Total synthesis and biological evaluation of the resveratrol-derived polyphenol natural products hopeanol and hopeahainol A

Article abstract of DOI:10.1021/ja102623j

The total synthesis and biological evaluation of the resveratrol-derived natural products hopeanol (2) and hopeahainol A (3) in their racemic and antipodal forms are described. The Friedel-Crafts-based synthetic strategy employed was developed from model studies that established the feasibility of constructing the C_7b quaternary center through an intramolecular Friedel-Crafts reaction and a Grob-type fragmentation to introduce an obligatory olefinic bond in the growing molecule. The final stages of the synthesis involved an epoxide substrate and an intramolecular Friedel-Crafts reaction, followed by oxidation to afford, upon global deprotection, hopeahainol A (3). The latter was converted under basic conditions to hopeanol (2), whereas the reverse transformation, previously suggested as a step in the biosynthesis of hopeahainol A (3), was not observed under a variety of conditions. Biological evaluation of the synthesized compounds confirmed the reported acetylcholinesterase inhibitory activity of hopeahainol A (3) but not the reported cytotoxic potencies of hopeanol (2).

Full text of DOI:10.1021/ja102623j

Published on Web 05/12/2010
Total Synthesis and Biological Evaluation of the
Resveratrol-Derived Polyphenol Natural Products Hopeanol
and Hopeahainol A
K. C. Nicolaou,* Qiang Kang, T. Robert Wu, Chek Shik Lim, and David Y.-K. Chen*
Chemical Synthesis Laboratory at Biopolis, Institute of Chemical and Engineering Sciences
(ICES), Agency for Science, Technology and Research (ASTAR), 11 Biopolis Way,
The Helios Block, 03-08, Singapore 138667
Received March 29, 2010; E-mail: kcn@scripps.edu; david_chen@ices.a-star.edu.sg
Abstract: The total synthesis and biological evaluation of the resveratrol-derived natural products hopeanol
(2) and hopeahainol A (3) in their racemic and antipodal forms are described. The Friedel-Crafts-based
synthetic strategy employed was developed from model studies that established the feasibility of constructing
the C7b quaternary center through an intramolecular Friedel-Crafts reaction and a Grob-type fragmentation
to introduce an obligatory olefinic bond in the growing molecule. The final stages of the synthesis involved
an epoxide substrate and an intramolecular Friedel-Crafts reaction, followed by oxidation to afford, upon
global deprotection, hopeahainol A (3). The latter was converted under basic conditions to hopeanol (2),
whereas the reverse transformation, previously suggested as a step in the biosynthesis of hopeahainol A
(3), was not observed under a variety of conditions. Biological evaluation of the synthesized compounds
confirmed the reported acetylcholinesterase inhibitory activity of hopeahainol A (3) but not the reported
cytotoxic potencies of hopeanol (2).
Introduction
The polyphenolic natural products represent a large and
growing class of structurally diverse compounds exhibiting a
wide range of biological activities.1 Despite of the large
membership of this resveratrol-derived collection of secondary
metabolites, most of the attention has focused primarily on the
parent compound, resveratrol (1, Figure 1), for which a variety
of potentially useful properties have been demonstrated. These
include anti-inflammatory,2 antiaging,3 antitumor,4 cardiovas-
cular,5 and neuroprotective6 properties in both in Vitro and in
ViVo assays. Taken together with its substantial concentration
in red wine (∼3-5 mg in a 750 mL bottle), this biological
profile gave support for the so-called “French Paradox”, the idea
(1) For representative reviews on the chemical and biological studies of
natural polyphenols, see: (a) Yang, C. S.; Lambert, J. D.; Sang, S.
Arch. Toxicol. 2009, 83, 11–21. (b) Bonfili, L.; Cecarini, V.; Amici,
M.; Cuccioloni, M.; Angeletti, M.; Keller, J. N.; Eleuteri, A. M. FEBS
J. 2008, 275, 5512–5526. (c) Habauzit, V.; Horcajada, M.-N. Phy-
tochem. ReV. 2008, 7, 313–344. (d) Lafay, S.; Gil-Izquierdo, A.
Phytochem. ReV. 2008, 7, 301–311. (e) Halliwell, B. Arch. Biochem.
Biophys. 2008, 476, 107–112. (f) Korkina, L. G.; Pastore, S.; De Luca,
C.; Kostyuk, V. A. Curr. Drug Metab. 2008, 9, 710–729, and
references cited within.
(2) (a) Udenigwe, C. C.; Ramprasath, V. R.; Aluko, R. E.; Jones, P. J.
Nutr. ReV. 2008, 66, 445–454. (b) Shapiro, H.; Singer, P.; Halpern,
Z.; Bruck, R. Gut 2007, 56, 426–435. (c) Lastra, D.; Catalina, A.;
Villegas, I. Mol. Nutr. Food Res. 2005, 49, 405–430.
Figure 1. Molecular structures of resveratrol (1), (+)-hopeanol [(+)-2],
and hopeahainol A [(+)-3].
(3) (a) Bertelli, A. A. A.; Das, D. K. J. CardioVasc. Pharmacol. 2009,
54, 468–476. (b) Das, D. K.; Maulik, N. Mol. InterV. 2006, 6, 36–47.
(c) Olas, B.; Wachowicz, B. Platelets 2005, 16, 251–260. (d)
Bradamante, S.; Barenghi, L.; Villa, A. CardioVasc. Drug ReV. 2004,
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405–430. (c) Brisdelli, F.; D’Andrea, G.; Bozzi, A. Curr. Drug Metab.
2009, 10, 530–546.
that a balanced consumption of red wine may neutralize the
harmful nutritional effects of foods high in fat and cholesterol.7
The increasing interest in the resveratrol-derived polyphenol
natural products is appropriately reflected in the recent spate of
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7540 J. AM. CHEM. SOC. 2010, 132, 7540–7548
10.1021/ja102623j  2010 American Chemical Society

Resveratrol-Derived Hopeanol and Hopeahainol A
A R T I C L E S
reports, notably from the Snyder group,8 describing the total
syntheses of natural products belonging to this class.
