Stereoselective synthesis of (2S,3S,4R,5S)-3,4-dihydroxy-2,5- dihydroxymethyl pyrrolidine from l-sorbose

Article abstract of DOI:10.1016/j.carres.2013.03.017

One of the most frequently synthesized iminosugar derivatives is DMDP. Starting from l-sorbose, a practical method for the synthesis of derivatives of this five-membered iminocyclitol has been developed, involving straightforward steps and a convenient selective reduction of a ketoxime intermediate.

Full text of DOI:10.1016/j.carres.2013.03.017

Carbohydrate Research 374 (2013) 14–22
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Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Stereoselective synthesis of (2S,3S,4R,5S)-3,4-dihydroxy-
2,5-dihydroxymethyl pyrrolidine from L-sorbose
Sébastien Balieu a, Arnaud Guilleret b, Romain Reynaud b, Agathe Martinez a,b, Arnaud Haudrechy a,
⇑
a Institut de Chimie Moléculaire de Reims, UMR CNRS 7312, Université de Reims, BP 1039, F-51687 REIMS Cedex, France
b Soliance SA, Route de Bazancourt, 51100 Pomacle, France
a r t i c l e i n f o
a b s t r a c t
Article history:
One of the most frequently synthesized iminosugar derivatives is DMDP. Starting from L-sorbose, a
Received 25 December 2012
Received in revised form 5 March 2013
Available online 29 March 2013
practical method for the synthesis of derivatives of this five-membered iminocyclitol has been developed,
involving straightforward steps and a convenient selective reduction of a ketoxime intermediate.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
L-Sorbose
Selective reduction
Ketoxime
Rare sugar
Iminosugar
H
N
HOH2C
CH2OH
1. Introduction
2,5-Dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP, 1,
Fig. 1), is a secondary metabolite first isolated from Derris elliptica1
which has since then been found in diverse microorganisms and
plant species, together with its unnatural analogues. These com-
pounds have been known to show interesting biological activities
(glycosidase inhibitors, antiviral and anticancer therapeutic drugs,
immunomodulators).2
Such a scope of useful activities makes this an interesting target
for synthetic chemists and many syntheses of DMDP 1 have been de-
scribed, most of them starting from diverse carbohydrates,3 such as
HO
OH
Figure 1. 2,5-Dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP 1).
OR
N
H
N
BnOH2C
CH2OPMB
R"OH2C
CH2OR'
BnO
OBn
HO
OH
L
-sorbose,3a
under catalytic conditions,
key step,3b,c or a SN2-type cyclisation,3f,q
mercury cyclisation,3e use of a nitrone with an hydride reduction,3n
or a nucleophilic addition,3o
-mannitol with a ring contraction on a
mesylate,3g,h or less usual derivatives like -xylose3i,m and
-pyroglutamic acid,4
D D
-glucose,3d or -fructose,3j,k,l involving hydrogenation
2
3
D-glucose with an epoxide opening as
D
-arabinose through a
Scheme 1. Selectively protected DMDP derivative 2 and possible transformations.
D
be useful,3m we decided to develop a strategy starting from
-sorbose, with compound 2 as a key intermediate (Scheme 1). It
should be noted, however, that if -sorbose has been a cheap start-
ing material because of its availability in the synthesis of vitamin C,
this source is no longer easily accessible.8 Other sources are now
available such as the technology of Izumoring.9 Our partner
L
-glucose3p using SN2-type cyclisations,
L
L
L
following an enzymatic5 or asymmetric approaches.6
L
Interestingly, the first synthetic effort towards DMDP3a was
greatly influenced by the preliminary study of Cheng,3o and in-
volved L-sorbose as the starting material. In our opinion, this com-
Soliance,
amount of
a
French cosmetic company produces
a significant
pound has been highly neglected in the context of total synthesis of
natural products.7 This efficient approach was only applied to
DMDP, and as a library of O-alkylated DMDP analogues might also
L-sorbose on a multi-ton scale as a side-product during
industrial dihydroxyacetone preparation by regio-controlled dehy-
drogenation of
D
-sorbitol using Gluconobacter oxydans.10
Selective hydride-type reductions of diverse nitrones have been
studied (Table 1).3n Interestingly, Cheng and collaborators have
⇑
Corresponding author. Tel.: +33 (0)3 2691 3236; fax: +33 (0)3 2691 3166.
E-mail address: arnaud.haudrechy@univ-reims.fr (A. Haudrechy).
0008-6215/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2013.03.017

S. Balieu et al. / Carbohydrate Research 374 (2013) 14–22
15
Table 1
Selective hydride-type reductions of nitrones
O-
OH
+
N
N
R1
R2
Reduction conditions
R1
R2
BnO
OBn
BnO
OBn
Entry
R1
R2
Reduction conditions
Yield (%)
a:b
1
2
3
4
5
BnOCH2
BnOCH2
BnOCH2
BnOCH2
Ph
CH2OBn
CH2OBn
CN
Ph
CH2OBn
NaBH4
L-Selectride
NaBH4
DIBAH—80 °C
L-Selectride
100
100
100
100
96
43:57
5:95
>3:97
>4:96
>3:97
OR
N
OR
OMs
N
BnOH2C
CH2OPMB
BnOH2C
CH2OPMB
BnO
OBn
BnO
OBn
2
4
O
OH
OH
O
O
O
L-sorbose
O
BnO
O
BnO
OBn
OBn
6
5
Scheme 2. Retrosynthetic approach to DMDP derivatives 2.
also studied the reduction of related imines under hydride
conditions.3o
Starting from the observation that these hydride-reductions
gave DMDP derivatives only as very minor diastereoisomers, we
decided to study conveniently functionalised open chain deriva-
yield (Scheme 3). It is important to note that no silica gel chroma-
tography was necessary at this point and a simple filtration allow
to eliminate the remaining starting material and tin salts.
Initially, we had planned to selectively deprotect the 4,6 posi-
tion, in order to benzylate the three free hydroxyl functions, but
the overall yield of this approach was very low, probably due to
solubility problems of intermediates. An additional step was added
to the synthesis and this decision proved to be very efficient.
Monobenzylation in position 3, giving 6 followed by a clean isopro-
pylidene deprotection gave 8 in 68% yield (interestingly, in this
step, it is easy to incorporate another benzyl-type substituent to
individualise this position).15 Then, a clean dibenzylation of the
tives of L-sorbose, following the retrosynthetic Scheme 2, expecting
that the diastereoselective reductions of ketoximes 4 would be eas-
ier, compared to benzylimines, because of their higher stability and
easy purification.
Interestingly, oxime cyclisations with a leaving group to obtain
nitrone derivatives related to our target11 have only been described
with aldehyde derived oximes. Several interesting silyloximes
proved to be efficient, with a TBDMS12 or a TBDPS13 protecting
group, and we wondered if we could apply this concept to bulkier
ketone-derived oximes.
