Highly Enantioselective Construction of Quaternary Stereocenters on β‐Keto Esters by Phase‐Transfer Catalytic Asymmetric Alkylation and Michael Reaction

Abstract

The construction of organic molecules containing chiral quaternary carbon centers by catalytic enantioselective reactions represents a very challenging and demanding area in organic synthesis, [1] because in addition to the inherent difficulty of developing an appropriate catalyst system, chiral fully substituted carbon centers are often essential for the biological activity of natural products and pharmaceuticals. Among the various transformations suitable for this purpose, the catalytic asymmetric alkylation of b-keto esters facilitates the direct stereocontrolled formation of quaternary stereocenters with structurally diverse substituents, which offers ample opportunity for further structural elaboration. However, few examples have been demonstrated to date, and only palladium-catalyzed asymmetric allylic alkylation has proved to be promising as an alternative strategy.[2] Although a method for asymmetric alkylation under phase-transfer catalysis should provide a simple yet potential solution to this problem, it is far being a synthetically useful method. [3, 4] Herein we wish to report highly enantioselective phasetransfer alkylation of b-keto esters catalyzed by N-spiro C 2 -symmetric chiral quaternary ammonium salt 1, [5] which results in the catalytic asymmetric establishment of a quaternary stereogenic center (Scheme 1). We also describe further utilization of our approach to establishing chirality by asymmetric Michael addition to a,b-unsaturated carbonyl compounds.As expected based on the relatively low reactivity of metal enolates of 1,3-dicarbonyl compounds, attempted treatment of 2-tert-butoxycarbonyl-1-indanone (2) with benzyl bromide (1.2 equiv) in toluene/50 % KOH aqueous solution at 0 8C for several hours led to gradual formation of the alkylation product 3 a (13 % yield after 6 h). In marked contrast, however, the benzylation in the presence of 1 mol % of chiral ammonium bromide 1 under otherwise similar conditions proceeded instantaneously to give 3 a in 94 % yield and, fortunately, the selectivity was determined to be 89 % ee (Scheme 1). To improve the enantioselectivity, we examined the effect of temperature on the reaction with solid inorganic bases and found that vigorous stirring of the mixture of 2, benzyl bromide (1.2 equiv), 1 (1 mol %), and powdered KOH (5 equiv) in toluene at À20 8C for 1.5 h afforded 3 a in 87 % yield with 92 % ee.[6] Even higher selectivity (94 % ee) was achieved by conducting the reaction at À40 8C, though the reaction was slower. The reactivity was improved when CsOH·H 2 O was used as a base, leading to the production of 3 a in 90 % yield with 95 % ee after a reaction time of 3 h. [7] With these optimized conditions in hand, we explored the general applicability of the present phase-transfer catalytic asymmetric alkylation system; the results are summarized in Table 1. The catalytic asymmetric creation of quaternary carbon centers by introduction of methyl and allylic substituents to substrate 2 has been demonstrated with appropriate electrophiles. Excelle...

Ethynylbenziodoxolones (EBX) as Reagents for the Ethynylation of Stabilized Enolates

“…In particular, we became interested by the chiral tetraaminophosphonium salts introduced by Ooi and co-workers in 2008 [17] and the binaphthylbased ammoniums developed by Maruoka and coworkers. [18] Indeed, the first results obtained using these catalysts were promising (Scheme 5). Phosphonium catalysts 11a and 11b led to an increase of the enantioselectivity up to 51%.…”

“…General procedure 2 (GP2): Following the reported procedure, [18] a solution of Boc-LVal-OMe (50) (4.00 g, 17.3 mmol, 1.00 equiv) in 8.65 mL of THF was added to a solution of Grignard reagent in THF (1 M, 86.5 mmol, 5.00 equiv). The final mixture was stirred for 1 h at 0 °C and then poured into ice-cooled aqueous NH4Cl solution.…”

“…1,145.0,128.5,128.1,126.7,126.4,126.0,125.6,79.8,60.2,27.9,23.1,16.2. IR ν 3087 (w) [18] Preparation of amino alcohol hydrochloride 55 and 56…”

“…General procedure 4 (GP4): Following the reported procedure, [18] sodium azide (5.0 equiv) was added portionwise carefully to TFA (0.2 M) at 0 °C, followed by portionwise addition of amino alcohol hydrochloride (1.0 equiv). The resulting mixture was stirred for 6 h at RT.…”

“…The characterization data corresponded to the reported values. [18] (2S)-3-methyl-1,1-di-p-tolylbutane-1,2-diamine (60)…”