Recent Advances in the Catalytic Asymmetric Construction of Phosphorus-Substituted Quaternary Carbon Stereocenters

Abstract

Phosphorus-substituted quaternary carbon stereocenters exist widely in drugs and biologically active compounds. Catalytic asymmetric synthesis of such quaternary carbon stereogenic centers is of significant importance, with four synthetic strategies being established. This review summarizes the recent progress in this field, including the advantages and limitations of each strategy, briefly discusses the reaction mechanisms and challenges, and outlines synthetic opportunities still open.1 Introduction2 Asymmetric Hydrophosphonylation3 Asymmetric Electrophilic Phosphination4 Asymmetric Functionalization of P-Substituted Methine Compounds5 Asymmetric Addition to α-Keto- or α-Ketiminophosphonates6 Conclusion

Recent Advances in the Construction of Phosphorus‐Substituted Heterocycles, 2009–2019

“…Secondly, the synthesis of chiral phosphorus‐substituted heterocycles is highly desirable, but remains very limited. Currently, the catalytic asymmetric phospha‐Michael, phospha‐Mannich [80.81,89,90,92] and phospha‐aldol reactions have demonstrated broad applications in the construction of enantioenriched phosphorus‐substituted heterocycles featuring a phosphorus‐containing stereocenter . Some reactions involving heterocycle ring formation based on phosphorus compounds bearing C( sp 3 )−P and C( sp 2 )−P bonds have also been employed to synthesize optically active carbon‐centered and phosphorus‐centered phosphorus‐substituted heterocycles.…”

“…Although several methods have been developed toward chiral α‐aminophosphonic acid derivatives, only few asymmetric approaches to cyclic α‐aminophosphonic acids are available, despite their prominent abundance in biologically active molecules . In 2016, the Mukherjee group utilized silyl phosphites as higly reactive phosphorus nucleophiles to realize the enantioselective dearomatization of isoquinolines via the acyl activation and nucleophilic addition of silyl phosphites to synthesize optically chiral cyclic phosphorylated α‐aminophosphonates (Scheme ) .…”

“…Recently, Wojaczyńska and Olszewski reported a catalyst‐free asymmetric phospha‐Mannich reaction of substituted hexahydroquinoxalin‐2(1 H )‐one derivatives, leading to new chiral bicyclic aminophosphonates 258 containing a phosphorus‐substituted quaternary stereogenic center (Scheme ) . Further research revealed that the use of the commercially available and stable P(OTMS) 3 could improve the dr value up to >98:2.…”

“…The groups of Guo and Peng have recently demonstrated that α‐substituted diazophosphonates 446 could be also employed in the asymmetric 1,3‐dipolar cycloaddition with 3‐acryloyl‐2‐oxazolidinone 454 under the catalysis of a chiral Mg(II)/BOX complex, which provided an efficient procedure for the synthesis of chiral 5,5‐disubstituted 1 H ‐pyrazoline‐5‐phosphonates 455 in good yields with excellent ee values (Scheme ) . This reaction allowed the construction of highly functionalized pyrazolines 455 with a phosphorus‐substutited quaternary center, which could be further converted to pyrazolidine and bicyclic pyrazolidine derivatives.…”

Catalyst‐Dependent Chemoselective Formal Insertion of Diazo Compounds into C−C or C−H Bonds of 1,3‐Dicarbonyl Compounds

“…2‐Naphthyl‐ ( 1 p ), 2‐thienyl‐ ( 1 q ), and 3‐indolyl‐substituted ( 1 r ) diazoacetates also proved to be suitable reaction partners, and the connectivity of 3 r was confirmed by single‐crystal X‐ray analysis . The present method was not restricted to α‐diazoesters, with diazophosphonates 1 s and 1 t also reacting efficiently to afford products 3 s and 3 t , featuring a phosphorus‐substituted α‐quaternary center . Relatively non‐stabilized diazo compounds, such as (1‐diazo‐2,2,2‐trifluoroethyl)benzene ( 1 u ), the sterically hindered substrate diphenyldiazomethane ( 1 v ), and tricyclic 9‐diazo‐9 H ‐fluorene ( 1 w ), were also compatible with the reaction conditions, delivering 3 u – 3 w in 45–77 % yield.…”