 3 organometallics will be utilized as catalysts in a wide range of processes for the construction of complex organic molecules from rather simple, readily available precursors. A family of organometallic complexes will be synthesized exhibiting significant reactivity, selectivity, and catalytic turnover in the processes outlined. This requires substantial "tuning" of the metal and the ligand. Processes to be developed are expected to exhibit a high degree of regioselectivity and diastereoselectivity. At the outset, the chemistry to be carried out will be focused on fundamental aspects of the new synthetic methods. However, ready access to compounds generated by these methods will provide more efficient and economical means to synthesize biologically active materials of interest to the pharmaceutical industry. For example, the reactions can be sequenced to provide a dramatic increase in molecular complexity from simple starting materials to the final products. Furthermore, the methods are environmentally sound in that they proceed in a manner where no byproducts are generated (i.e., they proceed with "atom economy"). Several diverse areas, all catalyzed by the same class of organometallics, have been targeted for study. These include 1) Development of hydrosilylation, hydroboration, and hydrocupration reactions. 2) Cyclization reactions of polyolefins and dienynes involving sequential reactions wherein the cyclizations are terminated by silylation or boration. The synthesis of both carbocycles and nitrogen heterocycles will be explored. 3) The further development of hydroamination reactions. We will focus on hydroamination/cyclization sequences and applications to the synthesis of complex nitrogen heterocycles. 4) Carbometalation/cyclization reactions will be explored utilizing organochromium species. 5) Ligands and catalytic systems designed for asymmetric synthesis will be explored.
Keywords: catalyst, chemical synthesis, organometallic compound, stereochemistry, amination, boron, chromium, cyclization, hydrolysis, nitrogenous heterocyclic compound, protonation, rare earth element, silicon compound
Project start date: 1993-08-01
Project end date: 2006-11-30
5R01GM048580-12 (2005): $315165
5R01GM048580-11 (2004): $405984
3R01GM048580-10S1 (2003): $72590
2R01GM048580-09A1 (2002): $293792
INTRAMOLECULAR REDUCTIVE COUPLING REACTIONS
Gary A Molander, Professor
University Of Colorado At Boulder 572 Ucb Boulder, Co 80309
Grant 2R01GM035249-04 from National Institute Of General Medical Sciences IRG: MCHA
Abstract: Carbocyclic and heterocyclic rings are present in nearly all pharmacologically active compounds. Consequently, the development of highly selective, yet general procedures for the synthesis of various ring systems is an essential aspect of synthetic organic chemistry. The primary goal outlined in this proposal is the invention of useful new strategies for selective generation of carbocycles and heterocycles by reductive cyclization processes. Samarium diiodide (SmI2) is a remarkably versatile reducing agent, one that can adequately serve as a template for many of the processes proposed. Two distinct areas have been targeted for study. First, continued development of cyclization reactions promoted by SmI2 as well as other reductants will be pursued, providing entry into highly functionalized carbocycles and heterocycles difficult to access by more conventional approaches. A survey of the scope of difunctional organic substrates suitable for reductive cyclization will be initiated, and stereoselectivity in these processses will be determined. It is aniticipated that several novel approaches to carbocycles and heterocycles will be uncovered as a result of these studies, and that new methods for formation of carboncarbon bonds will also emerge. Approaches to highly functionalized, chiral, non-racemic carbocycles and heterocycles are also outline. The second major area of proposed research involves SmI2-promoted reductive coupling of various organic substrates with transition metal catalysts or stoichiometric complexes, establishing unique carbon-carbon bond-forming transformations. Oxidative-reductive transmetalation processes incorporating organic substrates, a reductant like SmI2, and Pd(0) or Ni(0) catalysts will constitute one aspect of the initial studies. Reaction of cationic transition meal complexes with suitable elecrophiles in the presence of a reductant like SmI2 will comprise the second research area. These combinations of reagents will allow access to new or imporoved reactivity patterns for selective formation of carbon-carbon bonds, and contributions to both acyclic stereochemical control as well as efficient carbocyclic generation are expected.
