A versatile route to 2,4,6-trideoxy-4-aminohexoses: Stereoselective syntheses of D-vicenisamine and its epimers via iodocyclization of carbamate

Article abstract of DOI:10.1016/j.tet.2017.10.009

Stereoselective syntheses of the 2,4,6-trideoxy-4-amino sugar D-vicenisamine and its epimers 3-epi- and 4-epi-D-vicenisamine were accomplished via stereoselective nitrogen functional group introduction and iodocyclization of carbamate. This versatile synt

Full text of DOI:10.1016/j.tet.2017.10.009

Tetrahedron xxx (2017) 1e9
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A versatile route to 2,4,6-trideoxy-4-aminohexoses: Stereoselective
syntheses of
carbamate
D
-vicenisamine and its epimers via iodocyclization of
,
Yoshitaka Matsushima a *, Jun Kino b
a Department of Applied Biology and Chemistry, Tokyo University of Agriculture, Sakuragaoka, Setagaya-ku 156-8502, Japan
b Department of Chemistry, Hamamatsu University School of Medicine, Handayama, Hamamatsu 431-3192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective syntheses of the 2,4,6-trideoxy-4-amino sugar D-vicenisamine and its epimers 3-epi- and
4-epi-D-vicenisamine were accomplished via stereoselective nitrogen functional group introduction and
iodocyclization of carbamate. This versatile synthetic route started from the enantiomerically pure diol
obtained from ethyl sorbate by Sharpless asymmetric dihydroxylation.
© 2017 Elsevier Ltd. All rights reserved.
Received 23 August 2017
Received in revised form
29 September 2017
Accepted 6 October 2017
Available online xxx
Keywords:
Deoxyamino sugar
Iodocyclization
Vicenisamine
Asymmetric synthesis
Sharpless asymmetric dihydroxylation
1. Introduction
characteristic of this compound is its significant inhibitory activity,
especially against HL-60 (human leukemia) and COLO205 (human
Sugar components, especially deoxy and deoxyamino sugars,
are found in clinically important antibiotics, such as antimicrobial
macrolides and antitumor antibiotics.1 In most cases, the sugar
components of these antibiotics are essential for biological activity;
however, the functions of the sugar moieties have not been
investigated thus far.2 We envisaged that modification of the sugar
moieties of these antibiotics could serve as a tool for investigating
the significance of the corresponding sugars and their structur-
eeactivity relationships and for elucidating the biosynthetic route
for antibiotics.3 For this purpose, a versatile synthetic route for
deoxy and deoxyamino sugars is highly desirable. Thus far, we have
been interested in developing new synthetic routes, especially for
deoxyamino sugars4 and branched-chain sugars, such as noviose,5
from non-sugar materials.
colon carcinoma) in vitro and Co-3 (human colon carcinoma)
in vivo.6 The entire structure of vicenistatin, including its absolute
configuration, was proposed from degradation studies6,7 and was
confirmed during the course of synthetic studies toward the first
total synthesis.8
Vicenistatin has received considerable attention because of its
potential as a new anticancer drug. Similarly, the biosynthetic
pathway of vicenistatin has been extensively studied.9 Vicenistatin
was also recently identified as a biologically active molecule from
the National Cancer Institute (NCI) libraries using
a high-
throughput yeast halo assay.10 In addition, a novel macrolactam
antibiotic, sannastatin, whose structure is closely related to that of
vicenistatin Fig. 1, i.e. it has the same deoxyamino sugar vicenis-
amine, was newly isolated, together with vicenistatin, as a growth
inhibitor against brine shrimp (Artemia salina) larvae.11 Recently, a
total synthesis of vicenistatin was newly reported, along with its
structureeactivity relationship, especially for the macrolactam
skeleton.12 In this study, the vicenisamine sugar moiety was syn-
thesized as a protected glycosyl donor using an intramolecular
epoxide opening reaction via the carbamate. Further, the Tsukuba
Vicenistatin (1), an antitumor antibiotic isolated from Strepto-
myces sp. HC-34, has a unique structure that includes a 20-
membered macrocyclic lactam aglycone and an unprecedented
deoxyamino sugar,
D
-vicenisamine Fig. 1.6 A major biological
group very recently suggested that vicenistatin is
a novel
* Corresponding author.
E-mail address: ym205308@nodai.ac.jp (Y. Matsushima).
https://doi.org/10.1016/j.tet.2017.10.009
0040-4020/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Matsushima Y, Kino J, A versatile route to 2,4,6-trideoxy-4-aminohexoses: Stereoselective syntheses of D-
vicenisamine and its epimers via iodocyclization of carbamate, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.009

2
Y. Matsushima, J. Kino / Tetrahedron xxx (2017) 1e9
precursor for deoxyamino sugars with a 3,4-aminoalcohol moiety,
especially vicenisamine. Notably, oxazolidinone derivatives B could
be prepared by iodocyclization of the carbamate based on the (E)-
a,b-unsaturated ester moiety indigenous to the starting materials
expectantly with 1,2-asymmetric induction. Moreover, carbamates
C could be prepared, in turn, from chiral diol 2 via regioselective
introduction of a nitrogen functional group with inversion or
retention of the stereochemistry of the 4-hydroxy group. Evidently,
both enantiomers of the starting chiral diol 2 are easily obtained by
Sharpless AD.
Starting chiral diol 217 was acquired in 88% yield from
commercially available ethyl sorbate18 by Sharpless AD (AD-mix
b)
using (DHQD)2PHAL (dihydroquinidine phthalazine) as a chiral
ligand.19 A similar chiral diol obtained from tert-butyl sorbate and
its epimer were reported by the Kitasato group as chiral starting
materials for macrosphelides.20
The first stage in this synthesis involved the introduction of the
nitrogen functional group with inversion of the stereochemistry of
the 4-hydroxy group of diol 2. In our preliminary report,4a we
conducted this transformation in 51% yield (three steps). Protection
of the 5-hydroxy group of diol 2 with a tert-butyldimethylsilyl (TBS)
group furnished the corresponding ether with moderate selectivity
and 64% yield, along with substantial amounts of the starting diol
(7%), its regioisomer (8%), and di-TBS ether (20%). Subsequent sul-
fonylation of the 4-hydroxy group was followed by azide ion
nucleophilic displacement (80%, two steps). The enantiomeric pu-
rity of diol 2 was estimated as 93% ee by 1H NMR analysis of the
thus-obtained 5-OH mono-TBS-protected alcohol as its
Fig. 1. Structures of vicenistatin and related compounds.
compound that induces the formation of early endosome-derived
vacuole-like structures in cells by activating Rab5 and by
increasing the fluidity of the membrane surface.13
Interestingly, instead of vicenisamine, a new congener, vice-
nistatin M, which contains a neutral sugar moiety, D-mycarose (2,6-
(þ)/(ꢀ)-MTPA
(a-methoxy-a-trifluoromethylphenylacetic acid)
dideoxy-3-C-methyl-D-ribo-hexose) Fig. 1 and shows no cytotox-
ester, as described previously.4a,4b In this report, we successfully
conducted selective transformation via a cyclic thionocarbonate in
icity, was isolated during the course of biosynthetic studies.14 This
finding strongly suggests that the vicenisamine amino sugar plays
an important role in the cytotoxicity of vicenistatin.
Methyl D-vicenisaminide has been previously synthesized from
a sugar material,15 a chiral epoxy alcohol,8b ethyl sorbate,4a and
methyl sorbate.16 However, practical and generic approaches for
obtaining vicenisamine and its isomers are still desirable from the
viewpoint of producing vicenistatin derivatives or biosynthetic
tools. In our opinion, the previously reported synthetic routes are
not fully satisfactory in all these respects. In this paper, we describe
a versatile strategy for the synthesis of
D-vicenisamine and its
epimers (3-epi- and 4-epi- -vicenisamine) starting from a chiral
D
diol (2). The diol is afforded in both enantiomers by Sharpless
asymmetric dihydroxylation (AD) of commercially available ethyl
sorbate.
2. Results/discussion
From the retrosynthetic analysis of vicenisamine and its isomers
A Scheme 1, we assumed that oxazolidinones B would be a suitable
Scheme 1. Retrosynthetic analysis of vicenisamine and its isomers.
Scheme 2. Synthesis of vicenisamine and 3-epimer from chiral diol 2.
Please cite this article in press as: Matsushima Y, Kino J, A versatile route to 2,4,6-trideoxy-4-aminohexoses: Stereoselective syntheses of D-
vicenisamine and its epimers via iodocyclization of carbamate, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.009

Y. Matsushima, J. Kino / Tetrahedron xxx (2017) 1e9
3
excellent yield Scheme 2. Diol 2 was transformed to cyclic thio-
nocarbonate 3 and selective nucleophilic attack by the azide ion
was performed.21 The resulting free 5-hydroxy group of compound
4 was then protected with a TBS group to afford compound 5 in 81%
yield (three steps).
