Activated carboxylic acids

AT-Acyl-L-HSL can be conveniently prepared in excellent yields by the acylation of l-HSL either with the corresponding carboxylic acids activated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) in a water/ 1,4-dioxane (1 1) solvent system or with the corresponding acid chlorides in dichloromethane (DCM) in the presence of triethylamine (Scheme 4) [15,16, 37,53]. 

The linear telomerization reaction of dienes was one of the very first processes catalyzed by water soluble phosphine complexes in aqueous media [7,8]. The reaction itself is the dimerization of a diene coupled with a simultaneous nucleophilic addition of HX (water, alcohols, amines, carboxylic acids, active methylene compounds, etc.) (Scheme 7.3). It is catalyzed by nickel- and palladium complexes of which palladium catalysts are substantially more active. In organic solutions [Pd(OAc)2] + PPhs gives the simplest catalyst combination and Ni/IPPTS and Pd/TPPTS were suggested for mnning the telomerizations in aqueous/organic biphasic systems [7]. An aqueous solvent would seem a straightforward choice for telomerization of dienes with water (the so-called hydrodimerization). In fact, the possibility of separation of the products and the catalyst without a need for distillation is a more important reason in this case, too. 

Notes Useful for carboxylic acids activation towards the preparations of esters, thioesters and amides ... 

The synthetic procedures mentioned in this section certainly do not cover all the known routes leading to depsipeptides. Some seldom-used or potentially useful but not yet practically employed techniques are inevitably missing. For example, such potential might be attributed to the method of carboxylic acid activation by pyrocarbonates suggested by Pozdnev in 1992J120i In particular, this author has shown in some model cases that Boc20 in the presence of pyridine and a catalytic amount of 4-(dimethylamino)pyridine forms an ester link between an amino acid and an a-hydroxy acid in 80-90% yield. 

The Feltzin mechanism 73) takes account of the presence of proton donors at the beginning of copolymerization. However, initiation probably proceeds in two ways 74) and depends on the type of the proton donor and its concentration in the copolymerization mixture. If HA in Eq. (45) is alcohol, phenol or moisture, initiation occurs according to Eq. (46), i.e. through interaction with the anhydride yielding an ammonium salt of the monoester. The formation of monoesters as primary active centres accounts here for the lower cocatalytic effect of phenols as compared with alcohols. If the proton donor is a carboxylic acid, activation of the tertiary amine (Eq. (63)) is followed by reaction with the epoxide according to Eq. (76)74. ... 

Reduction of multiple bonds with samarium diiodide has been reviewed. Chemo-and stereo-selective reduction of various compounds such as conjugated alkenes, c/,/3-unsaturated carboxylic acids, activated alkynes, carbonyl, azides, nitriles, and nitro compounds, under mild conditions, has been discussed. Recent developments in the use of samarium metal in this field have also been discussed.381... 

Like the related fatty acid synthases (FASs), polyketide synthases (PKSs) are multifunctional enzymes that catalyze the decarboxylative (Claisen) condensation of simple carboxylic acids, activated as their coenzyme A (CoA) thioesters. While FASs typically use acetyl-CoA as the starter unit and malonyl-CoA as the extender unit, PKSs often employ acetyl- or propionyl-CoA to initiate biosynthesis, and malonyl-, methylmalonyl-, and occasionally ethylmalonyl-CoA or pro-pylmalonyl-CoA as a source of chain-extension units. After each condensation, FASs catalyze the full reduction of the P-ketothioester to a methylene by way of ketoreduction, dehydration, and enoyl reduction (Fig. 3). In contrast, PKSs shortcut the FAS pathway in one of two ways (Fig. 4). The aromatic PKSs (Fig. 4a) leave the P-keto groups substantially intact to produce aromatic products, while the modular PKSs (Fig. 4b) catalyze a variable extent of reduction to yield the so-called complex polyketides. In the latter case, reduction may not occur, or there may be formation of a P-hydroxy, double-bond, or fully saturated methylene additionally, the outcome may vary between different cycles of chain extension (Fig. 4b). This inherent variability in keto reduction, the greater variety of... 

Another carboxylic acid activation in a neutral environment together with all mechanistic details is shown in Figure 6.13 carboxylic acids and carbonyldiimidazole (A) react to form the reactive carboxylic acid imidazolide B. 

