A stereoselective total synthesis of the HCl salts of mycestericins F, G and ent-F

Article abstract of DOI:10.1016/j.tetasy.2012.12.003

The total synthesis of the HCl salts of two natural sphingolipid-related amino acid derivatives, mycestericins F 4 and G 5 together with unnatural ent-4·HCl, starting from the four crucial scaffolds 6, 8, 9, 11 and utilizing the Wittig reaction to build the C₂₀ backbone, has been achieved. The selection of selective functional group interconversions accompanied with suitable protection-deprotection protocols in the coupling products 20 and 34 gave the desired structures.

Full text of DOI:10.1016/j.tetasy.2012.12.003

Tetrahedron: Asymmetry 24 (2013) 121–133
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Tetrahedron: Asymmetry
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A stereoselective total synthesis of the HCl salts of mycestericins F, G and ent-F
Miroslava Martinková a, , Jozef Gonda a, Alena Uhríková a, Jana Špaková Raschmanová a, Mária Vilková a,
⇑
Beáta Oroszová b
a Institute of Chemical Sciences, Department of Organic Chemistry, P.J. Šafárik University, Moyzesova 11, Sk-040 01 Košice, Slovak Republic
b Institute of Chemical Technology, Department of Chemistry of Natural Compounds, Technická 5, 166 28 Prague 6, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 November 2012
Accepted 13 December 2012
The total synthesis of the HCl salts of two natural sphingolipid-related amino acid derivatives, mycester-
icins F 4 and G 5 together with unnatural ent-4ꢀHCl, starting from the four crucial scaffolds 6, 8, 9, 11 and
utilizing the Wittig reaction to build the C20 backbone, has been achieved. The selection of selective func-
tional group interconversions accompanied with suitable protection–deprotection protocols in the cou-
pling products 20 and 34 gave the desired structures.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
HO
OH
OH
H2N
HO2C
Mycestericins (Fig. 1) are an interesting group of sphingolipid-
related compounds which have been isolated from the culture
broth of Mycelia sterilia (ATCC 20349) and fully characterized by
Fujita et al.1 It has been reported that the mycestericins possess
a remarkable immuno suppressive activity in terms of suppressing
the proliferation of lymphocytes in the mouse allogenic mixed
lymphocyte reaction (MLR) with IC50 values in the nanomolar
range1 and have similar potential to that of myriocin.2 Their struc-
OH
mycestericin A 1
HO
O
H2N
HO2C
ture showed the presence of the
a
-substituted serine scaffold,3
R1 R2
which constitutes the common feature of all members of the
mycestericin family.1 Both the significant biological activity and
the unique structure of the mycestericins continue to gain interest
with regard to their total synthesis.
R1 = H, R2 = OH: mycestericin D 2
R1 = OH, R2 = H: mycestericin E 3
Recently, Chida et al.4 reported the first total synthesis of
mycestericin A 1 (Fig. 1) and its 14-epimer4 from tartrates and also
realized the degradation studies of the aforementioned compounds
with the aim of confirming the proposed absolute structure of
natural mycestericin A 1.1a In their study, they employed the Over-
man rearrangement and the Negishi or Suzuki–Miyaura coupling
as the key reactions. The synthesis of mycestericin D 2 by Node
HO
O
H2N
HO2C
R2
R1
R1 = H, R2 = OH: mycestericin F 4
R1 = OH, R2 = H: mycestericin G 5
et al.5 utilized the
L-threonine aldolase-catalysed reaction of
Figure 1. Some selected structures of the mycestericins.
4-benzyloxybutanal and glycine, followed by the selective hydrox-
ymethylation of a more advanced oxazoline derivative for the
formation of a quaternary stereocentre and a Wittig reaction to
build the non-polar side chain. The total synthesis of mycestericin
E 3 has been reported by two groups. Fujita et al.6 applied the
the E-olefin. Hatakeyama et al.7 employed an asymmetric Baylis–
Hillman reaction of an achiral aldehyde and Lewis acid-promoted
cyclization of an epoxytrichloroacetimidate as the key steps.
Recently, two syntheses of mycestericin G 5 have been reported.
Kumagai and Shibasaki8 developed the catalytic asymmetric
stereoselective acylation of an oxazolidine derived from D-serine
for both; to generate the tetrasubstituted carbon and construct
a-amination of a cyclic a-alkoxycarbonyl amide to incorporate
the tetrasubstituted stereogenic centre, and utilized cross-metath-
esis to extend the side chain. They also succeeded in the total
⇑
Corresponding author. Tel.: +421 55 6228332; fax: +421 55 62342329.
E-mail address: miroslava.martinkova@upjs.sk (M. Martinková).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.12.003

122
M. Martinková et al. / Tetrahedron: Asymmetry 24 (2013) 121–133
synthesis of mycestericin
F
4
based on
a
diastereoselective
group in 12 with aqueous TFA followed by Wittig reaction
(Ph3P@CHCO2Et, benzoic acid) afforded the corresponding ,b-
reduction of the C@O group in the coupling product obtained.