Among many methods for the heterofunctionalization of al-
kenes, iodocyclization of carbamates, so-called iodocyclocarbama-
tion, is a well-documented method.22 However, examples of
reaction with the electron-deficient olefins are exceptional.23
Usefully, iodocyclization of carbamates involving electron-
deficient olefins has been reported to be greatly facilitated by sil-
ver triflate.24 In an attempt to establish our strategy for synthe-
sizing 2,4,6-trideoxy-4-amino sugars, we successfully used
give alcohol 10 in 94% yield. Thus-obtained primary alcohol 10 was
oxidized using DesseMartin periodinane to furnish the corre-
sponding aldehyde, which was subsequently treated with p-tol-
uenesulfonic acid (p-TsOH) in MeOH in the presence of methyl
orthoformate to afford crystalline dimethyl acetal 11 (85% yield,
two steps). Finally, the TBS protective group and cyclic carbonate
group of acetal 11 were removed by alkaline hydrolysis with
refluxing NaOH in H2O/MeOH to furnish corresponding aminodiol
12. Compound 12 was subsequently reacted with HCl-MeOH to
afford methyl 3-epi- -vicenisaminide 13 (72% yield, two steps). The
D
spectral data (1H and 13C NMR, IR) of 13 derived from chiral diol 2
were identical to those previously reported.8b Present synthetic
scheme was started from the readily available chiral starting ma-
terial 2 and, the total yield (41%) was satisfactorily improved than
that of previous report (15%).8b The transformation of compound 13
iodocyclization of the carbamate based on the (E)-a,b-unsaturated
ester moiety indigenous to the starting materials Scheme 2. First,
the azide group of compound 5 was effectively reduced to a pri-
mary amine by treatment with triphenylphosphine and water in
THF with gentle warming (50 ꢁC). The thus-obtained primary
amine was subsequently immediately protected with a carbo-
benzoxy (Cbz) group, which could be used as the origin of an ox-
ygen functional group, i.e. the 3-hydroxy group, to furnish
compound 6 (93% yield, two steps). The methyl group on the amino
nitrogen of vicenisamine was introduced at this point. Notably,
reverse addition of sodium hydride to the substrate and excess
methyl iodide afforded compound 7 in quantitative yield. Next is
the iodocyclization of the carbamate to form key intermediate
oxazolidinone 8 (¼ B). The reaction was performed with iodine in
acetonitrile in the presence of sodium hydrogen bicarbonate, which
was used to prevent removal of the TBS protecting group during the
course of the reaction. However, in the absence of silver triflate,
compound 7 underwent facile cyclization at 0 ꢁC with extremely
high diastereoselective formation of trans-product 8 in excellent
yield (95%), along with a trace amount of cis-product 8′ (1.5%). For
oxazolidinone rings, it has been reported that a large NMR coupling
constant corresponds to the cis form and a small one to the trans
form.25 Therefore, the observation of a small coupling constant (JH-
to methyl
After establishing a synthetic strategy for synthesizing
nisamine and its 3-epimer, the synthesis of another diastereomer,
4-epi- -vicenisamine, was performed Scheme 3. Starting chiral diol
D
-vicenisaminide 14 was also reported.8b
D-vice-
D
2 was transformed to cyclic carbonate 1517c in 93% yield and then
submitted to a subsequent azide substitution reaction with reten-
tion of the stereochemistry. For this purpose, Pd(0)-catalyzed ste-
reospecific azidation26 was effectively carried out in the presence of
tetrakis(triphenylphosphine)palladium(0), Pd(PPh3)4, in degassed
wet THF to give compound 16 in 77% yield. The mechanism
involving SN2 nucleophilic displacement of the leaving group (cy-
clic carbonate) by Pd(0) followed by a second displacement of Pd by
the nucleophilic nitrogen of azide is commonly known as the
palladium-mediated double inversion process. Silica gel chroma-
tography afforded azide alcohol 16 as an approximately 10:1
mixture with its (4S,5S)-epimer 4. As chromatographic separation
of 16 and 4 was not possible at this stage, the subsequent reactions
¼ 2.8 Hz) implied that compound 8 had trans stereochemistry.
3,4
Further, the stereochemistry of trans-product 8 was also confirmed
by a nuclear Overhauser enhancement (NOE) experiment as fol-
lows: irradiation of H-4 yielded an NOE of approximately 10% on H-
2, whereas a relatively small NOE (3%) was observed on H-3. The
stereoselectivity of this cyclization reaction can be explained using
the transition state (TS) models Fig. 2. Owing to steric hindrance
between the side chain R and the alkenyl group, the cis-TS model is
obviously less favorable than the trans-TS model. Therefore, the
cyclization reaction is thought to proceed through the trans-TS
model to give the trans-oxazolidinone product, i.e. trans-product
8.25
The final manipulation in this work was transformation to the
intermediate compound for vicenisamine synthesis. For this pur-
pose, reductive deiodination of compound 8 was conducted with
tri-n-butyltin hydride in the presence of 2,20-azobis(isobutyroni-
trile) (AIBN) in boiling benzene to afford compound 9 in quanti-
tative yield. Next, reduction of the ester group of compound 9 was
readily realized using sodium borohydride with lithium chloride to
Fig. 2. Proposed transition state models for iodocyclization of carbamate 7.
Scheme 3. Synthesis of 4-epi-vicenisamine from chiral diol 2.
Please cite this article in press as: Matsushima Y, Kino J, A versatile route to 2,4,6-trideoxy-4-aminohexoses: Stereoselective syntheses of D-
vicenisamine and its epimers via iodocyclization of carbamate, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.009

4
Y. Matsushima, J. Kino / Tetrahedron xxx (2017) 1e9
were carried out using this mixture.
solvent signal (CDCl3 dC ¼ 77.0) as reference. IR spectra were
recorded on a HORIBA FT-720 Fourier-transform infrared spec-
trometer. Optical rotations were measured on a Rudolph Research
From intermediate azide alcohol 16, the successive trans-
formations to methyl 2,4,6-trideoxy-4-methylamino- -xylo-hex-
opyranoside, i.e. methyl 4-epi- -vicenisaminide 25 Scheme 3, were
essentially the same as those used in the synthesis of -vicenis-
D
D
Analytical AUTOPOLV polarimeter and [
a]D values are given in units
D
of 10ꢀ1 deg cm2 ꢀ1. Mass spectra were measured on a Shimadzu
g
amine and its 3-epimer Scheme 2. The hydroxy group of compound
16 was protected by a TBS group, and the azide group of resulting
compound 17 was transformed to a Cbz-protected amino group to
give compound 18 (94% yield, two steps). Subsequent N-methyl-
ation afforded compound 19 in 98% yield. The key iodocyclo-
carbamation reaction was also performed with iodine in
acetonitrile in the presence of sodium hydrogen bicarbonate;
however, unlike for compound 7, in this case, the reaction did not
proceed substantially at 0 ꢁC. However, although addition of silver
triflate24 certainly hastened the reaction, it was not effective in this
case because the reaction proceeded with substantial degradation.
Instead, the reaction was performed at r.t. for several days to afford
the cyclized product with high diastereoselectivity and excellent
yield (trans-20: 90%; cis-20′: 2.7%). This reaction might have pro-
ceeded slowly because the steric hindrance between the side chain
R and the alkenyl group in the cis-TS model of compound 19 is
thought to be smaller than that in compound 7.
Reductive deiodination of compound 19 afforded ethyl ester 21,
which was then reduced to alcohol 22 in 84% yield with recovery of
the starting ester (7%). Chromatographic separation of the isomer
derived from the Pd-catalyzed azidation was fully realized at this
stage. Thus-obtained pure alcohol 22 was oxidized to the corre-
sponding aldehyde, which was then transformed to crystalline
dimethyl acetal 23 by treatment with a catalytic amount of p-TsOH
in MeOH in the presence of methyl orthoformate (77% yield, two
steps). Alkaline hydrolysis of the cyclic carbonate group and the TBS
protective group of compound 23 gave corresponding aminodiol
24, which is a previously unknown compound. Reaction with HCl-
LCMS-IT-TOF mass spectrometer. Flash silica gel column chroma-
tography was carried out on KANTO CHEMICAL CO., INC. Silica Gel
60 N (spherical, neutral, 40e50 mm).
4.2. Ethyl (2E,4R,5R)-4,5-dihydroxyhex-2-enoate 2
The mixture of AD-mix-b {9.93 g, containing with K3Fe(CN)6
(6.95 g, 21.1 mmol), K2CO3 (2.92 g, 21.1 mmol), (DHQD)2-PHAL
(52.7 mg, 0.0676 mmol), and K2OsO4$H2O (10.9 mg, 0.0295 mmol)}
and MeSO2NH2 (0.85 g, 8.9 mmol) in t-BuOH (36 mL) and H2O
(36 mL) was stirred at r.t. for 15 min. The resulting clear solution
was then cooled to 0 ꢁC. To this solution was added ethyl sorbate
(1.00 g, 7.13 mmol) in t-BuOH (1 mL). The reaction mixture was
stirred at 0 ꢁC for ca. 24 hr. The reaction was quenched with sodium
sulfite (4.77 g, 37.8 mmol) and the mixture was stirred at r.t. for 1 h.
