Stereoselective synthesis of novel five-membered homoazasugars. A convenient route to all-cis tetrasubstituted pyrrolidines

Article abstract of DOI:10.1016/j.tetlet.2006.10.128

We present a highly stereoselective procedure for the preparation of (2S and 2R,3S,4R,5S)-5-methyl-3,4-dihydroxy-2- ethoxycarbonylmethylpyrrolidines based on conjugate addition of ammonia to unsaturated aldonic esters derived from d-ribose followed by tan

Full text of DOI:10.1016/j.tetlet.2006.10.128

Tetrahedron Letters 48 (2007) 159–162
Stereoselective synthesis of novel five-membered
homoazasugars. A convenient route to all-cis
tetrasubstituted pyrrolidines
Elena Moreno-Clavijo, Ana T. Carmona,* Antonio J. Moreno-Vargas and
Inmaculada Robina*
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica, Universidad de Sevilla, Apartado 553, E-41071 Sevilla, Spain
Received 11 September 2006; revised 23 October 2006; accepted 25 October 2006
Available online 21 November 2006
Abstract—We present a highly stereoselective procedure for the preparation of (2S and 2R,3S,4R,5S)-5-methyl-3,4-dihydroxy-2-
ethoxycarbonylmethylpyrrolidines based on conjugate addition of ammonia to unsaturated aldonic esters derived from D-ribose fol-
lowed by tandem cyclization. Derivatisation of these compounds to 2-hydroxyethyl-, benzymidazolylmethyl-, biphenyl-1-amino-
ethyl and naphthalene-l-aminoethyl-pyrrolidines is also presented.
Ó 2006 Elsevier Ltd. All rights reserved.
Hydroxylated pyrrolidines, which constitute one type of
azasugars or iminosugars, have attracted considerable
interest in recent years due to their therapeutic potential.
This is due to their inhibitory activity towards carbo-
hydrate processing enzymes such as glycosidases and
glycosyltransferases.1 Recently, they have also attracted
attention because of their application as catalysts,2
chiral ligands for asymmetric catalysis and chiral
auxiliaries.3
through unspecific contributions to the binding to the
enzyme.7 We and other authors have reported that the
attachment of aromatic moieties to the pyrrolidine
framework greatly improves the activity and selectivity
towards glycosidases.8–10 We have recently reported a
stereoselective route to (2S,3S,4R,5S)-5-methylpyrrol-
idine-3,4-diol-2-carbaldehyde (1) having fuco-configura-
tion and explored its use in the preparation of highly
selective a-L-fucosidase inhibitors, such as benzymid-
azolyl derivative 2 with inhibitory activity in the nM
range (Fig. 1).10d
Among the iminosugars, those having a carbon chain
linked to the carbon adjacent to nitrogen, the so-called
homoazasugars (aza-C-glycosides) have achieved special
importance due to their stability towards chemical and
enzymatic degradation, maintaining their biological
activity.4 Homoazasugars bearing a hydroxymethyl
group or 1,2-dihydroxyethylene group as side chains
have been recently described.5 With regard to their enzy-
matic inhibitory activity, it has been reported that some
homoanalogues of 1,4-dideoxy-1,4-iminoalditol deriva-
tives are more active than the parent compounds.6 It
has been also claimed that hydrophobic groups attached
to the iminosugar improve their inhibitory activity
In this letter, we report a stereoselective synthesis of sev-
eral homoanalogue derivatives of compound 1 (3–5) and
the transformation of 3 into an imino-C-heterocycle and
aryl aminoethyl pyrrolidines (Fig. 2).
Compounds 3, 5–8 are tetrasubstituted all-cis pyrrol-
idines. As far as we are aware, a small number of pyrrol-
idine derivatives with this stereochemical arrangement
have been described.11
OH
O
H
H
N
N
O
N
Me
Me
Me
OH
H
N
Keywords: Pyrrolidines; Azasugars; Iminosugars; Imino-C-glycosides;
Homoazasugars; Glycosidase inhibitors.
OH
HO
OH
HO
H
OH
HO
1
2
*
Corresponding authors. Tel.: +34 954556858; fax: +34 954624960
(I.R.); tel.: +34 954557150; fax: +34 954624960 (A.T.C.); e-mail
addresses: anatere@us.es; robina@us.es
Ki = 81 nM
Figure 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.128

