Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes. Part 2: Synthesis of (1S,2R,3S,4S,5R)-3,4,5-trihydroxy-2-aminocyclopentanecarboxylic acid

Article abstract of DOI:10.1016/j.tetasy.2004.11.034

A recent new strategy for the transformation of nitrohexofuranoses into cyclopentylamines, based on intramolecular cyclization followed by controlled opening of the resulting 2-oxabicyclo[2.2.1]heptane derivatives, allowed the first total synthesis of (1S

Full text of DOI:10.1016/j.tetasy.2004.11.034

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 205–211
Stereocontrolled transformation of nitrohexofuranoses
into cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes.
Part 2: Synthesis of (1S,2R,3S,4S,5R)-3,4,5-trihydroxy-
2-aminocyclopentanecarboxylic acid
*
´ ´ ´ ´
Raquel G. Soengas, M. Begon˜a Pampın, Juan C. Estevez and Ramon J. Estevez
´ ´
Departamento de Quımica Organica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Received 1 November 2004; accepted 17 November 2004
Available online 21 December 2004
Abstract—A recent new strategy for the transformation of nitrohexofuranoses into cyclopentylamines, based on intramolecular
cyclization followed by controlled opening of the resulting 2-oxabicyclo[2.2.1]heptane derivatives, allowed the first total synthesis
of (1S,2R,3S,4S,5R)-2,3,4-trihydroxy-5-aminocyclopentanecarboxylic acid from L-idose.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
of trans-2-aminocyclopentanecarboxylic acid have a
high propensity to adopt a 12-helical folding pattern.6
cis-2-aminocyclopentanecarboxylic acid oligomers were
later shown to be unnatural foldamers more suitable
for rational design of new peptides showing novel ter-
tiary structures, because they can adopt sheet like struc-
tures by switching from helix to nonpolar strands.7
Although less abundant than a-amino acids, b-amino
acids have been receiving considerable attention in re-
cent years mainly due to their structural, chemical and
biological properties and their utility as chiral auxiliaries
and building blocks.1 Moreover, b-amino acids have
been easily incorporated into peptides, which proved
to be more stable metabolically2 and to have more ten-
dency to fold than their a-amino counterparts.3 In par-
ticular, peptides incorporating cyclic b-amino acids
exhibit a strong tendency to adopt very stable secondary
structures in short peptide sequences, due to the limited
conformational mobility of the cyclic monomers.
Several methods have been described for the synthesis of
cyclopentane b-amino acids.1c However, very few syn-
theses of polyhydroxylated derivatives have been re-
ported.8 We have recently reported the synthesis of the
polyhydroxylated trans-2-aminocyclopentanecarboxylic
acid 3 from a D-glucose derivative 1 by a novel route
including a key step consisting of an stereoselective
preparation of bicyclic sugarnitrolactone 2 (Scheme 1).9
Among the known carbocyclic b-amino acids, the four
isomers of 2-aminocyclopentanecarboxylic acids have
been the most commonly investigated.3 Thus (1R,2S)-
2-aminocyclopentanecarboxylic acid (cispentacin) is a
natural compound isolated independently by two groups
from Bacillus cereus and Streptomyces setonii, which has
been shown to exhibit potent antifungal activity in vivo
against Candida albicans.4 This amino acid was used to
replace the proline subunit in the tetrapeptide morphi-
ceptin resulting in a peptidomimetic pharmacologically
more active than the former.5 b-Oligopeptides consisting
OBn
O2N
BnO
OH
O
HO
HO
NH2
O
O
NO2
OBn
O
CO2H
BnO
OTf
1
2
3
Scheme 1.
The extension of this promising novel synthetic
methodology to the plethora of hexofuranoses is of
evident interest in order to expand the limited range of
known 2-aminocyclopentanecarboxylic acids by the
*
Corresponding author. Tel.: +34 981 563100; fax: +34 981 591014;
e-mail: qorjec@usc.es
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.034

206
R. G. Soengas et al. / Tetrahedron: Asymmetry 16 (2005) 205–211
preparation of several isomeric trihydroxylated penta-
cyclic b-amino acids.
2. Results and discussion
Such studies will enhance the potential impact of these
novel compounds and allow the preparation of hydro-
philic and hydrophobic cyclopentane b-peptides.
Accordingly, we describe herein the synthesis of enantio-
merically pure 3,4,5-trihydroxy-2-aminocyclopentane-
carboxylic acid 16 from L-idose (Scheme 2). Selective
protection of the hydroxy group at the C-6 position of
known L-idofuranose derivative 410 with tert-butyldi-
phenylsilyl chloride followed by benzylation of the
resulting furanose 5 with benzyl bromide and sodium
hydride and further treatment of fully protected fura-
nose 6 with TBAF in THF allowed us to obtain idose
derivative 7. This compound was next converted into
the desired nitrofuranose 10 via 8 and 9, a known proto-
col for the replacement of hydroxyl groups by nitro
groups.11 The acetonide of the nitroidofuranose 10
was removed with trifluoroacetic acid and water and
the anomeric position of the resulting derivative 11
was selectively oxidized to idonolactone 12 by treatment
with bromine and barium carbonate. Reaction of this
lactone 12 with triflic anhydride and pyridine allowed
us to obtain the key compound 13, which when directly
reacted with TBAF in THF readily underwent the
expected intramolecular C-alkylation of the initially
formed nitronate. The resulting bicyclic compound 14,
which was obtained in moderate yield, was easily identi-
fied from its spectroscopic and analytical data. Addi-
tionally, this assignment was supported by the X-ray
crystal structure of closely related bicyclic nitrolactol
21 (Fig. 1).12
Figure 1. Molecular structure of compound 21 in the solid state.
