The effect of host structure on the selectivity and mechanism of supramolecular catalysis of Prins cyclizations

Article abstract of DOI:10.1039/c4sc02735c

The effect of host structure on the selectivity and mechanism of intramolecular Prins reactions is evaluated using K₁₂Ga₄L₆ tetrahedral catalysts. The host structure was varied by modifying the structure of the chelating moieties and the size of the aromatic spacers. While variation in chelator substituents was generally observed to affect changes in rate but not selectivity, changing the host spacer afforded differences in efficiency and product diastereoselectivity. An extremely high number of turnovers (up to 840) was observed. Maximum rate accelerations were measured to be on the order of 10⁵, which numbers among the largest magnitudes of transition state stabilization measured with a synthetic host-catalyst. Host/guest size effects were observed to play an important role in host-mediated enantioselectivity.

Full text of DOI:10.1039/c4sc02735c

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The effect of host structure on the selectivity and
mechanism of supramolecular catalysis of Prins
cyclizations†
Cite this: DOI: 10.1039/c4sc02735c
William M. Hart-Cooper, Chen Zhao, Rebecca M. Triano, Parastou Yaghoubi,
*
*
Haxel Lionel Ozores, Kristen N. Burford, F. Dean Toste, Robert G. Bergman
*
and Kenneth N. Raymond
The effect of host structure on the selectivity and mechanism of intramolecular Prins reactions is evaluated
using K12Ga4L6 tetrahedral catalysts. The host structure was varied by modifying the structure of the
chelating moieties and the size of the aromatic spacers. While variation in chelator substituents was
generally observed to affect changes in rate but not selectivity, changing the host spacer afforded
differences in efficiency and product diastereoselectivity. An extremely high number of turnovers (up to
840) was observed. Maximum rate accelerations were measured to be on the order of 105, which
numbers among the largest magnitudes of transition state stabilization measured with a synthetic host-
catalyst. Host/guest size effects were observed to play an important role in host-mediated
enantioselectivity.
Received 5th September 2014
Accepted 18th November 2014
DOI: 10.1039/c4sc02735c
www.rsc.org/chemicalscience
a purely synthetic active site mimic.29 In contrast to catalysis
in acidic aqueous solution, which affords cyclic diol prod-
Introduction
ucts, host-catalyzed cyclizations resulted in high selectivity
for alkene products. This example of selectivity parallels that
of terpene synthases such as limonene synthase.30 In a more
recent development, a chiral ligand that self-assembles in an
enantiopure fashion was prepared, affording enantiomeric
terephthalamide-based hosts (L4- or D4-2). These hosts were
observed to effect an enantioselective variant of the Prins
reaction.31 Inhibition experiments have indicated that catal-
ysis proceeds initially through substrate encapsulation,
which is reversible and rapid.24,32,33 In light of these devel-
opments, investigation into the sources of the observed
chemo-, diastereo-, and enantioselectivities of these reac-
tions was pursued.
We present a mechanistic study of the Prins cyclization in
supramolecular host catalysts whose structures were
systematically varied in the choice of chelator (CAM ¼ cat-
echolamide, TAM ¼ terephthalamide) and spacer (Nap ¼
naphthalene, Pyr ¼ pyrene; Fig. 1). Differences in catalytic
rate, as well as product chemo-, diastereo- and enantiose-
lectivity were found. The nature of host-mediated enan-
tioinduction was investigated through the kinetic resolution
of racemic substrates. These studies are supported by kinetic
analysis and quantitative rate accelerations that provide an
improved understanding of host structure on a chemo-
selective and stereochemically complex reaction.
Enzymes use precisely tailored binding pockets to mediate
stereoselective catalysis.1–5 For example, terpene synthases
catalyze the cyclization of simple precursors to over 70 000
known small molecule natural products.6–8 While these
enzymes clearly demonstrate a high degree of chemical diver-
gence, precisely how they do so is an area of continuing and
fruitful investigation.
In recent years, the eld of supramolecular catalysis has
progressed toward understanding the role of chemical micro-
environments during catalysis.9–23 Analogous to the active sites
of many enzymes, synthetic hosts mediate catalysis through the
organization of catalytically relevant functional groups that
lower activation barriers relative to those that would be present
in bulk solution. These strategies have relied on local concen-
tration effects, electrostatics, pKa shis and the use of host–
guest orientation to stabilize high-energy intermediates and
transition states.
We have previously reported the use of a racemic, homo-
chiral (L4 or D4) K12Ga4L6 tetrahedron ((ꢀ)-1) to catalyze the
Prins cyclization of monoterpene derivatives.24 While cata-
lytic antibodies25–28 have been shown to mimic key properties
of terpene synthases, the tetrahedron described above acts as
Chemical Sciences Division, Lawrence Berkeley National Laboratory, Department of
Chemistry, University of California, Berkeley, California 94720, USA. E-mail:
fdtoste@berkeley.edu; rbergman@berkeley.edu; knraymond@socrates.berkeley.edu
† Electronic supplementary information (ESI) available: Kinetics plots are
available free of charge. See DOI: 10.1039/c4sc02735c
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100 mM phosphate buffer cosolvent. Aer heating, the organic
portions of the reaction mixtures were extracted and product
distributions measured by 1H NMR integration. During these
trials product ratios were found to be insensitive to moderate
changes in cosolvent composition, temperature, time and pD.
