Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes. Part 6: Synthesis and incorporation into peptides of the first reported 2,3- dihydroxycyclopentanecarboxylic acid

Article abstract of DOI:10.1016/j.tetasy.2014.03.005

Herein we report the intramolecular alkylation of nitronates of methyl-5-O-benzyl-3,6-deoxy-6-nitro-β-d-glucofuranoside and methyl-5-O-benzyl-3,6-deoxy-6-nitro-α-d-glucofuranoside into the corresponding 2-oxabicyclo[2.2.1]heptane derivatives. Similarly, m

Full text of DOI:10.1016/j.tetasy.2014.03.005

Tetrahedron: Asymmetry 25 (2014) 583–590
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereocontrolled transformation of nitrohexofuranoses into
cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes. Part 6: synthesis
and incorporation into peptides of the first reported
2,3-dihydroxycyclopentanecarboxylic acid
⇑
Amalia Estévez, Raquel G. Soengas, Pablo Thomas, Miguel Alegre, Rosalino Balo, Juan Carlos Estévez ,
Ramón J. Estévez
⇑
Departamento de Química Orgánica and Centro Singular de Investigación en Química Biológica y Materiales Moleculares, Campus Vida, Universidad de Santiago de Compostela, Calle
Jenaro de la Fuente s/n, 15782 Santiago de Compostela, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 February 2014
Accepted 5 March 2014
Herein we report the intramolecular alkylation of nitronates of methyl-5-O-benzyl-3,6-deoxy-6-nitro-b-D-
glucofuranoside and methyl-5-O-benzyl-3,6-deoxy-6-nitro-
2-oxabicyclo[2.2.1]heptane derivatives. Similarly, methyl-3-O-benzyl-5-deoxy-5-nitromethyl-b-
furanoside and methyl-3-O-benzyl-5-deoxy-5-nitromethyl- -xylofuranoside were cyclized to (1R,3R,
a
-D
-glucofuranoside into the corresponding
D-xylo-
a-D
4S,5R,7R)-7-benzyloxy-3-methoxy-5-nitro-2-oxabicyclo[2.2.1]heptane and (1R,3S,4S,5R,7R)-7-benzyl-
oxy-3-methoxy-5-nitro-2-oxabicyclo[2.2.1]heptane, respectively. These 2-oxabicyclo[2.2.1]heptane
derivatives were eventually transformed into enantiopure methyl (1S,2S,3R,4S,5R)-2-amino-2,3-dihydr-
oxycyclopentanecarboxylate and this novel b-amino acid was incorporated into peptides.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
sugar derivatives I to give bicyclic compounds II has allowed us
to develop the first approach for the synthesis of polyhydroxylated
The design and synthesis of new amino acids and peptidomi-
metics has attracted considerable attention in recent times, due
to the pharmacological limitations of bioactive peptides, which
have been related to their conformational flexibility and their
metabolic instability.1 Particular attention has been devoted to
b-amino acids, on account of the metabolic and conformational
stability of b-peptides.2 Among them, cyclopentane b-amino acids
have become attractive candidates for the stabilization of bioactive
peptides, due to the high tendency of their homopolymers to fold
in rigid secondary structures in short peptide sequences.3
Carbohydrates are an abundant source of useful scaffolds
for the stereoselective synthesis of functionalized carbo- and
heterocycles.4 One of the approaches developed for this purpose
involves the generation of a bicyclic derivative constituted by the
original sugar ring and a new ring, followed by the opening of
the sugar ring (approach a). Alternatively, a new ring results from
the cyclization of an open chain carbohydrate derivative (approach
b). Among the variants of the approach a that have been developed,
the one involving an intramolecular alkylation of nitronates of
cyclopentane b-amino acids III (Scheme 1).5 Stereocontrolled
access to these richly functionalized alicyclic b-amino acids is
limited to hexoses that fit the stereochemical requirements for
the intramolecular displacement of –OTf leaving groups at C-2 by
nitronates at C-6 (
D-glucose, D-idose, D-allose, D-talose, and their
respective -hexose enantiomers). Moreover, our previous studies
L
in this field allowed us to recognize that the efficiency of the key
cyclization leading to compounds II depends on a number of
structural factors of their precursors I: the sp2 or sp3 character of
the carbon atom at C-1, the configuration of the stereogenic centers
at C-1(sp3), C-3 and C-5, and the nature of the substituents at C-3
and C-5.5
R1
O2N
R2
OH
5
X
1
O
Y
R2
R2
R1
several
steps
O
TBAF
THF
3
R1
Y
OTf
H2N
CO2H
NO2
X
III: R1, R2 = H or OH
I: X + Y = O or H + OMe
II: X + Y = O or H + OMe
R1, R2 = H or OBn
R1, R2 = H or OBn
⇑
Corresponding authors. Tel.: +34 881 815 731; fax: +34 981 591 014.
E-mail address: ramon.estevez@usc.es (R.J. Estévez).
Scheme 1.
http://dx.doi.org/10.1016/j.tetasy.2014.03.005
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

584
A. Estévez et al. / Tetrahedron: Asymmetry 25 (2014) 583–590
In order to gain more insight into the factors influencing the key
and 5a was obtained. This ratio was established from the relative
intensities of the two singlets that appear in its 1H NMR at
3.34 ppm and 3.46 ppm, due to the anomeric methoxy substituents
of 4a and 5a, respectively. On the other hand, the configuration at the
anomeric stereogenic center of 5a was deduced from a doublet at
4.83, ppm due to its anomeric proton, which is coupled with the pro-
ton at C-2. The coupling constant value (J1,2 = 4.4 Hz) requires a cis-
configuration of both protons. This is in accordance with the config-
uration proposed for anomer 4a. As expected, its anomeric proton
showed a singlet (d = 4.78 ppm), due to a trans-configuration of
the protons H1 and H2.
The reaction of this mixture of compounds 4a and 5a with Tf2O
and pyridine, under the same conditions as for 2a, provided the
corresponding mixture of compounds 4b and 5b, which was trea-
ted directly with TBAF in THF. The intramolecular displacement of
the triflate group at C-2 by the nitronate at C-6 resulted in the for-
mation of a 20:1 mixture of bicyclic anomers 6a and 7a, which was
separated by column chromatography and identified from their
analytical and spectroscopic properties. The anomeric proton at
5.17 ppm of anomer 6a showed a doublet with a coupling constant
of J3,4 = 2.7 Hz, due to an endo disposition of its methoxy group. On
the other hand, the exo disposition of the methoxy group of its iso-
mer 7a was easily deduced from a singlet at 4.67 ppm, due to its
anomeric proton.
The stereochemical outcome of the key step to compound 6a
can be explained by assuming that both bicyclic compounds 6a
and 6a0 should be formed from nitronate 4b0 (Scheme 4). Under
the reaction conditions, however, compounds 6a and 6a0 should
be in equilibrium with their common nitronate 6a00. At equilibrium,
the thermodynamically more stable compound 6a should be
favoured over compound 6a0, where the NO2 and the OBn substit-
uents are eclipsed. This explains the remarkably high stereoselec-
tivity of the cyclization. A similar behavior could explain the
selective transformation of compound 5b into bicyclic compound
7a.
cyclization involved in this synthesis of polysubstituted cyclopen-
tane b-aminoacids, we herein report its extension to additional ni-
tro sugars I.
