Enantioselectivity formation

An achiral reagent cannot distinguish between these two faces. In a complex with a chiral reagent, however, the two (phantom ligand) electron pairs are in different (enantiotopic) environments. The two complexes are therefore diastereomeric and are formed and react at different rates. Two reaction systems that have been used successfully for enantioselective formation of sulfoxides are illustrated below. In the first example, the Ti(0-i-Pr)4-f-BuOOH-diethyl tartrate reagent is chiral by virtue of the presence of the chiral tartrate ester in the reactive complex. With simple aryl methyl sulfides, up to 90% enantiomeric purity of the product is obtained. 

Accordingly, cyclic nitronates can be a useful synthetic equivalent of functionalized nitrile oxides, while reaction examples are quite limited. Thus, 2-isoxazoline N-oxide and 5,6-dihydro-4H-l,2-oxazine N-oxide, as five- and six-membered cyclic nitronates, were generated in-situ by dehydroiodination of 3-iodo-l-nitropropane and 4-iodo-l-nitrobutane with triethylamine and trapped with monosubstituted alkenes to give 5-substituted 3-(2-hydroxyethyl)isoxazolines and 2-phenylperhydro-l,2-oxazino[2,3-fe]isoxazole, respectively (Scheme 7.26) [72b]. Upon treatment with a catalytic amount of trifluoroacetic acid, the perhydro-l,2-oxazino[2,3-fe]isoxazole was quantitatively converted into the corresponding 2-isoxazoline. Since a method for catalyzed enantioselective nitrone cycloadditions was established and cyclic nitronates should behave like cyclic nitrones in reactivity, there would be a good chance to attain catalyzed enantioselective formation of 2-isoxazolines via nitronate cycloadditions. 

A breakthrough in the area of asymmetric epoxidation came at the beginning of the 1990s, when the groups of Jacobsen and Katsuki more or less simultaneously discovered that chiral Mn-salen complexes (15) catalyzed the enantioselective formation of epoxides [71, 72, 73], The discovery that simple achiral Mn-salen complexes could be used as catalysts for olefin epoxidation had already been made... 

Imidate esters can also be generated by reaction of imidoyl chlorides and allylic alcohols. The lithium anions of these imidates, prepared using lithium diethylamide, rearrange at around 0°C. When a chiral amine is used, this reaction can give rise to enantioselective formation of 7, 8-unsaturated amides. Good results were obtained with a chiral binaphthylamine.265 The methoxy substituent is believed to play a role as a Li+ ligand in the reactive enolate. 

The key to the success of the synthesis was the development of a novel method for enantioselective formation of a-arylpyrrolidines. In this method, (-)-sparteine-mediated, enantioselective lithiation of N-Boc-pyrrolidine 19 was followed by an in situ transmetallation to zinc and Pd-catalyzed coupling reaction with aryl bromide 3, which afforded 2-arylpyrrolidine in 63% isolated yield and 92% ee. Notably, the acidic aniline NH2 group was tolerated under the coupling reaction conditions. 

Optically active Diels-Alder adducts were also prepared by using a one-pot preparative method and enantioselective formation of inclusion complex with optically active hosts in a water suspension medium.68 For example, A-ethylmaleimide reacts with 2-methyl-1,3-butadiene in water to give the racemic adduct 1. Racemic 1 and the optically active host 2 form enantioselectively a 1 1 inclusion complex of 2 with (+)-l in a water suspension. The inclusion complex can be filtered and heated to release (+)-l with 94% ee (Eq. 12.23). 

Scheme 4.38. Enantioselective formation of [Mactams from nitrones and alkynes.

Over the years of evolution, Nature has developed enzymes which are able to catalyze a multitude of different transformations with amazing enhancements in rate [1]. Moreover, these enzyme proteins show a high specificity in most cases, allowing the enantioselective formation of chiral compounds. Therefore, it is not surprising that they have been used for decades as biocatalysts in the chemical synthesis in a flask. Besides their synthetic advantages, enzymes are also beneficial from an economical - and especially ecological - point of view, as they stand for renewable resources and biocompatible reaction conditions in most cases, which corresponds with the conception of Green Chemistry [2]. 

Most remarkably, the homoallylic halides 214 not only yield the thermodynamically unfavored ris-cyclopropanes 215 preferentially (see Sect. 2.2.3), but also give rise to enantioselective formation of the (1/ ) configuration, in contrast to the cyclopropanation of 1,3-butadienes with the same catalysts (see Table 15). Only in the case of olefin 214 (X = CF3, Y = Cl), may the (1 S)-trans isomer be obtained enantioselecti-vely, depending on the catalyst (Table 16, entries 8-11). In these few cases, optical induction occurs at C(3) of the cyclopropane rather than at C(l). 

