1985 — 1987 |
Davis, Franklin A [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Synthesis of a-Hydroxycarbonyl Compounds
The aim of the proposed work is to develop methodology for the direct oxidation and asymmetric oxidation of enolates to Alpha-hydroxycarbonyl compounds (R2C(OH)C(O)-Z). Compounds having the Alpha-hydroxycarbonyl structural unit are ubiquitous in nature and responsible, for the biological activity of many compounds having this subunit. These goals will be achieved by exploring the oxidation of enolates (enol silyl ethers, enamines, metaloenamines) using 2-sulfonyloxaziridines, aprotic and neutral oxidizing agents. Oxidation of chiral enolates using these reagents is anticipated to give optically active Alpha-hydroxycarbonyl compounds in high optical purity. Studies of enolate oxidations with chiral 2-sulfonyl- and 2-sulfamyloxaziridines will provide insights into the origins of asymmetric induction and new information on electrophile-enolate trajectories. Metal assisted asymmetric oxidations using 2-sulfamyloxaziridines having metal chelating functional groups are anticipated to give Alpha-hydroxycarbonyl compounds in high enantiotopic purity. This methodology will be applied to the chiral synthesis of (-)-Eucomol and (+)-demethoxydaunomycinone; the latter compound is a potent anti-tumor agent. The feasibility of direct enolate and asymmetric enolate oxidation as a viable synthetic route to Alpha-hydroxycarbonyl compounds has been demonstrated by preliminary studies.
|
0.907 |
1988 — 1995 |
Davis, Franklin A [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Synthesis of Alpha-Hydroxy Carbonyl Compounds
A feature common to many biologically relevant molecules is the alpha-hydroxy carbonyl array [RR'C(OH)C(O)Z]. Compounds containing this moiety are also important auxiliaries and synthons for the asymmetric synthesis of many natural products including antitumor agents, antibiotics, pheromones and sugars. Of particular significance in these structures is the stereochemistry of the hydroxyl group attached to stereogenic carbon; biological activity often critically depends upon its orientation. The principal objective of the proposed work continues to be development of practical methodology for the enantioselective hydroxylation of metal enolates in high enantiopurity (>95% ee) with predictable stereochemistry; the ultimate goal is reagent-controlled asymmetric oxidation of prochiral enolate species. A second major objective is understanding and controlling the various factors that define the molecular recognition. These goals will be achieved by exploring the asymmetric oxidation of prochiral acyclic and cyclic enolates derived from esters (including beta-keto esters), lactones and amides as well as azaenolates; little is known about the stereoselectivity of hydroxylation for these compounds. As chiral oxidants we will employ the readily available, enantiopure (camphorylsulfonyl)oxaziridines 3. The influence of the enolate .substitution pattern and solution structure and the structure of the oxaziridine active-site on the ee's will be evaluated, leading to elucidation of the origins of the molecular recognition and the rational design of more effective reagents. In this regard new procedures for altering the structure of 3 will be devised, particularly methods for introducing metal-chelating groups near the active-site oxygen. Kinetic resolution (the diastereoselective oxidation of racemic enolates with substoichiometric amounts of 3), and double asymmetric synthesis, (the asymmetric oxidation of chiral enolates) will be pursued as methods for preparation of enantiopure materials not readily accessible by other means. Concurrent with the above studies, we will apply the asymmetric enolate oxidation protocol to the synthesis of biologically relevant molecules or their chiral nonracemic precursors. Antitumor synthetic targets include the aglycones of the anthracycline antibiotics, adriamycin and daunomycin, the lactone camptothecin, and the C- 13 side chain of taxol. Site-specific fluorination often profoundly affects the physical, chemical and biological properties of a parent molecule. New enantiopure N-fluoro sultams 4 will be prepared and evaluated as enantioselective fluorinating reagents for the synthesis of chiral nonracemic alpha-fluoro carbonyl compounds. This project win extend our studies of asymmetric enolate hydroxylation; the molecular recognition parameters for the two processes are likely to be similar and the precursor of 3 will serve as the precursor to 4.
