A Broad Substrate Scope of Aza-Friedel-Crafts Alkylation for the Synthesis of Quaternary α-Amino Esters

Article abstract of DOI:10.1021/acs.orglett.0c01895

A versatile synthetic protocol of aza-Friedel-Crafts alkylation has been developed for the synthesis of quaternary α-amino esters. This operationally simple alkylation proceeds under ambient conditions with high efficiency, regioselectivity, and an exceptionally broad scope of arene nucleophiles. A key feature of this alkylation is the role associated with the silver(I) salt counteranions liberated during the reaction. Taking advantage of a phase-transfer counteranion/Br?nsted acid pair mechanism, we also report a catalytic enantioselective example of the reaction.

Full text of DOI:10.1021/acs.orglett.0c01895

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Letter
A Broad Substrate Scope of Aza-Friedel−Crafts Alkylation for the
Synthesis of Quaternary α‑Amino Esters
́
Guangkuan Zhao, Shyam S. Samanta, Jessica Michieletto, and Stephane P. Roche*
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ABSTRACT: A versatile synthetic protocol of aza-Friedel−Crafts alkylation has been developed for the synthesis of quaternary α-
amino esters. This operationally simple alkylation proceeds under ambient conditions with high efficiency, regioselectivity, and an
exceptionally broad scope of arene nucleophiles. A key feature of this alkylation is the role associated with the silver(I) salt
counteranions liberated during the reaction. Taking advantage of a phase-transfer counteranion/Brønsted acid pair mechanism, we
also report a catalytic enantioselective example of the reaction.
α,α-Disubstituted α-amino acids found in carbonaceous
chondritic meteorites1 have been suggested to be at the origin
of symmetry breaking (up to 20% ee) on earth, eventually
leading to the homochirality (single enantiomeric form) of
terrestrial proteinogenic α-amino acids.2 Although several
aspects of abiogenesis remain unclear, the role of α,α-
disubstituted amino acids in transferring chirality to other
proteinogenic α-amino acids renders these building blocks
unique in nature. α,α-Disubstituted “quaternary” α-amino
acids are also essential motifs of small molecules and
nonribosomal peptides having a variety of biological activities
(e.g., enzyme inhibitors, ion-channel blockers, or antibiotics).3
Given that these building blocks are highly constrained
compared to monosubstituted α-amino acids (Thorpe−Ingold
effect), they impart valuable conformational rigidity when
embedded in synthetic molecules.4 Notably, α,α-disubstituted
amino acids have a remarkable influence on peptide secondary
structures, often producing well-defined helical conformations
characteristic of many classes of biomolecules.5 Even so, the
asymmetric synthesis of this class of noncanonical amino acids
remains mostly untapped and complicated.6 On the other
hand, fluorinated amino acids have recently attracted
considerable attention owing to their unique medicinal and
physicochemical properties (i.e., high stability to metabolic
degradation, increased lipophilicity, and hydrogen bond
acceptor ability).7 Therefore, establishing a scalable and
practical (optically active) synthesis of α,α-disubstituted α-
trifluoromethyl amino esters is desirable.
