9-membered carbocycle formation: Development of distinct friedel-crafts cyclizations and application to a scalable total synthesis of (±)-caraphenol A

Article abstract of DOI:10.1002/anie.201311299

Explorations into a series of different approaches for 9-membered carbocycle formation have afforded the first reported example of a 9-exo-dig ring closure via a Au^III-promoted reaction between an alkyne and an aryl ring as well as several addi

Full text of DOI:10.1002/anie.201311299

Angewandte
Chemie
DOI: 10.1002/anie.201311299
Natural Product Synthesis
9-Membered Carbocycle Formation: Development of Distinct Friedel–
Crafts Cyclizations and Application to a Scalable Total Synthesis of
(ꢀ)-Caraphenol A**
Nathan E. Wright and Scott A. Snyder*
Abstract: Explorations into a series of different approaches for
9-membered carbocycle formation have afforded the first
reported example of a 9-exo-dig ring closure via a AuIII-
promoted reaction between an alkyne and an aryl ring as well
as several additional, unique Friedel–Crafts-type cyclizations.
Analyses of the factors leading to the success of these trans-
formations are provided, with the application of one of the
developed 9-membered ring closures affording an efficient and
scalable synthesis of the bioactive resveratrol trimer caraphe-
nol A. That synthesis proceeded with an average yield of 89%
per step (7.8% overall yield) and has provided access to more
than 600 mg of the target molecule.
addition leading to enediyne 6,[8] and ring-closing olefin
metathesis (not shown).[9] Given this landscape, as well as the
unique and sp2-rich patterning of 1 and 2 (and 11 other related
molecules)[10] that effectively precludes the application of
these three established strategies, we sought to identify
additional approaches capable of forging strained, 9-mem-
bered carbocycles. Herein, we show that a variety of Friedel–
W
hile forming any medium-sized ring requires an approach
capable of overcoming significant entropic and enthalpic
penalties,[1] the challenge in meeting that requirement is often
more pronounced in systems composed only of carbon atoms,
such as the 9-membered rings of caraphenol A (1)[2] and a-
viniferin (2),[3] two oligomeric forms of the natural product
resveratrol (3)[4,5] which are bioactive (including acetylcholin-
esterase inhibition, anti-inflammatory properties, and poten-
tial value as probes for elucidating key pathways in Alzheim-
erꢀs disease and drug resistance in tumors) (Scheme 1).[6]
Indeed, without the more obvious and established array of
productive cyclization strategies afforded by heteroatoms,
only a handful of approaches have proven capable of
accessing fully carbocyclic variants. For 9-membered rings,
that includes Grob fragmentations (such as 4!5),[7] highly
ꢁ
context specific C C bond constructions such as the acetylide
[*] N. E. Wright, Prof. Dr. S. A. Snyder
Dept. of Chemistry, Columbia University
3000 Broadway, New York, NY 10027 (USA)
Prof. Dr. S. A. Snyder
Dept. of Chemistry, The Scripps Research Institute
130 Scripps Way, Jupiter, FL 33458 (USA)
E-mail: ssnyder@scripps.edu
Homepage: http://www.scripps.edu/snyder/index.htm
[**] We thank Dr. John Decatur and Dr. Yasuhiro Itagaki for NMR
spectroscopic and mass spectrometric assistance, Alison Xiang
Gao for the synthesis of some intermediates, and Marian Deuker for
early studies. We also thank NSF (CHE-0619638) for an X-ray
diffractometer and Prof. Gerard Parkin, Dr. Aaron Sattler, and Dr.
Wesley Sattler for performing crystallographic analyses that aided
our design. Financial support was provided by the National
Institutes of Health (R01-GM84994), Bristol-Myers Squibb, Eli Lilly,
Amgen, the NSF (Predoctoral Fellowship to N.E.W.), and the
Research Corporation for Science Advancement (Cottrell Scholar
Award to S.A.S.).
Scheme 1. Strategies and tactics for the synthesis of 9-membered rings
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311299.
pertinent to natural products such as caraphenol A (1) and a-viniferin
(2).
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Crafts-type reactions promoted by either AuIII or Brønsted
acids are competent in this regard with functionally rich
substrates. In addition to providing what we believe is the first
example of a 9-exo-dig ring closure, late-stage application of
one of the developed approaches has enabled the completion
of an efficient and highly scalable total synthesis of caraphe-
nol A (1).
significantly more strain, while the strain accompanying 9-
membered ring formation appeared to be relatively
unchanged. As a result, perhaps the balance would be shifted
to larger ring synthesis.
