Diastereoselective Synthesis of the ABCD Ring System of Rubriflordilactone B

Abstract

A novel nine-step diastereoselective route to the ABCD ring system of the natural product rubriflordilactone B is reported. Use of an α-substituted butenolide derived from maleic anhydride facilitated a 1,4-conjugate addition to provide a diene. The order in which a ring-closing metathesis and enolate oxidation were performed on this compound dictated the relative stereochemistry of the target. The final product exhibited anisotropic effects during room-temperature NMR studies, requiring elevated-temperature experiments to confirm its identity.

Since its isolation in 2006 by Sun and co-workers, rubriflordilactone B (1; Figure [1]) has been of interest to synthetic chemists due to its structural complexity and modest anti-HIV-1 activity.[2]

Several groups have published efforts toward 1, resulting in a few partial syntheses,[3] [4] [5] and two complete routes.[6,7] The western half (A–D rings) of 1 consists of a 5–5–7–6 ring system exhibiting a geminal dimethyl group on the B ring and a cycloheptadiene C ring. Access to this portion of the natural product has been accomplished in a variety of ways, including an intramolecular [2+2+2] cycloaddition, as reported by Xie and co-workers,[3] and an oxidative 6π-electrocyclization, which Li used in his synthesis of 1 and the closely related natural product rubriflordilactone A.[8]

Whereas Li and co-workers were able to develop an efficient and convergent route to 1, they discovered that although their sample’s crystal structure matched that of the authentic sample isolated by Sun, the ¹H NMR data did not.[2] [6] Based on this result, Li proposed that Sun had isolated a mixture of two closely related diastereomers. The major species, which Li termed pseudo-rubriflordilactone B, was responsible for the NMR data reported by Sun, whereas the minor diastereomer 1 crystallized and produced the x-ray structure.

A computational NMR study by the group of Sarotti and Kaufman allowed them to propose a structure for pseudo-rubriflordilactone B (2; Figure [2]) by simulating spectra for dozens of diastereomers of 1.[9] 1 and 2 differ only in their stereochemistry at the EF ring junction. Recently, Anderson and co-workers reported a synthesis of both 1 and 2, providing evidence for Li’s original proposal and resolving the mystery surrounding the isolation and characterization of rubriflordilactone B.[7]

Our interest in 1 has led to the development of an efficient diastereoselective synthesis of the ABCD ring system 3 of this molecule. As this system is identical in 1 and 2, this route could be used to access the western half of either molecule.

We envisioned accessing the ABCD ring system by starting with a conjugate addition reaction between butenolide 4 and alkyne 5. The 1,4-addition product 6 would then be used in a Lindlar reduction to give the requisite Z-alkene, followed by a reductive cyclization to form the tricyclic intermediate 7. Lastly, α-hydroxylation of 7 would permit the formation of the A ring according to one of two methods reported for analogous compounds (Scheme [1]).[8] [10]

We unfortunately found 4 to be a noncompetent electrophile under a variety of conjugate addition reaction conditions employing copper, zinc, palladium, or rhodium as the source of the organometallic nucleophile. We subsequently switched to using the α-phosphonate butenolide 8,[11] [12] as this species would not only increase the electrophilicity of the substrate for a conjugate addition reaction, but would also facilitate introduction of the desired exo-methylene group through a Horner–Wadsworth–Emmons (HWE) reaction. We were pleased to find that 8 underwent a conjugate addition reaction with 5 in good yield, but conventional Lindlar reduction conditions resulted in overreduction and/or protodebromination of the arene. However, a copper-mediated syn-hydrogenation method reported by Lalic[13] gave Z-alkene 10 in good yield and a subsequent HWE reaction with formaldehyde afforded the reductive cyclization substrate 11 (Scheme [2]).

Neither radical cyclization nor intramolecular reductive Heck coupling conditions gave the desired cycloheptadiene. Instead, radical conditions isomerized the exo-cyclic alkene to an internal alkene through a 1,5-hydrogen atom abstraction, whereas reductive Heck coupling conditions resulted in conjugate reduction, with sodium formate serving as the hydride source. To circumvent these issues, we investigated the formation of ring C through a ring-closing metathesis (RCM).

Due to the significant amounts of 1,2-addition that were observed when 4 was used in a conjugate addition with vinyl cuprate, we synthesized the α-substituted butenolide 15 in four steps starting with the Diels–Alder reaction between cyclopentadiene and maleic anhydride.[14] We found the presence of an α-substituent in 15 was able to mitigate the 1,2-addition observed with 4, giving diene 16 in moderate yield (Scheme [3]).