2. Results and discussion
At first, we studied the cyclization of 6-nitro-3,6-dideoxy-2-O-
triflyl-
and 17.3% overall yield from the known
following a protocol previously developed in our group for the
preparation of 6-nitro-6-dehydro-
-hexofuranosides (Scheme 2).5a
D
-gluconolactone 2b, which was obtained in seven steps
D
-glucose derivative 1a,7
D
Benzylation of the free OH group of 1a by treatment with NaH
and BnBr was followed by a TBAF mediated removal of the TBDPS
protecting group of the resulting derivative 1b. This afforded com-
pound 1c, which in turn easily provided its O-tosyl derivative 1d
upon treatment with TsCl for 10 h, in the presence of pyridine.6
The reaction of this compound with NaI resulted in the efficient
formation of iodo derivative 1e,6 which yielded the key nitrosugar
1f, after reaction with NaNO2 and trihydroxybenzene (phloroglu-
cinol),5a a scavenger that avoids nitrite ester formation. Removal
of the isopropylidene protecting group of 1f with aqueous TFA, fol-
lowed by oxidation of the anomeric position of the resulting 3-
deoxy furanose with Br2 and BaCO3, furnished the expected sugar
lactone 2a, which was directly converted into its –OTf derivative
2b, when reacted with Tf2O and pyridine (Scheme 2).5c Finally,
compound 2b was directly allowed to react with TBAF in dry
THF, but the expected cyclization leading the bicyclic lactone 3a
did not occur. This unsuccessful result allowed us to confirm that
a substituent at the C-3 position of type 2b substrates is required
for the success of these cyclizations.5c
However, satisfactory results were achieved when we explored
the alternative nitronate alkylation route depicted in Scheme 3.5c
Thus, when nitroglucofuranose derivative 1f was now reacted with
AcCl in MeOH, a 6:1 ratio of an inseparable anomeric mixture of 4a
TBDPSO
HO
TBDPSO
BnO
HO
X
i
ii
iii
O
O
O
O
O
O
O
BnO
O
BnO
O
O
O
O
O
1a
O2N
1b
O2N
1c
1d: X=OTs
iv
1e:
X=I
O2N
H
O
v
vii
viii X
vi
O
O
NO2
O
O
BnO
O
BnO
BnO
O
OBn
H
O
1f
2a
2b
3a
OH
OTf
Scheme 2. Reagents and conditions: (i) (a) NaH, NBu4I, BnBr, DMF, 50 °C, 1 h; (b) MeOH, 50 °C, 2 h; (ii) TBAF, THF, rt, 4 h; (iii) TsCl, Py, rt, 10 h; (iv) NaI, acetone, reflux, 15 h;
(v) NaNO2, phloroglucinol, DMSO, rt, 96 h; (vi) (a) TFA, H2O, rt, 12 h; (b) Br2, BaCO3, dioxane, H2O, rt, 14 h; (vii) Tf2O, pyridine, CH2Cl2, ꢀ30 °C, 1.5 h; (viii) TBAF, THF, rt, 1.5 h.
O2N
BnO
O2N
BnO
1
2
H
O
OMe
H
OMe
H
O
O
4
NO2
OBn
3
iii
iii
H
ii
O2N
BnO
H
MeO
H
H
HO
OTf
6a
4a
4b
O
i
O
J3,4 = 2.7 Hz
O2N
BnO
O2N
BnO
O
1f
H
O
H
H
O
1
ii
O
NO2
OBn
MeO
OMe
OMe
OTf
2
H
H
H
5a
OH
5b
7a
J1,2 = 4.4 Hz
Scheme 3. Reagents and conditions: (i) AcCl, MeOH, 0 °C, 14 h; (ii) Tf2O, pyridine, CH2Cl2, ꢀ30 °C, 1.5 h; (iii) TBAF, THF, rt, 1.5 h.

A. Estévez et al. / Tetrahedron: Asymmetry 25 (2014) 583–590
585
singlet at 4.55 exhibited by the 1H NMR spectrum of 7b was in
accordance with an exo disposition of its methoxy group.
H
O
NO2
OBn
H
Bicyclic glycosides 6b and 7b were converted into the disubsti-
tuted trans-2-aminocyclopentane carboxylic acid derivative 10b
(Scheme 6), following the protocol previously developed for the
preparation of polyhydroxylated cyclopentane b-amino acids.5c
Thus, acidic hydrolysis of the mixture of anomers 6b and 7b re-
sulted in the formation of a tricomponent mixture 6c+8+7c, which
was directly subjected to an oxidation with sodium chlorite. This
provided b-nitro acid 9a, which was then reacted with trimethylsi-
lyldiazomethane, to give the corresponding methyl ester derivative
9b. The same results were achieved when compounds 6b and 7b
were separately subjected to this reaction sequence. Reduction of
the nitro group of 9b by catalytic hydrogenation, followed by pro-
tection of the amino group of the resulting b-amino acid derivative
10a, by reaction with tert-butoxycarbonyl anhydride, yielded the
desired cyclopentane b-amino acid derivative 10b. Its absolute
configuration was confirmed by means of nOe experiments
(Fig. 1). Thus, a 1.9% nOe enhancement from proton H-1 to proton
H-3 confirmed the stated cis-disposition of both protons. More-
over, a 2.8% nOe enhancement from proton H-5 to proton H-2, con-
firmed the cis-disposition of these protons.
OMe
O2N
BnO
H
6a
H
O
OMe
H
O
H
OBn
O
N
OMe
O
OTf
H
O
4b'
H
6a''
H
OBn
NO2
OMe
6a'
Scheme 4.
We next considered the transformation of the C-5 unsubstitut-
ed nitrosugar 1g7 into its bicyclic lactone derivative 3b (Scheme 5,
route a). Thus, proceeding as for its analogue 1f, compound 1g was
easily converted into the key 2-O-triflyl lactone 2d, via lactone 2c.
However, unsatisfactory results were also achieved, because the
nitronate of 2d did not cyclize to the desired lactone 3b. Accord-
ingly, it was further confirmed that substituents were required at
both the C-3 and C-5 positions of type 2 nitrosugar lactones for
successful cyclization to the corresponding bicyclic nitrosugar lac-
tones 3.5
In view of the unsatisfactory results for the cyclization 2d?3b,
we decided to consider nitrosugar 1g for the alternative nitronate
alkylation involved in route b of Scheme 5, which is similar to those
previously developed for its analogue 1f. The reaction of compound
1g with AcCl in methanol provided a 1:1 anomeric mixture of com-
pounds 4c and 5c, as established by the isolation of both compo-
nents by column chromatography. Treatment of this mixture of
anomers 4c and 5c with triflic anhydride and pyridine allowed
us to obtain a mixture of their O-Tf derivatives 4d and 5d, which
was directly reacted with TBAF in THF. The result was the forma-
tion of a 10:10.6 anomeric mixture of bicyclic glycosides 6b and
7b, which were obtained in 71% overall yield for the two steps
and were isolated by column chromatography. The endo disposi-
tion of the methoxy group at the anomeric center of 6b was de-
duced from the coupling constant J3,4 = 3.1 Hz of the doublet at
5.01 ppm present in its 1H NMR spectrum. On the other hand, a
HO
H
1.9%
OBn
H
3
4
2
5
1
BocHN
H
H
CO2Me
2.8%
Figure 1. nOe enhancements observed for amino acid derivative 10b.
Finally, the incorporation of amino acid derivative 10b into
peptides was studied, by means of the incorporation of glycine
subunits to either the N- or the C-terminal position of this amino
acid.5d Basic hydrolysis of the methoxycarbonyl moiety of 10b
(Scheme 6) afforded the corresponding carboxylic acid 10c, which
upon treatment with HCl-Gly-OMe, in the presence of DIEA
and TBTU, gave dipeptide 11a in 61% yield. Removal of the
O2N
O2N
OBn
H
O2N
route a
O
O
O
O
O
O
ii
i
iii
O
NO2
X
O
O
BnO
BnO
OH
BnO
OTf
1g
2c
2d
3b
route b
O2N
iv
OBn
O2N
OMe
H
OMe
H
O
O
O
NO2
H
H
O
MeO
BnO
OH
BnO
OTf
H
4c
6b
4d
ii
iii
J3,4 = 3.1 Hz
O2N
O2N
OBn
H
H
O
O
NO2
MeO
OMe
OH
OMe
OTf
H
BnO
BnO
H
7b
5c
5d
Scheme 5. Reagents and conditions: (i) (a) TFA, H2O, rt, 19 h; (b) Br2, BaCO3, dioxane, H2O, rt, 6 h; (ii) Tf2O, pyridine, CH2Cl2, ꢀ30 °C, 1.5 h; (iii) TBAF, THF, rt; (iv) AcCl, MeOH,
0 °C, 14 h.

586
A. Estévez et al. / Tetrahedron: Asymmetry 25 (2014) 583–590
OBn
OBn
H
O
O
NO2
NO2
H
H
OH
OH
OH
H
OMe
OBn
O
6b
6c
OBn
O
ii
i
O2N
O2N
OBn
OBn
MeO
H
8
9 a
b
: X=OH
: X=OMe
O
O
NO2
NO2
HO
MeO
iii
H
H
H
H
7b
7c
OH
OH
OH
OBn
OBn
OBn
iv
v
O
H
H
N
N
N
YHN
O
YHN
CbzHN
CO2Me
CO2Me
H
O
O
X
12
11 a
: Y=Boc
10 a: X=OMe, Y=H
b: X=OMe, Y=Boc
c: X=OH, Y=Boc
b: Y=NH2
Scheme 6. Reagents and conditions: (i) (a) TFA/H2O 3:1, rt, 3 h; (b) 2-methyl-2-butene, NaClO2, NaH2PO4, t-BuOH/H2O 1:1, 1 h; (ii) TMSCHN2, Et2O/MeOH 7:2, 15 min; (iii)
(a) 1 M HCl, 10% Pd/C, H2 (1 atm), MeOH, rt, 48 h; (b) NaHCO3, (Boc)2O, rt, 16 h; (iv) (a) Ba(OH)2, THF/H2O, 1 h; (b) HCl-Gly-OMe, TBTU, DIEA, 12 h; (v) (a) TFA, THF, rt, 1 h; (b)
Cbz-Gly-OH, TBTU, DIEA, 6 h.
tert-butoxycarbonyl protecting group of 11a under acidic condi-
tions resulted in the formation of dipeptide derivative 11b, which
when reacted with Cbz-Gly-OH, DIEA and TBTU, provided the
expected tripeptide 12 in 45% overall yield for the two steps. The
presence of its two glycine subunits was confirmed by its 13C
NMR spectrum, which showed at 41.5 and 44.4 ppm the signals
due to its methylene groups and at 170.0 and 170.3 ppm the
signals corresponding to their amide carbonyls.
magnetic resonance spectra were recorded on a Bruker DPX-250
apparatus. Mass spectra were obtained on a Hewlett Packard
5988A mass spectrometer and high resolution mass spectra on a
VG Autospect 20-250 spectrometer. Elemental analyses were ob-
tained from the Elemental Analysis Service at the University of
Santiago de Compostela. Thin layer chromatography (TLC) was per-
formed using Merck GF-254 type 60 silica gel and ethyl acetate/
hexane mixtures as eluents; the TLC spots were visualized with
Hanessian mixture. Column chromatography was carried out using
Merck type 9385 silica gel.
