Total syntheses of heimiol A, hopeahainol D, and constrained analogues

Article abstract of DOI:10.1002/anie.201103575

IDSI to the rescue: Use of a carefully designed cascade process empowered by the unique reagent IDSI [(Et₂SI)₂ClaSbCl ₆] provided the entire [3.2.2] bicyclic core of both targets 1 and 2 in a single, stereocontrolled operation. Use of strain energies assisted in the completion of the natural products. Copyright

Full text of DOI:10.1002/anie.201103575

DOI: 10.1002/anie.201103575
Natural Products
Total Syntheses of Heimiol A, Hopeahainol D, and Constrained
Analogues**
Scott A. Snyder,* Nathan E. Wright, Jason J. Pflueger, and Steven P. Breazzano
Although synthetic chemists have become quite adept at
preparing individual ring systems of diverse size and complex-
ity, there remains a pressing need for more powerful tools and
strategies to address their concurrent formation, particularly
in contexts where they are fused together into compact and
constrained frameworks. In 2001, Weber and co-workers
reported their isolation and characterization of an architec-
tural challenge in need of such solutions in the form of the
oxidized resveratrol dimer 1 (Scheme 1).[1] This compound,
which they named heimiol A, after its plant source (Neo-
balanacarpus heimii), merges one six-membered and two
seven-membered ring systems into a [3.2.2] bicycle that
displays four chiral centers, and it has since been shown to
possess some antioxidant activity.[2] Eight years later, a team
led by Tan reisolated the same material (1) from a different
plant along with a much smaller amount of a compound they
assigned as hopeahainol D (2);[3] its structure differs from 1
only in its stereochemistry about the highlighted position
(Scheme 1). Upon initial inspection, and as drawn in the first
orientation shown in Scheme 1 that is typical of the isolation
papers, the synthetic challenge of these molecules is hidden,
much in the way that the two fused seven-membered rings
and lone chiral center of colchicine (8)[4] look deceptively
simple. However, if one considers the two additional drawings
that are provided for these targets, then a better appreciation
for their true three-dimensional shape and overall synthetic
challenge can be gleaned. Indeed, the third set of these
renderings indicates that both materials provide the difficult
task of arraying two aromatic rings and a bridging oxygen
atom on the same side of a conserved seven-membered
carbocyclic core, while the second set shows that the lone
stereochemical change impacting the orientation of ring D in
1 and 2 imparts a significant thermodynamic strain penalty to
[*] Prof. Dr. S. A. Snyder, N. E. Wright, J. J. Pflueger, S. P. Breazzano
Department 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/
[**] We thank the NSF (CHE-0619638) for an X-ray diffractometer and
Prof. Gerard Parkin, Wesley Sattler, and Aaron Sattler for performing
all of the crystallographic analyses. We also thank Adel ElSohly for
performing the calculations. Financial support was provided by
Columbia University, the National Institutes of Health
(R01GM84994), Bristol-Myers Squibb, Eli Lilly, the NSF (Predoctoral
Fellowships to N.E.W. and S.P.B.), the ACS Division of Organic
Chemistry (summer fellowship to J.J.P.), and the Research Corpo-
ration for Science Advancement (Cottrell Scholar Award to S.A.S.).
Scheme 1. Drawing from the lessons of colchicine (8) and the chal-
lenges of seven-membered ring synthesis: a retrosynthetic analysis of
heimiol A (1) and hopeahainol D (2) empowered by thermodynamic
strain energies and a novel halonium-induced cascade.
hopeahainol D (calculated as 1.79 kcalmolꢀ1).[5] Herein, we
describe a synthetic approach empowered by a novel electro-
philic iodine source which forged the entire bicyclic core in a
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103575.