Diene 16 could subsequently be converted into the α-hydroxy lactone required to synthesize the A ring in two steps, enolate oxidation and RCM, which could be performed in either order (Scheme [4]). However, we found different diastereomers formed depending on the reaction sequence. The first route resulted in an anti-5,7 ring junction, due to enolate oxidation on 16 favoring an anti-relationship between the α-benzylic group and the β-vinyl substituent.[15] In the second route, a syn-5,7 ring junction formed to minimize ring strain.[16] [17] The latter sequence gave the desired diastereomer and higher-yielding transformations, as fewer incompatible functional groups were present in the RCM and enolate oxidation reactions.

To finish the route, we first attempted a reduction, HWE olefination, oxy-Michael, and lactonization cascade reported by the group of Chen and Yang in their work on micrandilactone A to access the A ring (Scheme [5]).[10] Whereas reduction of 19 with DIBAL-H to lactol 20 went well, the subsequent cascade process resulted in elimination of the α-hydroxy group and gave none of the desired product. We made several attempts to mitigate this elimination, but any deviations from the reported conditions resulted in no reaction.

We next performed an acetylation on 19 to access 21 (this species can also be accessed directly from 7 by quenching the enolate oxidation with Ac₂O; see the Supporting Information for details). Subsequent intramolecular aldol and cationic deoxygenation reactions, as reported by Li,[8] gave a species with the correct mass by GC/MS, but an inconclusive ¹H NMR spectrum. To determine the identity of the product, we took 22 and performed a dehydration with Martin’s sulfurane to access 23, which could be reduced to 2 with L-Selectride[18] Upon isolation of the corresponding product, we obtained a compound with identical characterization data to those of the molecule formed in the cationic deoxygenation conditions, suggesting 2 was formed in both cases (Scheme [6]).

Due to the presence of broad signals in the ¹H NMR spectrum, we wondered if the rigidity of the ABCD ring system was causing slow conformational changes on the NMR timescale, resulting in anisotropic effects at room temperature. To test this, we conducted variable-temperature NMR studies and observed resolution of the broad signals at 60 °C; this result, along with X-ray crystallography data,[19] allowed us to confirm the formation of 2.

In conclusion, we have successfully completed a diastereoselective synthesis of the ABCD ring system of rubriflordilactone B. The sequence begins with a Diels–Alder reaction between maleic anhydride and cyclopentadiene. The relative stereochemistry was set based on the order of RCM and enolate oxidation steps, and the final structure was verified by X-ray crystallography and variable-temperature NMR experiments. Studies to complete the synthesis of rubriflordilactone B are a part of continuing efforts in our laboratory.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We would like to thank Dr. Peter White and Dr. Josh Chen for performing the X-ray crystallography experiments and Dr. Marc ter Horst for assistance with the variable-temperature NMR experiments.

• References and Notes

• 1 New address: Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA.
• 2 Xiao W.-L, Yang L.-M, Gong N.-B, Wu L, Wang R.-R, Pu J.-X, Li X.-L, Huang S.-X, Zheng Y.-T, Li R.-T, Lu Y, Zheng Q.-T, Sun H.-D. Org. Lett. 2006; 8: 991 ; corrigendum: Org. Lett. 2021, 23, 2392
  CrossrefPubMedSearch in Google Scholar
• 3 Wang Y, Li Z, Lv L, Xie Z. Org. Lett. 2016; 18: 792
  CrossrefPubMedSearch in Google Scholar
• 4 Wang Y, Zhang Y, Li Z, Yang Z, Xie Z. Org. Chem. Front. 2016; 4: 47
  CrossrefSearch in Google Scholar
• 5 Peng Y, Duan S.-M, Wang Y.-W. Tetrahedron Lett. 2015; 56: 4509
  CrossrefSearch in Google Scholar
• 6 Yang P, Yao M, Li J, Li Y, Li A. Angew. Chem. Int. Ed. 2016; 55: 6964
  CrossrefPubMedSearch in Google Scholar
• 7 Mohammad M, Chintalapudi V, Carney JM, Mansfield SJ, Sanderson P, Christensen KE, Anderson EA. Angew. Chem. Int. Ed. 2019; 58: 18177
  CrossrefPubMedSearch in Google Scholar
• 8 Li J, Yang P, Yao M, Deng J, Li A. J. Am. Chem. Soc. 2014; 136: 16477 ; corrigendum: J. Am. Chem. Soc. 2015, 137, 12730
  CrossrefPubMedSearch in Google Scholar
• 9 Grimblat N, Kaufman TS, Sarotti AM. Org. Lett. 2016; 18: 6420
  CrossrefPubMedSearch in Google Scholar
• 10 Zhang Y.-D, Tang Y.-F, Luo T.-P, Shen J, Chen J.-H, Yang Z. Org. Lett. 2006; 8: 107
  CrossrefPubMedSearch in Google Scholar
• 11 Janecki T, Baszczyk E. Synthesis 2001; 403
  Thieme Connect
• 12 Janecki T, Kuś A, Krawczyk H, Baszczyk E. Synlett 2000; 611
• 13 Cox N, Dang H, Whittaker AM, Lalic G. Tetrahedron 2014; 70: 4219
  CrossrefSearch in Google Scholar
• 14 Canonne P, Akssira M, Lemay G. Tetrahedron Lett. 1983; 24: 1929
  CrossrefSearch in Google Scholar
• 15 CCDC 2100716 contains the supplementary crystallographic data for compound 18. The data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/structures.
• 16 Hudlický T, Reed JW. The Way of Synthesis: Evolution of Design and Methods for Natural Products. Wiley-VCH; Weinheim: 2007
  Search in Google Scholar
• 17 CCDC 2100717 contains the supplementary crystallographic data for compound 19. The data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/structures.
• 18 Han Y.-X, Jiang Y.-L, Li Y, Yu H.-X, Tong B.-Q, Niu Z, Zhou S.-J, Liu S, Lan Y, Chen J.-H, Yang Z. Nat. Commun 2017; 8: 14233
  CrossrefPubMedSearch in Google Scholar
• 19 CCDC 2100973 contains the supplementary crystallographic data for compound 2. The data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/structures.

