α-boryl isocyanides enable facile preparation of bioactive boropeptides

Article abstract of DOI:10.1002/anie.201302818

Entry to bioactive boropeptides: MIDA-containing α-boryl isocyanides are isolable molecules which allow one-step access to boroalkyl-functionalized heterocycles as well as biologically active boropeptides through a multicomponent approach. Among these derivatives are 6-boromorpholinones, novel borocycles with nanomolar IC₅₀ values for 20S proteasome inhibition. MIDA=N-methyliminodiacetyl. Copyright

Full text of DOI:10.1002/anie.201302818

Angewandte
Chemie
Communications
Multicomponent Reactions
Entry to Bioactive Boropeptides: MIDA-
containing a-boryl isocyanides are isol-
able molecules which allow one-step
access to boroalkyl-functionalized het-
erocycles as well as biologically active
boropeptides through a multicomponent
approach. Among these derivatives are 6-
boromorpholinones, novel borocycles
with nanomolar IC50 values for 20S pro-
teasome inhibition. MIDA=N-methyli-
minodiacetyl.
A. Zajdlik, Z. Wang, J. L. Hickey, A. Aman,
A. D. Schimmer,
A. K. Yudin*
&&&& — &&&&
a-Boryl Isocyanides Enable Facile
Preparation of Bioactive Boropeptides
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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Communications
DOI: 10.1002/anie.201302818
Multicomponent Reactions
a-Boryl Isocyanides Enable Facile Preparation of Bioactive
Boropeptides**
Adam Zajdlik, Zezhou Wang, Jennifer L. Hickey, Ahmed Aman, Aaron D. Schimmer, and
Andrei K. Yudin*
Boronic acids and their derivatives have found utility as
reagents, we considered an isocyanide/boron combination as
an entry into pivotal B-C-N motifs. At the outset, we were
aware of the known propensity of tricoordinate boron to react
[
1]
[2]
synthetic building blocks, chemosensors, and as biologi-
[
3]
cally active targets of synthesis. Both the biological activity
and chemical reactivity of boronic acids stem from boronꢀs
Lewis acidity. While useful in a broad range of applications,
boronꢀs propensity to undergo reactions with Lewis bases
becomes problematic for functional-group compatibility
during synthesis. Reagents that streamline
[
9]
with isocyanides. Rapid decomposition upon exposure to air
has been an additional impediment to synthetic application of
[
10]
boron-containing isocyanides. To circumvent this undesired
reactivity, we focused our search on fragments with tetra-
coordinate boron. In N-methyliminodiacetyl (MIDA) boro-
nates, an intramolecular coordinative stabilization of the
empty p orbital on boron effectively masks its Lewis acid-
installation of a carbon–boron bond in ste-
reochemically complex, heteroatom-rich
environments, are expected to find applica-
[
11]
ity.
The tetracoordinate boronate fragment tolerates
tion not only as starting materials but also as
late-stage precursors to the endpoints of
synthesis. In regards to the latter, the boryl-
a diverse range of functional-group transformations, thus
allowing access to a variety of borylated derivatives. These
include a-boryl aldehydes, which contain a carbon–boron
Figure 1. The
[12]
borylamide
motif.
amide motif (Figure 1), found in the struc-
bond adjacent to an electrophilic aldehyde, and a-boryl
isocyanates 1 (for structure see Table 1), reagents which are
now readily available.
tures of biologically active boropeptides, is of
[3g]
[13]
particular significance.
Our recent efforts have been focused on the development
of amphoteric molecules for the synthesis of bioactive
The structural stability of the a-boryl isocyanates 1 in
various reactions prompted us to attempt a trichlorosilane-
[
4]
[14]
peptides and peptidomimetics. In our studies, we seek
functionally dense, heteroatom-rich environments where
a kinetic barrier prevents two otherwise reactive functional
mediated deoxygenation, which afforded the correspond-
ing isocyanides 2 as solid materials stable to column
chromatography (Table 1). To explore the properties of
[
5]
groups from prematurely reacting with each other. Herein
we expand the scope of this methodology to include boron-
containing isocyanides for use in multicomponent preparation
of boropeptides and their derivatives. Our study has resulted
in the synthesis of a novel heterocyclic motif—the boromor-
pholinone. This scaffold has enabled us to identify a novel
proteasome inhibitor with nanomolar activity.
