Chiral compounds enantioselective Michael addition

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]. 

As mentioned above, the enantioselective Michael addition of P-keto esters to a,P-unsaturated carbonyl compounds represents a useful method for the construction of densely functionalized chiral quaternary carbon centers. One characteristic feature of designer chiral phase-transfer catalyst lh in this type of transformation is that it enables the use of a,p-unsaturated aldehydes as an acceptor, leading to the... 

Akiyama s group employed naturally occurring L-quebrachitol 6 to prepare the C2-symmetrical 18-membered chiral crown ether 7 [14]. Compound 7 was found to be an active catalyst for the enantioselective Michael additions of glycine enolates. Thus, deprotonation of ester 8 using potassium tert-butoxide in dichloromethane (DCM) in the presence of crown ether 7 (20 mol %), followed by addition of a Michael acceptor, gave amino-acid derivatives 9 with up to 96% ee, as shown in Scheme 8.4. 

The axially chiral guanidine catalyst (155) (0.4-5 mol%) has been developed to facilitate the highly enantioselective Michael addition of 1,3-dicarbonyl compounds (g to a broad range of conjugated nitroalkenes (<98% ee).211... 

In another study Feringa et al. [20] reported a catalytic enantioselective three-component tandem conjugate addition-aldol reaction of dialkyl zincs. Here, zinc enolates were generated in situ via catalytic enantioselective Michael addition of dialkylzinc compounds to cydohexenone in the presence of a chiral Cu catalyst. Their diastereoselective reaction with an aldehyde then gave trans-2,3-disubstituted cyclohexanones in up to 92% yields and up to >99% ees (Scheme 9.11). 

The catalytic enantioselective addition of aromatic C - H bonds to alkenes would provide a simple and attractive method for the formation of optically active aryl substituted compounds from easily available starting materials. The first catalytic, highly enantioselective Michael addition of indoles was reported by Jorgensen and coworkers. The reactions used a,fl-unsaturated a-ketoesters and alkylidene malonates as Michael acceptors catalyzed by the chiral bisoxazoline (BOX)-metal(II) complexes as described in Scheme 27 [98,99]. 

This type of reaction attracted broad interest when it was discovered that high regioselectivity can also be effected with organoaluminum compounds and other nucleophiles in the presence of Lewis acids and that by employing chiral cyclic acetals (from optically active 1,2- or 1,3-diols) diastereoselective transformations can be realized. - Such reactions are synthetically very valuable when considering that the overall process represents an enantioselective Michael addition, where the chiral auxiliary can be recycled (Scheme 39). ... 

S,S)-2,3-Butanediol (see Section 4.1.2. for access to this compound) was the starting material for the synthesis of (S,S)-2,3-dimethyl-18-ciown-6 (6) which has been used as a chiral catalyst in the enantioselective Michael addition reaction (Sections D.1.5.2.1. and D.I.5.2.4.). Chain elongation of the diol by reaction with ethyl diazoacetate and lithium aluminum hydride reduction, followed by cyclization with triethyleneglycol ditosylate, gives the crown ether 610. 

A chiral diol was obtained from the asymmetric Diels-Alder reaction of anthracene with dimen-thyl fumarate (see Section 3.5.1. for the dienophile) in 99% ee (for details on this reaction, see ref 17). Conversion of the diol to the crown ether 13 was achieved with pentaethyleneglycol ditosylate and potassium hydroxide18. As for the other crown ethers discussed here, the compound has been used as a catalyst in enantioselective Michael additions (Section D. 1.5.2.1.). 

The Pd diaquo complex of BINAP 19 efficiently catalyzed the diastereoselective and enantioselective Michael addition of the y3-keto ester 20 to 3-penten-2-one (21), and the Michael adduct 22 was obtained in 89 % yield (diastereomeric ratio = 8/1) and the ee of the major isomer was 99%. Thus, congested vicinal tertiary and quaternary carbon centers were constructed. It is interesting to know that the Pd aquo complex 19 allows the successive supply of a Bronsted base and a Bronsted acid. The former activates the carbonyl compound to give the chiral palladium enolate and the latter cooperatively activates e enone [4]. 

Scheme 4.33 Chiral guanidine-catalyzed enantioselective Michael addition of 1,3-dicarbonyl compounds to enones.

Scheme 2.33 Enantioselective Michael additions of a-substituted nitroacetates to a,P-unsaturated carbonyl compounds with the use of chiral sodium(i) binaphtholate.

