Disparate Catalytic Scaffolds for Atroposelective Cyclodehydration

Article abstract of DOI:10.1021/jacs.9b01911

Catalysts that control stereochemistry are prized tools in chemical synthesis. When an effective catalyst is found, it is often explored for other types of reactions, frequently under the auspices of different mechanisms. As successes mount, a unique cata

Full text of DOI:10.1021/jacs.9b01911

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Article
Disparate Catalytic Scaffolds for Atroposelective Cyclodehydration
Yongseok Kwon, Junqi Li, Jolene P Reid, Jennifer M. Crawford,
Roxane Jacob, Matthew S Sigman, F. Dean Toste, and Scott J. Miller
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 28 Mar 2019
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Disparate Catalytic Scaffolds for Atroposelective Cyclodehydration
Yongseok Kwon,† Junqi Li,†,‡ Jolene P. Reid,# Jennifer M. Crawford,# Roxane Jacob,‡ Matthew S. Sigman,*,# F.
Dean Toste,*,‡ and Scott J. Miller*,†
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†Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States
‡Department of Chemistry, University of California, Berkeley, California 94720, United States
#Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
ABSTRACT: Catalysts that control stereochemistry are prized tools in chemical synthesis. When an effective catalyst is found, it is often
explored for other types of reactions, frequently under the auspices of different mechanisms. As successes mount, a unique catalyst scaffold may
become viewed as “privileged”. However, the mechanistic hallmarks of privileged catalysts are not easily enumerated, nor readily generalized
to genuinely different classes of reactions or substrates. We explored the concept of scaffold uniqueness with two catalyst types for an unusual
atropisomer-selective cyclodehydration: (a) C2-symmetric chiral phosphoric acids, and (b) phosphothreonine-embedded, peptidic phosphoric
acids. Pragmatically, both catalyst scaffolds proved fertile for enantioselective/atroposelective cyclodehydrations. Mechanistic studies revealed
that the determinants of often equivalent and high atroposelectivity are different for the two catalyst classes. A data-descriptive classification of
these asymmetric catalysts reveals an increasingly broad set of catalyst chemotypes, operating with different mechanistic features, that creates
new opportunities for broad and complementary application of catalyst scaffolds in diverse substrate space.
■ INTRODUCTION
Chemists rarely know what type of catalyst will be well-suited to a
new substrate class or reaction type a priori. The closer to precedent
the desired transformation is, the more readily chemists can predict
an effective catalyst scaffold.1,2 To that extent, a few principles have
emerged to guide chemists in uncharted reaction territory.3 Among
these, the evaluation of catalysts deemed “privileged” is a common
starting point for the consideration of a catalyst chemotype.4,5 This
leads to questions: How unique are privileged catalysts? To what ex-
tent are privileged catalysts exclusively matched for a number of re-
actions proceeding through a common mode of activation? Can a
different catalyst scaffold also achieve high selectivity for the same
reactions through alternative modes of action? In addition, do privi-
leged catalysts remain effective beyond simple substrates, or can
there be a different catalyst scaffold that offers complementarity
when substrates become more complex? Episodic disclosures of dif-
ferent catalysts classes for the same transformation, on the same sub-
strate, exist in several widely-explored asymmetric reactions such as
the catalytic hydrogenation,6 aldol7 and Diels-Alder reactions8
(Scheme 1). Harnessing different catalyst designs for effective en-
antiocontrol is therefore possible, but direct comparative studies of
the substrate preferences, and their different mechanistic underpin-
nings has been difficult to achieve rigorously and retrospectively,
given the multiple laboratories and diverse reaction conditions often
engaged. The present study confronts these questions in an experi-
mentally and computationally driven manner through the compara-
tive study of two distinct catalyst classes that are effective for the en-
antioselective and atropisomer-selective cyclodehydration of o-sub-
stituted aniline derivatives to deliver optically enriched benzimidaz-
oles,9 N-heterocycles of high interest in drug-like molecules10 as
shown in Figure 1c.
Scheme 1. Selected Examples of Asymmetric Reactions that In-
volve Same Substrate with Different Chiral Catalysts
(a) Hydrogenation
H2
Rh Cat.
ligand
CO2R
NHAc
CO2R
*
Ph
Ph
NHAc
MeO
nPr
Me
PCy2
P
P
nPr
nPr
Me
P
P
Ph
PPh2
Fe
nPr
Knowles,6a 1972
Burk,6b 1993
Togni,6c 1994
Beller,6d 2002
R = Me, 95% ee
R = H, 85% ee
R = Me, >99% ee
R = Me, 96% ee
(b) Aldol Reaction
O
OH
O
O
Cat.
H
Me
Me
Me
O2N
Me
O2N
CO2H
NH2
H
HO
Ph
Me
H
S
N
Ph
N
NH
COOH
N
N
N
H
H
O
Barbas,7a 2001
Gong and Wu,7b 2003
Maruoka,7c 2005
Liu,7d 2007
56% ee
86% ee
95% ee
93% ee
(c) Diels-Alder Reaction
Me
CHO
Me
Cat.
