Tetrahydropyrans, 2- substituted

The incorporation of heteroatoms can result in stereoelectronic effects that have a pronounced effect on conformation and, ultimately, on reactivity. It is known from numerous examples in carbohydrate chemistry that pyranose sugars substituted with an electron-withdrawing group such as halogen or alkoxy at C-1 are often more stable when the substituent has an axial, rather than an equatorial, orientation. This tendency is not limited to carbohydrates but carries over to simpler ring systems such as 2-substituted tetrahydropyrans. The phenomenon is known as the anomeric ect, because it involves a substituent at the anomeric position in carbohydrate pyranose rings. Scheme 3.1 lists... 

There are two possible ways for the ring opening of 35 in the polymerization The C1—O7 bond cleavage leads to the formation of a substituted tetrahydropyran ring 36 in the polymer chain, while the C1—O2 bond cleavage produces a substituted tetrahydrofuran ring 37. Product analysis of the acid-catalyzed hydrolysis of the... 

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>. 

Aubele et al. studied the aqueous Prins cyclization using cyclic unsaturated acetals as oxocarbenium ion progenitors and allylsilanes are used as nucleophiles. Cyclizations proceed efficiently inside Lewis acidic micelles (of cerium salt) in water. A variety of vinyl- and aryl-substituted tetrahydropyrans with excellent stereocontrol was obtained (Eq. 3.26).113... 

Scheme 2.68. Diastereoselective formation of substituted tetrahydropyran-4-ones.

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... 

In a different study, a d-allenyl alcohol 81 containing a chiral substituent was oxidized by DMDO and then cyclized to afford the substituted tetrahydropyran 82 with good diastereoselectivity [19] (Scheme 17.24). Interestingly, when oxone was used instead of DMDO, the eight-membered cyclic ether 83 was formed via the allene oxide intermediate. 

Tetrahydrofuran itself can be opened using either the stoichiometric or the catalytic version of arene-promoted lithiation, but both cases need the activation by boron trifluoride. The catalytic reaction was performed by treating the solvent THF 324 with the complex boron trifluoride-etherate and a catalytic amount (4%) of naphthalene. The intermediate 325 was formed. Further reaction with carbonyl compounds and flnal hydrolysis yielded the expected 1,5-diols 326 (Scheme 95), which could be easily cyclized to the corresponding substituted tetrahydropyrans under acidic conditions (concentrated FlCl). 

H. Booth, K. A. Khedhair, and S. A. Readshaw, Experimental studies of the anomeric effect Part I. 2-substituted tetrahydropyrans, Tetrahedron, 43 (1987) 4699-4723. 

Recall that in the latter, certain types of substituents adjacent to oxygen in the ring actually prefer axial arrangements. This observation has been codified in what is commonly referred to as the anomeric effect and is responsible in part for the conformations of carbohydrates. Is it possible that conformational preferences seen in substituted tetrahydropyrans will carry over into preferences in transition-state geometries for Claisen rearrangements ... 

Conformational studies of substituted tetrahydropyran-2-ones (valerolactones) have utilized NMR spectroscopy (67TL5119). 

From a study of a range of 2-substituted tetrahydropyrans it was concluded that the effects of an electronegative substituent were to deshield C-2 by about 30 p.p.m. and C-3 to a much reduced extent (ca. 4 p.p.m.), but to cause small upheld shifts in the signals from C-4, C-5 and C-6 (740MR(6)233). The influence of a 2-substituent on the chemical shift of C-4 can be used for quantitative conformational analysis provided suitable reference compounds are available. A comparatively large shielding of the C-4 signal indicates a preference of the 2-substituent for the axial position. 

The low temperature reaction of pentanedial with a range of alkyl Grignard reagents leads to 6-substituted tetrahydropyran-2-ols (72HCA249). The major side reaction involves addition of the organometallic compound to both carbonyl groups. 

The reaction of dihydropyran with water in the presence of a trace of mineral acid gives an equilibrium mixture of 2-hydroxytetrahydropyran and 5-hydroxypentanal. However, the products from the addition of alcohols to dihydropyrans are stable under basic conditions and can be isolated after destruction of the acid catalyst (47JA2246). A wide range of substituted tetrahydropyrans has been made in this way and the diastereoisomers separated by gas chromatography (68JOC3754). 

Other molecules such as chlorine will add to the double bond to give substituted tetrahydropyrans (56JCS136). 

Carbon-13 shift values of parent heterocycloalkanes [408] collected in Table 4.61 are essentally determined by the heteroatom electronegativity, in analogy to the behavior of open-chain ethers, acetals, thioethers, thioacetals, secondary and tertiary amines. Similarly to cyclopropanes, three-membered heterocycloalkanes (oxirane, thiirane, and azirane derivatives) display outstandingly small carbon-13 shift values due to their particular bonding state. Empirical increment systems based on eq. (4.1) permit shift predictions of alkyl- and phenyl-substituted oxiranes [409] and of methyl-substituted tetrahydropyrans, tetrahydrothiapyrans, piperidines, 1,3-dithianes, and 1,3-oxathianes [408], respectively. Methyl increments of these heterocycloalkanes are closely related to those derived for cyclohexane (Table 4.7) due to common structural features of six-membered rings. 

