Synthesis of Quaternary -Amino Esters: A Remarkably Broad Substrate Scope in aza-Friedel−Crafts Alkylation.. high stability to metabolic degrada-tion, increased lipophilicity and hyd
Trang 1Synthesis of Quaternary -Amino Esters: A Remarkably
Broad Substrate Scope in aza-Friedel−Crafts Alkylation
Guangkuan Zhao,a Shyam S Samanta,a,‡ Jessica Michieletto,a,‡ and Stéphane P Rochea,b*
a Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431, United States
b Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter, Florida 33458, United States
Supporting Information Placeholder
ABSTRACT: A versatile synthetic protocol of
aza-Friedel−Crafts alkylation has been developed for the
syn-thesis of quaternary -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
coun-teranions liberated during the reaction Taking advantage
of a phase-transfer counteranion/BrØnsted acid pair
mech-anism, a catalytic enantioselective version of the reaction
is also reported
-Disubstituted -amino acids found in carbonaceous
chondritic meteorites1 have been suggested to be at the origin
of symmetry-breaking (up to 20% e.e.) on earth leading
even-tually to the homochirality (single enantiomeric form) of
terres-trial proteinogenic -amino acids.2 Although several aspects of
abiogenesis remain unclear, the role of -disubstituted amino
acids in transferring chirality to other proteinogenic -amino
acids renders these building blocks unique in nature
-Di-substituted “quaternary” -amino acids are also essential motifs
of small molecules and non-ribosomal peptides having all kinds
of biological activity (e.g enzyme inhibitors, ion-channel
blockers or antibiotics).3 Given that these building blocks are
highly constrained compare to monosubstituted -amino acids
(Thorpe−Ingold effect), they impart valuable conformational
ri-gidity when embedded in synthetic molecules.4 Notably,
-disubstituted amino acids exert a remarkable influence on
pep-tide secondary structures, often producing well-defined helical
conformations characteristic of many classes of biomolecules.5
Even so, this class of non-canonical amino acids remain mostly
untapped and their asymmetric syntheses complicated.6 On the
other hand, fluorinated amino acids have recently attracted
con-siderable attention owing to their unique medicinal and
physi-cochemical properties (i.e high stability to metabolic
degrada-tion, increased lipophilicity and hydrogen-bond acceptor
abil-ity).7 Therefore, establishing a scalable and practical (optically
active) synthesis of -disubstituted -trifluoromethyl amino
esters is desirable
In stark contrast to the activation of -imino glycinate A into
iminium B which is one of the most studied and versatile
enan-tioselective strategy to synthesize monosubstituted
non-protein-ogenic -amino esters,8 only few diastereo-9 and
enantioselec-tive10 methods are currently available for the synthesis of
acy-clic -disubstituted -trifluoromethyl amino esters 4 Indeed,
the important electrophilicity of -imino ester 3 results in a
weak Lewis basicity of the imine nitrogen, seemingly contrib-uting to a lack of reactivity towards Lewis and BrØnsted acid catalysts (Scheme 1) Of particular interest, the synthesis -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 -trifluoromethyl
ketoes-ters often limit the choice of N-protecting groups, leading to a
two-step condensation/dehydration with water scavengers via
hemiaminal 1.13 A milder alternative was also devised from the direct aza‐Wittig reaction with phosphazenes to prepare the most moisture-sensitive -imino ester 3.14 The lack of conven-ient synthesis and reactivity of -trifluoromethyl -iminoesters
3 (weak Lewis basicity) combined with a high moisture
sensi-tivity (hydration: 3 1) are factors that largely hindered the
use of this approach To address this methodological gap, we
initially envisioned to avoid the isolation of 3 by studying the
Scheme 1 Challenging Activation of α-Trifluoromethyl Imino Py-ruvate versus the Typical Imino Glycinate Reactivity
Trang 2direct reactivity of chloroaminal 2 Given that glycinyl
chloro-aminals were successfully exploited as effective surrogate of
-imino glycinates A by halogen abstraction and anion-binding
catalysis for carbon–carbon bond formation at the -center,15
we intuitively hypothesized that if a similar maneuver could be
achieved from a tetrasubstituted chloroaminal 2, several classes
of -disubstituted -trifluoromethyl amino esters 4 could
be-come synthetically accessible Herein, we report a highly
prac-tical and general Friedel–Crafts alkylation via a
silver(I)-medi-ated halogen abstraction combined with hydrogen-bonding that
enables the addition of a broad range of arene nucleophiles to
the -trifluoromethyl -iminopyruvate 3
The starting material -trifluoromethyl chloroaminal 2
bear-ing a common N-carbamoyl protectbear-ing group (Cbz) can be
syn-thesized in >90% yield and preserved intact for >8 weeks away
from moisture In collaboration with scientists at Eli Lilly, a
sil-ver(I)-mediated Friedel–Crafts alkylation of chloroaminal 2
