Mukaiyama aldol condensation using

Various other sequential, clean, multistep transformations based solely on PSRs have been described. Starting from alcohols 152, which were oxidized to the corresponding carbonyl compounds (153), a,fi-unsaturated ketones 158 were prepared by a Mukaiyama aldol condensation using Nafion-TMS 159 as silylating agent and... 

A series of chiral binaphthyl ligands in combination with AlMe3 has been used for the cycloaddition reaction of enamide aldehydes with Danishefsky s diene for the enantioselective synthesis of a chiral amino dihydroxy molecule [15]. The cycloaddition reaction, which was found to proceed via a Mukaiyama aldol condensation followed by a cyclization, gives the cycloaddition product in up to 60% yield and 78% ee. 

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... 

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. 

Mukaiyama Aldol Condensation. The BINOL-derived titanium complex BINOL-T1CI2 is an efficient catalyst for the Mukaiyama-type aldol reaction. Not only ketone silyl enol ether (eq 25), but also ketene silyl acetals (eq 26) can be used to give the aldol-type products with control of absolute and relative stereochemistry. 

Mukaiyama Aldol Condensation. As expected, the chiral titanium complex is also effective for a variety of carbon-carbon bond forming processes such as the aldol and the Diels-Alder reactions. The aldol process constitutes one of the most fundamental bond constructions in organic synthesis. Therefore the development of chiral catalysts that promote asymmetic aldol reactions in a highly stereocontrolled and truly catalytic fashion has attracted much attention, for which the silyl enol ethers of ketones or esters have been used as a storable enolate component (Mukaiyama aldol condensation). The BINOL-derived titanium complex BINOL-TiCl2 can be used as an efficient catalyst for the Mukaiyama-ty pe aldol reaction of not only ketone si ly 1 enol ethers but also ester silyl enol ethers with control of absolute and relative stereochemistry (eq 11). ... 

Because the aldol reaction is one of the most fundamental bond-construction processes in organic synthesis [86], much attention has been focused on the development of asymmetric catalysts for aldol reactions, using silyl enol ethers of ketones or esters as storable enolate components (the Mukaiyama aldol condensation) [87]. 

It seems likely that the reaction proceeds through a prototropic ene reaction pathway, a pathway that has not been previously recognized as a possible mechanism in the Mukaiyama aldol condensation. Usually an acyclic antiperiplanar transition-state model has been used to explain the formation of the syn diastereomer from either ( )- or (Z)-silyl enol ethers [91]. The cyclic ene mechanism, however, now provides another rationale for the syn diastereoselectivity irrespective of enol silyl ether geometry (Sch. 32). 

In their second approach (Scheme 12), Johnson and his co-workers used the acetal 96 derived from (3S)-butane-l,3-diol instead of from (/ ,/ )-2,4-pentanediol (22). As in the earlier work, the Mukaiyama aldol condensation of acetal 96 with acetone trimethylsilyl ether gave a mixture of diastereoisomers 97 and 98 in a ratio of 96 4. In contrast, however, the removal of the chiral auxiliary was achieved without the need for first reducing the ketone group. Oxidation of the aldol... 

Few other asymmetrie reactions have been performed using insoluble or soluble polymer-supported ligands. The first example is a Mukaiyama-aldol condensation between silyl ketene acetal and different aldehydes using polymeric Box analog of 99 as chiral ligands and Cu(OTf)2 as metal soiu ce in water (Scheme 147) [216]. When using benzaldehyde as substrate, yields were very low (12-34%) and ee were moderate (40-62%) whatever the polymer-supported Box. The same level of enantioseleetivity was observed with other aldehydes while the yield was better with all the ligand/Cu complexes used. 

We urge you to try to write a mechanism for the above process. You may find it useful to think of silyl groups as fat protons. Start off with silylating the carbonyl oxygen and proceed from there. Silyl enol ethers function as less reactive analogs of enolate anions. Thus, with titanium tetrachloride as a catalyst, silyl enol ethers undergo aldol condensations with a variety of carbonyl compounds. This is the Mukaiyama aldol condensation ... 

