Concise synthesis of ω-borono-α-amino acids

Article abstract of DOI:10.1039/b618750a

A short protocol for the practical scale synthesis of several ω-borono-α-amino acids is described via the alkylation of benzophenone glycinimines with various electrophiles. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b618750a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Concise synthesis of x-borono-a-amino acids
Venkata Jaganmohan Reddy, J. Subash Chandra and M. Venkat Ram Reddy*
Received 22nd December 2006, Accepted 23rd January 2007
First published as an Advance Article on the web 1st February 2007
DOI: 10.1039/b618750a
A short protocol for the practical scale synthesis of several
x-borono-a-amino acids is described via the alkylation of
benzophenone glycinimines with various electrophiles.
Owing to the general importance of aminoboronic acids in
various areas of medicinal chemistry, and also their being the pre-
cursors in our ongoing project involving the synthesis of boronic
acid based folate antagonists, we required multigram quantities of
x-borono-a-amino acids. However, the current procedures avail-
able for preparing aminoboronic acids are somewhat limited for
large scale applications.5 Hence highly tunable, inexpensive, and
practical procedures for the synthesis of aminoboronic acids are
highly desirable. We envisaged that the alkylation of glycinimine
Schiff base 6, with halomethyl boronate electrophiles 7a–b should
provide protected aminoboronates that upon acidic hydrolysis
could readily afford b-boronoaspartic acid 1.6 In addition, we
also envisioned that the glycine esters alkylated at the a-position
with terminal alkenyl groups upon hydroboration and subsequent
hydrolysis should provide the remaining x-borono-a-amino acids
2a–d. Our results on the synthesis of x-borono-a-amino acids are
described below.
Boronic acids –B(OH)2 often function as inhibitors for various
enzymes due to their unique electronic and physicochemical
properties.1 The pKa values and stereo-electronics of boronic
acids are similar to those of carboxylic acids. Aminoboronic
acids mimic natural amino acids and act as bioisosteres in many
biochemical reactions. The mechanism of action is believed to be
the nucleophilic attack of an enzyme on to the electron deficient sp2
boron of boronic acid, resulting in the sp3 hybridized boron “ate”
complex.1,2 While the carboxylic acid–enzyme tetrahedral complex
is unstable, the corresponding boronic acid–enzyme “ate” complex
is highly stable resulting in the inhibition of the enzyme (Fig. 1).
We initiated the synthesis of b-boronoaspartic acid 1 with
the preparation of halomethylboronates 7a–b. Bromomethyl
pinanediolboronate 7a was prepared by the reaction of dibro-
momethane with triisopropylborate in the presence of nBuLi
and TMSBr, followed by transesterification with pinanediol.7a
a-Iodomethylpinacol boronate 7b was synthesized by the reac-
tion of B-isopropoxypinacolboronate with lithiated CH2I2.7b The
alkylation of benzophenone glycinimine 6 with both 7a and 7b
provided the unstable intermediates 8a–b. Heating 8a–b with 6
N HCl at 70 C led to the simultaneous hydrolysis of the butyl
ester to carboxylic acid, benzophenone imine to the amine, and
the pinacol/pinanediolboronate to the boronic acid. Washing with
CH2Cl2 to remove the organic by-products such as benzophenone,
and pinanediol/pinacol, followed by concentration of the aqueous
layer and trituration with acetone provided the b-boronoaspartic
acid 1 as a white hygroscopic powder. The reaction with the
more stable pinanediolboronate 7a provided higher yield (80%) as
compared with the relatively unstable pinacolboronate 7b (72%)
(Scheme 1).
Fig. 1 Binding of boronic acids with enzymes.
◦
t
It is well established that x-borono-a-amino acids (1, 2a–d,
Fig. 1) act as potent inhibitors of several enzymes such as serine
protease, arginase, dihydroorotase and dipeptidyl peptidase.3
There have been numerous reports in the literature about the utility
R
of aminoboronic acids as pharmaceutical agents e.g. Velcadeꢀ 3,
Talabostat 5, etc. (Fig. 2).4
Scheme 1 Synthesis of b-borono-a-aspartic acids.
Fig. 2 Aminoboronic acids as pharmaceutical agents.