In stark contrast to the activation of α-iminoglycinate A into
iminium B, which is one of the most studied and versatile
enantioselective strategies for synthesizing monosubstituted
nonproteinogenic α-amino esters,8 few diastereo-9 and
enantioselective10 methods are currently available for the
synthesis of acyclic α,α-disubstituted α-trifluoromethyl amino
esters 4. Indeed, the important electrophilicity of α-imino ester
3 results in a weak Lewis basicity of the imine nitrogen,
seemingly contributing to a lack of reactivity toward Lewis and
Brønsted acid catalysts (Scheme 1). Of particular interest, the
synthesis of α,α-trifluoromethyl-aryl amino esters by Friedel−
Crafts reactions remains challenging by both diastereo-11 and
enantioselective strategies.12 Seemingly, the relatively harsh
acidic conditions required for condensing amines with α-
trifluoromethyl ketoesters often limit the choice of N-
protecting groups, leading to a two-step condensation/
Received: June 5, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01895
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a,b
Scheme 1. Challenging Activation of α-Trifluoromethyl
Imino Pyruvate versus the Typical Imino Glycinate
Reactivity
Table 1. Reaction Optimization
b,c
product yield
(%)
b
conversion ratio (2:3:1:4)
silver
source
entry arene
1 h
4 h
1 day
d
1
2
3
4
5
6
7
−
−
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOTf
AgOTf
AgOTf
66:34:0:0
61:36:3:0
53:45:2:0
70:2:2:0
54:9:5:32
42:0:17:20
0:0:32:42
0:0:40:39
25:40:35:0
39:59:2:0
17:78:5:0
26:70:1:0
36:9:5:50
0:0:16:15
0:0:52:33
0:0:24:53
>95 (1)
98 (3)
5a
5b
5c
5b
5b
5b
>95 (3)
>98 (3)
e
dehydration with water scavengers via hemiaminal 1.13
A
98 (4c)
36 (4b)
54 (4b)
71 (4b)
milder alternative was also devised from the direct aza-Wittig
reaction with phosphazenes to prepare the most moisture-
sensitive α-imino ester 3.14 The lack of convenient synthesis
and reactivity of α-trifluoromethyl α-imino esters 3 (weak
Lewis basicity) combined with a high moisture sensitivity
(hydration, 3 → 1) are factors that largely hindered the use of
this approach. To address this methodological gap, we initially
envisioned avoiding the isolation of 3 by studying the direct
reactivity of chloroaminal 2. Given that glycinyl chloroaminals
were successfully exploited as effective surrogates of α-
iminoglycinates A by halide abstraction and anion binding
catalysis for carbon−carbon bond formation at the α-center,15
we intuitively hypothesized that if a similar maneuver could be
achieved from a tetrasubstituted chloroaminal 2, several classes
of α,α-disubstituted α-trifluoromethyl amino esters 4 could
become synthetically accessible. Herein, we report a highly
practical and general Friedel−Crafts alkylation via a silver(I)-
mediated halide abstraction combined with hydrogen bonding
that enables the addition of a broad range of arene
nucleophiles to the α-trifluoromethyl α-iminopyruvate 3.16
The starting material, α-trifluoromethyl chloroaminals
( )-2a and ( )-2b bearing common N-carbamoyl protecting
groups (Cbz or Fmoc), can be synthesized in >90% yield and
kept intact for >8 weeks under low-moisture conditions. In
collaboration with scientists from Eli Lilly, a silver(I)-mediated
Friedel−Crafts alkylation of chloroaminal ( )-2a was exten-
sively assessed through the screening of solvents, nucleophiles,
and other reaction parameters on the Automated Synthesis
laboratory (ASL) platform.17,18 As a result of this screen, a
couple of silver(I) salts emerged as efficient stoichiometric
reagents capable of generating Friedel−Crafts products cleanly
via a putative halide abstraction mechanism.19 The initial
results obtained via the robot synthesizer were further
optimized manually to study both reaction intermediates
(e.g., 3) and any potential byproducts formed during the
reaction by 1H and 19F NMR (Table 1). Indeed, using Ag2CO3
as a promoter, the halide abstraction took place rather slowly,
leading to ∼60% conversion of imine 3 after 4 h (entries 1 and
2). The reaction carried out without a desiccant (entry 1)
produced imine 3, which rapidly transformed into hemiaminal
1 (∼1:1 ratio after 4 h), leading to a >95% yield of 1 after 24 h.
