Nucleophile to carbonyl groups

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

The addition of carbon nucleophile, including organometallic compounds, enolates, or enols, and ylides to carbonyl gro is an important method of formation of carbon-carbon bonds. Such reactions are- ctremely important in synthesis and will be discussed extensively in Part B. Here, we will examine some of the fundamental mechanistic aspects of addition of carbon nucleophiles to carbonyl groups. 

SECTION 8.3. ADDITION OF CARBON NUCLEOPHILES TO CARBONYL GROUPS... 

Asymmetric addition of small-molecule nucleophiles to carbonyl groups and their derivatives are catalyzed by either Lewis acids or Lewis bases. Carbon dioxide is now a promising building block for as5mimetric organic synthesis. 

The anion then adds to the carbonyl group of a second molecule of ethanal in a manner analogous to the addition of other nucleophiles to carbonyl groups (e.g., cyanide ion, Section 16-4A). The adduct so formed, 8, rapidly adds a proton to the alkoxide oxygen to form the aldol, 3-hydroxybutanal. This last step regenerates the basic catalyst, OH ... 

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. 

It has been found that amines frequently are effective catalysts for addition of other nucleophiles to carbonyl groups.108 The reason for this catalysis is that amines can add rapidly to the carbonyl compound to form an imine the imine in turn is subject to the same kinds, of addition reactions as are carbonyl compounds, but reacts faster because it is more easily protonated. Scheme 16 illus-... 

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... 

Unsubstituted vinyl-lithium and vinyl Grignard 14 reagents can be made directly from the halide by oxidative insertion of Li(0) and Mg(0). Vinyl-lithium is available as a 2M solution in THF from Alfa and vinyl magnesium bromide, which must be prepared in THF, is available in THF from Aldrich. These are quite stable o-complexes because alkenyl anions are more stable than saturated alkyl anions. They add as nucleophiles to carbonyl groups, e.g. cyclobutanone to give 15 and prefer direct to conjugate addition with enones to give e.g. 13. We have already used them in enone synthesis (chapter 5). 

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... 

Stereoselective formation of C-C bonds in nature is assisted by enzymes named lyases, which catalyze usually reversible addition of carbon nucleophiles to carbonyl group. Aldolases belong to the group of lyases. They occur in all organisms being involved in the metabolism of carbohydrates as well as amino- and hydroxy acids. Over 30 aldolases have been identified to date. 

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. 

Thiamine pyrophosphate (13) is the co-factor for a number of enzymes that can be described as stabilizing hypothetical acyl anion intermediates. For instance, it is the coenzyme for the enzyme carboxylase that catalyses the conversion of pyruvic acid to acetaldehyde. We had early shown that this mechanism involves a thiazolium anion (14) whose second resonance form (15) is a carbene. Ionization of the C-2 proton of the thiazolium ring generates this species that can add nucleophilically to carbonyl groups such as that in pyruvic acid, forming an intermediate whose decarboxylation generates a stabilized anion. 

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... 

Note that the new Nu-C bond is made up entirely of the electron pair of the nucleophile. The transformation is reminiscent of an Sn2 reaction. In that process, a leaving group is displaced. Here, an electron pair is moved from a shared position between carbon and oxygen to one solely on the oxygen atom. Additions of strongly basic nucleophiles to carbonyl groups typically follow the nucleophilic addition-protonation pathway. 

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