Efficient macrocyclization achieved via conformational control using intermolecular noncovalent π-cation/arene interactions

Article abstract of DOI:10.1021/ja106053x

Quinolinium salt 3 is an effective additive that acts as a conformation control element (CCE) to promote macrocyclization to form rigid cyclophanes via olefin metathesis or Glaser-Hay coupling, which do not cyclize in the absence of the additive. The additives are easily synthesized and highly modifiable and have solubility profiles which allow for simple recovery via filtration.

Full text of DOI:10.1021/ja106053x

Published on Web 08/25/2010
Efficient Macrocyclization Achieved via Conformational Control Using
Intermolecular Noncovalent π-Cation/Arene Interactions
Philippe Bolduc, Alexandre Jacques, and Shawn K. Collins*
UniVersite´ de Montre´al, De´partement de Chimie, C.P. 6128 Station Downtown, Montre´al, Que´bec, H3C 3J7, Canada
Received July 8, 2010; E-mail: shawn.collins@umontreal.ca
In searching for potential CCEs that would interact with
Abstract: Quinolinium salt 3 is an effective additive that acts as
a conformation control element (CCE) to promote macrocycliza-
tion to form rigid cyclophanes via olefin metathesis or Glaser-Hay
coupling, which do not cyclize in the absence of the additive. The
additives are easily synthesized and highly modifiable and have
solubility profiles which allow for simple recovery via filtration.
molecules through noncovalent interactions with arenes,9 our
attention was drawn to biological systems, where cation/arene
interactions are well documented to enforce a conformational bias.10
We decided to investigate using π-cations as CCEs in the
macrocyclization of [12]paracyclophanes, as these systems are found
in natural product structures and had already been demonstrated
as challenging and difficult macrocyclizations.7
Macrocycles are prevalent in numerous fields of chemistry and
are key structural motifs in natural products,1 pharmaceuticals,2
Table 1. Optimization of Conformational Control Element (CCE)
materials science,3 and supramolecular chemistry.4 Rigidified or
strained macrocycles are of particular interest as their shape persistent
structures can be exploited in medicinal chemistry2 and for well-defined
carbon-based materials.5 However, the desired strain or rigidity in the
resulting macrocycle can render macrocyclization problematic unless
some form of conformational control is exerted over the precursors.
This is exemplified in the synthesis of cyclophane-containing natural
products that possess inflexible aromatic cores, where increased dilution
does not enable cyclizations.6
a Isolated yields after chromatography.
Figure 1. Strategies for achieving conformation control in acyclic
Thus, we began our investigations with the macrocyclization of
precursors prior to macrocyclization.
ester 1 via olefin metathesis. Upon treating ester 1 under standard
The traditional strategy to enforce conformational control
involves installing a substituent on the macrocyclization precursor
(Figure 1). The substituent can be placed next to the aromatic core3
or, alternatively, attached onto the aromatic moiety.7 In either case,
these conformational control elements (CCEs) help orient the acyclic
precursors in a conformation that is conducive to ring closure.
Although macrocyclization can be achieved using these methods,
a disadvantage is that a number of synthetic steps may be required
to install and/or remove the CCE (an additional two or more steps).
An alternative strategy would be to control the conformation of
the macrocyclic precursor via an intermolecular noncovalent
interaction with an inexpensive, readily available additive that can
be easily separated through simple workup procedures. Herein we
report that difficult macrocyclizations can be achieved through the
use of quinolinium cations as intermolecular CCEs.8
macrocyclization conditions (Table 1, entry 1), only linear dimers
and higher oligomers were observed.11 Upon repeating the mac-
rocyclization with the addition of the N-Me-pyridinium iodide, the
desired macrocycle 2 was isolated in 31% yield. Further increases
in yield were observed upon changing the counterion to PF6- (40%
yield).12 Further substitution of the pyridine nucleus was also not
beneficial, as the inclusion of electron-withdrawing groups (entries
4, 5, and 6), electron-donating groups (entry 7), or N-substitution
(entries 8 and 9) did not result in an increase in the isolated yield
of 2. Finally, we investigated increasing the size of the CCE. Both
-
N-Me-benzo[h]quinolinium and isoquinolinium PF6 were unsuc-
cessful at increasing the yield of 2. However, both the quinolinium
3 and its 3-cyano analog afforded a 45% yield of 2. Upon
identifying 3 as an optimal CCE for olefin metathesis-mediated
macrocyclizations, we next probed its substrate scope (Table 2).
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12790 J. AM. CHEM. SOC. 2010, 132, 12790–12791
10.1021/ja106053x  2010 American Chemical Society