Pleasingly, that inference from models proved true as the
exposure of substrate 18 to the same conditions (AuCl3/
AgOTf in 1,2-chloroethane at 258C for 2 h) afforded 9-exo-
dig cyclization product 19 in > 90% yield.[18] We believe this
reaction constitutes the first example of such a cyclization
mode and that its success is indeed the result of high
conformational control. In support of that assertion, 18
exists as a mixture of atropisomers about the bond highlighted
at 258C and only atropisomer 18b underwent productive
cyclization; 18a was recovered unchanged (noting that it can
be equilibrated to a mixture favoring 18b in a ca. 2.5:1 ratio
through separate heating in toluene at 808C).[19] Thus, it
would appear that the productive atropisomer forces the
alkyne into close proximity with its nucleophilic partner while
the other (18a) prevents this pair from effectively interacting
at all in either a 7-endo-dig or 9-exo-dig cyclization.
Despite this success, compound 19 proved to be a dead-
end in terms of a potential total synthesis of either 1 or 2 in
that its newly generated exocyclic olefin could not be
manipulated further using a variety of standard approaches.
Specifically, exposure to stoichiometric OsO4 in the presence
of several activators afforded only recovered starting mate-
rial, while ozonolysis and hydroboration led to decomposi-
tion. The additional, more three-dimensional, representation
of 19 within Scheme 2 may explain these outcomes, as it
highlights that the exocyclic alkene is blocked from the a-face
by the benzene ring of the seemingly remote dihydrobenzo-
furan ring system, while the neighboring methoxy substituent
blocks the b-approach. As such, a final cyclization attempt
was made with substrate 20, hoping that its allylic alcohol
could afford a 9-membered ring through acid-catalyzed
generation of an allylic cation and subsequent Friedel–
Crafts reaction. This transformation would concurrently
generate a pendant vinyl group removed from the above
described steric crowding to hopefully allow for further
manipulation. The price for that new handle, however, was
the addition of several competitive cyclization pathways, in
that the reactive cation could lead to both 6- and 8-membered
carbocycles if ring A attacked, while both 9- and 11-
membered carbocycles could result from ring B attack. In
the event, exposure of 20 to an excess of MsOH (50 equiv) in
THF at 258C[20] afforded only the 9-membered carbocycle as
a single diastereomer about the new stereocenter and in 80%
yield. Equally pleasing, the vinyl group within that material
could be converted to the exocyclic aldehyde of 21 through
oxidative cleavage.
Our interest in exploring Friedel–Crafts chemistry to
forge 9-membered rings derived, in part, from the published
conversion of 7 into 8.[11] This transformation constitutes one
of only three examples (both involving benzylic alcohols)[12]
we have identified where this ring size has resulted from such
a reaction without the possible intervention of a heteroatom
within the substrate; those two additional cases afforded a 9-
membered ring in 2.5% yield[13a] and bicyclic alkaloids in
a more efficient process.[13b–d] That rarity within constrained
systems may not be surprising in light of the potential
reversibility and rearrangement potential of such processes.
Although the specific application of this transformation to
the synthesis of caraphenol A (1) or a-viniferin (2) is
precluded by the inability to directly convert 3,5-dimethoxy-
benzyl alcohol into the same type of framework as well as the
facile rearrangement of frameworks such as 8 into smaller
carbocycles like 9 upon oxidation,[14] it did lead us to
synthesize model compound 11 over 6 steps (see Supporting
Information) as an initial model for cyclization. Gratifyingly,
we were able to obtain 9-membered ring 12 in 60% yield
following exposure of 11 to BCl3 in CH2Cl2; an additional
19% was recovered as the benzyl chloride. Worth noting is
that despite the possibility for both 6- and 9-membered ring
formation via the respective attack of the highlighted carbons
in rings A and B onto the benzylic cation derived from
ionization of the benzylic alcohol attached to ring C, no 6-
membered ring formation was observed (i.e. 11!10).[15,16]
With this result in hand, we elected to probe variants of
such Friedel–Crafts transformations via different electro-
philic activation (i.e. non-primary benzylic cations) with more
highly functionalized materials. That approach is shown here
in generalized format as precursor 13, where the goal was to
effect cyclizations that could incorporate additional function-
ality on the 9-membered ring to access 1 and/or 2 based on the
oxidation state of the bond highlighted in yellow. Unclear was
whether the presence of dihydrofuran or furan-ring systems
on the core test framework would aid or detract from the ease
of cyclization given the restrictions on rotational freedom that
their presence would impart.
