A Case Study in Catalyst Generality: Simultaneous, Highly-Enantioselective Br?nsted- And Lewis-Acid Mechanisms in Hydrogen-Bond-Donor Catalyzed Oxetane Openings

Article abstract of DOI:10.1021/jacs.1c03992

Generality in asymmetric catalysis can be manifested in dramatic and valuable ways, such as high enantioselectivity across a wide assortment of substrates in a given reaction (broad substrate scope) or as applicability of a given chiral framework across a variety of mechanistically distinct reactions (privileged catalysts). Reactions and catalysts that display such generality hold special utility, because they can be applied broadly and sometimes even predictably in new applications. Despite the great value of such systems, the factors that underlie generality are not well understood. Here, we report a detailed investigation of an asymmetric hydrogen-bond-donor catalyzed oxetane opening with TMSBr that is shown to possess unexpected mechanistic generality. Careful analysis of the role of adventitious protic impurities revealed the participation of competing pathways involving addition of either TMSBr or HBr in the enantiodetermining, ring-opening event. The optimal catalyst induces high enantioselectivity in both pathways, thereby achieving precise stereocontrol in fundamentally different mechanisms under the same conditions and with the same chiral framework. The basis for that generality is analyzed using a combination of experimental and computational methods, which indicate that proximally localized catalyst components cooperatively stabilize and precisely orient dipolar enantiodetermining transition states in both pathways. Generality across different mechanisms is rarely considered in catalyst discovery efforts, but we suggest that it may play a role in the identification of so-called privileged catalysts.

Full text of DOI:10.1021/jacs.1c03992

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Article
A Case Study in Catalyst Generality: Simultaneous, Highly-
Enantioselective Brønsted- and Lewis-Acid Mechanisms in
Hydrogen-Bond-Donor Catalyzed Oxetane Openings
Daniel A. Strassfeld, Russell F. Algera, Zachary K. Wickens, and Eric N. Jacobsen*
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ABSTRACT: Generality in asymmetric catalysis can be manifested in
dramatic and valuable ways, such as high enantioselectivity across a wide
assortment of substrates in a given reaction (broad substrate scope) or as
applicability of a given chiral framework across a variety of mechanistically
distinct reactions (privileged catalysts). Reactions and catalysts that display
such generality hold special utility, because they can be applied broadly and
sometimes even predictably in new applications. Despite the great value of
such systems, the factors that underlie generality are not well understood.
Here, we report a detailed investigation of an asymmetric hydrogen-bond-
donor catalyzed oxetane opening with TMSBr that is shown to possess
unexpected mechanistic generality. Careful analysis of the role of
adventitious protic impurities revealed the participation of competing
pathways involving addition of either TMSBr or HBr in the enantiodetermining, ring-opening event. The optimal catalyst induces
high enantioselectivity in both pathways, thereby achieving precise stereocontrol in fundamentally different mechanisms under the
same conditions and with the same chiral framework. The basis for that generality is analyzed using a combination of experimental
and computational methods, which indicate that proximally localized catalyst components cooperatively stabilize and precisely orient
dipolar enantiodetermining transition states in both pathways. Generality across different mechanisms is rarely considered in catalyst
discovery efforts, but we suggest that it may play a role in the identification of so-called privileged catalysts.
the discovery of new enantioselective, catalytic processes.
