Hemiacetals preparation

The methyl enol ether 37 is oxidized to the a,/3-unsaturated aldehyde 39 via hemiacetal 38. Unsaturated aldehyde 39, elongated one carbon from the aldehyde 36, is prepared by the Wittig reaction of 36 to give 37, and application of this reaction[ 88]. 

One of the mdustnal processes for the preparation of phenol discussed in Section 24 6 includes an acid catalyzed rearrangement of cumene hydroperoxide as a key step This reaction proceeds by way of an intermediate hemiacetal... 

An alternative approach to the use of a-aminoketones involves acetals (72JOC221) and pyrazine-2,3-diones have been synthesized by this route (Scheme 58). The acetals are readily available from the phthalimido derivatives via the a-chloroketones. Hemiacetals have also served as a starting point for pyrazine synthesis, although in most cases hemiacetals are too labile to be easily prepared examples are common in the 2-amino-2-deoxy sugar series 2-amino-2-deoxy-D-glucose for example dimerizes to the pyrazine (101) when generated in situ from the hydrochloride salt (68JAP6813469). 

When the carbonyl group is very electron-deficient, thus stabilizing the hemiacetal, a dioxolane can be prepared under basic conditions. 

Similarly 11,19-hemiacetals have been prepared from lljS-hydroxy-19-16... 

A more general route to 4-acetoxy-l,3-dioxanes utilizes the reductive acylation of l,3-dioxane-4-ones [46] (Scheme 21). l,3-Dioxane-4-ones 126 are prepared from the corresponding -hydroxy carboxylic acids. Low temperature reduction with DIBALH generates a diisobutylaluminum hemiacetal (127) which undergoes acylation in situ with AC2O in the presence of pyridine and DMAP. This method allows for the preparation of a wide range of 4-acetoxy-l,3-dioxanes, without the problem of a-epimerization. This method also represents a general approach to acylic a-acetoxy ethers, which are themselves useful synthetic intermediates [47,48]. 

Three independent syntheses of ( + )-peshawarine (43) have been carried out. Shamma et al. (3,30), in a biogenetictype transformation, prepared it from ( )-aobamine (1) which had been obtained from coptisine (14) (see Scheme 2, Section II,A,l,a). Under the action of ethyl chloroformate, 1 was converted to cyclic hemiacetal 46, whose methyl acetal was reduced to the tertiary base 47. 

The pyranocoumarin 105 can be prepared via a three-component Diels-Alder reaction between 4-hydroxycoumarin, ethyl vinyl ether and an a-dicarbonyl compound. Similarly to the above, upon treatment of 105 with sulfuric acid in THF, hydrolysis and rearrangement occur to give the furofurochromenone 106. The hemiacetal functionality in 106 may then be oxidized with pyridinium chlorochromate (PCC) to give the lactone 107 <2001EJ03711> (Scheme 28). 

Butyl alcohol is not the principal use of butanal obtained by propene hydro formylation. Rather its major market is 2-ethylhexanol that is prepared via aldol condensation followed by hydrogenation. [4] Thus formation of alcohols when aldehydes are desired is not only a direct efficiency loss, but also the alcohol impurity will form hemiacetals and acetals that complicate refining and lead to increased operating costs. 

An intermediate a-bromo-a-formylacetate hemiacetal has been prepared by reaction of ethyl (3-ethoxyacrylate with A-bromosuccinimide (NBS). Cyclizat-ion of the in situ formed hemiacetal with thioureas affords 2-amino-1,3-thiazole-5-carboxylates (Scheme 58).141... 

An interesting variant involves the use of an allylic alcohol as the alkene component. In this process, re-oxidation of the catalyst is unnecessary since the cyclization occurs with /Uoxygen elimination of the incipient cr-Pd species to effect an SN2 type of ring closure. Both five- and six-membered oxacycles have been prepared in this fashion using enol, hemiacetal, and aliphatic alcohol nucleophiles.439,440 With a chiral allylic alcohol substrate, the initial 7r-complexation may be directed by the hydroxyl group,441 as demonstrated by the diastereoselective cyclization used in the synthesis of (—)-laulimalide (Equation (120)).442 Note that the oxypalladation takes place with syn-selectivity, in analogy with the cyclization of phenol nucleophiles (1vide supra). 

