2,6-disubstituted tetrahydropyrans

As a strategy for the construction of cyclic ethers, the radical cyclization of jS-alkoxyacrylates was used for the preparation of czs-2,5-disubstituted tetrahy-drofurans and cis-2,6-disubstituted tetrahydropyrans. An example is given with S-alkoxymethacrylate 38 as precursor of the optically active benzyl ether of (+)-methyl nonactate, exclusively formed as the threo product (Reaction 44). ° ... 

The base-catalysed ring contraction of 1,3-dioxepanes offers an attractive route to 4-formyl tetrahydropyrans (Scheme 14) , whilst fused exo-cyclic dienes 27 result from the radical cyclisation of alkenyl iodides 26 (Scheme 15) <00OL2011>. Intramolecular radical addition to vinylogous sulfonates is highly stereoselective, leading to the ci s-2,6-disubstituted tetrahydropyran (Scheme 16) . 

The cross-coupling reaction of homoallylic alcohols with aldehydes in the presence of bismuth trichloride in solvent-free conditions under microwave irradiation generated 4-chloro-2,6-disubstituted tetrahydropyrans with high c/.v-diastereos-electivity [15]. The reaction of benzaldehyde with l-phenyl-3-buten-l-ol in the presence of bismuth trichloride under microwave irradiation gave the corresponding... 

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... 

Chiral molybdenum complexes of llil-pyran.1 Enantiomerically pure Mo-com-plexes, (S)- and (R)-l, of 2//-pyran have been prepared by known methods (13, 194-195) from d- and L-arabinose, respectively. They react with a wide range of nucleophiles at an allylic position with 96% ee. The resulting complex can react with a second nucleophile at the other allylic position to form c/y-disubstituted complexes, also with high enantioselectivity. The sequence can be used to obtain chiral cis-2,6-disubstituted tetrahydropyrans such as 2, a component of the scent gland of the civer cat. 

An intramolecular acyl radical cyclization of acyl selenide 1024 uses a (Z)-vinylogous sulfonate to control rotamer population, affording ry -2,6-disubstituted tetrahydropyran-4-one 1025, a key intermediate during synthesis of the tetrahydropyran unit of mucocin (Equation 399) <1997TL5249>. This methodology is also applicable to the synthesis of polycyclic ethers <1996JOC4880>. 

Methylene-2,6-disubstituted tetrahydropyrans are formed from the In-catalysed reaction of aldehydes with homoallylic alcohols which proceeds by an intramolecular oxonium-ene cyclisation and exhibits excellent diastereoselectivity <02TL7193>. 

A common intermediate, a 2-sulfonyltetrahydropyran derived from a protected homoallylic alcohol, is used to obtain both the cis and trans isomers of 2,6-disubstituted tetrahydropyrans. Deprotonation followed by an alkylation and reduction sequence affords the former, while ionisation using AICI3 and subsequent reaction with a nucleophile leads to the latter isomer (Scheme 10). The bis-tetrahydropyran portion of phorboxazole has been constructed using this chemistry <07AG(E)6874>. 

Purely aliphatic systems also react with good diastereoselectivity, but only if remote substituents cause an energetic differentiation of the competing transition states [8, 9]. For instance, Z-con-figurated substrates of type 22 are suitable starting materials for the construction of 2,6-disubstituted tetrahydropyrans of type 23 [8a]. 

Cyclization of allenic alcohols. Silver nitrate (1-2 equiv.) promotes cyclization of the secondary allenic alcohols 1 to give mainly t7.v-2,6-disubstituted tetrahydropyranes (2). Catalytic amounts of the salt can be used, but then the reaction is very slow. 

Beau, J M, Sinay, P, D-Glycopyranosyl phenyl sulfones their use in a stereocontrolled synthesis of cA-2,6-disubstituted tetrahydropyrans ((3-D-C-glycosides), Tetrahedron Lett., 26, 6189-6192, 1985. Schmidt, R R, Preuss, R, Betz, R, Vinyl carbanions. 33. C-1 lithiation of C-2 activated glucals. Tetrahedron Lett., 28, 6591-6594, 1987. 

Hansson, S, Miller, J F, Liebskind, L S, Synthesis and reactions of enantiomerically pure molybdenum rr-complexes of 2H-pyran. A general approach to the enantiospecihc synthesis of cA-2,5-disubstituted-5,6-dihydro-2H-pyrans and cA-2,6-disubstituted tetrahydropyrans, J. Am. Chem. Soc., 112, 9660-9661, 1990. 

The first total synthesis of (+)-zampanolide and (+)-dactylolide was achieved in the laboratory of A.B. Smith. The key step of these syntheses was the application of the modified Petasis-Ferrier rearrangement to construct the central c/s-2,6-disubstituted tetrahydropyran moiety in a stereocontrolled fashion. The treatment of the enol acetal with 1 equivalent of Me2AICI at -78 °C effected the rearrangement to furnish the desired c/s-tetrahydropyranone in 59% yield. 

