Synthesis of 5-substituted-3,4-dihydroxycyanopyrrolidines. An easy access to polyhydroxyprolines

Article abstract of DOI:10.1016/j.tet.2009.01.108

A novel procedure for the synthesis of cyanopyrrolidines is presented. Starting from conveniently functionalized d-ribose, d-mannose, d-(l)-arabinose, the compounds were efficiently synthesised in four steps in overall good yields. Transformation into pro

Full text of DOI:10.1016/j.tet.2009.01.108

Tetrahedron 65 (2009) 2766–2772
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 5-substituted-3,4-dihydroxycyanopyrrolidines. An easy
access to polyhydroxyprolines
*
´
Marina Moura, Sebastien Delacroix, Denis Postel, Albert Nguyen Van Nhien
Laboratoire des glucides UMR6219, Universite´ de Picardie Jules Verne, Faculte´ des Sciences, 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:
A novel procedure for the synthesis of cyanopyrrolidines is presented. Starting from conveniently
Received 19 December 2008
Received in revised form 28 January 2009
Accepted 28 January 2009
Available online 6 February 2009
functionalized D-ribose, D-mannose, D-(L)-arabinose, the compounds were efficiently synthesised in four
steps in overall good yields. Transformation into proline derivatives and preliminary evaluation of these
derivatives in organocatalysis is also described.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
A great interest in new synthetic procedures giving access to
chiral non-racemic pyrrolidines has regained attention.1 These
small molecules, densely functionalized and rich in stereochemis-
try make them attractive for their chemotherapeutic properties
against cancer2 and as potent glycosidases.3 Amongst these de-
rivatives, 2-cyanopyrrolidine could be found in peptide sequence as
dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment
of diabetes and obesity. For example, I (DPP728), II (LAF-237), III
(BMS-477118) have entered into human clinical trials in diabetic
patients (Fig. 1).4–7
Our approach to the synthesis of 5-substituted-polyhydroxy-2-
cyanopyrrolidine C could be planned according to the retro-
synthetic paths outlined in Scheme 1.
It could be envisioned that the pyrrolidines could be generated
from aminonitriles B by cyclisation. The diastereomeric mixture (in
major cases) of aminonitrile B could be easily prepared by our
modified Strecker reaction14 with the readily known available al-
dose A.
According to our previous work,14 Strecker conditions, using
2 equiv of HCOONH3Bn and 2 equiv of Ti(OiPr)4 as the Lewis acid,
applied to the anomeric position of derivatives 1a,15 2a,16 3a,17 and
commercially available 4a, 5a, 6a, followed by TMSCN addition gave
One of the most interesting applications of 2-cyanopyrrolidines
in organic synthesis is their transformation to proline analogues.
Synthetically, the interest in this reaction lies in the cyanide ad-
the a-aminonitriles 1b–6b (Table 1). The a-aminonitriles de-
8,9
ducts being precursors of proline derivatives
and chiral 1,2-di-
rivatives were obtained with yields ranging from 63% to 90%, in an
unseparable diastereomeric mixture (except for 2bR) or with a ratio
in favour of the desired 2-(R)-derivatives. The stereoselectivity of
TMSCN addition could be easily explained by a Cram-chelate model
between [Ti], the iminium and the substituent in position 2 leaving
a preferential attack of the anion ꢀCN from the side of the smallest
remaining substituent, hence favouring the R-configuration for
derivatives 1b, 2b, 3b, 5b, 6b and S-configuration for compound 4b.
Next, we investigated the two steps cyclisation. Compounds 1b–
6b reacting with methanesulfonyl chloride, in pyridine at 80 ꢁC
afforded the key cyanopyrrolidines 1c–6cR in 57–91% overall yield
(Table 1). Interestingly, at room temperature, competition between
the formation of cyanopyrrolidine and dimesylation occurred in
favour of the O,N-dimesyl derivatives.
amines.10 Therefore, general methods for the synthesis of
2-cyanopyrrolidines are of great interest. In most cases these
compounds are chiral, and stereoselective approaches to their
synthesis are often required.11–13
As a part of our ongoing program to utilise glyco-a-amino-
nitriles derivatives,14 we wish now to report a detailed account of
our approach and its extension to the synthesis of 5-substituted-
polyhydroxy-2-cyanopyrrolidine starting from conveniently func-
tionalized pentoses and their transformation to proline de-
rivatives. Preliminary results in organocatalysis will also be
disclosed.
Purification by flash chromatography afforded each stereoiso-
mer where the major compound derivative is (R) with a ratio R/S
consistent with our previous results.
Among the various functional groups resulting from the chem-
ical transformation of a cyano group, the hydrolysis into carboxylic
* Corresponding author. Tel.: þ33 3 22828812; fax: þ33 3 22827568.
E-mail address: albert.nguyen-van-nhien@u-picardie.fr (A.N. Van Nhien).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.108

M. Moura et al. / Tetrahedron 65 (2009) 2766–2772
2767
OH
OH
NC
CN
CN
O
O
CN
O
H
N
H
N
N
N
H
N
N
N
NH2
I
II
Figure 1. Structures of selected DPPIV inhibitors.
III
With these derivatives in our hands, we tested the poly-
hydroxyprolines 1d, 2d and 3d versus natural -proline in orga-
nocatalysis since the pioneering work of List, Barbas and their co-
n(RO)
n(RO)
n(RO)
L
CN
CN
OH
N
O
OH NHBn
Bn
workers29 have demonstrated that
L-proline or functionalized
4-hydroxyproline30 could work as a catalyst in the intermolecular
direct aldol reaction.
C
B
A
Scheme 1. Retrosynthetic analysis.
Despite a number of effective chiral organocatalytic systems
have emerged and particularly the concept of small organic mole-
cules as highly efficient and enantioselective catalysts, few exam-
ples were exploiting the introduction of hydroxyl groups in proline
with a substituent in position 5,31 and consequently examined their
influence. We disclose now some preliminary results in the known
direct aldol reaction catalysed by polyhydroxyprolines using 4-
nitrobenzaldehyde and acetone (Table 3).32
In our initial experiment, the reaction was performed in DMSO
using a catalytic amount (20 mol %) of catalyst as previously
reported32 for direct asymmetric aldol reaction and the results are
summarised in Table 3. It is interesting to find out that the aldol
products were obtained with similar enantioselectivity than
acid is easily accessible. Indeed, it is well established that hydroxy-
lated prolines influence the polypeptide secondary structure in
antibiotics.18 Furthermore, 3,4-trans or cis dihydroxyprolines (DHP,
IV,19 V,20 VI,21 Fig. 2) are also found as substructures in bioactive
natural compounds and an effective methodology for their syn-
thesis has been the subject of much attention in recent years.22–28
In order to obtain the proline analogues, we selected the (R)-
derivatives 1cR, 2cR and 3cR to be submitted to acidic hydrolysis
(concentrated HCl at 100 ꢁC in a sealed tube) followed by hydro-
genolysis (H2 atmosphere, Pd/C) to afford the corresponding
hydroxyprolines 1d, 2d and 3d in 78%, 76% and 77%, respectively
(Table 2).
L-proline but with decreased yields. These results demonstrated
that the catalytic process is not affected by the presence of the
Table 1
Formation of cyanopyrrolidines
n(RO)
n(RO)
n(RO)
1) Ti(OiPr)4, MeOH
HCOO- +NH3Bn
2) TMSCN
n(RO)
O
MsCl, pyr.
