Quinine Michael addition

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

The Soos group, in 2005, prepared the first thiourea derivatives from the cinchona alkaloids quinine QN (8S, 9R-121), dihydroquinidine DHQD (8S, 9S-122), C9-epi-QN (8S, 9P-123), and quinidine QD (SR, 9R-124) via an experimentally simple one-step protocol with epimerization at the C9-position of the alkaloid starting material (Figure 6.39) [278]. The catalytic efficiency of these new thiourea derivatives and also of unmodified QN and C9-epi-QN was evaluated in the enan-tioselective Michael addition [149-152] of nitromethane to the simple model chal-cone 1,3-diphenyl-propenone resulting in adduct 1 in Scheme 6.119. After 99h reaction time at 25 °C in toluene and at 10 mol% catalyst loading QN turned out to be a poor catalyst (4% yield/42% ee (S)-adduct) and C9-epi-QN even failed to accelerate the screening reaction. In contrast, the C9-modified cinchona alkaloid... 

Figure 6.39 Cinchona alkaloid-thioureas prepared from quinine (121), dihydroquinine (122), C9-epi-quinine (123), and quinidine (124) catalytic efficiency evaluated in the Michael addition of nitromethane to tram-chalcone 1,3-diphenyl-propenone at 10mol% loading and rt.

The c 5-23-dimethylchionian-4-one 53 is obtained with fair enantioselectivity through an asymmetric Michael addition in the presence of (-)-quinine (Scheme 32) <99TL3777>. Directed metallation of protected phenols and subsequent reaction of the li derivative with enantiopure Weinreb amides of glycidic acids feature in a route to stereoisomers of 2-alkyl-3-hydroxychroman-4-ones (Scheme 33) <99JOC3489>. 

Tandem intramolecular Michael addition - intramolecular alkylation can lead to cyclopropanes. Matthew J. Gaunt of the University of Cambridge has shown (Angew. Chem. Int. Ed. 2004,43, 2681) that this intramolecular Michael addition also responds to organocatalysis. In this case, the catalyst, a quinine-derived amine, covalently binds to the substrate, then is released at the end of the reaction. 

Evidently, many simple chiral organic compounds that act as catalysts can be covalently bound to polymer backbones. Polymer-anchored quinine catalyzes the asymmetric Michael addition of a jS-keto ester to methyl vinyl ketone, which proceeds in 22-42% optical yield (Scheme 13) (29). 

The first examples of asymmetric Michael additions of C-nudeophiles to enones appeared in the middle to late 1970s. In 1975 Wynberg and Helder demonstrated in a preliminary publication that the quinine-catalyzed addition of several acidic, doubly activated Michael donors to methyl vinyl ketone (MVK) proceeds asymmetrically [2, 3], Enantiomeric excesses were determined for addition of a-tosylnitro-ethane to MVK (56%) and for 2-carbomethoxyindanone as the pre-nudeophile (68%). Later Hermann and Wynberg reported in more detail that 2-carbomethoxy-indanone (1, Scheme 4.3) can be added to methyl vinyl ketone with ca 1 mol% quinine (3a) or quinidine (3b) as catalyst to afford the Michael-adduct 2 in excellent yields and with up to 76% ee [2, 4], Because of their relatively low basicity, the amine bases 3a,b do not effect the Michael addition of less acidic pre-nucleophiles such as 4 (Scheme 4.3). However, the corresponding ammonium hydroxides 6a,b do promote the addition of the substrates 4 to methyl vinyl ketone under the same mild conditions, albeit with enantioselectivity not exceeding ca 20% [4],... 

