Total syntheses of hopeanol and hopeahainol a empowered by a chiral br?nsted acid induced pinacol rearrangement

Article abstract of DOI:10.1002/anie.201107730

Rearranging complexity: The total synthesis of resveratrol dimers hopeanol (1) and hopeahainolA (2, see scheme) is described. By using a reagent-driven pinacol rearrangement coupled with specific oxidation chemistry, the frameworks are constructed concisely and on scale. Moreover, the route has biogenetic implications that trace the origin of these compounds to more common dimeric family members. Copyright

Full text of DOI:10.1002/anie.201107730

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DOI: 10.1002/anie.201107730
Natural Products
Total Syntheses of Hopeanol and Hopeahainol A Empowered by
a Chiral Brønsted Acid Induced Pinacol Rearrangement**
Scott A. Snyder,* Stephen B. Thomas, Agathe C. Mayer, and Steven P. Breazzano
Although the stilbene resveratrol is simple in terms of its size
and functional group array, it possesses high chemical
reactivity, a property that enables its conversion into hun-
dreds of architecturally diverse bioactive oligomeric natural
products.[1–3] Among recent dimeric isolates, hopeanol and
hopeahainol A (1 and 2, Scheme 1) are two of the most
intriguing given their constrained, partially dearomatized
bicyclic cores and potent activity in antitumor and acetyl-
cholinesterase inhibition assays.[4] Indeed, these molecules
have already been the subject of synthetic interest, with
reports by Nicolaou et al. describing racemic and enantiose-
lective syntheses of 1 and 2 in 15 linear steps.[5] Their route
featured several cascade-based bond constructions[6] and the
discovery that hopeahainol A (2) could be converted into
hopeanol (1) upon treatment with base, an idea counter to the
original biosynthetic proposal.[4b] Herein, we describe a dis-
tinct approach for the total synthesis of these natural products
empowered by a unique, reagent-driven pinacol rearrange-
ment and substrate-specific oxidation chemistry. Significantly,
it has potential for scaleability as well as biogenetic implica-
tions.
Our retrosynthetic analysis is shown in the lower portion
of Scheme 1, wherein our key disconnections were focused on
rapidly constructing the seven-membered ring and attendant
quaternary carbon center (C7b) found in both natural
products, as best noted by a redrawing of 1 and 2. Critical
insights came following a change in the oxidation state of 2 to
that of 3, in that we anticipated that the all carbon-based
quaternary center (C7b) could potentially arise from diol 5
through a pinacol rearrangement.[7] Although such events
often possess modest selectivity as a result of ambiguity in the
site of carbocation formation and/or migrating group, we
hoped that the specific patterning of 5 could avoid such issues.
Also, assuming that such a rearrangement could proceed with
any stereoisomeric variant of 5, then issues of diastereocon-
trol would not be a relevant concern, as all isomers of 3 should
be able to be funneled to racemic 2 through oxidation
chemistry. Issues in diastereocontrol occurred several times in
the approach of Nicolaou et al. to this same ring system.[5]
Additionally, we felt the complete route should be concise if
the materials needed for this key rearrangement step could
arise from ketone 6, variants of which we synthesized
previously through acid-induced cyclizations of alcohol 7.[8]
These materials have already enabled controlled syntheses of
nearly 20 dimeric and higher-order natural products within
the resveratrol class through several distinct, cascade-based
constructions of diverse C C and C O bonds.[8,9] Finally, the
route had two additional appealing elements. First, it is redox
economic.[10] Second, it might possess biogenetic relevance
given the structures of other seven-membered ring natural
products. For example, if reactive compounds 8–10 were
precursors[11] for natural products 11–14[12] by proton cycliza-
