Rapid and Selective Cleavage of Amide Groups at Neutral pH: Applications from Hyaluronic Acid to Small Molecules

Article abstract of DOI:10.1002/ejoc.201800304

During our investigation to find suitable conditions to prepare very high molecular weight partially de-acetylated hyaluronic acid (HA), we discovered a powerful new method to cleave amide bonds using hydroxylamine salts at neutral pH with remarkable sele

Full text of DOI:10.1002/ejoc.201800304

A Journal of
Accepted Article
Title: Rapid and selective cleavage of amide groups at neutral pH:
Applications from hyaluronic acid to small molecules
Authors: Craig Harris
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10.1002/ejoc.201800304
European Journal of Organic Chemistry
COMMUNICATION
Rapid and selective cleavage of amide groups at neutral pH:
Applications from hyaluronic acid to small molecules
Jing Jing,[a] Johan Bankefors,[b] Céline Bonneaud,[a] Elin Sawen,[b] Thibaud Gerfaud,[a] Jonatan
Westin,[b] Ghizlane El-Bazbouz,[a] Lina Kandelin,[b] Antoine Rousseau,[a] Johan Olsson,[b] Anders
Karlsson,[b] Lars Nord,[b] Claire Bouix-Peter,[a] Anne Helander Kenne,[b] Jean-Guy Boiteau,[a] Loic
Tomas,[a] Laurent Hennequin,[a] Craig S. Harris*[a]
Abstract: During our investigation to find suitable conditions to
prepare very high molecular weight partially de-acetylated hyaluronic
acid (HA), we discovered a powerful new method to cleave amide
bonds using hydroxylamine salts at neutral pH with remarkable
selectivity over common carbamate protecting groups and other
carbonyl functionality including unhindered esters.
describe how we identified hydroxylamine as an efficient
transamidation nucleophile to de-acetylate HA. We also report
that this finding could extend to the de-acetylation of small
molecules and demonstrate remarkable functional group
tolerance and chemoselectivity at neutral pH using simple
hydroxylamine salts.
Hyaluronic acid (HA) is a natural linear polysaccharide widely
distributed in human tissue.[1] An average adult contains 15 g of
hyaluronic acid that is located principally in synovial fluid and in
the epidermis and dermis. In terms of the skin, hyaluronic acid
serves as a scaffold to maintain firmness and hydration.[2] During
the aging process, humans produce less and less hyaluronic
acid that leads to voids appearing as wrinkles on the surface of
the skin.[2],[3] Historically, many materials have been used to fill
wrinkles[4] by injection directly into the void including HA.
However, HA undergoes rapid in vivo enzymatic degradation by
hyaluronidases with a half-life of less than 1 day in skin.[2],[5] In
order to improve in vivo longevity of HA-based filling agents, HA
must be chemically-modified by cross-linking.[6] The dominant
chemical process used involves cross-linking HA (1) by an
alkylation reaction with 1,4-butanediol diglycidyl ether (BDDE)
(2) under basic conditions to form water insoluble hydrogels (3)
which are processed into various formulations for filling with high
longevity in vivo.[6] This simple discovery was responsible for the
launch of HA-based dermal fillers that now account for about
80% of all marketed injectable fillers today.[6] While there are
many products on the market, the chemical reaction used is
essentially the same cross-linking process and only the process
conditions (cross-linking degree, starting HA molecular weight
(MW), reaction time and temperature) change (Figure 1).[7]
Figure 1. Simplified representation of the chemistry used for all marketed HA-
based dermal fillers
Figure 2. Our crude disconnection to our target biopolymer, partially de-
acetylated HA (5).
The biggest challenge facing us during this exploration was
achieving an acceptable degree of de-acetylation while
maintaining a significantly high molecular weight to prepare
hydrogels. HA is a very sensitive polysaccharide that undergoes
rapid depolymerisation under the action of heat, enzymes, U.V.,
ultrasound and, in particular, extreme changes in pH (Figure
3).[9]
As part of one of our ongoing projects looking for the fillers of
tomorrow, we wanted to prepare 100% HA gels (4)[8] thereby
eliminating the need to use a chemical cross-linker such as
BDDE.[3] To achieve this ambitious goal, we envisaged a
completely novel approach which would be based on the partial
cleavage of the acetamide group to prepare high molecular
weight de-acetylated HA (5) and cross-link simply by adding an
amide coupling agent (Figure 2).[8] In this communication, we
[a]
[b]
Dr. Craig S. Harris
Research Chemistry
Nestlé Skin Health
06902 Sophia-Antipolis, France
E-mail: craig.harris@galderma.com
Research Chemistry
Figure 3. Depolymerisation of HA with respect to pH at r.t.
Nestlé Skin Health
Seminariegatan 21
A careful inspection of the literature revealed there were just two
reported methods to partially de-acetylate HA: a chemical
method using hydrazine;[10] and a recent enzymatic method for
E-752 28 Uppsala, Sweden
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800304
European Journal of Organic Chemistry
COMMUNICATION
which no final average molecular weight was disclosed.[11] We
decided to focus on finding an appropriate chemical method[12]
using strong organic nucleophiles such as hydrazine,[10] ethylene
diamine[12] and hydroxylamine. In the case of the latter, there
were very few relevant references in the literature.[13][14]
7[b]
50 wt.% NH2OH
50 wt.% NH2OH
50 wt.% NH2OH
50 wt.% NH2OH
50% wt. NH2OH
50% wt. NH2OH
40 °C, 72 h
55 °C, 72 h
55 °C, 72 h
40 °C, 72 h
40 °C, 24 h
40 °C, 24 h
10
10
10
10
8
2500
2500
2500
2500
2500
2500
5
980
8[b]
14
11
5
740
9[b],[d]
10[b],[d]
11[b]
12[b]
1050
1870
840
We screened >100 different conditions looking at reaction time,
temperature, pH, co-solvents using commercially-available
hydrazine monohydrate and 50 wt. % hydroxylamine as both the
solvent and nucleophile. Table 1 shows a selection of the results
obtained during our screening studies. We carried out all our
reactions in tubes protected from light and under a blanket of
14
21
7
490
[a] Reaction performed on a 200 mg scale under argon and protected from
light;[b] Aqueous solutions;[c] 5% wt of NH2NH2.H2SO4 was added;[d] Reaction
performed on a 20 g scale; [e] 50 volumes of solvent were used;[f] pH of the
reaction medium;[g] DoM corresponds to the degree of modification which in
this case is the % of amines liberated on the HA backbone
argon
to
eliminate
other
contributory
factors
to
depolymerisation.[9] As demonstrated in Figure 3, NaOH was
very inefficient resulting in massive depolymerisation and very
little cleavage of the acetamide bond (entries 1 and 2). On the
other hand, results obtained using hydrazine as the nucleophile
were much more encouraging (entries 3-6) with our best results
obtained at 40 °C for 2 days affording a final MW of 260 kDa
with 4% of free amines (entry 5). Heating the reaction mixture
further to 55 °C liberated 17% of free amines but the final MW
was just 40 kDa (entry 6).[15] In general, we had great difficulty in
finding robust conditions to produce de-acetylated HA of high
molecular weight when using hydrazine as the solvent. The pH
of the reaction medium is 13 which could explain the low MW
observed (Figure 3). We postulated that the use of
hydroxylamine, also a powerful nucleophile thanks to the α-
effect,[16] should allow the transamidation to proceed while
reducing significantly the in situ depolymerisation owing to the
lower pH of the reaction medium (10). To our delight, under
identical conditions, hydroxylamine gave a comparable de-
acetylation degree (eg., entry 5 v entry 7) and the MW of the
final polymer was significantly higher. The latter point became
particularly evident at 55 °C whereby the final MW obtained
using hydrazine was just 40 kDa compared to 740 kDa when
using hydroxylamine (eg., entry 6 v entry 8). Finally, scaling-up
the reaction to 20 g appeared to actually improve the product
profile compared to the 200 mg scale tube experiments (entries
7 v 10 and 8 v 9).[17] Moreover, hydroxylamine is also much less
toxic than hydrazine and potential trace impurities such as
primary hydrazides are more genotoxic than their hydroxamic
acid counterparts.[18]
During our investigations on the reactivity of HA, we also
explored in parallel the de-acetylation process on a small
representative probe molecule to confirm that the reaction was
indeed occurring by UV-LCMS. Our model substrate 6 was
prepared by reduction of commercially-available 6-trityloxy-N-
acetyl-glucosamine. We also used this opportunity to study the
effect of pH on the reaction rate. As we were interested in
complete de-acetylation, we raised the reaction temperature to
80 °C to favor the process (Table 2).
Table 2. Selected results from conditions’ screening with 6
Time (h) required
Entry
Solvent[b]
Acid
pH
to go to
completion
1
NH2NH2.H2O
-
-
13
10
7
120
72
12
9
2
50 wt.% NH2OH
50 wt.% NH2OH
50 wt.% NH2OH
50 wt.% NH2OH
50 wt.% NH2OH
50 wt.% NH2OH
50 wt.% NH2OH
50 wt.% NH2OH
50 wt.% NH2OH
3
HCl
4
HBr
7
5[a]
6
HI
7
5
Table 1. Selected results from conditions’ screening[a]
H2SO4
7
29
7
CH3COOH
CF3COOH
(CH3)3COOH
CH3CH2COOH
7
6
4
8
7
9
7
5
8
Start
MW
1(kDa)
End
MW
5(kDa)
%
Entry
Nucleophile[e]
Conditions
pH[f]
DoM[g]
10
7
[a] Reaction mixture was a suspension due to precipitation of NH2OH.HI; [b]5
volumes of solvent were used
1[b]
2[b]
3[c]
4[c]
5[c]
6[c]
0.1 N NaOH
1 N NaOH
23 °C , 24 h
65 °C, 4 h
14
14
13
13
13
13
1300
1300
2500
2500
2500
2500
2
1
70
10
From our experimentation using the glucosamine derivative 6,
we confirmed that hydroxylamine cleaves the acetamide bond
significantly quicker than hydrazine without lowering the pH
(Table 2, entry 1 v entry 2). The surprise came, however, when
we looked at lowering the pH of the reaction medium to neutral
with a vision to decrease further depolymerisation of HA during
the reaction. In practice, we simply added the acid dropwise at 0
°C to a 50 wt. % aqueous NH2OH solution while monitoring
NH2NH2.H2O
NH2NH2.H2O
NH2NH2.H2O
NH2NH2.H2O
30 °C, 24 h
30°C, 120 h
40 °C, 48 h
55 °C, 72 h
-
220
320
260
40
2
4
17
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10.1002/ejoc.201800304
European Journal of Organic Chemistry
COMMUNICATION
closely the change in pH with an internal pH probe. 6 was then
added once pH 7 was reached. Among the mineral acids
evaluated, HI was the one leading to the quickest consumption
As attested by the results compiled in Table 3, we reconfirmed
that hydroxylamine is a better transamidation nucleophile than
hydrazine (entry 1 v entry 2). Notably, a clear effect on reaction
rate was observed when NH2OH.HI was used as an additive
(entries 1-2 v 3-4). The most important result we obtained during
this study is the fact that neither hydrated hydrazine or 50% (aq)
hydroxylamine had to be used as the solvent since very similar
reaction rates were observed using just 5 equivalents of
hydroxylamine hydrogen iodide (entry 5) or trifluoroacetate
(entry 12) in a mixture of EtOH/H2O (entry 5 v entries 3-4). In
contrast, the use of 4N NaOH afforded only 14% conversion to
11 under the same conditions (entry 6) and the addition of
commercially-available hydroxylamine hydrochloride or sulfate
salts afforded just 17% and 1% conversion, respectively, in the
same solvent (entries 7,11). The use of commercially-available
alkylated hydroxylamine hydrochloride salts (entries 8-10) all led
to poor conversions as compared to simple hydroxylamine
hydrochloride (entry 7).
of 6, affording
a complete deprotection after just 5 h.
Comparatively, the reaction with sulfuric acid required 29 h to go
to completion (Table 2, entries 3-6). We also investigated a
series of organic acids which all led to positive results, with TFA
providing the shortest reaction times affording 7 after just 4 h.
Encouraged by our results using 6, we re-examined HA as the
substrate at pH 7 and 8. While the deacetylation rate was much
higher affording a MoD of 21% and 14%, respectively, after just
24 h, significant depolymerisation (Table 1, entries 11-12) was
observed compared to using 50% wt. NH2OH alone for 72 h
(Table 1, entry 7).
With this knowledge in hand, we decided to study the
chemoselectivity and functional group tolerance of this new
process. For this study, we prepared a second probe molecule
10 (Table 3). A selective acetylation of commercially-available 4-
(2-aminoethyl)aniline (8) was carried out in neat p-cresyl acetate
to afford 9 in excellent yield. Surprisingly, all attempts to
selectively acetylate 8 using acetic anhydride or acetyl chloride
even under controlled conditions afforded mixtures of products
that were difficult to separate. Finally, a protection of the aniline
moiety with a Boc group afforded 10 (Table 3).
Next, we decided to test further the limits of chemoselectivity
and functional group tolerance using a series of substrates
derived
from
8. We
chose
NH2OH.TFA
as
the
hydroxylaminolysis agent as it gave the best reaction rates and
can be prepared as a solution so it is easily dispensed.
Compared to solid NH2OH.HI, it was also considered as a
potentially more selective de-acetylating agent since the
presence of nucleophilic iodide ions could lead to side reactions
through de-alkylation. Table 4 shows that the chemoselective
cleavage of acetamide groups in the presence of the most
commonly used amine protecting groups could be generally
achieved in high conversions and isolated yields (entries 1-9).
As expected, increasing steric hindrance around the carbonyl
group of the amide moiety resulted in lower conversions (entries
1-4). We also faced an issue with retaining the Fmoc group that
underwent in situ deprotection after the reaction had reached
about 60% completion. However, lowering further the pH of the
mixture to 6.5 led to a selective deprotection without affecting
the reaction rate. Under the same conditions, the Alloc group
was quantitatively reduced to the n-propyl carbamate analogue
presumably due to the formation of diimide through activation of
hydroxylamine via an in situ O-trifluoroacetylation.[19] To
overcome this issue, we simply changed the salt to NH2OH.HI
(entry 9). Finally and perhaps surprisingly, we could not find
satisfactory experimental conditions permitting the selective
cleavage of the weaker aniline acetamide despite various
studies on the variation on the number of equivalents of
NH2OH.TFA and general reaction conditions (entry 10).
Table 3. Selected results from conditions’ screening using 10
% Conversion
after 4 h
Entry
Solvent[a]
Additive (5 eq)
pH
1
NH2NH2.H2O
-
13
10
7
35
83
97
97
93
14
17
2
2
50 wt. % NH2OH
NH2NH2.H2O
-
3
NH2OH.HI
NH2OH.HI
NH2OH.HI
4N NaOH
4
50 wt. % NH2OH
EtOH / H2O (4:1)
EtOH / H2O (4:1)
EtOH / H2O (4:1)
EtOH / H2O (4:1)
EtOH / H2O (4:1)
EtOH / H2O (4:1)
EtOH / H2O (4:1)
EtOH / H2O (4:1)
7
5
7
Table 4. Selected examples looking at the chemoselective cleavage of
acetamides in the presence of commonly-used amine protecting groups
6
7
7
NH2OH.HCl
MeNHOH.HCl
NH2OMe.HCl
MeNHOMe.HCl
NH2OH.H2SO4
NH2OH.TFA[b]
7
8
7
9
7
2
% Conversion
by LCMS
%
Yield
10
11
12
7
0
Entry
1
R
R’
pH
7
0.7
7
CH3
Boc (10)
96
89
87
7
91
(80) [c]
[a]5 Volumes of solvent were used; [b] 48% wt. solution, only 0.31 eq of TFA
required to reduce the pH of commercial 50 wt.% NH2OH(aq) to 7
2
CH2CH3
Boc (14)
7
69
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10.1002/ejoc.201800304
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COMMUNICATION
3
4
5
CH(CH3)2
C(CH3)3
CH3
Boc (15)
Boc (16)
Cbz (17)
7
7
7
21
2
N/I
N/I
77
89
6
27
28
100
(79)[c]
7[a]
52
100
90
37
88
72
98
(83) [c]
8[a]
29
30
6
CH3
Troc (18)
7
98
78
(65) [c]
9[b]
7
CH3
CH3
CH3
CH3
Teoc (19)
Fmoc (20)
Alloc (21)
Ac
7
6.5
7
93
85
94
21
72
62
88
N/I
8[a]
9[b]
10
[a] Reaction took just 1 h to go to completion;[b] only 5% cleavage of internal
amide bond observed;[c] yields obtained under microwave conditions (110 °C/
30 min).; N/D = not determined
7
In conclusion, we have shown that hydroxylaminolysis is an
efficient process to cleave amide bonds with an excellent
substrate scope. Firstly, we have shown that commercially-
available 50 wt. % hydroxylamine solution can be used for the
preparation of very high molecular weight de-acetylated HA, a
valuable novel biomaterial.[17] Secondly, we have extended this
transamidation process to the de-acetylation of small molecules
at neutral or slightly acidic pH using hydroxylamine salts. In this
regard, hydroxylamine trifluoroacetate and hydroxylamine
hydrogen iodide were identified as the more efficient reagents.
Not only, can they be prepared readily in the laboratory, but only
a 5 fold excess of them was required to selectively cleave amide
bonds at moderate temperatures in the presence of a wide
range of common amine protecting groups and other frequently
encountered functional groups.
[a]
51 wt.% solution, only 0.42 eq of TFA required to reduce the pH of
commeercial 50 wt.% NH2OH(aq) to 6.5;[b] NH2OH.HI was used in EtOH-H2O
(5 vols, 4:1) ; N/I = not isolated;[c] yields obtained under microwave conditions
(110 °C/ 30 min).
We concluded our investigation looking at the effect of the
electronic environment and differentiation over other amides and
esters (Table 5). As expected, in the same electronic
environment, the Boc group was retained in high yield (entry 1).
While no differentiation was observed with primary benzamides
(entry 2), chemoselective cleavage of acetamides over
secondary and tertiary benzamides could be achieved (entries
3-4) with the corresponding hydroxamic acid observed as the
major by-product. Moreover, while the observed differentiation
with a hindered t-butyl ester was expected (entry 5), we were
very surprised to observe a clear differentiation over the methyl
ester (entry 6)[20] and ethyl ester (entry 7) with low levels of
hydroxamic acid impurities. Generally, weaker aromatic amides
were cleaved within 1 h at 80 °C as opposed to 5 h for the
aliphatic amides (eg., entry 6, Table 5 v entry 1,Table 4).
Perhaps most interestingly, these conditions also permitted the
selective cleavage of the external acetamide bond over the
internal peptidic bond with a selectivity of 95:5 (entry 9). It
should be noted that the use of microwave irradiation (110°C)
allows for the same efficiency and selectivity while shortening
the reaction time to just 30 minutes (Table 4, entries 1,5 and 6
and Table 5, entry 6).
Acknowledgements
The authors would like to acknowledge the additional analytical
talents of Grégoire Mouis, Christine Marty, Cédric Martin, Eric
Vilèn Morssing, Michèle Aurelly and Myriam Le Normand during
the course of this work.
Keywords: transamidation ; hydroxylaminolysis ; hydroxylamine
salts • hyaluronic acid
Key topic: synthetic methods ; protecting groups
Table 5. Selected examples showing the chemoselective cleavage of the
acetamide groups over other Boc, other amides and esters
[1]
[2]
[3]
J. Necas, L. Bartosikova, P. Brauner, J. Kolar, Vet. Medicina, 53, 2008
397–411;
E. Papakonstantinou, M. Roth, G. Karakiulakis, Dermatoendocrinol.
2012, 4, 253–258.
For relevant reviews, see: a) G. Jenkins, Mech. Ageing Devel. 2002,
123, 801–810; b) L. J. M. Meyer; R. Stern, J. Investig. Dermatol. 1994,
102, 385-389.
%
[4]
[5]
[6]
a) T. C. Kontis, A. Rivkin, Facial Plast. Surg. 2009, 25, 67-72; b) E.
Gilbert, A. Hui, H. A. Waldorf, J. Drugs. Dermatol. 2012, 11, 1059-1068.
B. Agerup, P. Berg, C. Akermark, Biodrugs 2005, 19, 23-30 and
references cited therein.
%
Yield
Entry[a]
Compound
R Group
Conversion
by LCMS
1
2
3
4
5
22
23
24
25
26
100
N/D
65
83
N. H. Attenello, C. S. Maas, Facial Plast. Surg. 2015, 31, 29–34: a) P.
M. Freidman, E. A. Mafong, A. N. B. Kauvar, R. G. Geronemus,
Dermatol. Surg. 2012, 38, 1170–1179; c) M. H. Gold. Clin. Interv.
Aging, 2007 2, 369–376.
-
[7]
[8]
K. Edsman, L. Nord, A. Öhrlund, H. Lärkner, A. Helander Kenne,
Dermatol. Surg. 2012, 38, 1170–1179; b) A. Tezel, G; H; Frederickson,
J. Cosmet. Laser Ther. 2008, 10, 35-42.
48
56
69
From our analysis, the only patent claiming the preparation of 100% HA
gels with no supporting gel characterization data and using NaOH to
de-acetylate their HA, also with no characterization data, was described
by T-S. Moon, J-Y. Lee, J-H. Kim, K-B. Han, PCT Appl. US6903199,
76
O
O
78
*
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10.1002/ejoc.201800304
European Journal of Organic Chemistry
COMMUNICATION
2005.
[9]
R. Stern, G. Kogan, M. J. Jedrzejas, L. Soltés, Biotechnol. Adv. 2007,
25, 537–557.
[10] a) W. Zhang, H. Mu, A. Zhang, G; Cui, H. Chen, J. Duan, S. Wang,
Glycoconj. J. 2012, 30, 577-583; b) D. Bellini, WO0001733A1 2000; c)
V. Crescenzi, A. Francescangeli, A. L. Segre, D. Capitani, L. Mannina,
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Shimzu, M. Noshita, Y. Mukai, H. Morimoto, T. Ohshima, Chem.
Comm. 2014, 50, 12623-12625; e) In our hands, inferior reaction rates
and selectivity issues, notably due to hydrazinolysis of carbamate
protecting groups and other carbonyl functionality, were observed when
using hydrazine or mixtures thereof on HA and a selection of substrates
presented in this manuscript.
[11] C-H. Kim, J-I, Kim. WO 2011/155800B, 2011.
[12] For recent examples describing mild conditions to cleave amide bonds
see a) Y. Shimizu, H. Morimoto, M. Zhang, T. Ohshima. Ang. Chem.
Int. Ed., 2012, 51, 8564 –8567; b) Y. Seki, K. Tanabe, D. Sasaki, Y.
Sohma, K. Oisaki, M. Kanai. Ang. Chem. Int. Ed., 2014, 53, 6501-6505;
c) Y. Kita, Y. Nishii, T. Higuchi, K. Mashima. Ang. Chem. Int. Ed., 2014,
51, 5723-5726; d) K. Yamada, Y. Karuo, Y. Tsukada, M. Kunishima.
Chem Eur J. 2016, 39, 14042-14047.
[13] W. P. Jencks, M. Gilchrist, JACS 1964, 86, 5616-5620.
[14] B. Gómez-Reyes, A. K. Yatsimirsky, OBC 2003, 1, 866-872.
[15] Molecular weight analysis was carried out using SEC-MALS or SEC-UV
calibrated with HA standards not PES standards that are not reliable to
help predict the MW of halyuronan. Please consult: a) L. K. Kostanski,
D. M. Keller, A. E. Hamielec, J. Biochem. Biophys. Methods, 2004, 58,
159–186; b) M. Potschka, Anal. Biochem. 1987, 162, 47-64.
[16] N. J. Fina, J. O. Edwards, Chem. Kinetics 1973, 5, 1-26.
[17] C. S. Harris, J. Olsson. WO2017114861, 2017; WO2017114859, 2017;
WO 2017207564; 2017.
[18] a) D. J. Snodin, Org. Process Res. Dev. 2010, 14, 960–976; b) R.
Benigni, C. Bossa, Curr. Computer-Aided Drug Design 2006, 2, 169-
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W.W. Bishop, Cancer. Res. 1980, 40, 4704-4708.
[19] a) A. S. Kleinke, T. F. Jamison. Org. Lett. 2013,15, 710-713; b) P. A.
Wade, N. V. Amin, Synth. Commun. 1982, 12, 287-291.
[20] From a previous study, we showed that methyl benzoate was readily
transformed to the corresponding hydroxamic acid using 50 wt. %
NH2OH (aq) in MeOH at r.t. in less than 1 h, please see A. Beillard, Y.
Bhurruth-Alcor, C. Bouix-Peter, K. Bouquet, S. Chambon, L. Clary, C.
S. Harris, C. Millois, G. Mouis, G. Ouvry, R. Pierre, A. Reitz, L. Tomas,
Tetrahedron Lett. 2016, 57, 2165-2170.
.
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COMMUNICATION
Jing Jing, Johan Bankefors, Céline
Bonneaud, Elin Sawen, Thibaud
Gerfaud, Jonatan Westin, Ghizlane El-
Bazbouz, Lina Kandelin, Antoine
Rousseau, Johan Olsson, Anders
Karlsson, Lars Nord, Claire Bouix-Peter,
Anne Helander-Kenne, Jean-Guy
Boiteau, Loic Tomas, Laurent
Hydroxylaminolysis. The use of just a few equivalents of hydroxylammonium
trifluoroacetate or iodide permits cleavage of secondary amide bonds at neutral pH
with remarkable selectivity over common amine protecting groups and other
carbonyl group functionality.
Hennequin, Craig S. Harris*
Page No. – Page No.
Rapid and selective cleavage of amide
groups at neutral pH: Applications
from hyaluronic acid to small
molecules
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