Chiral Secondary Amine

In all the reactions described so far a chiral Lewis acid has been employed to promote the Diels-Alder reaction, but recently a completely different methodology for the asymmetric Diels-Alder reaction has been published. MacMillan and coworkers reported that the chiral secondary amine 40 catalyzes the Diels-Alder reaction between a,/ -unsaturated aldehydes and a variety of dienes [59]. The reaction mechanism is shown in Scheme 1.73. An a,/ -unsaturated aldehyde reacts with the chiral amine 40 to give an iminium ion that is sufficiently activated to engage a diene reaction partner. Diels-Alder reaction leads to a new iminium ion, which upon hydrolysis af-... 

Subsequently Turner and coworkers were able to show that the Asn336Ser variant possessed broad substrate specificity, with the ability to oxidize a wide range of chiral amines of interest [19]. They also discovered a second mutation, Ile246Met, which conferred enhanced activity toward chiral secondary amines as exemplified by the deracemization of racemic 1-methyltetrahydroisoquinoline (MTQ) (9) (Figure 5.9)[20j. 

Methyl-1 -(N-dipheny lmethyleneamino)-2-hydroxy methylpy rrolidinium salts catalyse C-alkylation of (V-benzylimines leading to chiral secondary amines in high yield (>70%) and high stereoselectivity (>90% ee) [18],... 

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

List was the first to explore this possibility, examining the Hantzsch ester mediated reduction of a,P-unsaturated aldehydes [209], Using 20 mol% of the binaphthyl derived phosphonate salt of morpholine (153) in dioxane at 50 °C, a series of P-aryl a,P-unsaturated aldehydes underwent transfer hydrogenation with Hantzsch ester 154 with excellent levels of absolute stereocontrol (96-98% ee) (Scheme 63). The method was also applied to the aliphatic substrates ( )-citral and famesal to give the mono-reduced products in 90% and 92% ee, respectively. Significantly, in line with many of the chiral secondary amine catalysed transformations described above the reactions follow a simple and practical procedure without the need for exclusion of moisture and air. 

The 1,3-dipolar cycloaddition of azomethine yUdes with olefins gives rise to pyrrolidines which represent structural elements of organocatalysts, natural products, and drug candidates. Asymmetric metal-catalyzed variants attracted considerable attention over the last few years [64], Recently, Vicario et al. reported an organo-catalytic [3 -i- 2] cycloaddition of azomethine ylides and a,p-unsaturated aldehydes mediated by a chiral secondary amine [65]. 

In order to extend the approach to include deracemization of chiral secondary amines, this group carried out directed evolution on the monoamine oxidase (MAO) enzyme MAO-N (Scheme 2.32). A new variant was identified with improved catalytic properties towards a cyclic secondary amine 64, the substrate used in the evolution experiments. This new variant had a single point mutation, lle246Met, and was found to have improved catalytic properties towards a number of other cyclic secondary amines. The new variant was used in the deracemization of rac-64 yielding (R)-64 in high yield and enantiomeric excess [34]. 

J. Aube, Chemtracts Org. Chem. 2, 46-49 (1989) New C2-Symmetrical Chiral Secondary Amines". 

The alkylation of caclohexanone has been studied as a model reaction in detail. Generally, enamino compounds (126) are allowed to react with alkyl halides or a, 3-unsaturated carbonyl compounds. The enamine (126a) is prepared directly from the ketone and a chiral secondary amine (route A). A metalloenamine (126b) can be synthesized from chiral azomethine, derived from the model ketone and a primary chiral amine (route B). The primary amine used for the formation of (126b) must possess an oxygen function. This oxygen function plays a key role in the coordination of the lithium ion in the complex (126b). 

Prior to the beginning of our work on sitagliptin, there had been some reports in the literature of catalytic asymmetric hydrogenation of enamines to access chiral secondary amines [19]. The synthesis of P-amino acids had also been established by catalytic asymmetric hydrogenation of enamides [20]. All these reports relied on N-acylenamines as substrates, since it was believed that the N-acyl group was required in order to achieve good reactivity and selectivity [21]. 

Catalytic reduction of chiral 2-(2-pyridyl)-l,3-oxazolidines and of 2-pyridyl imines, which are easily produced by standard synthetic means, followed by oxidation, results in the formation of chiral secondary amines as shown in equation 83333. The reaction occurs with a reasonable diastereoselectivity. 

Being inspired by Maruoka s results with the C2-symmetric binaphthyl-derived quaternary ammonium salt [21], Lygo and colleagues designed a quaternary ammonium salt 23, comprising conformationally flexible biphenyl units and commercially available chiral secondary amines [22], A library of 40 quaternary ammonium salt was synthesized and evaluated for their catalytic efficiency in the asymmetric alkylation of... 

Direct enantioselective catalytic a-fluorination of aldehydes has been carried out using jV-fluorobenzenesulfonimide [F-N-(02SPh)2] and a chiral secondary amine (an imidazolidinone) to provide enamine organocatalysis.295... 

In another approach to control the absolute configuration of enone photocycloaddition products, an intermediate iminium ion with a chiral secondary amine was employed by Mariano et al. (Scheme 6.28) [80]. Irradiation of substrate 73 at relatively short wavelength (direct nn excitation) led, via intermediate 74, to the chiral... 

Independently, MacMillan et al. developed an efficient catalyst system that is based on a chiral secondary amine (Tuttle et al. 2006). 

