Cyclolignan Synthesis Streamlined by Enantioselective Hydrogenation of Tetrasubstituted Olefins

doi:10.21203/rs.3.rs-2924400/v1

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Cyclolignan Synthesis Streamlined by Enantioselective Hydrogenation of Tetrasubstituted Olefins

https://doi.org/10.21203/rs.3.rs-2924400/v1

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All Birds with One Stone: Natural products have long been valuable sources of inspiration for drug discovery. Unfortunately, the inherent limitations of direct semisynthetic derivatizations have become more and more obvious, and the need to overcome these limitations is particularly urgent nowadays because the most valuable natural products tend to be isolated in minute amounts. Therefore, de novo synthesis with ideal modularity and diversity, have been a critical goal in drug discovery research. However, this endeavor of complex natural products is highly challenging, and only limited success has been achieved so far. Herein, we report a powerful, general platform for cyclolignan synthesis involving challenging rhodium-catalyzed enantioselective hydrogenation of tetrasubstituted 1,2-dihydronaphthalene esters (> 40 examples; up to 99% y, >99% ee). This unique platform allows ready access to various types of cyclolignans, as exemplified by the expedient and mostly protecting-group-free synthesis of over thirty cyclolignans, including many that have not previously been synthesized, such as 6-methoxy podophyllotoxin, cleistantoxin, picrobursenin, austrobailignan-4, aglacins D and F-H (with three revised structures), (+)-lirionol, ovafolinin D, and fimbricalyxoid A. We expect this work to inspire modular, de novo diversity-oriented syntheses of other important classes of natural products and thus to rejuvenate the role of natural products in drug discovery and development.

Physical sciences/Chemistry/Chemical synthesis/Asymmetric synthesis

Physical sciences/Chemistry/Chemical synthesis/Diversity-oriented synthesis

Cyclolignans also known as aryltetralins, are a family of miscellaneous lignan natural products that are found in many plant species and that display intriguing structural diversity and biological activities (such as anticancer, anti-tubulin polymerization, antiviral, antibacterial, antineoplastic, cytotoxic, and antimalarial activities).^19,²⁰ For example, podophyllotoxin (PPT),²¹one of the most well-known cyclolignans, shows exceptional cytotoxicity to a variety of cancer cell lines through binding to the colchicine site of the tubulin subunit and thus inhibiting microtubule assembly. Accordingly, PPT has for decades been the focus of chemical synthesis and the development of related anticancer drugs.^22,23 Considerable structural modification of PPT has led to numerous derivatives with activities against various types of cancers, and several derivatives are currently in clinical use, including the DNA-topoisomerase II inhibitors teniposide and etoposide (which is on the WTO’s list of essential medicines).Unfortunately, the therapeutic potential of PPT derivatives is often hampered by their poor bioavailability and the development of drug resistance. In addition, subtle changes in the aromatic rings of the parent PPT scaffold have been reported to dramatically influence their inhibitory activities. Tackling these issues will require that inherently exhaustible classical semisynthetic derivatization approaches to cyclolignans, which rely heavily on natural sources and are handicapped by the inflexible structural features of such sources, be supplemented with more powerful, diversity-oriented de novo strategies.^24,25

