Stereoselective Syntheses of Tetrahydropyrans: Applications to the Synthesis of (+)-Leucascandrolide A, (+)-Dactylolide and (±)-Diospongin A

• Main Author: Lee, Kiyoun
• Other Authors: Hong, Jiyong
• Published: 2012
• Subjects: Chemistry
• Online Access: http://hdl.handle.net/10161/6164

<p>Substituted tetrahydropyrans are prevalent in natural products that show interesting biological and pharmacological activities. Therefore, demand for new synthetic approaches for the construction of substituted tetrahydropyrans has recently increased. Specifically, quick and facile access to substrates, excellent stereoselectivity and yield, versatility in substrate scope, and mild reaction conditions compatible with various functional groups are highly desirable characteristics in tetrahydropyran synthesis.</p><p>The first part of the dissertation details studies of the tandem and organocatalytic oxa-conjugate addition reactions in conjunction with a dithiane coupling reaction promoted by the <italic>gem</italic>-disubstituent effect for the stereoselective synthesis of 2,3,6-trisubstituted tetrahydropyrans. The reactions were applicable to a broad range of substrates and proceeded with excellent stereoselectivity. It is of note that the present protocol provides an access to thermodynamically less favorable 2,6-<italic>trans</italic>-tetrahydropyrans through a reagent controlled, organocatalytic oxa-conjugate addition. In addition, a temperature-dependent configurational switch allowed the preparation of both 2,3-<italic>trans</italic>-2,6-<italic>trans</italic>- and 2,3-<italic>cis</italic>-2,6-<italic>cis</italic>-tetrahydropyrans from a common substrate. The synthetic utility of a combination of the tandem and organocatalytic oxa-conjugate addition reaction and the dithiane coupling reaction was demonstrated in the formal synthesis of the cytotoxic macrolide (+)-leucascandrolide A, which possesses both the 2,6-<italic>cis</italic>-disubstituted tetrahydropyran and the 2,3-<italic>trans</italic>-2,6-<italic>trans</italic>-tetrahydropyran. We also demonstrated the potential of the organocatalytic 1,6-oxa-conjugate addition for the formation of the 2,6-<italic>cis</italic>-tetrahydropyran in the total synthesis of (+)-dactylolide.</p><p>The second part describes the facile and efficient approach to the synthesis of 2,6-cis-4-hydroxy-tetrahydropyrans via a tandem CM/thermal SN2&#8242; reaction. The strategic placement of the hydroxy group at C(4) in the tether resulted in an enhancement of the diastereoselectivity in ring closure. The mildness of the thermal conditions allowed for the synthesis of 2,6-<italic>cis</italic>-4-hydroxy tetrahydropyrans from base-sensitive substrates without the use of protecting groups. The tandem reaction enabled a protecting-group-free synthesis of (±)-diospongin A.</p> === Dissertation