A fast, efficient and stereoselective synthesis of hydroxy-pyrrolidines

Article abstract of DOI:10.1016/j.carres.2010.03.016

A five-step, protecting group free synthesis of 2,3-cis substituted hydroxy-pyrrolidines is presented. Key steps in the synthesis are the chemoselective formation of a primary amine via a Vasella reductive amination using ammonia as the nitrogen source, and the stereoselective formation of a cyclic carbamate from an alkenylamine. Improvement of the reductive amination, by way of the use of α-picoline borane as a more environmentally benign reducing agent, is also presented.

Full text of DOI:10.1016/j.carres.2010.03.016

Carbohydrate Research 345 (2010) 1360–1365
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
A fast, efficient and stereoselective synthesis of hydroxy-pyrrolidines
Emma M. Dangerfield a,b, Shivali A. Gulab c, Catherine H. Plunkett a,b, Mattie S. M. Timmer b,
,
*
Bridget L. Stocker a,
*
a Malaghan Institute of Medical Research, PO Box 7060, Wellington, New Zealand
b School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand
c Industrial Research Ltd, PO Box 31-310, Lower Hutt, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
A five-step, protecting group free synthesis of 2,3-cis substituted hydroxy-pyrrolidines is presented. Key
steps in the synthesis are the chemoselective formation of a primary amine via a Vasella reductive ami-
nation using ammonia as the nitrogen source, and the stereoselective formation of a cyclic carbamate
Received 14 January 2010
Received in revised form 10 March 2010
Accepted 13 March 2010
from an alkenylamine. Improvement of the reductive amination, by way of the use of
as a more environmentally benign reducing agent, is also presented.
a-picoline borane
Available online 17 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrolidine
Iminosugar
Carbamate
Reductive amination
Green chemistry
Protecting group free
1. Introduction
topic.1,4,5 Traditional methodologies have included the synthesis
of compounds with few competing reactivities,6 protection by pro-
tonation,7 and biomimetic synthesis,8 while more recent strategies
have incorporated new chemistries involving the development of
new chemoselective reagents and processes.1,4,5 With an interest
in developing efficient syntheses of iminosugars,9 we turned our
attention to the development of new synthetic methodologies that
would enable pyrrolidines to be synthesised without the need for
protecting groups. The initial focus of our work was the synthesis
of 2,3-cis-substituted pyrrolidines (Fig. 1). Of these pyrrolidines,
The constant pressure to prepare compounds in a more efficient
manner has placed the process by which traditional synthetic
chemistry is conducted under scrutiny.1 The ‘ideal synthesis’ has
been described as one that uses readily available, inexpensive
starting materials and proceeds in a simple, safe, environmentally
acceptable and efficient manner.2
Key in improving the efficiency and atom economy of a synthe-
sis is the omission of protecting groups in the synthetic plan.1
Although the use of protecting groups has undoubtedly led to a
surge in the successful completion of increasingly complex syn-
thetic targets, and justifies the continual development of new
and specialised protecting groups,3 the incorporation and subse-
quent removal of a protecting group adds to the total number of
steps in a synthetic sequence and leads to reductions in overall
yield and atom economy.4 In addition, the material that corre-
sponds to the protecting group (and the reagents used for its intro-
duction/removal) must be separated from the desired compound
and discarded, leading to an increase in overall waste production.
There are a number of strategies that can be applied so as to
achieve a total synthesis without the need for protecting groups,
and a number of elegant reviews have been devoted to this
1,4-dideoxy-1,4-imino-D-xylitol (1), isolated from the Pteridophyte
Arachniodes standishii,10 is a weak glycogen phosphorylase b inhib-
itor,11 while its
L
-isomer, 1,4-dideoxy-1,4-imino-L-xylitol (2), and
HO
HO
HO
H
N
H
N
H
N
HO
HO
OH
HO
OH
3
1
2
HO
HO
H
H
N
N
HO
HO
OH
OH
* Corresponding authors. Tel.: +64 4 499 6914x813; fax: +64 4 499 6915.
E-mail addresses: mattie.timmer@vuw.ac.nz (M.S.M. Timmer), bstocker@
malaghan.org.nz (B.L. Stocker).
4
5
Figure 1. 2,3-cis-Substituted pyrrolidines.
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.03.016

E. M. Dangerfield et al. / Carbohydrate Research 345 (2010) 1360–1365
1361
the trideoxy analogue, 1,2,4-trideoxy-1,4-imino-
yet to be isolated or tested for biological activity. Of the lyxitol pyr-
rolidines, 1,4-dideoxy-1,4-imino- -lyxitol (4), the structure tenta-
tively assigned to a pyrrolidine found from Raispalia sp.,12 is a
potent
-galactosidase inhibitor,13,14 while 1,4-dideoxy-1,4-imi-
no- -lyxitol (5) has not been isolated or assayed. A fast, efficient
L
-xylitol (3), are
synthesis of 1,4-dideoxy-1,4-imino-
D
-lyxitol (4) (Scheme 3). How-
ever, unlike most other iodo-pentofuranosides,18 literature prece-
D
dent for the formation of the iodinated methyl glycoside 13
involved either a six-step synthesis commencing with
nose23 or a five-step synthesis from 1,2-O-cyclohexylidene-
xylofuranose.24 Being keen to develop a shorter, and potentially
more efficient synthesis, we subjected -lyxose (11) to a solution
D-man-
a
a-D-
L
synthesis of pyrrolidines such as these will undoubtedly aid in a
more thorough assessment of their therapeutic activities.
