Enol ethers enantioselective hetero-Diels-Alder reaction

The chiral bis(oxazoline)/Cu(II) complex with OTf or SbFg as a counter anion effectively promotes the enantioselective hetero Diels-Alder reaction of enol ethers with acyl phosphonates to give chiral enol phosphonates as synthetically useful chiral building blocks [64] (Eq. 8A.40). 

The enantioselective hetero-Diels-Alder reactions of a,p-unsaturated acylphosphonates with enol ethers catalyzed by Cu(II)bzT(oxazoline) complexes have been investigated in depth. It was found that Cu(II)bA(oxazoline) complexes activate a,p-unsaturated acylphosphonates to the extent that they undergo facile cycloaddition reactions at low temperature with electron-rich alkenes. For example, dimethyl ( )-l-oxo-2-butenylphosphonate reacts with ethyl vinyl ether in the presence of Cu[(S,5)-t-Bu-box] (OTf)2 complex (10 mol% catalyst) to generate the cycloadduct in 89% yield (Scheme 7.86) with exceptional stereoselectivity (endo/exo = 99/1, 99% ee). Cyclic enol ethers also undergo stereoselective reactions with dimethyl ( )-l-oxo-2-butenylphosphonate. It specifically reacts with 2,3-dihydrofuran in the presence of Cu[(5,5)-t-Bu-box] (OTf)2 to deliver the bicyclic enolphosphonate. Of particular merit is the fact that a large variety of p.y-unsaturated acylphosphonates may be tolerated with no loss in selectivity for the derived cycloadducts. ... 

Evans, D.A., and Johnson, J.S., Catalytic enantioselective hetero Diels-Alder reactions of a,P-unsat-urated acyl phosphonates with enol ethers, J. Am. Chem. Soc., 120, 4895, 1998. 

Following this route, the authors achieved the synthesis of 10 analogues of compound 58, in a high global yield, where the crucial step of this total synthesis was the efficient catalytic enantio-, regio-, EIZ-, and diastereoselective three-component inverse electron demand hetero-[4+2] cycloaddition/allylboration sequence. This key process provides a rare example of an enantioselective hetero-Diels-Alder reaction involving acyclic 2-substituted enol ethers. Additionally, these compounds were evaluated for antimicrobial activity, and two of them showed more activity than the original thiomarinol H. 

Chiral cationic coppei(Il)-bis(oxazoline) complexes such as 162 are effective in promoting enantioselective hetero-Diels-Alder reactions with a broad variety of substrates [124]. Evans has reported that complex 162 catalyzes the inverse-electron-demand hetero-Diels-Alder reaction between enol ether 245 and enone 246 to give dihydropyran 247 in 97 % ee and 94 6 dr (Scheme 17.35) [125]. After diastereoselective reduction of the tetrasubsti-tuted olefin in 247, tetrahydropyran 248 was isolated in 95 % yield and dr= 98 2. This tetrahydropyran served as a common intermediate to access the 1,3-syn dimethyl motifs embedded in both the E- and the Hl-ring fragments 249 and 250, which served as key intermediates in an efficient synthesis of the marine shellfish toxin azaspiracid-1 (251). 

Jorgensen s group44a carried out the reaction using the anhydrous form of chiral bis(oxazoline) coordinated copper complex. Complex 106 containing 83 as the chiral ligand was found to be the most effective. As shown in Scheme 5-32, the asymmetric hetero Diels-Alder reaction of //.y-unsaturated a-keto esters with acyclic enol ethers results in products with excellent yield and enantioselectivity. 

A similar enantiomer-selective activation has been observed for aldol " and hetero-Diels-Alder reactions.Asymmetric activation of (R)-9 by (/f)-BINOL is also effective in giving higher enantioselectivity (97% ee) than those by the parent (R)-9 (91% ee) in the aldol reaction of silyl enol ethers (Scheme 8.12a). Asymmetric activation of R)-9 by (/f)-BINOL is the key to provide higher enantioselectivity (84% ee) than those obtained by (R)-9 (5% ee) in the hetero-Diels-Alder reaction with Danishefsky s diene (Scheme 8.12b). Activation with (/ )-6-Br-BINOL gives lower yield (25%) and enantioselectivity (43% ee) than the one using (/f)-BINOL (50%, 84% ee). One can see that not only steric but also electronic factors are important in a chiral activator. 

Recently, Wada et al. [175,176] have observed an excellent enantioselectivity for the intermolecular hetero Diels-Alder reactions of ( )-2-oxo-l-phenylsul-fonyl-3-alkenes 2-197 - 2-199 with enol ethers 2-200 to give the dihydropyrans 2-201 - 2-203 using the Narasaka catalyst 2-204. The best results were obtained with the iso-propyl vinyl ether 2-200c (Fig. 2-56). 

Inverse electron demand hetero-Diels-Alder reactions of acyl phosphonates or a-keto ester heterodienes and enol ethers are also catalyzed by (5, iS )-t-Bu-box complexes. High levels of enantioselectivity are obtained with y-alkyl-, -aryl-, -alkoxy-... 

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