Merging C–H and C–C Activation in Pd(II)-Catalyzed Enantioselective Synthesis of Axially Chiral Biaryls

Abstract

The merging of C-H and C-C bond cleavage into one single chemical process remains a daunting challenge, especially in an asymmetric manner. Herein, a Pd(II)-catalyzed enantioselective tandem C-H/C-C activation for the synthesis of axially chiral biaryls is described. Two types of simple cyclopropanes, such as vinylcyclopropanes and cyclopropanols, were used as efficient and readily available coupling partners. This catalytic system features good functional group compatibility, excellent enantiocontrol (up to >99% ee) and the first use of palladium catalyst in this process. The synthetic utility of this protocol was demonstrated by gram-scale synthesis and further synthetic transformations to access various axially chiral biaryls with high enantiopurity. Two distinct but closely related C-C cleavage pathways of cyclopropanes were achieved in the enantioselective C-H/ C-C activation process, which represents a novel platform to further utilize the ring-opening attribute of cyclopropanes in asymmetric catalysis. Preliminary mechanistic studies provide insights into the role of cyclopropanols, which may pave the way for the development of novel catalytic transformations.

Pd‐Catalyzed Atropselective C−H Olefination Promoted by a Transient Directing Group

“…A plausible mechanism was proposed based on these preliminary experiments (Figure 1). The reaction possibly proceeds by forming imine intermediate ( I ) via reversible interaction of chiral amino acid with biaryl aldehyde liberating water [8,13i] with the help of acetic acid. Intermediate I in the presence of Pd(II)‐catalyst forms axially stereo‐enriched biaryl palladacycle ( II ).…”

Transient Directing Groups in Metal−Organic Cooperative Catalysis

“…[63b] As a note, other alkylation agents can be used, such as aldehydes that can insert in the CÀ H activated rhodacycle complex yielding phthalides resulting from an in situ condensation followed by β-hydride elimination, a reaction that can even be done in an enantioselective manner when using a chiral benzylic amine as the transient directing mediator, [64] or cyclo- propanols through palladium-catalyzed ring-opening for atroposelective processes. [65] If the transient imine-directed alkylation of C(sp 2 )À H bonds in arenes provides a useful and efficient alternative to more classical processes for the synthesis of alkylated arenes, despite some processes being still of too narrow scope, the use of transient imines for the functionalization of arene C(sp 2 )À H bonds was also met with quite some success for related alkenylations that will now be overviewed.…”

“…As a note, this process was also extended to 3-arylbenzothiophenes and -furans, [63b] 2aryl-enals, N-arylindole-2-carboxaldehydes, [71,72] as well as cyclopropanols and vinylcyclopropanes as alkenylation reagents. [65] The synthetic utility of this process was further highlighted as a key step in the total synthesis of the anticancer agent TAN-1085 that featured a highly atroposelective palladium-catalyzed olefination of a properly functionalized biaryl aldehyde with butyl acrylate. In this key transformation, a Pd(OAc) 2 , L-tertleucine, silver(II) carbonate catalytic system in a mixture of HFIP and AcOH was selected to deliver the corresponding intermediate in 75 % yields and 99 % ee (Scheme 36).…”

Catalytic asymmetric synthesis of 3,4′-indole–pyrazole derivatives featuring axially chiral bis-pentatomic heteroaryls

“…3 Elegant achievements have been made in the synthesis of chiral hexatomic (6,6-)biaryl systems, in which two hexatomic aryls or heteroaryls are linked by a chiral axis. 4,5 Recently, breakthroughs in the construction of 5,6-biaryl systems have also been achieved. 6,7…”