Indeed, there are examples of extraordinarily useful new
transformations5 and new modes of catalysis6 or new classes of
reactions7 that were developed with reliance on chiral
frameworks which were identified previously for different
purposes. Analysis of privileged chiral scaffolds identified to
date has provided some insight into their common features:
most notably, structural rigidity achieved through chelation of
a ligand to a reactive metal center and C2 symmetry to create
stereochemically equivalent reactive sites.4a,8 However, these
characteristics are also common to many chiral frameworks
that are not broadly applicable in asymmetric catalysis and are
absent from several of the privileged frameworks that have
been identified. Unfortunately, fuller elucidation of the
structural features that underlie the privileged nature of such
catalysts is confounded by the difficulty of studying systems
that differ not only in mechanism but also in nearly every other
INTRODUCTION
■
The birth of the field of modern asymmetric catalysis can be
tied to the discovery made over a half century ago that chiral
small molecules can promote reactions of interest with very
high, “enzyme-like” levels of enantioselectivity.1 The practical
and fundamental implications of such transformations became
well-appreciated, fueling intensive research in the ensuing years
that has produced a continuously expanding list of
enantioselective catalytic organic reactions. A small subset of
those reactions has proven to be remarkably accommodating of
changes in substrate structure, enabling their broad application
(e.g., Figure 1A).2 The development of such reactions remains
a challenging and rarely met objective, but from a conceptual
standpoint, their generality can be rationalized fairly simply: in
such processes, the chiral catalyst exerts precise geometric
control on the prochiral reaction site, but selectivity does not
rely on interactions with the variable substituents on the
substrate.3 Another, quite different type of generality emerged
unexpectedly throughout the development of the field of
asymmetric catalysis, wherein certain chiral scaffolds have
proven to be effective at inducing high levels of enantiose-
lectivity across a wide range of mechanistically unrelated
reactions (e.g., Figure 1B).4 These so-called privileged chiral
catalysts or frameworks have proven enormously enabling for
Received: April 15, 2021
Published: June 21, 2021
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direct activation of electrophiles via LUMO lowering.9 As part
of this body of work, we recently reported that squaramide 1a
catalyzes the highly enantioselective opening of a structurally
diverse set of 3-substituted oxetanes with TMSBr (Figure
2A).9l Here, we report a detailed mechanistic investigation
Figure 1. (A) The Sharpless epoxidation represents a prototypical
example of substrate generality in an asymmetric catalytic reaction.
Even though the reaction scope is limited to allylic alcohols, it
tolerates extensive variation in the alkenyl substituents, thereby
enabling its broad application in synthesis. (B) The cinchona alkaloids
are prototypical privileged chiral frameworks for asymmetric catalysis.
Such systems are capable of inducing high enantioselectivity across a
range of mechanistically unrelated reactions (refs 4a, 10). (C) Dual
H-bond donors containing an aryl-pyrrolidne-tert-leucine motif with
the general structure 1 have emerged as a privileged class of chiral
organocatalysts. (D) The addition of TMSBr to oxetanes catalyzed by
chiral squaramide 1a can proceed simultaneously by fundamentally
different, yet highly enantioselective Lewis- and Brønsted-acid
mechanisms.
Figure 2. (A) Chiral squaramide-catalyzed addition of TMSBr to
oxetanes (ref 9l). (B) Original mechanistic hypothesis for the oxetane
ring-opening reaction. (C) Catalyst 1a reproducibly affords highly
enantioenriched products, but reactions catalyzed by other structur-
ally similar H-bond donors fail to provide reproducible levels of
enantioselectivity.
revealing that the reaction proceeds through competing
Brønsted-acid and Lewis-acid mechanisms (Figure 1D), both
of which contribute significantly to product formation under
typical reaction conditions. The participation of multiple,
highly enantioselective reaction channels leading to the same
enantiomer of product in a single transformation provided an
opportunity to study the catalyst features that underlie
mechanistic generality without the confounding variables that
typically hinder such comparisons. Analysis of the mechanism
of stereoinduction in the competing pathways revealed the
engagement of colocalized, reinforcing secondary interactions
that cooperatively stabilize the transition state leading to the
major enantiomer of product in both mechanisms. We advance
that the presence of such reinforcing sites may be a common
feature in privileged catalysts that operate via attractive
noncovalent interactions.
key reaction parameter (e.g., identity of substrates, additives,
and other reagents, solvents, temperature, etc.)
