Enantioselective Synthesis of α-Aryl-β2-Amino-Esters by Cooperative Isothiourea and Br?nsted Acid Catalysis

Article abstract of DOI:10.1002/anie.202016220

The synthesis of α-aryl-β²-amino esters through enantioselective aminomethylation of an arylacetic acid ester in high yields and enantioselectivity via cooperative isothiourea and Br?nsted acid catalysis is demonstrated. The scope and limitatio

Full text of DOI:10.1002/anie.202016220

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 11892–11900
International Edition:
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doi.org/10.1002/anie.202016220
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Asymmetric Catalysis
Enantioselective Synthesis of a-Aryl-b2-Amino-Esters by Cooperative
Isothiourea and Brønsted Acid Catalysis
Feng Zhao+, Chang Shu+, Claire M. Young, Cameron Carpenter-Warren,
Alexandra M. Z. Slawin, and Andrew D. Smith*
Dedicated to Professor Steve Davies upon his retirement for his friendship and mentorship
Abstract: The synthesis of a-aryl-b2-amino esters through
enantioselective aminomethylation of an arylacetic acid ester in
high yields and enantioselectivity via cooperative isothiourea
and Brønsted acid catalysis is demonstrated. The scope and
limitations of this process are explored (25 examples, up to
94% yield and 96:4 er), with applications to the synthesis of
(S)-Venlafaxine·HCl and (S)-Nakinadine B. Mechanistic stud-
ies are consistent with a C(1)-ammonium enolate pathway
being followed rather than an alternative dynamic kinetic
resolution process. Control studies indicate that (i) a linear
effect between catalyst and product er is observed; (ii) an acyl
ammonium ion can be used as a precatalyst; (iii) reversible
isothiourea addition to an in situ generated iminium ion leads
to an off-cycle intermediate that can be used as a productive
precatalyst.
contain an a-aryl-b2-amino motif (Figure 1a). Biologically
active a-aryl-b2-amino acid derivatives include amide GDC-
0068 3 (ipatasertib), an effective pan-Akt inhibitor,[7] while
amino-alcohol derivative Venlafaxine·HCl 4 is a therapeuti-
cally approved treatment for depression.[8]
Enantioselective routes to b-amino acids and their
derivatives therefore represent an important synthetic chal-
lenge with a range of methods developed for their synthesis.
Until recently, synthetic routes to b3-amino acid derivatives
typically relied upon the elegant and versatile lithium amide
conjugate addition approach developed by Davies,[9] or the
use of chiral auxiliaries for the preparation of b2-amino
acids.[10,11] Catalytic, enantioselective routes to b2-amino acid
derivatives have been established, and include the use of
metal complexes with chiral ligands[12] or complexes that
exhibit metal-centered chirality.[13] Organocatalytic routes
have also been reported, predominantly employing secondary
amine Lewis base catalysts and aldehydes to access b-amino
aldehydes through enamine intermediates.[14] Additionally,
a thiourea-catalyzed route to enantioenriched nitro-com-
Introduction
b-Amino acids are important functional groups in an
abundance of natural products and medicinally relevant
compounds. Although less common than their a-homologues,
many naturally occurring compounds contain the b-amino
acid motif as a key structural feature.[1] The incorporation of
b-amino acids within bioactive peptides allows access to
structures with modulated conformations and properties such
as antimicrobial peptides,[2] while b-amino acid containing
oligomers have important applications in the chemistry of
unnatural peptides such as foldamers.[3] Many examples of
pharmaceutically active compounds contain a b-amino car-
bonyl motif,[4] with a-aryl-b2-amino acids representing an
important subclass. For example, natural products (S)-Naki-
nadine B 1 isolated from the marine sponge Amphimedon
sp.[5] and Bishyocyamine 2 from Anisodus acutangulus[6] both
[*] Dr. F. Zhao,[+] Dr. C. Shu,[+] Dr. C. M. Young, C. Carpenter-Warren,
Prof. A. M. Z. Slawin, Prof. A. D. Smith
EaStCHEM, School of Chemistry, University of St Andrews
St Andrews, Fife, KY16 9ST (UK)
E-mail: ads10@st-andrews.ac.uk
[+] These authors contributed equally to this work.
