Phase-Transfer Catalyzed Michael Additions

The first successful results of the asymmetric Michael addition under phase transfer catalyzed conditions were achieved by use of ingeniously designed chiral crown ethers 13 and 52.1441 The 3-keto ester 49 reacted with methyl vinyl ketone by use of 13 to give the Michael product 50 with excellent enantioselectivity but in moderate yield, as shown in Scheme 18. The Michael addition of methyl 2-phenylpropionate 51 to methyl acrylate afforded the diester 53 by use of another crown ether 52 in good yield with good enantioselectivity.1441 Various chiral crown ethers were studied to... 

Recently, chiral phase-transfer-catalyzed asymmetric Michael addition has received much attention, and excellent enantioselectivity (up to 99% ee) has been reported using cinchona alkaloid-derived chiral phase-transfer catalysts [40]. Among noncinchona alkaloid-derived chiral phase-transfer catalysts Shibasaki s tartrate derived C2-symmetrical two-center catalyst provided a Michael adduct with up to 82% ee [41]. 

LiN(SiMe3)2 to form crixivan intermediate 4 [13]. The reactivity of bases may be dependent on the nature of the alkali metal portion of the base, as seen in the hetero-Michael additions shown in Figure 3.7 [14]. Phase-transfer catalyzed reactions (PTC) are often overlooked [15], and can provide safe, economic, and very productive alternatives to reactions using strong bases (see Figure 2.18). 

The asymmetric Michael addition of active methylene or methyne compounds to electron deficient olefins, particularly a,P-unsaturated carbonyl compounds, represents a fundamental and useful approach to construct functionalized carbon frameworks [51]. The first successful, phase-transfer-catalyzed process was based on the use of well-designed chiral crown ethers 69 and 70 as catalyst. In the presence of 69, P-keto ester 65 was added to methyl vinyl ketone (MVK) in moderate yield but with virtually complete stereochemical control. In much the same way, crown 70 was shown to be effective for the reaction of methyl 2-phenylpropionate 67 with methyl acrylate, affording the Michael adduct 68 in 80% yield and 83% ee (Scheme 11.15) [52]. 

The enantioselective phase-transfer catalyzed Michael addition of A-(diphenyl-methylene)glycine fert-butyl ester to several Michael acceptors such as methyl acrylate, cyclohex-2-enone and ethyl vinyl ketone was initially studied by Corey et al. employing 0(9)-aUyl-Af-9-anlhraceny]melhylcinchonidimum bromide (173) (Fig. 2.24) as catalyst and cesium hydroxide as base [272]. Different studies followed this pioneering woik, presenting diverse modifications over the standard procedure such as the employment of non-ionic bases [273], variations of the nucleophile functionality [274], and using new chiral phase-transfer catalysts, the most attention paid to this latter feature. For instance, catalyst 173 was successfully employed in the enantioselective synthesis of any of the isotopomers of different natural and unnatural amino acids... 

In 2006, Shibasaki and co-workers [91] developed phase-transfer-catalyzed asymmetric Michael addition of glycine Schiff base 237 and dienone 238 to afford dienone 240 in 84% isolated yield and 82% ee for the total synthesis of (+)-cylin-dricine C (242) and a formal synthesis of (—)-lepadiformine (244), using a chiral two center organocatalyst 239 (TaDiAS Tartrate-derived Di-Ammonium Salt) (Scheme 17.41). (+)-cylindricine C (242) was achieved three steps from 240 using... 

Scheme 93 Phase-transfer catalyzed Michael addition in the syntheses of the tricyclic alkaloids (-i-)-cylindricine C (420) and (—)-lepadiformine (421)...

Phase Transfer Catalyzed Michael Addition (Merck Sharp Dohme). A phase transfer (PT) catalyzed Michael addition for the synthesis of an estrogen receptor beta selective antagonist was scaled up to the kilogram scale despite the fact that only moderate ee values were obtained because the ee could easily be upgraded in a later stage. Best results were obtained with alV-(2-naphthylmethyl)-cinchoninium bromide (90). 

We have also recently described the use of a polystyrene resin with pendant sulflnate groups (Ref. 64) in phase transfer catalyzed reactions with various electrophiles. The reactions afford sulfones in excellent yields, often nearly quantitative, even though sulfinates are not reputed to be very good nucleophiles. In contrast, the same reactions without any added phase transfer catalyst give only very low conversions. The sulfinate resins have also been used extensively in a number of Michael additions and have proved to be excellent for use as regenerable separation media in the removal of allergenic substances from some plant extracts used in the perfume and cosmetics Industry (Ref. 61, 62). 

The field of organocatalyzed Michael addition has rapidly evolved to reach its maturity as exemplified by the number of applications of the most classic reactions in total synthesis. It is not surprising that the methodologies first developed with enantioselectivities in a practical range and with broad scope were the first ones widely accepted and used by the synthetic community. The best examples are the addition of aldehydes to methyl vinyl ketone, iminium nucleophilic carbon addition to enals, or phase-transfer-catalyzed addition to vinyl ketones. 

Maruoka and coworkers [65] also reported the total synthesis of (+) mono-morine (127) using a phase-transfer-catalyzed conjugate addition of glycine ester 128 to Michael acceptor 129 as an early key step in the synthesis sequence. Monomorine (127) is a bicyclic amine, known to be the trail pheromone of Monomorium pharanois [66]. The conjugate addition product 131 was subjected to an intramolecular reductive amination and acetal hydrolysis in one pot reaction with Hantzsch ester 132 and trifluoroacetic acid in aqueous... 

