An efficient synthesis of moronic and heterobetulonic acids from allobetulin

Article abstract of DOI:10.1016/j.tetlet.2015.11.086

The reaction of acetoxyallobetulin with HClO₄ in refluxing Ac₂O led to a mixture of diacetoxyheterobetulin (3β,28-diacetoxy-18α,19βH-urs-20-ene), diacetoxymoradiol (3β,28-diacetoxy-olean-18(19)-ene), 3β-acetoxy-21β-acetyl-20β,28-epoxy-18α,19βH-ursane, and diacetoxy-δ-erythrodiol (3β,28-diacetoxy-olean-13(18)-ene), which were isolated by column chromatography in yields of 18%, 37%, 39%, and 2%, respectively. Deacetylation of diacetoxyheterobetulin and diacetoxymoradiol followed by Jones oxidation of the corresponding triterpene 3β,28-diols led to heterobetulonic and moronic acids with overall yields of 17% and 35% from acetoxyallobetulin, respectively. The reported route makes possible the medium-to-large scale preparation of these pharmacologically important triterpenic acids.

Full text of DOI:10.1016/j.tetlet.2015.11.086

Accepted Manuscript
An efficient synthesis of moronic and heterobetulonic acids from allobetulin
El’mira F. Khusnutdinova, Natalya I. Medvedeva, Dmitri V. Kazakov, Olga S.
Kukovinets, Alexander N. Lobov, Kirill Yu. Suponitsky, Oxana B. Kazakova
PII:
S0040-4039(15)30394-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.11.086
TETL 47026
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 August 2015
18 November 2015
26 November 2015
Please cite this article as: Khusnutdinova, E.F., Medvedeva, N.I., Kazakov, D.V., Kukovinets, O.S., Lobov, A.N.,
Suponitsky, K.Y., Kazakova, O.B., An efficient synthesis of moronic and heterobetulonic acids from allobetulin,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.11.086
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

An efficient synthesis of moronic and heterobetulonic acids from allobetulin
El’mira F. Khusnutdinova a, Natalya I. Medvedeva a, Dmitri V. Kazakov a, Olga S. Kukovinets a,
Alexander N. Lobov a, Kirill Yu. Suponitsky b, Oxana B. Kazakova a*
aUfa Institute of Chemistry of the Russian Academy of Sciences, 71 pr. Oktyabrya, 450054 Ufa,
Russian Federation
bA.N. Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences,
28 Vavilova St, V-334, GSP–1, 119991 Moscow, Russian Federation
*Corresponding author. Fax: +73472356066; e-mail: obf@anrb.ru
Abstract:
The reaction of acetoxyallobetulin with HClO4 in refluxing Ac2O led to a mixture of
diacetoxyheterobetulin (3β,28-diacetoxy-18α,19βH-urs-20-ene), diacetoxymoradiol (3β,28-
diacetoxy-olean-18(19)-ene),
3-acetoxy-21β-acetyl-20,28-epoxy-18,19Н-ursane
and
diacetoxy-δ-erythrodiol (3β,28-diacetoxy-olean-13(18)-ene), which were isolated by column
chromatography in yields of 18%, 37%, 39% and 2%, respectively. Deacetylation of
diacetoxyheterobetulin and diacetoxymoradiol followed by Jones oxidation of the corresponding
triterpene 3β,28-diols led to heterobetulonic and moronic acids with overall yields of 17% and
35% from acetoxyallobetulin, respectively. The reported route makes possible the medium-to-
large scale preparation of these pharmacologically important triterpenic acids.
Keywords: Triterpenoids; Oleanane; Ursane; Taraxastane; Allobetulin; Moronic acid;
Heterobetulonic acid; Synthesis
Introduction
Natural pentacyclic triterpenoids possess a wide range of unique biological activities. Recently,
intense pharmacological and mechanistic studies on natural triterpenoids have been carried out in
order to exploit their therapeutic potential. Up to now, bioactivities have included, amongst
others, antitumor, antiviral, antidiabetic, anti-inflammatory, antimicrobial, antiparasitic, cardio-
hepato- and gastro-protective, analgesic and wound-healing effects. Nowadays, several
triterpenoids are marketed as therapeutic agents and some synthetic triterpenoid derivatives are
currently under clinical trial.1 Current studies include chemical transformations and
pharmacological activities,2,3,4 the total synthesis of triterpenoids5-8 and the investigation of
reactions leading to new types9,10 or already known triterpenoids with high potential, but which
are not easily accessible from natural sources.11-14
Results and discussion
Allobetulin 1 is a member of the germanicane-type triterpene family, a rare class of
natural compounds.15 Allobetulin 1 and related compounds (for example, 28-oxoallobetulone,16
3β-acetoxy-18α-oleanane-28,19β-lactame17) can be easily obtained by the Wagner-Meerwein
rearrangement of the more abundant lupane triterpenoids, especially betulin and its derivatives,
in the presence of Lewis or solid acids.18,19
Taking into account examples of the cleavage of the tetrahydrofuran ring in allobetulin by
nucleophilic and acidic reagents,9,10,20-23 we have previously found24 that, under treatment with
HClO4 in Ac2O, which is used for the cleavage of epoxides25 and С-acylation,26 allobetulin was
converted into the unexpected 3-acetoxy-21β-acetyl-20,28-epoxy-18,19Н-ursane 4, which
1

