Michael-type reactions stereoselectivity

The formation of cyclopropanes from 7C-deficient alkenes via an initial Michael-type reaction followed by nucleophilic ring closure of the intermediate anion (Scheme 6.26, see also Section 7.3), is catalysed by the addition of quaternary ammonium phase-transfer catalysts [46,47] which affect the stereochemistry of the ring closure (see Chapter 12). For example, equal amounts of (4) and (5) (X1, X2 = CN) are produced in the presence of benzyltriethylammonium chloride, whereas compound (4) predominates in the absence of the catalyst. In contrast, a,p-unsatu-rated ketones or esters and a-chloroacetic esters [e.g. 48] produce the cyclopropanes (6) (Scheme 6.27) stereoselectively under phase-transfer catalysed conditions and in the absence of the catalyst. Phenyl vinyl sulphone reacts with a-chloroacetonitriles to give the non-cyclized Michael adducts (80%) to the almost complete exclusion of the cyclopropanes. 

Cyclopropane derivatives have been prepared from reactions of arsonium ylides with conjugated enones " and a, jS-unsaturated esters "" . Initial Michael-type reaction is followed by intramolecular elimination of triphenylarsine, e.g. equation 22. These reactions often give high yields and show high stereoselectivity. 

The potential of metal carbenes in stereoselective synthesis is based on both the pronounced acidity of the a-CH in the alkyl side chain - which may be exploited in aldol and Michael-type reactions - and on cycloaddition reactions centered either on the metal or the carbene ligand. The incorporation of a carbohydrate backbone into the carbene ligand generally allows for an asymmetric modification of these carbon-carbon bond-forming reactions. Deprotonation of 2-oxacyclopen-tylidene complexes 76a/b and 270-279 generates the conjugate bases that can be... 

Wada E., Yasuoka H., Pei W., Chin U., Kanemasa S. Lewis Add-Catalyzed Stereoselective Hetero Diels-Alder Reactions of (E)-l-Phenylsulfonyl-3-Alken-2-Ones With Vinyl Ethers. Synthetically Equivalent to Stereoselective Michael Type... 

If the carbanion has even a short lifetime, 6 and 7 will assume the most favorable conformation before the attack of W. This is of course the same for both, and when W attacks, the same product will result from each. This will be one of two possible diastereomers, so the reaction will be stereoselective but since the cis and trans isomers do not give rise to different isomers, it will not be stereospecific. Unfortunately, this prediction has not been tested on open-chain alkenes. Except for Michael-type substrates, the stereochemistry of nucleophilic addition to double bonds has been studied only in cyclic systems, where only the cis isomer exists. In these cases, the reaction has been shown to be stereoselective with syn addition reported in some cases and anti addition in others." When the reaction is performed on a Michael-type substrate, C=C—Z, the hydrogen does not arrive at the carbon directly but only through a tautomeric equilibrium. The product naturally assumes the most thermodynamically stable configuration, without relation to the direction of original attack of Y. In one such case (the addition of EtOD and of Me3CSD to tra -MeCH=CHCOOEt) predominant anti addition was found there is evidence that the stereoselectivity here results from the final protonation of the enolate, and not from the initial attack. For obvious reasons, additions to triple bonds cannot be stereospecific. As with electrophilic additions, nucleophilic additions to triple bonds are usually stereoselective and anti, though syn addition and nonstereoselective addition have also been reported. 

Addition of (TMS)3SiH to a-chiral ( )-alkene 7 was found to take place with a complete Michael-type regioselectivity (Reaction 5.8) [26]. A complete syn stereoselectivity was observed for R = Me, and it was rationalized in terms of Felkin-Ahn transition state 8, which favours the syn product similar to nucleophilic addition. 

Novel aldol-type reactions under Cinchona-deriwed chiral thiourea catalysis was reported by Wang et al. [78]. In their report, a novel cascade Michael-aldol reaction was presented. The reaction involves a tandem reaction catalyzed via hydrogen-bonding with as little as 1 mol% catalyst loading to generate a product with three stereogenic centers (Scheme 28). hi the reaction of 2-mercaptobenzaldehyde 128 and a,P-unsatnrated oxazolidinone 129, the desired benzothiopyran 130 was formed smoothly in high yield and excellent stereoselectivity. 

In 2006, Xu and Xia et al. revealed the catalytic activity of commercially available D-camphorsulfonic acid (CS A) in the enantioselective Michael-type Friedel-Crafts addition of indoles 29 to chalcones 180 attaining moderate enantiomeric excess (75-96%, 0-37% ee) for the corresponding p-indolyl ketones 181 (Scheme 76) [95], This constitutes the first report on the stereoselectivity of o-CSA-mediated transformations. In the course of their studies, the authors discovered a synergistic effect between the ionic liquid BmimBr (l-butyl-3-methyl-l/f-imidazohum bromide) and d-CSA. For a range of indoles 29 and chalcone derivatives 180, the preformed BmimBr-CSA complex (24 mol%) gave improved asymmetric induction compared to d-CSA (5 mol%) alone, along with similar or slightly better yields of P-indolyl ketones 181 (74-96%, 13-58% ee). The authors attribute the beneficial effect of the BmimBr-D-CSA combination to the catalytic Lewis acid activation of Brpnsted acids (LBA). Notably, the direct addition of BmimBr to the reaction mixture of indole, chalcone, d-CSA in acetonitrile did not influence the catalytic efficiency. 

From the retrosynthetic perspective (Fig. 2), the tetracyclic structure is expected to be accessible by tandem Michael-Dieckmann type reaction of 59 with 60. The suitably substituted chiral intermediate 59 would be synthesized by Diels-Alder reaction of the cyclohexenone 57 and the silyloxybutadiene 58. The regio- and stereoselectivities are established as a consequence of the dienophile geometry according to Gleiter s theory (29). Compound 57 could be obtained from 51 through Ferrier reaction of 54. 

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]. 

Y. Yamamoto, S. G. Pyne, D. Schinzer, B. L. Feringa, J. F. G. A. Jansen, Formation of C-C Bonds by Reactions Involving Olefinic Double Bonds - Addition to a,/3-Unsaturated Carbonyl Compounds (Michael-Type Additions), in Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952, Stereoselective Synthesis (G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann, Eds.), Vol. E21b, 2041, Georg Thieme Verlag, Stuttgart, 1995. 

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. 

Three-component coupling reaction of a-enones, silyl enolates, and aldehydes by successive Mukaiyama-Michael and aldol reactions is a powerful method for stereoselective construction of highly functionahzed molecules valuable as synthetic intermediates of natural compounds [231c]. Kobayashi et al. recently reported the synthesis of y-acyl-d-lactams from ketene silyl thioacetals, a,/l-urisalu-rated thioesters, and imines via successive SbCl5-Sn(OTf)2-catalyzed Mukaiyama-Michael and Sc(OTf)3-catalyzed Mannich-type reactions (Scheme 10.87) [241]. 

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 strain between the N-... 

Figure 6.6 shows our synthetic plan for testudinariol A (149). Because the structural feature of target molecule 149 is its C2-symmetry, 149 can be obtained by dimerization or its equivalent operation of A. The intermediate A may be prepared from B by (Z)-selective installation of the two-carbon appendage. For the stereoselective construction of the cyclopentane portion of B, an intramolecular ene reaction is appropriate employing C as the substrate. The intramolecular oxy-Michael-type cyclization of D has been adopted to prepare the tetrahydropyran ring of C. The intermediate D can be synthesized from F [(R)-glycidol] via the known diol E. 

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