Bicyclic compounds 17 and 14 (Scheme 3) should be
formed from the nitronate of compound 13. Under the
reaction conditions, however, compounds 17 and 14
should be in equilibrium with their common nitronate
18. At equilibrium, the thermodynamically more stable
compound 14 should be favoured with respect to com-
pound 17, where the NO2 and the OBn substituents
are eclipsed. This explains the highly remarkable stereo-
selectivity of the cyclization.
Hydrogenation of nitrolactone 14 in an acidic medium
allowed the reduction of the nitro group to the amine
and the removal of the benzyl protecting groups to be
carried out in a single step. Finally, the resulting amino-
lactone 15 was directly opened to the desired amino acid
16 by treatment with barium hydroxide.
A slight modification of the above route to amino acid
16 allowed the formation of the expected bicyclic nitro-
lactol derivative 21 (Scheme 4). Reaction of nitroido-
furanose derivative 10 with acetyl chloride and
HO
HO
TBDPSO
TBDPSO
ClTBDPS
Imidazole
NaH, BrBn
NBu4I
O
O
O
O
BnO
HO
BnO
HO
O
O
O
O
NBu4F
DMF
(80% yield)
DMF
(90%yield)
THF
(94% yield)
O
O
O
O
BnO
HO
BnO
HO
7
4
5
6
TsCl, Py
(95% yield)
O2N
O2N
BnO
X
BnO
O2N
BnO
TFA/H2O
(1:1)
Br2, BaCO3
O
NaNO2
O
O
O
O
OH
O
O
BnO
Dioxane/H2O
(81% yield, 2 steps)
DMSO
(53% yield)
O
O
BnO
BnO
BnO
OH
BnO
11
OH
12
10
8: X=OTs
NaI, COMe2
reflux
(89% yield)
TfO2, Pyridine
CH2Cl2, -30oC
9: X=I
OBn
NO2
OH
O2N
BnO
OH
H2, Pd-C
Ba(OH)2
O
O
NBu4F
THF
(58% yield, 2 steps)
HO
NH2
CO2H
OBn
OH
O
O
Dioxane/
H2O/HCl
H2O
O
O
(56% yield, 2 steps)
HO
NH2
BnO
OTf
13
14
15
16
Scheme 2.

R. G. Soengas et al. / Tetrahedron: Asymmetry 16 (2005) 205–211
207
were recorded on a Bruker WM-250 apparatus or a Bru-
ker AMX-500. Mass spectra were obtained on a Kratos
MS 50 TC mass spectrometer. Elemental analyses were
obtained from the Elemental Analysis Service at the
University of Santiago de Compostela. Thin layer chro-
matography (TLC) was performed using Merck GF-254
type 60 silica gel and ethyl acetate/hexane mixtures as
eluants; the TLC spots were visualized with Hanessian
mixture. Column chromatography was carried out using
Merck type 9385 silica gel. Solvents were purified as per
Ref. 13. Solutions of extracts in organic solvents were
dried with anhydrous sodium sulfate.
OBn
OBn
NO2
O
O
OBn
17
O2N
BnO
OBn
O
O
O
O
O
N
O
OBn
BnO
OTf
OBn
13
18
O
O
NO2
14
4.1. 6-O-t-Butyldiphenylsilyl-1,2-O-isopropyl-b-L-ido-
furanose 5
Scheme 3.
methanol provided derivative 19 as a 1:1 epimeric mix-
ture, which was treated with triflic anhydride in pyridine
to convert its hydroxyl group at C-2 into an OTf leaving
group, as before.
tert-Butyldiphenylsilyl chloride (2.40 mL, 9.05 mmol)
and imidazole (1.23 g, 10.10 mmol) were sequentially
added to a solution of 1,2-O-isopropyl-b-L-idofuranose
4 (2.00 g, 9.05 mmol) in dry DMF (18 mL) at ꢀ20 ꢁC
under argon. The reaction mixture was stirred at this
temperature for 2 h and then the solvent was eliminated
under reduced pressure and the residue was dissolved in
ethyl acetate (100 mL). The resulting solution was
washed with water (3 · 20 mL) and the organic layers
were dried with anhydrous sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by flash
column chromatography (eluant 1:3 ethyl acetate/hex-
ane) to yield 6-O-t-butyldiphenylsilyl-1,2-O-isopropyl-
Treatment of the resulting mixture 20 with TBAF
provided the nitrolactol derivative 21, its stereochemis-
try being firmly established by X-ray crystallography
(Fig. 1).12 The selectivity of the formation of compound
21 from furanose 20 can be explained in a similar way to
the stereoselectivity of the formation of compound 14
(Scheme 3).
