Preparation of sugar derived β,β′-dihydroxy α,α-disubstituted α-amino acids

Article abstract of DOI:10.1016/j.tetasy.2012.08.003

A novel strategy for the preparation of β,β′-dihydroxy α,α-disubstituted α-amino acids bearing a sugar moiety has been developed. The procedure is based on two Henry reactions: the first Henry reaction involves a sugar aldehyde and nitroethanol to furnish a sugar derived α-hydroxymethyl α-nitroalkanol while the second Henry reaction is between this nitro sugar and formaldehyde. This sequence provided the expected epimers of sugar derived α,α-dihydroxymethyl α -nitroalkanols, from which the corresponding β,β′-dibenzyloxy α-N-benzyloxycarbonylamino esters were easily obtained.

Full text of DOI:10.1016/j.tetasy.2012.08.003

Tetrahedron: Asymmetry 23 (2012) 1238–1242
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Preparation of sugar derived b,b0-dihydroxy
a,
a-disubstituted a-amino acids
⇑
⇑
Raquel G. Soengas , Amalia M. Estévez, Juan C. Estévez, Ramón J. Estévez
Departamento de Química Orgánica (Facultade de Química) and Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares, Campus Vida,
Universidade de Santiago de Compostela, C/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
A novel strategy for the preparation of b,b0-dihydroxy
a,a-disubstituted a-amino acids bearing a sugar
Article history:
Received 6 June 2012
Accepted 1 August 2012
Available online 15 September 2012
moiety has been developed. The procedure is based on two Henry reactions: the first Henry reaction
involves a sugar aldehyde and nitroethanol to furnish a sugar derived -hydroxymethyl -nitroalkanol
while the second Henry reaction is between this nitro sugar and formaldehyde. This sequence provided
the expected epimers of sugar derived -dihydroxymethyl -nitroalkanols, from which the corre-
a
a
a
,
a
a
sponding b,b0-dibenzyloxy
a
-N-benzyloxycarbonylamino esters were easily obtained. All rights reserved.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
OH
Despite the fact that proteins play a crucial role in biology, their
use as therapeutics suffers from their poor metabolic stability and
transport properties,1 together with their limited structural diver-
sity, which is related to the limited number of secondary structures
and backbones resulting from the small number of proteinogenic
amino acids.2 Moreover, the conformational flexibility of short
HO2C
H2N
nC6H13
OH
5
OH
O
HO2C
H2N
HO
R
sphingofungin E
HO
β,β'-Dihydroxy
peptides constituted by natural
a-amino acids allows them to
OH
OH
α,α-disubstituted
α-amino acid
interact with more than one receptor and side effects are usually
observed when these systems are used as drugs. Accordingly,
intensive work carried out in this field in recent times includes
the synthesis of non-natural amino acids. This is a first step in
the development of peptidomimetics with high levels of diversity
and rigidity, and such compounds may act as new drugs that
overcome the pharmacological limitations of proteins.3 In this
HO2C
H2N
nC6H13
5
OH
O
HO
mycesterycin G
Figure 1. Natural products containing a b,b0-dihydroxy-
a
-amino acid unit.
context, enantiomerically pure
a,a-disubstituted a-amino acids
are of increasing interest for the agrochemical and pharmaceutical
industries.4 The structural feature common to these amino acids is
the presence of an additional substituent compared with their a-H
to these amino acids for the subsequent preparation of novel
peptidomimetics of potential pharmacological interest and for
the discovery of new immunosuppressive treatments.10
Nitro sugars are valuable compounds that are powerful
synthetic intermediates of growing chemical interest. This is due
to the combination of the synthetic potential of sugars for the
creation of chemical diversity and the chemical versatility of nitro
compounds for the construction of carbon-carbon bonds prior to
the transformation of the nitro group into a variety of other
chemical functionalities.11
counterparts. Peptides that incorporate one or more such amino
acids are less prone to epimerization, display enhanced metabolic
stability and show different folding properties.5
Specifically, b,b0-dihydroxy
a-amino acid subunits are present
in biologically active natural compounds, such as sphingofungin
E106 and mycestericin G,7 which display high levels of immuno-
suppressant activity8 (Fig. 1). Structure–activity studies have
strongly suggested the crucial role played by the polar b,b0-
dihydroxy
a
-amino acid head groups.9 Accordingly, several
Our continued interest in nitro sugars led us to embark on a
study of the chemistry of 6-nitroheptofuranosides and the corre-
efficient synthetic routes have been developed to provide access
sponding a
-nitro acids.12 As a new contribution to this programme,
we herein report the synthesis of 5a and 5b, the first two reported
⇑
Corresponding authors.
