Visible-Light-Mediated Carbonyl Alkylative Amination to All-Alkyl α-Tertiary Amino Acid Derivatives

Article abstract of DOI:10.1021/jacs.0c12162

The all-alkyl α-tertiary amino acid scaffold represents an important structural feature in many biologically and pharmaceutically relevant molecules. Syntheses of this class of molecule, however, often involve multiple steps and require activating auxiliary groups on the nitrogen atom or tailored building blocks. Here, we report a straightforward, single-step, and modular methodology for the synthesis of all-alkyl α-tertiary amino esters. This new strategy uses visible light and a silane reductant to bring about a carbonyl alkylative amination reaction that combines a wide range of primary amines, α-ketoesters, and alkyl iodides to form functionally diverse all-alkyl α-tertiary amino esters. Br?nsted acid-mediated in situ condensation of primary amine and α-ketoester delivers the corresponding ketiminium species, which undergoes rapid 1,2-addition of an alkyl radical (generated from an alkyl iodide by the action of visible light and silane reductant) to form an aminium radical cation. Upon a polarity-matched and irreversible hydrogen atom transfer from electron rich silane, the electrophilic aminium radical cation is converted to an all-alkyl α-tertiary amino ester product. The benign nature of this process allows for broad scope in all three components and generates structurally and functionally diverse suite of α-tertiary amino esters that will likely have widespread use in academic and industrial settings.

Full text of DOI:10.1021/jacs.0c12162

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Visible-Light-Mediated Carbonyl Alkylative Amination to All-Alkyl
α‑Tertiary Amino Acid Derivatives
J. Henry Blackwell, Roopender Kumar, and Matthew J. Gaunt*
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ABSTRACT: The all-alkyl α-tertiary amino acid scaffold represents an important structural feature in many biologically and
pharmaceutically relevant molecules. Syntheses of this class of molecule, however, often involve multiple steps and require activating
auxiliary groups on the nitrogen atom or tailored building blocks. Here, we report a straightforward, single-step, and modular
methodology for the synthesis of all-alkyl α-tertiary amino esters. This new strategy uses visible light and a silane reductant to bring
about a carbonyl alkylative amination reaction that combines a wide range of primary amines, α-ketoesters, and alkyl iodides to form
functionally diverse all-alkyl α-tertiary amino esters. Brønsted acid-mediated in situ condensation of primary amine and α-ketoester
delivers the corresponding ketiminium species, which undergoes rapid 1,2-addition of an alkyl radical (generated from an alkyl
iodide by the action of visible light and silane reductant) to form an aminium radical cation. Upon a polarity-matched and
irreversible hydrogen atom transfer from electron rich silane, the electrophilic aminium radical cation is converted to an all-alkyl α-
tertiary amino ester product. The benign nature of this process allows for broad scope in all three components and generates
structurally and functionally diverse suite of α-tertiary amino esters that will likely have widespread use in academic and industrial
settings.
methodologies that allow streamlined access to α-tertiary
amino acids has been an important challenge for chemical
synthesis.3
INTRODUCTION
■
Unnatural amino acids and their derivatives constitute an
important class of molecule, being pervasive as key motifs in a
wide range of pharmaceutical agents, agrochemicals, and
biologically relevant natural products (Figure 1A).1 As a
subset of these bifunctional scaffolds, α-tertiary amino acids
(ATAAs) have emerged as a valuable variant of these
molecules due to a number of distinct properties arising
from their fully substituted carbon center. ATAAs, when
incorporated into polypeptides or peptidomimetics, can have a
dramatic effect on the physical properties of the molecule by
influencing conformation, lipophilicity, and proteolytic stabil-
ity.2 Beyond the amino acid functionality, the two non-
hydrogen groups are projected along well-defined exit vectors,
which can be exploited as a useful feature in the design of small
molecules that interact with biological receptors. Finally, the
intrinsic functionalities of ATAAs make them versatile
precursors for the synthesis of more architecturally complex
compounds. As a consequence, the development of new
Over the past 50 years a range of methodologies have been
developed for the synthesis of ATAAs and can be divided
(mainly) into four direct strategic bond disconnection
strategies (Figure 1B). By far the most frequently adopted
strategy has involved bond disconnection of the ATAA back to
an enolate equivalent and a carbon electrophile (Figure 1B,
strategy 1). A benchmark protocol for this bond formation has
been the coupling of enolates of Schiff-base-derived α-amino
esters with reactive or activated carbon electrophiles.4,5 More
Received: November 20, 2020
Published: January 11, 2021
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Figure 1. (A) Examples of ATAA-derived pharmaceutically relevant molecule. (B) Strategies 1−4 for the synthesis of ATAAs. (C) Alkyl-
organometallic additions to imine derivatives of α-keto esters: the problems arising from competitive deprotonation and regioselective addition
pathways. (D) Alkyl-radical additions to imine derivatives of α-ketoesters. (E) Carbonyl alkylative amination as a straightforward method for the
synthesis of all-alkyl ATAEs.
