Bases chiral

Quite a number of asymmetric thiol conjugate addition reactions are known [84], but previous examples of enantioselective thiol conjugate additions were based on the activation of thiol nucleophiles by use of chiral base catalysts such as amino alcohols [85], the lithium thiolate complex of amino bisether [86], and a lanthanide tris(binaphthoxide) [87]. No examples have been reported for the enantioselective thiol conjugate additions through the activation of acceptors by the aid of chiral Lewis acid catalysts. We therefore focussed on the potential of J ,J -DBFOX/ Ph aqua complex catalysts as highly tolerant chiral Lewis acid catalyst in thiol conjugate addition reactions. 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

Chinchona alkaloids, such as quinine, are readily available quinuclidine chiral bases which have been used extensively in catalytic Michael additions239 243. Methy 1-2,3-dihydro-1-oxo-l/f-in-dene-2-carboxylate (1) is most frequently used as the Michael donor in these studies. Enantiose-lectivities as high as 76% are reached in the additions to 3-buten-2-one. Modest enantioselec-tivities (< 67%) were also obtained with ethyl 2-oxo-l-cyclohexanecarboxylate and methyl l,3-dihydto-3-oxo-l-isobcnzol urancarboxylate244 245. 

The stereogenic sulfur atom in sulfoxides is usually configurationally stable at room temperature thus, sulfoxides may be chiral based on this property alone1. In fact, there are many examples of optically active sulfoxides of both synthetic and natural origin. This chapter reviews the important methods for obtaining optically active sulfoxides, and discusses some reactions at sulfur which either leave the coordination number at three or increase it to four, generally with preservation of optical activity. It also describes briefly some recent studies on the conformational analysis and chiroptical properties of sulfoxides. 

Efficient enantioselective alkylations are known.In another method, enantio-selective alkylation can be achieved by using a chiral base to form the enolate. 

In the case of the ketone (12), a racemic mixture was converted to an optically active mixture (optical yield 46%) by treatment with the chiral base (13). This happened beeause 13 reacted with one enantiomer of 12 faster than with the other (an example of kinetic resolution). The enolate (14) must remain coordinated with the chiral amine, and it is the amine that reprotonates 14, not an added proton donor. 

Elimination gave also here the azirines 32. The use of chiral base in these cases did not result in a chirality transfer. Attempts were also made to prepare the corresponding 2-sulfinyl-2ff-azirines. It turned out that these compounds... 

Palacios et al. utilized the modified Neber reaction for the preparation of 2ff-azirine-2-phosphonates 33 as shown in Scheme 18 [28 a]. The use of quini-dine and dihydroquinidine as the chiral base resulted in moderate chirality transfer (20-52% ee). Similarly, 2-phosphinoyl-2H-azirines could be obtained by the Neber 1,3-elimination reaction [28bj. 

In 2003, Sigman et al. reported the use of a chiral carbene ligand in conjunction with the chiral base (-)-sparteine in the palladium(II) catalyzed oxidative kinetic resolution of secondary alcohols [26]. The dimeric palladium complexes 51a-b used in this reaction were obtained in two steps from N,N -diaryl chiral imidazolinium salts derived from (S, S) or (R,R) diphenylethane diamine (Scheme 28). The carbenes were generated by deprotonation of the salts with t-BuOK in THF and reacted in situ with dimeric palladium al-lyl chloride. The intermediate NHC - Pd(allyl)Cl complexes 52 are air-stable and were isolated in 92-95% yield after silica gel chromatography. Two diaster corners in a ratio of approximately 2 1 are present in solution (CDCI3). 

Even if organocatalysis is a common activation process in biological transformations, this concept has only recently been developed for chemical applications. During the last decade, achiral ureas and thioureas have been used in allylation reactions [146], the Bayhs-Hillman reaction [147] and the Claisen rearrangement [148]. Chiral organocatalysis can be achieved with optically active ureas and thioureas for asymmetric C - C bond-forming reactions such as the Strecker reaction (Sect. 5.1), Mannich reactions (Sect. 5.2), phosphorylation reactions (Sect. 5.3), Michael reactions (Sect. 5.4) and Diels-Alder cyclisations (Sect. 5.6). Finally, deprotonated chiral thioureas were used as chiral bases (Sect. 5.7). 

Axially chiral Pd-NHC complexes reported by Shi and co-workers [26-28] have shown high selectivity in the oxidative kinetic resolution of alcohols without the need of addition of a chiral base. Enantiomeric excesses of up to 99% were obtained (Scheme 10.7). 

A combination of the Lewis acid zinc triflate and the bases NEt, or pyridine acted as an achiral catalyst for this reaction. Instead, using a chiral base which incorporates a bipy ligand to bind zinc gave 26% ee of the product (Scheme 5-42a). Alternatively, diethylzinc was an active precatalyst, but attempts to use chiral amino alcohols as ligands in this system gave low ees (Scheme 5-42b) [31]. 

