Michael addition chiral enolates

Besides of these main types of the chiral TAA salts, numerous other chiral TAA salts and crown ethers acting as moderately enantioselective PT catalysts were reported. Chiral PTC was mostly used for enantioselective formation of chiral carbon centers via alkylation of carbanions (enolates), Michael addition, the Darzens reaction and other reactions of carbanions. There are also numerous examples of enantioselective PTC epoxidation of electron deficient alkenes (for review, see Ref 105). 

Asymmetric Michael addition of chiral enolates to nltroalkenes provides a useful method for the preparation of biologically important compotmds. The Michael addition of doubly deprotonated, optically active fi-hydroxycarboxylates to nltroalkenes proceeds v/ith high dias-tereoselecdvity to give fityr/iro-hydroxynitroesters fEq, 4,58, ... 

When chiral enolates or chiral Michael acceptors are used, for instance, when stereogenic centers are present in the substrate or when X or Y are chiral auxiliaries, both simple and induced diastereoselectivity is observed. This results, in principle, in the formation of four diastereomers 1 -4. The diastereoselectivity in the Michael addition of lithium enolates to enones can be rationalized by consideration of chelated transition states A-D372. 

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. 

The asymmetric Michael addition of chiral nonracemic ketone enolates has most frequently been used as part of the Robinson annulation methodology in the synthesis of natural products171-172. The enolates are then derived from carbocyclic chiral ketones such as (+)-nopinone, (-)-dihydrocarvone, or (-)-3-methylsabinaketone. 

The application of auxiliary control in the asymmetric Michael addition of chiral enolates derived from ketones is rare the only example known is the use of (27 ,37 )-2,3-butancdiol as an auxiliary. The ketal of (27 ,37 )-2,3-butanediol with 3-methyl-l,2-cyclohexanedione reacts with 3-buten-2-one using as base a catalytic amount of sodium ethoxide in ethanol195. 

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. 

Thus the product in such cases can exist as two pairs of enantiomers. In a di-astereoselective process, one of the two pairs is formed exclusively or predominantly as a racemic mixture. Many such examples have been reported. In many of these cases, both the enolate and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters, (E) enolates gave the syn pair of enantiomers (p. 146), while (Z) enolates gave the anti pair. Addition of chiral additives to the reaction, such as proline derivatives, or (—)-sparteine lead to product formation with good-to-excellent asynunetric induction. Ultrasound has also been used to promote asymmetric Michael reactions. Intramolecular versions of Michael addition are well known. ... 

This finding is also in agreement with another three-component Michael/aldol addition reaction reported by Shibasaki and coworkers [14]. Here, as a catalyst the chiral AlLibis[(S)-binaphthoxide] complex (ALB) (2-37) was used. Such hetero-bimetallic compounds show both Bronsted basicity and Lewis acidity, and can catalyze aldol [15] and Michael/aldol [14, 16] processes. Reaction of cyclopentenone 2-29b, aldehyde 2-35, and dibenzyl methylmalonate (2-36) at r.t. in the presence of 5 mol% of 2-37 led to 3-hydroxy ketones 2-38 as a mixture of diastereomers in 84% yield. Transformation of 2-38 by a mesylation/elimination sequence afforded 2-39 with 92 % ee recrystallization gave enantiopure 2-39, which was used in the synthesis of ll-deoxy-PGFla (2-40) (Scheme 2.8). The transition states 2-41 and 2-42 illustrate the stereochemical result (Scheme 2.9). The coordination of the enone to the aluminum not only results in its activation, but also fixes its position for the Michael addition, as demonstrated in TS-2-41. It is of importance that the following aldol reaction of 2-42 is faster than a protonation of the enolate moiety. 

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... 

Deprotection of 2,2-disubstituted-l,3-dithiolanes to give carbonyl compounds can be achieved using Oxone with KBr in aq. MeCN <06TL8559> and a review of silylated heterocycles as formyl anion equivalents includes reference to 64 <06CC4881>. A method for transformation of propargylic dithiolanes 43 into tetrasubstituted furans has been reported <06SL1209> and Michael addition of enolates to the chiral dithiolane dioxide 65 takes place... 

Oare, D. A., Stereochemistry of the Base-Promoted Michael Addition Reaction, 19, 227 Acyclic Stereocontrol in Michael Addition Reactions of Enamines and Enol Ethers, 20, 87 Okamoto, Yoshio, Optically Active Polymers with Chiral Recognition Ability, 24, 157. 

