An efficient synthesis of the polar part of sulfamisterin and its analogs

Article abstract of DOI:10.1016/j.carres.2012.02.019

An efficient synthesis of the polar part of sulfamisterin and its analogs starting from d-xylose is described. The corresponding allylic thiocyanates and trichloroacetimidates were subjected to aza-Claisen rearrangement that effectively generated a quaternary carbon having an amino group as one of the substituents. Subsequent functional group interconversions afforded the highly functionalized branched aminopolyol 29 that is expected to have the crucial application in the construction of sulfamisterin. On the other hand, the second diastereoisomer 34 would be transformed to 2-epi-congener. With respect to the appropriate stereochemical arrangement, the prepared polar segments 29 and 34 can also be utilized for the synthesis of mycestericins (E, G) and their analogs.

Full text of DOI:10.1016/j.carres.2012.02.019

Carbohydrate Research 352 (2012) 23–36
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
An efficient synthesis of the polar part of sulfamisterin and its analogs
Miroslava Martinková a, , Jozef Gonda a, Alena Uhríková a, Jana Špaková Raschmanová a, Juraj Kuchár b
⇑
a Institute of Chemical Sciences, Department of Organic Chemistry, P.J. Šafárik University, Moyzesova 11, Sk-040 01 Košice, Slovak Republic
b Institute of Chemical Sciences, Department of Inorganic Chemistry, P.J. Šafárik University, Moyzesova 11, Sk-040 01 Košice, Slovak Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of the polar part of sulfamisterin and its analogs starting from D-xylose is described.
Received 14 December 2011
Received in revised form 16 February 2012
Accepted 17 February 2012
Available online 3 March 2012
The corresponding allylic thiocyanates and trichloroacetimidates were subjected to aza-Claisen
rearrangement that effectively generated a quaternary carbon having an amino group as one of the sub-
stituents. Subsequent functional group interconversions afforded the highly functionalized branched
aminopolyol 29 that is expected to have the crucial application in the construction of sulfamisterin.
On the other hand, the second diastereoisomer 34 would be transformed to 2-epi-congener. With respect
to the appropriate stereochemical arrangement, the prepared polar segments 29 and 34 can also be uti-
lized for the synthesis of mycestericins (E, G) and their analogs.
Keywords:
Sulfamisterin
Mycestericins
Aza-Claisen rearrangement
Isothiocyanates
Ó 2012 Elsevier Ltd. All rights reserved.
Trichloroacetamides
Microwave irradiation
1. Introduction
details of this study that involved both aza-Claisen rearrangements
and utilized substrates derived from D-xylose.
In recent years, naturally occurring a-substituted a-amino acids
such as sphingofungin E and F,1 mycestericins A–G,2 sulfamisterin,3
myriocin,4 (Fig. 1) have received growing attention as attractive syn-
thetic targets possessing remarkable biological properties. These
above-mentioned fungal metabolites, representinga group of sphin-
golipid-based molecules, are reported to be inhibitors of serine pal-
mitoyltransferase (SPT),5 a key enzyme involved in the biosynthesis
of sphingolipids. Moreover, myriocin4d,6 and mycestericins A–G2
have been shown to have a potent immunosuppressive activity with
IC50 values in the nanomolar range in the mouse allogenic mixed
lymphocyte reaction. The common structural feature of these highly
functionalized compounds is the quaternary amino acid motif con-
nected with hydroxylated alkyl chain. Due to their unique structure
and impressive biological activity, several total syntheses of these
antifungal compounds have been developed.7–10 Our previous suc-
2. Results and discussion
As seen from our synthetic plan (Scheme 1), the aza-Claisen
rearrangement of chiral allylic thiocyanates 17–19 and imidates
14i–16i produced the corresponding isothiocyanates 20a,b–22a,b
and trichloroacetamides 23a,b–25a,b. These structures represent
attractive precursors of the natural
a-substituted a-amino acids
such as sulfamisterin, mycestericins (E, G) and their analogs. In this
respect, the vinyl group of the rearranged products can be trans-
formed to the hydroxymethyl moiety. One of the two protected
primary hydroxyl groups is the source of the carboxylic acid group,
while the other is necessary for the construction of the non-polar
side chain5g with C@O and/or C@C functionalities at the required
positions via the Wittig reaction or using Grubb’s catalyst-medi-
ated olefin cross metathesis.
cess with the construction of a-substituted a
-amino acids9h,11 from
The known12b,c 3,5-di-O-benzyl-
D-xylofuranose 1 served as the
sugar molecules suggested that aza-Claisen rearrangement on the
structurally appropriate chiral allylic thiocyanates would install
the tertiary carbon linked to an amino group precursor and in con-
tinuation of the above-mentioned, we decided to extend our meth-
odology to other chiral thiocyanate scaffolds and illustrate their
potential for the stereoselective approach to sulfamisterin, myces-
tericins (E, G) and their 2-epi-analogues. Herein we describe the full
starting material and was easily reached on a large scale, applying
modifications of the combined literature protocols.12 Its oxidative
cleavage with NaIO4 in CH3OH/H2O and subsequent reduction of
in situ generated aldehyde12c with NaBH4 afforded alcohol 2 in
96% isolated yield over two steps (Scheme 2). The treatment of 2
with 2,2-dimethoxypropane and catalytic amounts of CSA resulted
in the formation of the corresponding isopropylidene derivate 3
(95%, Scheme 2). Catalytic hydrogenation of 3 on 10% Pd–C in EtOH
removed the O-benzyl protecting groups to give compound 4 in
⇑
Corresponding author. Tel.: +421 55 6228332; fax: +421 55 62342329.
E-mail address: miroslava.martinkova@upjs.sk (M. Martinková).
89% yield (Scheme 2). Its preparation starting with D-xylose was
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2012.02.019

24
M. Martinková et al. / Carbohydrate Research 352 (2012) 23–36
With allylic thiocyanates 17–19 in hand, we then explored the
thermal aza-Claisen rearrangement (Scheme 3), which was carried
out in n-heptane and o-xylene either at 70 °C or at 90 °C under a
nitrogen atmosphere to produce the rearranged products 20a,b–
22a,b in very good yields (Table 1), as easily separable mixtures of
diastereoisomers; their ratio in the crude reaction mixtures was
determined by 1H NMR spectroscopic analysis. The corresponding
measurements were performed in CDCl3 and in the case of a mixture
of isothiocyanates 20a and 20b in C6D6 because in CDCl3 solution the
necessary proton signals were overlapping and we were not able to
assign the diastereomeric ratio. The microwave-promoted11a,15
thermal [3,3]-sigmatropic rearrangement of thiocyanates 17–19
led to significantly shorter reaction times (Table 1), with isolated
yields similar to those observed for the thermally driven reaction.
The attempted microwave induced rearrangement of thiocyanates
17–19 under solvent-free conditions on a silica gel15a led only to
the decomposition of the starting thiocyanates. The trichloroacetim-
idates 14i–16i, employed in this study were obtained from allylic
alcohols 14–16 by a standard procedure (NaH, Cl3CCN, THF)16c and
were used immediately in the next step without purification. The
thermal Overman rearrangement17 mediated by microwave irradia-
tion16a,b was realized in o-xylene in the presence of K2CO318 either at
170 °C or 190 °C and afforded the corresponding trichloroaceta-
mides 23a,b–25a,b in good yields (Table 2). Chida and his co-work-
ers7 described the very similar diastereoselectivity in the thermal
Overman rearrangement of imidate derived from (4R,2E)-2-{4-
[(tert-butyldiphenylsilyloxy)methyl]-2,2-dimethyl-1,3-dioxan-5-
ylidene}ethanol (ent-16) which was carried out in o-xylene in a
sealed tube at 140 °C for 48 h. In our cases, the use of microwave irra-
diation and higher temperatures led to substantial shortening of the
reaction times (4.8 or 12 times, see Table 2, entries 5 and 6) com-
pared to the thermal Chida’s reaction. The observed diastereoselec-
tivities in the studied aza-Claisen rearrangements were found to be
lower or moderate for both the conventional heating and sealed ves-
sel microwave irradiation conditions (Tables 1 and 2). The results
summarized in these tables suggest that the ratio of the rearrange-
ments is not influenced by the bulky protecting groups on the
primary alcohol function in thiocyanates 17–19 and trichloroace-
timidates 14i–16i as well as the use of microwave-assisted synthesis
had practically no impact on the diastereomeric outcome. In order to
rationalize the observed stereoselectivity in the [3,3]-sigmatropic
rearrangement, high-level density functional theory (DFT) calcula-
tions, which include electron correlation effects were carried out.
The solvent effects were also taken into account, in order to obtain
a more realistic model of the reaction. Geometries of the transition
states were optimized using B3LYP/6-311G(d,p) with JAGUAR 7.7
programme.19 The nature of vacuum B3LYP transition states was
Figure 1. Structures of SPT inhibitors.
achieved through a relatively economic approach in six reaction
steps with 48% overall yield. The primary alcohol function present
in 4 was selectively protected as tert-butyldimethylsilyl, triisopro-
pylsilyl and tert-butyldiphenylsilyl ethers using the corresponding
silylating reagents (TBDMSCl, TIPSCl and TBDPSCl) and imidazole
in dry CH2Cl213 to furnish 5, 6, 7 in 97%, 98% and 98% yields, respec-
tively (Scheme 2). Their oxidation with IBX14 in acetonitrile gave
ketones 8–10, which were subsequently treated with the stabilized
ylide (Ph3P@CHCO2Et) to afford (E)-a,b-unsaturated esters 11
(98%), 12 (99%), 13 (99%) as the single isomers; the E-geometry
of the double bonds was determined by NMR spectroscopic analy-
sis, including NOE experiments. Reduction of the ester function in
11–13 using standard procedure with DIBAL-H resulted in the for-
mation of allylic alcohols 14–16 in 96%, 99% and 91% yields, respec-
tively (Scheme 2). Thiocyanates 17–19 were prepared from the
corresponding alcohols 14–16 by a standard two stage proce-
dure,11a,b with very good overall yields (Scheme 2).
OH
O
O
CO2H
NH2
O
O
23b-25b, X = NHCOCCl3
20b-22b, X = N=C=S
HO
R
RO
RO
NH
X
OH
O
O
O
O
2-epi congeners
29
D-xylose
oxidation
[3,3]-sigmatropic
rearrangement
RO
OH
CO2H
Y
O
O
O
O
R
14i-16i
, Y = O(C=NH)CCl3,
HO
NH2
17-19, Y = SCN
OH
NH
O
X
O
Polar part of
mycestericins E, G
and sulfamisterin
23a-25a, X = NHCOCCl3
20a-22a, X = N=C=S
34
Scheme 1. Synthetic plan.

M. Martinková et al. / Carbohydrate Research 352 (2012) 23–36
25
O
OH OH
O
O
OH
3 steps
(ref. 12)
c
BnO
a
b
BnO
RO
D
-xylose
O
BnO
RO
OH
BnO
RO
OBn
OBn
2
3
1
2
3
O
O
O
1
O
O
O
O
g
d
4
6
e
f
5
HO
7
O
OH
OH
COOEt
4
8, R = TBDMS, 2.5 h, 85%
9, R = TIPS, 3 h, 87%
5, R = TBDMS,1.5 h, 97%
6, R = TIPS, 6 h, 98%
11, R = TBDMS, 2 h, 98%
12, R = TIPS, 2 h, 99%
10, R = TBDPS, 3 h, 81%
7, R = TBDPS, 0.6 h, 98%
13, R = TBDPS, 1.5 h, 99%
2
2
O3 1 O
O3 1 O
4
6
4
6
h
RO
RO
5
5
7
7
SCN
OH
8
8
17, R = TBDMS, 1 h, 95%
18, R = TIPS, 1.5 h, 83%
19, R = TBDPS, 1 h, 84%
14, R = TBDMS, 96%
15, R = TIPS, 99%
16, R = TBDPS, 91%
Scheme 2. Reagents and conditions: (a) (i) NaIO4, CH3OH/H2O (1:1), rt; (ii) NaBH4, EtOH, 0 °C?rt, 96%; (b) 2,2-DMP, p-TsOH, CH2Cl2, rt, 95%; (c) H2, 10% Pd/C, EtOH, rt, 89%;
(d) TBDMSCl or TIPSCl or TBDPSCl, imidazole, CH2Cl2, rt; (e) IBX, CH3CN, reflux; (f) Ph3P@CHCO2Et, toluene, reflux; (g) DIBAL-H, CH2Cl2, ꢁ78 °C; (h) (i) MsCl, Et3N, CH2Cl2, 0 °C;
(ii) KSCN, CH3CN, 0 °C?rt.
verified with frequency calculations, yielding only one large imagi-
nary frequency. Harmonic zero-point energy corrections at B3LYP/
6-311G(d,p) obtained from the frequency calculations of the vac-
uum transition states were applied to the transition state energies.
Single-point energies were computed with B3LYP density functional
method and the cc-pvTZ(+) basis set.20 The solvent effect was taken
into account via single-point calculation in a dielectric continuum
representing o-xylene as the solvent. A standard Poisson–Boltz-
mann continuum solvation model was applied as implemented in
JAGUAR 7.7.19
The starting geometries for thiocyanate 17 were determined by
a conformational search in which the torsional angle C3–C4–C5–S
was varied as shown in Figure 2. We found pair a of stable con-
formers 17a and 17b with torsional angles 102.9° and 260.8° which
are separated with transition state TS3 with torsional angle 6.6°.
These particular conformations result in a minimization of 1,3-
allylic strain.
The allylic rearrangement of conformer 17a occurs via transi-
tion states TS1 with relative free energy 0.31 kcal/mol and rear-
rangement of conformer 17b via transition state TS2 with energy
0.0 kcal/mol (Fig. 2). The process is concerted but asynchronous
and calculated geometries are in good agreement with Houk’s re-
sults.21 From the calculations, for the pathway 17a?TS1?20a,
the activation energy was found to be 0.88 kcal/mol lower than
for the pathway 17b?TS2?20b. Thus, the predicted diastereo-
meric ratio of 20a:20b at 90 °C was 77:23 at the level of theory un-
der study. These results are in relatively good agreement with the
experimental data (20a:20b ꢀ 2:1 ratio) for rearrangement of thio-
cyanate 17 with the correct prediction of isothiocyanate 20a as the
predominant diastereoisomer. Further investigations to under-
stand factors determining the diastereomeric outcome of these
studied [3,3]-sigmatropic rearrangements are underway.
The stereochemistry of the newly incorporated quaternary cen-
tre bearing the isothiocyanate function was assigned by X-ray dif-
fraction analysis of single crystal prepared by slow evaporation of
O
O
O
O
O
O
a
+
R1O
RO
RO
SCN
SCN
SCN
20a, R1= TBDMS
1
20b
, R = TBDMS
17 19
-
1
21b, R1= TIPS
21a
, R = TIPS
22a, R1= TBDPS
1
22b
, R = TBDPS
O
O
O
O
O
O
c
R1O
R1O
R1O
+
OR2
Cl3COCHN
Cl3COCHN
1
2
1
14
23a, R1= TBDMS
, R = TBDMS, R = H
23b
, R = TBDMS
b
b
14i, R1 = TBDMS, R2= -(C=NH)CCl3
15,
, R = TIPS
1
24b, R1= TIPS
24a
25a, R1= TBDPS
R1 = TIPS, R2= H
15i, R1 = TIPS, R2= -(C=NH)CCl3
1
25b
, R = TBDPS
1
2
16
, R = TBDPS, R = H
b
16i, R1 = TBDPS, R2= -(C=NH)CCl3
Scheme 3. Reagents and conditions: (a)
D or MW (Table 1); (b) Cl3CCN, NaH, THF, 0 °C; (c) o-xylene, K2CO3, MW (Table 2).