b-L-idofuranose 5 (3.741 g, 90%) as a pale yellow oil:
22
3. Conclusion
½aŠ ¼ ꢀ7:0 (c, 2.8 in CHCl3); IR (NaCl, cmꢀ1) 3425
D
(–OH); 1H NMR (250 MHz, CDCl3) d 1.07 (s, 9H,
3 · –CH3), 1.33, 1.48 (2 · s, 6H, –CH3), 2.76 (d, 1H,
J = 5.2 Hz, –OH), 3.68–4.23 (m, 4H), 4.32–4.34 (m,
1H), 4.55 (d, 1H, J1,2 = 3.6 Hz, H2), 6.00 (d, 1H,
J1,2 = 3.6 Hz, H1), 7.38–7.64 (m, 10H, 10 · H–Ph); 13C
NMR (62.8 MHz, CDCl3) d 19.57, 26.65, 27.22, 65.43,
71.56, 78.02, 79.68, 85.77, 105.25, 112.15, 128.33,
130.42, 135.94, 135.99, 132.97, 133.02; MS (EI) m/z
428 (M+ꢀ2 · –CH3, 1%), 323 (10%), 221 (100%).
The b-amino acid 16 now obtained has the same config-
uration as cispentacin at its amino acid moiety, making
it a serious candidate for pharmacological studies in
order to establish if its antifungal activity is greater than
that of cispentacin. This is now under investigation.
Work is also in progress to test the incorporation of this
new b-amino acid into peptides in order to study the
folding properties of its homopolymer.
4.2. 3,5-Di-O-benzyl-6-O-t-butyldiphenylsilyl-1,2-O-iso-
propyl-b-L-idofuranose 6
The preparation of the isomer of b-amino acid 16 result-
ing from similar synthesis on D-idose is also under
investigation.
A solution of 6-O-t-butyldiphenylsilyl-1,2-O-isopropyl-
5
b-L-idofuranose
(2.60 g, 5.68 mmol) in DMF
(26 mL) was added to a mixture of sodium hydride
(60% in mineral oil, 0.57 g, 14.2 mmol) in dry DMF
(4 mL) under argon. The reaction mixture was stirred
at rt for 1 h and benzyl bromide (2.00 mL, 17.03 mmol)
and tetrabutylammonium iodide (0.53 g) were added.
The resulting mixture was stirred at rt for 24 h, when
methanol was added. After stirring the reaction mixture
for 20 min, the solvent was evaporated in vacuo and the
4. Experimental
Melting points were determined using a Kofler Thermo-
gerate apparatus and are uncorrected. Specific rotations
were recorded on a JASCO DIP-370 optical polarime-
ter. Infrared spectra were recorded on a MIDAC FTIR
spectrophotometer. Nuclear magnetic resonance spectra
OBn
O2N
O2N
BnO
O2N
BnO
OBn
O
O
O
O
OMe
OTf
OMe
OH
BnO
O
TfO2, Py
NBu4F
AcCl
MeOH
(92% yield)
THF
CH2Cl2
-30oC
OMe NO2
O
BnO
10
BnO
20
BnO
19
(36% yield, 2 steps)
21
Scheme 4.

208
R. G. Soengas et al. / Tetrahedron: Asymmetry 16 (2005) 205–211
1
residue was dissolved in diethyl ether (100 mL) and fil-
tered through Celite. The filtrate was concentrated in
vacuo and the residue was purified by flash column
chromatography (eluant 1:5 ethyl acetate/hexane) to
1.1, CHCl3); IR (NaCl, cmꢀ1) 1363 (–SO2–); H NMR
(250 MHz, CDCl3) d 1.31, 1.46 (2 · s, 6H, –CH3), 2.40
(s, 1H, –CH3), 3.94–3.99 (m, 2H), 4.14 (ABq, 2H,
J = 4.2 Hz), 4.25–4.30 (m, 1H), 4.41 (d, 1H,
J = 11.5 Hz), 4.53–4.70 (m, 4H), 5.92 (d, 1H,
J1,2 = 3.9 Hz, H1), 7.21–7.36 (m, 12H, 12 · H–Ph), 7.71
(ABq, 2H, J = 7.7 Hz); 13C NMR (62.8 MHz, CDCl3)
22.08, 26.83, 27.28, 70.59, 72.20, 73.88, 76.51, 80.59,
82.43, 82.54, 105.35, 112.42, 128.01, 128.20, 128.26,
128.44, 128.52, 128.67, 129.02, 130.22, 133.09, 137.36,
138.61, 145.18; MS (EI) m/z 554 (M+, 0.2%), 277
(15%), 107 (54%), 91 (100%); found C 64.62, H 6.28, S
5.64 C30H34O8S requires C 64.96, H 6.18, S 5.78.
yield
3,5-di-O-benzyl-6-O-t-butyldiphenylsilyl-1,2-O-
isopropyl-b-L-idofuranose 6 (2.90 g, 80%) as a pale yel-
22
D
low oil: ½aŠ ¼ ꢀ15:0 (c 3.0, CHCl3); 1H NMR
(250 MHz, CDCl3) d 1.05 (s, 9H, 3 · –CH3), 1.33, 1.51
(2 · s, 6H, –CH3), 3.68–3.94 (m, 4H), 4.19 (d, 1H,
J = 11.6 Hz), 4.50–4.79 (m, 5H), 5.99 (d, 1H,
J1,2 = 3.9 Hz, H1), 7.15–7.69 (m, 20H, 20 · H–Ph); 13C
NMR (62.8 MHz, CDCl3) d 19.75, 27.01, 27.33, 64.28,
72.13, 73.33, 79.52, 81.30, 82.51, 83.33, 105.44, 112.15,
127.66, 128.11, 128.36, 128.63, 128.92, 136.21, 133.93,
133.99, 137.70, 139.70; MS (EI) m/z 520 (M+ꢀ2 ·
–CH3–Ph, 1%), 355 (10%), 91 (100%).
