Polyhydroxylated pyrrolidines: Synthesis of trideoxy-2,5-iminohexitols

Article abstract of DOI:10.1055/s-2008-1072566

A series of naturally occurring pyrrolidine alkaloids and analogues, with the general structure of trideoxy-2,5-iminohexitols (imino- or azasugars), have been enantiosynthesized using triorthogonally protected pyrrolidines, previously prepared from commercial D-fructose, as homochiral starting materials. The inhibitory activity of some of the described compounds against glycosidases and glycosyltransferases makes them potential therapeutic agents. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072566

PAPER
1373
Polyhydroxylated Pyrrolidines: Synthesis of Trideoxy-2,5-iminohexitols1
S
ynthesi
s
s
of
T
ride
i
oxy-2,5
d
-iminohexit
o
Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
Fax +34(958)243845; E-mail: isidoro@ugr.es
Received 30 November 2007
HO
OH
HO
H
H
H
Abstract: A series of naturally occurring pyrrolidine alkaloids and
analogues, with the general structure of trideoxy-2,5-iminohexitols
(imino- or azasugars), have been enantiosynthesized using trior-
thogonally protected pyrrolidines, previously prepared from com-
mercial D-fructose, as homochiral starting materials. The inhibitory
activity of some of the described compounds against glycosidases
and glycosyltransferases makes them potential therapeutic agents.
N
N
N
HO
OH
HO
OH
HO
OH
ent-2 (3)*
6-deoxy-DGDP (1)
1-deoxy-DGDP (2)
HO
OH
H
H
N
N
Key words: natural products, alkaloids, carbohydrates, azasugars,
stereoselective synthesis
HO
OH
HO
OH
1-deoxy-DALDP* (4)
ent-4 (5)
In 1991 Wong and co-workers2 described, for the first
time, a synthetic methodology that combined an enzymat-
ic aldol condensation reaction, giving a key intermediate
5-azido-5-deoxyhexulose, with a highly stereocontrolled
intramolecular reductive amination, which afforded a tri-
hydroxylated pyrrolidine identified as 2,5,6-trideoxy-2,5-
imino-D-glucitol (6-deoxy-DGDP, 1). Two years later,3
Wong’s group, using the same methodology, reported the
synthesis of 1 as well as of three new trideoxy-2,5-imino-
hexitols, named as 1,2,5-trideoxy-2,5-imino-D-glucitol
(1-deoxy-DGDP, 2), 1,2,5-trideoxy-2,5-imino-L-altritol
(ent-4 = 5), and 1,2,5-trideoxy-2,5-imino-D-mannitol (1-
deoxy-DMDP, 7)4 (see Figure 1). Compound 7 was isolat-
ed in the same year by Molyneux and co-workers from
seeds5 of Angylocalyx pynaertii (Leguminosae) and more
recently, together with compounds 3 and 4, from the bark6
and pods7 of this plant. The structure and absolute config-
uration of 7 was confirmed by an unambiguous synthesis
from diacetone D-glucose.5 Bisseret and co-workers8 re-
ported a new synthesis of 7 using lithiation of an aziridine
ring, whereas a highly diastereoselective reductive benzyl-
oxymethylation of protected tartarimide was the method-
ology chosen by Huang and co-workers9 in order to
achieve the synthesis of 7. Compound 2 has also been syn-
thesized by Lee and Jeong10 from commercial D-glucu-
rono-d-lactone and by Clapés and co-workers,11 together
with 3, 5, 2,5,6-trideoxy-2,5-imino-D-altritol (6-deoxy-
DALDP, 6), 7, and ent-7 (= 8), through an enzymatic re-
action similar to that mentioned above. Pyrrolidines 4 and
6 were also prepared by Defoin and co-workers12 from
chiral 1,2-oxazines, while the former has recently been
described by Moriarty and co-workers who employed an
exo- to endo-iminocyclitol rearrangement.13 Compound 7
was shown to be a moderate competitive inhibitor versus
OH
OH
HO
H
H
H
N
N
N
HO
OH
HO
OH
HO
OH
6-deoxy-DALDP (6)
ent-7 (8)
1-deoxy-DMDP (7)*
Figure 1 Some naturally occurring (starred) and synthetic trihydro-
xylated pyrrolidines
b-mannosidase (IC50 380 mM),5 as well as a potent inhib-
itor of bovine epididymis a-L-fucosidase (IC50 150 mM),
rat epididymis b-mannosidase (IC50 93 mM), and bovine
liver b-galactosidase (IC50 30 mM).6,7 Compounds 1, 2, 5,
and 7 have potent inhibitory activity against a-L-fucosi-
dase from bovine kidney with close Ki values of 4, 8, 1.4,
and 22 mM, respectively,3,6,14 and a moderate inhibition
against a-1,3-fucosyltransferase, with 1 and 5 showing a
potent synergistic effect in the presence of GDP.15 In ad-
dition, compound 4 shows a competitive inhibitory activ-
ity versus b-D-glucosidase (IC50 100 mM),12 whereas
compound 6 is a potent inhibitor against a-D-mannosidase
(IC50 53 mM), a-L-fucosidase (IC50 9 mM), and a-L-galac-
tosidase (IC50 5 mM).12 Finally, pyrrolidine 3 is a potent
inhibitor of bovine epididymis a-L-fucosidase (IC50
1
mM).6,7
With the aim of exploring the whole area of chemistry oc-
cupied by the trideoxy-2,5-iminohexitols, new syntheses
of these compounds must continue to be developed. In ad-
dition, naturally occurring azasugars are scarcely present
in the natural sources and are often difficult to purify from
them;16 therefore, synthetic routes to these azasugars and
analogues are also required. In this context, in recent years
our group has put into practice a synthetic methodology
consisting of the use of commercial D-fructose as homo-
chiral starting material for the preparation of orthogonally
protected tetrahydroxylated pyrrolidines.17,18 Such protec-
tion allows the easy chemical manipulation of the free
SYNTHESIS 2008, No. 9, pp 1373–1378
x
x
.
x
x
.2
0
0
8
Advanced online publication: 27.03.2008
DOI: 10.1055/s-2008-1072566; Art ID: P14007SS
© Georg Thieme Verlag Stuttgart · New York

1374
I. Izquierdo et al.
PAPER
Cbz
Cbz
N
R
N
R1
OPG
HO
OPG
PGO
OH
OH
H
N
N
c
15
OBz
BnO
OBn
BnO
BnO
OBn
RO
d
OR
16 R = Bn
13 R = Cbz; R1 = OH
14 R = Cbz; R1 = I
15 R = R1 = H
9
13
a
2
R = H
b
PG = TBDPS
HO
OPG
PG = TBDPS
Cbz
N
Boc
N
OPG
HO
Scheme 2 Synthesis of 2 from 13. Reagents and conditions: a) I2,
Ph3P, imidazole, THF, reflux; b) H2, Raney Ni, MeOH, 3.4 × 103
mbar, r.t.; c) TBAF·3H2O, THF, r.t.; d) H2, 10% Pd/C, MeOH, H+,
4 × 103 mbar, r.t.; then Amberlite IRA-400 (OH– form).
