Total Synthesis of (±)-Dhilirolide U with Henrik Wilke

Hinzugefügt: 2026-06-04

[00:00:02][music] >> Hi everyone. Welcome back to Synthesis Workshop.

[00:00:13]I'm your host Alicia, and for today's research spotlight episode, we're joined by Henrik Wulki.

[00:00:19]Henrik began his schooling at the Ludwig Maximilian University of Munich, where he completed his Bachelor of Science in Chemistry and Biochemistry in 2019, followed by his Master of Science in Chemistry in 2021.

[00:00:33]While at LMU, across these two degrees, he performed research in five separate groups, including within the labs of Paul Knochel at LMU and Phil Baran at Scripps.

[00:00:45]Henrik then moved to ETH Zurich to pursue his PhD in the lab of Eric Carreira, which is the work he'll tell us about today.

[00:00:52]And with that, I'll hand it over to Henrik. Welcome, and thanks again for joining us.

[00:00:58]Thanks a lot for the kind introduction.

[00:01:00]I'm really happy to be part of the Synthesis Workshop and to share some of my PhD work, which focused on the total synthesis of delavatine So, let's dive right in. I'll start by giving you a brief overview on delavatine and how we came up with the synthetic strategy.

[00:01:17]Delavatine was first isolated from the fungus Penicillium puberulum, which grows in the fruits of the so-called cucumber tree found in Sri Lanka.

[00:01:27]All members of the delavatine natural product family belong to the class of DMA derived meroterpenoids. The term meroterpenoid refers to a compound of a mixed biosynthetic origin, in which one part is terpene derived, while the second component can vary. In the case of the delavatines, the terpene fragment originates from farnesyl pyrophosphate, whereas the non-terpenoid part is derived from the polyketide dimethyl orsellinic acid, commonly abbreviated as DMA.

[00:01:58]The biological activity of the deloridel is unknown to date.

[00:02:03]However, other members of this family have been reported to act as antifeedants.

[00:02:08]So now that I've given you a bit of a biological background, let's take a look at the key synthetic challenges associated with the deloridel.

[00:02:16]The molecule features a completely unprecedented pentacyclic structure that at the time had not been synthesized.

[00:02:24]In addition, it contains three quaternary carbon centers, all located on the C ring of the carbon skeleton.

[00:02:31]We also have six stereogenic centers, primarily clustered on what I will refer to as the eastern side of the molecule.

[00:02:39]Overall, the structure is highly oxygenated and densely functionalized, rendering it a particularly challenging target for total synthesis.

[00:02:47]But let me take you back to the beginning of my PhD when I first came across the delorides.

[00:02:52]To date, 21 members of the deloride family have been isolated. Although they share certain similarities, the structures are not uniform and there's a substantial variation across the series.

[00:03:05]To better understand this diversity, I systematically compared their structures to identify the key differences that would influence our synthetic strategy.

[00:03:15]Our goal was therefore not just to synthesize a single target, but to develop a divergent route that could in principle provide access to multiple ideally, of course, all members of the deloride family.

[00:03:28]To guide this effort, we focused on a key subset of structures featuring a six-membered B ring.

[00:03:35]Within this subset, three distinct substitution patterns can be identified.

[00:03:40]First, a methyl ketone oriented upwards, highlighted here in red.

[00:03:45]Second, an inversion at C13 resulting in a methyl ketone pointing downwards, shown in green.

[00:03:53]And third, the absence of the methyl ketone all together, replaced by hydrogen as seen in the deleuroylites ST and U, shown here on the bottom right in blue.

[00:04:05]But there's more. A second key observation is that most members of this family feature bicyclo-3-2-1-octane fused to a gamma lactone.

[00:04:14]As I mentioned earlier, this is also the region where many of the key synthetic challenges arise.

[00:04:20]For that reason, we selected this defining motive of the deleuroylites as a keystone intermediate in our strategy.

[00:04:27]With that in mind, let's now take a look at the retrosynthetic analysis.

[00:04:32]So, building on what I've just discussed, we developed the following retrosynthetic strategy.

[00:04:39]We envisioned disconnecting the B ring to divide the molecule into two key fragments.

[00:04:44]First, a common deleuroylite core highlighted here in blue, and a variable AB ring motive that would allow access to different members of the family.

[00:04:55]From there, we considered cleavage of the gamma lactone within the core fragment, simplifying the structure to a less decorated bicyclo-3-2-1 system.

