Syntheses of cyclotriveratrylene analogues and their long elusive triketone congeners

Article abstract of DOI:10.1021/ol501284s

Although interest in cyclotriveratrylene and its analogues has been significant, limitations in the ability to adjust its structure fully have hampered studies into their complete range of properties. A unique strategy to synthesize a previously unobtainable cyclotriveratrylene analogue and a procedure which adjusts the inner methylene bridges of that material to a triketone is reported. A second triketone synthesis and computational studies indicate the parameters needed for success.

Full text of DOI:10.1021/ol501284s

Letter
pubs.acs.org/OrgLett
Syntheses of Cyclotriveratrylene Analogues and Their Long Elusive
Triketone Congeners
Nathan E. Wright,† Adel M. ElSohly,† and Scott A. Snyder*,†,‡
†Department of Chemistry, Columbia University, 3000 Broadway, New York, New York 10027, United States
‡Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States
S
* Supporting Information
ABSTRACT: Although interest in cyclotriveratrylene and its analogues has been significant, limitations in the ability to adjust its
structure fully have hampered studies into their complete range of properties. A unique strategy to synthesize a previously
unobtainable cyclotriveratrylene analogue and a procedure which adjusts the inner methylene bridges of that material to a
triketone is reported. A second triketone synthesis and computational studies indicate the parameters needed for success.
ince its correct structural assignment in 1965,1,2 cyclo-
Yet, despite the increasing number of applications for this class
Striveratrylene (1, Figure 1) has received significant attention of molecules, the ability to access a full array of structural
congeners to maximize properties remains an unattained goal. At
present, elaborating the aromatic rings, or “outer rim” of
cyclotriveratrylene and its analogues, has proven achievable. For
instance, aryl derivatives of 2 have been accessed that allow for
the controlled appendage of additional groups to obtain
extended-cavity cyclotriveratrylenes with greater affinity for
certain guest molecules.10 By contrast, synthetic manipulation of
the methylene bridges, or “inner rim” of these molecules, to other
cyclotriveratrylene congeners has proven far more challenging.
For instance, Cookson and co-workers reported in 1968 that
the oxidation of cyclotriveratrylene (obtained in a single step
from alcohol 4 as shown in Scheme 1) with chromic acid could
afford its corresponding monoketone (5) and a small amount of
symmetric triketone 6.11 However, the Baldwin group refuted
this claim later that same year, proving that spirocycle 8, not 6,
was the obtained fully oxidized product; that material likely
resulted through the indicated transannular rearrangement of 6
by way of intermediate 7.12 Indeed, a similar result was observed
in 1997 upon oxidation of the parent unfunctionalized
[1,1,1]orthocyclophane 9,13 with mono- and diketone products
10 and 11 obtained alongside an analogous spirocycle (12).14 In
fact, no report of successfully accessing the triketone of
cyclotriveratrylene or any related analogue has ever been issued,
with some authors suggesting that such an outcome is
unachieveable.12,13,15 Herein, we disclose a unique route to
synthesize a novel cyclotriveratrylene-like analogue, one that may
prove extendable to other synthetically challenging congeners,
and a procedure that successfully oxidized that material to a
triketone. In addition, we show that a second cyclotriveratrylene-
due its unique, three-dimensional shape. Indeed, with a rigid
bowl-like architecture as shown in the additional depiction, one
also referred to as a “crown conformation”,3 this compound and
many of its close analogues (such as 2) have been studied in an
array of host−guest complexes, several of which have led to
exciting applications.4 Among these are size-selective buckmin-
sterfullerene hosting,5 anion and cation binding,6 as well as the
generation of self-assembled organic frameworks.7 When these
units are explicitly combined into a dimeric framework, as with
cryptophane 3,8 entirely new opportunities for binding result.
Compound 3 and its close analogues, for instance, show a
particularly high affinity for xenon, a property that is being
exploited for improved MRI-based diagnostic techniques,
including the detection of matrix metalloproteinase activity.9
Received: May 5, 2014
Figure 1. Structure of cyclotriveratrylene (1) and analogues (2 and 3).
© XXXX American Chemical Society
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Scheme 1. Synthesis of Cyclotriveratrylene (1) and Its (a)
Oxidation to Spirocycle 8, Presumably through Triketone 6,
and (b) Similar Reactivity Observed with 9
Scheme 2. (a) Inspiration for 9-Membered Ring Exploration
and (b) Synthesis and Attempted Oxidation of
Cyclotriveratrylene Derivative 15
like substrate is capable of forming a similar triketone,
establishing in the process what we believe are the structural
guidelines for when triketones can be formed with electron-rich
substrates in preference to the spirocycles observed in past
studies.
