Enantioselective synthesis of hydroxylated pyrrolidines via Sharpless epoxidation and olefin metathesis

Article abstract of DOI:10.1016/j.tetasy.2006.12.023

The enantioselective synthesis of polyhydroxylated pyrrolidines from enantiomerically pure 2,3-epoxy-pent-4-en-1-ol 5 is described herein. The epoxy alcohol, readily available in any configuration by Sharpless epoxidation, was submitted to regioselective C-3 ring-opening with allyl amine, Boc-protection and ring-closing metathesis to yield dehydropyrrole derivative 7. From this key intermediate, 1,4-dideoxy-1,4-imino-d-ribitol (+)-3 and 1,4-dideoxy-1,4-imino-d-allitol (+)-4 were prepared in high yields. The enantiomers of these compounds can be obtained by the same sequence starting from an epoxy alcohol with the opposite configuration.

Full text of DOI:10.1016/j.tetasy.2006.12.023

Tetrahedron: Asymmetry 18 (2007) 149–154
Enantioselective synthesis of hydroxylated pyrrolidines
via Sharpless epoxidation and olefin metathesis
Caterina Murruzzu and Antoni Riera*
`
Unitat de Recerca en Sı´ntesi Asimetrica (URSA-PCB), Institute for Research in Biomedicine (IRB) and Departament de
Quı´mica Organica, Universitat de Barcelona, Parc Cientıfic de Barcelona, Josep Samitier, 1-5, Barcelona 08028, Spain
`
´
Received 18 December 2006; accepted 27 December 2006
Abstract—The enantioselective synthesis of polyhydroxylated pyrrolidines from enantiomerically pure 2,3-epoxy-pent-4-en-1-ol 5 is
described herein. The epoxy alcohol, readily available in any configuration by Sharpless epoxidation, was submitted to regioselective
C-3 ring-opening with allyl amine, Boc-protection and ring-closing metathesis to yield dehydropyrrole derivative 7. From this key inter-
mediate, 1,4-dideoxy-1,4-imino-D-ribitol (+)-3 and 1,4-dideoxy-1,4-imino-D-allitol (+)-4 were prepared in high yields. The enantiomers
of these compounds can be obtained by the same sequence starting from an epoxy alcohol with the opposite configuration.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
HO
OH
HO
HO
OH
HO
OH
H
OH
OH
Iminosugars, or azasugars, are compounds in which the
ring oxygen of a monosaccharide has been replaced by
an imino group. Many of these compounds and their de-
oxygenated derivatives are naturally occurring, including
several powerful and specific glycosidase inhibitors.1 The
bioactivity of these molecules has been attributed to their
ability to ‘mimic’ the oxocarbenium ion formed during
the hydrolysis of the carbohydrate–glycosidic bond, as
the heterocyclic nitrogen is positively charged at physiolog-
ical pH.2 As glycolysis is crucial to many biological pro-
cesses, several iminosugars and related compounds have
demonstrated activities against cancer, diabetes, and viral
infections.3 Although polyhydroxylated piperidines are
structurally more similar to monosaccharides than poly-
hydroxylated pyrrolidines, the latter are also surprisingly
active and selective glycosidase inhibitors.1 Some represen-
tative examples are found in Figure 1.
HO
OH
OH
OH
N
H
N
H
N
H
DMDP, 1
DDIA, (+)-4
DRB, (+)-3
HO
OH
OH
HO
OH
H
OH
OH
OH
N
H
N
H
N
H
DAB1, 2
LDIA, (-)-4
LRB, (-)-3
Figure 1. Glycosidase inhibitors with the polyhydroxylated pyrrolidine
structure.
trees (Morus alba), is also a potent inhibitor of glucosidase
and of eukaryotic DNA polymerases.6 Its enantiomer, 1,4-
dideoxy-1,4-imino-L-ribitol (ꢀ)-3, prepared for the first
time in 1987 from mannose,7j has since been prepared by
various syntheses and extensively studied.7 Lesser well
known are the corresponding dihydroxyethyl pyrrolidines.