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.202016220.
ꢀ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
Figure 1. a) Naturally occurring and medicinally active a-aryl-b2-amino
acid derivatives. b) State of the art organocatalytic enantioselective
synthesis of a-alkyl-b2-amino esters.
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pounds has been developed that can be effectively reduced to
b-amino acids,[15] as have Brønsted acid catalyzed routes that
harness the stereodirecting effect of a chiral anion.[16]
In 2015, Chi and co-workers reported an enantioselective
NHC-catalyzed route to a-alkyl-b2-amino esters 6 from enals
using NHC-precatalyst 7 and hemiaminal ether 5 as a pre-
cursor to an in situ generated iminium ion.[17] This method
incorporates Brønsted acid activation of amino-ether 5 with
the NHC-catalyzed formation of azolium enolates, generating
a range of a-alkyl-b2-amino esters in good yields and excellent
enantioselectivity (up to 97:3 er). Important to this method
was the use of catalytic weak base (NEt3) that served a dual
purpose; firstly to generate the free NHC, but secondly to
allow the in situ acid-catalyzed formation of a formyl iminium
ion (as its conjugate acid). Despite its synthetic utility, one
inherent limitation of this methodology is that the resulting
products are restricted to a-alkyl-b2-amino esters, and limited
mechanistic understanding of this process has been devel-
oped. Given their importance, the development of a simple
and effective enantioselective route to a-aryl-b2-amino esters
would be of significant synthetic value.
Figure 2. a) Precedent for using acyl imidazole and isothiourea·HCl
salts in C(1)-ammonium enolate generation. b) Proposed dual-catalytic
enantioselective synthesis of a-aryl-b2-amino esters.
C(1)-Ammonium enolates are powerful catalytically gen-
erated synthetic intermediates that have been widely used in
a range of enantioselective C-C and C-X bond forming
processes through reaction with suitable electrophilic part-
ners.[18] In recent years the reactivity of C(1)-ammonium
enolate intermediates has been significantly broadened
through the development of aryl esters as precursors using
isothioureas as catalysts.[19] These substrates allow aryloxide
promoted catalyst turnover and have been applied to
enantioselective [2,3]-sigmatropic rearrangements,[20] co-
operative catalysis with Pd-, Ir- and Cu-derived electro-
philes,[21] as well as base free ammonium enolate catalysis.[22]
Building upon this work, we proposed that enantioselective
aminomethylation of C(1)-ammonium enolates, catalytically
generated from chiral isothioureas and arylacetic acid esters,
would provide ready access to enantioenriched a-aryl-b2-
amino esters.
used to enable the catalytic enantioselective synthesis of a-
aryl-b2-amino esters.
The protocol harnesses Brønsted acid and isothiourea
Lewis base catalysis for the catalytic activation of both
reaction partners. The Brønsted acid promotes in situ
generation of a reactive iminium species from a hemiaminal
ether presumably through initial N-protonation, generating
the free isothiourea that is required for generation of a C(1)-
ammonium enolate (Figure 2b). Comprehensive control
studies aimed at understanding the mechanism of this process
are consistent with a C(1)-ammonium enolate pathway and
highlight the subtle equilibria between species along the
productive reaction pathway that lead to off-cycle intermedi-
ates.