OBn
BnO
BnO
OBn
17
21
R
R1
OPG
R
N
Figure 2 Starting orthogonally protected polyhydroxylated pyrroli-
dines for the synthesis of trideoxy-2,5-iminohexitols
OH
N
c
19
R
HO
PGO
R1
H
BnO
OBn
R1O
20 R = Boc; R1 = Bn
R = R1 = H
OR1
N
N
c
11
17 R = Boc; R1 = OH
18 R = Boc; R1 = I
19 R = Boc; R1 = H
a
d
6
b
RO
12 R = Bn; R1 = Bz
R = R1 = H
OR1
BnO
OBz
PG = TBDPS
9
R = Cbz; R1 = OH
d
a
10 R = Cbz; R1 = I
11 R = R1 = H
1
Scheme 3 Synthesis of 6 from 17. Reagents and conditions: a) I2,
Ph3P, imidazole, THF, reflux; b) H2, Raney Ni, Et3N, MeOH, balloon,
r.t.; c) TBAF·3H2O, THF, r.t.; d) (i) H2, 10% Pd/C, MeOH, H+,
4 × 103 mbar, r.t., (ii) neutralization with NaOMe, MeOH; then chro-
matography on Dowex® 50WX8 (200–400 mesh) with 1 N aq
NH4OH.
b
PG = TBDPS
Scheme 1 Synthesis of 1 from 9. Reagents and conditions: a) I2,
Ph3P, imidazole, THF, reflux; b) H2, Raney Ni, Et3N, MeOH,
3.4 × 103 mbar, r.t.; then H2, 10% Pd/C, MeOH, 4 × 103 mbar, r.t.; c)
TBAF·3H2O, THF, r.t.; d) (i) NaOMe (cat.), MeOH, r.t., (ii) H2, 10%
Pd/C, MeOH, H+, 4 × 103 mbar, r.t.; then Amberlite IRA-400 (OH–
form).
R
R1
OPG
OH
H
N
N
d
24
functional groups in order to prepare different trihydroxy-
lated pyrrolidines from a particular isomer. Figure 2 dis-
plays the starting pyrrolidines used in the present work.
BnO
OBn
RO
e
OR
25 R = Bn
21 R = Cbz; R1 = OH
22 R = Cbz; R1 = I
23 R = Cbz; R1 = H
24 R = R1 = H
a
b
c
7
R = H
As shown in Scheme 1, reaction of (2S,3R,4R,5R)-4-(ben-
zoyloxy)-3-(benzyloxy)-1-(benzyloxycarbonyl)-2-[(tert-
butyldiphenylsilyloxy)methyl]-5-(hydroxymethyl)pyrro-
lidine (9)17 under Garegg’s conditions19 gave the corre-
PG = TBDPS
Scheme 4 Synthesis of 7 from 21. Reagents and conditions: a) I2,
sponding 5-iodomethyl derivative 10. Catalytic Ph3P, imidazole, THF, reflux; b) H2, Raney Ni, Et3N, MeOH, balloon,
hydrogenation of 10 with Raney nickel20 resulted in deh-
alogenation concomitant with partial N-deprotection
which was finally achieved after further hydrogenation
r.t.; c) H2, 10% Pd/C, MeOH, balloon, r.t.; d) TBAF·3H2O, THF, r.t.;
e) H2, 10% Pd/C, MeOH, H+, 4 × 103 mbar, r.t.; then Amberlite IRA-
400 (OH– form).
over 10% palladium on carbon to afford 11. Compound 11
was straightforwardly deprotected to the required 6-
{[a]D24 +16 (c 1.0, MeOH), [a]D24 +17 (c 0.5, H2O); Lit.3
25
20
[a]D +22.7 (c 1.2, MeOH), Lit.11a [a]D +16 (c 0.4,
deoxy-DGDP (1) which has spectroscopic data in close
agreement with those previously reported2b for a mixture
of the 5R:5S-isomers in a 6:1 ratio; thus, for the first time,
physical and spectroscopic data for pure 1 are included
herein.
MeOH)}. In addition, some other minor signals were ob-
1
served in the H NMR spectrum of 3,6 with the authors
giving an explanation for these minor signals as being a
consequence of the presence of conformational isomers;
however, we think that 3 could be contaminated with an
unresolved isomer.
Following the above synthetic protocol starting with pyr-
rolidine 1318a (see Scheme 2), 1-deoxy-DGDP (2) could
be synthesized, but in this case N-deprotection was con-
comitant during the dehalogenation step. Although the 1H
NMR spectrum of our synthetic 2 is in accordance with
those spectra reported by Wong’s group3 and Espelt and
co-workers,11a and with those reported for the natural sup-
posed enantiomer 3,6,7 the value and sign of the optical ro-
tation of the latter {[a]D +23.3 (c 0.64, H2O)}6 indicates
that 3 actually has the configuration of our synthetic 2
For the synthesis of 2,5,6-trideoxy-2,5-imino-D-altritol
(6-deoxy-DALDP, 6), the chiral starting material was pyr-
rolidine 1721 (see Scheme 3). Garegg’s OH Æ I inter-
change gave 18 which was dehalogenated as above to the
5-methylpyrrolidine 19. Conventional total deprotection
of 19 yielded 6 which has analytical and spectroscopic
data in total accordance with those previously report-
ed.11,12
Synthesis 2008, No. 9, 1373–1378 © Thieme Stuttgart · New York

PAPER
Synthesis of Trideoxy-2,5-iminohexitols
1375
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-1-(benzyloxycarbonyl)-2-
[(tert-butyldiphenylsilyloxy)methyl]-5-(iodomethyl)pyrrolidine
(14)
The naturally occurring pyrrolidine alkaloid 7 was pre-
pared as follows (see Scheme 4): compound 2122 was
transformed into its 5-iodomethyl derivative 22, which
was dehalogenated and N-deprotected as above to afford
the 5-methylpyrrolidine 24. Conventional O-desilylation
of 24 to 25 and subsequent total O-debenzylation by cata-
lytic hydrogenation gave the expected 7 which has analyt-
ical and spectroscopic data in total agreement with those
already reported.3,5,11
Obtained as a colorless syrup, from 1318a (0.42 mmol); yield: 240
mg (69%); [a]D29 +32 (c 0.7).