Our interest in this unique class of compounds derived from
our efforts16 to synthesize 9-membered rings within the
resveratrol natural products family, of which α-viniferin (13)17
is representative (Scheme 2a). In one design, we viewed
triketone 14 as a key intermediate, hoping that simultaneous
elaboration of all three of its carbonyl moieties would lead to the
rapid construction of the natural product. Our first attempted
route to that triketone invoked cyclotriveratrylene analogue 15 as
a precursor, hoping we could find conditions capable of effecting
its oxidation without rearrangement to a spirocycle. We began
our efforts by attempting to trimerize 16, in line with the
precedents discussed earlier (cf. Scheme 1). Unfortunately, we
did not observe any 9-membered ring formation.
This outcome was not unexpected since all successful
instances of one-step trimerizations involve substrates with an
electron-donating substituent para to the benzylic alcohol, a
group that likely assists in cation generation and thus increases
the reaction rate toward desired processes. As a result, we
embarked on an alternate, stepwise strategy to achieve the
desired intermediate as shown in Scheme 2b. Here, site-specific
monobromination and protection of benzylic alcohol 16 gave
coupling precursor 17 in 94% overall yield. This material, upon
lithiation, was then added into aldehyde 18 to give bis-benzylic
alcohol 19. Subsequent reductive removal of the hydroxyl group
then furnished the methylene bridge of 20, with repetition of the
same general sequence ultimately affording cyclization pre-
cursors 21/22. As previously reported,16,18 we found that
treatment of 21 with BCl3 accomplished the desired cyclization
to 15 in 60% yield through a Friedel−Crafts cyclization,19 with X-
ray crystallographic analysis revealing that 15 adopts a crown
conformation much like cyclotriveratrylene.
Overall, this result was gratifying in that not only had the core
carbon framework of our targeted natural product been formed,
but we had also synthesized an entirely new cyclotriveratrylene
analogue. Furthermore, the facility of the sequence and
possibilities for interchanging the three aromatic coupling
partners could potentially serve as a roadmap for the
construction of other cyclotriveratrylene analogues unobtainable
B
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Scheme 3. Attempted Cyclization of Preoxidized Intermediate
24
Scheme 4. (a) Successful Oxidation of 15 to 14 and (b)
Application to a Two-step Synthesis of Triketone Analogue 29
by the conventional, one-step acid-catalyzed trimerization
method. Unfortunately, attempted oxidation of this material
(15) with chromic acid afforded minimal oxidation of any type
with no 14 observed. Attempts to deploy other conventional
benzylic oxidations (such as Pd(OAc)2/t-BuOOH20 and DDQ)
were likewise met with poor conversion. Given the similar
electronic environment of 15 and cyclotriveratrylene (1), we
reasoned that the positioning of a methoxy group ortho to the
methylenes within 15 might be responsible, with its steric bulk
effectively blocking any incoming oxidant.
Given this failure, we next sought to preinstall the needed
carbonyls before 9-membered ring formation so as to obviate the
need for any benzylic oxidation postcyclization. Starting from the
previously synthesized TIPS-protected bromide 19 (Scheme 3),
protection of its free hydroxyl with a PMB group, followed by
lithiation and addition of the final aromatic ring, smoothly
furnished triaryl 23 in 74% yield. Next, TIPS removal using
TBAF, oxidation of the two free alcohol groups with Dess−
Martin periodinane, and PMB excision followed by in situ
alcohol oxidation smoothly delivered diketoaldehyde 24, poised
to attempt closure to a 9-membered ring.21
support of NMR, mass spectrometry, and a preliminary X-ray
crystal structure (see the Supporting Information), we were able
to identify this product as the elusive triketone (14).
As indicated, diketone 26 is the favored product of this
process, and interestingly, despite recovery of a small amount of
starting material 15, no trace of the monoketone was observed.23
Significantly, resubmission of diketone 26 to the same conditions
gave additional triketone 14 in 20% yield along with 30%
recovered 26. On the basis of these results, the first and third
oxidations would appear to occur slowly, while the second
oxidation to the diketone is more rapid.24,25 X-ray crystallog-
raphy revealed that diketone 26 and triketone 14 possess a
saddle-like conformation (shown explicitly for 14).