80 °C
CN
CN
+
CN
O
OH
N
OH NHBn
OH NHBn
Bn
(R/S)
A
B
C
O
O
O
O
O
O
O
O
O
+
CN
CN
+
R
OH
R
R
R
CN
R
CN
O
N
N
OH NHBn
OH NHBn
Bn
Bn
1a, R= CH3
2a, R= CH2OTr
3a, R= CH2N3
1bR 80%
2bR 86%
3bR 50%
1bS 5%
-
1cR 85%
2cR 84%
3cR 77%
1cS 6%
3bS 13%
3cS 4%
O
O
O
O
O
O
O
O
O
O
+
+
CN
OH NHBn
CN
OH NHBn
O
O
O
O
O
CN
CN
OH
N
N
O
Bn
Bn
O
O
O
O
O
4a
OBn
4bR 24%
BnO OBn
4bS 74%
BnO OBn
4cR 16%
4cS 44%
OBn
BnO
BnO
BnO
+
BnO
BnO
BnO
BnO
BnO
CN
OH NHBn
5bR 54%
CN
OH NHBn
5bS 18%
CN
Bn
5cS 57%
OH
N
O
5a
BnO
OBn
CN
OH NHBn
6bR 70%
BnO
OBn
CN
OH NHBn
6bS 8%
BnO
OBn
OBn
OH
+
BnO
BnO
BnO
CN
Bn
6cR 84%
N
O
6a

2768
HO
M. Moura et al. / Tetrahedron 65 (2009) 2766–2772
annelation product 8 in 4% yield. This process did not occur with
catalyst 1d or 2d emphasising our hypothesis.
Moreover, we were delighted to observe that catalyst 1d pre-
senting a methyl group led to the aldol derivative in 25% yield and
also to the bicyclic 1,3-oxazolidine 9a and 9b (Scheme 3). Similar
OH
COOH
HO
OH
COOH
HO
OH
COOH
N
H
N
H
N
H
IV
V
VI
results leading to the formation of oxazolidine with
known in literature33 and is attributed to a poor reactivity when
-proline was used below 20 mol %.
L-proline is well
Figure 2. 3,4-Dihydroxyprolines from natural sources.
L
3. Conclusion
Table 2
Synthesis of polyhydroxyprolines
In conclusion, a synthesis of 2-cyanopyrrolidine 1c–6c was
achieved via a simple reaction sequence in four steps starting from
HO
OH
COOH
D-ribose, D-mannose, D-(L)-arabinose involving a cyclisation step of
1) HClc., 100 °C
O
O
2) H2, Pd/C
a mesyl intermediate. This approach is helpful in obtaining proline
derivatives by simple conversion of the nitrile group into the car-
boxylic acid. This methodology will be applied to the other sub-
strates in order to obtain configurationally and conformationally
diversified polyhydroxyprolines to get insights into the influence of
3) dowex resin 50W-X8
R
N
H
R
Substrate
1cR
CN
N
Bn
Product
Yield
78%
the OH groups compared to L-proline pattern. This study will be
HO
OH
COOH
OH
COOH
OH
COOH
reported in due course. Furthermore, these catalysts showed un-
usual reactivity (Scheme 2) and paved the way for further
improvements.
1d
N
H
HO
HO
4. Experimental
4.1. General
2cR
3cR
2d
3d
76%
77%
N
H
HO
Materials and methods. Melting points are uncorrected. Optical
rotations were recorded in CHCl3 or MeOH solutions. 1H NMR
(300.13 MHz) and 13C NMR (75.47 MHz) spectra were recorded in
CDCl3, DMSO-d6 or MeOD-d4 (internal Me4Si), respectively. TLC was
performed on Silica F254 and detection by UV light at 254 nm or by
charring with phosphomolybdic–H2SO4 reagent. FTIR spectra were
obtained on an AVATARÔ 320 neat using ATR and are reported in
cmꢀ1. Mass spectral data were acquired on a WATERS Micromass
ZQ spectrometer or a WATERS Micromass Q-TOFF spectrometer.
H2N
N
H
hydroxyl groups in the proline scaffold. Nevertheless, an amino
group seems to act as a basic catalytic centre leading and probably
performing the dehydration of the
during the first addition step.
g-hydroxyiminium intermediate
Then using an equimolar quantity of catalyst 3d, the aldol de-
rivative (entry 3) was submitted to an hypothetic dehydration fol-
lowed by a Michael addition (Scheme 2) to afford 7 in 12% yield.
Interestingly, the process can be pursued probably due to the ba-
sicity of the –NH2 group leading to the unexpected Robinson
HPLC analysis was performed on Waters-Breeze (2487 Dual
l Ab-
sorbance Detector and 1525 Binary HPLC Pump). Chiralpak AS
columns were purchased from Daicel Chemical Industries. Column
chromatography was effected on Silica Gel 60 (230 mesh). Cyclo-
hexane and ethyl acetate were distilled before use.
4.2. General method for the synthesis of a-aminonitriles (A)
Table 3
Ti(OiPr)4 (2 equiv) was added to a solution of aldose and
HCOONH3Bn (2 equiv) in MeOH. The reaction mixture was stirred
at room temperature overnight, and then TMSCN (1.2 equiv) was
added and the mixture stirred for 5 h. Water (5 mL) and EtOAc were
added until oxidation of the titanium residue was complete. The
solvent was evaporated to dryness and the crude was triturated in
EtOAc and filtered through a silica pad. After elimination of the
solvent, the crude was purified by flash chromatography (EtOAc/
cyclohexane).
Catalyst screen for the direct asymmetric aldol reaction of 4-nitrobenzaldehyde with
acetone
CHO
OH
*
O
cat. 1d-3d
O
+
(10-100 mol %)
O2N
DMSO, rt.
O2N
Yielda [%]
Entry
Time [h]
Cat. (equiv)
eeb [%]
1
2
3
4
5
6
7
19
72
24
72
48
72
72
Proline (0.2)
3d (0.2)
3d (1)
1d (0.2)
1d (1)
69
76
69
d
11
dc
4.3. General method for the synthesis of imino-
pyrrolidines (B)
Traces
25d
Traces
40
nd
85
nd
71
2d (0.2)
2d (1)
Methanesulfonyl chloride (5 equiv) was added dropwise to
a
a
-aminonitrile in pyridine at 80 ꢁC. The reaction
Isolated yield.
a solution of
b
Enantiomeric excess was determined by chiral HPLC. The absolute configuration
mixture was stirred at 80 ꢁC for 1–2 h. After cooling, water and
CH2Cl2 were added. The organic layer was separated, dried over
Na2SO4, and removed under vacuum. The crude product was pu-
rified by flash chromatography.
was determined by comparison of the HPLC retention time of the product with
reported data.31
c
See Scheme 2.
d
Bicyclic 1,3-oxazolidine 9a/9b were isolated as a by-product in 18% overall yield.

M. Moura et al. / Tetrahedron 65 (2009) 2766–2772
2769
R
O
H
HO
OH
O
OH
O
H2N
O
HO
OH
CO2H
CO2H
N
HO
OH
O2N
H2N
H2N
N
CO2H
H
N
H
- H2O
H2N
- H2O
OH
NO2
H
R
8 (4%)
OH
HO
H
OH
HO
O
CO2H
H2N
N
N
OH
H
H3C
HO
R
R
HO
OH
R
HO
OH
O
H2N
H2N
O
O
N
N
HO
OH
N
H
OH
O
H2N
O
O
R
O
R
O
- H2O
O
O
NO2
7 (12%)
Scheme 2. Aldol–aldol reaction and cyclodehydration.
