Enantioselective synthesis of the antiinflammatory agent (-)-acanthoic acid

Article abstract of DOI:10.1021/jo0159035

An enantioselective synthesis of the potent antiinflammatory agent (-)-acanthoic acid (1) is described. The successful strategy departs from (-)-Wieland-Miescher ketone (10), which is readily available in both enantiomeric forms and constitutes the starting point toward a fully functionalized AB ring system of 1. Conditions were developed for a regioselective double alkylation at the C4 center of the A ring, which produced compound 32 as a single stereoisomer. Construction of the C ring of 1 was accomplished via a Diels-Alder reaction between sulfur-containing diene 43 and methacrolein (36), which after desulfurization and further functionalization yielded synthetic acanthoic acid. The described synthesis confirms the proposed stereochemistry of the natural product and represents a fully stereocontrolled entry into an underexplored class of biologically active diterpenes.

Full text of DOI:10.1021/jo0159035

J . Org. Chem. 2001, 66, 8843-8853
8843
En a n tioselective Syn th esis of th e An tiin fla m m a tor y Agen t
(-)-Aca n th oic Acid
Taotao Ling,† Chinmay Chowdhury,† Bryan A. Kramer,† Binh G. Vong,†
Michael A. Palladino,‡ and Emmanuel A. Theodorakis*,†
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive,
La J olla, California 92093-0358, and Nereus Pharmaceuticals, Inc., 9393 Towne Centre Drive, Suite 210,
San Diego, California 92121
email: etheodor@ucsd.edu
Received J uly 9, 2001
An enantioselective synthesis of the potent antiinflammatory agent (-)-acanthoic acid (1) is
described. The successful strategy departs from (-)-Wieland-Miescher ketone (10), which is readily
available in both enantiomeric forms and constitutes the starting point toward a fully functionalized
AB ring system of 1. Conditions were developed for a regioselective double alkylation at the C4
center of the A ring, which produced compound 32 as a single stereoisomer. Construction of the C
ring of 1 was accomplished via a Diels-Alder reaction between sulfur-containing diene 43 and
methacrolein (36), which after desulfurization and further functionalization yielded synthetic
acanthoic acid. The described synthesis confirms the proposed stereochemistry of the natural product
and represents a fully stereocontrolled entry into an underexplored class of biologically active
diterpenes.
In tr od u ction a n d Ba ck gr ou n d
of such successful endeavors are the plant-derived me-
tabolites camptothecin, podophyllotoxin, and Taxol.4
Another more recent example of a traditional medicinal
plant is Acanthopanax koreanum Nakai, a deciduous
shrub that grows indigenously in Cheju Island of The
Republic of Korea.5 It has been reported that wine made
from the root bark of this bush has been used tradition-
ally by local populations for treatment of neuralgia,
hypertension, rheumatism, and diabetes. Although the
beneficial analgesic and tonic effects of this plant were
known since ancient times, it was only recently that a
systematic study of its extracts was undertaken. Notably,
in 1988 Chung and co-workers isolated and structurally
characterized from these extracts a novel diterpene,
which was subsequently named acanthoic acid (1).6
Following its isolation, the biological mode of action of
this natural product was more methodically examined.7
To this end, in vitro studies with activated human
monocytes and macrophages revealed that acanthoic acid
inhibits up to 90% of the production of the pro-inflam-
matory cytokines, tumor necrosis factor-alpha (TNF-R),
and interleukin-1 (IL-1).8 This inhibition was concentra-
tion dependent and cytokine specific since, under the
For thousands of years, mankind has known about the
benefit of drugs from nature. Among them, plants and
extracts thereof have formed the basis for numerous
traditional medicines, which even today continue to play
an important role in health care worldwide.1,2 Although
the medical use of folkloric recipes and rituals is still
ongoing in some parts of the world, it has become
increasingly essential to develop drugs in a form of
purified, single compounds, that are well understood in
terms of biology, pharmacology, and overall medical
value. With this concept in mind, traditional medicines
are constantly being examined in an effort to isolate and
structurally characterize the active ingredients that
provide starting points for further biological and medici-
nal studies. In fact, it has been estimated that 77% of
all currently used drugs were discovered as a result of
chemical studies and structural modifications of active
substances used in folkloric medicines.3 Notable examples
* Corresponding author. Phone: 858-822-0456. Fax: 858-822-0386.
† University of California, San Diego.
‡ Nereus Pharmaceuticals, Inc.
(1) For selected monographs on this subject, see: Kinghorn, A. D.,
Balandrin, M. F., Eds. Human Medicinal Agents from Plants; ACS
Symposium Series 534: American Chemical Society, Washington, DC,
1993. Gullo, V. P., Ed. The Discovery of Natural Products with
Therapeutic Potential; Butterworth-Heinemann: Boston, 1994. Kauf-
man, P. B., Cseke, L. J ., Warber, S., Duke, J . A., Brielmann, H. L.,
Eds. Natural Products from Plants; CRC Press: Boca Raton, FL and
Boston, 1999. Grabley, S., Thiericke, R., Eds. Drug Discovery from
Nature; Springer: Berlin, 2000.
(2) . For selected recent reviews, see: Pandley, R. C. Med. Res. Rev.
1998, 18, 333-346. Shu, Y.-Z. J . Nat. Prod. 1998, 61, 1053-1071.
Nisbet, L. J .; Moore, M. Curr. Opin. Biotechn. 1997, 8, 708-712.
Newman, D. J .; Cragg, G. M.; Snader, K. M. Nat. Prod. Rep. 2000, 17,
215-234.
(3) Farnsworth, N. R.; Akerele, O.; Bingel, A. S.; Soejarto, D. D.;
Guo, Z. Bull. WHO 1985, 63, 965-981. Cragg, G. M.; Newman, D. J .;
Snader, K. M.; J . Nat. Prod. 1997, 60, 52-60.
(4) Cragg, G. M. Med. Res. Rev. 1998, 18, 315-331. Suffness, M.
Ann. Rep. Med. Chem. 1993, 28, 305-314. J oel, S. P. Chem. Ind. 1994,
172-175. Lee, K.-H. Med. Res. Rev. 1999, 19, 569-596. Lee, K.-H. J .
Biomed. Sci. 1999, 6, 236-250. Wall, M. E. Med. Res. Rev. 1998, 18,
299-314.
(5) Medicinal Plants of East and Southeast Asia; Perry, L. M.,
Metzger, J ., Eds.; MIT Press: Cambridge, MA and London, 1980.
(6) Kim, Y.-H.; Chung, B. S.; Sankawa, U. J . Nat. Prod. 1988, 51,
1080-1083. More recently, acanthoic acid was also isolated from root
extracts of Coleonema pulchellum Williams, a shrub found in South
Africa: Brader, G.; Bacher, M.; Hofer, O.; Greger, H. Phytochemistry
1997, 45, 1207-1212.
(7) (a) Kang, H.-S.; Kim, Y.-H.; Lee, C.-S.; Lee, J .-J .; Choi, I.; Pyun,
K.-H. Cellular Immunol. 1996, 170, 212-221. (b) Kang, H.-S.; Song,
H. K.; Lee, J .-J .; Pyun, K.-H.; Choi, I. Mediators Inflamm. 1998, 7,
257-259.
10.1021/jo0159035 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/22/2001

8844 J . Org. Chem., Vol. 66, No. 26, 2001
Ling et al.
same conditions, the production of IL-6 or interferon-
gamma (IFN-γ) was not altered.7a Moreover, experiments
performed in mice treated with silica to induce silicosis
(chronic lung inflammation) and carbon tetrachloride to
induce cirrhosis (liver inflammation) demonstrated that
treatment with 1 led to a substantial reduction of fibrotic
granulomas in the lungs and a remarkable reduction of
hepatic liver enzyme elevations, respectively.7b In addi-
tion, acanthoic acid was found to be active upon oral
administration and showed minimal toxicity in experi-
ments performed in rats. Taken together, these data
support the folkloric reports surrounding the parent plant
and demonstrate clearly the medicinal potential of acan-
thoic acid as an antiinflammatory agent.
From a structural point of view, acanthoic acid (1)
belongs to a large family of tricyclic diterpenes of the
pimarane structure (2).9 Interestingly, however, the
structure of 1 is distinguished by an uncommon con-
nectivity across the rigid tricyclic core that may be held
accountable for its pharmacological profile. The combina-
tion of unusual structural constitution and promising
pharmacological activity of 1 prompted us to initiate a
synthetic program toward this family of biologically
important metabolites.10,11 Our major objective was to
develop a concise and fully stereocontrolled synthetic
entry to acanthoic acid. Herein, we present a full account
of our studies toward this goal, culminating in the
expedient and stereoselective synthesis of (-)-acanthoic
acid.12 These studies confirm the structure and establish
the absolute stereochemistry of this natural product and
pave the way for a more precise study of its structure-
activity relationship.13
F igu r e 1. Retrosynthetic analysis of acanthoic acid (1).
Resu lts a n d Discu ssion
Retr osyn th etic An a lysis a n d Bon d Discon n ec-
tion s. Close analysis of the structure of acanthoic acid
indicated the possibility of constructing the C ring using
a Diels-Alder reaction (Figure 1).14 In the forward sense,
this could be accomplished by reacting dienophile 3 with
diene 4, thereby forming the C9-C11 double bond and
introducing simultaneously stereochemistry at the C8
and C13 carbon centers. At the onset of our studies, we
had concerns regarding the stereofacial accessibility of
diene 4, which could be responsible for the stereochemical
outcome at centers C8 and C13. Nonetheless, we felt that
a wrong outcome could be influenced in favor of the
desired stereoisomer with the use of chiral auxiliaries or
by performing the cycloaddition in the presence of chiral
catalysts.
(8) 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. Cytok-
ines: Interleukins and Their Receptors; Kluwer Academic Publishers:
Norwell, MA, 1995. Galvani, D. W.; Cawley, J . C. Cytokine Therapy;
Cambridge University Press: New York, 1992. Szekanecz, Z.; Kosh,
A. E.; Kunkel, S. L.; Strieter, R. M. Clinical 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.
(9) For general reviews in this area, see: Natural Products Chem-
istry; Nakanishi, K., Goto, T., Ito, S., Natori, S., Nozoe, S., Eds.;
Academic Press: New York, 1974; Vol. 1. Glasby, J . S. Encyclopaedia
of the Terpenoids; J . Wiley and Sons: New York, 1982; Vols. 1-2. Dev,
S. Ed. CRC Handbook of Terpenoids; CRC Press: Boca Raton, FL,
1986.
(10) For a comprehensive review on the synthesis of diterpenes,
see: ApSimon, J ., Ed. The Total Synthesis of Natural Products; J . Wiley
and Sons: New York, 1990; Vol. 8. See also: 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, 4367-4369. Wenkert, E.; Chamberlin, J .
W. J . Am. Chem. Soc. 1959, 81, 688-693.
(11) 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.
(12) Ling, T.; Kramer, B. A.; Palladino, M. A.; Theodorakis, E. A.
Org. Lett. 2000, 2, 2073-2076.
Diene 4 was envisioned to be produced by manipula-
tion of ketone 5, which represents a fully functionalized
AB ring system of acanthoic acid. Compound 5 was
projected to be derived by functional group manipulation
of ketoester 6, which in turn could be made by anneal-
ing 2-methyl-1,3-cyclohexane dione (7) with ester 8.15 An
alternative strategy for the preparation of 5 would invoke
stereocontrolled alkylation of â-ketoester 9, suggest-
ing the use of (-)-Wieland-Miescher ketone 10 as a
putative starting material. As in the previous strategy,
this approach also converges to use diketone 7 during
an annulation reaction with methylvinyl ketone (11)
(Figure 1).