O
O
O
O
AcOH
O
NaH / THF
O
O
HO
2. Results and discussion
7
H2O
68%
BnBr
94%
O
HO
OBn
OBn
Our synthesis started with the kinetic diprotection in the 1,2
6
8
and 4,6 positions of L-sorbose with acetonide moieties using a pre-
viously described procedure14 to give the compound 7 with a 61%
BnBr
94%
NaH / THF
OH
OH
OBn
O
O
O
O
O
Me2C(OMe)2
AcOH
O
O
BnO
BnO
BnO
O
L-Sorbose
SnCl2 (catalytic)
DME
H2O 50°C
78%
BnO
OBn
O
OH
7
5
9
Scheme 3. Kinetic diprotection of
L
-sorbose.
Scheme 4. Formation of the hemiketal 5 in the L-sorbose series.

16
S. Balieu et al. / Carbohydrate Research 374 (2013) 14–22
OTBDPS
CH2OH
OMe
OH
N
OH
N
MeONH2; HCl
BnOH2C
TBDPSONH2
BnOH2C
CH2OH
5
AcOK MeOH
88%
PPTS Toluene
MgSO4
BnO
OBn
BnO
OBn
Reflux
70%
10b
10a
Scheme 5. Formation of ketoximes 10a and 10b.
OR
OR
OH
N
MsO
N
MsCl
NaH THF
BnOH2C
BnOH2C
CH2OPMB
CH2OPMB
10a,b
Et3N
CH2Cl2
PMBBr
71% (R = Me)
BnO
OBn
BnO
OBn
11a,b
66% (R = TBDPS)
4a,b
62% (R = Me)
Et2O
LiAlH4
60% (R = TBDPS)
OR
N
BnOH2C
CH2OPMB
BnO
OBn
2a,b
Scheme 6. Formation of cyclised structures 2a and 2b.
free hydroxyl functions, followed by acid treatment gave the key
hemiketal 5 (Scheme 4).
resulting ketoxime mixture 4a (R = Me) or 4b (R = TBDPS) was re-
duced with lithium aluminum hydride, nicely giving the targeted
In order to introduce the nitrogen on the future skeleton of the
pyrrolidine, we decided to study the selective reduction of ketoxi-
mes. Protected hydroxylamines were synthesized in high yield,
giving the expected ketoximes 10a and 10b in a ratio 2/1 in favor
of the E-isomers (Scheme 5).
pyrrolidine 2a (R = Me), with an
(R = TBDPS), with a complete diastereoselectivity for the
a
:b ratio of 4.6:1 and 2b
a
config-
uration (Scheme 6). After several attempts to improve the reduc-
tion selectivity of 2a, we were unable to find a better result
(NaBH4 in MeOH; Zn(BH4)2 in Et2O; R-CBS/BH3ꢀTHF in THF). Note-
worthy, the NMR data observed for 2b, even after NOE experiments
and high field NMR experiments, were not sufficiently convincing
and the configuration was established after the final step by com-
parison of the DMDP with data described in the literature.
After a selective protection with a PMB group in position 1, giv-
ing 11a and 11b in correct yield and mesylation in position 5, the
This final ratio can be explained by considering the different
chelation of the diastereoisomeric ketoximes, the E-ketoxime giv-
ing predominantly a reduction resulting in a-pyrrolidine 2, the Z-
OMe
MeO
N
N
BnO
OPMB
RO
OPMB
ketoxime being presumably unselective (Scheme 7). We think that
in the case of 4b, because of the steric hindrance, the chelated Z
isomer is largely unfavored.
It would have been very interesting to individually reduce pure
E- and Z-oximes, however even if their separation was possible by
HPLC on a small scale, we were surprised to observe their rapid
interconversion when dissolved in a usual organic solvent. This
point was checked by NMR measurements.
R'
R'
E-4
Z-4
E : Z = 2 : 1
OMe
MeO
M
M
N
N
In the a series, despite the fact that several methods have been
described in the literature for such a clivage,12b,13a,d,f,16 all attempts
were unsuccessful to deprotect the OMe part (H2/Pd on C in AcOH
or in AcOH with 1.2 M HCl; H2, Raney Nickel in MeOH; Zn in wet
AcOH). Compound 2b however could be deprotected in two suc-
cessive steps, with tetra-n-butylammonium fluoride17 and direct
catalytic hydrogenation process,16c,18 using Pearlman’s reagent,
giving 1 in overall 90% yield, this compound having properties
identical to the one described in the literature (Scheme 8).
BnO
BnO
OPMB
BnO
OPMB
R'
R'
Reduction on both faces
Reduction
OMe
MeO
HN
NH
OPMB
BnO
OPMB
R'
R'
3. Conclusion
α : β = 4.6 : 1
We have developed a short and efficient procedure to synthe-
sise 2,5-dihydroxymethyl-3,4-di-hydroxypyrrolidine (DMDP) in
Scheme 7. Reduction of diastereoisomeric ketoxime mixtures 4a and 4b.

S. Balieu et al. / Carbohydrate Research 374 (2013) 14–22
17
H
N
OH
nBu4N+ F-
THF
H2 20 atm
N
HOH2C
CH2OH
BnOH2C
CH2OPMB
2b
Pd(OH)2 / C
HCl / MeOH
overall 90%
HO
OH
BnO
OBn
1
12
Scheme 8. Final deprotection to give DMDP 1.
an approach which will be easy to generalise to O-alkylated ana-
logues. We hope this methodology will help chemists interested
in these kinds of compounds and, more generally will lead to a
4.3. 3-O-Benzyl-1,2-4,6-di-O-isopropylidene
L-sorbose (6)
wider use of L-sorbose as a starting material in the total synthesis
of natural products.
