Michael stereoisomers

Tetrahydropyridines 103 undergo a Michael reaction to afford [ran.s-(2,3)-cis-(2,6)-trisubstituted piperidines 104 (97T9553). The reaction is stereoselective (a single stereoisomer was obtained) and provides a convenient route to the 5,8-disubstituted indolizidine 105 and 1,4-disubstituted quinolizidine system 106 (found in Dendrobates alkaloids) by introduction of various alkyl, alkenyl, or... 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

The reactions with preformed enol derivatives provide a way to control the stereoselectivity of the aldol reaction. As with the Michael reaction (15-16), the aldol reaction creates two new chiral centers, and, in the most general case, there are four stereoisomers of the aldol product, which can be represented as... 

Michael/Dieckmann strategy illustrated in Scheme 2.34 was envisaged [73], Treatment of the oxazolidine 2-149, derived from D-serine (2-148), with LDA followed by addition of acrylate gave the bicyclic compound 2-150 as a single stereoisomer in 62% yield after recrystallization. Finally, hydrolysis of 2-150 with 6 M HC1 provided the desired HMG derivative(2-151) in 90% yield. 

The utilization of the Robinson annellation method for the synthesis of cory-nanthe-type alkaloids has been thoroughly investigated by Kametani and coworkers (149-152). The tetracyclic ring system was efficiently formed via the Michael addition of dimethyl 3-methoxyallylidenemalonate (247) to the enamine derived from 3,4-dihydro-1 -methyl-(3-carboline (150). Alkylation of 248, followed by hydrolysis and decarboxylation, resulted in a mixture of stereosiomeric enamides 250 and 251. Hydrogenation of 250 afforded two lactams in a ratio of 2 1 in favor of the pseudo stereoisomer 253 over the normal isomer 252. On the other hand, catalytic reduction of 251 gave 254 as the sole product in nearly quantitative yield. Deprotection of 254, followed by lithium aluminum hydride reduction, yielded ( )-corynantheidol (255) with alio relative configuration of stereo centers at C-3, C-15 and C-20. Similar transformations of 252 and 253 lead to ( )-dihydrocorynantheol and ( )-hirsutinol (238), respectively, from which the latter is identical with ( )-3-epidihydrocorynantheol (149-151.). 

Similar schemes can be developed easily for analogous reactions of acceptor-substituted polyenes. For example, a triene with an acceptor group in 1-position can form six regioi-someric products of Michael addition and electrophilic capture, and each of these exists as E/Z stereoisomers, diastereomers and/or enantiomers. Thus, reactions of this type are only useful if both the regio- and stereoselectivity can be controlled fortunately, only one isomeric Michael adduct is formed in many cases. This is true in particular for polyunsaturated Michael acceptors which bear at least one triple bond besides one or more double bonds. An additional feature of the latter substrate type is that nucleophilic additions can... 

The regio- and diastereo-selectivity of the Michael addition of 2-phenylcyclo-hexanone with a,p-unsaturated ketones are dependent on the reaction conditions. Mixtures of all six diastereoisomers resulting from reaction at either the 2- or 6-position of the cyclohexanone ring can be obtained using solid potassium hydroxide with tetra-n-butylammonium or A-benzylephcdrinium bromide catalysts. At 20°C with tetra-n-butylammonium bromide, the ratio of the 2,2- and 2,6-disubstituted cyclohexanones is ca. 3 2, but at higher temperatures with solid potassium f-butoxide the kinetically formed 2,6-isomer predominates (ca. 5 1) with the (2S,6R, R )-stereoisomer dominant, whereas greater amounts of the thermodynamically preferred 2,2-(2S,lR )-isomer are obtained with the chiral catalyst [61]. 

The c 5-23-dimethylchionian-4-one 53 is obtained with fair enantioselectivity through an asymmetric Michael addition in the presence of (-)-quinine (Scheme 32) <99TL3777>. Directed metallation of protected phenols and subsequent reaction of the li derivative with enantiopure Weinreb amides of glycidic acids feature in a route to stereoisomers of 2-alkyl-3-hydroxychroman-4-ones (Scheme 33) <99JOC3489>. 

Nitrones can be generated by Michael reaction of oximes with appropriate conjugated substrates.25 If a generated nitrone has a built-in dipolarophile, cyclization can ensue (Scheme 15). There are three synthetic variations on this theme.25a,b First, the oxime may contain the dipolarophile as in (56). Reaction of (56) with phenyl vinyl sulfone provided a quantitative yield of the tandem product as one stereoisomer. Alternatively, die dipolarophile can reside in the Michael substrate as in (57). Reaction of (57) with cyclohexanone oxime produced two isoxazolidines from competitive cyclization of the intermediate nitrone through six- and seven-membered carbocyclic transition states. It is also possible to carry out an intramolecular Michael addition followed by an intramolecular nitrone cyclization as in thermolysis of (58) to produce a tricyclic isoxazolidine. Very recently several examples of a tandem Diels-Alder, Michael addition, nitrone cyclization sequence have been reported.250... 

Thiophene 231 reacted with excess DMAD 51 in refluxing MeOH or EtOH to give a thermally stable thiepine 235 (two stereoisomers, ca. 80 20) in 23% yield <1994J(P1)2191 >. A plausible reaction mechanism for the early steps was similar to Scheme 30 (1) cycloaddition of thiophene 231 to DMAD 51, (2) isomerization of the 1 1 cycloadduct 232 to thianocaradiene 233, and (3) valence isomerization of the latter to thiepine 234, which might then undergo two Michael additions to DMAD 51 to yield thiepine 235 (Scheme 31). 

Reduction of 2,2-dimethyl-cyclohexane-1,3-dione (50) with Baker s yeast gave alcohol (ee 98.3%) whose tetrahydropyranyl derivative on methoxycarbonylation produced (51) quantitatively. Michael addition of (51) with methyl vinyl ketone followed by heating the adduct under reflux with pyrrolidine in benzene yielded (52) in 85% yield as stereoisomeric mixture whose separation presented problems. In order to eliminate the complexity due to a chiral center in tetrahydropyranyl protective group, deprotection of (52) was achieved by treatment with p-toluenesulphonic acid in methanol. The product obtained was a mixture of the lactone (53) and hydroxy ester (54). Probably the stereoisomer of... 

A sugar-derived vinyl sulfone (92) was found to undergo a Michael-initiated ring closure (MIRC) process to build up a chiral polysubstituted oxolan system with high stereoselectivity, yielding the all-syn stereoisomer (93) (Scheme 25).61 The observed MIRC selectivity demonstrates that the 5-exo-trig process is strongly... 

Gordon and Danishefsky [112] used the reaction of a chromium Fischer car-bene complex 164 with a cycloalkine 163 to build the naphthoquinone core 165 (Dotz reaction, review [113]), a procedure often used for synthesis of the linearly condensed anthracyclinones (e.g., [114]). The quinone ketone 165 has nucleophilic and electrophilic centers correctly positioned to furnish a ben-zo[fl]anthraquinone. However, treatment with NaH or Triton B gave the spiro-compounds 166 as a mixture of two stereoisomers. These products evidently arose from Michael addition of the ketone enolate to the naphthoquinone double bond. But the weaker base DBU induced cyclization at ambient temperature to the benzo[a]anthraquinone 167 in 65% yield (Scheme 42). The primary aldol adduct apparently eliminated water and the resulting dihydrobenzo[a]anthraquinone aromatized under basic conditions in the presence of air. This is an instructive example of the influence of the base on the cyclization mode. 

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