In 2002, Itoh and Kanemasa found that the combined use of both amine and chiral Lewis acid (R,R)-DBFOX-Ph complex of Ni(II) can be an active catalyst for enantioselective Michael addition of nitromethane or malononitrile to unsaturated carbonyl compounds [37a,b]. Recently, they have reported a new enol ketone synthesis through the reactions between cyclic 1,3-dicarbonyl donors and a,p-unsaturated carbonyl acceptors under the double catalytic activation conditions (10mol% each) of Ni(11)-perchlorate hexahydrate and (2,2,6,6-tetramethylpiperidine (TMP) (114))(Scheme 16.33) [38a,b]. Thus, 1,3-cyclohexanedione (112) is allowed to react with 4-bromo-l-crotonoyl-3,5-dimethylpyrazole (113), in THF at room temperature in the presence of both catalytic amounts to give 4,7,7-trimethyl-3,4,5,6,7,8-hexahy-drobenzopyran-2(H),5-diones (115) in good yields along with high enantioselectivity up to 99% ee. 

Du et al. reported the chiral Zn( 11)-catalyzed enantioselective Michael addition of nitroalkanes to nitroalkenes to synthesize optically active 1,3-dinitro compounds... 

Enantioselective Michael addition catalyzed by chiral aluminum Lewis acid is one of the most important methods to obtain enantiomerically pure compounds. As an early work in this fleld, in 1986, Shibasaki and coworkers reported catalytic enantioselective Michael addition of malonates to cyclic enones catalyzed by Li-Al bimetallic catalyst (72) (ALB) derived by premixing LiAlH4 and 2 equivalent of (R)-BINOL in THF (Scheme 6.86) [106, 107]. The structure of (R)-ALB was confirmed by X-ray crystallographic analysis of ALB-cyclohexenone complex. One notable advantage of ALB catalyst is that it works nicely in the tandem Michael-aldol sequence. 

A chiral quinine-derived squaramide catalysed the highly enantioselective Michael addition of malononitrile to chalcones. The reactions take place at a very low catalyst loading (0.5 mol%) and provide the Michael adducts with high yields and good enan-tioselectivities (up to 96% ee). Chiral bifunctional squaramides have also been used as multiple hydrogen-bond donor-acceptor organocatalysts for the asymmetric Michael addition of nitroolefins to 1,3-dicarbonyl compounds. ... 

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 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... 

Some chiral quaternary ammonium salts are also effective in Michael addition reactions. The Merck catalysts 7 (R=4-CF3, X=Br) and 9 (R=4-CF3, X=Br, 10,11-dihydro) were used tor the Michael additions of 59,61, and 64 to vinyl ketones to give the adducts 60,62, and 65 (isolated as 66), respectively,148,491 with excellent enantioselectivity, as shown in Scheme 19. The Michael addition of the O Donnell imine 23 to the a,(3-unsaturated carbonyl compounds also efficiently proceeded by use of the N-anthracenyl-methyl catalyst 12 (R=allyl, X=Br), giving the Michael adducts 67 (Scheme 20).1251... 

Several examples exist of the application of chiral natural N-compounds in base-catalyzed reactions. Thus, L-proline and cinchona alkaloids have been applied [35] in enantioselective aldol condensations and Michael addition. Techniques are available to heterogenize natural N-bases, such as ephedrine, by covalent binding to mesoporous ordered silica materials [36]. 

Dicarbonyl compounds are widely used in organic synthesis as activated nucleophiles. Because of the relatively high acidity of the methylenic C—H of 1,3-dicarbonyl compounds, most reactions involving 1,3-dicarbonyl compounds are considered to be nucleophilic additions or substitutions of enolates. However, some experimental evidence showed that 1,3-dicarbonyl compounds could react via C—H activations. Although this concept is still controversial, it opens a novel idea to consider the reactions of activated C H bonds. The chiral bifunctional Ru catalysts were used in enantioselective C C bonds formation by Michael addition of 1,3-dicarbonyl compounds with high yields and enantiomeric excesses. ... 

Compound 388 is an acylating agent for electron-deficient alkenes, in a Michael addition process. It is formed by treating molybdenum hexacarbonyl with an organolithium compound, followed by quenching the intermediate 387 with boron trifluoride (equation 104). The structure of 388 (R = Ph) can be elucidated by NMR spectroscopy. Other examples of enantioselective and diastereoselective Michael-type additions involving lithium-containing intermediates in the presence of chiral additives can be found elsewhere in the literature . 

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