Total synthesis of 3,4-dihydroxyprolines, D-threo-L-norvaline and (2S,3R,4R)-2-amino-3,4-dihydroxytetrahydrofuran-2-carboxylic acid methyl ester

Article abstract of DOI:10.1016/j.tetasy.2003.10.005

The Henry reaction between D-glyceraldehyde and ethyl nitroacetate allowed the practical development of a diastereoselective synthesis of 3,4,5-trihydroxy-2-nitropentanoic acid esters, which were reduced to polyoxamic acids, which were used in a new diastereoselective synthesis of 3,4-dihydroxyprolines and new enantioselective syntheses of D-threo-L-norvaline and (2S,3R,4R)-2-amino-3,4-dihydroxytetrahydrofuran-2-carboxylic acid methyl ester.

Full text of DOI:10.1016/j.tetasy.2003.10.005

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3955–3963
Total synthesis of 3,4-dihydroxyprolines,
D
-threo-
L
-norvaline and
(2S,3R,4R)-2-amino-3,4-dihydroxytetrahydrofuran-2-carboxylic
acid methyl ester
Raquel G. Soengas, Juan C. Este´vez and Ramo´n J. Este´vez*
Departamento de Qu´ımica Orga´nica, Universidade de Santiago, 15782 Santiago de Compostela, Spain
Received 13 September 2003; accepted 1 October 2003
Abstract—The Henry reaction between
D-glyceraldehyde and ethyl nitroacetate allowed the practical development of a
diastereoselective synthesis of 3,4,5-trihydroxy-2-nitropentanoic acid esters, which were reduced to polyoxamic acids, which were
used in a new diastereoselective synthesis of 3,4-dihydroxyprolines and new enantioselective syntheses of
(2S,3R,4R)-2-amino-3,4-dihydroxytetrahydrofuran-2-carboxylic acid methyl ester.
© 2003 Elsevier Ltd. All rights reserved.
D-threo-L-norvaline and
1. Introduction
As part of a broader programme on the synthesis and
synthetic applications of nitroalkanoic acids derived
from sugars,6 we describe herein practical conditions
The Henry reaction, or nitroaldol reaction, couples a
carbonyl compound and a nitroalkane bearing an a
hydrogen atom, thereby creating an a-nitroalkanol. It is
a powerful tool for the construction of CꢀC bonds, and
can result in the formation of one or two stereogenic
centres.1 Following the condensation reaction, the nitro
group can be subjected to a diverse range of chemical
transformations, including reduction to an amino
group or oxidation to the corresponding ketone (the
Nef reaction).2
for the Henry reaction between
D-glyceraldehyde and
ethyl nitroacetate, which gives 2-nitro-3,4,5-trihydroxy-
pentanoic acids. We also describe the reduction of these
products to polyoxamic acids, and the use of the latter
in a new diastereoselective synthesis of 3,4-dihydrox-
yprolines 14 and 15 and new enantioselective
syntheses of
D-threo-L-norvaline 19 and (2S,3R,4R)-2-
amino-3,4-dihydroxytetrahydrofuran-2-carboxylic acid
methyl ester 25.
Nitroacetic acid esters are a class of nitroalkanes that
have received considerable attention due to their special
chemical properties.3 The presence of an active methyl-
ene group makes these esters particularly efficient in the
formation of carbon–carbon bonds. For example, they
readily execute nucleophilic attack on a wide range of
electrophiles, including alkyl halides, carbonyl com-
pounds and Michael acceptors. Accordingly, they are
convenient starting materials for the synthesis of 2-
nitroalkanoic acids. Thus, methyl nitroacetate has
thereby proved to be a versatile equivalent of glycine
for the preparation of non-natural a-amino acids.4
Somewhat surprisingly, the preparation of a-amino
acids by the Henry reaction of sugars with alkyl
nitroacetates has received very little attention.5
2. Results and discussion
Condensation of
D
-glyceraldehyde 17 with ethyl
nitroacetate under typical Henry reaction conditions
gave a 45% yield the data of which showed it to be an
unstable 6:5 mixture of pentanoic acid ester epimers 2
and 3 (Scheme 1). The 1H NMR spectrum of this
mixture included a multiplet between 1.33 and 1.44
ppm due to the methyl groups of the ethyl ester moi-
eties, and the IR spectrum showed bands at 3502 cm−1
(due to the hydroxyl group), at 1753 cm−1 (the carbonyl
signal) and at 1565 and 1375 cm−1 (two typical nitro
group bands). The stereochemistry of 2 and 3 were
tentatively elucidated by reasoning analogous to that
applied to a similar, previously reported reaction:7 the
(S)-configuration of the two nitroaldols C3 epimers is
explained in terms of preferential attack by the nucleo-
* Corresponding author. Tel.: +34-981-563100; fax: +34-981-591014;
e-mail: qorjec@usc.es
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.10.005

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R. G. Soengas et al. / Tetrahedron: Asymmetry 14 (2003) 3955–3963
Scheme 1. Reagents and conditions: (i) Ethyl nitroacetate/KF/isopropanol; (ii) DHP/PPTS/CH2Cl2.
phile at the re face of the aldehyde and the preferred
conformation of the latter.
furolactone in order to establish its configuration.
However, following protection of the amino group of
6a as its benzyloxycarbonyl derivative (by treatment
with benzyloxycarbonylchloride and sodium carbonate)
and reaction of the resulting compound 7a with trifl-
uoroacetic acid (to remove the THP and acetonide
groups), subsequent lactonization gave a crude product
that when purified by column chromatography afforded
a mixture of the two epimeric lactones 8a and 8b (28%
yield) and a mixture of the four diastereomeric lactones
9a–d (42% yield). The same result was obtained on
starting from 6b, 6c and 6d. This unexpected outcome
implies that three processes accompany lactonization:
epimerization at the stereogenic centre bearing the
NHZ group,8 deprotection of the OH group at C3 and
transfer of the protecting group to the less hindered OH
group at position C5. Since treatment of the mixture of
8a and 8b with DHP and p-TsOH under the same
conditions as for 2+3 led to the mixture 9a–d, and
treatment of the mixture of 9a–d with pyridinium p-
toluenesulfonate gave 8a+8b, it seems like that 9a–d are
formed from compound 7a via 8a and 8b.
To avoid the easy retro-Henry reaction we decided to
protect the free OH group of compounds 2 and 3 as
soon as this mixture was isolated. After several unsuc-
cessful attempts at protection with benzyl trichloroace-
timidate in an acidic medium, reaction of the mixture
2+3 with DHP and pyridinium p-toluenesulfonate gave
an 80% yield of the expected mixture of alkanoic acid
esters, which comprised the epimeric pairs 4a+4b and
5a+5b. The IR spectrum of this mixture contained the
typical nitro bands at 1562 and 1374 cm−1, but not the
free OH of the starting compounds. Attempts to sepa-
rate compounds 4 and 5 failed, both the chromato-
graphic fractions that were isolated seeming to consist
of both 4 and 5; both fractions gave a mixture of
compounds 2 and 3 upon treatment with pyridinium
p-toluenesulfonate to remove the THP protecting
group.
