Enantiospecific synthesis of the sugar amino acid (2S,5S)-5-(aminomethyl)- tetrahydrofuran-2-carboxylic acid

Article abstract of DOI:10.1016/j.tetasy.2010.08.013

An enantiospecific synthesis of the tetrahydrofuran amino acid (2S,5S)-5-(aminomethyl)-tetrahydrofuran-2-carboxylic acid 1 is reported. The sugar enone 2-(S)-octyl 6-O-acetyl-3,4-dideoxy-α-d-glycero-hex-3- enopyranosid-2-ulose 2a, derived from galactose, was employed as a chiral precursor. The enone 2a was converted by chemical manipulation of the functional groups into the 6-azido-2-O-tosyl-3,4,6-trideoxy-d-erythro-hexono-1,5-lactone 9 as key intermediate. Methanolysis of 9 induced the opening of the lactone and the attack of the hydroxyl group at C-5 to C-2 with the displacement of the tosylate. This reaction led to the formation of the tetrahydrofuran ring of methyl (2S,5S)-5-(azidomethyl)-tetrahydrofuran-2-carboxylate 10, which was readily converted into 1. The overall yield of the sequence was 35%, and all the intermediates and the final product have been fully characterized. In addition, the preferential conformations in solution of lactone 9 and target molecule 1 have been established.

Full text of DOI:10.1016/j.tetasy.2010.08.013

Tetrahedron: Asymmetry 21 (2010) 2435–2440
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantiospecific synthesis of the sugar amino acid (2S,5S)-5-(aminomethyl)-
tetrahydrofuran-2-carboxylic acid
⇑
María Laura Uhrig, Mario J. Simirgiotis, Oscar Varela
CIHIDECAR-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantiospecific synthesis of the tetrahydrofuran amino acid (2S,5S)-5-(aminomethyl)-tetrahydrofu-
ran-2-carboxylic acid 1 is reported. The sugar enone 2-(S)-octyl 6-O-acetyl-3,4-dideoxy-a-D-glycero-
hex-3-enopyranosid-2-ulose 2a, derived from galactose, was employed as a chiral precursor. The enone
2a was converted by chemical manipulation of the functional groups into the 6-azido-2-O-tosyl-3,4,6-tri-
Received 13 August 2010
Accepted 20 August 2010
Available online 29 September 2010
deoxy-D-erythro-hexono-1,5-lactone 9 as key intermediate. Methanolysis of 9 induced the opening of the
lactone and the attack of the hydroxyl group at C-5 to C-2 with the displacement of the tosylate. This
reaction led to the formation of the tetrahydrofuran ring of methyl (2S,5S)-5-(azidomethyl)-tetrahydro-
furan-2-carboxylate 10, which was readily converted into 1. The overall yield of the sequence was 35%,
and all the intermediates and the final product have been fully characterized. In addition, the preferential
conformations in solution of lactone 9 and target molecule 1 have been established.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
lished.1,2,4,5,8,9 In particular, 3,4-dideoxy furanoid SAAs, related to
this work, have been synthesized and used as dipeptide isosteres
Pyranoid and furanoid amino acids are extensively used as con-
formationally constrained building blocks for the design of pepti-
domimetics and peptide scaffolds.1,2 These amino acids are hybrid
structures that carry both amino and carboxyl groups on an anhydro
sugar ring; they are often referred to as sugar amino acids (SAAs)
although other terms have also been used (glycosamino acids, car-
bopeptoids, etc.).3 The stereochemical arrangement of the substitu-
ents of the sugar ring, the ring-size as well as the presence of
additional functional groups provides monomers that lead to oligo-
meric libraries.4 These building blocks, with predictable folding pat-
terns (‘foldamers’), are useful in the design and development of
biologically active molecules.5 Insertion of furanoid SAAs, known
as ‘turn inducers’, into cyclic peptides leads to compounds stabilized
by intramolecular hydrogen bonding between the stacked rings.6,7
Thus, SAAs can be assembled rationally to create molecules with
well-defined structures, which are employed to combat diseases
and are used in the development of new materials.8
Furanoid d-amino acids have been involved in the generation of
new peptide nucleic acids, since the six-atom length of these amino
acid homologs correspond to the optimal distance to mimic the
ribose unit found in nucleic acids (RNA and DNA).9 The structures
of SAAs based on oxygen heterocycles with three to six-membered
rings have also been recently reviewed,3 while many surveys on
their synthesis and relevant applications have been pub-
to induce turn structures in small linear peptides. Thus, Chakraborty
et al.10 reported the synthesis of the N-Boc derivative of racemic cis-
5-(aminomethyl)-tetrahydrofuran-2-carboxylic acid by the hydro-
genation of 5-(aminomethyl)-furan-2-carboxylic acid prepared
from D-fructose. Each component of the racemic mixture has also
been synthesizedin an enantiomerically pureform. The N-Fmoc der-
ivate of (2S,5R)-5-(aminomethyl)-tetrahydrofuran-2-carboxylic
acid was obtained from
(2R,5S)-enantiomer was prepared from
L
-glutamic acid, and the corresponding
D
-glucose.11 These SAAs
have been inserted as dipeptide isosteres in place of the TyrIII-ProIV
segment of the receptor-binding inhibitor of the vasoactive intesti-
nal peptide. The conformation of the resulting analogs has been
studied and tested for their anticancer activities for human cancer
cell lines.12 The (2S,5R)- and (2R,5S)-tetrahydrofuran amino acids
have also been employed for the synthesis of C2 symmetric cyclic oli-
gopeptides and their conformations have been established.7 A third
diastereoisomer with the (2R,5R)-configuration has been synthe-
sized (but not characterized) and used in peptidomimetic studies.13
Herein, we report a convenient and enantiospecific synthesis of
(2S,5S)-5-(aminomethyl)-tetrahydrofuran-2-carboxylic acid, the
remaining fourth estereoisomer of the series.
2. Results and discussion
The retrosynthetic analysis applied to the target furanoid amino
acid 1 (Scheme 1) suggests a 5-azidomethyl precursor that may be
synthesized from synthon I via the intramolecular displacement of
⇑
Corresponding author. Tel./fax: +54 11 4576 3352.
