Mechanism-Guided Development of a Highly Active Bis-thiourea Catalyst for Anion-Abstraction Catalysis

Article abstract of DOI:10.1021/jacs.6b09205

We describe the rational design of a linked, bis-thiourea catalyst with enhanced activity relative to monomeric analogues in a representative enantioselective anion-abstraction reaction. Mechanistic insights guide development of this linking strategy to f

Full text of DOI:10.1021/jacs.6b09205

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Communication
Mechanism-Guided Development of a Highly Active
Bis-Thiourea Catalyst for Anion-Abstraction Catalysis
C. Rose Kennedy, Dan Lehnherr, Naomi S. Rajapaksa, David D. Ford, Yongho Park, and Eric N. Jacobsen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b09205 • Publication Date (Web): 05 Oct 2016
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Mechanism-Guided Development of a Highly Active Bis-Thiourea
Catalyst for Anion-Abstraction Catalysis
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C. Rose Kennedy,‡ Dan Lehnherr,‡ Naomi S. Rajapaksa, David D. Ford, Yongho Park, Eric N. Jacob-
sen*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
Supporting Information Placeholder
enhanced catalytic activity. The linked units would also
need to adopt a relative orientation closely resembling
that accessed by the untethered monomers in order to
promote reactions with similar levels of enantioselectivi-
ty. Analogous linking strategies have afforded reactivity
enhancements in other systems displaying a bimolecular
dependence on chiral catalyst.6 However, this case poses
an additional challenge, because the tether must also
disfavor unproductive ground-state aggregation. Herein,
we describe the mechanism-guided development of a
highly active bis-thiourea catalyst for anion-abstraction
catalysis. In addition to providing a platform for future
catalyst design, the linking strategy validates computa-
tional analyses shedding light on the cooperative mecha-
nism of anion abstraction.
ABSTRACT: We describe the rational design of a linked,
bis-thiourea catalyst with enhanced activity relative to
monomeric analogs in a representative enantioselective
anion-abstraction reaction. Mechanistic insights guide
development of this linking strategy to favor substrate
activation though the intramolecular cooperation of two
thiourea subunits while avoiding nonproductive aggrega-
tion. The resulting catalyst platform overcomes many of
the practical limitations that have plagued hydrogen-
bond donor catalysis and enables use of catalyst loadings
as low as 0.05 mol %. Computational analyses of possi-
ble anion-binding modes provide detailed insight into
the precise mechanism of anion-abstraction catalysis
with this pseudo-dimeric thiourea.
Chiral dual hydrogen-bond (H-bond) donors such as
urea, thiourea, and squaramide derivatives comprise an
important class of enantioselective catalysts for reactions
proceeding through ion-pair intermediates.1,2 While the-
se air- and moisture-stable organocatalysts have enabled
the development of numerous, highly enantioselective
transformations, these methods typically suffer from sev-
eral practical constraints that impede widespread appli-
cation. These include requirements for high catalyst
loadings (5–20 mol %), long reaction times (≥24 h), and
dilute reaction conditions (≤0.1 M in substrate) to
achieve maximal levels of enantioinduction.3
In an effort to understand the basis for these limita-
tions and thereby develop strategies to overcome them,
we recently undertook a detailed mechanistic study of a
representative
transformation
involving
anion-
abstraction catalysis by a chiral amido-thiourea (1, Fig-
ure 1A).2c,4,5 This analysis revealed that thiourea catalyst
1 forms nonproductive dimeric aggregates in the resting
state; these aggregates must dissociate before two mole-
cules of catalyst recombine with substrates to promote
rate- and enantioselectivity-determining C–C bond for-
mation (Figure 1B).4a We hypothesized that appropriate
linkage of the monomers should result in stabilization of
the dominant transition-state complex and, therefore,
Figure 1. (A–C.) Anion-abstraction catalysis involving the
cooperative action of two amido-thiourea catalysts. Ar = 4-
fluorophenyl, ArF = 3,5-bis(trifluoromethyl)phenyl.