4.5. 3,5-Di-O-benzyl-6-deoxy-6-iodo-1,2-O-isopropyl-b-
L-idofuranose 9
4.3. 3,5-Di-O-benzyl-1,2-O-isopropyl-b-L-idofuranose 7
Sodium iodide (8.87 g, 59.21 mmol) was added to a solu-
tion of 3,5-di-O-benzyl-6-O-p-toluenesulfonyl-1,2-O-iso-
propyl-b-L-idofuranose 8 (1.64 g, 2.96 mmol) in acetone
(92 mL) and the resulting mixture was refluxed for 15 h.
The reaction mixture was cooled down to rt and then fil-
tered and the filtrate was concentrated in vacuo. The res-
idue was dissolved in diethyl ether (180 mL) and washed
with water (180 mL). The aqueous layer was extracted
with diethyl ether (2 · 70 mL) and the combined organic
layers were washed with 1 N aqueous sodium thiosulfate
solution (180 mL), dried with anhydrous sodium sulfate,
filtered and the solvent eliminated under reduced
pressure. The residue was purified by flash column
chromatography (eluant: 1:9 ethyl acetate/hexane) to
give 3,5-di-O-benzyl-6-deoxy-6-iodo-1,2-O-isopropyl-
A 1 M solution of tetrabutylammonium fluoride in THF
(9 mL) was added to a solution of 3,5-di-O-benzyl-6-O-
t-butyldiphenylsilyl-1,2-O-isopropyl-b-L-idofuranose
6
(2.90 g, 4.54 mmol) in dry THF (30 mL) and the mixture
was stirred at rt for 38 h under argon. The solvent was
eliminated under reduced pressure and the residue was
dissolved in dichloromethane (120 mL), washed with
water (3 · 60 mL) and the organic layer was dried with
anhydrous sodium sulfate, filtered and concentrated in
vacuo. The residue was purified by flash column chro-
matography (eluant: 1:3 ethyl acetate/hexane) and
the 3,5-di-O-benzyl-1,2-O-isopropyl-b-L-idofuranose 7
(1.71 g, 94%) was isolated as
a
yellow oil:
22
½aŠ ¼ ꢀ53:0 (c 2.3, CHCl3); IR (NaCl, cmꢀ1) 3474
b-L-idofuranose 9 (1.34 g, 89%) as a yellow amorphous
D
20
D
(–OH); 1H NMR (250 MHz, CDCl3) d 1.33, 1.50
(2 · s, 6H, –CH3), 2.13 (t, 1H, J = 6.2 Hz, –OH), 3.60–
3.68 (m, 1H), 3.85–3.94 (m, 2H), 4.32 (dd, 1H,
J = 3.4 Hz, J = 8.2 Hz), 4.45 (d, 1H, J = 11.6 Hz),
4.58–4.70 (m, 3H), 4.92 (d, 1H, J = 11.6 Hz), 6.01 (d,
1H, J1,2 = 4.0 Hz, H1), 7.28–7.40 (m, 10H, 10 · H–Ph);
13C NMR (62.8 MHz, CDCl3) d 26.77, 27.19, 62.34,
72.13, 73.91, 79.19, 81.87, 82.05, 82.49, 105.41, 112.16,
128.13, 128.42, 128.63, 128.86, 129.03, 137.32, 139.11;
MS (EI) m/z 402 [(M+H)+, 3%], 401 (M+, 2%), 181
(85%), 91 (100%).
solid: ½aŠ ¼ ꢀ38:4 (c 1.0, CHCl3); 1H NMR
(250 MHz, CDCl3) d 1.34, 1.49 (2 · s, 6H, –CH3),
3.07–3.11 (m, 2H), 3.71–3.73 (m, 1H), 4.44 (d, 1H,
J = 11.8 Hz), 4.58–4.85 (m, 3H), 6.00 (d, 1H,
J1,2 = 3.9 Hz, H1), 7.26–7.45 (m, 10H, 10 · H–Ph); 13C
NMR (62.8 MHz, CDCl3) 5.99, 26.92, 27.29, 72.07,
74.95, 77.65, 82.26, 83.73, 105.53, 112.44, 128.02,
128.13, 128.48, 128.60, 128.69, 128.76, 128.95, 129.16,
137.10, 138.76; MS (EI) m/z 511 (M++1, 2%), 510
(M+, 3%), 509 (M+ꢀ1, 5%), 345 (20%), 181 (76%), 91
(100%); found 509.0834. HRMS (EI) calcd for:
C23H26O5I (MꢀH)+ 509.0825.
