Total Synthesis of ent-Plagiochianin B

Article abstract of DOI:10.1021/acs.orglett.0c04219

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

Full text of DOI:10.1021/acs.orglett.0c04219

Made available through a Creative Commons CC-BY-NC-ND License
pubs.acs.org/OrgLett
Letter
Total Synthesis of ent-Plagiochianin B
Richard K. Jackson, III and John L. Wood*
Cite This: Org. Lett. 2021, 23, 1243−1246
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: 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.
lagiochianin B (1a) was isolated in 2018 from the Chinese
Scheme 2. Initial Retrosynthetic Analysis
P
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
Scheme 1. Plausible Biosynthetic Pathway
Scheme 3. Initial Synthetic Route
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.
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
52 which is derived from commercially available (+)-3-Carene.
Given the inherent stereochemistry of (+)-3-Carene we
anticipated producing ent-plagiochianin B (1b).
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 electro-
cyclization of an intermediate allenyl imine.4a Gratifyingly we
found that condensation of 4 with propargylamine and
Received: December 21, 2020
Published: January 30, 2021
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
https://dx.doi.org/10.1021/acs.orglett.0c04219
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1243−1246
1243

Organic Letters
pubs.acs.org/OrgLett
Letter
subsequent addition of DBU furnished fused pyridine 3 in
good yield.
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).
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 experimen-
tation, 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 temper-
atures 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
Scheme 5. Evolution of an Oxidation Strategy
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 incorpo-
ration of CuCl.
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
Scheme 4. Synthesis of Vinyl Pryidine (8) and Revision of
Retrosynthesis
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
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.
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
1244
https://dx.doi.org/10.1021/acs.orglett.0c04219
Org. Lett. 2021, 23, 1243−1246

Organic Letters
pubs.acs.org/OrgLett
Letter
Author
Scheme 6. Completion of the Total Synthesis
Richard K. Jackson, III − Department of Chemistry and
Biochemistry, Baylor University, Waco, Texas 76798, United
States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04219
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
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 founda-
tional mentorship provided by Prof. Yu-Wen Huang of
National Tsing Hua University, Taiwan (R.O.C.).
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 7. NOESY Correlation and Optical Rotation
REFERENCES
■
(1) Han, J.-J.; Zhang, J.-Z.; Zhu, R.-X.; Li, Y.; Qiao, Y.-N.; Gao, Y.;
Jin, X.-Y.; Chen, W.; Zhou, J.-C.; Lou, H.-X. Plagiochianins A and B,
Two ent-2,3-seco-Aromadendrane Derivatives from the Liverwort
Plagiochila duthiana. Org. Lett. 2018, 20, 6550−6553.
(2) Satoh, T.; Kaneko, Y.; Okuda, T.; Uwaya, S.; Yamakawa, K.
Studies on the Terpenoids and Related Alicyclic Compounds. XXXV.
Studies Directed toward a Total Synthesis of Ingenol Esters: Synthesis
of the C/D-Ring Moiety of Ingenol Esters from (+)-3-Carene via
Tin(IV) Chloride-Promoted Intramolecular Directed Aldol Reaction.
Chem. Pharm. Bull. 1984, 32, 3452−3460.
(3) Behenna, D. C.; Stockdill, J. L.; Stoltz, B. M. Synthesis of the
Carbocyclic Core of Zoanthenol: Implementation of an Unusual
Acid-Catalyzed Cyclization. Angew. Chem., Int. Ed. 2007, 46, 4077−
4080.
(4) (a) Wei, H.; Li, Y.; Xiao, K.; Cheng, B.; Wang, H.; Hu, L.; Zhai,
H. Synthesis of Polysubstituted Pyridines via a One-Pot Metal-Free
Strategy. Org. Lett. 2015, 17, 5974−5977. (b) Zhao, Z.; Wei, H.; Xiao,
K.; Cheng, B.; Zhai, H.; Li, Y. Facile Synthesis of Pyridines from
Propargyl Amines: Concise Total Synthesis of Suaveoline. Angew.
Chem., Int. Ed. 2019, 58, 1148−1152.
(5) Liu, B.; Jin, F.; Wang, T.; Yuan, X.; Han, W. Wacker-Type
Oxidation Using an Iron Catalyst and Ambient Air: Application to
Late-Stage Oxidation of Complex Molecules. Angew. Chem., Int. Ed.
2017, 56, 12712−12717.
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.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04219.
(6) (a) Conia, J. M.; Limasset, J. C. L’utilisation du t-amylate de
sodium dans les reacions de Wittig. Bull. Soc. Chim. Fr. 1967, 6,
1936−1938. (b) Dauben, W. G.; Walker, D. M. Formal total synthesis
of ( )-isocomene. J. Org. Chem. 1981, 46, 1103−1108.
General information; Experimental Section; NMR
spectra (PDF)
(7) For an additional application of these modified Wittig
conditions, see: Short, R. P.; Revol, J. M.; Ranu, B. C.; Hudlicky,
T. General method of synthesis of cyclopentanoid terpenic acids.
Stereocontrolled total syntheses of ( )-isocomenic acid and
( )-epiisocomenic acid. J. Org. Chem. 1983, 48, 4453−4461.
(8) Dihydroxylation of (2) proved sluggish, and efforts to advance
small quantities of the corresponding diol acetonide by oxidation of
the methyl pyridine with chromium (V) failed. For similar successful
pyridine oxidations with chromium, see: Schuppe, A. W.; Huang, D.;
Chen, Y.; Newhouse, T. R. Total Synthesis of (−)-Xylogranatopyr-
idine B via a Palladium-Catalyzed Oxidative Stannylation of Enones. J.
Am. Chem. Soc. 2018, 140, 2062−2066.
FAIR data, including the primary NMR FID files, for
compounds 1b−16, and SI 1-SI 9 (ZIP)
AUTHOR INFORMATION
■
Corresponding Author
John L. Wood − Department of Chemistry and Biochemistry,
Baylor University, Waco, Texas 76798, United States;
orcid.org/0000-0002-9066-5588;
Email: John_L_Wood@baylor.edu
1245
https://dx.doi.org/10.1021/acs.orglett.0c04219
Org. Lett. 2021, 23, 1243−1246