The utilization of copper complexes (47) based on bisisoxazolines allows various silyl enol ethers to be added to aldehydes and ketones which possess an adjacent heteroatom e.g. pyruvate esters. An example is shown is Scheme 43[126]. C2-Symmetric Cu(II) complexes have also been used as chiral Lewis acids for the catalysis of enantioselective Michael additions of silylketene acetals to alkylidene malonates[127]. 

L. Toke, P. Bako, G. M. Keserii, M. Albert, L. Fenichel, Asymmetric Michael Addition and Deracemization of Enolate by Chiral Crown Ether , Tetrahedron 1998, 54, 213-222. 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

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. ... 

Enantiocontrolled anti-selective Michael additions of the metalated ylides derived from a-(alkylideneamino)alkanoates are attractive as a new synthetic route to enantiomers of a-amino esters. Although there are a variety of chiral glycine equivalents available, only the enolates derived from 1,4-dihydropyrazine have been successfully applied to asymmetric Michael additions (Scheme 11.22) (103-105). In these reactions, the diastereoselectivities are high. 

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... 

A double ir-face selective aptotic Michael addition of the lithium dienolate, derived from the chiral senecioate (119), to cyclopentenone served for the total synthesis of (-)-kushimone (120 Scheme 45).137-138 The selectivity of the key reaction was rationalized by the assumption of a transition state as shown in (121a). A related approach involves the Michael addition of enolates, derived from chiral propionates, to methyl ( )-crotonate (Scheme 46).139 The formation of the threo isomer (122) as the major product indicates a transition state structure as shown in (121b). This method was utilized in the synthesis of the marine natural product 7,20-diisocyanoadociane (123 Scheme 47).140... 

Diastereoselective Michael additions of enolates, prepared from the chiral amides (127) and (128), to prochiral a.p-unsaturated esters were utilized in the synthesis of (+)-dehydroiridodiol (129) and its isomer (130 Scheme 49).143... 

When Michael additions of chiral enolates to nitroalkenes were studied, it was found that lithium enolates (132) of l,3-dioxolan-4-ones (131), derived from the corresponding a-hydroxy acids, afford the adducts (133) with high diastereoselectivity (Scheme 50).144 Recrystallization leads, in general, to diastereomerically pure products, which in turn can efficiently be converted to homochiral compounds like (134), (135) or (136). A number of other chiral enolates (137M140) were also shown to undergo highly selective additions to nitroalkenes however, product configurations were not determined in these cases. 

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... 

The heterobimetallic multifunctional complexes LnSB developed by Shibasaki and Sasai described above are excellent catalysts for the Michael addition of thiols [40]. Thus, phenyl-methanethiol reacted with cycloalkenones in the presence of (R)-LSB (LaNa3tris(binaphthox-ide)) (10 mol %) in toluene-THF (60 1) at -40°C, to give the adduct with up to 90% ee. A proposed catalytic cycle for this reaction is shown in Figure 8D.9. Because the multifunctional catalyst still has the internal naphthol proton after deprotonation of the thiol (bold-H in I and II), this acidic proton in the chiral environment can serve as the source of asymmetric protonation of the intermediary enolate, which is coordinated to the catalyst II. In fact, the Michael addition of 4-/en-butylbenzcnethiol to ethyl thiomethacrylate afforded the product with up to 93% ee using (R)-SmSB as catalyst. The catalyst loading could be reduced to 2 mol % without affecting enantioselectivity of the reaction. 

The enantioselective aldol and Michael additions of achiral enolates with achiral nitroolefins and achiral aldehydes, in the presence of chiral lithium amides and amines, was recently reviewed354. The amides and amines are auxiliary molecules which are released on work-up (equation 90 shows an example of such a reaction). 

The use of chiral crown ethers as asymmetric phase-transfer catalysts is largely due to the studies of Bako and Toke [6], as discussed below. Interestingly, chiral crown ethers have not been widely used for the synthesis of amino acid derivatives, but have been shown to be effective catalysts for asymmetric Michael additions of nitro-alkane enolates, for Darzens condensations, and for asymmetric epoxidations of a,P-unsaturated carbonyl compounds. 

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. 

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