Conformational Control of Chiral Amido-Thiourea Catalysts Enables Improved Activity and Enantioselectivity

Article abstract of DOI:10.1021/acs.orglett.6b01435

While aryl pyrrolidinoamido-thioureas derived from α-amino acids are effective catalysts in a number of asymmetric transformations, they exist as mixtures of slowly interconverting amide rotamers. Herein, the compromising role of amide bond isomerism is analyzed experimentally and computationally. A modified catalyst structure that exists almost exclusively as a single amide rotamer is introduced. This modification is shown to result in improved reactivity and enantioselectivity by minimizing competing reaction pathways.

Full text of DOI:10.1021/acs.orglett.6b01435

Letter
pubs.acs.org/OrgLett
Conformational Control of Chiral Amido-Thiourea Catalysts Enables
Improved Activity and Enantioselectivity
Dan Lehnherr, David D. Ford, Andrew J. Bendelsmith, C. Rose Kennedy, and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
S
* Supporting Information
ABSTRACT: While aryl pyrrolidinoamido-thioureas derived
from α-amino acids are effective catalysts in a number of
asymmetric transformations, they exist as mixtures of slowly
interconverting amide rotamers. Herein, the compromising
role of amide bond isomerism is analyzed experimentally and
computationally. A modified catalyst structure that exists
almost exclusively as a single amide rotamer is introduced.
This modification is shown to result in improved reactivity and enantioselectivity by minimizing competing reaction pathways.
ual hydrogen-bond (H-bond) donors, such as chiral urea
and thiourea derivatives, have come to define an important
Scheme 1. Chiral Amido-Thiourea-Mediated Anion-
Abstraction Catalysis
a
D
class of catalysts for a range of highly enantioselective
transformations.1 Catalysts bearing the 2-aryl pyrrolidino
amide motif have been of particular utility for promoting
transformations via anion-binding or anion-abstraction path-
ways.2,3 However, reactions enabled by these catalysts are
frequently hampered by low efficiencies, requiring high catalyst
loadings (5−20 mol %), long reaction times (>24 h), and/or
dilute conditions (≤0.1 M in initial substrate concentration) to
achieve optimal results.
In an effort to elucidate the basis for these practical limitations
to H-bond donor-mediated anion-abstraction catalysis, we
recently reported a detailed mechanistic study of a representative
transformation,4 the enantioselective amido-thiourea-catalyzed
alkylation of α-chloroisochroman (2, Scheme 1A).3a This study
revealed several key features of the reaction system, including:
(1) The catalyst resting state under typical reaction conditions
(0.1 M in substrate, 10 mol % of catalyst) is a nonproductive
dimeric aggregate; (2) Two molecules of thiourea catalyst 1 are
involved in the cooperative activation of the α-chloroether
electrophile; (3) Catalyst 1 exists as a mixture of slowly
interconverting (E)- and (Z)-amide rotamers in solution
(Scheme 1B).
Taken together, these observations imply that each of the
pairwise combinations of the catalyst amide rotamers could
participate in the alkylation transition state (ZZ-TS, EE-TS, ZE-
TS, and EZ-TS)5 and would likely make different, and potentially
conflicting, contributions to the overall rate and enantioselectiv-
ity of the reaction. As such, we conjectured that constraining this
catalyst system to operate through a single conformation could
result in improved efficiency by funneling reactivity through a
single enantioselective pathway. Herein we report the realization
of this proposal through the mechanism-driven design and
development of a conformationally biased catalyst that exhibits
improved activity and enantioselectivity.
a
ArF = 3,5-bis(trifluoromethyl)phenyl, Ar = 4-fluorophenyl, E =
generic electrophile, Nu = generic nucleophile.
thiourea-catalyzed alkylation of α-chloroisochroman (Scheme
1A). While only the (Z)-amide rotamer of catalyst 1 is observed
in the solid state, 1D and 2D H NMR analysis provides
6
1
We sought first to identify the catalyst rotamer(s) responsible
for controlling reactivity and enantioselectivity in the amido-
Received: May 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01435
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Letter
Figure 1. (A) Simplified catalyst 5 was utilized as a proxy for 1 in computational investigation. (B) A comparison of the relative energies of the lowest
energy transition structures involving each of the four possible homodimeric and heterodimeric complexes of catalyst 5. See ref 5. Lowest energy
computed transition structures involving the homodimeric (Z)-5/(Z)-5 catalyst complex en route to the (C) major and (D) minor enantiomers of
isochroman product 4a. All calculations performed with B3LYP/6-31G+(d,p)//B3LYP/6-31G(d). Atom coloring scheme: C = silver, H = white, O =
red, N = blue, S = yellow, Cl = magenta, Si = gold. Carbon-bound H atoms omitted for clarity.
