Michael reactions sulfoxide

The intramolecular Michael reaction is also a powerful transformation. In the cyclizations reported by Tetsuaki Tanaka of Osaka University (J. Org. Chem. 2004, 69, 6335), the stereochemical outcome is controlled by the chirality of the sulfoxide. Remarkably, subsequent alkylation or aldol condensation leads to one or two additional off-ring stereocenters with high diastereocontrol. Note that the high stereoselectivity in the cyclization is only observed with the (Z)-unsaturated ester. 

As with the Michael reaction (5-17) the 1,4 addition of organometallic compounds has been performed diastereoselectively517 and enantioselectively.518 In one example of the latter,519 a, (3-unsaturated sulfoxides that are optically active because of chirality at sulfur (p. 100) have given high enantiomeric excesses, e.g.,520... 

A large part of the usefulness of the Michael reaction in organic synthesis derives from the fact that almost any activated alkene can serve as an acceptor7—a, 3-unsaturated ketones, esters, aldehydes, amides, acids, lactones, nitriles, sulfoxides, sulfones, nitro compounds, phosphonates, phosphoranes, quinones,... 

The use of a-thiophenyl enones (106 Scheme 12) allows the preparation of phenols such as (107) from cyclic ketones (18).30 The same product can also be obtained by normal Robinson annulation of methyl vinyl ketone (30) and the p-keto sulfoxide (lOS).30 Acceptors other than a, 3-unsaturated carbonyls have been used in both the Michael reaction and the Robinson annulation process. For example, nu-... 

The conjugate addition of heteronucleophiles to activated alkenes has been used very often in organic synthesis to prepare compounds with heteroatoms [3 to various activating functional groups, e.g. ketones, esters, nitriles, sulfones, sulfoxides and nitro groups. As in the Michael reaction, a catalytic amount of a weak base is usually used in these reactions (with amines as nucleophiles, no additional base is added). 

Asymmetric synthesis by a Michael reaction. Japanese chemists report that Michael addition to a, -unsaturated sulfoxides proceeds readily. Thus /vtolyl vinyl sulfoxide (2) reacts with diethyl malonatc and ethyl acctoaoctate in the presence of an equimolar amount of. sodium ethoxide in ethanol to give the Michael adducts (3) and (4). 

NaBHj/NiC or Raney nickel, the menthyloxy group is removed with NaBH /KOH to give 3,4-disubstituted butyrolactones with a high diastereo- and enantioselectivity (Figure 7.69). Corey and Houpis [1458] have described asymmetric Michael reactions of ketone enolates with a 2-thiophenyl crotonate of 8-phenmenthol. Chirality has also been introduced on the amino group of 2-ami-nomethyiacrylates to perform the asymmetric addition of the anion of the tert-Bu ester of cyclopentanecarboxylate [1459], More important developments have been reported with chiral a,p-unsaturated sulfoxides and nitro compounds as Michael acceptors (see below). 

The term Michael addition has been used to describe 1,4- (conjugate) additions of a variety of nucleophiles including organometallics, heteroatom nucleophiles such as sulfides and amines, enolates, and allylic organometals to so-called Michael acceptors such as a,p-unsaturated aldehydes, ketones, esters, nitriles, sulfoxides, and nitro compounds. Here, the term is restricted to the classical Michael reaction, which employs resonance-stabilized anions such as enolates and azaenolates, but a few examples of enamines are also included because of the close mechanistic similarities. 

Recendy, we described a useful sequence where Michael-acceptor sulfoxides 30 were obtained in two steps from homopropargylic alcohols 29 by radical addition of thiophenol and oxidation with sodium periodate. The unsaturated sulfoxides were used in a highly stereoselective intramolecular oxa-Michael reaction. The sequence provided stereoselective functionalization of the sulfoxide moiety, and the products 31 proved to be useful in the synthesis of modified furanosides 32. This represents a good exanple where sugars are prepared from acyclic precursors. The Michael addition was followed by a hydrolytic Pummerer reaction, yielding protected a-hydroxy aldehydes tScheme 20.8) that upon acidic treatment afforded 3-substituted ribofuranoses. 

The Pd-catalyzed allylic alkylation strategy was also applied to the synthesis of allyl sulfoxides 318 by Poli et al. The use of sulfenate anions 319 (Scheme 46.37), generated from 3-sullinylesters 317 by a retro-Michael reaction under biphasic conditions, is noteworthy. 

An intramolecular version of enolate Michael addition to enantiomerically pure vinylic sulfoxides is represented by reaction of a cyclopentenone sulfoxide with dichloroketene (Scheme 5)90 this type of additive Pummerer rearrangement has been developed by Marino and coworkers91 into a highly effective way of constructing variously substituted lactones in very high enantiomeric purity (equation 43). 

In the Michael addition reaction depicted in eq. [146] the diastereomeric sulfoxides 312 are formed under kinetic control conditions, therefore, the addition of sodium diethyl malonate is an irreversible process. On the contrary, addition of sodium methoxide to the sulfoxide 311 is a thermodynamically controlled process and leads to a mixture of diastereomeric ]3-methoxysulfoxides 313 in a 31 69 ratio (320). 

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