Initially, differences in product selectivity resulting from the
choice of host chelator were examined by comparing product
mixtures following treatment of various substrates with (ꢀ)-1
and 2. The extent to which enantiopure 2 distinguishes between
enantiomers (S)-5a and (R)-5a was tested. Note that this exper-
iment is not possible with resolved (ꢀ)-1 due to the presence of
+
residual NMe4 , which inhibits catalysis.31,42,43 Product ratios
varied between these treatments, with a higher trans selectivity
observed between D4-2 and (R)-5a (trans/cis: 69/31, entry 3a)
than with D4-2 and (S)-5a (trans/cis: 48/52, entry 2a). The aver-
aged product trans/cis selectivity resulting from these treat-
ments (58/42) is similar to that resulting from treatment of
racemic 5a with host (ꢀ)-1 (65/35, entry 1a). In order to achieve
similar levels of conversion under otherwise identical condi-
tions, it was necessary for catalyst loadings of D4-2 to vary by a
factor of two between treatments of (R)-5a and (S)-5a, an
observation which suggests a moderate degree of recognition
between D4-2 and enantiomers of 5a. Likewise, trans/cis ratios
were within error between treatments of (ꢀ)-1 or D4-2 with 5c,
although a difference in selectivity between (ꢀ)-3 and L4-4
(entries 4a and 5a) with substrate (ꢀ)-5a was observed for
reasons that are unclear. Nonetheless, in the majority of trials
completed, varying the host chelator did not affect product
Fig. 1 K12Ga4L6 assemblies discussed in this work. Spheres represent
Ga3+ centers and lines represent ligands as depicted (CAM ¼ cat-
echolamide, TAM ¼ terephthalamide, Nap ¼ naphthalene, Pyr ¼ pyr-
ene). Only one ligand enantiomer is shown for 2 and 4. Potassium ions
are omitted for clarity.
Results and discussion
Effects of host structure on product selectivity
Differences in selectivity were examined by varying the struc- selectivities by more than a small margin.
tures of both hosts and substrates. It has been established that
Next, product distributions from naphthalene-based cata-
host catalysts oen exhibit strict substrate selectivity based on lysts were compared to those resulting from treatment with
guest size.34,35 Following this precedent, the interaction of host larger pyrene analogues (ꢀ)-3 and 4. In contrast to the selectivity
and substrate size was tested by examining the effect of observed from catalysis by D4-2, treatment of 5c with pyrene-
increasing host cavity volume on reaction stereoselectivity. based L4-4 resulted in the rapid formation of trans product with
Earlier reports have documented the difficulty of preparing high selectivity (trans/cis: 98/2: entry 4b), demonstrating that
pyrene-core host (ꢀ)-3 in the absence of a strongly-bound increasing host cavity size through the use of a larger spacer can
template.36 However, treatment of reaction mixtures containing enhance stereoselectivity for trans products. In contrast, the
appropriate metal and ligand components with KOH and high trans selectivities in entries 8a and 9a reect the stereo-
acetone allowed for the isolation of (ꢀ)-3 and 4, in analogy with chemical preference of substrate 5b due to a substantial 1,3-
the procedure reported for the preparation of solvent-occupied diaxial repulsion. When corrected for catalyst concentration,
(ꢀ)-1.37 Previously, D4-1 mediated enantioselectivities of up to cyclization of 5c by L4-4 proceeds more efficiently than that of
78% in the aza-Cope rearrangement of enammonium cations D4-2 based on pseudo-rst-order ts to the levels of conversion
and 69% in intramolecular Prins reactions were observed, a presented in Scheme 1 (krel z 5; DDG‡ ¼ 1 kcal molꢁ1). This
result which attests to the potentially high degree of enantio- preference for trans products was also observed between treat-
differentiation between D4-1 and catalytically relevant ment of (ꢀ)-5a with naphthalene host (ꢀ)-1 and pyrene
substrates.31,38 These examples of molecular recognition have analogues (ꢀ)-3 and L4-4 (entries 1a, 4a and 5a). From these
been attributed to predominantly steric and p-interactions, as results, it is clear that exchanging a naphthalene for a pyrene
chiral induction is thought to proceed through contact of guest spacer can affect a change in product diastereoselectivity that is
with naphthalene spacers. Given this precedent, the investiga- consistent among different substrates (5a and 5c), as well as
tions reported herein were focused on a class of substrates that different hosts ((ꢀ)-3, L4-4).
differ in their alkyl substituents at the b-position but are other-
Collectively these observations suggest that the nature of
wise identical with regard to functional groups. This modica- chelator (CAM or TAM) used has little effect on the diaster-
tion was aimed at avoiding the introduction of additional eoselectivity of this reaction. An exception to this trend results
functional groups39–41 in the substrate that could dramatically when the enantiopure hosts D4-2 or D4-4 interact in a diaste-
alter the mechanism or stability of these compounds. Toward reomeric fashion with substrate enantiomers (i.e. (S)- and (R)-
this end, terpene derivatives 5a–c were separately treated with 5a). In contrast, the choice of spacer has a clear effect on
catalysts in either pure phosphate buffer solution or MeOD-d4/ product distributions, as is apparent from product selectivities
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factor (s; eqn (1)),44 which is determined by DDG‡ between dia-
stereomeric transition states. It was hypothesized that if the size
of substrates was increased, an increase in s may be observed due
to increased steric interactions between encapsulated substrate
and the aromatic walls of L4-2, which are presumably the surfaces
that induce enantioselectivity in these reactions.31,38
Toward this end, selectivity factors were measured for chiral
starting materials 5a and 5b (1 : 1 MeOD-d4/100 mM phosphate
buffer cosolvent, pD 5.00, 25 ꢂC). While L4-2 exhibited low
chiral discrimination for 5a (s ¼ 1.8; DDG‡ ¼ 0.35 kcal molꢁ1),
selectivity increased for larger substrate 5b (s ¼ 4.45; DDG‡ ¼
0.88 kcal molꢁ1). Following this observation, product ee's
resulting from the cyclization of 5c with hosts D4-2 and L4-4
were compared. In the latter case, an analogous trend was
observed; product enantioselectivity was greater when a smaller
cavity was used (entry 2b, 61% ee; DDG‡ ¼ 1.14 kcal molꢁ1
;
Scheme 1)31 relative to a larger one (entry 4b, ꢁ33% ee; DDG‡ ¼
0.56 kcal molꢁ1; Scheme 1). In further support of this notion, a
smaller degree of recognition (indicated by small differences in
product selectivity and conversion) was observed between
enantiomers of 5a and host D4-4 (entries 6a and 7a) compared to
analogous trials with smaller host D4-2 (entries 2a and 3a).