The mixture was extracted with EtOAc (150 mL, 2 ꢂ 50 mL) and the
combined extracts were washed with brine, dried (MgSO4) and
concentrated in vacuo. The residue was purified by column chro-
matography on silica gel (hexane: EtOAc ¼ 3: 2 to 1: 1) to give the
diol 2 (1.09 g; 88% yield) as a colorless oil. A small amount of less
polar regioisomer 2′(Ethyl (4E,2S,3R)-2,3-dihydroxyhex-4-enoate)
was also obtained in pure form.
27.2
diol 2: colorless oil; [
a
]
þ 64.7ꢁ (c 1.45, EtOH) {lit. 17(b)
D
[a
]
24 þ 64.0ꢁ (c 1.10, EtOH); lit. 17(c) [
a]
D þ 63.0ꢁ (c 1.0, EtOH)}; nmax
D
(neat)/cmꢀ1 3402, 2981, 1705, 1658, 1369, 1309, 1282, 1182, 1036
and 985; dH (270 MHz, CDCl3) 6.92 (dd, J ¼ 5.1, 15.8 Hz, 1 H), 6.15
(dd, J ¼ 1.7, 15.8 Hz, 1 H), 4.21 (q, J ¼ 7.1 Hz, 2 H), 4.07 (ddd, J ¼ 1.4,
4.9, 6.3 Hz, 1 H), 3.73 (ddq, J ¼ 4.2, 6.3, 6.3 Hz, 1 H), 2.70 (br. d,
J ¼ 4.7 Hz,1 H), 2.41 (br. d, J ¼ 4.1 Hz,1 H),1.30 (t, J ¼ 7.2 Hz, 3 H) and
1.25 (d, J ¼ 6.4 Hz, 3 H); dC (67.8 MHz, CDCl3) 166.4, 146.5, 122.5,
MeOH led to methyl 4-epi-
mixture. Notably, before the isolation of vicenistatin, the synthesis
of methyl 2,4,6-trideoxy-4-methylamino- -xylo-hexopyranoside
(methyl 4-epi- -vicenisaminide, the antipode of 25) from 3,4-di-O-
Ac-
D
-vicenisaminide 25 as an anomeric
L
75.6, 70.2, 60.6, 19.0 and 14.1.
L
27.7
diol 2′:colorless oil; [
a
]
þ 22.7ꢁ (c 1.57, EtOH); nmax (neat)/
D
L
-rhamnal (3,4-di-O-acetyl-6-deoxy-L
-glucal) was reported.27
cmꢀ1 3435, 2983, 1736, 1446, 1271, 1207, 1097, 1032 and 968; dH
(270 MHz, CDCl3) 5.82 (ddq, J ¼ 1.0, 6.4, 15.4 Hz, 1 H), 5.64 (ddq,
J ¼ 1.5, 6.6, 15.4 Hz, 1 H), 4.40e4.32 (m, 1H), 4.29 (q, J ¼ 7.2 Hz, 2 H),
4.13 (dd, J ¼ 2.8, 5.8 Hz, 1 H), 3.13 (br. d, J ¼ 6.0 Hz, 1 H), 2.28 (br. d,
J ¼ 7.1 Hz, 1 H), 1.74 (ddd, J ¼ 0.6, 1.5, 6.4 Hz, 3 H) and 1.32 (t,
J ¼ 7.2 Hz, 3 H); dC (67.8 MHz, CDCl3) 172.9, 129.3, 129.2, 73.8, 73.4,
62.1, 17.8 and 14.1; Anal. Calcd for: C8H14O4: C 55.16; H 8.10. Found:
C 54.98; H 8.30%.
The spectral data (1H and 13C NMR) of 25 derived from chiral diol
2 were identical to those of this previously reported compound.27
3. Conclusion
In conclusion, we successfully realized the syntheses of
D-vice-
nisamine and its epimers (3-epi- and 4-epi- -vicenisamine) by
D
using stereoselective nitrogen functional group introduction and
iodocyclization of carbamates as the key reactions. Our synthetic
strategy is simple and easy to operate and superior to the previous
ones in accessibility to the isomers from the same starting material
without using Mitsunobu inversion. Thus, our versatile synthetic
strategy is generally applicable to the synthesis of 2,4,6-trideoxy-4-
amino sugars. Furthermore, in addition to these types of amino
sugars, our strategy also has the potential to be applicable to other
types of molecules with amino alcohol moieties in the structure.
For example, the importance of the 1,2-aminoalcohol motif in
synthetic chemistry is illustrated by its occurrence in a vast range of
natural products and other biologically active compounds.28
4.3. Ethyl (E)-3-((4R,5R)-5-methyl-2-thioxo-1,3-dioxolan-4-yl)
acrylate 3
To a solution of the diol 2 (217 mg, 1.25 mmol) in anhydrous
CH2Cl2 (5.5 mL) was added 1,10-thiocarbonyldiimidazole (TCDI)
(362 mg, 2.03 mmol) and DMAP (25.3 mg, 0.207 mmol). The re-
action mixture was stirred at r.t. for ca. 2.5 h. The mixture was
directly purified by flash column chromatography on silica gel
(hexane: EtOAc ¼ 1: 1) to give the cyclic thionocarbonate 3
(243.9 mg; 91% yield).
Colorless oil; [a]
22.6e7.97ꢁ (c 0.605, CHCl3); nmax (neat)/cmꢀ1
D
4. Experimental section
2983, 1720, 1367, 1346, 1311, 1273, 1188, 1038 and 978; dH (270 MHz,
CDCl3) 6.84 (dd, J ¼ 6.1, 15.7 Hz, 1 H), 6.22 (dd, J ¼ 1.4, 15.7 Hz, 1 H),
4.96 (ddd, J ¼ 1.4, 6.0, 8.0 Hz, 1 H), 4.71 (dq, J ¼ 6.3, 8.0 Hz, 1 H), 4.24
(q, J ¼ 7.1 Hz, 2 H),1.59 (d, J ¼ 6.2 Hz, 3 H) and 1.31 (t, J ¼ 7.2 Hz, 3 H);
dC (67.8 MHz, CDCl3) 190.4, 164.6, 137.4, 126.2, 85.5, 82.6, 61.3, 17.9
and 14.1; Anal. Calcd for: C9H12O4S: C 49.99; H 5.59. Found: C 49.93;
H 5.60%.
4.1. General
All mps are uncorrected. NMR spectra were recorded on a JEOL
GSX-270 spectrometer. 1H NMR and 13C NMR chemical shifts were
reported in
d
-values based on internal tetramethylsilane (dH ¼ 0), or
Please cite this article in press as: Matsushima Y, Kino J, A versatile route to 2,4,6-trideoxy-4-aminohexoses: Stereoselective syntheses of D-
vicenisamine and its epimers via iodocyclization of carbamate, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.009

Y. Matsushima, J. Kino / Tetrahedron xxx (2017) 1e9
5
4.4. Ethyl (2E,4S,5R)-4-azide-5-hydroxyhex-2-enoate 4
500; dH (270 MHz, CDCl3) 7.51e7.35 (m, 5H), 6.91 (dd, J ¼ 6.7,
15.7 Hz, 1 H), 5.97 (d, J ¼ 15.8 Hz, 1 H), 5.12 (d, J ¼ 12.2 Hz, 1 H), 5.09
(d, J ¼ 12.2 Hz, 1 H), 5.07 (br. s, 1H), 4.30e4.16 (m, 1 H), 4.19 (q,
J ¼ 7.1 Hz, 2 H), 3.97 (br. dq, J ¼ 4.0, 6.1 Hz, 1 H), 1.29 (t, J ¼ 7.2 Hz,
3 H), 1.13 (d, J ¼ 6.4 Hz, 3 H), 0.88 (s, 9 H) and 0.06 (s, 6 H); dC
(67.8 MHz, CDCl3) 166.0, 155.6, 143.6, 136.3, 128.5, 128.1, 128.0,
123.4, 70.0, 66.9, 60.4, 57.7, 25.7, 20.3, 17.9, 14.2, ꢀ4.4 and ꢀ5.0;
Anal. Calcd for: C22H35NO5Si: C 62.67; H 8.37; N 3.32. Found: C
62.92; H 8.40; N 3.42%.
To an ice-cooled solution of the cyclic thionocarbonate 3
(243.9 mg, 1.13 mmol) in anhydrous DMF (8.0 mL) was added so-
dium azide (248.7 mg, 3.83 mmol) and PPTS (579.5 mg, 2.31 mmol).
The reaction mixture was allowed to warm to r.t. and stirred for ca.
5 hr. The mixture was poured into H2O (20 mL) and extracted with
EtOAc (2 ꢂ 50 mL) and the combined extracts were washed suc-
cessively with sat. aq NaHCO3 and brine, dried (MgSO4) and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (hexane: EtOAc ¼ 3: 2) to give the
4.7. Ethyl (2E,4S,5R)-4-N-benzyloxycarbonyl-N-methylamino-5-
tert-butyldimethylsilyloxyhex-2-enoate 7
azide 4 (214.8 mg; 96% yield).