tions, then the same starting materials could lead to the C7b
quaternary carbon center of 1 and 2 by initial oxidation (to
generate 5 or a related congener) followed by acid treatment
as likely needed to initiate pinacol rearrangement.[13]
ꢀ
ꢀ
We began our efforts by synthesizing diols of type 5. As
shown in Scheme 2, that goal was accomplished through
a unique protocol starting from ketone 15 (prepared in five
steps from commercial resveratrol in 48% overall yield, see
Supporting Information),[14] a methyl ether protected version
of 6 (compare with Scheme 1) redrawn with three-dimen-
sional structure.[15] Following Corey–Chaykovsky epoxida-
tion,[16] which afforded 16 with complete relative stereocon-
trol, subsequent dissolution in CH2Cl2 and stirring with
AcOH at 258C generated what we believe to be the
acetate-opened epoxide and/or an intermediate diol with
inverted chirality at the C7b-position;[17] subsequent exposure
to the Dess–Martin periodinane, followed by Grignard attack,
afforded separable diols 19 and 20 in a 1:1.3 ratio.[18] Critically,
the two ring-based chiral centers were formed with complete
relative stereocontrol, an outcome that can be rationalized by
the steric bulk of the remote aryl ring within 17,[19] and one
that proved essential to the success of the later sequence (see
below). Worth noting is that other routes towards pinacol-
type precursors were attempted, largely by trying to add
nucleophiles to the ketone in 15. However, none provided the
expected materials with the exception of the Tebbe reagent;
in this case, the resultant methylene group could not be
functionalized further.
[*] Prof. Dr. S. A. Snyder, S. B. Thomas, Dr. A. C. Mayer,[+]
S. P. Breazzano[+]
Dept. of Chemistry, Columbia University
Havemeyer Hall, 3000 Broadway, New York, NY 10027 (USA)
E-mail: sas2197@columbia.edu
Homepage: http://www.columbia.edu/cu/chemistry/groups/
snyder/
[+] These authors contributed equally to initial studies.
[**] We thank the NSF (CHE-0619638) for an X-ray diffractometer and
Prof. Gerard Parkin, Wesley Sattler, Aaron Sattler, and Ashley Zuzek
for performing the crystallographic analyses. We thank Adel ElSohly
for NMR assistance and Jason Pflueger for early work. Financial
support was provided by Columbia University, the National
Institutes of Health (R01-GM84994), Bristol-Myers Squibb, Eli Lilly,
the NSF (Predoctoral Fellowships to S.B.T. and S.P.B.), the DFG
(Postdoctoral Fellowship to A.C.M.), and the Research Corporation
for Science Advancement (Cottrell Scholar Award to S.A.S.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107730.
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Nevertheless, with 19 and 20 in hand, explorations into the
critical pinacol rearrangement could begin. Pleasingly, many
protic and Lewis acids, such as p-toluenesulfonic acid (p-
TsOH), pyridinium p-toluenesulfonate (PPTS), and trime-
thylsilyl trifluoromethanesulfonate (TMSOTf), could gener-
ate the desired quaternary carbon center of 22 and 23, though
there were some, such as benzoic acid, that did not. However,
those that worked did so in low to moderate yield and with
modest diastereocontrol, a critical issue as only 22 proved
competent in later chemistry. Several side products were also
observed in varying amounts, the most significant and
consistent of which was epoxide 24, a material whose
structure was confirmed by X-ray analysis and which could
not be converted into a pinacol rearranged product under any
conditions.[20] A small subset of these initial results are
Scheme 2. Synthesis and pinacol rearrangement of 19 and 20.
a) Me3SI (10 equiv), nBuLi (8.0 equiv), THF, 08C, 1 h. b) AcOH,
CH2Cl2, 258C, 30 min; then Dess–Martin periodinane (1.2 equiv),
258C, 1 h, 45% over two steps. c) 4-OMePhMgBr (5.0 equiv), THF,
0!258C, 1.5 h, 87%, ca. 1.3:1 of 20:19. d) (R)-21 (1.0 equiv), CHCl3,
microwave, 1008C, 1 h, 56% 22/23 as a >18:1 mix of diastereomers.