CHO
Ar
O
H
Ar
N
O
O
O
O
N
B
H
OTf
Me
B
N
Cu
N
Me
O
H
O
tBu
tBu
Ar =
2SbF6
Me
Evans,8b 1995
92% ee
Yamamoto,8a 1994
Corey,8c 2002
98% ee
96% ee
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(b) Examples of chiral phosphoric acid-catalyzed asymmetric reactions14,15
‘C2-type’ CPA
Hantsch Ester
(a) Chiral phosphoric acids (CPA)
(c) This work:
Comparative study between two catalyst scaffolds
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8
Rueping et al.14a
‘C2-type’ CPA
H
*
N
up to >99% e.e.
‘C2-type’ CPA
or
‘pThr-type’ CPA
F3C
N
N
R
N
H
R
Ar
F3C
N
O
X
HN
O
O
‘pThr-type’ CPA
Hantsch Ester
O
Reference 14b
up to 88% e.e.
P
*
X
OH
N
R
N
H
R
R = Me, R′ = NHPh
pThr-Cat, 64% e.e.
(R)-TRIP, −72% e.e.
O
NH
R
O
NH
Drug-like scaffold
Dehydration
Ar
R′
R′
H
P
O
P
‘pThr-type’ CPA
‘C2-type’ CPA
H2O2
O
O
O
Ding et al.15a
up to 93% e.e.
O
H
O
H
H
H
N
R
R2
O
F3C
N
O
R3
HO
F3C
O
P
Me
N
HN
H
O
9
BnO
HO
O
Cyclization
Reference 15b
up to 88% e.e.
O
N
HN
OCONHR′
OCONHR′
O
O
‘pThr-type’ CPA
H2O2
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X
HN
O
P
X
O
R4
NH
R′ = Ph
pThr-Cat, 88% e.e.
(R)-TRIP, 54% e.e.
R1
O
O
O
X
Figure 1. (a) Chemical structures of ‘C2-type’ CPA and ‘pThr-type’ CPA (b) Examples of chiral phosphoric acid-catalyzed asymmetric reactions (Top:
Asymmetric transfer hydrogenation, Bottom: Asymmetric Baeyer-Villiger oxidation). (c) Atroposelective cyclodehydrations.
The two catalyst classes hail from disparate realms of the asym-
metric catalysis landscape. One catalyst class, C2-symmetric chiral
phosphoric acids derived from BINOL (C2-type),11 is widely ac-
cepted as a privileged scaffold, which has been effectively utilized in
an exceedingly large number of reports (Figure 1a).12 The second
class incorporates peptide-based phosphoric acids, inspired by the
ubiquitous biochemically relevant moiety, phosphothreonine
(pThr) as shown in Figure 1a. pThr is formed by enzymatic phos-
phorylation, resulting in numerous biochemical signal transduction
cascades.13 Interestingly, this motif is not to our knowledge known
to play a catalytic role implicated in bond formation or cleavage in
any enzyme. Yet, pThr-based catalysts have recently been found to
be effective for asymmetric reactions such as transfer hydrogena-
tion14 and the Baeyer-Villiger oxidation of cyclobutanones15 (Figure
1b). Critically, in each case good selectivity was found for C2-type-
and peptide-based chiral phosphoric acids. In the case of Baeyer-Vil-
liger oxidation, the pThr-type catalyst actually gives better selectivity
than a canonical C2-type catalyst with a functionalized substrate.
Detailed below is the experimental documentation that both C2-
type and pThr-type CPAs can catalyze a wide array of atroposelec-
tive cyclodehydrations in very high enantioselectivity. Challenging
each catalyst class with a range of substrate types reveals not only in-
triguing strengths and weaknesses for each as a function of substrate,
but perhaps even more curiously, high functional homology for
other substrates. Catalyst and substrate structure-selectivity rela-
tionships (SSRs) and context dependent mechanistic studies point
to subtle but a distinct set of control elements that lead to common
selectivity outcomes in many cases.16
tially examined 19 pThr-type catalysts for the atropisoselective cy-
clization. Catalyst P1 (with a canonical DPro-Aib sequence at the
i+1 and i+2 positions)21 was evaluated to benchmark the catalyst-de-
pendent enantioselectivity against a well-studied β-turn inducing
peptide sequence resulting in product, 2a with a 43% e.e. at 74% con-
version (Table 1A, entry 1). Standard variations of the peptide se-
quence led to significant improvements. Essentially all residues
transmit stereochemical information to the reaction coordinate,
whether the individual residues are locally chiral or not.22 While ex-
tended commentary could be provided about the complete set, sig-
nificant conclusions pointed to the critical nature of a DPro residue
at i+1 (Table 1A, entry 1 versus entry 2), as well as a synergistic ad-
vantage conferred by an aminocyclopropane carboxylic acid residue
(Acpc; Table 1A, entries 4, 10−19) at the i+2 position, and a
branched L-configured cyclohexylglycine residue (Chg; Table 1A,
entries 15−19) at the i+3 residue. An N-terminal benzoyl group was
also found to be optimal, such that catalyst P19 was declared the lead
catalyst, delivering 2a with a 94% e.e. at 94% conversion (Table 1A,
entry 19).23
In parallel, we asked exactly the same question with C2-type CPAs.
