Nucleophilic organocatalysts

The KR of aryl alkyl sec-alcohols using various chiral nucleophilic N-heterocyclic carbenes (NHCs) has also recently been achieved by the groups of Suzuki [125, 126] and Maruolca [127]. These studies build on an emerging body of information showing that achiral NHCs are extremely efficient nucleophilic organocatalysts for transesterification [128]. The levels of selectivity achieved by Maruoka using the Cj-symmetric NHC 29b for the KR of aryl alkyl sec-alcohols (and two allylic alcohols) lie in the range 16 to 80 (Scheme 8.8). 

The recent development of polymers containing imidazolium, thiazolium and related structures as supported equivalents of ionic liquids (i.e. 148 and 149, Scheme 10.23) is an interesting development of this field [356-361], The corresponding salts containing basic counter-anions can act as basic catalysts but can also be transformed, depending on the exact structure, into N-heterocydic car-benes that can act as nucleophilic organocatalysts [362]. As an example, resins 148... 

Ahmad, S.M., Braddock, D.C., Cansell, G. and Hermitage, S.A. (2007) Dimethylforma-mide, dimethylacetamide and tetramethylguanidine as nucleophilic organocatalysts for the transfer of electrophilic bromine from A-bromosuccinimide to alkenes. Tetrahedron Letters, 48, 915 918. 

FIGURE 2.27. Representative Lewis base (nucleophilic) organocatalysts. 

Particularly interesting new work includes the development of remote and abnormal NHCs (see Chapter 5 for further details). Also, NHCs have not only been used as ligands in transition metal chemistry but also as nucleophilic organocatalysts. In an extension of this concept, Lavallo and Grubbs presented recently the first organometallic transformation catalyzed by NHCs. This illustrate nicely that almost 20 years after Arduengo s first report on an N-heterocyclic carbene, new NHCs as well as new applications for these interesting and versatile molecules are still and will be for some time the subject of intensive research. 

The total syntheses of the iridoids (-i-)-geniposide (255) and 7-deoxyloganin (256) are two illustrative cases where achiral nucleophilic organocatalysts have been successfully used to facihtate cyclization reactions of chiral starting materials. 

In addition to metal catalysts, organocatalysts could also be used in asymmetric cyanation reactions. Chiral Lewis bases, modified cinchona alkaloids, catalyzed asymmetric cyanation of ketones by using ethyl cyanoformate as the cyanide source (Scheme 5.34)." Similar to metal-catalyzed reactions, ethyl cyanoformate was first activated by chiral Lewis bases to form active nucleophiles. Various acyclic and cyclic dialkyl ketones were transformed into the desired products. Because of using... 

In the 1990s, short peptides,and other nucleophiles °° ° were used as organocatalysts for a number of enantioselective acyl transfer processes transformations that set the stage for the more recent research in the area of nucleophilic catalysis.One of the most appealing approaches to enantioselective acyl transfer was outlined by Fu using an azaferrocene catalyst (6) [Eq. (11.6)]. While these pyridyl systems are not organic catalysts in the strictest sense, these azaferrocene compounds function as chiral dimethylaminopyridine equivalents for a broad range of acyl transfer processes ... 

After having proven that BINOL phosphates serve as organocatalysts for asymmetric Mannich reactions, Akiyama and Terada et al. reasoned that the concept of electrophilic activation of imines by means of chiral phosphoric acids might be applicable to further asymmetric transformations. Other groups recognized the potential of these organocatalysts as well. They showed that various nucleophiles can be used. Subsequently, chiral phosphates were found to activate not only imines, but also other substrates. 

As demonstrated in a series of kinetic experiments by Wittkopp and Schreiner, nitrone N-benzylideneanihne N-oxide can be activated for 1,3-dipolar cycloadditions through double hydrogen-bonding 9 [Ij. Takemoto and co-workers, in 2003, published the nucleophilic addition of TMSCN and ketene silyl acetals to nitrones and aldehydes proceeding in the presence of thiourea organocatalyst 9 (Figure 6.4) [147]. 

In contrast to monofunctional (thio)urea organocatalysts, bifunctional catalyst structures enable simultaneous coordination, activation, and suitable relative orientation of both reaction components (the electrophile and the nucleophile) resulting in high... 

Examples of nonasymmetric organocatalysts that were introduced in the 1950s include analogs of thiamine reported by Breslow in 1957 as an alternative to cyanide as a catalyst for the benzoin condensation [8]. Asymmetric versions of these thiazolium catalysts were used in organocatalytic benzoin condensations by Sheehan and Hunneman in 1966 [9]. In another important development, in 1969 the nucleophilic catalyst 4-(dimethylamino)pyridine (DMAP), which is now widely used for difficult esterifications, was reported by Steglich [10]. 