(13) For synthetic studies towards 1, see: Suh, Y.-G.; Park, H.-J .;
J un, R.-O. Arch. Pharm. Res. 1995, 18, 217-218. Suh, Y.-G.; J un, R.-
O.; J ung, J .-K.; Ryu, J .-S. Synth. Commun. 1997, 27, 587-593.
(14) Oppolzer, W. In Comprehensive Org. Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Elmsford, NY, 1991; pp 315-399. Woodward,
R. B.; Katz, T. J . Tetrahedron 1959, 5, 70-89.
(15) For a general review in annulation chemistry, see: J ung, M.
E. Tetrahedron, 1976, 32, 3-31.

Enantioselective Synthesis (-)-Acanthoic Acid
J . Org. Chem., Vol. 66, No. 26, 2001 8845
Sch em e 1a
Sch em e 2a
a
Reagents and conditions: (a) 1.2 equiv Et3N, 1.1 equiv
Bu2BOTf, 1.5 equiv 13, CH2Cl2, from -78 to 0 °C, 2 h; phosphate
buffer, MeOH, 10 equiv H2O2, from 0 to 25 °C, 1 h, 57%; (b) 1.2
equiv Dess-Martin periodinane, CH2Cl2, 25 °C, 1.5 h, 81%; (c)
1.2 equiv 7, 2.2 equiv KF, MeOH, 25 °C, 12 h, 53%.
selective ketalization upon treatment with ethylene glycol
and catalytic acid to afford ketoester 16 in 74% yield. The
C3 carbonyl group of 16 was then reduced with sodium
borohydride and cerium chloride to produce alcohol 17
as a mixture of diastereomers at the C3 center.19 Without
separation of the diastereomers, this mixture of alcohols
16 was subsequently transformed to ester 18 using the
Barton-McCombie radical deoxygenation protocol (60%
yield over two steps).20 Treatment of R,â-unsaturated
ester 18 with lithium in ammonia afforded enolate 19,
which upon alkylation with methyl iodide gave rise to
compound 20, as a single stereoisomer at the C4 center.
The stereochemistry of 20 was initially assigned on the
basis of previously published studies, indicating that
alkylation of the exocyclic enolate 19 proceeds from
the more accessible â-face of the bicyclic system.21
Subsequently, this prediction was confirmed on the basis
of the alkylation results of the similar enolate 31 (see
Scheme 4).
a
Reagents and conditions: (a) 1.1 equiv LDA, 1.5 equiv 13, -78
°C, 1 h, 76%; (b) J ones [O], from 0 to 25 °C, 6 h, 56%; (c) 1.4 equiv
14, 1.0 equiv 7, 2.2 equiv KF, MeOH, 25 °C, 16 h, 74%; (d) 0.1
equiv PTSA, 1.15 equiv (CH2OH)2, C6H6, reflux, 4 h, 74%; (e) 1.1
equiv NaBH4, 1.1 equiv CeCl3, EtOH, from 0 to 25 °C, 2 h, 82%;
(f) 1.3 equiv NaH, 1.5 equiv CS2, 2.5 equiv MeI, THF, from 0 to 25
°C, 4 h, 89%; (g) 1.5 equiv nBu3SnH, 0.05 equiv AIBN, C6H6, reflux,
2 h, 68%; (h) 2.5 equiv Li, liquid NH3, 1.0 equiv tBuOH, from -45
to -50 °C, 40 min; isoprene (excess), 2.0 equiv MeI, 0 °C, 3 h, 71%.
Having achieved the construction of a fully function-
alized AB ring of acanthoic acid as a racemic mixture,
we focused our attention on developing an enantioselec-
tive entry into this structure. In principle, this could be
accomplished by constructing enone 15 as a single
enantiomer. To this end, the condensation of 14 with 7
was attempted in the presence of D-proline methyl ester
(0.1 and 1.0 equiv in CH2Cl2), (S)-camphorsulfonic acid
(0.1 and 1.0 equiv in CH2Cl2), L-proline (0.1 and 1.0 equiv
in MeOH and DMSO), and L-phenylalanine (0.1 and 1.0
In itia l Ap p r oa ch to th e AB Rin g System of 1. Our
initial synthetic plan benefited from published reports
related to the synthesis of ketoester 14, which is also
known as Nazarov reagent (Scheme 1).16 Compound 14
was formed by reaction of ethyl acetate (12) with LDA
and quenching of the anion with acrolein (13). The
resulting alcohol was subsequently oxidized to ketone 14
using J ones oxidation (two steps, 43% yield).17 Condensa-
tion of Nazarov reagent (14) with diketone 7 proceeded
smoothly in methanol or ethyl acetate using KF or
triethylamine, respectively, to produce compound 15 in
74% yield as a racemate. Despite the rather conspicuous
absence from the literature of an enantioselective variant
of this reaction,18 we decided to look initially at the
feasibility of using 15 as a precursor of a fully function-
alized AB ring system of acanthoic acid and defer until
later the task of an enantioselective strategy. To this end,
the more basic C9 carbonyl group of 15 underwent
(18) For selected synthetic applications of Nazarov reagent, see:
Wenkert, E.; Alfonso, A.; Bredenberg, J . B.-S.; Kaneko, C.; Tahara, A.
J . Am. Chem. Soc. 1964, 86, 2038-2042. Watson, A. T.; Park, K.;
Wiemer, D. F.; Scott, W. J . J . Org. Chem. 1995, 60, 5102-5106. Stork,
G.; Guthikonda, R. N. Tetrahedron Lett. 1972, 2755-2758. Caselli, A.
S.; Collins, D. J .; Stone, G. M. Aust. J . Chem. 1982, 35, 799-808.
Schkeryantz, J . M.; Luly, J . R.; Coghlan, M. J . Synlett 1998, 723-
724. Padwa, A.; Kulkarni, Y. S.; Zhang, Z. J . Org. Chem. 1990, 55,
4144-4153.
(19) Gemal, A. L.; Luche, J .-L. J . Am. Chem. Soc. 1981, 103, 5454-
5459. Barnier, J .-P.; Morisson, V.; Volle, I.; Blanco, L. Tetrahedron:
Asymmetry 1999, 10, 1107-1117. Dumortier, L.; Van der Eycken, J .;
Vandewalle, M. Tetrahedron Lett. 1989, 30, 3201-3204.
(20) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin Trans.
1 1975, 1574-1585.
(16) Nazarov, I. N.; Zavyalov, S. I. Zh. Obshch. Khim. 1953, 23, 1703;
Engl. Transl. 1953, 23, 1793-1794; Chem. Abstr. 1954, 48, 13667h.
Zibuck, R.; Streiber, J . M. Org. Synth. 1993, 71, 236-241.
(17) The only chiral derivative of the Nazarov reagent is the (-)-
bornyl 3-hydroxy-4-pentenoate. See: Zibuck, R.; Streiber, J . M. J . Org.
Chem. 1989, 54, 4717-4719. However, to the best of our knowledge,
there are no reports on enantioselective annulations based on this type
of reagent.
(21) For selected applications of this method to the synthesis of other
diterpenes, see: Welch, S. C.; Hagan, C. P. Synth. Comm. 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.

8846 J . Org. Chem., Vol. 66, No. 26, 2001
Ling et al.
Sch em e 3a
equiv in MeOH and DMSO). The best results were
obtained when the annulation was performed in the
presence of 1.0 equiv of L-proline in MeOH at 25 °C for
24 h. Nonetheless, under these conditions, the bicycle 15
was isolated in 40% yield and with 60% enantiomeric
excess (ee) (analyzed by chiral HPLC).22
The disappointing results above prompted us to con-
sider construction of the desired AB ring system of
acanthoic acid in an enantioselective way by embedding
chirality on the ester part of the bicyclic system. In
principle, this could be achieved by using a modified
Nazarov reagent covalently attached to an Evans chiral
oxazolidinone.23 The construction of the AB ring system
along these lines is shown in Scheme 2.
The modified Nazarov reagent was prepared by react-
ing oxazolidinone 21 with acrolein (13) in the presence
of dibutyl boron triflate to afford alcohol 22. Treatment
of 22 with Dess-Martin periodinane produced the de-
sired R,â-unsaturated ketone, which was subjected to
several annulation conditions in the presence of diketone
7. A variety of Lewis acid conditions (ZnCl2, TiCl4) were
attempted but did not yield any annulated products.
Among other conditions tried, including THF/Et3N, MeOH/
KOH (cat), MeOH/K2CO3, and MeOH/MeONa at 25 and
60 °C, the best yields of annulated product were obtained
with KF/MeOH at 25 °C. In this case, we isolated a 1:1
mixture of bicyclic products 23 and 24 in 53% overall
yield. Gratifyingly, the less polar spot, corresponding to
compound 23, was crystalline and its structure was
unambiguously assigned on the basis of X-ray studies
(Supporting Information). By analogy, the more polar
stereoisomer was assigned to structure 24, containing the
desired (R) absolute configuration at the C10 quaternary
center.
a
Reagents and conditions: (a) 0.1 equiv PTSA, 1.05 equiv
(CH2OH)2, benzene, 80 °C, 4 h, 90%; (b) 2.2 equiv Li, 1.0 equiv
tBuOH, NH3, from -78 to -45 °C, 30 min, then isoprene (excess),
from -78 to -45 °C; (c) 1.1 equiv NCCO2Me, Et2O, from -78 to 0
°C, 2 h, 87%.
Sch em e 4a
Secon d Ap p r oa ch to th e AB Rin g System of 1. In
light of the problems associated with the construction of
the AB system of acanthoic acid as a single enantiomer
using Nazarov reagent (or modifications thereof), we
decided to pursue its synthesis from the less-functional-
ized Wieland-Miescher enone 10 (Scheme 3).
Enone 10 was readily available through a D-proline-
mediated asymmetric Robinson annulation, followed by
two successive crystallizations (from Et2O/hexane) (70-
75% yield, >95% ee).24 After selective protection of the
C9 carbonyl group (90% yield), ketal 25 was subjected to
reductive alkylation across the enone functionality. To
this end, treatment of 25 with lithium in ammonia
containing tBuOH, followed by quenching of the resulting
enolate with methyl cyanoformate, afforded the desired
compound 28 together with variable amounts of 29.25 We
found that the ratio of products 28 and 29 depends on
the temperature at which enolate 26 is allowed to be
warmed during the necessary evaporation of the excess
ammonia. For example, if the entire reductive alkylation
sequence is performed at -78 °C, the adduct 28 is formed
in low yield (ca. 30%) and is accompanied with substan-
a
Reagents and conditions: (a) 1.1 equiv NaH, 25 °C, 3 h; 1.1
equiv MOMCl, 25 °C, 2h, 95%; (b) 7.0 equiv Li, NH3, from -78 to
-30 °C, 20 min; CH3I (excess), from -78 to -30 °C, 1 h, 61%; (c)
1 N HCl, THF, 25 °C, 15 min, 95%; (d) 1.6 equiv Li acetylide, Et2O,
25 °C, 1 h, 91%.
