A versatile approach to pyrrolidine azasugars and homoazasugars based on a highly diastereoselective reductive benzyloxymethylation of protected tartarimide

Article abstract of DOI:10.1016/j.tet.2007.02.087

A highly diastereoselective synthesis of enantio-enriched all trans-3,4-dibenzyloxyl-5-benzyloxymethyl-2-pyrrolidinone 13a was developed based on SmI₂-mediated benzyloxymethylation of O,O′-dibenzyltartarimide. The versatility of 13a and its antipode as the key building blocks for the asymmetric synthesis of pyrrolidine azasugars and homoazasugars has been demonstrated by elaborating them into naturally occurring DAB 1 (1), LAB 1 (2), N-hydroxyethyl-DAB 1 (4), 6-deoxy-DMDP 7, and 5-epi-radicamine B 36 as well as the reductive ring-opening product 35.

Full text of DOI:10.1016/j.tet.2007.02.087

Tetrahedron 63 (2007) 6346–6357
A versatile approach to pyrrolidine azasugars and
homoazasugars based on a highly diastereoselective
reductive benzyloxymethylation of protected tartarimide
*
Xiang Zhou, Wen-Jun Liu, Jian-Liang Ye and Pei-Qiang Huang
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, PR China
Received 2 January 2007; revised 15 February 2007; accepted 21 February 2007
Available online 24 February 2007
Abstract—A highly diastereoselective synthesis of enantio-enriched all trans-3,4-dibenzyloxyl-5-benzyloxymethyl-2-pyrrolidinone 13a was
developed based on SmI2-mediated benzyloxymethylation of O,O0-dibenzyltartarimide. The versatility of 13a and its antipode as the key
building blocks for the asymmetric synthesis of pyrrolidine azasugars and homoazasugars has been demonstrated by elaborating them into
naturally occurring DAB 1 (1), LAB 1 (2), N-hydroxyethyl-DAB 1 (4), 6-deoxy-DMDP 7, and 5-epi-radicamine B 36 as well as the reductive
ring-opening product 35.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
II diabetes,5c and was one of the most powerful anti-HIV
agents among 47 aminosugar derivatives screened.5c–e
Structurally related nectrisine (FR 900483) (3) is a fungal
metabolite isolated from Nectria lucida.6 DAB 1 and nectri-
sine exhibit extremely potent yeast a-glucosidase inhibitory
activities [IC50¼1.8ꢀ10ꢁ7 M4b and 4.8ꢀ10ꢁ8 M,7 respec-
tively]. The N-hydroxyethylated derivative of DAB 1,
namely, N-hydroxyethyl-DAB 18 (4) was isolated from the
seeds of African legume Angylocalyx pynaertii, while the
oxidation product of DAB 1, L-2,3-trans-3,4-trans-dihy-
droxyproline (DHP) (5), was isolated from the acid hydroly-
zates of the toxic mushroom Amanita virosa.9
Many pyranoses and furanoses with the ring oxygen re-
placed by an amino group, known as imino sugars or aza-
sugars,1 are sugar mimics, which have been found to inhibit
specific enzymes such as glycosidases.1 Because glycosi-
dases are involved in several important biological processes,
these polyhydroxylated alkaloids have stimulated interest in
the development of specific glycosidase inhibitors for study-
ing and treating metabolic disorders such as diabetes, or as
antiviral, antibacterial, and anticancer agents or as immuno-
modulators, and are providing biochemists with molecular
tools for probing several important processes, such as the
metastasis of some cancers, the immune response, and virus
replication. In particular, a-glucosidase inhibitors have
shown potential as therapeutic agents for type II diabetes2a
and HIV-1 infection.2b
Moreover, many C-5 carbon-substituted derivatives of DAB
1, known as homoazasugars or aza-C-glycosides are either
natural products or sugar mimics showing enhanced bio-
activities and at the same time exhibiting higher stability
toward chemical and enzyme degradation.10 For example,
2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP) 6
occurs in many disparate species of plants,11a and was also
isolated from Streptomyces;11b the 6-deoxy analog of
DMDP (6-deoxy-DMDP)12,8 7, a unique molecule in inhib-
iting b-mannosidase,11 was isolated from the seeds of Afri-
can legume A. pynaertii; radicamine B (8) and broussonetine
W (9) are two structurally related compounds recently iso-
lated from Lobelia chinensis Lour (Campanulaceae), which
also show a-glucosidase inhibitory activity.13
1,4-Dideoxy-1,4-imino-D-arabinitol (1, known as DAB 1)
was isolated from two types of leguminose plants Arachnio-
des standishii3a,4a and Angylocalyx boutiqueanus.3b The
antipode of DAB 1 is a synthetic product.4 LAB 1 was shown
to be a potent inhibitor of the a-L-arabinofuranosidase III of
Monilinia fructigena,5a and a much more powerful inhibitor
of sucrase and some mouse gut a-glucosidases than DAB
1.5b It is also a promising candidate for treatment of type
Keywords: Azasugars; DAB 1; LAB 1; 6-Deoxy-DMDP; epi-Radicamine B;
Alkaloids; Pyrrolidine; Hydroxymethylation; Diastereoselective synthesis.
* Corresponding author. Tel.: +86 592 2182240; fax: +86 592 2186400;
e-mail: pqhuang@xmu.edu.cn
Consequently, the synthesis of polyhydroxylated pyrrolidine
alkaloids/azasugars has attracted much attention, and a num-
ber of methods have been developed.4,14–17 In view of the
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.02.087

X. Zhou et al. / Tetrahedron 63 (2007) 6346–6357
6347
presence of a-hydroxymethyl-dihydroxypyrrolidine1a 1 as
HO
OH
OH
HO
OH
HO
HO
OH
the common structural feature in many azasugars, an attrac-
tive approach to these compounds would be that allowing in-
stallation of the a-hydroxymethyl group in a straightforward
manner. Although optically active tartaric acid has been used
to synthesize this class of compounds,15i,s,16d such as DAB 1
(1), LAB 115i,s (2), nectrisine (3),16d and broussonetine C,18
methods for the introduction of the hydroxymethyl group
into the a-position of a pyrrolidine or a piperidine ring
have generally been accomplished by indirect and multi-
step procedures.15s,18,19 In some of these approaches, low
diastereoselectivities have been observed.15i,16d As a part
of our ongoing project aimed at the development of mali-
mide/3-hydroxyglutarimide-based synthetic methodolo-
gies,20 and in continuation of our studies on the
asymmetric synthesis of azasugars and related com-
pounds,21 we report herein a short and highly diastereoselec-
tive approach for the enantioselective synthesis of DAB 1
(1), LAB 1 (2), N-hydroxyethyl-DAB 1 (4), 6-deoxy-
DMDP 7, and 5-epi-radicamine B 36 as well as the
reduced-ring-opening product 35 based on the direct intro-
duction of a benzyloxymethyl group via the reductive benzy-
loxymethylation of tartarimide 14 or ent-14.
HO
HO
N
H
N
H
N
(3)
nectrisine
HO
2
( )
(1)
DAB 1
LAB 1
HO
OH
HO
OH
HO
R
HO
HO
N
H
N
H
N
O
OH
DMDP 6 (R = OH)
6-deoxy-DMDP 7
(R = H)
N-hydroxyethyl
-DAB 1 4
DHP 5
HO
OH
HO
OH
HO
N
HO
OH
N
H
7
H
O
broussonetine W (9)
radicamine B (8)
Figure 1. Some naturally occurring five-membered azasugars and related
polyhydroxylated pyrrolidine alkaloids.
HO
OH
R2
BnO
OBn
O
BnO
OBn
O
−
*
*
*
BnOCHR
*
R
R
N
O
N
PMB
14
N
OH R1
OBn PMB
13a. R=H
13b. R≠H
2. Results and discussion
(H; alkyl, Ar)
12
reduction or
reductive
alkylation
R=H
In our recent efforts to develop a flexible method for the
synthesis of 2-benzyloxymethyl-2-piperidinone by the step-
wise reductive 2-benzyloxymethylation of the protected
3-hydroxyglutarimides (Scheme 1),21b several abnormal
phenomena have been observed. For example, the 2-benzyl-
oxymethylation of the O-benzyl protected 3-hydroxyglutari-
mide 10a led, unexpectedly, to two regioisomeric carbinols
in a 1:1 ratio; while although the 2-benzyloxymethylation
of the O-tert-butyldimethylsilyl protected 3-hydroxyglutar-
imide 10b proceeded with an 81:19 regioselectivity (C-2/
C-6), the subsequent reductive dehydroxylation could only
be achieved after O-debenzylation, and led, unexpectedly,21b
to cis-diastereomer 11 as the major product.
ref. 16d,16e
HO
HO
OH
P
PO
OP
ref. 16e
O
PO
N
O
N
OH
H
H
3. P = H
15. P = Bn
16
Scheme 2.
method (Scheme 3),23 which allows using cheaper reagents
and affords higher yields.
HO
OH
BnO
OBn
NaH, BnBr, DMF
OTBS
OH
OP
O
− 20 ~ 0 °C
BnOCH2
ROOC
COOR
ROOC
COOR
BnOCH2
(80-88%)
1: 1
D-tartaric acid
(17, R = H)
18. R = Et
O
N
PMB
EtOH
O
N
PMB
H2, Pd/C;
F3B OEt2
Et3SiH, CH2Cl2
(from 10b)
LiOH aq.
EtOH
19. R = Et
20. R = H
OBn
regioisomeric
mixture (from 10a)
SOCl2, rt
quantitative
0 - 5 °C
10a. P = Bn
10b. P = TBS
cis-11
(ref. 21b)
quantitative
BnO
O
AcCl, reflux
PMBNH2, CH2Cl2
Scheme 1.