E-mail addresses: rgsoengas@ua.pt (R.G. Soengas), ramon.estevez@usc.es (R.J.
examples of sugar amino acids that incorporate a b,b0-dihydroxy
a-amino acid subunit.
Estévez).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.08.003

R. G. Soengas et al. / Tetrahedron: Asymmetry 23 (2012) 1238–1242
1239
chromatography. Reduction of the nitro group in epimers 4a and
4b using zinc and hydrochloric acid afforded amino sugar epimers
5a and 5b, respectively.
The absolute configuration at the C-6 stereocentre of amino
sugars 5a and 5b was established by NMR experiments carried
out with compound 6, which was easily obtained by treatment of
5a with triphosgene. The nOe effect observed between H4 and H7
is only consistent with an (S)-configuration at the C-6 stereocentre.
According to our plan (Scheme 2), protection of the amino
group of 5a as the N-Cbz derivative by reaction with benzyl
2. Results and discussion
A Henry reaction between D-mannose-derived aldehyde 1 and
nitroethanol,12a using sodium methoxide as a base, provided an
epimeric mixture of nitro sugars 2 (dr 38:62) (Scheme 1). Protec-
tion of the free hydroxy groups with benzyl 2,2,2-trichloroacetim-
idate and catalytic trifluoromethanesulfonic acid afforded a 39:61
epimeric mixture 3, which upon treatment with paraformaldehyde
and tetrabutylammonium fluoride resulted in a 43:57 mixture of
epimers 4a and 4b, which were easily isolated by column
O
O2N
HO
O2N
OH
O
OBn
O
O
OBn
ii
i
H
OBn
OBn
BnO
O
O
O
O
O
O
1
2 (68% yield, d.r. 38:62)
3 (51% yield,d.r. 39:61)
OH
OBn
OH
O2N
BnO
O2N
BnO
OBn
O
O
OBn
OBn
iii
O
O
O
O
4a (17% yield)
4b
(23% yield)
iv
iv
O
OBn
OH
H
OH
OBn
H2N
BnO
H2N
BnO
H
N
O
H
OBn
O
OBn
O
v
O
O
OBn
OBn
H
BnO
H
O
O
O
O
O
5a
6 (67% yield)
5b
Scheme 1. Reagents and conditions: (i) NO2CH2CH2OH, NaOMe, MeOH, rt, 4 h; (ii) BTA, TfOH, DCM, C6H12, rt, 12 h; (iii) (HCHO)n, TBAF, THF, rt, 12 h; (iv) Zn, 1 M HCl, iPrOH,
rt, 2 h; (v) triphosgene, Et3N, rt, 1 h.
O
OH
OBn
OH
OBn
Y
H2N
BnO
CbzHN
BnO
CbzHN
BnO
OBn
O
O
O
i
ii
OBn
OBn
OBn
O
O
O
O
O
O
5a
7a
(78% yield)
8a: Y=H
iii
iv
9a
: Y=OH
10a
: Y=OMe (34% yield, 3 steps)
O
OH
OBn
OH
Y
H2N
CbzHN
BnO
CbzHN
BnO
OBn
O
OBn
O
i
ii
O
OBn
OBn
BnO
OBn
O
O
O
O
O
O
5b
7b
(72% yield)
8b: Y=H
iii
iv
9b
: Y=OH
10b
: Y=OMe (43% yield, 3 steps)
Scheme 2. Reagents and conditions: (i) ClCbz, aq NaHCO3, EtOAc, rt, 2 h; (ii) Dess–Martin, CH2Cl2, rt, 1 h; (iii) NaClO2, 2-methyl-2-butene, NaH2PO4, MeOH, H2O, rt, 6 h; (iv)
TMSCH2N2, MeOH, Et2O, rt, 15 min.

1240
R. G. Soengas et al. / Tetrahedron: Asymmetry 23 (2012) 1238–1242
chloroformate, followed by oxidation of the resulting 7a with
Dess–Martin periodinane, provided -amino aldehyde 8a, which
(M+Na)+; 370.15 (M+H)+; HRMS: Calcd for (M+H)+: 370.1496.
Found, 370.1499.
a
was directly oxidized to its carboxylic acid 9a by treatment with
sodium chlorite, 2-methyl-2-butene and dihydrogen phosphate.
