Chiral tertiary amines

A very interesting approach to optically active sulphoxides, based on a kinetic resolution in a Pummerer-type reaction with optically active a-phenylbutyric acid chloride 269 in the presence of /V,A -dimethyIaniline, was reported by Juge and Kagan332 (equation 149). In contrast to the asymmetric reductions discussed above, this procedure afforded the recovered sulphoxides in optical yields up to 70%. Chiral a, /1-unsaturated sulphoxides 270 were prepared via a kinetic resolution elaborated by Marchese and coworkers333. They found that elimination of HX from racemic /i-halogenosulphoxides 271 in the presence of chiral tertiary amines takes place in an asymmetric way leading to both sulphoxides 270 and 271, which are optically active (optical yields up to 20%) with opposite configurations at sulphur (equation 150). 

A very interesting approach to chiral a unsaturated sulfoxides 39 based on a kinetic resolution was elaborated by Marchese (69), who found that asymmetric elimination of racemic j3-halogenosul-foxides 40 takes place in the presence of chiral tertiary amines. 

A new and general approach to chiral aliphatic or aromatic sulfinates has been recently described by Mikofajczyk and Drabowicz (107). It consists of the asymmetric condensation of racemic sulfinyl chlorides at low temperature with achiral alcohols in the presence of chiral tertiary amines as asymmetric reagents. The optical purity (up to 45%) of the sulfinates formed is strongly dependent on the structure of all the reaction components. 

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. 

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. 

Interestingly, the alkene to allene conversion can be carried out directly without isolation of the intermediate dihalocyclopropane. This process involves the treatment of the alkene with 1 equiv. of carbon tetrabromide and 2 equiv. of methyllithium in ether at -65 °C.163 Ultrasonic irradiation facilitates the formation of cyclopropylidenes, and therefore the allenes, from dihalocyclopropanes under the influence of Li, Na or Mg.1 The reactions are usually complete in 5-15 min. A report165 on the use of n-butyllithium complexed with the chiral tertiary amine (-)-sparteine, leading to optically active allenes, seems to be of questionable value. 

Cycloaddition of ketene to chloral. Quinidine (1) catalyzes the addition of ketene to chloral to give the / -propiolactone (2) in 89% yield and in 98% ee. As expected, quinine (C.,-cpimer of 1) also catalyzes this reaction to give (R)-(-+-)-2 in 76% ee. Examination of 15 chiral tertiary amines has led to certain conclusions the chirality of the product depends on the chirality of the carbon adjacent to the amine function, and the presence or absence of a hydroxyl group [1 to the amine is unimportant in this case. Even simple amines such as 1,2-dimethylpyrrolidine or N,N-dime thyl-z-phenyle thy 1 amine are fairly effective (60 and 77% ee, respectively). 

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),... 

Table 5.6 The chiral tertiary amine/thiourea-catalyzed MBH reaction of dihydrocinnamaldehyde with cyclohexenone.

Interestingly, this substitution reaction can be applied to the stereoselective assembly of chiral quaternary centers and has been extended to the preparation of chiral tertiary alcohols via a stereoselective Baeyer-Villiger rearrangement, and chiral tertiary amines via a stereoselective Curtius rearrangement (Scheme 15)130>130a... 

Noncovalent MTPA Derivatives. The enantiomeric purity of some chiral amines can be determined by H NMR with (S)- or (J )-MTPA as a chiral solvating agent. The method is particularly useful for chiral tertiary amines that are not amenable to conversion into MTPA amides, e.g. (18) and (19), although it has been utilized for primary and secondary amines as well, e.g. (20). ... 

Planar chiral compounds should also be accessible from the chiral pool. An example (with limited stereoselectivity) of such an approach is the formation of a ferrocene derivative from a -pinene-derived cyclopentadiene (see Sect. 4.3.1.3 [81]). A Cj-symmetric binuclear compound (although not strictly from the chiral pool, but obtained by resolution) has also been mentioned [86]. Another possibility should be to use the central chiral tertiary amines derived from menthone or pinene (see Sect. 4.3.1.3 [75, 76]) as starting materials for the lithiation reaction. In these compounds, the methyl group at the chiral carbon of iV,iV-dimethyl-l-ferrocenyl-ethylamine is replaced by bulky terpene moieties, e.g., the menthane system (Fig. 4-2 le). It was expected that the increase in steric bulk would also increase the enantioselectivity over the 96 4 ratio, as indicated by the results with the isopropyl substituent [118]. However, the opposite was observed almost all selectivity was lost, and lithiation also occurred in the position 3 and in the other ring [134]. Obviously, there exists a limit in bulkiness, where blocking of the 2-position prevents the chelate stabilization of the lithium by the lone pair of the nitrogen. 

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. 

Scheme 7.5 Chiral tertiary amine catalyzed addition of heteroatomic nucleophiles on ketenes.

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. 

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