While these observations are consistent with the notion that the
magnitude of host-mediated enantioinduction increases with
guest size (or decreases with host cavity size), it should be noted
an analogous trend was not observed between two previously
reported achiral Prins substrates.31
‡
kfast
DDG
RT
s ¼
¼ e
(1)
kslow
Scheme 1 General conditions effective in the cyclizations of (a) chiral
substrates 5a–c and (b) achiral substrate 5c with catalysts 1–4. a50 mM
phosphate buffer, pH 7.50; b100 mM phosphate buffer, pD 8.00; c1 : 1
MeOD-d4/100 mM phosphate buffer, pD 8.00; d1 : 1 MeOD-d4/100
mM phosphate buffer, pD 5.00; eproduct not observed by 1H NMR
spectroscopy or GC-MS. fA single trans product was exclusively
formed; the relative stereochemistry at the 1-position (–Me/–nPr)
could not be unambiguously determined. Selectivity measurements
have an estimated error of #3%.
Mechanistic considerations
In order to determine the role of catalyst, substrate and bulk
solution acidity on reaction rate, the order in (ꢀ)-1, 5c and D+ were
determined using initial rate measurements (1H NMR spectros-
copy). Because this reaction proceeds initially by a reversible
encapsulation pre-equilibrium, saturation of catalyst by substrate
is possible in principle. In practice, however, saturation by 5c was
not observed due to the low affinity of this substrate for (ꢀ)-1 or 2
and the limited solubility of substrate in MeOD-d4/phosphate
buffer cosolvent. Consequently, the rate of reaction was measured
to be rst-order in (ꢀ)-1 as well as substrate 5c. In contrast, a
0.4(1)-order dependence was measured between kobs and D+ over
the pD range 6.9–8.0. Taken together, these experiments
demonstrate that the (ꢀ)-1-catalyzed cyclization of 5c obeys the
empirical rate law: rate ¼ kobs[substrate][host][D+]0.4(1), which at
constant pD reduces to rate ¼ kobs[substrate][host]. These
measurements and subsequent observations described below are
consistent with the mechanisms proposed in Scheme 2.
resulting from treatment of 5a–c with hosts (ꢀ)-1 and 2
compared to (ꢀ)-3 and 4. Generally, it was observed that trans
selectivity increases with cavity size, which may also accompany
an improvement in catalytic efficiency. Consistent with these
observations, gas-phase DFT calculations. Suggest that the
barrier for the cyclization of 5a is slightly lower for the transition
state leading to the major trans product compared to that
leading to the corresponding cis product.40 Based on these
results, it is likely that the constrictive cavities of (ꢀ)-1 and 2
may destabilize the transition state leading to trans products, an
effect that also results in higher selectivity for cis products
relative to analogous reactions in larger hosts (ꢀ)-3 and 4.
Effect of host and guest size on enantioselective catalysis
Investigation of the catalytic steps
Aldehyde-hydrate (Khyd) and encapsulation (K1) pre-equilibria
The relationship between guest volume and catalyst enantiose-
lectivity was investigated in the kinetic resolution of chiral starting
material. In a catalytic kinetic resolution, the relative reaction Under aqueous conditions, aldehyde-containing substrates
rates of substrate enantiomers can be expressed as a selectivity underwent reversible hydration, a process which was observed
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Scheme 2 Proposed mechanisms for host-catalyzed Prins cyclizations, where stepwise (k1, k2) or concerted (k3) pathways are plausible.
1
by H NMR spectroscopy. Evidence for the assignment of the attributable to the higher solvation of hydrate compared to
hydrate was obtained by varying the proportion of MeOD-d4 to aldehyde in the aqueous cosolvent employed. Increasing the
phosphate buffer cosolvent. While the hydrate C–H resonance ratio of (ꢀ)-1 to 5c resulted in an increase in the integrals of the
was absent in pure MeOD-d4, the ratio of hydrate to aldehyde encapsulated aldehyde resonances, accompanied by a decrease
integrals increased with increasing proportion of aqueous in the integral of the corresponding unencapsulated aldehyde
phosphate buffer. During these experiments, the sum of alde- resonance and R(OH)2C–H hydrate resonance. These results
hyde to hydrate resonances remained constant and was equal to conrm that encapsulation perturbs the aldehyde-hydrate
the sum of corresponding alkene C–H resonances. Extraction of equilibrium by selective encapsulation of aldehyde over
1
this mixture into CDCl3 and subsequent analysis by H NMR hydrate.
spectroscopy resulted in the quantitative recovery of aldehyde,
It was hypothesized that the encapsulation of substrate
conrming that hydration is reversible. The magnitude of the aldehyde is driven by the hydrophobic effect, a process that has
aldehyde-hydrate ratio also varied considerably between been shown to be controlled entropically by the release of
substrates; the ratio of aldehyde to hydrate was lower for less encapsulated solvent.48,49 In order to examine this effect, the
hydrophobic substrates in aqueous solution.45 Following these inuence of organic cosolvent on catalysis was investigated.