(22) The HPLC analysis was performed in
a CHIRALPAK AD
tial amounts of recovered enone (25). Alternatively,
allowing enolate 26 to be warmed at temperatures higher
than -40 °C resulted in substantial formation of com-
pound 27. The desired compound 28 is obtained in the
best yield (87%) if enolate 26 is formed at temperatures
between -50 and -45 °C, the excess ammonia is evapo-
rated under vacuum at -45 °C, and the resulting enolate
is subsequently alkylated at -78 °C. Under these condi-
tions, formation of compound 29 was not observed.
column (No. 19025) with a 4.6 nm diameter and a 250 nm length that
was purchased from Chiral Techn. Inc., Exton, PA. The compounds
were eluted with 100% hexanes (HPLC grade).
(23) Evans, D. A. Aldrichimica Acta 1982, 15, 23-32. Evans, D. A.;
Ripin, D. H. B.; J ohnson, J . S.; Shaughnessy, E. A. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2119-2121.
(24) Buchschacher, P.; Fuerst, A.; Gutzwiller, J . Org. Synth. Coll.
Vol. VII 1990, 368-3372.
(25) Crabtree, S. R.; Mander, L. N.; Sethi, P. S. Org. Synth. 1992,
70, 256-263. Stork, G.; Rosen, P.; Goldman, N.; Coombs, R. V.; Tsuji,
J . J . Am. Chem. Soc. 1965, 87, 275-286.

Enantioselective Synthesis (-)-Acanthoic Acid
J . Org. Chem., Vol. 66, No. 26, 2001 8847
(over two steps).28 The Diels-Alder cycloaddition between
35 and methacrolein (36) proceeded smoothly under neat
conditions at 25 °C and afforded in quantitative yield a
mixture of two diastereomeric aldehydes 37 and 38 in a
3.4:1 ratio and 100% overall yield. Since the obtained
mixture of aldehydes could not be separated via silica
gel chromatography, it was subjected to reduction with
sodium borohydride to afford alcohols 39 and 40 in 94%
yield. The resulting alcohols 39 and 40 were separable
via flash chromatography and, upon treatment with
Dess-Martin periodinane, afforded aldehydes 37 and 38
in 95 and 88% yields, respectively, thereby allowing
adequate spectroscopic characterization of the Diels-
Alder adducts.
F igu r e 2. Chem3D representations of ORTEP drawings of
28 and 29 (for clarity, only selected hydrogens are shown).
Formation of compound 29 can be explained mecha-
nistically if we consider epimerization of the kinetically
formed enolate 26 to the thermodynamically more stable
enolate 27, in which the double bond is located between
the C2 and C3 carbon centers. Interestingly, the enolate
character of 29 is also shown in the crystal structure of
this compound, while in comparison, the X-ray structure
of compound 28 suggests its preference to exist in the
â-ketocarbonyl form (Figure 2).
Sch em e 5a
Further functionalization of the AB ring of acanthoic
acid is accomplished as shown in Scheme 4 and is based
on a Coates and Shaw “double reduction” of â-ke-
toesters.26 With this concept in mind, ketoester 28 was
selectively O-alkylated with methoxymethyl chloride and
sodium hydride to afford MOM ether 30 in 95% yield.
Treatment of 30 with lithium in liquid ammonia resulted
in deoxygenation at the C3 center and formation of
enolate 31, which upon reaction with iodomethane pro-
duced ester 32 in 61% yield. Similar to the conversion of
18 to 20 (shown in Scheme 1), it was expected that the
stereoselectivity of this addition will arise from the strong
preference of the presumed intermediate enolate 31 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 was achieved.
Syn th etic Stu d ies Tow a r d th e C Rin g of 1. Having
completed the synthesis of the AB ring system of acan-
thoic acid, we sought to attach the C ring across centers
C8 and C9. To this end, ketal 32 was subjected to acid-
catalyzed deprotection (1 N HCl, 95% yield) and the
resulting ketone 33 was alkylated with lithium acetylide‚
ethylenediamine complex.27 This sequence afforded alkyne
34 as an 8:1 diasteromeric mixture at C9 (in favor of the
isomer shown) and in 86% overall yield (Scheme 4).
Attachment of the alkyne part at C9 of compound 34
was strategically planned to allow flexibility in introduc-
ing a heteroatom at the terminal position (corresponding
to the C12 center), thereby influencing the outcome of
the Diels-Alder reaction. Nonetheless, at this point, it
was deemed important to examine the diastereofacial
selectivity of the Diels-Alder cycloaddition and evaluate
the overall feasibility of our plan using a nonfunctional-
ized diene such as 35 (Scheme 5). With this concept in
mind, the diastereomeric mixture of propargyl alcohols
34 was partially reduced (H2, Lindlar’s catalyst) and
dehydrated (BF3‚Et2O) to produce diene 35 in 90% yield
a
Reagents and conditions: (a) Lindlar’s catalyst (20% per
weight), H2, 10:1 dioxane/pyridine, 25 °C, 10 min, 95%; (b) 4.4
equiv BF3‚Et2O, 4:1 benzene/THF, 80 °C, 5 h, 95%; (c) 13 equiv
36, neat, 8 h, 25 °C, 100%; (d) 1.4 equiv NaBH4, 10:1 THF/MeOH,
30 min, 25 °C, 94%; (e) 1.6 equiv Dess-Martin [O], CH2Cl2, 0 °C,
3 h, 95% for 39, 88% for 40; (f) 1.1 equiv pBr-C6H4-COCl, 1.5
equiv pyridine, 0.1 equiv DMAP, CH2Cl2, 25 °C, 2 h, 95% for 41,
97% for 42.
Unambiguous proof of structures for compounds 39 and
40 was obtained after derivatization to the corresponding
p-bromobenzoate esters (41 and 42, respectively), which
upon recrystallization with dichloromethane/ethanol
yielded crystals suitable for X-ray analysis (Supporting
Information). The results of the X-ray studies clarified
several key issues related to the overall strategy toward
acanthoic acid. First, they demonstrated that the C4
carbon center had the desired configuration, thereby
confirming the predictions of the alkylation outcome of
the C4 enolates 19 and 31 (shown in Schemes 1 and 4,
respectively). More importantly, they revealed that the
Diels-Alder cycloaddition of 35 with 36 proceeded with
(26) 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.
(27) Das, J .; Dickinson, R. A.; Kakushima, M.; Kingston, G. M.; Reid,
G. R.; Sato, Y.; Valenta, Z. Can. J . Chem. 1984, 62, 1103-1111.
(28) Coisne, J .-M.; Pecher, J .; Declercq, J .-P.; Germain, G.; van
Meerssche, M. Bull. Soc. Chim. Belg. 1980, 89, 551-557.

8848 J . Org. Chem., Vol. 66, No. 26, 2001
Ling et al.
exclusive endo orientation29 and good stereofacial prefer-
ence (from the R-face of diene 35, as shown in Supporting
Information).30 In addition, these data indicated that
synthesis of acanthoic acid would require an inversion
in the orientation of the incoming dienophile 36. In
principle, this could be accomplished by inverting the
atomic orbital coefficients at the termini of diene 35,
supporting the notion to attach strong electron-donating
groups at its C12 center. The synthesis of acanthoic acid
based on this strategy is shown in Scheme 6.
Sch em e 6a
Tota l Syn th esis of Aca n th oic Acid . Treatment of
alkyne 34 with thiophenol under free-radical conditions
afforded vinyl sulfide 43 in 86% yield (Scheme 6).31
Dehydration of allylic alcohol 43 was found to be more
difficult and unsuccessful under the previously employed
BF3‚Et2O treatment. Nonetheless, a stonger POCl3-
mediated dehydration process gave rise to diene 44 in
81% yield, presumably through an unstable allyl chloride
intermediate.32 With a substantial amount of 44 on hand,
we investigated the Diels-Alder reaction using 36 as the
dienophile. Several thermal- (from -78 to 80 °C) and
Lewis acid- (BF3‚Et2O, TiCl4, AlCl3, and SnCl4) catalyzed
Diels-Alder conditions were tested. The best results were
obtained with SnCl4 in methylene chloride at -20 °C and
afforded aldehyde 45 in 84% yield as a 4.2:1 mixture of
diastereomers.33
To simplify the product characterization and allow
adequate separation, the unseparable mixture of alde-
hydes 45 was reduced with NaBH4 and reductively
desulfurized using Raney Ni to produce alcohols 46 and
47 in 91% overall yield (Scheme 6). The structure of these
compounds, which were easily separable in silica gel, was
assigned by comparison to the products isolated from the
reaction between 35 and 36. Treatment of the major
diastereomer 46 with Dess-Martin periodinane,34 fol-
lowed by Wittig methylenation, installed the alkene
(29) 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. For a
recent report on the endo-exo selectivity of certain Diels-Alder
reactions, see: Ge, M.; Stoltz, B. M.; Corey, E. J . Org. Lett. 2000, 2,
1927-1929.
(30) The Diels-Alder reaction has been utilized toward the synthe-
ses of polycyclic terpenes and steroids. In these studies, its facial
selectivity was found to be critically dependent on the structures of
both the diene and the dienophile. For selected references on this topic,
see: Das, J .; Kubela, R.; MacAlpine, G. A.; Stojanac, Z.; Valenta, Z.
Can. J . Chem. 1979, 57, 3308-3319. Kakushima, M.; Allain, L.;
Dickinson, R.; White, P. S.; Valenta, Z. Can. J . Chem. 1979, 57, 3354-
3356. Kakushima, M.; Das, J .; Reid, G. R.; White, P. S.; Valenta, Z.
Can. J . Chem. 1979, 57, 3356-3358. Das, J .; Dickinson, R. A.;
Kakushima, M.; Kingston, G. M.; Reid, G. R.; Sato, Y.; Valenta, Z. Can.
J . Chem. 1984, 62, 1103-1111. Schuster, T.; Bauch, M.; Durner, G.;
Goebel, M. W. Org. Lett. 2000, 2, 179-181. Minuti, L.; Selvaggi, R.;
Taticchi, A. Synth. Comm. 1992, 22, 1535-1542. Lee, J .; Li, J .; Oya,
S.; Snyder, J . J . Org. Chem. 1992, 57, 5301. Antonaroli, S.; Berettoni,
M.; Cifarelli, G.; Lupi, A.; Bettolo, R. M.; Romeo, S. Gazz. Chim. Ital.
1992, 122, 55-57. Kolaczkowski, L.; Reusch, W. J . Org. Chem. 1985,
50, 4766-4768.
a
Reagents and conditions: (a) 3.0 equiv PhSH, 0.05 equiv
AIBN, xylenes, 120 °C, 18 h, 86%; (b) 1.1 equiv POCl3, HMPA, 25
°C, 1 h; 1.1 equiv pyridine, 150 °C, 18 h, 81%; (c) 3.0 equiv 36, 0.2
equiv SnCl4 (1 M in CH2Cl2), CH2Cl2, from -20 to 0 °C, 20 h, 84%;
(d) 1.4 equiv NaBH4, EtOH, 25 °C, 30 min; (e) Raney Ni (excess),
THF, 65 °C, 10 min, 91% (over two steps); (f) 1.3 equiv Dess-
Martin periodinane, CH2Cl2, 25 °C, 30 min; (g) 2.7 equiv
Ph3PCH3Br, 2.2 equiv NaHMDS (1.0 M in THF), THF, 25 °C, 18
h, 86% (over two steps); (h) 3.0 equiv LiBr, DMF, 160 °C, 3 h,
93%.
functionality at the C13 center and produced 48 in two
steps and in 86% overall yield. The final step of our
synthesis was the deprotection of the C19 carboxylic acid.