This novel polymeric aluminum complex is used to catalyze the Mukaiyama aldol condensation [71] of benzaldehyde, 88, with 1-phenyl-1-(trimethylsilyloxy)-ethylene, 89, to form 90 (Scheme 38). In the presence of 16 mol % (/ )-87, the reaction is completed in less than 3.5 h at -78°C. The polymeric catalyst, rac- 87, made from the reaction of diethylaluminum chloride with rac-81 can also catalyze... 

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]. 

In 1993, Mikami and Matsukawa reported on an interesting reactivity while attempting enantioselective catalysis of the Mukaiyama aldol reaction using the 1, r-binaphthyl-2,2 -diol (BINOL) system (Scheme 10.21). ° The method used condensation of 3-pentanone-derived enoxysilane 91 with glyoxalate 92 in the presence of enantiomerically pure catalyst 93. Silyl enol ether 94 was obtained as an c/jc-type product with excellent diastereo- and enantioselectivity. 

The Mukaiyama aldol reaction is a highly selective cross aldol condensation using a silyl enol ether as nucleophile and a Lewis acid-coordinated carbonyl compound as electrophile. 

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... 

One of the early syntheses of orlistat (1) by Hoffmann-La Roche utilized the Mukaiyama aldol reaction as the key convergent step. Therefore, in the presence of TiCU, aldehyde 7 was condensed with ketene silyl acetal 8 containing a chiral auxiliary to assemble ester 9 as the major diastereomer in a 3 1 ratio. After removal of the amino alcohol chiral auxiliary via hydrolysis, the a-hydroxyl acid 10 was converted to P-lactone 11 through the intermediacy of the mixed anhydride. The benzyl ether on 11 was unmasked via hydrogenation and the (5)-7V-formylleucine side-chain was installed using the Mitsunobu conditions to fashion orlistat (1). 

It has been reported that the chiral NMR shift reagent Eu(DPPM), represented by structure 19, catalyzes the Mukaiyama-type aldol condensation of a ketene silyl acetal with enantiose-lectivity of up to 48% ee (Scheme 8B1.13) [29-32]. The chiral alkoxyaluminum complex 20 [33] and the rhodium-phosphine complex 21 [34] under hydrogen atmosphere are also used in the asymmetric aldol reaction of ketene silyl acetals (Scheme 8BI. 14), although the catalyst TON is quite low for the former complex. 

The Mukaiyama reaction is a versatile crossed-aldol reaction that uses a silyl enol ether of an aldehyde, ketone, or ester as the carbon nucleophile and an aldehyde or ketone activated by a Lewis acid as the carbon electrophile. The product is a /1-hydroxy carbonyl compound typical of an aldol condensation. The advantages to this approach are that it is carried out under acidic conditions and elimination does not usually occur. 

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. 

A unique condensation is observed between 1,3-dimethoxy-l-trimethylsiloxybuta-diene (35) and cinnamaldehyde (36) producing the acyclic adduct 37 in 72 % yield when catalyzed by Ag(fod) (Sch. 8). In contrast, when Eu(fod)3 or Yb(fod)3 is used as the catalyst, a hetero-Diels-Alder reaction takes place exclusively [17]. The acyclic adduct 37 is believed to be formed by a [2 -i- 2] cycloaddition via an oxetane rather than through a six-membered ring transition state (Mukaiyama aldol type reaction). 

Combining the D-erythrose derivative 26 obtained by L-proline-catalyzed dimerization of (t-Bu)Ph2SiOCH2CHO with enoxysilane 27 in Mukaiyama aldol reactions catalyzed by various Lewis acid, MacMillan and co-workers have realized efficient, two-step syntheses of semi-protected D-glucose (28G), L-mannose (28M) and L-allose (28A) (O Scheme 23) [148]. Using D-proline to generate tetrose 29 and its condensation with 27b, the semi-protected D-glucose derivative 30 was obtained in two steps [149]. 

LLC networks containing catalytic headgroups have also been shown to be useful for heterogeneous Lewis acid catalysis. The Sc(III)-exchanged cross-linked Hu phase of a taper-shaped sulfonate-functionalized LLC monomer has been shown to be able to catalyze the Mukaiyama aldol and Mannich reactions [115] with enhanced diastereoselectivity. This Sc(III)-functionalized Hu network affords condensation products with syn-to-anti diastereoselectivity ratios of 2-to-l, whereas Sc(III) catalysts in solution or supported on amorphous polymers show no reaction diastereoselectivity at all. 

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