Chiral tertiary amine catalyst

Catalytic Asymmetric Induction with Chiral Lewis Bases 31.4.2.1 Chiral Tertiary Amine Catalysts 

R = C0H5, / -MeOC0H4, / -MeC0H4, P-CF3C0H4, yt -NO2C0H4,1-naphthyl, PhCH=CH, /Pr, c-hexyl 

Ar = 2-NO2-C6H4, 2-CF3-C6H4, 4-a-CeH3, 4-CF3-C6H4, 4-C02Me-C6H4, 4-CN-C6H4, 

Conversion after 180 min. Conversion after 30 min in parentheses 

148a R = TBS 148b R = TDS 148c R = TBDPS 148d R = TIPS 148e R = TMS 

Ar = p-CF3C6H4, m-UsC Hi, /7 -CIC0H4, o-MeOC0H4, p-CIC6H4, 2-furyl, CeHs 

R = 2-furyl, 4-MeOC6H4.2,4-diMeO-C6H3 r2 = ph, 4-F-C6H4.4-a-C6H4,4-MeO-C6H4, 4-NC-C6H4.2-Naphthyl, 4-Br-C6H4 

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Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

The first catalytic asymmetric Staudinger reaction to be described used chiral tertiary amines 14 and 15 derived from the Cinchona alkaloids as the nucleophile to activate the ketene via zwitterion formation. The ketene was conveniently generated in situ from the acid chloride. Because the HCl generated in the elimination would consume the chiral tertiary amine catalyst, a nonnucleophilic strong base (e.g.. Proton Sponge) was included to remove the HCl formed. Yields of -lactams were on the order of 60% in 99% ee. 

Suitable chiral tertiary amine catalysts for this rearrangement are cinchona-alkaloid derivatives, and Jorgensen et al. found that the best conditions involved the use of the well-known Sharpless [DHQDJ2PHAL ligand 18 and dioxane as solvent (Scheme 40.26). 

NMM catalyst. This system was expanded to the enantio-selective reaction using chiral tertiary amine catalyst (Scheme 2.52). 

Based on prior results where Ricci used Cinchona alkaloids as phase-transfer-catalysts, the group proceeded to look at hydrophosphonylation of imines [48], Employing the chiral tertiary amine as a Brpnsted base, a-amino phosphonates products were synthesized in high yields and good selectivities. 

Asymmetric addition of ketenes to aldehydes is a highly attractive synthetic access to yfi-lactones with perfect atom economy [134, 135]. This reaction can be catalyzed efficiently by using chiral amines as organocatalysts. As early as 1967 Borr-mann et al. described an organocatalytic asymmetric ketene addition to aldehydes [136] chiral tertiary amines, in particular (—)-N,N-dimethyl-a-phenylethylamine or (—)-brucine, were used as catalysts [136]. The resulting lactones were obtained with modest enantioselectivity of up to 44% ee. 

The kinetic resolution of racemic alcohols is probably the most intensively studied aspect of organocatalysis, and its beginnings can be traced back to the 1930s [2, 3]. In these early attempts naturally occurring alkaloids such as (—)-brucine and (+)-quinidine were used as catalysts. Synthetic chiral tertiary amines also were introduced and examined, and enantiomeric excesses up to ca. 45% were achieved up to the early 1990s [4, 5]. 

Natural products having chiral tertiary amine functions were tested among the first catalysts in asymmetric MBH reactions [24, 60]. The importance of the proton donor capacity of the catalyst in the rate and selectivity of the MBH reaction was recognized very quickly, and attention was turned to genuine a-amino alcohol structures, such as the compounds listed in Scheme 5.8 [61]. Results were modest, however. Apart from the earlier discussed (R)-3-HDQ, which catalyzed the MBH reaction at atmospheric pressure (though with no enantioselectivity),... 

The nucleophilic addition on substituted ketenes is a well-known method to generate a prochiral enolate that can be further protonated by a chiral source of proton. Metallic nucleophiles are used under anhydrous conditions therefore, the optically pure source of proton must be added then (often in a stoichiometric amount) to control the protonation. In the case of a protic nucleophile, an alcohol, a thiol, or an amine, the chiral inductor is usually present at the beginning of the reaction since it also catalyzes the addition of the heteroatomic nucleophile before mediating the enantioselective protonation (Scheme 7.5). The use of a chiral tertiary amine as catalyst generates a zwitterionic intermediate B by nucleophilic addition on ketene A, followed by a rapid diastereoselective protonation of the enolate to acylammonium C, and then the release of the catalyst via its substitution by the nucleophile ends this reaction sequence. 

Despite the obvious potential of cinchona alkaloids as bifunctional chiral catalysts of the nucleophilic addition/enantioselective protonation on prochiral ketenes, no further contribution has appeared to date and only a few papers described this asymmetric reaction with other catalysts [13], When the reaction is carried out with soft nucleophiles, the catalyst, often a chiral tertiary amine, adding first on ketene, is covalently linked to the enolate during the protonation. Thus, we can expect an optimal control of the stereochemical outcome of the protonation. This seems perfectly well suited for cinchona analogues and we can therefore anticipate successful applications of these compounds for this reaction in the near future. 

In contrast to the hydrogenation of N acetyl enamides, there are very few examples of successful asymmetric hydrogenation of N,N dialkyl enamines, which provides a direct approach to the synthesis of chiral tertiary amines. The reason is that an N acetyl group in the enamides is considered indispensable for the substrates to form a chelate complex with the metal of catalyst in transition state, giving good reactivity and enantioselectivity, while there is no N acetyl group in N,N dialkyl enamines. 

Scheme 2.115). Among the phosphine catalysts screened, 2,2 -bis(diphe-nylphosphino)-1,1 -binaphthyl (BINAP) CPS was found to be the best catalyst and the corresponding products were obtained with up to 44% ee, which is comparable with those of reported enantioselective methods using chiral tertiary amines under high pressures (Scheme 2.115). For the MBH reaction of substituted pyrimidine 5-carboxaldehyde and other acrylates, the yield and ee were dependent on the bulk of the acrylate. The less bulky acrylate gave the higher yield and ee (Scheme 2.116). 

In the previons section, secondary chiral amines were employed that give rise to enamine formation npon reaction with ketones or aldehydes. Chiral tertiary amines, unable to form enamines, are nevertheless capable of inducing enantioselectivity in case substrates are used that contain sufficiently acidic protons such as aldehydes, ketones or active methylene compounds [33]. The cinchona alkaloids, by far the most versatile source of Brpnsted base catalysts, have played a prominent role in various types of asymmetric organocatalytic reactions [34], which is also true for the Mannich reaction. 

In many examples of Brpnsted base catalysis, the combination of a chiral tertiary amine and a hydrogen-bonding donor, such as a urea or thiourea moiety, significantly enhances the selectivity of the formation of carbon-carbon bonds. Catalysts possessing this combination of functional groups have proven useful due to their ability to simultaneously stabilize and activate both electrophilic and nucleophilic components. 

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