Enantioselective synthesis of trifluoromethyl-substituted cyclopropanes

The reaction of 1-aryl-2,2,2-trifluorodiazoethanes with alkenes, catalyzed by the adamantylglycine-derived dirhodium complex Rh2(R-PTAD)4, generates trifluoromethyl-substituted cyclopropanes with high diastereoselectivity (>94%) and enantioselectivity (88->98%).     

Enantioselective Cyclopropanation Catalyzed by Gold(I)-Carbene Complexes

The formation of polysubstituted cyclopropane derivatives in the gold(I)-catalyzed reaction of olefins and propargylic esters is a potentially useful transformation to generate diversity, therefore any method in which its stereoselectivity could be controlled is of significant interest. We prepared and tested a series of chiral gold(I)-carbene complexes as a catalyst in this transformation. With a systematic optimization of the reaction conditions, we were able to achieve high enantioselectivity in the test reaction while the cis:trans selectivity of the transformation was independent of the catalyst. Using the optimized conditions, we reacted a series of various olefins and acetylene derivatives to find that, although the reactions proceeded smoothly and the products were usually isolated in good yield and with good to exclusive cis selectivity, the observed enantioselectivity varied greatly and was sometimes moderate at best. We were unable to establish any structure-property relationship, which suggests that for any given reagent combination, one has to identify individually the best catalyst.     

Stereospecific synthesis of trifluoromethyl-substituted polyfunctionalized cyclopropanes

Treatment of methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate 1 with active methylene compounds 2 in the presence of NaH as base affords a stereospecific synthetic route to trifluoromethyl substituted cyclopropanes in good yields.     

Synthesis of trifluoromethyl-substituted cyclopropanes via sequential Kharasch-dehalogenation reactions

A two-step process for the synthesis of trifluoromethyl-substituted cyclopropanes is described. Halothane, an anesthetic agent, is added to olefins in a ruthenium-catalyzed Kharasch reaction. The resulting 1,3-dihalides are converted into cyclopropanes by dehalogenation with magnesium. This procedure represents an alternative to metal-catalyzed cyclopropanations involving trifluoromethyl diazomethane.     

Enantioselective synthesis of 3-substituted-4-aryl piperidines useful for the preparation of paroxetine

The asymmetric conjugate addition reaction between 4-fluorophenylmagnesium bromide and various chiral α,β-unsaturated esters and enoylsultam substrates was explored to prepare a key intermediate useful in the preparation of paroxetine. The most selective auxiliary was found to be Oppolzer's (1S)-(−)-camphorsultam. Interestingly, the diastereoselection was opposite to that reported for acyclic enoylsultams.     

Enantioselective Oxidative Gold Catalysis Enabled by a Designed Chiral P,N‐Bidentate Ligand

A newly developed P,N‐bidentate ligand enables enantioselective intramolecular cyclopropanation by a reactive α‐oxo gold carbene intermediate generated in situ. The ligand design is based on our previously proposed structure (with a well‐organized triscoordinated gold center) of the carbene intermediate in the presence of a P,N‐bidentate ligand. A C₂‐symmetric piperidine ring was incorporated in the ligand as the nitrogen‐containing moiety. A range of racemic transformations of α‐oxo gold carbene intermediates have been developed recently, and this new class of chiral ligands could enable their modification for asymmetric synthesis, as demonstrated in this study.     

Enantioselective synthesis of paraconic acids

The development of a new method for the enantioselective synthesis of disubstituted gamma-butyrolactones is reported. Based on this strategy, the total synthesis of three paraconic acids, that is (-)-roccellaric acid, (-)-nephrosteranic acid and (-)-protopraesorediosic acid, and the formal total synthesis of (-)-methylenolactocin and (-)-protolichesterinic acid is described, which are important because of their antibiotic and antitumor properties. Key steps of the synthesis are copper(I)-catalyzed asymmetric cyclopropanations of furans, highly diastereoselective Sakurai allylations, Lewis acid or Lewis base catalyzed retroaldol/lactonization cascades, and ruthenium(II)-catalyzed, intermolecular cross metathesis reactions.     

Enantioselective intramolecular cyclopropanation of α-diazo-β-keto sulfones: asymmetric synthesis of bicyclo[4.1.0]heptanes and tricyclo[4.4.0.0]decenes

Catalytic asymmetric synthesis of some new chiral building blocks useful for natural product synthesis is described. The intramolecular cyclopropanation (IMCP) reaction of α-diazo-β-keto sulfones affording bicyclo[4.1.0]heptanes such as 9a-d is found to proceed with high enantioselectivity (93-98% ee). The yield is moderate due to the competing intramolecular C-H insertion reaction. As intramolecular C-H insertion reaction is not observed in the reaction of the substrates possessing a quaternary carbon at the allylic position, the reactions of 19a and 19b proceed with high enantioselectivity (95% ee) and yield. It was also found that the substrates possessing an ether group, such as 19a and 19b, could be used in this enantioselective IMCP reaction.