In the work presented herein, we report on the applicability of
D
of AcCl in MeOH and stirred the reaction for 18 h at room temper-
ature (Scheme 3). Though a sometimes fickle reaction,25 with the
major impediment being the formation of the undesired thermo-
dynamically more stable methyl pyranoside, these conditions nev-
ertheless lead to the formation of the desired methyl glycoside 12
in 87% yield (with 8% of the pyranose isomer). Next, glycoside 12
was subjected to a solution of triphenylphosphine, iodine and
imidazole in THF to install the iodide at the primary position. This
transformation proceeded smoothly, with the iodo precursor 13
being prepared in good yield (76%).
With the iodinated methyl glycoside 13 in hand, this was then
subjected to our reductive amination conditions. Again, transfor-
mation to the linear alkenylamine proceeded smoothly with alke-
nylamine 14 being prepared in 90% yield. The alkenylamine 14 was
then treated with iodine and NaHCO3 to give carbamate 15 in 99%
our novel protecting group free strategy15,16 to the synthesis of
L-
xylitol 2 and D-lyxitol 4 and provide an explanation for the remark-
able diastereoselectivity observed in our carbamate annulation
methodology. Our efforts to improve the overall protecting group
free strategy via the implementation of more environmentally
favourable reductive amination protocols will also be presented.
For a summary of other synthetic strategies that can be used to
prepare pyrrolidines, there are a number of recent reviews pub-
lished in this area.17
2. Results and discussion
To achieve a protecting group free synthesis of 1,4-dideoxy-
pyrrolidines, we envisioned a retrosynthetic analysis that involved
three key synthetic transformations: carbamate hydrolysis (A?B),
carbamate annulation (B?C) and Vasella reductive amination
(C?D) (Scheme 1). Central to this work was the development of a
novel tandem halo-cyclisation–carbonylation using sodium bicar-
bonate as the source of carbon dioxide (B?C).15 An efficient reduc-
tive amination protocol that uses ammonia, instead of a protected
amine, as the nitrogen source to directly yield a primary amine
was also key in achieving this protecting group free strategy. Such
a transformation has been difficult to effect in the past.19
yield (>20:1 d.s.). Following hydrolysis, 1,4-dideoxy-1,4-imino-D-
lyxitol (4) was then obtained and NMR spectral data and optical
rotation values were used to confirm the stereochemistry of the
final product.14
Having established a general procedure for the synthesis of
iminopentitols, attempts were then made to improve the overall
HO
I
O
OH 1) MeOH, AcCl
2) PPh3, I2,
O
OMe
OH
HO
OH
The synthesis of 1,4-dideoxy-1,4-imino-L-xylitol (2) commenced
HO
Imid., THF
64% (2 steps)
7
6
with the uneventful transformation of -arabinose (6) to the corre-
D
sponding iodinated methyl glycoside 7,19 although, with iodine,
triphenylphosphine and imidazole used in excess, this represents
the least environmentally benign aspect of the sequence (Scheme
2). Glycoside 7 was then treated with activated zinc, NaCNBH3, a sat-
urated solution of NH4OAc in ethanol and aqueous NH3. Following
18 hours at reflux and purification via Dowex H+ resin, the corre-
sponding linear alkenylamine 8 was isolated in an excellent yield
(93%). When ammonia is used as a nucleophile during reductive
amination, typically over-alkylation occurs, resulting in the dimeric
product20 (e.g., 9). Our modified conditions, however, lead to the
exclusive formation of monomer 8 and no trace of dimer 9. Alkenyl-
amine 8 was then subjected to our iodine-mediated carbamate
annulation methodology, which gave carbamate 10 in an excellent
yield (93%) and as the major product (>20:1 d.s., as determined by
1H NMR of the crude reaction mixture). Hydrolysis of the carbamate
and comparison of the NMR spectral data and optical rotation values
of the hydrolysed product with those in the literature21,22 confirmed
the identity of the resulting pyrrolidine to be that of 1,4-dideoxy-
Zn, NH4OAc
NaCNBH3
EtOH,reflux
18 h, 93%
OH
OH
OH
H
N
NH2
OH
OH
OH
8
9 (not observed)
I2, NaHCO3
H2O, rt, 18 h, 93%
O
N
HO
H
O
N
NaOH, EtOH
reflux, 2 h, 97%
OH
HO
1,4-imino-L-xylitol (2). With an overall yield of 54%, this five-step
synthesis is remarkably efficient.
OH
HO
2
10
Given our success in preparing 1,4-dideoxy-1,4-imino-L-xylitol
Scheme 2. Protecting group free synthesis of 1,4-dideoxy-1,4-imino-L-xylitol.
(2), we anticipated employing a similar synthetic strategy for the
O
HO
O
H
N
I
NH2
O
(OH)n
N
OMe
(OH)n
(OH)n
(OH)n
A
B
C
D
Scheme 1. Retrosynthesis for the formation of 1,4-dideoxy-pyrrolidines.