Corresponding Author

Publication History

Received: 10 September 2021

Accepted after revision: 01 October 2021

Accepted Manuscript online:
01 October 2021

Article published online:
22 October 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
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• References and Notes

• 1 New address: Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA.
• 2 Xiao W.-L, Yang L.-M, Gong N.-B, Wu L, Wang R.-R, Pu J.-X, Li X.-L, Huang S.-X, Zheng Y.-T, Li R.-T, Lu Y, Zheng Q.-T, Sun H.-D. Org. Lett. 2006; 8: 991 ; corrigendum: Org. Lett. 2021, 23, 2392
  CrossrefPubMedSearch in Google Scholar
• 3 Wang Y, Li Z, Lv L, Xie Z. Org. Lett. 2016; 18: 792
  CrossrefPubMedSearch in Google Scholar
• 4 Wang Y, Zhang Y, Li Z, Yang Z, Xie Z. Org. Chem. Front. 2016; 4: 47
  CrossrefSearch in Google Scholar
• 5 Peng Y, Duan S.-M, Wang Y.-W. Tetrahedron Lett. 2015; 56: 4509
  CrossrefSearch in Google Scholar
• 6 Yang P, Yao M, Li J, Li Y, Li A. Angew. Chem. Int. Ed. 2016; 55: 6964
  CrossrefPubMedSearch in Google Scholar
• 7 Mohammad M, Chintalapudi V, Carney JM, Mansfield SJ, Sanderson P, Christensen KE, Anderson EA. Angew. Chem. Int. Ed. 2019; 58: 18177
  CrossrefPubMedSearch in Google Scholar
• 8 Li J, Yang P, Yao M, Deng J, Li A. J. Am. Chem. Soc. 2014; 136: 16477 ; corrigendum: J. Am. Chem. Soc. 2015, 137, 12730
  CrossrefPubMedSearch in Google Scholar
• 9 Grimblat N, Kaufman TS, Sarotti AM. Org. Lett. 2016; 18: 6420
  CrossrefPubMedSearch in Google Scholar
• 10 Zhang Y.-D, Tang Y.-F, Luo T.-P, Shen J, Chen J.-H, Yang Z. Org. Lett. 2006; 8: 107
  CrossrefPubMedSearch in Google Scholar
• 11 Janecki T, Baszczyk E. Synthesis 2001; 403
  Thieme Connect
• 12 Janecki T, Kuś A, Krawczyk H, Baszczyk E. Synlett 2000; 611
• 13 Cox N, Dang H, Whittaker AM, Lalic G. Tetrahedron 2014; 70: 4219
  CrossrefSearch in Google Scholar
• 14 Canonne P, Akssira M, Lemay G. Tetrahedron Lett. 1983; 24: 1929
  CrossrefSearch in Google Scholar
• 15 CCDC 2100716 contains the supplementary crystallographic data for compound 18. The data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/structures.
• 16 Hudlický T, Reed JW. The Way of Synthesis: Evolution of Design and Methods for Natural Products. Wiley-VCH; Weinheim: 2007
  Search in Google Scholar
• 17 CCDC 2100717 contains the supplementary crystallographic data for compound 19. The data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/structures.
• 18 Han Y.-X, Jiang Y.-L, Li Y, Yu H.-X, Tong B.-Q, Niu Z, Zhou S.-J, Liu S, Lan Y, Chen J.-H, Yang Z. Nat. Commun 2017; 8: 14233
  CrossrefPubMedSearch in Google Scholar
• 19 CCDC 2100973 contains the supplementary crystallographic data for compound 2. The data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/structures.

• Supplementary Material