A new simple route to deoxyamino sugars from non-sugar material: Synthesis of D-tolyposamine and 4-epi-D-tolyposamine and formal synthesis of D-vicenisamine

Article abstract of DOI:10.1016/j.tetlet.2005.09.195

A new, simple strategy has been formulated for the synthesis of deoxyamino sugars from a non-sugar starting material. Starting from the enantiomerically pure diol obtained from ethyl sorbate by Sharpless asymmetric dihydroxylation, the synthesis of two ty

Full text of DOI:10.1016/j.tetlet.2005.09.195

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8609–8612
A new simple route to deoxyamino sugars from non-sugar
material: synthesis of D-tolyposamine and 4-epi-D-tolyposamine
and formal synthesis of D-vicenisamine
Yoshitaka Matsushima* and Jun Kino
Department of Chemistry, Hamamatsu University School of Medicine, Handayama, Hamamatsu 431-3192, Japan
Received 17 August 2005; revised 22 September 2005; accepted 26 September 2005
Available online 20 October 2005
Abstract—A new, simple strategy has been formulated for the synthesis of deoxyamino sugars from a non-sugar starting material.
Starting from the enantiomerically pure diol obtained from ethyl sorbate by Sharpless asymmetric dihydroxylation, the synthesis of
two types of 2,3,4,6-tetradeoxy-4-amino sugars—D-tolyposamine and 4-epi-D-tolyposamine—, and formal synthesis of 2,4,6-tri-
deoxy-4-amino sugar—D-vicenisamine—were performed.
Ó 2005 Elsevier Ltd. All rights reserved.
Amino sugars, especially deoxyamino sugars, are found
in clinically important antibiotics such as antimicrobial
macrolides and anthracycline antitumor antibiotics.1
In most instances, the sugar parts of these antibiotics
are essential for biological activity; however, the func-
tions of the sugar moieties have not yet been evaluated.2
and was recently found in P371 A1—a novel angucy-
cline compound that possesses antigastrin and gastric
mucosal protective properties in the form wherein its
amino group is substituted for an ureido group.7 Vice-
nisamine is a novel deoxyamino sugar component of
the antitumor antibiotic vicenistatin isolated from Strep-
tomyces sp. HC-34.8
We envisaged that a modification of the sugar moieties
of these antibiotics may serve as a tool for investigating
the significance of amino sugars and the structure–activ-
ity relationship. For this purpose, a versatile and syn-
thetic route for deoxyamino sugars is highly desirable.
Furthermore, we expected that such a route would also
be beneficial for elucidating the biosynthetic route of
antibiotics.3,4 We were especially interested in develop-
ing a new synthetic route for deoxyamino sugars from
a non-sugar material.5
In this letter, we describe a novel strategy to synthesise
methyl N-Ts-D-tolyposaminide and methyl N-Ts-4-
epi-D-tolyposaminide, and a formal synthesis of methyl
D-vicenisaminide starting from the same chiral diol
available in both enantiomers by Sharpless asymmetric
dihydroxylation (AD). Methyl N-Ac-L-tolyposaminide9
and methyl N-Boc-4-epi-D-tolyposaminide10 were previ-
ously synthesised from ethyl (S)-3-hydroxybutyrate
and L-threonine derivative, respectively, using different
approaches.11 In addition, methyl D-vicenisaminide
was previously synthesised from a sugar material12 and
a chiral epoxy alcohol.5
Our target deoxyamino sugars were tolyposamine and
its diastereomers, namely, two types of 2,3,4,6-tetra-
deoxy-4-aminohexoses—the simplest class among
deoxyamino sugars and a kind of 2,4,6-trideoxy-4-amino-
hexose—D-vicenisamine. Tolyposamine is recognised as
an amino sugar moiety of the antibiotic tolypomycin Y6
Starting chiral diol 113,14 was obtained from commer-
cially available ethyl sorbate15 by Sharpless asymmetric
dihydroxylation using dihydroquinidine phthaladine
[(DHQD)2PHAL] as a chiral ligand (AD-mix b) in an
86% yield (Scheme 1). The selective protection of the
5-hydroxyl group of diol 1 by the tert-butyldimethylsilyl
(TBS) group furnished the ether 216 in a 64% yield.
Although, the resulting compound was the desired regio-
isomer 2 just as anticipated, it was actually confirmed
Keywords: Deoxyamino sugar; Sharpless asymmetric dihydroxylation;
Tolyposamine; Iodocyclisation; Vicenisamine.
