Visible-Light-Mediated, Chemo- and Stereoselective Radical Process for the Synthesis of C-Glycoamino Acids

Article abstract of DOI:10.1021/acs.orglett.9b00724

An approach for efficient synthesis of C-glycosyl amino acids is described. Different from typical photoredox-catalyzed reactions of imines, the new process follows a pathway in which α-imino esters serve as electrophiles in chemoselective addition reactions with nucleophilic glycosyl radicals. The process is highlighted by the mild nature of the reaction conditions, the highly stereoselectivity attending C-C bond formation, and its applicability to C-glycosylations using both armed and disarmed pentose and hexose derivatives.

Full text of DOI:10.1021/acs.orglett.9b00724

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Mediated, Chemo- and Stereoselective Radical Process
for the Synthesis of C‑Glycoamino Acids
Peng Ji,† Yueteng Zhang,† Yongyi Wei,† He Huang,† Wenbo Hu,† Patrick A. Mariano,*,‡
and Wei Wang*,†
†Department of Pharmacology and Toxicology and BIO5 Institute, University of Arizona, Tucson, Arizona 85721, United States
‡Chemedit Co., 4601 North Lamar Boulevard, Austin, Texas 78751, United States
S
* Supporting Information
ABSTRACT: An approach for efficient synthesis of C-
glycosyl amino acids is described. Different from typical
photoredox-catalyzed reactions of imines, the new process
follows a pathway in which α-imino esters serve as
electrophiles in chemoselective addition reactions with
nucleophilic glycosyl radicals. The process is highlighted by
the mild nature of the reaction conditions, the highly
stereoselectivity attending C−C bond formation, and its
applicability to C-glycosylations using both armed and disarmed pentose and hexose derivatives.
Scheme 1. Representative Natural Products Containing C-
Glycoamino Acids and Traditional and New Approaches for
Synthesis of C-Glycosyl Amino Acids
C-Glycosyl amino acids are a unique class of compounds
widely present in nature that have an enormously diverse array
of biological properties.1 Notable examples of substances in
this family include the peptidyl nucleoside antibiotics
amipurimycin, polyoxins, and nikkomycin, which have potent
antimycotic activities against various human pathogenic fungi
and bacteria (Scheme 1A).2,3 More pronounced impacts of C-
glycosyl amino acids arise from their broad application in
biomedical and drug discovery studies of glycopeptides and
proteins.4,5 Finally, the presence of C−C linkages to anomeric
centers gives members of this family higher metabolic
stabilities and lipophilicities than those of O−C bond-
containing counterparts. In many instances, this feature leads
to improved biological activities, membrane permeabilities, and
bioavailabilities.4,5
In routes developed to date for the synthesis of C-glycosyl
amino acids, installation of an amino acid moiety onto a
glycosyl framework has relied on the use of well-established α-
amino acid synthesis strategies, such as alkylation of α-amino
acid equivalents, Strecker reactions, hydrogenation of dehy-
droamino acids, and multicomponent Ugi reactions with sugar
derivatives (Scheme 1B).6 In addition, de novo synthesis of C-
glycosyl amino acids has been shown to be a viable approach to
access unnatural substances in this family. Although often
reliable, these polar bond disconnection based methods are
inherently limited by a number of factors including the need
for lengthy synthetic sequences, harsh reaction conditions,
and/or a limited substrate scope.7
As part of a recent program to develop radical-based cross-
coupling processes for selective C−C bond formation,8 we
envisaged that an open-shell pathway might be applicable to
the concise synthesis of C-glycosyl amino acids under mild
conditions.9,10 Specifically, we believed that addition of
glycosyl radicals, generated from appropriate glycosyl pre-
cursors, to readily available α-imino esters would constitute a
viable approach to the preparation of these substances
(Scheme 1C). To our knowledge, a strategy of this type has
Received: February 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00724
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Letter
not been documented previously. However, we were aware
oxalates17 do not serve as efficient glycosyl radical precursors in
visible-light and PS-promoted reactions with α-imino ethyl
ester 2a (see Table S1). As expected, direct reduction of
glycosyl derivatives and/or the imine occurs in these cases.
We turned our attention on N-hydroxyphthalimide-derived
RAEs.13,14 Based on these earlier observations, we envisioned
that incorporation of N-hydroxytetrachlorophthalimide esters
into sugars would give rise to glycosyl RAEs (1) that might
serve as a new class of glycosyl radical progenitors (Scheme 3).