Catalytic hydrogenation of the mixture 4+5 gave the
expected mixture of polyoxamic acid esters 6a–d
(Scheme 2). The success of the reaction was evidenced
by the IR spectrum, in which the nitro bands had been
replaced by a band at 3391 cm−1, due to the NH2
group. The four components of this mixture were sepa-
rated by column chromatography, and it was planned
to convert each amino acid ester into the corresponding
In view of these results, in subsequent experiments the
mixture of polyoxamic acid esters 6a–d was trans-
formed directly, and in better yield, into the above
mixture of lactones 8a, 8b and 9a–d. Reaction of this
mixture with pyridinium p-toluenesulfonate gave a
quantitative yield of the mixture 8a+8b, from which a
Scheme 2. Reagents and conditions: (i) H2/Raney-Ni/methanol; (ii) BnOCOCl/NaHCO3/ethyl acetate; (iii) TFA/H2O/THF; (iv)
PPTS/ethanol, 50°C; (v) DHP/PPTS/CH2Cl2.

R. G. Soengas et al. / Tetrahedron: Asymmetry 14 (2003) 3955–3963
3957
small amount of the major component, 8a, was isolated
by column chromatography and tentatively identified
on the basis of its spectroscopic properties.
barium hydroxide, followed by ring-closing intramolec-
ular displacement of the OTs group by the NH2 group.
Compounds 14 and 15 were not separated, but their
separation has been described previously following their
preparation by a different method.16
Via lactones 8a and 8b it was possible to transform
polyoxamic acids 6 into 3,4-dihydroxyprolines 14 and
15,9 members of a family that include compounds with
inhibitory activity,10 anti-HIV activity,11 immunostimu-
latory properties,12 or the ability to induce secondary
structures in peptides.13 In an initial attempt to trans-
form pure lactone 8a into 14 via 10a and 10b, selective
tosylation of the C5 OH group by reaction with p-tolue-
nesulfonyl chloride in pyridine gave a mixture of lac-
tones 10a and 11a as a result of epimerization at
position C2 (Scheme 3). The mixture 10a+11a was also
obtained, albeit in better yield, starting from the mix-
ture 8a+8b. Removal of the benzyloxycarbonyl group
of 10a+11a by catalytic hydrogenation in the presence
of hydrochloric acid, followed by treatment of the
resulting mixture, 10b+11b, with aqueous barium
hydroxide, afforded a mixture of 3,4-dihydroxyprolines
1414 and 15 in 68% yield.15 Since lactone 11b cannot be
converted directly into the corresponding proline 15 (its
stereochemistry prevents internal displacement of the
OTs group by the amino group), we deduce that this
transformation must have involved the opening of 10b
and 11b to polyoxamic acids 12 and 13 by the action of
As a second application of the derivatives of poly-
oxamic acids 6, we converted the mixture 9a–d into
D
-threo-L
-norvaline17 19 (Scheme 4), an abundant non-
proteogenic natural amino acid that has been used as a
key precursor in the synthesis of clavalanine,18 a potent
b-lactam antibiotic isolated19 from Streptomyces
clavuligerus, and has previously been synthetized from
D
-glucose and D
-ribose.20
Treatment of 9a–d with methanesulfonyl chloride in
pyridine resulted in the formation of a mixture of
O-mesyl derivatives 16a–d, which upon treatment with
PPTS in ethanol gave 17a+17b through elimination of
MsOH and formation of the carbon–carbon double
bond. Removal of the benzyloxycarbonyl protecting
group provided lactone 18a, which was transformed
into the target compound 19 in 63% yield stereoselec-
tive reduction of the carbonꢀcarbon double bond and
subsequent treatment of the resulting lactone, 18b, with
barium hydroxide and Amberlite 120-IR.20b
Scheme 3. Reagents and conditions: (i) TsCl/pyridine; (ii) a. H2/Pd–C, HCl, b. Ba(OH)2, Amberlite 120-IR.
Scheme 4. Reagents and conditions: (i) MsCl, pyridine; (ii) PPTS, ethanol; (iii) H2/Pd–C, acetic acid; (iv) Ba(OH)2.

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R. G. Soengas et al. / Tetrahedron: Asymmetry 14 (2003) 3955–3963
Scheme 5. Reagents and conditions: (i) TBDMSiCl, imidazole, DMF; (ii) PPTS, ethanol; (iii) NBS, acetonitrile; (iv) HCl (1% in
methanol); (v) Bu4NF, THF.
We also transformed 9a–d into furan a-amino acid 25
(Scheme 5). Although a number of sugar a-amino acids
of this kind the amino and carboxylate groups at the
anomeric position, have been incorporated into pep-
tides and/or converted into spirodiketopiperazine
derivatives or hydantoins such as the natural herbicide
hydantocidin,22,23 25 is the only member of this class
with no substituents at C4.21
now in progress on a more efficient synthesis of
nitroalkanoic acids using synthetic equivalents of ethyl
nitroacetate that can stabilize the corresponding Henry
adducts and allow better stereochemical results to be
obtained. Transformation of nitroalkanoic acids into
derivatives other than amino acids by exploiting the
wide reactivity of nitro groups is also under
investigation.2
Following the efficient protection of the free OH group
of 9a–d by treatment with t-butyldimethylsilyl chloride
and imidazole, the THP group of the resulting lactones,
20a–d, was efficiently removed with pyridinium p-tolue-
nesulfonate in ethanol, giving a mixture of lactones 21a
and 21b in 75% yield. Reaction of this mixture with
NBS in acetonitrile then gave a 42% yield of the
bicyclic lactone 23, probably through oxidation of 21 to
the imino intermediate 22 followed by intramolecular
attack by the free OH group on the carbon–nitrogen
double bond.24 Finally, 23 was opened with methanol
and sodium carbonate, and the resulting aminoester 24
was transformed into amino acid 25 by removal of the
silyl protecting group.
4. Experimental
Melting points were determined using a Kofler Ther-
mogerate apparatus and are uncorrected. Specific rota-
tions were recorded on a JASCO DIP-370 optical
polarimeter. Infrared spectra were recorded on a
MIDAC FTIR spectrophotometer. Nuclear magnetic
resonance spectra were recorded on a Bruker WM-300
apparatus or a Bruker AMX-500, using deuterochloro-
form solutions containing tetramethylsilane as internal
standard. Mass spectra were obtained on a Kratos MS
50 TC mass spectrometer. Elemental analyses were
obtained from the Elemental Analysis Service at the
University of Santiago de Compostela. Thin layer chro-
matography (tlc) was performed using Merck GF-254
type 60 silica gel and ethyl acetate/hexane mixtures as
eluants; the tlc spots were visualized with Hanesian
mixture. Column chromatography was carried out
using Merck type 9385 silica gel. Solvents were purified
as per Ref. 26. Solutions of extracts in organic solvents
were dried with anhydrous sodium sulfate.