Carbery et al.9 reported the synthesis of mycestericin G 5 and its
enantiomer ent-5 in which the Ireland–Claisen rearrangement of
serine-derived oxazolidine enol ether substrates for the construc-
a
unsaturated ester 13 as a single isomer in 70% overall yield from
12. Due to the overlap of the proton signals in 13 in CDCl3 and
C6D6 solutions, it was not possible to find all values of the vicinal
interaction constants and therefore ester 13 was fully character-
ized as its diacetate 14 (Ac2O, pyridine DMAP, 79%, Scheme 2).
The observed coupling constant in 14 (J = 15.6 Hz) clearly sug-
gested the trans-configuration of the double bond. Hydrogenation
of 13 under standard conditions (5% Pd/C, EtOH) removed both
the double bond and O-benzyl protecting group to produce the cor-
responding derivative 15 (71%, Scheme 2). Its oxidative fragmenta-
tion with NaIO4 in CH3OH/H2O followed by NaBH4 treatment
provided alcohol 16 in 81% yield after two steps. Analysis of its
NMR spectra led to the same problems as those for compound
13; therefore 16 was also transformed into diacetate 17 (Ac2O, pyr-
idine, DMAP). Isopropylidene protection of the 1,3-diol moiety in
16 with 2,2-dimethoxypropane in dry acetone, in the presence of
CSA gave 18 in 83% yield (Scheme 2). To continue the synthesis,
ethyl ester 18 was reduced with diisobutylaluminum hydride in
THF at ꢁ15 °C, providing the corresponding alcohol 19 (68%). Its
subsequent oxidation with IBX12 in CH3CN furnished the desired
aldehyde 6 in 80% yield.
Having established the synthetic route to the segment 6, which
possessed the required functionalities, we were in a position to
explore the Wittig reaction, which has been utilized to construct
the C20 framework in our final molecules. The coupling of aldehyde
6 with a ylide derived from the known phosphonium salt 811
produced an inseparable mixture of olefins 20 (Z:E ꢂ 3.5:1 ratio,
determined by 1H NMR analysis) in 81% yield (Scheme 3).
Debenzylation of the N-benzyloxazolidinone fragment in 20 with
Li in EtNH2/t-BuOH13 followed by reduction using Pearlman’s
catalyst14 [Pd(OH)2/C] produced the saturated derivative 21.
Protection of the carbamate nitrogen atom with a Boc group
using Boc2O and DMAP in CH3CN afforded derivative 22 in 95%
yield. Its exposure to mildly basic conditions (Cs2CO3, CH3OH)15
tion of a b,b0-dihydroxy
a-amino acid scaffold and cross-metathe-
sis to establish the requisite lipophilic chain were used. As part
of our research aimed at the construction of the naturally occurring
bioactive
a
a-substituted a-amino acids as well as the advanced
-substituted serine frameworks,10 we herein report our total
synthesis of mycestericins 4ꢀHCl, 5ꢀHCl and ent-4ꢀHCl according
to the synthetic plan outlined in Scheme 1.
2. Results and discussion
Retrosynthetically (Scheme 1), the carbon backbone of our
target molecules 4ꢀHCl, 5ꢀHCl and ent-4ꢀHCl could be disconnected
into the highly functionalized polar scaffolds, aldehydes 6 and 9,
and the lipophilic frameworks, the corresponding phosphonium
salts 811 and 11. Segments 6 and 9 could be derived from the
known chiral oxazolidinones 710f and 10,10g developed and
prepared in our laboratory. On the other hand, the hydrophobic
C14 and C16 counterparts 811 and 11 were proposed to be
synthesized from the known 14-hydroxytetradecan-7-one 25.11
The Wittig reaction of
phosphonium salts 8 and 11 was expected to complete the carbon
backbone in these structures.
6 and 9 with the corresponding
2.1. Preparation of mycestericin FꢀHCl 4ꢀHCl
At first, we began with the synthesis of aldehyde 6 (Scheme 1),
the key substrate for the Wittig reaction, starting with the 3-C-
branched xylofuranose-oxazolidinone 7,10f readily prepared on a
large scale in our laboratory. Treatment with benzyl bromide in
the presence of NaH and TBAI resulted in the formation of com-
pound 12 in 98% yield (Scheme 2). Hydrolysis of the acetonide
P+Ph3Br-
5
5
O
O
2511
811
mycestericin F.HCl 4.HCl
+
O
O
O
O
HO
O
O
HN
O
BnN
O
O
O
710f
6
O
O
O
O
O
HO
HN
O
HN
O
O
O
5.HCl
mycestericin G.HCl
and
1010g
9
ent-F.HCl ent-4.HCl
+
P+Ph3Br-
5
7
5
5
OH
O
O
O
2511
11
Scheme 1. Synthetic plan.

