Silver-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with β-boryl acrylates

Article abstract of DOI:10.1021/jo1024915

The Ag-catalyzed 1,3-dipolar cycloaddition of (?)-β-borylacrylates with azomethine ylides is described. The resulting 3-borylpyrrolidine derivatives were obtained in high yields and complete endo selectivities using AgOAc/ dppe as catalyst system and B(dam) as boryl group. Transformation of the B(dam) group into pinacol borane and oxidation afforded 3-hydroxyproline derivatives in high yields.

Full text of DOI:10.1021/jo1024915

NOTE
pubs.acs.org/joc
Silver-Catalyzed 1,3-Dipolar Cycloaddition of Azomethine Ylides with
β-Boryl Acrylates
Ana L ꢀo pez-P ꢀe rez, Marwin Segler, Javier Adrio,* and Juan C. Carretero*
Departamento de Química Org ꢀa nica, Facultad de Ciencias, Universidad Aut ꢀo noma de Madrid, Cantoblanco, 28049 Madrid, Spain
S Supporting Information
b
ABSTRACT: The Ag-catalyzed 1,3-dipolar cycloaddition of
(Ε)-β-borylacrylates with azomethine ylides is described.
The resulting 3-borylpyrrolidine derivatives were obtained
in high yields and complete endo selectivities using AgOAc/
dppe as catalyst system and B(dam) as boryl group. Trans-
formation of the B(dam) group into pinacol borane and oxidation afforded 3-hydroxyproline derivatives in high yields.
ydroxypyrrolidines are widely present in natural products
and biologically active compounds. For instance, the
-hydroxypyrrolidine scaffold is found in a variety of alkaloids
temperature (Table 1). We found the best reactivity using
1
18
H
AgOAc as catalyst (Table 1, entry 1). However, all the attempts
1
9
3
aimed to purify the boryl-substituted pyrrolidine adduct, as well
with varied and potentially useful biological activities, such as
as the direct oxidation of the C-B bond in the crude reaction
2
3
4
5
20
salinosporamide C, barnidipine, retronecine, preussin, and
mixture, resulted in extensive decomposition.
6
detoxin A1. Furthermore, 3-hydroxyproline derivatives are
In order to increase the stability of the 3-borylpyrrolidine
adduct, the alkenylboronic acid 3 and their derivatives 4-6 were
prepared and examined under similar reaction conditions
(entries 2-5). The reaction of boronic acid 3 afforded a complex
present in peptides and cyclopeptides with great therapeutic
7
potential.
Because of this interest, a variety of methods have been
8
21
reported for the synthesis of hydroxypyrrolidines. However,
mixture of pyrrolidines, while no reaction was observed from
22
23
there is room for improvement, especially in the context of the
stereoselective synthesis of densely functionalized hydroxypyr-
rolidines. The 1,3-dipolar cycloaddition of azomethine ylides
derived of R-iminoesters with activated alkenes constitutes a
powerful and convergent tool for the preparation of substituted
the trifluoroalkylborate salt 4 or the mida boronate 5, likely
due to the insolubility of these species in typical organic solvents
(entries 3 and 4). More encouraging, the 1,8-diaminonaphtalene
24
(dam) derivative 6 afforded the pyrrolidine 7a with high endo
selectivity in 20% yield after standard column chromatography
(entry 5). Gratifyingly, further optimization of the reaction
conditions, mainly by changing the solvent and, especially, the
base, allowed a dramatic increase in the efficiency of the process
(entries 6-8), reaching 77% yield in pyrrolidine 7a using
LiHMDS as base in toluene (entry 8). Interestingly, after a
9
pyrrolidines and proline derivatives. Since the pioneering re-
1
0
ports by Grigg, different catalytic systems based on the com-
bination of a metal salt with a mild base have been developed,
11
including a wide variety of catalytic asymmetric procedures.
One of the main synthetic limitations of this strategy is that it is
only applicable to low LUMO dipolarophiles, mainly electron-
deficient conjugated alkenes, hampering the preparation of
pyrrolidines with electron-donating oxygenated substituents at
position 3 of the pyrrolidine ring. Taking into account that
alkenylboron derivatives have been successfully employed as
1
8
survey of other commercially available biphosphines, a com-
plete endo selectivity and excellent yield (93%) was obtained
when dppe was used as ligand (entry 9). The relative configura-
tion of pyrrolidine endo-7a was unequivocally established by
25
X-ray diffraction.
1
2
olefin partners in 1,3-dipolar cycloadditions of diazoalkanes,
With these optimal reaction conditions in hand, we next
studied the scope of the reaction with regard to the azomethine
ylide precursor (Table 2). Similar to the behavior of the model
iminoester 1a, only the endo isomer was observed in all of the
examples studied. All aryl imine glycinate derivatives afforded
good to excellent yields, after silica gel chromatographic purifica-
tion, regardless of the electronic character of the substituents at
the ortho, meta, or para position of the aromatic ring (entries 1-7).
Similar results were obtained with heteroaromatic R-imino-
esters (entries 8 and 9). The procedure can be also applied to
1
3
14
15
nitrones, nitrile oxides, and nonstabilized azomethine ylides,
we envisaged that 3-borylacrylates could be suitable dipolaro-
philes in the metal-catalyzed 1,3-dipolar cycloaddition of R-
iminoesters (Scheme 1). To the best of our knowledge only an
16
isolated example of this strategy has been previously described.
Given the synthetic versatility of alkylboronates, this approach
could lead to the straightforward stereoselective preparation of
proline derivatives, especially 3-hydroxypyrrolidines.
Our initial studies were focused on the reaction between
N-benzylideneglycine methyl ester (1a) and the activated pina-
1
7
col boronate 2 in the presence of a variety of copper and silver
Received: December 16, 2010
Published: February 21, 2011
salts, (()-Binap as ligand, and Et N as base in THF at room
3
r 2011 American Chemical Society
1945
dx.doi.org/10.1021/jo1024915
|J. Org. Chem. 2011, 76, 1945–1948