[
a]
Table 1: Preparation of MIDA a-boryl isocyanides.
[
6]
Acting as 1,1-amphoteric molecules, isocyanides enable
[7]
[b]
heterocycle synthesis and participate in multicomponent
Starting Material
R
Product
Yield [%]
[
8]
reactions (MCRs) such as Ugi and Passerini processes. As
part of our effort to develop amphoteric boron-transfer
1
1
1
a
b
c
isobutyl
cyclohexyl
phenyl
2a
2b
2c
75
31
30
[
*] A. Zajdlik, J. L. Hickey, Prof. Dr. A. K. Yudin
Davenport Research Laboratories
Department of Chemistry, University of Toronto
[
(
a] The reactions were carried out by stirring a-boryl isocyanate
1.0 equiv), trichlorosilane (1.6 equiv), and triethylamine (3.6 equiv) in
anhydrous CH Cl at 08C for 30 min and subsequent stirring for 6 h at
2
2
80 St. George St., Toronto, ON M5S3H6 (Canada)
2
38C. [b] Yields of isolated products after silica gel chromatography.
E-mail: ayudin@chem.utoronto.ca
Dr. Z. Wang, Dr. A. D. Schimmer
Ontario Cancer Institute, Princess Margaret Cancer Center
University Health Network, Toronto, ON M5G2M9 (Canada)
these compounds we first investigated the possibility of
[7a]
deprotonation a to the isocyanide nitrogen atom. During
an attempted a-deprotonation using weak bases (10 equiv of
Et N or 15 equiv of NaHCO ) in deuterated solvents (D O or
Dr. A. Aman
Ontario Institute for Cancer Research, MaRS Centre, South Tower
3
3
2
101 College St. S., Suite 800 Toronto, ON M5G0A3 (Canada)
[
D ]MeOH) there was no observable decrease in the integra-
4
[
**] We would like to thank the Natural Science and Engineering
Research Council (NSERC) and Canadian Institutes of Health
Research (CIHR) for financial support.
1
tion of the a-proton signal in the H NMR spectra. Under
strongly basic conditions (1 equiv of potassium tert-butoxide)
and subsequent exposure to [D ]MeCN, a similar stability
towards a deprotonation was observed. Interestingly, tetra-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302818.
3
2
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Chemie
[
19]
deuteration of the MIDA moiety was seen in both the
H NMR and HRMS spectra. This example supports the
isolation (Scheme 2). In a number of other reactions, we
have found that methanol solvolyzes the MIDA moiety, thus
yielding decomposition products. The reaction was attempted
in 2,2,2-trifluoroethanol (TFE) given its decreased nucleo-
philicity relative to methanol. However, the desired product
was not obtained.
1
notion that competitive enolization of the MIDA protons
[
15]
offers a protective function.
The configurational stability of the a proton led us to
focus our efforts on a variety of isocyanide functionalizations
(
Scheme 1). Selenium-catalyzed sulfurization gave rise to the
We shifted our focus to U4CRs using N-protected amino
acids or peptides as the carboxylic acid component and
ammonia as the amine. The reactions proceeded at room
temperature to give the desired diastereomers of the pro-
tected boropeptides 9 in moderate to excellent yields
[
8e]
(Table 2). In most cases, the diastereomers were separable
by HPLC. For larger peptides separation became more
difficult as a result of considerable peak overlap.
[
a]
Table 2: Preparation of protected boropeptides using 2a.
Scheme 1. Functionalization of 2a. a) a-Boryl isocyanide 2a
(
(
(
2
(
1.0 equiv), sulfur (1.2 equiv), selenium (5.0 mol%) and triethylamine
2.4 equiv) in THF at 808C for 15 min. b) a-Boryl isothiocyanate 3a
1.0 equiv) and amine (2.0 equiv) in THF at 238C. c) a-Boryl isocyanide
[b]
[c]
Entry
Peptide/AA
R
Product
t [d]
Yield [%]
1
2
3
4
5
6
7
8
G
G
F
V
GG
FA
PLF
PGLF
benzyl
9a
9b
9c
9d
9e
9f
7
6
10
6
6
6
69
79
74
57
92
91
63
76
a (1.0 equiv), HCl (2.0 mol%), and TMSN (1.5 equiv) in THF/Et O
isopropyl
isopropyl
benzyl
benzyl
benzyl
3
2
1:1) at 608C for 6.5 h. [a] Yields of isolated products after silica gel
chromatography. TMS=trimethylsilyl.
