Enantioselective synthesis of ammonium cations

Article abstract of DOI:10.1038/s41586-021-03735-5

Control of molecular chirality is a fundamental challenge in organic synthesis. Whereas methods to construct carbon stereocentres enantioselectively are well established, routes to synthesize enriched heteroatomic stereocentres have garnered less attention^1–5. Of those atoms commonly present in organic molecules, nitrogen is the most difficult to control stereochemically. Although a limited number of resolution processes have been demonstrated^6–8, no general methodology exists to enantioselectively prepare a nitrogen stereocentre. Here we show that control of the chirality of ammonium cations is easily achieved through a supramolecular recognition process. By combining enantioselective ammonium recognition mediated by 1,1′-bi-2-naphthol scaffolds with conditions that allow the nitrogen stereocentre to racemize, chiral ammonium cations can be produced in excellent yields and selectivities. Mechanistic investigations demonstrate that, through a combination of solution and solid-phase recognition, a thermodynamically driven adductive crystallization process is responsible for the observed selectivity. Distinct from processes based on dynamic and kinetic resolution, which are under kinetic control, this allows for increased selectivity over time by a self-corrective process. The importance of nitrogen stereocentres can be revealed through a stereoselective supramolecular recognition, which is not possible with naturally occurring pseudoenantiomeric Cinchona alkaloids. With practical access to the enantiomeric forms of ammonium cations, this previously ignored stereocentre is now available to be explored.

Full text of DOI:10.1038/s41586-021-03735-5

Article
Enantioselective synthesis of ammonium
cations
1
1
1
1
1
ꢀ✉
https://doi.org/10.1038/s41586-021-03735-5
Received: 1 March 2020
Mark P. Walsh , Joseph M. Phelps , Marc E. Lennon , Dmitry S. Yufit & Matthew O. Kitching
Accepted: 17 June 2021
Control of molecular chirality is a fundamental challenge in organic synthesis.
Whereas methods to construct carbon stereocentres enantioselectively are well
Published online: 1 September 2021
Check for updates
established, routes to synthesize enriched heteroatomic stereocentres have garnered
less attention1–5. Of those atoms commonly present in organic molecules, nitrogen is
the most difcult to control stereochemically. Although a limited number of
resolution processes have been demonstrated6–8, no general methodology exists to
enantioselectively prepare a nitrogen stereocentre. Here we show that control of the
chirality of ammonium cations is easily achieved through a supramolecular
recognition process. By combining enantioselective ammonium recognition
mediated by 1,1′-bi-2-naphthol scafolds with conditions that allow the nitrogen
stereocentre to racemize, chiral ammonium cations can be produced in excellent
yields and selectivities. Mechanistic investigations demonstrate that, through a
combination of solution and solid-phase recognition, a thermodynamically driven
adductive crystallization process is responsible for the observed selectivity. Distinct
from processes based on dynamic and kinetic resolution, which are under kinetic
control, this allows for increased selectivity over time by a self-corrective process.
The importance of nitrogen stereocentres can be revealed through a stereoselective
supramolecular recognition, which is not possible with naturally occurring
pseudoenantiomeric Cinchonaalkaloids. With practical access to the enantiomeric
forms of ammonium cations, this previously ignored stereocentre is now available to
be explored.
The difficulty in enantioselective preparation of stereogenic nitrogen first isolation of an enantioenriched ammonium cation in 189917, only
centres originates from their conformational instability. Carbon stereo- a handful of approaches based on kinetic resolution6–8 and spontane-
centres are conformationally and configurationally locked (Fig. 1a). In ous resolution18–20 have allowed the isolation of enriched ammonium
contrast, the stereogenicity of nitrogen atoms in tertiary amines is often cations. So far, no synthetic process for the enantioselective construc-
overlooked because of this centre’s generally rapid conformational tion of ammonium cations has been known.
interconversion through inversion of nitrogen’s lone pair enabled by
We reasoned that the enantioselective synthesis of ammonium
quantum tunnelling9. Quaternization to form the ammonium cation cations requires three conditions to be met (Fig. 1c). First, a general
prevents this inversion and locks the configuration of the nitrogen recognition process is required allowing discrimination between the
stereocentre. Diastereoselective synthesis of ammonium stereocentres two enantiomeric forms of an ammonium stereocentre. Second, the
is successful under two regimes. When inversion of nitrogen’s lone pair configuration of the nitrogen stereocentre must be rendered temporar-
is prevented, chiral ammonium cations with defined configuration are ily dynamic, allowing interconversion between the two enantiomeric
generated, as in the rigid bicyclic Cinchonaalkaloids (Fig. 1b)10. Alterna- forms. By placing the ammonium ion under conditions where alkyla-
tively, the configuration of nitrogen is set by transferring stereochemi- tion is reversible, the ammonium centre can de-alkylate, affording the
cal information from the carbon skeleton to the ammonium centre in conformationally labile amine. In this state, inversion of the nitrogen
a diastereoselective fashion, as in pharmaceuticals such as Relistor, centre is rapid and non-selective re-alkylation leads to racemization of
Atrovent and Buscopan (Fig. 1b)11. However, the conformational rigidity the ammonium stereocentre. Third, by combining these two processes
of these systems and the influence of neighbouring stereocentres pre- under conditions where both the recognition and racemization are
vent direct preparation of the nitrogen epimer. Accessing compounds compatible, the stabilization of the preferred quaternary ammonium
where nitrogen is the sole stereogenic element has proved challeng- enantiomer will lead to a thermodynamically driven dynamic resolution
ing. In cases where inversion at nitrogen can be slowed (for example of the ammonium species.
in N-chloroaziridines12, oxaziridines13 and diaziridines14) or prevented
To discriminate between the enantiomeric forms of the ammonium
(as in the rare case of Tröger’s base)15,16, compounds containing a ste- cation, we examined its interaction with the well-known chiral species
reogenic nitrogen centre can be synthesized and isolated. Since the 1,1′-bi-2-naphthol (BINOL). The use of enantiopure alkylated natural
1
✉
Department of Chemistry, Durham University, Durham, UK. e-mail: matthew.o.kitching@durham.ac.uk
70 | Nature | Vol 597 | 2 September 2021