*
Corresponding author. Tel./fax: +81 53 435 2319; e-mail: ymatsu@
hama-med.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.195

8610
Y. Matsushima, J. Kino / Tetrahedron Letters 46 (2005) 8609–8612
TBSO
HO
TBSO
a
c
b
5
CO2Et
CO2Et
CO2Et
CO2Et
ethyl sorbate
4
N3
OH
OH
2 (93% e.e.)
1
3
O
Me
TBSO
O
e
d
f
O
Ts
N
H
CO2Et
NHTs
OMe
NHTs
5
4
methyl N-Ts-α-D-tolyposaminide 6
Scheme 1. Reagents and conditions: (a) AD-mix-b, CH3SO2NH2, ButOH–H2O, 0 °C (86%); (b) TBSCl, Et3N, DMAP, CH2Cl2, rt (64%; SM: 7%, 4-
isomer: 8%, di-isomer: 20%); (c) (i) p-NO2–C6H4SO2Cl, DMAP, pyridine, 0 °C; (ii) NaN3, DMF, rt (80%, two steps); (d) (i) H2, cat. 10% Pd–C,
EtOAc, rt; (ii) TsCl, Na2CO3, toluene–H2O, rt (80%, two steps); (e) CF3CO2H, THF–H2O, 0 °C–rt (82%); (f) (i) DIBAL, THF–toluene, ꢀ78 °C; (ii)
PPTS, CH(OCH3)3, MeOH, rt (91%, two steps).
in the next step.17 The enantiomeric purity of 2 was
determined to be 93% ee by H NMR analysis of the
gen of 5-carbamate is commonly known as the palla-
dium-mediated double inversion process. This reaction
involving the same substrate using tetrakis(tri-
isopropylphosphite)palladium(0), Pd[P(OPri)3]4 as a pal-
ladium(0) catalyst was reported by Xu and Sharpless.19
However, the use of commercially available tetrakis(tri-
phenylphosphine)palladium(0), Pd(PPh3)4 improved the
chemical yield and availability of the reaction. The dou-
ble bond of the obtained cyclic carbamate 7 was then
hydrogenated in the presence of 10% Pd–C catalyst,
and the product was successively subjected to alkaline
hydrolysis and treatment with trifluoroacetic acid for a
smooth formation of the d-lactone 8 (72%, two steps).
Penultimate half reduction by DIBAL at ꢀ78 °C and
subsequent final methyl acetal formation were success-
fully carried out to produce the desired methyl 4-epi-
N-Ts-D-tolyposaminide 9 exclusively as a-anomer in a
94% yield.
1
corresponding ester with (+)/(ꢀ)-MTPA (a-methoxy-
a-trifluoromethylphenylacetic acid).18 The next step
was the introduction of the nitrogen functional group.
Sulfonylation of the hydroxy group of compound 2 fol-
lowed by azide ion nucleophilic displacement afforded
azide 3 (80% yield, two steps). The azide group of 3
was then hydrogenated in the presence of a 10% Pd–C
catalyst to produce the amino group, which was succes-
sively protected by the p-toluenesulfonyl (Ts) group.
During the course of the reduction, the double bond
was also hydrogenated to obtain 4 (80% yield, two
steps). Removal of the TBS protecting group of 4 and
spontaneous lactone formation were carried out by
treatment with trifluoroacetic acid (TFA) in THF and
water to afford d-lactone 5 (82%). Half reduction of
d-lactone 5 was effected by using diisopropylaluminium
hydride (DIBAL) in THF–toluene at ꢀ78 °C to produce
hemiacetal (lactol). The obtained lactol was immedi-
ately dissolved in methanol and treated with pyridinium
p-toluenesulfonate (PPTS) and trimethyl orthoformate
to produce the desired methyl N-Ts-D-tolyposaminide
as an anomeric mixture, which was converged to an
almost single a-anomer 6 during the course of the reac-
tion in an excellent yield (91%, two steps).