3. Conclusion
In conclusion, we have studied the synthesis of 5-nitro-2-oxabi-
cyclo[2.2.1]heptan-3-ones 3a and 3b by intramolecular alkylation
of nitronates of 6-deoxy-6-nitro-2-O-trifluoromethanesulfonyl-
hexonolactones 2b and 2d, respectively. The results reported here,
combined with results from previous similar studies,5 allowed us
to establish that these cyclizations take place only when substitu-
ents are present at both their C-3 and C-5 positions of the starting
2-O-triflyl-hexonolactones 2. On the other hand, the successful
cyclizations of 4b?6a, 5b?7a, 4d?6b, and 5d?7b constitute
further confirmation of our previous findings that the above
limitation regarding the cyclization of 2-O-trifluoromethanesulfo-
nyl-hexonolactones 2 can be easily overcome when starting from
the corresponding glycofuranosides. Finally, as a further applica-
tion of this chemistry, we have reported the synthesis of the novel
cyclopentane b-amino acid derivative 10b and a protocol for its
incorporation into peptides.
4.2. 5-O-Benzyl-6-O-tert-butyldiphenyl-3-deoxy-1,2-O-isopro-
pylidene-a-D-glucofuranose 1b
To a suspension of sodium hydride (120 mg, 3.06 mmoles) and
tetrabutylammoniun iodide (10 mg, 0.03 mmoles) in DMF cooled
at 0 °C, a solution of 3-deoxy-1,2-O-isopropylidene-6-O-tert-butyl-
diphenylsilyl-a-D-glucofuranose 1a (151 mg, 7.38 mmol) in dry
DMF (8 mL), was added and the resulting mixture was stirred at
rt for 1 h. Benzyl bromide (0.4 mL, 3.31 mmol) was then added
and the resulting mixture was stirred at 50 °C for 1 h. Next, meth-
anol (2 mL) was added and the mixture was stirred at 50 °C under
argon for 2 h. The reaction mixture was cooled to rt, the solid was
filtered off through Celite and the solution was concentrated to
dryness under reduced pressure. The resulting residue was purified
by flash column chromatography (ethyl acetate/hexane 1:9), to
give compound 1b (830 mg, 63% yield) as
a yellow oil.
Work is currently in progress aimed at extending these studies
to sugar-based 3-nitropropionic acids and sugar-based 4-nitrobu-
tyric acids.
½
a 2D5
ꢁ
¼ ꢀ13:8 (c 1.1, CHCl3); 1H NMR (CDCl3, 250 MHz, ppm):
1.07 (s, 9H, –tBuSi); 1.28 (s, 3H, –CH3); 1.49 (s, 3H, –CH3); 1.78–
1.90 (m, 1H, H-3); 2.00 (dd, 1H, J3 ,4 = 4.4 Hz, J3 ,3 = 13.5 Hz, H-30);
3.69–3.83 (m, 3H, H–5, H-6, H-60); 4.45–4.52 (m, 1H, H–4); 4.61–
4.68 (m, 3H, H–2, –CH2Ph); 5.75 (d, 1H, J1,2 = 3.6 Hz, H-1); 7.10–
7.42 (m, 9H, 9 ꢂ Ar–H); 7.50–7.75 (m, 6H, 6 ꢂ Ar–H); 13C NMR
(CDCl3, 62.5 MHz, ppm): 19.2 (C); 26.0 (CH3); 26.6 (CH3); 26.8
(3 ꢂ CH3); 33.5 (CH2); 63.8 (CH2); 73.1 (CH2); 78.2 (CH); 79.4
(CH); 80.4 (CH); 105.0 (CH); 110.8 (C); 127.3 (CH); 127.4
(2 ꢂ CH); 127.6 (3 ꢂ CH); 128.0 (2 ꢂ CH); 129.5 (CH); 129.6 (CH);
133.0 (2 ꢂ C); 134.7 (CH); 135.4 (2 ꢂ CH); 135.5 (2 ꢂ CH); 138.6
(C); MS-CI (m/z, %): 533 (5, [M+H]+); 517 (15, [MꢀCH3]+); 417
0
0
4. Experimental
4.1. General
Melting points were determined using a Kofler Thermogerate
apparatus and are uncorrected. Specific rotations were recorded
on a JASCO DIP-370 optical polarimeter. Infrared spectra were
recorded on a MIDAC Prospect-IR spectrophotometer. Nuclear

A. Estévez et al. / Tetrahedron: Asymmetry 25 (2014) 583–590
587
(30, [MꢀC6H11O2]+); 288 (95, [MꢀC12H10]+); 91 (100, [PhCH2]+);
Anal. Calcd for C32H40O5Si: C, 72.14; H, 7.57. Found: C, 72.00; H,
7.78.
the solution was washed with water (75 mL) and a 1 M aqueous
solution of sodium thiosulfate (75 mL), dried (sodium sulfate),
and filtered. Removal of the solvent in vacuo was followed by puri-
fication of the residue by flash column chromatography (ethyl ace-
tate/hexane 1:7), and compound 1e (420 mg, 90% yield) was
4.3. 5-O-Benzyl-3-deoxy-1,2-O-isopropylidene-a-D-glucofura-
nose 1c
isolated as a yellow oil. ½a D20
ꢁ
¼ ꢀ11 (c 1.3, CHCl3). 1H NMR (CDCl3,
250 MHz, ppm): 1.32 (s, 3H, –CH3); 1.51 (s, 3H, –CH3); 1.71–1.82
(m, 1H, H-3); 2.20 (dd, 1H, J2,3 = 4.6 Hz, J3,3 = 13.5 Hz, H-30);
0
0
To a solution of 5-O-benzyl-3-deoxy-1,2-O-isopropylidene-6-O-
tert-butyldiphenylsilyl- -glucofuranose 1b (830 mg, 1.58 mmol)
0
a-
D
3.31–3.34 (m, 2H, H-5, H-6); 3.45 (dd, 1H, J6 ,5 = 4.6 Hz,
J6 ,6 = 10.7 Hz, H-60); 4.31–4.39 (m, 1H, H-4); 4.57 (d, 1H,
0
in dry THF (52 mL), TBAF (3.5 mL, 1 M in THF) was added and the
resulting mixture was stirred at rt for 4 h. The solvent was re-
moved under reduced pressure and the residue was dissolved in
dichloromethane (50 mL). The solution was washed with water
(3 ꢂ 30 mL), dried (sodium sulfate), filtered, and concentrated to
dryness in vacuo. The resulting residue was purified by flash col-
umn chromatography (ethyl acetate/hexane 1:2), to give com-
J7,7 = 6.5 Hz, –CHHPh); 4.70–4.76 (m, 2H, H-2, –CHHPh); 5.76 (d,
1H, J1,2 = 3.6 Hz, H-1); 7.25–7.39 (m, 5H, 5 ꢂ Ar–H); 13C NMR
(CDCl3, 62.5 MHz, ppm): 6.3 (CH2); 26.1 (CH3); 26.7 (CH3); 34.3
(CH2); 72.4 (CH2); 78.4 (CH); 79.1 (CH); 80.2 (CH); 105.0 (CH);
111.2 (C); 127.6 (CH); 127.7 (2 ꢂ CH); 128.1 (2 ꢂ CH); 137.5 (C);
MS-ESI (m/z, %): 405 (30, [M+H]+); 389 (50, [MꢀCH3]+); 347 (80,
[MHꢀC3H6O]+); 277 (15, [MꢀI]+); 91 (100, [PhCH2]+); Anal. Calcd
for C16H21IO4: C, 47.54; H, 5.24; encontrado C, 47.77; H, 5.48.