E-mail address: varela@qo.fcen.uba.ar (O. Varela).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.08.013

2436
M. L. Uhrig et al. / Tetrahedron: Asymmetry 21 (2010) 2435–2440
Table 1
the 2-tosyloxy substituent by the alcohol group at C-5. Chemical
manipulation of functional groups indicates that diol intermediate
II is a convenient precursor of I. Subsequently, the diol II may be
obtained by hydrogenation and carbonyl reduction from the sugar
enone 2, the product of glycosylation of 2,3,4,6-tetra-O-acetyl-1,5-
Sodium borohydride reduction of the 2-uloses 4a and 4ba
Starting
2-ulose
Major product
Temperature
Time
(h)
Diastereomeric
(
a-
D-erythro)
(°C)
ratiob erythro:threo
4a
4a
4b
4b
5a
5a
5b
5b
25
ꢀ18
25
ꢀ18
1
3
1
3
40:
>90:
20:
1
1
1
1
anhydro-D-lyxo-hex-1-enitol (2-hydroxy-D-galactal peracetate, 3).
To establish the influence of a chiral anomeric substituent on
the reduction of the carbonyl group of the enone, a chiral alcohol
was employed for the glycosylation of 3 (Scheme 2). Thus glycal
50:
a
Reduction followed by O-deacetylation (see Section 4).
Determined by the integral of the signals of the anomeric protons from the 1H
b
3, readily prepared from D
-galactose,14 was treated with 2-(S)-oct-
NMR spectrum of the crude reaction mixture.
anol in the presence of tin(IV) chloride to afford the enone 2a in
88% isolated yield. The anomeric configuration of 2a was assigned
as
a on the basis of the NMR spectra, as already reported for
the reduction of the 2-(S)-octyl uloside 4a showed higher diaste-
reofacial selectivity than that of the 2-isopropyl analog 4b. The
increased selectivity in favor of 5a may be attributed to the addi-
tional stereocenter located at the anomeric substituent and/or to
the larger size of the octyl group compared to that of the isopropyl
in 4b. As the separation of the diastereomeric mixtures of diols by
column chromatography was difficult, we selected the 2-(S)-octyl
enulose 2a as the starting material in view of the high selectivity
achieved in the reduction of the carbonyl group at ꢀ18 °C. Thus,
the overall yield of the preparative scale synthesis of diol 5a from
glycal 3, under optimized conditions, was 83% after four steps.
Tosylation of 5a with 2.5 M equiv of p-tolylsulfonyl chloride (to-
syl chloride) afforded the 2,6-di-O-tosyl derivative 6 in 88% yield
(Scheme 3). Treatment of 6 with an excess of sodium azide in
DMF at 125 °C for 2 h produced selective substitution of the tosyl-
ate group of the primary alcohol at C-6, whereas the tosylate at C-2
remained unreactive. The 6-azido derivative 7 was isolated in 92%
yield. The 1H NMR spectrum of 7 showed shielding (>0.7 ppm) of
the signals of H-6 and H-60; compared with the same signals in
6. Also, as expected for the introduction of the azide at C-6, the
13C NMR spectrum of 7 showed a strong upfield shifting of the C-
6 resonance, with respect to that in 6.
analogous 2-alkoxypyran-3-one derivatives.14–16 Catalytic hydro-
genation of the double bond of 4 gave quantitatively the 2-ulose
4a. A similar reaction sequence from 3, using 2-propanol as a gly-
cosylating agent, afforded the 2-keto derivative 4b via the interme-
diate 2b.17
The reduction of the carbonyl group of 4a and 4b was per-
formed with sodium borohydride in MeOH at two different
temperatures (25 °C and ꢀ18 °C). We observed that during the
reduction and workup, partial O-deacetylation of the product took
place. Therefore, at the end of the reduction of 4a and 4b, the acet-
oxy group was completely removed by the treatment with sodium
methoxide to afford the corresponding diols 5a and 5b. The
coupling constant values J1,2, J2,3ax, and J2,3eq from the 1H NMR
spectrum of 5a were similar to those of 5b, and confirmed the
a-
D
-erythro configuration for these major products.18 They were
accompanied by variable proportions of the respective -threo
a-D
diastereoisomers, formed by the addition of the hydride from the
more hindered face of the molecule that contained the axially
oriented anomeric alkoxy group.
The reductions conducted at lower temperature resulted in an
increase in the diastereoselectivity in favor of the erythro isomers.
Thus, the reduction of 4a at ꢀ18 °C (Table 1) afforded 5a as practi-
cally the only product [diastereomeric excess (de) >98%]; whereas
a smaller de (95%) was obtained at 25 °C. Similarly, the reduction of
4b gave diastereomeric excesses of 96% and 90% when the temper-
ature was raised from ꢀ18 °C to 25 °C. At the same temperature,
Hydrolysis of glycoside 7 with aqueous trifluoroacetic acid
afforded the hexopyranose derivative 8, as a mixture of anomers.
The 1H NMR spectrum of 8 showed two signals in the anomeric re-
gion at 5.20 (J1,2 = 3.3 Hz) and 4.67 ppm (J1,2 = 7.5 Hz) in a 6:4 ratio.
The smaller coupling constant value indicated an equational–axial
OH
O
N3
OH
O
H2N
O
O
O
OR
OH
OR
O
CO2H
OTs
1
I
II
2
Scheme 1. Retrosynthetic analysis of the target amino acid 1.
OAc
O
OAc
O
OH
O
OAc
O
6
AcO
H2/Pd
NaBH4
5
ROH
SnCl4
(80%)
1
4
OAc
(100%)
MeOH
(94%)
3
2
OR
OR
OR
O
O
OH
OAc
3
Me
Me
Me
Me
Me
Me
4a R =
4b R = Me2CH
2a R =
2b R = Me2CH
5a R =
5b
5
5
5
R = Me2CH
Scheme 2. Glycosylation and reduction of glycal 3.

M. L. Uhrig et al. / Tetrahedron: Asymmetry 21 (2010) 2435–2440
2437
N3
O
OTs
O
OH
O
NaN3
TsCl
TFA/H2O
(82%)
Me
Me
Me
Me
Me
Me
C5H5N
(88%)
DMF
O
OTs
O
O
OTs
5
5
5
(92%)
OH
5a
6
7
N3
O
N3
H2N
N3
N3
H2,Pd/C
O
O
O
(COCl)2,DMSO
K2CO3
TFA/H2O
(94%)
O
OH
O
EtOAc
(90%)
CH2Cl2,Et3N
(88%)
MeOH
(86%)
CO2H
CO2Me
CO2H
OTs
OTs
1
8
9
10
11
Scheme 3. Synthesis of the tetrahydrofuran amino acid 1 from the diol 5a.
disposition for H-1 and H-2 (
a anomeric configuration), whereas
the larger one (7.5 Hz) is in agreement with the diaxial orientation
of those protons (b configuration).
