Total synthesis of (-)-jaspine B and its 4-epi-analogue from d-xylose

Article abstract of DOI:10.1016/j.tetasy.2014.04.002

The total synthesis of the HCl salts of (-)-jaspine B ent-1 and its 4-epi-congener ent-4 was accomplished starting from the common template 13 derived from d-xylose. The cornerstone of our synthesis was [3,3]- heterosigmatropic rearrangements, which effec

Full text of DOI:10.1016/j.tetasy.2014.04.002

Tetrahedron: Asymmetry 25 (2014) 750–766
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Tetrahedron: Asymmetry
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Total synthesis of (ꢀ)-jaspine B and its 4-epi-analogue from D-xylose
⇑
Miroslava Martinková , Eva Mezeiová, Jozef Gonda, Dominika Jacková, Kvetoslava Pomikalová
Institute of Chemical Sciences, Department of Organic 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:
Received 10 February 2014
Accepted 4 April 2014
The total synthesis of the HCl salts of (ꢀ)-jaspine B ent-1 and its 4-epi-congener ent-4 was accomplished
starting from the common template 13 derived from D-xylose. The cornerstone of our synthesis was [3,3]-
heterosigmatropic rearrangements, which effectively provided scaffolds with a chiral amino group. A
subsequent Wittig olefination installed a C14 alkyl side chain and acid-mediated ring-closing reaction
established the tetrahydrofuran core.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
its stereoisomers, an attractive and timely target for total
synthesis. So far, many synthetic efforts towards jaspine B and its
(+)-Jaspine B 11a (also known as pachastrissamine,1b Fig. 1) is a
natural anhydrophytosphingosine that has been isolated indepen-
dently from two marine sponges.1a,b The aforementioned com-
pound has been reported to possess remarkable cytotoxic activity
against several cancer cell lines1 with IC50 values in the submi-
cromolar range. Further biological screening of 1 and its three dia-
stereoisomers with different configurations at C-2 and/or C-3
(compounds 2, 3 and ent-4, see Fig. 1) of the tetrahydrofuran moi-
ety, realized by Delgado et al.2a revealed the role of stereochemis-
try for the cytotoxic potential. Génisson et al.2b also confirmed its
decisive function for the biological activity of 1. Fujii et al. revealed
that all members of the pachastrissamine family inhibit sphingo-
sine kinases (SphK1 and SphK2)2c while compounds 1, ent-3 and
4 have been reported to be inhibitors of atypical PKCs (PKCf and
analogues have been reported1d,2–4 and over the past five years,
several useful approaches employing various starting materials,
such as achiral 2-vinyl-oxirane4i and (E)-(benzyloxy)but-2-en-
1-ol,4h (S)-Garner0s aldehyde,1d,2d,4d,o (R)-Garner’s aldehyde,2c
L
-ascorbic acid,4k protected
deoxy-
-ribose,4n -mannose,4v
-isoascorbic acid,4e diethyl -tartrate4c and
D
L
-threitols,4b,j
-glucose,4g,p,5
-erythronolactone2b
D
-ribose,4l 3-amino-3-
D
D
D
D
-glyceraldehyde,4f
D
D
have been developed. The most straightforward routes still appear
to be those that utilize both Garner’s aldehydes and carbohydrates
since their asymmetric centres can be included directly in the
construction of chiral fragments, which are present in the final
products. Our recent success with the total synthesis of phytosp-
hingosines4v,6 and two pachastrissamine diastereoisomers4v ent-2
and 3 (Fig. 1) from sugar templates confirmed that [3,3]-hetero-
sigmatropic rearrangements of chiral allylic thiocyanates and
trichloroacetimidates effectively install a nitrogen-bearing stereo-
centre and generate substructures with the vicinal amino alcohol
motif contained in the various sphingosine-related compounds.
In order to verify the effectiveness of our approach,4v we herein
report a pathway leading to the two isomers of jaspine B,
PKCi
).2c Moreover, Fujii’s biological study on the side-chain modi-
fied analogues2d showed that the C14 aliphatic chain length was the
most convenient for a potent inhibitory profile against SphKs. The
significant biological properties and noteworthy structural fea-
tures, that is, the presence of the tetrahydrofuran backbone with
three consecutive stereogenic centres, have made 1, together with
OH
H2N
OH
OH
H2N
OH
H2N
H2N
C14H29
4-epi-jaspine B 4
C14H29
(+)-jaspine B 1
C14H29
2-epi-jaspine B 2
Figure 1. (+)-Jaspine B 1 and its stereoisomers.
C14H29
O
O
O
O
3-epi-jaspine B 3
⇑
Corresponding author. Tel.: +421 55 2342329; fax: +421 55 2342124.
E-mail address: miroslava.martinkova@upjs.sk (M. Martinková).
http://dx.doi.org/10.1016/j.tetasy.2014.04.002
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
751
ent-12b,c,4g,j,m,p,z,5 and ent-42a,d,4d,g,i,o (Fig. 1), because they have
[3,3]-sigmatropic rearrangements of the common allylic scaffolds
attracted less attention due to their unnatural character.
(E)-10 and/or (E)-11, which were envisioned as arising from the
isopropylidene derivative 13.8a For the preparation of 13,
D-xylose
was selected as a starting material.
2. Results and discussion
The synthesis commenced with the known 1,2-O-isopropylid-
enne-
a
-D
-xylofuranose 149 (90%), which was converted into tri-
The general retrosynthetic plan of our synthetic route is illus-
trated in Scheme 1. For both pachastrissamine isomers ent-1 and
ent-4, segments 5 and 6 could be prepared from the cyclic carba-
mates 7 and 8, respectively, via the Wittig reaction with the known
side chain unit 9.6b,7 Oxazolidinones 7 and 8 could be derived from
phenylmethyl ether 1510 (88%) using trityl chloride in DMF in
the presence of Et3N and DMAP (Scheme 2). Its treatment with
benzyl bromide and NaH in DMF afforded compound 1610 in 98%
yield. The Tr group in 16 was removed by acid hydrolysis (p-TsOH)
followed by benzoate ester formation of the resulting 5-hydroxy
function in 1711 (88%) to give derivative 18 in 98% yield (Scheme 2).
Cleavage of the acetonide moiety in 18 employing TFA in H2O at
0 °C gave lactol 1912 (88%), whose oxidative fragmentation with
NaIO4 followed by subsequent reduction (NaBH4) produced diol
20 in 93% after two steps. Its modification into ketal 21 (91%)
was achieved with 2,2-DMP in CH2Cl2 in the presence of catalytic
amounts of p-TsOH. Exposure of 21 to conventional conditions
(K2CO3, CH3OH) furnished the desired building block 13, which
R2
R1
OH
C14H29
O
1.HCl
ent-
: R1 = NH2.HCl, R2 = H
ent-4.HCl: R1 = H, R2 = NH2.HCl
was prepared in nine steps in 47% overall yield from
D-xylose
(53% from 14, Scheme 2). On the other hand, our initial attempts
OBn
OBn
to apply the modification of a published three-step protocol8 fur-
C12H25
and
C12H25
nishing 13 to dimethyl D-tartrate turned out to be impractical; a
O
O
O
low yield of 13, approximately 16%, was recorded. In order to
obtain multi-gram quantities of 13, we therefore decided to start
from the easily accessible furanose 14 (Scheme 2).
NBn OBn
NBn OBn
5
6
O
Wittig
Having paved the way for a satisfactory gram-scale preparation
of 13, we next turned our attention to the synthesis of thiocyanate
(E)-10 and trichloroacetimidates (E)-11 and (Z)-12, substrates for
the key [3,3]-sigmatropic rearrangements, as shown in Scheme 3.
Thus, the unprotected hydroxyl group in 13 was oxidized with o-
iodoxybenzoic acid (IBX)13 in CH3CN to give an aldehyde, which
was immediately submitted to a Horner–Wadsworth–Emmons
(HWE) olefination with (EtO)2P(O)CH2CO2Et to provide an easily
O
O
O
O
Ph3P+Br-
+
+
11
96b,7
O
O
O
NH
OBn
NH
OBn
7
8
O
[3,3]-sigmatropic
rearrangements
O
O
O
O
separable mixture of the a,b-unsaturated esters (E)-22 and (Z)-23
(E:Z = 88:12, as determined by 1H NMR spectroscopy in the crude
reaction mixture, E:Z = 87:13 after chromatography) in 77% and
11% isolated yields, respectively (Scheme 3). The geometries of
their double bonds were determined from the vinyl proton cou-
pling constant values; J3,2 = 15.7 Hz for (E)-22 and J3,2 = 11.8 Hz
for (Z)-23. All further transformations were then realized with
HO
D-xylose
R
OBn
138a
OBn
10
(E)- : R = SCN
(E)- : R = O(C=NH)CCl3
11
Scheme 1. Retrosynthetic analysis of ent-1ꢁHCl and ent-40ꢁHCl.
D-xylose
(ref. 9)
O
O
O
O
O
O
O
O
O
b
a
TrO
c
TrO
HO
HO
O
O
O
O
HO
BnO
BnO
HO
15 10
16,10 98%
17,11 88%
14,9 90%
,
88%
d
OH
O
O
O
O
OH
BzO
BzO
BzO
BzO
e
g
f
OH
OH
19 12 88%
O
BnO
OBn
OBn
BnO
21, 91%
20, 93%
,
18, 98%
h
O
O
HO
OBn
8a 95%
13
,
Scheme 2. Reagents and conditions: (a) TrCl, DMAP, Et3N, DMF, rt; (b) BnBr, NaH, DMF, TBAI, 0 °C ? rt; (c) p-TsOH, CH2Cl2/CH3OH, rt; (d) BzCl, pyridine, DMAP, 0 °C ? rt; (e)
TFA/H2O, 0 °C ? rt; (f) NaIO4, CH3OH/H2O, rt, then NaBH4, EtOH/H2O, 0 °C ? rt; (g) 2,2-DMP, CH2Cl2, p-TsOH, rt; (h) K2CO3, CH3OH, 0 °C ? rt.

752
M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
13
a
O
O
O
O
O
O
O
HO
b
NCS
c
EtOOC
OBn
OBn
OBn
(E)-24, 97%
(E)-22, 77%
(Z)-23, 11%
(E)-10, 85%
25
(Z)- , 90%
e
d
O
O
O
O
O
+
HN
O
NCS OBn
NCS OBn
CCl3
OBn
O
11
(E)-
(Z)-12
26
27
f
O
O
O
+
Cl3C
NH
OBn
Cl3C
NH
28
OBn
29
O
O
Scheme 3. Reagents and conditions: (a) (i) IBX, CH3CN, reflux; (ii) (EtO)2P(O)CH2COOEt, NaH, THF, ꢀ10 °C; (b) DIBAl-H, CH2Cl2, ꢀ50 °C; (c) (i) MsCl, Et3N, CH2Cl2 0 °C ? rt, (ii)
KSCN, CH3CN, 0 °C ? rt; (d) NaH, CCl3CN, THF, 0 °C; (e) Table 1; (f) Table 2.
Table 1
(E)-22 as the major isomer. The minor a,b-unsaturated ester (Z)-23
[3,3]-Sigmatropic rearrangement of thiocyanate (E)-10
was utilized only for the construction of imidate (Z)-12 in order to
determine the influence on the dr of the Overman reaction because
the configuration of the olefinic bond in the starting imidates (E)-
11 and (Z)-12 should be an important factor for the facial selectiv-
ity of this rearrangement. To obtain a reasonable amount of (Z)-23,
it can be easily prepared by standard Wittig reaction conditions
(Ph3P = CHCO2Et, CH2Cl2, rt, (E)-22:(Z)-23 = 67:33, determined by
1H NMR spectroscopy in the crude reaction mixture, E:Z = 65:35,
after chromatography).
Both ethyl esters (E)-22 and (Z)-23 were reduced with diisobu-
tylaluminum hyride in CH2Cl2 at ꢀ50 °C, to give the corresponding
alcohols (E)-24 and (Z)-25 in 97% and 90% yields, respectively. The
transformation of (E)-24 into thiocyanate (E)-10 (85%) was
achieved in a two-step sequence involving mesylation of the allylic
alcohol functionality in (E)-24 with methanesulfonyl chloride
(MsCl) followed by treatment with KSCN. Imidates (E)-11 and
(Z)-12 were prepared directly from (E)-24 and (Z)-25, respectively,
by the reaction of trichloroacetonitrile and NaH in THF (Scheme 3)
and were used in the crude state. Initial attempts to purify the
aforementioned imidates (E)-11 and (Z)-12 were unsuccessful;
extremely rapid decomposition of these compounds on silica gel
was observed.
With allylic substrates (E)-10 and (E)-11 and (Z)-12 in hand, we
were now in a position to explore a crucial step, the [3,3]-hetero-
sigmatropic rearrangement. The thermal reaction of the major
thiocyanate (E)-10 was carried out in heptane at 70 °C and 90 °C
and afforded the corresponding isothiocyanates 26 and 27 as a
readily separable mixture of diastereoisomers in high yields (90–
96%) and with good diastereoselectivity (Table 1, entries 1 and 3).
On the other hand, the application of a microwave energy
allowed a more rapid production of the rearranged products 26
and 27 (Table 1, entries 2 and 4) with yields and stereoselectivities
similar to thermally driven reactions. The Overman rearrangement
of trichloroacetimidate (E)-11 was realized under both the conven-
tional thermal and microwave irradiation conditions in o-xylene in
the presence of potassium carbonate14 and provided the corre-
sponding easily separable, amides 28 and 29 in very good yields
(71–89%), although practically no diastereoselectivity was
Entry
Thiocyanate
Conditionsa
Time
(h)
Ratiob
26:27
Ratioc
26:27
Yieldd
(%)
1
2
3
4
(E)-10
(E)-10
(E)-10
(E)-10
D
, 70 °C
MW, 70 °C
, 90 °C
MW, 90 °C
8
1.5
2
88:12
86:14
86:14
88:12
86:14
83:17
85:15
80:20
90
86
96
90
D
0.5
a
b
c
In n-heptane.
Ratio in the crude reaction mixtures. Determined by 1H NMR analysis.
Isolated diastereoselective ratio.
d
Isolated combined yields.
Table 2
Overman rearrangement of imidates (E)-11 and (Z)-12
Entry
Imidate
Conditionsa
Time
(h)
Ratiob
28:29
Ratioc
28:29
Yieldd
(%)
1
2
3
4
5
(E)-11
(E)-11
(E)-11
(E)-11
(Z)-12
MW, 130 °C
MW, 150 °C
MW, 170 °C
2
1.5
0.5
54
2
55:45
52:48
55:45
55:45
64:36
51:49
52:48
56:44
52:48
68:32
81
89
82
71
48
D
, 140 °C
MW, 150 °C
a
b
c
In o-xylene, in the presence of K2CO3.
Ratio in the crude reaction mixtures. Determined by 1H NMR analysis.
Isolated diastereoselective ratio.
d
Isolated combined yields.
attempted rearrangement of (Z)-12, which was prepared from
(Z)-25 according to the same conditions described for (E)-11, was
not very successful. Although TLC showed the complete consump-
tion of the starting material (Z)-12, we isolated the desired rear-
ranged products 28 and 29 in only a maximum combined yield
of 48% (Table 2, entry 5). The low yield was most likely due to
the decomposition of (Z)-12 and the formation of unidentified
products, which were difficult to separate from the desired struc-
tures, together with smaller amounts of the allylic alcohol (Z)-25
(28:29:(Z)-25 = 53:29:18, as judged by 1H NMR analysis in the
crude reaction mixture). In this case, the observed ratio of the rear-
rangement (Table 2, entry 5) suggests that the facial selectivity of
observed (28:29 = 55:45, Table 2, entries 1,
3 and 4). The

M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
753
the rearrangement should be slightly influenced by the geometry
of the double bond in (Z)-12.
at 90 °C was 82.8:17.2. These results are in very good agreement
with the experimental data (26:27 = 86:14) with the correct pre-
diction of isothiocyanate 26 as being the predominant
diastereoisomer.
In order to rationalize the observed stereoselectivity in the
[3,3]-sigmatropic rearrangement of thiocyanate (E)-10, high-level
density functional theory (DFT) calculations, including electron
correlation effects, were carried out. A thorough conformational
search was performed on all transition states, although only the
lowest energy conformers are discussed herein. The potential
energy surface scans were used to explore the conformational
space of transition states TS1 and TS2 with the constrained transi-
tion bond lengths CAN and CAS. The systematic conformational
search with rotation around the single bonds C4AC10, C5AOBn
and OACH2Ph was performed using semiempirical PM3 methodol-
ogy. The conformers within a 3 kcal/mol energy range were then
optimized using B3LYP/6-31G(d) for a more accurate description
of the conformer distribution. The low energy conformers of the
transition states were later fully optimized using B3LYP/6-
311+G(d,p). It is worth noting that the rearranged part possesses
an equatorial arrangement, while the OBn group is axial in all of
the low energy conformers. The potential energy surface scans
were used to explore the conformational space of the reactant
and products [thiocyanate (E)-10 and isothiocyanates 26 and 27]
with the later full optimization using the same level of theory;
however we only focused on the energy differences between the
TSs as being crucial for the explanation of the observed diastere-
oselectivities. The geometries of the transition states were opti-
mized using B3LYP/6-311+G(d,p) with the Jaguar 7.7 program.15
The nature of the vacuum B3LYP transition states was verified with
frequency calculations, yielding only one large imaginary fre-
With the key scaffolds 26, 27 and 28, 29 in place, we turned our
attention to the determination of the configuration of the newly
installed stereocentre with nitrogen. This was achieved by the fol-
lowing sequence. Treatment of the major isothiocyanate 26 with
sodium methoxide followed by the replacement of the sulfur atom
by oxygen with mesitylnitrile oxide (MNO)16 afforded the crystal-
line carbamate 30 in 87% yield over two steps (Scheme 4), whose
X-ray crystallographic analysis (Fig. 3) clearly showed that the con-
structed stereogenic centre bearing an amine functionality in 30
had an (R)-configuration. In parallel fashion, minor diastereoiso-
mer 27 was elaborated into the corresponding derivative 31
(87%) over two steps. Compounds 30 and 31 were then submitted
to ozonolysis followed by reduction with NaBH4 to furnish alcohols
32 (85%) and 33 (88%). The reaction of 32 and 33 with sodium
hydride in THF directly afforded the desired oxazolidinones 7
and 8 in 95% and 93% yields, respectively (Scheme 4).
Although both Overman’s products 28 and 29 were isolated as
crystalline compounds, their crystals were not suitable for X-ray
measurements. In order to confirm the stereochemistry in trichlo-
roacetamides 28 and 29, chemical correlations of these compounds
to the aforementioned cyclic carbamates 7 and 8 were carried out
(Scheme 5). Thus, oxidation (O3, ꢀ78 °C) of the terminal double
bond in 28 and 29 followed by reduction with NaBH4 provided
alcohols 34 (63%) and 35 (85%) together with smaller amounts of
products of the intramolecular cyclization 7 and 8 in 35% and
11% yields, respectively. Finally, DBU treatment of 34 and 35 fur-
nished the desired oxazolidinones 7 (95%) and 8 (93%, Scheme 5).
The materials obtained had spectroscopic data and specific rota-
tions in excellent agreement with those reported for 7 and 8 previ-
ously prepared from the corresponding isothiocyanates 26 and 27
revealing the same (R)-configuration of the major amide 28.
Having successfully completed a preparation of the common
derivatives 7 and 8 from the corresponding rearranged products
26/28 and 27/29, respectively, our remaining task was to develop
a suitable synthetic route leading to the final molecules ent-1
and ent-4. As shown in Scheme 6, removal of the isopropylidene
moiety by a acid hydrolysis (p-TsOH, CH3OH) in both oxazolidinon-
es 7 and 8 afforded the corresponding diols 36 and 37 in 87% and
97% yields, respectively (Scheme 6). The primary hydroxyl group in
36 and 37 was selectively protected as a triphenylmethyl ether
quency (TS1 = ꢀ228.97 cmꢀ1
,
TS2 = ꢀ239.53 cmꢀ1). Harmonic
zero-point energy corrections at B3LYP/6-311+G(d,p) obtained
from the frequency calculations of the vacuum transition states
were applied to the transition-state energies. Single-point energies
were computed by the B3LYP density functional method and the
cc-pvTZ basis set. The solvent effect was taken into account via a
single-point calculation in a dielectric continuum representing
heptane as the solvent. A standard PBF solvation model was
applied as implemented in the Jaguar 7.7 program.15The Overman
rearrangement of (E)-10 occurs via transition states TS1 and TS2
with relative free energies 0 and 1.135 kcal/mol (Fig. 2). The pro-
cess is concerted but asynchronous. From the calculations, for
the pathway (E)-10 ? TS1 ? 26, the activation energy was found
to be 1.135 kcal/mol lower than for the pathway (E)-
10 ? TS2 ? 27. Thus, the predicted diastereomeric ratio of 26:27
Figure 2. Transition structures for the rearrangement (E)-10 ? [TS1]/[TS2] ? 26 + 27. Relative energies of transition states (in kcal/mol) and bond distances (in Å) are shown.

