Michael additions chiral donors

Successful methodology for diastereoselective Michael additions with chirality in the donor is so far limited to chiral cyclic enolates. The stereocontrol is mainly due to shielding of one of the jr-faces of the enolate by the ring substituent that resides at the stereogenic center. The (nmv-diastereoselective Michael addition of (5)-2-methyl-3-vinylcyclopentanonc illustrates this principle154-157. 

Asymmetric Michael additions using chiral auxiliary containing donors have attracted widespread attention and various methods are now available that give high enantiomeric excess. 

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. 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

Williams group observed low enantioselectivities for the Michael addition of a prochiral nucleophile, ethyl 2-cyanopropionate 623, to methyl vinyl ketone 624 catalyzed by chiral platinum complexes (Scheme 8.196)." The NMR analysis indicated that these cationic Pt complexes act as Lewis acids toward nitriles. The X-ray crystal structure as well NMR analysis showed that the solvent ligand that is readily displaced by an organic substrate is situated cis to the nitrogen donor in the Pt complex and, therefore, is in a chiral pocket created by the oxazoline ring. 

The chiral, nonracemic oxazepine derivative (46 Scheme 18) was studied as donor in the Michael addition to prochiral a,p-unsaturated carbonyl compounds.134-133 The products were obtained with 44-55% ee after removal of the chiral auxiliary group. With 1-nitrocyclohexene as acceptor, somewhat better se-lectivities (62% ee) were observed.136... 

In the first attempts to use a chiral a-sulfinyi ester enolate as donor in Michael additions to a -un-saturated esters, only low selectivities were observed.185 186 Better results are obtained when the a-lithio sulfoxide (174), a chiral acyl anion equivalent, is employed. Conjugate addition of (174) to cyclopent-enone derivatives occurs with reasonably high degrees of asymmetric induction, as exemplified by the preparation of the 11-deoxy prostanoid (175 Scheme 63).187 188 Chiral oxosulfonium ylides and chiral li-thiosulfoximines can be used for the preparation of optically active cyclopropane derivatives (up to 49% ee) from a, -unsaturated carbonyl compounds.189... 

Quaternary stereocenters can be obtained with high selectivity with ot-amino acid amides as chiral auxiliaries, which were first converted with P-oxo esters to give enamines such as compounds 58. According to a combinatorial strategy, various enamino esters 58 were screened in Michael additions with MVK (41a) and several metal salts as catalysts. With FeCl3, however, the maximum stereoselectivity achieved was only 77% ee (with enamine 58a derived from L-isoleucine dimethylamide). Cu(0Ac)2H20 turned out be the optimal catalyst for this transformation. With L-valine diethylamide as chiral auxiliary in compound 58b, reaction proceeds with 86% yield and 98% ee after aqueous workup [79]. Importantly, this valuable method for the construction of quaternary stereocenters [80] under ambient conditions seems to be generally applicable to a number of Michael donors [81]. In all cases, the auxiliary can be quantitatively recovered after workup. 

As described in Section 6.2.1.1, earlier application of conjugate addition involved transferable aluminum hydrides and alkyls. This section is devoted to asymmetric conjugate addition using a chiral aluminum catalyst and newer aspects that enable substrate generality wifh respect to both Michael acceptor and donor components, by use of well-designed aluminum reagents. 

The nucleophilic properties of enamines uncovered by Stork have found a wide application in Michael additions. Secondary enamines are usually in equilibrium with the corresponding imines. These imines are generally more stable, unless the tautomeric enamine is stabilized by conjugation (Figure 7.71). The primary product of the reaction of an enamine with an a,P-unsaturated carbonyl compound is a dipolar intermediate 7.108. This intermediate is converted to a 1,5-dicarbonyl compound on exposure to aqueous add. Proton transfers can take place before hydroysis to the ketone occurs, and the stereoselectivity of the process may be determined by such steps. Moreover, the enamine addition reaction can be reversible. These problems notwithstanding, the use of chiral amines to generate imines or enamines for use as Michael donors has been widely developed. The chiral imine/enamine can be preformed or, espedally in the case of intramolecular reactions, the amine can be added to the reaction medium in stoichiometric amounts. 