Iodocyclisation of the carbamate, so-called iodocyclo-
carbamation, is a well-documented method for the
heterofunctionalisation of alkenes,20 however, the exam-
ples involving electron deficient olefins are rare.21 In
an attempt to expand our strategy to the synthesis of
2,4,6-trideoxy-4-aminosugars, we successfully used the
iodocyclisation of the carbamate based on the (E)-a,b-
unsaturated ester moiety indigenous to the starting
materials (Scheme 3). Firstly, the azide group of the
intermediate 13 in the tolyposamine synthesis was
reduced to primary amine by treatment with triphenyl-
phosphine and water in THF with gentle warming. Thus
obtained primary amine was subsequently protected
by carbobenzoxy (Cbz) group, which should be used
as an origin of the oxygen functional group, namely
3-hydroxy group, to furnish compound 10 (89%, two
steps). The methyl group on the amino nitrogen was
Next, a nitrogen functional group was intramolecularly
introduced to the diastereomeric isomer 4-epi-D-tolypos-
amine via the intermediary 4,5-di-carbamates from the
same starting diol 1 (Scheme 2). The reaction was effec-
tively carried out in the presence of the Pd(0) catalyst to
form a cyclic carbamate 7 in an 86% yield.19 The mech-
anism involving the SN2 nucleophilic displacement of
the leaving group (4-carbamate) by Pd(0) followed by
a second displacement of Pd by the nucleophilic nitro-
O
Ts
NH
O
Me
a
c
b
O
CO2Et
1
O
NTs
O
OMe
methyl 4-epi-N-Ts-α-D-tolyposaminide 9
NHTs
8
7
Scheme 2. Reagents and conditions: (a) Ts-N@C@O, cat. Pd(PPh3)4, THF, reflux (86%); (b) (i) H2, cat. 10% Pd–C, EtOAc, rt; (ii) 4 M NaOH,
MeOH, rt; evaporation; CF3CO2H, THF, rt (72%, two steps); (c) (i) DIBAL, THF–toluene, ꢀ78 °C; (ii) PPTS, CH(OCH3)3, MeOH, rt (94%, two
steps).

Y. Matsushima, J. Kino / Tetrahedron Letters 46 (2005) 8609–8612
8611
TBSO
O
TBSO
TBSO
3
c
b
a
CO2Et
CO2Et
CO2Et
4
N
R
N
N3
Me
O
R
Cbz
10: R = H
11: R = Me
3
12: R = I
13: R = H
TBSO
Me
O
R1
R2
HO HO OMe
Me
Me
lit. 5
O
d
HN
OMe
N
NH
HO
OMe
Me
O
14: R1 = H; R2 = OH
15: R1 = R2 = OMe
methyl α-D-vicenisaminide
16
Scheme 3. Reagents and conditions: (a) (i) PPh3, H2O, THF, 50 °C; (ii) benzyl chloroformate, NaHCO3, dioxane, H2O, 0 °C (89%, two steps); (b) (i)
iodine, NaHCO3, CH3CN, 0 °C (94%); (ii) Bun3SnH, AIBN, benzene, reflux (quantitative); (c) (i) NaBH4, LiCl, THF–EtOH, rt (94%); (ii) Dess–
Martin periodinane, CH2Cl2, 0 °C; (iii) p-TsOHÆH2O, CH(OCH3)3, CH3OH (77%, two steps); (d) 10% NaOH aq, CH3OH, reflux (60%).
Ph
O
O
Ph
O
O
Me
I+
Me
O
H
N
N
O
Me
R
I
O
N
Me
R
O
N
<<
H
CO2Et
H
EtO2C
H
I
EtO2C
H
R
H
H
H
H
H
H
R
EtO2C
H
I+
cis-2-oxazolidinone 12′
trans-2-oxazolidinone 12
cis-TS model
unfavorable
trans-TS model
favorable
OTBS
R =
Figure 1. Proposed transition state models for iodocyclocarbamation.
introduced at this point to give compound 11 in excel-
lent yield (98%). The next key iodocyclocarbamation
was performed with iodine in acetonitrile at 0 °C in
the presence of sodium hydrogen bicarbonate, which
was used to prevent TBS protecting group from being
removed during the course of the reaction. Conse-
quently, compound 11 underwent a facile cyclisation
with extremely high diastereoselective formation of the
trans-product 12 in 94% yield along with a small amount
of the cis-product (2%). It was reported that in an oxa-
zolidinone ring the large coupling constant corre-
sponded to cis form and the small one to trans form.22
Therefore, its small coupling constant (JH-3,4 = 2.8 Hz)
implied trans stereochemistry of compound 12. Addi-
tionally, the stereochemistry of the trans-product 12
was confirmed by nuclear Overhauser enhancement
(NOE) experiment as follows: irradiation of H-4 yielded
an NOE of ca. 10% on the H-2, whereas a relatively
small NOE (3%) was observed on H-3. Stereoselectivity
as described above in the cyclisation can be explained
using the transition state (TS) models shown in Figure
1. The cyclisation is thought to proceed through the
trans-TS model to give the trans-oxazolidinone product,
namely the trans-product 12, since cis-TS model is obvi-
ously unfavourable than trans-TS model due to its steric
hindrance between the side chain R and the alkenyl
group.22
in the presence of 2,20-azobis(isobutyronitrile) (AIBN)
in boiling benzene to furnish compound 13 in quantita-
tive yield. Then, the reduction of the ester group of com-
pound 13 was readily achieved by sodium borohydride
and lithium chloride to give alcohol 14 in 94% yield.