Over the past decade, thioureas, ureas, and squaramides with
the general structure 1 (Figure 1C) have emerged as a
privileged class of organocatalysts capable of inducing high
levels of enantioselectivity in transformations proceeding
through a variety of mechanisms, including ion-pairing
catalysis involving nucleophilic addition to sp2 and sp3-
hybridized cationic electrophiles, concerted nucleophilic
substitution reactions, enantioseletive proton transfers, and
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RESULTS AND DISCUSSION
■
Earlier studies from our lab established that chiral squaramide
derivatives capable of dual H-bond-donor interactions promote
heterolysis of silyl triflates via anion abstraction and activate
the resulting electrophile-triflate ion-pairs through anion-
binding catalysis.9e,h,11 We initially reasoned that a similar
Lewis-acid-activation mechanism could be operative in the
oxetane-opening with TMSBr (Figure 2B).9l However,
observations made during the development of that reaction
provided compelling evidence that this proposal was at best
incomplete. In particular, the rate of the reaction was found to
decrease quite dramatically with increasing scale (Figure S4),
an effect that could not be ascribed simply to changes in mass
transport given the homogeneous nature of the reaction
mixtures. Additionally, an important difference was observed
between the behavior of optimal catalyst 1a and other chiral
squaramide dertivatives in the same family: the reaction
catalyzed by 1a afforded product 3 with reproducibly high
levels of enantioselectivity (e.e.), whereas suboptimal catalysts
such as 1b-1d afforded product with highly variable e.e.’s
(Figure 2C).
The hydrolysis of Lewis acids or metal salts to yield
Brønsted acids as potentially active reagents is well
documented in racemic chemistry12,13 and has also been
considered in the context of asymmetric catalysis.14−18 One
example directly relevant to the system analyzed here can be
found in the asymmetric chiral phosphoric acid-catalyzed
oxetane opening developed by Sun and co-workers, which
relies on the controlled hydrolysis of a silyl chloride to generate
HCl.19 We considered whether HBr generated by the
hydrolysis of TMSBr could account for the observed variability
in reaction performance. Using the enantioselective conversion
of 3-phenyloxetane (2) to trimethylsilyl-protected bromohy-
drin 3 as a model reaction, we tested this hypothesis through
the controlled introduction of HBr into the reaction medium.
High levels of enantioselectivity were maintained in the
presence of catalytic levels of HBr,20 but reaction rates were
increased by over an order of magnitude compared to the
reaction carried out with the rigorous exclusion of HBr (Figure
3A/Table S1).21,22
The positive rate dependence on added proton sources
suggested that HBrrather than TMSBrcould be the active
reagent in the oxetane-opening reaction. Consistent with that
hypothesis, stoichiometric quantities of squaramide 1a were
shown to mediate the reaction of oxetane 2 with HBr23 to
afford bromohydrin 4 in 98% e.e. (Figure 3B). In addition, 1a
proved effective as a catalyst (2 mol % loading) for the opening
of 2 with HCl, affording the chlorohydrin analogue of 4 in 92%
e.e. at 4 °C (Figure S42).24 Taken together, these results
implicate a mechanism involving cocatalysis by 1a and HBr
wherein enantioselective oxetane ring opening by HBr is
followed by silylation of bromohydrin 4 by TMSBr to afford 3
and regenerate HBr.
Figure 3. (A) Effect of HBr (generated by the photochemical reaction
of Br2 in toluene) on reaction rate (black dots) and enantioselectivity
(red dots) ([1a] = 0.002 M, [2]0 = 0.1 M, [TMSBr]0 = 0.2 M). The
reaction with [HBr] = 0 was conducted in the presence of TMSCHN2
as a base (see text). Reaction rates were determined via in situ FTIR
monitoring using a ReactIR (see General Procedure for ReactIR
experiments in the Supporting Information). (B) Enantioselective
addition of HBr to 2 promoted by 1a.
uncatalyzed ring-opening addition of HBr to the oxetane.