The hemiacetal (lactol) function of 8 was oxidized using Swern
conditions,19 to afford lactone 9 in 92% yield. The lactone could not
be purified by column chromatography since it was highly sensitive
to silica gel, undergoing hydrolysis to the corresponding hydroxy
acid, thus lowering the yield considerably. However, the crude lac-
tone 9 was pure enough to be used for the next step. Furthermore,
crystals of 9 could be obtained by crystallization from a concen-
trated solution in EtOAc. The 1H NMR spectrum of 9 showed nicely
resolved signals and the coupling constants could be accurately
measured. With these data in hand it was possible to estimate the
conformational preference for the 1,5-lactone ring. Assuming a Kar-
plus-type dependence of J values, the conformationof deoxy aldono-
1,5-lactones and their derivatives was described as an equilibrium
between half-chair (H) and boat (B) conformations.20,21 Molecular
mechanics calculations indicated that these two forms corre-
sponded to the two minimum-energy conformations, with the H
conformer being the more stable.22 The 1H NMR spectrum of 9
showed large values for J2,3ax (11.0 Hz), J4ax,5 (11.4 Hz), and espe-
cially for J3ax,4ax (13.0 Hz) thus suggesting a strong preference of
the lactone ring for the 4H3 conformer. In this conformation the
bulky substituents at C-2 and C-5 are equatorially (or quasi-
equatorially) oriented. Horton et al.23 reported that the half-chair
conformation prevails when bulky substituents at C-2 and C-5 are
trans-disposed, which is the case for lactone 9. This stereochemistry
Figure 1. Calculated conformation for compound 9 (AM1 method).
usually takes place with inversion of configuration. This assign-
ment was later confirmed by NOE experiments performed on the
target molecule 1.
Hydrolysis of the ester group of 10 with 1:1 (v/v) trifluoroacetic
acid (TFA)/water afforded acid 11, which was purified by reverse
phase chromatography. Finally, target molecule 1 was obtained
by catalytic hydrogenation of the azide function of 11. The free tet-
rahydrofuran amino acid 1 exhibited a high degree of purity,
according to the NMR spectra. However, it required an additional
purification through a column filled with Dowex 50W(H+) resin,
which was eluted with water and then with 0.1 M aqueous pyri-
dine, to afford the target molecule 1 in 90% yield. In contrast with
the 1H NMR spectra of 10 and 11, the spectrum of 1 revealed a first
order analysis, in spite of the highly coupled protons (H-3, H-30, H-
4 and H-40) of the ethylene fragment of the ring. The separation of
the signals facilitated the interpretation of the NOE correlations in
the NOESY spectrum of 1. The cross-peak between H-60 and H-2
confirmed the (S)-configuration for C-2. The additional NOE corre-
lation observed for H-60 with H-40 and the intense cross-peaks be-
tween H-2, H-3 and H-4, H-5 confirmed these assignments.
Furthermore, the large J5,6 value (8.6 Hz) indicated that H-60 is ori-
ented anti to H-5 and directed towards the tetrahydrofuran ring,
which explains the cross-peaks observed.
The zwitterionic form of compound 1 was constructed on the
GAUSSIAN 03 platform and calculations were performed using the
DFT/B3LYP method that employs the 6-31G(d,p) basis set. The pre-
liminary calculations led to the 2T0 conformation for compound 1
(Fig. 2). This structure seems to be stabilized by hydrogen bonding
between one of the protons of the ammonium group and the ring-
oxygen atom (estimated distance Hꢁ ꢁ ꢁO: 2.28 Å). Such a hydrogen
bonding should restrict the rotation through the C-5–C-6 bond,
resulting in a preferred g,t-rotamer, which is also predicted from
is also found in D-glucono-1,5-lactone that, similar to 9, preferen-
tially adopts the 4H3 conformation in solution23,24 and in the crystal-
line state.25 We have also studied the structure of lactone 9 through
HyperChem 8.0 calculations using the semi-empirical method AM1.
The geometry obtained (4H3), depicted in Figure 1, shows dihedral
angles between vicinal protons associated to J magnitudes that are
in excellent agreement with the coupling constant values measured
from the 1H NMR spectrum of 9. Furthermore, for the exocyclic
aminomethyl group, spectroscopic data and calculations support a
large contribution to the equilibrium of the g,g-rotamer.
We have previously described26,27 the formation of oxirane
rings by methanolysis of derivatives that bear a sulfonyloxy sub-
stituent vicinal to the ring-oxygen atom. The hydroxyl group in-
volved in the lactone function is released by methanolysis and
promotes the intramolecular displacement of the vicinal sulfo-
nate, with the formation of the oxirane ring. Fleet et al. have ap-
plied
a similar methanolysis step to triflate derivatives of
aldonolactones for the construction of oxetane,28 tetrahydrofu-
ran,29 and tetrahydropyran rings.30 The potassium carbonate-cat-
alyzed methanolysis of lactone 9 afforded the tetrahydrofuran
derivative 10 in 86% yield.
The configuration of the C-2 stereocenter in 10 was assigned as
(S), since the nucleophilic displacement of the sulfonyloxy group

2438
M. L. Uhrig et al. / Tetrahedron: Asymmetry 21 (2010) 2435–2440
ꢀ18 °C (ice-salt bath) and SnCl4 (870
lL, 7.43 mmol) was added.
H-4’
H-2
H-6’
The mixture was stirred at 0 °C for 2 h, when TLC showed complete
consumption of the starting material and formation of a new spot
of Rf = 0.80 (hexane/EtOAc 2:1). Upon dilution with CH2Cl2 the
solution was extracted twice with saturated aqueous (satd aq)
NaHCO3, and then with brine. The organic extract was dried
(MgSO4) and concentrated. The residue was purified by column
chromatography (hexane/EtOAc 20:1) to afford syrupy 2a (1.59 g,
H-6
H-3
H-3’
H-5
88% yield); [
6.94 (dd, 1H, J4,5 = 2.0, J3,4 = 10.6 Hz, H-4), 6.16 (dd, 1H,
a]
D = +18.5 (c 1.1, CHCl3); 1H NMR (CDCl3, 500 MHz)
d
J3,5 = 2.5, J3,4 = 10.6 Hz, H-3), 4.96 (br s, 1H, H-1), 4.78 (m, 1H, H-
5), 4.33 (dd, 1H, J5,6a = 5.6, J6a,6b = 11.7 Hz, H-6a), 4.25 (dd, 1H,
J5,6b = 4.5, J6a,6b = 11.7 Hz, H-6b), 3.88 (m, 1H, J = 6.1 Hz, H-20),
2.09 (s, 3H, CH3CO), 1.65–1.25 (m, 10H, CH2-30 to CH2-70), 1.20
(d, 3H, J = 6.1 Hz, CH3-1), 0.89 (t, 3H, J = 6.1 Hz, CH3-80); 13C NMR
(CDCl3, 50.3 MHz) d 188.8 (C-2), 170.6 (MeCO), 146.8 (C-4), 126.4
(C-3), 95.6 (C-1), 74.9 (C-20), 67.0 (C-5), 64.7 (C-6), 37.0, 31.8,
29.2, 25.7, 22.6 (C-30 to C-70), 20.7 (C-10), 19.4, 14.0 (C-80). Anal.