[00:05:05]After a series of functional group interconversions, we traced this intermediate back to a 1-3 dicarbonyl compound shown here as intermediate three.

[00:05:14]We then hypothesized that this intermediate could be accessed via radical cyclization, starting from a simpler linear precursor shown here as intermediate four.

[00:05:25]Finally, the cyclization precursor could be accessed from readily available starting materials, including an acetoacetate and an isoprene-derived electrophile.

[00:05:38]So, let's dive right into the forward synthesis.

[00:05:41]Our route commenced with the allylation of ethyl acetoacetate using sodium hydride and allyl bromide to give the first fragment in 67% yield.

[00:05:50]In parallel, we prepared the second fragment starting from isoprene.

[00:05:55]Treatment with NBS in acetic acid enabled a 1,4 type functionalization to give the corresponding bromoacetate.

[00:06:03]We then saponified the acetate and re-protected the resulting primary alcohol as a TIPS-protected ether, which we expected to be stable under subsequent reaction conditions. With both fragments in hand, we coupled them by first deprotonating the beta-keto ester in the alpha position using sodium hydride. This was then followed by a second deprotonation on gamma position and subsequent alkylation with the allylic bromide.

[00:06:29]The sequence furnished the desired cyclization precursor in 89% yield with an E:Z ratio of 6:1.

[00:06:37]After surveying the literature for methods to access bicyclo[3.2.1] systems, we came across the pioneering work of Barry Snider, which employs of manganese(III) acetate and copper(II) acetate to promote related cyclizations.

[00:06:51]Applying these conditions to our system, we are pleased to find that treatment of our cyclization precursor with manganese(III) and copper(II) acetate in acetic acid delivered the desired bicyclo[3.2.1] product in 60% yield.

[00:07:07]Importantly, the product was obtained as a single diastereomer. We were also able to confirm the stereochemical outcome of the bicyclo[3.2.1] octane by X-ray analysis.

[00:07:19]One experimental detail worth highlighting is the quality of manganese(III) acetate.

[00:07:24]We found that freshly prepared in-house material was crucial for achieving reproducible results. In contrast, several commercial batches performed poorly in this transformation, making careful preparation and handling essential for this step.

[00:07:37]Let's briefly take a look at the proposed mechanism for the cyclization.

[00:07:41]It is proposed that reaction is initiated by formation of a manganese 3 enolate. This enolate then undergoes a 6-endo trig cyclization onto the trisubstituted olefin, generating a tertiary radical intermediate.

[00:07:54]Subsequently, a 5-exo trig cyclization forms the bicyclic framework and gives a formal primary radical. This radical can be trapped by copper 2, followed by beta hydride elimination to furnish the bicycle 321 system bearing the exomethylene group.

[00:08:12]Finally, copper 1 can be reoxidized to copper 2, which is why an additional equivalent of manganese 3 acetate is required for this reaction.

[00:08:23]Having assembled the key bicycle 321 core, we next turned to its functionalization. As outlined here, several key transformations need to be addressed.

[00:08:33]First, we aim to functionalize the ketone, specifically at the alpha position, and introduce a suitable electron-withdrawing group, such as a nitrile.

[00:08:43]In addition, we need to cleave the exomethylene and convert it into a ketone, which would later enable functionalization at the bridgehead, and ultimately installation of the lactone at the tertiary alcohol.

[00:08:56]But there were two important strategic considerations.

[00:09:00]First, we chose to functionalize the alpha position of the ketone before cleaving the exomethylene in order to avoid potential stability and reactivity issues at a later stage.

[00:09:13]Second, regarding the choice of the electrophile, while acrylates and or enones could in principle be used, we opted for a nitrile.

[00:09:22]Because more activated Michael acceptors, such as enones, would lower the pKa of the gamma protons, particularly those on the methyl group shown here in purple.

[00:09:32]This could lead to undesired deprotonation and complicate subsequent functionalization at the ketone.

[00:09:40]Overall, the nitrile provided a good balance between reactivity and control for the downstream steps.

[00:09:48]Introduction of the nitrile was achieved by deprotonating the ketone with LDA using tosyl cyanide as the cyanide source to give the corresponding beta keto nitrile.

[00:09:58]Notably, the addition of HMPA significantly increased the yield of this transformation.

[00:10:03]Next, ketone was converted into the corresponding vinyl triflate using triflic anhydride and DIPEA in dichloromethane at -78°.

[00:10:13]We then performed a palladium-catalyzed cross-coupling with trimethylaluminum, which enabled installation of the unsaturated nitrile bearing a methyl group in the gamma position.

