Hydrogen-Bond-Enabled Dynamic Kinetic Resolution of Axially Chiral Amides Mediated by a Chiral Counterion

Article abstract of DOI:10.1002/anie.201814362

Non-biaryl atropisomers are valuable in medicine, materials, and catalysis, but their enantioselective synthesis remains a challenge. Herein, a counterion-mediated O-alkylation method for the generation of atropisomeric amides with an er up to 99:1 is outlined. This dynamic kinetic resolution is enabled by the observation that the rate of racemization of atropisomeric naphthamides is significantly increased by the presence of an intramolecular O?H???NCO hydrogen bond. Upon O-alkylation of the H-bond donor, the barrier to rotation is significantly increased. Quantum calculations demonstrate that the intramolecular H-bond reduces the rotational barrier about the aryl–amide bond, stabilizing the planar transition state for racemization by approximately 40 kJ mol^?1, thereby facilitating the observed dynamic kinetic resolution.

Full text of DOI:10.1002/anie.201814362

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Hydrogen bond enabled dynamic kinetic resolution of axially
chiral amides mediated by a chiral counterion
Authors: Alison Fugard, Antti Lahdenperä, Aroonroj Mekareeya,
Jaqueline Tan, Robert Paton, and Martin Derwyn Smith
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201814362
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10.1002/anie.201814362
Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Counterion-Directed Catalysis
Hydrogen bond enabled dynamic kinetic resolution of axially chiral
amides mediated by a chiral counterion
Alison J. Fugard, Antti S. K. Lahdenperä, Jaqueline S. J. Tan, Aroonroj Mekareeya, Robert S. Paton*
& Martin D. Smith*
Abstract: Non-biaryl atropisomers are valuable in medicine,
Previous catalytic enantioselective approaches to axially chiral amides
materials and catalysis but their enantioselective synthesis remains a
NiPr2
O
NiPr2
OH
O
O
challenge. Here we outline a counterion-mediated O-alkylation
method for the generation of atropisomeric amides with er up to 99:1.
This dynamic kinetic resolution is enabled by the observation that the
rate of racemization of atropisomeric naphthamides is significantly
increased by the presence of an intramolecular O-H···NCO hydrogen
bond. Upon O-alkylation of the H-bond donor, the barrier to rotation
is significantly increased. Quantum calculations demonstrate the
intramolecular H-bond reduces the rotational barrier about the aryl-
amide bond, stabilizing the planar transition state for racemization
by approximately 40 kJ mol-1, facilitating the observed dynamic
kinetic resolution.
O
cat.
O
H
N
acetone
H
OH
H
N
Me
Me
O
Br
O
N
H
O
cat.
HO
R
HO
Br
R
O
Ph
Me2N
Boc
O
N
N
R
HN
N
Br-X
R
O
Br
OMe
OHC
cat.
R1
N
O
CHO
R2
N
N
R1
H
N
N
R2
R3
O
N
H
O
N
R2
R3
Axially chiral molecules are of fundamental importance across a
Hydrogen bond donor groups influence rotational barriers in naphthamides
range of different fields including catalysis, medicine and materials.