Bi(III) is an efficient catalyst for the formation of tetrahydropyran-4-ols from homoallylic alcohols by the Prins reaction application to styrenes leads to 1,3-dioxanes <05SC1177> cr i-2,6-Disubstituted tetrahydropyrans are selectively formed in a Bi-mediated intramolecular oxa-conjugate addition of a,P-unsaturated ketones 10 the actual catalyst is considered to be the Bronsted acid derived from the Bi salt <05TL5625>. cat. BiXa... 

In studies using tetrahydropyran formation as part of a synthesis of frenolicin and other naphthoquinone antibiotics50 53, this reaction proceeds with high stereoselectivity. Thus, palladium-catalyzed intramolecular alkoxycarbonylation of various 6-hydroxyaIkenes (e.g., 1) leads to 2,6-disubstituted tetrahydropyrans 2 with up Lo 97 % diastereoselectivity. The configuration of the exocyclic stereocenter depends on the E or Z geometry of the substrate double bond34... 

Rychnovsky has systematically examined 5-, 6-, 7-, and 8-membered a-oxygenated radicals as intermediates in reductive decyanations and the diastereoselectivities associated with their reactions (Scheme 18) [27]. In eaeh case, reductive decyanation with lithium in ammonia proceeds in good yield, but the selectivity varies from >20 1 in the case of the 2,6-disubstituted tetrahydropyran to 1 1 in the case of the 2,5-disubstituted tetrahydrofuran. The observed stereoselectivities in these anomeric radical reductions correlate with the conformational rigidity of the parent ring systems. 

The related -vinylsulfones (9) are stereoselectively cyclised to the cA-2,6-disubstituted tetrahydropyran by potassium hexamethyldisilazide <97SL1318>. 

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>. 

Intramolecular oxyanion conjugate addition has also been applied to the stereoselective synthesis of cw-2,6-disubstituted tetrahydropyrans by Mandai [59]. Of particular interest was an application to the enantioselective synthesis of (cis-6-methyltetrahydropyran-2-yl) acetic acids such as (+)-(83a) and (-)-(83b). These naturally occurring compounds have been isolated from the glandular secretions of the civet cat Viverra civetta). 

Smith utilized Petasis-Ferrier rearrangement [17] in the total syntheses of zampanoUde (Sect. 3.2.1) and phorboxazole [18,19]. The l,3-dioxan-4-ones 11 are transformed into 4-methylene-1,3-dioxanes 12, which are treated with Lewis acids to give oxonium intermediates 13. like the Prins reaction described above, the cfs-2,6-disubstituted tetrahydropyran-3-ones 14 are preferentially synthesized via the C - C bond formation (Scheme 5). 

The retrosynthetic analysis is outlined in Scheme 22. The amide was introduced by the Curtius rearrangement, and the macrolide 117 was formed by Horner-Emmons macrocyclization at the C2-C3 bond. The C17-C18 bond was constructed by the ring-opening of epoxide 118. 119 was formed via the Kocienski-Julia olefination at the C8-C9 bond. The cis-2,6-disubstituted tetrahydropyran in 120 was constructed by the Petasis-Ferrier rearrangement. The C4-C5 (Z)-trisubstituted alkene in 121 was formed by carbomet-allation to an alkyne. 

The key skeleton of 120 was constructed via the Petasis-Ferrier rearrangement [17], established by Smith as a powerful, stereocontrolled entry to ci5-2,6-disubstituted tetrahydropyran (Scheme 24) [18,19]. Brown asymmetric allylation of the known aldehyde 124 [69] installed the C-11 asymmetric center in 91% ee to give 125 after silylation. Oxidative cleavage of the terminal alkene, followed by silylation, delivered the /8-hydroxy ester 126, which was condensed with aldehyde 127 mediated by TMSOTf (but the actual catalyst was found to be TfOH) to furnish an inseparable mixture of the... 

Panek s synthesis is highUghted by the efficient construction of a cis-and trans-2,6-disubstituted tetrahydropyran ring. As described in Sect. 2.4, Panek s annulation between aldehydes and chiral allylsilanes can be regarded as a Hosomi-Sakurai-Prins reaction, in which the stereochemistry of cis-... 

With 1,5-disubstitued 5-hexenols cis- and Ira 5-2,6-disubstituted tetrahydropyrans are formed in a 1 1 ratio when the substituent in 5-position is a methyl group however, only the cw-product is observed if this substituent is a methoxy group (Scheme 7). The reason for this is the preference of the methoxy group to take an axial position (anomeric... 

The stereoselective intramolecular reductive etherification of 5-trialkylsiloxy substituted ketones with catalytic bismuth tribromide and triethylsilane provides a convenient method for the construction of cis-2,6-disubstituted tetrahydropyrans (Equation 28) [46]. This method was highlighted in the key step of an expeditious total synthesis of the antibiotic (—)-centrolobine. 

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