Scheme 1. Structures of hopeanol (1) and hopeahainol A (2) and
retrosynthetic analysis based on a pinacol rearrangement as well as
site-specific oxidations inspired by a potential biogenesis from 8–10.
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Table 1: Exploration of the key pinacol rearrangement step.
promoter size was changed to that of vapol·HPO4
(21, Table 1, entries 13–15).[25] In these cases, high
diastereoselection (greater than 18:1) and similar
throughput efficiency (56% yield of 22 and 23; trace
24) was achieved when a single enantiomer was used.
At present, it is too preliminary to provide a rationale
for these unexpected outcomes between the use of
racemic or single enantiomer forms of these pro-
moters other than to state that it is a reproducible
result over several runs. We do note, however, that
this effect may be specific to materials of the binol
and vapol scaffolds in that both chiral and racemic
camphorsulfonic acid (CSA) gave nearly identical
results (Table 1, entries 16–18).[26] Current work is
directed at understanding the parameters of this
event more fully, especially determining whether
chiral acids have value in other pinacol rearrange-
ments where incongruities exist in diastereomer
reactivity and stereoselection. What we believe we
can state is that, to the best of our knowledge, this
event constitutes the first use of a chiral Brønsted
acid for this rearrangement in a total synthesis.
With this key quaternary carbon center forged
with good efficiency, our next goal was to effect the
remaining oxidations needed to access the natural
products. These steps had to install the missing
ketone located at the C8a-position, convert the
hindered aldehyde into a carboxylic acid, and gen-
Ent Acid
Equiv Solvent
T
t
Yield
d.r.
[8C]
[h] [%]
1
2
3
4
5
6
7
8
9
p-TsOH
PPTS
H3PO4
(R)-binol·HPO4 1.0
(S)-binol·HPO4
rac-binol·HPO4
(R)-binol·HPO4 1.0
(R)-binol·HPO4 1.0
(R)-binol·HPO4 1.0
5.0
3.0
3.0
toluene
toluene
THF
25
100
25
24 40–60[a] 2.5:1[a]
1
39
3.3:1
5.5:1
3.9:1
3.9:1
3.0:1
>10:1
1.8:1
5.0:1
24 38
CHCl3
CHCl3
CHCl3
CHCl3
DMSO
CHCl3/
MeOH (5:1)
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
100[b]
100[b]
100[b]
25
1
1
1
63
62
55
1.0
1.0
24 32
24 33
24 41
25
25
10
11
12
13
14
15
16
17
18
(R)-binol·HPO4 0.7
100[b]
100[b]
100[b]
100[b]
100[b]
100[b]
50
1
1
1
1
1
1
2
2
2
55
54
50
56
56
59
54
56
53
4.5:1
4.6:1
3.1:1
18.4:1
18.9:1
13.6:1
4.0:1
4.1:1
(S)-binol·HPO4
rac-binol·HPO4
(R)-21
(S)-21
rac-21
(R)-CSA
(S)-CSA
rac-CSA
0.7
0.7
1.0
1.0
1.0
2.0
2.0
2.0
50
50
4.0:1
[a] Both yield and d.r. proved highly variable between runs; d.r. as high as 4:1 for 22/
23 were observed, but 2.5:1 was more common, especially on a large scale.
[b] Under microwave irradiation.