754
M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
O
O
O
O
OH
O
O
O
O
c
a
b
O
O
NCS OBn
H3CO
NH
OBn
H3CO
NH
OBn
NH
OBn
7
, 95%
26
30, 89%
32, 85%
O
O
O
O
O
O
OH
O
O
O
O
a
c
b
O
NH
8, 93%
NCS OBn
H3CO
NH
OBn
H3CO
NH
OBn
OBn
O
33, 88%
27
31, 98%
O
O
Scheme 4. Reagents and conditions: (a) (i) CH3ONa, CH3OH, 0 °C ? rt, 98% from 26, 89% from 27; (ii) MNO, CH3CN, rt; (b) (i) O3, EtOH or EtOH/CH2Cl2, ꢀ78 °C; (ii) NaBH4,
EtOH or EtOH/CH2Cl2, ꢀ78 °C ? rt; (c) NaH, THF, 0 °C.
7
8
a
a
OH
OH
OH
OH
O
O
O
O
NH
NH
OBn
, 87%
NH
NH
OBn
37
, 97%
36
b
b
OH
OH
OTr
OTr
O
O
O
O
OBn
38, 99%
OBn
39, 93%
c
c
OBn
OBn
OTr
OH
OTr
OH
O
O
O
O
Figure 3. ORTEP structure of 30 showing the crystallographic numbering.
NBn
OBn
NBn
NBn
OBn
40, 98%
d
41, 95%
d
using trityl chloride in pyridine at 60 °C to form derivatives 38
(99%) and 39 (93%). Exposure of 38 and 39 to benzyl bromide in
DMF in the presence of NaH and catalytic amounts of TBAI pro-
duced compounds 40 and 41 in 98% and 95% yields, respectively.
Treatment with p-TsOH in CH2Cl2/CH3OH resulted in the cleav-
age of the trityl group to afford alcohols 42 (88%) and 43 (91%). The
liberated hydroxy functionality in 42 and 43 was oxidized with
IBX, and the in situ generated aldehydes were immediately used
for a Wittig reaction with the non-stabilized ylide derived from
OBn
OBn
O
O
O
O
NBn
OBn
OBn
43, 91%
42, 88%
Scheme 6. Reagents and conditions: (a) p-TsOH, CH3OH, rt; (b) TrCl, DMAP,
pyridine, 60 °C; (c) BnBr, NaH, DMF, TBAI, 0 °C ? rt; (d) p-TsOH, CH2Cl2/CH3OH, rt.
tridecyltriphenylphosphonium bromide (C13H27PPh3Br,
9
6b,7),
using LHMDS (freshly prepared from n-BuLi and NH(SiMe3)2)17 as
a base. This resulted in the formation of mixtures of olefins 5 and
6 (Z:E = 83:17 for 5, Z:E = 91:9 for 6, determined by 1H NMR spec-
troscopic analysis after chromatographic purification, we were not
able to confirm the corresponding ratio in the crude reaction mix-
ture) with 76% and 83% isolated yields, respectively (Scheme 7). A
small amount of a mixture of 6 was re-chromatographed on silica
gel to furnish only (Z)-6 in pure form as an analytical sample. Its
structure, including the stereochemistry of the double bond was
identified by NMR spectra (Jcis = 11.0 Hz). Attempts to separate
the corresponding alkenes 5 were not successful, although from
the 1H and 13C NMR spectra of the obtained mixture we were able
to find several data for the major isomer (Z)-5 (Jcis = 11.1 Hz, see
Section 4). The next step was the deprotection of both types of
the benzyl protecting groups and the reduction of the double bond
in 5 and 6. Initial attempts to achieve this in a one-step hydrogena-
tion protocol using 20% Pd(OH)2 (purchased from Acros Organics)
in EtOH at 60 °C (in the case of 5 was used a solution of 35% HCl)
were ineffective and the desired derivatives 44 and 47 were iso-
lated in maximum yields of 46% and 57%, respectively. The lower
yields of these transformations were due to unexpected formation
of the N-cyclohexylmethyl derivatives 45 (this was isolated
together with the N-benzyl derivative 46 as an inseparable mix-
ture, 45:46 = 50:50, as determined by 1H NMR analysis of the crude
O
O
OH
OH
O
O
a
a
8, 93%
+
28
7
+
, 95%
29
Cl3C
NH
OBn
34, 63%
Cl3C
NH
OBn
35, 85%
b
b
O
O
Scheme 5. Reagents and conditions: (a) O3, CH3OH/CH2Cl2, ꢀ78 °C; (ii) NaBH4, ꢀ78 °C ? rt, 7, 35%, 8, 11%; (b) DBU, CH2Cl2, 0 °C ? rt.

M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
755
42
43
reaction mixture) and 48 (36%, Scheme 7). Therefore, we decided to
prepare the oxazolidinone form of D-lyxo and D-xylo phytosphingo-
a
a
OBn
OBn
sines 44 and 47, respectively, through a more convenient two-
stage approach. This involved the removal of two O-benzyl moie-
ties and saturation of the olefinic residue in 5 and 6 under standard
conditions (H2, 10% Pd/C, EtOH) followed by N-debenzylation (H2,
10% Pd/C, EtOH, HCl, 60 °C) in 46 (87%) and 49 (89%) to provide 44
and 47 in 84% and 83% yields, respectively (Scheme 8). Finally,
hydrolysis of the cyclic carbamate fragment and the formation of
the tetrahydrofuran core in 44 and 47 were achieved in a single-
step procedure by treatment with 6 M HCl at reflux to give the
HCl salts of ent-1 (92%) and ent-4 (quant). Subsequently, exposure
of the isolated salts to Ac2O in dry pyridine and in the presence of
catalytic amounts of DMAP produced the known diacetates 50 and
51 in 88% and 85% yields, respectively (Scheme 8).
C12H25
C12H25
C12H25
C12H25
O
O
O
O
NBn
OBn
NBn
OBn
5, 76%
6, 83%
b
b
OH
OH
C12H25
O
O
NH
OH
NH
OH
O
O
47, 57%
44, 46%
+
+
OH
OH
The spectroscopic data and the specific rotation of 50
C12H25
+
a]
21 = +25.0 (c 0.14, CHCl3)} were in good agreement with those
D
O
O
{[
reported for 50 {lit.4p
25 = +29.0 (c 1.0, CHCl3)} or matched the known spectroscopic
O
O
OH
[a]
26 = +26.8 (c 1.2, CHCl3), lit.5
D
46
NR
OH
NR
45
48, 36%
[a]
D
values and comparable magnitudes of [a]
D for ent-50.4b,k,5,18 More-
R = CH2C6H11
over, the structure of 50 was unambiguously assigned by single
crystal X-ray analysis (Fig. 4, shows crystal structures of ent-50
which have been published before, see CCDC 61617018c and CCDC
6172435). The NMR properties and the melting point for com-
Scheme 7. Reagents and conditions: (a) (i) IBX, CH3CN, reflux; (ii) LHMDS,
13H27PPh3Br, THF, rt; (b) H2, 20% Pd(OH)2/C, EtOH, 60 °C.
C
pound 51 {[a] [a]
23 = +9.9 (c 0.26, CHCl3), lit.4g 28 = +7.4 (c 0.002,
D D
5
6
a
CHCl3)} were in full accord with the published data.4g
a
OH
OH
3. Conclusions
C12H25
C12H25
O
O
O
O
NBn
NBn
OH
OH
In conclusion, we have completed a synthesis of (ꢀ)-jaspine B
(ent-1) and its 4-epi-analogue ent-4 from inexpensive and com-
46, 87%
49, 89%
b
mercially available D-xylose. We have carried out a multi-gram
b
preparation of the advanced building block 13 whose transforma-
tion into the common oxazolidinone derivatives 7 and 8 utilized
[3,3]-sigmatropic rearrangements to incorporate the chiral amino
group. The versatility of 7 and 8 allowed us to install the hydropho-
bic side chain and to build the tetrahydrofuran ring. Our strategy is
flexible enough to allow variations in the length of the side chain to
synthesize diverse analogues, as well as showing the further possi-
bilities of the application of rearrangements in natural product
synthesis. Our efforts to construct jaspine B and its 4-epi-congener
4 from ent-7 and ent-8, respectively, are currently underway in our
laboratory and progress will be reported in due course.
OH
OH
OH
C12H25
C12H25
O
O
O
O
NH
NH
OH
44, 84%
47, 83%
c
c
OH
OH
HCl.H2N
HCl.H2N
C14H29
C14H29
O
O
ent-1, 92%
ent-4, quant
d
d
4. Experimental
4.1. General
OAc
OAc
AcHN
AcHN
C14H29
C14H29
O
O
51, 85%
50, 88%
All commercial reagents were used in the highest available pur-
ity from Aldrich, Merck or Acros Organics without further purifica-
tion. Solvents were dried and purified before use according to
Scheme 8. Reagents and conditions: (a) H2, 10% Pd/C, EtOH, rt; (b) H2, 10% Pd/C,
EtOH, 35% HCl, 60 °C; (c) 6 M aq HCl, reflux; (d) Ac2O, pyridine, DMAP, rt.
Figure 4. ORTEP structure of 50 showing the crystallographic numbering.

756
M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
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 use. 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 heating. 1H NMR and 13C NMR spec-
tra were recorded in CDCl3, CD3OD and C6D6 on a Varian Mercury
Plus 400 FT NMR (400.13 MHz for 1H and 100.6 MHz for 13C) spec-
trometer using TMS as internal reference. For 1H, d are given in
parts per million (ppm) relative to TMS (d = 0.0), CD3OD
(d = 4.84), CD3OCD3 (d = 2.05) and C6D6 (d = 7.15) and for 13C rela-
tive to CDCl3 (d = 77.0), CD3OD (d = 49.05), CD3OCD3 (d = 30.83)
and C6D6 (d = 128.02). The multiplicity of the 13C NMR signals con-
cerning 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) spectra were mea-
temperature for further 20 min. The excess hydride was decom-
posed by the addition of CH3OH (2 mL), the mixture was poured
into ice-water (240 mL) and extracted with Et2O (260 mL). The
aqueous phase was washed with
a further portion of Et2O
(260 mL), the combined organic layers were dried over Na2SO4,
stripped of solvent, and the residue was subjected to flash chroma-
tography on silica gel (n-hexane/ethyl acetate, 5:1) to give 34.5 g
(98%) of compound 16 as a white foam; [
a
]
23 = ꢀ37.2 (c 0.36,
D
CHCl3); {lit10
[a]
RT} = ꢀ26.8 (c 1.0, CHCl3)}. IR (neat) mmax 3058,
D
2932, 1596, 1448, 1213, 1071 cmꢀ1 1H NMR (400 MHz, CDCl3): d
;
1.32 (s, 3H, CH3), 1.53 (s, 3H, CH3), 3.31 (dd, 1H, J5,5 = 9.4 Hz,
J5,4 = 6.8 Hz, H-5), 3.54 (dd, 1H, J5,5 = 9.3 Hz, J5,4 = 5.7 Hz, H-5),
4.00 (d, 1H, J4,3 = 3.1 Hz, H-3), 4.37–4.40 (m, 1H, H-4), 4.42 (d,
1H, JH,H = 12.1 Hz, OCH2Ph), 4.56–4.59 (m, 2H, H-2, OCH2Ph), 5.90
(d, 1H, J2,1 = 3.8 Hz, H-1), 7.09–7.11 (m, 2H, Ph), 7.20–7.29 (m,
12H, Ph), 7.43–7.45 (m, 6H, Ph); 13C NMR (100 MHz, CDCl3): d
26.2 (CH3), 26.8 (CH3), 61.3 (C-5), 72.0 (OCH2Ph), 79.5 (C-4), 81.6
(C-3), 82.4 (C-2), 86.9 (CqTr), 105.0 (C-1), 111.6 (Cq), 127.0
(3 ꢂ CHPh), 127.5 (2 ꢂ CHPh), 127.7 (CHPh), 127.8 (6 ꢂ CHPh),
128.3 (2 ꢂ CHPh), 128.7 (6 ꢂ CHPh), 137.5 (Ci), 143.9 (3 ꢂ Ci). Anal.
Calcd for C34H34O5: C, 78.14; H, 6.56. Found: C, 78.10; H, 6.59.
sured with a Nicolet 6700 FT-IR spectrometer and expressed in
values (cmꢀ1). Specific rotations were measured on a P-2000 Jasco
polarimeter and reported as follows: [ (c in grams per 100 mL,
m
a
]
D
4.4. 3-O-Benzyl-1,2-O-isopropylidene-a-D
-xylofuranose 1711
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 con-
tent of the vessel was monitored using a calibrated infrared sensor
mounted under the vessel. At the end of all reactions the contents
of vessel were cooled rapidly using a stream of compressed air.
Small quantities of reagents (lL) were measured with appropriate
syringes (Hamilton). All reactions were performed under an atmo-
sphere of nitrogen, unless otherwise noted.
To a solution of the known 1610 (33.6 g, 64 mmol) in a mixture
of 2:1 CH2Cl2/CH3OH (657 mL) was added p-TsOH (12.8 g,
67.5 mmol), and the resulting mixture was stirred at room temper-
ature for 1 h. The reaction was quenched by neutralization with
Et3N (8.8 mL), the solvent was evaporated in vacuo, and the residue
was purified by flash chromatography on silica gel (n-hexane/ethyl
acetate, 3:1) to furnish 15.9 g (88%) of compound 17 as a colourless
oil; [
a
]
D
21 = ꢀ67.0 (c 0.30, CHCl3); (lit.11
[
a]
not reported). IR
D
(neat) mmax 3483, 2985, 2935, 1455, 1373, 1213, 1164 cmꢀ1 1H
;
4.2. 1,2-O-Isopropylidenene-5-O-trityl-
a-
D
-xylofuranose 1510
NMR (400 MHz, CDCl3): d 1.34 (s, 3H, CH3), 1.49 (s, 3H, CH3),
2.14 (dd, 1H, J5,OH = 8.7 Hz, J5,OH = 3.8 Hz, OH), 3.86 (ddd, 1H,
J5,5 = 12.0 Hz, J5,OH = 8.7 Hz, J5,4 = 4.8 Hz, H-5), 3.95 (ddd, 1H,
J5,5 = 12.0 Hz, J5,4 = 5.2 Hz, J5,OH = 3.8 Hz, H-5), 4.27–4.30 (m, 1H,
H-4), 4.02 (d, 1H, J4,3 = 3.5 Hz, H-3), 4.50 (d, 1H, JH,H = 12.0 Hz,
OCH2Ph), 4.65 (d, 1H, J2,1 = 3.8 Hz, H-2), 4.72 (d, 1H, JH,H = 12.0 Hz,
To a solution of the known 149 (14.71 g, 77 mmol) in dry DMF
(45 mL) were successively added Et3N (12 mL, 85 mmol), trityl
chloride (23.7 g, 85 mmol) and DMAP (0.76 g, 6.2 mmol). The
resulting mixture was stirred for 18 h at room temperature, then
poured into ice-water (140 mL) and extracted with Et2O
(2 ꢂ 140 mL). The combined organic extracts were dried over
Na2SO4, the solvent was evaporated under reduced pressure, and
the residue was chromatographed on silica gel (n-hexane/ethyl
acetate, 5:1) to afford 29.4 g (88%) of compound 15 as a white
OCH2Ph), 5.99 (d, 1H, J2,1 = 3.8 Hz, H-1), 7.30–7.39 (m, 5H, Ph); 13
C
NMR (100 MHz, CDCl3): d 26.3 (CH3), 26.8 (CH3), 61.0 (C-5), 71.9
(OCH2Ph), 80.0 (C-4), 82.4 (C-3), 82.7 (C-2), 105.1 (C-1), 111.8
(Cq), 127.7 (2 ꢂ CHPh), 128.2 (CHPh), 128.6 (2 ꢂ CHPh), 137.0 (Ci).
Anal. Calcd for C15H20O5: C, 64.27; H, 7.19. Found: C, 64.23; H, 7.20.
foam; [
CHCl3)}. IR (neat) mmax 3458, 3058, 2982, 2933, 1448, 1213,
1069 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.33 (s, 3H, CH3), 1.49
a] [a]
22 = +10.9 (c 0.22, CHCl3); {lit10 RT = +54.4 (c 1.0,
D D
4.5. 5-O-Benzoyl-3-O-benzyl-1,2-O-isopropylidene-a-D-xylofura-
nose 18
;
(s, 3H, CH3), 3.17 (d, 1H, J4,3 = 2.8 Hz, H-3), 3.47 (dd, 1H,
J5,5 = 10.2 Hz, J5,4 = 3.2 Hz, H-5), 3.57 (dd, 1H, J5,5 = 10.2 Hz,
J5,4 = 5.2 Hz, H-5), 4.25–4.28 (m, 1H, H-4), 4.53 (d, 1H,
J2,1 = 3.7 Hz, H-2), 6.01 (d, 1H, J2,1 = 3.7 Hz, H-1), 7.23–7.26 (m,
3H, Ph), 7.29–7.33 (m, 6H, Ph), 7.43–7.46 (m, 6H, Ph); 13C NMR
(100 MHz, CDCl3): d 26.1 (CH3), 26.8 (CH3), 61.8 (C-5), 76.3 (C-4),
78.4 (C-3), 85.1 (C-2), 87.5 (CqTr), 105.0 (C-1), 111.5 (Cq), 127.3
(3 ꢂ CHPh), 128.1 (6 ꢂ CHPh), 128.4 (6 ꢂ CHPh), 143.2 (3 ꢂ Ci). Anal.
Calcd for C27H28O5: C, 74.98; H, 6.53. Found: C, 75.02; H, 6.49.
To a solution of 17 (15.8 g, 56 mmol) in dry pyridine (255 mL)
that had been pre-cooled to 0 °C were added successively benzoyl
chloride (7.8 mL, 68 mmol) and DMAP (0.7 g, 5.6 mmol). The reac-
tion mixture was stirred for 10 min at 0 °C and then for a further
1.5 h at room temperature before pyridine was evaporated. The
obtained residue was dissolved in EtOAc (280 mL), washed with
water (140 mL), the organic layer was dried over Na2SO4 and the
solvent was removed under reduced pressure. Purification by flash
chromatography on silica gel (n-hexane/ethyl acetate, 9:1) affor-
4.3. 3-O-Benzyl-1,2-O-isopropylidene-5-O-trityl-
a
-
D
-xylofura-
ded 21.2 g (98%) of compound 18 as
a
colourless oil;
nose 1610
[a]
25 = ꢀ46.1 (c 0.28, CHCl3). IR (neat) mmax 2987, 2933, 1717,
D
1451, 1270, 1164 cmꢀ1 1H NMR (400 MHz, C6D6): d 1.11 (s, 3H,
;
Sodium hydride (4.0 g, 101 mmol, 60% dispersion in mineral oil)
was added portionwise to a solution of the known 15 (29.1 g,
67 mmol) in dry DMF (163 mL) that had been pre-cooled to 0 °C,
and then benzyl bromide (9.7 mL, 81 mmol) and tetrabutylammo-
nium iodide (0.5 g, 1.3 mmol) were added successively. The reac-
tion mixture was stirred for 10 min at 0 °C and then at room
CH3), 1.39 (s, 3H, CH3), 3.85 (d, 1H, J4,3 = 3.3 Hz, H-3), 4.08 (d, 1H,
JH,H = 12.0 Hz, OCH2Ph), 4.28 (d, 1H, JH,H = 12.0 Hz, OCH2Ph), 4.33
(d, 1H, J2,1 = 3.8 Hz, H-2), 4.60–4.64 (m, 1H, H-4), 4.70 (dd, 1H,
J5,5 = 11.4 Hz, J5,4 = 6.8 Hz, H-5), 4.78 (dd, 1H, J5,5 = 11.4 Hz,
J5,4 = 5.0 Hz, H-5), 5.89 (d, 1H, J2,1 = 3.7 Hz, H-1), 6.98–7.16 (m,
8H, Ph), 8.06–8.08 (m, 2H, Ph); 13C NMR (100 MHz, CDCl3): d