a
cations without an additional recognition handle (Fig. 2). Screens of
commonly available BINOL derivatives and other recognition spe-
cies showed that simple unfunctionalized BINOL proved optimal in
this process (Extended Data Fig. 1 and Supplementary Information).
Addition of (R)-BINOL (0.5 equivalent (equiv)) to racemic ammonium
1 under concentrated conditions (0.6 M) rapidly generated a diastere-
omerically enriched ternary complex 2 (Fig. 2a). The enrichment of 2
was quantified by 1H NMR analysis using the NMR chiral shift reagent
(R,Λ)-BINPHAT35–37 forming diastereomeric salt 3, which is taken to
reflect the enrichment of the ammonium salt. The absolute configura-
tion of each sample was confirmed by X-ray crystallography. Exami-
nation of the scope of this process provided three key observations
(Fig. 2b). First, sufficient difference in steric bulk between the substitu-
ents on nitrogen proved essential to achieve high levels of selectivity.
For example, the ethyl-substituted ammonium used to form complex
2a in good yield was poorly discriminated (Fig. 2b, entry 2a, 59:41 d.r.).
In contrast, BINOL-mediated recognition of isopropyl ammonium
afforded higher levels of selectivity (Fig. 2b, entry 2b, 82:18 d.r.). Sec-
ond, this level of enrichment could be improved through recrystal-
lization. Complexation of 1c initially yielded complex 2c (80:20 d.r.)
which was enhanced with a single recrystallization providing 2cʹ with
higher levels of enrichment (90:10 d.r.). Third, a variety of anilinium
(2a–d, 2f, 2k, 2l), indolinium (2e, 2g–i) and benzyl ammonium (2j)
cores synthesized with common alkylation agents such as alkyl (2l),
allyl (2a, 2b, 2e, 2f, 2k), crotyl (2c, 2g), benzyl (2d, 2i) and propargyl
(2h, 2j) halides proved readily resolvable in good to excellent yields
(53–89% based on 0.5 equiv of BINOL, 26–44% based on 1 equiv of the
ammonium cation) with levels of enrichment from modest (2f, 57:43
d.r.) to excellent (2l, 99:1 d.r.). This process allowed equally facile iso-
lation of the enantiomeric form of the ammonium ion (Fig. 2b, (ent)-
2a–(ent)-2l), with similar yields and selectivities, by simply using the
opposite enantiomer of BINOL.
Ammonium
cation
Carbon
C
Amine
N
+
N
N
N
C
N
+
Stereochemically
locked
Stereochemically
labile
Stereochemically
locked
–
–
b
Br
OH
Br
–
N
Br
+
+
OH
+
N
N
n-Bu
H
O
OH
H
O
OH
+
N
O
O
O
–
O
O
H
Cl
N
Ph
OH
Cinchona
alkaloids
Phase transfer
catalysts
R-Methylnaltrexone
Relistor
(Progenics/Wyeth)
Ipratropium
bromide
Atrovent
Hyoscine
butylbromide
Buscopan
WHO Essential
Medicine List
asthma drug
No lone pair
inversion
Nitrogen conꢀguration diastereoselectively
set using adjacent carbon stereocentres
c
Racemization
Recognition
*
*
*
X
+
+
– x
N
N
N
N
–
–
Favoured
X
X
X
X
–
*
+
+
x
N
N
X
Disfavoured
Enantioselective synthesis of ammonium cations
d
Tayama & Tanaka (2007)
Ph
This work
Experimental evidence indicates the mechanism of recognition
has both a solution and solid phase component. On the addition of
(R)-BINOL (0.5 equiv) to a sample of 1b in deuterated chloroform, dis-
tinctive shifts were observed in the 1H NMR spectrum (Fig. 2c). Reso-
nance signals for aliphatic proton environments directly around the
ammonium centre (Fig. 2c(II), proton signals a–g) showed both an
increase in multiplicity and considerable upfield shifts, consistent with
binding of the BINOL to the ammonium halide in solution forming a
mixture of two diastereomeric complexes. To probe the importance
of the role of hydrogen-bond donation from the BINOL species, we
synthesized the monomethylated and bismethylated variants (see Sup-
plementary Information). When the bismethylated species was used in
the recognition process, no solution-state recognition was observed
by 1H NMR, and the solution remained homogenous. The monometh-
ylated species, with one free hydrogen-bond donor, showed minor
perturbations in chemical shift which related to weak solution-state
+
X-
H
N
–
HO
HO
Br
HO
HO
OH
+
H
H
N
R
• Requires hydroxyl
recognition handle
• Direct recognition
of ammonium centre
Fig. 1 | Nitrogen stereocentres. a, A comparison of the stability of carbon and
nitrogen based stereocentres. Carbon is both configurationally and
conformationally stable. Amines exhibit conformational instability due to
their inversion behaviour. Quaternization of amines to form ammonium salts
renders the nitrogen centre conformationally stable. b, Examples of
bridgehead-locked amines and diastereoselective alkylations to synthesize
enriched ammonium centres. c, Proposed conditions for enantioselective
synthesis of ammonium cations. d, Recognition of β-hydroxyammonium salts
by Tayama and Tanaka29 and the current direct recognition of ammonium
cations by BINOL.
products (for example, the Cinchona alkaloids) in the resolution of binding occurring. However, these diastereomeric complexes remained
BINOL is well established21,22. However, the reverse process—the rec- in solution, owing to the disruption of the continuous hydrogen-bond
ognition of ammonium centres using enantioenriched BINOL—has network required for nucleation and abstraction to occur. This high-
received little attention, despite its use in other resolution strate- lights the structural importance of two hydrogen-bond donors present
gies23–28. Tayama and co-workers29,30 have demonstrated kinetic reso- in the BINOL scaffold in recognizing and separating the diastereomeric
lution of ammonium centres by structurally mimicking the Cinchona complexes.
alkaloids. When an ammonium cation bears a hydroxyl group functional
To understand the differences between these diastereomeric com-
handle, formation of a ternary complex between the ammonium, the plexes, they were independently prepared. First, the complex result-
counterion and BINOL occurs, mediated by strong hydrogen bonding ing from treatment of the racemic ammonium 1b with (R)-BINOL (2b)
between these three species (Fig. 1d)29,30. Given that tetra-alkyl ammo- was recrystallized to higher diastereomeric enrichment, affording
nium centres are known to behave as distributed cations31, with a similar the matched pair (S)-1b·(R)-BINOL (see Fig. 2d and Extended Data
hydrogen-bond donor ability (hydrogen-bond donor parameter α= 2.7 Fig. 2), and the BINOL was removed through extraction. The recov-
for N+C–H···X)32, to alcohols (α = 2.7 for O–H···X)33, we postulated that ered enantioenriched ammonium (S)-1b was then complexed with
hydrogen bonding directly to the ammonium cation itself would be (S)-BINOL yielding the unfavoured diastereomer (S)-1b·(S)-BINOL (the
possible34
Initial investigations demonstrated that formation of the
.
mismatched pair).
Crystallographic analysis of these diastereomers yielded interest-
BINOL·X−·ammonium complex enables the resolution of ammonium ing results (Fig. 2d, the matched pair, versus Fig. 2e, the mismatched
Nature | Vol 597 | 2 September 2021 | 71

