A Copper‐Catalyzed, pH‐Neutral Construction of High‐Enantiopurity Peptidyl Ketones from Peptidic S‐Acylthiosalicylamides in Air at Room Temperature

Abstract

Described herein is a Cu-catalyzed transformation of peptidic thiol esters and boronic acids into peptidyl ketones that takes place at room temperature in DMF or in DMF/H 2 O open to air and uses only catalytic quantities of a Cu carboxylate to mediate the reaction. This aerobic transformation occurs only at a thiol ester capable of coordinating to Cu through its S-appendage and is hampered neither by racemization of the reactants or products, nor by the presence of disulfides or of unprotected phenols, alcohols, or indoles. KeywordsC-C coupling; Cross-coupling; Synthetic methods; Copper; Peptidomimetics; Protein modifications In recent decades great strides have been made in uncovering novel methods for the metalcatalyzed construction of C-C and C-X bonds from organic halides/sulfonates/ phosphonates [1][2][3][4][5][6][7][8][9][10][11] and through C-H functionalization. [12][13][14][15][16][17][18][19][20][21][22][23][24] The great majority of these metal-catalyzed couplings are now carried out using mild organic transfer agents such as boronic acids, organostannanes, and organosilanes. The synthetic power and breadth of impact of these modern methods for the efficient and selective generation of a variety of bond types in a vast array of target molecules is unquestioned. And, yet, significant unmet challenges remain for the synthetic scientist to address. One holy grail is the highly chemoselective, nonenzymatic formation of a C-C or C-X bond at a specific site on a functionally complex biomolecule under biologically relevant conditions (i.e., minimal or no protecting groups, ambient temperatures, neutral pH reaction conditions, aerobic or anaerobic conditions, compatibility with protic solvents). [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] NIH Public Access In probing the value of Cu-catalyzed, aerobic, desulfitative coupling for the construction of peptidyl ketones, a control experiment using tryptophan-derived thiol esters validated the importance of the nature of the thiol ester S-pendant on the substrate reactivity (Scheme 1): at 50 °C in DMF with 5 mol % Cu I 3-methylsalicylate (CuMeSal) the reaction occurred only with the tryptophan derived thiophenyl ester bearing an ortho CONHt-Bu group and not with the simple thiophenyl ester.This result clearly confirmed that a coordinating moiety on the pendant group of the thiol ester is a requisite condition for this Cu-catalyzed, aerobic reaction. As described in the initial manuscript disclosing the "second generation" desulfitative coupling,[73] the reaction is rendered catalytic in Cu under aerobic conditions through "scavenging" of the thiolate residue with a second sacrificial equivalent of the boronic acid. A Cu-centered transmetalation/ reductive elimination sequence generates a thioether thus removing thiolate from the reaction system and regenerating Cu I for subsequent reaction with O 2 and continuation of the catalytic cycle.A brief study of the influence of the nature of the ortho-positioned amide group on the obs...

Mobilizing Cu(I) for Carbon−Carbon Bond Forming Catalysis in the Presence of Thiolate. Chemical Mimicking of Metallothioneins

“…Since the synthesis of ketones from thiol esters and boronic acids/organostannanes is well-known, 14b,15a,17 the significance of the work described here lies not in the specific synthetic demonstration, but rather in the underlying principles of catalysis by Cu in sulfur-rich systems that are revealed by the study. The requisite thiol ester substrates ( 3 ), which bear an MT-mimicking sulfur pendant, were easily prepared by standard procedures from the stable and storable O -methyl oxime of 2-mercaptoacetophenone, 2 , which, in turn, was generated from commercially available mercaptosalicylic acid, 1 , in a straightforward fashion (Scheme 3).…”

“…This reaction system takes place aerobically and requires only catalytic quantities of Cu. 14 The aerobic 2 nd generation desulfitative reaction therefore circumvents two limitations of the 1 st generation family of reactions: it requires no Pd and it turns over using only catalytic quantities of Cu. However, this mechanistically different aerobic reaction system (which currently is limited to thiol ester reactants) imposes a new limitation by requiring a second, sacrificial equivalent of the boronic acid in order to complete the catalytic cycle.…”

“…This new anaerobic reaction system constitutes an alternative approach to known Cu-only catalysis in the presence of thiolates that is based upon aerobic Cu-thiolate chemistry. 14 …”

“…7a,13 A newer 2 nd -generation system takes place under aerobic reaction conditions, is palladium-free, and uses only catalytic quantities of Cu. 14 Organostannanes are also effective partners in desulfitative couplings. 7a,15 …”

A one-pot preparation of N-2-mercaptobenzoyl-amino amides

“…10,11,12,13,14 Liebeskind and coworkers have coupled alkyl- and aryl-amines to make disulfides analogous to 8 then cleaved the disulfide with sodium borohydride to access the reactive thiols (general structure 4 , R = -Me, -Et, - t -Bu, -aryl, -morphonlino). 15,16 Unfortunately, the free thiols of our amino-amides (general structure 7 ) were exceptionally prone to disulfide formation even under anaerobic conditions and this method was unsuccessful in our system for the preparation of pure thiols and subsequent thioesters. Although we were unable to avoid the formation of disulfide, we could drive disulfide formation to completion by modification of the workup conditions.…”