ꢀ
erate the C C bond leading to the dearomatized p-
quinone ring essential to hopeanol (1). After an
exhaustive screen of oxidants, including 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ), hypervalent
collated in Table 1, entries 1–3. However, the most important
and consistent observation in all experiments was that diol
diastereomer 19 transformed into 22 quickly and with high
diastereoselectivity (typically greater than 10:1), while 20
reacted much more slowly, provided more side products, and
required increased reaction temperatures for any conversion
(leading to 22 and 23).[21]
iodine, and Pd(OAc)2/H2O2,[27] we discovered that the Jones
reagent could uniquely accomplish two of these tasks when it
was added to an acetone solution of 22 at 08C and stirred for
30 min (Scheme 3). This step leading to 26 proceeded in 27%
overall yield, with only the drawn diastereomer of 22 reacting
productively.[28] Equally intriguing, this event appears to
proceed by the initial formation of 25, as a trace amount of
this material was obtained when insufficient Jones reagent
was available to drive the reaction to completion; this
material (that is, 25) was quickly converted into 26 following
re-exposure to the Jones reagent. Surprisingly, the aldehyde
within 22 was not oxidized in this step; thus, a different
oxidant (NaClO2) proved necessary. Then, following treat-
ment with TMSCHN2, protected hopeanol (27) was obtained
in 75% yield (4.3% overall from 15). Despite much effort,
however, this material could not be deprotected,[29] including
use of the conditions of Nicolaou et al.[5]
As such, efforts were made to deprotect the phenolic
methyl ether groups earlier in the sequence, such as at the
stage of aldehyde 26 and intermediate 22. Unfortunately, in
both cases (as well as many others not explicitly described
here), these attempts consistently led to rearrangement
reactions and/or decomposition, one of which is denoted in
the Supporting Information section. Pleasingly, when carbox-
ylic acid 28 was treated with BBr3 in CH2Cl2, methyl ether
cleavage was attended by lactone formation to afford 29;
a small amount of decarboxylated material was also observed.
As such, the goal for optimization became finding an acid
source with a suitable pKa value capable not only of
rearranging 19 smoothly, but also improving the throughput
of 20. Our first significant advance based on this analysis
occurred when a mixture of both 19 and 20 was stirred with
one equivalent of (R)-binol·HPO4[22] in CHCl3 at 1008C under
microwave irradiation for 1 h. These conditions led to
pinacol-rearranged products 22 and 23 in 63% yield and
3.9:1 diastereocontrol in favor of 22 (Table 1, entry 4) along-
side varying amounts of epoxide 24 (ca. 10–15%).[23] Other
solvents and conditions with this promoter afforded
decreased selectivity and/or yield (Table 1, entries 7–9) for
22. Interestingly, while use of the opposite enantiomer of
promoter [(S)-binol·HPO4] under these conditions afforded
nearly identical results, its racemic form provided inferior
stereoselection (Table 1, entries 5 and 6).[24] The same phe-
nomenon was also observed when decreased quantities of
phosphoric acid were used, though these cases afforded
improved diastereoselectivity (4.5:1) at the price of yield
(Table 1, entries 10–12). It was also observed when the
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key precursor for the controlled preparation of the resveratrol
family (that is, 7) through a pathway that traces both of these
structures to a more common manifold within this fascinating
oligomer family. Critical steps involved a pinacol rearrange-
ment empowered by a chiral phosphoric acid and multistage,
substrate-specific oxidation processes. Current efforts are
directed towards developing asymmetric syntheses of these
materials and probing their chemical biology.
Received: November 2, 2011
Revised: February 15, 2012
Published online: March 16, 2012
Keywords: hopeahainol A · hopeanol · natural products ·
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resveratrol · total synthesis
[1] For reviews, see: a) S. Quideau, D. Deffieux, C. Douat-Casassus,
L. Pouysꢀgu, Angew. Chem. 2011, 123, 610 – 646; Angew. Chem.
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Weinheim, 2011, pp. 695 – 721.
