Catalytic enantioselective one-pot aminoborylation of aldehydes: A strategy for construction of nonracemic α-amino boronates

Article abstract of DOI:10.1021/ja402569j

We report a strategy for the conversion of aldehydes to enantiomerically enriched α-amino boronates through the intermediacy of in situ-generated silylimines. This transformation is brought about by Pt-catalyzed asymmetric addition of B₂(pin)

Full text of DOI:10.1021/ja402569j

Communication
pubs.acs.org/JACS
Catalytic Enantioselective One-pot Aminoborylation of Aldehydes: A
Strategy for Construction of Nonracemic α‑Amino Boronates
Kai Hong and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
(eq 2).5,6 We considered that a catalytic enantioselective
ABSTRACT: We report a strategy for the conversion of
aldehydes to enantiomerically enriched α-amino boronates
through the intermediacy of in situ-generated silylimines.
This transformation is brought about by Pt-catalyzed
asymmetric addition of B2(pin)2 across the imine double
bond. An attractive feature of the intermediate diboration
adduct is that it can be acylated directly and provides
convenient access to important N-acyl α-amino boronic
ester derivatives.
approach that employs readily available substrates and reagents
may streamline access to these important motifs. Along these
lines, we describe herein the direct conversion of aldehydes to
α-amino boronic esters in a catalytic asymmetric fashion (eq 3).
An important feature of this reaction strategy is that acylation
of the amino boronic ester occurs after C−B bond formation
such that diverse arrays of peptidic α-amino boronates may be
accessed in a simple fashion.
Recent studies conducted in our laboratory have demon-
strated that chiral platinum−phosphonite complexes can
catalyze the enantioselective addition of B2(pin)2 across the π
systems found in isolated terminal alkenes and in conjugated
dienes.7,8 It was considered that analogous enantioselective
addition of B2(pin)2 across imine double bonds would provide
a straightforward route to α-amino boronic acid derivatives.9 As
design criteria, we targeted a reaction where (a) substrates are
readily available and (b) the reaction product is readily
converted to N-acyl α-amino boronic acid derivatives. These
criteria obviated the use of N-aryl and N-sufonyl imines as
suitable substrates. Initially, we considered that N-acyl imines,
compounds that are isoelectronic with dienes, might participate
in enantioselective diboration and directly provide N-acyl α-
amino boronates. However, studies with a range of such
substrates provided reaction products with moderate levels of
selectivity and yield. N-Silyl imines also appeared to satisfy the
reaction design criteria. To develop a broadly useful method,
studies were focused on the reaction of substrate 1 (Table 1)
wherein it was reasoned that the lability of the N−Si bond
might enhance the versatility of the reaction products.10 While
it was later determined (vide infra) that in situ-prepared
silylimines are suitable substrates, initial exploratory efforts
employed purified silylimine 1, conveniently prepared from
benzaldehyde and LiHMDS.11 As depicted in Table 1, a small
collection of substituted taddol-derived phosphonite ligands
was surveyed in the Pt-catalyzed diboration of 1. After 14 h of
reaction, the mixtures were concentrated and, to facilitate
purification, treated with pivaloyl chloride. This set of
experiments revealed that efficient reactivity and good levels
of stereoselection could be obtained with many Pt−
phosphonite catalysts. Notably, in contrast to alkene and
diene diboration, there is relatively little dependence of
stereoselectivity on the size of the meta substituents in
taddol-based phosphonite ligands; however, it was clear that
hiral α-amino boronic acids have found widespread use as
Cpharmacologically active agents, most notably as protease
inhibitors, and have appeared as motifs in clinically relevant
therapeutics for the treatment of multiple myeloma.1,2 These
structures have also found use as chiral intermediates in
asymmetric synthesis, thereby further extending their impor-
tance in organic chemistry.3 As important as N-acyl α-amino
boronic acids are, there are only two effective methods available
for their synthesis in an asymmetric fashion. Matteson has
established a diastereoselective homologation of pinanediol-
derived boronic esters that is accomplished by treatment with
dichloromethyllithium; the product of this reaction is a chiral α-
chloro boronic ester that may undergo stereospecific
substitution with amine nucleophiles providing α-amino
boronates (eq 1, Scheme 1).4 In another approach, Ellman
has introduced a copper-catalyzed diastereoselective borylation
of chiral sulfinylimines that furnishes α-amino boronic esters
Scheme 1
Received: March 12, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja402569j | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Catalytic Enantioselective Diboration of 1
Table 2. Catalytic Enantioselective Aminoborylation of
Aldehydes
a
entry
ligand
R
yield (%)
e.r.
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
H
76
80
64
79
70
71
72
84:16
89:11
83:17
90:10
89:11
73:27
81:19
Me
F
Et
i-Pr
Ph
t-Bu
a
Reactions were conducted as described in the text. The percent value
given refers to the isolated yield of purified material and is an average
of two experiments.
the readily available meta-xylyl derivative L2 (entry 2) was
among the most effective.12
With the above-described observations in hand, a number of