M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
757
26.2 (CH3), 26.8 (CH3), 62.4 (C-5), 71.9 (OCH2Ph), 78.1 (C-4), 81.5
(C-3), 82.1 (C-2), 105.3 (C-1), 111.8 (Cq), 127.7 (2 ꢂ CHPh), 128.0
(CHPh), 128.3 (2 ꢂ CHPh), 128.5 (2 ꢂ CHPh), 129.7 (2 ꢂ CHPh),
129.8 (Ci), 133.1 (CHPh), 137.1 (Ci), 166.2 (C@O). Anal. Calcd for
13.2 g (91%) of compound 21 as white crystals; mp 47.5–48.5 °C
(recrystallized from n-hexane/ethyl acetate); [
a]
25 = ꢀ52.7 (c
D
0.26, CHCl3). IR (neat) mmax 2986, 2946, 1714, 1602, 1267,
1084 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.47 (s, 3H, CH3), 1.48
;
(s, 3H, CH3), 3.37–3.38 (m, 1H, H-50), 3.93 (dd, 1H, J6 ,6 = 13.0 Hz,
0
0
C22H24O6: C, 68.74; H, 6.29. Found: C, 68.69; H, 6.32.
J6 ,5 = 2.2 Hz, H-60), 4.07 (dd, 1H, J6 ,6 = 13.0 Hz, J6 ,5 = 2.1 Hz, H-
0
0
0
0
0
0
60), 4.27 (m, 1H, H-40), 4.44 (dd, 1H, J1,1 = 11.1 Hz, J4 ,1 = 6.3 Hz, H-
0
4.6. (2R,3R)-3-(Benzyloxy)-2,4-dihydroxybutyl benzoate 20
1), 4.48–4.53 (m, 2H, H-1, OCH2Ph), 4.78 (d, 1H, JH,H = 12.3 Hz,
OCH2Ph), 7.20–7.36 (m, 5H, Ph), 7.40–7.43 (m, 2H, Ph), 7.54–7.57
(m, 1H, Ph), 7.93–7.95 (m, 2H, Ph); 13C NMR (100 MHz, CDCl3): d
19.1 (CH3), 28.9 (CH3), 61.1 (C-60), 64.1 (C-1), 69.1 (C-50), 69.5 (C-
40), 70.9 (OCH2Ph), 98.9 (Cq), 127.8 (CHPh), 128.0 (2 ꢂ CHPh),
128.3 (2 ꢂ CHPh), 128.4 (2 ꢂ CHPh), 129.6 (2 ꢂ CHPh), 129.9 (Ci),
133.0 (CHPh), 137.8 (Ci), 166.2 (C@O). Anal. Calcd for C21H24O5: C,
70.77; H, 6.79. Found: C, 70.73; H, 6.84.
Compound 18 (19.5 g, 51 mmol) was treated with a mixture of
4:1 TFA/H2O (89 mL) at 0 °C. The resulting solution was stirred for
6 h at the same temperature before EtOAc (200 mL), water
(180 mL) and solid NaHCO3 (84 g) were added. The insoluble mate-
rials were removed by filtration and the obtained filtrate was
extracted with EtOAc (2 ꢂ 180 mL). The combined organic layers
were dried over Na2SO4, stripped of solvent and the residue was
flash-chromatographed through a short silica gel column (n-hex-
ane/ethyl acetate, 1:1) to give 15.4 g (88%) of the known 5-O-ben-
4.8. [(40R,50R)-50-(Benzyloxy)-20,20-dimethyl-10,30-dioxan-40-yl]
zoyl-3-O-benzyl-
D
-xylofuranose 1912 as a white amorphous solid.
methanol 138a
Its spectroscopic data were in good agreement with those previ-
ously reported.12
To a solution of 21 (12.9 g, 36 mmol) in CH3OH (378 mL) that
had been pre-cooled to 0 °C was added solid K2CO3 (1.5 g,
10.8 mmol). The reaction mixture was stirred for 15 min at 0 °C,
and then for a further 4.5 h at room temperature, before dilution
with Et2O (510 mL) and the addition of solid Na2SO4. The insoluble
part was filtered off, the solvent was evaporated and the residue
was purified by flash chromatography on silica gel (n-hexane/ethyl
acetate, 1:1) to furnish 8.7 g (95%) of compound 138a as white crys-
tals; mp 60–62 °C (recrystallized from n-hexane/ethyl acetate);
To a solution of 19 (15.2 g, 44 mmol) in a mixture of 1:1 CH3OH/
H2O (102 mL) was added NaIO4 (11.3 g, 53 mmol), and the result-
ing suspension was stirred for 1 h at room temperature before
dilution with CH2Cl2 (300 mL). The insoluble solid parts were
removed by filtration, and the filtrate was concentrated in vacuo.
The obtained residue was partitioned between a saturated NaHCO3
solution (110 mL) and CH2Cl2 (200 mL), and the aqueous phase
was then extracted with a further portion of CH2Cl2 (200 mL).
The combined organic layers were dried over Na2SO4, the solvent
was evaporated and the crude aldehyde was used immediately in
the subsequent reaction without further purification.
[a
]
D
23 = ꢀ69.4 (c 0.32, CHCl3); [lit.8a mp 61–62 °C; [
a]
24 = ꢀ65.0
D
(c 1.55, CHCl3)]. IR (neat) mmax 3501, 2992, 2960, 2940, 2868,
1464, 1393, 1170 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.46 (s, 3H,
;
To a solution of the previously obtained aldehyde (14.1 g,
44 mmol) in a mixture of 4:1 CH3OH/CH2Cl2 (180 mL), pre-cooled
to 0 °C, was added NaBH4 (2.1 g, 89 mmol) portion wise. The
resulting mixture was stirred for 10 min at 0 °C and then for fur-
ther 50 min at room temperature. The reaction was quenched by
neutralization with Amberlite IR-120 (H+), the insoluble materials
were filtered off and the solvent was evaporated in vacuo. The res-
idue was subjected to flash chromatography on silica gel (n-hex-
ane/ethyl acetate, 1:2) to afford 13.1 g (93%) of crystalline diol
20; mp 85–87 °C (recrystallized from n-hexane/ethyl acetate);
CH3), 1.47 (s, 3H, CH3), 2.02 (dd, 1H, JOH,1 = 8.7 Hz, JOH,1 = 3.4 Hz,
OH), 3.31–3.32 (m, 1H, H-50), 3.63 (ddd, 1H, J1,1 = 11.5 Hz,
0
JOH,1 = 8.7 Hz, J4 ,1 = 4.7 Hz, H-1), 3.68–3.70 (m, 1H, H-1), 3.91 (dd,
1H, J6 ,6 = 12.9 Hz, J6 ,5 = 2.3 Hz, H-60), 3.98 (ddd, 1H, J4 ,1 = 6.9 Hz,
0
0
0
0
0
J4 ,1 = 4.7 Hz, J5 ,4 = 2.2 Hz, H-40), 4.03 (dd, 1H, J6 ,6 = 12.9 Hz,
0
0
0
0
0
J6 ,5 = 2.2 Hz, H-60), 4.44 (d, 1H, JH,H = 12.3 Hz, OCH2Ph), 4.76 (d,
1H, JH,H = 12.3 Hz, OCH2Ph), 7.28–7.37 (m, 5H, Ph); 13C NMR
(100 MHz, CDCl3): d 19.1 (CH3), 28.9 (CH3), 61.1 (C-60), 62.9 (C-1),
70.0 (C-50), 70.8 (OCH2Ph), 71.6 (C-40), 98.8 (Cq), 127.9 (CHPh),
128.0 (2 ꢂ CHPh), 128.5 (2 ꢂ CHPh), 137.8 (Ci). Anal. Calcd for
0
0
[
a]
D
25 = ꢀ30.7 (c 0.28, CHCl3). IR (neat) mmax 3309, 3065, 3034,
C14H20O4: C, 65.65; H, 7.99. Found: C, 65.62; H, 7.95.
2958, 2922, 2858, 1714, 1449, 1274, 1091 cmꢀ1
;
1H NMR
(400 MHz, CD3OD): d 3.54–3.58 (m, 1H, H-3), 3.72 (dd, 1H,
J4,4 = 11.4 Hz, J4,3 = 5.4 Hz, H-4), 3.79 (dd, 1H, J4,4 = 11.4 Hz,
J4,3 = 5.7 Hz, H-4), 4.04–4.08 (m, 1H, H-2), 4.28 (dd, 1H,
J1,1 = 10.0 Hz, J2,1 = 5.3 Hz, H-1), 4.32 (dd, 1H, J1,1 = 10.0 Hz,
J2,1 = 4.5 Hz, H-1), 4.56 (d, 1H, JH,H = 11.7 Hz, OCH2Ph), 4.71 (d,
1H, JH,H = 11.7 Hz, OCH2Ph), 7.15–7.35 (m, 5H, Ph), 7.39–7.43 (m,
2H, Ph), 7.53–7.57 (m, 1H, Ph), 7.93–7.95 (m, 2H, Ph); 13C NMR
(100 MHz, CD3OD): d 61.8 (C-4), 66.9 (C-1), 70.1 (C-2), 73.9
(OCH2Ph), 80.6 (C-3), 128.8 (CHPh), 129.3 (2 ꢂ CHPh), 129.4
(2 ꢂ CHPh), 129.5 (2 ꢂ CHPh), 130.7 (2 ꢂ CHPh), 131.4 (Ci), 134.3
(CHPh), 139.8 (Ci), 167.9 (C@O). Anal. Calcd for C18H20O5: C,
68.34; H, 6.37. Found: C, 68.30; H, 6.39.
4.9. Ethyl (E)-3-[(40R,50R)-50-(benzyloxy)-20,20-dimethyl-10,30-
dioxan-40-yl]acrylate (E)-22 and ethyl (Z)-3-[(40R,50R)-50-(ben-
zyloxy)-20,20-dimethyl-10,30-dioxan-40-yl]acrylate (Z)-23
To a solution of 13 (7.1 g, 28.2 mmol) in CH3CN (256 mL) was
added IBX (19.7 g, 70.3 mmol), and the resulting mixture was stir-
red and heated at reflux for 1 h. After cooling to room temperature,
the solid part was filtered off, the solvent was removed under
reduced pressure and the crude aldehyde was used immediately
in the subsequent reaction without further purification.
To a suspension of NaH (1.53 g, 38.4 mmol, 60% dispersion in
mineral oil) in dry THF (60 mL) that had been pre-cooled to
ꢀ10 °C was added dropwise (EtO)2P(O)CH2COOEt (6.7 mL,
31 mmol), and the resulting mixture was stirred for 25 min at
0 °C. A solution of the crude aldehyde (7.0 g, 28.2 mmol) in dry
THF (12.2 mL) was then added, and the mixture was stirred at
0 °C. After 1.5 h, the starting material was completely consumed
(judged by TLC), the mixture was poured into a saturated NH4Cl
solution (21.5 mL) and extracted with EtOAc (2 ꢂ 55 mL). The com-
bined organic layers were dried over Na2SO4, the solvent was evap-
orated and the residue was subjected to flash chromatography on
silica gel (n-hexane/ethyl acetate, 3:1) to afford 6.94 g (77%) of
(E)-22 and 0.99 g (11%) of (Z)-23.
4.7. [(40R,50R)-50-(Benzyloxy)-20,20-dimethyl-10,30-dioxan-40-yl]
methyl benzoate 21
To a solution of 20 (12.9 g, 41 mmol) in dry CH2Cl2 (226 mL)
were successively added 2,2-DMP (15.2 mL, 122 mmol) and p-
TsOH (0.31 g, 1.6 mmol), and the resulting mixture was stirred
for 2 h at room temperature before washing with a saturated
NaHCO3 solution (2 ꢂ 220 mL). The organic layer was dried over
Na2SO4, the solvent was evaporated in vacuo and the residue was
chromatographed on silica gel (n-hexane/ethyl acetate, 5:1) to give

