Synthesis of new boron analogues of cyclic carboxylic α-amino acids using ring-closing metathesis reactions

Article abstract of DOI:10.1016/j.tetlet.2004.09.112

Ruthenium catalyzed ring-closing metathesis has been used as a key step for the synthesis of cyclic α-aminoboronic esters as, for example, boron-containing mimics of pipecolic, 2-azepanecarboxylic acid or baikiain.

Full text of DOI:10.1016/j.tetlet.2004.09.112

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8749–8751
Synthesis of new boron analogues of cyclic carboxylic a-amino
acids using ring-closing metathesis reactions
Alain Hercouet, Catherine Baudet and Bertrand Carboni*
´
UMR 6509 CNRS-Universite de Rennes 1, Institut de Chimie, Campus de Beaulieu, 35042 Rennes Cedex, France
Received 27 August 2004; revised 14 September 2004; accepted 15 September 2004
Available online 12 October 2004
Abstract—Rutheniumcatalyzed ring-closing metathesis has been used as a key step for the synthesis of cyclic a-aminoboronic esters
as, for example, boron-containing mimics of pipecolic, 2-azepanecarboxylic acid or baikiain.
Ó 2004 Elsevier Ltd. All rights reserved.
The enzyme inhibiting activity of boronic acid deriva-
tives was first discovered three decades ago with (S)-N-
acetyl-borophenyl-alanine.1 This compound acts as a
reversible transition state analogue inhibitor of chymo-
trypsin due to the close similarity between a tetrahedral
borate fragment and the key intermediate in the enzy-
matic sequence.2 Since these pioneering works, there
was an intense interest in synthesizing new other amido-
boronic acids and derivatives andÒexamining their bio-
logical properties.3 Thus, Velcade , a boropeptide, has
recently received approval fromthe US Food and Drug
Administration for the treatment of multiple myeloma.
This class of compounds has also been examined as car-
riers of 10B for treatment of cancer in boron neutron
capture therapy (BNCT) strategy.4
lot of attention for the construction of nitrogen-contain-
ing systems.7 Thus, ring-closing metathesis became a
major tool in synthetic organic chemistry and was
shown to tolerate a range of functional groups.8
In the present work, we investigated the synthesis of new
a-amino boronic esters using this reaction as key step
(Scheme 1). Besides the potential biological interest of
these mimics of carboxylic amino acids, it seems also
important to determine the stability of the B–C–N link-
age in such a catalytic process.
R2
H
R3
N
R1
( )
Cyclic carboxylic a-amino acids, as proline or pipecolic
acid for example, display significant biological activities
and are valuable constituents in peptides. To our know-
ledge, boroproline, prepared by borylation of N-Boc-
pyrrolidine or pyrrole,5 and an analogue of N-acetyl-
kainic acid, obtained by an intramolecular nucleophilic
substitution reaction,6 were the only boron analogues
of cyclic carboxylic a-amino acid described in the
literature.
(RO)2B
H
m
(RO)2B
( )
n
R4
or
+
N
H
N
X
R1
R
1 = Boc, Tos
X = Br, I n, m = 0, 1, 2
R3, R4 = H or Me
R2 = H or Me
Scheme 1. Access to boron analogues of cyclic a-amino acids.
However, the reported syntheses of these compounds
seem restricted to some isolated examples. The transi-
tion metal-mediated cyclization reactions have drawn a
Starting a-bromoboronates were first prepared in good
yields, either frompinacol dibromomethylboronate by
reaction with an unsaturated organomagnesium com-
pound (1a–c) or by insertion of a CHBr moiety into
the carbon–boron bond of an x-alkenylboronic ester
(1d).9 The reactivity of 1 in the amidation reaction was
found to be low, except for 1a where the halogen is in
an allylic position.
Keywords: Aminoboronic esters; Ring-closing metathesis; Aminoacids
analogues.
*
Corresponding author. Tel.: +33 02 99 28 67 47; fax: +33 02 23 23 69
78; e-mail: bertrand.carboni@univ-rennes1.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.112

