A Deep Cavitand Templates Lactam Formation in Water

Article abstract of DOI:10.1021/jacs.5b10028

Cyclization reactions are common processes in organic chemistry and show familiar patterns of reaction rates vs ring size. While the details vary with the nature of bond being made and the number of unsaturated atoms, small rings typically form quickly despite angle strain, medium size rings form very slowly due to internal strains, and large rings form slowly (when they form at all) because fewer and less probable conformations bring the ends of the substrate together. High dilution is commonly used to slow the competing bi- and higher molecular processes. Here we apply cavitands to the formation of medium size lactams from ω-amino acids in aqueous (D₂O) solution. The cavitands bind the amino acids in folded conformations that favor cyclization by bringing the ends closer together. Yields of a 12-membered lactam are improved 4.1-fold and 13-membered lactam 2.8-fold by the cavitand template. The results open possibilities for moving organic reactions into water even when the processes involve dehydration.

Full text of DOI:10.1021/jacs.5b10028

Communication
pubs.acs.org/JACS
A Deep Cavitand Templates Lactam Formation in Water
Simone Mosca,‡,†,⊥ Yang Yu,‡,⊥ Jesse V. Gavette,‡ Kang-Da Zhang,‡ and Julius Rebek, Jr.*,§,‡
§Department of Chemistry, Fudan University, Shanghai 200433, China
‡The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037,
United States
†Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano 20126, Italy
S
* Supporting Information
favorable shapes for cyclization and overcome the factors that
otherwise thwart the reaction.
ABSTRACT: Cyclization reactions are common pro-
cesses in organic chemistry and show familiar patterns of
reaction rates vs ring size. While the details vary with the
nature of bond being made and the number of unsaturated
atoms, small rings typically form quickly despite angle
strain, medium size rings form very slowly due to internal
strains, and large rings form slowly (when they form at all)
because fewer and less probable conformations bring the
ends of the substrate together. High dilution is commonly
used to slow the competing bi- and higher molecular
processes. Here we apply cavitands to the formation of
medium size lactams from ω-amino acids in aqueous
(D2O) solution. The cavitands bind the amino acids in
folded conformations that favor cyclization by bringing the
ends closer together. Yields of a 12-membered lactam are
improved 4.1-fold and 13-membered lactam 2.8-fold by
the cavitand template. The results open possibilities for
moving organic reactions into water even when the
processes involve dehydration.
There are many reports of bent alkanes inside container
molecules, but reactions performed on the folded states appear to
be overlooked. The earliest folded alkyl was deduced by Turro10
for a surfactant bound inside a γ-cyclodextrin. Bola-amphiphiles
folded in cucurbiturils were observed by Kim,11 both in solution
and the solid state. More recently, Gibb has described folded and
other shapes of alkanes in capsules by NMR methods.12 We also
reported a water-soluble, deep cavitand 1 (Figure 1) capable of
igh dilution and template effects are tactics often used to
Henhance cyclization reactions. The templates frequently
involve metal ions: Pedersen1 discovered that K+ templated the
synthesis of 18-crown-6, while Sauvage used Cu+ to enhance the
synthesis of catenanes.2 Pedersen’s result was unexpected and
subsequently became the foundation of host/guest chemistry.
Sauvage’s was carefully planned and gave the first mechanically
linked devices.3 Modern supramolecular chemistry has also
applied template effects. Synthetic capsules in water were used as
templates to facilitate five- or six-membered ring formation4−8 or
channel reaction pathways along otherwise unlikely paths.9 The
concave inner surfaces of capsules and cavitands bend guests into
conformations that bring the termini close together, favorable for
cyclization reactions.
Medium to large rings pose problems in addition to mere size:
Transition structures for medium-sized rings create transannular
and torsional strains along saturated alkyl chains and bringing the
ends together for cyclization limits the otherwise free rotations of
several single bonds. These enthalpic and entropic factors
contribute to high activation energies and slow cyclization rates.
Here we show that a water-soluble, deep cavitand is a template
for 12- and 13-membered lactam synthesis. Hydrophobic effects
bend the alkyl chains of the appropriate α,ω-amino acids into
Figure 1. (Left) Structures of the water-soluble, deep cavitands 1 and 2.
(Right) Modeled structure of the cavitand form; the four bridging water
molecules on the corners stabilize the vase conformation. The “feet”
have been deleted.
sequestering hydrophobic guests in unusual conformations from
aqueous solutions.13−15 Bola-amphiphiles such as ω-amino acids
fold to fit their hydrophobic parts into 1 and expose the polar
termini to the solvent water (D2O):15 The close proximity of the
functional ends suggest cyclization reactions. The pyridinium
ions of 1 are effective in imparting water solubility at
concentrations of typical NMR investigations (1 mM), but
bound guests were partially released when reagents were
introduced that altered the reaction medium. The substrates
liberated to the solvent can react independently and compromise
the efficiency of the cavitand as container for the intramolecular
pathway. The pyridinium feet of 1 were replaced with
Received: September 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b10028
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Journal of the American Chemical Society
Communication
methylimidazolium ions of the cavitand 2 (Figure 1) which
conferred higher solubility and somewhat greater stability to the
complexes.
