Boroalkyl group migration provides a versatile entry into α-aminoboronic acid derivatives

Article abstract of DOI:10.1021/ja304173d

A reaction exemplifying migration of boron-substituted carbon is described. We show that α-boroalkyl groups of transient boroalkyl acyl azide intermediates readily migrate from carbon to nitrogen. This process allows access to a new class of stable molecules, α-boryl isocyanates, from α-borylcarboxylic acid precursors. The methodology facilitates synthesis of a wide range of α-aminoboronic acid derivatives, including α,α-disubstituted analogues.

Full text of DOI:10.1021/ja304173d

Communication
pubs.acs.org/JACS
Boroalkyl Group Migration Provides a Versatile Entry into α-
Aminoboronic Acid Derivatives
Zhi He, Adam Zajdlik, Jeffrey D. St. Denis, Naila Assem, and Andrei K. Yudin*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada
M5S 3H6
S
* Supporting Information
reactions of this type can be used in skeletal rearrangement of
ABSTRACT: A reaction exemplifying migration of
boron-substituted carbon is described. We show that α-
boroalkyl groups of transient boroalkyl acyl azide
intermediates readily migrate from carbon to nitrogen.
This process allows access to a new class of stable
molecules, α-boryl isocyanates, from α-borylcarboxylic acid
precursors. The methodology facilitates synthesis of a wide
range of α-aminoboronic acid derivatives, including α,α-
disubstituted analogues.
boron-containing precursors. To the best of our knowledge,
reactions accompanied by migration of boron-substituted
carbon are presently unknown. Here we show that the
migration of an α-boroalkyl group from carbon to nitrogen
occurs under mild conditions, allowing access to a class of
hitherto unknown bench-stable α-boryl isocyanates.6 α-Boryl
isocyanates were found to afford new opportunities to
efficiently prepare a range of α-amino boronic acid derivatives,
including urea-containing boronic acids, boropeptides, and α,α-
disubstituted variants.
Recent reports from our laboratory and from that of Martin
Burke disclosed the synthesis of α-boryl aldehydes.7 As part of
our efforts aimed at demonstrating synthetic applications of
these molecules, we showcased their oxidative conversion into
configurationally stable α-borylcarboxylic acids. With these
molecules in hand, we questioned the possibility of α-boroalkyl
migration as a general means of assembling gem-aminoboron
compounds. When 1a was subjected to one-pot diphenylphos-
phoryl azide (DPPA)/Et3N-mediated Curtius rearrangement
conditions (50 °C, 1 h),8,9 we detected a clean conversion of
the starting material to α-boryl isocyanate 2a, which exhibited
an IR stretch of 2244 cm−1 and a 13C NMR chemical shift of
122.9 ppm, consistent with the presence of isocyanate
functionality. 2a was isolated in 71% yield as a white powder
after silica gel chromatography and was found to be stable to
storage at ambient temperature. This result prompted us to test
the generality of the preparation of stable α-boryl isocyanates. A
range of monosubstituted α-borylcarboxylic acids 1a−i were
subjected to one-pot Curtius rearrangement conditions (Table
1). The reaction worked well with aryl substrates 1a,b. Primary
and secondary alkyl-substituted α-borylcarboxylic acids 1d−h
also afforded the desired isocyanates in good to excellent yields.