qualitative experiments, it was next investigated whether Previously, the use of organic cosolvents had been observed to
substrate-dependent Khyd pre-equilibria could affect guest inhibit the (ꢀ)-1-catalyzed hydrolysis of orthoformates, an effect
binding and catalysis.
which results from the lower affinity of host and guest in
To determine the effect of encapsulation on aldehyde- nonaqueous solvents due to attenuation of the hydrophobic
hydrate equilibria, homogenous solutions of (ꢀ)-5a and 5c were effect.46,50,51 In contrast to purely aqueous conditions where the
treated with host (ꢀ)-1. 1H NMR analysis revealed signicant appearance of broad upeld resonances conrms a comparably
broadening of aldehyde C–H resonances, indicating guest high degree of guest association, guest binding is attenuated in
exchange.33,46,47 In contrast, hydrate resonances underwent no a 1 : 1 (v/v) aqueous phosphate buffer/MeOD-d4 cosolvent.
such broadening, indicating a negligible degree of encapsula- Under homogenous conditions, encapsulated aldehyde, unen-
tion between hydrates of (ꢀ)-5a, 5c and (ꢀ)-1. This result is capsulated aldehyde and total host concentrations were
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measured against an internal standard, from which dissocia- in kobs with D+ may correlate with the pKa of a general acid
tion constants were calculated (see KM values, Table 1). involved in catalysis. In principle, a gallium-bound cat-
In spite of the low magnitudes of association between host echolamide functionality could act as a general acid catalyst in
and substrate while using this cosolvent, catalysis in a 1 : 1 this regard.56,57 These measurements suggest that host-cata-
MeOD-d4/phosphate buffer proceeded with an efficiency similar lyzed Prins reactions are promoted by bulk solution acidity,
to that observed under pure aqueous buffer conditions. Catal- albeit in a complex manner.
ysis did not proceed in pure methanol under otherwise identical
Previous investigations have demonstrated that (ꢀ)-1 can
conditions. The maintenance of catalytic efficiency in this enforce a chair conformation of acyclic guests.51,58,59 Based on
cosolvent can be attributed in part to the higher concentrations this precedent, it is likely that cyclization is accelerated by steric
of soluble guest in homogenous solutions, which, to some constraints afforded through encapsulation. Following proton-
extent, offsets the lower degree of association observed. These ation of the encapsulated substrate, cyclization could conceiv-
experiments collectively suggest that host-catalyzed Prins ably proceed through either a step-wise (k1, k2) or concerted (k3;
cyclizations proceed initially through the displacement of cf. Scheme 2) pathway. These mechanisms could, in principle,
solvent from the host cavity by substrate, an event that is driven be distinguished by the direct observation of carbocation I-4
by the hydrophobic effect.
(Scheme 2). However, under the catalytic conditions employed,
guest binding is too weak to permit the denitive character-
ization of this possible species. To address whether a stepwise
or concerted pathway was likely operative in host-catalyzed
cyclizations, prior mechanistic investigations of 5a cyclizations
were consulted. Under anhydrous Lewis acidic conditions, the
cyclization of 5a is thought to proceed through a concerted
mechanism and results in trans or cis products, depending on
the nature of the catalyst.59–61 In contrast, Brønsted acid-cata-
lyzed cyclizations proceeding under either aqueous or anhy-
drous conditions have been shown to afford predominantly cis
products resulting from nucleophilic capture of carbocation I-
4.40,62–65 It has been suggested that the cis selectivity in the latter
cases results from ion pairing with carbocation I-4, which would
stabilize this intermediate, leading to products of nucleophilic
capture by water or anion.64 In support of this notion, a Lewis
Protonation of aldehyde oxygen (K2), nucleophilic capture by
alkene (k1) and proton elimination (k2); concerted pathway
(k3)
Aer encapsulation, we propose that the host activates the
substrate by stabilization of its conjugate acid, driving proton-
ation of the carbonyl oxygen, followed by intramolecular
nucleophilic attack by the pendant alkene. In principle,
protonation of the carbonyl could occur prior to encapsulation.
However, the latter scenario seems unlikely based on prior
studies where the catalytic resting states for (ꢀ)-1-mediated
orthoformate hydrolysis and Nazarov cyclizations were identi-
ed as the neutral guest species, whose ether- and alcohol-
based oxygen atoms have a basicity similar to those of carbonyl
oxygen functionalities.33,52 To examine equilibrium K2, the rate
of cyclization of 5c by (ꢀ)-1 was measured to be slightly
nonlinear between pD 6.9 and 8.0. Over this range, the depen-
dence of kobs on bulk solution was approximately 0.4(1)-order.
This result bears analogy to the 0.5(1)-order relationship
between kobs and pD previously measured in the 1-catalyzed
Nazarov cyclization.52 Because the aldehyde-hydrate equilib-
rium was perturbed slightly toward aldehyde at lower pD in the
Prins reactions, the less than rst-order dependence could not
be due to a bulk solution effect on this pre-equilibrium.53–55
These observations suggest that host-catalyzed Prins reactions
are only indirectly promoted by increasing acidity of the bulk
solution, a result that is inconsistent with a mechanism that
proceeds exclusively through specic acid catalysis by D3O+.
General acid catalysis could be operative, wherein the changes
ˇ
´
acid catalyst reported by Kocovsky et al. afforded ene products
under anhydrous conditions, but diols were observed when
trace amounts of water were present in the reaction mixture.66
DFT calculations have also suggested that the preference for
trans over cis ene products for 5a cyclization decreases when
moving from concerted to stepwise mechanisms.40 These
studies suggested to us that the presence of water or an
appropriate anion could, by stabilizing a carbocation interme-
diate, inuence not only product chemoselectivity, but dia-
stereoselectivity as well.