Article
X–
X–
X–
a
(R)-BINOL (0.5 equiv)
(S)-BINOL (0.5 equiv)
H2O (5.0 equiv)
H2O (5.0 equiv)
N+
N+
N+
OH
OH
HO
HO
•
•
18 h
18 h
Racemic
1
(1) Et2O/H2O
(1) Et2O/H2O
– (S)-BINOL
2
(ent)-2
– (R)-BINOL
(2) (R,Λ)-BINPHAT
(2) (R,Λ)-BINPHAT
(i)
(ii)
(iii)
O
O
P-
O
P–
O
O
O
O
O
O
O
N+
N+
*
*
O
O
3.4
3.3
Br–
3.4
G
3.3
3.4
3.3
epi-3 = (ent)-1*·(R,Λ)-BINPHAT
G
G
1*·(R,Λ)-BINPHAT
= 3
b
Br–
N+
Br–
Br–
N+
N+
N+
·(R)-BINOL
2a
·(R)-BINOL
·(S)-BINOL
(ent)-2b
·(S)-BINOL
62:38 d.r.a,c
(ent)-2a
a
91%
59:41 d.r.a,c
70%
82:18 d.r.
78:22d.r.a
72%
97%
2b
Br–
N+
Br–
Br–
Br–
N+
N+
N+
·(R)-BINOL
2c
2c'
·(S)-BINOL
·(R)-BINOL
·(S)-BINOL
80:20 d.r.a,d
90:10 d.r.a,d
80:20 d.r.a,d
(ent)-2c
(ent)-2c′
b
b
76%
89%
64%
53%
2d 96:4 d.r.a
(ent)-2d 93:7 d.r.a
66%
56%
70%
a,d
88:12 d.r.
Br–
N+
Br–
N+
Br–
N+
Br–
N+
·(R)-BINOL
·(R)-BINOL
·(S)-BINOL
·(S)-BINOL
(ent)-2e
75:25 d.r.a
57:43 d.r.a
60:40 d.r.a
74:26 d.r.a
100%
78%
2e
2f
(ent)-2f
Br–
N+
Br–
N+
Br–
Br–
N+
N+
·(R)-BINOL
·(R)-BINOL
·(S)-BINOL
(ent)-2h
·(S)-BINOL
90:10 d.r.a
(ent)-2g
a
84:16 d.r.a
79%
79%
80:20 d.r.a
2h
73:28 d.r.
87%
2g
83%
N+
N+
Br–
N+
Br–
Br–
Br–
N+
·(R)-BINOL
2i
·(R)-BINOL
·(S)-BINOL
(ent)-2j
·(S)-BINOL
94:6 d.r.a
(ent)-2i
91:9 d.r.a
I–
80:20 d.r.a
81:19 d.r.a
89%
75%
79%
56%
2j
81%
54%
I–
I–
I–
N+
N+
N+
N+
·(R)-BINOL
2k
·(R)-BINOL
·(S)-BINOL
(ent)-2l
·(S)-BINOL
85:15 d.r.a
(ent)-2k
89:11 d.r.a
89%
99:1 d.r.a
99:1 d.r.a
2l
c
(I) 1b
d
e
e
g
Br–
e
f
g′
c
N+
g
g′
a
d/d′
b
H2O
b
a
(S)-1b·(R)-BINOL
(S)-1b·(S)-BINOL
f
d′
d
c
(II) 1b + (R)-BINOL
e
2.4
2.0
1.6
1.2
0.8
2.4
2.4
C–H···Br
C–H···Br
C–H···Br
2.0
1.6
1.2
0.8
2.0
1.6
1.2
0.8
g
H2O
g′
C–H···O
C–H···O
C–H···O
C–H···H
C–H···H
C–H···H
f
d′
Cation I
Cation II
a
b
d
c
0.8 1.2 1.6 2.0 2.4
i (Å)
0.8 1.2 1.6 2.0 2.4
i (Å)
0.8 1.2 1.6 2.0 2.4
i (Å)
d
d
d
E = –215.7 kJ mol–1 U = 1.343 g cm–3
E = –197.6 kJ mol–1 U = 1.328 g cm–3
5.5
5.0
4.5 3.5
3.0
1.5
1.0 G (ppm)
Fig. 2 | General enantioselective ammonium recognition. a, Recognition of
chiral ammonium salts 1 with enantiopure BINOL, forming ternary complexes 2
and (ent)-2. A counterion exchange with chiral shift reagent (R,Λ)-BINPHAT
forms diastereomeric salts 3 for analysis. δ, chemical shift scale in parts per
million. b, Substrate scope of ammonium·X−·BINOL ternary complexes, with
X-ray crystal structures identifying the configuration of each ammonium
centre. Isolated yields calculated based on the equivalences of BINOL used.
c, 1H NMR spectra of (I) 1b and (II) 1b upon the addition of BINOL (0.5 equiv),
demonstrating solution phase recognition of the ammonium salt. d, Unit cell
and Hirshfeld plot of (S)-1b·(R)-BINOL—the matched pair 2b (Z′ = 1). e, Unit cell
and Hirshfeld plot of (S)-1b·(S)-BINOL—the mismatched pair (Z′ = 2), showing
both independent cations in the unit cell (cations I and II). de, di, distance from
the nearest nucleus external to and internal to the Hirshfeld surface,
respectively. aDiastereomeric ratios (d.r.) of 2 were determined by
de-complexing a portion of the isolated material by aqueous extraction
(Et2O/H2O). A counterion exchange of the isolated ammonium halide salt with
the chiral shift reagent (R,Λ)-BINPHAT was performed, and the resulting
diastereomeric salt 3 was analysed by 1H NMR spectroscopy. bAfter isolation of
the precipitate, a re-crystallization in ethanol was performed to further enrich
the complex. cOverlapping peaks used in chiral shift analysis resolved using
line fitting. dOverlapping Zisomer resonances deconvoluted via line fitting of
the 1H NMR used in the determination of d.r. *Denotes enantioenriched
material of unspecified absolute configuration.
72 | Nature | Vol 597 | 2 September 2021

