Acyl transfer product

The rationale for the cyclopent[Z>]indole design discussed above was that the quinone methide would build up in solution and intercalate/alkylate DNA. Enriched 13C-NMR studies indicate that the quinone methide builds up in solution and persists for hours, even under aerobic conditions (Fig. 7.21). In contrast, the quinone methide species formed by known antitumor agents (mitomycin C) are short lived and highly reactive. The spectrum shown in Fig. 7.21 also shows the N to O acyl transfer product that we isolated and identified. However, we could not determine if the quinone methide structure actually has the acetyl group on the N or O centers. 

Besides the intramolecular acyl-transfer reactions, electrophilic activation is shown to occur with intermolecular Friedel-Craft-type reactions.18 When the simple amides (45a,b) are reacted in the presence of superacid, the monoprotonated species (46a,b) is unreactive towards benzene (eq 18). Although in the case of 45b a trace amount of benzophenone is detected as a product, more than 95% of the starting amides 45a,b are isolated upon workup. In contrast, amides 47 and 48 give the acyl-transfer products in good yields (eqs 19-20). It was proposed that dications 49-50 are formed in the superacidic solution. The results indicate that protonated amino-groups can activate the adjacent (protonated) amide-groups in acyl-transfer reactions. 

The activating effects of ammonium groups on carboxonium electrophiles has also been exploited in the Friedel-Crafts acylations with amides.50 For example, in comparing the superacid-catalyzed reactions of acetanilide, the monoprotonated species (198) is found to be unreac-tive towards benzene (eq 67), while the diprotonated, superelectrophilic species (199) reacts with benzene to give the acyl transfer product in reasonably good yield (eq 68). 

Other related distonic superelectrophiles (200-201) were also shown to provide acyl-transfer products with benzene, and in the case of the aminopyridine derivative (202) intramolecular reaction produces the indanone (eq 69). 

Enzymatic transfer of phosphate is also of great interest, and examples and a proposed mechanism have been given by Morton H). All reactions of hydrolytic enzyme will involve the acyl-enzyme formation proposed above, and the subsequent step will depend on whether the acyl-enzyme reacts with water to give the hydrolysis products or with another nucleophilic reagent to form the acyl-transfer product. 

The formation of 4-1 from 4-2 probably proceeds through a carboxyl attack on the N-acetyl pyridinium salt to give an anhydride intermediate before imidazole displacement. This represents the first isolation and unequivocal characterization of a labile acyl tetrahedral intermediate 4-1 capable of a migration to give an acyl-transfer product 4-3/... 

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... 

The product of this reaction is an imide (Section 20 16) a diacyl derivative of an amine Either aqueous acid or aqueous base can be used to hydrolyze its two amide bonds and liberate the desired primary amine A more effective method of cleaving the two amide bonds is by acyl transfer to hydrazine... 

Triacylglycerols arise not by acylation of glycerol itself but by a sequence of steps m which the first stage is acyl transfer to l glycerol 3 phosphate (from reduction of dihy droxyacetone 3 phosphate formed as described m Section 25 21) The product of this stage IS called a phosphatidic acid... 

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. 

A potential liability associated with such reductive hydroacylations resides in the fact that only one acyl residue of the symmetric anhydride is incorporated into the coupling product. For more precious carboxylic acids, selective acyl transfer from mixed anhydrides is possible. Mixed anhydrides derived from pivalic acid are especially convenient, as they may be isolated chromato-graphically in most cases. In practice, mixed anhydrides of this type enable completely branch-selective hydroacylation with selective delivery of the aromatic and a,()-unsalurated acyl donors (Scheme 19). 

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... 

Acyl-transfer reactions are some of the most important conversions in organic chemistry and biochemistry. Recent work has shown that adjacent cationic groups can also activate amides in acyl-transfer reactions. Friedel-Crafts acylations are known to proceed well with carboxylic acids, acid chlorides (and other halides), and acid anhydrides, but there are virtually no examples of acylations with simple amides.19 During studies related to unsaturated amides, we observed a cyclization reaction that is essentially an intramolecular acyl-transfer reaction involving an amide (eq 15). The indanone product is formed by a cyclization involving the dicationic species (40). To examine this further, the related amides 41 and 42 were studied in superacid promoted conversions (eqs 16-17). It was found that amide 42 leads to the indanone product while 41... 