22.3
Colorless oil; [
a
]
þ 55.1ꢁ (c 0.950, CHCl3); nmax (neat)/cmꢀ1
D
3450, 2981, 2104, 1718, 1658, 1369, 1269, 1180, 1038 and 984; dH
(270 MHz, CDCl3) 6.83 (dd, J ¼ 7.4, 15.7 Hz, 1 H), 6.11 (dd, J ¼ 1.2,
15.7 Hz, 1 H), 4.23 (q, J ¼ 7.1 Hz, 2 H), 3.94 (ddd, J ¼ 1.1, 6.4, 7.5 Hz,
1 H), 3.77 (dq, J ¼ 4.5, 6.3 Hz, 1 H), 2.39 (br. d, J ¼ 4.7 Hz, 1 H), 1.32 (t,
J ¼ 7.2 Hz, 3 H) and 1.23 (d, J ¼ 6.4 Hz, 3 H); dC (67.8 MHz, CDCl3),
165.4, 141.0, 125.3, 69.3, 69.0, 60.9, 19.4 and 14.1; HRMS (ESI-TOF)
calcd for: C8H14N3O3 [MþH]þ: 200.1029, found: 200.1055.
To an ice-cooled solution of the compound 6 (280.7 mg,
1.08 mmol) in anhydrous DMF (17 mL) was added successively MeI
(830 mL, 13.3 mmol) and NaH (55% mineral oil suspension; 35.4 mg,
0.811 mmol). The reaction mixture was stirred at 0 ꢁC for ca. 45 min.
The reaction was quenched by the addition of sat. aq NH4Cl and
crushed ice and the mixture was extracted with EtOAc
(2 ꢂ 100 mL). The combined extracts were washed with brine, dried
(MgSO4) and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (hexane: EtOAc ¼ 4: 1)
to give the carbamate 7 (288.7 mg; quantitative yield).
4.5. Ethyl (2E,4S,5R)-4-azide-5-tert-butyldimethylsilyloxyhex-2-
enoate 5
Colorless oil; [a]
24.4e12.4ꢁ (c 0.660, CHCl3); nmax (neat)/cmꢀ1
D
To an ice-cooled solution of the alcohol 4 (214.8 mg, 1.08 mmol)
in anhydrous CH2Cl2 (7.0 mL) was sequentially added 2,6-lutidine
(650 mL, 5.58 mmol) and TBSOTf (400 mL, 1.74 mmol). The reac-
2956, 2931, 1718,1705,1657, 1473,1398, 1304, 1257, 1178, 1147, 1092,
1041, 985, 835, 777 and 698; dH (270 MHz, CDCl3) for major rotamer
7.42e7.23 (m, 5H), 7.11 (dd, J ¼ 6.0, 15.6 Hz, 1 H), 5.88 (d, J ¼ 15.6 Hz,
1 H), 5.15 (s, 2H), 4.47 (br. dd, J ¼ 6.7, 6.7 Hz, 1 H), 4.20 (q, J ¼ 7.1 Hz,
2 H), 4.04 (br. dq, J ¼ 6.5, 6.5 Hz, 1 H), 2.85 (s, 3H), 1.29 (t, J ¼ 7.2 Hz,
3 H), 1.16 (d, J ¼ 6.2 Hz, 3 H), 0.88 (s, 9 H), 0.07 (s, 3H) and 0.05 (s,
3H); for minor rotamer 7.42e7.23 (m, 5H), 7.07 (dd, J ¼ 6.0, 15.8 Hz,
1 H), 5.83 (d, J ¼ 15.2 Hz, 1 H), 5.15 (s, 2H), 4.31 (br. dd, J ¼ 6.6,
6.6 Hz, 1 H), 4.20 (q, J ¼ 7.1 Hz, 2 H), 3.93 (br. dq, J ¼ 6.6, 6.6 Hz, 1 H),
2.85 (s, 3H), 1.29 (t, J ¼ 7.2 Hz, 3 H), 1.13 (d, J ¼ 6.4 Hz, 3 H), 0.88 (s,
9 H), 0.03 (s, 3H) and 0.02 (s, 3 H); dC (67.8 MHz, CDCl3) 166.1, 156.4,
156.2,143.8,143.4,136.6,136.4,128.5,128.0,127.8,123.7,123.2, 68.6,
68.5, 67.5, 67.3, 63.8, 63.5, 60.4, 31.8, 31.6, 25.7, 21.2, 17.9, 14.2, ꢀ4.2
and ꢀ4.9; Anal. Calcd for: C23H37NO5Si: C 63.41; H 8.56; N 3.22.
Found: C 63.77; H 8.60; N 3.23%.
tion mixture was stirred at 0 ꢁC for ca. 45 min. The mixture was
poured into H2O (20 mL) and extracted with EtOAc (50 mL) and the
extract was washed successively with 0.5 M HCl, sat. aq NaHCO3
and brine, dried (MgSO4) and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (hexane:
EtOAc ¼ 20: 1) to give the TBS ether 5 (314.8 mg; 93% yield).
29.2
Colorless oil; [
a
]
þ 7.8ꢁ (c 0.44, CHCl3); nmax (neat)/cmꢀ1
D
2956, 2931, 2104, 1724, 1658, 1257, 1178, 1097, 1041, 987, 837 and
777; dH (270 MHz, CDCl3) 6.80 (dd, J ¼ 6.2, 15.6 Hz, 1 H), 6.05 (dd,
J ¼ 1.3, 15.6 Hz, 1 H), 4.21 (q, J ¼ 7.1 Hz, 2 H), 3.99 (ddd, J ¼ 1.5, 4.5,
6.2 Hz, 1 H), 3.92 (dq, J ¼ 4.6, 6.1 Hz, 1 H), 1.30 (t, J ¼ 7.2 Hz, 3 H), 1.16
(d, J ¼ 6.0 Hz, 3 H), 0.89 (s, 9 H) and 0.08 (s, 6 H); dC (67.8 MHz,
CDCl3) 166.5, 141.9, 124.3, 70.8, 68.1, 60.6, 25.7, 19.4, 17.9, 14.2, ꢀ4.6
and ꢀ4.9; Anal. Calcd for: C14H27N3O3Si: C 53.64; H 8.68; N 13.40.
Found: C 53.91; H 8.64; N 13.32%.
4.8. Ethyl (S)-2-((4S,5S)-4-((R)-1-tert-butyldimethylsilyloxyethyl)-
3-methyl-2-oxooxazolidin-5-yl)-2-iodoacetate trans-8 and Ethyl
(R)-2-((4S,5R)-4-((R)-1-tert-butyldimethylsilyloxyethyl)-3-methyl-
2-oxooxazolidin-5-yl)-2-iodoacetate cis-80
4.6. Ethyl (2E,4S,5R)-4-N-benzyloxycarbonylamino-5-tert-
butyldimethylsilyloxyhex-2-enoate 6
To an ice-cooled solution of the carbamate 7 (288.7 mg,
0.663 mmol) and NaHCO3 (7.03 g, 83.7 mmol) in anhydrous CH3CN
(34 mL) was added iodine (535 mg, 2.11 mmol). The reaction
mixture was stirred at 0 ꢁC for 2 days. The reaction was quenched
by the addition of 10% aq Na2S2O3 and the mixture was allowed to
warm to r.t. The resulting mixture was extracted with EtOAc
(2 ꢂ 100 mL). The combined extracts were washed with brine, dried
(MgSO4) and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (hexane: EtOAc ¼ 3: 1)
to give the cyclic carbamate trans-8 (297.3 mg; 95% yield) along
with a small amount of the less polar cis-8′ (4.8 mg; 1.5% yield).
To a solution of the azide 5 (247.1 mg, 0.788 mmol) in THF
(9.0 mL) was added triphenylphosphine (531 mg, 2.02 mmol) and
H2O (3.0 mL). The reaction mixture was stirred at 55 ꢁC for ca. 22 hr.
The mixture was diluted with EtOAc and dried (MgSO4) and
concentrated in vacuo. To an ice-cooled solution of the residue in
1,4-dioxane (22 mL) and H2O (4.5 mL) was added successively
NaHCO3 (1.13 g, 13.5 mmol) and CbzCl (281.4 mL, 1.97 mmol). The
reaction mixture was stirred at 0 ꢁC for ca. 1 hr. To the mixture was
added ice water and the mixture was allowed to warm to r.t. The
whole mixture was extracted with EtOAc (2 ꢂ 50 mL) and the
combined extracts were washed with brine, dried (MgSO4) and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (hexane: EtOAc ¼ 5: 1) to give the
compound 6 (307.9 mg; 93% yield in 2 steps) as a colorless solid.