26
M. Martinková et al. / Carbohydrate Research 352 (2012) 23–36
Table 1
[3,3]-Sigmatropic rearrangement of thiocyanates 17–19
Entry
Thiocyanate
Conditions
, Heptane, 70 °C
MW, heptane, 70 °C
, Heptane, 90 °C
MW, Heptane, 90 °C
, o-Xylene, 70 °C
MW, o-xylene, 70 °C
, o-Xylene, 90 °C
MW, o-xylene, 90 °C
, Heptane, 70 °C
MW, heptane, 70 °C
, Heptane, 90 °C
MW, Heptane, 90 °C
, o-Xylene, 70 °C
MW, o-xylene, 70 °C
, o-Xylene, 90 °C
MW, o-xylene, 90 °C
, Heptane, 70 °C
MW, heptane, 70 °C
, Heptane, 90 °C
MW, heptane, 90 °C
, o-Xylene, 70 °C
MW, o-xylene, 70 °C
, o-Xylene, 90 °C
MW, o-xylene, 90 °C
Time
Ratioa 20a–22a:20b–22b
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
17
17
17
17
17
17
17
17
18
18
18
18
18
18
18
18
19
19
19
19
19
19
19
19
D
5 h
45 min
1 h
15 min
5 h
45 min
1 h
15 min
6 h
1.5 h
75 min
20 min
7 h
1 h
1 h
20 min
5 h
1.5 h
1 h
40 min
7.5 h
2.5 h
1.5 h
1 h
63:37
62:38
63:37
60:40
62:38
63:37
68:32
62:38
62:38
66:34
60:40
60:40
62:38
55:45
70:30
63:37
56:44
52:48
55:45
55:45
56:44
55:45
56:44
58:42
89
80
77
83
77
78
89
81
91
62
88
87
82
56
90
84
84
93
98
80
95
31
90
60
D
D
D
D
D
D
D
D
D
D
D
a
Ratio in the crude reaction mixtures. Determined by 1H NMR.
Isolated combined yields.
b
an ethereal solution of compound 20a and showed that the major
diastereoisomer of the rearrangement has (5R)-configuration
(Fig. 3). Similar to the previous case, we suppose that the same
configuration at the quaternary stereogenic centre must have com-
pound 21a bearing TIPS and also isothiocyanate 22a with TBDPS
protecting group. In order to correlate the stereochemical assign-
ment in 20a with that in 23a at C-5, compound 20a was converted
into carbamate 26 via a two-step sequence. Thus, exposure of 20a
to sodium methoxide in CH3OH produced the relatively unstable
thiocarbamate, in which the replacement of the sulfur atom by
oxygen was accomplished under very mild conditions by the
action of mesitylnitrile oxide22 (MNO) in CH3CN to afford carba-
mate 26 in 72% overall yield after two reaction steps (Scheme 4).
Table 2
Microwave induced Overman rearrangement of imidates 14i–16i
Entry Imidate Temperature
Time
(h)
Ratioa 23a–
25a:23b–25b
Yieldb
(%)
(°C)
1
2
3
4
5
6
14i
14i
15i
15i
16i
16i
170
190
170
190
170
190
11
4
21
4
10
4
66:34
62:38
63:37
68:32
62:38
63:37
77
70
65
47
83
72
a
Ratio in the crude reaction mixtures. Determined by 1H NMR.
Isolated combined yields.
b
Figure 2. Transition structures for the rearrangement 17a/17b?[TS1/TS2]?20a+20b. Relative energies of transition states (in kcal/mol) and bond distances (in Å) are shown.

M. Martinková et al. / Carbohydrate Research 352 (2012) 23–36
27
tuted-a-amino acids such as sulfamisterin, mycestericins (E, G)
and their analogues.
3. Conclusions
In conclusion, our study on the rearrangement of chiral allylic
thiocyanates 17–19 and trichloroacetimidates 14i–16i, which uti-
lize microwave irradiation for an acceleration of the corresponding
aza-Claisen rearrangements, have led to the development of the
branched aminopolyols 29 and 34 in very good yields with moder-
ate diastereoselectivities. From the obtained results, supported by
DFT calculations, we can conclude that the diastereomeric out-
come of the [3,3]-sigmatropic rearrangement seems to depend
on many factors that are still to be explored. The prepared oxazo-
lidinones 29 and 34 have the requisite functionalities, the appro-
priate stereochemical arrangement and therefore may serve as
polar parts either for synthesis of sulfamisterin and its 2-epimer
or for construction of mycestericins (E, G) and their 2-epi-congen-
ers. Their modifications toward the mentioned molecules are in
progress in our laboratory.
Figure 3. ORTEP structure of isothiocyanate 20a.
Its ozonolysis, followed by treatment with NaBH4, resulted in the
formation of alcohol 27, (74%, Scheme 4), which on intramolecular
cyclization (NaH, THF) yielded the corresponding oxazolidinone 28
(96%). On the other hand, ozonolysis of the rearranged product 23a,
followed by NaBH4 reduction, afforded the desired cyclic carba-
mate 28 (42%), together with alcohol 30 (42%), whose treatment
with DBU produced 28 in 98% yield (Scheme 4). A comparison of
1H and 13C NMR data of 28 prepared from isothiocyanate 20a with
those for 28 obtained from trichloroacetamide 23a demonstrated
that the stereochemistry at C-5 in 23a is (5R). Similar to the pre-
ceding case, minor isothiocyanate 20b and trichloroacetamide
23b were converted into oxazolidinone 33 as described in Scheme
4. Finally, the exposure of both compounds 28 and 33 to Bu4NF in
THF provided the corresponding product 29 (95%) and its 5-epi-
congener 34 (83%, Scheme 4), which represent the highly function-
alized branched aminopolyols and are expected to have important
4. Experimental
4.1. General methods
All commercial reagents were used in the highest available pur-
ity from Aldrich, Fluka, Merck or Acros Organics without further
purification. Solvents were dried and purified before use according
to standard procedures. For flash column chromatography on silica
gel, Kieselgel 60 (0.040–0.063 mm, 230–400 mesh, Merck) was
used. Solvents for flash chromatography (hexane, ethyl acetate,
methanol, dichloromethane) were distilled before usage. Thin layer
chromatography was run on Merck Silica Gel 60 F254 analytical
plates; detection was carried out with either ultraviolet light
(254 nm), or spraying with a solution of phosphomolybdic acid, a
basic potassium permanganate solution, or a solution of concen-
trated H2SO4, with subsequent charring. 1H NMR and 13C NMR
spectra were recorded in CDCl3, CD3OD and C6D6 on a Varian
applications in the synthesis of the above-mentioned
a
-substi-
O
O
O
O
O
O
b
a
c
20a
23a
20b
RO
HO
RO
HN
O
HN
O
H3COOCHN
O
28
O
26
29
e
O
O
O
O
d
d
RO
+
23b
RO
28
Cl3COCHN
e
Cl3COCHN
OH
OH
30
35
R = TBDMS
O
O
O
O
O
O
HO
RO
c
b
a
RO
HN
O
HN
O
H3COOCHN
O
O
33
31
34
Scheme 4. Reagents and conditions: (a) (i) CH3ONa, CH3OH, rt; (ii) MNO, CH3CN, rt, 26 (72% after two steps) or 31 (91% after two steps); (b) (ii) O3, CH3OH (EtOH), ꢁ78 °C; (ii)
NaBH4, ꢁ78 °C?rt; 27 (74%); 32 (70%); (iii) NaH, THF, 0 °C?rt; 28 (96%) or 33 (91%) (c) TBAF, THF, 0 °C?rt, 29 (95%) or 34 (83%); (d) O3, CH3OH (EtOH), ꢁ78 °C; (ii) NaBH4,
ꢁ78 °C?rt; 28 (42%), 30 (42%) or 35 (63%); (e) DBU, CH2Cl2, 0 °C?rt, 28 (98%) or 33 (94%).

28
M. Martinková et al. / Carbohydrate Research 352 (2012) 23–36
Mercury Plus 400 FT NMR (400.13 MHz for 1H and 100.6 MHz for
13C) spectrometer using TMS as internal reference. For 1H d are gi-
ven in parts per million (ppm) relative to TMS (d = 0.0) or C6D6
(d = 7.15) and for 13C relative to CDCl3 (d = 77.0), CD3OD
(d = 49.05) and C6D6 (d = 128.02). The multiplicity of the 13C NMR
signals concerning the 13C–1H coupling was determined by the
DEPT method. Chemical shifts (in ppm) and coupling constants
(in Hz) were obtained by first-order analysis; assignments were
derived from COSY and H/C correlation spectra. Infrared (IR) spec-
tra were measured with a Nicolet Avatar 330 FT-IR spectrometer
(9:1 hexane–EtOAc) to provide 18.9 g (95%) of 3 as a colourless
oil: ½a 2D0
ꢃ
ꢁ5.0 (c 0.30, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.45
(s, 6H, 2 ꢂ CH3), 3.31–3.32 (m, 1H, H-5), 3.58 (dd, J4,H = 5.9 Hz,
JH,H = 9.4 Hz, 1H, CH2O), 3.69 (dd, J4,H = 6.6 Hz, JH,H = 9.4 Hz, 1H,
CH2O), 3.89 (dd, J6,5 = 2.1 Hz, J6,6 = 12.9 Hz, 1H, H-6), 3.99 (dd,
J6,5 = 2.0 Hz, J6,6 = 12.9 Hz, 1H, H-6), 4.13 (ddd, J5,4 = 2.1 Hz,
J4,H = 5.9 Hz, J4,H = 6.6 Hz, 1H, H-4), 4.47 (d, JH,H = 11.9 Hz, 1H,
OCH2Ph), 4.49 (d, JH,H = 12.3 Hz, 1H, OCH2Ph), 4.55 (d,
JH,H = 11.9 Hz, 1H, OCH2Ph), 4.70 (d, JH,H = 12.3 Hz, 1H, OCH2Ph),
7.24–7.35 (m, 10H, 2 ꢂ Ph). 13C NMR (100 MHz, CDCl3): d 18.9
(CH3), 29.1 (CH3), 61.6 (C-6), 69.6 (C-5), 69.6 (CH2O), 70.7 (C-4),
71.1 (CH2Ph), 73.5 (CH2Ph), 98.6 (C-2), 127.6 (2 ꢂ CHPh), 127.8
(2 ꢂ CHPh), 127.9 (2 ꢂ CHPh), 128.3 (2 ꢂ CHPh), 128.3 (2 ꢂ CHPh),
138.1 (Ci), 138.2 (Ci). Anal. Calcd for C21H26O4: C, 73.66; H, 7.65.
Found: C, 73.63; H, 7.69.
and are expressed in
sured on a P-2000 Jasco polarimeter and reported as follows: [
m
values (cmꢁ1). Optical rotations were mea-
a]
D
(c in grams per 100 mL, solvent). Melting points were recorded on a
Kofler hot block, and are uncorrected. Microwave reactions were
carried out on the focused microwave system (CEM Discover).
The temperature content of the vessel was monitored using a cal-
ibrated infrared sensor mounted under the vessel. At the end of all
reactions the contents of vessel were cooled rapidly using a stream
4.4. (4R,5R)-4-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-ol
(4)
of compressed air. Small quantities of reagents (lL) were measured
with appropriate syringes (Hamilton). All reactions were per-
formed under an atmosphere of nitrogen, unless otherwise noted.
10% Pd/C (3.78 g) was added to a solution of derivative 3 (18.9 g,
55.2 mmol) in EtOH (437 mL). The reaction mixture was stirred un-
der an atmosphere of hydrogen for 1 h, then filtered through a
short pad of Celite and concentrated in vacuo. The resulting residue
was subjected to flash chromatography on silica gel (20:1 CH2Cl2–
MeOH) to give 7.97 g (89%) of crystalline alcohol 4: mp 82–83.5 °C;
4.2. (2R,3R)-2,4-Bis(benzyloxy)butane-1,3-diol (2)
A solution of 1 (20.0 g, 60.5 mmol) in methanol (140 mL) was
treated with a solution of NaIO4 (15.5 g, 72.5 mmol) in H2O
(140 mL). The resulting mixture was stirred at room temperature
for 30 min, then diluted with CH2Cl2 (293 mL) and the insoluble
materials were removed by filtration. The aqueous layer was
washed with portions of EtOAc (4 ꢂ 360 mL). The organic phases
were combined, dried over Na2SO4, stripped of solvent, and the res-
idue was used immediately in the next step without further puri-
fication. To a solution of the crude aldehyde (19.9 g, 60.5 mmol) in
EtOH (281 mL) that was pre-cooled to 0 °C, was added NaBH4
(4.58 g, 121 mmol) portionwise. The resulting mixture was stirred
for 10 min at 0 °C and for an additional 20 min at room tempera-
ture. The reaction was quenched by neutralization with Amberlite
IR-120 (H+), the solid parts were filtered off before evaporation of
the solvent, and the residue was partitioned between a saturated
NaCl solution (127 mL) and EtOAc (50 mL). The aqueous phase
was extracted with further portions of EtOAc (2 ꢂ 180 mL). The
combined organic layers were dried over Na2SO4, the solvent was
taken down, and the residue was subjected to flash chromatogra-
phy on silica gel (1:1 hexane–EtOAc) to afford 17.6 g (96%) of com-
½
a 2D0
ꢃ
ꢁ8.1 (c 0.26, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.46 (s, 3H,
CH3), 1.49 (s, 3H, CH3), 2.24–2.35 (m, 1H, OH), 2.92–2.98 (m, 1H,
OH), 3.54–3.56 (m, 1H, H-5), 3.72–3.83 (m, 2H, CH2O), 3.83 (dd,
J6,5 = 2.0 Hz, J6,6 = 12.4 Hz, 1H, H-6), 3.98 (dt, J5,4 = 1.3 Hz,
J4,H = 5.8 Hz, J4,H = 5.8 Hz, 1H, H-4), 4.07 (dd, J6,5 = 1.5 Hz,
J6,6 = 12.4 Hz, 1H, H-6). 13C NMR (100 MHz, CDCl3): d 18.4 (CH3),
29.4 (CH3), 62.9 (CH2O), 64.1 (C-5), 65.7 (C-6), 72.0 (C-4), 99.1
(C-2). Anal. Calcd for C7H14O4: C, 51.84; H, 8.70. Found: C, 51.81;
H, 8.71.
4.5. (4R,5R)-4-[(tert-Butyldimethylsilyloxy)methyl]-2,2-
dimethyl-1,3-dioxan-5-ol (5)
To a solution of 4 (2.65 g, 16.3 mmol) in dry CH2Cl2 (207 mL)
were successively added imidazole (3.34 g, 49.1 mmol) and tert-
butyldimethylsilyl chloride (3.20 g, 21.2 mmol) and the resulting
mixture was stirred at room temperature. After 1.5 h no starting
material was detected (judged by TLC), the reaction was stopped,
washed with a saturated NH4Cl solution (205 mL), and the aqueous
layer was extracted with further portions of CH2Cl2 (2 ꢂ 205 mL).
The combined organic phases were dried over Na2SO4, the solvent
was taken down, and the residue was purified by flash chromatog-
raphy on silica gel (9:1 hexane–EtOAc) to yield 4.38 g (97%) of 5 as
pound 2 as white solids: mp 54.5–56 °C; ½a D25
ꢁ23.3 (c 0.34, CHCl3).
ꢃ
1H NMR (400 MHz, CDCl3): d 2.46 (br s, 1H, OH), 2.75 (br s, 1H, OH),
3.53–3.61 (m, 3H, 2 ꢂ H-1, H-2), 3.69 (dd, J4,3 = 4.4 Hz,
J4,4 = 11.9 Hz, 1H, H-4), 3.81 (dd, J4,3 = 4.6 Hz, J4,4 = 11.9 Hz, 1H, H-
4), 3.95–3.98 (m, 1H, H-3), 4.52 (s, 2H, OCH2Ph), 4.58 (d,
JH,H = 11.6 Hz, 1H, OCH2Ph), 4.67 (d, JH,H = 11.6 Hz, 1H, OCH2Ph),
7.27–7.36 (m, 10H, 2 ꢂ Ph). 13C NMR (100 MHz, CDCl3): d 61.7
(C-4), 70.8 (C-1), 71.1 (C-3), 72.7 (CH2Ph), 73.5 (CH2Ph), 79.1 (C-
2), 127.8 (3 ꢂ CHPh), 127.9 (3 ꢂ CHPh), 128.4 (2 ꢂ CHPh), 128.5
(2 ꢂ CHPh), 137.7 (Ci), 137.9 (Ci). Anal. Calcd for C18H22O4: C,
71.50; H, 7.33. Found: C, 71.39; H, 7.48.
a colourless oil: ½a D20
ꢃ
ꢁ10.8 (c 0.25, CHCl3). 1H NMR (400 MHz,
CDCl3): d 0.08 (s, 3H, CH3), 0.08 (s, 3H, CH3), 0.90 (s, 9H,
3 ꢂ CH3), 1.42 (s, 3H, CH3), 1.47 (s, 3H, CH3), 2.79 (d, J5,OH = 10.1 Hz,
1H, OH), 3.54–3.57 (m, 1H, H-5), 3.64 (dd, J4,H = 5.1 Hz,
JH,H = 10.0 Hz, 1H, CH2O), 3.80 (dd, J4,H = 7.0 Hz, JH,H = 10.1 Hz, 1H,
CH2O), 3.84 (dd, J6,5 = 2.0 Hz, J6,6 = 12.2 Hz, 1H, H-6), 3.90–3.93
(m, 1H, H-4), 4.05 (dd, J6,5 = 1.5 Hz, J6,6 = 12.2 Hz, 1H, H-6). 13C
NMR (100 MHz, CDCl3): d ꢁ5.4 (2 ꢂ CH3), 18.3 (Cq), 18.4 (CH3),
25.8 (3 ꢂ CH3), 29.5 (CH3), 62.8 (CH2O), 63.4 (C-5), 66.0 (C-6),
72.2 (C-4), 98.9 (C-2). Anal. Calcd for C13H28O4Si: C, 56.48; H,
10.21. Found: C, 56.50; H, 10.18.
4.3. (4R,5R)-5-(Benzyloxy)-4-(benzyloxymethyl)-2,2-dimethyl-
1,3-dioxane (3)
To a solution of alcohol 2 (17.6 g, 58.2 mmol) and 2,2-dime-
thoxypropane (21.7 mL, 175 mmol) in CH2Cl2 (324 mL) was added
p-TsOH (0.44 g, 2.31 mmol). After being stirred at room tempera-
ture for 1.5 h, the reaction mixture was washed with a saturated
NaHCO3 solution (2 ꢂ 418 mL). The organic layer was dried over
Na2SO4, the solvent was removed under reduced pressure, and
the residue was purified by flash chromatography on silica gel
4.6. (4R,5R)-2,2-Dimethyl-4-[(triisopropylsilyloxy)methyl]-2,2-
dimethyl-1,3-dioxan-5-ol (6)
Using the same procedure as described for the preparation of
derivative 5, alcohol 4 (2.65 g, 16.3 mmol), imidazole (3.34 g,
49.1 mmol) and TIPSCl (4.54 mL, 21.2 mmol) afforded after flash

