Other Acyl Initiators

See Other ACYL AZIDES, FRICTIONAL INITIATION INCIDENTS... 

See other acyl azides, frictional initiation incidents... 

The biosynthesis of polyketides (including chain initiation, elongation, and termination processes) is catalyzed by large multi-enzyme complexes called polyketide synthases (PKSs). The polyketides are synthesized from starter units such as acetyl-CoA, propionyl-CoA, and other acyl-CoA units. Extender units such as malonyl-CoA and methylmalonyl-CoA are repetitively added via a decarboxylative process to a growing carbon chain. Ultimately, the polyketide chain is released from the PKS by cleavage of the thioester, usually accompanied by chain cyclization [49]. 

Reactions of organomagnesium compounds with /V,/V-disubstituted amides differ from those of other acyl derivatives (Section 6.2) in that the initial adducts are much more stable. However, although examples are known where a carbinolamine may be isolated following careful hydrolysis, acid hydrolysis without special precautions usually gives the... 

With respect to this sequence of observed reactions, experimental evidence shows that 21 reacts with the base (NaOEt) to form an enolate anion, and the nucleophilic carbon atom of that enolate anion attacks the carbonyl of a second aldehyde to give the alkoxide of 22. This is a normal acyl addition reaction, and the nucleophile is the a-carbon of the enolate anion. Treatment of this initial alkoxide product with aqueous acid under mild conditions simply generates alcohol 22, as with all other acyl addition reactions (see Chapter 18). Product 22 is called an alilol or an aldolate. The reaction of an aldehyde or a ketone with a base generates an aldol product. Vigorous acid hydrolysis led to protonation of the OH unit in 22 by the strong acid (to form an oxonium ion), which eliminated a molecule of water (dehydration) to give the alkene unit in 23. 

CFaiN RfCOF + hvRr + COF Rr + CFjiN- -> RpN CFj. Extension of this to the bis-acyl fluorides FOC (CF2)3-COF and FOC-(CF2>4-COF, however, gives low yields of perfluoro-(Af-methylpyirolid-2-one) (15 %) and perfluoro-(A -methylplperidin-2-one) ca. 10%), respectively, instead of the imines CFg N-(CF2) N CF2 (a = 3 or 4), presumably via the sequence of events shown in Scheme 39. Fluoride-initiated (CsF) reactions between the formaldazine and these, and other, acyl fluorides leads to novel heterocyclic carbonyl compounds which suffer decarbonylation when irradiated with u.v. light (see Scheme 40). Carbonyl fluoride and oxalyl fluoride react with the formaldazine in the presence of caesium fluoride to yield the acylic and cyclic product (57) (70%) and (58) (ca. 55%), respectively the latter fragments to trifluoromethyl isocyanate when exposed to u.v. light. 

Isovaleryl CoA is oxidized in a reaction similar to that found for other acyl CoA compounds to senecioyl CoA. This imsaturated thioester is a substrate for crotonase and is hydrated to j3-hydrosyisovaleryl CoA (HIV CoA). An unusual type of reaction converts this product to /3-hydroxy- 8-methyl glutaryl CoA (HMG CoA). Free CO2 is not fixed directly, but is first activated in a reaction with ATP. The activating enzyme H enzyme was purified as a hydroxylamine and bicarbonate dependent ATP-splitting enzyme the initial products are believed to be AMP-CO2 and pyrophosphate. This enzyme is different from a fluoride, bicarbonate dependent ATPase that has been shown to form... 

The synthesis of phenols via the acetate-malonate pathway shows similarities to the synthesis of the fatty acids. In the case of the latter acetyl CoA was the initiator, and here various other acyl CoAs serve this purpose. Three units of malonyl CoA are added to the initiator with accompanying decarboxylation. We may remember that in the case of the fatty acids malonyl CoA was also added with decarboxylation until the final chain length was obtained. In the present case, a polyketoacid is formed which can cyclize in different ways. We are interested here only in the so-called 1-6 C acylation which gives rise to the phenols with the hydroxyl pattern of phloroglucinol. They differ in the nature of their R substituent and, in addition, can be subjected to further modifications. 

In the reaction with 2-octanol catalyzed by C. antarctica lipase B, Ohmer et al. compare four acyl donors differing only in (heir leaving groups [7] (Table 2). In the case of octanoic acid, its low compared with the other acyl donors makes it beneficial at high conversions since it competes well with the product ester for the free enzyme (Scheme 5). However, the initial rate is lower than for other acyl donors, resulting in a slightly longer reaction time than for the thio ester and vinyl ester. 

Other carbon electrophiles which are frequently employed include aldehydes, ketones, esters, nitriles and amides of the type RCONMei. An indirect method of acylation involves the initial reaction of a lithio compound with an aldehyde followed by oxidation of the resulting secondary alcohol to the corresponding acyl derivative. 

In an initial step the reactive formylating agent is formed from N,N-dimethylformamide (DMF) 2 and phosphorus oxychloride. Other N,N-disubstituted formamides have also found application for example A -methyl-A -phenylformamide is often used. The formylating agent is likely to be a chloromethyl iminium salt 4—also called the Vilsmeier complex (however its actual structure is not rigorously known)—that acts as the electrophile in an electrophilic substitution reaction with the aromatic substrate 1 (see also Friedel-Crafts acylation reaction) ... 

The exact mechanism has still not been completely worked out. Opinions have been expressed that it is completely intermolecular, completely intramolecular, and partially inter- and intramolecular. " One way to decide between inter- and intramolecular processes is to run the reaction of the phenolic ester in the presence of another aromatic compound, say, toluene. If some of the toluene is acylated, the reaction must be, at least in part, interraolecular. If the toluene is not acylated, the presumption is that the reaction is intramolecular, though this is not certain, for it may be that the toluene is not attacked because it is less active than the other. A number of such experiments (called crossover experiments) have been carried out sometimes crossover products have been found and sometimes not. As in 11-14, an initial complex (40) is formed between the substrate and the catalyst, so that a catalyst/substrate molar ratio of at least 1 1 is required. 

Similar additions have been successfully carried out with carboxylic acids, anhydrides, acyl halides, carboxylic esters, nitriles, and other types of compounds. These reactions are not successful when the alkene contains electron-withdrawing groups such as halo or carbonyl groups. A free-radical initiator is required, usually peroxides or UV light. The mechanism is illustrated for aldehydes but is similar for the other compounds ... 

Acyl chlorides are highly reactive acylating agents and react very rapidly with alcohols and other nucleophiles. Preparative procedures often call for use of pyridine as a catalyst. Pyridine catalysis involves initial formation of an acyl pyridinium ion, which then reacts with the alcohol. Pyridine is a better nucleophile than the neutral alcohol, but the acyl pyridinium ion reacts more rapidly with the alcohol than the acyl chloride.103... 

---