Cross-aldolizations, Mukaiyama

The crossed aldol reaction of silyl enol ethers with carbonyl compounds (Mukaiyama-aldol) was studied by Lubineau and co-workers... 

In the Mukaiyama cross-aldol reaction, an aldehyde and a ketene silyl acetal [e.g. (43)] react via Lewis acid catalysis to give a jS-silyloxy ester (44). The reaction... 

The aldehyde-aldehyde aldol reactions were first nsed in a natural product synthesis setting by Pihko and Erkkila, who prepared prelactone B in only three operations starting from isobutyraldehyde and propionaldehyde (Scheme 40). Crossed aldol reaction under proline catalysis, followed by TBS protection, afforded protected aldehyde 244 in >99% ee. A highly diastereoselective Mukaiyama aldol reaction and ring closure with aqueous HE completed the synthesis [112]. 

Analysis of the Mukaiyama-type aldol coupling (Eq. 2) and the well-known hydrosilyla-tion of a,/l-unsaturated carbonyl compounds 11 in the presence of a rhodium catalyst, indicate that both can be explained by the intervention of the rhodium enolate 13. This line of reasoning provided the impetus to develop a new crossed aldol coupling using a hydrosilane, an a,yS-unsaturated ketone 11, and an aldehyde to form 15 (Scheme 6.4). 

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. 

S)-Proline-catalyzed cross-aldol reaction of aldehydes followed by Mukaiyama aldol reaction sequence was used for the synthesis of prelactone B [27]. The products of the aldol reactions of O-protected a-oxyaldehydes are protected carbohydrates, and were also transformed to highly enantiomerically enriched hexose derivatives, again through a second Mukaiyama aldol reaction (Scheme 2.5) [28]. The products of the aldol reactions of N-protected a-aminoaldehyde donor were easily converted to the corresponding highly enantiomerically enriched /Miydroxy-a-amino acids and their derivatives (Scheme 2.6) [24]. (For experimental details see Chapter 14.1.1). 

A very elegant asymmetric synthesis of D-ribose from achiral starting materials has been presented by Mukaiyama and coworkers [36]. It is based on the cross-aldolization of crotonaldehyde and enoxysilane 74 in the presence of an enantiomerically pure diamine 75, the chiral inducer (Scheme 13.33). High diastereoselectivity anti syn > 98 2) and high... 

Mukaiyama and coworkers [37] (Scheme 13.72) have prepared 4-C-methyl-D-ribose via their asymmetric cross-aldolization between a-methylacrolein and enoxysilane 74 (Scheme 13.33). 

An enantioselective synthesis of 3-deoxypentoses from (—)-myrtenal has been proposed by Franck-Neumann and co-workers (O Scheme 54) [251], It features the Mukaiyama cross-aldolization of benzyloxyacetaldehyde and the tricarbonyliron complex 124 derived from the condensation of (—)-myrtenal with acetone. The diastereomeric aldols 125 andl26 are separated and converted (O Scheme 54) into 3-deox) entoses 127 and 128 [251]. 

The Mukaiyama Reaction —Lewis Acid-Catalyzed Crossed Aldol Reactions... 

Mukaiyama, T., Banno, K., Narasaka, K. New cross-aldol reactions. Reactions of silyl enol ethers with carbonyl compounds activated by titanium tetrachloride. J. Am. Chem. Soc. 1974, 96, 7503-7509. 

Ellis, W. W., Bosnich, B. Mechanisms of the catalyzed Mukaiyama cross-aldol reaction. Organic Synthesis via Organometallics, Proceedings of the Symposium, 5th, Heidelberg, Sept. 26-28, 19961997, 209-227. 

The discovery of the Lewis acid-mediated addition of enol silanes to aldehydes and acetals by Mukaiyama and coworkers pioneered a novel approach to the construction of molecules via the crossed aldol reaction (Eq. 1) [6a6bj. Importantly, this development proved to be a key lead for the subsequent evolution of this C-C bond forming reaction into a catalytic Si atom-transfer process. Typical enol silanes derived from esters, thioesters, and ketones are unreactive towards aldehydes at ambient temperatures. However, stoichiometric quantities of Lewis acids such as TiCl4, SnCl4, AlClj, BClj, BF3-OEt2, and ZnCl2 were found to pro-... 

Concerning BiCl3, this weak Lewis acid proved an unexpected catalyst in the Mukaiyama-cross aldol and -Michael reactions from enoxysilanes (ref. 28), because other metallic chlorides (TiCl4, A1C13, SnCl4...) and stronger Lewis acids, are required in stoichiometric proportion for these reactions (ref. 29). On the other hand, more recently, i has been shown that ... 

In 1974, Mukaiyama and his coworkers reported on the Lewis acid promoted condensation of enol silyl ethers with carbonyl compounds to give the cross-aldol products." The reaction usually proceeds with retention of the regiochemical integrity of the starting enol silyl ethers as shown by those illustrated in Scheme 34. However, occasional examples of loss of regiointegrity of the starting enol silyl ethers have been noted in the literature. "... 

The cross-aldol reaction between propionaldehyde (5a, R =Me in Scheme 4.12) and p-nitrobenzaldehyde gave the corresponding compound anti-29 (> 88% yield, 88% de and 99% ee), which has been used as the asymmetric key step in the synthesis of trichostatin A [76], In a similar way, using propionaldehyde (Sa, R =Me in Scheme 4.12) and an excess isobutyraldehyde (4 equiv, R =j-Pr) catalyzed by proline (10 mol%), product anti-29 (98% de and 99% ee) was obtained. Subsequent diastereoselective Mukaiyama aldol reaction followed by lactonization gave prelactone B [77]. The synthesis of (-)-enterolactone has been achieved by a cross-aldol reaction between methyl 4-oxobutyrate and 3-methoxybenzaldehyde catalyzed by proline (20 mol%) as a key step [78],... 

Lewis acid for this last Mukaiyama-aldol reaction afforded the diastereomeric mannose derivative with similarresults. Thehomo-aldolreaction depicted in Schetne4.13 showed a positive non-linear effect [83], which was attributed to the formation of the inactive imidazolidinone derivative of both enantiomers of proline with anti-21 (R=Bn) in the different reaction rates, resulting in a kinetic resolution of proline by the final product. The cross-aldol reaction between a-silyloxyacetaldehydes of type 30 with propanal has been used in the synthesis of one key fragment for the preparation of (H-)-spongistatin 1 [84]. 

Mukaiyama T, Baimo K, Narasaka K (1974) New Cross-Aldol Reactions — Reactions of Silyl Enol Ethers with Carbonyl-Compotmds Activated by Titarrium TetrachlOTide. J Am Chem Soc 96 7503... 

Mukaiyama pioneered the cross aldol reaction involving dialkylboron triflates (28) (Figure 5). Later developments by Evans, Masamune, and others brought this area to new heights (29). However, research in this direction was not complete until we developed a procedure to prepare ann -aldols using fi-chlorodicyclohexylborane (30). This reagent has been utilized in several syntheses, especially in situations where the substrate controls the chirality. 

The crossed aldol reaction of silyl enol ethers with carbonyl compounds (Mukaiyama aldol) was first studied by Lubineau and coworkers in aqueous solvents. Without any acid catalyst, these reactions took several days to complete. A major development was the use of water-tolerant Lewis acids for such reactions, pioneered by Kobayashi and coworkers. ... 

The aldol or aldol-type reaction is well recognized as one of the most important carbon-carbon bond forming reactions in organic synthesis. As shown in Scheme 8.1, two stereogenic centers could be generated in this aldol reaction. The classical aldol condensation between an aldehyde and a ketone is often catalyzed by a base or an acid. Another approach is the acid-catalyzed cross-aldol reaction of silyl enol ethers with carbonyl compounds, the so-called Mukaiyama reaction. 

A number of Lewis acids such as PhsCOTf and TiCp2(OT02 which apparently catalyse Mukaiyama cross-aldols actually proceed via catalysis by trimethyl triflate, due to exchange with the silyl enol ether under the influence of adventitious moisture. The range of mechanisms operating in this reaction is also reviewed (23 references). 

The cross-aldol addition of a ketone to an aldehyde (Claisen-Schmidt reaction) is profitably carried out by using the silyl enol ether of the ketone in an organic solvent in the presence of TiCh (Mukaiyama reaction) [2], but this protocol is not suitable for acid-sensitive substrates. High pressure may be employed in place of the catalyst, but longer reaction times are required [4]. 

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