M. Martinková et al. / Tetrahedron: Asymmetry 24 (2013) 121–133
OR OR
123
O
O
O
O
BnO
BnN
BnO
HO
O
a
c
b
CO2Et
HN
BnN
O
O
O
O
O
O
O
710f
12
13: R = H
d
14: R = Ac, 79%
O
O
OR
OR
OH
OH
g
HO
f
e
CO2Et
CO2Et
CO2Et
BnN
BnN
O
BnN
O
O
O
O
O
18
15
16: R = H
17: R = Ac, 60%
d
O
O
O
O
OH
CHO
h
BnN
O
BnN
O
O
O
19
6
Scheme 2. Synthesis of aldehyde 6. Reagents and conditions: (a) BnBr, NaH, TBAI, DMF, 0 °C?rt, 98%; (b) (i) TFA/H2O (8:2), rt, (ii) Ph3P@CHCO2Et, CH2Cl2, PhCO2H, rt, 70%
(over 2 steps); (c) H2, 5% Pd/C, EtOH, rt, 71%; (d) Ac2O, pyridine, DMAP, rt; (e) (i) NaIO4, CH3OH/H2O (1:1), rt, (ii) NaBH4, EtOH, 0 °C?rt, 81% (over 2 steps); (f) 2,2-DMP,
acetone, CSA, rt, 83%; (g) DIBAl-H, CH2Cl2, ꢁ15 °C, 68%; (h) IBX, CH3CN, reflux, 80%.
O
O
O
O
O
O
b
a
5
O
BnN
O
O5
O5
CHO
HN
O
O5
BnN
O
21
6
O
20
O
O
O
O
O
O
5
O
c
5
O
5
e
d
BocN
O
O5
BocHN
O
O
23
22
24
HO
OH
OH
O
O
f
5
5
5
O5
ClH.H2N
COOH
BocHN
COOH
O
O
mycestericin F.HCl 4.HCl
Scheme 3. Synthesis of the HCl salt of mycesterin F 4. Reagents and conditions: (a) LHMDS, 8,11 THF, rt, 81%; (b) (i) Li, EtNH2/t-BuOH, ꢁ78 °C ? ꢁ20 °C, 77%, (ii) H2, 20%
Pd(OH)2/C, EtOH, rt, 99%; (c) Boc2O, DMAP, CH3CN, rt, 95%; (d) Cs2CO3, CH3OH, rt, 94%; (e) (i) PDC, DMF, rt, 87%, (ii) NaClO2, CH3CN/t-BuOH/2-methylbut-2-ene, 0 °C, 95%; (f)
6 M HCl, 100 °C, 87%.
resulted in the formation of the corresponding amino alcohol 23
(94%, Scheme 3). The unprotected hydroxyl group in 23 was oxi-
dized using pyridinium dichromate (PDC) in DMF to afford the
aldehyde whose immediate treatment with NaClO2 furnished ami-
no acid 24. Due to the relatively rapid decomposition of 24 in the
standard NMR solvents (CD3OD, CDCl3 and C6D6), it was not possi-
ble to correctly determine its structure, therefore further at-
tempted measurements were abandoned and this acid was
directly subjected to the deprotection step. Finally, removal of
the N-Boc, O-isopropylidene and ethyleneketal protecting groups
in 24 upon acid hydrolysis (6 M HCl) provided the desired product,
the HCl salt of mycestericin FꢀHCl 4ꢀHCl (87%, Scheme 3). The 1H
NMR data for derivative 4ꢀHCl matched the known values,8 but
the magnitude of the specific rotation was distinct from the value
published8 and in the 13C NMR spectrum we found the quaternary
carbon (C-2) at d = 71.2 ppm together with C-3 (see Section 4).

124
M. Martinková et al. / Tetrahedron: Asymmetry 24 (2013) 121–133
2.2. Preparation of ent-4ꢀHCl and mycestericin GꢀHCl 5ꢀHCl
With the C16 counterpart 11 in hand, we next carried out the
synthesis of ent-21, the common substrate for the construction of
ent-4ꢀHCl and mycestericin GꢀHCl 5ꢀHCl as shown in Scheme 5.
After several experiments, we found that the Wittig reaction of
aldehyde 9 with a non-stabilized ylide, prepared from 11, provided
a moderate yield (58%) of the coupling product 34 (isolated as an
inseparable mixture of alkenes, Z:E ꢂ 4.5:1, as determined by 1H
NMR analysis). A mixture of the geometrical isomers 34 obtained
was subjected to hydrogenation under atmospheric pressure in
EtOH containing 20% Pd(OH)2/C to furnish the saturated compound
ent-21 in 98% yield (Scheme 5). In order to obtain ent-4ꢀHCl, deriv-
ative ent-21 was converted into alcohol ent-23 (87% from ent-21)
by the same series of functional group manipulations as those used
in Scheme 4. Stepwise oxidation of ent-23 (DMSO, oxalyl chloride
followed by NaClO2) afforded acid ent-24 whose treatment with
6 M HCl led to the formation of the HCl salt of ent-4 in 64% yield
(Scheme 5). The spectroscopic and specific rotation data were in
good agreement with those reported for mycestericin FꢀHCl 4ꢀHCl.
Having successfully accomplished the synthesis of ent-4ꢀHCl,
our next task was to establish a convenient synthetic protocol for
the transformation of ent-21 to mycestericin GꢀHCl 5ꢀHCl. Thus,
the removal of the isopropylidene protection within ent-21 by acid
hydrolysis resulted in the production of diol 35 (79%, Scheme 6).