Biphenyl derivatives with restricted rotation about the biaryl axis
have been intensively investigated since the seminal report of Kenner
and Christie in 1922[1] and are exemplars of the field, both in their
study and their applications. More recently, non-biaryl atropisomers
including anilides, amides and imides have also been investigated,[2]
amid a growing realization of the importance of these molecules in
medicine[3] and other fields such as catalysis.[4] Appropriately
substituted tertiary amides can possess significant barriers to
rotation,[5] and this has been exploited for stereoselective ortho-
functionalization reactions[6] and for long range stereocontrol.[7]
Several approaches to the catalytic enantioselective synthesis of
atropisomeric amides have been disclosed including metal
catalysed[8] and organocatalytic methods.[9] Walsh has described an
enantioselective proline-catalysed aldol reaction on a naphthamide-
1
2
H
Bn
ΔG‡ = 97.5 kJ mol-1
(in CH2Cl2, 298K)
ΔG‡ = 129.3 kJ mol-1
(in m-xylene, 394K)
O
iPr
O
iPr
Br
Br
O
N
iPr
O
N
iPr
This work: H-bond mediated counterion-directed enantioselective O-alkylation
base, BnI
Bn
R4+N
O
H
R2
O
H
R2
O
R2
R1
R1
R1
O
N
R2
O
N
R2
O
N
R2
intramolecular hydrogen bond
reduces barrier to rotation
er up to 99:1
Figure 1. Previous work and approach to DKR of atropisomeric naphthamides
derived aldehyde, and Miller has demonstrated an elegant peptide
catalysed atropselective bromination.[10] More recently, the Sparr
group described a proline catalysed aldol-elimination procedure for
the enantioselective synthesis of axially chiral aromatic amides.[11] As
part of a programme focussed on the catalytic enantioselective
synthesis of axially chiral molecules, we observed that the barrier to
rotation of certain napthamides was dependant on the presence of a
hydrogen bond donor proximal to the amide group (Figure 1).
Napthamide 1, which bears a 2-hydroxy group, has a barrier to
rotation about the Caryl-Camide bond of 97.5 kJ mol-1 at 298K in CH2Cl2
solution, which is close to the boundary for atropisomerism as defined
by Oki.[12] In contrast, amide 2, in which the 2-naphthol is derivatized
as a benzyl ether, has a significantly higher barrier to rotation of 129.3
kJ mol-1 (394K in m-xylene), which is sufficient to essentially
preclude rotation at ambient temperature. As the steric difference
between an OH group and OBn group is too small to explain this
[*]
Dr Alison J. Fugard, Dr Antti S. K. Lahdenperä, Jaqueline S. J. Tan,
Dr Aroonroj Mekareeya, Prof. Dr Martin D. Smith
Chemistry Research Laboratory, University of Oxford
12 Mansfield Road, Oxford, OX1 3TA (UK).
E-mail: martin.smith@chem.ox.ac.uk
Homepage: http://msmith.chem.ox.ac.uk
Prof. Dr Robert S. Paton
Department of Chemistry, Colorado State University
Fort Collins, CO 80523 (USA).
E-mail: robert.paton@colostate.edu
Supporting information for this article and the ORCID identification
number(s) for the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201xxxxxx.
1
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10.1002/anie.201814362
Angewandte Chemie International Edition
observation, we postulated that the difference in rotational barrier was
likely due to the presence of an intramolecular hydrogen bond
between the naphthol OH and the amide nitrogen. In principle, this
could stabilize the planar transition state for interconversion of the
two enantiomeric forms.[13] To probe this, we also determined the
barrier to rotation of 1 about the Caryl-Camide bond in isopropanol, as a
hydrogen bonding solvent. The measured barrier was 113.6 kJ mol-1
(298K), a significant increase versus the barrier in CH2Cl2. This is
consistent with solvation of the phenolic group leading to disruption
of the intramolecular hydrogen bond and an overall increase in
size.[14] We reasoned that the presence of this hydrogen bond offered
an opportunity to carry out an enantioselective synthesis of axially
chiral amides via atropselective O-functionalization.[15,16] In this
scenario, the increased barrier to rotation of O-functionalized
materials precludes room temperature racemization and enables a
dynamic kinetic resolution. To probe the feasibility of this procedure
we needed access to a model atropisomeric amide, and this was
synthesized through a three-step procedure from cheap and readily
incrementally more selective, which may reflect increased solubility
in the organic phase. To explore this further, catalyst 11, which bears
three aryl groups and four tert-butyl groups was evaluated; this
afforded O-benzylated product 6 with 83:17 er (Table 1, entry 5).