M. Martinková et al. / Carbohydrate Research 352 (2012) 23–36
29
chromatography on silica gel (9:1 hexane–EtOAc) 5.1 g (98%) of
J6,4 = 1.5 Hz, J4,H = 2.7 Hz, J4,H = 6.0 Hz, 1H, H-4). 13C NMR
(100 MHz, CDCl3): d 11.9 (3 ꢂ CH), 17.8 (3 ꢂ CH3), 17.9 (3 ꢂ CH3),
23.5 (CH3), 24.3 (CH3), 62.2 (C-6), 66.9 (CH2O), 77.0 (C-4), 100.6
(C-2), 208.0 (C@O). Anal. Calcd for C16H32O4Si: C, 60.72; H, 10.19.
Found: C, 60.78; H, 10.12.
compound 6 as a colourless oil: ½a D20
ꢃ
ꢁ13.4 (c 0.32, CHCl3). 1H
NMR (400 MHz, CDCl3): d 1.04–1.09 (m, 21H, 6 ꢂ CH3, 3 ꢂ CH),
1.41 (s, 3H, CH3), 1.47 (s, 3H, CH3), 2.83 (d, J5,OH = 9.8 Hz, 1H,
OH), 3.60–3.62 (m, 1H, H-5), 3.71 (dd, J4,H = 4.1 Hz, JH,H = 8.8 Hz,
1H, CH2O), 3.84 (dd, J6,5 = 2.1 Hz, J6,6 = 12.2 Hz, 1H, H-6), 3.87–
3.94 (m, 2H, H-4, CH2O), 4.05 (dd, J6,5 = 1.5 Hz, J6,6 = 12.2 Hz, 1H,
H-6). 13C NMR (100 MHz, CDCl3): d 11.9 (3 ꢂ CH), 17.9 (6 ꢂ CH3),
18.5 (CH3), 29.5 (CH3), 63.1 (CH2O), 63.5 (C-5), 66.0 (C-6), 72.3
(C-4), 98.9 (C-2). Anal. Calcd for C16H34O4Si: C, 60.33; H, 10.76.
Found: C, 60.39; H, 10.70.
4.10. (4R)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2,2-dimethyl-
1,3-dioxan-5-one (10)
According to the same procedure described for the preparation
of 8, compound 7 (6.42 g, 16.0 mmol) and IBX (8.98 g, 32.1 mmol)
afforded after flash chromatography on silica gel (35:1 hexane–
4.7. (4R,5R)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2,2-
dimethyl-1,3-dioxan-5-ol (7)
EtOAc) 5.18 g (81%) of ketone 10 as a colourless oil: ½a D20
ꢃ
+120.3
(c 0.30, CHCl3). 1H NMR (400 MHz, CDCl3):
d 1.04 (s, 9H,
3 ꢂ CH3), 1.47 (s, 3H, CH3), 1.48 (s, 3H, CH3), 3.96–4.06 (m, 2H,
H-6, CH2O), 4.04 (dd, J4,H = 2.9 Hz, JH,H = 11.2 Hz, 1H, CH2O), 4.27
(dd, J6,4 = 1.5 Hz, J6,6 = 16.7 Hz, 1H, H-6), 4.35 (ddd, J6,4 = 1.5 Hz,
J4,H = 2.9 Hz, J4,H = 5.4 Hz, 1H, H-4), 7.35–7.44 (m, 6H, Ph), 7.67–
7.72 (m, 4H, Ph). 13C NMR (100 MHz, CDCl3): d 19.3 (Cq), 23.5
(CH3), 24.4 (CH3), 26.7 (3 ꢂ CH3), 62.5 (C-6), 67.0 (CH2O), 76.6 (C-
4), 100.5 (C-2), 127.6 (2 ꢂ CHPh), 127.8 (2 ꢂ CHPh), 129.7
(2 ꢂ CHPh), 133.3 (Ci), 133.4 (Ci), 135.7 (4 ꢂ CHPh), 207.7 (C@O).
Anal. Calcd for C23H30O4Si: C, 69.31; H, 7.59. Found: C, 69.37; H,
7.53.
By the same procedure as described for the preparation of 5,
alcohol 4 (2.65 g, 16.3 mmol), imidazole (3.34 g, 49.1 mmol) and
TBDPSCl (5.5 mL, 21.2 mmol) provided after flash chromatography
on silica gel (9:1 hexane–EtOAc) 6.42 g (98%) of compound 7 as a
colourless oil: ½a D25
ꢃ
ꢁ14.8 (c 0.25, CHCl3). 1H NMR (400 MHz,
CDCl3): d 1.06 (s, 9H, 3 ꢂ CH3), 1.39 (s, 3H, CH3), 1.42 (s, 3H,
CH3), 2.75 (d, J5,OH = 10.2 Hz, 1H, OH), 3.62 (ddd, J6,5 = 1.7 Hz,
J6,5 = 3.2 Hz, J5,OH = 10.2 Hz, 1H, H-5), 3.68 (dd, J4,H = 5.2 Hz,
JH,H = 10.0 Hz, 1H, CH2O), 3.83–3.86 (m, 1H, CH2O), 3.86–3.89 (m,
1H, H-6), 3.94–3.97 (m, 1H, H-4), 4.04 (dd, J6,5 = 1.7 Hz,
J6,6 = 12.2 Hz, 1H, H-6), 7.36–7.44 (m, 6H, Ph), 7.67–7.72 (m, 4H,
Ph). 13C NMR (100 MHz, CDCl3): d 18.4 (CH3), 19.2 (Cq), 26.8
(3 ꢂ CH3), 29.4 (CH3), 63.4 (CH2O), 63.5 (C-5), 66.0 (C-6), 72.2 (C-
4), 98.8 (C-2), 127.6 (4 ꢂ CHPh), 129.7 (2 ꢂ CHPh), 133.2 (Ci),
133.5 (Ci), 135.6 (2 ꢂ CHPh), 135.7 (2 ꢂ CHPh). Anal. Calcd for
4.11. Ethyl (4S,2E)-2-{4-[(tert-butyldimethylsilyloxy)methyl]-
2,2-dimethyl-1,3-dioxan-5-ylidene}acetate (11)
To a solution of ketone 8 (3.68 g, 13.4 mmol) in dry toluene
(140 mL) was added the stabilized ylide, Ph3P@CHCO2Et, (9.33 g,
26.8 mmol), and the resulting mixture was stirred at reflux. After
the starting material was completely consumed (2 h, judged by
TLC), the reaction was stopped and allowed to cool to room tem-
perature, before evaporating of the solvent. The obtained residue
was diluted with hexane, the salts were filtered off, the solvent
was taken down, and the crude product was chromatographed
on silica gel (70:1 hexane–EtOAc). This procedure yielded 4.52 g
C23H32O4Si: C, 68.96; H, 8.05. Found: C, 68.91; H, 8.11.
4.8. (4R)-4-[(tert-Butyldimethylsilyloxy)methyl]-2,2-dimethyl-
1,3-dioxan-5-one (8)
o-Iodoxybenzoic acid (8.87 g, 31.7 mmol) was added to a solu-
tion of alcohol 5 (4.38 g, 15.8 mmol) in CH3CN (147 mL), and the
mixture was stirred at reflux. After 2.5 h, the starting material
was completely consumed (judged by TLC), the reaction was
stopped and allowed to cool to room temperature. The insoluble
materials were removed by filtration, the solvent was evaporated
under reduced pressure, and the residue was subjected to flash
chromatography on silica gel (15:1 hexane–EtOAc) to give 3.70 g
(98%) of ester 11 as a colourless oil: ½a D20
ꢃ
+77.2 (c 0.25, CHCl3). 1H
NMR (400 MHz, CDCl3): d 0.08 (s, 6H, 2 ꢂ CH3), 0.90 (s, 9H,
3 ꢂ CH3), 1.27 (t, J = 7.1 Hz, 3H, CH3), 1.38 (s, 3H, CH3), 1.41 (s,
3H, CH3), 3.78 (dd, J4,H = 5.8 Hz, JH,H = 10.6 Hz, 1H, CH2O), 3.84
(dd, J4,H = 5.8 Hz, JH,H = 10.6 Hz, 1H, CH2O), 4.11–4.20 (m, 2H,
CH2), 4.38 (tt, J7,4 = 2.0 Hz, J6,4 = 2.0 Hz, J4,H = 5.8 Hz, J4,H = 5.8 Hz,
1H, H-4), 4.67 (td, J7,6 = 2.0 Hz, J6,4 = 2.0 Hz, J6,6 = 17.7 Hz, 1H, H-
6), 5.03 (dd, J7,6 = 2.0 Hz, J6,6 = 17.7 Hz, 1H, H-6), 5.79 (m, 1H, H-
7). 13C NMR (100 MHz, CDCl3): d ꢁ5.4 (CH3), ꢁ5.3 (CH3), 14.2
(CH3), 18.2 (Cq), 24.2 (CH3), 25.1 (CH3), 25.8 (3 ꢂ CH3), 60.1
(CH2), 61.6 (C-6), 64.3 (CH2O), 71.4 (C-4), 100.1 (C-2), 112.3 (C-
7), 158.8 (C-5), 165.9 (C@O). Anal. Calcd for C17H32O5Si: C, 59.27;
H, 9.36. Found: C, 59.24; H, 9.38.
(85%) of ketone 8 as a colourless oil: ½a D20
ꢃ
+176.5 (c 0.20, CHCl3).
1H NMR (400 MHz, CDCl3): d 0.06 (s, 3H, CH3), 0.07 (s, 3H, CH3),
0.88 (s, 9H, 3 ꢂ CH3), 1.46 (s, 3H, CH3), 1.47 (s, 3H, CH3), 3.88
(dd, J4,H = 5.9 Hz, JH,H = 11.5 Hz, 1H, CH2O), 3.97 (d, J6,6 = 16.7 Hz,
1H, H-6), 4.01 (dd, J4,H = 2.8 Hz, JH,H = 11.5 Hz, 1H, CH2O), 4.24
(dd, J6,4 = 1.5 Hz, J6,6 = 16.7 Hz, 1H, H-6), 4.30 (ddd, J6,4 = 1.5 Hz,
J4,H = 2.8 Hz, J4,H = 5.9 Hz, 1H, H-4). 13C NMR (100 MHz, CDCl3): d
ꢁ5.3 (2 ꢂ CH3), 18.3 (Cq), 23.5 (CH3), 24.3 (CH3), 25.8 (3 ꢂ CH3),
61.7 (CH2O), 66.9 (C-6), 76.7 (C-4), 100.6 (C-2), 207.9 (C@O). Anal.
Calcd for C13H26O4Si: C, 56.90; H, 9.55. Found: C, 56.88; H, 9.56.
4.12. Ethyl (4S,2E)-2-{2,2-dimethyl-4-
[(triisopropylsilyloxy)methyl]-1,3-dioxan-5-ylidene}acetate
(12)
4.9. (4R)-2,2-Dimethyl-4-[(triisopropylsilyloxy)methyl]-1,3-
dioxan-5-one (9)
According to the same procedure described for the preparation
of ester 11, ketone 9 (4.36 g, 13.8 mmol) and Ph3P@CHCO2Et
(9.60 g, 27.6 mmol) provided after flash chromatography on silica
gel (35:1 hexane–EtOAc) 5.27 g (99%) of compound 12 as a colour-
Using the same procedure as described for the preparation of
compound 8, alcohol 6 (5.07 g, 15.9 mmol) and IBX (8.91 g,
31.8 mmol) yielded after flash chromatography on silica gel (35:1
less oil: ½a 2D0
ꢃ
+60.7 (c 0.30, CHCl3). 1H NMR (400 MHz, CDCl3): d
hexane–EtOAc) 4.38 g (87%) of ketone 9 as a colourless oil: ½a D20
ꢃ
1.05–1.10 (m, 21H, 6 ꢂ CH3, 3 ꢂ CH), 1.27 (t, J = 7.1 Hz, 3H, CH3),
1.37 (s, 3H, CH3), 1.41 (s, 3H, CH3), 3.87 (dd, J4,H = 5.6 Hz,
JH,H = 10.3 Hz, 1H, CH2O), 3.92 (dd, J4,H = 6.2 Hz, JH,H = 10.3 Hz, 1H,
CH2O), 4.12–4.20 (m, 2H, CH2), 4.39–4.42 (m, 1H, H-4), 4.65–4.71
(m, 1H, H-6), 5.01–5.06 (m, 1H, H-6), 5.86 (dd, J7,6 = 2.2 Hz,
+151.2 (c 0.30, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.04–1.08
(m, 21H, 6 ꢂ CH3, 3 ꢂ CH), 1.46 (s, 3H, CH3), 1.47 (s, 3H, CH3),
3.96 (dd, J4,H = 6.0 Hz, JH,H = 11.1 Hz, 1H, CH2O), 3.97 (d,
J6,6 = 16.9 Hz, 1H, H-6), 4.10 (dd, J4,H = 2.7 Hz, JH,H = 11.1 Hz, 1H,
CH2O), 4.26 (dd, J6,4 = 1.5 Hz, J6,6 = 16.9 Hz, 1H, H-6), 4.34 (ddd,
J7,6 = 4.1 Hz, 1H, H-7). 13C NMR (100 MHz, CDCl3):
d 11.9