758
M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
Isomer (E)-22: colourless oil; [
a
]
22 = +12.3 (c 0.26, CHCl3). IR
vided, after flash chromatography through a short silica gel
D
(neat) mmax 2988, 2940, 2868, 1713, 1662, 1367, 1261 cmꢀ1
;
1H
column (n-hexane/ethyl acetate, 2:1) 0.23 g (90%) of alcohol (Z)-
NMR (400 MHz, CDCl3): d 1.30 (t, 3H, J = 7.1 Hz, CH3), 1.46 (s, 3H,
25 as a colourless viscous oil; [
a
]
18 = ꢀ37.3 (c 0.22, CHCl3). IR
D
CH3), 1.50 (s, 3H, CH3), 3.31–3.32 (m, 1H, H-50), 3.95 (dd, 1H,
(neat) mmax 3436, 3034, 2988, 2943, 2885, 1453, 1373,
J6 ,6 = 12.9 Hz, J6 ,5 = 2.3 Hz, H-60), 4.01 (dd, 1H, J6 ,6 = 12.9 Hz,
;
1197 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.48 (s, 3H, CH3), 1.49
0
0
0
0
0
0
J6 ,5 = 2.2 Hz, H-60), 4.22 (q, 2H, J = 7.1 Hz, CH2), 4.50 (d, 1H,
(s, 3H, CH3), 3.20 (q, 1H, J6 ,5 = 2.2 Hz, J6 ,5 = 2.2 Hz, J5 ,4 = 2.2 Hz,
0
0
0
0
0
0
0
0
JH,H = 12.6 Hz, OCH2Ph), 4.56–4.58 (m, 1H, H4 ), 4.70 (d, 1H,
H-50), 3.93 (dd, 1H, J6 ,6 = 12.9 Hz, J6 ,5 = 2.2 Hz, H-60), 4.01 (dd,
0
0
0
0
0
1H, J6 ,6 = 12.9 Hz, J6 ,5 = 2.2 Hz, H-60), 4.04–4.07 (m, 1H, H-1),
4.22 (dd, 1H, J1,1 = 13.0 Hz, J2,1 = 5.6 Hz, H-1), 4.52 (d, 1H,
JH,H = 12.4 Hz, OCH2Ph), 4.72–4.75 (m, 2H, H-40, OCH2Ph), 5.77–
5.87 (m, 2H, H-2, H-3), 7.26–7.37 (m, 5H, Ph); 13C NMR
(100 MHz, CDCl3): d 19.1 (CH3), 29.1 (CH3), 59.0 (C-1), 61.5 (C-60),
68.4 (C-40), 71.3 (OCH2Ph), 71.4 (C-50), 98.9 (Cq), 127.8 (CHPh),
128.1 (2 ꢂ CHPh), 128.3 (2 ꢂ CHPh), 129.2 (C-2 or C-3), 132.2 (C-2
or C-3), 137.9 (Ci). Anal. Calcd for C16H22O4: C, 69.04; H, 7.97.
Found: C, 69.08; H, 7.94.
0
0
0
0
0
JH,H = 12.6 Hz, OCH2Ph), 6.13 (dd, 1H, J3,2 = 15.7 Hz, J4 ,2 = 1.9 Hz,
0
H-2), 6.91 (dd, 1H, J3,2 = 15.7 Hz, J4 ,3 = 4.3 Hz, H-3), 7.25–7.34 (m
5H, Ph); 13C NMR (100 MHz, CDCl3): d 14.3 (CH3), 19.1 (CH3),
28.8 (CH3), 60.3 (CH2), 61.6 (C-60), 70.9 (C-50), 70.9 (C-40), 71.1
(OCH2Ph), 99.0 (Cq), 121.8 (C2), 127.8 (CHPh), 128.0 (2 ꢂ CHPh),
128.3 (2 ꢂ CHPh), 137.7 (Ci), 144.5 (C-3), 166.2 (C@O). Anal. Calcd
for C18H24O5: C, 67.48; H, 7.55. Found: C, 67.50; H, 7.51.
Isomer (Z)-23: white crystals, mp 41.5–43 °C (recrystallized
from n-hexane/ethyl acetate); [
a]
D
22 = ꢀ203.0 (c 0.28, CHCl3). IR
(neat) mmax 2989, 2958, 2889, 1704, 1644, 1372, 1185 cmꢀ1 1H
;
NMR (400 MHz, CDCl3): d 1.26 (t, 3H, J = 7.1 Hz, CH3), 1.48 (s, 3H,
4.12. (4R,5R)-5-(Benzyloxy)-2,2-dimethyl-4-[(E)-30-thiocyanat-
oprop-10-en-10-yl]-1,3-dioxan (E)-10
CH3), 1.49 (s, 3H, CH3), 3.58–3.60 (m, 1H, H-50), 3.97 (dd, 1H,
J6 ,6 = 12.9 Hz, J6 ,5 = 2.0 Hz, H-60), 4.01 (dd, 1H, J6 ,6 = 12.9 Hz,
0
0
0
0
0
0
J6 ,5 = 2.1 Hz, H-60), 4.09 (q, 2H, J = 7.1 Hz, CH2), 4.45 (d, 1H,
JH,H = 12.4 Hz, OCH2Ph), 4.67 (d, 1H, JH,H = 12.4 Hz, OCH2Ph),
To a solution of (E)-24 (2.35 g, 8.4 mmol) in dry CH2Cl2 (102 mL)
that had been pre-cooled to 0 °C were successively added Et3N
(1.8 mL, 12.7 mmol) and methanesulfonyl chloride (1.0 mL,
12.7 mmol). The resulting mixture was stirred for 30 min at 0 °C
and then for a further 10 min at room temperature. After evapora-
tion of the solvent, the residue was diluted with Et2O (25 mL), the
salts were filtered off and washed with Et2O. The solvent was evap-
orated in vacuo to give a crude mesylate that was used in the next
reaction without purification.
0
0
5.50–5.53 (m, 1H, H-40), 5.80 (dd, 1H, J3,2 = 11.8 Hz, J4 ,2 = 1.5 Hz,
0
0
H-2), 6.39 (dd, 1H, J3,2 = 11.8 Hz, J4 ,3 = 6.8 Hz, H-3), 7.23–7.30 (m,
5H, Ph); 13C NMR (100 MHz, CDCl3): d 14.1 (CH3), 19.1 (CH3),
29.2 (CH3), 60.2 (CH2), 61.6 (C-60), 69.4 (C-40), 71.2 (C-50), 71.4
(OCH2Ph), 98.7 (Cq), 119.6 (C-2), 127.6 (CHPh), 128.1 (2 ꢂ CHPh),
128.1 (2 ꢂ CHPh), 138.0 (Ci), 148.3 (C-3), 166.7 (C@O). Anal. Calcd
for C18H24O5: C, 67.48; H, 7.55. Found: C, 67.50; H, 7.51.
To a solution of the crude mesylate (3.0 g, 8.4 mmol) in dry CH3-
CN (72 mL) was added KSCN (1.4 g, 14.4 mmol) at 0 °C, and the
resulting mixture was stirred for 15 min at 0 °C and then for a fur-
ther 6 h at room temperature before evaporation of the solvent. To
the obtained residue, Et2O (25 mL) was added to give salts, which
were removed by filtration. The filtrate was concentrated to pro-
vide an orange oil, which was subjected to flash chromatography
on silica gel (n-hexane/ethyl acetate, 3:1) to afford 2.29 g (85%)
of compound (E)-10 as white crystals; mp 50–52 °C (recrystallized
4.10. (E)-3-[(40R,50R)-50-(Benzyloxy)-20,20-dimethyl-10,30-dioxan-
40-yl]prop-2-en-1-ol (E)-24
To a solution of (E)-22 (5.43 g, 17 mmol) in dry CH2Cl2 (128 mL)
that had been pre-cooled to ꢀ50 °C was added diisobutylalumi-
num hydride (42.4 mL, 50.8 mmol, ꢃ1.2 M toluene solution) drop-
wise, and the resulting mixture was then stirred for 30 min at
ꢀ30 °C. The reaction was quenched with CH3OH (16.7 mL), and
after warming to room temperature was poured into a 30% solu-
tion of K/Na tartrate (357 mL). After stirring for 1 h at room tem-
perature, the aqueous phase was extracted with CH2Cl2
(2 ꢂ 200 mL). The combined organic layers were dried over Na2-
SO4, stripped of solvent and the residue was chromatographed on
silica gel (n-hexane/ethyl acetate, 1:1) to furnish 4.58 g (97%) of
compound (E)-24 as white crystals; mp 40.5–42.5 °C (recrystal-
from n-hexane/ethyl acetate); [
a]
23 = ꢀ49.6 (c 0.26, CHCl3). IR
D
(neat) mmax 2990, 2867, 2152, 1379, 1195, 1132 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d 1.47 (s, 3H, CH3), 1.48 (s, 3H, CH3), 3.25–3.26
(m, 1H, H-5), 3.53–3.58 (m, 1H, H-30), 3.59–3.64 (m, 1H, H-30),
3.93 (dd, 1H, J6,6 = 12.9 Hz, J6,5 = 2.2 Hz, H-6), 3.99 (dd, 1H,
J6,6 = 12.9 Hz, J6,5 = 2.1 Hz, H-6), 4.47–4.48 (m, 1H, H-4), 4.54 (d,
1H, JH,H = 12.5 Hz, OCH2Ph), 4.71 (d, 1H, JH,H = 12.5 Hz, OCH2Ph),
5.84–5.96 (m, 2H, H-10, H-20), 7.27–7.36 (m, 5H, Ph); 13C NMR
(100 MHz, CDCl3): d 19.1 (CH3), 29.0 (CH3), 35.8 (C-30), 61.5 (C-6),
71.3 (OCH2Ph), 2 ꢂ 71.5 (C-4, C-5), 98.9 (Cq), 111.8 (SCN), 124.5
(C-10 or C-20), 127.7 (CHPh), 128.0 (2 ꢂ CHPh), 128.3 (2 ꢂ CHPh),
134.5 (C-10 or C-20), 137.9 (Ci). Anal. Calcd for C17H21NO3S: C,
63.92; H, 6.63; N, 4.39. Found: C, 63.95; H, 6.60; N, 4.36.
lized from n-hexane/ethyl acetate); [
a
]
23 = ꢀ31.9 (c 0.26, CHCl3).
D
IR (neat) mmax 3452, 2992, 2866, 1718, 1370, 1197, 1064 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.47 (s, 3H, CH3), 1.48 (s, 3H, CH3),
3.20–3.22 (m, 1H, H-50), 3.93 (dd, 1H, J6 ,6 = 12.8 Hz, J6 ,5 = 2.2 Hz,
0
0
0
0
H-60), 4.00 (dd, 1H, J6 ,6 = 12.8 Hz, J6 ,5 = 2.1 Hz, H-60), 4.13 (m,
0
0
0
0
2H, 2 ꢂ H-1), 4.41 (dd, 1H, J4 ,3 = 4.5 Hz, J5 ,4 = 2.1 Hz, H-40), 4.50
(d, 1H, JH,H = 12.6 Hz, OCH2Ph), 4.73 (d, 1H, JH,H = 12.6 Hz, OCH2Ph),
5.83–5.93 (m, 2H, H-2, H-3), 7.27–7.36 (m, 5H, Ph); 13C NMR
(100 MHz, CDCl3): d 19.1 (CH3), 29.1 (CH3), 61.7 (C-60), 63.0 (C-1),
71.3 (OCH2Ph), 71.8 (C-50), 72.1 (C-40), 98.8 (Cq), 127.7 (CHPh),
128.1 (2 ꢂ CHPh), 128.2 (2 ꢂ CHPh), 128.6 (C-2 or C-3), 131.8 (C-2
or C-3), 138.0 (Ci). Anal. Calcd for C16H22O4: C, 69.04; H, 7.97.
Found: C, 69.00; H, 8.01.
0
0
0
4.13. (4R,5R)-5-(Benzyloxy)-4-[(10R)-10-isothiocyanatoallyl]-2,2-
dimethyl-1,3-dioxan 26 and (4R,5R)-5-(benzyloxy)-4-[(10S)-10-
isothiocyanatoallyl]-2,2-dimethyl-1,3-dioxan 27
4.13.1. Conventional method
Thiocyanate (E)-10 (0.1 g, 0.31 mmol) was dissolved in n-hep-
tane (2.6 mL), and the resulting solution was stirred and heated
under a nitrogen atmosphere (for the reaction times and tempera-
tures, see Table 1). After cooling to room temperature, the solvent
was evaporated in vacuo and the residue was chromatographed on
silica gel (n-hexane/ethyl acetate, 5:1) to give the corresponding
isothiocyanates 26 and 27 as colourless oils (for the combined
yields, see Table 1).
4.11. (Z)-3-[(40R,50R)-50-(Benzyloxy)-20,20-dimethyl-10,30-dioxan-
40-yl]prop-2-en-1-ol (Z)-25
Using the same procedure as described for the preparation of
(E)-24, compound (Z)-23 (0.3 g, 0.936 mmol) and diisobutylalumi-
num hydride (2.3 mL, 2.8 mmol, ꢃ1.2 M toluene solution) pro-

M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
759
Requiring a greater amount of the pure rearranged products 26
and 27, they were obtained on a multi-gram scale by the conven-
tional method in n-heptane at 90 °C.
the resulting mixture was heated in a sealed tube for 54 h at
140 °C. After cooling to room temperature, the solvent was evapo-
rated in vacuo, and the residue was chromatographed on silica gel
(n-hexane/ethyl acetate, 3:1) to furnish trichloroacetamides 28 and
29, both as white crystals in 71% combined yield.
4.13.2. Microwave-assisted synthesis
Thiocyanate (E)-10 (0.1 g, 0.31 mmol) was weighed in a 10 mL
glass pressure microwave tube equipped with a magnetic stirbar.
n-Heptane (2.6 mL) was then added, the tube was closed with a sil-
icon septum and the resulting mixture was subjected to micro-
wave irradiation (for the temperatures and reaction times, see
Table 1). Evaporation of the solvent and chromatography on silica
gel (n-hexane/ethyl acetate, 5:1) gave isothiocyanates 26 and 27
(for the combined yields, see Table 1).
4.14.2. Microwave-assisted synthesis
Imidate (E)-11 (0.10 g, 0.24 mmol) was weighed into a 10-mL
glass pressure microwave tube equipped with a magnetic stirbar.
o-Xylene (3.2 mL) and anhydrous K2CO3 (37.3 mg, 0.27 mmol)
were then added, the tube was closed with a silicone septum,
and the reaction mixture was subjected to microwave irradiation
(for the temperatures and reaction times, see Table 2). Removal
of the solvent and chromatography on silica gel (n-hexane/ethyl
acetate, 3:1) afforded the corresponding trichloroacetamides 28
and 29 (for the combined yields, see Table 2).
Diastereoisomer 26: [
a
]
D
23 = ꢀ61.4 (c 0.28, CHCl3). IR (neat) mmax
2991, 2871, 2170, 2087, 1453, 1377, 1197 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d 1.40 (s, 3H, CH3), 1.42 (s, 3H, CH3), 3.47–3.49
0
(m, 1H, H-5), 3.79 (dd, 1H, J4,1 = 9.4 Hz, J5,4 = 2.0 Hz, H-4), 3.89
Requiring a greater amount of 28 and 29, the aforementioned
procedure was repeated several times at 150 °C using the same
amount of the starting imidate (E)-11.
According to the procedure described for the rearrangement of
(E)-11, imidate (Z)-12 (0.10 g, 0.24 mmol) provided, after flash
chromatography on a short silica gel column (n-hexane/ethyl ace-
tate, 5:1) trichloroacetamides 28 and 29 (for the corresponding
yield and reaction time, see Table 2).
(dd, 1H, J6,6 = 13.1 Hz, J6,5 = 2.1 Hz, H-6), 4.07 (dd, 1H,
J6,6 = 13.1 Hz, J6,5 = 2.0 Hz, H-6), 4.59 (d, 1H, JH,H = 11.7 Hz, OCH2-
Ph), 4.61–4.66 (m, 1H, H-10), 4.75 (d, 1H, JH,H = 11.7 Hz, OCH2Ph),
0
0
0
0
0
0
0
5.28 (ddd, 1H, J3 ,2 = 10.4 Hz, J3 ,1 = 1.5 Hz, J3 ,3 = 0.7 Hz, H-3 cis),
5.44 (ddd, 1H, J3 ,2 = 17.0 Hz, J3 ,1 = 1.7 Hz, J3 ,3 = 0.7 Hz, H-3 trans),
0
0
0
0
0
0
0
5.95 (ddd, 1H, J3 ,2 = 17.0 Hz, J3 ,2 = 10.4 Hz, J2 ,1 = 4.7 Hz, H-20),
7.28–7.44 (m, 5H, Ph); 13C NMR (100 MHz, CDCl3): d 19.0 (CH3),
28.8 (CH3), 58.1 (C-10), 61.0 (C-6), 69.1 (C-5), 71.4 (OCH2Ph), 74.0
(C-4), 99.2 (Cq), 117.0 (C-30), 128.0 (CHPh), 128.2 (2 ꢂ CHPh),
128.5 (2 ꢂ CHPh), 132.7 (C-20), 133.8 (NCS), 137.5 (Ci). Anal. Calcd
for C17H21NO3S: C, 63.92; H, 6.63; N, 4.39. Found: C, 63.95; H,
6.60; N, 4.37.
0
0
0
0
0
0
Diastereoisomer 28: mp 96–97 °C (recrystallized from n-hexane/
ethyl acetate); [
a]
24 = +27.3 (c 0.22, CHCl3). IR (neat) mmax 3352,
D
2990, 2984, 2857, 1720, 1508, 1046 cmꢀ1
;
1H NMR (400 MHz,
CDCl3): d 1.42 (s, 3H, CH3), 1.45 (s, 3H, CH3), 3.49–3.50 (m, 1H,
00 00
00 00
H-500), 3.90 (dd, 1H, J6
= 13.3 Hz, J6
= 1.7 Hz, H-600), 4.04–
,6
,5
25 = ꢀ41.9 (c 0.32, CHCl3). IR (neat) mmax
4.06 (m, 1H, H-400), 4.16 (dd, 1H, J6
= 13.3 Hz, J6
= 1.8 Hz, H-
00 00
00 00
Diastereoisomer 27: [
a
]
D
,6
,5
3030, 2990, 2873, 2045, 1454, 1378, 1197 cmꢀ1
;
1H NMR
600), 4.28 (d, 1H, JH,H = 10.4 Hz, OCH2Ph), 4.67–4.71 (m, 1H, H-10),
0
0
(400 MHz, CDCl3): d 1.49 (s, 3H, CH3), 1.51 (s, 3H, CH3), 3.25–3.26
4.70 (d, 1H, JH,H = 10.4 Hz, OCH2Ph), 5.28 (ddd, 1H, J3 ,2 = 10.4 Hz,
0
0
0
0
0
0
0
0
(m, 1H, H-5), 3.82 (dd, 1H, J4,1 = 9.1 Hz, J5,4 = 2.0 Hz, H-4), 3.87
J3 ,1 = 1.6 Hz, J3 ,3 = 1.0 Hz, H-3 cis), 5.33 (ddd, 1H, J3 ,2 = 17.2 Hz,
0
0
0
0
0
0
0
(dd, 1H, J6,6 = 13.2 Hz, J6,5 = 2.1 Hz, H-6), 4.11 (dd, 1H,
J6,6 = 13.2 Hz, J6,5 = 2.1 Hz, H-6), 4.37 (dd, 1H, JH,H = 11.8 Hz, OCH2-
Ph), 4.61–4.65 (m, 1H, H-10), 4.73 (m, 1H, JH,H = 11.8 Hz, OCH2Ph),
5.23–5.26 (m, 1H, H-30cis), 5.40–5.45 (m, 1H, H-30trans), 5.53 (ddd,
J3 ,1 = 1.7 Hz, J3 ,3 = 1.0 Hz, H-3 trans), 5.71 (ddd, 1H, J3 ,2 = 17.2 Hz,
J3 ,2 = 10.4 Hz, J2 ,1 = 5.2 Hz, H-20), 7.32–7.36 (m, 5H, Ph), 8.35 (d,
0
0
0
0
1H, J1 ,NH = 7.4 Hz, NH); 13C NMR (100 MHz, CDCl3): d 18.8 (CH3),
0
28.9 (CH3), 56.1 (C-10), 60.3 (C-600), 70.3 (C-400), 71.0 (OCH2Ph),
71.6 (C-500), 92.8 (CCl3), 98.9 (Cq), 117.7 (C-30), 128.4 (CHPh),
128.5 (2 ꢂ CHPh), 128,9 (2 ꢂ CHPh), 132.1 (C-20), 136.6 (Ci), 162.0
(C@O). Anal. Calcd for C18H22Cl3NO4: C, 51.14; H, 5.25; N, 3.31.
Found: C, 51.11; H, 5.21; N, 3.35.
1H, J3 ,2 = 16.9 Hz, J3 ,2 = 9.9 Hz, J2 ,1 = 5.5 Hz, H-20), 7.30–7.38 (m,
5H, Ph); 13C NMR (100 MHz, CDCl3): d 18.9 (CH3), 28.8 (CH3),
60.5 (C-10), 60.6 (C-6), 69.1 (C-5), 70.4 (OCH2Ph), 74.5 (C-4), 99.6
(Cq), 119.6 (C-30), 127.9 (3 ꢂ CHPh), 128.5 (2 ꢂ CHPh), 130.2 (C-20),
135.8 (NCS), 137.4 (Ci). Anal. Calcd for C17H21NO3S: C, 63.92; H,
6.63; N, 4.39. Found: C, 63.94; H, 6.60; N, 4.36.
0
0
0
0
0
0
Diastereoisomer 29: mp 86–87 °C (recrystallized from n-hexane/
ethyl acetate); [
a]
24 = ꢀ28.7 (c 0.30, CHCl3). IR (neat) mmax 3368,
D
3243, 2993, 2877, 1693, 1523 cmꢀ1 1H NMR (400 MHz, CDCl3): d
;
4.14. N-{(10R)-1-[(400R,500R)-500-(Benzyloxy)-200,200-dimethyl-100,300-
dioxan-400-yl]allyl}-2,2,2-trichloroacetamide 28 and N-{(10S)-1-
[(400R,500R)-500-(benzyloxy)-200,200-dimethyl-100,300-dioxan-400-yl]
allyl}-2,2,2-trichloroacetamide 29
1.44 (s, 3H, CH3), 1.47 (s, 3H, CH3), 3.32–3.33 (m, 1H, H-500), 3.86
00 00
00 00
(dd, 1H, J6
= 13.0 Hz, J6
= 2.0 Hz, H-600), 4.03–4.07 (m, 2H, H-
,6
,5
400, H-600), 4.45 (d, 1H, JH,H = 12.0 Hz, OCH2Ph), 4.45–4.48 (m, 1H,
H-10), 4.69 (d, 1H, JH,H = 12.0 Hz, OCH2Ph), 5.21–5.24 (m, 1H, H-
30cis), 5.26–5.31 (m, 1H, H-3 trans), 5.81 (ddd, 1H, J3 ,2 = 17.1 Hz,
0
0
0
To a suspension of NaH (0.29 g, 12 mmol, 60% dispersion in
mineral oil) in dry THF (8.7 mL) that had been pre-cooled to 0 °C
was added a solution of (E)-24 (1.5 g, 5.4 mmol) in dry THF
(8.7 mL). The resulting mixture was stirred for 30 min at 0 °C,
and then CCl3CN (0.66 mL, 6.6 mmol) was added dropwise. After
stirring for a further 30 min at 0 °C, the mixture was filtered
through a small pad of Celite, the solvent was evaporated and
the crude trichloroacetimidate (E)-11 was used immediately in
the subsequent rearrangement without further purification.
According to the same procedure described for the preparation
of (E)-11, compound (Z)-25 (0.1 g, 0.36 mmol) was converted into
imidate (Z)-12, which was used for the next reaction without
chromatography.
J3 ,2 = 10.3 Hz, J2 ,1 = 6.8 Hz, H-20), 7.28–7.35 (m, 6H, Ph, NH); 13C
NMR (100 MHz, CDCl3): d 19.0 (CH3), 28.8 (CH3), 55.2 (C-10), 60.9
(C-600), 70.1 (C-500), 70.7 (OCH2Ph), 71.5 (C-400), 92.8 (CCl3), 99.3
(Cq), 118.3 (C-30), 127.9 (CHPh), 128.2 (2 ꢂ CHPh), 128.5 (2 ꢂ CHPh),
133.3 (C-20), 137.4 (Ci), 161.1 (C@O). Anal. Calcd for C18H22Cl3NO4:
C, 51.14; H, 5.25; N, 3.31. Found: C, 51.16; H, 5.22; N, 3.34.
0
0
0
0
4.15. Methyl {(1R)-1-[(40R,50R)-50-(benzyloxy)-20,20-dimethyl-
10,30-dioxan-40-yl]allyl}carbamate 30
To a solution of 26 (1.49 g, 4.7 mmol) in dry CH3OH (46 mL) that
had been pre-cooled to 0 °C was added sodium methoxide (0.3 g,
5.6 mmol). After stirring for 30 min at 0 °C and then at room tem-
perature for 13.5 h, the solvent was evaporated, and the residue
was partitioned between CH2Cl2 (35 ml) and water (18 mL). The
aqueous phase was extracted with further portions of CH2Cl2
(2 ꢂ 35 mL). The combined organic layers were dried over Na2SO4,
4.14.1. Conventional procedure
To a solution of imidate (E)-11 (0.10 g, 0.24 mmol) in o-xylene
(3.2 mL) was added anhydrous K2CO3 (37.3 mg, 0.27 mmol), and