IR (neat): 3068 and 3031 (aromatic), 1709 (CO, Cbz), 739 and 699
cm–1 (aromatic).
1H NMR (400 MHz): d = 7.60–7.19 (m, 25 H, 5 × Ph), 5.25–5.03
(m, 2 H, CH2Ph), 4.60 and 4.57 (2 × s, 4 H, 2 × CH2Ph), 4.42–3.18
(3 × m, 8 H, H-2,2¢a,2¢b,3,4,5,5¢a,5¢b), 1.05 (s, 9 H, CMe3).
In conclusion, we have enantiosynthesized four meth-
ylpyrrolidines with the general structure of trideoxy-2,5-
iminohexitols: 6-deoxy-DGDP (1), 1-deoxy-DGDP (2),
6-deoxy-DALDP (6) and 1-deoxy-DMDP (7), from D-
fructose.
13C NMR (100 MHz): d (inter alia) = 154.55 (CO, Cbz), 80.59 and
77.52 (C-3,4), 71.92 (CH2Ph), 69.83 (Cbz), 65.60 and 61.49 (C-2¢,
two rotamers), 64.86 and 61.75 (C-2,5), 25.43 (CMe3), 17.80
(CMe3), 0.00 (C-5¢).
HRMS (LSIMS): m/z [M + Na]+ calcd for C44H48INO5NaSi:
848.2244; found: 848.2246.
Solutions were dried over MgSO4 before concentration under re-
duced pressure. 1H and 13C NMR spectra were recorded with Bruker
AMX-300, AM-300, ARX-400, and AMX-500 spectrometers for
solutions in CDCl3 (internal TMS), unless otherwise indicated. IR
spectra were recorded with a Perkin–Elmer FT-IR Spectrum One
instrument and mass spectra were recorded with a Hewlett–Packard
HP-5988-A and Fisons mod. Platform II and VG Autospec-Q mass
spectrometers. Optical rotations were measured for solutions in
CHCl3, unless otherwise indicated, in a 1-dm tube with a Jasco DIP-
370 polarimeter. TLC was performed on precoated silica gel 60 F254
aluminum sheets; detection was achieved by employing a mixture
of 10% ammonium molybdate (w/v) in 10% aqueous sulfuric acid
containing 0.8% cerium sulfate (w/v), and heating. Column chro-
matography was performed on silica gel (Merck, 7734). The non-
crystalline compounds were shown to be homogeneous by
chromatographic methods and were characterized by NMR, MS,
and HRMS data.
(2R,3S,4R,5S)-3,4-Bis(benzyloxy)-1-(tert-butoxycarbonyl)-2-
[(tert-butyldiphenylsilyloxy)methyl]-5-(iodomethyl)pyrrolidine
(18)
Obtained as a colorless syrup, from 1721 (1.47 mmol); yield: 970 mg
(83%); [a]D25 +14, [a]40525 +46 (c 1.1).
IR (neat): 3069 and 3031 (aromatic), 1698 (CO, Boc), 737 and 700
cm–1 (aromatic).
1H NMR (400 MHz): d = 7.77–7.23 (2 × m, 20 H, 4 × Ph), 4.84–
4.60 (m, 4 H, 2 × CH2Ph), 4.40–2.96 (8 × m, 8 H, H-
2,2¢a,2¢b,3,4,5,5¢a,5¢b), 1.44 and 1.27 (2 × s, 9 H, OCMe3, two rot-
amers), 1.06 and 1.04 (2 × s, 9 H, SiCMe3, two rotamers).
13C NMR (100 MHz): d (inter alia) = 154.04 (CO, Boc), 81.27,
80.61 and 77.25 (C-3,4, two rotamers), 73.02 and 72.21 (2 ×
CH2Ph), 63.14 (C-2¢), 62.45, 61.55 and 61.41 (C-2,5, two rotamers),
28.60 and 28.42 (OCMe3, two rotamers), 27.22 and 27.11 (SiCMe3,
two rotamers), 19.41 (2 × CMe3), 7.99 (C-5¢).
HRMS (LSIMS): m/z [M + Na]+ calcd for C41H50INO5NaSi:
814.2401; found: 814.2393.
OH ÆI Interchange in Orthogonally Protected Pyrrolidines 9,
13, 17, and 21; General Procedure
To a soln of the protected 5-(hydroxymethyl)pyrrolidine (0.5–2
mmol) in anhyd THF (10–20 mL) was added Ph3P (2 equiv), imida-
zole (4 equiv), and I2 (2 equiv) at r.t. The mixture was refluxed (30
min–2 h) until TLC (Et2O–hexane mixtures) revealed the absence
of the starting material and the presence of a compound with higher
mobility. The solvent was evaporated and the residue was dissolved
in Et2O (20–30 mL), washed with Na2S2O3 (15–20 mL) and concen-
trated. Column chromatography (Et2O–hexane mixtures) of the res-
idue gave the corresponding 5-(iodomethyl)pyrrolidine.
(2R,3R,4R,5S)-3,4-Bis(benzyloxy)-1-(benzyloxycarbonyl)-2-
[(tert-butyldiphenylsilyloxy)methyl]-5-(iodomethyl)pyrrolidine
(22)
Obtained as a colorless syrup, from 2122 (2 mmol); yield: 1.55 g
(94%); [a]D26 +3.7, [a]40526 +29.4 (c 0.7).
IR (neat): 3068 and 3032 (aromatic), 1705 (CO, Cbz), 739 and 699
cm–1 (aromatic).
1H NMR (400 MHz): d = 7.64–7.10 (m, 25 H, 5 × Ph), 5.21, 5.01,
5.00 and 4.95 (4 × d, 2 H, J = 12.3 Hz, CH2Ph, two rotamers), 4.65–
4.48, 4.34–4.15, 4.07–3.47 and 3.34–3.32 (4 × m, 12 H, CH2Ph,
Cbz, H-2,2¢a,2¢b,3,4,5,5¢a,5¢b, two rotamers), 1.07 and 1.02 (2 × s,
9 H, CMe3, two rotamers).
13C NMR (100 MHz): d (inter alia) = 154.68 and 154.39 (CO, Cbz,
two rotamers), 84.62, 83.65, 82.66 and 81.80 (C-3,4, two rotamers),
71.80, 71.67, 71.17, 67.33, 62.16 and 61.34 (3 × CH2Ph, C-2¢, two
rotamers), 66.34, 66.10, 65.87 and 65.84 (C-2,5, two rotamers),
27.15 and 27.06 (CMe3, two rotamers), 19.56 and 19.46 (CMe3, two
rotamers), 5.89 and 5.26 (C-5¢, two rotamers).