Michael additions of C-nudeophiles such as the indanone 1 have been the subject of numerous further studies For example, the reaction between the indanone 1 and methyl vinyl ketone was effected by a solid-phase-bound quinine derivative in 85% yield and with remarkable 87% ee by d Angelo, Cave et al. [5], Co-polymers of cinchona alkaloids with acrylonitrile effected the same transformation Kobaya-shi and Iwai [6a] achieved 92% yield and 42% ee and Oda et al. [6b] achieved almost quantitative yield and up to 65% ee. Similarly, partially resolved 2-(hydroxy-methyl)quinudidine was found to catalyze the reaction between 1 and acrolein and a-isopropyl acrolein with induction of asymmetry, but no enantiomeric excesses were determined [7]. As shown in Scheme 4.4, the indanone 7 could be added to MVK with up to 80% ee under phase-transfer conditions, by use of the Cinchona-derived PT-catalysts 9a and 9b, affording the Michael-product 8 or enf-8, respectively [8]. The adducts 8 or ent-8 were intermediates in the stereoselective Robinson anellation of a cydohexenone ring to the indanone 7 [8],... 

Only three examples of intramolecular organocatalyzed and enantioselective Michael additions of C-nucleophiles seem to have been reported in the literature. In 1979 Wynberg and ten Hoeve reported the (—)-quinine-catalyzed double Michael addition of the 1,3-diones 74a,b to the 1,5-disubstituted pentadien-3-ones 75a-c (Scheme 4.37) [61]. 

Modified cinchona alkaloids 18 and 19, derived from quinine and quinidine, respectively, were utilized by Deng and co-workers for the catalytic asymmetric Michael additions of malonates to nitroolefins [49]. These catalysts effectively promoted the conjugate additions of methylmalonate to a variety of aromatic (90-99% yield 96-98% ee), heteroaromatic (97-99% yield 96-98% ee) and aliphatic (71-86% yield 94% ee) -substituted nitroolefins (Table 6.7). As the two alkaloids... 

Further reports on asymmetric synthesis in the presence of Cinchona alkaloids have been made.142 " For example, hydrogenation of methyl pyruvate with a platinum-alumina catalyst containing quinine gives (+)-(/ )-methyl lactate in 87% optical yield.1426 Asymmetric induction with optical yields up to 36 and 26% has been observed in the Michael addition of thiols and nitro-alkanes to ct/ -unsaturated ketones in the presence of quaternary salts derived from the Cinchona alkaloids.142"... 

Roush WR, Hall SE (1981) Studies on the total synthesis of chlorothricol-ide stereochemical aspects of the intramolecular Diels-Alder reactions of methyl undeca-2,8,10-trienoates. J Am Chem Soc 103 5200-5211 Rudler H, Denise B, Xu Y, Parlier A, Vaissermann J (2005) Bis(trimethylsilyl)-ketene acetals as C,0-dinucleophiles one-pot formation of polycyclic y-and 8-lactones from pyridines and pyrazines. Eur J Org Chem 3724-2744 Sekino E, Kumamoto T, Tanaka T, Ikeda T, Ishikawa T (2004) Concise synthesis of anti-HIV-1 Active (+)-inophyllum B and (+)-calanolide A by application of (-)-quinine-catalyzed intramolecular oxo-michael addition. J Org Chem 69 2760-2767... 

Using ( )-Quinine Catalyzed Intramolecular oxo-Michael Addition ... 

Ishikawa et al. reported that ( )-quinine-catalyzed asymmetric intramolecular oxo-Michael addition (IMA) of 7-hydroxy-8-tigloylcoumarin gave cis-2,3-dimethyl-4-chromanone systems with high enantioselectivity and moderate diaster-eoselectivity, especially when chlorobenzene was used as a solvent. " Therefore, total synthesis of (+)-calanolide A (1) was achieved by application of the (—)-quinine-catalyzed asymmetric IMA. However, the synthetic route starting from 1,3,5- trimethoxybenzene was too long (13 steps with 3.5% overall yield) to practice. Finally, the authors improved and shortened the original synthetic route by application of Mgl2-assisted demethylation. 

Sekino, E. Kumamoto, T. Tanaka, T. Ikeda, T. Ishikawa, T. Concise synthesis of anti-HIV-1 active (-l-)-inophyllum B and (-l-)-calanolide A by application of (—)-quinine-catalyzed intramolecular oxo-Michael addition. J. Org. Chem., 2004, 69 2760-2769. 

Tanaka, T. Kumanoto, T. Ishikawa, T. Solvent effects on stereoselectivity in 2,3-dimethyM- chromanone cyclization by quinine-catalyzed asymmetric intromolecular oxo-Michael addition. Tetrahedron-Asymmetry, 2000, 11 4633 637. 