1362
E. M. Dangerfield et al. / Carbohydrate Research 345 (2010) 1360–1365
HO
HO
I
O
O
PPh3, I2, Imid., THF
reflux, 2 h, 76%
O
MeOH, AcCl
rt, 18 h, 87%
OH
OH
OMe
OH
OMe
OH
HO
HO
HO
11
12
13
Zn, NH4OAc,
NH3, NaCNBH3
EtOH, reflux,
18 h, 90%
O
N
H
N
O
OH
HO
NaOH, EtOH
I2, NaHCO3
NH2
reflux, 2 h, 97%
H2O, rt, 18 h, 99%
OH
HO
OH
OH
HO
4
14
15
Scheme 3. Protecting group free synthesis of 1,4-dideoxy-1,4-imino-D-lyxitol.
strategy by modifying the choice of reducing agent used during the
Vasella reductive amination. Given the toxicity of NaCNBH3, which
carries the risk of leaving residual cyanide in the product as well as
in the work-up stream, it was desirable to substitute this reagent
for a ‘greener’ reducing agent, such as sodium triacetoxyborohy-
in the right direction for the development of a synthesis with
reduced environmental impact.
In sum, our reductive amination–carbamate annulation protocol
has proven effective for the formation of a number of pyrrolidines,
with each iminosugar being prepared in five steps, in good overall
yield, and without the need for protecting groups. The overall yield
dride [NaBH(OAc)3]26 or -picoline borane.27 Though NaBH(OAc)3
a
selectively reduces imines over carbonyl compounds in 1,2-dichlo-
roethane or THF, solvents such as ethanol lead to the rapid reduc-
tion of the carbonyl compound or the decomposition of the
for the formation of 1,4-dideoxy-1,4-imino-
supersedes that of the next most efficient synthesis (three steps, 48%
total yield, commencing from 2,3,5-tri-O-benzyl- -arabinofura-
nose).22 The total yield for the synthesis of
-lyxitol (4) was slightly
L-xylitol (2) was 54% and
D
reducing agent and thus was not suitable for our purposes.
a
-Pic-
D
oline borane, however, has been successfully used in the one-pot
higher at 57%. This synthesis is the shortest to date and is compara-
ble with the most efficient published strategy—that by Blanco and
reductive amination of aldehydes and ketones in alcoholic sol-
vents.27 With methyl 5-deoxy-5-iodo-
a
/b-
as our model substrate (Table 1), the reductive amination was re-
peated using NaCNBH3 or -picoline borane with varying equiva-
D
-ribofuranoside (16)
Sardinia that commences with trans-4-hydroxy-
57% yield).28 We have previously reported on the preparation of
1,4-dideoxy-1,4-imino- -xylitol (1) (57% total yield), 1,2,4-tride-
oxy-1,4-imino- -xylitol (3) (48% total yield) and 1,4-dideoxy-1,4-
imino-
-lyxitol (5) (55% total yield).15,16 Again, all three syntheses
L-proline (six steps,
a
D
lents of the reducing agent. The benchmark reaction was that
with 3 equiv of NaCNBH3, which gave the linear alkenylamine 17
exclusively and in 91% isolated yield (entry 1). The number of
equivalents of NaCNBH3 was then reduced to 1.1 equiv to deter-
mine the minimal amount of reducing agent that could be used
to affect the transformation (entry 2). Here, the yield of alkenyl-
amine 17 decreased to 82%, though only the primary amine prod-
uct was observed, following purification by Dowex H+ resin. With
L
L
were performed in five steps and with the highest reported yields
to date.In addition to the high yields and short number of linear
steps, another remarkable feature of our strategy is the high degree
of diastereoselectivity observed in the carbamate annulation reac-
tion. The reaction favours the formation of the 2,3-cis pyrrolidine,
with the stereochemistry at the 3-position exerting stereocontrol
on the cyclisation. This high diastereoselectivity can be explained
by considering a transition state model originally proposed by
Chamberlin et al.29–31 and more recent theoretical studies presented
by Gouverneur and co-workers.32 In these models, attack of the
amine on the I2–ethylene complex is thought to take place via a
five-membered ring transition structure in which the nitrogen ap-
proaches the double bond in an envelope conformation and follows
a Bürgi–Dunitz-like trajectory33 (Fig. 2). The hydroxylsubstituent on
the ring (depicted in blue) can now be positioned either in the plane
of the double bond (A, O-in-plane), or almost perpendicular to that
plane (B, H-in-plane). Of these two transition states, A has minimal
overlap between the electron-withdrawing rꢀC—O and reacting pc@O
a-picoline borane as the reducing agent, similar results were ob-
served. Gratifyingly, 3 equiv of -picoline borane led to the smooth
a
formation of alkenylamine 17 in 88% yield and with good chemose-
lectivity (entry 3). Decreasing the amount of reducing agent
slightly lowered the reaction yield (entries 4 and 5) with
borane yielding similar results to NaCNBH3. Though this methodol-
ogy is not without fault, for stoichiometric amounts of -picoline
a-picoline
a
borane must still be used, this adaptation is nevertheless a step
Table 1
Optimisation of the Vasella eductive amination using
a
-picoline borane
I
Zn, NH4OAc, NH3
O
OH
OMe
reducing agent
NH2
H
N
H
H
OH
H
H
H
OH
π
H
HO
H
OH
OH
I
EtOH, reflux,18 h
π
OH
I
N
H
H
16
17
H
HO
H
I
H
σ*
σ*
H
I
H
Entry
Reducing agent
Equivalents
Yield (%)
H
H
H
1
2
3
4
5
NaCNBH3
NaCNBH3
3
1.1
3
2
1.1
91
82
88
81
78
A OH-in-plane
B H-in-plane
Not observed
a-Picoline borane
a-Picoline borane
a-Picoline borane
Only product
Figure 2. Proposed transition state for the iodo-cyclisation.

