Ambient Temperature Synthesis of High Enantiopurity N-ProtectedPeptidyl Ketone by Desulfitative Cross Coupling of Peptidyl ThiolEsters and Boronic Acids Público

Yang, Hao (2009)

Permanent URL: https://etd.library.emory.edu/concern/etds/gm80hv832?locale=es
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Abstract

Abstract

Two efficient desulfitative cross coupling methodologies were developed to synthesize high enantiopurity peptidyl ketones. The first methodology was developed from the first generation of the Liebeskind-Srogl desulfitative cross coupling reaction. In the presence of catalytic Pd2(dba)3/triethyl phosphite and stoichiometric Cu(I)-thiophene-2- carboxylate, a great variety of N-protected peptidyl thiol esters couple efficiently with boronic acids to yield the corresponding peptidyl ketones in satisfactory yields without racemization or epimerization. In the second generation of desulfitative peptidyl ketone synthesis, high enantiopurity peptidyl ketones were synthesized from peptidyl S- acylthiosalicylamide esters and boronic acids by using Cu(I)-3-methylsalicylate as the only metal catalyst. The reaction takes place at room temperature under air. Eighteen examples have been synthesized to demonstrate the efficiency and a broad tolerance of functional groups for this new reaction.

Table of Contents

Table of Contents Chapter 1.

Ambient Temperature Synthesis of High Enantiopurity N-Protected -Amino Ketone by Thiol Ester-Boronic Acid Cross Coupling 1.1.Introduction.......................................................................................2 1.1.1 Desulfitative Thioorganic and Boronic Acid Cross Coupling.....................2 1.1.2 Current Progress of Synthesis of High Enantiopurity N-Protected -Amino Ketone.............................................................................................6 1.2.Results and Discussion........................................................................10 1.2.1 Preliminary Study.....................................................................10 1.2.2 Ligand Screening........................................................................15 1.2.3 General Method for Synthesis of N- bis-Boc Protected -Amino Ketone......16 1.2.4 General Condition for Synthesis of N-Cbz Protected -Amino Ketone.........17 1.3.Conclusions......................................................................................23 1.4.Experimental section...........................................................................24 1.5.References......................................................................................62 Chapter 2. Room Temperature Synthesis of High Enantiopurity N-Protected Di, Tri-Peptidyl Ketones by Peptidyl Thiol Ester and Boronic Acid Cross Coupling 2.1 Introduction....................................................................................69

2.2 Results and Discussion........................................................................70 2.2.1 Synthesis of Dipeptidyl and Tripeptidyl Thiolphenyl Esters.....................70 2.2.2 Peptidyl Thiophenyl Ester and Boronic Acid Cross Coupling..................73 2.3 Conclusions....................................................................................80 2.4 Experimental Section........................................................................80 2.5 References.......................................................................................94 Chapter 3. Synthesis of High Enantiopurity Peptidyl Ketone from Copper Catalyzed, Aerobic, 2nd Generation of Liebeskind Desulfitative Cross Coupling 3.1 Introduction....................................................................................97 3.2 Results and Discussion.....................................................................100 3.2.1 S-Pendant Structure and Reactivity Study.......................................100 3.2.2 Synthesis of N-Cbz Protected Peptidyl S-acylthiosalicylamide...............104 3.2.3 The Examples of Cross Coupling Reaction.......................................105 3.3 Conclusions.................................................................................109 3.4 Experimental Section........................................................................109 3.5 References....................................................................................150

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