N
O
AcCl, reflux
(90%)
PMB
14
Because the above-mentioned regioselection is no longer
a problem for tartarimide,22 a normal stepwise trans-
diastereoselective reductive benzyloxymethylation could
be expected. Thus, a general approach for the asymmetric
synthesis of azasugars such as those shown in Figure 1,
and homoazasugars10 such as phosphonoazasugar 1616e is
depicted retrosynthetically in Scheme 2, in which
(3S,4R,5R)-5-benzyloxymethyl-3,4-dibenzyloxyl-2-pyrroli-
dinones 13 have been selected as the common intermediates.
To test the feasibility of our approach, we first focused on the
synthesis and applications of 2-pyrrolidinone 13a.
Scheme 3.
For the introduction of the benzyloxymethyl group,24 we first
attempted HgCl2-mediated Grignard reaction24e,h under
Barbier-type conditions (Scheme 4). Thus a THF solution
of benzyloxymethyl chloridewas added to a mixture of tartar-
imide 14, Mg, and a catalytic amount of HgCl2 at rt to give the
desired N,O-acetal 21 as a diastereomeric mixture. The subse-
quent BF3$OEt2-mediated reductive dehydroxylation of the
diastereomeric mixture under standard conditions20 led to
the desired trans-benzyloxymethylated product 13a as the
only isolable diastereomer in 62% overall yield from 14.
The requisite D-O,O0-dibenzyltartarimide 14 was prepared
from D-tartaric acid by the modification of the known

6348
X. Zhou et al. / Tetrahedron 63 (2007) 6346–6357
Method 1:
The different behaviors (reactivity and diastereoselectivity)
BnOCH2Cl, Mg
of the N,O-acetal derived from TBS protected 3-hydroxy-
glutarimide 10b (Scheme 1) and that derived from O,O0-
dibenzyl protected tartarimide 14 (Scheme 4) toward the
reductive dehydroxylation (21/13a) demonstrates once
again the remarkable protecting group effect.29
BnO
O
OBn
O
BnO
HO
OBn
O
HgCl2 (cat.), THF
−
78 °C, 9 h
N
PMB
14
N
PMB
21
Method 2:
BnOCH2Cl, THF
0.1 M SmI2 in THF
0.01 equiv. FeCl3
0 °C ~ rt
BnO
ent-21
ent-14
(no shown,
from ent-14)
(no shown)
With the conditions for the desired reductive benzyloxy-
methylation of tartarimide 14 secured, we then investigated
the synthetic applications of 13a. Thus the PMB group in
13a was cleaved under oxidative conditions30 (CAN,
MeCN–H2O¼9:1 v/v, 0 ꢂC, 1.5 h, then rt, 4 h) to give the
known lactam 2215g in 84% yield (Scheme 5). Attempt to re-
duce amide 22 by borane complex (BH3$SMe2, THF, rt,
48 h) was far from satisfactory. After reaction for two
days, the desired product 24 and its borane adduct 23 were
obtained in only 10% and 16% yields, respectively, along-
side with 39% of the recovered starting material 22. How-
ever, when lithium aluminum hydride was used instead,
the desired product 2415g was obtained in 92% yield. Under
the catalytic transfer hydrogenolytic conditions, triple de-
benzylation was achieved quantitatively to afford DAB 1
(1), which was characterized as its hydrochloride salt
{[a]2D0 +36.1 (c 0.2, H2O); lit.15a [a]2D0 +37.9 (c 0.53,
H2O); lit.15g [a]D20 +32.5 (c 0.5, H2O)}. Except for the minor
differences in the optical rotation values, compounds 22, 24,
and DAB 1 (1) hydrochloride salt show identical spectral
data as those reported in the literature, confirming thus the
4,5-trans stereochemistry of lactam 13a.
BnO
OBn
Et3SiH, BF3 OEt2
BnO
N
CH2Cl2
−78 °C ~ rt
O
PMB
13a
(J4,5 = 5.1 Hz)
ent-13a
(no shown,
from ent-14)
(13a: by method 1: 62% yield over 2 steps)
(13a: by method 2: 61% yield over 2 steps)
(ent-13a: by method 2: 69% yield over 2 steps)
Scheme 4.
In addition to this approach, we also investigated a variant
featuringthesamariumdiiodide-mediatedbenzyloxymethyl-
ation. Treatment of a mixture of tartarimide 14 and benzyl-
oxymethyl chloride with a freshly prepared 0.1 M THF
solution of SmI2 containing 1% mol equiv of anhydrous
FeCl3 at rt for 1 h led to the desired N,O-acetal 21 in
84% yield. The subsequent BF3$OEt2-mediated reductive
dehydroxylation20,21b,22d–i,27 led to trans-diastereomer 13a
in 61% overall yield from 14.
25
26
The stereochemistry of compound 13a (J4,5¼5.1 Hz)
deserves comment. While the vicinal coupling constants
(J4,5>6.0 Hz for cis-diastereomers B, D and J4,5¼0–4.4 Hz
for trans-diastereomers A, C) (Fig. 2) are commonly used
to determine the 4,5-relative stereochemistries of 4,5-
disubstituted g-lactams,22d,28 substituted lactam 13a seems
to be a singular example which does not obey this empirical
rule because it shows a larger vicinal coupling constant
(J4,5¼5.1 Hz) and is in a marginal situation. The 4,5-trans
stereochemistry of lactam 13a was confirmed by converting
13a to the known compounds 22, 24 and to the target
molecules described in this paper.
BnO
BnO
OBn
O
BnO
BnO
OBn
O
CAN
CH3CN:H2O = 9:1
N
H
22
N
PMB
13a
0 °C, 4 h; rt, 1.5 h
(84%)
BnO
BnO
OBn
BnO
BnO
OBn
22
+
+
N
N
H
H
BH3
23
24
BH3•SMe2, THF
23 (16%) + 24 (10%) + 22 (39%)
24 (92%)
LiAlH4, THF,
60 °C, 12 h
10% Pd/ C, HCOOH
(100%)
MeOH, rt, 24 h; HCl
PO
H
PO
H
HO
HO
OH
4
5
4
5
H
N
P'
O
R
N
P'
O
N
H
R
H
• HCl
A (trans-isomer)
B (cis-isomer)
DAB 1 (1) • HCl
J
4,5 = 0 ~ 2.5 Hz
(P = Bn, Ac, TBS; P' = Bn, PMB, Me, t-Boc)
4,5 = 3.4 ~ 4.4 Hz
(for P = TBS; P' = H)28g
J4,5 = > 6.0 Hz
Scheme 5.
J
Starting from L-tartaric acid, and following the procedures
described for the synthesis of DAB 1 (Schemes 3–5), the
synthesis of LAB 1 (2) hydrochloride salt {[a]2D0 ꢁ41.1 (c
0.2, MeOH); lit.15a [a]D20 ꢁ34.6 (c 0.37, H2O); lit.15g [a]2D0
ꢁ36.5 (c 0.37, H2O)} was achieved in high overall yield
(Scheme 6). The 1H and 13C spectral data were identical to
those of hydrochloride salt of DAB 1 (1).
TBSO
H
OTBS
O
TBSO
H
OTBS
O
4
5
4
5
H
N
R'
R
N
R'
R
H
C (trans-isomer)
D (cis-isomer)
J
4,5 = 2.0 Hz22d
4,5 = 4.4 Hz28h
J
4,5 = 6.2 Hz22d
4,5 = 6.7 Hz28h
J
J
For the synthesis of azasugar 4, simple treatment of 24 with
2-bromoethanol in DMF and in the presence of K2CO3 led to
Figure 2. Vicinal coupling constants (J4,5) of 4,5-disubstituted g-lactams.

X. Zhou et al. / Tetrahedron 63 (2007) 6346–6357
6349
BnO
BnO
OBn
O
BnO
BnO
OBn
O
BnO
BnO
OBn
O
BnO
BnO
OBn
O
CAN
(Boc)2O, DMAP
Et3N / CH2Cl2
CH3CN:H2O = 9:1
N
N
H
22
N
Boc
26
N
PMB
0 °C, 1.5 h; rt, 4 h
rt, 4 h
(95%)
(80%)
t-
H
ent-22
ent-13a
BnO
BnO
OBn
BnO
OBn
Et3SiH, BF3 OEt2
10% Pd/C,H2
MeMgI, CH2Cl2
CH3
OH
LiAlH4, THF
MeOH, conc.HCl
LAB 1 • HCl
(2 • HCl)
CH2Cl2
−78 °C ~ rt, 14 h
(80%)
−20 °C, 2 h
(82%)
N
Boc
27
N
60 °C, 12 h
(91%)
rt, 10 h
(100%)
t-
OBn H
ent-24
BnO
BnO
OBn
BnO
OBn
Me
Scheme 6.
BnO
+
N
H
Me
N
R
the desired product 25 in 54% yield alongside with 22% of
the recovered starting material (Scheme 7). The yield was
improved to 80% by using MeOH as the solvent. Compound
25 was subjected to catalytic transfer hydrogenolytic condi-
tions to give N-hydroxyethyl-DAB 1 (4) in quantitative
yield, whose spectroscopic data were identical with those
reported for the natural product.8 However, the sense of
optical rotation was opposite to that reported {[a]2D0 ꢁ46.7
(c 0.3, H2O); lit.8 [a]D20 +54.7 (c 0.38, H2O); [a]2D0 ꢁ37.1
(c 0.2, H2O) for its hydrochloride salt}. Because N-hydroxy-
ethyl-DAB 1 (4) has also been obtained from DAB 1 (1),8 the
reason for these contrasting results is still unclear.
28 (28: 29 > 9.4 : 1) 29. R = H
BnBr, K2CO3
MeOH, rt
75%
(impure)
10% Pd/ C, HCOOH
MeOH, rt, 24 h; HCl
(98%)
HO
30. R = Bn
OH
HO
N
H
Me
• HCl
.
6-deoxy-DMDP 7•HCl
Scheme 8.
