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Enantioselective Organocatalytic Reaction Cascades of Substituted Pyrroles
and their Application in Complex Alkaloid Natural Product Synthesis

Final Report Summary - ENACASCASYN (Enantioselective Organocatalytic Reaction Cascades of Substituted Pyrroles<br/>and their Application in Complex Alkaloid Natural Product Synthesis)

The retrosynthetic analysis for daphniyunnine B identified the tetracyclic core structure III (Scheme 1) as an advanced precursor, bearing all the stereocenters present in the target molecule. Further functionalization of the double bond could lead to substrates of type IV and subsequently formation of ring E could be achieved via intramolecular aldol condensation. On the other hand, ring D would be installed through intramolecular ring closing metathesis (RCM) from precursor II and the five-membered C ring through intraintramolecular Michael addition using methodologies previously developed in our group1.

Results and discussion:
A) Optimisation and scale up of a synthetic route towards the tetracycle III
The route started with the reduction of (S)-carvone followed by TMS-protection of the resulting secondary alcohol in a two-step sequence without any need for purification and in 93% overall yield. This protocol was efficiently performed in 20 g scale. Hydroboration and oxidative cleavage of the double bond leading to the mixture of diastereomers (Scheme 2,4) proceeded smoothly and proved to be an easily scalable reaction. The subsequent cleavage of the silyl ether with TBAF/THF afforded the desirable diol 5 quantitatively. Some epimerization was observed when the removal of the silyl group was tried under slightly acidic conditions, i.e. PPTS/MeOH. Submission of the diol 5 to standard conditions for TEMPO oxidation led to the selective oxidation of the primary alcohol to the aldehyde followed by an intramolecular nucleophilic attack of the secondary alcohol to render a cyclic hemiacetal. The subsequent oxidation of this specie afforded the epimeric lactones 6. Pleasingly, the product was obtained in one-pot procedure in 72% yield. Conversion of the diatereomeric mixture to the optically pure lactone 7 was performed under kinetic control. Reduction of the obtained product with LiAlH4 afforded the crystalline diol 8 in quantitative yield. The spectroscopic data and optical rotation of compound 8 perfectly matched those reported in the literature2. Selective TBSprotection of the primary alcohol was accomplished in excellent yields. Interestingly, attempts to form the analogous TBDPS-derivative was unsuccessfully tried. The key Overman rearrangement for the introduction of the amino functionality with the required stereochemistry was performed as reported previously for a similar system and afforded the formation of the trichlororoacetamide 10 in good yield3. The imidate, which is an intermediate in this procedure proved to be extremely sensitive to silica gel and its purification through flash column chromatography should be performed very quick in order to get the best overall yields. Cleavage of the TBS group and basic hydrolysis of the trichoroacetamide amide 10 followed by Boc-protection afforded the alcohol 11 in 76% overall yield. The exhaustive extraction of the amino-alcohol from the aqueous mixture after the basic hydrolysis determines the yield of this three-step sequence. Introduction of the tosyl group followed by an intramolecular cyclization under basic conditions led to the formation of bicycle 12 with retention of stereochemistry. The important allylic oxidation of substrate 12 was first tried using several methodologies based on tertbutyl hydroperoxide (TBHP) as the oxidant and in combination with a metal catalyst such as copper iodide4, dirhodium caprolactamate5,6,7,8,9, chromium compounds10, palladium(II) salts11 or manganese(III) acetate12. Unfortunately, the desired product 8 was either obtained in very low yield and with the formation of several side products, or no reactivity was observed at all. Alternatively, the oxidation of the more reactive allylic position to the alcohol was attempted by with SeO2 either in catalytic or stoichiometric amounts13,14. None of these methods showed selectivity in the oxidation and undesirable side products were obtained. Lack of selectivity was also observed when NBS was tried for the allylic oxidation15. The best results for the selective allylic oxidation of substrate 12 were obtained by the use of CrO3 and 3,5-DMP in CH2Cl2. However, the high toxicity associated to Cr (VI) compounds constitutes a drawback of this methodology. Following the above described synthetic path, 2.5 g of the bicyclic product 13 were prepared in 10% overall yield. Boc deprotection of the bicycle 13 led to the trifluoroacetate salt 14, which smoothly reacted with acid chloride 15 to provide amide 16 as a mixture of two inseparable diastereomers. When amide 16 was treated with KHMDS in THF, it was cleanly converted to the expected Michael addition product with complete stereocontrol. A more convenient approach is to perform a tandem enolate allylation reaction through sequential addition of KHMDS followed by 17 and catalytic 18-crown-6 ether. This protocol allowed the isolation of enol ether 18 in 81% yield, as a single diastereomer, starting from precursor 16. Heating enol ether 18 in refluxing mesitylene rendered the Claisen product 19 which was perfectly poised for the subsequent RCM step. Refluxing 19 in dry CH2Cl2 with 15 mol% of Grubbs-Hoveyda II catalyst furnished the tetracyclic core 20 in good yield. Allyltosylate and catalytic 18-crown-6 furnished the O-alkylated product 21 upon reaction with 20 in excellent yield and with complete regioselectivity. Subsequent Claisen rearrangement afforded the carbon allylated product in 78% yield. Overall, the preparation of the tetracycle III could be accomplished in 21 steps from commercially available materials through a synthetic route that proved to be scaleable.

