Transacylation

Table 10. Synthesis of Cyanohydrins by Oxynitrilase-Catalyzed Transacylation...

Anionic copolymerization of lactams presents an interesting example of copolymerization. Studies of the copolymerization of a-pyrrolidone and e-caprolactam showed that a-pyrrolidone was several times more reactive than e-caprolactam at 70 °C, but became less reactive at higher temperatures due to depropagation210 2U. By analyzing the elementary reactions Vofsi et al.I27 concluded that transacylation at the chain end occurred faster than propagation and that the copolymer composition was essentially determined by the transacylation equilibrium and the acid-base equilibrium of the monomer anion together with the usual four elementary reactions of the copolymerization. 

Substitution on the carbon atoms of the azole rings has the expected effect electron-withdrawing substituents such as nitro or halogen increase the reactivity of the azolides, whereas alkyl substituents lead to a decrease in transacylation rates. 101... 

The preparation of imidazolides by acylation of imidazole with acid chlorides is sometimes limited by the inaccessibility or instability of the required acid chlorides (e.g., formyl chloride, highly unsaturated acid chlorides, etc.) or by side-reactions in the case of multifunctional systems. For these reasons and due to the availability of an easy and convenient procedure involving very mild conditions, imidazolides today are usually prepared directly from the corresponding carboxylic acids with jV -carbonyldiimida-zole (CDI) or one of its analoga (see page 16). Use of these reagents has become more and more the preferred method for activation of carboxylic acids to azolides and their further transacylation to esters, amides, peptides, etc. (see subsequent Chapters). 

A V -Carbonyldiimidazole (CDI) is prepared in a convenient and safe procedure from phosgene and imidazole as a non-toxic crystalline compound (m.p. 116-118 °C).[5],[6] It reacts almost quantitatively at room temperature or by short and moderate heating with an equimolar quantity of a carboxylic acid in tetrahydrofuran, chloroform, or similar inert solvents within a few minutes to give the corresponding carboxylic acid imidazolide, which is formed under release of carbon dioxide, together with one equivalent of readily separable and recyclable imidazole.Thus, this reaction leads under very mild conditions to the activation of a carboxylic acid appropriate for transacylation onto a nucleophile with an alcohol to an ester, with an amino compound to an amide or peptide, etc. 

Since the imidazolide method proceeds almost quantitatively, it has been used for the synthesis of isotopically labeled esters (see also Section 3.2), and it is always useful for the esterification of sensitive carboxylic acids, alcohols, and phenols under mild conditions. This advantage has been utilized in biochemistry for the study of transacylating enzymes. A number of enzymatic transacylations (e.g., those catalyzed by oc-chymo-trypsin) have been shown to proceed in two steps an acyl group is first transferred from the substrate to the enzyme to form an acyl enzyme, which is then deacylated in a second step. In this context it has been shown[21] that oc-chymotrypsin is rapidly and quantitatively acylated by Af-fraw.s-cinnamoylimidazole to give /ra/w-cinnamoyl-a-chymotrypsin, which can be isolated in preparative quantities and retains its enzymatic activity (see also Chapter 6). 

An imidazolide-supported polymer was used for transacylation of phosphatidylcholine. The polymer was obtained from a chloromethylated polystyrene with two mol-% divinylbenzene. The imidazolide group was anchored by reaction with 3-hydroxymethyl-1-tritylimidazole, cleavage of the trityl group, and condensation with palmitic acid 122]... 

Catalysts for Transacylation Reactions of Carboxylic and Phosphoric Acid Derivatives... 

Poly(methyl 3-(l-oxypyridinyl)siloxane) was synthesized and shown to have catalytic activity in transacylation reactions of carboxylic and phosphoric acid derivatives. 3-(Methyldichlorosilyl)pyridine (1) was made by metallation of 3-bromopyridine with n-BuLi followed by reaction with excess MeSiCl3. 1 was hydrolyzed in aqueous ammonia to give hydroxyl terminated poly(methyl 3-pyridinylsiloxane) (2) which was end-blocked to polymer 3 with (Me3Si)2NH and Me3SiCl. Polymer 3 was N-oxidized with m-ClC6H4C03H to give 4. Species 1-4 were characterized by IR and H NMR spectra. MS of 1 and thermal analysis (DSC and TGA) of 2-4 are discussed. 3-(Trimethylsilyl)-pyridine 1-oxide (6), l,3-dimethyl-l,3-bis-3-(l-oxypyridinyl) disiloxane (7) and 4 were effective catalysts for conversion of benzoyl chloride to benzoic anhydride in CH2Cl2/aqueous NaHCC>3 suspensions and for hydrolysis of diphenyl phosphorochloridate in aqueous NaHCC>3. The latter had a ti/2 of less than 10 min at 23°C. 