Angew. Chem. Int. Ed. 2011, 50, 8629 –8633
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8629

Communications
single, stereocontrolled operation from an acyclic precursor.
hol 13 into carboxylic acid 15 through a sequence employing
an oxidation, a Corey–Chaykovski reaction[9]/ZnI2 rearrange-
ment[10] to generate aldehyde 14, and a terminating Pinnick
oxidation.[11] Critical to the yield of this sequence (68%
overall) was benzyl protection of the highlighted phenol as its
methyl ether analogue (i.e. 9), which led to only 30–40% yield
overall. Given the observed instability of the intermediate
epoxide, we attribute this yield difference to its more rapid
decomposition when a methyl ether was present as a result of
its slightly greater electron-donating capability through the
conjugated p system.
With these operations setting the stage for the key
transformation of the sequence, 15 was then exposed to a
number of standard, stoichiometric halogen sources in a
variety of solvents in hopes of forging 16 in a single operation
(see inset box for selected reagents). Unfortunately, none
afforded any evidence of the cyclized material irrespective of
the rate and/or order of addition. However, we found that if
electrophilic iodine in the form of iodine/hypoiodide was
generated in situ either by reacting PhI(OAc)2 with I2 or
under heterogeneous conditions with Oxone and KI,[12] the
desired [3.2.2] bicyclic system of 16 could be formed in
modest amounts (ca. 20% in the latter case) alongside several
uncharacterized side products that were suggestive of over-
and/or nonselective halogenation. While this finding was
encouraging, a superior material throughput was needed for
effective prosecution of the sequence.
We then highlight how both (ꢁ)ꢀ1 and (ꢁ)ꢀ2 can be
synthesized from the same advanced intermediate by taking
into account that final strain energy difference, and show how
the developed strategy can also afford unique [3.2.1] dimeric
resveratrol cores possessing even higher strain energy differ-
ences than 1 and 2.
Our retrosynthetic analysis of heimiol A (1) and hopea-
hainol D (2) is shown in the bottom half of Scheme 1. Given
the indicated strain difference between these natural prod-
ucts,[6] we anticipated that 2 might be a biosynthetic precursor
to 1, an idea that had not been advanced by the original
isolation team, but one that is hinted at circumstantially based
on the relative amounts of 1 and 2 obtained. We then excised
ring D from 2, projecting that it could be added with
stereocontrol through an appropriate, substrate-controlled
strategy onto protected lactone 3. Though specific phenol
protecting groups have not been defined for this new
compound, particularly mild excision conditions were antici-
pated to be necessary given the fragile positioning of the ether
linkage within the final targets (1 and 2) relative to one of
their phenols (see below). Overall, while these initial
operations appear simple, they have set the stage for the
key retrosynthetic disconnection of these targets, one which
we hoped could readily address the challenge of forming their
cis-disposed cores.
Indeed, as shown, we anticipated that the entire
[3.2.2] bicycle of 3 could arise from the acyclic precursor 7
in a single, stereocontrolled step through a halolactonization/
Friedel–Crafts cascade that would sequentially forge two new
bonds and three rings without leaving any trace of the
electrophilic halogen activator. The initial stereochemical
requirements of the opening operations of this process (7!5),
coupled with a likely kinetic preference for the quinone
methide of 4 to exist on the b face as shown to minimize
strain, was expected to produce 3 with the desired, and
necessary relative stereochemistry following the final cycliza-
tion. Of course, this plan was fully dependent on the ability of
some electrophilic halogen to chemoselectively engage the
lone double bond of 7 in advance of and/or in lieu of
potentially deleterious electrophilic aromatic substitution
reactions with its electron-rich systems, substitutions which
could prevent the Friedel–Crafts reaction. However, if the
requisite chemoselectivity could be achieved, then the
approach would afford an expeditious solution for a challeng-
ing ring synthesis. Moreover, it would solve a stereochemical
problem that our past work towards resveratrol oligomers had
not achieved.[7] Indeed, as shown in Scheme 2A, we could
readily fashion seven-membered rings with a trans disposition
of groups (such as 10 and 11) through electrophile-induced
cascades from alcohol 9, materials pertinent to vast majority
of the family such as vaticanol A (12).[8] However, we have
been unable to convert these materials into anything resem-
bling the much more unique, all-cis disposed frameworks of
heimiol A (1) and hopeahainol D (2).