Referring to a mechanistic classification of organocatalysts (Seayad and List 2005), currently the two most prominent classes are Brpnsted acid catalysts and Lewis base catalysts. Within the latter class chiral secondary amines (enamine, iminium, dienamine activation for a short review please refer to List 2006) play an important role and can be considered as—by now—already widely extended mimetics of type I aldolases, whereas acylation catalysts, for example, refer to hydrolases or peptidases (Spivey and McDaid 2007). Thiamine-dependent enzymes, a versatile class of C-C bond forming and destructing biocatalysts (Pohl et al. 2002) with their common catalytically active coenzyme thiamine (vitamin Bi), are understood to be the biomimetic roots ofcar-bene catalysis, a further class of nucleophilic, Lewis base catalysis with increasing importance in the last 5 years. 

An enantioselective aryloxylation of aldehydes is based on their prior conversion to an enamine through reaction with a chiral secondary amine catalyst. A subsequent inverse HDA reaction with o-quinones leads to 3-alkyl-2-hydroxy-l,4-benzodioxins with ee ca. 80% (Scheme 47). Manipulation allows the synthesis of (S)-2-alkyl-2,3-dihydro-l,4-benzodioxins <07TL1605>. In like manner, racemic nitidanin, which possesses antimalarial properties, has been synthesised through a regioselective cycloaddition of an o-quinone with a protected 3-arylpropen-l-ol <07TL771>. 

A variety of piperidines are formed by intramolecular cyclization of y-aminoolefins via bromination of the double bond. Chiral secondary amines provide diastereoselectivity <03CC1918>. 

It was shown by Shonenberger et al. that thermal decomposition of the separated diastereomeric (a-methylbenzyl) urea derivatives produced by the reaction of [19] and chiral secondary amines is a convenient technique for the retrieval of the optically pure amines (93). 

Arylamines. Primary," secondary, and tertiary arylamines have been prepared by Pd(0)-catalyzed IV-arylation methods. The most common and effective catalytic system contains (dbaljPd, r-BuONa, and a tertiary phosphine such as BINAP. The nucleophilic species for the synthesis of primary anilines is a Ti-N complex formed from (i-PrO) Ti, Li, and McjSiCl in THF under nitrogen at room temperature (8 h). N-Arylation of chiral secondary amines proceeds without affecting the stereocenters. Arylation with Arl is facile because it can be carried out at room temperature. More recent development indicates that employment of 2-dimethylamino-2 -dicyclohexylphosphinobiphenyl as ligand in the amination of unactivated chloroarenes under mild conditions is also possible. 

Two representative organocatalytic reaction systems can be considered for nucleophilic a-substitution of carbonyl compounds, the issue of this chapter. One involves the in situ formation of a chiral enamine through covalent bond between organo-catalyst (mainly a chiral secondary amine such as proline) and substrate (mainly an aldehyde), followed by asymmetric formation of new bond between the a-carbon of carbonyl compound and electrophile. Detachment of organocatalyst provides optically active a-substituted carbonyl compound, and the free organocatalyst then participates in another catalytic cycle (Figure 6.1a) [2]. 

In recent years, the in situ generation of chiral iminium ions from a chiral secondary amine and the Michael acceptor, mostly a,P-unsaturated aldehydes and ketones, is used as a powerful strategy for a range of asymmetric cycloaddition reactions [24]. However, the chiral a,P-unsaturated iminium ions, provided by reversible condensation from a,P-unsaturated ketones with secondary amine, could not always work well in this asymmetric approach, probably because of poor generation of the corresponding iminium cations [25],... 

Chiral secondary amines such as nonracemic imidazolidin-4-ones have been found to be effective asymmetric organocatalysts in the Diels-Alder cyclization of cyclopentadiene and a,p-unsaturated aldehydes [60]. A tyrosine-derived imidazoli-din-4-one was immobilized on PEG to provide a soluble, polymer-supported catalyst 110. In the presence of 110, Diels-Alder cycloaddition of acrolein 112 to 1,3-cyclohexadiene 111 proceeded smoothly to afford the corresponding cycloadduct 113 with high endo selectivity and enantioselectivity up to 92% ee (Scheme 3.31) [61]. 

The enantioselective hydrogenation of imines is a powerful approach to the synthesis of chiral secondary amines. The series of complexes 7 (Scheme 5) either with or without the 3-H F -substituent and containing various anions was synthesized to investigate the influence of the ligand substitution pattern and the anion on the catalytic efficiency in SCCO2 [23]. As expected, the substitution in the ligand increased the solubility of the complexes, but had very little impact on the enantioselectivity. The anion, however, did not only exhibit an effect on... 

Using the optimum conditions (Table 28, entry 6), a variety of chiral secondary amines have been investigated. The results are shown in Table 29. The most effective auxiliary for preparation of the enantiomeric aldol (242b) is the phenylglycine-derived amine (Table 29, entry 8). 

Two further contributions illustrate how chiral lithium amides can be used as catalysts in asymmetric deprotonation reactions (Schemes 2 and 3). The first example of catalytic chiral lithium amide chemistry was reported [13] by Asami (Scheme 2). In this process an achiral base, in this case LDA, provides a stoichiometric reservoir of amidoli-thium reagent. However, deprotonation of the epoxide is affected primarily by the chiral lithium amide 11 rather than the relative excess of LDA. Turnover is possible since the resulting chiral secondary amine 10 can be deprotonated by the remaining reservoir of LDA thus regenerating the chiral base 11. For example, the deprotonation of cyclohexene oxide 8 in the presence of DBU as an additive gives the allylic alcohol 9 in 74 % ee (82 % yield) using 50 mol% of chiral base 11. 

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