The same reaction in the presence of molecular sieves
delivered imine 3 in a quantitative manner as the sole reaction
product (entry 2). Initial Friedel−Crafts conditions were
tested with rather weak π-nucleophile arenes (entries 3 and 4)
f
f g
8 ,
a
Reactions were carried out under argon with 2 (0.10 mmol) with
arenes 5a−c (2.0 equiv), silver reagent [1.5 equiv in Ag(I)], and 30
b
mg of 4 Å molecular sieves in CDCl3 (2.0 mL). NMR ratios and
yields determined for the crude reaction mixture by 19F NMR with
c
C6F6 as the internal standard. NMR yields determined for the crude
reaction mixture by 1H NMR with mesitylene as the internal standard.
d
e
Reaction carried out without 4 Å molecular sieves. The reaction was
also carried out at higher temperatures (up to 60 °C), and the
formation of 4b was not observed. Reaction carried out in anhydrous
Et2O. Reaction carried out at 0.3 M.
f
g
such as furan 5a (N ∼ 1.3) and 1,3-dimethoxybenzene 5b (N
∼ 2.5).20 In both cases, the desired arylation did not take place
as suggested by the large amount of imine 3 being formed over
time (>95% NMR yield). These results suggest that arenes 5a
and 5b are not nucleophilic enough to engage in the Friedel−
Crafts alkylation with imine 3. Therefore, a stronger
nucleophile, N-methylindole 5c (N ∼ 5.8), was tested under
the same reaction conditions. While small amounts of imine 3
were observed, the desired product 4c formed rapidly over the
course of the reaction (entry 5, ≤98% NMR yield after 24 h).
To circumvent the lack of reactivity of weak arene nucleophiles
and expand the initial success to a broader scope of arenes,
other common silver salts were evaluated.18 While reactions
with AgOAc or the more ionizing AgBF4 and AgSbF6 do not
deliver the desired Friedel−Crafts products, several silver salts
such as AgNO3, AgOTs, and AgOTf enabled the reaction to
occur with 5b as the nucleophile. Optimum reactivity was
observed with AgOTf, leading to the formation of arylated
product 4b in a 36% yield (entry 6). Reaction conditions were
further optimized by evaluating several solvents and concen-
trations.18 Reactions in diethyl ether showed a cleaner profile,
leading to the formation of 4b in 54% and 71% yields at
concentrations of 0.1 and 0.3 M, respectively (entries 7 and 8,
respectively). The presence of molecular sieves in addition to
AgOTf did not affect the reaction outcome, leading to the full
conversion of ( )-2a after only 1 h, but significant amounts of
hemiaminal intermediate 1 persisted [entries 6−8 (vide infra)].
The fact that imine 3 was not observed in these reactions
suggested that AgOTf or TfOH, a byproduct of halide
abstraction, might account for activating imine 3 in the
Friedel−Crafts alkylation.
B
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Two silver-mediated methods therefore emerged to cover a
broad scope of arene nucleophiles encompassing (a) electron-
rich substrates using Ag2CO3 and (b) electron-poor arenes by
switching the reagent to AgOTf (Scheme 2). For reactions
C6F6 (see Scheme 3A).21 To test our reactivity hypothesis,
imine 3 was synthesized, isolated (highly hydroscopic → 1),
a
Scheme 3. (A) Reaction Profile Monitored by 19F NMR
and (B) Mechanistic Information from Control
Experiments
b
Scheme 2. Substrate Scope for the Synthesis of α,α-
Disubstituted Amino Esters 4a−p by Friedel−Crafts
a-b-c
Reactions
a
Standard reactions carried out on a 0.2 mmol scale for 2 (1.0 equiv)
with arenes 5a−o (2.0 equiv) in CH2Cl2 (0.2 M) with Ag2CO3 (0.75
b
equiv). Isolated yields reported. Standard reactions carried out on a
0.2 mmol scale for 2 (1.0 equiv) with arenes 5a−o (2.0 equiv) in
a
1
Crude reactions analyzed by H and 19F NMR with C6F6 as the
CH2Cl2 (0.2 M) with AgOTf (2.0 equiv). Isolated yields reported.
internal chemical shift reference set at −161.64 ppm in CDCl3.
c
Major regioisomers drawn for the sake of simplicity. Regioisomers
b
Reagents and conditions for imine 3 (1.0 equiv) with arenes 5b, 5d,
separated by chromatography (see the Supporting Information).