recently, a wide range of transformations have been reported
with enolate-type intermediates of azlactones in combination
with Michael-type additions or with metal-activated π-electro-
philes.6 Notably, many of these reactions can be rendered
enantioselective through the action of asymmetric catalysts.
Disconnection through the C−N bond of ATAAs most
conveniently reveals an enolate precursor (such as a malonate
or enamine) and a nitrogen-based π-acceptor, such as a
diimide (strategy 2).7,8 Syntheses based on addition of acyl
anion equivalents to ketimine derivatives have also proved to
be effective for the preparation of ATAAs (strategy 3).
Strecker-type reactions using cyanide anions to react with
activated imine derivatives are the most frequently adopted
variants of this transformation and can be rendered
enantioselective.9 Alternative approaches using 2-lithiated
furans or carbamoyl anions as precursors to the carboxylate
equivalent of ATAAs have also found success.10 Finally,
through a dipole-reversed disconnection variant of strategy 1,
the addition of organometallic nucleophiles into imine
derivatives of α-ketoesters can also produce ATAAs (strategy
4).11 In addition to these direct methods for the synthesis of
ATAAs, there exists a number of indirect methods involving
the addition of alkyl groups to more highly functionalized
substrates, followed by a structural rearrangement to form the
fully substituted amino acid framework.12
Many of the protocols summarized in Figure 1B require the
deployment of activating nitrogen auxiliaries, bespoke sub-
strates, or the inclusion of reactivity-inducing, but scope-
limiting, functionality in one or more of the reaction
components. This means that while the preparation of many
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ATAAs has been served by methods based on these
disconnection strategies, a number of additional chemical
steps are needed to prepare the reactive “high-energy” building
blocks, such as activated imine derivatives or nitrogen
electrophiles, and to convert products into the target
molecules. Furthermore, there are certain classes of ATAAs
to which direct access is nontrivial via these methods. All-alkyl
ATAAs (N-alkyl α,α′-dialkyl-amino acids) are difficult to
access via concise synthetic sequences, and yet derivatives of
these molecules are often very important pharmaceutical
candidates, for example, as arginase inhibitors (Figure 1A).13
The synthesis of all-alkyl ATAAs is most commonly
achieved via the classical O’Donnell-type Schiff-base-enolate
alkylation (strategy 1), but generally this protocol still requires
activated carbon electrophiles for a successful reaction. To the
best of our knowledge, no general examples exist for the C−N
bond formation between nitrogen electrophiles and dialkyl-
substituted enolate equivalents (see strategy 2) or acyl anion
additions to dialkyl-ketimine derivatives (see strategy 3).
