Acyl transfer, nucleophilic

Of the numerous examples of asymmetric reactions catalyzed by Lewis bases, this chapter focuses mainly on the activation of silicon reagents and related processes. Various other types of Lewis basic (nucleophilic) activation, namely the Morita-Baylis-Hillman (MBH) reaction, acyl transfer, nucleophilic carbenes, and carbonyl reduction, are described in the other chapters of this book. 

Thioesters undergo the same kinds of reactions as esters and by similar mechanisms Nucleophilic acyl substitution of a thioester gives a thiol along with the product of acyl transfer For example... 

Acylium ion (Section 12 7) The cation R—C=0 Acyl transfer (Section 20 3) A nucleophilic acyl substitution A reaction in which one type of carboxylic acid derivative IS converted to another... 

Ester hydrolysis can also be promoted by nucleophilic catalysis. If a component of the reaction system is a more effective nucleophile toward the carbonyl group than hydroxide ion or water under a given set of conditions, an acyl-transfer reaction can take place to form an intermediate ... 

When a Br nsted base functions catalytically by sharing an electron pair with a proton, it is acting as a general base catalyst, but when it shares the electron with an atom other than the proton it is (by definition) acting as a nucleophile. This other atom (electrophilic site) is usually carbon, but in organic chemistry it might also be, for example, phosphorus or silicon, whereas in inorganic chemistry it could be the central metal ion in a coordination complex. Here we consider nucleophilic reactions at unsaturated carbon, primarily at carbonyl carbon. Nucleophilic reactions of carboxylic acid derivatives have been well studied. These acyl transfer reactions can be represented by... 

We consider first the Sn2 type of process. (In some important Sn2 reactions the solvent may function as the nucleophile. We will treat solvent nucleophilicity as a separate topic in Chapter 8.) Basicity toward the proton, that is, the pKa of the conjugate acid of the nucleophile, has been found to be less successful as a model property for reactions at saturated carbon than for nucleophilic acyl transfers, although basicity must have some relationship to nucleophilicity. Bordwell et al. have demonstrated very satisfactory Brjinsted-type plots for nucleophilic displacements at saturated carbon when the basicities and reactivities are measured in polar aprotic solvents like dimethylsulfoxide. The problem of establishing such simple correlations in hydroxylic solvents lies in the varying solvation stabilization within a reaction series in H-bond donor solvents. 

FIGURE 18.24 Acyl transfer from acyl-CoA to a nucleophile is more favorable than transfer of an acyl group from an oxygen ester. 

Steps 1-2 of Figure 29.5 Acyl Transfers The starting material for fatty-acid synthesis is the thioesteT acetyl CoA, the ultimate product of carbohydrate breakdown, as we ll see in Section 29.6. The synthetic pathway begins with several priming reactions, which transport acetyl CoA and convert it into more reactive species. The first priming reaction is a nucleophilic acyl substitution reaction that converts acetyl CoA into acetyl ACP (acyl carrier protein). The reaction is catalyzed by ACP transacyla.se. 

Step 5 of Figure 29.11 Acyl Transfer Acetyl dihydrolipoamide. a thioester, undergoes a nucleophilic acyl substitution reaction with coen/.yrne A to yield acetyl CoA plus dihydrolipoamide. The dihydrolipoamide is then oxidized back... 

This work has been extended to transesterification with secondary alcohols [23], and of phosphonate esters [24], Movassaghi and co-workers have demonstrated that NHCs effectively catalyse the amidation of esters with amino alcohols, although an alternative mechanism involving the NHC acting as a Brpnsted base, resulting in nucleophilic activation of the alcohol for an initial transesterification event, followed by rapid O- to iV-acyl transfer, has been proposed [25, 26],... 

For acyl transfer, phosphoryl transfer, and sulfonyl transfer, the primary kind of evidence in favor of concerted mechanisms for some reactions is a linear Bronsted plot of log k versus for a range of nucleophiles, spanning p/ir/ = - p r s = 0, coupled... 

There are only a few examples of low-temperature conditions reported to lead to a species behaving as an o-QM. All of these, except for our O-acyl transfer methods that will be discussed later, use a fluoride ion to trigger the formation of the o-QM in an almost instantaneous manner. In these examples, a high concentration of the intended nucleophile is necessary to prevent any side reactions with the o-QM, because given the low-temperature conditions its formation is usually irreversible. 

