Mukaiyama aldol reaction pathway

Danshefsky s diene [19] is the 1,3-butadiene with amethoxy group at the 1-position and a trimethylsiloxy group at the 3-position (Scheme 18). This diene and Lewis acids extended the scope of hetereo-Diels-Alder reactions with aldehydes [20], This diene reacts with virtually any aldehyde in the presence of Lewis acids whereas dienes usually react with only selected aldehydes bearing strongly electron accepting a-substituents. There are two (Diels-Alder and Mukaiyama aldol) reaction pathways (Scheme 18) identified for the Lewis acids catalyzed reactions of Danishefsky diene with aldehydes [21, 22]. The two pathways suggest that these reactions occur on the boundary between the delocahzation band (the pericyclic... 

There are two different modes of cyclizations in hetero [4+2] cycloadditions involving Danishefsky s diene 1) concerted (pericyclic) and 2) stepwise. When carbonyl compounds are reacted with Danishefsky s diene, the stepwise pathway is often referred to as the Mukaiyama aldol reaction pathway. The concerted process is called the Diels-Alder pathway. The mode of cyclization in the case of Lewis acid catalyzed reactions depends on the Lewis acid itself and whether it is present in stoichiometric or catalytic amounts. The Mukaiyama aldol pathway has been... 

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

As can be seen from Fig. 19, the activation energy of the reaction in the presence of the 1-naphthyl substituted TADDOL catalyst was reduced by 10.2 kcal mol, in comparison with the uncatalyzed reaction (20.2 kcal moF ). The reaction proceeds via a concerted but asynchronous pathway, and no zwitterionic intermediate or transition state corresponding to a stepwise Mukaiyama-aldol type pathway could be located. 

The Lewis acid-mediated reactions of 2-aza-l,3-dienes and aldehydes, resulting in tetrahydro-l,3-oxazin-4-one derivatives, were explained in terms of the competitive existence of two reaction pathways a [4+2] hetero-Diels-Alder cycloaddition reaction and a Mukaiyama aldol reaction <2001TA439>. 

It appears likely that the reaction proceeds through the ene reaction pathway, although such an ene reaction pathway has not been previously recognized as a possible mechanism in the Mukaiyama aldol reaction. In general, an acyclic antiperiplanar transition-state model has been used to explain the formation of the syn-diastereomer from either ( )- or (Z)-silyl enol ethers [58]. However, the cyclic ene mechanism now provides another rationale for the. vyra-diastereose-lection regardless of the enol silyl ether geometiy (Figure 8C.7). 

Ab initio calculations indicate that a model uncatalysed Mukaiyama aldol reaction - that of formaldehyde and trihydrosilylenol ether - proceeds via a concerted pathway involving a twist-boat six-membered transition state.138 A wide range of substituents on both reactants have been explored, and some combinations give rise to particularly low barriers, hopefully identifying cases that should work below room temperature. 

The influence of substituents on the energetics of the uncatalyzed Mukaiyama aldol reaction was studied using ab initio molecular orbital calculations at the G3(MP2) level <2005JOC124>. For the reaction between formaldehyde and trihydrosilyl enol ether, a concerted pathway via a six-membered transition state was favored over a stepwise pathway and an oxetane intermediate. 

The second major class of non-umpolung nucleophilic carbene catalysis comprises reactions by initial NHC-activation of various silicon compounds. Their proposed common pathway is thought to lead to a hypervalent silicon complex4 and thus provide carbene-catalyzed activation of the corresponding nucleophiles such as TMSCN, TMSCF3 etc. (Kano et al. 2006 Song et al. 2005 2006). It is not only certain carbon-silicon bonds that can be effectively activated, but a comparable activation of Si-O bonds, e.g. of trimethylsily enol ethers etc., allows for mild, NHC-promoted Mukaiyama aldol reactions (Scheme 6 Song et al. 2007). 

Mukaiyama aldol reaction Good yields of adducts are obtained in the Zr-catalyzed process. However, due to operation of two possible competing reaction pathways, low diastereoselectivities are generally observed. 