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Figure 2. (A–C.) Identification of a linking strategy for bis-thiourea anion-abstraction catalysts. Carbon atoms represented in
silver (for 5), slate blue (for 6), or light pink (for 7). Linkage sites highlighted in cyan. Carbon-bound hydrogen atoms omitted
for clarity. N = blue, O = red, F = lime, Si = gold, S = yellow, Cl = magenta. Computations performed with B3LYP-
D3(BJ)/6-31G(d,p)/PCM(toluene)//B3LYP/6-31G(d). Corrected free energies reported relative to the lowest energy transi-
tion state identified with each catalyst. See Supporting Information for additional discussion.
While the cooperative action of thioureas such as 1 in
anion-abstraction catalysis has been well established,
uncertainty remains regarding the precise mode of elec-
trophile activation by two catalyst units. Two different
cooperative arrangements, which we term “2H-” and
“4H-” anion abstraction (Figure 1C), are consistent with
experimental data and kinetically indistinguishable.7
Furthermore, preliminary computational analyses of
[1]2•Cl– complexes using density functional theory
(DFT) did not reveal a clear energetic preference for one
over the other.4 We postulated that dimeric catalysts
designed to enable Cl– abstraction through only one of
these two arrangements could help reveal which of the
two activation modes is operative in the enantioselective
alkylation of α-chloroisochroman and in related anion-
binding pathways promoted by this class of chiral H-
bond donor. Given that these catalysts have been shown
to form [cat]2•NMe4Cl complexes with a 4H-Cl–-
binding geometry in the solid state (Figure 2A),4,8 we
chose to target linkage strategies that would favor the
4H-activation mode. Introduction of a methyl substitu-
ent in the arylpyrrolidine component of 1 has been
demonstrated to confer improved reactivity and enanti-
oselectivity by minimizing competing reaction path-
ways,8 and accordingly, we used this modified structure
(5a) as the starting point for further catalyst design.
In order to link two units of 5a in a manner that might
stabilize the reactive conformation of the resulting dimer
selectively, we sought to identify linkage points that
would allow access to the 4H-Cl–-bound complex, but
disfavor formation of the inactive, self-aggregated com-
plex.9 The structures of both the nonproductive aggre-
gate (5a•5a) and
a
4H-Cl–-bound complex
([5a]2•NMe4Cl) have been characterized by X-ray dif-
fraction.4,8,10 We noted that, in the solid state, the dis-
tance between the backbone tert-butyl group of one mol-
ecule and the aryl thiourea of the other is considerably
greater in the nonproductive aggregate than in the Cl–-
bound complex (Figure 2A). This observation suggested
that linkage through these sites might fulfill the intended
purpose. We deemed that an appropriate linker between
these two sites would need to meet the following strin-
gent criteria: 1) it should cause minimal structural and
electronic perturbation to the key catalyst features identi-
fied in the original optimization efforts;2c 2) it must be
long enough to allow the same 4H-binding arrangement
that is accessible to the unlinked monomers; but, 3) it
must be short enough to prevent intramolecular for-
mation
of
the
nonproductive
aggregate.
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Figure 3. A. Alkylation of α-chloroisochroman with 3b catalyzed by mono- (1 and 5a,c,d at 0.5 mol %) and bis-thioureas
(6a and 7a at 0.25 mol %) at low loading. Relative rates at 15% conversion. B. Alkylation exhibits a first-order dependence
on catalyst 6a with dramatic rate acceleration over catalyst 1. See ref. 4a. Rates at 30% conversion. C. The enantiomeric
excess of product 4a shows a linear dependence on the ee of bis-thiourea 6a (0.25 mol %); this stands in contrast to the non-
linear dependence on the ee of catalyst 1 (0.50 mol %).