4.3. 1,5,7-Tri-O-benzyl-6-deoxy-2,3-di-O-isopropyliden-6-nitro-
Finally, 9a was directly converted into
a-amino acid ester 10a by
D,L
-glycero-
a-D-manno-heptofuranoses 3
reaction with trimethylsilyldiazomethane. Amino sugar 5b was
similarly converted into
a-amino acid ester 10b, via compounds
To a solution of the mixture of nitrosugars 2 (1.65 g, 4.46 mmol)
7b, 8b and 9b.
in dichloromethane (16 mL) and cyclohexane (32 mL) was added
benzyl 2,2,2-trichloroacetimidate (1.5 mL, 8.04 mmol) and trifluo-
romethanesulfonic acid (0.01 mL) and the resulting solution was
stirred at rt for 16 h. The reaction mixture was filtered and the fil-
trate was washed with saturated aqueous sodium hydrogen car-
bonate and water, dried (anhydrous sodium sulfate), filtered and
evaporated under reduced pressure. The residue was purified by
flash column chromatography (ethyl acetate/hexane 1:8 ? 1:6) to
give 1,5,7-tri-O-benzyl-6-deoxy-2,3-di-O-isopropyliden-6-nitro-
3. Conclusion
In conclusion, a strategy for the preparation of novel b,b0-
dihydroxy sugar -amino acids has been developed. Key steps
involve a nitroaldol-mediated hydroxymethylation of a 6-nitrohe-
ptofuranoside, followed by the generation of an amino acid moiety
by reduction of the nitro to an amino group and subsequent oxida-
tion of a hydroxymethyl group to a carboxyl group.
a
D,L-glycero-a-D-manno-heptofuranoses 3 (1.25 g, 51%) as a yellow
oil. 1H NMR (250 MHz, CDCl3): 1.36, 1.37, 1.54, 1.59 (4 ꢀ s, 12H,
4 ꢀ –CH3), 3.87–3.89 (m, 2H), 4.03–4.15 (m, 2H), 4.31–4.40 (m,
2H), 4.53–4.85 (m, 16H), 5.00–5.12 (m, 2H), 5.35, 5.37 (2 ꢀ s, 2H,
2 ꢀ H-1); 7.28–7.44 (m, 30H, 10 ꢀ Ar–H). 13C NMR (62.8 MHz,
CDCl3): 24.9, 25.0, 26.0, 26.2 (4 ꢀ –CH3); 66.3, 66.5, 73.5, 73.6,
74.5, 74.7 (8 ꢀ –CH2–), 76.5, 77.4, 78.8, 79.0, 79.8, 79.6, 86.6, 86.8,
88.3, 88.1 (10 ꢀ –CH–), 101.4, 101.6 (2 ꢀ –CH–), 112.5, 112.7
(2 ꢀ –C–), 127.7, 127.9, 120.0, 128.1, 128.2, 128.3, 129.0 (30 ꢀ –
CH–), 136.2, 136.4, 136.8, 137.0, 137.3, 137.6, (6 ꢀ –C–).
Work is currently in progress that aimed at the incorporation of
these a,a-disubstituted sugar a-amino acids into peptides in order
to study their structural properties and applications. Subsequent
work in this field will involve the extension of these studies to hex-
oses other than D-mannose in order to access a library of these no-
vel branched-chain sugar amino acids, which would be useful for
the preparation of conformationally restricted peptidomimetics
and novel immunosuppressants.
4. Experimental
4.1. General
4.4. 1,5,7-Tri-O-benzyl-6-deoxy-6-C-hydroxymethyl-2,3-di-O-
isopropyliden-6-nitro-
and 1,5,7-tri-O-benzyl-6-deoxy-6-C-hydroxymethyl-2,3-di-O-
isopropyliden-6-nitro- -glycero- -manno-heptofuranose 4b
D-glycero-a-D-manno-heptofuranose 4a
L
a-D
Nuclear magnetic resonance spectra were recorded on a Varian
DPX-200 or a Bruker 300 apparatus. Mass spectra were obtained on
a Hewlett Packard 5988A mass spectrometer. Thin layer chroma-
tography (TLC) was performed using Merck GF-254 type 60 silica
gel and ethyl acetate/hexane mixtures as eluants; TLC spots were
visualized with Hanessian mixture. Column chromatography was
carried out using Merck type 9385 silica gel.