After selective tritylation of 35 (TrCl, pyridine and DMAP), the
Having successfully completed the synthesis of mycestericin
FꢀHCl, our next efforts were aimed at the preparation of ent-4ꢀHCl,
as shown in Scheme 1. Our first task was to realize the crucial cou-
pling reaction between the aldehyde 9, prepared on a large scale
from 10,10g and the C16 hydrophobic side chain 11. The formation
of the phosphonium salt 11 from the known 14-hydroxytetradec-
an-7-one 2511 proceeded without problems. Exposure of 25 to
Ac2O in pyridine produced acetate 26 in 98% yield (Scheme 4). Its
ketalization with the freshly prepared (TMSOCH2)2 in the presence
of TMSOTf16 afforded compound 27 (99%). After removal of the
acetyl group (K2CO3, CH3OH, 99%), Swern oxidation of the resultant
alcohol 286,11a led to the corresponding aldehyde 296,17 (93%,
Scheme 4). The Wittig reaction of 29 with a stabilized ylide
(Ph3P@CHCO2Et) followed by the catalytic hydrogenation of 30
(93%), resulted in the formation of saturated ester 31 in 95% yield
(Scheme 4). The LiAlH4 mediated reduction of the ester function in
31 gave alcohol 32 (98%), whose hydroxy group was replaced with
a bromide to produce 33 (86%). Finally, the resulting bromide 33
was converted into phosphonium salt 11 (76%) by treatment with
Ph3P in CH3CN at reflux in the presence of anhydrous Na2CO3. Thus,
the synthesis of 11 was accomplished in nine steps from 25 and
with 51% overall yield.
a
e
b
f
c
d
5
5
5
5
5
O
5
5
5
OAc
OH
5
5
7
OH
O
OAc
OH
O
O
O
O
O
O
26
2511
27
28
11
CO2Et
g
P+Ph3Br-
7
5
O
7
5
5
O
O
O
O
O
O
29
31
32
Scheme 4. Synthesis of phosphonium salt 11. Reagents and conditions: (a) Ac2O, pyridine, DMAP, rt, 98%; (b) (TMSOCH2)2, TMSOTf, CH2Cl2, 0 °C, 99%; (c) K2CO3, CH3OH,
0 °C?rt, 99%; (d) DMSO, (COCl)2, Et3N, CH2Cl2, ꢁ78 °C, 93%; (e) (i) Ph3P@CHCO2Et, CH2Cl2, rt, 30, 93%, (ii) H2, Pd(OH)2/C, rt, 95%; (f) LiAlH4, Et2O, 0 °C?rt, 98%; (g) (i) NBS, Ph3P,
DMF, 10 °C, 33, 86%, (ii) Ph3P, Na2CO3, CH3CN, reflux, 76%.
O
O
O
O
O
O
O
5
5
c
a
5
O
5
1010g
b
HN
O
O
O
HN
O
O
HN
O
O
O
O
ent-21
34
9
O
O
O
O
5
5
d
e
f
5
5
O
O
BocN
O
O
O
BocHN
O
HO
OH
ent-22
ent-23
O
O
OH
g
5
O
5
5
5
O
BocHN
ent-24
CO2H
ClH.H2N
CO2H
O
ent-4.HCl
Scheme 5. Synthesis of ent-4ꢀHCl. Reagents and conditions: (a) IBX, CH3CN reflux, 94%; (b) LHMDS, 11, THF, 58%; (c) H2, Pd(OH)2/C, EtOH, 98%; (d) Boc2O, DMAP, CH3CN, 94%,
rt; (e) Cs2CO3, CH3OH, 92%, rt; (f) (i) DMSO, (COCl)2, CH2Cl2, Et3N, ꢁ78 °C, 93%, (ii) NaClO2, CH3CN/t-BuOH/2-methylbut-2-ene, 0 °C?rt, 88%; (g) 6 M HCl, 100 °C, 64%.

M. Martinková et al. / Tetrahedron: Asymmetry 24 (2013) 121–133
OH OH
125
OH
OTr
b
c
a
ent-21
5
5
5
5
HN
HN
O
35
O
36
O
O
O
O
OBz OTr
OBz OH
e
d
5
5
5
5
HN
HN
O
O
O
37
39
38
O
O
O
O
OH
OBz
CO2H
f
CO2H
5
5
5
5
ClH.H2N
HN
O
O
HO
O
mycestericin G.HCl 5.HCl
Scheme 6. Synthesis of mycestericin GꢀHCl 5ꢀHCl. Reagents and conditions: (a) AcOH/H2O, 80 °C?40 °C, 79%; (b) TrCl, pyridine, DMAP, 60 °C, 88%; (c) BzCl, pyridine, DMAP,
rt, 80%; (d) p-TsOH, CH3OH/CH2Cl2, rt, 91%; (e) (i) IBX, CH3CN, reflux, (ii) NaClO2, CH3CN/t-BuOH/2-methylbut-2-ene, 0 °C?rt, 84% (over 2 steps); (f) (i) 10% NaOH, CH3OH,
80 °C, (ii) 6 M HCl, rt, 80 °C, 62%.
resulting unprotected secondary alcohol function in 36 was treated
with BzCl in pyridine to deliver the corresponding benzoate ester
37 in 80% yield (Scheme 6). Exposure of 37 to p-TsOH in CH3OH/
CH2Cl2 afforded the requisite alcohol 38 (91%) with the liberated
hydroxymethyl group, whose two-step oxidation (IBX followed
by NaClO2) furnished carboxylic acid 39 in 84% yield (Scheme 6).
