Sulfoxides derived from Cinchona alkaloids—chiral ligands in palladium-catalyzed asymmetric allylic alkylation

Phenyl sulfides derived from Cinchona alkaloids, 9-PhS-epi-CD, 9-PhS-epi-QN, 9-PhS-epi-QD, and 9-PhS-QN were oxidized into the corresponding sulfoxides. Regardless of the oxidation system used (NaIO4, TEMPO/NaOCl, VO(acac)2/chiral Schiff base/H2O2) a similar stereochemical outcome of the oxidation was observed. Four pure epimers of sulfoxides 9-PhSO-epi-CD and 9-PhSO-epi-QN were isolated and fully characterized (X-ray, CD, 1H NMR-pattern). The chiral sulfoxides as well as the corresponding sulfides and sulfones were tested in the Pd-catalyzed allylic alkylation of dimethyl malonate with rac-1,3-diphenyl-2-propenyl acetate. The sulfoxides obtained from Cinchona alkaloids bearing the additional stereogenic center gave the main product of configuration dependent on the chirality of alkaloid framework only. Similar ees (up to 60%) but significantly higher yields (90%) were obtained as compared to the reaction with the corresponding thioethers. The results were in agreement with nucleophilic attack directed at the allylic carbon located trans to the sulfur atom in the M-shaped intermediate η3-allylpalladium complex.

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(1S,3R,4S,8S,9S,RS)-9-PhenylsulfinylcinchonanC25H26N2OS[α]D20≈0 (c 0.20, CH2Cl2)Source of chirality: chiral substrate, chromatographic separation of epimers followed by crystallizationAbsolute configuration: (1S,3R,4S,8S,9S,RS) (by X-ray measurement, chemical correlation and CD spectrum)

(1S,3R,4S,8S,9S,SS)-9-PhenylsulfinylcinchonanC25H26N2OS[α]D20=-185.0 (c 0.26, CH2Cl2)Source of chirality: chiral substrate, chromatographic separation of epimers followed by crystallizationAbsolute configuration: (1S,3R,4S,8S,9S,SS) (by chemical correlation and CD spectroscopy)

(1S,3R,4S,8S,9S,RS)-6′-Methoxy-9-phenylsulfinylcinchonanC26H28N2O2S[α]D20=-123 (c 0.86, CH2Cl2)Source of chirality: chiral substrate, chromatographic separation of epimersAbsolute configuration: (1S,3R,4S,8S,9S,RS) (by chemical correlation and CD spectroscopy)

(1S,3R,4S,8S,9S,SS)-6′-Methoxy-9-phenylsulfinylcinchonanC26H28N2O2S[α]D20=-215 (c 0.52, CH2Cl2)Source of chirality: chiral substrate, chromatographic separation of epimersAbsolute configuration: (1S,3R,4S,8S,9S,SS) (by chemical correlation and CD spectroscopy)

(1S,3R,4S,8S,9S)-9-PhenylsulfonylcinchonanC25H26N2O2S[α]D20=+31.1 (c 0.74, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: (1S,3R,4S,8S,9S) (by chemical correlation)

(1S,3R,4S,8S,9S)-6’-methoxy-9-phenylsulfonylcinchonanC26H28N2O3S[α]D20=-22.7 (c 1.23, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: (1S,3R,4S,8S,9S) (by chemical correlation)