Versatile route to 2,6-dideoxyamino sugars from non-sugar materials: Syntheses of vicenisamine and kedarosamine

Article abstract of DOI:10.1039/b008878l

A new strategy for the synthesis of 2,6-dideoxyamino sugars from non-sugar starting materials has been developed. The key reaction in this strategy is the acid-catalyzed intramolecular cyclization, by which a nitrogen functional group is introduced with simultaneous control of vicinal chiral centers. The synthesis of two kinds of 2,6-dideoxyamino sugars, D-vicenisamine and L-kedarosamine, by this strategy is described.

Full text of DOI:10.1039/b008878l

View Article Online / Journal Homepage / Table of Contents for this issue
Versatile route to 2,6-dideoxyamino sugars from non-sugar
materials: Syntheses of vicenisamine and kedarosamine
Yoshitaka Matsushima,a Takuya Nakayama,a Shigehiro Tohyama,b Tadashi Eguchib
and Katsumi Kakinuma*a
1
a Department of Chemistry, Tokyo Institute of Technology, O-okayama, Meguro-ku,
Tokyo 152-8551, Japan
b Department of Chemistry and Materials Science, Tokyo Institute of Technology,
O-okayama, Meguro-ku, Tokyo 152-8551, Japan
Received (in Cambridge, UK) 6th November 2000, Accepted 24th January 2001
First published as an Advance Article on the web 21st February 2001
A new strategy for the synthesis of 2,6-dideoxyamino sugars from non-sugar starting materials has been
developed. The key reaction in this strategy is the acid-catalyzed intramolecular cyclization, by which a nitrogen
functional group is introduced with simultaneous control of vicinal chiral centers. The synthesis of two kinds
of 2,6-dideoxyamino sugars, -vicenisamine and -kedarosamine, by this strategy is described.
Amino sugars, especially deoxyamino sugars, are found in
various clinically important antibiotics such as antimicrobial
macrolides and anthracycline antitumor antibiotics.1 The sugar
moieties of those antibiotics are essential for exerting biological
activity in most cases; however, the more detailed functions of
such sugars have yet to be evaluated.2
Vicenistatin, an antitumor antibiotic isolated from Strepto-
myces sp. HC-34, is unique in its structure, which includes a
20-membered macrocyclic lactam aglycone and an amino
sugar, vicenisamine, as shown in Fig. 1.3,4 Recently the whole
20-membered macrolactam ring skeleton was successfully
synthesized and the absolute configuration was verified.5
More recently, we have isolated a new congener, vicenistatin M,
having a neutral sugar, -mycarose, and have shown that it has
no cytotoxicity.6 This strongly suggests that the vicenisamine
amino sugar plays an important role in exerting the cytotoxicity
of vicenistatin.
We envisaged that modification of the sugar part of viceni-
statin may serve as a tool for investigating the significance of
the amino sugar and the structure–activity relationship. To this
end, a versatile synthetic method for vicenisamine and modified
amino sugars was most desirable. Particularly, we were inter-
ested in developing a synthetic route for amino sugars from
non-sugar materials.
Our prime targets were vicenisamine and kedarosamine. The
Fig. 1 Structure of vicenistatin and kedarcidin chromophore.
latter is an homologous stereoisomer of the former and is a
component of the antitumor antibiotic kedarcidin’s chromo-
phore7–9 and that of the antifungal macrolide A82548A.10
In this paper we describe a novel synthesis of methyl -
vicenisaminide 1 and methyl -kedarosaminide 2 via the same
strategy. Methyl -vicenisaminide11 and methyl -kedarosamin-
ide12–14 were previously synthesized by different approaches.
alent to the oxazoline 5. The key transformation was to control
the stereochemistry of nitrogen introduction, i.e., an acid-
catalyzed intramolecular cyclization15–17 of epoxytrichloro-
acetimidate 6 should give rise to the oxazoline 5. Evidently
both enantiomers of the starting chiral trans-epoxy alcohol 7
are easily obtained by Sharpless asymmetric epoxidation.18
Methyl kedarosaminide 2 should also be obtained according to
this strategy by employing cis-epoxy alcohol 1218 as a starting
material.
The first key manipulation of our work was the acid-
catalyzed intramolecular cyclization, by which a nitrogen
functional group was introduced with simultaneous control
of vicinal chiral centers, and subsequent transformation to an
important intermediate 4 as shown in Scheme 2. At first,
trans-epoxy alcohol 718 was easily converted into epoxytri-
Results and discussion
Our general strategy for the construction of vicenisamine and
kedarosamine is based on the retrosynthetic analysis shown
in Scheme 1. Methyl vicenisaminide 1 was anticipated to be
synthesized by oxidative cleavage of the side chain of 3,
followed by hydrolysis and acidic treatment. The side chain of
the oxazolidinone 3 could be introduced by diastereoselective
allylation of the intermediary aldehyde derived from chiral
oxazolidinone alcohol 4. The latter was supposed to be equiv-
DOI: 10.1039/b008878l
J. Chem. Soc., Perkin Trans. 1, 2001, 569–577
This journal is © The Royal Society of Chemistry 2001
569

View Article Online
Scheme 1 Retrosynthetic analysis of vicenisamine and kedarosamine.
Scheme 2 Introduction of nitrogen functional group.
chloroacetimidate 6, which was subsequently subjected to
acidic rearrangement with several kinds of catalyst as reported
by Schmidt16 and Hatakeyama.17 The course of the reaction
to form either the five-membered ring (5-exo-cyclization) or six-
membered ring (6-endo-cyclization) is known to be controlled
by the structure of the starting epoxide, and occasionally,
also by the catalysts as well.15–17 In the case of our substrate
6, methanesulfonic acid afforded the desired 5-exo-cyclization
product 5 in good yield. The ratio of the oxazoline 5 to the
aldehyde 16, which was obtained by Dess–Martin oxidation of
4, was subjected to allylation conditions without purification.
Originally diastereoselective allylation using chiral auxiliary
was supposed to be the most reliable way to obtain signifi-
cant diastereoselectivity. Brown’s diisopinocamphenylborane,
(IPC)2B, was examined as the chiral auxiliary, since it was
known to have been applied to a variety of aldehydes and the
stereochemical outcome of the reaction was predictable.19 The
attempted allylation reaction, however, led to almost the same
results with low and undesired diastereoselectivity† (anti-3:
syn-3Ј = 15 : 85, 79% yield in 2 steps) regardless of whether (ϩ)-
or (Ϫ)-(IPC)2B was employed. Similarly, almost complete syn-
selectivity was observed in the case of achiral allyltin reagent.
We thus turned our attention to higher selectivity under the
achiral conditions, especially focusing on the indium-promoted
allylation. An advantage of the latter conditions was that the
reaction could be carried out in an aqueous medium;20 in other
words, extraction of the intermediary polar aldehyde 16 from
the quenching aqueous medium was not necessary.
1
dihydrooxazine 5Ј was found to be 81 to 19 by H NMR anal-
ysis, but unfortunately, the desired oxazoline 5 was inseparable
from the minor isomer 5Ј.
The mixture of these isomers was treated with triphosgene
and triethylamine, by which the intermediary imidatonium ion
was gradually hydrolyzed with water to the oxazolidinone 13.
The trichloroacetyl group of compound 13 was replaced by a
tert-butyldimethylsilyl (TBDMS) group, and a methyl group
was introduced on the nitrogen of oxazolidinone 14 to give 15.
The silyl protecting group of 15 was removed by treatment with
tetrabutylammonium fluoride (TBAF). The resulting alcohol
4 was able to be favorably separated from the isomer 4Ј by
recrystallization. Enantiomeric purity of 4 was determined
This one-pot oxidation–allylation procedure allowed us to
obtain homoallyl alcohol 3Ј in good yield (71%, 2 steps).
Although, the resulting alcohol was the undesired stereoisomer
1
to be almost 100% ee by the H NMR analysis of the corre-
sponding methoxy(trifluoromethyl)phenylacetate (MTPA)
ester.
The next stage was the diastereoselective allylation to
construct the (1ЈS) alcohol group, as shown in Scheme 3. The
† The stereochemistry of the resulting alcohols was respectively deter-
mined after their conversion into the corresponding hexopyranosides
vide infra.
570
J. Chem. Soc., Perkin Trans. 1, 2001, 569–577

View Article Online
protected by an Fmoc (fluoren-9-ylmethoxycarbonyl) group to
give 20. The stereochemistry at C-3 of 20 was inverted by the
reduction of the corresponding ketone 21 by NaBH4 to give
diastereoisomeric alcohols 22. Finally, the Fmoc proctective
group of 22 was removed by 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU)21 to give methyl α-D-vicenisaminide 1. A portion of 1
was transformed into the β-anomer by heating in HCl–MeOH.
