Fast Amide Couplings in Water: Extraction, Column Chromatography, and Crystallization Not Required

Article abstract of DOI:10.1021/acs.orglett.0c01676

In the micelle of PS-750-M, the presence of 3° amides from the surfactant proline linker mimics dimethylformamide, dimethylacetamide, and N-methyl-2-pyrrolidone. The resultant micellar properties enable extremely fast amide couplings mediated by 1-ethyl-3

Full text of DOI:10.1021/acs.orglett.0c01676

pubs.acs.org/OrgLett
Letter
Fast Amide Couplings in Water: Extraction, Column
Chromatography, and Crystallization Not Required
Sudripet Sharma, Nicklas W. Buchbinder, Wilfried M. Braje, and Sachin Handa*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c01676
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: In the micelle of PS-750-M, the presence of 3°
amides from the surfactant proline linker mimics dimethylforma-
mide, dimethylacetamide, and N-methyl-2-pyrrolidone. The
resultant micellar properties enable extremely fast amide couplings
mediated by 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide
(without hydroxybenzotriazole), rather than expensive and
specialized coupling agents. Conditions have been developed
wherein products precipitate, and isolation by filtration completely
avoids the use of organic solvent. This methodology is scalable and
avoids product epimerization.
demonstrated its use in water for micellar amide couplings.10
n 2018, the ACS Green Chemistry Institute Pharmaceutical
IRoundtable (GCIPR) included sustainable amide couplings However, this methodology requires organic solvents for
in their 10 green chemistry key research areas.1 The reason for
product extraction and purification (column chromatography).
Therefore, many solvent molecules are sacrificed, although
reactions are conducted in water.
this inclusion is the absence of an ideal methodology in the
literature. In terms of sustainability and efficiency, the current
methods are far from Nature’s ribosomal peptide synthesis and
other enzymatic pathways.2 Although many synthetic method-
ologies relevant to amide couplings are available,3 sustainable
practices are still predominantly lacking.1,4 Catalytic rather
than stoichiometric methods are generally preferred. However,
they still have drawbacks, such as the toxicity and cost of
catalysts, the use of less readily available alcohols as coupling
partners, limited substrate generality, scalability issues, and the
need for catalyst removal from product.5 Therefore, to date,
stoichiometric methods are heavily used for this trans-
formation.4b,6 The current best stoichiometric methods
generate enormous waste that sacrifices a large number of
molecules during the formation of an amide bond. It includes
waste in the form of organic solvent used as a reaction
medium, water used for product extraction, and solvents
needed for product purification.
The common reagents used for amide couplings are
carbodiimides, with 1-ethyl-3-(3-(dimethylamino)propyl)-
carbodiimide (EDC) being the most common.4b However,
EDC always requires a benzotriazole-based activator, such as 1-
hydroxy-7-azabenzotriazole (HOAt) or hydroxybenzotriazole
(HOBt) to enhance the reaction rate and prevent epimer-
ization.3h,7 These activators are explosive and not safe to use
on a large scale.8 Alternatively, oxyma-derived uronium salt,
i.e., (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)-
dimethylamino-morpholino-carbenium hexafluorophosphate
(COMU), does not require benzotriazole-based activators for
suppression of epimerization.9 Lipshutz and co-workers have
Our group has recently devised the L-proline-based
amphiphile PS-750-M, which structurally mimics dimethylfor-
mamide (DMF), N-methyl-2-pyrrolidone (NMP), and dime-
thylacetamide (DMAc) solvents.11 (See Figure 1.) Besides, its
micelle’s broad range of size distribution, dynamic nature, and
exchange processes of PS-750-M micelles assist in mimicking a
variety of dipolar-aprotic solvents.11,12 These solvents are
proven excellent for the EDC-mediated peptide couplings.6b
PS-750-M also has a chiral proline component that may further
assist in reaction rate acceleration. If chemistry happens in the
micellar interior or at the polar-nonpolar interface, epimeriza-
tion13 should not occur, even with the only use of EDC as a
coupling agent (without HOBt). Besides, the anticipated
reaction rate should be faster than the rate in traditional
methods, because of the higher concentration of reactants,
coupling agents, and 3° amide groups of amphiphile molecules
inside the micellar interior. The extrusion of urea byproduct
from micelles due to its higher water solubility further drives
the desired amide coupling at a faster rate.
Herein, we report a completely organic solvent-free
synthetic methodology for amide couplings with the fast
Received: May 16, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01676
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 1. Substrate Scope of Amide Couplings
Figure 1. Hypothesis of completely organic solvent-free amide
couplings in micelles of PS-750-M in water.
Table 1. Optimization Studies of Completely Organic
a
Solvent-Free Fast Amide Couplings
b
entry
deviation from the standard procedure
none
DCC instead of EDC·HCl
2,6-lutidine instead of pyridine
DIPEA instead of pyridine
1.5 equiv of pyridine
1 M global concentration instead of 0.5 M
0.25 M global concentration instead of 0.5 M
2 wt % PS-750-M instead of 3 wt %
1.2 equiv of EDC·HCl instead of 1.3 equiv
no EDC
3
(%)
1
2
3
4
5
6
7
8
9
99
38
22
27
97
93
62
84
92
10
traces
a
Conditions: carboxylic acid (0.25 mmol), amine (0.25 mmol), EDC·
HCl (0.32 mmol), pyridine (0.5 mmol), 0.5 mL 3 wt % PS-750-M in
H2O, 60 °C (on a preheated oil bath), 15 min. All yields are based
on GC conversion.
b
a
Conditions: carboxylic acid (0.25 mmol), amine (0.25 mmol), EDC·
HCl (0.32 mmol), pyridine (0.5 mmol), 0.5 mL 3 wt % PS-750-M in
H2O, 60 °C (on a preheated oil bath), 10−45 min. All yields are
isolated.
reaction rates in water, using a catalytic amount of PS-750-M
and EDC as a coupling agent. The success of this methodology
is dependent on several variables, including the choice of a
base, the stoichiometry of coupling partners, surfactant loading,
and the global concentration (for details, see the Supporting
Information (SI)). Reaction conditions were optimized using
amine 1 and acid 2. The excellent yield of 3 was obtained using
optimized conditions (see Table 1, entry 1). Typically, after
reaction completion, product precipitates due to the use of a
1:1 ratio of acid and amine coupling partners and the relatively
low solubility of the amide product in the micellar core of PS-
750-M. Notably, DCC, COMU, and HATU were not as
effective as EDC, presumably because of their poor solubility
in PS-750-M (Table 1, entry 2; also see the SI). Because of the
relatively polar inner core of PS-750-M, the polar base was
found to be more effective. Pyridine was found to be the
optimal base (see the SI). Replacing pyridine with 2,6-lutidine
or DIPEA drastically lowered the yield and reduced the
reaction rate (Table 1, entries 3 and 4). The yield was slightly
less when 1.5 equiv of base was used (Table 1, entry 5).
Scheme 2. Scalability Test on a Protecting Group-Free
Coupling
Besides, 3 wt % aqueous PS-750-M and 0.5 M global
concentration were optimal. Increasing the global concen-
tration to 1 M or decreasing to 0.25 M lowered the yield
(Table 1, entries 6 and 7). 3 wt % PS-750-M and 1.3 equiv
EDC were optimal (Table 1, entries 8 and 9). Only traces of
B
https://dx.doi.org/10.1021/acs.orglett.0c01676
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 3. General Reproducibility on Gram-Scale
Reactions
Scheme 4. Epimerization Study
a
a
Conditions: carboxylic acid (1.0 g, 1.0 equiv), amine (1.0 equiv),
EDC·HCl (1.3 equiv), pyridine (2 equiv), 3 wt % PS-750-M in H2O
(0.5 M), 60 °C (on a preheated oil bath), 10−30 min. All yields are
isolated.
the product were observed in the absence of EDC (Table 1,
entry 10).
Next, the scope of this organic solvent-free technology was
examined over a broad range of substrates (Scheme 1).
Notably, the reaction rate was fast in all cases with reaction
times of 10−45 min. Again, based on the design of our
technology, no column chromatography, extraction, or
recrystallization was required for obtaining the pure products.
Good to excellent yields were obtained in all the examples.
Excellent functional group tolerance was observed in the
examples containing Fmoc (4−9, 12, 19, 22), Cbz (10, 21,
27), and Boc (4, 9, 11, 12, 15, 16, 18, 22, 24) groups on N-
terminus. Alkyl (4, 5, 7−9, 11, 13−16, 18, 21−24) and benzyl
esters (6, 10, 12, 17−19, 25, 26) on C-terminus remained
intact in the products. Generally, methyl esters can be easily
hydrolyzed under basic conditions, no such hydrolysis was
observed in any substrate containing this functional group (4,
5, 14, 16, 21, 23, 24). Notably, under basic aqueous
conditions, no traces of Fmoc deprotection was observed in
any example (4−9, 12, 19, 22). This aqueous nanotechnology
is also amenable to sulfonamide (13, 14), bromo (15, 16, 18),
carbonate (15, 16, 18), hydroxy (20), and thioether (25)
functional groups. No side reactions, including esterification
and SNAr, were observed in 20 and 18, respectively. Notably,
the 2-bromobenzylcarbonate group generally cleaves under
basic conditions, and amide couplings in the presence of this
functional group are found very limited.14 However, 2-
bromobenzylcarbonate group remained intact in examples
15, 16, and 18. Similarly, in methionine-derived amino acids,
the S atom oxidizes to sulfoxide;15 no such unwanted oxidation
was observed in product 25. Good reactivity was also observed
in the substrates with significant steric hindrance (9−11, 15−
18).
Although, in the formation of product 20, no side
esterification was observed in a small-scale reaction, it does
not rule out the possibility of such side reaction on a large-
scale reaction. Therefore, we have also investigated the
possibility of side esterification in a large-scale reaction. Our
technology is reproducible on a gram-scale reaction. As
illustrated in Scheme 2, a reaction between amine 28 and
acid 29 affords clean product 20 in a reproducible yield. After
reaction completion, the product was isolated via simple
filtration. Notably, product 20 is a precursor for the synthesis
of radiation-sensitizing agent efaproxiral, which is used for the
treatment of cancer.16
Similarly, the challenging examples from Scheme 1 were
picked for reproducibility on gram-scale reactions. As
illustrated in Scheme 3, all the reactions were reproducible
in terms of yields and reaction times. Again, in these reactions,
pure products were isolated by simple filtration.
A primary concern in the development of this technology
was whether product epimerization occurs or not. Generally,
epimerization occurs in the absence of benzotriazole. The
activated complex Ia slowly reacts with the amine (Scheme 4a,
pathway I), allowing sufficient time for the racemization of Ia
via the formation of Ib. Both the enantiopure Ia and rac-Ia
simultaneously react with the amine and form an epimerized
product. Similarly, the activated complex IIa cyclizes to the
oxazolone IIb (pathway II). Under basic conditions, an
intermediate IIb tautomerizes to IIc and rac-IIb, leading to
C
https://dx.doi.org/10.1021/acs.orglett.0c01676
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(c) Petchey, M. R.; Grogan, G. Adv. Synth. Catal. 2019, 361, 3895−
3914.
racemization. Under the influence of micelles of PS-750-M,
where each micelle has multiple numbers of DMF or DMAc
equivalents, the anticipated reaction rate is faster for the
desired pathways, not allowing the formation of undesired rac-
Ia or cyclization of IIa to prevent epimerization. HPLC
analysis was performed for the products 23 and 27 to test the
correlation of epimerization and fast reaction rate (also see the
SI). No epimerization was evidenced in our analysis (see
Scheme 4b).
In summary, while harnessing the higher concentration of
DMF or DMAc equivalents in the micelles of PS-750-M, we
have developed a totally organic solvent- and HOBt-free
methodology for fast and clean amide couplings. The method
is scalable and reproducible on different reaction scales. It also
significantly meets the standards established by ACS GCIPR.
(3) For selected review and articles, see: (a) Sabatini, M. T.;
Boulton, L. T.; Sneddon, H. F.; Sheppard, T. D. Nat. Catal. 2019, 2,
10−17. (b) Lanigan, R. M.; Starkov, P.; Sheppard, T. D. J. Org. Chem.
2013, 78, 4512−4523. (c) Lanigan, R. M.; Sheppard, T. D. Eur. J. Org.
Chem. 2013, 2013, 7453−7465. (d) Shen, B.; Makley, D. M.;
Johnston, J. N. Nature 2010, 465, 1027−1032. (e) Pattabiraman, V.
R.; Bode, J. W. Nature 2011, 480, 471−479. (f) de Figueiredo, R. M.;
Suppo, J.-S.; Campagne, J.-M. Chem. Rev. 2016, 116, 12029−12122.
Massolo, E.; Pirola, M.; Benaglia, M. Eur. J. Org. Chem. 2020,
DOI: 10.1002/ejoc.202000080. (h) El-Faham, A.; Albericio, F. Chem.
Rev. 2011, 111, 6557−6602.
(4) (a) Sabatini, M. T.; Boulton, L. T.; Sheppard, T. D. Sci. Adv.
2017, 3, No. e1701028. (b) Dunetz, J. R.; Magano, J.; Weisenburger,
G. A. Org. Process Res. Dev. 2016, 20, 140−177. Schuhmacher, A.;
Shiro, T.; Ryan, S. J.; Bode, J. W. Chem. Sci. 2020, DOI: 10.1039/
D0SC01330G. (d) Sayes, M.; Charette, A. B. Green Chem. 2017, 19,
5060−5064.
(5) (a) Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H. Chem.
Soc. Rev. 2014, 43, 2714−2742. (b) Ben Halima, T.; Vandavasi, J. K.;
Shkoor, M.; Newman, S. G. ACS Catal. 2017, 7, 2176−2180.
(c) Zheng, Y.-L.; Newman, S. G. ACS Catal. 2019, 9, 4426−4433.
(d) Piszel, P. E.; Vasilopoulos, A.; Stahl, S. S. Angew. Chem., Int. Ed.
2019, 58, 12211−12215. (e) Wang, Y.; Zhu, D.; Tang, L.; Wang, S.;
Wang, Z. Angew. Chem., Int. Ed. 2011, 50, 8917−8921.
(6) (a) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606−631.
(b) MacMillan, D. S.; Murray, J.; Sneddon, H. F.; Jamieson, C.;
Watson, A. J. B. Green Chem. 2013, 15, 596−600.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01676.
Materials and methods, supplementary figures, supple-
mentary tables, supplementary schemes, and analytical
data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(7) Albericio, F.; El-Faham, A. Org. Process Res. Dev. 2018, 22, 760−
772.
(8) Wehrstedt, K. D.; Wandrey, P. A.; Heitkamp, D. J. Hazard.
Mater. 2005, 126, 1−7.
(9) (a) El-Faham, A.; Funosas, R. S.; Prohens, R.; Albericio, F.
Sachin Handa − Department of Chemistry, University of
Louisville, Louisville, Kentucky 40292, United States;
orcid.org/0000-0002-7635-5794; Email: sachin.handa@
louisville.edu
́
Chem. - Eur. J. 2009, 15, 9404−9416. (b) Subiros-Funosas, R.;
Prohens, R.; Barbas, R.; El-Faham, A.; Albericio, F. Chem. - Eur. J.
2009, 15, 9394−9403.
Authors
Sudripet Sharma − Department of Chemistry, University of
Louisville, Louisville, Kentucky 40292, United States
Nicklas W. Buchbinder − Department of Chemistry, University
of Louisville, Louisville, Kentucky 40292, United States
Wilfried M. Braje − Neuroscience Discovery Research, AbbVie
Deutschland GmbH & Co. KG, Ludwigshafen, Germany
(10) (a) Gabriel, C. M.; Keener, M.; Gallou, F.; Lipshutz, B. H. Org.
Lett. 2015, 17, 3968−3971. (b) Cortes-Clerget, M.; Berthon, J.-Y.;
Krolikiewicz-Renimel, I.; Chaisemartin, L.; Lipshutz, B. H. Green
Chem. 2017, 19, 4263−4267.
(11) (a) Brals, J.; Smith, J. D.; Ibrahim, F.; Gallou, F.; Handa, S. ACS
Catal. 2017, 7, 7245−7250. (b) Bihani, M.; Bora, P.; Nachtegaal, M.;
Jasinski, J.; Plummer, S.; Gallou, F.; Handa, S. ACS Catal. 2019, 9,
7520−7526. (c) Handa, S.; Ibrahim, F.; Ansari, T. N.; Gallou, F.
ChemCatChem 2018, 10, 4229−4233.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01676
(12) Smith, J. D.; Ansari, T. N.; Andersson, M. P.; Yadagiri, D.;
Ibrahim, F.; Liang, S.; Hammond, G. B.; Gallou, F.; Handa, S. Green
Chem. 2018, 20, 1784−1790.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
(13) Fray, M. J. J. Chem. Educ. 2014, 91, 136−140.
́
(14) Isidro-Llobet, A.; Alvarez, M.; Albericio, F. Chem. Rev. 2009,
109, 2455−2504.
Notes
(15) Stadtman, E. R.; Van Remmen, H.; Richardson, A.; Wehr, N.
B.; Levine, R. L. Biochim. Biophys. Acta, Proteins Proteomics 2005,
1703, 135−140.
The authors declare no competing financial interest.
(16) Shi, H.; Cao, J.; Hu, Y. Ind. Eng. Chem. Res. 2008, 47, 2861−
2866.
ACKNOWLEDGMENTS
■
We warmly acknowledge the financial support from AbbVie.
N.W.B. thanks the University of Louisville for providing
financial support in the form of SROP. We also thank Justin
Smith for valuable suggestions.
REFERENCES
■
(1) Bryan, M. C.; Dunn, P. J.; Entwistle, D.; Gallou, F.; Koenig, S.
G.; Hayler, J. D.; Hickey, M. R.; Hughes, S.; Kopach, M. E.; Moine,
G.; Richardson, P.; Roschangar, F.; Steven, A.; Weiberth, F. J. Green
Chem. 2018, 20, 5082−5103.
(2) (a) McIntosh, J. A.; Donia, M. S.; Schmidt, E. W. Nat. Prod. Rep.
2009, 26, 537−559. (b) Tamura, K. J. Biosci. 2011, 36, 921−928.
D
https://dx.doi.org/10.1021/acs.orglett.0c01676
Org. Lett. XXXX, XXX, XXX−XXX