In 2006, Tan and co-workers disclosed the structural elucida-
tion and cytotoxic properties (IC50 ) 0.52-19.36 µM) against
a panel of selected cancer cell lines (KB, AGS, Hela, BEL-
7402, SW1116, and BGC-803) of hopeanol (2, Figure 1), a
polyphenol secondary metabolite isolated from the bark of
Hopea exalata.9 A subsequent investigation of H. hainanensis
led to, in addition to hopeanol (2), the isolation of the structurally
related hopeahainol A (3, Figure 1).10 The latter exhibited
inhibitory activity against acetylcholinesterase (IC50 ) 4.33 µM),
an enzyme implicated and exploited for the treatment of
Alzheimer’s disease.10 A radical-based biosynthetic hypothesis
has been put forward by the isolation chemists for the biosyn-
thesis of hopeanol (2) and hopeahainol A (3) from resveratrol
(1) that postulated the former (i.e., 2) as the precursor of the
latter (i.e., 3).10 In 2009, we reported11 the first total synthesis
of hopeanol (2) and hopeahainol A (3) in their racemic forms
through a short and efficient route involving a series of cascade
reactions12 and novel skeletal rearrangements. In this article,
we provide the full account of our studies in this area, including
the enantioselective total synthesis of both enantiomeric forms
of 2 and 3, and biological evaluation of selected synthesized
compounds.
Figure 2. Final synthetic strategy toward (+)-hopeahainol A [(+)-3], and
(+)-hopeanol [(+)-2] shown in retrosynthetic format. TBS ) tert-
butyldimethyl silyl.
in retrosynthetic format, was derived from a number of model
studies which will be described below. Thus, the key reactions
for the assembly of the hopeahainol A structure were a
lactonization, a Grignard reaction (C1b-C7b bond), an intramo-
lecular Friedel-Crafts-type13 reaction (C7b-C14a bond), and an
intramolecular epoxide opening (C7a-C10b bond, C8a oxygen)
(see Figure 2, structure 3). Its proposed conversion to hopeanol
(3 f 2, Figure 2) runs counter to the proposed biosynthetic
hypothesis10 which postulated the reverse transformation (2 f
3, Figure 2), although at the outset both interconversions were
considered plausible. Central to the successful strategy was the
stepwise construction of the C7b quaternary stereocenter, residing
at the heart of the structure, starting from ketoester 4 (Figure
2), whose origin from the corresponding hydroxyl and carboxy-
late components was obvious.
Results and Discussion
Below we lay out the details of these investigations as they
evolved, beginning from the initial considerations of a synthetic
strategy toward hopeanol (2) and hopeahainol A (3) and ending
with the biological evaluation of selected synthesized compounds.
Retrosynthetic Analysis. Our final synthetic strategy toward
hopeanol (2) and hopeahainol A (3), as presented in Figure 2
(5) (a) Bastianetto, S.; Dumont, Y.; Han, Y.; Quirion, R. CNS Neurosci.
Ther. 2009, 15, 76–83. (b) Raval, A. P.; Lin, H. W.; Dave, K. R.;
DeFazio, R. A.; Della Morte, D.; Kim, E. J.; Perez-Pinzon, M. A.
Curr. Med. Chem. 2008, 15, 1545–1551. (c) Spasic, M. R.; Callaerts,
P.; Norga, K. K. Neuroscientist 2009, 15, 309–316. (d) Sun, A. Y.;
Wang, Q.; Simonyi, A.; Sun, G. Y. Neuromol. Med. 2008, 10, 259–
274.
Model Studies for the Construction of the Quaternary
Center (C7b) of Hopeahainol A and Hopeanol. Our designed
model studies were intended to explore methods for building
the quaternary center of hopeahainol A (3) and hopeanol (2)
with appropriate appendages. In our first foray (see Scheme 1a),
we targeted the simple triaryl methyl ester 12 through an
intermolecular Friedel-Crafts-type reaction involving tertiary
alcohol 9 as the main substrate and phenol (11) as the external
nucleophile. Thus, sequential addition of Grignard reagents 6
and 8 to dimethyl oxalate (5) furnished tertiary alcohol methyl
ester 9, through ketoester 7, in 66% overall yield (based on 5).
Pleasantly, exposure of a solution of tertiary alcohol 9 and
phenol (11) in CH2Cl2 to an excess p-TsOH·H2O (23 f 40
°C) led to the formation of the desired product 12 in excellent
yield (97%), presumably through the intermediacy of carboca-
tion 10 as shown in Scheme 1a.
(6) (a) Delmas, D.; Lancon, A.; Colin, D.; Jannin, B.; Latruffe, N. Curr.
Drug Targets 2006, 7, 423–442. (b) Kraft, T. E.; Parisotto, D.;
Schempp, C.; Efferth, T. Crit. ReV. Food Sci. Nutr. 2009, 49, 782–
799. (c) Shakibaei, M.; Harikumar, K. B.; Aggarwal, B. B. Mol. Nutr.
Food Res. 2009, 53, 115–128. (d) Chillemi, R.; Sciuto, S.; Spatafora,
C.; Tringali, C. Nat. Prod. Commun. 2007, 2, 499–513. (e) Garg, A. K.;
Buchholz, T. A.; Aggarwal, B. B. Antioxid. Redox Signaling 2005, 7,
1630–1647. (f) Aggarwal, B. B.; Bhardwaj, A.; Aggarwal, R. S.;
Seeram, N. P.; Shishodia, S.; Takada, Y. Anticancer Res. 2004, 24,
2783–2840.
(7) For reviews, see: (a) Saiko, P.; Szakmary, A.; Jaeger, W.; Szekeres,
T. ReV. Mutat. Res. 2007, 658, 68–94. (b) Walle, T.; Hsieh, F.;
DeLegge, M. H.; Oatis, J. E.; Walle, U. K. Drug Metab. Dispos. 2004,
32, 1377–1382. (c) Athar, M.; Back, J. H.; Tang, X.; Kim, K. H.;
Kopelovich, L.; Bickers, D. R.; Kim, A. L. Toxicol. Appl. Pharmacol.
2007, 224, 274–278. (d) Soleas, G. J.; Diamandis, E. P.; Goldberg,
D. M. Clin. Biochem. 1997, 30, 91–113. (e) Kopp, P. Eur. J.
Endocrinol. 1998, 138, 619–620.
