Michael Additions to Vinyl Sulfones

In the course of total synthesis of maytansine 1 (Fig. 8.1), an ansa-macrocyclic lactam from Maytenus serrata, M. buchananii, etc., the heteroconjugate addition [1-3] of methyllithiiun to the pyranosyl heteroolefin such as 2 (Fig. 8.2) proceeded with the complete acyclic stereoselection [1]. The authors explained the high diastereoselective C-C bond formation by efficient conformational and chelational control. 

Das and Pathak [4] were interested in the synthesis of amino sugars by 

On the other hand, sterically bulky ferf-butylamine only reacted with (and not 4a) at elevated temperature to give o-gluco derivative 7 in high yield 

During the synthesis of vinyl sulfone-modihed hex-5-enofuranosides, Das and Pathak [4] observed that the variation of the substituent at the C3 carbon of furanoside to some extent affected the E/Z ratios of olefins. Thus, by changing 

Miljkovic, Electrostatic and Stereoelectronic Effects in Carbohydrate Chemistry, 225 

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Acceptor-substituted alkenes that are employed as substrates in Michael additions include a./l-unsaturated ketones (for example, see Figure 10.59), a,/3-unsaturated esters (Figure 10.60), and a,/3-unsaturatcd nitriles (Figure 10.61). The corresponding reaction products are bifunctional compounds with C=0 and/or C=N bonds in positions 1 and 5. Analogous reaction conditions allow Michael additions to vinyl sulfones or nitroalkenes. These reactions lead to sulfones and nitro compounds that carry a C=0 and/or a O N bond at the C4 carbon. 

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... 

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). 

Cory and Renneboog53 have devised an efficient bicycloannulation for the synthesis of tricyclo[3.2.1.02,7]octane-6-one (66) as shown in equation 63. The method involves three steps (1) the enolate undergoes an initial conjugate addition to phenyl vinyl sulfone, (2) the resulting sulfone-stabilized carbanion undergoes an intramolecular Michael addition to the enone, and (3) the resulting enolate displaces phenylsulfinyl moiety from the tricyclooctanone. The amount of HMPA (3 mol equivalents) is critical for effective cyclization of the enolate. 

Scheme 6.66 Products of the 12-catalyzed asymmetric Michael addition of a-alkyl cyanoacetates to vinyl sulfone and exemplary conversion of one adduct to the respective 3 amino acid. The values in parentheses were obtained after single recrystallization the absolute configurations of the products were not determined.

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... 

Cinchona alkaloids and their derivatives have been reported to catalyse the Michael addition of (V-heterocycles, such as benztriazole, to nitroalkenes in moderate to high enantioselectivities (<94% ee) 15 The thiourea derivative (149) catalysed Michael addition of thioacetic acid to a range of frafts-/f-nitrostyrenes to afford RCH(SAc)- CH2NO2 (<70% ee) 16 The thiourea derivative (149) and its congeners have been identified as efficient organocatalysts for the Michael addition of a-substituted cyano-acetates RCH(CN)C02Et to vinyl sulfones CH2=C(R)S02Ph (72-96% ee) 17 ... 

The first asymmetric direct Michael addition of enolizable aldehydes RCH2CH=0 to vinyl sulfones CH2=C(S02Ph)2 catalysed by /V-Pr -2,2 -bipyrrolidine (146) has been reported. The 1,4-adducts were obtained in good yields and enantioselectivities... 

Octahydronapthalene synthesis.1 An intramolecular version of this annelation using a Michael addition to a vinyl sulfone provides the octahydronapthalene unit (1) of compactin (2), a mevinic acid of interest as an inhibitor of cholesterol synthesis. 

The Michael addition of enolates to vinyl sulfones allows one-pot tandem reactions to be devised to achieve cyclisations as illustrated in Scheme 55. In the first reaction, the enolate (131) is transformed into the cyclic p-hydroxy sulfone (132) in good yield. In the second reaction, the enolate (133) yields the tricyclic compound (134) as a result of a double Michael reaction followed by intramolecular elimination of the benzenesulfonyl group. 

The Michael addition of enolates to vinyl sulfones is facilitated by the introduction of carbanion-stabiIising groups at the a-vinylic position, as illustrated in Scheme 56. 

Very recently, Lu and coworkers successfully applied aminocatalysis via the enamine intermediate to the Michael addition of cyclic ketones to vinyl sulfones 181 [56]. In the presence of the cinchonidine-derived primary amine salt 179, the Michael reactions between vinyl sulfones 181 and cyclic ketones 180 proceeded smoothly, affording the desired adduct 182 in very high yield and with excellent enantioselectivity (up to 97% ee) (Scheme 9.63). They also successfully applied this methodology to the synthesis of sodium cyclamate. However, this protocol gave poor yields and ee values for acyclic ketones. 

Michael addition of cyclic ketones to vinyl sulfone... 

Scheme 4.46 Enantioselective Michael addition of a-alkyl a-cyanoketones to vinyl sulfones catalyzed by 84c.

The Michael-type addition reaction of carbon nucleophiles to vinyl sulfone-modified carbohydrates should be considered as an efficient route for the synthesis of branched-chain sugars because almost all carbohydrates in pyranose and furanose form could be converted to their vinyl sulfone derivatives very easily [5, 12-14]. Moreover, the product of the reaction carrying sulfone functionality has the potential to undergo a wide variety of transformations [15]. For a review on desulfonylation reaction, see Ref. [16]. 

Scheme 8.5 Michael addition of aldehydes to vinyl sulfones.

The constrained tricyclic chiral secondary amine 43 was proposed hy Loh et al. in 2011 for the highly enantioselective organocatalytic Michael addition of aliphatic aldehydes to vinyl sulfones (Scheme 11.44). DFT calculations revealed that only 42-derived sy -enamine is formed due to steric congestions and that the naphthyl ring is puckered in the chiral pocket of the tricyclic system, efficiently shielding only one of the diastereotopic faces of the reactive enamine. ... 

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. 

S.2.2.3. a, -Unsaturated Sulfones, Malononitriles, and Maleimides as Acceptors, Base on their previous achievements on the asymmetric Michael addition of aldehydes [24], Lu and co-workers [55] developed the first enantiose-lective conjugate addition of cyclic ketones to vinyl sulfone catalyzed by a primary amine 57 (Scheme 5.28). Various cyclic ketones could be applied, affording the corresponding adducts in good yields and with high to excellent enantioselectivities. However, linear ketones were not suitable substrates for this catalytic system. Performing the desulfonylation procedure on a-substituted ketones and in combination... 

Michael Addition. Methallyl phenyl sulfone has been a good partner with a variety of different Michael receptors. Addition to enones using / BuLi as base at —78 °C gave the desired products in good yields. Methyl vinyl ketone afforded the Michael adduct in 61% yield (eq 7). Reaction of methallyl sulfone with 2-hexenone and 2-methyl-2-pentenone in the presence of HMPA provided the conjugate addition products in 91% yield and 79% yield, respectively (eqs 8 and 9).lO.Ha... 

Similar Michael additions of various aldehydes to vinyl sulfones to some of those depicted above have also been developed by Alexakis et al. in the presence of an aminal-pyrrolidine organocatalyst derived from proline, albeit leading to... 

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