The fragmentation of the carbamate ring in 39 was realized with
concomitant debenzoylation via exposure to 10% aqueous NaOH
in CH3OH at 80 °C, followed by treatment with 6 M HCl to give
the final HCl salt of mycestericin G 5 in 62% yield (Scheme 6).
The spectroscopic and specific rotation data were in excellent
agreement with those reported.8
concentrated H2SO4, with subsequent heating. 1H NMR and 13C
NMR spectra 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) or on a Varian Premium Compact 600 (599.87 MHz for 1H
and 150.84 MHz for 13C) spectrometers using TMS as the internal
reference. For 1H NMR, d are given in parts per million (ppm) rela-
tive to TMS (d = 0.0) and for 13C NMR are relative to CDCl3
(d = 77.0), CD3OD (d = 49.05) and C6D6 (d = 128.02). The multiplic-
ity of the 13C NMR signals concerning the 13C–1H coupling was
determined by the DEPT method. Chemical shifts (in ppm) and
coupling constants (in Hz) were obtained by first-order analysis;
assignments were derived from COSY and H/C correlation spectra.
Optical rotations were measured on a P-2000 Jasco polarimeter
and reported as follows: [
Melting points were recorded on a Kofler hot block and are uncor-
rected. Small quantities of reagents ( L) were measured with
appropriate syringes (Hamilton). All reactions were performed un-
der an atmosphere of nitrogen, unless otherwise noted.
a
]
(c in grams per 100 mL, solvent).
D
3. Conclusion
l
We have accomplished an efficient total synthesis of the HCl
salts of two sphingolipid-related amino acid products, mycesteri-
cin F 4 and G 5 together with unnatural ent-F ent-4ꢀHCl. For the
construction of the carbon backbone of these molecules two pairs
of important scaffolds 6/8 and 9/11 were used. Their coupling reac-
tion together with the subsequent execution of suitably selective
functional group manipulations accompanied by protection–
deprotection protocols gave the final structures.
4.2. (3aR,40S,5S,6aR)-30-Benzyl-5-[(benzyloxy)methyl]-2,2-dimeth-
yldihydro-3aH-spiro[furo[2,3-d][1,3]dioxole-6,40-oxazolidin]-
20-one 12
To a solution of 710f (5.81 g, 23.7 mmol) in DMF (58 mL), which
was pre-cooled to 0 °C, was added NaH (2.88 g, 0.12 mol, 60% dis-
persion in mineral oil) and the resulting suspension was stirred for
15 min at 0 °C. Next, BnBr (6.80 mL, 56.8 mmol) and TBAI (0.17 g,
0.46 mmol) were added at 0 °C and the mixture was stirred for an-
other 1.5 h at room temperature. The excess hydride was decom-
posed by the addition of CH3OH (1 mL), after which the mixture
was poured into ice water (58 mL) and extracted with Et2O
(3 ꢃ 180 mL). The combined organic layers were dried over
Na2SO4, the solvent was evaporated and the residue was chro-
matographed on silica gel hexane/EtOAc (3:1) to afford 9.86 g
4. Experimental
4.1. General methods
All commercial reagents were used in the highest available pur-
ity from Aldrich, Fluka, Merck or Acros Organics without further
purification. Solvents were dried and purified before use according
to standard procedures. For flash column chromatography on silica
gel, Kieselgel 60 (0.040–0.063 mm, 230–400 mesh, Merck) was
used. Solvents for flash chromatography (hexane, ethyl acetate,
methanol and dichloromethane) were distilled before using. Thin
layer chromatography was run on Merck silica gel 60 F254 analyti-
cal plates; detection was carried out with either ultraviolet light
(254 nm), or spraying with a solution of phosphomolybdic acid, a
(98%) of crystalline compound 12. Mp 97.5–98 °C, ½a D25
¼ þ32:8
ꢄ
(c 0.35, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.11 (3H, s, CH3),
1.43 (3H, s, CH3), 3.58 (1H, dd, J5,H = 6.9 Hz, JH,H = 10.0 Hz, CH2O),
3.75 (1H, dd, J5,H = 5.4 Hz, JH,H = 10.0 Hz, CH2O), 4.13 (1H, d,
JH,H = 15.8 Hz, NCH2), 4.15 (1H, d, J6a,3a = 3.8 Hz, H-3a), 4.17 (1H,
basic potassium permanganate solution or
a
solution of

126
M. Martinková et al. / Tetrahedron: Asymmetry 24 (2013) 121–133
dd, J5,H = 5.4 Hz, J5,H = 6.9 Hz, H-5), 4.22 (1H, d, J5 ,5 = 9,7 Hz, H-50),
trated in vacuo, and the residue was chromatographed on silica gel
0
0
4.53 (2H, s, OCH2Ph), 4.55 (1H, d, J5 ,5 = 9.7 Hz, H-50), 4.85 (1H, d,
JH,H = 15.8 Hz, NCH2), 5.65 (1H, d, J6a,3a = 3.8 Hz, H-6a), 7.28–7.39
(10H, m, 2 ꢃ Ph). 13C NMR (100 MHz, CDCl3): d 25.8 (CH3), 26.3
(CH3), 46.7 (NCH2), 64.5 (C-50), 66.7 (CH2O), 70.4 (C-40), 74.0
(OCH2Ph), 80.7 (C-5), 83.4 (C-3a), 104.1 (C-6a), 112.3 (C-2), 127.6
(2 ꢃ CHPh), 127.9 (2 ꢃ CHPh), 128.0 (CHPh), 128.1 (CHPh), 128.5
(2 ꢃ CHPh), 128.8 (2 ꢃ CHPh), 137.2 (Ci), 137.4 (Ci), 158.7 (C-20).