(8) (a) Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y.; Zografos,
A. L. J. Am. Chem. Soc. 2009, 131, 1753–1765. (b) Snyder, S. A.;
Zografos, L.; Lin, Y. Angew. Chem., Int. Ed. 2007, 46, 8186–8191.
(9) Ge, H. M.; Xu, C.; Wang, X. T.; Huang, B.; Tan, R. X. Eur. J. Org.
Chem. 2006, 5551–5554.
Encouraged by this initial result, we proceeded to test the
feasibility of synthesizing the more relevant and advanced model
system 18 as shown in Scheme 1b. In this instance, the desired
(10) Ge, H. M.; Zhu, C. H.; Shi, D. H.; Zhang, L. D.; Xie, D. Q.; Yang,
J.; Ng, S. W.; Tan, R. X. Chem.sEur. J. 2008, 14, 376–381.
(11) Nicolaou, K. C.; Wu, R. T.; Kang, Q.; Chen, D. Y.-K. Angew. Chem.,
Int. Ed. 2009, 48, 3340–3343.
(13) For reviews, see: (a) Olah, G. A. Friedel-Crafts and Related Reactions;
Wiley: New York, 1963. (b) Olah, G. A. Friedel-Crafts Chemistry;
Wiley: New York, 1973. (c) Olah, G. A.; Krishnamurti, R.; Prakash,
G. K. S. ComprehensiVe Organic Synthesis; Pergamon: Oxford, 1991;
Vol. 3, pp 293.
(14) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–
2012.
(12) (a) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun.
2003, 5, 551–564. (b) Tietze, L. F.; Brasche, G.; Gericke, K. M.
Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim,
2006. (c) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew.
Chem., Int. Ed. 2006, 45, 7134–7186.
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A R T I C L E S
Nicolaou et al.
Scheme 1. Synthesis of (a) Model Methyl Ester 12 and (b) Model
γ-Lactone 18 through Intermolecular Friedel-Crafts Reactionsa
Scheme 2. Attempted Synthesis of (a) γ-Lactone 22 and (b)
Methyl Ester 26 through Intermolecular Friedel-Crafts Reactionsa
a Reagents and conditions: (a) dimethyl oxalate (5) (2.0 equiv), 3,5-
dimethoxyphenylmagnesium bromide (6, prepared from 1-bromo-3,5-
dimethoxybenzene and magnesium turnings) (1.0 M in THF, 1.0 equiv),
THF, -78 °C, 0.5 h, 80%; (b) 2,4-dimethoxyphenylmagnesium bromide
(8, prepared from 1-bromo-2,4-dimethoxybenzene and magnesium turnings)
(0.23 M in THF, 1.9 equiv), THF, 0 °C, 0.5 h, 83%; (c) phenol (11) (3.0
equiv), p-TsOH·H2O (3.0 equiv), CH2Cl2, 23 f 40 °C, 4 h, 97%; (d)
4-methoxyphenylmagnesium bromide (13, prepared from 1-bromo-4-
methoxybenzene and magnesium turnings) (0.4 M in THF, 2.0 equiv), THF,
0 °C, 0.5 h, 81%; (e) resorcinol (16, 3.0 equiv), p-TsOH·H2O (3.0 equiv),
toluene, 23 f 75 °C, 20 min, 90%. p-TsOH ) para-toluenesulfonic acid.
a Reagents and conditions: (a) 19 (3.0 equiv), p-TsOH ·H2O (3.0 equiv),
CH2Cl2, 23 f 50 °C, 4 h; (b) 23 or 24 (3.0 equiv), p-TsOH·H2O (3.0
equiv), CH2Cl2, 23 f 50 °C, 2 h, 27:80% (from 23).
was anticipated that using diphenol 19 as the nucleophilic partner
in the Friedel-Crafts reaction employing tertiary alcohol methyl
ester 14 would enable us to obtain a product (20 f 21 f 22,
Scheme 2a) containing five of the six rings of hopeahainol A
and equipped with an olefinic bond that could serve as a handle
to forge the final ring of the molecule through formation of the
C7a-C10b bond. In the event, however, and under the previously
employed conditions, neither the lactone 22 nor methyl ester
21 were observed.
In a second attempt (see Scheme 2b) to construct such an
advanced intermediate (i.e., 26), we employed protected nu-
cleophilic partner 23, but unfortunately, again to no avail.
Instead, regioisomeric product 27 was formed in 80% yield
under the previously developed conditions for the Friedel-Crafts
reaction. A last-ditch attempt to avoid the latter outcome by
employing bromide 24, where the bromine residue was expected
tertiary alcohol methyl ester substrate 14 was prepared from
methyl glyoxalate derivative 7 by addition of Grignard reagent
13 (81% yield). The latter underwent a smooth Friedel-Crafts-
type reaction with resorcinol (16) under conditions similar to
those in Scheme 1a (p-TsOH·H2O, 23 f 75 °C) to afford the
expected tetracyclic model system 18 (90% yield), presumably
through transient intermediate carbocation 15 and diphenolic
methyl ester 17, the latter apparently undergoing spontaneous
lactonization under the reaction conditions employed.
The successful construction of model system 18 (containing
four of the six ring systems of hopeahainol A) gave impetus to
our next logical step, which was to attempt to apply the
developed technology to assemble the entire carbon backbone
of hopeahainol A (3). Scheme 2 summarizes these attempts. It
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Resveratrol-Derived Hopeanol and Hopeahainol A
A R T I C L E S
Scheme 3. Synthesis of Lactone 33 through Intramolecular
Friedel-Crafts Reactiona
Scheme 4. Synthesis of Methyl Ester 42 through Intramolecular
Friedel-Crafts Reactiona
a Reagents and conditions: (a) THF/NaOH (2.0 N aq) (1:1), 23 °C, 0.5 h,
98%; (b) 28 (1.5 equiv), 29 (1.0 equiv), DCC (3.0 equiv), 4-DMAP (0.3
equiv), CH2Cl2, 23 °C, 12 h, 85%; (c) 4-methoxyphenylmagnesium bromide
(13, prepared from 1-bromo-4-methoxybenzene and magnesium turnings)
(0.1 M in THF, 1.8 equiv), THF, -10 °C, 5 min, 81%; (d) BF3 ·Et2O (3.0
equiv), CH2Cl2, 0 °C, 2 h, 86%. DCC ) dicyclohexylcarbodiimide, 4-DMAP
) 4-dimethylaminopyridine.
to block the undesired pathway, also failed, leading to a complex
mixture of unwanted materials.
