Enantioselective Carbonyl-Ene Reaction

A full account5 describes the enantioselective carbonyl-ene reaction of... 

Ding22 has performed an enantioselective carbonyl-ene reaction under quasi-solvent-free conditions. For example, 22 g of 24 was produced using 1 ml of toluene and 100 pi of dichloromethane (Equation (13)). A variety of substrates were examined, and high yields and high ee s were reported. 

The idea of enantioselective activation was first reported by Mikami and Matsukawa111 for carbonyl-ene reactions. Using an additional catalytic amount of (R)-BINOL or (/ )-5.5 -dichloro-4,4, 6,fi -tctramcthyl biphenyl as the chiral activator, (R)-ene products were obtained in high ee when a catalyst system consisting of rac-BINOL and Ti(OPri)4 was employed for the enantioselective carbonyl ene reaction of glyoxylate (Scheme 8-54). Amazingly, racemic BINOL can also be used in this system as an activator for the (R)-BINOL-Ti catalyst, affording an enhanced level of enantioselectivity (96% ee). 

A full account5 describes the enantioselective carbonyl-ene reaction of glyoxylate esters catalyzed by a binaphthol-derived chiral titanium complex that is potentially useful for the asymmetric synthesis of a-hydroxy esters of biological and synthetic importance.6 The present procedure is applicable to a variety of 1,1-disubstituted olefins to provide ene products in extremely high enantiomeric purity by the judicious choice of the dichloro or dibromo chiral catalyst (see Table). In certain glyoxylate-ene reactions involving removal of a methyl hydrogen, the dichloro catalyst... 

Mikami reported a highly enantioselective carbonyl-ene reaction where a chiral titanium complex 11 prepared from enantiomerically pure binaphthol (BINOL) and Ti(0-i-Pr)2Br2 catalyzed a glyoxylate-ene reaction with a-methylstyrene to give chiral homoallyl alcohol 12 with 94.6% ee [22]. In this reaction, a remarkable asymmetric amplification was observed and almost the same enantioselectivity (94.4% ee) was achieved by using chiral catalyst prepared... 

Substituted allylsilanes are subject to ene reaction with aldehydes and a,/3-unsaturated carbonyl compounds in the presence of a Lewis acid. The Et2AlCl-promoted reaction of /3-siloxymethyl-substituted allylsilane 27 with aldehydes gives more functionalized allylsilanes (Equation (37)).148 The use of TiCU instead of Et2AlCl leads to the Hosomi-Sakurai allylation. Catalytic enantioselective carbonyl-ene reactions of methallylsilanes have been achieved by using chiral Ti and A1 complexes.149,150... 

Based on their early study in the enantioselective carbonyl-ene reaction [23], Nakai, Mikami, and Terada have found that the asymmetric hetero-Diels-Alder reaction of prochiral glyoxylate with methoxydiene can be catalyzed by the chiral titanium complex, producing the a s-dihydropyran carboxylate as a major product in high enantiomeric purity (Scheme 11) [24]. 

Evans, D.A., Tregey, S.W., Burgey, C.S. er a/. (2000) C2-Symmetric copper(II) complexes as chiral Lewis acids. Catalytic enantioselective carbonyl-ene reactions with glyoxylate and pyruvate esters. Journal of the American Chemical Society, 122, 7936-7943. 

Scheme 7.46 Enantioselective carbonyl-ene reaction using polymeric catalyst 76.

In 1989, Mikami reported a highly enantioselective carbonyl-ene reaction using a Ti-BINOL catalyst (Equation 24) [198]. The ene reaction proceeded smoothly with glyoxylates as highly electrophilic carbonyl substrates and a variety of 1,1-disubstituted olefins such as 327. Optimal enantioselectivlty was obtained with methyl glyoxylate (328). 

In analogy with the enantioselective carbonyl-ene reactions (Chapter 2, Section 2.11), an attractive but much less well precedented alternative to imine allylations is enantioselective imino-ene reactions. The first such example was reported by Lectka, who found that the Tol-BINAP copper complex 216 promoted the addition of unactivated alkenes to N-tosyl imine 110 (Equation 27) [31, 153, 173]. This transformation provided the homoallylic a-amino acid 270 in 90 % yield and 99 % ee. 