The Journal of Organic Chemistry
NOTE
Scheme 1. Strategy for the Stereoselective Synthesis of Sub-
stituted 3-Hydroxypyrrolidines
Table 2. Scope for the Azomethine Ylide Precursor
Table 1. Optimization Experiments for the Model Reaction
1
2
a
entry
R
R
product
yield (%)
1
2
p-BrC
p-ClC
6
H
H
4
H
H
H
H
H
H
H
H
H
H
H
Me
7b
7c
7d
7e
7f
82
68
64
95
83
88
67
98
78
49
71
27
6
4
3
p-MeOC
o-MeC
m-MeC
m-FC
6
H
4
4
6 4
H
5
6 4
H
6
6
H
4
7g
7h
7i
7
naphthyl
thienyl
furyl
8
9
7j
a
b
10
Cy
7k
7l
entry
BX
2
ligand
base
endo/exo
yield (%)
t
1
1
2
Bu
c
1
B(pin) (2)
B(OH) (3)
BF K(4)
(()-binap Et
(()-binap Et
(()-binap Et
3
N
N
N
N
N
N
>98/<2
1
Ph
7m
c
a
2
2
3
3
3
3
3
Isolated yield of endo adduct.
c
3
4
c
4
B(mida) (5) (()-binap Et
d
Scheme 2
5
B(dam) (6)
B(dam) (6)
B(dam) (6)
B(dam) (6)
B(dam) (6)
(()-binap Et
(()-binap Et
87/13
69/31
66/34
88/12
20
48
58
77
93
e
6
e
7
(()-binap KHMDS
e
8
(()-binap LiHMDS
e
f
9
dppe
LiHMDS
>98/<2
b
a
1
By H NMR from the crude reaction mixtures. Isolated yield of endo-
c
d
e
f
7
2
a. THF as solvent. Et O as solvent. Toluene as solvent. dppe: 1,2-
bis(diphenylphosphino)ethane.
the more challenging alkyl-substituted imines, providing 5-al-
kylpyrrolidines 7k and 7l in reasonable yields (entries 10 and
1
1). In contrast, the alanine-based iminoester 1m was much
less reactive, affording the pyrrolidine adduct 7m, with a
quaternary center at C-2, in 27% yield (entry 12).
To highlight the synthetic interest of 3-borylpyrrolidines 7,
the oxidation to the corresponding alcohols was next ex-
plored. The best result was obtained by treatment of the
N-protected Cbz derivative 8 with pinacol borane under
acidic conditions, followed by direct oxidation of the result-
ing pinacol borane mixture using standard conditions (H O ,
imines. In the presence of DTBM-Segphos as chiral ligand the
model 1,3-dipolar cycloaddition took place with moderate
enantioselectivity (60% ee). The oxidation of the 3-boryl sub-
stituted aducts highlights the usefulness of this method for the
preparation of 3-hydroxypyrrolidines.
2
2
NaOH; Scheme 2).
Finally, we explored the viability of developing a catalytic
asymmetric version of this 1,3-dipolar cycloaddition. To this end,
a set of commercially available chiral biphosphines were tested as
’
EXPERIMENTAL SECTION
2
6
27,28
ligands. The P,P axially chiral DTBM-Segphos ligand
Typical Procedure for the 1,3-Dipolar Cycloaddition:
proved to be the best ligand, providing the cycloadduct 2 in
(
[
2S*,3S*,4S*,5R*)-Dimethyl 3-(2,3-Dihydro-1H-naphtho-
1,8-de]-1,3,2-diazoborinyl)-5-phenylpyrrolidine-2,4-dicar-
29
7
8% yield and moderate 60% ee (Scheme 3). No improvement
in the enantioselectivity was observed when this reaction was
performed at 0 °C instead of room temperature.
In summary, 3-borylacrylates are suitable dipolarophiles in
