Enantioselective Dicarbofunctionalization of Unactivated Alkenes by Palladium‐Catalyzed Tandem Heck/Suzuki Coupling Reaction

Abstract

A highly enantioselective dicarbofunctionalization of unactivated alkenes was implemented by a Pd‐catalyzed asymmetric tandem Heck/Suzuki coupling reaction. This reaction represents the first example of a highly enantioselective intramolecular cyclization/cross‐coupling of olefin‐tethered aryl halides with alkyl‐, alkenyl‐ or arylboronic acids, and provides rapid access to a number of chiral compounds, such as dihydrobenzofurans, indolines, chromanes, and indanes bearing a quaternary stereocenter, in good yields with excellent enantioselectivities. The practicality of this reaction was validated in the modification of biologically complex molecules such as peptides, piperitol, CB2 receptor agonists, etc. Moreover, the synthesis of two enantiomers can be easily realized by simple change in the order of the steps in the coupling sequence.

Enantioselective Difunctionalization of Alkenes by a Palladium‐Catalyzed Heck/Sonogashira Sequence

“…With the N ‐allyl carboxamide 1 a and phenylacetylene ( 2 a ) as the model substrates, we conducted a preliminary study with commercially available chiral ligands such as ( R )‐SEGPHOS ( L1 , 11 % ee ), ( R )‐DTBM‐SEGPHOS ( L2 , racemic), ( R )‐BTFM‐BIPHEP ( L3 , 2 % ee ), ( R )‐BINAP ( L4 , 3 % ee ), ( R , R )‐DIOP ( L5 , 37 % ee ), phosphoramidite ligands ( L6 , 3 % ee ), ( R , S )‐ i Pr‐FOXAP ( L7 , NR), and ( S )‐ i PrPHOS ( L8 , NR) in toluene (80 °C) for 48 h with Pd(OAc) 2 as the precatalyst and Cs 2 CO 3 as the base, but no satisfactory results were obtained (see Table S1 and the Supporting Information for details). We then examined the performance of a series of Sadphos (Ming‐Phos, Xiang‐Phos, Xu‐Phos, and PC‐Phos) ligands in this asymmetric reaction (Figure ). Whereas the use of PC‐Phos ( PC1 ), Xiang‐Phos ( X1 , N ‐Me‐X1 ), and Xu‐Phos ( Xu1 , N ‐Me‐Xu1 ) still led to low enantioselectivity, Ming‐Phos ( M1 ) with a phenyl ring gave moderate enantioselectivity.…”

“…The groups of Fu and Brown developed Ni‐ or Cu‐catalyzed highly enantioselective aryl‐alkylation and diarylation reactions of aryl‐Bpin/9‐BBN‐tethered olefins with alkyl or aryl halides (Scheme A), respectively. Only very recently, highly enantioselective diarylation, aryl‐alkylation, and aryl‐alkenylation reactions of alkenes were implemented by Ni‐ or Pd‐catalyzed asymmetric tandem Heck/cross‐coupling reactions of aryl‐halide‐tethered alkenes with organohalides (Scheme B) and organoboronic acids (Scheme A) . Alternatively, cross‐couplings of in situ generated σ‐alkyl Pd II intermediates instead of alkyl halides with terminal alkynes have emerged as an elegant strategy for the synthesis of racemic alkyl‐substituted internal alkynes .…”

“…Transition metal (TM)‐catalyzed dicarbofunctionalization reactions of alkenes via σ‐alkyl Pd II intermediates followed by nucleophilic trapping has attracted much attention . Meanwhile, we recently developed palladium‐catalyzed asymmetric hydroarylation, aryl‐iodination, and dicarbofunctionalization reactions of alkenes. However, the more challenging Heck/Sonogashira reaction of alkenes with terminal alkynes for the construction of valuable chiral alkyl‐substituted internal alkynes has not been realized thus far.…”

Dimeric Manganese‐Catalyzed Hydroarylation and Hydroalkenylation of Unsaturated Amides

“…Compared to arylboronic acids, alkenyl boronic acids have rarely been studied in manganese catalysis . The major challenge in the reaction stems from the facile protodemetalation side reactions that occur as a result of the high reactivity of metal alkenyl compounds.…”

Ming‐Phos/Gold(I)‐Catalyzed Stereodivergent Synthesis of Highly Substituted Furo[3,4‐d][1,2]oxazines†

“…Therefore, the simple and easily prepared chiral ligands with multi sites for modification are highly desirable. Recently, our group developed a new type of SadPhos (Ming‐Phos, Xiang‐Phos, PC‐Phos, Xu‐Phos, WJ‐Phos and Xiao‐Phos), which have diverse sites for modification and could be easily prepared in good yields from inexpensive commercially available chiral tert ‐butylsulfinamide and could be applied to address many challenging reactions. For example, we reported a gold‐catalyzed diastereo‐ and enantioselective [3+3] cycloaddition of 2‐(1‐alkynyl)‐2‐alken‐1‐ones with nitrones to afford an efficient synthetic route to construct chiral highly substituted furo[3,4‐ d ][1,2]oxazines (Scheme ) [5a] .…”