Having failed to apply the developed intermolecular Friedel-
Crafts-based sequence to an advanced intermediate toward
hopeahainol A, and recognizing the factors responsible for these
failures, we decided to explore the intramolecular version of
this venerable reaction in order to accomplish this task. We
reasoned that by tethering the two partners and postponing the
introduction of the desired olefinic bond until after the
Friedel-Crafts reaction, we could perhaps avoid the pitfalls
encountered in the intermolecular version of the process, namely
the wrong regioselectivity (by virtue of enforced proximity) and
the interference from the olefinic bond (by virtue of its absence).
To test the former hypothesis (regarding regioselection), we
designed the simple model study directed toward the construc-
tion of model system 33 as summarized in Scheme 3. Thus,
saponification (NaOH) of methyl glyoxalate 7, followed by
esterification of the resulting carboxylic acid (28) with benzylic
alcohol 29 (DCC), led to R-ketoester 30 (83% overall yield).
Reaction of the latter with p-methoxyphenyl Grignard reagent
13 furnished tertiary alcohol 31 in 81% yield. Exposure of the
latter to BF3 ·Et2O in CH2Cl2 at 0 °C resulted in the formation
of the desired tetracyclic product 33 in 86% yield, presumably
through intermediate 32.
The initial success with the intramolecular Friedel-Crafts
approach to model system 33 set the stage for the next advance.
Thus, in an effort to include in our growing molecule all the
carbon atoms needed for the synthesis of hopeahainol A, we
undertook the study shown in Scheme 4. Treatment of aldehyde
34 with the lithioderivative obtained from aryl bromide 35 and
n-BuLi, followed by esterification of the resulting alcohol (36)
with carboxylic acid 28 (DCC), furnished R-ketoester 37 in 71%
overall yield. Addition of Grignard reagent 13 to the latter gave
a Reagents and conditions: (a) 34 (1.1 equiv), 35 (1.0 equiv), n-BuLi
(1.6 M in THF, 1.1 equiv), THF, -78 °C, 0.5 h, 75%; (b) 28 (1.5 equiv),
36 (1.0 equiv), DCC (2.0 equiv), 4-DMAP (0.1 equiv), CH2Cl2, 0 f 23
°C, 2 h, 95%; (c) 4-methoxyphenylmagnesium bromide (13, prepared from
1-bromo-4-methoxybenzene and magnesium turnings) (0.1 M in THF, 1.9
equiv), THF, 0 °C, 0.5 h, 84% (∼2:1 mixture of diastereoisomers); (d)
BF3 ·Et2O (2.0 equiv), CH2Cl2, 0 °C, 1 h, 74% (∼2:1 mixture of
diastereoisomers); (e) KOt-Bu (5.7 equiv), THF, 0 f 23 °C, 2 h; (f)
TMSCHN2 (2.0 M in Et2O, 5.7 equiv), MeOH/THF (1:1), 23 °C, 10 min,
95% for the two steps from 40 (∼2:1 mixture of Z/E stereoisomers).
tertiary alcohol 38 as a mixture of diastereoisomers (∼2:1 dr)
in 84% yield. The intended cyclization proceeded under the
established Lewis acid conditions (BF3 ·Et2O, CH2Cl2, 0 °C),
affording the desired pentacyclic system 40 (∼2:1 dr) through
the presumed intermediacy of oxocation 39 (74% yield). The
unmasking of the desired olefinic bond hidden behind the lactone
moiety was achieved by treatment of the latter compound with
KOt-Bu to furnish, through a fragmentation reaction, carboxylic
acid 41, whose methylation (TMSCHN2) led to olefinic methyl
ester 42 (∼2:1 ratio of Z/E isomers) in 95% yield. However,
attempts to complete the ring framework of hopeahainol A
(formation of C7a-C10b bond) through a second Friedel-Crafts
reaction under a variety of conditions (e.g., Lewis or protic
acids) failed, leading instead to decomposition and/or recovery
of starting material. Under these circumstances, a new plan had
to be devised.
Total Synthesis of (-)-Hopeahainol A [(-)-(3)], (-)-Hopea-
nol [(-)-(2)], (+)-Hopeahainol A [(+)-(3)], and (+)-Hopeanol
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A R T I C L E S
Nicolaou et al.
Scheme 5. Synthesis of Diastereomeric Lactones 52 and 53a
[(+)-(2)]. While the synthesis of advanced intermediate 42
(Scheme 4) was a significant development, the difficulties
encountered in its attempted elaboration to the target molecule
called for further deliberation. We hypothesized that by locking
the conformation of the ultimate precursor of hopeahainol A
through formation of the γ-lactone moiety present in the natural
product we might facilitate the casting of the last ring. We also
considered the employment of an epoxide moiety in place of
the olefinic bond as the enabling handle to effect the desired
carbon-carbon bond formation (C7a-C10b) upon suitable activa-
tion. It was with these inspiring rationales that we proceeded
to the next phase of the campaign, which required first the
construction of the diphenolic γ-lactone 52 and/or 53 through
hydroxyester 49 (see Scheme 5). The synthesis of the latter
(∼1:1 dr) proceeded along the lines delineated above for 40
(Scheme 4) with an appropriate modification as shown in
Scheme 5. Thus, addition of the lithioderivative obtained from
bis-TBS aryl bromide 43 to aldehyde 34 furnished, after PCC
oxidation of the resulting alcohol (44, 75% yield), ketone 45
(99% yield). (+)-CBS reduction [(S)-(+)-2-methyl-CBS-ox-
azaborolidine, catecholborane] of the latter led to benzylic
alcohol 46 in 85% yield and 96% ee (chiral HPLC analysis).