E. M. Dangerfield et al. / Carbohydrate Research 345 (2010) 1360–1365
1363
orbitals, thereby forming the lowest energy transition state. The H-
in-plane structure (B) has overlapping hydroxyl rꢀC—O and double
bond pc@O orbitals, which destabilises the complex and is hence
disfavoured.
flash chromatography (MeOH–EtOAc, 1:9, v/v) to give the pure
methyl furanosides.
4.2.1. Methyl
By subjecting
procedure for the synthesis of methyl furanosides, methyl
inofuranoside was isolated as a colourless oil (19.1 g, 118 mmol,
D
-arabinofuranoside
-arabinose (6) (20.1 g, 134 mmol) to the general
-arab-
D
D
3. Conclusion
88%). Rf = 0.48 and 0.36 for
a
and b, respectively (MeOH–EtOAc,
+91.0 (c 1.0, MeOH); IR (film), 3356, 2924, 2481,
1H NMR (300 MHz, CD3OD) d 4.88 (d,
), 3.94 (dd, J1,2 = 1.5 Hz, J2,3 = 3.5 Hz, 1H, H-
), 3.91 (ddd, J4,5a = 3.3 Hz, J4,5b = 5.3 Hz, J3,4 = 6.1 Hz, 1H, H-4 ),
3.83 (dd, J2,3 = 1.5 Hz, J3,4 = 6.1 Hz, 1H, H-3 ), 3.75 (dd,
J4,5a = 3.3 Hz, J5a,5b = 11.6 Hz, 1H, H-5a ), 3.64 (dd, J4,5b = 5.3 Hz,
J5a,5b = 11.6 Hz, 1H, H-5b
), 3.37 (s, 3H, OMe); 13C NMR (75 MHz,
Herein, we have reported on the expansion of our novel, stereose-
lective, five-step strategy for the synthesis of important pyrrolidines,
1:9, v/v); ½a 1D9
ꢄ
1455, 1119, 972, 824 cmꢃ1
;
namely 1,4-dideoxy-1,4-imino-L-xylitol (2) and 1,4-dideoxy-1,4-imi-
J1,2 = 1.5 Hz, 1H, H-1
a
no- -lyxitol (4). Our strategy is not only competitive in terms of yield
D
2a
a
and number of steps but also allows for the achievement of total syn-
theses without the need for protecting groups. Improvements to the
Vasella reductive amination reaction were also made, with NaCNBH3
a
a
a
being substituted with the more environmentally benign a-picoline
CD3OD) d 109.2 (C-1), 84.1 (C-4), 82.0 (C-2), 77.3 (C-3), 61.6 (C-
5), 53.9 (OMe); HRMS-ESI m/z calcd for [C6H12O5+Na]+: 187.0582,
obsd: 187.0581.
borane as the reducing agent. The expansion of our novel reductive
amination and carbamate annulation methodologies towards the
synthesis of other iminosugars is currently being explored in our
laboratory.
4.2.2. Methyl
Subjection of
dure for the synthesis of methyl furanosides gave pure methyl
a
-
D
D
-lyxofuranoside (12)
-lyxose 11 (1.00 g, 6.67 mmol) to the general proce-
4. Experimental
a-D-
lyxofuranoside (12) as a white crystalline powder (0.95 g, 5.81 mmol,
4.1. General methods
87%). Rf = 0.49 (MeOH–EtOAc, 1:9, v/v); mp 96.8–98.2 °C; ½a D20
ꢄ
+131.2
(c 0.5, MeOH); IR (film), 3320, 2943, 2832, 1449, 1106, 1020 cmꢃ1; 1H
NMR (500 MHz, CDCl3): d 4.84 (s, 1H, H-1), 4.64 (br s, 1H, OH), 4.52
(dd, J2,3 = 5.0 Hz, J3,4 = 6.6 Hz, 1H, H-3), 4.19 (br s, 1H, OH), 4.16
(ddd, J4,5b = 2.9 Hz, J4,5a = 3.7 Hz, J3,4 = 6.6 Hz, 1H, H-4), 3.99 (d,
J2,3 = 5.0 Hz, 1H, H-2), 3.85 (dd, J4,5a = 3.7 Hz, J5a,5b = 11.9 Hz, 1H, H-
5a), 3.80 (dd, J4,5b = 2.9 Hz, J5a,5b = 11.9 Hz, 1H, H-5b), 3.36 (s, 3H,
OMe); 13C NMR (125 MHz, CDCl3) d 107.5 (C-1), 78.6 (C-3), 74.8 (C-
4), 71.7 (C-2), 60.4 (C-5), 55.1 (OMe); HRMS-ESI m/z calcd for
[C6H12O5+Na]+: 187.0582, obsd: 187.0578.