The b-glucosidase inhibitor 1,4-dideoxy-1,4-imino-D-allitol
(+)-4 can be isolated from natural sources such as glyceral-
dehydes and D-gulonolactone.8 Its enantiomer (ꢀ)-4 is a
moderate inhibitor of human liver a-mannosidases, and
demonstrates other biological activities.9 The majority of
the various reported synthetic routes to these compounds
are based on the transformations of sugar derivatives.
2,5-Dideoxy-2,5-imino-D-mannitol 1 (DMDP), one of the
most widely occurring natural iminosugars, has been tho-
roughly studied.4 1,4-Dideoxy-1,4-imino-D-arabinitol 2
(DAB1), among the most important glycosidase inhibitors,
is a promising therapeutic candidate.5 1,4-Dideoxy-1,4-imi-
no-D-ribitol (+)-3 (DRB), which was found in mulberry
*
Corresponding author. Tel.: +34 93 4037093; fax: +34 93 4037095;
e-mail: ariera@pcb.ub.es
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.12.023

150
C. Murruzzu, A. Riera / Tetrahedron: Asymmetry 18 (2007) 149–154
diol 6 was ultimately obtained from epoxy alcohol 5 in a
65% overall yield (Scheme 1).
OH
HO
H
H
R
OH
N
Boc
N
H
OH
OH
H
N
7
NH2
Ti(OiPr)4, CH2Cl2
3, R = H,
O
4, R = CH2OH
OH
OH
OH
(-)-5
Boc
OH
65%
N
Boc2O,
O
(two steps)
THF, 70 ºC
OH
OH
(-)-5
H
Grubbs cat
CH2Cl2
Boc
N
OH
N
Boc
(-)-6
OH
OH
OH
Figure 2. Retrosynthetic analysis of polyhydroxylated pyrrolidines.
(-)-7
90%
(-)-6
Scheme 1.
Over the past few years, we have prepared several poly-
hydroxylated alkaloids (e.g., pyrrolines, piperidines, and
indolizines)10 starting from unsaturated epoxides, which
are readily obtained through Sharpless epoxidation,11 and
subsequent ring-closing metathesis (RCM).12,13 We envi-
sioned that our strategy could be extended to prepare poly-
hydroxylated pyrrolidines 3 and 4 in any enantiomeric
form starting from the proper enantiomer of unsaturated
epoxide 5. The retrosynthetic analysis of these compounds
is shown in Figure 2. The desired compounds would be
obtained from key intermediate 7 via side chain directed
stereoselective dihydroxylation of the double bond. Com-
pound 7 would in turn be synthesized by the RCM of ami-
no diol 6, the stereochemistry of which would be
conveniently set by a nucleophilic C-3 ring-opening of
enantiomerically enriched epoxide 5 using allyl amine.
Treatment of (ꢀ)-6 with first generation Grubbs’s cata-
lyst12 (5–10%) in CH2Cl2 at room temperature gave key
intermediate (ꢀ)-7 in an excellent yield. Much to our satis-
faction, dihydroxylation with catalytic OsO4 and NMO18
took place with a high diastereoselectivity anti to the
dihydroxyethyl chain (only one diastereomer was observed
1
by H NMR). Subsequent protection of the vicinal diols
with 2,2-dimethoxypropane afforded diastereomerically
pure (ꢀ)-9. This protection facilitated the purification
and characterization of the compound, which is highly
polar and water soluble. Hydrolysis with HCl/MeOH
cleanly afforded the hydrochloride of 1,4-dideoxy-1,4-
imino-D-allitol (+)-4ÆHCl in a 90% yield (Scheme 2).8
OH
HO
H
OsO4, NMO
acetone-H2O
H
2. Results and discussion
OH
OH
N
Boc
N
Boc
OH
OH
In line with our retrosynthetic analysis, we began the syn-
thesis of the polyhydroxypyrrolidines by preparing epoxy
alcohol 5. Although this epoxide can be obtained by classi-
cal Sharpless asymmetric epoxidation of 2,4-pentadienol,
we used the kinetic resolution methodology as developed
by Jagger et al.14 as it provides much higher enantiomeric
excess. Sharpless epoxidation of the readily available
bis-allylic alcohol 1,4-pentadien-3-ol followed by Payne
rearrangement15 afforded epoxy alcohol 5 in the desired
configuration with >99% ee.
