Stereochemistry asymmetric catalysis

Annis, D. A. Helluin, 0. Jacobsen, E. N. (1998) Stereochemistry as a diversity element solid-phase synthesis of cyclic RGD peptide derivatives via asymmetric Catalysis., Chem., Int. Ed. Engl, 37, 1907-1909. 

The stereochemistry of the addition can be controlled through the attachment of a chiral auxiliary or using asymmetric catalysis. Addition of 0-benzylhydroxylamine to unsaturated imide 51 (equation 33) bearing a chiral auxiliary was found to proceed with high diastereoselectivity at the a-position". ... 

R. Noyori, Asymmetric Catalysis in Organic Synthesis, John Wiley Sons, New York, 1994. E. Juaristi, Introduction to Stereochemistry and Conformational Analysis, John Wiley Sons, New York, 1991. 

The observed activation of allyltrihalosilanes with fluoride ion and DMF and the proposition that these agents are bound to the silicon in the stereochemistry-determining transition structures clearly suggested the use of chiral Lewis bases for asymmetric catalysis. The use of chiral Lewis bases as promoters for the asymmetric allylation and 2-butenylation of aldehydes was first demonstrated by Denmark in 1994 (Scheme 10-31) [55]. In these reactions, the use of a chiral phos-phoramide promoter 74 provides the homoallylic alcohols in high yield, albeit modest enantioselectivity. For example, the ( )-71 and benzaldehyde affords the anti homoallylic alcohol 75 (98/2 antUsyn) in 66% ee. The sense of relative stereoinduction clearly supports the intermediacy of a hexacoordinate silicon species. The stereochemical outcome at the hydroxy center is also consistent with a cyclic transition structure. 

In an effort to address the medicinal chemist s need for new synthetic methods for the preparation of unnatural carbohydrates, new de novo methods for carbohydrate synthesis have been developed. These routes use asymmetric catalysis to set the sugar absolute stereochemistry, a palladium-catalyzed glycosylation reaction to stereoselectively control the anomeric center, and subsequent diastereoselective post-glycosylation to install the remaining sugar stereocenters. The utility of this method has been demonstrated by the syntheses of several classes of mono-, di- and tri-saccharides. 

Chiral phosphoramides, particularly C2-symmetric examples, are widely used in asymmetric synthesis (see section 3.2). One example is the asymmetric catalysis of Aldol reactions, where the phosphoramide catalyst is used in combination with a Lewis base. A solid state and solution study of the structure of chiral phosphoramide-tin complexes used in such reactions has now been reported. A number of chiral, non-racemic cyclic phosphoramide receptors (387) have been synthesised and their interactions with homochiral amines studied using electrospray ionisation MS. Although (387) bind the amines strongly, no evidence of chiral selectivity was found. Evidence from a combination of its X-ray structure, NMR, and ab initio calculations suggests that the cyclen phosphorus oxide (388) has an N-P transannular interaction in the solid state. A series of isomers of l,3,2-oxazaphosphorino[4,3-a]isoquinolines(389), containing a novel ring-system, have been prepared and their stereochemistry and conformation studied by H, C, and P NMR spectroscopy and X-ray crystallography... 

A number of important review articles have appeared in the area of pentaco-ordinate and hexaco-ordinate phosphorus chemistry. Robert Holmes has provided an extremely informative comparison of the hypervalency, stereochemistry and reactivity of silicon and phosphorus including the application of the latter to enzyme systems. The coordination chemistry of hydrophosphoranes including the formation of complexes from bicyclic-, tricyclic- and tetracyclic hydrophosphoranes has also been the subject of a comprehensive review with literature coverage to 1995. Numerous metal complexes are mentioned including Rh, Ru, Pd, Co, Fe, Mo, and W and the relevance to asymmetric catalysis is discussed. Neutral six-coordinate compounds of phosphorus, including mono-, di-, tri-, and tetracyclic examples, have also been reviewed. 

Asymmetric catalysis is an especially appealing aspect of asymmetric synthesis. Small amounts of a catalyst (frequently less than 1 mol%) can be used to control the stereochemistry of the bulk reaction. The use of a catalyst often makes the isolation of a product easier, since there is less unwanted material to remove at the end of a reaction. 

A more general qualitative survey of reactivity shows that 5-ring chelate complexes are much less reactive than 6- or 7-ring chelates where turnovers in excess of 0.3 Ms may be observed. The nature of the substrate is also important, and in dip amp complex catalyzed hydrogenations almost any structural change in the substrate leads to a depression of reactivity. This includes N-methylation (which also profoundly affects the stereoselectivity) conversion of the carboxylic acid moiety into a nitrile and changing from z- to E-stereochemistry about the double bond. The latter further indicates the stringent structural requirements of asymmetric catalysis. 

As with many asymmetric processes, there are three ways to control absolute stereochemistry in the Nazarov cyclization Asymmetry transfer, the use of chiral auxiliaries, or asymmetric catalysis. It is important to realize, however, that there are two distinct processes operating that determine the stereochemistry of the product. To control the absolute stereochemistry of the p-carbon atom(s), it is necessary to control the sense of conrotation, clockwise or counterclockwise (torquoselectivity, see Section 3.4.3). To control the absolute stereochemistry of the a-carbon atom however, it is necessary to control the facial selectivity for enol protonation. 

Perhaps the most elegant and attractive method to control absolute stereochemistry, however, is the use of asymmetric catalysis, and several examples of this approach have been applied to the Nazarov cyclization. Traimer and co-workers were the first to report a single example of a successfiil asymmetric Nazarov cyclization catalyzed by chiral scandium complex in 2003. In the exact same issue of the journal however, Aggarwal and co-workers reported a more in-depth study using copper pyBOX complexes. ... 

In 34 and 35, there is one more element of chirality in the phosphite or phosphinite moiety, such as the binaphthyl system [44]. These modifications could potentially influence the origin of the stereochemistry in the asymmetric catalysis process, and sometimes excellent results have been obtained (quantitative conversions and enantiomeric excess values higher than 99%) in the case of 34 (R = Ph, = H, R = Ph) that is better than other known catalyst systems for the asymmetric hydrogenation of unfunctionalized 1,1-disubstituted terminal alkenes [44]. 

The final synthesis we will consider uses asymmetric catalysis to establish absolute stereochemistry. Thus, treatment of cyclohexenone (172) with dimethylzinc and catalytic Cu(I) in the presence of chiral ligand 173 proceeded with good asymmetric induction. Alkylation of the intermediate enolate using allyl acetate in the presence of Pd(0) provided 174 with 96% ee. This ketone was reduced to provide a mixture of alcohols which were separated and converted to 171 by degrading the allylic side chain to a carboxyl group, and displacing the alcohol with a nitrogen nucleophile. 

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