Kinetic Resolution of 2-Substituted Indolines by N-Sulfonylation using an Atropisomeric 4-DMAP-N-oxide Organocatalyst

Article abstract of DOI:10.1002/anie.201700977

The first catalytic kinetic resolution by N-sulfonylation is described. 2-Substituted indolines are resolved (s=2.6–19) using an atropisomeric 4-dimethylaminopyridine-N-oxide (4-DMAP-N-oxide) organocatalyst. Use of 2-isopropyl-4-nitrophenylsulfonyl chloride is critical to the stereodiscrimination and enables facile deprotection of the sulfonamide products with thioglycolic acid. A qualitative model that accounts for the stereodiscrimination is proposed.

Full text of DOI:10.1002/anie.201700977

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201700977
German Edition: DOI: 10.1002/ange.201700977
Kinetic Resolution
Kinetic Resolution of 2-Substituted Indolines by N-Sulfonylation using
an Atropisomeric 4-DMAP-N-oxide Organocatalyst
James I. Murray, Nils J. Flodꢀn, Adriano Bauer, Nico D. Fessner, Daniel L. Dunklemann,
Opetoritse Bob-Egbe, Henry S. Rzepa, Thomas Bꢁrgi, Jeffery Richardson, and Alan C. Spivey*
Abstract: The first catalytic kinetic resolution by N-sulfony-
lation is described. 2-Substituted indolines are resolved (s =
2.6–19) using an atropisomeric 4-dimethylaminopyridine-N-
oxide (4-DMAP-N-oxide) organocatalyst. Use of 2-isopropyl-
4-nitrophenylsulfonyl chloride is critical to the stereodiscrimi-
nation and enables facile deprotection of the sulfonamide
products with thioglycolic acid. A qualitative model that
accounts for the stereodiscrimination is proposed.
T
he global demand for enantiomerically pure alcohols and
amines is steadily increasing[1] and kinetic resolution (KR) of
racemates provides a useful and scalable approach to access-
ing such compounds.[2,3] Whilst several efficient non-enzy-
matic methods for the Lewis base (LB) catalyzed[4] KR of
alcohols via acylation,[5] silylation,[5,6–9] phosphorylation[5,10,11]
and sulfonylation[5,8,12] have been developed, analogous pro-
tocols for the KR of amines are less common.[5,13,14] This
situation mainly reflects the challenge in achieving efficient
catalysis, as most amines are themselves significantly Lewis
basic.[5,13]
Optically active 2-substituted and 2,3-disubstituted indo-
lines[15] occur in many natural products,[16] drugs,[17] and drug
candidates.[18] This and the proximity of the moderately Lewis
basic indoline nitrogen to the C2/C3 stereogenic centers,
makes them attractive for KR[19] via LB-catalyzed N-func-
tionalization. So far, only Arp and Fu[20] have achieved this,
using planar chiral LB catalyst 1 to effect KR via N-acylation
(Scheme 1A), although others, notably Hou and Zheng[21]
and Akiyama et al.,[22] have reported non-acylative KRs
(Scheme 1B,C). Asymmetric hydrogenation of indoles also
provides efficient access to this type of indoline.[23]
Scheme 1. Comparison of previous KRs of indolines with this
work.[21,22]
.
parative study of amines vs. N-oxides as catalysts for the
acylation, sulfonylation and silylation of alcohols, revealing
that N-oxides are generally more efficient catalysts for
sulfonylation and silylation.[26] Cognisant that 4-DMAP-N-
oxide promotes the sulfonylation of aniline with benzene
sulfonyl chloride around 20-fold faster than 4-DMAP.[27] we
envisioned that a suitable chiral pyridine-N-oxide derivative
would catalyze sulfonylative KR of indolines. Herein, we
report the development of such a process employing an
atropisomeric 2-aryl-4-DMAP-N-oxide catalyst (4) with 2-
isopropyl-4-nitrophenylsulfonyl chloride as the sulfonylating
agent (Scheme 1D).
The challenge of achieving chirality transfer via an
sulfonyloxypyridinium salt intermediate during N-oxide-cat-
alyzed sulfonylation as compared to via an acylpyridinium salt
intermediate during pyridine-catalzed acylation (i.e. I vs. II,
Scheme 2A), accrues from two key differences. Firstly, there
is an additional rotatable bond between the pyridine ring and
the electrophilic sulfur atom (cf. the carbonyl carbon atom).