A 1.0 M solution of tetrabutylammonium fluoride in tetrahydro-
furan (3.2 mL, 3.2 mmol, 2.5 eq) was added to a suspension of para-
formaldehyde (0.76 g, 25.2 mmol, 20 eq) and 1,5,7-tri-O-benzyl-6-
deoxy-2,3-di-O-isopropyliden-6-nitro-D,L-glycero-a-D-manno-hep-
tofuranose 3 (0.69 g, 1.26 mmol) in anhydrous tetrahydrofuran
(8 mL) and the reaction mixture was stirred under a nitrogen atmo-
sphere at room temperature for 24 h. Dichloromethane (40 mL) was
added and the organic layer was washed with saturated aqueous
ammonium chloride (3 ꢀ 20 mL), dried with anhydrous sodium
sulfate, filtered and evaporated in vacuo. The crude product was
purified by flash column chromatography (ethyl acetate/hexane
1:9) to give heptofuranoses 4a (0.13 g, 0.22 mmol, 17%) and 4b
4.2. 1-O-Benzyl-6-deoxy-2,3-di-O-isopropyliden-6-nitro-
D,L
-
glycero- -manno-heptofuranose 2
a-D
To
a
solution of 1-O-benzyl-2,3-O-isopropyliden-
a-
D-lyxo-
pentodialdo-1,4-furanose 1 (1.22 g, 4.27 mmol) in dry methanol
(30 mL) was added nitroethanol (0.9 mL, 12.91 mmol) and sodium
methoxide (0.66 g, 12.32 mmol). The resulting mixture was stirred
at rt for 14 h. The reaction was neutralized with DOWEX 50 W
resin, filtered and the filtrate was evaporated to dryness under
reduced pressure. The residue was partitioned between water and
dichloromethane and the organic layer was dried (magnesium sul-
fate), filtered and evaporated in vacuo. The residue was purified by
flash column chromatography (ethyl acetate/hexane 1:2) to afford
(0.17 g, 0.29 mmol, 23%). 4a: ½a D25
ꢁ
¼ þ20:2 (c 1.4, CHCl3); 1H NMR
(200 MHz, CDCl3): 1.33, 1.51 (2 ꢀ s, 6H, 2 ꢀ –CH3), 4.10–4.53 (m,
12H), 4.63–4.78 (m, 2H), 5.03 (s, 1H, H-1), 7.31–7.36 (m, 15H, Ar–
H); 13C NMR (25.1 MHz, CDCl3): 25.3, 26.35 (–C(–CH3)2), 62.9,
68.9, 69.3, 74.1, 75.6 (5 ꢀ –CH2–), 77.8, 78.3, 80.4, 84.5 (4 ꢀ –CH–
), 95.2 (C-6), 105.9 (C-1), 113.0 (–C(–CH3)2), 127.9, 128.1, 128.2,
128.3, 128.6, 128.7, 128.3 (15 ꢀ ArC–H), 137.00, 137.24, 137.51
(3 ꢀ ArC). 4b: ½a 2D5
ꢁ
¼ þ36:7 (c 1.2, CHCl3); 1H NMR (200 MHz,
a mixture of 1-O-benzyl-6-deoxy-2,3-di-O-isopropyliden-6-nitro-
D
CDCl3): 1.36, 1.54 (2 ꢀ s, 6H, 2 ꢀ –CH3), 4.04–4.39 (m, 6H), 4.51–
4.72 (m, 6H), 4.78–4.84 (m, 2H), 5.06 (s, 1H, H-1), 7.27–7.35 (m,
15H, Ar–H). 13C NMR (25.1 MHz, CDCl3): 25.3, 26.5 (–C(–CH3)2),
62.9, 68.9, 69.3, 74.1, 75.6 (5 ꢀ –CH2–), 77.8, 78.3, 80.4, 84.5
(4 ꢀ –CH–), 95.2 (C-6), 105.9 (C-1), 113.0 (–C(–CH3)2), 127.9,
128.1, 128.2, 128.3, 128.6, 128.7, 128.3 (15 ꢀ ArC–H), 137.01,
137.36, 137.79 (3 ꢀ ArC). LRMS (ESI+, m/z, %): 602.24 (M+Na)+;
HRMS: Calcd for (M+Na)+: 602.2369. Found, 602.2361.
and -glycero- -manno-heptofuranose 2a and 2b (1.48 g, 64%).
