Chiral compounds asymmetric variants

Azirines (three-membered cyclic imines) are related to aziridines by a single redox step, and these reagents can therefore function as precursors to aziridines by way of addition reactions. The addition of carbon nucleophiles has been known for some time [52], but has recently undergone a renaissance, attracting the interest of several research groups. The cyclization of 2-(0-tosyl)oximino carbonyl compounds - the Neber reaction [53] - is the oldest known azirine synthesis, and asymmetric variants have been reported. Zwanenburg et ah, for example, prepared nonracemic chiral azirines from oximes of 3-ketoesters, using cinchona alkaloids as catalysts (Scheme 4.37) [54]. 

Axial Chirality. For a system with four groups arranged out of the plane in pairs about an axis, the system is asymmetric when the groups on each side of the axis are different. Such a system is referred to as an axial chiral system. This structure can be considered a variant of central chirality. Some axial chiral molecules are allenes, alkylidene cyclohexanes, spiranes, and biaryls (along with their respective isomorphs). For example, compound 7a (binaphthol), which belongs to the class of biaryl-type axial chiral compounds, is extensively used in asymmetric synthesis. Examples of axial chiral compounds are given in Figure 1-5. 

The Pictet-Spengler reaction is the method of choice for the preparation of tetrahydro-P-carbolines, which represent structural elements of several natural products such as biologically active alkaloids. It proceeds via a condensation of a carbonyl compound with a tryptamine followed by a Friedel-Crafts-type cyclization. In 2004, Jacobsen et al. reported the first catalytic asymmetric variant [25]. This acyl-Pictet-Spengler reaction involves an N-acyliminium ion as intermediate and is promoted by a chiral thiourea (general Brpnsted acid catalysis). 

A successful asymmetric variant of the imino-Stetter reaction has recently been presented by Miller et al., who employed chiral peptidic thiazolium salts similar to compound 43 (see Fig. 9.6) [51]. 

The most successful asymmetric variants of the Abramov reaction employ chiral substrates, either chiral carbonyl compounds or aldimines, or chiral phosphorus(III) reagents.5,51,86,88 However, the Pudovik reaction using chiral catalysts is a superior route for the asymmetric synthesis of a-hydroxy- and a-aminophosphonates (Section 6). 

Considerable efforts have been made to develop asymmetrical variants of the classical Pauson-Khand reaction. Initial investigations have shown that compounds derived from cobalt complexes of type 1, in which a carbonyl ligand is replaced by a chiral phosphane (glyphos), react with high enantioselectivity [22], However, the procedure is too complex to be of preparative value. The concept of Kerr et al., who achieved significant enantioselectivities (max. 44 % ee) in intermolecular Pauson-Khand reactions by... 

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. 

The Darzens reaction (tandem aldol-intramolecular cyclization sequence reaction) is a powerful complementary approach to epoxidation (see Chapter 5) that can be used for the synthesis of a,P-epoxy carbonyl and a,p-epoxysulfonyl compounds (Scheme 8.32). Currently, all catalytic asymmetric variants of the Darzens reactions are based on chiral phase-transfer catalysis using quaternary ammonium salts as catalysts. 

The first attempts to develop a heterazolium-catalyzed asymmetric variant of the Stetter reaction were carried out by our group [44,45,46], employing the chiral thiazolium salt 9 to catalyze the addition of butanal to chalcone. The resultant 1,4-dicarbonyl compound 10 was obtained in 29% yield with enantiomeric excesses up to 30% (Scheme 6). 

Arenes suffer dearomatization via cyclopropanation upon reaction with a-diazocarbonyl compounds (Btlchner reaction) [76]. Initially formed norcaradiene products are usually present in equilibrium with cycloheptatrienes formed via electrocyclic cyclopropane ring opening. The reaction is dramatically promoted by transition metal catalysts (usually Cu(I) or Rh(II) complexes) that give metal-stabilized carbenoids upon reaction with diazo compounds. Inter- and intramolecular manifolds are known, and asymmetric variants employing substrate control and chiral transition metal catalysts have been developed [77]. Effective chiral catalysts for intramolecular Buchner reactions include Rh Cmandelate), rhodium carboxamidates, and Cu(I)-bis(oxazolines). While enantioselectivities as high as 95% have been reported, more modest levels of asymmetric induction are typically observed. 