The feasibility of bonding pyridinyl groups to silicon which contains a hydrolytically sensitive functional group has recently been demonstrated 15-71. 2-Fluoro-3-(dimethylchlorosilyl)pyridine and 3-fluoro-4-(dimethylchloiosilyl)pyridine as well as 2-, 3-, and 4-(dimethylchlorosilyl)pyridine were prepared by the reaction of the corresponding lithiopyridines with excess Me2SiCl2- Hydrolysis of the pyridinyl substituted chlorosilanes gave disiloxanes which were insoluble in water. In the present report we will describe extension of this work to include pyridinyl dichlorosilanes which can be hydrolyzed to polysiloxanes. These polymers can be N-oxidized and the resultant derivatives have been shown to be effective hydrophobic transacylation catalysts. 

Catalysis in Transacylation Reactions. The principal objective of the study was to evaluate 4 as an effective organic soluble lipophilic catalyst for transacylation reactions of carboxylic and phosphoric acid derivatives in aqueous and two-phase aqueous-organic solvent media. Indeed 4 catalyzes the conversion of benzoyl chloride to benzoic anhydride in well-stirred suspensions of CH2CI2 and 1.0 M aqueous NaHCC>3 (Equations 1-3). The results are summarized in Table 1 where yields of isolated acid, anhydride and recovered acid chloride are reported. The reaction is believed to involve formation of the poly(benzoyloxypyridinium) ion intermediate (5) in the organic phase (Equation 1) and 5 then quickly reacts with bicarbonate ion and/or hydroxide ion at the interphase to form benzoate ion (Equation 2 and 3). Apparently most of the benzoate ion is trapped by additional 5 in the organic layer or at the interphase to produce benzoic anhydride (Equation 4), an example of normal phase-... 

The importance of hydrophobic binding interactions in facilitating catalysis in enzyme reactions is well known. The impact of this phenomenon in the action of synthetic polymer catalysts for reactions such as described above is significant. A full investigation of a variety of monomeric and polymeric catalysts with nucleophilic sites is currently underway. They are being used to study the effect of polymer structure and morphology on catalytic activity in transacylation and other reactions. 

Kumar, P., Koppisch, A.T., Cane, D.E. and Khosla, C. (2003) Enhancing the modularity ofthe modular polyketide synthases transacylation in modular polyketide synthases catalyzed by malonyl-CoA ACPtransacylase. Journal of the American Chemical Society, 125, 14307. 

In contrast, the opposite result was observed when these materials were used in the acylation of a bulky substrate (2-methoxynaphthalene, 2-MN). In this case, l-acetyl-2-metoxynaphthalene (1-A,2-MN) and 6-acetyl-2-metoxynaphthalene (6-A,2-MN) are the main reaction products (Scheme 2). The latter is an intermediate for the preparation of Naproxen (antiinflammatory drug) and, therefore, the most interesting product. Initially, 2-MN acylation leads to 1-A,2-MN (the kinetically controlled product). However, at long times, the selectivity to 6-A,2-MN usually increases due to two secondary reactions transacylation of 1-A,2-MN with a molecule of 2-MN and protodeacylation of 1-A,2-MN yielding 2-MN [7],... 

The catalytic activity of hierarchical and conventional Beta zeolites for acylation of 2-MN is displayed in Figure 2(a) The Beta (PHAPTMS) sample shows a superior catalytic activity than the conventional one, due to its enhanced textural properties. In this case, the bulky nature of both substrate and products may cause the existence of diffusional problems inside the zeolitic channels, which are attenuated in the modified Beta sample due to the presence of the hierarchical porosity. Regarding the product distribution (Figure 2(b)), two main products are observed and a third isomer, 8-A,2-MN isomer is produced just in minor amounts. Interestingly, the selectivity towards the desired isomer increases in the material obtained from silanized seeds, reaching values around 75%. Probably, the active sites located on the surface of the secondary porosity are able to catalyze also the formation of 6-A,2-MN by transacylation. However, this reaction is expected to be strongly hindered in the conventional Beta zeolite since it requires the participation of two bulky molecules as reactants. 

