Nucleophilic substitution catalyzed by a supramolecular cavity proceeds with retention of absolute stereochemistry

Article abstract of DOI:10.1021/ja508799p

While the reactive pocket of many enzymes has been shown to modify reactions of substrates by changing their chemical properties, examples of reactions whose stereochemical course is completely reversed are exceedingly rare. We report herein a class of wa

Full text of DOI:10.1021/ja508799p

Communication
pubs.acs.org/JACS
Nucleophilic Substitution Catalyzed by a Supramolecular Cavity
Proceeds with Retention of Absolute Stereochemistry
Chen Zhao, F. Dean Toste,* Kenneth N. Raymond,* and Robert G. Bergman*
Chemical Sciences Division, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California,
Berkeley, California 94720, United States
S
* Supporting Information
ABSTRACT: While the reactive pocket of many enzymes
has been shown to modify reactions of substrates by
changing their chemical properties, examples of reactions
whose stereochemical course is completely reversed are
exceedingly rare. We report herein a class of water-soluble
host assemblies that is capable of catalyzing the
substitution reaction at a secondary benzylic carbon center
to give products with overall stereochemical retention, while
reaction of the same substrates in bulk solution gives
products with stereochemical inversion. Such ability of a
biomimetic synthetic host assembly to reverse the
stereochemical outcome of a nucleophilic substitution
reaction is unprecedented in the field of supramolecular
host−guest catalysis.
s one of the fundamental transformations of organic
Figure 1. (a) Schematic representations of the Ga4L6 assemblies 1 and 2,
with only one ligand shown for clarity. (b) X-ray crystal structure of
ΛΛΛΛ-1 (after resolution). (c) X-ray crystal structure of ΔΔΔΔ-2.
Achemistry, the nucleophilic substitution reaction can be
defined as the displacement of an electron-pair acceptor (leaving
group) with an electron-pair donor (nucleophile or entering
group). When the reaction takes place at an sp3-hybridized
carbon atom, the mechanism is classified with reference to two
canonical pathways (SN1 and SN2) that furnish products with
different stereochemical outcomes.1 One mechanism, favored
with substrates where a developing carbocation can be stabilized
through hyperconjugation or extensive π-delocalization from the
neighboring substituents, is typically characterized by the initial
generation of a planar sp2-hybridized carbocation and subse-
quent attack by a nucleophile from either side of the intermediate
to give racemized product.1,2 In contrast, the other mechanism,
involving simple primary and secondary substrates, is stereo-
specific, and substitution proceeds through a transition state via
back-side attack of the carbon reaction center by a nucleophile to
yield products with inversion of stereochemistry.1,3,4 This
includes the overwhelming majority of solvolyses at simple
secondary benzylic centers.5−7
In recent decades, synthetic chemists have drawn inspiration
from nature to design supramolecular host complexes that mimic
the properties of enzymes.8 Some of these properties include the
ability to induce pKa shifts and maintain function in aqueous
environments at physiological pH.9 More importantly, many
such species contain well-defined and sterically constrictive
binding pockets capable of stabilizing otherwise reactive species
via encapsulation.10,11 Such complexes can thus catalyze
chemical reactions with degrees of selectivity different from
those observed in bulk solution.8c,12 We report herein an
example of a nucleophilic substitution reaction of secondary
benzylic substrates catalyzed by K12Ga4L6 supramolecular host
complexes that proceeds with overall stereochemical retention.
Initially prepared by the Raymond group, complex 1 is a
tetrahedral supramolecular cluster or nanovessel composed of
K12Ga4L6 stoichiometry (L = N,N-bis(2,3-dihydroxybenzoyl)-
1,5-diaminonaphthalene) with metal ions occupying the vertices
and bridging ligands spanning each edge (Figure 1b).13
Mechanical coupling enforces chirality transfer between the
metal vertices, leading to formation of a racemic mixture of
resolvable homochiral enantiomers ΔΔΔΔ-1 and ΛΛΛΛ-1.