[16]
benzyl
benzyl
9g
9h
7
12
a-boryl isothiocyanate 3a in moderate yield. Reaction of
3
4
2
a with various amines afforded the corresponding thioureas
[17]
[
(
a] The reactions were carried out by stirring a-boryl isocyanide 2a
1.0 equiv), aldehyde (1.0 equiv), ammonia (1.5 equiv, 7n solution in
MeOH), and peptide (1.0 equiv) in TFE at 238C. [b] Boc-protected at
N terminus; written from N to C terminus using standard one-letter
amino acid abbreviations. [c] Yield of diastereomeric products deter-
mined by comparison of the integration of the H NMR signals of the
product with that for 3,4,5-triiodobenzoic acid, which was used as an
internal standard.
aa and ab in excellent yields. Reaction of the isocyanide
a with in situ generated hydrazoic acid yielded the a-boryl
[
7b]
tetrazole 5a in moderate yield.
Successful retention of the carbon–boron bond during
functionalization of the isocyanide moiety further prompted
us to investigate more challenging transformations. We found
that 2a participated in an Ugi four-component reaction
1
(
U4CR) with 2-pyrazinyl carboxylic acid, phenylacetalde-
hyde, and ammonia. This reaction affords a streamlined
[
18]
approach to the bortezomib analogue 7a in 55% yield upon
isolation (Scheme 2).
The successful participation of 2a in U4CRs led us to
explore its applicability in the Passerini three-component
[
8e–g]
We attempted to generalize the U4CR reaction of 2a by
employing amino acids as both the acid and amine compo-
nents. When 2a was reacted with l-proline and isobutyralde-
hyde, the borodipeptide 8a was obtained in 7% yield upon
reaction (P3CR).
We found this reaction to proceed
smoothly with a variety of aldehydes, thus affording minimal
by-products (Table 3). Generally, the P3CR products 10 could
be isolated in an acceptably pure form with simple aqueous
workup. The two diastereomers could be separated by flash
column chromatography on silica gel in the vast majority of
cases. The reaction proceeded with moderate to excellent
yields. The rate of the reaction could be increased at elevated
temperature and pressure (1008C, mwave, 25 min), however,
this occurred at the expense of selectivity for the desired
product. Dichloromethane was found to be an ideal solvent as
protic solvents did not yield the desired product and the
isocyanide was not soluble in diethyl ether or tetrahydro-
furan.
We then attempted to remove the MIDA group from the
the P3CR product syn 10ad under aqueous basic conditions
[12c]
to afford the corresponding free boronic acid (Scheme 3).
Scheme 2. U4CRs involving 2a.
We found that under the deprotection conditions, hydrolysis
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Angewandte
Communications
[
a]
Table 3: P3CRs involving a-boryl isocyanides.
1
2
[b]
Entry
1
R
R
Product
t [d]
Yield [%]
isobutyl
isobutyl
isobutyl
isobutyl
isobutyl
isobutyl
isobutyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
phenyl
phenyl
isopropyl
4-FC H4
benzyl
3-pyridinyl
4-MeC H4
2-BrC H4
phenyl
isopropyl
benzyl
3-pyridinyl
benzyl
10aa
10ab
10ac
10ad
10ae
10af
10ag
10ba
10bb
10bd
10be
10ca
7
4
4
4
2
4
7
7
7
4
2
7
81
68
60
56
79
50
93
53
46
57
42
61
[
c]
2
3
4
5
6
7
8
9
1
1
1
6
6
Figure 2. In vitro cytosolic chymotrypsin-like 20S proteasome inhibition
by anti-11ad. The results were obtained in triplicate and averaged.
Errors shown indicate one standard deviation.
6
0
1
2
linone anti-11ad selectively inhibited the CT-L enzymes over
both the caspase-like (C-L) and trypsin-like (T-L) enzymes
with a C-L IC50 value of 2.0 mm (bortezomib: 3.2 nm) and no
observable inhibition of the T-L enzymes under 10 mm (see
the Supporting Information). The diastereomer syn-11ad was
prepared from anti-10ad and exhibited inhibition of the CT-L
enzymes with an IC50 value roughly 20 times greater than that
of the anti-11ad (52 nm versus 2.9 nm in the same assay), thus
suggesting that the correct relative stereochemistry is critical
to activity.