L
a-D
2a: 1H NMR (500 MHz, CDCl3): 1.33, 1.50 (2 ꢀ s, 6H, 2 ꢀ –CH3),
3.98–4.22 (m, 3H), 4.48–4.72 (m, 5H), 4.86–4.88 (m, 1H, H-6),
5.12 (s, 1H, H-1), 7.26–7.32 (m, 5H, Ar–H); 13C NMR (62.8 MHz,
CDCl3): 24.6, 25.9 (–C(–CH3)2), 60.1, 69.6 (2 ꢀ –CH2–), 79.0, 79.6,
84.7, 88.6 (5 ꢀ –CH–), 105.8 (C-1), 113.1 (–C(–CH3)2), 128.0,
128.1, 128.6 (5 ꢀ –CH–), 137.1 (–C@O). 2b: 1H NMR (500 MHz,
CDCl3): 1.33, 1.48 (2 ꢀ s, 6H, 2 ꢀ –CH3), 4.04–4.23 (m, 3H), 4.31–
4.43 (m, 2H), 4.51–4.64 (m, 2H), 4.81–4.84 (m, 2H), 5.11 (s, 1H,
H-1), 7.26–7.32 (m, 5H, Ar–H); 13C NMR (62.8 MHz, CDCl3): 24.5,
25.9 (–C(–CH3)2), 61.7, 69.3 (2 ꢀ –CH2–), 78.8, 79.6, 84.6, 89.7
(5 ꢀ –CH–), 105.4 (C-1), 113.0 (–C(–CH3)2), 128.0, 128.1, 128.3,
128.6 (5 ꢀ –CH–), 136.8 (–C–); LRMS (ESI+, m/z, %): 392.13
4.5. 6-Amino-1,5,7-tri-O-benzyl-6-deoxy-6-C-hydroxymethyl-
2,3-di-O-isopropyliden-D-glycero-a-D-manno-heptofuranose 5a
To a stirred solution of nitro sugar 4a (0.071 g, 0.123 mmol) in
isopropanol (2.4 mL) and 1 M aqueous hydrochloric acid (1.3 mL)

R. G. Soengas et al. / Tetrahedron: Asymmetry 23 (2012) 1238–1242
1241
was added zinc dust in four portions (0.161 g, 2.463 mmol) and the
resulting mixture was stirred at rt. After 2 h, the reaction mixture
was basified by the addition of saturated aqueous sodium bicar-
bonate and filtered through a Celite pad, washing with ethyl ace-
tate. The layers were separated and the aqueous layer was
further extracted with dichloromethane. The combined organic
layers were dried (magnesium sulfate), filtered and evaporated un-
der reduced pressure to afford 6-amino-1,5,7-tri-O-benzyl-6-
0.313 mmol) and the resulting mixture was stirred at rt. After
1 h, dichloromethane (5 mL) and a solution of thiosulfate in satu-
rated aqueous sodium bicarbonate (5 mL) were added and the bi-
phasic mixture was stirred for 15 min. The layers were separated
and the aqueous layer was further extracted with dichlorometh-
ane. The combined organic layers were dried (magnesium sulfate),
filtered and evaporated under reduced pressure. The residue was
dissolved in methanol/water 10:1 (12 mL) and 2-methyl-2-butene
(0.021 mL, 1.390 mmol), sodium chlorite (0.024 g, 0.258 mmol)
and sodium dihydrogen phosphate (0.033 g, 0.238 mmol) were
added and the mixture was stirred at rt. After 2 h, more sodium
chlorite (0.024 g, 0.258 mmol) and sodium dihydrogen phosphate
(0.033 g, 0.238 mmol) were added and stirring was continued.
After 4 h the reaction mixture was diluted with water, acidified
with aqueous hydrochloric acid 10% and extracted with ethyl ace-
tate. The combined organic layers were dried (magnesium sulfate),
filtered and evaporated under reduced pressure. The residue was
dissolved in a 7:3 mixture of diethyl ether/methanol (1.3 mL)
and trimethylsilyldiazomethane was added (0.07 mL, 0.125 mmol).
After 15 min the reaction mixture was evaporated in vacuo and the
residue was purified by flash column chromatography (ethyl ace-
tate/hexane 1:5) to yield methyl heptofuranoate 10a (25.4 mg,
deoxy-6-C-hydroxymethyl-2,3-di-O-isopropyliden-D-glycero-a-D-
manno-heptofuranose (5a) (0.068 g), which was used without
further purification.
4.6. (4R,5R)-4-(Benzyloxymethyl)-4-[-5-(1,5-di-O-benzyl-2,3-di-
O-isopropyliden-a-D-lyxofuran-5-C-yl)]oxazolidin-2-one 6
To a solution of 5a (0.15 g, 0.27 mmol) in dichloromethane
(2 mL) and DIEA (0.60 mmol, 0.10 mL) was added triphosgene
(0.08 g, 0.27 mmol) and the mixture was stirred at rt for 1 h. The
reaction mixture was diluted with dichloromethane and quenched
by the addition of water. The organic layer was separated, dried
(MgSO4), filtered and evaporated under reduced pressure. The res-
idue was purified by flash column chromatography (ethyl acetate/
hexane 1:3) to afford oxazolidinone 6 (0.10 g, 67%) as a clear oil.
