Stereoselective synthesis of (-)-acanthoic acid.

Article abstract of DOI:10.1021/ol0060578

[reaction: see text] The first stereoselective synthesis of (-)-acanthoic acid (1) has been designed and accomplished. Our synthetic plan departs from (-) Wieland-Miesher ketone (7) and calls upon a Diels-Alder cycloaddition reaction for the construction

Full text of DOI:10.1021/ol0060578

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2073-2076
Stereoselective Synthesis of
(−)-Acanthoic Acid
Taotao Ling, Bryan A. Kramer, Michael A. Palladino, and
Emmanuel A. Theodorakis*
Department of Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe, La Jolla, California 92093-0358
etheodor@ucsd.edu
Received May 13, 2000
ABSTRACT
The first stereoselective synthesis of (−)-acanthoic acid (1) has been designed and accomplished. Our synthetic plan departs from (−) Wieland−
Miesher ketone (7) and calls upon a Diels−Alder cycloaddition reaction for the construction of the C ring of 1. The described synthesis
confirms the proposed stereochemistry of 1 and represents an efficient entry into an unexplored class of biologically active diterpenes.
The root bark of Acanthopanax koreanum Nakai (Arali-
aceae), a deciduous shrub that grows in the Republic of
Korea, has been used traditionally as a tonic, a sedative, and
a remedy for rheumatism and diabetes.1 In their study of
the pharmacologically active extracts of this folk medicine,
Chung and co-workers have isolated and structurally char-
acterized a novel diterpene, (-)-pimara-9(11),15-dien-19-
oic acid, which was subsequently named acanthoic acid (1).2
held accountable for its pharmacological profile. Indeed, the
recent isolation of this compound has allowed studies into
its biological activity and verified its medicinal potential.2b,c
More specifically, acanthoic acid was found to exhibit
promising antiinflammatory and antifibrotic activities that
presumably arise by inhibiting the production of the pro-
inflammatory cytokines: tumor necrosis factor-alpha (TNF-
R) and interleukin-1 (IL-1).4 This inhibition was concentra-
tion dependent and cytokine-specific since under the same
conditions the production of IL-6 or IFN-γ (interferon-
gamma) were not affected. In addition, acanthoic acid was
found to be active upon oral administration in animal models
and showed minimal toxicity in experiments performed in
mice.
(1) Medicinal Plants of East and Southeast Asia; Perry, L. M., Metzger,
J., Eds.; MIT Press: Cambridge, MA and London, 1980.
(2) (a) Kim, Y.-H.; Chung, B. S.; Sankawa, U. J. Nat. Prod. 1988, 51,
1080-1083. (b) Kang, H.-S.; Kim, Y.-H.; Lee, C.-S.; Lee, J.-J.; Choi, I.;
Pyun, K.-H. Cellular Immunol. 1996, 170, 212-221. (c) Kang, H.-S.; Song,
H. K.; Lee, J.-J.; Pyun, K.-H.; Choi, I. Mediators Inflammation 1998, 7,
257-259.
(3) Ruzicka, L.; Sternbach, L. J. Am. Chem. Soc. 1948, 70, 2081-2085.
Ireland, R. E.; Schiess, P. W. Tetrahedron Lett. 1960, 25, 37-43. Wenkert,
E.; Buckwalter, B. L. J. Am. Chem. Soc. 1972, 94, 4367-4372. Wenkert,
E.; Chamberlin, J. W. J. Am. Chem. Soc. 1959, 81, 688-693.
From the biosynthesis standpoint, 1 belongs to a rather
large family of pimaradiene diterpenes, which may be best
represented by pimaric acid (2).3 Interestingly, however, the
structure of acanthoic acid is distinguished by an uncommon
connectivity across the rigid tricyclic core, which may be
10.1021/ol0060578 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/17/2000

The combination of uncommon structure and promising
pharmacological activity displayed by 1 prompted us to
extend our synthetic studies5 to this family of biologically
important metabolites. In this paper we report a stereo-
selective total synthesis of (-)-acanthoic acid. In addition
to constituting the inaugural synthetic entry into this class
of bioactive diterpenes,6 our studies confirm the structure
and absolute stereochemistry of 1.