The initially examined saponification methods (LiOH/
THF/H2O, NaOH/THF/H2O at 25-100 °C) failed, pre-
sumably due to the steric hindrance created by the
methyl group attached at the C10 center and the axial
orientation of the acid function. Gratifyingly, exposure
of 48 to LiBr in refluxing DMF gave rise to acanthoic
acid 1 in 93% yield, presumably via an SN2-type displace-
ment of the acyloxyl functionality.35
Synthetic acanthoic acid had spectroscopic and ana-
lytical data identical to those reported for the natural
product. Additional evidence for the desired relative
stereochemistry of the C ring of 1 was obtained by NOE
difference experiments, which showed that the H17 and
H8 protons are at the same face of the tricyclic scaffold
(Scheme 6).
(31) Greengrass, C. W.; Hughman, J . A.; Parsons, P. J . J . Chem.
Soc., Chem. Commun. 1985, 889-890.
(32) Trost, B. M.; J ungheim, 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.
(33) 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.
(34) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277-
7287. Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(35) Bennet, C. R.; Cambie, R. C. Tetrahedron 1967, 23, 927-941.

Enantioselective Synthesis (-)-Acanthoic Acid
J . Org. Chem., Vol. 66, No. 26, 2001 8849
Eth yl-3-oxo-4-p en ten oa te (14).17 To a well stirred solution
of ethyl-3-hydroxy-4-pentenoate (5 g, 34.74 mmol) in acetone
(60 mL) at 0 °C was added J ones reagent (40 mL, 40 mmol) in
four portions over a period of 2 h. After complete addition of
the reagent, the reaction mixture was allowed to stir for
another 4 h at 25 °C. The reaction mixture was extracted with
ethyl ether (3 × 80 mL) and washed with water (80 mL) and
brine (80 mL). The organic layers were combined, dried over
MgSO4, and concentrated under reduced pressure. The residue
was purified via a Kugelrohr distillation to afford compound
14 (2.76 g, 19.45 mmol, 56%). 14: 1H NMR (300 MHz, CDCl3)
δ 11.80 (s, enol OH), 6.48-5.95 (m, 2H), 5.58 (m, 1H), 5.06 (s,
1H), 4.22-4.17 (m, 2H), 3.63 (s, 2H), 1.31-1.25 (m, 3H).
Ketoester 15. A suspension of â-ketoester 14 (1.65 g, 11.6
mmol), diketone 7 (1.05 g, 8.3 mmol), and KF (1.06 g, 18.3
mmol) in methanol (10 mL) was stirred at 25 °C for 16 h. The
solvent was removed under reduced pressure, and the crude
mixture was chromatographed (silica, 20-50% ether in hex-
anes) to afford ketoester 15 (1.54 g, 6.1 mmol, 74%). 15: light
yellow solid; mp ) 67-69 °C; Rf ) 0.15 (silica, 50% ether in
In conclusion, we present herein a concise, enantiose-
lective synthesis of acanthoic acid (1). The synthetic
strategy departs from the Wieland-Miescher enone 10,
in which the desired stereochemistry at the C10 center
was introduced via an enantioselective Robinson annu-
lation. The relative stereochemistry at the C4 and C5
centers was subsequently introduced via a sequence of
substrate-controlled reductive alkylations. Finally, the
sterochemistry at C8 and C13 centers was introduced via
a Diels-Alder reaction between the sulfur-containing
diene 44 and methacrolein (36). The described synthesis
of 1 requires 14 steps (starting with enone 10) and
proceeds in 9% overall yield. Moreover, the overall
efficiency and versatility of our strategy sets the founda-
tion for the preparation of designed analogues with
improved pharmacological profiles.
1
Exp er im en ta l Section
hexanes); H NMR (400 MHz, CDCl3) δ 4.25 (m, 2H), 2.72-
2.50 (m, 3H), 2.49-2.40 (m, 3H), 2.15-2.05 (m, 3H), 1.77-
1.64 (m, 1H), 1.43 (s, 3H), 1.29 (t, 3H, J ) 7.2 Hz); 13C NMR
(100 MHz, CDCl3) δ 209.6, 293.6, 166.1, 161.7, 132.1, 61.4,
50.2, 37.2, 33.2, 29.0, 28.6, 23.3, 21.8, 14.2; HRMS calcd for
Gen er a l Tech n iqu es. All reagents were commercially
obtained (Aldrich, Acros) at the highest commercial quality
and used without further purification except where noted. Air-
and moisture-sensitive liquids and solutions were transferred
via syringe or stainless steel cannula. Organic solutions were
concentrated by rotary evaporation below 45 °C at about 20
mmHg. All nonaqueous reactions were carried out using flame-
dried glassware under an argon atmosphere in dry, freshly
distilled solvents under anhydrous conditions, unless otherwise
noted. Tetrahydrofuran (THF) and diethyl ether (Et2O) were
distilled from sodium/benzophenone, dichloromethane (CH2-
Cl2) and toluene were distilled from calcium hydride, and
benzene was distilled from potassium. N,N-Diisopropylethy-
lamine, diisopropylamine, pyridine, triethylamine, and boron
trifluoride etherate were distilled from calcium hydride prior
to use. Dimethyl sulfoxide and dimethylformamide were
distilled from calcium hydride under reduced pressure (20
mmHg) and stored over 4 Å molecular sieves. Yields refer to
chromatographically and spectroscopically (1H NMR) homo-
geneous materials, unless otherwise stated. Reactions were
monitored by thin-layer chromatography carried out on 0.25
mm E. Merck silica gel plates (60F-254) using UV light as a
visualizing agent and 7% ethanolic phosphomolybdic acid or
p-anisaldehyde solution and heat as developing agents. E.
Merck silica gel (60, particle size ) 0.040-0.063 mm) was used
for flash chromatography. Preparative thin-layer chromatog-
raphy separations were carried out on 0.25 or 0.50 mm E.
Merck silica gel plates (60F-254). NMR spectra were recorded
on Varian Mercury 300, 400, and/or Unity 500 MHz instru-
ments and calibrated using residual undeuterated solvent as
an internal reference. The following abbreviations were used
to explain the multiplicities: s ) singlet, d ) doublet, t )
triplet, q ) quartet, m ) multiplet, b ) broad. IR spectra were
recorded on a Nicolet 320 Avatar FT-IR spectrometer, and
values are reported in cm-1 units. Optical rotations were
recorded on a J asco P-1010 polarimeter. High-resolution mass
spectra (HRMS) were recorded on a VG 7070 HS mass
spectrometer under chemical ionization (CI) conditions or on
a VG ZAB-ZSE mass spectrometer under fast atom bombard-
ment (FAB) conditions.
C
14H18O4 (M + Na+) 273.1103, found 273.1121.
Ketoester 16. A solution of enone 15 (5.95 g, 23.8 mmol),
p-TsOH (0.41 g, 2.38 mmol), and ethylene glycol (1.7 g, 27.4
mmol) in benzene (100 mL) was heated in a Dean-Stark
apparatus under reflux for 4 h with azeotropic removal of
water. After the end of the reaction, the solution was treated
with Et3N (5 mL) and the solvent was evaporated under
reduced pressure. The crude mixture was purified through
flash chromatography (silica, 5-40% ether in hexanes) to
afford the protected ketone 16 (5.18 g, 17.6 mmol, 74%). 16:
colorless oil; Rf ) 0.45 (silica, 50% ether in hexanes); IR (film)
1
νmax 2952, 1728, 1674; H NMR (300 MHz, CDCl3) δ 4.23 (q,
2H, J ) 6.9 Hz), 3.98-3.89 (m, 4H), 2.46-2.41 (m, 2H), 2.33-
2.25 (m, 3H), 1.9-1.61 (m, 5H), 1.34 (s, 3H), 1.25 (t, J ) 6.9
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 194.9, 166.2, 164.0,
132.1, 112.1, 65.4, 65.1, 61.2, 44.9, 33.6, 29.8, 28.4, 26.3, 21.4,
20.9, 14.3; HRMS calcd for C16H22O5 (M + H+) 295.1545, found
295.1552.
Alcoh ol 17. To a well stirred solution of ketoester 16 (1.87
g, 6.36 mmol) in dry ethanol (30 mL) at 0 °C were added CeCl3
(1.71 g, 6.99 mmol) and NaBH4 (265 mg, 6.99 mmol). The
reaction mixture was allowed to warm to 25 °C and stirred
for 2 h. The reaction was then quenched with aqueous
saturated ammonium chloride (10 mL), and the mixture was
extracted with ethyl ether (3 × 30 mL). The organic layers
were combined, dried over MgSO4, and concentrated under
reduced pressure. The crude residue was subjected to chro-
matography (10-40% ether in hexanes) to afford alcohol 17
(1.54 g, 5.21 mmol, 82%). 17: colorless oil; Rf ) 0.35 (silica,
50% ether in hexanes); IR (film) νmax 3436, 2943, 1708; 1H NMR
(400 MHz, CDCl3) δ 4.35 (bs, 1H), 4.23-4.21 (q, J ) 8 Hz,
2H), 4.15-3.90 (m, 4H), 3.04-3.01 (m, 1H), 2.19-2.09 (m, 3H),
1.89-1.83 (m, 2H), 1.73-1.55 (m, 5H), 1.31 (t, J ) 8 Hz, 3H),
1.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 149.6, 129.9,
113.1, 67.3, 65.2, 65.0, 60.6, 45.0, 30.2, 27.8, 26.6, 25.8, 23.7,
22.5, 14.4; HRMS calcd for C16H24O5 (M + Na+) 319.1522,
found 319.1541.
Eth yl-3-h yd r oxy-4-p en ten oa te.17 To a stirred solution of
THF (200 mL) and diisopropylamine (7.7 mL, 55 mmol) at -78
°C was added n-BuLi (22 mL, 55 mmol, 2.5 M in hexane). The
reaction mixture was stirred at -78 °C for 15 min, treated
with ethyl acetate (50 mmol) added slowly, and then stirred
for another 45 min. Distilled acrolein (3.35 mL, 50 mmol) in
10 mL THF was added dropwise, and the whole reaction
mixture was allowed to stir at -78 °C for another 10 min. The
reaction was then quenched by saturated ammonium chloride
solution (10 mL), and the mixture was extracted with ether
(3 × 150 mL). Evaporation of solvent and purification over
silica gel chromatography afforded the desired allylic alcohol
(5.47 g, 38 mmol, 76% yield).
