Exploiting Synergistic Effects in Organozinc Chemistry for Direct Stereoselective C‐Glycosylation Reactions at Room Temperature

Abstract

Pairing a range of bis(aryl) zinc reagents ZnAr with the stronger Lewis acidic [(ZnAr )] (Ar =C F ), enables highly stereoselective cross-coupling between glycosyl bromides and ZnAr without the use of a transition metal. Reactions occur at room temperature with excellent levels of stereoselectivity, where ZnAr acts as a non-coupling partner although its presence is crucial for the execution of the C(sp )-C(sp ) bond formation process. Mechanistic studies have uncovered a unique synergistic partnership between the two zinc reagents, which circumvents the need for transition-metal catalysis or forcing reaction conditions. Key to the success of the coupling is the avoidance of solvents that act as Lewis bases versus diarylzinc compounds (e.g. THF).

Formation of a hydride containing amido-zincate using pinacolborane

“…[(TMEDA) 2 Na 2 (μ-dpa) 2 Zn( t Bu) 2 ], A , and [Na(THF) 6 {Zn( t Bu) 2 (dpa)Zn( t Bu) 2 }], B ) 19 and L 2 ZnPh 2 systems, e.g. TMEDA·ZnPh 2 ) 20 and in the solid state by single crystal X-ray diffraction studies. It should be noted that 1 H DOSY NMR studies are consistent with 2 persisting as an oligomer in solution by comparison to parameters derived from 1 H DOSY studies on monomeric 4 (see ESI, Fig.…”

Towards a Paradigm Shift in Polar Organometallic Chemistry

“…In addition, in a collaboration with Janssen Pharmaceutica, we have developed a highly efficient method, which enables the diastereoselective arylation of bromosugars without the need for transition-metal catalysis while operating at room temperature (Scheme 5c). [38] This new approach relies on the stepwise cooperation of homobimetallic arylzinc mixtures, where the close interplay between two distinct zinc reagents, ZnAr 2 with the strong Lewis acid [(ZnAr F 2)] (Ar F =C 6 F 5 ) (10), enables direct C(sp2)-C(sp3) bond formation. Remarkably while it operates at room temperature, this Zn/Zn bimetallic approach offers greater levels of stereoselectivity and superior yields than those reported in the literature using transition-metal catalysis.…”

Atom-efficient transition-metal-free arylation of N,O-acetals using diarylzinc reagents through Zn/Zn cooperativity

“…Related to Knochel's work, we have reported the stereoselective cross-coupling between glycosyl bromides and ZnAr 2 reagents facilitated by Lewis acidic bis(pentafluorophenyl)zinc, Zn(C 6 F 5 ) 2 . 6 These processes are underpinned by the special cooperation between the two different types of arylzinc reagents, with Zn(C 6 F 5 ) 2 facilitating bromine abstraction of the substrate, forming a highly electrophilic oxocarbenium species that, in turn, reacts with ZnAr 2 to give the desired arylated product. Extending the scope of this Zn/Zn′ cooperative partnership beyond glycosylation reactions, here we report a new transition-metal free method to access synthetically relevant functionalised diarylmethylamines, assessing the role played by each organozinc component.…”

“… 6 By-product PhZnOMe reacts in turn with Zn(C 6 F 5 ) 2 to form (C 6 F 5 )ZnOMe (the ultimate by-product of the reaction, Scheme 1a and b ), along with the regeneration of 0.5 equivalents of ZnPh 2 and Zn(C 6 F 5 ) 2 , resulting from the redistribution of PhZn(C 6 F 5 ) ( Scheme 1b ). 6,12 The regenerated ZnPh 2 can react further with N , O -acetal, whilst the unreacted 0.5 equivalents of Zn(C 6 F 5 ) 2 enable the continued recycling of PhZnOMe that is formed in the reaction. In this regard almost identical 19 F NMR spectra are obtained when combining isolated [PhZnOMe] 4 ( 4 ) with Zn(C 6 F 5 ) 2 (0.25 : 1 ratio), or a mixture of isolated [(C 6 F 5 )ZnOMe] 4 ( 6 ), ZnPh 2 and Zn(C 6 F 5 ) 2 (0.25 : 0.5 : 0.5 ratio) (Fig.…”

“…5,11 The marked solvent effect observed in these transformations, with Lewis donor THF completely inhibiting formation of 3, supports the key role of the coordination Zn(C6F5)2 to the substrate to facilitate the arylation process. 6 By-product PhZnOMe reacts in turn with Zn(C6F5)2 to form (C6F5)ZnOMe (the ultimate by-product of the reaction, Scheme 1a and 1b), along with the regeneration of 0.5 equivalents of ZnPh2 and Zn(C6F5)2, resulting from the redistribution of PhZn(C6F5) (Scheme 1b). 6,12 The regenerated ZnPh2 can react further with N,O-acetal, whilst the unreacted 0.5 equivalents of Zn(C6F5)2 enable the continued recycling of PhZnOMe that is formed in the reaction.…”