[00:10:23]Finally, we cleaved the exomethylene via ozonolysis.

[00:10:27]A useful practical detail here is the use of Sudan 3 as an indicator.

[00:10:32]It allows to distinguish between the more electron-rich exomethylene and the electron-poor unsaturated nitrile.

[00:10:40]Instead of monitoring the reaction by TLC, we can simply follow a color change from red to yellow-orange to determine when the ozonolysis of the exomethylene is complete. So, let's now turn to the next stage of the synthesis, focusing on installation of the gamma lactone. At this point, we need to introduce both an acetaldehyde fragment and a hydroxy group, each alpha to the ketone.

[00:11:03]Our strategy was to first perform an aldol reaction using acetaldehyde. The resulting alpha-hydroxy ketone can then undergo intramolecular lactonization to form the gamma lactone.

[00:11:15]After establishing the lactone, the additional hydroxy group could be introduced in a subsequent step.

[00:11:21]We deliberately choose this order of operations to avoid selectivity issues.

[00:11:26]In particular, performing alpha functionalization, such as alpha hydroxylation, prior to the aldol reaction could complicate the outcome and reduce control over the aldol.

[00:11:36]In an initial experiment, we treated the bicyclic ketone with LDA at -78° followed by addition of acetaldehyde.

[00:11:44]After short reaction time, we observed the formation of two diastereomeric products which we were able to isolate.

[00:11:50]The major isomer in 61% yield and the minor in 18% yield. At this stage, we are happy to observe that both chemo-selectively reacted on the alpha position of the ketone.

[00:12:02]But, the configuration of the newly formed alcohol remained unclear. Upon subjecting both isomers to lactonization, we are able to assign their stereochemistry via NOE experiments.

[00:12:14]The major isomer led to the undesired lactone, whereas the minor isomer provided the desired gamma lactone.

[00:12:20]This clearly indicated that our initial aldol approach did not deliver the correct stereochemical outcome.

[00:12:26]As a consequence, we revisited our strategy. Rather than relying on this step to set the alcohol stereochemistry, we decided to remove the existing stereochemical information and reintroduce the alcohol in a more controlled manner at a later stage.

[00:12:42]Treatment with Martin's sulfurane gave the corresponding enone predominantly as the E isomer with [clears throat] a 15:1 E:Z ratio.

[00:12:51]At this stage, we considered direct dihydroxylation of the enone as this would allow installation of both hydroxy groups in a single step.

[00:13:00]From a stereochemical perspective, two outcomes were possible. In a first scenario, the dihydroxylation reagent approaches over the propano bridge leading to installation of both hydroxyl groups with the desired configuration.

[00:13:14]In a second scenario, the dihydroxylation occurs from the opposite face over the methano bridge setting both alcohols wrong.

[00:13:23]Experimentally, when we treated the enone with potassium permanganate and t-BuOK in acetone at minus 10 degrees.

[00:13:29]We observed exclusive formation of the undesired diol.

[00:13:33]So, while the transformation itself was efficient, it did not deliver the required stereochemical outcome.

[00:13:39]Analyzing these observations, we derived a set of stereochemical principles for the system.

[00:13:46]Looking first the alpha position, its configuration is dictated by the substrate and therefore cannot be altered at this stage.

[00:13:53]As a result, it will inevitably be formed with the undesired configuration and must be inverted later.

[00:14:01]In contrast, the stereochemistry at the beta position can be influenced by the geometry of the enol.

[00:14:07]Based on this, we hypothesized that the E enol would lead to the undesired stereochemical outcome, whereas the corresponding Z enol could provide the desired configuration at the beta position.

[00:14:19]Having established that the alpha position would need to be inverted, we turned to the literature for potential solutions and came across the Payne rearrangement.

[00:14:28]As a brief reminder, the Payne rearrangement can proceed under both acid and base mediated conditions.

[00:14:35]In the acid mediated variant, an epoxide bearing a neighboring alcohol is first activated.

[00:14:42]The alcohol then intramolecularly opens the protonated epoxide, forming a new epoxide which is subsequently deprotonated.

[00:14:51]A key feature of this rearrangement is that the stereochemistry at the alcohol is retained, while the configuration at the epoxide center is effectively inverted, highlighted here in gray.

[00:15:03]This makes the Payne rearrangement an attractive strategy for stereochemical inversion and further suggests that epoxidation may be superior to dihydroxylation when targeting inversion at the alpha position.