Calcd for C16H26O5: C, 64.41; H, 8.78. Found: C, 64.29; H, 8.91.
Figure 2. Stereoview of the DFT/B3LYP calculated structure of 1.
0
the observed J5,6 (3.4 Hz) and J5,6 (8.6 Hz) values. Furthermore, in
the 2T0 conformer H-2 lies out of the angle formed by the vicinal
methylene protons and the values of the dihedral angles H2–C2–
C3–H3 (43°) and H2–C2–C3–H30 (163°), estimated from the calcu-
lated structure, are in agreement with those expected from the
0
measured coupling constants (J2,3 ꢂ J2,3 = 7.5 Hz).
3. Conclusion
4.2.2. 2-(S)-Octyl 3,4-dideoxy-a-D-erythro-hexopyranoside 5a
Compound 2a (1.59 g, 5.33 mmol) dissolved in EtOAc (120 mL)
and 10% Pd/C (160 mg) was subjected to catalytic hydrogenation at
45 psi (3 atm) for 3 h. The product showed similar chromato-
graphic behavior as the starting material, although it was not UV
reactive. Crude compound 4a (1.60 g, quantitative) was pure en-
ough to be used in the next step. 1H NMR (CDCl3, 500 MHz) d
4.68 (br s, 1H, H-1), 4.40 (dddd, 1H, J4eq,5 = 1.3, J5,6a = 3.7,
J5,6b = 6.2, J4ax,5 = 11.6 Hz, H-5), 4.10 (dd, 1H, J5,6a = 3.7,
J6a,6b = 11.7 Hz, H-6a), 4.06 (dd, 1H, J5,6b = 6.2, J6a,6b = 11.7 Hz, H-
6b), 3.78 (m, 1H, J = 6.1 Hz, H-20), 2.75 (ddd, 1H, J3ax,4eq = 6.6,
J3ax,4eq = 13.2, J3ax,3eq = 14.9 Hz, H-3ax), 2.37 (dddd, 1H, J1,3eq = 0.8,
J3eq,4eq = 2.5, J3eq,4ax = 4.5, J3ax,3eq = 14.9 Hz, H-3eq), 2.03 (s, 3H,
CH3CO), 2.00 (m, 1H, H-4eq), 1.87 (dddd, 1H, J3eq,4ax = 4.8,
J4ax,5 = 11.6, J3ax,4ax = 13.2, J4ax,4eq = 13.4 Hz, H-4ax), 1.58–1.20 (m,
10H, CH2-30 to CH2-70), 1.08 (d, 3H, J = 6.1 Hz, CH3-10), 0.83 (t, 3H,
J = 6.1 Hz, CH3-80); 13C NMR (CDCl3, 50.3 MHz) d 202.3 (C-2),
170.7 (MeCO), 97.2 (C-1), 74.0 (C-20), 66.5 (C-6), 65.8 (C-5), 37.1,
34.8, 31.8, 29.3, 29.1, 25.8, 22.6 (C-3, C-4, C-30 to C-70), 20.8
(CH3CO), 19.2 (CH3-10), 14.1 (CH3-80).
The sugar amino acid (2S,5S)-5-(aminomethyl)-tetrahydrofuran-2-
carboxylic acid 1 has been synthesized through an enantiospecific
route in 35% overall yield, starting from per-O-acetyl-2-hydroxyga-
lactal (3). The sequence involves two highly selective reactions:
(i) the diastereoselective (de >98%) reduction of the carbonyl group
of the 2-ulose 4a, obtained by SnCl4-promoted glycosylation of 3
followed by hydrogenation; and (ii) the regioselective substitution
with the azide of the tosyloxy group at C-6 in the di-O-tosyl deriv-
ative 6, while the one at C-2 remained intact. The key step of the
synthetic route was the construction of the tetrahydrofuran ring
of 1 by methanolysis of the lactone group of 9, with intramolecular
displacement of the tosylate at C-2 by HO-5. This is the first report
on the synthesis of the (2S,5S) diastereoisomer of 1, which was
obtained as the free amino acid. The syntheses of the derivatives
of the other three isomers of 1 have been previously described.
Compound 1 may be incorporated into linear or cyclic oligopep-
tides as a dipeptide isostere.
4. Experimental parts
4.1. General
A solution of the crude 2-(S)-octyl 6-O-acetyl-3,4-dideoxy-a-D-
erythro-hexopyranoside-2-ulose 4a obtained (1.30 g, 4.33 mmol)
in MeOH (100 mL) was cooled at ꢀ18 °C and NaBH4 (189 mg,
5 mmol) was added. After 3 h analysis of the reaction mixture by
TLC, two products of Rf = 0.67 and 0.27 were seen (hexane/EtOAc,
1:1). A solution of 0.05 M NaMeO in MeOH (55 mL) was added,
and the reaction was continued for 1 h, when TLC showed the dis-
appearance of the spot of Rf = 0.67. The solution was adjusted to pH
5 by the addition of Dowex 50W(H+) resin, and then filtered and
concentrated. The 1H NMR spectrum of the crude mixture showed
a large proportion of the erythro isomer 5a (de >98%). Column chro-
matography (hexane/EtOAc 85:15) of the residue led to 5a (1.06 g,
Solvents were reagent grade and in most cases were dried prior to
use, according to standard procedures. Melting points were deter-
minedwitha Fisher-Johnsapparatus and are uncorrected. Analytical
thin-layer chromatography (TLC) was performed on 0.2 mm Silica
Gel 60 F-254 (Merck) aluminum-supported plates. Visualization of
the spots was effected by exposure to UV light or charring with a
solution of 5% sulfuric acid in EtOH, containing 0.5% p-anisaldehyde.
Column chromatography was performed with Silica Gel 60 (230–
400 mesh, Merck). Optical rotations were measured with a Perkin–
Elmer 343 digital polarimeter at 25 °C. Nuclear magnetic resonance
(NMR) spectra were recorded on a Bruker AC 200 or on a Bruker AMX
500 instruments using tetramethylsilane as an internal standard.
The spectra were assigned by the assistance of 2D-COSY and HSQC
experiments. High resolution mass spectrometry (HRMS-ESI) was
performed in a Bruker microTOF-Q II instrument.
