Michael addition diastereoselective reaction

A complete diastereoselective triple Michael addition to form a bicyclic ring structure is also known. In this reaction the new ring is formed by a M1MIRC reaction (see also Sec-... 

A broad range of enantiomericaUy pure 4,5-dihydrobenzo[r [l,3]diox-epines 177 have been prepared via a four-component Mannich reaction and subsequent intramolecular oxo-Michael reaction (14CC2196). The reactions proceeded with both high enantio- and diasteroselectivity, utilizing a dual catalytic system of Rh2(OAc)4 and a chiral phosphoric acid 178. The rhodium catalyst forms the protic oxonium ylide 174 from a diazo compound 171 and this subsequently adds to imine 175, formed in situ. The resulting enantiomericaUy enriched intermediate 176 then undergoes an intramolecular and diastereoselective oxo-Michael addition to form the final product 177. 

Da Silva, RM. and Jones, J., Jr., Organic reaction in water. Part 3 Diastereoselectivity in Michael additions of thiophenol to nitro olefins in aqueous media, /. Braz. Chem. Soc., 2001,12, 135-137. 

Dramatic rate accelerations of [4 + 2]cycloadditions were observed in an inert, extremely polar solvent, namely in5 M solutions oflithium perchlorate in diethyl ether(s 532 g LiC104 per litre ). Diels-Alder additions requiring several days, 10—20 kbar of pressure, and/ or elevated temperatures in apolar solvents are achieved in high yields in some hours at ambient pressure and temperature in this solvent (P.A. Grieco, 1990). Also several other reactions, e.g, allylic rearrangements and Michael additions, can be drastically accelerated by this magic solvent. The diastereoselectivities of the reactions in apolar solvents and in LiClO EtjO are often different or even complementary and become thus steerable. 

The stereochemical outcome of the Michael addition reaction with substituted starting materials depends on the geometry of the a ,/3-unsaturated carbonyl compound as well as the enolate geometry a stereoselective synthesis is possible. " Diastereoselectivity can be achieved if both reactants contain a stereogenic center. The relations are similar to the aldol reaction, and for... 

For amide enolates (X = NR2), with Z geometry, model transition state D is intrinsically favored, but, again, large X substituents favor the formation of nt/-adducts via C. Factors that influence the diastereoselectivity include the solvent, the enolate counterion and the substituent pattern of enolate and enonc. In some cases either syn- or unh-products are obtained preferentially by varying the nature of the solvent, donor atom (enolate versus thioeno-late), or counterion. Most Michael additions listed in this section have not been examined systematically in terms of diastereoselectivity and coherent transition stale models are currently not available. Similar models to those shown in A-D can be used, however all the previously mentioned factors (among others) may be critical to the stereochemical outcome of the reaction. 

An interesting approach to zr n.v-2,3-disubstituted cyeloalkanones is offered by auxiliary controlled intramolecular Michael additions. The diastereoselectivity depends on the chiral alcohol used193> l94. When the borneol derivative 7 was used as substrate, a single diastereomer of 8 resulted when the reaction was performed at 25 "C under thermodynamic control with a catalytic amount of sodium hydride in benzene. 

The enolate of the 1,4-adduct, obtained after the stereoselective Michael addition step, as discussed in the previous sections, may be quenched in situ with various electrophiles. The fact that additional stereogenic centers may be formed via such tandem Michael addition/quench-ing procedures, giving products with high diastereoselectivity in many cases, extends the scope of these methods substantially. Furthermore these procedures occasionally offer the possibility of reversing the syn/anti diastereoselection. In the next sections pertinent examples of diastereoselective inter- and intramolecular quenching reactions will be discussed. 

When the cnolate of an enone is brought into reaction with an enone, usually a carbocyclic system is prepared by two consecutive Michael additions (M1MIRC reactions). Due to the lower temperatures employed and the absence of diene polymerization these reactions are useful alternatives for Diels-Alder reactions and proceed in general with high diastereoselectivities. When neither enolate nor enone is cyclic a monocyclic system is formed 338 which can be converted into a bicyclic system when the Michael addition is followed by an aldol reaction339. When, however, the enolate is cyclic a bicyclic or a tricyclic system is formed340 341. 

The reactions of the lithium enolates of substituted 2-cyclohexenones and 2-cyclopentenones with ( )-l-nitropropene give a mixture of syn- and ami-products3. The lithium enolate of 3,5,5-trimethyl-2-cyclohexenone gives a mixture of the syn- and //-3.5,5-trimethyl-6-(l-methyl-2-nitroethyl)-2-cyclohexcnoncs in modest diastereoselection when the reaction mixture is quenched with acetic acid after. 30 minutes at —78 =C. When the reaction mixture is heated to reflux, tricyclic products are obtained resulting from intramolecular Michael addition of the intermediate nitronate ion to the enone moiety. 

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. 

By contrast, L-phenylalanine methyl ester does not react with BENA generated from 1-nitropropane (R =H) due apparently to low nucleophilicity of the amino group. However, the N, C -coupling reaction of the ester of this amino acid with another internal BENA (R = CC>2Me) proceeds rather readily but is characterized by extremely low diastereoselectivity. Probably, the last N,C-coupling does not occur via an intermediate a-nitroso alkene but by a classical Michael addition to BENA MeCH=C(C02Me)N(05i )2 as to Michael substrate. 

The Ir(lll) complex also funchoned as a catalyst in a tandem Nazarov cyclization-Michael addition. The reaction of monocyclic a-alkylidene-P-keto-y.b-unsaturated ester with nitroalkene gave bicyclic cyclopentenones which possessed an alkyl side chain, with high yield and diastereoselectivity (Scheme 11.36) [47]. 

Wang identified a series of Michael/Michael and Michael/aldol sequences catalysed by diarylprolinol ethers that led directly to densely functionalised five-mem-bered rings [172-174]. For example, highly diastereoselective and enantioselective double Michael addition reactions were achieved by treatment of a,p-unsaturated aldehydes with triester 113 catalysed by 30 (Scheme 45). Initial conjugate addition... 

The asymmetric allylic C-H activation of cyclic and acyclic silyl enol ethers furnishes 1,5-dicarbonyl compounds and represents a surrogate of the Michael reaction [136]. When sufficient size discrimination is possible the C-H insertion is highly diastereoselective, as in the case of acyclic silyl enol ether 193 (Eq. 22). Reaction of aryldia-zoacetate 192 with 193 catalyzed by Rh2(S-DOSP)4 gives the C-H insertion product 194 (>90% de) in 84% enantiomeric excess. A second example is the reaction of the silyl enol ether 195 with 192 to form 196, a product that could not be formed from the usual Michael addition because the necessary enone would be in its tautomeric naphthol form (Eq. 23). 

Maraval et al 39) synthesized core- and periphery-functionalized ruthenium and palladium dendritic diphosphines (Fig. 12) that were applied in three reactions (Stille coupling, Knoevenagel condensation, and diastereoselective Michael addition). The catalyst was recovered by using the precipitation strategy. 

Enantiocontrolled anti-selective Michael additions of the metalated ylides derived from a-(alkylideneamino)alkanoates are attractive as a new synthetic route to enantiomers of a-amino esters. Although there are a variety of chiral glycine equivalents available, only the enolates derived from 1,4-dihydropyrazine have been successfully applied to asymmetric Michael additions (Scheme 11.22) (103-105). In these reactions, the diastereoselectivities are high. 

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