BnO
BnO
OBn
R
N
Br
Boc
BF4
BnO
BnO
OBn
BnO
BnO
OBn
OH
E. R = Me
OH
F. R = C6H4(OBn)-p
K2CO3, MeOH
rt., 2 d
N
H
N
Figure 3. Plausible N-acyliminium intermediates E and F generated from
27 and 32/33, respectively.
(80%)
24
25
10% Pd/ C, H2
MeOH, rt, 2 d
(100%)
HO
HO
OH
The cleavage of the three O-benzyl groups in 28 under trans-
fer hydrogenolytic conditions furnished quantitatively 6-
deoxy-DMDP 7, which exhibits identical spectral data as
those reported in the literature {[a]2D0 +41.2 (c 0.1, H2O)
for 7$HCl; lit.17d [a]2D0 +45.0 (c 1.4, MeOH)}.
N
or
OH
10% Pd/ C, HCOOH
MeOH, rt, 24 h; HCl
N-hydroxyethyl-DAB 1 4
4-HCl
(100%)
Finally, we tackled the synthesis of radicamine B.33 Addition
of Grignard reagent 3113c with imide 26 (CH2Cl2, ꢁ20 ꢂC)
yielded 32 as a diastereomeric mixture alongside with the
tautomer 33 (Scheme 9). In the light of the results obtained
recently from these laboratories,34 this isomeric mixture
was used in the subsequent step without further separation.
Thus the mixture 32/33 was treated with Et3SiH–BF3$OEt2
to give, via the N-acyliminium intermediate F (Fig. 3), the de-
sired reductive dehydroxylation/N-deprotection product 34
in high diastereoselectivity (only one diastereomer was ob-
tained) and in 58% overall yield from 26. This result is
surprising, since the attempt to perform the reductive dehy-
droxylation of similar carbinol 37 was reported to give pyr-
role type product in high yield.22g Subjection of 34 to
hydrogenolytic conditions (H2, 1 atm, 10% Pd/C, MeOH,
rt) for 4 h led directly to exhaustive debenzylation product
35 in 96% yield. Pyrrolidine 36 was obtained in 92% yield
by using PdCl2 as a pro-catalyst (H2, 1 atm, PdCl2, EtOH,
rt, 12 h).13c,33 The synthesis of 36 also provides a method
for constructing the skeleton of Schramm’s C-nucleoside
3835 with three stereocenters correctly established. More-
over, the possibility for a selective oxidative cleavage of
p-alkoxyphenyl group into a carboxyl group36 makes pyrrol-
idine 34 and compound 35 plausible intermediates for the
Scheme 7.
Next, we turned our attention to the synthesis of 2,5-
disubstituted pyrrolidine alkaloid 7. To this end, lactam 22
was first converted to Boc-activated derivative 26 (Scheme
8). For the subsequent introduction of the methyl group,
a second stepwise reductive alkylation31 (methylation) was
investigated. Thus, treatment of methyl magnesium iodide
with imide 26 led smoothly to N,O-acetal 27 as a diastereo-
meric mixture in 82% yield. This mixture, without further
separation, was subjected to boron trifluoride etherate medi-
ated triethylsilane reduction,27 which afforded, in one-pot,
the reductive dehydroxylation/N-deprotection products 28
and 29 (characterized as its N-benzyl derivative 30) in
9.4:1 ratio with a combined yield of 80%. It was interesting
to observe that by allowing the reaction to warm up and
reacting at rt, deprotection of Boc could be achieved in
one-pot. The stereochemistries of 28 and 29 were deduced
from compounds 7 and 30. The stereoconvergent formation
of 29 from the diastereomeric mixture of N,O-acetal 27
implicates that the reductive dehydroxygenation proceeds
through the intermediacy of the N-acyliminium intermediate
E (Fig. 3).32

6350
X. Zhou et al. / Tetrahedron 63 (2007) 6346–6357
BnO
BnO
OBn
O
BnO
BnO
OBn
OH
OBn O
p-BnOC6H4MgBr (31)
CH2Cl2
BnO
+
N
Boc
26
N
Boc
32
–20 °C, 2 h
NH OBn
OBn
OH
Boc
OBn
33
BnO
BnO
OBn
OH
10% Pd/C, H2
Et3SiH, BF3 OEt2
HO
MeOH, rt, 4 h
(96%)
CH2Cl2
−78 °C ~ rt, 14 h
(58% over two steps)
N
H
34
NH2 OH
OBn
35
HO
OH
HO
HO
OH
PdCl2, H2
EtOH, rt, 12 h
BnO
OBn
OH
HO
N
H
(92%)
N
H
N
Boc
37
NH2
OH
OMe
5-epi-radicamine B 36
Schramm's C-nucleoside 38
Scheme 9.
asymmetric synthesis of other homoazasugars36b and 3,4-
dihydroxyglutamic acid,28h respectively.
synthesized by direct reductive benzyloxymethylation of
O,O0-dibenzyltartarimide in highly diastereoselective man-
ner, and 13a is a versatile building block for the asymmetric
synthesis of pyrrolidine type azasugars and homoazasugars.
In addition, the possibility to perform a selective oxidation
of a primary alcohol, in the presence of secondary
alcohol,39,40 to a carboxylic acid makes 24 a potential pre-
cursor for the synthesis of all trans-L-dihydroxyproline
(DHP) (5).15d,36b Further studies on the synthesis of 13a
and use of 13a/13b for the enantiospecific syntheses of other
homoazasugars and other alkaloids are in progress in these
laboratories.
The stereochemistries of 28 and 34 were determined, first by
1H–1H COSYexperiments to confirm the proton assignment,
and then by NOESY experiments. As shown in Figure 4,
these experiments not only allow determining the C2/C5-
trans relationship for 28 and the C2/C5-cis relationship for
34, but also confirming the C2/C3-trans stereochemistries
for both compounds.
3.90
BnO
H
H
3.64
H
BnO
3.88
3.63
OBn
Ar
3
2
H
3.90H
4. Experimental
4.1. General
OBn
H 3.24
CH3
5
3
2
3.53
H
H
N
H
5
3.70BnO3.40
H
H
3.53
H
N
H
4.35
H
BnO3.42
1.22
weak
strong
34 (Ar = C6H4-OBn-p)
Melting points were determined on an X-4 digital micro
melting point apparatus and were uncorrected. Infrared
spectra were measured with a Nicolet Avatar 330 FT-IR
spectrometer using film KBr pellet technique. 1H NMR
spectra were recorded in CDCl3 on a Bruker AV400 or a
Varian unity +500 spectrometer with tetramethylsilane as
an internal standard. Chemical shifts are expressed in
d (ppm) units downfield from TMS. Mass spectra were
recorded by Bruker Dalton Esquire 3000 plus LC–MS
apparatus.41 Optical rotations were measured with a Per-
kin–Elmer 341 automatic polarimeter. Flash column chro-
matography was carried out on silica gel (300–400 mesh).
THF was distilled over sodium. Dichloromethane was dis-
tilled over P2O5. Petroleum ether (60–90 ꢂC) is abbreviated
as P.E.
28
Figure 4. Observed NOE enhancements of compounds 28 and 34 in the
NOESY experiments.
As regards the stereoselection of the reactions, Woerpel et al.
have undertaken systematic studies to reveal the factors con-
trolling the stereoselective reaction of five-membered ring
oxocarbenium ions,37 and concluded that the C-3 alkoxyl
group principally governs the selectivity, leading to cis-
selective addition. They also reclaimed37 that the observa-
tions and analysis for the 3-alkoxyl oxocarbenium ion are
relevant for the related nitrogen-containing compounds.28a,38
In the present studies, the predominant formations of both
3,5-cis-28 (via N-acyliminium intermediate E, Fig. 3) and
3,5-trans-34 (via N-acyliminium intermediate F) might
implicate that in our cases, the presence of the bulky N-
protecting group (Boc) in both E and F makes them different
from the five-membered ring oxocarbenium ions, and the
factors controlling their stereoselective reduction require
further mechanistic investigations.
4.1.1. (3S,4S)-1-(4-Methoxybenzyl)-3,4-dibenzyloxyl-2,5-
pyrrolidinedione (14). To a solution of D-tartaric acid
(10.00 g, 66.67 mmol) in EtOH (100 mL) was added drop-
wise SOCl2 (10.7 mL, 146.7 mmol). The mixture was stirred
at rt overnight. The solvent was evaporated in vacuum and
CH2Cl2 (20 mL) was added to the mixture. The resulting
mixture was washed with saturated aqueous NaHCO3 and
the aqueous layer was extracted with CH2Cl2. The combined
organic extracts were washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated in vacuum. The
3. Conclusion
In summary, we have demonstrated that all trans-5-benzyl-
oxymethyl-3,4-dibenzyloxyl-2-pyrrolidinone 13a can be

X. Zhou et al. / Tetrahedron 63 (2007) 6346–6357
6351
residue was purified by flash column chromatography on
silica gel eluting with ethyl acetate–P.E. (1:1) to give the
known diethyl tartarate 1823 (13.7 g, yield, 100%) as a color-
less oil. [a]2D0 ꢁ25.0 (c 0.2, H2O). IR (film): 3328, 2985,
PhCH2N), 4.61 (d, J¼14.3 Hz, 1H, PhCH2N), 4.74 (d,
J¼11.6 Hz, 2H, 2PhCH2O), 4.97 (d, J¼11.6 Hz, 2H,
2PhCH2O), 6.83 (d, J¼8.3 Hz, 2H, Ar), 7.24–7.37 (m,
12H, Ar) ppm; 13C NMR (100 MHz, CDCl3) d 41.7, 55.3,
73.5 (2C), 78.8 (2C), 114.1, 127.2, 128.3, 128.5, 130.5,
136.5, 159.4, 172.4 (2C) ppm; MS (ESI, m/z): 432 (M+H+,
100). Anal. Calcd for [C26H25NO5+2/3H2O]: C, 70.41; H,
5.98; N, 3.16. Found: C, 70.33; H, 6.02; N, 3.34.