3. Conclusion
In conclusion, new synthetic applications have been
developed for D-glyceraldehyde, which has proved to be
a valuable chiral synthon that can be used an alterna-
tive to tartaric, malic and lactic acids in the preparation
of optically active naturally occurring compounds.25
The applications developed include the first practical
synthesis of nitroalkanoic acids and their transforma-
tion into polyoxamic acids; a new transformation of
these latter into 3,4-dihydroxyprolines; and novel total
syntheses of norvaline 19 and amino acid 25. Work is
4.1. (3S)-3-{(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl}-3-
hydroxy-2-nitropropionic acid ethyl ester 2+3
Ethyl nitroacetate (1.9 mL, 16.8 mmol) and potassium
fluoride (0.80 g, 13.8 mmol) were added to a solution of

R. G. Soengas et al. / Tetrahedron: Asymmetry 14 (2003) 3955–3963
3959
D
-glyceraldehyde derivative 1 (2 g, 15.3 mmol) in iso-
3.41–3.55 (m, 2H, –OTHP); 3.74–4.35 (m, 12H); 4.49–
4.62 (m, 1H); 4.72, 4.79 (2×s, 2H); 5.42 (d, 1H, J2,3 5.5
Hz, H-2); 5.75 (d, 1H, J2,3 3.8 Hz, H-2). lC (75.3 MHz,
CDCl3): 13.80, 13.85 (2×q, 2×–CH3); 19.30, 19.42 (2×t,
2×–CH2); 24.82 (2×q, 2×–CH3); 24.93, 24.98 (2×t, 2×–
CH2–); 26.27, 26.42 (2×t, 2×–CH3); 30.58, 30.67 (2×t,
2×–CH2–); 62.89, 62.99, 63.15, 63.22, 66.55, 66.58 (6×t,
6×–CH2–); 74.40, 74.57, 77.32, 78.20, 89.11, 89.33 (6×d,
6×–CH–); 100.71, 101.80 (2×d, 2×–CH–); 109.67,
109.92 (2×s, 2×–C–); 162.47, 162.69 (2×s, 2×–CꢁO). m/z
(%): 332 (M+−15, 1.7); 248 (5); 158 (5); 101 (51); 85
(100).
propanol (80 mL) and the resulting mixture was stirred
at room temperature for 24 h. The solvent was evapo-
rated in vacuo, the resulting residue dissolved in ethyl
ether (100 mL), and the solution was washed with water
(20 mL), dried and evaporated to dryness. The resulting
oil was purified by flash column chromatography (ethyl
acetate/hexane 2:7) to give a 6:5 mixture of nitropropi-
onic acid ethyl esters 2+3 (0.89 g, 45%), which showed
the following spectroscopic properties: wmax (NaCl,
cm−1): 3502 (–OH); 1753 (–CꢁO); 1565, 1375 (–NO2).
lH (300 MHz, CDCl3): 1.33–1.44 (m, 18H, 4×–CH3,
2×–OCH2CH6 3); 4.02–4.43 (m, 12H); 5.48 (d, 1H, J2,3
1.2 Hz, H-2); 5.49 (d, 1H, J2,3 2.4 Hz, H-2). lC (75.3
MHz, CDCl3): 13.83, 13.86 (2×q, 2×–CH3); 24.81, 24.88
(2×q, 2×–CH3); 26.77, 26.88 (2×q, 2×–CH3); 63.34,
63.49 (2×t, 2×–CH2–); 67.15, 67.32 (2×t, 2×–CH2–);
72.36, 72.87 (2×d, 2×–CH–); 74.66 (2×d, 2×–CH–);
87.87, 88.08 (2×d, –CH–); 110.35, 110.43 (2×s, 2×–C–);
163.01, 163.27 (2×s, 2×–CꢁO). m/z (%): 248 (M+−15,
42); 218 (2); 142 (9); 101 (100). HRMS: calcd for
C9H14NO7 (M+) 248.0770; found 248.0766. Dm=4×
10−4.
4.3. (3S)-2-Amino-3-{(4R)-2,2-dimethyl-[1,3]dioxolan-4-
yl}-3-(tetrahydropyran-2-yloxy)propionic acid ethyl
ester 6a–d
Raney nickel (50% in water) (0.5 mL) was added to a
deoxygenated solution of propionic acid ethyl esters
4+5 (2.14 g, 6.18 mmol) in methanol (150 mL) and the
suspension was stirred at room temperature under a
hydrogen atmosphere for 5 h. The reaction mixture was
then filtered through a Celite plug, which was eluted
with methanol. The filtrate was evaporated in vacuo to
give a mixture of polyoxamic acid ethyl esters 6a–d as a
clear gum. The mixture was used without purification.
4.2. (3S)-3-{(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl}-2-
nitro-3-(tetrahydropyran-2-yloxy)propionic acid ethyl
ester 4+5
4.3.1. Spectroscopic data for the mixture 6a–d. wmax
(NaCl, cm−1): 3391 (–NH2); 1731 (–CꢁO). m/z (%, CI):
318 [(M+H)+, 23]; 316 [(M−H)+, 1.2]; 302 (35); 244 (69);
218 (100). HRMS: calcd for C15H27NO6 (M+H)+
318.1995; found 318.1999.
DHP (1.9 mL, 20.8 mmol) and PPTS (0.42 g, 1.67
mmol) were added to a solution of 2-nitropropionic
acid ethyl esters 2+3 (2.18 g, 8.28 mmol) in dry
dichloromethane (70 mL) and the resulting mixture was
stirred at room temperature under argon for 14 h. Ethyl
ether (90 mL) was then added and the mixture was
washed with saturated aqueous sodium chloride solu-
tion (90 mL), dried and evaporated in vacuo. Flash
column chromatography (ethyl acetate/hexane 2:7) of
the resulting residue gave two diastereomeric mixtures
of pentanoic acid ethyl esters (4+5) (2.32 g, 80%) (mix-
ture 1 and mixture 2), which showed the following
spectroscopic properties.
Careful flash column chromatography (CH2Cl2/
methanol 98:2) of a small fraction of the mixture 6a–d
led to the isolation of small pure fractions of amino
acid esters 6a, 6b, 6c and 6d, which showed the follow-
ing spectroscopic data.