O
O
O
O
O
O
NaH / THF
BnBr
O
O
4. Experimental
O
O
OH
OBn
4.1. General methods
7
6
To a suspension of sodium hydride 60% in mineral oil (10 g,
250 mmol) in THF (300 mL) at 0 °C was added dropwise a solution
of 7 (52.3 g, 200 mmol) in THF (300 mL). After addition of tetra-n-
butylammonium iodide (2.5 g, 6.8 mmol), benzyl bromide
(27.3 mL, 230 mmol) was added dropwise and then the yellow sus-
pension was stirred at room temperature for 3 h. The reaction was
quenched by the addition of methanol (10 mL) at 0 °C and after
addition of water (50 mL), reaction mixture has been extracted
with CH2Cl2 (3 ꢁ 500 mL). Combined organic phases have been
dried with MgSO4, and after filtration and evaporation to dryness,
the residue was purified by column chromatography to give 6
All reactions were carried out under argon. Dry solvents were
used in all experiments. Thin layer chromatography was per-
formed on E. Merck pre-coated 60 F254 plates and compounds were
observed by UV or by charring the plates with an acidic anisalde-
hyde system. Flash column chromatography separations (silica
gel, 15–40 lm or 40–63 lm) were carried out with light petroleum
ether–ethyl acetate mixtures as eluent. NMR spectra were re-
corded on DRX 500 Bruker spectrometer (250 MHz for 1H and
63 MHz for 13C), using standard pulse programs. Chemical shifts
(d) reported are referred to internal tetramethylsilane. FT IR spec-
tra were recorded on Nicolet Avatar 320 FT-IR as films. Optical
rotations were measured on a Perkin–Elmer 341 polarimeter. Ele-
mental analyses were performed with a Thermo Flash EA 1112 Ser-
ies. Electrospray ionization mass spectrometry experiments (MS
and HRMS) were obtained on a hybrid tandem quadrupole/time-
of-flight (Q-TOF) instrument, equipped with a pneumatically as-
sisted electrospray (Z-spray) ion source (Micromass, Manchester,
UK) operated in positive mode (EV = 30 V, 80 °C, injection flow
(70 g, 200 mmol, quantitative) as a colourless oil. ½a D20
ꢃ17.5° (c
ꢂ
1.18, CHCl3); 1H NMR (CDCl3): d 7.37–7.26 (m, 5H, HAr), 4.78 (d,
1H, Jgem 12.5 Hz, CH2Ph), 4.69 (d, 1H, CH2Ph), 4.29 (m, 1H, H-4),
4.20 (m, 1H, J5,6b 3.1 Hz, H-5), 4.17 (d, 1H, Jgem 9.3 Hz, H-1a), 4.03
(d, 1H, H-1b), 3.97 (dd, 1H, Jgem 12.5 Hz, J6a,5 3.2 Hz, H-6a), 3.86
(dd, 1H, H-6b), 3.81 (m, 1H, H-3), 1.55 (s, 3H, 1 CH3), 1.49 (s, 3H,
1 CH3), 1.39 (s, 3H, 1 CH3), 1.34 (s, 3H, 1 CH3); 13C NMR (CDCl3):
d 138.2 (CqAr), 128.8 (CAr), 128.3 (CAr), 111.3 (Cq isopropylidene),
111.2 (C-2), 98.3 (Cq isopropylidene), 85.3 (C-3), 74.3 (C-4), 73.7
(C-1), 73.4 (CH2Ph), 72.5 (C-5), 61.0 (C-6), 28.4 (CH3 isopropyli-
dene), 26.6 (CH3 isopropylidene), 26.4 (CH3 isopropylidene), 20.6
5 lL/min).
4.2. 1,2-4,6-Di-O-isopropylidene
L-sorbose (7)
(CH3 isopropylidene); IR (neat)
mmax: 2990, 2936, 2876, 1497,
1455, 1377, 1265, 1196, 1116, 1069, 1009, 856, 741, 700 cmꢃ1
;
O
O
HRMS (m/z, ESI) calculated for C19H26O6Na: (M+Na) = 373.1627
(calculated), 373.1632 (found).
O
Me2C(OMe)2
O
L-Sorbose
SnCl2
DME
4.4. 3-O-Benzyl-1,2-O-isopropylidene
L
-sorbose (8)
O
OH
7
L
-Sorbose (50 g, 277 mmol) was suspended in 1,2-dimethoxy-
O
O
O
ethane (10 mL) containing SnCl2 (250 mg, 1.3 mmol), and then
2,2-dimethoxypropane (150 mL) was added. The reaction mixture
was heated to 70 °C for 2 h. After quench with Et3N (1.25 mL), a
simple filtration on wool and sand gave after evaporation, 7 as a
crude syrup which could be used for the next step without any fur-
ther purification (43.9 g, 169 mmol, 61%) having the same physical
characteristics as described in the literature.8 1H NMR (CDCl3): d
4.16 (m, 1H, CH), 4.07 (m, 3H, 1 CH + CH2), 3.88 (m, 3H, CH + CH2),
2.89 (large s, 1H, OH), 1.45 (s, 3H, CH3), 1.37 (s, 3H, CH3), 1.33 (s,
3H, CH3), 1.26 (s, 3H, CH3); 13C NMR (CDCl3): d 111.2 (C-2), 110.5
(C-8), 97.4 (C-7), 79.3 (C-6), 74.3 (C-4), 72.9, 72.4 (C-1, C-5), 60.3
(C-3), 28.2 (CH3 isopropylidene), 26.4 (CH3 isopropylidene), 25.4
(CH3 isopropylidene), 19.2 (CH3 isopropylidene).
O
AcOH
O
O
O
HO
H2O
O
HO
OBn
OBn
6
8
A solution of 6 (70 g, 200 mmol) in a mixture AcOH/water
(360 mL/40 mL) was stirred overnight at room temperature. The
reaction mixture was then diluted with ethyl acetate (1 L) and
slowly washed with a saturated sodium bicarbonate solution until
acid was quenched. After extraction with ethyl acetate
(3 ꢁ 100 mL), organic phases were combined, dried with MgSO4,
and after filtration and evaporation to dryness, the residue was

18
S. Balieu et al. / Carbohydrate Research 374 (2013) 14–22
purified by column chromatography to give 8 (42.2 g, 136 mmol,
3), 3.69–3.50 (m, 2H, H-6); 13C NMR (CDCl3): d 137.9 (CqAr), 137.0
(CqAr), 129.1 (CAr), 129.0 (CAr), 128.9 (CAr), 128.8 (CAr), 128.5 (CAr),
128.4 (CAr), 128.3 (CAr), 128.1 (CAr), 106.0 (C-2), 82.3 (C-3), 81.9 (C-
1), 73.9 (CH2Ph), 73.8 (CH2Ph), 72.5 (CH2Ph), 72.5 (C-4), 72.5 (C-5),
68%) as a white solid. mp = 102 °C; ½a D20
ꢂ
ꢃ48.3° (c 0.92, CHCl3); 1H
NMR (CDCl3): d 7.43–7.25 (m, 5H, HAr), 4.76 (m, 2H, CH2Ph), 4.55
(t, 1H, J4,3 6.5 Hz, J4,5 6.5 Hz, H-4), 4.24 (m, 1H, J5,6 2.7 Hz, H-5),
4.06 (d, 1H, Jgem 9.2 Hz, H-1a), 3.98 (d, 1H, H-1b), 3.85 (d, 2H, H-6),
3.79 (d, 1H, H-3), 2.74 (large s, 2H, 2 OH), 1.51 (s, 3H, 1 CH3), 1.46
(s, 3H, 1 CH3); 13C NMR (CDCl3): d 137.9 (CqAr), 128.6 (CAr), 128.0
(CAr), 127.9 (CAr), 111.7 (Cq isopropylidene), 108.3 (C-2), 84.7 (C-
3), 76.9 (C-4, C-5), 72.4 (CH2Ph), 71.3 (C-1), 61.6 (C-6), 26.7 (CH3 iso-
69.0 (C-6); IR (neat)
m
max: 3450, 3063, 3030, 2925, 2869, 1455,
HRMS (m/z, ESI) calculated for
27H30O6Na: (M + Na) = 473.1940 (calculated), 473.1928 (found).