160
E. Moreno-Clavijo et al. / Tetrahedron Letters 48 (2007) 159–162
3.07)/H2a,H2b(d = 2.41, 2.33), indicating
a
trans
H
H
H
OEt
N
N
relationship between H3/H4 and H3/H6. The stereo-
chemical account of the reaction indicates a selectivity
towards the 3,4-syn adduct in the conjugate addition.
Subsequent intramolecular displacement led to pyrrol-
idine 3 as the major compound. This is in accordance
with that described for other sugar derived a,b-unsatu-
rated esters.15 A Felkin type transition state model
may account for the results for the E-isomer, whereas
in the case of the Z-alkene, the strong interaction in that
conformation with the acetal ring suggests an alternative
transition state resembling the Conforth model and
model B1 of Felkin.16
N
Me
Me
Me
O
OH
HO
OR
OH
OR
RO
O
RO
4
5
3
OEt
OH
R = C(CH3)2
H
H
Me
N
N
Me
7, R' =
8, R' =
OH
HO
N
HO
6
HN
HN
R'
Figure 2.
The preparation of hydroxyethyl-dihydroxypyrrolidine
5 was carried out starting from all-cis-pyrrolidine 3. N-
Boc protection, reduction with LiBH4 and subsequent
acidic deprotection furnished 5 in a 80% overall yield
(Scheme 2).
Starting from D-ribose, the known hemiacetal 9 was
obtained by applying Bols’s procedure.12 Reaction of
lactol 9 with methyl triphenylphosphoranylidene acetate
in dichloromethane under reflux afforded a mixture of
alkenes 10 and 11 in a 90% yield and a ratio
Z:E = 5.2:1. The stereoselectivity in the Wittig reaction
is in accordance with that described in the literature
for other ribo-lactols.13 Mesylation of the free OH group
in 10 and 11 followed by treatment with ammonia in
ethanol furnished the corresponding pyrrolidines
through tandem conjugate addition-internal SN2 dis-
placement. Starting from Z-alkene, pyrrolidine 3 was
obtained as the unique stereoisomer in a 76% overall
yield, whereas the same procedure applied to E-alkene
afforded a mixture of 3 and 4 in a 60% overall yield,
and a ratio, 3:4 = 10:1 (Scheme 1).
The preparation of benzymidazolyl derivative 6 started
from pyrrolidine 3 that was protected as t-butyl carb-
amate 13. Saponification gave the corresponding
carboxylic acid that was made to react with o-phenyl-
enediamine in the presence of PyBOP and DIPEA to
give amide 14 in a 70% overall yield. Heating in AcOH
at 55–60 °C followed by acidic deprotection afforded
benzymidazolyl pyrrolidine derivative 6 in a good yield
(Scheme 3).
The synthesis of biphenylaminoethyl pyrrolidine 7 has
been carried out starting from ethyl ester 13. Saponifica-
tion and reaction with biphenyl-4-amine in the presence
of PyBOP and DIPEA gave amide 16 in a 69% yield.
The structure of 3 and 4 was based on spectroscopic and
analytical data.14 NOESY spectrum of 3 showed NOEs
between proton signals H3(d = 3.14)/H4(d = 4.62) and
H3/H6(d = 2.86), and between pair of protons H5(d =
4.47)/H6(d=2.86), thus indicating an all-cis configu-
ration between the corresponding protons. NOESY
spectrum of 4 showed NOEs between H4,H5(d =
4.48)/H2a,H2b(d = 2.41, 2.33) and between H6(d =
Boc
.HCl
H
N
N
OH
OH
a, b
c
Me
Me
3
(87%)
(92%)
O
12
OH
O
5
HO
COOEt
OH
OH
O
Me
Me
Me
Scheme 2. Synthesis of hydroxyethyl pyrrolidine 5. Reagents and
conditions: (a) Boc2O/Py; (b) LiBH4, THF and (c) HCl (1 N), THF.
OH
a
COOEt
+
(90%)
O
O
O
O
O
O
11
9
10
Boc
N
Boc
N
NH2
10 : 11 = 5.2 : 1
H
Me
(76%)
Me
N
a
COOEt
b
H
3
NH
2 COOEt
OMs
N
O
Me
Me
(92%)
COOEt
b, c
4
O
O
3
O
O
10
11
14
13
(76%)
O
O
O
O
3
c
(quant.)
Boc
H
N
b, c
H
N
Me
H
NH
2 COOEt
OMs
3:4 = 10 : 1
Me
N
N
Me
d
(60%)
3
4
N
H
N
(64%)
N
HO
OH
Me
O
O
O
COOEt
O
6
15
4
O
O
Scheme 3. Synthesis of benzymidazolyl pyrrolidine 6. Reagents and
conditions: (a) Boc2O/Py; (b) (1) NaOH, EtOH; (2) o-phenylenedi-
amine, PyBOP, DIPEA, DMF; (c) AcOH, 55–65 °C and (d) (1) HCl
1 N, THF; (2) NH4OH.
Scheme 1. Synthesis of pyrrolidines 3 and 4. Reagents and conditions:
(a) Ph3P@CH2COOEt, DCM reflux; (b) MsCl, Py and (c) NH3, EtOH.