4.4. 3,5-Di-O-benzyl-6-O-p-toluenesulfonyl-1,2-O-isoprop-
yl-b-L-idofuranose 8
4.6. 3,5-Di-O-benzyl-6-deoxy-6-nitro-1,2-O-isopropyl-b-
L-idofuranose 10
p-Toluenesulfonyl chloride (1.35 g, 7.01 mmol) was
added to a solution of 3,5-di-O-benzyl-1,2-O-isoprop-
yl-b-L-idofuranose 7 (1.41 g, 3.53 mmol) dry pyridine
(14 mL) and the mixture was stirred at rt for 10 h under
argon. The reaction mixture was then concentrated in
vacuo and the residue was dissolved in dichloromethane
(150 mL). The resulting solution was washed with
hydrochloric acid 2 M (1 · 60 mL) and water (2 ·
60 mL) and the organic layers were dried with anhy-
drous sodium sulfate, filtered and concentrated in
vacuo. The residue was purified by flash column
chromatography (eluant: 1:4 ethyl acetate/hexane) to
give 3,5-di-O-benzyl-6-O-p-toluenesulfonyl-1,2-O-iso-
Sodium nitrite (0.40 g, 5.36 mmol) and 1,3,5-trihydroxy-
benzene (0.82 g, 4.67 mmol) were added to a solution of
3,5-di-O-benzyl-6-deoxy-6-iodo-1,2-O-isopropyl-b-L-ido-
furanose 9 (1.29 g, 2.52 mmol) in dry DMSO (16 mL)
and the resulting mixture was stirred at rt for 4 days
under argon. The reaction mixture was concentrated in
vacuo and the residue was dissolved in water (30 mL)
and extracted with ethyl acetate (4 · 60 mL). The com-
bined organic layers were dried with anhydrous sodium
sulfate, filtered and the solvent eliminated under reduced
pressure. The residue was purified by flash column chro-
matography (eluant: 1:7 ! 1:5 ethyl acetate/hexane) to
give 3,5-di-O-benzyl-6-deoxy-6-nitro-1,2-O-isopropyl-b-
L-idofuranose 10 (0.58 g, 53%) as a yellow solid: mp
propyl-b-L-idofuranose 8 (1.86 g, 95%) as a white solid:
23
D
mp 102–104 ꢁC (ethyl acetate/hexane); ½aŠ ¼ ꢀ23:9 (c

R. G. Soengas et al. / Tetrahedron: Asymmetry 16 (2005) 205–211
209
23
D
85–87 ꢁC (diethyl ether/hexane); ½aŠ ¼ ꢀ51:0 (c 1.0,
dry THF (4 mL) and the mixture was stirred at rt for
4 h under argon. The solvent was removed under re-
duced pressure and the residue was dissolved in dichlo-
romethane (25 mL). The resulting solution was washed
with water (3 · 13 mL) and the organic layers were dried
with anhydrous sodium sulfate, filtered and concen-
trated in vacuo. The residue was purified by flash col-
umn chromatography (eluant: 1:5 ethyl acetate/hexane)
to give the (5R,6S,7R)-6,7-dibenzyloxy-5-nitro-2-oxabi-
CHCl3); IR (NaCl, cmꢀ1) 1557, 1376 (–NO2); 1H
NMR (250 MHz, CDCl3) d 1.33, 1.45 (2 · s, 6H, –
CH3), 3.91 (d, 1H, J = 3.4 Hz), 4.22–4.25 (m, 2H),
4.30–4.80 (m, 7H), 5.97 (d, 1H, J1,2 = 3.8 Hz, H1),
7.25–7.35 (m, 10H, 10 · H–Ph); 13C NMR (62.8 MHz,
CDCl3) 26.77, 27.26, 72.12, 74.73, 75.84, 80.46, 81.84,
82.14, 105.59, 112.52, 128.40, 128.52, 128.73, 128.89,
129.22, 137.03, 137.23; MS (EI) m/z 429 (M+, 4%), 428
(M+ꢀ1, 15%), 271 (25%), 181 (82%), 91 (100%); found
C 64.64, H 6.55, N 3.29 C23H27NO7 requires C 64.32,
H 6.34, N 3.26.
cyclo[2.2.1]heptan-3-one 14 (0.10 g, 58%) as a yellow
)
22
D
oil: ½aŠ ¼ ꢀ2:0 (c 0.90, CHCl3); IR (NaCl, cmꢀ1
1
1811 (C@O), 1554, 1363 (–NO2); H NMR (500 MHz,
CDCl3) d 3.42–3.44 (m, 1H, H7), 3.42–3.44 (m, 1H,
H7), 4.37 (m, 1H, H1), 4.48–4.52, 4.65–4.79 (2 · m,
6H, 2 · –OCH2Ph, H5, H6), 5.45 (dd, 1H,
J4,7 = 3.4 Hz, J4,5 = 3.4 Hz, H4), 7.26–7.37 (m, 10H,
10 · H–Ph); 13C NMR (62.8 MHz, CDCl3) 49.79,
72.20, 73.37, 78.94, 81.32, 82.20, 87.46, 128.04, 128.10,
128.46, 128.55, 128.63, 128.67, 135.77, 136.15, 167.95;
MS (EI) m/z 370 [(M+H)+, 6%], 369 (M+, 15%), 368
[(MꢀH)+, 8%], 278 (52%), 181 (66%), 91 (100%); found
C 65.03, H 5.18, N 3.79 C20H19NO6 requires C 64.63, H
5.42, N 3.70.