5h, and 5i (2.0 equiv) at rt: (a) AgOTf or Ag2CO3 (Ag+, 1.5 equiv) in
CDCl3, no reaction observed; (b) TfOH (30 mol %) in CDCl3; (c) 4
Å molecular sieves (50 wt %) in CDCl3; (d) 4 Å molecular sieves (50
wt %) with (R)-TRIP (10 mol %) in CDCl3 for 24 h, C3/C2 rr of
86:14, (+)-4d er determined by chiral NP-HPLC analysis.
mediated by Ag2CO3 (0.75 equiv), reaction times varied from
18 to 72 h to deliver the quaternary α-trifluoromethyl amino
esters 4c−j in a range of yields of 56−89% with high
regioselectivity in most cases. Using the same method, Fmoc-
chloroaminal ( )-2b can also be functionalized in good yield,
as shown by the synthesis of 4f in 89% yield. Interestingly,
reactions with 1,3-dimethoxybenzene (N ∼ 2.5) did not
proceed after 3 days under these conditions, or at a higher
temperature, thus delineating the limit of reactivity of Ag2CO3-
mediated Friedel−Crafts alkylation. Even so, the reactivity of 3
with weaker π-nucleophiles (N ≤ 2.5) requires the use of
AgOTf (2.0 equiv) to promote the Friedel−Crafts reactions.
Under the optimum reaction conditions described in Scheme
2, reaction times could be decreased (<3 h) and α-
trifluoromethyl amino esters 4a, 4b, and 4k−p were obtained
in a remarkable range of yields of 71−90% with high
regioselectivity.
and further reacted with the moderately reactive arene 5b (N
∼ 2.5) and stoichiometric amounts of either AgOTf, Ag2CO3,
or catalytic TfOH (Scheme 3B). Analysis of reaction progress
by 19F NMR revealed no measurable formation of 4b in the
presence of silver salts, while using 30 mol % TfOH afforded
product 4b in 37% yield. The innate electrophilicity of imine 3
was further evaluated with arenes 5b, 5h, and 5i without any
external additive. Arenes 5b and 5i were shown to be
unreactive, while pyrrole 5h (N ∼ 4.6) reacted adequately
with 3 (20% yield). The electrophilicity factor of imine 3 can
therefore be roughly estimated to be E = −5.0 − [(3.6 + 4.6)/
2] = −9.1,20b which is in line with some of the most
electrophilic imines reported to date in the empirical Ofial−
Mayr reactivity scale.22 Taken together, these results suggest
that the TfOH byproduct formed during halide abstraction on
2 plays a pivotal role in catalyzing the Friedel−Crafts
alkylations.11a With this piece of mechanistic information, a
catalytic enantioselective activation of imine 3 was evaluated
with (R)-TRIP as the Brønsted acid catalyst and indole 5d as
Given the innate sensitivity of the 19F nucleus, and the large
chemical shift dispersion δF(CF3) observed among the starting
material 2 (−76.14 ppm), products 4b and 4c (−71.20 and
−71.70 ppm, respectively), imine 3 (−70.05 ppm), and
hemiaminal 1 (−80.63 ppm), reactions can be easily and
quantitatively monitored by 19F NMR spectra calibrated on
C
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the arene nucleophile.23 While the uncatalyzed reaction yielded
( )-4d in 20% as a single C3 regioisomer, the TRIP-catalyzed
reaction delivered the same regioisomer product (+)-4d
(79:21 er) along with the C2 regioisomer in a 86:14 ratio.
The C2/C3 regioisomers could not be separated by either
silica gel chromatography or reverse-phase HPLC, but the
comparable er and rr suggest that (+)-4d might be obtained
with high enantiomeric purity.18
Given the role played by TfOH and (R)-TRIP as Brønsted
acid catalysts in the key C−C bond-forming step from imine
3,24 we became interested in evaluating such a catalyst in
combination with Ag2CO3 for halide abstraction. In principle,
the cooperative action of an achiral transition metal with a
chiral Brønsted acid could translate into a chiral counteranion
catalysis approach (Scheme 4).25 In this reaction, (R)-TRIP
optimizations will be necessary to avoid the formation of
regioisomers. The Friedel−Crafts alkylation with indole 5d
was successfully scaled up to 1.0 mmol of ( )-2a with 5 mol %
TRIP catalyst loading to afford product (+)-4d in 70% yield
and >99% ee, which is more efficient than the original reaction
of Bolm at −78 °C.11 In comparison to this study, the absolute
configuration of α-amino ester (+)-4d should be (R) as
depicted.
