Total synthesis of hopeahainol A and hopeanol

Full text of DOI:10.1002/anie.200900438

Communications
DOI: 10.1002/anie.200900438
Natural Product Synthesis
Total Synthesis of Hopeahainol A and Hopeanol**
K. C. Nicolaou,* T. Robert Wu, Qiang Kang, and David Y.-K. Chen*
Angewandte
Chemie
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The polyphenols are a large and growing class of secondary
metabolites with diverse molecular structures and biological
activities.[1] Resveratrol and its oligomeric descendents are
particularly interesting owing to their unique structures and
important physiological properties as evidenced by the recent
surge of research on their chemistry and biology.[2] Hope-
ahainol A[3] (1, Scheme 1) and hopeanol[3,4] (2, Scheme 1) are
cascade reactions and a number of unusual skeletal rear-
rangements.
Scheme 2 shows the retrosynthetic analysis that led to the
design of the synthetic strategy toward both hopeahainol A
(1) and hopeanol (2), in that order. Despite a hypothesis that
Scheme 1. Molecular structures of hopeahainol A (1) and hopeanol
(2).
two recently disclosed molecules, each thought to be biosyn-
thetically derived from two molecules of resveratrol.
Although closely related in structure and biosynthetic
origin, their promising biological properties are diverse.
Originally isolated from Hopea exalata[4] and subsequently
from Hopea hainanensis,[3] hopeanol (2) is a cytotoxic agent
which is active against a variety of tumor cells, including KB
cells (IC50 = 0.52 mm). Hopeahainol A (1), on the other hand,
was isolated from Hopea hainanensis[3] and exhibited inhib-
itory activity against acetylcholinesterase (IC50 = 4.33 mm), an
enzyme implicated and exploited for the treatment of
Alzheimerꢀs disease. The novel molecular architecture of
these natural products, coupled with their impressive biolog-
ical properties, prompted us to undertake their synthesis.
Herein we report their first total synthesis, in racemic form,
through a short and efficient strategy that involves a series of
Scheme 2. Retrosynthetic analysis of hopeahainol A (1) and hopeanol
(2). TBS=tert-butyldimethylsilyl, Ac=acetyl.
defined hopeanol (2) as the biosynthetic precursor to hope-
ahainol A (1),[3] we envisioned this transformation to be
reversible under suitable conditions. With this expectation,
we targeted hopeahainol A (1) first through precursors 3
[*] Prof. Dr. K. C. Nicolaou, Dr. T. R. Wu, Dr. Q. Kang, Dr. D. Y.-K. Chen
Chemical Synthesis Laboratory@Biopolis
Institute of Chemical and Engineering Sciences (ICES)
Agency for Science, Technology and Research (A*STAR)
11 Biopolis Way, The Helios Block, 03-08, Singapore 138667
(Singapore)
ꢀ
(epoxide ring-opening and formation of C7a C10b, hope-
ahainol A numbering) and then 4 (Friedel–Crafts-type reac-
tion to link C14a and C7b). Hydroxy ester precursor 4 was
traced back to simple building blocks through the indicated
disconnections (Grignard reaction and esterification) as
shown in Scheme 2.
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
david_chen@ices.a-star.edu.sg
Prof. Dr. K. C. Nicolaou
The Department of Chemistry
Scheme 3 summarizes the assembly of epoxide 3 and its
conversion into hydroxy g-lactone 15. Thus, benzylic alcohol 6
(prepared by the reaction of 3,5-bis(OTBS)phenyl lithium[5]
and p-methoxyphenylacetaldehyde) was esterified with 3,5-
dimethoxy-a-oxophenylacetic acid (7)[6] (DCC, DMAP, 95%
yield) and afforded keto ester 5. Reaction of the latter with p-
methoxyphenylmagnesium bromide furnished the bis-TBS
derivative 8 (mixture of diastereoisomers, ca. 1:1 d.r.), whose
silyl ethers were cleaved through the action of TBAF, and led
to hydroxy ester 4 (mixture of diastereoisomers, ca. 1:1 d.r.) in
79% overall yield. Exposure of the tetracyclic substrate 4 to
and The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] We thank Ms. Doris Tan (ICES) for assistance with high resolution
mass spectroscopy (HRMS) measurements. Financial support for
this work was provided by A*STAR, Singapore.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200900438
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Communications
pTsOH in CH2Cl2 at ambient temperature then led to
pentacyclic product 10 (65% yield, mixture of diastereoiso-
mers, ca. 2.4:1 d.r.). The observed difference of the diaste-
reomeric ratios in going from starting material to product
(4!10) in this carbon–carbon bond-forming reaction sug-
gests the intermediacy of reactive species 9. The stereochem-
ical outcome of this reaction, however, is inconsequential
since one of the stereocenters is erased in the subsequent step.