4.7. 3,5-Di-O-benzyl-6-deoxy-6-nitro-b-L-idono-1,4-
lactone 12
A solution of 3,5-di-O-benzyl-6-deoxy-6-nitro-1,2-O-
isopropyl-b-L-idofuranose 10 (0.25 g, 0.58 mmol) in a
1:1 mixture of trifluoroacetic acid/water (10 mL) was
stirred at rt for 16 h. The solvent was concentrated in
vacuo and coevaporated with toluene (3 · 5 mL) in
order to remove traces of trifluoroacetic acid. The resi-
due was dissolved in a mixture 2:1 of dioxane and water
(12 mL) and stirred with barium carbonate (0.13 g,
0.64 mmol) and bromine (0.08 mL, 1.45 mmol) for 6 h.
The resulting mixture was extracted with ethyl acetate
(3 · 25 mL) and the combined organic layers were dried
with anhydrous sodium sulfate, filtered and the solvent
was removed under reduced pressure. The residue was
purified by flash column chromatography (eluant: 2:5
ethyl acetate/hexane) to give 3,5-di-O-benzyl-6-deoxy-
6-nitro-1,2-O-isopropyl-b-L-idono-1,4-lactone 12 (0.18
g, 81%) as a yellow oil: IR (NaCl, cmꢀ1) 3443 (–OH),
4.10. (1S,2R,3S,4S,5R)-2,3,4-Trihydroxy-5-aminocyclo-
pentanic acid 16
Palladium–carbon (10%, 20 mg) was added to a solu-
tion of (5R,6S,7R)-6,7-dibenzyloxy-5-nitro-2-oxabicy-
clo[2.2.1]heptan-3-one 14 (34 mg, 0.09 mmol) in a 2:1
mixture of dioxane and water (1.5 mL) and one drop
of hydrochloric acid was added. The mixture was stirred
at rt for 36 h under hydrogen, filtered through Celite
and the filtrate was concentrated in vacuo. The residue
was stirred with 0.1 N aqueous solution of barium
hydroxide (3 mL) at rt for 3 h and the resulting mixture
was acidified with an acidic resin (Amberlite IR-120) to
pH = 1 and stirred with the resin for 24 h. The mixture
was then filtered and the resin washed with water until
the filtrate remained colourless on addition of silver
nitrate. The resin was stirred with a 1N aqueous solution
of ammonia (6 mL), filtered and the filtrate concentrated
in vacuo to give the (1S,2R,3S,4S,5R)-2,3,4-trihydroxy-
1
1791 (C@O), 1555, 1380 (–NO2); H NMR (250 MHz,
CDCl3) d 2.64 (d, 1H, J = 3.1 Hz, –OH), 3.91 (d, 1H,
J = 3.4 Hz), 4.44–4.73 (m, 9H), 4.89 (d, 1H,
J = 11.6 Hz), 7.16–7.41 (m, 10H, 10 · H–Ph); MS (EI)
m/z 388 [(M+H)+, 3%], 386 [(MꢀH)+, 2%], 296 (36%),
181 (59%), 91 (100%).
4.8. 3,5-Di-O-benzyl-2-O-trifluoromethanesulfonyl-6-
deoxy-6-nitro-b-L-idofurano-1,4-lactone 13
Trifluoromethanesulfonyl anhydride (0.11 mL, 0.68
mmol) was slowly added to a solution of 3,5-di-O-benz-
yl-6-deoxy-6-nitro-1,2-O-isopropyl-b-L-idono-1,4-lac-
tone 12 (0.17 g, 0.45 mmol) and pyridine (0.11 mL,
1.36 mmol) in dry dichloromethane (3 mL) at ꢀ30 ꢁC
under argon. The reaction mixture was stirred at this
temperature for 1.5 h and then diluted with dichlorome-
thane (25 mL). The resulting solution was washed with
2 N aqueous hydrochloric acid solution (12 mL), which
5-aminocyclopentanic acid 16 (9 mg, 56%) as an amor-
22
D
phous white solid: ½aŠ ¼ ꢀ27:8 (c 0.3, water); 1H
NMR (250 MHz, D2O) d 3.42–3.44 (m, 1H, H7), 3.42–
3.44 (m, 1H, H7), 4.37 (m, 1H, H1), 4.48–4.52, 4.65–
4.79 (2 · m, 6H, 2 · –OCH2Ph, H5, H6), 5.45 (dd, 1H,
J4,7 = 3.4 Hz, J4,5 = 3.4 Hz, H4), 7.26–7.37 (m, 10H,
10 · H–Ph); 13C NMR (62.8 MHz, CDCl3) 49.79,
72.20, 73.37, 78.94, 81.32, 82.20, 87.46, 128.04, 128.10,
128.46, 128.55, 128.63, 128.67, 135.77, 136.15, 167.95;
MS (EI) m/z 370 [(M+H)+, 6%], 369 (M+, 15%),
368 [(MꢀH)+, 8%], 278 (52%), 181 (66%), 91 (100%);
found C 65.03, H 5.18, N 3.79 C20H19NO6 requires C
64.63, H 5.42, N 3.70.
was
further
extracted
with
dichloromethane
(2 · 19 mL). The combined organic layers were dried
with anhydrous sodium sulfate, filtered and concen-
trated in vacuo and the residue was used in the next step
without further purification.