However, under the relevant, low [HBr] reaction conditions,
the uncatalyzed reaction is very slow and cannot account for
the observed variability in e.e. (Figure S48). Thus, the data are
most consistent with competing catalytic mechanisms being
involved, and we hypothesized that the originally proposed
silyl-Lewis-acid mechanism might also be operative. To test
this possibility, we sought to identify a base that could
completely suppress the HBr pathway without interfering with
the activity of the HBD catalyst. The additive had to be
selected carefully, because salts introduced either as anionic
bases or as the conjugate acids of neutral bases are generally
strong inhibitors of anion-binding pathways due to competitive
association to the hydrogen-bond-donor active site.25 Gratify-
ingly, trimethylsilyldiazomethane, which has previously been
demonstrated to function as a noninterfering base in hydrogen-
bond-donor catalyzed cation-olefin cyclizations,9p was found to
neutralize HBr rapidly and quantiatively without any
deleterious effect on the squaramide catalyst under the
standard reaction conditions (Figure 4A). In the presence of
TMSCHN2 the reaction of oxetane 2 with TMSBr was
observed to proceed at appreciable rates but more slowly and
with similar levels of enantioselectivity relative to the HBr-co-
The identification of the HBr cocatalyed mechanism
accounts for the variation of rate with reaction scale given
that adventious water is expected to be present in greater ratios
in small-scale reactions. However, it does not provide a
satisfactory explanation for the irreproducible enantioselecti-
vies observed with suboptimal catalysts (Figure 2C). Provided
temperature is well controlled, variability in enantioselectivity
is indicative of competing reaction mechanisms. The obvious
candidate for such a competing pathway would be the racemic,
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trations of squaramide 1a, oxetane 2, and TMSBr, which is
consistent with rate-determining oxetane ring-opening via
bromide addition.27 In the absence of TMSCHN2, both the
Lewis-acid and Brønsted-acid pathways are operative. Under
these conditions and at steady-state,28 a first-order dependence
on TMSBr, a first-order dependence on [1a], and a positive
order in [2] with a nonzero y-intercept are observed. The
positive order in [2] can be ascribed to contribution of the
Lewis-acid pathway, while the nonzero intercept reflects a
zeroth-order dependence on [2] for the Brønsted-acid
pathway. On the basis of the combination of this zeroth-
order dependence and positive orders for TMSBr, 1a, and HBr
concentrations (Figure 3A), the alcohol silylation step that
affords 3 with regeneration of the squaramide-HBr complex29
is proposed to be rate-determining in the Brønsted acid
pathway. A primary kinetic isotope effect was observed in a
one-pot competition experiment between unlabeled and
2,4-13C2-2 in the presence of TMSCHN2 (see Supporting
Information for details). Taken together with the previously
reported9l primary KIE observed in an analogous experiment
in the absence of TMSCHN2, we conclude that bromide
delivery is enantiodetermining for both mechanisms.
The recognition that two distinct catalytic pathways are
operative in the enantioselective oxetane-opening reaction
catalyzed by 1a enabled the successful development of a
scalable protocol. In the case of substrate 2, the challenge of
reproducibly achieving optimal rates without compromising
enantioselectivity can be met by maximizing the HBr-co-
catalyzed pathway, without participation of the racemic
uncatalyzed reaction which intervenes at high [HBr] (Figure
3A).30 The conversion of 1 g of 2 to 3 was thus achieved in
89% yield and 97% e.e. using 1 mol % of 1a and 6.5 mol %
added H2O (Figure 5). Catalyst 1a was reisolated from the
reaction in 90% yield and displayed undiminished activity and
enantioselectivity in a subsequent reaction (Figure S6).
Figure 4. (A) Reaction time-course measured using in situ FTIR
monitoring. Upon the addition of TMSCHN2 (green -4000 s), the
rate of consumption of 2 (black) decreases but continues at a lowered
rate. Upon the addition of HCl (8000 s), the TMSCHN2 is rapidly
consumed. Following complete consumption of TMSCHN2 the rate
of oxetane consumption increases. (B) The reaction run in the
presence of TMSCHN2 proceeds with high enantioselectivity and at a
rate that is slower but still competitive with the HBr cocatalyzed
pathway.
