Silyl enol ethers stereochemistry

Although ethereal solutions of methyl lithium may be prepared by the reaction of lithium wire with either methyl iodide or methyl bromide in ether solution, the molar equivalent of lithium iodide or lithium bromide formed in these reactions remains in solution and forms, in part, a complex with the methyllithium. Certain of the ethereal solutions of methyl 1ithium currently marketed by several suppliers including Alfa Products, Morton/Thiokol, Inc., Aldrich Chemical Company, and Lithium Corporation of America, Inc., have been prepared from methyl bromide and contain a full molar equivalent of lithium bromide. In several applications such as the use of methyllithium to prepare lithium dimethyl cuprate or the use of methyllithium in 1,2-dimethyoxyethane to prepare lithium enolates from enol acetates or triraethyl silyl enol ethers, the presence of this lithium salt interferes with the titration and use of methyllithium. There is also evidence which indicates that the stereochemistry observed during addition of methyllithium to carbonyl compounds may be influenced significantly by the presence of a lithium salt in the reaction solution. For these reasons it is often desirable to have ethereal solutions... 

When there is also a stereogenic center in the silyl enol ether, it can enhance or detract from the underlying stereochemical preferences. The two reactions shown below possess reinforcing structures with regard to the aldehyde a-methyl and the enolate TBDMSO groups and lead to high stereoselectivity. The stereochemistry of the (3-TBDMSO group in the aldehyde has little effect on the stereoselectivity. 

The synthesis in Scheme 13.44 is also based on a carbohydrate-derived starting material. It controlled the stereochemistry at C(2) by means of the stereoselectivity of the Ireland-Claisen rearrangement in Step A (see Section 6.4.2.3). The ester enolate was formed under conditions in which the T -enolate is expected to predominate. Heating the resulting silyl enol ether gave a 9 1 preference for the expected stereoisomer. The... 

Reactions of 1 with epoxides involve some cycloaddition products, and thus will be treated here. Such reactions are quite complicated and have been studied in some depth.84,92 With cyclohexene oxide, 1 yields the disilaoxirane 48, cyclohexene, and the silyl enol ether 56 (Eq. 29). With ( )- and (Z)-stilbene oxides (Eq. 30) the products include 48, ( > and (Z)-stilbenes, the E- and Z-isomers of silyl enol ether 57, and only one (trans) stereoisomer of the five-membered ring compound 58. The products have been rationalized in terms of the mechanism detailed in Scheme 14, involving a ring-opened zwitterionic intermediate, allowing for carbon-carbon bond rotation and the observed stereochemistry. 

In 1992, Thornton et al. reported that Mn(salen) (43) catalyzed the asymmetric oxidation of silyl enol ethers to give a mixture of a-siloxy and a-hydroxy ketones, albeit with moderate enantioselectivity (Scheme 28).135 Jacobsen et al. examined the oxidation of enol esters with Mn(salen) (27) and achieved good enantioselectivity.136 Adam et al. also reported that the oxidation of enol ethers with (27) proceeded with moderate to high enantioselectivity.137 Good substrates for these reactions are limited, however, to conjugated enol ethers and esters. Based on the analysis of the stereochemistry,137 enol ethers have been proposed to approach the oxo-Mn center along the N—Mn bond axis (trajectory c, vide supra). 

The reaction of pyrazine and quinoxaline with methyl chloroformate and bis-silyl enol ethers gave fused tetrahydropyrazine lactones 88, in an extension of previous work. There was little consistency with the variation of R in the stereochemistry of the products <06T12084>. 

The stereochemistry of the silyl enol ether Claisen rearrangement is controlled not only by the stereochemistry of the double bond in the allyhc alcohol but also by the stereochemistry of the silyl enol ether. For the chair transition state, the configuration at the newly formed C—C bond is predicted to be determined by the E- or Z-configuration of the silyl enol ether. 

The stereochemistry of the silyl enol ether can be controlled by the conditions of preparation. The base that is usually used for enolate formation is LDA. If the enolate is prepared in pure THF, the is-enolate is generated, and this stereochemistry is maintained in the silylated derivative. The preferential formation of the A-enolate can be explained in... 

Aldol condensation. The aldol condensation of silyl enol ethers with an aldehyde in the presence of 1 (0.1 5 equivalents) results mainly or even exclusively in erythro-adducts (equations I and II) regardless of the stereochemistry of the cnolatc. 

Recently, Yamamoto et al. have shown that the chiral acyloxyborane complex 31 is an excellent catalyst for the asymmetric Mukaiyama condensation of simple silyl enol ethers (Scheme 8B1.19 Table 8B1.11 entries 1-7) [43], The syn-aldol adducts are formed preferentially with high enantiomeric excess regardless of the stereochemistry (EI7) of the silyl enol ethers, suggesting an extended transition state (entries 4, 7). This methodology has been... 