Mukaiyama aldol reactions using a catalytic amount of a Lewis acidic metal salt afford silylated aldols (silyl ethers) as major products, but not free aldols (alcohols). Three mechanistic pathways which account for the formation of the silylated aldols are illustrated in Scheme 10.14. In a metal-catalyzed process the Lewis acidic metal catalyst is regenerated on silylation of the metal aldolate by intramolecular or intermolecular silicon transfer (paths a and b, respectively). If aldolate silylation is slow, a silicon-catalyzed process (path c) might effectively compete with the metal-catalyzed process. Carreira and Bosnich have concluded that some metal triflates serve as precursors of silyl triflates, which promote the aldol reaction as the actual catalysts, as shown in path c [46, 47]. Three similar pathways are possible in the triarylcarbenium ion-catalyzed reaction. According to Denmark et al. triarylcarbenium ions are the actual catalysts (path b) [48], whereas Bosnich has insisted that hydrolysis of the salts by a trace amount of water generates the silicon-based Lewis acids working as the actual catalysts (path c) [47]. Otera et al. have reported that 10-methylacridinium perchlorate is an efficient catalyst of the aldol reaction of ketene triethylsilyl acetals [49]. In this reaction, the perchlorate reacts smoothly with the acetals to produce the actual catalyst, triethylsilyl perchlorate. 

The ZnCh reaction seems to pass through a pericylic mechanistic pathway while the BF3-OEt2-cata-lyzed reaction resembles a Mukaiyama aldol reaction. Danishefsky described the process in which an activated diene is condensed with an aldehyde as a cyclocondensation reaction, thus avoiding the implication of a concerted reaction pathway in cases where aldol products are unambiguously isolated (Scheme 2). 

Mechanistically, the cycloaddition reaction is rather complex. Depending on the catalyst or solvent used and the reaction substrates, pericyclic and/or Mukaiyama aldol-like pathways may be involved.43 The pericyclic mechanism, generally favored by zinc chloride and the lanthanide catalysts, tends to produce adducts having the cis relative stereochemistry at C-5,6. It is assumed that chelation of the aldehyde with the Lewis acid occurs in an anti fashion and that the steric bulk of R is less than that of the Lewis acid-solvent complex L [Eq. (11)], thus favoring a Diels-Alder transition state with R endo. 

Hetero-Diels-Alder reaction/ Dihydropyran synthesis, in the manner reported by Danishefsky, from monoactivated dienes and aldehydes is best catalyzed by BF -OEtj. The Mukaiyama aldol condensation pathway does not operate in such cases. 

The major developments of catalytic enantioselective cycloaddition reactions of carbonyl compounds with conjugated dienes have been presented. A variety of chiral catalysts is available for the different types of carbonyl compound. For unactivated aldehydes chiral catalysts such as BINOL-aluminum(III), BINOL-tita-nium(IV), acyloxylborane(III), and tridentate Schiff base chromium(III) complexes can catalyze highly diastereo- and enantioselective cycloaddition reactions. The mechanism of these reactions can be a stepwise pathway via a Mukaiyama aldol intermediate or a concerted mechanism. For a-dicarbonyl compounds, which can coordinate to the chiral catalyst in a bidentate fashion, the chiral BOX-copper(II)... 

The silatropic ene pathway, that is, direct silyl transfer from an silyl enol ether to an aldehyde, may be involved as a possible mechanism in the Mukaiyama aldol-type reaction. Indeed, ab initio calculations show that the silatropic ene pathway involving the cyclic (boat and chair) transition states for the BH3-promoted aldol reaction of the trihydrosilyl enol ether derived from acetaldehyde with formaldehyde is favored [60], Recently, we have reported the possible intervention of a silatropic ene pathway in the catalytic asymmetric aldol-type reaction of silyl enol ethers of thioesters [61 ]. Chlorine- and amine-containing products thus obtained are useful intermediates for the synthesis of carnitine and GABOB (Scheme 8C.26) [62],... 

A f/ireo-selective siloxonium (aldol-like) pathway II was favored when BF3 OEt2 was used as catalyst (Sch. 3) [11]. The reaction of benzaldehyde by quenching after 5 min resulted in 48 % yield of the final cyclic products 3 (1 8 cisitrans ratio) and 46 % yield of the Mukaiyama-like aldol products 5 (1 2 threolerythro ratio). When either threo or erythro adduct was re-subjected to trifluoroacetic acid media, each underwent conversion to the corresponding y-pyrones 3. 