Pleasingly, we discovered that when we used our recently
developed unique iodonium source, IDSI,[13] in MeCN at
258C, 16 could be produced much more smoothly and in
higher yield with just a total of 2 minutes for the reaction time.
This reagent was the only stoichiometric, direct halogen
source that gave product in any yield, suggesting its potential
for other unique iodonium-induced cyclizations. Intriguingly,
its brominated counterpart (BDSB) also afforded cyclized
material, but effected bromination of the aromatic rings also
(presumably following cyclization), thus indicating that IDSI
has unique chemoselectivity for this event. With this key step
accomplished, the methyl ethers were removed by exposure
to BBr3, thus affording an overall yield of 36% for these two
critical operations.
Reprotection with benzyl ethers (to provide a protecting
group that could later be cleaved under mild conditions) then
provided a lactone to test the stereocontrolled incorporation
of the final aryl ring in the form of reagent 17. We hoped that
the bulk of the C ring would afford diastereocontrol in that
addition and, in line with our expectations, intermediate 18
was formed smoothly as a single stereoisomer. Much more
importantly, the same selectivity was subsequently observed
with a much smaller nucleophile (Et3SiH) after the tertiary
alcohol was ionized with BF3·OEt2, thereby forming protected
hopeahainol D (20) cleanly in 57% overall yield. Hydro-
genation over catalytic Pd/C then excised the benzyl ethers to
afford a concise, and fully stereocontrolled, total synthesis of
hopeahainol D (2) in just 10 operations from key the starting
material 13. Finally, as a test of our proposed biogenetic
theory, exposure of hopeahainol D (2) to a mixture of
BF3·OEt2 and BCl3 in MeOH at 258C resulted in complete
and quantitative epimerization of the desired chiral center to
Fortunately, we were able to reduce the general plan
outlined in Scheme 1 to practice, though there were several
subtle, and unexpected, elements of chemical reactivity en
route. Initial operations (Scheme 2B) converted triaryl alco-
8630 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8629 –8633

Scheme 2. A) The challenges of heimiol A (1) and hopeahainol D (2) in context: forming cis-disposed systems where past efforts have given trans-
materials. B) Total synthesis of 1 and 2 through an IDSI-empowered cascade: a) Dess–Martin periodinane (1.2 equiv), NaHCO3 (10 equiv),
CH2Cl2, 258C, 2 h, 99%; b) Me3SI (10 equiv), nBuLi (9.0 equiv), THF, 08C, 1 h; c) ZnI2 (1.0 equiv), benzene, 258C, 5 min, 80% over 2 steps;
d) NaClO2 (3.0 equiv), NaH2PO4 (8.0 equiv), resorcinol (10 equiv), THF/tBuOH (1:1), 258C, 12 h, 85%; e) IDSI (2.0 equiv), MeCN, 258C, 2 min;
f) BBr3 (1.0m in CH2Cl2, 25 equiv), CH2Cl2, 258C, 24 h, 36% over 2 steps; g) BnBr (30 equiv), K2CO3 (30 equiv), nBu4NI (2.0 equiv), acetone,
reflux, 89%; h) 4-benzyloxybromobenzene (50 equiv), nBuLi (50 equiv), THF, ꢀ788C, 20 min; i) BF3·OEt2 (10 equiv), Et3SiH (50 equiv), CH2Cl2,
ꢀ78!258C, 10 min, 57% over 2 steps; j) H2 (1 atm), Pd/C (10%, 5.0 equiv), EtOAc/MeOH (1:1), 258C, 12 h, 79%; k) BF3·OEt2 (8.0 equiv), BCl3
(1.0m in CH2Cl2, 2.0 equiv), MeOH, 258C, 2.5 h, 99%. Bn=benzyl, IDSI=(Et2SI)2Cl·SbCl6, NBS=N-bromosuccinimide, NIS=N-iodosuccinimide,
THF=tetrahydrofuran.
