Michael enantioselectivity

P. Lehwald, R. Michael, R. Caroline, L. Hung-Wen, M. Michael, Enantioselective intermolecular aldehyde-ketone cross-coupling through an enzymatic carboligation reaction, Angew. Chem. Int. 49 (2010) 2389-2392. 

Progress has been made toward enantioselective and highly regioselective Michael type alkylations of 2-cyclohexen-l -one using alkylcuprates with chiral auxiliary ligands, e. g., anions of either enantiomer of N-[2-(dimethylamino)ethyl]ephedrine (E. J. Corey, 1986), of (S)-2-(methoxymethyl)pyrrolidine (from L-proline R. K. EHeter, 1987) or of chiramt (= (R,R)-N-(l-phenylethyl)-7-[(l-phenylethyl)iinino]-l,3,5-cycloheptatrien-l-amine, a chiral aminotro-ponimine G. M. Villacorta, 1988). Enantioselectivities of up to 95% have been reported. 

There are a number of powerful synthetic reactions which join two trigonal carbons to form a CC single bond in a stereocontrolled way under proper reaction conditions. Included in this group are the aldol, Michael, Claisen rearrangement, ene and metalloallyl-carbonyl addition reactions. The corresponding transforms are powerfully stereosimplifying, especially when rendered enantioselective as well as diastereoselective by the use of chiral controller groups. Some examples are listed in Chart 20. 

As shown above, it was not so easy to optimize the Michael addition reactions of l-crotonoyl-3,5-dimethylpyrazole in the presence of the l ,J -DBFOX/ Ph-Ni(C104)2 3H20 catalyst because a simple tendency of influence to enantio-selectivity is lacking. Therefore, we changed the acceptor to 3-crotonoyl-2-oxazolidi-none in the reactions of malononitrile in dichloromethane in the presence of the nickel(II) aqua complex (10 mol%) (Scheme 7.49). For the Michael additions using the oxazolidinone acceptor, dichloromethane was better solvent than THF and the enantioselectivities were rather independent upon the reaction temperatures and Lewis base catalysts. Chemical yields were also satisfactory. 

Finally we have performed the Michael addition reactions of malononitrile and 3-(2-alkenoyl)-2-oxazolidinones in dichloromethane in the presence of the R,R-DBF0X/Ph-Ni(C104)2-31 20 and TMP (10 mol% each). Enantioselectivities were a little lower than 90% ee for acceptors having a variety of / -substituents. The best selectivity was 94% ee in the reaction of t-butyl-substituted acceptor (Scheme 7.50). 

With the use of chiral reagents a differentiation of enantiotopic faces is possible, leading to an enantioselective reaction. The stereoselective version of the Michael addition reaction can be a useful tool in organic synthesis, for instance in the synthesis of natural products. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Methods for the catalytic enantioselective Michael addition have been developed using three different approaches ... 

High enantioselectivities may be reached using the kinetic controlled Michael addition of achiral tin enolates, prepared in situ, to a,/i-unsaturated carbonyl compounds catalyzed by a chiral amine. The presence of trimethylsilyl trifluoromethanesulfonate as an activator is required in these reactions236. Some typical results, using stoichiometric amounts of chiral amine and various enolates are given below. In the case of the l-(melhylthio)-l-[(trimethylsilyl)thio]ethene it is proposed that metal exchange between the tin(II) trifluoromethanesulfonate and the ketene acetal occurs prior to the 1,4-addition237,395. 

The highest enantioselectivities in the base-catalyzed Michael additions have so far been obtained using achiral bases complexed to chiral crown ethers. The addition of methyl 2,3-dihydro-l-oxo-1//-indene-2-carboxylate (1) to 3-buten-2-one using 4 mol% of a [l,T-binaphthalcnc]-2,2 -diol derived optically active crown ether 3 in combination with potassium AY/-butoxide as the base illustrates this successful method 259 260 It is assumed that the actual Michael donor is the potassium enolate complex of 1 and crown ether 3. 

Johnson J. S., Evans D. A. Chiral Bis(Oxazoline) Copper(II) Complexes Versatile Catalysts for Enantioselective Cycloaddition, Aldol, Michael, and Carbonyl Ene Reactions Acc. Chem. Res. 2000 33 325-335... 