E. Moreno-Clavijo et al. / Tetrahedron Letters 48 (2007) 159–162
161
Boc
N
and for the award of a Grant to E.M.-C., the European
Commission (FP6, TRIoH, LSHG-CT-2003-503480)
Boc
N
Me
Me
Me
c
Me
COOEt
CHO
´
and the Junta de Andalucıa (FQM-345). We also thank
(74%)
Professor P. Vogel for helpful discussions.
O
O
13
O
O
17
a
d
(85%)
(69%)
References and notes
Boc
Boc
H
H
N
N
N
N
Me
Ar
Ar
1. (a) Iminosugars as Glycosidase Inhibitors. Nojirimycin and
O
Beyond; Stutz, A. E., Ed.; Wiley-VCH: Weinheim, Ger-
¨
O
O
b
O
O
18
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Vargas, A. J.; Carmona, A. T.; Vogel, P. Curr. Drug
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16
Ar:1-biphenyl
Ar: 1-naphtyl
e
(84%)
(62%)
H
N
H
H
N
H
N
N
Me
HO
2. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004,
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OH
8
HO
OH
7
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Scheme 4. Synthesis of aryl aminoethyl pyrrolidines 7 and 8. Reagents
and conditions: (a) (1) NaOH, EtOH; (2) biphenyl-4-amine, PyBOP,
DIPEA, DMF; (b) (1) BH3, SMe2, THF; (2) HCl, THF; (3) NH4OH;
(c) DIBALH, CH2Cl2, À78 °C; (d) naphthalene-1-amine, NaBH-
(OAc)3, (CH2Cl)2 and (e) (1) HCl, THF; (2) NH4OH.
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applied to the preparation of 8 gave a poor yield. Thus,
compound 8 was obtained by the reductive amination of
aldehyde 17 with naphthalene-1-amine (85%) followed
by acidic deprotection. Carbaldehyde 17 was obtained
from 13 by reduction with DIBALH in a 74% yield
(Scheme 4).
´
alez, M. S.; Lopez-Herrera, F. J. Tetrahedron Lett. 2004,
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In summary, we have presented a highly stereoselective
procedure for the preparation of (2S and 2R,3S,4R,5S)-
5-methyl-3,4-dihydroxy-2-ethoxycarbonylmethylpyrrol-
idines based on the conjugate addition of ammonia to
unsaturated aldonic esters derived from D-ribose and
tandem cyclization. Derivatisation of these compounds
to hydroxyethyl-pyrrolidine 5, benzymidazolyl-pyrrol-
idine 6 and biphenyl- and naphthalene-l-aminoethyl-
pyrrolidines 7 and 8 is also presented.
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The new compounds presented in this letter show the
introduction of several structural modifications to our
reported pyrrolidine derivatives10d such as, the spacer
between the N of the pyrrolidine ring and the amino-
alkyl side chain, the configuration of the pyrrolidine
moiety at C-2, and the nature of the substituent attached
to the pyrrolidine framework (CH2CH2OH, CH2CH2-
NHAr, CH2Ar). This diversity will hopefully provide
useful information on the structure/activity relation-
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Acknowledgements
´
We thank the Ministerio de Educacion y Ciencia of
9. For results on a-glucosidases, see: (a) Lysek, R.; Vogel, P.
Tetrahedron 2006, 62, 2733–2768; (b) Lysek, R.; Schutz,
Spain for financial support (CTQ2004-00649/BQU)

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E. Moreno-Clavijo et al. / Tetrahedron Letters 48 (2007) 159–162
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14. Selected data for 3: 1H NMR (300 MHz, CDCl3, d ppm, J
Hz) d 4.62 (dd, 1H, J4,3 = 4.1, J4,5 = 4.2, H-4), 4.47 (dd,
1H, J5,6 = 4.0, H-5), 4.15 (q, 2H, JH,H = 7.1, CH2CH3),
3.14 (dt, 1H, J3,2a = J3,2b = 6.6, H-3) 2.86 (dq, 1H,
J6,Me = 6.6, J5,6 = 4.0, H-6), 2.66 (dd, 1H, J2a,2b =16.5,
H-2a), 2.57 (dd, 1H, H-2b), 1.88 (br s, 1H, NH) 1.44, 1.30
(2s, 3H each, C(CH3)2), 1.26 (t, 3H, CH2CH3) 1.20 (d, 3H,
Me-6). 13C NMR (75.5 MHz, CDCl3, d ppm) d 172.1
(C@O), 110.9 (C(CH3)2), 83.2 (C-5), 82.4 (C-4), 60.7
(CH2CH3), 58.8 (C-3), 57.7 (C-6), 33.6 (C-2), 25.8 and 24.3
(C(CH3)2), 14.3 (Me-6) and 13.4 (CH2CH3). CIHRMS m/
z Calcd for C12H22NO4: 244.1549. Found 244.1551.
Selected data for 4: 1H NMR: 4.48 (m, 2H, H-4, H-5),
10. For results on a-L-fucosidases, see: (a) Robina, I.;
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4.16 (q, 2H,
J
= 6.9, CH2CH3), 3.59 (t, 1H,
J3,2a = J3,2b = 7.8, H-3), 3.07 (m, 1H, H-6), 2.41 (dd, 1H,
2J2a,2b = 15.3 s, H-2a), 2.33 (dd, 1H, H-2b), 1.97 (br s, 1H,
NH), 1.46, 1.30 (2s, 3H each, C(CH3)2), 1.25 (t, 3 H,
CH2CH3), 1.20 (d, 3H, J6ÀMe = 6.6, Me-6). 13C NMR:
171.5 (C@O), 111.2 (C(CH3)2), 86.5, 83.2 (C-4, C-5), 61.2
(C-3), 60.7 (CH2CH3), 59.2 (C-6), 36.8 (C-2), 26.2, 24.2
(C(CH3)2), 14.3 (CH2CH3), 13.5 (Me-6). CIHRMS m/z
Calcd for C12H22NO4: 244.1549. Found 244.1548.
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