Scheme 1. Studies toward the Tricyclic Core of 1a
The retrosynthetic strategy toward acanthoic acid is
illustrated in Figure 1. The C ring of 1 was envisioned to be
Figure 1. Retrosynthetic analysis of (-)-acanthoic acid (1).
constructed by a Diels-Alder cycloaddition reaction, thereby
revealing dienophile 3 and an appropriately substituted diene,
such as 4, as ideal coupling partners.7 If successful, this
reaction could introduce both the unsaturation at the C9-
C11 bond and the desired stereochemistry at the C8 and C13
carbons. Diene 4 could be produced by functionalization of
ketone 5, whose C4 quaternary center was projected to be
formed by a stereocontrolled alkylation of â-ketoester 7. This
analysis suggested the use of (-) Wieland-Miesher ketone
7 as a putative starting material. Application of such a plan
to the synthesis of acanthoic acid is shown in the Scheme
1.8
a Reagents and conditions: (a) 0.1 equiv of PTSA, 1.05 equiv
of (CH2OH)2, benzene, 80 °C, 4 h, 90%; (b) 2.2 equiv of Li, liquid
NH3, 1.0 equiv of t-BuOH, -78 to -30 °C, 30 min then isoprene
(excess), -78 to 50 °C; 1.1 equiv of NC-CO2Me, Et2O, -78 to 0
°C, 2 h, 55%; (c) 1.1 equiv of NaH, HMPA, 25 °C, 3 h; 1.1 equiv
of MOMCl, 25 °C, 2 h, 95%; (d) 7.0 equiv of Li, liquid NH3, -78
to -30 °C, 20 min; CH3I (excess), -78 to -30 °C, 1 h, 61%; (e)
1 N HCl, THF, 25 °C, 15 min, 95%; (f) 1.6 equiv of Li acetylide,
Et2O, 25 °C, 1 h, 91%; (g) Lindlar’s catalyst (20% per weight),
H2, dioxane/pyridine, 10/1 25 °C, 10 min, 95%; (h) 4.4 equiv of
BF3‚Et2O, benzene/THF: 4/1, 80 °C, 5 h, 95%; (i) 13 equiv of 3,
neat, 8 h, 25 °C, 100%; (j) 1.4 equiv of NaBH4, THF/MeOH:10/1,
30 min, 25 °C, 94% (14:15 ) 3.3:1); (k) 1.1 equiv of p-Br-
C6H4COCl, 1.5 equiv of pyridine, 0.1 equiv of DMAP, CH2Cl2,
25 °C, 2 h, 95% for 16, 97% for 17.
(4) For recent reviews on TNF-R and IL-1, see: Tumor Necrosis Factors.
The Molecules and their Emerging Role in Medicine; Beutler, B., Ed.; Raven
Press: New York, 1992. Aggarwal, B.; Puri, R. Human Cytokines: Their
Role in Disease and Therapy; Blackwell Science, Inc.: Cambridge, MA,
1995. Thorpe, R.; Mire-Sluis, A. Cytokines; Academic Press: San Diego,
1998. Kurzrock, R.; Talpaz, M. Cytokines: Interleukins and Their Receptors;
Kluwer Academic Publishers: Boston, 1995. Szekanecz, Z.; Kosh, A. E.;
Kunkel, S. L.; Strieter, R. M. Clin. Pharmacol. 1998, 12, 377-390. Camussi,
G.; Lupin, E. Drugs 1998, 55, 613-620. Newton, R. C.; Decicco, C. P. J.
Med. Chem. 1999, 42, 2295-2314.
(5) For related recent syntheses from our laboratories, see: Xiang, A.
