Stereoselective Mukaiyama reaction

There have been many elegant approaches to podophyllotoxin and its derivatives, some of which have already been highlighted. In the approach of Kaneko and Wong the advanced precursor (143) was prepared by a stereoselective Mukaiyama reaction of the key intermediate (142). The product (143) was then converted into podophyllotoxin (113) (scheme 56)... 

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... 

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... 

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... 

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. 

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). 

Azaborolyl complex (- -)-218 has been used in a stereoselective Mukaiyama aldol reaction as illustrated in Scheme 32 <2005JA15352>. Complex (- -)-218 reacts with electron rich aromatic aldehydes and silyl ketene acetals to generate adduct 220. X-ray structures indicate the stereochemistry is as illustrated. This stereochemistry is... 

Mukaiyama, T, Matsubara, K, Stereoselective glycosylation reaction starting from 1-0-trimethylsilyl sugars by using diphenyltin sulfide and a catalytic amount of active acidic species, Chem. Lett., 1041-1044, 1992. 

Stereoselective Mukaiyama-Michael reactions, Heathcock et alJ have investigated the syn anti stereoselectivity in the reaction of twelve silyl enol ethers with a variety of acyclic and cyclic enones catalyzed by TiCh or SnCh. Preliminary results suggest that the stereoselectivity is independent of the geometry of the silyl enol ether, and that silyl enol ethers derived from aliphatic ketones show a preference for (2n /-addition ranging from 1.5 1 to 10 1. The preference for a/ift-addition is even higher in the case of (Z)-silyl enol ethers of aromatic ketones (10 1 to >20 1). However, high 5y/i-selectivity is observed with acyclic -butyl enones. 

Given this problem, the attachment of the butanone synthon to aldehyde 74 prior to the methyl ketone aldol reaction was then addressed. To ovenide the unexpected. vTface preference of aldehyde 74, a chiral reagent was required and an asymmetric. syn crotylboration followed by Wacker oxidation proved effective for generating methyl ketone 87. Based on the previous results, it was considered unlikely that a boron enolate would now add selectively to aldehyde 73. However, a Mukaiyama aldol reaction should favour the desired isomer based on induction from the aldehyde partner. In practice, reaction of the silyl enol ether derived from 87 with aldehyde 73, in the presence of BF3-OEt2, afforded the required Felkin adduct 88 with >97%ds (Scheme 9-29). This provides an excellent example of a stereoselective Mukaiyama aldol reaction uniting a complex ketone and aldehyde, and this key step then enabled the successful first synthesis of swinholide A. 

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 course of other types of reactions which are also accelerated in aqueous solutions can help for a better understanding. For instance, in the Mukaiyama reaction between a silylenol ether and a carbonyl compound we obtained, in water, without any catalyst and in a similar yield, the same stereoselectivity than under 1(XX)0 atmospheres in dichloromethane that is the reverse of the normal stereoselectivity obtained by TiC catalysis(22,25). We and others have also described such a rate enhancement in the Claisen rearrangement (24 5), All these reactions, including the Diels Alder reaction have in common their negative activation volume. We anticipate that a reaction under kinetic control, between two small hydrophobic molecules (or between the hydrophobic moieties of amphiphilic molecules) for which the activation volume AVt is negative must be accelerated in water as it is under pressure. When several transition states are possible, the more compact should be favored. Actually, this hypothesis is verified for all our aqueous reactions, especially the Diels-Alder reactions which give virtually pure endo transition state which is also the transition state favored under external pressure. 

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)." ... 

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. 

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. 

Camphor derived acetates 1 (Helmchen-type65) and 3 (Oppolzer-lype66) add to aldehydes in a stereoselective manner when the Mukaiyama variation via the corresponding silylketene acetals is undertaken. Careful optimization of the reaction conditions provides predominantly... 

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... 

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