1060, 1028, 736, 698 cmꢃ1
;
C
4.7. 3,4,6-Tri-O-benzyl-
L
-xylo-Hex-2-ulose methyloxime (10a)
propylidene), 26.3 (CH3 isopropylidene); IR (neat) mmax: 3357, 3033,
OMe
2996, 2928, 1455, 1370, 1246, 1210, 1124, 1107, 1065, 1033, 900,
885, 757, 740, 700 cmꢃ1; HRMS (m/z, ESI) calculated for C16H22O6Na:
(M+Na) = 333.1314 (calculated), 333.1298 (found).
OH
O
OH
N
BnOH2C
MeONH2; HCl
AcOK MeOH
CH2OH
OH
BnO
BnO
OBn
BnO
OBn
4.5. 3,4,6-Tri-O-benzyl-1,2-O-isopropylidene
L
-sorbose (9)
10a
5
O
O
O
O
To a solution of 5 (9 g, 20 mmol) in methanol (220 mL) were
successively added sodium acetate (4.41 g, 45 mmol) and meth-
oxylammonium chloride (3.36 g, 40 mmol). After stirring for 4 days
at room temperature, the reaction mixture was evaporated to dry-
ness et directly purified by column chromatography to give 10a
(8.44 g, 88%) as a colorless oil, unseparable mixture of E and Z ster-
eoisomers (ratio 2:1).
NaH / THF
O
O
HO
BnO
BnBr
HO
BnO
OBn
OBn
8
9
To a suspension of sodium hydride 60% in mineral oil (20.24 g,
506 mmol) in THF (300 mL) at 0 °C was added dropwise a solution
of 8 (72 g, 232.2 mmol) in THF (500 mL). After addition of tetra-n-
butylammonium iodide (2.88 g, 7.8 mmol), benzyl bromide
(56 mL, 471 mmol) was added dropwise and then the yellow sus-
pension was stirred overnight at room temperature. The reaction
was quenched by the addition of methanol (20 mL) at 0 °C and
after addition of water (50 mL), reaction mixture has been ex-
tracted with ethyl acetate (3 ꢁ 500 mL). Combined organic phases
have been dried with MgSO4, and after filtration and evaporation to
dryness, the residue was purified by column chromatography to
E stereoisomer: 1H NMR (CDCl3): d 7.32–7.13 (m, 15H, HAr), 4.88
(d, 1H, Jgem 11.1 Hz, CH2Ph), 4.65 (d, 1H, Jgem 11.5 Hz, CH2Ph), 4.61
(d, 1H, CH2Ph), 4.55 (m, 1H, H-1a), 4.52 (d, 1H, CH2Ph), 4.52 (m,
1H, H-3), 4.51 (d, 1H, Jgem 11.8 Hz, CH2Ph), 4.45 (d, 1H, CH2Ph),
4.44 (m, 1H, H-4), 4.40 (m, 1H, H-1b), 3.86 (m, 1H, H-5), 3.93 (s,
3H, OMe), 3.52 (m, 1H, H-6a), 3.44 (m, 1H, H-6b); 13C NMR (CDCl3):
d 158.5 (C@N), 138.5 (CqAr), 138.3 (CqAr), 137.9 (CqAr), 128.9 (CAr),
128.8 (CAr), 128.3 (CAr), 128.2 (CAr), 81.7 (C-3), 79.9 (C-1), 75.6
(CH2Ph), 73.8 (CH2Ph), 72.7 (CH2Ph), 71.4 (C-4), 70.3 (C-5), 62.8
(OMe), 57.9 (C-6).
Z stereoisomer: d 7.32–7.13 (m, 15H, HAr), 4.77 (d, 1H, Jgem
11.0 Hz, CH2Ph), 4.60 (m, 2H, CH2Ph), 4.38 (d, 1H, CH2Ph), 4.55
(m, 1H, H-1a), 4.52 (m, 1H, H-3), 4.44 (m, 1H, H-4), 4.40 (m, 1H,
H-1b), 4.31 (d, 1H, Jgem 14.8 Hz, CH2Ph), 3.86 (m, 1H, H-5), 3.93
(s, 3H, OMe), 3.52 (m, 1H, H-6a), 3.44 (m, 1H, H-6b); 13C NMR
(CDCl3): d 158.2 (C@N), 138.5 (CqAr), 138.3 (CqAr), 137.9 (CqAr),
128.9 (CAr), 128.8 (CAr), 128.3 (CAr), 128.2 (CAr), 81.7 (C-3), 79.9
(C-1), 75.8 (CH2Ph), 73.8 (CH2Ph), 72.7 (CH2Ph), 71.1 (C-4), 70.8
(C-5), 62.8 (OMe), 61.5 (C-6).
give 9 (93.8 g, 218.2 mmol, 94%) as a colourless oil. ½a D20
ꢃ32.3°
ꢂ
(c 1.12, CHCl3); 1H NMR (CDCl3): d 7.45–7.25 (m, 15H, HAr), 4.77
(d, 1H, Jgem 12.0 Hz, CH2Ph), 4.68 (d, 1H, CH2Ph), 4.60 (m, 4H, 2
CH2Ph), 4.48 (m, 1H, J5,6a 4.7 Hz, J5,6b 5.0 Hz, H-5), 4.34 (t, 1H, J4,3
5.7 Hz, J4,5 5.0 Hz, H-4), 4.11 (d, 1H, Jgem 9.2 Hz, H-1a), 4.05 (d,
1H, H-3), 3.97 (d, 1H, H-1b), 3.75 (dd, 1H, Jgem 10.2 Hz, H-6a),
3.64 (dd, 1H, H-6b), 1.58 (s, 3H, 1 CH3), 1.52 (s, 3H, 1 CH3); 13C
NMR (CDCl3): d 138.3 (CqAr), 138.0 (CqAr), 137.9 (CqAr), 128.5
(CAr), 128.4 (CAr), 127.9 (CAr), 127.8 (CAr), 127.7 (CAr), 127.6 (CAr),
111.2 (Cq isopropylidene), 108.5 (C-2), 82.8 (C-3), 82.3 (C-4), 76.6
(C-5), 73.4 (CH2Ph), 72.9 (CH2Ph), 72.3 (CH2Ph), 72.3 (C-1), 68.9
(C-6), 26.5 (CH3 isopropylidene), 26.3 (CH3 isopropylidene); IR
IR (neat)
1360, 1262, 1210, 1048, 899, 827, 736, 698 cmꢃ1; HRMS (m/z, ESI)
calculated for 28H34NO6Na: (M+Na) = 480.2386 (calculated),
480.2387 (found).
mmax: 3448, 3063, 3031, 2934, 2866, 1496, 1454, 1396,
C
(neat)
1212, 1109, 1065, 889, 738, 698 cmꢃ1; HRMS (m/z, ESI) calculated
for 30H34O6Na: (M + Na) = 513.2253 (calculated), 513.2249
mmax: 3064, 3031, 2989, 2930, 2869, 1497, 1454, 1374,
C
4.8. 3,4,6-Tri-O-benzyl-
silyloxime (10b)
L
-xylo-Hex-2-ulose tertiobutyldiphenyl
(found).
4.6. 3,4,6-Tri-O-benzyl-
L
-sorbose (5)
OTBDPS
OH
O
OH
N
O
O
OH
OH
BnOH2C
TBDPSONH2
CH2OH
O
OH
BnO
AcOH
PPTS Toluene
MgSO4
O
BnO
BnO
BnO
OBn
BnO
OBn
H2O 50°C
BnO
OBn
BnO
Reflux
10b
OBn
5
70%
9
5
To a solution of 5 (4.62 g, 10.1 mmol) in toluene (46 mL) under
argon was added anhydrous magnesium sulfate (1.09 g, 4.2 mmol).
After stirring for 20 min, were successively added tertiobutyldi-
phenylsilyloxylamine (4.25 g, 15.7 mmol) and pyridinium paratol-
A solution of 9 (9.8 g, 20 mmol) in a mixture AcOH/water (45 mL/
5 mL) was stirred overnight at 50 °C. The reaction mixture was then
evaporated to dryness and the residue was purified by column chro-
matography to give 5 (7.0 g, 15.6 mmol, 78%) as a colourless oil. ½a D20
ꢂ
+2.8° (c 0.97, CHCl3); 1H NMR (CDCl3): d 7.36–7.12 (m, 15H, HAr),
4.55–4.39 (m, 4H, 2 CH2Ph), 4.43 (m, 1H, H-4), 4.32 (large s, 2H, Jgem
12.0 Hz, CH2Ph), 4.30 (m, 1H, H-5), 4.05 (m, 2H, H-1), 3.94 (m, 1H, H-
uenesulfonate (3 ꢁ 20 mg, 3 ꢁ 366
lmol). After reflux for 48 h, the
reaction mixture was directly subjected to column chromatogra-
phy to give 10b (4.98 g, 70%) as a slightly yellow oil, unseparable

S. Balieu et al. / Carbohydrate Research 374 (2013) 14–22
19
mixture of E and Z stereoisomers (ratio approximately 2:1 in each
case).
(d, 1H, Jgem 11.2 Hz, CH2Ph on C-4⁄), 4.85 (d, 1H, Jgem 11.2 Hz,
CH2Ph on C-4), 4.66 (d, 1H, Jgem 11.6 Hz, CH2Ph on C-1⁄), 4.60 and
4.57 (2 d, 2H, Jgem 11.2 Hz, Jgem 10.0 Hz, 2 CH2Ph on C-4 and C-4⁄),
4.55 (d, 1H, J3,4 5.0 Hz, C-3⁄), 4.55 (s, 2H, CH2Ph on C-3), 4.49 (m,
2H, CH2Ph on C-1), 4.46 (s, 1H, OH), 4.43 (large s, 2H, CH2Ph on
C-3⁄), 4.36 (d, 1H, Jgem 13.2 Hz, C-1a⁄), 4.31 (d, 1H, Jgem 11.6 Hz,
C-1a), 4.16 (d, 1H, C-1b⁄), 4.06 (d, 1H, C-1b), 4.04 (dd, 1H, J4,5
8.2 Hz, C-4⁄), 4.01 (dd, 1H, J4,5 7.2 Hz, C-4), 3.95 (s, 3H, NOMe),
3.94 (s, 3H, NOMe), 3.92 (m, 1H, C-5⁄), 3.90 (m, 1H, C-5), 3.81 (s,
3H, PhOMe), 3.80 (s, 3H, PhOMe), 3.50 (dd, 1H, J6a,5 6.6 Hz, J6a,6b
9.6 Hz, C-6a⁄), 3.45 (dd, 1H, J6b,5 6.2 Hz, C-6b⁄), 3.40 (dd, 1H, J6a,5
5.7 Hz, J6a,6b 9.6 Hz, C-6a), 3.37 (dd, 1H, J6b,5 5.7 Hz, C-6b); 13C
NMR (CDCl3): d 159.5 (CqArOMe), 156.4 (C@N), 155.4 (C@N), 138.6
(CqAr), 138.4 (CqAr), 138.2 (CqAr), 137.6 (CqAr), 129.6 (CAr), 129.5
(CAr), 128.4 (CAr), 128.3 (CAr), 128.1 (CAr), 127.9 (CAr), 127.8 (CAr),
127.7 (CAr), 127.6 (CAr), 113.7 (CAr ortho/OMe), 80.6 (C-3⁄), 79.3
(C-4⁄), 79.1 (C-4), 76.0 (C-3), 75.3 (CH2Ph on C-4), 75.2 (2 CH2Ph
on C-4 and C-4⁄), 75.0 (CH2Ph on C-4⁄), 73.1 (CH2Ph on C-3), 73.0
(CH2Ph on C-3), 72.6 (CH2Ph on C-1), 72.2 (CH2Ph on C-1⁄), 71.4
(C-6⁄), 70.9 (C-6), 69.9 (C-5), 69.7 (C-5⁄), 67.1 (C-1), 62.3 (NOMe),
E stereoisomer: 1H NMR (CDCl3): d 7.71–7.67 (m, 6H, HAr), 7.45–
7.19 (m, 19H, HAr), 5.28 (d, 1H, J3/4 5.3 Hz, H-3 min), 4.78 (d, 1H,
Jgem 10.9 Hz, CH2Ph maj), 4.66 (d, 1H, Jgem 10.9 Hz, CH2Ph min),
4.62 (large d, 2H, 2 H-1 maj), 4.55 (d, 1H, Jgem 10.9 Hz, CH2Ph
maj), 4.54 (d, 1H, Jgem 10.9 Hz, CH2Ph min), 4.54 (d, 1H, Jgem
11.5 Hz, CH2Ph maj), 4.54 (m, 2H, CH2Ph maj + CH2Ph min), 4.37
(m, 2H, CH2Ph maj + CH2Ph min), 4.40 (collapsed d, 1H, H-1a
min), 4.40 (m, 1H, CH2Ph min), 4.36 (m, 1H, CH2Ph min), 4.36 (d,
1H, H-3 maj), 4.35 (d, 1H, Jgem 11.5 Hz, CH2Ph maj), 4.33 (collapsed
d, 1H, H-1b min), 4.05 (dd, 1H, J4/5 4.7 Hz, H-4 min), 3.95 (m, H-