Coupling of benzylic alcohol 46 with R-ketoacid 28 (DCC,
4-DMAP) gave R-ketoester 4 (95% yield), and reaction of the
latter with Grignard reagent 13 led to diphenolic hydroxyester
49 after desilylation (TBAF, 79% overall yield, ∼1:1 dr) of
the resulting bis-TBS product (48). Exposure of substrate 49
(∼1:1 dr) to BF3 ·Et2O in CH2Cl2 at ambient temperature
furnished diastereomeric products 52 and 53 (86% yield,
∼1:1.3 dr), presumably through diastereomeric transition states
50 and 51, respectively. Since the ratio of the two products
(diastereomeric at C7b) would be reflected in the enantiomeric
ratio of the expected downstream olefinic γ-lactones (i.e.,
structures ent-57 and 57, Scheme 6), we sought to optimize the
diastereoselectivity of this intramolecular Friedel-Crafts reac-
tion. Screening of a variety of Lewis and protic acids was
revealing. Thus, and as shown in Table 1, a number of
promoters, such as p-TsOH ·H2O, TFA, Sc(OTf)3, and Yb(OTf)3,
were found to be effective (entries 7, 8, 10, and 11), with
p-TsOH · H2O resulting in the highest diastereoselectivity
(52:53 ∼1:2.4 dr) and the lanthanide Lewis acids in the highest
yields (91% and 88% yield, respectively, 52:53 ∼1:1.5 dr).
Apparently, from the two competing transition states (50 and
51, Scheme 5), the one leading to 53 (i.e., 51) is energetically
somewhat more stable than the one leading to 52 (i.e., 50).
Chromatographic separation of the two diastereomeric products
allowed crystallization of the major compound (53), whose
X-ray crystallographic analysis provided unambiguous confir-
mation of its structure, including its absolute configuration (see
ORTEP, Figure 3),15 and, thereby, that of its minor diastere-
oisomer (52).
a Reagents and conditions: (a) 43 (1.0 equiv), 34 (1.16 equiv), n-BuLi
(1.6 M in THF, 1.1 equiv), THF, -78 °C, 0.5 h, 75%; (b) PCC (3.0 equiv),
CH2Cl2, 0 f 23 °C, 12 h, 99%; (c) (S)-(+)-2-methyl-CBS-oxazaborolidine
(0.2 equiv), catecholborane (1.0 equiv), toluene, 0 °C, 0.5 h, 85% (96% ee
as determined by chiral HPLC); (d) 28 (1.5 equiv), 46 (1.0 equiv), DCC
(2.3 equiv), 4-DMAP (0.3 equiv), CH2Cl2, 23 °C, 12 h, 95%; (e)
4-methoxyphenylmagnesium bromide (13, prepared from 1-bromo-4-
methoxybenzene and magnesium turnings) (0.26 M in THF, 1.3 equiv),
THF, -10 °C, 0.5 h; (f) TBAF (1.0 M in THF, 2.0 equiv), THF, 0 °C,
0.5 h, 79% for the two steps from 4 (∼1:1 mixture of diastereoisomers);
(g) BF3 ·Et2O (3.0 equiv), CH2Cl2, 23 °C, 4 h, 86% (52:53 ∼1:1.3 dr) (see
also Table 1). PCC ) pyridinium chlorochromate, TBAF ) tetra-n-
butylammonium fluoride.
With intermediates 52 and 53 structurally secured, their
independent advancement to the corresponding olefinic γ-lac-
tones was undertaken and successfully completed as outlined
in Scheme 6. Initial attempts to apply the same conditions as
previously employed for the conversion of 40 to 41 (KOt-Bu,
see Scheme 4) led to translactonization, as evidenced by the
isolation of the dihydroxy γ-lactones 54 and 55, rather than
formation of the expected olefinic product. Upon considerable
experimentation, this problem was circumvented by the use of
KOt-Bu in the presence of 18-crown-6 in THF, conditions that
completely suppressed the formation of the undesired translac-
tonization products and led to the generation of the desired
(15) CCDC-769640 contains the supplementary crystallographic data for
compound 53. This data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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7544 J. AM. CHEM. SOC. VOL. 132, NO. 21, 2010

Resveratrol-Derived Hopeanol and Hopeahainol A
A R T I C L E S
Scheme 6. Synthesis of Lactones ent-58 and 58a
Figure 3. X-ray-derived ORTEP of lactone 53 with thermal ellipsoids
shown at the 50% probability level.15
olefinic γ-lactones ent-57 (72% yield, from 52) and 57 (78%
yield from 53) after quenching with aq NH4Cl. These reactions
presumably proceed through trianion intermediates ent-56 and
56, respectively. Compounds ent-57 and 57 were converted to
their acetate derivatives (ent-58 and 58, respectively) under
standard conditions (Ac2O, 4-DMAP, py) in quantitative yields.
At this juncture we chose the major enantiomer 58 (Scheme
6) for further elaboration due to its abundance, even though it
was destined to yield (-)-hopeahainol A [(-)-3], rather than
the natural enantiomeric form of (+)-hopeahainol A [(+)-3].
We, of course, planned to return to the minor enantiomer ent-
58 for its elaboration to the natural product once the final stages
of the route had been worked out, or even backtrack to the CBS
reduction step to obtain the opposite enantiomer of benzylic
alcohol 46 (i.e., ent-46, see Scheme 5), which would lead us to
the correct diastereoisomer ent-58 as the major product, thereby
resulting in an enantioselective synthesis of hopeahainol A (3).
According to our latest strategy for the total synthesis of
hopeahainol A (3), the next objective was to forge the seven-
membered carbocycle, this time relying on the premise that the
conformationally more restricted substrate 58 (by virtue of the
presence of the γ-lactone moiety, Scheme 7) would prove
beneficial. Furthermore, given the functionalities present in the
natural product, we focused our attention on the C7a-C8a
epoxide, since its anticipated intramolecular Friedel-Crafts-
type opening (from C10b) would form the ideal structural motifs
around the C7a-C8a bond for further elaboration. Thus, as shown
in Scheme 7, epoxidation of olefinic lactone 58 with m-CPBA
furnished epoxide 59 (∼1:1 dr). The Lewis acid-induced ring
closure of epoxide 59 was next investigated, and the results are
listed in Table 2. Of the conditions employed, those involving
SnCl4 in CH2Cl2 at -60 f -30 °C proved the highest yielding
(62%), and led to the two diastereomeric cyclized products 63
(major) and 62 (minor) in ∼2:1 ratio (entry 1). Similar results
were obtained under the promoting influence of BF3 ·Et2O (entry
2, 58% yield) and ZnCl2 (entry 3, 53% yield). TiCl4 (entry 4,
37% yield), CeCl3 (entry 5, 34% yield), and Me2AlCl (entry 6,
30% yield) gave lower yields of the now exclusively formed
diastereoisomer 63. The structure of the major isomer (63, mp
) 230-231 °C from CH2Cl2/hexane) was determined through
X-ray crystallographic analysis (see ORTEP, Figure 4).16 It was
interesting to note that the diastereoisomeric ratio (dr) of the
starting epoxides 59 (∼1:1) did not faithfully translate into the
dr of the products 63 and 62 (∼2:1 or higher) in these
experiments. To rationalize these observations, we propose that
a Reagents and conditions: (a) 52 or 53, KOt-Bu (10.0 equiv), 18-crown-6
(11 equiv), THF, 0 f 23 °C, 20 h, ent-57:72% or 57:78%; (b) Ac2O (1.4
equiv), 4-DMAP (0.1 equiv), pyridine, 0 f 23 °C, 1 h, 100%. Ac ) acetyl.