Shown in Table 1B are the results of atroposelective cyclodehydra-
tions with 14 variously substituted common BINOL-derived CPAs.
Notably, the results, from a purely enantioselectivity-centric per-
spective are comparable to the results obtained with the pThr-type
catalysts. For example, p-substituted catalysts B1 and B2 provide a
modest level of initial selectivity at good conversion (58% e.e. and
52% e.e., respectively; Table 1B, entries 1 and 2). o-Substitution with
B3, B4, and B5 leads to improvement, with up to 89% e.e. (Table
1B, entries 3−5). Apparent electronic effects also emerged, as the m-
substituted catalysts B6, B7, and B8 gave a range of results (Table
1B, entries 6−8), with B9, the m,m-diphenyl substituted catalyst, giv-
ing 89% e.e. in excellent conversion (Table 1B, entry 9). Further
substitution leveraged apparent combinations of various features
(vide infra). Tris-substitution on the BINOL-aryl substituent gave a
set of catalysts that were quite effective for the atropoisomer-selec-
tive cyclodehydration, as B10−13 all converged to give 2a with be-
tween 90% and 92% e.e. for the canonical TRIP catalyst24 (Table 1B,
entries 10−13). Catalyst B14 bearing 9-anthracenyl groups afforded
the highest selectivity observed, delivering 2a with 96% e.e. at full
conversion (Table 1B, entry 14).
■ RESULTS AND DISCUSSION
Catalyst optimizations. The context for this study is in the area
of catalytic asymmetric synthesis of atropisomers, which is a rela-
tively young subfield of asymmetric catalysis, with a variety of ap-
proaches now reported,17,18 including asymmetric cross-coupling19
and dynamic kinetic resolutions.20 Few catalytic atropisomer-selec-
tive methods target medicinally relevant heterocycles, and accord-
ingly this study began with the targeted conversion of 1a to 2a (Ta-
ble 1, Eq 1). While the precedent for the atroposelective cyclodehy-
dration was initially focused on diastereoselectivity,9 we commenced
the comparative study by expanding this finding to an enantioselec-
tive method for atropisomer-selective synthesis of axially chiral ben-
zimidazoles with both the pThr-type and C2-type of CPA. We ini-
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Table 1. Catalyst Optimizations
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Reaction conditions (unless otherwise noted): 1a (0.02 mmol), catalyst (P1−19 or B1−14) (0.002 mmol, 10 mol %), PhMe (0.2 mL, 0.1 M), 60
oC, 24 h. Conversions (as a percentage) were determined by 1H NMR integrations of the aromatic peaks for the substrate and product. Enantiomeric
excesses were determined by chiral HPLC analysis. Abbreviations: Aib, 2-aminoisobutyric acid; Acpc, 1-aminocyclopropane carboxylic acid; Acbc, 1-
aminocyclobutane carboxylic acid; Cle, cycloleucine (1-aminocyclopentane carboxylic acid); Aic, 2-aminoindane carboxylic acid; Achc, 1-aminocyclo-
hexane carboxylic acid; Phg, phenylglycine; Tle, tert-Butylleucine; Chg, cyclohexylglycine.
Substrate evaluation. From these optimization studies a ques-
tion arises: is the privileged C2-symmetric type catalyst B14 (96%
e.e., 100% conversion) clearly better than peptidic catalyst P19 (94%
e.e., 97% conversion)? Analysis of each against a panel of 22 system-
atically modified substrates allows a data-driven inquisition (Figure
2). Noteworthy, cyclodehydrations procced efficiently with both
catalysts, while moderate conversions were observed with sterically
congested o,o’-disubstituted substrates.23 We first evaluated three
additional 6-substituted substrates, 2b−d (Figure 2a). Removing
the remote tBu group (i.e., 1b to 2b) impacted enantioselectivity, as
both P19 and B14 process this substrate with a slightly lower level
of selectivity (P19, 91% e.e., B14, 88% e.e.). An electron donating
group also leads to a slight drop in selectivity for both catalysts (P19,
92% e.e.; B14, 94% e.e.), while an electron withdrawing group en-
hances the asymmetric catalysis (P19, 97% e.e.; B14, 97% e.e.). But,
most noteworthy is that P19 and B14 are all but indistinguishable
with these substrates. Substitution at the 7-position, however, cre-
ates an entirely different scenario. For five different substrates
(1e−i), peptidic catalyst P19 appears to offer more generality, as
benzimidazoles 2e−i are delivered with 89−93% e.e. for this class
(Figure 2b). In contrast, C2-type catalyst B14 seems poorly suited
to these substrates, as the products are obtained with 44−76% e.e.