30
M. Martinková et al. / Carbohydrate Research 352 (2012) 23–36
(3 ꢂ CH), 14.2 (CH3), 17.9 (6 ꢂ CH3), 24.2 (CH3), 25.1 (CH3), 60.1
(CH2), 61.7 (C-6), 64.7 (CH2O), 71.6 (C-4), 100.1 (C-2), 112.4 (C-
7), 159.0 (C-5), 166.0 (C@O). Anal. Calcd for C20H38O5Si: C, 62.14;
H, 9.91. Found: C, 62.19; H, 9.98.
4.16. (4S,2E)-2-{4-[(tert-Butyldiphenylsilyloxy)methyl]-2,2-
dimethyl-1,3-dioxan-5-ylidene}ethanol (16)
According to the same procedure described for the preparation
of 14, compound 13 (6.0 g, 12.9 mmol) was converted to alcohol 16
(5.0 g, 91%, colourless oil, 3:1 hexane–EtOAc): ½a D20
ꢃ
+38.4 (c 0.25,
CHCl3). 1H NMR (400 MHz, CDCl3): d 1.06 (s, 9H, 3 ꢂ CH3), 1.36
(s, 3H, CH3), 1.40 (s, 3H, CH3), 3.82 (dd, J4,H = 6.0 Hz, JH,H = 10.7 Hz,
1H, CH2O), 3.91 (dd, J4,H = 5.0 Hz, JH,H = 10.7 Hz, 1H, CH2O), 4.04
(dd, J8,7 = 6.3 Hz, J8,8 = 13.0 Hz, 1H, H-8), 4.12 (dd, J8,7 = 7.3 Hz,
J8,8 = 13.0 Hz, 1H, H-8), 4.27 (d, J6,6 = 14.2 Hz, 1H, H-6), 4.35 (d,
J6,6 = 14.2 Hz, 1H, H-6), 4.39–4.42 (m, 1H, H-4), 5.47–5.50 (m, 1H,
H-7), 7.35–7.44 (m, 6H, Ph), 7.68–7.71 (m, 4H, Ph). 13C NMR
4.13. Ethyl (4S,2E)-2-{4-[(tert-butyldiphenylsilyloxy)methyl]-
2,2-dimethyl-1,3-dioxan-5-ylidene}acetate (13)
Using the same procedure as described for the preparation of
(E)-11, ketone 10 (5.18 g, 13.0 mmol) was converted to ester 13
(6.0 g, 99%, colourless oil, 35:1 hexane–EtOAc): ½a D20
ꢃ
+49.8 (c
0.50, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.06 (s, 9H, 3 ꢂ CH3),
1.27 (t, J = 7.1 Hz, 3H, CH3), 1.35 (s, 3H, CH3), 1.36 (s, 3H, CH3),
3.84 (dd, J4,H = 5.7 Hz, JH,H = 10.7 Hz, 1H, CH2O), 3.90 (dd,
J4,H = 5.8 Hz, JH,H = 10.7 Hz, 1H, CH2O), 4.09–4.21 (m, 2H, CH2),
4.40–4.43 (m, 1H, H-4), 4.62 (td, J7,6 = 2.0 Hz, J6,4 = 2.0 Hz,
J6,6 = 17.7 Hz, 1H, H-6), 5.02 (dd, J7,6 = 2.0 Hz, J6,6 = 17.7 Hz, 1H, H-
6), 5.78–5.79 (m, 1H, H-7), 7.35–7.44 (m, 6H, Ph), 7.68–7.71 (m,
4H, Ph). 13C NMR (100 MHz, CDCl3): d 14.2 (CH3), 19.2 (Cq), 24.2
(CH3), 25.1 (CH3), 26.8 (3 ꢂ CH3), 60.1 (CH2), 61.7 (C-6), 64.8
(CH2O), 71.5 (C-4), 100.1 (C-2), 112.4 (C-7), 127.7 (4 ꢂ CHPh),
129.7 (2 ꢂ CHPh), 133.3 (2 ꢂ Ci), 135.6 (2 ꢂ CHPh), 135.7 (2 ꢂ CHPh),
158.7 (C-5), 165.8 (C@O). Anal. Calcd for C27H36O5Si: C, 69.20; H,
7.74. Found: C, 69.27; H, 7.80.
(100 MHz, CDCl3):
d 19.3 (Cq), 23.3 (CH3), 26.4 (CH3), 26.8
(3 ꢂ CH3), 58.1 (C-8), 59.2 (C-6), 65.5 (CH2O), 71.9 (C-4), 99.7 (C-
2), 121.2 (C-7), 127.6 (4 ꢂ CHPh), 129.6 (2 ꢂ CHPh), 133.5 (Ci),
133.6 (Ci), 135.6 (2 ꢂ CHPh), 135.7 (2 ꢂ CHPh), 137.9 (C-5). Anal.
Calcd for C25H34O5Si: C, 70.38; H, 8.03. Found: C, 70.31; H, 8.09.
4.17. (4S,2E)-tert-Butyl{[2,2-dimethyl-5-(2-thiocyanato
ethylidene)-1,3-dioxane-4-yl]methoxy}dimethylsilane (17)
At first, Et3N (2.50 mL, 18.0 mmol) was added to a solution of
alcohol 14 (3.63 g, 12.0 mmol) in dry CH2Cl2 (102 mL) pre-cooled
to 0 °C, followed by the dropwise addition of methanesulfonyl
chloride (1.11 mL, 14.4 mmol). After stirring at 0 °C for 20 min,
the solvent was evaporated under reduced pressure. The residue
was diluted with Et2O (53 mL), salts were filtered off and washed
with another portion of Et2O. Evaporation of the solvent afforded
the crude mesylate that was used in the subsequent reaction di-
rectly without further purification. The isolated product (4.57 g,
12.0 mmol) was dissolved in dry CH3CN (102 mL). To this solution
pre-cooled to 0 °C, was added KSCN (1.75 g, 18.0 mmol), and the
resulting mixture was stirred for a further 15 min at 0 °C and then
at room temperature for 45 min. After completion of the reaction
(monitored by TLC), the solvent was taken down, the crude product
was diluted with Et2O (53 mL), and the salts were removed by fil-
tration. Evaporation of solvent and chromatography of the residue
on silica gel (11:1 hexane–EtOAc) yielded 3.92 g (95%) of thiocya-
4.14. (4S,2E)-2-{4-[(tert-Butyldimethylsilyloxy)methyl]-2,2-
dimethyl-1,3-dioxan-5-ylidene}ethanol (14)
Diisobutylaluminum hydride (30.6 mL of a 1.2 M toluene solu-
tion) was added dropwise to a solution of ester 11 (4.52 g,
13.1 mmol) in dry CH2Cl2 (55 mL) pre-cooled to ꢁ78 °C. The result-
ing mixture was stirred at the same temperature for another
30 min, then quenched with MeOH (10 mL), and poured into 30%
aq K/Na tartrate (155 mL). After being stirred for 45 min, the mix-
ture was then extracted with CH2Cl2 (2 ꢂ 204 mL). The combined
organic layers were dried over Na2SO4, the solvent was taken
down, and the residue was subjected to flash chromatography on
silica gel (3:1 hexane–EtOAc) to give 3.81 g (96%) of allylic alcohol
nate 17 as amorphous solids: mp 26–27 °C; ½a D20
ꢃ
+38.3 (c 0.30,
14 as a colourless oil: ½a D20
ꢃ
+59.5 (c 0.20, CHCl3). 1H NMR (400 MHz,
CHCl3). 1H NMR (400 MHz, CDCl3): d 0.08 (s, 3H, CH3), 0.09 (s,
3H, CH3), 0.90 (s, 9H, 3 ꢂ CH3), 1.37 (s, 3H, CH3), 1.44 (s, 3H,
CH3), 3.57 (dd, J8,7 = 6.3 Hz, J8,8 = 11.1 Hz, 1H, H-8), 3.62 (dd,
J8,7 = 6.9 Hz, J8,8 = 11.1 Hz, 1H, H-8), 3.77 (dd, J4,H = 5.4 Hz,
JH,H = 10.6 Hz, 1H, CH2O), 3.83 (dd, J4,H = 5.8 Hz, JH,H = 10.6 Hz, 1H,
CH2O), 4.37–4.45 (m, 3H, H-4, 2 ꢂ H-6), 5.58–5.64 (m, 1H, H-7).
13C NMR (100 MHz, CDCl3): d –5.3 (CH3), –5.2 (CH3), 18.2 (Cq),
23.3 (CH3), 25.8 (3 ꢂ CH3), 26.3 (CH3), 30.7 (C-8), 58.7 (C-6), 64.7
(CH2O), 71.6 (C-4), 99.9 (C-2), 111.7 (SCN), 114.4 (C-7), 143.6 (C-
5). Anal. Calcd for C16H29NO3SSi: C, 55.94; H, 8.51; N, 4.08. Found:
C, 55.80; H, 8.67; N, 4.19.
CDCl3): d 0.07 (s, 3H, CH3), 0.08 (s, 3H, CH3), 0.90 (s, 9H, 3 ꢂ CH3),
1.37 (s, 3H, CH3), 1.43 (s, 3H, CH3), 3.74 (dd, J4,H = 6.2 Hz,
JH,H = 10.7 Hz, 1H, CH2O), 3.84 (dd, J4,H = 5.2 Hz, JH,H = 10.7 Hz, 1H,
CH2O), 4.10 (dd, J8,7 = 6.3 Hz, J8,8 = 12.9 Hz, 1H, H-8), 4.16 (dd,
J8,7 = 7.2 Hz, J8,8 = 12.9 Hz, 1H, H-8), 4.31–4.40 (m, 3H, H-4, 2 ꢂ H-
6), 5.54–5.58 (m, 1H, H-7). 13C NMR (100 MHz, CDCl3): d ꢁ5.3
(CH3), ꢁ5.1 (CH3), 18.3 (Cq), 23.2 (CH3), 25.9 (3 ꢂ CH3), 26.4
(CH3), 58.1 (C-8), 59.2 (C-6), 65.0 (CH2O), 71.8 (C-4), 99.7 (C-2),
121.1 (C-7), 138.0 (C-5). Anal. Calcd for C15H30O4Si: C, 59.56; H,
10.00. Found: C, 59.58; H, 10.02.
4.18. (4S,2E)-{[2,2-Dimethyl-5-(2-thiocyanatoethylidene)-1,3-
dioxane-4-yl]methoxy}triiisopropylsilane (18)
4.15. (4S,2E)-2-{2,2-Dimethyl-4-[(triisopropylsilyloxy)methyl]-
1,3-dioxan-5-ylidene}ethanol (15)
Using the same procedure as described for the preparation of
17, alcohol 15 (4.51 g, 13.1 mmol) afforded after flash chromatog-
raphy on silica gel (9:1 hexane–EtOAc) 4.19 g (83%) of compound
Using the same procedure as described for the preparation of
14, ester 12 (5.25 g, 13.6 mmol) was transformed to compound
15 (4.64 g, 99%, colourless oil, 3:1 hexane–EtOAc): ½a D20
ꢃ
+48.8 (c
18 as a colourless oil: ½a D20
ꢃ
+37.8 (c 0.32, CHCl3). 1H NMR
0.34, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.05–1.10 (m, 21H,
6 ꢂ CH3, 3 ꢂ CH), 1.37 (s, 3H, CH3), 1.44 (s, 3H, CH3), 3.82 (dd,
J4,H = 5.8 Hz, JH,H = 10.4 Hz, 1H, CH2O), 3.92 (dd, J4,H = 5.5 Hz,
JH,H = 10.4 Hz, 1H, CH2O), 4.08–4.19 (m, 2H, 2 ꢂ H-8), 4.32–4.41
(m, 3H, 2 ꢂ H-6, H-4), 5.60–5.54 (m, 1H, H-7). 13C NMR
(100 MHz, CDCl3): d 12.0 (3 ꢂ CH), 17.9 (6 ꢂ CH3), 23.3 (CH3),
26.4 (CH3), 58.2 (C-8), 59.2 (C-6), 65.3 (CH2O), 72.1 (C-4), 99.7
(C-2), 121.1 (C-7), 138.2 (C-5). Anal. Calcd for C18H36O4Si: C,
62.74; H, 10.53. Found: C, 62.79; H, 10.47.
(400 MHz, CDCl3): d 1.05–1.07 (m, 21H, 6 ꢂ CH3, 3 ꢂ CH), 1.36 (s,
3H, CH3), 1.43 (s, 3H, CH3), 3.56 (dd, J8,7 = 7.9 Hz, J8,8 = 12.8 Hz,
1H, H-8), 3.63 (dd, J8,7 = 8.6 Hz, J8,8 = 12.8 Hz, 1H, H-8), 3.85 (dd,
J4,H = 5.2 Hz, JH,H = 10.2 Hz, 1H, CH2O), 3.90 (dd, J4,H = 6.1 Hz,
JH,H = 10.2 Hz, 1H, CH2O), 4.38–4.46 (m, 3H, H-4, 2 ꢂ H-6), 5.65–
5.70 (m, 1H, H-7). 13C NMR (100 MHz, CDCl3): d 11.9 (3 ꢂ CH),
18.0 (6 ꢂ CH3), 23.3 (CH3), 26.3 (CH3), 30.8 (C-8), 58.8 (C-6), 65.2
(CH2O), 71.8 (C-4), 99.9 (C-2), 111.6 (SCN), 114.4 (C-7), 143.8 (C-