5 min), 3.88 (dd, 1H, J4/3 7.3 Hz, J4/5 2.6 Hz, H-4 maj), 3.80 (m, H-
5 maj), 3.43 (m, 2H, J6a/6b 9.6 Hz, 2 H-6 min), 3.39 (dd, 1H, J6a/6b
9.5 Hz, J6a/5 5.5 Hz, H-6a maj), 3.35 (dd, 1H, J6b/5 5.9 Hz, H-6b
maj), 2.75 (m, 1H, OH), 2.28 (d, 1H, J 5.6 Hz, OH), 1.13 (s, 9H,
tBu); 13C NMR (CDCl3): d 163.6 (C@N maj), 163.2 (C@N min),
138.0 (CqAr maj), 137.9 (CqAr maj), 137.8 (CqAr min), 137.6 (CqAr
min), 137.2 (CqAr maj), 136.7 (CqAr min), 135.5, 135.4, 132.9,
132.8, 132.7, 130.0, 129.9, 128.6, 128.4, 128.3, 128.2, 128.0, 127.9
(CAr), 81.0 (C-3 maj), 79.4 (C-4 maj), 79.1 (C-4 min), 75.7 (CH2Ph
min), 75.3 (C-3 min), 75.0 (CH2Ph maj), 73.3 (CH2Ph min), 73.2
(CH2Ph maj), 72.0 (CH2Ph maj), 70.7 (C-6 maj), 70.6 (C-6 min),
70.5 (C-5 min), 70.0 (C-5 maj), 61.3 (C-1 min), 58.2 (C-1 maj),
62.2 (NOMe), 62.2 (C-1⁄), 55.2 (PhOMe); IR (neat)
mmax: 3512,
3489, 3454, 3066, 3033, 3006, 2938, 2864, 1613, 1514, 1457,
1396, 1358, 1303, 1248, 1211, 1177, 1093, 1044, 902, 821, 738,
698 cmꢃ1
;
HRMS (m/z, ESI) calculated for C36H42NO7Na:
27.2 (C(Me)3 min), 27.1 ((C(Me)3 maj); IR (neat)
mmax: 3443,
(M+Na) = 600.2961 (calculated), 600.2962 (found).
3069, 3030, 2931, 2859, 1496, 1472, 1454, 1428, 1392, 1362,
1217, 1115, 1028, 923, 822, 755, 699, 667, 611 cmꢃ1; HRMS (m/z,
ESI) calculated for C43H49NO6NaSi: (M+Na) = 726.3227 (calcu-
lated), 726.3227 (found).
4.10. 3,4,6-Tri-O-benzyl-1-O-(4-methoxybenzyl)-L-xylo-Hex-2-
ulose tertiobutyldiphenylsilyloxime (11b)
OTBDPS
OTBDPS
OH
OH
N
N
NaH THF
PMBBr
BnOH2C
BnOH2C
CH2OH
CH2OPMB
BnO
OBn
BnO
OBn
10b
11b
4.9. 3,4,6-Tri-O-benzyl-1-O-(4-methoxybenzyl)-L-xylo-Hex-2-
ulose methyloxime (11a)
To a suspension of sodium hydride 60% in mineral oil (255 mg,
6.3 mmol) in anhydrous THF (17 mL) at 0 °C was added dropwise a
OMe
OMe
OH
OH
N
N
NaH THF
PMBBr
BnOH2C
BnOH2C
CH2OH
CH2OPMB
BnO
OBn
BnO
OBn
10a
11a
To a suspension of sodium hydride 60% in mineral oil (734 mg,
18.3 mmol) in anhydrous THF (50 mL) at 0 °C was added dropwise
a solution of 10a (8 g, 16.68 mmol) in THF (100 mL). After addition
of tetra-n-butylammonium iodide (416 mg, 1.1 mmol), 4-
methoxybenzyl bromide (2.43 mL, 16.68 mmol) was added drop-
wise and then the yellow suspension was stirred overnight at room
temperature. The reaction was quenched by the addition of meth-
anol (10 mL) at 0 °C and after addition of water (10 mL), reaction
mixture has been extracted with ethyl acetate (3 ꢁ 200 mL). Com-
bined organic phases have been dried with MgSO4, and after filtra-
tion and evaporation to dryness, the residue was purified by
column chromatography to give 11a (7.1 g, 11.84 mmol, 71%) as
a colourless oil.
solution of 10b (4 g, 5.69 mmol) in THF (35 mL). After addition of
tetra-n-butylammonium iodide (143 mg, 379 mol), 4-methoxy-
benzyl bromide (838 L, 5.69 mmol) was added dropwise and then
the yellow suspension was stirred overnight at room temperature.
The reaction was quenched by the addition of methanol (4 mL) at
0 °C and after addition of water (4 mL), reaction mixture has been
extracted with ethyl acetate (3 ꢁ 70 mL). Combined organic phases
have been dried with MgSO4, and after filtration and evaporation to
dryness, the residue was purified by column chromatography to
give 11b (3.09 g, 2.78 mmol, 66%) as a colourless oil.