[2] For recent papers concerning the bioactivity of resveratrol itself,
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Scheme 3. Completion of hopeanol (1) and hopeahainol A (2).
a) Jones reagent (20 equiv), acetone, 08C, 30 min, 27%. b) Resorcinol
(15 equiv), NaH2PO4·H2O (10 equiv), NaClO2 (5 equiv), THF/tBuOH/
H2O (1:1:2), 258C, 3 days, 70%. c) TMSCHN2 (5 equiv), THF/MeOH
(4:1), 08C, 15 min, 98%. d) Resorcinol (15 equiv), NaH2PO4·H2O
(10 equiv), NaClO2 (5 equiv), THF/tBuOH/H2O (1:1:2), 258C, 3 days.
e) BBr3 (18 equiv), CH2Cl2, ꢀ78!08C, 3 h. f) BnBr (20 equiv), K2CO3
(20 equiv), nBu4NI (1.0 equiv), acetone, 258C, 12 h, 29% over three
steps. g) CAN (8.0 equiv), DMSO, 258C, 12 h, 65–89%. h) BCl3
(12 equiv), CH2Cl2, ꢀ788C, 15 min, 75%. i) NaOMe (1.2 equiv),
MeOH, 258C, 4 days, 69%.
[4] a) H. M. Ge, C. Xu, X. T. Wang, B. Huang, R. X. Tan, Eur. J. Org.
Chem. 2006, 5551 – 5554; b) 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.
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[5] a) K. C. Nicolaou, T. R. Wu, Q. Kang, D. Y.-K. Chen, Angew.
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D. Y.-K. Chen, J. Am. Chem. Soc. 2010, 132, 7540 – 7548.
[6] For a recent review on cascade reactions, see: K. C. Nicolaou,
D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006, 118, 7292 –
7344; Angew. Chem. Int. Ed. 2006, 45, 7134 – 7186.
[7] For examples using the pinacol reaction to forge quarternary
carbon centers in natural product synthesis, see: a) J. Li, S. Jeong,
L. Esser, P. G. Harran, Angew. Chem. 2001, 113, 4901 – 4906;
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[8] a) S. A. Snyder, A. L. Zografos, Y. Lin, Angew. Chem. 2007, 119,
8334 – 8339; Angew. Chem. Int. Ed. 2007, 46, 8186 – 8191; b) S. A.
Although all attempts at oxidizing this material directly to
1 or 2 failed, its benzyl ether analogue could be oxidized with
ceric ammonium nitrate (CAN) to afford protected hope-
ahainol A in 65–89% yield, depending on the scale. No other
oxidant succeeded. Finally, deprotection with BCl3 then
delivered the natural product (2) in 75% yield, a portion of
which was converted into hopeanol (1) following the exact
conditions developed by Nicolaou et al.[5] In total, the route to
hopeahainol A (2) is 14 steps long, and as one reflection of its
overall efficiency (4.0% overall from 15), we have prepared
over 60 mg of it along with 180 mg of its protected precursor
to date.
In conclusion, we have accomplished an efficient total
synthesis of both hopeanol (1) and hopeahainol (2) from our
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Snyder, S. P. Breazzano, A. G. Ross, Y. Lin, A. L. Zografos, J.
Am. Chem. Soc. 2009, 131, 1753 – 1765.
were performed as a single step without intervening chromatog-
raphy.
[9] For our work towards other resveratrol-based structures, see:
a) S. A. Snyder, A. Gollner, M. I. Chiriac, Nature 2011, 474, 461 –
466; b) S. A. Snyder, N. E. Wright, J. J. Pflueger, S. P. Breazzano,
Angew. Chem. 2011, 123, 8788 – 8792; Angew. Chem. Int. Ed.
2011, 50, 8629 – 8633; c) S. A. Snyder, Z. G. Brill, Org. Lett. 2011,
13, 5524 – 5527.
[18] Extensive efforts to characterize 19 and 20 by crystallization
failed; the current assignment is based on nOe experiments as
noted in the Supporting Information.
[19] As evidence for the existence of 17, the pendant aryl ring could
form a disubstituted quinone methide in 11% yield (see the
Supporting Information).
[10] For reviews, see: a) N. Z. Burns, P. S. Baran, R. W. Hoffmann,
Angew. Chem. 2009, 121, 2896 – 2910; Angew. Chem. Int. Ed.
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Hoffmann, Chem. Soc. Rev. 2009, 38, 3010 – 3021.
