Tetrahydropyran enantioselective synthesis

The enantioselective synthesis of the C(18)-C(25) segment of lasanolide A 324 can be achieved via an oxonia-Cope-Prins cascade cyclization of a-acetoxy ether 325. The in situ reduction of the oxocarbenium ion intermediate 326 with Bu3SnH prevents the formation of a tetrahydropyran 4-one side product (Scheme 81) <20050L1589>. 

Catalyst 36 was also used for the enantioselective synthesis of functionalized tetrahydropyrans, important building blocks in several biologically active molecules (Scheme 29) [78]. The enantioselectivity of such a reaction was significantly improved by using a ruthenium iodide complex 37. This halogen effect has been previously observed in the ring-closing metathesis (vide supra) [52]. 

Allin, S. M., Baird, R. D., Lins, R. J. Synthetic applications of the amino-Cope rearrangement enantioselective synthesis of some tetrahydropyrans. Tetrahedron Lett. 2002, 43, 4195-4197. 

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). 

Waldmann and coworkers " (Scheme 7.12) described the enantioselective synthesis of a library of 2,4,6-trisubstituted tetrahydropyrans by an oxa-Diels-Alder reaction. The corresponding pyrane ring is prevalent in a number of natural products. To access it stereoselectively with a solid-phase synthesis strategy, cycloaddition reaction of Danishefsky s diene 59 with resin-bound aldehydes 58 was carried out in the presence of 5 mol% of the chromium catalyst 63. After the release of resin, the product (61) was... 

As a final method for the enantioselective synthesis of tetrahydropyrans, we will mention the discovery by Hayashi that diphenyl prolinol silyl ether 41 catalyzes the formation of 3-nitrotetrahydropyrans 68 from nitrostyrenes, aldehydes, and ethyl glyoxylate in enantiomeric excesses higher than 90% (Scheme 3.17) [54]. This... 

Iqbal, M., Mistry, N., Clarke, P. A. (2011). An asymmetric Maitland-Japp reaction a highly enantioselective synthesis of tetrahydropyran-4-ones. Tetrahedron, 67,4960-4966. 

In 2004, the group of Blechert described the first enantioselective synthesis of (-)-gilbertine (Scheme 13.7) [8], the key step of which featured a cationic cascade reaction for the formation of a tetrahydropyrane and piperidine ring and the pentacyclic framework in one step. 

While the notion that the alkoxides derived from aliphatic alcohols are poor nucleophiles toward 7r-allylmetal complexes has prevailed over the years, much progress made in the recent past has rendered the transition metal-catalyzed allylic alkylation a powerful method for the O-allylation of aliphatic alcohols. In particular, owing to the facility of five- and six-membered ring formation, this process has found extensive utility in the synthesis of tetrahydrofurans (THFs) (Equation (29))150-156 and tetrahydropyrans (THPs).157-159 Of note was the simultaneous formation of two THP rings with high diastereoselectivity via a Pd-catalyzed double allylic etherification using 35 in a bidirectional synthetic approach to halichondrin B (Equation (30)).157 The related ligand 36 was used in the enantioselective cyclization of a Baylis-Hillman adduct with a primary alcohol (Equation (31)).159... 

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... 

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). ... 

Sanz, M. A., Voigt, X., Waldmann, H. Enantioselective catalysis on the solid phase synthesis of natural product-derived tetrahydropyrans employing the enantioselective oxa-Diels-Alder reaction. Adv. Synth. Cat. 2006,348, 1511-1515. 

Extension of the method to the synthesis of enantiomerically enriched tetrahydrofurans or tetrahydropyrans was possible by using chiral phosphine ligands on the gold catalyst. In the presence of chiral gold pre-catalyst [Au2 (.S)-3,5-r-Bu-4-MeO-MeOBIPHEP Cl2] and AgOTs, prochiral allenes afforded the desired heterocycles with high enantioselectivity (Scheme 4-101). 

SCHEME 16.18. Synthesis of tetrahydropyrans through an enantioselective Michael/ acetalization organocascade. 

In addition, silver-catalyzed asymmetric aza-Diels-Alder reactions provide a useful route to optically active nitrogen-heterocyclic compounds such as piperidines or pyrid-azines. Substituted dihydrobenzofurans can also be enantioselectively prepared through silver-promoted allylation of aldehydes. Other types of silver-mediated cyclizations can also be used in the synthesis of tetrahydrofnrans, tetrahydropyrans, 1,2-dioxetanes, 1,2-dioxolanes, medium-sized lactones, dihydroisoqninolines, and so on. Silver salts can also be used as cocatalysts with other transition metals. Unique activity was observed for these silver-based systems in several cases. Conseqnently, the use of silver can enrich several available heterocyclization methods, and fnrther developments in the application of chiral silver complexes will hopefnlly appear in the near future. 

As a first extension of the new overall enantioselective a-alkylation of 2-ke-toesters we developed an efficient asymmetric synthesis of 3-substituted cyclic hemiketals of (o-hydroxy-2-oxoesters [42]. As is depicted in scheme 15, the metalated SAMP-hydrazones were trapped with a number of O-benzyl- and O-silyl-protected co-hydroxy-l-iodoalkanes, which after hydrazone cleavage and deprotection afforded the cyclic hemiketals (de, ee > 98%), structurally modified deoxygenated analogs of ulosonic acids. To our knowledge only two methods have been reported for the synthesis of similar simple tetrahydropyran derivatives [43,44]. 

The utility of the bismuth tribromide-mediated reductive etherification for the construction of 3-hydroxy-2,6-disubstituted tetrahydropyrans was also highlighted in the enantioselective total synthesis of the annonaceous acetogenin(—)-mucocin [46c]. 

Chiral cationic coppei(Il)-bis(oxazoline) complexes such as 162 are effective in promoting enantioselective hetero-Diels-Alder reactions with a broad variety of substrates [124]. Evans has reported that complex 162 catalyzes the inverse-electron-demand hetero-Diels-Alder reaction between enol ether 245 and enone 246 to give dihydropyran 247 in 97 % ee and 94 6 dr (Scheme 17.35) [125]. After diastereoselective reduction of the tetrasubsti-tuted olefin in 247, tetrahydropyran 248 was isolated in 95 % yield and dr= 98 2. This tetrahydropyran served as a common intermediate to access the 1,3-syn dimethyl motifs embedded in both the E- and the Hl-ring fragments 249 and 250, which served as key intermediates in an efficient synthesis of the marine shellfish toxin azaspiracid-1 (251). 

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