Site-Selective Acylations with Tailor-Made Catalysts

Article abstract of DOI:10.1002/chem.201600790

The acylation of alcohols catalyzed by N,N-dimethylamino pyridine (DMAP) is, despite its widespread use, sometimes confronted with substrate-specific problems: For example, target compounds with multiple hydroxy groups may show insufficient selectivity for one hydroxyl, and the resulting product mixtures are hardly separable. Here we describe a concept that aims at tailor-made catalysts for the site-specific acylation. To this end, we introduce a catalyst library where each entry is constructed by connecting a variable and readily tuned peptide scaffold with a catalytically active unit based on DMAP. For selected examples, we demonstrate how library screening leads to the identification of optimized catalysts, and the substrates of interest can be converted with a markedly enhanced site-selectivity compared with only DMAP. Furthermore, substrate-optimized catalysts of this type can be used to selectively convert "their" substrate in the presence of structurally similar compounds, an important requisite for reactions with mixtures of substances. Substrate-optimized catalysts: Site- selective acylations were achieved using substrate-optimized catalysts (see scheme) as identified from a library screening. The catalysts are composed of low-molecular-weight peptides that are readily tuned through variation of the amino acid sequence, and one amino acid was connected to DMAP to ensure catalytic activity. These substrate-optimized catalysts were also applied to selectively convert one substrate in the presence of a structurally similar compound.

Full text of DOI:10.1002/chem.201600790

DOI: 10.1002/chem.201600790
Communication
&
Acylation
Site-Selective Acylations with Tailor-Made Catalysts
Florian Huber and Stefan F. Kirsch*[a]
mum number of compounds of a certain class (i.e., “broad-
spectrum catalysts”). Although recently it became accepted
that the development of catalytic methods should involve the
assessment of the robustness to various functional groups,[3]
current research endeavors typically do not aim to find the
one catalyst that is tailor-made for one substrate. As a result,
only a quite small number of concepts exist to identify
substrate-optimized catalysts by mimicking natural evolution,
that is, the selection from diversity, in the laboratory.[4]
Abstract: The acylation of alcohols catalyzed by N,N-dime-
thylamino pyridine (DMAP) is, despite its widespread use,
sometimes confronted with substrate-specific problems:
For example, target compounds with multiple hydroxy
groups may show insufficient selectivity for one hydroxyl,
and the resulting product mixtures are hardly separable.
Here we describe a concept that aims at tailor-made cata-
lysts for the site-specific acylation. To this end, we intro-
duce a catalyst library where each entry is constructed by
connecting a variable and readily tuned peptide scaffold
with a catalytically active unit based on DMAP. For select-
ed examples, we demonstrate how library screening leads
to the identification of optimized catalysts, and the
substrates of interest can be converted with a markedly
enhanced site-selectivity compared with only DMAP.
Furthermore, substrate-optimized catalysts of this type
can be used to selectively convert “their” substrate in the
presence of structurally similar compounds, an important
requisite for reactions with mixtures of substances.
In the context of our recent studies on the defunctionaliza-
tion of polyhydroxylated compounds, we became interested in
the site-selective benzoylation of those compounds. However,
our benzoylation results with DMAP as the catalyst were con-
sistently disappointing, and product mixtures were obtained
that were mostly inseparable. For example, the catalyzed ben-
zoylation of ouabagenin-derived acetonide 1 led to a hardly
useful 3:1:1 mixture of the benzoates 2a and 2b and the di-
benzoylated compound 2c (Figure 1a).[5,6] We then developed
the concept to boost the site-selectivity by connecting DMAP
with a peptide scaffold. The DMAP unit of the new system
should still be accountable for catalyzing the acylation[7] while
the peptidic chain was expected to influence the selectivity,
ultimately affording substrate-optimized catalysts (i.e.,
“narrow-scope catalysts”, Figure 1b).
