Glyoxylic acid Diels-Alder reactions

A combination of the promoting effects of Lewis acids and water is a logical next step. However, to say the least, water has not been a very popular medium for Lewis-acid catalysed Diels-Alder reactions, which is not surprising since water molecules interact strongly with Lewis-acidic and the Lewis-basic atoms of the reacting system. In 1994, when the research described in this thesis was initiated, only one example of Lewis-acid catalysis of a Diels-Alder reaction in water was published Lubineau and co-workers employed lanthanide triflates as a catalyst for the Diels-Alder reaction of glyoxylate to a relatively unreactive diene . No comparison was made between the process in water and in organic solvents. 

Bronsted-acid-catalyzed Diels-Alder reactions are not frequent because of the proton sensitivity of many dienes and cycloadducts, especially when long reaction times and high temperatures are required. Examples in aqueous medium involving imines activated by protonation as dienophiles and a proton-promoted Diels-Alder reaction of glyoxylic acid with cyclopentadiene are considered in Section 6.1. 

Lubineau and coworkers [18] have shown that glyoxal 8 (Ri = R2 = H), glyoxylic acid 8 (Ri = H, R2 = OH), pyruvic acid 8 (Ri = Me, R2 = OH) and pyruvaldehyde 8 (Ri = H, R2 = Me) give Diels-Alder reactions in water with poor reactive dienes, although these dienophiles are, for the most part, in the hydrated form. Scheme 6.6 illustrates the reactions with (E)-1,3-dimethyl-butadiene. The reaction yields are generally good and the ratio of adducts 9 and 10 reflects the thermodynamic control of the reaction. In organic solvent, the reaction is kinetically controlled and the diastereoselectivity is reversed. 

C-Disaccharide analogs of trehalose were recently [20c] prepared by using as a key step an aqueous Diels-Alder reaction between the sodium salt of glyoxylic acid and the water soluble homochiral glucopyranosil-l,3-pentadiene 19 (Equation 6.1). A mixture of four diastereoisomers in a 41 24 21 14 proportion was obtained after esterification with methanol and acetylation. The main diaster-eoisomer 20 was isolated and characterized as benzoyl-derivative. 

Acyclic dienes react with glyoxylic acid via an oxo-Diels-Alder reaction to give dihydropyran derivatives (Eq. 12.53). An excellent application of the oxo-Diels-Alder reaction is reported by Lubineau et al. in the synthesis of the sialic acids, 3-deoxy-Z)-manno-2-octulosonic acid (KDO) and 3-deoxy-D-glycero-D-galacto-2-nonulosonic acid (KDN).123... 

Under the influence of 20 mol% of the chiral aluminum complex (S)-26, 2,3-dimethyl-1,3-butadiene adds to ethyl glyoxylate in dichloromethane at —78 °C to room temperature during 20 h to produce a mixture of the cycloadduct 23 (R2 = Et) (73% yield, 97% ee) and the ene product 24 (R2 = Et) (9% yield, 88% ee)17. The analogous aluminum complexes (R)-27 and (S)-27 (Ar = Ph or 3,5-xylyl) (10 mol% in toluene) catalyze the Diels-Alder reaction of benzaldehyde with the diene 28 to give, after the addition of trifluoroacetic acid, the dihydropyrone 29 in 95% ee, accompanied by a small amount of the corresponding fraws-isomer (equation 19)18. 

Bi(0Tf)3xH20 has been found to catalyze carbonyl-Diels-Alder reactions in water involving glyoxylic acid as the dienophile (Scheme 14) [72]. In contrast to other Lewis acids (such as Sn(OTf)2, Yb(OTf)3, Nd(OTf)3, Ce(OTf)3 and Sc(OTf)3), the strong catalytic power of Bi(0Tf)3-xH20 made it necessary to reduce its amount as well as the reaction temperature. Bi(0Tf)3-xH20 enhanced the reaction rate but with some dienes the reaction led to competitive formation of the ene reaction product. 

In hetero-Diels-Alder reactions, the effect of ligand structure and acidity on the catalytic activity of lanthanide catalysts has been reviewed.191 The effect of different C(2)-symmetric bisoxazolines on the zinc(II)-catalysed hetero-Diels-Alder reaction of ethyl glyoxylate with conjugated 1,3-dienes has been investigated.192 The hetero-Diels-Alder reaction 4-dimethylamino-2-phenyl-l-thiabuta-1,3 -diene with methyl acrylate and /V-cnoyloxazolidinone produces cw-3,4-disubstituted 3,4-dihydro-2//-... 

The choice of solvent has had little, if any, influence on the majority of Diels-Alder reactions.210,211 Although the addition of a Lewis acid might be expected to show more solvent dependence, generally there appears to be little effect on asymmetric induction.118129 However, a dramatic effect of solvent polarity has been observed for chiral metallocene triflate complexes.212 The use of polar solvents, such as nitromethane and nitropropane, leads to a significant improvement in the catalytic properties of a copper Lewis acid complex in the hetero Diels-Alder reaction of glyoxylate esters with dienes.213... 

A chiral Lewis acid prepared in situ from magnesium iodide and (/ ,f )-DPEN efficiently catalyzes asymmetric aza-Diels-Alder reaction of a methyl glyoxylate/p-anisidine derived imine with the Danishefsky diene to give the cyclic adduct in 97% ee (eq 11). ... 

It should also be noted that it has recently been found that chiral Lewis acid catalysts promote glyoxylate Diels-Alder reactions, but enantiomeric excesses are usually low. ... 

In the course of a formal total synthesis of 3-deoxy-D-maimo-2-octulosonic acid (KDO), a chiral (salen)Co(II) complex was used to catalyze a highly double-stereoselective hetero-Diels-Alder reaction between an electron-rich chiral diene and ethyl glyoxylate (Sch. 56) [201]. This reaction was subsequently extended to achiral dienes [202]. 

A mechanism has been proposed for the enantioselective Mikami ene reaction of a terminal alkene with a glyoxylic aldehyde using a chiral binaphthol as Lewis acid. Stereoselective synthesis of 5-amino esters via asymmetric aldol-type and aza-Diels-Alder reactions has been reviewed. Siliranes react cleanly with benzaldehyde to produce oxasilacyclopentanes—with inversion— under conditions of Bu OK catalysis enolizable aldehydes yield sdyl enol ethers. ... 

Scheme 13. Oxa-Diels-Alder reaction between cyclopentadiene and glyoxylic acid...

Two groups have investigated N-sulfonyl imines of glyoxylate esters, derived from scalemic alcohols, in Diels-Alder reactions [67b, 73]. Prato and coworkers reported that glyoxylate N-sulfonyl imines bearing (-)-menthyl, (-)-bornyl and (-)-8-phenylmethyl auxiliaries reacted with cydopentadiene either thermally or using Lewis acids to give only very modest diastereomeric product ratios (56 44, 53 47,60 40, respectively) [67b]. 

In an extensive study Jurczak et al. examined asymmetric induction in the Diels-Alder reactions of a number of achiral dienes with several optically active esters of glyoxylic acid. Cycloadditions were run both at atmospheric pressure and at high pressures (6-10 kbar). To summarize these studies, asymmetric induction using glyoxylate esters of... 

The stereochemical outcome of the hetero Diels-Alder reaction of the erythrose based diene with sodium glyoxylate was further rationalized by preparing the same compounds via decarboxylation of 2-carboethoxy-2-deoxy-2-ulosonic acid esters, obtained by cycloaddition with diethyl ketomalonate [146], A range of 2-nonulosonic acid derivatives - KDN analogues - were prepared including protected form of 2-deoxy-KDN,... 

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