Cis-2,6-Disubstituted tetrahydropyranes

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). ° ... 

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. 

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

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 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. 

The adducts of tosyl iodide to co-ethylenic alcohols have been used as intermediates in the preparation of 2-substituted heterocycles (equation (53)) [109]. While the K2C03-promoted cyclization affords a 1 1 mixture of diastereomers, the NaH-promoted reaction led to a 27 1 mixture where the cis 2,6-disubstituted tetrahydropyran predominates. This last reaction is likely to proceed via conjugated addition to an intermediate vinyl sulfone. Several examples of the cyclization of -unsaturated sulfonyl radicals have also been reported [110]. 

In the cyclization of the corresponding cis-epoxides, with the aim of obtaining the corresponding cis-2,3-disubstituted tetrahydropyrans, a similar trend was observed. For these systems, however, the 6-endo pathway was less favored, which was ascribed to difficulties in attaining a TS conformation that would allow for maximum stabilization of the developing p-orbital with the adjacent 7t-system. Alternatively, palladium-catalyzed cyclization of the tetrabutylammonium alkoxide derived from 33b results in the corresponding ris-2,3-disubstituted tetrahydro-pyran in excellent yield and selectivity (90%, dr >99 1), while the ris-epoxide gives stereoisomer 37b (86%, dr 98 2) [112]. 

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) . 

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>. 

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). 

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... 

Domino reactions consisting of a CM and an oxa-Michael addition provide an efficient access to 2,6-cis disubstituted tetrahydropyrans [39]. Coupling of the... 

The intramolecular Michael addition of alkoxide anions to a, /S-unsaturated esters is often seen in the preparation of tetrahydropyrans (Scheme 2). Usually, 2,6-cis-disubstituted tetrahydropyrans are obtained with high stereoselectivity via the 6-membered transition state model 1. In the total syntheses... 

After these initial snccesses, the use of acyclic substrates has systematically been in-vestigated.f " " In the reaction of E- or Z-conflgured) 1,6-disubstituted 5-hexenols only one diastereomer of the resnlting tetrahydropyrans could be isolated (Scheme 5). The 2,6-cis arrangement of side chains could be explained in terms of a pseudochair conformation in the transition state of the nucleophilic addition. The tram stereochanistry is disfavored because it would require the TjAaikene-Pdfll) moiety to adopt a pseudoaxial position (Scheme 6). 

Wacker-type chemistry can be combined with other aspects of palladium chemistry to create tandem reactions. For instance, the -intermediate can be intercepted by carbon monoxide giving ester products. This chemistry has been found to be useful in the formation of tetrahydrofurans and tetrahydropyrans as the stereochemistry of the newly formed ring is usually eontroUed quite well (Scheme 6.21 For tetrahydrofuran formation, the substituent in the allylic position seems to have the most stereochemical-directing effect (Scheme 6.22). For tetrahydropyran formation, the 2,6-cis isomer, with both a-substituents equatorial, is favoured. If a disubstituted alkene is used, an additional ehiral eentre is created, and the two geometrical isomers of the alkene starting material give different diastereoisomers of the product (Scheme 6.23). The stereochemistry is consistent with nucleophilic attack trans to palladium, followed by CO insertion with retention. For most substrates, eyehzation is found to be exo, but there are exceptions (Scheme 6.24). 

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