1
2939, 1742, 1642, 1235, 1090 cmꢁ1. H NMR (400 MHz,
CDCl3) d 1.33 (t, J¼7.2 Hz, 6H, 2ꢀCH3), 3.38 (d, J¼
6.9 Hz, 2H, 2ꢀOH), 4.32 (q, J¼7.2 Hz, 4H, 2ꢀMeCH2),
4.55 (d, J¼6.9 Hz, 2H, 2ꢀOCH) ppm; 13C NMR
(100 MHz, CDCl3) d 14.0 (2C), 62.4 (2C), 72.0 (2C),
171.5 (2C) ppm. Anal. Calcd for C8H14O6: C, 46.60; H,
6.84. Found: C, 46.42; H, 7.28.
4.1.2. (3S,4R,5R)-5-Benzyloxymethyl-3,4-dibenzyloxyl-
1-(4-methoxybenzyl)-pyrrolidin-2-one (13a).
4.1.2.1. Method 1: by Mg/HgCl2-mediated benzyloxy-
methylation. To a two-necked, 100-mL round-bottomed
bottle containing tartarimide 14 (770 mg, 1.79 mmol), mag-
nesium turnings (357 mg, 14.88 mmol), mercury(II) chlo-
ride (55 mg), and anhydrous THF (12 mL) was added, at rt
and under an N2 atmosphere, a solution of benzyloxymethyl
chloride (60% purity, 2.49 mL, 10.74 mmol) in THF
(18 mL) over 1 h. The mixture was stirred at rt for 7 h.
The resulting mixture was diluted with water (30 mL), and
a 2 N solution of HCl was added until a clear solution
formed. The mixture was extracted with dichloromethane
(3ꢀ35 mL). The combined extracts were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated in
vacuum. The residue was purified by a short column of silica
gel eluting with ethyl acetate–P.E. (1:3) to give 21 (800 mg,
yield, 81%) as a diastereomeric mixture, which was used in
the next step without further purification.
To a suspension of NaH (60% in mineral oil, 1.36 g,
34.07 mmol) in dry DMF (40 mL) was added dropwise a
solution of 18 (3.51 g, 17.04 mmol) in DMF (10 mL) at
ꢁ20 ꢂC. The reaction was stirred for 30 min at the same tem-
perature, then to the mixture was added BnBr (6.1 mL,
51.12 mmol) and the stirring was continued for 40 min.
The mixture was stirred at 0 ꢂC for 1 h. The reaction was
quenched by cautionary addition of water (250 mL) and ex-
tracted with Et2O (5ꢀ40 mL). The combined extracts were
washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated in vacuum. The residue was purified by
flash column chromatography on silica gel eluting with ethyl
acetate–P.E. (1:6) to give 1923 (5.59 g, 85%) as a colorless
oil. [a]2D0 ꢁ133.8 (c 0.8, CHCl3). IR (film): 2982, 2904,
1
1755, 1731, 1454, 1269, 1106 cmꢁ1. H NMR (400 MHz,
CDCl3) d 1.18 (t, J¼7.1 Hz, 6H, 2ꢀCH3), 4.07 (dq,
J¼10.7, 7.1 Hz, 2H, 2ꢀMeCH2), 4.20 (dq, J¼10.7, 7.1 Hz,
2H, 2ꢀMeCH2), 4.39 (s, 2H, 2ꢀBnOCH), 4.45 (d, J¼
12.0 Hz, 2H, 2ꢀPhCH2O), 4.87 (d, J¼12.0 Hz, 2H, 2ꢀ
PhCH2O), 7.20–7.35 (m, 10H, Ar) ppm; 13C NMR
(100 MHz, CDCl3) d 14.0 (2C), 61.2 (2C), 73.1 (2C), 78.3
(2C), 127.8, 128.2, 128.3, 136.9, 169.1 (2C) ppm; MS
(ESI, m/z): 387 (M+H+, 100).
To a cooled (ꢁ78 ꢂC) solution of diastereomeric mixture of
21 (800 mg, 1.45 mmol) in dry dichloromethane (20 mL)
was added under argon atmosphere triethylsilane (3.3 mL,
20.93 mmol) and boron trifluoride etherate (0.54 mL,
4.34 mmol). After stirring at ꢁ78 ꢂC for 8 h, the stirring
was continued overnight while the temperature was allowed
to rise. The reaction was quenched with saturated aqueous
sodium bicarbonate (15 mL) and extracted with dichloro-
methane (3ꢀ25 mL). The combined extracts were dried
(Na2SO4), filtered, and concentrated in vacuum. The residue
was chromatographed on a column of silica gel eluting with
ethyl acetate–P.E. (3:2) to give 13a (777 mg, yield, 62% over
two steps) as a white solid. Mp 90 ꢂC (P.E–ethyl
acetate¼6:1). [a]2D0 +4.0 (c 1.2, CHCl3).
A mixture of 19 (12.77 g, 33.08 mmol) and LiOH$H2O
(5.56 g, 132.38 mol) in a mixture of EtOH–H2O (v/v 3:1,
136 mL) was stirred at 0–5 ꢂC overnight. After removal of
ethanol under reduced pressure, the residue was acidified
with concd HCl to reach pH 2 and the resultant mixture
was extracted with ethyl acetate. The combined organic
extracts were washed with brine, dried over anhydrous
Na2SO4, and filtered. The solvent was removed under
reduced pressure to give 2023 (10.9 g, yield, 100%) as a
colorless oil, which was used in the next step without further
purification.
4.1.2.2. Method 2: by SmI2/FeCl3-mediated benzyloxy-
methylation. A freshly prepared solution of SmI2 (0.1 M in
THF) containing anhydrous FeCl3 (1.6 mg, 0.01 mmol) in
anhydrous THF (10 mL) was quickly added to a mixture of
14 (226 mg, 0.53 mmol) and benzyloxymethyl chloride
(60% purity, 0.35 mL, 1.57 mmol) in anhydrous THF
(4 mL) under argon atmosphere at 0 ꢂC. The mixture was
allowed to react at rt for 1 h. The reaction was quenched with
saturated aqueous sodium bicarbonate (5 mL) and extracted
with ether (3ꢀ20 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated in vacuum. The residue was purified by
flash column chromatography on silica gel eluting with ethyl
acetate–P.E. (1:3) to give N,O-acetal 21 (246 mg, yield,
84%) as a mixture of two diastereomers, which was used
in the next step without further purification.
A mixture of 20 (10.9 g, 33.03 mmol) and acetyl chloride
(20 mL) was refluxed for 4 h. After concentrating under
reduced pressure, the residue was dissolved in CH2Cl2
(15 mL), to which was added a solution of p-methoxy-
benzylamine (5.2 mL, 39.64 mmol) in CH2Cl2 (15 mL) at
0 ꢂC. The resultant mixture was refluxed for 5 h, and then
concentrated in vacuum. The residue was dissolved in acetyl
chloride (20 mL) and refluxed for 6 h. After concentration of
the reaction mixture in vacuum, the residue was purified by
column chromatography on silica gel eluting with ethyl ace-
tate–P.E. (1:4) to give 14 (12.81 g, yield, 90%) as white crys-
tals. Mp 137–138 ꢂC (ethyl acetate–P.E.). [a]2D0 ꢁ148.8 (c
0.8, CHCl3). IR (KBr pellet): 2936, 1715, 1514, 1343,
1
1249, 1106 cmꢁ1. H NMR (400 MHz, CDCl3) d 3.77 (s,
Following the procedure described above, the diastereomer-
ic mixture of 21 (246 mg, 0.44 mmol) was converted to
3H, CH3O), 4.36 (s, 2H, 2CH), 4.57 (d, J¼14.3 Hz, 1H,

6352
X. Zhou et al. / Tetrahedron 63 (2007) 6346–6357
13a (172 mg, yield, 61% from 14) as white crystals. Mp
86–87 ꢂC (ethyl acetate–P.E.). [a]D20 +3.4 (c 1.7, CHCl3).
IR (KBr pellet): 3031, 2902, 2868, 1699, 1451, 1247,
4.1.5. (2R,3R,4R)-2-Benzyloxymethyl-3,4-dibenzyloxy-
pyrrolidine (24).
4.1.5.1. Method 1: amide reduction using BH3$SMe2.
To a solution of 22 (332 mg, 0.80 mmol) in anhydrous THF
(8 mL) was added BH3$SMe2 (0.4 mL, 4.00 mmol) at 0 ꢂC.
After stirring at rt for two days, the reaction was quenched
with MeOH (2 mL) and H2O (3 mL). The resulting mixture
was further stirred at 60 ꢂC for 3 h, and then extracted with
Et2O (3ꢀ10 mL). The combined extracts were successively
washed with saturated aqueous sodium bicarbonate and
brine, dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuum. The residue was purified by flash column
chromatography on silica gel eluting with ethyl acetate–
P.E. (1:10, then 5:1) to give 23 (53 mg, yield, 16%) and 24
(32 mg, yield, 10%) and recovered starting material 22
(129 mg, yield, 39%). Compound 23: white crystals; mp
55–56 ꢂC (ethyl acetate–P.E.). [a]D20 +34.8 (c 0.4, CHCl3).
