Enantiopure 2-aryl-2-methyl cyclopentanones by an asymmetric chelation-controlled Heck reaction using aryl bromides: increased preparative scope and effect of ring size on reactivity and selectivity

Quaternary 2-aryl-2-methyl cyclopentanones were obtained in 85–94% ee via Pd(0)-catalyzed chelation-controlled asymmetric arylation of a cyclopentenyl ether with aryl bromides and subsequent hydrolysis. Two new cyclohexenyl ethers were synthesized and evaluated as Heck substrates with both aryl iodides and bromides under different reaction conditions. Arylations of the six-membered vinyl ether 1-methyl-2-(S)-(cyclohex-1-enyloxymethyl)-pyrrolidine with aryl bromides were achieved with t-Bu3P-promoted palladium catalysis using either classical or microwave heating. Isolated Heck products were also obtained in high diastereoselectivities (94–98% de).

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[2-(R)-2-(1-Methyl-pyrrolidine-2-(S)-ylmethoxy)-cyclohex-2-enyl]-naphthaleneC22H27NODe = 95% (conditions A) and 98% (conditions B)[α]D23=-31 (c 1, CHCl3)Source of chirality: chelation-controlled asymmetric synthesisAbsolute configuration: (R)

[(R)-2-(1-Methyl-pyrrolidine-2-(S)-ylmethoxy)-cyclohex-2-enyl]-benzeneC18H25NODe = 98% (conditions A) and 98% (conditions B)[α]D23=-52 (c 1, CHCl3)Source of chirality: chelation-controlled asymmetric synthesisAbsolute configuration: (R)

{2-[1-(R)-2-(1-Methyl-pyrrolidine-2-(S)-ylmethoxy)-cyclohex-2-enyl]-methyl}-benzeneC19H27NODe = 94% (conditions A) and 98% (conditions B)[α]D23=-54 (c 1, CHCl3)Source of chirality: chelation-controlled asymmetric synthesisAbsolute configuration: (R)

{4-[1-(R)-2-(1-Methyl-pyrrolidine-2-(S)-ylmethoxy)-cyclohex-2-enyl]-methyl}-benzeneC19H27NODe = 96% (conditions A) and 98% (conditions B)[α]D23=-40 (c 1, CHCl3)Source of chirality: chelation-controlled asymmetric synthesisAbsolute configuration: (R)

{3-[1-(R)-2-(1-Methyl-pyrrolidine-2-(S)-ylmethoxy)-cyclohex-2-enyl]-methyl}-benzeneC19H27NODe = 97% (conditions A) and 98% (conditions B)[α]D23=-50 (c 1, CHCl3)Source of chirality: chelation-controlled asymmetric synthesisAbsolute configuration: (R)