760
M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
the solvent removed and the crude product was purified by flash
tion with a 1 M aqueous HCl solution. The solvent was evaporated
in vacuo, and the residue was partitioned between CH2Cl2 (65 mL)
and water (25 mL), and the aqueous phase was then washed with a
further portion of CH2Cl2 (65 mL). The combined organic layers
were dried over Na2SO4, the solvent was removed and the crude
product was purified by flash chromatography on silica gel (n-hex-
ane/ethyl acetate, 1:2). This procedure yielded 1.0 g (85%) of deriv-
ative 32 as white crystals; mp 127–129 °C (recrystallized from
chromatography on silica gel (n-hexane/ethyl acetate, 3:1) to pro-
vide 1.61 g (98%) of thiocarbamate as a colourless oil, [a]
23 = +24.1
D
(c 0.34, CHCl3), which was used immediately in the subsequent
reaction without spectroscopic characterization.
Mesitylnitrile oxide (0.94 g, 5.8 mmol) was added to a solution
of the previous prepared thiocarbamate (1.58 g, 4.5 mmol) in dry
CH3CN (44 mL). After stirring for 1.5 h at room temperature, the
solvent was removed under reduced pressure, and the residue
was flash-chromatographed through a small column of silica gel
(n-hexane/ethyl acetate, 2:1) to furnish 1.34 g (89%) of white crys-
talline compound 30; mp 88–90 °C (recrystallized from n-hexane);
ethyl acetate); [
a
]
D
23 = ꢀ42.3 (c 0.26, CHCl3). IR (neat) mmax 3431,
3359, 2993, 2947, 1693, 1525, 1359, 1238 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d 1.44 (br s, 6H, 2 ꢂ CH3), 3.36–3.37 (m, 1H,
H-50), 3.64 (m, 4H, H-2, OCH3), 3.85 (m, 1H, H-1), 3.88 (dd, 1H,
22 = +7.3 (c 0.30, CHCl3). IR (neat)
m
max 3300, 2985, 2942, 1692,
1H NMR (400 MHz, CDCl3): d 1.43 (s, 3H,
CH3), 1.44 (s, 3H, CH3), 3.38–3.39 (m, 1H, H-50), 3.64 (s, 3H,
J6 ,6 = 13.0 Hz, J6 ,5 = 1.9 Hz, H-60), 4.01 (m, 1H, H-2), 4.06 (dd, 1H,
0
0
0
0
[
a
]
D
1541, 1351, 1268 cmꢀ1
;
J6 ,6 = 13.0 Hz, J6 ,5 = 2.0 Hz, H-60), 4.14–4.15 (m, 1H, H-40), 4.46
(d, 1H, JH,H = 11.9 Hz, OCH2Ph), 4.72 (d, 1H, JH,H = 11.9 Hz, OCH2Ph),
5.40 (br s, 1H, NH), 7.29–7.40 (m, 5H, Ph); 13C NMR (100 MHz,
CDCl3): d 18.9 (CH3), 20.0 (CH3), 52.1 (OCH3), 53.3 (C-1), 61.1 (C-
60), 62.5 (C-2), 70.2 (C-50), 70.9 (OCH2Ph), 71.4 (C-40), 99.0 (Cq),
127.9 (CHPh), 128.1 (2 ꢂ CHPh), 128.5 (2 ꢂ CHPh), 137.6 (Ci), 157.1
(C@O). Anal. Calcd for C17H25NO6: C, 60.16; H, 7.42; N, 4.13. Found:
C, 60.13; H, 7.45; N, 4.16.
0
0
0
0
OCH3), 3.83 (dd, 1H, J6 ,6 = 13.1 Hz, J6 ,5 = 1.9 Hz, H-60), 3.94 (m,
0
0
0
0
1H, H-40), 4.03 (dd, 1H, J6 ,6 = 13.1 Hz, J6 ,5 = 2.1 Hz, H-60), 4.43 (d,
1H, JH,H = 11.7 Hz, OCH2Ph), 4.43–4.48 (m, 1H, H-1), 4.68 (d, 1H,
JH,H = 11.7 Hz, OCH2Ph), 5.14–5.18 (m, 1H, H-3cis), 5.23–5.28 (m,
1H, H-3trans), 5.73–5.85 (m, 2H, H-2, NH), 7.28–7.36 (m, 5H, Ph);
13C NMR (100 MHz, CDCl3): d 18.9 (CH3), 28.9 (CH3), 51.9 (OCH3),
55.3 (C-1), 61.0 (C-60), 70.6 (C-50), 70.8 (OCH2Ph), 71.3 (C-40),
98.9 (Cq), 116.4 (C-3), 127.9 (CHPh), 128.1 (2 ꢂ CHPh), 128.4
(2 ꢂ CHPh), 134.8 (C-2), 137.4 (Ci), 156.9 (C@O). Anal. Calcd for
0
0
0
0
4.18. Methyl {(1S)-1-[(40R,50R)-50-(benzyloxy)-20,20-dimethyl-
10,30-dioxan-40-yl]-2-hydroxyethyl}carbamate 33
C18H25NO5: C, 64.46; H, 7.51; N, 4.18. Found: C, 64.44; H, 7.47;
N, 4.22.
According to the same procedure described for the preparation
of 32, ozonolysis of the compound 31 (145 mg, 0.432 mmol) fol-
lowed by NaBH4 (74 mg, 1.95 mmol) reduction gave after flash
chromatography on silica gel (n-hexane/ethyl acetate, 1:2)
129 mg (88%) of derivative 33 as white crystals; mp 125–127 °C
4.16. Methyl {(1S)-1-[(40R,50R)-50-(benzyloxy)-20,20-dimethyl-
10,30-dioxan-40-yl]allyl}carbamate 31
Using the same procedure as described for the preparation 30,
compound 27 (172 mg, 0.538 mmol) and sodium methoxide
(38 mg, 0.7 mmol) afforded after flash chromatography on silica
gel (n-hexane/ethyl acetate, 3:1), 168 mg (89%) of thiocarbamate
(recrystallized from ethyl acetate); [
a]
23 = ꢀ26.5 (c 0.26, CHCl3).
D
IR (neat) mmax 3566, 3255, 3092, 2981, 2875, 1706, 1685, 1565,
1270 cmꢀ1 1H NMR (400 MHz, CD3OD): d 1.37 (s, 3H, CH3), 1.45
;
(s, 3H, CH3), 3.37–3.38 (m, 1H, H-50), 3.46 (dd, 1H, J2,2 = 11.4 Hz,
J2,1 = 4.3 Hz, H-2), 3.52–3.60 (m, 4H, H-2, OCH3), 3.82–3.86 (m,
as white crystals [mp 118–120 °C, [
a
]
23 = ꢀ58.1 (c 0.32, CHCl3)],
D
1H, H-1), 3.94 (dd, 1H, J6 ,6 = 13.1 Hz, J6 ,5 = 1.8 Hz, H-60), 4.07
0
0
0
0
which was used in the subsequent transformation without spec-
troscopic characterization. Its treatment (160 mg, 0.455 mmol)
with MNO (81 mg, 0.5 mmol) furnished after purification by flash
chromatography on silica gel (n-hexane/ethyl acetate, 2:1) 0.15 g
(98%) of white crystalline compound 31; mp 132.5–134 °C (recrys-
(dd, 1H, J6 ,6 = 13.1 Hz, J6 ,5 = 1.9 Hz, H-60), 4.08–4.14 (m, 1H, H-
40), 4.43 (d, 1H, JH,H = 11.6 Hz, OCH2Ph), 4.69 (d, 1H, JH,H = 11.6 Hz,
OCH2Ph), 7.25–7.39 (m, 5H, Ph); 13C NMR (100 MHz, CD3OD): d
19.3 (CH3), 29.4 (CH3), 52.6 (OCH3), 55.5 (C-1), 62.0 (C-60), 63.2
(C-2), 70.3 (C-40), 73.8 (OCH2Ph), 82.3 (C-50), 100.4 (Cq), 128.6
(CHPh), 129.2 (2 ꢂ CHPh), 129.3 (2 ꢂ CHPh), 140.1 (Ci), 159.5
(C@O). Anal. Calcd for C17H25NO6: C, 60.16; H, 7.42; N, 4.13. Found:
C, 60.12; H, 7.44; N, 4.15.
0
0
0
0
tallized from n-hexane/ethyl acetate);
[
a]
23 = ꢀ49.3 (c 0.30,
D
CHCl3). IR (neat) mmax 3265, 3065, 2982, 2948, 2872, 1706, 1688,
1555, 1363 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.42 (s, 3H, CH3),
1.45 (s, 3H, CH3), 3.31–3.32 (m, 1H, H-50), 3.61 (s, 3H, OCH3),
3.85 (dd, 1H, J6 ,6 = 13.0 Hz, J6 ,5 = 2.1 Hz, H-60), 3.83–3.87 (m, 1H,
0
0
0
0
H-40), 4.04 (dd, 1H, J6 ,6 = 13.0 Hz, J6 ,5 = 2.1 Hz, H-60), 4.32–4.37
(m, 1H, H-1), 4.43 (d, 1H, JH,H = 11.8 Hz, OCH2Ph), 4.68 (d, 1H,
JH,H = 11.8 Hz, OCH2Ph), 5.09 (m, 1H, NH), 5.15–5.18 (m, 1H, H-
4.19. (4R)-4-[(40R,50R)-50-(Benzyloxy)-20,20-dimethyl-10,30-dioxan-
0
0
0
0
40-yl]oxazolidin-2-one 7
3
cis), 5.23–5.28 (m, 1H, H-3trans), 5.72–5.80 (m, 1H, H-2), 7.28–
Sodium hydride (0.23 g, 9.7 mmol, 60% dispersion in mineral oil)
was added to a solution of 32 (0.98 g, 2.89 mmol) in dry THF
(5.8 mL) that had been pre-cooled to 0 °C. After stirring for 10 min
at 0 °C and then for a further 10 min at room temperature, the reac-
tion was quenched with CH3OH (1 mL). The solvent was evaporated
in vacuo, and the residue was partitioned between CH2Cl2 (18 mL)
and a saturated NaCl solution (10 mL). The aqueous phase was then
extracted with further portions of CH2Cl2 (2 ꢂ 18 mL). The com-
bined organic layers were dried over Na2SO4, the solvent was
removed and the crude product was subjected to flash chromatog-
raphy on silica gel (n-hexane/ethyl acetate, 1:2) to give 0.84 g (95%)
of white crystalline derivative 7; mp 177–179 °C (recrystallized
7.36 (m, 5H, Ph); 13C NMR (100 MHz, CDCl3): d 19.0 (CH3), 28.8
(CH3), 51.9 (OCH3), 54.6 (C-1), 61.2 (C-60), 70.2 (C-50), 70.8 (OCH2-
Ph), 72.8 (C-40), 99.2 (Cq), 117.2 (C-3), 127.7 (CHPh), 127.9
(2 ꢂ CHPh), 128.3 (2 ꢂ CHPh), 135.4 (C-2), 137.8 (Ci), 156.8 (C@O).
Anal. Calcd for C18H25NO5: C, 64.46; H, 7.51; N, 4.18. Found: C,
64.43; H, 7.48; N, 4.21.
4.17. Methyl {(1R)-1-[(40R,50R)-50-(benzyloxy)-20,20-dimethyl-
10,30-dioxan-40-yl]-2-hydroxyethyl}carbamate 32
Ozone was introduced to a solution of 30 (1.18 g, 3.52 mmol) in
EtOH (35 mL) at ꢀ78 °C for 15 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 ozone. Next,
NaBH4 (0.6 g, 15.8 mmol) was added portionwise, and the reaction
mixture was stirred for 30 min at ꢀ78 °C. After warming to 0 °C
(approximately 20 min), the reaction was quenched by neutraliza-
from n-hexane/ethyl acetate); [
a
]
23 = ꢀ71.3 (c 0.30, CHCl3). IR
D
(neat) mmax 3377, 2990, 2879, 1749, 1041, 1026 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d 1.43 (s, 6H, 2 ꢂ CH3), 3.31–3.32 (m, 1H, H-50),
3.77 (dd, 1H, J4,4 = 7.8 Hz, J5 ,4 = 1.7 Hz, H-40), 3.92 (dd, 1H,
0
0
0
J6 ,6 = 13.1 Hz, J6 ,5 = 1.9 Hz, H-60), 3.98–4.03 (m, 1H, H-4), 4.09
0
0
0
0
(dd, 1H, J6 ,6 = 13.1 Hz, J6 ,5 = 1.8 Hz, H-60), 4.29 (dd, 1H,
0
0
0
0