[
(
a] The reactions were carried out by stirring a-boryl isocyanide
1.0 equiv), aldehyde (1.0 equiv), and phenylacetic acid (1.0 equiv) in
CH Cl at 238C. [b] Yields of isolated products after silica gel chroma-
2
2
tography. [c] The two diastereomeric products could not be separated by
silica gel chromatography. Boc=tert-butoxycarbonyl.
While unprotected boropeptides are known to inhibit
members of the 20S proteasome, the instability of the free
[
1]
boronic acid moiety under biological conditions limits the
feasibility of oral administration. We therefore questioned
whether the protected nature of MIDA-protected boropep-
tides, which exhibit improved stability under biological
[
1]
Scheme 3. Deprotection/condensation of P3CR product syn-10ad.
conditions, would shut down their biological activity. To
investigate this, we subjected each diastereomer of 7a to the
CT-L 20S proteasome inhibition assay with unprotected
bortezomib as a control. We observed low nanomolar
inhibition of the CT-L enzymes for both diastereomers
(IC50 values of 22 and 71 nm for diastereomers A and B,
respectively; bortezomib 0.15 nm).
of the ester also occurred, followed by condensation of the
resulting free hydroxyl group with the newly formed boronic
acid. This process yielded the disubstituted 6-boromorpholi-
none anti-11ad as an air-stable white solid. The relative
stereochemistry of the novel borocycle anti-11ad was deter-
mined by computational modeling of the starting material.
The similarity in potency and selectivity of anti-11ad and
7a compared to bortezomib led us to question whether their
structural differences might give rise to differences in cell
permeability. We subjected each of these compounds to
[20]
Computational predictions (MPW1PW91, 6-311G(2d, p))
1
of several H NMR chemical-shift differences between the
two diastereomers (syn and anti) of 10ad correlated well with
experimental observations, thus allowing an inference of the
[
22]
a Caco-2 screening assay and found that anti-11ad exhib-
ited greatly improved cell permeability compared to both 7a
and bortezomib. The latter two yielded similar cellular
permeability (see the Supporting Information). In a control
experiment, we found that in the absence of cells and cell
lysates, 7a is partially hydrolyzed to the free boronic acid
when incubated at 378C in buffered aqueous solution (see the
Supporting Information). We therefore attribute the results of
both the 20S proteasome inhibition and Caco-2 assays for this
compound to its buffer-mediated hydrolysis forming the
active species during the assay.
relative stereochemistry. We determined the pK value of the
a
boron center in anti-11ad to be approximately 9.0 in aqueous
1
1
methanol by using a titration monitored by B NMR/ESI
[
21]
MS. This is an important value towards the prediction of 6-
boromorpholinone behavior during in vitro and in vivo stud-
ies based on accessible pH.
Given the known propensity of boropeptide analogues to
[
3e–g]
inhibit members of the 20S proteasome
we decided to
investigate the interaction of anti-11ad with various members
of this protease family. We found that anti-11ad inhibited the
In summary, we have outlined the preparation and utility
of bench-stable a-boryl isocyanides. These novel amphoteric
reagents can be applied to the synthesis of boron-containing
building blocks (tetrazoles, isothiocyanates, and thioureas)
[21]
chymotrypsin-like (CT-L) members of the 20S proteasome
with an IC50 value of 19 nm (Figure 2). In the same assay,
bortezomib gave an IC50 value of 0.4 nm. The boromorpho-
4
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and as boron transfer agents in MCR-based preparation of
biologically active boropeptides. As part of this study we have
demonstrated a one-step synthesis of MIDA-protected bor-
tezomib diastereomers. Our studies of a-boryl isocyanides
also afforded a new class of boron-containing heterocycles (6-
boromorpholinones). These air-stable solids exhibited selec-
tive inhibition of CT-L members of the 20S proteasome with
IC50 values in the low nanomolar range. We expect that a-
boryl isocyanides will enable access to many other novel
biologically active boropeptide derivatives using readily
available starting materials and will enable synthesis of
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Published online: && &&, &&&&
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Keywords: boron · inhibitors · isocyanides ·
multicomponent reactions · peptides
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