Secondly, the trajectory of the incoming nucleophile relative
Our laboratory has developed atropisomeric 3-aryl-4-
DMAP derivatives as LB catalysts for the acylative KR of sec-
alcohols[24] and amines.[25] Recently, we also reported a com-
[*] Dr. J. I. Murray, N. J. Flodꢀn, A. Bauer, N. D. Fessner,
D. L. Dunklemann, Dr. O. Bob-Egbe, Prof. H. S. Rzepa,
Prof. A. C. Spivey
Department of Chemistry, Imperial College London
South Kensington Campus, London, SW7 2AZ (UK)
E-mail: a.c.spivey@imperial.ac.uk
Prof. T. Bꢁrgi
Universitꢀ de Genꢂve, Dꢀpartement de Chimie Physique
Quai Ernest-Ansermet 30, 1211 Genꢂve 4 (Switzerland)
Dr. J. Richardson
Eli Lilly and Company Limited
Erl Wood Manor, Windlesham, Surrey, GU20 6PH (UK)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.201700977.
À
to the S O bond in the asynchronous SN2 transition state is
=
linear (cf. the Bꢀrgi–Dunitz trajectory towards the C O
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(s = 13.8, entry 7, Table 1). We also examined the perfor-
mance of bis-perfluorobutyl catalyst (+)-4b under these
conditions; this catalyst promoted reaction of the opposite
indoline enantiomer as expected but the reaction was slower
and offered no advantage in terms of selectivity (s = 8.2 after
24 h, entries 8 and 9, Table 1). The efficiency of several
additives commonly used in LB-catalyzed KRs were also
evaluated,[23b,c,31] but to no avail (see the Supporting Informa-
tion).
Scheme 2. A) Schematic comparison of reaction trajectories for sulfo-
nylation vs. acylation. B) Structures of atropisomeric catalysts 4a and
4b.
Next, we evaluated the substrate scope of this sulfonyla-
tive KR (Table 2). 2-Alkyl- and 2-siloxymethylindolines were
found to undergo sulfonylative KR with good selectivity (s =
10.1–17.2, entries 1–6, Table 2). 2-Alkyl-5-substituted indo-
lines were also resolved efficiently (entries 9–11, Table 2),
although 2-Me-5-OMe indoline 5k was resolved with the
lowest selectivity (s = 4.8), likely because of the relatively
high nucleophilicity of this derivative due to conjugation
between the OMe and NH groups. Similarly, the 6-NMe2
derivative 5l displayed high reactivity but low selectivity (s =
2.6, entry 12, Table 2). Unfortunately, sterically encumbered
2-Ph and 2-CO2Me substituted indoline derivatives proved
unreactive both under standard conditions and at elevated
temperature (entries 7 and 8, Table 2). 7-Substituted indo-
lines also proved unreactive, presumably due to steric
hindrance of the reactive nitrogen center (data not shown).
Preparative sulfonylative KR of 2-methylindoline was per-
formed using catalyst (À)-4a, affording similar selectivity and
conversion after 3 h as the analytical run (s = 11.6, C = 61%,
cf. entry 1, Table 2). The enantioenriched sulfonylated prod-
uct (2R)-6a underwent facile deprotection with thioglycolic
acid[33] and DBU in MeCN (93%) with no detectable erosion
bond).[28] Our design of catalysts 4a and 4b incorporated an
atropisomeric axis at the 2-position of the pyridine to address
these challenges, as well as an electron deficient 2,4-bis(per-
fluoroalkyl)phenyl motif to impart high reactivity by analogy
with achiral congeners as catalysts for O-phosphorylation
(Scheme 2B).[29]
We began our investigations using the bis-trifluoromethyl
catalyst (À)-4a and (Æ)-2-methylindoline (5a, Table 1, see
the Supporting Information for full details). Initial evaluation
of the sulfonylating agent revealed that 4-nitrophenylsulfonyl
chloride (4-NsCl) was reactive but unselective whereas 2-
NsCl was similarly reactive and delivered s = 1.3 at 08C
(entries 1 and 2, Table 1). Lowering the reaction temperature
resulted in increased selectivity[3] (s = 5.7 at À788C, entries 3–
5, Table 1). Encouraged by these results and aiming to
combine a bulky 2-substituent capable of relaying stereo-
chemical information[30] with favorable reactivity imparted by
the nitro group, we next investigated the use of 2-isopropyl-6-
NsCl and 2-isopropyl-4-NsCl as sulfonylating agents. Whilst
the former proved unreactive (entries 10 and 11, Table 1), the
latter resulted in a significant increase in selectivity at À788C
Table 2: Evaluation of scope of indoline sulfonylative KR.
Table 1: Optimization of N-sulfonylative KR of (Æ)-2-methylindoline 5a.