M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
761
J5,5 = 9.0 Hz, J5,4 = 4.6 Hz, H-5), 4.37–4.43 (m, 2H, H-5, OCH2Ph),
4.78 (d, 1H, JH,H = 12.0 Hz, OCH2Ph), 5.17 (br s, 1H, NH), 7.35–7.40
(m, 5H, Ph); 13C NMR (100 MHz, CDCl3): d 19.2 (CH3), 28.6 (CH3),
51.6 (C-4), 60.5 (C-60), 68.0 (C-2 or C-5), 68.1 (C-2 or C-5), 70.4
(OCH2Ph), 72.9 (C-40), 99.0 (Cq), 128.3 (2 ꢂ CHPh), 128.4 (CHPh),
128.8 (2 ꢂ CHPh), 137.5 (Ci), 159.5 (C@O). Anal. Calcd for
OD): d 19.2 (CH3), 29.5 (CH3), 55.6 (C-10), 61.0 (C-20), 61.7 (C-600),
69.9 (C-400), 72.3 (OCH2Ph), 72.4 (C-500), 94.0 (CCl3), 100.2 (Cq),
129.1 (CHPh), 129.5 (2 ꢂ CHPh), 130.0 (2 ꢂ CHPh), 139.0 (Ci), 163.9
(C@O). Anal. Calcd for C17H22Cl3NO5: C, 47.85; H, 5.20; N, 3.28.
Found: C, 47.82; H, 5.22; N, 3.29.
C
16H21NO5: C, 62.53; H, 6.89; N, 4.56. Found: C, 62.56; H, 6.92; N,
4.22. N-{(10S)-10-[(400R,500R)-500-(Benzyloxy)-200,200-dimethyl-100,300-
4.52.
dioxan-400-yl]-20-hydroxyethyl}-2,2,2-trichloroacetamide 35
4.20. (4S)-4-[(40R,50R)-50-(Benzyloxy)-20,20-dimethyl-10,30-dioxan-
Using the same procedure as described for the preparation of
34, ozonolysis of compound 29 (0.68 g, 1.61 mmol) followed by
NaBH4 (0.27 g, 7.2 mmol) treatment furnished after flash chroma-
tography on silica gel (n-hexane/ethyl acetate, 1:1) 54 mg (11%)
of derivative 8 and 0.58 g (85%) of alcohol 35 which after NMR
spectroscopic analysis were immediately converted into the oxa-
zolidinone 8.
40-yl]oxazolidin-2-one 8
Using the same procedure as described for the preparation of 7,
compound 33 (120 mg, 0.354 mmol) and NaH (29 mg, 1.19 mmol,
60% dispersion in mineral oil) afforded after flash chromatography
on silica gel (n-hexane/ethyl acetate, 1:2) 101 mg (93%) of deriva-
tive 8 as a colourless oil; [
a]
23 = ꢀ7.7 (c 0.22, CHCl3). IR (neat) mmax
Modification of alcohol 35 into 8: According to the same proce-
dure described for the transformation of 34 into 7, compound 35
D
3312, 2990, 2871, 1753, 1197, 1082, 1041 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d 1.42 (s, 3H, CH3), 1.45 (s, 3H, CH3), 3.30–3.31
(0.57 g, 1.34 mmol) and DBU (20 lL, 0.13 mmol) afforded after
flash chromatography on silica gel (n-hexane/ethyl acetate, 1:1),
(m, 1H, H-50), 3.76 (dd, 1H, J4,4 = 5.9 Hz, J5 ,4 = 2.5 Hz, H-40), 3.85
0
0
0
0
0
(dd, 1H, J5,5 = 8.6 Hz, J5,4 = 5.0 Hz, H-5), 3.90 (dd, 1H, J6 ,6 = 13.0 Hz,
0.38 g (93%) of oxazolidinone 8.
J6 ,5 = 2.5 Hz, H-60), 4.03 (dd, 1H, J5,5 = 8.6 Hz, J5,4 = 5.6 Hz, H-5),
4.04–4.15 (m, 2H, H-4, H-60), 4.34 (d, 1H, JH,H = 12.1 Hz, OCH2Ph),
4.75 (d, 1H, JH,H = 12.1 Hz, OCH2Ph), 5.51 (br s, 1H, NH), 7.28–
7.40 (m, 5H, Ph); 13C NMR (100 MHz, CDCl3): d 19.3 (CH3), 28.3
(CH3), 52.9 (C-4), 60.3 (C-60), 65.8 (C-5), 69.1 (C-50), 70.5 (OCH2Ph),
72.4 (C-40), 99.2 (Cq), 128.2 (2 ꢂ CHPh), 128.3 (CHPh), 128.7
(2 ꢂ CHPh), 137.0 (Ci), 159.1 (C@O). Anal. Calcd for C16H21NO5: C,
62.53; H, 6.89; N, 4.56. Found: C, 62.55; H, 6.90; N, 4.52.
Alcohol 35: colourless oil; [a]
D
24 = ꢀ10.0 (c 0.30, CHCl3). IR
0
0
(neat) mmax 3411, 3348, 2991, 2876, 1692, 1510, 1379,
1199 cmꢀ1
;
1H NMR (400 MHz, CD3OD): d 1.36 (s, 3H, CH3), 1.45
(s, 3H, CH3), 3.37–3.38 (m, 1H, H-500), 3.52 (dd, 1H, J2 ,2 = 11.3 Hz,
0
0
J2 ,1 = 5.5 Hz, H-20), 3.56 (dd, 1H, J2 ,2 = 11.3 Hz, J2 ,1 = 5.0 Hz, H-
0
0
0
0
0
0
20), 3.95 (dd, 1H, J6 ,6 = 13.1 Hz, J6 ,5 = 1.7 Hz, H-600), 4.06–4.11
00 00
00 00
(m, 2H, H-10, H-600), 4.30 (dd, 1H, J4 ,1 = 6.6 Hz, J5 ,4 = 1.9 Hz, H-
400), 4.46 (d, 1H, JH,H = 11.9 Hz, OCH2Ph), 4.69 (d, 1H, JH,H = 11.9 Hz,
OCH2Ph), 7.25–7.38 (m, 5H, Ph); 13C NMR (100 MHz, CD3OD): d
19.4 (CH3), 29.4 (CH3), 55.8 (C-10), 60.6 (C-20), 61.7 (C-600), 70.3
(C-400), 71.6 (OCH2Ph), 72.0 (C-500), 94.2 (CCl3), 100.4 (Cq), 128.9
(CHPh), 129.4 (2 ꢂ CHPh), 129.5 (2 ꢂ CHPh), 139.4 (Ci), 163.4
(C@O). Anal. Calcd for C17H22Cl3NO5: C, 47.85; H, 5.20; N, 3.28.
Found: C, 47.82; H, 5.22; N, 3.31.
00
0
00 00
4.21. N-{(10R)-10-[(400R,500R)-500-(Benzyloxy)-200,200-dimethyl-100,300-
dioxan-400-yl]-20-hydroxyethyl}-2,2,2-trichloroacetamide 34
Ozone was introduced to a solution of 28 (0.81 g, 1.9 mmol) in
CH3OH/CH2Cl2 (72 mL, 5:1) at ꢀ78 °C for 15 min. After the com-
plete consumption of the starting material (as judged by TLC),
nitrogen was passed through the cold solution in order to remove
excess ozone. Next, NaBH4 (0.21 g, 8.6 mmol) was added portion-
wise, and the resulting mixture was stirred for 30 min at ꢀ78 °C.
After warming to room temperature (approximately 30 min), the
solvent was evaporated in vacuo, and the residue was partitioned
between EtOAc (55 mL) and a saturated NH4Cl solution (28 mL).
The aqueous solution was washed with a further portion of EtOAc
(55 mL). The combined organic layers were dried over Na2SO4,
stripped of solvent and the crude product was chromatographed
on silica gel (n-hexane/ethyl acetate, 1:1). This procedure yielded
0.2 g (35%) of derivative 7 and 0.52 g (63%) of alcohol 34 which
after NMR spectroscopic analysis was immediately converted into
oxazolidinone 7.
4.23. (4R)-4-[(10R,20R)-20-(Benzyloxy)-10,30-dihydroxypropyl]oxaz-
olidin-2-one 36
To a solution of 7 (0.51 g, 1.66 mmol) in CH3OH (32.7 mL) was
added p-TsOH (31.6 mg, 0.17 mmol). After stirring for 1.5 h at
room temperature, the solvent was removed under reduced pres-
sure, and the solid residue was washed three times with Et2O.
The obtained white crystals were dried on a pump for 10 h at room
temperature. This procedure yielded 0.39 g (87%) of compound 36;
mp 122–124 °C (recrystallized from ethyl acetate); [
a
]
D
23 = ꢀ16.7
(c 0.24, CH3OH). IR (neat) mmax 3460, 3293, 2948, 2927, 2873,
1731, 1413, 1085 cmꢀ1 1H NMR (400 MHz, CD3OD): d 3.52 (dt,
;
1H, J3 ,2 = 5.6 Hz, J3 ,2 = 5.6 Hz, J2 ,1 = 2.8 Hz, H-20), 3.72–3.77 (m,
3H, H-10, 2 ꢂ H-30), 3.99 (td, 1H, J5,4 = 8.8 Hz, J5,4 = 5.5 Hz,
0
0
0
0
0
0
Modification of alcohol 34 into 7: DBU (17 lL, 0.12 mmol) was
0
added to a solution of 34 (0.49 g, 1.15 mmol) in dry CH2Cl2
(13.7 mL) that had been pre-cooled to 0 °C. The resulting mixture
was stirred 10 min at 0 °C and then for a further 6 h at room tem-
perature. Evaporation of the solvent and chromatography of the
residue on silica gel (n-hexane/ethyl acetate, 1:2) gave 0.34 g
(95%) of compound 7.
J4,1 = 5.5 Hz, H-4), 4.35 (t, 1H, J5,4 = 8.8 Hz, J5,5 = 8.8 Hz, H-5), 4.47
(dd, 1H, J5,5 = 8.9 Hz, J5,4 = 5.7 Hz, H-5), 4.56 (d, 1H, JH,H = 11.4 Hz,
OCH2Ph), 4.73 (d, 1H, JH,H = 11.4 Hz, OCH2Ph), 7.26–7.39 (m, 5H,
13
Ph); C NMR (100 MHz, CD3OD): d 55.9 (C-4), 61.6 (C-30), 68.4
(C-5), 72.9 (C-10), 73.8 (OCH2Ph), 81.1 (C-20), 128.9 (CHPh), 129.2
(2 ꢂ CHPh), 129.5 (2 ꢂ CHPh), 139.8 (Ci), 162.5 (C@O). Anal. Calcd
for C13H17NO5: C, 58.42; H, 6.41; N, 5.24. Found: C, 58.46; H,
6.43; N, 5.21.
Alcohol 34: colourless oil; [
a
]
D
24 = ꢀ18.0 (c 0.30, CHCl3). IR
(neat) mmax 3350, 2991, 2876, 1702, 1510, 1374, 1241,
1198 cmꢀ1
;
1H NMR (400 MHz, CD3OD): d 1.35 (s, 3H, CH3), 1.47
(s, 3H, CH3), 3.51–3.52 (m, 1H, H-500), 3.60 (dd, 1H, J2 ,2 = 11.2 Hz,
4.24. (4S)-4-[(10R,20R)-20-(Benzyloxy)-10,30-dihydroxypropyl]oxaz-
olidin-2-one 37
0
0
J2 ,1 = 5.8 Hz, H-20), 3.67 (dd, 1H, J2 ,2 = 11.2 Hz, J2 ,2 = 5.3 Hz,
0
0
0
0
0
0
H-2 ), 3.97 (dd, 1H, dd, J6 ,6 = 13.3 Hz, J6 ,5 = 1.6 Hz, H-600), 4.12
0
00 00
00 00
(dd, 1H, J6 ,6 = 13.3 Hz, J6 ,5 = 1.8 Hz, H-600), 4.17–4.22 (m, 1H, H-
According to the same procedure described for the preparation
of 36, compound 8 (0.49 g, 1.59 mmol) and p-TsOH (30.3 mg,
0.16 mmol) furnished, after stirring (2 h) and flash chromatogra-
phy through a small pad of silica gel (EtOAc), 0.41 g (97%) of
00 00
00 00
10), 4.32 (dd, 1H, J4 ,1 = 7.1 Hz, J5 ,4 = 1.9 Hz, H-400), 4.41 (d, 1H,
JH,H = 10.7 Hz, OCH2Ph), 4.64 (d, 1H, JH,H = 10.7 Hz, OCH2Ph), 7.25–
7.34 (m, 3H, Ph), 7.39–7.41 (m, 2H, Ph); 13C NMR (100 MHz, CD3-
00
0
00 00

762
M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
compound 37 as a colourless oil; [
a
]
24 = +3.2 (c 0.36, CH3OH). IR
60% dispersion in mineral oil), BnBr (0.34 mL, 2.82 mmol) and
TBAI (9 mg, 0.02 mmol) afforded after flash chromatography on
D
(neat) mmax 3323, 2881, 1720, 1409, 1242, 1040 cmꢀ1
;
1H NMR
(400 MHz, CD3OD): d 3.40–3.43 (m, 1H, H-20), 3.61 (dd, 1H,
silica gel (n-hexane/ethyl acetate, 5:1) 0.8 g (98%) of derivative
J4,1 = 5.6 Hz, J2 ,1 = 3.8 Hz, H-10), 3.73 (dd, 1H, J3 ,3 = 11.6 Hz,
40 as a white foam; [
a]
22 = +13.5 (c 0.20, CHCl3). IR (neat) mmax
0
0
0
0
0
D
J3 ,2 = 4.6 Hz, H-30), 3.78 (dd, 1H, J3 ,3 = 11.6 Hz, J3 ,2 = 5.5 Hz, H-
3029, 2872, 1744, 1492, 1448, 1223, 1065 cmꢀ1
;
1H NMR
0
0
0
0
0
0
30), 3.97 (td, 1H, J5,4 = 8.9 Hz, J5,4 = 5.6 Hz, J4,1 = 5.6 Hz, H-4), 4.10–
(400 MHz, CDCl3): d 3.01 (dd, 1H, J3 ,3 = 9.1 Hz, J3 ,2 = 3.2 Hz, H-
30), 3.29–3.36 (m, 2H, H-20, H-30), 3.47 (dd, 1H, J5,4 = 9.3 Hz,
J5,4 = 5.7 Hz, H-4), 3.54 (d, 1H, JH,H = 15.4 Hz, NCH2Ph), 3.86 (t,
0
0
0
0
0
4.18 (m, 2H, 2 ꢂ H-5), 4.54 (d, 1H, JH,H = 11.6 Hz, OCH2Ph), 4.72
(d, 1H, JH,H = 11.6 Hz, OCH2Ph), 7.26–7.39 (m, 5H, Ph); 13C NMR
(100 MHz, CD3OD): d 55.9 (C-4), 61.1 (C-30), 68.5 (C-5), 73.3 (C-
10), 73.5 (OCH2Ph), 80.5 (C-20), 127.0 (CHPh), 129.5 (4 ꢂ CHPh),
139.6 (Ci), 162.5 (C@O). Anal. Calcd for C13H17NO5: C, 58.42; H,
6.41; N, 5.24. Found: C, 58.46; H, 6.44; N, 5.21.
0
0
1H, J5,5 = 9.0 Hz, J5,4 = 9.0 Hz, H-5), 3.97 (d, 1H, J2 ,1 = 4.1 Hz, H-
10), 4.31–4.34 (m, 2H, H-5, OCH2Ph), 4.46 (d, 1H, JH,H = 11.5 Hz,
OCH2Ph), 4.53 (d, 1H, JH,H = 11.5 Hz, OCH2Ph), 4.56 (d, 1H,
JH,H = 15.3 Hz, NCH2Ph), 4.60 (d, 1H, JH,H = 11.5 Hz, OCH2Ph),
7.06–7.36 (m, 30H, 6 ꢂ Ph); 13C NMR (100 MHz, CDCl3): d 45.6
(NCH2Ph), 55.9 (C-4), 62.0 (C-30), 62.9 (C-5), 72.8 (OCH2Ph), 73.8
(C-10), 74.0 (OCH2Ph), 79.1 (C-20), 87.3 (CqTr), 127.2 (3 ꢂ CHPh),
127.8 (CHPh), 127.9 (2 ꢂ CHPh), 127.9 (8 ꢂ CHPh), 128.1 (3 ꢂ CHPh),
128.3 (2 ꢂ CHPh), 128.5 (8 ꢂ CHPh), 128.7 (3 ꢂ CHPh), 135.7 (Ci),
137.6 (Ci), 137.7 (Ci), 143.6 (3 ꢂ Ci), 158.5 (C@O). Anal. Calcd for
C46H43NO5: C, 80.09; H, 6.28; N, 2.03. Found: C, 80.12; H, 6.25;
N, 2.06.
4.25. (4R)-4-[(10R,20R)-20-(Benzyloxy)-10-hydroxy-30-(trityloxy)
propyl]oxazolidin-2-one 38
To a solution of 36 (0.34 g, 1.27 mmol) in dry pyridine (12.3 mL)
were successively added trityl chloride (1.06 g, 3.82 mmol) and
DMAP (0.16 g, 1.27 mmol). The resulting mixture was stirred at
60 °C for 7 h, and then another portion of TrCl (0.35 g, 1.27 mmol)
and DMAP (0.16 g, 1.27 mmol) was added. After stirring for further
15 h at 60 °C, the mixture was allowed to cool to room tempera-
ture, and then poured into ice-water (25 ml). After extraction with
Et2O (3 ꢂ 35 mL), the combined organic layers were dried over
Na2SO4, stripped of solvent and the residue was chromatographed
on silica gel (n-hexane/ethyl acetate, 2:1). This procedure yielded
4.28. (4S)-3-Benzyl-4-[(10R,20R)-10,20-bis(benzyloxy)-30-(trityloxy)
propyl]oxazolidin-2-one 41
Using the same procedure as described for the preparation of
16, compound 39 (0.6 g, 1.18 mmol) was transformed into deriva-
tive 41 (0.77 g, 95%, white foam, n-hexane/ethyl acetate, 5:1);
0.64 g (99%) of compound 38 as a white foam; [
a]
D
24 = ꢀ33.0 (c
0.30, CHCl3). IR (neat) mmax 3291, 3029, 1739, 1448, 1217, 1062,
[a]
22 = +10.0 (c 0.24, CHCl3). IR (neat) mmax 3029, 2870, 1745,
D
1029 cmꢀ1
;
1H NMR (400 MHz, CD3OD): d 3.33–3.37 (m, 1H, H-
1447, 1225, 1065 cmꢀ1 1H NMR (400 MHz, CDCl3): d 3.28 (dd,
;
30), 3.39 (dd, 1H, J3 ,3 = 10.0 Hz, J3 ,2 = 5.5 Hz, H-30), 3.61 (dt, 1H,
1H, J3 ,3 = 9.9 Hz, J3 ,2 = 6.6 Hz, H-30), 3.33 (dd, 1H, J3 ,3 = 9.9 Hz,
0
0
0
0
0
0
0
0
0
0
J3 ,2 = 5.4 Hz, J3 ,2 = 5.4 Hz, J2 ,1 = 2.9 Hz, H-20), 3.76 (dd, 1H,
J3 ,2 = 5.2 Hz, H-30), 3.49–3.53 (m, 1H, H-20), 3.55–3.59 (1H, m, H-
4), 3.73 (t, 1H, J5,5 = 9.0 Hz, J5,4 = 9.0 Hz, H-5), 3.78 (dd, 1H,
0
0
0
0
0
0
0
0
J4,1 = 4.6 Hz, J2 ,1 = 2.8 Hz, H-10), 3.89–3.94 (m, 1H, H-4), 4.25 (t,
1H, J5,4 = 8.9 Hz, J5,5 = 8.9 Hz, H-5), 4.41 (dd, 1H, J5,5 = 8.9 Hz,
J5,4 = 5.7 Hz, H-5), 4.51 (d, 1H, JH,H = 11.5 Hz, OCH2Ph), 4.66 (d,
1H, JH,H = 11.5 Hz, OCH2Ph), 7.22–7.46 (m, 20H, 4 ꢂ Ph); 13C NMR
(100 MHz, CD3OD): d 56.0 (C-4), 64.5 (C-30), 68.1 (C-5), 73.2 (C-
10), 74.1 (OCH2Ph), 80.3 (C-20), 88.6 (CqTr), 128.3 (3 ꢂ CHPh), 128.9
(CHPh), 128.9 (6 ꢂ CHPh), 129.2 (2 ꢂ CHPh), 129.5 (2 ꢂ CHPh),
129.9 (6 ꢂ CHPh), 139.8 (Ci), 145.4 (3 ꢂ Ci), 162.4 (C@O). Anal. Calcd
for C32H31NO5: C, 75.42; H, 6.13; N, 2.75. Found: C, 75.39; H, 6.15;
N, 2.78.
0
0
0
J4,1 = 7.6 Hz, J2 ,1 = 2.5 Hz, H-10), 4.07 (d, 1H, JH,H = 14.8 Hz, NCH2-
Ph), 4.24 (dd, 1H, J5,5 = 9.0 Hz, J5,4 = 4.7 Hz, H-5), 4.32–4.38 (m,
2H, OCH2Ph), 4.45 (d, 1H, JH,H = 11.5 Hz, OCH2Ph), 4.51 (d, 1H,
JH,H = 11.6 Hz, OCH2Ph), 4.79 (d, 1H, JH,H = 14.8 Hz, NCH2Ph),
7.08–7.38 (m, 30H, 6 ꢂ Ph); 13C NMR (100 MHz, CDCl3): d 47.7
(NCH2Ph), 53.7 (C-4), 61.7 (C-30), 64.7 (C-5), 72.8 (OCH2Ph), 73.9
(OCH2Ph), 76.2 (C-20), 78.6 (C-10), 87.3 (CqTr), 127.2 (3 ꢂ CHPh),
127.8 (CHPh), 127.9 (6 ꢂ CHPh), 128.0 (CHPh), 128.0 (CHPh), 128.2
(2 ꢂ CHPh), 128.3 (4 ꢂ CHPh), 128.4 (7 ꢂ CHPh), 128.5 (3 ꢂ CHPh),
128.6 (2 ꢂ CHPh), 136.0 (Ci), 137.3 (Ci), 137.4 (Ci), 143.6 (3 ꢂ Ci),
159.0 (C@O). Anal. Calcd for C46H43NO5: C, 80.09; H, 6.28; N,
2.03. Found: C, 80.05; H, 6.33; N, 2.00.
0
0
0
4.26. (4S)-4-[(10R,20R)-20-(Benzyloxy)-10-hydroxy-30-(trityloxy)
propyl]oxazolidin-2-one 39
Using the same procedure as described for the preparation of
38, compound 37 (0.36 g, 1.35 mmol) was converted into deriva-
tive 39 (0.64 g, 93%, colourless foam, n-hexane/ethyl acetate,
4.29. (4R)-3-Benzyl-4-[(10R,20R)-10,20-bis(benzyloxy)-30-hydroxy-
propyl]oxazolidin-2-one 42
2:1); [
a
]
D
24 = ꢀ20.5 (c 0.38, CHCl3). IR (neat) mmax 3316, 3057,
p-Toluenesulfonic acid (0.19 g, 1.01 mmol) was added to a solu-
tion of 40 (0.7 g, 1.01 mmol) of CH2Cl2/CH3OH (2:1, 13 mL). The
resulting mixture was stirred for 3.5 h at room temperature before
quenching by neutralization with Et3N. The solvents were evapo-
rated in vacuo, and the residue was subjected to flash chromatog-
raphy on silica gel (n-hexane/ethyl acetate, 1:1) to afford 0.40 g
(88%) of compound 42 as white crystals; mp 134–135 °C (recrystal-
2875, 1739, 1448, 1237, 1043 cmꢀ1 1H NMR (400 MHz, CD3OD):
;
d 3.27–3.31 (m, 1H, H-30), 3.41–3.45 (m, 2H, H-20, H-30), 3.61 (dd,
1H, J4,1 = 5.4 Hz, J2 ,1 = 3.7 Hz, H-10), 3.74–3.79 (m, 1H, H-4),
4.02–4.08 (m, 2H, 2 ꢂ H-5), 4.47 (d, 1H, JH,H = 11.6 Hz, OCH2Ph),
4.63 (d, 1H, JH,H = 11.6 Hz, OCH2Ph), 7.18–7.43 (m, 20H, 4 ꢂ Ph);
13C NMR (100 MHz, CD3OD): d 55.6 (C-4), 64.2 (C-30), 68.5 (C-5),
73.6 (C-10), 73.8 (OCH2Ph), 79.8 (C-20), 88.5 (CqTr), 128.3 (4 ꢂ CHPh),
129.0 (6 ꢂ CHPh), 129.5 (2 ꢂ CHPh), 129.5 (2 ꢂ CHPh), 129.9
(6 ꢂ CHPh), 139.6 (Ci), 145.3 (3 ꢂ Ci), 162.4 (C@O). Anal. Calcd for
0
0
0
lized from n-hexane/ethyl acetate); [a]
22 = +31.7 (c 0.18, CHCl3).
D
IR (neat) mmax 3452, 3029, 2920, 1720, 1439, 1242, 1052 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 3.43–3.46 (m, 1H, H-20), 3.54–3.57
(m, 1H, H-30), 3.66 (d, 1H, JH,H = 15.3 Hz, NCH2Ph), 3.68–3.72 (m,
1H, H-30), 3.78 (dd, 1H, J5,4 = 9.4 Hz, J5,4 = 5.5 Hz, H-4), 3.84 (d,
C32H31NO5: C, 75.42; H, 6.13; N, 2.75. Found: C, 75.38; H, 6.16;
N, 2.78.
1H, J2 ,1 = 5.1 Hz, H-10), 4.15 (t, 1H, J5,5 = 9.1 Hz, J5,4 = 9.1 Hz, H-5),
4.44 (d, 1H, JH,H = 11.6 Hz, OCH2Ph), 4.48 (d, 1H, JH,H = 11.6 Hz,
OCH2Ph), 4.51–4.58 (m, 3H, H-5, OCH2Ph), 4.59 (d, 1H, JH,H = 15.2 -
Hz, NCH2Ph), 7.16–7.39 (m, 15H, 3 ꢂ Ph); 13C NMR (100 MHz,
CDCl3): d 45.7 (NCH2Ph), 55.5 (C-4), 60.1 (C-30), 63.1 (C-5), 72.5
(OCH2Ph), 73.5 (C-10), 73.6 (OCH2Ph), 78.3 (C-20), 127.8 (2 ꢂ CHPh),
0
0
4.27. (4R)-3-Benzyl-4-[(10R,20R)-10,20-bis(benzyloxy)-30-(trityloxy)
propyl]oxazolidin-2-one 40
According to the same procedure described for the preparation
of 16, compound 38 (0.60 g, 1.18 mmol), NaH (0.14 g, 5.9 mmol,