pound 1c (440 mg, 95% yield) as a yellow oil. ½a D27
¼ ꢀ0:2 (c 1.0,
ꢁ
CHCl3) 1H NMR (CDCl3, 250 MHz, ppm): 1.23 (s, 3H, –CH3); 1.42
0
(s, 3H, –CH3); 1.67–1.78 (m, 1H, H-3); 2.00 (dd, 1H, J3 ,4 = 4.4 Hz,
J3 ,3=13.5 Hz, H-30); 2.19 (br s, 1H, –OH); 3.47–3.66 (m, 3H, H-5,
4.6. 5-O-Benzyl-3,6-dideoxy-1,2-O-isopropylidene-6-nitro-a-D-
glucofuranose 1f
0
H-6, H-60); 4.21 (dt, 1H, J4,3 = J4,5 = 4.4 Hz, J4,3 = 10.7 Hz, H–4);
0
4.58–4.65 (m, 3H, H-2, –CH2Ph); 4.69 (d, 1H, J1,2 = 3.6 Hz, H-1);
7.18–7.27 (m, 5H, 5 ꢂ Ar–H); 13C NMR (CDCl3, 62.5 MHz, ppm):
26.0 (CH3); 26.6 (CH3); 34.5 (CH2); 62.3 (CH2); 73.2 (CH2); 78.6
(CH); 79.7 (CH); 80.3 (CH); 104.9 (CH); 111.1 (C); 127.7 8
1,3,5-Trihydroxybenzene (phloroglucinol) (380 mg, 2.36 mmol)
and sodium nitrite (230 mg, 3.29 mmol) were added to a solution
of 5-O-benzyl-3-deoxy-6-iodo-a-D-glucofuranose 1e (380 mg,
(3 ꢂ CH); 128.35 (2 ꢂ CH); 138.21 (C); IR (
m
, cmꢀ1): 3484 (b, OH);
0.94 mmol) in dry DMSO (9 mL), and the resulting mixture was
stirred at rt for 96 h. Next, water was added (15 mL) and the mix-
ture was extracted with ethyl acetate (4 ꢂ 30 mL). The combined
organic layers were dried (sodium sulfate), filtered, and concen-
trated to dryness under reduced pressure. The residue was purified
by flash column chromatography (ethyl acetate/hexane 1:3), to
MS-CI (m/z, %): 295 (15, [M+H]+); 279 (25, [MꢀCH3]+); 237 (60,
[MꢀC3H5O]+); 181 (55, [MꢀC6H9O2]+); 91 (100, [PhCH2]+); Anal.
Calcd for C16H22O5: C, 65.29; H, 7.53. Found: C, 64.90; H, 7.45.
4.4. 5-O-Benzyl-3-deoxy-1,2-O-isopropylidene-6-O-p-toluenesul-
phonyl-
a
-D
-glucofuranose 1d
give compound 1f (240 mg, 80% yield) as a yellow oil. ½a D20
¼ ꢀ12
ꢁ
(c 1.0, CHCl3). 1H NMR (CDCl3, 250 MHz, ppm): 1.30 (s, 3H, –
Tosyl chloride (0580 mg, 3.02 mmol) was added to a solution of
5-O-benzyl-3-deoxy- -glucofuranose 1c (440 mg, 1.51 mmol) in
CH3); 1.48 (s, 3H, –CH3); 1.68–1.79 (m, 1H, H-3); 2.14 (dd, 1H,
0
0
a-D
J3 ,4 = 4.4 Hz, J3 ,3 = 13.5 Hz, H-30); 4.17–4.25 (m, 1H, H-5); 4.28–
4.34 (m, 1H, H-4); 4.48–4.61 (m, 2H, H-2, H-6); 4.63 (s, 2H, –CH2-
Ph); 4.70–4.75 (m, 1H, H-60); 5.75 (d, 1H, J1,2 = 3.6 Hz, H-1); 7.23–
7.35 (m, 5H, 5 ꢂ Ar–H); 13C NMR (CDCl3, 62.5 MHz, ppm): 25.7
(CH3); 26.3 (CH3); 35.0 (CH2); 73.8 (CH2); 76.6 (CH2); 77.0 (CH);
77.2 (CH); 79.9 (CH); 105.0 (CH); 111.2 (C); 127.6 (2 ꢂ CH);
dry pyridine (91 mL), and the resulting mixture was stirred at rt for
10 h and filtered over Celite. The liquids were evaporated off under
reduced pressure, the residue was dissolved in dichloromethane
(50 mL), and the solution was washed with a 2 M aq solution of
hydrochloric acid (20 mL), water (2 ꢂ 20 mL) and brine
(2 ꢂ 20 mL), dried (sodium sulfate), and filtered. After removal of
the solvents under reduced pressure, the residue was purified by
flash column chromatography (ethyl acetate/hexane 1:4), to give
127.7 (CH); 128.1 (2 ꢂ CH); 136.8 (C); IR (
m
, cmꢀ1): 1554 (s,
NO2); 1376 (s NO2); MS-CI (m/z, %): 324 (27, [M+H]+); 266 (100,
[MꢀC3H6O]+); 250 (62, [MHꢀC3H6O2]+); 91 (100, [PhCH2]+); Anal.
Calcd for C16H21NO6: C, 59.43; H, 6.55; N, 4.33. Found: C, 59.24;
H, 6.42; N, 4.15.
compound 1d (660 mg, 98% yield) as a yellow oil. ½a D20
¼ ꢀ12 (c
ꢁ
0.5, CHCl3); 1H NMR (CDCl3, 250 MHz, ppm): 1.30 (s, 3H, –CH3);
1.47 (s, 3H, –CH3); 2.04–2.12 (m, 2H, H-3, H-30); 2.44 (s, 3H, –
CH3); 3.72–3.79 (m, 1H, H-5); 3.98–4.09 (m, 1H, H-6); 4.11–4.25
(m, 2H, H-60, H-4); 4.55–4.69 (m, 3H, H-2, –CH2Ph); 5.72 (d, 1H,
J1,2 = 3.6 Hz, H-1); 7.24–7.34 (m, 7H, 7 ꢂ Ar–H), 7.75–7.80 (m, 2H,
2 ꢂ Ar–H); 13C NMR (CDCl3, 62.5 MHz, ppm): 21.5 (CH3); 26.0
(CH3); 26.6 (CH3); 34.8 (CH2); 70.0 (CH2); 73.4 (CH2); 77.3
(2 ꢂ CH); 80.2 (CH); 105.2 (CH); 111.1 (C); 127.6 (CH); 127.7
(2 ꢂ CH); 127.8 (2 ꢂ CH); 128.2 (2 ꢂ CH); 129.8 (2 ꢂ CH); 132.5
4.7. 5-O-Benzyl-3,6-dideoxy-6-nitro-
D
-glucono-1,4-lactone 2a
-gluco-
5-O-Benzyl-3,6-dideoxy-1,2-O-isopropylidene-6-nitro-
D
furanose 1f (180 mg, 0.54 mmol) was dissolved in a 1:1 trifluoro-
acetic acid/water mixture (20 mL) and the reaction mixture was
stirred at rt for 12 h. The solvent was evaporated in vacuo and
the residue was coevaporated with toluene (3 ꢂ 10 mL) to give 5-
(C); 137.6 (C); 144.8 (C); IR (
m
, cmꢀ1): 1598 (SO2); MS-CI (m/z,
O-benzyl-3,6-dideoxy-6-nitro-D-glucofuranose as a clear gum. This
%): 449 (40, [M+H]+); 433 (45, [MꢀCH3]+); 373 (65, [MꢀC3H7O2]+);
crude product was dissolved in a 2:1 dioxane/water mixture
(10 mL), barium carbonate (150 mg, 0.75 mmol) and then bromine
(0.08 mL, 0.75 mmol) were added, after which the reaction mixture
was stirred at rt in darkness for 6 h. The reaction mixture was then
quenched with saturated aq sodium thiosulfate solution (until col-
orless) and extracted with ethyl acetate (3 ꢂ 20 mL). The combined
organic extracts were dried over sodium sulfate and evaporated to
dryness under reduced pressure. The crude residue was purified by
flash column chromatography (ethyl acetate/hexane 1:2), to give
299 (75, [MꢀC9H9O2]+); 91 (100, [PhCH2]+).
4.5. 5-O-Benzyl-3,6-dideoxy-6-iodo-1,2-O-isopropylidene-a-D-
glucofuranose 1e
Sodium iodide (523 mg, 35.0 mmol) was added to a solution of
5-O-benzyl-3-deoxy-6-O-p-toluenesulphonyl- -glucofuranose
a-D
1d (520 mg, 1.16 mmol) in acetone (29 mL), and the resulting mix-
ture was refluxed for 15 h. After cooling to rt, the mixture was fil-
tered and the filtrate was concentrated to dryness under reduced
pressure. The residue was dissolved in diethyl ether (75 mL) and
2a (60 mg, 41% yield) as a clear oil. ½a D25
¼ þ39:6 (c 1.8, CHCl3).
