Chemoselective Amide-Forming Ligation Between Acylsilanes and Hydroxylamines Under Aqueous Conditions

Article abstract of DOI:10.1002/anie.202012459

We report the facile amide-forming ligation of acylsilanes with hydroxylamines (ASHA ligation) under aqueous conditions. The ligation is fast, chemoselective, mild, high-yielding and displays excellent functional-group tolerance. Late-stage modifications of an array of marketed drugs, peptides, natural products, and biologically active compounds showcase the robustness and functional-group tolerance of the reaction. The key to the success of the reaction could be the possible formation of the strong Si?O bond via a Brook-type rearrangement. Given its simplicity and efficiency, this ligation has the potential to unfold new applications in the areas of medicinal chemistry and chemical biology.

Full text of DOI:10.1002/anie.202012459

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Accepted Article
Title: Chemoselective amide-forming ligation between acylsilanes and
hydroxylamines under aqueous conditions
Authors: Rajavel Srinivasan, Xingwang Deng, Guan Zhou, and Jing
Tian
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Chemoselective amide-forming ligation between acylsilanes and
hydroxylamines under aqueous conditions
Xingwang Deng, [a] Guan Zhou, [a] Jing Tian, [a] and Rajavel Srinivasan*[a]
Dedicated to the memory of Professor Chris Abell
[a]
X. Deng, G. Zhou, J. Tian, and Prof. Dr. R. Srinivasan
School of Pharmaceutical Science and Technology (SPST)
Tianjin University, 92 Weijin Road, Building 24, Nankai District
Tianjin, 300072 (P. R. China)
E-mail: rajavels@tju.edu.cn
Supporting information for this article is given via a link at the end of the document.
Abstract: We report the facile amide-forming ligation of AcylSilanes
with HydroxylAmines (ASHA ligation) under aqueous conditions. The
ligation is fast, chemoselective, mild, high-yielding and displays
excellent functional group tolerance. Late-stage modifications of an
array of marketed drugs, peptides, natural products and biologically
active compounds showcase the robustness and functional group
tolerance of the reaction. The key to the success of the reaction could
be the possible formation of the strong Si-O bond via a Brook-type
rearrangement. Given its simplicity and efficiency, this ligation has the
potential to unfold new applications in the areas of medicinal
chemistry and chemical biology.
reactions are highly chemoselective, can take place under mild
aqueous conditions and are capable of stitching protein fragments
together.[12] However, the slower reaction rate is the major
limitation of NCL and KAHA ligations. Conversely, KAT ligation is
rapid with a second-order rate constant of up to 100 M-1s-1 and
can occur under dilute concentrations with equimolar reactants,
thus making it ideal when dealing with macromolecules;[11d]
however, the lack of rapid methods to access diverse KATs limits
its wider application, especially in the areas of fragment-based
drug discovery and compound library synthesis, where a few
hundreds to thousands of diverse small-molecule fragments are
usually involved.
Amide bond formation is among the most extensively
employed reactions in chemical industries and academic
settings[1] due to the prevalence of this functional group in
numerous life-saving pharmaceutical products,[1,2a] peptides,[2b]
biological conjugates,[2c,2d] agrochemicals[2e] and materials such
as
polymers,[2f,2g] MOFs[2h]
and
hydrogels.[2i] Recent
cheminformatics analysis of around 420,000 bioactive molecules
from the ChEMBL database has identified the amide bond as the
most occurring functional group in 40.3% of all molecules.[3]
Furthermore, amide bonds are known to be crucial for modulating
the structures and functions of proteins and other small molecule-
based drugs.[4] Hence, amide functionality is of central importance
in modern research, and new methods to generate amide bonds
in sustainable and chemoselective ways are in demand.
The most common method to access amide bonds is by
condensing a carboxylic acid and amine in the presence of
stoichiometric amount of a coupling reagent and a base in organic
solvent.[5] The lack of chemoselectivity, aqueous incompatibility
and the generation of copious amounts of organic waste along
with other safety complications[6] makes this method less
appealing or even unfit, especially for chemical biology and
chemical library synthesis applications. Numerous non-classical
amide-bond forming reactions have been reported in the last two
decades that overcome the limitations associated with the
traditional methods.[7] Among these reactions, native chemical
ligation (NCL),[8] α-ketoacid-hydroxylamine (KAHA)[9] and
potassium acyltrifluoroborate (KAT)[10] ligations are in the frontline
when it comes to applications pertaining to peptide and protein
chemistry, bioconjugation and inhibitor discovery.[11,12] These
Figure 1. Traditional amide bond formation reaction, KAT and KAHA ligations,
and the present work.
In our quest to discover efficient amide-forming ligation from
easily accessible starting materials, we considered acylsilanes
(also called silyl ketones), a class of fascinating compounds with
established chemistry[13] yet underexplored in medicinal chemistry
and chemical biology. In many instances, these compounds
behave entirely different from ketones in terms of reactivity and
1
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10.1002/anie.202012459
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spectroscopic properties due to the positive inductive effect of the
silicon atom.[13e] It is known that ketones condense with N-
alkylhydroxylamines, generally under harsh conditions to
generate hemiaminals via nitrone intermediates,[14] but similar
reactions with acylsilanes are unknown. Other distinct reactions
of acylsilanes in forging amide-based linkages are also known.
The electrochemical oxidation of acylsilanes with the derivatives
of N-methylcarbamate and p-toluenesulfonamide furnished the
respective diamide and N-tosylamide derivatives.[15] Recently, Yu
et al. reported an elegant amide synthesis method via an
intermolecular Schmidt reaction of acylsilanes with alkyl azides
mediated by trifluoromethanesulfonic acid.[16] However, the
requirement of a strong acid, use of undesirable dichloromethane
as the solvent, a narrow substrate scope consisting of mostly
unfunctionalized simple alkyls and aryls, and requirements of an
excess of azide reactant severely limits the application of this
method. Apart from these studies, acylsilanes are unexplored in
the amide-bond forming reaction. Interestingly, Denmark et al.
had speculated on the possibility of ligation of acylsilanes with
hydroxylamines.[17] Further, inspired by Bode's work on KAHA and
KAT ligations, we questioned whether hydroxylamines could react
with acylsilanes in a similar fashion to that of α-ketoacids/KATs to
deliver amide linkages. We hypothesized that this new acylsilane-
hydroxylamine (ASHA) ligation could be driven by the formation
of a strong Si-O bond via a Brook-type rearrangement [18] (Figure
3, pathway A). Moreover, boron and silicon show diagonal
relationships [19] and as such, acylsilanes could behave in a similar
fashion to acylboronate derivatives, including KATs and MIDA
acylboronates, upon treatment with hydroxylamines under
suitable conditions. [20]
benzylhydroxylamine hydrochloride) and O-Me-hydroxylamine
(i.e., N,O-dimethylhydroxylamine hydrochloride). Although the
desired amides were observed, the conversions were either poor
or not clean. Hence, we turned our attention towards O-
diethylcarbamoyl-derived hydroxylamines, which are known to be
robust coupling partners in KAT ligation.[10b] For the optimization
studies, we used 3-phenylpropionyltrimethylsilane 1a and O-
diethylcarbamoyl-N-phenethylhydroxylamine 2a’ as model
substrates (Table 1). The reactions were performed at room
temperature. No measures were taken to exclude air and
moisture from the reaction flask. Initially, we screened polar
solvents such as DMSO, CH3CN and t-BuOH in the absence of
any additives (entry 1). However, the starting materials remained
intact and no traces of the desired product formation were
observed in all these cases even after two hours. Next, we
explored the reaction in CH3CN using 0.5 N aq. HCl (0.4 mL) as
an additive and isolated 60% of the desired product 3a after two
hours of the reaction (entry 2). Encouraged by the product
formation, we chose CH3CN as a solvent and screened various
organic acids, including formic, oxalic and citric acids. To our
delight, the reaction was completed within two hours, and the
desired amide product 3a was isolated in 78, 92 and 96% yields,
respectively (entries 3-5). When the reaction was performed in
CH3CN/H2O in a 1:1 ratio and in the presence of 0.1 M of citric
acid, the reaction proceeded to completion within 15 minutes in
quantitative yield (entry 6). When acetonitrile co-solvent was
replaced with other polar solvents such as t-BuOH, DMSO and
DMF, the yield dropped to 85, 72 and 75%, respectively (entries
7-9). Finally, it was encouraging to note that the reaction can be
performed in water in the absence of any organic co-solvent
furnishing the desired amide in 61% yield, yet the reaction was
incomplete even after 2 hours as the starting materials were not
soluble in water. In general, we found that the acylsilanes are
quite stable under aqueous conditions. No noticeable
decomposition of acylsilane 1d was observed at 40 °C in the
presence of 1 equiv. of citric acid for over 2 days in CH3CN:H2O
(1:1). However, the presence of a strong acid (table 1, entry 2)
compromised the stability of the acylsilane 1a to a certain extent.
Table 1. Optimization of ASHA ligation[a]
Entry
solvent
Additive (%)
Yield(%)[b]
1
2
DMSO (or) CH3CN (or) t-BuOH
CH3CN
nil
N.R.
60
78
92
96
99
85
72
75
61
0.5 N HCl (aq.)
HCOOH
3
CH3CN
4
CH3CN
Oxalic acid
Citric acid
Citric acid
Citric acid
Citric acid
Citric acid
Citric acid
5
CH3CN
6[c]
7
CH3CN/H2O (1:1)
t-BuOH/H2O (1:1)
DMSO/H2O (1:1)
DMF/H2O (1:1)
H2O
8
9
10
[a] Reaction condition: acylsilane 1a (0.2 mmol, 1.0 equiv), O-diethylcarbamoyl-
N-phenethylhydroxylamine 2a’ (0.2 mmol, 1.0 equiv, acid additive (0.1 M, 0.2
mmol, 1.0 equiv), solvent(s) (2 mL), r.t., 2 h; [b] isolated yield; [c] reaction time:
15 min. DMSO = Dimethyl sulfoxide, DMF = Dimethylformamide. N.R. = no
reaction.
At the outset of the study, we quickly investigated any possible
Scheme 1. Substrate scope of acylsilanes. Reactions were carried out on a 0.2
reactions of acylsilane 1d with a simple hydroxylamine (i.e.,
mmol scale. Acylsilane (1 equiv.) and hydroxylamine (1 equiv.).
2
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Scheme 2: Scope of hydroxylamines and late stage modifications of drugs, peptides and biologically active natural products. Reactions were carried out with
acylsilane (1.05 equiv, 0.21 mmol) and hydroxylamine (1 equiv, 0.2 mmol).
Having optimized the reaction conditions (Table 1, entry 6),
we studied the substrate scope of diverse acylsilanes 1a-1l with
hydroxylamine 2a’ (scheme 1). These acylsilanes can be easily
prepared from their acid or aldehyde derivatives using established
procedures.[13] O-Diethylcarbamoyl protected hydroxylamine was
prepared following Bode’s protocol.[10b] Aralkyl acylsilane 1a
reacted with 2a’ to furnish the desired amide 3a in quantitative
yield in just 15 min Similarly, alkyl acylsilane 1b furnished the
amide 3b in 93% yield in 15 min. Aryl acylsilanes 1c-1k consisting
of substituents with varying steric and electronic properties (-CH3,
-tBu, -OCH3, -COOCH3, -Cl and -Br) underwent the reaction
smoothly to afford the desired amides 3c-3k in 91-99% yields.
Thiophene acylsilane 1l also underwent the reaction smoothly to
furnish the desired amide 3l in 96% yield. All these reactions were
completed within 30 min.
Impressed by the efficiency of this ligation, we next
investigated the chemoselectivity of the reaction by using various
O-diethylcarbamoyl-derived hydroxylamines tethered to diverse
substrates, including approved drugs, peptides, complex
molecules and natural products containing unprotected
functionalities (scheme 2). The tethering was achieved by either
a ether, ester or amide linkage. A total of 24 hydroxylamines 2a-
2x were synthesized for this purpose (see supporting information).
Hydroxylamine 2a bearing azide moiety, reacted smoothly with
acylsilane 1a to furnish amide 4a in quantitative yields. It is
interesting to note that the competing intramolecular Schmidt
3
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reaction was not observed between the azide functionality and
acylsilane. Hydroxylamines 2b-2e underwent the ligation with
acylsilane 1a smoothly to furnish amides 4b-4e in quantitative
yields. Hydroxylamines bearing reactive functional groups such
as aldehyde (2f), ketone (2g), ester (2h), alkyne (2i), alcohol (2j)
and Fmoc- protected amine (2k) underwent the reaction smoothly
with acylsilane 1a to afford the desired amides 4f-4k in 94-99%
yield. Further, it is interesting to note the hydroxylamine 2l,
derived from L-phenylalanine bearing a free amino group,
underwent the reaction smoothly with acylsilanes 1a and 1d to
afford the desired amides 4l and 4l’ in 92 and 94% yield,
respectively, leaving the free amino group untouched. In all these
cases, the reaction completed within 15-25 minutes.
above substrates showcase the promising aspects of ASHA
ligation in terms of orthogonal reactivity, chemoselectivity,
aqueous compatibility, fast kinetics, mostly near-perfect yields
and the capability to modify complex molecules in a late-stage
fashion under mild conditions. As such, this new ligation holds the
potential to open up new applications. HPLC monitoring of the
ligation between acylsilane 1f and indomethacin derived
hydroxylamine 2r and is shown in figure 2 for different time
intervals. The reaction was completed cleanly within 40 min.
Further, the antigout drug, probenecid-derived hydroxylamine
2o, underwent the ligation with acylsilane 1e in 1-mmol scale to
furnish the desired amide 6 in 91% yield in 5 h, thus
demonstrating the amenability of the reaction for scale-up
operations (Scheme 3).
M+Na
Scheme 3. Evaluation of a scale-up reaction
m/z
Amide 5,after
purification
Next, we investigated the ligation (0.2 mmol scale) between
acylsilane 1d and hydroxylamine 2a’ at different concentrations at
25 °C (refer SI, section 12) to find out the amenability of the
reaction for bioconjugation applications. At 20 mM concentration,
the reaction was promising and completed in 9 hours to furnish
the amide 3d in 96% yield. On further dilution to 2 mM, we
observed only traces of the product even after three days of
reaction. However, on warming the reaction to 40 °C for three
days, 36% of the desired product was isolated, whilst the reaction
remained incomplete.
Desired amide 5
T = 40 min
(unpurified reaction
mixture
Desired amide 5
T = 10 min, in the
presence of citric acid
Acylsilane 1f
Hydroxylamine 2r
T = 0 min, in the
absence of citric acid
Subsequently, we subjected a N-Phth protected α-amino
acyl(dimethylphenyl)silane,[21] 9 derived from L-phenylalanine to
ASHA ligation with hydroxylamine, 2a’ at 40 °C for over 36 h
(Scheme 4). Nevertheless, we observed only traces of the desired
amide 10. We speculate the –SiPhMe2 could be too hindered to
effect the ligation, coupled with the steric congestion from the N-
phthalimide group. Practical and rapid synthetic methods to
access diverse α-amino acyl(trimethyl)silanes are necessary for
the further development of ASHA ligation for peptide synthesis
applications
Figure 2. ASHA ligation of indomethacin derivative 2r with acylsilane 1f, and
HPLC monitoring of the reaction at different time intervals
Subsequently, hydroxylamine-tethered small molecule drugs
(2m-2s) were treated with acylsilane 1a under standard
conditions to furnish the amide modified drugs 4m-4s in 93-98%
yield. All these reactions were completed within an hour with
complete functional group tolerance, thus reinforcing the potential
of this ligation in the late-stage modification of complex molecules.
Various heterocyclic scaffolds present in the drugs were also well-
tolerated. Next,
enzyme (ACE)
a
dipeptide-based angiotensin-converting
inhibitor, captopril, functionalized to
Scheme 4. Unsuccessful ASHA ligation of α-amino acylsilane 9
hydroxylamine, underwent the ligation with acylsilane 1a
smoothly to afford the amide product 4t in 93% yield and leaving
the free thiol group intact. Further, a tripeptide 2u bearing a free
carboxylic acid group underwent the ligation efficiently with
acylsilane 1a. Other reactive groups, including the free –NH of the
indole moiety in tryptophan and the phenolic –OH in the tyrosine
unit, were completely unaffected under the ASHA ligation
conditions. The desired modified peptide 4u was obtained in 83%
yield. Finally, hydroxylamines tethered to other biologically active
compounds (2v-2x), including estrone, gibberellic acid and biotin,
all underwent the ligation effectively with acylsilane 1a to afford
the respective amides (4v-4x) in excellent yield of 86-98%. The
When ASHA ligation was carried out in the presence of one
equivalent of TEMPO, the yield was unaffected, suggesting that
the reaction does not operate via a free radical pathway. Two
general mechanistic pathways (A and B) for the amide formation
can be postulated (Figure 3). In both pathways, the first step is
the nucleophilic addition of the hydroxylamine nitrogen to the
activated carbonyl of the acylsilane to form a tetrahedral
hemiaminal intermediate a. In pathway A, intermediate a
undergoes a Brook-type rearrangement via a [1,2]-silyl migration
forging a new Si-O bond to form imine b, which can be hydrolyzed
4
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In conclusion, we have disclosed a chemoselective amide-
forming ligation between acylsilane and hydroxylamine under
aqueous conditions. The key to the success of the reaction could
be the potential formation of the strong Si-O bond. The reaction is
high-yielding, operationally simple and can be carried out open to
the air. Further, the reaction is fast and tolerates a wide range of
reactive functional groups such as alkene, alkyne, aldehyde,
ketone, ester, lactone, acid, nitrile, amine, aniline, azide, alcohol,
phenol and thiol. The electronics of the substitutes on the starting
materials had no observable influence on the ligation and should
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unprotected peptides, natural products and other biologically
active compounds was modified using the developed ligation in a
late-stage fashion demonstrating the robustness of the reaction.
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Acylsilanes
are
established
functionalities
but
are
underappreciated in chemical biology and medicinal chemistry.
This ligation could potentially revive the use of acylsilanes and
lead to new applications in multiple research areas, including
fragment-based drug discovery, chemical biology and materials
science. Further development of this ligation and its variants
(including acylgermanes) as well as detailed mechanistic studies
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Acknowledgements
RS acknowledges the School of Pharmaceutical Science and
Technology (SPST), Tianjin University and the Tianjin Young
1000-Talents Program for the funding support. The authors are
thankful to Dr. Subramanian Govindan for useful discussions.The
authors also thank Ms. Shuyu Yang, Ms. Yan Gao and Mr. Zhi Li
(Instrumental Analysis Center of SPST, Tianjin University) for
their help with recording HRMS and IR spectra.
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Keywords: ligation reactions • acylsilanes • amides
•chemoselectivity • aqueous reactions
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10.1002/anie.202012459
Angewandte Chemie International Edition
COMMUNICATION
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ASHA ligation: A fast, easy-to-perform, mild and high-yielding chemoselective amide-forming ligation of acylsilanes with O-
diethylcarbamoyl-derived hydroxylamines under aqueous conditions is reported. The reaction is mediated by citric acid and tolerates a
wide range of reactive functional groups as demonstrated by the late-stage modifications of a panel of drugs, peptides, natural products
and biologically active molecules. We believe this ligation will revive the use of acylsilanes and be a valuable addition to the synthetic
toolbox of medicinal chemists and chemical biologists for creating amide linkages between diverse chemical fragments.
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