Stereoselective Addition to Carbonyl Groups

The sample solution to Problem 17.20(a) showed the preparation of 3-methyl-3-heptene by a Wittig reaction involving the ylide shown. Write equations showing the formation of this ylide beginning with 2-bromobutane. 

Nucleophilic addition to carbonyl groups sometimes leads to a mixture of stereoisomeric products. The direction of addition is often controlled by steric factors, with the nucleophile approaching the carbonyl group at its less hindered face. Sodium borohydride reduction of 7,7-dimethylbicyclo[2.2.1]heptan-2-one illustrates this point  

Approach of borohydride to the top face of the carbonyl group is sterically hindered by one of the methyl groups. The bottom face of the carbonyl group is less congested, and the major product is formed by hydride transfer from this direction. 

Approach of nucleophile from this direction is hindered by methyl group. 

Preferred direction of approach of borohydride is to less hindered face of carbonyl group. 

Normally the ylides are not isolated. Instead, the appropriate aldehyde or ketone is added directly to the solntion in which the ylide was generated. 

You may find it helpful to make molecular models of the reactant and products in the reaction shown. 

The reduction is stereoselective. A single starting material can form two stereoisomers of the product but yields one of them in greater amounts than the other or even to the exclusion of the other. 

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Stereoselective addition to carbonyl groups is a powerful tool in organic synthesis and has received a great deal of attention. Addition to imines can be equally as powerful, but has received much less attention. Denmark and co-workers first introduced the use of bis(oxazoline) ligands in the addition reactions of imines.The most successful ligand has been the modified bu-box ligand 182. This ligand was used both stoichiometrically and catalytically in the reaction between various imines and several alkyllithium species. Selected examples are summarized in Table 9.32 (Fig. 9.54). 

G. Solladie, Formation of C-C Bonds by Addition to Carbonyl Groups (0=0) - Metalated Sulfoxides or Sulfoximides, in Methoden Org. Chem. (Houben-Weyl) 4th ed., 1952, Stereoselective Synthesis (G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann, Eds.), Vol. E21b, 1793, Georg Thieme Verlag, Stuttgart, 1995. 

More recently the stereoselectivity of the addition of sulfinyl anions to carbonyl groups was improved by introducing a sulfide group in the a-position30,31. The sulfoxide ( + )-(S)-(4-methylphcnylsulfinyl)(4-methylphenylthio)metliane was added to benzaldehyde to give the adduct 1 as a mixture of three diastereomers [(S5,15,27 )/(SS,17 ,2/J)/(S5,15,25) 55 30 15] which could be transformed into the corresponding a-methoxyaldehydc 4 in 67% yield with 70 % ee. The same reaction, when applied to phenylacetaldehyde, led to a product in 43 % yield with lower ee (46%). 

The stereoselectivity of reduction of carbonyl groups is effected by the same combination of steric and stereoelectronic factors which control the addition of other nucleophiles, such as enolates and organometallic reagents to carbonyl groups. A general discussion of these factors on addition of hydride is given in Section 3.10 of Part A. 

Complete details are available concerning stereoselective addition of these reagents to chiral aldehydes or ketones and of crotyltitanium compounds to carbonyl groups (12, 354).2 The most diastereoselective additions to cyclohexanones known to date are effected with organotitanium reagents. 

There are many examples of the stereoselective addition of nucleophiles to carbonyl groups in which chelation to the titanium center should be critical—reported examples include the stereoselective hydride reduction of a- or /3-hydroxyketones (Eq. 305) [684-686], of a-phosphino ketones [687], of a-sulfonylketones [688], and of an a,/3-unsaturated carbonyl compound in a 1,4-fashion [689]. The stereoselective addition of organometallic compounds such as Grignard [669,690], zinc [691,692], copper [693], and other reagents [11] to carbonyl and related compoimds Ijy taking advantage of titanium chelation is a well established method in the stereoselective... 

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