4.4. General method for the synthesis of polyhydroxy-
prolines (C)
H-A NCH2Ph), 3.96 (d, J1,2¼3.1 Hz, 1H, H-1), 3.89 (dd, J2,3¼6.1 Hz,
J3,4¼8.9 Hz, 1H, H-3), 3.80 (d, JA,B¼12.8 Hz, 1H, H-B NCH2Ph), 1.46 (s,
3H, CH3), 1.34 (s, 3H, CH3), 1.26 (m, 3H, CH3); 13C NMR (CDCl3,
The cyanopyrrolidine was placed into a reinforced flask. Con-
centrated HCl was added to the flask, and the flask was sealed. The
reaction mixture was heated at 80 ꢁC for 1–2 days then cooled to
room temperature. The solvent was removed under vacuum then
the crude mixture was redissolved in water, washed with a spatula
of Pd/C and filtered. Pd/C (wet, 10 mol %) was added to the water
layer and the mixture was vigorously stirred under 1H2 atmosphere
for 2 days at rt. After filtration, the filtrate was concentrated in
vacuo. The residue was purified by ion exchange resin (Dowex
50W-X8, 100–200 mesh) and eluted with NH4OH 0.1 M. After re-
moval of the solvent, the solid was lyophilisated to afford pure
polyhydroxyproline as a brownish solid.
75 MHz) d 137.8, 129.3–128.2 (C6H5), 118.7 (CN), 109.3 [OC(CH3)2],
81.7 (C-3), 76.9 (C-2), 65.5 (C-4), 52.0 (NCH2Ph), 50.2 (C-1), 27.4,
25.2, 21.5 (3ꢂCH3). HRMS: C16H22O3N2Na calcd 313.1528, found
313.1527.
HO
OH
CO2H
HO
OH
HO
OH
O
N
H
N
H
N
O
O
O
R
R
O
R
R
H
R
HO
OH
CO2H
HO
OH
4.4.1. (1R)-1-N-Benzylamino-1-C-cyano-1,5-dideoxy-2,3-O-
N
isopropylidene-D-ribose (1bR) and (1S)-1-N-benzylamino-1-C-
N
O
cyano-1,5-dideoxy-2,3-O-isopropylidene-D-ribose (1bS)
Following the general method A, 1a (8.0 g, 45.97 mmol),
HCOONH3Bn (14.06 g, 91.95 mmol), Ti(OiPr)4 (27.5 mL, 91.95 mmol)
and TMSCN (7.39 mL, 55.16 mmol) in MeOH (100 mL) gave, after
flash chromatography (EtOAc/cyclohexane, 25/75) an unseparable
R
OH
O2N
NO2
9a/9b (18%)
OH
O
mixture of 1bR and 1bS (12.1 g, 90%) as a white syrup. A pure
20
fraction of 1bR has been isolated for analysis: [
a
]
D
ꢀ77 (c 0.05,
MeOH); 1H NMR (CDCl3, 300 MHz)
d
7.34 (m, 5H, C6H5), 4.36 (dd,
O2N
25%
J1,2¼3.1 Hz, J2,3¼6.1 Hz,1H, H-2), 4.21 (dd, J3,4¼8.9 Hz, J4,CH3¼6.1 Hz,
Scheme 3. Formation of bicyclic 1,3-oxazolidine.
1H, H-4), 4.10 (q, JOH,CH3¼7.1 Hz, 1H, OH), 4.08 (d, JA,B¼12.8 Hz, 1H,

2770
M. Moura et al. / Tetrahedron 65 (2009) 2766–2772
4.4.2. (1R)-1-N-Benzylamino-1-C-cyano-1-deoxy-2,3-O-
isopropylidene-5-O-trityl- -ribose (2bR)
and TMSCN (0.79 mL, 5.92 mmol) in MeOH (20 mL) gave, after flash
chromatography (EtOAc/cyclohexane, 25/75) an unseparable mix-
D
Following the general method A, 2a (1.83 g, 4.23 mmol),
HCOONH3Bn (1.29 g, 8.47 mmol), Ti(OiPr)4 (2.53 mL, 8.47 mmol)
and TMSCN (0.68 mL, 5.07 mmol) in MeOH (20 mL) gave, after flash
ture of 5bR and 5bS (1.90 g, 72%) as a white solid; IR (ATR)
3288, 3068, 3030, 2920, 2878, 1496, 1453, 1213, 1129, 1086, 1055,
1028 cmꢀ1 1H NMR (CDCl3, 300 MHz)
7.44–7.28 (m, 40H,
n 3433,
;
d
chromatography (EtOAc/cyclohexane, 20/80) 2bR (1.8 g, 77%) as
8ꢂC6H5), 4.92–4.59 (m,12H, 6ꢂOCH2Ph), 4.19–3.65 (m,16H, 2ꢂH-1,
20
a white solid. Mp¼46–48 ꢁC; [
a
]
ꢀ48 (c 0.13, CH2Cl2); IR (ATR)
n
2ꢂH-2, 2ꢂH-3, 2ꢂH-4, 4ꢂH-5, 2ꢂNCH2Ph); 13C NMR (CDCl3,
D
3059, 3032, 2985, 2926, 2850, 1491, 1448, 1373, 1213, 1157,
75 MHz)
d
138.8, 129.1–128.1 (8ꢂC6H5), 119.7, 119.5 (2ꢂCN), 80.5,
1060 cmꢀ1
;
1H NMR (CDCl3, 300 MHz)
d
7.47–7.32 (m, 20H,
80.4, 80.3, 79.8, 78.5, 78.1 (2ꢂC-2, 2ꢂC-3, 2ꢂC-4), 76.1, 75.5, 75.4,
75.2, 72.3, 71.9 (6ꢂOCH2Ph), 61.0, 60.2 (2ꢂC-5), 52.1, 51.9 (NCH2Ph),
52.7, 51.8 (2ꢂC-1). HRMS: C34H36O4N2 calcd 537.2753, found
537.2758.
4ꢂC6H5), 4.45 (dd, J1,2¼2.7 Hz, J2,3¼6.4 Hz, 1H, H-2), 4.34 (m, 1H, H-
4), 4.27 (dd, J2,3¼6.4 Hz, J3,4¼8.5 Hz, 1H, H-3), 4.12 (d, JA,B¼12.8 Hz,
1H, H-A NCH2Ph), 4.04 (d, J1,2¼2.7 Hz, 1H, H-1), 3.82 (d,
JA,B¼12.8 Hz, 1H, H-B NCH2Ph), 3.38 (dd, J4,5a¼3.3 Hz, J5a,5b¼9.6 Hz,
1H, H-5a), 3.31 (dd, J4,5b¼5.3 Hz, J5a,5b¼9.6 Hz, 1H, H-5b), 1.43 (s,
4.4.6. (1R)-1-N-Benzylamino-1-C-cyano-2,3,5-tri-O-benzyl-
arabinose (6bR) and (1R)-1-N-benzylamino-1-C-cyano-2,3,5-tri-O-
benzyl- -arabinose (6bS)
L-
3H, CH3), 1.36 (s, 3H, CH3); 13C NMR (CDCl3, 75 MHz)
d 144.0, 138.2,
129.0–127.6 (4ꢂC6H5), 118.9 (CN), 109.5 [OC(CH3)2], 87.4
[OC(C6H3)3], 77.2 (C-2, C-3), 69.0 (C-4), 65.5 (C-5), 52.0 (NCH2Ph),
50.2 (C-1), 27.1, 24.9 (2ꢂCH3). HRMS: C35H36O4N2Na calcd 571.2573,
found 571.2585.
