Stereochemistry Mukaiyama aldol reaction

Scheme 2.6. Control of Stereochemistry of Aldol and Mukaiyama Aldol Reactions Using...

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

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... 

The asymmetric total syntheses of mtamycin B and oligomycin C was accomplished by J.S. Panek et al. In the synthesis of the C3-C17 subunit, they utilized a Mukaiyama aldol reaction to establish the C12-C13 stereocenters. During their studies, they surveyed a variety of Lewis acids and examined different trialkyl silyl groups in the silyl enol ether component. They found that the use of BFs OEta and the sterically bulky TBS group was ideal with respect to the level of diastereoselectivity. The stereochemical outcome was rationalized by the open transition state model, where the orientation of the reacting species was anti to each other, and the absolute stereochemistry was determined by the chiral aldehyde leading to the anti diastereomeric Felkin aldol product. 

The Mukaiyama aldol reaction of ethyl ketones can lead to the controlled introduction of two adjacent stereocenters. While enolate geometry may not be trans-fened faithfully to the relative stereochemistry of the aldol product syn versus anti), stereoconvergent reactions are possible. In the example shown in Scheme 9-5, it should be noted that 7i-facial control from the chiral aldehyde is strong as both products 7 and 8 arise from Felkin selectivity [5]. 

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. 

Since the 1950s there have been many variants of the basic phospho-aldol reaction published for the stoichiometric synthesis of a-functionalised phos-phonates. For example, the widely studied Abramov reaction outlined in Scheme 1 b (when R = SiMej, this process can be considered to be a close relative of the Mukaiyama aldol reaction) has been used as a method of building a-functionalised phosphonates both without [4], and more recently with, control over stereochemistry at the a-carbon atom [5]. 

Bolm and coworkers have developed a synthetic procedure for the efficient synthesis of enantiomerically enriched alcohols from pyruvates. As an alternative to the popular PYBOX and BUBOX complexes pioneered by Evans, new Ci-symmetric aryl-bridged aminosulfoximene ligands 71 and 72 were synthesized for use in the copper(II)-catalyzed Mukaiyama aldol reaction. By varying the stereochemistry of the sulfoximine, it is possible to... 

Evans et al. applied the Mukaiyama aldol reaction to the total synthesis of the squalene synthase inhibitor zaragozic acid C (Scheme 8.23). ° Di-f-butyl tartrate 135 was protected as acetal 137, which was converted into silyl enol ether 138. The partner aldehyde 141 was synthesized by the Evans aldol reaction (139 —> 140). The Mukaiyama aldol reaction with silyl enol ether 138 and aldehyde 141 in the presence of (i-PrO)TiCl3 gave adduct 142 as a single isomer. These transformations gave the desired stereochemistry at the C3 to C7 positions. 

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 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. 

BINOL-derived titanium complex was found to serve as an efficient catalyst for the Mukaiyama-type aldol reaction of ketone silyl enol ethers with good control of both absolute and relative stereochemistry (Scheme 8C.24) [57]. It is surprising, however, that the aldol products were obtained in the silyl enol ether (ene product) form, with high syn-diastereoselec-tivity from either geometrical isomer of the starting silyl enol ethers. 

A diastereoselective Mukaiyama aldol lactonization between thiopyridylsilylketene acetals and aldehydes was used to form the /3-lactone ring in the total synthesis of (-)-panclicin D <1997T16471>. Noyori asymmetric hydrogenation was a key step in a total synthesis of panclicins A-E and was used to establish the stereocenter in aldehyde 140, which in turn directed the stereochemistry of subsequent reactions <1998J(P1)1373>. The /3-lactone ring was then formed by a [2+2] cycloaddition reaction of 140 with alkyl(trimethylsilyl)ketenes and a Lewis acid catalyst. 

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]. 

Mukaiyama Aldol Condensation. The BINOL-derived titanium complex BINOL-T1CI2 is an efficient catalyst for the Mukaiyama-type aldol reaction. Not only ketone silyl enol ether (eq 25), but also ketene silyl acetals (eq 26) can be used to give the aldol-type products with control of absolute and relative stereochemistry. 

Mukaiyama Aldol Condensation. As expected, the chiral titanium complex is also effective for a variety of carbon-carbon bond forming processes such as the aldol and the Diels-Alder reactions. The aldol process constitutes one of the most fundamental bond constructions in organic synthesis. Therefore the development of chiral catalysts that promote asymmetic aldol reactions in a highly stereocontrolled and truly catalytic fashion has attracted much attention, for which the silyl enol ethers of ketones or esters have been used as a storable enolate component (Mukaiyama aldol condensation). The BINOL-derived titanium complex BINOL-TiCl2 can be used as an efficient catalyst for the Mukaiyama-ty pe aldol reaction of not only ketone si ly 1 enol ethers but also ester silyl enol ethers with control of absolute and relative stereochemistry (eq 11). ... 

Boron enolates (other names are vinyloxyboranes, enol borinates, or boron enol ethers) are often employed in the aldol reaction because they show higher stereoselectivity than alkali and magnesium enolates. Extensive developmental work in this area has been carried out by Evans, Masamune and Mukaiyama, and their respective coworkers. - - The correspondence between enolate geometry and aldol stereochemistry is exceptional (Z)-enolates give syn/erythro aldol products, whereas ( )-enolates give anti/threo aldol products, albeit with slightly lower selectivity. 

Mechanistically, the cycloaddition reaction is rather complex. Depending on the catalyst or solvent used and the reaction substrates, pericyclic and/or Mukaiyama aldol-like pathways may be involved.43 The pericyclic mechanism, generally favored by zinc chloride and the lanthanide catalysts, tends to produce adducts having the cis relative stereochemistry at C-5,6. It is assumed that chelation of the aldehyde with the Lewis acid occurs in an anti fashion and that the steric bulk of R is less than that of the Lewis acid-solvent complex L [Eq. (11)], thus favoring a Diels-Alder transition state with R endo. 

The chemistry of alkali enolates is subject of a number of extensive reviews [5-13]. The stereochemistry of directed aldol reactions with lithium enolates is discussed in the review of Mukaiyama [5]. 

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