Mukaiyama aldol additions

The key step in the synthesis of A-ring fragment 50 [56] is the chelation-controlled addition of allylstannane 53 to aldehyde 52, which sets the C7 stereocenter and introduces the C8 gem-dimethyl moiety. Aldehyde 52 is itself prepared from 1,3-propanediol using the author s protocol for titanium-catalyzed enantioselective allylstannation [57], which sets the C5 stereocenter, followed by chelation-controlled Mukaiyama aldol addition [58] to establish the C3 stereocenter (Scheme 5.6). 

Ligands for catalytic Mukaiyama aldol addition have primarily included bidentate chelates derived from optically active diols,26 diamines,27 amino acid derivatives,28 and tartrates.29 Enantioselective reactions induced by chiral Ti(IY) complex have proved to be one of the most powerful stereoselective transformations for synthetic chemists. The catalytic asymmetric aldol reaction introduced by Mukaiyama is discussed in Section 3.4.1. 

Fig. 13). The cross-linked scandium-modified dendrimer was tested in a number of Lewis acid-catalyzed reactions, including Mukaiyama aldol additions to aldehydes and aldimines, Diels-Alder reactions, and Friedel-Crafts acylations. The dendritic catalyst was recovered by a simple filtration. The Mukaiyama aldol... 

In the Mukaiyama aldol additions of trimethyl-(l-phenyl-propenyloxy)-silane to give benzaldehyde and cinnamaldehyde catalyzed by 7 mol% supported scandium catalyst, a 1 1 mixture of diastereomers was obtained. Again, the dendritic catalyst could be recycled easily without any loss in performance. The scandium cross-linked dendritic material appeared to be an efficient catalyst for the Diels-Alder reaction between methyl vinyl ketone and cyclopentadiene. The Diels-Alder adduct was formed in dichloromethane at 0°C in 79% yield with an endo/exo ratio of 85 15. The material was also used as a Friedel-Crafts acylation catalyst (contain-ing7mol% scandium) for the formation of / -methoxyacetophenone (in a 73% yield) from anisole, acetic acid anhydride, and lithium perchlorate at 50°C in nitromethane. 

Auto-tandem hydroformylation-cyclization, catalyzed by [RhCl(cod)]2, enables expansion of the organic skeleton of unsaturated silyl enol ethers (Scheme 10). Linear aldehydes generated in the hydroformylation step subsequently undergo Rh-catalyzed, intramolecular Mukaiyama aldol addition. Bicyclic ketones are also accessible from cyclic silyl enol ethers. 

An important reaction of silylenol ethers is their use as enolate equivalent in Mukaiyama aldol additions. An example of the synthetic utility of this reaction with a magnesium enolate as starting reagent is shown below. 

Cu PS-macro bis-oxazoline asymmetric (Mukaiyama) aldol addition [98]... 

Oxamborolidenes. There are noteworthy advances in the design, synthesis, and study of amino acid-derived oxazaborolidene complexes as catalysts for the Mukaiyama aldol addition. Corey has documented the use of complex 1 prepared from A-tosyl (S)-tryptophan in enantioselective Mukaiyama aldol addition reactions [5]. The addition of aryl or alkyl methyl ketones 2a-b proceeded with aromatic as well as aliphatic aldehydes, giving adducts in 56-100% yields and up to 93% ee (Scheme 8B2.1, Table 8B2.1). The use of 1-trimethylsilyloxycyclopentene 3 as well as dienolsilane 4 has been examined. Thus, for example, the cyclopentanone adduct with benzaldehyde 5 (R = Ph) was isolated as a 94 6 mixture of diastereomers favoring the syn diastereomer, which was formed with 92% ee, Dienolate adducts 6 were isolated with up to 82% ee it is important that these were shown to afford the corresponding dihydropyrones upon treatment with trifuoroacetic acid. Thus this process not only allows access to aldol addition adducts, but also the products of hetero Diels-Alder cycloaddition reactions. 

Catalysis with Bisoxazoline Complexes of Sn(II) and Cu(II). The bisoxazoline Cu(IT) and Sn(II) complexes 81-85 that have proven successful in the acetate additions with aldehydes 86,87, 88 also function as catalysts for the corresponding asymmetric propionate Mukaiyama aldol addition reactions (Scheme 8B2.8) [27]. It is worth noting that eithersyn or anti simple diastereoselectivity may be obtained by appropriate selection of either Sn(II) or Cu(II) complexes (Table 8B2.12). 

Significant efforts have extended the scope of catalytic enantioselective Mukaiyama aldol addition reactions beyond the acetate and propionate enoxysilanes and have been used traditionally. Recent reports describe novel addition reactions of silyl dienolates along with isobutyrate-derived enol silanes. 

As shown in Scheme 8, the synthesis of aldehyde 45 was achieved in eight steps utilizing the common precursor 31 [46-48], Remarkably, the Mukaiyama aldol addition of silyl enol ether 46 to aldehyde 47 proceeded with anti-Felkin selectivity, which was attributed to involvement of the Weinreb amide and aldehyde carbonyl... 

Figure 9.32 adds the information of how enol ethers are normally produced, i.e., enol ethers with no conjugation between the C=C- and the neighboring C=0 double bond 0,0-Acetals are subjected to an acid-catalyzed elimination of one equivalent of alcohol, via an El mechanism, that is, via an oxocarbenium ion intermediate that is deprotonated to give the respective enol ether (i.e., the product presented in the first line of Figure 9.32) or dienol ether (the product shown in the second line of Figure 9.32). Among other things, enol ethers are required for the Mukaiyama aldol addition (example Figure 12.23).

