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. 2021 Jan 30;23(4):1243–1246. doi: 10.1021/acs.orglett.0c04219

Total Synthesis of ent-Plagiochianin B

Richard K Jackson III 1, John L Wood 1,*
PMCID: PMC7901668  PMID: 33517659

Abstract

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An enantioselective total synthesis of plagiochianin B is described that employs (+)-3-carene as its point of departure and delivers the enantiomer of the natural product. Key features of the synthesis include a palladium-mediated regioselective oxidative cleavage of an olefin residing on a pyridine derived from a 6π-azatriene electrocyclization.

Plagiochianin B (1a) was isolated in 2018 from the Chinese liverwort Plagiochila duthiana and possesses a unique 6/7/3 pyridine-containing tricyclic structure.1 Biosynthetically, plagiochianin B is the first example of a sesquiterpene alkaloid isolated from liverworts and, as illustrated in Scheme 1, is believed to arise from aromadendrane via a ring-opening event followed by a succession of oxidations that deliver plagiochilal A, a natural product which has been isolated from the genus Plagiochila. Condensation of plagiochilal A with ammonia forms an intermediate pyridine which, upon further oxidation, furnishes plagiochianin B.

Scheme 1. Plausible Biosynthetic Pathway.

Scheme 1

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From a retrosynthetic perspective (Scheme 2), we initially envisioned ent-plagiochianin B as arising from exomethylene 2 via a sequence of late-stage oxidations. We believed 2 could be derived from methylpyridine (3) through a Wacker-type oxidation and Wittig olefination. To deliver the requisite 3 we planned to advance enal 4 by condensation with propargyl amine followed by 6π-azatriene electrocyclization. Access to 4 would be gained by reductive carbonylation of known enone 5(2) which is derived from commercially available (+)-3-Carene. Given the inherent stereochemistry of (+)-3-Carene we anticipated producing ent-plagiochianin B (1b).

Scheme 2. Initial Retrosynthetic Analysis.

Scheme 2

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In a forward sense (Scheme 3), kinetic deprotonation of enone 5 and trapping with McMurry’s reagent furnished an enol triflate which, without purification, was advanced in good yield to enal 4 by employing a slightly modified reductive carbonylation procedure reported by Stoltz.3 Targeting enal 4 as an intermediate was inspired by recent efforts from Zhai who demonstrated that condensation of cinnamaldehyde with propargyl amine followed by treatment with DBU delivers the corresponding 3-methyl pyridine via 6π-azatriene electrocyclization of an intermediate allenyl imine.4a Gratifyingly we found that condensation of 4 with propargylamine and subsequent addition of DBU furnished fused pyridine 3 in good yield.

Scheme 3. Initial Synthetic Route.

Scheme 3

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Having completed the tricyclic core, we turned attention to the remaining largely oxidative modifications of the periphery. To this end, we attempted to advance 3 via palladium-mediated Wacker type oxidations but did not observe any appreciable product formation. After considerable experimentation, we discovered an iron-catalyzed variant recently developed by Han to be very effective in delivering the corresponding ketone (6).5 With ketone 6 in hand, the stage was set for a seemingly simple methylenation to 2. However, typical Wittig olefination conditions using cryogenic temperatures and strong bases led to consistently low yields of the desired product and the predominant return of starting material. Presuming ketone enolizability as the culprit, we turned to conditions originally developed by Conia (employing sodium tert-amylate), and effectively deployed by Dauben to overcome issues with both substrate sterics and acidity.6 In the event, exposure of 6 to methyltriphenylphosphonium bromide and potassium tert-butoxide in toluene at reflux furnished the desired exocyclic methylene (2) in good yield.7 Unfortunately, efforts to install the vicinal hydroxyl unit were met with little or extraordinarily sluggish reactivity.8 Additionally, oxidation of the methylpyridine on compounds 3 and 6 also proved remarkably challenging, resulting in either undesirable or no reactivity.9

Unable to advance methylpyridine substrates to the corresponding ester, we decided to modify our plan. As illustrated in Scheme 4, we focused on altering the 6π-azatriene electrocyclization substrate so as to deliver a more malleable vinylpyridine intermediate (8), an approach that was advantaged by continued efforts from Zhai.4b Selective oxidations of the external and internal olefins would then deliver 1b. While implementing this revised strategy, it was found that exposure of enal 4 to benzoyloxy propargylamine (7), with minor alteration to conditions reported by Zhai, delivered the corresponding vinylpyridine (8) in useful yields.

Scheme 4. Synthesis of Vinyl Pryidine (8) and Revision of Retrosynthesis.

