2-Substituted dihydropyrans

In the case of terminal alkynes having oxygenated functions in the linear chain (Scheme 10, route D), Martin, Padron, and coworkers found that homopropargylic alcohols reacted properly, yielding 2-substituted dihydropyrans as sole products, probably via a Prins-type cyclization. This cyclization provides a new approach toward 2-alkyM-halo-5,6-dihydro-2//-pyrans through a concomitant C-C and C-O bond formation (Scheme 21) [35]. 

Methods for forming carbon-carbon bonds at the anomeric position of cyciic ethers are important processes in organic synthesis. We have shown how iactols and their derivatives can be readiiy converted into the corresponding 2-benzenesuifonyi cyclic ethers.3> These versatile intermediates can then be transformed into the corresponding dihydropyrans. 2-substituted dihydropyrans, spiroacetais, and tetrahydropyranyl ethers (Scheme 1). 

Reaction with enol ethers. 2-Substituted dihydropyrans and dihydrofurans are reduced to the ( )-alkenols with isopropylmagnesium bromide in the presence of a nickel chloride complex. The reaction has been applied to a formal synthesis of recifeiolide. 

The application of RCM to dihydropyran synthesis includes a route to 2,2-disubstituted derivatives from a-hydroxycarboxylic acids. In a one-pot reaction, the hydroxy esters undergo sequential O-allylation, a Wittig rearrangement and a second O-allylation to form allyl homoallyl ethers 8. A single RCM then yields the 3,6-dihydro-2//-pyran 9. The process is readily adapted not only to variably substituted dihydropyrans but also to 2-dihydrofuranyl and 2-tetrahydrooxepinyl derivatives and to spirocycles e.g. 10 through a double RCM (Scheme 4) <00JCS(P1)2916>. 

Aiming at the pyranose form of sugars, normal type hetero-Diels-Alder reactions were extensively used for the synthesis of functionally substituted dihydropyran and tetrahydropyran systems (5-10) (see routes A - D in the general Scheme 1) which are also important targets in the "Chiron approach" to natural product syntheses (2.) Hetero-Diels-Alder reactions with inverse electron demand such as a, p-unsaturated carbonyl compounds (l-oxa-1,3-dienes) as heterodienes and enol ethers as hetero-dienophiles, are an attractive route for the synthesis of 3,4-dihydro-2H-pyrans (11). 

Also propiogeninic type macrolide moieties should be accessible via this inverse type hetero-Diels-Alder methodology. This was recently exhibited starting from cis-propenylether as heterodienophile (Schmidt, R.R. Haag-Zeino, B. Hoch, M. Liebigs Ann. Chem., in press). In a highly endo-selective cycloaddition reaction and in subsequent diastereoselective transformations of the methyl substituted dihydropyran obtained a 2,4-dimethyl-... 

Fig. 7. Oxepine isomers 134-136 that vary as to which ring C—C bond is unsaturated the substituted dihydropyran 137 possesses the enol ether functionality of a glycal, akin to oxepine 136.

A substituted dihydropyran, 3,4-dihydro-2-(hydroxymethyl)-2ff-pyran (176), was employed by R. K. Brown and coworkers76 77 as the substrate in a total synthesis of hexoses (see Section III,2). The first steps in this method consisted in (1) intramolecular addition of the hydroxyl group to the double bond, to afford the bicyclic compound 177, and (2) bromination of 177 to the monobromo derivative 178. 

Electron-rich conjugated dienes add across the carbon-oxygen double bond of ketene to give substituted dihydropyrans (424) which rearrange to pyran-4-ones (Scheme 143) (82S500). 

Titanium(IV) chloride is used as the catalyst in a Knoevenagel reaction between various 2,2-disubstituted 3-hydroxypropanals and malonic acid or its esters. The products are substituted dihydropyran-2-ones (536) (79LA751). The reaction, which occurs cleanly and in good yield, utilizes an excess of the titanium halide and is thought to involve a cyclic complex which undergoes an ester exchange to a lactone complex (Scheme 198). 

