Reactions Mukaiyama

It has been proposed that there may be a single electron transfer mechanism for the Mukaiyama reaction under certain conditions.72 For example, photolysis of benzaldehyde dimethylacetal and 1-trimethylsilyloxycyclohexene in the presence of a... 

In the discussion of the stereochemistry of aldol and Mukaiyama reactions, the most important factors in determining the syn or anti diastereoselectivity were identified as the nature of the TS (cyclic, open, or chelated) and the configuration (E or Z) of the enolate. If either the aldehyde or enolate is chiral, an additional factor enters the picture. The aldehyde or enolate then has two nonidentical faces and the stereochemical outcome will depend on facial selectivity. In principle, this applies to any stereocenter in the molecule, but the strongest and most studied effects are those of a- and (3-substituents. If the aldehyde is chiral, particularly when the stereogenic center is adjacent to the carbonyl group, the competition between the two diastereotopic faces of the carbonyl group determines the stereochemical outcome of the reaction. 

Mukaiyama reactions of a-methyl aldehydes proceed through an open TS and show a preference for the 3,4-syn stereoisomer, which is consistent with a Felkin TS.80... 

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... 

Scheme 2.4. Examples of Facial Selectivity in Aldol and Mukaiyama Reactions Based on... 

In general, BF3 -catalyzed Mukaiyama reactions lack a cyclic organization because of the maximum coordination of four for boron. In these circumstances, the reactions show a preference for the Felkin type of approach and exhibit a preference for syn stereoselectivity that is independent of silyl enol ether structure.119... 

Scheme 2.6 shows some examples of the use of chiral auxiliaries in the aldol and Mukaiyama reactions. The reaction in Entry 1 involves an achiral aldehyde and the chiral auxiliary is the only influence on the reaction diastereoselectivity, which is very high. The Z-boron enolate results in syn diastereoselectivity. Entry 2 has both an a-methyl and a (3-benzyloxy substituent in the aldehyde reactant. The 2,3-syn relationship arises from the Z-configuration of the enolate, and the 3,4-anti stereochemistry is determined by the stereocenters in the aldehyde. The product was isolated as an ester after methanolysis. Entry 3, which is very similar to Entry 2, was done on a 60-kg scale in a process development investigation for the potential antitumor agent (+)-discodermolide (see page 1244). 

Scheme 2.8 gives some examples of chiral Lewis acids that have been used to catalyze aldol and Mukaiyama reactions. 

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... 

These reagents initiate a catalytic cycle that regenerates the active silyation species.92 (See p. 83 for a similar cycle in the Mukaiyama reaction.)... 

A tandem combination initiated by a Mukaiyama reaction generates an oxonium ion that cyclizes to give a tetrahydropyran rings.48... 

In the synthesis shown in Scheme 13.15, racemates of both erythro- and threo-juvabione were synthesized by parallel routes. The isomeric intermediates were obtained in greater than 10 1 selectivity by choice of the E- or Z-silanes used for conjugate addition to cyclohexenone (Michael-Mukaiyama reaction). Further optimization of the stereoselectivity was achieved by the choice of the silyl substituents. The observed stereoselectivity is consistent with synclinal TSs for the addition of the crotyl silane reagents. 

An enantiospecific synthesis of longifolene was done starting with camphor, a natural product available in enantiomerically pure form (Scheme 13.31) The tricyclic ring was formed in Step C by an intramolecular Mukaiyama reaction. The dimethyl Multistep Syntheses substituents were formed in Step E-l by hydrogenolysis of the cyclopropane ring. 

Another Japanese group developed the Baccatin III synthesis shown in Scheme 13.58. The eight-membered B-ring was closed early in the synthesis using a Lewis acid-induced Mukaiyama reaction (Step B-l), in which a trimethylsilyl dienol ether served as the nucleophile. 

On the other hand, Li and Wang recently developed a highly efficient asymmetric Mukaiyama reaction by using chiral gallium catalysts with Trost s chiral semicrown ligands (Eq. 8.106).287 Such a system can achieve high enantioselectivity even in pure water. The combination... 

The stereochemical outcome of the Mukaiyama reaction can be controlled by the type of Lewis acid used. With bidentate Lewis acids the aldol reaction led to the anti products through a Cram chelate control [366]. Alternatively, the use of a monoden-tate Lewis acid in this reaction led to the syn product through an open Felkin-Anh... 

Mukaiyama reaction (Lewis acid-catalyzed Michael reaction) with electron-poor olefins, ketals and acetals, and enones 32... 

The Mukaiyama Reaction. The Mukaiyama reaction refers to Lewis acid-catalyzed aldol addition reactions of enol derivatives. The initial examples involved silyl enol ethers.40 Silyl enol ethers do not react with aldehydes because the silyl enol ether is not a strong enough nucleophile. However, Lewis acids do cause reaction to occur by activating the ketone. The simplest mechanistic formulation of the Lewis acid catalysis is that complexation occurs at the carbonyl oxygen, activating the carbonyl group to nucleophilic attack. 

Quite a number of Lewis acids besides TiCLt and BF3 can catalyze the Mukaiyama reaction, including Bu2Sn(03SCF3)2 45 Bu3SnC10446 Sn(03SCF3)2 47 Zn(03SCF3)248 and LiClC>4.49 Triaryl perchlorate salts are also very active catalysts.50 Examples of these reactions are included in Scheme 2.5. 

In addition to aldehydes, acetals and ketals can serve as electrophiles in Mukaiyama reactions.56... 

Considerable effort has been devoted to finding Lewis acid or other catalysts that could induce high enantioselectivity in the Mukaiyama reaction. As with aldol addition reactions involving enolates, high diastereoselectivity and enantioselectivity requires involvement of a transition state with substantial facial selectivity with respect to the electrophilic reactant and a preferred orientation of the nucleophile. Scheme 2.4 shows some examples of enantioselective catalysts. 

The copper-catalyzed conjugate addition of methyhnagnesium iodide to cyclohexenone and trapping of the resulting enolate as its trimethylsilyl enolate, followed by TrSbCle-catalyzed Mukaiyama reaction, are the first steps of an elegant synthesis of enantiomeri-caUy pure clerodanes (equation 45). 

The copper-catalyzed conjugate addition of methyl magnesium iodide to cyclohexenone and trapping the enolate as its trimethylsilyl enol ether, followed by a trityl hexachloro-antinomate-catalyzed Mukaiyama reaction, is apphed to / -(—jcarvone. C-2, C-3 functionalized chiral cyclohexanones are converted into their a-cyano ketones, which are submitted to Robinson annulation with methyl vinyl ketone. Highly functionalized chiral decalones are obtained that can be used as starting compounds in the total synthesis of enantiomerically pure clerodanes (equation 70). 

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