Synthesis of 2-aminocyclopropyl pyrrolidines from glycoaminonitriles

Article abstract of DOI:10.1016/j.tetlet.2009.02.135

We have developed an expedient method for the synthesis of 2-aminocyclopropyl pyrrolidines from carbohydrate-derived α-aminonitriles involving up to five or six steps, the key step being the titanium-mediated aminocyclopropanation on the aminonitrile moie

Full text of DOI:10.1016/j.tetlet.2009.02.135

Tetrahedron Letters 50 (2009) 2171–2173
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2-aminocyclopropyl pyrrolidines from glycoaminonitriles
*
Delphine Declerck, Solen Josse, Albert Nguyen Van Nhien, Denis Postel
Laboratoire des glucides, UMR-CNRS 6219 Université de Picardie-Jules Verne, 33 rue Saint Leu, 80039 Amiens, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an expedient method for the synthesis of 2-aminocyclopropyl pyrrolidines from car-
Received 3 October 2008
Revised 2 February 2009
Accepted 4 February 2009
Available online 25 February 2009
bohydrate-derived a-aminonitriles involving up to five or six steps, the key step being the titanium-med-
iated aminocyclopropanation on the aminonitrile moiety, followed by cleavage of the protecting groups.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Glycoaminonitriles
Cyclopropylamine
Titanium isopropoxide
Pyrrolidine
The iminosugar moiety is found in a number of natural prod-
ucts, such as nojirimycin1 (5-amino-5-deoxy-
-glucose, 1) and 1-
tion between Ti(OiPr)4 and EtMgBr and subsequent b-hydrogen
fragmentation. Insertion of the nitrile into A affords the azatitana-
cycle B. Addition of a Lewis acid activates the azatitanacycle, which
then undergoes ring-contraction to give the corresponding cyclo-
propylamine (Scheme 1).
D
deoxynojirimycin (1,5-dideoxy-1,5-imino-D-glucitol, 2) (Fig. 1).
These compounds are notably reversible glycosidase inhibitors.2–
14
For instance, 2,5-dideoxy-2,5-imino-
D
-mannitol15 (DMDP) (3)
inhibits
a
- and b-glucosidases.16 and displays some anti-HIV activ-
In order to convert tertiary amides into cyclopropylamines, De
Meijere and co-workers26–28 have reported the same strategy,
but using of methyltitanium triisopropoxide instead of Ti(OiPr)4,
as a more efficient reagent, that in addition requires only 1 equiv
of Grignard reagent to generate titanacyclopropane, thus limiting
the formation of side reactions (Scheme 2).
ity. However its high cytotoxicity has precluded its use as an effec-
tive antiviral drug.17 In this active area of research the
development of new, chiral and differently functionalized imino-
sugars would allow the identification of more potent and selective
glycosidase inhibitors.
Cyclopropane rings are present in many bioactive molecules.18–
21 Replacement of a methylene group in an iminosugar by a cyclo-
propane ring could induce electronic and conformational modifica-
tions, and consequently, enhance the binding with biological
receptors. Szymoniak and Bertus22–25 have recently reported a con-
venient synthesis of cyclopropylamines from nitriles and Grignard
reagents in the presence of titanium isopropoxide. In this reaction,
a titanacyclopropane intermediate A is generated by transmetala-
Plantier-Royon and co-workers29 described an original applica-
tion of this chemistry on a cyanosugar scaffold for the synthesis of
a-
L-fucosidase inhibitors. The cyclopropanation step occurs in 40–
45% yield.
Ti(OiPr)2 (A)
N
R
R
Ti(OiPr)2
R-CN
(B)
BF3.Et2O
OH
-
HO
BF3
H
H
N
NH2
N
+
R
N
OH
OH
OH
R
Ti(OiPr)2
OH
OH
: 2,5-dideoxy-2,5-imino-D-mannitol
OH
Scheme 1. Cyclopropanation mechanism.
1 : R=OH : nojirimycin
2 : R=H : 1-deoxynojirimycin
3
Figure 1.
-CH4
Ti(OiPr)3Me
(A)
EtMgBr
Ti(OiPr)2
* Corresponding author. Tel.: +33 322827570; fax: +33 322827568.
E-mail address: denis.postel@u-picardie.fr (D. Postel).
Scheme 2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.135