4.3.2. Amino acid ester 6a. [h]2D2=+89.4 (c 1.8, chloro-
form). lH (300 MHz, CDCl3): 1.28 (t, 3H, J 7.1 Hz,
–OCH2CH6 3); 1.33, 1.42 (2×s, 6H, 2×–CH3); 1.45–1.75
4.2.1. Spectroscopic data for mixture 1. wmax (NaCl,
cm−1): 1742 (–CꢁO); 1562, 1374 (–NO2). lH (300 MHz,
CDCl3): 1.30–1.76 (m, 30H, 6×–CH3, 6×–CH2–OTHP);
3.51–3.58 (m, 2H, –OTHP); 3.84–3.92 (m, 2H,
–OTHP); 4.10–4.36 (m, 10H); 4.43–4.51 (m, 2H); 4.69
(dd, 1H, J3,4 3.0 Hz, J4,5 5.5 Hz, H-4); 4.86 (dd, 1H, J3,4
2.5 Hz, J4,5 5.9 Hz, H-4); 5.48 (d, 1H, J2,3 5.4 Hz, H-2);
5.63 (d, 1H, J2,3 2.1 Hz, H-2). lC (75.3 MHz, CDCl3):
13.80, 14.01 (2×q, 2×–CH3); 20.08, 20.26 (2×t, 2×–CH2–
); 24.93 (2×t, 2×–CH3); 25.04 (2×d, 2×–CH2–) 26.36,
26.74 (2×q, 2×–CH3); 30.77, 30.85 (2×t, 2×–CH2–);
62.85, 62.99, 63.96, 64.19, 67.44, 67.60 (6×t, 6×–CH2–);
74.55, 75.19, 77.24, 77.65, 88.74, 89.07 (6×d, 6×–CH–);
100.50, 101.54 (2×d, 2×–CH–); 109.96, 110.03 (2×s,
2×–C–); 162.65, 162.86 (2×s, 2×–CꢁO). m/z (%): 332
(M+−15, 1.7); 248 (5); 158 (5); 101 (51); 85 (100).
(m, 6H, 3×–CH2–OTHP); 3.06 (bs, 2H, –NH2); 3.39–
3.44 (m, 1H); 3.83 (s, 1H); 3.85 (s, 1H); 4.06–4.22 (m,
6H); 4.40 (s, 1H). lC (75.3 MHz, CDCl3): 14.21 (q,
–CH3); 20.19, 25.06 (2×t, 2×–CH2–); 25.14, 26.93 (2×q,
2×–CH3); 30.97 (t, –CH2–); 54.74 (d, –CH–); 61.33,
63.08, 67.46 (3×t, 3×–CH2–); 74.44, 79.36 (2×d, 2×–
CH–); 100.18 (d, –CH–); 109.43 (s, –C–); 174.05 (s,
–CꢁO).
4.3.3. Amino acid ester 6b. [h]2D4=+6.5 (c 1.0, chloro-
form). lH (300 MHz, CDCl3): 1.24–1.28 (m, 6H, 2×–
CH3); 1.32 (s, 3H, –CH3); 1.42–1.72 (m, 6H,
3×–CH2–OTHP); 3.11 (bs, 2H, –NH2); 3.48–3.51 (m,
1H); 3.83–4.00 (m, 2H); 4.03–4.25 (m, 6H); 4.69 (s, 1H).
lC (75.3 MHz, CDCl3): 14.11 (q, –CH3); 20.05 (t,
–CH2–); 25.09 (q, –CH3); 25.14 (t, –CH2–); 26.34 (q,
–CH3); 30.93 (t, –CH2–); 55.24 (d, –CH–); 61.18, 63.61,
67.72 (3×t, 3×–CH2–); 73.75, 78.95 (2×d, 2×–CH–);
98.06 (d, –CH–); 109.38 (s, –C–); 171.72 (s, –CꢁO).
4.2.2. Spectroscopic data for mixture 2. wmax (NaCl,
cm−1): 1742 (–CꢁO); 1562, 1374 (–NO2). lH (300 MHz,
CDCl3): 1.29–1.72 (m, 30H, 6×–CH3, 6×–CH2–OTHP);

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R. G. Soengas et al. / Tetrahedron: Asymmetry 14 (2003) 3955–3963
4.3.4. Amino acid ester 6c. [h]2D4=−17.7 (c 1.5, acetone).
lH (300 MHz, CDCl3): 1.21–1.72 (m, 15H, 3×–CH3,
3×–CH2–OTHP); 3.32 (bs, 2H, –NH2); 3.29–3.33 (m,
1H); 3.60 (s, 1H); 4.70–4.23 (m, 7H); 4.53 (s, 1H). lC
(75.3 MHz, CDCl3): 14.11 (q, –CH3); 20.39, 24.96 (2×t,
2×–CH2–); 25.22, 26.79 (2×q, 2×–CH3); 30.93 (t, –CH2–
); 55.29 (d, –CH–); 61.10, 63.72, 66.49 (3×t, 3×–CH2–);
75.77, 79.60 (2×d, 2×–CH–); 101.42 (d, –CH–); 108.96
(s, –C–); 174.03 (s, –CꢁO).
4.5.1. Spectroscopic data for compound 8a. wmax (NaCl,
cm−1): 3399 (–OH, –NH–); 1776 (CꢁO); 1703 (CꢁO). lH
(250 MHz, MeOD): 3.70, 3.72 (2×s, 2H); 4.28–4.32 (m,
2H); 4.80 (d, 1H, J2,3 5.7 Hz, H-2); 5.05 (s, 2H,
–OCH2Ph); 7.23–7.29 (m, 5H, 5×Ar–H). lC (75.4 MHz,
MeOD): 55.87 (d, –CH–); 62.55, 68.21 (2×t, 2×–CH2–);
70.68 (d, –CH–); 73.03 (d, –CH–); 129.17, 129.25,
129.67 (5×d, 5×–CH–); 138.19 (s, –C–); 159.06 (s, CꢁO);
177.12 (s, CꢁO). m/z (%, CI): 282 [(M+H)+, 10]; 264
(13); 238 (21); 91 (100). HRMS (FAB): calcd for
C13H15NO6, 281.0899. Found, 281.0897. Dm=2×10−4.
4.3.5. Amino acid ester 6d. [h]2D4=−48.9 (c 1.6, chloro-
form). lH (300 MHz, CDCl3): 1.25 (t, 3H, J 7.2 Hz,
–OCH2CH3); 1.28, 1.33 (2×s, 6H, 2×–CH3); 1.48–1.75
(m, 6H, 3×–CH2–OTHP); 2.40 (bs, 2H, –NH2); 3.48–
3.52 (m, 1H); 3.81–4.26 (m, 8H); 4.65 (s, 1H). lC (75.3
MHz, CDCl3): 14.13 (q, –CH3); 20.14, 25.09 (2×t, 2×–
CH2–); 25.11, 26.45 (2×q, 2×–CH3); 31.03 (t, –CH2–);
56.36 (d, –CH–); 61.00, 63.74, 66.55 (2×t, 3×–CH2–);
74.58, 81.80 (2×d, 2×–CH–); 101.67 (d, –CH–); 109.03
(s, –C–); 172.21 (s, –CꢁO).
