Optically active organofluorine compounds are attractive in both modern pharmaceutical chemistry and materials science, [1] especially the simple chiral vicinal fluorohydrins that are employed as important building blocks in the synthesis of polyfunctional bioactive molecules.[2] Fluorinated malonates with a fluorine atom at a quaternary carbon center are a class of versatile and important monofluorinated chiral synthons [2] utilized in the synthesis of liquid crystals, [3] antitumor agents, [4] enzyme inhibitors, [5] antiviral agents, [6a] antibiotics, [6b] and anti-Alzheimer agents.[6c] A variety of enantioselective syntheses of fluorinated compounds have been developed for the elaboration of optically active fluorinated malonates, as well as their synthetic equivalents such as vicinal fluorohydrins and fluorinated half hydroxy esters.[2] These approaches include the enzymatic desymmetrization of substituted 2-fluoromalonic diesters, 2-fluoropropane-1,3-diols, and 2-fluoro-1,3-diacetoxypropane derivatives, which lead in each case to similar 2-fluorinated synthons (Scheme 1). [2,7] These microbial transformations are more practical than the chemical approaches [8] for obtaining the target compounds; unfortunately, the resulting enantioselectivity is highly dependent on the substrate and thus significantly limits the applicability of this process.We have recently reported a highly enantioselective fluorination [9] of b-keto esters and oxindoles catalyzed by BoxÀPh/Cu(OTf) 2 or DBFOXÀPh/Ni(ClO 4 ) 2 (Box = bisoxazoline, Tf = triflate, DBFOX = 4,6-dibenzofurandiyl-2,2'-bisoxazoline. [9a, b] In response to the limitations associated with the use of microbial desymmetrization for the preparation of chiral fluorinated malonates and hydroxy esters, we have now extended our protocol to the desymmetrization-like enantioselective fluorination of malonates 1 and herein show that a DBFOXÀPh/Zn(OAc) 2 complex is an effective catalyst to give the optically active 2-fluorinated malonates 2 with very high enantioselectivity (up to 99 % ee). The 2-fluoromalonates 2 can be selectively converted into 2-fluorinated hydroxy esters 3. The synthetic utility of the method was demonstrated by the syntheses of pharmaceutically attractive compounds, namely, chiral fluorinated a-benzyl-b-alanine 4, fluorinated b-lactam 5, and fluoro-alacepril (6); Scheme 2. The synthesis of an HIV-1 protease inhibitor was also achieved through the chemoselective ester-amide exchange reaction of chiral malonates 2.Diastereoselective fluorination of malonates has been reported by Fukumoto and co-workers.[8b-d] l-Menthylphenyl esters of malonates were fluorinated with fluoropyridinium triflate in high yield with moderate diastereoselectivities by Scheme 1. Enzymatic desymmetrization approach for the synthesis of simple fluorinated synthons.Scheme 2. Desymmetrization-like approach for the synthesis of 2 and its application to pharmaceutically attractive molecules.