M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
763
127.9 (CHPh), 128.1 (CHPh), 128.1 (CHPh), 128.2 (2 ꢂ CHPh), 128.2
(2 ꢂ CHPh), 128.5 (2 ꢂ CHPh), 128.6 (2 ꢂ CHPh), 128.8 (2 ꢂ CHPh),
4.32. (4S)-3-Benzyl-4-[(10R,20R,30Z)-10,20-bis(benzyloxy)hexadec-
30-en-10-yl]oxazolidin-2-one (Z)-6 and (4S)-3-benzyl-4-[(10R,20R,
30E)-10,20-bis(benzyloxy)hexadec-30-en-10-yl]oxazolidin-2-one
(E)-6
135.7 (Ci), 137.4 (2
ꢂ
Ci), 158.6 (C@O). Anal. Calcd for
C27H29NO5: C, 72.46; H, 6.53; N, 3.13. Found: C, 72.42; H, 6.56;
N, 3.10.
According to the same procedure described for the preparation
of 5, compound 43 (0.35 g, 0.78 mmol) was converted into a mix-
ture of olefins 6 (0.4 g, 83%, n-hexane/ethyl acetate, 7:1). Repeated
chromatography on silica gel (n-hexane/ethyl acetate, 7:1) affor-
ded only (Z)-6 in pure form as a colourless oil.
4.30. (4S)-3-Benzyl-4-[(10R,20R)-10,20-bis(benzyloxy)-30-hydroxy-
propyl]oxazolidin-2-one 43
Using the same procedure as described for the preparation of
42, compound 41 (0.67 g, 0.97 mmol) and p-TsOH (0.18 g,
0.97 mmol) provided after flash chromatography on silica gel (n-
hexane/ethyl acetate, 1:1) 0.39 g (91%) of alcohol 43 as a colourless
Alkene (Z)-6: [
a
]
D
23 = ꢀ12.0 (c 0.20, CHCl3); IR (neat)
m
max 3030,
2922, 2852, 1750, 1454, 1417, 1228, 1062 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d 0.88 (t, 3H, J = 6.7 Hz, CH3), 1.26 (m, 20H,
0
oil; [
a
]
D
22 = +5.0 (c 0.30, CHCl3). IR (neat) mmax 3427, 3030, 2873,
10 ꢂ CH2), 1.87–2.00 (m, 2H, 2 ꢂ H-50), 3.64 (dd, 1H, J4,1 = 7.3 Hz,
1721, 1422, 1231, 1054 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.76
J2 ,1 = 3.6 Hz, H-10), 3.69–3.74 (m, 1H, H-4), 4.03 (t, 1H,
J5,5 = 9.0 Hz, J5,4 = 9.0 Hz, H-5), 4.14 (d, 1H, JH,H = 14.8 Hz, NCH2Ph),
4.26–4.33 (m, 3H, H-20, H-5, OCH2Ph), 4.48 (d, 1H, JH,H = 11.4 Hz,
OCH2Ph), 4.57 (d, 1H, JH,H = 11.7 Hz, OCH2Ph), 4.67 (d, 1H,
JH,H = 11.4 Hz, OCH2Ph), 4.81 (1H, d, JH,H = 14.8 Hz, NCH2Ph),
0
0
(m, 1H, OH), 3.50–3.58 (m, 2H, H-20, H-30), 3.66–3.78 (m, 3H, H-
10, H-30, H-4), 3.99 (t, 1H, J5,5 = 8.8 Hz, J5,4 = 8.8 Hz, H-5), 4.23 (d,
1H, d, JH,H = 14.9 Hz, NCH2Ph), 4.39 (dd, 1H, J5,5 = 9.2 Hz,
J5,4 = 4.2 Hz, H-5), 4.50 (1H, d, JH,H = 11.5 Hz, OCH2Ph), 4.52 (1H,
d, JH,H = 11.5 Hz, OCH2Ph), 4.53–4.56 (m, 1H, OCH2Ph), 4.57 (d,
1H, d, JH,H = 11.6 Hz, OCH2Ph), 4.80 (d, 1H, JH,H = 14.9 Hz, NCH2Ph),
7.14–7.39 (m, 15H, 3 ꢂ Ph); 13C NMR (100 MHz, CDCl3): d 48.0
(NCH2Ph), 54.3 (C-4), 60.4 (C-30), 64.7 (C-5), 72.8 (OCH2Ph), 73.7
(OCH2Ph), 77.3 (C-20), 79.2 (C-10), 127.8 (CHPh), 128.2 (5 ꢂ CHPh),
128.3 (CHPh), 128.3 (2 ꢂ CHPh), 128.6 (4 ꢂ CHPh), 128.7 (2 ꢂ CHPh),
136.2 (Ci), 137.1 (Ci), 137.2 (Ci), 159.1 (C@O). Anal. Calcd for
5.30–5.35 (m, 1H, H-30), 5.71 (ddd, 1H, J4 ,3 = 11.0 Hz, J5 ,4 = 7.6 Hz,
0
0
0
0
J5 ,4 = 7.6 Hz, H-40), 7.14–7.34 (m, 15H, 3 ꢂ Ph); 13C NMR
(100 MHz, CDCl3): d 14.1 (CH3), 22.7 (CH2), 28.1 (CH2), 29.3
(CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2), 29.6 (2 ꢂ CH2), 29.6
(2 ꢂ CH2), 31.9 (CH2), 47.7 (NCH2Ph), 54.2 (C-4), 64.8 (C-5), 70.2
(OCH2Ph), 73.5 (C-20), 74.1 (OCH2Ph), 82.5 (C-10), 125.5 (C-30),
127.7 (CHPh), 127.7 (CHPh), 128.0 (3 ꢂ CHPh), 128.0 (2 ꢂ CHPh),
128.4 (4 ꢂ CHPh), 128.4 (2 ꢂ CHPh), 128.6 (2 ꢂ CHPh), 136.1 (Ci),
136.4 (C-40), 137.4 (Ci), 137.8 (Ci), 158.9 (C@O). Anal. Calcd for
0
0
C27H29NO5: C, 72.46; H, 6.53; N, 3.13. Found: C, 72.41; H, 6.55;
N, 3.17.
C
40H53NO4: C, 78.52; H, 8.73; N, 2.29. Found: C, 78.56; H, 8.70;
4.31. (4R)-3-Benzyl-4-[(10R,20R,30Z)-10,20-bis(benzyloxy)hexadec-
30-en-10-yl]oxazolidin-2-one (Z)-5 and (4R)-3-benzyl-4-[(10R,20R,
30E)-10,20-bis(benzyloxy)hexadec-30-en-10-yl]oxazolidin-2-one
(E)-5
N, 2.32.
4.33. (4R)-4-[(10R,20R)-10,20-Dihydroxyhexadecyl]oxazolidin-2-
one 44
To a solution of 42 (0.35 g, 0.78 mmol) in CH3CN (4 mL) was
added IBX (0.44 g, 1.56 mmol) at room temperature. After stirring
and heating at reflux for 30 min, the solid parts were removed by
filtration, the solvent was evaporated in vacuo and the obtained
crude aldehyde was immediately used in the next reaction without
further purification.
A solution of compound 46 (62 mg, 0.14 mmol) in EtOH
(11.6 mL) was treated with 10% Pd/C (41 mg) and 35% HCl
(0.14 mL), and the reaction mixture was stirred at 60 °C under an
atmosphere of hydrogen for 4 h. The catalyst was removed by fil-
tration through a pad of Celite and the filtrate concentrated in
vacuo. Chromatography of the residue on silica gel (n-hexane/ethyl
acetate, 1:3) provided 41.3 mg (84%) of white crystalline com-
pound 44; mp 91–93 °C (recrystallized from ethyl acetate);
To a solution of 1,1,1,3,3,3-hexamethyldisilazane (0.47 mL,
2.19 mmol) in dry THF (2.3 mL) was added n-BuLi (1.37 mL,
2.19 mmol, a 1.6 M solution in n-hexane) at room temperature.
The solution of hexamethyldisilazide (LHMDS) thus generated
was treated with the known salt 96a,7 (1.31 g, 2.5 mmol), and
the resulting dark mixture was stirred for 5 min at the same tem-
perature. Next, a solution of the obtained aldehyde (0.348 g,
0.78 mmol) in dry THF (2.3 mL) was added. After stirring for
25 min, the mixture was poured into a saturated NH4Cl solution
(15 mL), and the aqueous phase was washed with EtOAc
(2 ꢂ 30 mL). The combined organic layers were dried over Na2-
SO4, the solvent removed, and the residue was purified by flash
chromatography on silica gel (n-hexane/ethyl acetate, 7:1) to
afford 0.36 g (76%) of an inseparable mixture of olefins 5 as a col-
ourless oil. Some selected data for the major (Z)-5: 1H NMR
(400 MHz, CD3OCD3): d 3.89 (dd, 1H, J5,4 = 9.4 Hz, J5,4 = 5.5 Hz,
[a]
22 = +8.7 (c 0.38, CHCl3). IR (neat) mmax 3280, 2916, 2847,
D
1772, 1719, 1469, 1245 cmꢀ1 1H NMR (400 MHz, CD3OD): d 0.90
;
(t, 3H, J = 6.9 Hz, CH3), 1.29 (m, 24H, 12 ꢂ CH2), 1.50–1.57 (m,
2H, 2 ꢂ H-03), 3.43 (dd, 1H, J4,1 = 5.6 Hz, J2 ,1 = 2.2 Hz, H-10), 3.52
0
0
0
(ddd, 1H, J3 ,2 = 7.8 Hz, J3 ,2 = 5.4 Hz, J2 ,1 = 2.2 Hz, H-20), 3.98 (td
0
0
0
0
0
0
0
1H, J5,4 = 8.6 Hz, J5,4 = 5.9 Hz, J4,1 = 5.9 Hz, H-4), 4.43 (t, 1H,
J5,5 = 8.8 Hz, J5,4 = 8.8 Hz, H-5), 4.50 (dd, 1H, J5,5 = 8.8 Hz,
J5,4 = 6.1 Hz, H-5); 13C NMR (100 MHz, CD3OD): d 12.4 (CH3), 21.7
(CH2), 24.9 (CH2), 28.4 (CH2), 28.7 (8 ꢂ CH2), 31.0 (CH2), 32.5 (C-
30), 53.9 (C-4), 66.5 (C-5), 70.4 (C-20), 73.1 (C-10), 160.5 (C@O). Anal.
Calcd for C19H37NO4: C, 66.43; H, 10.86; N, 4.08. Found: C, 66.46; H,
10.82; N, 4.11.
4.34. (4R)-3-(Cyclohexylmethyl)-4-[(10R,20R)-10,20-dihydroxyhex-
adecyl]oxazolidin-2-one 45
H-4), 3.93 (d, 1H, J2 ,1 = 5.3 Hz, H-10), 3.98 (d, 1H, JH,H = 15.4 Hz,
NCH2Ph), 4.20 (m, 1H, H-5), 4.35 (d, 1H, JH,H = 12.0 Hz, OCH2Ph),
4.37–4.40 (m, 1H, H-20), 4.48–4.58 (m, 4H, H-5, NCH2Ph, OCH2-
0
0
A solution of a mixture of alkenes 5 (77 mg, 0.13 mmol) in
EtOH (10.2 mL) was treated with 20% Pd(OH)2 (44 mg). After stir-
ring under an atmosphere of hydrogen for 3 h at 60 °C, 35% HCl
(0.13 mL) was added, and the mixture was hydrogenated for fur-
ther 22 h at the same temperature. The catalyst was filtered
through a pad of Celite, the filtrate was concentrated under
reduced pressure and the residue subjected to flash chromatogra-
0
0
Ph), 4.78 (d, 1H, JH,H = 11.5 Hz, OCH2Ph), 5.27 (dd, 1H, J4 ,3 = 11.0 -
Hz, J3 ,2 = 9.7 Hz, H-30), 5.72 (td, 1H, J4 ,3 = 11.1 Hz, J5 ,4 = 7.4 Hz,
0
0
0
0
0
0
J5 ,4 = 7.4 Hz, H-40); 13C NMR (100 MHz, CD3OCD3): d 15.4 (CH3),
29.6 (C-50), 47.4 (NCH2Ph), 57.7 (C-4), 64.4 (C-5), 71.7 (OCH2Ph),
75.5 (OCH2Ph), 76.8 (C-10), 78.9 (C-20), 128.1 (C-30), 138.1 (C-40),
160.0 (C@O).
0
0