The spectroscopic properties of the β-anomer were confirmed
to be identical with those of the naturally derived product.
Next, the synthesis of kedarosamine was pursued starting
from the cis-epoxy alcohol 12.18 We were interested in the
cyclization reaction of cis-epoxytrichloroacetimidate 11 in
comparison with its trans-counterpart 6. Although racemic
cis-isomer had previously been reported, its reactivity was not
discussed in detail.15
It was unexpectedly found that the cis-isomer 11 was sig-
nificantly more reactive than the trans-isomer 6. In fact,
exothermic cyclization spontaneously took place during its
purification by silica gel chromatography to quantitatively give
the desired threo-oxazoline 10 as a single isomer in 2 steps
(Scheme 5). Subsequently the oxazoline 10 was transformed
Scheme 3 Selectivity of allylation-1.
3Ј just as anticipated, its stereochemistry was actually inverted
at a later stage, vide infra.
Ozonolysis of the terminal olefin of 3Ј in MeOH, followed by
work-up with dimethyl sulfide and a catalytic amount of
toluene-p-sulfonic acid (p-TsOH), quantitatively yielded dimethyl
acetal 17 (Scheme 4). Alkaline hydrolysis of the oxazolidinone
Scheme 5 Synthesis of trans-oxazolidinone from cis-epoxy alcohol.
into oxazolidinone 24 via 23 in 3 steps. It should also be noted
that there was a marked difference in reactivity between threo-
oxazoline 10 and erythro-isomer 5, that is, acidic conditions
(2 M HCl) were required for the reaction of threo-oxazoline
10, whereas erythro-isomer 5 was easily converted into the
oxazolidinone 13 under neutral aqueous conditions. These
results may probably be due to different steric repulsion
between the methyl group and a hydrogen in the imidatonium
ions as illustrated in Fig. 2.
The oxazolidinone 24 was subsequently converted into
alcohol 9 by the same reaction as described for the vicenisamine
synthesis. Repeated recrystallization of 9 raised its enantio-
meric purity up to 97% ee.
Dess–Martin oxidation of 9 cleanly afforded threo-aldehyde
25, which was further subjected to an allylation reaction. A
different trend of reactivity was observed in this case from that
of erythro-aldehyde 16 as depicted in Scheme 6. In every case,
relatively low to moderate yields were attained, probably
because of the instability of 25. The second concern was the
diastereoselectivity. Almost no diastereoselectivity was
observed in the case of using an achiral reagent, and the desired
anti-isomer was obtained with a moderate selectivity (anti-
8 : syn-8Ј = 75 : 25; 53% yield in 2 steps) by the use of (Ϫ)-
(IPC)2B. On the other hand, when (ϩ)-(IPC)2B was employed,
Scheme 4 Synthesis of methyl vicenisaminide.
ring in 17 liberated free amino alcohol 18, which was subse-
quently cyclized to hexopyranoside in HCl–MeOH, producing
mainly an α-anomer 19. The free amino group of 19 was then
J. Chem. Soc., Perkin Trans. 1, 2001, 569–577
571

View Article Online
Fig. 2 Lability of intermediary imidatonium ions to hydrolytic
conditions.
Scheme 7 Synthesis of methyl kedarosaminide.
erythro-aldoses into 2,3-threo-aldoses by treatment with K2CO3
in MeOH.22 Accordingly, the erythro-aldehyde 16 was subjected
to a similar epimerization. Unfortunately, however, decom-
position or complex reaction was observed in this case, mainly
because of the unstable nature of threo-aldehyde 25.
In conclusion, we have successfully synthesized -vicenis-
amine and -kedarosamine as their methyl hexopyranosides,
showing our synthetic strategy for 2,6-dideoxyamino sugars
using easily accessible non-sugar starting materials to be
versatile.
Experimental
All mps are uncorrected. NMR spectra were recorded on
a JEOL LA-300, or a Bruker DRX-500 spectrometer. 1H NMR
and 13C NMR chemical shifts were reported in δ-values based
on internal tetramethylsilane (TMS) (δH = 0), or solvent signal
(CDCl3 δC = 77.0; CD3OD δH = 4.78, δC = 49.0) as reference. IR
spectra were recorded on a Horiba FT-710 Fourier-transform
infrared spectrometer. Optical rotations were measured on a
JASCO DIP-360 polarimeter. [α]D-Values are given in units
of 10Ϫ1 deg cm2 gϪ1. Mass spectra were measured on a JEOL
AX-505HA mass spectrometer. Silica gel column chrom-
atography was carried out with Merck Kieselgel 60, Art. Nr.
7734, and flash silica gel column chromatography was carried
out with Merck Kieselgel 60, Art. Nr. 9385.
Scheme 6 Selectivity of allylation-2.
the reaction led to high syn-selectivity (8 : 8Ј = 3 : 97; 55% yield
in 2 steps).
It seems relevant here to discuss the stereochemical differ-
ences of the allylations of 16 and 25. Steric repulsion by the
cis-methyl group in the erythro-aldehyde 16 appeared to be
responsible for the result that the undesired diastereomer 3Ј was
obtained as a major isomer regardless of the conditions. On
the other hand, the stereochemistry of allylation from the
threo-aldehyde 25 was mainly dependent on the chirality of the
auxiliary employed.
The allylation products from 25 were transformed into
the corresponding p-nitrobenzoates, which were fortunately
chromatographically separable. Furthermore, the undesired
compound 8Ј could be converted into 8 by Mitsunobu inversion
and hydrolysis of the resulting p-nitrobenzoate 26.
Thus the obtained compound 8 was transformed into
hexopyranoside 27 by the same sequential transformations as
in the vicenisamine synthesis, i.e., ozonolysis, hydrolysis and
subsequent cyclization. Finally, N-methylation was carried out
to yield methyl -kedarosaminide 2 as a mixture of anomers
(α : β = 4 : 1) as shown in Scheme 7. Its spectroscopic data were
identical with those described in the literature.8
In order to develop a more convenient route to the target
amino sugars, we attempted simple conversion of erythro-
oxazolidinone 4 into threo-isomer 9, but with little success.
Previously, Masamune and Sharpless and co-workers had
reported efficient conversion of acetonide-protected 2,3-
(2R,3R)-2,3-Epoxybutyl trichloroacetimidate 6
To an ice-cooled solution of (2R,3R)-2,3-epoxybutan-1-ol18
7 (420 mg, 4.77 mmol) and trichloroacetonitrile (550 mm3,
5.49 mmol) in CH2Cl2 (6 cm3) was added dropwise DBU
(82 mm3, 0.55 mmol) and the mixture was stirred at rt for
1 h. The solvent was removed in vacuo, and the residue was
purified by silica gel chromatography (hexane–EtOAc, 5 : 1
to 4 : 1) to afford 6 (1.04 g, 94%) (Found: C, 30.86; H, 3.63;
N, 5.76. Calc. for C6H8Cl3NO2: C, 31.00; H, 3.47; N, 6.02%);
[α]D28 ϩ31.7 (c 1.04, CHCl3); νmax (neat)/cmϪ1 3344, 1668,
1331, 1300, 1084, 1022, 1001, 989, 830, 800 and 647; δH (300
MHz; CDCl3) 1.37 (d, J 5.1 Hz, 3H), 3.01–3.11 (m, 2H),
4.23 (dd, J 5.6, 12.2 Hz, 1H) and 4.56 (dd, J 2.9, 12.2 Hz,
1H); δC (75 MHz; CDCl3) 17.2, 52.3, 55.9, 69.0, 91.0 and
162.6.
572
J. Chem. Soc., Perkin Trans. 1, 2001, 569–577

View Article Online
(4S)-4-[(1ЈR)-1Ј-Hydroxyethyl]-2-trichloromethyl-4,5-dihydro-
oxazole 5
(40 cm3). The mixture was warmed to rt, and stirred for 0.5 h.