84%
8
(-)-7
O
O
80%
O
acetone
OH
HO
Cl-
O
H
H
HCl/MeOH
OH
N
H H
O
N
Boc
(-)-9
Subsequent regioselective and regiospecific ring-opening of
5 with allyl amine, followed by Boc protection, gave amino
diol 6. This reaction sequence required some development.
Crotti’s conditions16 using a large excess of reagents
(15 equiv of LiClO4, and 10 equiv of allyl amine) at 60 ꢁC
gave the desired product in moderate yields as a mixture
of regioisomers. Sharpless17 conditions (2 mol of allyl-
amine, 1 mol of Ti(OiPr)4 and room temperature) provided
the corresponding amino diol with a total selectivity. Boc
protection of the amine however was not straightforward;
standard treatment with Boc2O and base afforded com-
pound 6 only in low yields. The best results were obtained
using Boc2O in THF at 70 ꢁC without any base. Amino
OH
O
90%
.
(+)-4 HCl
Scheme 2.
Our second synthetic target from intermediate (ꢀ)-7 was
1,4-dideoxy-1,4-imino-D-ribitol (+)-3. Our first approach
started with the synthesis of alcohol 10. The oxidation of
diol (ꢀ)-7 with sodium periodate, followed by the reduc-
tion of the resulting aldehyde with DIBALH or LiBH4,
afforded alcohol (ꢀ)-10 (Scheme 3). Since the transforma-
tion of 10 (although in racemic form) into DAB1 2 has

C. Murruzzu, A. Riera / Tetrahedron: Asymmetry 18 (2007) 149–154
151
3. Conclusion
1) NaIO ,
THF-H2O
4
CH2OH
OH
N
Boc
N
Boc
LiBH , MeOH-Et O
2)
4
2
In conclusion, we have developed a novel synthetic route
for the preparation of polyhydroxy pyrrolidines 3 and 4
starting from the enantiomerically enriched unsaturated
epoxy alcohol 5. Since the alcohol can be prepared in any
configuration by asymmetric Sharpless epoxidation, both
enantiomers of 3 and 4 are equally accessible.
OH
(-)-7
(-)-10
30%
O
OH
O
HO
OsO4 cat
DMP
acetone
CH2OH
CH2OH
N
N
NMO
acetone-H2O
4. Experimental
Boc
Boc
11
(-)-12
4.1. General methods
Scheme 3.
Optical rotations were measured at room temperature
(23 ꢁC) and concentrations were measured in g/100 mL.
Infrared spectra were recorded using NaCl film. 1H
NMR Spectra were obtained at 400 MHz with tetramethyl-
silane as the internal standard. 13C NMR Spectra were
obtained at 100 MHz. Signal multiplicities were assigned
by DEPT experiments. Chromatographic separations were
carried out using SiO2 (70–230 mesh) pre-treated with NEt3
(2.5% v/v), and hexanes/ethyl acetate mixtures as the
eluent. Compound 5 was prepared according to known
procedures.14
described in the literature,7e the present approach constitutes
a formal synthesis of enantiomerically enriched DAB1.
Dihydroxylation with catalytic OsO4 afforded compound
11 with a diastereomeric ratio of 10:1 (82%). Subsequent
protection with 2,2-dimethoxypropane gave the diastereo-
merically pure (ꢀ)-12 in a 95% yield. This compound19 is
a protected form of 1,4-dideoxy-1,4-imino-D-ribitol (+)-3
and has previously been used in the synthesis of trans-
2,3-cis-3,4-dihydroxyproline20 and epi-swainsonine.21
In order to further improve the diastereomeric ratio of the
dihydroxylation, we thought of protecting the alkoxy func-
tionality of 10 with a bulky group, which would favor the
approach of the osmium oxide toward the opposite side of
the molecule. Thus, we protected compound 10 with a tert-
butyl diphenylsilyl group in order to give compound 13 in
an excellent yield (Scheme 4). As expected, dihydroxylation
with OsO4 gave diol 14 in a very high diastereomeric ratio
(again, only one diastereomer observed by 1H NMR).