Carboxylic acids can also be activated by converting them to their anhydrides. For this purpose they are dehydrated with concentrated sulfuric acid, phosphorus pentoxide, or 0.5 equivalents of SOCl2 (1 equivalent of SOCl2 reacts with carboxylic acids to form acid chlorides rather than anhydrides). However, carboxylic anhydrides cannot transfer more than 50% of the original carboxylic acid to a nucleophile. The other 50% is released—depending on the pH value—either as the carboxylic acid or as a carboxylate ion and is therefore lost. Consequently, in laboratory chemistry, the conversion of carboxylic acids into anhydrides is not as relevant as carboxylic acid activation. Nonetheless, acetic anhydride is an important acetylat-ing agent because it is commercially available and inexpensive. 

Fig. 6.15. Carboxylic acid activation with DCC. [1,3] means the intramolecular substitution of the oxygen atom 01 by the N atom "3" via a cyclic four-membered tetrahedral intermediate. From the point of view of the heteroatoms, this SN reaction corresponds to a migration of the acyl group R-C=0 from the oxygen to the nitrogen. (Examples for amino acid activations in the form of the pentafluorophenyl ester C or the benzotriazolyl ester D are given in Figure 6.32 (oligopeptide synthesis) and Figure 6.31 (dipeptide synthesis), respectively.

RC02H or RC02 Formation of anhydrides carboxylic acid activation (Section 6.3.3) ... 

The conversion of a carboxylic acid into a carboxylic acid derivative, which is a more reactive acylating agent, is called carboxylic acid activation. One can also convert an... 

Urea A is the starting material for preparing the carbodiimide C, which activates carboxylic acids according to the same mechanism and for the same reason as DCC, with which you are already familiar (Figures 6.15 and 6.26). If the carbodiimide C from Figure 7.5 were not so much more expensive than DCC, everybody would use the former instead of the latter for carboxylic acid activation. There is a practical reason for this. When a heteroatom nucleophile is acylated with the DCC adduct of a carboxylic acid, besides the desired carboxylic acid derivative one obtains dicyclohexyl urea (formula B in Figure 7.5). This (stoichiometric) by-product must be separated from the acylation product, which is relatively laborious when realized by chromatography or by crystallization. When a carboxylic add has been activated with the carbodiimide C and the subsequent acylation of a heteroatom nucleophile has been effected, one also obtains a urea as a stoichiometric by-product. It has the structure D and is therefore... 

This reagent, benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (14, PyBOP)P l (Scheme 4), was designed in order to avoid the formation of toxic HMPA during acylation. As with BOP, it is assumed that the first step is the carboxylic acid activation which involves formation of an acyloxyphosphonium salt.P This initial salt is then attacked by the benzotriazolyloxy anion to form the benzotriazolyl active ester which then reacts with the amino component. PyBOP can easily replace the BOP reagent and is especially suitable for solid-phase peptide synthesis. It is soluble in a wide range of solvents such as DMF, di-chloromethane, THF, and NMP. PyBOP is more useful in peptide synthesis on solid support than in solution. The byproduct, tris(pyrrolidino)phosphine oxide is partially water-soluble and is easily removed by washing. PyBOP is used under the same experimental conditions as BOP. Note that PyBOP is a white, crystalline and non-hygroscopic solid. It can be kept as a solid, but solutions of PyBOP cannot be stored for more than 24 hours. 

The use of the mixed carboxylic-carbonic anhydrides is also a powerful method of carboxylic acids activation for the formation of amide bounds in peptide chemistry (see vol. 2, section 4-4). 

Pd-catalyzed deallylalion, carboxylic acid activation with Pfp-OH [97,98)... 

The linear telomerization reaction [1] of dienes (the taxogen) with nucleophiles (the telogen) such as alcohols, amines, carboxylic acids, active methylene compounds, phenols, or water provides an elegant method for the synthesis of various useful compounds (Eq. 1). 

The ester-amine reaction is slow and requires long reaction times (see Chapter IV). Many active carboxylic acid derivatives such as the azides, p-nitrophenyl esters, and thiazolidine-2-thiones as well as carboxylic acid activators, such as dicyclohexylcarbodimide (DCCI), have been used to improve this reaction (see Chapter IV) (Kimura et al., 1989a, 1989b Krakowiak et al., 1989, 1990a Nagao et al., 1980, 1981 Uoto et al., 1990). These cyclization reactions seldom need high-dilution conditions. Even though ex-... 

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