8750
A. Hercouet et al. / Tetrahedron Letters 45 (2004) 8749–8751
Br
R'MgX
(RO)2B
THF, -78°C
Br
Br
R'
I
NaI
(RO)2B
1a-d
(RO)2B
acetone
R'
CH2Br2, LiNiPr2,
THF, -78°C
2b-d
(RO)2B
R'
B
R' = CH=CH-CH3
R' = CH2-CH=CH2
1a (71%)
O
O
1b (86%)
1c (75%)
1d (60%)
2b (91%)
2c (70%)
2d (83%)
B(OR)2
=
R' = CH(CH3)-CH=CH2
R' = (CH2)2-CH=CH2
Scheme 2. Synthesis of a-haloboronates 1a–d and 2b–d.
R3
( )
R3
Li
N
R2
(RO)2B
R1
THF
R4
(RO)2B
( )
n
R4
+
n
R1
( )
N
-78°C
m
X
( )
m
4a-j
1a, 2b-d
3
R2
Li
N
(RO)2B
(RO)2B
THF
+
R1
N
R1
-78°C
I
2b
3
4k-l
Scheme 3. Synthesis of dienes 4a–j and enynes 4k–l.
To overcome this difficulty, bromine/iodide exchange
was performed by treatment with NaI in acetone at
reflux for 12h (Scheme 2).
Next, we turned our attention to the ring-closing reac-
tions. Three different catalysts were used (Fig. 1). The
results are summarized in Scheme 4 and Table 2.
Having in hand the a-halogenoboronates 1a and 2b–d,
we then examined their reactivity toward the lithium
salts of N-Boc- or N-Tos-allyl- and propargylamines
3.10 N-Boc- or N-tosyl-aminoboronates 4b–i and 4k–l
were obtained in reasonable to good yields after purifi-
cation by chromatography on silica gel (Scheme 3, Table
1). In our hands, 2c, with a methyl group a to the iodine
atom, afforded only traces of 4j, while a-bromoallyl-
boronic ester 1a gave 4a in a disappointing and unopt-
imized 23% yield.
Cl
Cl
Mes
Cl
Cl
N
N
Mes
Ph
PCy3
Ru
Ru PCy3
O
Ph
Cl
Cl
Ru
PCy3
PCy3
5a
5b
5c
Figure 1. Rutheniumcatalysts.
Rutheniumcatalyst 5a was found to be effective for six-
and seven-membered ring a-amidoboronic esters 6b–e
and 6h–k, which were isolated in 54–90% yields in
Table 1. Synthesis of a-amidoboronic esters 4a–l
(RO)2B
( )
Product
X
R1
R2
R3
R4
n
m
Yield (%)
R4
n
4a
4b
4c
4d
4e
4f
Br Tos
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
—
—
Me
H
H
H
H
H
H
H
H
H
—
—
0
1
23
78
N
R1
( )
I
I
I
I
I
I
I
I
I
I
I
Boc
Tos
Boc
Tos
1
1
m
1
1
82
64
(RO)2B
R1
( )
[Ru]
R2
4a-j
1
2
n
or
1
2
67
56
CH2Cl2
reflux, 4h
N
( )
R5
Boc Me
Tos Me
1
1
(RO)2B
R1
m
4g
4h
4i
1
1
60
55
6a-j
Boc
Tos
Tos
Boc
Tos
H
H
H
—
—
2
1
N
2
1
68
4j
1
1
Traces
75
92
4k-l
Scheme 4. Ring-closing metathesis of 4a–l.
4k
4l
—
—
—
—