4.5.2. Spectroscopic data for the diastereoisomeric mix-
ture 9a–d. wmax (NaCl, cm−1): 3397 (–OH, –NH–); 1767
(CꢁO); 1709 (CꢁO). lH (300 MHz, CDCl3): 1.26–1.75
(m, 12H, 6×–CH2–OTHP); 3.52–4.47 (m, 12H); 4.67–
4.78 (m, 4H); 5.16 (s, 4H, 2×–OCH2Ph); 5.69 (bs, 2H,
2×–NH–); 7.38 (s, 10H, 10×Ar-H). lC (75.3 MHz,
CDCl3): 19.01, 19.14, 25.05, 25.22, 30.19, 30.22 (6×t,
6×–CH2–); 59.48 (2×d, 2×–CH–); 62.02, 62.15, 64.34,
65.50, 67.70, 67.90 (6×t, 6×–CH2–); 74.04, 74.33 (2×d,
2×–CH–); 81.45, 81.56 (2×d, 2×–CH–); 98.97 (2×d,
2×–CH–); 128.21, 128.57, 128.68 (5×d, 5×Ar-H); 135.42
(2×s, 2×–C–); 171.04, 171.14 (2×s, 2×–CꢁO). m/z (%,
FAB): 366 [(M+H)+, 25]; 282 (100). HRMS (FAB):
calcd for C18H24NO7 (M+H)+, 366.1553. found,
366.1561. Dm=8×10−4.
4.4. (3S)-2-Benzyloxycarbonylamino-3-{(4R)-2,2-
dimethyl-[1,3]dioxolan-4-yl}-3-(tetrahydropyran-2-
yloxy)propionic acid ethyl ester 7a–d
Saturated sodium bicarbonate solution (38 mL) was
added to a solution of polyoxamic acid ethyl esters
6a–d in ethyl acetate (90 mL). The solution was then
cooled to 0°C, benzyl chloroformate (1.3 mL, 9.27
mmol) was added and the reaction was stirred at room
temperature for 2 h. The organic layer was separated
and the aqueous phase was extracted with ethyl acetate
(3×80 mL). The combined organic layers were washed
with saturated sodium chloride solution (100 mL),
dried and concentrated to dryness. The residue was
purified by flash column chromatography (ethyl ace-
tate/hexane 1:4) to give a mixture 2-benzyloxycarbonyl-
amino pentanoic acid ethyl esters 7a–d (2.56 g, 92%) as
a yellow oil, which showed the following spectroscopic
properties: wmax (NaCl, cm−1): 3040 (–NH–); 1748, 1709
(2×–CꢁO). lH (300 MHz, CDCl3): 1.22–1.75 (m, 15H,
3×–CH3, 3×–CH2–OTHP); 3.53–3.57 (m, 1H, –OTHP);
3.75–4.40 (m, 7H); 5.14, 5.15 (2×s, 2H, –CH2Ph); 7.34–
7.38 (m, 5H, 5×ArH). m/z (%): 352 (M+−99, 0.5); 266
(2); 237 (9); 176 (6); 131 (4); 91 (100); 85 (88).
4.6. (4S,5R)-(4-Hydroxy-5-hydroxymethyl-2-oxo-tetra-
hydrofuran-3-yl)carbamic acid benzyl ester 8a–b
A solution of lactones 9a–d (0.14 g, 0.39 mmol) and
pyridinium p-toluenesulfonate (0.02 g, 0.08 mmol) in
ethanol (13 mL) was heated at 50°C for 10 h. The
ethanol was evaporated and the residue submitted to
flash column chromatography (dichloromethane/
methanol, 95:5) to give lactones 8a–b (44 mg, 40%) as a
clear gum.
4.7. (4S,5R)-[4-Hydroxy-2-oxo-5-(tetrahydropyran-2-
yloxymethyl)tetrahydrofuran-3-yl]carbamic acid benzyl
esters 9a–b
PPTS (36 mg, 0.14 mmol) and DHP (0.05 mL, 0.52
mmol) were added to a solution of lactones 8a–b (0.10
g, 0.35 mmol) in dichloromethane (3 mL). The mixture
was stirred at room temperature for 3 d, concentrated
to dryness and the residue was submitted to flash
column chromatography (hexane/ethyl acetate 1:1 and
then dichloromethane/methanol 95:5) to give a mixture
of lactones 9a–d (49 mg, 89% calculated on the basis of
recovered starting material).
4.5. (4S,5R)-(4-Hydroxy-5-hydroxymethyl-2-oxo-tetra-
hydrofuran-3-yl)carbamic acid benzyl esters 8a–b and
(4S,5R)-[4-hydroxy-2-oxo-5-(tetrahydropyran-2-
yloxymethyl)tetrahydrofuran-3-yl]carbamic acid benzyl
esters 9a–d
A solution of 2-benzyloxycarbonylaminopentanoic acid
ethyl esters 7a–d (1.75 g, 3.87 mmol) in a mixture of
THF/trifluoroacetic acid/water 6:6:1 was stirred at
room temperature for 3 h. The mixture was evaporated
in vacuo, coevaporated with toluene (3×6 mL) and the
resulting residue was purified by flash column chro-
matography (ethyl acetate/hexane 1:1 and then
dichloromethane/methanol 10:0.6) to give a mixture of
lactones 8a–b (0.3 g, 28%) and a mixture of 5-(tetra-
hydropyran-2-yloxymethyl)lactones 9a–d (0.59 g, 42%).