To obtain stereochemical insight into this novel migratory
process, α-borylcarboxylic acids 3a,b were prepared as single
diastereomers (dr > 95:5) using diastereoselective epoxidation
of vinyl boronates7b followed by stereospecific rearrangement
and oxidation (see Supporting Information). 3a,b were
subjected to one-pot Curtius rearrangement conditions
(Scheme 1). 1H NMR analysis revealed that α-boryl isocyanate
4b was produced from alkyl-substituted acid 3b with complete
retention of stereochemistry (dr > 95:5). The rearrangement of
phenyl-substituted acid 3a resulted in the isocyanate product 4a
with a slightly eroded diastereomeric ratio (dr = 85:15). This
rganoboron compounds are widely used in material
O
science and medicinal chemistry,1 but their efficient
preparation remains a long-term challenge. Over the past
decade, the use of boronic acids containing a unique gem-
aminoboron motif has drawn attention both in academia and in
the pharmaceutical industry. A number of studies have
documented the utility of aminoboronic acid derivatives as
biochemical probes of protein function.2 These studies hinge
on reversible covalent interactions that are possible between
boron and nucleophilic protein residues. The realization of gem-
aminoboronic acids as promising drug candidates culminated in
the recent success of Bortezomib (Velcade), an FDA-approved
boropeptide used for the treatment of multiple myeloma.3 Such
studies have resulted in increased interest in the design of
boron-containing peptides. The emergence of biotechnology
companies that are focused on the boropeptide platform further
underscores the growing interest in this area.4
Figure 1. Migration of an α-boroalkyl group.
Despite the significance of the gem-aminoboron functionality,
the application of these molecules in chemical biology and drug
discovery programs is made difficult by the lack of methods
adaptable to synthesis under mild reaction conditions.5 The
vast majority of established synthetic routes to organoboron
reagents involve late-stage installation of a new carbon−boron
σ-bond, which presents chemoselectivity challenges. We have
been interested in developing reactions that transpose carbon−
boron bonds under mild conditions (Figure 1). If successful,
Received: April 30, 2012
Published: June 4, 2012
© 2012 American Chemical Society
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Communication
functionality. Interestingly, reactions between α-boryl isocya-
nates and different types of amines were found to occur
smoothly at room temperature in THF with retention of the
boronate groups. A series of α-boryl urea products 6 (α-ureido
MIDA boronates) were obtained in good to excellent yields
(Scheme 2). All aliphatic amines afforded the desired products
Table 1. Preparation of α-Boryl Isocyanates via Curtius
Rearrangement
a
a
Scheme 2. Preparation of α-Boryl Ureas
a
The reactions were carried out using 1.0 equiv of α-boryl isocyanate
a
The reactions were carried out using 1.0 equiv of α-boryl acid, 1.1
b
and 1.5 equiv of amine in anhydrous THF at 23 °C for 1−12 h. All
yields in parentheses are isolated yields after silica gel chromatography.
equiv of DPPA, and 1.1 equiv of Et3N in anhydrous MeCN at 50 °C
for 1 h. Isolated yields after silica gel chromatography.
b
in full conversion within 1−5 h, although reactions with
aromatic amines, such as aniline, reached 50% completion only
after 12 h (Scheme 2, 6e). In contrast to the facile reactions
between amines and α-boryl isocyanates, alcohols were found
to be reactive only in the presence of CuCl in DMF.10 By
choosing different alkoxy nucleophiles, a series of α-amino
MIDA boronates 7 with representative amino-protecting
groups were obtained (Scheme 3). In view of the wide use of
Scheme 1. Stereochemical Investigation of the α-Boroalkyl
Migration
a
a
a
1
Scheme 3. Preparation of α-Boryl Carbamates
Diastereomeric ratios (dr) were determined by H NMR analysis of
crude reaction mixtures.
could be attributed to the vulnerability of the acidic α-proton in
either the acid starting material or the isocyanate product to the
basic reaction conditions.
The facile preparation of α-boryl isocyanates encouraged us
to investigate their downstream transformations to generate α-
aminoboronic acid derivatives. To explore this possibility, we
first tried to generate the free amino group from α-boryl
isocyanates by direct acid hydrolysis. Treatment of α-boryl
isocyanate 2d with 3.0 M HCl aqueous solution in MeCN
afforded α-aminoboronic acid 5 (eq 1). The hydrolysis not only
a
Unless specified otherwise, reactions were carried out using 1.0 equiv
of α-boryl isocyanate, 3.0 equiv of alcohol, and 1.0 equiv of CuCl in
b
anhydrous DMF at 23 °C for 3 h. All yields in parentheses are
c
isolated yields after silica gel chromatography. The reaction was
carried out using 10.0 equiv of t-BuOH at 70 °C for 24 h.
resulted in the formation of an amine from the isocyanate
functional group but also converted the N-methyliminodiacetyl
boronate (MIDA boronate) to the free boronic acid.