Mujica, M. T., Afonso, M. M., Galindo, A., Palenzuela, J. A. Hetero Diels-Alder vs Mukaiyama aldol pathways in the reaction of monoactivated dienes and aldehydes. A Lewis acid study. Tetrahedron 1996, 52, 2167-2176. 

Roberson, M., Jepsen, A. S., Jorgensen, K. A. On the mechanism of catalytic enantioselective hetero-Diels-Alder reactions of carbonyl compounds catalyzed by chiral aluminum complexes-a concerted, step-wise or Mukaiyama-aldol pathway. Tetrahedron 2001, 57, 907-913. Monnat, F., Vogel, P., Rayon, V. M., Sordo, J. A. Ab Initio and Experimental Studies on the Hetero-Diels-Alder and Cheletropic Additions of Sulfur Dioxide to (E)-I-Methoxybutadiene A Mechanism Involving Three Molecules of S02. J. Org. Chem. 2002, 67, 1882-1889. 

Recent developments in the field have also identified novel mechanistic pathways for the development of catalytic, asymmetric aldol processes. Thus in addition to Lewis acid catalysts that mediate the Mukaiyama aldol addition by electrophilic activation of the aldehyde reactant, metal complexes that lead to enolate activation by the formation of a metalloenolate have been documented. Additionally, a new class of Lewis-base-catalyzed addition reactions is now available for the asymmetric aldol addition reaction. 

Shortly after the discovery of the Lewis acid-mediated Mukaiyama aldol addition reaction of enol silanes the general mechanistic aspects of the reaction were intensely investigated [30a, 30b, 30c, 30d]. These processes are considered to proceed by electrophilic activation of the aldehyde towards addition by the nucleophilic enol silane. However, aldol addition processes that proceed by alternative mechanistic pathways have been documented and studied. It is worth considering those systems that have been developed for catalytic, enantioselec-tive aldehyde addition reactions through metaiioenoiate intermediates. 

It appears likely that the reaction proceeds through an ene reaction pathway. Such an ene reaction pathway has not been previously recognized as a possible mechanism in the Mukaiyama aldol condensation. Usually, an acyclic antiperi-... 

Mikami reported that BINOL derived titanium complex efficiently catalyzed the aldol reaction of silyl enol ether with excellent control of both absolute and relative stereochemistry [106] (Scheme 14.37). The reaction was proposed to proceed via a prototropic ene reaction pathway that is different from that of Mukaiyama aldol condensation. A cyclic antiperiplanar transition-state model was proposed to explain the pref erential formation of the syn diastereomer from either (E)- or (Z)-silyl enol ethers [106]. Further modifications of the catalyst system include the use of perfluorophenols and other activating additives [107], or performing the reaction in supercritical fluids [108]. Furthermore, the nucleophile could be extended to enoxysilacyclobutane derivatives [109]. 

Another mechanistic interpretation of the Mukaiyama aldol invokes an ene reaction pathway accounting for bond formation. Following complexation, the ene reaction occurs via the organized chair-like transition state 16, providing the syn-stereochemistry observed in the adduct 17. Steric interactions between the methyl group and the glyoxylate ester result in the... 

The low-temperature NMR experiment implied that the catalytic reaction proceeded via the concerned [4-f2] cycloaddition pathway rather than the stepwise (Mukaiyama-aldol) mechanism. Furthermore, the phebox-Rh-catalyzed reaction proceeds via the cn fo-transition state on the basis of the c -selectivity of 11 in the reaction of 2,4-dimethyl diene with n-butyl glyoxylate (Scheme 5). The absolute configurations of the dihydropyrans proved to be 2R, indicating that the Re face attack of the diene to the C=0 group is a favorable pathway. 

Fig. 1.2 The Mukaiyama-aldol and the Diels-Alder pathway in HDA reactions...

Roberson M, Jepsen AS, J0rgensen KA (2001) On the mechanism of catalytic enantioselective hetero-Diels-Alder reactions of carbonyl compounds catalyzed by chiral aluminum complexes—a concerted, step-wise or Mukaiyama-aldol pathway. Tetrahedrrai 57 907—913... 

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