Cluster complex 1 contains a well-defined hydrophobic internal
cavity, as created by the naphthalene walls of its ligands, with an
approximate volume of 300−500 Å3. Such a pocket has been
demonstrated to cause pKa shifts of up to 4 pKa units,
preferentially encapsulate monocationic molecules, and stabilize
reactive intermediates such as the phosphine−acetone adducts
and iminium cations that would otherwise decompose. Nano-
vessel 1 has also been applied as an effective catalyst that
enhances the rate and selectivity of a variety of reactions, such as
the Nazarov cyclization14 and C−H activation of aldehydes by an
encapsulated iridium complex.15
Received: August 26, 2014
Published: September 29, 2014
© 2014 American Chemical Society
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More recently, we reported the synthesis of a new K12Ga4L6
host complex, 2 (Figure 1c), composed of a terephthalamide-
based ligand bearing a chiral amide functional group that self-
assembles in solution to form cationic guest-free and enantiopure
clusters.16 Complex 2, which varies only in modification to the
assembly’s exterior as compared to 1, shows increased thermal,
aerobic, and low pH solution stabilities, as well as increased
catalytic efficiency for enantioselective neutral guest catalysis.
In a continuing effort to better understand the enzyme-like
behavior of our synthetic nanovessels and explore their
application as catalysts for organic synthesis, we initially sought
to investigate the ability of 2’s cavity to stabilize carbocations and
affect their asymmetric nucleophilic addition. We envisioned that
compound 3 would be an ideal substrate to test our hypothesis,
since the trichloroacetimidate functional group is an acid-
activated leaving group. While the protonation of such a
functional group in bulk solution requires the use of strong
organic acids, such as 4-nitrobenzenesulfonic17 and phosphoric
acids,18 we recently showed that host 2 is capable of both
encapsulating and protonating trichloroacetimidate-containing
molecules.16 Initial reaction between substrate 3 and 5 mol% of
ΔΔΔΔ-2 in CD3OD at room temperature for 124 h gave the
desired benzyl ether product 4 in high yield but only 15% ee
(Scheme 1). Reaction catalyzed by ΛΛΛΛ-2 gave product with
Scheme 2. Catalyst-Controlled Divergent Stereospecific
Substitutions of (S)-3
Table 1. Stereoretentive Substitution Reactions of (S)-3
Catalyzed by Nanovessel Hosts 1, ΛΛΛΛ-2, and ΔΔΔΔ-2
Scheme 1. Solvolytic Substitution Reaction of Racemic 3
Catalyzed by Enantiopure ΔΔΔΔ-2
a
1
the same level of enantioselectivity, but in the opposite direction.
Though no encapsulated species were observed by H NMR
spectroscopy during the course of the reaction, experiments with
either PEt4-blocked 2 or no catalyst gave only trace amounts of 4,
strongly suggesting that the formation of enantioenriched benzyl
ether 4 from racemic 3 is catalyzed by the cavity of 2.
Product ratios were determined by H NMR spectrometry with an
1
b
error limit estimated to be 5%. Enantiomeric ratios were determined
by GC fitted with a chiral column with an error limit estimated to be
5%. Reaction at 25 °C.
c
We next studied this stereoretentive substitution reaction in a
cosolvent system of a 1:1 mixture of CD3OD/D2O buffered at
pD 8 in order to neutralize any potential acid and ensure that the
desired reactions take place inside the cavities of the host
complexes. Although nanovessels 1 and 2 have been shown to
exclude water from their cavities due to the hydrophobic effect,
hydrolysis of 3 inside the cavity of the host catalysts to give 6 can
occur. Indeed, reaction of (S)-3 with either ΔΔΔΔ-2 or ΛΛΛΛ-
2 as the catalyst at 50 °C gave a mixture of the desired ether
product 4, with improved selectivity for the retention product
(S)-4 (Table 1, entries 1 and 2), and the corresponding alcohol 6.
When host 1 (30 mol%) was used as the catalyst, substitution of
(S)-3 also proceeded to give 4 with a high level of retention
(90%). Longer reaction times were required for substitution
reactions of 3 at room temperature in the presence of either
racemic or enantiopure host complexes (entries 4 and 5).
Similarly, reactions of enantiopure (R)-3 in the presence of
nanovessels 1 and 2 also gave the desired ether product 4 with
moderate to high levels of stereochemical retention (Table 2).
Control reactions of (S)-3 in the presence of PEt4-blocked 2 gave
low yields of 4 with inversion of stereochemistry (entry 6).