Ester 18. NaH (104 mg, 2.6 mmol, 60% suspension in
mineral oil) was washed twice with hexanes and added slowly
to a well-stirred and precooled (0 °C) solution of alcohol 17
(601 mg, 2 mmol) in THF (10 mL). Immediately thereafter,
CS2 (231 mg, 3.0 mmol) was added and the red-orange solution
was allowed to warm at 25 °C at which temperature it was
stirred over a period of 3 h. The reaction mixture was then
re-cooled at 0 °C and treated with methyl iodide (720 mg, 5.1
mmol). After being stirred at 25 °C for an additional 30 min,
the colorless solution was quenched with ice-water (50 mL)
and extracted with ethyl ether (3 × 30 mL). The combined
ethereal layers were washed with aqueous saturated sodium
bicarbonate (50 mL) and brine (50 mL). The organic layers

8850 J . Org. Chem., Vol. 66, No. 26, 2001
Ling et al.
were combined, dried over MgSO4, and concentrated under
reduced pressure. The crude residue was subjected to chro-
matography (0-20% ether in hexanes) to afford the corre-
sponding xanthate (697 mg, 1.8 mmol, 89%) as a light yellow
liquid. This liquid was dissolved in dry benzene (50 mL) and
treated with Bu3SnH (787 mg, 2.7 mmol). The reaction mixture
was preheated at 80 °C and treated with AIBN (15 mg, 0.09
mmol) added in four portions over a period of 2 h. After the
end of the reaction, the solvent was removed under reduced
pressure and the crude residue was purified through flash
chromatography (silica, 5-30% ether in hexanes) to produce
ester 18 (344 mg, 1.22 mmol, 68%). 18: colorless oil; Rf ) 0.7
(silica, 50% ether in hexanes); IR (film) νmax 2933, 1717; 1H
NMR (400 MHz, CDCl3) δ 4.15 (q, J ) 8 Hz, 2H), 3.98-3.88
(m, 4H), 2.89-2.70 (m, 1H), 2.40-2.20 (m, 4H), 2.03-1.49 (m,
7H), 1.38-1.25 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 169.5,
147.2, 126.2, 113.4, 65.3, 60.1, 51.3, 44.9, 37.8, 30.5, 28.9, 27.7,
26.3, 23.7, 22.7, 14.4; HRMS calcd for C16H24O4 (M + H+)
281.1747, found 281.1754.
Martin periodinane (2.03 g, 4.8 mmol), which was added
portionwise at 25 °C. After the disappearance of the starting
material (TLC, 1.5 h), the reaction was quenched with aqueous
saturated sodium bicarbonate (10 mL) and aqueous saturated
sodium thiosulfate (10 mL). The organic phase was extracted
with ether (3 × 10 mL), and the combined ethereal layers were
dried (MgSO4) and concentrated under reduced pressure. The
resulting ketone (884 mg, 3.24 mmol, 81%) was used in the
following step without any further purification. The resulting
ketone (450 mg, 1.65 mmol) was added dropwise to a well-
stirred solution of 2-methyl-1,3-cyclohexanone (7) (270 mg, 2.10
mmol) and potassium fluoride (210 mg, 3.57 mmol) in metha-
nol (8 mL). After the mixture was stirred at 25 °C for 12 h,
the methanol was removed under reduced pressure and the
residue was diluted with brine (10 mL) and extracted with
dichloromethane (3 × 10 mL). The organic phases were
combined, dried over MgSO4, and concentrated. The residue
was purified through chromatography (silica, 5-30% AcOEt
in hexanes) to afford compounds 23 and 24 in a 1:1 ratio and
53% overall yield. 23: top diastereomer, white solid (crystal-
lized from ethyl ether); Rf ) 0.62 (silica, 50% ether in hexanes);
Ester 20. To a solution of lithium (31 mg, 4.4 mmol) in
liquid ammonia (50 mL) at -78 °C was added dropwise a
solution of ester 18 (495 mg, 1.76 mmol) and tert-butyl alcohol
(132 mg, 1.76 mmol) in THF (5 mL). The resulting blue
mixture was allowed to warm to -50 °C and stirred for 40
min. The reaction was then cooled to -78 °C and treated with
isoprene (3 mL). The mixture was then warmed to -45 °C,
and the excess ammonia was evaporated under reduced
pressure. After an additional 5 min under high vacuum, the
argon atmosphere was restored and the white residue was
diluted with 20 mL of dry THF. The reaction mixture was
cooled to 0 °C and treated with methyl iodide (502 mg, 3.51
mmol) added dropwise. After being stirred for 2 h, the reaction
was quenched with water (30 mL), warmed to 25 °C, and
extracted with ether (2 × 50 mL). The organic layers were
combined, dried over MgSO4, and concentrated. The crude
product was purified through chromatography (silica, 5-30%
ether in hexanes) to afford ester 20 (371 mg, 1.26 mmol, 71%).
20: colorless oil; Rf ) 0.75 (silica, 50% ether in hexanes); IR
mp ) 159-161 °C; [R]25 +127.9 (c ) 1, CH2Cl2); IR (neat)
D
1
2955, 1786, 1689, 1669, 1619; H NMR (400 MHz, CDCl3) δ
7.37-7.24 (m, 5H), 4.81-4.76 (m, 1H), 4.29-4.15 (m, 2H),
3.57-3.46 (m, 1H), 2.84-2.47 (m, 7H), 2.18-2.08 (m, 3H),
1.85-1.82 (m, 1H), 1.55 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
(major rotamer) 209.9, 194.5, 165.8, 161.1, 155.1, 134.8, 129.3,
128.9, 127.1, 66.7, 55.1, 50.4, 38.4, 37.4, 33.1, 29.1, 28.1, 23.5,
21.9; HRMS calcd for C22H23NO5 (M + H+) 382.1649, found
382.1637. 24: bottom diastereomer, colorless oil; Rf ) 0.60
(silica, 50% ether in hexanes); [R]25 +1.9 (c ) 1, CH2Cl2); IR
D
1
(neat) 2959, 1778, 1693, 1619; H NMR (400 MHz, CDCl3) δ
7.36-7.17 (m, 5H), 4.80-4.73 (m, 1H), 4.32-4.07 (m, 2H),
3.55-3.4 (m, 1H), 2.89-2.34 (m, 7H), 2.18-2.08 (m, 2H), 1.85-
1.66 (m, 2H), 1.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 210.1,
194.7, 166.0, 161.5, 152.7, 135.2, 129.4, 128.8, 127.1, 69.7, 66.4,
53.9, 50.4, 41.5, 37.4, 29.7, 29.0, 28.2, 22.0, 21.2; HRMS calcd
for C22H23NO5 (M + H+) 382.1649, found 382.1629.
1
(film) νmax 1726; H NMR (400 MHz, CDCl3) δ 4.10 (q, J ) 8
Wiela n d -Miesch er En on e (10). This compound was
synthesized on the basis of the procedure reported in ref 24
using D-proline as the chiral reagent. After chromatography
purification (silica 10-40% ether in hexanes), the resulting
liquid was crystallized twice using ether/hexanes at -30 °C.
Hz, 2H), 3.94-3.84 (m, 4H), 2.18-2.03 (m, 2H), 1.81-1.60 (m,
3H), 1.57-1.40 (m, 5H), 1.45-1.32 (m, 3H), 1.30-1.20 (m, 3H),
1.23 (s, 3H), 0.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.2,
112.9, 65.2, 64.9, 60.0, 50.9, 43.8, 38.1, 30.8, 30.3, 29.8, 28.9,
23.4, 22.7, 19.0, 15.0, 14.3; HRMS calcd for C17H28O4 (M + Na+)
319.1885, found 319.1899.
10: Rf ) 0.25 (silica, 50% ether in hexanes); [R]25 -96.0 (c )
D
1, C6H6); 1H NMR (400 MHz, CDCl3) δ 5.85 (s, 1H), 2.72-2.66
(m, 2H), 2.51-2.42 (m, 4H), 2.14-2.10 (m, 3H), 1.71-1.68 (m,
1H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 210.7, 198.0,
165.6, 125.7, 50.6, 37.7, 33.7, 31.8, 29.7, 23.4, 23.0.
Oxa zolid in on e 22. A solution of oxazolidinone 21 (5.01 g,
22.8 mmol) in dichloromethane (40 mL) was cooled to 0 °C
and treated with dibutylboron triflate (25.1 mL, 25.1 mmol,
1.0 M in CH2Cl2) followed by Et3N (3.86 mL, 27.5 mmol). The
reaction mixture was stirred at 0 °C for 1 h, cooled at -78 °C,
and treated with a solution of acrolein (13) (2.2 mL, 34.25
mmol) in dichloromethane (5 mL). The mixture was stirred
at -78 °C for 30 min and then warmed to 0 °C at which
temperature it was stirred for another 1 h. The reaction was
quenched by the addition of 25 mL of aqueous phosphate buffer
(pH ) 7.2) and 75 mL of methanol. To this cloudy mixture
was added another 75 mL of a 2:1 solution of methanol:30%
aqueous H2O2, and the mixture was allowed stir for another 1
h. The organic phase was washed with aqueous saturated
sodium bicarbonate (20 mL) and brine (20 mL) and extracted
with dichloromethane (3 × 50 mL). The combined organic
extracts were dried over anhydrous MgSO4 and concentrated
under reduced pressure. The crude residue was purified by
chromatography (silica, 20-50% ether in hexanes) to afford
the alcohol 22 (3.58 g, 13.0 mmol, 57%). 22: colorless oil; Rf )
0.5 (silica, 50% ether in hexanes); IR (neat) 3464, 2932, 1778,
1693; 1H NMR (400 MHz, CDCl3) δ 7.51-7.20 (m, 5H), 5.96-
5.91 (m, 1H), 5.36 (d, J ) 17.2 Hz, 1H), 5.19 (d, J ) 10 Hz,
1H), 4.71-4.65 (m, 2H), 4.25-4.18 (m, 1H), 3.31-3.14 (m, 3H),
2.80 (t, J ) 12 Hz, 1H), 1.24 (s, 2H); 13C NMR (75 MHz, CDCl3)
δ 171.8, 153.2, 138.5, 134.9, 129.3, 128.9, 128.4, 127.3, 115.4,
68.7, 66.4, 55.1, 42.34, 38.0; HRMS calcd for C15H17NO4 (M +
Na+) 298.1050, found 298.1058.
Keta l 25. A solution of ketone 10 (43 g, 0.24 mol) in benzene
(700 mL) was treated with p-toluenesulfonic acid (4.6 g, 0.024
mol) and ethylene glycol (15 mL, 0.27 mol). The reaction was
refluxed with a Dean-Stark apparatus and condenser at 120
°C. Once water stopped collecting in the Dean-Stark ap-
paratus, the reaction was complete (approximately 4 h).
Leaving the reaction for longer periods of time tended to
darken the reaction mixture and lower the overall yield. The
reaction mixture was cooled to 25 °C, and the reaction was
quenched with triethylamine (5 mL, 0.036 mol); the mixture
was then poured into a separatory funnel containing water
(300 mL) and saturated sodium bicarbonate (200 mL). The
resulting mixture was then extracted with ether (3 × 800 mL).
The organic layers were combined, dried over MgSO4, concen-
trated, and subjected to chromatography (10-40% ether in
hexanes) to afford ketal 25 (48 g, 0.22 mol, 90%). 25: yellow
oil; Rf ) 0.30 (silica, 50% ether in hexanes); [R]25 -77 (c ) 1,
D
1
C6H6); IR (film) νmax 2943, 2790, 1667, 1450, 1325, 1250; H
NMR (400 MHz, CDCl3) δ 5.80 (s, 1H), 3.98-3.93 (m, 4H),
2.43-2.35 (m, 3H), 2.34-2.20 (m, 3H), 1.94-1.82 (m, 1H),
1.78-1.60 (m, 3H), 1.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
198.9, 167.5, 125.5, 112.2, 65.4, 65.1, 45.1, 34.0, 31.5, 30.1, 26.9,
21.8, 20.6.