Enzymes are the standard catalysts of nature: With their vari-
ably shaped proteinogenic framework, they possess an unri-
valed specificity for one substrate, optimized through multiple
rounds of evolution. Enzymes are capable of fulfilling their
function in a highly selective manner, and structurally similar
substances in the biological system are not problematic. From
a synthetic chemist’s point of view, the arguably most aston-
ishing feature is that this way nature can avoid less economic
pathways as, for example, protecting group manipulations one
might find in numerous synthetic organic strategies.[1,2]
In quite a range of inspiring studies, Miller and co-workers
demonstrated that low-molecular weight peptides are highly
selective and readily tuned catalysts for a number of transfor-
mations.[8,9] In particular, the site-selectivities obtained with
polyfunctional targets underline the potential of short peptidic
sequences to create high degrees of selectivity and substrate
specificity, even in comparison with full grown proteins.[10] Our
idea was not to use the peptide by itself as the catalyst but to
attach a catalytically active unit to the peptide core. Thus, we
set out to discover DMAP-based small-molecule peptides that
could convert specific substrates with a significantly higher
site-selectivity than one would achieve by using mere DMAP
as the acylation catalyst.
The purpose of homogeneous catalysts as used in synthetic
chemistry is completely different: These catalysts are optimized
for an average substrate and the goal is to have a broadly ap-
plicable catalyst that is competent enough to convert a maxi-
It was planned to connect the DMAP unit through chemo-
selective alkyne–azide cycloaddition[11] to the peptide. To this
end, pyridine 3 bearing an azide group was constructed as
summarized in Figure 2a. The Fmoc-protected amino acid 4
with an additional alkyne moiety was the designed point of at-
tachment; the synthesis of Fmoc-4 is outlined in Figure 2b.[12]
We then created a random peptide library using automated
solid-phase synthesis with Fmoc chemistry.[13] To start the proj-
ect with a reasonable number of variants, each member of the
library contained between five and eight amino acids with one
amino acid being 4 (Figure 2c, see Supporting Information for
further details). Regarding the other amino acids, we decided
[a] Dr. F. Huber, Prof. Dr. S. F. Kirsch
Organic Chemistry
Bergische Universitꢀt Wuppertal
Gaußstr. 20, 42119 Wuppertal (Germany)
Fax: (+49)0202-439-2648
E-mail: sfkirsch@uni-wuppertal.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201600790.
ꢁ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of Creative Commons Attri-
bution NonCommercial License, which permits use, distribution and repro-
duction in any medium, provided the original work is properly cited and is
not used for commercial purposes.
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ethanol with Ac2O and NEt3 in CH2Cl2 at room tem-
perature. On the other hand, the peptides with
amino acid 4 (i.e., no DMAP attached) showed no
catalytic activity, and ester formation was typically
not observed when attempting the acetylation of 1-
phenylethanol. If otherwise, those sequences were
not considered any further.
We then began to study whether it is possible to
optimize the DMAP-catalyzed acylation of dihydroxy-
lated substrates with regard to the site-selectivity
(Figure 3). The sample reactions were typically run
with almost equimolar amounts of the acylating
agent and were stopped before full conversion was
reached. The benzoylation of glucose-derived diol 6,
for example, gave only a poor selectivity with DMAP
(7a/7b = 2.8:1), and significant amounts of the di-
benzoylated product were found. Our library was
then screened for the reaction, and we were able to
obtain a strikingly higher selectivity (7a/7b = 28:1)
Figure 1. a) Insufficient selectivity in the DMAP catalyzed benzoylation of ouabagenin-
derived 1. b) Catalyst design consisting of peptide scaffold and DMAP unit.
to focus on a selection of 11 amino acids, Ala, Val, Leu, Pro,
Phe, Thr, Ser, Gln, Asp, His, and Lys; this selection should cover
the most important characteristics of the side chains, and the
conceivable diversity should be suitable for a proof of concept.
Of note, the peptide structures we generated possessed an
acetyl group at the N-terminus and the C-terminus was the
amide instead of the free carboxylic acid. While still attached
to the solid-phase, the small peptides were connected with
DMAP derivative 3 under standard copper-catalyzed cycloaddi-
tion conditions, thus forming the artificial amino acid 5. Upon
cleavage from the solid support, the stage was set for the
activity screening of our DMAP-peptide conjugates (Figure 2d).
