Macrocyclic skeletal modification approach to the anti-trypanosomal macrolides, actinoallolides

Abstract

Herein, we report the construction of 16-membered macrocycles that were designed as intermediates toward the unified synthesis of actinoallolides. Key to our synthesis was the use of Mitsunobu macrocyclization, followed by a sequence of Birch reduction and oxidative C–C cleavage to edit the macrocycle.

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Polyketide natural products, in particular macrolides, represent a remarkable class of bioactive compounds with diverse therapeutic applications such as antibacterial, antifungal, and anticancer agents. Their complex architectures, often including multiple stereocenters and intrinsic macrocyclic ring systems, pose challenges in chemical synthesis.¹ Therefore, the development of new synthetic methodologies and strategies could contribute to the foundation of drug discovery research through efficient synthesis of these compounds and their analogs.²

Our group has had a long-standing interest in total synthesis and derivatization of macrolide natural products³ in order to improve their functions as drug lead compounds.⁴ In our structure–activity relationship (SAR) study through semi-synthesis of erythromycins, we revealed that translactonization of the 14-membered aglycon to form 12-membered ring systems attenuated the antibacterial activities but enhanced selective anti-inflammatory and/or immunomodulatory properties.⁵ This approach led us to pursue a synthetic study of actinoallolides (i.e., 1 and 2) that were isolated as anti-trypanosomal 12- and 14-membered macrolides at our institute (Fig. 1).⁶ Through the total synthesis campaign, we envisaged that access to the adjacent chemical space, which might not be otherwise explored using the naturally occurring products, would be beneficial to delving into further SAR studies.

Fig. 1 Structures of actinoallolides A and E.

In 2020, the Paterson group achieved the first total synthesis of actinoallolides using ring-closing metathesis to forge the macrocycle.⁷ In addition, we previously reported the construction of a linear all-carbon framework of actinoallolides via divergent fragment synthesis, followed by Negishi and Stille cross-coupling reactions.⁸ Herein, our efforts to elaborate the designed 16-membered macrocycle toward the total synthesis of actinoallolides are disclosed.

In the isolation study of actinoallolides,⁶ the treatment of 1 with acidic conditions effected β-elimination and partial translactonization, affording the 14-membered natural congener 2. Inspired by this reaction, our retrosynthesis hinged on the assertion that the actinoallolide family including both 12- and 14-membered macrolides might be prepared by translactonization(s) of a common 16-membered ring intermediate such as 4via 14-membered macrolactone 3, followed by installation of the side chain⁸ using a cross-coupling reaction (Scheme 1). Not only could this allow access to all congeners and new chemical space in the macrolactone ring system, but it could also provide the opportunity to optimize the side chain structure that was suggested to be important for their biological activities in the preliminary SAR of the natural product.⁶

Scheme 1 Our retrosynthesis of the actinoallolide family.

We envisioned that the β-ketolactone in 4 could be constructed by a skeletal modification of the macrocyclic aryl ether 6.⁹ In the forward sense, Birch reduction of the substituted benzene ring in 6 and subsequent oxidative C–C cleavage of skipped diene 5 would provide the common intermediate. The macrocycle 6 could arise from phenol 7 by an intramolecular Mitsunobu etherification, leveraging preorganization effect using a cyclic protecting group as the turn-inducer.¹⁰ This strategy could allow us to handle the generally reactive β-ketoester functionality as stable arene precursors through the synthesis sequence. Additionally, it could serve as an alternative approach for macrolide syntheses that have relied on macrocyclization by macrolactonization or ring-closing metathesis.¹¹

Key to the preparation of 7 would be the construction of the tetrasubstituted carbon center at C8. We envisaged that neighboring participation of the hydroxy group could induce the requisite stereochemistry, tracing back diene 8 as its precursor. Disconnection of the diene moiety in 8 divided the molecule into two fragments, vinyl iodide 9 and vinylboronic ester 10, which could be stitched together by a Suzuki–Miyaura cross-coupling reaction.¹² In our previous work,⁸ an analogous diene with an all-carbon framework was prepared by Stille coupling of a vinyl stannane derived from 9 with the corresponding vinyl iodide (Schemes S1 and S2 in the ESI†). Due to the regioselectivity issue in preparing the electrophile and low-yielding Stille coupling, we sought a different approach to construct the diene moiety. Because we have reported the synthesis of vinyl iodide 9 over 12 steps,⁸ this work commenced with investigation to synthesize vinylboronic ester 10.

