Unusual orthogonality in the cleavage process of closely related chelating protecting groups for carboxylic acids by using different metal ions

Article abstract of DOI:10.1002/chem.201302708

Three structurally related relay protecting groups for carboxylic acids that are based on chelating amines have been developed. These protecting groups can easily be introduced by coupling the carboxylic acid and the corresponding amine in the presence of 2-(1Hbenzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU). In addition to being stable to a whole array of reaction conditions, these protecting groups are also stable under acidic and basic conditions, allowing them to be used in combination with the ester protection of carboxylic acids. The cleavage of these protecting groups is activated by the chelation of metal ions, involving an unusual coordination of the amide nitrogen. Despite their similarity, cleavage of these protecting groups is possible in both a stepwise and an orthogonal fashion by applying different metal salts.

Full text of DOI:10.1002/chem.201302708

DOI: 10.1002/chem.201302708
Communication
&
Protecting Groups
Unusual Orthogonality in the Cleavage Process of Closely Related
Chelating Protecting Groups for Carboxylic Acids by Using
Different Metal Ions
Stephan Mundinger, Uwe Jakob, and Willi Bannwarth*[a]
group under mild conditions to produce either the methyl
Abstract: Three structurally related relay protecting
groups for carboxylic acids that are based on chelating
amines have been developed. These protecting groups
can easily be introduced by coupling the carboxylic acid
and the corresponding amine in the presence of 2-(1H-
benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoro-
borate (TBTU). In addition to being stable to a whole array
of reaction conditions, these protecting groups are also
stable under acidic and basic conditions, allowing them to
be used in combination with the ester protection of car-
boxylic acids. The cleavage of these protecting groups is
activated by the chelation of metal ions, involving an un-
usual coordination of the amide nitrogen. Despite their
similarity, cleavage of these protecting groups is possible
in both a stepwise and an orthogonal fashion by applying
different metal salts.
ester or the carboxylic acid (Scheme 1).
This reaction is based on the unusual involvement of the
amide nitrogen atom in the complexation to CuII, leading to 2.
This involvement prevents the resonance of the amide func-
tion, rendering it susceptible to nucleophilic attack by MeOH.
Nucleophilic attack results in a mild and quantitative transfor-
mation of the amide, at room temperature, into the methyl
ester. Alternatively, methanolysis mediated by this complexa-
tion can be performed in the presence of Ba(OH)2·8H2O, lead-
ing, after acidic workup, to the carboxylic acid.[4–6]
The protection of carboxylic acids by using multidentate
chelators and deprotection by complexation to a metal ion
had previously not been exploited, despite the fact that this
complexation could offer a further degree of orthogonality to
commonly applied deprotection strategies. The chelating
entity is inert towards many different reaction conditions and
the protection reaction is easily performed. The carboxylic
acid, for example, aromatic acids, aliphatic acids, and amino
acids, and bpa were coupled by using 2-(1H-benzotriazole-1-
Carboxylic acids are commonly
protected as esters and in most
cases deprotection is achieved
under acidic or basic condi-
tions.[1,2] Owing to the higher
stability of amides, compared
with that of esters, the protec-
tion of carboxylic acids as
amides is desirable, but is ham-
pered by the harsh conditions
Scheme 1. Principle of the bpa protection and deprotection.
required for amide cleavage.
Recently, we have established
the use of chelating amides as
yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) as the
coupling reagent.[7] The disadvantages of this method are the
relatively slow deprotection time and the use of rather expen-
sive Cu(OTf)2 as the copper ion source. The latter becoming an
issue in large-scale synthesis because Cu(OTf)2 has to be em-
ployed in equimolar amounts. CuCl2 would be more desirable,
but unfortunately leads to a significant reduction of the reac-
tion rate, and hence to even longer deprotection times.
a new and innovative protecting group strategy for carboxylic
acids that circumvents the difficulties associated with protect-
ing carboxylic acids as amides.[3] This strategy was demonstrat-
ed by using carboxamides of bis(picolyl)amine (bpa), for exam-
ple, carboxamide 1, and allowed removal of the protecting
[a] S. Mundinger, U. Jakob, W. Bannwarth
Institut fꢀr Organische Chemie
For this reason we have initiated a comprehensive optimiza-
tion study of the chelating unit which resulted in dimethylami-
noethylpicolylamine (dmepa) as best candidate. It can be
easily obtained by reductive amination of pyridine-2-carboxal-
dehyde with N,N-dimethylethylenediamine and was used for
the protection of carboxylic acids to yield amides of type 4.[8]
Albert-Ludwigs-Universitꢁt Freiburg
Albertstrasse 21, 79104 Freiburg (Germany)
Fax: (+49)761-203-8705
E-mail: willi.bannwarth@organik.chemie.uni-freiburg.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201302708.
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To our surprise, the efficiency of the deprotection reaction,
with respect to the copper source, was now reversed; CuCl2
led to fast and quantitative methanolysis after about 1.5 h,
whereas this process was significantly slower with Cu(OTf)2.
These results confirm the importance of the identity of the
counter ion.
pyridine and a tertiary-amino function as potentially vulnerable
entities, we demonstrated their chemical stability under vari-
ous reaction conditions. Pure samples of amides 11 and 12
were exposed to acidic (10% TFA/CH2Cl2) or basic conditions
(1m NaOH) and analyzed by HPLC after 6 h, after which time
the amides remained unchanged. This was also true after treat-
ment with NaBH4 (reductive conditions). Owing to the poten-
tial formation of N-oxides, the stability of the amides under ox-
idative conditions is limited to weak oxidizing agents, such as
iodine.
In addition to 3 and 4 (Figure 1), we have synthesized
amides of type 5. These amides are closely related to 4, but
The three different amides, 10–12, were then converted into
the corresponding benzoic acid methyl ester by using either
Cu(OTf)2, CuCl2, FeCl3, or Zn(OTf)2. On screening the methanoly-
sis reaction of 10 with the four different metal ions we ob-
served that this reaction was not only feasible with CuCl2 and
Cu(OTf)2, but also occurred in the presence of FeCl3 and
Zn(OTf)2. In addition, the methanolysis with FeCl3 was far supe-
rior to that with Cu(OTf)2 (Figure 2). In contrast, the deprotec-
tion of dmepa-derived amide 11 was specific to CuII ions. No
methanolysis was observed with FeCl3, and with Zn(OTf)2 it
was only marginal. (Figure 3).
Figure 1. Structures of chelating amides 3, 4, and 5.
contain an additional pyridine moiety as an extra coordina-
tion entity. The synthesis of the relevant bis-
(picolyl)ethylenediamine-derived amine (bped), 9, started with
reductive amination by using N-Boc-ethylenediamine (Boc=
tert-butoxycarbonyl), pyridine-2-carboxaldehyde, and NaBH-
(OAc)3 as the reducing reagent. The resulting secondary amine,
6, was then heated at reflux in MeCN, in the presence of an
excess of n-propylbromide, leading to the tertiary amine 7. The
subsequent Boc deprotection with trifluoroacetic acid (TFA) al-
lowed for a second reductive amination step (Scheme 2). The
Figure 2. Rate of methanolysis of 10 with different metal salts.
Scheme 2. Synthesis of bped 9. Reagents and conditions: a) NaBH(OAc)3,
1,2-DCE (DCE=dichloroethane), room temperature; b) n-propylbromide,
N,N-diisopropylethylamine (DIPEA), MeCN, 908C, c) TFA, CH2Cl2, room tem-
perature, d) NaBH(OAc)3, 1,2-DCE, room temperature.
resulting secondary amine was obtained and was acylated
with carboxylic acids by using TBTU and Hꢁnig’s base accord-
ing to the general procedure outlined in the Supporting Infor-
mation.
For the initial methanolysis studies we prepared amides 10–
12, which are derived from benzoic acid. For bpa-protected
carboxylic acids, such as amide 10, we have previously demon-
strated chemical robustness under a variety of reaction condi-
tions.[3] Although the related amides 11 and 12 feature only
Figure 3. Rate of methanolysis of 11 with different metal salts.
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Figure 5. Amides used to prove orthogonality.
was complete after approximately 80 min. A selective metha-
nolysis reaction was also observed between 14 and 15. A mix-
ture of 14 and 15 in MeOH was treated with Zn(OTf)2 to yield
exclusively the p-propylbenzoic acid methyl ester 18. ZnII ions
were removed by EDTA, followed by treatment with CuCl2 to
yield the p-methylbenzoic acid methyl ester 16. Theoretically,
this selectivity should also be possible when the metal salts
are added in the reverse order, however, this was not ob-
served.
Figure 4. Rate of methanolysis of 12 with different metal salts.
The methanolysis of amide 12 was also investigated in the
presence of the previously applied metal salts. The results, de-
picted in Figure 4, were even more intriguing. The fastest
cleavage was observed in the presence of Zn(OTf)2 and was
also possible, at a much slower rate, with Cu(OTf)2. No metha-
nolysis could be observed after treatment with CuCl2 or FeCl3.
From these results we surmised that orthogonality with re-
spect to the applied metal salts and between the three chelat-
ing ligands could be possible. To explore this possibility we
synthesized amides 13–15 (Figure 5).
The results from the above experiments encouraged us to
investigate the possibility of selectively deprotecting all three
chelating amides by applying different metal salts. Treatment
of a mixture of amides 13–15 with FeCl3 should specifically
cleave amide 13 without affecting amides 14 and 15. Treat-
ment with Zn(OTf)2 should then lead to a selective methanoly-
sis of 14, and finally, CuCl2 could be applied for the cleavage of
amide 15.
To substantiate this assumption, we treated a mixture of
amides 13–15 with metal salts in the order outlined above.
The stepwise transformation into the corresponding methyl
Amides 13–15 differ in their parent benzoic acid, so that the
corresponding methyl esters, formed by methanolysis, can
easily be distinguished by RP-
HPLC (RP=reverse phase).
A
mixture of amides 13 and 14, in
MeOH, was treated with FeCl3
and yielded, quantitatively and
exclusively, the p-iodobenzoic
acid methyl ester of 13. Under
these conditions amide 14 re-
mained unchanged. After re-
moval of the FeIII ions by
ethylenediaminetetraacetic acid
(EDTA), the solution was treated
with Zn(OTf)2, resulting in the p-
propylbenzoic acid methyl ester
18 as the only product. To differ-
entiate amide 13 from 15, a mix-
ture of both amides in MeOH
was again treated with FeCl3 to
yield exclusively the p-iodoben-
zoic acid methyl ester 17. After
removal of the FeIII ions by
EDTA, the methanolysis of 15
was initiated with CuCl2. The
methanolysis of 15 proceeded
relatively slowly, but could be
enhanced significantly by per-
forming the reaction at 508C; at
this temperature the reaction
Figure 6. HPLC analysis showing the stepwise and orthogonal methanolysis of a mixture of amides 13–15 result-
ing in the methyl esters 16–18 by using different metal salts in the order: FeCl3, Zn(OTf)2, and CuCl2 at 508C.
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esters was followed by RP-HPLC by using phenol as standard
for quantification. The reactions were carried out both at room
temperature and at 508C to enhance the rate of conversion
into the methyl esters. Increasing the temperature to 508C had
no negative effect on the selectivity (see Figure 6).
We then synthesized the chelating amides 19–21
(Scheme 3), derived from either glutamic acid, alanine, or
lysine, to demonstrate that the selectivity and the resulting or-
thogonality of the methanolysis, employing the three different
chelating entities, is not limited to aromatic amides, but is also
possible for aliphatic amides. These amides were prepared
from the corresponding amino acid derivative, carrying the
free carboxylic acid functionality, and the chelating amines by
using TBTU (amides 19 and 21) or N,N-dicyclohexylcarbodii-
mide (DCC) (amide 20) as the coupling agent. The expected
methyl esters, 22–24, showed such differences in their HPLC
retention times that they could be easily distinguished and
quantified by using a calibration curve, which was created by
using pure samples of independently synthesized methyl
esters. Phenol was used as stan-
Scheme 3. Stepwise selective methanolysis of amino acids protected as che-
lating amides.
amine (dmepa) to yield compound 32 or coupled with bped
(9) to provide intermediate 30. The subsequent reductive ami-
dard. Initial studies had revealed
that the rate of methanolysis for
aliphatic bpa amides with FeCl3
is generally slower than that of
aromatic amides and the reac-
tion time for the methanolysis
was adapted accordingly.
For the selectivity study, a mix-
ture of three amides 19–21 was
treated, over 2 days, with FeCl3
in MeOH at reflux temperature.
This reaction was followed by
methanolysis with Zn(OTf)2, and
finally, with CuCl2. The results
(see the Supporting Information)
clearly confirmed that selective
orthogonal cleavage is possible
for aliphatic chelating amides.
Furthermore, in order to corrob-
orate the possibility of an or-
thogonal methanolysis, we syn-
thesized protected tricarboxylic
acid 33 (Scheme 4), in which
each carboxylic acid functionality
is protected as one of the chelat-
ing amides 3, 4, or 5.
The synthesis of 33 began
with the protection of p-amino-
methyl benzoic acid 25 as its
Boc-derivative, followed by cou-
pling with bis(picolyl)amine
(bpa) by using TBTU as the cou-
pling reagent. The removal of
the Boc-protecting group result-
ed in amine 28. p-Formyl benzo-
ic acid 29 was either coupled
Scheme 4. Synthesis of tris(amide) 33. Reagents and conditions: a) Boc2O, THF/water, room temperature, b) TBTU,
with dimethylaminoethylpicolyl- DIPEA, CH2Cl2, room temperature, c) TFA, CH2Cl2, room temperature, d) NaBH(OAc)3, 1,2-DCE, room temperature.
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Communication
agents, these protecting groups
are also stable under acidic and
basic conditions, allowing them
to be used in combination with
the commonly used ester pro-
tection of carboxylic acids. The
amides described can be cleaved
by using the same principle, that
is, the chelation of metal ions in-
volving an unusual coordination
of the amide nitrogen atom. De-
spite their similarity, the cleav-
age of the protecting groups is
possible in both a stepwise and
an orthogonal fashion by apply-
ing different metal salts. Owing
to high selectivity, the stepwise
reaction is possible without iso-
lation or purification of any in-
termediates. In addition, we
were able to exemplify the or-
thogonal cleavage principle in
a molecule containing all three
chelating amides.
The obtained results could, for
example, have implications in
the side chain modifications of
peptides containing several Asp
or Glu residues as side chains.
Scheme 5. Stepwise orthogonal cleavage of different chelating amides within the same molecule.
nation between amine 28 and aldehyde 30 gave secondary
amine 31, which was also subjected to reductive amination,
but this time with aldehyde 32, resulting in the desired tris-
(amide) 33. A special feature of compound 33 is that all three
chelators have the same chemical environment; hence, any dif-
ferences in the rate of methanolysis can be directly attributed
to the individual chelating protecting group.
The application is not restrictive and could be used for the se-
lective protection and deprotection of a diverse range of syn-
thetic targets that contain carboxylic acid functionalities. For
this reason, we believe that the outlined orthogonality could
be of general value. Future work will be focused on gaining in-
sight into the mechanistic aspects of this phenomenon.
Tris(amide) 33, containing the different chelators, was then
evaluated in a preparative orthogonal cleavage procedure ac-
cording to Scheme 5. The bpa group was selectively removed
by using FeCl3 in MeOH at 508C and intermediate 34 was iso-
lated in a yield of 70%. This rather moderate yield was the
result of difficulties during the chromatographic purification of
the highly polar basic compound. In the second step, the
methanolysis of the tetradentate amide was achieved in the
presence of Zn(OTf)2 at 508C; the resulting compound, 35, was
obtained in a high yield. Finally, the dmepa group was cleaved
with CuCl2 in MeOH at room temperature to result in trimethyl
ester 36.
In summary, we have developed a set of three structurally
related relay protecting groups for carboxylic acids that are
based on chelating amines. These protecting groups can easily
be introduced by coupling the carboxylic acid with the corre-
sponding amine by using TBTU as the coupling reagent. All
three protecting groups are chemically very robust. In addition
to being stable to reductive conditions and weak oxidizing re-
Keywords: amides · protecting groups · carboxylic acids ·
orthogonality · chelators
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Received: July 11, 2013
Revised: September 13, 2013
Published online on January 8, 2014
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