IR (KBr pellet): 3244, 3030, 2918, 2366, 2320, 2273, 1453,
1
1106 cmꢁ1. H NMR (400 MHz, CDCl3) d 3.38–3.45 (m,
2H, H-5, H-6), 3.52 (dd, J¼5.2, 11.6 Hz, 1H, H-6), 3.77
(s, 3H, CH3O), 3.94 (d, J¼14.8 Hz, 1H, PhCH2N), 4.05
(dd, J¼5.1, 5.2 Hz, 1H, H-4), 4.21 (d, J¼5.2 Hz, 1H, H-3),
4.35 (d, J¼12.0 Hz, 1H, PhCH2O), 4.42 (d, J¼12.0 Hz,
1H, PhCH2O), 4.45 (d, J¼11.7 Hz, 1H, PhCH2O), 4.56 (d,
J¼11.7 Hz, 1H, PhCH2O), 4.83 (d, J¼11.7 Hz, 1H,
PhCH2O), 4.94 (d, J¼14.8 Hz, 1H, PhCH2N), 5.13 (d,
J¼11.7 Hz, 1H, PhCH2O), 6.78 (d, J¼8.7 Hz, 2H, Ar),
7.05 (d, J¼8.7 Hz, 2H, Ar), 7.20–7.48 (m, 15H, Ar) ppm;
13C NMR (100 MHz, CDCl3) d 43.7, 55.3, 59.4, 67.4,
72.1, 72.4, 73.2, 78.8, 81.1, 114.0, 127.6, 127.7, 127.8,
127.9, 128.0, 128.2, 128.3, 128.4, 128.5, 128.6, 129.4,
129.7, 137.5, 137.6, 137.8, 159.0, 171.3 ppm; MS (ESI, m/
z): 560 (M+Na+, 21), 538 (M+H+, 100). Anal. Calcd for
C34H35NO5: C, 75.95; H, 6.56; N, 2.61. Found: C, 75.56;
H, 6.54; N, 2.56.
1362, 1168, 1096 cmꢁ1 1H NMR (400 MHz, CDCl3)
.
d 1.60 (br s, 3H, BH3), 2.99–3.05 (m, 1H, H-2), 3.09 (dd,
J¼4.3, 12.4 Hz, 1H, H-5), 3.37 (dd, J¼4.3, 12.4 Hz, 1H,
H-5), 3.57 (dd, J¼1.2, 10.1 Hz, 1H, H-6), 3.94 (ddd,
J¼1.2, 4.3, 4.3 Hz, 1H, H-4), 4.01 (dd, J¼3.2, 10.1 Hz, 1H,
H-6), 4.13 (dd, J¼1.2, 5.3 Hz, 1H, H-3), 4.42–4.60 (m, 6H,
3PhCH2O), 4.63 (br s, 1H, NH), 7.20–7.40 (m, 15H,
Ar) ppm; 13C NMR (100 MHz, CDCl3) d 59.0, 64.5, 70.6
(2C), 71.9, 73.2, 79.9, 83.4, 127.3, 127.4, 127.5, 127.6, 127.7,
127.8, 128.2, 128.3, 136.9, 137.0, 137.1 ppm; MS (ESI, m/z):
418 (M+H+, 100). Anal. Calcd for [C26H32NO3B+2H2O]: C,
68.88; H, 8.00; N, 3.09. Found: C, 68.60; H, 7.89; N, 3.33.
4.1.2.3. (3R,4S,5S)-5-Benzyloxymethyl-3,4-dibenzyl-
(ent-13a).
oxyl-1-(4-methoxybenzyl)-pyrrolidin-2-one
Starting from L-tartaric acid, and using the method described
in Sections 4.1.1 and 4.1.2.2, ent-13a was synthesized as
white crystals. Mp 86–87 ꢂC. [a]D20 ꢁ3.1 (c 1.73, CHCl3).
4.1.3. (3S,4R,5R)-5-Benzyloxymethyl-3,4-dibenzyloxy-
pyrrolidin-2-one (22). To a solution of 13a (279 mg,
0.52 mmol) in a mixed solvent system (MeCN–H2O 9:1,
v/v, 10 mL) was added ceric ammonium nitrate (1.423 g,
2.60 mmol) at 0 ꢂC. After stirring at the same temperature
for 4 h, the mixture was allowed to react at rt for 1.5 h.
The reaction was quenched with H2O (10 mL) and extracted
with ethyl acetate (3ꢀ10 mL). The combined extracts were
washed with saturated aqueous sodium bicarbonate and
brine, dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuum. The residue was purified by flash column
chromatography on silica gel eluting with ethyl acetate–P.E.
(1:2) to give 22 (182 mg, yield, 85%) as white crystals. Mp
58–59 ꢂC (ethyl acetate–P.E.) (lit.15g mp 54.5–56 ꢂC). [a]2D0
ꢁ2.1 (c 1.1, CHCl3) {lit.15g [a]D ꢁ3.9 (c 0.77, CHCl3)}. IR
(KBr pellet): 3223, 3031, 2866, 1714, 1453, 1358, 1106,
4.1.5.2. Method 2: amide reduction using LiAlH4. A
solution of 22 (201 mg, 0.48 mmol) in anhydrous THF
(5 mL) was added dropwise to a stirred suspension of
LiAlH4 (96 mg, 2.53 mmol) in anhydrous THF (5 mL) at
0 ꢂC. After stirring at 60 ꢂC for 12 h, the reaction was cooled
and quenched cautiously with water (2 mL). The resulting
mixture was filtered and the solid was washed with EtOAc.
The filtrate was dried over anhydrous Na2SO4, filtered, and
concentrated in vacuum. The residue was purified by flash
column chromatography on silica gel eluting with ethyl ace-
tate–P.E. (5:1) to give 24 (178 mg, yield, 92%) as a colorless
oil. [a]2D0 +7.1 (c 1.2, CHCl3) {lit.15g [a]D +3.5 (c 0.79,
CHCl3)}. IR (film): 3058, 3030, 2862, 1453, 1365, 1206,
1
1027 cmꢁ1. H NMR (400 MHz, CDCl3) d 3.32 (dd, J¼
1
8.5, 9.2 Hz, 1H, H-6), 3.61 (dd, J¼3.5, 9.2 Hz, 1H, H-6),
3.67 (ddd, J¼3.5, 5.9, 8.5 Hz, 1H, H-5), 3.89 (dd, J¼5.9,
6.1 Hz, 1H, H-4), 4.22 (d, J¼6.1 Hz, 1H, H-3), 4.48 (s,
2H, PhCH2O), 4.51 (d, J¼11.7 Hz, 1H, PhCH2O), 4.60 (d,
J¼11.7 Hz, 1H, PhCH2O), 4.80 (d, J¼11.6 Hz, 1H,
PhCH2O), 5.12 (d, J¼11.6 Hz, 1H, PhCH2O), 6.03 (br s,
1H, NH), 7.20–7.45 (m, 15H, Ar) ppm; 13C NMR
(100 MHz, CDCl3) d 56.1, 71.4, 72.3, 72.6, 73.5, 80.8,
81.1, 127.7, 127.8, 127.9, 128.0, 128.3, 128.4, 128.5,
128.6, 137.4, 137.5, 137.6, 173.1 ppm; MS (ESI, m/z): 418
(M+H+, 96), 440 (M+Na+, 100). Anal. Calcd for
C26H27NO4: C, 74.80; H, 6.52; N, 3.35. Found: C, 74.39;
H, 6.54; N, 3.31.
1097, 1029 cmꢁ1. H NMR (400 MHz, CDCl3) d 2.11 (br
s, 1H, NH), 3.07 (d, J¼3.8 Hz, 2H, H-5), 3.22 (ddd, J¼
4.7, 5.2, 5.4 Hz, 1H, H-2), 3.53 (dd, J¼5.4, 9.4 Hz, 1H, H-
6), 3.59 (dd, J¼5.2, 9.4 Hz, 1H, H-6), 3.85 (dd, J¼1.8,
4.7 Hz, 1H, H-3), 3.99 (ddd, J¼1.8, 3.8, 3.8 Hz, 1H, H-4),
4.41–4.55 (m, 6H, 3PhCH2O), 7.21–7.40 (m, 15H, Ar) ppm;
13C NMR (100 MHz, CDCl3) d 51.1, 64.1, 70.4, 71.0, 71.8,
73.1, 84.5, 85.7, 127.4, 127.5, 127.6, 127.7, 127.8, 128.2,
128.3, 138.0, 138.1, 138.2 ppm; MS (ESI, m/z): 404 (M+H+,
100). Anal. Calcd for C26H29NO3: C, 77.39; H, 7.24; N,
3.47. Found: C, 77.55; H, 7.22; N, 3.70.
4.1.6. (2S,3S,4S)-2-Benzyloxymethyl-3,4-dibenzyloxy-
pyrrolidine (ent-24). Starting from ent-22, and using the
method described in Section 4.1.5.2, ent-24 was synthesized
as a colorless oil. [a]2D0 ꢁ4.7 (c 1.2, CHCl3).
4.1.4. (3R,4S,5S)-5-Benzyloxymethyl-3,4-dibenzyloxy-
pyrrolidin-2-one (ent-22). Starting from ent-13a, and using
the method described in Section 4.1.3, ent-22 was synthe-
sized as white crystals. Mp 58–59 ꢂC. [a]D20 +1.9 (c 2.56,
CHCl3).
4.1.7. (2R,3R,4R)-3,4-Dihydroxy-2-hydroxymethylpyr-
rolidine hydrochloride (1$HCl). A methanolic solution

X. Zhou et al. / Tetrahedron 63 (2007) 6346–6357
6353
(5 mL) of 24 (46 mg, 0.11 mmol) was stirred at rt in the pres-
ence of 10% Pd/C (130 mg) and a catalytic amount of
HCOOH for 24 h. The catalyst was removed by filtration
and the reaction mixture was concentrated. To the crude
was slowly added at 0 ꢂC a mixture of MeOH (5 mL) and
acetyl chloride (0.01 mL). After stirring for 30 min at
0 ꢂC, the resulting mixture was evaporated in vacuum, fur-
ther evaporation under high vacuum gave DAB 1 hydro-
chloride salt (1$HCl) (19 mg, yield, 100%), which is pure
enough to give satisfactory physical and spectral data. Pale
yellow syrup. [a]D20 +36.1 (c 0.2, H2O); [a]2D0 +38.0 (c 0.2,
MeOH) {lit.15a [a]2D0 +37.9 (c 0.53, H2O); lit.15g [a]2D0
+32.5 (c 0.5, H2O)}. IR (film): 3346, 2929, 1593, 1450,
d 2.45–2.54 (m, 2H), 2.72 (dd, J¼5.6, 11.2 Hz, 1H, H-5),
2.90–2.96 (m, 1H), 2.98 (dd, J¼2.4, 11.2 Hz, 1H, H-5),
3.57–3.63 (m, 4H), 3.85 (dd, J¼2.7, 4.8 Hz, 1H, H-3),
4.03 (ddd, J¼2.4, 2.7, 5.6 Hz, 1H, H-4) ppm; 13C NMR
(100 MHz, D2O) d 56.3, 58.7, 59.2, 60.8, 72.1, 75.4,
78.7 ppm; HRESIMS calcd for [C7H15NO4+H]+:
178.1074; found: 178.1075.