M. Martinková et al. / Carbohydrate Research 352 (2012) 23–36
31
5). Anal. Calcd for C19H35NO3SSi: C, 59.18; H, 9.15; N, 3.63. Found:
C, 59.11; H, 9.10; N, 3.69.
1.52 (s, 3H, CH3), 3.49 (dd, J4,H = 7.2 Hz, JH,H = 11.3 Hz, 1H, CH2O),
3.70 (dd, J4,H = 3.5 Hz, JH,H = 11.3 Hz, 1H, CH2O), 3.74 (d,
J6,6 = 11.1 Hz, 1H, H-6), 4.01 (d, J6,6 = 11.1 Hz, 1H, H-6), 4.02 (dd,
J4,H = 3.5 Hz, J4,H = 7.2 Hz, 1H, H-4), 5.32 (d, JBcis,A = 10.7 Hz, 1H,
H-Bcis), 5.46 (d, JBtrans,A = 17.1 Hz, 1H, H-Btrans), 6.22 (dd, JBci-
s,A = 10.7 Hz, JBtrans,A = 17.1 Hz, 1H, H-A). 13C NMR (100 MHz,
CDCl3): d –5.3 (CH3), –5.1 (CH3), 18.3 (Cq), 18.8 (CH3), 25.8
(3 ꢂ CH3), 28.4 (CH3), 61.9 (C-5), 62.9 (CH2O), 69.3 (C-6), 76.2 (C-
4), 99.9 (C-2), 116.2 (CH2), 132.3 (CH), 135.1 (NCS). Anal. Calcd
for C16H29NO3SSi: C, 55.94; H, 8.51; N, 4.08. Found: C, 55.70; H,
8.39; N, 4.25.
4.19. (4S,2E)-tert-Butyl{[2,2-dimethyl-5-(2-thiocyanato
ethylidene)-1,3-dioxane-4-yl]methoxy}diphenylsilane (19)
According to the same procedure described for the preparation
of 17, compound 16 (4.82 g, 11.3 mmol) was converted to thiocya-
nate 19 (4.44 g, 84%, colourless oil, 9:1 hexane–EtOAc): ½a D20
ꢃ
+30.3
(c 0.35, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.07 (s, 9H, 3 ꢂ CH3),
1.34 (s, 3H, CH3), 1.38 (s, 3H, CH3), 3.50 (dd, J8,7 = 7.7 Hz,
J8,8 = 12.9 Hz, 1H, H-8), 3.61 (dd, J8,7 = 8.8 Hz, J8,8 = 12.9 Hz, 1H, H-
8), 3.84 (dd, J4,H = 5.3 Hz, JH,H = 10.7 Hz, 1H, CH2O), 3.89 (dd,
J4,H = 5.7 Hz, JH,H = 10.7 Hz, 1H, CH2O), 4.37–4.42 (m, 3H, H-4,
2 ꢂ H-6), 5.54–5.59 (m, 1H, H-7), 7.36–7.46 (m, 6H, Ph), 7.67–
7.70 (m, 4H, Ph). 13C NMR (100 MHz, CDCl3): d 19.2 (Cq), 23.2
(CH3), 26.2 (CH3), 26.8 (3 ꢂ CH3), 30.8 (C-8), 58.8 (C-6), 65.3
(CH2O), 71.6 (C-4), 99.9 (C-2), 111.6 (SCN), 114.4 (C-7), 127.8
(4 ꢂ CHPh), 129.7 (2 ꢂ CHPh), 133.4 (2 ꢂ Ci), 135.7 (4 ꢂ CHPh),
143.6 (C-5). Anal. Calcd for C26H33NO3SSi: C, 66.77; H, 7.11; N,
2.99. Found: C, 66.70; H, 7.19; N, 2.92.
4.21. Triisopropyl{[(4S,5R)-5-isothiocyanato-2,2-dimethyl-5-
vinyl-1,3-dioxan-4-yl]methoxy}silane (21a) and triisopropyl
{[(4S,5S)-5-isothiocyanato-2,2-dimethyl-5-vinyl-1,3-dioxan-4-
yl]methoxy}silane (21b)
4.21.1. Conventional method
According to the same procedure described for the preparation
of isothiocyanates 20a and 20b, thiocyanate 18 (0.10 g, 0.26 mmol)
was converted to compounds 21a and 21b which were isolated
after flash chromatography on silica gel (hexane–EtOAc, 35:1) as
colourless oils (for the combined yields, see Table 1).
4.20. tert-Butyl{[(4S,5R)-5-isothiocyanato-2,2-dimethyl-5-vinyl-
1,3-dioxan-4-yl]methoxy}dimethylsilane (20a) and tert-butyl
{[(4S,5S)-5-isothiocyanato-2,2-dimethyl-5-vinyl-1,3-dioxan-4-
yl]methoxy}dimethylsilane (20b)
4.21.2. Microwave-assisted synthesis
Using the same procedure as described for the preparation of
20a and 20b, compound 18 (50 mg, 0.13 mmol) was transformed
to the corresponding isothiocyanates 21a and 21b (for the com-
bined yields, see Table 1).
4.20.1. Conventional method
Thiocyanate 17 (0.10 g, 0.29 mmol) was dissolved in the corre-
sponding solvent (7.1 mL, see Table 1) and the resulting solution
was heated under a nitrogen atmosphere (for the temperatures
and reaction times, see Table 1). Removal of the solvent and chro-
matography on silica gel (35:1 hexane–EtOAc) gave isothiocya-
nates 20a and 20b (for the combined yields, see Table 1).
Requiring a great amount (more than 2 g) of the pure rear-
ranged products 20a and 20b, they were easily obtained on a mul-
tigram scale by the conventional method in heptane at 70 °C.
Diastereoisomer 21a: Rf = 0.33 (35:1 hexane–EtOAc):
½ ꢃ
a 2D0
ꢁ68.8 (c 0.54, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.05–1.08 (m,
21H, 6 ꢂ CH3, 3 ꢂ CH), 1.49 (s, 3H, CH3), 1.51 (s, 3H, CH3), 3.64
(d, J6,6 = 12.1 Hz, 1H, H-6), 3.72 (dd, J4,H = 6.3 Hz, JH,H = 10.9 Hz,
1H, CH2O), 3.83 (dd, J4,H = 4.0 Hz, JH,H = 10.9 Hz, 1H, CH2O), 3.93
(d, J6,6 = 12.1 Hz, 1H, H-6), 4.01 (dd, J4,H = 4.0 Hz, J4,H = 6.3 Hz, 1H,
H-4), 5.28 (dd, JBcis,Btrans = 1.5 Hz, JBcis,A = 9.8 Hz, 1H, H-Bcis), 5.53
(dd, JBcis,Btrans = 1.5 Hz, JBtrans,A = 16.9 Hz, 1H, H-Btrans), 5.60 (dd, JBci-
s,A = 9.8 Hz, JBtrans,A = 16.9 Hz, 1H, H-A). 13C NMR (100 MHz, CDCl3):
d 11.9 (3 ꢂ CH), 17.9 (6 ꢂ CH3), 18.5 (CH3), 28.6 (CH3), 63.4 (CH2O),
65.2 (C-6), 68.3 (C-5), 76.3 (C-4), 99.3 (C-2), 118.2 (CH2), 132.2
(CH), 140.6 (NCS). Anal. Calcd for C19H35NO3SSi: C, 59.18; H,
9.15; N, 3.63. Found: C, 59.24; H, 9.10; N, 3.58.
4.20.2. Microwave-assisted synthesis
Thiocyanate 17 (50 mg, 0.15 mmol) was weighed in a 10-mL
glass pressure microwave tube equipped with a magnetic stirbar.
The corresponding solvent (3.6 mL, see Table 1) was added and
the tube was closed with a silicone septum, and the reaction mix-
ture was subjected to microwave irradiation (for temperatures and
reaction times, see Table 1). Evaporation of the solvent and chro-
matography on silica gel (35:1 hexane–EtOAc) provided isothiocy-
anates 20a and 20b (for the combined yields, see Table 1).
Diastereoisomer 20a: Rf = 0.20 (35:1 hexane–EtOAc); colourless
Diastereoisomer 21b: Rf = 0.55 (35:1 hexane–EtOAc): ½a D20
ꢃ
+42.6
(c 0.48, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.03–1.08 (m, 21H,
6 ꢂ CH3, 3 ꢂ CH), 1.43 (s, 3H, CH3), 1.52 (s, 3H, CH3), 3.56 (dd,
J4,H = 7.2 Hz, JH,H = 11.0 Hz, 1H, CH2O), 3.74 (d, J6,6 = 11.0 Hz, 1H,
H-6), 3.75 (dd, J4,H = 3.4 Hz, JH,H = 11.0 Hz, 1H, CH2O), 4.02 (d,
J6,6 = 11.0 Hz, 1H, H-6), 4.04–4.06 (m, 1H, H-4), 5.32 (d, JBci-
s,A = 10.7 Hz, 1H, H-Bcis), 5.47 (d, JBtrans,A = 17.2 Hz, 1H, H-Btrans),
6.22 (dd, JBcis,A = 10.7 Hz, JBtrans,A = 17.2 Hz, 1H, H-A). 13C NMR
(100 MHz, CDCl3): d 12.0 (3 ꢂ CH), 17.9 (6 ꢂ CH3), 18.9 (CH3),
28.4 (CH3), 61.9 (C-5), 63.2 (CH2O), 69.4 (C-6), 76.5 (C-4), 99.9
(C-2), 116.1 (CH2), 132.4 (CH), 135.3 (NCS). Anal. Calcd for
crystals: mp 73–74 °C; ½a D20
ꢁ54.0 (c 0.30, CHCl3). IR (KBr) mmax
ꢃ
(cmꢁ1) 2929, 2856, 2028, 1127, 830. 1H NMR (400 MHz, CDCl3): d
0.06 (s, 6H, 2 ꢂ CH3), 0.88 (s, 9H, 3 ꢂ CH3), 1.49 (s, 3H, CH3), 1.51
(s, 3H, CH3), 3.63 (d, J6,6 = 12.1 Hz, 1H, H-6), 3.65 (dd,
J4,H = 6.5 Hz, JH,H = 11.2 Hz, 1H, CH2O), 3.77 (dd, J4,H = 4.0 Hz,
JH,H = 11.2 Hz, 1H, CH2O), 3.92 (d, J6,6 = 12.1 Hz, 1H, H-6), 3.99
(dd, J4,H = 4.0 Hz, J4,H = 6.5 Hz, 1H, H-4), 5.28 (dd, JBcis,Btrans = 2.4 Hz,
JBcis,A = 8.8 Hz, 1H, H-Bcis), 5.53 (dd, JBcis,Btrans = 2.4 Hz, JBtran-
s,A = 16.9 Hz, 1H, H-Btrans), 5.58 (dd, JBcis,A = 8.8 Hz, JBtrans,A = 16.9 Hz,
1H, H-A). 13C NMR (100 MHz, CDCl3): d –5.3 (CH3), –5.1 (CH3), 18.3
(Cq), 18.5 (CH3), 25.8 (3 ꢂ CH3), 28.7 (CH3), 63.1 (CH2O), 65.2 (C-5),
68.2 (C-6), 76.0 (C-4), 99.3 (C-2), 118.3 (CH2), 132.1 (CH), 140.7
(NCS). Anal. Calcd for C16H29NO3SSi: C, 55.94; H, 8.51; N, 4.08.
Found: C, 55.90; H, 8.55; N, 4.11.
C19H35NO3SSi: C, 59.18; H, 9.15; N, 3.63. Found: C, 59.12; H,
9.21; N, 3.69.
4.22. tert-Butyl{[(4S,5R)-5-isothiocyanato-2,2-dimethyl-5-vinyl-
1,3-dioxan-4-yl]methoxy}diphenylsilane (22a) and tert-butyl
{[(4S,5S)-5-isothiocyanato-2,2-dimethyl-5-vinyl-1,3-dioxan-4-
yl]methoxy}diphenylsilane (22b)
Diastereoisomer 20b: Rf = 0.38 (35:1 hexane–EtOAc); colourless
oil: ½a 2D0
ꢃ
+36.6 (c 0.30, CHCl3). IR (neat) mmax (cmꢁ1) 2954, 2928,
4.22.1. Conventional method
According to the same procedure described for the preparation
of compounds 20a and 20b, thiocyanate 19 (0.10 g, 0.21 mmol)
2857, 2082, 1121, 837. 1H NMR (400 MHz, CDCl3): d 0.06 (s, 3H,
CH3), 0.06 (s, 3H, CH3), 0.89 (s, 9H, 3 ꢂ CH3), 1.44 (s, 3H, CH3),

