Expanding the scope of asymmetric electrophilic atom-transfer reactions: Titanium- and ruthenium-catalyzed hydroxylation of β-ketoesters

Abstract

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...

Enantioselective Ficini Reaction: Ruthenium/PNNP‐Catalyzed [2+2] Cycloaddition of Ynamides with Cyclic Enones

“…An X-ray study of enantiomerically pure tert-butyl-7-[Nbenzyl-4-methylphenylsulfonamido]-6-cyclohexyl-2-oxobicyclo[3.2.0]hept-6-ene-1-carboxylate (5 a) shows the 1R,5S absolute configuration (Figure 1), [11] and is in agreement with an attack of the ynamide from the upper enantioface of the coordinated enone (Figure 2). The shielding by one phenyl ring of the PNNP ligand ensures high enantiofacial selectivity, as we have shown for the Diels-Alder reactions with 2 a and catalyst 1/(Et 3 O)PF 6 (2 equiv), [8] as well as for the analogous saturated b-keto esters.…”

Palladium-catalysed enantioselective α-hydroxylation of β-ketoesters

“…2 Asymmetric catalytic reactions were first accomplished by Mezzetti et al, who set an important benchmark of 94% ee by using a TADDOL-Ti(IV) catalyst and N-arylsulfonyloxaziridine as oxidant. 3 To date, this was matched only by Shibata et al, who attained up to 97% ee in the reactions of cyclic substrates, by employing a catalyst generated from DPFOX/Ni(ClO 4 ) 2 and a saccharin-derived oxaziridine (Fig. 1).…”

7.07 α-Oxygenation of Carbonyl Compounds

“…This was demonstrated in the a-hydroxylation of b-ketoesters, giving enantiomeric excesses up to 94% using titanium catalysis. 69 The selectivity was, however, highly substrate-dependent and rather low for many substrates. Proline-derived organocatalysts could also be used, but only moderate selectivities were achieved.…”