Access to Cyclic Amino Boronates via Rhodium-Catalyzed Functionalization of Alkyl MIDA Boronates

Article abstract of DOI:10.1021/acs.orglett.5b02861

Herein, we describe the rhodium-catalyzed C-H amination reaction of 1,2-boryl sulfamate esters derived from amphoteric α-boryl aldehydes. Depending on the substitution pattern of the boryl sulfamate ester, a diverse range of five- or six-membered ring heterocycles are accessible using this transformation. The highly chemoselective nature of the C-H functionalization reaction preserves the alkyl boronate functional group, which enables the synthesis of B-C-N and B-C-C-N motifs that are present in a number of hydrolase inhibitors.

Full text of DOI:10.1021/acs.orglett.5b02861

Letter
pubs.acs.org/OrgLett
Access to Cyclic Amino Boronates via Rhodium-Catalyzed
Functionalization of Alkyl MIDA Boronates
Jeffrey D. St. Denis, C. Frank Lee, and Andrei K. Yudin*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6,
Canada
S
* Supporting Information
ABSTRACT: Herein, we describe the rhodium-catalyzed C−
H amination reaction of 1,2-boryl sulfamate esters derived
from amphoteric α-boryl aldehydes. Depending on the
substitution pattern of the boryl sulfamate ester, a diverse
range of five- or six-membered ring heterocycles are accessible
using this transformation. The highly chemoselective nature of
the C−H functionalization reaction preserves the alkyl
boronate functional group, which enables the synthesis of B−C−N and B−C−C−N motifs that are present in a number of
hydrolase inhibitors.
lkyl and arylboronic acids are known to interact covalently
with a number of enzymes including thrombin, β-
the strongly basic conditions present chemoselectivity issues
and limit functional group compatibility. Recently, the
diastereoselective copper-catalyzed addition of B2Pin2 to
Ellman imines and enamides (N-tert-butylsulfinylimines and
-enamides) has provided a convenient entry into secondary and
tertiary amino boronates.8 An enantioselective platinum-
catalyzed variant has also been reported;8e however, these
methods are ineffective for the synthesis of cyclic derivatives.
Our synthetic studies of the amino boronate motif have
uncovered that α-N-methyliminodiacetyl (MIDA) boryl acyl
azides undergo a concerted carbon−boron bond transposition
to afford the linear α-amino boronic acid derivatives.9 Since this
initial disclosure, our group has been interested in other
processes that introduce amine functional groups to alkyl
MIDA boronates. Herein, we describe the rhodium-catalyzed
amination of alkyl MIDA boronates to afford borylated
heterocycles (Figure 2).
A
lactamase, HCV NS3/4A protease, and the 20S proteasome.1
As shown by Matteson and Leinhard, α-amino alkylboronic
acids mimicking the native peptide substrates confer greater
specificity and higher potency of inhibition.2 The mechanism of
protease inhibition is based on the favored interaction between
the nucleophilic amino acid residues, typically serine and
threonine residues, and the boron center.3 Lewis acid/base
interaction forms the sp3-boronate that acts as the transition-
state analogue for amide bond cleavage. Thus, α-amino
boronates are important motifs that have been incorporated
into several classes of protease inhibitors.4 Bortezomib
(Velcade), an FDA-approved treatment for multiple myeloma,
exhibits high selectivity as a reversible, covalent inhibitor for the
20S proteasome.5 Another peptidase inhibitor, Val-boroPro
(Talabostat), contains an exocyclic boronic acid that has been
successful through Phase II clinical trials.6 From the success of
these compounds, there has been an increased interest in other
α-amino boronate-containing small molecules for the identi-
fication and elucidation of biological activity (Figure 1).
Figure 2. Intramolecular insertion of [M]-nitrenoid to alkyl boronates.
In an effort to evaluate the amination process, we sought to
utilize alkyl MIDA boryl sulfamate esters as substrates.
Previously reported α-MIDA boryl aldehydes served as
appropriate starting materials for the synthesis of the sulfamate
esters.10 The 1,2-boryl alcohol is a sensitive functional group
Figure 1. Selected biologically active amino boronates.
In contrast to the large number of studies into the biological
properties of α-amino boronates, there are few general methods
for the synthesis of α-amino boronates using late-stage
introduction of the boron functional group. The most common
process utilizes metalated amines for halide displacement of α-
halo alkyl boronates.7 While effective for simple alkyl boronates,
Received: October 2, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02861
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
due to the facile borono-Peterson elimination;11 however, the
reduction of the starting boryl aldehyde with NaBH(OAc)3
afforded the desired 1,2-MIDA boryl alcohol as a white solid
(see the Supporting Information). The increased stability of
this motif is attributed to the MIDA ligand on the boron atom.
Synthesis of the requisite sulfamate ester was next attempted
with a mixture of ClSO2NCO/formic acid.12 Initially, the
formation of the sulfamate was accompanied by the production
of the corresponding formate ester.13 However, we later found
that ester formation could be suppressed by quenching the
reaction with water prior to removal of the solvent. As a result
of the modified workup, the desired boryl sulfamate esters were
obtained in good yields (Scheme 1).
Rh2(OAc)4 for Du Bois’ Rh2(esp)2 system resulted in the