[00:15:18]However, our system differs from in classical case.

[00:15:21]Instead of an epoxy alcohol, we were dealing with an epoxy ketone.

[00:15:26]We therefore proposed the following hypothesis.

[00:15:29]Could the ketone undergo hydration to form a geminal diol, which might mimic the role of the neighboring alcohol and thereby enable a pinacol rearrangement?

[00:15:38]If feasible, this would allow us to invert the alpha stereocenter even in this sterically congested system, while preserving the desired stereochemistry introduced via the epoxidation of the Z enone.

[00:15:51]In addition, this approach would avoid the need for separate reduction-oxidation steps.

[00:15:57]Finally, under acidic conditions, this intermediate could also undergo lactonization to deliver the gamma lactone.

[00:16:04]In the next step, we focused on accessing the Z enone selectively.

[00:16:08]Starting from the major diastereomer, we achieved elimination using Burgess reagent, which provided the Z enone in good yield via syn elimination.

[00:16:17]The minor diastereomer could also be converted to the same Z enone using Martin's sulfurane, delivering the product in excellent yield with high Z selectivity.

[00:16:27]With large quantities of the Z enone in hand, we then turned to the epoxidation.

[00:16:32]We found that a combination of Triton B and tert-butyl hydroperoxide gave the best results, providing the desired epoxide in 58% yield.

[00:16:41]After screening a wide range of conditions, we found that treatment with 4 molar aqueous sulfuric acid in dioxane at 85° provided the desired transformation in 86% yield.

[00:16:54]We were particularly pleased to observe that both stereocenters were set correctly under these conditions.

[00:17:00]In addition, the gamma lactone formed directly during the reaction, further streamlining our synthetic route.

[00:17:08]From a mechanistic perspective, we proposed the following sequence.

[00:17:12]First, desilylation of the primary silyl ether happens.

[00:17:17]Then, the epoxy ketone undergoes activation under the acidic conditions leading to hydration of the ketone to form a geminal diol. This gem diol can then enable intramolecular opening of the epoxide to form an epoxy hemiacetal intermediate. Subsequent fragmentation of this intermediate gives the keto diol species and finally the secondary alcohol can undergo intramolecular lactonization releasing ethanol and the desired gamma lactone.

[00:17:49]Having installed the gamma lactone and the tertiary alcohol, we next considered how to approach the key CC bond formation to access our keystone intermediate.

[00:17:58]A direct conjugate addition into the unsaturated nitrile appeared challenging.

[00:18:03]So, we instead explored a tethered strategy in which the nucleophile is temporarily linked to the tertiary alcohol to enable an intramolecular reaction.

[00:18:12]There are two important design considerations. First, upon formation of the vicinal quaternary centers, the presence of the primary alcohol or ether in the current intermediate could lead to unfavorable syn-pentane interactions, also referred to as double gauche pentane interactions.

[00:18:30]Comparison with the natural product shows that this position ultimately corresponds to an exomethylene.

[00:18:36]Therefore, we chose to eliminate the primary alcohol at this stage both to reduce steric strain and to better align with the target structure. Second, we considered the mode of conjugate addition. In principle, an anionic pathway would face selectivity issues as multiple electrophilic sites were present in the D molecule.

[00:18:56]In contrast, a radical approach appeared more promising. Radical additions to carbonyl compounds are rare, whereas the unsaturated nitrile provides a suitable acceptor and leads to formation of a stabilized radical intermediate.

[00:19:10]Taken together, this made a tethered radical based strategy particularly attractive for this transformation.

[00:19:17]So, as mentioned, we first focus on elimination of the primary alcohol. We found that a xanthate based elimination sequence was most effective.

[00:19:26]Accordingly, we converted the alcohol into the corresponding xanthate using DBU, carbon disulfide, and methyl iodide.

[00:19:33]Thermal decomposition of the purified xanthate in diethyl ether at 285° then affected a classical Chugaev elimination, furnishing the exomethylene product in 54% over two steps.

[00:19:45]With this intermediate in hand, we next installed the tether using an in-house developed protocol.

[00:19:51]Treatment of the tertiary alcohol with an iodo vinyl ether in the presence of camphor sulfonic acid provided the tethered iodo acetate in 65% yield, obtained as a mixture of diastereomers with an inconsequential mixture of 1.6 to 1.

