Diastereoselective synthesis of protected 4-epi-vancosamine from (S)-N-Boc-N,O-isopropylidene-α-methylserinal

Article abstract of DOI:10.1016/S0957-4166(03)00119-8

An efficient diastereoselective synthesis of methyl N,O-dibenzoyl-L-4-epi-vancosamine is described. The key step involves Sharpless asymmetric dihydroxylation of a Z olefin derived from (S)-N-Boc-N,O-isopropylidene-α-methylserinal.

Full text of DOI:10.1016/S0957-4166(03)00119-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1037–1043
Diastereoselective synthesis of protected 4-epi-vancosamine from
(S)-N-Boc-N,O-isopropylidene-a-methylserinal
Alberto Avenoza,* Jesu´s H. Busto, Francisco Corzana, Jesu´s M. Peregrina,*
David Sucunza and Mar´ıa M. Zurbano
Departamento de Qu´ımica, Universidad de La Rioja, Grupo de S´ıntesis Qu´ımica de La Rioja, U.A.-C.S.I.C.,
26006 Logron˜o, Spain
Received 5 December 2002; accepted 28 January 2003
Abstract—An efficient diastereoselective synthesis of methyl N,O-dibenzoyl-L-4-epi-vancosamine is described. The key step
involves Sharpless asymmetric dihydroxylation of a Z olefin derived from (S)-N-Boc-N,O-isopropylidene-a-methylserinal. © 2003
Elsevier Science Ltd. All rights reserved.
1. Introduction
cocci (VRE) and methicillin-resistant Staphylococcus
aureus (MRSA) and are now undergoing clinical trials.5
The structure of vancomycin is shown in Fig. 1 and
consists of a disaccharide moiety (a glucose and a
vancosamine) attached to a rigid cyclic heptapeptide
framework aglycon. The structures of the vancomycin
derivatives previously mentioned are also shown.
During the last decade, glycopeptide antibiotics have
been the subject of intensive investigation.1 Two gly-
copeptide antibiotics, vancomycin and teicoplanin, are
in clinical use and are of great utility in the treatment of
infections by bacteria that are resistant to many other
classes of antibiotics. Indeed, vancomycin is considered
to be the last line of defense for many severe bacterial
infections.
Taking into account the importance of glycopeptide
antibiotics,6 and in order to construct combinatorial
libraries of vancomycin analogs for biological screen-
ing, the synthesis of vancosamine donors has been the
focus of many researchers. To this end, several stereose-
lective syntheses of protected vancosamines have been
described.7 Nevertheless, the synthesis of 4-epi-van-
cosamine derivatives has received little attention. In
fact, although some derivatives have been isolated from
several antibiotics,8 they have only been synthesized de
novo on a few occasions9 and these approaches have
involved three methodologies.10–12
However, resistance to vancomycin is unfortunately
now on the increase.2 Although the SAR of the gly-
copeptide antibiotics has been extensively studied,3 the
modifications necessary to improve the resistance situa-
tion are not clear. Because of this, many investigations
aimed at enhancing the activity of the vancomycin
group of glycopeptide antibiotics are in progress.4
In this sense, different vancomycin derivatives are cur-
rently under investigation; for example A82846B (van-
comycin plus one additional carbohydrate substituent:
4-epi-vancosamine) and LY333328 (a vancomycin
derivative that features both the chlorobiphenyl side
chain and the additional sugar substituent of A82846B)
are highly efficient against vancomycin-resistant entero-
2. Results and discussion
In this context, we wished to explore the chemistry of
our chiral building block (S)-N-Boc-N,O-isopropyli-
dene-a-methylserinal13 1 for the asymmetric synthesis of
suitably protected 4-epi-vancosamine. Our synthesis
started with the Wittig olefination of a-amino aldehyde
* Corresponding authors. Tel./fax: +34-941-299655; e-mail: alberto.
avenoza@dq.unirioja.es; jesusmanuel.peregrina@dq.unirioja.es
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00119-8

1038
A. A6enoza et al. / Tetrahedron: Asymmetry 14 (2003) 1037–1043
Scheme 1. Synthesis of olefin 2 by Wittig olefination of serinal
1.
Scheme 2. Reagents and conditions: (a) i. AD-mix-a,
MeSO2NH2, t-BuOH/H2O (1:1), 0°C, 12 h; (b) i. HClc./THF
(2:3), 25°C, 2 h, ii. Boc2O (1.3 equiv.), Na2CO3·10H2O (2.5
equiv.), H2O/THF (1:5), 25°C, 24 h, 79%; (c) i. HClc./THF (2:3),
25°C, 2 h, ii. CbzCl (1.3 equiv.), Na2CO3·10H2O (2.5 equiv.),
H2O/THF (1:5), 25°C, 24 h, 51%.
reasons the mixture of diols, without purification, was
transformed into compounds 3a and 4a (79% from olefin
2) by acid hydrolysis using hydrochloric acid and subse-
quenttreatmentofthecorrespondingaminoalcoholswith
Boc2O in the presence of sodium carbonate (Scheme 2).
Figure 1. Important glycopeptide antibiotics corresponding to
the vancomycin group.
1, using ethyltriphenylphosphonium bromide and potas-
sium bis(trimethylsilyl)amide (KHMDS) as base, to give
the olefin 2 in 91% yield (Scheme 1).
Compounds 3a and 4a were easily separated by column
chromatography and, in order to determine the absolute
configuration of their stereogenic centers by X-ray anal-
ysis, we attempted to crystallize them. Unfortunately,
monocrystals could not be obtained in this way so we
changed the carbamate group by hydrolyzing the mixture
of diols and treating the resulting material with CbzCl
in sodium carbonate to give compounds 3b and 4b
(Scheme 2). These compounds were separated by column
chromatography and a monocrystal of the minor com-
pound 3b could now be obtained and studied by X-ray
analysis, which showed the stereochemistry to be
1S,2S,3R. The stereochemistry of the major compound,
4a, is therefore 1S,2R,3S (Fig. 2).†
As one would expect in the Wittig reaction with non-sta-
bilized ylides,14 the stereochemistry of olefin 2 was
assigned as Z on the basis of the coupling constants
1
(Ja–b=11.1 Hz and 12.3 Hz) observed for the H NMR
signals corresponding to the vinylic protons Ha of the two
conformers that appear in solution as a result of the slow
interconversion around the N-Boc bond.15
Taking into account the Z stereochemistry of this olefin,
the best method to obtain the required diol of 1%R,2%S
configuration involved asymmetric cis-dihydroxylation
of olefin 2 (Scheme 2). However, when the dihydroxyla-
tion of 2 was carried out with RuO4 the reaction occurred
with low stereoselectivity (anti/syn=48/52, 86%).16 Given
this poor result, we decided to assess the double asymmet-
ric induction using the Sharpless asymmetric dihydroxy-
lation (AD)17 on this olefin. Nevertheless, the treatment
of olefin 2 with AD-mix-b gave the ‘mismatched pair’,
with poor stereoselectivity obtained once again (anti/
syn=51/49, 77%). Fortunately, the use of AD-mix-a
provided good stereoselection in favor of the syn diol
(anti/syn=20/80, 82%).
† Crystal data: C14 H21 N O5, Mw=283.32, colorless prism of 0.68×
0.25×0.22 mm, T=173(2) K, orthorhombic, space group P212121,
,
Z=4, a=6.1566(3), b=12.9469(7), c=18.8239(9) A, V=1500.43(13)
A , dcalcd=1.254 g cm−3, F(000)=608, u=0.71073 A (Mo, Ka),
v=0.095 mm−1, Nonius Kappa CCD diffractometer, q range 1.91–
27.89°, 5867 collected reflections, 3312 unique (Rint=0.0349), full-
matrix least-squares (SHELXL97a), R1=0.0530, wR2=0.1153,
(R1=0.0834, wR2=0.1319 all data), goodness of fit=1.043, residual
3
,
,
electron density between 0.237 and −0.220 e A−3. Hydrogen atoms
,
were located from mixed methods (electron-density maps and theo-
retical positions). Further details on the crystal structure are avail-
able on request from Cambridge Crystallographic Data Center, 12
Union Road, Cambridge, UK on quoting the depository number
198872. (a) Sheldrick, G. M. SHELXL97. Program for the refine-
ment of crystal structures. University of Go¨ttingen, Germany, 1997.
The anti and syn diols could not be separated by column
chromatography and all attempts to carry out selective
deprotection of their acetonide moiety failed. For these

A. A6enoza et al. / Tetrahedron: Asymmetry 14 (2003) 1037–1043
1039
Scheme 3. Reagents and conditions: (a) PivCl (1.1 equiv.),
TEA (1.1 equiv.), CH2Cl2, 25°C, 12 h, 65%; (b) MOMCl (3.0
equiv.), DIEA (3.0 equiv.), CH2Cl2, 25°C, 24 h, 88%; (c) i.
DMP (13.0 equiv.), p-TsOH (0.02 equiv.), toluene, reflux, 4 h,
ii. DIBAL-H (2.2 equiv.), CH2Cl2, −78°C, 12 h, 84%; (d) i.
Dess–Martin periodinane (1.5 equiv.), CH2Cl2, 25°C, 6 h, ii.
(Ph3P+Me)Br− (3.0 equiv.), KHMDS (3.0 equiv.), THF, 25°C,
15 h, iii. BH3–THF complex (2.0 equiv.), LiBH4 (0.3 equiv.),
THF, 25°C, 12 h, iv. H2O/20% NaOH/30% H2O2 (1:1:1),
25°C, 3 h, 67%.
Figure 2. ORTEP drawing (arbitrary numbering of the het-
eroatoms) of the molecular structure of compound 3b.
Once the major compound 4a had been separated, we
continued to explore a variety of protective groups to
orthogonally protect the three hydroxyl groups. It has
been reported that PivCl is an excellent reagent for
selective reaction with primary hydroxyl groups in the
presence of secondary ones.18 We therefore carried out
the reaction of triol 4a with PivCl (1.1 equiv.) using
triethylamine (TEA) as base. This reaction gave the
triol protected at the primary alcohol, i.e. compound 5
with excellent selectivity (Scheme 3).
The reagent selected to protect the two secondary alco-
hols was chloromethyl methyl ether (MOMCl), since
the MOM group is stable to the conditions required for
deprotection the Piv group.19 With this strategy in
mind, we investigated the reaction of diol 5 with
MOMCl (3.0 equiv.) in the presence of DIEA. This
reaction led to the formation of compound 6 in which,
curiously, only one hydroxyl group was protected. The
structure of this compound was determined by X-ray
analysis of a monocrystal obtained by crystallization
from chloroform/hexane (Fig. 3).‡
Figure 3. ORTEP drawing (arbitrary numbering of the het-
eroatoms) of the molecular structure of compound 6.
without prior purification, in order to deprotect the
primary alcohol and give alcohol 7 in an 84% yield
(Scheme 3).
Having established the structure of 6, the NH and OH
groups were protected simultaneously as the oxazo-
lidine by addition of 2,2-dimethoxypropane (DMP) and
catalytic amounts of p-TsOH under reflux. The result-
ing compound was treated with DIBAL-H at −78°C,
In order to synthesize the required 4-epi-vancosamine
skeleton from compound 7, we needed to increase the
chain length by one additional carbon. The transforma-
tion of the CH2OH group into the CH2CH2OH group
was investigated by several methods. The best results
were obtained upon using the following reaction
sequence: oxidation of the alcohol to the aldehyde
(Dess–Martin periodinane),20 followed by Wittig
methylenation of this aldehyde (methyltriphenylphos-
phonium bromide and KHMDS) and regioselective
hydroboration/oxidation of the terminal olefin to give
primary alcohol 8 (BH3–THF complex combined with
LiBH4 as a borane reagent followed by oxidation with
hydrogen peroxide and sodium hydroxide) (Scheme 3).
‡ Crystal data: (a) C18H35NO7, Mw=377.47, colorless prism of 0.63×
0.25×0.25 mm, T=298 K, monoclinic, space group P21, Z=2,
a=9.1497(3), b=10.0060(4), c=12.0612(6), i=100.5353(17)°, V=
3
1085.61(8) A , dcalcd=1.155 g cm−3, F(000)=412, u=0.71073 A
(Mo Ka), v=0.088 mm−1, Nonius Kappa CCD diffractometer, q
range 3.04–27.94°, 3992 unique reflections, full-matrix least-squares
(SHELXL97a), R1=0.0444, wR2=0.1132, (R1=0.0544, wR2=
0.1177 all data), goodness of fit=1.465, residual electron density
,
,
between 0.278 and -0.201 e A−3. Hydrogen atoms fitted at theoreti-
,
cal positions. Further details on the crystal structure are available
on request from Cambridge Crystallographic Data Center, 12
Union Road, Cambridge, UK on quoting the depository number
198873. (a) Sheldrick, G. M. SHELXL97. Program for the refine-
ment of crystal structures. University of Go¨ttingen, Germany, 1997.
Finally, suitably protected enantiomerically pure 4-epi-
vancosamine 9 was obtained from compound 8 in three
steps (Scheme 4). The first step involved oxidation of

1040
A. A6enoza et al. / Tetrahedron: Asymmetry 14 (2003) 1037–1043
(13C) and are reported in ppm downfield from TMS.
Mass spectra were obtained by electronic impact (EI)
and electrospray ionization (ESI).
4.1.1. (R)-(Z)-2,2,4-Trimethyl-4-propenyloxazolidine-3-
carboxylic acid tert-butyl ester, 2. Ethyltriphenylphos-
phonium bromide (4.63 g, 12.3 mmol) was suspended in
THF (60 mL) at 25°C and KHMDS (0.5 M in toluene,
24.7 mL, 12.3 mmol) was added. The resulting red
suspension was stirred at 25°C for 1 h. Then, it was
cooled to −78°C and a solution of aldehyde (S)-N-Boc-
Scheme 4. Reagents and conditions: (a) i. Dess–Martin period-
inane (1.5 equiv.), CH2Cl2, 25°C, 6 h, ii. 6N HCl/MeOH (2:3),
25°C, 3 h, iii. BzCl (4.0 equiv.), pyridine, 25°C, 20 h, 60%.
N,O-isopropylidene-a-methylserinal
1 (1.01 g, 4.2
mmol) in THF (20 mL) was added dropwise. The
cooling bath was removed, the mixture allowed to
reach rt over 2 h and then warmed to 35°C for a further
12 h. The reaction was quenched with MeOH (10 mL)
and the resulting mixture was poured into a solution of
saturated potassium sodium tartrate and water (1:1,
v/v, 75 mL). Extraction with ethyl ether (2×50 mL),
drying and evaporation of the solvent gave a pale oil
which was purified by flash chromatography (hex-
ane:ethyl acetate, 9.5:0.5) to give compound 2 as a
colorless liquid (0.97 g, 3.81 mmol); yield: 91%. [h]2D5=
the primary alcohol group of compound 8 to the alde-
hyde using the Dess–Martin periodinone. In the second
step, this aldehyde was treated with methanol in acidic
medium, in order to cleave the N,O-acetal, to hydrolyze
the N-Boc group to NH2, to recover the OH group
from the OMOM protecting group and to form the
corresponding arabino-hexose skeleton. The last step
involved the protection of the OH and NH2 groups
with benzoyl chloride in the presence of pyridine. In
this way, methyl N,O-dibenzoyl-4-epi-vancosamine was
obtained as a mixture of the two anomers 9a (a) and 9b
(b) in a 75:25 ratio from compound 8 with an overall
yield of 60% (11% from serinal 1). These anomers could
be separated by column chromatography.
1
−48.0 (c 1.28, CHCl3). H NMR (CDCl3): l 1.44–1.59
(m, 18H), 1.66 (d, 3H, J=7.2 Hz), 3.83–3.94 (m, 2H),
5.35–5.50 (m, 1H), 5.56, 5.72 (2d, 1H, J=11.1 Hz,
J=12.3 Hz). 13C NMR (CDCl3): l 14.0, 24.0, 24.8,
25.3, 25.7, 26.2, 27.5, 28.5, 62.9, 63.5, 74.8, 75.1, 79.5,
79.8, 94.1, 95.0, 123.5, 123.9, 134.2, 135.2, 151.3, 151.8.
MS (EI) (m/z)=41, 57, 140, 184, 255. ESI+ (m/z)=256.
Anal. calcd for C14H25NO3: C, 65.85; H, 9.87; N, 5.49.
Found: C, 65.53; H, 9.91; N, 5.52.
3. Conclusions
In summary, we have developed a diastereoselective
synthesis of an important C-branched sugar with an
amine-bearing C-3 quaternary center—i.e. the protected
4-epi-vancosamine 9—which will be used as a 4-epi-
vancosamine donor in order to construct different com-
binatorial libraries of vancomycin analogs for
4.1.2.
(1S,2S,3R)-(2,3-Dihydroxy-1-hydroxymethyl-1-
methylbutyl)carbamic acid tert-butyl ester, 3a and
(1S,2R,3S)-(2,3-dihydroxy-1-hydroxymethyl-1-methyl-
butyl)carbamic acid tert-butyl ester, 4a. A round-bot-
tomed flask was charged with tert-butylic alcohol (27
mL), water (27 mL), AD-mix-a (7.35 g) and methane-
sulfonamide (0.50 g). The mixture was stirred at rt until
both phases were clear, and then cooled to 0°C, where-
upon the inorganic salts partially precipitated. Olefin 2
(1.34 g, 5.25 mmol) was added and the heterogeneous
slurry was stirred vigorously at 0°C for 12 h. The
reaction was quenched at 0°C by addition of sodium
sulphite (7.88 g) and then stirred for 1 h. The reaction
mixture was extracted with ethyl acetate (3×30 mL) and
then dried and concentrated to give a mixture of both
diols (syn and anti ) with a diastereoselectivity of 4:1 in
favor of the diol syn. Without further purification the
mixture was dissolved in THF (15 mL) and concen-
trated HCl (10 mL) was added. The solution was stirred
at 25°C for 2 h. Then, HCl was removed to give the
corresponding mixture of amino alcohols, which were
dissolved in water/THF (1/5, 60 mL) and
Na2CO3·10H2O (3.76 g, 13.14 mmol) and Boc2O (1.42
g, 6.31 mmol) were added. The mixture was stirred at
25°C for 24 h and then, quenched with saturated
NH4Cl (20 mL) and extracted with ethyl acetate (3×30
mL). The combined organic layers were dried and
concentrated. The residue was purified by column chro-
biological screening. The
2,3,6-trideoxy-3-C-methyl-3-aminohexopyranose
epi-vancosamine or -eremosamine), has been prepared
L-arabino-hexose skeleton, L-
(L-4-
L
by Sharpless AD on a Z olefin derived from (S)-N-Boc-
N,O-isopropylidene-a-methylserinal followed by func-
tional group transformations.
4. Experimental
4.1. General procedures
Melting points are uncorrected. All the manipulations
with air-sensitive reagents were carried out under a dry
argon atmosphere using standard Schlenk techniques.
Solvents were purified according to standard proce-
dures. The chemical reagents were purchased from the
Aldrich Chemical Co. Analytical TLC was performed
using Polychrom SI F254 plates. Column chromatogra-
phy was performed using Kieselgel 60 (230–400 mesh).
Organic solutions were dried over anhydrous Na2SO4
and, when necessary, concentrated under reduced pres-
sure using a rotary evaporator. wmax (cm−1) of IR spec-
tra are given for the main absorption bands. NMR
spectra were recorded at 300 MHz (1H) and at 75 MHz

A. A6enoza et al. / Tetrahedron: Asymmetry 14 (2003) 1037–1043
1041
matography (hexane/ethyl acetate, 3:7) to give 3a (0.19
g, 0.77 mmol) as a white solid and the required diol 4a
(0.85 g, 3.42 mmol) as a white solid; yield of 4a: 62%.
Overall yield: 79%. Compound 3a: mp: 67°C. [h]2D5=
−2.4 (c 1.23, MeOH). 1H NMR (CDCl3): l 1.30 (s, 3H),
1.35 (d, 3H, J=6.3 Hz), 1.42 (s, 9H), 3.29 (m, 1H), 3.53
(d, 1H, J=12.0 Hz), 3.69 (d, 1H, J=12.0 Hz), 3.71–
3.81 (m, 1H), 4.78 (br s, 1H), 5.18 (br s, 1H), 5.55 (br
s, 1H). 13C NMR (CDCl3): l 20.5, 21.2, 28.2, 59.0, 68.4,
80.0, 80.3, 157.4. ESI+ (m/z)=250. Anal. calcd for
C11H23NO5: C, 52.99; H, 9.30; N, 5.62. Found: C,
52.82; H, 9.22; N, 5.60%. Compound 4a: mp: 74°C.
58.9, 66.9, 67.3, 68.5, 78.2, 128.0, 128.2, 128.5, 136.0,
156.7. ESI+ (m/z)=284. Anal. calcd for C14H21NO5: C,
59.35; H, 7.47; N, 4.94. Found: C, 59.25; H, 7.45; N,
4.92%.
4.1.4. (2%S,3%R,4%S)-2,2-Dimethylpropionic acid 2%-tert-
butoxycarbonylamino - 3%,4% - dihydroxy - 2% - methylpentyl
ester, 5. Triol 4a (1.22 g, 4.89 mmol) was dissolved in
dichloromethane (30 mL) and triethylamine (TEA)
(0.75 mL, 5.38 mmol) and pivaloyl chloride (0.66 mL,
5.38 mmol) were added at 25°C. The reaction was
stirred for 12 h and then, quenched with water (20 mL)
and extracted with ethyl acetate (40 mL). The organic
layer was dried and concentrated. The residue was
purified by column chromatography (hexane/ethyl acet-
ate, 3:2) to give compound 5 as a white solid (1.06 g,
3.18 mmol); yield: 65%. Mp: 129°C. [h]2D5=−2.5 (c 1.04,
1
[h]2D5=−1.3 (c 0.87, MeOH). H NMR (CDCl3): l 1.26–
1.28 (m, 6H), 1.40 (s, 9H), 3.62–3.88 (m, 5H), 4.25 (br
s, 1H), 4.62 (br s, 1H), 5.27 (br s, 1H). 13C NMR
(CDCl3): l 19.6, 20.1, 28.3, 58.8, 67.2, 68.5, 78.2, 80.2,
156.7. ESI+ (m/z)=250. Anal. calcd for C11H23NO5: C,
52.99; H, 9.30; N, 5.62. Found: C, 52.78; H, 9.25; N,
5.58%.
1
MeOH). H NMR (CDCl3): l 1.21 (s, 9H), 1.29 (d, 3H,
J=6.3 Hz), 1.34 (s, 3H), 1.41 (s, 9H), 3.50–3.54 (m,
1H), 3.84–3.90 (m, 1H), 4.24 (d, 1H, J=11.1 Hz), 4.43
(d, 1H, J=11.1 Hz), 4.74–4.80 (m, 2H). 13C NMR
(CDCl3): l 19.3, 21.6, 27.1, 28.2, 38.9, 57.8, 66.0, 68.3,
77.9, 80.5, 156.4, 178.2. MS (EI) (m/z)=28, 57, 100,
144, 281. ESI+ (m/z)=334. Anal. calcd for C16H31NO6:
C, 57.64; H, 9.37; N, 4.20. Found: C, 57.52; H, 9.35; N,
4.18%.
4.1.3.
(1S,2S,3R)-(2,3-Dihydroxy-1-hydroxymethyl-1-
methylbutyl)carbamic acid benzyl ester, 3b and
(1S,2R,3S)-(2,3-dihydroxy-1-hydroxymethyl-1-methyl-
butyl)carbamic acid benzyl ester, 4b. A round-bottomed
flask was charged with tert-butylic alcohol (12 mL),
water (12 mL), AD-mix-a (3.29 g) and methanesulfon-
amide (0.21 g). The mixture was stirred at rt until both
phases are clear, and then cooled to 0°C, whereupon
the inorganic salts partially precipitate. Olefin 2 (0.6 g,
2.35 mmol) was added and the heterogeneous slurry
was stirred vigorously at 0°C for 12 h. The reaction was
quenched at 0°C by addition of sodium sulphite (3.53 g)
and then stirred for 1 h. The reaction mixture was
extracted with ethyl acetate (3×20 mL) and then dried
and concentrated to give a mixture of both diols (syn
and anti ) with a diastereoselectivity of 4:1 in favor of
the diol syn. Without further purification the mixture
was dissolved in THF (7 mL) and concentrated HCl (7
mL) was added. The solution was stirred at 25°C for 2
h. Then, HCl was removed to give the corresponding
mixture of amino alcohols, which were dissolved in
water/THF (1/5, 30 mL) and Na2CO3·10H2O (1.68 g,
5.88 mmol) and ClCO2CH2Ph (0.46 mL, 3.06 mmol)
were added. The mixture was stirred at 25°C for 48 h
and then, quenched with saturated NH4Cl (10 mL) and
extracted with ethyl acetate (3×15 mL). The combined
organic layers were dried and concentrated. The residue
was purified by column chromatography (hexane/ethyl
acetate, 3:7) to give 3b as a white solid (67 mg, 0.23
mmol) and 4b as an oil (270 mg, 0.96 mmol); yield of
4b: 41%. Overall yield: 51%. Compound 3b: mp: 88°C.
[h]2D5=+1.4 (c 0.90, MeOH). 1H NMR (CDCl3): l
(ppm): 1.30 (s, 3H), 1.35 (d, 3H, J=6.0 Hz), 3.36 (‘t’,
1H, J=6.0 Hz), 3.60–3.83 (m, 3H), 4.20 (br s, 1H), 5.05
(d, 1H, J=12.3 Hz), 5.10 (d, 1H, J=12.3 Hz), 5.81 (br
s, 1H), 7.36 (s, 5H). 13C NMR (CDCl3): l (ppm): 20.3,
21.6, 59.3, 67.0, 68.2, 68.5, 79.3, 128.0, 128.3, 128.6,
136.1, 157.4. ESI+ (m/z)=284. Anal. calcd for
C14H21NO5: C, 59.35; H, 7.47; N, 4.94. Found: C,
59.27; H, 7.46; N, 4.92%. Compound 4b: [h]2D5=−0.4 (c
4.1.5. (2%S,3%R,4%S)-2,2-Dimethylpropionic acid 2%-tert-
butoxycarbonylamino-3%-hydroxy-4%-methoxymethoxy-2%-
methylpentyl ester, 6. Compound 5 (500 mg, 1.50 mmol)
was dissolved in dichloromethane (25 mL) and diiso-
propylethylamine (DIEA) (0.78 mL, 4.50 mmol) and
methoxymethyl chloride (MOMCl) (0.34 mL, 4.50
mmol) were added at 25°C. The reaction was stirred for
24 h and then, quenched with water (20 mL) and
extracted with ethyl acetate (40 mL). The organic layer
was dried and concentrated. The residue was purified
by column chromatography (hexane/ethyl acetate, 4:1)
to give compound 6 as a white solid (498 mg, 1.32
mmol); yield: 88%. Mp: 82°C. [h]2D5=−7.1 (c 0.95,
1
MeOH). H NMR (CDCl3): l 1.19 (s, 9H), 1.26 (d, 3H,
J=6.3 Hz), 1.34 (s, 3H), 1.39 (s, 9H), 3.35 (s, 3H),
3.57–3.61 (m, 1H), 3.78–3.82 (m, 1H), 4.20–4.30 (br s,
1H), 4.21 (d, 1H, J=10.8 Hz), 4.36 (d, 1H, J=10.8
Hz), 4.60 (d, 1H, J=6.9 Hz), 4.67 (d, 1H, J=6.9 Hz),
4.83 (br s, 1H). 13C NMR (CDCl3): l 16.0, 21.3, 27.1,
28.2, 38.8, 55.6, 57.5, 65.9, 74.0, 76.5, 80.1, 94.9, 156.0,
178.0. MS (EI) (m/z)=45, 57, 114, 144, 158, 304. ESI+
(m/z)=378. Anal. calcd for C18H35NO7: C, 57.27; H,
9.35; N, 3.71. Found: C, 57.01; H, 9.31; N, 3.69%.
4.1.6.
(1%S,4S,5R)-4-Hydroxymethyl-5-(1%-methoxy-
methoxyethyl) - 2,2,4 - trimethyloxazolidine - 3 - carboxylic
acid tert-butyl ester, 7. A solution of 6 (550 mg, 1.46
mmol), 2,2-dimethoxypropane (DMP) (2.33 mL, 18.9
mmol) and p-TsOH (6 mg, 0.03 mmol) in toluene (20
mL) was heated under reflux for 2 h and then slowly
distilled over 15 min to eliminate the MeOH formed.
DMP (2.33 mL, 18.9 mmol) was added and the proce-
dure was repeated until TLC showed no starting mate-
rial remained. The solvent was removed and the residue
partitioned between water (10 mL) and ethyl acetate
1
1.36, MeOH). H NMR (CDCl3): l (ppm): 1.20–1.30
(m, 6H), 3.62–3.97 (m, 6H), 5.06 (s, 2H), 5.57 (s, 1H),
7.34 (br s, 5H). 13C NMR (CDCl3): l (ppm): 19.5, 19.6,

1042
A. A6enoza et al. / Tetrahedron: Asymmetry 14 (2003) 1037–1043
(50 mL). The organic layer was dried (Na2SO4), con-
centrated and the crude was dissolved in
dichloromethane (15 mL). The solution was cooled to
mg, 0.40 mmol) as a colorless oil; yield: 67%. [h]2D5=
+13.8 (c 0.80, MeOH). H NMR (CDCl3): l 1.23–1.30
1
(m, 6H), 1.46 (s, 12H), 1.53 (s, 3H), 2.06–2.13 (m, 2H),
3.38 (s, 3H), 3.60–3.90 (m, 4H), 4.60 (d, 1H, J=6.9
Hz), 4.73 (d, 1H, J=6.9 Hz). 13C NMR (CDCl3): l
18.0, 19.5, 20.6, 24.3, 25.2, 27.0, 28.5, 38.2, 38.5, 56.2,
59.0, 64.4, 72.7, 79.9, 80.5, 92.6, 95.1, 151.7. MS (EI)
(m/z)=28, 57, 111, 170, 232, 332. ESI+ (m/z)=348.
Anal. calcd for C17H33NO6: C, 58.77; H, 9.57; N, 4.03.
Found: C, 58.28; H, 9.41; N, 4.22%.
−78°C before addition of DIBAL-H (1.0
M in
dichloromethane, 3.2 mL, 3.2 mmol). The reaction was
stirred for 12 h at −78°C and then quenched by addi-
tion of MeOH (5 mL). The mixture was warmed to rt,
poured into a solution of potassium sodium tartrate (5
g) in water (15 mL) and the biphasic mixture was
stirred vigorously for 2 h. The phases were separated
and the aqueous layer was extracted with diethyl ether
(2×25 mL). The combined organic layers were dried
and concentrated. The residue was purified by column
chromatography (hexane/ethyl acetate, 4:1) to give 7
(408 mg, 1.23 mmol) as a colorless oil; yield: 84%.
4.1.8. a- and b-Methyl N,O-dibenzoyl- -4-epi-vancos-
L
amine, 9. Compound 8 (90 mg, 0.26 mmol) was dis-
solved in dichloromethane (5 mL) and Dess–Martin
periodinane (160 mg, 0.39 mmol) was added at 25°C.
The reaction was stirred for 6 h and then, quenched
with a solution of NaOH 1 M (5 mL) and extracted
with diethyl ether (10 mL). The organic layer was dried
and concentrated. Without further purification the mix-
ture were dissolved in methanol (3 mL) and HCl 6N (2
mL) was added. The solution was stirred at 25°C for 3
h. Then, HCl was removed to give the corresponding
1
[h]2D5=+4.0 (c 1.37, MeOH). H NMR (CDCl3): l 1.25–
1.29 (m, 6H), 1.39–1.51 (m, 15H), 3.36 (s, 3H), 3.42 (d,
1H, J=8.1 Hz), 3.63 (d, 1H, J=6.9 Hz), 3.76–3.84 (m,
1H), 3.95–4.01 (m, 1H), 4.57 (d, 1H, J=6.9 Hz), 4.71
(d, 1H, J=6.9 Hz), 4.72 (br s, 1H). 13C NMR (CDCl3):
l 14.9, 18.0, 25.2, 28.2, 28.4, 56.1, 67.2, 67.6, 72.3, 80.1,
80.7, 92.9, 95.1, 153.2. MS (EI) (m/z)=45, 57, 170, 202,
318. ESI+ (m/z)=334. Anal. calcd for C16H31NO6: C,
57.64; H, 9.37; N, 4.20. Found: C, 57.27; H, 9.30; N,
4.25%.
methyl
L-4-epi-vancosamine, which was dissolved in
pyridine (5 mL) and BzCl (0.12 mL, 1.04 mmol) was
added. The reaction mixture was stirred for 20 h at
25°C. Ethyl acetate (15 mL) was added and the solution
was washed with HCl 1N (7 mL) and saturated
aqueous NaHCO3 (7 mL). The organic layer was dried
and concentrated. The residue was purified by silica gel
flash column chromatography (dichloromethane/ethyl
acetate, 9.5:0.5) to give the two isomeric N,O-dibenzoyl
methylglycosides 9a(a) and 9b(b) (60 mg, 0.16 mmol)
with a relationship a/b of 75:25; Overall yield: 60%. A
further silica gel column chromatography (dichloro-
methane/ethyl acetate, 9.5:0.5) allowed the separation
of both compounds. The physical data are identical
4.1.7. (1%S,4S,5R)-4-(2%%-Hydroxyethyl)-5-(1%-methoxy-
methoxyethyl) - 2,2,4 - trimethyloxazolidine - 3 - carboxylic
acid tert-butyl ester, 8. Compound 7 (200 mg, 0.60
mmol) was dissolved in dichloromethane (6 mL) and
Dess–Martin periodinane (380 mg, 0.90 mmol) was
added, at 25°C. The reaction was stirred for 6 h and
then, quenched with a solution of NaOH 1 M (5 mL)
and extracted with diethyl ether (15 mL). The organic
layer was dried and concentrated. The residue, without
further purification, was used in next reaction. Methyl-
triphenylphosphonium bromide (656 mg, 1.80 mmol)
was suspended in THF (10 mL) at rt and KHMDS (0.5
M in toluene, 3.6 mL, 1.80 mmol) was added. The
resulting yellow suspension was stirred at rt for 1 h.
Then, it was cooled to −78°C and a solution of alde-
hyde achieved after Dess–Martin reaction in THF (5
mL) was added dropwise. The cooling bath was
removed and the mixture was allowed to reach 25°C
over 15 h. The reaction was quenched with MeOH (2
mL) and the resulting mixture was poured into a solu-
tion of saturated potassium sodium tartrate and water
(1:1, v/v, 15 mL). Extraction with ethyl ether (2×15
mL), drying and evaporation of the solvent gave a pale
oil which was purified by flash chromatography (hex-
ane/ethyl acetate, 9.5:0.5) to give the corresponding
olefin (160 mg, 0.49 mmol, 82%) which was dissolved in
THF (5 mL) at −25°C. Lithium borohydride (72 ml of 2
M in THF, 0.15 mmol) and the BH3–THF complex
(0.97 mL of 1 M in THF, 0.97 mmol) were added
dropwise. After the reaction mixture was stirred
overnight at 25°C, it was carefully quenched with water
(0.3 mL) followed by 20% NaOH (0.3 mL) and 30%
hydrogen peroxide solutions (0.3 mL), stirred for an
additional 3 h and extracted with ethyl acetate (2×15
mL). The combined organic layers were dried and
concentrated. The residue was purified by column chro-
matography (hexane/ethyl acetate, 7:3) to give 8 (140
1
to that described in the literature.8b In the H NMR
spectra of each compound, recorded at 25°C, it was
observed the presence of two conformers, due to the
ring interconversion.
Acknowledgements
We thank the Ministerio de Ciencia y Tecnolog´ıa (pro-
ject PPQ2001-1305), the Gobierno de La Rioja (project
ANGI2001/30 and grant of D.S.) and the Universidad
de La Rioja (project API-01/B02). F.C. thanks the
Ministerio de Educacio´n y Cultura for a grant.
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