Ketones chiral additives

Although the conversion of an aldehyde or a ketone to its enol tautomer is not generally a preparative procedure, the reactions do have their preparative aspects. If a full mole of base per mole of ketone is used, the enolate ion (10) is formed and can be isolated (see, e.g., 10-105). When enol ethers or esters are hydrolyzed, the enols initially formed immediately tautomerize to the aldehydes or ketones. In addition, the overall processes (forward plus reverse reactions) are often used for equilibration purposes. When an optically active compound in which the chirality is due to an asymmetric carbon a to a carbonyl group (as in 11) is treated with acid or base, racemization results. If there is another asymmetric center in the molecule. 

Thus the product in such cases can exist as two pairs of enantiomers. In a di-astereoselective process, one of the two pairs is formed exclusively or predominantly as a racemic mixture. Many such examples have been reported. In many of these cases, both the enolate and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters, (E) enolates gave the syn pair of enantiomers (p. 146), while (Z) enolates gave the anti pair. Addition of chiral additives to the reaction, such as proline derivatives, or (—)-sparteine lead to product formation with good-to-excellent asynunetric induction. Ultrasound has also been used to promote asymmetric Michael reactions. Intramolecular versions of Michael addition are well known. ... 

The titanium reagent also dimethylates aromatic aldehydes." Triethylaluminum reacts with aldehydes, however, to give the mono-ethyl alcohol, and in the presence of a chiral additive the reaction proceeds with good asymmetric induction." A complex of Me3Ti-MeLi has been shown to be selective for 1,2 addition with conjugated ketones, in the presence of nonconjugated ketones." ... 

Mukaiyama aldol reactions have been reported, usually using chiral additives although chiral auxiliaries have also been used. This reaction can also be run with the aldehyde or ketone in the form of its acetal R R C(OR )2> in which case the product is the ether R COCHR2CR R OR instead of 27. Enol acetates and enol ethers also give this product when treated with acetals and TiCLi or a similar catalyst. When the catalyst is dibutyltin bis(triflate), Bu2Sn(OTf)2, aldehydes react, but not their acetals, while acetals of ketones react, but not the ketones themselves. 

The addition of HCN to aldehydes or ketones produces cyanohydrins. This is an equilibrium reaction. For aldehydes and aliphatic ketones the equilibrium lies to the right therefore the reaction is quite feasible, except with sterically hindered ketones such as diisopropyl ketone. However, ketones ArCOR give poor yields, and the reaction cannot be carried out with ArCOAr since the equilibrium lies too far to the left. With aromatic aldehydes the benzoin condensation (16-54) competes. With oc,p-unsaturated aldehydes and ketones, 1,4 addition competes (15-33). Ketones of low reactivity, such as ArCOR, can be converted to cyanohydrins by treatment with diethylaluminum cyanide (Et2AlCN see OS VI, 307) or, indirectly, with cyanotrimethylsilane (MesSiCN) in the presence of a Lewis acid or base, followed by hydrolysis of the resulting O-trimethylsilyl cyanohydrin (52). The use of chiral additives in this latter reaction leads to cyanohydrins with good asymmetric... 

C in a TH F-toluene-hexane mixture. After the mixture was cooled below —50 °C, ketone 41 was added. After 60min, the reaction was quenched with aqueous citric acid. The organic layer was then solvent switched into toluene, and the product 50 was crystallized by the addition of heptane (91-93% isolated yield, >99.5% ee). The chiral modifier 46 is easily recycled from the aqueous layer by basification with NaOH and extraction into toluene to recover 46 (>99% purity, 98% recovery yield). The modifier has been recycled up to nine times in subsequent chiral addition reactions without any problem. 

The enantioselective addition of a nucleophile to a carbonyl group is one of the most versatile methods for C C bond formation, and this reaction is discussed in Chapter 2. Trifluoromethylation of aldehyde or achiral ketone via addition of fluorinated reagents is another means of access to fluorinated compounds. Trifluoromethyl trimethylsilane [(CF SiCFs] has been used by Pra-kash et al.87 as an efficient reagent for the trifluoromethylation of carbonyl compounds. Reaction of aldehydes or ketones with trifluoromethyltrime-thylsilane can be facilitated by tetrabutyl ammonium fluoride (TBAF). In 1994, Iseki et al.88 found that chiral quaternary ammonium fluoride 117a or 117b facilitated the above reaction in an asymmetric manner (Scheme 8-42). 

The majority of recent publications still deal with the chiral hydrogenation of ketones containing other functional groups as well. The general characteristics of these reactions are illustrated by the asymmetric hydrogenation of a./f-unsaturated ketones. In addition, the purpose of the present review is to summarize the latest results of the chiral hydrogenation of ketones which do not contain other functional groups (dialkyl ketones and alkyl aryl ketones). 

