The Carbonyl ene Reaction

The carbonyl-ene reaction is also very useful, and often gives synthetically... 

The best carbonyl components for these reactions are highly electrophilic compounds such as glyocylate, pyruvate, and oxomalonate esters, as well as chlorinated and fluorinated aldehydes. Most synthetic applications of the carbonyl-ene reaction utilize Lewis acids. Although such reactions may be stepwise in character, the stereochemical outcome is often consistent with a cyclic TS. It was found, for example, that steric effects of trimethylsilyl groups provide a strong stereochemical influence.28... 

Visual models, additional information and exercises on the Carbonyl-Ene Reaction can be found in the Digital Resource available at Springer.com/carey-sundberg. 

The use of Lewis acid catalysts greatly expands the synthetic utility of the carbonyl-ene reaction. Aromatic aldehydes and acrolein undergo the ene reaction with activated alkenes such as enol ethers in the presence of Yb(fod)3.35 Sc(03SCF3)3 has also been used to catalyze carbonyl-ene reactions.36... 

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. 

Fig. 10.2. Structures of complexed aldehyde reagent (a) and transition structure (b) for enantios-elective catalysis of the carbonyl-ene reaction by BINOL-Ti(IV). Reproduced from Tetrahedron Lett., 38, 6513 (1997), by permission of Elsevier.

Pinacol Rearrangement in Tandem with the Carbonyl-Ene Reaction. Overman and co-workers have developed protocols in which pinacol rearrangement... 

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. 

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

The alkene 1-decene (24) was poorly reactive in the carbonyl-ene reaction with ethyl mesoxalate and required a temperature up to 170 °C for a very long time (5 h) [42]. When performed in a homogeneous liquid medium at the same temperature but under the action of MW irradiation the reaction gave a similar result. Reaction time was appreciably shortened by use of GS/MW coupling [30]. Thus, irradiation at 60 W for only 10 min led to the ene adduct 25 in 50% yield (Scheme 7.2). Under these conditions a maximum temperature of 230 °C was measured. To obtain the same yield with conventional heating at 170 °C reaction for 1 h is required. The stereoselectivity of the reaction was not related to the mode of heating. A higher con-... 

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. 

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. 

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). 

The class of ene reactions which involves a carbonyl compound as the enophile and what we refer to as the carbonyl-ene reaction [2c], constitutes a useful synthetic method for the stereocontrolled construction of carbon skeleton using either a stoichiometric or catalytic amount of various Lewis acids [3,4] (Scheme 8C.1). From the synthetic point of view, the carbonyl-ene reaction should—in principle—constitute a more-efficient alternative to the allylmetal carbonyl addition reaction, which has currently been one of the most useful methods for stereocontrol [5],... 

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... 

Scheme 10. The carbonyl-ene-reaction a synthetic alternative to the Mukaiyama aldol reaction.

Besides the Mukaiyama aldol and the carbonyl-ene reactions another successful application of asymmetric catalysis is the nitro-aldol reaction... 

Carbonyl-Ene Reaction. BINOL-TiX2 reagent exhibits a remarkable level of asymmetric catalysis in the carbonyl-ene reaction of prochiral glyoxylates, thereby providing practical access to a-hydroxy esters. These reactions exhibit a remarkable positive nonlinear effect (asymmetric amplification) that is of practical and mechanistic importance (eq 19). The desymmetrization of prochiral ene substrates with planar symmetry by the enantiofacial selective carbonyl-ene reaction provides an efficient solution to remote internal asymmetric induction (eq 20). The kinetic resolution of a racemic allylic ether by the glyoxylate-ene reaction also provides efficient access to remote but relative asymmetric induction (eq 21). Both the dibromide and dichloride catalysts provide the (2R,5S)-syn product with 97% diastereoselectivity and >95% ee. 

FeCl3 mediates the carbonyl-ene reaction of a 5-(2-propenyl)-imidazolidinone with butyl glyoxylate to give the ene product without the subsequent rearrangements observed when SnCl4 is used in this reaction (Sch. 63) [210]. 

FeCls mediates the carbonyl-ene reaction between methyl glyoxylate and simple alkenes [213]. 

Ene reactions are promoted by titanium compounds as Lewis acids [405-409]. The carbonyl ene reaction of methylenedihydrofuran with aldehyde (Eq. 161) [410] and intramolecular reaction of an unsaturated aldehyde (Eq. 162) [411] are illustrated below. The cyclization of a conjugated ketone in the presence of a mixture of TiCU and Ti(0-/-Pr)4, as shown in Eq. (163), cleanly afforded the bicyclic ketone this might be considered as the product of a vinylogous ene reaction [412]. 