metal-catalyzed 1,3-dipolar cycloadditions of azomethine ylides.
Using AgOAc/dppe as catalyst system, LiHMDS as base, and
B(dam) as boryl group, good yields and complete endoselec-
tivities were achieved in the reaction with a variety of glycinate
boxylate (endo-7a). To a solution of dppe ligand (5.2 mg, 0.013
mmol) and AgOAc (2.0 mg, 0.013 mmol) in toluene (0.5 mL), under
nitrogen atmosphere, at room temperature, were successively added a
solution of methyl (E)-N-benzylideneglycinate (27 mg, 0.15 mmol) in
toluene (0.5 mL) and LiHMDS (1 M in THF, 35.0 μL, 0.035 mmol).
The resulting solution was added to a suspension of trans-methyl 3-(1H-
naphtho[1,8-de][1,3,2]diazoborinin-2(3H)-yl)-acrylate (30 mg, 0.12 mmol)
1
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The Journal of Organic Chemistry
NOTE
Scheme 3. Catalytic Asymmetric Version
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1
2
7
09-210 °C; H NMR (300 MHz, CDCl ) δ 7.34-7.29 (m, 5H), 7.13-
3
.08(m, 2H), 7.04-7.01 (m, 2H), 6.35-6.33 (m, 2H), 6.10(bs, 2H), 4.66
(
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13
0.6, 8.8 Hz,1H), 3.27(s,3H), 3.11(bs, 1H),2.33(t, J=10.6Hz,1H); C
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27.5, 127.1, 119.8, 117.8, 106.0, 65.2, 63.0, 54.1, 52.7, 51.6 (the boron-
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1
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Mishiro, A.; Sato, H. Angew. Chem., Int. Ed. 2010, 49, 7895–7898.
g) Shimizu, K.; Ogata, K.; Fukuzawa, S.-i. Tetrahedron Lett. 2010, 51,
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Corresponding Author
(
5
*E-mail: javier.adrio@uam.es; juancarlos.carretero@uam.es.
Lett. 2010, 12, 1752–1755. (i) Xue, Z.-Y.; Liu, T.-L.; Lu, Z.; Huang, H.;
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’
ACKNOWLEDGMENT
(j) Robles-Machín, R.; Gonz ꢀa lez-Esguevillas., M.; Adrio, J.; Carretero,
Financial support of this work by the Ministerio de Ciencia e
J. C. J. Org. Chem. 2010, 75, 233–236. (k) Arai, T.; Mishiro, A.;
Yokoyama, N.; Suzuki, K.; Sato, H. J. Am. Chem. Soc. 2010, 132,
5338–5339. (l) Robles-Machín, R.; Alonso, I.; Adrio, J.; Carretero,
J. C. Chem.—Eur. J. 2010, 16, 5286–5291. (m) Yamashita, Y.; Guo,
X.-X.; Takashita, R.; Kobayashi, S. J. Am. Chem. Soc. 2010, 132, 3262–
Innovaci ꢀo n (Grant No. CTQ2009-07791) and Consejería de
Educaci ꢀo n de la Comunidad de Madrid (project AVANCAT;
S2009/PPQ-1634) are gratefully acknowledged. A.L.-P. thanks
the CAM for a predoctoral contract. We thank Takasago Co. (Dr.
Wataru Kuriyama) for generous loans of Segphos and DTBM-
Segphos chiral ligands.
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The Journal of Organic Chemistry
NOTE
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1
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