Based on the previous work,⁸ known alcohol 11 was prepared from (R)-Roche ester over two steps.¹³ Considering scalability of the previously employed Krische crotylation¹⁴ that required a sealed tube, we sought an alternative to prepare known alcohol 12 (Scheme 2).¹⁵ Thus, treatment of 11 with Swern oxidation conditions afforded the corresponding aldehyde, which was followed by a Brown crotylation, providing 12 in excellent yield and diastereoselectivity. Protection of 12 with a MOM group under thermal conditions afforded acetal 13 in 89% yield. Because ozonolysis of 13 was somehow capricious, presumably due to competitive oxidation of the acetal and/or PMB moieties, two-step Malaprade–Lemieux–Johnson oxidation was used for this purpose. Subjection of 13 to modified dihydroxylation conditions using micro-encapsulated (MC) osmium tetroxide¹⁶ gave the corresponding diols as a mixture of diastereomers in 97% yield. Subsequent oxidative cleavage in the presence of 2,6-lutidine reproducibly provided aldehyde 14. With the reliable route to aldehyde 14, we investigated propargylation reactions to set the requisite stereochemistry at C11.

Scheme 2 Selective fragment synthesis.

Although previous propargylation was not stereoselective,⁸ we found that treatment of 14 with propargyl bromide in the presence of zinc and 1,2-dibromoethane (EDB)¹⁷ as a crucial additive gave rise to alcohol 15 in 75% yield over two steps as a single diastereomer. We later confirmed the stereochemistry by a single-crystal X-ray diffraction (vide infra). The resulting hydroxy group in 15 was protected with a TBS group, which was followed by methylation of the terminal alkyne, affording propyne 17 in 81% yield. To our delight, the internal alkyne moiety in 17 was engaged regioselectively in a copper-catalyzed hydroboration¹⁸ to provide 10 in 82% yield as a single isomer. Consequently, we prepared the fragment in a highly selective manner over 11 steps from the commercial material.

With both vinyl iodide 9 and boronic ester 10 in hand, we investigated Suzuki–Miyaura cross-coupling. In the event, treatment of 9 and 10 with the palladium precatalyst in the presence of barium hydroxide provided diene 8 (Scheme 3). Importantly, this coupling reaction proceeded in excellent yield with a slight excess amount of 10 (1.1 equiv.) on a multi-gram scale, setting the stage to manipulate the diene moiety. It turned out that chemo-, regio- and stereo-selective manipulation of the diene in 8 was quite challenging using a variety of hydroalkoxylation conditions.¹⁹ Therefore, we sought an alcohol-directed transformation to construct the requisite tetrasubstituted carbon center. To this end, we found that vanadium-catalyzed epoxidation in the presence of TBHP²⁰ effected chemo- and stereo-selective epoxidation to give rise to epoxide 18 in 88% yield as a single diastereomer. Treatment of 18 with phenyl isocyanate provided the corresponding phenylcarbamate in 88% yield, which was followed by epoxide ring-opening involving intramolecular cyclization,²¹ affording cyclic carbonate 19 in 98% yield. Although the resulting hydroxy group needed to be removed in downstream transformations, this three-step sequence allowed us to construct the challenging tetrasubstituted carbon in a highly selective and scalable manner.

Scheme 3 Cross-coupling, macro-etherification and skeletal modification to elaborate 16-membered macrocycles.

