Enantio- and diastereoselective synthesis of β-substituted-δ- aminoboronic esters from nitriles

Article abstract of DOI:10.1016/j.tetlet.2013.06.076

The first stereocontrolled synthesis of the title δ-aminoboronic esters - proceeding from commercially available nitriles - via a reduction, Brown's 'allyl' boration reaction, a Boc-protection, a hydroboration, an oxidative elimination of α-pinene, and an esterification reaction, has been reported in excellent enantio- and diastereoselectivities.

Full text of DOI:10.1016/j.tetlet.2013.06.076

Tetrahedron Letters 54 (2013) 4830–4833
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantio- and diastereoselective synthesis of b-substituted-d-
aminoboronic esters from nitriles q
⇑
P. Veeraraghavan Ramachandran , Wataru Mitsuhashi, Debanjan Biswas, Daniel R. Nicponski
Herbert C. Brown Center for Borane Research, Department of Chemistry, Purdue University, 560 Oval Dr., West Lafayette, IN 47907, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The first stereocontrolled synthesis of the title d-aminoboronic esters—proceeding from commercially
Received 18 April 2013
Revised 13 June 2013
Accepted 16 June 2013
Available online 26 June 2013
available nitriles—via a reduction, Brown’s ‘allyl’ boration reaction, a Boc-protection, a hydroboration,
an oxidative elimination of
a-pinene, and an esterification reaction, has been reported in excellent enan-
tio- and diastereoselectivities.
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Keywords:
Amino-boronic ester
Allylboration
Crotylboration
Methoxyallylboration
Nitriles
Aminoboronic acids have been shown capable of mimicking
natural amino acids, and have also been demonstrated to act as
bioisosteres in many biochemical reactions.1,2 These unusual
amino acid mimetics can function as potent inhibitors of several
enzymes, and can also effectively serve as immunosuppressants.
O
OH
B
H
N
N
H
OH
O
a-Aminoboronic acids have also recently acquired special
pharmaceutical significance with the recent approval of bortezo-
mib (Velcade™) (Fig. 1), the first boron-containing compound to
be approved for pharmaceutical use by the FDA. Indeed, bortezo-
mib has shown its potential to function as a successful proteasome
inhibitor.3 Owing to the clear and growing importance of aminobo-
ronic acids in various areas of medicinal chemistry, several classes
of these important molecules have been synthesized.3,4 Despite
this recent interest, there remains only a limited amount of litera-
ture precedence for the asymmetric preparation of aminoboronic
acids.5
Figure 1. Bortezomib (Velcade™).
esters in a series of two papers.8 Their synthetic route, shown in
Scheme 1, involved the hydrodibromoboration of a halide-contain-
ing alkene, followed by hydrolysis, azidation, and hydrogenative
reduction. One consequence of this synthetic route is that the
use of primary azides necessitates that the resultant d-amino-
boronic acids remain achiral.
It is not inconceivable that this group of interesting compounds
remains underreported in the literature because their synthesis
can be difficult. Quite possibly, this is due to the fact that these
compounds are often unstable, and to the incompatibility of the
varying functional groups that are needed to serve as synthetic
handles during their synthesis.9
As part of a separate research project in our laboratory, we re-
cently developed and reported a number of convenient syntheses
for a series of aldimine–borane and N-aluminoimine complexes.10
Their subsequent allyl-, crotyl-, and methoxyallylborations provide
access to homoallylic amines in high yields and very good to excel-
lent enantio- and diastereoselectivities. We envisaged that the use
of these homoallylic amines as synthons could provide easy access
through a novel route to a new class of functionalized, chiral
The preparation of functionalized aminoboronic acids has re-
mained challenging. While a few methods have been reported for
the preparation of a c
-,6 b-,7 and -aminoboronic acids,7 the prepa-
ration of d-aminoboronic acids and esters remains almost entirely
unexplored. In perhaps the most significant example of the latter,
Vaultier and co-workers reported the preparation of simple
d-aminoboronic acids by the reduction of azide-containing boronic
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-No Derivative Works License, which per-
mits non-commercial use, distribution, and reproduction in any medium, provided
the original author and source are credited.
⇑
Correponding author. Tel.: +1 765 494 5303.
E-mail address: chandran@purdue.edu (P.V. Ramachandran).
0040-4039/$ - see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.076

