Hydroxymethylene derivatives synthesis

The reaction of a-bromoacetals with trimethylsilylenolates catalyzed by titanium tetrachloride provides /3-alkoxy-y-bromoketones, which are useful furan precursors (Scheme 33) (75CL527). A new synthesis of acylfurans is exemplified by the formation of the 3-acetyl derivative (146) by heating the brdmoalkene (145) (78JOC4596). 2,2-Dimethyl-3(2//)-furanone (148) has been synthesized from 3-hydroxy-3-methylbutan-2-one treatment with sodium hydride and ethyl formate gave the hydroxymethylene derivative (147), which was cyclized and dehydrated to the furanone (148) with hydrochloric acid (Scheme 34) (71TL4891). O... 

Piers et have completed the synthesis of eremophilenolide (347), using the hydroxymethylene derivative of (336). Thus, dehydrogenation of this compound gave the cross-conjugated keto-aldehyde (348) which was converted in four... 

The second synthesis of septicine used as starting material ethyl homovera-trate, which was formylated to the a-hydroxymethylene derivative (24). Controlled reduction of (24) with sodium borohydride gave mainly the desired )5-hydroxyester, which was converted into the chloride and condensed with ethyl 2-pyrrolidinyl acetate to yield the diester (25). Dieckmann cyclisation of... 

Fig.(5). An alternative synthesis of the decalone (50) from the Wieland-Miescher ketone (1) is described, its hydroxymethylene derivative on subjection to selenenation followed by oxidation afforded the unsaturated aldehyde (52) in excellent yield. The protection of the aldehyde moiety of (52) followed by the conversion of the resulting product to the adduct (54) led to the formation of the enol ether (55) which on hydroxylation yielded a mixture of hydroxy-aldehyde (56) and (57). This on acid hydrolysis afforded muzgadial (58) in 85% yield.

In 1992, Desmaele utiUzed enamine chemistry in a Michael addition to obtain chiral precursor 193 that gave vertinolide s tetronic ring (194) afler ketahzation, oxidation to lactone, and elimination (Scheme 1.31) [108]. After 4years, Matsuo and Sakaguchi [109] employed their chiral l,3-dioxolan-4-one 195 to obtain the central unsaturated lactone 196 after side-chain functionalization and condensation with triethyl-2-phosphonopropionate derived anion. Finally, in 2006, Takabe and coworkers [110], based on their previous work on the synthesis of racemic vertinolide, applied a lipase-catalyzed resolution on a 5-hydroxymethylene derivative of 197 to reach the natural enantiomer after five more synthetic steps (Scheme 1.31). 

The Reformatsky reaction has been applied to the synthesis of fused pyranones and provides an example of selective isomer formation by careful choice of substrate. Hydroxy-methylenecyclohexanone (315) and methyl bromoacetate give 5,6,7,8-tetrahydro-l-benzopyran-2-one (316) through alkylation at the hydroxymethylene carbon atom (54JA6388). However, the benzoyl derivative (317) is unable to form an enolate salt and alkylation occurs at the carbonyl carbon atom, leading to 5,6,7,8-tetrahydro-2-benzopyran-3-one (318) (45HCA771). 

Compounds of this type are regarded as 4,5-disubstituted isoxazoles, and as such they react. Their formation from 2-acylcyclohexanones and hydroxylamine is a special case of the general method of isoxazole formation from /9-diketones. 2-Formyl (hydroxymethylene) cyclohexanones, obtained from the respective cyclohexanones and ethyl formate, give 3-unsubstituted derivatives [Eq. (7)].84-91 This reaction has been applied to a stereospecific synthesis of estrone.87,89... 

In 1887, Claisen and Lowman reported that the condensation of 2 mol of an ester, such as ethyl acetate, in the presence of base gave the p-keto ester, ethyl acetoacetate (ethyl 3-oxobutanoate equation 1). The intramolecular equivalent was recognized by Dieckmann in 1894. He found that heating an adipic acid ester with sodium and a trace of alcohol led to cyclization, with the formation of a cyclopentanone (equation 2). The reaction was, at an early stage, extended to the acylation of ketones. Claisen himself reported the base-catalyzed reaction of acetophenone and ethyl benzoate to give dibenzoylmethane in 1887. This reaction, too, has an intramolecular parallel. The acylation of ketones with esters and other acid derivatives is sometimes called a Claisen condensation, although this usage is criticized by some writers and avoided by others. A widely used example of ketone acylation is the synthesis of a-formyl (hydroxymethylene) ketones (equation 3). Intramolecular variants of this reaction include the classical synthesis of dimedone (Scheme 1). 

The method has been recently improved, in collaboration with Fiisfero (Scheme 5) (36). In fact, lithium derivative of (6>naphthyl methyl sulfoxide 21 was found to provide much better stereocontrol in the condensation with A -PMP fluoroalkyl imines 15a,b,f. The resulting A -PMP naphthyl derivatives 22 were transformed into the enantiomeric (5)-P-fluoroalaninols 20 following an identical sequence of reactions, in high overall yields and stereoselectivity. Oxidation of the hydroxymethylene group, according to the method of Sharpless (37), extended the field of application of this strategy to the synthesis of enantiopure p-fluoro alanines 23. The wide scope of the NOP reaction is demonstrated by the fact that also naphthyl sulfoxides, like 22, can be successfully submitted to the reaction. 

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