Acetoxymethyl carbamates of primary amines behaved differently from the pathway depicted in Fig. 8.19, the predominant reaction being intramolecular acyl transfer to generate the A-acetylated amine as the major product [209]. This parasitic reaction was observed in buffer and proportionally less in plasma, disqualifying (acyloxy)methyl carbamates for use as prodrugs of primary amines. However, this type of derivative appears well suited for the preparation of prodrugs of secondary amines, as documented below. 

A proposed mechanism for this transformation, provided in Scheme 42, is based on the identification of alcohol-carbene complexes by Movassaghi and Schmidt. Mesityl substituted imidazolinylidine carbene acts as a Brpnsted base as transesterification occurs to produce LXVII. Upon O N acyl transfer, the observed product is formed. The evidence provided for this mechanism includes the control experiment in which LXVII is resubjected to the reaction conditions and proceeds with amide formation. A similar mechanism has recently been reported in a theoretical study of transesterification by Hu and co-workers [139], In light of this work, it seems reasonable to suggest a similar that mechanism is operative in the transesterification reactions discussed throughout this section. 

The preparation of stereochemically-enriched compounds by asymmetric acyl transfer using chiral nucleophihc catalysts has received significant attention in recent years [1-8]. One of the most synthetically useful and probably the most studied acyl transfer reaction to date is the kinetic resolution (KR) of ec-alcohols, a class of molecules which are important building blocks for the synthesis of a plethora of natural products, chiral ligands, auxiliaries, catalysts and biologically active compounds. This research area has been in the forefront of the contemporary organocatalysis renaissance [9, 10], and has resulted in a number of attractive and practical KR protocols. 

Hulshof et al. introduced 10 as an alcohol racemization catalyst [31]. Alcohol DKR was performed with 0.1mol% of 10, CALB, isopropyl butyrate as the acyl donor, potassium carbonate and about 20mol% of the corresponding ketone at 70°C (Scheme 1.23). Without the ketone, yield and optical purity of the product ester were decreased significantly. 2-Propanol produced by the acyl transfer reaction was removed at reduced pressure during the DKR to shift the equilibrium to acylated products. 

Unfortunately, the authors performed little detailed product analyses and did not take into account the possibility that many of the reactions they were monitoring were acyl transfer processes that led to hydroxamic acid products (Scheme 20). They also failed to maintain control of pH and ionic strength in their reactions. Underwood and co-workers showed that scrambling did not occur in carbonyl- 0-labeled esters 39a,b,c,e, and f during their... 

In addition, at very low water contents, ampicillin accumulation curves do not exhibit a clear-cut maximum, inherent in the enzymatic acyl transfer reactions in aqueous medium (including quite concentrated heterogeneous aqueous solution-precipitate systems), because of the secondary hydrolysis of the target product by penicillin acylase (Figure 12.6) [84]. 

Mackay, L.G., Wylie, R.S. and Sanders, J.K.M. (1994) Catalytic acyl transfer by a cyclic porphyrin trimer - efficient turnover without product inhibition. J. Am. Chem. Soc., 116, 3141-3142. 

Several polymeric acyl-transfer reactants have been used to give am-ide/ester products in the solution phase. The excess polymer-bound acyl-transfer reactants and polymer-bound nucleofuge byproducts are easily removed after completion of the reactions. One such application involved the activated nitrophenyl esters 25 (reaction 8).40 A mixture of 10 acid chlorides was converted to an equimolar mixture of 10 amide products a potent preemergent herbicide was discovered using this parallel synthetic approach.41... 

As in the case of DNA synthesis, discussed in Section n, the quantity kf is the product of the usual chemical forward reaction rate constant and the monomer concentration. Again we are treating here only the special case in which it is assumed that all monomer concentrations, as well as all forward rate constants, are equal and invariant. An analogous comment applies to the quantity kb, utilized below for the back reaction. In this case of protein synthesis, which probably involves 60-different types of monomer unit (amino-acyl transfer-RNA species), some of which may be present in only minor amounts, this restriction may be a very severe one. 

Transpeptidation experiments. The pepsin-catalyzed hydrolysis of Leu-Tyr-Leu gives the product Leu-Leu, which can be formed from the acyl transfer shown in equation 16.31.166,167... 

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