To the reaction mixture was added dropwise methyl iodide (3.3
cm3, 53 mmol) at 0 ЊC, and the mixture was warmed to rt and
stirred for 0.5 h. The reaction was quenched by the addition of
cold water and saturated aq. NH4Cl at 0 ЊC. The mixture was
extracted five times with Et2O, and the combined extract was
washed successively with water, saturated aq. NaHCO3 and
brine, dried (MgSO4), and concentrated in vacuo. The residue
was purified by silica gel chromatography (hexane–EtOAc, 3 : 1
to 1 : 3) to afford 15 (4.11 g, 91%), which was contaminated with
a corresponding isomer derived from 5Ј (Found: C, 55.48;
H, 9.93; N, 5.41. Calc. for C12H25NO3Si: C, 55.56; H, 9.71; N,
5.40%); [α]D22 Ϫ1.6 (c 1.06, CHCl3); νmax (neat)/cmϪ1 1753, 1431,
1400, 1255, 1132, 1088 and 837; δH (300 MHz; CDCl3) 0.08
(s, 6H), 0.89 (s, 9H), 1.43 (d, J 6.6 Hz, 3H), 2.88 (s, 3H), 3.59 (m,
1H), 3.72 (dd, J 3.9, 11.0 Hz, 1H), 3.78 (dd, J 4.6, 11.0 Hz, 1H)
and 4.68 (dq, J 6.6, 7.8 Hz, 1H); δC (75 MHz; CDCl3) Ϫ5.7,
14.6, 17.8, 25.6, 29.6, 58.9, 61.2, 72.7 and 158.6.
To a solution of 6 (1.69 g, 7.27 mmol) in dry CH2Cl2 (72 cm3)
was added methanesulfonic acid (71 mm3, 1.09 mmol) and the
mixture was stirred at rt for 2 h. To the mixture was added
saturated aq. NaHCO3 and the CH2Cl2 layer was separated.
The organic layer was washed with saturated aq. NaHCO3,
dried (MgSO4), and concentrated in vacuo. The residue was
purified by silica gel chromatography (hexane–EtOAc, 5 : 1 to
1 : 2) to afford a mixture of 5 and 5Ј (1.44 g, 85%; 5 : 5Ј = 81 : 19
1
by H NMR), which was used for the next reaction without
further purification; νmax (neat)/cmϪ1 3388, 1662, 1238, 1028,
991, 843, 823, 795 and 665; δH (300 MHz; CDCl3) 1.22 (d, J 6.6
Hz, 3H), 4.14–4.20 (m, 1H), 4.32 (dt, J 3.7, 9.2 Hz, 1H) and
4.65 (dd, J 3.5, 9.1 Hz, 2H); δC (75 MHz; CDCl3) 19.1, 67.6,
71.6, 72.3, 86.4 and 164.0.
(4S,5R)-5-Methyl-4-(trichloroacetoxymethyl)oxazolidin-2-one
13
(4S,5R)-4-Hydroxymethyl-3,5-dimethyloxazolidin-2-one 4
To an ice-cooled solution of a mixture of 5 and 5Ј (75.0 g, 323
mmol) and triethylamine (58.5 cm3, 419 mmol) in dry CH2Cl2
(1520 cm3) was added triphosgene (38.3 g, 129 mmol) in
portions, and the mixture was stirred at rt for 3 h. The reaction
mixture was poured into saturated aq. NH4Cl (1600 cm3) at
0 ЊC and stirred for 10 h. The organic layer was separated, and
the aqueous layer was extracted twice with CH2Cl2. The com-
bined organic extract was dried (MgSO4), and concentrated in
vacuo. The residue was purified by silica gel chromatography
(hexane–EtOAc, 3 : 1 to 1 : 50) to afford 13 (70.1 g, 79%), which
was contaminated with a corresponding isomer derived from
5Ј (Found: C, 30.67; H, 3.11; N, 4.82. Calc. for C7H8Cl3NO4: C,
30.41; H, 2.92; N, 5.07%); [α]D28 Ϫ18.4 (c 4.76, CHCl3); νmax
(neat)/cmϪ1 3284, 1766, 1751, 1389, 1377, 1238, 1097, 991, 850,
828 and 678; δH (300 MHz; CDCl3) 1.49 (d, J 6.6 Hz, 3H), 4.10–
4.13 (m, 1H), 4.33 (dd, J 6.3, 11.5 Hz, 1H), 4.53 (dd, J 4.9, 11.5
Hz, 1H), 4.92 (dq, J 6.8, 7.8 Hz, 1H) and 6.38 (br s, 1H); δC (75
MHz; CDCl3) 14.5, 53.5, 66.1, 75.1, 89.0, 159.8 and 161.4.
To a solution of 15 (41.2 g, 159 mmol) in dry THF (1060 cm3)
was added dropwise TBAF (1.0 M solution in THF; 167 cm3,
167 mmol) at 0 ЊC, and the mixture was stirred at rt for 0.5 h.
The solvent was removed in vacuo, and the residue was purified
by silica gel chromatography (CHCl3–MeOH, 100 : 1 to 5 : 1) to
afford a mixture of 4 and 4Ј (22.6 g, 98%). Recrystallization
from EtOAc and hexane (30 : 1) gave pure 4 (15.4 g, 67%, almost
1
100% ee by H NMR analysis of the corresponding Mosher
ester) (Found: C, 49.56; H, 7.81; N, 9.64. Calc. for C6H11NO3:
C, 49.65; H, 7.64; N, 9.65%); mp 72.7–76.0 ЊC; [α]D17 Ϫ17 (c 1.07,
CHCl3); νmax (CHCl3)/cmϪ1 3629, 3420, 1743, 1435, 1406, 1234,
1072 and 1045; δH (300 MHz; CDCl3) 1.47 (d, J 6.6 Hz, 3H),
2.92 (s, 3 H), 3.65 (m, 1H), 3.82 (m, 2H), 4.73 (dq, J 6.6, 7.8 Hz,
1H); δC (75 MHz; CDCl3) 14.6, 29.5, 58.3, 61.1, 73.2 and 158.9.
(4S,5R)-4-[(1ЈR)-1Ј-Hydroxybut-3Ј-enyl]-3,5-dimethyloxazol-
idin-2-one 3Ј
To a solution of 4 (4.07 g, 28.0 mmol) in dry CH2Cl2 (140 cm3)
was added Dess–Martin periodinane (16.0 g, 42.5 mmol) at
0 ЊC. The mixture was stirred for 0.5 h at rt, treated with 10%
aq. Na2S2O3, and then CH2Cl2 was removed in vacuo. To the
residual aqueous suspension were added indium powder (4.83
g, 42.0 mmol) and allyl bromide (4.85 cm3, 56.0 mmol). After
sonication for several minutes, the mixture was stirred for 23 h
at rt. To complete the reaction, additional amounts of indium
(1.60 g, 13.9 mmol) and allyl bromide (2.50 cm3, 28.9 mmol)
were necessary. To the mixture was added EtOAc and the mix-
ture was stirred for 2 h. After filtration through a pad of Celite,
the layers were separated. The aqueous layer was extracted
seven times with EtOAc, and the combined organic layer was
dried (MgSO4), and concentrated in vacuo. The residue was
purified by flash silica gel chromatography (hexane–EtOAc 3 : 1
to 1 : 5) to afford 3Ј (3.71 g, 71% in 2 steps) as a white solid
(Found: C, 58.23; H, 8.44; N, 7.44. Calc. for C9H15NO3: C,
58.36; H, 8.16; N, 7.56%); mp 64.3–66.5 ЊC; [α]D22 Ϫ27 (c 1.13,
CHCl3); νmax (KBr)/cmϪ1 3359, 1716, 1670, 1645, 1408, 1294,
1234, 1068, 1032, 1011, 933, 850, 766 and 675; δH (300 MHz;
CDCl3) 1.48 (d, J 6.6 Hz, 3H), 2.37 (t, J 6.8 Hz, 2H), 3.04 (s,
3H), 3.57 (dd, J 3.7, 7.6 Hz, 1H), 3.87 (dt, J 3.7, 6.8 Hz, 1H),
4.68 (dq, J 6.6, 7.6 Hz, 1H), 5.17–5.24 (m, 2H) and 5.81 (ddt,
J 7.1, 10.5, 16.6 Hz, 1H); δC (75 MHz; CDCl3) 14.8, 32.2, 39.7,
63.0, 68.9, 73.8, 118.4, 133.8 and 158.9.
