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. pmc Recyclable polystyrene-supported siloxane-transfer agent for palladium-catalyzed cross-coupling reactions
    Minh H Nguyen
    Department of Chemistry, Laboratory for Research on the Structure of Matter and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
    Org Lett 16:2070-3. 2014
  2. pmc Spirastrellolide B: construction of the C(26)-C(40) northern hemisphere and a related [5,5,7]-bis-spiroketal analogue
    Xiaozhao Wang
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 14:3998-4001. 2012
  3. pmc Validation of diethoxyphosphonate as an effective agent for charge transfer in Anion Relay Chemistry (ARC)
    Alexander Sokolsky
    Department of Chemistry, Laboratory for Research on the Structure of Matter, and the Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 14:4470-3. 2012
  4. pmc Total synthesis of (-)-irciniastatin B and structural confirmation via chemical conversion to (+)-irciniastatin A (psymberin)
    Chihui An
    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 14:4350-3. 2012
  5. pmc Long-range anion relay chemistry (LR-ARC): a validated ARC tactic
    Luis Sanchez
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
    Org Lett 14:6314-7. 2012
  6. pmc The design, synthesis and validation of recoverable and readily reusable siloxane transfer agents for Pd-catalyzed cross-coupling reactions
    Dionicio Martinez-Solorio
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
    Org Lett 15:2454-7. 2013
  7. pmc Polymer-supported siloxane transfer agents for Pd-catalyzed cross-coupling reactions
    Minh H Nguyen
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 15:4258-61. 2013
  8. pmc Benzyl and phenylthiomethyl silanes: a new class of bifunctional linchpins for type II anion relay chemistry (ARC)
    Amos B Smith
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 12:1260-3. 2010
  9. pmc (+)-Rimocidin synthetic studies: construction of the C(1-27) aglycone skeleton
    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 74:5987-6001. 2009
  10. pmc An efficient, second-generation synthesis of the signature dioxabicyclo[3.2.1]octane core of (+)-sorangicin A and elaboration of the (Z,Z,E)-triene acid system
    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 11:1099-102. 2009

Scientific Experts

  • AMOS SMITH
  • Cheon Gyu Cho
  • Simon J Shaw
  • Minh H Nguyen
  • Dionicio Martinez-Solorio
  • Adam T Hoye
  • Xiaozhao Wang
  • Alexander Sokolsky
  • Chihui An
  • Luis Sanchez
  • Catherine Peyrot des Gachons
  • Thomas J Paxton
  • Ningkun Li
  • Bruce Bryant
  • Paul A S Breslin
  • Asako Shima
  • Luba Dankulich-Nagrudny
  • Kunitoshi Uchida
  • Gary K Beauchamp
  • Makoto Tominaga
  • Jeffrey B Sperry