L
Following the general method A, 6a (5.2 g, 12.38 mmol),
HCOONH3Bn (3.78 g, 24.76 mmol), Ti(OiPr)4 (7.40 mL, 24.76 mmol)
and TMSCN (1.99 mL, 14.85 mmol) in MeOH (30 mL) gave, after
flash chromatography (EtOAc/cyclohexane, 20/80) 6bR (2.47 g,
4.4.3. (1R)-1-C-Cyano-5-azido-1-N-benzylamino-1,5-dideoxy-2,3-
37%) and a mixture of 6bR and 6bS (4/1) (2.73 g, 41%); IR (ATR)
3429, 3288, 3064, 3030, 2921, 2878, 1496, 1453, 1128, 1086, 1055,
1028 cmꢀ1 1H NMR (CDCl3, 300 MHz)
7.45–7.31 (m, 20H,
n
O-isopropylidene-D-ribose (3bR) and (1S)-1-C-cyano-5-azido-1-N-
benzylamino-1,5-dideoxy-2,3-O-isopropylidene-D-ribose (3bS)
;
d
Following the general method A, 3a (15.8 g, 73.4 mmol),
HCOONH3Bn (22.4 g, 146.8 mmol), Ti(OiPr)4 (43.9 mL, 146.8 mmol)
and TMSCN (11.8 mL, 88.1 mmol) in MeOH (200 mL) gave, after
flash chromatography (EtOAc/cyclohexane, 20/80) an unseparable
4ꢂC6H5), 4.95–4.62 (m, 6H, 3ꢂOCH2Ph), 4.16–3.70 (m, 8H, H-1, H-2,
H-3, H-4, 2ꢂH-5, NCH2Ph); 13C NMR (CDCl3, 75 MHz)
d 138.8–
138.2, 129.2–127.9 (4ꢂC6H5), 119.4 (CN), 81.0, 80.7, 79.3 (C-2, C-3, C-
4), 75.9, 75.1, 72.6 (3ꢂOCH2Ph), 61.6 (C-5), 52.2 (C-1), 52.0
(NCH2Ph). HRMS: C34H36O4N2 calcd 537.2753, found 537.2752.
mixture of 3bR/3bS (15.5 g, 56%) as a slight yellow syrup. A pure
20
fraction of 3bR has been isolated for analysis: [
CH2Cl2); IR (ATR)
1H NMR (CDCl3, 300 MHz)
a
]
ꢀ74 (c 0.4,
D
n
2988, 2934, 2102, 1454, 1382, 1214, 1062 cmꢀ1
7.43–7.28 (m, 5H, C6H5), 4.41 (dd,
;
4.4.7. (2R,3S,4R,5S) 1-N-Benzyl-2-cyano-3,4-O-isopropylidene-5-
methylpyrrolidine (1cR) and (2S,3S,4R,5S) 1-N-benzyl-2-cyano-3,4-
O-isopropylidene-5-methylpyrrolidine (1cS)
Following the general method B, 1bR/1bS (6.69 g, 23.06 mmol),
MsCl (8.92 mL, 115.34 mmol) in pyridine (100 mL) for 1 h 20 min
gave, after flash chromatography (EtOAc/cyclohexane, 20/80), 1cS
d
J1,2¼2.7 Hz, J2,3¼6.3 Hz, 1H, H-2), 4.26 (ddt, J4,5a¼2.7 Hz,
J4,5b¼5.8 Hz, J3,4¼9.1 Hz, 1H, H-4), 4.10 (m, 2H, H-3, H-A NCH2Ph),
4.01 (d, J1,2¼2.7 Hz, 1H, H-1), 3.82 (d, JA,B¼12.8 Hz, 1H, H-B
NCH2Ph), 3.56 (dd, J4,5a¼2.7 Hz, J5a,5b¼12.7 Hz, 1H, H-5a), 3.39 (dd,
J4,5b¼5.8 Hz, J5a,5b¼12.7 Hz, 1H, H-5b), 1.48 (s, 3H, CH3), 1.36 (s, 3H,
(430 mg, 6%) as an orange syrup and 1cR (5.37 g, 85%) as a slight
20
CH3); 13C NMR (CDCl3, 75 MHz)
d
137.7, 129.2–128.4 (C6H5), 118.5
yellow solid. Compound 1cR: mp¼73–75 ꢁC; [
a
]
D
ꢀ85 (c 0.2,
(CN), 109.8 [OC(CH3)2], 77.1, 76.6 (C-2, C-3), 68.7 (C-4), 54.9 (C-5),
52.0 (NCH2Ph), 49.7 (C-1), 27.3, 25.0 (2ꢂCH3). HRMS:
C16H21O3N5Na calcd 354.1542, found 354.1539.
CHCl3); IR (ATR) n 3031, 2987, 2936, 2812, 1454, 1380, 1211, 1147,
1127, 1076, 1001 cmꢀ1 1H NMR (CDCl3, 300 MHz)
; d 7.31 (m, 5H,
C6H5), 4.59 (t, J2,3¼J3,4¼5.4 Hz, 1H, H-3), 4.47 (dd, J4,5¼4.5 Hz,
J3,4¼5.4 Hz, 1H, H-4), 3.98 (s, 2H, NCH2Ph), 3.19 (d, J2,3¼5.4 Hz, 1H,
H-2), 2.42 (dd, J5,CH3¼6.2 Hz, J4,5¼4.5 Hz, 1H, H-5), 1.62 (s, 3H, CH3),
4.4.4. (1R)-1-N-Benzylamino-1-C-cyano-2,3:5,6-di-O-isopropyl-
idene-
D
-mannose (4bR) and (1S)-1-N-benzylamino-1-C-cyano-
-mannose (4bS)
1.44 (s, 3H, CH3), 1.28 (t, 3H, CH3); 13C NMR (CDCl3, 75 MHz)
d 133.8,
2,3:5,6-di-O-isopropylidene-
D
130.2–128.2 (C6H5), 116.4 (CN), 113.6 [OC(CH3)2], 81.7 (C-3), 77.9 (C-
Following the general method A, 4a (5.0 g, 19.23 mmol),
HCOONH3Bn (5.88 g, 38.46 mmol), Ti(OiPr)4 (10.91 mL, 38.46 mmol)
and TMSCN (3.09 mL, 23.07 mmol) in MeOH (50 mL) gave, after
flash chromatography (EtOAc/cyclohexane, 35/65) a mixture of 4bR
4), 59.6 (C-5), 57.8 (C-2), 52.5 (NCH2Ph), 26.6 (CH3), 26.2 (CH3), 12.8
(CH3). HRMS: C16H20O2N2Na calcd 295.1422, found 295.1422.
20
Compound 1cS: [
a
]
D
ꢀ78 (c 0.1, CHCl3); IR (ATR)
n 3019, 2986,
2966, 2937, 2864, 2246, 1454, 1376, 1267, 1243, 1207, 1123, 1104,
and 4bS (25/75) (7.09 g, 98%); IR (ATR)
2906, 1454, 1378, 1266, 1254, 1205, 1157, 1136, 1061 cmꢀ1
(CDCl3, 300 MHz)
n
3297, 2980, 2960, 2935,
1H NMR
7.36 (m, 5H, C6H5), 4.56 (dd, J1,2¼1.5 Hz,
1026 cmꢀ1; 1H NMR (CDCl3, 300 MHz)
d
7.36 (m, 5H, C6H5), 4.73 (d,
;
J3,4¼6.2 Hz, 1H, H-3), 4.63 (dd, J4,5¼4.3 Hz, J3,4¼6.2 Hz, 1H, H-4),
4.12 (d, JA,B¼13.2 Hz, 1H, H-A NCH2Ph), 3.75 (s, 1H, H-2), 3.36 (d,
JA,B¼13.2 Hz, 1H, H-B NCH2Ph), 2.77 (dd, J5,CH3¼6.2 Hz, J4,5¼4.3 Hz,
1H, H-5), 1.53 (s, 3H, CH3), 1.32 (m, 6H, 2ꢂCH3); 13C NMR (CDCl3,
d
J2,3¼7.7 Hz, 1H, H-2), 4.48 (d, J2,3¼7.7 Hz, 1H, H-3), 4.17–4.06 (m, 4H,
H-4, H-5, H-6a, H-A NCH2Ph), 4.06 (dd, J5,6b¼4.5 Hz, J6a,6b¼7.7 Hz,
1H, H-6b), 3.87 (d, JA,B¼12.4 Hz, 1H, H-B NCH2Ph), 3.74 (d,
J1,2¼1.5 Hz, 1H, H-1), 3.27 (d, J4,5¼8.3 Hz, 1H, H-4), 1.52 (s, 3H, CH3),
1.42 (s, 3H, CH3), 1.35 (s, 6H, 2ꢂCH3); 13C NMR (CDCl3, 75 MHz)
75 MHz)
d 137.6, 129.0–127.9 (C6H5), 115.3 (CN), 113.0 [OC(CH3)2],
82.1 (C-4), 81.0 (C-3), 61.0 (C-5), 59.6 (C-2), 52.7 (NCH2Ph), 26.7,
26.2 (2ꢂCH3), 12.8 (CH3). HRMS: C16H20O2N2Na calcd 295.1422,
found 295.1421.