The Strecker reaction [1] starting from an aldehyde, ammonia, and a cyanide source is an efficient method for the preparation of a-amino acids. A popular version for asymmetric purposes is based on the use of preformed imines 1 and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst [2], Besides asymmetric cyanations catalyzed by metal-complexes [3], several methods based on the use of organocatalysts have been developed [4-14]. The general organocatalytic asymmetric hydrocyanation reaction for the synthesis of a-amino nitriles 2 is shown in Scheme 5.1. 

An asymmetric Mannich reaction was recently successfully achieved by means of different types of catalyst, metal- and organocatalysts [20, 21]. With the latter the reaction can be performed asymmetrically by use of L-proline and related compounds as chiral organocatalyst [22-35]. A key advantage of the proline-catalyzed route is that unmodified ketones are used as donors, which is synthetically highly attractive. In contrast, many other asymmetric catalytic methods require preformed enolate equivalents as nucleophile. 

In addition to proline, other types of organocatalyst have been found to catalyze the Mannich-type reaction efficiently. The Jacobsen group developed an elegant and highly enantioselective route to N-Boc-/i-amino acid esters via nucleophilic ad-... 

The asymmetric catalytic hydrophosphonylation is an attractive approach for the synthesis of optically active a-amino phosphonates [84]. The first example of this type of reaction was reported by the Shibasaki group in 1995 using heterobimetal-lie lanthanoid catalysts for the hydrophosphonylation of acyclic imines [85a]. This concept has been extended to the asymmetric synthesis of cyclic a-amino phosphonates [85b—d]. Very recently, the Jacobsen group developed the first organocatalytic asymmetric hydrophosphonylation of imines [86], In the presence of 10 mol% of thiourea-type organocatalyst 71, the reaction proceeds under formation of a-amino phosphonates 72 in high yield (up to 93%) and with enantioselectivity of up to 99% ee [86], A selected example is shown in Scheme 5.42. Di-o-nitrobenzyl phosphite 70 turned out to be the preferred nucleophile. 

Trichlorosilylenolates of type 13 were used as nucleophiles. Such enolates are highly activated ketone derivatives and react spontaneously with several aldehydes at room temperature. At —78 °C, however, the uncatalyzed reaction can be suppressed almost completely (formation of the undesired racemic aldol adduct is only 4%). Thus, at —78 °C and in the presence of the chiral organocatalyst 14 the acetone-derived enolate and benzaldehyde gave the desired adduct in high yield... 

Aldol reactions using a quaternary chinchona alkaloid-based ammonium salt as orga-nocatalyst Several quaternary ammonium salts derived from cinchona alkaloids have proven to be excellent organocatalysts for asymmetric nucleophilic substitutions, Michael reactions and other syntheses. As described in more detail in, e.g., Chapters 3 and 4, those salts act as chiral phase-transfer catalysts. It is, therefore, not surprising that catalysts of type 31 have been also applied in the asymmetric aldol reaction [65, 66], The aldol reactions were performed with the aromatic enolate 30a and benzaldehyde in the presence of ammonium fluoride salts derived from cinchonidine and cinchonine, respectively, as a phase-transfer catalyst (10 mol%). For example, in the presence of the cinchonine-derived catalyst 31 the desired product (S)-32a was formed in 65% yield (Scheme 6.16). The enantioselectivity, however, was low (39% ee) [65],... 

Replacing 30a by the bulky alkyl enolate 30b as nucleophile led to an improved enantioselectivity (up to 62% ee) (Scheme 6.16). In both reactions the (S) enantiomer was preferably formed. The organocatalyst derived from cinchonine 31 was more efficient than that derived from cinchonidine [66],... 

Aldol reactions using phosphoramides as organocatalysts The organic base-catalyzed asymmetric intermolecular aldol reaction with ketone-derived donors can be successfully applied to the construction of aldol products with two stereogenic centers [82-86]. Trichlorosilyl enolates of type 51 have been used as nucleophiles. Such enolates are strongly activated ketone derivatives and react spontaneously with several aldehydes at —80 °C. A first important result was that in the aldol reaction of 51 catalytic amounts of HMPA led to acceleration of the rate of reaction. After screening several optically active phosphoramides as catalysts in a model reaction the aldol product anti-53 was obtained with a diastereomeric... 

In addition to the classic aldol reaction described, e.g., in Sections 6.2.1 and 6.2.2, several modified versions have been reported. These methods are based on the use of nucleophiles related to the standard ketones. In particular, y-dienolates, nitromethane, and nitrones are interesting carbon nucleophiles in aldol reactions and the use of these types of substrate has been investigated in aldol reactions catalyzed by organocatalysts. 

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