The enantioselective 1,4-addition addition of organometaUic reagents to a,p-unsaturated carbonyl compounds, the so-called Michael reaction, provides a powerful method for the synthesis of optically active compounds by carbon-carbon bond formation [129]. Therefore, symmetrical and unsymmetrical MiniPHOS phosphines were used for in situ preparation of copper-catalysts, and employed in an optimization study on Cu(I)-catalyzed Michael reactions of di-ethylzinc to a, -unsaturated ketones (Scheme 31) [29,30]. In most cases, complete conversion and good enantioselectivity were obtained and no 1,2-addition product was detected, showing complete regioselectivity. Of interest, the enantioselectivity observed using Cu(I) directly in place of Cu(II) allowed enhanced enantioselectivity, implying that the chiral environment of the Cu(I) complex produced by in situ reduction of Cu(II) may be less selective than the one with preformed Cu(I). 

The enantioselective Michael reaction of malonates to nitroolefins catalysed by bifunctional amino-thioureas has recently been reported by Take-moto [161]. Excellent ee (75-93%) were obtained with diethylmalonate after solvent optimisation, toluene being the best solvent both for the activity and for the selectivity. Substituted malonates were then reacted with various nitroolefins under the same conditions. Excellent enantioselectivities were observed (Scheme 45). 

Ferrocen-l,l -diylbismetallacycles are conceptually attractive for the development of bimetal-catalyzed processes for one particular reason the distance between the reactive centers in a coordinated electrophile and a coordinated nucleophile is self-adjustable for specific tasks, because the activation energy for Cp ligand rotation is very low. In 2008, Peters and Jautze reported the application of the bis-palladacycle complex 56a to the enantioselective conjugate addition of a-cyanoacetates to enones (Fig. 31) [74—76] based on the idea that a soft bimetallic complex capable of simultaneously activating both Michael donor and acceptor would not only lead to superior catalytic activity, but also to an enhanced level of stereocontrol due to a highly organized transition state [77]. An a-cyanoacetate should be activated by enolization promoted by coordination of the nitrile moiety to one Pd(II)-center, while the enone should be activated as an electrophile by coordination of the olefinic double bond to the carbophilic Lewis acid [78],... 

Kinetic, spectroscopic, and enantioselectivity data provided strong evidence for a mechanism involving bimetallic catalysis. The configurational outcome depends upon the face selectivity of the enol approaching the Michael acceptor in 59 (Fig. 32). To differentiate between the enantiotopic faces, the catalyst has thus... 

Fig. 32 Proposed cooperative bimetallic intramolecular mechanism for the enantioselective Michael addition of a-cyanoesters 57 to vinylketones...

Jautze S, Peters R (2008) Enantioselective bimetallic catalysis of Michael additions forming quaternary stereocenters. Angew Chem Int Ed 47 9284-9288... 

An enantioselective Michael addition reaction was also accomplished in an inclusion complex with a chiral host compound. Treatment of a 1 1 complex of 10c and 66b with 2-mercaptopyridine (137) in the solid state gave (+)-138 of 80% ee in 51% yield. By a similar method, 3-methyl-3-buten-2-one (139) gave (+)-140 of 49% ee in 76% yield [30]. 

The intramolecular asymmetric Stetter reaction of aliphatic aldehydes is generally more difficult to achieve due to the presence of acidic a-protons. Rovis and co-workers have demonstrated that the NHC derived from pre-catalyst 130 promotes the intramolecular Stetter cyclisation with enoate and alkyhdene malonate Michael acceptors 133. Cyclopentanones are generally accessed in excellent yields and enantioselectivities, however cyclohexanones are obtained in significantly lower yields unless very electron-deficient Michael acceptors are employed... 

Hoashi, Y., Yabuta, T., Takemoto, Y. (2004) Bifunctional Thiourea-Catalyzed Enantioselective Double Michael Reaction of y,5-Unsaturated fS-Ketoesterto Nitroalkene Asymmetric Synthesis of (—)-Epibatidine. Tetrahedron Letters, 45, 9185-9188. 