We applied the cavitand 2 to cyclize the inexpensive ω-amino-
dodecanoic acid 3 (Scheme 1). The NMR traces of the
Cavitand 2 showed solubility in water (D2O) of up to 17 mM,
and solutions for typical NMR investigations (1 mM) in D2O
were achieved with brief shaking at room temperature. In the
absence of guests, both vase and kite conformations of 1 and 2
are present in D2O solutions: the vases correspond to the minor
species and show methine C−H signals at ∼5.7 and ∼5.6 ppm,
respectively (see SI).16,17 The kites show the (multiple) aryl C−
H signals consistent with two-fold symmetry18 and likely exist as
dimeric velcraplexes that reduce solvent-exposed hydrophobic
surfaces.19,20 Appropriate guests that fit into, fill, and solvate the
cavitand host’s hydrophobic interior shift the equilibrium to the
vase conformation. The 1H NMR signals for bound guests appear
hugely upfield-shifted (to nearly −5 ppm).21,22 The capacity of 2
for organic guests in aqueous solutions23−30 was explored using
different bolamphiphiles (e.g., α,ω-amino acids, α,ω-diamines,
α,ω-diacids, α,ω-diols) with C11 and C12 alkyl spacers (Figure 2
and SI). These spacers were selected for their availability and
optimal affinity for the congener cavitand 1.15
Scheme 1. (Top) Cyclization of 3 to 4 with EDC and Sulfo-
NHS in the Presence of 2 and (Bottom) Models of the
Complexes of 2 with Folded 3 (Left) and 4 (Right)
Figure 2. 1H NMR (600 MHz, D2O, 298 K) spectra of the complexes of
1 (1.0 mM) and 2 (1.0 mM) with (a) substoichiometric amounts and
(b) excess of ω-amino-dodecanoic acid 3; the characteristic methine
signals of the vase forms are indicated with arrows. Spectra after addition
of NaOD (c) 1 equiv, (d) 2 equiv, (e) 4 equiv The NaOD was added as
1% (v/v) solution in D2O.
1
Figure 3. Partial H NMR (600 MHz, D2O, 298 K) spectra of the
lactamization of 3 (1 mM) with 2 (excess) and sulfo-NHS (1 mM) using
sequential additions of 2 equiv EDC. (a) 3 (1 mM) with 2 (excess); (b)
sample (a), sulfo-NHS (1 mM), and EDC (2 equiv); (c) sample (a) and
EDC (6 equiv); (d) sample (a) and EDC (12 equiv); (e) sample (a) and
EDC (18 equiv); (f) the target product, 4 (1 mM) with 2 (excess). (g)
Solution control experiment: 3 (1 mM), sulfo-NHS (1 mM), and EDC
(18 equiv) were allowed to react; after complete consumption of EDC,
cavitand 2 (excess) was added to sequester the lactam product.
Competitive binding experiments with 1 revealed that
generally 2 shows higher affinity for these guests. The cavitands
1 and 2 were dissolved in D2O (1 mM), and substoichiometric
amounts of guest were sequentially added until the kite
conformation was no longer observed. The ratio between the
methine signals of 1 to 2 increases (up to ∼1) as the guests were
added, indicating the higher affinity of 2 before saturation occurs
and all of 1 also assumes the complexed vase conformation
(Figure 2 and SI). Complexes of 2 also showed higher stability to
strong base (NaOD), while both 1 and 2 were stable to strong
acid (DCl) (Figure 2 and SI).
Both cavitands 1 and 2 feature the same hydrophilic urea rims
and hydrophobic interior of the binding site, so equal binding
affinities for different guests would be expected. Perhaps the
better binding of 2 involves its improved solubility. The
mechanism of binding by these deep cavitands requires the
dissociation of the velcrand dimer, and a conformational change
from the kite to vase forms at an energetic cost of ca. 10−12 kcal
mol−1.19 The increased solubility of the monomeric forms of 2
could lower the conformational energy costs for binding.
complexed substrate are shown in Figure 3, where 9 of the 11
methylenes are seen within the shielding manifold of the cavitand
and shifted upfield. The amino acid lies in a U-shaped
arrangement inside the cavitand, with its polar functions exposed
to the solvent water and relatively close together.
The water-soluble dehydrating agent (1-ethyl-3-(3-
(dimethylamino)propyl) carbodiimide, EDC) was used with
the additive sulfo-N-hydroxy-succinimide (sulfo-NHS) (Scheme
1). Sulfo-NHS enhances the water solubility of its esters and was
expected to keep the active ester of the ω-amino-dodecanoate
exposed to the reaction medium and near the amino end. The
stacked spectra (Figure 3) show the lactam signals grow in with
B
DOI: 10.1021/jacs.5b10028
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
time and added EDC. The pH (pD) of the solution gradually
rose from 5.4 to 6.8 during the course of the reaction (see SI).