ꢁ
1H NMR (CDCl3, 250 MHz, ppm): 2.02–2.34 (m, 2H, H-3, H-30);
3.59 (br s, 1H, –OH); 4.16–4.51 (m, 7H, H-2, H-4, H-5, H-6, H-60,

588
A. Estévez et al. / Tetrahedron: Asymmetry 25 (2014) 583–590
–CH2Ph); 7.01–7.22 (m, 5H, 5 ꢂ Ar–H); 13C NMR (CDCl3, 62.5 MHz,
ppm): 31.0 (CH2); 66.8 (CH); 74.7 (CH2); 75.4 (CH2); 76.3 (CH);
76.8 (CH); 128.3 (2 ꢂ CH); 128.5 (CH); 128.6 (2 ꢂ CH); 136.1 (C);
4.11. (1S,3R,4R,5S,6R)-6-(Benzyloxy)-3-methoxy-5-nitro-2-oxa-
bicyclo[2.2.1]heptane 6a and (1S,3S,4R,5S,6R)-6-(benzyloxy)-3-
methoxy-5-nitro-2-oxabicyclo[2.2.1]heptane 7a
177.0 (C); IR (m
, cmꢀ1): 3445 (b, OH); 1798 (CO); 1555 (s, NO2);
1380 (s, NO2); MS-CI (m/z, %): 282 (10, [M+H]+); 237 (25,
[MꢀCO2]+); 207 (56, [MꢀC2H2O3]+); 91 (100, [PhCH2]+); Anal. Calcd
for C13H15NO6: C, 55.51; H, 5.38; N, 4.98. Found: C, 55.72; H, 5.43;
N, 5.02.
A 1 M solution of tetrabutylammonium fluoride in THF (1.1 mL)
was added to a solution of a recently obtained mixture of 4b and
5b in THF (5 mL) and the resulting mixture was stirred at rt under ar-
gon for 1.5 h. The solvent was removed in vacuo and the residue was
dissolved in dichloromethane (10 mL). The solution was washed
with water (3 ꢂ 10 mL), and the organic layer was dried (sodium
sulfate), filtered, and concentrated in vacuo. The resulting gum
was purifiedby flashcolumn chromatography (ethyl acetate/hexane
1:5) to give bicycle 6a (100 mg, 97% yield from 4a), as an orange oil,
and bicycle 7a (5 mg 28% yield from 5a), as a yellow oil. Data for 6a:
4.8. 5-O-Benzyl-3,6-dideoxy-6-nitro-2-O-trifluoromethanesul-
phonyl-
D-glucono-1,4-lactone 2b
5-O-Benzyl-3,6-dideoxy-6-nitro-D-glucono-1,4-lactone
2a
(60 mg, 0.21 mmol) was dissolved in dry dichloromethane
(1.4 mL) and the solution was then cooled down to ꢀ30 °C under
argon. Dry pyridine (0.05 mL, 0.63 mmol) and trifluoromethanesul-
phonic anhydride (0.06 mL, 0.27 mmol) were added and the mix-
ture was stirred at ꢀ30 °C for 1.5 h. The reaction was diluted
with dichloromethane (10 mL), and washed with dilute aq hydro-
chloric acid (10 mL) and brine (10 mL). The organic layer was dried
(sodium sulfate) and concentrated to dryness to give lactone 2b as
a clear gum, which was used in the next step without further puri-
fication, after keeping it in vacuo overnight.
½
a 2D7
ꢁ
¼ þ58 (c 0.5, CHCl3); 1H NMR (CDCl3, 250 MHz, ppm): 1.88–
2.07 (m, 2H, H-7, H-70); 3.17 (m, 1H, H-4); 3.52 (s, 3H, –OCH3);
4.29–4.33 (m, 2H, H-1, H-6); 4.75 (ABq, 2H, J = 12.3 Hz, –CH2Ph);
5.10 (t, 1H, J5,4 = J5,6 = 2.5 Hz, H-5); 5.17 (d, 1H, J3,4 = 2.7, H-3);
7.26–7.44 (m, 5H, 5 ꢂ Ar–H); 13C NMR (CDCl3, 62.5 MHz, ppm):
34.4 (CH2), 47.1 (CH), 56.6 (CH3), 71.8 (CH2), 78.4 (CH), 84.2 (CH),
84.7 (CH); 104.5 (CH); 127.9 (3 ꢂ CH); 128.4 (2 ꢂ CH); 137.1 (C);
MS-CI (m/z, %): 280 (5, [M+H]+); 248 (25, [MꢀOCH3]+); 233 (10,
[MꢀNO2]+); 91 (100, [PhCH2]+); IR (
m
, cmꢀ1): 1552 (s, NO2), 1373
(s, NO2); Anal. Calcd for C14H17NO5: C, 60.21; H, 6.14; N, 5.02. Found:
4.9. Methyl-5-O-benzyl-3,6-deoxy-6-nitro-b-
D-glucofuranoside-
C, 60.47; H, 6.32; N, 5.17. Data for 7a: ½a D25
ꢁ
¼ þ32 (c 1.0, CHCl3) 1H
4a and methyl-5-O-benzyl-3,6-deoxy-6-nitro-
a-
D-
NMR (CDCl3, 250 MHz, ppm): 1.81–1.84 (m, 1H, H-7); 2.09–2.12
(m, 1H, H-70); 3.05 (m, 1H, H-4); 3.41 (s, 3H, –OCH3); 4.26–4.31
(m, 2H, H-1, H-6); 4.42–4.44 (m, 1H, H-5); 4.67 (s, 1H, H-3); 4.69
(m, 2H, –CH2Ph); 7.26–7.39 (m, 5H, 5 ꢂ Ar–H); 13C NMR (CDCl3,
62.5 MHz, ppm): 34.2 (CH2), 47.0 (CH), 56.5 (CH3), 71.6 (CH2), 78.2
(CH), 84.0 (CH), 84.5 (CH); 104.3 (CH); 127.7 (3 ꢂ CH); 128.2
(2 ꢂ CH); 136.7 (C); MS-CI (m/z, %): 280 (5, [M+H]+); 248 (17,
glucofuranoside 5a
Acetyl chloride (0.31 mL, 4.44 mmol) was added to a cooled
(0 °C) solution of 1f (240 mg, 0.74 mmol) in dry methanol (5 mL)
and the resulting mixture was stirred at 0 °C for 14 h. After neutral-
ization with Na2CO3, the mixture was filtered and the filtrate was
concentrated to dryness under reduced pressure. Flash column
chromatography (ethyl acetate/hexane 1:1) of the residue afforded
a chromatographically pure 6:1 mixture of anomers 4a and 5a
(150 g, 70% yield), which was used directly without further purifi-
cation. 1H NMR (CDCl3, 250 MHz, ppm): 2.00–2.08 (m, 4H, H-3a, H-
3b, H-30a, H-30b); 2.22 (br s, 2H, –OHa, –OHb); 3.34 (s, 3H, –CH3a);
3.46 (s, 3H, –CH3b); 4.07–4.17 (m, 2H, H-5a, H-5b); 4.19–4.25 (m,
2H, H-2a, H-2b); 4.48–4.65 (m, 9H, H-6a, H-6b, H-6a0, H-6b0, H-4a,
H-4b, –CHHPha, –CH2Phb); 4.74 (d, 1H, J = 13.2 Hz, –CHHPha); 4.78
(s, 1H, H-1a); 4.83 (d, 1H, J1,2 = 4.4 Hz, H-1b); 7.25–7.37 (m, 10H,
5 ꢂ Ar–Ha, 5 ꢂ Ar–Hb); 13C NMR (CDCl3, 62.5 MHz, ppm): 34.4
(CH2b); 36.1 (CH2a); 55.5 (CH3a); 56.0 (CH3b); 74.0 (CH2a); 74.6
(CH2b); 76.0 (CHa); 76.9 (CHb); 77.0 (CH2b); 77.7 (CH2a); 78.5
(CHb); 78.8 (CHa); 80.5 (CHa, CHb); 102.9 (CHb); 110.0 (CHa),
128.4 (2 ꢂ CHa); 128.5 (2 ꢂ CHb); 128.6 (CHa); 128.7 (CHb);
[MꢀOCH3]+); 233 (30, [MꢀNO2]+); 91 (100, [PhCH2]+); IR (
m,
cmꢀ1): 1551 (s, NO2), 1372 (s, NO2); Anal. Calcd for C14H17NO5: C,
60.21; H, 6.14; N, 5.02. Found: C, 60.31; H, 6.04; N, 5.24.