Our first substrate for evaluation was alkyne 15 (see
Supporting Information for preparation), a material that we
hoped to convert into 16 through a 9-exo-dig closure
(Scheme 2). When it was exposed to a variety of cationic
Au complexes, only the combination of AuCl3 and AgOTf[17]
activated the alkyne for nucleophilic attack. In this case,
however, it exclusively afforded 7-endo-dig cyclization prod-
uct 17 (typically in > 90% yield). Fortunately, conformational
analysis using simple molecular models suggested a possible
solution to this issue of positional control. Namely, if one of
the dihydrobenzofuran rings systems within 15 was replaced
with its fully oxidized benzofuran variant, the reaction
trajectory leading to the 7-membered ring would incur
With model studies complete, we then set out to utilize
appropriately protected intermediates[21] to attempt a total
synthesis of caraphenol A (1). Starting from ketone 22
(Scheme 3, prepared in 3 steps from commercially-available
3,5-dibenzyloxybenzyl alcohol, see Supporting Information),
the dihydrofuran ring system of the target was first obtained
via a four-pot, 7-operation process involving Corey–Chay-
kovsky epoxidation,[22] ZnI2-mediated Meinwald rearrange-
ment,[23] and Grignard addition to afford triaryl 24, followed
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by benzyl ether cleavage, acid-catalyzed dihydrofuran for-
mation and silyl deprotection, and phenol reprotection. These
operations collectively provided 25 in 80% yield from 24 as
a 10:1 mixure of separable, trans- and cis-disposed dihydro-
furan diastereomers. With an eye now towards appending the
needed benzofuran ring onto this material, the free alcohol
within 25 was oxidized to a carboxylic acid and esterified to
generate 27. Subsequent treatment with nBuLi in THF at
ꢁ948C with warming to 258C over the course of 30 min,
followed by treatment with TBDPSCl, effected an anionic
Fries rearrangement[24] and in situ protection of the resulting
alcohol to afford ketone 28 in 80% yield. Then, use of the
same three-step homologation/Grignard sequence that
opened the synthesis, followed by oxidation, provided
ketone 30 as a 1:1 mixture of diastereomers about the
undefined center.
With all the atoms of the core now in place, the stage was
set to attempt benzofuran formation. Pleasingly, treatment
with HCl in a 1:1 mixture of THF and MeOH at 408C for 12 h
effected MOM ether cleavage and subsequent cyclodehydra-
tion to afford the desired aromatic system; solvent removal,
and in situ exposure to TBAF then completed the one-pot
synthesis of alcohol 31. This material was obtained as
a mixture of atropisomers that could be equilibrated to
a separable 2.8:1 mixture in favor of 31b, the isomer which in
model systems was capable of productive 9-membered ring
formation under Friedel–Crafts conditions; recycling of 31a
through additional equilibrations and separation enriched
material supplies of 31b. With this key material (31b) in hand,
it was converted into the allylic alcohol cyclization precursor
32 through Dess–Martin oxidation and vinyllithium addi-
tion.[25] Pleasingly, conditions developed in the model sub-
strate worked effectively here in cyclizing 32 to the desired 9-
membered ring in 73% yield, needing only some additional
heat (508C) to initiate and complete the desired event.
Subsequent oxidative cleavage to 33, addition of the final
aromatic ring, benzyl ether cleavage, and acid-catalyzed
closure of the final dihydrofuran afforded (ꢀ)-caraphenol A
(1). This material was identical in all respects (1H NMR,
13C NMR, HRMS) to that obtained from natural sources.[2]
Overall, the route to 1 required 23 steps from commercial
materials and, while highly linear, it was extremely efficient.
Indeed, the average yield per step was 89.5% (accounting for
an overall yield of 7.8%), each transformation was performed
on gram scale, and more than 600 mg of the final target was
synthesized overall. To put that amount of material in
perspective, it not only reflects the largest amount of any
resveratrol trimer yet synthesized,[5c] but also affords a favor-
able alternative to natural isolation where 60 kg of dried plant
material afforded 60 mg of 1 following extensive purifica-
tion.[2]
In conclusion, a number of substrates and cyclization
conditions were identified that could overcome an array of
entropic and enthalpic penalties to form strained, 9-mem-
bered carbocycles successfully from acyclic precursors. These
processes are arguably the most complex examples of
medium-sized ring formations utilizing Friedel–Crafts-type
processes and are remarkable given that a number of
additional reaction pathways could also have occurred to
Scheme 2. Explorations into key 9-membered ring formation and
further elaboration: a) AuCl3 (0.1 equiv), AgOTf (0.3 equiv),
ClCH2CH2Cl, 258C, 2 h, >90%; b) toluene, 808C, 24 h, 99%; c) AuCl3
(0.1 equiv), AgOTf (0.3 equiv), ClCH2CH2Cl, 258C, 2 h, >90%;
a) MsOH (50 equiv), THF, 258C, 3 h, 80%; b) OsO4 (0.4 equiv), NMO
(10 equiv), acetone/H2O (5/1), 258C, 12 h; c) NaIO4/SiO2 (3 equiv),
CH2Cl2, 258C, 20 min, 75% over 2 steps. Tf=triflate, Ms=methane-
sulfonate, THF=tetrahydrofuran, NMO=N-morpholine N-oxide.