Transformations based on strategy 4 in Figure 1, however,
would offer a seemingly straightforward synthesis of all-alkyl
ATAAs. While the addition of alkyl-organometallics to the N-
alkylimine of an alkyl-substituted α-ketoester derivative
appears to represent a logical approach to all-alkyl ATAAs,
methods for the successful execution of the strategy (4) toward
these targets are restricted. The C−H bonds adjacent to the
imine motif are acidic and are readily deprotonated by the
basic organometallic reagent (Figure 1C). Furthermore,
controlling the regioselectivity of the addition step is
complicated by the viability of an alternative pathway wherein
the alkyl nucleophile adds to the N atom of the imine motif to
form the corresponding enolate.14 As a result, only a very
limited number of examples exist for the addition of alkyl-
organometallics reagents to imine derivatives of α-ketoesters,
exemplified by the Zr-catalyzed method of Snapper and
Hoveyda, which sees dimethyl or diethyl zinc reagents add,
enantioselectively, to ortho-anisidine-derived α-iminoesters.11c
As a result, there remains a need to develop flexible,
multicomponent methodologies for the synthesis of all-alkyl
ATAAs from α-ketoester that exploit readily available alkyl
nucleophiles and primary amine feedstocks in order to expedite
further exploration of the chemical space around this
important motif.
readily available primary amines, α-ketoesters, and alkyl iodides
to form a wide range of all-alkyl α-tertiary amino esters in a
single step (Figure 1E). The potential efficacy of such a
strategy is evidenced by the modular nature of this multi-
component transformation that would exploit the combination
of sets of established building blocks to access new product
classes, which would require multistep syntheses using other
methods. Here, we report the successful realization of this idea
through the design, development, and demonstration of a new
visible-light-mediated carbonyl alkylative amination method
for the synthesis of all-alkyl α-tertiary amino esters (ATAEs).
Factors that distinguish this method from previously
documented transformations are its wide substrate scope
within each component, the mild reaction conditions, and the
use of abundant building blocks requiring no activating or
stabilizing auxiliary. Given the proclivity for C(sp3)-rich polar
scaffolds in pharmaceuticals candidates, we expect that this
method will be of significant interest to practitioners of
synthetic and medicinal chemistry in both academic and
pharmaceutical industry settings.
RESULTS AND DISCUSSION
■
Recently, our group reported a general method for 1,2-addition
of alkyl radicals to in situ generated alkyl-substituted
aldiminium ions through a process that was facilitated by
visible-light irradiation (Figure 2A).17 A critical factor in the
Given the limitations of basic organometallic reagents in
reactions with substrates displaying acidic C−H bonds, interest
has arisen in the addition of nucleophilic, but importantly
charge neutral, alkyl radicals to activated imine derivatives.
While radical addition to the carbon nitrogen double bond of
N-activated glyoxalate-derived aldimines to make α-amino acid
precursors is relatively well established,15 only a limited
number of analogous transformations have been reported for
imine derivatives of α-ketoesters to generate ATAAs (Figure
1D).16 Generally, these methodologies rely on the use of an
auxiliary group on the N-atom of the imine derivative in order
to both activate the electrophile and stabilize the resulting
aminium-derived radical. Furthermore, reactions of this type
have only been demonstrated on simple α-ketoesters, such as
ethyl pyruvate. Together, these stringent requirements
significantly limit the modularity, efficiency, and hence, utility
in the context of all-alkyl ATAA synthesis.
Figure 2. Initial proposal for CAA to all-alkyl ATAEs.
successful execution of carbonyl alkylative amination (CAA)
proved to be the rapid termination of the process by hydrogen
atom transfer (HAT) between an intermediate aminium
radical cation and tris(trimethylsilyl)silane [(Me3Si)3Si−H].
Notably, ketones proved recalcitrant to the carbonyl alkylative
amination protocol, presumably because the condensation of
secondary amine with the more sterically hindered carbonyl
group of the ketone was slow compared to the other
competing processes and that all-alkyl ketiminium ions are
We reasoned that leveraging the intuitive nature of the bond
disconnection outlined in strategy 4 with a radical carbonyl
alkylative amination (CAA) process would effectively combine
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inherently less electrophilic than their aldehyde counterparts as
a result of their four inductively donating alkyl substituents.
