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Pyrrole synthesis - Organic chemistry
In order to complete the total synthesis of marineosin A, we wanted to ensure that our strategy to form the spiroaminal lactam 2 from 3 through an acid-mediated cyclization strategy was viable. With intermediate 6 in hand, we thought it prudent to explore this chemistry on a properly functionalized, yet minimized model system, before committing advanced material. Reductive removal of the pivalate 6 with DIBAL-H proceeded smoothly to give primary alcohol 29 in 93% yield, which was then oxidized under Parikh-Doering conditions to provide aldehyde 30 in 93% yield (). Pinnick oxidation rapidly afforded the corresponding carboxylic acid which was coupled to ammonium chloride under standard coupling conditions to deliver the primary amide 31 in 78% yield for the two steps.[,] Hydrogenolysis of the benzyl ether and concomitant hydrogenation of the olefin provided a secondary alcohol that was immediately oxidized under Ley conditions to the ketone 32 in 84% yield over the two steps. After surveying a number of conditions, we found that 0.01 M HCl in MeOH affected the acid-mediated cyclization strategy providing 8 in 82% yield as a single diastereomer. Interestingly, the TIPS ether was hydrolysed under these conditions and intercepted by MeOH to afford the methyl ether, which was confirmed by 1D and 2D NMR studies. Efforts are under way to more thoroughly study this transformation. Extensive analysis of HMBC, HSQC, COSY and NOESY NMR experiments confirmed the absolute structure of 8 as the marineosin A isomer based on the stereochemistry relative to the axial methyl group within the pyran ring, which was set by the (S)-methyl oxirane at the outset of the synthesis. From 6, overall yield to 8 was 44.7%. Thus, advanced intermediate 6 provided access to both the macrocyclic pyran core 4 of marineosin A (1), as well as validated our acid-mediated cyclization strategy of a hydroxyketoamide into the spiroaminal lactam model 8.
In summary, we have developed an enantioselective synthetic route from a chiral pool starting material, (S)-propylene oxide, to access the 12-membered macrocyclic pyrrole core 4 of marineosin A (1), as well as a highly functionalized spiroaminal lactam 8 derived from the acid-mediated cyclization of a hydroxyketoamide. These efforts validate our retrosynthetic approach for the total synthesis of marineosin A, and efforts are underway to complete the total synthesis employing these tactics and strategies with final step pyrrole incorporation. Further refinements, applications to the related alkaloids, and biological investigations are in progress and will be reported in due course.
The Knorr pyrrole synthesis is a ..
Herein, we describe the enantioselective construction of the 12-membered macrocyclic pyrrole core 4 of marineosin A in 5.1% overall yield from (S)-propylene oxide. The route features a key Stetter reaction to install a 1,4-diketone, which is then subjected to Paal-Knorr pyrrole synthesis and ring closing metathesis (RCM) to afford macrocycle 4. A divergence point in the synthetic scheme also enabled access to a highly functionalized spiroaminal model system 8 via an acid-mediated hydroxyketoamide cyclization strategy.
Our retrosynthetic analysis for marineosin A (1) is shown in , and relies on late stage introduction of the C1–C4 pyrrole. Spiroaminal 2 can be formed by acid-mediated cyclization of advanced intermediate 3. A Paal-Knorr pyrrole synthesis and ring closing metathesis (RCM) allow for the formation of macrocycle 4 from 1,4-diketone 5. The Stetter reaction will be employed as a key carbon-carbon bond forming reaction en route to 5 from 6. Poly-functionalized 6 is a critical intermediate derived ultimately from Evans’ auxiliary phosphonate 7, vinyl magnesium bromide and (S)-propylene oxide, which sets the stereochemistry. Intermediate 6 also serves as a divergence point to validate the acid-mediated cyclization strategy for 2, and provides access to model system 8.
Paal-Knorr Pyrrole Synthesis - Organic chemistry
Reported is a Ru(PPh3)3(CO)H2- and XantPhos-catalyzed conversion of various 1,4-alkynediols into pyrrole derivatives. The reaction starts with an isomerization of the diol into a 1,4-diketone effected by the XantPhos-Ru complex and continues with a Paal-Knorr cyclization to the pyrrole. The amine component, as well as the alkyne component were quite thoroughly investigated. The reaction fails for anilines containing strong EWGs and for strongly hindered substrates. The conversion is in almost all cases complete (one exception), but the reaction sometimes stops at the diketone stage or leads to furan byproducts, thus the lower yields. Variation in catalyst loading was not studied.
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