On the other hand, chiral sulfur-containing but noncoordinating ligands such as sulfonamides have been widely used in the asymmetric Michael reaction. In 1997, Sewald et al. reported the use of a series of chiral sulfonamides depicted in Scheme 2.25 in the Cu-catalysed conjugate addition of ZnEt2 to 2-cyclohexenone. Even the use of a stoichiometric amount of catalyst did not allow the enantioselectivity to be higher than 31% ee. 

On the other hand, the enantioselective 1,4-addition of carbanions such as enolates to linear enones is an interesting challenge, since relatively few efficient methods exist for these transformations. The Michael reaction of p-dicarbonyl compounds with a,p-unsaturated ketones can be catalysed by a number of transition-metal compounds. The asymmetric version of this reaction has been performed using chiral diol, diamine, and diphosphine ligands. In the past few years, bidentate and polydentate thioethers have begun to be considered as chiral ligands for this reaction. As an example, Christoffers et al. have developed the synthesis of several S/O-bidentate and S/O/S-tridentate thioether... 

After the initial two reports of Rh- and Co-catalyzed reductive aldol couplings, further studies did not appear in the literature until the late 1990s. Beyond 1998, several stereoselective and enantioselective reductive aldol reactions were developed, which are catalyzed by a remarkably diverse range of metal complexes, including those based upon Pd, Cu, Ir, and In. In this chapter, transition metal-catalyzed aldol, Michael, and Mannich reactions that proceed via transition metal hydride-promoted conjugate reduction are reviewed. 

The selectivity of the aldol addition can be rationalized in terms of a Zimmer -man-Traxler transition-state model with TS-2-50 having the lowest energy and leading to dr-values of >95 5 for 2-51 and 2-52 [18]. The chiral copper complex, responsible for the enantioselective 1,4-addition of the dialkyl zinc derivative in the first anionic transformation, seems to have no influence on the aldol addition. To facilitate the ee-determination of the domino Michael/aldol products and to show that 2-51 and 2-52 are l -epimers, the mixture of the two compounds was oxidized to the corresponding diketones 2-53. 

Scheme 2.22. Enantioselective domino Michael/aldol process.

Krische and coworkers [44] developed a Rh-catalyzed asymmetric domino Michael/aldol reaction for the synthesis of substituted cyclopentanols and cyclohex-anols. In this process, three contiguous stereogenic centers, including a quaternary center, are formed with excellent diastereo- and enantioselectivity. Thus, using an enantiopure Rh-BINAP catalyst system and phenyl boronic acid, substrates 2-108 are converted into the correspondding cyclized products 2-109 in 69-88% yield and with 94 and 95% ee, respectively (Scheme 2.24). 

In a recently published report by MacMillan s group [121] on the enantioselective synthesis of pyrroloindoline and furanoindoline natural products such as (-)-flustramine B 2-219 [122], enantiopure amines 2-215 were used as organocatalysts to promote a domino Michael addition/cyclization sequence (Scheme 2.51). As substrates, the substituted tryptamine 2-214 and a, 3-unsaturated aldehydes were used. Reaction of 2-214 and acrolein in the presence of 2-215 probably leads to the intermediate 2-216, which cyclizes to give the pyrroloindole moiety 2-217 with subsequent hydrolysis of the enamine moiety and reconstitution of the imidazolid-inone catalyst. After reduction of the aldehyde functionality in 2-217 with NaBH4 the flustramine precursor 2-218 was isolated in very good 90 % ee and 78 % yield. 

Yamamoto s group recently published a highly enantioselective chiral amine-catalyzed domino O-nitroso aldol/Michael reaction of 2-268 and 2-269 (Scheme 2.63) [141]. As products, the formal Diels-Alder adducts 2-271 were obtained with >98% 66, which is probably due to the selective attack of an enamine, temporarily formed from amine 2-270 and enone 2-268, onto the nitroso functionality. 

The asymmetric Michael addition of 1,3-dicarbonyl compounds to nitrostyrene is promoted by chiral alkaloid catalysts to give the addition products in good chemical yield, but the enantioselectivity is rather low (Eq. 4.47).62... 

Enantioselective synthesis of the antidepressant rolipram can be done by the asymmetric Michael addition of the enolate of IV-acetyloxazolidone to nitrostyrene. Chirally branched pyrrolidones like rolipram are highly active antidepressants with novel postsynaptic modes of action. The synthesis is shown in Scheme 4.13.78... 

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