d
136.4, 129.3–128.7 (C6H5), 117.9 (CN), 109.9, 109.8 (2ꢂ[OC(CH3)2]),
76.8, 76.7 (C-2, C-3), 75.8 (C-5), 70.5 (C-4), 68.1 (C-6), 51.9 (NCH2Ph),
49.1 (C-1), 27.2, 26.4, 25.6, 24.9 (4ꢂCH3). HRMS: C20H28O5N2Na
calcd 399.1896, found 399.1902.
4.4.8. (2R,3S,4R,5S)-1-N-Benzyl-2-cyano-3,4-O-isopropylidene-5-
trityloxymethylpyrrolidine (2cR)
Following the general method B, 2bR (600 mg,1.09 mmol), MsCl
(0.48 mL, 5.45 mmol) in pyridine (20 mL) for 2 h gave, after flash
4.4.5. (1R)-1-N-Benzylamino-1-C-cyano-2,3,5-tri-O-benzyl-
arabinose (5bR) and (1R)-1-N-benzylamino-1-C-cyano-2,3,5-
tri-O-benzyl- -arabinose (5bS)
Following the general method A, 5a (2.0 g, 4.93 mmol),
HCOONH3Bn (1.51 g, 9.86 mmol), Ti(OiPr)4 (2.95 mL, 9.86 mmol)
D-
chromatography (EtOAc/cyclohexane, 15/85) through a silica pad,
20
D
2cR (458 mg, 79%) as a slight yellow solid. Mp¼53–55 ꢁC; [
a
]
D
þ16
(c 0.15, CH2Cl2); IR (ATR) n 3056, 2986, 2932, 2847, 2373, 1491, 1448,
1380, 1213, 1163, 1074 cmꢀ1; 1H NMR (CDCl3, 300 MHz)
d 7.59–7.08

M. Moura et al. / Tetrahedron 65 (2009) 2766–2772
2771
(m, 20H, 4ꢂC6H5), 4.82 (dd, J3,4¼6.0 Hz, J4,5¼4.7 Hz, 1H, H-4), 4.65
(dd, J2,3¼5.0 Hz, J3,4¼6.0 Hz, 1H, H-3), 3.93 (d, JA,B¼14.8 Hz, 1H, H-A
NCH2Ph), 3.86 (d, JA,B¼14.8 Hz, 1H, H-B NCH2Ph), 3.67 (dd,
J5,6a¼7.6 Hz, J6a,6b¼9.1 Hz, 1H, H-6a), 3.42 (dd, J5,6b¼4.7 Hz,
J6a,6b¼9.1 Hz, 1H, H-6b), 3.26 (d, 1H, H-2), 2.62 (m, 1H, H-5), 1.58 (s,
H-4), 4.41 (d, JA,B¼13.6 Hz, 1H, H-A NCH2Ph), 4.34 (q,
J5,6¼J6,7b¼J6,7a¼6.7 Hz,1H, H-6), 4.13 (dd, J6,7a¼6.7 Hz, J7a,7b¼8.6 Hz,
1H, H-7a), 3.98 (d, 1H, H-2), 3.90 (dd, J6,7b¼6.7 Hz, J7a,7b¼8.6 Hz, 1H,
H-7b), 3.68 (d, JA,B¼13.6 Hz, 1H, H-B NCH2Ph), 3.19 (dd, 1H, H-5),
1.49, 1.44, 1.38, 1.34 (s, 12H, 4ꢂCH3); 13C NMR (CDCl3, 75 MHz)
3H, CH3), 1.46 (s, 3H, CH3); 13C NMR (CDCl3, 75 MHz)
d
144.3, 133.9,
d
137.3, 129.2–128.1 (C6H5), 116.1 (CN), 114.5, 110.6 (2ꢂ[OC(CH3)2]),
130.3–127.5 (4ꢂC6H5), 116.4 (CN), 113.7 [OC(CH3)2], 87.6
[OC(C6H5)3], 80.4 (C-4), 78.0 (C-3), 64.5 (C-5), 61.3 (C-6), 58.2 (C-2),
53.8 (NCH2Ph), 26.7, 26.6 (2ꢂCH3). HRMS: C35H34O3N2Na calcd
553.2467, found 553.2462.
81.0 (C-4), 77.4 (C-3), 76.8 (C-6), 69.9 (C-5), 66.7 (C-7), 59.0 (C-2),
54.7 (NCH2Ph), 26.9, 26.2, 25.6, 25.5 (4ꢂCH3). HRMS: C20H26O4N2
calcd 381.1790, found 381.1793.
4.4.11. (3S,4R,5R,6S)-1-Cyano-2,3,5-tri-O-benzyl-1-N-benzyl-
pyrrolidine (5cS)
Following the general method B, 5bR/5bS (5.9 g, 11.0 mmol),
MsCl (4.26 mL, 55.03 mmol) in pyridine (100 mL) for 1 h 30 min
gave, after flash chromatography (EtOAc/cyclohexane, 25/75)
4.4.9. (2R,3S,4R,5S) 5-Azidomethyl-1-N-benzyl-2-cyano-3,4-O-
isopropylidenepyrrolidine (3cR) and (2S,3S,4R,5S) 5-azidomethyl-1-
N-benzyl-2-cyano-3,4-O-isopropylidenepyrrolidine (3cS)
Following the general method B, 3bR/3bS (8.0 g, 24.16 mmol),
MsCl (9.35 mL, 120.84 mmol) in pyridine (150 mL) for 3 h gave,
after flash chromatography (EtOAc/cyclohexane, 2/8) through
through a silica pad, 5cS (3.28 g, 57%) as a white solid. Mp¼132–
20
133 ꢁC; [
a
]
ꢀ50 (c 0.21, MeOH); IR (ATR)
n 3063, 3031, 2877, 2809,
D
a silica pad, 3e (300 mg, 4%) as an orange syrup followed by 3cS
1496, 1452, 1368,1153,1114,1090,1059,1027 cmꢀ1; 1H NMR (CDCl3,
300 MHz)
20
(5.82 g, 77%) as a white solid. Compound 3cR: mp¼78 ꢁC; [
a
]
þ1
d
7.43–7.23 (m, 20H, 4ꢂC6H5), 4.89–4.59 (m, 6H,
D
(c 0.9, CHCl3); IR (ATR)
n
2991, 2978, 2944, 2108, 2092, 1454, 1373,
3ꢂOCH2Ph), 4.15 (dd, J2,3¼5.3 Hz, J3,4¼9.5 Hz, 1H, H-3), 4.00 (d,
J2,3¼5.3 Hz, 1H, H-2), 3.77 (m, 1H, H-5), 3.70 (dd, J3,4¼9.5 Hz,
J4,5¼3.3 Hz, 1H, H-4), 3.66 (s, 2H, 2ꢂH-6), 2.96 (dt, JA,B¼13.2 Hz,
J1,A¼J4,A¼1.5 Hz, 1H, H-A NCH2Ph), 2.42 (d, JA,B¼13.2 Hz, 1H, H-B
1272, 1203, 1095 cmꢀ1 1H NMR (CDCl3, 300 MHz)
; d 7.34 (m, 5H,
C6H5), 4.80 (dd, J3,4¼6.2 Hz, J4,5¼4.1 Hz, 1H, H-4), 4.76 (d,
J3,4¼6.2 Hz,1H, H-3), 4.12 (d, JA,B¼13.4 Hz,1H, H-A NCH2Ph), 3.81 (s,
1H, H-2), 3.74 (dd, J5,6a¼7.8 Hz, J6a,6b¼12.2 Hz, 1H, H-6a), 3.53 (d,
JA,B¼13.4 Hz, 1H, H-B NCH2Ph), 3.54 (dd, J5,6b¼4.8 Hz,
J6a,6b¼12.2 Hz, 1H, H-5b), 2.90 (m, 1H, H-4), 1.54 (s, 3H, CH3), 1.35 (s,
NCH2Ph); 13C NMR (CDCl3, 75 MHz)
d 138.9–136.8, 129.3–128.0
(4ꢂC6H5), 115.2 (CN), 80.2 (C-4), 75.3 (C-3), 74.0, 73.3, 71.9
(3ꢂOCH2Ph), 72.9 (C-5), 59.7 (C-6), 57.8 (C-2), 50.1 (NCH2Ph).