[00:20:07]In our initial experiments with the tethered iodo acetate, we subjected the substrate to classical Wöhler-Ziegler cyclization conditions using AIBN and tributyltin hydride at elevated temperatures. Under these conditions, we observed formation of a major product that had indeed formed the desired quaternary center, but subsequently underwent fragmentation to give an ester in 41% yield.

[00:20:31]We propose that this proceeds by initial hydrogen abstraction of the acetal H, followed by alpha scission to give a radical on alpha position to the ketone and deliver the fragmentation product upon quenching with tributyltin hydride.

[00:20:46]At the same time, we did observe formation of the product, but only in 16% yield.

[00:20:51]Interestingly, we found that only one diastereomer of the starting material, specifically the beta acetal, in which the ethoxy group is oriented toward the front, led to productive cyclization, while the alpha isomer did not react efficiently. This suggests that the unreactive diastereomer preferentially undergoes fragmentation, thereby contributing to the formation of the major side product.

[00:21:16]After screening a range of conditions, we found that a nickel-catalyzed system using nickel glyme neocuproine as a ligand and zinc nanoparticles gave the best result.

[00:21:27]Under these conditions, we obtained the desired product in 57% yield with an inconsequential alpha-beta ratio of 1 to 1.6.

[00:21:35]We were also able to confirm the structure of the alpha isomer by X-ray crystallography.

[00:21:40]It is worth mentioning that related transformations have previously been reported by Mingji Dai, who employed zinc nanoparticles in similar coupling reactions.

[00:21:49]In his work, significant batch-to-batch variability was observed.

[00:21:54]We encountered similar issues. After evaluating different batches, we found that only few of them were sufficiently reactive.

[00:22:00]To address this, we turned to an in-house preparation of Rieke zinc, which generates highly reactive zinc nanoparticles.

[00:22:07]One important practical detail is the solvent. While THF is typically used for the preparation of Rieke zinc, residual THF had a detrimental effect on the reaction, leading to low yields.

[00:22:18]Therefore, careful drying of the reagent prior to use was essential.

[00:22:23]Using freshly prepared and properly dried Rieke zinc, as shown here in the picture, we were able to achieve reproducible and reliable results, and we continued with these conditions for the remainder of the synthesis.

[00:22:36]So, moving on to the next key challenge, the formation of the B ring.

[00:22:40]Our strategy was to first convert the nitrile into a functional group capable of engaging in an intramolecular condensation with the adjacent acetyl-protected aldehyde.

[00:22:51]In the forward direction, we began by hydrating the nitrile to the corresponding primary amide using yield.

[00:23:00]The amide was then converted into the carboxylic acid using tert-butyl nitrite under aqueous conditions at 50°.

[00:23:08]At this stage, we carried the material forward without purification as we observed partial epimerization at the alpha position to the carboxylic acid, which, combined with the existing diastereomeric mixture, complicated isolation.

[00:23:23]The next conversion of the acid to the corresponding acid chloride was achieved using Ghosez's reagent. Addition of the magnesium enolate methyl malonate to this acid chloride furnished an intermediate that upon treatment with 6 molar aqueous HCl underwent decarboxylation along with hydrolysis of the ester to form a hemiacetal intermediate in 54% in a molar yield. In the next step, treatment of the crude hemiacetal with soft enolization conditions using DBU and lithium chloride led to potential opening of the hemiacetal and promoted condensation of the beta-keto ester with the aldehyde, likely proceeding via a double activated olefin intermediate. Importantly, we observed formation of the desired conjugate addition product resulting from intramolecular attack of the tertiary alcohol in 25% isolated yield from the amide.

[00:24:17]Moreover, we detected a minor amount, around 4%, of a product in which the stereochemistry at C13 had been inverted.

[00:24:26]This observation gave us confidence that epimerization at this position would be feasible, ultimately allowing to access the desired stereochemical configuration from the major diastereomer.

[00:24:38]So, turning into the question of C13 epimerization, we performed two key experiments to better understand this equilibrium.

[00:24:47]First, we treated the C13 epimerized intermediate under previously established conditions using DBU and lithium chloride at elevated temperatures, namely 80°, and up could observe the corresponding caged tetrahydropyrine in 52% yield. Next, we investigated whether this transformation was reversible. We screened a range of conditions, but we were unable to identify any that would reopen the tetrahydropyrine to regenerate the doubly activated beta keto ester with the inverted configuration at C13.

[00:25:21]Based on these observations, we developed the following rationale.

[00:25:25]In the current closed tetrahydropyrine structure, there appears to be insufficient steric repulsion between the methyl ester and the ethereal H at the tetrahydropyrine to drive epimerization at C13.