Table 1. Optimization: atropselective O-alkylation of naphthamides[a]
cat. (0.05 equiv)
base
Bn-X
solvent
O
H
iPr
O
H
iPr
OBn
iPr
N
O
N
iPr
O
N
iPr
O
iPr
5. ΔG‡ = 95.4 kJ mol-1
(hexane, 294K)
6. ΔG‡ = 131.4 kJ mol-1
(m-xylene, 394K)
Entry
Cat.
Base[b]
Solvent
Bn-X
er[c]
1
2
7
Cs2CO3 (50% aq.)
Cs2CO3 (50% aq.)
Cs2CO3 (50% aq.)
Cs2CO3 (50% aq.)
Cs2CO3 (50% aq.)
KF (25% aq.)
toluene
toluene
toluene
toluene
toluene
toluene
benzene
benzene
benzene
benzene
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnI
77:23
72:28
82:18
87:13
83:17
93:7
8
3
9
4
10
11
11
11
11
11
11
available 1-naphthylacetic acid using
Dieckmann condensation (Scheme 1).
a key photo-mediated
5
6
7
KF (25% aq.)
94:6
CO2Et
(i) Pd(OAc)2, Ac-Ala-OH
CO2Et
8
KF (25% aq.)
95:5
9
Cs2CO3 (50% aq.)
Cs2CO3 (50% aq.)
BnI
96:4[d]
97:3[e]
(iii) LiHMDS
OH
10
BnI
(ii) (COCl)2, DMF
then NH(iPr)2
OH
then hυ
N(iPr)2
O
O
N(iPr)2
O
3
4
5
tBu
CF3
X-
Ar
9
R
N
7
Scheme 1. Synthesis of atropisomeric amides. Reaction conditions: (i) Pd(OAc)2
(0.1 equiv.), Ac-Ala-OH (0.2 equiv.), ethyl acrylate (2.0 equiv.), KHCO3 (2.0
equiv.), 2-methyl butan-2-ol, 90˚C. (ii) (COCl)2 (2.0 equiv.), DMF (0.1 equiv.),
CH2Cl2; then NH(iPr)2 (2 equiv.). (iii) LiHMDS, (2.1 equiv.), THF, 0˚C, 5 mins; then
12 W blue LED, RT, 30 mins. Yields are for isolated and purified materials.
X = Br
R = OMe
X = Cl
R = OMe
tBu
OH
Ar
CF3
N+
11
X = Br
R = H
tBu
H
10
X = Br
R = OMe
8
tBu
tBu
X = Br
R = H
tBu
A palladium(II) mediated oxidative Heck reaction using the method
disclosed by Yu[17] enabled selective C-2 functionalization of 3 in
92% yield, and this was transformed into amide 4 via the
intermediacy of an acid chloride in 63% yield. The alkene in 4 is
incorrectly configured for the Dieckmann reaction, but we reasoned
that a cascade energy transfer[18] isomerization-cyclization process
could be effective.[19] Treatment of 4 with 2.1 equivalents LiHMDS
in THF followed by irradiation with blue LED light afforded 2-
naphthol 5 in 77% yield. This is a scalable and operationally simple
procedure and demonstrates the compatibility of visible light
isomerization with strong anionic bases.
With this material in hand we examined the catalytic
enantioselective O-alkylation of 5 with a range of different conditions
and ammonium salts (table 1).[20] Upon exposure of 5 to
tetrabutylammonium bromide (TBAB) and 50% aqueous cesium
carbonate in toluene at room temperature, we observed O-alkylation
to afford 6. Use of N-benzyl quininium chloride 7 and aqueous cesium
carbonate gave good conversion to the desired product with er of
77:23 (Table 1, entry 1), and we subsequently explored a range of
different N-aryl groups on this catalyst scaffold. N-
Anthracenylmethyl catalyst 8 was less selective (72:28 er) but
bistrifluoromethylaryl catalyst 9 afforded augmented er (82:18).