Br–
h
pair). An immediate difference in the unit cell length and number
of molecules present within the asymmetric unit of the matched
(number of molecules in the asymmetric unit Z′ = 1) and mismatched
(Z′ = 2) pair was observed, owing to the latter hosting two independ-
ent ammonium cation conformations (see Fig. 2e, cation I and cation
II)38. Close C–H···O contacts were present in the mismatched pair in
both cation I (d = 2.451 Å, θ = 156.79°, where d is the interatomic dis-
tance and θis bond angle) and cation II (d= 2.347 Å, θ= 147.97°), which
are absent from the matched pair. Instead, C–H···Br contacts on the
α-carbon centres of the ammonium cation in the matched pair were
observed (C–H···Br, d = 3.224 Å, θ = 144.51°, d = 3.253 Å, θ = 159.58°).
a
f
e
50 °C
H
c
N+
d/d′
C
N
Br
I
i
a
b
A
+
CDCl3
B
j
J
1b
(I) 1b, CDCl3, 60 mM, t = 0 h
4
5
CHCl3
i
j
h
b
a
f
d′
c
d
(II) 1b, CDCl3, 60 mM, 50 °C, t = 16 h
CHCl3
1b:4 (2:98)
The relative importance of all contacts present in both crystal struc
-
tures is difficult to decipher. As such, they were globally represented
on a 3D surface and portrayed as Hirshfeld fingerprint plots39. Here,
trends in contacts within the crystal can be visually identified, with
the most distinct differences between the matched and mismatched
structures being the presence of the C–H···O contact in cations I and
II of the mismatched pair (Fig. 2e, red trace). Also, the more diffuse
Hirshfeld plot is indicative of less efficient packing present in both
ammonium forms of the mismatched pair, in contrast to the more
compact plot of the matched pair. Melting point (m.p.) analysis also
indicates a greater stability of the matched (m.p. = 150–152ꢀ°C) than the
mismatched (m.p. = 137–139ꢀ°C) pair. Binding energy calculations40,41 are
in agreement with the matched pair (E= ‒215.7 kJ mol−1) proving more
stable than the mismatched structure (E= ‒197.6 kJ mol−1). This stabil-
ity appears to originate from a more efficient packing of the matched
ternary complex (packing density ρ = 1.343 g cm−3) compared with its
mismatched congener (ρ = 1.328 g cm−3). These results are consistent
with a solution-phase recognition of the ammonium cation through for-
mation of the BINOL·X−·ammonium ternary complex, subsequently act-
ing as a nucleation centre, allowing its selective abstraction to the solid
(III) 4 (1 equiv), 5 (2 equiv), CDCl3, 600 mM, t = 0
H
I
J
B
A
C
(IV) 4 (1 equiv), 5 (2 equiv), CDCl3, 600 mM, 50 °C, t = 16 h
1b:4 (50:50)
8.5
8.0
7.5
7.0
6.5
G (ppm)
6.0
5.5
5.0
b
e
Br–
Br
N+
Ph
1d*
(I) (R)-1d, MeCN, 50 °C
50 °C
Br
+
N
MeCN
(0.4 M)
+
Ph
E
Ph
(8 equiv)
6
4
6
(II) (R)-1d, CDCl3, t = 425 min
e
8.0
Br–
+
1d:4 (53:47)
E
phase through an adductive crystallization (Extended Data Fig. 3)42
.
N
6.0
4.0
2.0
0
R:S (50:50)
We next sought to establish conditions for the racemization of the
nitrogen stereocentre. Modification of Lehn’s43 conditions showed
that 1b (Fig. 3a (I)) fully dissociates when heated at dilute concentra-
tions affording aniline 4 and allyl bromide 5 (Fig. 3a (II))43. At higher
concentrations, the position of equilibrium is biased in favour of the
ammonium salt. When 4 and 5 were heated at 50ꢀ°C (Fig. 3a (III)), the
ratio of 4 to 1b at equilibrium was determined to be equal by 1H NMR
(Fig. 3a (IV), 4:1b, 50:50). To observe the stereochemical integrity of
the ammonium directly, a sample of enriched (R)-1d was dissolved in
acetonitrile (0.4 M) with an excess (8 equiv) of benzyl bromide 6 and
heated. Analysis of the rate of decay of optical activity demonstrated
that stereochemical information was eroded under pseudo-first-order
kinetics (Fig. 3b (I), halflife t1/2 = 56.5 min, λ = 0.012) with no measur-
able optical activity after 425 min. (S)-1d showed identical behaviour
Ph
(R)-1d
53.40
46.60
100
200
t (min)
300
400
400
3.5
3.0
2.5
G (ppm)
(III) (S)-1d, MeCN, 50 °C
t (min)
(IV) (S)-1d, CDCl3, t = 425 min
100
200
300
e
0
–2.0
–4.0
–6.0
–8.0
1d:4 (54:46)
R:S (50:50)
Ph
+
N
–
Br
E
(S)-1d
54.02
45.98
(Fig. 3b (III)). Such results are consistent with an SN2 process43–46
.
3.5
3.0
2.5
G (ppm)
1H NMR analysis of the end points of these measurements showed that
substantial quantities of the ammonium remained in the solution con-
firming that the loss in optical activity was due to racemization of the
Fig. 3 | Dynamic behaviour of ammonium cations. a, (I) 1b in dilute
conditions (60 mM) and (II) after heating this solution at 50ꢀ°C (16 h), observing
nitrogen stereocentre rather than simple dissociation (Fig. 3b (II, IV)). complete de-alkylation. (III) Aniline 4 and allyl bromide 5 in concentrated
solution (600 mM) and (IV) the resulting 50:50 equilibrium of salt 1b and
aniline 4 observed. b, Racemization of enriched salt 1d*, monitored by optical
rotation over 425 min (I) and (III). 1H NMR spectroscopy (II) and (IV) confirmed
the presence of ammonium salt 1d in the sample with no measurable optical
activity after heating.
The combination of these dynamic conditions with our recogni-
tion process allowed the enantioselective synthesis of ammonium
stereocentres in a single pot (Fig. 4a). Here, the aniline 4, the alkylating
agent (2 equiv) and (R)-BINOL (1 equiv) were combined under concen-
trated conditions (0.6–2.5 M) and stirred at 50ꢀ°C for 48 h generating
the ternary complexes 2 as white solids. Gratifyingly, both bromide
and iodide counterions mediated this process with a range of allylated,
crotylated and benzylated chiral ammonium complexes generated delivered excellent yields of the quaternary ammonium halides (Fig. 4b
directly from the precursor anilines (see Supplementary Information). 1b–d, 1k, 1m, 1o, 1p; 63–99% yield; 30–77% yield overall) and reclaimed
The absolute configuration of each new ammonium cation was con- BINOL (62–98%). Using (S)-BINOL allowed access to the complimentary
firmed crystallographically (Fig. 4c 2m, 2o–2q, (ent)-2m, (ent)-2o–q). enantiomers in comparable yields and selectivities (Fig. 4b (ent)-1b–d,
To generate material where stereochemical information is solely pre- (ent)-1k, (ent)-1m, (ent)-1o, (ent)-1p).
sent at a nitrogen stereocentre, isolation of the enriched ammonium
Control reactions demonstrated key parameters that are essen-
halides was conducted. Simple extraction with diethyl ether and water tial to the process (Extended Data Fig. 4a). Balancing temperature,
Nature | Vol 597 | 2 September 2021 | 73

