Quinidine diastereoselectivity

The use of a heteroatom a to the ester carbonyl group allows for the formation of a chelate with the metal counterion hence, the geometry of the ester enolate can be assured.336-338358359 This approach was used in the rearrangement of the glycine allylic esters 13 to y,8-unsaturated amino acids in good yields and excellent diastereoselectivity (Scheme 26.13).358 The enantioselectivity could be reversed by using quinidine instead of quinine. 

Another catalytic application of chiral ketene enolates to [4 + 2]-type cydizations was the discovery of their use in the diastereoselective and enantioselective syntheses of disubstituted thiazinone. Nelson and coworkers described the cyclocondensations of acid chlorides and a-amido sulfones as effective surrogates for asymmetric Mannich addition reactions in the presence of catalytic system composed of O-TM S quinine lc or O-TMS quinidine Id (20mol%), LiC104, and DIPEA. These reactions provided chiral Mannich adducts masked as cis-4,5 -disubstituted thiazinone heterocycles S. It was noteworthy that the in situ formation of enolizable N-thioacyl imine electrophiles, which could be trapped by the nucleophilic ketene enolates, was crucial to the success of this reaction. As summarized in Table 10.2, the cinchona-catalyzed ketene-N-thioacyl-imine cycloadditions were generally effective for a variety of alkyl-substituted ketenes and aliphatic imine electrophiles (>95%ee, >95%cis trans) [12]. 

Moreover, as is usually found in most of the asymmetric reactions catalyzed by cinchona alkaloid derivatives, the opposite enantiomer of each diaster-eomeric Michael adduct could also be obtained by simply changing the catalyst to the corresponding pseudoenantiomeric quinidine-based compounds of type 83 or 71. Once again, a model was proposed to account for the observed results, involving a conformationally rigid intermediate in which both the pronucleophile and the electrophile were attached to the catalyst by the formation of multiple H-bonds, explaining the reversal of the diastereoselection by the epimeric nature of C-9 in catalyst 71b with respect to 84c. The stereochemical... 

Somewhat between diastereoselective and enantioselective approaches is the Cram s synthesis involving the oxazolines with chiral alkoxide leaving groups [26]. In this manner, bromine in oxazoline 596 was substituted with sodium alkoxides, derived from readily available natural alcohols such as menthol (597), fenchyl alcohol (598), bomeol (599), quinine (600), and quinidine (601) to give the respective chiral oxazolines 602-606, Scheme 10. The Meyers reaction of oxazolines 602-606 and 1-naphthylmagnesium bromide (608) was effected at low temperatures (-42 °C) affording the expected biaryl 609 with respective chiral induction. 

The mechanism of enamine catalysis has been established the enamine is the active form of nucleophile. Other modes of activation are less developed and are limited to a certain group of donors and acceptors. Quinidine was found to catalyze the reaction of hydroxyacetone with aldehydes to yield the desired 5y -aldols with moderate diastereoselectivity and low enantioselectivity [169]. This represents the first example of a tertiary amine catalyzing the direct aldol reaction. Even (3, y-unsaturated a-keto ester 154 was successfidly coupled with protected hydroxyacetone 51 in the presence of 20 mol% of 9-amino-9-deoxy-cpi-cinchonine 155 and a small amount of TEA (Scheme 3.27). 

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