Silyl Mukaiyama reaction

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... 

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 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. 

This reactionis similar to the Mukaiyama Reaction, which employs silyl enol ethers ... 

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. 

Silyl enol ethers of acyl silanes have been used in Lewis acid-mediated Mukaiyama reactions with acetals. Treatment of the resulting /1-alkoxy acyl silanes with tetrabutylammonium hydroxide or tetrabutylammonium fluoride gave the corresponding a,/J-unsaturated aldehydes (Scheme 99)210. 

Mukaiyama found that Lewis acids can induce silyl enol ethers to attack carbonyl compounds, producing aldol-like products.22 The reaction proceeds usually at -78 °C without selfcondensation and other Lewis acids such as TiCl4 or SnCI4 are commonly used. The requisite silyl enol ether 27 was prepared by treatment of ketone 13 with lithium hexamethyl disilazide (LiHMDS) and trapping the kinetic enolate with chlorotrimethylsilane. When the silyl enol ether 27 was mixed with aldehyde 14 in the presence of BF3-OEt2 a condensation occurred via transition state 28 to produce the product 29 with loss of chlorotrimethylsilane. The induced stereochemistry in Mukaiyama reactions using methylketones and a, -chiral aldehydes as substrates... 

Aldol reactions with enol silyl ethers5 (Mukaiyama reaction). Although TiCl4 is commonly used to effect aldol reactions with enol silyl ethers, BF3 etherate is more effective for aldol reactions of tetrasubstituted enol ethers such as (Z)- and (E)-3-methyl-2 (trimethylsilyloxy)-2-pentene (1). These enolates react with aldehydes in the same sense as the corresponding metal enolates, but with generally higher levels... 

Carbonyl activation and deactivation.1 Aldehydes, but not ketones, undergo aldol condensation with silyl enol ethers at —78° in the presence of dibutyltin bistriflate. In contrast, the dimethyl acetals of ketones, but not of aldehydes, can undergo this condensation (Mukaiyama reaction) with silyl enol ethers at -78° with almost complete discrimination, which is not observed with the usual Lewis-acid catalysts. Thus dibutyltin bistriflate activates aldehydes, but deactivates acetals of... 

Asymmetric aldol reactions.4 The borane complex 3 can also serve as the Lewis acid catalyst for the aldol reaction of enol silyl ethers with aldehydes (Mukaiyama reactions).5 Asymmetric induction is modest (80-85% ee) in reactions of enol ethers of methyl ketones, but can be as high as 96% ee in reactions of enol ethers of ethyl ketones. Moreover, the reaction is syn-selective, regardless of the geometry of the enol. However, the asymmetric induction is solvent-dependent, being higher in nitroethane than in dichloromethane. 

A catalytic asymmetric vinylogous Mukaiyama reaction between silyl dienolate 896 and aliphatic ketone 897 provides the 5,6-dihydropyran-2-one 898, a key intermediate during a formal synthesis of enantiopure taurospongin A (Equation 361) <2005JA7288>. 

Transformations involving chiral catalysts most efficiently lead to optically active products. The degree of enantioselectivity rather than the efficiency of the catalytic cycle has up to now been in the center of interest. Compared to hydrogenations, catalytic oxidations or C-C bond formations are much more complex processes and still under development. In the case of catalytic additions of dialkyl zinc compounds[l], allylstan-nanes [2], allyl silanes [3], and silyl enolethers [4] to aldehydes, the degree of asymmetric induction is less of a problem than the turnover number and substrate tolerance. Chiral Lewis acids for the enantioselective Mukaiyama reaction have been known for some time [4a - 4c], and recently the binaphthol-titanium complexes 1 [2c - 2e, 2jl and 2 [2b, 2i] have been found to catalyze the addition of allyl stannanes to aldehydes quite efficiently. It has been reported recently that a more active catalyst results upon addition of Me SiSfi-Pr) [2k] or Et2BS( -Pr) [21, 2m] to bi-naphthol-Ti(IV) preparations. 

As we mentioned before, a classical Grignard reaction is formally described by the coupling of a covalent (albeit polarized) electrophile with an anionic nucleophile. Reactions shown in Scheme 2.41 (opposite) exemplify the alternative approach involving an interaction between cationic intermediates generated from carbonyl compounds (or their derivatives) under the action of Lewis acids and a purely covalent nucleophile, an allylsilane such as I09a or 109b. Similar electrophiles used in reactions with covalent silyl enolates such as 110 result in the formation of the aldol-Iike products (the Mukaiyama reaction ). 

As above (eq 1), a major drawback of this reagent is the lack of a readily available enantiomer. There are many alternative methods for the enantioselective propionate aldol reaction. The most versatile chirally modified propionate enolates or equivalents are N-propionyl-2-oxazolidinones, a-siloxy ketones, boron enolates with chiral ligands, as well as tin enolates. Especially rewarding are new chiral Lewis acids for the asymmetric Mukaiyama reaction of 0-silyl ketene acetals. Most of these reactions afford s yw-aldols good methods for the anri-isomers have only become available recently. ... 

Lewis acid catalyzed intramolecular alkylations of silyl enol ethers containing 5n1-reactive functionality provide useful routes to a variety of carbocyclic systems. - Smith et al have employed an intramolecular Mukaiyama reaction of the enol derivative (76) to produce the tetracyclic system (77) (equation 7). This transformation was a key step in their elegant synthesis of jatrophone. The synthesis... 

