Deconstructing Quinine. Part 1. Toward an Understanding of the Remarkable Performance of Cinchona Alkaloids in Asymmetric Phase Transfer Catalysis

Abstract

A study of catalyst structure-activity/selectivity relationships for Cinchona alkaloid-based asymmetric phase transfer catalysis (APTC) is described. An array of substituent modifications at C(9) and the quinuclidine nitrogen were introduced to examine the role of steric and electronic effects on rate and selectivity. The synthesis of the catalysts began with manipulation of the C(9) hydroxyl group followed by alkylation of the quinuclidine nitrogen to generate the quaternary ammonium salt. Catalysts that contained large substituents attached to the quinuclidinium nitrogen were found to be the most selective and those in which the hydroxyl group was protected generally afforded faster catalysts. The presence of a polar group at C(9) significantly impacted catalyst activity.

Asymmetric Ion‐Pairing Catalysis

“…A particularly strong dependence of catalyst performance on the identity of the N(1)-arylmethyl substituent has been noted. [12] In 1997, Corey [13] and Lygo [14] independently reported that replacement of the N -benzyl group of 1b with a bulky N -9-anthracenylmethyl group resulted in the highly efficient and enantioselective catalysts 1c – d (Scheme 2a). Subsequently, Park and Jew took advantage of the positive influence of sterically bulky N(1)-substituents to develop dimeric and trimeric cinchona alkaloid-derived catalysts linked via the quinuclidinium nitrogen.…”

Recoverable Dendritic Phase‐Transfer Catalysts that Contain (+)‐Cinchonine‐Derived Ammonium Salts

“…The next step consisted in the nucleophilic substitution of the chlorine atoms of the outer shell of the dendrimers with commercially available (+)-cinchonine, 5a, and with other three derivatives resulted from its O-9-alkylation with allyl bromide, 5b, benzyl bromide, 5c, and trimethylsilyl chloride, 5d, [27] forming the corresponding quaternary ammonium salts (75-80 % yield.) (Scheme 2).…”

“…[26,27,32,33] All electrophiles used were commercially available. Products 9-22 were previously described in the literature, 18a,31 1 H, 13 C NMR and chiral GC retention time are indicated to probe purity.…”

Neue Entwicklungen bei asymmetrischen Phasentransferreaktionen

“…Die systematische Untersuchung der Struktur-Aktivitäts/ Selektivitäts-Beziehungen der Cinchonidin-Phasentransferkatalysatoren 2 in der asymmetrischen Benzylierung von 7 durch Denmark et al ergab für den Lygo-Corey-Katalysator 2 a hçhere Enantioselektivität (Schema 3). [6] Park et al beschrieben die Wirkung einer Reihe dimerer und trimerer, von Cinchona-Alkaloiden abgeleiteter quartä-rer Ammoniumsalze des Typs 9 auf die asymmetrische Alkylierung von 7 (Schema 4). [7] Dabei war die dimere Verbindung 9 a einer der wirksamsten Katalysatoren für die Reaktion.…”