Based on these reports, it was unclear whether the exclusion
of water during host-catalyzed Prins cyclizations of 5a could
explain the observed trans product diastereoselectivity. This
stereoselectivity is unlikely to have resulted from constrained
steric interactions, as increased steric connement has been
Table 1 Kinetic parameters for host-catalyzed Prins reactionsa
Entry
Substrate
Catalyst
KM (mM)
kcat (sꢁ1
)
kcat/KM (Mꢁ1 sꢁ1
)
(kcat/KM)/kuncat (Mꢁ1
)
kcat/kuncat
1
2
3
4
5
5c
5c
(ꢀ)-5a
(S)-5a
(R)-5a
(ꢀ)-1
L4-2
(ꢀ)-1
D4-2
D4-2
5.4 ꢃ 102
5.8 ꢃ 102
2.0 ꢃ 102
3.3 ꢃ 102
1.8 ꢃ 102
8.9 ꢃ 10ꢁ4
5.4 ꢃ 10ꢁ3
5.5 ꢃ 10ꢁ4
1.0 ꢃ 10ꢁ3
2.1 ꢃ 10ꢁ3
1.6 ꢃ 10ꢁ3
9.3 ꢃ 10ꢁ3
2.7 ꢃ 10ꢁ3
3.0 ꢃ 10ꢁ3
1.2 ꢃ 10ꢁ2
2.9 ꢃ 104
1.6 ꢃ 105
2.5 ꢃ 105
2.8 ꢃ 105
1.1 ꢃ 106
1.6 ꢃ 104
9.5 ꢃ 104
5.0 ꢃ 104
9.1 ꢃ 104
1.9 ꢃ 105
a
kuncat for 5c: 5.7(6) ꢃ 10ꢁ8 sꢁ1; (S)-5a: 1.1(1) ꢃ 10ꢁ8 sꢁ1; KM measurements have an estimated error of 10%; conditions for all runs: 1 : 1 MeOD-d4/
100 mM phosphate buffer, pD 8.00; 25 ꢂC.
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shown to accompany increased cis product selectivity (see treated with equal concentrations of (ꢀ)-5a and heated, aer
Scheme 1). To probe whether a low concentration of water in the which the organic portions were extracted and rst-order rate
host cavity could account for the observed trans diaster- constants determined based on the level of conversion the
eoselectivity, 5a was treated with various MeOH/100 mM starting material had undergone. From these measurements, a
aqueous phosphate buffer (pH 3.20) cosolvents in the absence small but measurable degree of catalytic inhibition was
of host, where the volumetric ratio of MeOH to buffer varied observed for the (ꢁ)-menthyl chloride case relative to the
between 0 and 1.5. Aer heating, products were extracted and condition with (ꢁ)-menthol (krel ¼ 0.7(1)). Consequently, it is
analyzed by 1H NMR spectroscopy. While the proportions of conceivable that the formation of alcohol-containing products
alkene products formed from these treatments were minor (10– from aldehyde-containing starting materials drives turnover
20% product selectivity), the trans selectivity of these products through a preferential hydrogen bonding interaction between
increased monotonically with an increasing proportion of product and aqueous solvent, a trait that correlates with the
MeOH (at 0% MeOH, trans/cis ¼ 0.84; at 60% MeOH, trans/cis ¼ greater solubility of alcohol-containing products compared to
1.56). We speculate that this correlation between an increasing aldehyde-containing starting materials. Combined with the
ratio of MeOH and trans product selectivity results from the high thermal persistence of 2, this catalytic property allows for
destabilization of a stepwise cyclization mechanism in the high turnover numbers to be achieved. Under dilute conditions
presence of a lower dielectric bulk cosolvent. In principle, this (0.049 mM, 0.045 mol% L4-2), catalysis proceeded with up to
change in mechanism could be accomplished through lowering 840 turnovers over two weeks, which is among the highest
the effective concentration of water in bulk solution, the reported for intramolecular Prins or carbonyl-ene
absence of which would conceivably destabilize the stepwise cyclizations.60,75–79
transition state leading to cis products. Based on these experi-
ments, it is possible that host-catalyzed cyclizations may be
more concerted in character than stepwise processes occurring
Michaelis–Menten analysis, rate accelerations
under conventional Brønsted acid catalysis. Furthermore,
simply the exclusion of water from the host cavity during
catalysis could account for the observed trans product
selectivity.
The observation that host–substrate complexes undergo fast
chemical exchange,80 accompanied by a relatively slow rate of
catalysis, implies a mechanism involving a fast pre-equilibrium
including encapsulation followed by a rate-limiting process that
was irreversible under the reaction conditions used (eqn (2)).
Based on these characteristics, guest-binding and subsequent
catalytic steps were deconvoluted with Michaelis–Menten
analysis. As mentioned previously, the cyclization of 5c was
measured to be rst-order in substrate and (ꢀ)-1, both of which
are consistent with the rate law given below (eqn (3)).81,82
Product displacement and turnover (K3)
In order to test whether cyclization was reversible under the
reaction conditions employed, a mixture of alkene products
(ꢀ)-6–9a was treated with an aqueous solution of (ꢀ)-1 (7 mM, 8
mol%) and subjected to heating. Aer extraction, no starting
material (ꢀ)-5a or changes in product distribution were
observed, suggesting that catalysis is irreversible under cata-
lytically relevant conditions.
Although product inhibition is a common challenge in
cavity-mediated catalysis,67–73 no deviation from rst-order
kinetics was seen through 90% conversion of 5c with 4 mol%
L4-2, an observation which demonstrates that inhibition is
largely negligible and implies that K1 > Kꢁ3. It was hypothesized
that the absence of product inhibition results from the high
solvation of product alcohol by the bulk solution. In this
k1
kcat
ƒƒƒ!