Keywords: CHEMICAL STRUCTURE--BIOLOGICAL ACTIVITY, CYCLICS, CARBOPOLYCYCLICS, DRUGS SYNTHESIS, DESIGN AND PRODUCTION, OXIDATION-REDUCTION, REDUCTION, chemical structure, CHEMICAL REACTIONS (DYNAMICS), CHEMICAL STRUCTURE, STEREOCHEMISTRY, DRUGS SCREENING AND EVALUATION, METAL COMPLEXES, LIGANDS, CHELATING AGENTS, PHOSPHONIUM COMPOUNDS
Project start date: 1985-09-01
Project end date: 1993-08-31
CATALYTIC PROCESSES FOR SELECTIVE ORGANIC SYTHESIS
Gary A Molander, Professor
University Of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104
Grant 3R01GM048580-08S1 from National Institute Of General Medical Sciences IRG: ZRG3
Abstract: applicant s ) Catalytic processes for selective organic synthesis are described. Organolanthanides, group 3 organometallics, and group 4 cationic complexes will be utilized as catalysts in a wide range of processes for the construction of complex organic molecules from rather simple, readily available precursors. A family of organometallic complexes will be synthesized exhibiting significant reactivity, selectivity, and catalytic turnover in the processes outlined. This requires substantial "tuning" of the metal, the ligand, and, in the case of cationic complexes, the counterion of the catalyst. Processes to be developed are expected to exhibit a high degree of regioselectivity and diastereoselectivity. A long-term objective will be to develop chiral, nonracemic catalysts for use in asymmetric synthesis of organic molecules. At the outset, the chemistry to be carried out will be focused on fundamental aspects of the new synthetic methods. However, ready access to compounds generated by these methods will provide more efficient and economical means to biologically active materials of interest to the pharmaceutical industry. For example, the reactions can be sequenced to provide a dramatic increase in molecular complexity from simple starting materials to the final products. Furthermore, the methods are environmentally sound in that they proceed in a manner where no byproducts are generated (i.e., they proceed with "atom economy"). Several diverse areas, all catalyzed by the same class of organometallics, have been targeted for study. These include 1) Hydrosilylation and hydroboration reactions. 2) Silylmetalation reactions. 3) Olefin amination reactions. 4) Cyclization reactions of polyolefins, dieneynes, enediynes, etc. involving sequential reactions wherein the cyclizations are terminated by silylation, boration, hydrogenolysis, or beta-hydride elimination.
Keywords: catalyst, chemical synthesis, organometallic compound, stereochemistry, alkene, amination, boron, chemical elimination, cyclization, hydrolysis, protonation
Project start date: 1993-08-01
Project end date: 2002-06-14
3R01GM048580-08S1 (2002): $80759
2R01GM048580-04A1 (1998): $203226
5R01GM048580-08 (2001): $229196
Sponsored Links Excellgen http://Excellgen.com
5R01GM048580-07 (2000): $222410
STEREOCONTROLLED [M+N] ANNULATION REACTIONS
Gary A Molander, Professor
University Of Colorado At Boulder 572 Ucb Boulder, Co 80309
Grant 5R01GM038066-02 from National Institute Of General Medical Sciences IRG: MCHA
Abstract: A comprehensive new strategy for stereocontrolled construction of carbocycles via [m+n] annulation is outlined. For the first time, a unified approach to five-, six- and seven-membered rings will be accessible through common intermediates. In addition to allowing generation of several different ring sizes, this entry to carbocycles comprises several other advantageous features. Procedures outlined are anticipated to be highly chemoselective. Enhanced stereoselectivity is also expected, and incorporation of quaternary centers on carbocycles is possible with complete stereochemical control. Isolated rings as well as fused rings (either linearly fused or spirocyclic systems) are accessible. Most acyclic substrates we propose to utilize can be readily accessed in chiral, non-racemic form, allowing synthesis of optically active carbocyclic ring systems. Few other synthetic methods boast the flexibility and scope of application that we envision for these synthetic methods. As a demonstration of the methods described, syntheses of (-)-aristeromycin, pentenomycin, chokol A, and methylenomycin analogs are proposed.
Keywords: CHEMICAL STRUCTURE, STEREOCHEMISTRY, CHEMICAL STRUCTURE--BIOLOGICAL ACTIVITY, CYCLICS, CARBOPOLYCYCLICS, DRUGS SYNTHESIS, DESIGN AND PRODUCTION, ANTIBIOTICS, ANTINEOPLASTIC AGENTS, COMMUNICABLE DISEASE CONTROL AGENTS, ANTIFUNGAL, METAL COMPLEXES, LIGANDS, CHELATING AGENTS, OXIDES, EPOXIDES
Project start date: 1987-04-01
Project end date: 1990-03-31
Coupling Reactions-Methods Development And Applications
Gary A Molander, Professor
University Of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104
Grant 3R01GM035249-22S1 from National Institute Of General Medical Sciences IRG: MCHA
Project start date: 1993-09-01
Project end date: 2008-07-31
3R01GM035249-22S1 (2007): $24549
3R01GM035249-20S1 (2004): $58942
INTRAMOLECULAR REDUCTIVE COUPLING REACTIONS
Gary A Molander, Professor
University Of Colorado At Boulder 572 Ucb Boulder, Co 80309
Grant 3R01GM035249-07S1 from National Institute Of General Medical Sciences IRG: MCHA
Project start date: 1985-09-01
Project end date: 1993-08-31
3R01GM035249-07S1 (1992): $29403
NOVEL STEREOCONTROLLED ADDITION REACTIONS
Gary A Molander, Professor
University Of Colorado At Boulder 572 Ucb Boulder, Co 80309
Grant 3R01GM035249-01S1 from National Institute Of General Medical Sciences IRG: MCHA
Project start date: 1986-05-01
Project end date: 1988-08-31