HRMS: C34H34O3N2 calcd 519.2666, found 519.2657.
3H, CH3); 13C NMR (CDCl3, 75 MHz)
d 136.9, 129.1–128.2 (C6H5),
114.9 (CN), 113.5 [OC(CH3)2], 80.7, 80.4 (C-3, C-4), 64.9 (C-5), 59.8
(C-2), 53.7 (NCH2Ph), 49.8 (C-6), 26.6, 25.9 (2ꢂCH3). HRMS:
4.4.12. (3R,4S,5S,6R)-1-Cyano-2,3,5-tri-O-benzyl-1-N-benzyl-
pyrrolidine (6cR)
Following the general method B, 6bR/6bS (2.59 g, 4.83 mmol),
MsCl (1.87 mL, 24.16 mmol) in pyridine (50 mL) for 1 h gave, after
C16H19O2N5Na calcd 336.1436, found 336.1440. Compound 3cS:
20
[
a]
þ122 (c 0.59, CH2Cl2); IR (ATR)
n
2989, 2936, 2102, 1454, 1373,
D
1274, 1210 cmꢀ1
;
1H NMR (CDCl3, 300 MHz)
d
7.41–7.28 (m, 5H,
C6H5), 4.67 (m, 2H, H-3, H-4), 4.04 (d, JA,B¼14.8 Hz, 1H, H-A
NCH2Ph), 3.90 (d, JA,B¼14.8 Hz, 1H, H-B NCH2Ph), 3.64 (dd,
J5,6a¼8.6 Hz, J6a,6b¼12.0 Hz, 1H, H-6a), 3.48 (dd, J5,6b¼4.8 Hz,
J6a,6b¼12.0 Hz, 1H, H-6b), 3.36 (d, J2,3¼4.4 Hz, 1H, H-2), 2.63 (m, 1H,
H-5), 1.63 (s, 3H, CH3), 1.39 (s, 3H, CH3); 13C NMR (CDCl3, 75 MHz)
flash chromatography (EtOAc/cyclohexane, 15/85) through a silica
20
pad, 6cR (2.12 g, 84%) as a white solid. Mp¼129–130 ꢁC; [
a
]
þ50
D
(c 0.23, MeOH); IR (ATR) n 3064, 3031, 2852, 2809, 1496, 1452, 1368,
1153, 1114, 1090, 1059, 1027 cmꢀ1 1H NMR (CDCl3, 300 MHz)
;
d
7.50–7.27 (m, 20H, 4ꢂC6H5), 4.88–4.53 (m, 6H, 3ꢂOCH2Ph), 4.15
d
134.2, 129.9–128.5 (C6H5), 116.0 (CN), 114.1 [OC(CH3)2], 79.9, 77.7
(dd, J2,3¼5.3 Hz, J3,4¼9.6 Hz, 1H, H-3), 4.00 (d, J2,3¼5.3 Hz, 1H, H-2),
3.76–3.66 (m, 4H, H-4, H-5, 2ꢂH-6), 2.97 (d, JA,B¼13.3 Hz, 1H, H-A
NCH2Ph), 2.43 (d, JA,B¼13.3 Hz, 1H, H-B NCH2Ph); 13C NMR (CDCl3,
(C-3, C-4), 64.2 (C-5), 58.6 (C-2), 54.1 (NCH2Ph), 49.6 (C-6), 26.5,
26.0 (2ꢂCH3). HRMS: C16H19O2N5Na calcd 336.1436, found
336.1444.
75 MHz)
d
138.9–136.8, 129.3–128.0 (4ꢂC6H5), 115.2 (CN), 80.2 (C-
4), 75.3 (C-3), 74.0, 73.3, 71.9 (3ꢂOCH2Ph), 73.0 (C-5), 59.7 (C-6),
57.8 (C-2), 50.2 (NCH2Ph). HRMS: C34H34O3N2 calcd 519.2648,
found 519.2655.
4.4.10. (2S,3R,4S,5S,6R)-1-N-Benzyl-2-cyano-3,4:6,7-di-O-
isopropylidenepyrrolidine (4cS) and (2R,3R,4S,5S,6R)-1-N-benzyl-2-
cyano-3,4:6,7-di-O-isopropylidenepyrrolidine (4cR)
Following the general method B, 4bR/4bS (1/1.5) (2.39 g,
6.35 mmol), MsCl (2.45 mL, 31.75 mmol) in pyridine (100 mL) for
1 h 10 min gave, after flash chromatography (EtOAc/cyclohexane, 3/
7) through a silica pad, 4cS (990 mg, 43.5%) as an orange solid
4.4.13. (2S,3S,4R,5S)-3,4-Dihydroxy-5-methylproline (1d)
Following the general method C, 800 mg (2.94 mmol) of com-
pound 1cR, 20 mL of concd HCl (37%) for 24 h followed by addition
of Pd/C (500 mg) in water (10 mL) gave after lyophilisation 370 mg
20
followed by 4cR (370 mg, 16.3%) as a white solid. Compound 4cS:
(78%) of compound 1d as a slight brown solid. Mp¼220 ꢁC; [
a
]
ꢀ9
D
20
mp¼108–109 ꢁC; [
a]
þ140 (c 0.19, MeOH); IR (ATR)
n
2986, 2877,
(c 0.32, H2O); IR (ATR)
n
3367, 3064, 2949, 2532, 2465, 1599, 1438,
D
2843, 2813, 2357, 1454, 1384, 1373, 1260, 1210, 1146, 1102, 1069,
1394, 1367, 1319, 1157, 1132, 1049, 1022, 985, 877, 808 cmꢀ1
NMR (D2O, 300 MHz)
;
1H
1015 cmꢀ1
;
1H NMR (CDCl3, 300 MHz)
d
7.43–7.28 (m, 5H, C6H5),
d
4.49 (dd, J2,3¼6.3 Hz, J3,4¼4.5 Hz, 1H, H-3),
4.88 (dd, J2,3¼3.8 Hz, J3,4¼6.3 Hz, 1H, H-3), 4.41 (dd, J3,4¼6.3 Hz,
J4,5¼2.4 Hz, 1H, H-4), 4.25 (d, JA,B¼13.7 Hz, 1H, H-A NCH2Ph), 4.23
(d, JA,B¼13.7 Hz, 1H, H-B NCH2Ph), 4.05–3.98 (m, 2H, H-6, H-7a),
3.75 (dd, J6,7b¼7.0 Hz, J7a,7b¼8.3 Hz, 1H, H-7b), 3.60 (d, J2,3¼3.8 Hz,
1H, H-2), 3.25 (dd, J4,5¼2.4 Hz, J5,6¼6.8 Hz, 1H, H-5), 1.49, 1.43, 1.36,
4.25 (t, J3,4¼4.5 Hz, J4,5¼4.5 Hz, 1H, H-4), 4.04 (d, J2,3¼6.3 Hz, 1H, H-
2), 3.72 (m, 1H, H-5), 1.34 (d, J5,CH3¼6.9 Hz, 3H, CH3); 13C NMR (D2O,
75 MHz)
d 170.6 (CO), 70.9, 70.8 (C-3, C-4), 62.4 (C-2), 56.4 (C-5),
12.0 (CH3). HRMS: C6H12O4N calcd 162.0766, found 162.0767.