Article
a
X–
X–
X–
X–
R1
N+
R2
R1
N+
R2
R1
N
R1
N+
R2
R1
N+
R2
(S)-BINOL (1 equiv)
R2
(R)-BINOL (1 equiv)
R2
Et2O/H2O
X
X
(2 equiv)
Et2O/H2O
(2 equiv)
50 °C, 48 h
HO
HO
OH
OH
50 °C, 48 h
1*
2
4
(ent)-2
(ent)-1*
(R)-BINOL
(S)-BINOL
b
Br–
Br–
Br–
Br–
I–
–I
Br–
Br–
N+
N+
N+
N+
N+
N+
N+
N+
RM
RM
RS
RS
N+
+
N
RL
RL
Me
Me
(S)-1b
(S)-1c
(S)-1d
(S)-1k
69%
97:3 e.r.a
(R)-1k
(R)-1d
(R)-1c
(R)-1b
77%
73%
71%
68%
65%
76%
70%
(S)-BINOL
(R)-BINOL
66:34 e.r.a
84:16 e.r.a,b
96:4 e.r.a
90:10 e.r.a
95:5 e.r.a
82:18 e.r.a,b 67:33 e.r.a
RM
RM
RS
+
RS
N+
Br–
Br–
I–
I–
–I
–I
Br–
Br–
N+
N+
N+
N+
N+
N+
N+
N+
N
RL
(R)-BINOL
Selectivity rules
RL
(S)-BINOL
(R)-1m
58%
(R)-1o
(S)-1p
56%
(R)-1q
33%
(S)-1q
30%
(R)-1p
50%
(S)-1o
58%
(S)-1m
59%
55%
91:9 e.r.a
80:20 e.r.a
96:4 e.r.a
81:19 e.r.a
79:21 e.r.a
97:3 e.r.a
80:20 e.r.a
95:5 e.r.a
c
d
2m
2o
2p
2q
(ent)-2q
(ent)-2p
(ent)-2o
(ent)-2m
e
100
100:0
90:10
80:20
70:30
60:40
50:50
R2
N+
R1
R2
X-
R2
X-
X-
1
2
80
60
40
20
Racemization
X
X
R2
Et
2O/H2O
(R) -BINOL
N
N
N+
N+
R1
(R)-BINOL
(R)-BINOL
R1
R1
R1
Favoured
50°C
In situ alkylation
Thermodynamic
chiral selection
3
4
OH
OH
(R)- BINOL
R1
R1
R2
(R) -BINOL
N+
X-
Disfavoured
N+
X-
Isolate salt and
reclaim BINOL
50°C
R2
R2
0
0
12
24
t (h)
36
1
2
3
4
f
Cl
Cl
N
Cl
Cl
N
N
Ph
HO
N
(c)
(c)
97%
8:92 e.r.
(a)
(a)
HO
HO
OH
OH
Ph
Ph
OH
Ph
OH
88%
100%
96%
15:85 e.r.
HO
·
8
(R)-BINOL
·
(R)-BINOL
N
N
N
N
7
9
Cinchonidine
Cinchonine
10
(d)
Pseudoenantiomeric relationship
(d)
(d)
(R)
HO (S)
HO
OH
OH
(d)
BINOL
Racemate
Br
Br
Br
Br
N
N
N
N
(c)
(c)
(b)
(b)
HO
HO
OH
OH
99%
3:97 e.r.
68%
65%
99%
99:1 e.r.
·
(R)-BINOL
·(S)-BINOL
(ent)-2d
2d
(S)-1d
(R)-1d
Enantiomeric relationship
Fig. 4 | Enantioselective synthesis of ammonium cations. a, Reaction
conditions for the enantioselective synthesis of ammonium cations,
combining the previously investigated chiral recognition and racemization
behaviour in one pot. b, Substrate scope of the asymmetric synthesis,
demonstrating the formation and isolation of both enantiomeric forms of
quaternary ammonium halide salts. Rs, smallest substituent; Rm, medium
substituent; Rl, largest substituent, where size is determined by Taft
parameter. c, X-ray crystal structures of ternary complexes (2m, 2o–2q,
(ent)-2m, (ent)-2o–2q) not present in Fig. 2. d, Isolated yield of 2d and
enantioenrichment of (S)-1d as the reaction progresses (representative
experiments), which are in agreement with a thermodynamically driven
process. e, Proposed mechanism of the reaction. f, The importance of nitrogen
stereochemistry in supramolecular recognition. Conditions (a), (b) and (c)
described in Supplementary Information. (d), Chiral high-performance liquid
chromatography traces (see Supplementary Information). aEnantiomeric ratio
(e.r.) was determined by performing a counterion exchange of the isolated
ammonium halide salt with the chiral shift reagent (R,Λ)-BINPHAT. The
resulting diastereomeric salt was analysed by 1H NMR spectroscopy.
bOverlapping Zisomer resonances deconvoluted via line fitting of the 1H NMR
used in the determination of e.r.
74 | Nature | Vol 597 | 2 September 2021