Entry (substrate)
R
R1
t [h] Conv. [%][a] s[a,b]
1 (5a)
2 (5b)
3 (5c)
4 (5d)
5 (5e)
6 (5 f)
7 (5g)
8 (5h)
9 (5i)
Me
H
H
H
H
H
H
H
H
3
6
5
5
6
3
4
4
2
6
1
2
52
34
13.8(R)[c]
14.8
CH2OTES
CH2OTIPS
CH2OTBS
i-Pr
n-Bu
Ph
CO2Me
Me
Me
Me
Me
Entry Cat.
R
T [8C] t [h] Conv. [%][a] s[a]
33[d]
47[d]
40
10.1[e]
17.2(S)
16.2(S)[e]
12.9(R)
N.D.
1
2
3
4
5
6
7
8
(À)-4a 4-NO2
(À)-4a 2-NO2
(À)-4a 2-NO2
(À)-4a 2-NO2
(À)-4a 2-NO2
0
0
À40
À60
À78
4
3
4
3
3
3
3
3
24
3
100
60
53
23
15
54
52
<5
48
0
N.D.
1.3
1.4
1.9
5.7
56
<1
<1
46
41
52
69
N.D.
(À)-4a 2-i-Pr, 4-NO2 À60
(À)-4a 2-i-Pr, 4-NO2 À78
(+)-4b 2-i-Pr, 4-NO2 À78
(+)-4b 2-i-Pr, 4-NO2 À78
(À)-4a 2-i-Pr, 6-NO2 À78
8.9
5-Cl
5-Me
5-OMe
6-NMe2
13.8(R)
11.0(R)[e]
4.8
13.8[b]
N.D.[c]
8.2[c]
N.D.
N.D.
10 (5j)
11 (5k)
12 (5l)
9
10
11
2.6
[a] Conversions and s values calculated from chiral HPLC data.
(À)-4a 2-i-Pr, 6-NO2
r.t.
3
0
[b] Indicated absolute configurations are of recovered starting materials
established by comparison with literature data, see the Supporting
Information. Note: Although the CIP designations vary, all entries using
catalyst (À)-4a give the configuration depicted. [c] Same experiment as
Table 1, entry 7. [d] Conversion measured by 1H NMR, s determined by
chiral HPLC of starting material or product. [e] Catalyst (+)-4a was used
and gave enantiomeric starting material or product to those depicted.
N.D.=not determined.
[a] Conversions and s values calculated from chiral HPLC data. Absolute
configuration of recovered starting materials 5a established as (2R) by
comparison with literature data, see the Supporting Information.
[b] There is no detectable conversion in the absence of catalyst under
these optimized conditions. [c] Gives enantiomeric starting material and
product to those depicted [that is, (S)-5a and (R)-6a]. N.D.=not
determined.
2
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of its enantiopurity. Concomitantly, catalyst (À)-4a was
lone pair to the s*S-O orbital such that the C2/C3 positions can
recovered quantitatively as a single enantiomer (see the
Supporting Information).
avoid clashing with elements A/B then leads to the preferred
sulfonylation of (2R)-5a as shown in Figure 2C. The 2-
substituents of indolines 5a–f are presumably able to rotate to
avoid a steric clash with element B, allowing them to be
resolved efficiently (entries 2–6, Table 2). By contrast, the less
flexible 2-Ph and 2-CO2Me substituents in indolines 5g and
5h (entries 7 and 8, Table 2) cannot avoid clashing with
element B, making them poor substrates for KR. 7-Substi-
tuted indolines are also poor substrates for this resolution due
to steric interactions with element A.
The absolute configuration of the dextrorotatory enan-
tiomer of catalyst 4a was assigned by comparison of its optical
rotation value and electronic and vibrational circular dichro-
ism (ECD and VCD) spectra with those computed by DFT.[34]
All three datasets led to (+)-4a being assigned the (Sa)
configuration.[32] The VCD data was most compelling as the
match in the 1000–1250 cmÀ1 region was largely independent
of conformation (Figure 1).
This qualitative model predicts that 2,3-disubstituted
indolines will require cis-stereochemistry for efficient KR
and that trans derivatives will resolve poorly as one alkyl
group would necessarily protrude into element B. To test
these hypotheses, we investigated the sulfonylative KR of cis
and trans 2,3-dimethylindolines 5m and 5n and tricyclic
indolines 5o–q (Table 3).
Table 3: Sulfonylative KR of 2,3-disubstituted indolines 5m–q.
Entry Cat.
Substrate
t [h] Conv. [%][a] s[a,b]
1
(+)-4a
3
62
9.7(2S,3S)
Figure 1. Experimental VCD spectrum for (+)-4a (blue) and computed
VCD spectrum for (Sa)-4a (orange) [at the wB97XD/Def2-TZVPP/
SCRF=chloroform level, weighted by the Boltzmann conformer pop-
ulations calculated using B3LYP+D3BJ/6-311G(2df,p)/SCRF=chloro-
form free energies].[32] For further details see the Supporting Informa-
tion.