(2S,3R,4R,5S)-4-(Benzoyloxy)-3-(benzyloxy)-1-(benzyloxycar-
bonyl)-2-[(tert-butyldiphenylsilyloxy)methyl]-5-(iodometh-
yl)pyrrolidine (10)
Obtained as a colorless syrup, from 917 (1.57 mmol); yield: 1.2 g
(91%); [a]D26 –6, [a]40526 –7.6 (c 1.4).
IR (neat): 3069 and 3033 (aromatic), 1709 (CO, Bz and Cbz), 739
and 701 cm–1 (aromatic).
1H NMR (400 MHz): d = 8.05–7.20 (m, 25 H, 5 × Ph), 5.86 (t, 1 H,
J3,4 = J4,5 = 1.6 Hz, H-4), 5.20–5.00 (m, 2 H, CH2Ph), 4.89 and 4.69
(2 × d, 2 H, J = 10.9 Hz, CH2Ph), 4.40–3.20 (3 × m, 7 H, H-
2,2¢a,2¢b,3,5,5¢a,5¢b), 1.05 (s, 9 H, CMe3).
13C NMR (100 MHz): d (inter alia) = 165.56 (CO, Bz), 155.00 (CO,
Cbz), 82.00 and 77.77 (C-3,4), 73.60 (CH2Ph), 67.50 (Cbz), 65.04,
62.85, 62.29, 61.43 and 61.05 (C-2,2¢,5, two rotamers), 27.14
(CMe3), 19.42 (CMe3), 4.54 (C-5¢).
HRMS (LSIMS): m/z [M + Na]+ calcd for C44H48INO5NaSi:
848.2244; found: 848.2245.
(2S,3R,4R,5R)-4-(Benzoyloxy)-3-(benzyloxy)-2-[(tert-butyl-
diphenylsilyloxy)methyl]-5-methylpyrrolidine (11)
To a soln of compound 10 (1.17 g, 1.39 mmol) in MeOH (20 mL),
Et3N (0.39 mL, 2.8 mmol) was added. The mixture was hydrogenat-
ed at 3.4 × 103 mbar over wet Raney nickel (500 mg, Fluka) for 24
h; TLC (Et2O–hexane, 3:1) then revealed the presence of a com-
Anal. Calcd for C44H46INO6Si: C, 62.93; H, 5.52; N, 1.67. Found:
C, 62.70; H, 5.83; N, 2.19.
Synthesis 2008, No. 9, 1373–1378 © Thieme Stuttgart · New York

1376
I. Izquierdo et al.
PAPER
pound with lower mobility. The catalyst was filtered off and washed
with MeOH (15 mL), and the combined filtrate and washings were
concentrated to a residue that was submitted to column chromatog-
raphy (Et2O–hexane, 1:1) to afford a mixture of the N-Cbz-protect-
ed 5-methylpyrrolidine (600 mg) and the free amine 11 (80 mg).
The N-Cbz derivative was then hydrogenated in MeOH (10 mL) at
4 × 103 mbar over 10% Pd/C (80 mg) for 24 h; TLC showed the end
of the reaction. The catalyst was filtered off and washed with MeOH
(15 mL), and the combined filtrate and washings were concentrated
to a residue that was submitted to column chromatography (Et2O–
hexane, 1:1) to afford colorless syrupy 11; yield: 500 mg (63%);
[a]D23 +6, [a]40523 –6 (c 1).
IR (neat): 3070 (aromatic), 1721 (CO, Bz), 739 and 701 cm–1 (aro-
matic).
1H NMR (400 MHz): d = 8.08–7.28 (m, 20 H, 4 × Ph), 5.11 (br s, 1
H, H-4), 4.84 and 4.60 (2 × d, 2 H, J = 11.7 Hz, CH2Ph), 4.06 (br s,
1 H, H-3), 3.98–3.87 (m, 2 H, H-2¢a,2¢b), 3.44 and 3.31 (2 × m, 2 H,
H-2,5), 1.37 (d, 3 H, J5,Me = 6.7 Hz, Me), 1.07 (s, 9 H, CMe3).
13C NMR (100 MHz, MeOH-d4): d = 81.40 (C-4), 75.94 (C-3),
64.16 (C-2), 62.29 (C-5), 57.99 (C-2¢), 16.41 (Me).
HRMS (LSIMS): m/z [M + Na]+ calcd for C6H13NO3Na: 170.0793;
found: 170.0791.
(2R,3R,4R,5S)-3,4-Bis(benzyloxy)-2-[(tert-butyldiphenylsilyl-
oxy)methyl]-5-methylpyrrolidine (15)
A soln of compound 14 (464 mg, 0.56 mmol) in MeOH (15 mL)
was hydrogenated at 3.4 × 103 mbar over wet Raney nickel (500
mg, Fluka) for 24 h; TLC (Et2O–hexane, 1:1) then revealed the
presence of a compound with lower mobility. The catalyst was fil-
tered off and washed with MeOH (15 mL), and the combined filtrate
and washings were concentrated to a residue that was submitted to
column chromatography (Et2O–hexane, 1:1 Æ 5:1) to afford syrupy
15; yield: 200 mg (63%); [a]D24 +26 (c 1).
IR (neat): 3069, 738 and 700 cm–1 (aromatic).
1H NMR (400 MHz): d = 7.67–7.65 and 7.36–7.32 (2 × m, 20 H, 4
× Ph), 4.60 and 4.46 (2 × d, 2 H, J = 12.1 Hz, CH2Ph), 4.51 and 4.47
(2 × d, 2 H, J = 12.1 Hz, CH2Ph), 3.98 (d, 1 H, J2,3 = 4.3, J3,4 = 0.0
Hz, H-3), 3.85 (dd, 1 H, J2,2¢a = 4.7, J2¢a,2¢b = 12.5 Hz, H-2¢a), 3.82
(dd, 1 H, J2,2¢b = 4.3 Hz, H-2¢b), 3.76 (d, 1 H, J4,5 = 3.9 Hz, H-4),
3.32 (dq, 1 H, H-5), 3.18 (q, 1 H, H-2), 1.98 (br s, 1 H, NH), 1.27
(d, 3 H, J5,Me = 6.7 Hz, Me), 1.05 (s, 9 H, CMe3).
13C NMR (100 MHz): d (inter alia) = 85.30 and 85.25 (C-3,4),
72.00 and 71.22 (2 × CH2Ph), 66.35 and 57.44 (C-2,5), 63.78 (C-2¢),
27.08 (CMe3), 19.53 (CMe3), 14.03 (Me).
13C NMR (100 MHz): d (inter alia) = 166.24 (CO, Bz), 83.82 and
83.63 (C-3,4), 71.69 (CH2Ph), 63.90 and 59.97 (C-2,5), 63.61 (C-
2¢), 27.12 (CMe3), 20.09 (Me), 19.45 (CMe3).