evidence that (Z,Z), (Z,E), and (E,E) dimeric catalyst complexes
all exist in solution.4a,c Density functional theory (DFT)
calculations with simplified catalyst 5 (Figure 1A)7 were
employed to identify transition structures with each of the
possible dimeric rotamer combinations.8,9 Energetically acces-
sible transition structures, each possessing a single imaginary
frequency along the reaction coordinate, were located in all cases,
lending credence to the hypothesis that multiple reaction
pathways are competing under typical reaction conditions.
Comparison of the transition structures en route to the major
and minor enantiomers of product 4a from each of the dimeric
catalyst complexes (Figure 1B) revealed that the lowest energy
Figure 2. (A) Select NOE correlations utilized to assign Me-1 as the
(Z)-amide conformation. Correlations Ha ↔ Hb and Hb ↔ Hd are
observed; correlations Hd ↔ He and Hc ↔ Hd are not. (B) Overlay of the
H-bonded (Z)-1·(Z)-1 (light pink) and Me-1·Me-1 (slate blue)
homodimeric complexes determined by X-ray crystallographic analysis.
CF3 groups and carbon-bound H atoms omitted for clarity.
structures (ZZ-(S)-TS-4a and ZZ-(R)-TS-4a) are accessed
when both catalyst units are in the (Z)-conformation (Figure
1C,D).
Given these insights, we next sought to design an analogous
catalyst scaffold that exists exclusively in the (Z)-rotameric form.
The relative energies of the (E)- and (Z)-rotamers of amido-
thiourea catalysts bearing a variety of substituents on the
pyrrolidine moiety were determined computationally. From this
analysis, the 2-aryl-2-methylpyrrolidine-derived amido-thiourea
Me-1 (Figure 2) was identified as a particularly promising
candidate; this structure is predicted to favor the (Z)-amide
rotamer by 2.8 kcal/mol. This energetic preference can be
attributed to destabilizing syn-pentane interactions between the
methyl substituent on the pyrroldine and the amide α-C−H
bond in the (E)-amide conformation.10 Furthermore, the
optimized transition structure obtained with simplified catalyst
Me-5 is calculated to possess a very similar conformation to ZZ-
(S)-TS-4a (vide infra.)
In order to test these computational predictions, catalyst Me-1
was prepared,11 and its structural and functional properties were
evaluated experimentally. Unlike catalyst 1, only a single amide
rotamer of Me-1 can be observed by 1D 1H and 13C NMR in a
variety of solvents. The structural assignment of the (Z)-amide
rotamer was corroborated by 2D NOESY experiments in which
diagnostic NOE correlations are observed (Figure 2A).
Furthermore, the solid-state conformations of 1 and Me-1
determined by single crystal X-ray diffraction analysis are nearly
perfectly superimposable (Figure 2B).
The new thiourea derivative, Me-1, was evaluated in the model
oxocarbenium alkylation reaction. This conformationally rigid
catalyst was found to exhibit improved activity and enantiose-
lectivity relative to 1, affording 4a with quantitative conversion in
97% ee after only 4 h (Table 1, entries 1 and 2).12 Catalyst Me-1
also displays a 2-fold rate enhancement relative to catalyst 1 for
epimerization of α-chloroisochroman-d3 (Figure 3).4b,c This rate
acceleration can be rationalized by the fact that (Z)-1 and (E)-1
exist in a 1:1 mixture under these conditions. If it is assumed that
(E)-1 is inactive in the epimerization process, then (Z)-1 and
Me-1 can be concluded to display the same activity. This analysis
lends credence to the assumption that Me-1 operates through
the same anion-abstraction mechanism elucidated to be
operative with 1.
In principle, the improved activity observed with catalyst Me-1
could be due either to an increase in the effective concentration
B
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intrinsically higher stereoinduction imparted by introduction of
the methyl substituent. These possibilities were distinguished by
comparing the lowest energy transition structures for C−C bond
formation located with catalysts (Z)-5 and Me-5 (B3LYP/6-31G
+(d,p)//B3LYP/6-31G(d)). Catalyst methylation was found to
have very little effect on the geometry of the transition structure
leading to the major enantiomer of the product (Figure 1C; see
Supporting Information for an overlay of the two computed
structures), and the differential energy of activation was found to
be similar between Me-5 (ΔΔE‡ = 1.13 kcal/mol) and (Z)-5.
