Lewis acid Michael reactions

Lewis acid catalyzed reaction of oximes 172 (equation 113) with divinyl ketone (173) provided l-aza-7-oxabicyclo[3.2.1]octan-4-ones 174 through a sequential Michael addition and [3 + 2] cycloaddition. The reaction occurred with complete stereoselectivity giving the same product with both cis- and frawi-oximes . 

The second chapter, by David A. Oare and Clayton H. Heathcock, deals with the stereochemistry of uncatalyzed Michael reactions of enamines and of Lewis acid catalyzed reactions of enol ethers with a,/ -unsaturated carbonyl compounds. It is effectively a continuation of their definitive review of base-promoted Michael addition reaction stereochemistry that appeared in the preceding volume of the series. 

To date, the focus has been on Lewis acid catalyzed reactions in water [149, 150]. In particular, Cu -catalyzed Diels-Alder (D-A), Michael addition, and fluorination reactions have been investigated (Fig. 13). 

Lewis Acid Catalyzed Reactions. S amarium iodide catalyzes several transformations by presumably acting as a Lewis acid. For example, it is an efficient catalyst for the imino-Diels-Alder (eq 70) and for imino-aldol reactions. Tandem Mukaiyama-Michael-aldol (eq 71) and Michael imino-aldol processes have also been reported. ... 

Whereas the foregoing Diels-Alder based strategies involve vertical disconnections a recent approach to 11-deoxyanthracyclinones employs a diagonal disconnection [125]. Lewis acid catalysed reaction of the acryloyl quinone 164 with various pentadienyl tins resulted in a tandem Michael/Diels-Alder sequence to give the tetracyclic products 166 in one step. These were converted to ( )-11-deoxyanthracyclinones via the epoxides 167. Another diagonal ... 

Allyltributylstannanes are common reagents in both radical and Lewis acid-mediated reactions, although they are unknown to react with enones. However, there has been the first report of a reaction of an electrophilic allylstannane with an enone (Scheme 1). While the parent allylstannane does not react with enones, those substituted with an ester substitute smoothly at the y3-position of enones. The authors claim this to be the first non-basic and non-nucleophilic alternative to the Michael reaction. 

The anions, generated in situ by desilylation of silylacetylenes, allylsilanes, propargylsilanes, a-silyloxetanones, bis(trimethylsilylmethyl) sulfides, and other silane derivatives,can undergo nucleophilic addition to ketones and aldehydes (eq 11). Al-(C,C-bis(trimethylsilyl)methyl) amido derivatives can add to aldehydes followed by Peterson alkenation to form acyl enamines. Treatment of 2-trimethylsilyl-l,3-dithianes can generate dithianyl anions, which are capable of carbocyclization via direct addition to carbonyl or Michael addition (eq 12). The fluoride-catalyzed Michael additions are more general than Lewis acid-catalyzed reactions and proceed well even for those compounds with enolizable protons and/or severe steric hindrance (eq 13). ... 

The powerful nucleophilicity of enaimnes illows the dclthcion of rutro ilkenes to take place without the presence of Lewis acids The isolanon of secondary products, which can be explained by an initial Michael addition, suggests the participation of zwitlerionic intermediates m the mechanism of the reaction fEq 8 97i... 

Similar additions may be performed with the enamine 13. However, with 3-buten-2-one or methyl 2-propenoate Lewis acid catalysis is needed to activate the Michael acceptor chloro-trimethylsilane proved to be best suited for this purpose. A remarkable solvent effect is seen in these reactions. A change from THF to HMPA/toluene (1 1) results in a reversal of the absolute configuration of the product 14, presumably due to a ligand effect of HMPA235. 

Hydrazoic acid can be added to certain Michael-type substrates (Z is as defined on p. 975) to give 3-azido compounds. The reaction apparently fails if R is phenyl. Ammonia also adds to enol ethers CH2=CHOR to give CH3—CH(OR)N3, and to silyl enol ethers, but it does not add to ordinary alkenes unless a Lewis acid catalyst, such as TiCU, is used, in which case good yields of azide can be obtained. Ammonia can also be added indirectly to ordinary alkenes by azidomercuration, followed by demercuration, analogous to the similar procedures mentioned in... 

The optically active a-sulfinyl vinylphosphonate 122 prepared in two different ways (Scheme 38) is an interesting reagent for asymmetric synthesis [80]. This substrate is an asymmetric dienophile and Michael acceptor [80a]. In the Diels-Alder reaction with cyclopentadiene leading to 123, the endo/exo selectivity and the asymmetry induced by the sulfinyl group have been examined in various experimental conditions. The influence of Lewis acid catalysts (which also increase the dienophilic reactivity) appears to be important. The 1,4-addition of ethanethiol gives 124 with a moderate diastereoselectivity. 