catalyzed reaction (Figure 4B). A distinct TMSBr-mediated
reaction must therefore be operative alongside the HBr
cocatalyzed pathway, with both pathways contributing to the
formation of product 3 with high levels of enantioenrichment
in the presence of catalyst 1a. Moreover, this phenomenon is
not limited to model oxetane 2. A survey of the 1a-catalyzed
opening of 2 and 6 additional oxetanes selected to represent
the diversity of the originally reported reaction scope (3-aryl,
3-alkyl, 3-heteratomic, and 3,3-disubstituted oxetanes) revealed
an average difference of <5% e.e. between the two
mechanisms.26
The observations outlined above and extensive ground state
and kinetic analyses conducted in the absence (Figures S9,
S12−S24) and presence (Figures S36−S41) of added
TMSCHN2 are consistent with a scenario in which the two
catalytic mechanisms outlined in Figure 6A are operating
simultaneously in the 1a-catalyzed ring-opening addition of
TMSBr to oxetanes. In the Lewis-acid pathway, which is the
only pathway operative in the presence of TMSCHN2, kinetic
analysis revealed a first-order dependence on the concen-
Figure 5. Addition of trace water allows for high reactivity and
enantioselectivity with reduced loadings of squaramide 1a in a gram-
scale reaction of oxetane 2 with TMSBr.
The enantiodetermining ring-opening transition states for
the Brønsted and Lewis acid pathways were modeled
computationally in order to assess the catalyst features
responsible for high stereocontrol in both pathways (complete
computational details and computational references are
provided in the SI). In the Brønsted acid cocatalyzed pathway,
TSprotic-R and TSprotic-S were identified as the lowest energy
transition states leading to the major and minor product
enantiomers (Figure 6B). TSsilyl-R and TSsilyl-S were the lowest
energy enantiomeric transition states located for the Lewis acid
pathway (Figure 6C). The computational model was validated
by comparison of predicted and measured enantioselectivity
for a series of chiral catalysts with varied aryl pyrrolidine
fragments (Figure 7). Although the computational models
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Figure 6. (A) Proposed reaction mechanisms consisting of competing Brønsted and Lewis acid pathways. (B) Computed lowest energy major (R)
and minor (S) transition states for the Brønsted acid pathway (ΔΔE‡ = 2.6 kcal/mol). (C) Computed lowest energy major (R) and minor (S)
transition states for the Lewis acid pathway (ΔΔE‡ = 2.5 kcal/mol). Transition states were optimized at SMD (Et2O) − B97D/def2-SVP. The
electronic energies were corrected by single-point refinement at SMD (Et2O) − B97D3/def2-TZVP.
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Figure 7. Predicted ΔΔE‡ vs experimental ΔΔG‡ for the Lewis acid
pathways for catalysts 1a−1g and the Brønsted acid pathway for
catalyst 1a. See Figure 8 for catalyst structures, Table S11 for
tabulated data, and Figures S7 and S34 for experimental details.
overestimate the magnitude of the enantioselectivities, the
model reproduces the trends in the data (R2 = 0.92) including
the inversion in the sense of enantioinduction for the Lewis
acid pathway with catalyst 1g.31
Qualitative analysis of TSsilyl-R and TSsilyl-S reveals
significant similarity between the two transition structures: in
both, the forming C−Br and breaking C−O bonds are
positioned almost identically relative to the catalyst, and the
two transition structures can be overlaid to a significant degree
(Figure S63). However, the developing α-silyloxy methylene
group, which is predicted to bear much of the positive
electrostatic potential (Figure S62), is positioned differently in
the two structures. In TSsilyl-R, this methylene group points
toward the amide and the 9-phenanthryl substituent of the
catalyst, in an ideal orientation for stabilizing cation-π and
cation-dipole interactions.32 In contrast, the methylene is
oriented away from the arene and amide in TSsilyl-S, resulting
in attenuated stabilizing interactions relative to those in the
major pathway. In the Brønsted acid pathway, additional
conformational constraint is provided by a hydrogen-bonding
interaction between the protonated oxetane and the amide.