C O M M U N I C A T I O N S
Importantly, we first determined the ester functionality of 1 was
not necessary and that additional substituents were tolerated, as the
[12]paracyclophanes 5 and 6 were isolated in 50% and 45% yield
respectively. Larger macrocycles such as the [13]paracyclophanes 8
as well as [14]paracyclophane 9 were isolated in good yields. Similarly,
[12]metacyclophanes 7 and 10 could also be isolated in good yields
(61% and 45% respectively). All paracyclophanes shown in Table 2
are not observed when macrocyclizations are carried out in the absence
of additive, except 9, which is formed in 50% yield.
These observations demonstrate the potential applicability of the
cationic CCEs to improve general macrocyclizations by allowing
the reactions to be conducted at much higher concentrations.
The mechanism by which 3 interacts with the macrocyclization
substrates merits some discussion. There is precedent in the literature
both experimentally8b and theoretically8c to support a face-to-face
pyridinium/arene interaction, although recent theoretical studies have
shown that T-shaped conformations are also energetically possible.8d
In summary, the quinolinium salt 3 is an effective additive that acts as
a CCE to promote macrocyclization to form rigid cyclophanes via olefin
metathesis or Glaser-Hay coupling, which do not cyclize in the absence
of the additive. The additives are easily synthesized and highly modifiable,
have solubility profiles which allow for recovery via filtration, and have
demonstrated the ability to enforce conformational control to promote
macrocyclization at higher concentrations and temperatures. Further study
is directed toward determining the exact mechanism by which 3 promotes
macrocyclization and examining applications in asymmetric and natural
product synthesis.
Table 2. Macrocyclizations via Metathesis Employing 3 as a CCE
Acknowledgment. The authors thank NSERC (Canada) and
Merck Frosst (Canada) for generous financial support and Materia
Inc. for generous donation of catalyst 4.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Table 3. Glaser-Hay Macrocyclizations Employing 3 as a CCE
References
(1) (a) Shu, Y. Z. J. Nat. Prod. 1998, 61, 1053–1071. (b) Newman, D. J.;
Cragg, G. M.; Snader, K. M. Nat. Prod. Rep. 2000, 17, 215–234. (c)
Fu¨rstner, A. Eur. J. Org. Chem. 2004, 5, 943–958.
(2) Driggers, E. M.; Hale, S. P.; Lee, J.; Terrett, N. K. Nat. ReV. Drug Dis.
2008, 7, 608–624.
(3) Seo, S. H.; Jones, T. V.; Seyler, H.; Peters, J. O.; Kim, T. H.; Chang,
J. Y.; Tew, G. N. J. Am. Chem. Soc. 2006, 128, 9264–9265.
(4) For reviews on macrocyclization in synthesis, see: (a) Blankenstein, J.;
Zhu, J. Eur. J. Org. Chem. 2005, 10, 1949–1964. (b) Yeung, K.-S.; Paterson,
I. Angew. Chem., Int. Ed. 2002, 41, 4632–4653.
(5) (a) Zhang, W.; Moore, J. S. Angew. Chem., Int. Ed. 2006, 45, 4416–4439.
(b) Haley, M. M. Pure Appl. Chem. 2008, 80, 519–532.
(6) (a) Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002,
124, 773–775. (b) Commeureuc, A. G. J.; Murphy, J. A.; Dewis, M. L.
Org. Lett. 2003, 5, 2785–2788.
To demonstrate the generality of the quinolinium based CCEs,
Glaser-Hay couplings were also investigated (Table 3). Three
diyne-containing macrocycles were also prepared using 3 as a CCE.
Macrocyclization under standard conditions afforded the corre-
sponding metacyclophanes 11 and 12 in 42% and 40% yields
respectively. The paracyclophane 13 was also prepared in 42%
yield. Note that all macrocyclization products shown above are not