With these limitations in mind and the overarching goal of
developing a method for the synthesis of all-alkyl ATAEs, we
reasoned that combining the use of primary amines with more
electrophilic α-ketoesters and an activating Brønsted acid
might circumvent the reactivity problems precluding our
inability to add alkyl radicals to ketiminium ions (Figure 2B).
Imine formation (to Int I) and subsequent addition of the alkyl
radical (formed from alkyl iodide via visible-light-mediated
initiation) should be promoted in this design plan.
Furthermore, the hydridic (Me3Si)3Si−H would be polarity-
matched to the unstabilized and, hence, reactive secondary N-
alkyl aminium radical cation (ARC, Int II) emanating from the
addition step, enabling a favorable HAT to form the product.
Investigations to form N-alkyl ATAEs began by employing
the reaction conditions that had proved successful in our
previously reported visible-light-mediated carbonyl alkylative
amination protocol.17 Surprisingly, visible-light irradiation of a
reaction deploying (Me3Si)3Si−H, TBS−OTf, and 4 Å
molecular sieves to combine butylamine 1a, α-ketoester 2a,
and isopropyl iodide 3a failed to produce any of the desired
product (Table 1, entry 1); modest reaction was observed on
(Me3Si)3Si−H in orchestrating a successful reaction is likely
linked to its ability to perform a kinetically and thermodynami-
cally favored HAT to the reactive secondary N-alkyl aminium
radical cation (Figure 2B, Int II) and contrasts with previously
reported radical additions to activated imine derivatives
adorned with auxiliary groups, which consequently stabilize
the corresponding aminium radical cation and require more
forcing conditions to terminate the process. As such, a visible-
light-enabled carbonyl alkylative amination to all-alkyl-ATAEs
using (Me3Si)3Si−H obviates the need for auxiliary groups on
the nitrogen atom of the imine electrophile and is directly
responsible for the mild and straightforward conditions that
lead to a successful reaction.
Equipped with a set of optimized reaction conditions, the
scope of the carbonyl alkylative amination to all-alkyl ATAEs
was first explored by varying the amine component using α-
ketoester 2a and isopropyl iodide 3a as representative coupling
partners. A variety of primary amines, containing a range of
different structural and functional features, were found to be
highly effective in the reaction (Figure 3, 4a−4r). In addition
to deployment of butylamine 1a, the primary amine
component could incorporate cyclic hydrocarbon substituents
with the reaction providing good yields throughout (4b−4f).
Amines with linear substituents displaying cyclopropyl, benzyl
and distal electron rich arene and heteroarenes, ether, and
acetal features produced the all-alkyl ATAEs in good to
moderate yields (4i−4n). The benzylamine example provides a
product that can be readily transformed into the corresponding
primary amine and will be useful for downstream diversifica-
tion, for example, to non-alkyl N-substituted ATAEs (Figure
1A). A selection of α-branched alkylamines substituted with
saturated heterocyclic groups also performed well as coupling
partners (4o−4r). Of particular note was the deployment of a
N-Boc-protected piperidine-derived primary amine, which gave
an orthogonally protected ATAE suitable for further
functionalization using classical transformations. We identified
some primary amines that generated product but in low yield
(4s−4x). In particular, reactions with aniline or alkyl amines
with proximal electron withdrawing groups or amines bearing
electron deficient aromatic moieties resulted in byproduct
formation arising from reductive amination. The use of
methylamine proved to be problematic due to difficulties
associated with handling a gaseous reagent on a laboratory
scale; unfortunately, the use of the commercial hydrochloride
salt was complicated by its insolubility in the reaction solvent
and resulted in no reaction.
We also noted that reactions involving amines displaying
proximal basic sites, such as pendant tertiary amine, failed to
record any product formation, most likely due to the electron
withdrawing effects of the, inevitably, protonated functionality
formed under the reaction conditions.
