Catalytic, Asymmetric Dimerization of Methylketene

Abstract

We hope to develop quick, inexpensive routes to biologically important classes of molecules using catalytic, asymmetric transformations. Toward this goal, we are exploring reactions catalyzed by chrial tertiary amines. Tertiary amines are attractive catalysts, as these compounds are generally stable, inexpensive, and less toxic than most transition metals. Although the asymmetric variants of some tertiary amine-catalyzed processes are known, 1 many such reactions have not been attempted with chiral catalysts. One example of the latter case is the tertiary amine-catalyzed dimerization of methylketene (Scheme 1). 2,3 We report here that cinchona alkaloids and their derivatives catalyze the dimerization of methylketene with high enantioselectivity, yielding a product that easily transforms into a useful synthon for polypropionate synthesis.The tertiary amine-catalyzed dimerization of methylketene yields -lactone 1 via a formal Claisen condensation (Scheme 1). We reasoned that a chiral tertiary amine might impose a facial bias on ammonium enolate 2, eventually producing -lactone 1 in an optically enriched form. We were encouraged in this respect by the high enantioselectivity (98% ee) realized by Wynberg in the related cycloaddition of ketene to chloral catalyzed by cinchona alkaloids. 4 We also assumed that 1 would be a useful polypropionate precursor. Accordingly, we studied the dimerization of methylketene catalyzed by various chiral, nonracemic tertiary amines.We used Ward's procedure to prepare a -78°C solution of methylketene in tetrahydrofuran (THF). 5 In this procedure, the ketene distilled away from the reaction pot as it formed, yielding a reactant solution free of any starting materials or byproducts. We then added the ketene solution to 1 mol % of the amine catalyst in THF at -78°C (Scheme 2). The volatility and instability to silica gel of 1 hampered the isolation of this compound, so we added LiAlH 4 to the reaction mixture to produce primary alcohol 3 (Table 1). 6 Either enantiomer of 3 is produced with high enantiocontrol from the dimerization of methylketene with readily available catalysts. Quinidine and its derivatives afford uniformly high enantioselectivities, while quinine and propionylquinine are notably less selective catalysts. This trend is similar to trends observed in numerous processes utilizing cinchona alkaloids as catalysts or ligands. 1 The overall yield for this reaction sequence is 20% based on bromopropionyl bromide, regardless of the identity of the catalyst. The following results indicate that the dimerization reaction is quantitative; reaction of the methylketene with aniline afforded approximately 30% of the corresponding amide, and reduction of purified 1 afforded a 70% yield of 3. While the yield for this reaction sequence is lower than that for the existing route to 3, 7 the low cost of the starting material (100 g/$18.25 for 2-bromopropionyl bromide from Aldrich) and the lack of intermediate isolations make this route attractive. We are currently exploring the asymmetr...

Catalytic, asymmetric reactions of ketenes and ketene enolates

“…With an eye toward utilizing the chiral dimers as synthetic intermediates,50 his early work focused on the cinchona alkaloid catalyzed dimerization of pregenerated methylketene (Scheme 3.10). 51 He screened a number of cinchona alkaloid derivatives, finding that quinidine ( 7b ), or its silylated derivative 7d , was most effective, with the two giving the same high selectivity (98% ee). Quinine ( 6b ) gave only moderate results (70% ee) but its silylated derivative 6d proved to be effective (90% ee).…”

Enantioselective Organocatalysis

“…[53] This reaction was used to prepare the C 1' ± C 10' segment of the macrocyclic antibiotic pamamycin 621A. [54] 3.2.…”

Computational study on the mechanism and enantioselectivity of Rh2(S-PTAD)4catalyzed asymmetric [4+3] cycloaddition between vinylcarbenoids and dienes

“…[11][12][13][14][15][16][17][18] As shown in eqn (1)-(3), [19][20][21][22][23] in practical experiments the stable phenylcarbenoid obtains a relatively high level of diastereoselectivity. [30][31][32][33] Specic metal-ligands combinations can lead to a high asymmetric induction because the given metal carbenoid intermediates can distinguish between the potentially competing carbenoid reactions and/or the paths to different stereoisomers. 24 Furthermore, the carbenoid intermediate with a donor siloxy group tends to favor the formation of the target product with high enantioselectivity.…”