|
0.907 |
1995 — 2006 |
Davis, Franklin A [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Asymmetric Synthesis of Bioactive Primary Amines
DESCRIPTION (provided by applicant): Chiral nonracemic amines containing nitrogen attached to a stereogenic carbon are ubiquitous in nature and found in many biologically active materials including drugs and drug candidates. Relevant examples include proteinogenic and nonproteinogenic alpha- and beta-amino acids and diverse alkaloids. Such amines are also widely used as chiral building blocks for the enantioselective construction of bioactive materials. The principal objective of the proposed work is to employ enantiopure sulfinimines [N-sulfinyl imines, R1S(O)N=CR2R3] and four sulfinimine-derived building blocks--beta-amino Weinreb amides, delta-amino beta-ketoesters, 3,4-dihydroisoquinolines, and 3,5-dihydro-1(2H)-isoquinolones--in new methodology for the enantioselective syntheses of biologically relevant amines and alkaloids. Important advantages conferred by the N-sulfinyl auxiliary include (i) powerful stereodirecting effects; (ii) activation of the C=N bond toward nucleophilic addition; (iii) ability to be removed under mild conditions without epimerization; and (iv) ready availability of single enantiomers via separation of diastereomeric intermediates. Beta-amino Weinreb amides will be used in new syntheses of beta-amino aldehydes and ketones that in turn will be employed in the asymmetric syntheses of 1,3-amino alcohols and 1,3-diamines, important ligands and structural units of natural products. New methods for the enantioselective synthesis of polyfunctionalized piperidine and pyrrolidine alkaloids will utilize delta-amino beta-ketoesters as building blocks. In this context new chemistry will be devised for the construction of trans 2,6- and 2,5-disubstituted analogs. Addition of laterally lithiated nitriles and amides to sulfinimines provide 3,4-dihydroisoquinolines and 3,5-dihydro-1 (2H)-isoquinolones, building blocks with substitution patterns not easily accessible by other means. A further major objective in these studies is elucidation of the factors responsible for molecular recognition. Concurrently we will exploit this new chemistry in concise syntheses of biologically relevant molecules or their chiral nonracemic precursors. Targets include (i) densely substituted piperidine and pyrrolidine alkaloids, classes of compounds that exhibit diverse biological activities; (ii) polysubstituted prolines, important building blocks and modifiers of proteins; and (iii) tetrahydroisoquinolines, medicinally valuable alkaloids.
|
0.907 |
1998 — 2001 |
Davis, Franklin A [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Efficient Synthesis of Enantiopure Alpha Amino Acids
DESCRIPTION: (Principal Investigator's) Alpha-Amino acids are the basic building blocks of peptides and proteins, which are responsible for the structure and function of most living things. They are extensive employed as chiral templates and subunits in the asymmetric construction of many biologically and pharmacologically active compounds, and are widely used in the pharmaceutical, agrochemical and food industries. In addition non- proteinogenic D- and L-alpha-amino acids are increasingly utilized to study enzyme mechanism and to modify and enhance protein activity. The principal objective of the proposed work is to develop a practical and efficient asymmetric Strecker synthesis of alpha-amino acids, exploiting the diastereoselective addition of "Et2AlCN/ROH" to chiral non-racemic sulfinimines (ArS(O)N=CRR'). Important advantages conferred by the N- sulfinyl group include (i) powerful stereodirecting effects; (ii) activation of the C-N double bond toward addition; and (iii) auxiliary removal and hydrolysis of the N-sulfinyl alpha-amino nitrile (ARs(o)- NHC(CN)RR') to alpha-amino acids under exceedingly mild conditions, such that racemization does not occur. A second major objective is the elucidation of the factors responsible for the molecular recognition, which in turn should permit the rational design of improved methodology. Complementary studies will focus on the chemistry of the N-sulfinyl alpha- amino nitrile products (ArS(O)-NHRR'CN. We will examine the conversion of these species to: (i) N-alkyl alpha-amino acids constituents of antibiotics such as vancomycin; (ii) alpha-alkyl alpha-amino acids, modifiers of protein activity; and (iii) piperidines and pyrrolidines, classes of alkaloids possessing a range of significant biological and medicinal properties. Concurrently we will employ this chemistry in syntheses of biologically relevant amino-acid that are difficult or impossible to prepare via other methodologies. Targets include: (i) the amino acids in the clinically important antibiotic vancomycin (i.e., arylglycines, beta-hydroxy alpha- amino acids, and bis(alpha-amino acids)); (ii) vinyl glycines, which inhibit amino acid decarboxylase enzymes; (iii) beta-amino, beta-hydroxy and beta-fluoro alpha-amino acids, constituents of a number of antibiotics and antitumor agents, respectively; (iv) cyclic amino acids such as D- proline and D-homoproline; and (v) oxo and halo alpha-amino acids, important non-racemic building blocks for the synthesis of more complex derivatives.