Analytical pure sample was obtained by recrystallization from
trans-8: colorless oil; [a]
23.3e18.2ꢁ (c 0.695, CHCl3); nmax (neat)/
D
cmꢀ1 2956, 2929,1766,1745,1435,1375,1255,1236,1120,1020, 987,
837 and 777; dH (270 MHz, CDCl3) 4.47 (dd, J ¼ 2.8, 8.5 Hz, 1 H), 4.38
(d, J ¼ 8.8 Hz, 1 H), 4.24 (q, J ¼ 7.1 Hz, 2 H), 4.06 (dq, J ¼ 1.6, 6.4 Hz,
1 H), 3.54 (dq, J ¼ 1.9, 2.8 Hz, 1 H), 2.95 (s, 3 H), 1.29 (t, J ¼ 7.2 Hz,
3 H), 1.20 (d, J ¼ 6.4 Hz, 3 H), 0.89 (s, 9 H), 0.094 (s, 3 H) and 0.087 (s,
3 H); dC (67.8 MHz, CDCl3) 168.6, 156.8, 74.0, 67.9, 67.0, 62.5, 30.3,
25.6, 23.0, 18.2, 17.7, 13.7, ꢀ4.5 and ꢀ4.9; Anal. Calcd for:
hexane.
24.0
Colorless prism; mp 65.3e66.0 ꢁC; [
a]
þ 2.59ꢁ (c 0.580,
D
CHCl3); nmax (KBr)/cmꢀ1 3373, 2958, 2929, 1716, 1697, 1657, 1525,
1373, 1263, 1186, 1149, 1097, 1045, 1005, 993, 837, 773, 756, 696 and
C16H30INO5Si: C 40.77; H 6.41; N 2.97. Found: C 40.95; H 6.44; N
Please cite this article in press as: Matsushima Y, Kino J, A versatile route to 2,4,6-trideoxy-4-aminohexoses: Stereoselective syntheses of D-
vicenisamine and its epimers via iodocyclization of carbamate, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.009

6
Y. Matsushima, J. Kino / Tetrahedron xxx (2017) 1e9
2.81%.
MeOH (9.0 mL) was added successively CH(OMe)3 (560 mL,
cis-8′: colorless oil; dH (270 MHz, CDCl3) 4.97 (dd, J ¼ 7.3,12.0 Hz,
5.11 mmol) and p-TsOH$H2O (26.1 mg, 0.137 mmol). The reaction
mixture was stirred at r.t. for ca. 2 hr. The reaction was quenched by
the addition of NaHCO3 (2.5 g, 30 mmol). The mixture was diluted
with EtOAc (150 mL), filtered through a pad of Celite and the filtrate
was concentrated in vacuo. The residue was purified by flash col-
umn chromatography on silica gel (hexane: EtOAc ¼ 1: 1) to give
the acetal 11 (149.2 mg; 85% yield in 2 steps). Analytical pure
1 H), 4.29 (q, J ¼ 6.1 Hz, 1 H), 4.25 (q, J ¼ 7.0 Hz, 2 H), 4.20 (d,
J ¼ 12.0 Hz, 1 H), 3.83 (d, J ¼ 7.3 Hz, 1 H), 3.05 (s, 3 H), 1.29 (t,
J ¼ 7.2 Hz, 3 H), 1.19 (d, J ¼ 6.2 Hz, 3 H), 0.90 (s, 9 H), 0.14 (s, 3 H) and
0.11 (s, 3 H); dC (67.8 MHz, CDCl3), 168.1, 157.1, 76.5, 67.3, 64.5, 62.7,
31.9, 25.6, 19.1, 17,7, 14.4, 13.6, ꢀ4.6 and ꢀ4.7.
4.9. Ethyl 2-((4S,5R)-4-((R)-1-tert-butyldimethylsilyloxyethyl)-3-
methyl-2-oxooxazolidin-5-yl)acetate 9
sample was obtained by recrystallization from hexane.
28.3
Colorless prism; mp 50.2e51.5 ꢁC; [
a
]
D
þ 51.5ꢁ (c 0.710,
CHCl3); nmax (KBr)/cmꢀ1 2958, 2925, 1755, 1736, 1450, 1408, 1261,
1157, 1124, 1099, 1061, 1039, 1011, 958, 945, 904, 837, 781 and 760;
dH (270 MHz, CDCl3) 4.56 (dd, J ¼ 3.8, 7.3 Hz, 1 H), 4.43 (ddd, J ¼ 4.4,
4.4, 8.7 Hz, 1 H), 3.96 (dq, J ¼ 1.9, 6.3 Hz, 1 H), 3.41 (s, 3 H), 3.35 (s,
3 H), 3.27 (dd, J ¼ 1.8, 4.4 Hz,1 H), 2.90 (s, 3 H), 1.97 (ddd, J ¼ 3.8, 8.3,
14.1 Hz, 1 H), 1.85 (ddd, J ¼ 4.9, 7.3, 14.2 Hz, 1 H), 1.11 (d, J ¼ 6.2 Hz,
3 H), 0.88 (s, 9 H), 0.07 (s, 3 H) and 0.05 (s, 3 H); dC (67.8 MHz,
CDCl3), 158.0, 101.9, 71.0, 68.0, 66.5, 54.7, 53.6, 39.6, 30.0, 25.6, 18.3,
17.8, ꢀ4.4 and ꢀ5.0; Anal. Calcd for: C16H33NO5Si: C 55.30; H 9.57;
N 4.03. Found: C 55.13; H 9.49; N 3.84%.
To a solution of the compound 8 (480.9 mg, 1.02 mmol) in
anhydrous benzene (28 mL) was added AIBN (188 mg, 1.14 mmol)
and tri-n-butyltin hydride (560
mL, 2.08 mmol). The reaction
mixture was refluxed for ca. 1.5 h. The mixture was cooled to r.t. and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (hexane: EtOAc ¼ 5: 2) to give the
compound 9 (353.0 mg; quantitative yield).
22.4
Colorless oil; [
a]
þ 16.5ꢁ (c 0.530, CHCl3); nmax (neat)/cmꢀ1
D
2956, 2929, 1765, 1743, 1437, 1406, 1377, 1254, 1184, 1149, 1084,
1030, 837 and 777; dH (270 MHz, CDCl3) 4.65 (ddd, J ¼ 3.9, 6.0,
6.7 Hz,1 H), 4.17 (q, J ¼ 7.1 Hz, 2 H), 4.03 (dq, J ¼ 1.7, 6.4 Hz,1 H), 3.34
(dd, J ¼ 1.8, 3.7 Hz, 1 H), 2.73 (dd, J ¼ 5.8, 16.0 Hz, 1 H), 2.65 (dd,
J ¼ 7.2, 15.9 Hz, 1 H), 1.28 (t, J ¼ 7.2 Hz, 3 H), 1.13 (d, J ¼ 6.4 Hz, 3 H),
0.88 (s, 9 H), 0.08 (s, 3 H) and 0.06 (s, 3 H); dC (67.8 MHz, CDCl3),
169.3, 157.6, 70.3, 67.5, 66.8, 61.1, 40.1, 30.1, 25.6, 18.3, 17.7, 14.1, ꢀ4.4
and ꢀ5.1; Anal. Calcd for: C16H31NO5Si: C 55.62; H 9.04; N 4.05.
Found: C 55.48; H 8.98; N 4.17%.
4.12. (2R,3R,4R)-6,6-dimethoxy-3-(methylamino)hexane-2,4-diol
12
A solution of 11 (80.0 mg, 0.230 mmol) in MeOH (7 mL) and 10%
aq. NaOH (4.2 mL, 10.5 mmol) was gently refluxed for 17 h. The
reaction mixture was cooled, and concentrated in vacuo. The res-
idue was dissolved in a minimum amount of water and extracted
with EtOAc (5 ꢂ 10 mL). The combined organic extract was dried
(MgSO4), and concentrated in vacuo. Thus obtained amino diol 12
(47.7 mg, quantitative) was sufficiently pure for spectrometric
analysis and the most part (41.3 mg) was used for the next reaction.
4.10. (4S,5R)-4-((R)-1-tert-butyldimethylsilyloxyethyl)-5-(2-
hydroxyethyl)-3-methyloxazolidin-2-one 10
To a solution of the compound 9 (333.0 mg, 1.08 mmol) in
anhydrous THF (8.5 mL) and EtOH (17 mL) was added successively
LiCl (240 mg, 5.66 mmol) and NaBH4 (215 mg, 5.68 mmol). The
reaction mixture was stirred at r.t. for ca. 4.5 h. The reaction was
quenched by the addition of acetone (4.0 mL). The mixture was
diluted with CH2Cl2 (250 mL), dried (MgSO4) and concentrated in
vacuo. The residue was purified by flash column chromatography
on silica gel (hexane: EtOAc ¼ 1: 5) to give the alcohol 10 (273.8 mg;
94% yield). Analytical pure sample was obtained by recrystallization
Colorless oil; [a] a]
28.4e3.43ꢁ (c 0.530, CHCl3) {lit. 8(b) [ 24 e 3.3ꢁ
D D
(c 1.06, CHCl3)}; nmax (neat)/cmꢀ1 3406, 3356, 2962, 2933, 1738,
1572, 1448, 1385, 1375, 1242, 1192, 1124, 1057, 966, 916 and 820; dH
(270 MHz, CDCl3) 4.60 (dd, J ¼ 5.0, 5.9 Hz, 1 H), 4.12 (ddd, J ¼ 2.9,
2.9, 9.6 Hz,1 H), 4.02 (dq, J ¼ 4.0, 6.6 Hz,1 H), 3.45 (br. s, 3H), 3.38 (s,
6 H), 2.52 (s, 3 H), 2.21 (dd, J ¼ 2.9, 4.0 Hz,1 H),1.98 (ddd, J ¼ 4.9, 9.5,
14.3 Hz, 1 H), 1.74 (ddd, J ¼ 2.9, 6.0, 14.2 Hz, 1 H) and 1.26 (d,
J ¼ 6.4 Hz, 3 H); dC (67.8 MHz, CDCl3)103.5, 67.3, 67.1, 66.9, 53.7,
53.4, 37.5, 35.5 and 19.9; HRMS (ESI-TOF) calcd for: C9H22NO4
[MþH]þ: 208.15488, found: 208.1565.
from hexane-EtOAc at 4 ꢁC.