In 2014, Thomson and coworkers reported diversity-oriented synthesis (DOS) of six cyclolignans by means of novel tandem stereoselective oxidative [3,3]-sigmatropic rearrangement/Friedel-Crafts arylation reactions between electron-rich arenes and N-allylhydrazones (Fig. 1a),²⁶ and Maimone and Ting reported DOS of PPT and some 7’-aryl analogs via elegant Pd-catalyzed C(sp³)–H arylation reactions (Fig. 1b).²⁷ These pioneering studies provoked further exploration of divergent syntheses of cyclolignans.^28-33 Recently, the groups of Renata,³⁰ and Kroutil, Fuchs and colleagues³¹ independently reported the intriguing chemoenzymatic total syntheses of (−)-PPT and a few related lactone cyclolignans by means of a nonheme dioxygenase 2-ODD-PH-catalyzed intramolecular oxidative cyclizations (Fig. 1c). Meanwhile, Zhu and coworkers developed a method for unusual radical-cation cascade reactions of dicinnamyl ethers that involved visible-light photoredox catalysis to facilitate concise, diastereoselective syntheses of several cyclic ether cyclolignans (Fig. 1d).³² More recently, Gao and coworkers achieved asymmetric total syntheses of cyclic ether cyclolignans aglacins A, B, and E via interesting chiral Ti-mediated photoenolization/Diels–Alder reactions between electron-rich 2-methylbenzaldehydes and unsaturated γ-lactones (Fig. 1e).³³ Motivated by these impressive advances and coupled with our continuing interest in natural products as leads for drug development by de novo DOS,³⁴ we embarked on a search for a far more general platform for cyclolignan synthesis with the hope of achieving ideal modularity and diversity.

Cognizant of the fact that cyclolignans share a common feature: the aryl substituent at C-7′ is either syn- or anti- to the substituent at C-8′,^19-25 we conjectured that the asymmetric hydrogenation of 1,2-dihydronaphthalene tetrasubstituted olefins 1 as information-rich hidden retrons,³⁵ comprising the vital scaffold and functionalities of cyclolignans and have a deliberately installed ester group to serve as a handle for subsequent epimerization and other manipulations, might provide a universal platform for cyclolignan synthesis (Fig. 1f). In addition, we expected that olefins 1 would be easily accessible from readily available 1-tetralones. However, we also envisioned the pivotal asymmetric hydrogenation of the tetrasubstituted olefins 1 to present a paramount challenge; as work on hydrogenation of tetrasubstituted olefins has progressed relatively slowly and appears to be rather limited,^36-39 in marked contrast to di- and trisubstituted olefins. Furthermore, to the best of our knowledge, there have been only a few studies, with limited success, on hydrogenation of simple unfunctionalized or non-activated tetrasubstituted α,β-unsaturated carboxylic acid esters; and the reported instances all require chiral Ru or Ir catalysis.^40-42

Asymmetric hydrogenation of unfunctionalized 1,2-dihydronaphthalene tetrasubstituted olefins (e.g., 3a and 3b) was pioneered by Buchwald and coworkers,⁴³ who used a highly active chiral Zr catalyst, and was later investigated by the groups of Pfaltz⁴⁴ and others,^45-46 who frequently used more practical chiral Ir or Ru catalysts; almost concurrently, Zhang and coworkers⁴⁷ reported the first and only example of amino-functionalized olefin 5 utilizing a chiral Rh-PennPhos Catalyst (Fig. 1g). However, good reactivities and enantiomeric outcomes were observed for only a handful of 1,2-dihydronaphthalene tetrasubstituted olefins with these catalysts. Indeed, we found asymmetric hydrogenation of the desired dihydronaphthalene-based tetrasubstituted olefins bearing an ester group (1) to be very challenging (see Supplementary Information for detailed optimization data). After considerable investigation, we finally succeeded with the aid of a powerful new chiral Rh catalyst generated in situ from a combination of Rh(COD)₂BAr^F₄ and relatively less hindered (R,R) or (S,S)-BDPP as a ligand (Fig. 2). Notably, to our knowledge, this represents the first successful application of Skewphos for enantioselective hydrogenation of tetrasubstituted olefins.^48,49

This new chiral Rh catalyst generally afforded excellent results (Fig. 2). We began by evaluating olefins with various substituents at C-7′ (2a–v). The reactions of all the substrates with aromatic substituents (2a–s) proceeded smoothly and gave excellent results, regardless of the steric or electronic properties of their ortho, meta, and para substituents (90–99% y and 90–99% ee). Pleasingly, olefins with a vinyl (1t) or an alkyl substituent (1u and 1v) were also suitable, giving hydrogenation products 2t–v with excellent outcomes (95–99% y and 90–95% ee). Next, we examined substrates with various substituents on the dihydronaphthalene ring (2w–o′). To our delight, substrates with a single electron-withdrawing or electron-donating para substituent gave excellent results (2w–c′, 90–97% y and 96–99% ee). Moreover, substrates with a meta (1d′ and 1e′) or ortho (1f′) substituent or multiple substituents (1g′–o′) were also amenable to this transformation, giving corresponding hydrogenation products 2d′–o′ in 94–99% y with 93–99% ee. Notably, good tolerance of various functional groups was generally observed as well.