P. V. Ramachandran et al. / Tetrahedron Letters 54 (2013) 4830–4833
4831
boration of 1-aminobut-3-enes, as we considered that they could
provide direct access to the desired d-aminoboranes, which, upon
oxidative elimination of a-pinene and esterification, would furnish
1. HBBr2 SMe2
2. Hydrolysis
Br
OH
NaN3
EtOH
B
Br
OH
the desired d-aminoboronic esters.
We began our efforts by searching for a method that would
allow for both the symmetric and asymmetric production of the req-
uisite 1-aminobut-3-enes. To this end, we decided to extend our
previous methodology10 in which we had described a one-pot pro-
cess of imine allylation. In that case, metalated imines were pro-
duced in situ by the reduction of a variety of substituted nitriles.
Building on our previous work, these 1-substituted-1-amino-
but-3-enes were then protected at the amine position with the
tert-butoxycarbonyl group. The resultant Boc-protected homoal-
lylic amines were then subjected to hydroboration conditions,
thereby furnishing the expected alkylamines possessing the de-
N3
OEt
H3N+
Cl-
OH
H2, Pd/C
B
B
OEt
OH
Scheme 1. d-Aminoboronic acid production by Vaultier and co-workers by means
of an azide-containing pathway.
BEt3
H
R
N
1. LiHBEt3
2. MeOH
sired
x-boryl group. Oxidation of the two boron diisopinocamphe-
Y
nyl ligands with acetaldehyde (akin to a DIP-ClÒ reduction),13
followed by hydrolysis with diluted mineral acid provided the de-
sired d-boronic acids. Unfortunately, these products were not read-
ily purifiable. As such, these compounds were directly converted
into their ester analogs by esterification with pinacol. In this
way, the pinacolato d-aminoboronic esters were prepared in very
good overall yields.
H
N
R
(-)-Ipc2B
X
aldimine-borane
Al(i-Bu)2
N
DIBAL-H
R
H
N-aluminoimine
The use of Brown’s chiral isopinocampheyl ligand14 during the
allylboration stage was found to provide excellent enantiomeric ra-
tios of the desired 1-substituted-1-aminobut-3-enes. Expectedly,
this high enantiomeric enrichment was carried through to the
boronic esters, providing, to the best of our knowledge, the first
such stereocontrolled synthesis of d-aminoboronic acids and es-
ters. Generally speaking, enantiomeric ratios of between 6:1 and
99:1 were obtained with this process (Table 1).
1. Protection
2. Ipc2BH
NH2
Y
NHBoc
O
B
R
R
O
3. Acetalization
4. Transesterification
X
Y
X
Scheme 2. Synthetic route employed in the production of d-aminoboronic esters.11
The synthesis of a series of N-protected-1-aryl-1-amino-d-boro-
nic esters was then performed as follows (Table 1). An aromatic ni-
trile (1) was first reduced with lithium triethylborohydride to
furnish the lithium triethyl(alkylidenylamino)borate complex.
d-aminoboronic esters and their substituted analogs. The synthetic
approach to this class of compounds is outlined in Scheme 2.
The hydroboration of functionalized olefins can lead to the syn-
thesis of a variety of substituted alkylborons and boron-containing
heterocycles, and also to those alcohols and functionalities that re-
sult from the oxidation and further synthetic manipulation of these
borane intermediates.12 We believed that the application of this
After
a controlled protonation with methanol, the resulting
imminium–borane adduct was allylated with (-)-B-ally-
diisopinocampheylborane [(-)-Ipc2B(allyl)] which, upon oxidative
workup and column chromatography, provided the intermediate
homoallylic amines 2 in very good yields and excellent enantio-
meric ratios. After protection of the amine functionality by reaction
with di(t-butyloxycarbonyl) anhydride, hydroboration with the
hydroboration methodology to (aminoalkyl)-
x-olefins would nec-
essarily lead to the production of amino- -borylated compounds.
x
For our purposes, we were interested in investigating the hydro-
Table 1
Asymmetric synthesis of Boc-protected d-aminoboronic esters
1. Boc2O, Et3N
2. Ipc2BH
1. LiHBEt3
2. MeOH
N
NH2
NHBoc
O
B
3. MeCHO
R
4. HCl (aq)
R
1
O
3.
(-)-Ipc2B
R
5. Pinacol
2
3
Entry
Nitrile
Homoallylic amine
d-Aminoboronic ester
No.
R=
No.
Yielda (%)
No.
Yieldb (%)
erc
1
2
3
4
5
1a
1b
1c
1d
1e
C6H5–
2a
2b
2c
2d
2e
79d
86d
90d
82d
71e
3a
3b
3c
3d
3e
59
67
65
55
54
96:4
97:3
97:3
>99:1
88:12
4-Me-C6H4–
4-MeO-C6H4–
2-Thiophenyl–
2-F-C6H4–
a
b
c
Yields refer to analytically pure material (flash chromatography) after three steps.
Yields refer to analytically pure material (flash chromatography) after five steps.
Enantiomeric ratios were determined by Mosher amide analysis using 19F NMR.
Yields are from previous report.11
d
e
Reduction was performed using DIBAL-H.