l
l
Mixtureoftwo ketoximestereoisomers (themajorbeingdesigned
by ⁄): 1H NMR (CDCl3): d 7.75–7.65 (m, 8H, HAr), 7.47–7.18 (m, 34H,
H
2HAr
Ar), 6.87 (d, 2H, J 8.7 Hz, 2HAr ortho/OMe), 6.85 (d, 2H, J 8.7 Hz,
Mixture of two ketoxime stereoisomers (one of each designed
by ⁄): 1H NMR (CDCl3): d 7.36–7.23 (m, 34H, HAr), 6.85 (2 d, 4H, J
8.7 Hz, J 8.7 Hz, 4HAr ortho/OMe), 5.12 (d, 1H, J3,4 7.3 Hz, C-3), 4.91
⁄), 5.16 (d, 1H, J3,4 7.8 Hz, C-3), 5.12 (d, 1H, Jgem
ortho/OMe
11.4 Hz, CH2Ph), 5.03 (s+d, 3H, CH2Ph + 2CH2Ph⁄), 4.92 (d, 1H,
Jgem 11.1 Hz, CH2Ph⁄), 4.85 (d, 1H, Jgem 11.3 Hz, CH2Ph), 4.66 (d, 1H,

20
S. Balieu et al. / Carbohydrate Research 374 (2013) 14–22
J3,4 4.4 Hz, C-3⁄), 4.64 (d, 1H, Jgem 14.3 Hz, C-1a⁄), 4.62 (d, 1H, Jgem
11.1 Hz, CH2Ph⁄), 4.60 (d, 1H, Jgem 11.1 Hz, CH2Ph⁄), 4.56 (d, 1H,
Jgem 11.3 Hz, CH2Ph), 4.54 (d, 1H, Jgem 12.2 Hz, C-1a), 4.52 (d, 1H, Jgem
11.1 Hz, CH2Ph⁄), 4.47 (m, 2H, Jgem 11.1 Hz, CH2Ph⁄ + CH2Ph), 4.42 (m,
2H, CH2Ph⁄ + CH2Ph), 4.36 (s, 2H, CH2Ph), 4.33 (d, 1H, C-1b⁄), 4.20 (d,
1H, C-1b), 4.17 (dd, 1H, J4,5 7.8 Hz, C-4⁄), 4.10 (dd, 1H, J4,5 2.2 Hz, C-4),
3.94 (m, 1H, C-5⁄), 3.94 (m, 1H, C-5), 3.80 (s, 3H, PhOMe), 3.79 (s, 3H,
PhOMe⁄), 3.51 (dd, 1H, J6a,5 6.9 Hz, J6a,6b 9.5 Hz, C-6a⁄), 3.46 (dd, 1H,
J6a,5 6.8 Hz, J6a,6b 9.5 Hz, C-6a), 3.42 (dd, 1H, J6b,5 5.7 Hz, C-6b⁄), 3.34
(dd, 1H, J6b,5 5.0 Hz, C-6b), 1.05 (s, 9H, tBu), 1.03 (s, 9H, tBu⁄); 13C
NMR (CDCl3): d 159.6 (CqArOMe), 159.2 (CqArOMe⁄), 158.1 (C@N),
157.1 (C@N⁄), 138.5 (2CqAr), 138.1 (3CqAr), 137.5 (CqAr), 135.8–
135.7 (CAr), 132.9 (CqAr), 132.8 (CqAr), 132.7 (CqAr⁄), 132.6 (CqAr⁄),
128.4 (CAr), 128.3 (3CAr), 128.2 (2CAr), 128.1 (CAr), 128.0 (CAr), 127.9
(CAr), 127.8 (2CAr), 127.7 (2CAr), 127.6 (2CAr), 127.5 (CAr), 113.9
5H, C-2 and C-5, NOMe), 3.43 (m, 7H, C-1 and C-6, PhOMe); 13C
NMR (CDCl3): d 159.1 (CqArOMe), 138.2 (CqAr), 130.3 (CAr), 129.4
(CAr), 128.3 (CAr), 128.2 (CAr), 128.0 (CAr), 127.8 (CAr), 127.6 (CAr),
113.7 (CAr ortho/OMe), 84.5 (C-3 and C-4), 73.3 (CH2Ph), 72.9 (CH2Ph),
71.6 (CH2Ph), 68.7 (C-2 and C-5), 68.1 and 67.7 (CH2OBn and
CH2OPMB), 61.4 (NOMe), 55.2 (PhOMe); IR (neat)
mmax: 3451,
3090, 3065, 3033, 2934, 2869, 2813, 1955, 1876, 1812, 1605,
1497, 1455, 1397, 1364, 1310, 1257, 1208, 1099, 911, 815, 740,
699 cmꢃ1
;
HRMS (m/z, ESI) calculated for C36H42NO6Na:
(M+Na) = 584.3012 (calculated), 584.3008 (found).
Minor stereoisomer (S): 1H NMR (CDCl3): 7.36–7.17 (m, 17H, HAr),
6.85 (d, 2H, Jgem 10 Hz, 2 HAr ortho/OMe), 4.55, 4.48 and 4.37 (m, 8H, 4
CH2Ph), 3.93 (m, 2H, C-3 and C-4), 3.78 (s, 3H, NOMe), 3.71 (m, 3H, C-
2, C-5 and CH2OPMB), 3.55 (m, 4H, CH2OPMB and PhOMe), 3.46 (m,
1H, CH2OBn), 3.22 (m, 1H, CH2OBn); 13C NMR (CDCl3): d 159.2
(CqArOMe), 138.3 (CqAr), 138.2 (CqAr), 130.5 (CAr), 129.5 (CAr), 128.4
(CAr), 128.0 (CAr), 127.9 (CAr), 127.7 (CAr), 113.8 (CAr ortho/OMe), 84.7
and 82.5 (C-3 and C-4), 73.3 (CH2Ph), 73.2 and 69.9 (C-2 and C-5),
72.8 (CH2Ph), 72.0 (CH2Ph), 71.2 (CH2Ph), 70.3 and 67.2 (CH2OBn
and CH2OPMB), 63.3 (NOMe), 55.3 (PhOMe).
(CAr ortho/OMe), 113.7 (CAr
⁄), 81.0 (C-3⁄), 80.0 (C-4), 79.3
ortho/OMe
(C-4⁄), 76.7 (C-3), 75.1 (CH2Ph⁄), 76.5 (CH2Ph), 76.0 (CH2Ph⁄), 75.4
(CH2Ph), 73.4 (CH2Ph⁄ + CH2Ph), 72.9 (CH2Ph), 72.1 (CH2Ph⁄), 71.5
(C-6⁄), 71.3 (C-6), 70.3 (C-5), 70.3 (C-5⁄), 62.4 (C-1), 62.2 (NOMe),
57.4 (C-1⁄), 55.3 (2PhOMe), 26.8 (CMe3⁄ + CMe3), 19.2 (CMe3), 19.1
(CMe3⁄); IR (neat)
mmax: 3508, 3030, 2931, 2061, 1959, 1886, 1813,
4.12. (2S,3S,4R,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)-2-
(4-methoxybenzylmethyl)-1-tertiobutyldiphenylsilyloxy
pyrrolidine (2b)
1776, 1612, 1587, 1514, 1497, 1454, 1428, 1361, 1303, 1248, 1175,
1112, 823, 738, 700,
613 cmꢃ1; HRMS (m/z, ESI) calculated for C51H57NO7NaSi: (M+Na) =
846.3802 (calculated), 846.3810 (found).