Next, we examined the preliminary scope in the nature of
the α-ketoester component. First, an efficient protocol for the
assembly of these substrates was required. By adapting
procedures reported by the groups of Overman18a and Yo
and Wang,18b we were able to effectively render these versatile
building blocks readily available by following a straightforward
two-step method starting from a representative aldehyde (5b)
and an α-(OTBS)-substituted Wadsworth−Horner−Emmons
reagent (6). A variety of aldehydes were smoothly transformed
to the trisubstituted enol silane in good yields. Treatment of
this intermediate with CsF and 1 equiv of acetic acid afforded
Table 1. Selected Optimization for CAA to All-Alkyl ATAEs
a
R3Si−H (3 equiv)
acid (equiv)
solvent yield 4a, %
1
2
3
4
5
6
7
8
9
10
11
12
13
(Me3Si)3Si−H
(Me3Si)3Si−H
(Me3Si)3Si−H
(Me3Si)3Si−H
(Me3Si)3Si−H
Et3Si−H
TBS-OTf (1 equiv)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
DCE
0
15
39
53
85
0
0
0
28
61
0
EtCO2H (0.2 equiv)
EtCO2H (0.2 equiv)
EtCO2H (1 equiv)
EtCO2H (1 equiv)
EtCO2H (1 equiv)
EtCO2H (1 equiv)
EtCO2H (1 equiv)
EtCO2H (1 equiv)
EtCO2H (1 equiv)
EtCO2H (1 equiv)
EtCO2H (1 equiv)
b
b
Ph3Si−H
PhSiH3
(Me3Si)3Si−H
(Me3Si)3Si−H
(Me3Si)3Si−H
(Me3Si)3Si−H
(Me3Si)3Si−H
MeOH
EtOAc
THF
15
10
a
Yields were determined by 1H NMR using 1,1,2,2-tetrachloroethane
as internal standard. Primary amine 1a, α-ketoester 2a, and EtCO2H
were stirred for 3 h before the addition of isopropyl iodide 3a and
(Me3Si)3Si−H, and iradiation was with visible light.
b
omission of TBS−OTf (entry 2). On testing alternative means
to promote the reaction, the combination of 0.2 equiv of
EtCO2H, 4 Å molecular sieves, and 3 equiv of (Me3Si)3Si−H
was found to affect CAA between 1a, 2a. and 3a to give a 39%
yield of ATAE 4a, when irradiated with a 40 W Kessel lamp for
6 h (entry 3); the addition of EtCO2H was believed to
facilitate imine formation. An assessment of the reaction
parameters ultimately revealed an optimal procedure that
involved stirring a dichloromethane solution of primary amine
1a (1 equiv), α-ketoester 2a (2 equiv), and EtCO2H (1 equiv)
for 3 h before adding isopropyl iodide 3a (3 equiv) and
(Me3Si)3Si−H (3 equiv) and reaction under visible-light
1
irradiation for 6 h, which produced an 85% yield (by H
NMR) of the desired ATAE 4a (entry 5). The role of
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Figure 3. Scope of the carbonyl alkylative amination to ATAEs in the primary amine component.
Figure 4. (A) Synthesis of the α-ketoester component based on a modified literature protocol (yield over two steps from aldehyde).18 *Substrate
was prepared by addition of the corresponding Grignard reagent into diethyl oxalate.18b (B) Scope of the CAA to ATAEs in the α-ketoester
component.
the desired α-ketoesters (Figure 4A, 2b−d,f,g) in synthetically
We were pleased to find that a range of α-ketoesters worked
well in the CAA reaction when assessed using n-butylamine 1a
useful yields.18a
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Figure 5. (A) Scope of the carbonyl alkylative amination to ATAEs in the 2° alkyl iodide component; *0.2 equiv of EtCO2H and 1 equiv of TBS-
OTf employed. (B) Scope of the carbonyl alkylative amination to ATAEs in the 1° and 3° alkyl iodide components.