4832
P. V. Ramachandran et al. / Tetrahedron Letters 54 (2013) 4830–4833
Table 2
Asymmetric synthesis of methylated and methoxylated d-aminoboronic esters
1. Boc2O,Et3N
2. Ipc2BH
Y
1. DIBAL-H
NH2
Y
N
NHBoc
O
B
2.
(-)-Ipc2B
X
3. MeCHO
R
4. HCl(aq)
3. MeOH
O
R
5. Pinacol
R
X
Y
X
1
X = Y =
X = Y =
4
5
6
7
8
9
Me
H
H
Me
H
H
Me
Me
H
MeO
H
MeO
Nitrile
R=
Homoallylic amine
Yielda (%)
d-Aminoboronic ester
Entry
No.
No.
No.
Yieldb (%)
drc
erd
1
2
3
4
5
6
1b
1b
1b
1c
1c
1c
4-Me-C6H4–
4-Me-C6H4–
4-Me-C6H4–
4-MeO-C6H4–
4-MeO-C6H4–
4-MeO-C6H4–
4b
5b
6b
4c
5c
6c
69
56
63
59
63
56
7b
8b
9b
7c
8c
9c
64
52
53
57
58
51
>99:1
>99:1
98:2
>99:1
>99:1
99:1
95:5
93:7
>99:1
84:16
84:16
94:6
a
b
c
Yields refer to analytically pure material (flash chromatography) after three steps.
Yields refer to analytically pure material (flash chromatography) after five steps.
Diastereomeric ratios were determined by 1H NMR analysis of the crude reaction mixture.
d
Enantiomeric ratios were determined by Moscher amide analysis of the major diastereomer using both 1H and 19F NMR.
bulky Ipc2BH,15 followed by oxidation with excess acetaldehyde,
hydrolysis with dilute hydrochloric acid, and esterification with
pinacol provided the product 1-aryl-1-amino-d-boronic esters 3
in very good overall yields and excellent enantiomeric ratios. The
product boronate esters, which were stable under conditions of
column chromatography, were obtained as the major enantiomer
shown in Table 1. A comparison with literature values of similar
compounds11,16 was used as confirmation that the stereochemical
outcome was the one expected for imine allylation. This stereo-
chemistry, when considered in the context of the stereochemical
consistency of other reports of analogous imine allylations,17 is
very reasonable.
Acknowledgments
We would like to sincerely thank the Herbert C. Brown Center
for Borane Research for the financial support of this project.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
06.076.
References and notes
The application of these conditions to Brown’s crotyl-18 and
methoxyallylboration19 reactions was also studied. These synthetic
analogs provide an excellent means to introduce further substitu-
tions or functionalities vicinal to the amine. We initially explored
these reactions, again using lithium triethylborohydride as the ni-
trile reductant. We found, however, that the use of the less expen-
sive diisobutylaluminum hydride (DIBAL-H)10 offered comparably
high enantio- and diastereoselectivities at the expense of only a
slight decrease in isolated yield (Table 2).
By following a methodology similar to that above, the formation
of crotyl-derived amines was realized. For example, the use of
4-methyl and 4-methoxybenzonitriles, when subjected to the
sequential reduction and crotylation conditions, resulted in the
formation of the expected products. Again, protection, followed
by hydroboration, controlled ligand oxidation, hydrolysis, and
esterification, furnished the desired d-aminoboronic esters. In
these cases, the use of the chiral isopinocampheyl ligand provided
very high levels of stereoinduction, with enantiomeric ratios as
high as 99:1 or better. As expected, the crotylation of the imines
proceeded with excellent diasteromeric ratios.10,17
1. (a) Kinder, D. H.; Frank, S. K.; Ames, M. M. J. Med. Chem. 1990, 33, 819–823; (b)
Kettner, C. A.; Shenvi, A. B. J. Biol. Chem. 1984, 259, 15106–15114.
2. Snow, R. J.; Bachovchin, W. W.; Barton, R. W.; Campbell, S. J.; Coutts, S. J.;
Freeman, D. M.; Gutheil, W. G.; Kelly, T. A.; Kennedy, C. A.; Krolikowski, D. A.;
Leonard, S. F.; Pargellis, C. A.; Tong, L.; Adams, J. J. Am. Chem. Soc. 1994, 116,
10860–10869.
3. Matteson, D. S. Med. Res. Rev. 2007, 28, 233–246.
4. Reddy, V. J.; Chandra, J. S.; Reddy, M. V. R. Org. Biomol. Chem. 2007, 5, 889–891.
5. Georgiou, I.; Ilyashenko, G.; Whiting, A. Acc. Chem. Res. 2009, 42, 756–768.
6. Beenen, M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6910–6911.
7. Dicko, A.; Montury, M.; Baboulene, M. Synth. Commun. 1988, 18, 459–463.
8. (a) Jego, J. M.; Carboni, B.; Vaultier, M. J. Organomet. Chem. 1992, 435, 1–8; (b)
Jego, J. M.; Carboni, B.; Vaultier, M.; Carrié, R. J. Chem. Soc., Chem. Commun.
1989, 142–143; (c) Collet, S.; Bauchat, P.; Danion-Bougot, R.; Danion, D.
Tetrahedron: Asymmetry 1998, 9, 2121–2131; (d) Kotoku, N.; Guo, X.-H.; Arai,
M.; Kobayashi, M. Bioorg. Med. Chem. Lett. 2010, 20, 4152–4155.
9. Touchet, S.; Carreaux, F.; Carboni, B.; Bouillon, A.; Boucher, J.-L. Chem. Soc. Rev.
2011, 40, 3895–3914.
10. Ramachandran, P. V.; Burghardt, T. E. Chem. Eur. J. 2005, 11, 4387–4395.
11. Ramachandran, P. V.; Biswas, D. Org. Lett. 2007, 9, 3025–3027.
12. Brown, H. C. Organic Synthesis via Boranes; John Wiley & Sons: New York, 1975.
13. (a) Brown, H. C.; Kim, K.-W.; Cole, T. E.; Singaram, B. J. Am. Chem. Soc. 1986, 108,
6761–6764; (b) Brown, H. C.; Jadhav, P. K.; Desai, M. C. J. Am. Chem. Soc. 1982,
104, 4303–4304; (c) Kamabuchi, A.; Moriya, T.; Miyaura, N.; Suzuki, A. Synth.
Commun. 1993, 23, 2851–2859.
14. Brown, H. C.; Randad, R. S. Tetrahedron 1990, 46, 4457–4462.
15. Racemic Ipc2BH was used for hydroboration. Although hydroboration with
Br2BH followed by hydrolysis can be used (Ref. 8a,b), we opted instead for the
use of Ipc2BH, followed by oxidative elimination with acetaldehyde, since this
In conclusion, we have presented herein the first synthesis of d-
aminoboronic esters in a fully stereocontrolled manner.20 The very
high levels of enantio- and diastereoselectivity, when considered in
the context of the high synthetic yields obtained, make this a very
attractive methodology, and opens a new route for the exploration
of these potentially useful d-aminoboronic esters.
protocol is more economical on
catalog). Furthermore,
during this process.
a
molar basis (Sigma–Aldrich chemical
a-pinene is completely eliminated and is recoverable

