Mukaiyama addition

As with aldol and Mukaiyama addition reactions, the Mannich reaction is subject to enantioselective catalysis.192 A catalyst consisting of Ag+ and the chiral imino aryl phosphine 22 achieves high levels of enantioselectivity with a range of N-(2-methoxyphenyljimines.193 The 2-methoxyphenyl group is evidently involved in an interaction with the catalyst and enhances enantioselectivity relative to other A-aryl substituents. The isopropanol serves as a proton source and as the ultimate acceptor of the trimethyl silyl group. 

Effective catalysts include TiCL,57 SnCl4,58 (CH3)3Si03SCF3,59 and Bu2Sn03SCF3.60 61 Indium trichloride catalyzes Mukaiyama additions in aqueous solution. The reaction is best conducted by preforming the aldehyde-InCl3 complex and then adding the silyl enol ether and water. 

Mukaiyama addition stereoselectivity Me3Si < Et3Si < (7-Bu)Me2Si < (i-Pr)3Si 15... 

Type and geometry of substrate coordiation plays a key role in the final stereochemistry of the product [245,246]. Organolanthanide catalyzed condensation of carbonyl compounds with silylenolethers, known as the Mukaiyama addition reaction, is assumed to contain a 6-membered transition state with Ln-O linkages [247]. Formation of a 6-membered organolanthanide aldolate moiety was structurally proven in the reaction of Cpf LnR with ketones (Sect. 6.2.3) [248]. 

Our synthesis of (9S)-dihydroerythronolide A, which constitutes a formal synthesis of erythronolideA (226), depends on a key aldol reaction between the racemic aldehyde 244 and imide auxiliary 245 (Scheme 9-66) [84]. In this reaction, the auxiliary overrides any aldehyde facial bias, thus leading to an equimolar mixture of separable syn adducts 246 and 247. These two compounds were then processed separately and together provide five of the ten necessary stereocenters of erythronolideA (C9 will be oxidized). This synthesis also features the thioalkyla-tion of silyl enol ether 248 giving ketone 249, a process which can be compared with the Mukaiyama addition to aldehydes. Presumably, Felkin selectivity controls the Cii stereocenter while the mixture of C12 epimers was not detrimental as epi-merization could be effected in the subsequent elimination step. 

Two benzosilacyclohexadienones (100 R = Me, Ph) have been prepared and their reactivities characterized. " These new cyclic )8-silyl-a,)8-unsaturated ketones undergo stereoselective Diels-Alder reactions, cyanocuprate addition to the carbonyl, and a Michael-Mukaiyama addition with an ethoxysilyloxy ketene acetal. 

In the Mukaiyama addition of the aldol reaction [16], silyl ketene acetals or silyl enol ethers are added to aldehydes in a reaction mediated by Lewis acids or fluoride. Here again the Z-syn correlation is sometimes not observed [69, 70]. Thus, the Z-syn, E-anti correlation seems to be a rule with several exceptions [71]. 

Corey examined and documented another class of amino-acid-derived N-sulfonamide oxazaborolidines, characterized by their convenient synthesis, for the catalytic asymmetric Mukaiyama aldol reaction. Oxazaborolidine 256, for example, can be assembled from the condensation of L-N-tosyl-tryp-tophan and n-butylboronic acid. It was shown to be an effective catalyst for the Mukaiyama addition of enoxysilanes with a variety of aldehydes (Equation 25) [127]. 

Mukaiyama reported tlie conjugate addition of a-ditliioalkylcuprates to 2-enones i73-9496 yields) for tlie syntliesis of 1,4-diketones, and tlie reaction was exploited in a syntliesis of t )-diliydtojasmone [ 141]. Few reports on a-tliioalkylcuprates have appeared since tlien. Cuprates formed from litliiated ketene ditliioacetals and... 

A confusing picture emerges from the stereochemical outcome of the Mukaiyama variation of the aldol addition. The titanium(IV) chloride mediated addition of silylketene acetals to isobutyraldehyde confirms this statement while there is a reasonable correlation between the predominance of the (/t)-silylkctenc acetal 2 over the (Z)-acetal, and the favored formation of the an/t -carboxylic ester over the. svn-product, the pure (Z)-diastereomer displays no syn selectivity26. 

