Synthesis of a dicyano abietane, a key intermediate for the anti-inflammatory agent TBE-31

Article abstract of DOI:10.1021/ol403289y

The synthesis of dicyano abietane 11, a potential precursor to the biologically active tricyclic bis-cyano enone 6 (TBE-31), was accomplished in eight steps from epoxide 13. The synthesis features a Lewis acid promoted stereoselective cyclization of epoxide 13 to generate the tricyclic ring system 12 in one step.

Full text of DOI:10.1021/ol403289y

Letter
pubs.acs.org/OrgLett
Synthesis of a Dicyano Abietane, a Key Intermediate for the Anti-
inflammatory Agent TBE-31
Evans O. Onyango,† Liangfeng Fu,† and Gordon W. Gribble*
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, United States
S
* Supporting Information
ABSTRACT: The synthesis of dicyano abietane 11, a
potential precursor to the biologically active tricyclic bis-
cyano enone 6 (TBE-31), was accomplished in eight steps
from epoxide 13. The synthesis features a Lewis acid promoted
stereoselective cyclization of epoxide 13 to generate the
tricyclic ring system 12 in one step.
leanolic acid (1), ursolic acid (2), and betulinic acid (3),
Othe most common pentacyclic triterpenoids, exhibit
modest biological activity.1 Over the past 15 years, our
triterpenoid research program entailed the modification of the
ring-A C-3 hydroxy, ring-C double bond, and the C-28
carboxylic acid of both oleanolic and ursolic acid.2,3 This led to
the syntheses of several highly biologically active oleanolic acid
derivatives, such as CDDO methyl ester (2-cyano-3,12-
dioxooleana-1,9(11)-dien-28-oic acid methyl ester) (Bardox-
olone Methyl) (4), CDDU methyl ester, and their derivatives
(Figure 1).4−8 For example, 4 completed successful phase 1 and
2 clinical trials for some cancers and chronic kidney disease.1,5
Figure 2. Synthetic design of tricyclic bis-enones.
Our previous synthesis12 of TBE-31 (6) was adopted in part
from that of 11 and featured a 12-step synthesis from
commercially available 2-carbomethoxycyclohexanone (7)13
(Scheme 1). We described a second synthesis of 6,14 but the
Scheme 1. Reported Synthesis of TBE-31 (6)
Figure 1. Pentacyclic triterpenoids.
key steps were impractical for further customization. Thus,
excess lithium in liquid ammonia and carefully controlled
conditions were necessary for the reductive methylation of
enone 8 to a mixture of ketones 9a, 9b, and 9c. Nine additional
steps were required to convert 9 to TBE-31 (6).
Retrosynthetically, abietane-type diterpenoid 11 is involved
as the key intermediate to furnish TBE-31, while 11 can be
obtained from alcohol 12 through the installation of a cyano
enone in ring A and a cyano group in ring C. A Lewis acid
catalyzed cyclization reactions would afford alcohol 12, from
readily available epoxide 13 (Scheme 2).
The ring-A cyano enone and ring-C enone moieties are
essential for the biological activity of 4. To this end, we
synthesized a series of tricyclic analogues having these same
functionalities in rings A and C (i.e., the A−B−C ring
pharmacophore) and tested their biological activity.9 Thus, the
inhibitory activity of 11 against the production of nitric oxide in
RAW 264.7 cells stimulated with interferon-γ (IFNγ) was
found to be twice that of hydrocortisone, a well-known anti-
inflammatory drug.10 This promising biological activity of 11
ultimately led to the discovery of TBE-31 (6), which is 10 times
more active than CDDO-Me (4) (Figure 2).11 The higher
potency and lower molecular weight of TBE-31 (6) make it
especially attractive for further biological studies.
Received: November 14, 2013
Published: December 4, 2013
© 2013 American Chemical Society
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Organic Letters
Letter
advanced intermediate (vide infra). The observed diastereose-
lectivity can be attributed to the preorganized chair−chair
conformation as postulated by Stork and Eschenmosher.25 We
also examined and were encouraged by the fact that the
reactions leading to 13 led to the preparation of its
trifluoromethanesulfonate analogue (Tf replacing TIPS in 13,
not shown), a sequence with a potential of reducing the
number of steps required to reach 11. Unfortunately, attempted
cyclization of this trifluoromethanesulfonate analogue under the
same conditions gave an intractable mixture.
Scheme 2. Retrosynthetic Analysis
Oxidation of alcohol 12 using 4 equiv of iodobenzoic acid
(IBX)3 in DMSO at 85 °C furnished the enone 19 in 90% yield
(Scheme 4). TBAF removal of the silyl group followed by
We now describe an efficient synthesis of tricycle 11, which
we view as viable for the synthesis of TBE-31 (6). The
synthesis of epoxide 13 began with thioacetalization of
isovanillin tri-isopropylsilyl 1615 to yield dithiane 14 in 98%
yield, using silica gel treated with thionyl chloride (SOCl2-
SiO2) (Scheme 3).16 Lithiation of dithiane 14 under standard
Scheme 4. Synthesis of Enone 21
Scheme 3. Synthesis and Epoxyolefin Cyclization of 13
reaction of the resultant phenol with triflic anhydride in
