Chiral mediator

Chiral 1,3-dicarbonyl compounds such as 2-765 and 2-766 have also been used for the preparation of enantiopure products [381, 382]. In addition, chiral mediators such as 2-767 have been employed with great success (Scheme 2.169) [375, 376]. 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

Uemura and coworkers utilized (R)-binaphthol 85 as chiral ligand in place of DET in association with Ti(IV)/TBHP, which not only mediated the oxidation of sulfides to (R)-configurated sulfoxides, but also promoted the kinetic resolution of sulfoxides (equation 50). In this latter process the two enantiomers of the sulfoxide are oxidized to sulfone by the chiral reagent at different rates, with decrease of the chemical yield, but increase of the ee values. Interestingly, the presence of ortho-nilro groups on the binaphthol ligand lead to the reversal of enantioselectivity with formation of the (5 )-configurated sulfoxide. Non-racemic amino triols and simple 1,2-diols have been successfully used as chiral mediators. 

A solid-phase sulfur oxidation catalyst has been described in which the chiral ligand is structurally related to Schiff-base type compounds (see also below). A 72% ee was found using Ti(OPr-i)4, aqueous H2O2 and solid-supported hgand 91 . More recently, a heterogeneous catalytic system based on WO3, 30% H2O2 and cinchona alkaloids has been reported for the asymmetric oxidation of sulfides to sulfoxides and kinetic resolution of racemic sulfoxides. In this latter case 90% ee was obtained in the presence of 92 as chiral mediator. ... 

A better accessible chiral mediator is the (acyloxy)borane (CAB) 2-64 prepared in situ from a tartaric acid derivative and arylboronic acid at room temperature. Hetero Diels-Alder reaction of benzaldehyde and Danishefsky s diene 2-10 in the presence of 2-64 gave the corresponding pyrone after acidic work up with 52 - 95 % ee depending on R. The best results were obtained with R = 2,4,6-Me3Ph and 2,4,6-iPr3Ph. Similarly, with 2-60 the pyrone 2-61 with up to 97% ee was found [107]. 

Chiral Lewis acids have been employed by Yamamoto et al. [197 -199] in order to carry out enantioselective aza Diels-Alder reactions starting from achiral substrates however, these transformations required stoichiometric amounts of the chiral mediator 3-16 which was generated in situ from (fl)-binaphthol and triphenylborate. The best results were obtained with the pyridine derivative 3-14 which afforded the desired cycloadduct 3-15 in high optical purity (Fig. 3-5). Using chiral imines, the authors found a high level of double asymmetric induction, and this methodology could be applied to the enantioselective total synthesis of two piperidine alkaloids. 

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. 

This reaction type has also been used for the diastereoselective reduction of a variety of structurally related o -amino-/3-keto esters (equations 9 and 10). Treatment of rac-73 with a substoichiometric amount of chiral mediator 72, using formic acid and triethylamine as the hydrogen source, gave the enantiomerically pure a-amino-/ -hydroxy ester (R,S)-syn-74 in 100% yield with 95 5 dr and 99% ee (equation 9), via the diastereoselective reduction of (S)-73. The unreacted R)-73 efficiently racemizes through tautomerization under these reaction conditions. 

Reduction of C=0 and C=N Bonds. Asymmetric reductions of prochiral ketones (19) to the corresponding chiral alcohols (20) using (S)-proline-modified borohydride reagents as the reductant have been published. The borane reductions of ketones (19) employing (S)-proline as chiral mediator proceeds with enantiomeric... 

Hattori and Yamamoto have investigated double stereodifferentiation by the combined use of a chiral mediator and a chiral imine derived from a simple a-methylben-zylamine auxiliary (Eq. 43) [40c]. 

An obvious instance where the driving force is not a determining factor is in the reaction of chiral mediators. The inherent chirality of proteins implies that they should exhibit chiral discrimination between enantiomers and this has been widely exploited in the selective transformation of one enantiomer in a racemic mixture by enzymes. 

Alberts and Wynberg studied the addition of ethyllithium to PhCHO, mediated by the lithiated product (k)-l-phenyl-l-propanol-dj [40]. The (i )-l-phenyl- 1 -propanol enantiomer was formed in 17% enantiomeric excess in the reaction. For this asymmetric induction rendered by the product, the authors coined the expression enantioselective autoinduction . It was suggested that the formation of mixed aggregates consisting of the labeled chiral mediator and the or-ganoHthium reagent influences the stereochemistry of subsequent C-C bond formation [41]. 

Oxone sulfoxidations can show appreciable diastereoselectiv-ity in appropriate cases, as demonstrated in eq 26. Enantios-elective oxidations of sulfides to sulfoxides have been achieved by buffered aqueous Oxone solutions containing bovine serum albumin (BSA) as a chiral mediator (eq 27). As little as 0.05 equiv of BSA is required and its presence discourages further oxidation of the sulfoxide to the sulfone. Oxone can be the active oxidant or reaction can be performed in the presence of acetone. 

Figure 7.9b shows aspartame. You can see here two isomers with a chiral carbon pointed out by the arrow. It turns out that one of these chiral isomers is sweet and is a component of the artificial sweetener Nutrasweet, and the other is bitter. As receptor proteins (which are chiral) mediate our sense of taste, our taste is inherently chiral. Thus, some, if not all, of our senses are chiral For example, lemons and oranges may contain the two different enantiomers of a molecule (called limonene), which gives these fruits their distinctive but different smells. So our sense of smell is chiral, and likewise our sense of touch could also be chiral since it utilizes our chiral hands. 

A DKR of a 5-hydroxytricyclodecadienone using (S)-prolinol or its methyl ether as the chiral mediator led to the corresponding enaminones. This approach, which constituted an asymmetric desymmetrisation of a Diels Alder... 

Electrochemical synthesis of non-chiral substrates using suitable chiral source might occur by asymmetric induction to afford optically active product. Chiral electrolytes, chiral mediators, chiral modified electrodes, and/or chiral catalysts as chiral sources were examined [3]. 

Methods (3 and 4) are not asymmetric (Section 2.3.2) as they do not involve chiral mediators or catalysts. The chirality of the starting molecules is merely transmitted to the final products. In contrast, method (5) may be asymmetric provided that a chiral gold catalyst is used. However, the ee s achieved up to now are still unsatisfactory [44]. None of these three methods has been used as yet for the synthesis of natural dihydropyranones. 

Scheme 1.6 2-Cyanoheptaheticene as a chiral mediator in the classical Payne epoxidation...

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