This interaction can be readily accommodated in the transition
state leading to the major enantiomer, such that the position
and conformation of the oxetane as it undergoes ring opening
in the catalyst active site is similar in TSsilyl-R and TSprotic-R,
allowing the cation-π interaction to be maintained. However,
in TSprotic-S, maintenance of the anchoring H-bond requires
the disrupting of the rest of the network of interactions
between the catalyst and substrate, including the proposed
cation-π interaction.
The computationally derived hypothesis that cation-π
interactions play a critical role in enantioinduction was tested
experimentally by evaluating the extended series of aryl-
pyrrolidinosquaramides 1a−1g in the reactions of 2 with
TMSBr and HBr (Figure 8A). In consistency with the models,
selectivity for the R-enantiomer in both pathways was observed
to correlate with the ability of the aryl substituent to engage in
a cation-π interaction, with electron-deficient or less polar-
izable arenes affording decreased selectivity for the R-
enantiomer.32,33 Furthermore, all catalysts induced higher
selectivity for the R-product in the HBr cocatalyzed reactions
of 2 relative to the Lewis acid pathway, consistent with the
proposed reinforcing hydrogen-bonding interaction in the
Brønsted acid mechanism. The results in Figure 8A,B also
provide a clear explanation for why enantioselectivities under
Figure 8. (A) Enantioselectivity for the reaction of 2 catalyzed by 1a−
1g determined both for the HBr-promoted reaction and with TMSBr
in the presence of TMSCHN2 (average of two runs, see Figures S7
and S33 for details). (B) Graphical representation of relative
enantioselectivities of the Brønsted and Lewis acid mechanisms for
reactions of 2 catalyzed by 1a−1g.
the original screening conditions were more consistent with
catalyst 1a than with less selective catalysts (Figure 2C):
squaramide 1a is the only catalyst tested that is highly
enantioselective for both the Brønsted acid and the Lewis acid
pathways, with every other catalyst showing large differences in
e.e. or even favoring alternate enantiomers of product for the
two pathways. Under the original reaction conditions
employed for the catalyst optimization studiesin which the
concentration of HBr was not controlled carefullyboth
pathways are kinetically competent and therefore contribute
significantly to product formation. As the optimization
experiments were designed, only a catalyst that is highly
enantioselective for both mechanisms can generate product in
consistently high e.e.’s.
The fact that catalyst 1a induces high enantioselectivity
across different mechanisms in the oxetane ring-opening is
intriguing and touches on the broader phenomenon of
privileged chiral catalysts.4a The electrostatic potential map
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of 1a (Figure 9A) reveals an electron-rich pocket (in red)
defined by the amide and 9-phenanthryl substituent positioned
that high enantioselectivity can be manifested despite the
availability of distinct mechanistic pathways to the same
product. It is noteworthy that the participation of competing
mechanisms remained unrecognized throughout the course of
our reaction development and scope studies, only becoming
apparent upon scale-up efforts and subsequent careful
mechanistic analysis. Thus, in optimizing enantioselectivity in
the oxetane opening, we unwittingly optimized a catalyst for
generality across two different mechanisms. Caution should of
course be exercised before attempting to draw general
conclusions from a specific case study such as this one, but
given that detailed mechanistic investigations of new
asymmetric reactions rarely if ever precede catalyst optimiza-
tion efforts, such scenarios could be more common than is
generally appreciated. Given the truism that “you get what you
screen for,”36 this study raises the intriguing question of
whether the discovery of remarkably general chiral catalysts
over the past several decades might be tied in part to the
optimization of reactions that are not always “well behaved.”
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03992.
Procedures and analytical data for enantioselective
reactions, details of mechanistic studies, and computa-
tional studies (PDF)
Figure 9. (A) Electrostatic potential map of catalyst 1a using the
geometry from TSsilyl-R (scale from −0.03 to +0.03). (B) Electrostatic
potential map of the Lewis acid transition state using the geometry
from TSsilyl-R (scale from −0.06 to +0.06). (C) Electrostatic potential
map of the Brønsted acid transition state using the geometry from
TSprotic-R (scale from −0.06 to +0.08). All ESPs were computed at
SMD (Et2O) − B97-D3/Def2-TZVP and plotted with a density
isovalue of 0.0004.