4.8. (4S,5R)-Toluene-4-sulfonic acid 4-benzyloxycar-
bonylamino-3-hydroxy-5-oxo-tetrahydrofuran-2-yl
methyl ester 10a+11a
A mixture of lactones 8a–b (0.31 g, 1.09 mmol) and
molecular sieves (0.65 g) in dry pyridine (5 mL) was
cooled to −20°C and tosyl chloride (0.23 g, 1.20 mmol)
was added. The resulting mixture was stirred at −20°C
for 20 h and then filtered through Celite. The filtrate
was
concentrated
to
dryness,
dissolved
in

R. G. Soengas et al. / Tetrahedron: Asymmetry 14 (2003) 3955–3963
3961
dichloromethane (30 mL) and the solution washed with
saturated aqueous copper sulfate (30 mL). The aqueous
phase was extracted with dichloromethane (2×20 mL)
and the combined organic layers were washed with
water (2×20 mL), dried, filtered and evaporated in
vacuo. The residue was submitted to flash column
chromatography (ethyl acetate/hexane 4:5) to give an
epimeric mixture of lactones 10a+11a (0.32 g, 70%).
wmax (NaCl, cm−1): 1769, 1737 (2×–CꢁO). lH (300 MHz,
CDCl3): 2.04, 2.44 (2×s, 6H, 2×–CH3); 4.07–4.73 (m,
8H); 5.12 (s, 4H, 2×–OCH2Ph); 5.56–5.70 (m, 2H,
2×H-2); 7.33–7.79 (m, 14H, 14×Ar-H) lC (75.3 MHz,
CDCl3): 21.36 (2×q, 2×–CH3); 53.39, 58.29 (2×s, 2×–
CH–); 66.81, 67.31, 67.85 (4×t, 4×–CH2–); 68.41, 72.06,
78.62, 82.71 (4×d, 4×–CH–); 128.00, 128.06, 129.84,
129.95 (8×d, 8×–CH–); 131.27, 131.59 (2×s, 2×–C–);
135.39, 135.53 (2×s, 2×–C–); 145.28, 145.48 (2×s, 2×–
C–); 156.57, 156.77 (2×s, 2×CꢁO); 170.83, 173.57 (2×s,
2×–CꢁO). m/z (%, CI): 436 [(M+H)+, 6]; 392 (14); 173
(100); 91 (79). HRMS (CI): C20H22NO8S (M+H)+, calcd
436.1066; found 436.1066.
dichloromethane (20 mL) and the solution was washed
with saturated aqueous copper sulfate (20 mL). The
aqueous phase was extracted with dichloromethane (2×
20 mL) and the combined organic layers were washed
with saturated aqueous copper sulfate (1×20 mL) and
water (2×20 mL), dried, filtered and evaporated in
vacuo. The residue was submitted to flash column
chromatography (ethyl acetate/hexane 1:3) to give lac-
tones 17a–b (0.28 g, 83% yield) as a clear oil. wmax
(NaCl): 1769, 1737 (2×CꢁO). lH (250 MHz, CDCl3):
1.43–1.80 (m, 12H); 3.49–3.97 (m, 8H); 4.63–4.68 (m,
2H); 5.18 (s, 2H); 5.20 (s, 4H, 2×–OCH2Ph); 7.12, 7.14
(2×bs, 4H, 2×H-3, 2×–NH–); 7.32–7.38 (m, 10H, 10×
Ar–H). lC (62.8 MHz, CDCl3): 18.73, 18.79, 25.09,
30.00, 30.04 (6×t, 6×–CH2–); 61.70, 61.80, 67.09, 67.59,
67.69 (6×t, 6×–CH2–); 80.16, 80.80 (2×d, 2×–CH–);
98.60, 98.78 (2×d, 2×–CH–); 123.38, 123.97 (2×–CH–);
126.79, 126.94 (2×–CH–); 128.05, 128.39, 128.48 (10×d,
10×–CH–); 135.19 (2×s, 2×–C–); 152.90 (2×s, 2×CꢁO);
168.77, 168.83 (2×s, 2×CꢁO). m/z (%): 347 (M+, 2); 245
(1); 233 (3); 91 (69); 85 (100).
4.9. (2S,3S,4R)-3,4-Dihydroxypyrrolidine-2-carboxylic
acid 14 and (2R,3S,4R)-3,4-dihydroxypyrrolidine-2-car-
boxylic acid 15
4.11. (3E,5S)-(5-Hydroxymethyl-2-oxo-2,5-dihydro-
furan-3-yl)carbamic acid benzyl ester 18a
A solution of lactones 17a–b (0.24 g, 0.68 mmol) and
pyridinium p-toluenesulfonate (34 mg, 0.14 mmol) in
ethanol (23 mL) was heated at 50°C for 9 h. The
solvent was evaporated to dryness and the resulting
residue was submitted to flash column chromatography
(ethyl acetate/hexane 4:5) to give lactone 18a (0.16 g,
86%) as a white solid. Mp 109–113°C (ethyl acetate).
[h]D23=+21.4 (c 1.0, methanol). wmax (NaCl, cm−1): 3422
(–OH); 1765, 1736 (–CꢁO). lH (500 MHz, MeOD): 3.69
(dd, 1H, J6,6% 12.3 Hz, J5,6 4.8 Hz, H-6); 3.89 (dd, 1H,
J6,6% 12.3 Hz, J5,6% 3.5 Hz, H-6%); 5.11–5.13 (m, 1H, H-5);
5.24 (s, 2H, –OCH2Ph); 7.16 (bs, 1H, H-4); 7.35–7.48
(m, 5H, H–Ph). lC (75.4 MHz, MeOD); 63.43, 68.48
(2×–CH2–); 83.87 (C-5); 126.08 (C-4); 129.37, 129.49,
129.75 (5×–CH–, C-3); 135.77 (–CPh); 155.70 (–NH–
CꢁO); 170.89 (CꢁO). m/z (%, CI): 264 [(M+H)+, 4]; 263
(M+, 0.2); 220 (5); 188 (2); 91 (100). Anal. calcd for
C13H13NO5: C, 59.31; H: 4.98; N, 5.32. Found: C,
58.96; H: 4.72; N, 5.16.
Pd/C (10%) (13 mg) and concentrated hydrochloric acid
solution (2 drops) were added to a deoxygenated solu-
tion of lactones 10a+11a (0.13 g, 0.31 mmol) in diox-
ane/water (1:1) (4 mL). The resulting mixture was
stirred at room temperature under hydrogen (1 atm.)
for 3 h. The reaction mixture was filtered through
Celite, the filtrate was evaporated to dryness and the
residue dissolved in water (10 mL). Barium hydroxide
(0.16 g) was added and the resulting mixture was stirred
at room temperature for 3 h. The reaction mixture was
acidified with Amberlite 120-IR up to pH 1, stirred at
room temperature for 24 h, filtered and the resin was
washed with water until the filtrate was inactive to the
addition of aqueous silver nitrate solution. The resin
was stirred with a solution of ammonium hydroxide 1
N (30 mL) for 3 h, filtered and the filtrate evaporated
to dryness to give an epimeric mixture of 3,4-dihydroxy-
prolines 14 and 15 (31 mg, 68%) as an amorphous
solid. wmax (NaCl, cm−1): 3326, 3249, 3131 (–OH);1623
(–CꢁO). lH (250 MHz, D2O): 3.07–3.12 (m, 2H, 2×H-
5); 3.36–4.54 (m, 2H, 2×H-5%); 3.76 (d, 1H, J2,3 5.0 Hz,
H-2); 4.02 (d, 1H, J2,3 2.0 Hz, H-2); 4.18–4.33 (m, 4H,
2×H-3, 2×H-4). lC (62.8 MHz, D2O): 49.52, 51.14 (2×t,
2×–CH2–); 66.98, 67.20 (2×d, 2×–CH–); 72.80, 73.44
(2×d, 2×–CH–); 73.13, 77.01 (2×d, 2×–CH–); 173.48,
175.80 (2×s, 2×–CꢁO). m/z (%, FAB): 148 [(M+H)+, 3];
132 (2); 114 (7).