Much more important than these reactions, however, are the reactions of CDI and its analogues with carboxylic acids, leading to AAacylazoles, from which (by acyl transfer) esters, amides, peptides, hydrazides, hydroxamic acids, as well as anhydrides and various C-acylation products may be obtained. The potential of these and other reactions will be shown in the following chapters. In most of these reactions it is not necessary to isolate the intermediate AAacylazoles. Instead, in the normal procedure the appropriate nucleophile reactant (an alcohol in the ester synthesis, or an amino acid in the peptide synthesis) is added to a solution of an AAacylimidazole, formed by reaction of a carboxylic acid with CDI. Thus, CDI and its analogues offer an especially convenient vehicle for activation of... 

In most cases the esterolysis takes place by nucleophilic attack of an ionized hydroxyl of the CD (VanEtten et al., 1967a), leading to acyl transfer (VanEtten et al., 1967b). Under the reaction conditions the acylated CD... 

This section describes the nucleophilic reactions—acyl transfer reactions mostly—promoted by micelles and polysoaps. The nucleophiles are imidazoles, oxyanions and thiols, the same catalytic groups found ubiquitously in the enzyme active site. These nucleophiles are remarkably activated in the anionic form in the presence of cationic micelles and cationic polysoaps. These results are explained by the concept of the hydrophobic ion pair (Kunitake et al.,... 

A similar bait and switch approach has been exploited for acyl-transfer reactions (Janda et al., 1990b, 1991c). The design of hapten [10] incorporates both a transition state mimic and the cationic pyridinium moiety, designed to induce the presence of a potential general acid/base or nucleophilic amino acid residue in the combining site, able to assist in catalysis of the hydrolysis of substrate [11] (Appendix entry 2.6). 

Some enzymes are nonfunctional until posttranslationally modified. Examples of these enzymes include the acyl- and carboxyltransferases. While lipoate and phosphopantetheine are necessary for acyl transfer chemistry, tethered biotin is used in carboxyl transfer chemistry. Biotin and lipoate tethering occur under a similar mechanism the natural small molecule is activated with ATP to form biotinyl-AMP or lipoyl-AMP (Scheme 20). A lysine from the target protein then attacks the activated acid and transfers the group to the protein. The phosphopantetheine moiety is transferred using its own enzyme, the phosphopantetheinyltrans-ferase (PPTase). The PPTase uses a nucleophilic hydroxy-containing amino acid, serine, to attach the phosphopantetheinyl (Ppant) arm found in coenzyme A to convert the apo (inactive) carrier protein to its holo (active) form. The reaction is Mg -dependent. 

In the 1990s, short peptides,and other nucleophiles °° ° were used as organocatalysts for a number of enantioselective acyl transfer processes transformations that set the stage for the more recent research in the area of nucleophilic catalysis.One of the most appealing approaches to enantioselective acyl transfer was outlined by Fu using an azaferrocene catalyst (6) [Eq. (11.6)]. While these pyridyl systems are not organic catalysts in the strictest sense, these azaferrocene compounds function as chiral dimethylaminopyridine equivalents for a broad range of acyl transfer processes ... 

When 2,2-dichloro-3-phenylpropanal 203 is subjected to standard reaction conditions with chiral triazolium salt 75c, the desired amide is produced in 80% ee and 62% yield Eq. 20. This experiment suggests that the catalyst is involved in an enantioselec-tive protonation event. With this evidence in hand, the proposed mechanism begins with carbene addition to the a-reducible aldehyde followed by formation of activated car-boxylate XLII (Scheme 32). Acyl transfer occurs with HOAt, presumably due to its higher kinetic nucleophilicity under these conditions, thus regenerating the carbene. In turn, intermediate XLin then undergoes nucleophilic attack by the amine and releases the co-catalyst back into the catalytic cycle. 

As shown in previous sections, NHCs promote acyl transfer in transesterification reactions. In a similar manner, O C acyl transfer can be achieved with substrates such as 351 in the presence of 0.9 mol% of triazolium pre-catalyst 353 and KHMDS (Scheme 53). Moderate yields are obtained by varying substitution of the oxazole from R = Me, Ph, t-Bu, and t-Pr [171], Deprotonation of the triazolium salt followed by nucleophilic addition to the carbonate moiety of the oxazole results in enolate intermediate LXXXIII and activated carboxylate LXXXIV. Enolate addition and regeneration of the active catalyst provides quaternary stereocenters 352. 

The mechanism by which chiral nucleophiles catalyze asymmetric acyl transfer in the KR of, yec-alcohols can be seen as a three-step process (Scheme 1) [2]. 

In general, catalytic asymmetric acyl transfer reactions can be classified into two main types depending on the nature of the nucleophile and the acyl donor (Scheme 2) [2]. 

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