Anal. Calcd for C24H27NO6: C, 67.75; H, 6.40; N, 3.29. Found: C,
67.70; H, 6.35; N, 3.30.
hexane/EtOAc (1:2) to give 4.12 g (71%) of crystalline compound 15.
0
0
Mp 90–91 °C, ½a 2D5
ꢄ
¼ ꢁ23:1 (c 0.76, CHCl3). 1H NMR (400 MHz,
CDCl3): d 1.26 (3H, t, J = 7.2 Hz, CH3), 1.46–1.56 (1H, m, H-3),
1.84–1.91 (1H, m, H-3), 2.48 (2H, m, 2 ꢃ H-2), 2.74 (1H, br s, OH),
00 00
2.93 (1H, br s, OH), 3.10 (1H, br s, OH), 3.58 (1H, dd, J2 ,1 = 6.2 Hz,
J2 ,2 = 11.4 Hz, H-200), 3.72 (1H, dd, J2 ,1 = 3.8 Hz, J2 ,2 = 11.3 Hz,
00 00
00 00
00 00
00
00
0
H-2 ), 3.82–3.84 (1H, m, H-4), 4.01–4.04 (2H, m, H-5 , H-1 ), 4.13
(2H, q, J = 7.1 Hz, CH2), 4.18 (1H, d, J5 ,5 = 9.1 Hz, H-50), 4.73 (2H, s,
NCH2), 7.27–7.37 (3H, m, Ph), 7.46–7.48 (2H, m, Ph). 13C NMR
(100 MHz, CDCl3): d 14.1 (CH3), 25.4 (C-3), 30.9 (C-2), 46.2
(NCH2), 61.0 (CH2), 62.3 (C-200), 65.4 (C-50), 69.4 (C-40), 71.9 (C-100),
72.0 (C-4), 128.1 (2 ꢃ CHPh), 128.2 (CHPh), 129.2 (2 ꢃ CHPh), 138.3
(Ci), 159.5 (C-20), 174.5 (C-1). Anal. Calcd for C18H25NO7: C, 58.84;
H, 6.86; N, 3.81. Found: C, 58.80; H, 6.82; N, 3.85.
0
0
4.3. Ethyl (4S,2E)-4-{(40R)-30-benzyl-40-[(100S)-200-(benzyloxy)-100-
hydroxyethyl]-20-oxooxazolidin-40-yl}-4-hydroxybut-2-enoate
13
Compound 12 (9.80 g, 23.0 mmol) was treated with a mixture
of 4:1 TFA/H2O (194 mL). The resulting mixture was stirred for
3 h at room temperature and then concentrated. The residue was
subjected to flash chromatography through a short column of silica
gel hexane/EtOAc (1:1) to give 7.19 g (81%) of furanoses, which
were used immediately in the next reaction. To a solution of the
anomers obtained (7.10 g, 18.4 mmol) in dry CH2Cl2 (125 mL) were
added stabilized ylide (Ph3P@CHCO2Et, 19.3 g, 55.4 mmol) and
benzoic acid (225 mg, 1.84 mmol). After stirring for 26.5 h at room
temperature, the solvent was removed, and the residue was chro-
matographed on silica gel hexane/EtOAc (3:2) to furnish 7.30 g
4.6. Ethyl (4S)-4-[(40R)-30-benzyl-40-(hydroxymethyl)-20-oxooxaz
olidin-40-yl]-4-hydroxybutanoate 16
To a solution of 15 (4.0 g, 10.9 mmol) in CH3OH (18 mL) was
added NaIO4 (2.80 g, 13.1 mmol) in water (18 mL). After stirring
for 1 h at room temperature, CH2Cl2 (70 mL) was added, the solid
was filtered off and the filtrate was concentrated in vacuo. Chro-
matography on silica gel hexane/EtOAc (1:2) afforded 3.61 g
(99%) of aldehyde, which was used in the next reaction after a ra-
pid 1H NMR analysis. 1H NMR (400 MHz, CDCl3): d 1.26 (3H, t,
J = 7.1 Hz, CH3), 1.57 (1H, m, H-3), 1.81 (1H, m, H-3), 2.50 (2H, m,
2 ꢃ H-2), 2.81 (1H, m, OH), 4.08 (1H, m, H-4), 4.14 (2H, q,
(87%) of ester 13 as a colourless oil. ½a D25
¼ þ17:6 (c 0.30, CHCl3).