For a start, it was verified that all 154 DMAP-containing
peptides of our library catalyzed the acetylation of 1-phenyl-
when employing 10 mol% of Ac-Val-Pro-Phe-5-Leu-Asp-NH2;
the dibenzoylated product was hardly found under the reac-
tion conditions.[14] Since the selective modification of sugar de-
rivatives is of great interest, and a range of valuable strategies
were developed to achieve this goal,[15,16,17] we continued to
review the performance of our screening concept in this realm.
When optimizing the benzoylation of diol 8, a compound
closely similar to 6 but with an additional nitro group, Ac-Ala-
Thr-5-Val-Pro-Ser-Asp-NH2 was found to be the best hit (Fig-
ure 3b). This result highlights how subtle changes in substrate
structure can influence the screening outcome. The screening
also led to optimized catalysts for the benzoylation of man-
nose- and galactose-derived substrates. For example, manno-
side 10 was monobenzoylated with a selectivity up to 5:1 for
the C3-hydroxyl using Ac-Val-5-Val-Phe-Val-His-Lys-NH2. Re-
markably, the screening also revealed a catalyst (i.e., Ac-Pro-5-
Asp-Val-Ser-Asp-Gln-NH2) that gave the inversed selectivity
(11 a/11 b = 2:1), albeit with low conversion. In the case of gal-
actose-derived diol 12, we were capable of boosting the site-
selectivity of the acetylation to a ratio of 15.5 to 1 by using Ac-
Ala-Thr-5-Val-Pro-Ser-Asp-NH2, a ten-fold increase in compari-
son to DMAP (Figure 3d). The optimization of the benzoylation
of rhamnoside 14 was also successful: An excellent selectivity
for the benzoylation of the C3-hydroxyl was found with
10 mol% of Ac-Asp-Ser-Ala-Pro-Phe-5-Pro-NH2. Last of all, we
turned back to our starting question of how to improve the
benzoylation of ouabagenin-derived acetonide 1 (Figure 3 f).
To our delight, we could significantly raise the ratio between
the benzoates 2a and 2b from 3:1 to 33.3:1 by applying our
concept. It was found through screening of the library of
DMAP-peptide conjugates that the catalyst of choice was Ac-
Val-5-Phe-Pro-Ala-Leu-Lys-NH2, in this case.
We then questioned whether our screening hits were also
suited to make preparative scale acylations possible. To this
end, several substrates were examined, and the respective acy-
lation reactions were run until complete conversion, in the
presence of 10 mol% of the optimized catalysts that were
identified from the screening. We were pleased to find that
Figure 2. a) Synthesis of 3. b) Synthesis of Fmoc-4. c) Creation of peptide
libraries through Fmoc-SPPS. d) Synthesis of DMAP-peptide conjugates.
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Figure 3. Selected examples for the optimization of the site-selectivity of acylations by use of DMAP-peptide conjugates. Product ratios were determined as
detailed in the supporting information.
the selected catalysts performed their specific tasks properly
with high isolated yields for the desired products (Scheme 1).
For example, benzoate 7a was obtained in 91% yield from
diol 6; Ac-Val-Pro-Phe-5-Leu-Asp-NH2 was tailor-made for this
transformation. Despite the huge excess of Bz2O and elongat-
ed reaction times, the formation of the dibenzoylated product
7c was not observed. Other substrates (e.g., 8 and 12) reacted
equally well with their optimized catalysts. Of particular impor-
tance to us was the reaction of ouabagenin-derived acetonide
1 that gave benzoate 2a in excellent 86% yield by use of
10 mol% of Ac-Val-5-Phe-Pro-Ala-Leu-Lys-NH2.