34%). ½a 2D4
ꢁ
¼ þ26:3 (c 0.9, chloroform); 1H NMR (300 MHz, CDCl3):
½
a 2D3
ꢁ
¼ þ2:2 (c 1.0, chloroform); 1H NMR (300 MHz, CDCl3): 1.33,
1.33, 1.50 (2 ꢀ s, 6H, 2 ꢀ –CH3), 3.73 (s, 3H, –OCH3), 4.14 (d, 1H, J =
10.0 Hz), 4.31–4.57 (m, 10H), 4.79–4.83 (m, 2H), 4.96 (s, 1H), 5.08–
5.21 (m, 2H), 6.73 (s, 1H, –NH–), 7.21–7.31 (m, 20H, H–Ph); 13C
NMR (62.8 MHz, CDCl3): 25.2, 26.5 (–C(–CH3)2), 52.7 (–OCH3),
66.2 (–C–); 66.8, 67.3, 68.3, 73.7, 75.3 (5 ꢀ –CH2–), 78.6, 79.0,
81.0, 84.3 (4 ꢀ –CH–), 105.2 (C-1), 112.6 (–C(–CH3)2), 127.7,
127.8, 127.9, 128.0, 128.2, 128.4 (20 ꢀ –CHPh), 136.8, 136.9,
138.4, 138.5 (4 ꢀ –CPh), 155.2, 171.5 (2 ꢀ – C@O); LRMS (ESI+,
m/z, %): 734.29 (M+Na)+; 712.31 (M+H)+, HRMS: Calcd LRMS
(ESI+, m/z, %): 734.29 (M+Na)+, 712.31 (M+H)+; HRMS: Calcd for
(M+H)+: 712.3122. Found, 712.3129.
1.49 (2 ꢀ s, 6H, 2 ꢀ –CH3), 3.56 (d, 1H, J 9.4 Hz, H-70), 3.66 (d, 1H,
J 9.4 Hz, H-7), 3.95 (dd, 1H, J 9.4 Hz, J 3.2 Hz, H-4), 4.10 (d, 1H, J
9.4 Hz, H-5), 4.25–4.49 (m, 5H), 4.61–4.68 (m, 3H), 4.74–4.76 (m,
1H, H-3), 4.83 (d, 1H, J 10.9 Hz, –CHPh), 4.99 (s, 1H, H-1), 5.20
(bs, 1H, –NH–), 7.21–7.38 (m, 15H, H-Ph); 13C NMR (62.8 MHz,
CDCl3): 26.1, 26.3 (–C(–CH3)2), 38.9 (–C–), 61.9, 69.8, 70.9, 71.0,
71.2, 73.3 (5 ꢀ –CH2–), 75.8, 79.6, 80.1, 81.2 (4 ꢀ –CH–), 105.8
(C-1), 112.8 (–C(–CH3)2), 127.7, 127.8, 127.9, 128.0, 128.1, 128.3,
128.4 (15 ꢀ –CHPh), 136.5, 138.0, 141.2 (3 ꢀ –CPh), 159.1 (–C@O).
4.7. 1,5,7-Tri-O-benzyl-6-benzyloxycarbonylamino-6-deoxy-6-
C-hydroxymethyl-2,3-di-O-isopropyliden-
D-glycero-a-
D-manno-
4.9. 6-Amino-1,5,7-tri-O-benzyl-6-deoxy-6-C-hydroxymethyl-
heptofuranose 7a
2,3-di-O-isopropyliden-L-glycero-a-D-manno-heptofuranose 5b
Amine 5a was dissolved in ethyl acetate (1.7 mL) and saturated
aqueous sodium bicarbonate (0.7 mL) was added. The biphasic mix-
ture was cooled to 0 °C and benzyloxycarbonyl chloride (0.020 mL,
0.028 g, 0.164 mmol) was added dropwise and the resulting mix-
ture was stirred at rt for 2 h. The layers were separated and the
aqueous layer was further extracted with ethyl acetate. The com-
bined organic layers were washed with brine, dried (magnesium
sulfate), filtered and evaporated under reduced pressure. The resi-
due was purified by flash column chromatography (ethyl acetate/
hexane 1:3) to give methyl 1,5,7-tri-O-benzyl-6-benzyloxycarbon-
To a stirred solution of nitro sugar 4b (0.054 g, 0.092 mmol) in
isopropanol (1.8 mL) and 1 M aqueous hydrochloric acid (1 mL)
was added zinc dust in four portions (0.121 g, 1.848 mmol) and
the resulting mixture was stirred at rt. After 2 h, the reaction
mixture was basified by the addition of saturated aqueous sodium
bicarbonate and filtered through a Celite pad, washing with ethyl
acetate. The layers were separated and the aqueous layer was
further extracted with dichloromethane. The combined organic
layers were dried (magnesium sulfate), filtered and evapo-
rated under reduced pressure to afford 1,5,7-tri-O-benzyl-6-C-
ylamino-6-deoxy-6-C-hydroxymethyl-2,3-di-O-isopropyliden-
D
-
hydroxymethyl-2,3-di-O-isopropyliden-L-glycero-a-D-manno-hep-
tofuranose 5b (0.051 g), which was used without further
purification.