concentration and equivalences of alkylating agent allowed for the enriched in (R)-BINOL (see Fig. 4f 8 and 10), which once liberated were
ammonium stereocentre to be in dynamic exchange while allow- observed in high enantiomeric enrichment (for 8, 92:8 e.r., R:S; for
ing compatible recognition to occur. Analysis of the solution-phase 10, 85:15 e.r., R:S). In contrast, when pure enantiomeric forms of our
component of these reactions (Extended Data Fig. 4b) showed that ammonium stereocentres were used, the supramolecular recognition
the uncomplexed ammonium remaining in solution was also biased of BINOL can be achieved, with (R)-1d forming a complex with (S)-BINOL
towards the (S)-enantiomer. Demonstrating that both the solid and (Fig. 4f for 2d, >1:99 e.r.) and its enantiomer (S)-1d providing (R)-BINOL
solution-phase ammonium cations have the same sense of enrichment (Fig. 4F for (ent)-2d, 97:3 e.r.) in excellent selectivity, surpassing their
offers unambiguous confirmation of the enantioselective synthesis of Cinchona-based counterparts. Given that both cinchonine and cin-
an ammonium stereocentre.
chonidine bear the same configuration at nitrogen, these results are
Analysis of the progression of the reaction over time gave evidence consistent with stereogenic nitrogen providing a fundamental role in
of a self-corrective process (Fig. 4d). In the time-course analysis of the the supramolecular recognition observed in the Cinchona alkaloids.
preparation of 2d, the yield of the complex rapidly increased over the These observations present a new opportunity to interrogate the role
initial 12 h before slowly climbing to 75% after 26 h. A similar increase was of ammonium stereocentres in all disciplines where tetra-alkylated
observed for the level of enantioenrichment of (S)-1d, the ammonium ammonium cations are used.
component of complex 2d, progressing from an initial value (t = 2 h,
In summary, we describe an operationally simple enantioselective
84:16 e.r.) to a final equilibrium value (97:3 e.r.) after approximately synthesis of quaternary ammonium cations. In addition, the impor-
16 h. Such results are in stark contrast to processes based on kinetic tance of controlling the stereochemistry of nitrogen has been demon-
resolution, where a decrease in selectivity is to be expected as the reac- strated through the supramolecular recognition of both enantiomers
tion proceeds47. This ‘error checking’ feature offers further evidence of BINOL using the now synthetically accessible enriched ammonium
of a thermodynamically driven process.
cations, a process that cannot be achieved with naturally occur-
A model for the selectivity observed can be tentatively suggested ring Cinchona-derived pseudoenantiomers. With proven access to
in correlation with the results obtained so far, based on steric con- stable nitrogen stereocentres, we hope that the importance of this
siderations. When the largest group is co-planar with the smallest often-overlooked stereogenic centre will be further explored in fields
group, either through free rotation or locked through the presence that rely on tetra-alkylated ammonium cations.
of a ring, the next largest group will occupy the proximal position when
(R)-BINOL is used (Fig. 4b, inset box).
Taking the above observations into account, we propose that this
Online content
one-pot process occurs as outlined in Fig. 4e. The conformationally Any methods, additional references, Nature Research reporting sum-
labile amine can undergo a reversible, non-selective alkylation forming maries, source data, extended data, supplementary information,
an equilibrium mixture of racemic ammonium cations and the initial acknowledgements, peer review information; details of author con-
amine. With the ammonium halides now present, BINOL complexation tributions and competing interests; and statements of data and code
results in selection of the preferred enantiomer from solution forming availability are available at https://doi.org/10.1038/s41586-021-03735-5.
the enriched ternary complex. Formation of the mismatched ternary
complex also occurs, leading to initially moderate enantiomeric enrich-
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76 | Nature | Vol 597 | 2 September 2021

Author contributions The project was conceived by M.O.K. and M.P.W. Experiments were
devised by M.O.K. and M.P.W. M.P.W., J.M.P. and M.E.L. carried out starting material synthesis
for the project. M.P.W. carried out experimental work to develop the enantioselective
recognition, dynamic studies and enantioselective syntheses. X-ray crystallography was
conducted by M.P.W. and D.S.Y. The manuscript was prepared by M.O.K. and M.P.W. with input
from all authors.
Data Availability
Full crystallographic details in CIF format have been deposited in the
Cambridge Crystallographic Data Centre database (deposition num-
bers: CCDC-1987042–1987058; 1987061–1987068; 1987165–1987180;
2047299–2047303). All other data are available from the corresponding
author upon request.
Competing interests The authors have filed a patent on this work (GB2017799.4).
Acknowledgements We acknowledge funding from The Royal Society to M.O.K in the form of
a University Research Fellowship (UF150536) and equipment grant (RGS\R2\180467) award.
Durham University is acknowledged for providing a doctoral studentship (M.P.W.). J.M.P
acknowledges support from the Laidlaw Undergraduate Research and Leadership programme
in the form of a scholarship. The Royal Society is also acknowledged for providing M.E.L. with
funding for a summer studentship. We thank our colleagues at Durham University and beyond,
as well as members of the Kitching group, for input and advice during the preparation of this
manuscript.
Additional information
Supplementary information The online version contains supplementary material available at
https://doi.org/10.1038/s41586-021-03735-5.
Correspondence and requests for materials should be addressed to M.O.K.
Peer review information Nature thanks the anonymous reviewer(s) for their contribution to the
peer review of this work.
Reprints and permissions information is available at http://www.nature.com/reprints.

Article
Extended Data Fig. 1 | Recognition screening. Addition of recognition species (0.5 equiv) to 60 mM solution (CDCl3) of (rac)-1b. Recognition was monitored by
observing changes in chemical shift and increased multiplicities of 1H resonances of salt (rac)-1b.

Extended Data Fig. 2 | Crystal structure of ternary complex 2b. a, The asymmetric unit (P43). b, Viewed along the baxis. c, Viewed along the caxis.

Article
Extended Data Fig. 3 | BINOL–halide network. The (R)-BINOL and bromide counterions of complex 2d are shown as a van der Waals surface (teal), displaying the
chiral hydrogen-bond network that encapsulates the ammonium cation (S)-1d.

Extended Data Fig. 4 | Control reactions. a, Table of control reactions,
demonstrating the requirement for correct balance of temperature, alkylating
agent and concentration for optimal results. b, Analysis of both the solid and
solution phases of the reaction mixture. Both phases show bias towards the (S)
enantiomer of the quaternary ammonium cation.

Article
Extended Data Fig. 5 | Ammonium hexafluorophosphate salts. a, X-ray
crystal structures of enantioenriched hexafluorophosphate salts (S)-1t and (R)-
1t. b, Evaluation of the stereochemical stability of (S)-1t and (R)-1t by exposing
both enantiomers to conditions previously used to racemize ammonium halide
salts, while also observing minimal changes to their optical activity after 24 h.