possesses antiviral activity against HPV-11. 2,3-Indolo-21β-acetyl-20,28-epoxy-18,19Н-
ursane27 also shows significant cytotoxic activity against Leukemia SR cells.. Herein, we report
the reaction of acetoxyallobetulin with HClO4 in Ac2O as an efficient method for the chemical
preparation of pharmacologically important platforms – moronic28-32 and heterobetulonic23 acids.
When acetoxyallobetulin 1 was treated with HClO4 in Ac2O at reflux for 5 h, a mixture of
four compounds was obtained, which were separated by column chromatography and determined
to be diacetoxyheterobetulin (3β,28-diacetoxy-18α,19βH-urs-20-ene) 2, diacetoxymoradiol
(3β,28-diacetoxy-olean-18(19)-ene) 3, 3-acetoxy-21β-acetyl-20,28-epoxy-18,19Н-ursane 4
and diacetoxy-δ-erythrodiol (3β,28-diacetoxy-olean-13(18)-ene) 5 in 18%, 37%, 39% and 2%
yields respectively (Scheme 1).
A preliminary review of the spectral data for compound 3 suggested that it was
1
structurally related to compound 2.33 In fact, the H and 13C NMR chemical shifts of atoms
associated with the A, B, and C rings and HMBC correlations for those rings were practically
identical. However, there were significant differences between the functional groups present on
the E rings of these two compounds. For compound 3, the position of the C18-C19 double bond
(δC 138.09 and 133.62 ppm) was determined by HMBC correlations of the H13 methine
hydrogen with the С18 quaternary carbon and the С19 methine carbon, as well as the HMBC
cross-peaks HB28/C18 (δ 3.98/138.09 ppm), Heq21/C19 (δ 1.30/133.62 ppm), and the methyl
protons H29, H30 with C19. In the NOESY spectra, cross peaks between H13/H19, Heq12/H19
and H30/H19 were observed. The position of the C13-C18 double bond of compound 5 was
determined by HMBC correlations of the methylene hydrogens HA(B)28 with С18 and H27/С13,
and also HMBC cross-peaks Heq19/C13 (δ 2.32/138.73 ppm), Heq12/C18 (δ 2.70/128.89 ppm)
(Figure 1).
Scheme 1. Reaction of аcetoxyallobetulin 1 with HClO4 in Ac2O. Conditions: (a) HClO4 in Ac2O, 140 °С, 5 h; (b)
i. KOH/EtOH, 78 °С, 1 h; ii. Jones reagent, 0 °C, 4 h.
2

Figure 1. Key NOESY and HMBC correlations of compounds 3 and 5
We propose the following mechanism for the formation of compounds 2 – 5 (Figure 2). First,
under the action of the acylium cation on acetoxyallobetulin 1, oxonium ion I is formed, which
opens and generates intermediate II, which then undergoes elimination and formation of
diacetoxymoradiol 3. On the other hand, carbocation II can form carbocation III via migration
of H-18 to H-19, which, after elimination of H-13 leads to diacetoxy-δ-erythrodiol 5. Migration
of the methyl group at С(20), [1,2]-sigmatropic hydrogen shift and deprotonation of IV leads to
the formation of 3β,28-diacetoxy-18α,19βH-urs-20-en 2. The acylium cation can also undergo
electrophilic addition with the trisubstituted С(20)-С(21) unsaturated bond of compound 2,
followed by attack of oxygen at the C28 position of intermediate V leading to the formation of
compound 4. The structure of 4 was confirmed also by single crystal X-Ray analysis (Figure 3).
Figure 2. Plausible mechanism for the formation of triterpenoids 2 - 5 from acetoxyallobetulin 1
Figure 3. General view of the structure of 3-acetoxy-21β-acetyl-20,28-epoxy-18,19Н-ursane 4 (atoms are
represented by thermal displacements ellipsoids with 50% probability). Hydrogen atoms are omitted for clarity
3