Table 1. Intramolecular Friedel-Crafts Reaction of Tertiary
Alcohol 49 Leading to Pentacyclic Lactones 52 and 53a
entry
promoter
conversion (%)b
time (h)
yield (%)c
52:53 (ratio)
1
2
3
4
5
6
7
8
BF3 ·Et2O
TiCl4
Ti(Oi-Pr)4
AlCl3
Me2AlCl
ZnCl2
p-TsOH·H2O
TFA
CeCl3
Sc(OTf)3
Yb(OTf)3
100
100
100
100
100
0
100
100
0
4
2
2
4
4
12
12
12
12
12
12
86
0d
1:1.3
-
0d
-
tracee
0d
1:1
-
-
1:2.4
1:1.2
-
1:1.5
1:1.5
0f
65
85
0f
91
88
9
10
11
100
100
a Reactions were carried out under the following conditions: 49 (0.1
mmol), promoter (3.0 equiv), CH2Cl2 (3.0 mL), 23 °C. b Based on crude
1H NMR spectroscopic analysis. c Yields refer to chromatographically
and spectroscopically homogeneous materials. d Decomposition was
observed. e Based on crude 1H NMR spectroscopic analysis. f Starting
material recovered.
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J. AM. CHEM. SOC. VOL. 132, NO. 21, 2010 7545

A R T I C L E S
Nicolaou et al.
Scheme 7. Synthesis of Hexacyclic Hydroxy γ-Lactones 62 and
undergo undesirable reaction pathways. Since both C7a and C8a
carbons in the target molecule (hopeahainol A) are sp2-
hydridized (p-quinonemethide and carbonyl), it seemed logical
that neither the epoxidation nor the cyclization diastereoselec-
tivity outcome in this sequence is of stereochemical conse-
quence. However, as we shall see later, stereoselectivity at this
stage has important downstream consequences which arise from
drastically different reactivities of the two diastereoisomeric
alcohols (62 and 63).
63a
The final stages of the total synthesis of (-)-hopeahainol A
[(-)-3)] and (-)-hopeanol [(-)-2)], as summarized in Scheme
8, proved interesting despite the presumption that all that was
required to convert the mixture of hydroxy lactones 62/63 to
(-)-hopeahainol A [(-)-3)] was oxidation and deprotection. To
this end, oxidation conditions were sought first. Table 3
summarizes the results of this investigation that led to the
adoption of IBX as the preferred oxidant (entry 1). Indeed,
treatment of 62/63 (∼1:2 dr) with IBX in DMSO at ambient
temperature for 24 h led to ketone p-quinonemethide 66 (66%
yield) and ketone 64 (26% yield), the former apparently formed
from ketone 65 whose oxidation proved facile under the reaction
conditions. In contrast, its C7a diastereoisomeric ketone 64
proved intransigent to oxidation, not only under these conditions
but also under a variety of other protocols including those listed
in Table 3. These conclusions were based on oxidation experi-
ments (IBX) using pure diastereoisomers 62 and 63 and their
partially oxidized counterparts 64 and 65. Attempts to epimerize
ketone 64 to its oxidizable epimer 65 under a variety of
conditions (e.g., LDA, KOt-Bu, DBU, KHMDS, NaOMe) failed.
From the practical point of view, the desired ketone p-
quinonemethide 66 was obtained through the IBX oxidation of
the mixture 62/63, followed by chromatographic separation,
which removed the intransigent ketone 64. Removal of the
acetate group from 66 was then achieved under mild conditions
(NaHCO3, MeOH) to afford phenol 67 in quantitative yield.
Before moving forward with the synthesis, the latter intermediate
was methylated (K2CO3, MeI, 90% yield) to afford ent-
tetramethyl hopeahainol A (68), the 1H NMR spectrum (acetone-
d6, -30 °C) of which exhibited identical signals to those
reported for permethylated natural hopeahainol A.10 Having
confirmed, through this exercise, the skeletal identity of
intermediate 67 to that of hopeahainol A (3), all that remained
for us to accomplish before arriving at the latter was its complete
demethylation. This was conveniently performed under the
influence of BBr3 in CH2Cl2 at -78 f -20 °C, conditions that
led initially to a labile intermediate, presumed to be 69 (likely
X ) Br or OH), whose exposure to SiO2 led to its collapse to
(-)-hopeahainol A [(-)-3)] in 84% overall yield. The projected
conversion of (-)-hopeahainol A [(-)-3)] to (-)-hopeanol [(-)-
2)] was realized by careful treatment of the former with one
equivalent of NaOMe in MeOH, presumably through the
intermediacy of methyl ester 70 resulting from methanolysis
of the γ-lactone moiety. Indeed, it is presumed that the latter
event is essential for the final carbon-carbon bond (C7a-C1b)-
forming reaction to occur, since the lactone ring imposes
prohibitive conformational constraints on the hopeahainol A
structure (distance between C7a and C1b too long, manual
molecular modeling) for it to undergo the desired skeletal
a Reagents and conditions: (a) m-CPBA (77 wt %/wt, 4.0 equiv),
NaHCO3 (6.0 equiv), CH2Cl2, 0 °C, 0.5 h, (∼1:1 mixture of diastereoiso-
mers); (b) see Table 2.