32
M. Martinková et al. / Carbohydrate Research 352 (2012) 23–36
was converted to isothiocyanates 22a and 22b which were isolated
after flash chromatography on silica gel (35:1 hexane–EtOAc) as
colourless oils (Table 1).
Diastereoisomer 23a: Rf = 0.11 (35:1 hexane–EtOAc): mp 40–
42 °C; ½a 2D0
ꢃ
ꢁ3.3 (c 0.30, CHCl3). 1H NMR (400 MHz, CDCl3): d
0.11 (s, 3H, CH3), 0.12 (s, 3H, CH3), 0.91 (s, 9H, 3 ꢂ CH3), 1.45 (s,
3H, CH3), 1.48 (s, 3H, CH3), 3.72 (m, 1H, H-4), 3.81 (d,
J6,6 = 12.2 Hz, 1H, H-6), 3.84 (dd, J4,H = 3.5 Hz, JH,H = 11.7 Hz, 1H,
CH2O), 3.96 (dd, J4,H = 2.5 Hz, JH,H = 11.7 Hz, 1H, CH2O), 4.54 (d,
J6,6 = 12.2 Hz, 1H, H-6), 5.30 (d, JBtrans,A = 17.6 Hz, 1H, H-Btrans),
5.36 (d, JBcis,A = 11.0 Hz, 1H, H-Bcis), 5.78 (dd, JBcis,A = 11.0 Hz, JBtran-
s,A = 17.6 Hz, 1H, H-A), 8.42 (br s, 1H, NH). 13C NMR (100 MHz,
CDCl3): d ꢁ5.1 (CH3), ꢁ5.0 (CH3), 18.8 (CH3), 18.9 (Cq), 25.9
(3 ꢂ CH3), 28.9 (CH3), 59.5 (C-5), 62.7 (CH2O), 63.7 (C-6), 73.8 (C-
4), 93.3 (Cq), 99.1 (C-2), 117.3 (CH2), 133.6 (CH), 161.1 (C@O). Anal.
Calcd for C17H30Cl3NO4Si: C, 45.69; H, 6.77; N, 3.13. Found: C,
45.75; H, 6.83; N, 3.19.
4.22.2. Microwave-assisted synthesis
Using the same procedure as described for the preparation of
20a and 20b, compound 19 (50 mg, 0.11 mmol) was transformed
to the corresponding isothiocyanates 22a and 22b (for the com-
bined yields, see Table 1).
Diastereoisomer 22a: Rf = 0.18 (35:1 hexane–EtOAc):
½ ꢃ
a 2D0
ꢁ60.3 (c 0.30, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.05 (s, 9H,
3 ꢂ CH3), 1.44 (s, 3H, CH3), 1.50 (s, 3H, CH3), 3.58 (d,
J6,6 = 12.1 Hz, 1H, H-6), 3.74 (dd, J4,H = 6.6 Hz, JH,H = 11.3 Hz, 1H,
CH2O), 3.80 (dd, J4,H = 3.9 Hz, JH,H = 11.3 Hz, 1H, CH2O), 3.85 (d,
J6,6 = 12.1 Hz, 1H, H-6), 3.95 (dd, J4,H = 3.9 Hz, J4,H = 6.6 Hz, 1H, H-
4), 5.16 (dd, JBcis,Btrans = 1.0 Hz, JBcis,A = 10.3 Hz, 1H, H-Bcis), 5.31
Diastereoisomer 23b: Rf = 0.40 (35:1 hexane–EtOAc): mp 48.5–
50 °C; ½a 2D0
ꢃ
ꢁ3.0 (c 0.30, CHCl3). 1H NMR (400 MHz, CDCl3): d 0.11
(s, 3H, CH3), 0.13 (s, 3H, CH3), 0.91 (s, 9H, 3 ꢂ CH3), 1.43 (s, 3H,
CH3), 1.54 (s, 3H, CH3), 3.61 (dd, J4,H = 3.7 Hz, JH,H = 9.6 Hz, 1H,
CH2O), 3.77 (t, J4,H = 9.6 Hz, JH,H = 9.6 Hz, 1H, CH2O), 4.03 (dd,
J4,H = 3.7 Hz, J4,H = 9.6 Hz, 1H, H-4), 4.04 (d, J6,6 = 11.7 Hz, 1H, H-
6), 4.75 (d, J6,6 = 11.7 Hz, 1H, H-6), 5.37 (d, JBtrans,A = 17.6 Hz, 1H,
H-Btrans), 5.43 (d, JBcis,A = 10.9 Hz, 1H, H-Bcis), 6.26 (dd, JBci-
s,A = 10.9 Hz, JBtrans,A = 17.6 Hz, 1H, H-A), 8.12 (br s, 1H, NH). 13C
NMR (100 MHz, CDCl3): d ꢁ5.2 (CH3), ꢁ5.0 (CH3), 18.7 (CH3),
18.9 (Cq), 26.1 (3 ꢂ CH3), 28.9 (CH3), 58.5 (C-5), 64.8 (CH2O), 66.3
(C-6), 72.3 (C-4), 92.8 (Cq), 99.1 (C-2), 116.0 (CH2), 132.3 (CH),
161.1 (C@O). Anal. Calcd for C17H30Cl3NO4Si: C, 45.69; H, 6.77; N,
3.13. Found: C, 45.63; H, 6.71; N, 3.18.
(dd, JBcis,A = 10.3 Hz, JBtrans,A = 16.8 Hz, 1H, H-A), 5.43 (dd, JBcis,B
-
trans = 1.0 Hz, JBtrans,A = 16.8 Hz, 1H, H-Btrans), 7.35–7.45 (m, 6H,
Ph), 7.65–7.68 (m, 4H, Ph). 13C NMR (100 MHz, CDCl3): d 18.4
(CH3), 19.2 (Cq), 26.8 (3 ꢂ CH3), 28.6 (CH3), 63.6 (C-5), 65.0
(CH2O), 68.3 (C-6), 75.9 (C-4), 99.3 (C-2), 118.3 (CH2), 127.8
(4 ꢂ CHPh), 129.7 (2 ꢂ CHPh), 131.9 (CH), 133.1 (Ci), 133.5 (Ci),
135.7 (4 ꢂ CHPh), 140.8 (NCS). Anal. Calcd for C26H33NO3SSi: C,
66.77; H, 7.11; N, 2.99. Found: C, 66.73; H, 7.19; N, 3.03.
Diastereoisomer 22b: Rf = 0.30 (35:1 hexane–EtOAc): ½a D20
ꢃ
+42.5
(c 0.86, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.05 (s, 9H, 3 ꢂ CH3),
1.42 (s, 3H, CH3), 1.50 (s, 3H, CH3), 3.56 (dd, J4,H = 7.2 Hz,
JH,H = 11.3 Hz, 1H, CH2O), 3.72 (d, J6,6 = 11.1 Hz, 1H, H-6), 3.75
(dd, J4,H = 3.4 Hz, JH,H = 11.3 Hz, 1H, CH2O), 3.99 (d, J6,6 = 11.1 Hz,
1H, H-6), 4.07 (dd, J4,H = 3.4 Hz, J4,H = 7.2 Hz, 1H, H-4), 5.21 (d, JBci-
s,A = 10.7 Hz, 1H, H-Bcis), 5.37 (d, JBtrans,A = 17.1 Hz, 1H, H-Btrans),
6.13 (dd, JBcis,A = 10.7 Hz, JBtrans,A = 17.1 Hz, 1H, H-A), 7.35–7.45
(m, 6H, Ph), 7.66–7.69 (m, 4H, Ph). 13C NMR (100 MHz, CDCl3): d
18.9 (CH3), 19.2 (Cq), 26.7 (3 ꢂ CH3), 28.3 (CH3), 62.0 (C-5), 63.4
(CH2O), 69.5 (C-6), 76.1 (C-4), 99.9 (C-2), 116.1 (CH2), 127.6
(2 ꢂ CHPh), 127.7 (2 ꢂ CHPh), 129.6 (CHPh), 129.7 (CHPh), 132.3
(CH), 133.3 (Ci), 133.4 (Ci), 135.6 (NCS), 135.6 (2 ꢂ CHPh), 135.7
(2 ꢂ CHPh). Anal. Calcd for C26H33NO3SSi: C, 66.77; H, 7.11; N,
2.99. Found: C, 66.82; H, 7.07; N, 2.94.
4.24. 2,2,2-Trichloro-N-{(4S,5R)-4-[(triisopropylsilyloxy)
methyl]-2,2-dimethyl-5-vinyl-1,3-dioxan-5-yl}acetamide (24a)
and 2,2,2-trichloro-N-{(4S,5S)-4-[(triisopropylsilyloxy)methyl]-
2,2-dimethyl-5-vinyl-1,3-dioxan-5-yl}acetamide (24b)
Using the same procedure as described for the preparation of
23a and 23b, alcohol 15 (0.10 g, 0.29 mmol) was converted to imi-
date 15i (0.14 g, 0.29 mmol) that after microwave irradiation pro-
vided the corresponding rearranged products 24a and 24b (for
temperatures, reaction times and combined yields, see Table 2).
Diastereoisomer 24a: Rf = 0.13 (35:1 hexane–EtOAc); white
crystals: mp 70–72 °C;
½
a 2D0
ꢃ
ꢁ5.0 (c 0.30, CHCl3). 1H NMR
4.23. N-{(4S,5R)-4-[(tert-Butyldimethylsilyloxy)methyl]-2,2-
dimethyl-5-vinyl-1,3-dioxan-5-yl}-2,2,2-trichloroacetamide
(23a) and N-{(4S,5S)-4-[(tert-butyldimethylsilyloxy)methyl]-
2,2-dimethyl-5-vinyl-1,3-dioxan-5-yl}-2,2,2-trichloroacetamide
(23b)
(400 MHz, CDCl3): d 1.04–1.14 (m, 21H, 6 ꢂ CH3, 3 ꢂ CH), 1.44 (s,
3H, CH3), 1.48 (s, 3H, CH3), 3.76 (t, J4,H = 3.0 Hz, J4,H = 3.0 Hz, 1H,
H-4), 3.82 (d, J6,6 = 12.1 Hz, 1H, H-6), 3.90 (dd, J4,H = 3.0 Hz,
JH,H = 11.3 Hz, 1H, CH2O), 3.98 (dd, J4,H = 3.0 Hz, JH,H = 11.3 Hz, 1H,
CH2O), 4.50 (d, J6,6 = 12.1 Hz, 1H, H-6), 5.30 (d, JBtrans,A = 17.6 Hz,
1H, H-Btrans), 5.36 (d, JBcis,A = 11.1 Hz, 1H, H-Bcis), 5.80 (dd, JBci-
s,A = 11.1 Hz, JBtrans,A = 17.6 Hz, 1H, H-A), 8.22 (br s, 1H, NH). 13C
NMR (100 MHz, CDCl3): d 12.0 (3 ꢂ CH), 17.8 (3 ꢂ CH3), 17.9
(3 ꢂ CH3), 18.8 (CH3), 28.9 (CH3), 59.3 (C-5), 62.6 (CH2O), 63.9 (C-
6), 74.5 (C-4), 93.2 (Cq), 99.2 (C-2), 117.1 (CH2), 133.6 (CH), 161.1
(C@O). Anal. Calcd for C20H36Cl3NO4Si: C, 49.13; H, 7.42; N, 2.86.
Found: C, 49.07; H, 7.53; N, 2.80.
To a suspension of sodium hydride (26.5 mg, 1.10 mmol, 60%
dispersion in mineral oil) in THF (0.8 mL) pre-cooled to 0 °C, was
added alcohol 14 (0.15 g, 0.50 mmol) in THF (0.8 mL). After stirring
at 0 °C for 30 min, trichloroacetonitrile (61 lL, 0.61 mmol) was
added dropwise, and the resulting mixture was stirred for further
30 min at the same temperature. After removal of the insoluble
materials by filtration through a pad of Celite, the resulting solu-
tion was concentrated under vacuum and the crude product was
used immediately in the next reaction without further purification
to avoid problems connected with its possible instability. The ob-
tained trichloroacetimidate 14i (50 mg, 0.11 mmol) was weighted
in to a 10-mL glass pressure microwave tube equipped with a mag-
netic stirbar. o-Xylene (1.6 mL) and K2CO3 (17.6 mg, 0.13 mmol)
were added, the tube was closed with a silicone septum and the
reaction mixture was subjected to microwave irradiation (for tem-
peratures and reaction times, see Table 2). Evaporation of the sol-
vent and chromatography on silica gel (13:1 hexane–EtOAc)
afforded trichloroacetamides 23a and 23b as crystalline com-
pounds (for the combined yields, see Table 2).
Diastereoisomer 24b: Rf = 0.47 (35:1 hexane–EtOAc); colourless
oil: ½a 2D0
ꢃ
ꢁ4.1 (c 0.68, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.07–1.21
(m, 21H, 6 ꢂ CH3, 3 ꢂ CH), 1.43 (s, 3H, CH3), 1.54 (s, 3H, CH3), 3.60
(dd, J4,H = 3.4 Hz, JH,H = 10.0 Hz, 1H, CH2O), 3.85 (dd, J4,H = 9.2 Hz,
JH,H = 10.0 Hz, 1H, CH2O), 4.02 (dd, J4,H = 3.4 Hz, J4,H = 9.2 Hz, 1H, H-
4), 4.04 (d, J6,6 = 11.7 Hz, 1H, H-6), 4.75 (d, J6,6 = 11.7 Hz, 1H, H-6),
5.38 (dd, JBcis,Btrans = 0.9 Hz, JBtrans,A = 17.6 Hz, 1H, H-Btrans), 5.44 (dd,
JBcis,Btrans = 0.9 Hz, JBcis,A = 11.0 Hz, 1H, H-Bcis), 6.26 (dd, JBci-
s,A = 11.0 Hz, JBtrans,A = 17.6 Hz, 1H, H-A), 7.98 (br s, 1H, NH). 13C
NMR (100 MHz, CDCl3): d 11.9 (3 ꢂ CH), 17.9 (6 ꢂ CH3), 18.7 (CH3),
28.8 (CH3), 58.7 (C-5), 64.5 (CH2O), 66.3 (C-6), 72.9 (C-4), 92.8 (Cq),
99.2 (C-2), 116.1 (CH2), 132.4 (CH), 161.2 (C@O). Anal. Calcd for

