MUKAIYAMA Stereoselective aldol condensation

A stereoselective aldol condensation is known as Mukaiyama reaction." It consists in the reaction of an silyl enol ether of 3-pentanone with an aldehyde (2-methyl-butanal) in presence of TiCl to yield an aldol product, Manicone, an alarm pheromone (Scheme 32)." ... 

Although in the recent years the stereochemical control of aldol condensations has reached a level of efficiency which allows enantioselective syntheses of very complex compounds containing many asymmetric centres, the situation is still far from what one would consider "ideal". In the first place, the requirement of a substituent at the a-position of the enolate in order to achieve good stereoselection is a limitation which, however, can be overcome by using temporary bulky groups (such as alkylthio ethers, for instance). On the other hand, the ( )-enolates, which are necessary for the preparation of 2,3-anti aldols, are not so easily prepared as the (Z)-enolates and furthermore, they do not show selectivities as good as in the case of the (Z)-enolates. Finally, although elements other than boron -such as zirconium [30] and titanium [31]- have been also used succesfully much work remains to be done in the area of catalysis. In this context, the work of Mukaiyama and Kobayashi [32a,b,c] on asymmetric aldol reactions of silyl enol ethers with aldehydes promoted by tributyltin fluoride and a chiral diamine coordinated to tin(II) triflate... 

Amino-3-tetrahydrofurancarboxylic acid 17, an oxygen cycloleucine analog, has been synthesized from D,L-homoserine by an intramolecular Mukaiyama aldol condensation in six steps (89TL1181). From o-Thr, l-muscarine 18 was synthesized in eight steps. The synthesis is highly stereoselective (85T5321). 

Mukaiyama aldol condensation (6, 590-591).8 This reaction can be effected in the absence of a Lewis acid catalyst under high pressure (10 kbar). Surprisingly the stereoselectivity is the reverse of that of the TiCl4-catalyzed reaction (equation I). The reaction can also be effected in water with the same stereoselectivity, but the yield is low because of hydrolysis of the silyl enol ether. Yields are improved by use of water-oxolane (1 1) and by sonication.9... 

Stereoselective aldot condensations. Mukaiyama et al. have reported that ketones are converted into vinyloxyboranes by reaction with dialkylboron triflates and a tertiary amine and that these enolates undergo regioselective aldol reactions with aldehydes (equation I). Mukaiyama used di-n-butylboryl triflate in combination... 

Other important aldol condensations are the Mukaiyama-type aldol reactions of silyl enol ethers with aldehydes that usually require catalyst activation. Yamamoto reported that such reactions under high pressure proceed (i) without catalyst even at room temperature, (ii) without isomerization of the formed adducts and (iii) with a reversed synlanti stereoselectivity compared with that of the TiCU-catalysed reactions. ... 

Heathcock and Filippin investigated the effect of the chirality of aldehydes on 1,2-diastereoselection in aldol condensations, and they found that the Mukaiyama aldol reaction enhanced the stereoselectivity to give syn adduct (Scheme 8.29). In the case of the aldehyde ent-l6S,... 

The Mukaiyama aldol reaction of carbonyl substrates with silyl enol ethers is the most widely accepted of Lewis acid-promoted reactions. Many Lewis acids for the reaction have been developed and used enantioselectively and diastereoselectively. In 1980, catalytic amounts of la were found by Noyori et al. to effect aldol-type condensation between acetals and a variety of silyl enol ethers with high stereoselectivity [2c,20]. Unfortunately, la has poor Lewis acidity for activation of aldehydes in Mukaiyama s original aldol reaction [21]. Hanaoka et al. showed the scope and limitation of 11-cat-alyzed Mukaiyama aldol reaction, by varying the alkyl groups on the silicon atom of silyl enol ethers [22]. Several efforts have been since been made to increase the reactivity and/or the Lewis acidity of silicon. One way to enhance the catalyst activity is to use an additional Lewis acid. 

Importantly, with a-silyloxy acetaldehyde, the syn aldol is the major dimer (threose derivative). Thus, applying Mukaiyama condensations with 27 (see O Scheme 23), hexoses such as idose, gulose, and galactose can be prepared. A highly stereoselective protocol for the cross coupling of aldehydes and ketones with a-thioacetal aldehydes has been developed... 

CAB 3a is also an excellent catalyst (20 mol%) for the Mukaiyama condensation of simple enol silyl ethers of achiral ketones with various aldehydes. Furthermore, the reactivity of aldol-type reactions can be improved without reducing the enantioselec-tivity by using 10-20 mol% of 3c. Enantioselectivity can also be improved without reducing the chemical yield by using 20 mol% of 3b. The 3-catalyzed aldol process allows for the formation of adducts in a highly diastereo- and enantioselective manner (up to 99% ee) under mild reaction conditions [41a, cj. These reactions are catalytic, and the chiral source is recoverable and reusable (Equation 41). The observed high syn selectivities, together with their lack of dependence on the stereoselectivity of the silyl enol ethers, in 3-catalyzed reactions are fully consistent with Noyori s TMSOTf-catalyzed aldol reactions of acetals, and thus may reflect the acyclic extended transition state mechanism postulated in the latter reactions. 

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