*
S þ H )
kꢁ1
S3H
P þ H
(2)
d½pꢄ kcat½Hꢄ½Sꢄ
¼
(3)
(4)
dt
½Sꢄ þ KM
kcat þ k
ꢁ1
KM
¼
k1
Because guest exchange is fast with respect to cyclization,
instance, the higher degree of product solvation compared to experimentally determined Kd ¼ KM. Uncatalyzed cyclizations
that of the starting material could provide a driving force for proceeded slowly; less than een percent of starting materials
turnover. Consistent with this notion, the water solubility of 5a (S)-5a and 5c were observed to cyclize over the course of four
(0.9 mM) is lower than that of (ꢁ)-menthol (4.0 mM) by a factor weeks. Nonetheless, these low levels of conversion were suffi-
of 4.4.74 In order to test the effect of the alcohol functionality on cient to quantify the uncatalyzed rates of reaction in bulk
encapsulation and catalysis, a stock solution of (ꢀ)-1 was par- solution. The experimental kuncat for 5a is roughly an order of
titioned to two identical reaction asks which were treated with magnitude faster than the calculated gas-phase value, a differ-
an equimolar stock solution of either (ꢁ)-menthol or ence which can be accounted for by the stabilizing role of water
1
(ꢁ)-menthyl chloride in an aqueous methanolic cosolvent. H on the calculated transition state.83 Notably, the uncatalyzed
NMR analysis revealed that, although encapsulation was cyclization of 5c proceeds approximately ve times faster than
evident for (ꢁ)-menthyl chloride, no encapsulation was that of (S)-5a. The magnitude of this difference in rate is small
observed for (ꢁ)-menthol. This observation attests to the compared to other examples of the gem-disubstituent effect.84 In
importance of alcohol hydrogen bonding in guest solvation and contrast, catalysis by 1–4 proceeds relatively quickly, with half-
consequently, host–substrate affinity. These mixtures were lives on the order of hours to a day, depending on the
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experimental conditions. Specicity factors (kcat/KM) were constant. Mass spectral data were obtained at the QB3 Mass
largest for (R)-5a and 5c with host 2. These properties are a Spectrometry Facility operated by the College of Chemistry,
reection of (a) the generally higher rate of catalysis with 2 University of California, Berkeley. Electrospray ionization
compared to (ꢀ)-1, (b) the slightly more hydrophobic nature of (ESI) mass spectra were recorded on a Finnigan LTQ FT mass
5c compared to 5a, which favors encapsulation both through spectrometer. Chiral GC analyses were conducted using a HP
the hydrophobic effect and aldehyde-hydrate equilibria, and (c) 6850 series GC system tted with a chiral column, BetaDex
the complementarity of the (R)-5a/D4-2 diastereomeric pairing 120 Fused Silica Capillary Column (30 m ꢃ 0.25 mm ꢃ 0.25
in catalysis. Catalytic prociencies ((kcat/KM)/kuncat), as measures um lm thickness). Unless otherwise noted, chemicals were
of transition state stabilization afforded through encapsulation obtained from commercial suppliers and used without
relative to the uncatalyzed reactions, were consistently higher further purication. Preparations of 1, 2 and 5c have been
for less hydrophobic substrates (R)-, (S)- and (ꢀ)-5a. This trend described.24,31 Compound 3 was prepared by the route
is a reection of the tendency for host to drive substrate cycli- previously reported36 and precipitated with acetone. Unless
zation through the selective encapsulation of aldehyde over otherwise noted, reported pD values are uncorrected for the
hydrate. In the case of (S)-5a, kuncat is low in part due to the glassy electrode artifact (i.e. pDcorr ¼ pDread + 0.40).91
relatively hydrate-favored aldehyde-hydrate equilibrium. The
tendency for hosts to compensate for the gem-disubstituent
General preparation of (6–11) used for selectivity
effect also likely contributes to this trend.24 Catalytic rates (kcat
)
determination and ee determination of starting material and
product
for all substrates were consistently higher in 2 than (ꢀ)-1 by less
than an order of magnitude. On the whole, rate accelerations
ranged between 104 and 105 (5.7–7.2 kcal molꢁ1), the latter of This procedure is adapted from earlier reports.24,31 Aldehyde
which are among the largest observed with a synthetic supra- starting material (45 mmol), 1, 2, 3 or 4 (4.2 mmol), 250 mL MeOD-
molecular cavity.69,85–90
d4 and 250 mL phosphate buffer (for example, 100 mM K2DPO4,
pD 8.00) were added to a standard NMR tube. This slightly
heterogeneous mixture was heated in an oil bath for a period of
time as indicated, aer which the organic components were
Conclusion
While variation in the host chelator was generally observed to extracted (3 ꢃ 300 mL CDCl3) and passed through a pipet con-
produce no signicant changes in product selectivity, catal- taining a thin lter of glass ber. Selectivity and conversion
ysis in TAM-based 2 proceeded with consistently higher effi- were determined by 1H NMR integration. Cis and trans product
ciency than CAM-based (ꢀ)-1. In contrast, variation in host isomers were differentiated by characteristic alcohol C–H
spacer (Nap or Pyr) resulted in changes in efficiency and coupling24 and accompanying alkene C–H resonances (ca. 4.9
product selectivity. Up to 840 turnovers were observed, which ppm). GC-MS analysis of these samples conrmed the presence
numbers among the highest known for intramolecular Prins of only aldehyde starting material and alkene products. Prod-
cyclizations. Rate accelerations for the catalyzed reactions ucts and starting material were isolated by silica gel chroma-
are on the order of 104–105 relative to uncatalyzed treat- tography (10% EtOAc in hexanes) prior to ee determination by
ments, which are likewise among the highest reported in the chiral-GC and characterization. Selectivity factors were deter-
eld of host–guest catalysis. The trends reported herein mined by direct rate measurement ((R)- and (S)-5a) or based on
enable a better understanding of enzyme-mimic microenvi- conversion and ee (5b), as described in ref. 44. Turnover was
ronment in the context of chemo-, diastereo- or enantiose- assessed following treatment of L4-2 (7.0 mg, 0.0015 mmol)
lective catalysis. In a broader sense, this work aims to build a with 5c (540 mg, 3.2 mmol) in 1 : 1 MeOH/100 mM phosphate
ꢂ
fundamental understanding of biological catalysts using buffer, pH 5.40 (30 mL, 13 days 2 h, 50 C) and this heteroge-
simple synthetic models.
