Thiol esters enolates

Both ketones and aldehydes, as well as acylsilanes can be employed as carbonyl substrates in the new p-lactone synthesis (Table). Reactions involving ketones are most conveniently carried out by adding the neat carbonyl compound to the thiol ester enolate solution. Under these conditions aliphatic aldehydes react to form substantial quantities of 2 1 adducts however, formation of these side products can be suppressed simply by slowly adding the aldehyde component as a precooled (-78°C) solution to the reaction mixture. Wide variation is also possible in the thiol ester component, although a few limitations of the method have been noted. For example, a,p-unsaturated ketones such as methyl vinyl ketone and cyclohexenone fail to yield p-lactones, and attempts to generate p-lactones with severe steric crowding have also met with limited success.3... 

Not surprisingly, thiol ester enolates combine with ketones (and many aldehydes) to form predominantly the less sterically crowded p-lactone diastereomers,... 

Not surprisingly, thiol ester enolates combine with ketones (and many aldehydes) to form predominantly the less sterically crowded p-lactone diastereomers, in some cases with excellent stereoselectivity. However, the stereochemical course of reactions involving aldehydes has proved to be rather complicated, and further studies are required to clarify the factors that control the stereochemical outcome of these reactions. 

The reaction of thiol esters with lithium ynolates (equation 67) takes place by a route different than the one shown in equation 65 for alcohol esters. Thiol esters (162) undergo a two-carbon homologation to S-keto thiol esters 165 in good yield. Intermediates 163 undergo a two-step rearrangement to a S-keto thiol ester enolate (165), via elimination of lithium thiolate to yield a ketene (164), followed by the nucleophilic attack of the thiolate on 164. Finally, the homologated S-keto thioester (165 ) is obtained on acidification of the reaction mixture . ... 

Amyes TL, Richard JP. Generation and stability of a simple thiol ester enolate in aqueous-solution. J. Am. Chem. Soc. 1992 114 10297-10302. 38. 

Knochel and Seebach similarly converted 239 to 242 by condensation with 241. The successful reaction of the thiol ester enolate anion of 239 with electrophiles seems to result from the higher kinetic acidity of the thiol ester as compared to the acidity of the normal ester . 

The first example of catalytic enantioselective protonation of metal enolates was achieved by Fehr and coworkers (Scheme 3) [44]. They found the enantioselective addition of a lithium thiolate to ketene 41 in the presence of an equimolar amount of (-)-iV-isopropylephedrine (23) with up to 97% ee. Based on the results, they attempted the catalytic version for example, slow addition of p-chlo-rothiophenol to a mixture of ketene 41 (1 equiv) and lithium alkoxide of (-)-N-isopropylephedrine 23-Li (0.05 equiv) gave thiol ester 43 with 90% ee. First, the thiol is deprotonated by 23-Li to generate lithium p-chlorothiophenoxide and 23. The thiophenoxide adds to the ketene 41 leading to Z-thiol ester enolate which is presumed to react with the chiral amino alcohol 23 via a four-membered cyclic transition state 42 to form the product 43 and 23-Li. The hthium alkoxide 23-Li is reused in the catalytic cycle. The key to success in the catalytic process is that the rate of introduction of thiophenol to a mixture of the ketene 41 and 23-Li is kept low, avoiding the reaction of the thiol with the intermediate hthium enolate. 

Enantioselective protonation. This chiral amino alcohol is an excellent proton source for thiol ester enolates. 

Danheiser and co-worker describe a convenient one-step preparation of P-lac-tones based on the addition of thiol ester enolates to carbonyl compounds. Treatment of thiol esters with 1 equiv of LDA in THF at -78 °C for 30 min furnishes lithium enolates, which smoothly combine with ketones and aldehydes at -78 °C. Subsequent gradual warming results in the formation of p-lactones in good to high yields (Eq. 28) [57]. 

Fehr C, Stempf I, Galindo J. Highly enantioselective protonation of thiol ester enolates. Angew. Chem. Int. Ed. 1993 32 1042-1044. 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

The boron enolates of a-substituted thiol esters also give excellent facial selectivity.135 CH(CH3)2 (CHg"/ -CH2)2BCI... 

It is supposed that the nickel enolate intermediate 157 reacts with electrophiles rather than with protons. The successful use of trimethylsilyl-sub-stituted amines (Scheme 57) permits a new carbon-carbon bond to be formed between 157 and electrophiles such as benzaldehyde and ethyl acrylate. The adduct 158 is obtained stereoselectively only by mixing nickel tetracarbonyl, the gem-dibromocyclopropane 150, dimethyl (trimethylsilyl) amine, and an electrophile [82]. gem-Functionalization on a cyclopropane ring carbon atom is attained in this four-component coupling reaction. Phenyl trimethyl silylsulfide serves as an excellent nucleophile to yield the thiol ester, which is in sharp contrast to the formation of a complicated product mixture starting from thiols instead of the silylsulfide [81]. (Scheme 58)... 