R-(R, S )]-p-Methyl-a-phenyl-1-pyrrolidineethanol is an important chiral mediator for the enantioselective addition of an acetylide to a prochiral ketone.2 3 This reaction has been successfully applied to the synthesis of the reverse transcriptase inhibitor efavirenz (DMP-266) (Scheme 1).3.4 Preparation of the enantiomer, (1S,2R)-N-pyrrolidinylnorephedrine, has been reported.2 The method used potassium carbonate (K2CO3) as base, but the yield of the product was only 33%. The submitters have extensively studied the formation of the pyrrolidinyl ring under various conditions as summarized in Table I. Eventually they found that the reaction was extremely efficient when it was run in toluene using sodium bicarbonate (NaHCC>3) as base (entry 8, Table I),5 which gave [R-(R, S )]-p-methyl-a-phenyl-1-pyrrolidineethanol quantitatively. Enantioselective (up to 99% ee) addition of cyclopropylacetylene to the ketoaniline 1 is achieved when the solution of [R-(R, S )]-p-methyl-a-phenyl-1-pyrrolidineethanol is used as a chiral additive.3 In addition, this method is also applicable to the preparation of a variety of alkylated norephedrines and other amino alcohols in excellent yields as Illustrated in Table II. These amino alcohols are potentially useful in asymmetric syntheses. 

Chiral -substituted ketones Conjugate addition of (CH,)iAI to the kctal (2) of cyclohexenone derived from (S,S)-1 followed by acetylation results in the adduct 3, which is hydrolyzed by acid to (S)-3-mcthylcyclohcxanonc (4) in 77% ee. The ketal derived from (2R,3R)-2,3-butanediol undergoes a similai conjugate addition with low a.symmetric... 

Enantioselective Reduction of Imines and Ketoxime O-Ethers. In addition to the reduction of prochiral ketones, chiral oxazaborolidines have been employed as enantioselective reagents and catalysts for the reduction of imines (eq 11) and ketoxime O-ethers (eq 12) - to give chiral amines. It is interesting to note that the enantioselectivity for the reduction of ketoxime O-ethers is opposite that of ketones and imines. For more information, see 2-Amino-3-methyl-l,l-diphenyl-I-butanol. 

Nucleophilic addition to less reactive ketone carbonyls by Lewis acid activation is also possible. Evans and co-workers have reported enol silane addition to pyruvate esters mediated by chiral copper Lewis acids (Sch. 36) [72]. The aldol reactions proceed with high facial selectivity to provide the tertiary alcohol products 153. The chemical efficiency is, however, reduced when a bulky alkyl group is present at the ketone carbonyl. Addition of more functionalized enol silanes (155) to keto esters enables the establishment of two contiguous chiral centers, a substitution pattern present in a variety of natural products. The stereochemistry of the major product is syn, irrespective of the enol silane geometry. Once again, bidentate coordination of the substrate to the Lewis acid was essential for obtaining high selectivity. 

These reactions can also be made enantioselective (in which case only one of the four isomers predominates) ° ° by using chiral enol derivatives, chiral aldehydes or ketones, or both. ° " Chiral bases can be used, such as prohne, ° prohne derivatives, or chiral additives, used in conjunction with the base. ° A chiral binaphthol dianion has been used to catalyze the reaction. Chiral auxiharies ° ° have been developed that can be used in conjunction with the aldol condensation, as well as chiral catalysts and chiral ligands " ... 

The Darzens reaction has been performed enantioselectively, by coupling optically active a-bromo-p-hydroxy esters with aldehydes.Chiral phase-transfer agents have been used to give epoxy ketones with modest enantioselectivity. Chiral additives have proven to be effective. 

Saponification. The mil in a synthesis of chiral 2-alkyl 3-keto esters with 2-triflyloxy Emmons-Wadsworth olefi base to effect the olefination of with ketones, slow addition of il... 

We sought to examine the enzymatic dioxygenation of aryl silanes using a number of different aromatic dioxygenases in order to determine if such transformations were possible and to define the substrate-specificity profile. We were also motivated by the rich chemistry of silicon-based materials, which includes the hydrosilylation of alkenes and ketones, the addition of electrophiles to vinyl and allyl silanes, and palladium catalyzed cross-coupling of vinyl silanes with aryl halides (13). As a result, silyl functional cw-diols have potential as chiral intermediates for drug development, as polymer precursors/modifiers and as elements in non-linear optical materials. 

In some cases, it is possible to form a chiral, nonracemic alcohol from a prochiral ketone and a Grignard reagent by adding an asymmetric ligand (a chiral additive) to the reaction mixture, which is differentiated from... 

---