Michael enantioselective protonation

Scheme 7.9 Enantioselective protonation induced by Michael additions.

Despite the importance of the Michael addition in organic synthesis, the tandem conjugate addition/enantioselective protonation has been little explored [14] and only a few publications have involved cinchona alkaloids as bifunctional catalysts B for controlling the configuration of the chiral carbon created during protonation (Scheme 7.9). 

Pracejus and coworkers reported the first Michael addition/enantioselective protonation mediated by cinchona alkaloids [15]. The authors put a special emphasis on the requirement of using chiral P-N,N-dialkylamino alcohol to achieve significant inductions. The addition of benzyl thiol 16 on 2-phthalimidoacrylate 17 catalyzed by 5 mol% of quinidine 3 gave the best selectivity (Scheme 7.10). 

Scheme 7.15 Deng s tandem Michael addition/enantioselective protonation [19].

Scheme 7.16 Deng s Michael addition/enantioselective protonation with acyclic cyanoacetates [19].

The. V-alkylation of ephedrine is a convenient method for obtaining tertiary amines which are useful as catalysts, e.g., for enantioselective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.), and as molybdenum complexes for enantioselective epoxidation of allylic alcohols (Section D.4.5.2.2.). As the lithium salts, they are used as chiral bases, and in the free form for the enantioselective protonation of enolates (Section D.2.I.). As auxiliaries, such tertiary amines were used for electrophilic amination (Section D.7.I.), and carbanionic reactions, e.g., Michael additions (Sections D. 1.5.2.1. and D.1.5.2.4.). For the introduction of simple jV-substituents (CH3, F.t, I-Pr, Pretc.), reductive amination of the corresponding carbonyl compounds with Raney nickel is the method of choice13. For /V-substituents containing further functional groups, e.g., 6 and 7, direct alkylations of ephedrine and pseudoephedrine have both been applied14,15. 

Enantioselective organocatalytic synthesis of 3,4-dihydro-2H-pyran-2-ones can be accomplished through a nucleophile-catalyzed Michael addition-proton transfer—enol lactonization of a,P-unsaturated acyl chlorides and 1,3-dicarbonyl compounds (Scheme 47) (13AGE13688). 

Michael addition of thioacetic acid to a series of a-substituted (V-acryloyloxazolidin-2-ones, followed by enantioselective protonation, catalysed by the cinchonidine-derived thiourea (288a), has been reported to proceed with <97% ee The pseudo-enantiomeric, cinchonine-derived thiourea (289a) can catalyse the Michael addition of dimedone to enone RCH=CHCO( -Py) with <98% ee The isosteviol-derived thiourea (290) represents yet another variation this organocatalyst has been reported to facilitate the Michael addition of a-substituted cyanoacetates NCCH(Ar)C02R and maleimides in toluene at -30 °C (with <93% ee and <98 2 dr) as a method for the construction of quaternary chiral centres " ... 

In this chapter, the enantioselective protonation of preformed and a-stabilized carbanions is disclosed. A second part is devoted to the asymmetric protonation of enolate species obtained in situ through a first chemical transformation with activated double bonds (i.e., ketenes or Michael acceptors). Herein, among all the advances made using these two main approaches, methodologies that have been used in total synthesis of natural and pharmacologically active products are emphasized. 

Sibi and co-workers explored the power of the radical chemistry through a terminal proton abstraction to achieve the enantioselective proton transfer (Scheme 31.31). Indeed, the formation of a bidentate complex by coordination of a chiral Mg complex to a Michael acceptor bearing an achiral template can promote the 1,4-radical addition followed by an enantioselective hydrogen transfer. This strategy is believed to form a bidentade complex aimed to control the enolate geometry, which is a key point of the enantiodetermining step of the reaction. 

However, despite the considerable efforts devoted to address the fundamental issues toward the development of asymmetric protonation, its applications to natural or bioactive synthesis remain sporadic. Herein, two main strategies, namely the enantioselective protonation of metal enolates, especially silicon enolates and the protonation of polar double bonds, i.e., Michael acceptors, were depicted trough the most relevant synthetic applications. These two strategies led to the synthesis of fragrance, natural products, ° bioactive compoundsand... 

Hamashima Y, Tamura T, Suzuki S, Sodeoka M. Enantioselective protonation in the aza-Michael reaction using a combination of chiral Pd-p,-hydroxo complex with an amine salt. SyM/e 2009 1631-1634. 

Kumar A, Salunkhe RV, Rane RA, Dike SY. Novel catalytic enantioselective protonation (proton transfer) in Michael addition of benzenethiol to a-acrylacrylates synthesis of (5)-naproxen and a-arylpropionic acids or esters. J. Chem. Soc. Chem. Commun 1991 485-486. 

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... 

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. 

