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Title: Synthesis of aza analogs of podophyllotoxin
Other Titles: Synthese van aza-analoga van podophyllotoxine
Authors: Aigret, Benoit; M0316513
Issue Date: 26-Jun-2013
Abstract: <span style="font-size:10.0pt;line-height:115%">Podophyllotoxin and its related lignans have been known andused in crude extracts for hundreds of years in traditional medicine. Eversince its introduction for the treatment of Condylomata acuminata by Kaplanalmost seven decades ago, extensive research efforts have been made towards theexploration of these natural products and their synthetic analogues. Thiseventually led to the clinical introduction of the semisynthetic analoguesetoposide, teniposide and etopophos for the treatment of a variety of cancers.In view of the unwanted side effects caused by the use of these drugs and thedrug resistance developed by cancer cells, development of new analogues basedon podophyllotoxin remains an area of valuable research. This is encouragedeven further as podophyllotoxin and its derivatives have been shown to possessa broad range of other biological activities besides their well known anti-tumoractivity. Although there are many reports regarding its total synthesis, theseare still not economically viable and nature remains the principal source forthese compounds, although the lack of a responsible and sustainable cultivationis putting increasing strain on its future availability. <span style="font-size:10.0pt;line-height:115%">For these reasons, many research groups have made substantialefforts towards the synthesis of aza-analogues with simplified, readilyaccessible structures, of which the 4-aza-analogues have already shownpromising results. In this project, we set out to devise a total synthesis of anovel 1-aza-substituted podophyllotoxin scaffold to form the basis for thedevelopment of new biologically active molecules. <span style="font-size:10.0pt;line-height:115%">Our synthesis strategy was based around the combination oftwo achiral precursors in an asymmetric Mannich reaction, thereby creating the requiredchiral centers. Ring closure using a Buchwald-Hartwig cross-coupling leads tothe basic tetracyclic skeleton from which further derivatization could takeplace.<span style="font-size:10.0pt;line-height:115%">Although the synthesis of the precursors did not pose toomany problems and could be optimized to excellent results, many problems wereencountered from thereon.<span style="font-size:10.0pt;line-height:115%">The asymmetric Mannich reaction around which our strategy wasbased did not proceed according to literature results and had to be reoptimizedwith a model system, which eventually led to a reliable protocol that could beused for our substrate. The obtained product was then cyclized to thetetracyclic ring structure, but incorrectly characterized as having the desired2,3-trans lactone. This error wasonly discovered at a much later stage into the project, when the derivativepossessing the 3,4,5-trimethoxyphenyl-moiety had been synthesized. An X-raystructure of this compound showed that an epimerization occurred during theBuchwald-Hartwig ring closure, which could not be avoided by changing thereaction conditions.<span style="font-size:10.0pt;line-height:115%">In the mean while, we had already explored the functionalizationof the 4-position and the removal of the PMP-protecting group. Results showedthat our compounds were unstable towards the oxidative conditions needed for thesetransformations. As these steps were necessary for the derivatization of the basicskeleton, 2 alternative routes were evaluated. Although the precursors for thesenew strategies were eventually synthesized, these proved unreactive in theasymmetric Mannich reaction, which remained the key step for constructing thebasic skeleton. <span style="font-size:10.0pt;line-height:115%">Only after that did we finally succeed in synthesizing the3,4,5-trimethoxy-substituted analogue with the use of our initial strategy. Unfortunately,this turned out to be the less interesting picropodophyllotoxin analogue due toepimerization of the labile 2-position during the Buchwald-Hartwig ringclosure. A final modification of the strategy led to the desired 1-aza-4-deoxypodophyllotoxin,but only a marginal fraction could be obtained in pure form and its rapiddecomposition illustrates its unstable character. <span style="font-size:10.0pt;line-height:115%;font-family:&quot;Calibri&quot;,&quot;sans-serif&quot;;mso-fareast-font-family:Calibri;mso-bidi-font-family:&quot;Times New Roman&quot;;mso-ansi-language:EN-US;mso-fareast-language:EN-US;mso-bidi-language:AR-SA">Toconclude, the strategies described in this thesis could only be used reliablyfor the synthesis of 1-aza-4-deoxypicropodophyllotoxin, due to the unavoidableepimerization of the strained trans-lactone.As the small amount of 1-aza-4-deoxypodophyllotoxin obtained through the finalmodified strategy decomposed shortly after its characterization, we suspectthat the proposed 1-aza-substituted scaffold is too unstable to be of greatvalue. The cis-fused picro-derivativehowever is stable, but is suspected to possess much diminished antineoplasticactivity. However, it might find application as an immunosupressing agent forthe treatment of autoimmune diseases. Biological evaluation of this compound isintended but could not be incorporated into this thesis due to timerestrictions. 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Publication status: published
KU Leuven publication type: TH
Appears in Collections:Molecular Design and Synthesis

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