Enol acyl, formation lactone

Scheldt and co-workers have also accessed enolate equivalents from enals to furnish cyclopentanes 236 asymmetrically. Formation of the enolate equivalent from enals 235 with the NHC, followed by an intramolecular Michael reaction and 0-acylation, gives the lactone products 236, which are readily opened by either alcohols or amines to generate functionalised cyclopentane derivatives 237 in excellent ee. 

Figure 13.50 outlines how esters in general (not shown) and especially lactones (shown) can be prepared for a one-step aldol condensation with an aldehyde they are exposed to a mixed ( crossed ) Claisen condensation with formic acid methyl ester (cf. Figure 13.59, first line). Like all Claisen condensations (Section 13.5.1), this also first leads to the formation of the enolate of the acylated ester. Unlike other Claisen condensations, this enolate is isolated. 

Kinetic enolate formation must occur at the methyl group of the ketohe followed by acylation with the lactone. Lactones are rather more electrophilic than noncyclic esters, but the control in this sequence is still remarkable, Notice how a stable enolate is formed by proton transfer within the first-fofmed product. 

An alternate approach, which also uses enzyme-catalyzed ring-opening of a lactone to generate a mechanism-activated inhibitor, was developed by Katzenellenbogen and his co-workers [183], who found enol lactones, exemplified by (13-8) and (13-9), to be potent, selective inhibitors of HLE. The haloenol lactone (13-9) was an irreversible inactivator of HLE and chymotrypsin, and after exposure to (13-9), active enzyme could not be regenerated even upon treatment with hydrazine. Enol lactone (13-8), on the other hand, was an alternate-substrate inhibitor, which produced only transient inhibition of HLE and chymotrypsin. These results have been interpreted to mean that, with the halo-substituted compounds, ring opening results in formation of an acyl-enzyme that contains a reactive halomethyl ketone, which then alkylates His-57. That these compounds... 

The first step of the Stobbe condensation is the deprotonation of the succinate at the a-carbon to afford an ester enolate that in situ undergoes an aldol reaction with the carbonyl compound to form a 3-alkoxy ester intermediate. The following intramolecular acyl substitution gives rise to a y-lactone intermediate which undergoes ring-opening and concomittant double bond formation upon deprotonation by the alkoxide ion. Under certain conditions the lactone intermediate can be isolated. 

Spiroannelation.2 Acylation of 1 by the enol lactone 2 results in formation of only one (3) of the two possible spiro[4.5]decenes. The bulky isopropyl group is... 

In 1982, Evans reported that the alkylation of oxazolidinone imides appeared to be superior to either oxazolines or prolinol amides from a practical standpoint, since they are significantly easier to cleave [83]. As shown in Scheme 3.17, enolate formation is at least 99% stereoselective for the Z(0)-enolate, which is chelated to the oxazolidinone carbonyl oxygen as shown. From this intermediate, approach of the electrophile is favored from the Si face to give the monoalkylated acyl oxazolidinone as shown. Table 3.6 lists several examples of this process. As can be seen from the last entry in the table, alkylation with unactivated alkyl halides is less efficient, and this low nucleophilicity is the primary weakness of this method. Following alkylation, the chiral auxiliary may be removed by lithium hydroxide or hydroperoxide hydrolysis [84], lithium benzyloxide transesterification, or LAH reduction [85]. Evans has used this methology in several total syntheses. One of the earliest was the Prelog-Djerassi lactone [86] and one of the more recent is ionomycin [87] (Figure 3.8). 

Formation of the unexpected oxazolidinone in G18 proved to be crucial because models showed that direct C-acylation of the C-9 enolate derived from G17 was sterically disfavored. However, treatment of G18 with sodium meth-oxide did afford lactone G20 in 70% yield. Enolate G19 is postulated as the intermediate, and as in the case of the actinobolin analogue (E8, Scheme 18), regioisomeric enolization at C-7 is of no consequence, since acylation at that site is a less favored reaction. 

Other reactions of carbohydrates include those of alcohols, carboxylic acids, and their derivatives. Alkylation of carbohydrate hydroxyl groups leads to ethers. Acylation of their hydroxyl groups produces esters. Alkylation and acylation reactions are sometimes used to protect carbohydrate hydroxyl groups from reaction while a transformation occurs elsewhere. Hydrolysis reactions are involved in converting ester and lactone derivatives of carbohydrates back to their polyhydroxy form. Enolization of aldehydes and ketones leads to epimerization and interconversion of aldoses and ketoses. Addition reactions of aldehydes and ketones are useful, too, such as the addition of ammonia derivatives in osazone formation, and of cyanide in the Kiliani-Fischer synthesis. Hydrolysis of nitriles from the Kiliani-Fischer synthesis leads to carboxylic acids. 

Besides the more often-used acyl donors mentioned above, others which would also ensure an irreversible type of reaction have been investigated [170]. Bearing in mind that most of the problems of irreversible enzymatic acyl transfer arise from the formation of unavoidable byproducts, emphasis has been put on finding acyl donors that possess cyclic structures, which would not liberate any byproducts at all. However, with candidates such as lactones, lactams, cyclic anhydrides (e.g., succinic acid anhydride [171]), enol lactones (e.g., diketene [172, 173]), and oxazolin-5-one derivatives [174], the drawbacks often outweighed their merits. 

Ketene [2 + 2] cycloaddition with disubstituted ketones or aldehydes with phosphine catalysis gives P-lactone formation with a preference for the traws-diastereomer (Scheme 4.32). The formation ofphosphonium eno-late intermediates was monitored using NMR, and based on the NMR observation of the intermediates a mechanism was proposed in which the phosphonium enolate 158 reacted with a second molecule of the ketene forming intermediate 159, which then was acylated by the aldehyde followed by loss of 158 and formation of the product p-lactone. The use of the chiral phosphine catalyst BINAPHANE gave enantioselective product formation. 

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