X.; Watson, D. A.; Ling. T.; Theodorakis, E. A. J. Org. Chem. 1998, 63,
6774-6775. Ling, T.; Xiang, A. X.; Theodorakis, E. A. Angew. Chem.,
Int. Ed. 1999, 38, 3089-3091.
(6) For synthetic studies toward 1, see: Suh, Y.-G.; Park, H.-J.; Jun,
R.-O. Arch. Pharm. Res. 1995, 18, 217-218. Suh, Y.-G.; Jun, R.-O.; Jung,
J.-K.; Ryu, J.-S. Synth. Commun. 1997, 27, 587-593.
(7) Oppolzer, W. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Oxford, NY; Pergamon Press: 1991; pp 315-399.
Our synthetic venture departed with optically pure enone
7, which was readily available through a D-proline-mediated
asymmetric Robinson annulation (75-80% yield, >95% ee).9
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Org. Lett., Vol. 2, No. 14, 2000

Selective ketalization of the C9 ketone group of 7, followed
by reductive alkylation across the enone functionality with
methyl cyanoformate, afforded ketoester 6 in 50% overall
yield.10 To introduce the desired functionalization at the C4
position we sought to implement a second reductive alkyl-
ation procedure, originally reported by Coates and Shaw.11
With this in mind, compound 6 was first transformed to the
corresponding methoxymethyl ether 8, which upon treat-
ment with lithium in liquid ammonia and iodomethane gave
rise to ester 10 in 58% overall yield and as a single
diastereomer.12 It was expected that the stereoselectivity of
this addition would arise from the strong preference of the
presumed intermediate enolate 9 to undergo alkylation at the
less hindered equatorial side. Nonetheless, unambiguous
confirmation of this structure was deferred until assembly
of the entire backbone of acanthoic acid.
Figure 2. Chem3D representation of ORTEP drawings of 16 and
17. (For clarity only selected hydrogens are shown.)
With the bicyclic core in hand, our attention shifted toward
construction of the C ring, which was projected to be formed
via a Diels-Alder reaction between methacrolein (3) and
the sulfur-containing diene 4. The synthesis of 4 was initiated
with an acid-catalyzed deprotection of the C9 ketal of 10,
followed by alkylation of the resulting ketone 5 with lithium
acetylide‚ethylenediamine complex.13 This sequence afforded
alkyne 11 as an 8:1 diasteromeric mixture at C9 (in favor of
the isomer shown) and in 86% overall yield. At this point,
it was deemed important to examine the diastereofacial
selectivity of the Diels-Alder reaction and evaluate the
overall feasibility of our plan using a nonfunctionalized diene,
such as 12. To this end, the diastereomeric mixture of
propargyl alcohols 11 was partially reduced (H2, Lindlar’s
catalyst) and dehydrated (BF3‚Et2O) to produce diene 12 in
90% yield.14 The Diels-Alder cycloaddition between 12 and
methacrolein (3) proceeded smoothly under neat conditions
at 25 °C and afforded in quantitative yield a mixture of two
diastereomeric aldehydes that could be separated only after
reduction with sodium borohydride. The resulting alcohols
14 and 15 (3.3:1 in favor of 14) were transformed to the
corresponding p-bromobenzoate esters (16 and 17, respec-
tively), which upon recrystallization with dichloromethane/
ethanol yielded crystals suitable for X-ray analysis (Figure
2).
The results of the X-ray studies were instrumental in
several ways. First, they established that the tricyclic system
had the expected stereochemistry at the C4 position and
confirmed that the Diels-Alder reaction proceeded with
exclusive endo orientation.15 Second, after reduction, the
major product of the cycloaddition was shown to be alcohol
14, which had the desired stereochemistry at the C8 center,
thereby demonstrating a strong preference for diene 12 to
undergo reaction with 3 from the R-face (bottom side attack).