HRMS (LSIMS): m/z [M + Na]+ calcd for C36H41NO4NaSi:
602.2703; found: 602.2697.
(2S,3R,4R,5R)-4-(Benzoyloxy)-3-(benzyloxy)-2-(hydroxymeth-
yl)-5-methylpyrrolidine (12)
To a stirred soln of 11 (500 mg, 0.86 mmol) in THF (15 mL) was
added TBAF·3H2O (400 mg, 1.29 mmol) and the mixture was kept
at r.t. for 12 h; TLC (Et2O) then showed the presence of a new com-
pound with lower mobility. The mixture was concentrated to a res-
idue that was submitted to column chromatography (Et2O Æ Et2O–
MeOH, 10:1), which gave pure 12 as a colorless syrup; yield: 240
mg (82%); [a]D26 +7 (c 1).
HRMS (LSIMS): m/z [M + Na]+ calcd for C36H43NO3NaSi:
588.2910; found: 588.2914.
(2R,3R,4R,5S)-3,4-Bis(benzyloxy)-2-(hydroxymethyl)-5-meth-
ylpyrrolidine (16)
To a stirred soln of 15 (200 mg, 0.35 mmol) in THF (10 mL) was
added TBAF·3H2O (167 mg, 0.5 mmol) and the mixture was kept at
r.t. for 12 h; TLC (Et2O) then showed the presence of a new com-
pound with lower mobility. The mixture was concentrated to a res-
idue that was submitted to column chromatography (Et2O Æ Et2O–
MeOH, 10:1), which gave pure 16 as a colorless syrup; yield: 100
mg (88%); [a]D25 +35 (c 1, MeOH).
IR (neat): 3279 (OH), 1716 (CO, Bz) and 712 cm–1 (aromatic).
1H NMR (300 MHz): d = 8.07, 7.63 and 7.49 (d, t, t, 5 H, Bz), 7.35
(br s, 5 H, CH2Ph), 5.14 (dd, 1 H, J3,4 = 1.2, J4,5 = 4.2 Hz, H-4), 4.88
and 4.62 (2 × d, 2 H, J = 11.9 Hz, CH2Ph), 4.13 (dd, 1 H, J2,3 = 4.8
Hz, H-3), 3.99 (dd, 1 H, J2,2¢a = 3.6, J2¢a,2¢b = 12.0 Hz, H-2¢a), 3.88
(dd, 1 H, J2,2¢b = 4.5 Hz, H-2¢b), 3.42–3.32 (m, 1 H, H-5), 2.82–2.68
(m, 2 H, H-2, OH), 1.44 (d, 3 H, J5,Me = 6.5 Hz, Me).
13C NMR (75 MHz): d (inter alia) = 166.18 (CO, Bz), 86.46 and
84.01 (C-3,4), 71.71 (CH2Ph), 62.52, 61.28 and 59.60 (C-2,2¢,5),
19.59 (Me).
IR (neat): 3275 (OH), 3064, 3031, 737 and 698 cm–1 (aromatic).
1H NMR (500 MHz, MeOH-d4): d = 7.33–7.25 (br m, 10 H, 2 × Ph),
4.56 and 4.43 (2 × d, 2 H, J = 11.7 Hz, CH2Ph), 4.52 (s, 2 H,
CH2Ph), 3.88 (d, 1 H, J2,3 = 3.4, J3,4 = 0.0 Hz, H-3), 3.73 (d, 1 H,
J4,5 = 3.7 Hz, H-4), 3.63 (d, 2 H, J2,2¢ = 5.6 Hz, H-2¢,2¢), 3.24 (dq, 1
H, H-5), 3.10 (dt, 1 H, H-2), 1.22 (d, 3 H, J5,Me = 6.6 Hz, Me).
13C NMR (125 MHz, MeOH-d4): d (inter alia) = 88.73 and 88.34
(C-3,4), 75.53 and 75.04 (2 × CH2Ph), 70.64 and 61.03 (C-2,5),
66.11 (C-2¢), 16.48 (Me).
HRMS (LSIMS): m/z [M + Na]+ calcd for C20H23NO4Na: 364.1525;
found: 364.1527.
(2S,3R,4R,5R)-3,4-Dihydroxy-2-(hydroxymethyl)-5-methylpyr-
rolidine (6-Deoxy-DGDP, 1)
HRMS (LSIMS): m/z [M + Na]+ calcd for C20H25NO3Na: 350.1743;
NaOMe (2 N, 0.1 mL) was added to a soln of 12 (210 mg, 0.62
mmol) in anhyd MeOH (10 mL), and the reaction mixture was
maintained at r.t. for 12 h; TLC (Et2O–MeOH, 3:1) showed the
presence of a compound with lower mobility. The reaction mixture
was acidified with concd HCl and hydrogenated at 4 × 103 mbar
over 10% Pd/C (60 mg) for 24 h. The catalyst was filtered off and
washed with MeOH (15 mL). The mixture was neutralized with
Amberlite IRA-400 (OH– form), the resin was filtered off and
washed with MeOH (20 mL), and the filtrate and washings were
concentrated to afford 1 as a colorless syrup; yield: 70 mg (78%);
[a]D27 +3.5, [a]40528 –62 (c 1, MeOH).
1H NMR (400 MHz, MeOH-d4): d = 4.09 (dd, 1 H, J2,3 = 3.5,
J3,4 = 1.5 Hz, H-3), 3.92 (dd, 1 H, J2,2¢a = 5.1, J2¢a,2¢b = 11.7 Hz, H-
2¢a), 3.87 (dd, 1 H, J2,2¢b = 8.2 Hz, H-2¢b), 3.85 (dd, 1 H, H-4), 3.69
(br dt, 1 H, H-2), 3.38 (dq, 1 H, J4,5 = 3.1 Hz, H-5), 1.47 (d, 3 H,
J5,Me = 7.0 Hz, Me).
found: 350.1737.
(2R,3R,4R,5S)-3,4-Dihydroxy-2-(hydroxymethyl)-5-methylpyr-
rolidine (1-Deoxy-DGDP, 2)
A soln of 16 (100 mg, 0.3 mmol) in MeOH (10 mL) was acidified
with concd HCl and hydrogenated at 4 × 103 mbar over 10% Pd/C
(50 mg) for 24 h. The catalyst was filtered off and washed with
MeOH (15 mL). The combined filtrate and washings were neutral-
ized with Amberlite IRA-400 (OH– form), the resin was filtered off
and washed with MeOH (20 mL), and the filtrate and washings were
concentrated to afford 2 as a colorless syrup; yield: 38 mg (86%);
[a]D24 +16 (c 1, MeOH), [a]D24 +17 (c 0.5, H2O) {Lit.3 [a]D25 +22.7
(c 1.2, MeOH), Lit.11a [a]D20 +16 (c 0.4, MeOH)}.
