?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F10018%2F&rft.title=SYNTHETIC%2C+CHEMICAL%2C+AND+BIOLOGICAL+STUDIES+OF+FR901464+AND+STUDIES+OF+THE+SILVER+AND+ZIRCONIUM+PROMOTED+ALKYNYL+ADDITION+REACTION&rft.creator=Albert%2C+Brian+J.&rft.description=The+total+synthesis+of+FR901464+was+accomplished+in+at+total+of+29+steps%2C+which+is+the+shortest+synthesis+to+date.+Degradation+studies+were+performed+on+the+fully+functionalized+right+fragment+of+FR901464+and+this+insight+was+used+to+rationally+design+a+more+stable+analog%2C+which+led+to+the+rational+development+of+meayamycin%2C+an+FR901464+analog+with+enhanced+biological+properties.+Additional+analogs+were+synthesized+examining+the+A-ring%2C+C4'+position%2C+and+the+C3+position+of+the+B-ring.+These+analogs+demonstrated+that+the+A-ring+of+FR901464+is+optimal%2C+the+C4'+acetate+should+remain+intact+for+higher+potency%2C+and+the+spiroepoxide+is+required+for+antiproliferative+properties.+The+low+potency+of+the+desepoxy+analogs+indicate+that+FR901464+covalently+modifies+is+target(s)+via+its+epoxide%2C+which+led+to+the+synthesis+of+cold+iodide-containing+analog%2C+which+could+be+used+for+target+identification+experiments.+Due+to+the+concern+of+non-specific+reactions+of+epoxides+with+endogenous+thiols%2C+a+method+was+developed+to+study+the+consumption+of+epoxides+with+thiols.+Experiments+of+common+epoxide+motifs+showed+that+these+reactions+were+negligible+under+biologically+relevant+conditions.+Moreover%2C+a+model+system+for+the+amide+chain+of+FR901464+demonstrated+that+its+Z-enamide+will+not+react+non-specifically+with+endogenous+thiols.There+was+a+need+for+a+general+method+for+the+alkynyl+addition+to+epoxides+to+give+propargylic+alcohols+as+products.+Towards+this+end%2C+the+Ag%2FZr-promoted+alkynyl+addition+methodology+discovered+in+the+Koide+laboratories+was+successfully+applied.+These+studies+began+with+the+preparation+of+11+silver+acetylides+and+examining+their+safety+as+reagents+for+organic+synthesis.+Subsequently%2C+these+silver+acetylides+were+shown+to+add+to+epoxides+via+1%2C2-shifts+to+give+propargylic+alcohols+in+the+presence+of+Cp2ZrCl2+and+AgOTf.+The+scope+and+limitations+of+both+the+epoxide+and+alkyne+were+realized+and+was+demonstrated+in+over+20+successful+reactions.+Moreover%2C+the+11+new+silver+acetylides+used+in+the+epoxide+alkynyl+addition+methodology+should+be+readily+applicable+to+the+aldehyde+alkynyl+addition+methodology.+Finally%2C+mechanistic+studies+were+undertaken+and+were+crucial+in+understanding+the+roles+of+all+additives+necessary+for+this+alkynyl+addition+reaction+to+be+successful%2C+culminating+in+the+generation+of+a+proposed+mechanism.&rft.date=2008-01-18&rft.type=University+of+Pittsburgh+ETD&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F10018%2F1%2FAlbertBJ-2007.pdf&rft.identifier=++Albert%2C+Brian+J.++(2008)+SYNTHETIC%2C+CHEMICAL%2C+AND+BIOLOGICAL+STUDIES+OF+FR901464+AND+STUDIES+OF+THE+SILVER+AND+ZIRCONIUM+PROMOTED+ALKYNYL+ADDITION+REACTION.++Doctoral+Dissertation%2C+University+of+Pittsburgh.++++(Unpublished)++