23.3
Colorless flake; mp 106.5e108.0 ꢁC; [
a
]
þ 39.7ꢁ (c 0.540,
D
CHCl3); nmax (KBr)/cmꢀ1 3410, 2954, 2929, 1726, 1471, 1464, 1441,
1414, 1373, 1362, 1255, 1225, 1142, 1090, 1070, 1045, 982, 951, 914,
841, 777, 764 and 501; dH (270 MHz, CDCl3) 4.52 (ddd, J ¼ 4.4, 4.4,
8.8 Hz, 1 H), 3.99 (dq, J ¼ 1.8, 6.4 Hz, 1 H), 3.90e3.79 (m, 2 H), 3.26
(dd, J ¼ 1.7, 4.5 Hz, 1 H), 2.90 (s, 3 H), 2.01e1.75 (m, 2 H), 1.71 (br. s,
1 H), 1.14 (d, J ¼ 6.4 Hz, 3 H), 0.88 (s, 9 H), 0.08 (s, 3 H) and 0.06 (s,
3 H); dC (67.8 MHz, CDCl3), 158.0, 71.9, 68.2, 66.4, 58.7, 38.6, 29.9,
25.6, 18.5, 17.8, ꢀ4.3 and ꢀ5.0; Anal. Calcd for: C14H29NO4Si: C
55.41; H 9.63; N4.62. Found: C 55.29; H 9.51; N 4.40%.
4.13. Methyl 2,4,6-trideoxy-4-methylamino-a-D-arabino-
hexopyranoside (methyl 3-epi- -vicenisaminide) 13
D
To an HCl-MeOH solution, which had been prepared by adding
AcCl (0.120 mL, 1.69 mmol) to ice-cooled dry MeOH (1.2 mL), was
added a solution of 12 (41.3 mg, 0.199 mmol) in anhydrous MeOH
(1.2 mL) at 0 ꢁC and the reaction mixture was refluxed for 2 h. After
the addition of 2 M NaOH (1.25 mL, 2.50 mmol) at 0 ꢁC, the mixture
diluted with EtOAc, dried (MgSO4), and concentrated in vacuo. The
residue was purified by flash silica gel chromatography (EtOAc-
MeOH, 6: 1 to 4: 1) to afford 13 (25.2 mg, 72%, 2 steps).
4.11. (4S,5R)-4-((R)-1-tert-butyldimethylsilyloxyethyl)-5-(2,2-
dimethoxyethyl)-3-methyloxazolidin-2-one 11
To an ice-cooled solution of the alcohol 10 (153.7 mg,
0.506 mmol) in anhydrous CH2Cl2 (6.0 mL) was added Dess-Martin
periodinane (520 mg, 1.22 mmol). The reaction mixture was stirred
at r.t. for ca. 1.5 h. The reaction was quenched by the addition of 10%
aq Na2S2O3 and the mixture was allowed to warm to r.t. and stirred
for 0.5 h. The resulting mixture was extracted with EtOAc
(2 ꢂ 50 mL). The combined extracts were washed successively with
sat. aq NaHCO3 þ 10% aq Na2S2O3 and brine, dried (MgSO4) and
concentrated in vacuo. To the solution of the residual aldehyde in
Colorless oil; [
a
]
27.1 þ122ꢁ (c 0.690, CHCl3) {lit. 8(b) [
a
]
19 þ 123ꢁ
D
D
(c 1.05, CHCl3)}; nmax (neat)/cmꢀ1 3333, 2933, 2900, 1446, 1379,
1215, 1192, 1126, 1105, 1049, 972, 908 and 756; dH (270 MHz, CDCl3)
4.75 (br. d, J ¼ 3.4 Hz, 1 H), 3.81 (ddd, J ¼ 5.1, 9.9, 11.3 Hz, 1 H), 3.70
(dq, J ¼ 6.2, 9.8 Hz, 1 H), 3.32 (s, 3 H), 2.48 (s, 3 H), 2.29 (br. s, 2 H),
2.19 (ddd, J ¼ 1.2, 5.0,12.8 Hz,1 H), 2.06 (dd, J ¼ 9.8, 9.8 Hz,1 H),1.66
(ddd, J ¼ 3.7,11.4,12.8 Hz,1 H),1.30 (d, J ¼ 6.2 Hz, 3 H); dC (67.8 MHz,
CDCl3) 98.6, 67.8, 66.9, 65.5, 54.6, 37.9, 33.2 and 18.6.
Please cite this article in press as: Matsushima Y, Kino J, A versatile route to 2,4,6-trideoxy-4-aminohexoses: Stereoselective syntheses of D-
vicenisamine and its epimers via iodocyclization of carbamate, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.009

Y. Matsushima, J. Kino / Tetrahedron xxx (2017) 1e9
7
4.14. Ethyl (E)-3-((4R,5R)-5-methyl-2-oxo-1,3-dioxolan-4-yl)
acrylate 15
carbamate 18 (213 mg, 94%) as a colorless oil.
Colorless oil; nmax (neat)/cmꢀ1 3443, 3342, 2956, 2929, 1720,
1660, 1525, 1500, 1304, 1255, 1184, 1068, 1049, 837, 777 and 698; dH
(270 MHz, CDCl3) 7.43e7.26 (m, 5 H), 6.88 (dd, J ¼ 5.1, 15.6 Hz, 1 H),
5.94 (dd, J ¼ 1.7, 15.6 Hz,1 H), 5.17 (br. d, J ¼ 9.0 Hz,1 H), 5.12 (s, 2 H),
4.33e4.21 (m, 1 H), 4.19 (q, J ¼ 7.1 Hz, 2 H), 4.06e3.92 (m, 1H), 1.27
(t, J ¼ 7.2 Hz, 3 H), 1.19 (d, J ¼ 6.2 Hz, 3 H), 0.85 (s, 9 H), 0.04 (s, 3 H)
and 0.01 (s, 3 H); dC (67.8 MHz, CDCl3) 165.9, 156.2, 147.1, 136.2,
128.6, 128.2, 121.9, 69.6, 67.1, 60.3, 57.6, 25.7, 20.9, 17.9, 14.2, e 4.5
and e 5.0.
To an ice-cooled solution of the diol 2 (522 mg, 2.99 mmol) in
anhydrous CH2Cl2 (4.5 mL) and pyridine (1.8 mL) was added
dropwise triphosgene (451 mg, 1.52 mmol) in anhydrous CH2Cl2
(3.0 mL). The reaction mixture was stirred at 0 ꢁC for ca. 2 hr. The
reaction mixture was poured into ice-cooled sat. aq NH4Cl and the
mixture was extracted with EtOAc (2 ꢂ 50 mL). The combined ex-
tracts were washed with brine, dried (MgSO4) and concentrated in
vacuo. The residue was purified by flash column chromatography
on silica gel (hexane: EtOAc ¼ 3: 2) to give the known cyclic car-
4.18. Ethyl (2E,4R,5R)-4-N-benzyloxycarbonyl-N-methylamino-5-
tert-butyldimethylsilyloxyhex-2-enoate 19
bonate 15 (556 mg; 93% yield).
29.9
Colorless oil;
[
a
]
þ
18.2ꢁ (c 0.850, CHCl3) {lit. 17(c)
D
[
a]
23.8 þ 23.8ꢁ (c 1.03, CH2Cl2)}; nmax (neat)/cmꢀ1 2985, 1809, 1716,
In the same procedure as described in the synthesis of the
compound 7, the carbamate 18 (413 mg, 0.980 mmol) was meth-
ylated to give the compound 19 (419.9 mg, 98%) as a colorless oil.