neous mixture stirred vigorously, aer which organic portions
were extracted (3 ꢃ 30 mL DCM), dried over MgSO4, solvent
removed in vacuo and the combined yield of 10 and 11 assessed
using an internal standard of mesitylene in CDCl3 (38% yield,
Experimental procedures
Unless otherwise noted, reactions and manipulations were 1.2 mmol). Due to the elevated temperature and long reaction
performed using standard Schlenk techniques or in an time employed, a modest amount of background reactivity was
oxygen-free wet box under nitrogen atmosphere. All solvents evident in the production of p-menthane-3,8-diols (ꢅ10%
were degassed under nitrogen for 20 min before use. Glass- yield).24 Treating a higher concentration of L4-2 (0.30 mM) with
ware was dried in an oven at 150 ꢂC overnight or by ame 530 equivalents of 5c afforded 455 turnovers aer 3 d and only
before use. Column chromatography was carried out on a trace (<1% yield) p-menthane-3,8-diols. Characterization of
Biotage SP1 MPLC instrument with prepacked silica gel trans-5-methyl-2-(prop-1-en-2-yl)-5-propylcyclohexan-1-ol (8/9b):
columns. NMR spectra were obtained on a Bruker AV 400 (400 1H NMR (600 MHz, CDCl3): d (ppm) 4.91 (s, 1H), 4.85 (s, 1H),
MHz), AV 500 (500 MHz) or AV 600 (600 MHz) spectrometer. 3.64 (dt, 1H), 1.90–1.76 (m, 2H), 1.75 (s, 3H), 1.35–1.45 (m, 2H),
Chemical shis are reported as d in parts per million (ppm) 1.23–1.35 (m, 6H), 1.09 (t, 2H), 0.90 (s, 3H), 0.85 (t, 3H); 13C NMR
relative to residual protiated solvent resonances. NMR data (151 MHz, CDCl3): d (ppm) 146.96, 112.63, 67.76, 54.88, 48.93,
are reported according to the format s ¼ singlet, d ¼ doublet, 45.08, 36.92, 35.45, 25.58, 21.91, 19.07, 16.34, 14.49; HRMS
t ¼ triplet, m ¼ multiplet, b ¼ broad; integration; coupling (FTMS ESI) calculated for C13H24O: 196.1827; found: 196.1824.
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that time, volatile materials were removed in vacuo to afford a
tan oil. Methylene chloride (2 ꢃ 2 mL) was added and evapo-
rated to afford the acid chloride 14 as a colorless powder, which
was used without further purication. 14 was added to a solu-
tion of 13 and triethylamine (0.180 mL, 1.28 mmol) in CH2Cl2 (7
mL) at ambient temperature, and the resulting yellow solution
was stirred for 40 h at ambient temperature. This yellow solu-
tion was diluted with CH2Cl2 (50 mL) and washed with aqueous
HCl (1 N, 2 ꢃ 20 mL), aqueous NaOH (1 N, 2 ꢃ 20 mL), and
brine (1 ꢃ 20 mL), and dried over Na2SO4. Solvent was removed
and the resulting yellow powder reprecipitated from CH2Cl2/
hexanes to afford 15 (130 mg, 51%) as a yellow powder. 1H NMR
(600 MHz, CDCl3) d 10.71 (s, 2H), 8.91 (d, J ¼ 8.4 Hz, 2H), 8.19 (d,
J ¼ 8.3 Hz, 2H), 8.15 (d, J ¼ 8.3 Hz, 2H), 8.09 (q, J ¼ 9.2 Hz, 4H),
8.02 (d, J ¼ 8.4 Hz, 2H), 7.86 (d, J ¼ 9.4 Hz, 2H), 4.25 (s, 6H), 4.17
(dq, J ¼ 9.5, 6.8 Hz, 2H), 4.12 (s, 3H), 1.23 (d, J ¼ 6.7 Hz, 6H),
1.04 (s, 18H). 13C NMR (151 MHz, CDCl3) d 163.44, 162.66,
151.65, 151.48, 131.69, 131.42, 129.73, 128.39, 128.28, 127.12,
127.09, 125.58, 125.54, 122.61, 121.35, 118.79, 62.52, 62.12,
53.55, 34.45, 26.53, 16.28. HRMS (FTMS ESI) calculated for
[C48H54N4O8]: 814.3942, found 837.3818.
General procedure for rate measurements
In a typical experiment, a homogenous solution of aldehyde
starting material (20 mmol), host 1 or 2 (2 mmol), 250 mL MeOD-
d4 and 250 mL 100 mM phosphate buffer (from K3PO4/HCl; pD
5.00 or 8.00) was prepared and added to a standard NMR tube.