Notably, at the outset of the study, we were unclear as to
whether our screening concept can produce a substrate-specif-
ic hit with markedly better performance than DMAP as our
random library was, admittedly, rather small (154 entries). This
lack of diversity was a particular concern since we had deliber-
ately abstained from any models and assumptions on what
peptide sequences would be optimal. Therefore, we were
delighted to find that efficient catalysts, superior to DMAP in
terms of site-selectivity, were identified for all the challenges
where the concept was put to test.[18]
We briefly demonstrated that the library screening can also
produce substrate-optimized catalysts that can be used to se-
lectively convert one substrate in the presence of structurally
similar compounds (Figure 4).[19] For example, an equimolar
mixture of glucose-derived diol 6 and the analogous mannose
derivative 10 yielded a hardly separable mixture of the
benzoates 7a, 7b, 11 a and 11 b when treated with Bz2O and
catalytic amounts of DMAP. On the contrary, our best hit from
the library was Ac-Lys-Leu-Leu-Gln-Ala-Pro-5-NH2, which gave
an excellent selectivity for the formation of the benzoylated
glucoside 7a while leaving mannoside 10 mostly untouched
(Figure 4a). On a preparative scale, we were able to isolate 7a
in 91% yield, and 52% of the starting compound 10 could be
recovered under the reaction conditions: 6 (1 equiv), 10
Scheme 1. Isolated yields for selected acylations by use of tailor-made
DMAP-peptide conjugates.
(1 equiv), Ac-Lys-Leu-Leu-Gln-Ala-Pro-5-NH2 (10 mol%), Bz2O
(5 equiv), NEt3 (15 equiv), À158C, 38 h, CHCl3. Although most
of the substrates we tested so far were derived from carbohy-
drates, our concept is not restricted to this class of substrates.
As shown in Figure 4b, we were able to selectively convert
deoxycholic acid (16) into its acetate 18; with Ac-Asp-Thr-Lys-
5-Ser-Asp-His-Leu-NH2 as the catalyst of choice, the present
cholesterol (17) remained mainly unreacted, even after 12 h of
reaction and with an excess of Ac2O. Under the same set of
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Figure 4. Selective acylations with mixtures of substrates.
conditions, DMAP gave an almost 1:1 mixture of acetates 18
and 19.
to the selection of catalysts tailor-made for the site-selective
acylation of the target molecules. We have also shown that
this concept has potential in optimizing the reactions of com-
pound mixtures, where the desired acylation of one compound
is to be paired with the other compound remaining
unreactive.
Finally, we intend to highlight how the site-selective benzoy-
lation can be used to rapidly produce deoxygenated molecules
if the benzoates are fully removed through photosensitized de-
oxygenation with, for example, 3,6-dimethyl-9-ethylcarbazole
(DMECZ) as the photosensitizer.[20] As outlined in Scheme 2,
the combination of the two methodologies, that is, the
catalyzed benzoylation followed by the photosensitized deoxy-
genation, has potential to streamline synthetic sequences by
reducing the need for protecting groups. Glucopyranoside 6
was converted into the 2-deoxy compound 20 in a highly
straightforward manner with this two-step sequence (70%
yield over two steps). Galactopyranoside 12 was deoxygenated
in 70% yield using the same sequence. Further applications
will be reported in due course.
Acknowledgements
We gratefully acknowledge the experimental works by M.Sc.
Arik Mçller on the ouabagenin defunctionalization.
Keywords: acylations
· catalysis · libraries · peptides ·
regioselectivity
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Published online on && &&, 0000
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COMMUNICATION
Substrate-optimized catalysts: Site-
selective acylations were achieved using
substrate-optimized catalysts (see
scheme) as identified from a library
screening. The catalysts are composed
of low-molecular weight peptides that
are readily tuned through variation of
the amino acid sequence, and one
amino acid was connected to DMAP to
ensure catalytic activity. These sub-
strate-optimized catalysts were also
applied to selectively convert one sub-
strate in the presence of a structurally
similar compound.
&
Acylation
F. Huber, S. F. Kirsch*
&& – &&
Site-Selective Acylations with Tailor-
Made Catalysts
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