́
that Gagne had developed a related yet indirect approach to C-
glycosyl amino acids (Scheme 1D)10 in which C-glycosyl
aldehydes, serving as key intermediates, are generated by using
[Ru(dmb)3]2+-photocatalyzed radical addition reactions of
glycosyl bromide derived radicals to acrolein. It is noteworthy
that a non-photochemical process mediated by Et3B/O2 was
developed using α-alkoxyacyl tellurides and glyoxylic oxime
ether as the key reagents.9b
The role of imines in photoredox-catalyzed reactions11,12 has
typically been in the context of their single-electron transfer
(SET) promoted conversion to nucleophilic radical anions that
react with electrophiles (Scheme 2A). In contrast, photo-
Scheme 3. Design of Glycosyl RAEs as Radical Progenitor
for Direct Coupling with α-Imino Esters
Scheme 2. Roles of Imines in Photoredox Catalysis
catalyzed processes, in which imines act as electrophiles in
reactions with nucleophilic radicals, are very rare.12 This is
likely a consequence of the occurrence of competitive reactions
of intermediate radicals and SET-mediated imine reduction.
Furthermore, N-hydroxyphthalimide-derived redox-active es-
ters (RAEs) have been demonstrated as effective radical
precursors in transition-metal and photoredox-catalyzed C−C
bond-forming processes.13 Nonetheless, to the best of our
knowledge, such radicals have not been reported in the
reaction with a CN bond.14
Accordingly, we reasoned that it would be possible to generate
glycosyl radicals by photoredox processes using visible light
and PSs. A consideration of the reduction potential of RAE 1
(E1/2 = −0.81 V vs SCE in MeCN, Figure 2S) suggests that its
SET-promoted reduction would be thermodynamically favor-
able. We reasoned that the formed radical anion of 1i would be
capable of producing glycosyl radical 1i′ by loss of CO2 and
tetrachlorophthalimide anion. In contrast, the imino ester
substrate would be less prone to reduction because of its more
negative reduction potential (for example, 2a = −1.52 V vs
SCE in MeCN, Figures 2S and 3S).
In the investigation described below, we developed a direct
photochemical process for preparation of C-glycosyl amino
acid derivatives that utilizes readily available α-imino esters
(Scheme 1C). Differing from the role played by imines in
typical photoredox-catalyzed reactions, α-imino esters in the
new process serve as electrophiles in reactions with in situ
generated nucleophilic glycosyl radicals (Scheme 2B). More-
over, in this effort, we demonstrated that glycosyl radicals can
be generated using RAE of saccharides, a new class of bench-
stable and readily prepared C-glycosylation reagents. More-
over, in this effort, we demonstrated that glycosyl radicals can
be generated using RAEs of saccharides, a new class of bench-
stable and readily prepared C-glycosylation reagents. As far as
we are aware, this study represents the first case of the addition
of RAE-derived radicals to a CN rather than a CC bond.
In addition, we showed that the process does not require the
use of an often expensive photosensitizer (PS), consistent with
Melchiorre’s work.15 Instead, inexpensive Hantzsch ester (HE,
ca. $0.071/mmol) can play the role of both a PS and hydrogen
atom transfer donor in the new process. Finally, the preparative
power of the new PS and metal-free strategy is a consequence
of the mildness of the conditions employed and its application
to reactions of both armed and disarmed pentoses and hexoses,
in which the integrities of preexisting anomeric carbons are
preserved.
In initial experiments designed to evaluate the feasibility of
the new radical process for producing C-glycosyl amino acid
derivatives, we explored the reaction of the RAE of α-D-
glycopyranosiduronic acid 1a with ethyl 2-[(4-fluorophenyl)-
imino]acetate (2a) (Table 1 and S1). The results showed that
irradiation of a solution of 1a (0.1 mmol), 2a (0.15 mmol), the
PS 4CzIPN (0.002 mmol), HE (0.15 mmol), and iPr2NEt·
HBF4 (0.1 mmol) in MeCN (0.05 M 1a) using 34 W Kessil
blue LEDs leads to formation of the glucosyl amino ester 3a in
83% yield (entry 2, Table 1). It should be noted that in this
reaction the configuration of the anomeric carbon (C-1) is
conserved. Moreover, in the reaction, the new C−C bond is
installed in an α-stereoselective manner as a likely consequence
of a combination of stereoelectronic and steric factors (Figure
9S).9a,b Moreover, a nearly 1:1 mixture of diastereomers is
formed as a consequence of the lack of stereocontrol at C-6, a
finding that is consistent with those made in a previous
investigation.9b
Other PSs including Ir[dF(CF3)ppy]2(dtbpy)PF6, (Ru-
(bpy)3(BF4)2, Ir(ppy)2(dtbpy)PF6, and Ir(ppy)3 also promote
similarly efficient coupling reactions (entries 3 and 4 in Table 1
and Table S1), but a change in solvent to DCM causes a
significant decrease in the yield of the process (27%, entry 5).
