Chiral Michael addition: methyl vinyl ketone addition catalyzed by Cinchona alkaloid derivatives

Abstract

Chiral Michael additions of methyl vinyl ketone (MVK) to indanone 2-carboxylic esters are well precedented in the literature.1 However, many of these methods are not applicable to 2-alkylindanones such as 1, containing a proton less acidic than the /3-keto ester.2 Here we report j.®-a an addition of MVK to indanone 1 catalyzed by the quaternary salts of Cinchona alkaloids in 95% yield and up to 80% enantiomeric excess (ee). This chiral Michael addition,3 followed by aldol condensation to complete the Robinson annelation, was the key step in our preparation of drug candidate 3.4 Cinchona alkaloids are not basic enough to catalyze Michael additions to the 2-propylindanone 1. Wynberg reportslb that the corresponding quaternary salts are not as effective as catalysts as the free bases.5 However, excellent results have been obtained in these laboratories in phase-transfer alkylations with quaternary Cinchona alkaloid catalysts6 leading to a synthesis of 3 employing

Cinchona‐Catalyzed Nucleophilic Conjugate Addition to Electron‐Deficient CC Double Bonds

“…Conn and coworkers conducted the Michael addition of 2-propyl-1-indanone (13) to methyl vinyl ketone under biphasic conditions (aq 50% NaOH/toluene) using the cinchonine/cinchonidine-derived chiral phase-transfer catalysts (PTCs), 14a and 14b, as a catalyst (Scheme 9.5). However, only low to moderate ee values were obtained (40-80% ee) [6]. Of note, the parent cinchona alkaloids are not basic enough to catalyze this reaction, since 2-alkylindanones contain a less acidic proton than the b-keto esters.…”

Enantioselective Organocatalysis

“…[139] Furthermore, it was demonstrated that substrates with stronger electron-withdrawing substituents on the adjacent position increase the catalyst selectivity. [140] In particular, the alkylation of the tert-butylglycinatebenzophenone Schiff base, [143] which is considered to form a tight catalyst ± substrate complex, gave impressive results. A series of natural and unnatural a-amino acid derivatives were prepared with enantioselectivities of up to 400:1 by using catalyst 46 d (Scheme 39).…”

“…The use of 47 a, b (R CF 3 ; X Br) as catalysts in the enantioselective alkylation reaction was shown to be particularly efficient in the construction of quaternary carbons. [143] The therapeutically useful GABA B receptor agonist (R)-baclofen´HCl was prepared by using the enantioselective Michael addition of nitromethane to the chalcone-derived a,b-unsaturated ketone. [144] Also, 9-anthracenylmethyl-substituted cinchonidium chloride 47 c (X Cl) mediated the addition of the dimethyl malonate anion to a cyclopentanone derivative in the enantioselective synthesis of methyl-dihydrojasmonate (Scheme 40).…”

Phase‐Transfer Catalysis

“…As part of a research effort for the stereoselective functionalization of indanone derivative 1, the Merck group reported the Michael addition of 1b to MVK 49 catalyzed by their original catalyst 2a, which proceeded smoothly in toluene-50% aqueous NaOH to give diketone 56b in 95% yield with 80% ee (Scheme 10.21) [27]. This approach can be extended to the reaction of phenylindanone derivative 1a with 49, though the chemical yield and enantioselectivity were only moderate as indicated in Scheme 10.21 [28].…”

“…The proper choice of the achiral palladium ligand (PhO) 3 P was crucial to achieving high enantioselectivity, but with no chiral phosphine ligand on palladium, the Other types of chiral phase-transfer catalysis are also employable for the enantioselective alkylation of alanine-derived imines 24. Enantiopure (4R,5R)-or (4S,5S)-2,2-dimethyl-, , , -tetraphenyl-1,3-dioxolane-4,5-dimethanol (26, TAD-DOL) and 2-hydroxy-2 -amino-1,1 -binaphthyl (27,NOBIN), upon in situ deprotonation with solid NaOH or NaH, act as chiral bases [16,17]. Their chelating ability toward the sodium cation is crucial for making the sodium enolate soluble in toluene as well as for achieving the enantiofacial differentiation in the transition state (Scheme 10.10).…”