formation of 3a in 78% yield (Table 1, entry 4). Application of
the optimized reaction conditions to other boryl sulfamates
found no observable influence of the aryl substituent on the
recovered yields of the cyclic α-amino boronate (Scheme 2,
2a−d).15 In addition, we did not detect any products from C−
B bond engagement, which underscores that the MIDA ligand
is inhibiting transmetalation to the rhodium center.16
Scheme 2. Five-Membered Borylated Heterocycles via C−H
Amination
Scheme 1. Synthesis of the 1,2-Borysulfamate Ester
In contrast to boryl sulfamates 2a−d, alkyl-substituted
sulfamates 2e−h possess multiple reactive C−H bonds. To
probe the regioselectivity of the alkyl boronate amination
process, benzyl boryl sulfamate (2e) was subjected to the
optimized reaction conditions, which resulted in the isolation of
the β-amination product, and the relative stereochemistry was
confirmed by single-crystal X-ray analysis (Scheme 3, 3e).
Other alkyl-substituted boryl sulfamates (2f−h) afforded a
mixture of 5- and 6-membered ring products.17 Attempts to
ring-open the cyclic products with a variety of nucleophiles
resulted in a complex reaction mixture or recovered starting
material.
A mixture of regioisomers obtained for 3f−h from the C−H
amination reaction is thought to result from a radical
intermediate.18,19 This intermediate is proposed given that α-
boryl radicals are reactive species and have been utilized in
oxygenation,20a photoredox alkylation,20b and halogenation
reactions.21 To provide insight, we exposed the cyclo-
propylboryl sulfamate ester (2i) to the optimized reaction
With the boryl sulfamate ester 2a in hand, we sought to
promote the C−N bond formation via RhII catalysis. The initial
attempt with 5 mol % of Rh2(OAc)4 in the presence of
PhI(OAc)2 afforded the quaternary α-amino boronate (3a) in
56% conversion by 1H NMR. The reduced conversion is
attributed to the decomposition of the catalyst.14 Exchanging
1
conditions. Analysis of the crude material by H NMR found
a
Table 1. Optimization of C−H Amination Reaction
b
entry
catalyst
oxidant
solvent
i-PrOAc
time (h)
conversion (%)
yield (%)
1
2
3
Rh2(OAc)4
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
none
Phl(OAc)2
18
6
56
38
83
100
85
0
ND
ND
ND
78
Phl(OAc)2
DCM
Phl(OAc)2
i-PrOAc
6
c
4
c,d
Phl(O2C-t-Bu)2
Phl(O2C-t-Bu)2
Phl(O2C-t-Bu)2
i-PrOAc
18
10
10
5
6
i-PrOAc/MeCN
i-PrOAc
40
ND
a
b
Reaction conditions: 1.25 equiv of oxidant, 2.5 equiv of MgO, in N2-sparged anhydrous solvent. Measured by comparison of corresponding NCH3
c
d
1
of SM/product by crude H NMR. 2.5 mol % of Rh2(esp)2. 4:1 i-PrOAc/MeCN. ND = not determined.
B
DOI: 10.1021/acs.orglett.5b02861
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 3. Boryl Sulfamate Cyclization
Figure 3. (A) α- and β-boryl cation stabilization and α-boryl radical
destabilization. (B) Proposed stabilization of incipient α-cation by
electron-rich sp3-boronate and n → σ* hyperconjugation observed by
Davis and co-workers that favors five-membered ring formation.27 (C)
Formation of β-carbocation results in [1,2]-boryl migration to quench
electron deficiency.
sulfamate esters provide a mixture of five and six-membered
ring products. This chemistry should provide access to other
boron-containing functional group arrays that are difficult to
synthesize via other methods.
no discernible cyclopropane fragmentation products, and
product 3i was obtained in 59% yield (Scheme 4). This
suggests that the amination reaction does not proceed via long-
lived α-boryl radical species.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02861.
■
S
Scheme 4. Radical Clock Experiment
X-ray crystallographic data for 1c (CIF)
X-ray crystallographic data for 3e (CIF)
Experimental data; HRMS and H, 11B, and 13C NMR
1
spectra of all novel products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ayudin@chem.utoronto.ca. Fax: (+1)416-946-7676.
Notes
The absence of radical fragmentation products suggests that
the C−H amination reaction of boryl sulfamate esters is
heterolytic.22,23 In this process, hydride is transferred to the
electrophilic rhodium nitrene, resulting in a transient positive
charge at the reactive carbon.24 Therefore, substitution of
electron-rich groups at the reactive site is typically beneficial.25
In addition to benzylic cation stabilization (for aryl
substituents), the electron-rich sp3-boron center is proposed
to stabilize the α- and β-cations via hyperconjugation (Figure
3A,B).26 This is similarly invoked in the C−H amination of
mannose-derived sulfamate esters (Figure 3B)27 as well as
[1,2]-boryl migration of oxiranyl-MIDA boronates (Figure
3C).9a,28 These factors presumably contribute to the single
regioisomer (3e). In contrast to 2e, sulfamates 2f−h lack the
reinforcing aryl substitution, and a mixture of α- and β-
regioisomers was obtained (Scheme 3, 3f−h). Further efforts
into understanding the factors affecting the regioselectivity are
ongoing.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding for this work was provided by the Natural Science and
Engineering Research Council (NSERC) and University of
Toronto. J.D.S.D. thanks NSERC for PGS-D funding and the
Government of Ontario for OGS funding. Dr. Alan Lough at
the Department of Chemistry, University of Toronto, is
thanked for obtaining the reported crystal structures. We
acknowledge the Canadian Foundation for Innovation, Project
No. 19119, and the Ontario Research Fund for funding of the
Centre for Spectroscopic Investigation of Complex Organic
Molecules and Polymers.
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