4.12. 3-O-Benzyl-5-deoxy-5-nitromethyl-D-xylono-1,4-lactone
2c
When compound 1g (0.18 g, 0.56 mmol) was subjected to the
conditions used for the preparation of 2a, D-xylono-1,4-lactone 2c
(0.09 g, 0.32 mmol, 57%) was obtained as a yellow oil. ½a D23
¼ þ32
ꢁ
(c 1.8, MeOH); 1H NMR (CDCl3, 250 MHz, ppm): 2.21–2.34 (m, 1H,
H-5); 2.55–2.67 (m, 1H, H-50); 3.00 (br s, 1H, –OH); 4.31–4.84 (m,
7H, H-2, H-3, H-4, H-6, H-60, –CH2Ph); 7.28–7.43 (m, 5H, 5 ꢂ Ar–H);
13C NMR (CDCl3, 62.5 MHz, ppm): 27.4 (CH2); 71.5 (CH2); 71.6 (CH);
72.5 (CH2); 76.4 (CH); 79.6 (CH2); 127.9 (2 ꢂ CH); 128.3 (CH); 128.7
128.9 (2 ꢂ CHa); 129.0 (2 ꢂ CHb); 136.1 (Ca); 136.2 (Cb); IR (
m
,
(2 ꢂ CH); 174.7 (C); IR (
m
, cmꢀ1): 3413 (b, OH); 1786 (s, CO); 1554
cmꢀ1): 3443 (b, OH); 1553 (s, NO2); 1375 (s, NO2); MS-CI (m/z,
%): 298 (76, [M+H]+); 280 (80, [MHꢀH2O]+); 207 (61, [MHꢀC7H7]+);
91 (100, [PhCH2]+). Anal. Calcd for C14H19NO6: C, 56.56; H, 6.44; N,
4.71. Found: C, 56.39; H, 6.30; N, 4.67.
(s, NO2); 1376 (s, NO2); MS-CI (m/z, %): 264 (1, [MꢀOH]+); 145
(25, [MꢀCH3]+); 91 (100, [PhCH2]+). Anal. Calcd for C13H15NO6: C,
55.51; H, 5.38; N, 4.98. Found: C, 55.63, H, 5.43, N, 5.04.
4.13. 3-O-Benzyl-5-deoxy-5-nitromethyl-2-O-trifluoromethane-
4.10. Methyl-5-O-benzyl-3,6-deoxy-6-nitro-2-O-trifluorometh-
sulphonyl-D-xylono-1,4-lactone 2d
anesulfonyl-b-D-glucofuranoside 4b and methyl-5-O-benzyl-
3,6-deoxy-6-nitro-2-O-trifluoromethanesulfonyl-
anoside 5b
a
-
D
-glucofur-
Applying the conditions used for the preparation of compound
2b, lactone 2c was transformed into its 2-O-triflyl derivative 2d,
which was used without further purification after keeping it in va-
cuo overnight.
A mixture of compounds 4a and 5a (0.13 g, 0.47 mmol) was
subjected to the same procedure as for the transformation of com-
pound 2a into compound 2b, for a period of 25 min. The reaction
was quenched with 2 M HCl (2 mL), diluted with water (20 mL),
and extracted with dichloromethane (3 ꢂ 20 mL). The combined
organic layers were dried (sodium sulfate) and concentrated to
dryness under reduced pressure to a mixture of 4b and 5b, which
was used without further purification.
4.14. Methyl-3-O-benzyl-5-deoxy-5-nitromethyl-b-D-xylofura
noside 4c and methyl-3-O-benzyl-5-deoxy-5-nitromethyl-a-D-
xylofuranoside 5c
5-Nitromethyl-
a-D-xylofuranose 1g (370 mg, 1.15 mmol), un-
der the conditions used for the transformation of compound 1f

A. Estévez et al. / Tetrahedron: Asymmetry 25 (2014) 583–590
589
to give a mixture of 4a and 5a, provided a residue that was purified
by flash column chromatography (ethyl acetate/hexane 1:2), to
give compound 4c (150 mg, 44% yield) and its anomer 5c
(160 mg, 45% yield), both as colorless oils. Data for 4c:
4.16. (1S,2R,3R,5R)-Methyl 2-(benzyloxy)-3-hydroxy-5-nitrocyc-
lopentanecarboxylate 9b
A solution of a mixture of bicycles 6b and 7b (120 mg,
0.432 mmol) in a 3:1 TFA/H2O mixture (1.38 mL) was stirred at rt
for 4 h. The reaction mixture was evaporated to dryness and
coevaporated with toluene (3 ꢂ 2 mL). Next, 2-methyl-2-butene
(1.05 mL, 9.92 mmol), NaClO2 (280 mg), and NaH2PO4ꢃH2O
(240 mg) were added to a solution of the resulting residue in 1:1
t-BuOH/H2O (2.30 mL) and the resulting mixture was stirred at rt
for 1 h. After the addition of water (2 mL), the mixture was ex-
tracted with ethyl acetate (4 ꢂ 4 mL), and the combined organic
layers were dried (sodium sulfate), filtered, and concentrated to
dryness under reduced pressure. To a solution of the resulting
crude acid 9a in 7:2 Et2O/MeOH (1 mL), TMSCHN2 (0.025 mL/2 M
in hexane) was added and the mixture was stirred at rt for
15 min and then evaporated to dryness. The resulting residue
was purified by flash column chromatography (ethyl acetate/hex-
ane 1:1) to give methyl 5-nitrocyclopentanecarboxylate 9b
½
a 2D7
ꢁ
¼ ꢀ59 (c 1.0, CHCl3). 1H NMR (CDCl3, 250 MHz, ppm): 2.28–
2.38 (m, 2H, H-5, H-50), 2,54 (s, 1H, –OH), 3.38 (s, 3H, –OCH3),
3.91 (dd, 1H, J3,2 = J3,4 = 3.3 Hz, H-3), 4.20–4.33 (m, 2H, H-2, H-6),
4.47–4.51 (m, 2H, H-4, H-60), 4.52 (d, 1H, J = 12.1 Hz, –CHHPh),
4.68 (d, 1H, J = 12.1 Hz, –CHHPh), 4.75 (d, 1H, J1,2 = 1.9 Hz, H-1),
7.29–7.39 (m, 5H, 5 ꢂ Ar–H); 13C NMR (CDCl3, 62.5 MHz, ppm):
28.4 (CH2), 55.9 (CH3), 72.3 (CH2), 72.6 (CH2), 74.4 (CH), 77.2
(CH), 83.5 (CH), 104.5 (CH), 127.8 (2 ꢂ CH), 128.0 (CH), 128.5
(2 ꢂ CH), 137.3 (C); IR (
m
, cmꢀ1): 3445 (b, OH); 1555 (s, NO2);
1374 (s, NO2); MS-CI (m/z, %): 298 (47, [M+H]+); 280 (95, [MHꢀH2-
O]+); 207 (73, [MHꢀC7H7]+); 91 (100, [PhCH2]+); Anal. Calcd for
C
14H19NO6: C, 56.56; H, 6.44; N, 4.71. Found: C, 56.64; H, 6.52;
N, 4.77. Data for 5c: ½a D27
ꢁ
¼ ꢀ15 (c 1.0, CHCl3). 1H NMR (CDCl3,
250 MHz, ppm): 2.27–2.39 (m, 2H, H-5, H-50), 2,80 (d, 1H,
J=6.9 Hz, –OH), 3.44 (s, 3H, –OCH3), 3.91 (dd, 1H,
J3,2 = J3,4 = 3.3 Hz, H-3), 4.18–4.28 (m, 2H, H-2, H-6), 4.56–4.64
(m, 3H, H-4, H-60, –CHHPh), 4.76 (d, 1H, J = 6.8 Hz, –CHHPh), 4.93
(d, 1H, J1,2 = 4.7 Hz, H-1), 7.26–7.39 (m, 5H, 5 ꢂ Ar–H); 13C NMR
(CDCl3, 62.5 MHz, ppm): 27.3 (CH2), 55.6 (CH3), 71.5 (CH2), 72.5
(CH2), 74.8 (CH), 77.9 (CH), 83.6 (CH), 101.4 (CH), 127.6 (2 ꢂ CH),
(85 mg, 87% yield) as a clear yellow oil. ½a D23
¼ þ113:0 (c 1.15,
ꢁ
CHCl3); 1H NMR (CDCl3, 250 MHz, ppm): 2.01 (br s, 1H, OH), 2.41
0
(ddd, 1H, J4,5 = 3.2 Hz, J4.3 = 7.6 Hz, J4,4 = 13.9 Hz, H-4), 2.64 (ddd,
1H, J4 ,3 = 5.2 Hz, J4 ,5 = 7.6 Hz, J4 ,4 = 13.9 Hz, H-40), 3.72–3.75 (m,
1H, H-1), 3.76 (s, 3H, –OCH3), 4.09–4.12 (m, 1H, H-2), 4.29–4.33
(m, 1H, H-3), 4.55 (d, 1H, J = 11.8 Hz, –CHPh), 4.68 (d, 1H,
J = 11.8 Hz, –CHPh); 5.63–5.45 (m, 1H, H-5), 7.30–7.37 (m, 5H,
5 ꢂ Ar–H); 13C NMR (CDCl3, 62.5 MHz, ppm): 37.5 (CH2), 52.8
(CH), 53.0 (OCH3), 71.7 (CH2), 75.0 (CH), 84.5 (CH), 86.6 (CH),
127.7 (2 ꢂ CH), 128.0 (CH), 128.4 (2 ꢂ CH), 137.1 (C), 171.3
(C@O); MS-CI (m/z, %): 296 [(M+H)+, 72], 295 [(M)+, 20], 294
0
0
0
127.8 (CH), 128.4 (2 ꢂ CH), 137.5 (C), IR (
m
, cmꢀ1): 3442 (b, OH),
1557 (s, NO2), 1374 (s, NO2), MS-CI (m/z, %): 298 (63, [M+H]+),
280 (80, [MHꢀH2O]+), 207 (65, [MHꢀC7H7]+), 91 (100, [PhCH2]+);
Anal. Calcd for C14H19NO6: C, 56.56; H, 6.44; N, 4.71. Found: C,
56.69; H, 6.57; N, 4.80.