94%); [a]
D = +113.4 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz) d 4.91
(d, 1H, J1,2 = 3.8 Hz, H-1), 3.84 (m, 1H, H-5), 3.81 (m, 1H, J = 6.1 Hz,
H-20), 3.61 (dd, 1H, J5,6a = 3.3, J6a,6b = 11.4 Hz, H-6a), 3.59 (ddd, 1H,
J1,2 = 3.8, J2,3eq = 5.0, J2,3ax = 11.8, Hz, H-2), 3.50 (dd, 1H, J5,6b = 6.5,
J6a,6b = 11.4 Hz, H-6b), 1.90 (dddd, 1H, J3eq,4ax = 3.7, J3eq,4eq = 4.4,
J2,3eq = 5.0, J3eq,3ax = 12.0 Hz, H-3eq), 1.82 (br s, 2H, HO), 1.69 (dddd,
1H, J3ax,4eq = 4.1, J2,3ax = 11.8, J3ax,3eq = 12.0, J3ax,4ax = 13.3 Hz, H-
3ax), 1.63–1.58 (m, 1H, H-4 eq), 1.48 (dddd, 1H, J3eq,4ax = 3.7,
J4ax,5 = 11.7, J4ax,4eq = J3ax,4ax = 13.1 Hz, H-4ax), 1.36–1.22 (m, 10H,
CH2-30 to CH2-70), 1.15 (d, 3H, J = 6.1 Hz, CH3-10), 0.89 (3H,
J = 6.1 Hz, CH3-80); 13C NMR (CDCl3, 50.3 MHz) d 95.4 (C-1), 74.6,
72.3, 69.0 (C-2, C-5, C-20), 65.5 (C-6), 37.4, 31.8, 29.3, 27.2, 26.0,
25.8, 22.7 (C-3, C-4, C-30 to C-70), 19.3, 14.1 (CH3-10, CH3-80). Anal.
Calcd for C14H28O4: C, 64.58; H, 10.84. Found: C, 64.36; H, 11.09.
4.2. Synthesis
4.2.1. 2-(S)-Octyl 6-O-acetyl-3,4-dideoxy-a-D-glycero-hex-3-
enopyranosid-2-ulose 2a
A solution of glycal 3 (2.00 g, 6.06 mmol) and 2-(S)-octanol
(1.88 mL, 12.12 mmol) in dry CH2Cl2 (120 mL) was cooled to

M. L. Uhrig et al. / Tetrahedron: Asymmetry 21 (2010) 2435–2440
2439
The same reduction of 5a conducted at 25 °C, afforded a mixture
of 6a and its -threo isomer (Table 1). Anomeric signals for 2-(S)-
-threo-hexopyranoside: dH-1 = 4.81 ppm, dC-1
for 6 h. TLC showed a single spot of Rf = 0.55 (hexane/EtOAc 2:1).
After evaporation of the solvent under reduced pressure, and fur-
ther purification by column chromatography, compound 8 was iso-
a
-D
octyl 3,4-dideoxy-
a-D
=
96.5 ppm.
lated (410 mg, 82%); [
200 MHz) 7.82, 7.35 (2d, 4H, H-aromatic), 5.20 (d, 0.6H,
J1,2 = 3.3 Hz, H-1 ), 4.67 (d, 0. 4H, J1,2 = 7.5 Hz, H-1b), 4.45 (dd,
0.6H, J1,2 = 3.3, J2,3ax = 4.9, J2,3ax = 12.0 Hz, H-2 ), 4.23–4.05 (m,
1H, H-2b, H-5 ), 3.67 (m, 0. 4H, H-5b), 3.42–3.19 (m, 2H, H-6 /b,
H-60a/b), 2.45 (s, 3H, ArCH3), 2.29–1.37 (m, 4H, H-3 /b, H-30a/b,
H-4
/b, H-40a/b); 13C NMR (CDCl3, 50.3 MHz) d 130.0, 129.8,
128.8, 127.8 (C-aromatic), 95.9 (C-1b), 90.1 (C-1 ), 79.2, 76.8,
74.8, 66.9 (C-2 /b, C-5 /b), 54.3, 54.0 (C-6 /b), 28.5, 27.4, 22.8,
21.7 (C-3 /b, C-4 /b). Anal. Calcd for C13H17N3O5S: C, 47.70; H,
5.23; N, 12.84. Found: C, 47.90; H, 5.46; N, 13.03.
a]
D = +14.0 (c 1.1, CHCl3). 1H NMR (CDCl3,
d
4.2.3. 2-Propyl 3,4-dideoxy-
a
-
D
-erythro-hexopyranoside 5b
a
The reduction of the keto compound 4b15 with NaBH4 was per-
formed at ꢀ18 °C and 25 °C as described above for 4a. After O-
deacetylation the crude product was analyzed by NMR which
a
a
a
a
showed the presence of 5b and its
a-
D-threo isomer (Table 1). Ano-
a
meric signals for 2-propyl 3,4-dideoxy-
a
-D
-threo-hexopyranoside:
a
dH-1 = 4.79 ppm, dC-1 = 97.4 ppm.
