SYNTHESIS OF BIOACTIVE NATURAL PRODUCTS

Summary

Principal Investigator: AMOS SMITH
Affiliation: University of Pennsylvania
Country: USA
Abstract: The principal goal of this research program (GM-29028) has been and will continue to be, the development of efficient, enantiospecific synthetic strategies for the construction of architecturally novel macrolides possessing significant pharmacological properties. During the first grant period (01-03), we achieved the first total synthesis of milbemycin beta 3, the simplest member of the avermectin-milbemycin family of anthelmintic macrolide antibiotics. Currently we have underway two viable strategies for the southern hemisphere of the milbemycin-avermectin targets. Prospects for the completion of milbemyucin alpha 1 are excellent. As a new target for the 08-11 years, we have selected the immunosuppressant FK506 (12), a novel 23-membered macrolide recently isolated by the Fujisawa Pharmaceutical Co., Ltd. from Streptomyces tsukubaensis no. 9993. Over the past ten years, the introduction of powerful immunosuppressants has led to tremendous advances in the area of human organ transplantation. Post-operative graft rejection however continues to be the foremost problem currently faced by transplant surgeons. The discovery and development of new immunosuppressant drugs is therefore of utmost importance to transplant surgery. FK506 appears to be an exceptionally promising candidate: in vivo, it inhibits T-lymphocytes, MLR, generation of killer T cells and appearance of IL-2 receptors, and thereby hypersensitivity reactions, at 30-100 times lower concentration than cyclosporin A, the most effective immunosuppressant available to date. FK506 is therefore an important target for total synthesis, not only for its intrinsic synthetic challenge, but also due to its extrinsic worth to the field of medicine.
Funding Period: 1981-04-01 - 1992-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Design, synthesis, and evaluation of carbamate-substituted analogues of (+)-discodermolide
    Amos B Smith
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 7:311-4. 2005
  2. ncbi A new modular indole synthesis. Construction of the highly strained CDEF parent tetracycle of nodulisporic acids A and B
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, 19104, USA
    Org Lett 8:2167-70. 2006
  3. ncbi Total synthesis of the marine natural product (-)-clavosolide A. A showcase for the Petasis-Ferrier union/rearrangement tactic
    Amos B Smith
    Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 8:3315-8. 2006
  4. ncbi The [1,5]-Brook rearrangement: an initial application in anion relay chemistry
    Amos B Smith
    Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Am Chem Soc 128:12368-9. 2006
  5. ncbi Indole diterpene synthetic studies. Total synthesis of (+)-nodulisporic acid F and construction of the heptacyclic cores of (+)-nodulisporic acids A and B and (-)-nodulisporic acid D
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Org Chem 72:4596-610. 2007
  6. ncbi Indole diterpene synthetic studies: development of a second-generation synthetic strategy for (+)-nodulisporic acids A and B
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Org Chem 72:4611-20. 2007
  7. ncbi Anion relay chemistry extended. Synthesis of a gorgonian sesquiterpene
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 9:3307-9. 2007
  8. ncbi The spirastrellolides: construction of the southern C(1)-C(25) fragment exploiting anion relay chemistry
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center, and Laboratory for Research on Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 9:3311-4. 2007
  9. ncbi Syntheses of (-)-oleocanthal, a natural NSAID found in extra virgin olive oil, the (-)-deacetoxy-oleuropein aglycone, and related analogues
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Org Chem 72:6891-900. 2007
  10. doi Evolution of the Petasis-Ferrier union/rearrangement tactic: construction of architecturally complex natural products possessing the ubiquitous cis-2,6-substituted tetrahydropyran structural element
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Acc Chem Res 41:675-87. 2008

Detail Information

Publications31

  1. ncbi Design, synthesis, and evaluation of carbamate-substituted analogues of (+)-discodermolide
    Amos B Smith
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 7:311-4. 2005
    ..Structure-activity relationships of the C(19) carbamate were defined, exploiting two synthetically simplified scaffolds, as well as the parent (+)-discodermolide framework...
  2. ncbi A new modular indole synthesis. Construction of the highly strained CDEF parent tetracycle of nodulisporic acids A and B
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, 19104, USA
    Org Lett 8:2167-70. 2006
    ..The new indole synthesis holds the promise of rapid assembly of diverse, highly substituted indoles possessing uncommon substitution patterns...
  3. ncbi Total synthesis of the marine natural product (-)-clavosolide A. A showcase for the Petasis-Ferrier union/rearrangement tactic
    Amos B Smith
    Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 8:3315-8. 2006
    ..A one-pot esterification/lactonization employing the Yamaguchi protocol, followed by bis-glycosidation, furnished (-)-clavosolide A...
  4. ncbi The [1,5]-Brook rearrangement: an initial application in anion relay chemistry
    Amos B Smith
    Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Am Chem Soc 128:12368-9. 2006
    ..That the mode of silyl migration is intramolecular was demonstrated by a crossover experiment. Finally, the tricomponent anion relay chemistry (ARC) coupling tactic was demonstrated employing the [1,5]-Brook rearrangement...
  5. ncbi Indole diterpene synthetic studies. Total synthesis of (+)-nodulisporic acid F and construction of the heptacyclic cores of (+)-nodulisporic acids A and B and (-)-nodulisporic acid D
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Org Chem 72:4596-610. 2007
    ....
  6. ncbi Indole diterpene synthetic studies: development of a second-generation synthetic strategy for (+)-nodulisporic acids A and B
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Org Chem 72:4611-20. 2007
    ..This strategy evolved due to the considerable acid instability of the C(24) hydroxyl group observed in several advanced intermediates during our first-generation approach...
  7. ncbi Anion relay chemistry extended. Synthesis of a gorgonian sesquiterpene
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 9:3307-9. 2007
    ..The synthesis proceeded in five steps with an overall yield of 22%...
  8. ncbi The spirastrellolides: construction of the southern C(1)-C(25) fragment exploiting anion relay chemistry
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center, and Laboratory for Research on Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 9:3311-4. 2007
    ..Central to this venture was the use of four dithiane unions, including the highly effective deployment of the anion relay chemistry (ARC) tactic recently introduced by our laboratory...
  9. ncbi Syntheses of (-)-oleocanthal, a natural NSAID found in extra virgin olive oil, the (-)-deacetoxy-oleuropein aglycone, and related analogues
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Org Chem 72:6891-900. 2007
    ..To demonstrate the utility of the second-generation synthesis, multigram quantities of (-)-oleocanthal were prepared in 10 steps (14% overall yield) from commercially available D-lyxose...
  10. doi Evolution of the Petasis-Ferrier union/rearrangement tactic: construction of architecturally complex natural products possessing the ubiquitous cis-2,6-substituted tetrahydropyran structural element
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Acc Chem Res 41:675-87. 2008
    ....
  11. pmc Ortho-TMS benzaldehyde: an effective linchpin for type II anion relay chemistry (ARC)
    Amos B Smith
    Department of Chemistry, Penn Center for Molecular Discovery and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, PA 19104, USA
    Angew Chem Int Ed Engl 47:7082-6. 2008
  12. pmc Total synthesis of (-)-aplaminal
    Amos B Smith
    Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 10:4363-5. 2008
    ..Overall, the synthesis entailed 9 steps and proceeded in 19% overall yield...
  13. pmc Total synthesis of (+)-sorangicin A
    Amos B Smith
    Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Am Chem Soc 131:12109-11. 2009
    ....
  14. ncbi Evolution of a total synthesis of (-)-kendomycin exploiting a Petasis-Ferrier rearrangement/ring-closing olefin metathesis strategy
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center, and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Am Chem Soc 128:5292-9. 2006
    ....
  15. ncbi Indole diterpenoid synthetic studies. Construction of the heptacyclic core of (-)-nodulisporic acid D
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 8:1669-72. 2006
    ....
  16. ncbi Indole diterpenoid synthetic studies. The total synthesis of (+)-nodulisporic acid F
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 8:1665-8. 2006
    ....
  17. ncbi Design, synthesis, and evaluation of analogues of (+)-14-normethyldiscodermolide