Protection with 2,2-dimethoxypropane to give acetal 15
facilitated the purification. Finally, hydrolysis of both
protecting groups with HCl/MeOH yielded hydrochloride
(+)-3 in an 80% yield.
4.2. (2S,3S)-3-(N-Allyl-N-tert-butoxycarbonyl)-4-penten-
1,2-diol (ꢀ)-6
To a solution of epoxide (ꢀ)-5 (2.3 g, 23 mmol) in CH2Cl2
(100 mL) were added allyl amine (6.9 mL, 92 mmol) and
titanium isopropoxide (13.7 mL, 46 mmol). The reaction
was monitored by TLC. After 48 h, 10 mL of 10% NaOH
was added, and stirring was maintained for 24 h. The sus-
pension was filtered, and the aqueous phase extracted with
CH2Cl2 (3 · 20 mL). The organic phases were dried over
MgSO4. The solvent was evaporated, and the resulting res-
idue dissolved in THF (50 mL). Boc2O (5.52 g, 25.3 mmol)
was then added, and the mixture was heated at 70 ꢁC for
15 h. Evaporation of the solvent followed by chromato-
graphic purification yielded 3.8 g of (ꢀ)-6 (65%) as a yellow
oil. [a]D = ꢀ22.6 (c 1.0, CHCl3). IR (film, mmax) 3419, 1669,
1559, 1456, 1368 cmꢀ1. 1H NMR (400 MHz, CDCl3) d 6.04
(m, 1H), 5.78 (m, 1H), 5.23 (m, 2H), 5.12 (m, 2H), 4.19 (br
s, 1H), 3.79 (m, 2H), 3.59 (s, 2H), 3.20 (s, 1H), 3.05 (br s,
1H), 2.79 (br s, 1H), 1.46 (s, 9H) ppm. 13C NMR
(100 MHz, CDCl3) d 157.5 (CO), 134.8 (CH), 134.4
(CH), 119.8 (CH2), 117.2 (CH2), 81.2 (C), 72.5 (CH),
63.4 (CH2), 61.0 (CH), 49.9 (CH2), 25.5 (CH3) ppm. MS
(EI) m/z: 202.2 [(Mꢀ55), 100%], 258.1 [(M+H)+, 64%].
HRMS (m/z): calcd for C13H24NO4, 258.1708. Found:
258.1705.
TBDPSiCl,
CH2OH
CH2OTBDPS
N
Boc
N
Boc
imidazole, DMF
94%
(-)-10
(-)-13
OH
HO
O
O
OsO4, NMO
acetone,H2O
CH2OTBDPS
acetone
85%
N
Boc
80%
14
4.3. (2S)-N-tert-Butoxycarbonyl-2-[(10S)-10,20-dihydroxy-
ethyl]-2,5-dihydropyrrole (ꢀ)-7
OH
HO
Cl-
O
O
HCl
To a stirred solution of (ꢀ)-6 (0.53 g, 2.06 mmol) in
CH2Cl2 (150 mL) was added a solution of Grubbs’s cata-
lyst (0.21 g, 0.17 mmol) in CH2Cl2 (100 mL). The solution
was heated at 40 ꢁC for 4 h. Evaporation of the solvent fol-
lowed by chromatographic purification yielded 0.42 g of
(ꢀ)-7 (90% yield) as a brown oil. [a]D = ꢀ108.1 (c 0.97,
CH2OH
N
CH2OTBDPS
N
H
H
MeOH
Boc
.
(+)-3 HCl
80%
(-)-15
Scheme 4.

152
C. Murruzzu, A. Riera / Tetrahedron: Asymmetry 18 (2007) 149–154
CHCl3). IR (film, mmax) 3855, 1696, 1676, 1456, 1368 cmꢀ1
.
4.6. (2S)-N-tert-Butoxycarbonyl-2-hydroxymethyl-2,5-di-
hydro-1H-pyrrole (ꢀ)-10
1H NMR (400 MHz, CDCl3) d 5.83 (m, 1H), 4.74 (m, 1H),
4.32 (s, 1H), 4.20 (d, J = 7.8 Hz, 1H), 4.01 (dd, J = 2.3,
5.6 Hz, 1H), 3.76 (m, 1H), 3.59 (m, 2H), 3.10 (s, 1H),
2.09 (s, 1H), 1.48 (s, 9H) ppm. 13C NMR (100 MHz,
CDCl3) d 156.9 (CO), 128.3 (CH), 126.6 (CH), 81.2 (C),
75.1 (CH), 67.3 (CH2), 63.2 (CH), 54.7 (CH2), 28.6
(CH3). ppm. MS (EI) m/z: 112.1 [(Mꢀ117), 100%]. HRMS
calcd for C11H19NO4: 229.1315. Found: 229.1314.
To a solution of aminodiol (ꢀ)-7 (0.13 g, 0.57 mmol) in
THF (1 mL) and H2O (3 mL) was added NaIO4 (0.18 g,
0.85 mmol). The mixture was stirred until no starting mate-
rial was observed by TLC (ca. 2 h). H2O (10 mL) was then
added, and the aqueous phase extracted with CH2Cl2
(3 · 5 mL). The organic layers were dried over MgSO4
and dried by evaporation. The crude was dissolved in a
mixture of MeOH (1 mL) and Et2O (10 mL). To this solu-
tion was added LiBH4 (0.02 g, 0.85 mmol). The mixture
was stirred for 4 h and monitored by TLC. HCl (3 M,
2 mL) was added, and the mixture washed with Et2O
(3 · 5 mL). The aqueous layer was basified with saturated
aq NaHCO3 (5 mL) and extracted with EtOAc
(3 · 5 mL). The organic phases were dried over MgSO4,
and the solvent was evaporated. Chromatographic purifi-
cation of the crude yielded 0.04 g of (ꢀ)-10 (30% yield) as
4.4. 1,4-Dideoxy-1,4-imino-D-allitol bis-isopropylidene
acetal (ꢀ)-9
To a solution of (ꢀ)-7 (0.05 g, 0.21 mmol) and NMO
monohydrate (0.065 g, 0.48 mmol) in acetone (6 mL) and
H2O (0.6 mL) was added a 0.05 M solution of OsO4 in
tBuOH (0.22 mL, 0.017 mmol). After 48 h of stirring at
room temperature, Na2S2O3 (0.14 g, 0.88 mmol) was
added, and the mixture was allowed to continue stirring.
After 2 h, MgSO4 was added, the suspension was filtered
over Celite, and the solvent was evaporated to yield 8
(0.05 g, 0.02 mmol). The resulting crude was dissolved in
acetone (5 mL) and 2,2-dimethoxypropane (8 lL,
0.06 mmol), and a catalytic amount of p-toluenesulfonic
acid was added. The mixture was stirred at room tempera-
ture for 4 h, and monitored by TLC. CH2Cl2 (5 mL) was
then added, and the solution then washed with saturated
aq NaHCO3 (3 · 5 mL). The organic layer was dried over
MgSO4, and the solvent was evaporated. Chromatographic
purification of the crude yielded 0.035 g of (ꢀ)-9 (80%
yield) as a yellow oil. [a]D = ꢀ58.5 (c 1.0, CHCl3). IR (film,
a yellow oil. [a]D = ꢀ124.6 (c 1.0, CHCl3). IR (film, mmax
)
1
3416, 1697, 1407, 1367, 1173 cmꢀ1. H NMR (400 MHz,
CDCl3) d 5.81 (dd, J = 1.6, 6.4 Hz, 1H), 5.63 (dd, J = 2,
6.4 Hz, 1H), 4.73 (s, 1H), 4.08 (m, 2H), 3.76 (d,
J = 10.4 Hz, 1H), 3.56 (dd, J = 7.6, 11.6 Hz, 1H), 1.58 (s,
1H), 1.49 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3) d
156.8 (CO), 127.0 (CH), 126.9 (CH), 80.8 (C), 67.9
(CH2), 67.5 (CH), 54.4 (CH2), 28.7 (CH3) ppm. MS (CI–
NH3) m/z: 200.1 [(M+H)+, 95%], 144.0 [(Mꢀ56), 100%].
HRMS calcd for C10H18NO3: 200.1286. Found: 200.1283.
4.7. (2R,3R,4S)-N-tert-Butoxycarbonyl-2-hydroxymethyl-
3,4-isopropylidendioxy-pyrrolidine (ꢀ)-12
m
max) 2983, 1697, 1405, 1369, 1160 cmꢀ1 1H NMR
.
(400 MHz, CDCl3) d 4.71 (m, 2H), 4.35 (m, 1H), 4.11 (m,
2H), 3.86 (m, 2H), 3.42 (ddd, J = 4, 12.8, 34 Hz, 1H),
1.46 (s, 6H), 1.43 (s, 6H), 1.31 (s, 9H) ppm. 13C NMR
(100 MHz, CDCl3) d 154.5 (CO), 111.8 (C), 110.1 (C),
81.5 (CH), 80.5 (CH), 80.22 (CH), 79.5 (CH), 75.6 (C),
66.7 (CH), 53.3 (CH2), 28.6 (CH3), 27.1 (CH3), 26.7
(CH3) ppm. MS (CI–NH3) m/z: 344.0 [(M+H)+, 61%],
288.1 [(Mꢀ56), 100%]. Anal. Calcd for C17H29NO6: C,
59.46; H, 8.51; N, 4.08. Found: C, 59.47; H, 8.68; N, 4.02.
To a solution of (ꢀ)-10 (0.5 g, 0.25 mmol) and NMO
monohydrate (0.07 g, 0.55 mmol) in acetone (9 mL) and
H2O (1 mL) was added 0.4 mL of a 0.05 M solution of
OsO4 in tBuOH (0.02 mmol). The mixture was stirred until
no starting material was observed by TLC (ca. 24 h).
Na2S2O3 (0.05 g, 0.3 mmol) was added and, after 2 h,
MgSO4 was also added. The suspension was filtered over
Celite and the solvent was removed at reduced pressure.
The crude (0.05 g, 82% yield) showed a 10:1 diastereomeric
1
ratio of triol 11 by H NMR and 13C NMR. This crude
4.5. 1,4-Dideoxy-1,4-imino-D-allitol hydrochloride (+)-4
(0.05 g) was dissolved in acetone (5 mL) and 2,2-dimeth-
oxypropane (0.07 mL, 0.54 mmol), and a catalytic amount
of p-toluenesulfonic acid was added to the solution. The
mixture was stirred until no starting material was observed
by TLC (ca. 4 h). CH2Cl2(5 mL) was then added, and the
organic layer washed with saturated aq NaHCO3
(3 · 5 mL). The organic phase was dried over MgSO4,
and the solvent was evaporated. Chromatography of the
crude afforded 0.06 g of diastereomerically pure (ꢀ)-12
(95% yield) as a colorless oil. [a]D = ꢀ30.3 (c 0.3, CHCl3).
A solution of (ꢀ)-9 (0.1 g, 0.03 mmol) in HCl/MeOH
(2 mL) was stirred at room temperature until no starting
material was observed by TLC (ca. 5 h). The solvent was
removed and the crude triturated with Et2O (3 · 3 mL) to
yield 0.06 g of (+)-4 (95% yield) as a white solid.
Mp = 110–111 ꢁC. [a]D = +28.4 (0.6, H2O). (Lit8e
1
[a]D = +29.4 (c 0.56, H2O)). H NMR (400 MHz, D2O) d
4.29 (dd, J = 4.4, 12.4 Hz, 1H), 4.25 (dd, J = 2.4, 4.6 Hz,
1H), 4.01 (dd, J = 3.6, 5 Hz, 1H), 3.61 (d, J = 4 Hz, 2H),
3.55 (dd, J = 3.2, 8 Hz, 1H), 3.33 (dd, J = 3.6, 12.8 Hz,
1H), 3.24 (dd, J = 1.6, 12.8 Hz, 1H) ppm. 13C NMR
(100 MHz, D2O) d 70.3 (CH), 69.9 (CH), 68.6 (CH), 62.5
(CH2), 61.9 (CH), 50.1 (CH2) ppm. MS (CI–NH3) m/z:
164.0 [(Mꢀ35), 100%]. HRMS calcd for C7H14NO4:
164.0922. Found: 164.0919.
IR (film, mmax) 3448, 2990, 2927, 1697, 1410 cmꢀ1 1H
.
NMR (400 MHz, CHCl3) d 4.27 (m, 2H), 3.76 (m, 3H),
3.51 (m, 2H), 1.46 (s, 9H), 1.25 (s, 6H) ppm. 13C NMR
(100 MHz, CHCl3) d 158.0 (CO), 111.9 (C), 82.0 (CH),
80.4 (C), 79.1 (CH), 65.2 (CH2), 63.7 (CH), 57.2 (CH2),
27.1 (CH3), 21.5 (CH3) ppm. MS (CI–NH3) m/z: 438
[(Mꢀ56), 100%].

C. Murruzzu, A. Riera / Tetrahedron: Asymmetry 18 (2007) 149–154
153
4.8. (2R)-N-tert-Butoxycarbonyl-2-tert-butyldiphenylsilyl-
oxymethyl-2,5-dihydro-1H-pyrrole (ꢀ)-13
[a]D = ꢀ36.1 (c 1.05, CHCl3). IR (film) mmax 1696, 1403,
1175, 1112, 1055 cmꢀ1 1H NMR (400 MHz, CHCl3) d
.
7.63 (m, 5H), 7.41 (m, 5H), 4.78 (m, 2H), 4.12 (m, 2H),
4.03 (m, 1H), 3.68 (m, 2H), 1.49 (s, 6H), 1.37 (s, 9H),
1.05 (s, 9H) ppm. 13C NMR (100 MHz, CHCl3) d 154.2
(CO), 135.8 (CH), 132.9 (CH), 130.2 (CH), 130.0 (CH),
128.2 (CH), 128.1 (CH), 111.6 (C), 83.5 (CH), 82.9 (CH),
79.9 (CH2), 64.8 (CH), 54.4 (CH2), 28.7 (CH3), 27.3
(CH3), 25.3 (CH3), 19.3 (C) ppm. MS (CI–NH3) m/z:
512.5 [(M+H)+, 100%], 455.7 [(Mꢀ56), 93%]. Anal. Calcd
for C29H41NO5Si: C, 68.00; H, 8.27; N, 2.78. Found: C,
68.07; H, 8.08; N, 2.74.
To a solution of (ꢀ)-10 (0.25 g, 1.18 mmol) and imidazole
(0.2 g, 2.95 mmol) in DMF (10 mL) was added tert-butyl-
chlorodiphenylsilane (0.37 mL, 0.39 mmol). The mixture
was stirred until no starting material was observed by
TLC (ca. 24 h). Water (10 mL) was added, and the mixture
was extracted with Et2O (3 · 5 mL). The organic solution
was dried over MgSO4, the solvent was evaporated, and
the crude was chromatographed to yield 0.5 g of (ꢀ)-13
(94% yield) as a colorless oil. [a]D = ꢀ24.6 (1, CHCl3). IR
1
(film, mmax) 2924, 2831, 1701, 1455, 1113 cmꢀ1. H NMR
(400 MHz, CHCl3) d 7.71 (m, 5H), 7.41 (m, 5H), 5.88 (m,
2H), 4.22 (m, 1H), 4.03 (ddd, J = 4.8, 5.6, 19.9 Hz, 2H),
3.83 (ddd, J = 2.8, 8.0, 26.3 Hz, 1H), 3.67 (dd, J = 6.8,
9.2 Hz, 1H), 1.47 (s, 9H), 1.02 (s, 9H) ppm. 13C NMR
(100 MHz, CHCl3) d 154.1 (CO), 135.5 (CH), 134.7 (CH),
133.5 (CH), 129.5 (CH), 128.6 (CH), 127.6 (CH), 126.2
(CH), 79.4 (C), 65.5 (CH2), 63.6 (CH), 54.2 (CH2), 28.5
(CH3), 26.7 (CH3), 19.3 (C) ppm. MS (CI–NH3) m/z:
438.2 [(M+H)+, 100%], 338.1 [(Mꢀ99), 40%]. HRMS calcd
for C26H36NO3Si: 438.2464. Found: 438.2463.