a
a
a
a
a
4.2.4. 2-(S)-Octyl 2,6-di-O-tosyl-3,4-dideoxy-a-D-erythro-
hexopyranoside 6
Diol 5b (1.00 g, 3.84 mmol) and tosylchloride (1.82 g, 9.60mmol)
were dissolved in pyridine (50 mL) and the reaction mixture was
stirred at room temperature for 20 h. Next, MeOH was added at
0 °C and the solventwas evaporated in vacuo. Purificationby column
chromatography (hexane/EtOAc, 9:1) afforded the ditosylate 6
4.2.7. 6-Azido-2-O-tosyl-3,4,6-trideoxy-D-erythro-hexono-1,5-
lactone 9
A solution of oxalyl chloride (1.03 mL, 12.22 mmol) in dry
CH2Cl2 (13 mL) was prepared in a round-bottomed flask, under
an Ar atmosphere, and it was cooled to ꢀ78 °C (dry ice/acetone
bath). A solution of DMSO (1.73 mL, 24.44 mmol) dissolved in
CH2Cl2 (2 mL) was added dropwise over a period of 15 min. After
stirring the mixture for 10 min, a solution of compound 8 (2.00 g,
6.11 mmol) in dry CH2Cl2 (6 mL) was added dropwise and stirring
maintained for 1 h. Triethylamine (3 mL) was added and, after
15 min, water (20 mL) was added. The mixture was allowed to
reach room temperature and extracted with 5% aq HCl. The organic
layer was concentrated to afford 9 (1.67 g, 88%) as a white solid
(Rf = 0.70, hexane/EtOAc 1:1). The lactone did not resist purifica-
tion by column chromatography, but the crude product was pure
enough to be used in the following step. Recrystallization from a
minimum amount of EtOAc afforded an analytical sample. Mp
(1.92 g, 88%, Rf = 0.60 hexane/EtOAc 2:1); [a]D = +68.9 (c 1.0, CHCl3);
1H NMR (CDCl3, 500 MHz) d 7.76, 7.78 (2d, 4H, J = 8.0 Hz, H-aro-
matic), 7.33 (2d, 4H, J = 8.0 Hz, H-aromatic), 4.78 (d, 1H, J = 3.5 Hz,
H-1), 4.33 (ddd, 1H, J1,2 = 3.5, J2,3eq = 4.8, J2,3ax = 12.4 Hz, H-2), 3.99
(m, 1H, H-5), 3.96 (dd, 1H, J5,6a = 5.2, J6a,6b = 10.1 Hz, H-6a), 3.91
(dd, 1H, J5,6a = 3.8, J6a,6b = 10.1 Hz, H-6b), 3.60 (m, 1H, J = 6.1 Hz,
H-20), 2.02 (ddd, 1H, J3ax,4eq = 4.0, J2,3ax = J3ax,3eq = J3ax,4ax = 12.4 Hz,
H-3ax), 1.72–1.62 (m, 2H, H-3eq, H-4ax), 1.54 (m, 1H, H-4b), 1.55–
1.22 (m, 10H, CH2-30 to CH2-70), 1.03 (d, 3H, J = 6.1 Hz, CH3-10), 0.88
(t, 3H, J = 6.1 Hz, CH3-80); 13C NMR (CDCl3, 50.3 MHz) d 144.9,
129.9 (ꢃ2), 127.9, 127.8 (C-aromatic), 93.5 (C-1), 76.2 (C-2), 73.5
(C-20), 71.2 (C-5), 65.6 (C-6), 37.0, 31.8, 29.3, 26.5, 25.8, 23.4, 22.6
(C-3, C-4, C-30 to C-70), 21.6 (2 ꢃ CH3Ar), 19.0, 14.1 (CH3-10, CH3-80).
Anal. Calcd for C28H40O8S2: C, 59.13; H, 7.09; S, 11.28. Found: C,
59.09; H, 7.19; S, 11.13.
77 °C; [a]
D = +9.2 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz) d 7.86
(d, 2H, J = 8.2 Hz, H-aromatic), 7.36 (d, 2H, J = 8.2 Hz, H-aromatic),
4.91 (dd, 1H, J2,3eq = 6.1, J2,3ax = 11.0 Hz, H-2), 4.53 (dddd, 1H,
0
J5,6 = 4.1, J4eq,5 = 4.3, J5,6 = 4.8, J4ax,5 = 11.4 Hz, H-5), 3.52 (dd, 1H,
4.2.5. 2-(S)-Octyl 6-azido-2-O-tosyl-3,4,6-trideoxy-a-D-erythro-
hexopyranoside 7
0
0
0
J5,6 = 4.1, J6,6 = 14.2 Hz, H-6), 3.42 (dd, 1H, J5,6 = 4.8, J6,6
=
14.2 Hz, H-60), 2.48 (m, 1H, H-3eq), 2.44 (s, 3H, CH3Ar), 2.20 (dddd,
1H, J3ax,4eq = 4.3, J2,3ax = 11.0, J3ax,3eq = J3ax,4ax = 13.0 Hz, H-3ax), 2.03
(dddd, 1H, J3ax,4eq = J3eq,4eq = J4eq,5 = 4.3, J4ax,4eq = 14.6 Hz, H-4eq),
Compound 6 (1.78 g, 3.13 mmol) was dissolved in DMF (30 mL)
and NaN3 (427 mg, 6.57 mmol) was added. The reaction mixture
was stirred at 125 °C for 2 h, when TLC showed complete con-
sumption of the starting material and formation of a less polar
product (Rf = 0.75, hexane/EtOAc 2:1). The mixture was filtered
and the solvent evaporated in vacuo. The residue was purified by
column chromatography (hexane/EtOAc 96:4) to give 7 (1.27 g,
1.94 (dddd, 1H, J3eq,4ax = 4.3, J4ax,5 = 11.4, J3ax,4ax = 13.0, J4ax,4eq
=
14.6 Hz, H-4ax); 13C NMR (CDCl3, 125.7 MHz) d 165.0 (C-1), 145.4,
132.8, 129.8, 128.2 (C-aromatic), 79.2 (C-5), 73.4 (C-2), 53.9
(C-6), 27.2 (C-3), 24.4 (C-4), 21.7 (CH3Ar). Anal. Calcd for
C13H15O5SN3: C, 47.99; H, 4.65; S, 9.86; N, 12.92. Found: C,
92%); [a]
D = +77.9 (c 1.0, CHCl3). 1H NMR (CDCl3, 500 MHz) d 7.80
48.20; H, 4.60; S, 9.95; N, 12.83.
(d, 2H, J = 8.2 Hz, H-aromatic), 7.34 (d, 2H, J = 8.2 Hz, H-aromatic),
4.85 (d, 1H, J1,2 = 3.3 Hz, H-1), 4.41 (ddd, 1H, J1,2 = 3.3, J2,3eq = 4.8,
J2,3ax = 12.3 Hz, H-2), 3.98 (dddd, 1H, J4eq,5 ꢂ J5,6b = 3.6, J4ax,5 = 9.6,
4.2.8. Methyl (2S,5S)-5-(azidomethyl)-tetrahydrofuran-2-
carboxylate 10
J5,6a = 7.0 Hz, H-5), 3.71 (m, J = 6.1 Hz, H-20), 3.21 (dd, 1H, J5,6a
=
A solution of 9 (200 mg, 0.61 mmol) in MeOH (12 mL) was
stirred with potassium carbonate (84 mg, 0.61 mmol) at 20 °C.