Detail Information

Publications52

  1. pmc Recyclable polystyrene-supported siloxane-transfer agent for palladium-catalyzed cross-coupling reactions
    Minh H Nguyen
    Department of Chemistry, Laboratory for Research on the Structure of Matter and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
    Org Lett 16:2070-3. 2014
    ..Drawbacks of a previous polymer-supported siloxane-transfer agent, relating to reaction efficiency and polymer stability after repeated cycles, have been addressed. ..
  2. pmc Spirastrellolide B: construction of the C(26)-C(40) northern hemisphere and a related [5,5,7]-bis-spiroketal analogue
    Xiaozhao Wang
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 14:3998-4001. 2012
    ..Central to this venture is the regiocontrolled functionalization of a C(31-32) alkyne, exploiting different transition metal catalysts (cf. Pt(II) and Au(I))...
  3. pmc Validation of diethoxyphosphonate as an effective agent for charge transfer in Anion Relay Chemistry (ARC)
    Alexander Sokolsky
    Department of Chemistry, Laboratory for Research on the Structure of Matter, and the Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 14:4470-3. 2012
    ..In the absence of an exogenous electrophile, the anion derived via phosphorus migration undergoes internal displacement of the phosphonate group to produce a diastereomeric mixture of cyclopropanes...
  4. pmc Total synthesis of (-)-irciniastatin B and structural confirmation via chemical conversion to (+)-irciniastatin A (psymberin)
    Chihui An
    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 14:4350-3. 2012
    ....
  5. pmc Long-range anion relay chemistry (LR-ARC): a validated ARC tactic
    Luis Sanchez
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
    Org Lett 14:6314-7. 2012
    ..This tactic permits "long-range" relocation of negative charge across space, to generate reactive distal nucleophilic centers for both alkylation and palladium-catalyzed coupling reactions...
  6. pmc The design, synthesis and validation of recoverable and readily reusable siloxane transfer agents for Pd-catalyzed cross-coupling reactions
    Dionicio Martinez-Solorio
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
    Org Lett 15:2454-7. 2013
    ..Drawbacks of the first-generation siloxane-transfer agent (1), relating to facile recovery for potential recycling, have been addressed. ..
  7. pmc Polymer-supported siloxane transfer agents for Pd-catalyzed cross-coupling reactions
    Minh H Nguyen
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 15:4258-61. 2013
    ..The solubility properties of the polymer facilitate not only product purification but also polymer recycling without significant loss of cross-coupling activity. ..
  8. pmc Benzyl and phenylthiomethyl silanes: a new class of bifunctional linchpins for type II anion relay chemistry (ARC)
    Amos B Smith
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 12:1260-3. 2010
    ....
  9. pmc (+)-Rimocidin synthetic studies: construction of the C(1-27) aglycone skeleton
    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 74:5987-6001. 2009
    ....
  10. pmc An efficient, second-generation synthesis of the signature dioxabicyclo[3.2.1]octane core of (+)-sorangicin A and elaboration of the (Z,Z,E)-triene acid system
    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 11:1099-102. 2009
    ..Assembly of the triene acid system was then achieved via Stille cross-coupling with the ethyl ester of (Z,Z)-5-tributylstannyl-2,4-pentadienoic acid, followed by mild hydrolysis preserving the triene configuration...
  11. pmc Unusual pungency from extra-virgin olive oil is attributable to restricted spatial expression of the receptor of oleocanthal
    Catherine Peyrot des Gachons
    Monell Chemical Senses Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 31:999-1009. 2011
    ..These findings provide an anatomical and molecular explanation for a distinct oral sensation that is elicited by oleocanthal and ibuprofen and that is commonly experienced around the world when consuming many extra-virgin olive oils...
  12. pmc Diversity-oriented synthesis of 2,4,6-trisubstituted piperidines via type II anion relay chemistry
    Amos B Smith
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Org Lett 13:3328-31. 2011
    ....
  13. pmc Design and synthesis of (+)-discodermolide-paclitaxel hybrids leading to enhanced biological activity
    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 Med Chem 54:6319-27. 2011
    ..Biological evaluation reveals a two- to eight-fold increase in antiproliferative activity compared to the parent molecule using the A549 and MCF-7 cancer cell lines...
  14. pmc Unification of anion relay chemistry with the Takeda and Hiyama cross-coupling reactions: identification of an effective silicon-based transfer agent
    Amos B Smith
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19128, United States
    J Am Chem Soc 134:4533-6. 2012
    ..g., Suzuki organoboron, Negishi organozinc, Stille organotin, Kumada organomagnesium, etc.)...
  15. 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
    ....
  16. 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
    ....
  17. 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...
  18. 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...
  19. 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
  20. 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
    ....
  21. 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...
  22. 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...
  23. 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)...
  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 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...
  26. 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...
  27. 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
    ....
  28. 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...
  29. 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...
  30. 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...
  31. 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...
  32. 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...
  33. 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
    ....
  34. 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...
  35. 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...
  36. 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%...
  37. 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...
  38. 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
    ....
  39. 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...
  40. 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...
  41. 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...
  42. 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
    ....
  43. 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
    ....
  44. 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...