Unless otherwise stated all reactions were performed under
atmospheric air. THF (Lab-Scan) was distilled from LiAlH4 prior
to use. H2O, MeOH (Pure Science) and EtOAc (Pure Science) were
distilled prior to use. EtOH (absolute, Pure Science), DCM (LabServ),
30% aqueous NH3 (J. T. Baker Chemical Co.), arabinose (Sigma–Al-
drich), lyxose (Sigma–Aldrich), AcCl (B&M), PPh3 (Merck), imidaz-
ole (Aldrich), I2 (BDH), NaCNBH3 (Aldrich),
a-picoline borane
(Aldrich), NaOH (Pure Science) and NH4OAc (AnalaR) were used
as received. Zn dust was activated by the careful addition of con-
centrated H2SO4 washed with EtOH (3ꢁ) and hexanes (3ꢁ), and
stored under dry hexanes. All solvents were removed by evapora-
tion under reduced pressure. Reactions were monitored by TLC-
analysis on Macherey–Nagel silica gel coated aluminium sheets
(0.20 mm, Silica Gel 60) with detection by UV-absorption
(254 nm), by spraying with 20% H2SO4 in EtOH followed by char-
ring at ꢂ150 °C, by dipping in I2 in silica or by spraying with a solu-
tion of ninhydrin in EtOH followed by charring at ꢂ150 °C. Column
chromatography was performed on Pure Science silica gel (40–
4.3. General procedure for the synthesis of methyl 5-deoxy-5-
iodo-furanosides
To a solution of methyl furanoside (164 mg, 1 mmol) in dry THF
(5.5 mL) under an atmosphere of N2, PPh3 (393 mg, 1.5 mmol) and
imidazole (136 mg, 2 mmol) were added. I2 (380 mg, 1.5 mmol) in
dry THF (1.5 mL) was cannulated into the reaction vessel. The reac-
tion was heated at reflux for 2 h, then cooled, filtered and concen-
trated. The product was taken up in hexanes–EtOAc, 3:1, v/v, and
filtered through a silica plug to remove excess iodine, then purified
using reverse phase HP-20 beads (MeOH–H2O, 5:1, v/v) to give the
63 l
m). DowexÒ W50-X8 acidic resin (Sigma) and DowexÒ 1X4-
50 basic resin (Sigma) were used for ion exchange chromatography
and HP-20 (Supelco) for reverse phase chromatography. High-res-
olution mass spectra were recorded on a Waters Q-TOF Premier™
Tandem Mass Spectrometer using positive electro-spray ionisation.
Optical rotations were recorded using a Perkin–Elmer 241 polarim-
eter at the sodium D-line. Infrared spectra were recorded as thin
films using a Bruker Tensor 27 FTIR spectrometer, equipped with
an Attenuated Total Reflectance (ATR) sampling accessory, and
are reported in wave numbers (cmꢃ1). Nuclear magnetic resonance
spectra were recorded at 20 °C in D2O, CD3OD or CDCl3 using either
a Varian Unity-INOVA operating at 300 MHz or a Varian Unity
operating at 500 MHz. Chemical shifts are given in parts per mil-
lion (ppm) (d) relative to tetramethylsilane. NMR peak assign-
ments were made using COSY, HSQC and HMBC 2D experiments.
methyl 5-iodo-D-furanosides.
4.3.1. Methyl 5-deoxy-5-iodo-
By subjecting methyl -arabinoside (4.20 g, 28 mmol) to the
general procedure for the synthesis of methyl 5-deoxy-5-iodo-
D-arabinofuranoside (7)
D
D-
furanosides, arabinoside 7 was obtained as a colourless oil (5.62 g,
20.5 mmol, 73%). Rf = 0.60 (MeOH–EtOAc, 85:15, v/v); ½a D20
ꢄ
+37.0
(c 2.2, CHCl3); IR (film), 3435, 1216, 770 cmꢃ1 1H NMR (CDCl3,
;
300 MHz): d 4.96 (s, 1H, H-1
a
), 4.86 (d, J1b,2b = 4.6 Hz, 1H, H-1b),
), 4.12 (dd, J1b,2b = 4.6 Hz,
J2b,3b = 7.0 Hz, 1H, H-2b), 4.07 (dt, J3 = 3.9 Hz, J4 = 5.9 Hz,
4.17 (d, J2 = 1.9 Hz, 1H, H-2
a
a,3a
a
,4a
a,5a
1H, H-4
1H, H-4b), 3.95 (dd, J3b,4b = 3.2 Hz, J2b,3b = 7.0 Hz, 1H, H-3b), 3.91
(dd, J2 = 1.9 Hz, J3 = 3.9 Hz, 1H, H-3 ) 3.48 (s, 3H, b-OMe),
= 5.8 Hz, J5a = 10.5 Hz,
a), 4.04 (ddd, J3b,4b = 3.2 Hz, J4b,5ab = 6.1 Hz, J4b,5bb = 7.0 Hz,
a
a
,3
a
a,4a
4.2. General procedure for the synthesis of methyl furanosides
3.42 (s, 3H,
1H, H-5a ), 3.37 (dd, J4
5b ), 3.33 (dd, J4b,5ab = 6.1 Hz, J5ab,5bb = 10.0 Hz, H-5ab), 3.30 (dd,
J4b,5bb = 7.0 Hz, J5ab,5bb = 10.0 Hz, H-5a
); 13C NMR (CDCl3,
75 MHz) d 108.9 (C-1 ), 101.9 (C-1b), 84.7 (C-4 ), 81.5 (C-3b),
81.0 (C-3 ), 80.8 (C-2 ), 80.6 (C-4b), 78.6 (C-2b), 55.6 (C-6b), 55.2
a-OMe), 3.41 (dd, J4
a,5aa
a,5ba
a
= 5.8 Hz, J5a
= 10.5 Hz, 1H, H-
,5ba
a,5ba
a
To a solution of pentose (150 mg, 1 mmol) in MeOH (5 mL), AcCl
(15 lL) was added and the reaction was stirred at room tempera-
a
a
ture for 18 h. The reaction was quenched by the addition of Dowex
a
a
(OHꢃ), filtered and concentrated. The resulting oil was purified by
a
a

1364
E. M. Dangerfield et al. / Carbohydrate Research 345 (2010) 1360–1365
(C-6
a
), 8.0 (C-5b), 6.6 (C-5
a); HRMS-ESI m/z calcd for [C6H11O4I+-
4.5. General procedure for the iodo-cyclisation–carbamate
formation
Na]+: 296.9600, obsd: 296.9598.
To a solution of the alkenylamine hydrochloride (154 mg,
4.3.2. Methyl 5-deoxy-5-iodo-
By subjecting methyl -lyxose 12 (1.60 g, 9.75 mmol) to the gen-
eral procedure for the synthesis of methyl 5-deoxy-5-iodo- -fur-
D-lyxofuranoside (13)
1 mmol) in water (5 mL) were added NaHCO3 (126 mg, 1.5 mmol)
and I2 (279 mg, 1.1 mmol). The solution was stirred 18 h at room
temperature, filtered and concentrated under reduced pressure.
The product was purified by silica gel chromatography (1–5%
MeOH in EtOAc, v/v).
D
D
anosides, lyxoside 13 was obtained as a colourless syrup (2.03 g,
7.41 mmol, 76%). Rf = 0.61 (MeOH–EtOAc, 1:9, v/v); ½a D20
ꢄ
+68.0 (c
1.5, CHCl3); IR (film), 3445, 1214, 770 cmꢃ1 1H NMR (500 MHz,
;
CDCl3): d 4.91 (d, J1,2 = 2.9 Hz, 1H, H-1), 4.37 (dd, J2,3 = 4.8 Hz,
J3,4 = 3.8 Hz, 1H, H-3), 4.30 (ddd, J3,4 = 3.8 Hz, J4,5a = J4,5b = 6.2 Hz,
8.2 Hz, 1H, H-4), 4.17 (dd, J1,2 = 2.9 Hz, J2,3 = 4.8 Hz, 1H, H-2) 3.48
(br s, 1H, OH), 3.40 (s, 3H, OMe), 3.37 (dd, J4,5a = 8.2 Hz, J5a,5b = 9.7 Hz,
1H, H-5a), 3.27 (dd, J4,5b = 6.2 Hz, J5a,5b = 9.7 Hz, 1H, H-5b); 13C NMR
(125 MHz, CDCl3): d 108.4 (C-1), 79.6 (C-4), 76.3 (C-3), 70.5 (C-2),
55.0 (OMe), ꢃ0.8 (C-5); HRMS-ESI m/z calcd for [C6H11O4I+Na]+:
296.9600, obsd: 296.9604.
4.5.1. (6R,7R,7aR)-6,7-Dihydroxy-tetrahydro-pyrrolo[1,2-
c]oxazol-3-one (10)
By subjecting alkenylamine 8 (40 mg, 0.26 mmol) to the general
procedure for the iodo-cyclisation–carbamate formation, carba-
mate 10 was isolated as an amorphous white powder (38.5 mg,
0.24 mmol, 93%). ½a D18
ꢄ
+20.1 (c 0.6, EtOH); IR (film) 3372, 2954,
2845, 1715, 1635, 1416, 1253, 1079, 955 cmꢃ1
;
1H NMR
(300 MHz, D2O) d 4.51 (t, J4,5a = J5a,5b = 9.2 Hz, 1H, H-5a) 4.38 (dd,
J4,5b = 2.9 Hz, J5a,5b = 9.2 Hz, 1H, H-5b), 4.27 (d, J1a,2 = 5.1 Hz, 1H,
H-2), 4.17 (dt, J4,5a = 9.2 Hz, J4,5b = J3,4 = 2.9 Hz, 1H, H-4), 3.90 (d,
J3,4 = 2.9 Hz, 1H, H-3), 3.67 (dd, J1a,2 = 5.1 Hz, J1a,1b = 12.5 Hz, 1H,
H-1a), 3.01 (d, J1a,1b = 12.5 Hz, 1H, H-1b); 13C NMR (75 MHz, D2O)
d 164.4 (C@O), 76.5 (C-2), 74.3 (C-3), 64.0 (C-5), 62.0 (C-4), 52.2
(C-1); HRMS-ESI m/z calcd for [C6H9O4N+Na]+: 182.0429, obsd:
182.0424.
4.4. General procedure for the synthesis of alkenylamines
To a solution of iodo-pyranoside (274 mg, 1 mmol) in a satu-
rated solution of NH4OAc in EtOH (20 mL) were added activated
Zn (327 mg, 5 mmol), reducing agent (NaCNBH3 or a-picoline bor-
ane, 3 mmol) and 30% aqueous NH3 (8 mL). The mixture was stir-
red at reflux for 18 h, cooled to room temperature, filtered to
remove excess zinc and concentrated under reduced pressure.
The residue was redissolved in H2O, loaded onto a Dowex H+ ion
exchange resin and washed several times with H2O to remove ex-
cess salt. The amine product was then eluted with 15–30% aqueous
NH3. The eluent was concentrated under reduced pressure then
converted to the HCl salt using 1 m HCl. If necessary, further
purification could be achieved using gradient flash chromatogra-
phy (DCM–EtOH–MeOH–30% aqueous NH3, 25:2:2:1?5:2:2:1,
v/v/v/v).
4.5.2. (6R,7S,7aR)-6,7-Dihydroxy-tetrahydro-pyrrolo[1,2-c]-
oxazol-3-one (15)
By subjecting alkenylamine 14 (6.5 mg, 55 lmol) to the general
procedure for the iodo-cyclisation–carbamate formation, carba-
mate 15 was isolated as an amorphous white powder (8.5 mg,
55
l
mol, 99%). ½a 2D0
ꢄ
ꢃ30.5 (c 0.1, EtOH); IR (film) 3332, 2977,
1717, 1474, 1411, 1250, 1130, 1068 cmꢃ1
;
1H NMR (300 MHz,
D2O) d 4.52 (m, 3H, H-2, H-5a and H-5b), 4.14 (ddd, J3,4 = 3.1 Hz,
J4,5a = 5.0 Hz, J4,5b = 7.9 Hz, 1H, H-4), 4.01 (dd, J3,4 = 3.1 Hz,
J2,3 = 3.3 Hz, 1H, H-3), 3.51 (dd, J1a,2 = 8.1 Hz, J1a,1b = 10.8 Hz, 1H,
H-1a), 3.15 (dd, J1b,2 = 7.9 Hz, J1a,1b = 10.8 Hz, 1H, H-1b); 13C NMR
(75 MHz, D2O) d 164.1 (C@O), 73.2 (C-2), 70.6 (C-3), 64.3 (C-5),
61.5 (C-4), 48.6 (C-1); HRMS-ESI m/z calcd for [C6H9O4N+Na]+:
182.0429, obsd: 182.0433.
4.4.1. (2R,3R)-1-Amino-pent-4-ene-2,3-diol hydrochloride (8)
By subjecting iodide 7 (274 mg, 1 mmol) to the general procedure
for the synthesis of alkenylamines, alkenylamine 8 was obtained as
the HCl salt (143 mg, 93 mmol, 93%). Rf = 0.61 (DCM–EtOH–MeOH–
30% aqueous NH3, 5:2:2:1, v/v/v/v); ½a D20
ꢄ
+50.6 (c 1.0, EtOH); IR (film)
3412, 3252, 3045, 1632, 1432, 1013 cmꢃ1; 1H NMR (300 MHz, D2O) d
5.74 (ddd, J3,4 = 5.3 Hz, J4,5-cis = 10.5 Hz, J4,5-trans = 17.3 Hz, 1H, H-4),
5.23 (d, J4,5-trans = 17.3 Hz, 1H, H-5-trans), 5.17 (d, J4,5-cis = 10.5 Hz,
1H, H-5-cis), 3.99 (t, J3,4 = J2,3 = 5.3 Hz, 1H, H-3), 3.70 (ddd,
J1a,2 = 2.8 Hz, J2,3 = 5.3 Hz, J1b,2 = 9.9 Hz, 1H, H-2), 3.03 (dd,
J1a,2 = 2.8 Hz, J1a,1b = 13.1 Hz, 1H, H-1a), 2.87 (dd, J1b,2 = 9.9 Hz,
J1a,1b = 13.1 Hz, 1H, H-1b); 13C NMR (75 MHz, D2O) d 135.4 (C-4),
118.2 (C-5), 73.7 (C-3), 69.7 (C-2), 41.5 (C-1); HRMS-ESI m/z calcd
for [C5H11O2N+H]+: 118.0868, obsd: 118.0869.
4.6. General procedure for the synthesis of 2-hydroxymethyl-
pyrrolidine-3,4-diols
To a solution of carbamate (159 mg, 1 mmol) in EtOH (5 mL)
was added NaOH (400 mg, 10 mmol). The solution was stirred at
reflux for 2 h then cooled and purified directly using Dowex (H+).
The product was eluted in 5–15% aqueous NH3 and the eluent con-
centrated under reduced pressure then converted to the HCl salt
using 1 M HCl.