In the absence of cavitand under these conditions, mostly
oligomeric products were formed, even though the low solubility
of the amino acid in D2O ensured high-dilution conditions. The
small amount of lactam formed was detected by adding 2 after
the reaction (Figure 3g). The yield of 13-membered laurolactam
(4) was improved 2.8-fold in the presence of 2 (see SI). The
effect of the cavitand was more dramatic when ω-amino-
undecanoic acid 5 was employed as substrate (Figure 4). In the
absence of cavitand the amount of lactam formed was negligible,
and addition of 2 provided 4.1-fold improved yield, as measured
by NMR integration (see SI).
Figure 5. (Top) Structure of C11PNP (left) and cartoon of the complex
with 2 (right). The relative positions of the C atoms in the cavitand
correspond to their NMR signals and the NICS calculations21 (see SI).
(Bottom) 1H NMR spectra (600 MHz, D2O, 298 K) of the attempted
lactamization of C11PNP. (a) C11PNP hydrochloride salt (1 mM) with
2 (excess); (b) sample (a) after addition of NaOD (3 equiv); (c)
authentic amino acid 5 (1 mM) with 2 (excess).
receptors are seen to have parallel features. Species unknown
in solution emerge in the protected space of container molecules:
reactive intermediates such as activated acids,33 hemiaminals, and
other tetrahedral intermediates have been stabilized,34 and
contortions of alkyl groups into helices35 are common.
Admittedly, the lactamization described here is stoichiometric
in the cavitand and classical product inhibition places limits on its
application. The efficient extraction of the (neutral) lactam
products from their cavitand complexes with organic solvents
bodes well for a future catalytic version of this reaction in a two-
phase system. But the present study reveals a more pressing
need: How to effect dehydration reactions in water? Nature’s
reagent, ATP, is ineffective in the absence of enzymes, but
chemists have few alternatives such as EDC, used here in
spectacular excess. One of the main themes of “green” chemistry
is the wholesale movement of chemical reactions out of organic
solvents and into water.36 Complex formation between cavitands
and these guests requires water, and subsequent reactions cannot
require “dry” conditions. Can additives be found that modify the
water’s reactivity? The successful application of hexafluoroiso-
propanol, particularly in remote functionalization reactions,37
offers promise in this regard.
1
Figure 4. Partial H NMR spectra (600 MHz, D2O, 298 K) of the
lactamization of 5 with 2 and sulfo-NHS (1 mM) using sequential
additions of 2 equiv EDC. (a) 5 (1 mM) with 2 (excess); (b) sample (a),
sulfo-NHS (1 mM), and EDC (2 equiv); (c) sample (a) and EDC (4
equiv); (d) sample (a) and EDC (8 equiv); (e) sample (a) and EDC (12
equiv); (f) the target product, 6 (1 mM) with 2 (excess). (g) Solution
control experiment: 5 (1 mM), sulfo-NHS (1 mM), and EDC (12
equiv) were allowed to react; after complete consumption of EDC,
cavitand 2 (excess) was added to sequester the lactam product.
We also prepared the p-NO2-phenyl ester of 5 (C11PNP).
Earlier reported attempts at cyclization of 5 under high dilution
had failed to give reasonable yields of ω-amino-undecanoic acid
lactam (6).31 The amino ester was expected to adopt a U-shape
in the cavitand, appropriate for cyclization. Indeed, C11PNP as
the hydrochloride formed a stable complex with 2 (Figure 5).
However, neutralization of the complex with NaOD (3 equiv)
gave neither the free amine of the PNP ester nor lactam 6.
Instead, the complexed amino acid 5 was formed. Apparently, the
p-NO2-phenyl group becomes exposed to D2O and suffers
hydrolysis.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b10028.
Additional information and figures (PDF)
Outlook. One of the lessons emerging from the study of
synthetic container compounds is that molecules in dilute
solutions do not behave as they do in confined spaces; spaces like
enzyme or receptor active sites. The keys to how enzymes work32
comprise creating specialized microenvironments that alter the
reactivity of catalytic groups, shielding the groups from contact
with bulk solvent, and distorting the substrates to adopt high-
energy conformations with increased reactivity. Synthetic
AUTHOR INFORMATION
■
Corresponding Author
*jrebek@scripps.edu
Author Contributions
⊥These authors contributed equally.
Notes
The authors declare no competing financial interests.
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DOI: 10.1021/jacs.5b10028
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Journal of the American Chemical Society
Communication
(31) Peng, P. P.; Hodge, P. Polymer 1998, 39, 981−990.
ACKNOWLEDGMENTS
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(32) Ringe, D.; Petsko, G. A. Science 2008, 320, 1428−1429.
(33) Restorp, P.; Rebek, J., Jr. J. Am. Chem. Soc. 2008, 130, 11850−
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This research was supported by National Science Foundation
(CHE 1506266) and a Marie Curie International Outgoing
Fellowship within the seventh European Community Frame-
work Programme. Grant PIOF-GA-2013-627403 provided a
postdoctoral fellowship to S.M.
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DOI: 10.1021/jacs.5b10028
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX