Tetrahydropyrans, 2- substituted synthesis

Pyrans, pyrones, pyrilium salts, mutual transformations of 85UK1971. 2-Pyrones, 6-substituted, synthesis and reactivity of 83MI6. Tetrahydropyrans, 2.6-disubstituted, synthesis of 83CRV379. 47/-Tetrahydropyrans, 4-functionalized, chemistry of 81AKZ728. Tetrahydropyrans, synthesis via intramolecular cyclization of unsaturated... 

In a series of papers culminating in the report of a total synthesis of hemibrevetoxin B, Nakata and co-workers utilised a zinc catalysed ring expansion of poly-substituted tetrahydropyrans, exemplified by the transformation of 34 to 35 (Scheme 7) <96TL213, 96TL217, 96TL6365>. 

The structure of the antibiotic, 9, which has been variously named lacto-quinomycin-A and medermycin, was first reported by Okabe and coworkers in 1985.58 In early 2002,59 a communication was published reporting that the original structure, 9, was incorrect based on synthesis and that the substituted tetrahydropyran ring was attached to the 6-position to give 10, rather than the 8-position as originally reported. The authors based their conclusion on the fact that a key intermediate was identified as 6-bromo-3-hydroxybenzaldehyde rather than the 4-bromo-3-hydroxy benzaldehyde as previously reported.60... 

Starting from substituted allyl bis-(2,4-dimethyl-3-pentyl)-L-tartrate boronic acid, synthesis of a,/l-disubstituted tetrahydrofurans (134, n = 1) or tetrahydropyrans (134, n = 2) can be accomplished with high enantioselectivity (Scheme 3-46).79... 

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). 

The unsubstituted pentanedial yields the parent 4/f-pyran on successive treatment with hydrogen chloride and A AT-diethylaniline (62AG465). This two-step approach involving elimination of hydrogen chloride from the initially formed tetrahydropyran has been extended to the synthesis of substituted 4/f-pyrans (Scheme 15) (67MI22400). 

Triflic acid has been successfully used in the stereocontrolled synthesis of substituted tetrahydropyrans. 2,4,6-Trisubstituted tetrahydropyrans have been synthesized by an intramolecular Prins reaction-pinacol sequence694 [Eq. (5.250)]. 

The Maitland-Japp synthesis of highly substituted tetrahydropyran-4-ones152a (e.g. 

The synthesis of 5- -methylene tetrahydropyrans 378 can be accomplished by a regioselective ruthenium catalyzed C-C coupling reaction of prop-2-yn-l-ols 379 and allylic alcohol (Equation 156) <1999JOC3524>. A ruthenium catalyzed alkylative cycloetherification reaction between allene 380 and vinyl ketones furnishes 2-substituted tetrahydropyrans 381 in high yield (Equation 157) <1999JA10842>. 

A highly enantio- and diastereoselective hDA reaction between substituted hexadiene 1033 and aldehydes is catalyzed by Jacobsen s chiral tridentate chromium(m)-catalyst 1034 furnishing tetrahydropyran-4-ones 1035 (Equation 401, Table 48) <1999AGE2398>. This methodology is incorporated into a stereocontrolled total synthesis of (+)-leucascandrolide A <2003AGE343> and the synthesis of the C(20)-C(32) segment of the phorboxazoles... 

A ruthenium-catalyzed ring opening cross-metathesis of 8-oxabicyclo[3.2.1]oct-6-en-3-one 1049 with alkenes provides an efficient method for the preparation of substituted tetrahydropyran-4-ones 1050 (Equation 408, Table 50) <1999X8169, 20010L4275>. Similarly, ozone can be used to cleave the same ring system during the synthesis of chiral tetrahydropyran-4-ones <2006T257>. 

Use of allylsilanes as 1,2-dipole equivalents is valuable also for the construction of six-membered rings. f3-Oxyaldehydes undergo Lewis acid-promoted cycloadditions with allylsilanes to provide substituted tetrahydropyrans (Equation (52)). 3 A similar [4 + 2]-cycloaddition of /V-/-butoxycarbonyl-0,Ar-acetals is available for the synthesis... 

Many examples of the synthesis of tetrahydropyrans are based on the cyclization of 1,5-diols and related compounds which can provide an electrophilic site for ring closure . Thus, pentane-1,5-diols can be quantitatively cyclized to the pyran in the presence of BuSnCl3 <1988G483> or via an intramolecular Mitsunobu condensation with cyanomethylenetributylphosphorane <1996TL2463>. Tetrahydrothiopyrans are prepared similarly by cyclizations of suitably substituted thiols . 

Phenylsulfonyl)tetrahydropyran 369 has been lithiated with w-BuLi at — 78 °C to give the anion 370, which has been allowed to react with alkyl halides and carbonyl compounds (Scheme 97)548. The corresponding 2-substituted derivatives suffered after aqueous work-up spontaneous /3-elimination of benzenesulfmic acid to give products 371. When the alkyl halide has an additional protected hydroxy group at the y- or 5-position (such as in compound 372), spiroketals (e.g. compound 373, Scheme 97) were obtained, this methodology having been applied to the synthesis of ionophore antibiotic CP 61,405 (routiennocin)550. 

The formation of poly substituted tetrahydropyran-4-ones through a Pd-catalysed intramolecular Michael addition of (3-hydroxyenones proceeds with the retention of stereocentres in the enones. The route is simple and is particularly attractive for the synthesis of the 2,6-a ft -substituted heterocycles (Scheme 26) <06CEJ7190>. 

A related transformation was reported by the gronp of Floreancig for the synthesis of substituted tetrahydropyrans (equation 11). This transformation initially involves a hydration of the alkyne and then an elimination of a leaving group at the P position, followed by a conjngate addition. 

Dihydropyrones are valuable intermediates for the synthesis of a variety of substituted tetrahydropyran rings. Recently, stereoselective aldol reactions of p-chlorovinyl ketones using the dienol boronate derivative derived from chiral IpC2BOTf was utilized for enantioselective formation of dihydropyrones. No detectable racemization was reported on the cyclization step (eq 4). ... 

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