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. 

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... 

Unhindered aliphatic ketones usually react with LDA to form L-cnolates. However, in this case the steric demand of the alkyl side chain provokes strong 1,2-interactions disfavoring transition state 25. Thus the stereochemistry of the enolization proceeds preferred via 24 yielding Z-enolate 26, which is subsequently trapped by TMSCI to give the corresponding silyl enol ether 6. 

Presumably the silyl enol ether of 37 adds in a conjugate fashion to the unsaturated ester 39 and the intermediate enolate then cyclises onto the cation 40 to give 38. This will happen only if the stereochemistry of 40 is the same as that of the product 38 as the 4/5 and 4/6 ring fusions must both be cis. This suggests that the first step is reversible. The formation of the cyclobutane requires that particular relationship between ketone and unsaturated ester so this kind of reaction is less versatile than photochemical cyclisation. Asymmetric versions of these reactions are also known.14 Probably the most versatile thermal method to make cyclobutanes uses ketenes and is the subject of the next chapter. 

Substrates containing an electron-rich double bond, such as enol ethers and enol acetates, are easily oxidized by means of PET to electron-deficient aromatic compounds, such as dicyanoanthracene (DCA) or dicyanonaphthalene (DCN), which act as photosensitizers. Cyclization reactions of the initially formed silyloxy radical cation in cyclic silyl enol ethers tethered to an olefinic or an electron-rich aromatic ring, can produce bicyclic and tricyclic ketones with definite stereochemistry (Scheme 9.14) [20, 21]. 

Lithiated silyl enol ethers related to 124 have been used in the synthesis of polyunsaturated aldehydes by chain extension, as shown below.109110 The stereospecificity (or otherwise) of the reaction is irrelevant to the stereochemistry of the products 131 and 132, which is under thermodynamic control. 

A number of other acyclic Z and E lithium enolates were quenched similarly. In all cases the stereochemistry at the enol double bond was retained, as shown by subsequent conversion into the corresponding silyl enol ether. Upon reacting the titanium enolates with aldehydes, very clean aldol addition occured (>90% conversion at —78 °C). Generally, erythro-selectivity was observed irrespective of the geometry of the enolate. Equations 64 and 65 are typical25). 

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). ... 

The ( )/ (Z) substrate-dependent absolute stereochemistry and the steric influence of 5n-substituents on the enantioselectivity observed in these reactions suggest that the mechanism is essentially different from that of silyl enol ethers. Although the detailed stereochemical course has not been ascertained, it is possible that the protonation occurs via a two-chlorine-bridged intermediate between allyltrimethyltin and LBA. Keck et al. have reported that transmetalation between allyltributyltin and free... 

The absolute stereochemistries observed are best explained in terms of the acyclic extended transition-state mechanism which Noyori postulated in the TMSOTf-cata-lyzed aldol reactions of dimethyl acetals (Fig. 6) [144]. In the reaction of aromatic silyl enol ethers, the left transition state, which is stabilized by the jr-attractive interaction between the phenyl and naphthyl groups, is favored over the right. In the reaction of... 

This sequence transforms acyclic ketones and aldehydes into a-methylene ketones and a-methyl-a,)5-unsaturated ketones and aldehydes It has been illustrated by the synthesis of eucarvone, ( )-nuciferal and ( )-manicone This ring-opening of chlorosiloxycyc-lopropanes with ClSiMea elimination appears to be a practical route to Z or a,)5-ethylenic aldehydes and ketones depending on the stereochemistry of the reactants. For example, conversion in MeOH-NEta at 20°C of the 2-chloro-2-methyl-3-pentyl-l-trimethylsiloxycyclopropanes (derived from the addition of the chloromethylcarbene to the E and Z silyl enol ethers of n-heptanal) leads either to or Z 2-methyl-oct-2-enal (equation 65). ... 

To avoid complications with the reactive enolates and to preserve the stereochemistry it has proven practical to employ the derived silyl enol ethers, formed by trapping the enolates with chlorotrialkyl-silane instead of the enolates themselves. The rearrangement of the silyl enol ethers takes place under mild conditions, too, often at room temperature, and exhibits all the characteristics of 3,3-sigmatropic rearrangements, namely high stereoselectivity in the formation of double bonds and stereocenters. 

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. 

Jauch, J. Stereochemistry of the Rubottom oxidation with bicyclic silyl enol ethers synthesis and dimerization reactions of bicyclic a-hydroxy ketones. Tetrahedron 1994, 50,12903-12912. 

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