The process would require a cooperative Brønsted acid Results and Discussion
co-catalyst to generate an iminium ion in situ from an amino
ether precursor. This contrasts with the typical necessity to
generate the C(1)-ammonium enolate using a chiral tertiary
amine in the presence of a stoichiometric Brønsted base. The
addition of this auxiliary base is usually considered necessary
to neutralize acidic by-products, and to prevent protonation
(and thus deactivation) of the Lewis base catalyst. The use of
tertiary amine salts as Lewis base catalysts has limited
precedent, with DMAP (4-dimethylaminopyridine) salts
having been used as acylation catalysts,[23] and sub-stoichio-
metric acid additives used sporadically with other tertiary
amine Lewis base catalysis.[24,25] In previous work we demon-
strated the use of an isothiourea hydrochloride salt as
a catalyst for C(1)-ammonium enolate generation from N-
acyl imidazole precursors (Figure 2a). N-Protonation of the
acyl imidazole (acting as a Brønsted base) both activated the
substrate to nucleophilic attack and generated free isothio-
urea for Lewis base catalysis.[26] Taking inspiration from this
work, in this manuscript isothiourea hydrochloride salts are
Investigation of Optimal Reaction Conditions
The effective enantioselective construction of a-aryl-b2-
amino ester 9 was realized via the benzotetramisole·HCl
(BTM·HCl, 5 mol%) catalyzed Mannich addition of penta-
fluorophenyl ester pronucleophile 8 to hemiaminal ether
iminium precursor 5 in THF at room temperature in the
presence of 4 Š molecular sieves (MS). Subsequent addition
of MeOH gave the isolable methyl ester 9 in excellent yield
(81%) and with high enantioselectivity (96:4 er) (Table 1,
entry 1).[27] Control experiments indicated that without the
hydrochloric acid co-catalyst, yield and enantioselectivity
were significantly reduced even after extended reaction time
(entry 2). Other halide salts gave high product yield but the er
values were lower than for BTM·HCl (entries 3 and 4). Other
classes of Brønsted acid co-catalysts again led to high product
yield but significantly diminished enantioselectivity com-
pared with halide salts (entries 5–7).[28] Removing molecular
sieves led to reduced yield while maintaining product
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Table 1: Variation of Reaction Conditions.[a]
aminal ether 5 under the developed conditions (Table 2A).
Importantly, arylacetic esters bearing electron-donating (4-
dimethylamino-, 4-methoxy- and 4-tolyl) substituents, as well
as halogen substituents (4-bromo-, 4-chloro- and 4-fluoro-)
and electron-withdrawing substituents (4-trifluoromethyl-)
were all tolerated, with a-aryl-b2-amino esters 10–16 all
obtained with excellent yields (77% to 94%) and enantiose-
lectivity ( ꢀ 95:5 er). The absolute configuration of (S)-13 was
determined by single crystal X-ray crystallography, with all
other products assigned by analogy.[29] This stereochemical
outcome is consistent with the expected configuration at C(2)
if this process proceeds through a C(1)-ammonium enolate
intermediate.[19c] Only the introduction of a 4-nitro-substitu-
ent led to the product 17 in reduced yield and enantioselec-
tivity. Further variation of the arylacetic ester showed that
incorporation of substituents at both the 3-position (such as
3,4-dimethoxy-, 3-methoxy- and 3-bromo- to give 18–21) and
the 2-position (2-methoxy- and 2-bromo- to give 22–23) gave
products with consistently high yields and er. Notably, the 2-
substitution pattern frequently provides reduced stereoselec-
tivity in related isothiourea-catalyzed methods.[30] b2-Amino
esters 24 and 25 with 1- and 2-naphthyl substituents were
readily prepared, as was heteroaromatic 2-thienyl 26. Beyond
aryl acetic acid derivatives, the use of (E)-pent-3-enoic acid
pentafluorophenyl ester was also productive, providing 3-
alkenyl-substituted b2-amino ester 27 in excellent er. The
consistent yield and enantiocontrol observed with variation in
both steric and electronic aryl substitution within the ester
component indicate that neither provide a significant bias in
this process. Further investigations probed the effect of N-
substituents within the hemiaminal ether reaction partner
(Table 2B). Halogen- (4-fluoro and 4-bromo) and electron
donating (4-methoxy) substituents were readily incorporated
within the N-benzyl groups, giving a-aryl-b2-amino esters 28–
30 in consistent yield and enantioselectivity. The hemiaminal
ether derived from diallylamine also worked well in catalysis,
giving b2-amino ester 31 in 80% yield and 94:6 er.