After 1 h, TLC (hexane/EtOAc 1:1) showed total conversion of
the starting material into a less polar product (Rf = 0.73). The
reaction mixture was neutralized with Dowex 50W(H+), filtered
and was concentrated. The residue was subjected to flash chro-
7.0, J6a,6b = 13.0 Hz, H-6a), 3.12 (dd, 1H, J5,6b = 3.6, J6a,6b = 13.0 Hz,
H-6b), 2.44 (s, 3H, CH3Ar), 2.07 (dddd, 1H, J3ax,4eq = 4.3, J2,3ax
J3ax,4ax ꢂ J3ax,3eq = 12.3 Hz, H-3ax), 1.74 (dddd, 1H, J3eq,4ax = J3eq,4eq
ꢂ
=
3.8, J2,3eq = 4.8, J3ax,3eq = 12.3 Hz, H-3eq), 1.68–1.57 (m, 2H, H-4ax,
H-4eq), 1.51–1.23 (m, 10H, CH2-30 to CH2-70), 1.07 (d, 3H,
J = 6.1 Hz, CH3-10), 0.88 (t, 3H, J = 6.1 Hz, CH3-80); 13C NMR (CDCl3,
50.3 MHz) d 144.8, 134.0, 129.9, 127.7 (C-aromatic), 93.5 (C-1),
76.5 (C-2), 73.6 (CHO), 67.4 (C-5), 54.4 (C-6), 37.1, 31.8, 29.3,
27.8, 25.8, 23.6, 22.6 (C-3, C-4, C-30 to C-70), 21.6 (CH3Ar), 19.1,
14.1 (2 ꢃ CH3). Anal. Calcd for C21H33N3O5S: C, 57.38; H, 7.57; N,
9.56. Found: C, 57.49; H, 7.77; N, 9.61.
matography (hexane/EtOAc 9:1) to afford 10 as
a syrup
(106 mg, 86%);
[a]
D = ꢀ8.8 (c 0.2, CHCl3); 1H NMR (CDCl3,
500 MHz) d 4.63 (dd, 1H, J = 5.3, 8.0 Hz, H-2), 4.43 (dddd, 1H,
J = 4.1, 4.6, 7.0, 7.0 Hz, H-5), 3.78 (s, 3H, CH3O), 3.52 (dd, 1H,
J = 4.1, 12.9 Hz, H-6), 3.26 (dd, 1H, J = 4.7, 12.9 Hz, H-60), 2.37
(m, 1H, H-3), 2.09 (m, 2H, H-30, H-4), 1.84 (m, 1H, H-40); 13C
NMR (CDCl3, 125.7 MHz) d 173.4 (C-1), 79.0 (C-5), 77.3 (C-2),
54.1 (C-6), 52.1 (CH3O), 30.2 (C-3), 27.9 (C-4). HRMS-ESI: Calcd
for (C7H11N3O3 + H+) = 186.0873. Found = 186.0877. Calcd for
(C7H11N3O3 + Na+) = 208.0697. Found = 208.0697.
4.2.6. 6-Azido-2-O-tosyl-3,4,6-trideoxy-a,b-D-erythro-
hexopyranose 8
Compound 7 (673 mg, 1.53 mmol) was suspended in a mixture
of TFA (5 mL) and water (1.40 mL) and externally heated at 90 °C

2440
M. L. Uhrig et al. / Tetrahedron: Asymmetry 21 (2010) 2435–2440
4.2.9. (2S,5S)-5-(Azidomethyl)-tetrahydrofuran-2-carboxylic
acid 11
References
1. (a) Galeazzi, R.; Mobbili, G.; Orena, M. Curr. Org. Chem. 2004, 8, 1799–1829; (b)
Charkraborty, T. K.; Ghosh, S.; Jayaprakasha, S.; Sharma, J. A. R. P.; Ravikanth,
V.; Diwan, P. V.; Nagaraj, R.; Kunwar, A. C. J. Org. Chem. 2000, 65, 6441–6457.
2. Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev. 2002, 102, 491–
514.
3. Risseeuw, M. D. P.; Overhand, M.; Fleet, G. W. J.; Simone, M. I. Tetrahedron:
Asymmetry 2007, 18, 2001–2010.
4. Schweizer, F. Angew. Chem., Int. Ed. 2002, 41, 230–253.
5. Gruner, S. A. W.; Truffault, V.; Voll, G.; Locardi, E.; Stöckle, M.; Kessler, H. Chem.
Eur. J. 2002, 8, 4366–4376.
6. Charkraborty, T. K.; Roy, S.; Koley, D.; Dutta, S. K.; Kunwar, A. C. J. Org. Chem.
2006, 71, 6240–6243.
7. Karle, I. L.; Perozzo, M. A.; Mishra, V. K.; Balaram, P. Proc. Natl. Acad. Sci. 1998,
95, 5501–5504.
8. Charkraborty, T. K.; Srinivasu, P.; Tapadar, S.; Mohan, B. K. Glycoconjugate J.
2005, 22, 83–93.
9. Trabocchi, A.; Guarna, F.; Guarna, A. Curr. Org. Chem. 2005, 9, 1127–1153.
10. Charkraborty, T. K.; Tapadar, S.; Kumar, S. K. Tetrahedron Lett. 2002, 43, 1317–
1320.
A mixture of 10 (70 mg, 0.38 mmol) and 1:1 TFA/H2O (4 mL)
was stirred at room temperature for 14 h, when TLC (hexane/EtOAc
1:1) revealed the presence of a single product (Rf = 0.25). The sol-
vent was evaporated in vacuo and the residue, dissolved in water
(2 mL), was purified by reverse phase chromatography (Amprep
Amersham TM C-18), equilibrated with water and eluted with a
gradient of MeOH/water, to give 11 as a pure oil (60 mg, 94%);
[
a
]
D = ꢀ5.0 (c 0.7, H2O); 1H NMR (CDCl3, 500 MHz) d 4.57 (dd,
J = 6.1, 7.9 Hz, H-2), 4.31 (dddd, 1H, J = 3.4, 6.2, 6.8 Hz, H-5), 3.47
(dd, 1H, J = 3.4, 13.3 Hz, H-6), 3.26 (dd, 1H, J = 6.2, 13.3 Hz, H-60),
2.36 (m, 1H, H-3), 2.01 (m, 2H, H-30, H-4), 1.73 (m, 1H, H-40); 13C
NMR (CDCl3, 125.7 MHz) d 177.2 (C-1), 79.6 (C-5), 76.8 (C-2),
53.7 (C-6), 29.9 (C-3), 27.5 (C-4). HRMS-ESI: Calcd for
(C6H9N3O3 + Na+) = 194.0536. Found = 194.0536.
11. Charkraborty, T. K.; Reddy, V. R.; Sudhakar, G.; Kumar, S. U.; Reddy, T. J.; Kumar,
S. K.; Kunwar, A. C.; Mathur, A.; Sharma, R.; Gupta, N.; Prasad, S. Tetrahedron
2004, 60, 8329–8339.
12. Prasad, S.; Mathur, A.; Jaggi, M.; Sharma, R.; Gupta, N.; Reddy, V. R.; Sudhakar,
G.; Kumar, S. U.; Kumar, S. K.; Kunwar, A. C.; Charkraborty, T. K. J. Peptide Res.
2005, 66, 75–84.