4.12. (2S,4S)-2-Amino-4,5-dihydroxypentanoic acid 19
Pd/C (10%) (10 mg) was added over a deoxygenated
solution of lactone 18a (82 mg, 0.31 mmol) in acetic
acid (3 mL) and the resulting mixture was stirred at
room temperature under hydrogen (1 atm.) for 12 h.
The reaction was filtered through Celite, the filtrate was
evaporated to dryness, the residue was dissolved in
water (10 mL) and barium hydroxide (0.16 g) was
added. The resulting mixture was stirred at room tem-
perature for 3 h, acidified to pH 1 with Amberlite
120-IR, stirred at room temperature for 24 h and
filtered. The resin was washed with water until the
filtrate was inactive to the addition of aqueous silver
nitrate solution. The residue was stirred with a 1N
solution of ammonium hydroxide (30 mL) for 3 h,
filtered and the filtrate evaporated to dryness to give
pentanoic acid 19 (29 mg, 63%) as an amorphous solid.
4.10. (3E,5S)-[2-Oxo-5-(tetrahydropyran-2-yloxy-
methyl)-2,5-dihydrofuran-3-yl]carbamic acid benzyl ester
17a–b
Methanesulfonyl chloride (0.16 mL, 1.91 mmol) was
added to a solution of lactones 9a–d (0.35 g, 0.96
mmol) in dry pyridine (4 mL) and the resulting mixture
was stirred at 0°C under argon for 2 h. The pyridine
was evaporated to dryness, the residue was dissolved in

3962
R. G. Soengas et al. / Tetrahedron: Asymmetry 14 (2003) 3955–3963
[h]2D3=−19.5 (c 1.7, water). wmax (NaCl): 3449 (–OH);
2536 (COO–H), 1627 (–CꢁO). lH (250 MHz, D2O):
1.83–1.87 (m, 2H); 3.33–3.49 (m, 2H); 3.69–3.79 (m,
2H). lC (62.8 MHz, D2O); 33.14 (–CH2–); 53.09 (–CH–
); 65.79 (–CH2–); 69.39 (–CH–); 175.32 (–CO2H). m/z
(%, FAB): 150 [(M+H)+, 4], 185 (glycerol, 100).
4.15.
(1S,4R,7R)-[7-(tert-Butyldimethylsilanyloxy)-6-
oxo-2,5-dioxabicyclo[2.2.1]hept-1-yl]carbamic acid ben-
zyl ester 23
A solution of lactones 21a–b (0.22 mg, 0.55 mmol) in
acetonitrile (45 mL) was deoxygenated by bubbling
argon through for 10 min. Ammonium acetate (0.22
mg, 1.65 mmol) and N-bromosuccinimide (0.26 g, 0.48
mmol) were added. The reaction mixture was stirred at
room temperature under argon for 24 h and filtered
through a Celite plug. The filtrate was dried and evapo-
rated in vacuo. The residue was submitted to flash
column chromatography (ethyl acetate/hexane 1:5) to
give the bicyclic lactone 23 (91 mg, 42%) as an amor-
phous solid. [h]D23=−44.4 (c 0.9, chloroform). wmax
(NaCl): 3344 (–NH); 1799 (CꢁO), 1740 (CꢁO). lH (500
MHz, CDCl3): 0.02, 0.09 (2×s, 6H, –SiMe2), 0.83 (s,
9H, –SitBu), 3.87 (d, 1H, J3,3% 9.2 Hz, H-3), 4.27–4.29
(m, 1H, H-3%), 4.75 (s, 1H, H7), 5.09–5.18 (m, 3H, H4
and –CH2–Ph), 5.89 (bs, 1H, –NH), 7.32–7.37 (s, 5H,
5×Ar–H). lC (300 MHz, CDCl3); −4.75, −5.25 (2×q,
2×–CH3, –SiMe2), 25.36 (q, 3×CH3, –SitBu), 54.06 (d,
–CH–), 61.67, 67.44 (2×t, 2×–CH2–), 70.63 (d, –CH–),
86.88 (d, C-2), 128.13, 128.24, 128.59 (3×d, 5×–CH–,
HC–Ph), 135.94 (s, 2×–CPh), 156.24 (s, –CꢁO), 174.50
(s, –CꢁO). m/z (%, CI): 394 [(M+H)+, 0.2]; 350 (0.3),
205 (1), 149 (4), 119 (3), 91 (100). HRMS (CI):
C19H27NO6Si (M+H)+, calcd 394.1686; found 394.1687.
4.13. (4S,5R)-[4-(tert-Butyldimethylsilanyloxy)-2-oxo-5-
(tetrahydropyran-2-yloxymethyl)tetrahydrofuran-3-yl]-
carbamic acid benzyl esters 20a–d
tert-Butyldimethylsilyl chloride (1.08 g, 7.15 mmol) was
added to a solution of lactones 9a–d (0.76 g, 2.1 mmol)
and imidazole (0.76 g, 11.19 mmol) in dry DMF (20
mL). and the mixture was stirred at room temperature
for 60 h. The solvent was removed in vacuo and the
residue was dissolved in chloroform (100 mL), washed
with water (2×60 mL) and with saturated aqueous
sodium chloride (60 mL). The organic layer was dried
with magnesium sulfate, filtered and evaporated in
vacuo. The residue was purified by flash column chro-
matography (ethyl acetate/hexane, 2:9) to give a mix-
ture of diastereomeric lactones 20a–d (0.79 mg, 80%) as
clear gum. wmax (NaCl): 1726 (CꢁO). lH (300 MHz,
CDCl3): 0.06, 0.07 (2×s, 6H, –SiMe2), 0.88 (s, 9H,
–SitBu), 1.59–1.76 (m, 6H, 3×–CH2–OTHP), 3.52–4.04
(m, 4H), 4.32–4.71 (m, 3H), 4.91–5.41 (s, 3H,
–OCH2Ph), 7.36 (s, 5H, 5×Ar–H).
4.16.
(2S,3R,4R)-2-Benzyloxycarbonylamino-3-(tert-
butyldimethylsilanyloxy)-4-hydroxytetrahydrofuran-2-
carboxylic acid methyl ester 24
4.14.