A. Hercouet et al. / Tetrahedron Letters 45 (2004) 8749–8751
8751
CH2Cl2 at reflux for 4h.11 Tetrahydropyridines 6f–g
References and notes
with a 1,1-disubstitution on the initial double bond were
only obtained, respectively, in 55% and 40% yields, in
the presence of second-generation Grubbs catalyst 5b.
In contrast, the B–C–N linkage is not stable in the pre-
sence of these catalysts and we were unable to obtain
any pyrroline starting from 4a in the presence of 5a or
5b. No starting material was recovered under these rea-
ction conditions. Gratifyingly, the cyclization has been
realized with Hoveyda catalyst 5c, albeit in a low yield.
The difficulties observed in this reaction are in agree-
ment with previous observations related to the carboxy-
lic analogue.12
1. Matteson, D. S.; Sadhu, K. M.; Lienhard, G. E. J. Am.
Chem. Soc. 1981, 103, 5241.
2. Weber, P. C.; Lee, S. L.; Lewandowski, F. A.; Schadt, M.
C.; Chang, C. W.; Kettner, C. A. Biochemistry 1995, 34,
3750.
3. Yang, W.; Gao, X.; Wang, B. Med. Res. Rev. 2003, 23,
346.
4. Soloway, A. H.; Tjarks, W.; Barnum, B. A.; Rong, F. G.;
Barth, R. F.; Codogni, I. M.; Wilson, J. G. Chem. Rev.
1998, 98, 1515.
5. Gibson, F. S.; Singh, A. K.; Soumeillant, M. C.; Manc-
hand, P. S.; Humora, M.; Kronenthal, D. R. Org. Process
Res. Dev. 2002, 6, 814; Dembitsky, V. M.; Srebnik, M.
Tetrahedron 2003, 59, 579.
6. Matteson, D. S.; Lu, J. Tetrahedron: Asymmetry 1998, 9,
2423.
Table 2. Synthesis of cyclic a-amidoboronic esters 6
Product
Cat.
R1
R5
n
m
Yield (%)
7. Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127.
8. Handbook of Metathesis Reactions; Grubbs, R. H., Ed.;
Wiley-VCH: Weinheim, 2003; For recent reviews on ring-
closing metathesis of nitrogen-containing systems, see:
Vernall, A. J.; Abell, A. D. Aldrichim. Acta 2003, 36, 93;
Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199; For
recent examples of reactions of unsaturated boronic esters,
see: (a) Renaud, J.; Ouellet, S. G. J. Am. Chem. Soc. 1998,
120, 7995; (b) Renaud, J.; Graf, C. D.; Oberer, L. Angew.
Chem., Int. Ed. 2000, 39, 3101; (c) Goldberg, S. D.;
Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41, 807; (d)
Morrill, C.; Grubbs, R. H. J. Org. Chem. 2003, 68, 6031.
9. Matteson, D. S. Tetrahedron 1998, 54, 10555.
10. Schlapbach, A.; Hoffmann, R. W. Eur. J. Org. Chem.
2001, 323.
11. Typical procedure for the ring closing metathesis: To a
solution of diene 4b (113mg, 0.335mmol) in CH2Cl2
(5mL) was added Cl2(Pcy3)2RuCHPh (5a, 14m g,
0.017mmol). The solution was refluxed under argon for
3h. The solvent was evaporated and the residue was
purified by flash chromatography on silica gel (10% ethyl
acetate in cyclohexane) to give 6b as a light yellow oil
(90mg, 87%). 1H NMR (300MHz, CDCl3): d 5.92–5.81
(m, 1H), 5.53–5.42 (m, 1H), 3.89–3.75 (dm, J = 17.7Hz,
1H), 3.53–3.42 (dm, J = 17.7Hz 1H), 2.43 (dd, J = 3.3 and
6.4Hz, 1H), 2.33–2.18 (m, 1H), 2.01–1.87 (m, 1H), 1.43 (s,
9H), 1.11 (s, 12H). 13C NMR (75.5MHz, CDCl3): d 160.2,
127.8, 120.7, 86.0, 80.1, 41.0, 28.2, 25.7, 25.1, 24.8.
12. Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am.
Chem. Soc. 1996, 118, 9606.
6a
6b
6c
6d
6e
6f
5c
5a
5a
5a
5a
5b
5b
5a
5a
5a
5a
Tos
Boc
Tos
Boc
Tos
Boc
Tos
Boc
Tos
Boc
Tos
H
0
1
1
1
1
1
1
2
2
1
1
1
1
1
2
2
1
1
1
1
1
1
42
87
90
85
86
40
55
58
54
67
75
H
H
H
H
Me
6g
6h
6i
Me
H
H
6k
6l
CH@CH2
CH@CH2
Since the synthesis of boropeptides required the NH
derivative of aminoboronic esters,5 deprotections of 6b
and 6h, selected as examples, were easily carried out with
HCl in diethylether (Scheme 5). Hydrogenation of the
double bond occurred in the presence of Pd/C to give
the corresponding saturated heterocycles, respectively,
in 75% and 86% overall yields.13 The order of these
two steps can be reversed with no significant modifica-
tion in terms of purity and yield.
B(OR)2
Boc
B(OR)2
( )
n
( )
(i), (ii)
n
N
N
Cl
H
or (ii), (i)
H
13. Amine deprotection: 6b (81mg, 0.28mmol) was treated
with a saturated solution of HCl in diethylether (10mL)
with stirring at 0°C for 12h. The solvent was evaporated
to yield the corresponding hydrochloride. 1H NMR
(300MHz, CDCl3): 1H NMR (300MHz, CDCl3): d
9.60–9.46 (m, 1H), 9.34–9.20 (m, 1H), 6.02–5.90 (m,
1H), 5.70–5.58 (m, 1H), 4.00–3.83 (m, 1H), 3.72–3.55 (m,
1H), 3.22–3.10 (m, 1H), 2.72–2.54 (m, 1H), 2.50–2.32
(m, 1H), 1.22 (s, 12H). 13C NMR (75.5MHz, CDCl3): d
126.1, 120.3, 85.2, 41.2, 29.6, 24.8, 24.7. Hydrogenation:
The crude hydrochloride (74mg, 0.24mmol) was dissolved
in ethanol (10mL). The reaction mixture was stirred in the
presence of Pd/C 5% (10mg) under H2 (10atm.) for 4h.
After filtration through Celite, the solvent was evaporated
6b (n=1), 6h (n=2)
7b (75%) 7h (86%)
Scheme 5. Synthesis of aminoboronate hydrochlorides 7. Reagents
and conditions: (i) HCl, EtOAc, 2h, rt; (ii) H2, Pd/C, EtOH, 10atm.
In conclusion, we have demonstrated a feasible route
into a variety of new N-protected cyclic a-aminoboron-
ates. In addition, the cleavage of the N-Boc group pro-
vided the corresponding boron analogues of carboxylic
amino esters that could be further engaged in
boropeptide synthesis. Further studies including the
development of an asymmetric version using enantio-
merically pure a-haloboronate as starting material
and the incorporation of the corresponding a-amino-
boronic acids in peptidic chains are currently under
investigation.
1
to give 7b (65mg, 75%). H NMR (300MHz, CDCl3): d
9.20 (bs, 1H), 8.72 (bs, 1H), 3.52–3.38 (m, 1H), 3.18–2.98
(m, 2H), 2.10–1.40 (m, 6H). 13C NMR (75.5MHz, CDCl3)
d 85.2, 44.2, 29.7, 24.9, 24.6, 22.6, 22.4.