modifications were probed to improve the reaction. First, high
efficiency was still observed when the reaction temperature was
lowered to 22 °C. Second, it was found that the diethyl ketal
analog (L8, see Table 2) of ligand L2 furnished enhanced
selectivity compared to the dimethyl ketal with the latter
converting the benzaldehyde-derived imine to the α-amino
boronate in 95:5 er. Third, pivalic acid was found to enhance
the rate of the acylation reaction resulting in shortened reaction
times and improved yield.4a In the absence of pivalic acid,
acylation of the diboron intermediate required 4 h at 50 °C;
however, when one equivalent of pivalic acid was employed, the
reaction time was shortened considerably such that the product
was generated in one hour at ambient temperature. Control
experiments (use of benzoic acid in place of pivalic acid)
suggested that the function of pivalic acid is not to generate
pivalic anhydride in situ, but to convert the diboron
intermediate to a more reactive species perhaps through
protodeboronation and/or protodesilylation. Lastly, it was
found that unpurified silylimines could be used in the reaction
such that direct conversion of aldehyde substrates to α-amino
boronic acid derivatives could be accomplished in a single-flask
process, without isolation of any intermediates and without
solvent-swapping operations. In connection with this last
feature, it was found that addition of TMSCl to the unpurified
silylimine mixture was critical to high yields and selectivity; it is
reasoned that addition of TMSCl converts LiOTMS (generated
in the imine synthesis) into less reactive LiCl and TMS2O. As
the data in Table 2, indicates, these improvements applied to a
range of substrates allowing direct conversion of aldehydes to
chiral α-amino boronates in an asymmetric fashion. Notably,
the reaction is insensitive to substrate electronic effects with
both electron-rich and electron-poor substrates performing
similarly. While both meta and para substituted aryl aldehydes
were converted to aminoboronates with high stereoselection,
an ortho-substituted aryl aldehyde reacted in a near-racemic
fashion. Fused-ring substrates also reacted with good selectivity
(compounds 13−16). Importantly, while the products are often
a
Reactions were conducted as described in the text. The percent value
given refers to the isolated yield of purified material and is an average
of two experiments. Purified silylimine was used as the starting
material for this experiment.
b
hydrolytically sensitive, the reaction mixtures could often be
purified with water-deactivated silica gel chromatography (see
Supporting Information for these details).13
As alluded to above, one feature of this strategy for
construction of α-amino boronates is that the amino group
can be acylated with a variety of different acyl donors. To
explore the possibility of coupling with activated amino acid
derivatives that might be used in peptide synthesis, a tandem
diboration/acylation sequence employing α-amino acid de-
rivatives was examined. It was considered that configurationally
stable α-amino acid fluorides might replace pivaolyl chloride
used in Table 2. As depicted in eqs 4 and 5, this strategy proved
highly effective and delivered peptidic amino boronates 17 and
18 in good yield and without significant epimerization of
stereogenic centers. An additional important feature in
considering the utility of the amino borylation reaction is the
proclivity of the pinacol boronate to undergo conversion to the
derived boronic acid. As depicted in eq 6, this transformation is
readily accomplished by treatment with BCl3.
In addition to serving as a simple route to α-aryl
aminoboronic ester derivatives, the aminoborylation strategy
described herein can offer accelerated routes to chiral
enantiomerically enriched benzhydryl amines. A recent report
B
dx.doi.org/10.1021/ja402569j | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
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by Ohmura and Suginome described the stereoinvertive cross-
coupling of N-pivaloyl protected α-aminoboronates.3 As
depicted in Scheme 2, this strategy was easily combined with
aminoborylation to give nonracemic 22, a potential precursor
to the more active enantiomer of the antihistamine agent
cetirizine (Zyrtec).
Scheme 2
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(11) For the synthesis of silylimines, see: Lou, S.; Moquist, P. N.;
Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398.
In summary, we report a catalytic enantioselective method
for the α-amino borylation of aldehydes. This transformation
can serve as a starting point for the construction of amino
boronic acid-derived peptides. Further studies addressing the
scope and utility of this process are in progress.
(12) Ligands L2, L4, and L5, as well as Pt(dba)3 are now
commerically available from Strem Chemicals.
(13) Aliphatic aldehydes are not converted to α-amino boronates
under these reaction conditions.
(14) (a) Ohmura, T.; Awano, T.; Suginome, M. J. Am. Chem. Soc.
2010, 132, 13191.
ASSOCIATED CONTENT
* Supporting Information
Procedures, characterization and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
morken@bc.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The NIH (GM-59417) is acknowledged for financial support;
AllyChem is acknowledged for donations of B2(pin)2.
■
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dx.doi.org/10.1021/ja402569j | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX