Reactive esters in amide ligation with β-hydroxyamines

Article abstract of DOI:10.1002/ejoc.201200624

Amide formation between mildly activated esters and 1,2-amino alcohols occurs without the need for coupling reagents. The reaction pathway involves facile intermolecular transesterification and intramolecular O→N transacylation. The method is environmentally friendly and offers no risk of racemization via highly activated acylating intermediates. Exploiting a surprisingly easy initial transesterification process, amides are formed from hydroxyamines and lactones or cyanomethyl esters. Reactions occur rapidly without risk of racemization. Copyright

Full text of DOI:10.1002/ejoc.201200624

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200624
Reactive Esters in Amide Ligation with β-Hydroxyamines
Michael C. Pirrung,*[a] Fa Zhang,[a] Sudhakar Ambadi,[a] and Tannya R. Ibarra-Rivera[a,b]
Keywords: Amides / Acylation / Green chemistry / Transesterification / Peptides
Amide formation between mildly activated esters and 1,2-
amino alcohols occurs without the need for coupling rea-
gents. The reaction pathway involves facile intermolecular
transesterification and intramolecular OǞN transacylation.
The method is environmentally friendly and offers no risk of
racemization via highly activated acylating intermediates.
Introduction
The preparation of amides is among the most heavily
investigated organic reactions. Methods and reagents for
amide formation developed for solid-phase peptide synthe-
sis are widely applied outside that field. However, these
methods are often unsuitable for solution-based preparative
processes because they use excessive amounts of expensive
coupling reagents and create significant waste streams.
Nonetheless, advances in amide formation continue to be
reported,[1] and these methods address such issues as cataly-
sis, sustainability, and versatility.
Results and Discussion
Scheme 1. Facile lactone amidation via transesterification.
During studies on the synthesis of non-ribosomal poly-
peptide natural products,[2] we observed a facile reaction
between lactone 1 (obtained by iodolactonization of allyl-
glycine)[3] and alaninol (2) to form β-hydroxyamide 3
(Scheme 1). We surmised that this process might occur via
reaction of the activated ester of the lactone by initial trans-
esterification, followed by rearrangement of the ester to the
more stable hydroxy amide. Good evidence for the pro-
posed transesterification/transacylation pathway was ob-
tained by substituting tBuMe2SiO–alaninol in this reaction;
only starting material was recovered.
known compound 6 (Scheme 2), to further examine amide
ligations via transesterification. Results are summarized in
Table 1. Reactions were performed at a 1-m initial ester con-
centration. Entry 1 (Table 1) gives the result for Movas-
saghi’s NHC-catalyzed reaction; however, he did not exam-
ine the uncatalyzed background reaction, which we studied
in Entry 2 (Table 1). It shows that the NHC provides only
a ca. twofold rate acceleration in the reaction of 4, with a
major decrease in convenience because it requires an inert
atmosphere.
Support for the proposed pathway is also found in the
work of Movassaghi,[4] who studied reactions of β-amino
alcohols with a range of esters employing a N-heterocyclic
carbene (NHC) catalyst. We chose one reaction from Mov-
assaghi’s study, γ-butyrolactone and ethanolamine giving
Scheme 2. Butyrolactone reaction with ethanolamine.
[a] Department of Chemistry, University of California,
Riverside, CA 92521 USA
Fax: +1-951-827-2722
Variations in reaction parameters (solvent, additives,
time, temperature) were examined to increase ligation effi-
ciency. To permit economy with more precious amino
alcohols, equimolar amounts of 5 and 4 were used. The
reaction of 4 is slower than 1, owing to the electron-with-
drawing α-amino group of 1. Patience or mild heating still
E-mail: michael.pirrung@ucr.edu
Homepage: faculty.ucr.edu/~michaelp/index.htm
[b] Current address: Department of Analytical Chemistry,
Autonomous University,
Nuevo León, Monterrey, Mexico
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200624.
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M. C. Pirrung, F. Zhang, S. Ambadi, T. R. Ibarra-Rivera
Table 2. Reaction scope for lactone hydroxyamidation.
SHORT COMMUNICATION
Table 1. Reaction optimization for the preparation of 6.
Entry Time [h] T [°C]
Solvent
Catalyst Yield [%]
Entry
Lactone
Aminol
Method A
Method B
1
2
3
4
5
6
7
8
6
6
60
6
25
25
25
reflux
25
25
THF
THF
CH2Cl2
CH2Cl2
toluene
toluene
toluene
NHC
none
none
none
none
none
none
none
none
none
TBD
TBD
TBD
TBD
88
51
83
79
74
79
84
85
84
84
88
78
86
92
1
2
3
4
5
6
7
8
4
4
4
4
7
7
7
7
7
8
8
8
8
8
2
9
10
11
5
2
9
10
11
5
2
9
10
11
38
25
27
65
90
87
83
83
92
84
64
59
60
38
81
70
74
79
58
48
60
58
55
73
40
36
31
55
6
12
18
1
6
6
6
1
1
1
25
120[a]
25
toluene
9
hexane[b]
cyclohexane[b]
toluene
9
10
11
12
13
14
25
25
25
25
10
11
12
13
14
toluene
hexane[b]
cyclohexane[b]
25
[a] Microwave heating. [b] Heterogeneous.
method B. Method B also works well with 3-amino-1-
propanol, so these reactions are not limited to β-amino
alcohols.
allows 6 to be obtained in high yield. The fastest reaction
occurs with microwave heating. Somewhat surprising was
that the reaction improves in nonpolar solvents, with the
best solvents being hydrocarbon-based. For hexanes and cy-
clohexane, the lactone was insoluble, so the reaction essen-
tially occurred neat.
A variety of transesterification catalysts were investi-
gated, including Et3N, TiIV salts, and carboxylic acids, but
all had no effect. However, triazabicyclodecene (TBD),[5]
a
recently identified catalyst, proved effective even at 5 mol-
% (earlier work used 10 mol-%). Fast reactions required the
combination of an amino alcohol with the TBD catalyst
and a nonpolar solvent.
Other available γ-lactones and amino alcohols (Figure 1)
were examined under the conditions from Entry 8 (Table 1,
method A) and Entry 14 (Table 1, method B). Yields from
each combination under the same conditions are given in
Table 2. To permit structure–reactivity relationships to be
discerned, reactions were not individually optimized. γ-
Butyrolactone is particularly efficient in TBD-catalyzed re-
actions, but Boc-homoserine lactone (7) and (R)-panto-
lactone (8) are better ligated under microwave heating.
Lactones 7 and 8 are expected to be more reactive than γ-
butyrolactone owing to their polar α-substituents, as ascer-
tained by method A. Their steric hindrance may inhibit re-
action with TBD.
Scheme 3. Chain length variation in each reactant.
While these results were interesting and useful, lactones
are only a small subset of carboxylic acid derivatives, so
another mildly activated ester was sought that could be pre-
pared from any acid. We were particularly interested in ap-
plying this ligation to α-amino acids. A number of examples
of transesterification reactions of cyanomethyl esters of
amino acid derivatives with nucleotide hydroxy groups are
known,[6] prompting our evaluation of their reactions with
amino alcohols. Because conventional formation of peptide
bonds at hindered valine residues can be challenging, valine
was used to test the idea.
Formation of the cyanomethyl ester of Boc-valine pro-
ceeded in quantitative yield with bromoacetonitrile
(2 equiv.) and Cs2CO3 in acetonitrile (1 h, r.t.). Conditions
for ligation of alaninol (1.5 equiv.) to 14 were then exam-
ined (Table 3, Scheme 4). All of these reactions were per-
formed at a concentration of 1 m. Adequate reactivity was
observed in THF, but reactions were faster with the ad-
dition of 20% acetic acid and heating at reflux. Other apro-
tic solvents were examined, and for the most part the sol-
vent effect was small, but cyclohexane again proved supe-
rior. The best results (Table 3, entries 16, 17) were seen with
Figure 1. Lactones and 1,2-amino alcohols studied in this amide
ligation.
δ-Caprolactone was nicely reactive under method A de- extended reaction at ambient temperature or a quick reac-
spite its reduced ring strain compared to butyrolactone tion with microwave heating. TBD was not a very effective
(Scheme 3), but results nearly as good were obtained with catalyst for this reaction.
2
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Reactive Esters in Amide Ligation with β-Hydroxyamines
Table 3. Reaction optimization for the preparation of 15.
Entry Time [h]
T [°C]
Solvent
Additive Yield [%]
1
2
3
4
5
6
7
8
60
1.5
24
60
60
1.5
24
60
60
1.5
60
1.5
1.5
60
1.5
60
1.5
1.5
25
100[a]
reflux
25
THF
THF
THF
MeCN
THF
THF
CH2Cl2
toluene
DCE
none
none
71
61
68
53
78
75
66
58
58
55
68
71
57
74
74
90
82
68
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
TBD
25
100[a]
reflux
25
9
25
10
11
12
13
14
15
16
17
18
100[a]
25
DCE
EtOAc
EtOAc
toluene
hexane
hexane
cyclohexane
cyclohexane
cyclohexane
Scheme 5. Ligations with oxazolidinones.
100[a]
100[a]
25
100[a]
25
Because serine and cysteine are simply more complex
amino alcohols and amino thiols, the idea of forming pept-
ide bonds through processes similar to these has a substan-
tial history. There are straightforward intellectual progeni-
tors, such as native chemical ligations, “isopeptides” or
“switch peptides”,[9] as well as more convoluted approaches
using auxiliary groupings.[10] Here, we took the simple ap-
proach of treating 18 with ethyl serinate, which gave dipept-
ide 19 without racemization and in adequate yield for an
initial investigation (Scheme 5).
100[a]
25
[a] Microwave heating.
Conclusions
To explain our observation of facile hydroxyamide lig-
ation of mildly activated esters, we hypothesize that the 1,2-
amino alcohol is especially reactive toward transesterifica-
tion, which could be due to an internal hydrogen bond be-
tween the amine and the OH group (Figure 2). This could
also explain the preference for nonpolar solvents, as they
do not compete with the internal nitrogen as H-bond ac-
ceptors.
Scheme 4. Ligation via cyanomethyl esters.
One potential drawback of ligations via cyanomethyl es-
ters is the coproduction of formaldehyde and the cyanide
ion (or glycolonitrile). Reactions were therefore completed
by addition of 2 equiv. of sodium ferrate, a mild oxidant
that destroys both,[7] and raising the pH of the solution to
9. The absence of cyanide was established with cyanide test
strips.
Ligations of diverse amino alcohols with 14 to give
amides 16 were then examined under the conditions of en-
try 6 (Table 3). An additional reactant examined was 17,
Figure 2. Internal hydrogen bonding may enhance amino alcohol
which gave the amide in 79% yield and demonstrated that transesterification.
secondary alcohols can participate in the postulated trans-
esterification step. The R isomer of alaninol provided au-
thentic samples of the diastereomer of 15 (71% yield) that
would be produced if the coupling of 2 with 14 caused race-
Experimental Section
mization. By comparing the 13C NMR spectra of these
products, it was possible to establish Ͼ99.5% retention of
configuration in this ligation. The other amino alcohols
studied here gave good results in reactions with 14: 5, 87%;
9, 83%; 10, 81%; 11, 92%.
This success stimulated investigation of α-amino acid es-
ters that combine lactone and acetal functionality: oxazol-
idinones. They can be derived in one step from Boc amino
acids under acidic or basic conditions[8] and offer the same
inductive activation from the α-amino group as 1. Here,
Boc-valine oxazolidinone 18 reacted with alaninol to give
d-(–)-Pantolactone (2.00 g, 15.4 mmol), ethanolamine (939 mg,
15.4 mmol), and anhydrous toluene (15.4 mL) were added to a
round-bottomed flask with a stir bar. The reaction mixture was
heated at 120 °C for 1 h in a CEM Discover monomode microwave
reactor. Temperature was monitored with the IR temperature fea-
ture of the reactor. After concentration, the residue was purified
by flash chromatography on silica gel (CH2Cl2/MeOH, 90:10) to
provide the product as a light yellow oil (2.666 g, 91% yield). The
1H NMR spectrum matched literature data.[11]
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra for key new com-
15 in high yield under the mildest of conditions (Scheme 5). pounds.
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M. C. Pirrung, F. Zhang, S. Ambadi, T. R. Ibarra-Rivera
SHORT COMMUNICATION
[6] a) Y. Goto, H. Suga, J. Am. Chem. Soc. 2009, 131, 5040–5041;
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[8] a) G. J. Friis, A. Bak, B. D. Larsen, S. Frøkjær, Int. J. Pharm.
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Received: May 11, 2012
Published Online: ᭿
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Reactive Esters in Amide Ligation with β-Hydroxyamines
Amide Ligation
M. C. Pirrung,* F. Zhang, S. Ambadi,
T. R. Ibarra-Rivera ............................ 1–5
Reactive Esters in Amide Ligation with β-
Hydroxyamines
Exploiting a surprisingly easy initial trans-
esterification process, amides are formed
from hydroxyamines and lactones or
cyanomethyl esters. Reactions occur rap-
idly without risk of racemization.
Keywords: Amides / Acylation / Green
chemistry / Transesterification / Peptides
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