At first surprising, we observed that irradiation of a solution of
1a and 2a not containing a PS under otherwise identical
conditions leads to generation of 3a in an excellent yield (93%,
dr = 1.1:1, entry 1).
In exploratory studies designed to assess the new approach
to the preparation of C-glycosyl amino acids, we found that
commonly used glycosyl bromides,10 carboxylic acids,16 and
B
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Letter
a
group (i.e., simple benzaldimines 3t−ai). The observations
show that the aldimines participate in coupling reactions that
take place in moderate to excellent yields (40−96%). Except
for that of 3s, reactions of N-arylimines containing electron-
attracting groups (2a, 2p, 2q, and 2s) are higher yielding (89−
93%) than those of electron-donating substituted analogues
(2n, 2o, 70−87%), and the efficiency of the reaction of ortho-
substituted N-arylimine 2r (49%) is lower than that of its meta-
analogue 3q (94%). Additionally, reactions of the benzaldi-
mine substrates tolerate a diverse range of functional groups,
including halogen (2u−x), nitrile (2z−ab), amide (2ac),
pyridyl (2y), methoxyl (2ad), allyloxy (2ae), methyl (2af), and
phenyl (2ag). Moreover, the position of the substituent on the
aromatic ring of these aldimines has a definite but small effect
on reaction efficiencies (e.g., para (2z, 87%) > meta (2aa,
70%) > ortho (2ab, 62%)). Of particular note is the fact that
the reaction of 2aj, which exemplifies N-alkylaldimine
substrates that are traditionally problematic in radical addition
reactions,12 reacts to form the corresponding adduct 3aj in a
modest 44% yield. Finally, the preparation of the N-protected
glycoamino acid derivatives, N-sulfonyl (3ah, 66%) and sulfinyl
(3ai, 40%), is readily accomplished using this approach.
To assess the potential synthetic value of this protocol, we
applied it to the synthesis of glycopeptide 4 using the amino
ester adduct 3o as the building block (Scheme 5). We found
that the N-methoxyphenyl group in 3o is easily removed by
oxidation with CAN (cerium ammonium nitrate)18 and that
the resulting amine reacts with the dipeptide (2-
benzyloxycarbonylaminoacetylamino)acetic acid to produce
the glycopeptide 4 in a yield of 69% for the two steps.
A few preliminary experiments were carried out to gain
insight into the role that HE plays in the process when no PS is
present. As can be seen by viewing Figure 1A, the absorption
spectrum of HE in acetonitrile extends into the visible region
(up to 430 nm). This observation suggests that the pathway
followed in the absence of a PS likely involves direct
photoexcitation of HE to form the corresponding excited-
state HE*, which then serves as the SET donor to the RAE. To
determine the effective roles played by HE and the PS in
promoting this process, time courses of reactions of 1i with 2a
and of 1a with 2d, carried out in the absence and presence of
the PS 4CzIPN, were elucidated. The results, displayed in
Figure 1B,C, show that the presence of 4CzIPN leads to a
significant enhancement in the observed rates of the radical
coupling reactions and that in some cases (but not all cases) it
has an effect on overall chemical yields. Although a more
detailed mechanistic study is required, we believe that the
greater observed rates and possibly efficiencies of reactions
carried out in the presence of a PS are associated with a
broader wavelength range of visible-light absorption by PS vs
HE.
Table 1. Optimization of Reaction Conditions
a
Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), HE (0.15
mmol), iPr2NEt·HBF4 (0.1 mmol), ACN (2 mL), rt, 34 W Kessil Blue
LEDs, 12 h. Yield is determined by H NMR spectroscopy with
b
1
c
1,1,2,2-tetrachloroethane as an internal standard. Isolated yield.