    Amos B Smith
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 7:315-8. 2005
    ..Simplification at the C(21)-C(24) terminal diene and at the C(1)-C(5) lactone moieties reveals significant structure-activity relationships...
  18. ncbi Total synthesis of (+)-discodermolide: a highly convergent fourth-generation approach
    Amos B Smith
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 7:1825-8. 2005
    ..Importantly, Wittig salt generation proceeded in excellent yield under ambient pressure...
  19. ncbi Toward understanding how the lactone moiety of discodermolide affects activity
    Simon J Shaw
    Kosan Biosciences, Inc, 3832 Bay Center Place, Hayward, CA 94545, USA
    J Am Chem Soc 127:6532-3. 2005
    ..These synthetic efforts have led to an unsubstituted butyrolactone 9 being generated, which shows improved activity over the natural product...
  20. ncbi Total synthesis of (-)-kendomycin exploiting a Petasis-Ferrier rearrangement/ring-closing olefin metathesis synthetic strategy
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center, and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, PA 19104, USA
    J Am Chem Soc 127:6948-9. 2005
    ....
  21. ncbi Discodermolide analogues as the chemical component of combination bacteriolytic therapy
    Amos B Smith
    Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA
    Bioorg Med Chem Lett 15:3623-6. 2005
    ..A single intravenous injection of (+)-3 plus genetically modified Clostridium novyi-NT spores caused rapid and complete regressions of tumors in mice bearing HCT116 colorectal cancer xenografts...
  22. ncbi (+)-Sorangicin A synthetic studies. Construction of the C(1-15) and C(16-29) subtargets
    Amos B Smith
    Department of Chemistry, Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, 19104, USA
    Org Lett 7:3099-102. 2005
    ....
  23. ncbi Total synthesis of the neotropical poison-frog alkaloid (-)-205B
    Amos B Smith
    Department of Chemistry, University of Pennsylvania, Philadelphia, 19104, USA
    Org Lett 7:3247-50. 2005
    ..The synthesis proceeded with a longest linear sequence of 19 steps, affording (-)-1 in 5.6% overall yield...
  24. ncbi A scalable route to trisubstituted (E)-vinyl bromides
    Cheon Gyu Cho
    Department of Chemistry, Hanyang University, Seoul, Korea 133 791
    Org Lett 7:3569-72. 2005
    ..reaction: see text]..
  25. ncbi Design, total synthesis, and evaluation of C13-C14 cyclopropane analogues of (+)-discodermolide
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center, and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 7:4613-6. 2005
    ..Biological evaluation revealed that neither orientation of the cyclopropyl methylene completely substitutes for the C14 methyl found in (+)-discodermolide (3)...
  26. ncbi Synthesis and assignment of absolute configuration of (-)-oleocanthal: a potent, naturally occurring non-steroidal anti-inflammatory and anti-oxidant agent derived from extra virgin olive oils
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center, Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, 19104, USA
    Org Lett 7:5075-8. 2005
    ..Both syntheses begin with d-(-)-ribose, proceed in 12 steps, and are achieved with an overall yield of 7%. Both enantiomers proved to be non-steroidal anti-inflammatory and anti-oxidant agents...
  27. ncbi Design, synthesis, and biological evaluation of potent discodermolide fluorescent and photoaffinity molecular probes
    Amos B Smith
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 7:5199-202. 2005
    ..Stereoselective olefin cross-metathesis comprised a key tactic for construction of two of the molecular probes. Three photoaffinity probes were radiolabeled with tritium...
  28. ncbi Design, synthesis, and biological evaluation of simplified analogues of (+)-discodermolide. Additional insights on the importance of the diene, the C7 hydroxyl, and the lactone
    Amos B Smith
    Department of Chemistry, Monell Chemical Senses Center, and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 7:5229-32. 2005
    ..Saturation of the terminal diene system, alteration of the substituents on the lactone, and alkylation of the C7-hydroxyl group reveal significant structure-activity relationships...
  29. ncbi Anion relay chemistry: an effective tactic for diversity oriented synthesis
    Amos B Smith
    Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, PA 19104, USA
    J Am Chem Soc 128:66-7. 2006
    ..Addition of HMPA or other polar solvents to trigger a solvent controlled 1,4-Brook rearrangement then leads to a new distal anion (8), which in turn is available to react with a variety of second electrophiles...
  30. pmc Uniting anion relay chemistry with Pd-mediated cross coupling: design, synthesis and evaluation of bifunctional aryl and vinyl silane linchpins
    Amos B Smith
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 12:588-91. 2010
    ..The synthetic tactic permits both alkylation and Pd-mediated CCR of the anions derived via 1,4-silyl C(sp(2))-->O Brook Rearrangements...