We then explored the reactivity of boryl isocyanates toward
amines and alcohols with the ultimate goal of preparing α-boryl
ureas and carbamates, respectively. We had initially suspected
that conditions required for nucleophilic attack at the
isocyanate would be incompatible with the adjacent boronate
ureas and carbamates in medicinal chemistry and material
science, these borylated analogues are expected to find utility in
solid-phase peptide synthesis. The orthogonality of protecting
groups in these building blocks will be useful in the synthesis of
complex boron-containing compounds.
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Journal of the American Chemical Society
Communication
A range of deprotection conditions were tested in the hopes
of chemoselective release of the free boronic acid or amino
group. For instance, treating 6c with 1.0 M aqueous NaOH in
THF at room temperature selectively removed the MIDA
protecting group to afford the α-ureidoboronic acid 8 (eq 2).
Scheme 5. Preparation of α,α-Disubstituted α-
Aminoboronic Acid Derivatives
The combination of boronic acid and urea functionality in the
same molecule has potential for applications in organocatalysis
and molecular recognition.11−14 A Pd(PPh3)4-catalyzed deal-
lylation of carbamate 7d gave stable α-amino boronate 9,
leaving the (MIDA)boryl group intact (Scheme 4).15 To the
Scheme 4. Preparation of Boro-dipeptide 10
a
All yields in parentheses are isolated yields after silica gel
chromatography.
expect that our discovery will find utility in synthesis and
medicinal chemistry.
ASSOCIATED CONTENT
* Supporting Information
a
■
All yields in parentheses are isolated yields after silica gel
S
chromatography.
Complete experimental details and characterization data for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
best of our knowledge, stable α-aminoboronic acid derivatives
containing an unsubstituted primary α-amino group are
presently unknown.16 Subsequent coupling of 9 with N-Cbz-
leucine successfully afforded the MIDA-protected boro-
dipepetide 10 as a mixture of two diastereomers, which were
easily separated by flash silica gel chromatography in good
yields.
AUTHOR INFORMATION
Corresponding Author
ayudin@chem.utoronto.ca
■
Notes
The authors declare no competing financial interest.
The successful preparation of monosubstituted α-amino-
boronic acids via boryl isocyanates encouraged us to further
pursue the synthesis of α,α-disubstituted derivatives. This type
of α-aminoboronic acid analogue is not easy to obtain due to
the difficulties in installing a quaternary α-carbon center using
known methodologies.17 To evaluate the feasibility of α-
boroalkyl migration for the synthesis of α,α-disubstituted
aminoboronic acids, we chose α-borylcarboxylic acid 12 as a
testing ground (Scheme 5). 12 can be prepared from the
corresponding monosubstituted α-boryl aldehyde by a
sequence of transformations involving palladium-catalyzed α-
allylation and oxidation.18 Gratifyingly, the Curtius rearrange-
ment of 12 occurred smoothly at 50 °C in MeCN. Although a
longer reaction time was required for full conversion, α-boryl
isocyanate product 13 was afforded in good yield. Further
transformations of 13, such as acidic hydrolysis and
nucleophilic attack, were conducted. The final α,α-disubstituted
aminoboronic acid products 14 and 15 were thus successfully
obtained.
In summary, we have realized the first example of an α-
boroalkyl group migration and accessed a range of α-boryl
isocyanates. These novel bench-stable molecules have enabled
mild and convenient access to a wide range of α-aminoboronic
acid derivatives, including carbamates, ureas, and peptides.
Additionally, this methodology allows for the facile preparation
of α,α-disubstituted analogues. Given the advances in
isocyanate chemistry19,20 and the recent developments in
cross-coupling applications of organoboron compounds,21 we
ACKNOWLEDGMENTS
We thank NSERC for financial support of this work.
■
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(15) An alternative approach to access 9, involving direct treatment
of α-boryl isocyanate 2a with a mild aqueous base (e.g., 5% NaHCO3,
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