OTBDPS
N
OTBDPS
1) MsCl Et3N
OH
N
BnOH2C
CH2Cl2
BnOH2C
CH2OPMB
CH2OPMB
2) LiAlH4
Et2O
BnO
OBn
BnO
OBn
11b
2b
4.11. (2S,3S,4R,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)-2-
(4-methoxybenzylmethyl)-1-methoxypyrrolidine (2a)
To a solution of compound 11b (1 g, 1.21 mmol) in methylene chlo-
ride (14 mL) at 0 °C, were added dropwise triethylamine (340 L,
l
OMe
N
OMe
1) MsCl Et3N
OH
N
BnOH2C
CH2Cl2
BnOH2C
CH2OPMB
CH2OPMB
2) LiAlH4
Et2O
BnO
OBn
BnO
OBn
11a
2a
To a solution of compound 11a (7.7 g, 12.85 mmol) in methylene
chloride (150 mL) at 0 °C, were added dropwise triethylamine
(3.6 mL, 25.7 mmol) and then methanesulfonyl chloride (1.32 mL,
17 mmol). After stirring for 15 min at room temperature, the mix-
ture was washed with water (3 ꢁ 30 mL). The organic phase was
dried with MgSO4, and after filtration and evaporation to dryness
(with a cold bath), dry diethyl ether (150 mL) was added. After cool-
ing down to 0 °C, a solution of lithium aluminum hydride 4 M in
diethyl ether (6.4 mL, 25.7 mmol) was added dropwise. The reaction
mixture was stirred at room temperature for 2 h. At 0 °C, a Rochelle
salt solution was slowly added to the reaction mixture and after stir-
ring for 15 min, the reaction mixture was washed with water
(3 ꢁ 25 mL). The combined organic phases have been dried with
MgSO4, and after filtration and evaporation to dryness, the residue
was purified by column chromatography to give 2a (4.64 g,
7.97 mmol, 62%) as a colourless oil (mixture of two stereoisomers
in ratio 4.6:1).
2.4 mmol) and then methanesulfonyl chloride (124 lL, 1.6 mmol).
After stirring for 15 min at room temperature, the mixture was washed
with water (3 ꢁ 3 mL). The organic phase was dried with MgSO4, and
after filtration and evaporation to dryness (with a cold bath), dry
diethyl ether (15 mL) was added. After cooling down to 0 °C, a solution
of lithium aluminum hydride 4 M in diethyl ether (600 lL, 2.4 mmol)
was added dropwise. The reactionmixturewas stirred atroom temper-
ature for 2 h. At 0 °C, a Rochelle salt solution was slowly added to the
reaction mixture and after stirring for 15 min, the reaction mixture
was washed with water (3 ꢁ 3 mL). The combined organic phases have
been dried with MgSO4, and after filtration and evaporation to dryness,
the residue was purified by column chromatography to give 2b
(588 mg, 728
l
mol, 60%) as a colourless oil. ½a D20
ꢃ16.3° (c 0.5, CHCl3);
ꢂ
1H NMR (CDCl3): d 7.70 (d, 4H, HAr from PhSi), 7.46–7.27 (m, 21H, HAr),
7.11 (d, 2H, Jgem 10 Hz, 2 HAr meta/OMe), 6.79 (d, 2H, 2 HAr orthoOMe),
4.57 (d, 1H, Jgem 12.0 Hz, CH2Ph on C-4), 4.56 (overlapped d, 2H, CH2Ph
on C-1), 4.55 (overlapped d, 2H, CH2Ph on C-3), 4.54 (overlapped d, 2H,
CH2Ph on C-6), 4.47 (d, 1H, CH2Ph on C-4), 4.15 (m, 1H, J4,3 3.2 Hz, C-4),
4.06 (dd, 1H, J3,2 5.9 Hz, C-3), 3.95 (dd, 1H, J1a,1b 10.5 Hz, J6a,5 4.6 Hz,
C-6a), 3.82 (m, 1H, C-6b), 3.80 (s, 3H, PhOMe), 3.77 (m, 1H, C-1a),
Major stereoisomer (R): ½a D20
ꢂ
ꢃ4° (c 2, CHCl3); 1H NMR (CDCl3): d
7.27–7.08 (m, 17H, HAr), 6.74 (d, 2H, Jgem 10 Hz, 2 HAr ortho/OMe),
4.47–4.30 (m, 8H, 4 CH2Ph), 3.89 (m, 2H, C-3 and C-4), 3.64 (m,

S. Balieu et al. / Carbohydrate Research 374 (2013) 14–22
21
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Lett. 2001, 11, 1063–1064; (z) Asano, N.; Yasuda, K.; Kizu, H.; Kato, A.; Fan, J. Q.;
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3.61 (dd, 1H, J1b,1a 9.8 Hz, J1b,2 5.9 Hz,C-1b), 3.52 (m, 1H, C-5), 3.50 (m,
1H, C-2), 1.08 (s, 9H, tBu); 13C NMR (CDCl3): d 159.4 (CqArOMe), 138.4 (2
CqAr), 135.7 (CqAr), 133.4 (CAr), 130.5 (CAr meta/OMe), 129.7 (CAr), 129.6
(CAr), 128.3 (CAr), 128.2 (CAr), 127.8 (CAr), 127.7 (CAr), 127.6 (CAr),
127.5 (CAr), 113.5 (CAr ortho/OMe), 84.5 (C-4), 84.2 (C-3), 75.6 (CH2Ph),
73.2 (CH2Ph), 71.6 (2 CH2Ph), 68.5 (C-2), 68.5 (C-5), 68.0 (C-1), 62.0
(C-6), 55.2 (PhOMe), 26.8 (CMe3), 19.1 (CMe3); IR (neat) mmax: 3067,
3030, 2930, 2857, 1611, 1513, 1496, 1454, 1428, 1390, 1362, 1302,
1249, 1209, 1174, 1112, 1029, 823, 739, 700, 612 cmꢃ1; HRMS (m/z,
ESI) calculated for
846.3810 (found).
C51H57NO6K: (M+K) = 846.3802 (calculated),
4.13. (2S,3S,4R,5S)-3,4-Dihydroxy-2,5-dihydroxymethyl
pyrrolidine (1)
H
OH
nBu4N+ F-
THF
H2 20 atm
N
N
HOH2C
CH2OH
BnOH2C
CH2OPMB
2b
Pd(OH)2 / C
HCl / MeOH
HO
OH
BnO
OBn
1
12
To a solution of 2b (520 mg, 640 lmol) in dry THF (20 mL) at
0 °C was added a solution of tetra-n-butylammonium fluoride
1 M in THF (1.2 mL). After stirring for 1 h at room temperature,
the mixture was evaporated to dryness, and then the residue was
dissolved in methanol (6 mL), was treated with Pd(OH)2 on C
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(15 mg) and a solution of HCl in methanol (100 lL, 1 M). The
resulting mixture was stirred under hydrogen (20 atm) for 6 h.
The catalyst was eliminated by filtration through a pad of Celite,
the filtrate was treated with HCl (1 mL, 3 M) in methanol, and
the resulting solution was stirred at room temperature for an addi-
tional 10 min. The solvent was eliminated under reduced pressure
to afford pure 1 (94 mg, 90%) as a white solid.
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8. Sigma–Aldrich: 250 g for 349.5 €; Acros Organics: 250 g for 382 $.
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Acknowledgments
S. Balieu thanks the ‘Region Champagne-Ardenne’ and FEDER
for financial support. We would like to thank Dr. K. Plé for helpful
discussions.
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