INTERMEDIATES FOR ORGANIC SYNTHESIS

Summary

Principal Investigator: PAUL WILLIARD
Affiliation: Brown University
Country: USA
Abstract: DESCRIPTION:(Principal Investigator's) The principal goal of this research program is to improve the efficiency by which relatively small organic compounds are synthesized. Large numbers of relatively small organic compounds are screened annually by the National Institutes of Health as a part of their mission to address specific public health concerns and to develop new therapeutic agents. For example, new therapeutic agents are constantly being developed and evaluated as effective agents to control and possibly to eradicate the HIV virus. The design and the reduction to practice of in vitro chemical syntheses of every small molecule in the NCI publication Chemical Structures of Interest to the Division of Cancer Treatment is critically dependent upon the availability of preparative synthetic methodology. Hence, procedures which decrease the effort required for in vitro chemical synthesis will assist the ongoing development and syntheses of physiologically active, small organic molecules. Synthetic efficiency of both naturally occurring and of non-naturally occurring analogs of small organic molecules will be improved through understanding of the precise details which control the key carbon-carbon bond forming reactions utilized in their preparation. The protocol utilized in this research project will be to complete a thorough structural analysis of common reactive intermediates which are utilized extensively in every synthetic organic chemistry laboratory. The structural results are obtained through a combination of techniques which include NMR spectroscopy, x-ray diffraction analysis and computational chemistry. The structural results manifest themselves as three dimensional pictures of aggregated species which have been shown by others to be reactive intermediates. The structural information will also be utilized to design synthetic methods and to explain, to control, and to predict the outcome of chemical reactions which are required to synthesize physiologically active compounds. Structural information will also be utilized to develop and to improve certain specific synthetic reagents for the asymmetric synthesis of organic chemicals. This research project is designed to complement the development of new synthetic reactions with a thorough understanding of the reaction processes themselves. Overall, a strict emphasis will be focused on those specific reactive species and reaction processes deemed most relevant to the development of synthetic organic chemistry used for the total synthesis of medicinal chemicals.
Funding Period: 1986-01-01 - 2002-02-28
more information: NIH RePORT

Top Publications

  1. ncbi On the mechanism of THF catalyzed vinylic lithiation of allylamine derivatives: structural studies using 2-D and diffusion-ordered NMR spectroscopy
    Madeleine A Jacobson
    Department of Chemistry, Brown University, Providence, RI 02912, USA
    J Am Chem Soc 127:4965-75. 2005
  2. pmc Oxidation of peptides by methyl(trifluoromethyl)dioxirane: the protecting group matters
    Maria Rosaria Rella
    Department of Chemistry, Brown University, Providence, Rhode Island 02912, USA
    J Org Chem 72:525-31. 2007
  3. pmc 13C INEPT diffusion-ordered NMR spectroscopy (DOSY) with internal references
    Deyu Li
    Department of Chemistry, Brown University, Providence, Rhode Island 02912, USA
    Org Lett 10:909-11. 2008
  4. doi Aggregation studies of complexes containing a chiral lithium amide and n-Butyllithium
    Deyu Li
    Department of Chemistry, Brown University, Providence, Rhode Island 02912, USA
    J Org Chem 73:2373-81. 2008
  5. doi Analysis of an asymmetric addition with a 2:1 mixed lithium amide/n-butyllithium aggregate
    Jia Liu
    Department of Chemistry, Brown University, Providence, RI 02912, USA
    J Org Chem 73:4045-52. 2008
  6. doi Characterization of a chiral enolate aggregate and observation of 6Li-1H scalar coupling
    Deyu Li
    Department of Chemistry, Brown University, Providence, Rhode Island 02912, USA
    J Am Chem Soc 130:11726-36. 2008
  7. pmc Characterization of reactive intermediates by multinuclear diffusion-ordered NMR spectroscopy (DOSY)
    Deyu Li
    Department of Chemistry, Brown University, Providence, Rhode Island 02912, USA
    Acc Chem Res 42:270-80. 2009

Detail Information

Publications8

  1. ncbi On the mechanism of THF catalyzed vinylic lithiation of allylamine derivatives: structural studies using 2-D and diffusion-ordered NMR spectroscopy
    Madeleine A Jacobson
    Department of Chemistry, Brown University, Providence, RI 02912, USA
    J Am Chem Soc 127:4965-75. 2005
    ..NMR evidence suggests that in THF the mixed aggregate has close contact between the olefin and the beta-CH(2) of nBuLi, while in the absence of THF, the allyl chain appears to be pointed away from the nearest nBuLi residues...
  2. pmc Oxidation of peptides by methyl(trifluoromethyl)dioxirane: the protecting group matters
    Maria Rosaria Rella
    Department of Chemistry, Brown University, Providence, Rhode Island 02912, USA
    J Org Chem 72:525-31. 2007
    ..Both are attractive transformations since they yield derivatized peptides that serve as valuable synthons...
  3. pmc 13C INEPT diffusion-ordered NMR spectroscopy (DOSY) with internal references
    Deyu Li
    Department of Chemistry, Brown University, Providence, Rhode Island 02912, USA
    Org Lett 10:909-11. 2008
    ..The correlation between log D and log FW of the linear least-squares fit to reference points of all components is exceptionally high: (r = 0.9985)...
  4. doi Aggregation studies of complexes containing a chiral lithium amide and n-Butyllithium
    Deyu Li
    Department of Chemistry, Brown University, Providence, Rhode Island 02912, USA
    J Org Chem 73:2373-81. 2008
    ..9900). (6)Li and (15)N NMR titration experiments also corroborated these results. These NMR experiments indicate that this mixed aggregate is the species that is responsible for asymmetric addition of n-BuLi to aldehydes...
  5. doi Analysis of an asymmetric addition with a 2:1 mixed lithium amide/n-butyllithium aggregate
    Jia Liu
    Department of Chemistry, Brown University, Providence, RI 02912, USA
    J Org Chem 73:4045-52. 2008
    ..This mixed aggregate strongly indicates the possibility of product-induced chirality inhibition that is detrimental to the enantioselectivity of asymmetric addition reaction...
  6. doi Characterization of a chiral enolate aggregate and observation of 6Li-1H scalar coupling
    Deyu Li
    Department of Chemistry, Brown University, Providence, Rhode Island 02912, USA
    J Am Chem Soc 130:11726-36. 2008
    ..The stereostructure of 1 provides a model for the origin of enantioselectivity of chiral lithium amide-induced enolate addition reactions...
  7. pmc Characterization of reactive intermediates by multinuclear diffusion-ordered NMR spectroscopy (DOSY)
    Deyu Li
    Department of Chemistry, Brown University, Providence, Rhode Island 02912, USA
    Acc Chem Res 42:270-80. 2009
    ..As highlighted by our efforts, DOSY techniques provide practical and feasible NMR procedures and hold the promise of even more powerful insights when extended to three-dimensional experiments...