In summary, a versatile aza-Friedel−Crafts alkylation has
been developed for the synthesis of quaternary α-trifluor-
omethyl-aryl amino esters. The combined halide abstraction/
alkylation process is operationally simple under ambient
conditions, highly efficient, regioselective, and amenable to a
remarkable broad scope of arenes, spanning 6 orders of
magnitude in nucleophilicity (indole, 5.5 ≥ N ≥ −1.2, anisole).
The key feature of this reaction is the role associated with the
silver(I) salt counteranions. In the course of silver-mediated
halide abstraction, the silver counteranion is liberated as a
conjugated Brønsted acid, likely resulting in an H-bond
activation of the trifluoromethyl imine intermediate. This
putative mechanism was exploited by replacing the achiral
silver counteranion with a chiral phosphate in a catalytic
enantioselective phase-transfer counteranion/Brønsted acid
pair system to achieve an initial example of halide abstraction
and aza-Friedel−Crafts alkylation with high stereoinduction
(>99% ee). Further development of this asymmetric aza-
Friedel−Crafts methodology for the synthesis of novel
quaternary α-amino esters is of ongoing interest to our
group. Ultimately, we anticipate that the present study will
offer a useful new approach for the asymmetric synthesis of
several classes of quaternary α-trifluoromethyl α-amino esters.
Scheme 4. Application to an Enantioselective Catalytic Aza-
a−c
Friedel−Crafts Transformation
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01895.
a
er determined by NP-HPLC using an enantiodiscriminating
Chiralcel OD-H stationary phase, and rr determined by 19F NMR.
b
Tables of selected results from the reaction optimization
screen at Eli Lilly, complete experimental procedures
The estimated er should be corrected on the basis of the measured rr
given that the minor C3 regioisomer co-elutes with the minor
1
and characterization data, including H, 13C, and 19F
enantiomer (−)-4d in NP-HPLC (see the text for explanations).
c
Reactions carried out at −20 and −78 °C afforded product (+)-4d
NMR spectra, and HPLC chromatograms for er
determination (PDF)
with a similar er.
should be easily deprotonated by Ag2CO3, leading to a
transient silver phosphate catalyst which could further achieve
the halide abstraction and a phase transfer resulting in a chiral
iminium-phosphate pair 6. An iminium/imine equilibrium 6/
6′ might be operating due to the low Brønsted basicity of
imine 6′, likely leading to a H-bonding catalysis for the facial
enantiodiscrimination of imine 6′. The addition of indole 5d
was selected as a model reaction. We tested this approach with
the enantiopure (R)-TRIP phosphoric acid catalyst (10 mol
%) and observed that lower loadings of Ag2CO3 (0.6 equiv)
and molecular sieves (50 wt %) reduced the proportion of the
undesired C2 regioisomer.18 Under the optimized conditions,
(+)-4d was obtained in 85% yield with a 90:10 er and a 91:09
rr. Crystallization of an EtOAc/EtOH solution of 4d by slow
evaporation delivered (+)-4d in the mother liquor as a single
regioisomer with an er of >99.5:0.5. The residual solid was
analyzed and shown to be rich in the C2 regioisomer (80:20
rr), similar to the measured er of 78:22. Taken together, these
results suggest that the enantiodiscrimination induced by the
TRIP catalyst is remarkable at rt (>99% ee), yet further
AUTHOR INFORMATION
Corresponding Author
■
́
Stephane P. Roche − Department of Chemistry and
Biochemistry and Center for Molecular Biology and
Biotechnology, Florida Atlantic University, Boca Raton, Florida
33431, United States; orcid.org/0000-0002-3019-2168;
Email: sroche2@fau.edu
Authors
Guangkuan Zhao − Department of Chemistry and Biochemistry,
Florida Atlantic University, Boca Raton, Florida 33431, United
States
Shyam S. Samanta − Department of Chemistry and
Biochemistry, Florida Atlantic University, Boca Raton, Florida
33431, United States
Jessica Michieletto − Department of Chemistry and
Biochemistry, Florida Atlantic University, Boca Raton, Florida
33431, United States
Complete contact information is available at:
D
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α-amino acid within the sequence of Aib residues. J. Pept. Sci. 2010,
https://pubs.acs.org/10.1021/acs.orglett.0c01895
̈
16, 621. (d) Maisch, D.; Wadhwani, P.; Afonin, S.; Bottcher, C.;
Koksch, B.; Ulrich, A. S. Chemical Labeling Strategy with (R)- and
(S)-Trifluoromethylalanine for Solid State 19F NMR Analysis of
Peptaibols in Membranes. J. Am. Chem. Soc. 2009, 131, 15596. For a
review discussing conformational analysis, see: (e) Tanaka, M. Design
and Synthesis of Chiral α,α-Disubstituted Amino Acids and
Conformational Study of Their Oligopeptides. Chem. Pharm. Bull.