Thus obtained alcohol 14 was oxidised by Dess–Martin
periodinane to furnish a corresponding aldehyde, which
was spontaneously transformed in dimethyl acetal 15
(77% in two steps). Finally, the cyclic carbonate group
along with the silyl protective group of acetal 15 was re-
moved by alkaline hydrolysis to give the advanced inter-
mediate 165 for the synthesis of methyl D-vicenisaminide
(60% yield). The spectral data (1H and 13C NMR, IR) of
16 derived from the chiral diol 1 were identical to those
of previously prepared sample.5
In conclusion, we have successfully synthesised N-Ts-D-
tolyposamine and N-Ts-4-epi-D-tolyposamine as their
methyl hexopyranosides,23 thus demonstrating our syn-
thetic strategy for 2,3,4,6-tetradeoxy-4-amino sugars
using easily available non-sugar starting chiral diol 1
in a versatile manner. Furthermore, we have described
a formal synthesis of methyl D-vicenisaminide using
iodocyclocarbamation, showing our synthetic strategy
was applicable to the synthesis of 2,4,6-trideoxy-4-
aminosugars.
The final manipulation of our work was the transforma-
tion to the intermediate compound for the vicenisamine
synthesis. To this end, reductive deiodination of com-
pound 12 was first realised with tri-n-butyltin hydride
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research (17780089) and a 21st century COE

8612
Y. Matsushima, J. Kino / Tetrahedron Letters 46 (2005) 8609–8612
17. The observed peak shift of the H-4 signal during the next
sulfonylation undoubtedly indicates the regioselectivity in
the TBS protection [2: dH-4 4.05 (ddd, J = 1.5,5.8,5.8 Hz)
and the corresponding p-nitrotoluenesulfonate: dH-4 5.95
(ddd, J = 1.5, 5.8, 5.8 Hz)].
18. The signals due to the H-2 appeared in distinctly different
fields [ester from (+)-MTPA: dH-2 5.82 (dd, J =
1.7,16.0 Hz) and ester from (ꢀ)-MTPA: dH-2 5.95 (dd,
J = 1.5, 15.8 Hz)].
program (Hamamatsu University School of Medicine,
Medical Photonics) from the Ministry of Education,
Culture, Sports, Science, and Technology of Japan.
The authors would like to thank the technical staff
(M. Suzuki and M. Toyama) and the students (N.
Watanabe and K. Katahashi) of Hamamatsu University
School of Medicine for their support.
19. Xu, D.; Sharpless, K. B. Tetrahedron Lett. 1993, 34, 951–
952.
References and notes
20. For a recent report on the use of iodocyclocarbamation in
natural product synthesis, see: Davies, S. G.; Haggitt, J.
R.; Ichihara, O.; Kelly, R. J.; Leech, M. A.; Mortimer, A.
J. P.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem.
2004, 2, 2630–2649.
21. For a few reports on the natural product synthesis,
especially amino acids containing hydroxyl group, see:
DellꢀUomo, N.; Giovanni, M. C. D.; Misiti, D.; Zappia,
G.; Monache, G. D. Liebigs Ann. Chem. 1994, 641–644,
and references cited therein.
1. Weymouth-Wilson, A. C. Nat. Prod. Rep. 1997, 14, 99–
110.
2. Paloma, L. G.; Smith, J. A.; Chazin, W. J.; Nicolaou,
K. C. J. Am. Chem. Soc. 1994, 116, 3697–3708.
3. Nedal, A.; Zotchev, S. B. Appl. Microbiol. Biotechnol.
2004, 64, 7–15.
4. Yu, T.-W.; Muller, R.; Muller, M.; Zhang, X.; Draeger,
¨
¨
G.; Kim, C.-G.; Leistner, E.; Floss, H. G. J. Biol. Chem.
2001, 276, 12546–12555.
5. Matsushima, Y.; Nakayama, T.; Tohyama, S.; Eguchi, T.;
Kakinuma, K. J. Chem. Soc., Perkin Trans. 1 2001, 569–
577.
