Prostereogenicity

I.3.I.6. Formation of C-C Bonds by Addition to Prostereogenic Carbonyl Compounds in the Presence of Chiral Additives... 

The first reports on enantioselective addition reactions of achiral organometallic reagents, modified by aprotic chiral additives, described the addition of Grignard reagents to prostereogenic carbonyl compounds in the presence of ( + )-(/ ,/J)-2,3-dimethoxybutane (l)4 5, (-)-tetrahydro-2-methylfuran (2)6, (-)-l-[(tetrahydro-2-furanyl)methyl]pyrrolidine (3)7 or (-)-sparteine (4)8. The enantioselectivity, however, was poor (0-22% ee). 

In most cases, the addition of prostereogenic benzyl anion reagents with prostereogenic aldehydes (or ketones) proceeds with low stereoselectivity. Some notable exceptions are reviewed later. 

With prostereogenic carbonyl components, the problem of simple diastereoselectivity arises, which is unsatisfactorily solved at present21. Both the intermediate alkoxides rearrange by migration of the carbonyl group at a different rate21 22, which might be used for the enrichment of one diastereomer. 

For a successful application in synthesis, several problems have to be solved regioselectivity, whether the C-C bond is formed with the 1- or 3-position in an unsymmetrical ambident anion, EjZ selectivity in the formation of the double bond, and simple diastereoselectivity, since two new stereogenic centers are created from prostereogenic compounds. Further, different types of induced stereoselectivity or enantioselectivity may be required. Allylmetals with a wide choice of substituents are accessible by various methods (Sections D. 1.3.3.3.1.-10.). 

The action of a (constitutionally and configurationally homogeneous) 1,3-disubstituted allylmetal on a prostereogenic carbonyl compound can give rise to up to four racemic diastereomers with the relative configurations (Z)-anti, (Z)-syn, (E)-anti and (E)-syn of one particular regioisomer. 

As a consequence of the pericyclic reaction path, the addition of a-stereogenic allylmctals to carbonyl compounds is accompanied by an effective 1,3-chirality transfer in the allylic moiety combined with 1,4-chira induction at the prostereogenic carbonyl group3032. The scheme also demonstrates the importance of the orientation of the substituent X in the six-membered transition state. By changing from a pseudo-axial to a pseudo-equatorial position, the cation-induced sy/i-attack addresses opposite faces of both prostereogenic moieties, leading to a Z-and an -isomer, these being enantiomeric in respect to the chiral moiety. 

In general, three cases may be given for the stereoselective introduction of the 2-propenyl (allyl) or the 2-methy1-2-propenyl (methallyl) residue, both of which are not prostereogenic at the termini. 

Transmetalation of lithium enolate 1 a (M = Li ) by treatment with tin(II) chloride at — 42 °C generates the tin enolate that reacts with prostereogenic aldehydes at — 78 °C to preferentially produce the opposite aldol diastereomer 3. Diastereoselectivities of this process may be as high as 97 3. This reaction appears to require less exacting conditions since similar results are obtained if one or two equivalents of tin(ll) chloride arc used. The somewhat less reactive tin enolate requires a temperature of —42 C for the reaction to proceed at an acceptable rate. The steric requirements of the tin chloride counterion are probably less than those of the diethyla-luminum ion (vide supra), which has led to the suggestion26 44 that the chair-like transition state I is preferentially adopted26 44. This is consistent with the observed diastereoselective production of aldol product 3, which is of opposite configuration at the / -carbon to the major product obtained from aluminum enolates. 

The exchange of tert-butyl for a smaller group, e.g., alkyl or 4-methylpheny], causes a decrease in the induced diastereoselectivity70. If a prostereogenic aldehyde is used, in addition. the problem of simple diastereoselectivity arises and four diastereomeric products are... 

High diastereoselectivity at the sulfinyl group bearing carbon and low diastereoselectivity at the prostereogenic carbonyl group resulted on addition of a chiral sulfoxide carbanion to an... 