M. Martinková et al. / Carbohydrate Research 352 (2012) 23–36
33
C20H36Cl3NO4Si: C, 49.13; H, 7.42; N, 2.86. Found: C, 49.18; H, 7.48;
N, 2.91.
3H, CH3), 1.47 (s, 3H, CH3), 3.63 (s, 3H, OCH3), 3.69 (t,
J4,H = 3.5 Hz, J4,H = 3.5 Hz, 1H, H-4), 3.77–3.80 (m, 3H, H-6, CH2O),
4.33 (d, J6,6 = 11.7 Hz, 1H, H-6), 5.22 (d, JBtrans,A = 17.8 Hz, 1H, H-
4.25. N-{(4S,5R)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2,2-
dimethyl-5-vinyl-1,3-dioxan-5-yl}-2,2,2-trichloroacetamide
(25a) and N-{(4S,5S)-4-[(tert-butyldiphenylsilyloxy)methyl]-2,2-
dimethyl-5-vinyl-1,3-dioxan-5-yl}-2,2,2-trichloroacetamide
(25b)
Btrans), 5.28 (d, JBcis,A = 11.4 Hz, 1H, H-Bcis), 5.86 (dd, JBcis,A = 11.4 Hz,
JBtrans,A = 17.8 Hz, 1H, H-A), 6.27 (br s, 1H, NH). 13C NMR (100 MHz,
CDCl3): d ꢁ5.4 (CH3), ꢁ5.3 (CH3), 18.2 (Cq), 18.7 (CH3), 25.7
(3 ꢂ CH3), 29.1 (CH3), 51.6 (OCH3), 56.8 (C-5), 62.4 (CH2O), 64.7
(C-6), 75.3 (C-4), 98.9 (C-2), 118.1 (CH2), 136.5 (CH), 156.0
(C@O). Anal. Calcd for C17H33NO5Si: C, 56.79; H, 9.25; N, 3.90.
Found: C, 56.73; H, 9.20; N, 3.97.
According to the same procedure described for the preparation
of 23a and 23b, compound 16i, prepared from the corresponding
allylic alcohol 16 (0.15 g, 0.35 mmol), was transformed to trichlo-
roacetamides 25a and 25b (for the combined yields, see Table 2).
Diastereoisomer 25a: Rf = 0.13 (21:1 hexane–EtOAc); colourless
During this reaction we recovered the starting isothiocyanate
20a in 21% yield.
4.27. Methyl (4S,5R)-4-[(tert-butyldimethylsilyloxy)methyl]-5-
(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (27)
oil: ½a 2D0
ꢃ
ꢁ9.7 (c 0.80, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.08 (s,
9H, 3 ꢂ CH3), 1.47 (s, 3H, CH3), 1.48 (s, 3H, CH3), 3.80 (d,
J6,6 = 12.0 Hz, 1H, H-6), 3.83 (dd, J4,H = 5.0 Hz, JH,H = 11.0 Hz, 1H,
CH2O), 3.88 (dd, J4,H = 2.9 Hz, J4,H = 5.0 Hz, 1H, H-4), 3.94 (dd,
J4,H = 2.9 Hz, JH,H = 11.0 Hz, 1H, CH2O), 4.30 (d, J6,6 = 12.0 Hz, 1H,
H-6), 5.16 (d, JBtrans,A = 17.8 Hz, 1H, H-Btrans), 5.27 (d, JBci-
s,A = 11.2 Hz, 1H, H-Bcis), 5.78 (dd, JBcis,A = 11.2 Hz, JBtrans,A = 17.8 Hz,
1H, H-A), 7.34–7.45 (m, 6H, Ph), 7.65–7.72 (m, 5H, Ph, NH). 13C
NMR (100 MHz, CDCl3): d 18.5 (CH3), 19.4 (Cq), 27.0 (3 ꢂ CH3),
29.2 (CH3), 58.3 (C-5), 63.0 (CH2O), 64.3 (C-6), 75.8 (C-4), 92.9
(Cq), 99.5 (C-2), 116.9 (CH2), 127.6 (2 ꢂ CHPh), 127.7 (2 ꢂ CHPh),
129.8 (2 ꢂ CHPh), 133.1 (2 ꢂ Ci), 133.3 (CH), 135.7 (2 ꢂ CHPh),
135.8 (2 ꢂ CHPh), 161.2 (C@O). Anal. Calcd for C27H34Cl3NO4Si: C,
56.79; H, 6.00; N, 2.45. Found: C, 56.85; H, 6.08; N, 2.40.
Ozone was introduced to a solution of 26 (0.76 g, 2.11 mmol) in
MeOH (57 mL) at ꢁ78 °C for 10 min. After the complete consump-
tion of the starting material (judged by TLC), nitrogen was passed
through the cold solution in order to remove excess of ozone. Then,
NaBH4 (0.36 g, 9.52 mmol) was added portionwise, and the result-
ing mixture was stirred at ꢁ78 °C for 30 min. The mixture was al-
lowed to warm to room temperature and stirring was continual for
another 30 min. The solvent was subsequently evaporated, and the
residue was partitioned between a saturated NH4Cl solution
(31 mL) and CH2Cl2 (42 mL). The aqueous layer was extracted with
further portions of CH2Cl2 (2 ꢂ 42 mL), the organic phases were
combined, dried over Na2SO4, stripped of solvent, and the crude
product was subjected to flash chromatography on silica gel (2:1
hexane–EtOAc) to afford 0.57 g (74%) of compound 27 as white sol-
Diastereoisomer 25b: Rf = 0.33 (21:1 hexane–EtOAc); white
crystals: mp 71–73 °C;
½
a 2D0
ꢃ
ꢁ0.9 (c 0.70, CHCl3). 1H NMR
(400 MHz, CDCl3): d 1.11 (s, 9H, 3 ꢂ CH3), 1.38 (s, 3H, CH3), 1.51
(s, 3H, CH3), 3.67 (dd, J4,H = 3.9 Hz, JH,H = 10.4 Hz, 1H, CH2O), 3.88
(dd, J4,H = 8.3 Hz, JH,H = 10.4 Hz, 1H, CH2O), 4.13 (d, J6,6 = 11.6 Hz,
1H, H-6), 4.20 (dd, J4,H = 3.9 Hz, J4,H = 8.3 Hz, 1H, H-4), 4.60 (d,
J6,6 = 11.6 Hz, 1H, H-6), 5.35 (d, JBtrans,A = 17.6 Hz, 1H, H-Btrans),
5.41 (d, JBcis,A = 11.0 Hz, 1H, H-Bcis), 6.25 (dd, JBcis,A = 11.0 Hz, JBtran-
s,A = 17.6 Hz, 1H, H-A), 7.36–7.44 (m, 6H, Ph), 7.61–7.68 (m, 5H,
Ph, NH). 13C NMR (100 MHz, CDCl3): d 18.9 (Cq), 19.5 (CH3), 27.3
(3 ꢂ CH3), 28.6 (CH3), 58.5 (C-5), 65.3 (CH2O), 66.1 (C-6), 72.8 (C-
4), 92.5 (Cq), 99.3 (C-2), 115.9 (CH2), 127.8 (4 ꢂ CHPh), 130.0
(2 ꢂ CHPh), 132.7 (Ci), 132.8 (Ci) 132.8 (CH), 135.5 (4 ꢂ CHPh),
161.2 (C@O). Anal. Calcd for C27H34Cl3NO4Si: C, 56.79; H, 6.00; N,
2.45. Found: C, 56.72; H, 6.06; N, 2.51.
ids: mp 66.5–67.5 °C;
½
a 2D0
ꢃ
ꢁ47.7 (c 0.60, CHCl3). 1H NMR
(400 MHz, CDCl3): d 0.06 (s, 3H, CH3), 0.07 (s, 3H, CH3), 0.89 (s,
9H, 3 ꢂ CH3), 1.42 (s, 3H, CH3), 1.46 (s, 3H, CH3), 3.55 (dd,
J4,H = 4.6 Hz, JH,H = 11.0 Hz, 1H, CH2O), 3.63–3.66 (m, 1H, CH2OH),
3.68 (s, 3H, OCH3), 3.74 (dd, J4,H = 5.6 Hz, JH,H = 11.0 Hz, 1H,
CH2O), 3.82 (d, J6,6 = 12.4 Hz, 1H, H-6), 3.83–3.85 (m, 1H, H-4),
4.04 (dd, JH,OH = 3.7 Hz, JH,H = 12.7 Hz, 1H, CH2O), 4.08 (d,
J6,6 = 12.4 Hz, 1H, H-6), 4.27–4.29 (m, 1H, OH), 5.74 (br s, 1H,
NH). 13C NMR (100 MHz, CDCl3): d ꢁ5.5 (CH3), ꢁ5.4 (CH3), 18.2
(Cq), 18.6 (CH3), 25.8 (3 ꢂ CH3), 29.1 (CH3), 52.3 (OCH3), 55.9 (C-
5), 62.4 (CH2O), 64.2 (C-6), 64.6 (CH2O), 74.7 (C-4), 99.0 (C-2),
157.6 (C@O). Anal. Calcd for C16H33NO6Si: C, 52.86; H, 9.15; N,
3.85. Found: C, 52.80; H, 9.20; N, 3.91.
4.26. Methyl (4S,5R)-4-[(tert-butyldimethylsilyloxy)methyl]-
4.28. (5S,6S)-6-[(tert-Butyldimethylsilyloxy)methyl]-8,8-
2,2-dimethyl-5-vinyl-1,3-dioxan-5-ylcarbamate (26)
dimethyl-3,7,9-trioxa-1-azaspiro[4.5]decan-2-one (28)
Sodium methoxide (0.24 g, 4.44 mmol) was added to a solution
of isothiocyanate 20a (1.0 g, 2.91 mmol) in dry MeOH (29 mL) pre-
cooled to 0 °C. After stirring for an additional 10 min at 0 °C and
then at room temperature for 77 h, the solvent was evaporated
in vacuo, and the residue was partitioned between CH2Cl2
(40 mL), water (27 mL) and a saturated NaCl solution (8 mL). The
aqueous phase was extracted with further portions of CH2Cl2
(2 ꢂ 30 mL). The organic layers were combined, dried over Na2SO4,
and stripped of solvent. The residue was purified through a short
column of silica gel (11:1 hexane–EtOAc) to give 0.80 g (73%) of
thiocarbamate as a colourless oil. The obtained product (0.80 g,
2.13 mmol) was dissolved in CH3CN (21 mL) and subsequently
treated with mesitylnitrile oxide (0.51 g, 3.19 mmol) at room tem-
perature. After 1.5 h the reaction mixture did not contain any start-
ing material (judged by TLC). Removal of the solvent under reduced
pressure and chromatography of the residue on silica gel (11:1
hexane–EtOAc) yielded 0.76 g (99%) of compound 26 as a colour-
NaH (126 mg, 5.27 mmol, 60% dispersion in mineral oil) was
added to a solution of 27 (0.57 g, 1.57 mmol) in dry tetrahydrofu-
ran (7.9 mL) pre-cooled to 0 °C, and the resulting mixture was stir-
red at the same temperature for 30 min. The excess hydride was
decomposed by the addition of MeOH (5 mL), the solvent was re-
moved under reduced pressure, and the residue was partitioned
between a saturated NaCl solution (12 mL) and CH2Cl2 (8.6 mL).
The aqueous phase was extracted with further portions of CH2Cl2
(2 ꢂ 15 mL), the organic layers were combined, dried over Na2SO4,
the solvent was taken down, and the residue was chromato-
graphed through a short column of silica gel (2:1 hexane–EtOAc)
to give 0.50 g (96%) of crystalline derivative 28: mp 98–99 °C;
½
a 2D0
ꢃ
ꢁ15.3 (c 0.30, CHCl3). IR (KBr) mmax (cmꢁ1) 3311, 2951, 2856,
1754, 1085, 1038, 832. 1H NMR (400 MHz, CDCl3): d 0.08 (s, 6H,
2 ꢂ CH3), 0.89 (s, 9H, 3 ꢂ CH3), 1.40 (s, 3H, CH3), 1.47 (s, 3H,
CH3), 3.62 (dd, J6,H = 4.1 Hz, JH,H = 10.1 Hz, 1H, CH2O), 3.71 (d,
J10,10 = 11.9 Hz, 1H, H-10), 3.79 (d, J4,4 = 8.9 Hz, 1H, H-4), 3.84 (dd,
J6,H = 7.1 Hz, JH,H = 10.1 Hz, 1H, CH2O), 3.85 (d, J10,10 = 11.9 Hz, 1H,
H-10), 3.89 (dd, J6,H = 4.1 Hz, J6,H = 7.1 Hz, 1H, H-6), 4.56 (d,
less oil: ½a 2D0
ꢃ
ꢁ5.5 (c 0.30, CHCl3). 1H NMR (400 MHz, CDCl3): d
0.06 (s, 3H, CH3), 0.08 (s, 3H, CH3), 0.90 (s, 9H, 3 ꢂ CH3), 1.45 (s,

