Intramolecular Mukaiyama aldol reaction

Scheme 2.10. Intramolecular Aldol and Mukaiyama Aldol Reactions... 

Under classical Mukaiyama conditions, silyl enol ether 2-372 and the Michael acceptors 2-373 and 2-374 underwent a twofold 1,4-addition to form an enolate in which an ideal set-up exists for an intramolecular aldol reaction. This led to 2-375 with the desired structural core of 2-376 in an overall yield of 42%. 

As described above, our synthetic strategy involves the convergent construction of the central cyclopentanone ring with a carbonylative cross-coupling reaction and a photo-Nazarov cyclization reaction (Chart 2.2). The electrophilic coupling component 51 was synthesized by an intramolecular Diels-Alder reaction [34] and the nucleophilic coupling component 52 by a vinyiogous Mukaiyama aldol reaction [35]. 

Owing to the high Lewis acidity the group 14 organometallic cations are polymerization catalysts par excellence. so Silanorbonyl cations and triethylsilyl arenium have been shown to be efficient catalysts for metal-free hydrosilylation reactions. Chiral silyl cation complexes with acetonitrile have been applied as cata -lysts in Diels Alder-type cyclization reactions °792 intramolecularly stabilized tetracoordinated silyl cations have been successfully used as efficient catalysts in Mukaiyama-type aldol reactions. 

The undefined mechanism of the aldol-type Mukaiyama and Sakurai allylation reactions arose the discussion and interest in mechanistic studies [143-145]. The proposed mechanism was proved to proceed through the catalytic activation of the aldehyde and its interaction with the silyl ketene acetal or allylsilane producing the intermediate. From that point the investigation is complicated with two possible pathways that lead either to the release of TMS triflate salt and its electrophihc attack on the trityl group in the intermediate or to the intramolecular transfer of the TMS group to the aldolate position resulting in the evolution of the trityl catalyst and the formation of the product (Scheme 51). On this divergence, series of experimental and spectroscopic studies were conducted. 

Intermolecular Michael addition [4.1] Intermolecular aldol reaction [6.2.1] Intramolecular aldol reaction [6.2.2] Aldol-related reactions (e.g. vinylogous Mukaiyama-type aldol) [6.2.3]... 

The antiviral marine natural product, (-)-hennoxazole A, was synthesized in the laboratory of F. Yokokawa." The highly functionalized tetrahydropyranyl ring moiety was prepared by the sequence of a Mukaiyama aldol reaction, cheiation-controiied 1,3-syn reduction, Wacker oxidation, and an acid catalyzed intramolecular ketalization. The terminal olefin functionality was oxidized by the modified Wacker oxidation, which utilized Cu(OAc)2 as a co-oxidant. Interestingly, a similar terminal alkene substrate, which had an oxazole moiety, failed to undergo oxidation to the corresponding methyl ketone under a variety of conditions. 

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. 

Danishefsky s total synthesis of avermectin (3a) was accomplished via an aldol reaction to join the northern and southern segments, intramolecular Nozaki aldol cyclization [138] to construct the southern ring system, Mukaiyama macro-lactonization, deconjugation to the C3-C4 double bond, and NIS-mediated gly-cosidation (Fig. 7). 

Rychnovsky reported synthesis of Leighton s macrolide 201 of leucascandrolide A, wherein the key reaction is the Mukaiyama aldol-Prins cascade reaction (Sect. 2.4). In this cascade reaction, oxonium cation, required for the Prins reaction, is prepared by a Lewis acid-mediated Mukaiyama aldol reaction of alkyl vinyl ether with aldehyde. Usually, alkyl vinyl ethers are not suitable for Mukaiyama-aldol, because of oligomerization of the resulting oxonium cation. Rychnovsky resolved this issue by trapping the cation with an intramolecular nucleophile, which resulted in Prins cyclization. 

SUylenol ethers such as 184 also undergo the hydroformylation-aldol reaction to give the sUylated aldol adducts 185 in good yields through a sequence of reactions involving the hydroformylation of the alkene and the intramolecular Mukaiyama type aldol reaction. [108]. Best results were achieved using the trimethylsilyl group. 

A formal [3 + 2]-cycloaddition reaction was developed featuring an aza-Cope rearrangement followed by an intramolecular Mukaiyama reaction to trap the resulting imine. Initially, compound 212 was prepared by a Mukaiyama aldol reaction between 210 and 211. This was followed by the 2-aza-Cope rearrangement of 212, resulting in 213. Following an intramolecular Mukaiyama aldol addition, 214 is produced in moderate yield. 

Scheme 7.37 Domino intramolecular hydrosilojgrlation-Mukaiyama aldol reaction catalysed by chiral phosphoramide catalysis and gold catalysis.

Numerous in-depth mechanistic studies have been performed on the Mukaiyama aldol reaction. " Although various mechanisms exist in the literature that take into account the various roles of the numerous catalysts used for the enantio- and diastereoselective Mukaiyama aldol reaction, the commonly accepted mechanism accounting for bond formation is shown below.The reaction begins with the coordination of a Lewis acid with aldehyde 4 to form complex 5. Due to its enhanced electrophilicity, complex 5 is attacked by the 7t-bond of the enol silane 6, giving rise to resonance stabilized cation 7. At this point, either intermolecular silyl cleavage upon hydrolysis or intramolecular silyl transfer to the product hydroxyl group occurs to give products such as 8 or 9. 

While the order of silyl transfer or cleavage is inconsequential to bond formation, it is one of the more important and hotly debated aspects of the mechanism owing to its importance in the development of catalytic enantioselective variants of the Mukaiyama aldol reaction. Intramolecular silyl transfer, as shown in the formation of 10, would regenerate the chiral,... 

Lewis acid, by enolsilane addition to chiral oxonium ions (cf. equation 40). Oxonium ions are also probably involved in the diastereoselective AlCb-mediated additions of enolsilanes to chiral 2-benzenesulfo-nyl cyclic ethers. In the diastereoselective additions to chiral acetals - (see Section 2.4.4.4), an extension of the methodology shown in Scheme 9 to the enantio differentiation of meso 1,2- and 1,4-diols was reported. An intramolecular Mukaiyama acetal-aldol reaction (see Section 2.4.4.S) was reported as the key step to construct the 11-memboed ring of hydroxyjatrophone A and B. "... 

Intramolecular Mukaiyama aldol condensation. This reaction can be used to obtain six-, seven-, and eight-membered rings. Thus the reaction of the r /.v-dioxolanc la with TiCL (1-2 equiv.) gives 2a as the exclusive product. The isomeric /ran.v-dioxolane lb under similar conditions gives a I I mixture of 2a and 2b (72% yield). No cyclization products are obtained with SnCL or ZnCL. 

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