Optically active organofluorine compounds are attractive in both modern pharmaceutical chemistry and materials science, [1] especially the simple chiral vicinal fluorohydrins that are employed as important building blocks in the synthesis of polyfunctional bioactive molecules.[2] Fluorinated malonates with a fluorine atom at a quaternary carbon center are a class of versatile and important monofluorinated chiral synthons [2] utilized in the synthesis of liquid crystals, [3] antitumor agents, [4] enzyme inhibitors, [5] antiviral agents, [6a] antibiotics, [6b] and anti-Alzheimer agents.[6c] A variety of enantioselective syntheses of fluorinated compounds have been developed for the elaboration of optically active fluorinated malonates, as well as their synthetic equivalents such as vicinal fluorohydrins and fluorinated half hydroxy esters.[2] These approaches include the enzymatic desymmetrization of substituted 2-fluoromalonic diesters, 2-fluoropropane-1,3-diols, and 2-fluoro-1,3-diacetoxypropane derivatives, which lead in each case to similar 2-fluorinated synthons (Scheme 1). [2,7] These microbial transformations are more practical than the chemical approaches [8] for obtaining the target compounds; unfortunately, the resulting enantioselectivity is highly dependent on the substrate and thus significantly limits the applicability of this process.We have recently reported a highly enantioselective fluorination [9] of b-keto esters and oxindoles catalyzed by BoxÀPh/Cu(OTf) 2 or DBFOXÀPh/Ni(ClO 4 ) 2 (Box = bisoxazoline, Tf = triflate, DBFOX = 4,6-dibenzofurandiyl-2,2'-bisoxazoline. [9a, b] In response to the limitations associated with the use of microbial desymmetrization for the preparation of chiral fluorinated malonates and hydroxy esters, we have now extended our protocol to the desymmetrization-like enantioselective fluorination of malonates 1 and herein show that a DBFOXÀPh/Zn(OAc) 2 complex is an effective catalyst to give the optically active 2-fluorinated malonates 2 with very high enantioselectivity (up to 99 % ee). The 2-fluoromalonates 2 can be selectively converted into 2-fluorinated hydroxy esters 3. The synthetic utility of the method was demonstrated by the syntheses of pharmaceutically attractive compounds, namely, chiral fluorinated a-benzyl-b-alanine 4, fluorinated b-lactam 5, and fluoro-alacepril (6); Scheme 2. The synthesis of an HIV-1 protease inhibitor was also achieved through the chemoselective ester-amide exchange reaction of chiral malonates 2.Diastereoselective fluorination of malonates has been reported by Fukumoto and co-workers.[8b-d] l-Menthylphenyl esters of malonates were fluorinated with fluoropyridinium triflate in high yield with moderate diastereoselectivities by Scheme 1. Enzymatic desymmetrization approach for the synthesis of simple fluorinated synthons.Scheme 2. Desymmetrization-like approach for the synthesis of 2 and its application to pharmaceutically attractive molecules.

The Conia-ene reaction of acetylenic b-dicarbonyl compounds represents one of the most direct methods for the formation of carbocycles, [1] and is particularly attractive for the preparation of cyclopentane derivatives. Although the classical method of the Conia-ene reaction has some limitations in its application because of the harsh experimental conditions [1,2] such as high temperature, strong base, strong acid, or photochemical activation, recent advances in the use of transition-metal catalysis [3] and organocatalysis [4] have dramatically expanded the diversity of this reaction. In 2005, the first enantioselective intramolecular Conia-ene reaction of b-ketoesters was reported by Toste and coworkers using a palladium(II)/ytterbium(III) catalyst system. [5] This work brought the enantioselective Conia-ene reaction to the attention of a number of organic chemists worldwide, and two more methods have since appeared. [6] However, all the enantioselective methods are limited to the 5-exo-dig cyclization of b-dicarbonyl compounds with terminal alkynes. An endocyclic variant of the Conia-ene reaction, that is, 5-endo-dig cyclization of b-dicarbonyl compounds with internal alkynes, is still a challenge (Scheme 1), although the transition-metal-catalyzed 5-endo-dig addition of heteroatom nucleophiles to internal alkynes are common. [7] In 2004, Toste and co-workers achieved a rare example of the gold(I)-catalyzed 5-endo-dig carbocyclization of 1,3dicarbonyl compounds with internal alkynes to provide cyclopentene adducts in high yields. [8] They surveyed several cationic group 11 metal triflates including copper(I) and silver(I) triflates as catalysts for the cyclization of b-ketoesters with internal alkynyl substituents, but only triphenylphosphine/gold(I) triflate gave the desired cyclization products. The gold(I)-catalyzed 5-endo-dig carbocyclization reported by Toste and co-workers is amenable to a wide range of b-ketoesters having an alkynyl unit, however, the corresponding asymmetric variants are difficult and give racemic products. [5] Meanwhile, we have been engaged for several years in the development of enantioselective a-functionalization of bdicarbonyl compounds as represented by enantioselective fluorination and hydroxylation reactions using nickel(II), zinc(II), or copper(II) complexes with a chiral 4,6-dibenzofurandiyl-2,2'-bis(4-phenyloxazoline) (DBFOX-Ph) or a 2,2'isopropylidinebis(4-phenyl-2-oxazoline) (Box-Ph) ligand. [9,10] As a part of this research program for the metal-catalyzed enantioselective functionalization of 1,3-dicarbonyls, we started to investigate the enantioselective 5-endo-dig cyclization of b-dicarbonyl compounds with internal alkynes. Before the completion of our work, a single example of an enantioselective 5-endo-dig cyclization of a substrate bearing an internal alkyne was reported (65 % yield with 52 % ee) in a paper focusing on an asymmetric exocyclic Conia-ene reaction of b-dicarbonyl compounds using a La/Ag heterobimetallic catalyst. [6b] On the basis of the work by T...