P. V. Ramachandran et al. / Tetrahedron Letters 54 (2013) 4830–4833
4833
16. Sugiura, M.; Hirano, K.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 7182–7183.
17. Ramadhar, T. R.; Batey, R. A. Synthesis 2011, 9, 1321–1346.
18. Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293–394.
19. Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 1535–1538.
20. Representative experimental:
0.5 mL H2O2 (30%) were added sequentially to the mixture. The mixture was
warmed to 25 °C over 12 h while maintaining a N2 atmosphere. The product
was extracted with Et2O, and the solvent was removed in vacuo. The crude
product 4b was then isolated via column chromatography in 69% yield. The
material (1.0 equiv) was then transferred into a RB flask, and dissolved in Et2O
(0.19 M). To this was added 1.1 equiv Boc2O, followed by 1.2 equiv Et3N. After
stirring for 6 h, the solvent was removed in vacuo. The crude material was
dissolved in THF (1 M), then was transferred into a suspension of 1.5 equiv
diisopinocampheylborane in THF (0.84 M). The reaction was stirred for 4 h,
then excess acetaldehyde was added. After stirring for 36 h, 1 M HCl (aq) was
added, then the product was then extracted with Et2O. The organic layer was
concentrated in vacuo, then 1.5 equiv pinacol were added. After stirring for an
additional 12 h, the product was extracted with Et2O, and the combined
organic layers were washed with brine, dried with Na2SO4, filtered, and
concentrated. Purification via column chromatography then furnished the
NH2
NHBoc
O
B
O
Me
Me
4b
7b
A RB flask was charged with 176 mg KO-t-Bu dissolved in 3 mL THF and cooled
to À78 °C. 0.34 mL of E-2-butene (2.5 equiv) was added to the solution, and the
mixture was stirred for 5 mins. 0.63 mL of n-butyllithium (1.3 equiv) was then
added, and the mixture was stirred for 45 mins at À55 °C. After re-cooling to
À78 °C, 1.5 equiv (À)-B-methoxydiisopinocamphenylborane (1.44 M in THF)
was added, and the mixture was stirred for 1 h. Subsequently, 1.0 equiv N-
aluminoimine (1 M in THF) was added, followed by the slow addition of
0.05 mL methanol. After stirring for 4 h at À78 °C, 0.8 mL 3 M NaOH (aq) and
desired
(1S,2S)-N-(t-butoxycarbonyl)-2-methyl-1-(4-methylphenyl)-4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-1-amine product 7b in
64% yield.