Having developed a protocol for asymmetric hydrogenation reactions to establish the two crucial vicinal stereocenters, we commenced work on the pivotal DOS of cyclolignans, beginning with the divergent synthesis of the well-known cyclolignan PPT and related natural products (Fig. 3). We found that three methods were feasible with comparable results for selective benzylic C–H oxidation⁵⁰ of hydrogenation product 2p: CrO₃-DMP-, copper-, and photoredox-mediated oxidations, gave desired ketone 7. An aldol reaction of 7 with formaldehyde and subsequent lactonization afforded podophyllone (8), along with some double aldol product 9. Mild Pd-catalyzed reduction of 8 with polymethylhydrosiloxane as the reductant⁵¹ was found to be a good alternative to previously reported reducing agents (such as LiBH₄ and L-Selectride) for accessing either (−)-PPT (10) or deoxypodophyllotoxin (11). Epimerization of deoxypodophyllotoxin (11) afforded deoxypicropodophyllotoxin (12), while sequential reductions of 11 completed the first total synthesis of austrobailignan-4 (14). In addition, a thermal retro-aldol reaction of 9 afforded isopicropodophyllone (15), which could be reduced to generate either epiisopicropodophyllotoxin (16)⁵² or epiisopicrodeoxypodophyllotoxin (17). Using this new protocol from either 2k′ or 2l′, we also synthesized β-peltatin-A-methyether (18) and accomplished the first total syntheses of epiisopicropodophyllotoxin (16), 6-methoxypodophyllotoxin (19), 6-methoxypodophyllotoxin-7-O-n-hexanoate (20),⁵³ cleistantoxin (21),⁵⁴ and picrobursenin (22)⁵⁵ (Fig. 3b).

Because of the electron-withdrawing ester group, 2p could be easily epimerized to provide 23, from which other types of cyclolignans could be readily accessed (Fig. 4). For example, podophyllic aldehyde A (25) was obtained from 23 via four simple transformations. Global reduction of 25, followed by selective oxidation of the resulting allylic alcohol, provided podophyllic aldehyde C (26), from which α-conidendrin analogue 27, oleralignan A analogue 28, and the nominal formosolactone (29)⁵⁶ were prepared via several simple transformations. Meanwhile, converting the ester group of 23 to a methyl group paved the way for the synthesis of analogues (33-36) of 8’-epi-aristoligone, cyclogalgravin analogue, galbulin/galcatin, and 8,8’-epi-aristoligone. We expect that the authentic natural products would be accessible from hydrogenation products 2l or 2n′–p′ by means of the same established sequences.

More types of interesting cyclolignans could be readily synthesized as exemplified from hydrogenation product 2j′ in Figs. 5 and 6. For instance, a one-pot selective C–H oxidation/bromination of ent-2j′ produced brominated ketone intermediate 44, from which 46 could be obtained through a one-pot Suzuki/epimerization procedure. Then, a third one-pot transformation, an oxidative cleavage/aldol cyclization, was developed to generate 47, which incorporates the key [3.3.1] structural framework of lirionol. The first asymmetric synthesis of (+)-lirionol (50) was then accomplished by several additional simple conversions (Fig. 5).⁵⁷ Meanwhile, direct selective benzylic oxidation of ent-2j’ with Cu catalysis could afford ketone 51. From this ketone, a compound with the structure reported for aglacin G (52) was synthesized by means of the protocol illustrated in Fig. 4 for the synthesis of podophyllic aldehyde C (26), and a compound with the structure reported for aglacin H (53) was synthesized by a two-step sequence (reduction of the carbonyl groups and selective oxidation of the benzylic alcohol). An aldol reaction of 53 with formaldehyde and subsequent tetrahydrofuran ring formation by a Mitsunobu-type cyclization completed the synthesis of a compound with the structure reported for aglacin D (55), acid-mediated epimerization of which provided 56. However, the spectroscopic data for all these synthetic aglacins do not agree with the previously reported data.^58,59