Moreover, these data indicated that synthesis of acanthoic
acid would require an inversion in the orientation of the
incoming dienophile. In principle, this could be accomplished
by altering the atomic orbital coefficients at the termini of
the diene, supporting the use of a heteroatom-containing
diene, such as 4, during the cycloaddition.16 The construction
of diene 4 and its utilization for the synthesis of 1 is shown
in Scheme 2.
Compound 4 was produced by a radical addition of
thiophenol onto alkyne 11,17 followed by POCl3-mediated
dehydration of the resulting allylic alcohol18 (two steps, 70%
yield). Interestingly, this dehydration was also attempted with
BF3‚Et2O but proved ineffective in this case. With a
substantial amount of 4 in hand, we investigated the Diels-
Alder reaction, using 3 as the dienophile. Several thermal
(-78 to 80 °C) and Lewis acid (BF3‚Et2O, TiCl4, AlCl3, and
SnCl4) catalyzed Diels-Alder conditions were tested. Best
results were obtained with SnCl4 in methylene chloride at
-20 °C and afforded aldehyde 18 in 84% yield as a 4.2:1
mixture of diastereomers. To simplify the product charac-
terization and allow adequate separation, this mixture was
reduced with NaBH4 and reductively desulfurized using
(8) All new compounds exhibited satisfactory spectral and analytical data
(see Supporting Information).
(9) Buchschacher, P.; Fuerst, A.; Gutzwiller, J. Organic Syntheses;
Wiley: New York, 1990; Collect. Vol. 7, pp 368-3372.
(10) Crabtree, S. R.; Mander, L. N.; Sethi, P. S. Org. Synth. 1992, 70,
256-263.
(11) Coates, R. M.; Shaw, J. E. J. Org. Chem. 1970, 35, 2597-2601.
Coates, R. M.; Shaw, J. E. J. Org. Chem. 1970, 35, 2601-2605.
(12) For selected applications of this method to the synthesis of other
diterpenes, see: Welch, S. C.; Hagan, C. P. Synth. Commun. 1973, 3, 29-
32. Welch, S. C.; Hagan, C. P.; Kim, J. H.; Chu, P. S. J. Org. Chem. 1977,
42, 2879-2887. Welch, S. C.; Hagan, C. P.; White, D. H.; Fleming, W.
P.; Trotter, J. W. J. Am. Chem. Soc. 1977, 99, 549-556.
(13) Das, J.; Dickinson, R. A.; Kakushima, M.; Kingston, G. M.; Reid,
G. R.; Sato, Y.; Valenta, Z. Can. J. Chem. 1984, 62, 1103-1111.
(14) Coisne, J.-M.; Pecher, J.; Declercq, J.-P.; Germain, G.; van
Meerssche, M. Bull. Soc. Chim. Belg. 1980, 89, 551-557.
(15) Interestingly, methacrolein was shown to produce exo Diels-Alder
products when reacting with cyclopentadiene: Kobuke, Y.; Fueno, T.;
Furukawa, J. J. Am. Chem. Soc. 1970, 92, 6548-6553. This unusual
observation was rationalized on the basis of the steric repulsion exhibited
by the methyl group: Yoon, T.; Danishefsky, S. J.; de Gala, S. Angew.
Chem., Int. Ed. Engl. 1994, 33, 853-855.
(16) For use of sulfur-containing dienes in Diels-Alder reactions, see:
Overman, L. E.; Petty, C. B.; Ban, T.; Huang, G. T. J. Am. Chem. Soc.
1983, 105, 6335-6338. Trost, B. M.; Ippen, J.; Vladuchick, W. C. J. Am.
Chem. Soc. 1977, 99, 8116-8118. Cohen, T.; Kozarych, Z. J. Org. Chem.
1982, 47, 4008-4010. Hopkins, P. B.; Fuchs, P. L. J. Org. Chem. 1978,
43, 1208-1217. Petrzilka, M.; Grayson, J. I. Synthesis 1981, 753-786.
(17) Greengrass, C. W.; Hughman, J. A.; Parsons, P. J. J. Chem. Soc.,
Chem. Commun. 1985, 889-890.