The limitations of this methodology were also probed
(Table 2C). Notably, the N-benzyl-N-methyl and cyclic N-
alkyl substituted hemiaminal ether variants 32–34 led to
complex product distributions that included < 5% product
formation in THF. In the case of 32 and 33, the corresponding
amides 37 and 38 were isolated in 30–39% yield upon
treatment with either BTM·HCl or BTM (5 mol%). The
formation of these amides is consistent with preferential N-
acylation of the corresponding hemiaminal ether with either
the pentafluorophenyl ester or an in situ generated acyl
ammonium ion, followed by fragmentation to generate the
corresponding amide. This is consistent with observations
from Bçhme and Sickmüller,[31] who demonstrated the
ambident nature of hemiaminal ethers in reactions with acyl
halides, with acyl transfer reactions leading to the formation
of amides and esters. That this fragmentation pathway is
preferred over iminium ion formation when using hemiaminal
ethers 32–34 presumably reflects the increased nucleophilicity
of these species relative to the corresponding N,N-diallyl- or
N,N-dibenzyl substituted hemiaminal ethers that lead to
constructive enantioselective aminomethylation. Alternative
pathways involving either iminium hydrolysis, or formation of
Entry
Variation
Yield[b] [%]
er[c]
1
–
81
40[d]
95
94
89
95
88
44
55[d]
61
75
70
60
96:4
72:28
93:7
89:11
71:29
72:28
66:34
94:6
93:7
85:15
94:6
87:13
95:5
2
without HCl
3
4
5
6
7
8
(R)-BTM·HBr (5 mol%)
(R)-BTM·HI (5 mol%)
(R)-BTM·HBF4 (5 mol%)
(R)-BTM·HO2CCF3 (5 mol%)
(R)-BTM·HOTf (5 mol%)
without 4 Š MS[e]
9
(R)-BTM·HCl (1 mol%)
HyperBTM·HCl (5 mol%)
Ester=4-nitrophenyl (OC6H44-NO2)
CH2Cl2 (0.1 m)
10
11
12
13
toluene (0.1 m)
[a] The mixture of 5 (0.3 mmol), 8 (0.2 mmol), (R)-BTM·HCl (5 mol%),
and 4 Š molecular sieves (MS, 100 mg) in dry THF (2 mL, 0.1 m) was
stirred at rt under a N2 atmosphere for up to 24 hours before treatment
with MeOH (0.5 mL) and DMAP (20 mol%) for 4 h. [b] Isolated yield.
[c] Determined by HPLC analysis on a chiral stationary phase. [d] In-
complete reaction after 2–3 days before addition of MeOH. [e] Molecular
sieves were activated in a furnace at 4008C for 16 h. THF=Tetrahy-
drofuran. TfOH=Triflic acid. rt=room temperature.
enantioselectivity (entry 8). This observation can be ration-
alized by the dual benefit of trapping adventitious water (to
suppress hydrolysis of either ester 8, or the in situ formed
iminium ion generated from 5) as well as trapping the in situ
generated methanol (that can lead to the unproductive
formation of the methyl ester of 8). Further reduction in
catalyst loading to 1 mol% gave reduced yield and slightly
reduced enantioselectivity (entry 9). Alternative catalysts
such as HyperBTM·HCl gave reduced enantioselectivity
(entry 10), while use of a 4-nitrophenyl ester led to compa-
rable yield and enantioselectivity (entry 11). A simple solvent
screen showed that CH2Cl2 led to reduced yield and
enantioselectivity (entry 12), while toluene gave comparable
enantioselectivity, but reduced yield, relative to THF (en-
try 13).