Indeed, exposure of d-lactone 10 to KOtBu in THF at 0!
258C led, upon quenching with aqueous NH4Cl solution, to
olefinic g-lactone 12, which was obtained through anion
formation, b-elimination, and ring closure, as a single isomer
(76% yield; Scheme 3). The remaining phenolic group was
then protected as an acetate (13, Ac2O, DMAP, quantitative
yield), and the resulting olefinic product was subjected to
epoxidation with mCPBA to afford epoxide 3 as a mixture of
diastereoisomers (ca. 1:1 d.r.). This mixture was treated with
SnCl4 in CH2Cl2 at ꢀ40!ꢀ208C to give hydroxy g-lactone 15
in 62% overall yield (mixture of diastereoisomers, ca.
2:1 d.r.), presumably through epoxide ring-opening and
carbon–carbon bond formation.[7] The fact that the d.r. of
product 15 does not reflect exactly the d.r. of the starting
material 3 may be explained by the different reactivities of the
two epoxide isomers.
With the entire hexacyclic framework of hopeahainol A
(1) in place, the stage was now set for the final drive towards
the target molecule. Scheme 4 depicts the devised steps
through which this task was completed, and that allowed our
second target molecule, hopeanol (2), to be reached as well
through a single step thereafter. Thus, oxidation of hydroxy
compound 15[8] (mixture of two diastereoisomers at C7a and
C8a) with IBX furnished keto quinoid compound 16 in 66%
yield, which was deacetylated with NaHCO3 in MeOH
(quantitative yield) to yield phenol 17. Methylation of this
compound (K2CO3, MeI) afforded tetramethyl hopeahai-
nol A (18, 90% yield), whose spectroscopic data (1H NMR)
matched those reported for this known derivative,[3] thus
supporting the close resemblance and skeletal identity of
structure 17 to that of hopeahainol A (1) through a cascade
reaction. Pleasingly, the latter was prepared from 17 by
treatment with BBr3 in CH2Cl2 (ꢀ78!ꢀ208C) in 84% yield.
Equally pleasant was the generation of hopeanol (2) from
hopeahainol A (1) in 80% yield upon exposure of the latter to
one equivalent of NaOMe in MeOH at 258C. Synthetic
racemic 1 and 2 exhibited identical physical properties (1H
and 13C NMR, and mass spectroscopic data) to those reported
in the literature.[3,4] The conversion of 17 into hopeahainol A
(1) appears to proceed through a labile intermediate (19: X =
OH or Br),[9] which collapses to the desired product when
placed on a preparative
Scheme 3. Construction of epoxide 3 and hexacyclic intermediate 15. Reagents and conditions: a) 7 (1.5 equiv),
DCC (2.3 equiv), DMAP (0.3 equiv), CH2Cl2, 258C, 12 h, 95%; b) 4-methoxyphenylmagnesium bromide (0.2m in
silica gel plate and
allowed to stand for a
few hours. It is also
interesting to speculate
that hopeahainol A (1)
is locked in its unique
structure by the g-lac-
tone ring which pushes
carbons C1b and C7a
THF, 1.3 equiv), THF, ꢀ108C, 10 min; c) TBAF (1.0m in THF, 2.0 equiv), THF, 08C, 30 min, 79% for two steps
(ca. 1:1 mixture of diastereoisomers); d) pTsOH (3.0 equiv), CH2Cl2, 258C, 48 h, 65% (ca. 2.4:1 mixture of
diastereoisomers); e) KOtBu (1.0m in THF, 5.0 equiv), THF, 0!258C, 4 h, then sat. aq NH4Cl, 76%; f) Ac2O
(1.5 equiv), DMAP (0.1 equiv), pyridine, 0!258C, 1 h, quant.; g) mCPBA (77% wt/wt, 4.0 equiv), NaHCO3
(6.0 equiv), CH2Cl2, 08C, 30 min, (ca. 1:1 mixture of diastereoisomers); h) SnCl4 (1.0m in CH2Cl2, 1.5 equiv),
CH2Cl2, ꢀ40!ꢀ208C, 20 min, 62% for two steps (ca. 2:1 mixture of diastereoisomers). DCC=N,N’-dicyclohex-
ylcarbodiimide, DMAP=4-dimethylaminopyridine, mCPBA=meta-chloroperoxybenzoic acid, pTsOH=para-tolu-
enesulfonic acid, TBAF=tetra-n-butylammonium fluoride, THF=tetrahydrofuran.
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Keywords: cascade reactions · natural products · polyphenols ·
.
total synthesis
[1] For representative reviews on the chemical and biological
studies of natural polyphenols, see: a) C. S. Yang, J. D. Lambert,
S. Sang, Arch. Toxicol. 2009, 83, 11 – 21; b) L. Bonfili, V.
Cecarini, M. Amici, M. Cuccioloni, M. Angeletti, J. N. Keller,
A. M. Eleuteri, FEBS J. 2008, 275, 5512 – 5526; c) V. Habauzit,
M.-N. Horcajada, Phytochem. Rev. 2008, 7, 313 – 344; d) S. Lafay,
A. Gil-Izquierdo, Phytochem. Rev. 2008, 7, 301 – 311; e) B.
Halliwell, Arch. Biochem. Biophys. 2008, 476, 107 – 112; f) L. G.
Korkina, S. Pastore, C. De Luca, V. A. Kostyuk, Curr. Drug
Metab. 2008, 9, 710 – 729, and reference therein.
[2] For resveratrol-derived natural products and synthetic studies
thereof, see: a) S. A. Snyder, S. P. Breazzano, A. G. Ross, Y. Lin,
A. L. Zografos, J. Am. Chem. Soc. 2009, 131, 1753 – 1765;
b) S. A. Snyder, L. Zografos, Y. Lin, Angew. Chem. 2007, 119,
8334 – 8339; Angew. Chem. Int. Ed. 2007, 46, 8186 – 8191, and
references therein.
[3] H. M. Ge, C. H. Zhu, D. H. Shi, L. D. Zhang, D. Q. Xie, J. Yang,
S. W. Ng, R. X. Tan, Chem. Eur. J. 2008, 14, 376 – 381.
[4] H. M. Ge, C. Xu, X. T. Wang, B. Huang, R. X. Tan, Eur. J. Org.
Chem. 2006, 5551 – 5554.
[5] D. R. Vutukuri, S. Basu, S. Thayumanavan, J. Am. Chem. Soc.
2004, 126, 15636 – 15637.
[6] R. A. Hudack Jr. , N. S. Barta, C. Guo, J. Deal, L. Dong, L. K.
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J. Med. Chem. 2006, 49, 1202 – 1206.
[7] G. A. Kraus, I. Kim, Org. Lett. 2003, 5, 1191 – 1192.
[8] It is interesting to note that, while the major diastereoisomer of
15 (unassigned) undergoes oxidation to 16 smoothly at 258C, its
minor diastereoisomer resisted complete oxidation under the
same reaction conditions, and led instead to partially oxidized
ketone 15b’.
Scheme 4. Total synthesis of tetramethyl hopeahainol A (18), hope-
ahainol A (1), and hopeanol (2). Reagents and conditions: a) IBX
(10 equiv), DMSO, 258C, 24 h, 66%; b) sat. aq NaHCO3, MeOH,
258C, 1 h, quant.; c) MeI (20 equiv), K2CO3 (5.0 equiv), acetone, 808C,
1 h, 90%; d) BBr3 (1.0m in CH2Cl2, 18 equiv), CH2Cl2, ꢀ78!ꢀ208C,
24 h, 84%; e) NaOMe (1.0 equiv), MeOH, 258C, 60 h, 80%. DMSO=
dimethyl sulfoxide, IBX=2-iodoxybenzoic acid.
too far apart for interaction, and that it is its rupture with
NaOMe (1!20) that allows the skeletal rearrangement (20!
2) to occur, thus allowing the emergence of hopeanol (2), as
shown in Scheme 4.
The described chemistry opens a path to the construction
of hopeahainol A (1) and hopeanol (2) and their analogues
for biological investigations, and further demonstrates the
power of cascade reactions in total synthesis.[10]
[9] Intermediate 19 was observed by TLC and 1H NMR spectro-
scopic analysis of the crude reaction mixture. Owing to its
lability the nature of X is still uncertain (most likely Br or OH).
[10] a) K. C. Nicolaou, T. Montagnon, S. A. Snyder, Chem. Commun.
2003, 551 – 564; b) L. F. Tietze, G. Brasche, K. M. Gericke
Domino Reactions in Organic Synthesis Wiley-VCH, Weinheim,
2006, p. 617; c) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger,
Angew. Chem. 2006, 118, 7292 – 7344; Angew. Chem. Int. Ed.
2006, 45, 7134 – 7186.
Received: January 22, 2009
Published online: March 11, 2009
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