I. SYNTHESIS OF BETA-LACTONES II. USE OF TEMPLATED HELICES TO DETERMINE ZIMM-BRAGG PARAMETERS by

A procedure for the synthesis of beta-lactones from thioesters and the conversion of betalactones to the corresponding olefins on a large scale has been investigated, showing that the reactions occur in good yield. Three simple N-terminal templated derivatives using AcHel(1) have been studied for potential intramolecular hydrogen bonding capacity. AcHel(l)Val-OH and the reduced template thiol corresponding to the Ac-Hel(l) template show no exceptional hydrogen bonding capacity. The derivative Ac-Hel(l)-NHMe shows intramolecular hydrogen bonding by NMR studies. Three templated oligopeptides containing multiple contiguous lysines at the C-terminus (AcHel(1)Ala(5)LysAla(4)Lys(n)-NH2, n = 2 to 4) show that the charge effect of proximal lysines offset the stabilizing effect of a terminal lysine in alpha helices. Circular dichroism studies of AcHel(1)Ala(4)LysAla(4)LysAla(n)-NH2, n = 2, 3 show per residue ellipticities within ranges reported in the literature. The s-value of glycine has been determined from a series of short templated peptides (AcHel(1)Ala(n-1)GlyAla(5-n)-NH2, n=2 to 5 to be ca. 0.22. The temperature dependent s-value of lysine and the passive role of alanine in stabilizing helices were determined from an independent analysis of AcHel(l)Ala(7)Lys-NH2 and AcHel(l)Ala(n-1)Gly(7-n)Lys-NH2, n = 1 to 7. The svalue of glycine from t/c ratios for this series at 25 deg C is ca. 0.20 to 0.35; the s-value of alanine was determined to be 1.00. AcHel(1)Ala(7)Lys-NH2 and AcHel(l)Ala(n)Gly(7-n)Lys-NH2, n = 1 to 7 were also studied by circular dichroism. Thesis Supervisor: Professor Daniel S. Kemp Title: Professor of Chemistry Acknowledgements Prof. Rick Danheiser taught me some interesting modern synthetic chemistry both on the bench and on paper, some not mentioned in this thesis. His understanding of the art of organic synthesis is respected and to be emulated. I thank Prof. Danheiser for research assistantships (1990-1993) and the Department of Chemistry for teaching assistantships (1989-1990). Prof. Daniel Kemp provided me with the opportunity to work on the alpha helix project. It is always a privilege to work for someone who is inspired. As a chemist of the Woodwardian era once said to me, Prof. Kemp is a chemist's chemist. I thank Prof. Kemp for research assistantships (1994-1997) and for his illuminating tangents and discussions. I thank the MIT Spectroscopy Laboratory and the Biemann group for mass spec analyses. Many graduate students and post-docs deserve gratitude: James Nowick of the Danheiser laboratory for his advice and discovery; Fari Firooznia, Kathy Lee (Sis), and other members of the Danheiser group for their support; Dave Chalfoun and Robert Carey for good advice; Z.Q. Li for his integrity and friendship ; Kim McClure and Peter Renold for incredible improvements in the Ac-Hel(1) synthesis; Evan Powers (Mr. E) for the things that will preclude his nomination to the Supreme Court; Peter R. for his friendship and translations; Jeff Rothman for being on our side of the thin line; Linda Szabo Shimizu for her friendship and support; Sam Tsang for helpful peptide advice; Tom Allen, Robert Bieganski, Katrin Groebke, Gene Hickey, Sherri Oslick, and Jonny Z. for group solidarity; Larry Williams for sans papier synthetic discussions on reserpine and other natural products; Kristian Kather for his Herzlichkeit; and Peter Wallimann for his singularity. I wish Evan and the newest line of offense (no pun intended) Songpon 'Ace' Deechongkit, Kristian, Robert Kennedy, Peter W., and Larry results, papers, personal happiness and good fortune. Thanks to Bob K., Evan, Kristian, Peter W., Sam, and Larry (and Prof. Kemp) for proofreading parts of this thesis. I cannot thank Prof. Jon C. Clardy of Cornell University enough. The years spent in your laboratory were priceless. Thanks. I am also mindful of the counsel and friendship of many of the graduate students of that era, though there are too many to name. But the scoundrels know who they are. A knowing glance is cast to Lisa 'Sunshine' Wang, a fine adventurer and friend, whose unswerving dedication to chemistry is admirable. I appreciate the support of my brother, Michael, and I thank him for not getting himself killed riding his donorcycle or while skydiving. Kit Sheung Lee, my Mom, has given me more love, care and support than I could ever qualify for. I am very grateful to her for my sound, yet unfettered, upbringing. Until I raise a 'demure' daughter of my own, I am sure that I shall not fully appreciate her sacrifices and her wisdom. Thanks, Mom. See the next page. The last four people mentioned have each been like a Rock of Gibraltar, but there is yet another and that is chemistry itself. To Mom and C., M.N. and A., the Untouchables