One important characteristic of the Michael addition reaction is that when the donor and acceptor contain suitably different substituents, one or two new chiral centers can be created, producing one or two pairs of enantiomers. When, on the other hand, either or both of the reactants has a chiral substituent, the reaction can be enantioselective. Enantioselective addition has also been achieved by use of chiral catalysts [2], Indeed, it is interesting to remark that in recent years much attention has been devoted to catalytic asymmetric Michael reactions because of the importance of the products as optically active intermediates for many functional compounds [30] many types of chiral catalyst have been reported [31],... 

Lithium diisopropylamide. 13, 163-164 15, 188-189 16, 196-197 17, 165-167 Ester enolates. Procedures for the preparation of ( )- and (Z)-ketene silyl acetals are well developed. Enolates have been generated from conjugate esters by way of Michael addition, and when a remote halide is present, they are quenched by cyclization. Chiral Michael donors such as carbanions of the SAMP/RAMP hydra-zones initiate formation of trani-2-(2 -oxoalkyl)cycloalkanecarboxylic esters with excellent diastereomer excess and enantiomer excess. 

There are also examples of enantioselective Michael reactions on helerogcni/ed chiral amines (cinchonidine and cinchonine) (Figure 20d) [I65. Further examples ol Michael additions use nitromcthane, maloniirile. diethyl malonaie. cyanoaceianiide or thiols as donors and methyl vinyl ketone, methyl aciylaic and simple and substituted chalconcs as acceptors 70. 81. 114. 245. 265, 266). As for the catalysts, they can be cation-promoted Ba(OM) [70], hydroxyapatite 1245]. supported KF (114). alkaline carbiuiaies (I02. hydrolalciies (2(>51... 

H-bond donor capability is also displayed by some cationic molecules such as the tetraminophosphonium 40 (Scheme 11.23). This type of the so-called chiral proton" catalysis [83] has been demonstrated by Ooi in the addition of aryl amines to nitroolefins [84]. The arylaminophosphonium barfate 40 was able to catalyze the aza-Michael addition to afford the corresponding adducts in excellent yields and enantioselectivities. The same group has extended the described protocol for the effective addition of aryl amines to propargyl-substituted nitroolefins [85]. 

Carbon-carbon bond forming reactions between carbanionic nucleophiles like enolates or deprotonated nitroalkanes and electron deficient alkenes and alkynes belong to the oldest and most versatile transformations known today (225-229). Moreover, stereoselective variants have proven to possess an enormous potential in the syntheses of complex molecules as already exemplified in Sect. 2.4. Whereas the applications depicted in this previous section utilized nucleophiles activated by enamine formation with a chiral secondary amine catalyst to achieve these highly selective C-C bond formations, the present discussirai will focus on the addition of carbon nucleophiles to iminium-activated Michael acceptors. Herein traditional Michael additions using e.g. enolate nucleophiles will be described whereas the use of aromatic Michael donors with iminium-activated acceptors in Friedel-Crafts type reactions will be discussed separately subsequently. 

An enantioselective Michael addition of 3-aryloxindole to PhCH=CHS02Ph, catalysed by the quinine-derived amine-thiourea (205) as a multiple hydrogen-bonding donor, has been developed. The resulting adducts, containing a chiral quaternary carbon centre at the 3-position of the oxindole, were obtained with <98% eeP" An... 

Yb(OTf)3 with native or-amino acids as chiral Ugands catalyzes asymmetric Michael addition reactions in water. Although the reaction conditions require only 5mol% of the Lewis acid, it provides enantiomeric excesses of up to 79% and is applicable to a wider range of donors and acceptors than previously demonstrated (Scheme 29). This catalyst might have potential for large-scale applications as it displays not... 

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. 

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