(2e−h), with the exception of 2i being isolated with 83% e.e. (cf. 89%
e.e. with P19). Several other substrates also reveal the differential
attributes of pThr-type and C2-type CPAs. For example, as shown in
Figure 2c, substitution at the 5-position (i.e., 2j) is better tolerated
with P19 (94% e.e.) than with B14 (90% e.e.). Incorporating differ-
ent substitution patterns on the bottom arene of the diarylaniline
moiety also reveals curious effects. Highly substituted axially chiral
benzimidazoles 2k−m (Figure 2d) are all formed with excellent en-
antioselectivity when either P19 (93−97% e.e.) or B14 (93−96%
e.e.) are used as the catalysts. Exceptions appear in the formation of
2n where B14 (95% e.e.) is slightly more effective than P19 (85%
e.e.) and vice versa in the formation of 2o (P19, 89% e.e.; B14, 88%
e.e.). Some striking differences also emerge with o,o′-disubstituted
substrates 2p−r (Figure 2e). In these cases, low enantioselectivities
are observed with both P19 and B14 as the catalyst. While B14 pro-
vides a somewhat higher enantioselectivity in the cases of 2p and 2r,
neither catalyst gives promising results. However, when a second R-
group is added to the remote arene, as in the case 2s and 2t, quite
good enantioselectivities are recorded by both catalysts. Benzannu-
lated analogue (2u) is slightly better accommodated with P19 (94%
e.e.) than with B14 (91% e.e.). Yet, both P19 and B14 are poor cat-
alysts for the formation of 2v, with a basic N-atom introduced re-
mote from the loci of bond formation (Figure 2i, 16% e.e. and 2%
e.e., respectively). The absolute configuration of 2a was determined
by X-ray crystallographic analysis after recrystallization (Figure 2j),
and those of other products in Figure 2 were displayed by analogy.
Mechanistic experiments for P19. As a synthetic method, per-
haps most would agree that P19 and B14 are promising new tools
for an underexplored area of enantioselective catalysis. However,
what do their similarities and differences in performance tell us
about their respective mode of stereoinduction? For this question,
we turned to mechanistic studies. The manner in which one can in-
terrogate the mechanistic details of P19 and B14 is different.
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O
H
4
R''
N
5
N
O
P
Me
N
HN
BnO
HO
P19 or B14
(10 mol %)
R''
R
R
O
O
O
O
O
6
N1
O
O
HN
HN
P
7
OH
PhMe (0.05 M)
60 oC, 24 h
NHBz
R'
O
R'
NMe2
P19
1a−v
2a−v
B14
8
9
(a)
(b)
(c)
e.e. (%)
Me
e.e. (%)
N
N
N
N
N
N
2
R
2
R
P19 B14
F3C
F3C
F3C
P19 B14
10
11
12
13
14
15
16
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19
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2e
2f
Me
Et
iPr
92 74
92 76
92 75
93 44
89 83
e.e. (%)
P19 B14
94 90
R
tBu
H
2a
2b
94 96
91 88
92 94
97 97
2
R
2g
2h
2i
2c OMe
2j
Ph
2d
CF3
OMe
(d)
(e)
(f)
e.e. (%)
P19 B14
89 88
e.e. (%)
N
N
N
N
N
N
2
R
R′
2
R
R′
P19 B14
F3C
F3C
F3C
tBu
tBu
2o Ph
H
2k Me
2l
iPr
H
H
H
F
96 95
93 93
97 96
85 95
R
R′
R
R′
Me
2p OMe Me 14 31
2q Et OMe 28 12
2r OiPr Me 25 46
e.e. (%)
P19 B14
94 96
2m Bn
2n Me
2
OMe
2s
(g)
(h)
(i)
(j)
N
N
N
N
N
F3C
F3C
N
F3C
N
tBu
Me
e.e. (%)
P19 B14
16
e.e. (%)
e.e. (%)
P19 B14
94 91
2
2
2
P19 B14
(X-ray, 2a)
2v
2t
2u
2
93 94
OMe
Figure 2. Substrate scopes. Reported results are the average of two trials. Reaction conditions (unless otherwise noted): 1 (0.02 mmol), catalyst (P19
o
or B14) (0.002 mmol, 10 mol %), PhMe (0.4 mL, 0.05 M), 60 C, 24 h. Enantiomeric excesses were determined by chiral HPLC analysis. Absolute
configuration of 2a was determined by single-crystal X-ray diffraction analysis as shown in Figure 2j. All other absolute configurations were drawn based
on analogy.
H
N
(a)
Computation, particularly at the DFT level, has emerged as a pow-
F3C
N
N
P20−22
(10 mol %)
F3C
Cat. conv. (%) e.e. (%)
erful tool for assessing the feasibility of mechanistic steps involved in
catalysis and the origins of enantioinduction.25 These techniques are
renowned for the interrogation of rigid C2-type catalysts like B1−14.