2007, 55, 349.
Author Contributions
S.S.S. and J.M. contributed equally to this work. This project
was conceived by S.P.R. The manuscript was written through
contributions of S.P.R. and G.Z. All authors have approved the
final version of the manuscript.
Notes
̀
(5) (a) Byrne, L.; Sola, J.; Boddaert, T.; Marcelli, T.; Adams, R. W.;
The authors declare no competing financial interest.
Morris, G. A.; Clayden, J. Foldamer-Mediated Remote Stereocontrol:
> 1,60 Asymmetric Induction. Angew. Chem., Int. Ed. 2014, 53, 151.
(b) Karnes, M. A.; Schettler, S. L.; Werner, H. M.; Kurz, A. F.; Horne,
W. S.; Lengyel, G. A. Thermodynamic and Structural Impact of α,α-
Dialkylated Residue Incorporation in a β-Hairpin Peptide. Org. Lett.
2016, 18, 3902. (c) Tomsett, M.; Maffucci, I.; Le Bailly, B. A. F.;
Byrne, L.; Bijvoets, S. M.; Lizio, M. G.; Raftery, J.; Butts, C. P.; Webb,
S. J.; Contini, A.; Clayden, J. A tendril perversion in a helical
oligomer: trapping and characterizing a mobile screw-sense reversal.
Chem. Sci. 2017, 8, 3007.
ACKNOWLEDGMENTS
■
The authors are very grateful for the financial support from the
National Institutes of Health (NIH) (National Institute of
General Medical Sciences Grant R15GM116025 to S.P.R. and
S.S.S. and Grant R21GM132754 to G.Z.). The authors thank
Dr. M. Zaghouani from Florida Atlantic University for
obtaining some preliminary data for this project and Dr. G.
Theodore from Theogen Corp. for manuscript proofreading
and editing. The authors also thank Dr. C. D. Beadle for the
training and mentoring of S.S.S, on the Automated Synthesis
laboratory platform at Eli Lilly. Finally, the authors thank Dr.
K. B. Basso at the Mass Spectrometry Research and Education
Center from the Department of Chemistry at the University of
Florida for the high-resolution mass spectrometry analysis
supported by the NIH (S10 OD021758-01A1).
̈
(6) For the most recent reviews, see: (a) Vogt, H.; Brase, S. Recent
approaches towards the asymmetric synthesis of α,α-disubstituted α-
amino acids. Recent approaches towards the asymmetric synthesis of
α,α-disubstituted α-amino acids. Org. Biomol. Chem. 2007, 5, 406.
(b) Metz, A. E.; Kozlowski, M. C. Recent Advances in Asymmetric
Catalytic Methods for the Formation of Acyclic α,α-Disubstituted α-
́
Amino Acids. J. Org. Chem. 2015, 80, 1. (c) Cativiela, C.; Ordonez,
̃
M.; Viveros-Ceballos, J. L. Stereoselective synthesis of acyclic α,α-
disubstituted α-amino acids derivatives from amino acids templates.
Tetrahedron 2020, 76, 130875.
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