The value of 2-acyl-1,3-dithiane 1-oxides in stereocontrolled syntheses has been extended to the enantioselective formation of (3-hydroxy-y-ketoesters through ester enolate aldol reactions <00JOC6027>. 

CATALYTIC ASYMMETRIC ADDITIONS OF DIALKYLZINC TO KETONES ENANTIOSELECTIVE FORMATION OF TERTIARY ALCOHOLS... 

Compared with many other reactions for enantioselective formation of C-C bonds, the asymmetric Darzens condensation66 has received less attention. Therefore, there is ample opportunity for chemists to improve the enantio-selectivity of the reaction, as well as to develop the reaction itself. 

In 1997, Whitby reported that treatment of 2,5-dihydrofuran with Et3Al in the presence of 5 mol% 31 leads to the enantioselective formation of 39 (Scheme 6.13), rather than the product obtained from catalytic carbomagnesations (40) [34]. This outcome can be rationalized on the basis of Dzhemilev s pioneering report that with Et3Al, in contrast to the mechanism that ensues with EtMgCl (see Scheme 6.2), the intermediate alumina-cyclopentane (i) is converted to the corresponding aluminaoxacyclopentane ii. To ensure the predominant formation of 39, catalytic alkylations must be carried out in absence of solvent. 

In addition to its utility in the enantioselective formation of C-0 bonds (cf. Scheme 15), Trost s chiral ligand 102 has been used in the catalytic asymmetric synthesis of C-N bonds. An impressive application of this protocol is in the enantioselective total synthesis of pancrastatin by Trost (Scheme 17) H9i Thus, Pd-catalyzed desymmetrization of 112 leads to the formation of 113 efficiently and in > 95 % ee. The follow-up use of the N3 group to fabricate the requisite cyclic amide via isocyanate 117 demonstrates the impressive versatility of this asymmetric technology. 

Scheme 41 Enantioselective formation of a piperidine ring system...

Due to its reliability, the SN2 substitution is often used in applications which require the highly enantioselective formation of the allene for example, Brummond et al. [19g] prepared the yneallene 19 (a starting material for intramolecular allenic Pauson-Khand cycloadditions) through the anti-selective SN2 substitution of the chiral propargylic mesylate 18 with a suitable magnesium cuprate (Scheme 2.6). 

A chair-like amino-zinc-enolate transition state has been used to explain how substituents on the ring affect the diastereoselective and enantioselective formation of polysubstituted pyrrolidines during intramolecular amino-zinc-enolate carbometalla-tion reactions. ... 

Fig. 12.6 Enantioselective formation of pinoresinol. Forsythia intermedia dirigent protein mediates selective formation of (-l-)-pinoresinol...

Fig. 12.10 Enantioselective formation of neolignans in Vinca rosea and Piper regnellii...

Another example of the enzymatic enantioselective formation of a C8-C5 neolignan was reported. A crude enzyme preparation from Piper regnellii catalyzed the enantioselective formation of (+)-conocarpan (85% e.e.) from j9-anol (Fig. 12.10) [67],... 

Chiral phosphoric acids mediate the enantioselective formation of C-C, C-H, C-0, C-N, and C-P bonds. A variety of 1,2-additions and cycloadditions to imines have been reported. Furthermore, the concept of the electrophilic activation of imines by means of phosphates has been extended to other compounds, though only a few examples are known. The scope of phosphoric acid catalysis is broad, but limited to reactive substrates. In contrast, chiral A-triflyl phosphoramides are more acidic and were designed to activate less reactive substrates. Asymmetric formations of C-C, C-H, C-0, as well as C-N bonds have been established. a,P-Unsaturated carbonyl compounds undergo 1,4-additions or cycloadditions in the presence of A-triflyl phosphoramides. Moreover, isolated examples of other substrates can be electrophil-ically activated for a nucleophilic attack. Chiral dicarboxylic acids have also found utility as specific acid catalysts of selected asymmetric transformations. 

The enantioselective formation of bicyclic ketones through enantioselective deprotonation of the bicyclooxiranes 147,148 and 149 (Scheme 64) by homochiral lithium amides (such as 50) and subsequent rearrangement have also been reported with moderate enantiomeric excesses and yields . 

In the last few years new aldolases have emerged as useful biocatalysts in the enantioselective formation of C-C bonds. For instance, the value of enzyme discovery has been illustrated in the synthesis of a precursor for the synthesis of... 

Bis(oxazoline) ligands have also been employed in the catalytic enantioselective aza-Claisen rearrangement of allylic imidates, " chirality recognition in the determination of the ee of l,l -bi-2-naphthol, " and the enantioselective formation of double and triple helicates. 

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