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Scheme 3. Total synthesis of caraphenol A (1): a) Me3SI (6 equiv), nBuLi (1.6m in hexanes, 5 equiv), THF, 08C, 1 h; b) ZnI2 (1 equiv), benzene,
258C, 15 min; c) 23 (1.0m in THF, 1.1 equiv), THF, 258C, 10 min, 74% over 3 steps; d) H2 (1 atm), 10% Pd/C (0.5 equiv Pd), NaHCO3
(0.2 equiv), EtOAc/MeOH (1/1), 258C, 6 h, filter, concentrate; then HCl (1.25m in MeOH, 4 equiv), MeOH, 258C, 6 h, concentrate; then BnBr
(8 equiv), K2CO3 (12 equiv), nBu4NI (0.5 equiv), acetone, 258C, 12 h, 80% (10:1 d.r.); e) Dess–Martin periodinane (1.2 equiv), CH2Cl2, 258C,
30 min; f) NaClO2 (3 equiv), NaH2PO4 (8 equiv), 2-methyl-2-butene (20 equiv), THF/tBuOH (1/1), 258C, 12 h; g) 26 (1.1 equiv), K2CO3 (5 equiv),
nBu4NI (0.1 equiv), acetone, reflux, 2 h, 81% over 3 steps; h) nBuLi (1.6m in hexanes, 1.5 equiv), THF, ꢁ94 to 258C, 30 min, then TBDPSCl
(4 equiv), DBU (1 equiv), 508C, 12 h, 80%; i) Me3SI (10 equiv), nBuLi (1.6m in hexanes, 8 equiv), THF, 08C, 1 h; j) ZnI2 (3 equiv), benzene, 258C,
30 min; k) 23 (1.0m in THF, 1.1 equiv), THF, 258C, 10 min, 74%; l) Dess–Martin periodinane (1.2 equiv), CH2Cl2, 258C, 30 min, 82% over 4
steps; m) HCl (1.25m in MeOH, 20 equiv), THF/MeOH (1/1), 408C, 12 h, concentrate; then TBAF (1.0m in THF, 1.2 equiv), THF, 508C, 12 h,
88%; n) Dess–Martin periodinane (1.2 equiv), CH2Cl2, 258C, 30 min, 93%; o) vinyllithium (~1.0m in THF, 2 equiv), THF, ꢁ788C, 10 min;
p) MsOH (72 equiv), THF, 508C, 45 min, 73% over 2 steps; q) OsO4 (2.5% in tBuOH, 0.2 equiv), NMO (3 equiv), acetone/H2O (10/1), 258C,
8 h; r) NaIO4 (0.7 mmolgꢁ1 on SiO2, 5 equiv), CH2Cl2, 258C, 1 h, 76% over 2 steps; s) 23 (1.0m in THF, 1.2 equiv), THF, 08C, 10 min, 95%; t) H2
(1 atm), 10% Pd/C (2 equiv Pd), EtOAc/MeOH (1/1), 258C, 2.5 h, filter then HCl (1.25m in MeOH), MeOH, 258C, 5 min, 83%.
afford alternate ring sizes. By exploring a number of different
modes of electrophilic activation, they also include the first
reported example of a 9-exo-dig ring closure, with key
conformational analyses providing a sense of the parameters
that rendered such processes possible. Finally, application of
one of the developed approaches affected the critical
cyclization that enabled a highly efficient and scalable total
synthesis of the natural product caraphenol A (1). Further
explorations of these processes are underway and will be
reported in due course. Moreover, with ample supplies of
1 now available, biochemical evaluations of its properties can
commence in earnest; given that other molecules in this class
have been identified as potential probes and treatments for
many disease areas,[6b–f] these future studies could be of high
value.
Received: December 30, 2013
Published online: February 23, 2014
Keywords: Friedel–Crafts reaction · gold · natural products ·
.
resveratrol · total synthesis
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[16] In addition to serving as a model compound, we believe
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[18] Deliberately conservative yields are given due to the small scale
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[19] For an early example of productive atropisomer equilibration,
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