4.1.11. (2R,3R,4R)-3,4-Dihydroxy-1-hydroxyethyl-2-
hydroxymethylpyrrolidine hydrochloride (4$HCl). A
methanolic solution (5 mL) of 25 (40 mg, 0.09 mmol) was
stirred at rt in the presence of 10% Pd/C (120 mg) and a
catalytic amount of HCOOH for 24 h. The catalyst was
removed by filtration and the reaction mixture was concen-
trated. To the crude was slowly added at 0 ꢂC a mixture of
MeOH (5 mL) and acetyl chloride (0.01 mL). After stirring
for 30 min at 0 ꢂC, the resulting mixture was evaporated in
vacuum, further evaporation under high vacuum gave N-
hydroxyethyl-DAB 1 hydrochloride salt (4$HCl) (18 mg,
yield, 98%), which is pure enough to give satisfactory phys-
ical and spectral data. Pale yellow syrup. [a]2D0 ꢁ35.7 (c 0.2,
MeOH); [a]2D0 ꢁ37.1 (c 0.2, H2O). IR (film): 3357, 2935,
1
1384, 1071 cmꢁ1. H NMR (400 MHz, D2O) d 3.28 (dd,
J¼2.5, 12.5 Hz, 1H, H-5), 3.46–3.54 (m, 2H, H-2, H-5),
3.76 (dd, J¼8.1, 12.2 Hz, 1H, H-6), 3.88 (dd, J¼4.7,
12.2 Hz, 1H, H-6), 3.99–4.03 (m, 1H), 4.22–4.28 (m,
1H) ppm; 13C NMR (100 MHz, D2O) d 50.0, 59.0, 66.6,
74.3, 75.7 ppm; HRESIMS calcd for [C5H11NO3+H]+:
134.0812; found: 134.0814.
4.1.8. (2S,3S,4S)-3,4-Dihydroxy-2-hydroxymethylpyrro-
lidine hydrochloride (2$HCl). Starting from ent-24, and
using the method described in Section 4.1.7, LAB 1 hydro-
chloride salt (2$HCl) was synthesized as pale yellow syrup
{[a]2D0 ꢁ41.1 (c 0.2, MeOH); lit.15a [a]2D0 ꢁ34.6 (c 0.37,
H2O); lit.15g [a]D20 ꢁ36.5 (c 0.37, H2O)}.
1
2844, 1591, 1442, 1386, 1074 cmꢁ1. H NMR (400 MHz,
D2O) d 3.19–3.27 (m, 1H), 3.42–3.52 (m, 3H), 3.60 (dd,
J¼1.2, 12.4 Hz, 1H, H-5), 3.79–3.92 (m, 4H, H-7, H-8), 4.01
(dd, J¼2.7, 3.1 Hz, 1H, H-3), 4.22–4.27 (m, 1H, H-4) ppm;
13C NMR (100 MHz, D2O) d 56.5, 58.0, 58.4, 59.2, 73.9,
75.0, 76.0 ppm; HRESIMS calcd for [C7H15NO4+H]+:
178.1074; found: 178.1075.
4.1.9. (2R,3R,4R)-2-Benzyloxymethyl-3,4-dibenzyloxyl-
1-hydroxyethylpyrrolidine (25). To a suspension of 24
(186 mg, 0.46 mmol) and K2CO3 (310 mg, 2.25 mmol) in
MeOH (6 mL) was added 2-bromoethanol (0.2 mL,
2.77 mmol). After stirring for 48 h at rt, the reaction mixture
was filtered and the solid was washed with CH2Cl2. The fil-
trate was concentrated in vacuum. The residue was purified
by flash column chromatography on silica gel eluting with
ethyl acetate–P.E. (1:1) to give 25 (165 mg, yield, 80%) as
a colorless oil. [a]D20 ꢁ25.2 (c 0.4, CHCl3). IR (film):
3440, 3062, 3030, 2914, 2863, 1459, 1454, 1366, 1209,
4.1.12. (3S,4R,5R)-5-Benzyloxymethyl-1-(tert-butoxycar-
bonyl)-3,4-dibenzyloxy-pyrrolidin-2-one (26). To a solu-
tion of 22 (725 mg, 1.74 mmol) and DMAP (29 mg,
0.09 mmol) in CH2Cl2 (15 mL) was successively added
NEt3 (0.53 mL, 3.82 mmol) and a solution of (Boc)2O
(0.8 mL, 3.47 mmol) in CH2Cl2 (5 mL). After stirring at rt
for 4 h, the reaction was quenched with saturated aqueous
sodium bicarbonate (5 mL) and extracted with CH2Cl2
(3ꢀ20 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered, and con-
centrated in vacuum. The residue was purified by flash col-
umn chromatography on silica gel eluting with ethyl
acetate–P.E. (1:6) to give 26 (852 mg, yield, 95%) as a color-
less oil. [a]2D0 ꢁ73.7 (c 0.6, CHCl3). IR (film): 3031, 2979,
1098 cmꢁ1 1H NMR (400 MHz, CDCl3) d 2.55 (dt,
.
J¼12.6, 3.8 Hz, 1H, H-6), 2.65 (dd, J¼5.3, 10.5 Hz, 1H,
H-5), 2.80–2.92 (m, 2H, H-2, OH, D2O exchangeable),
3.04 (ddd, J¼4.8, 8.9, 12.6 Hz, 1H, H-6), 3.24 (dd, J¼1.4,
10.5 Hz, 1H, H-5), 3.49–3.64 (m, 4H, H-7, H-8), 3.88 (dd,
J¼1.2, 3.8 Hz, 1H, H-3), 3.97 (ddd, J¼1.2, 1.4, 5.3 Hz,
1H, H-4), 4.40–4.54 (m, 6H, 3PhCH2O), 7.24–7.35 (m,
15H, Ar) ppm; 13C NMR (100 MHz, CDCl3) d 56.9, 57.1,
59.7, 68.9, 70.8, 71.1, 71.3, 73.2, 81.7, 84.9, 127.4, 127.5,
127.6, 127.7, 128.3, 128.4, 137.9, 138.0, 138.1 ppm; MS
(ESI, m/z): 448 (M+H+, 100); HRESIMS calcd for
[C28H33NO4+H]+: 448.2482; found: 448.2488.
1790, 1755, 1720, 1455, 1306, 1027 cmꢁ1 1H NMR
.
(400 MHz, CDCl3) d 1.49 (s, 9H, 3CH3), 3.65–3.72 (m,
2H, H-5, H-6), 4.05–4.14 (m, 3H, H-3, H-4, H-6), 4.45–
4.55 (m, 4H, 2PhCH2O), 4.72 (d, J¼11.8 Hz, 1H, PhCH2O),
4.94 (d, J¼11.8 Hz, 1H, PhCH2O), 7.20–7.50 (m, 15H,
Ar) ppm; 13C NMR (100 MHz, CDCl3) d 27.9 (3C), 61.2,
67.9, 71.6, 72.4, 73.2, 76.6, 80.5, 83.6, 127.6, 127.7, 127.9,
128.0, 128.2, 128.3, 128.4, 128.5, 137.1, 137.2, 137.7, 149.6,
170.7 ppm; MS (ESI, m/z): 540 (M+Na+, 100). Anal. Calcd
for C31H35NO6: C, 71.93; H, 6.82; N, 2.71. Found: C, 72.32;
H, 6.85; N, 2.75.
4.1.10. (2R,3R,4R)-3,4-Dihydroxy-1-hydroxyethyl-2-hy-
droxymethylpyrrolidine (4).