4.11. 1,4-Dideoxy-1,4-imino-D-ribitol hydrochloride (+)-3
A solution of (ꢀ)-15 (0.085 g, 0.16 mmol) in HCl/MeOH
(3 mL) was stirred at room temperature until no starting
material was observed by TLC (ca. 5 h). The solvent was
removed, and the crude triturated with Et2O (3 · 3 mL)
to yield 0.025 g of (+)-3 (80% yield) as a white solid. Mp
129–130 ꢁC. [a]D = +53.9 (c 1.0, H2O). IR (film, mmax
)
1
3404, 1617, 1406, 1139, 1041 cmꢀ1. H NMR (400 MHz,
CD3OD, d) 4.26 (ddd, J = 2, 3.9, 4 Hz, 1H), 4.13 (dd,
J = 3.6, 8 Hz, 1H), 3.92 (dd, J = 3.2, 12.3 Hz, 1H), 3.76
(dd, J = 5.6, 12 Hz, 1H), 3.56 (m, 1H), 3.40 (dd, J = 4,
12.4 Hz, 1H), 3.30 (m, 1H), 3.26 (dd, J = 1.8, 13 Hz, 1H)
ppm. 13C NMR (100 MHz, CD3OD, d) 71.8 (CH), 69.9
(CH), 62.8 (CH), 58.3 (CH2), 49.9 (CH2) ppm. MS (CI–
NH3) m/z: 134.1 [(Mꢀ35), 100%]. Anal. Calcd for
C5H12NO3Cl: C, 35.41; H, 7.13; N, 8.26. Found: C,
35.30; H, 6.86; N, 7.89.
4.9. (2R,3R,4S)-N-tert-Butoxycarbonyl-2-tert-butyldi-
phenylsilyloxymethyl-3,4-dihydroxypyrrolidine (ꢀ)-14
To a solution of (ꢀ)-13 (0.5 g, 1.11 mmol) and NMO
monohydrate (0.33 g, 2.44 mmol) in acetone (20 mL) and
H2O (2 mL) was added 1.78 mL of a 0.05 M solution of
OsO4 in tBuOH (0.09 mmol). The mixture was stirred until
no starting material was observed by TLC (ca. 48 h).
Na2S2O3 (1.0 g, 6.3 mmol) was then added and, after 2 h,
MgSO4 was also added. The suspension was filtered over
Celite, and the solvent was evaporated. The crude was
chromatographed to afford 0.42 g of diastereomerically
pure (ꢀ)-14 (80% yield) as a colorless oil. [a]D = ꢀ15.1 (c
1.0, CHCl31). IR (film) mmax 3396, 2930, 2857, 1696,
1426 cmꢀ1. H NMR (400 MHz, CHCl3) d 7.64 (m, 5H),
7.39 (m, 5H), 4.39 (m, 2H), 3.89 (m, 3H), 3.72 (d,
J = 3.6 Hz, 1H), 3.56 (d, J = 4.8 Hz, 1H), 2.78 (br s, 2H),
1.45 (s, 9H), 1.05 (s, 9H) ppm. 13C NMR (100 MHz,
CHCl3) d 154.9 (CO), 139.3 (CH), 135.7 (CH), 134.5
(CH), 134.3 (CH), 130.1 (CH), 128.1 (CH), 80.3 (C), 80.1
(CH), 74.9 (CH), 69.9 (CH2), 63.7 (CH), 51.5 (CH2), 28.5
(CH3), 26.7 (CH3), 19.3 (C) ppm. MS (EI) m/z: 473.1
[(M+H)+, 100%], 416.9 [(Mꢀ56), 60%]. HRMS calcd for
C26H38NO5Si: 472.2519. Found: 472.2522.
Acknowledgments
Financial support from MEC (CTQ2005-000623) is grate-
fully acknowledged. C.M. thanks DURSI (Generalitat de
Catalunya) for a fellowship.
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