AUTHOR INFORMATION
■
Corresponding Author
Eric N. Jacobsen − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States; orcid.org/0000-0001-7952-3661;
Email: jacobsen@chemistry.harvard.edu
adjacent to the H-bond donor motif (in blue). While the
protonated and silylated transition states in the oxetane
opening present dramatically different steric features, they
possess dipoles that display charge similarly within the catalyst
active site (Figure 9B,C). The precise nature (i.e., cation-π,
charge-dipole, H-bonding) and relative strengths of the
stabilizing interactions differ between the two pathways (see
Figure S67 and S68 for a detailed analysis), but through
cooperation between the arene and the amide, the catalyst can
stabilize positive charge in the major transition states to a
significant degree from both the protonated and the silylated
oxetane. The presence of multiple, reinforcing sites for
secondary interactions may be a general feature of privileged
scaffolds that underlies their ability to stabilize or destabilize a
diverse range of transition states.
Authors
Daniel A. Strassfeld − Department of Chemistry and
Chemical Biology, Harvard University, Cambridge,
Massachusetts 02138, United States
Russell F. Algera − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States
Zachary K. Wickens − Department of Chemistry and
Chemical Biology, Harvard University, Cambridge,
Massachusetts 02138, United States; orcid.org/0000-
0002-5733-5288
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c03992
Notes
The authors declare no competing financial interest.
CONCLUSION
■
Given the intrinsic challenges associated with attaining
stereocontrol with small-molecule catalysts, observation of
high enantioselectivity might, in principle, be taken as evidence
of a “well behaved” transformation that proceeds through a
single mechanistic pathway (or an ensemble of closely related
transition states) rather than through distinct, completing
mechanisms.34 The unexpected discovery detailed here, that
the squaramide-catalyzed ring opening of oxetanes with
TMSBr proceeds through competing Lewis- and Brønsted-
acid reaction pathways, adds to a growing body of evidence35
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the NIH
through GM043214 and a postdoctoral fellowship to Z.K.W.
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(21) TMSCHN2 was found to be uniquely effective at quenching
HBr rapidly without generating any byproducts that interfered with
the catalytic reaction. For additional details, see Figures 4 and S30−
S32. For a previous report of the use of TMSCHN2 as a
noninterfering base in H-bond-donor catalysis, see ref 9p.
(22) A similar rate and e.e. profile is produced with HBr generated
by the addition of i-PrOH to TMSBr (Figure S2). The reaction rate is
also depressed slightly at increased concentrations of added i-PrOH
(>3 × 10−2 M). No such inhibitory effect on rate is observed for HBr
generated from Br2 and toluene. For additional experiments probing
this effect see Figures S51-S53.
(23) Generated as an anhydrous solution in toluene through the
photochemical reaction of Br2 and toluene, see General Procedure C
in the Supporting Information for additional information.
(24) In contrast to HBr, at 4 °C HCl does not react with oxetane 2
at an appreciable rate in the absence of an H-bond donor catalyst.
(25) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N.
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(26) While the HBr cocatalyzed pathway is more enantioselective for
3-phenyloxetane (2) this was not true for all substrates. For some
substrates, the TMSBr pathway was found to be more enantiose-
lective, providing further evidence for a bona fide silyl Lewis acid
pathway (see Figures S8 and S35).
(27) Alternatively, rate-determining TMSBr heterolysis with
nucleophilic assistance by the oxetane cannot be ruled out on the
basis of the kinetic data. However, this proposal would require that
silyl transfer between 2-Me3Si+ and 2 is rapid relative to reversion to
the starting materials (i.e., TMSBr heterolysis is irreverisble) and that
the former process is rapid relative to bromide delivery to 2-Me3Si+ to
account for the 13C KIE observed for the silyl pathway in one-pot
competition experiments.
(28) At the start of the reaction the resting state is the squaramide-
HBr complex. In the first turnover, the HBr is consumed and the
steady-state regime depicted in Figure 6A is established. As
consumption of 2 approaches completion, the concentration of 2
will be much lower than that of TMSBr, because TMSBr is used in
excess. Consequently, the resting state can shift back to the catalyst-
HBr complex at high conversion. For a detailed discussion see Figure
S10.
