Michael reactions thioester

The success of bis(oxazoline)-copper(II) catalyzed Diels-Alder reactions involving acryloylimides as dienophiles has been extended to the Michael reaction, Eqs. 204 and 205. The observed enantiofacial discrimination in the Diels-Alder reactions was expected to translate well to Michael reactions involving enolsilanes as nucleophiles. Indeed, fumarate-derived imides afford Michael adducts of enolsilanes in high enantioselectivity (240). Diastereoselectivity in these reactions may be regulated by judicious choice of thioester and enolsilane geometry to provide either diastereomer in high selectivity (>99 1 syn or 95 5 anti). 

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). 

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. 

Horner-Wadsworth-Emmons Reactions of Phosphonate Anions. - As with the Horner modification of the Wittig reaction, the principal focus of papers that mention the Horner-Wadsworth-Emmons reaction relate to synthetic applications. The use of pressure to induce the synthesis of P-amino esters, p-thioesters and P-thionitriles via tandem Horner-Wadsworth-Emmons and Michael reactions has been reported. The reagent (l-tritylimidazol-4-yl)methylphosphonate (99) has been prepared and, when treated with aldehydes and ketones, affords (E)-vinylimidazoles in high yields. ... 

Ye, W., Jiang, Z., Zhao, Y. et a/. (2007) Chiral bicyclic guanidine as a versatile Brdnsted base catalyst for the enantioselective Michael reactions of dithiomalonates and P-keto thioesters. Advanced Synthesis and Catalysis, 349, 2454-2458. 

The Michael reaction occurs with a variety of a,/3-unsaturated carbonyl compounds, not just conjugated ketones. Unsaturated aldehydes, esters, thioesters, nitriles, amides, and nitro compounds can all act as the electrophilic acceptor... 

In addition, sUyl enol ethers of substituted acetophenones [93] or thioesters [94] react with a,P-unsaturated aldehydes under iminium-catalysis conditions in the sense of a Mukaiyama-Michael reaction (Scheme 4.24). Apphcations of this transformation can be found in the total syntheses of compactin [95] and ho mod trie acid lactone and its homolog [96]. 

The following example completes the section of threefold anionic domino processes initiated by a SN-type reaction. As discussed earlier in Section 2.2, the reaction of a five-membered cyclic phosphonium ylide with enones, a, 3-unsaturated esters, and a, 3-unsaturated thioesters provides cycloheptene or hydroazulene derivatives in a domino Michael/intramolecular Wittig reaction. This sequence... 

Kobayashi S, Akiyama R, Moriwaki M, Three-component or four-component coupling reactions leading to 6-lactams, Facile synthesis of y-acyl-6-lactams from silyl enolates, a, /l-unsaturated thioesters, and imines or amines and aldehydes via tandem Michael-imino aldol reactions, Tetrahedron Lett., 38 4819—4822, 1997. 

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. 

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). 

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. 

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]. 

Three-component coupling reaction of a-enones, silyl enolates, and aldehydes by successive Mukaiyama-Michael and aldol reactions is a powerful method for stereoselective construction of highly functionahzed molecules valuable as synthetic intermediates of natural compounds [231c]. Kobayashi et al. recently reported the synthesis of y-acyl-d-lactams from ketene silyl thioacetals, a,/l-urisalu-rated thioesters, and imines via successive SbCl5-Sn(OTf)2-catalyzed Mukaiyama-Michael and Sc(OTf)3-catalyzed Mannich-type reactions (Scheme 10.87) [241]. 

Realistically, we did not have the option of incorporating a second thio substituent to enhance the acidity of the substrate. Rather, we expected the twin effects of the thioester s electronic influence and the resonance stabilization of the Michael/ retro-Michael tandem to enable the formation of the enolate under mildly basic conditions. The electronic effect of the thioester was supported by a calculation, indicating that the pKa of the a-proton of the thioester would lower (by 1.5 p/C, units) in comparison with 9 [30]. It was not clear if this would be enough to permit racemization under reaction conditions that would support sufficient enzyme activity but relatively little work would be required to test the hypothesis. 

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. 

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>. 

Intramolecular asymmetric Stetter reactions enjoy a range of acceptable Michael acceptors and acyl anion precursors. These reactions can utilize aromatic, heteroaromatic, and aliphatic aldehydes with a tethered a,p-unsaturated ester, ketone, thioester, malonate, nitrile, or Weinreb amide. In this part, we will give a brief summary about asymmetric intramolecular Stetter reactions and selected recent results in this area (Scheme 7.17). 

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... 

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