Table 5.8 Self-supported Ti(IV) catalysts for enantioselective carbonyl-ene reaction."...

Johnson J. S., Evans D. A. Chiral Bis(Oxazoline) Copper(II) Complexes Versatile Catalysts for Enantioselective Cycloaddition, Aldol, Michael, and Carbonyl Ene Reactions Acc. Chem. Res. 2000 33 325-335... 

The function of the molecular sieves in this case is believed to be as a base that sequesters the protons, which otherwise would promote a variety of side reactions. With chiral catalysts, the carbonyl ene reaction becomes enantioselective. Among the successful catalysts are diisopropoxyTi(IV)BINOL and copper-BOX complexes. 

Chapter 10 considers the role of reactive intermediates—carbocations, carbenes, and radicals—in synthesis. The carbocation reactions covered include the carbonyl-ene reaction, polyolefin cyclization, and carbocation rearrangements. In the carbene section, addition (cyclopropanation) and insertion reactions are emphasized. Recent development of catalysts that provide both selectivity and enantioselectivity are discussed, and both intermolecular and intramolecular (cyclization) addition reactions of radicals are dealt with. The use of atom transfer steps and tandem sequences in synthesis is also illustrated. 

Synthetic activity associated with the carbonyl-ene reaction is extensive. During the past decade, the trend has been to perform these reactions in the presence of a Lewis acid in an enantioselective fashion. Efforts to find a general catalyst that affords homoallylic alcohols in high yields and enantioselectivities are continual. The synthetic utility of this reaction has been validated by its application to the synthesis of a number of natural products (see Section 10.12.6) and many structurally novel motifs that have found a place in drug discovery vide infra). It is the latter application that has resulted in research efforts aimed at large-scale production of carbonyl-ene adducts. 

Jacobsen and co-workers14 have shown that a tridentate Schiff base chromium complex 13 catalyzed an asymmetric carbonyl-ene reaction between a variety of aryl aldehydes (14, Equation (8)) and 2-methoxy propene 15 or 2-trimethylsiloxypropene. The highest yields were afforded when the aryl ring was substituted with an electron-withdrawing group however, the substituent did not seem to affect the enantioselectivity. 

Cationic cobalt(m) complexes have successfully been applied to the asymmetric carbonyl-ene reaction.15 The yield and enantioselectivity were dependent, to a large extent, upon the counterion, with SbF6- giving the best results (16, Equation (9)). The conditions were general for a variety of alkenes, but only glyoxaldehydes were used as the carbonyl component. 

Mikami and co-workers16-19 have done extensive work for developing catalysts for the asymmetric carbonyl-ene reaction. Excellent enantioselectivites are accessible with the binol-titanium catalyst 17 (Equation (10)) for the condensation of 2-methyl butadiene (R1 = vinyl) and glyoxalates (binol = l,T-binaphthalene-2,2 -diol).16 The products were further manipulated toward the total synthesis of (i )-(-)-ipsdienol. The oxo-titanium species 18 also provides excellent enantioselectivity in the coupling of a-methyl styrene with methyl glyoxalate.17 Reasonable yields and good enantioselectivites are also obtained when the catalyst 19 is formed in situ from titanium isopropoxide and the binol and biphenol derivatives.18... 

A number of insoluble or immobilized catalysts have been developed and applied to the carbonyl-ene reaction. As is evidenced by the entries below, the enantioselectivities are variable. Sasai23 has utilized a titanium-bridged polymer to effect an enantioselective carbonyl-ene (Equation (14)). A single substrate was examined, and the polymer could be reused up to five times without loss of enantioselectivity in the ene reaction. 

Chiral bisoxazolines (box) ligands have been attached to a polyethylene glycol (PEG) matrix 25.24 The supported ligands were tested on a variety of reactions for their enantioselectivity. The carbonyl-ene reaction between a-methyl styrene or methylene cyclohexane (26, Equation (15)) and ethylglyoxalate 12 afforded the corresponding ene adduct 27 in 96% and 91% yield and 95% and 85% ee, respectively. 