The low enantioselectivity of the cluster-catalyzed solvolysis
reaction prompted us to examine the possibility of a concerted
back-side attack mechanism since substitution reactions of
trichloroacetimidate have been reported to proceed by such
pathways.17 Indeed, the reaction of enantiopure (S)-3 with 5 mol
% of the achiral phosphoric acid 5 in CD3OD at room
temperature gave the desired benzyl ether 4 in quantitative
yield with an expected 84% inversion of stereochemistry, or a
5.25:1 ratio of (R)-4 to (S)-4, at the substituted carbon center
(Scheme 2). Surprisingly, repeating the substitution reaction of
(S)-3 in the presence of 5 mol% of ΔΔΔΔ-2 at 50 °C produced 4
in high yield with 74% retention of stereochemistry. Control
experiments using (S)-3 with either PEt4-blocked 2 or no catalyst
gave only trace amounts of product 4 with inversion of
stereochemistry. While supramolecular host complexes have
been shown to alter reactivity and selectivity via encapsulation
during the course of the reaction, the ability of complex 2 to
completely change the stereochemical outcome of a canonical
SN2 reaction to give products with high levels of overall retention
is unprecedented.
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Communication
Table 2. Stereoretentive Substitution Reactions of (R)-3
Catalyzed by Nanovessel Hosts 1, ΛΛΛΛ-2, and ΔΔΔΔ-2
Table 3. Stereoretentive Substitution Reactions of
Enantioenriched 7 Catalyzed by Host ΛΛΛΛ-2 or ΔΔΔΔ-2
a
1
Product ratios were determined by H NMR spectrometry with an
b
error limit estimated to be 5%. Enantiomeric ratios were determined
by GC fitted with a chiral column with an error limit estimated to be
c
5%. Reaction at 25 °C.
a
Ratios were determined by 1H NMR spectrometry with an error limit
b
Scheme 4. Encapsulation of (R)-8 by Racemic Complex 1
estimated to be 5%. Enantiomeric ratios were determined by GC
fitted with a chiral column with an error limit estimated to be 5%.
c
Reaction performed at 25 °C in 100% MeOH-d4.
Scheme 3. Solvolytic Substitution Reaction of Benzyl
Chloride 7 Catalyzed by Enantiopure ΛΛΛΛ-2
this intermediate. Since the cavity of K12Ga4L6 hosts has been
shown to increase the basicity of encapsulated guests, the
protonation of the trichloroacetimidate functional group of 3 and
its subsequent ionization to give the corresponding carbocation
should be considered favorable. Furthermore, complex
PMe3AuCl has been shown to undergo encapsulation and
chloride loss without any silver source in the presence of host 1 to
give host−guest complex [PMe3Au+⊂1] (where ⊂ denotes
encapsulation).19 The strong driving force for the formation of
[PMe3Au+⊂1] from PMe3AuCl could be operative for the
analogous encapsulation and ionization of neutral 7 in the
presence of host complex 2. Lastly, the reaction of the isomeric
benzylic trichloroacetamide 10 in the presence of 10 mol% of
host 1 gave no substitution after heating at 80 °C for 3 days.20
This rules out a preliminary 1,3-rearrangement of the leaving
group with inversion, followed by displacement with a second
inversion. In any case this mechanism is not available to the
corresponding chloride substrate.
More importantly, the substitution reactions of enantiopure 3
and enantioenriched 7 catalyzed by 1 and 2 proceed with
stereochemical retention regardless of the absolute configuration
or enantiopurity of the host complexes. This suggests that the
intermediate maintains a strong stereointegrity inside the cavity
of the host complexes. Furthermore, the low enantioselectivities
obtained with reactions of racemic 3 or 7 catalyzed by
enantiopure catalysts 2 suggest that the inherent stereochemistry
of the reaction overrides any effect of the cavity chirality during
catalysis. We propose that, during the course of reaction inside
the host catalyst, the electron density of the naphthalene walls
stabilizes the developing positive charge at the benzylic carbon in
the transition state through cation−π interaction (Figure 2),21
resulting in one face of the intermediate being blocked from
nucleophilic attack. The complexed cation can be thought of as
being limited from planarizing inside the sterically constrictive
cavities of 1 and 2, and is trapped by a nucleophile faster than the
We next examined the substitution of benzyl chloride substrate
7 catalyzed by supramolecular host complexes. Reaction of
racemic 7 in the presence of ΛΛΛΛ-2 gave the desired ether
product 4 with 14% ee (Scheme 3), similar to the results obtained
with racemic 3 (Scheme 1). Repeating the reaction with the other
enantiomer of the catalyst, ΔΔΔΔ-2, gave 4 with the same
enantiomeric excess but in the opposite direction. More
importantly, the substitution of enantioenriched 7 (80% ee)
catalyzed by either ΛΛΛΛ-2 or ΔΔΔΔ-2 proceeded to give 4 in
high yields and with high levels of stereochemical retention
(Table 3), and reaction without any assembly gave the ether
product 4 with stereochemical inversion.
