Selective Macrocycle Formation in Cavitands

Article abstract of DOI:10.1021/jacs.0c12302

The traditional end-to-end cyclization of long-chain linear precursors is difficult and often unpredictable because the unfavorable entropy of macrocyclic closure allows undesired intermolecular reactions to compete. Here, we apply cavitands to the selective intramolecular aldol/dehydration reaction of long-chain α,ω-dialdehydes in aqueous solution. Hydrophobic forces drive the dialdehydes into the cavitands in folded conformations and favor macrocyclization reactions over intermolecular reactions observed in bulk solution. The macrocyclic aldol reaction products are isolated in good yields (30-85%) over a wide range (11 to 17-membered rings). Unlike conventional templates that become guests inside their assembled hosts, cavitands reverse the roles and resemble the situation in biological catalysis - the templates are hosts for guests undergoing the assisted reaction processes.

Full text of DOI:10.1021/jacs.0c12302

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Selective Macrocycle Formation in Cavitands
Ji-Min Yang, Yang Yu, and Julius Rebek, Jr.*
Cite This: J. Am. Chem. Soc. 2021, 143, 2190−2193
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ABSTRACT: The traditional end-to-end cyclization of long-chain linear precursors is difficult and often unpredictable because the
unfavorable entropy of macrocyclic closure allows undesired intermolecular reactions to compete. Here, we apply cavitands to the
selective intramolecular aldol/dehydration reaction of long-chain α,ω-dialdehydes in aqueous solution. Hydrophobic forces drive the
dialdehydes into the cavitands in folded conformations and favor macrocyclization reactions over intermolecular reactions observed
in bulk solution. The macrocyclic aldol reaction products are isolated in good yields (30−85%) over a wide range (11 to 17-
membered rings). Unlike conventional templates that become guests inside their assembled hosts, cavitands reverse the roles and
resemble the situation in biological catalysisthe templates are hosts for guests undergoing the assisted reaction processes.
he efficient synthesis of macrocycles is challenging
because bringing together the two ends of a long-chain
precursor is improbable. Success requires the rate of the
intramolecular cyclization (I to II, Figure 1) to be faster than
preorganization.3 Accordingly, several methods have been
developed, comprising guest-mediated macrocyclization,4−6
ring-closing metathesis,7 foldamer-templated catalysis of
cyclization,8 and incorporation of curved components.9
T
Molecular container hosts can fundamentally change the
chemical and physical properties of guests and are relevant to
this issue.10−18 In earlier work, we developed a series of water-
soluble, deep cavitands19−22 in which long-chain guests such as
α,ω-dienes are bound in unique, bent conformations.23 Earlier,
folded alkyl chains were observed for guests bound by
cucurbiturils,24 especially when the guests bear polar temini.25
Cavitands such as 1 bind guests in their hydrophobic interiors
in a way that guest ends are near the open end of the container,
exposed to water and reagents in solution. The cavitand is a
template that “pushes” the guest termini closer together and
offers alternatives to ring expansion methods.26 Several
reactions including monofunctionalization27−29 and macro-
lactamization23,30,31 were chaperoned by the cavitand, and here
we describe its application to the intramolecular aldol
condensation of long-chain, linear dialdehydes.
Brief sonication of dialdehydes such as dodecanedial 2a (4
mM) with cavitand 1 (1 equiv) in D2O produces 1:1
complexes. Two species are seen to be present (complex A
and complex B) with characteristic 1H NMR spectra shown in
Figure 2 (see also the Supporting Information), and the
assignments were obtained by 2D COSY experiments (Figure
S1). Complex A is the complex of dialdehyde 2a with the
cavitand 1, and the bound dialdehyde shows five time-averaged
signals clustered around 0.2 to −1.3 ppm. The conformation of
dialdehyde inside the cavitand 1 is not fixed but moves rapidly
on the NMR chemical shift time scale. The motion is probably
Figure 1. (a) Macrocyclization vs bimolecular reaction. (b) Chemical
structure and the cartoon depiction of the water-soluble, deep
cavitand 1.
the competing intermolecular reaction (I to III, Figure 1), and
the common tactic used to overcome the problem is to use
high dilution conditions.1 This can reduce intermolecular
reaction rates remarkably but requires large volumes of solvent
and slow addition of reactants (e.g., using syringe drives) with
long reaction times and is often highly substrate dependent.
Alternative macrocyclization methods involve template effects,
controlling the conformation of the precursor by some
chemical or bioprocess2 to one favorable ring closure−
Received: November 25, 2020
Published: January 28, 2021
https://dx.doi.org/10.1021/jacs.0c12302
J. Am. Chem. Soc. 2021, 143, 2190−2193
© 2021 American Chemical Society
2190

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We evaluated the aldol reaction with the various dialdehyde
1
compounds in Figure 4 and monitored by H NMR in D2O
1
Figure 2. (a) Cartoons of complexes A and B. (b) Partial H NMR
spectrum of 2a@cavitand 1. The peaks labeled with red rectangles are
from the dynamic complex A, and the peaks labeled with blue
numbers are from the more static complex B.
“yo-yo like” between two J-shaped conformations. Complex B
is the complex of dialdehyde monohydrate 2a with the
cavitand 1, and the guest assumes a folded arrangement that is
more static. Earlier studies indicate that a typical methylene
group fixed at the bottom of the cavity appears at −2.7
ppm,23,29,32 and complex B features such upfield signals. The
ratio of complex A to B is about 0.6 to 0.4 based on 1H NMR
integration (Figure S2). This is unremarkable, as hydration
equilibria for simple aliphatic aldehydes in water are typically
near unity.33,34 The dihydrate is also expected to be present,
but it is soluble enough in water (D2O) to remain in bulk
solvent as shown by NMR signals between 1.5 to 2 ppm.
We used cavitand 1 as a chaperone to form a 12-membered
ring, cyclododecene-1-aldehyde 3b, from the corresponding
C13 dialdehyde 2b (Figure 3). The complex was prepared by
Figure 4. Scope of selective intramolecular aldol condensations in
cavitand 1. Yields are isolated, and conversions are based on the ratio
1
of the substrates and products from H NMR after extraction of the
reaction solution. a Reaction was conducted with 50 mg of 2c.
(Figures S4−S13). Reactions of dialdehydes with different
chain lengths proceeded smoothly (2b−2f), giving the desired
products in good yields. Dialdehydes bearing heteroatoms also
afford the desired macrocycles in moderate to good yields
(2g−2j). When the reaction was conducted with 50 mg of 2c,
the yield (75%) of 3c decreased slightly.
The chain length affects the rate of reaction. The reaction
rates forming 12-membered macrocycles were slow (2b, 2g,
2h), and dodecanedial (2a) did not react. These medium-sized
rings show large transannular strains, and perhaps the two
aldehydes are too deep in the cavity to interact with the acid
and base catalysts in bulk solution. Stoichiometric amounts of
cavitand 1 are required for the macrocyclization, but the
cavitand can be recovered and reused with no effect on the
reaction outcomes. Since direct competition experiments
showed macrocycle 3c to be a better guest than dialdehyde
2c, classic product inhibition is expected (Figures S14−S16).
Allyl deuterated product (55% D incorporation) was observed
when 2c was treated in D2O under standard conditions. After
further experimentation, higher deuteration (>95%) was
achieved by increasing the amount pyrrolidine from 1 to 3
equiv (Figure 5).35
Figure 3. Selective intramolecular aldol condensation in the cavitand.
Conversion based on the ratio of the substrates and products from 1H
NMR after extraction of the mixture. The yield of 3b was 71% while 4
was not detected.
stirring the dialdehyde and cavitand 1 for 2 h (2.0 mM),
followed by treatment with 1 equiv each of pyrrolidine,
propylamine, acetic acid, and triethylamine at 37 °C,
conditions based on precedents from Gellman’s studies.8 The
1
reaction was monitored by H NMR spectroscopy (in D2O,
In summary, intramolecular aldol condensation of dialde-
hydes for macrocyclization can be achieved in a cavitand
see Supporting Information), and the desired product 3b was
obtained in 71% isolated yield after 20 h. The cyclodimer 4
was not detected. In contrast, when the reaction was
performed in 4% H2O, 96% isopropanol in the absence of
cavitand 1, and under the same conditions, the desired
compound 3b was not obtained. Instead, the cyclodimer 4
(20% yield) was isolated. The same reaction was performed in
H2O in the absence of cavitand 1 and under the same
conditions, guaranteeing high dilution. The cyclic compound
3b or 4 was not detected (83% conv); instead, oligomers were
formed.
Figure 5. Formation of deuterated product.
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c12302.
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AUTHOR INFORMATION
Corresponding Author
Julius Rebek, Jr. − Skaggs Institute for Chemical Biology and
Department of Chemistry, The Scripps Research Institute, La
Jolla, California 92037, United States; orcid.org/0000-
0002-2768-0945; Email: jrebek@scripps.edu
■
Authors
Ji-Min Yang − Skaggs Institute for Chemical Biology and
Department of Chemistry, The Scripps Research Institute, La
Jolla, California 92037, United States
Yang Yu − Center for Supramolecular Chemistry & Catalysis
and Department of Chemistry, College of Science, Shanghai
University, Shanghai 200444, China; orcid.org/0000-
0001-5698-3534
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c12302
Notes
The authors declare no competing financial interest.
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G.; Ballester, P.; Rebek, J., Jr.; Yu, Y. Chalcogen Bonding and
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Soc. 2020, 142, 5876−5883.
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ACKNOWLEDGMENTS
■
We are grateful for the U.S. National Science Foundation
(CHE 1801153) for support; this is contribution 30048 from
the Scripps Research Institute. Dr. Yang Yu thanks the
Program for Professor of Special Appointment (Dongfang
Scholarship) of the Shanghai Education Committee.
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