Because our results suggested that the reported syn structures of aglacins D, G, and H were incorrect, we speculated the correct structures had anti configurations and were epimeric at C-7′ (i.e., the same configuration as most other cyclolignans). To confirm this assumption, we carried out some structure revision studies using 2j′ (Fig. 6). A two-step sequence (one-pot oxidation/bromination followed by epimerization) was used to produce intermediate 57 (direct epimerization of 2j′ showed an unsatisfied diastereoselectivity). Reduction of the carbonyl groups with concurrent debromination by LAH were followed by selective oxidation of the benzylic alcohol to afford 58, the spectroscopic data of which matched the data originally reported for aglacin H. Direct treatment of its MEM acetal derivative with TiCl₄-DBU in DCM at −20 °C could give the cyclization product 59, whose spectroscopic data matched the data originally reported for aglacin D.

Encouraged by these results, we set out to obtain the correct structures of aglacin G as well. Unfortunately, a direct aldol reaction of genuine aglacin H (58) under our previously established conditions (Fig. 4, 53 → 54) failed, perhaps because of higher steric hindrance in 57 than in previous substrates. Gratifyingly, however, an indirect Mukaiyama aldol reaction by means of Kobayashi’s protocol was successful, and desired hydroxy ketone was obtained in good yield with a diastereoselectivity of 4.8:1. Hydroxy-directed reduction utilizing Evans’ protocol gave desired key diol intermediate 60. From 60, we could obtain 61 in good yield via a two-step sequence involving selective oxidative dehydration that afforded the α,β-unsaturated aldehyde and free of the primary alcohol; the spectroscopic data of this compound matched the data originally reported for aglacin G.

In addition, lyoniresinol dimethyl ether (62) was obtained by selective benzylic deoxygenation with concurrent removal of the silyl group from 60. Subsequent selective demethylation mediated by MgI₂provided lyoniresinol (63), while formation of a tetrahydrofuran ring generated aglacin B (64). The direct oxidation of aglacin B to give aglacins E or F was then investigated, but various benzylic oxidation methods proved unsuccessful in this case.⁵⁰To our delight, the very recent advance by Parasram and co-workers,⁶⁰ via exploring the interesting synergistic nature of photoexcited nitroarenes, was found to be possible for this challenging case, and aglacins E (65) or F (66) were accessed albeit with poor conversions and low yields. From (+)-aglacin F (66), (+)-aglacin A (67) was obtained by simple acetylation. On the other hand, selective tosylation of the primary alcohol of intermediate 60, and subsequent tetrahydrofuran ring formation triggered by removal of the tert-butyldimethylsilyl group in one pot delivered (+)-aglacin E (65) in good yield. Its oxidation by PDC afforded ketone 68. Its reduction by CBS could also provide aglacins E (65) and F (66).

The first total synthesis of the distinctive cyclolignan ovafolinin D (72)⁶¹ was also accomplished from hydrogenation product 2k′. Following the established synthetic sequence for 54 (Fig. 5), its enantiomer ent-54 could be easily accessed from 2k′. After that, hydroxy-directed reduction of ent-54 followed by Lewis acid–promoted cyclization produced 69, which has one of the tetrahydrofuran rings of ovafolinin D; the absolute configuration of 69 was unambiguously confirmed by X-ray analysis of its ester derivative 70. The other tetrahydrofuran ring of ovafolinin D was then constructed via radical-initiated oxidative cyclization, and a final selective demethylation achieved by means of MgI₂ completed its first total synthesis.