Based on this, we explored the effect of substitution in the 3- and 5-
positions on the aryl ring. 3,5-Bis-tert-butyl catalyst 10 was
[a] Conditions: substrate 5 (0.02 mmol), catalyst (0.1 equiv.), base (1.0 equiv.),
solvent ([substrate] = 0.1 mol dm-3), rt, 48 h. [b] base: 50 % aq., w/w (10.0 equiv.)
[c] er determined by chiral stationary phase HPLC. [d] [substrate] = 0.025 mol
dm-3. [e] [substrate] = 0.01 mol dm-3.
A change of base to KF afforded higher er with catalyst 11 (93:7,
entry 6); screening solvents demonstrated that KF in benzene could
lead to significantly higher enantioselectivity (er 94:6, entry 7), and a
switch to benzyl iodide as electrophile continued the aggregation of
marginal gains (to 95:5 er). We reasoned that slowing the rate of
alkylation vs the rate of racemisation of the substrate through dilution
could also be effective; ultimately this led to an increase in selectivity
to 97:3 er (entry 10). With optimized conditions for the O-alkylation
established, we examined the scope of the reaction (Table 2). Clayden
has demonstrated that 1- and 8-substituted naphthamides can be
axially chiral, and we focussed on variations in these positions.[21]
Substrate 5 can be O-alkylated to afford 6 in 93% yield and 97:3 er.
Changing the N-alkyl group from iso-propyl to cyclohexyl as in 12 is
well tolerated (87% yield, 98:2 er).[22] Substituting the 4-position of
the phenanthrenyl system with a methyl group as in 13 maintained
selectivity (at 97:3 er and 83% yield). 8-Substituted naphthyl systems
are also well tolerated: substrates bearing electron donating
substituents such as 8-methoxy (14, 96:4 er, 80% yield), 8-methyl
(15, 98:2 er, 72% yield) and 5,8-dimethyl (16, 99:1 er and 85% yield)
2
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10.1002/anie.201814362
Angewandte Chemie International Edition
are all alkylated in good enantioselectivities and yields throughout.
Substrates bearing electron withdrawing groups such as 8-
trifluoromethyl (17, 96:4, 99% yield) are also O-alkylated in high
enantioselectivity. 8-Aryl systems such as 18 (98:2 er, 77% yield) are
similarly tolerated with high yield and high enantioselectivity.
Substitution on this arene is also possible and substrates bearing para-
electron withdrawing groups such as fluorine (19, 69% yield, 98:2 er)
and electron donating groups such as methoxy (20, 53% yield, 98:2
er) are also accommodated well.
alkylation of a substrate bearing a second rotational axis with a
significantly higher barrier. The 8-(1-naphthyl) starting naphthol
exists as a 2:1 mixture of racemic diastereoisomers. Treatment under
our standard alkylation conditions led to 22, a 3:2 mixture of
diastereoisomers, in 97:3 er for the major diastereoisomer, and 96:4
er for the minor diastereoisomer. These two diastereoisomers do not
interconvert at ambient temperature. The enantioselective synthesis
of 21 and 22 demonstrates that the restricted rotation about the biaryl
axis has little impact on the ability of the ammonium salt to effect the
enantioselective O-alkylation.
Table 2. Enantioselective O-alkylation of axially chiral amides[a]
The value of axially chiral amides is most likely to be realised in their
utility as building blocks for other purposes. To this end we have
demonstrated that the benzyl ether in 16 can be directly transformed
to aryl silane 23 without loss of enantiopurity (Scheme 2).[24]
OMe
Br-
OH
R3
R3
Cs2CO3(aq.)
N+
OH
R2
OBn
R2
0.05 equiv. 11
C6H6, BnI
R4
R1
R1
H
N
O
N
O
N
R2
R2
11
R4 = 3,5-C6H3(tBu)2
Scheme 2. Direct functionalization of benzyl ether to aryl silane[a]
R4
Me
Me
Me
Et3SiBPin
Ni(cod)2 (cat.)
