Ambient Temperature Synthesis of High Enantiopurity N-Protected Peptidyl Ketones by Peptidyl Thiol Ester−Boronic Acid Cross-Coupling

Abstract

Abstractα-Amino acid thiol esters derived from N-protected mono-, di-, and tripeptides couple with aryl, π-electron-rich heteroaryl, or alkenyl boronic acids in the presence of stoichiometric Cu(I) thiophene-2-carboxylate (CuTC) and catalytic Pd 2 (dba) 3 /triethylphosphite to generate the corresponding Nprotected peptidyl ketones in good to excellent yields and in high enantiopurity. Triethylphosphite plays a key role as a supporting ligand by mitigating an undesired palladium-catalyzed decarbonylation-β-elimination of the α-amino thiol esters. The peptidyl ketone synthesis proceeds at room temperature under non-basic conditions and demonstrates a high tolerance to functionality.

Expanding Roles for Organoboron Compounds – Versatile and Valuable Molecules for Synthetic, Biological and Medicinal Chemistry

“…[14] This chemistry has dramatically expanded the utility of organoboron compounds in synthetic and medicinal chemistry, and in the synthesis of new organic materials. In addition to many applications and new improvements in the Pd-catalyzed Suzuki coupling, [4,5,[15][16][17] several additional metal-catalyzed processes involving organoboron compounds were also developed in recent years, including: the Heck-type Pd-catalyzed cross-coupling with alkenes, [18,19] the Rhcatalyzed 1,2 addition to aldehydes or imines and 1,4 addition to unsaturated carbonyl compounds, [4,20] the Rh-catalyzed addition to alkenes or alkynes, [20] the Ni-catalyzed coupling with alkynes and imines, [21] the Cu-catalyzed cross-coupling forming C-O and C-N bonds, [22] the Pd/Cu catalyzed cross-coupling with thioesters, [23] and various metal-catalyzed methods for the C-H borylation and further transformation of aromatic compounds. [24][25][26] …”

New Synthetic Strategy for High‐Enantiopurity N‐Protected α‐Amino Ketones and their Derivatives by Asymmetric Hydrogenation

“…[4] Extensive efforts have been made on the construction of enantiopure a-amino ketones starting from chiral amino acids derivatives. [5][6][7] These metal-catalyzed coupling reactions now have achieved a sophisticated level in terms of mild reaction conditions, high enantiopurity and broad substrate scope. [6,7] Yet, one of the most significant challenges remains: stoichiometric or excess chiral reagents are required and consumed.…”

“…[5][6][7] These metal-catalyzed coupling reactions now have achieved a sophisticated level in terms of mild reaction conditions, high enantiopurity and broad substrate scope. [6,7] Yet, one of the most significant challenges remains: stoichiometric or excess chiral reagents are required and consumed. Herein, we address a new strategy to solve this issue: asymmetric hydrogenation of readily accessible and highly modular a-dehydroamino ketones as a direct entry to chiral a-amino ketones and their derivatives.…”

Copper‐Catalyzed CC Coupling of Thiol Esters and Boronic Acids under Aerobic Conditions

“…[8] In the past few years the usefulness of this Pd-catalyzed, Cu I -mediated C À C cross-coupling method in the absence of a base (generally referred to as Liebeskind-Srogl reaction) [9] has been explored. Successful CÀC bond formation with either boronic acids or organostannanes has been achieved for a wide variety of thioorganic starting materials such as peptidylthiol esters, [10] heteroaromatic thioethers, [11] benzylthiocyanates, [12] thioalkynes, [13] bis(arylthiobutenediones), [14] methyl thiopseudourea derivatives, [15] and cyclic thioamides. [16] Two recent applications of the Liebeskind-Srogl ketone synthesis for the preparation of the natural products (À)-d-erythro-sphingosine [17] and litseaverticillol B [18] are highlighted in Scheme 2.…”