Dihydropyranyl ethers

The enantiomerically pure indolizidine (—)-422 has been synthesized starting from L-malic acid diethyl ester 407. The hydroxyl function of L-malic acid diethyl ester 407 has been protected as dihydropyranyl ether 408 with 2/7-dihydropyran and Amberlyst 15 in pentane at room temperature. The diethyl ester 408 was then reduced with lithium aluminium hydride in diethyl ether under reflux and the newly generated hydroxyl functions then protected with mesyl chloride in the presence of triethylamine in dichloromethane at 0°C. This was converted into newly protected pyrroline nitrone 409 in 44% overall yield through a well-established method (Scheme 90). The regio-isomeric 5-pyrroline-iV-oxide 410 formed in 4% overall yield was easily separated by column chromatography <20000L2475>. 

The three-component domino-Knoevenagel-hetero-Diels-Alder reaction is especially fruitful if one uses aldehydes containing a protected amino function. In such cases the formed dihydropyranyl ether moiety can be used as a source of an aldehyde moiety that can undergo a condensation with the amino group after deprotection. Thus, several alkaloids such as hirsutine 108, dihydrocorynantheine... 

Velerianine (546), a monoterpene alkaloid, was synthesized by using a Diels-Alder cycloaddition of heterodiene 542 with enol ether 543 (Scheme 69) (70AG(E)891). Heating cyclopentenecarbaldehyde 542 with the enol ether at 200-203°C afforded a 47% yield of the dihydropyranyl ether 544, which consisted of three diastereomers. Hydrolysis of the ether 544 with acid gave iridodial (545), which was condensed with a nitrogen source to afford racemic valerianine (546). 

A more readily available Fe-complex for asymmetric Diels-Alder reaction is from chiral hydrobenzoin.Dienophiles derived from f7/ ,61 )-l-pivaloyloxyspiro[4.4]nonan-6-ol 5 give chiral adducts on reaction with dienes. A representative of axially chiral dienophiles is 65 which gives Diels-Alder reactions with high endo- and diastereoselectivity. An access to dihydropyranyl ethers by the hetero-Diels-Alder reaction, C2-syiiunetric Cu(II) complexes such as and yttrium tri[(7 )-l,l -binaphth-2,2 -diyl]phosphonate are... 

The free OH can be modified by further chemical manipulation, and reaction with benzoyl chloride (BzCl) and pyridine (Py) gives 146 (the 0-benzyl group is in blue in the illustration). Treatment of 146 with 10% aqueous acetic acid cleaves the orthoester and gives a 1 1 mixture of hydroxy acetates 147 and 148, where the acetate units are marked in cyan. If 147 is isolated and treated with dihydropyran (see Chapter 26, Section 26.4.2) and an acid catalyst, the 2 -hydroxyl is converted to a dihydropyranyl ether (149) where the P3rranyl ether unit is marked in green. It is therefore possible to protect and deprotect the 5 -, 3 -, and 2 -hydroxyl groups selectively, although the abihty to differentiate the 2 - and 3 -hydroxyls is more difficrdt to achieve. 

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