4.11. Methyl-3,5-di-O-benzyl-6-deoxy-6-nitro-a,b-L-ido-
furanoside 19
4.9. (5R,6S,7R)-6,7-Dibenzyloxy-5-nitro-2-oxabicyclo-
[2.2.1]heptan-3-one 14
Acetyl chloride (0.30 mL, 4.01 mmol) was added to a
solution of 3,5-di-O-benzyl-6-deoxy-6-nitro-1,2-O-iso-
propyl-b-L-idofuranose 10 (0.29 g, 0.67 mmol) in dry
A 1 M solution of tetrabutylammonium fluoride in THF
(0.45 mL) was added to a solution of the triflate 13 in

210
R. G. Soengas et al. / Tetrahedron: Asymmetry 16 (2005) 205–211
methanol (10 mL) at 0 ꢁC under argon. The reaction
mixture was stirred at rt for 13 h and sodium carbonate
was added to pH = 8. The mixture was filtered and the
filtrate was concentrated in vacuo. The residue was dis-
solved in dichloromethane (20 mL) and washed with
water (20 mL), which was further extracted with dichlo-
romethane (3 · 20 mL). The combined organic layers
were washed with brine (5 mL), dried with anhydrous
sodium sulfate, filtered and the solvent was removed
under reduced pressure. The residue was purified by
flash column chromatography (eluant: 2:5 ethyl acetate/
hexane) to give methyl-3,5-di-O-benzyl-6-deoxy-6-nitro-
a,b-L-idofuranoside 19 (0.25 g, 92%) as a mixture of
both anomers: IR (NaCl, cmꢀ1) 3454 (–OH), 1555,
1380 (–NO2); 1H NMR (250 MHz, CDCl3) d 3.46,
3.49 (2 · s, 6H, 2 · –OCH3), 3.90–3.93 (m, 1H), 3.97–
4.00 (m, 2H), 4.19–4.86 (m, 19H), 5.02 (d, 1H, J =
4.9 Hz), 7.28–7.36 (m, 20H, 20 · H–Ph); MS (EI) m/z
402 [(MꢀH)+, 1%], 370 (6%), 181 (65%), 91 (100%).
13C NMR (62.8 MHz, CDCl3) 48.04, 56.42, 72.57,
73.00, 78.12, 80.45, 82.05, 88.85, 102.53, 128.24,
128.32, 128.50, 128.59, 128.89, 128.95, 137.33, 138.23;
MS (EI) m/z 386 [(M+H)+, 14%], 385 (M+, 3%), 384
[(MꢀH)+, 9%], 354 (64%), 181 (14%), 91 (100%); found
C 65.44, H 6.33, N 3.62 C20H19NO6 requires C 65.44, H
6.02, N 3.63.
Acknowledgements
Special thanks are due to Professor G. W. J. Fleet for
helpful discussions on this chemistry. We also thank
the Xunta de Galicia and the Spanish Ministry of
Science and Technology for financial support, and the
latter for a grant to Raquel G. Soengas.
References
1. For a recent book, see: (a) Enantioselective Synthesis of b-
Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York,
1997; (b) See also: Abdel, A. F.; Cohen, J. H.; Marynoff,
C. A. Curr. Med. Chem. 1999, 6, 955; (c) Nag, J. S.; Topgi,
R. S. Curr. Opin. Drug. Disc. Dev. 1998, 1, 314–328; (d)
4.12. Methyl-3,5-di-O-benzyl-6-deoxy-6-nitro-2-O-tri-
fluoromethanesulfonyl-a,b-L-idofuranoside 20
Trifluoromethanesulfonyl anhydride (0.13 mL, 0.79
mmol) was slowly added to a solution of methyl-3,5-
Fulo¨p, F. Chem. Rev. 2001, 101, 2181.
¨
2. Griffith, O. W. Annu Rev. Biochem. 1986, 55, 855.
3. For a recent review on b-peptides, which includes refer-
ences to work by the Seebach and the Gellman groups, the
most active in this field, see: Cheng, R. P.; Gellman, S. H.;
DeGrado, W. Chem. Rev. 2001, 101, 3219.
4. (a) Konishi, M.; Nishio, M.; Saitoh, K.; Miyaki, T.; Oki,
T.; Kawaguchi, H. J. Antibiot. 1989, 42, 1749; (b)
Kawabata, K.; Inamoto, Y.; Sakana, K.; Iwamoto, T.;
Hashimoto, S. J. Antibiot. 1990, 43, 513; (c) Iwamoto, T.;
Tsujii, E.; Ezaki, M.; Fujie, A.; Hashimoto, S.; Okuhara,
M.; Kohsaka, M.; Imanaka, H.; Kawabata, K. J. Antibiot.
1990, 43, 1; (d) Oki, T.; Hirano, M.; Tomatsu, K.;
Numata, K.; Kamei, H. J. Antibiot. 1989, 42, 1756.
5. (a) Yamazaki, T.; Probstl, A.; Schiller, P. W.; Goodman,
M. Int. J. Pept. Prot. Res. 1991, 37, 364; (b) Janecka, A.;
Fichna, J.; Wiercioch, R.; Mirowski, M. Bioorg. Med.