glycero-
a
-
D
-manno-heptofuranoate 7a (0.066 g, 78%). ½a D23
ꢁ
¼ þ48:8
(c 1.35, chloroform); 1H NMR (300 MHz, CDCl3): 1.34, 1.49 (2 ꢀ s,
6H, 2 ꢀ –CH3), 3.46–3.49 (m, 1H), 3.95–3.99 (m, 3H), 4.29–4.55
(m, 7H), 4.74–5.23 (m, 5H), 5.98 (s, 1H, H-1), 7.27–7.35 (m, 20H,
H–Ph); 13C NMR (62.8 MHz, CDCl3): 25.4, 26.5 (–C(–CH3)2), 62.9
(C-6), 63.9, 66.9, 68.8, 73.8, 75.1 (6 ꢀ –CH2–), 79.2, 81.3, 84.4
(4 ꢀ –CH–), 105.9 (C-1), 112.6 (–C(–CH3)2), 127.7, 127.8, 127.9,
128.0, 128.2 (20 ꢀ –CHPh), 136.7, 137.3, 138.0, 139.1 (4 ꢀ –CPh),
157.1 (–C@O); LRMS (ESI+, m/z, %): 706.32 (M+Na)+, 684.30
(M+H)+; HRMS: Calcd for (M+H)+: 684.3167. Found, 684.3178.
4.10. 1,5,7-Tri-O-benzyl-6-benzyloxycarbonylamino-6-deoxy-6-
C-hydroxymethyl-2,3-di-O-isopropyliden-L-glycero-a-D-manno-
heptofuranose 7b
Amine 5b was dissolved in ethyl acetate (1.2 mL) and saturated
aqueous sodium bicarbonate (0.5 mL) was added. The biphasic
mixture was cooled to 0 °C and benzyloxycarbonyl chloride
(0.017 mL, 0.021 g, 0.123 mmol) was added dropwise and the
resulting mixture was stirred at rt for 2 h. The layers were sepa-
rated and the aqueous layer was further extracted with ethyl ace-
tate. The combined organic layers were washed with brine, dried
(magnesium sulfate), filtered and evaporated under reduced
pressure. The residue was purified by flash column chromatogra-
phy (ethyl acetate/hexane 1:3) to give 1,5,7-tri-O-benzyl-6-
4.8. Methyl 1,5,7-tri-O-benzyl-6-benzyloxycarbonylamino-6-
deoxy-6-C-hydroxymethyl-2,3-di-O-isopropyliden-
-manno-heptofuranoate 10a
D-glycero-a-
D
To a solution of amino sugar 7a (0.071 g, 0.104 mmol) in dichlo-
romethane (2 mL) was added Dess–Martin periodinane (0.132 g,

1242
R. G. Soengas et al. / Tetrahedron: Asymmetry 23 (2012) 1238–1242
benzyloxycarbonylamino-6-deoxy-6-C-hydroxymethyl-2,3-di-O-
isopropyliden- -glycero- -manno-heptofuranose 7b (0.045 g,
Acknowledgments
L
a-D
72%). 1H NMR (300 MHz, CDCl3): 1.33, 1.51 (2 ꢀ s, 6H, 2 ꢀ –CH3),
3.76–4.39 (m, 6H), 4.52–4.69 (m, 5H), 4.77–4.85 (m, 2H), 5.02–
5.13 (m, 3H), 5.87 (s, 1H, H-1), 7.25–7.42 (m, 20H, H-Ph); 13C
NMR (62.8 MHz, CDCl3): 25.3, 26.5 (–C(–CH3)2), 62.5 (C-6); 64.3,
66.8, 69.2, 73.6, 75.2 (6 ꢀ –CH2–), 79.2, 81.3, 84.4 (4 ꢀ –CH–),
105.9 (C-1), 112.6 (–C(–CH3)2), 127.7, 127.8, 127.9, 128.0, 128.2
(20 ꢀ –CHPh), 136.7, 137.3, 138.0, 139.1 (4 ꢀ –CPh), 157.1
(–C@O); LRMS (ESI+, m/z, %): 706.32 (M+Na)+, 684.30 (M+H)+;
HRMS: Calcd for (M+H)+: 684.3167. Found, 684.3178.