Scope, Limitations and Synthetic Applications
With the optimal conditions (Table 1, Entry 1) estab-
lished, the generality of this protocol was investigated through
variation of both the arylacetic ester and N-substituents of the
hemiaminal ether (Table 2). Initially, a range of substituted
arylacetic pentafluorophenyl esters with different steric and
electronic properties was tested through reaction with hemi-
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Table 2: Scope, Limitations and Synthetic Applications of the Enantioselective Aminomethylation.[a,b]
[a] Isolated yield; reaction progress followed by TLC analysis; see SI for reaction times; [b] er determined by HPLC analysis on a chiral stationary phase.
[c] Using (R)-BTM·HCl. [d] Using (R)-BTM. [e] Et2O·HCl, CH2Cl2. [f] H2 (30 bar), Pd/C, MeOH, rt. [g] HCHO (37 wt% in H2O), NaBH(OAc)3, MgSO4,
CH2Cl2, rt. [h] 1,5-dibromopentane, Mg, ether; recrystallization after treatment with Et2O·HCl. [i] 13-(pyridin-3-yl)tridecanal, NaBH(OAc)3, AcOH, 1,2-
dichloroethane, rt. [j] LiOH, THF:H2O (2:1), rt.
an oxonium ion and amine elimination, that subsequently
lead to amide formation cannot be ruled out at this stage.
Within the ester component, and consistent with common
observations using isothiourea catalysis, 3-phenylpropanoate
and phenylthioacetate pentafluorophenyl esters 35 and 36 led
to < 5% product,[32] showing that this process complements
the NHC-catalyzed protocol developed by Chi and co-work-
ers.[17]
Having demonstrated the scope and limitations of this
process, two target compounds, (S)-Venlafaxine·HCl 4[33] and
(S)-Nakinadine B 1,[34] were synthesized to demonstrate the
utility of this methodology (Table 2D). Each route began with
the preparation of a-aryl-b2-amino esters 11 and 9 on a > 1 g
scale, giving the products in excellent yield and er. For the
synthesis of (S)-Venlafaxine·HCl 4, 11 was subjected to
hydrogenolysis and reductive amination to give N,N-dimethyl
derivative 39 in 83% yield. Double addition of the Grignard
reagent derived from 1,5-dibromopentane, followed by re-
crystallization, afforded the target compound in 99:1 er and
47% overall yield over 5 steps. To prepare (S)-Nakinadine B
1, hydrogenolysis of 9, followed by reductive amination with
13-(pyridin-3-yl)tridecanal gave 40 in 73% yield and 95:5 er,
with ester hydrolysis giving 1 in 93:7 er and 44% overall yield
over 5 steps. In both cases correlation of the products with
literature data served as proof of both structure and config-
uration.
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Mechanistic Investigations
formed upon acylation of the isothiourea is typically invoked
as the functioning base for C(1)-ammonium enolate forma-
tion.[22] However, the reaction using acyl ammonium 43 as
precatalyst proceeded without pentafluorophenolate, leading
to the conclusion that the hemiaminal ether could function as
a Brønsted base to promote deprotonation and C(1)-ammo-
nium enolate formation in this instance. The effect of addition
of an amine base upon reaction conversion and product
enantioselectivity was therefore investigated (Table 3D).
Performing the reaction with one equivalent of Bn2NEt
(structurally similar to the hemiaminal ether 5) gave b-amino
ester product 9 in 87% yield and 96:4 er, while the use of
secondary amine Bn2NH also gave 9 in high er. However, the
use of i-Pr2NEt (a commonly used Brønsted base in tertiary
amine Lewis base catalysis) showed a significant reduction in
product conversion and reduced product er (22% yield, 89:11
er). As the addition of dibenzylamine did not lead to
significant deviation in er, an alternative iminium ion
precursor, tetra-N-benzylmethanediamine 44 was trialed in
this process, giving b-amino ester 9 in 47% yield and 93:7 er.
The nature of the base present in the reaction is therefore
highly significant, presumably effecting both iminium ion and
C(1)-ammonium enolate formation though modulation of
equilibrium distributions.