2
3
4
5
(+)-4a
(À)-4a
(À)-4a
(À)-4a
3
3
2
4
6
2.1
35
7.2
The lowest-energy potentially stereodiscriminating con-
former of the chiral sulfonyloxypyridinium salt 9a, derived
from (+)-4a/2-isopropyl-4-NsCl, as computed by DFT, was
used to construct a qualitative model to rationalize the sense
and scope of the indoline KR reactions (Figure 2A,B). This
conformer provides a chiral “pocket” for which the phenyl
ring of the arylsulfonate forms the base, the 2-isopropyl group
of the arylsulfonate forms one side (element A), and the
terphenyl group of the catalyst forms the other side (ele-
ment B, Figure 2C). The approach of the indoline nitrogen
37
11.7(4aR,9aR)
19.0
54[c]
[a] Conversions and s values calculated from chiral HPLC data.
[b] Absolute configurations of unreacted starting material established by
comparison with literature data, see the Supporting Information.
[c] Conversion measured by H NMR, s determined by chiral HPLC of
starting material or product.
1
As predicted, cis-2,3-
dimethylindoline
under-
goes efficient KR (s = 9.7,
entry 1, Table 3) whereas
the analogous trans deriva-
tive is a poor substrate (s =
2.1, entry 2, Table 3). Given
the prevalence of the tricy-
clic indoline motif in natu-
ral products,[19a,35] we were
pleased to find that these
substrates also undergo
efficient KR with good
Figure 2. A) Lowest free energy conformer of catalyst (+)-4a with Sa configuration by DFT at the
B3LYP+D3BJ/6-311G(2df,p)/SCRF=chloroform level (see the Supporting Information).[32] B) Lowest free
energy, potentially stereodiscriminating conformer of chiral sulfonyloxypyridinium salt (Sa)-9a (H atoms
removed for clarity) by DFT at the B3LYP+D3BJ/6-311++G(2df,p)/SCRF=toluene level (see the Supporting
Information).[32] C) Qualitative model for stereodiscrimination illustrated for the reactive (2R) enantiomer of
indoline 5a with the (+)-4a derived sulfonyloxypyridine salt (Sa)-9a.
selectivity
(s = 7.2–18.9,
entries 3–5, Table 3). Con-
gruent with the model,
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selectivity (cf. entries 3 and 4, Table 3) and N-Boc-b-carboline
provided the highest selectivity yet obtained in this
N-sulfonylative KR (s = 19.0, entry 5, Table 3).
In summary, we have developed the first protocol for
catalytic KR of amines by sulfonylation and demonstrated its
utility for the preparation of enantiomerically enriched 2-
substituted and 2,3-disubstituted indolines. The use of an
atropisomeric 2-aryl-4-DMAP-N-oxide catalyst 4a in combi-
nation with a 2-substituted-4-nitrophenylsulfonyl chloride is
crucial for achieving enantioselectivity and allows for facile
deprotection of the sulfonamide products using thioglycolic
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Acknowledgements
We thank the EPSRC, the Institute of Chemical Biology
(ICB, Imperial College London) and the SCI (Messel
Scholarship, J.I.M.) for funding. We also thank Aaron Trow-
bridge, Zhennan Liu, Mihaela Pop, Lisa Barbaro, Si Jia Lee
and Christian Nielsen (all Imperial College London) for
preliminary supporting studies.
Conflict of interest
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The authors declare no conflict of interest.
Keywords: asymmetric catalysis · indoline · kinetic resolution ·
organocatalysis · sulfonylation
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Angewandte
Communications
Chemie
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Manuscript received: January 27, 2017
Revised: March 27, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Kinetic Resolution
J. I. Murray, N. J. Flodꢁn, A. Bauer,
N. D. Fessner, D. L. Dunklemann,
O. Bob-Egbe, H. S. Rzepa, T. Bꢂrgi,
J. Richardson,
A. C. Spivey*
&&&& — &&&&
A practical (re)solution: The kinetic reso-
lution of 2-substituted indolines by cata-
lytic N-sulfonylation is reported using an
atropisomeric 4-dimethylaminopyridine-
N-oxide organocatalyst (see scheme).
Vibrational cicrcular dichroism is used to
assign the absolute configuration of the
catalyst and a qualitative model that
accounts for the stereodiscrimination is
proposed.
Kinetic Resolution of 2-Substituted
Indolines by N-Sulfonylation using an
Atropisomeric 4-DMAP-N-oxide
Organocatalyst
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!