Ethers chiral enol, dienophiles

Chiral dienophiles, e.g. enol ethers and enamines, allow to conduct these hetero Diels-Alder reactions in a highly stereoselective manner. In an exemplary transformation described by Backvall et al. the nitrone 4-50 was formed as a single diastereomer upon treatment of the chiral enamine 4-48 with the nitroalkene 4-49 which was generated in situ from the seleno compound 4-47 [387]. Interestingly, the enamine 4-48 did not only act as dienophile, it also catalysed the initial base induced elimination of PhSeH from 4-47 (Fig. 4-11). 

A very recent study presented by Dujardin et al. describes the complementary use of chiral enol ethers as dienophiles in oxa Diels-Alder reactions. This approach has yielded promising results with regard to the synthesis of enantio-merically pure carbohydrates [481]. Further noteworthy studies directed to the preparation of biologically active amino sugars from enaminoketones have been carried out in our group [110]. 

Inverse demand cycloaddition of isoquinolinium salt 1 to chiral enol ethers, acetals and ortho esters 2 gives diastereomeric tetralins 3 and 4 with the diastereoselectivity depending on the nature of the dienophile and on the chiral auxiliary1. The primary tricyclic adduct solvolyzes to the tetralinaldehyde acetal in acidified alcohol. 

In an original publication which describes the addition of diphenylmethyl chloride to the enolate of ( + )-camphor [( + )-2] and subsequent reduction, it was claimed that the endo, tWoalcohol 24 was formed in such a reaction sequence23. However, other authors found the exo.e.xo-alcoho]24 using the same procedure, and attributed this to possible differences in the reaction and/or work-up methods which were not described precisely in the original article. The alcohols 24 thus obtained were used for the formation of chiral enol ethers and esters used as dienophiles in Diels - Alder reactions (Section D. 1.6.1.1.1.2.2.1.). 

The transformation could also be performed using a chiral enantiopure enol ether as dienophile. The best results were achieved with the isopropenyl ether 182b derived from cheap and commercially available (—)-(lR,2S,5R)-menthol. The cycloadduct was obtained with an endo/exo-selectivity of 4.1 1 and an induced dia-stereoselectivity of 88 12. Treatment of 178b with trifluoroacetic acid/water 19 1 provided (S)-warfarin 175 in an overall yield of 61% referred to 4-hydroxy coumarin 55 and an enantiomeric excess of 76% (HPLC), which could be increased to 95% ee by recrystallization using the purified endo-product 178b as substrate for the hydrolysis. In the same manner (S)-coumachlor 176 and (S)-acenocoumarol 177 were obtained with 56% overall yield and 93% ee and 59% overall yield and 95% ee, respectively. 

Menthol [(—)-l] has been used as a chiral ligand for aluminum in Lewis acid catalyzed Diels-Alder reactions with surprising success2 (Section D.l.6.1.1.1.2.2.1). The major part of its application is as a chiral auxiliary, by the formation of esters or ethers. Esters with carboxylic acids may be formed by any convenient esterification technique. Esters with saturated carboxylic acids have been used for the formation of enolates by deprotonation and subsequent addition or alkylation reactions (Sections D.l.1.1.3.1. and D.l.5.2.3.), and with unsaturated acids as chiral dienes or dienophiles in Diels-Alder reactions (Section D. 1.6.1.1.1.), as chiral dipolarophiles in 1,3-dipolar cycloadditions (Section D.l.6.1.2.1.), as chiral partners in /(-lactam formation by [2 + 2] cycloaddition with chlorosulfonyl isocyanate (SectionD.l.6.1.3.), as sources for chiral alkenes in cyclopropanations (Section D.l.6.1.5.). and in the synthesis of chiral allenes (Section B.I.). Several esters have also been prepared by indirect techniques, e.g.,... 

The chiral alcohols are mainly employed as esters or enol ethers. Esters with carboxylic acids can be obtained by any convenient esterification technique. Dienol ethers were obtained by transetherification with the ethyl enol ether of a 1,3-diketone, followed by Wittig reaction8 silyldienol ethers were obtained by the method of Danishefsky11-12 and simple enol ethers by mercury-catalyzed transetherification13. Esters and enol ethers have been used as chiral dienophiles or dienes in diastereoselective Diels-Alder reactions (Section D. 1.6.1.1.1.1.). (R)-l-Phenylethanol [(R)-4] has been used for enantioselective protonation (Section C.) and the (S)-enantiomer as chiral leaving group in phenol ethers for the synthesis of binaphthols (Section B.2.) the phenol ethers are prepared as described for menthol in the preceding section. (S)-2-Octanol [(S)-2] has found applications in the synthesis of chiral allenes (Section B.I.). 

Lewis acids such as Cu(OTf)2, its chiral bisoxazoline complex Cu(oxaz)2(OTf)2, and BiCls catalyze the intramolecular Diels-Alder reaction of 1-azadienes (eq 21). The 2-cyano-l-azadienes (4), containing an electron rich enol ether dienophile component, undergo cycloaddition to give the oxazinopiperidines (5) in 59-80% yield. o... 

An important advantage of enol ether dienophiles is their use in asymmetric synthesis through attachment to a chiral auxiliary. Vinyl ethers derived from (+)-camphor, (l/ ,25)-2-phenylcyclohexanol, (7 )-2,2-diphenylcyclopenta-nol, and (l/ ,25)-2-(l-methyl-l-phenylethyl)cyclohexanol... 

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