Table 2. Intramolecular Friedel-Crafts Reaction of Epoxide 59
(∼1:1 dr) Leading to Hexacyclic Hydroxy γ-Lactones 62 and 63a
entry
promoter, conditions
yield (%)b
63:62 (ratio)
1
2
3
4
5
6
SnCl4, -60 f -30 °C, 1 h
BF3 ·Et2O, -78 f -50 °C, 1 h
ZnCl2, 0 f 23 °C, 8 h
62
58
53
37
34
30
∼2:1
∼2:1
∼2:1
TiCl4, -78 f -50 °C, 1 h
CeCl3, 0 f 23 °C, 12 h
63 only
63 only
63 only
Me2AlCl, 0 f 23 °C, 3 h
a Reactions were carried out using 1.5 equiv of promoter in CH2Cl2.
b Yields refer to chromatographically and spectroscopically homo-
geneous materials for the two steps from 58.
Figure 4. X-ray derived ORTEP of hexacyclic hydroxy γ-lactone 63 with
thermal ellipsoids shown at the 50% probability level.16
(16) CCDC-770505 contains the supplementary crystallographic data for
compound 63. This data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
the diastereoisomeric transition states 61 and 60 have different
reactivity profiles, with the latter having the propensity to
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7546 J. AM. CHEM. SOC. VOL. 132, NO. 21, 2010

Resveratrol-Derived Hopeanol and Hopeahainol A
A R T I C L E S
Scheme 8. Completion of the Total Synthesis of (-)-Hopeanol
[(-)-2)] and (-)-Hopeahainol A [(-)-3)]a
Table 3. Oxidation Studies of Alcohols 62 and 63a
entry
oxidant, conditions
products 64:65:66 yields (%)b
1
2
3
4
IBX, DMSO
DMP, NaHCO3 (20 equiv), CH2Cl2
PCC, CH2Cl2
SO3 ·py, Et3N (20 equiv),
DMSO/CH2Cl2 (1:5)
DDQ, MeCN
26:0:66
14:32:33
15:0:34
0:0:0c
5
6
0:0:0d
CAN, MeCN
15:0:0c
a Reactions were carried out under the following conditions: 62+63
(17 µmol, ∼1:2 mixture of diastereoisomers), oxidant (10.0 equiv), 23
°C, 24 h. b Yields refer to chromatographically and spectroscopically
homogeneous materials. c Starting material fully consumed. d 70%
recovered starting material.
opposite optical rotations to those reported for the naturally
occurring materials.9,10
Our attempts thus far to confirm the proposed biosynthetic
hypothesis10 postulating hopeanol (2) as the precursor of
hopeahainol A (3) failed, despite the employment of a plethora
of basic and nucleophilic conditions [e.g., LiOH, LiOOH,
NaOH, Ba(OH)2, KOt-Bu, LiI/py, TMSOK, EtSNa].
The above sequence leading from γ-lactone 58 (Scheme 7)
to (-)-hopeahainol A [(-)-3)] and (-)-hopeanol [(-)-2)] also
served to synthesize the naturally occurring forms of these
natural products from γ-lactone ent-58 (Scheme 6). Synthetic
(+)-hopeahainol A [(+)-3)] and (+)-hopeanol [(+)-2)] exhibited
physical properties identical to those of the natural substances,
and closely matching optical rotations.9,10,17 In addition, we
prepared ent-46 by using the antipodal CBS catalyst in Scheme
5 and employed it to enrich our supplies of ent-58 (see
Supporting Information for schemes and experimental details
for these two sequences).
Biological Evaluation of Synthesized Compounds. The syn-
thesized compounds [(()-2, (-)-2, (+)-2, (()-3, (-)-3, (+)-3]
were tested against a panel of cancer cells, including breast
(MCF-7), lung (NCI-H460), CNS (SF268), nasopharyngeal
(KB), and cervical (HeLa) cells using doxorubicin, Taxol, and
5-fluorouracil as standards; the results are summarized in Table
4. Whereas the absence of significant cytotoxicity for the
hopeahainols [(()-3, (-)-3 and (+)-3] (entries 4, 5, and 6,
respectively)] was not surprising (given the isolation reports),9,10
it was for the hopeanols [(()-2, (-)-2 and (+)-2] (entries 7, 8,
and 9, respectively)]. Thus, and in stark contrast to the previous
reports [IC50 ) 0.52 µM against KB cell line and IC50 ) 3.21
µM against Hela cell line for (-)-2],9 racemic [(()-2] and
enantiomerically pure [(-)-2 and (+)-2] hopeanols failed to
demonstrate strong cytotoxicity against the cell lines tested.
Interestingly, however, the unnatural enantiomer of hopeanol
[(-)-2] exhibited higher potencies than the natural enantiomer
[(+)-2] (see entry 9, Table 4).
On the other hand, acetylcholinesterase inhibition studies (see
Table 5) with synthetic hopeahainols [(()-3, (-)-3, and (+)-3]
and hopeanols [(()-2, (-)-2, and (+)-2] confirmed the previ-
ously reported results with hopeahainol A [(+)-3] (entry 5, IC50
) 3.63-4.92 µM, lit.10 IC50 ) 4.33 µM). All the other tested
a Reagents and conditions: (a) IBX (10.0 equiv), DMSO, 23 °C, 24 h,
66: 66%, plus 64: 26%; (b) NaHCO3 (sat. aq)/MeOH (1:3), 25 °C, 1 h,
100%; (c) MeI (20 equiv), K2CO3 (5.0 equiv), acetone, 80 °C, 1 h, 90%;
(d) BBr3 (1.0 M in CH2Cl2, 18 equiv), CH2Cl2, -78 f -20 °C, 24 h; then
SiO2, 84%; (f) NaOMe (1.0 equiv), MeOH, 25 °C, 60 h, 80%. IBX )
2-iodoxybenzoic acid; DMSO ) dimethylsulfoxide.