Following the mechanism given in Figure 12.23, the addition of an acetal to a simple enol ether (in contrast to the dienol ether B shown above) leads to a /3-alkoxy acetal. This reaction is known as the Mukaiyama aldol addition. If this is followed by a hydrolysis (of the... 

Fig. 12.23. A Mukaiyama aldol addition (-> C) and its reaction mechanism (bottom row). As shown here, this method can be exploited to obtain the poly-unsaturated aldehyde D. Under the conditions of the first reaction step the primary product C—which, like the substrate A, is an acetal—does not compete with A for still unconsumed enol ether B. This is due to the fact that the methoxy substituent in the oxocarbenium ion G, which would have to be regenerated from Cin order to undergo further reaction with B, destabilizes G because of its electron-withdrawing inductive (-1) effect.

Modem variants of the Mukaiyama aldol addition start from silyl enol ethers, not from enol ethers, and use an aldehyde instead of the acetal as the electrophile. Mukaiyama aldol additions of this kind have been included in the C,C coupling reactions that build the basic repertoire of modem synthetic chemistry and can even be performed in a catalytic enantioselective fashion. 

A highly yvn-diastereoselective and enantioselective vinylogous Mukaiyama aldol addition of trimethylsilyloxyfurans to aldehydes was achieved by using a cinchonidine-... 

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 12) [20a]. Shibasaki et al. [20b] used a chiral in situ generated lanthanide complex (64) as catalyst. The optically active lanthanide complex 66 is postulated as the basic intermediate, activating the nitromethane as shown in 67. However, in the case of the Mukaiyama aldol addition, lanthanide Lewis acids still give moderate ee values. 

Recently, the rapid preparation of carbohydrates has been facilitated by a synthetic route based on aldol coupling of three aldehydes used for the de novo production of polyol differentiated hexoses in only two chemical steps. The dimerization of alpha-oxyaldehydes, catalyzed by L-proline, is followed by a tandem Mukaiyama aldol addition-cyclization step catalyzed by a Lewis acid. Differentially protected glucose, allose, and mannose stereoisomers can each be selected, in high yield [46]. Microwave irradiation is becoming an increasingly popular method of carbohydrate synthesis and has been the subject of a recent review [47]. 

Obrecht, D., Zumbrunn, C., Mueller, K. Formal [3+2] Cycloaddition Reaction of [1,4]Oxazin-2-ones and a-Alkynyl Ketones via a Tandem Mukaiyama-Aldol Addition/Aza-Cope Rearrangement. J. Org. Chem. 1999, 64, 6891-6895. 

Reetz, M. T., Raguse, B., Marth, C. F., Huegel, H. M., Bach, T., Fox, D. N. A. A rapid injection NMR study of the chelation controlled Mukaiyama aldol addition TiCl4 versus LiCI04 as the Lewis acid. Tetrahedron 1992, 48, 5731-5742. 

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. 

Oxazaborolidenes. Corey has reported the use of a novel oxazaborolidene complex 41 prepared from borane and A-tosyl (5)-tryptophan. This complex functions in a catalytic fashion in enantioselective, Mukaiyama aldol addition reactions (Scheme 8-3) [17]. The addition of ketone-derived enol silanes 42-43 gives adducts in 56-100% yields and up to 93% ee. The use of 1-trimethylsilyloxycyclo-pentene 43 in the addition reactions to benzaldehyde affords adducts 46 as a 94 6 mixture of diastereomers favoring the syn diastereomer in 92% ee. Addition reactions with dienol silanes 44 furnishes products 47 in up to 82% ee. Corey also demonstrated the use of these adducts as important building blocks for the synthesis of corresponding dihydropyrones treatment of 47 with trifluoroacetic acid affords the cyclic product in good yields. 

Recently, Chen has synthesized and resolved chiral suberyl carbenium ions and utilized these as catalysts for enantioselective Mukaiyama aldol addition reactions (Eq. (8.22)) [34]. Thus the reaction of the ethyl acetate-derived silyl ketene acetal with benzaldehyde in the presence of 10-20 mol% of catalyst afforded the corresponding adduct in 50% ee. The enantioselectivity of the process proved sensitive to the nature of the cation, consistent with observations previously highlighted by Denmark in related studies [35]. Although at the current level of development the selectivities are modest, the study documents a novel class of metal-free Lewis acidic agents. 

In a landmark study of Mukaiyama aldol addition reactions, Heathcock proposed that the observed stereochemical outcome of the products in the Lewis acid-mediated addition of silyl ketene acetals to aldehydes was consistent with extended, open transition-state structures [38a, 38b]. This analysis has gained wide acceptance as a consequence of its predictive power. Alternative models involving cyclic, closed structures have also been postulated, in particular, the latter have been invoked with increasing regularity in the analyses of catalytic, enantioselective aldol addition reactions [7,30b,39a,39b. ... 

A number of structural and mechanistic studies of related nucleophilic addition processes deserve close scrutiny since they provide relevant parallels that are useful in the analysis of the Mukaiyama aldol addition reaction [43, 44]. 

Fig. 6. Proposed closed transition-state structures for the Mukaiyama aldol addition of enol silanes...

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