Thus, the inherent selectivity of a chiral aldehyde is much stronger in Mukaiyama-type aldol reactions than in the additions of lithium or magnesium enolates17. 

Mukaiyama aldol reactions have been reported, usually using chiral additives although chiral auxiliaries have also been used. This reaction can also be run with the aldehyde or ketone in the form of its acetal R R C(OR )2> in which case the product is the ether R COCHR2CR R OR instead of 27. Enol acetates and enol ethers also give this product when treated with acetals and TiCLi or a similar catalyst. When the catalyst is dibutyltin bis(triflate), Bu2Sn(OTf)2, aldehydes react, but not their acetals, while acetals of ketones react, but not the ketones themselves. 

As an extension of this work, these authors have applied this catalyst system to vinylogous asymmetric Mukaiyama-type aldol reactions, involving silyl vinyl ketene acetals and pyruvate esters. These reactions afforded the corresponding y,5-unsaturated a-hydroxy diesters with quaternary centres in high yields and enantioselectivities of up to 99% ee (Scheme 10.25). It was shown that the presence of CF3CH2OH as an additive facilitated the turnover of the catalyst. 

The Mukaiyama aldol reaction refers to Lewis acid-catalyzed aldol addition reactions of silyl enol ethers, silyl ketene acetals, and similar enolate equivalents,48 Silyl enol ethers are not sufficiently nucleophilic to react directly with aldehydes or ketones. However, Lewis acids cause reaction to occur by coordination at the carbonyl oxygen, activating the carbonyl group to nucleophilic attack. 

In addition to aldehydes, acetals can serve as electrophiles in Mukaiyama aldol reactions.64 Effective catalysts include TiCl4,65 SnCl4,66 (CH3)3Si03SCF3,67 and... 

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. 

Scheme 2.2 illustrates several examples of the Mukaiyama aldol reaction. Entries 1 to 3 are cases of addition reactions with silyl enol ethers as the nucleophile and TiCl4 as the Lewis acid. Entry 2 demonstrates steric approach control with respect to the silyl enol ether, but in this case the relative configuration of the hydroxyl group was not assigned. Entry 4 shows a fully substituted silyl enol ether. The favored product places the larger C(2) substituent syn to the hydroxy group. Entry 5 uses a silyl ketene thioacetal. This reaction proceeds through an open TS and favors the anti product. 

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. 

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... 

Conditions for effecting conjugate addition of neutral enolate equivalents such as silyl enol ethers in the presence of Lewis acids have been developed and are called Mukaiyama-Michael reactions. Trimethylsilyl enol ethers can be caused to react with electrophilic alkenes by use of TiCl4. These reactions proceed rapidly even at -78° C.308... 

Entries 5 to 9 illustrate some of the modified reagents and catalytic procedures. Entry 5 uses a phosphine-stabilized reagent, whereas Entry 6 includes BF3. Entry 7 involves use of TMS-C1. Entries 8 and 9 involve cyanocuprates. In Entry 9, the furan ring is closed by a Mukaiyama-aldol reaction subsequent to the conjugate addition (Section 2.1.4). 

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. 

The synthesis of Baccatin HI shown in Scheme 13.57, which was completed by a group led by the Japanese chemist Teruaki Mukaiyama, takes a different approach for the previous syntheses. Much of the stereochemistry was built into the B-ring by a series of acyclic aldol additions in Steps A through D. A silyl ketene acetal derivative... 

Chiral //A(oxazolinc) ligands disubstituted at the carbon atom linking the two oxazolines by Frechet-type polyether dendrimers coordinated with copper(II) triflate were found to provide good yields and moderate enantioselectivities for Mukaiyama aldol reactions in water that are comparable with those resulting from the corresponding smaller catalysts.291 AgPF6-BINAP is very active in this reaction and the addition of a small amount of water enhanced the reactivity.292... 

---