In our research on the asymmetric catalysis of the carbonyl-ene reaction, we found that the BINOL-Ti complexes (1) [30], prepared in situ, in the presence of 4-A molecular sieves, from diisopropoxytitanium dihalides (X2Ti(OPr )2 X = Br [31] or Cl [32]) and optically pure BiSfOL (vide infra), catalyze [33], rather than promote stoichiome-trically, the carbonyl addition reaction of allylic silanes and stannanes [34]. The addition to glyoxylate of ( )-2-butenylsilane and -stannane proceed smoothly to afford the syn product in high enantiomeric excess (Sch. 5). The s yn-product thus obtained could be readily converted to the iaetone portion of verrucaline A [35]. 

The class of ene reactions with carbonyl compounds as the enophile, which we denote the carbonyl-ene reaction [45], is an efficient alternative to the carbonyl addition reaction of allylic metals (Sch. 11). 

BINOL-Ti catalysis can also be used for the carbonyl-ene reaction with formaldehyde or vinyl and alkynyl analogs of glyoxylates in an asymmetric catalytic desymme-trization (vide infra) approach to the asymmetric synthesis of isocarbacycline analogs (Sch. 16) [61]. 

Achmatowicz, O., Bialecka-Florjanczyk, E. Mechanism of the carbonyl-ene reaction. Tetrahedron 1996, 52, 8827-8834. 

As described in the sections above, it is well established that reactions of Lewis acid-activated aldehydes and ketones with silyl enolates afford -hydroxy or /7-sil-oxy carbonyl compounds (Mukaiyama aldol reactions). Occasionally, however, ene-type adducts, that is /-siloxy homoallyl alcohols, are the main products. The first example of the carbonyl-ene reaction of silyl enolates was reported by Snider et al. in 1983 [176]. They found that the formaldehyde-MesAl complex reacted smoothly with ketone TMS enolates to give y-trimethylsiloxy homoallyl alcohols in good yield. Yamamoto et al. reported a similar reaction of formaldehyde complexed with methylaluminum bis(2,6-diphenylphenoxide) [177]. After these early reports, Kuwajima et al. have demonstrated that the aluminum Lewis acid-promoted system is valuable for the ene reactions of several aldehydes [178] and for-maldimine [179] with silyl enolates bearing a bulky silyl group. A stepwise mechanism including nucleophihc addition via an acyclic transition structure has been proposed for the Lewis acid-promoted ene reactions. 

Bids and Bi(OTf)3 catalyze the carbonyl-ene reaction [181] and Diels-Alder reaction [182] without diene polymerization (Scheme 14.89). The tandem [4-+2] cycloaddition reaction (Scheme 14.90) [183] and the Erlenmeyer synthesis of azalactones (Scheme 14.91) [184] are catalyzed by BiCl3 and by Bi(OAc)3, respectively. 

A bimetallic titanium complex of BINOL derivative can be used to catalyze the asymmetric carbonyl-ene reaction [46]. Insoluble polymeric catalyst 74 was prepared from a self-assembly of Ti(OiPr)4 and non-crosshnked copolymers with (R)-binaphthol pendant groups (Scheme 3.22) [47]. The self-assembled polymeric Ti complex is insoluble in organic solvent and catalyzed the carbonyl-ene reaction of glyoxylate 75 and a-methylstyrene 76. When the reaction of 75 and 76 was carried out with 20mol% of 74 in Gl pCf at room temperature, an 85% yield of the product with 88% ee was obtained. Following its recovery by filtration, this catalyst was reused five times with full retenhon of its activity and enantioselectivity, without further treatment... 

The first step 202 is now a pericyclic reaction. It looks like a cycloaddition, though it involves a hydrogen transfer as well. It is in fact a carbonyl (or oxo- ) ene reaction. It is like a Diels-Alder cycloaddition in which a C-H bond has replaced one of the double bonds in the diene and a C=0 group is the dienophile. Many Prins reactions are probably carbonyl ene reactions. In his excellent review30 in Comprehensive Organic Synthesis, B. J. Snider says The (carbonyl) ene reaction and the Prins reaction are not mechanistically distinct . Though this step is pericyclic, it is very polar and the transition state 203 no doubt contains partial charges. It is therefore stabilised and the reaction accelerated by protic acids 205 and Lewis acids 207. 

The carbonyl ene reaction is between a similarly reactive aldehyde and an alkene rather than aketene. Glyoxalate esters and chloral are typical of the carbonyl compounds involved. Asymmetric versions rely on Lewis acid catalysts similar to those used in Diels-Alder reactions based on Ti and A1 among other metals.43 A simple example is the formation of 190 from methyl glyoxalate and an alkene 189 catalysed by 0.5mol% of a BINOL-Ti complex 191. Other alkenes that react well are 192 -195. 

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