Thiol esters reaction with aldehydes

A new thiol auxiliary (45, R = COEt) participates in boron-mediated anti-aldol reactions with aldehydes with high yield and de.124 Reaction of the product with (g> nucleophiles displaces it (in the form of the thiol, 45 R = H), converting the aldol product under mild conditions into esters, thiolates, phosphonates, alcohols, or acids. 

Other Michael Acceptors, other Michael acceptors such as malei-mides [27], vinyl phosphonates [28], alkylidine malonates [29], ethyl 2-(dithox-yphosphoryl)acrylate [30], a-keto-a,(3-unsaturated esters [31], -Y-keto a, 3-unsaturated esters [32], and a,(3-unsaturated thiol esters [33] were also applicable in the enantioselective Michael reactions with aldehydes (Scheme 5.15). 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

Barrett and coworkers have explored hetero-substituted nitroalkenes in organic synthesis. The Michael addition of nucleophiles to 1-alkoxynitroalkenes or 1-phenylthionitroalkenes followed by oxidative Nef reaction (Section 6.1) using ozone gives a-substituted esters or thiol esters, respectively.41 As an alternative to nucleophilic addition to l-(phenylthio)-nitroalkenes, Jackson and coworkers have used the reaction of nucleophiles with the corresponding epoxides (Scheme 4.4).42 Because the requisite nitroalkenes are readily prepared by the Henry reaction (Chapter 3) of aldehydes with phenylthionitromethane, this process provides a convenient tool for the conversion of aldehydes into ot-substituted esters or thiol esters. 

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... 

The three-component method is applicable to the synthesis of various C(6)- or C(7)-functionalized PGs. Scheme 11 illustrates the tandem conjugate addition-aldol reaction that affords 7-hydroxy-PGE derivatives (18). Both saturated and unsaturated C7 aldehydes can be used as a side-chain units. The aldol adducts can be transformed to naturally occurring PGs (5a, 19) and, more importantly, to a variety of analogues such as tumor-suppressing A7-PGA, (20) or 7-fluoro-PGI2, a stabilized prostacyclin (21). The unique cellular behavior displayed by A7-PGA methyl ester is well correlated to its chemical reaction with thiols (20). 

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). 

One of the reported syntheses of ( )-9-oxodec-2-enoic acid 392, the queen substance of the honey bee Apis mellifera, uses two ylide reactions 222). Starting from pimelic acid 385 the resonance-stabilized ylide 386 is prepared by alkylation of methylene-triphenylphosphorane 209 and the former hydrolyzed to 7-oxooctanoic acid 387. Reduction of the corresponding thiol ester 389 and olefination of the resulting aldehyde 390 with phosphorane 67 gives the ( )-2-unsaturated ester 391. The latter was hydrolyzed to pheromone 392 222) (Scheme 69). 

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, 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 reduction of a carboxyl group to an aldehyde group can be effected by a reductive desulfurization of the thiol ester with Raney nickel. The thiol esters are prepared by the reaction of the acyl chloride with an excess of ethyl mercaptan in pyridine or by reaction with lead mercaptide in dry ether. The hydrogenolysis is then carried out by refluxing an ethanol ic solution of the thiol ester with Raney nickel for 6 hours. By this new synthesis, propionaldehyde and benzaldehyde have been prepared in 73% and 62% yields, respectively. ... 

This reaction was carried out on cyclic and acyclic allylic carbonates. The 5-allylic thiocarbamate products were hydrolyzed to the corresponding thiol or reacted with 2-chloropyrimidine in the presence of potassium hydroxide to provide the sulfide without any loss in stereochemical purity for either example. a-Acetoxysulfones can be regarded as acid-stable, but base-labile, chiral aldehyde equivalents. These can be accessed through the palladium(0)-cataly zed reaction of geminal esters with sodium benzenesulfinate under phase-transfer conditions (eq 12). ... 

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