Tetrahydropyrans synthesis cyclization strategies

The tetrahydopyran nucleus is found in many classes of secondary metabolites, and a variety of methods are now available for the synthesis of this saturated heterocycle.As one might expect, cyclization strategies to oxanes are manifold. However, relatively few of these approaches are able to generate heavily substituted tetrahydropyrans with complete stereocontrol. 

Hoye achieved the total synthesis of (-)-dactylolide via two distinct macro-cyclization strategies, involving Ti(IV)-mediated macrolactonization of an epoxy-acid (route A) and a RCM macrocyclization (route B) (Scheme 29). The czs-2,6-disubstituted-4-methylene tetrahydropyran was constructed by Prins... 

The intramolecular cyclization strategy is applied to efficient synthesis of oxa-cycles starting with trimethylsiloxy-containing allylic silanes (Scheme 5.8). Treatment of 30 with benzaldehyde in the presence of a catalytic amount of McjSiOTf and PrOSiMej gives tetrahydropyran 32. An oxonium ion intermediate (31) is considered to be generated first and then undergo intramolecular nucleophilic attack by an allylsilane part [15]. When ortholactones are employed in lieu of aldehydes, spiroketals are readily prepared. 

Recently, a new multicomponent condensation strategy for the stereocontrolled synthesis of polysubstituted tetrahydropyran derivatives was re-published by the Marko group, employing an ene reaction combined with an intramolecular Sakurai cyclization (IMSC) (Scheme 1.14) [14]. The initial step is an Et2AlCl-promoted ene reaction between allylsilane 1-50 and an aldehyde to afford the (Z)-homoallylic alcohol 1-51, with good control of the geometry of the double bond. Subsequent Lewis acid-media ted condensation of 1-51 with another equivalent of an aldehyde provided the polysubstituted exo-methylene tetrahydropyran 1-53 stereoselectively and... 

In their strategy, three methods were investigated for the synthesis of aldehyde 86. Initially, linalool was selected as the starting material (Scheme 19). Cyclization with TBCO afforded a mixture of tetrahydropyrans (89 and 90, 10 6.9) and tetrahydrofurans (88) in 56% and 24% yields respectively. The preference for the stereoselective formation of pyran 89 over the desired compound 90 was postulated to be associated with the chair transition states shown in Scheme 19. Presumably, the diaxial interaction between the Ci methyl group and the vinyl substituent R in intermediate 92 is less severe than those between the two methyl groups in intermediate 93, leading to the undesired tetrahydropyran 89 as the major product [51]. 

As demonstrated by the S5mthetic routes outlined above, each strategy is elegant and innovative in its own way. A discussion of the difficulties associated with the construction of the A-ring of th5 siferol is included in every publication. In addition, the stereoselective assembly of the tetrahydropyran central unit via hydroxyl group cyclizations onto epoxides has been shown to be an efficient tactic. An advantage is apparent in Forsyth s approach, with the construction of the A-ring independently and at the outset of the synthesis. 

The radical cyclization of jS-alkoxyacrylates also offers an attractive approach to the formation of 2,6-c/i-tetrahydropyrans [50, 51], A noteworthy strategy was demonstrated by the Lee group in the first total synthesis of lasonolide A [52, 53], Lee and coworkers illustrated the tandem radical cyclization of a,)S-alkoxyacrylate... 

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