print pageprinter friendly
Reports: ND152737-ND1: Catalytic Asymmetric Carbon-Carbon Bond Formation with Fluoroenolates Generated Detylated Prenucleophiles

Christian Wolf, Georgetown University

Chiral organofluorines have become increasingly attractive synthetic and medicinal targets because they often afford superior lipophilicity, bioavailability and resistance to metabolic degradation compared to the nonfluorinated parent compounds. The incorporation of a difluoromethylene group is particularly interesting because the high electronegativity of fluorine leads to increased dipole moments, conformational changes, carbonyl hydration and reduced pKa values of adjacent functionalities. The catalytic asymmetric formation of chiral compounds with a neighboring difluoromethylene group has remained a major problem, mostly because of the difficulty with forming difluoroenolates under conditions suitable for subsequent stereocontrolled C-C bond formation.

Scheme 1. Initial analysis of the catalytic difluoromethylation of aldehydes.     To address the challenges outlined above, we investigated the possibility of catalytic enantioselective aldol reactions using aldehydes and difluoroenolates generated in situ from gem-diol 1 and its derivatives (Scheme 1). During initial NMR and ReactIR analysis of the effect of additives, base, solvent and other parameters on this reaction we found that catalytic bond cleavage of 1 and subsequent C-C bond formation toward 2 is possible in the presence of 10-20 mol% of magnesium, copper and zinc salts. However, formation of substantial amounts of by-product 3 was observed. The testing of alternative starting materials 5-7 did not improve results. After screening of several reaction conditions, we decided to apply several bisoxazoline ligands to our general reaction protocol. While the results obtained in the presence of catalytic amounts of copper(II) triflate and L2-L9 varied considerably, L10-L12 showed remarkable promise (Figure 1). We were very pleased to find that 2 is formed in almost quantitative yields and 61-68% ee within 1 h when these ligands are employed in THF. Our screening results revealed that anionic ligands exhibiting a delocalized negative charge in the backbone, in particular semicorrin L12, allow completion of the reaction within 1 h. We rationalized that such a catalytically more active catalyst would enable us to perform the reaction at lower temperature to improve the enantioselectivity while the competing protonation of the enolate to by-product 3 would remain relatively slow and thus not affect yields. We therefore further modified the ligand structure and prepared L13 and L14 (Scheme 2). A change of the relative configuration of the adjacent phenyl rings in L10 to anti-derivative L13 improved the enantioselectivity and introduction of a cyano group to the methylene bridge further increased catalytic activity and yield. With L14 in hand, we were able to decrease the catalyst loading to 5 mol% and obtained 2 as well as analogues 8-10 in up to 98% yield and 92% ee using 1.2 equivalents of benzaldehyde at 10 oC (Scheme 3).      

Figure 1. Chiral ligand screening results and MOPAC computation of the loaded catalyst (hydrogens are omitted for clarity).        

Scheme 2. Synthesis and single crystal structure of L14.

 

 

 

Scheme 3. Scope of the enantioselective aldol reaction (selected ecxample).

 

 

  We then applied a wide range of aldehydes to evaluate the reaction scope. In general, high yields and enantiomeric excess were obtained with electron-rich and electron-deficient substrates. Importantly, this method tolerates the presence of amine, ketone, ester and other functional groups, and the reaction with sterically hindered aldehydes gave 14 and 15 with 79-85% yield and 84-87% ee. Our procedure provides unprecedented asymmetric access to important chiral building blocks, including 2,2-difluoro-1,3-propanols. For example, the reduction of 8 with DIBAL produces anti-19 in high yields and with excellent diastereoselectivity (Scheme 4). This establishes a convenient entry to C1- and C2-symmetric anti-1,3-diols motifs which appear in many natural products and are of great pharmaceutical interest. Alternatively, we realized that the Baeyer-Villiger oxidation followed by mild hydrolysis affords the first asymmetric route to 2,2-difluoro-3-hydroxy carboxylic acids which are crucial precursors of several enzyme inhibitors and other biologically active compounds. Oxidation of 20 with m-CPBA to the corresponding 2-naphthoate 21 and basic hydrolysis gave 2,2-difluoro-3-hydroxy acid 22 in 85% yield and 86% ee.  

Scheme 4. Formation of a representative anti-2,2-difluoro-1,3-diol and a 2,2-difluoro-3-hydroxy acid.     In conclusion, we have introduced a practical method for the catalytic enantioselective addition of α,α-difluoroenolates to aldehydes using 5 mol% of copper(II) triflate and a new bisoxazoline ligand which can be easily prepared in two steps. High yields and enantiomeric excess were obtained with a wide range of prenucleophiles and aldehydes, including aliphatic substrates, under mild conditions and in short reaction times. The value of this reaction is highlighted by the stereoselective reduction and Baeyer-Villiger oxidation of alpha,alpha-difluoro-beta-hydroxy ketones to an anti-2,2-difluoro-1,3-propanol and a 2,2-difluoro-3-hydroxy carboxylic acid, respectively.