Conjugate addition stereoselective Michael

The next series of syntheses is based on conjugate additions. A 2-arylcyclo-hexanone was regio- and stereoselectively added to nitroethylene to access the octahydroindole core present in the alkaloids. This has enabled the total synthesis of (+j-y-lycorane and (+)-crinane (280). Tomioka described a chemoselective conjugate addition - nitro Michael reaction sequence to prepare a- and -lycoranes in their racemic form (281). The addition of an arylcuprate to a D-mannitol-derived... 

Another inventive total synthesis of ( )-a- and ( )- lycorane is completed by sequential chemoseleclive conjugate addition-stereoselective nitro-Michael cyclization of a to-nitro-a,p,< ),a)-unsaturated ester [32]. This approach is based on the following retrosynthelic analysis (Scheme 9.21). 

In the synthesis shown in Scheme 13.15, racemates of both erythro- and threo-juvabione were synthesized by parallel routes. The isomeric intermediates were obtained in greater than 10 1 selectivity by choice of the E- or Z-silanes used for conjugate addition to cyclohexenone (Michael-Mukaiyama reaction). Further optimization of the stereoselectivity was achieved by the choice of the silyl substituents. The observed stereoselectivity is consistent with synclinal TSs for the addition of the crotyl silane reagents. 

Instead of a triflate, the electrophile on the glycosyl acceptor can be an a,(3-unsaturated carbonyl group. This is the case reported in Fig. 25, in which a stereoselective Michael addition of the 1-thiosugar 56 to the a,(3-conjugated system of levoglucosenone 57, generated after deprotection a couple of L-fucopyranosyl-4-thiodisaccharides 61 and 62 presenting inhibitory activity on a-L-fucosidase.54... 

As in the case of addition reactions of carbon nucleophiles to activated dienes (Section HA), organocopper compounds are the reagents of choice for regio- and stereoselective Michael additions to acceptor-substituted enynes. Substrates bearing an acceptor-substituted triple bond besides one or more conjugated double bonds react with organocuprates under 1,4-addition exclusively (equation 51)138-140 1,6-addition reactions which would provide allenes after electrophilic capture were not observed (cf. Section IV). 

Complexes of unsymmetrically substituted conjugated dienes are chiral. Racemic planar chiral complexes are separated into their enantiomers 84 and 85 by chiral HPLC on commercially available /f-cyclodextrin columns and used for enantioseletive synthesis [25]. Kinetic resolution was observed during the reaction of the meso-type complex 86 with the optically pure allylboronate 87 [26], The (2R) isomer reacted much faster with 87 to give the diastereomer 88 with 98% ee. The complex 88 was converted to 89 by the reaction of meldrum acid. Stereoselective Michael addition of vinylmagnesium bromide to 89 from the opposite side of the coordinated Fe afforded 90, which was converted to 91 by acetylation of the 8-OH group and displacement with EtjAl. Finally, asymmetric synthesis of the partial structure 92 of ikarugamycin was achieved [27],... 

Aluminum salen complexes have been identified as effective catalysts for asymmetric conjugate addition reactions of indoles [113-115]. The chiral Al(salen)Cl complex 128, which is commercially available, in the presence of additives such as aniline, pyridine and 2,6-lutidine, effectively catalyzed the enantioselective Michael-type addition of indoles to ( )-arylcrolyl ketones [115]. Interestingly, this catalyst system was used for the stereoselective Michael addition of indoles to aromatic nitroolefins in moderate enantiose-lectivity (Scheme 36). The Michael addition product 130 was easily reduced to the optically active tryptamine 131 with lithium aluminum hydride and without racemization during the process. This process provides a valuable protocol for the production of potential biologically active, enantiomerically enriched tryptamine precursors [116]. 

The stereoselectivity of the second and key Michael-type conjugate addition reaction can be rationalized as follows. The conformation of 63 will be restricted to 63-A due to A(l 3) strain between the N-methoxycarbonyl and w-propyl groups in 63-B. Attack of the vinyl anion from the stereoelectronically favored a-axial direction provides the adduct 64 exclusively. It is noteworthy that the stereochemical course of the above reaction is controlled by the stereoelectronic effect in spite of severe 1,3-diaxial steric repulsion between the axial ethyl group at the 5-position and the incoming vinyl anion. This remarkable stereoselectivity can be also explained by Cieplak s hypothesis[31]. On the preferred conformation 63-A, the developing a of the transition state is stabilized by the antiperiplanar donor Gc-h at the C-4 position. 

The prototype of copper-mediated conjugate addition reactions is the transformation of acceptor-substituted alkenes and alkynes into the corresponding adducts (Scheme 1). Whereas full control of the regio- and chemoselectivity in these Michael additions has been possible for a long time,3 the emphasis of the last decade has been put on the use of new copper reagents, the broadening of the substrate scope, and the control of the stereoselectivity of the conjugate addition. 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

The reaction afforded the tandem cyclization product 170 as a mixture of two separable isomers together with an a,p-unsaturated cyclic bisphosphonate, which is formed by a direct deprotonation of the vinylic a-proton of 168 and subsequent intramolecular Michael cyclization. The authors described the formation of 170 by the conjugated addition of 168 to 2.2 equivalents of PhLi and subsequent intramolecular Michael reaction in the intermediate 169. It is likely that coordination of the lithium atom to the oxygens of the phosphonates favors formation of the /raw.v-isomer. As shown in Scheme 52, the reactions with bulky naphthyllithiums gave only the fraws-170 isomer. This novel methodology can provide a rapid entry into a variety of cyclic bisphosphonates in good stereoselectivity. 

Michael addition of ketene silyl acetals,1 TASF catalyzes the conjugate addition of ketene silyl acetals to enones in THF at room temperature. A similar addition can be effected without a catalyst in a polar solvent, acetonitrile at 55° (ref. 2) or CH3N02 at 25°, in the case of some less hindered ketene silyl acetals. The addition shows no dia-stereoselection. The adducts can be alkylated to provide 2,3-disubstituted cycloalkanones as a 1 1 mixture of two diastereomers (both probably trans). 

Another frequent use of (1) and its enantiomer is the stereospecific conjugate addition of carbonyl compounds to a,p-unsaturated systems. Most published examples contain chiral imine derivatives of cyclic ketones, which add to a,p-unsaturated esters and ketones in a highly stereoselective manner (eq 13 and eq 14). When the ketone is not symmetrically substituted, reaction usually occurs at the most substituted a-position, including those cases where the ketone is a-substituted by oxygen (eq 15). High stereoselectivity can also be achieved when the Michael acceptor is other than an unsaturated ketone or ester, such as a vinyl sulfone (eq 16). Intramolecular variations of this transformation have also been described (eq 17). ... 

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