Amines asymmetric variants

The Gabriel-Cromwell aziridine synthesis involves nucleophilic addition of a formal nitrene equivalent to a 2-haloacrylate or similar reagent [29]. Thus, there is an initial Michael addition, followed by protonation and 3-exo-tet ring-closure. Asymmetric variants of the reaction have been reported. N-(2-Bromo)acryloyl camphor-sultam, for example, reacts with a range of amines to give N-substituted (azir-idinyl)acylsultams (Scheme 4.23) [30]. 

The addition of sulfonamides or alcohols to imines gives rise to aminals which represent structural elements of natnral prodncts and drugs. Recently, Antilla et al. reported the first catalytic asymmetric variants of both transformations. 

A very simple yet elegant method for efficient epoxidation of aromatic and aliphatic alkenes was presented by Beller and coworkers [63, 64], FeCl3 hexahydrate in combination with 2,6-pyridinedicarboxylic add and various organic amines gave a highly reactive and selective catalyst system. An asymmetric variant (for epoxidations of trans-stilbene and related aromatic alkenes) was published recently [65] using N-monosulfonylated diamines as chiral ligands (Scheme 3.7). 

The Stacker reaction has been employed on an industrial scale for the synthesis of racemic a-amino acids, and asymmetric variants are known. However, most of the reported catalytic asymmetric Stacker-type reactions are indirect and utilize preformed imines, usually prepared from aromatic aldehydes [24]. A review highlights the most important developments in this area [25]. Kobayashi and coworkers [26] discovered an efficient and highly enantioselective direct catalytic asymmetric Stacker reaction of aldehydes, amines, and hydrogen cyanide using a chiral zirconium catalyst prepared from 2 equivalents of Zr(Ot-Bu)4, 2 equivalents of (R)-6,6 -dibromo-1, l -bi-2-naphthol, (R)-6-Br-BINOL], 1 equivalent of (R)-3,3 -dibromo-l,l -bi-2-naphthol, [(R)-3-Br-BINOL, and 3 equivalents of N-methylimida-zole (Scheme 9.17). This protocol is effective for aromatic aldehydes as well as branched and unbranched aliphatic aldehydes. 

An asymmetric variant of this kind of allylic amination, based on their phenylcyclohexanol-derived chiral N-sulfinyl carbamates, was developed by Whitesell et al. (see also Sect. 3.2) (Scheme 34) [85]. After the asymmetric ene reaction with Z-configured olefins (not shown) had occurred, nearly di-astereomerically pure sulfinamides 127 were obtained which were found to be prone to epimerization. Their rapid conversion via O silylation and [2,3]-a rearrangement dehvered the carbamoylated allyhc amines 128 with around 7 1 diastereoselectivity as crystalline compounds that can be recrystallized to enhance their isomeric purity to 95 5. Obviously the imiform absolute configuration at Cl in the ene products 127 was difficult to transfer completely due to the already mentioned ease of epimerization. Unhke the sulfonamides of Delerit (Scheme 33) [84], the carbonyl moiety can easily be cleaved by base treatment. 

In an extension of this methodology, it has been demonstrated that in some cases the enantioselective alkylation of lithium enolates can be achieved by means of a catalytic amount of 1. As in the stoichiometric version (vide supra), the reaction conditions play a crucial role in determining the yield and % ee. One fundamental modification in the catalytic version is the addition of two equiv of an achiral bidentate amine [e.g. tetramethylethylenediamine (TMEDA) or Al,lV,7V, A -tetramethy-Ipropylene diamine (TMPDA)] to trap the large excess of lithium bromide present at the beginning of the reaction. This catalytic asymmetric variant is illustrated by the reaction of the lithium enolate of 1-tetralone with a variety of electrophiles (eq 7). In this example, the optimal reaction conditions were determined to be 0.05 equiv of 1,2.0 equiv of TMPDA, and 10.0 equiv of the alkyl halide. 

Since CIgSiH is known to be activated by DMF and other Lewis bases to effect hydrosilylation of imines (Scheme 4.2) [8], it is hardly surprising that chiral formamides, derived from natural amino adds, emerged as prime candidates for the development of an asymmetric variant of this reaction [8]. It was assumed that, if successful, this approach could become an attractive altemative to the existing enzymatic methods for amine production [9] and to complement another organo catalytic protocol, based on the biomimetic reduction with Hantzsch ester, which is being developed in parallel [5]. 