(29) Studies of catalyst 1a, the 1a-HBr complex, the corresponding
urea and thiourea, and their HBr complexes using in situ infrared
spectroscopy support the depicted structure wherein the t-leucine
amide is protonated by HBr. This is also supported by computational
modelling and comparisons between predicted and measured IR
spectra, which indicate a bridging interaction between the protonated
amide and the squaramide-bound bromide. See Figures S15-S17 for a
detailed discussion.
(30) With substrates for which the Lewis-acid pathway affords
higher levels of enantioselectivity than the Brønsted-acid pathway (see
Note. Twenty-six and Figures S8 and S35), reactions run on larger
scale are expected to provide product in higher levels of e.e. than
reactions run on screening scale and the addition of a proton source is
anticipated to be detrimental to enantioselectivity. The slow rate of
the uncatalyzed reaction at low [HBr] (Figure S48) allows an
alternate tactic for accelerating large-scale reactions of substrates
where the Lewis-acid pathway is more enantioselective: rather than
adding a proton source, the concentration of the reaction can be
increased. This approach was successfully implemented for the gram-
scale synthesis of pretomanid detailed in ref 9l. Prior to scaling up
reactions of interest, the relative enantioselectivities of the two
pathways for any substrate of interest should first be determined by
(33) These data offer a striking contrast to those obtained in an H-
bond-donor catalyzed multicomponent synthesis of chiral homoallylic
amines (ref 9h.), where (poly)fluorinated phenyl substituents on the
aryl pyrrolidine moiety of the catalyst provided higher levels of
enantioselectivity than phenylpyrrolidine. In that transformation,
differential stabilization by dispersive π-stacking interactions, rather
than differential cation-π interactions, were concluded to contribute
to enantioinduction.
(34) Indeed, the participation of competing catalyzed pathways
rather than poor enantioinduction in a single pathwaymay underlie
poor performance in many asymmetric catalytic reactions. For an
example where a Brønsted-acid pathway was demonstrated to be
deleterious to enantioselectivity in a Lewis-acid-catalyzed reaction,
necessitating the use of freshly distilled SiCl4, see ref 14b. See also:
(a) Denmark, S. E.; Fan, Y.; Eastgate, M. D. Lewis Base Catalyzed,
Enantioselective Aldol Addition of Methyl Trichlorosilyl Ketene
Acetal to Ketones. J. Org. Chem. 2005, 70, 5235−5248. (b) Fu, H.;
Look, G. C.; Zhang, W.; Jacobsen, E. N.; Wong, C.-H. Mechanistic
Study of a Synthetically Useful Monooxygenase Model Using the
Hypersensitive Probe trans-2-Phenyl-1-vinylcyclopropane. J. Org.
Chem. 1991, 56, 6497−6500. Mitigation of the effects of competing
catalytic pathways, when recognized, is typically addressed through
modification of the reaction conditions (ref 18a) or through catalyst
redesign to suppress the poorly enantioselective pathway. See for
example: (c) Denmark, S. E.; Fu, J. On the Mechanism of Catalytic,
Enantioselective Allylation of Aldehydes with Chlorosilanes and
Chiral Lewis Bases. J. Am. Chem. Soc. 2000, 122, 12021−12022.
(35) A recent study of flexible, peptide-based catalysts provides
evidence of how the transition state ensembles in enantioselective
reactions can include significant structural diversity: Crawford, J. M.;
Stone, E. A.; Metrano, A. J.; Miller, S. J.; Sigman, M. S.
Parametrization and Analysis of Peptide-Based Catalysts for the
Atroposelective Bromination of 3-Arylquinazolin-4(3H)-ones. J. Am.
Chem. Soc. 2018, 140, 868−871.
(36) Schmidt-Dannert, C.; Arnold, F. H. Directed evolution of
industrial enzymes. Trends Biotechnol. 1999, 17, 135−136.
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