Having explored the scope and limitations of this process,
further investigations focused on developing a mechanistic
understanding. Initial studies attempted to elucidate reaction
orders and track any potential intermediates through tempo-
ral reaction monitoring using 19F{1H} NMR spectroscopy and
19F labelled reactants (see SI). However, the heterogeneous
nature of the reaction, together with the observation of
multiple resonances that could not be fully deconvoluted
meant that these investigations were abandoned.[28] Instead,
a series of control experiments were performed to give insight
to the productive reaction mechanism. At the onset of these
investigations, two feasible mechanisms were considered that
involved either enantioselective aminomethylation of a C(1)-
ammonium enolate, or an alternative dynamic kinetic reso-
lution (DKR) process of a racemic (or scalemic) b-amino
pentafluorophenyl ester product. If a DKR were operative,
a racemic b-amino pentafluorophenyl ester added to an
enantioselective reaction would be predicted to become
enantioenriched over the reaction course. To test this
hypothesis, racemic b-amino ester 41 was prepared under
standard reaction conditions using racemic BTM·HCl
(10 mol%). b-Amino ester 41 proved difficult to isolate due
to the lability of the pentafluorophenyl ester and so was used
directly without purification. Subsequent addition of 2-
naphthyl substituted pentafluorophenyl ester 42, enantiopure
(R)-BTM·HCl (15 mol%) and 5 allowed potential DKR of
the b-amino ester 41 under the reaction conditions to be
assessed alongside the enantioselective aminomethylation of
42 (Table 3A). Upon isolation, 2-naphthyl b-amino ester 25
was obtained in 92:8 er and 81% yield, with 9 isolated in 61%
yield and racemic form. This is inconsistent with a DKR of the
b-amino pentafluorophenyl ester product being operative
under catalytically competent conditions, although DKR of
a post-aminomethylation acyl ammonium ion (prior to
catalyst release by phenoxide) cannot be currently ruled
out. Interestingly, while the overall BTM enantiomeric ratio
(after second charge of catalyst) is expected to be 80:20, the er
of product 25 was 92:8. As a linear correlation between the er
of b-amino ester product 9 and catalyst BTM·HCl was
observed (Table 3B), the er of 25 was higher than expected.
We assume that either partial degradation or deactivation of
racemic-BTM·HCl from the first charge had occurred under
the reaction conditions and may account for this discrepancy.
As DKR of the b-amino pentafluorophenyl ester can be
excluded, this reaction was proposed to proceed through
enantioselective aminomethylation of a C(1)-ammonium
enolate intermediate generated from an acyl ammonium
ion. To further probe this proposal, catalyst (R)-BTM was
acylated with phenylacetyl chloride to give isolable acyl
ammonium ion 43. Acyl ammonium 43 (5 mol%) was
subsequently used as a precatalyst in the reaction process
(Table 3C), giving b-amino ester 9 in comparable yield and er
(78% yield, 95:5 er) to using (R)-BTM·HCl, indicating that 43
is a competent precatalyst for this transformation. Further
studies considered the function of the hemiaminal ether
within this process. If a pentafluorophenyl ester is used as an
acyl ammonium ion precursor, the pentafluorophenolate
Further mechanistic investigations tested the feasibility of
an iminium ion intermediate in the reaction process
(Table 3E). N,N-Dibenzyliminium ion 45 was prepared from
hemiaminal ether 5 using TMSCl (trimethylsilyl chloride)[35]
and used as a stoichiometric electrophile in a reaction with
(R)-BTM and ester 8 in the presence of Bn2NEt. b-Amino
ester 9 was generated in 65% yield and 92:8 er, consistent
with iminium ion 45 being a potential intermediate in this
reaction process. Given the known ability of tertiary amines
to add reversibly to iminium ions,[36] further consideration led
to the possibility of the iminium ion 45 being intercepted in
situ by the Lewis base (R)-BTM. Addition of (R)-BTM to
N,N-dibenzyliminium chloride 45 showed complex behavior
1
and gave a mixture of products by H NMR analysis, with
aminomethylation of the Lewis base to give 46 tentatively