To gain information about the functions of HE and iPr2NEt·
HBF4 in the photoinduced process, we explored reactions
carried out in the absence of either substance using 4CzIPN as
the photocatalyst (entries 6 and 7). The results show that these
processes take place in a dramatically lower or only moderate
yield, respectively. However, no C-glycosyl amino ester
product is formed when neither HE nor iPr2NEt·HBF4 is
present (entries 9 and 10). The observations indicate that both
substances play essential roles in the reaction (see below).
Finally, 3a is not formed when visible-light irradiation is absent
(entry 8) or when TEMPO is present (Table S1).
We next evaluated the scope of the C−C coupling reaction
utilizing imine 2a and RAEs derived from various saccharides.
As can be seen by viewing the data in Scheme 4, coupling
reaction occurs efficiently (72−95%) with RAEs containing
both electron-donating (benzyl, acetonide, methyl, i.e., armed
sugars) and electron-deficient (benzoyl, acyl, i.e., disarmed
sugars) substituents on the saccharide scaffold, as well as with
pentoses (ribose, xylose) as well as hexoses (glucose, galactose,
mannose, trehalose). In most cases, reactions of saccharide
substrates bearing electron-rich and small protecting groups
are higher yielding (i.e., forming 3a (90%) > 3c (86%) > 3a
(81%), 3d (77%) > 3e (72%), 3g (95%) > 3f (86%), 3i (95%)
> 3h (93%)). Notably, the RAE of trehalose 2l, a biologically
important disaccharide, is efficiently converted to the
corresponding C-glycoamino ester 3l in 83% yield.
A scheme outlining the various mechanistic scenarios
possible for this photoinduced coupling reactions is displayed
in Scheme 6. The scheme shows the potential roles played by
HE and the PS as light-absorbing activating agents, the
catalytic function of the PS, the role played by HE as a
hydrogen atom donor, and the acid-catalysis function of
iPr2NEt·HBF4.
In the investigation described above, we developed a new
strategy for the synthesis of C-glycosyl amino acids that relies
on the photocatalyzed generation of C-glycosyl radicals from
redox-active esters of saccharides and their addition to
aldimines. Different from typical photoredox- catalyzed
We next examined the imine scope of the process using a
variety of structurally diverse imines, including those
containing N-aryl (2m-2ag), sulfonyl (2ah), sulfinyl (2ai),
and even benzyl (2aj) groups, and those that lack the ester
C
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a
Scheme 4. Scope of the C-Glycosylation Reaction
a
Reaction conditions: redox-active ester 1a−i (0.1 mmol), imines 2a−y (0.15 mmol), HE (0.15 mmol), iPr2NEt·HBF4 (0.1 mmol), ACN (2 mL),
b
rt, 34 W Kessil Blue LEDs, 6−18 h. Experiment is carried out in the presence of 4CzIPN (1 mol %). The dr values were determined by 1H NMR.
is found in the development of a new class of glycosyl radical
progenitors in the form of redox-active esters of saccharides.
The new method is both straightforward and mild, and it can
be utilized for the efficient production of synthetically and
biologically valued C-glycosyl amino acid derivatives. Fur-
thermore, the process proceeds in the presence or absence of
single-electron-donating photosensitizers that are generally
required to promote photoredox-catalyzed processes. In the
absence of PSs, the Hantzsch ester plays a unique dual role as
both as a light-activated electron donor to the redox-active
esters and a hydrogen atom source. The broad substrate scope
of the process encompassing both armed and disarmed
pentoses and hexoses and the preservation of the integrities
of the anomeric carbons in these substrates are advantageous
Scheme 5. Synthetic Application of the New Radical-
Coupling Reaction
reactions of imines, which generate polarity reversed
nucleophilic imine radical anions, imines in the newly
developed process serve as electrophiles in chemoselective
C−C bond-forming reactions with nucleophilic in situ
generated glycosyl radicals. An important feature of this effort
D
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Acknowledgment is made to the NSF (CHE-1903983), the
donors of the American Chemical Society Petroleum Research
Fund (57164-ND1), and the University of Arizona.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00724.
́
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AUTHOR INFORMATION
Corresponding Authors
■
(7) For a review, see: Yu, X.; O’Doherty, G. De Novo Synthesis in
Carbohydrate Chemistry: From Furans to Monosaccharides and
Oligosaccharides. ACS Symposium Series, Chemical Glycobiology;
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*E-mail: chemedit@yahoo.com.
*E-mail: wwang@pharmacy.arizona.edu.
ORCID
Wei Wang: 0000-0001-6043-0860
E
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