Scheme 4

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With the vinyl pyridine 8 in hand, we turned toward effecting a selective oxidation of the terminal olefin in the presence of the presumably more electron-rich internal one. Precedent regarding electrophilic oxidation strategies such as ozonolysis10 suggested the internal olefin would likely react first. However, our experiences in the methyl pyridine series suggested that the internal olefin would be inert to traditional Wacker oxidation conditions and led to our speculation that it would be possible to convert the exocyclic olefin of 8 to a methyl ketone which, in turn, might then be elaborated to carboxylic acid 9 via a Lieben Haloform reaction (see Scheme 5).

Scheme 5. Evolution of an Oxidation Strategy.

Scheme 5

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Much to our chagrin, it was found that exposure of 8 to traditional Wacker oxidation conditions resulted in no reaction. Efforts to push this chemistry led to the serendipitous discovery that exposure of 8 to 2 equiv of PdCl2, under an atmosphere of O2, results in the selective cleavage of the external olefin giving rise to pyridinecarboxaldehyde 10; neither oxidation to the corresponding acid nor reaction of the internal olefin was observed under these conditions. Intrigued by this reactivity we explored the literature for similar observations and discovered pioneering work performed by Spencer and Gaunt, who, when working on styrene-type compounds, found that 2 equiv of PdCl2 were able to effect anti-Markovnikov selectivity in the Wacker oxidation.11 Further, Spencer noted spontaneous degradation of the anti-Markovnikov aldehydes to analogous benzaldehydes in the presence of O2. Indeed, exposure of 8 to Spencer’s conditions using degassed solvents and an inert atmosphere produced anti-Markovnikov aldehyde 11 (see Scheme 5). Isolation of 11 and resubmission to the original, oxygenated, reaction conditions again furnished 10. Notably, conditions akin to those used by Spencer and Gaunt (2 equiv of PdCl2 in the presence of O2) were also found to produce 10; however, the efficiency of this transformation was increased by incorporation of CuCl.

With pyridinecarboxaldehyde 10 in hand, we employed a standard Pinnick oxidation followed by treatment with TMSCHN2 to provide the requisite methyl ester (12) (Scheme 6).12 Based on previous success, we turned to the iron-catalyzed Wacker-type oxidation to produce ketone 13 which, with this substrate, was accompanied by a mixture of diastereomeric alcohols (14) that were isolated and converted to 13 via a Swern oxidation.13 A modification of the Wittig olefination was employed to furnish exomethylene 15.6,7 Lastly, dihydroxylation, with potassium osmate dihydrate and NMO,14 provided a 1:3 mixture of diastereomers favoring the undesired diastereomer of ent-plagiochianin B (16).15 Separation of the diastereomers allowed for comparison of NOESY data which supported the isolation chemist’s proposed relative stereochemistry of plagiochianin B. Furthermore, analysis of the optical rotation of our synthetic product aided in confirmation of the absolute stereochemistry found in the natural product. As anticipated, our synthetic product bears an optical rotation of similar magnitude but opposite sign to plagiochianin B (see Scheme 7).

Scheme 6. Completion of the Total Synthesis.

Scheme 6

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Scheme 7. NOESY Correlation and Optical Rotation.

Scheme 7

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The total synthesis of ent-plagiochianin B (1b) has been completed. Introduction of the pyridine ring was accomplished by a 6π-azatriene electrocyclization with propargylamine 7 and enal 4. Differentiation of the two olefins found in the resultant vinylpyridine (8) was enabled by orthogonal reactivity between iron and palladium mediated Wacker-type oxidations. The latter conditions led to oxidative cleavage of the exocyclic olefin to selectively furnish a pyridinecarboxaldehyde (10). Subsequent iron-catalyzed Wacker-type oxidation then set the stage for synthesis completion.

Acknowledgments

The authors gratefully acknowledge financial support from Baylor University, the Welch Foundation (Chair, AA-006), the Cancer Prevention Research Institute of Texas (CPRIT, R1309), the National Science Foundation (NSF, CHE-1764240), and the National Institute of General Medical Sciences of the National Institutes of Health (NIGMS-NIH, R01GM136759). RKJ would like to acknowledge the foundational mentorship provided by Prof. Yu-Wen Huang of National Tsing Hua University, Taiwan (R.O.C.).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.0c04219.

  • General information; Experimental Section; NMR spectra (PDF)

  • FAIR data, including the primary NMR FID files, for compounds 1b–16, and SI 1-SI9 (ZIP)

Author Contributions

All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ol0c04219_si_001.pdf (5MB, pdf)
ol0c04219_si_002.zip (52.7MB, zip)

References

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Associated Data

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Supplementary Materials

ol0c04219_si_001.pdf (5MB, pdf)
ol0c04219_si_002.zip (52.7MB, zip)

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