Table 2. Control Experiments
entry
deviation from standard
yield (%)
entry
deviation from standard
yield (%)
1
2
3
4
no light
0
0
0
5
6
7
8
no light, stirring at 80 °C
with 1 equiv of TEMPO
long pass filter (>420 nm)
long pass filter (>450 nm)
0
0
60
0
no (Me3Si)3Si−H
under air and no light
no propionic acid
15
and isopropyl iodide 3a as representative coupling partners
(Figure 4B, 7a−7g). Notable features of this study included
the suitability of saturated heterocyclic substituents in the α-
ketoester component, which provide versatile products
displaying structural and functional features that will be useful
for the synthesis of small bioactive molecules to interact with
biological receptors. Interestingly, the use of the prolinyl-
derived α-ketoester led to the observation of a 4:1
diastereomeric ratio of the products from the CAA reaction
(7f). The diastereoselectivity observed in this reaction is
surprising given that the controlling stereogenicity is in the β-
position to reacting center, suggesting that the prolinyl-N-Boc
substitutent may engage the protonated imine through an
eight-membered ring hydrogen bonding interaction, leading to
facial selectivity in the cyclic species during the radical
addition. We also found that ethyl pyruvate worked in the
reaction to form the corresponding ATAE (7g), although the
yield with this α-ketoester was lower. We believe the high
enamine content of the corresponding α-iminoesters may be
compromising the reactivity of this substrate. Still, the
deployment of this substrate provides immediate access to
the methyl-substituted ATAE framework that frequently
appears in pharmaceutically relevant compounds.1 Further-
more, low yields (less than 10% assay yield) of the desired
product were obtained when β-branched α-ketoesters were
employed.
The scope of the reaction with respect to the alkyl iodide
was assessed using n-butylamine 1a and α-ketoester 2a.
Secondary alkyl iodides based on saturated cyclic and
heterocyclic groups were smoothly coupled under the
optimized reaction conditions to deliver the all-alkyl ATAE
products in good yields (Figure 5A, 8a−8f). However, when
primary and tertiary iodides were subjected to these
conditions, diminished conversions to products were observed.
In the case of primary iodides, the decreased conversion of the
reaction was deemed to be a result of the decreased
nucleophilicity of primary radicals relative to secondary alkyl
radicals.19 With tertiary alkyl iodides, the increased steric
demands on the addition were thought to be detrimental to the
yield. Therefore, for reactions employing these more
challenging substrate classes, modifications to the optimized
conditions were identified: a solution of butylamine 1a (1
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Figure 6. (A) Mechanistic experiments intercepting the aminium radical cation intermediate. (B) Deuterium labeling experiments. (C) Plausible
mechanism based on exploratory experiments.
equiv), α-ketoester 2a (2 equiv), and EtCO2H (0.2 equiv) in
dichloromethane was stirred for 4 h before the addition of the
iodide 3a (3 equiv) and TBS-OTf (1 equiv) and irradiation
with visible light for 6 h (Figure 5B). We believe that the use of
TBS-OTf increases the reactivity of the ketiminium ion
through counteranion exchange, overcoming the challenges
described previously in regard to the addition of the less
reactive alkyl radicals (vida supra). As a result, high
conversions could be obtained for primary and tertiary alkyl
halides displaying a variety of structural and functional features
(Figure 5B, 8g−8m). Notably, the use of tertiary alkyl halides
delivers all-alkyl ATAEs with vicinal fully substituted centers,
which are difficult to access by other methods.
