Enantioselective reactions basics

At the basis of the application of zeolites in fine chemicals reactions is the rich variety of catalytic functions with which zeolites can be endowed. Bronsted acidity, Lewis acidity and metallic functions are well known from classical bifunctional chemistry but for specific reactions, unusual sites, e.g. Lewis acid Ti4+ centres, have been introduced into zeolites. Moreover, zeolites can acquire more or less weakly basic properties metal complexes can be entrapped in zeolite pores or cavities, and enantioselective reactions have been performed by decorating the zeolite surface with chiral modifiers. 

In a simplified catalytic cycle, reversible coordination of the dienophile to the Lewis acid (LA) activates the substrate toward diene cycloaddition. In the catalyst turnover event, the Lewis acid-product complex dissociate to reveal the de-complexed cycloadduct and regenerated catalyst (Scheme 2). While this catalytic cycle neglects issues of product inhibition and nonproductive catalyst binding for dienophiles having more than one Lewis basic site, the gross features of this process are less convoluted than many other enantioselective reactions e.g., olefin dihydroxylation, aldol reactions), a fact which may provide insight as to why this process is frequently used as a test reaction for new Lewis acid catalysts. 

The amidine group can act as a binding site or a catalytic site at the same time. As will be described more in detail in Chapter 21, stable transition-state analogues for the basic ester hydrolysis like 14 or 16 can be used as bis-amidinium salts to get efficient enzyme mimics for the ester hydrolysis of 15 [29] and 17. In case of 17, even enantioselective reactions are possible [60]. 

Abstract The basics of stereoselective reactions and reaction stereochemistry—the relation of stereoselectivity to the topology of tetrahedral and planar units in organic molecules—are discussed. The kinetic control of enantioselective reactions and characteristics of enantioselective and diastereoslective reactions is presented. Asymmetric syntheses are exemplified by the hydrogenation of C=0 and C=NR bonds in prochiral substrates catalyzed by organometallic complexes with chiral phosphine ligands. The mechanism of asymmetric alkylation of stabilized carban-ions in specifically designed chiral substrates and the practicability of this mefliod in the preparation of optically pure a-alkyl carboxylic acids are discussed. The synthetic approach to chiral auxiliaries and importance of recycling are presented. 

The progress of modem synthetic organic chemistry is largely related to the discovery of new asymmetric or enantioselective reactions, particularly those catalyzed by chiral catalysts. In this chapter, basic knowledge on stereoisomerism and reaction stereochemistry is correlated with selected examples of asymmetric reactions to facilitate the discussion of stereoselective and asymmetric reactions in the next chapters. 

Diels-Alder reaction of 2-bromoacrolein and 5-[(ben2yloxy)meth5i]cyclopentadiene in the presence of 5 mol % of the catalyst (35) afforded the adduct (36) in 83—85% yield, 95 5 exo/endo ratio, and greater than 96 4 enantioselectivity. Treatment of the aldehyde (36) with aqueous hydroxylamine, led to oxime formation and bromide solvolysis. Tosylation and elimination to the cyanohydrin followed by basic hydrolysis gave (24). 

An expedient and stereoselective synthesis of bicyclic ketone 30 exemplifies the utility and elegance of Corey s new catalytic system (see Scheme 8). Reaction of the (R)-tryptophan-derived oxazaboro-lidine 42 (5 mol %), 5-(benzyloxymethyl)-l,3-cyclopentadiene 26, and 2-bromoacrolein (43) at -78 °C in methylene chloride gives, after eight hours, diastereomeric adducts 44 in a yield of 83 % (95 5 exo.endo diastereoselectivity 96 4 enantioselectivity for the exo isomer). After reaction, the /V-tosyltryptophan can be recovered for reuse. The basic premise is that oxazaborolidine 42 induces the Diels-Alder reaction between intermediates 26 and 43 to proceed through a transition state geometry that maximizes attractive donor-acceptor interactions. Coordination of the dienophile at the face of boron that is cis to the 3-indolylmethyl substituent is thus favored.19d f Treatment of the 95 5 mixture of exo/endo diastereo-mers with 5 mol % aqueous AgNC>3 selectively converts the minor, but more reactive, endo aldehyde diastereomer into water-soluble... 

Jacobsen subsequently reported a practical and efficient method for promoting the highly enantioselective addition of TMSN3 to meso-epoxides (Scheme 7.3) [4]. The chiral (salen)Cl-Cl catalyst 2 is available commercially and is bench-stable. Other practical advantages of the system include the mild reaction conditions, tolerance of some Lewis basic functional groups, catalyst recyclability (up to 10 times at 1 mol% with no loss in activity or enantioselectivity), and amenability to use under solvent-free conditions. Song later demonstrated that the reaction could be performed in room temperature ionic liquids, such as l-butyl-3-methylimidazo-lium salts. Extraction of the product mixture with hexane allowed catalyst recycling and product isolation without recourse to distillation (Scheme 7.4) [5]. 

Basically, there are three ways to tune enzyme enantioselectivity by means of additives (i) the additives are placed in the reaction medium together with the organic solvent, the enzyme, and the reagents (ii) the additives are co-lyophilized with the biocatalyst before use in the organic solvent (iii) the additives are complexed with the substrates before their transformation in the organic medium. 

Recently, enantioselective organo-catalytic procedures for the aza-Henry reaction have been disclosed. The presence of either an acidic or a basic function appears to be a requisite of the catalyst. In fact, the condensation of ni-tromethane with M-phosphinoyl arylimines 72 is catalyzed by the chiral urea 85 derived from (R,R)-l,2-diaminocyclohexane and gives the product (R)-74 with good yield and moderate enantioselectivity (Scheme 15) [50]. The N-phosphinoyl substituent is determinant, as the addition of nitromethane to the N-phenyl benzaldimine failed and the reaction of the N-tosyl ben-zaldimine gave the expected adduct with quantitative yield but almost no... 

Similarly, the reaction of nitro compounds with the M-Boc aromatic imines 86 occurred in the presence of the enantiopure protic catalyst 87, which is a white, crystalline bench-stable salt [52] (Scheme 15). The reactions of ni-tromethane, very slow at - 20 °C, were accelerated in the presence of 10 mol % of 87, and the /3-amino compounds 88 were obtained with moderate yields and moderate to high enantioselectivities. Positive results were also obtained in the corresponding reactions of nitropropane to give the products 90. Hence, the primary diamines 89 and 91 are available by this route, which is advantageous for the significantly lower cost and toxicity of the catalyst and its easy removal from the reaction mixture simply by a basic wash. These results should stimulate further research on the development of new acid-catalyzed systems. 

---