ꢄ
Anal. Calcd for C25H29NO7: C, 65.92; H, 6.42; N, 3.08. Found: C,
65.86; H, 6.49; N, 3.02. Compound 13 was fully characterized as
its diacetate 14.
J = 7.2 Hz, CH2), 4.24 (1H, d, J5 ,5 = 9.7 Hz, H-50), 4.28 (1H, d,
0
0
J5 ,5 = 9.7 Hz, H-50), 4.64 (1H, d, JH,H = 15.2 Hz, NCH2), 4.72 (1H, d,
JH,H = 15.2 Hz, NCH2), 7.32–7.40 (3H, m, Ph), 7.43–7.49 (2H, m,
Ph), 9.27 (1H, s, CHO). Anal. Calcd for C17H21NO6: C, 60.89; H,
6.31; N, 4.18. Found: C, 60.92; H, 6.39; N, 4.20.
0
0
4.4. Ethyl (4S,2E)-4-acetoxy-4-{(40R)-4-[(100S)-100-acetoxy-200-(benzyl
oxy)ethyl]-30-benzyl-20-oxooxazolidin-40-yl}but-2-enoate 14
Sodium borohydride (0.47 g, 12.4 mmol) was added to a solu-
tion of the aldehyde obtained (3.5 g, 10.4 mmol) in EtOH (47 mL)
that was pre-cooled to 0 °C. The resulting mixture was stirred for
10 min at 0 °C and then for a further 2 h at room temperature. After
neutralization with Amberlite IR-120 (H+ form), the insoluble
materials were removed by filtration, and the filtrate was concen-
trated in vacuo. The residue was chromatographed on silica gel
hexane/EtOAc (1:2) to give 2.85 g (81%) of diol 16 as white crystals.
To a solution of 13 (50 mg, 0.11 mmol) in dry pyridine (0.8 mL)