We also wanted to demonstrate the encapsulation of
benzylammonium 8, which has a size similar to that of the
reactive substrates 3 and 7, in the presence of host complex 1
(Scheme 4). As observed by 1H NMR spectroscopy, ammonium
salt 8 was readily encapsulated by 1 to give host−guest complex 9
as a 1:1 mixture of two diastereomers.20 While no further
reaction was observed when 9 was heated at 50−80 °C for 4 days,
the encapsulation of 8 suggests that such substrates, along with 3
and 7, are suitable guest molecules for the cavities of 1 and 2 in
terms of their size and volume.
Though the detailed mechanism of this nanovessel-catalyzed
substitution reaction with retention of stereochemistry for simple
benzylic molecules remains under investigation, the results
obtained thus far provide some insights into the origin of such
unique reactivity. The same level of enantioselectivity observed
from reactions with racemic 3 and 7 catalyzed by ΔΔΔΔ-2
suggests that a common intermediate was accessed during the
course of the reaction. We propose a benzylic carbocation to be
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(3) Pronin, S. V.; Reiher, C. A.; Shenvi, R. A. Nature 2013, 503, 300.
(4) Nucleophilic substitution of substrates involving back-side
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norbornyl systems, or an α-ferrocenyl moeity, has been observed to give
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Figure 2. Proposed intermediate showing a transient carbocation
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interactions (X = leaving group).
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cation can rotate, thus giving product with overall retention of
stereochemistry.
In conclusion, solvolytic displacement reactions that normally
undergo inversion of stereochemistry in bulk hydroxylic solvent
have their stereochemistry reversed when the substitution takes
place within the cavity of K12Ga4L6 nanovessels. To interpret
these results, we propose not only that the cavity of the host
assembly can stabilize the developing positively charged
intermediate in the transition state through cation−π interaction,
but also that the naphthalene walls of the complex block the back
side of the carbocation and thereby control the stereochemical
outcome of its substitution to give products with high levels of
overall retention. To our knowledge, this observation is
unprecedented in the field of catalysis by supramolecular host
complexes.
(12) (a) Hart-Cooper, W. M.; Clary, K. N.; Toste, F. D.; Bergman, R.
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493. (e) Wang, Z. J.; Clary, K. N.; Bergman, R. G.; Raymond, K. N.;
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(13) Caulder, D. L.; Powers, R. E.; Parac, T. N.; Raymond, K. N. Angew.
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(15) (a) Leung, D. H.; Fiedler, D.; Bergman, R. G.; Raymond, K. N.
Angew. Chem., Int. Ed. 2004, 43, 963. (b) Leung, D. H.; Bergman, R. G.;
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(16) Zhao, C.; Sun, Q.-F.; Hart-Cooper, W. M.; DiPasquale, A. G.;
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(17) Lin, S.; Jacobsen, E. N. Nat. Chem. 2012, 4, 817.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
fdtoste@berkeley.edu
raymond@socrates.berkeley.edu
rbergman@berkeley.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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). The authors thank
Kaking Yan for complex 1, and Rebecca Triano and William
Hart-Cooper for helpful discussions.
(20) See Supporting Information for experimental details.
(21) (a) Stauffer, D. A.; Barrans, R. E.; Dougherty, D. A. Angew. Chem.,
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97, 1303. (c) Mecozzi, S.; West, A. P.; Dougherty, D. A. J. Am. Chem. Soc.
1996, 118, 2307. (d) Tsuzuki, S.; Yoshida, M.; Uchimaru, T.; Mikami,
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