A general approach to the total synthesis of yeuhchukene and its analogues : a novel anti-implantation agent

• Main Author: Lopez Tapia, Francisco Javier
• Language: English
• Published: University of British Columbia 2010
• Subjects: Rutaceae; Plant physiology
• Online Access: http://hdl.handle.net/2429/29013

This thesis concerns a general approach to the total synthesis of yuehchukene 2 and its analogues. Yuehchukene has a potent anti-implantation activity. It also lacks the estrogenic side effect of most compounds with similar biological activity. However, it is somewhat unstable and this could bring some problems when administered to humans. Development of a versatile synthesis of yuehchukene capable of producing a variety of analogous structures in order to fully exploit the pharmacological properties of this novel molecular system and/or to make a more stable product without losing its biological properties was the central objective of this project. Specifically, the total synthesis of yuehchukene 2 and its analogue 6a-ep/-yuehchukene 25 are described. After some preliminary studies, it was found that a kinetic carboxylation (lithium 2,6-di-tert-butyl-4-methylphenoxide, CO₂) of isophorone 26 followed by a reduction (NaBH₄) produced stereoselectively cis-hydroxyacid 46 in good yield. The latter was transformed into indoleacid 48 by dibenzoylation (PhCOCI, DMAP) and treatment with indolylmagnesium iodide. The key intermediate trans-ketone 60 was obtained by treatment of 48 with oxalyl chloride followed by indolylmagnesium iodide. Epimerization of 60 to the more stable cis-ketone 24 was accomplished quantitatively under basic conditions (MeONa/MeOH, reflux). Reduction (LiAlH₄) and dibenzoylation (PhCOCI, DMAP, Et₃N) of 24 furnished the benzoate 68 which was subjected to a nucleophilic substitution with indolylmagnesium iodide to give N-benzoylyuehchukene 69. The latter transformation also gave the interesting compound 75 which was submitted to an X-Ray diffraction analysis. The total synthesis of yuehchukene 2 was then achieved by methanolysis (NaOMe/MeOH) of 69. As far as the synthesis of 6a-epi-yuehchukene 25 is concerned, it was found that, after a thorough study, it was best to transform trans-ketone 60 into its SEM-derivative 85 (SEM-CI,NaH). The latter was reduced (DIBAL) and acetylated (Ac₂O, DMAP, Et₃N) to produce stereoselectively the acetate 87 which, by treatment with indolylmagnesium iodide, furnished SEM-trans-yuehchukene 88. The newly incorporated indole group bears a 1,3-diaxial-like interaction with the β-methyl group at C-7. Unlike 88, tosylacetate 82 gave the compound 84. Finally, the total synthesis of 6a-epi-yuehchukene was accomplished by deprotection of the indole system. Various compounds from this study are now under investigation at WHO and in Hong Kong but, unfortunately, biological results are unavailable at present. [Formula Omitted] === Science, Faculty of === Chemistry, Department of === Graduate