Because anti/syn ratios in the product can be correlated to the E(0)/Z(0) ratio of the involved boron enolate mixture,10b initial experiments were aimed at the preparation of highly E(0)-enriched boron enolate. The E(0)/Z(0) ratio increases with the bulk of the alkanethiol moiety, whereas the formation of Z(O) enolates prevails with (S )-aryl thioates. (E/Z = 7 93 for benzenethiol and 5 95 for 2-naphthalene thiol esters). E(O) reagent can be formed almost exclusively by reaction of (5)-3,3-diethyl-3-pentyl propanethioate 64 with the chiral boron triflate. High reactivity toward aldehydes can be retained in spite of the apparent steric demand (Scheme 3-22).43... 

Alcohols can also be prepared from support-bound carbon nucleophiles and carbonyl compounds (Table 7.4). Few examples have been reported of the a-alkylation of resin-bound esters with aldehydes or ketones. This reaction is complicated by the thermal instability of some ester enolates, which can undergo elimination of alkoxide to yield ketenes. Traces of water or alcohols can, furthermore, lead to saponification or transesterification and release of the substrate into solution. Less prone to base-induced cleavage are support-bound imides (Entry 2, Table 7.4 see also Entry 3, Table 13.8 [42]). Alternatively, support-bound thiol esters can be converted into stable silyl ketene acetals, which react with aldehydes under Lewis-acid catalysis (Entries 3 and 4, Table 7.4). 

The foregoing discussion, in emphasizing the purely electrostatic energy barriers, does not address the question of whether there is an activation advantage in thiol esters relative to oxygen esters. Why thiol esters in preference to oxygen esters Thiol esters are more readily enolized than... 

This difference affects each stage of the CLaisen ester condensation in the same way. Thiol esters are more easily converted to enolate anions, they are more easily attacked by nucleophiles, and RS is a better leaving group than RO. In each case the reaction is better (faster or equilibrium further towards product), the Claisen thiol ester condensation... 

If we copy Nature rather more exactly, the Claisen ester condensation can be carried out under neutral conditions. This requires rather different reagents. The enol component is the magnesium salt of a malonate mono-thiol-ester, while the electrophilic component is an imidazolide—an amide derived from the heterocycle imidazole. Imidazole has a pK of about 7, Imidazolides are therefore very reactive amides, of about the same electrophilic reactivity as thiol esters. They are prepared from carboxylic acids with carbonyl diimidazole (CDI). 

Many other reactions in nature use enamines, mostly those of lysine. However, a more common enol equivalent is based on thiol esters derived from coenzyme A. 

Another reaction that goes better with thiol esters than with ordinary esters is enolization. This is an equilibrium reaction and the enol has lost the conjugation present in the ester. The thiol ester has less to lose so is more enolized. This is the reaction of acetyl CoA that we are now going to discuss. We have mentioned the citric acid cycle several times and it has appeared in two... 

CoA thiol esters are widely used in nature. Mostly they are acetyl CoA, but other thiol esters are also used to make enols. We will see more of this chemistry in the next chapter. The two enol equivalents that wc have met so far are quite general lysine enamines can be used for any aldehyde or ketone and CoA thiol esters for any ester. Another class of enol equivalent—the enol ester—has just one representative but it is a most important one. 

The rest of the biosynthesis does not need pyridoxal, but it does need two molecules of acetyl CoA. In Chapter 50 we noted that this thiol ester is a good electrophile and also enolizes easily. We need both reactivities now in a Claisen ester condensation of acetyl CoA. 

The new keto-ester is very like the acetoacetates we used in Chapter 27 to make stable enolates and the CoA thiol ester will exist mainly as its enol, stabilized by conjugation,... 

A different cyclization leads to the flavones and anthocyanidins. Reaction of the stable enol from a 1,3-diketone with the thiol ester as electrophile results in acylation at carbon in the manner of the Claisen ester condensation (Chapter 28) with loss of CoASH and the formation of a trihydroxyben-zene ring. 

The third molecule of acetyl CoA also functions as a nucleophilic enol and attacks the keto group of acetoacetyl CoA. This is not a Claisen ester condensation—it is an aldol reaction between the enol of a thiol ester and an electrophilic ketone. 

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