ASYMMETRIC SYNTHESIS OF NOVEL NATURAL PRODUCTS

Summary

Principal Investigator: MICHAEL CRIMMINS
Abstract: The specific aims of this program in organic synthesis have been to develop novel methods and strategies for the construction of complex organic molecules and to demonstrate their practical synthetic potential through their application to the total synthesis of biologically active and structurally complex natural products. The program has continued to (a) develop the utility and improve the stereocontrol of intramolecular [2+2] photochemical cycloaddition reactions, (b) develop new cyclobutane fragmentation sequences to improve the versatility and importance of intramolecular photocycloadditions, (c) develop new methods for the efficient preparation of highly substituted and functionalized photocycloaddition substrates and (d) demonstrate the synthetic potential of photocycloaddition-cyclobutane modification strategies through their application to the total synthesis of biologically active and structurally complex naturally occurring materials. In the most recent grant period a novel approach to carbocycles and heterocycles using an asymmetric aldol or alkylation in combination with a ring-closing metathesis has been developed. The total synthesis of ginkgolide B, (-)-Iaurencin, and (-)-isolaurallene as well as formal syntheses of (-)-Iaurencin and (+)-trehazolin have now been accomplished. Significant progress has been made toward the synthesis of CP-263,114. During the next grant period the specific aims of this program will be to continue extension of the double diastereoselective photocycloaddition studies through a novel strategy for entry into "crossed" adducts of intramolecular photocycloadditions applied to a synthesis of the novel natural products CP-263,114 and CP-225,917 which inhibit squalene synthase and ras farnesyl transferase. The recently developed radical initiated cyclobutane fragmentation in conjunction with the crossed photocycloaddition will be utilized in a synthesis of CP-263,114 and taxagifine. In the asymmetric aldol - olefin metathesis area, significant results for the enantioselective synthesis of eight and nine membered cyclic ethers has been obtained in the context of the total synthesis of the laurencia metabolites (-)-Iaurencin and (-)-isolaurallene. A practical asymmetric aldol has been further refined for aldol additions of alkenyl glycolates of oxazolidinethiones. An asymmetric glycolate alkylation has been developed for the enantioselective preparation of homoallylic ethers, specifically for their application in ring closing metathesis reaction for the synthesis of oxygen heterocycles. Synthesis of the biologically active agents guanacastepene, and SCH 351448 will also be pursued.
Funding Period: 1991-07-01 - 2007-06-30
more information: NIH RePORT

Top Publications

  1. pmc Enantioselective total synthesis of bistramide A
    Michael T Crimmins
    Department of Chemistry, Venable and Kenan Laboratories of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 3290, USA
    J Am Chem Soc 128:4936-7. 2006
  2. pmc Formal synthesis of 6-deoxyerythronolide B
    Michael T Crimmins
    Venable and Kenan Laboratories of Chemistry, University of North Carolina at Chapel Hill, 27599, USA
    Org Lett 8:2191-4. 2006
  3. ncbi Enantioselective total synthesis of (+)-SCH 351448
    Michael T Crimmins
    Venable and Kenan Laboratories of Chemistry, University of North Carolina at Chapel Hill, 27599, USA
    Org Lett 8:2887-90. 2006

Scientific Experts

Detail Information

Publications3

  1. pmc Enantioselective total synthesis of bistramide A
    Michael T Crimmins
    Department of Chemistry, Venable and Kenan Laboratories of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 3290, USA
    J Am Chem Soc 128:4936-7. 2006
    ..The synthetic strategy involves the use of a distereoselective glycolate alkylation, an aldol addition of a chlorotitanium enolate of N-acylthiazolidinthione, and a Sharpless asymmetric epoxidation to synthesize the three key fragments...
  2. pmc Formal synthesis of 6-deoxyerythronolide B
    Michael T Crimmins
    Venable and Kenan Laboratories of Chemistry, University of North Carolina at Chapel Hill, 27599, USA
    Org Lett 8:2191-4. 2006
    ..The remaining stereogenic center at C6 was set through a Myers alkylation employing a complex alkyl iodide...
  3. ncbi Enantioselective total synthesis of (+)-SCH 351448
    Michael T Crimmins
    Venable and Kenan Laboratories of Chemistry, University of North Carolina at Chapel Hill, 27599, USA
    Org Lett 8:2887-90. 2006
    ..structure: see text] A stereoselective synthesis of SCH 351448 has been completed. Twelve of the fourteen stereogenic centers were established through chiral enolate reactions, and six key C-C bonds were formed by metathesis reactions...