The direct a-amination of aldehydes and ketones provides a useful method for the synthesis of amino acids and, consequently, the asymmetric variant of this process using either metal-based complexes or organocatalysts has received much attention. 

In addition to tertiary amines, triphenylphosphine is also an effective promoter and the use of enantiomerically pure amines or phosphines to catalyse the reaction is an interesting prospect, since the products would be synthetically useful. In addition there is also the potential for Lewis acid/Bronsted acid-catalysed asymmetric MBH reactions. While early attempts at the development of a catalytic asymmetric variant were only moderately successful, providing products with up to 50% ee, some recent progress has been made in this area and high ees have been obtained in both the MBH and aza-Baylis-Hillman reaction of a,p-carbonyls with imines. 

The cycloaddition of in sitM-generated azomethine yhdes with electron-deficient alkenes is a useful method for the generation of stereodefined, substituted pyrrolidines, and there has been some recent interest in the development of a catalytic asymmetric variant. While a variety of methods for the generation of azomethine ylides have been developed, treatment of an a-iminoester (8.200) with an amine base in the presence of metal salts is the process most commonly employed in the asymmetric variant, which generally uses an enantiomerically pure metal complex of copper, silver or zinc to give an N-metallated ylide (8.201) (Figure 8.6). ... 

Kobayashi and coworkers exploited the use of lanthanide Lewis acid catalysts in various achiral reactions as described in the previous section, and they also successfully extended some of them into asymmetric variants. A series of their works commenced with catalytic asymmetric Diels-Alder reactions [50, 51]. The reaction was performed with a chiral ytterbium catalyst prepared from Yb(OTf)3, (R)-l,l -bi-2-naphthol (BINOL), and tertiary amine. The amine significantly influenced enantioselectivity of the reaction, and cis-l,2,6-trimethylpiperidine combined with 4 A molecular sieves (MS 4 A) aflhrded the best results (endo/exo = 89/11, endo = 95% ee, Yb catalyst A) (Scheme 13.20). Later, Nakagawa and coworkers improved reactivity and selectivity of the Yb catalyst by modification of chiral ligand. Use of l,l -(2,2 -bisacylamino)binaphthalene (Yb catalyst B) gave product in >98%ee [52]. 

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]. 

The stereocontrolled synthesis of a-hydroxyakylated piperidines, a motif frequently encountered in natural products, represents a difficult synthetic challenge that was recently tackled by Hall and co-workers using the aza-variant of the Vaultier-Lallemand three-component reaction described in Scheme 12.14 [62]. One interesting feature of this reaction is the use of hydrazines, as masked amines, which allows the hetero-Diels-Alder reaction to operate on a normal electron demand manifold. Toure and Hall recently applied this powerful MCR to the asymmetric synthesis of (—)-methyl dihydropalustramate 192 [91], a degradation product and postulated biosynthetic precursor of (+)-palustrine (Scheme 12.27) [92]. 

For example, N-(2-hydroxyphenyl)imines 9 (R = alkyl, aryl) together with chiral zirconium catalysts generated in situ from binaphthol derived ligands were used for the asymmetric synthesis of a-amino nitriles [17], the diastereo- and/or enantioselective synthesis of homoallylic amines [18], the enantioselective synthesis of simple //-amino acid derivatives [19], the diastereo- and enantioselective preparation of a-hydroxy-//-amino acid derivatives [20] or aminoalkyl butenolides (aminoalkylation of triisopropylsilyloxyfurans, a vinylogous variant of the Mannich reaction) [21]. A good example for the potential of the general approach is the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10)... 

Recently, two other groups have shown that exocyclic iminium salts can be useful mediators in asymmetric epoxidation. Komatsu has developed a system based on ketiminium salts [14], prepared through the condensation of aliphatic cyclic amines with ketones. A chiral variant was also produced, derived from prolinol and cyclohexanone, which gave 70% yield and 39% ee for cinnamyl alcohol (Scheme 5.7). 

Enantiomerically pure homoallylic amines are very important chiral building blocks for the synthesis of pharmacologically important molecules and natural products. The enantioselective synthesis of these compounds initially involved the chiral auxiUary-based asymmetric allylation of imines [41a, 4lb, 41c], and it is just recently that a few enantioselective variants have been reported. Although still in the regime of stoichiometric asymmetric synthesis, the first methods described below merit discussion for their synthetic utility and for establishing the groundwork for future development. 

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