(4S,5R)-4-tert-Butyldimethylsiloxymethyl-5-methyloxazolidin-
2-one 14
To a solution of 13 (1.04 g, 3.75 mmol) in dry MeOH (9 cm3)
was added powdered NaOH (37.5 mg, 0.94 mmol) and the mix-
ture was stirred at rt for 0.5 h and concentrated in vacuo. To an
ice-cooled solution of the residue and imidazole (765 mg, 11.2
mmol) in dry dimethylformamide (DMF) (8 cm3) was added
TBDMSCl (1.13 g, 7.50 mmol) and the mixture was stirred
for 0.5 h. To the reaction mixture was added crushed ice and
the mixture was stirred for 20 min before being extracted twice
with Et2O, and the combined organic extract was washed
successively with water, saturated aq. NaHCO3 and brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified
by silica gel chromatography (hexane–EtOAc, 3 : 1 to 1 : 3) to
afford 14 (747 mg, 81% in 2 steps), which was contaminated
with a corresponding isomer derived from 5Ј (Found: C, 53.58;
H, 9.53; N, 5.41. Calc. for C11H23NO3Si: C, 53.84; H, 9.45;
N, 5.71%); [α]D26 Ϫ27 (c 1.04, CHCl3); νmax (neat)/cmϪ1 3282,
1751, 1471, 1389, 1254, 1227, 1138, 1099, 837, 775 and 665;
δH (300 MHz; CDCl3) 0.07 (s, 6H), 0.89 (s, 9H), 1.40
(d, J 6.6 Hz, 3H), 3.61 (dd, J 6.8, 10.2 Hz, 1H), 3.67 (dd, J 4.9,
10.2 Hz, 1H), 3.76–3.84 (m, 1H) and 4.81 (dq, J 6.6, 7.6 Hz,
1H).
(4S,5R)-4-tert-Butyldimethylsiloxymethyl-3,5-dimethyloxazol-
idin-2-one 15
(4S,5R)-4-[(1ЈR)-1Ј-Hydroxy-3Ј,3Ј-dimethoxypropyl]-3,5-
dimethyloxazolidin-2-one 17
Sodium hydride (1.42 g, ≈60% dispersion in mineral oil; 35.5
mmol) was washed with dry hexane, and was then suspended
in dry DMF (65 cm3). To the ice-cooled suspension was added
dropwise a solution of 14 (4.26 g, 17.4 mmol) in dry DMF
Ozone was introduced into a solution of 3Ј (238 mg, 7.92
mmol) in MeOH (18 cm3) at Ϫ78 ЊC until the color of the
solution became slightly pale blue. Excess of ozone was purged
J. Chem. Soc., Perkin Trans. 1, 2001, 569–577
573

View Article Online
with a stream of argon. To the mixture were added sequentially
dimethyl sulfide (2.0 cm3, 27.2 mmol) and p-TsOH monohydrate
(30 mg, 0.174 mmol) at Ϫ78 ЊC. The bath was removed and the
solution was allowed to warm gradually to rt with stirring for
18 h. After the addition of NaHCO3 powder to the mixture, the
whole was concentrated in vacuo. The residue was mixed with
EtOAc, and the resulting suspension was filtered through a pad
of Celite, and then the solvent was removed in vacuo. The
residue was purified by silica gel chromatography (hexane–
EtOAc, 1 : 1 to 0 : 1) to afford 17 (297 mg, 99%) (Found: C,
51.46; H, 8.49; N, 5.76. Calc. for C10H19NO5: C, 51.49; H, 8.21;
N, 6.00%); [α]D24 Ϫ24 (c 1.02, CHCl3); νmax (neat)/cmϪ1 3438,
1734, 1442, 1392, 1230, 1122, 1082 and 1047; δH (300 MHz;
CDCl3) 1.48 (d, J 6.6 Hz, 3H), 1.74 (ddd, J 2.0, 4.4, 14.1 Hz,
1H), 1.97 (ddd, J 5.6, 10.3, 14.1 Hz, 1H), 2.99 (s, 3H), 3.40 (s,
3H), 3.42 (s, 3H), 3.53 (dd, J 4.0, 7.7 Hz, 1H), 4.09 (m, 1H), 4.57
(dd, J 4.6, 5.1 Hz, 1H) and 4.65 (dq, J 6.6, 7.3 Hz, 1H); δC (75
MHz; CDCl3) 15.1, 32.0, 37.3, 54.0, 54.6, 63.9, 66.6, 73.4, 104.2
and 159.0.
for the next reaction without further purification; [α]D28 ϩ47
(c 1.13, CHCl3); νmax (CHCl3)/cmϪ1 3587, 3438, 1689, 1450,
1311, 1149, 1126 and 978; δH (300 MHz; CDCl3) 0.91, 1.14 (d,
J 6.0 Hz, 3H), 1.52, 1.73 (ddd, J 3.4, 9.5, 12.9 Hz, 1H), 2.16,
2.22 (dd J 4.7, 12.9 Hz, 1H), 2.74, 2.76 (s, 3H), 3.26, 3.28
(s, 3H), 3.68–4.00 (m, 2H), 4.26 (t, J 6.3 Hz, 1H), 4.52, 4.62 (d,
J 6.4, 2H), 4.72 (dd, J 3.2, 12.9 Hz, 1H), 7.32 (t, J 7.3 Hz, 2H),
7.40 (t, J 7.3 Hz, 2H), 7.60 (d, J 6.6 Hz, 2H), 7.77 (d, J 7.3 Hz,
2H); δC (75 MHz; CDCl3) 17.5, 17.6, 28.3, 38.5, 39.0, 47.1, 54.6,
62.6, 63.2, 63.9, 64.3, 67.2, 77.2, 98.2, 98.4, 119.8, 124.8, 127.0,
127.5, 141.2, 143.8, 144.0 and 157.0.
Methyl 2,4,6-trideoxy-4-[(fluoren-9-ylmethoxycarbonyl)methyl-
amino]-ꢀ-D-erythro-hexopyranosid-3-ulose 21
To a solution of 20 (611 mg, 1.59 mmol) in dry CH2Cl2 (25 cm3)
was added Dess–Martin periodinane (1.33 g, 3.14 mmol) at
0 ЊC. The mixture was stirred for 1 h at rt. To the mixture were
added 10% aq. Na2S2O3 and saturated aq. NaHCO3, and the
mixture was extracted three times with Et2O. The organic layers
were dried (MgSO4), and concentrated in vacuo. The residue
was purified by silica gel chromatography (hexane–EtOAc, 5 : 1
to 1 : 1) to afford 21 (555 mg, 91%) {HRFAB-MS (NBA matrix)
m/z 396.1772 [(M ϩ H)ϩ. Calc. for C23H26NO5: m/z, 396.1811]};
[α]D28 ϩ43 (c 1.16, CHCl3); νmax (neat)/cmϪ1 1732, 1697, 1450,
1402, 1300, 1244, 1169, 1130, 1045, 759 and 743; δH (300 MHz;
CDCl3) 1.11, 1.33 (d, J 6.1 Hz, 3H), 2.54, 2.72 (d, J 4.4 Hz, 1H),
2.61, 2.66 (d, J 1.4 Hz, 1H), 2.77, 2.85 (s, 3H), 3.33, 3.38 (s, 3H),
4.20–4.31 (m, 2H), 4.41, 4.49 (d, J 6.8 Hz, 2H), 4.46–4.55 (m,
1H), 4.95, 5.00 (t, J 2.95 Hz, and d, J 3.9 Hz, 1H) and 7.26–7.75
(m, 8H); δC (75 MHz; CDCl3) 18.4, 18.7, 46.0, 46.3, 47.2, 54.7,
65.8, 67.0, 67.5, 67.9, 77.2, 98.8, 119.7, 124.4, 124.8, 126.8,
127.4, 141.1, 143.5, 143.7, 155.9, 156.8, 200.1 and 200.6.
(2R,3R,4R)-6,6-Dimethoxy-3-(methylamino)hexane-2,4-diol 18
A solution of 17 (1.51 g, 6.49 mmol) in MeOH (18 cm3) and
50% aq. NaOH (12 cm3) was refluxed for 3 h. The reaction
mixture was cooled, and concentrated in vacuo. The residue was
dissolved in a minimum amount of water and extracted four
times with EtOAc. The combined organic extract was dried
(MgSO4), and concentrated in vacuo. The residue was purified
by silica gel chromatography (CHCl3–MeOH, 20 : 1 to 5 : 1) to
afford 18 (1.11 g, 83%) (Found: C, 51.88; H, 10.34; N, 6.52.
