Stereocontrolled Synthesis of Highly Substituted Tetrahydropyrans

Key words

rhenium - tetrahydropyrans - Prins cyclization

Significance

A Re(VII) complex catalyzed the highly selective condensation of easily accessible starting materials using a very mild and simple protocol to give densely functionalized tetrahydropyrans 3 (THP). Aromatic aldehyde partners 2 give a single diastereomer where all substituents are equatorially oriented. Whereas aliphatic aldehydes give diastereomeric mixtures (4 and 5), ­alkenyl aldehydes provide an alternative, as illustrated by complex THP 11. Achieving high atom-efficiency, the catalytic Prins cyclization reported improves previous protocols using excess acid (the conjugate base moiety is generally incorporated into the THP at the end of the reaction).

Comment

Both ReO₃(OH) and Re₂O₇ were shown to be effective catalysts to mediate the transformation. The authors were inspired by seminal work on allylic alcohol isomerization done by Osborn and co-workers (Angew. Chem. Int. Ed. 1997, 36, 976), as well as later investigations done by Grubbs and co-workers (J. Am. Chem. Soc. 2005, 127, 2842). These early studies invoked a cationic intermediate suggesting that intermediate C might be a viable species in the above process. A potential limitation of the reaction is seen with aliphatic aldehydes 2, which are prone to form side-products arising from competing oxonia-Cope rearrangements under these conditions.