Having established a broad scope for the synthesis of all-
alkyl ATAEs, attention was focused on the mechanism of this
CAA reaction. Control experiments established visible light
and (Me3Si)3Si−H as essential components of the reaction
(Table 2, entries 1 and 2). Moreover, since oxygen is known to
generate the silyl radical,20 we tested the efficiency of the
reaction under air in the absence of light: no product was
observed, underscoring the pivotal role played by visible light
(entry 3). The reaction yield was greatly diminished when
EtCO2H was omitted, supporting its previously hypothesized
role in aiding imine formation and activation via protonation
(entry 4). An experiment conducted in the absence of light,
but at 80 °C, showed no reaction indicating that a thermal
radical initiation pathway was not operational (entry 5). The
intermediacy of a free radical was supported by a TEMPO
trapping experiment, which resulted in complete inhibition of
CAA (entry 6). A more detailed analysis of the role of visible
light revealed the reaction still proceeded with high conversion
to product when a 420 nm bandpass filter was employed (entry
7), suggesting that the reaction is not initiated by traces of UV-
light mediating homolysis of the carbon−iodine bond.17,21
Interestingly, the reaction did not proceed when a 455 nm
wavelength bandpass filter was employed (entry 8), indicating
that a narrow range of light is required in order to facilitate
initiation. This feature is in contrast to observations in our
previous work.17 While the nature of the initiation of the
radical chain is not well understood, we believe that it is
analogous to the mode of initiation disclosed in our previous
report; visible light activates an EDA-type complex between
enamine, alkyl halide, and (Me3Si)3Si−H. However, it should
be noted that in this case we were unable to observe the
relevant bathochromic shift when studying combinations of the
relevant reaction components, possibly due to the low
concentration of the active complex. This, of course, could
suggest that the initiation operates by an alternative, as yet
unknown, pathway.
Further evidence for the proposed radical addition to a
ketiminium ion was accrued from a free-radical clock
experiment (Figure 6A). The reaction of cyclopropylmethyl
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Figure 7. Application of CAA toward the concise and flexible synthesis of ATAE-derived arginase inhibitor analogues.
iodide 3b with 1b and 2a provided the expected terminal
alkene-derived product 9 in modest yield, reflecting the β-
scission of the cyclopropylmethyl radical in advance of addition
to the iminium ion. However, we also observed the formation
of two diastereomers of a trisubstituted pyrrolidine product,
10a and 10b (2:1 diastereomeric ratio). These products are
consistent with a mechanism first involving radical addition of
the linear alkenyl primary radical (from β-scission of the
cyclopropylmethyl radical) to the ketiminium ion to form the
corresponding aminium radical cation (Int I). This inter-
mediate would then engage the pendent terminal alkene via 5-
exo-trig ring closure delivering the incipient exocyclic radical,
which then undergoes HAT with (Me3Si)3Si−H.22 The radical
nature of the ring closure and subsequent HAT was confirmed
by a reaction employing (Me3Si)3Si−D, which showed
deuterium incorporation into the methyl group of each
diastereomer of the pyrrolidine product (Figure 6B, d-10a
and d-10b) (see Supporting Information for full details).23
Taken together, these experiments suggest that because no
intact cyclopropyl product was observed, the rate of addition of
the alkyl radical to the ketiminium ion is slower than the rate of
opening of the cyclopropylmethyl radical (k = 1 × 108 s−1 at 25
°C).24 Furthermore, the observed ratio of linear to cyclized
product (1:3) suggests that the rate of HAT from (Me3Si)3Si−
H to the aminium radical cation is comparable to that of the 5-
exo-trig ring closure of an aminium radical cation onto a
pendant alkene (k ≈ 107−108 M−1 s−1).25 Overall, we believe
that these data support a mechanism whereby radical addition
to intermediate ketiminium delivers N-centered radical cation
(Int III), followed by rapid HAT to (Me3Si)3Si−H. This
delivers the ammonium salt of the desired ATAE as well as the
(Me3Si)3Si· radical, which propagates the radical chain (Figure
6C).
molecules.26 Selecting two primary amines and two α-
ketoesters, we were able to use the CAA reaction to combine
these building blocks with 4-(Bpin)-butyl iodide (to 11a) and
5-(Bpin)-butyl iodide (to 11b−11d) to generate analogues of
all-alkyl ω-borono-α-amino ester scaffolds. Four highly
functionalized molecules, all containing the core components
of arginase inhibitors, were produced in a modest but
synthetically useful yield in a single step from the readily
available precursors.