OBn
iPr
SiEt3
iPr
tBuOK, PhMe
OBn
iPr
OBn
Cy
OBn
iPr
Me
Me
O
O
N
N
O
N
O
N
iPr
iPr
23. 63% yield, 95:5 e.r.
O
N
iPr
iPr
Cy
16. 95:5 e.r.
6. 93% yield
97:3 e.r.
ΔG‡395K = 131.4 kJ mol-1
12. 87% yield
98:2 e.r.
ΔG‡394K = 133.1 kJ mol-1
13. 83% yield
97:3 e.r.
ΔG‡394K = 130.1 kJ mol-1
[a] Conditions: substrate (0.1 mmol), Et3SiBPin (1.3 equiv.), Ni(cod)2 (0.1 equiv.),
tBuOK (2.2 equiv.), toluene ([substrate] = 0.1 mol dm-3), rt, 3 h. er determined by
chiral stationary phase HPLC. Yields are for isolated and purified materials.
Me
OBn
OBn
OBn
iPr
Treatment of benzyl ether 16 with triethylsilyl pinacol borane in the
presence of a nickel(0) catalyst and tert-butoxide afforded aryl silane
23 in 63% yield and without any erosion of er.
Me
O
OMe
O
iPr
Me
iPr
O
N
N
N
iPr
iPr
iPr
14. 80% yield
96:4 e.r.
ΔG‡394K = 136.0 kJ mol-1
16. 85% yield
99:1 e.r.
ΔG‡394K = 129.3 kJ mol-1
15. 72% yield
98:2 e.r.
ΔG‡394K = 128.0 kJ mol-1
To probe the influence of hydrogen bonding on the rate of
racemization we turned to quantum calculations. We modelled
compounds 24 and 25 (which bear a dimethyl- rather than a
diisopropylamide) and quantified the effect of O-alkylation upon the
rotational barrier (Figure 2).
OBn
iPr
OBn
OBn
iPr
CF3
O
iPr
O
N
O
N
N
iPr
iPr
iPr
F
17. 99% yield
95:5 e.r.
ΔG‡353K = 113.4 kJ mol-1
19. 69% yield
98:2 e.r.
ΔG‡374K = 118.8 kJ mol-1
18. 77% yield
98:2 e.r.
ΔG‡374K = 118.0 kJ mol-1
OH
Me
OMe
Me
O
N
O
N
Me
Me
OBn
iPr
OBn
iPr
OBn
iPr
24
25
φCCCN 3°
F
O
O
O
N
N
N
φCCCN
125°
‡
dOH-N 1.66Å
iPr
iPr
iPr
OMe
20. 53% yield
98:2 e.r.
ΔG‡374K = 120.1 kJ mol-1
21. 68% yield (dr 2:1)
96:4 e.r. (major)
96:4 (minor)
22. 76% yield (dr 3:2)
97:3 e.r. (major)
96:4 e.r. (minor)
dOH-O
1.85Å
[a] Conditions: substrate (0.1-0.2 mmol), catalyst (0.05 equiv.) Cs2CO3 (50% aq.,
5.0 equiv.), solvent ([substrate] = 0.01 mol dm-3), rt, 48 h. er determined by chiral
stationary phase HPLC. Yields are for isolated and purified materials. Rotational
barriers measured in m-xylene, at temperature stated; see SI for full details.
24
ΔΔG‡ 80.7 kJ mol-1
φCCCN 24°
‡
φCCCN
79°
The ability to incorporate substituents in the ortho-position on this
arene also enables the generation of compounds that possess multiple
rotational axes.[23] The ortho-fluoro substituent in 21 restricts rotation
about the biaryl axis to close to Oki’s definition,[12] so this material
equilibrates relatively rapidly leading to a 2:1 diastereoisomeric
mixture (96:4 er for both diastereoisomers). We also examined the O-
25
ΔΔG‡ 120.9 kJ mol-1
Figure 2. Optimized ground and transition state structures for model
napthamides 24 and 25.
