Synthesis of Spiromorpholinotetra-hydropyrans Through a Prins Bicyclization

Significance

The Prins cyclization is a powerful method for the construction of heterocyclic ring systems, and its application in the synthesis of natural products and biologically active molecules is resurfacing in current practice (see Review below). Subba Reddy and co-workers report the synthesis of spiromorpholinotetrahydropyran heterocycles through a diastereoselective Prins bicyclization. The resulting 1,9-dioxa-4-azaspiro[5.5]-undecane cores are of particular interest due to their anti-HIV (e.g., W. M. Kazmierski et al. Bioorg. Med. Chem. Lett. 2006, 16, 5226), anti-proliferative (P.-H. Storck et al. Patent WO/2009/037343), and anti-ischemic (M. C. Breschi et al. J. Med. Chem. 2006, 49, 7600) properties.

Review

X. Han, G. Peh, P. E. Floreancig Eur. J. Org. Chem. 2013, 1193–1208.

Comment

The scope of the presented methodology may be expanded beyond aromatic aldehydes and may be applied to acid-sensitive, aliphatic, heterocyclic, and sterically hindered starting materials. One limitation is the inability to apply the Prins cyclization on N-Boc- or N-Cbz-protected homoallyl alcohols. It seems reasonable that the tosyl group not only serves as an amine protecting group, but its electron-withdrawing nature also aids in the cyclization by lowering the LUMO of the carbocation intermediate through an inductive effect. The stereochemistry is rationalized in the context of the observation of trapping of the tertiary carbocation intermediate by the tethered alcohol approaching from the less sterically hindered equatorial side of the more stable chair conformation.