2172
D. Declerck et al. / Tetrahedron Letters 50 (2009) 2171–2173
Ti(OiPr)4 (2 eq)
In our current research programme aimed at the synthesis of
glycoaminonitriles and their conversion into new proline deriva-
tives, we chose the cyclopropanation of the cyano-pyrrolidine scaf-
BnNH3+COO- (2 eq)
TMSCN (1.2 eq)
NHBn
CN
O
OH
O
OH
OH
2 or 3 steps
Bn
(OH)n
(OR)n
fold 4 (Scheme 3) as the key step. The latter substrates bear an a-
(OR)n
aminonitrile moiety, which to the best of our knowledge has not
previously been studied in this type of reaction. Cleavage of protec-
tive groups should then afford iminosugars of type 5 with potential
as glycosidase inhibitors.
H
N
MsCl (5 eq)
Pyridine
N
CN
NH2
4
n(RO)
(OR)n
Pyrrolidines (4a–h) with a nitrile group at the anomeric posi-
tion have been synthesized according to our newly developed
methodology (Scheme 3).30 The cyclopropanation step was per-
formed on pyrrolidines 4a–h using the following synthetic se-
quence: (i) EtMgBr (1.5 equiv, 2 M in Et2O) was added at rt to a
solution of iminonitrile (1 equiv) and methyltitanium tri-
isopropoxyde (1.5 equiv) in THF, (ii) the reaction mixture was stir-
red for 1 h before adding BF3ꢀEt2O (2 equiv), and (iii) after a further
hour, a basic work-up followed by extractions with ethyl acetate
and flash chromatographic purification afforded 2-aminocyclopro-
pyl pyrrolidines. Cyclopropylamines 5a–i31 have been obtained fol-
lowing this protocol in moderate to good yields (Table 1). These
5 : 2-aminocyclopropyl
pyrrolidines
Scheme 3. General route for cyano pyrrolidine synthesis.30
Table 1
Cyclopropanation on cyano pyrrolidine
R
N
R
N
Cyclopropanation
CN
NH2
(OR)n
(OR)n
Entry
Cyano pyrrolidine
2-Amino cyclopropyl pyrrolidine
Yield (%)
results allow us to conclude that the reactivity of a-aminonitriles
Bn
N
Bn
N
4 is similar to that reported in the literature for related sugar deriv-
atives.29 We also observe that cyclopropanation of benzoyl-pro-
tected derivative 4h gives 5i with a free hydroxyl group on
position C5 as the major product (5h/5i: 1/3).
BnO
BnO
CN
NH2
1
57
O
O
O
O
Finally, and in order to test our derivatives as glycosidase inhib-
itors, the hydroxyl and amino groups need to be free. Conse-
quently, hydrogenolysis and/or cleavage of the isopropylidene
acetals (HCl 3 M) provided the target iminosugars 6–10 in 38% to
quantitative yields (Fig. 2), isolated as the corresponding chlorhy-
drate salts as confirmed by spectral analysis.
4a
Bn
N
5a
Bn
N
BnO
BnO
CN
2
3
45
28
NH2
OBn
BnO
OBn
BnO
4b
5b
Of particular interest is the confirmation of the chlorhydrate
form of the final products. According to the literature, protonation
BnO
BnO
BnO
BnO
of amines causes considerable upfield shift of the 13C
a–c signals
N
N
CN
OBn
and particularly in the position
b to the protonated group
NH2
OBn
(D
ꢁ ꢂ1.5; ꢂ5.5; ꢂ0.5, respectively).32 Analyses were performed
BnO
BnO
BnO
BnO
on the deprotected derivatives as chlorhydrate salts (1 6 pH 6 4)
and as the neutral form using NaOH to set the pH value to 12. As
example the chemical shifts for compound 9 at pH 1 were shifted
upfield compared to those in the carbon spectra at pH 12 (Fig. 3),
upfield shifts were observed for all the carbon atoms of the pyrrol-
idine scaffold except for that of the C5 atom (Table 2).
4c
5c
Bn
N
Bn
N
CN
OBn
4
5
37
38
NH2
OBn
4d
5d
Bn
N
Bn
N
Concerning the C2, C3 and C4, which are in the position b to the
protonated cyclopropylamino group and endocyclic amino group,
CN
NH2
respectively, we observed
= ꢂ2.3 to ꢂ3.2 ppm).
The signal corresponding to carbon (C7) of the cyclopropane
a sizeable pH dependent shift
O
O
O
O
O
O
(
D
4e
5e
was not influenced by variation in pH.
In summary, 2-aminocyclopropyl pyrrolidines have been
synthesized from 2-cyano pyrrolidines. The key step was tita-
Bn
N
Bn
N
CN
NH2
6
7
57
44
O
O
4f
5f
HO
Bn
N
Bn
N
O
O
HO
H
N
HO
H
N
H
N
CN
HO
O
O
NH2
NH2
.2HCl
NH2
NH2
.2HCl
.2HCl
HO
OH
HO
OH
O
O
O
O
HO
OH
4g
5g
6 (99 %) pH=1
7 (68 %) pH=1
8 (100 %) pH=1
Bn
N
Bn
N
RO
RO
H
N
H
HO
CN
N
NH2
NH2
NH2
8
65
O
O
O
O
.2HCl
.2HCl
HO
OH
HO
10
OH
R = Bz
5h:
R= Bz
4h
5i: R=OH
9
(50 %) pH=1
(38 %) pH=4
Reagents and conditions: Ti(OiPr)3Me (1.5 equiv), EtMgBr (1.5 equiv), THF, 1 h, rt
then BF3ꢀOEt2 (2 equiv), 1 h, rt.
Figure 2. Deprotected 2-amino cyclopropyl pyrrolidines.

D. Declerck et al. / Tetrahedron Letters 50 (2009) 2171–2173
2173
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Acknowledgements
To a solution of azasugar (1 equiv) and Ti(OiPr)3Me (1.5 equiv) in THF, was
slowly added at room temperature EtMgBr (1.5 equiv, 2 M solution in Et2O).
After stirring for 1 h, BF3ꢀOEt2 (2 equiv) was added, and the reaction mixture
further stirred for 1 h at room temperature. A solution of HCl 1 M was added
until two clear phases were formed. Then, a solution of NaOH (2 M) was added
until pH of aqueous layer was basic. The organic layer was extracted with ethyl
acetate and dried over Na2SO4. The solvent was evaporated under vacuum and
the residue was purified by column chromatography using EtOAc.Formula:
We thank the Conseil Régional de Picardie and the Ministère
Français de la Recherche for financial support and J. Szymoniac et
P. Bertus for helpful discussions.
References and notes
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ꢃ
ꢂ3.4° (c 1.04; CHCl3); IR (ATR):
m 2925,
1116, 1094, 1074, 849, 735, 698 cmꢂ1
;
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NCH2Ph, J = 12.0 Hz), 4.33 (d, 1H, NCH2Ph, J = 12.0 Hz), 3.90–3.74 (m, 3H,
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