A methanolic solution
(5 mL) of 25 (36 mg, 0.08 mmol) was stirred at rt in the pres-
ence of 10% Pd/C (108 mg) under 1 atm hydrogen pressure
for 48 h. The catalyst was removed by filtration and the re-
action mixture was concentrated. Further evaporation under
high vacuum gave 4 (14 mg, yield, 100%), which is pure
enough to give satisfactory physical and spectral data. Pale
yellow syrup. [a]D20 ꢁ49.6 (c 0.3, MeOH); [a]2D0 ꢁ46.7 (c
0.3, H2O) {lit.8 [a]D20 +54.7 (c 0.38, H2O)}. IR (film):
4.1.13. (2R,3R,4R,5R/S)-2-Benzyloxymethyl-3,4-diben-
zyloxyl-5-methylpyrrolidine (28 and 29). To a cooled
(ꢁ20 ꢂC) solution of 26 (391 mg, 0.76 mmol) in anhydrous
CH2Cl2 (10 mL) was added dropwise a solution of MeMgI
(2 M, 0.75 mL, 1.50 mmol) in diethyl ether under nitrogen
atmosphere. After stirring at the same temperature for 2 h,
the reaction was quenched with saturated aqueous solution
1
3359, 2926, 1407, 1048 cmꢁ1. H NMR (400 MHz, D2O)

6354
X. Zhou et al. / Tetrahedron 63 (2007) 6346–6357
of ammonium chloride (5 mL) and extracted with CH2Cl2
(3ꢀ20 mL). The combined extracts were dried over anhy-
drous Na2SO4, filtered, and concentrated in vacuum. The
residue was purified by flash column chromatography on
silica gel eluting with ethyl acetate–P.E. (1:1) to give
N,O-acetal 27 (332 mg, yield, 82%) as an inseparable mix-
ture of two diastereomers, which was used in the next step
without further separation.
methanolic solution (5 mL) of 28 (62 mg, 0.15 mmol) was
stirred at rt in the presence of 10% Pd/C (200 mg) and a
catalytic amount of HCOOH for 24 h. The catalyst was
removed by filtration and the reaction mixture was concen-
trated. To the crude was slowly added at 0 ꢂC a mixture of
MeOH (5 mL) and acetyl chloride (0.01 mL). After stirring
for 30 min at 0 ꢂC, the resulting mixture was evaporated in
vacuum, further evaporation under high vacuum gave hydro-
chloride salt of 6-deoxy-DMDP (7$HCl) (22 mg, yield,
98%), which is pure enough to give satisfactory physical
and spectral data. Compound 7: pale yellow syrup. [a]D20
+40.5 (c 0.3, MeOH); [a]2D0 +41.2 (c 0.1, H2O) {lit.17d
[a]2D0 +45.0 (c 1.4, MeOH)}. IR (film): 3373, 2938, 1636,
To a cooled (ꢁ78 ꢂC) solution of diastereomer mixture 27
(332 mg, 0.62 mmol) in anhydrous CH2Cl2 (10 mL) was
added dropwise triethylsilane (0.98 mL, 7.6 mmol) and bo-
ron trifluoride etherate (0.23 mL, 2.2 mmol) under nitrogen
atmosphere. After stirring at ꢁ78 ꢂC for 6 h, the mixture was
allowed to react at rt and stir overnight. The reaction was
quenched with saturated aqueous sodium bicarbonate and
extracted with CH2Cl2 (3ꢀ20 mL). The combined extracts
were washed with brine, dried over anhydrous Na2SO4, fil-
tered, and concentrated in vacuum. The residue was purified
by flash column chromatography on silica gel eluting with
ethyl acetate to give two diastereomers 28 and 29 (in 9.4:1
ratio, 208 mg, combined yield, 80%). Major diastereomer
28: colorless oil. [a]2D0 +16.4 (c 0.3, CHCl3). IR (film): 3030,
2864, 1453, 1364, 1099 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d 1.22 (d, J¼6.6 Hz, 3H, CH3), 2.10 (br s, 1H, NH), 3.22 (dq,
J¼5.4, 6.6 Hz, 1H, H-5), 3.39–3.44 (m, 1H, H-2), 3.52 (d,
J¼6.1 Hz, 2H, H-6), 3.64 (dd, J¼3.5, 5.4 Hz, 1H, H-4),
3.88 (dd, J¼3.5, 3.7 Hz, 1H, H-3), 4.48–4.56 (m, 6H,
3PhCH2O), 7.20–7.40 (m, 15H, Ar) ppm; 13C NMR
(100 MHz, CDCl3) d 19.5, 57.3, 61.7, 70.8, 71.8, 71.9, 73.2,
86.7, 91.1, 127.6, 127.7, 127.8, 127.9, 128.4, 138.1, 138.2,
138.3 ppm; MS (ESI, m/z): 418 (M+H+, 100); HRESIMS
calcd for [C27H31NO3+H]+: 418.2377; found: 418.2369.
1
1392, 1105, 1051 cmꢁ1. H NMR (400 MHz, D2O) d 1.35
(d, J¼6.8 Hz, 3H, CH3), 3.43 (dq, J¼7.0, 6.8 Hz, 1H, H-
5), 3.48 (ddd, J¼3.9, 6.8, 6.8 Hz, 1H, H-2), 3.75 (dd,
J¼6.8, 12.2 Hz, 1H, H-6), 3.80 (dd, J¼7.0, 7.2 Hz, 1H, H-
4), 3.84 (dd, J¼3.9, 12.2 Hz, 1H, H-6), 3.95 (dd, J¼6.8,
7.2 Hz, 1H, H-3) ppm; 13C NMR (100 MHz, D2O) d 14.4,
57.4, 58.2, 62.1, 74.4, 79.0 ppm; HRESIMS calcd for
[C6H13NO3+H]+: 148.0968; found: 148.0969.
4.1.16. (2R,3R,4R,5S)-2-(Benzyloxymethyl)-5-(4-benzyl-
oxyphenyl)-3,4-dibenzyloxy-pyrrolidine (34). To a cooled
(ꢁ20 ꢂC) solution of 26 (434 mg, 0.84 mmol) in anhydrous
CH2Cl2 (10 mL) was added dropwise a solution of 4-
benzyloxy-phenyl magnesium bromide13c (1 M, 2.5 mL,
2.50 mmol) in diethyl ether under nitrogen atmosphere.
After stirring at the same temperature for 2 h, the reaction
was quenched with saturated aqueous solution of ammoni-
um chloride (6 mL) and extracted with dichloromethane
(3ꢀ10 mL). The combined extracts were dried over anhy-
drous Na2SO4, filtered, and concentrated in vacuum. The
residue was purified by flash column chromatography on sil-
ica gel eluting with ethyl acetate–P.E. (1:6) to give a mixture
of 32 (a diastereomeric mixture) and its ring-opening tauto-
mer 33 (415 mg, combined yield, 81%).
4.1.14. (2R,3R,4R,5S)-1-Benzyl-2-benzyloxymethyl-3,4-
dibenzyloxyl-5-methylpyrrolidine (30). To a suspension
of 29 (20 mg, 0.05 mmol) and K2CO3 (30 mg, 0.22 mmol)
in MeOH (2 mL) was added benzyl bromide (0.04 mL,
0.30 mmol). After stirring for 24 h at rt, the reaction mixture
was filtered and the solid was washed with CH2Cl2. The fil-
trate was concentrated in vacuum. The residue was purified
by flash column chromatography on silica gel eluting with
ethyl acetate–P.E. (1:25) to give 30 (18 mg, yield, 75%) as
a colorless oil. [a]2D0 +43.1 (c 0.2, CHCl3). IR (film): 3029,
To a cooled (ꢁ78 ꢂC) solution of a mixture of 32 and 33
(415 mg, 0.59 mmol) in dry dichloromethane (10 mL) was
added dropwise triethylsilane (0.94 mL, 5.9 mmol) and bo-
ron trifluoride etherate (0.22 mL, 1.77 mmol) under nitrogen
atmosphere. After stirring at ꢁ78 ꢂC for 6 h, the mixture was
allowed to react at rt and stir overnight. The reaction was
quenched with saturated aqueous sodium bicarbonate and
extracted with dichloromethane (3ꢀ10 mL). The combined
extracts were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated in vacuum. The residue
was purified by flash column chromatography on silica gel
eluting with ethyl acetate–P.E. (1:4) to give 34 (287 mg,
yield, 58% from 26) as a white solid. Mp 79–80 ꢂC (ethyl
acetate–P.E.). [a]2D0 +34.0 (c 1.25, CHCl3). IR (KBr pellet):
2923, 2859, 1494, 1452, 1367, 1092 cmꢁ1 1H NMR
.
(400 MHz, CDCl3) d 1.23 (d, J¼6.4 Hz, 3H, CH3), 3.01–
3.09 (m, 2H, H-2, H-5), 3.19 (dd, J¼4.8, 9.5 Hz, 1H, H-6),
3.35 (dd, J¼9.2, 9.5 Hz, 1H, H-6), 3.65 (d, J¼1.2, 4.6 Hz,
1H, H-4), 3.70 (d, J¼14.0 Hz, 1H, PhCH2N), 3.84 (dd,
J¼1.2, 2.0 Hz, 1H, H-3), 3.93 (d, J¼14.0 Hz, 1H, PhCH2N),
4.30 (d, J¼12.0 Hz, 1H, PhCH2O), 4.33 (d, J¼12.2 Hz, 1H,
PhCH2O), 4.40 (d, J¼12.0 Hz, 1H, PhCH2O), 4.45 (d, J¼
12.1 Hz, 1H, PhCH2O), 4.50 (d, J¼12.2 Hz, 1H, PhCH2O),
4.52 (d, J¼12.1 Hz, 1H, PhCH2O), 7.20–7.35 (m, 20H,
Ar) ppm; 13C NMR (100 MHz, CDCl3) d 13.9, 57.4, 61.2,
68.6, 70.8, 71.4, 71.9, 72.9, 83.0, 83.9, 126.9, 127.3,
127.4, 127.5, 127.6, 127.7, 127.8, 128.1, 128.2, 128.3, 129.4,
138.4, 138.5, 139.0 ppm; MS (ESI, m/z): 508 (M+H+, 100);
HRESIMS calcd for [C34H37NO3+H]+: 508.2846; found:
508.2842.
1
3061, 2861, 1510, 1454, 1238 cmꢁ1. H NMR (400 MHz,
CDCl3) d 3.37–3.42 (m, 1H, H-2), 3.63 (dd, J¼6.3,
9.3 Hz, 1H, H-6), 3.70 (dd, J¼5.4, 9.3 Hz, 1H, H-6), 3.86
(dd, J¼1.3, 4.5 Hz, 1H, H-3), 3.90 (dd, J¼1.3, 4.6 Hz, 1H,
H-4), 4.04 (d, J¼12.0 Hz, 1H, PhCH2O), 4.12 (d,
J¼12.0 Hz, 1H, PhCH2O), 4.35 (d, J¼4.5 Hz, 1H, H-5),
4.50 (s, 2H, PhCH2O), 4.53 (d, J¼12.0 Hz, 1H, PhCH2O),
4.57 (d, J¼12.0 Hz, 1H, PhCH2O), 5.08 (s, 2H, PhCH2O),
6.91–6.98 (m, 4H, Ar), 7.19–7.46 (m, 20H, Ar) ppm; 13C
NMR (100 MHz, CDCl3) d 63.2, 64.6, 70.1, 71.6, 71.7,
71.9, 73.2, 85.0, 85.9, 114.4, 127.5, 127.6, 127.7, 127.8,
4.1.15. (2R,3R,4R,5R)-3,4-Dihydroxyl-2-hydroxymethyl-
5-methylpyrrolidine
hydrochloride
(7$HCl).