Treatment of allobetulin with benzoyl chloride in xylene at reflux led to derivatives of
heterobetulin (62%), moradiol (8%) and γ-erythrodiol (5%).21 According to the literature23
dibenzoylheterobetulin is the only product of the reaction, however the yield was not mentioned.
Deprotection of 2 and 3 followed by Jones oxidation led to heterobetulonic 6 and moronic 7 acids
with overall yields of 17% and 35% from acetoxyallobetulin 1, respectively. Recently reported
syntheses of moronic or morolic acids include five or eleven steps in 34% or 24% overall yields
starting from 28-oxoallobetulone or betulin, respectively.34,35 This makes possible the medium-
to-large scale preparation of these pharmacologically important triterpenic acids. Moreover,
modifications of substituents at C(3) of allobetulin allows the preparation of differently 3-
substituted 18(19)-oleanenes and taraxastanes in one stage with good yields.
Acknowledgments
This work was supported by the Russian Foundation for Basic Research (Projects No. 11-03-
12144; 14-03-31664). The calculations were performed and NMR spectra were recorded at the
Center for the Collective Use “Chemistry” of the Ufa Institute of Chemistry of the Russian
Academy of Sciences.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at…
References and notes
1. Sheng, H.; Sun, H. Nat. Prod. Rep. 2011, 28, 543-593.
2. Salvador, J. A.; Moreira, V. M.; Gonçalves, B. M.; Leal, A. S.; Jing, Y. Nat. Prod. Rep. 2012, 29, 1463-1479.
3. Liby, K. T.; Sporn, M. B. Pharmacol. Rev. 2012, 64, 972-1003.
4. Heller, L.; Schwarz, S.; Obernauer, A.; Csuk, R. Bioorg. Med. Chem. Lett.. 2015, 25, 2654-2656.
5. Corey, E. J.; Lee, J. J. Am. Chem. Soc. 1993, 115, 8873-8874.
6. Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 8865-8869.
7. Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2009, 131, 13928-13929.
8. Huang, A. X.; Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 9999-10003.
9. Kazakova, O. B.; Suponitsky, K. Ju.; Tolstikov, G. A. Russ. J. Bioorg. Chem. 2010, 36, 133-135.
10. Kazakova, O. B.; Khusnutdinova, E. F.; Tolstikov, G. A.; Suponitsky, K. Ju. Russ. J. Bioorg. Chem. 2010, 36,
512-515.
11. Urban, M.; Sarek, J.; Tisrelova, I.; Dzubak, P.; Hajduch, M. Bioorg. Med. Chem. 2005, 13, 5527-5535.
12. Flekhter, O. B.; Medvedeva, N. I.; Kukovinets, O. S.; Spirikhin, L. V.; Galkin, E. G.; Galin, F. Z.; Golovanov,
D. G.; Pavlova, N. I.; Savinova, О. V.; Boreko, Е. I.; Tolstikov, G. A. Russ. J. Bioorg. Chem. 2007, 33, 629-634.
13. Zhang, P. H. J.; Liu, J.; Jun, L.; Zhang, L.; Sun, H. Tetrahedron. 2009, 65, 4304-4309.
14. Kazakova, O. B.; Kazakov, D. V.; Yamansarov, E. Yu.; Medvedeva, N. I.; Tolstikov, G. A.; Suponitsky, K. Yu.;
Arkhipov, D. E. Tetrahedron Lett. 2011, 52, 976-979.
15. Ye, Y.; Kinoshita, K.; Koyama, K.; Takahashi, K.; Kondo, N.; Yuasa, H. J. Nat. Prod. 1998, 61, 456-460.
16. Flekhter, O. B.; Boreko, E. I.; Nigmatullina, L. P.; Pavlova, N. I.; Medvedeva, N. I.; Nikolaeva, S. N.;
Tretyakova, E. V.; Savinova, O. V.; Baltina, L. A.; Karachurina, L. T.; Galin, F. Z.; Zarudii, F. S.; Tolstikov, G. A.
Pharm. Chem. J. 2004, 38, 148-152.
17. Dorr, C. R.; Yemets, S.; Kolomitsyna, O.; Krasutsky, P.; Mansky, L. M. Bioorg. Med. Chem. Lett. 2011, 21,
542-545.
18. Medvedeva, N. I.; Flekhter, O. B.; Kukovinets, O. S.; Galin, F. Z.; Tolstikov, G. A; Baglin, I.; Cave, C. Russ.
Chem. Bull. Int. Ed. 2007, 56, 835-837.
19. Krasutsky, P. A. Nat. Prod. Rep. 2006, 23, 919-942.
20. Тhibeault, D.; Legault, J.; Gauthier, Ch.; Lavoie, S.; Bouchard, J.; Pichette, A. Synth. Commun. 2010, 20, 213-
221.
21. Klinot, J.; Vystrcil, A. Collect. Czech. Chem. Commun. 1964, 29, 516-530.
22. Ames, T. R.; Beton, J. L.; Bowers, A.; Halsall, T. G.; Jones, E. R. H. J. Chem. Soc. 1954, 12, 1902-1919.
23. Bradbury, B. J.; Huang, M. U.S. Patent WO 2007098247, 2007.
4