methylene chloride in the presence of pyridine gave the triflate
20 in 87% yield (2 steps). Slight modification of the cyanation
conditions (Zn(CN)2/Pd2(dba)3/dppf/DMF/110 °C) re-
ported by Treston and co-workers26 gave the carbonitrile 21
in 95% yield. A crystal of compound 21 was analyzed by X-ray
crystallography and confirmed the trans stereochemistry
between the AB ring junction methyl and hydrogen.
conditions17,18 followed by alkylation of the resultant anion
with the known chiral epoxy geranyl bromide 1519 gave the SN2
substitution product 17 in 89% yield, with no evidence of
nucleophilic epoxide ring opening by the organolithium. That
allylic substitution was achieved by employing only the
organolithium is noteworthy; in previously reported reactions
of this kind sequential transmetalation of organolithium to the
corresponding organocuprate was invariably required.20−22 We
had originally intended to cyclize 17 in order to allow for
further functionalization of ring B and therefore gain access to
recently isolated abietane-type diterpenoids,23 bearing a
hydroxyl or carbonyl moiety at C-7 (abietane skeleton
numbering, Scheme 2). However, attempted cyclization of 17
gave mainly monocyclization product and only a trace of the
desired product along with several unidentified byproducts. We
thus moved on with reductive desulfurization using n-butyltin
hydride18 to give the epoxy derivative 13 in 82% yield. After
removal of the dithiane protecting group, there was a significant
improvement in the yield of cyclized tricyclic products. Initial
cyclization of 13 performed with dialkyl aluminum catalysts
(Et2AlCl and Me2AlCl), MeAICl2, and InBr3 gave 1:1 mixtures
of 12 and 18 in 40−60% yield.
Halogenolysis of enone 21 with iodine in pyridine at ambient
temperature gave α-iodo enone 22 in 92% yield (Scheme 5).
Scheme 5. Synthesis of Abietane Analogue 11
Treatment of 22 with CuCN in DMF at 140 °C facilitated the
Rosenmund−von Braun type reaction to give 88% of cyano
enone 23.27 Finally, demethylation to 1110 was achieved in 80%
yield by exposure of 23 to BBr3. The reaction required 4 days at
room temperature, but complete consumption of the starting
material was achieved after 8 h in refluxing CH2Cl2.28
Furthermore, the 11 was also obtained in good yield (75%)
by demethylation in molten pyridinium chloride.29 In both
cases the product 11 was identical (spectral data) to that
reported earlier.10
In summary, an efficient and convenient synthesis of tricycle
11 was accomplished in five steps from readily accessible
epoxide 13. The synthesis features an epoxide-initiated
polycyclization for the installation of the tricyclic skeleton in
a single step. Synthetic efforts for the conversion of 11 to TBE-
24
Gratifyingly, BF3·OEt2 at −78 °C promoted the diaster-
eoselective (trans only product) cyclization of the dethiolated
epoxy olefin 13 to give 69% of a 2:1 regioisomeric mixture of
12 and 18. The regioisomers, easily separable by column
chromatography, were identified on the basis of their 1H NMR
spectra: alcohol 12 has the aromatic protons appear as two
singlets, whereas in 18 they are doublets (AX pattern). The
relative stereochemistry (trans geometry of the AB ring
juncture) was later determined by X-ray crystallography of an
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Organic Letters
Letter
(19) Corey, E. J.; Noe, M. C.; Wen-Chung, S. Tetrahedron Lett. 1993,
34, 5995.
31 (6) and other potentially bioactive cyano enones are
currently underway and will be reported in due course.
(20) Gansauer, A.; Justicia, J.; Rosales, A.; Worgull, D.; Rinker, B.;
̈
Cuerva, J. M.; Oltra, J. E. Eur. J. Org. Chem. 2006, 4115.
(21) Neighbors, J. D.; Topczewski, J. J.; Swenson, D. C.; Wiemer, D.
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ASSOCIATED CONTENT
* Supporting Information
■
S
(22) Gansaeuer, A.; Justicia, J.; Rosales, A.; Rinker, B. Synlett 2005,
2005, 1954.
(23) Yang, L.; Qiao, L.; Ji, C.; Xie, D.; Gong, N.; Lu, Y.; Zhang, J.;
Dai, J.; Guo, S. J. Nat. Prod. 2013, 76, 216.
Experimental procedures and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(24) Isaka, T.; Hasegawa, M.; Toshima, H. Biosci. Biotechnol. Biochem.
2011, 75, 2213.
AUTHOR INFORMATION
■
(25) Zhao, J.; Zhao, Y.; Loh, T. Chem. Commun. 2008, 1353.
(26) Suwandi, L. S.; Agoston, G. E.; Shah, J. H.; Hanson, A. D.; Zhan,
X. H.; LaVallee, T. M.; Treston, A. M. Bioorg. Med. Chem. Lett. 2009,
19, 6459.
Corresponding Author
*E-mail: ggribble@dartmouth.edu.
Author Contributions
†These authors contributed equally to this work.
Notes
(27) You, R.; Long, W.; Lai, Z.; Sha, L.; Wu, K.; Yu, X.; Lai, Y.; Ji, H.;
Huang, Z.; Zhang, Y. J. Med. Chem. 2013, 56, 1984.
(28) Wilson, M. PCT Patent WO/1980/000841,1980.
(29) Schmid, C. R.; Beck, C. A.; Cronin, J. S.; Staszak, M. A. Org.
Process Res. Dev. 2004, 8, 670.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge general support from Reata Pharmaceuticals
and thank Michael Sporn (Geisel School of Medicine) for his
interest in our work.
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