On initial reflection, it may seem curious that we did not see
rearrangement to the spirocyclic lactone 25 (cf. Scheme 3) from
triketone 14 as observed previously with very similar substrates;
we can stipulate that no observable trace of such a product was
obtained having already synthesized 25 by other means with full
knowledge of its spectral and chromatographic properties. We
originally postulated that the steric penalties of the requisite
intermediates needed in such a rearrangement, particularly those
of type 7 (cf. Scheme 1), might be prohibitively high when
methoxy groups are ortho- to the methylene positions, as
compared to those previous cases where no such substitution was
present. To test that theory, a series of DFT calculations
(B3LYP/6-31g*) were performed considering the energies of
the hypothetical triketone 6, triketone 14, and the corresponding
intermediates following transannular attack of both of those
triketones under acidic conditions. In the case of 6 to 7, that
process is downhill energetically by ∼3 kcal/mol; by contrast, the
same process with 14 is uphill by 0.7 kcal/mol. The difference
appears not to be due to sterics, but rather stabilization of the
protonated triketone by the neighboring o-methoxy groups in 14
that causes substantial twisting, forcing the attacking aryl group
to be orthogonal to the protonated ketone (see the Supporting
Information for structures), thereby preventing the transannular
rearrangement. To support this overall theory for successful
triketone formation from materials possessing a methoxy group
ortho to a methylene, and assuming the relative energies are
Our explorations focused on treating diketoaldehyde 24 with
various Lewis and Brønsted acids. Regrettably, these attempts
consistently afforded the same product after subsequent benzylic
oxidation with MnO2, namely spirocyclic lactone 25 as
confirmed by X-ray crystallographic analysis of a demethylated
analogue. Unclear is whether this spirocycle formed directly or if
9-membered ring formation occurred first and was followed by a
transannular rearrangement of the type detailed in Scheme 1. In
any event, resigned to the unattainability of the desired triketone
14 in line with past reports, we engaged other strategies toward
the synthesis of 9-membered ring-containing natural products,
ultimately synthesizing a related natural product through a
unique Friedel−Crafts cyclization.16
Quite some time after our initial pursuit of the triketone in the
context of Scheme 2, a publication appeared which reported new
conditions for the oxidation of cyclotriveratrylene (1) using
KMnO4 and MnO2 in refluxing pyridine.22 Although no
triketone was obtained, the authors did report a significantly
higher yield of the mono- and diketones than any previous
approach. With some 15 still in hand, we attempted its oxidation
using these same conditions. Much to our surprise, we obtained a
small amount of what appeared to be a fully oxidized product
distinct from the previously obtained spirocycle 25. Optimiza-
tion studies led to a slightly modified protocol which allowed us
to isolate that material in higher yield (Scheme 4), and with the
C
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118, 9567−9576. (b) Gawenis, J. A.; Holman, K. T.; Atwood, J. L.;
Jurisson, S. S. Inorg. Chem. 2002, 41, 6028−6031. (c) Abrahams, B. F.;
Fitzgerald, N. J.; Hudson, T. A.; Robson, R.; Waters, T. Angew. Chem.,
Int. Ed. 2009, 48, 3129−3132.
(7) Xu, D.; Warmuth, R. J. Am. Chem. Soc. 2008, 130, 7520−7521.
(8) Brotin, T.; Dutasta, J.-P. Chem. Rev. 2009, 109, 88−130.
(9) (a) Bartik, K.; Luhmer, M.; Dutasta, J.-P.; Collet, A.; Reisse, J. J. Am.
Chem. Soc. 1998, 120, 784−791. (b) Wei, Q.; Seward, G. K.; Hill, P. A.;
Patton, B.; Dimitrov, I. E.; Kuzma, N. N.; Dmochowski, A. J. J. Am.
Chem. Soc. 2006, 128, 13274−13283.
(10) Huerta, E.; Metselaar, G. A.; Fragoso, A.; Santos, E.; Bo, C.; de
Mendoza, J. Angew. Chem., Int. Ed. 2007, 46, 202−205.
(11) Cookson, R. C.; Halton, B.; Stevens, I. D. R. J. Chem. Soc. B 1968,
767−774.
(12) Baldwin, J. E.; Kelly, D. P. Chem. Commun. 1968, 1664−1665.
(13) The structure of 9 was also originally misassigned. It was first
prepared by Cannizaro in 1854 and reported as a cyclic hydrocarbon
with a general formula of (C7H6)n: (a) Cannizaro, S. Ann. Chem. Pharm.
1854, 90, 113−117. (b) Cannizaro, S. Ann. Chem. Pharm. 1854, 90,
252−254. Only in 2008 was the correct assignment made: (c) Grealis, J.
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2008, 49, 1527−1530.
similar under the basic conditions of our developed procedure,
we submitted cyclotriveratrylene analogue 29, obtained in one
step from 28,26 to the same oxidation protocol. As shown, our
prediction for oxidation without rearrangement proved correct,
with triketone 30 formed in 8% yield, just a mere two steps from
commercially available alcohol 28.27
In conclusion, we have developed a stepwise synthetic strategy
toward cycloveratrylene analogue 15, a compound unavailable
through the conventional single step approach previously
developed for cyclotriveratrylene and other related derivatives.
