Tetrahydropyrans synthesis natural products

Total syntheses of natural products featuring intramolecular O-alkylations involving positions P to a carbonyl group as the key step 13SL1623. Total synthesis of tetrahydropyran-containing natural products exploiting intramolecular oxa-conjugate cyclization 12H(85)1255. 

With the interest in facilitating access to biologically important natural products, we were next interested in applicability of the tandem and organocatalytic oxa-conjugate addition reactions of a, -unsaturated aldehydes to the stereoselective synthesis of structurally complex tetrahydropyrans and natural products. 

Mori et al. have demonstrated the most dramatic uses of lithiated epoxides in natural product synthesis [62]. By employing the chemistry developed by Jackson, and subsequently performing a Lewis acid-catalyzed (BF3 OEt2) cyclisation, tetra-hydrofuran, tetrahydropyran, and oxepane rings are readily accessed this strategy is demonstrated by the synthesis of the marine epoxy lipid 173 (Scheme 5.40) [63]. 

As six-membered heterocycles are present in a number of natural products and biologically important molecules, solid-phase synthesis of these has been reported very often (Fig. 3.9). Solid-phase synthesis for nearly every six-membered ring including one nitrogen atom are known piperidines (272) [376], tetrahydropyridines (273) [377, 378], dihydropyridines (274) [219, 379, 380], pyridines (275) [349, 381-386], (Scheme 3.37), piperidinones (276) [387], dihydropyridones (277-279) [313, 378, 388-390], pyridinones (280-281) [328, 329] and piperidindiones (282) [391] derivatives. In contrast, the synthesis of six-membered rings with one single oxygen is rarely described. Nevertheless, solid-phase synthesis of dihydropyrans (283-284) [392-394] and tetrahydropyrans (285) [335, 336] has been reported. 

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). 

Common substructural motifs in polyketide natural products are six-membered ring lactones, lactols, and tetrahydropyrans. It was recognized by Wuts and co-workers that hydroformylation of readily available homoaUyhc alcohols would provide a direct and efficient entry into these ring systems. Such an approach was employed in a synthesis of Prelog-Djerassi lactone (Scheme 5.11) [13]. 

Cross-cyclization of epoxides with homoallylic amines is an easy way to access tetrahydropyran moieties, which form the core structure of many biologically important natural products such as avermectins, aplysiatoxin, oscillatoxins, latrunculins, talaromycins, acutiphycins, and apicularens. Even though many methods are available for the synthesis of this moiety [14—24], its importance and wide applicability demands further methods. 

Viewed (and drawn) in a terpene-like perspective, C-glycosyl compounds are in fact functionalized tetrahydrofurans and tetrahydropyrans. As such, they can be considered as versatile chirons for the synthesis of a variety of natural products containing cyclic ether motifs, such as in the ionophores. 

Tetr 39 2323 (1983) (Recent Advances in the Preparation and Synthetic Applications of Oxiranes) 43 3309 (1987) (Synthetic Routes to Tetrahydrofuran, Tetrahydropyran, and Spiroketal Units of Polyether Antibiodcs and a Survey of Spiroketals of Other Natural Products) SO 8885 (1994) (Chemical and Biological Synthesis of Chiral Epoxides)... 

Let s now consider concerted skeletal rearrangements which allow the direct transformation of a sugar structure into a carbocyde. The Claisen rearrangement has been used for the direct conversion of sugar C-glycosides to eight membered carbocycles, respectively. The reaction has precedents in the transformation of 2-methylene-6-vinyl-tetrahydropyrans to cyclooctenone derivatives, a transformation that has been applied in the synthesis of several natural products [54],... 

Dihydropyrans represent an attractive and challenging class of compounds as many of them are key intermediates for the synthesis of several natural products [171]. In particular, their olefin function has great S3mthetic value for the further functionalization to obtain polysubstituted tetrahydropyrans [172] that constitute... 

The research group of T. Nakata developed a convergent synthesis for the construction of a frans-fused 6-6-6-6-membered tetracyclic ether ring system, a subunit, which is present in several polycyclic marine ether natural products. Late in their synthesis, they utilized a samarium diiodide mediated nucleophilic acyl substitution as the key step to form one of the tetrahydropyran rings. 

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. 

The total synthesis of the marine natural product (5Z)-dactomelyne (1) requires the elaboration of the c -linked pyranopyran skeleton and the stereoselective introduction of halogen atoms on the tetrahydropyran rings. Lee et al. [2] solved this problem by using of )9-alkoxy-acrylates twice as radical acceptors (Scheme 1). 

Strategies for the formation of tetrahydropyran rings in the synthesis of natural products 06EJ02045. 

Another natural product synthesis features that of a key domino ene-yne coupling/Michael reaction to a tetrahydropyran ring (Scheme 7.29) [22]. An in-depth Trost domino ene-yne/oxa-Michael reaction methodology process was first carried out prior to using the key substrates 143 and 144, with [CpRu(MeCN)3]PFg 145 as the catalyst The product 146 contained almost all the carbons of the natural product target (—)-exiguolide as well as most of its asymmetric centers. 

Keywords Macrolide Marine natural product Tetrahydropyran Total synthesis... 

Mechanistic studies are an important tool to understand how the biosynthesis of natural products occurs in nature and how to mimic their synthesis in the laboratory. Progress in this field includes the biomimetric synthesis of flavonolignan diastereomers in milk thistle (13JOC7594) and the chemoenzymatic synthesis of tetrahydropyran-containing polyketides (13AGE13215). In the synthetic domain, DFT calculations and experimental assays have been carried out to explain the multiple mechanisms involved in the palladium(II)-catalyzed Sn2 reactions of aUylic alcohols to prepare chiral tetrahydropyran derivatives (13JOC7664). 

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