was extensively assessed through the screening of solvents,
nu-cleophiles and other reaction parameters on the Automated
Syn-thesis laboratory (ASL) platform.16,17 As a result from this
screen, a couple of silver(I) salts have emerged as efficient
stoi-chiometric reagents capable of generating Friedel–Crafts
prod-ucts cleanly via a putative halogen abstraction mechanism.18
The initial results obtained on the robot synthesizer were further
optimized manually to study by 1H and 19F NMR both reaction
intermediates (e.g 3) and potential byproducts formed during
the reaction (Table 1) Indeed, using Ag2CO3 as promoter, the
halogen abstraction is taking place rather slowly, leading to
about 60% conversion in imine 3 after four hours (entries 1-2)
The reaction carried without desiccant (entry 1) produced imine
3 which rapidly transformed into hemiaminal 1 (~1:1 ratio after
4 hours) leading to >95% yield in 1 after 24 hours The same
reaction in 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
-nucle-ophile arenes (entries 3-4) such as furan 5a (N = 1.33) and 1,3-dimethoxybenzene 5b (N = 2.48).19 In both cases, the desired arylation did not take place as suggested by the large amount of
imine 3 being formed overtime (>95% NMR yield) These
re-sults suggest that arenes 5a-b (N < 2.48) are not nucleophilic
enough to engage in the Friedel–Crafts alkylation with imine 3
Therefore, a stronger nucleophile, N-methyl indole 5c (N =
5.75) was tested under the same reaction conditions, and while
small amounts of imine 3 were observed, the desired product 5a
formed rapidly over the course of the reaction (entry 5: up to 98% NMR yield after 24 hours) To circumvent the lack of re-activity of weak arene nucleophiles and expand the initial suc-cess to a broader scope of arenes, other common silver salts were evaluated.17 While reactions with AgOAc or the more ion-izing AgBF4 and AgSbF6 do not deliver the desired Friedel– Crafts products, several silver salts such as AgNO3 AgOTs and
AgOTf enable the reaction to occur with 5b as nucleophile
Op-timum reactivity is observed with AgOTf leading to the
for-mation of the arylated product 4b in 36% yield (entry 6)
Reac-tion condiReac-tions were further optimized by evaluating several solvents and concentrations.17 Reactions in diethyl ether
showed a cleaner profile, leading to the formation of 4b in 54%
and 71% yields at 0.1 and 0.3 M concentrations respectively (entries 7 and 8) The presence of molecular sieves in addition
to AgOTf did not affect the reaction outcome leading to the full
conversion of 2 after only one hour, but significant amounts of
hemiaminal intermediate 1 persisted (entries 6-8; vide infra)
The fact that imine 3 was not observed in these reactions
sug-gested that AgOTf or the byproduct from the halogen abstrac-tion, TfOH, might be accountable for activating the imine in the Friedel–Crafts alkylation Given the innate sensitivity of the 19F
Table 1 Reaction Optimization a,b
source
Yield b,c
a Reactions were carried out under argon on 2 (0.10 mmol) with arenes 5a-c (2.0
eq.), silver reagent (1.5 eq in Ag(I)) and 30 mg of 4Å MS in CDCl3 (2.0 mL) b
NMR ratios and yields determined on crude reaction mixture by 19F NMR with
C6F6 as internal standard. c NMR yields determined on crude reaction mixture
by 1H NMR with mesitylene as internal standard d Reaction carried without 4Å
MS e The reaction was also carried out at higher temperatures (up to 60 oC) and
the formation of 4b was not observed f Reaction carried in anh Et2O g Reaction
carried at 0.3 M
Scheme 2 A Reaction Profile Monitored by 19
F NMR.a
B Mech-anistic Information from Control Experimentsb
a Crude reactions analyzed by 1H and 19F NMR with C6F6 as internal chemical shift reference set at -161.64 ppm in CDCl3 b Reactions carried
Trang 3nucleus, and the large chemical shift dispersion F(CF3)
ob-served between the starting material 2 (-76.14 ppm), products
4b-c (-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
C6F6 (see Scheme 2A).20 To test our hypothesis of reactivity,
imine 3 was synthesized, isolated (highly hydroscopic 1) and
further reacted with the moderately reactive arene 5b (N = 2.48)
and stoichiometric amounts of either AgOTf, Ag2CO3 or
cata-lytic TfOH (Scheme 2B) Interestingly, no reaction progress
could be detected in presence of silver salts, but the presence of
TfOH in the reaction effectively afforded product 4b in 37%
yield Taken together, these results suggest that the TfOH
by-product formed during the halogen abstraction on 2 plays a
piv-otal role in catalyzing the Friedel–Crafts alkylations.11a
With this piece of mechanistic information, two
silver-medi-ated methods have emerged to cover a broad scope of arene
nu-cleophiles encompassing a) electron–rich substrates using
Ag2CO3 and b) electron–poor arenes by switching reagent to
AgOTf (Scheme 3) For reactions mediated by Ag2CO3 (0.75
eq.), reaction times varied from 18 to 72 hours to deliver
qua-ternary -trifluoromethyl amino esters 5a-b in a range of 55 to
88% yields Interestingly, reactions with furan (N = 1.33) and