Conditions for effecting conjugate addition of neutral enolate equivalents such as silyl enol ethers in the presence of Lewis acids have been developed and are called Mukaiyama-Michael reactions. Trimethylsilyl enol ethers can be caused to react with electrophilic alkenes by use of TiCl4. These reactions proceed rapidly even at -78° C.308... 

Modest diastereoselectivity was observed for the Michael addition reaction of rac-14 to 13 and these diasteromers 28-a/28-b could be separated and individually identified. The minor isomer 28-b was found to readily undergo conversion to benzoxathiin 30 when treated with BF3 etherate, presumably through the transient intermediate 29-b. The major isomer 28-a was converted by BF3 etherate to intermediate 29-a. Conversion to 30 required the use of the stronger Lewis acid TMSOTf, presumably due to the cis-stereochemistry between the methoxy and the neighboring hydrogen, making it more difficult to eliminate/aromatize. 

Jenner investigated the kinetic pressure effect on some specific Michael and Henry reactions and found that the observed activation volumes of the Michael reaction between nitromethane and methyl vinyl ketone are largely dependent on the magnitude of the electrostriction effect, which is highest in the lanthanide-catalyzed reaction and lowest in the base-catalyzed version. In the latter case, the reverse reaction is insensitive to pressure.52 Recently, Kobayashi and co-workers reported a highly efficient Lewis-acid-catalyzed asymmetric Michael addition in water.53 A variety of unsaturated carbonyl derivatives gave selective Michael additions with a-nitrocycloalkanones in water, at room temperature without any added catalyst or in a very dilute aqueous solution of potassium carbonate (Eq. 10.24).54... 

This finding is also in agreement with another three-component Michael/aldol addition reaction reported by Shibasaki and coworkers [14]. Here, as a catalyst the chiral AlLibis[(S)-binaphthoxide] complex (ALB) (2-37) was used. Such hetero-bimetallic compounds show both Bronsted basicity and Lewis acidity, and can catalyze aldol [15] and Michael/aldol [14, 16] processes. Reaction of cyclopentenone 2-29b, aldehyde 2-35, and dibenzyl methylmalonate (2-36) at r.t. in the presence of 5 mol% of 2-37 led to 3-hydroxy ketones 2-38 as a mixture of diastereomers in 84% yield. Transformation of 2-38 by a mesylation/elimination sequence afforded 2-39 with 92 % ee recrystallization gave enantiopure 2-39, which was used in the synthesis of ll-deoxy-PGFla (2-40) (Scheme 2.8). The transition states 2-41 and 2-42 illustrate the stereochemical result (Scheme 2.9). The coordination of the enone to the aluminum not only results in its activation, but also fixes its position for the Michael addition, as demonstrated in TS-2-41. It is of importance that the following aldol reaction of 2-42 is faster than a protonation of the enolate moiety. 

A fourfold anionic sequence which is not initiated by a Michael but an aldol reaction has been reported by the group of Suginome and Ito (Scheme 2.129) [295]. In this approach, the borylallylsilane 2-573 reacts selectively in the presence of TiCl4 with two different aldehydes which are added sequentially to the reaction mixture. First, a Lewis acid-mediated allylation of the aldehyde with 2-573 takes place to form a homoallylic alcohol which reacts with the second aldehyde under formation of the oxenium ion 2-574. The sequence is terminated by a Prins-type cyclization of 2-574 and an intramolecular Friedel-Crafts alkylation of the intermediate 2-575 with formation of the fraws-1,2-be rizoxadeca lines 2-576 as single diastereomers. 

The Michael type reaction of (3R)-5-t-butyldimethysiloxy-3-phenyl-17/-pyrrolo[ 1,2-c]oxazole with nitroethylene proceeds in the presence of Lewis acid to give the alkylated product in good chemical yield and diastereoselectivity. In the case of nitroethylene, the Diels-Alder type transition state is favored to give the yy/i-adduct selectively (Eq. 4.72).91... 

Heterobimetallic asymmetric complexes contain both Bronsted basic and Lewis acidic functionalities. These complexes have been developed by Shibasaki and coworkers and have proved to be highly efficient catalysts for many types of asymmetric reactions, including catalytic asymmetric nitro-aldol reaction (see Section 3.3) and Michael reaction. They have reported that the multifunctional catalyst (f )-LPB [LaK3tris(f )-binaphthoxide] controls the Michael addition of nitromethane to chalcones with >95% ee (Eq. 4.140).205... 

Furthermore, a neighboring group participation of a phenylthio function is observed in the Lewis acid-catalyzed nucleophilic substitution reaction of various P-nitrosulfides. Because the P-nitrosulfides are readily available, by the Michael addition of thiols to nitroalkenes (see Michael addition Chapter 4), this reaction is very useful. The P-nitrosulfides are prepared stereoselectively, and the reaction proceeds in a stereo-specific way (retention of configuration) as shown in Eqs. 31-34.35... 

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