In contrast, peptide-based catalysts like P19 present special chal-
lenges, and computational analyses of such flexible systems are far
from routine.26 The complication arises from the many plausible
ground state (GS) and transition state (TS) conformations, which
require exhaustive sampling and may require molecular dynamic
simulations for effective conformation generation, an inherently
time consuming process.27 A range of experimental techniques, how-
ever, offers a complementary way to probe the effect of the catalyst
structure on enantioselectivity, and in some instances are faster to
complete than computations. In this regard, we performed two types
of studies including, (a) evaluation of catalyst analogs, and (b) inves-
tigation of the catalyst structure by NMR techniques. For the former,
truncated peptides P20−22 were prepared and evaluated to isolate
the minimal determinants of selectivity and striking results were ob-
tained (Figure 3a). To begin, phosphorylated threonine monomer,
P20, shows moderate enantioselectivity favoring the enantiomeric
product of 2a, suggesting that the high enantioselectivity of P19 is
not dominated by the local stereoconfiguration of threonine, but ra-
ther on the global conformation of the peptide.28 Elongation to the
dipeptide (i.e., P21) also affords ent-2a as a major enantiomer (−42%
e.e.), while the tripeptide P22 gives almost racemic mixture of 2a.
High enantioselectivity was only observed with the Fmoc protected
tetrapeptide, P15.
O
tBu
tBu
HN
P20
P21
P22
P15
79
57
29
99
−25
−42
1
PhMe
60 oC, 24 h
88
1a
2a
H
H
O
O
O
Me NMe2
O
BnO
P
Me
N
O
P
Me
N
NMe2
HN
BnO
HO
BnO
HO
O
P
O
O
HO
O
O
O
O
Me2N
NHFmoc
NHFmoc
NHFmoc
P20
P21
P22
O
(b)
(c)
N
H
N
O
H
O
N
H
H
O
O
N
H
OBn
Me
O
O
P
Me
N
HN
O
Ph
O
O
P
NMe2
HO
O
O
O
O
H
O
HN
NH
O
H
O
F3C
N
N
Me
HN
Me
15 inter-residual
ROE contacts
P19
tBu
Figure 3. (a) Truncation study of peptide catalyst. Reaction conditions
(unless otherwise noted): 1a (0.02 mmol), catalyst (P20−22) (0.002
mmol, 10 mol %), PhMe (0.2 mL, 0.1 M), 60 oC, 24 h. Conversions (as
a percentage) were determined by 1H NMR integrations of the aromatic
peaks for the substrate and product. Enantiomeric excesses were deter-
mined by chiral HPLC analysis. (b) 15 inter-residue ROE contacts re-
vealed by 1H−1H ROESY NMR of P19. (c) Proposed structure of P19
and mechanistic model.
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These results also imply additional non-covalent interactions be-
be related through overlapping and varying sensitivities to the sub-
strate, providing insight into how these catalysts induce stereoselec-
tivity. We hypothesized that 2a−t offered the requisite changes to
both the electronic and steric environments of the substrate (Figure
5) but also incorporates sufficient overlapping features for analysis.
(a)
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tween the cyclohexyl group at i+3 residue and 1a and/or considera-
ble conformational changes induced by the introduction of i+3 resi-
due. For direct observation of the catalyst structure, 1H−1H ROESY
NMR studies of P19 were performed. We observed 15 non-sequen-
tial ROE correlations as shown in Figure 3b. Contacts (red arrows)
of N‒Hacpc with the bottom face of DPro and the proton of the ꢀC-H
of pThr suggest that the N‒H bond is likely located underneath the
DPro residue, in proximity to potential hydrogen bond acceptors
C=OThr and C=OBz. Considering ROE contacts (blue arrows) of the
cyclohexyl group with the protons of ꢀC‒H of DPro and βC-H of Thr,
a β-turn conformation appears supported by the hydrogen bond be-
tween N‒Hchg and C=OThr as shown in Figure 3c. Multiple correla-
tions (green arrows in Figure 3b) between the dimethylamide at the
C-terminus and benzylic and aromatic protons of -OBn/-NHBz of
pThr are consistent with our hypothetical conformation and also in-
dicate that the i+3 residue would be in proximity with the phos-
phoric acid. Given the steric effect of the i+3 residue as described in
Table 1A, secondary interaction between the cyclohexyl group and
substrate may have a beneficial influence on atroposelectivity.
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TSRe
TSSi
(b)
O
O
O
O
O
O
P
P
O
H
DFT calculations for B14. In evaluating the mechanism of C2-
type catalysts like B14, DFT and experimental results strongly sug-
gest that cyclization is both rate and enantiodetermining.23 To probe
the origins of enantioinduction, we performed geometry optimiza-
tions with ωB97XD/6-31G(d) followed by single-point calculations
at the ωB97XD/6-31G(d,p) level in toluene with the polarizable
continuum model, IEFPCM using optimal catalyst B14 containing
an anthryl group. The calculations corroborate the magnitude (exp.
96% e.e., calc. 93% e.e.) and sense of enantioinduction (Figure 4a).