2-methyl thiophene (N = 1.35) did not proceed under these
con-ditions even after 3 days, thus delineating the limit of reactivity
of imine 3 in the Friedel–Crafts alkylation Given that 2-methyl
furan (N = 3.61) is reactive enough towards 3, the
electrophilic-ity factor of imine 3 can be roughly estimated to E = -5.00 -
[(3.61 +1.35)/2] = -7.4819b which is in line with some of the
most electrophilic imines reported to date.21 Even so, the
reac-tivity of weaker -nucleophiles (N < 1.35) requires the use
AgOTf (2.0 eq.) to mediate the desired Friedel–Crafts reactions
Under the optimum reaction conditions described in Scheme 3,
reaction times were decreased (< 3 hours) and
-trifluorome-thyl amino esters 4a-b and 4j-o were obtained in an excellent
range 71% to 90% yields
Given the role played by TfOH as H-bond donor, we became interested to evaluate the potential of Ag2CO3 for halogen ab-straction combined with a Brønsted acid catalyst (Table 2).22 In principle, the cooperative action of achiral transition metal with
a chiral Brønsted acid could translate to a chiral counteranion catalysis approach We tested this approach with a relatively acidic enantiopure (R)-TRIP phosphoric acid catalyst and ob-served that the loading in Ag2CO3 played an important role in the achiral background reaction (Table 2, entries 1-2).23 Accord-ingly, (R)-TRIP would be easily deprotonated by Ag2CO3 lead-ing to a transient silver phosphate catalyst which could achieve halogen abstraction and a phase transfer resulting in a chiral
iminium-phosphate pair 6 Due to the low Brønsted basicity of imine 6’ in equilibrium with iminium 6, a H-bonding catalysis
in likely taking place to induce the facial enantiodiscrimination
of arylation Decreasing the amount of molecular sieves also re-duced the proportion of uncatalyzed background reaction lead-ing to reactions with important enantioselectivity in CH2Cl2 and even better in toluene with up to 81% e.e (entries 3-5) The
Friedel–Crafts alkylation with indole 5b was therefore
scaled-up to 1.0 mmol (±)-2 by reducing the TRIP-catalyst loading to
5 mol% to afford product (+)-4b in 70% yield and 75% e.e
which is in line with the original work of Bolm at -78 oC.11 By comparison to the previous literature, the synthetic -amino
es-ter (+)-4b should be of (R)-configuration as depicted
To sum-up, a versatile aza-Friedel−Crafts alkylation has been developed for the synthesis of quaternary -trifluoromethyl-aryl amino esters The combined halogen-abstraction/alkyla-tion process is operahalogen-abstraction/alkyla-tionally simple under ambient condihalogen-abstraction/alkyla-tions, highly efficient, regioselective, and amenable to a remarkable
broad scope of electron–poor and rich arenes (N ≥ -1.18) The
key feature for this reaction is the role associated with the sil-ver(I) salt counteranions During the silver-mediated halogen
Scheme 3 Substrate Scope for the Synthesis of α,α-Disubstituted
amino esters 4a-o by Friedel–Crafts Reactions.a,b
Standard reactions carried on 0.20 mmol scale of 2 (1.0 eq.) with arenes
5a-n (2.0 eq.) in CH2Cl2 (0.2 M) with: a Ag2CO3 (0.75 eq.) or b AgOTf
Re-gioisomers separated by chromatography, see Supporting Information
Table 2 Application to an Enantioselective Catalytic aza-Friedel– Crafts Transformation.a-d
Yield (%)
e.e (%)b
conditions at -20 oC afforded product 4d in 80% e.e d Reaction
scale-up with 1.0 mmol of (±)-2 and 5 mol% of TRIP catalyst
Trang 4abstraction, the silver counteranion is liberated as the
conju-gated BrØnsted acid resulting in an H-bond activation of the
tri-fluoromethyl imine intermediate This putative mechanism was
exploited in a catalytic enantioselective phase-transfer
coun-teranion/BrØnsted acid pair system to achieve an example of
aza-Friedel−Crafts alkylation with high stereoinduction (up to
81% e.e.) Ultimately, we anticipate that the present work will
offer useful new options for the asymmetric synthesis of several
classes of quaternary -trifluoromethyl -amino esters
ASSOCIATED CONTENT
Supporting Information
Tables of selected results from the reaction optimization screen at
Eli Lilly is reported Complete experimental procedures and
char-acterization data including 1H, 13C and 19F NMR spectra, as well as
HPLC chromatograms for e.e determination are available online
AUTHOR INFORMATION
Corresponding Author
* Correspondence should be addressed to S.P.R Email:
sroche2@fau.edu
Author Contributions
This project was conceived by S.P.R The manuscript was written
through contributions of S.P.R and G.Z All authors have given
approval to the final version of the manuscript
‡These two authors contributed equally to the work
ACKNOWLEDGMENT
We are very grateful for the financial support from the National
Institutes of Health (NIGMS Grant: R15GM116025 to S.P.R and
S.S.S., and Grant: R21GM132754 to G.Z.) The authors thank Dr
Mehdi Zaghouani for obtaining some preliminary data on this
pro-ject The authors also thank Dr Kari B Basso at the Mass
Spec-trometry 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)
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