It was observed that the cyclization of syn-123 produced mainly the dihydropyran 124a accompanied by dihydropyran 124b as a minor diastereoisomer. In contrast, the cyclization of anti-123 provided dihydropyran 125b as the major isomer and the all-cis-substituted dihydropyran 125a as the minor product. In all cases, the diastere-oselectivity ranged from good to excellent. 

Lewis acid treatment of a 2-furanylmethanol complexed to the 7t-base pentaamine osmium(n) in the presence of carbonyl compounds provides a route to 4-substituted dihydropyran-3-ones. However, the design of a protocol for efficient removal of the osmium from the products is in its early stages <2000T2313>. 

The photolysis of nonchiral acyl azides such as compounds 45 [22] (Sch. 13), 27, 41, and 43 [22,45] (Sch. 12) in the presence of the substituted dihydropyranes (compound 104, used as a racemate) yields two diastereo-mers that can be characterized as 44exo- and 44endocompounds (105) according to the position of the five-membered ring in relation to the alkoxy substituent (see Sch. 30). The d.e. values are about 30% and are not affected by the size of the alkoxy group of the dihydropyran. In contrast, substituents present in benzoyl azides do influence the diastereoselectivity (compounds 41 15% 43 10%) [46]. 

Pd-catalysed oxidative heterocyclisation features in a synthesis of substituted dihydropyran-4-ones from P-hydroxy-ynones. The process involves domino Wacker - Heck coupling of the ynones with ethyl acrylate and, although yields are only moderate, the stereochemistry of the ynone is retained in the product (Scheme 24) <06JOC8390>. 

Cyclobutenes possessing an angular O-functionality, obtained from a Lewis acid-mediated [2+2] cycloaddition of cyclic silyl enol ethers to ethyl propynoate and subsequent reduction and butenylation, undergo a ring-opening metathesis that produces a substituted dihydropyran that forms part of a c -diene. After desilylation, an oxy-Cope rearrangement leads to the fused tetrahydropyran 4 <03JA14901>. 

In the intermolecular alkoxyselenenylation of 2- or 3-substituted dihydropyrans a mixture of the two diastereomeric alkoxy selenides 16A and 16B is produced with the ratios and yields given in the table below29. 

The addition of alkoxycarbonyl nitrenes, generated photochemically from azides, to substituted dihydropyrans and tri-O-acetyl-D-glycal57"59 in alcoholic solution gave the products of alcoholysis 30 and 31-33 of the intermediate aziridines by a one-pot procedure59. The attack of the nitrene takes place mainly on the less hindered face of the double bond, but complete control of the diastereoselectivity was not accomplished even the ring opening of the aziridine can follow both anti and syn stereochemistry. 

Acyloxybutylphosphonium salts 8 produce 6-substituted dihydropyrans 9 by an intramolecular WiTTiG reaction ... 

Elimination reactions involving 2-acyloxy substituted dihydropyrans, e.g. 11. The latter are accessible by a Diels-Alder reaction with inverse electron demand between enones and vinyl esters. One of the earliest syntheses of the parent compound is based on this reaction ... 

Much of the early scientific work of the late Aleksander Zamojski focused on the total synthesis of racemic monosaccharides, based on stereocontrolled reactions of substituted dihydropyrans obtained by Diels—Alder cycloaddition. His article in Volume 40 of this series details many of his early studies in this area. His colleagues Jarosz and Chmielewski (Warsaw) here offer a broad insight into Zamojski s contributions, which later extended into chiral structures, higher sugars, and oligosaccharides. 

Application of RCM to acrylates derived from terpene aldehydes containing a remote double bond yielded the 6-substituted dihydropyran-2-ones <01TL6069> and oxabicyclo-[3.2.1]octane undergoes an efficient ring-opening cross-metathesis with electron-rich alkenes to give unsymmetrically 2,6-disubstituted tetrahydropyran-4-ones <01OL4275>. 

---