CONCLUSION
■
In summary, we have developed a modular protocol for the
synthesis of α-tertiary amino ester derivatives. This procedure
employs readily accessible or commercially available feedstocks
to deliver a suite of functionally and structurally diverse
products, which would otherwise be difficult to access under
such mild conditions in a single synthetic sequence. Our newly
developed ATAE protocol addresses many of the issues
associated with the use of high energy auxiliary-activated imine
derivatives and tailored intermediates that facilitate reactivity
and offers a practical one step protocol for rapid and
straightforward assembly of these important molecules.
Importantly, the visible-light-mediated CAA protocol requires
neither photocatalyst nor chemical initiators, rendering the
process exceptionally mild, and enables a broad scope in all
three components.6,16,22b Though this CAA process was found
to be robust in each reaction components, certain limitations
were identified: amines bearing electron withdrawing groups
adjacent to the nitrogen center were found to undergo
significant levels of reductive amination; highly reactive alkyl
radicals, such as that generated from iodomethane, were found
to undergo rapid hydrogen atom transfer with (Me3Si)3Si−H,
leading to competitive dehydrohalogenation; and β-branched
α-ketoesters returned low yields of product, presumably due to
deactivating steric hindrance around the iminium ion.
Although in some of these cases, synthetic usable yields were
returned, our future studies will focus on addressing these
problems toward the development of a more general process.
Despite these limitations, the broad utility of the reaction is
still demonstrated by a substantial substrate scope that
Finally, we sought to highlight the utility of the newly
developed radical alkylation through the synthesis of all-alkyl
ATAEs that resemble established ω-borono-α-amino acid
arginase inhibitors (Figure 7).13 Generally, the synthesis of
these important compounds relies on time-consuming multi-
step procedures, which also limits the modularity and flexibility
that would ideally be inherent in approaches to such
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generates highly functionalized and synthetically versatile
ATAEs, which would be difficult to prepare by other methods.
From a mechanistic perspective, radical clock and deuterium
labeling experiments suggest the intermediacy of an aminium
radical cation as a productive intermediate in this carbonyl
alkylative amination but also exemplify its innate reactivity
toward pendant π-acceptors. Despite the low yields observed
for 5-exo trig cyclization of aminium radical cation onto a
pendent alkene, this transformation represents a rare example
of the multicomponent assembly of a complex pyrrolidine
scaffold, which has the potential to offer flexible access to this
pharmaceutically relevant azacyclic scaffold. Moreover, we
were able to display the utility of this transformation by the
rapid assembly of analogues of an important class of arginase
inhibitor. As such, we anticipate that this platform will facilitate
modular, rapid access to this privileged class of hindered
unnatural amino acids, which are likely to be of interest to
practitioners of synthetic and medicinal chemistry in academic
and industrial settings.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c12162.
Experimental procedures and compound characteriza-
tion (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Matthew J. Gaunt − Department of Chemistry, University of
Cambridge, Cambridge CB2 1EW, United Kingdom;
orcid.org/0000-0002-7214-608X; Email: mjg32@
cam.ac.uk
Authors
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J. Henry Blackwell − Department of Chemistry, University of
Cambridge, Cambridge CB2 1EW, United Kingdom;
orcid.org/0000-0003-2003-6660
Roopender Kumar − Department of Chemistry, University of
Cambridge, Cambridge CB2 1EW, United Kingdom;
orcid.org/0000-0001-5454-0537
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c12162
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Funding
Funding sources are the following: AstraZeneca for a
studentship to J.H.B. through the AstraZeneca Cambridge
Ph.D. Program; Swiss National Science Foundation (Grant
P400P2_186730) for a fellowship to R.K.; The Royal Society
for a Wolfson Merit Award to M.J.G.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are grateful for useful discussions with Dr. Charlene Fallan
(AstraZeneca).
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Journal of the American Chemical Society
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Article
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Amino Acid-Based Arginase Inhibitors via the Ugi Reaction. Bioorg.
Med. Chem. Lett. 2013, 23, 4837−4841.
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https://dx.doi.org/10.1021/jacs.0c12162
J. Am. Chem. Soc. 2021, 143, 1598−1609