The tube was then inserted in a preheated NMR probe (25.0(1) ꢂC)
within three minutes of its preparation and the reaction fol-
lowed with single scan 1H experiments. In the case of more
slowly reacting substrate/host pairs, reactions were monitored
every 1–2 h over the course of 8–10 h, from which initial rates
(kobs/mM sꢁ1) were obtained. From these observed rates, kcat
values were calculated using initial substrate and host
concentrations during catalysis and Kd, which was substituted
for KM in eqn (2) in accordance with established procedure.46,47
Due to the low affinity of host and guest, Kd values were
obtained separately using higher concentrations of host (ca. 15
mM). Based on the observation that only aldehyde species (not
hydrate) were encapsulated, the effective aldehyde concentra-
tion at the beginning of the run was treated as [S] in eqn (3).
Quantitative mass balances of product and starting material
were observed during kinetic trials. Background rates (kuncat
/
sꢁ1) of cyclization were obtained by following an analogous
procedure where solutions were monitored every 1–2 days over
the course of a month. During initial trials it was observed that
many internal standards had an inhibitory effect on catalysis,
which presumably results from (a) internal or external associ-
ation of the standard to the host and (b) the low affinity of the
host for substrate in the cosolvent used. Consequently, rates of
product formation were referenced against the residual MeOH
solvent resonance, whose concentration was conrmed at the
end of the kinetic run by the addition of an internal standard of
3-(trimethylsilyl)-1-propanesulfonic acid, sodium salt. Rates
were reproducible within 10% among identically prepared
solutions.
Preparation of 16
To a suspension of 15 (82 mg, 0.10 mmol) in methylene chloride
(4 mL) was added BBr3 (0.076 mL, 0.80 mmol). The yellow
suspension instantly turned orange and was stirred at ambient
temperature for 16 h. The suspension was then poured over ice
and warmed to ambient temperature. The suspension was
ltered to give a yellow solid that was suspended in water (10
mL). The yellow suspension was heated at reux for 16 h and
then cooled to ambient temperature. The mixture was ltered to
1
afford 16 (55 mg, 72%) as a ne yellow powder. H NMR (500
MHz, DMSO-d6) d 12.87 (s, 2H), 12.15 (s, 2H), 11.30 (s, 2H), 8.51
(d, J ¼ 9.0 Hz, 2H), 8.46 (d, J ¼ 8.4 Hz, 2H), 8.40 (d, J ¼ 8.2 Hz,
2H), 8.28 (q, J ¼ 9.3 Hz, 4H), 7.72 (d, J ¼ 8.6 Hz, 2H), 7.65 (d, J ¼
9.4 Hz, 2H), 4.11–4.03 (m, 2H), 1.16 (d, J ¼ 6.9 Hz, 6H), 0.95 (s,
18H). 13C NMR (126 MHz, DMSO-d6, adduct with DCU) d 167.76,
167.03, 149.77, 148.63, 131.19, 128.71, 127.70, 125.29, 124.67,
124.44, 124.10, 121.42, 119.28, 118.19, 117.16, 52.52, 47.52,
34.67, 34.66, 33.34, 26.33, 26.29, 26.02, 25.32, 24.47, 15.34,
15.34. HRMS (FTMS ESI) calculated for [C44H46N4O8 ꢁ H]ꢁ:
757.3243, found 757.3239.
Preparation of 13
The previously-reported carboxylic acid 12 (ref. 31) (100 mg, 0.32
mmol) was dissolved in DMF (4 mL), and DCC (80 mg, 0.39
mmol) and HOBt (52 mg, 0.39 mmol) were added to the solu-
tion. The solution was stirred at ambient temperature for 30
minutes, and 1,6-diammoniumpyrene hydrogen sulfate (123
mg, 0.290 mmol) was added in one portion, followed by tri-
ethylamine (180 mL). The dark brown solution was stirred at
ambient temperature for 16 h. A white solid was ltered off, and
to the resulting solution was added H2O (20 mL), forming a
yellow precipitate. The suspension was ltered and washed with
H2O (3 ꢃ 2 mL). The precipitate was extracted with methylene
chloride (25 mL) and the solvent evaporated to afford a yellow
powder (13) that was used without further purication in the
next step.
Preparation of 4
In a glove box with a nitrogen atmosphere, KOD (3.52 mg, 0.064
mmol) was added to a suspension of 16 (24 mg, 0.032 mmol) in
MeOD (0.64 mL), and the reaction mixture was stirred until the
suspension became a homogeneous yellow solution. To this
solution was added a 100 mM phosphate buffered solution of
D2O at pD ¼ 8.0 (0.16 mL) and Ga(NO3)3 (5.44 mg, 0.021 mmol).
ꢂ
The reaction mixture was heated at 55 C for 14 h and subse-
quently cooled to ambient temperature and ltered. Solvent was
Preparation of 15
removed to form a yellow solid, which was recrystallized from
To a solution of carboxylic acid 12 (148 mg, 0.48 mmol) in MeOH/Et2O to afford 4 as a yellow solid (21 mg, 75%). 1H NMR
ꢂ
methylene chloride (7 mL) at 0 C was added thionyl chloride (500 MHz, MeOD) d 14.00 (br, NH), 8.90 (br, 2H), 8.28 (br, 2H),
(0.4 mL). The reaction mixture was stirred at 0 ꢂC for 2 h. Aer 7.56 (br, 4H), 7.17 (br, 2H), 6.98 (br, 2H), 4.52 (br, 12H), 1.06
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of propylmagnesium chloride in an analogous manner afforded
a complex mixture instead of the desired 1,4-addition product.
Acknowledgements
This research was supported by the Director, Office of Science,
Office of Basic Energy Sciences, and the Division of Chemical
Sciences, Geosciences, and Biosciences of the U.S. Department
of Energy at LBNL (DE-AC02-05CH11231). H.L.O. thanks the
Spanish MEC for his FPU fellowship. R.M.T is supported by an
NSF graduate research fellowship (DGE 1106400).
Notes and references
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