Calc. for C9H21NO4: C, 52.15; H, 10.21; N, 6.76%); [α]D24 Ϫ3.3
(c 1.06, CHCl3); νmax (neat)/cmϪ1 3356, 1448, 1423, 1383, 1124
and 1053; δH (300 MHz; CDCl3) 1.26 (d, J 6.6 Hz, 3H), 1.74
(ddd, J 2.9, 6.1, 14.1 Hz, 1H), 1.98 (ddd, J 4.9, 9.8, 14.1 Hz,
1H), 2.17 (dd, J 2.7, 4.2 Hz, 1H), 2.50 (s, 3H), 3.36 (s, 6H), 4.01
(dq, J 4.1, 6.6 Hz, 1H), 4.11 (dt, J 2.7, 9.8 Hz, 1H) and 4.60 (dd,
J 5.1, 5.9 Hz, 1H); δC (75 MHz; CDCl3) 19.9, 35.5, 37.5, 53.5,
53.7, 63.8, 67.1, 67.3 and 103.6.
Methyl 2,4,6-trideoxy-4-[(fluoren-9-ylmethoxycarbonyl)methyl-
amino]-ꢀ-D-ribo-hexopyranoside 22
To a solution of 21 (511 mg, 1.29 mmol) in MeOH (30 cm3) was
added NaBH4 (103 mg, 2.72 mmol) at Ϫ15 ЊC, and the mixture
was stirred for 5 min. To the mixture was added saturated aq.
NH4Cl, and MeOH was removed in vacuo. The residue was
dissolved in a minimum amount of water and extracted twice
with Et2O. The combined organic layer was dried (MgSO4), and
concentrated in vacuo. The residue was purified by flash silica
gel chromatography (hexane–EtOAc, 5 : 1 to 1 : 1) to afford 22
(391 mg, 76%) {HRFAB-MS (NBA matrix) m/z 398.1945
[(M ϩ H)ϩ. Calc. for C23H28NO5: m/z, 398.1967]}; [α]D29 ϩ124 (c
1.19, CHCl3); νmax (neat)/cmϪ1 3510, 1695, 1450, 1317, 1122,
1097 and 1049; δH (300 MHz; CDCl3) 1.03 (d, J 6.1 Hz, 3H),
1.22 (d, J 6.3 Hz, 3H), 1.60 (dt, J 3.3, 14.4 Hz, 1H), 1.90 (dd,
J 2.7, 14.4 Hz, 1H), 1.94–2.08 (m, 1H), 2.91 (s, 3H), 3.01 (s,
3H), 3.25 (dd, J 2.1, 10.5 Hz, 1H), 3.35 (s, 3H), 3.41 (s, 3H),
3.52–3.61 (m, 1H), 3.91 (d, J 9.8 Hz, 1H), 4.08 (m, 1H),
4.20–4.28 (m, 2H), 4.41 (s, 1H), 4.43 (d, J 1.0 Hz, 1H), 4.57 (dq,
J 5.4, 6.8 Hz, 2H), 4.72 (d, J 3.2 Hz, 1H), 4.81 (d, J 2.2 Hz, 1H)
and 7.28–7.78 (m, 8H); δC (75 MHz; CDCl3) 18.1, 31.0, 31.3,
36.3, 36.5, 47.3, 55.2, 59.3, 60.4, 60.6, 66.7, 67.4, 69.0, 77.2,
98.6, 98.8, 119.7, 119.9, 124.5, 125.0, 127.0, 127.6, 141.3, 144.0,
156.2 and 157.0; further elution with hexane–EtOAc (1 : 5) gave
20 (98 mg, 19%).
Methyl 2,4,6-trideoxy-4-methylamino-ꢀ-D-arabino-hexopyr-
anoside 19
To an HCl–MeOH solution, which had been prepared by
adding AcCl (1.80 cm3, 25.3 mmol) to ice-cooled dry MeOH
(18 cm3), was added a solution of 18 (633 mg, 3.05 mmol) in dry
MeOH (18 cm3) at 0 ЊC and the reaction mixture was refluxed
for 2 h. After the addition of Et3N (4 cm3, 28.7 mmol) at 0 ЊC,
the mixture was concentrated in vacuo. The residue was purified
by repeated flash silica gel chromatography (EtOAc–MeOH,
20 : 1 to 10 : 1) to afford 19 (443 mg, 83%) (Found: C, 54.66; H,
9.85; N, 7.69. Calc. for C8H17NO3: C, 54.84; H, 9.78; N, 7.99%);
[α]D19 ϩ123 (c 1.05, CHCl3); νmax (neat)/cmϪ1 3354, 1446, 1379,
1126, 1105, 972, 908 and 756; δH (300 MHz; CDCl3) 1.30 (d,
J 6.3 Hz, 3H), 1.66 (ddd, J 3.7, 11.2, 12.7 Hz, 1H), 2.06 (t, J 9.9
Hz, 1H), 2.19 (dd, J 5.1, 12.7 Hz, 1H), 2.48 (s, 3H), 3.31 (s, 3H),
3.70 (dq, J 6.3, 9.8 Hz, 1H), 3.81 (ddd, J 5.1, 9.8, 11.5 Hz, 1H)
and 4.75 (d, J 3.4 Hz, 1H); δC (75 MHz; CDCl3) 18.6, 33.1, 37.8,
54.7, 65.5, 66.9, 67.8 and 98.6.
Methyl 2,4,6-trideoxy-4-[(fluoren-9-ylmethoxycarbonyl)methyl-
amino]-ꢀ-D-arabino-hexopyranoside 20
Methyl 2,4,6-trideoxy-4-methylamino-ꢀ-D-ribo-hexopyranoside
(methyl ꢀ-D-vicenisaminide) 1
To a solution of 19 (70 mg, 0.40 mmol) in THF (1.8 cm3)–water
(0.9 cm3) were added sequentially potassium carbonate (341
mg, 2.47 mmol) and FmocCl (297 mg, 1.15 mmol) at 0 ЊC
and the mixture was stirred for 0.5 h. Water was added to the
mixture and the organic layer was separated. The aqueous layer
was extracted twice with Et2O. The combined organic layers
were dried (MgSO4), and concentrated in vacuo. The residue
was purified by flash silica gel chromatography (hexane–
EtOAc, 2 : 1 to 1 : 5) to afford 20 (145 mg, 91%), which was used
To a solution of 22 (236 mg, 0.61 mmol) in EtOAc (34 cm3) was
added DBU (138 cm3, 0.92 mmol), and the mixture was stirred
for 0.5 h at rt. The solvent was removed in vacuo and the residue
was purified by silica gel chromatography (16 g, CHCl3–
MeOH–water, 20 : 1 : 0 to 65 : 25 : 4) to afford 1 (70 mg, 65%)
{HRFAB-MS (glycerol matrix) m/z 176.1273 [(M ϩ H)ϩ. Calc.
for C8H18NO3: m/z, 176.1287]}; [α]D26 ϩ30 (c 0.23, CHCl3); δH (300
574
J. Chem. Soc., Perkin Trans. 1, 2001, 569–577

View Article Online
MHz; CDCl3) 1.32 (d, J 6.1 Hz, 3H, H3-6), 1.85 (ddd, J 3.4, 3.7,
14.6 Hz, 1H, H-2ax), 2.09 (dd, J 2.9, 10.0 Hz, 1H, H-4), 2.15
(ddd, J 1.0, 2.4, 14.6 Hz, 1H, H-2eq), 2.44 (s, 3H, NMe), 3.37 (s,
3H, OMe), 3.71 (dq, J 6.2, 10.0 Hz, 1H, H-5), 4.07 (dd, J 3.2
Hz, 1H, H-3) and 4.77 (d, J 3.4 Hz, 1H, H-1); δC (75 MHz;
CDCl3) 18.6, 33.7, 35.2, 55.1, 62.8, 63.7, 64.0 and 98.4.
mmol) was washed with dry hexane and suspended in dry DMF
(260 cm3). To the suspension was added dropwise the oxazol-
idinone 24 (12.6 g, 51.4 mmol) as a solution in dry DMF (20
cm3) at 0 ЊC and the mixture was stirred for 90 min at rt. The
mixture was recooled to 0 ЊC, and then methyl iodide (8.0 cm3,
128 mmol) was added. The resulting mixture was stirred for
2 h at rt. The reaction mixture was recooled, quenched with
saturated aq. NH4Cl, and extracted three times with Et2O. The
combined organic layer was washed with brine, dried (MgSO4),
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (hexane–EtOAc, 4 : 1 to 7 : 3) to afford
an intermediary TBDMS ether (11.5 g, 86%) as a colorless oil
(Found: C, 55.44; H, 9.91; N, 5.30. Calc. for C12H25NO3Si: C,
55.56; H, 9.71; N, 5.40%); δH (300 MHz; CDCl3) 0.08 (s, 6H),
0.89 (s, 9H), 1.40 (d, J 6.3 Hz, 3H), 2.87 (s, 3H), 3.29 (ddd, J 1.2,
4.6, 5.3 Hz, 1H), 3.70 (dd, J 1.2, 5.3 Hz, 2H) and 4.35 (quin,
J 6.1 Hz, 1H); δC (75 MHz; CDCl3) Ϫ5.7, 18.1, 18.0, 20.6, 25.6,
29.3, 62.3, 65.2 and 72.7.
This was partly transformed into the β-anomer (methyl
β--vicenisaminide) by heating in HCl–MeOH, and it was
confirmed that its spectroscopic data (1H, 13C NMR) as the
hydrochloride salt were identical with those described in ref. 3.
Specific rotation and spectroscopic properties in the NH free
form were identical with those of the naturally derived product;
[α]D23 Ϫ3.6 (NH free, c 0.52, MeOH) [natural origin: [α]D22 Ϫ5.4
(NH free, c 0.46, MeOH)]; δH (300 MHz; CD3OD) 1.16 (d, J 6.3
Hz, 3H, H3-6), 1.45 (ddd, J 2.9, 9.5, 13.4 Hz, 1H, H-2ax), 1.88
(ddd, J 2.2, 3.9, 13.4 Hz, 1H, H-2eq), 2.07 (dd, J 3.2, 9.5 Hz,
1H, H-4), 2.30 (s, 3H, NMe), 3.32 (s, 3H, OMe), 3.59 (dq,
J 6.3, 9.5 Hz, 1H, H-5), 4.10 (q, J 3.2 Hz, 1H, H-3) and 4.58
(dd, J 2.2, 9.5 Hz, 1H, H-1); δC (75 MHz; CD3OD) 19.3, 33.7,
39.3, 56.6, 64.2, 65.5, 71.0 and 100.4; HRFAB-MS (glycerol
matrix) m/z 176.1269 [(M ϩ H)ϩ. Calc. for C8H18NO3: m/z,
176.1287].
To an ice-cooled solution of the TBDMS ether (711 mg, 2.74
mmol) in THF (13.7 cm3) was added TBAF (3.02 cm3, 1.0 M
solution in THF; 3.02 mmol). After stirring for 30 min at rt, the
mixture was concentrated in vacuo. The residue was purified by
silica gel column chromatography (EtOAc) to afford 9 (301 mg,
76%, ≈86% ee by 1H NMR analysis of the corresponding
Mosher ester) as a white solid. After recrystallization from
EtOAc twice, enantiomeric purity was raised to ≈97% ee
(Found: C, 49.92; H, 7.85; N, 9.62. Calc. for C6H11NO3Si: C,
49.65; H, 7.64; N, 9.65%); mp 91.0–92.2 ЊC; [α]D24 Ϫ41.4 (c 1.0,
CHCl3); νmax (CHCl3)/cmϪ1 3629, 3421, 1743, 1437, 1408, 1387,
1250, 1072 and 1039; δH (300 MHz; CDCl3) 1.43 (d, J 6.3 Hz,
3H), 2.46–2.77 (br s, 1H), 2.89 (s, 3H), 3.29 (dt, J 6.1, 3.9 Hz,
1H), 3.62–3.73 (m, 1H), 3.82 (dt, J 11.5, 4.9 Hz, 1H) and 4.96
(quin, J 6.3 Hz, 1H); δC (75 MHz; CDCl3) 20.4, 29.3, 60.5, 65.5,
72.6 and 158.5.
(4S)-4-[(1ЈS)-1Ј-Hydroxyethyl]-2-trichloromethyl-4,5-dihydro-
oxazole 10
To an ice-cooled solution of (2R,3S)-2,3-epoxybutan-1-ol18 12
(7.96 g, 90.3 mmol) and trichloroacetonitrile (10.9 cm3, 108
mmol) in CH2Cl2 (200 cm3) was added DBU (1.41 cm3, 9.03
mmol, 10 mol%). After stirring for 15 min, the reaction mixture
was evaporated to dryness. The residue was subjected to silica
gel column chromatography (hexane–EtOAc, 7 : 3) to afford,
through a spontaneous epoxide opening, 10 (20.9 g, quant.) as
a colorless oil (Found: C, 30.70; H, 3.67; N, 5.84. Calc. for
C6H8Cl3NO2: C, 31.00; H, 3.47; N, 6.02%); δH (300 MHz;
CDCl3) 1.28 (d, J 6.4 Hz, 3H), 2.49 (br s, 1 H), 3.86 (br quin,
J 6.1 Hz, 1H), 4.32 (ddd, J 5.6, 8.3, 9.8 Hz, 1H), 4.46 (t, J 8.31
Hz, 1H) and 4.67 (dd, J 8.5, 9.8 Hz, 1H).
(4S,5S)-4-[(1ЈR)-1Ј-Hydroxybut-3Ј-enyl]-3,5-dimethyloxazol-
idin-2-one 8Ј
To an ice-cooled solution of 9 (2.26 g, 15.6 mmol) in dry
CH2Cl2 (52 cm3) was added Dess–Martin periodinane (9.88 g,
23.4 mmol), and the mixture was stirred for 10 min at the same
temperature and for 30 min at rt. The reaction was quenched
with 10% aq. Na2S2O3, and the mixture was extracted exhaust-
ively with CHCl3. The combined organic layer was washed with
brine, dried (MgSO4), and concentrated in vacuo. The residual
crude aldehyde 25 was used for the next reaction without
purification.
(4S,5S)-4-tert-Butyldimethylsiloxymethyl-5-methyloxazolidin-2-
one 24
To an ice-cooled solution of 10 (15.3 g, 65.8 mmol) and tri-
ethylamine (11.9 cm3, 85.5 mmol) in CH2Cl2 (330 cm3) was
added triphosgene (7.81 g, 26.3 mmol). After stirring of the
mixture for 2 h at rt, 2 M HCl (100 cm3) was added and stirring
was continued for 30 min at rt, and then the resulting mix-
ture was concentrated in vacuo. To a solution of the residue in
MeOH (130 cm3) was added NaOH (3.95 g, 98.7 mmol) and the
mixture was stirred for 30 min at rt. After filtration through a
small pad of Celite, the filtrate was evaporated to give a crude
alcohol.
To an ice-cooled mixture of the crude alcohol and imidazole
(13.4 g, 197 mmol) in DMF (130 cm3) was added TBDMSCl
(24.8 g, 165 mmol) and the resulting mixture was stirred for 2 h
at rt. The reaction was quenched with water, and the mixture
was extracted three times with Et2O. The combined organic
layer was washed with brine, dried (MgSO4), and concentrated
in vacuo. The residue was purified by silica gel column chrom-
atography (hexane–EtOAc, 4 : 1 to 7 : 3) to afford 24 (12.6 g,
78%, 3 steps) as a colorless oil (Found: C, 53.67; H, 9.57; N,
5.44. Calc. for C11H23NO3Si: C, 53.84; H, 9.45; N, 5.71%);
[α]D24 Ϫ29.9 (c 1.1, CHCl3); νmax (CHCl3)/cmϪ1 1755, 1725, 1529,
1434, 1268 and 1241; δH (300 MHz; CDCl3) 0.06 (s, 6H), 0.89 (s,
9H), 1.44 (d, J 6.4 Hz, 3H), 3.48 (q, J 5.3 Hz, 1H), 3.54–3.67 (m,
2H), 4.45 (quin, J 6.3 Hz, 1H) and 6.15–6.31 (br s, 1H); δC (75
MHz; CDCl3) Ϫ5.5 , 18.1, 20.7, 25.7, 60.5, 64.5, 76.1 and 159.4.
To a solution of (ϩ)-B-methoxydiisopinocamphenylborane
(IPC2BOMe) (14.8 g, 46.8 mmol) in freshly distilled THF
(52 cm3) was added dropwise allylmagnesium bromide (39.0
cm3, ≈1 M solution in Et2O; 39.0 mmol) under argon at Ϫ78 ЊC
and the mixture was stirred for 30 min at the same temperature
and for 1 h at rt. The mixture was recooled to Ϫ78 ЊC, a
solution of the crude aldehyde 25 in THF (5 cm3) was added
dropwise, and the resulting mixture was stirred for 2 h at
Ϫ78 ЊC and for 3 h at Ϫ25 ЊC. The reaction was quenched with
saturated aq. NH4Cl, and the mixture was extracted three times
with EtOAc. The combined organic layer was washed with
brine, dried (MgSO4), and concentrated in vacuo. The residue
was purified by flash silica gel column chromatography
(hexane–EtOAc, 3 : 2 to 2 : 3) to afford 8Ј (1.58 g, 55% in 2 steps,
94% de) as a white solid (Found: C, 58.52; H, 8.01; N, 7.49.
Calc. for C9H15NO3: C, 58.36; H, 8.16; N, 7.56%); mp 58.8–
59.2 ЊC; [α]D24 Ϫ37.4 (c 1.01, CHCl3); νmax (KBr)/cmϪ1 3388, 2981,
2902, 1754, 1708, 1411 and 1371; δH (300 MHz; CDCl3) 1.40
(d, J 6.3 Hz, 3H), 2.09–2.23 (m, 1H), 2.24–2.35 (m, 1H), 2.77
(br d, J 3.9 Hz, 1H), 2.90 (s, 3H), 3.33 (t, J 4.9 Hz, 1H), 3.83 (br
sex, J 5.1 Hz, 1H), 4.45 (dt, J 11.0, 6.3 Hz, 1H), 5.18 (d, 6.6 Hz,
1H), 5.23 (s, 1H) and 5.74–5.92 (m, 1H); δC (75 MHz; CDCl3)
21.5, 31.1, 36.5, 67.3, 70.5, 71.8, 119.3, 133.3 and 158.1.
(4S,5S)-4-Hydroxymethyl-3,5-dimethyloxazolidin-2-one 9
Sodium hydride (3.08 g, ≈60% dispersion in mineral oil; 77.1
J. Chem. Soc., Perkin Trans. 1, 2001, 569–577
575

View Article Online
(4S,5S)-3,5-Dimethyl-4-[(1ЈS)-1Ј-(p-nitrobenzoyl)but-3Ј-enyl]
oxazolidin-2-one 26
A solution of the resulting dimethyl acetal (234 mg, 1.00
mmol) in MeOH (3.5 cm3) and 10% aq. NaOH (2 cm3) was
refluxed for 3 h. The reaction mixture was cooled, and concen-
trated in vacuo. The residue was dissolved in a minimum
amount of water and extracted five times with EtOAc. The
combined organic layer was dried (MgSO4), and concentrated
in vacuo. The residue was purified by silica gel column chrom-
atography (EtOAc–MeOH, 10 : 1 to 7 : 3) to afford an amino
alcohol (151 mg, 73%) as a pale yellow syrup (Found: C, 51.85;
H, 10.26; N, 6.63. Calc. for C9H21NO4: C, 52.15; H, 10.21; N,
6.76%); [α]D22 ϩ12.3 (c 1.31, CHCl3); νmax (CHCl3)/cmϪ1 3479,
3006, 2969, 2937, 1456, 1415, 1375, 1124 and 1080; δH (300
MHz; CDCl3) 1.24 (d, J 6.6 Hz, 3H), 1.71–1.93 (m, 2H), 2.18
(br t, J 3.2 Hz, 1H), 2.53 (s, 3H), 3.37 (s, 3H), 3.38 (s, 3H), 3.82–
4.13 (m, 5H) and 4.62 (t, J 5.9 Hz, 1H); δC (75 MHz; CDCl3)
20.7, 35.8, 36.7, 53.3, 53.6, 66.0, 67.4, 68.3 and 103.6.
To an ice-cooled solution of 8Ј (886 mg, 4.78 mmol), triphenyl-
phosphine (1.88 g, 7.18 mmol) and p-nitrobenzoic acid (1.20 g,
7.18 mmol) in dry THF (25 cm3) was added dropwise diethyl
azodicarboxylate (DEAD) (1.13 cm3, 7.18 mmol) under argon
and the mixture was stirred for 10 h at rt. The reaction was
quenched with saturated aq. NaHCO3, and the mixture was
extracted three times with EtOAc. The combined organic layer
was washed with brine, dried (MgSO4), and concentrated
in vacuo. Crystalline by-product (diethylhydrazine-1,2-dicarb-
oxylate) was removed by recrystallization from EtOAc. The
filtrate was concentrated to dryness and the residue was purified
by flash silica gel column chromatography (hexane–EtOAc, 4 : 1
to 2 : 1) to afford 26 (1.28 g, 80%, 100% de) as a colorless syrup
(Found: C, 57.18; H, 5.60; N, 8.15. Calc. for C16H18N2O6: C,
57.48; H, 5.43; N, 8.34%); [α]D24 Ϫ0.2 (c 1.00, CHCl3); νmax
(CHCl3)/cmϪ1 1749, 1531, 1348 and 1101; δH (300 MHz;
CDCl3) 1.50 (d, J 6.3 Hz, 3H), 2.37–2.62 (m, 2H), 2.92 (s, 3H),
3.51 (dd, J 1.7, 4.1 Hz, 1H), 4.75 (d quin, J 4.4, 6.3 Hz, 1H),
5.12–5.26 (m, 2H), 5.50 (ddd, J 1.5, 6.1, 7.8 Hz, 1H), 5.71–5.86
(m, 1H), 8.12–8.19 (br d, J 9.0 Hz, 2H) and 8.27–8.33 (br d,
J 8.8 Hz, 2H); δC (75 MHz; CDCl3) 21.7, 29.6, 34.3, 65.8, 70.3,
70.7, 119.7, 123.7, 130.8, 131.5, 134.5, 150.7, 157.3 and 163.8.
To an HCl–MeOH solution, which had been prepared by
adding AcCl (365 mm3, 5.13 mmol) to ice-cooled dry MeOH
(7.3 cm3), was added a solution of the amino alcohol (151 mg,
0.730 mmol) in dry MeOH (1 cm3) at rt and the reaction
mixture was refluxed for 90 min. After cooling, 1 M NaOH
was added to the mixture, and the resulting mixture was con-
centrated in vacuo. The residual aqueous layer was extracted
five times with EtOAc. The combined organic layer was dried
(MgSO4), and concentrated in vacuo to afford 27 (112 mg,
88%, α : β ≈ 3 : 1) as a pale yellow syrup, which was used without
purification.
(4S,5S)-4-[(1ЈS)-1Ј-Hydroxybut-3Ј-enyl]-3,5-dimethyloxazol-
idin-2-one 8
Methyl 2,4,6-trideoxy-4-dimethylamino-L-lyxo-hexopyranoside
(methyl L-kedarosaminide) 2
To an ice-cooled solution of 26 (1.02 g, 3.06 mmol) in THF
(4 cm3) and MeOH (6 cm3) was added potassium carbonate
(12.7 mg, 9.18 × 10Ϫ2 mmol, 3 mol%) and the mixture was
stirred for 90 min at rt. After filtration through a pad of Celite,
the filtrate was concentrated in vacuo. The residue was purified
by silica gel column chromatography (hexane–EtOAc, 7 : 3 to
2 : 1) afforded 8 (548 mg, 97%) as a white solid (Found: C, 58.47;
H, 8.23; N, 7.56. Calc. for C9H15NO3: C, 58.36; H, 8.16; N,
7.56%); mp 81.2–82.0 ЊC; [α]D23 Ϫ41.1 (c 1.01, CHCl3); νmax
(KBr)/cmϪ1 3448, 2976, 2911, 1749, 1720, 1483, 1444, 1413 and
1157; δH (300 MHz; CDCl3) 1.40 (d, J 6.4 Hz, 3H), 2.09–2.32
(m, 2H), 2.83 (s, 3H), 3.23 (dd, J 1.7, 5.1 Hz, 1H), 3.32–3.39
(m, 1H), 3.92 (br t, J 5.9 Hz, 1H), 4.62 (quin, J 6.1 Hz, 1H), 5.14
(s, 1H), 5.18 (d, 4.1 Hz, 1H) and 5.76–5.92 (m, 1H); δC (75
MHz; CDCl3) 21.6, 29.2, 36.6, 67.2, 67.8, 70.1, 118.5, 133.7 and
158.5.
To a solution of 27 (112 mg, 0.639 mmol) in acetonitrile
(2 cm3)–aq. formaldehyde (274 mm3, 35% aq. solution; 3.20
mmol) was added sodium cyanoborohydride (121 mg, 1.92
mmol) at rt and the reaction mixture was stirred for 15 min,
neutralized with acetic acid, and concentrated in vacuo. The
residue was dissolved in a minimum amount of 1 M NaOH and
extracted five times with EtOAc. The combined organic layer
was dried (MgSO4), and concentrated in vacuo. The residue was
purified by silica gel column chromatography (EtOAc–MeOH,
10 : 1) to afford methyl -kedarosaminide 2 (100 mg, 82%) as a
pale yellow syrup, which was a mixture of isomers (α : β ≈ 4 : 1)
{HRFAB-MS (NBA matrix) m/z 190.1464 [(M ϩ H)ϩ. Calc. for
C9H20NO3: m/z, 190.1443]}; its spectroscopic data shown below
were identical with those described in ref. 8.