The levels of 1,5-asymmetric induction in the palladium-catalyzed alkoxy-carbonylations of alkenols to form 2,6-disubstituted tetrahydropyrans have been shown to be quite reasonable (Table 10 and equation 50).144 Recent studies have shown that cyclization with palladium(II) acetate in DMSO in the absence of CO results in controlled -hydride elimination to form vinyl-substituted tetrahydropyrans with high levels of 1,4- and 1,5-asymmetric induction (equation 51).144b... 

Under identical conditions, 6-silyl-5-penten-l-ols 87 cyclize to give 2-substituted tetrahydropyrans 88 and 89. Again cis addition is strongly favoured, as shown in... 

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)]. 

Another elegant way leading to tetrahydropyrans 20S was described by Overman et al. [93] In this case, homoallylic alcohol 206 was reacted with various aldehydes in the presence of TfOH to furnish the carbonyl-substituted tetrahydropyrans 205 along with its C4 stereoisomer 207 (Scheme 13.74). The reaction is highly stereoselective and the xyu-2,4,6-trisubstituted tetrahydropyrans 205 were obtained as the major products in good yields. 

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

A number of pyrans, including 3-hydroxy-tetrahydropyran (both axial conformer, 29 and equatorial conformer, 30), 2-methoxy-tetrahydropyran 33, 3-methyl-tetrahydropyran 32, and several 4-substituted tetrahydropyrans, along with 2-methyl-l,3-dioxolane and the rigid cyclic ethers 7-oxabicyclo[2.2.1]heptane and 1,8-cineole, were studied extensively by NMR. These empirical results, in conjunction with the literature data for a variety of acyclic and cyclic ethers, were used to examine the reliability of O-substituent chemical shift models in these systems. The empirical data correlate well with predictions made from the model and it is concluded that ethereal oxygen substituent chemical shifts are due to both steric and electrostatic terms <1998J(P2)1751>. 

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>. 

Transformation of the 5-oxopentanals 981 to 6-substituted tetrahydropyran-2-ones 982 can be achieved by synergistic catalysis using samarium diiodide and 2-propanethiol in excellent yield (Equation 382) <19990L1989>. 

The lithium anion of chloromethyl phenyl sulfoxide reacts with tetrahydrofuran-2-ones 1011 to afford a diastereo-meric mixture of hemiacetal adducts 1012, the potassium enolate of which is treated with /-BuLi followed by addition of a proton source leading to to-hydroxyalkyl ketenes 1013, which themselves cyclize to 6-substituted tetrahydropyran-2-ones in excellent overall yield (Scheme 263) <1998TL9215>. 

An intramolecular [2+2] photocycloaddition of allyl ethers with dioxinones followed by a base-induced fragmentation leads to substituted tetrahydropyran-4-ones <1997TL5579>. A one-pot scandium triflate catalyzed diastereoselec-tive cyclization between aldehydes and (3-hydroxy dioxinones 1046 followed by alkoxide addition to the resulting bicycles 1047 leads to 3-carboxy-substituted tetrahydropyran-4-ones 1048 with high levels of diastereoselectivity as a mixture of keto/enol tautomers (Scheme 268, Table 49) <20050L1113>. 

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>. 

Figure 1. Axial conformation of a 2-substituted tetrahydropyran ring allowing maximum overlap between the no and CTc-x-...

Comparison of Eq. (1) derived from the r(C-OR) versus pKz (ROH) plot for the anri-periplanar P-trimethylsilyl esters 98-102 with Eq. (3) derived for the 2-substituted tetrahydropyran derivatives 117 reveals a similar response of the C-OR bond distance to the electron demand of the OR substituent. This is consistent with the similar energies (and hence donor abilities) of a C-Si bond and an oxygen lone-pair orbital (Tables 1 and 2). Thus the above structural data suggest that the oc Si-Oj- o interaction in 98-102 is similar in magnitude to the n0-Oc o present in 117. Also consistent with the present interpretation is the plot of C-OR distance versus pKd (ROH) for structures derived from the gauche P-trimethylsilyl alcohol 118,97... 

The reductive lithiation of substituted tetrahydropyrans such as 82 is stereoselective, producing principally the axial organolithium at -78 °C.81 Since reductive lithiation proceeds by fast reduction of a more slowly formed radical, the stereochemical outcome of the reaction... 

Spirocyclic 4-substituted tetrahydropyrans are readily obtained through the Prins reaction involving cyclic ketones, homoallylic alcohols and MeS03H <02H(58)659>. The cationic species generated when alkyne-Co complexes derived from 8-valerolactone are treated with SnCl4 undergo a double cyclisation to yield the oxaspiro[5.5]undecane <02T2755>. 

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... 

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