Addition of Nucleophiles to Carbonyls

Our first example shows a reversal in stereoselectivity in the course of the nucle-ophihc addition of an organohthium reagent to 7-oxabicyclo[2.2.1]hept-5-en-2-one [1]. This building block is readily available in optically pure form and serves as a versatile building block in organic synthesis [2]. 

The nature of the organometal compound can of course only influence the diastereoselectivity of an addition reaction. If enantiocontrol is desired a chiral ligand is required. Here complementary stereoselectivity can be accomplished via the type of coordination of the metal atom, hence the influence of hi- versus tridentate ligands. Organozinc additions to aldehydes provide an illustrative example for such an enantiodivergent process. 

The catalytic enantioselective addition of organozinc species to aldehydes is a well-known process [9]. Over the past decades, a variety of different Hgands have been developed. 

An alternative process to the use of enantiodivergent ligands and applicable to add more functionalized organozinc species is the use of reagents 25a and 25b in a catalytic form [11]. This reaction is enantioselectively catalyzed in the addition process of organozinc compounds to generate 1,3-diols. 

They used both enantiopure forms of titanium-based catalysts 25a and 25b to generate diastereomeric 1,3-diol structure motifs 24 and 26 in good to excellent diastereomeric ratios [12], As an organometalhc reagent, diaUcylzinc species was used. This comprises an example of a catalytic reaction in which the catalyst fuUy controls the stereochemical outcome. 

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Chiral Titanium Complexes. Chiral titanium complexes are useful for the enantioselective addition of nucleophiles to carbonyl groups ... 

The experimental evidence favors the conclusion that in addition of nucleophiles to carbonyl groups the observed catalysis is true general acid catalysis. Table 8.2 presents selected data a decreases with increasing nucleophilicity of the addend. More specific techniques applicable to particular reactions lead to the same conclusion.27 For hydration, Mechanism I of Scheme 5, with true general acid catalysis in the forward direction and specific acid plus general base catalysis in the reverse direction, thus appears to be the most reasonable one. 

Thus far, all examples related to the addition of nucleophiles to carbonyls involve basic (anionic) conditions. However, such conditions are not required. Recalling that a carbonyl oxygen atom possesses a partial negative charge, we recognize that under acidic conditions it can be protonated. The protonation of carbonyl groups, illustrated in Scheme 7.13, was discussed in Chapter 3. Thus, as shown in Scheme 7.14 using acetone, treatment of... 

Scheme 7.14 Addition of nucleophiles to carbonyls can occur under acidic conditions.

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... 

Alcohols can be obtained from many other classes of compounds such as alkyl halides, amines, al-kenes, epoxides and carbonyl compounds. The addition of nucleophiles to carbonyl compounds is a versatile and convenient methc for the the preparation of alcohols. Regioselective oxirane ring opening of epoxides by nucleophiles is another important route for the synthesis of alcohols. However, stereospe-cific oxirane ring formation is prerequisite to the use of epoxides in organic synthesis. The chemistry of epoxides has been extensively studied in this decade and the development of the diastereoselective oxidations of alkenic alcohols makes epoxy alcohols with definite configurations readily available. Recently developed asymmetric epoxidation of prochiral allylic alcohols allows the enantioselective synthesis of 2,3-epoxy alcohols. 

The rates of addition of nucleophiles to carbonyl groups and the rates of elimination from the tetrahedral intermediates constitute another class, probably similar to the activated aromatic nucleophilic substitution. The carbonyl group is an electrophile, and no obvious source of any barrier exists, outside of desolvation. Therefore, a resemblance to Ritchies systems is found. No obvious relation between our kinetic nucleophilic characters (Nx) and the additions occurs, but a possible parallel to the equilibrium methylating powers, KYX (in Tables I and II), of the conjugate methylating agent of the... 

The benefits of pressure or Lewis acid catalysis for the addition of nucleophiles to carbonyl compounds is also well established, e.g. in various aldol processes or allylation reactions. The combination of the two methods, however, has rarely been applied. 

Common terms, the addition of nucleophiles to carbonyl compounds... 

R. O. Duthaler, A. Hafner, M. Riediker, Pure Appl. Chem. 1990, 62, 631 (Asymmetric C-C-Bond Formation With Titanium Carbohydrate Complexes)-, R. O. Duthaler, A. Hafner, Chem, Rev. 1992, 92, 807 (Chiral Titanium Complexes for Enantioselective Addition of Nucleophiles to Carbonyl Groups). 

The addition of nucleophiles to carbonyl groups is a fundamental process in organic synthesis. The addition of diethylzinc to aldehydes occurs with high ee in the presence of a wide range of aminoalcohol ligands and also titanium-based Lewis acids. This methodology has recently been extended to the enantioselective addition of alkenyl, alkynyl and arylzincs and also to the more challenging addition to ketones. 

There is some material of relevance in a review on chiral titanium complexes for the enantioselective addition of nucleophiles to carbonyl groups , in a short review on stereoselective transformations mediated by chiral CpM (M = Ti, Zr, Hf) complexes, and in a review on the preparation of organoaluminium and organomagnesium metallacycles from titanium and zirconium... 

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