We examined the catalytic enantioselective fluorination of 3-(2-arylacetyl)-2-thiazolidinones 1 with N-fluorobenzenesulfonimide (NFSI) by DBFOX-Ph/metal complexes under a variety of conditions. After optimization of the metal salts, solvents and additives, we found that the fluoro-2-thiazolidinones 2 were obtained in good to high yields with moderate to good enantioselectivities (up to 78% ee) when the reaction was carried out in the presence of DBFOX-Ph (11 mol%), Ni(ClO 4 ) 2 ·6H 2 O (10 mol%) and 2,6-lutidine (0 or 1.0 equiv) in CH 2 Cl 2 .

Chiral a-hydroxy malonates and their equivalents are a valuable class of compounds utilized in the synthesis of drug candidates such as chlozolinate and bicalutamide.[1] The synthesis of these compounds has been achieved by the enzymatic desymmetrization of prochiral malonate derivatives, [1a,d, 2] or by the enzymatic and chemical desymmetrization of prochiral glycerols. [1b,c, 3] Although in recent years significant progress has been made in the development of the catalytic asymmetric a-hydroxylation reaction of carbonyls, [4][5][6] there have been no reports of catalytic enantioselective hydroxylation of malonate derivatives in the literature, and the reaction remains a challenge. Recently we reported the desymmetrization-like enantioselective fluorination of malonate derivatives in the presence of an (R,R)-DBFOX-Ph/Zn II complex, [7,8] where chiral a-fluorinated malonate derivatives [9] were obtained in high yields with high enantioselectivities. Herein, we present the first dynamic kinetic asymmetric transformation in the a-hydroxylation of racemic malonate 1 using the (R,R)-DBFOX-Ph/Ni II complex with oxaziridine 3 a to provide the chiral a-hydroxy malonate 2, which has a quaternary stereocenter, in high yield with a high enantioselectivity of up to 98 % ee (Scheme 1). Application of this reaction to the synthesis of biologically attractive molecules illustrates the efficiency of this strategy.First, we attempted the direct a-hydroxylation of racemic 2-benzyl-tert-butyl methyl malonate (1 a) with oxaziridine 3 a under the best reaction conditions previously reported for the enantioselective fluorination of malonate derivatives: [7] the reaction was carried out in the presence of Zn(OAc) 2 and molecular sieves (M.S. 4 ) in CH 2 Cl 2 at room temperature. However, even after 24 hours, the reaction did not proceed (Table 1, entry 1). Under reflux the corresponding 2-hydroxy-2-benzyl-tert-butyl methyl malonate (2 a) was obtained in 15 % yield with 92 % ee (Table 1, entry 2). When the reaction was performed in the presence of Ni(ClO 4 ) 2 ·6 H 2 O in CH 2 Cl 2 at reflux, the yield was improved to 60 % with 91 % ee (Table 1, [c]