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Yoshihisa Kobayashi
Natural Product Synthesis; New Reaction and Catalyst; Heterocycles Synthesis; Elucidation of Stereostructure
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| Contact Information |
| Office: PACH 5100C |
| Phone: (858) 822-5870 |
| Fax: (858) 822-5870 |
| Email: ykoba@ucsd.edu |
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| Education and Appointments |
| 2003-1999 |
PostDoc, Harvard University, MA, USA
Chemistry
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| 1999 |
Ph.D., University of Tokyo, JAPAN
Pharmaceutical Science
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| 1994 |
B.A., University of Tokyo, JAPAN
Pharmaceutical Science
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| Awards and Academic Honors |
| 2005 |
Hellman Faculty Fellow |
| Research Interests |
My research interests center on synthetic organic chemistry, including the total synthesis of complex natural products containing nitrogen atom(s) and the development of novel methods for the construction of pharmaceutically important heterocyclic compounds.
The advent of new methodology in the area of synthetic organic chemistry has greatly improved accessibility to biologically important complex molecules. Particularly, in the case of nitrogen-containing heterocycles, I would consider that three major chemical concerns need to be addressed in order to construct such heterocycles: (a) an activation of a nitrogen-containing substrate to serve both inter- and intramolecular cycloaddition which gives control of several stereogenic centers at once. (b) a protecting group of a nitrogen atom in the synthetic intermediate.(c) a reagent to deliver a nitrogen atom to the substrate intermolecularly. Moreover, what I will especially emphasize in my research is: Control of the regio- and /or stereoselectivity of the transformation of the synthetic intermediates based on the understandings originated from the architectural feature of the synthetic intermediates.
Heterocycles, especially nitrogen-containing aromatics, are ubiquitous among pharmaceutically important compounds. As seen in the reported traditional methods, there are many known reactions to construct such molecules and the feasibility has been proved for some of those by an application to bulk-production of the specific heterocycles. Nevertheless, the flexibility of the preparation of substituted heterocycles is still limited especially when one needs synthetic methods which tolerate making various substituted heterocycles generally. The development of new methods to introduce each of the substituents step by step, with a perfect control of the position, is required. This could open the way to creating a substantial amount of libraries with heterocycle-scaffolds which, in turn, could greatly contribute to drug discovery in medicinal areas with diversity-oriented synthesis. It is within a quinoline-framework, which is one of the most important nitrogen-containing heterocycles, that I choose to demonstrate this idea.
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| Primary Research Area: |
Interdisciplinary Specialties: |
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Organic Chemistry
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Synthesis
Bioorganic
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| Image Gallery: |
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Figure 1: Indole-Isocyanide in the Ugi Reaction |
Figure 2: Bt-Isocyanide in the Ugi Reaction |
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Figure 3: Oxidation of Indole
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| Selected Publications |
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(1) Gilley, C. B.; Buller, M. J.; Kobayashi, Y. "New Entry to Convertible Isocyanides for the Ugi Reaction and its Application to the Stereocontrolled Formal Total Synthesis of the Proteasome Inhibitor Omuralide" Org. Lett. 2007, 9, 3631-3634. (2) Vamos, M.; Ozboya, K.; Kobayashi, Y. "Synthesis of Bicyclic Pyroglutamic Acid Featuring the Ugi Reaction and the Unique Stereoisomerization at the Angular Position by Grob Fragmentation followed by Transannular Ketene [2+2] Cycloaddition Reaction" Synlett 2007, 1595-1599. (3) Isaacson, J.; Gilley, C. B.; Kobayashi, Y. "Expeditious Access to Unprotected Racemic Pyroglutamic Acids." J. Org. Chem. 2007, 72, 3913-3916. (4) Buller, M. J.; Cook T. G.; Kobayashi, Y. "Versatile Synthesis of 2,2-Disubstituted Indolinones via Protected Indolones generated by One-Pot Multi-Oxidation of 2-Substituted Indoles" Heterocycles 2007, 72, 163-166.