Colorless oil; nmax (neat)/cmꢀ1 2956, 2931, 1720, 1697, 1658,
1473, 1400, 1308, 1257, 1176, 1147, 1039, 837, 777 and 698; dH
(270 MHz, CDCl3) for major rotamer 7.41e7.25 (m, 5 H), 6.98 (dd,
J ¼ 5.6, 15.8 Hz, 1 H), 5.91 (d, J ¼ 16.0 Hz, 1 H), 5.14 (s, 2H), 4.72 (br.
dd, J ¼ 4.8, 4.8 Hz, 1 H), 4.20 (q, J ¼ 7.1 Hz, 2 H), 4.15 (br. dq, J ¼ 6.1,
6.1 Hz,1 H), 2.96 (s, 3 H),1.29 (t, J ¼ 7.2 Hz, 3 H),1.18 (br. d, J ¼ 6.2 Hz,
3 H), 0.85 (s, 9 H) and 0.06 (s, 6 H); for minor romater 7.41e7.25 (m,
5 H), 6.92 (dd, J ¼ 5.3, 16.0 Hz, 1 H), 5.88 (d, J ¼ 16.0 Hz, 1 H), 5.14 (s,
2H), 4.60 (br. dd, J ¼ 4.4, 4.4 Hz, 1 H), 4.20 (q, J ¼ 7.1 Hz, 2 H), 4.06
(br. dq, J ¼ 5.9, 5.9 Hz, 1 H), 2.96 (s, 3 H), 1.29 (t, J ¼ 7.2 Hz, 3 H), 1.14
(br. d, J ¼ 6.6 Hz, 3 H), 0.85 (s, 9 H) and 0.05 (s, 6 H); dC (67.8 MHz,
CDCl3) 166.0, 156.9, 144.4, 144.2, 136.7, 136.6, 128.8, 128.4, 127.9,
127.7, 123.3, 123.2, 70.0, 69.8, 67.4, 67.3, 62.4, 60.4, 32.0, 25.6, 20.9,
17.8, 16.8, 14.2, e 4.3 and e 5.2.
D
1666, 1369, 1304, 1273, 1188, 1076, 1034, 980 and 773; dH (270 MHz,
CDCl3) 6.84 (dd, J ¼ 5.7, 15.7 Hz, 1 H), 6.20 (dd, J ¼ 1.4, 15.7 Hz, 1 H),
4.77 (ddd, J ¼ 1.4, 5.8, 7.4 Hz, 1 H), 4.50 (dq, J ¼ 6.2, 7.5 Hz, 1 H), 4.24
(q, J ¼ 7.1 Hz, 2 H),1.54 (d, J ¼ 6.4 Hz, 3 H) and 1.31 (t, J ¼ 7.2 Hz, 3 H);
dC (67.8 MHz, CDCl3) 164.8, 153.5, 138.6, 125.2, 81.3, 77.8, 61.2, 18.4
and 14.1.
4.15. Ethyl (2E,4R,5R)-4-azide-5-hydroxyhex-2-enoate 16
To a solution of the carbonate 15 (294.4 mg, 1.47 mmol) and
sodium azide (161 mg, 2.48 mmol) in degassed THF (14 mL) and
H2O (1.4 mL) was added tris(triphenylphosphine)palladium
(173 mg, 0.150 mmol). The reaction mixture was stirred at 45 ꢁC for
ca. 45 min. The reaction mixture was poured into H2O and the
mixture was extracted with EtOAc (2 ꢂ 50 mL). The combined ex-
tracts were washed with brine, dried (MgSO4) and concentrated in
vacuo. The residue was purified by flash column chromatography
on silica gel (hexane: EtOAc ¼ 5: 2) to give the azide alcohol 16
(225.9 mg; 77% yield), containing inseparable diastereomer 4 as by-
product. This was used for the next reaction without further
purification.
4.19. Ethyl (R)-2-((4R,5R)-4-((R)-1-tert-
butyldimethylsilyloxyethyl)-3-methyl-2-oxooxazolidin-5-yl)-2-
iodoacetate trans-20 Ethyl (S)-2-((4R,5S)-4-((R)-1-tert-
butyldimethylsilyloxyethyl)-3-methyl-2-oxooxazolidin-5-yl)-2-
iodoacetate cis-200
Colorless oil; nmax (neat)/cmꢀ1 3450, 2981, 2104, 1718, 1658,
1369, 1269, 1180, 1038 and 984; dH (270 MHz, CDCl3) 6.83 (dd,
J ¼ 7.4, 15.7 Hz, 1 H), 6.11 (dd, J ¼ 1.2, 15.7 Hz, 1 H), 4.23 (q, J ¼ 7.1 Hz,
2 H), 3.94 (ddd, J ¼ 1.1, 6.4, 7.5 Hz, 1 H), 3.77 (dq, J ¼ 4.5, 6.3 Hz, 1 H),
2.39 (br. d, J ¼ 4.7 Hz, 1 H), 1.32 (t, J ¼ 7.2 Hz, 3 H) and 1.23 (d,
J ¼ 6.4 Hz, 3 H); dC (67.8 MHz, CDCl3), 165.4, 141.0, 125.3, 69.3, 69.0,
60.9, 19.4 and 14.1.
In the same procedure as described in the synthesis of the cyclic
carbamate 8, the carbamate 19 (190.2 mg, 0.437 mmol) was treated
with iodine to give the cyclic carbamate trans-20 (184.3 mg, 90%) as
a colorless oil along with a small amount of the more polar cis-20′
(5.5 mg, 2.7%), however, in this case the reaction was need to
perform at r.t. for 5 days.
4.16. Ethyl (2E,4R,5R)-4-azide-5-tert-butyldimethylsilyloxyhex-2-
trans-20: colorless oil; nmax (neat)/cmꢀ1
; dH (270 MHz, CDCl3)
enoate 17
4.60 (dd, J ¼ 2.4, 8.3 Hz, 1 H), 4.38 (d, J ¼ 8.3 Hz, 1 H), 4.25 (dq,
J ¼ 7.2, 10.8 Hz, 1 H), 4.24 (dq, J ¼ 7.1, 10.8 Hz, 1 H), 4.05 (dq, J ¼ 3.8,
6.4 Hz, 1 H), 3.55 (dd, J ¼ 2.4, 3.6 Hz, 1 H), 2.95 (s, 3 H), 1.29 (t,
J ¼ 7.2 Hz, 3 H), 1.22 (d, J ¼ 6.4 Hz, 3 H), 0.91 (s, 9 H) and 0.11 (s, 6 H);
dC (67.8 MHz, CDCl3), 168.6, 156.9, 75.2, 68.2, 66.0, 62.4, 31.1, 25.8,
22.0, 19.0, 18.0, 13.7, ꢀ4.4 and ꢀ4.7.
In the same procedure as described in the synthesis of the TBS
ether 5, the alcohol 16 (365.2 mg, 1.83 mmol) was silylated in
anhydrous CH2Cl2 to give the TBS ether 17 (556.2 mg, 97%) as a
colorless oil.
Colorless oil; nmax (neat)/cmꢀ1 2956, 2931, 2858, 2104, 1724,
1660, 1257, 1178, 1134, 1092, 837 and 777; dH (270 MHz, CDCl3) 6.86
(dd, J ¼ 6.3, 15.7 Hz, 1 H), 6.07 (dd, J ¼ 1.4, 15.7 Hz, 1 H), 4.22 (q,
J ¼ 7.1 Hz, 2 H), 3.88 (dq, J ¼ 5.6, 6.1 Hz, 1 H), 3.81 (ddd, J ¼ 1.4, 5.4,
6.4 Hz, 1 H), 1.30 (t, J ¼ 7.1 Hz, 3 H), 1.19 (d, J ¼ 6.0 Hz, 3 H), 0.90 (s,
9 H), 0.10 (s, 3 H) and 0.09 (s, 3 H); dC (67.8 MHz, CDCl3),165.6,142.2,
124.2, 70.8, 68.0, 60.6, 25.7, 20.3, 18.0, 14.2, ꢀ4.6 and ꢀ5.0.
cis-20′: colorless oil; dH (270 MHz, CDCl3) 4.95 (dd, J ¼ 6.8,
11.5 Hz, 1 H), 4.45 (d, J ¼ 11.5 Hz, 1 H), 4.38 (q, J ¼ 7.1 Hz, 1 H), 4.24
(dq, J ¼ 7.2, 11.0 Hz, 1 H), 4.22 (dq, J ¼ 7.1, 11.0 Hz, 1 H), 3.65 (dd,
J ¼ 0.6, 6.8 Hz, 1 H), 3.03 (s, 3 H), 1.38 (d, J ¼ 6.6 Hz, 3 H), 1.27 (t,
J ¼ 7.1 Hz, 3 H), 0.89 (s, 9 H), 0.17 (s, 3 H) and 0.13 (s, 3 H); dC
(67.8 MHz, CDCl3), 168.4, 157.7, 77.2, 65.9, 64.3, 62.4, 32.6, 25.6, 22.7,
17.7, 15.2, 13.6, ꢀ2.9 and ꢀ5.1.
