Scott McN. Sieburth .. Professor, Organic and Medicinal Chemistry B.S., 1977, Worcester Polytechnic Instittute; Ph.D., 1983, Harvard University FMC Corporation, Agricultural Chemical Group, Senior Research Chemist 1982-1989 State University of New York at Stony Brook, 1989-2001 Department of Chemistry Temple University 1901 N. 13th Street Philadelphia, PA  19122 Voice: 215-204-7916   Fax: 215-204-1532 scott.sieburth@temple.edu

GROUP Webpage the Philadelphia Organic Chemists' Club (POCC) Webpage the other Sieburth faculty web pages, photo of Scott and Phil Lesh .

BIOREGULATORY SMALL MOLECULES AND NEW SYNTHETIC METHODS

Organosilanes and higher-order cycloadditions.

Organosilanes.

Silicon is carbon's nearest neighbor, a position that has spawned great interest in biologically active organosilanes.  Organosilanes have no intrinsic toxicity, and do not occur naturally. We have prepared the first silanediol-based polypeptide analogs, with the expectation that the silicon group will be a stable mimic of an unstable hydrated amide carbonyl, bind to the protease active site, and thereby inhibit proteolytic enzymes. Our silanediol-based structures inhibit angiotensin-converting enzyme (ACE) and the HIV protease at low nanomolar concentrations. These enzymes are important targets for control of hypertension and AIDS. more....

Development of efficient methodology to prepare these novel structures is a key component of this program. alpha -Aminosilanes, central to these structures, are not conveniently prepared by standard reactions. We have described two convergent approaches assembling readily available components, hydrosilylation of N-alkenyl urethanes and rearrrangment of N -silyl carbamates. The latter is the first useful nitrogen analog of the reverse-Brook rearrangement. In some cases, the reaction can also be performed with high enantioselectivity.

Cycloaddition.  2-Pyridone photodimerization transforms two achiral aromatics into a tricyclic cyclooctadiene with four stereogenic centers and functionality at every carbon Usually the trans isomer dominates the product. We seek to develop the synthetic potential of this reaction and have investigated both intramolecular and selectve cycloadditions of 2-pyridone mixtures, as well as cross cycloaddition with furan, naphthalene and 1,3-dienes. Our interest in this reaction stems, in part, from the overlap of the terpenoid carbon skeleton of the product with many complex natural products such as taxol, fusicoccin, ophiobolin, and variecolin.

Intramolecular cycloaddition of pyridones with a four or three-carbon tether yields a single diastereomeric product in each case. Further elaboration leads to regio- and stereospecific functionalization consistent with oxidation of the target molecules. more.....

The cyclooctadiene product can also be converted to polyquinanes. In the case of the head-to-head pyridone product, treatment of the cis-[4 + 4] product with chlorine yields a single pentacyclic product with eight stereogenic center. more....

SELECTED PUBLICATIONS

• Jaeseung Kim, Gregory Hewitt, Patrick Carroll and Scott McN. Sieburth, " Silanediol Inhibitors of Angiotensin-Converting Enzyme (ACE). Synthesis and Evaluation of Four Diastereomers of Phe[Si]Ala Dipeptide Analogues", Journal of Organic Chemistry, 2005 70, in the press.
• "Photochemical Reactivity of Pyridones" Scott McN. Sieburth, in CRC Handbook of Organic Photochemistry and Photobiology, W. Horspool, Ed., 2nd Ed., CRC, 2004, pp 103/1 – 103/18.
• "Photocycloaddition of alkenes (dienes) to dienes [4+4]/[4+4]" Scott McN. Sieburth, in Synthetic Organic Photochemistry, A. G. Griesbeck and J. Mattay, eds., 2005,chapter 9, pp 239-265.
• Guodong Liu and Scott McN. Sieburth, "a-Trialkylsilyl Amino Acid Stability." Organic Letters, 2005, 6, 665-668.
• "Silanediol Peptidomimetics. Evaluation of Four Diastereomeric ACE Inhibitors.." Jaeseung Kim and Scott McN. Sieburth, Bioorganic and Medicinal Chemistry Letters, 2004, 14, 2853-2856.
• "A Silanediol Inhibitor of the Metalloprotease Thermolysin: Synthesis and Comparison with a Phosphinic Acid Inhibitor." Jaeseung Kim and Scott McN. Sieburth, Journal of Organic Chemistry 2004, 69, 3008-3014.
• "Enantioselective α-Silyl Amino Acid Synthesis by Reverse-Aza-Brook Rearrangement." Guodong Liu and Scott McN. Sieburth, Organic Letters, 2003, 5, 4677 - 4679.
• "Asymmetric Synthesis of α-Amino Allyl, Benzyl and Propargyl Silanes by Metalation and Rearrangement " Scott McN. Sieburth, Heather K. O'Hare, Jiaji Xu, Yanping Chen and Guodong Liu, Organic Letters 2003, 5, 1859-1861.
• "Silanediol-Based Inhibitor of Thermolysin," Jaeseung Kim, Athanasios Glekas and Scott McN. Sieburth," Bioorganic and Medicinal Chemistry Letters, 2002, 12, 3625-3627.
• Yanping Chen and Scott McN. Sieburth, "A New beta-Keto Amide Synthesis" Synthesis 2002, 2191-2194.
• "Studies in Bicyclo[3.1.0]hexane Methanolysis. Ring Opening of Activated Cyclopropanes under Acidic and Basic Conditions." Lim, Y.-H.; McGee, Jr., K. F.; Sieburth, S. McN., Journal of Organic Chemistry 2002, 67, 6535-6538. pdf