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(5) Isaacson, J.; Loo, M.; Kobayashi, Y. "Total Synthesis of (±)-Dysibetaine" Org. Lett. 2008, 10, 1461-1463. (6) Vamos, M.; Kobayashi, Y. " Scalable Preparation of Both Enantiomers of 2-(1-Hydroxy-2-oxocyclohexyl)acetic Acid" J. Org. Chem. 2008, 73, 3938-3941. (7) Gilley, C. B.: Kobayashi, Y. "2-Nitrophenyl Isocyanide as a Versatile Convertible Isocyanide: Rapid Access to a Fused gamma-Lactam-beta-Lactone Bicycle" (Article) J. Org. Chem. 2008, 73, 4198-4204. (8) Nguyen, T. X.; Kobayashi, Y. "The Synthesis of the Common Propellane Core Structure of the Hasubanan Alkaloids" (Article) J. Org. Chem. 2008, 73, 5536-5541. (9) Buller, M. J.; Gilley, C. B.; Nguyen, B.; Olshansky, L.; Fraga, B.; Kobayashi, Y. "Synthesis of Functionalized Pyroglutamic Acids. Part 1: The Synthetic Utility of N-Acylindole and the Ugi Reaction with a Chiral Levulinic Acid." Synlett 2008, 2244-2248. (10) Gilley, C. B.; Buller, M. J.; Kobayashi,Y. "Synthesis of Functionalized Pyroglutamic Acids. Part 2: The Stereoselective Condensation of Multi-Functional Groups with Chiral Levulinic Acids." Synlett 2008, 2249-2252. (11) Born, S.; Kobayashi, Y. "A Stable Synthetic Equivalent of 2,3-Dihydropyridine" Synlett 2008, 2479-2482. (12) Born, S.; Bacani, G.; Olson, E. E.; Kobayashi, Y. "Microwave-Assisted Intramolecular Diels-Alder Reaction Towards the Total Synthesis of Symbioimine" Synlett 2008, 2877-2881.
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(13) Isaacson, J.; Kobayashi, Y. "An Ugi Reaction in the Total Synthesis of (-)-Dysibetaine" Angew. Chem. Int. Ed. 2009, 48, 1845-1848. (14) Vamos, M.; Kobayashi, Y. "Propellane as a Conformational Device for the Stabilization of the beta-Lactone of Salinosporamide A" (Article) Tetrahedron, 2009, 65, 5899-5903. (15) Alessandra Eustáquio, Ryan McGlinchey, Yuan Liu, Christopher Hazzard, Laura Beer, Galina Florova, Mamoun Alhamadsheh, Andrew Kale, Yoshihisa Kobayashi, Kevin Reynolds, Bradley Moore (Corr-auth). "Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S-adenosyl-L-methionine" Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 12295-12300. (16) Gilley, C. B.; Buller, M. J.; Kobayashi, Y. "Synthesis of Proteasome Inhibitor Omuralide Featuring Stereocontrolled Ugi Reaction and Novel Convertible Isocyanide" (Account) J. Synth. Org. Chem., Jpn. 2009, 67, 1183-1193.
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[Ph.D./MS Thesis] (1) Gilley, C. B. New Convertible Isocyanides for the Ugi Reaction; Application to the Stereoselective Synthesis of Omuralide. Ph.D. Thesis, University of California, San Diego, La Jolla, CA, June 2008. (2) Urbina, A. Synthesis of a Proteasome Inhibitor Containing a gamma-Lactam-beta-Lactone Fused Ring System. MS Thesis, University of California, San Diego, La Jolla, CA, Mar 2009. (3) Isaacson, J. Advancements in Isocyanide-Based Multicomponent Reactions. Ph.D. Thesis, University of California, San Diego, La Jolla, CA, April 2009. (4) Born, S. The Enantioselective, Biomimetic Total Synthesis of (+)-Symbioimine. Ph.D. Thesis, University of California, San Diego, La Jolla, CA, May 2009. (5) Buller, M. J. Synthetic Methods for the Installation of Nitrogen-Containing Quaternary Centers in Complex Bioactive Natural Products. Ph.D. Thesis, University of California, San Diego, La Jolla, CA, May 2009. (6) Nguyen, T. Progress Towards the Total Synthesis of the Hasubanan Alkaloids and Acutumine. Ph.D. Thesis, University of California, San Diego, La Jolla, CA, July 2009. (7) Vamos, M. Synthesis and Evaluation of a Stabilized Propellane Analog of the Proteasome Inhibitor Salinosporamide A and Total Synthesis of Mearsine and Synthetic Studies towards Grandisine B. Ph.D. Thesis, University of California, San Diego, La Jolla, CA, October 2009.
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