1H NMR (500 MHz, MeOH-d4): d = 3.89 (dd, 1 H, J2,3 = 3.0,
J3,4 = 1.3 Hz, H-3), 3.84 (dd, 1 H, J4,5 = 3.4 Hz, H-4), 3.79 (dd, 1 H,
Synthesis 2008, No. 9, 1373–1378 © Thieme Stuttgart · New York

PAPER
Synthesis of Trideoxy-2,5-iminohexitols
1377
J2,2¢a = 4.7, J2¢a,2¢b = 11.4 Hz, H-2¢a), 3.71 (dd, 1 H, J2,2¢b = 7.7 Hz, H-
2¢b), 3.52 (dq, 1 H, H-5), 3.21 (ddd, 1 H, H-2), 1.29 (d, 3 H,
J5,Me = 6.7 Hz, Me).
13C NMR (125 MHz, MeOH-d4): d = 82.40 (C-4), 81.86 (C-3),
72.30 (C-2), 65.03 (C-2¢), 61.59 (C-5), 15.09 (Me).
HRMS (LSIMS): m/z [M + H]+ calcd for C6H14NO3: 148.0974;
found: 148.0975.
1H NMR (500 MHz, MeOH-d4): d = 4.22 (t, 1 H, J2,3 = J3,4 = 3.8
Hz, H-3), 3.93 (dd, 1 H, J2,2¢a = 4.9, J2¢a,2¢b = 11.8 Hz, H-2¢a), 3.92
(dd, 1 H, J4,5 = 9.0 Hz, H-4), 3.88 (dd, 1 H, J2,2¢b = 8.4 Hz, H-2¢b),
3.75 (dt, 1 H, H-2), 3.56 (dq, 1 H, H-5), 1.45 (d, 3 H, J5,Me = 6.7 Hz,
Me).
13C NMR (125 MHz, MeOH-d4): d = 76.92 (C-4), 70.35 (C-3),
62.09 (C-2), 58.16 (C-2¢), 56.52 (C-5), 14.40 (Me).
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-1-(benzyloxycarbonyl)-2-
[(tert-butyldiphenylsilyloxy)methyl]-5-methylpyrrolidine (23)
To a soln of compound 22 (1.55 g, 1.9 mmol) in MeOH (20 mL),
Et3N (0.52 mL, 3.8 mmol) was added. The mixture was hydrogenat-
ed over wet Raney nickel (500 mg, Fluka) in a H2 atmosphere for 40
h; TLC (Et2O–hexane, 1:3) then revealed the presence of a com-
pound with lower mobility. The catalyst was filtered off and washed
with MeOH (15 mL), and the combined filtrate and washings were
concentrated to a residue that was submitted to column chromatog-
raphy (Et2O–hexane, 1:4) to afford 23 as a colorless syrup; yield:
1.02 g (78%); [a]D27 –3, [a]40527 –4 (c 0.9).
(2R,3S,4R,5R)-3,4-Bis(benzyloxy)-1-(tert-butoxycarbonyl)-2-
[(tert-butyldiphenylsilyloxy)methyl]-5-methylpyrrolidine (19)
To a soln of compound 18 (970 mg, 1.22 mmol) in MeOH (20 mL),
Et3N (0.4 mL, 2.9 mmol) was added. The mixture was hydrogenated
over wet Raney nickel (500 mg, Fluka) in a H2 atmosphere for 18 h;
TLC (Et2O–hexane, 1:1) then revealed the presence of a compound
with lower mobility. The catalyst was filtered off and washed with
MeOH (15 mL), and the combined filtrate and washings were con-
centrated to a residue that was submitted to column chromatography
(Et2O–hexane, 1:5) to afford pure syrupy 19; yield: 750 mg (91%);
[a]D28 +13 (c 1).
IR (neat): 3068 and 3032 (aromatic), 1702 (CO, Cbz), 736 and 699
cm–1 (aromatic).
IR (neat): 1694 (CO, Boc), 737 and 700 cm–1 (aromatic).
1H NMR (300 MHz): d = 7.64–7.26 (2 × br m, 20 H, 4 × Ph), 4.89–
3.69 (m, 10 H, 2 × CH2Ph, H-2,2¢a,2¢b,3,4,5, two rotamers), 1.46
and 1.30 (2 × s, 9 H, OCMe3, two rotamers), 1.11 (d, 3 H, J5,Me = 6.0
Hz, Me), 1.06 (s, 9 H, SiCMe3).
HRMS (LSIMS): m/z [M + Na]+ calcd for C41H51NO5NaSi:
688.3434; found: 688.3426.
1H NMR (400 MHz): d = 7.69–7.14 (2 × m, 25 H, 5 × Ph), 5.18 and
5.00 (2 × d, J = 12.1 Hz, CH2Ph, minor rotamer), 5.03 and 4.95 (2
× d, J = 12.1 Hz, CH2Ph, major rotamer), 4.72 and 4.54 (2 × d,
J = 11.7 Hz, CH2Ph, minor rotamer), 4.67 and 4.57 (2 × d, J = 12.1
Hz, CH2Ph, major rotamer), 4.47–3.65 (5 × m, 8 H, Cbz, H-
2,2¢a,2¢b,3,4,5), 1.40 and 1.31 (2 × d, 3 H, J5,Me = 6.7 Hz, Me, two
rotamers), 1.09 and 1.03 (2 × s, 9 H, CMe3, two rotamers).
13C NMR (100 MHz): d (inter alia) = 154.98 and 154.49 (CO, Cbz,
two rotamers), 87.33, 86.33, 82.95 and 81.99 (C-3,4, two rotamers),
71.53, 71.29, 67.04 and 66.83 (3 × CH2Ph, two rotamers), 65.36,
65.02, 60.42 and 60.11 (C-2,5, two rotamers), 62.56 and 61.79 (C-
2¢, two rotamers), 27.19 and 27.08 (CMe3, two rotamers), 19.59 and
19.46 (CMe3, two rotamers), 18.68 and 17.54 (Me, two rotamers).
(2R,3S,4R,5R)-3,4-Bis(benzyloxy)-1-(tert-butoxycarbonyl)-2-
(hydroxymethyl)-5-methylpyrrolidine (20)
To a stirred soln of 19 (715 mg, 1.08 mmol) in THF (15 mL) was
added TBAF·3H2O (372 mg, 1.2 mmol) and the mixture was kept at
r.t. for 6 h; TLC (Et2O–hexane, 4:1) then showed the presence of a
new compound with lower mobility. The mixture was concentrated
to a residue that was submitted to column chromatography (Et2O–
hexane, 2:1), which gave pure 20 as a colorless syrup; yield: 400 mg
(87%); [a]D28 –26 (c 1).