(18) Trost, B. M.; Jungheim, L. N. J. Am. Chem. Soc. 1980, 102, 7910-
7925. Mehta, G.; Murthy, A. N.; Reddy, D. S.; Reddy, A. V. J. Am. Chem.
Soc. 1986, 108, 3443-3452.
Org. Lett., Vol. 2, No. 14, 2000
2075

of major diastereomer 20 with Dess-Martin periodinane,
followed by Wittig methylenation, installed the alkene
functionality at the C13 center and produced 21 in 86%
overall yield. The final step of our synthesis was deprotection
of the C-19 carboxylic acid. The initially examined saponi-
fication methods failed, presumably due to steric hindrance
created by the nearby methyl group and the axial orientation
of the acid function. Gratifyingly, exposure of 21 to LiBr in
refluxing DMF gave rise to acanthoic acid 1 in 93% yield,
Scheme 2. Synthesis of Acanthoic Acid (1)a
2
presumably via an SN -type displacement of the acyloxyl
functionality.19 Synthetic 1 had spectroscopic and analytical
data identical to those reported for the natural product.20 In
addition, synthetic acanthoic acid (1) was found to inhibit
TNF-R and IL-1â synthesis, similar to the inhibition reported
for the natural product.2b,c
In conclusion, we present herein a concise, stereoselective
synthesis of acanthoic acid (1). The synthetic strategy is
highlighted by the implementation of a Diels-Alder reaction
between diene 4 and methacrolein (3), which set the
stereochemistry at the C13 and C8 carbon centers. The
described synthesis of 1 requires 14 steps (starting with enone
7) and proceeds in 9% overall yield. Moreover, the overall
efficiency and versatility of our strategy sets the foundation
for the preparation of designed analogues with improved
pharmacological profiles.
Acknowledgment. Financial support from BioSTAR and
Nereus Pharmaceuticals, Inc. is gratefully acknowledged. We
also thank the NSF (Shared Instrumentation Grant CHE-
9709183) and the Hellman Foundation (Faculty Research
Fellowship to E.A.T.) for partially supporting this research.
a Reagents and conditions: (a) 3.0 equiv of PhSH, 0.05 equiv
of AIBN, xylenes, 120 °C, 18 h, 86%; (b) 1.1 equiv of POCl3,
HMPA, 25 °C, 1 h; 1.1 equiv of pyridine, 150 °C, 18 h, 81%; (c)
3.0 equiv of 3, 0.2 equiv of SnCl4 (1 M in CH2Cl2), CH2Cl2, -20
to 0 °C, 20 h, 84%; (d) 1.4 equiv of NaBH4, EtOH, 25 °C, 30 min;
(e) Raney Ni (excess), THF, 65 °C, 10 min, 91% (over two steps);
(f) 1.3 equiv of Dess-Martin periodinane, CH2Cl2, 25 °C, 30 min;
(g) 2.7 equiv of Ph3PCH3Br, 2.2 equiv of NaHMDS (1.0 M in THF),
THF, 25 °C, 18 h, 86% (over two setps); (h) 3.0 equiv of LiBr,
DMF, 160 °C, 3 h, 93%.
Supporting Information Available: 1H and 13C NMR
spectra for compounds 1, 4-6, 8, 10-11, 14-17, and 20-
21 and X-ray data for compounds 16-17. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0060578
Raney Ni. Alcohols 19 and 20 (19:20 ) 1:4.2) were thus
obtained in 91% overall yield. The structure of these
compounds was assigned by comparison to the structures of
the products isolated from the reaction of 3 and 12. Treatment
(19) Bennet, C. R.; Cambie, R. C. Tetrahedron 1967, 23, 927-941.
(20) Additional evidence for the desired relative stereochemistry of the
C ring of 1 was obtained by NOE difference experiments, which showed
that H17 and H8 are located at the same face of the tricyclic scaffold.
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Org. Lett., Vol. 2, No. 14, 2000