The enantioselective formation of a quaternary stereogenic center coinciding with a hydroxylation process is a very rare reaction from a homogeneous catalysis point of view. Indeed, to our knowledge, no asymmetric transition-metal-catalyzed direct hydroxylation has been reported before. We describe here our initial study concerning the enantioselective ␣-hydroxylation of various ␤-ketoesters catalyzed by Lewis-acidic complexes. Specifically, it was found that the Ti complex [TiCl2((R,R)-1-Np-TADDOLato)(MeCN)2] affords the hydroxylated products in high yield and enantioselectivities up to 94% enantiomeric excess when using 2-(phenylsulphonyl)-3-(4-nitrophenyl)oxaziridine as the oxidizing agent. Chiral enantiopure compounds of the latter type have been used previously in stoichiometric asymmetric hydroxylation reactions. We also show that, in a complementary approach with H2O2 as the oxidant, the Ru(II) complex [RuCl(OE 2)((S,S)-PNNP)]PF6 catalyzes the same type of transformation in a case of substrates showing a very substantial extent of enolization under reaction conditions; being, however, unreactive toward only weakly enolized ␤-ketoesters.R eactions involving both the formation of new carbonheteroatom bonds and the concomitant generation of a new stereogenic center are prototypical transformations in asymmetric catalysis. Thus, for example, hydroboration, hydrosilylation, epoxidation, and aziridination of olefins, as well as allylic substitutions with heteroatom nucleophiles, have been extensively studied (1). However, catalytic halogenations, in particular fluorinations, and direct hydroxylations have received much less attention in the asymmetric catalysis community.Recently, we developed an enantioselective catalytic process in which ␤-ketoesters are fluorinated at the 2-position with an electrophilic fluorine donor such as Selectfluor [also called F-TEDA (TEDA, triethylenediamine), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis{tetrafluoroborate}] in the presence of a Lewis-acidic chiral titanium catalyst (1, Scheme 1, Fig. 1 (2-5). Our work inspired further developments involving chiral Pd catalysts (6) and chiral phase transfer catalysts for the same type of fluorination (7).The ␣-hydroxycarbonyl functional unit is ubiquitous in natural products and bioactive compounds, such as, e.g., carbohydrates, antibiotics, and antitumor agents; therefore, it is also present in synthetic intermediates and in chiral auxiliaries in view of the stereodirecting ability of the hydroxy group (8). The ␣-functionalization of carbonyl compounds most often relies on the reaction of enolate anions, or enol derivatives with electrophiles. The direct activation of the enol form of keto derivatives has recently been introduced as a new synthetic methodology to achieve ␣-amination (9) or, as already mentioned, ␣-halogenation (2-5). So far, the only straightforward enantioselective ␣-hydroxylation is the reaction of enolate salts with enantiopure N-sulfonyloxaziridines, acting as electrophilic oxygen sources, as dev...

The dichloro complexes [RuCl2(1a)] (2a) and [RuCl2(1b)] (2b) with the chiral tetradentate PNNP ligands (1S,2S)-N,N ‘-bis[o-(diphenylphosphino)benzylidene]cyclohexane-1,2-diamine (1a) and (1S,2S)-N,N ‘-bis[o-(bis(4-trifluoromethylphenyl)phosphino)benzylidene]cyclohexane-1,2-diamine (1b) react with AgSbF6 (1 equiv) to give the highly reactive five-coordinate complexes [RuCl(PNNP)]SbF6 (3aSbF6 or 3bSbF6), which were characterized in solution. The reaction of 2a or 2b with AgBF4 gives [RuCl(PNNP)]BF4 along with unidentified products. Complex [RuCl(1b)]SbF6 (3bSbF6) cyclopropanates 1-octene to ethyl 2-hexylcyclopropane-1-carboxylate (up to 66% overall isolated yield) in the presence of ethyl diazoacetate with unprecedented cis-diastereoselectivity (85:15 cis:trans ratio) and with excellent enantioselectivity (up to 99 and 98% ee for the cis and trans isomers, respectively). Complex 3bSbF6 is also an excellent cis-selective cyclopropanation catalyst for styrene (96% ee for the cis isomer, 99:1 cis:trans ratio) and α-methylstyrene (96% ee for the cis isomer, 92:8 cis:trans ratio). The catalyst activity depends on the counterion and increases in the order [BF4]- < [SbF6]- < [PF6]-, whereas the best stereoselectivity is observed with [SbF6]-. Molecular modeling calculations are extended to 1-octene and α-methylstyrene and revised to account for the absolute configuration of ethyl cis-2-phenylcyclopropane-1-carboxylate (1S,2R, incorrectly reported as 1R,2S in a former paper).

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The chiral complexes [Ru(2)(PNNP)]2+ (4a) and [Ru(3)(PNNP)]2+ (4b), containing the non-enolized 1,3-dicarbonyl compounds 2-((tert-butoxy)carbonyl)cyclopentanone (2) or α-acetyl-N-benzyl-δ-valerolactam (3), were deprotonated to the enolato complexes 5a,b. Complex 4a has a pseudo-aqueous pK a value of 4.6 ± 0.5 (with pK a(Ph3PH+) = 2.7 as reference) and catalyzes the 1,4-addition of 2 to methyl vinyl ketone with up to 79% ee.

The chiral dicationic complexes [Ru(4a)(PNNP)]2+ (2a) and [Ru(4h)(PNNP)]2+ (2h, PNNP is (1S,2S)-N,N′-bis[o-(diphenylphosphino)benzylidene]cyclohexane-1,2-diamine), containing non-enolized 2-tert-butoxycarbonylcyclopentanone (4a) or α-acetyl-N-benzyl-δ-valerolactam (4h), were prepared from [RuCl2(PNNP)] (1) by double chloride abstraction with (Et3O)PF6, followed by reaction with the 1,3-dicarbonyl compound. The estimated aqueous pK a values for 2a (3.3 ± 0.3) and 2h (4.7 ± 0.1) were determined by deprotonation with Ph2NH and pyridine, respectively. The corresponding monocationic enolato complexes 3a and 3h were isolated and structurally characterized. Complex 2a catalyzes the 1,4-addition of 4a to methyl vinyl ketone with up to 93% ee when a CH2Cl2/Et2O (1:1) solvent mixture is used. Oxygen-containing cosolvents enhance both the rate and enantioselectivity of the Michael addition with a number of substrates. This observation is discussed in the context of our previous observation that the combined addition of diethyl ether and of β-keto ester 4a favors and accelerates the deprotonation of 2a in dichloromethane.