that of heimiol A (1).[14] Such a conversion supports the
hypothesis that 2 may, in fact, be a biogenetic precursor to
1.[15] And, as confirmation of the necessity of the earlier
protecting group exchange (part of the 16 into 18 conversion),
we discovered that permethylated heimiol A could not be
successfully deprotected under standard BBr3 conditions;
thus, it was fortunate that the lactone scaffold (i.e. 16) was
robust enough to undergo such a methyl ether cleavage.16]
Finally, outside of these two natural products, there is one
other set of resveratrol-based dimers that are diastereomeric
about a single position and that have groups arrayed cis on a
similar seven-membered ring; several of these compounds are
shown in Scheme 3 (21–24),[17] but only ampelopsin F (21) has
been synthesized to date.[7,18] Pleasingly, application of the
lessons learned from the syntheses of 1 and 2 has afforded the
means to access such skeletons as well, thus leading to the
preparation of two highly strained dimeric resveratrol ana-
logues. Two operations proved key to this sequence. The first
onto the Lewis acid activated carbonyl to give 25; this
intermediate then undergoes a second cyclization to generate
the observed [3.2.1] bicycle, a structure reminiscent of ampe-
lopsin F (31), which is missing only the apical aromatic ring.
In the second key operation, the developed sequence used to
incorporate the final ring of the hopeahainol D architecture
(16!2) was applied with two different Grignard reagents and
the ketone derived from 26. This process afforded smooth
syntheses of both 28 and 29, structures containing the
uniquely positioned apical ring of gnetuhainin C (24) in a
highly strained format. To give a sense of that strain, 28 is
calculated to have 4.74 kcalmolꢀ1 more strain energy than
ampelopsin F (21).[5] We believe that both 28 and 29 are
structures that could reasonably be observed in nature given:
1) the general absence of diastereocontrol with the known
resveratrol-derived [3.2.1] cores and 2) their overall stability
despite such strain. For example, under no conditions could
we epimerize the other ring-based stereocenter of 29 through
a retro Friedel–Crafts/Friedel–Crafts center to generate
gnetuhainin C (24).[19]
ꢀ
was a C C bond construction cascade which forged the parent
[3.2.1] framework from aldehyde 15 using similar reaction
conditions (ZnI2) as the case previously discussed (i.e. 13!14,
Scheme 2), differing only in reaction time. We believe that
longer exposure enables an attack of the nucleophilic alkene
In conclusion, we have successfully accomplished the first
total syntheses of the unique resveratrol-derived dimers
heimiol A (1) and hopeahainol D (2) in a racemic, but
Angew. Chem. Int. Ed. 2011, 50, 8629 –8633
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8631

Communications
route coupled with elements of the overarching strategy has
afforded access to other complex architectures possessing
high strain analogous to the [3.2.1] cores of ampelopsin F and
gnetuhainin C. More globally, this work highlights the sym-
biotic relationship between efficiency-minded synthetic
designs and the need for reagents of appropriate power and
selectivity to reduce those plans to practice,[20] with IDSI and
its sister halogen reagents being tools which we believe have
much potential.
Received: May 25, 2011
Published online: July 26, 2011
Keywords: cascade reactions · heterocycles · natural products ·
.
polyphenols · total synthesis
[1] J.-F. F. Weber, I. A. Wahab, A. Marzuki, N. A. Thomas, A. A.
Kadir, A. H. A. Hadi, K. Awang, A. A. Latiff, P. Richomme, J.
Delaunay, Tetrahedron Lett. 2001, 42, 4895 – 4897.