α-Anomer: δH (500 MHz; CDCl3) 1.43 (d, J 7.0 Hz, 3H,
H3-6), 1.78 (ddd, J 3.9, 10.3, 13.7 Hz, 1H, H-2ax), 1.91 (ddd,
J 2.7, 5.7, 13.7 Hz, 1H, H-2eq), 2.51 (dd, J 3.3, 5.2 Hz, 1H, H-4),
2.62 (s, 6H, NMe2), 3.33 (s, 3H, OMe), 3.96 (dt, J 5.5, 10.3 Hz,
1H, H-3), 4.13 (dq, J 3.2, 7.0 Hz, 1H, H-5) and 4.82 (br t, J 3.2
Hz, 1H, H-1); δC (125 MHz; CDCl3) 17.9 (C-6), 35.5 (C-2), 44.8
(NMe2), 44.8 (NMe2), 54.8 (OMe), 63.4 (C-3), 63.9 (C-4), 67.6
(C-5) and 97.9 (C-1).
β-Anomer: δH (500 MHz; CDCl3) 1.48 (d, J 6.9 Hz, 3H, H3-6),
1.63 (ddd, J 9.0, 11.3, 13.1 Hz, 1H, H-2ax), 2.05 (ddd, J 2.6, 5.8,
13.2 Hz, 1H, H-2eq), 2.48 (dd, J 2.8, 5.4 Hz, 1H, H-4), 2.66 (s,
6H, NMe2), 3.49 (s, 3H, OMe), 3.71 (dq, J 3.0, 6.9 Hz, 1H, H-3),
3.75 (dt, J 5.7, 11.1 Hz, 1H, H-5) and 4.37 (dd, J 2.7, 9.0 Hz,
1H, H-1); δC (125 MHz; CDCl3) 18.5 (C-6), 37.1 (C-2), 44.9
(NMe2), 44.9 (NMe2), 56.2 (OMe), 63.2 (C-3), 65.8 (C-4), 72.5
(C-5) and 101.5 (C-1).
Methyl 2,4,6-trideoxy-4-methylamino-L-lyxo-hexopyranoside
(methyl N-demethyl-L-kedarosaminide) 27
Ozone was introduced into a solution of 8 (341 mg, 1.84 mmol)
in MeOH (20 cm3) at Ϫ78 ЊC until the color of the solution
became slightly pale blue. Excess of ozone was purged with
a stream of argon. To the mixture were added sequentially
dimethyl sulfide (2.7 cm3, 36.9 mmol) and p-TsOH monohydrate
(31.7 mg, 0.184 mmol, 10 mol%) at Ϫ78 ЊC. The bath was
removed and the solution was allowed to warm gradually to
rt with stirring for 18 h. After the addition of NaHCO3 powder
to the mixture, the whole was concentrated in vacuo. The
residue was suspended with EtOAc, the suspension was filtered
through a pad of Celite, and the solvent was removed in vacuo.
The residue was purified by silica gel column chromatography
(hexane–EtOAc, 1 : 4 to 1 : 9) to afford a dimethyl acetal (432
mg, quant.) as a colorless oil (Found: C, 51.64; H, 8.29; N, 5.84.
Calc. for C10H19NO5: C, 51.49; H, 8.21; N, 6.00%); [α]D23 Ϫ27.9
(c 1.10, CHCl3); νmax (CHCl3)/cmϪ1 3012, 2935, 1743, 1437,
1234 and 1122; δH (300 MHz; CDCl3) 1.40 (d, J 6.8 Hz, 3H),
1.60–1.80 (m, 2H), 2.93 (s, 3H), 3.22 (dd, J 2.2, 5.5 Hz, 1H),
3.28 (d, J 1.9 Hz, 1H), 3.40 (s, 3H), 3.42 (s, 3H), 4.03 (br dd,
J 2.0, 10.6 Hz, 1H), 4.44 (quin, J 5.6 Hz, 1H) and 4.61 (t, 5.3
Hz, 1H); δC (75 MHz; CDCl3) 21.6, 29.8, 34.4, 54.0, 54.5, 65.7,
68.4, 70.5, 103.7 and 158.3.
Acknowledgements
We thank Dr K. Shindo of Kirin Brewery Co. Ltd. for kindly
supplying natural vicenistatin.
This work was supported in part by the ‘Research for the
Future’ Program of The Japan Society for the Promotion of
Science (JSPS-RFTF96I 00302) and partly by a Grant in
Aid for Scientific Research (11480160 and 11760089) from the
Ministry of Education, Science, Sports and Culture.
576
J. Chem. Soc., Perkin Trans. 1, 2001, 569–577

View Article Online
11 Y. Ichikawa, M. Osada, I. I. Ohtani and M. Isobe, J. Chem. Soc.,
References
Perkin Trans. 1, 1997, 1449.
1 A. C. Weymouth-Wilson, Nat. Prod. Rep., 1997, 14, 99.
2 L. G. Paloma, J. A. Smith, W. J. Chazin and K. C. Nicolaou, J. Am.
Chem. Soc., 1994, 116, 3697.
3 K. Shindo, M. Kamishohara, A. Odagawa, M. Matsuoka and
H. Kawai, J. Antibiot., 1993, 46, 1076.
12 M. Hornyák, I. F. Pelyvás and F. J. Sztarieskai, Tetrahedron Lett.,
1993, 34, 4087.
13 T. Vuljanic, J. Kihlberg and P. Somfai, Tetrahedron Lett., 1994, 35,
6937; T. Vuljanic, J. Kihlberg and P. Somfai, J. Org. Chem., 1998, 63,
279.
4 H. Arai, Y. Matsushima, T. Eguchi and K. Kakinuma, Tetrahedron
Lett., 1998, 39, 3181.
5 Y. Matsushima, H. Itoh, T. Eguchi and K. Kakinuma, J. Antibiot.,
1998, 51, 688.
14 M. J. Lear and M. Hirama, Tetrahedron Lett., 1999, 40, 4897.
15 B. Bernet and A. Vasella, Tetrahedron Lett., 1983, 24, 5491.
16 U. Schmidt, M. Respondek, A. Lieberknecht, J. Werner and
P. Fischer, Synthesis, 1989, 256.
6 Y. Matsushima, T. Nakayama, M. Fujita, R. Bhandari, T. Eguchi,
K. Shindo and K. Kakinuma, J. Antibiot., in the press.
7 J. E. Leet, D. R. Schroeder, D. R. Langley, K. L. Colson,
S. Huang, S. E. Klohr, M. S. Lee, J. Golik, S. J. Hofstead, T. W.
Doyle and J. A. Matson, J. Am. Chem. Soc., 1993, 115, 8432; 1994,
116, 2233.
8 J. E. Leet, J. Golik, S. J. Hofstead and J. A. Matson,
Tetrahedron Lett., 1992, 33, 6107.
9 S. Kawata, S. Ashizawa and M. Hirama, J. Am. Chem. Soc.,
1997, 119, 12012.
17 S. Hatakeyama, H. Matsumoto, H. Fukuyama, Y. Mukugi and
H. Irie, J. Org. Chem., 1997, 62, 2275.
18 Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, S. Masamune and
K. B. Sharpless, J. Am. Chem. Soc., 1987, 109, 5765.
19 P. K. Jadhav, K. S. Bhat, P. T. Perumal and H. C. Brown, J. Org.
Chem., 1986, 51, 432.
20 C. J. Li and T. H. Chan, Tetrahedron Lett., 1991, 32, 7017; C. J. Li
and T. H. Chan, Tetrahedron, 1999, 55, 11149 and references cited
therein.
21 U. Schmidt, K. Mundinger, R. Mangold and A. Lieberknecht,
J. Chem. Soc., Chem. Commun., 1990, 1216.
10 H. A. Kirst, S. H. Larsen, J. W. Paschal, J. L. Occolowitz, L. C.
Creemer, J. L. Rios Steiner, E. Lobkovsky and J. Clardy, J. Antibiot.,
1995, 48, 990.
22 A. W. M. Lee, V. S. Martin, S. Masamune, K. B. Sharpless and
F. J. Walker, J. Am. Chem. Soc., 1982, 104, 3515.
J. Chem. Soc., Perkin Trans. 1, 2001, 569–577
577