Cinchona‐Alkaloid‐Catalyzed Enantioselective Direct Aldol‐Type Reaction of Oxindoles with Ethyl Trifluoropyruvate

Abstract

Heterocycles that contain a trifluoromethyl group are important compounds in agricultural and medicinal chemistry. Therefore, the development of a simple and flexible method for the generation of trifluoromethylated heterocyclic systems has received much attention.[1] We believed that the incorporation of a tertiary a-trifluoromethyl alcohol stereocenter (CF 3 C*(OH)R 1 R 2 ) into heterocycles could provide novel drug candidates with unusual biological activities as a result of the unique properties of the tertiary a-trifluoromethyl alcohol functionality.[2] We first became interested in the development of general methods for the synthesis of oxindoles with a tertiary a-trifluoromethyl alcohol moiety in a chiral environment. Oxindoles with a quaternary stereogenic center, especially spirooxindoles, are of potential medicinal interest owing to the unique biological activities of natural products and man-made compounds that contain such systems.[3] As part of our ongoing studies in medicinal fluorine chemistry, [4] we describe herein the highly enantioselective synthesis of oxindoles 3 with two contiguous asymmetric quaternary carbon atoms, including a tertiary a-trifluoromethyl alcohol center, [5] by an asymmetric direct aldol-type condensation of oxindoles with ethyl 3,3,3-trifluoropyruvate (2) under the catalysis of cinchona alkaloids.[6] The two enantiomeric products (S,S)-3 and (R,R)-3 are accessible selectively in high yields with up to 99 % ee with pseudoenantiomeric cinchona alkaloids (Scheme 1).Trifluoropyruvate is one of the most versatile building blocks for the synthesis of chiral trifluoromethylated compounds. Examples of enantioselective nucleophilic addition to trifluoropyruvate in the Friedel-Crafts reaction, the aldol reaction, the Henry reaction, and the carbonyl-ene reaction under the catalysis of chiral Lewis acids, cinchona alkaloids, or proline derivatives have been reported. [7] However, there is no information available on the use of oxindoles as nucleophiles in the corresponding asymmetric addition reactions. We first attempted the enantioselective aldol-type reaction of 3-methyl-2-oxindole (1 a; R 1 = Me, R 2 = H; Scheme 1) with 2 in the presence of cinchonidine as a catalyst.Cinchonidine was found to be an effective catalyst for the enantioselective Friedel-Crafts reaction of indoles reported by Prakash and co-workers; [7e] however, in the direct aldoltype reaction of 1 a with 2, the adduct 3 a was obtained in 67 % yield with poor diastereoselectivity and 50 % ee (Table 1, entry 1). At best only a slight improvement in the diastereomeric ratio and enantioselectivity was observed with other Scheme 1. Aldol-type reaction of oxindoles 1 with ethyl trifluoropyruvate (2) under the catalysis of cinchona alkaloids.

Organocatalysis

“…Toru has reported a related system for the reaction of oxindoles with ethyl trifluoropyruvate using the modified chinchona alkaloids (DHQD) 2 PHAL and (DHQ) 2 PHAL (Scheme 10). 20 Excellent levels of enantiomeric excess were observed and application of this methodology towards the core component of surugatoxin was achieved. Vincent and Landais have reported the enantioselective synthesis of a range of unnatural isotetronic acids using the aldol reaction between α-oxocarboxylic acids and aldehydes (Scheme 11).…”

Highly Enantioselective Synthesis of 3‐Amino‐2‐oxindole Derivatives: Catalytic Asymmetric α‐Amination of 3‐Substituted 2‐Oxindoles with a Chiral Scandium Complex

“…The other oxindoles were prepared according to the literature and references therein. [11][12][13][14][15][16] The N,N'-dioxide ligands were prepared according to the literature. [19] General procedure for the enantioselective a-amination of 3-substituted oxindoles with azodicarboxylates: N,N'-dioxide L6 (4.9 mg, 0.0075 mmol), scandium triflate (2.5 mg, 0.005 mmol), 3-methyloxindole (1 a; 14.7 mg, 0.10 mmol), and 4 molecular sieves (5 mg) were stirred in a dry reaction tube in CH 2 Cl 2 (1.0 mL) under nitrogen at 30 8C for 0.5 h and then cooled to À20 8C, at which point diisopropylazodicarboxylate (2 a; 20 mL, 0.1 mmol) was added.…”

“…[9] Furthermore, the application of prochiral 3-substituted oxindoles as nucleophiles provides a very simple and straightforward approach for the synthesis of optically active 3-amino-2-oxindole derivatives with a chiral quaternary center, and studies in this field have received special attention because oxindoles bearing C3-quaternary structures are widely distributed in a number of natural products and pharmaceutical molecules. [10] Several catalytic asymmetric reactions of 3-substituted oxindoles, including the aldol reaction, [11] conjugate addition reaction, [12] Mannich reaction, [13] fluorination, [14] and other types of reaction, [15] have been successively reported. However, relatively fewer examples have been documented for catalytic asymmetric a-amination of oxindoles, which is very useful for the generation of quaternary 3-amino-2-oxindole alkaloid compounds.…”

Catalytic Asymmetric Synthesis of Enantioenriched Heterocycles Bearing a CCF3 Stereogenic Center

“…Toward installing some unique chiral CF 3 -substituted heterocycles for drug surrogates, Shibata et al harnessed the bis-electrophilic nature of trifluoropyruvate 117 and elaborated a cinchona alkaloid/Ti(OiPr) 4 -catalyzed enantioselective tandem condensation-cyclization reaction of cyclic enamines 116 with diverse structures. [100] In the presence of different types of cinchona alkaloids, a range of highly substituted unsaturated g-lactam-cyclohexanones or g-lactam-dlactones featuring a conjugated enamine functionality were accessed in high yields (up to 99 %) along with good levels of enantioselectivity (up to 93 %), which facilitated the multipleoutput of several fused polycyclic heterocycles with interseting structures containing a trifluoromethylated lactam substructure (119-121) in few steps. In some cases, the target heterocycles with both enantiomers were generated by just tuning the configuration of the cinchona alkaloid (Scheme 37).…”