Takano s group reported the first enantioselective total synthesis of (—)-anti-rhine as well (146). Chiral product 235 was prepared via a number of stereoselective reactions. Reductive condensation of 235 with tryptamine, using sodium cyanoborohydride at pH 6, supplied lactam 236, which was reduced by di-isobutylalminum hydride to hemiacetal 237. The latter could be cyclized to (-)-antirhine by simple acid treatment (146). 

Representative Experimental Procedures 128 Representative Procedure for Preparation of Cl-Hemiacetal Donors Through a Peracylation-Selective Anomeric Deacylation Sequence 128... 

Yet another method involves the treatment of a hemiacetal with oxalyl chloride in DMF. The protocol allows for an efficient preparation of a-chlorides of 2-deoxy-L-hexopyranosides (Scheme 2.28) [128]. 

This chapter outlines the development, achievements and limitations of glycosyla-tion methods that rely on Cl-hemiacetal donors and Cl-O-acyl donors. These are among the simplest glycosyl donors to prepare in standard O-glycosylation reactions. As such, developments in the use of these donors constitute valuable advances in the field of synthetic carbohydrate chemistry. 

Indeed, a variety of Lewis acids have been shown to effed glycosylation with hemiacetal donors. Ernst and coworkers have used 5mol% of [Rh(III)(MeCN)3 (triphos)] tris(triflate) with 4 A molecular sieves to prepare glycoconjugates 18 and 19 [26]. Mukaiyama s group has used trityl tetrakis(pentafluorophenyl)borate (3-5 mol%) with Drierite in the preparation of disaccharides 20 and 21 [27,28]. In the synthesis of 21, the a-seledivity was shown to arise from in situ anomerization of the (1-pyranoside over time. 

This method has been used only a few times, despite the high yields reported. In the procedure, the hemiacetal was activated with tributylphosphine oxide (4.5 equiv) and triflic anhydride (2.1 equiv) for 2 h at 0 °C, followed by an addition of the giycosyi acceptor. As a result, the isopropyl riboside 46 was prepared in 93% and the cho-lestanyl riboside 47 was prepared in 75%, both with a-anomeric selectivity. 

In an early example, Mukaiyama and coworkers used hetaryl onium salts for nucleoside synthesis. The active hetaryl onium salt is generated in situ from the reaction of 2-chloro-3-ethylbenzoxazolium tetrafluoroborate 77 and the glycosyl acceptor. With benzimidazole as glycosyl acceptor, the resulting 2-(l-benzimida-zoyl)benzoxazolium tetrafluoroborate 78 was obtained. The reaction between the hetaryl onium salt 78 and hemiacetal donor 1 occurs at 60 °C to activate the hemiacetal and thereby reveal the glycosyl acceptor. This procedure led to the formation of nucleoside 80 with exclusive 1,2-trans selectivity [139]. The nucleoside 81 was similarly prepared. Alternatively, 2-fluoro-l-methylpyridinium tosylate 79 directly... 

A typical procedure calls for reaction of the hemiacetal donor with dicydohexyl carbodiimide and copper(I) chloride (0.1 equiv) at 80 °C, followed by an addition of the acceptor and continued heating. As an early demonstration of this protocol, oc-riboside 86 was prepared in moderate yield but with exclusive stereoselectivity [141]. Further measures were required for the glycosylation of monosaccharide acceptors, such as addition of p-toluenesulfonic add (0.1 equiv) to promote the formation of disaccharide 87 [144]. The method was more suitably applied to the synthesis of O-acyl glycopeptides, as evidenced by the formation of 88 in 60% yield [143,144]. Various peptides with non-nudeophilic side chains were found to be amenable to this stereoselective reaction. The [3-selectivity was suggested to arise from a preponderance of the a-isourea intermediate 85 in the activation step. 

This procedure has been demonstrated to provide moderate yields and anomeric selectivity in oligosaccharide synthesis. For instance, the disaccharide 110 was obtained in 50% yield as a 1 2 a p ratio. The reaction side products were mainly the self-condensed donor (10-25%) and unreacted hemiacetal (5-10% or higher). Alternatively, the a-linked glycosides were favored with diethyl ether solvent. In this way, trisaccharide 111 was prepared from the disaccharide hemiacetal donor in 49% yield, favoring the a-anomer by 4 1. 

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