22. Sugimura, H.; Miura, M.; Yamada, N. Tetrahedron:
Asymmetry 1997, 8, 4089–4099, and references cited
therein.
6. Kishi, T.; Yamana, H.; Muroi, M.; Harada, S.; Asai, M.;
Hasegawa, T.; Mizuno, K. J. Antibiot. 1972, 11–15, and
references cited therein.
7. Uesato, S.; Tokunaga, T.; Takeuchi, K. Bioorg. Med.
Chem. Lett. 1998, 8, 1969–1972.
8. Shindo, K.; Kamishohara, M.; Odagawa, A.; Matsuoka,
M.; Kawai, H. J. Antibiot. 1993, 46, 1076–1081.
9. Koskinen, A. M. P.; Otsomaa, L. A. Tetrahedron 1997, 53,
6473–6484.
10. Guanti, G.; Banfi, L.; Narisano, E.; Riva, R. Tetrahedron
Lett. 1992, 33, 2221–2222.
11. Syntheses of D, or L-tolyposamine from carbohydrate
precursors and non-stereospecific synthesis of DL-tolypos-
amine derivatives from non-sugar material have also been
reported. See Malik, A.; Afza, N.; Voelter, W. Liebigs
Ann. Chem. 1984, 636–640, and references cited therein.
12. Ichikawa, Y.; Osada, M.; Ohtani, I. I.; Isobe, M. J. Chem.
Soc., Perkin Trans. 1 1997, 1449–1455.
13. Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem.
Soc. 1992, 114, 7570–7571.
14. Becker, H.; Soler, M. A.; Sharpless, K. B. Tetrahedron
1995, 51, 1345–1376.
23. The data for compounds 6 and 9 are listed below. Meth-
yl 2,3,4,6-tetradeoxy-4-(p-toluenesulfonylamino)-a-D-ery-
29
thro-hexopyranoside 6: ½aꢁD ꢀ60.8 (c 1.08, CHCl3); mmax
(neat)/cmꢀ1 3512, 2978, 2937, 1344, 1213, 1161, 1093,
1068, 997 and 675; dH (270 MHz, CDCl3) 7.70 (d,
J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 5.06 (d,
J = 5.3 Hz, 1H), 4.15–4.04 (m, 1H), 3.60 (ddd, J = 1.7,
8.3, 8.3 Hz, 1H), 3.47 (s, 3H), 2.83 (br d, J = 3.8 Hz, 1H),
2.44 (s, 3H), 2.10–1.94 (m, 1H), 1.85–1.62 (m, 2H), 1.27–
1.08 (m, 1H), 1.14 (d, J = 6.4 Hz, 3H); dC (67.8 MHz,
CDCl3) 144.0, 153.3, 129.9, 127.3, 93.1, 68.2, 66.7, 55.3,
31.9, 23.1, 21.5 and 18.1. Anal. Calcd for C14H21NO4:
C, 56.16; H, 7.07; N, 4.68. Found: C, 56.03; H, 7.13;
N, 4.85. Methyl 2,3,4,6-tetradeoxy-4-(p-toluenesulfonyl-
29
amino)-a-D-threo-hexopyranoside 9: ½aꢁD +60.2 (c 1.01,
CHCl3); mmax (neat)/cmꢀ1 3494, 2981, 2937, 1342, 1213,
1161, 1093, 1074, 997 and 675; dH (270 MHz, CDCl3) 7.70
(d, J = 8.1 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 5.13 (d,
J = 5.1 Hz, 1H), 3.78–3.64 (m, 1H), 3.67 (br s, 1H), 3.48 (t,
J = 7.7 Hz, 1H), 3.44 (s, 3H), 2.44 (s, 3H), 1.83–1.68 (m,
3H), 1.21–1.03 (m, 1H), 1.17 (d, J = 6.2 Hz, 3H); dC
(67.8 MHz, CDCl3) 144.1, 135.1, 130.0, 127.4, 93.8, 71.4,
66.8, 55.0, 32.0, 26.7, 21.5 and 19.5. Anal. Calcd for
C14H21NO4: C, 56.16; H, 7.07; N, 4.68. Found: C, 56.43;
H, 7.24; N, 4.89.
15. Tokyo Kasei Kogyo Co. sells ethyl sorbate for ca. 40 yen/g.
16. All new compounds (2–6, 8–15) were fully characterised
with relevant spectroscopic data and elemental analyses.