It is also possible to achieve enantioselective enolate formation by using chiral bases. Enantioselective deprotonation requires discrimination between two enantiotopic hydrogens, such as in d.v-2,6-dimethylcyclohexanone or 4-(/-butyl)cyclohcxanonc. Among the bases that have been studied are chiral lithium amides such as A to D.22... 

Such enantioselective deprotonations depend upon kinetic selection between prochiral or enantiomeric hydrogens and the chiral base, resulting from differences in diastere-omeric TSs.27 For example, transition structure E has been proposed for deprotonation of 4-substituted cyclohexanones by base D.28 This structure includes a chloride generated from trimethylsilyl chloride. 

The asymmetric Baylis-Hillman reaction of sugar-derived aldehydes as chiral electrophiles with an activated olefin in dioxane water (1 1) proceeded with 36-86% de and in good yields of the corresponding glycosides (Eq. 10.47).104 The use of chiral /V-mcthylprolinol as a chiral base catalyst for the Baylis-Hillman reaction of aromatic aldehydes with ethyl acrylate or methyl vinyl ketone gave the adducts in good yields with moderate-to-good enantioselectivities in l,4-dioxane water (1 1, vol/vol) under ambient conditions.105... 

Catalytic enantioselective nucleophilic addition of nitroalkanes to electron-deficient alke-nes is a challenging area in organic synthesis. The use of cinchona alkaloids as chiral catalysts has been studied for many years. Asymmetric induction in the Michael addition of nitroalkanes to enones has been carried out with various chiral bases. Wynberg and coworkers have used various alkaloids and their derivatives, but the enantiomeric excess (ee) is generally low (up to 20%).199 The Michael addition of methyl vinyl ketone to 2-nitrocycloalkanes catalyzed by the cinchona alkaloid cinchonine affords adducts in high yields in up to 60% ee (Eq. 4.137).200... 

Scheme 4.60 Chiral base-induced [2,3]-Wittig rearrangement of a-(propargyloxy)acetic acid 234.

Table 9.4S Enantioselective additions of allenyl tributyl tin to aldehydes catalyzed by a Lewis acid-chiral base complex.

Kinetic data on the influence of the reaction temperature on the enantioselectivity using chiral bases and prochiral alkenes revealed a nonlinearity of the modified Eyring plot [16]. The observed change in the linearity and the existence of an inversion point indicated that two different transition states are involved, inconsistent with a concerted [3+2] mechanism. Sharpless therefore renewed the postulate of a reversibly formed oxetane intermediate followed by irreversible rearrangement to the product. 

We have studied this reaction in considerable detail (88) and have found that when one uses quinine (eq. [25]) or any one of the chiral bases, a variety of aldehydes react with ketene to form the corresponding p-lactones in excellent chemical and nearly quantitative enantiomeric yields. Equation [25] exemplifies the reaction. Note that mild basic hydrolysis of the lactone furnishes a trichlo-rohydroxy acid that was prepared earlier by McKenzie (89). If one uses quinidine as catalyst, the process furnishes the natural (S)-malic acid. Note that ketene first acylates the free hydroxyl group of quinine, so that the actual catalyst is the alkaloid ester. 

Okamura and coworkers151 studied the base catalyzed Diels-Alder reactions between 3-hydroxy-2-pyrone (224) and chiral l,3-oxazolidin-2-one based acrylate derivatives. Catalysis of the reaction between 224 and 225 by triethylamine gave fair to good de values, somewhat dependent on the solvent system used (equation 63, Table 7). Addition of 5% of water to the solvent isopropanol, for example, increased the de of the endo adduct 226 substantially. When the amount of water was increased, however, the triethylamine catalyzed reaction became less endo and diastereofacially selective, a small amount of exo 227 being obtained. Replacing triethylamine by the chiral base cinchonidine also improved the de, but now independently of the solvent system used. 

Many chiral catalysts are commercially available, but others are readily prepared by quatemization of the appropriate chiral base. The preparation of a selection of the more commonly used, or potentially interesting, chiral ammonium salts is presented in 12,1,1. 

Coupling A graphite felt electrode chemically modified with TEMPO led to the enantioselective electrocatalytic coupling of 2-naphthol, 2-methoxynaphth-alene and 10-hydroxyphenanthrene with high enantioselectivity (up to 98% ee) in the presence of (-)-sparteine as a chiral base [366]. 

The desymmetrization of the A -phenylcyclopropylsuccinimide (185) has been effected by its reaction at low temperature with a chiral base (186) and an in situ electrophile, trimethylsilyl chloride. The silylated product (187) was obtained in 80% yield and 95% ee (Scheme 18). ... 

---