Thioesters, Michael additions

In 2008, Barbas et al. developed the first enantioselective thioester Michael addition of simple trifluoroethyl thioesters, thereby establishing a new class of nucleophiles for direct catalytic reactions. Indeed, these nucleophiles were condensed onto a series of a,p-unsaturated aldehydes in the presence of 2-[bis(3,5-bistrifluoromethylphenyl)trimethylsilylanyloxymethyl]pyrrolidine as an... 

Tan also found that guanidine 21, acting as a base to activate the o [3], X [3] tautomers of diaryl phosphine oxides, catalyzes the asymmetric phospha-Michael reachon of aryl nitroalkenes (Scheme 5.42) [76]. He later employed 21 to realize highly enantioselective Michael additions of dithiomalonate and 3-keto thioesters with a range of acceptors, including maleimides, cyclic enones, furanone, and acyclic 1,4-dicarbonylbutenes [77]. 

Heterobimetallic asymmetric complexes developed by Shibasaki et al. are known as effective catalysts for asymmetric Michael additions. They achieved a catalytic asymmetric protonation in Michael additions of thiols to a,P-unsaturated carbonyl compounds using LaNa3tris(binaphthoxide) and SmNa3tris(binaphthoxide) complexes (SmSB) 37 [42]. For instance, treatment of thioester 48 with 4-fert-butyl(thiophenol) and 0.1 equivalents of (P)-SmSB 37 (Ln=Sm) in CH2C12 at -78°C gave the adduct 49 in 93% ee and in 86% yield (Scheme 4). The high enantiomeric ratio is considered to be attributable to an... 

Recently, thiols have also been shown to participate in a series of new reversible reactions suitable for DCC. Such reactions include (1) the thioester exchange reaction (Fig. 6b), (2) the thiazolidine exchange reaction (Fig. 6c), and (3) the reversible Michael addition of thiols (Fig. 6d). 

Fig. 6 (a) Thiol-disulfide exchange, (b) Thiol-thioester exchange, (c) Thiazolidine exchange, (d) Reversible Michael addition of thiols... 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

In a similar study by Dixon [19], acrylic esters, thioesters, and N-acryloyl pyrrole were also identified as effective acceptors in the Michael addition with [3-ketoesters catalyzed by 64b. Enantiomeric excesses of up to 98% and yields of up to 96% were reported (Scheme 9.22). 

The epi-quinine urea 81b was also found by Wennemers to promote an asymmetric decarboxylation/Michael addition between thioester 143 and 124 to afford the product 144 in good yield and high enantioselectivity (up to 90% ee) (Scheme 9.49). Here, malonic acid half-thioesters serve as a thioester enolate (i.e., enolate Michael donors). This reaction mimics the polyketide synthase-catalyzed decarboxylative acylation reactions of CoA-bound malonic acid half-thiesters in the biosynthesis of fatty adds and polyketides. The authors suggested, analogously with the enzyme system, that the urea moiety is responsible for activating the deprotonated malonic add half-thioesters that, upon decarboxylation, read with the nitroolefin electrophile simultaneously activated by the protonated quinuclidine moiety (Figure 9.5) [42]. 

The Mukaiyama-Michael addition of silyl enolates to a, -unsaturated thioesters is promoted by an SbCl5-Sn(OTf)2 binary catalyst to afford d-keto thioesters with high anti selectivity (Scheme 14.23) [60]. The successive treatment of lactones with a ketene silyl acetal and silyl nucleophiles in the presence of an SbCl5-Me3SiCl-Snl2 ternary catalyst yields a-mono- and a/ -disubstituted cyclic ethers (Scheme 14.24) [61]. SbFs promotes the condensation of a,y5-unsaturated aldehydes and ketones with a-diazo-carbonyl compounds to give cyclopropane derivatives in high isomeric purity [62]. 

Neither El nor E2, together or alone, mediated the formation of acrylyl- or lactyl-CoA from the respective acid plus CoA and acetyl phosphate or acetyl-CoA. However, a CoA transferase that catalyzes the formation of the CoA thioesters of lactate, acrylate, and propionate from acetyl-CoA has been isolated from C. propionicum (233). It is curious that acrylyl-CoA could not be isolated as a product with the crude or purified enzyme system, although acrylyl-CoA is readily converted to lactyl-CoA in the purified system. Abeles suggested that perhaps acrylyl-CoA exists as an enzyme-bound intermediate that requires the presence of a reductase for release as propionate. In this manner the organism is protected from buildup of toxic amounts of any acrylyl intermediates, which are known to undergo Michael addition reactions with biological nucleophiles. 