Kumar and coworkers described the Michael addition of thiophenol 13 to 2-phenylacrylates 19 using a catalytic amount of cinchona alkaloids [16]. Among the four natural alkaloids, quinine 20 and quinidine 3 afforded the best results with opposite enantioselectivity (Scheme 7.11). Methyl or isopropyl ester substrates 19a and 19b gave comparable selectivities whereas more sterically demanding esters (e.g., tBu or CH(iPr)2) gave lower optical inductions. Based on the previous considerations and a computational analysis, the authors suggested a transition state... 

When the Michael donors have a sufficiently low pKa, the Michael addition can be catalyzed by a base. The first catalytic asymmetric conjugate addition was achieved by Wynberg et al. in 1975 using cinchona bases [la]. They performed the reaction of cyclic P-ketoesters such as 1 with methyl vinyl ketone in the presence of quinine and... 

Figure 9.2 Transition-state model of quinine-catalyzed Michael addition ofthiol to cyclohexenone.

In 2006, Deng and coworkers reported that quinine/quinidine-derived catalysts (64a,b) bearing a free OH group at the C6 -position and bulky phenanthryl moiety at the 9( Opposition quite efficiently promoted the Michael addition of the a-substituted P-ketoesters 65 to the a,P-unsaturated ketones 66 (Scheme 9.21) [18]. The reaction with as little as 1.0mol% of catalyst 64 afforded excellent stereoselectivity and chemical yields (up to 98% ee with quantitative yield) for a wide range of both donors and acceptors. 

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]. 

As the reactivity of supported alkaloids was often lower than that of their homogeneous counterparts, a spacer was introduced between the catalytic centre and the polymer matrix to overcome this drawback. To this end polymer-supported quinine 60 derivatives with spacers of different length were prepared (Figure 3.2) and tested in the Michael addition of methyl 1-oxo-indane-2-carboxylate to methyl vinyl ketone (Scheme 3.20). ... 

The naturally occurring (-i-)-calanolide A 21, R = n-Pr, and (H-)-inophyllum B 21, R = Ph, are of interest in that the molecules possess chromene, coumarin and chromanol systems. Total syntheses of them start from a coumarin and generate the chromanone unit through an intramolecular Michael addition which under (-)-quinine catalysis affords cis and trans benzodipyrans with 97% and 52% ee, respectively. The chromene moiety is constructed using the phenylboronic acid assisted reaction with senecioaldehyde. Reduction of the chromanone to the chromanol completes the sequence <04JOC2760>. 

Asymmetric Michael addition. Michael addition of nitromethane to chalcone (equation I) in the presence of a chiral amine (quinine, N-methylephedrine) proceeds in methanol (but not in aprotic solvents) in 60-807) yield, but the optical yield at best is 17>. However, if these amines are converted into aminium fluorides, the addition takes place in aprotic solvents (CaHsCHg, CH3CN) in 50-100% yield of more interest, asymmetric inductions of 207, can be obtained. (- )-BenzyIquininium fluoride (1) is particularly effective. The hydroxyl group in these salts is believed to play an important role in the stereochemical outcome of the reaction. Moreover, the fluoride ion is important as a strong base. 

Nal chiral amines such as DBU, ° (S)-2-[bis(3,5-dimethylphenyl)methyl]pyrrolidine, C2-symmetric (2S,55)-2,5-diphenylpyrrolidine, (-)-quinine, and proline polymer catalysts such as antibody 38C2" and polymer-anchored chiral catalysts and solid base catalysts such as MgO and Mg-Al-O-r-Bu hydrotalcite. Furthermore, the solvent-free Michael addition has been established by application of CeCb 7H20-NaI as catalyst or microwave irradiation of reactants on BiCb or Cdh, EuCb, CeCb 5H20, and alumina surfaces. It is interesting that the thermal treatment or microwave irradiation of 1,5-ketodiesters or 1,5-diketones in DMSO in the presence of NaX (X = Cl, Br, I) results in the retro-Michael addition. ... 

---