Just as importantly, the current asymmetric hydrogenation protocol is also applicable to tetrasubstituted 1,2-dihydronaphthalene esters readily derivable from 2-tetralones. For instance, subjection of olefin 73 to the standard conditions with (R,R)-PTBP as the ligand provided the desired hydrogenation product 74 in good results (93% y, 84% ee); this paved the way for the first synthesis of fimbricalyxoid A (82, Fig. 7).⁶² Treatment of 74 with p-TSA in a mixture of acetone and water released the aldehyde functionality, which was trapped by phosphorus ylide to give alkene 75. Epimerization was observed under the Wittig reaction conditions, but this has no influence on the following vinylation. Its vinylation with ethyl Z-3-bromoacrylate delivered diene 76 in good yield. Subsequent ring-closing metathesis (RCM) promoted by a second-generation Grubbs' catalyst completed the construction of the carbon cyclic framework of fimbricalyxoid A to afford 77. Ensuing ketone formation by a one-pot selective allylic oxidation and followed by the introduction of the two methyl groups furnished key intermediate 78. Pleasantly, mono-demethylation of 78 was feasible, and the desired phenol 79 was obtained as the major product, while the undesired regioisomer and diphenol could be converted back to 78 though simple methylation. The vinyl group at C-14 was then introduced via Suzuki-Miyaura coupling. Afterwards, conjugate reduction of 80 by modifying a Pd-catalyzed hydrosilylation and ketone protection provided intermediate 81.^63,64 Finally, ester reduction followed by concurrent demethylation and oxybridge formation via ketone releasement and hemiketal formation,⁶⁵ completed the first total synthesis of (+)-fimbricalyxoid A (82).

To conclude, we have developed a powerful new platform for cyclolignan synthesis with ideal modularity and diversity. The syntheses were facilitated by unprecedented Rh-Skewphos-catalyzed enantioselective hydrogenation reactions of dihydronaphthalene tetrasubstituted α,β-unsaturated carboxylic acid esters, which exhibited excellent outcomes (>40 examples; up to 99% y, >99% ee). The generality of this DOS was demonstrated by our syntheses of over 30 cyclolignans, including the first total syntheses of 6-methoxypodophyllotoxin, 6-methoxypodophyllotoxin-7-O-n-hexanoate, cleistantoxin, picrobursenin, austrobailignan-4, aglacins D and F–H, (+)-lirionol, ovafolinin D and fimbricalyxoid A. Subsequent work on de novo DOS of other types of natural products via state-of-the-art asymmetric catalysis, as well as drug development based on the findings of this study, is underway in our laboratory.

Acknowledgements:

We are grateful to the National Natural Science Foundation of China (no. 22271236) and the Natural Science Foundation of Zhejiang Province (no. LXZ22B020001) for support of this research. We sincerely thank Professor Thomas J. Schmidt (University of Münster) as well as Professor Young Sook Yun (Tokyo University of Pharmacy and Life Sciences) for kindly providing us their original NMR spectra of 6-methoxypodophyllotoxin-7-O-n-hexanoate and ovafonin D respectively. We acknowledge the Instrumentation and Service Centre for Molecular Sciences at Westlake University for help with measurement and data interpretation.

Author contributions:

H.H.L. conceived the project, guided the studies, and wrote the manuscript. Z.P. developed the asymmetric hydrogenation and completed the synthesis of podophyllotoxins and related cyclolignans. W.X.X completed the syntheses of (+)-lirionol, aglacins, ovafolinin D and fimbricalyxoid A. Q.X.G., Y.Z. and L.H.Z. helped with the preparation of some intermediates. All the authors contributed to the analysis and interpretation of the results.

Supplementary Information:

• Experimental procedures and characterization data for all new compounds

• NMR and HPLC spectra for all for all new compounds

• X-ray data for compounds 2p, 9, 16, 47, and 70

Competing interests:

The authors declare no competing financial interests.

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Cyclolignan Synthesis Streamlined by Enantioselective Hydrogenation of Tetrasubstituted Olefins

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