With respect to the application of tartaric acid-derived PTCs [22,23] for natural product synthesis, the work of Shibasaki s group should be highlighted herein. Using his powerful bidentate TaDiAS PTCs, asymmetric phase-transfer-catalyzed alkylations, Michael addition reactions, and Mannich-type reactions have been systematically carried out. 

Whilst simple alkylations of enolates and Michael additions have been successfully catalyzed by phase-transfer catalysts, aldol-type processes have proved more problematic. This difficulty is due largely o the reversible nature of the aldol reaction, resulting in the formation of a thermodynamically more stable aldol product rather than the kinetically favored product. However, by trapping the initial aldol product as soon as it is formed, asymmetric aldol-type reactions can be carried out under phase-transfer catalysis. This is the basis of the Darzens condensation (Scheme 8.2), in which the phase-transfer catalyst first induces the deprotonation of an a-halo... 

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],... 

The asymmetric addition of glycine enolates to acrylates was also achieved by use of the tartaric acid-derived phase-transfer catalysts 27 and 28 (Scheme 4.9). Arai, Nishida and Tsuji [13] showed that the C2-symmetric ammonium cations 27a,b afford up to 77% ee when t-butyl acrylate is used as acceptor. The cations 28 are the most effective/selective PTC identified by broad variation of the substituents present on both the acetal moiety and nitrogen atoms [14], In this study by Shibasaki et al. enantiomeric excesses up to 82% were achieved by use of the catalyst 28a (Scheme 4.9) [14], Scheme 4.9 also shows the structure of the guanidine 29 prepared by Ma and Cheng in the absence of additional base this also catalyzes the Michael addition of the glycine derivative 22 to ethyl acrylate, albeit with modest ee of 30% [15],... 

Catalytic Michael additions of a-nitroesters 38 catalyzed by a BINOL (2,2 -dihydroxy-l,r-bi-naphthyl) complex were found to yield the addition products 39 as precursors for a-alkylated amino acids in good yields and with respectable enantioselectivities (8-80%) as shown in Scheme 9 [45]. Asymmetric PTC (phase transfer catalysis) mediated by TADDOL (40) as a chiral catalyst has been used to synthesize enantiomeri-cally enriched a-alkylated amino acids 41 (up to 82 % ee) [46], A similar strategy has been used to access a-amino acids in a stereoselective fashion [47], Using azlactones 42 as nucleophiles in the palladium catalyzed stereoselective allyla-tion addition, compounds 43 were obtained in high yields and almost enantiomerically pure (Scheme 9) [48]. The azlactones 43 can then be converted into the a-alkylated amino acids as shown in Scheme 4. 

The use of thiazolium salts enables the benzoin condensation to proceed at room temperature. It can also be performed in dipolar aptotic solvents or under phase transfer conditions. Thiazolium salts such as vitamin Bi, thiazolium salts attached to y-cyclodextrin, macrobicyclic thiazolium salts, thiazolium carboxylate, ° naphtho[2,l-d]thiazolium and benzothiazolium salts catalyze the benzoin condensation and quaternary salts of 1-methylbenzimidazole and 4-(4-chlorophenyl)-4//-1,2,4-triazole are reported to have similar catalytic activity. Alkylation of 2-hydroxyethyl-4-methyl-l,3-thiazole with benzyl chloride, methyl iodide, ethyl bromide and 2-ethoxyethyl bromide yields useful salts for catalyzing 1,4-addition of aldehydes to activated double bonds. Insoluble polymer-supported thiazolium salts are catalysts for the benzoin condensation and for Michael addition of aldehydes. Electron rich al-kenes such as bis(l,3-dialkylimidazolidin-2-ylidenes) bearing primary alkyl substituents at the nitrogen atoms or bis(thiazolin-2-ylidene) bearing benzyl groups at the nitrogen atoms are examples of a new class of catalyst for the conversion of ArCHO into ArCHOHCOAr. 

Wynberg and co-workers reported the first example of a chiral quaternary ammonium fluoride-catalyzed Michael addition of nitromethane to chalcone [48], Although the enantioselectivity in the initial report was modest, a range of chiral phase-transfer catalysts, in particular based on cinchona alkaloids, were reported. 

Ohtani et al. used polystyrene-supported ammonium fluoride as a phase transfer catalyst (triphase catalysis) for several base-catalyzed reactions, such as cyanoethylation, Knoevenage reaction, Claisen condensation and Michael addition. The catalytic activity of the polystyrene-supported ammonium fluid was comparable to that of tetrabutylammonium fluoride (TBAF). The ionic loading and the ammonium structure of the fluoride polymers hardly affected the catalytic efficiency. The reaction was fast in a non-polar solvent (e.g., octane or toluene) from which the rate-determining step of the base-catalyzed reaction is very similar to that of the nucleophilic substitution reactions. 

As one type of the most important organocatalysts, phase-transfer catalysts found wide application in asymmetric Michael addition reactions [50]. In 1986, Conn et al. [51] reported the asymmetric Michael addition of indanone derivative to methyl vinyl ketone (MVK) catalyzed by their original catalyst 54 (Scheme 5.25). The... 

Unsymmetrical sulfides possessing carbonyl groups beta to sulfur have been prepared by Michael addition of thiols to a,i8-unsaturated aldehydes, ketones, and esters in tetrahydrofuran under phase transfer conditions [17] (see Eq. 13.8). This reaction is catalyzed by fluoride ion. In this application, tetrabutylammonium fluoride (TBAF)... 

---