The relative disposition of the 5b units in the lowest
energy rate- and enantiodetermining 4H-alkylation tran-
sition structure predicted using DFT was found to be
very similar to that in the Cl–-bound complex character-
ized in the solid state.8,11–13 We used the computed tran-
sition structure to evaluate a variety of hypothetical
linked structures according to the criteria outlined
above. Through this analysis, pseudo-dimeric thiourea
catalyst 6b, which bears a 5-atom spacer between the
amino acid side chain of one thiourea unit and the aryl
group of another, was modeled and found to access 4H-
transition structures that overlay almost perfectly with
the transition structure calculated with 5b (Figure 2C,
left). In contrast, 7b, which possesses a linker just one
methylene unit shorter, was predicted to be incapable of
achieving similar conformations (Figure 2C, right). Both
catalysts were selected for experimental assessment.
relatively concentrated conditions (0.5 M initial substrate
concentration) to afford 4a with excellent yield and en-
antioselectivity after just 3 hours (Scheme 1). This stands
in stark contrast to the original conditions, in which a
24-hour reaction time with 10 mol % 1 at 0.1 M is re-
quired to achieve good yield with the same level of enan-
tioinduction.2c
Scheme 1. Improved Volumetric Throughput on
Preparatory Scale
The improved efficiency observed with pseudo-
dimeric catalyst 6a provides circumstantial evidence for
the validity of the cooperative mechanism for anion-
abstraction catalysis outlined in Figure 1B. In order to
establish rigorously whether the two linked thiourea
subunits act cooperatively within the same molecule, the
kinetic dependence of alkylation rate on catalyst concen-
tration was determined by reaction progress kinetic
analysis using in situ infrared spectroscopy (Figure
3B).4a,14 The reaction exhibits a strict first-order depend-
ence on catalyst at low [6a], under conditions where a
second-order dependence on [1] is observed.4a The in-
creased activity of 6a relative to monomeric catalyst 1 is
therefore magnified at very low catalyst loadings, and as
little as 0.05 mol % 6a can be employed while maintain-
ing useful reaction rates. Finally, an absence of a non-
linear effect is observed with catalyst 6a at low catalyst
concentrations (Figure 3C).15,16 Taken together, these
results provide strong evidence that the thiourea subunits
in catalyst 6a cooperate in an intramolecular fashion to
promote oxocarbenium alkylation.
Bis-thioureas 6a and 7a, along with their monomeric
analogs 5c and 5d, were synthesized and compared with
1 and 5a as catalysts for the alkylation of α-
chloroisochroman with silyl ketene acetal 3b. While
modification of the tert-leucine side chain (as in 5c) has a
negligible effect on enantioselectivity, replacement of the
trifluoromethyl group with an ester (as in 5d) does have
a slightly detrimental impact (Figure 3A). Nonetheless,
catalyst 6a displays markedly enhanced reactivity, af-
fording high conversion with a low catalyst loading and
short reaction time, while preserving the enantioselec-
tivity observed with 5a. In contrast, catalyst 7a exhibits
very similar reactivity to the monomeric analogs, con-
sistent with the prediction that the 4-atom linker is too
short to enable intramolecular formation of the optimal,
cooperative transition structure.
The improved efficiency of catalyst 6a allows us to
address several of the practical limitations presented by
the conditions optimized for catalyst 1. With just 0.1 mol
% 6a, the alkylation of α-chloroisochroman with silyl
ketene acetal 3a can be run on preparatory scale under
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(NSERC PDF), N.S.R. (Boehringer Ingelheim), and D.D.F.
Furthermore, the successful development of a highly
active pseudo-dimeric catalyst designed around the 4H-
activation mode suggests that the 4H-mechanism is most
likely operative under the conditions described above.
To evaluate whether the 2H-activation mode is also ac-
cessible to the dimeric catalysts, the intermediate
cat•oxocarbenium•Cl– complexes and the transition
structures for oxocarbenium alkylation promoted by the
2H- and 4H-arrangements of catalyst 6b were examined
computationally. Across a variety of functionals, both
the intermediate and transition structures in which the
bis-thiourea was forced to access a 2H-geometry were
predicted to be significantly higher in energy than the
alternative 4H-structures. (See Supporting Information
for additional discussion.)