(4S,5R)-[4-(tert-Butyldimethylsilanyloxy)-5-
hydroxymethyl-2-oxo-tetrahydrofuran-3-yl]carbamic acid
benzyl esters 21a–b
A mixture of acetyl chloride (0.05 mL) and methanol (5
mL) was stirred at room temperature for 20 min. The
resulting solution was added to lactone 23 (71 mg, 0.18
mmol) and the mixture was stirred at room temperature
overnight. The clear solution was neutralized with solid
sodium bicarbonate, preabsorbed onto silica gel and
purified by flash column chromatography (ethyl ace-
tate/hexane 1:3) to give amino acid derivative 24 (39
mg, 51%) as a yellow oil. [h]2D1=−30.4 (c 1.6, chloro-
form). wmax (NaCl): 3431 (–OH), 1785, 1735 (2×–CꢁO).
lH (400 MHz, CDCl3): 0.06, 0.10 (2×s, 6H, –SiMe2),
0.83 (s, 9H, –SitBu), 3.35 (s, 3H, –OMe), 3.84–3.87 (m,
2H, H-5, H-5%), 4.33–4.34 (m, 1H, H-4), 4.45 (d, 1H,
J3,4 2.2 Hz, H-3), 5.06–5.14 (m, 2H, –OCH2Ph), 5.65
(bs, 1H, –NH), 7.30–7.34 (m, 5H, Ar–H). lC (300 MHz,
CDCl3); (50.2 MHz, Cl3CD): −5.21, −4.72 (–SiMe2),
17.76 [–SiC(CH3)3] 17.76 [–SiC(CH3)3], 51.38 (–OCH3),
61.46, 67.38 (2×–CH2–), 73.00 (–CH–), 86.01 (C-2),
86.87 (–CH–), 128.30, 128.41, 128.60 (5×–CH–, Ar–C),
135.57 (–C–, Ar–C), 153.95, 169.81 (2×CꢁO). m/z (%,
FAB): 426 [(M+H)+, 100], 395 (25), 394 (61), 350 (71).
HRMS (FAB): calcd for C20H32NO7Si (M+H)+:
426.1948. Found: 426.1944.
A solution of lactones 20a–d (0.35 g, 0.74 mmol) and
pyridinium p-toluenesulfonate (40 mg, 0.15 mmol) in
ethanol (25 mL) was heated at 50°C for 10 h. The
solvent was removed in vacuo and the resulting residue
was dissolved in dichloromethane (40 mL). The solu-
tion was washed with saturated aqueous sodium chlo-
ride (1×25 mL) and water (1×15 mL). The organic layer
was dried, filtered and evaporated in vacuo. The residue
was submitted to flash column chromatography (ethyl
acetate/hexane 4:9) to give an epimeric mixture of
lactones 21a–b (0.22 g, 75%) as a gum. [h]2D6=−2.0 (c
1.7, methanol). wmax (NaCl): 3444, 3363 (–OH, –NH–),
1788 (CꢁO), 1710 (–CꢁO). lH (300 MHz, CDCl3): 0.03,
0.05 (2×s, 6H, –SiMe2), 0.87 (s, 9H, –SitBu), 3.18 (bs,
1H, –OH), 3.79–3.93 (m, 2H, H-5, H-5%), 4.38 (s, 1H),
4.50 (d, 1H, J 4.7 Hz), 4.90–4.95 (m, 1H, H-2), 5.12,
5.15 (2×s, 2H, –OCH2Ph), 5.33 (d, 1H, J2,NH 8.9 Hz
–NH–), 7.35 (s, 5H, 5×Ar–H). lC (300 MHz, CDCl3);
−5.14, −4.99 (2×c, 2×–CH3, –SiMe2), 25.59 (q, 3×CH3,
–SitBu), 54.06 (d, –CH–), 61.67, 67.44 (2×t, 2×–CH2–),
70.63 (d, –CH–), 86.88 (d, –CH–), 128.13, 128.24,
128.59 (3×d, 5×–CH–, 5×Ar–H), 135.94 (2×s, 2×–C–),
156.24 (s, –CꢁO), 174.50 (s, –CꢁO). m/z (%): 338 (M+−
57, 4); 294 (1); 230 (2); 108 (2); 91 (100). m/z (FAB,%):
396 (M++H, 27), 379 (12), 352 (100). HRMS: calcd for
C19H30NO6Si (M+H)+ 396.1842; found 396.1847. Dm=
5×10−4.
4.17.
(2S,3R,4R)-2-Benzyloxycarbonylamino-3,4-di-
hydroxytetrahydrofuran-2-carboxylic acid methyl ester
25
A 1 M solution of Bu4NF in THF (1 mL, 1 mmol) was
added over a solution of amino acid ester 24 (30 mg,

R. G. Soengas et al. / Tetrahedron: Asymmetry 14 (2003) 3955–3963
3963
0.07 mmol) in dry THF (10 mL) and the resulting
solution was stirred at room temperature for 12 h. The
reaction mixture was evaporated in vacuo and the
residue submitted to flash column chromatography
(ethyl acetate/hexane 1:1), to give (2S,3R,4R)-2-benzyl-
oxycarbonylamino-3,4-dihydroxytetrahydrofuran-2-car-
boxylic acid methyl ester 25 (20 mg, 91% yield) as a
clear gum. [h]2D0=−12.4 (c 1, chloroform). wmax (NaCl):
3405 (–OH), 1789, 1732 (2×–CꢁO). lH (400 MHz,
CDCl3): 3.41 (s, 3H, –OMe), 3.85–3.87 (m, 2H, H-5,
H-5%), 4.31–4.34 (m, 1H, H-4), 4.53 (d, 1H, J3,4 2.1 Hz,
H-3), 5.06–5.14 (m, 2H, –OCH2Ph), 5.65 (bs, 1H,
–NH), 7.30–7.34 (m, 5H, Ar–H). HRMS (FAB): calcu-
lated for C14H17NO7 (M+H)+: 312.1083. Found:
312.1079.
6. Soengas, R. G.; Este´vez, J. C.; Este´vez, R. J.; Maestro,
M. A. Tetrahedron: Asymmetry 2003, 14, 1653.
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9. Hudson, C. B.; Roberston, A. V.; Simpson, R. J. Aust. J.
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10. (a) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2,
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23. For the previous synthesis of amino acid 25, see: Hanes-
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25. Ghosh, A. K.; Koltun, E. S.; Bilcer, G. Synthesis 2001,
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26. Perrin, D. D.; Armarego, W. L. F. Purification of Labo-
ratory Chemicals; Pergamon Press: New York, 1988.
Special thanks are due to Professor G. W. J. Fleet for
helpful discussions on this chemistry. We also thank the
Xunta de Galicia and the Spanish Ministry of Science
and Technology for financial support, and the latter for
a grant to Raquel G. Soengas.
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