Catalytic highly enantioselective alkylation of aldehydes with deactivated grignard reagents and synthesis of bioactive intermediate secondary arylpropanols.
Because of the high reactivity of Grignard reagents, a direct, highly enantioselective Grignard reaction with aldehydes has rarely been disclosed. In this report, Grignard reagents were introduced with bis[2-(N,N'-dimethylamino)ethyl] ether (BDMAEE) to effectively deactivate their reactivity; thus, a highly enantioselective alkylation of aldehydes with Grignard reagents resulted from catalysis by (S)-BINOL-Ti(O(i)Pr)(2). It is thought that BDMAEE chelates the in situ generated salts MgBr(2) from a Schlenk equilibrium of RMgBr and Mg(O(i)Pr)Br from transmetalation of RMgBr with Ti(O(i)Pr)(4). The Mg salts can actively promote the undesired background reaction to give the racemate. The chelation definitely inhibits the catalytic activity of the Mg salts, suppresses the unwanted background reaction, and enables the highly enantioselective addition catalyzed by (S)-BINOL-Ti(O(i)Pr)(2). Consequently, the Mg salt byproducts were not removed, less Ti(O(i)Pr)(4) than RMgBr was used, and extremely low temperature was avoided in this catalytic asymmetric reaction in comparison with the research disclosed before. Various alkyl Grignard reagents were investigated in the asymmetric addition, and (i)BuMgBr resulted in the highest enantioselectivity, >99%. Furthermore, important intermediate secondary arylpropanols for chiral drug synthesis were effectively synthesized with high enantioselectivity, up to 97%, in one step.
Liu
Yi
Y
Institute of Biochemistry & Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, People’s Republic of China.
Da
Chao-Shan
CS
Yu
Sheng-Li
SL
Yin
Xiao-Gang
XG
Wang
Jun-Rui
JR
Fan
Xin-Yuan
XY
Li
Wei-Ping
WP
Wang
Rui
R
D000447:Aldehydes / Q000737:chemistry*; D000478:Alkylation; D002384:Catalysis; D008024:Ligands; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D020005:Propanols / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D000447:Aldehydes; D008024:Ligands; D009942:Organometallic Compounds; D020005:Propanols