A second generation route to this class of compound using sulphoxide chiral auxiliaries has already been described in section 5.3.5. The third-generation method here is an asymmetric variant of the Wittig reaction.ti l The asymmetric reagent is derived from (5, 5)- or (R, / )- ,2-diaminocyclohexane (note the C2 symmetry). Deprotonation and reaction with a 4-substituted cyclohexanone leads to one or other enantiomer of the axially chiral alkylidenecyclohexane (43) with a good e.e. of 70-90%. The origin of this selectivity is not yet fully understood. 

The high value of catalytically performed reactions as compared to non-catalytic variants is particularly evidenced in the field of enantioselective reactions. Chemists cannot complete enantioselective reactions without certain chiral information in the reacting system. This information is regularly derived from the chiral compounds present in nature, collectively named the chiral pool of the nature. Their availability is often limited, which is not an issue when they are used as catalysts, but causes significant costs of non-catalytic reactions when they are needed in equimolar quantities. The practical value of the catalytic approach to enantioselective processes cannot be overestimated. Asymmetric catalysis characterizes the amplification of chirality one chiral molecule of the catalyst generates an enormous number of chiral molecules of the product in the optically pure form. This results with high chiral economy of catalytically performed enantioselective syntheses. 

Importantly, asymmetric variants of the foregoing reactions have been developed by using the cationic or neutral rhodium(I)/axially chiral biaryl bisphosphine complexes as catalysts. Although the rhodium-based catalysts are expensive, these are highly stable and can be handled readily using conventional laboratory equipment. Therefore, I believe that rhodium-catalyzed [2 - - 2 - - 2] cycloaddition reactions wiU be employed continuously for the synthesis of complex aromatic compounds. 

Mannich reactions give rise to (i-amino carbonyl compounds which are amenable to further synthetic manipulations. Numerous stereoselective variants have been achieved by means of different types of catalysts including both metal complexes and organic molecules. In 2004, the groups of Akiyama and Terada independently selected this transformation as a model reaction for the introduction of a novel chiral motif to asymmetric catalysis [14, 15]. 

A number of chiral bisphosphines related to DiPAMP(l) were prepared and evaluated in asymmetric catalysis. Many variants were closely equivalent but none were superior to the parent compound. In addition, some monophosphines containing sulfone substituents were quite effective. These had the particular advantage of being usable in water solution. Several new DIOP derivatives were tried in the hydroformylation of vinyl acetate but only modest enantiomeric excesses were achieved. A 72% enantiomeric excess was achieved on dehydrovaline under relatively forcing conditions using DiCAMP(3). This result was remarkable since these phosphine ligands generally work very poorly, if at all, on tetrasubstituted olefins. 

Recent developments in enantioselective protonation of enolates and enols have been reviewed, illustrating the reactions utility in asymmetric synthesis of carbonyl compounds with pharmaceutical or other industrial applications.150 Enolate protonation may require use of an auxiliary in stoichiometric amount, but it is typically readily recoverable. In contrast, the chiral reagent is not consumed in protonation of enols, so a catalytic quantity may suffice. Another variant is the protonation of a complex of the enolate and the auxiliary by an achiral proton source. Differentiation of these three possibilities may be difficult, due to reversible proton exchange reactions. 

Two main attributes are ascribed to natural shikimic acid the first, of practical nature, is related to its use as a chiral source for asymmetric synthesis, the second, of biochemical prominence, is connected to the key role it exerts in the production of benzenoid rings of natural aromatic amino acids and other important metabolites [45]. The biological relevance of shikimic acid and the challenging nature of its multichiral structure have motivated an active search for the development of viable asymmetric syntheses of this compound and novel structural variants [46],... 

The importance of fluorinated organic componnds both in medicinal chemistry and biochemistry has resulted in much recent attention towards efficient carbon fluorine bond formation [30]. The reactions developed include a very successful electrophilic asymmetric mono-fluormation of 1,3-dicarbonyl compounds [31]. A nucleophilic variant was also investigated. In this context, the groups of Togni and Mezzetti have established that ruthenium Lewis acids could efficiently catalyze fluorination reactions [32]. In the presence of [Ru(l,2-bis(diphenylphosphino)ethane)2Cl][PF6] (8) (10 mol%), fert-butyl iodide reacted at room temperature with TIF (1.1 equiv.) to yield fert-butyl fluoride (84% yield). This reaction was extended successfully to a range of organic halides (Entries 1-3, Scheme 10.19). The use of the chiral complex [Ru((lS,2S)-N,N bis[2-diphenylphos-phino)benzylidene]diaminocydohexane))Cl][PF6] (9) showed modest chiral induction at the outset of the reaction (Entry 4, Scheme 10.17). The near-racemic mixture obtained at completion points to an SNl-type process in this nucleophilic halide... 

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