764
M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
phy on silica gel (n-hexane/ethyl acetate, 1:2) to produce 20 mg
(46%) of compound 44 and an inseparable mixture of 45 and 46
(15 mg, 45:46 = 50:50, as determined by 1H NMR analysis). A
small amount of the mixture was re-chromatographed to give
derivative 45 in its pure form as an analytical sample. Carbamte
45: white crystals, mp 86–87 °C (recrystallized from n-hexane/
4.37. (4S)-3-(Cyclohexylmethyl)-4-[(10R,20R)-10,20-dihydroxyhex-
adecyl]oxazolidin-2-one 48
At first, 20% Pd(OH)2 (45 mg) was added to a solution of 6
(78 mg, 0.13 mmol) in EtOH (10.4 mL), and the resulting mixture
was stirred under an atmosphere of hydrogen for 22.5 h at 60 °C,
then filtered through a pad of Celite and concentrated under
reduced pressure. Purification of the residue by flash chromatogra-
phy on silica gel (n-hexane/ethyl acetate, 1:1) gave 25 mg (57%) of
compound 47 and 20 mg (36%) of derivative 48. Carbamte 48:
white crystals, mp 84–86 °C (recrystallized from n-hexane/ethyl
ethyl acetate); [
a]
D
23 = +14.0 (c 0.20, CHCl3). IR (neat) mmax 3404,
3274, 2918, 2815, 1715, 1456, 1261 cmꢀ1
;
1H NMR (400 MHz,
CDCl3): d 0.90 (t, 3H, J = 6.8 Hz, CH3), 0.95–1.02 (m, 2H, CH2),
1.29–1.74 (m, 35H, CH, 17 ꢂ CH2), 2.95 (1H, dd, JH,H = 14.2 Hz,
JH,CH = 5.2 Hz, CH2C6H11), 3.25–3.30 (m, 1H, CH2C6H11), 3.46–3.50
(m, 1H, H-20), 3.75 (m, 1H, H-10), 3.96 (ddd, 1H, J5,4 = 9.1 Hz,
acetate); [
a]
D
21 = ꢀ9.5 (c 0.38, CHCl3). IR (neat) mmax 3396, 3266,
J5,4 = 6.7 Hz, J4,1 = 4.9 Hz, H-4), 4.31 (t, 1H, J5,5 = 9.0 Hz,
2919, 2850, 1721, 1445, 1238, 1064 cmꢀ1 1H NMR (400 MHz,
;
0
J5,4 = 9.0 Hz, H-5), 4.56 (dd, 1H, J5,5 = 8.8 Hz, J5,4 = 6.5 Hz, H-5);
13C NMR (100 MHz, CDCl3): d 14.5 (CH3), 23.8 (CH3), 26.8 (CH2),
26.9 (CH2), 27.0 (CH2), 27.6 (CH2), 30.5 (CH2), 30.8 (8 ꢂ CH2),
31.5 (CH2), 32.1 (CH2), 33.1 (CH2), 34.8 (CH2), 36.8 (CH), 48.6 (CH2-
C6H11), 60.0 (C-4), 64.6 (C-5), 70.1 (C-10), 73.6 (C-20), 161.5 (C@O).
Anal. Calcd for C26H49NO4: C, 71.03; H, 11.23; N, 3.19. Found: C,
71.07; H, 11.19; N, 3.24.
CDCl3): d 0.88 (t, 3H, J = 6.8 Hz, CH3), 0.92–1.02 (m, 2H, CH2),
1.17–1.74 (m, 35H, CH, 17 ꢂ CH2), 2.40 (br s, 1H, OH), 3.05 (br s,
1H, OH), 3.11 (dd, 1H, JH,H = 13.9 Hz, JH,CH = 5.6 Hz, CH2C6H11),
3.36 (dd, 1H, JH,H = 13.9 Hz, JH,CH = 8.8 Hz, CH2C6H11), 3.52–3.61
(m, 2H, H-10, H-20), 3.95 (ddd, 1H, J5,4 = 8.6 Hz, J4,1 = 6.7 Hz,
0
J5,4 = 4.9 Hz, H-4), 4.19 (dd, 1H, J5,5 = 8.9 Hz, J5,4 = 4.8 Hz, H-5),
4.30 (t, 1H, J5,5 = 8.8 Hz, J5,4 = 8.8 Hz, H-5); 13C NMR (100 MHz,
CDCl3): d 14.1 (CH3), 22.7 (CH2), 25.6 (2 ꢂ CH2), 25.8 (CH2), 26.3
(CH2), 29.3 (CH2), 29.5 (CH2), 29.6 (CH2), 29.6 (3 ꢂ CH2), 29.7
(CH2), 29.7 (CH2), 30.3 (CH2), 30.9 (CH2), 31.9 (CH2), 34.5 (CH2),
34.5 (CH2), 35.7 (CH), 49.9 (CH2C6H11), 57.3 (C-4), 64.4 (C-5),
69.7 (C-20), 74.1 (C-10), 159.2 (C@O). Anal. Calcd for C26H49NO4:
C, 71.03; H, 11.23; N, 3.19. Found: C, 71.07; H, 11.20; N, 3.22.
4.35. (4R)-3-Benzyl-4-[(10R,20R)-10,20-dihydroxyhexadecyl]oxaz-
olidin-2-one 46
At first, 10% Pd/C (19 mg) was added to a solution of the mix-
ture of olefins 5 (0.10 g, 0.16 mmol) in EtOH (13.2 mL), and the
resulting mixture was stirred at room temperature under an
atmosphere of hydrogen for 4 h. The catalyst was removed by fil-
tration through a pad of Celite and the filtrate concentrated under
reduced pressure. Purification of the residue by flash chromatog-
raphy on silica gel (n-hexane/ethyl acetate, 2:1) gave 62 mg (87%)
of compound 46 as white crystals; mp 90–92 °C (recrystallized
4.38. (4S)-3-Benzyl-4-[(10R,20R)-10,20-dihydroxyhexadecyl]oxaz-
olidin-2-one 49
Using the same procedure as described for the preparation of
46, the mixture of alkenes 6 (103 mg, 0.17 mmol) and 10% Pd/C
(20 mg) under an atmosphere of H2 afforded after flash chromatog-
raphy on silica gel (n-hexane/ethyl acetate, 2:1) 65 mg (89%) of
crystalline compound 49, mp 95–96.5 °C (recrystallized from n-
from n-hexane/ethyl acetate); [
a]
25 = +4.4 (c 0.52, CHCl3). IR
D
(neat) mmax 3318, 2917, 2849, 2452, 1720, 1435, 1347 cmꢀ1
;
1H
NMR (400 MHz, CD3OD): d 0.89 (t, 3H, J = 6.9 Hz, CH3), 1.29 (m,
24H, 12 ꢂ CH2), 1.40–1.45 (m, 2H, 2 ꢂ H-30), 3.31 (m, 1H, H-20),
3.73–3.77 (m, 2H, H-10, H-4), 4.17 (d, 1H, JH,H = 15.4 Hz, NCH2Ph),
4.27 (t, 1H, J5,5 = 9.0 Hz, J5,4 = 9.0 Hz, H-5), 4.57 (dd, 1H,
J5,5 = 8.9 Hz, J5,4 = 6.9 Hz, H-5), 4.79–4.83 (m, 1H, NCH2Ph), 7.27–
7.38 (m, 5H, Ph); 13C NMR (100 MHz, CD3OD): d 14.5 (CH3),
23.8 (CH2), 26.7 (CH2), 30.5 (CH2), 30.7 (3 ꢂ CH2), 30.8
(5 ꢂ CH2), 33.1 (CH2), 34.7 (C-30), 46.7 (NCH2Ph), 59.3 (C-4), 64.4
(C-5), 69.9 (C-10), 73.4 (C-20), 129.0 (CHPh), 129.2 (2 ꢂ CHPh),
130.0 (2 ꢂ CHPh), 137.3 (Ci), 161.4 (C@O). Anal. Calcd for
hexane/ethyl acetate); [a]
21 = +6.7 (c 0.76, CHCl3). IR (neat) mmax
D
3444, 2916, 2848, 1712, 1442, 1364 cmꢀ1; 1H NMR (400 MHz, CD3-
OD): d 0.87 (t, 3H, J = 6.7 Hz, CH3), 1.26 (m, 24H, 12 ꢂ CH2), 1.39–
1.45 (m, 2H, 2 ꢂ H-30), 3.39–3.41 (m, 1H, H-20), 3.52 (dd, 1H,
J4,1 = 6.8 Hz, J2 ,1 = 1.6 Hz, H-10), 3.83–3.89 (m, 1H, H-4), 4.26–
4.30 (m, 2H, 2 ꢂ H-5), 4.52 (d, 1H, JH,H = 15.1 Hz, NCH2Ph), 4.73
(d, 1H, JH,H = 15.1 Hz, NCH2Ph), 7.25–7.34 (m, 5H, Ph); 13C NMR
(100 MHz, CD3OD): d 14.5 (CH3), 23.8 (CH2), 26.9 (CH2), 30.5
(CH2), 30.8 (3 ꢂ CH2), 30.9 (5 ꢂ CH2), 33.1 (CH2), 34.8 (C-30), 48.4
(NCH2Ph), 58.0 (C-4), 66.4 (C-5), 71.7 (C-20), 76.5 (C-10), 128.8
(CHPh), 129.3 (2 ꢂ CHPh), 129.8 (2 ꢂ CHPh), 138.2 (Ci), 161.8
(C@O). Anal. Calcd for C26H43NO4: C, 72.02; H, 10.00; N, 3.23.
Found: C, 71.98; H, 10.04; N, 3.20.
0
0
0
C26H43NO4: C, 72.02; H, 10.00; N, 3.23. Found: C, 72.06; H, 9.97;
N, 3.26.
4.36. (4S)-4-[(10R,20R)-10,20-Dihydroxyhexadecyl]oxazolidin-2-
one 47
4.39. (2R,3R,4R)-4-Amino-2-tetradecyltetrahydrofuran-3-ol
hydrochloride ent-1ꢁHCl
According to the same procedure described for the prepara-
tion of 44, compound 49 (65 mg, 0.15 mmol) was transformed
to derivative 47 (43 mg, 83%, n-hexane/ethyl acetate, 1:5, white
crystals); mp 105–107 °C (recrystallized from ethyl acetate);
Compound 44 (41.3 mg, 0.12 mmol) was treated with a 6 M
aqueous HCl solution (5.5 mL), and the resulting mixture was stir-
red and heated at 120 °C for 2.5 h. After cooling to room tempera-
ture, the solvent was evaporated in vacuo, and the residue was
diluted with Et2O. The solid part was filtered off and dried on a
pump for 10 h at room temperature. This procedure yielded
36.9 mg (92%) of compound ent-1ꢁHCl as a white amorphous solid;
[a]
22 = +24.0 (c 0.20, CHCl3). IR (neat) mmax 3383, 2949, 2918,
D
2847, 1745, 1709, 1469, 1429 cmꢀ1 1H NMR (400 MHz, CD3OD):
;
d 0.90 (t, 3H, J = 6.8 Hz, CH3), 1.28–1.32 (m, 24H, 12 ꢂ CH2), 1.46–
1.54 (m, 2H, 2 ꢂ H-30), 3.34–3.36 (m, 1H, H-10), 3.48–3.52 (m, 1H,
H-20), 4.03 (td, 1H, J5,4 = 9.0 Hz, J5,4 = 5.8 Hz, J4,1 = 5.8 Hz, H-4),
0
4.25 (dd, 1H, J5,5 = 8.6 Hz, J5,4 = 6.2 Hz, H-5), 4.46 (t, 1H,
J5,5 = 8.8 Hz, J5,4 = 8.8 Hz, H-5); 13C NMR (100 MHz, CD3OD): d
14.5 (CH3), 23.8 (CH2), 26.9 (CH2), 30.5 (CH2), 30.8 (3 ꢂ CH2),
30.8 (4 ꢂ CH2), 30.9 (CH2), 33.1 (CH2), 34.7 (C-30), 55.6 (C-4),
68.8 (C-5), 73.2 (C-20), 75.5 (C-10), 162.7 (C@O). Anal. Calcd for
[
a
]
27 = ꢀ2.9 (c 0.28, CH3OH), for 1ꢁHCl lit.18a {[
a]
23 = +2.6 (c 0.38,
D
D
CH3OH)}. IR (neat) mmax 3384, 2953, 2919, 2848, 1574, 1509, 1464,
1035 cmꢀ1 1H NMR (400 MHz, CD3OD): d 0.90 (t, 3H, J = 6.8 Hz,
;
CH3), 1.29 (m, 24H, 12 ꢂ CH2), 1.62–1.67 (m, 2H, 2 ꢂ H-10), 3.72
0
0
(dt, 1H, J2,1 = 6.7 Hz, J2,1 = 6.7 Hz, J3,2 = 3.4 Hz, H-2), 3.80 (dd, 1H,
J5,5 = 7.7 Hz, J5,4 = 4.2 Hz, H-5), 3.87–3.95 (m, 2H, H-4, H-5), 4.26
(m, 1H, H-3); 13C NMR (100 MHz, CD3OD): d 14.5 (CH3), 23.8
C19H37NO4: C, 66.43; H, 10.86; N, 4.08. Found: C, 66.47; H,
10.84; N, 4.05.

M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
765
(CH2), 27.3 (CH2), 29.8 (CH2), 30.5 (CH2), 30.7 (2 ꢂ CH2), 30.8
(5 ꢂ CH2), 30.9 (CH2), 33.1 (CH2), 54.4 (C-4), 69.0 (C-5), 70.9 (C-
3), 84.4 (C-2). Anal. Calcd for C18H38ClNO2: C, 64.35; H, 11.40; N,
4.17. Found: C, 64.37; H, 11.38; N, 4.19.
29.6 (3 ꢂ CH2), 29.7 (3 ꢂ CH2), 31.9 (C-10), 57.0 (C-4), 71.0 (C-5),
78.2 (C-3), 80.2 (C-2), 169.9 (C@O), 170.4 (C@O). Anal. Calcd for
C22H41NO4: C, 68.89; H, 10.77; N, 3.65. Found: C, 68.93; H, 10.75;
N, 3.68.
4.40. (2R,3R,4S)-4-Amino-2-tetradecyltetrahydrofuran-3-ol
hydrochloride ent-4ꢁHCl
Table 3
Crystal data and structure refinement parameters for compound 30
According to the same procedure described for the preparation
Compound 30
of ent-1ꢁHCl, compound 47 (39 mg, 0.114 mmol) was transformed
into ent-4ꢁHCl (38 mg, quant, white amorphous solid); [
a]
27 = +7.5
D
mmax 3379, 2950, 2916, 2848, 1594, 1529,
Empirical formula
Formula weight
Temperature, T (K)
Wavelength, k (Å)
Crystal system
C18H25NO5
335.39
173(2)
0.71073
Orthorhombic
P 212121
(c 0.52, CH3OH). IR (neat)
1470, 1146 cmꢀ1 1H NMR (400 MHz, CD3OD): d 0.85 (t, 3H,
;
J = 6.9 Hz, CH3), 1.24 (m, 24H, 12 ꢂ CH2), 1.54ꢀ1.60 (m, 2H,
2 ꢂ H-10), 3.54ꢀ3.58 (m, 2H, H-4, H-5), 3.84 (dt, 1H, J2,1 = 6.7 Hz,
0
Space group
0
J2,1 = 6.7 Hz, J3,2 = 4.2 Hz, H-2), 4.12ꢀ4.13 (m, 1H, H-3), 4.17 (dd,
Unit cell dimensions
1H, J5,5 = 11.4 Hz, J5,4 = 7.3 Hz, H-5); 13C NMR (100 MHz, CD3OD):
d 14.5 (CH3), 23.8 (CH2), 27.4 (CH2), 29.4 (CH2), 30.5 (CH2), 30.8
(3 ꢂ CH2), 30.9 (4 ꢂ CH2), 30.9 (CH2), 33.1 (CH2), 51.3 (C-4), 70.0
(C-5), 73.4 (C-3), 81.2 (C-2). Anal. Calcd for C18H38ClNO2: C,
64.35; H, 11.40; N, 4.17. Found: C, 64.39; H, 11.35; N, 4.21.
a (Å)
8.7851(3)
b (Å)
9.0007(4)
c (Å)
22.5393(7)
1782.23(11)
4
1.250
0.091
V (Å3)
Formula per unit cell, Z
Dcalcd (g/cm3)
Absorption coefficient,
F(000)
l
(mmꢀ1
)
720
4.41. (2R,3R,4R)-4-Acetamido-2-tetradecyltetrahydrofuran-3-yl
acetate 50
Crystal size (mm)
h Range for data collection (°)
0.6767 ꢂ 0.5553 ꢂ 0.1307
3.24–26.50
Index ranges
ꢀ11 6 h 6 10
ꢀ11 6 k 6 11
ꢀ28 6 l 6 28
3639(0.0215)
Analytical
To a solution of ent-1ꢁHCl (36.9 mg, 0.11 mmol) in dry pyridine
(3.5 mL) were successively added Ac2O (0.2 mL, 2.2 mmol) and
DMAP (6.7 mg, 0.05 mmol). The resulting mixture was stirred at
room temperature for 18.5 h, then concentrated and coevaporated
three times with toluene. The residue obtained was subjected to
flash chromatography on silica gel (n-hexane/ethyl acetate, 1:3)
to afford 37 mg (88%) of crystalline compound 50; mp 114–
Independent reflections (Rint)
Absorption correction
Max. and min. transmission
Refinement method
0.989 and 0.954
Full-matrix least-squares on F2
3639/0/220
Data/restraints/parameters
Goodness-of-fit on F2
1.058
Final R indices [I > 2
r
(I)]
R1 = 0.0351, wR2 = 0.0746
R1 = 0.0447, wR2 = 0.0794
0.170 and ꢀ0.192
115 °C (recrystallized from ethyl acetate); [
CHCl3). IR (neat) mmax 3210, 3065, 2992, 2946, 2914, 2849, 1747,
a]
23 = +25.0 (c 0.14,
D
R indices (all data)
Largest diff. peak and hole (e/Åꢀ3
)
1738 cmꢀ1 1H NMR (400 MHz, CDCl3): d 0.88 (t, 3H, J = 6.8 Hz,
;
CH3), 1.25 (m, 24H, 12 ꢂ CH2), 1.42–1.52 (m, 2H, 2 ꢂ H-10), 1.99
(s, 3H, CH3), 2.17 (s, 3H, CH3), 3.60 (t, 1H, J5,5 = 8.2 Hz,
0
0
J5,4 = 8.2 Hz, H-5), 3.91 (ddd, 1H, J2,1 = 8.7 Hz, J2,1 = 5.1 Hz,
J3,2 = 3.5 Hz, H-2), 4.08 (t, 1H, J5,5 = 8.4 Hz, J5,4 = 8.4 Hz, H-5),
4.78–4.86 (m, 1H, H-4), 5.38 (dd, 1H, J4,3 = 5.2 Hz, J3,2 = 3.4 Hz, H-
3), 5.61 (d, 1H, J4,NH = 8.0 Hz, NH); 13C NMR (100 MHz, CD3OD): d
14.1 (CH3), 20.7 (CH3), 22.7 (CH2), 23.2 (CH3), 26.0 (CH2), 29.3
(CH2), 29.3 (CH2), 29.5 (CH2), 29.6 (CH2), 29.6 (2 ꢂ CH2), 29.6
(2 ꢂ CH2), 29.7 (2 ꢂ CH2), 31.9 (CH2), 51.3 (C-4), 70.0 (C-5), 73.4
(C-3), 81.2 (C-2), 169.8 (C@O), 169.9 (C@O). Anal. Calcd for
Table 4
Crystal data and structure refinement parameters for compound 50
Compound 50
Empirical formula
Formula weight
Temperature, T (K)
Wavelength, k (Å)
Crystal system
C22H41NO4
383.57
173(2)
0.71073
Monoclinic
P21
C22H41NO4: C, 68.89; H, 10.77; N, 3.65. Found: C, 68.92; H, 10.74;
Space group
N, 3.68.
Unit cell dimensions
a (Å)
7.3215(3)
4.42. (2R,3R,4S)-4-Acetamido-2-tetradecyltetrahydrofuran-3-yl
acetate 51
b (Å)
9.2463(3) b = 101.205(4)°
17.2570(7)
1145.97(8)
c (Å)
V (Å3)
Formula per unit cell, Z
2
Using the same procedure as described for the preparation of
50, compound ent-4ꢁHCl (37 mg, 0.11 mmol), Ac2O (0.21 mL,
2.2 mmol) and DMAP (6.7 mg, 0.06 mmol) in pyridine (3.5 mL)
afforded after flash chromatography on silica gel (n-hexane/ethyl
acetate, 1:5) 36 mg (85%) of derivative 51 as white crystals; mp
Dcalcd (g/cm3)
1.112
0.075
424
Absorption coefficient,
F(000)
l
(mmꢀ1
)
Crystal size (mm)
h Range for data collection (°)
Index ranges
0.4 ꢂ 0.2 ꢂ 0.2
3.263–26.498
ꢀ9 6 h 6 9
71.5–73.5 °C (recrystallized from CH2Cl2/n-heptane); [
(c 0.26, CHCl3). IR (neat) mmax 3277, 2914, 2848, 1746, 1651,
1552, 1372 cmꢀ1 1H NMR (400 MHz, CDCl3): d 0.88 (t, 3H,
a]
23 = +9.9
D
ꢀ11 6 k 6 11
ꢀ21 6 l 6 21
Independent reflections (Rint
Absorption correction
Max. and min. transmission
Refinement method
)
4735 (0.0243)
Semi-empirical from equivalents
1.00000 and 0.76854
Full-matrix least-squares on F2
4735:1:251
;
J = 6.8 Hz, CH3), 1.25 (m, 24H, 12 ꢂ CH2), 1.45–1.55 (m 2H, 2 ꢂ H-
10), 1.99 (s, 3H, CH3), 2.10 (s, 3H, CH3), 3.52 (dd, 1H, J5,5 = 8.4 Hz,
0
0
J5,4 = 3.8 Hz, H-5), 3.92 (td, 1H, J2,1 = 9.0 Hz, J2,1 = 9.0 Hz,
J3,2 = 4.4 Hz, H-2), 4.23–4.30 (m, 2H, H-4, H-5), 5.15 (dd, 1H,
J3,2 = 4.5 Hz, J4,3 = 1.9 Hz, H-3), 5.88 (1H, br s, NH); 13C NMR
(100 MHz, CDCl3): d 14.1 (CH3), 20.8 (CH3), 22.7 (CH2), 23.2
(CH3), 26.2 (CH2), 28.7 (CH2), 29.3 (CH2), 29.5 (CH2), 29.5 (CH2),
Data/restraints/parameters
Goodness-of-fit on F2
1.020
Final R indices [I > 2
r
(I)]
R1 = 0.0337, wR2 = 0.0785
R1 = 0.0466, wR2 = 0.0847
0.147 and ꢀ0.0124
R indices (all data)
Largest diff. peak and hole (e/Åꢀ3
)

766
M. Martinková et al. / Tetrahedron: Asymmetry 25 (2014) 750–766
ˇ
4. (a) Enders, D.; Terteryan, V.; Palecek, J. Synthesis 2008, 2278–2282. For recent
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4.43. X-ray techniques
Single crystals of 30 and 50 suitable for X-ray diffraction were
obtained from n-hexane and ethyl acetate, respectively, by the
slow evaporation at room temperature. The intensities were col-
lected for both compounds at 173 K on an Oxford Diffraction XCal-
ibur2 CCD diffractometer using Mo K
a radiation (k = 0.71073 Å).
Selected crystallographic and other relevant data for compounds
30 and 50 are listed in Tables 3 and 4, respectively (for the crystal
data and structure refinement parameters for ent-50, see the liter-
ature18c). The structures were solved by direct methods.19 All non-
hydrogen atoms were refined anisotropically by full-matrix least
squares calculations based on F2.19 All hydrogen atoms were
included in calculated positions as riding atoms, with SHELXL9719
defaults. The PLATON20 program was used for structure analysis
and molecular and crystal structure drawings.
4.44. Crystallographic data
Complete crystallographic data for the structural analysis have
been deposited with the Cambridge Crystallographic Data Centre,
CCDC No. 877661 for compound 30 and CCDC No. 967930 for com-
pound 50. 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: depos-
it@ccdc.cam.ac.uk or via: www.ccdc.cam.ac.uk).
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Acknowledgements
The present work was supported by the Grant Agency (No. 1/
0568/12 and No. 1/0398/14) of the Ministry of Education, Slovak
Republic and Grant of P.J. Šafárik University (VVGS No. 2013-
117). We wish to thank Dr. Juraj Kuchár (P. J. Šafárik University,
Košice) for his excellent assistance in X-ray measurements.
ˇ
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