Sulfones, vinyl Michael acceptors

At the same time as the emergence of the vinyl sulfones as Michael acceptors in organocatalyzed conjugate additions, a new type of acceptor appeared in the form of vinyl selenones. 

The formed vinyl sulfones are powerful Michael acceptors, which by treatment of the y-emti-product with base, undergo ring closure to diastereomerically pure 4-sulfonyltetrahydrofurans39. 

Vinyl sulfones, being good Michael acceptors, have been regarded as useful reagents for carbon-carbon bond formation. Nucleophiles used often are organometallic reagents, enamines and enolate anions and the Michael addition products are usually obtained in... 

From the same zirconocene intermediates, Huang and co-workers have prepared vinyl sulfides [24,35] and sulfones [26] through use of the appropriate quenching agents (Scheme 4.6). Treatment of vinyl zirconocenes with an equivalent of a disulfide in THF at 60 °C affords, after work-up and purification, (E)-vinyl sulfides in good isolated yields. Vinyl sulfones, which as a class are generally useful as Michael acceptors and Diels—Alder dienophiles, are obtained in about two hours upon treatment of (fc)-vinyl zirconocenes with various sulfonyl chlorides in THF at 40°C. 

The most promising tools developed for this sort of analysis are active-site-directed irreversible inhibitors of DUBs. These inhibitors are ubiquitin or ubiquitin-like proteins chemically modified at the C-terminus by an electrophilic moiety such as a Michael acceptor or alkyl halide. The modified ubiquitin can be incubated with a purified DUB or a cell lysate containing DUB activity. Ubiquitin vinyl sul-fone (UbVS) is one such irreversible inhibitor because the vinyl sulfone moiety reacts with the active-site cysteine of the DUB, forming a thioether linkage. The covalent adduct is stable and can be detected in a variety of ways. Labeling of DUBs is specific, as only a DUB active-site cysteine will efficiently react with the vinyl sulfone moiety. 

Also known as Morita-Baylis-Hillman reaction, and occasionally known as Rauhut-Currier reaction. It is a carbon—carbon bond-forming transformation of an electron-poor alkene with a carbon electrophile. Electron-poor alkenes include acrylic esters, acrylonitriles, vinyl ketones, vinyl sulfones, and acroleins. On the other hand, carbon electrophiles may be aldehydes, a-alkoxycarbonyl ketones, aldimines, and Michael acceptors. 

The vinyl substituent at C-2 can also act as a Michael acceptor and reaction with certain nucleophiles gives rise to 1,4-addition compounds. For example, p-toluene-sulfonic acid catalyzed addition of thiols to 2-vinyl- or 2-isopropenyl-5(47/)-oxazolones 136 gave, almost exclusively, the Michael adducts 137 that were used... 

The procedure for oxidation of the sulfide to the sulfone is based on that reported earlier by Bordwell and Pitt. The synthetic utility of phenyl vinyl sulfone and sulfoxide derives not only from their ability to serve as excellent Michael acceptors toward such reagents as enolate anions and... 

Other synthetic approaches via sulfones make use of the Michael addition and cycloaddition to vinyl sulfones (see [401] and [402] for reviews on vinyl sulfones as dienophiles and Michael acceptors). The... 

Various peptide Michael acceptors have been described as a new class of inactivators for cysteine proteases. 5-7 The carbonyl group of the scissile peptide bond in the substrate is replaced by a nucleophile trapping moiety such as a vinylogous structure. An amino acid vinyl sulfone, l-(methylsulfonyl)-4-phenylbut-l-en-3-amine [H2NCH(Bzl)CH=CHS02Me] and a dipeptide derivative, Gly-HNCH(Bzl)CH=CHS02Me have both been prepared as inhibitors of cysteine proteases, leucine aminopeptidase and dipeptidyl peptidase I, respectively.1 5 A series of peptide vinyl sulfones has been synthesized as potent inhibitors for different cysteine proteases. 1A8 ... 

Nitroalkenes, vinyl sulfones and vinylphosphonium salts have been shown as good Michael acceptors for 2-lithio-l,3-dithiane derivatives. Nitroalkene sugar derivative 246 has been used as electrophile for the synthesis of branched-chain cyclitols397 - 399. Seebach and Langer studied the addition to simple nitroalkenes using the chiral solvent (,S ,.S )-DDB (247) with some degree of diastereoselectivity400,401. 

Another frequent use of (1) and its enantiomer is the stereospecific conjugate addition of carbonyl compounds to a,p-unsaturated systems. Most published examples contain chiral imine derivatives of cyclic ketones, which add to a,p-unsaturated esters and ketones in a highly stereoselective manner (eq 13 and eq 14). When the ketone is not symmetrically substituted, reaction usually occurs at the most substituted a-position, including those cases where the ketone is a-substituted by oxygen (eq 15). High stereoselectivity can also be achieved when the Michael acceptor is other than an unsaturated ketone or ester, such as a vinyl sulfone (eq 16). Intramolecular variations of this transformation have also been described (eq 17). ... 

Recent investigations into the chemistry of vinyl sulfones have revealed that they are versatile synthetic intermediates, serving either as dienophiles or Michael acceptors. Methods for the preparation of vinyl sulfones from unactivated olefins have customarily involved the catalyzed (boron trifluoride or benzoyl peroxide) addition of PhS02X (X Cl, Br, I, or SePh), followed by elimination of HX. However, when phenylsulfonyl halides are employed, yields are variable, reactions are frequently incomplete, and the Lewis acid or free-radical catalyst employed can potentially interfere... 