[2] a) S. Atun, N. Aznam, R. Arianingrum, Y. Takaya, N. Masatake,
J. Phys. Sci. 2008, 19(2), 7 – 21; b) E. H. Sahidin, L. D. Juliawaty,
Y. M. Syah, L. Din, E. L. Ghisalberti, J. Latip, I. M. Said, S. A.
Achman, Z. Naturforsch. C 2005, 60, 723 – 727.
[3] H. M. Ge, W.-H. Yang, J. Zhang, R.-X. Tan, J. Agric. Food Chem.
2009, 57, 5756 – 5761.
[4] For an excellent review on total syntheses of colchicine, see: T.
Graening, H.-G. Schmalz, Angew. Chem. 2004, 116, 3292 – 3318;
Angew. Chem. Int. Ed. 2004, 43, 3230 – 3256.
[5] Calculations were performed with the B3LYP functional in
conjunction with the 6–31G(d) basis set. Electronic energies are
from single-point calculations on the optimized geometrics.
[6] Using thermodynamic strain energy to dictate synthetic planning
is rare, though kinetic energies have been used to great effect
with one example being calculation of atropisomeric equilibra-
tions to determine the ordering of bond constructions for the
vancomycin aglycon: D. L. Boger, S. Miyazaki, S. H. Kim, J. H.
Wu, S. L. Castle, O. Loiseleur, Q. Jin, J. Am. Chem. Soc. 1999,
121, 10004 – 10011.
[7] 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.
Snyder, S. P. Breazzano, A. G. Ross, Y. Lin, A. L. Zografos, J.
Am. Chem. Soc. 2009, 131, 1753 – 1765.
[8] T. Tanaka, T. Ito, K. Nakaya, M. Iinuma, S. Riswan, Phytochem-
istry 2000, 54, 63 – 69.
Scheme 3. A) Resveratrol dimers also diastereomeric about one or two
centers. B) Application of the developed cascade-based approach to
forge other strained, cis-disposed resveratrol dimers with a different
bicyclic framework: a) ZnI2 (1.0 equiv), benzene, 258C, 3 h, 63% from
16; b) (COCl)2 (5.0 equiv), DMSO (10 equiv), CH2Cl2, ꢀ30!258C, 1 h,
then Et3N (15 equiv), 80%; c) 4-MeOC6H4MgBr (1.0m in THF,
10 equiv), THF, 258C, 20 min, 83%; d) BF3·OEt2 (10 equiv), Et3SiH
(30 equiv), CH2Cl2, ꢀ78!258C, 10 min, 99%; e) BBr3 (1.0m in CH2Cl2,
30 equiv), CH2Cl2, 258C, 24 h, 74%; f) (COCl)2 (5.0 equiv), DMSO
(10 equiv), CH2Cl2, ꢀ30!258C, 1 h, then Et3N (15 equiv), 86%; g) 2,4-
(MeO)2C6H3MgBr (0.5m in THF, 5.0 equiv), THF, 258C, 20 min, 99%;
h) BF3·OEt2 (10 equiv), Et3SiH (30 equiv), CH2Cl2, ꢀ78!258C, 10 min,
84%; i) BBr3 (1.0m in CH2Cl2, 30 equiv), CH2Cl2, 408C, 24 h, 82%.
[9] E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1353 –
1364.
[10] a) S. E. Snyder, F. A. Aviles-Garay, R. Chakraborti, D. E.
Nichols, V. J. Watts, R. B. Mailman, J. Med. Chem. 1995, 38,
2395 – 2409; b) N. J. Bach, E. C. Kornfeld, N. D. Jones, M. O.
Chaney, D. E. Dorman, J. W. Paschal, J. A. Clemens, E. B.
Smalstig, J. Med. Chem. 1980, 23, 481 – 491.
[11] B. O. Lindgren, T. Nilsson, Acta Chem. Scan. 1973, 27, 888 – 890.
[12] a) M. Curini, F. Epifano, M. C. Marcotullio, F. Montanari, Synlett
2004, 368 – 370; b) H. Gottam, T. K. Vinod, J. Org. Chem. 2011,
76, 974 – 977.