HRMS (LSIMS): m/z [M + Na]+ calcd for C44H49NO5NaSi:
722.3278; found: 722.3284.
IR (neat): 3447 (OH), 3065 and 3031 (aromatic), 1693 and 1665
(CO, Boc), 737 and 698 cm–1 (aromatic).
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-[(tert-butyldiphenylsilyl-
oxy)methyl]-5-methylpyrrolidine (24)
1H NMR (400 MHz): d = 7.33 (br s, 10 H, 2 × Ph), 4.75, 4.70, 4.66,
4.60, 4.57 and 4.49 (6 × d, 4 H, J = 12.1 Hz, 2 × CH2Ph, two rota-
mers), 4.24–3.39 (several m, 6 H, H-2,2¢a,2¢b,3,4,5, two rotamers),
2.50 (br s, 1 H, OH), 1.48 and 1.46 (2 × s, 9 H, OCMe3, two rota-
mers), 1.16 and 1.15 (2 × d, 3 H, J5,Me = 6.8 Hz, Me, two rotamers).
13C NMR (100 MHz): d (inter alia) = 155.74 and 154.23 (CO, Boc,
two rotamers), 81.85, 80.40, 80.25 and 77.64 (C-3,4, two rotamers),
72.54, 72.39 and 72.11 (2 × CH2Ph, two rotamers), 62.09 and 59.76
(C-2¢, two rotamers), 60.82, 59.34, 57.58 and 57.14 (C-2,5, two rot-
amers), 28.70 and 26.80 (OCMe3, two rotamers), 19.76 and 19.06
(Me, two rotamers), 19.74 and 19.10 (OCMe3, two rotamers).
Compound 23 (1.0 g, 1.43 mmol) was hydrogenated in MeOH (10
mL) over 10% Pd/C (180 mg) in a H2 atmosphere for 4 h; TLC
(Et2O–hexane, 1:3) then showed the presence of a compound with
lower mobility. The catalyst was filtered off and washed with
MeOH (15 mL), and the combined filtrate and washings were con-
centrated to a residue that was submitted to column chromatography
(Et2O–hexane, 1:3) to afford pure syrupy 24; yield: 590 mg (71%);
[a]D24 +16.5 (c 1.0).
IR (neat): 3068, 3030, 738 and 700 cm–1 (aromatic).
1H NMR (300 MHz): d = 7.69–7.31 (2 × m, 20 H, 4 × Ph), 4.63 and
4.60 (2 × d, 2 H, J = 12.0 Hz, CH2Ph), 4.55 and 4.48 (2 × d, 2 H,
J = 12.0 Hz, CH2Ph), 4.01 (t, 1 H, J2,3 = 3.7 Hz, H-3), 3.78 (d, 2 H,
HRMS (LSIMS): m/z [M + Na]+ calcd for C25H33NO5Na: 450.2256;
found: 450.2260.
J
2,2¢ = 6.1 Hz, H-2¢,2¢), 3.70 (dd, 1 H, J3,4 = 3.2, J4,5 = 5.4 Hz, H-4),
3.36 (dt, 1 H, H-2), 3.25 (br quin, 1 H, H-5), 1.25 (d, 3 H, J5,Me = 6.6
(2R,3S,4R,5R)-3,4-Dihydroxy-2-(hydroxymethyl)-5-methylpyr-
rolidine (6-Deoxy-DALDP, 6)
Hz, Me), 1.11 (s, 9 H, CMe3).
13C NMR (75 MHz): d (inter alia) = 91.41 and 86.78 (C-3,4), 72.14
(2 × CH2Ph), 64.38 (C-2¢), 63.89 and 57.47 (C-2,5), 27.20 (CMe3),
19.76 (Me), 19.56 (CMe3).
HRMS (LSIMS): m/z [M + H]+ calcd for C36H44NO3Si: 566.3090;
found: 566.3094.
A soln of 20 (400 mg, 0.94 mmol) in MeOH (10 mL) was acidified
with concd HCl (2 mL) and hydrogenated at 4 × 103 mbar over 10%
Pd/C (75 mg) for 48 h. The catalyst was filtered off and washed with
MeOH (15 mL). The mixture was neutralized with 1 N NaOMe in
MeOH. Evaporation of the solvent afforded a residue that was re-
tained onto a column of Dowex® 50WX8 (200–400 mesh). The col-
umn was thoroughly washed with MeOH (30 mL), H2O (30 mL),
and then 1 N NH4OH (20 mL) to afford pure 6 as a colorless thick
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-(hydroxymethyl)-5-meth-
ylpyrrolidine (25)
To a stirred soln of 24 (560 mg, 1.0 mmol) in THF (15 mL) was add-
20
syrup; yield: 54 mg (39%); [a]D25 +36.3 (c 1, MeOH) {Lit.12a [a]D
+36 (c 0.83, MeOH), Lit.11b [a]D20 +37.9 (c 1.4, MeOH)}.
ed TBAF·3H2O (472 mg, 1.5 mmol) and the mixture was kept at r.t.
Synthesis 2008, No. 9, 1373–1378 © Thieme Stuttgart · New York

1378
I. Izquierdo et al.
PAPER
for 12 h; TLC (Et2O–hexane, 5:1) then showed the presence of a
new compound with lower mobility. The mixture was concentrated
to a residue that was submitted to column chromatography (Et2O Æ
Et2O–MeOH, 10:1), which gave pure 25 as a colorless syrup; yield:
270 mg (83%); [a]D26 +24.5 (c 1.0).
(3) Wang, Y.-F.; Dumas, D. P.; Wong, C.-H. Tetrahedron Lett.
1993, 34, 403.
(4) Compound 7 was erroneously named as 6-deoxy-DMDP.
(5) 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.
(6) 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.
(7) 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.
IR (neat): 3307 (OH), 3064, 3031, 738 and 698 cm–1 (aromatic).
1H NMR (300 MHz): d = 7.36 (br s, 10 H, 2 × Ph), 4.61 (s, 2 H,
CH2Ph), 4.59 and 4.54 (2 × d, 2 H, J = 12.1 Hz, CH2Ph), 3.83 (t, 1
H, J2,3 = J3,4 = 3.2 Hz, H-3), 3.65 (dd, 1 H, J4,5 = 5.4 Hz, H-4), 3.59
(br d, 2 H, J2,2¢ = 5.9 Hz, H-2¢,2¢), 3.39 (m, 1 H, H-2), 3.23 (br quin,
1 H, H-5), 2.71 (br s, 2 H, NH, OH), 1.28 (d, 3 H, J5,Me = 6.5 Hz,
Me).