An extensive study was undertaken to optimize the carbonyl-ene reaction between benzaldehyde (143, Scheme 30) and 3-methylene-2,3-dihydrofuran 144, which was utilized in the enantioselective synthesis of fluoxetine hydrochloride, a selective seratonin reuptake inhibitor.89 The degree of hydration of the molecular sieves proved important in the stereoselectivity of the reaction, with lower enantioselectivities reported both with highly active... 

The self-assembly of a chiral Ti catalyst can be achieved by using the achiral precursor Ti(OPr )4 and two different chiral diol components, (R)-BINOL and (R,R)-TADDOL, in a molar ratio of 1 1 1. The components of less basic (R)-BINOL and the relatively more basic (R,R)-TADDOL assemble with Ti(OPr )4 in a molar ratio of 1 1 1, yielding chiral titanium catalyst 118 in the reaction system. In the asymmetric catalysis of the carbonyl-ene reaction, 118 is not only the most enantioselective catalyst but also the most stable and the exclusively formed species in the reaction system. 

Reactions where NLE have been discovered include Sharpless asymmetric epoxi-dation of allylic alcohols, enantioselective oxidation of sulfides to sulfoxides, Diels-Alder and hetero-Diels-Alder reactions, carbonyl-ene reactions, addition of MesSiCN or organometallics on aldehydes, conjugated additions of organometal-lics on enones, enantioselective hydrogenations, copolymerization, and the Henry reaction. Because of the diversity of the reactions, it is more convenient to classify the examples according to the types of catalyst involved. 

The Ti(0 Pr)2Cl2/D-DIPT poison has also been used for the Ti(0 Pr)2Cl2/ BINOL-catalyzed asymmetric carbonyl-ene reaction with chloral (Scheme 8.8). With the Ti(0 Pr)4/D-DIPT poison in a 1 3 ratio, both the regioselectivity and the enantioselectivity of the ene product are improved. 

The role of multicomponent ligand assembly into a highly enantioselective catalyst is shown in the enantioselective catalysis for the carbonyl-ene reaction (Table 8.9). The catalyst is prepared from an achiral precatalyst, Ti(0 Pr)4 and a combination of BINOL with various chiral diols such as TADDOL and 5-Cl-BIPOL in a molar ratio of 1 1 1 (10mol% with respect to the olefin and glyoxylate) in... 

The enantiopure BIPHEP-Pt complexes can act as chiral Lewis acids for the enantioselective Diels-Alder and carbonyl-ene reactions. The Diels-Alder products are obtained in 92-94% ee (93 7 = endo exo) and 92-94% ee (94 6 = endo exo) by (R)- and (5)-36, respectively (Scheme 8.3 la)." In the carbonyl-ene reaction catalyzed by the dication species generated from BlPHEP-PtCL 35 and AgSbFs, the (S )- and (/ )-ene products are obtained with 71% ee (99% conversion at room temperature) and 70% ee (90% conversion at room temperature) from (/ )- and (S)-35, respectively (Scheme 8.31b). 

An asymmetric intermolecular carbonyl-ene reaction catalyzed by 1 mol% of chiral A-triflyl phosphoramide (/ )-4t (1 mol%, R = 4-MeO-CgH ) was developed by Rueping and coworkers (Scheme 69) [88], Various a-methyl styrene derivatives 163 underwent the desired reaction with ethyl a,a,a-trifluoropyruvate 164 to afford the corresponding a-hydroxy-a-trifluoromethyl esters 165 in good yields along with high enantioselectivities (55-96%, 92-97% ee). The presence of the trifluoromethyl group was crucial and the use of methyl pyruvate or glyoxylate instead of 164 resulted in lower reactivities or selectivities. 

K., Matsukawa, S., Volk, T, and Terada, M. (1998) Self-assembly of several components into a highly enantioselective Ti catalyst for carbonyl-ene reactions. Angew. Chem., Int. Ed., 36, 2768-2771. 

A useful synthetic alternative to the Mukaiyama aldol addition is the carbonyl-ene reaction [17], This reaction of an aldehyde 51 with an enol ether 55, bearing at least one hydrogen atom in the allylic position, under Lewis-acid catalysis, yields a ff-hydroxy-enol ether of type 56 (Scheme 10). By use of a chiral Lewis acid (L ) enantioselectivity can be achieved. For the... 

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