Ketoester 28. A solution of lithium (0.72 g, 0.10 mol) in
liquid ammonia (400 mL) at -78 °C was treated dropwise with
a solution of the ketal 25 (10 g, 0.045 mol) and tert-butyl
alcohol (3.7 mL, 0.045 mol) in ether (40 mL). The resulting
En on es 23 a n d 24. Allylic alcohol 22 (1.1 g, 4.0 mmol) was
dissolved in dichloromethane (8 mL) and treated with Dess-

Enantioselective Synthesis (-)-Acanthoic Acid
J . Org. Chem., Vol. 66, No. 26, 2001 8851
blue mixture was allowed to warm to -45 °C over a period of
30 min and then cooled to -78 °C again. Sufficient isoprene
(approximately 8 mL) was added dropwise to discharge the
residual blue color of the reaction mixture. The reaction was
then warmed at -45 °C at which temperature the excess
ammonia was quickly evaporated under vacuum. The remain-
ing ether was removed under reduced pressure to leave a white
foam. After an additional 5 min under high vacuum, the
nitrogen atmosphere was restored, and the lithium enolate was
suspended in dry ether (150 mL) and cooled to -78 °C. Methyl
cyanoformate (4.0 mL, 0.050 mol) was then added and the
reaction stirred for 40 min at -78 °C. The reaction was
warmed to 0 °C and stirred for an additional 1 h. Water (300
mL) and ether (200 mL) were added, and the mixture was
poured into a separatory funnel containing saturated sodium
chloride (100 mL). After the organic layer was separated, the
aqueous phase was extracted with ether (2 × 400 mL). The
combined organic layers were dried over MgSO4, concentrated,
and subjected to chromatography (10-40% ether in hexanes)
to afford ketoester 28 (11 g, 0.039 mol, 87%). 28: white
combined ethereal extracts were dried over MgSO4, concen-
trated, and subjected to chromatography (silica, 10-30% ether
in hexanes) to yield acetal 32 (4.1 g, 0.014 mol, 61%). 32: white
solid; Rf ) 0.80 (silica, 50% ether in hexanes); [R]25 +16.9 (c
D
)10, C6H6); IR (film) νmax 2934, 1728, 1466, 1379, 1283, 1125,
942; 1H NMR (400 MHz, CDCl3) δ 3.95-3.80 (m, 4H), 3.64 (s,
3H), 2.17-2.15 (m, 1H), 1.84-1.37 (m, 11H), 1.16 (s, 3H),
1.05-1.00 (m, 1H), 0.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
177.7, 112.9, 65.2, 64.9, 51.2, 44.0, 43.7, 38.1, 30.7, 30.3, 28.8,
23.4, 19.1, 14.7; HRMS calcd for C16H26O4 (M + H+) 283.1904,
found 283.1904.
Keton e 33. A solution of ester 32 (4.1 g, 0.014 mol) in THF
(50 mL) was treated with 1 M HCl dropwise (approximately
15 mL) at 25 °C with stirring. The reaction was monitored by
thin-layer chromatography and neutralized with sodium bi-
carbonate (30 mL) once the starting material disappeared. The
resulting mixture was poured into a separatory funnel con-
taining water (100 mL) and ether (100 mL). After the layers
were separated, the aqueous layer was extracted with ether
(3 × 100 mL). The combined ethereal extracts were dried over
MgSO4, concentrated, and subjected to chromatography (silica,
10-20% ether in hexanes) to yield ketone 33 (3.14 g, 0.013
mol, 95%). 33: white solid; Rf ) 0.70 (silica, 50% ether in
hexanes); [R]25D +3.5 (c ) 1.0, C6H6); IR (film) νmax 2943, 1728,
1449, 1239, 1143, 1095, 985; 1H NMR (400 MHz, CDCl3) δ 3.62
(s, 3H), 2.55-2.45 (m, 1H), 2.92-1.95 (m, 5H), 1.8-1.6 (m, 2H),
1.50-1.30 (m, 4H), 1.14 (s, 3H), 0.98-0.96 (m, 1H), 0.90 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 214.8, 177.0, 54.4, 51.3,
49.3, 44.2, 37.9, 37.7, 33.1, 28.6, 26.4, 22.8, 18.8, 17.0; HRMS
calcd for C14H22O3 (M + Na+) 261.1461, found 261.1482.
Alk yn e 34. A solution of ketone 33 (2.0 g, 8.3 mmol) in ether
(50 mL) was treated with lithium acetylide (0.40 g, 13 mmol).
The reaction mixture was stirred at 25 °C for 1 h, and then
the reaction was quenched with sodium bicarbonate (20 mL)
and water (30 mL). The mixture was poured into a separatory
funnel, and the layers were separated. The aqueous layer was
extracted with ether (3 × 50 mL). The organic layers were
combined, dried with MgSO4, concentrated, and subjected to
chromatography (silica, 10-30% ether in hexanes) to afford
alkyne 34 (2.0 g, 7.6 mmol, 91%). 34: white solid; Rf ) 0.65
crystals; Rf ) 0.40 (silica, 50% ether in hexanes); [R]25 -4.1
D
1
(c ) 1, C6H6); IR (film) νmax 2943, 1746, 1700; H NMR (400
MHz, CDCl3) δ 4.00-3.96 (m, 2H), 3.95-3.86 (m, 2H), 3.74 (s,
3H), 3.23 (d, 1H, J ) 13.2 Hz), 2.50-2.42 (m, 3H), 2.05-1.92
(m, 1H), 1.79-1.50 (m, 5H), 1.32-1.28 (m, 2H), 1.21 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 205.4, 170.0, 111.9, 65.2, 65.1,
59.9, 52.0, 43.7, 41.6, 37.5, 30.3, 29.8, 26.2, 22.5, 14.0; HRMS
calcd for C15H22O5 (M + Na+) 305.1365, found 305.1354.
Ketoester 29. This compound was obtained in 81% yield
when enolate 26, formed as indicated above, was allowed to
equilibrate to enolate 27 at -33 °C for 1 h before and after
the reaction with isoprene. 29: white crystals; Rf ) 0.40 (silica,
20% ether in hexanes); [R]25 +41.1 (c ) 1.6, C6H6); IR (film)
D
ν
max 2932.2, 1654.6, 1615.2; 1H NMR (400 MHz, CDCl3) δ 12.1
(s, 1H), 3.95 (s, 4H), 3.74 (s, 3H), 2.35-2.18 (m, 2H), 2.15-1.2
(m, 9H), 0.94 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 173.5,
170.1, 112.1, 96.2, 65.0, 64.7, 51.2, 40.7, 36.0, 32.9, 31.5, 30.1,
27.9, 27.2, 22.5, 13.6; HRMS calcd for C15H22O5 (M + Na+)
305.1365, found 305.1387.
Ester 30. A solution of ketoester 28 (7.0 g, 0.025 mol) in
HMPA (50 mL) (or DME 50 mL) was treated with sodium
hydride (0.71 g, 0.030 mol). After being stirred for 3 h at 25
°C, the resulting yellow-brown reaction mixture was quenched
with chloromethyl methyl ether (2.3 mL, 0.030 mol) and the
reaction allowed to stir an additional 2 h at 25 °C. The
resulting white-yellow mixture was then poured into a sepa-
ratory funnel containing ice-water (100 mL), saturated so-
dium bicarbonate (50 mL), and ether (200 mL). After the layers
were separated, the aqueous layer was extracted with ether
(3 × 200 mL). The combined ethereal extracts were dried over
MgSO4, concentrated, and subjected to chromatography (silica,
10-40% ether in hexanes) to yield ester 30 (7.7 g, 0.024 mol,
95%). 30: yellow oil; Rf ) 0.45 (silica, 50% ether in hexanes);
[R]25D +26.3 (c ) 1, C6H6); IR (film) νmax 2951, 1728, 1690, 1430,
1170; 1H NMR (400 MHz, CDCl3) δ 4.89 (dd, 2H, J ) 22.8, 6.4
Hz), 3.93-3.91 (m, 2H), 3.90-3.84 (m, 2H), 3.69 (s, 3H), 3.40
(s, 3H), 2.72-2.68 (m, 1H), 2.24 (bs, 2H), 1.80-1.42 (m, 4H),
1.37-1.15 (m, 2H), 0.96 (s, 3H), 0.95-0.80 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 168.7, 150.5, 115.8, 112.1, 93.0, 65.2, 65.1,
56.3, 51.3, 40.7, 40.3, 30.3, 26.4, 23.6, 22.9, 22.3, 13.9; HRMS
calcd for C17H26O6 (M + Na+) 349.1622, found 349.1621.
Aceta l 32. A solution of lithium (1.1 g, 0.17 mol) in liquid
ammonia (400 mL) at -78 °C was treated dropwise with a
solution of ester 30 (7.7 g, 0.024 mol) in 1,2-DME (30 mL).
The blue reaction mixture was allowed to warm and stir at
reflux (-33 °C) for 20 min. The reaction mixture was then
cooled to -78 °C again and the reaction rapidly quenched with
excess iodomethane (15 mL, 0.24 mol). The resulting white
slurry was allowed to stir at reflux (-33 °C) for 1 h, after which
time the reaction was warmed in a water bath (50 °C) with
stirring for 1 h, allowing the ammonia to evaporate. The
reaction was quenched with water (100 mL), sodium bicarbon-
ate (100 mL), and ether (200 mL) and the mixture poured into
a separatory funnel. After the layers were separated, the
aqueous layer was extracted with ether (3 × 200 mL). The
1
(silica, 50% ether in hexanes); H NMR (400 MHz, CDCl3) δ
3.64 (s, 3H), 2.56 (s, 1H), 2.18-2.10 (m, 1H), 1.92-1.40 (m,
12H), 1.18 (s, 3H), 1.17-1.01 (m, 1H), 0.81 (s, 3H); 13C NMR
(100 MHz, CDCl3) 177.6, 86.8, 76.5, 75.0, 51.2, 50.5, 43.9, 42.5,
37.9, 35.3, 33.4, 28.8, 23.5, 22.5, 19.1, 11.5; HRMS calcd for
C
16H24O3 (M + H+- H2O) 247.1693, found 247.1697.
Alk en e 35. A solution of alkyne 34 (0.50 g, 1.9 mmol) in
1,4-dioxane (20 mL) and pyridine (2 mL) was treated with
Lindlar’s catalyst (100 mg). The mixture was hydrogenated
under pressure (30 lbs/in2) for 7 min. The reaction mixture
was then diluted with ether (10 mL), filtered through a pad
of Celite, and washed with ether (2 × 50 mL). The solvent was
evaporated under reduced pressure to afford the corresponding
alkene (0.48 g, 1.8 mmol, 95%). This alkene was redissolved
in benzene (80 mL) and THF (20 mL) and treated with boron
trifluoride etherate (1 mL, 7.9 mmol), and the reaction mixture
was refluxed at 80 °C for 5 h. After the mixture was cooled,
the reaction was quenched with 1 N NaOH (1 mL, 26 mmol);
the mixture was then poured into a separatory funnel contain-
ing water (100 mL) and ether (100 mL). After the layers were
separated, the aqueous layer was extracted with ether (3 ×
100 mL). The organic layers were combined, dried with MgSO4,
concentrated, and subjected to chromatography (silica, 5%
ether in hexanes) to afford diene 35 (0.42 g, 1.7 mmol, 95%).