Taddol has been widely used as a chiral auxiliary or chiral ligand in asymmetric catalysis [17], and in 1997 Belokon first showed that it could also function as an effective solid-liquid phase-transfer catalyst [18]. The initial reaction studied by Belokon was the asymmetric Michael addition of nickel complex 11a to methyl methacrylate to give y-methyl glutamate precursors 12 and 13 (Scheme 8.7). It was found that only the disodium salt of Taddol 14 acted as a catalyst, and both the enantio- and diastereos-electivity were modest [20% ee and 65% diastereomeric excess (de) in favor of 12 when 10 mol % of Taddol was used]. The enantioselectivity could be increased (to 28%) by using a stoichiometric amount of Taddol, but the diastereoselectivity decreased (to 40%) under these conditions due to deprotonation of the remaining acidic proton in products 12 and 13. Nevertheless, diastereomers 12 and 13 could be separated and the ee-value of complex 12 increased to >85% by recrystallization, thus providing enantiomerically enriched (2S, 4i )-y-methyl glutamic add 15. 

The general reaction mechanism of the Michael reaction is given below (Scheme 4). First, deprotonation of the Michael donor occurs to form a reactive nucleophile (A, C). This adds enantioselectively to the electron-deficient olefin under the action of the chiral catalyst. In the final step, proton transfer to the developed enolate (B, D) occurs from either a Michael donor or the conjugate acid of a catalyst or a base, affording the desired Michael adduct. It is noteworthy that the large difference of stability between the two enolate anions (A/B, C/D) is the driving force for the completion of the catalytic cycle. 

Mechanistically, this catalytic reaction proceeds via enantioselective Michael addition and the subsequent protonation of the transient enol intermediate in a stereoselective manner (Scheme 9.27). Thus, the authors proposed that the catalysts serve as a dual-function catalyst for this tandem reaction namely, the stereochemical outcome of this tandem reaction resulted from a network of hydrogen-bonding interactions between the catalyst with the reacting donor and acceptor in the addition step and, subsequently, with the putative enol intermediate (78) in the protonation step (Scheme 9.28). 

Soon afterward, various types of carbon [40-44], oxygen [45], and phosphorous [46] Michael donors were successfully employed in the thiourea-catalyzed addition to nitroalkenes. In the presence of the bifunctional epi-9-amino-9-deoxy cinchonine-based thiourea catalyst 79a, the 5-aryl-l,3-dioxolan-4-ones 138 bearing an acidic a-proton derived from mandelic acid derivatives and hexafluoroacetone were identified by Dixon and coworkers as effective pronucleophiles in diastereo- and enantioselective Michael addition reactions to nitrostyrenes 124 [40]. While the diastereoselectivity obtained exceeded 98%, the enantiomeric excess recorded... 

The epi-quinine urea 81b was also found by Wennemers to promote an asymmetric decarboxylation/Michael addition between thioester 143 and 124 to afford the product 144 in good yield and high enantioselectivity (up to 90% ee) (Scheme 9.49). Here, malonic acid half-thioesters serve as a thioester enolate (i.e., enolate Michael donors). This reaction mimics the polyketide synthase-catalyzed decarboxylative acylation reactions of CoA-bound malonic acid half-thiesters in the biosynthesis of fatty adds and polyketides. The authors suggested, analogously with the enzyme system, that the urea moiety is responsible for activating the deprotonated malonic add half-thioesters that, upon decarboxylation, read with the nitroolefin electrophile simultaneously activated by the protonated quinuclidine moiety (Figure 9.5) [42]. 

In alcoholic medium, NaBH, converts a,P-unsaturated nitriles into cyanoethyl compounds under more severe conditions (refluxing alcohol for several hours). - i jpig enantioselective reduction of the double bond of each ( )- and (Z)-isomer of a,P-unsaturated nitriles derived from ketones has been evaluated using NaBH in EtOH/diglyme in the presence of semicorrin (/oCT catalyst the yields are good (about 75%), but the enantioselectivity remains modest (53-69%). - In contrast, it has been found that copper(l) hydride, a reagent that presumably operates by a mechanism akin to the Michael reaction, 754 cleanly and stereoselectively effects the reduction of a,P-iinsaturatcd to saturated nitriles in the presence of 2-butanol, as proton donnor, in THE. The use of LAH in THF at room temperature has also been reported in the stereoselective reduction of a,P-iinsaturatcd nitriles. 

R,2S)-Ephedrine has found most application, e.g., as a catalyst in photochemical proton transfer reactions (Section D.2.1.). and as its lithium salt in enantioselective deprotonations (Section D.2.1.). The amino function readily forms chiral amides with carboxylic acids and enamines with carbonyl compounds these reagents perform stereoselective carbanionic reactions, such as Michael additions (Sections D.1.5.2.1. and D. 1.5.2.4.), and alkylations (Section D.1.1.1.3.1.). They have also been used to obtain chiral alkenes for [1 +2] cycloadditions (Section D. 1.6.1.5.). 

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