4.4.2. (2R,3S)-1-Amino-pent-4-ene-2,3-diol hydrochloride (14)
By subjecting iodide 13 (50 mg, 0.18 mmol) to the general pro-
cedure for the synthesis of alkenylamines, alkenylamine 14 was
obtained as the HCl salt (25 mg, 0.16 mmol, 90%). Rf = 0.41
4.6.1. (2S,3R,4R)-2-Hydroxymethyl-pyrrolidine-3,4-diol (2)
By subjecting cyclic carbamate 10 (13 mg, 0.082 mmol) to the
general procedure for the synthesis of 2-hydroxymethyl-pyrroli-
dine-3,4-diols,
L-imino-xylitol 2 was isolated as the HCl salt
(DCM–EtOH–MeOH–30% aqueous NH3, 5:2:2:1, v/v/v/v);
ꢃ8.0 (c 0.1, EtOH); IR (film) 3345, 2946, 2835, 1651, 1450,
1018 cmꢃ1 1H NMR (500 MHz, D2O) d 5.88 (ddd, J3,4 = 6.6 Hz,
J4,5-cis = 10.5 Hz, J4,5-trans = 17.1 Hz, 1H, H-4), 5.35 (d, J4,5-trans
½
a 2D0
ꢄ
(13 mg, 0.077 mmol, 97%). Rf = 0.21 (DCM–EtOH–MeOH–30%
aqueous NH3, 5:2:2:1, v/v/v/v); ½a D20
ꢄ
+8.2 (c 0.5, H2O); IR (film)
3317, 2944, 2832, 1654, 1449, 1415, 1113, 1021 cmꢃ1
;
1H NMR
;
=
(300 MHz, D2O)
d 4.26 (d, J1a,2 = 4.5 Hz, 1H, H-2), 4.19 (d,
17.1 Hz, 1H, H-5-trans), 5.31 (d, J4,5-cis = 10.5 Hz, 1H, H-5-cis), 4.12
(dd, J2,3 = 5.6 Hz, J3,4 = 6.6 Hz, 1H, H-3), 3.81 (ddd, J1a,2 = 3.0 Hz,
J2,3 = 5.6 Hz, J1b,2 = 9.7 Hz, 1H, H-2), 3.23 (dd, J1a,2 = 3.0 Hz,
J1a,1b = 13.2 Hz, 1H, H-1a), 2.95 (dd, J1b,2 = 9.7 Hz, J1a,1b = 13.2 Hz,
1H, H-1b); 13C NMR (125 MHz, D2O) d 135.4 (C-4), 118.3 (C-5),
74.0 (C-3), 69.8 (C-2), 41.1 (C-1); HRMS-ESI m/z calcd for
[C5H11O2N+H]+: 118.0868, obsd: 118.0871.
J3,4 = 3.8 Hz, 1H, H-3), 3.89 (dd, J4,5a = 5.5 Hz, J5a,5b = 11.5 Hz, 1H,
H-5a), 3.77 (dd, J4,5b = 7.7 Hz, J5a,5b = 11.5 Hz, 1H, H-5b), 3.62
(ddd, J3,4 = 3.8 Hz, J4,5a = 5.5 Hz, J4,5b = 7.7 Hz, 1H, H-4), 3.46 (dd,
J1a,2 = 4.5 Hz, J1a,1b = 12.8 Hz, 1H, H-1a), 3.04 (d, J1a,1b = 12.8 Hz,
1H, H-1b); 13C NMR (75 MHz, D2O) d 74.6 (C-2), 74.5 (C-3), 62.5
(C-4), 57.6 (C-5), 50.4 (C-1); HRMS-ESI m/z calcd for
[C5H11O3N+H]+: 134.0817, obsd: 134.0817.

E. M. Dangerfield et al. / Carbohydrate Research 345 (2010) 1360–1365
1365
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4.6.2. (2R,3S,4R)-2-Hydroxymethyl-pyrrolidine-3,4-diol (4)
By subjecting cyclic carbamate 15 (3.0 mg, 19 mol) to the gen-
eral procedure for the synthesis of hydroxymethyl-pyrrolidine-3,4-
diols, -imino-lyxitol 4 was isolated as the HCl salt (3.1 mg,
18
l
D
l
mol, 97%). Rf = 0.89 (DCM–EtOH–MeOH–30% aqueous NH3,
5:2:2:1, v/v/v/v); ½a D20
ꢄ
+20.8 (c 0.1, H2O); IR (film) 3369, 3198,
2956, 2857, 1456, 1266, 1127, 1056 cmꢃ1
;
1H NMR (300 MHz,
D2O) d 4.47 (dt, J2,3 = 4.1 Hz, J1a,2 = J1b,2 = 7.4 Hz, 1H, H-2), 4.32 (t,
J2,3 = J3,4 = 4.2 Hz, 1H, H-3), 3.96 (dd, J4,5a = 5.0 Hz, J5a,5b = 12.1 Hz,
1H, H-5a), 3.86 (dd, J4,5b = 8.4 Hz, J5a,5b = 12.1 Hz, 1H, H-5b), 3.71
(ddd, J3,4 = 4.2 Hz, J4,5a = 5.0 Hz, J4,5b = 8.4 Hz, 1H, H-4), 3.50 (dd,
J1a,2 = 7.4 Hz, J1a,1b = 12.2 Hz, 1H, H-1a), 3.18 (dd, J1b,2 = 7.4 Hz,
J1a,1b = 12.2 Hz, 1H, H-1b); 13C NMR (75 MHz, D2O) d 69.9 (C-2),
69.7 (C-3), 62.4 (C-4), 57.6 (C-5), 46.9 (C-1); HRMS-ESI m/z calcd
for [C5H11O3N+H]+: 134.0817, obsd: 134.0813.
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Acknowledgements
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The authors would like to thank the Wellington Medical Re-
search Foundation for financial assistance, Industrial Research
Ltd. Capability Fund (S.A.G.), the Tertiary Education Commission
NZ (fellowship E.M.D.), Victoria University of Wellington (fellow-
ship C.H.P.), and the Curtis-Gordon Scholarship (fellowship C.H.P.).
Supplementary data
19. Skaanderup, P. R.; Poulsen, C. S.; Hyldtoft, L.; Jørgensen, M. R.; Madsen, R.
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Supplementary data (1H NMR and 13C NMR spectra) associated
with this article can be found, in the online version, at doi:10.1016/
j.carres.2010.03.016.
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