The key controlling element appears to be a steric interaction be-
tween the naphthyl group on the substrate and the 3,3′ substituents
on the catalyst (Figure 4a). To precisely explore the contributions of
the t-butyl and the naphthyl substituents on the substrate structure
to the TS energies, two truncation studies were performed compu-
tationally. Firstly, the t-butyl substituent was replaced for a proton
and a single-point energy was taken of the resulting structures with-
out re-optimization.29 The energy difference (ΔΔE‡) between the
competing structures increased from 2.4 to 4.0 kcal mol-1, which sug-
gests that the t-butyl group is not a major element in the catalyst-
substrate interactions. However, replacing the naphthyl group for a
phenyl group led to a significant decrease in ΔΔE‡ from 2.4 to 0.8
kcal mol-1. These truncation studies are consistent with the primary
determinants of enantioselectivity being the interactions between
the 3,3′ substituents on the catalyst and the naphthyl substituent of
the substrate. Further interrogation of the mechanistic basis for the
selectivity afforded by C2-type catalysts was accomplished using sta-
tistical comparison of catalysts substituent changes to reaction enan-
tioselectivity (expressed as ΔΔG‡).30 Collected parameters for the
correlations included IR vibrational frequencies and intensities, tor-
sion angles, NBO charges and Sterimol steric descriptors (L, B1, B5).
A simple model prioritizes steric effects measured though torsion
and two other terms: the P=Oas stretch likely describing H-bond
O
H
O
HN
NH
H
N
H
O
R1
R1
R1
R1
N
F3C
CF3
TSRe
TSSi
ΔΔG‡ = 0 kcal mol-1
ΔΔGsol = 0 kcal mol -1
ΔΔG‡ = +2.2 kcal mol-1
ΔΔGsol = +2.0 kcal mol -1
Figure 4. (a) Cyclization TS calculated at ωB97XD/6-31G(d,p)-
IEFPCM(toluene)//ωB97XD/6-31G(d) level of theory. Noncritical
hydrogen atoms omitted for clarity. (b) Qualitative model describing
the origins of enantioinduction. The repulsive steric interactions be-
tween the naphthyl and the 3-substituent cause TSSi to be energetically
disfavored. Reducing the size of the 3,3ʹ substituents reduces the inter-
action between them and would lead to lower e.e’s.
To define the parameter library, DFT optimizations were per-
formed on these substrates at the M06-2X/def2-TZVP level of the-
ory wherein NBO charges, IR vibrations and Sterimol values were
collected to probe structural effects.31 A statistical model consisting
of four terms was determined for the BINOL-derived phosphoric ac-
ids. The included parameters suggest that the process proceeds via a
TS that minimizes steric repulsions between the large 3,3′ groups on
the catalyst and the substrate (Figure 5a), which is consistent with
both the DFT and catalyst correlation studies detailed above. For ex-
ample, the negative coefficient with the LC7 term describes likely re-
pulsive interactions in TSRe with the C7 substituent and the 3,3′ sub-
stituents. The terms B5C6 and the B1ortho both describe the preferred
orientation of the bottom ring in the TS. Reducing the size of the
substituent at C6 decreases the repulsion between the top and the
bottom rings in the cyclization step. In this case, the more compact,
the third TS, in which the larger substituent on the bottom aromatic
ring points towards the top aromatic ring (second TS structure in
Figure 5b), would be more plausible leading to decreased enantiose-
lectivity. Complementary to the catalyst statistical model (Figure 4b
and 5a), the NBOO term is likely describing H-bond contacts be-
tween the catalyst and substrate.
contacts and the cross term ꢀ*B1C3,a steric correction for the inclu-
sion of 9-anthryl, as additional selectivity discriminants.
Comprehensive model and determinants. Perhaps the most
powerful analysis of the differences between the two catalyst classes
can be achieved by using a substrate profiling technique wherein the
performance of each catalyst is analyzed through correlation of sub-
strate outcomes. Specifically, we anticipated that the subtle differ-
ences in substrate performance as a function of catalyst class could
Intriguingly, the pThr-type catalysts counterparts do not function
through an analogous model of enantioinduction, despite the same
catalytic apparatus for bond formation (i.e., the CPA moiety itself).
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(a)
C2-Type Catalyst Model
pThr Substrate Model
C2-Type Substrate Model
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Parameters Used
Conserved Terms Across Substrate Models
C2 Type Specific for Substrate Model
(b)
*
O
R
*
*
O
α
B1C3
O
O
O
O
O
O
P
O
P
P
P
O
O
O
P
O
O
O
O
O
O
HN
O
νPOas
H
O
HN
HN
H
N
H
O
H
O
HN
O
H
N
H
N
H
O
H
N
R1
R1
F3C
F3C
F3C
H
N
F3C
F3C
NBOO
O
HN
R
B5C6
NBOO
B5C6
B1ortho
Similar sterics
LC7
R
R
Hydrogen bonding
Large substituent introduces
steric repulsion
Steric repulsion in TSRe between
B1ortho
LC7
catalyst and substrate
substrate preferences
Figure 5. (a) Evaluation of 3,3ʹ-substituent features dictating enantioselectivity in the cyclodehydration reaction using an MLR model for a truncated
C2-type CPA (left) in addition to MLR models derived from substrate parameters for both the C2-type CPA (center) and pThr-type CPA (right). (b)
Parameter assignments and MLR model deconstruction.