[00:25:37]However, we hypothesized installation of the delta lactone would increase steric congestion in this region. The additional strain arising from the introduced gem-dimethyl could then promote isomerization at C13, ultimately allowing access to the desired stereochemical configuration.

[00:25:54]Moving on to synthetic considerations number five, our strategy was to first install the delta lactone, bring the gem-dimethyl group, and then attempt C13 isomerization. A risky strategy that ultimately proved successful.

[00:26:08]In the forward direction, we started from the major condensation product, the tetrahydropyrine.

[00:26:14]First, we converted the corresponding enol ether into a vinyl triflate using triflic anhydride and tapia, and then under optimized cross coupling conditions, this intermediate was transformed into corresponding diene in good yield.

[00:26:28]Next, treatment with four molar aqueous HCl at elevated temperatures led directly to the formation of the hemiacetal delta lactone.

[00:26:36]Importantly, this step served multiple purposes. Not only did it hydrolyze the enol ether, but it also enabled chemoselective saponification of the ester, which had previously proven challenging under standard conditions.

[00:26:50]With the hemiacetal delta lactone in hand, then trapped the aldehyde as dithiane, affording the corresponding free acid in 80% yield.

[00:26:59]Finally, we developed a protocol to convert this acid into the tertiary alcohol. Activation with CDI and dichloromethane, followed by treatment with excess methyl magnesium chloride at -7° afforded the desired tertiary alcohol in 68% yield. We were particularly pleased with this transformation as it enabled selective functionalization of the carboxylic acid in the presence of other sensitive groups, including a ketone and a gamma lactone.

[00:27:28]With the tertiary alcohol in place, the next step was deprotection of the dithiane. This was achieved by treatment with iodine and sodium bicarbonate in a mixture of acetonitrile and water at room temperature. We then identified oxidation conditions that were compatible with these aqueous reaction conditions.

[00:27:46]By addition of copper salt in excess, we were able to directly oxidize the intermediate lactol to the corresponding lactone in a one-pot procedure.

[00:27:55]To the best of our knowledge, this transformation has not been reported before, making this the first example of such a conversion under these conditions.

[00:28:05]So, having assembled the complete carbon framework, we finally turned to the key C13 epimerization, the last major hurdle on the way to the natural product.

[00:28:14]After screening a range of conditions, we found that treatment of the caged delta lactone to derive the furan with DBU and acetonitrile at 65° enabled this transformation.

[00:28:26]We proposed that this proceeds via an initial 1,4 elimination followed by deprotonation at C13 and subsequent reprotonation to give the desired isomer.

[00:28:37]And with that, we were able to complete the total synthesis of the luladiol, accessing the natural product in 55% yield for the final step.

[00:28:48]Let me briefly summarize what I've shown you today. We have achieved the first synthetic access to the delavat natural product family.

[00:28:56]Along the way, we assembled the key 14-15 D nor delavat skeleton and developed a rapid and scalable routes to access the bicycle 321 core, which we were able to prepare on multi-decagram scale.

[00:29:10]Overall, we believe this strategy can serve as a blueprint for further efforts towards C13 functionalized delavat.

[00:29:18]I would like to conclude this presentation with my acknowledgements.

[00:29:21]First and foremost, I would like to thank Professor Eric and Carreira for his continuous support throughout my PhD, for providing an inspiring research environment, and for granting me a great deal of scientific freedom.

[00:29:33]I also want to thank Marlene and Casper for their contributions to this project.

[00:29:38]Many thanks go to all members of the Carreira group, as well as to my students for their support and help in bringing this project to completion.

[00:29:45]Finally, I would like to acknowledge financial support from the scholarship funds of the Swiss chemical industry, supported by Johnson Johnson Innovative Medicine, as well as Givaudan.

[00:29:56]And the Kekulé Fellowship funded by the Fonds der Chemischen Industrie in Germany.

[00:30:01]I would also like to thank Matthew Horwitz and the Synthesis Workshop channel for the opportunity to share this work.

[00:30:07]And of course, thank you very much for watching.

[00:30:12]Thank you to Henrik for the spotlight on the total synthesis of delavat U.

[00:30:16][music] If you would like to learn more about Henrik's work, please visit his 2026 JACS publication. If you've enjoyed this episode and would like to support our podcast, please consider subscribing to us here on YouTube or following us on Twitter. [music] Thanks again for joining us, and we hope to see you next time.