[(MꢀH)+, 80], 181 (99), 91 [(PhCH2)+, 100]; IR (
m
, cmꢀ1): 3467
4.15. (1R,3R,4S,5R,7R)-7-Benzyloxy-3-methoxy-5-nitro-2-oxabi-
cyclo[2.2.1]heptane 6b and (1R,3S,4S,5R,7R)-7-benzyloxy-3-
methoxy-5-nitro-2-oxabicyclo[2.2.1]heptane 7b
(OH); 1737 (CO); 1552, 1373 (NO2). Anal. Calcd for C14H17NO6: C,
56.94, H, 5.80, N, 4.74. Found: C, 56.99; H, 5.71; N, 4.63.
4.17. (1S,2R,3R,5R)-Methyl 2-(benzyloxy)-5-(tert-butoxycarbon-
ylamino)-3-hydroxy-cyclopentanecarboxylate 10b
Proceeding as for the mixture of 4a and 5a, a mixture of ano-
mers 4c and 5c (310 mg, 1.05 mmol) was transformed into a mix-
ture of their O-triflyl derivatives 4d and 5d, which were directly
converted into a mixture of their respective bicylic glycosides 6b
and 7b (220 mg, 71% yield) The residue was purified by flash col-
umn chromatography (ethyl acetate/hexane 1:4) to give bicycle
6b (107 mg) and bicycle 7b (113 g), as yellow oils. Data for 6b:
At first, 1 M aq HCl (0.02 mL) and 10% Pd/C (50 mg) were added
sequentially to a deoxygenated solution of 9b (50 mg, 0.15 mmol)
in MeOH (5 mL). After deoxygenation, the mixture was stirred at rt
for 48 h under a hydrogen atmosphere (1 atm). The reaction mix-
ture was filtered over a pad of Celite, which was then washed with
MeOH. The filtrate was concentrated to dryness under reduced
pressure. Saturated aq NaHCO3 was added to a solution of the
resulting crude amine 10a and (Boc)2O (110 mg, 0.50 mmol) in
dioxane (2 mL) until basic pH and the mixture was stirred at rt
for 16 h. Next, 10% HCl (5 mL) was added and the mixture was ex-
tracted with AcOEt (3 ꢂ 5 mL). The combined organic layers were
dried (sodium sulfate), filtered, and concentrated to dryness under
reduced pressure. The residue was subjected to flash column chro-
matography (AcOEt/hexane 1:1) to give 10b (30 mg, 0.09 mmol,
½
a 2D7
ꢁ
¼ ꢀ40:5 (c 2.0, CHCl3); 1H NMR (CDCl3, 250 MHz, ppm):
0
2.41 (dd, 1H, J6,5 = 8.7 Hz, J6,6 = 14.7 Hz, H-6), 2.72–2.92 (m, 1H,
H-60), 3.38 (s, 3H, –OCH3), 3.64–3.74 (m, 1H, H-4), 4.00–4.10 (m,
1H, H-7), 4.20–4.28 (m, 1H, H-1), 4.41 (ABq, 2H, J = 6.7 Hz, –CH2-
Ph), 4.86–5.00 (m, 1H, H-5), 5.01 (d, 1H, J3,4 = 3.1 Hz, H-3), 7.17–
7.40 (m, 5H, 5 ꢂ Ar–H); 13C NMR (CDCl3, 62.5 MHz, ppm): 34.7
(CH2), 47.7 (CH), 56.0 (CH3), 71.8 (CH2), 77.9 (CH), 78.4 (CH), 81.1
(CH), 101.4 (CH), 127.6 (2 ꢂ CH), 127.9 (CH), 128.4 (2 ꢂ CH),
136.8 (C); MS-CI (m/z, %): 280 (50, [M+H]+); 248 (65, [MꢀOCH3]+);
233 (70, [MꢀNO2]+); 91 (100, [PhCH2]+); IR (
m
, cmꢀ1): 1552 (s,
NO2), 1373 (s, NO2). Anal. Calcd for C14H17NO5: C, 60.21; H, 6.14;
57% from 9b) as a yellow oil. ½a D27
ꢁ
¼ ꢀ3:7 (c 1.1, CHCl3); 1H NMR
(CDCl3, 250 MHz, ppm): 1.35 (s, 9H, 3 ꢂ CH3), 1.92 (dt, 1H,
J4a,4b = 13.9 Hz, J4a,3 = J4a,5 = 7.1 Hz, H-4a), 2.15 (ddd, 1H,
J4b,4a = 13.9 Hz, J4b,5 = 7.6 Hz, J4b,3 = 3.5 Hz, H-4b), 2.74 (dd, 1H,
J1,5 = 7.1 Hz, J1,2 = 5.4 Hz, H-1), 2.78 (br s, 1H, –OH); 3.72 (s, 3H, –
OCH3), 4.02–4.09 (m, 1H, H-2), 4.21 (dt, 1H, J3,4a = 7.1 Hz,
J3,2 = J3,4b = 3.5 Hz, H-3), 4.37–4.45 (m, 1H, H-5), 4.55 (d, 1H,
N, 5.02. Found: C, 60.37; H, 6.18; N, 5.14. Data for 7b:
½
a 2D5
ꢁ
¼ ꢀ14:8 (c 1.5, CHCl3); 1H NMR (CDCl3, 250 MHz, ppm):
2.29 (dd, 1H, J6,5 = 8.8 Hz, J6.6 = 14.5 Hz, H-6), 2.77 (m, 1H, H-60);
3.35 (s, 3H, –OCH3), 3.52 (s, 1H, H-4), 4.25 (s, 1H, H-7), 4.29–4.40
(m, 2H, –CH2Ph); 4.49 (d, 1H, J = 11.4 Hz, –CHNO2), 4.55 (s, 1H,
H-3), 7.15–7.39 (m, 5H, 5 ꢂ Ar–H). 13C NMR (CDCl3, 62.5 MHz,
ppm): 35.2 (CH2), 48.2 (CH), 55.1 (CH3), 72.0 (CH2), 75.7 (CH),
80.3 (CH), 81.2 (CH), 103.3 (CH), 127.7 (2 ꢂ Ar–H), 127.9 (Ar–H),
128.4 (2 ꢂ Ar–H), 137.0 (C). MS-CI (m/z, %): 280 (50, [M+H]+);
248 (53, [MꢀOCH3]+); 233 (85, [MꢀNO2]+); 91 (100, [PhCH2]+); IR
0
0
0
JH,H = 11.8 Hz, –CHPh), 4.61 (d, 1H, JH,H = 11.8 Hz, –CHPh), 4.90
(d, 1H, JNH,5 = 8.2 Hz, –NH), 7.28–7.40 (m, 5H, 5 ꢂ Ar–H). 13C
NMR (CDCl3, 62.5 MHz, ppm): (3 ꢂ CH3), 39.7 (CH2), 52.3 (CH3 +
CH), 56.4 (CH), 72.0 (CH2), 75.2 (CH), 79.6 (C), 87.8 (CH), 127.7
(2 ꢂ CH-Ar); 127.8 (CH-Ar); 128.4 (2 ꢂ CH-Ar); 137.6 (C-Ar);
(m,
cmꢀ1): 1551 (s, NO2), 1372 (s, NO2). Anal. Calcd for
155.0 (C@O); 173.8 (C@O). IR (m
, cmꢀ1): 3372 (b, OH + NH); 1715
C14H17NO5: C, 60.21; H, 6.14; N, 5.02. Found: C, 60.12; H, 6.26; N,
(s, C@O); 1694 (s, NAC@O). MS-CI (m/z, %): 366 (41, [MH]+); 308
4.94.

590
A. Estévez et al. / Tetrahedron: Asymmetry 25 (2014) 583–590
t
(100, [Mꢀ Bu]+); 91 (88, [CH2Ph]+). Anal. Calcd for C19H27NO6: C,
(1 mL) was added and the new mixture was stirred at rt for 6 h.
The reaction mixture was washed with 10% aq HCl (3 mL) and
the organic layer was dried (sodium sulfate) and concentrated to
dryness in a rotary evaporator. Flash column chromatography
((AcOEt) of the resulting residue gave tripeptide 12 (20 g, 45% yield
62.45; H, 7.45; N, 3.83. Found: C, 62.71; H, 7.83; N, 3.75.
4.18. (1S,2R,3R,5R)-Methyl 2-(benzyloxy)-5-(tert-butoxycarbon-
ylamino)-3-hydroxy-1-(methoxycarbonylglycylcarbamoyl)cy-
clopentane 11a
from 11a) as a colorless oil. ½a D20
ꢁ
¼ þ6:0 (c 1.0, CHCl3); 1H NMR
(CDCl3, 250 MHz, ppm): 1.87–2.00 (m, 1H, H-4a); 2.13–2.23 (m,
1H, H-4b); 2.86 (br s, 1H, H-1); 3.71 (s, 3H, –OCH3); 3.75 (br s,
At first, Ba(OH)2ꢃ8H2O (80 mg, 0.24 mmol) was added to a solu-
tion of compound 10b (30 mg, 0.08 mmol) in 1:2 THF/H2O
(1.5 mL), and the mixture was stirred at rt for 1 h. The reaction
mixture was then neutralized with DOWEX 50WX4-50 and the re-
sin was filtered off and washed with MeOH. Removal of the solvent
under reduced pressure, provided carboxylic acid 10c, which was
directly dissolved in dry CH2Cl2 (1 mL). Next, TBTU (30 mg,
0.10 mmol) and DIEA (0.05 mL, 0.26 mmol) were added and the
mixture was stirred at rt for 15 min, after which HCl-Gly-OMe
(0.01 g, 0.08 mmol) was added and the stirring was continued for
12 h. The reaction mixture was diluted with CH2Cl2 (5 mL) and
washed with 10% aq HCl (5 mL). The organic layer was dried
(sodium sulfate), filtered, and concentrated to dryness under re-
duced pressure. Flash column chromatography of the solid residue
(AcOEt/hexane 2:1), gave dipeptide 11a (20 mg, 0.04 mmol, 61%
0
1H, –OH) 3.80 (2 ꢂ d, 2H, JH,H = 5.2 Hz, 2 ꢂ CH-Gly); 4.00 (2 ꢂ d,
0
2H, JH,H = 5.2 Hz, 2 ꢂ CH-Gly); 4.20–4.32 (m, 2H, H-2 + H-3);
4.40–4.51 (m, 1H, H-5); 4.52–4.60 (m, 2H, –CH2Ph); 5.06–5.12
(m, 2H, –CH2Ph); 5.63 (br s, 1H, –NH); 6.84 (br s, 1H, –NH);
7.27–7.37 (m, 10H, 10 ꢂ Ar–H); 8.07 (br s, 1H, –NH); 13C NMR
(CDCl3, 62.5 MHz, ppm): 39.3 (CH2), 41.5 (CH2), 44.4 (CH2), 52.3
(CH3), 53.3 (CH), 57.6 (CH), 67.3 (CH2), 72.0 (CH2), 75.1 (CH), 86.0
(CH), 127.9 (4 ꢂ CH–Ar), 128.1 (2 ꢂ CH–Ar), 128.3 (4 ꢂ CH–Ar),
128.5 (CH–Ar), 128.6 (C–Ar), 135.9 (C–Ar), 137.8 (C–Ar), 156.7
(C@O), 170.0 (C@O), 170.3 (C@O), 173.8 (C@O); IR (m
, cmꢀ1):
3299 (s, NH + OH), 1728 (s, C@O), 1692 (s, NAC@O), 1656 (s,
t
NAC@O). MS-CI (m/z, %): 515 (31, [MH]+); 457 (79, [Mꢀ Bu]+); 91
(100, [CH2Ph]+); Anal. Calcd for C26H31N3O8: C, 60.81; H, 6.08; N,
8.18. Found: C, 60.60; H, 5.80; N, 7.94.
from 10b), as a colorless oil. ½a D20
ꢁ
¼ þ21:6 (c 1.4, CHCl3); 1H NMR
(CDCl3, 250 MHz, ppm): 1.43 (s, 9H, 3 ꢂ CH3), 1.79–1.90 (m, 1H,
H-4a), 2.15–2.26 (m, 1H, H-4b), 2.87 (br s, 1H, H-1), 3.32 (br s,
1H, –OH), 3.74 (s, 3H, –OCH3), 4.03–4.05 (m, 2H, 2 ꢂ CH-Gly),
Acknowledgements
We thank the Spanish Ministry of Science and Innovation for
financial support (CTQ2009-08490) and for F.P.U. grant to A.E.,
and the Xunta de Galicia for financial support and for a fellowship
to Rosalino Balo.
0
4.20–4.35 (m, 3H, H-2 + H-3 + H-5), 4.57 (2 ꢂ d, 2H, JH,H = 12.7 Hz,
2 ꢂ CHPh), 4.97 (br s, 1H, N-H), 7.28–7.34 (m, 5H, 5 ꢂ Ar–H), 8.05
(br s, 1H, –NH). 13C NMR (CDCl3, 62.5 MHz, ppm): 28.3 (3 ꢂ CH3),
39.8 (CH2), 41.5 (CH2), 52.3 (CH3), 54.4 (CH), 58.3 (CH), 71.9
(CH2), 75.1 (CH), 80.2 (C), 85.9 (CH), 127.7 (2 ꢂ CH–Ar), 127.8
(CH–Ar), 128.4 (2 ꢂ CH–Ar), 137.8 (C–Ar), 156.2 (C@O), 170.1
References
(C@O), 174.2 (C@O). IR (m
, cmꢀ1): 3310 (s NH + OH), 1737 (s,
1. (a) Guichard, G. In Pseudo-Peptides in Drug Discovery; Nelson, P. E., Ed.; Wiley-
VCH: Weinheim, 2004; pp 33–120; (b) Seebach, D.; Hook, D. F.; Glättli, A.
Biopolymers 2006, 84, 23.
2. Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008, 41, 1366. and references therein.
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T. A.; Forró, E.; Fülöp, F. Eur. J. Org. Chem. 2008, 3724–3730.
C@O), 1678 (s, NAC@O), 1629 (s, NAC@O). MS-CI (m/z, %): 423
(24, [MH]+); 365 (64, [Mꢀ Bu]+); 91 (100, [CH2Ph]+). Anal. Calcd
t
for C21H30N2O7: C, 59.70; H, 7.16; N, 6.63. Found: C, 59.59; H,
7.31; N, 6.89.
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The Chiron Approach; Pergamon: Oxford, 1983; For reviews, see (b) Jarosz, S.
Chim. Oggi 2006, 24, 58–61; (c) Timmer, M. S. M.; Verhelst, S. H. L.; Grotenbreg,
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4.19. 1S,2R,3R,5R)-Methyl 2-(benzyloxy)-5-(benzyloxycarbonyl-
glycylamino)-3-hydroxy-1-(methoxycarbonylglycylcarbamoyl)-
cyclopentane 12
At first, TFA (0.2 mL) was added to a solution of dipeptide 11a
(20 mg, 0.05 mmol) in THF (0.5 mL) and the mixture was stirred
at rt for 1 h. The liquids were coevaporated with toluene
(3 ꢂ 2 mL) in a rotary evaporator and the remaining crude amine
11b was used directly without any further treatment.
A solution of TBTU (30 mg, 0.09 mmol) and DIEA (0.03 mL,
0.14 mmol) in dry CH2Cl2 (0.5 mL) was stirred at rt for 15 min, then
Cbz-Gly-OH (0.01 g, 0.08 mmol) was added and the stirring was
continued for 15 min. Next, a solution of crude 11b in dry CH2Cl2
6. Rondot, B.; Durand, T.; Rossi, J.-C.; Rollin, P. Carbohydr. Res. 1994, 261, 149–156.
7. Goddard-Borger, E. D.; Brigitte Fiege, B.; Kwan, E. M.; Withers, S. G.
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