After accomplishing the synthesis of b-boronoaspartic acid 1,
we embarked upon the synthesis of the other x-borono-a-amino
acids 2a–d. We chose commercially available and inexpensive
x-halo-1-alkenes 9a–d as the electrophiles for the alkylation of
Departments of Chemistry and Biochemistry and Pharmacy Practice and
Pharmaceutical Sciences, University of Minnesota Duluth, Duluth, MN
55812, USA. E-mail: vmereddy@d.umn.edu; Fax: 1-218-726-7394; Tel: 1-
218-726-6766
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glycinimine. The requisite a-substituted glycine esters 10a–d were
obtained via the alkylation of Schiff base 6 with various x-
bromo-1-alkenes (9a–d) in very good yields. Pinacolborane 11 was
chosen as the hydroborating agent because of its relative inertness
towards several functional groups for achieving chemoselective
hydroboration. Moreover, the corresponding pinacolboronates
obtained via hydroboration are also air-stable and can be readily
chromatographed over silica gel without decomposition or hy-
drolysis. Hydroboration of alkenes with pinacolborane proceeds
very slowly even at elevated temperatures. However, the rate of
hydroboration can be tremendously increased by the addition of
transition metal catalysts.8 Accordingly, hydroboration of these
terminal olefins 10a–d with pinacolborane 11 was performed in
the presence of Wilkinson’s catalyst. To our delight, hydroboration
proceeded with utmost ease and the corresponding pinacol-
boronates 12a–d were obtained in high regioselectivity favoring
the terminal position of the olefin. Hydrolysis of the resulting
boronates by heating with 6 N HCl, followed by trituration
with acetone provided the x-borono-a-amino acids 2a–d as white
hygroscopic solids (Scheme 2). As compared with the previous
synthesis of these x-borono-a-amino acids, the current protocol is
operationally simple and readily assembles the boronic acids in 3
steps in an overall yield of 40–45% starting from the glycinimine
Schiff base. We were able to demonstrate the robustness of the
protocol via the synthesis of multigram quantities of b-borono
aspartic acid 1 as well as c-boronoarginine 2a.
Experimental
Synthesis of b-boronoaspartic acid 1
To a stirred solution of benzophenone glycinimine 6 (5.90 g,
20 mmol) in THF, was added LiHMDS (22 mL, 22 mmol, 1 M so-
lution) at −78 ◦C followed by a-bromomethylpinanediolboronate
7a (6.56 g, 24.0 mmol) dissolved in 10.0 mL THF and stirred for
5 h. The reaction mixture was worked up with ether and water.
The combined organic layers were dried (MgSO4), concentrated,
and the complete hydrolysis of the crude mixture was achieved
◦
by heating at 70 C for 4 h in the presence of 6 N HCl (40 mL).
The organic by-products were removed by washing the aqueous
layer repeatedly with CH2Cl2 (3 × 40 mL). The aqueous layer
◦
was concentrated in vacuum at 40 C to afford a white powder.
Trituration with acetone and CH2Cl2 provided 2.72 g of pure b-
boronoaspartic acid 1 in 80% overall yield. 1H-NMR (500 MHz,
D2O): d 4.17 (1H, dd, J 7.0 and 9.7), 1.37 (1H, dd, J 7.0 and
14.9), 1.20 (1H, dd, J 10.0 and 15.0); 13C-NMR (125 MHz, D2O):
d 175.2, 52.5, 18.7 (br); ESI-MS: 191 [(M − H + Na)+, 100%]+.
Synthesis of x-borono-a-amino acids
Pinacolborane 11 (0.86 mL, 6 mmol) was added to a solution
of Wilkinson’s catalyst (277 mg, 0.3 mmol, 5 mol%) in 10 mL
dry THF and stirred for 30 minutes. Alkene 10c (1.6 g, 4 mmol)
was added slowly and stirred overnight. The reaction mixture
was worked up with ether and water. The organic layer was
concentrated in vacuo and the residue was heated at 70 ◦C for
4 h in the presence of 6 N HCl (20 mL) so as to affect complete
hydrolysis. Work up with CH2Cl2 to remove organic by-products
and concentration of the aqueous layer in vacuo at 40 ◦C yielded
a white powder. Trituration with acetone provided 0.56 g (62%
1
combined yield for two steps) of the aminoboronic acid 2c. H-
NMR (500 MHz, D2O): d 3.82 (1H, t, J 6.2), 1.70–1.90 (2H, m),
1.05–1.45 (6H, m), 0.77 (2H, t, J 7.9); 13C-NMR (125 MHz, D2O):
d 172.4, 53.6, 31.4, 30.1, 28.1, 24.0, 17.0; ESI-MS: 244 [(M + H +
H2O)+, 100%], 226 (M + H)+.
Acknowledgements
This research was supported by grants from the Research Cor-
poration (CC6961), the American Cancer Society (IRG-58-001-
46-IRG51), and the Grant-in-Aid (20206) administered by the
University of Minnesota. We also thank the Aldrich Chemical
Company for the financial support.
Scheme 2 Synthesis of x-borono-a-amino acids.
In conclusion, we have developed a preparative scale procedure
for the synthesis of b-boronoaspartic acid via the alkylation of
benzophenone glycinimine Schiff base with halomethyl boronates.
We have also developed a simple and practical procedure for the
synthesis of various other x-borono-a-amino acids via the alkyla-
tion of benzophenone glycinimine with bromoalkenes, followed by
catalytic hydroboration with pinacolborane and hydrolysis. As the
chemical tolerance of pinacolborane towards several functional
groups is well precedented, the present methodology provides
an opportunity for the synthesis of several boronated analogs of
amino acids. Given the simple experimental techniques, inexpen-
sive starting materials, and the importance of aminoboronic acids,
we believe that the present methodology would be highly amenable
for large scale synthesis and would attract the attention of organic
and medicinal chemists.
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