Stereogenic centre diastereoselectivity

The presence of the stereogenic centre at C(l) introduces an additional factor in the asymmetric epoxidation now, besides the enantiofacial selectivity, the diastereoselectivity must also be considered, and it is helpful to examine epoxidation of each enantiomer of the allylic alcohol separately. As shown in Fig. 10.2, epoxidation of an enantiomer proceeds normally (fast) and produces an erythro epoxy alcohol. Epoxidation of the other enantiomer proceeds at a reduced rate (slow) because the steric effects between the C(l) substituent and the catalyst. The rates of epoxidation are sufficiently significative to achieve the kinetic resolution and either the epoxy alcohol or the recovered allylic alcohol can be obtained with high enantiomeric purity [9]. 

The diastereoselectivity in the ene reaction of O2 with chiral alkenes bearing a stereogenic centre at the a-position with respect to the double bond has been extensively studied. Chiral alkenes which bear a substituent on the asymmetric carbon atom other than the hydroxy or amine functionality afford predominately erythro allylic hydroperoxides. The erythro selectivity was attributed to steric and electronic repulsions between... 

Additional studies, concerning the influence of 1,2-allylic strain caused by a geminal substituent near the stereogenic centre of allylic alcohols , showed that it does not effectively compete with 1,3-allylic strain in differentiating the diastereoselectivity of the... 

SCHEME 37. Threo/erythro diastereoselectivity in the photooxygenation of chiral olefins without heteroatoms at the stereogenic centre... 

For the photooxygenation of chiral alkenes in solution bearing a stereogenic centre at the or more remote position with respect to the double bond, low or negligible diastereoselection is expected. The photooxygenation of 2-methyl-5-phenyl-2-hexene 156, a chiral alkene that bears a stereogenic centre at the /3-position with respect to the double bond, gave in solution low diastereoselectivity ca 10% By Na-Y... 

When a new stereogenic centre is added, diastereoselection is no longer perfect but still quite high (Scheme 10)60a. 

The phenyl or butyl substituent preferentially occupies a pseudo-equatorial position in the chair-like transition state which accounts for the observed diastereoselectivity. Since this extra stereogenic centre is quite far from the reacting centres diastereoselection is no longer complete. 

The complex of o-substituted anisole 203 is planar chiral, and can be used for diastereoselective generation of two new stereogenic centres in the products. Propargylation and allylation of 203 gave 204 regio- and stereoselectively. Hydrolysis of 204 afforded the cyclohexenone 205, and its intramolecular Pauson-Khand reaction gave 206 diastereoselectively. The two reactions were completely diastereoselective, and the planar chirality in 203 was efficiently transferred to the three new stereogenic centers in 206 [51]. 

By this way, from two prochiral vinylic carbon atoms, two stereogenic centres were created with good diastereoselectivity. Knowing that the chelation between zinc and heteroatoms in w-heterosubstituted dialkylzinc reagents has already been shown by NMR studies,14 the allylzincation of substituted y-heterosubstituted vinyl metals has been studied.13,15 In all cases, the chelation promotes a difference between the two prochiral faces of the vinyl moiety since one is shielded by the alkyl group, and then the allyl13,15,16 or the substituted allylmetal13,1517 (Equation 7.4 and Protocol 6) reacts diastereoselectively. 

The enolate is a ds-substituted alkene, because either O- or OEt must be cis to the stereogenic centre, so that to explain the stereoselectivity, we need consider only the conformation with H eclipsing the double bond. Notice how the diastereoselectivity increases at the group R gets bigger, because there is then more contrast between the size of Me and R. In each case, the electrophile adds to the less hindered face, opposite R. 

Only one new stereo genic centre is created, so there is no question of diastereoselectivity. But with substituted enolates, two new stereogenic centres are created, and we need to be able to predict which diastereoisomer will be formed. Here is an example from p. 699. We did not consider stereochemistry at that stage, but we can now reveal that the syn diastereoisomer is the major product of the reaction. 

For targets with more than one stereogenic centre, only one need be borrowed from the chiral pool, provided diastereoselective reactions can be used to introduce the others with control over relative stereochemistry. Because the first chiral centre has defined absolute configuration, any diastereoselective reaction that controls the relative stereochemistry of a new chiral centre also defines its absolute configuration. In this synthesis of the rare amino sugar methyl mycaminoside, only one chiral centre comes directly from the chiral.pool—the rest are introduced diastereoselectively. 

These bulkier boranes enhance the regio selectivity of hydrobora tion of trisubstituted alkenes in particular and may also lead to high diastereoselectivity when there is a stereogenic centre next to the alkene. In this next examplej an allylic alcohol is hydroborated with thexyl borane. Oxidation reveals complete regioselectivity and a 9 1 stereoselectivity in favour of hydroboration on the same side as the OH group. 

The challenge with Crixivan, as with any drug, is to make it efficiently—high yields few steps. It has five stereogenic centres, so the chemists developing the synthesis needed to address the issue of diastereoselectivity. And it is a single enantiomer, so an asymmetric synthesis was required. We can start by looking at some likely disconnections, summarized in the scheme above. They are all disconnections of the sorts you met in Chapter 30, and they all correspond to reliable reactions. 

A new diastereoselective and enantioselective synthesis of a-amino-y-oxo acid esters has been reported involving the alkylation of enamines with acyliminoacetates (78). The stereocontrol is attributed to formation of a Diels-Alder like transition state (79). Ring opening of the adduct leads to a zwitterion or alkylated enamine, hydrolysis of which gives the single diastereoisomer (80 de > 96%)174 (Scheme 71). The use of a chiral ester [R = ( + )- or ( —)-menthyl or (—)-8-phenylmenthyl] converted this process into an enantioselective reaction (de and ee 24-67%). Since the reaction proceeds with complete anti-diastereoselectivity the two stereoisomers, enantiomeric at the two new stereogenic centres, could readily be separated by fractional crystallization. The main isomer of 80 (X = CH2), obtained in 80% yield, was shown to have the (l S, 2R)-configuration174. 

A major trend in fine chemicals and pharmaceuticals is towards increasingly complex molecules, which translates to a need for high degrees of chemo-, regio- and stereoselectivity. An illustrative example is the synthesis of an intermediate for the Roche HIV protease inhibitor, Saquinavir (Fig. 1.14) [55]. It involves a chemo- and diastereoselective hydrogenation of an aromatic while avoiding racemisation at the stereogenic centre present in the substrate. 

The earliest reaction to be studied showing open-chain diastereoselectivity was nucleophilic attack on a carbonyl group, either a carbonyl group with a stereogenic centre adjacent to it or a carbonyl group like that in 4-fert-butylcyclohex-anone, where the diastereotopic surfaces are distinguished by being axial or equatorial. 

Schmidt B, Westhus M (2000) Diastereoselectivity in a ring closing metathesis reaction with a remote stereogenic centre leading to quaternary dihydropyrans. Tetrahedron 56 2421-2426... 

In order to maximize the diastereoselectivity observed for an auxiliary, it would appear reasonable that the stereo controlling functional group is in a position in space as close as possible to the newly forming stereogenic centre. Chiral imide auxiliaries such as Evans N-acyloxazolidinones (1.43) are used for asymmetric alkylation and asymmetric aldol condensation (Scheme 1.10). 

Several examples of chiral auxiliaries that rely on relatively remote stereogenic centres to control diastereoselectivity are known. Eor example, alkylation of the enolates of 1.44 and 1.46 to 1.45 and 1.47 is controlled via 1,4- and 1,3-asymmetric induction, respectively. 

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