(8) Bisseret, P.; Bouix-Peter, C.; Jacques, O.; Henriot, S.;
13C NMR (75 MHz): d (inter alia) = 91.26 and 86.85 (C-3,4), 72.30
and 72.12 (2 × CH2Ph), 63.71 and 57.37 (C-2,5), 62.31 (C-2¢), 19.44
(Me).
HRMS (LSIMS): m/z [M + Na]+ calcd for C20H25NO3Na: 350.1732;
found: 350.1731.
Eustache, J. Org. Lett. 1999, 1, 1181.
(9) Zhou, X.; Liu, W.-J.; Ye, J.-L.; Huang, P.-Q. Tetrahedron
2007, 63, 6346.
(10) Lee, S. G.; Jeong, H. J. Bull. Korean Chem. Soc. 1998, 19,
598.
(11) (a) Espelt, L.; Parella, T.; Bujons, J.; Solans, C.; Joglar, J.;
Delgado, A.; Clapés, P. Chem. Eur. J. 2003, 9, 4887.
(b) Espelt, L.; Bujons, J.; Parella, T.; Calveras, J.; Joglar, J.;
Delgado, A.; Clapés, P. Chem. Eur. J. 2005, 11, 1392.
(12) (a) Defoin, A.; Sifferlen, T.; Streith, J.; Dosbaâ, I.; Foglietti,
M.-J. Tetrahedron: Asymmetry 1997, 8, 363. (b) Sifferlen,
T.; Defoin, A.; Streith, J.; Le Nouën, D.; Tarnus, C.; Dosbaâ,
I.; Foglietti, M.-J. Tetrahedron 2000, 56, 971.
(13) Moriarty, R. M.; Mitan, C. I.; Branza-Nichita, N.; Phares, K.
R.; Parrish, D. Org. Lett. 2006, 8, 3465.
(2R,3R,4R,5R)-3,4-Dihydroxy-2-(hydroxymethyl)-5-methyl-
pyrrolidine (1-Deoxy-DMDP, 7)
A soln of 25 (270 mg, 0.83 mmol) in MeOH (10 mL) was acidified
with concd HCl and hydrogenated at 4 × 103 mbar over 10% Pd/C
(75 mg) for 24 h. The catalyst was filtered off and washed with
MeOH (15 mL). The mixture was neutralized with Amberlite IRA-
400 (OH– form), the resin was filtered off and washed with MeOH
(20 mL), and the filtrate and washings were concentrated to afford
pure 7 as a colorless syrup; yield: 100 mg (82%); [a]D25 +43 (c 0.8,
MeOH) {Lit.5 [a]D23 +42.9 (c 0.72, MeOH), Lit.11a [a]D20 +45 (c 1.4,
MeOH)}.
1H NMR (300 MHz, MeOH-d4): d = 3.98 (t, 1 H, J2,3 = J3,4 = 6.2
Hz, H-3), 3.90 (dd, 1 H, J2,2¢a = 4.1, J2¢a,2¢b = 12.0 Hz, H-2¢a), 3.82
(dd, 1 H, J2,2¢b = 6.5 Hz, H-2¢b), 3.81 (dd, 1 H, J4,5 = 5.9 Hz, H-4),
3.51 (dt, 1 H, H-2), 3.47 (br quin, 1 H, H-5), 1.48 (d, 3 H, J5,Me = 6.9
Hz, Me).
(14) Dumas, D. P.; Kajimoto, T.; Liu, K. K.-C.; Wong, C.-H.
Bioorg. Med. Chem. Lett. 1992, 2, 33.
(15) (a) Wong, C.-H.; Dumas, D. P.; Ichikawa, I.; Koseki, K.;
Danishefsky, S. J.; Weston, B. W.; Lowe, J. B. J. Am. Chem.
Soc. 1992, 114, 7321. (b) Ichikawa, I.; Lin, Y.-C.; Dumas,
D. P.; Shen, G.-J.; Garcia-Junceda, E.; Williams, M. A.;
Bayer, R.; Ketcham, C.; Walker, L. E.; Paulson, J. C.; Wong,
C.-H. J. Am. Chem. Soc. 1992, 114, 9283. (c) Qiao, L.;
Murray, B. W.; Shimazaki, M.; Schultz, J.; Wong, C.-H.
J. Am. Chem. Soc. 1996, 118, 7653.
13C NMR (75 MHz, MeOH-d4): d = 80.17 (C-4), 75.64 (C-3), 64.31
(C-2), 58.80 (C-2¢), 58.75 (C-5), 14.51 (Me).
HRMS (LSIMS): m/z [M + H]+ calcd for C6H14NO3: 148.0974;
(16) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2, 199.
(17) Izquierdo, I.; Plaza, M. T.; Yáñez, V. Tetrahedron 2007, 63,
1440.
found: 148.0977.
(18) (a) Izquierdo, I.; Plaza, M. T.; Robles, R.; Franco, F.
Carbohydr. Res. 2001, 330, 401. (b) Izquierdo, I.; Plaza, M.
T.; Franco, F. Tetrahedron: Asymmetry 2002, 13, 1503.
(c) Izquierdo, I.; Plaza, M. T.; Rodríguez, M.; Franco, F.;
Martos, A. Tetrahedron 2005, 61, 11697. (d) Izquierdo, I.;
Plaza, M. T.; Rodríguez, M.; Franco, F.; Martos, A.
Tetrahedron 2006, 62, 1904. (e) Izquierdo, I.; Plaza, M. T.;
Rodríguez, M.; Tamayo, J. A.; Martos, A. Tetrahedron
2006, 62, 2693.
Acknowledgment
Major support for this project was provided by the Ministerio de
Educación y Ciencia of Spain (Project Ref. No. CTQ2006-14043).
Additional support was provided by Junta de Andalucía (Group
CVI-250). Two of us (F.S.-C. and D.L.R.) acknowledge Fundación
Ramón Areces and the University of Granada, respectively, for a
grant.
(19) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem.
Commun. 1979, 978.
References
(20) In general, hydrogenations were conducted under either
neutral or weak-basic conditions, in order to avoid partial
debenzylation.
(21) Izquierdo, I.; Plaza, M. T.; Tamayo, J. A.; Sánchez-
Cantalejo, F. Eur. J. Org. Chem. 2007, 6078.
(22) Izquierdo, I.; Plaza, M. T.; Tamayo, J. A. Tetrahedron 2005,
61, 6527.
(1) Part VI of the series. For Part V, see reference 17.
(2) (a) Kajimoto, T.; Chen, L.; Liu, K. K.-C.; Wong, C.-H.
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Synthesis 2008, No. 9, 1373–1378 © Thieme Stuttgart · New York