MUKAIYAMA Stereoselective aldol

Stereoselectivities of 99% are also obtained by Mukaiyama type aldol reactions (cf. p. 58) of the titanium enolate of Masamune s chired a-silyloxy ketone with aldehydes. An excess of titanium reagent (s 2 mol) must be used to prevent interference by the lithium salt formed, when the titanium enolate is generated via the lithium enolate (C. Siegel, 1989). The mechanism and the stereochemistry are the same as with the boron enolate. 

A stereoselective Mukaiyama-type aldol reaction of bis(trimethylsilyl)ketene acetals produces silyl aldols with syn stereoselectivity, predominantly due to steric effects.23... 

To achieve a stereoselective aldol reaction that does not depend on the structural type of the reacting carbonyl compounds, many efforts have been made to use boron enolates. Based on early studies by Mukaiyama et al.8a and Fenzl and K0ster,8b in 1979, Masamune and others reported a highly diastereoselective aldol reaction involving dialkylboron enolates (enol borinates)9... 

Mukaiyama and Kobayashi et al. have developed the use of Sn(OTf)2 in diastereose-lective and enantioselective aldol-type reactions [26,27]. Initially, the stereoselective aldol reactions were performed with a stoichiometric amount of Sn(OTf)2 [28], The reaction between 3-acylthiazolidine-2-thione and 3-phenylpropionaldehyde is a representative example of a diastereoselective syn-aldol synthesis (Eq. 17). 

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. ... 

The authors found that the addition of TMEDA before oxidation was necessary to increase both reproducibility and yields of this sequential process, presumably due to the inhibition of the oxidative dimerization [98], a side reaction known in the chemistry of organocopper compounds. Alkynes with electron-withdrawing groups directly bound to the sp carbon were also employed in the stereoselective carbocupration [99]. For example, the carbocupration of alkynoates 341 promoted by Lewis acids, such as trimethylsilyl triflate, leads to the isomeric TMS-allenoate compounds, which on hydrolysis or a Mukaiyama-type aldol reaction produce the corresponding di- and trisubstituted acrylates 342 (Scheme 10.116) [100]. 

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)." ... 

The aldol reaction is one of the most useful carbon-carbon bond forming reactions in which one or two stereogenic centers are constructed simultaneously. Diastereo-and enantioselective aldol reactions have been performed with excellent chemical yield and stereoselectivity using chiral catalysts [142]. Most cases, however, required the preconversion of donor substrates into more reactive species, such as enol silyl ethers or ketene silyl acetals (Scheme 13.45, Mukaiyama-type aldol addition reaction), using no less than stoichiometric amounts of silicon atoms and bases (Scheme 13.45a). From an atom-economic point of view [143], such stoichiometric amounts of reagents, which afford wastes such as salts, should be excluded from the process. Thus, direct catalytic asymmetric aldol reaction is desirable, which utilizes unmodified ketone or ester as a nucleophile (Scheme 13.45b). Many researchers have directed considerable attention to this field, which is reflected in the increasing... 

The camphor-derived propionates 1 ( Helmchen type ) [101] and 188 ( Oppolzer type ) [102] were utilized almost at the same time for obtaining nonracemic, ti-configured P-hydroxy esters through Mukaiyama-type aldol additions, while aldol additions of the lithium enolate (cf Scheme 4.1) led to insufficient stereoselectivity. From both esters, the trans-silicon enolates 186... 

In the Mukaiyama variation of the aldol reaction, 3-benzoyloxy-2-trimethylsiloxy-l-butene adds to 2-methylpropanal in a stereoselective manner. Best results are obtained in the presence of titanium(IV) chloride, giving the adducts 9/10 in a diastereomeric ratio of 92 8. Hydrolysis of the benzoyl group and subsequent oxidative cleavage of the 1,2-diol moiety liberates / -hy-droxycarboxylic acids593. 

The Mukaiyama aldol reaction can provide access to a variety of (3-hydroxy carbonyl compounds and use of acetals as reactants can provide (3-alkoxy derivatives. The issues of stereoselectivity are the same as those in the aldol addition reaction, but the tendency toward acyclic rather than cyclic TSs reduces the influence of the E- or Z-configuration of the enolate equivalent on the stereoselectivity. 

Dipole-dipole interactions may also be important in determining the stereoselectivity of Mukaiyama aldol reactions proceeding through an open TS. A BF3-catalyzed reaction was found to be 3,5-anti selective for several (3-substituted 5-phenylpentanals. This result can be rationalized by a TS that avoids an unfavorable alignment of the C=0 and C-X dipoles.97... 

Scheme 2.3 shows reactions of several substituted aldehydes of varying complexity that illustrate aldehyde facial diastereoselectivity in the aldol and Mukaiyama reactions. The stereoselectivity of the new bond formation depends on the effect that reactant substituents have on the detailed structure of the TS. The 3,4-syn stereoselectivity of Entry 1 derives from a Felkin-type acyclic TS. 

Scheme 2.3. Examples of Aldol and Mukaiyama Reactions with Stereoselectivity Based... 

Summary of Facial Stereoselectivity in Aldol and Mukaiyama Reactions. The examples provided in this section show that there are several approaches to controlling the facial selectivity of aldol additions and related reactions. The E- or Z-configuration of the enolate and the open, cyclic, or chelated nature of the TS are the departure points for prediction and analysis of stereoselectivity. The Lewis acid catalyst and the donor strength of potentially chelating ligands affect the structure of the TS. Whereas dialkyl boron enolates and BF3 complexes are tetracoordinate, titanium and tin can be... 

Another anionic/radical one-pot sequence was developed by Guindon and coworkers for the stereoselective synthesis of substituted pentanoates 2-718 (Scheme 2.158) [365]. Such structures are found in polyketides and are, therefore, of great interest. The described approach offers a diastereoselective access to all four possible stereoisomers of 2-718 through a Mukaiyama aldol/radical defunctionalization sequence starting from 2-716 and 2-717 with addition of Bu3SnH after completion of the first step. 

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. 

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). 

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