For the pThr-type catalysts, the mathematical model consists of
three conserved terms. Two of these terms essentially describe the
bottom ring orientation preferences, an apparent locus of critical cat-
alyst-substrate interactions. The NBO term is likely indicative of the
hydrogen bonding features of phosphoric acid with the substrate.
However, most notably, the peptide system does not include an ad-
ditional penalizing steric term in the model. Despite steric effects
and the proximity of the i+3 residue to the phosphoric acid as ob-
served in Table 1A and Figure 3, this catalyst class still provides an
alternative mode of enantioinduction. This effect may be consistent
with the enhanced generality in scope for substrate variation in this
vicinity; the flexible peptide system may also be adaptive to substrate
steric demands, as is evidenced in other peptide-based catalysts.26,27
Comparison of the magnitudes of the coefficient terms can provide
further insight into the stereocontrolling elements responsible for
enantioinduction. Intriguingly, the B5C6 term is statistically more
significant for the C2-type CPAs. This suggests that due to steric re-
pulsion between the catalyst 3,3′ substituents and the bottom aro-
matic ring of the substrate that a compact arrangement may be more
readily favored. The proposed physical meaning behind each of the
terms in the mathematical equations have been summarized in Fig-
ure 5b.
to the differential energies of competing transition states within an
ensemble. In the present study, steric effects from reasonably large
groups on both the catalyst and substrate appear to dictate enanti-
oselectivity for C2-type CPAs. In contrast, pThr-type CPAs appear
to work through an alternative mode of enantioinduction, where
conformational adaptation presumably limits repulsive interactions.
These experimental and computational findings allow us to revisit
some of the questions posed in our introduction. For example, it
seems ever clearer that various catalyst types may be found to
achieve high levels of enantioselectivity for a given transformation of
interest, and that if the mode of activation is general (e.g.,
Lewis/Brønsted acid activation, bifunctional catalysis, etc.), applica-
tion to other reactions with mechanistic similarity can follow. Yet,
the redundancy of mechanistic solutions to common overall trans-
formations may expand the concept of the privileged catalyst. In this
sense, as the field evolves, it seems there may be less privilege, indeed
less uniqueness of solution, as more catalyst types are discovered for
a given type of enantioselectivity transformation. The expanded ar-
ray of catalyst available also enables exploration of ever-expanding
substrate space. Accordingly, new layers of mechanistic complexity
are introduced when unusual substrate types are evaluated. Therein,
situations emerge where catalyst functional equivalences may be
lifted. In such situations, mechanistic complementarity among cat-
alyst types may be particularly critical for broad spectrum success
with highly diverse substrates. And of course, these same issues will
likely emerge as each catalyst type is profiled in an ever-expanding
list of reaction types. In this sense, a case may exist for an ever ex-
panding, perhaps less privileged catalyst catalog, placing a premium
■ CONCLUSIONS
Although the general principles of energetic differentiation under-
lying asymmetric catalysis by distinct catalyst families are essentially
the same, significant mechanistic differences can lead to similar se-
lectivity outcomes. Fundamentally, destabilizing effects and stabiliz-
ing noncovalent interactions of a variety of types can all contribute
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5.
6.
Zhou, Q. L., Privileged Chiral Ligands and Catalysts. Wiley: 2011.
(a) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L.,
on catalytic structural diversity and diverse catalytic mechanisms
that control secondary, outer sphere interactions. This is a hallmark
of enzymatic catalysis, where diversity of function on common cata-
lyst scaffolds has emerged alongside an impressive array of catalyst
specificities.32
1
2
3
4
5
6
7
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Preparation and use of C2-symmetric bis(phospholanes): production of
.alpha.-amino acid derivatives via highly enantioselective hydrogenation
reactions. J. Am. Chem. Soc. 1993, 115, 10125−10138; (b) Junge, K.;
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Pub-
lications website.
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7.
(a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., Amino Acid
Experimental details, procedures, compound characteriza-
1
tion data, computational details, and copies of H and 13C
Catalyzed Direct Asymmetric Aldol Reactions:ꢀ A Bioorganic Approach to
Catalytic Asymmetric Carbon−Carbon Bond-Forming Reactions. J. Am.
Chem. Soc. 2001, 123, 5260−5267; (b) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.;
Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D., Novel Small Organic
Molecules for a Highly Enantioselective Direct Aldol Reaction. J. Am. Chem.
Soc. 2003, 125, 5262−5263; (c) Kano, T.; Takai, J.; Tokuda, O.; Maruoka,
K., Design of an Axially Chiral Amino Acid with a Binaphthyl Backbone as
an Organocatalyst for a Direct Asymmetric Aldol Reaction. Angew. Chem.