This work was supported by the Spanish Ministry of Science
and Innovation (CTQ2009-08490) and Xunta de Galicia (Ayuda
para la consolidación y estructuración de unidades de investiga-
ción competitiva del Sistema Universitario de Galicia CN2011/
037). A.M.E. thanks the University of Santiago de Compostela for
a postdoctoral research Grant.
References
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4.11. Methyl 1,5,7-tri-O-benzyl-6-benzyloxycarbonylamino-6-
deoxy-6-C-hydroxymethyl-2,3-di-O-isopropyliden-
-manno-heptofuranoate 10b
L-glycero-a-
D
To a solution of amino sugar 7b (0.042 g, 0.061 mmol) in dichlo-
romethane (1 mL) was added Dess–Martin periodinane (0.077 g,
0.183 mmol) and the resulting mixture was stirred at rt. After
1 h, dichloromethane (5 mL) and a solution of thiosulfate in satu-
rated aqueous sodium bicarbonate (5 mL) were added and the bi-
phasic mixture was stirred for 15 min. The layers were separated
and the aqueous layer was further extracted with dichlorometh-
ane. The combined organic layers were dried (magnesium sulfate),
filtered and evaporated under reduced pressure. The residue was
dissolved in methanol/water 10:1 (6 mL) and 2-methyl-2-butene
(0.012 mL, 0.812 mmol), sodium chlorite (0.014 g, 0.151 mmol)
and sodium dihydrogen phosphate (0.019 g, 0.139 mmol) were
added and the mixture was stirred at rt. After 2 h, more sodium
chlorite (0.014 g, 0.151 mmol) and sodium dihydrogen phosphate
(0.019 g, 0.139 mmol) were added and stirring was continued.
After 4 h the reaction mixture was diluted with water, acidified
with 10% aqueous hydrochloric acid and extracted with ethyl ace-
tate. The combined organic layers were dried (magnesium sulfate),
filtered and evaporated under reduced pressure. The residue was
dissolved in a 7:3 mixture of diethyl ether/methanol (1 mL) and
trimethylsilyldiazomethane (0.04 mL, 0.038 mmol) was added.
After 15 min the reaction mixture was evaporated in vacuo and
the residue was purified by flash column chromatography (ethyl
acetate/hexane 1:5) to yield methyl heptofuranoate 10b
(18.5 mg, 43%).
½
a 2D4
ꢁ
¼ þ26:3 (c 0.9, chloroform); 1H NMR
(300 MHz, CDCl3): 1.31, 1.51 (2 ꢀ s, 6H, 2 ꢀ –CH3), 3.71 (s, 3H, –
OCH3), 4.28 (s, 2H, H-7, H-70), 4.41–4.44 (m, 3H), 4.53–4.73 (m,
5H), 4.78–4.87 (m, 2H), 5.06 (s, 2H, –CH2Ph), 5.08 (s, 1H, H-1),
6.79 (s, 1H, –NH–), 7.27–7.34 (m, 20H, H–Ph); 13C NMR
(62.8 MHz, CDCl3): 26.3, 26.5 (–C(–CH3)2), 59.5 (–OCH3), 66.2 (–
C–), 66.8, 66.9, 68.7, 73.4, 75.3 (5 ꢀ –CH2–), 76.0, 79.0, 81.2, 84.2
(4 ꢀ –CH–), 105.7 (C-1), 112.6 (–C(–CH3)2), 127.7, 127.8, 127.9,
128.0, 128.2, 128.4 (20 ꢀ –CHPh), 137.0, 138.5, 138.6 (4 ꢀ –CPh),
155.4, 170.8 (2 ꢀ –C@O); LRMS (ESI+, m/z, %): 734.29 (M+Na)+,
712.31 (M+H)+; HRMS: Calcd for (M+H)+: 712.3122. Found,
712.3128.
9. Kiuchi, M.; Adachi, K.; Kohara, T.; Minoguchi, M.; Hanano, T.; Aoki, Y.; Mishina,
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