A

X. Zhou et al. / Tetrahedron 63 (2007) 6346–6357
6355
Asymmetry 2005, 11, 1645–1680; (f) Legler, G. Iminosugars
€
as Glycosidase Inhibitors; Stutz, A. E., Ed.; Wiley-VCH:
New York, NY, 1998; Chapter 3.
127.9, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 129.4, 131.0,
137.2, 138.1, 138.2, 138.4, 158.0 ppm; MS (ESI, m/z): 608
(M+Na+, 8), 586 (M+H+, 100). Anal. Calcd for
[C39H39NO4+2H2O]: C, 75.34; H, 6.97; N, 2.25. Found: C,
75.89; H, 6.97; N, 2.36.
2. (a) Horii, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N.;
Matsui, K. J. Med. Chem. 1986, 29, 1038–1046; (b) Fischer,
P. B.; Collin, M.; Karlsson, G. B.; James, M.; Butters, T. D.;
Davis, S. J.; Gordon, S.; Dwek, R. A.; Platt, F. M. J. Virol.
1995, 69, 5791–5797.
3. (a) Furukawa, J.; Okuda, S.; Saito, K.; Hatanaka, S.-I.
Phytochemistry 1985, 24, 593–594; (b) Nash, R. J.; Bell,
E. A.; Williams, J. M. Phytochemistry 1985, 24, 1620–1622.
4. (a) Jones, D. W. C.; Nash, R. J.; Bell, E. A.; Williams, J. M.
Tetrahedron Lett. 1985, 26, 3125–3126; (b) Fleet, G. W. J.;
Nicholas, S. J.; Smith, P. W.; Evans, S. V.; Fellows, L. E.; Nash,
R. J. Tetrahedron Lett. 1985, 26, 3127–3130.
5. (a) Scofield, A. M.; Fellows, L. E.; Nash, R. J.; Fleet, G. W. Life
Sci. 1986, 39, 645–650; (b) Axamawaty, M. T. H.; Fleet,
G. W. J.; Hannah, K. A.; Namgoong, S. K.; Sinnott, M. L.
Biochem. J. 1990, 266, 245–249; (c) Mackay, P.; Ynddal, L.;
Andersen, J. V.; McCormack, J. G. Diabetes Obes. Metab.
2003, 5, 397–407; (d) Fleet, G. W. J.; Karpas, A.; Dwek,
R. A.; Fellows, L. E.; Tyms, A. S.; Petursson, S.; Namgoong,
S. K.; Ramsden, N. G.; Jacob, G. S.; Rademacher, T. W.
FEBS Lett. 1988, 237, 128–132; (e) Karpas, A.; Fleet,
G. W. J.; Dwek, R. A.; Petursson, S.; Namgoong, S. K.;
Ramsden, N. G.; Jacob, G. S.; Rademacher, T. W. Proc. Natl.
Acad. Sci. U.S.A. 1988, 85, 9229–9233.
6. (a) Shibata, T.; Nakayama, O.; Tsurumi, Y.; Okuhara, M.;
Terno, H.; Kohsaka, M. J. Antibiot. 1988, 41, 296–301; (b)
Kayakiri, H.; Yakase, S.; Setoi, H.; Uchida, I.; Terano, H.;
Hashimoto, M. Tetrahedron Lett. 1988, 29, 1725–1728.
7. Ysujii, E.; Muroi, M.; Shiragami, N.; Takatsuki, A. Biochem.
Biophys. Res. Commun. 1996, 220, 459–466.
4.1.17. 4-[(2R,3R,4R)-4-Amino-2,3,5-trihydroxypentyl]-
phenol (35). A methanolic solution (4 mL) of 34 (40 mg,
0.07 mmol) was stirred at rt in the presence of 10% Pd/C
(200 mg) under 1 atm hydrogen pressure for 4 h. The cata-
lyst was removed by filtration and the reaction mixture
was concentrated. Further evaporation under high vacuum
gave 35 (14 mg, yield, 96%), which is pure enough to give
satisfactory physical and spectral data. Pale yellow syrup.
[a]2D0 +21.0 (c 0.3, MeOH). IR (film): 3372, 2925, 1611,
1
1385, 1036 cmꢁ1. H NMR (400 MHz, D2O) d 2.69 (dd,
J¼8.5, 13.8 Hz, 1H, H-1), 2.77 (dd, J¼5.6, 13.8 Hz, 1H,
H-1), 3.42–3.47 (m, 1H, H-4), 3.67–3.73 (m, 2H, H-5),
3.80–3.86 (m, 2H, H-2, H-3), 6.79 (d, J¼8.6 Hz, 2H, Ar),
7.10 (d, J¼8.6 Hz, 2H, Ar) ppm; 13C NMR (100 MHz,
D2O) d 38.2, 55.5, 58.1, 69.0, 72.1, 115.4, 129.7, 130.7,
154.0 ppm; MS (ESI, m/z): 228 (M+H+, 100); HRESIMS
calcd for [C11H17NO4+H]+: 228.1230; found: 228.1236.
4.1.18. (2R,3R,4R,5S)-2-(Hydroxymethyl)-5-(4-hydroxy-
phenyl)pyrrolidine-3,4-diol (36). An ethanolic solution
(4 mL) of 34 (34 mg, 0.06 mmol) was stirred at rt in the pres-
ence of PdCl2 (183 mg) under 1 atm hydrogen pressure for
12 h. The catalyst was removed by filtration and the reaction
mixture was concentrated. Further evaporation under high
vacuum gave 36 (12 mg, yield, 92%), which is pure enough
to give satisfactory physical and spectral data. Pale yellow
syrup. [a]2D0 +47.7 (c 0.3, MeOH). IR (film): 3388, 2925,
1619, 1408, 1072 cmꢁ1
.
1H NMR (400 MHz, D2O)
8. Yasuda, K.; Kizu, H.; Yamashita, T.; Kameda, Y.; Kato, A.;
Nash, R. J.; Fleet, G. W. J.; Molyneux, R. J.; Asano, N.
J. Nat. Prod. 2002, 65, 198–202.
9. (a) Buku, A.; Faulstich, H.; Wieland, T.; Dabrowski, J. Proc.
Natl. Acad. Sci. U.S.A. 1980, 77, 2370–2371; (b) Faulstich,
H.; Buku, A.; Bodenmueller, H.; Wieland, T. Biochemistry
1980, 19, 3334–3343.
d 3.51–3.58 (m, 1H, H-2), 3.61–3.66 (m, 1H), 3.85 (dd,
J¼8.6, 12.2 Hz, 1H, H-6), 3.95 (dd, J¼4.8, 12.2 Hz, 1H,
H-6), 4.12 (dd, J¼1.2, 2.2 Hz, 1H), 4.31 (d, J¼2.3 Hz, 1H,
H-5), 6.88 (d, J¼8.5 Hz, 2H, Ar), 7.32 (d, J¼8.5 Hz, 2H,
Ar) ppm; 13C NMR (100 MHz, D2O) d 59.4, 64.5, 67.2,
75.9, 76.4, 115.7, 121.8, 129.7, 156.2 ppm; MS (ESI, m/z):
226 (M+H+, 100); HRESIMS calcd for [C11H15NO4+H]+:
226.1074; found: 226.1077.
10. Dondoni, A.; Giovannini, P. P.; Perrone, D. J. Org. Chem. 2002,
67, 7203–7214.
11. (a) Welter, A.; Jadot, J.; Dardenne, G.; Marlier, M.; Casimir, J.
Phytochemistry 1976, 15, 747–749; (b) Nash, R. J.; Asano, N.;
Eatson, A. A. Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Elsevier Science: Oxford,
1996; Vol. 11, pp 345–376.
12. (a) Molyneux, R. J.; Pan, Y. T.; Tropea, J. E.; Elbein, A. D.;
Lawyer, C. H.; Hughes, D. J.; Fleet, G. W. J. J. Nat. Prod.
1993, 56, 1356–1364; (b) Asano, N.; Yasuda, K.; Kizu, H.;
Kato, A.; Fan, J.-Q.; Nash, R. J.; Fleet, G. W. J.; Molyneux,
R. J. Eur. J. Biochem. 2001, 268, 35–41.
Acknowledgements
The authors are grateful to the NSF of China (20390050;
20572088), Qiu Shi Science & Technologies Foundation
(Hong Kong), and the program for Innovative Research
Team in Science & Technology (University) in Fujian Prov-
ince for financial support.
13. (a) Shibano, M.; Tsukamoto, D.; Masuda, A.; Tanaka, Y.;
Kusano, G. Chem. Pharm. Bull. 2001, 49, 1362–1365; (b)
Tsukamoto, D.; Shibano, M.; Kusano, G. Chem. Pharm. Bull.
2001, 49, 1487–1491; For revision of absolute configuration
of radicamines, see: (c) Yu, C. Y.; Huang, M. H. Org. Lett.
2006, 8, 3021–3024.
14. For reviews on the enantiomeric synthesis of 2-hydroxymethyl-
pyrrolidine alkaloids, see: (a) Ref. 1c; (b) El-Ashry, E.-S. H.; El
Nemr, A. Carbohydr. Res. 2003, 338, 2265–2290; (c) Ayad, T.;
Genisson, Y.; Baltas, M. Curr. Org. Chem. 2004, 8, 1211–
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References and notes
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