1
35: colorless oil; Rf ) 0.95 (silica, 50% ether in hexanes); H
NMR (400 MHz, CDCl3) δ 6.26-6.23 (dd, 1H), 5.70 (s, 1H),
5.253 (d, 1H, J ) 19.2 Hz), 4.91 (d, 1H, J ) 12.8 Hz), 3.64 (s,
3H), 2.22-2.12 (m, 2H), 2.10-1.94 (m, 2H) 1.92-1.67 (m, 3H),
1.60-1.44 (m, 3H), 1.378 (d, 1H, J ) 13.6), 1.21 (s, 1H), 1.19-
1.00 (m, 2H), 0.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.7,
146.7, 136.1, 121.9, 113.3, 53.0, 51.2, 43.9, 38.0, 37.9, 37.4, 28.5,
27.8, 20.5, 19.5, 18.3; HRMS calcd for C16H24O2 (M + H+)
249.1854, found 249.1871.
Ald eh yd es 37 a n d 38. A solution of methacrolein (36, 0.5
mL, 5.2 mmol) and diene 35 (0.1 g, 0.40 mmol) was stirred for

8852 J . Org. Chem., Vol. 66, No. 26, 2001
Ling et al.
8 h at 25 °C under neat conditions. The excess methacrolein
(36) was then removed under reduced pressure. The crude
product was subjected to chromatography (silica, 10-20%
ether in hexanes) to afford aldehydes 37 and 38 (0.13 g, 0.40
mmol, 100%) as a mixture of diastereomers at C8 and C14
(3:1-4:1 ratio). Spectroscopic characterization of 37 and 38
was achieved by reduction with sodium borohydride, followed
by reoxidation of alcohols 39 and 40, to aldehydes 37 and 38.
8.4 Hz), 7.60 (d, 2H, J ) 8.4 Hz), 5.54 (m, 1H), 4.15 (m, 2H),
3.64 (s, 3H), 2.21-1.78 (m, 7H), 1.77-1.41 (m, 6H), 1.39-1.20
(m, 3H), 1.18 (s, 3H), 1.07 (s, 3H), 0.91 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 178.1, 166.2, 149.0, 131.7, 131.0, 129.5, 127.9,
118.2, 68.8, 51.1, 47.3, 44.2, 41.2, 40.3, 38.9, 38.0, 34.7, 30.2,
28.2, 23.7, 22.3, 21.9, 20.3, 19.7; HRMS calcd for C27H35BrO4
(M + H+) 503.1796, found 503.1781. 42: 47 mg, 97%; colorless
crystals (from ether/hexanes); Rf ) 0.40 (silica, 25% ether in
37: colorless oil; Rf ) 0.55 (silica, 25% ether in hexanes); [R]25
hexanes); [R]25 +42 (c ) 1.0, C6H6); 1H NMR (400 MHz,
D
D
-58.8 (c ) 1, C6H6); IR (film) νmax 3441, 2936, 1726, 1451, 1233,
1152; 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 5.58 (m, 1H),
3.62 (s, 3H), 2.38-2.25 (m, 1H), 2.21-2.18 (m, 1H), 2.17-1.98
(m, 4H), 1.96-1.62 (m, 6H), 1.61-1.58 (m, 1H), 1.57-1.43 (m,
2H),1.40-1.23 (m, 1H), 1.17 (s, 3H), 1.04 (s, 3H), 0.92 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 207.6, 177.7, 148.3, 188.6, 51.3,
47.8, 47.0, 44.2, 41.2, 39.3, 38.8, 38.1, 29.5, 28.4, 22.9, 22.5,
21.8, 20.6, 20.5, 19.7; HRMS calcd for C20H30O3 (M + H+)
319.2273, found 319.2261. 38: colorless oil; Rf ) 0.55 (silica,
CDCl3) δ 7.91 (d, 2H, J ) 8.8 Hz), 7.61 (d, 2H, J ) 8.4 Hz),
4.40 (m, 1H), 4.11 (s, 2H), 3.66 (s, 3H), 2.2-1.85 (m, 8H), 1.61-
1.40 (m, 6H), 1.30-1.20 (m, 2H), 1.14 (s, 3H), 1.00 (s, 3H), 0.86
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.9, 166.1, 148.7,
131.8, 131.1, 129.5, 128.0, 114.5, 71.6, 55.9, 51.2, 44.4, 41.9,
40.1, 38.2, 37.5, 34.9, 30.2, 28.6, 27.4, 24.2, 22.4, 22.0, 19.8,
18.7; HRMS calcd for C27H35BrO4 (M + H+) 503.1796, found
503.1790.
Su lfid e 43. A solution of alkyne 34 (1.1 g, 4.2 mmol),
thiophenol (1.37 g, 12.4 mmol), and AIBN (34.5 mg, 0.21 mmol)
in xylenes (25 mL) was stirred at 120 °C under argon for 18
h. The reaction mixture was cooled to 25 °C, diluted with
aqueous saturated sodium bicarbonate, and extracted with
ethyl ether (3 × 50 mL). The organic layers were combined,
dried (MgSO4), and concentrated, and the residue was chro-
matographed (silica, 2-5% ethyl ether in hexane) to afford
sulfide 43 (1.35 g, 3.6 mmol, 86%). 43: colorless liquid; Rf )
25% ether in hexanes); [R]25 +36.8 (c ) 0.7, C6H6); IR (film)
D
1
νmax 3441, 2936, 1726, 1451, 1233, 1152; H NMR (400 MHz,
CDCl3) δ 9.64 (s, 1H), 5.42 (m, 1H), 3.66 (s, 3H), 2.29-2.10
(m, 4H), 2.09-1.84 (m, 4H), 1.81-1.77 (m, 2H), 1.75-1.63 (m,
2H), 1.62-1.58 (m, 2H), 1.57-1.45 (m, 1H), 1.43 (s, 1H), 1.13
(s, 3H), 1.03 (s, 3H), 0.87 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 207.3, 177.5, 147.4, 114.6, 55.8, 51.3, 47.3, 44.5, 40.7, 40.4,
38.4, 37.5, 31.5, 28.6, 25.0, 24.2, 21.9, 19.9, 19.6, 18.7; HRMS
calcd for C20H30O3 (M + H+) 319.2273, found 319.2288.
Alcoh ols 39 a n d 40. A solution of adehydes 37 and 38
(mixture of diastereomers) (0.13 g, 0.40 mmol) in THF (30 mL)
and methanol (2 mL) was treated with sodium borohydride
(22 mg, 0.56 mmol). The reaction mixture was stirred for 30
min at 25 °C, and then the reaction was quenched with sodium
bicarbonate (20 mL) and water (30 mL). The mixture was
poured into a separatory funnel containing ether (30 mL). After
the layers were separated, the aqueous layer was extracted
with ether (3 × 50 mL). The organic layers were combined,
dried with MgSO4, and concentrated, and the residue was
subjected to chromatography (silica, 0-5% ether in hexanes)
to afford enantiomerically pure alcohols 39 and 40 (0.122 g,
0.38 mmol, 3.3:1 ratio in favor of 39, 94% overall yield). 39:
94.1 mg, 0.29 mmol, 72%; colorless oil; Rf ) 0.12 (silica, 25%
0.5 (silica, 5% ethyl ether in hexanes); [R]25 +24.2 (c ) 1.0,
D
benzene); IR (film) νmax 2946, 1724, 1472, 1438; 1H NMR (400
MHz, CDCl3) δ 7.5 (m, 2H), 7.3-7.2 (m, 3H), 5.24 (d, 1H, J )
8.4 Hz), 5.11 (d, 1H, J ) 8.4 Hz), 3.6 (s, 3H), 2.2-2.1 (m, 2H),
1.9-1.1 (m, 9 H), 1.10 (s, 3H), 0.9 (m, 3 H), 0.68 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 177.7, 151.7, 133.9, 128.7, 127.9,
118.2, 54.9, 53.5, 51.1, 44.3, 40.4, 38.0, 37.2, 28.7, 27.7, 25.4,
23.4, 19.5, 18.5; HRMS calcd for
397.1814, found 397.1830.
C
22H30O3S (M + Na+)
Dien e 44. To a solution of sulfide 43 (1.10 g, 2.94 mmol) in
hexamethyl phosphoramide (HMPA, 10 mL) was added drop-
wise phosphorus oxychloride (0.50 g, 3.3 mmol), and the
mixture was stirred at 25 °C until it became clear. Pyridine
(0.26 mL, 3.23 mmol) was then added, and the mixture was
stirred at 150 °C (under argon) for 18 h. The reaction mixture
was cooled to 25 °C, and the reaction was quenched with
aqueous saturated sodium bicarbonate (50 mL). The organic
layer was extracted with ethyl ether (3 × 60 mL), collected,
dried (MgSO4), and concentrated, and the residue was chro-
matographed (silica, 2-5% ethyl ether in hexane) to afford
diene 44 (0.85 g, 2.38 mmol, 81%); 44: colorless liquid; Rf )
0.60 (silica, 5% ethyl ether in hexanes); [R]25D -17.3 (c ) 1.08,
benzene); IR (film) νmax 2957.0, 1726.6, 1581.6, 1478.3, 1439.0,
1234.7, 1190.8, 1094.8, 1024.4, 739.1; 1H NMR (500 MHz,
CDCl3) δ 7.20-7.60 (m, 5H), 6.43 (d, 1H, J ) 15.0 Hz), 6.36
(d, 1H, J ) 14.5 Hz), 5.72 (m, 1H), 3.64 (s, 3H), 1.48-2.32 (m,
10H), 1.21 (s, 3H), 1.05 (m, 1H), 0.88 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 177.9, 133.7, 129.1, 128.9, 128.6, 127.5, 126.2,
123.4, 120.9, 52.8, 51.1, 43.7, 37.7, 37.3, 30.2, 28.3, 27.7, 20.1,
19.3, 18.3; HRMS calcd for C22H28O2S (M + Cs+) 489.0861,
found 489.0882.
ether in hexanes); [R]25 -64.5 (c ) 0.5, C6H6); IR (film) νmax
D
3446, 2933, 1725, 1459, 1375, 1228; 1H NMR (400 MHz, CDCl3)
δ 5.51 (m, 1H), 3.63 (s, 3H), 3.42 (m, 2H, J ) 10.4 Hz), 2.22-
2.14 (m, 1H), 2.13-2.04 (m, 1H), 2.03-1.92 (m, 3H), 1.91-
1.72 (m, 4H), 1.64-1.57 (m, 2H), 1.53-1.40 (m, 5H), 1.33-
1.18 (m, 1H), 1.17 (s, 3H), 0.96 (s, 3H), 0.88 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 178.1, 149.0, 118.1, 67.3, 51.2, 47.7, 44.2,
41.0, 39.3, 39.2, 38.1, 35.8, 28.8, 28.4, 22.9, 22.6, 22.3, 21.4,
20.5, 19.9; HRMS calcd for C20H32O3 (M + Cs+) 453.1404, found
453.1421. 40: 28.2 mg, 0.085 mmol, 22%; colorless oil; Rf )
0.10 (silica, 25% ether in hexanes); [R]25D +29.6 (c ) 0.7, C6H6);
IR (film) νmax 3446, 2934, 1725, 1456, 1375, 1230, 1157, 1030;
1H NMR (400 MHz, CDCl3) δ 5.35 (m, 1H), 3.65 (s, 3H), 3.48
(d, 1H, J ) 10.8 Hz), 3.35 (d, 1H, J ) 10.8 Hz), 2.18-2.14 (m,
1H), 2.07-1.88 (m, 6H), 1.61-1.40 (m, 5H), 1.38-1.18 (m, 4H),
1.13 (s, 3H), 1.12-0.95 (m, 1H), 0.90 (s, 3H), 0.83 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 177.7, 149.0, 114.1, 70.1, 56.1, 51.3,
44.6, 41.2, 40.3, 38.5, 37.6, 36.0, 30.4, 28.6, 26.9, 24.5, 22.3,
21.6, 20.0, 18.6; HRMS calcd for C20H32O3 (M + Cs+) 453.1404,
found 453.1428.