1.30 (s, 12H, 4ꢂCH3); 13C NMR (CDCl3, 75 MHz)
d
136.0, 129.7–128.3
4.4.14. (2S,3S,4R,5S)-3,4-Dihydroxy-5-hydroxymethylproline (2d)
Following the general method C, 645 mg (1.21 mmol) of com-
pound 2cR, 20 mL of concd HCl (37%) for 2 days followed by ad-
dition of Pd/C (300 mg) in water (10 mL) gave after lyophilisation
(C6H5), 118.6 (CN), 114.1, 110.4 (2ꢂ[OC(CH3)2]), 82.5, 81.4, 75.9, 69.7
(C-3, C-4, C-5, C-6), 66.8 (C-7), 59.3 (C-2), 55.4 (NCH2Ph), 27.4, 26.9,
25.6, 25.4 (4ꢂCH3). HRMS: C20H26O4N2 calcd 381.1790, found
20
381.1799. Compound 4cR: mp¼87–88 ꢁC; [
a
]
D
þ1 (c 0.46, MeOH);
164 mg (76%) of compound 2d as a slight brown solid. Mp¼223 ꢁC;
20
IR (ATR)
n
2989, 2947, 2891, 2850, 2242, 1375, 1251, 1210, 1157, 1084,
[a
]
ꢀ41 (c 0.17, H2O); IR (ATR)
n 3196, 3113, 1622, 1562, 1417, 1396,
D
1071, 1047, 1028 cmꢀ1
;
1H NMR (CDCl3, 300 MHz)
d
7.33 (m, 5H,
1319, 1282, 1132, 1041, 1018, 902, 873 cmꢀ1
;
1H NMR (D2O,
C6H5), 4.58 (t, J2,3¼J3,4¼6.7 Hz, 1H, H-3), 4.42 (dd, J4,5¼4.0 Hz, 1H,
300 MHz) 4.42 (m, 2H, H-3, H-4), 4.05 (m, 1H, H-2), 3.86–3.76 (m,
d

2772
M. Moura et al. / Tetrahedron 65 (2009) 2766–2772
3H, H-5, H-6a, H-6b); 13C NMR (D2O, 75 MHz)
70.3 (C-2, C-3), 62.7, 60.8 (C-2, C-5), 57.6 (C-6). HRMS: C6H11O5NNa
calcd 200.0535, found 200.0535.
d
170.0 (CO), 70.7,
J6,7¼5.0 Hz, J7,8¼3.0 Hz, 1H, H-7), 3.82 (d, J2,3¼7.9 Hz, 1H, H-3), 3.34
(m, 1H, H-5), 1.06 (d, J5,CH3¼6.5 Hz, 3H, CH3); 13C NMR (CDCl3,
75 MHz)
d
147.8,144.8,127.9,127.1, 124.0 (2ꢂC6H4), 104.0 (C-8), 88.8
(C-2), 76.6, 76.4, 76.2 (C-6, C-7, C-3), 65.2 (C-5), 14.7 (CH3). HRMS:
C19H19O7N3 calcd 402.1301, found 402.1301.
4.4.15. (2S,3S,4R,5S)-5-Aminomethyl-3,4-dihydroxyproline (3d)
Following the general method C, 5.0 g (15.97 mmol) of com-
pound 3cR, 80 mL of HClc. (37%) for 2 days followed by addition of
Acknowledgements
Pd/C (500 mg) in water (100 mL) gave after lyophilisation 2.17 g
20
(77%) of compound 3d as a slight brown solid. Mp¼99–100 ꢁC; [
a]
D
´
MM thanks the Conseil Regional de Picardie. A.NVN and DP
ꢀ17 (c 0.45, H2O); IR (ATR)
n 3151, 3105, 3014, 2160, 2034, 1979,
1624, 1560, 1417, 1398, 1354, 1321, 1284, 1120, 1043, 1018, 902,
´
`
thanks le Conseil Regional de Picardie and the Ministere Français de
la Recherche for financial support.
875 cmꢀ1 1H NMR (D2O, 300 MHz)
;
d
4.64 (m, 2H, H-2, H-3), 4.49
(m, 1H, H-4), 4.16 (m, 1H, H-5), 3.59 (dd, J5,6a¼6.5 Hz, J6a,6b¼13.9 Hz,
References and notes
1H, H-6a), 3.46 (dd, J5,6b¼5.7 Hz, J6a,6b¼13.9 Hz, 1H, H-6b); 13C NMR
1. Compain, P.; Martin, O. R. Iminosugars: From Synthesis to Therapeutic Applica-
tions; John Wiley and Sons Ltd: Chichester, UK, October 2007.
2. Cheng, X.-C.; Wang, Q.; Fang, H.; Tang, W.; Xu, W.-F. Bioorg. Med. Chem. 2008,
16, 7932–7938.
(D2O, 75 MHz)
d 168.2 (CO), 70.5 (C-3), 70.0 (C-4), 62.7 (C-2), 56.5
(C-5), 37.0 (C-6). HRMS: C6H13O4N2 calcd 177.0875, found 177.0875.
4.4.16. 4-para-Nitrophenylhepta-2,6-dione (7) and 3-methyl-5-
para-nitrophenylcyclohex-3-enone (8)
3. Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645–1680.