[20] This outcome suggests that semipinacol processes from 24 are
not operative.
[21] The basis for the differential diastereoselectivity of 19 and 20 in
the pinacol rearrangement is not obvious based on simple
molecular models, though it is clear based on experimental
observations that diol 19 has a lower energy barrier for the
conversion.
[22] For the pioneering use of such species in related rearrangements,
see: T. Liang, Z. Zhang, J. C. Antilla, Angew. Chem. 2010, 122,
9928 – 9930; Angew. Chem. Int. Ed. 2010, 49, 9734 – 9736.
[23] Neither 22 nor 23 were generated with optical activity.
[24] Racemic binol·HPO4, prepared from racemic binol or a mixture
of both (S)- and (R)-forms of the reagent, gave the same results.
[25] A. A. Desai, L. Huang, W. D. Wulff, G. B. Rowland, J. C. Antilla,
Synthesis 2010, 2106 – 2109.
[11] Although these exact precursors are not known isolates, there
are natural products where the putative double bond of 8 – 10 is
reduced. For an example, see: K. Baba, Y. Tabata, K. Maeda, M.
Doi, M. Kozawa, Chem. Pharm. Bull. 1986, 34, 4418 – 4421.
[12] For the isolation of these natural products, see: a) Y. Oshima, Y.
Ueno, H. Hikino, L. L. Yang, K. Y. Yen, Tetrahedron 1990, 46,
5121 – 5126; b) T. Ito, T. Tanaka, M. Iinuma, K. Nakaya, Y.
Takahashi, R. Sawa, J. Murata, D. Darneadi, J. Nat. Prod. 2004,
67, 932 – 937; c) J.-F. F. Weber, I. A. Wahab, A. Marzuki, N. F.
Thomas, A. A. Kadir, A. H. A. Hadi, K. Awang, A. A. Latiff, P.
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d) H. M. Ge, W.-H. Yang, J. Zhang, R.-X. Tan, J. Agric. Food
Chem. 2009, 57, 5756 – 5761.
[13] If this proposal is accurate, it would mean that these dimers
result from the reorganization of bonds within a dimeric frame-
work, rather than a union of resveratrol monomers as originally
proposed (Ref. [4]).
[14] This route is shorter than our previously published procedures
(Ref. [8]) because of a change in commercial starting material.
See the Supporting Information for full details.
[26] Globally, we believe that the overall success of these processes is
related to the pKa value of the acids used, though exact values
for their acidity across the range of solvents used in this study are
not known.
[27] a) J.-Q. Yu, E. J. Corey, Org. Lett. 2002, 4, 2727 – 2730; b) J.-Q.
Yu, E. J. Corey, J. Am. Chem. Soc. 2003, 125, 3232 – 3233.
[28] The chemospecificity of this oxidation process is intriguing. For
related examples of high reagent/substrate specificity, see: S. A.
Snyder, T. C. Sherwood, A. G. Ross, Angew. Chem. 2010, 122,
5272 – 5276; Angew. Chem. Int. Ed. 2010, 49, 5146 – 5150.
[29] Other deprotections include: a) S. J. OꢁMalley, K. L. Tan, A.
Watzke, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2005,
127, 13496 – 13497; b) K. C. Nicolaou, M. Takayanagi, N. F. Jain,
S. Natarajan, A. E. Koumbis, T. Bando, J. M. Ramanjulu, Angew.
Chem. 1998, 110, 2881 – 2883; Angew. Chem. Int. Ed. 1998, 37,
2717 – 2719.
[15] The drawn orientation of 15 is based on a crystal structure of
a closely related compound (see the Supporting Information)
indicating the pseudoaxial orientation of the pendant aryl ring
on the seven-membered ring as well as the positioning of the
ketone relative to the neighboring aryl substituents.
[16] E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1353 –
1364.
[17] The intermediate acetate was never observed and likely hydro-
lyzes on work-up; in practice, the AcOH reaction and oxidation
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