B) An attempt to synthesise a bicycle of type I via a gold-catalysed cyclisation as the key step.
As highlighted above, compounds of type I (Scheme 1) are extremely important in our synthetic design. Although bicycle 13 was prepared on a multi-gram scale, we were still in need of a more straightforward pathway towards its synthesis. Consequently, we envisioned a new synthetic route involving a late stage gold-catalyzed cyclization as the key step (shown below). Our synthetic path started with the one-pot esterification and intramolecular cyclization of commercially available D-glutamic acid to render (R)-Pyroglutamic ethyl ester in quantitative yields. Amide bond alkylation proceeded smoothly under standard conditions to give the functionalized lactam 23. As expected, a chemoselective double addition of methyl lithium on this substrate led to the desired secondary alcohol 24 in 61% yield. Gratifyingly, formation of alkene 25 was promoted by activation of the alcohol moiety of precursor 24 with thionyl chloride followed by slow addition of triethylamine. Notably, under these conditions the desired regioisomer was only obtained. The internal, more substituted alkene was the major product when other standard elimination reagents were tried. At this stage, ring-opening of the lactam 25 was unsuccessfully attempted. Alternatively, cleavage of the benzyl group followed by introduction of the Boc-protecting group to give carbamate 26 was accomplished in 71% yield over the two steps. Pleasingly, vinyl addition proceeded then under mild conditions but in moderate yields. RCM on diene 27 with Grubbs-Hoveyda II catalyst led to the enantiomerically pure cyclohexenone 28. The optical purity of this compound was determined by HPLC analysis, in comparison with its racemic counterpart. Completion of the synthesis was accomplished by taking advantage of a gold-catalysed cyclisation from the N-tosylate amine 29. This precursor proved to be very reactive towards the cyclisation reaction, whereas the N-Boc protected analog appeared to be inert under the same reaction conditions. Unfortunately, the desired compound 30 was only obtained as the minor product of the gold-catalysed cyclisation reaction and with the trans- diastereomer (i.e. in regard to the relative stereochemistry of the methyl group and the hydrogen on the newly generated stereogenic centers) as the favoured product. A wide range of catalysts and reaction conditions were tried in order to tune the diastereoselectivity of this cyclisation. Unfortunately, from sulfonamide 29, the best results only afforded the bicycle 30 in a synthetically useless diastereomeric ratio of 1:7 (i.e favouring the wrong diastereomer). To overcome this issue several alternative strategies are currently ongoing in the Dixon research group.

C) Development of a reaction cascade towards the perhydroindole ring structure.
Initial studies focused on the development of a new reaction cascade towards the perhydroindole ring structure were performed. The proposed synthetic path relies on the Birch reduction of 4- methoxyphenethyl amine 33 which was prepared through a three step sequence and from commercially available 4- methoxyphenethyl alcohol. A reaction cascade starting from either 35 or 37 was discovered. Enol ether hydrolysis, double bond migration and an intramolecular Michael addition rapidly occurred under anhydrous acidic conditions leading to the formation of a saturated 6,5- fused bicycle containing a nitrogen at the 1-position. The reaction cascade tolerates different types of substitution at the amino functionality. As expected, the single formation of the cis-diastereomer was observed. Studies oriented towards the development of an enantioselective variant of this kind of cyclisation are in progress.

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