Organic Letters
pubs.acs.org/OrgLett
Letter
(9) Although not fully delineated, undesired allylic oxidation of 3 to
enone (i) appeared to be the predominant reaction event, whereas no
oxidation was observed with ketone (6).
(10) Hu, X.; Musacchio, A. J.; Shen, X.; Tao, Y.; Maimone, T. J.
Allylative Approaches to the Synthesis of Complex Guaianolide
Sesquiterpenes from Apiaceae and Asteraceae. J. Am. Chem. Soc. 2019,
141, 14904−14915.
(11) Wright, J. A.; Gaunt, M. J.; Spencer, J. B. Novel Anti-
Markovnikov Regioselectivity in the Wacker Reaction of Styrenes.
Chem. - Eur. J. 2006, 12, 949−955.
(12) Diethelm, S.; Carreira, E. M. Total Synthesis of Gelsemoxonine
through a Spirocyclopropane Isoxazolidine Ring Contraction. J. Am.
Chem. Soc. 2015, 137, 6084−6096.
(13) Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec, J. M.;
Tata, J. R.; Dake, G. R. The First Stereoselective Total Synthesis of
Quinine. J. Am. Chem. Soc. 2001, 123, 3239−3242.
(14) Uwamori, M.; Osada, R.; Sugiyama, R.; Nagatani, K.; Nakada,
M. Enantioselective Total Synthesis of Cotylenin A. J. Am. Chem. Soc.
2020, 142, 5556−5561.
(15) Efforts to improve the selectivity in the dihydroxylation with
chiral ligands were met with limited success. In particular, no reaction
was observed with addition of AD Mix β and, with (DHQD)2AQN,
<50% conversion was observed after 6 days with a moderate
improvement in stereoselectivity (1:1.6).
1246
https://dx.doi.org/10.1021/acs.orglett.0c04219
Org. Lett. 2021, 23, 1243−1246