4. Sattigeri, J. A.; Andappan, M. M. S.; Kishore, K.; Thangathirupathy, S.; Sundaram,
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4-Nitrobenzaldehyde (100 mg, 0.66 mmol) and catalyst 3d
(116 mg, 0.66 mmol) were dissolved in DMSO (5.3 mL) and acetone
(1.3 mL) and stirred overnight at room temperature. Addition of
NH4Cl (20 mL) followed by extraction with EtOAc (ꢂ2) led succes-
sively after flash chromatography (EtOAc/cyclohexane, 3/7) to 8
5. Simpkins, L. M.; Bolton, S.; Pi, Z.; Sutton, J. C.; Kwon, C.; Zhao, G.; Magnin, D. R.;
Augeri, D. J.; Gungor, T.; Rotella, D. P.; Sun, Z.; Liu, Y.; Slusarchyk, W. S.; Marcin-
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A.; Goti, A. Tetrahedron: Asymmetry 2003,14, 367–379; (b) Marradi, M.; Cicchi, S.;
Ignacio Delso, J.; Rosi, L.; Tejero, T.; Merino, P.; Goti, A. Tetrahedron Lett. 2005, 46,
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(6 mg, 4%) and 7 (19 mg, 12%, EtOAc/cyclohexane, 4/6) as slight
20
yellow solid. Compound 8: mp¼115–116 ꢁC; [
a
]
ꢀ2 (c 0.09,
D
CHCl3); IR (ATR)
n 2925, 1656, 1605, 1596, 1518, 1510, 1339, 1313,
1298, 1254 cmꢀ1; 1H NMR (CDCl3, 300 MHz)
d
8.28 (d, Jo,m¼6.8 Hz,
2H, C6H4), 7.45 (m, 2H, C6H4), 6.04 (s, 1H, CH]), 3.49 (m, 1H, CH),
2.74–2.55 (m, 4H, 2ꢂCH2), 2.06 (s, 3H, CH3); 13C NMR (CDCl3,
75 MHz)
d 197.6 (CO), 160.8 (C]), 150.5, 127.7, 126.7, 124.1 (CH],
C6H4), 43.2 (CH2), 40.5 (CH), 38.2 (CH2), 24.3 (CH3). HRMS:
C13H13O3NNa calcd 254.0793, found 254.0798. Compound 7:
mp¼49–50 ꢁC; IR (ATR)
n 3403, 2907, 1704, 1597, 1501, 1341, 1219,
1158 cmꢀ1
;
1H NMR (CDCl3, 300 MHz)
d
8.15 (d, Jo,m¼8.6 Hz, 2H,
C6H4), 7.42 (m, 2H, C6H4), 3.83 (m, 1H, CH), 2.88 (dd, JH,HA¼6.5 Hz,
JHA,HB¼17.3 Hz, 2H, 2ꢂH-A CH2), 2.80 (dd, JH,HB¼7.5 Hz,
JHA,HB¼17.3 Hz, 2H, 2ꢂH-B CH2), 2.09 (s, 3H, CH3); 13C NMR (CDCl3,
75 MHz)
d
206.4 (CO),151.8, 147.1, 128.8, 124.2 (C6H4), 49.2 (2ꢂCH2),
36.1 (CH), 30.6 (2ꢂCH3). HRMS: C13H15O4NNa calcd 272.0899,
found 272.0905.
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142–150.
4.4.17. 5-Methyl-2,3-bis-(4-nitrophenyl)-hexahydro-pyrrolo[2,1-
b]oxazole-6,7-diol (9a) and 5-methyl-2,3-bis-(4-nitrophenyl)-
hexahydro-pyrrolo[2,1-b]oxazole-6,7-diol (9b)
18. (a) Waite, J. H.; Tanzer, M. L. Science 1981, 212, 1038–1040; (b) Bann, J. G.;
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1980, 77, 2370–2371.
4-Nitrobenzaldehyde (100 mg, 0.66 mmol) and catalyst
1
21. Taylor, S. W.; Waite, J. H.; Ross, M. M.; Shabanowitz, J.; Hunt, D. G. J. Am. Chem.
Soc. 1994, 116, 10803–10804.
(106 mg, 0.66 mmol) were dissolved in DMSO (5.3 mL) and acetone
(1.3 mL) and stirred for 48 h at room temperature. Addition of
NH4Cl (20 mL) followed by extraction with EtOAc (ꢂ2) led succes-
sively after flash chromatography (EtOAc/cyclohexane, 4/6) to the
known aldol derivative (34 mg, 25%) followed by 9a (24 mg, 9%,
22. Fujii, M.; Miura, T.; Kajimoto, T.; Ida, Y. Synlett 2000, 1046–1048.
23. Martı´n, R.; Alco´n, M.; Perica`s, M. A.; Riera, A. J. Org. Chem. 2002, 67, 6896–6901.
24. Taylor, C. M.; Barker, W. D.; Weir, C. A.; Park, J. H. J. Org. Chem. 2002, 67, 4466–4474.
25. Garcia, A. L. L.; Correia, C. R. D. Tetrahedron Lett. 2003, 44, 1553–1557.
26. Weir, C. A.; Taylor, C. M. Org. Lett. 1999, 1, 787–789.
27. Taylor, C. M.; Jones, C. E.; Bopp, K. Tetrahedron 2005, 61, 9611–9617.
28. McCort, I.; Dure´ault, A.; Depezay, J.-C. Tetrahedron Lett. 1998, 39, 4463–4466.
29. (a) Chem. Rev. 2007, 107, 5413–5883, special issue: organocatalysis. And refer-
ences cited herein; (b) Gro¨ger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40,
529–532; (c) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481–2495; (d)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726–3748; (e) List, B.;
Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395–2396; (f) Notz,
W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386–7387; (g) Alcaide, B.; Almendros, P.
Angew. Chem., Int. Ed. 2008, 47, 4632–4634; (h) Guillena, G.; Na´jera, C.; Ramo´ n,
D. J. Tetrahedron: Asymmetry 2007, 18, 2249–2293.
30. (a) Wang, Y.; Wei, S.; Sun, J. Synlett 2006, 3319–3323; (b) Bellis, E.; Kokotos, G.
Tetrahedron 2005, 61, 8669–8676; (c) Hayashi, Y.; Sumiya, T.; Takahashi, J.;
Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958–961.
31. Moreno-Vargas, A. J.; Robina, I.; Petricci, E.; Vogel, P. J. Org. Chem. 2004, 69,
4487–4491.
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J. Am. Chem. Soc. 2003, 125, 5262–5263.
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3057.
EtOAc/cyclohexane, 6/4) and 9b (24 mg, 9%, EtOAc/cyclohexane, 1/
20
0). Compound 9a: mp¼65–66 ꢁC; [
a
]
D
þ92 (c 0.15, MeOH); IR
(ATR)
n ;
3308, 2925, 1729, 1600, 1514, 1343, 1108, 1041 cmꢀ1 1H
NMR (CD3OD, 300 MHz)
d
7.96, 7.34, 7.18 (m, 8H, 2ꢂC6H4), 5.50 (d,
J7,8¼4.8 Hz, 1H, H-8), 5.46 (d, J2,3¼5.7 Hz, 1H, H-2), 4.62 (d,
J2,3¼5.7 Hz, 1H, H-3), 4.19 (t, J6,7¼J7,8¼4.7 Hz, 1H, H-7), 4.08 (dd,
J5,6¼3.0 Hz, J6,7¼4.7 Hz, 1H, H-6), 3.43 (m, 1H, H-5), 1.25 (d,
J5,CH3¼6.4 Hz, 3H, CH3); 13C NMR (CD3OD, 75 MHz)
d 147.0, 144.8,
128.6, 127.3, 122.5, 122.1 (2ꢂC6H4), 103.2 (C-8), 78.0, 69.8 (C-2, C-3),
77.3 (C-7), 74.1 (C-6), 62.6 (C-5), 14.5 (CH3). HRMS: C19H19O7N3
20
calcd 402.1301, found 402.1301. Compound 9b: mp¼49–50 ꢁC; [
a]
D
þ72 (c 0.10, MeOH); IR (ATR)
n 3382, 2929, 1733, 1600, 1516, 1343,
1244, 1105, 1044 cmꢀ1 1H NMR (CDCl3, 300 MHz)
; d 8.22, 7.42 (m,
8H, 2ꢂC6H4), 5.26 (d, J7,8¼3.0 Hz, 1H, H-8), 4.80 (d, J2,3¼7.9 Hz, 1H,
H-2), 4.52 (dd, J5,6¼3.0 Hz, J6,7¼5.0 Hz, 1H, H-6), 4.30 (dd,