assigned as a significant component.[37] The use of this mixture
as a potential precatalyst (20 mol%) gave b-amino ester 9 in
80% yield and 93:7 er upon treatment with pentafluorophen-
yl ester 8 and hemiaminal ether 5. These control studies
indicate that while 46 may be a potential reaction intermedi-
ate it is inconsequential to the outcome of the reaction
process, presumably due to its reversible formation. The
enantiodetermining step of the reaction was next investigat-
ed. Aminomethylation of the C(1)-ammonium enolate was
proposed to proceed enantioselectively, and the observed
product configuration at C(2) is consistent with the known
facial bias of the Lewis base catalyst. However, during
optimization, variation of the counterion of the (R)-BTM·HX
salt led to significant variation in product er, and so further
experiments considered the effect of a chiral counterion
through use of chiral acid additives. Performing the reaction
using either (R)- or (S)-BTM alongside chiral acids 47–49
resulted in enantiocontrol being essentially completely dic-
tated by the isothiourea, though with significant erosion of
product er observed compared with the use of (R)-BTM·HCl
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Table 3: Mechanistic Control Studies and Proposed Mechanism for Cooperative Lewis Base and Brønsted Acid Catalysis.
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(Table 3F). To further probe the factors leading to product
Acknowledgements
enantioselectivity, the effect of using a chiral iminium ion was
investigated. Using a single enantiomer of (S)-hemiaminal
ether 50, and both enantiomers of BTM·HCl, gave b-amino
esters 51 and 52 as a single diastereoisomer in each case,
consistent with the isothiourea catalyst determining enantio-
selectivity and overriding any control from the chiral iminium
ion (Table 3G).
The research leading to these results has received funding
from the Royal Society (Newton Fellowship Programme,
F.Z.; C.S.). A.D.S. thanks the Royal Society for a Wolfson
Research Merit Award.
Based on these experiments, the reaction is proposed to
proceed via cooperative Lewis base and Brønsted acid
catalytic cycles (Table 3H). Reversible proton transfer from
(R)-BTM·HCl to the hemiaminal ether generates the free
isothiourea catalyst (for the Lewis base cycle) and the N-
protonated hemiaminal ether for the Brønsted acid cycle. In
the Brønsted acid cycle, proton transfer generates I, with
subsequent formation of the iminium ion chloride salt II. In
the Lewis base cycle, (R)-BTM can undergo reversible
addition to the iminium ion II to give aminomethylated
catalyst III as an off-cycle intermediate that is inconsequential
to the outcome of the reaction.[38] For the constructive
formation of the b-amino ester, N-acylation of (R)-BTM with
the pentafluorophenyl ester generates an acyl ammonium
pentafluorophenolate ion pair IV. Subsequent deprotonation
generates the (Z)-C(1)-ammonium enolate V, with a key 1,5-
O···S contact,[39] that can be classified as either a chalcogen-
chalcogen interaction[40,41] or chalcogen bond (nO to s*C-S),[42]
providing a conformational bias and ensuring coplanarity
between the 1,5-O- and S- atoms. Enantioselective amino-
methylation proceeds preferentially through reaction of the
Re-face of the C(1)-ammonium enolate with the iminium ion
II, leading to intermediate VI. Subsequent reaction with the
pentafluorophenol generated in situ leads to the desired b2-
amino ester and regenerates the isothiourea Lewis base and
Brønsted acid catalysts.
Conflict of interest
The authors declare no conflict of interest.
Keywords: aminomethylation ·cooperative catalysis ·
isothiourea ·mechanistic studies · a-aryl-b-amino acid
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The development of an operationally simple, scalable and
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enolate.
a BTM-derived C(1)-ammonium
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Manuscript received: December 6, 2020
Accepted manuscript online: March 1, 2021
Version of record online: May 1, 2021
11900 www.angewandte.org ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH Angew. Chem. Int. Ed. 2021, 60, 11892 –11900