observed when carried out in the absence of the additive. The results
also demonstrate the ability of the CCEs to promote conformational
control even under elevated temperatures and in the presence of a
competing π-rich solvent like toluene.
(7) (a) El-Azizi, Y.; Schmitzer, A.; Collins, S. K. Angew. Chem., Int. Ed. 2006,
45, 968–973.
(8) N-Alkylpyridinium salts have been used to effect facial bais in other synthetic
transformations. See: (a) Yamada, Y. S.; Morita, C. J. Am. Chem. Soc. 2002,
124, 8184–8185. For more on pyridinium/arene interactions, see: (b) Yamada,
S.; Tokugawa, Y. J. Am. Chem. Soc. 2009, 131, 2098–2099. (c) Yamada, S.;
Yamamoto, J.; Ohta, E. Tetrahedron Lett. 2007, 48, 855–858. (d) Tsuzuki,
S.; Mikami, M.; Yamada, S. J. Am. Chem. Soc. 2007, 129, 8656–8662.
(9) Perfluorarene/arene interactions were also investigated but were unsuc-
cessful. For some recent uses of quadrupolar interactions, see: (a) Woll,
M. G.; Hadley, E. B.; Mecozzi, S.; Gellman, S. H. J. Am. Chem. Soc. 2006,
15932–15933. (b) Watt, S. W.; Dai, C.; Scott, A. J.; Burke, J. M.; Thomas,
R. L.; Collings, J. C.; Viney, C.; Clegg, W.; Marder, T. B. Angew. Chem.,
Int. Ed. 2004, 43, 3061–3063.
(10) (a) Torrice, M. M.; Bower, K. S.; Lester, H. A.; Dougherty, D. A. Proc.
Natl. Acad. Sci. U.S.A. 2009, 106, 11919–11924. (b) Hanek, A. P.; Lester,
H. A.; Dougherty, D. A. J. Am. Chem. Soc. 2008, 130, 13216–13218. (c)
Dougherty, D. A. Science 1996, 271, 163–168.
The quinolinium additives are easily recyclable;13 following
cyclization, the reaction mixture is concentrated and the addition
of Et2O or ethyl acetate causes the precipitation of the additive as
a white solid that is easily collected via filtration (>95% recovered)
and can be reused in subsequent macrocyclizations.14 Furthermore,
the CCEs can improve the yields of macrocyclizations that normally
function without the need for conformational control, even at higher
concentrations (Table 2).15 Macrocyclization afforded the macro-
cycle 9 in 50% yield in the absence of additive ([M] ) 2 × 10-4).
At identical concentrations, the addition of 3 as a CCE greatly
improved the isolated yield, affording the macrocycle in 89%
isolated yield. As such, we increased the concentration 2-fold and
observed an isolated yield of 67% for 9. Following increasing the
concentration 4-fold, the isolated yield of the macrocycle was 61%.
(11) More reactive catalysts resulted in ring opening of the desired macrocycle.
Thus, 4 was required at higher catalyst loadings to ensure 100% conversion.
(12) When reduced amounts of 3 are used, the yields decrease (10 equiv of 3
) 27%, 1 equiv of 3 ) 25%). Increasing the amount of additive also did
not improve the reaction (50 equiv of 3 ) 22%). Possible explanations for
these effects are under investigation.
(13) See Supporting Information for details.
(14) The additives are hygroscopic and are placed in an oven (>100°C) overnight
before use. Quinolinium 3 has been reused in the macrocyclization of 1
without any drop in yields.
(15) For an example of scaling a macrocyclization reaction to industrially relevant
scales, see: (a) Farina, V.; Shu, C.; Zeng, X.; Wei, X.; Han, Z.; Yee, N. K.;
Senanayake, C. H. Org. Process Res. DeV. 2009, 13, 250–254. (b)
Tsantrizos, Y. S.; Ferland, J.-M.; McClory, A.; Poirier, M.; Farina, V.;
Yee, N. K.; Wang, X.-j.; Haddad, N.; Wei, X.; Xu, J.; Zhang, L. J.
Organomet. Chem. 2006, 691, 5163–5171.
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