34
M. Martinková et al. / Carbohydrate Research 352 (2012) 23–36
J4,4 = 8.9 Hz, 1H, H-4), 5.91 (br s, 1H, NH). 13C NMR (100 MHz,
CDCl3): d ꢁ5.7 (2 ꢂ CH3), 18.1 (Cq), 18.6 (CH3), 25.8 (3 ꢂ CH3),
28.7 (CH3), 56.3 (C-5), 62.5 (CH2O), 67.6 (C-10), 68.0 (C-4), 73.5
(C-6), 99.3 (C-8), 158.2 (C@O). Anal. Calcd for C15H29NO5Si: C,
54.35; H, 8.82; N, 4.23. Found: C, 54.30; H, 8.88; N, 4.29.
trans = 1.3 Hz, JBcis,A = 10.9 Hz, 1H, H-Bcis), 6.26 (dd, JBcis,A= 10.9 Hz,
JBtrans,A = 17.6 Hz, 1H, H-A), 6.33 (br s, 1H, NH). 13C NMR
(100 MHz, CDCl3): d ꢁ5.8 (CH3), ꢁ5.7 (CH3), 18.0 (Cq), 18.7 (CH3),
25.7 (3 ꢂ CH3), 29.1 (CH3), 51.8 (OCH3), 58.5 (C-5), 64.0 (CH2O),
67.1 (C-6), 72.4 (C-4), 98.9 (C-2), 115.3 (CH2), 134.6 (CH), 155.0
(C@O). Anal. Calcd for C17H33NO5Si: C, 56.79; H, 9.25; N, 3.90.
Found: C, 56.84; H, 9.30; N, 3.84.
4.29. (5S,6S)-6-(Hydroxymethyl)-8,8-dimethyl-3,7,9-trioxa-1-
azaspiro[4.5]decan-2-one (29)
4.32. Methyl (4S,5S)-4-[(tert-butyldimethylsilyloxy)methyl]-5-
A 1 M solution of TBAF in THF (1.51 mL, 1.51 mmol) was added
dropwise to a solution of 28 (0.5 g, 1.51 mmol) in dry tetrahydro-
furan (14.9 mL) that was pre-cooled to 0 °C. The resulting mixture
was stirred for a further 10 min at 0 °C and then at room temper-
ature for 1.5 h. The solvent was evaporated under reduced pressure
and the residue was chromatographed through a short column of
silica gel (EtOAc) to give 0.31 g (95%) of crystalline compound
(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (32)
Ozone was introduced to a solution of 31 (0.79 g, 2.20 mmol) in
EtOH (22 mL) at ꢁ78 °C for 30 min. After the complete consumption
of the starting material (judged by TLC), nitrogen was passed
through the cold solution in order to remove excess of ozone. Then,
NaBH4 (0.37 g, 10.0 mmol) was added portionwise and the resulting
mixture was stirred at ꢁ78 °C for 30 min. The reaction was
quenched by the neutralization with a 1 M HCl solution (2.5 mL)
at 0 °C, the solvent was taken down, and the residue was partitioned
between CH2Cl2 (30 mL) and H2O (33 mL). The aqueous phase was
washed with further portions of CH2Cl2 (2 ꢂ 30 mL). The combined
organic layers were dried over Na2SO4, stripped of solvent, and the
residue was subjected to flash chromatography on silica gel (3:1
hexane–EtOAc) to afford 0.64 g (80%) of compound 32 as a colour-
29: mp 128–130 °C;
½
a 2D0 +15.3 (c 0.32, CHCl3). 1H NMR
ꢃ
(400 MHz, CD3OD): d 1.45 (s, 3H, CH3), 1.52 (s, 3H, CH3), 3.61
(dd, J6,H = 6.8 Hz, JH,H = 11.5 Hz, 1H, CH2O), 3.70 (d, J10,10 = 12.0 Hz,
1H, H-10), 3.77 (dd, J6,H = 4.2 Hz, JH,H = 11.5 Hz, 1H, CH2O), 3.93
(d, J4,4 = 9.5 Hz, 1H, H-4), 3.98–4.01 (m, 2H, H-10, H-6), 4.37 (d,
J4,4 = 9.5 Hz, 1H, H-4). 13C NMR (100 MHz, CD3OD): d 19.3 (CH3),
28.9 (CH3), 57.7 (C-5), 62.1 (CH2), 68.8 (C-10), 69.5 (C-4), 75.8 (C-
6), 100.6 (C-8), 161.4 (C@O). Anal. Calcd for C9H15NO5: C, 49.76;
H, 6.96; N, 6.45. Found: C, 49.70; H, 6.93; N, 6.40.
less oil: ½a 2D0
ꢃ
+12.5 (c 0.32, CHCl3). 1H NMR (400 MHz, CDCl3): d
0.10 (s, 3H, CH3), 0.13 (s, 3H, CH3), 0.91 (s, 9H, 3 ꢂ CH3), 1.40 (s,
3H, CH3), 1.54 (s, 3H, CH3), 3.44 (m, 1H, CH2O), 3.62 (s, 3H, OCH3),
3.66 (d, J6,6 = 11.6 Hz, 1H, H-6), 3.76 (dd, J4,H = 4.7 Hz, JH,H = 12.0 Hz,
1H, CH2O), 3.86 (dd, J4,H = 2.2 Hz, JH,H = 12.0 Hz, 1H, CH2O), 4.26 (m,
1H, OH), 4.33 (dd, JH,OH = 3.7 Hz, JH,H = 11.8 Hz, 1H, CH2O), 4.40–4.45
4.30. N-{(4S,5R)-4-[(tert-Butyldimethylsilyloxy)methyl]-5-
(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl}-2,2,2-
trichloroacetamide (30)
Using the same procedure as described for the preparation of 27,
ozonolysis of compound 23a (0.13 g, 0.29 mmol) followed by NaBH4
(49.5 mg, 1.31 mmol) treatment afforded after flash chromatography
on silica gel (5:1 then 1:1 hexane–EtOAc) 40 mg (42%) of 28 and
55 mg (42%) of 30 which after a rapid 1H NMR analysis was immedi-
ately converted into 28 according to the procedure listed below.
(m, 1H, H-4), 4.60 (d, J6,6 = 11.6 Hz, 1H, H-6), 5.71 (br s, 1H, NH). 13
C
NMR (100 MHz, CDCl3): d ꢁ5.6 (CH3), ꢁ5.3 (CH3), 18.2 (Cq), 19.2
(CH3), 25.6 (3 ꢂ CH3), 28.7 (CH3), 51.9 (OCH3), 54.0 (C-5), 61.7
(CH2O), 62.7 (CH2O), 64.7 (C-6), 70.0 (C-4), 99.3 (C-2), 156.1
(C@O). Anal. Calcd for C16H33NO6Si: C, 52.86; H, 9.15; N, 3.85.
Found: C, 52.80; H, 9.10; N, 3.80.
Modification of alcohol 30 into 28: DBU (1.79 lL, 12.0 lmol) was
added to a solution of 30 (54 mg, 0.12 mmol) in dry CH2Cl2
(1.4 mL) pre-cooled to 0 °C. The resulting mixture was stirred for
a further 10 min at 0 °C and then at room temperature for 1.5 h.
Evaporation of the solvent and chromatography on silica gel (3:1
hexane–EtOAc) provided 39 mg (98%) of compound 28.
4.33. (5R,6S)-6-[(tert-Butyldimethylsilyloxy)methyl]-8,8-
dimethyl-3,7,9-trioxa-1-azaspiro[4.5]decan-2-one (33)
Using the same procedure as described for the preparation of
28, alcohol 32 (0.64 g, 1.76 mmol) and NaH (142 mg, 5.91 mmol,
60% dispersion in mineral oil) afforded after flash chromatography
on silica gel (2:1 hexane–EtOAc) 0.53 g (91%) of compound 33 as
Alcohol 30: colourless oil; 1H NMR (400 MHz, CDCl3): d 0.09 (s,
6H, 2 ꢂ CH3), 0.90 (s, 9H, 3 ꢂ CH3), 1.43 (s, 3H, CH3), 1.48 (s, 3H,
CH3), 3.59 (dd, JH,OH = 4.6 Hz, JH,OH = 10.0 Hz, 1H, OH), 3.66 (dd,
J4,H = 4.2 Hz, JH,H = 11.1 Hz, 1H, CH2O), 3.76 (dd, JH,OH = 10.0
Hz, JH,H = 12.9 Hz, 1H, CH2OH), 3.78 (dd, J4,H = 6.0 Hz, JH,H = 11.1
Hz, 1H, CH2O), 3.88 (d, J6,6 = 12.5 Hz, 1H, H-6), 3.97 (dd,
J4,H = 4.2 Hz, J4,H = 6.0 Hz, 1H, H-4), 4.14 (dd, JH,OH = 4.6 Hz,
JH,H = 12.9 Hz, 1H, CH2OH), 4.16 (d, J6,6 = 12.5 Hz, 1H, H-6), 7.79
(br s, 1H, NH). Anal. Calcd for C16H30Cl3NO5Si: C, 42.62; H, 6.71;
N, 3.11. Found: C, 42.68; H, 6.65; N, 3.17.
white solids: mp 99–101 °C; ½a D20
ꢃ
+13.8 (c 0.30, CHCl3). 1H NMR
(400 MHz, CDCl3): d 0.06 (s, 3H, CH3), 0.07 (s, 3H, CH3), 0.89 (s,
9H, 3 ꢂ CH3), 1.37 (s, 3H, CH3), 1.47 (s, 3H, CH3), 3.67 (d,
J10,10 = 11.4 Hz, 1H, H-10), 3.75 (dd, J6,H = 6.6 Hz, JH,H = 12.2 Hz,
1H, CH2O), 3.85–3.89 (m, 3H, H-10, H-6, CH2O), 4.27 (d,
J4,4 = 9.4 Hz, 1H, H-4), 4.65 (dd, J6,4 = 0.9 Hz, J4,4 = 9.4 Hz, 1H, H-4),
6.29 (br s, 1H, NH). 13C NMR (100 MHz, CDCl3): d ꢁ5.4 (2 ꢂ CH3),
18.3 (Cq), 18.6 (CH3), 25.8 (3 ꢂ CH3), 28.6 (CH3), 55.7 (C-5), 62.0
(CH2O), 68.2 (C-10), 70.1 (C-4), 74.4 (C-6), 99.4 (C-8), 159.2
(C@O). Anal. Calcd for C15H29NO5Si: C, 54.35; H, 8.82; N, 4.23.
Found: C, 54.30; H, 8.88; N, 4.18.
4.31. Methyl (4S,5S)-4-[(tert-butyldimethylsilyloxy)methyl]-2,2-
dimethyl-5-vinyl-1,3-dioxan-5-ylcarbamate (31)
According to the same procedure described for the preparation
of compound 26, isothiocyanate 20b (0.83 g, 2.42 mmol) was
transformed to carbamate 31 (0.79 g, 91% after two steps, colour-
4.34. (5R,6S)-6-(Hydroxymethyl)-8,8-dimethyl-3,7,9-trioxa-1-
azaspiro[4.5]decan-2-one (34)
less oil, 13:1 hexane–EtOAc): ½a D20
ꢃ
ꢁ14.3 (c 0.30, CHCl3). 1H NMR
Using the same procedure as described for the preparation of
29, compound 33 (0.53 g, 1.60 mmol) and TBAF (1.58 mL,
1.60 mmol) yielded after flash chromatography on silica
gel (EtOAc) 0.29 g (83%) of alcohol 34 as white solids: mp
(400 MHz, CDCl3): d 0.07 (s, 3H, CH3), 0.08 (s, 3H, CH3), 0.91 (s,
9H, 3 ꢂ CH3), 1.41 (s, 3H, CH3), 1.52 (s, 3H, CH3), 3.51 (dd,
J4,H = 4.1 Hz, JH,H = 9.7 Hz, 1H, CH2O), 3.60–3.68 (m, 4H, OCH3,
CH2O), 3.97 (dd, J4,H = 3.8 Hz, J4,H = 9.1 Hz, 1H, H-4), 4.06 (d,
J6,6 = 11.6 Hz, 1H, H-6), 4.57 (d, J6,6 = 11.6 Hz, 1H, H-6), 5.27 (dd,
168.5–170.5 °C; ½a D20
ꢃ
+21.7 (c 0.26, CH3OH). IR (KBr) mmax (cmꢁ1
)
3341, 3142, 2959, 2883, 1739, 1036. 1H NMR (400 MHz, CD3OD):
JBcis,Btrans = 1.3 Hz, JBtrans,A = 17.6 Hz, 1H, H-Btrans), 5.37 (dd, JBcis,B
-
d 1.35 (s, 3H, CH3), 1.49 (s, 3H, CH3), 3.64 (m, 2H, H-10, CH2),

M. Martinková et al. / Carbohydrate Research 352 (2012) 23–36
35
Table 3
intensities were collected at 200 K on an Oxford Diffraction XCali-
bur2 CCD diffractometer using Mo Ka radiation (k = 0.71073 ÅA). Se-
0
Crystal data and structure refinement parameters for compound 20a
lected crystallographic and other relevant data for the compound
20a are listed in Table 3. The structure was solved by direct meth-
ods.23 All non-hydrogen atoms were refined anisotropically by full-
matrix least squares calculations based on F2.23 All hydrogen atoms
were included in calculated positions as riding atoms, with SHEL-
20a
Empirical formula
Formula weight
Temperature, T (K)
Wavelength, k (Å)
Crystal system
Space group
C16H29NO3SSi
343.55
200(2)
0.71073
Orthorhombic
P212121
24
XL9723 defaults. The PLATON programme was used for structure
analysis and molecular and crystal structure drawings.
Unit cell dimensions
a (Å)
7.8547(15)
4.37. Supplementary data
b (Å)
11.1256(19)
23.811 (6)
2080.8(7)
c (Å)
V (Å3)
Complete crystallographic data for the structural analysis have
been deposit with the Cambridge Crystallographic Data Centre,
CCDC No. 823561. These data can be obtained free of charge from
the Director, Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, CB2 1EZ, UK (fax: +44 1223 336033; e-mail: de-
posit@ccdc.cam.ac.uk or via: www.ccdc.cam.ac.uk).
Formula per unit cell, Z
4
Dcalcd (g/cm3)
1.102
0.244
744
Absorption coefficient,
F(000)
l
(mmꢁ1
)
Crystal size (mm)
h Range for data collection (°)
Index ranges
0.49 ꢂ 0.32 ꢂ 0.01
3.11–24.99
ꢁ9 6 h 6 9
ꢁ13 6 k 6 13
ꢁ28 6 l 6 28
Acknowledgements
Independent reflections (Rint)
Absorption correction
Max. and min. transmission
Refinement method
3639 (0.0702)
Semi-empirical from equivalents
1.00000 and 0.76854
Full-matrix least-squares on F2
3639/0/206
The present work was supported by the Grant Agency (Nos.
1/0100/09 and No. 1/0433/11) of the Ministry of Education,
Slovak Republic. NMR measurements provided by the Slovak
State Programme Project No. 2003SP200280203 are gratefully
acknowledged.
Data/restraints/parameters
Goodness-of-fit on F2
1.062
Final R indices [I > 2
R indices (all data)
r
(I)]
R1 = 0.0686, wR2 = 0.1671
R1 = 0.1069, wR2 = 0.1914
0.460 and ꢁ0.339
Largest diff. peak and hole (e/Å-3
)
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(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl}-2,2,2-
trichloroacetamide (35)
Using the same procedure as described for the preparation of
32, ozonolysis of trichloroacetamide 23b (88 mg, 0.20 mmol) fol-
lowed by NaBH4 (33.5 mg, 0.89 mmol) reduction afforded after
flash chromatography on silica gel (5:1 hexane–EtOAc) 56 mg
(63%) of 35 which was converted into cyclic derivative 33
(39 mg, 94%, 3:1 hexane–EtOAc) by the same procedure as de-
scribed for the transformation of alcohol 30 to compound 28.
Alcohol 35: white solids: mp 63–65 °C; ½a D25
ꢃ
+10.3 (c 0.58,
CHCl3). 1H NMR (400 MHz, CDCl3): d 0.13 (s, 3H, CH3), 0.15 (s,
3H, CH3), 0.92 (s, 9H, 3 ꢂ CH3), 1.42 (s, 3H, CH3), 1.57 (s, 3H,
CH3), 3.39–3.45 (m, 1H, CH2O), 3.57 (d, J6,6 = 11.5 Hz, 1H, H-6),
3.81 (dd, J4,H = 3.8 Hz, JH,H = 12.5 Hz, 1H, CH2O), 3.87 (dd,
J4,H = 1.6 Hz, JH,H = 12.5 Hz, 1H, CH2O), 4.46–4.55 (m, 2H, CH2O,
OH), 4.59–4.60 (m, 1H, H-4), 4.88 (d, J6,6 = 11.5 Hz, 1H, H-6), 7.70
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(CH3), 18.4 (Cq), 19.1 (CH3), 25.7 (3 ꢂ CH3), 28.6 (CH3), 55.9 (C-5),
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6.71; N, 3.11. Found: C, 42.68; H, 6.65; N, 3.17.
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36
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