Stereospecific reactions Michael addition

Carbocyclization of m-alkcnyl-z-methoxybcnzy I lithiums to form five- or six-membered rings has been studied 101 the five-membered ring is formed with a cis-stereochemical relationship between the methoxy substituent and the adjacent methyl group. Intramolecular carbolithiation of vinyl sulfides at — 105°C in THF has been found to occur non-stereospecifically with regard to the newly formed C—Li centre.102. The stereochemistry of selective tandem Michael addition alkylation reactions of vinylphosphonates has been explored.103... 

Michael addition to a complexed styrene. A key step in a synthesis of 11-deoxy-anthracyclinone (3) involves the regioselective reaction of 1 with the carbanion of a protected acetaldehyde cyanohydrin to give 2 by stereospecific earo-addition. 

Ylides can cyclopropanate unsaturated systems which are susceptible to Michael additions, i.e. a,jS-unsaturated ketones, esters, amides, nitriles, sulfones, sulfonamides, and nitro compounds. Enhancement of electron withdrawal from the carbon-carbon double bond facilitates the reaction. The reaction is non-stereospecific. The intermediacy of zwitterions has generally been accepted, and hence the stereochemistry of the product may be predictable on the basis of the stepwise mechanism. Namely, the Michael addition of the ylide will occur predominantly from the less hindered side of the double bond in a given molecule and the subsequent cyclization will take place in the conformation which minimizes the non-bonded repulsions. 

Sulfides were also involved in a unique three-component, stereospecific Michael addition. The reaction described in Scheme 29 can be explained as follows regiospecific addition of the nucleophile to the exocyclic double bond of the a-methylenecyclopentenone, followed by trapping of the resulting enolate by methyl acrylate, and attack of the anion thus formed on the endocyclic double bond of the cy-clopentenone moiety to result, after protonation, in the bicyclo[2.2.1]heptan-6-one as a single stereoisomer (68% overall yield Scheme 29). 

Hydroxylamine derivatives add to activated double bonds in the presence of a base to give aziridines where intermediates of the type illustrated above have not been isolated or observed. These reactions may proceed via stereospecific addition of nitrenoid intermediates to the double bonds. However, in some instances, both isomeric aziridines are produced and these are included in Table 21 of the Tabular Survey since the possibility exists that they are formed by a Michael addition/cyclization process. An example is shown in Eq. 172.495... 

Phosphosulfolactate synthase (ComA), catalyzes the first step in coenzyme M biosynthesis (Figure 20), which is the stereospecific Michael addition of sulfite to phosphoenolpyruvate to form phosphosulfolactate as shown in Figure 23. On the basis of the reaction catalyzed, ComA was predicted to be related to the enolase superfamily of enzymes however, the overall structure and active-site architecture of ComA are unlike any member of the enolase superfamily. This suggests that ComA is not a member of the enolase superfamily but instead acquired an enolase-type mechanism through convergent evolution. ... 

A new synthesis of chiral cyclopentanoid intermediates involves the stereospecific reaction of the carbanion (30) with the tartaric acid derived epoxide (31). An intramolecular enolate anion alkylation, induced by a Michael reaction, has been utilized in the preparation of cyclopentanes (Scheme 6). Additionally, variation... 

Stereospecific Michael addition reactions also may be catalyzed by hydrolytic enzymes (Scheme 2.205). When ot-trifluoromethyl propenoic acid was subjected to the action of various proteases, lipases and esterases in the presence of a nucleophile (NuH), such as water, amines, and thiols, chiral propanoic acids were obtained in moderate optical purity [1513]. The reaction mechanism probably involves the formation of an acyl enzyme intermediate (Sect. 2.1.1, Scheme 2.1). Being an activated derivative, the latter is more electrophilic than the free carboxylate and undergoes an asymmetric Michael addition by the nucleophile, directed by the chiral environment of the enzyme. In contrast to these observations made with crude hydrolase preparations, the rational design of a Michaelase from a lipase-scaffold gave disappointingly low stereoselectivities [1514-1517]. 

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