Int. Ed. 2005, 44, 3055−3057; (d) Zheng, B.-L.; Liu, Q.-Z.; Guo, C.-S.;
Wang, X.-L.; He, L., Highly enantioselective direct aldol reaction catalyzed
by cinchona derived primary amines. Org. Biomol. Chem. 2007, 5,
2913−2915; (e) Trost, B. M.; Brindle, C. S., The direct catalytic asymmetric
aldol reaction. Chem. Soc. Rev. 2010, 39, 1600−1632.
NMR spectra of new compounds (PDF)
X-ray crystallographic data for 2a (CIF)
AUTHOR INFORMATION
Corresponding Author
*matt.sigman@utah.edu
*fdtoste@berkeley.edu
*scott.miller@yale.edu
8.
(a) Ishihara, K.; Yamamoto, H., Bronsted Acid Assisted Chiral
ORCID
Lewis Acid (BLA) Catalyst for Asymmetric Diels-Alder Reaction. J. Am.
Chem. Soc. 1994, 116, 1561−1562; (b) Evans, D. A.; Murry, J. A.; von Matt,
P.; Norcross, R. D.; Miller, S. J., C2-Symmetric Cationic Copper(II)
Complexes as Chiral Lewis Acids: Counterion Effects in the
Enantioselective Diels–Alder Reaction. Angewandte Chemie International
Edition in English 1995, 34, 798−800; (c) Corey, E. J.; Shibata, T.; Lee, T.
W., Asymmetric Diels−Alder Reactions Catalyzed by a Triflic Acid Activated
Chiral Oxazaborolidine. J. Am. Chem. Soc. 2002, 124, 3808−3809; (d) Ma,
S., Asymmetric catalysis of Diels-Alder reaction in Handbook of cyclization
reactions, Vol. 1. Wiley-VCH: Weinheim, 2010.
Junqi Li: 0000-0003-0336-2544
Matthew S. Sigman: 0000-0002-5746-8830
F. Dean Toste: 0000-0001-8018-2198
Scott J. Miller: 0000-0001-7817-1318
Notes
The authors declare no competing financial interest.
9.
Kwon, Y.; Chinn, A. J.; Kim, B.; Miller, S. J., Divergent Control
ACKNOWLEDGMENT
of Point and Axial Stereogenicity: Catalytic Enantioselective C−N Bond‐
Forming Cross‐Coupling and Catalyst‐Controlled Atroposelective
Cyclodehydration. Angew. Chem. Int. Ed. 2018, 57, 6251−6255.
M.S.S., F.D.T., and S.J.M. are grateful to the National Institute of Gen-
eral Medical Sciences of the National Institutes of Health for support
(GM-121383). The authors are grateful to Christopher R. Shugrue, Aa-
ron L. Featherston and Dr. Anthony J. Metrano for preparation of cata-
lysts and helpful discussions. We also would like to thank Dr. Brandon
Q. Mercado for solving our X-ray crystal structures. J.M.C. acknowl-
edges the support of the NSF Graduate Research Fellowship Program.
Computational resources were provided by the Center for High Perfor-
mance Computing at the University of Utah and the Extreme Science
and Engineering Discovery Environment (XSEDE), which is supported
by the NSF (ACI-1548562).
10.
Taylor, R. D.; MacCoss, M.; Lawson, A. D. G., Rings in Drugs. J.
Med. Chem. 2014, 57, 5845−5859.
11.
Enantioselective Mannich-Type Reaction Catalyzed by a Chiral Brønsted
Acid. Angew. Chem. Int. Ed. 2004, 43, 1566−1568; (b) Uraguchi, D.; Terada,
M., Chiral Brønsted Acid-Catalyzed Direct Mannich Reactions via
Electrophilic Activation. J. Am. Chem. Soc. 2004, 126, 5356−5357.
(a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K.,
12.
(a) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M., Complete
Field Guide to Asymmetric BINOL-Phosphate Derived Brønsted Acid and
Metal Catalysis: History and Classification by Mode of Activation; Brønsted
Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates. Chem. Rev.
2014, 114, 9047−9153; (b) Maji, R.; Mallojjala, S. C.; Wheeler, S. E., Chiral
phosphoric acid catalysis: from numbers to insights. Chem. Soc. Rev. 2018,
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H
N
N
F3C
N
‘pThr-type’ CPA
F3C
R
R
or
O
HN
X
‘C2-type’ CPA
Benzimidazole scaffold
22 examples
up to 97% e.e.
X
6
O
Ar
7
8
9
O
Me
N
HN
O
O
O
BnO
HO
O
P
P
vs
O
O
OH
HN
NHBz
O
Ar
10
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NMe2
Ar = 9-anthracenyl
‘C2-type’
‘pThr-type’
■ NMR study
■ Transition state analysis
■ Comparative multivariate
linear regression
! Comprehensive comparison between catalysts
! Mechanistic insight
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