13. Charkraborty, T. K.; Ghosh, S.; Jayaprakash, S.; Sharma, J. A. R. P.; Ravikanth, V.;
Diwan, P. V.; Nagaraj, R.; Kunwar, A. C. J. Org. Chem. 2002, 65, 6441–6457.
14. Manzano, V. E.; Reppeto, E.; Uhrig, M. L.; Baráth, M.; Varela, O. Proven Methods
Carbohydr. Chem., in press.
15. De Fina, G. M.; Varela, O.; Lederkremer, R. M. Synthesis 1988, 891–893.
16. Varela, O.; De Fina, G.; Lederkremer, R. M. Carbohydr. Res. 1987, 165, 187–196.
17. Zunszain, P. A.; Varela, O. Tetrahedron: Asymmetry 1998, 9, 1269–1276.
18. (a) Iriarte Capaccio, C. A.; Varela, O. Tetrahedron: Asymmetry 2000, 11, 4945–
4954; (b) Varela, O.; De Fina, G.; Lederkremer, R. M. Carbohydr. Res. 1993, 246,
371–376.
4.2.10. (2S,5S)-5-(Aminomethyl)-tetrahydrofuran-2-carboxylic
acid 1
Compound 11 (60 mg 0.35 mmol) dissolved in EtOAc (10 mL)
was hydrogenated at 45 psi in the presence of 10% Pd/C (10 mg).
After 3 h, TLC (hexane/EtOAc 1:1) revealed complete consumption
of the starting material. The catalyst was removed by filtration, the
residue was washed with water and the combined liquids were
concentrated to afford crude 1. This product was dissolved in water
and loaded onto a Dowex 50W(H+) column which was rinsed with
water and eluted with 0.1 M pyridine to give pure 1 as an oil
(46 mg, 90%); Rf = 0.2 (MeCN/EtOH/H2O/AcOH, 13:4:2:1) positive
to the ninhydrin test;
[
a
]
D = +20.4 (c 1.0, H2O); 1H NMR
19. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660.
20. Kefurt, K.; Snatzke, G.; Snatzke, F.; Triska, R.; Jary´, J. Collect. Czech. Chem.
Commun. 1976, 41, 3324–3334.
21. Varela, O.; Fernández Cirelli, A.; Lederkremer, R. M. Carbohydr. Res. 1979, 70,
27–37.
0
(500 MHz, D2O) d 4.34 (t, 1H, J2,3 ꢂ J2,3 = 7.5 Hz, H-2), 4.29 (dddd,
0
0
1H, J4,5 = 6.8, J4 , 5 = 8.0, J5,6 = 3.4, J5,6 = 8.6 Hz, H-5), 3.09 (dd, 1H,
0
0
0
J5,6 = 3.4, J6,6 = 13.2 Hz, H-6), 2.93 (dd, 1H, J5,6 = 8.6, J6,6 = 13.2 Hz,
22. Philip, T.; Cook, R. L.; Malloy, T. B.; Allinger, N. L.; Chang, S.; Yuh, Y. J. Am. Chem.
Soc. 1981, 103, 2151–2156.
H-60), 2.27 (dddd, 1H, J2,3 = 7.5, J3,4 = 5.2, J3,4 = 8.0, J3,3 = 12.8 Hz,
0
0
0
0
H-3), 2.04 (dddd, 1H, J3,4 = 5.2, J3 ,4 = 8.0, J4,5 = 6.8, J4,4 = 12.8 Hz,
23. Walszek, Z.; Horton, D.; Ekiel, I. Carbohydr. Res. 1982, 106, 193–201.
24. Bierenstiel, M.; Schlaf, M. Eur. J. Chem. 2004, 1474–1481.
25. Hackert, M. L.; Jacobson, R. A. J. Acta Crystallogr., Ser. B 1971, 27, 203–209.
26. Varela, O.; Zunszain, P. A. J. Org. Chem. 1993, 58, 7860–7864.
27. Zunszain, P. A.; Varela, O. Tetrahedron: Asymmetry 2000, 765–771.
28. (a) Lopez-Ortega, B.; Jenkinson, S. F.; Claridge, T. D. W.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2008, 19, 976–983; (b) Witty, D. R.; Fleet, G. W. J.;
Choi, S.; Vogt, K.; Wilson, F. X.; Wang, Y.; Storer, R.; Myers, P. L.; Wallis, C. J.
Tetrahedron Lett. 1990, 31, 6927–6930.
H-4), 1.87 (ddd, 1H, J2,3 = 7.5, J3 ,4 = J3 ,4 = 8.0, J3,3 = 12.8 Hz, H-30),
0
0
0
0
0
1.61 (ddd, 1H, J3,4 = J3 ,4 = J4 ,5 = 8.0, J4,4 = 12.8 Hz, H-40); 13C NMR
(125.7 MHz, D2O) d: 180.8 (C-1), 78.7 (C-2), 75.8 (C-5), 42.7 (C-6),
30.1 (C-3), 28.1 (C-4). HRMS-ESI: Calcd for (C6H11NO3 + H+) =
146.0812. Found = 146.0816.
0
0
0
0
0
29. (a) Edwards, A. A.; Sanjayan, G. J.; Hachisu, S.; Soengas, R.; Stewart, A.; Tranter,
G. E.; Fleet, G. W. J. Tetrahedron 2006, 62, 4110–4119; (b) Sanjayan, G. J.;
Stewart, A.; Hachisu, S.; Gonzalez, R.; Watterson, M. P.; Fleet, G. W. J.
Tetrahedron Lett. 2003, 44, 5847–5851; (c) Watterson, M. P.; Edwards, A. A.;
Leach, J. A.; Smith, M. D.; Ichihara, O.; Fleet, G. W. J. Tetrahedron Lett. 2003, 44,
5853–5857; (d) Choi, S. S.; Myerscough, P. M.; Fairbanks, A. J.; Skead, B. M.;
Bichard, C. J. F.; Mantell, S. J.; Son, J. C.; Fleet, G. W. J.; Saunders, J.; Brown, D. J.
Chem. Soc., Chem. Commun. 1992, 1605–1607.
Acknowledgments
Support of this work by the National Agency for Promotion of
Science and Technology (ANPCyT, Project PICT 2007-00291), the
National Research Council of República Argentina (CONICET, Pro-
ject PIP N° 0064), and the University of Buenos Aires (Project UBA-
CyT N° 227) is gratefully acknowledged. The authors are research
members of CONICET.
30. (a) Estevez, J. C.; Fairbanks, A. J.; Fleet, G. W. J. Tetrahedron 1998, 54, 13591–
13620; (b) Hsia, K. Y.; Ward, P.; Fleet, G. W. J. Tetrahedron Lett. 1994, 35, 3361–
3364.