(17) While the optical rotation of synthetic (+)-hopeahainol A [(+)-3] was
in close agreement to that reported in the literature [[R]2D5 ) +650.0
[MeOH, c ) 0.075; lit.: [R]2D5 ) +673.5 (MeOH, c ) 0.09)]],10 that
of synthetic (+)-hopeanol [(+)-2], although it showed the same sign,
differed significantly in absolute value to that reported in the literature
[[R]2D5 ) +193.0 (MeOH, c ) 0.070); lit.: [R]2D5 ) +40.1 (MeOH, c
) 0.23)]].9
rearrangement. The spectral data (1H and 13C NMR spectro-
scopic and mass spectrometric data) for synthetic (-)-2 and
(-)-3 matched those reported for natural hopeanol and hopea-
hainol A.9,10 As expected, the synthetic compounds exhibited
9
J. AM. CHEM. SOC. VOL. 132, NO. 21, 2010 7547

A R T I C L E S
Nicolaou et al.
Table 4. Cytotoxicity of Synthetic Racemic and Enantiomerically Pure Hopeanols [(()-2, (-)-2, and (+)-2] and Hopeahainols [(()-3, (-)-3,
and (+)-3] Against Selected Cancer Cell Lines (GI50 values in µM)a
cell line
entry
compound
MCF-7b
NCI-H460b
SF268b
KBc
HeLac
1
2
3
4
5
6
7
8
9
doxorubicin
Taxol
5-fluorouracil
(()-3
0.085 ( 0.009
0.007 ( 0.001
6.42 ( 0.50
88.45
64.00 ( 2.02
99.05 ( 8.34
>100
89.56 ( 13.24
28.04 ( 1.30
0.052 ( 0.009
0.007 ( 0.001
6.38 ( 0.42
>100
0.481 ( 0.019
0.030 ( 0.009
66.14 ( 17.12
>100
0.201 ( 0.082
0.007 ( 0.001
71.55 ( 5.88
>100
0.094 ( 0.004
0.008 ( 0.001
8.06 ( 0.76
>100
(-)-3
63.29 ( 5.19
>100
65.79 ( 0.26
>100
72.43 ( 12.81
>100
>100
(+)-3
>100
(()-2
>100
76.44 ( 4.74
32.69 ( 8.13
>100
>100
>100
33.19 ( 11.05
>100
(-)-2
>100
>100
(+)-2
29.22 ( 6.42
25.71 ( 5.62
a Antiproliferative effects of tested compounds against human tumor cell lines and drug-resistant cell lines in a 48 h growth inhibition assay using the
sulphorhodamine B staining methods. Human cancer cell lines: breast (MCF-7), lung (NCI-H460), CNS (SF268), nasopharyngeal (KB) and cervical
(HeLa). Growth inhibition of 50% (GI50) is calculated as the drug concentration which caused a 50% reduction in the net protein increase in control
cells during drug incubation. GI50 values for each compound are given in µM and represent the mean of 1-4 independent experiments ( standard error
of the mean. b These cell lines were provided by the National Cancer Institute (NCI), Division of Cancer Treatment and Diagnosis (DCTD). c These cell
lines were provided by ATCC.
Table 5. Inhibition of Acetylcholinesterase Activity by Synthetic Racemic and Enantiomerically Pure Hopeanols [(()-2, (-)-2, and (+)-2] and
Hopeahainols [(()-3, (-)-3, and (+)-3] (IC50 values in µM)a
time (min)
entry
compound
10
20
30
40
50
60
1
2
3
4
5
6
7
8
galanthamine
huperzine
(()-3
0.173 ( 0.092
0.036 ( 0.016
>50
0.249 ( 0.089
0.035 ( 0.007
>50
0.270 ( 0.077
0.034 ( 0.005
>50
0.278 ( 0.063
0.033 ( 0.005
>50
0.338 ( 0.048
0.033 ( 0.004
>50
0.373 ( 0.033
0.034 ( 0.003
>50
(-)-3
>50
>50
>50
>50
>50
>50
(+)-3
4.92 ( 0.09
>50
>50
>50
4.78 ( 1.07
>50
>50
>50
3.67 ( 0.39
>50
>50
>50
3.63 ( 0.03
>50
>50
>50
3.82 ( 0.09
>50
>50
>50
3.96 ( 0.25
>50
>50
>50
(()-2
(-)-2
(+)-2
a Acetylcholinesterase inhibitory activities of tested compounds in kinetic-based experiments using Ellman’s method. Inhibition of 50% (IC50) of
acetylcholinesterase activity is calculated as the drug concentration which caused a 50% reduction in the enzyme activity as compared to that with a
negative control. IC50 values for each compound are given in µM and represent the mean of 2-5 independent experiments (standard error of the mean.
compounds failed to exhibit any inhibitory activity in this assay
at below 50 µM concentrations.
related compounds as potential tools and drug candidates for
the treatment of diseases such as cancer and Alzheimer’s.
Conclusion
Acknowledgment. Professor K. C. Nicolaou is also at the
Department of Chemistry and The Skaggs Institute for Chemical
Biology, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037 (U.S.A.), and the Department of
Chemistry and Biochemistry, University of California, San Diego,
9500 Gilman Drive, La Jolla, California 92093 (U.S.A.). We thank
Mr. Rong-Ji Sum (CSL-ICES) for his assistance in the biological
studies, Dr. Aitipamula Srinivasulu (ICES) and Ms. Chia Sze Chen
(ICES) for X-ray crystallographic analysis, and Ms. Doris Tan
(ICES) for high-resolution mass spectrometric (HRMS) assistance.
Financial support for this work was provided by A*STAR,
Singapore.
The chemistry described herein demonstrates the power of
cascade reactions in complex molecule construction12 and
provides access to (+)-hopeanol [(+)-2] and (+)-hopeahainol
A [(+)-3], two structurally intriguing resveratrol-derived natural
products. While our biological studies with synthetic material
confirmed the reported acetylcholinesterase inhibitory activity
of hopeahainol A, they failed to reveal the reported cytotoxicity
potency for hopeanol. The latter discrepancy may be due to
contaminant(s) of the natural product or a variation of the
biological assays employed. We have also failed to produce
experimental evidence for the proposed biosynthetic step that
would implicate hopeanol as the precursor to hopeahainol A.10
On the contrary, we realized the reverse transformation whereby
hopeahainol A was smoothly converted to hopeanol under
alkaline methanolic conditions. The reported synthetic strategies
and technologies are expected to facilitate further developments,
including the design, synthesis, and biological evaluation of
Supporting Information Available: Experimental procedures,
and compound characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA102623J
9
7548 J. AM. CHEM. SOC. VOL. 132, NO. 21, 2010