When chloromethylsulfinylmethane is reacted with unsymmetrical ketones in the presence of potassium rm-butoxide in fert-butanol, diastereomeric mixtures of oxiranes are formed, showing that the asymmetric induction at the prostereogenic carbonyl carbon atom is low21. 

While in first experiments the diastereomeric ratios were not determined, the addition of optically active /erf-butyl 2-(4-methylphenylsulfinyl)acetate to prostereogenic carbonyl compounds proceeded with high asymmetric induction34-38. 

The big difference between the extent of asymmetric induction on the addition to a prostereogenic carbonyl group of simple carbanions a to a chiral sulfoxide on the one hand and enolates of sulfinyl esters on the other, can be attributed to the capacity of the ester function to chelate magnesium in the transition states and intermediates. The results already described for the addition of chiral thioacetal monosulfoxide to aldehydes (see Section 1.3.6.5.) underscore the importance of other functions, e.g., sulfide, for the extent of asymmetric induction. 

Boranc complexes of optically active /j -hydroxysulfoximines have been developed as highly reactive asymmetric reducing agents of prostereogenic ketones5. The required /(-hydroxysul-... 

The diastereomeric /1-hydroxysulfoximines derived from prostereogenic ketones are generally separable by medium-pressure liquid chromatography (WLC) on silica gel. Subsequent desulfurization of the separated adducts affords both enantiomers of the tertiary alcohols with high optical purity58,59. 

One diastereomer 5 was formed in large excess (98-76% de) on addition of the 2-(l-dimethyl-aminoethyl)phenyl group from the corresponding lithium dialkylcuprate and or lithium alkyl(2-thienyl)cuprate to prostereogenic enones64. 

In contrast to the usual anti selectivity a remarkably high syn selectivity is observed in the addition of thioester enolates to 2-alkylidenealkanones297. The syn selectivity is probably due to a stereoselective internal autoprotonation of the resulting enolates by the dithioester a-pro-tons298 in these cases where the prostereogenic centers reside exclusively in the enone part (see also Section D.2.I.). 

In 2000, these authors also developed a very efficient diphosphine-bithiophene ligand, tetraMe-BITIOP, which is depicted in Scheme 8.29. The ruthenium complex of this electron-rich diphosphine was used as the catalyst in asymmetric hydrogenation reactions of prostereogenic carbonyl functions of a-... 

Novel C2-symmetric thiophene-containing ligands have recently been prepared and utilized in asymmetric synthesis. Dithiophene 158 was utilized as a ligand in the asymmetric reduction of p-ketoesters (prostereogenic carbonyl) and acrylic acids (carbon-carbon double bond) <00JOC2043>. Dibenzo[b]thiophene 159 was utilized as a ligand in enantioselective Heck reactions of 2-pyrrolines <00SL1470>. 

Oxidation of arylolefins, enolethers, or dienes yields intermolecular homocoupling products in moderate to good yield (see Sect. 13.2.1.4) however, no pronounced diastereoselectivity was observed. This is also due to the fact that the coupling sites do not tolerate substituents that would make up a prostereogenic center. Furthermore, the fairly stable cations of the dimerized radical cation solvolyze stereounselectively. The same holds for the intermolecular coupling of aromatic compounds, in... 

Enantioselective addition of diethylzinc to benzaldehyde has been promoted by indole-containing chiral oxazolidines (which are able to use both O and N atoms to effect metal coordination in the transition state), and by chiral o-hydroxyphenyl diaza-phospholidine oxide,and by chiral aziridino alcohols.Enantioselective addition of dialkylzinc to prostereogenic ketones has been promoted using chiral camphorsul-fonamide derivatives. 

Table 2. Prostereogenic Units and Topic Relationships of Constitutionally F.quivalent Groups...

Prochiral (Prochirality). - These terms should be avoided. More appropriate is the term prostereogenic (see Section 1.1.4.3.). 

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