• "Silicon-Based Metalloprotease Inhibitors: Synthesis and Evaluation of Silanol and Silanediol Peptide Analgos as Inhibitors of Angiotensin-Converting Enzyme (ACE)," Mutani, M. wa; Nittoli, T.; Guo, L.; Sieburth, S. McN.   J. Am. Chem. Soc. 2002124, 7363-7375.  
• "Drug Design with a New Transition State Analog of the Hydrated Carbonyl: Silicon-Based Inhibitors of the HIV Protease," Chen, C.-A.; Sieburth, S. McN., et al. Chem. Biol. , 2001, 8, 1161-1166.   pdf .
• "Polyquinanes by [4 + 4] Cycloaddition-Transannular Cyclization," Ader, T. A.; Champey, C. A.; Kuznetsova, L. V.; Li, T.; Lim, Y.-H.; Rucando, D.; Sieburth, S. McN. Org. Lett. 2001 , 3 , 2165-2167.   pdf
• "Pyridone Annulation by 4 + 2 Coupling of Dienolates with Nitriles and Nitrile Equivalents. A Solution to the Acetonitrile Problem," Chen, Y.; Li, T.; Sieburth, S. McN. J. Org. Chem. 2001, 66, 6826-6828.   pdf
• "Fusicoccin Synthesis by Intramolecular [4+4] Photocycloaddition of 2–Pyridones" McGee, K. F., Jr.; Al-Tel, T. H.; Sieburth, S. McN. Synthesis 2001 , 1185-1196.
• "Diastereoselectivity During 2-Pyridone Photo-[4 + 4] Cycloaddition. The Tribenzylsilyl Protecting Group," Sieburth, S. McN.; Madsen-Duggan, C. B.; Zhang, F. Tetrahedron Lett. 2001, 42 , 5155-5157.
• Synthesis of alpha-Alkyl-alpha-Aminosilanes by Rhodium-Catalyzed Hydrosilylation of Boc-Protected Vinyl Amines," Hewitt, G. W.; Somers, J. J.; Sieburth, S. McN. Tetrahedron Lett. 2000, 41, 10175–10179-
• "Studies in Silanol Synthesis: Internal Nucleophiles and Steric Hindrance," Glekas, A.; Sieburth, S. McN. Tetrahedron Lett. 2001, 42, 3799-3801.
• "A [4+4] 2-Pyridone Approach to Taxol. 3. Stereocontrol During Elaboration of the Cyclooctane," Lee, Y.-g..; McGee, K. F.; Chen, J. H.; Rucando, D.; Sieburth, S. McN. J. Org. Chem. 2000, 65,6676–6681.   pdf
• "Photoreactivity of 2-Pyridones with Furan, Benzene and Naphthalene. Inter- and Intramolecular Photocycloadditions," Sieburth, S. McN.; McGee, K. F., Jr.; Zhang, F.; Chen, Y. J. Org. Chem. 2000, 65, 1972-–977.  
• "The Inter- and Intramolecular [4 + 4] Photocycloaddition of 2-Pyridones and Its Application to Natural Product Synthesis," Sieburth, S. McN. In Advances in Cycloaddition ; M. Harmata, Ed.; JAI: Greenwich, CT, 1999; Vol. 5; pp 85–118.

complete publication list.....

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Last modified: June 2003     Temple Chemistry Home