The Beta material prepared by seed silanization show interesting catalytic properties in aromatic acylation reaction, especially when using a bulky substrate, such as 2-methoxynaphthalene. The superior activity and selectivity exhibited by this sample has been related to the presence of a hierarchical porosity, which decreases the steric and diffusional hindrances, favoring the accessibility to the active sites and allowing the occurrence of the transacylation reaction. 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

Cram and co-workers have been successful in modifying certain of their cavitands such that reactions with a bound substrate are promoted. Such systems provide a first step towards the synthesis of rudimentary enzymes (Cram, Katz, Dicker, 1984). One example of this type, involving a binding step followed by a fast acylation step, is illustrated by Figure 5.1. This sequence resembles part of the mechanism used by chymo-trypsin to cleave a peptide bond. Thus, the enzymic process entails several stages but, like the model system, begins with a binding step followed by a crucial transacylation step. 

In addition, the fulvestrant could be glycosylated effectively at its 17-OH position with pivaloylated glycosyl trichloroacetimidates, which suppressed the competing transacylation side reaction and led to improved yields of the desired glycosides (Scheme 3.48d) [503]. In this synthesis, the inverse procedure (i.e. addition of a trichloroacetimidate donor to a mixture of an acceptor and a promoter) was found to be superior for glycosylations. Very recently, a stepwise synthesis of branched... 

In the last 5 years, catalytic antibodies have been generated for several reaction types, including the various types of hydrolysis, transesterification, amide bond formation, /3-elimination, cycloreversion, transacylation, redox reactions, E-Z isomerization, epoxidation, and Diels-Alder reactions. For more information on these and other recent developments, such as semi-synthetic antibodies, site-directed mutagenesis, and the bait-and-switch strategy, the reader should consult the appropriate authorities (Schultz, 1988, 1989a,b Benkovic et al., 1990 Janda et al., 1990, 1991 Janjic and Tramontano, 1990 Lerner et al., 1991). 

Chiral discrimination between enantiomeric amino-acid />-nitrophenyl ester hydrobromides in addition to enhanced rate of transacylation were reported by Chao and Cram (1976) for chiral 3,3 -Ws(mercaptomethyl)dinaphthyl-20-crown-6 [323]. Compared with a non-cyclic reference compound (5)-[324] the rates for a series of amino-acid esters are enhanced by factors of 102 to 103, except for L-proline. This once more demonstrates that reaction takes place in... 

The reluctance of tertiary amides to undergo hydrolysis, especially those produced in the Birch reduction-alkylation with a quaternary center next to the carbonyl group, has inspired the development of a variety of intramolecular transacylation reactions as illustrated by the cleavage of the SEM ether in 16... 

We were interested in applications of the high level of stereocontrol associated with the asymmetric Birch reduction-alkylation to problems in acyclic and heterocyclic synthesis. The pivotal disconnection of the six-membered ring is accomplished by utilization of the Baeyer-Villiger oxidation (Scheme 7). Treatment of cyclohexanones 25a and 25b with MCPBA gave caprolactone amides 26a and 26b with complete regiocon-trol. Acid-catalyzed transacylation gave the butyrolactone carboxylic acid 27 from 26a and the bis-lactone 28 from 26b cyclohexanones 31a and 31b afforded the diastereomeric lactones 29 and 30. ... 

Cyclohexenones 34 also undergo a highly diastereoselective dihydroxylation to give cii-diols 39 (Scheme 11).22 These diol amides are converted to hydroxylactones 40 by an acid-catalyzed process involving retro aldol-realdolization prior to transacylation. The enantiomers of hydroxylactones 40 are obtained from iodolactones 35 by iodide exchange with 2,2,6,6-tetramethylpiperidin-l-yloxy free radical (TEMPO) followed by reductive cleavage of the TEMPO derivative with Zn in ElOAc. The enantiomeric purity of the hydroxylactones prepared by either route is 95-98% ee. 

Bobowsky and Shavel found an interesting intramolecular reductive transacylation reaction, in which substituted cyclopent[e][l,3]oxazin-2-ones and l,3-perhydrobenzoxazin-2-ones (90) were formed (80JHC277). In the reactions of 4-(2 -oxocycloalkyl)-3,4-dihydro-3-methyl-2//-l,3-benzoxazin-2-ones 88 and potassium borohydride, the 2 -hydroxycycloalkyl products 89 obtained underwent intramolecular transacylation reactions, resulting in the dihydro-1,3-oxazine derivatives 90. In this way, the 4-(2 -oxocycloalkyl)... 

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