4.17. Ethyl (2E,4R,5R)-4-N-benzyloxycarbonylamino-5-tert-
4.20. Ethyl 2-((4R,5S)-4-((R)-1-tert-butyldimethylsilyloxyethyl)-3-
butyldimethylsilyloxyhex-2-enoate 18
methyl-2-oxooxazolidin-5-yl)acetate 21
In the same procedure as described in the synthesis of the
carbamate 6, the azide 17 (168.1 mg, 0.536 mmol) was reduced and
the resulting amine was protected by Cbz group to give the
In the same procedure as described in the synthesis of the
compound 9, the trans-20 (404 mg, 0.857 mmol) was treated with
AIBN and tri-n-butyltin hydride to afford the compound 21
Please cite this article in press as: Matsushima Y, Kino J, A versatile route to 2,4,6-trideoxy-4-aminohexoses: Stereoselective syntheses of D-
vicenisamine and its epimers via iodocyclization of carbamate, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.009

8
Y. Matsushima, J. Kino / Tetrahedron xxx (2017) 1e9
(251 mg, 85%) as a colorless oil.
[MþH]þ: 208.15488, found: 208.1531.
Colorless oil; nmax (neat)/cmꢀ1 2956, 2931, 1766, 1433, 1398,
1254, 1184, 1111, 1038, 837 and 779; dH (270 MHz, CDCl3) 4.72 (ddd,
J ¼ 4.6, 5.2, 6.3 Hz, 1 H), 4.17 (q, J ¼ 7.2 Hz, 2 H), 4.08 (dq, J ¼ 4.7,
6.3 Hz, 1 H), 3.43 (dd, J ¼ 4.6, 4.6 Hz, 1 H), 2.89 (s, 3 H), 2.67 (dd,
J ¼ 5.3, 16.0 Hz, 1 H), 2.65 (dd, J ¼ 6.5, 16.0 Hz, 1 H), 1.27 (t, J ¼ 7.1 Hz,
3 H), 1.15 (d, J ¼ 6.4 Hz, 3 H), 0.88 (s, 9 H), 0.09 (s, 3 H) and 0.08 (s,
3 H); dC (67.8 MHz, CDCl3), 169.2, 157.6, 70.9, 67.5, 65.8, 61.0, 40.3,
30.4, 25.7, 17.9, 17.5, 14.1, ꢀ4.5 and ꢀ5.0.
4.24. Methyl 2,4,6-trideoxy-4-methylamino-D-xylo-hexopyranoside
(methyl 4-epi- -vicenisaminide) 25
D
In the same procedure as described in the synthesis of methyl 3-
epi- -vicenisaminide 13, the compound 24 (67.3 mg) was treated
D
with HCl-MeOH solution to afford crude product. This was purified
by flash silica gel chromatography (EtOAc-MeOH, 7: 1 to 3: 1) to
afford 25 (35.5 mg, %, 2 steps) as a mixture of a- and b-anomer.
4.21. (4R,5S)-4-((R)-1-tert-butyldimethylsilyloxyethyl)-5-(2-
hydroxyethyl)-3-methyloxazolidin-2-one 22
Colorless oil; [a] L-isomer) a-
22.3e8.91ꢁ (c 0.550, CHCl3); {lit.27 (
D
anomer: [
a
]
20 e 117ꢁ (c ¼ 0.7, CHCl3);
b
-anomer: [
a
]
20 þ 51ꢁ (c ¼ 2,
D
D
CHCl3)}; nmax (neat)/cmꢀ1 3354, 3321, 2933, 1448, 1389, 1192, 1169,
1130, 1090, 1082, 984, 891 and 727; dH (270 MHz, CDCl3) for
In the same procedure as described in the synthesis of the
alcohol 10, the compound 21 (227 mg, 0.658 mmol) was treated
with LiCl and NaBH4 to afford the compound 22 (168 mg, 84%) as a
colorless oil along with the compound 21 (15.2 mg, 6.7%) as the
recovery starting material. Separation from the isomer derived
from the Pd-catalyzed azidation was fully conducted at this stage.
major ¼ -anomer 4.69 (dd, J ¼ 3.0, 7.5 Hz, 1 H), 4.17 (dq, J ¼ 2.9,
b
6.7 Hz, 1 H), 4.20e4.12 (m, 1 H), 3.46 (s, 3 H), 2.49 (s, 3 H), 2.33 (ddd,
J ¼ 0.64, 2.8, 5.1 Hz, 1 H), 2.36 (br. s, 2 H), 1.85 (ddd, J ¼ 3.4, 7.5,
13.7 Hz, 1 H), 1.75 (dddd, J ¼ 0.64, 3.0, 5.1, 13.7 Hz, 1 H) and 1.30 (d,
J ¼ 6.8 Hz, 3 H); for minor ¼ -anomer 4.76 (br. d, J ¼ 3.2 Hz, 1 H),
a
Colorless oil; [a]
27.2e35.4ꢁ (c 0.780, CHCl3); nmax (neat)/cmꢀ1
4.32 (dq, J ¼ 2.1, 6.6 Hz,1 H), 4.10e3.96 (m, 1 H), 3.36 (s, 3 H), 2.51 (s,
3 H), 2.40e2.37 (m, 1H), 2.36 (br. s, 2 H), 1.80e1.72 (m, 1 H) and 1.25
(d, J ¼ 6.6 Hz, 3 H); dC (67.8 MHz, CDCl3), 99.7, 69.0, 66.2, 62.4, 56.0,
35.1, 35.0 and 16.7; 99.1, 66.2, 61.9, 61.4, 55.1, 35.6, 30.3 and 17.0;
HRMS (ESI-TOF) calcd for: C8H8NO3 [MþH]þ: 176.1281, found:
176.1298.
D
3437, 2954, 2929, 1747, 1473, 1439, 1408, 1255, 1113, 1057, 1041, 837
and 777; dH (270 MHz, CDCl3) 4.56 (ddd, J ¼ 4.4, 4.4, 8.5 Hz, 1 H),
4.08 (dq, J ¼ 4.8, 6.3 Hz, 1 H), 3.82 (br. t, J ¼ 5.8 Hz, 1 H), 3.37 (dd,
J ¼ 4.5, 4.5 Hz, 1 H), 2.88 (s, 3 H), 2.00e1.78 (m, 3 H including OH),
1.12 (d, J ¼ 6.4 Hz, 3 H), 0.89 (s, 9 H), 0.10 (s, 3 H) and 0.09 (s, 3 H); dC
(67.8 MHz, CDCl3), 157.8, 72.4, 67.3, 66.5, 58.7, 38.6, 30.1, 25.7, 18.0,
17.2, ꢀ4.5 and ꢀ4.9; Anal. Calcd for: C14H29NO4Si: C 55.41; H 9.63; N
4.62. Found: C 55.19; H 9.37; N 4.43%.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2017.10.009.
4.22. (4R,5S)-4-((R)-1-tert-butyldimethylsilyloxyethyl)-5-(2,2-
dimethoxyethyl)-3-methyloxazolidin-2-one 23
References
In the same procedure as described in the synthesis of the acetal
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periodinane, and the resulting aldehyde was transformed to afford
the acetal 23 (175 mg, 77%) as a colorless solid. Analytical pure
sample was obtained by recrystallization from hexane at 0 ꢁC.
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a]
D
nmax (KBr)/cmꢀ1 2958, 2933,1766,1759,1738,1473,1437,1390,1261,
1248, 1138, 1103, 1078, 1039, 1007, 891, 775 and 758; dH (270 MHz,
CDCl3) 4.62 (dd, J ¼ 5.4, 6.3 Hz, 1 H), 4.48 (ddd, J ¼ 4.5, 6.2, 6.8 Hz,
1 H), 4.04 (dq, J ¼ 4.9, 6.3 Hz, 1 H), 3.37 (s, 3 H), 3.34 (s, 3 H), 3.31
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9.34; N 3.97%.
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27.1e11.8ꢁ (c 0.730, CHCl3); nmax (neat)/cmꢀ1
D
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3406, 3354, 2964, 2933, 1736, 1448, 1408, 1375, 1192, 1126, 1057 and
966; dH (270 MHz, CDCl3) 4.60 (dd, J ¼ 5.4, 5.4 Hz, 1 H), 3.86 (ddd,
J ¼ 2.9, 2.9, 9.8 Hz, 1 H), 3.80 (dq, J ¼ 4.6, 6.4 Hz, 1 H), 3.392 (s, 3 H),
3.386 (s, 3 H), 3.01 (br. s, 3 H), 2.58 (s, 3 H), 2.07 (dd, J ¼ 3.0, 4.5 Hz,
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1 H), 1.24 (d, J ¼ 6.4 Hz, 1 H); dC (67.8 MHz, CDCl3) 103.8, 69.4, 68.9,
68.3, 53.9, 53.5, 38.2 and 20.8; HRMS (ESI-TOF) calcd for: C9H22NO4
Please cite this article in press as: Matsushima Y, Kino J, A versatile route to 2,4,6-trideoxy-4-aminohexoses: Stereoselective syntheses of D-
vicenisamine and its epimers via iodocyclization of carbamate, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.009

Y. Matsushima, J. Kino / Tetrahedron xxx (2017) 1e9
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Please cite this article in press as: Matsushima Y, Kino J, A versatile route to 2,4,6-trideoxy-4-aminohexoses: Stereoselective syntheses of D-
vicenisamine and its epimers via iodocyclization of carbamate, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.009