Lewis acid catalyzed reactions of silyl enol derivatives of esters (ketene acetals) with 5n1-reactive alkylation agents are well known, but space limitations have prevented coverage of this subject here. The reaction shown in equation (11), which was employed by Pattenden and coworkers in their synthetic studies on forskolin, provides an example of an intramolecular Mukaiyama reaction of a silyl enol ester derivative. 

Catalytic asymmetric aldol reactions provide one of the most powerful carbon-carbon bond-forming processes affording synthetically useful chiral )ff-hydroxy ketones and esters [25]. Chiral Lewis acid-catalyzed reactions of silyl enol ethers with aldehydes (the Mukaiyama reaction) [3] are among the most convenient and promising, and several successful examples have been reported since the first chiral tin(II)-cat-alyzed reactions appeared in 1990 [26]. Some common characteristics of these cat-... 

The titanium(IV) chloride-promoted reactions of enol silyl ethers with aldehydes, ketones, and acetals, known as Mukaiyama reaction, are useful as aldol type reactions which proceed under acidic conditions (eq (23)) [20], Enol silyl ethers also undergo the Michael type reactions with enones or p.y-unsaturated acetals (eq (24)) [21]. Under similar reaction conditions, enol silyl ethers are alkylated with reactive alkyl halides such as tertiary halides or chloromethyl sulfides (eq (25)) [22], and acylated with acid halides to give 1,3-diketones (eq (26)) [23]. 

The Mukaiyama reaction is an aldol-type reaction between a silyl enol ether and an aldehyde in the presence of a stoichiometric amount of titanium chloride. The reaction, which displays a negative volume of activation, could be performed without acidic promoter under high pressure [58]. In this case, the major product is the syn hydroxy ketone, not as for the TiCl4-promoted reactions which lead mostly to the anti addition product. Since the syn or anti selectivity is the result of two transition states with different activation volumes (AV n < AVfnti), it was of great interest to investigate the aldol reaction in water. Indeed, the reaction of the silyl enol ether of cyclohexanone with benzaldehyde in aqueous medium was shown to proceed without any catalyst and under atmospheric pressure, with the same syn... 

Although the mechanism of the Mukaiyama reaction is not yet fully understood, several points have now been firmly established (a) a Lewis acid enolate is not involved (b) the Lewis acid activates the carbonyl group for the nucleophilic addition and (c) the Si—O bond is cleaved by nucleophilic attack of the anionic species, generally halide, on silicon. Point (a) has been established by the use of INEPT- Si NMR spectroscopy. Moreover, trichlorotitanium enolates have been synthesized, characterized and shown to give a completely different stereochemical outcome than the TiCU-mediated reactions of silyl enol ethers. Complexes between Lewis acids and carbonyl compounds have been isolated and characterized by X-ray crystallography and recently by NMR spectrometry. On the basis of these observations closed transition structures will not be considered here open transition structures with no intimate involvement between the silyl enol ether and the Lewis acid offer the best rationale for the after the fact interpretation of the stereochemical results and the best model for stereochemical predictions. 

Acetate-derived silyl ketene acetals (11, 13 and 14) react with aldehydes with good stereoselectivity (equation 10) significant results are reported in Table 5. Removal of the auxiliary, with methanolic KOH, gave the corresponding (3-hydroxy acids in good enantiomeric excess (ee). The asymmetric variants of the Mukaiyama reaction also helped to solve the long-standing problem of an efficient anti selec-... 

The use of chiral Lewis acids for enantioselective Diels-Alder and hetero Diels-Alder reactions and for other processes of C—C bond formation has recently received great attention. Reetz and coworkers reported that a stoichiometric amount of the chiral Lewis acid (137) effectively promotes the reaction of silyl ketene acetal (98) to give the aldol product in 57% yield and 90% ee (equation 48, R = Me2CHCH2—). When a catalytic amount (5 mol %) of the chiral rhodium perchlorate (138) is used, the aldol product is obtained in >75% yield and 12% ee (equation 48 R = Ph). ° Both reactions probably proceed through the corresponding metal enolates. - The development of new efficient chiral catalysts for the Mukaiyama reaction is certainly one of the challenges of the 1990s. 

The total synthesis of ( )-trichostatin A has been carried out by two routes [67] one uses the y-alkylation of a silyl dienol ether with an acetal which gives the ether in a Mukaiyama reaction. A Wittig olefination followed by DDQ oxidation gives a ketoester which reacts with hydroxylamine to give trichostatin A in 22% overall yield (Scheme 20). 

This review covers the catalytic literature on condensation reactions to form ketones, by various routes. The focus is on newer developments from the past 15 years, although some older references are included to put the new work in context. Decarboxylative condensations of carboxylic acids and aldehydes, multistep aldol transformations, and condensations based on other functional groups such as boronic acids are considered. The composition of successful catalysts and the important process considerations are discussed. The treatment excludes enantioselective aldehyde and ketone additions requiring stoichiometric amounts of enol silyl ethers (Mukaiyama reaction) or other silyl enolates, and aldol condensations catalyzed by enzymes (aldolases) or catalytic antibodies with aldolase activity. It also excludes condensations catalyzed at ambient conditions or below by aqueous base. Recent reviews on these topics are those of Machajewski and Wong, Shibasaki and Sasai, and Lawrence. " The enzymatic condensations produce mainly polyhydroxyketones. The Mukaiyama and similar reactions require a Lewis acid or Lewis base as catalyst, and the protecting silyl ether or other group must be subsequently removed. However, in some recent work the silane concentrations have been reduced to catalytic amounts (or even zero) this work is discussed. 

---