Because the cyclic carbonate group that was necessary to set the stereochemistry at C8 could induce the templated preorganization for macrocyclization,¹⁰ we turned our attention to the planned Mitsunobu macro-etherification. In this regard, allylic alcohol 19 was first protected with an acetyl group (74% yield), and subsequent cleavage of the PMB group provided the corresponding alcohol in 85% yield. Selective deprotection of the phenol was achieved by treatment with TBAF to afford 20 quantitatively. To our delight, Mitsunobu 16-membered cyclization proceeded smoothly using TMAD and Bu₃P under thermal conditions to give macrocycle 21 in 92% yield. After removal of the acetyl group, Barton–McCombie deoxygenation using a perfluorophenyl thiocarbonate group²² to suppress the undesired sigmatropic rearrangement furnished the product 22 in 71% yield. In this way, the stage was set for our key skeletal modification of the macrocycle.

Our preliminary efforts to effect Birch reduction using 22 proved unsuccessful due to the competitive reactivity of the cyclic carbonate moiety. In addition, the trisubstituted alkene moiety was not compatible under ozonolysis conditions despite the excess substituents on the arene ring that were installed to make the corresponding skipped diene moiety more electron rich.²³ These observations necessitated us to implement the following three-step transformation. After hydrolysis of 22 and subsequent protection to provide acetonide 23, we attempted protection of the alkene group with an epoxide ring. For this purpose, treatment of 23 with m-CPBA gave rise to epoxides 24a and 24b as a separable 1 : 1 mixture in quantitative yield. We determined the structure of 24b unambiguously by X-ray crystallographic analysis.

After a survey of reaction conditions, we found that DMDO-mediated epoxidation selectively provided 24a in 88% yield. Gratifyingly, subjection of 24a to Birch reduction conditions converted the arene ring to skipped diene 25, followed by ozonolysis to construct the desired β-ketolactone in 40% yield. To the best of our knowledge, this is the first example of the sequence applying to a multi-functional macrocyclic scaffold, demonstrating the power of this strategy in a complex system.

In order to implement translactonization, global deprotection provided diol 26 in 74% yield. Unfortunately, our extensive efforts to effect the planned translactonization proved difficult due to competitive side reactions. This suggests that direct 12-membered macrocyclization would be desirable to elaborate this class of molecules. Nevertheless, our current results underscore the utility of the skeletal modification approach to convert the aryl ether to the β-ketolactone in the context of a complex natural product synthesis.

In conclusion, we demonstrated macro-etherification using a Mitsunobu reaction to forge the designed 16-membered macrocycle en route to actinoallolides. We showcased that the key macrocyclic carbon skeletal editing of the aryl ether to β-ketolactone was achieved by Birch reduction, followed by oxidative C–C cleavage of the skipped diene. We believe that this study should inform future synthetic design plans to elaborate this class of molecules as well as to adopt the core modification approach in total synthesis. Additional efforts toward the interception of the desired 12- and 14-membered macrolactones are currently underway in our laboratory.

This work was partially supported by a Grant-in-Aid for Transformative Research Areas (A) “Latent Chemical Space” [JP24H01789] for G. S. from the Ministry of Education, Culture, Sports, Science and Technology, Japan, JSPS KAKENHI Grant No. 24K18256 (G. S.), 15K07866, 22K06535 (T. H.), and Research Support Project for Life Sciences Research and Drug Discovery (BINDS) from AMED (Grant No. JP24ama121035). The authors are grateful to Distinguished Emeritus Professor Satoshi Ōmura (Kitasato University). We acknowledge Dr Kenichiro Nagai, Ms Noriko Sato, Ms Reiko Seki (Kitasato University), and Dr. Takashi Matsumoto (Rigaku Co.) for spectroscopic and analytical assistances.

Data availability

Crystallographic data for 24b has been deposited at CCDC under 2453344† and can be obtained from https://doi.org/DOI:10.5517/ccdc.csd.cc2md85h.

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, spectroscopic data, NMR spectra, and X-ray data (PDF). CCDC 2453344. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5cc01915j

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