1
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8
(Eli Lilly). The authors thank Dr. Shao-Liang Zheng (Har-
vard X-Ray Laboratory) for collection and refinement of
X-ray crystallographic data, Dr. Robert Knowles (Prince-
ton) for early crystallographic analyses, Dr. Alison E.
Wendlandt and Andrew J. Bendelsmith (Harvard) for syn-
thetic assistance, and Daniel A. Strassfeld (Harvard) for
helpful discussion.
REFERENCES
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(1) For reviews, see: (a) Zhang, Z.; Schreiner, P. R. Chem. Soc.
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In conclusion, the design of highly active and efficient
anion abstraction catalyst 6a represents the culmination
of a series of mechanistic insights. The mechanism-
driven design strategy has afforded a linked, bis-thiourea
catalyst system that overcomes many of the practical
limitations traditionally associated with H-bond-donor-
mediated anion-abstraction catalysis. Key insights ena-
bled formation of a pseudo-dimeric complex for cooper-
ative activation of a chloroether electrophile by a 4H-
mechanism while disfavoring nonproductive ground-
state aggregation. The high efficiencies enabled by this
catalyst design hold promise for application of dual hy-
drogen-bond-donor-mediated anion-abstraction catalysis
to historically challenging transformations. In this vein,
the development of highly stereoselective reactions with
tertiary alkyl chloride and glycosyl chloride electrophiles
is the focus of our ongoing attention.
(2) For select examples of enantioselective anion-binding catal-
ysis with dual H-bond donors, see: (a) Taylor, M. S.; Tokunaga, N.;
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on
the ACS Publications website.
Experimental procedures; spectroscopic data; kinetic data
(tabulated and graphical); discussion, geometries, and ener-
gies of calculated stationary points; summary of alternative
linking
strategies
(PDF).
X-ray crystallographic structures for synthetic intermediates
and select urea and thiourea catalysts (CCDC 1478174,
1482963–1482976, 1501460) (CIF)
AUTHOR INFORMATION
Corresponding Author
jacobsen@chemistry.harvard.edu
Author Contributions
‡These authors contributed equally.
Funding Sources
No competing financial interest has been declared.
ACKNOWLEDGMENT
(7) For examples in which intramolecular H-bonding has been
proposed to increase the “2H” anion- or neutral Lewis base-binding
ability of a urea or thiourea catalyst, see: (a) Jones, C. R.; Pantoş, G.
This work was supported by the NIH (GM-43214) and
through fellowships to C.R.K. (NSF, DGE1144152), D.L.
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(16) A nonlinear effect would be expected if 6a were undergo-
ing self-aggregation to a measurable extent under the catalytic condi-
tions, or if 6a achieves cooperative anion abstraction through an in-
termolecular pathway. In the latter scenario, the magnitude of the
nonlinear effect would depend on the degree of stereochemical com-
munication between the thiourea subunits in the ee-determining tran-
sition structure.
(8) While 1 exists as a slowly interconverting mixture of amide
rotamers, 5a exists exclusively in the more active and enantioselective
(Z)-rotameric form. This constraint has been demonstrated to lead to
improved activity and enantioselectivity in the alkylation of α-
chloroisochroman. See: Lehnherr, D.; Ford, D. D.; Bendelsmith, A.
J.; Kennedy, C. R.; Jacobsen, E. N. Org. Lett. 2016, 18, 3241–3217.
(9) The extent of this challenge was further illustrated by the
poor efficiencies of symmetrically linked catalysts. See Supporting
Information for details.
(10) The solution-state structures of the nonproductive aggre-
gates 1•1 and 5a•5a have also been determined via DFT-aided 2D
NMR analysis; see refs. 4a, 8. These structures are similar to the solid-
state structures and position the backbone tert-butyl group of one mol-
ecule distal from the aryl thiourea of the other.
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(11) Catalyst 5b provides a significantly reduced computational
cost relative to catalyst 5a. For experimental validation, see ref. 8.
(12) Frisch, M. J. et al. Gaussian 09, Revision D.02. Gaussian
Inc.: Wallingford, CT, 2009; see Supporting Information for full cita-
tion.
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ACS Paragon Plus Environment