(ΔΔE‡ = 1.28 kcal/mol).
These results suggest that improvement in the observed
enantioselectivity with Me-1 can be ascribed entirely to
minimization of competing pathways involving the (E)-rotamer.
This conclusion is corroborated by the observation that the
enantioselectivity differences between catalysts 1 and Me-1 are
greatest under conditions in which the Z/E rotamer ratio of 1 is
low.16
Table 1. Enantioselective Oxocarbenium Alkylation Enabled
by Designed Catalyst Me-1
a
b
entry
nucleophile
time (h)
4
cat.
conv (%)
ee (%)
c
1
2
3
4
5
6
3a
1
66
92
c
Me-1
1
>95
81
97
d
3b
3c
1
85
d
Me-1
1
91
91
d
24
82
88
d
Me-1
>95
96
a
We anticipate that the conformational-control strategy
outlined above will prove broadly beneficial in enantioselective
anion-abstraction pathways. For example, Me-1 is found to be
significantly superior to 1 in the alkylation of 2 with a silyl enol
ether nucleophile (3c, Table 1, entries 5 and 6).
Reactions were run on 0.2 or 0.3 mmol scale and quenched after the
designated time with 0.5 M NaOMe in MeOH. See ref 12.
b
1
Conversion was determined from the relative integration of the H
NMR resonances of the product and quenched α-methoxyisochroman.
c
d
Determined by CSP−GC. Determined by CSP−HPLC.
In conclusion, experimental and theoretical analyses have shed
light on the detrimental role that catalyst amide rotamers play in
anion-abstraction catalysis by aryl pyrrolidinoamido-thiourea
derivatives. We have demonstrated the successful application of
these mechanistic insights to the design of a new catalyst in which
amide conformational control enables improved reaction
efficiency and enantioselectivity. This design is likely to provide
a general strategy for suppressing competing pathways in other
transformations catalyzed by chiral amido-thioureas and related
H-bond donor catalysts. The application of this design principle
to development of highly efficient transformations is the focus of
ongoing research.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01435.
Full experimental procedures, characterization data
including NMR spectra for all new compounds, and
geometries and energies of all calculated stationary points
(PDF)
Figure 3. Observed first-order rate constant for epimerization of α-
chloroisochroman-d3 (6) via anion abstraction catalyzed by 1 (green
circles) or Me-1 (blue diamonds). In all cases [6a] + [6b] = 0.10 M.
Crystallographic data for Me-1 (CCDC 1477622 and
1478394), catalyst analogues (CCDC 1478392, 1478393,
1478395), and a synthetic intermediate en route to Me-1
(CCDC 1477623) (CIF)
of the active (Z)-rotameric form of the catalyst or to
deaggregation of nonproductive ground state dimers. In order
to differentiate between these possibilities, the self-dimerization
equilibrium constants for catalysts 1 and Me-1 were determined
AUTHOR INFORMATION
1
■
from the changes in the chemical shifts of diagnostic H NMR
signals observed upon serial dilution.13 Catalyst Me-1 was
determined to possess a similar dimerization constant (Kdim = 3.1
Corresponding Author
*E-mail: jacobsen@chemistry.harvard.edu.
0.1 × 102 M−1) to those determined for (E)- and (Z)-1 (Kdim
=
Notes
4.6 1.2 × 102 M−1 for (E)-1 and Kdim = 2.0 0.3 × 102 M−1 for
(Z)-1).14 Thus, increased activity cannot be ascribed to selective
deaggregation of the catalyst and must rather be attributed to the
increased population of the more active (Z)-amide conforma-
tion.15
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NIH (GM-43214) and by
fellowships to D.L. (NSERC PDF), D.D.F. (Eli Lilly and Co.),
and A.J.B. and C.R.K. (NSF DGE1144152). We thank Dr. Shao-
Liang Zheng (Harvard X-ray Laboratory) for X-ray crystallo-
Similarly, the improved enantioselectivity could, in principle,
be due either to minimization of competing pathways involving
rotameric forms of the catalysts (as originally proposed) or to
C
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Letter
graphic structure determination and Erica D’Amato (Harvard
University) for experimental assistance.
REFERENCES
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D
DOI: 10.1021/acs.orglett.6b01435
Org. Lett. XXXX, XXX, XXX−XXX