24. Kazakova, O. B.; Giniyatullina, G. V.; Yamansarov, E. Yu.; Tolstikov, G. A. Bioorg. Med. Chem. Lett. 2010,
20, 4088-4090.
25. Fieser, L. F.; Fieser, M. Reagents for organic synthesis, Wiley. 1967, 1, 797-802.
26. Dorofeenko, N.; Zdanov, U. A.; Dulenko, U. I.; Krivun, S. V. Perchloric acid and it’s derivatives in organic
synthesis, Rostov State University. 1965, 75 p.
27. Kazakova, O. B.; Smirnova, I. E.; Khusnutdinova, E. F.; Zhukova, O. S.; Fetisova, L. V.; Apryshko, G. N.;
Medvedeva, N. I.; Yamansarov, E. Yu.; Baikova, I. P.; Nguen, T. T.; Thi Thu, H. Do. Russ. J. Bioorg. Chem. 2014,
40, 558-567.
28. Sun, I. C.; Kashiwada, Y.; Morris-Natschke, S. L.; Lee, K.-H. Curr. Top. Med. Chem. 2003, 3, 155-169.
29. Yu, D.; Sakurai, Y.; Chen, C. H.; Chang, F. R.; Huang, L.; Kashiwada, Y.; Lee, K.-H. J. Med. Chem. 2006, 49,
5462-5469
30. Lee, K.-H.; Chang, F. R.; Sakurai, Y.; Chen, C. H. Patent WO 2006001964 (2006).
31. Ramírez-Espinosa, J. J.; García-Jiménez, S.; Rios, M. Y.; Medina-Franco, J. L.; López-Vallejo, F.; Webster, S.
P.; Binnie, M.; Ibarra-Barajas, M.; Ortiz-Andrade, R.; Estrada-Soto, S. Phytomedicine. 2013, 20, 571-576.
32. Gehrke, I. T.; Neto, A.T.; Pedroso, M.; Mostardeiro, C. P.; Mânica Da Cruz, I. B.; Silva, U. F.; Ilha, V.; Dalcol,
I. I.; Morel, A. F. J. Ethnopharmacol. 2013, 148, 486-491.
33. Kazakova, O. B.; Khusnutdinova, E. F.; Medvedeva, N. I.; Lobov, A. N.; Suponitskii, K.Yu. J. Struct. Chem.
2012, 53, 954–957.
34. Flekhter, O. B.; Medvedeva, N. I.; Tolstikov, G. A.; Galin, F. Z.; Yunusov, M. S.; Mai, H. N. T.; Tien, L. V.;
Savinova, I. V.; Boreko, E. I.; Titov, L. P.; Glukhov, I. V. Russ. J. Bioorg. Chem. 2009, 35, 233-239.
35. Zhang, P.; Hao, J.; Liu, J.; Zhang, L.; Sun, H. Tetrahedron 2009, 65, 4304-4309.
5

Graphical abstract
6