|
0.907 |
2002 — 2005 |
Davis, Franklin A [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Syntheses of Amino Acids and Amino Phosphonic Acids
[unreadable] DESCRIPTION (provided by applicant): Alpha-amino acids are the basic building blocks of peptides and proteins, which are responsible for the structure and function of most living things. They are extensively employed as chiral templates and subunits in the asymmetric construction of many biologically and pharmacologically active compounds. Nonproteinogenic examples are increasingly utilized to study enzyme mechanisms and to modify and enhance protein activity. Alpha-amino phosphonic acids are structural analogs of amino acids and as such exhibit a broad range of biological activities: enzyme inhibitors, antitumor agents, anti-bacterial agents, and fungicides. [unreadable] [unreadable] The principal objective of the proposed work is to develop practical and efficient methodology for the asymmetric synthesis of functionalized alpha amino acids and alpha amino phosphonic acids by exploiting the diastereoselective addition of CN and phosphite anions to chiral nonracemic sulfinimines [N-sulfinyl imines, R'S(o)N=CR2R3]. Important advantages conferred by the N-sulfinyl group include (i) powerful stereodirecting effects, (ii) activation of the C-N double bond toward addition, and (iii) facile auxiliary removal and hydrolysis of the N-sulfinyl alpha amino nitrile and alpha amino phosphonate to amino acids and amino phosphonic acids under such exceedingly mild conditions that racemization does not occur. [unreadable] [unreadable] Complementary studies will focus on the synthesis and regioselective and stereoselective ring-opening reactions of N-sulfinyl aziridine 2-phosphonates as sources of novel alpha amino phosphonic acids. The imino-Diels-Alder reactions of 2H-azirine phosphonates, a new chiral dienophile, will be exploited as sources of novel aziridine 2-phosphonates and azabicyclic systems; the latter compounds are important chiral building blocks and exhibit a range of biological activities. Such studies are expected to provide new information on the chemical reactivity/selectivity of the phosphonate group as compared to carboxylate esters. [unreadable] [unreadable] Concurrently we will employ this chemistry in syntheses of biologically relevant, functionalized alpha amino acids and alpha amino phosphonates that are difficult or impossible to prepare via other methodologies. Targets include cyclic, unsaturated, and, beta substituted derivatives (beta amino, beta hydroxy, and beta fluoro).
|
0.907 |
2007 |
Davis, Franklin A [⬀] |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Asymmetric Synthesis of Amino Acids and Amino Phosphonic Acids
The objective of this research program is to design and synthesize new sulfmimine (N-sulfinyl imine)-derived chiral building blocks, and to invent related methodologies for the asymmetric synthesis of amine structures that are presently difficult to prepare but necessary for the synthesis of biologically important anticancer, antiviral, antibacterial, antifungal, and other bioactive molecules of medicinal relevance. Examples include novel a- and ([unreadable]-amino acids, pyrrolidine, and piperidine alkaloids. These amine types are also widely used as chiral building blocks for the enantioselective construction of bioactive materials, including drug and drug candidates. Four sulfinimine-derived chiral building blocks (a-substituted ([unreadable]-amino ketones, d-amino ([unreadable]- ketophosphonates, 2,[unreadable]-diamino esters, and 2-substituted 2H-azirine [unreadable]-carboxylates) will be employed to accomplish our objectives. a-Substituted ([unreadable]-amino Weinreb amides, prepared by addition of prochiral Weinreb amides to sulfinimines, on reaction with Grignard reagents, represent a general solution.to the problem of a-substituted ([unreadable]-amino ketone synthesis. Using our intramolecular Mannich cyclization protocol, these new ([unreadable]-amino ketones will be employed in syntheses of toxic frog skin polysubstituted piperidines not previously prepared. d-Amino ([unreadable]-ketophosphonates will be used in new stereocontrolled syntheses of cis- 2,5- and trans-2,5 disubstituted ring functionalized pyrrolidine alkaloids from a common [unreadable]-oxo pyrrolidine 2- phosphonate intermediate. Sulfinimine derived syn- and anti-2,[unreadable]-diamino esters are expected to provide access to several biorelevant diamino compounds including the unknown anti isomer of (+)-CP99,994, a potent neurokinin substrate P receptor antagonist. Analogues of the architecturally unique marine antibiotic (-)-agelastatin A will be prepared for biological evaluation. (-)-Agelastatin A has significant activity against a variety of human cancer cell lines, but its mechanism of activity remains undetermined. The reaction of new sulfinimine-derived 2-substituted 2H-azirine [unreadable]-carboxylates with nucleophiles and with dienes in aza-Diels-Alder reactions, will provide unique routes to enantiopure 2-substituted aziridine 2- carboxlates and bicyclic and tricyclic aziridine carboxylates. Stereoselective ring opening of these aziridines affords novel a- and ([unreadable]-amino acids not easily assessable by other means. The photodesulfmylation of sulfinamides represents an important new protocol, not requiring acids or bases, for the removal of the valuable amine N-sulfinyl protecting group.
|
0.907 |