Magnesium enolates synthesis

Synthesis, structure, and transformations of a-pyrone derivatives, viz., xanthy-rones, glaucyrones, and chelated magnesium enolates 98T8243. 

Still s synthesis of monensin (1) is based on the assembly and union of three advanced, optically active intermediates 2, 7, and 8. It was anticipated that substrate-stereocontrolled processes could secure vicinal stereochemical relationships and that the coupling of the above intermediates would establish remote stereorelationships. Scheme 3 describes Still s synthesis of the left wing of monensin, intermediate 2. This construction commences with an aldol reaction between the (Z) magnesium bromide enolate derived from 2-methyl-2-trimethylsilyloxy-3-pentanone (21) and benzyloxymethyl-protected (/ )-/ -hydroxyisobutyraldehyde (10).2° The use of intermediate 21 in aldol reactions was first reported by Heathcock21 and, in this particular application, a 5 1 mixture of syn aldol diastereoisomers is formed in favor of the desired aldol adduct 22 (85% yield). The action of lithium diisopropylamide (LDA) and magnesium(n) bromide on 21 affords a (Z) magnesium enolate that... 

Among the preformed enol derivatives used in this way have been enolates of magnesium, lithium, titanium, zirconium, and tin, ° silyl enol ethers, enol borinates,and enol borates, R CH=CR"—OB(OR)2. The nucleophilicity of silyl enol ethers has been examined. In general, metallic Z enolates give the syn (or erythro) pair, and this reaction is highly useful for the diastereoselective synthesis of these products. The ( ) isomers generally react nonstereoselectively. However, anti (or threo) stereoselectivity has been achieved in a number of cases, with titanium enolates, with magnesium enolates, with certain enol bor-inates, and with lithium enolates at — 78°C. ... 

The magnesium enolates are prepared by treatment of malonic acid half ester either with magnesium ethylate[24],[32] or with isopropylmagnesium bromide[24] or chloride.t26] Ref. [23] describes the synthesis of a 13C-labelled ethyl acetoacetate. Concerning the synthesis of porphyrin / -ketoesters,[3 1 it was noticed that the method via imidazolides is more efficient than the other approach via acid chlorides and sodiomalonic esters. 

The chelation between a Boc group and Mg(II) is often used to control the stereochemistry in aldol reactions. For instance, Donohoe and House have reported the diasteroselec-tive reductive aldol reactions of Boc-protected electron-deficient pyrroles. The key step of the synthesis is the preparation of an exocyclic magnesium enolate of Boc-protected 2-substituted pyrroles. ... 

In view of the importance currently attached to the usefulness and synthesis of magnesium enolates, these different aspects are discussed in this section. 

A similar procedure for the synthesis of a-acyl aminoesters has been proposed using a MgCl2/R3N base system to generate the magnesium enolates of a series of a-carboxy aminoesters. These reagents react smoothly at 0 °C with a variety of acid chlorides to give a-acyl aminoesters in good to excellent yields (equation 58). 

To develop new electrophilic reagents, Ricci and coworkers have described the synthesis of trimethylsilyloxy and hydroxy compounds from magnesium enolates and bis(trimethyl-silyl)peroxide. Magnesium enolates, generated using magnesium diisopropylamide, (DA)2Mg, give the hydroxycarbonyl compounds in excellent yields (equation 72, Table 8). 

TABLE 8. Synthesis of trimethylsiloxy and hydroxy compounds from magnesium enolates and bis(trimethylsilyl)peroxide... 

Magnesium enolates react with aldehydes and ketones to give aldol products after hydrolysis. The reaction proceeds both regio- and stereoselectively and has found many applications in the synthesis of natural products. 

In addition to the structural effects due to the geometry of a substituted magnesium enolate, the stereochemistry of the reaction with a chiral aldehyde can be controlled, as described in equation 85. The aldol reaction based on the addition of magnesium enolate 56 to aldehyde 55 has been applied to the synthesis of monensin. The chiral center in the aldehyde induces the preferential approach of one diastereotopic face of the aldehyde by... 

Having identified the (+)-stereoisomer as the biologically active isomer, several independent enantioselective syntheses of this stereoisomer were developed. The initial synthesis developed in discovery chemistry employed the diastereoselective aldol condensation pioneered by Braun as the key component. Thus, treatment of aldehyde 13 from the racemic synthesis with the magnesium enolate of (5)-(+)-2-acetoxy-l,l,2-triphenylethanol at -70 °C, afforded 17 in 60% yield as a 97 3 mixture of the / ,5 5,5-diastereomers by HPLC (Scheme 3). Ester exchange employing sodium methoxide provided the methyl ester in quantitative yield. Reaction of this ester with three equivalents of lithio-f-butylacetate at -40 °C afforded the nearly enantiomerically pure r-butyl ester analog of racemic 14 in 75% yield. 

Preparative Methods the synthesis of this compound was first reported by methylation of (R)-(+)-t-Butyl 2-(p-Tolylsulfinyl)acetate via enolate generation with lithium bases such as n-Butyllithium or t-Butyllithium at 0 °C and with only lodomethane as the alkylating agent (eq 1). The diastereomeric ratio was shown by H NMR to be 50 50 with BuLi and 42 58 with t-BuLi. The title compound was also prepared from (-)-(1R,2S,5R)-Menthyl (S)-p-Toluenesulfinate and the magnesium enolate of t-butyl propionate in 68% yield as a 1 1 ratio of the two possible diastereomers (eq 2). ... 

Silyl enol ethers react with aldehydes in the presence of chiral boranes or other additives " to give aldols with good asymmetric induction (see the Mukaiyama aldol reaction in 16-35). Chiral boron enolates have been used. Since both new stereogenic centers are formed enantioselectively, this kind of process is called double asymmetric synthesis Where both the enolate derivative and substrate were achiral, carrying out the reaction in the presence of an optically active boron compound ° or a diamine coordinated with a tin compound ° gives the aldol product with excellent enantioselectivity for one stereoisomer. Formation of the magnesium enolate anion of a chiral amide, adds to aldehydes to give the alcohol enantioselectively. 

The halogen-magnesium exchange of a-halo carbonyl compounds has been reported to afford magnesium enolates which react with aldehydes to yield aldol products [107, 108]. The application of this reaction to the synthesis of penicillin derivatives has been reported (Scheme 3.94) [109-111]. 

The reactions of aldehydes with enolates of acetic esters (MeCOOG ) 1.18 (R = H) are often poorly selective [66, 147, 209, 408, 1186, 1258], For this reason, the asymmetric synthesis of acetate aldols is usually performed by reduction of a-bromo analogs with BU3S11H [1254] or from sulfoxides [1049] (see below). However, the reactions of lithium or magnesium enolates of monoacetates of (hols... 

Ketone (27) and reagents related to it have been used in synthesis. In equation (50) is shown an application of the magnesium enolate in Still s synthesis of monensin the facial selectivity in this case is 5 1 and the reaction proceeds in 85% yield. The lithium enolate of (27) has been employed in a synthesis of the C-l.C-7 segment of eiythronolide A (equation 51) the facial selectivity in this case is 6 1. Ketone (31) was used in a synthesis of the basic nucleus of crassin acetate (equation 52). The aldol reaction of (31) with (32), derived from geraniol, occurs in 58% yield to give only one isomer. Four further... 

---