3
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10.1002/anie.201814362
Angewandte Chemie International Edition
2001, 371. (c) J. Clayden, Chem. Commun. 2004, 127. (d) J. Clayden, L. W.
Lai, M. Helliwell, Tetrahedron 2004, 60, 4399.
Calculations were performed at the DLPNO-CCSD(T)/def2-
TZPD//M062X/6-31G(d) level, with SMD solvation for toluene and
CH2Cl2. The increase in activation barrier, DDG‡, from O-alkylation
of 24 is 39.7 kJ mol-1, which compares favourably with experiment
(36.0 kJ mol-1).[25] An intramolecular OH—O H-bond (1.85Å) is
present in the ground state structure of napthamide 24. Rotation about
the exocyclic C-C bond results in a transition structure with a non-
planar amide. In this structure, the pyramidalized nitrogen atom is in
very close contact with the hydroxyl proton (1.66 Å). In the absence
of a free naphthol, rotation proceeds via a transition structure in which
the non-planar amide cannot be similarly stabilized. Amide
pyramidalization (a consequence of steric demands) enhances the
nitrogen atom’s hydrogen-bond basicity, leading to a stronger
hydrogen bond in the transition structure than in the ground state, and
contributes to a pronounced reduction in barrier height.
[7]
966.
[8]
6593.
[9]
J. Clayden, A. Lund, L. Vallverdffl, M. Helliwell, Nature 2004, 431,
T. Suda, K. Noguchi, M. Hirano, K. Tanaka, Chem. Eur. J. 2008, 14,
(a) V. Chan, J. G. Kim, C. Jimeno, P. J. Caroll, P. J. Walsh, Org. Lett.
2004, 6, 2051. (b) S. Brandes, M. Bella, A. Kjaersgaard, K. A. Jørgensen,
Angew Chem. Int. Ed. 2006, 45, 1147. (c) S. Brandes, B. Niess, M. Bella, A.
Prieto, J. Overgaard, K. A. Jørgensen, Chem. Eur. J. 2006, 12, 6039.
[10] K. T. Barrett, S. J. Miller, J. Am. Chem. Soc. 2013, 135, 2963.
[11] V. C. Fäseke, C. Sparr, Angew. Chem. Int. Ed. 2016, 55, 7261.
[12] M. Oki, Top. Stereochem. 1983, 14, 1
[13] (a) W.-M. Dai, Y. Zhang, Y. Zhang, Tetrahdron: Asymm. 2004, 15,
525. (b) C. Roussel, N. Vanthuyne, M. Bouchekara, A. Djafri, J. Eleguero, I.
Alkorta, J. Org. Chem. 2008, 73, 403.
[14] For examples of a related phenomenon see: (a) B. E. Dial, P. J.
Pellechia, M. D. Smith, K. D. Shimizu, J. Am. Chem. Soc. 2012, 134, 3675.
(b) Y. Iwasaki, R. Morisawa, S. Yokojima, H. Hasegawa, C. Roussel, N.
Vanthuyne, E. Caytan, O. Kitagawa, Chem. Eur. J. 2018, 24, 4453.
[15] For enantioselective counterion mediated O-functionalization see: J. D.
Jolliffe, R. J. Armstrong, M. D. Smith, Nature Chem. 2017, 9, 558.
[16] For a proposed mechanism for enantioselective O-functionalization
relevant to this study see: H. Li, W. Fan, X. Hong, Org. Biomol. Chem. 2018,
DOI: 10.1039/C8OB02173B.
[17] D.-H. Wang, K. M. Engle, B.-F. Shi, J.-Q. Yu, Science 2010, 327, 315.
[18] For other organic reactions mediated by metal-containing
photocatalysts via energy transfer see: (a) E. P. Farney, T. P .Yoon, Angew.