Chem. 2003, 11, 3855.
di-O-benzyl-6-deoxy-6-nitro-a,b-L-idofuranoside
19
(0.25 g, 0.61 mmol) and pyridine (0.15 mL, 1.82 mmol)
in dry dichloromethane (5 mL) at ꢀ30 ꢁC under argon.
The reaction mixture was stirred at this temperature
for 1.5 h and then diluted with dichloromethane
(40 mL). The resulting solution was washed with 2 N
aqueous hydrochloric acid solution (20 mL), which
was
further
extracted
with
dichloromethane
(2 · 30 mL). The combined organic layers were dried
with anhydrous sodium sulfate, filtered and concen-
trated in vacuo and the residue was used in the next step
without further purification.
4.13. (3R,5R,6S,7R)-6,7-Dibenzyloxy-3-methoxy-5-nitro-
2-oxabicyclo[2.2.1]heptane 21
6. Apella, D. H.; Christianson, L. A.; Klein, D. A.; Powell,
D. R.; Huang, X.; Barchl, J. J.; Gellman, S. H. Nature
1997, 387, 381.
A 1 M solution of tetrabutylammonium fluoride in THF
(1.2 mL) was added to a solution of the triflate 20 in dry
THF (6 mL) and the mixture was stirred at rt for 14 h
under argon. The solvent was removed under reduced
pressure and the residue was dissolved in dichlorome-
thane (40 mL). The resulting solution was washed with
water (3 · 20 mL) and the organic layers were dried with
anhydrous sodium sulfate, filtered and concentrated in
vacuo. The residue was purified by flash column chro-
matography (eluant: 1:8 ! 1:6 ethyl acetate/hexane) to
give the (3R,5R,6S,7R)-6,7-dibenzyloxy-3-methoxy-5-
nitro-2-oxabicyclo[2.2.1]heptane 21 (85 mg, 36%) as a
´ ´
7. Martinek, T. A.; Toth, G. K.; Vass, E.; Hollosi, M.;
Fulo¨p, F. Angew. Chem., Int. Ed. 2002, 41, 1718.
¨
8. Elliott, R. P.; Hui, A.; Fairbanks, A. J.; Nash, R. B.;
Bryan, G.; Winchester, B. G.; Way, G.; Smith, C.;
Lamont, R. B.; Storer, R.; Fleet, G. W. J. Tetrahedron
Lett. 1993, 34, 7949.
´ ´
9. Soengas, R. G.; Estevez, J. C.; Estevez, R. J. Org. Lett.
2003, 5, 1423.
10. Compound 4 was easily prepared according to: Blanc-
Muesser, M.; Defaye, J.; Horton, D.; Tsai, J.-H. Meth.
Carbohydrate Chem. 1980, 8, 177.
11. Kornblum, N.; Powers, J. W. J. Org. Chem. 1957, 22, 455.
12. Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC 254540 21. Copies of the
data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK fax:
(+44)1223-336-033; email: deposit@ccdc.cam.ac.uk. Crys-
tallographic data for 21. C21H23NO6, M = 385.41,
T = 293(2) K. Monoclinic, space group P2 with
white solid: mp 98–100 ꢁC (ethyl acetate/hexane);
24
½aŠ ¼ ꢀ45:6 (c 1.5, CHCl3); IR (NaCl, cmꢀ1) 1553,
D
1
1365 (–NO2); H NMR (500 MHz, CDCl3) d 3.27 (s, 3
H, –OCH3), 3.40–3.41 (m, 1H, H4), 4.16 (d, 1H,
J1,4 = 3.4 Hz, H1), 4.33 (s, 1H, H7), 4.47 (d, 1H, J =
11.1 Hz, –OCHPh), 4.60 (d, 1H, J = 11.1 Hz, –OCHPh),
4.67–4.68 (m, 1H, H6), 4.71 (d, 1H, J = 11.7 Hz,
–OCHPh), 4.78 (d, 1H, J = 11.7 Hz, –OCHPh), 4.99
(d, 1H, J3,4 = 2.5 Hz, H3), 5.18 (dd, 1H, J5,6 = 4.0 Hz,
J5,4 = 4.0 Hz, H5), 7.26–7.36 (m, 10H, 10 · H–Ph);
˚
a = 12.2964(3), b = 12.2971(3), c = 13.6330(3) A, a = 90ꢁ,

R. G. Soengas et al. / Tetrahedron: Asymmetry 16 (2005) 205–211
211
3
V = 1932.52 A ,
(Z = 4) = Ônot measuredÕ. F(000) = 816, Absorption coef-
ficient = 0.807 cmꢀ1. Data were obtained on an Enraf-
Nonius CAD4-Mach3 diffractometer (graphite crystal
monochromator, 1 = 1.5418 A) using the w = 2q scan
method; absorption corrections were applied. Refinement,
˚
b = 110.3710(10)ꢁ,
c = 90ꢁ,
Dc
with anisotropic displacement parameters applied to each
of the nonhydrogen atoms, was by full-matrix least
squares on F2 (SHELXL-93) using all data;
2
2 1=2
wR2 ¼ ½SwðF o2 ꢀ F c2Þ =SwðF o2Þ Š
.
˚
13. Perrin, D. D.; Armarego, W. L. F. Purification of
Laboratory Chemicals; Pergamon: New York, 1988.