[13] S. A. Snyder, D. S. Treitler, A. P. Brucks, J. Am. Chem. Soc. 2010,
132, 14303 – 14314.
concise, stereoselective, and efficient manner. In the process,
we established a potential biogenetic relationship between
these materials. Critical elements of the developed sequence
include an iodolactonization/intramolecular Friedel–Crafts
cascade reaction empowered by the unique iodonium source
IDSI which constructed the entire [3.2.2] bicycle with the
requisite all-syn stereochemistry from an acyclic precursor.
Also required were orchestrated and stereocontrolled elab-
orations to create the strained framework of hopeahainol D
(2). In addition, the controlled diversion of intermediates en
[14] Intriguingly, use of either of these reagents separately did not
afford the desired product.
[15] It is worth noting that if 17 was first added to aldehyde 14, no
attempt at subsequent haloetherification to reach 20 directly
succeeded in any observable yield (although at best only 50% of
material could be advanced to the desired product due to the
extra stereogenic center).
8632
www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8629 –8633

[16] Earlier protection of the phenols as benzyl ethers prevented the
[19] Conditions attempted included exposure to acid and heat, as
well as the trityl cation to try and establish
equilibrium.
a dynamic
smooth preparation of alcohol 13 because of issues of additional
ꢀ
strain imparted by these groups in forging critical C C bonds.
[20] For recent examples with other unique polyphenolic natural
products, see: a) S. A. Snyder, T. C. Sherwood, A. G. Ross,
Angew. Chem. 2010, 122, 5272 – 5276; Angew. Chem. Int. Ed.
2010, 49, 5146 – 5150; b) K. C. Nicolaou, Q. Kang, T. R. Wu, C. S.
Lim, D. Y.-K. Chen, J. Am. Chem. Soc. 2010, 132, 7540 – 7548.
For an excellent review on synthetic approaches to polyphenolic
natural products in general, see: c) S. Quideau, D. Deffieux, C.
Douat-Casassus, L. Pouysꢀgu, Angew. Chem. 2011, 123, 610 –
646; Angew. Chem. Int. Ed. 2011, 50, 586 – 621. For recent work
to prepare oligomeric polyphenols beyond the dimer level, see:
d) S. A. Snyder, A. Gollner, M. I. Chiriac, Nature 2011, 474, 461 –
466; e) K. Ohmori, T. Shono, Y. Hatakoshi, T. Yano, K. Suzuki,
Angew. Chem. 2011, 123, 4964 – 4969; Angew. Chem. Int. Ed.
2011, 50, 4862 – 4867.
[17] For the isolation of these molecules, see: a) Y. Oshima, Y. Ueno,
K. Hisamichi, M. Takeshita, Tetrahedron 1993, 49, 5801 – 5804;
b) T. Tanaka, M. Ohyama, K. Morimoto, F. Asai, M. Iinuma,
Phytochemistry 1998, 48, 1241 – 1243; c) T. Tanaka, I. Iliya, T. Ito,
M. Furusawa, K. Nakaya, M. Iinuma, Y. Shitataki, N. Matsuura,
M. Ubukata, J. Murata, F. Simozono, K. Hirai, Chem. Pharm.
Bull. 2001, 49, 858 – 862; d) K.-S. Huang, Y.-H. Wang, R.-L. Li,
M. Lin, J. Nat. Prod. 2000, 63, 86 – 89.
[18] For syntheses of this molecule in both protected and non-
protected form, see: a) S. S. Velu, I. Buniyamin, L. K. Ching, F.
Feroz, I. Noorbatcha, L. C. Gee, K. Awang, I. B. Wahab, J.-F. F.
Weber, Chem. Eur. J. 2008, 14, 11376 – 11384; b) W. Li, H. Li, Y.
Luo, Y. Yang, N. Wang, Synlett 2010, 1247 – 1250.
Angew. Chem. Int. Ed. 2011, 50, 8629 –8633
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8633