The procedure for oxidation of the sulfide to the sulfone is based on that reported earlier by Bordwell and Pitt. The synthetic utility of phenyl vinyl sulfone and sulfoxide derives not only from their ability to serve as excellent Michael acceptors toward such reagents as enolate anions and organometallics, but also as moderately reactive dienophiles in Diels-Alder reactions. " The resulting adducts, in turn, can be chemically modified so that these electron-deficient olefins serve as useful synthons for acetylene,ethylene,terminal olefins,vinylsilanes, and ketene in [4 + 2] cycloadditions. Phenyl vinyl sulfone undergoes ready cycloaddition to Danishefsky s diene in the first step of a protocol for the regiospecific y-alkylation of 2-cyclohexenones. Furthermore, the ready lithiation of phenyl... 

For example, the addition to vinyl sulfones has attracted a lot of attention mainly because of the synthetic possibilities that the sulfone group affords in terms of its wide possibilities to undergo a wide variety of transformations. iPBP 15a and prolinal-deiived aminal 12b catalysts have proved their usefulness in the Michael addition of aldehydes to this particular class of Michael acceptors, showing that good yields of the desired Michael adducts could be obtained under the optimized conditions, although with moderate enantios-electivities (Scheme One of the main problems of this particular... 

Continuing with the use of cinchona alkaloid-based quaternary ammonium salts as catalysts, phenyl vinyl sulfones have also been employed as Michael acceptors in the reaction with glycine imines using cinchonidinium salt 103a as catalyst both in solution or in a solid-supported version (Scheme 5.33), furnishing similar results to those provided by the corresponding vinyl ketones and acrylates shown in Schemes 5.8 and 5.23. ... 

The functionalization of an exocyclic carbon atom of the pyranose or furanose ring using vinyl sulfone-modified carbohydrate has not been explored in spite of the efficient use of vinyl sulfone-modified pyranose derivative as a Michael acceptor for the synthesis of maytansinol [1]. 

Other Michael acceptors that were used in addition of aldehydes were vinyl sulfones. Zhu and Lu showed that the most efficient catalyst for this reaction was catalyst C2a with 3,5-bis(trifluoromethyl)phenyl groups (Scheme 8.5). It provided the corresponding products in high yields, with good to high diastereomeric and high enantiomeric purities. Palomo and coworkers also came to the same conclusion. They also extended the scope of the addition to E-a-ethoxycarbonyl vinyl sulfones. 

Since vinyl sulfoxides are poorer Michael acceptors than vinyl sulfones, the DABCO-catalyzed MBH reaction of vinyl sulfoxide with aldehydes required more forcing conditions to achieve a satisfactory yield, albeit with low diastereo-selectivity (Scheme 1.40). No reaction was observed at ambient pressure. Phenyl vinyl sulfonate is surprisingly reactive (Scheme 1.41), but only one example of this class of compounds has been reported. 

Because a different stereochemistry for the aza-MBH reaction involving different Michael acceptors was observed, in a continuation of our work, we reinvestigated systematically the reaction of iV-sulfonated imines with various activated olefins, including ethyl vinyl ketone (EVK), acrolein, phenyl acrylate and a-naphthyl acrylate. An interesting inversion of absolute configuration between the adducts derived from MVK or EVK and those from acrolein, methyl acrylate, phenyl acrylate or a-naphthyl acrylate was observed, indicating that the substitution patterns of the olefin may alter or even invert this trend.Similar to the addition to HFIPA, the (3-ICD-mediated addition of methyl, phenyl and naphthyl acrylates 149 to V-sulfonyl imines afforded adducts 150 with an (5) configuration, which is opposite to that observed with aldehydes (Scheme 2.71). ... 

A wide variety of carbon nucleophiles have been successfully used in the organocatalytic asymmetric inter- and intramolecular Michael addition to different a,p-unsaturated systems. Among them, the addition of aldehydes to diverse Michael acceptors such as, a,p-unsaturated ketones, alkylidene malonates, P-nitrostyrenes, and vinyl sulfones, is one of the most studied reactions. Enamine catalysis is the most frequently employed chiral activation found in the literature. 

The asymmetric conjugate addition of activated methylenes is one of the most studied organocatalytic reactions. A wide variety of Michael acceptors such as enals, enones, a,P-unsaturated nitriles, nitroolefins, a,(i-unsaturated imides, and vinyl sulfones have been successfully employed as elechophiles with high degree of stereocontrol. 

Further extension of the scope of Michael acceptors to vinyl sulfones was realized by Alexakis and co-workers [112] recently. 7>an5-4-hydroxyprolylamide 117 was found to be the optimal catalyst to promote the intramolecular Michael addition of aldehydes to vinyl sulfone, furnishing the desired products 116 in good yields, together with good diastereoselectivities and enantioselectivities (Scheme 5.54). 

Addition of Nucleophiles 1,2 vs 1,4. The addition of various nucleophiles to PhS02CHD-epoxide can be controlled, with some exceptions, by careful choice of reaction conditions. The use of soft nucleophiles takes advantage of the propensity of the vinyl sulfone to act as a Michael acceptor (eq 1). Neutral amines, eno-lates and their equivalents, cuprates, and sodium borohydride all provide the l,4-ira/j5 addition adduct in excellent yields. Alternatively, use of Lewis acids reverses this trend. For instance, amines with LiC104, MgBr2, Me2AlCl, and TMSN3 with Yb(OTf)3 furnish the 1,2-trans-addition product as the major isomer. Table 1 lists a variety of nucleophiles that add in a 1,2-fashion, and Table 2 lists a variety of nucleophiles that add in a 1,4-fashion. ... 

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