Scheme 4.11 Enantioselective Michael addition of malonic acid half-thioesters to nitroalkenes catalyzed by 70b.

High yields of 2-substituted chromans are readily attained from the asymmetric intramolecular oxa-Michael addition reaction of phenols bearing an (f -a,P-unsaturated ketone or thioester moiety mediated by a cinchona-alkaloid-urea-based bifunctional organocatalyst (140BC119). Molecular iodine-catalyzed reaction of phenols with a,P-unsaturated alcohols affords a wide range of 2,2-disubstituted chromans (14T5221). Chiral derivatives result from the intramolecular allylic alkylation of phenols bearing an... 

An intramolecular retro-Michael/Michael addition process can also cause racemization. For example, the thioester of 3-aryl-4,5-dihydroisoxazol-5-ylacetic acid can be hydrolysed by lipase in the presence of amine, giving the corresponding acid with 98% ee quantitatively (Scheme 5.39) [112]. Equihbrium between the enol(ate) and the enone/oxime anion intermediates has been proposed to explain this reaction. 

Scheme 1.9 Silylated biarylprolinol-catalysed Michael additions of thioesters to a,P-unsaturated aldehydes.

Acrylic esters, thioesters and A-acryloyl pyrrole have been identified by Dixon and Rigby as elfective electrophiles in the enantioselective Michael addition reaction with p-keto esters catalysed by a cinchona alkaloid bearing a bulky phenanthrene group (Scheme 1.27). High yields combined with excellent enantioselectivities of up to 96% ee were obtained in almost all cases of substrates. 

Scheme 1.27 Michael additions of P-keto esters to acrylic esters, thioesters and N-acryloyl pyrrole catalysed by cinchona alkaloid.

The tandem Michael addition-intramolecular Wittig reaction of the five-membered cyclic phosphonium ylide (174), generated from the phosphonium salt (173), with Q, /3-unsaturated thioester (175) afforded a diastereoisomeric mixture of cycloheptene derivatives (176a,b), in which the cw-diastereoisomer (176a) prevailed (Scheme 27). The reaction can be rationalized as proceeding via a rigid phosphabicyclic intermediate... 

Michael Additions. In the presence of a catalytic amount of trityl salts (2-3 mol%), thioester silyl ketene acetals react stereoselectively with acyclic a, 8-unsaturated ketones to give the Michael adducts in high yield (eq 11). ... 

Cinchona-alkaloid-catalysed conjugate cyanation of enones has enabled the synthesis of trifluoromethyl-substituted diarylpyrroles with ee<96%P° Thiochro-manes have been formed by asymmetric domino sulfa-Michael-aldol reactions of 2-mercaptobenzaldehyde with a,/ -unsaturated A-acylpyrazoles. Asymmetric organocatalysed oxy-Michael addition to y-hydroxy a,/ -unsaturated thioesters on reaction with t-BuCHO has been used to form -hydroxy carbonyl compounds HOCH2C H(OH)CH2CO.SAr via cyclic hemiacetal intermediates. 

Tan and co-workers reported the Michael reactions of di-thiomalonates and P-keto-thioesters to a range of acceptors, including maleimides, cyclic enones, furanones and acyclic dioxobutenes [129]. Unlike dimethyl malonate, additions with acidic thioesters proceeded in higher yields, and overall better enantioselectivities (Scheme 74). 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

Michael reactions of silyl enolates or ketene silyl acetals with a, -unsaturated carbonyl compounds are among the most important carbon-carbon bond-forming processes in organic synthesis. Sc(OTf)3 was found to be effective [4], and the reactions proceeded smoothly in the presence of a catalytic amount of Sc(OTf)3, under extremely mild conditions, to give the corresponding 1,5-dicarbonyl compounds in high yields after acid work-up (Eq. 2). Silyl enolates derived from ketones, thioesters, and esters were applicable, and no 1,2-addition products were obtained. The products could, furthermore, be isolated as synthetically valuable silyl enol ethers (I) when acid-free work-up was performed. The catalyst could be recovered almost quantitatively and could be re-used. 

A novel entry into 1,2-thiazin-3-ones (203) can be achieved by a base-catalyzed ring expansion of the 1,2-thiazetidine 1,1-dioxide (204). This reaction is initiated by a retro-Michael process leading to the a)S-unsaturated thioester (205), which cyclizes to the thiazinone (206). Thiophenoxide addition to (206) gives the heterocycle (203) in an overall yield of 90% (Scheme 41) <94LA251>. 

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