Ald eh yd e 45. To a stirred solution of diene 44 (0.51 g, 1.43
mmol) and methacrolein (0.30 g, 4.3 mmol) in dichloromethane
(5 mL) at -20 °C was added dropwise tin(IV) chloride (0.29
mL of 1 M solution in dichloromethane, 0.29 mmol). The
mixture was allowed to warm slowly to 0 °C and stirred at
that temperature for 18 h. The reaction was quenched with
aqueous sodium bicarbonate (15 mL) and the mixture ex-
tracted with ethyl ether (3 × 20 mL). The organic layers were
collected, dried (MgSO4), and concentrated, and the residue
was chromatographed (silica, 10-15% ether in hexanes) to
afford aldehyde 45 (0.51 g, 1.19 mmol, 84%). 45: colorless
liquid; Rf ) 0.5 (silica, 10% ethyl ether in hexanes); [R]25D +30.0
(c ) 1.13, benzene); IR (film) νmax 2930, 2871, 1724, 1458, 1226;
1H NMR (400 MHz, CDCl3) δ 9.5 (s, 1H), 7.4 (m, 2H), 7.25 (m,
3H), 5.58 (d, 1H, J ) 4.4 Hz), 3.64 (s, 3H), 2.3-2.0 (m, 4H),
1.9-1.1 (m, 11H), 1.16 (s, 3H), 1.05 (s, 3H), 0.91 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 203.6, 178.0, 153.7, 133.6, 133.5,
129.0, 128.9, 127.7, 117.1, 51.3, 51.2, 49.1, 47.7, 44.2, 41.6, 38.7,
Ben zoyl Der iva tives 41 a n d 42. A solution of alcohol 39
(or 40) (30 mg, 0.094 mmol) in dichloromethane (20 mL) was
treated with p-bromobenzoyl chloride (23 mg, 0.10 mmol) and
DMAP (2.3 mg, 0.019 mmol). The reaction mixture was stirred
at 25 °C for 2 h, and then the reaction was quenched with
sodium bicarbonate (5 mL) and water (20 mL). The reaction
mixture was poured into a separatory funnel, and the layers
were separated. The aqueous layer was extracted with dichlo-
romethane (3 × 30 mL), and the organic layers were combined,
dried with MgSO4, concentrated, and subjected to chromatog-
raphy (silica, 10-30% ether in hexanes) to afford benzoyl ester
41 (or 42). 41: 45 mg, 95%; colorless crystals (from ether/
hexanes); Rf ) 0.40 (silica, 25% ether in hexanes); [R]25D +68.6
(c ) 1.0, C6H6); 1H NMR (400 MHz, CDCl3) δ 7.90 (d, 2H, J )

Enantioselective Synthesis (-)-Acanthoic Acid
J . Org. Chem., Vol. 66, No. 26, 2001 8853
38.1, 31.2, 28.3, 27.8, 26.9, 21.7, 20.2, 19.2, 18.7; HRMS calcd
for C26H34O3S (M + H+) 427.2306, found 427.2320.
alkene 48 (16.8 mg, 0.05 mmol, the overall yield for the two-
step reaction is 86%); 48: colorless liquid; Rf ) 0.74 (silica, 5%
Alcoh ols 46 a n d 47. To a solution of aldehyde 45 (mixture
of diastereomers) (0.50 g, 1.17 mmol) in anhydrous ethanol (5
mL) was added portionwise sodium borohydride (62 mg, 1.63
mmol), and the mixture was stirred for 30 min. Aqueous
saturated sodium bicarbonate (10 mL) was then added, and
the mixture was extracted with ethyl ether (3 × 20 mL). The
organic layer was collected, dried (MgSO4), and concentrated.
The residue was redissolved in tetrahydrofuran (5 mL) and
treated with an excess of Raney Nickel under argon at 65 °C
for 10 min. The reaction mixture was filtered, and the filtrate
was dried (MgSO4) and concentrated; the residue was chro-
matographed (silica, 2-5% ethyl ether in hexane) to afford
alcohols 46 and 47 (0.34 g, 1.07 mmol, 4.2:1 ratio in favor of
46, 91% overall). 46: 0.27 g, 0.86 mmol, 74%; colorless liquid;
ethyl ether in hexanes); [R]25 -29.40 (c ) 0.50, benzene); IR
D
(film) νmax 2929.5, 2873.4, 1726.8, 1637.7, 1460.7, 1376.8,
1225.1, 1150.4, 997.8, 908.7; 1H NMR (500 MHz, CDCl3) δ 5.82
(dd, 1H, J ) 10.5, 17.5 Hz), 5.39 (m, 1H), 4.93 (d, 1H, J ) 17.5
Hz), 4.86 (d, 1H, J ) 10.5 Hz), 3.64 (s, 3H), 2.3-1.4 (m, 14 H),
1.18 (s, 3H), 0.96-1.08 (m, 2H), 0.95 (s, 3H), 0.89 (s, 3H); 13
C
NMR (125 MHz, CDCl3) δ 178.3, 150.4, 125.6, 116.6, 109.2,
51.2, 47.9, 44.3, 41.9, 41.8, 38.3, 37.4, 34.8, 30.2, 29.6, 28.6,
28.4, 27.8, 22.1, 20.4, 19.0; HRMS calcd for C21H32O2 (M + Cs+)
449.1455, found 449.1471.
Aca n th oic Acid (1). To a solution of alkene 48 (16.8 mg,
0.05 mmol) in N,N-dimethylformamide (2 mL) was added
lithium bromide (13.0 mg, 0.15 mmol), and the mixture was
refluxed at 160 °C for 3 h. The reaction mixture was then
cooled to 25 °C, diluted with H2O (5 mL), and extracted with
ethyl acetate (3 × 10 mL). The organic layer was collected,
dried (MgSO4), and concentrated, and the residue was chro-
matographed (silica, 15-20% ethyl ether in hexane) to afford
acanthoic acid (1) (14.9 mg, 0.05 mmol, 93%). 1: white solid;
Rf ) 0.4 (silica, 30% ethyl ether in hexanes); [R]25 -16.70 (c
D
) 1.0, C6H6); IR (film) νmax 3436.8, 2929.0, 2872.2, 1728.1,
1433.9, 1260.6, 1029.7, 801.6; 1H NMR (500 MHz, CDCl3) δ
5.37 (m, 1H), 3.62 (s, 3H), 3.30 (m, 2H), 2.28 (bs, 1H), 2.06-
2.20 (m, 2H), 1.20-2.00 (m, 13H), 1.16 (s, 3H), 0.99 (m, 1H),
0.86 (s, 3H), 0.84 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 178.2,
150.4, 116.4, 73.6, 51.2, 47.9, 44.2, 41.9, 38.8, 38.23, 38.20, 34.3,
33.9, 28.3, 28.2, 27.8, 22.1, 20.3, 20.1, 18.9; HRMS calcd for
Rf ) 0.20 (silica, 30% ethyl ether in hexanes); [R]25 -26.0 (c
D
) 0.33, benzene); IR (film) νmax 3080.6, 2928.9, 2857.6, 1693.6,
1638.2, 1464.7, 1413.8, 1376.4, 1263.1, 1179.3, 1095.9, 1027.5,
999.2, 909.2, 801.7; 1H NMR (500 MHz, CDCl3) δ 5.82 (dd, 1H,
J ) 10.5, 17.5 Hz), 5.40 (m, 1H), 4.92 (d, 1H, J ) 17.5 Hz),
4.86 (d, 1H, J ) 10.5 Hz), 2.30 (bs, 1H), 2.16-1.2 (m, 14H),
C
20H32O3 (M + Cs+) 453.1404, found 453.1419. 47: 63.6 mg,
0.2 mmol, 17%; colorless liquid; Rf ) 0.35 (silica, 30% ethyl
ether in hexanes); [R]25 -40.7 (c ) 1.0, C6H6); IR (film) νmax
D
3436.8, 2929.0, 2872.2, 1728.1, 1433.9, 1260.6, 1029.7, 801.6;
1H NMR (500 MHz, CDCl3) δ 5.39 (m, 1H), 3.65 (s, 3H), 3.30
(m, 2H), 2.26-2.20 (m, 3H), 1.20-2.00 (m, 14H), 1.17 (s, 3H),
0.88 (s, 3H), 0.86 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 178.2,
150.5, 116.4, 73.7, 51.2, 47.9, 44.2, 41.9, 38.9, 38.29, 38.26, 34.3,
33.9, 29.6, 28.4, 27.8, 22.1, 20.3, 20.1, 19.0; HRMS calcd for
1.24 (s, 3H), 1.00-1.10 (m, 2H), 0.99 (s, 3H), 0.95 (s, 3H); 13
C
NMR (125 MHz, CDCl3) δ 185.0, 150.3, 149.9, 116.7, 109.2,
47.9, 41.8, 41.7, 38.3, 38.2, 37.4, 34.8, 31.8, 28.6, 28.5, 27.7,
22.4, 22.1, 20.3, 18.9; HRMS calcd for C20H30O2 (M + Cs+)
435.1298, found 435.1302.
20H32O3 (M + Cs+) 453.1404, found 453.1400.
Alk en e 48. To a solution of alcohol 46 (20.0 mg, 0.062 mmol)
Ack n ow led gm en t. Financial support from the Bio-
STAR and Nereus Pharmaceuticals, Inc., is gratefully
acknowledged. We also thank the NSF (Shared Instru-
mentation Grant CHE-9709183) for partially supporting
this research and Dr. P. Gantzel (UCSD, X-ray Facili-
ties) for performing the reported crystallographic stud-
ies.
C
in dichloromethane (2 mL) was added Dess-Martin periodi-
nane (35 mg, 0.08 mmol) in portions, and the mixture was
stirred at 25 °C for 30 min. The reaction was quenched with
aqueous saturated sodium bicarbonate (5 mL) and the mixture
extracted with ethyl ether (3 × 10 mL). The organic layer was
collected, dried (MgSO4), and concentrated. The residue was
redissolved in tetrahydrofuran (0.5 mL) and added under
argon to a yellow suspension of (methyl) triphenyl-phospho-
nium bromide (60 mg, 0.17 mmol) and sodium bis(trimethyl-
silyl) amide (0.14 mL of 1.0 M in THF) in THF (1.5 mL). After
being stirred at 25 °C for 18 h, the mixture was diluted with
aqueous saturated sodium bicarbonate (5 mL) and extracted
with ethyl ether (3 × 10 mL). The organic layer was collected,
dried (MgSO4), and concentrated, and the residue was chro-
matographed (silica, 2-5% ethyl ether in hexane) to afford
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 10, 15-18, 20, 22-25, 28-30, 32-48,
and 1; X-ray data for compounds 23, 28, 29, 41, and 42;
Chem3D representations of ORTEP drawings of compounds
23, 41, and 42; and Chem3D representations of reaction
between compounds 35 and 36. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O0159035