We believe this strategy may be generalized for other
cyclotriveratrylene analogues that do not possess the necessary
substitution pattern for a one-step, acid-catalyzed trimerization.
Furthermore, we have accomplished the first reported examples
of synthesizing cyclotriveratrylene-like triketones. Not only does
this key finding address a longstanding challenge in the field, it
also illustrates the conditions and structural requirements needed
for the formation of such materials, opening the door to further
elaboration and study of these previously unexplored “inner rim”
cycloveratrylene derivatives for new applications.
(14) Yamato, T.; Sakaue, N. J. Chem. Res., Synop. 1997, 21, 440−441.
(15) (a) Lutz, M. R.; Zeller, M.; Sarsah, S. R. S.; Filipowicz, A.;
Wouters, H.; Becker, D. P. Supramol. Chem. 2012, 24, 803−809. For
examples of related oxidation difficulty with congeners possessing
double bonds in place of the aromatic rings of the cycloveratrylene
structure, see: (b) Person, G.; Keller, M.; Prinzbach, H. Liebigs. Ann.
ASSOCIATED CONTENT
* Supporting Information
Full experimental details, copies of spectral data, computational
details/structures, X-ray crystal structures, and crystallographic
data (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
1996, 507−527. (c) Pleschke, A.; Grier, J.; Keller, M.; Worth, J.; Knothe,
̈
L.; Prinzbach, H. Eur. J. Org. Chem. 2007, 4867−4880.
(16) Wright, N. E.; Snyder, S. A. Angew. Chem., Int. Ed. 2014, 53,
3409−3413.
AUTHOR INFORMATION
Corresponding Author
■
(17) Pryce, R. J.; Langcake, P. Phytochemistry 1977, 16, 1452−1454.
(18) Although we disclosed the key Friedel−Crafts step in this
precedent, the route utilized to prepare the cyclization precursor (i.e.,
22) was not delineated.
*Email: ssnyder@scripps.edu.
Notes
(19) An additional 20% of the material was recovered as the
corresponding benzyl chloride; it could be resubmitted to the reaction
conditions and increase material throughput.
(20) (a) Yu, J.-Q.; Corey, E. J. Org. Lett. 2002, 4, 2727−2730. (b) Yu, J.-
Q.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 3232−3233. (c) Snyder, S.
A.; Sherwood, T. C.; Ross, A. G. Angew. Chem., Int. Ed. 2010, 49, 5146−
5150.
(21) For example, see: Torricelli, F.; Bosson, J.; Besnard, C.; Chekini,
M.; Burgi, T.; Lacour, J. Angew. Chem., Int. Ed. 2013, 52, 1796−1800.
(22) Sarsah, S. R. S.; Lutz, M. R.; Zeller, M.; Crumrine, D. S.; Becker, D.
P. J. Org. Chem. 2013, 78, 2051−2058.
(23) Original explorations of this process with the conditions of ref 22
did afford a small amount of the monoketone, obtained impure upon all
attempted isolations. A pure sample of that monoketone was obtained,
albeit in poor yield, from a slightly modified approach for character-
ization purposes (see the Supporting Information).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. John Decatur and Dr. Yasuhiro Itagaki of
Columbia University for NMR spectroscopic and mass
spectrometric assistance, respectively. We also thank the NSF
(CHE-0619638) for an X-ray diffractometer and Prof. Gerard
Parkin, Serge Ruccolo, Wesley Sattler, and Aaron Sattler of
Columbia University for performing crystallographic analyses.
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
A.M.E.), and the Research Corporation for Science Advance-
ment (Cottrell Scholar Award to S.A.S.).
(24) For reasons presently unclear, in each KMnO4 oxidation we could
cleanly recover only ∼50−55% of the material balance, with no other
products or decomposition observed.
REFERENCES
■
(1) This molecule was first synthesized in 1915 but was misassigned as
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(25) In ref 22., the authors report heating compound 1 with KMnO4
for 1 day; we have re-exposed 1 to our optimized conditions (3 days of
reaction time), and observed no formation of triketone or spirocycle 8.
(26) Ding, Y.; Li, B.; Zhang, G. ARKIVOC 2007, 14, 322−326.
(27) The reaction can be performed on both small and large scales (up
to ∼1 mmol). On a larger scale, the yield for the triketone products is
typically less, with the ideal for improved throughput being several
smaller scale reactions and doing a single purification. KMnO4
equivalents can range from 100−140, but less leads to inefficient
oxidation.
D
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