Chem. Int. Ed. 2014, 53, 793. (b) S. O. Scholz, E. P. Farney, S. Kim, D. M.
Bates, T. P. Yoon, Angew. Chem. Int. Ed. 2016, 55, 2239. (c) K. Singh, S. J.
Staig, J. D. Weaver, J. Am. Chem. Soc. 2014, 136, 5275. (d) E. R. Welin, C.
C. Le, D. M. Arias-Rotondo, J. K. McCusker, D. W. C. MacMillan, Science
2017, 355, 380. (e) M. J. James, J. L. Schwarz, F. Strieth-Kalthoff, B.
Wibbeling, F. Glorius, J. Am. Chem. Soc. 2018, 140, 8624. (f) F. Streith-
Kalthoff, M. J. James, M. Teders, L. Pitzer, F. Glorius, Chem. Soc. Rev. 2018,
47, 7190.
In conclusion we have developed a highly enantioselective route to
axially chiral napthamides. This approach relies on a transition-state
hydrogen bond to mediate substrate racemization that enables a
dynamic kinetic resolution via O-alkylation. These molecules may
find application in supramolecular chemistry, catalysis and medicinal
chemistry programmes.
Acknowledgements
We are grateful for support from EPSRC (EP/R005826/1, to AM), the
EPSRC Centre for Doctoral Training in Synthesis for Biology and
Medicine (EP/L015838/1, for a studentship to AF), the People
Programme (Marie Curie Actions) of the European Union's Seventh
Framework Programme for funding (FP7/2007–2013, REA grant
agreement no. 316955, to AL) and the Agency for Science,
Technology and Research (A*STAR) Singapore for a National
Science Scholarship (to JSJT).
[19] (a) J. B. Metternich, R. Gilmour, Synlett 2016, 27, 2541. (b) K. Zhan,
Y. Li, Catalysts 2017, 7, 337.
[20] For full details of optimization please see supporting information
[21] J. Clayden, C. McCarthy, M. Helliwell, Chem. Commun. 1999, 2059.
[22] Changing the amide substituent to N, N-diethyl or N, N-diphenyl led to
significantly lower enantioselectivity.
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Conflict of Interest
The authors declare no conflict of interest.
differences in DDG‡ predicted (51.5 and 44.1 kJ mol-1, respectively). See SI
for full details.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: visible light • energy transfer • isomerization • counterion •
phase transfer • catalyst • axial chirality
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4
This article is protected by copyright. All rights reserved.

10.1002/anie.201814362
Angewandte Chemie International Edition
Counterion-Directed Catalysis
base, BnI
Bn
O
R2
Alison Fugard, Antti Lahdenpera,
Jaqueline Tan, Aroonroj Mekareeya,
Robert S. Paton* & Martin D. Smith*
__________ Page – Page
R4+N
O
H
R2
O
H
R2
R1
R1
R1
O
N
R2
O
N
R2
O
N
R2
intramolecular hydrogen bond
reduces barrier to rotation
er up to 99:1
Hydrogen bond enabled dynamic kinetic
resolution of axially chiral amides
mediated by a chiral counterion
Non-biaryl atropisomers are valuable in medicine, materials and catalysis but their
enantioselective synthesis remains a challenge. Here we outline a counterion-
mediated O-alkylation method for the generation of atropisomeric amides with er up
to 99:1. This dynamic kinetic resolution is enabled by the observation that the rate of
racemization of atropisomeric naphthamides is significantly increased by the
presence of an intramolecular O-H···NCO hydrogen bond. Upon O-alkylation of the
H-bond donor, the barrier to rotation is significantly increased. Quantum calculations
demonstrate the intramolecular H-bond reduces the rotational barrier about the aryl-
amide bond, stabilizing the planar transition state for racemization by approximately.
40 kJ mol-1, facilitating the observed dynamic kinetic resolution.
5
This article is protected by copyright. All rights reserved.