Stereoselectivity Mukaiyama aldol reaction

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... 

SCHEME 21. Synthesis of N-protected a-amino acids and aldehydes by stereoselective addition of bromohthioalkene 5 -41 to sulfonyhmines. Mukaiyama aldol reaction of a-aminoaldehydes... 

The indium trichloride-catalyzed Mukaiyama aldol reaction of 3-aminoketoesters with various silylenolethers gave under solvent-free conditions 1,3-amino alcohols with high stereoselectivity [36], Several Robinson annelation reactions have been carried out enantio-selectively using (S)-proline as a chiral catalyst [37]. Remarkably, the enantioselectivity was distinctly higher in the absence of solvent than in DMSO. 

The Mukaiyama aldol reaction could be catalyzed by chiral bis(oxazoline) copper(II) complexes resulting in excellent enantioselectivities (Fig. 7) [23]. A wide range of silylketene acetals 46 and 49 were added to (benzyloxy[acetaldehyde 45 and pyruvate ester 48 in a highly stereoselective manner. The authors were also able to propose a model to predict the stereochemical outcome of these reactions. 

Mukaiyama aldol reactions of silylketene acetal and pyruvate ester (eq 14) in the presence of 10 mol % Cu[(5,5)-/-Bu-box] (OTf)2 catalyst furnish the corresponding aldol product in excellent enantiomeric excess (98%). Furthermore, the addition reactions of ketene acetals derived from /-butyl thioacetate and ben-zyloxyacetaldehyde with only 5 mol % catalyst afford the aldol product in 91% ee (eq 15). It is also noteworthy that the addition of both propionate-derived (Z)- and ( )-silylketene acetals stereoselectively forms the jyn-adduct in 97% and 85% ee, respectively. 

The Mukaiyama aldol reaction of carbonyl substrates with silyl enol ethers is the most widely accepted of Lewis acid-promoted reactions. Many Lewis acids for the reaction have been developed and used enantioselectively and diastereoselectively. In 1980, catalytic amounts of la were found by Noyori et al. to effect aldol-type condensation between acetals and a variety of silyl enol ethers with high stereoselectivity [2c,20]. Unfortunately, la has poor Lewis acidity for activation of aldehydes in Mukaiyama s original aldol reaction [21]. Hanaoka et al. showed the scope and limitation of 11-cat-alyzed Mukaiyama aldol reaction, by varying the alkyl groups on the silicon atom of silyl enol ethers [22]. Several efforts have been since been made to increase the reactivity and/or the Lewis acidity of silicon. One way to enhance the catalyst activity is to use an additional Lewis acid. 

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... 

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. 

TiCl4 is used extensively as a Lewis acid in numerous organic transformations, forming adducts that mediate reactivity. Such reactions include Diels Alder, 54,355 hetero Diels Alder,356 cyclization of olefinic aldehydes,357 Flosomi Sakurai allylic coupling reactions,358 cyclopropanations,359 chal-cogen-Baylis Flillman,360 Mukaiyama Aldol reactions,36 363 reductions of ketones to alcohols 364 and stereoselective nucleophilic additions to aldehydes.365... 

In the nineteen-eighties many researchers developed a variety of Lewis acid catalysts of the Mukaiyama aldol reaction. In particular, TrClO4 [23] and TMSOTf [24] effectively promote reaction of silyl enolates with aldehydes or acetals. These studies suggested that introduction of a soft Lewis base such as the CIO4 or OTf anion into the Lewis acidic center should lead to effective catalysts. Based on this concept, further studies have been continued to develop novel Lewis acid catalysts with higher catalytic activity or higher chemo- and stereoselectivity. 

Loh et al have demonstrated the stereoselective synthesis of 1,3-amino alcohols based on the InCla-catalyzed Mukaiyama aldol reaction of a keto ester under solvent-free conditions. The high selectivity has been explained by the influence of a remote group present in the keto ester (Scheme 5.45). 

Diene (14) reacted with a series of aldehydes under BFs-OEtz catalysis in CH2CI2 to give predominantly trans products (Table lO). " Aldol-type products, such as p-hydroxy enones, are isolated (along with dihydropyrones) from the reaction mixtures. Using TFA as a catalyst, the p-hydroxy enones are, as previously described, converted into dihydropyrones. The stereoselectivity of these reactions is consistent with a Mukaiyama-aldol reaction rather than a Diels-Aider cycloaddition. The stereochemistry of the P-hydroxy enones is also consistent with the observation that the (Z)-alkoxysilane reacts with the aldehyde in an extended transition state to give anti (threo) aldol products (Scheme 16). In the cases using ZnCh or lanthanide ions as catalysts aldol products have not been detected. 

The same catalyst 2a was able to promote with good yields and stereoselectivities the Mukaiyama aldol reaction of silylenolate 17 to a-ketoesters 16 as well as to acetylphosphonates 19/ while in the addition to alde-hydes derivative 2d was more effective (Scheme 24.7). All these experiments... 

The change from a free alkyne to a bulky complexed alkyne can also affect the stereoselectivity in some reactions. One reaction where this is important is the aldol reaction. In a Mukaiyama aldol reaction, the presence of bulky substituents often leads to higher stereoselectivity. A free alkynyl aldehyde reacted with... 

Pioneering work by Lubineau and coworkers showed that the aldol type reaction between a silyl enol ether and an aldehyde (the so-called Mukaiyama aldol reaction) occurred in water at room temperature with high syn stereoselectivity, albeit in low yields.However, the development of water-tolerant Lewis acids for this reaction has led to improved rates and chemical yields. Various lanthanides triflates, such as ytterbium triflate [Yb(OTf)3], scandium triflate [Sc(OTf)3], gadolinium triflate [Gd(OTf)3], or lutetium triflate [Lu(OTf)3], have been found to afford the aldol products between various aldehydes and silyl enol ethers in high yields in aqueous media, with good to moderate syn/anti diastereoselectivi-ties (Scheme 8.3, Table 8.1). ... 

Cyclohepta-3,5-dienone)iron complexes can be stereoselectively methylated and hydroxylated. The electrophile adds exclusively anti to the tricarbonyliron fragment. Double methylation or hydroxylation of the a and a positions is accomplished in high overall yield (Scheme 4-146). Silyl enol ethers adjacent to tricarbonyl(Ti -diene)iron units can be subjected to Mukaiyama aldol reaction with aldehydes to provide aldol adducts with varying diastereoselectivity. This methodology has, for example, been applied to the enantioselective synthesis of the dienetriols streptenol C and D (Scheme 4-147). ... 

Dideoxyhexoses can be obtained in a stereoselective manner from lact-aldehyde as well as 3-deoxypentoses from (-)-myrtenal using the same reaction as a key step. Mukaiyama aldol reaction has also been an integral part of the synthesis of an elaborate chlorohydrin intermediate of amphotericin Tin enolates can be... 

Heathcock and Filippin investigated the effect of the chirality of aldehydes on 1,2-diastereoselection in aldol condensations, and they found that the Mukaiyama aldol reaction enhanced the stereoselectivity to give syn adduct (Scheme 8.29). In the case of the aldehyde ent-l6S,... 

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