were successively added DMAP (1.33 mg, 11
lmol) and Ac2O
(16.0 L, 0.17 mmol). The resulting mixture was stirred for 18 h
l
at room temperature, then concentrated and coevaporated three
times with toluene. The residue was purified by flash chromatogra-
phy on silica gel hexane/EtOAc (2:1) to afford 47 mg (79%) of com-
pound 14 as a colourless oil. ½a D20
ꢄ
¼ þ11:9 (c 0.47, CHCl3). 1H NMR
(400 MHz, CDCl3): d 1.29 (3H, t, J = 7.1, CH3), 1.91 (3H, s, CH3), 2.10
Mp 85–86.5 °C, ½a D25
¼ ꢁ46:1 (c 0.31, CHCl3). Anal. Calcd for
ꢄ
00 00
00 00
00
(3H, s, CH3), 3.35 (1H, dd, J2 ,1 = 3.3 Hz, J2 ,2 = 11.6 Hz, H-2 ), 3.61
C17H23NO6: C, 60.52; H, 6.87; N, 4.15. Found: C, 60.59; H, 6.80; N,
00 00
00 00
00
(1H, dd, J2 ,1 = 3.1 Hz, J2 ,2 = 11.6 Hz, H-2 ), 4.09 (1H, d,
4.20. Compound 16 was fully characterized as its diacetate 17.
J5 ,5 = 10.0 Hz, H-50), 4.19 (2H, q, J = 7.1 Hz, CH2), 4.37 (1H, d,
JH,H = 11.8 Hz, OCH2Ph), 4.41 (1H, d, JH,H = 11.8 Hz, OCH2Ph), 4.47
(1H, d, JH,H = 15.6 Hz, NCH2), 4.61 (1H, d, JH,H = 15.6 Hz, NCH2),
0
0
4.7. Ethyl (4S)-4-acetoxy-4-[(40R)-40-(acetoxymethyl)-30-benzyl-
20-oxooxazolidin-40-yl]butanoate 17
4.63 (1H, d, J5 ,5 = 10.0 Hz, H-50), 5.04 (1H, t, J2 ,1 = 3.2 Hz, H-1 ),
5.48 (1H, dd, J4,2 = 1.3 Hz, J4,3 = 6.3 Hz, H-4), 5.91 (1H, dd,
J4,2 = 1.3 Hz, J3,2 = 15.6 Hz, H-2), 6.61 (1H, dd, J4,3 = 6.2 Hz,
J3,2 = 15.6 Hz, H-3), 7.23–7.38 (10H, m, 2 ꢃ Ph). 13C NMR
(100 MHz, CDCl3): d 14.1 (CH3), 20.8 (CH3), 20.9 (CH3), 46.1
(NCH2), 61.0 (CH2), 65.9 (C-50), 67.4 (C-40), 67.9 (C-200), 70.7 (C-
100), 73.7 (OCH2Ph), 74.0 (C-4), 127.3 (C-2), 127.7 (2 ꢃ CHPh),
127.9 (CHPh), 128.2 (CHPh), 128.4 (2 ꢃ CHPh), 128.6 (4 ꢃ CHPh),
136.7 (Ci), 137.2 (Ci, C-3), 158.7 (C-20), 164.6 (C-1), 168.6 (C@O),
169.2 (C@O). Anal. Calcd for C29H33NO9: C, 64.55; H, 6.16; N,
2.60. Found: C, 64.60; H, 6.10; N, 2.50.
0
0
00 00
00
According to the same procedure described for the preparation
of 14, compound 16 (0.10 g, 0.30 mmol), Ac2O (85.0
lL, 0.90 mmol)
and DMAP (7.3 mg, 60 mol) in dry pyridine (2.2 mL) yielded after
l
flash chromatography on silica gel hexane/EtOAc (1:1) 75 mg (60%)
of derivative 17 as a colourless oil. ½a D25
ꢄ
¼ ꢁ14:9 (c 0.52, CHCl3). 1H
NMR (400 MHz, CDCl3): d 1.27 (3H, t, J = 7.1 Hz, CH3), 1.67–1.78
(1H, m, H-3), 1.83 (3H, s, CH3), 1.89–1.97 (1H, m, H-3), 2.12 (3H,
s, CH3), 2.29–2.39 (2H, m, H-2), 3.82 (1H, d, JH,H = 12.1 Hz, CH2O),
3.92 (1H, d, JH,H = 12.1 Hz, CH2O), 4.12–4.18 (3H, m, CH2, H-50),
4.19 (1H, d, JH,H = 15.8 Hz, NCH2), 4.35 (1H, d, J5 ,5 = 9.2 Hz, H-50),
4.79 (1H, d, JH,H = 15.8 Hz, NCH2), 5.31 (1H, dd, J4,3 = 2.4 Hz,
J4,3 = 10.9 Hz, H-4), 7.24–7.35 (5H, m, Ph). 13C NMR (100 MHz,
CDCl3): d 14.1 (CH3), 20.3 (CH3), 20.6 (CH3), 24.1 (C-3), 29.7 (C-2),
45.5 (NCH2), 60.8 (CH2), 63.3 (CH2O), 65.3 (C-40), 66.1 (C-50), 71.2
(C-4), 127.8 (3 ꢃ CHPh), 128.5 (2 ꢃ CHPh), 137.3 (Ci), 158.4 (C-20),
169.7 (C@O), 169.9 (C@O), 172.0 (C@O). Anal. Calcd for
0
0
4.5. Ethyl (4S)-4-{(40R)-30-benzyl-40-[(100S)-100,200-dihydroxyethyl]-
20-oxooxazolidin-40-yl}-4-hydroxybutanoate 15
To a solution of ester 13 (7.20 g, 15.8 mmol) in dry EtOH
(128 mL) was added 5% Pd/C (2.22 g). The resulting mixture was
stirred under a hydrogen atmosphere for 19 h at room temperature,
then filtered through a short pad of Celite. The filtrate was concen-
C
21H27NO8: C, 59.85; H, 6.46; N, 3.32. Found: C, 59.90; H, 6.30; N,
3.35.

M. Martinková et al. / Tetrahedron: Asymmetry 24 (2013) 121–133
127
4.8. Ethyl 3-[(50R,60S)-10-benzyl-80,80-dimethyl-20-oxo-30,70,90-
1.48 (3H, s, CH3), 1.61–1.70 (1H, m, H-3), 1.95–2.02 (1H, m, H-3),
trioxa-10-azaspiro[40.50]decan-60-yl]propanoate 18
2.48–2.68 (2H, m, 2 ꢃ H-2), 3.70 (1H, d, J4 ,4 = 9.4 Hz, H-40), 3.71
0
0
(1H, d, J10 ,10 = 12.7 Hz, H-100), 3.75 (1H, d, J10 ,10 = 12.7 Hz, H-
0
0
0
0
100), 3.82 (1H, d, J6 ,3 = 2.0 Hz, J6 ,3 = 10.6 Hz, H-60), 4.06 (1H, d,
0
0
To a solution of 16 (2.7 g, 8.0 mmol) in dry acetone (10.4 mL)
were successively added 2,2-dimethoxypropane (20.8 mL,
0.17 mol) and CSA (186 mg, 0.80 mmol). After stirring at room
temperature for 4 h, the solvent was removed, and the residue
was partitioned between CH2Cl2 (100 mL) and a saturated aqueous
NaHCO3 solution (28 mL). The organic layer was dried over Na2SO4,
the solvent was evaporated in vacuo and the residue was chro-
matographed on silica gel hexane/EtOAc (2:1) providing 2.51 g
J4 ,4 = 9.4 Hz, H-40), 4.74 (1H, d, JH,H = 15.3 Hz, NCH2), 4.89 (1H, d,
JH,H = 15.3 Hz, NCH2), 7.24–7.34 (3H, m, Ph), 7.46–7.48 (2H, m,
Ph), 9.74 (1H, br s, H-1). 13C NMR (100 MHz, CDCl3): d 18.5 (CH3),
21.3 (C-3), 28.6 (CH3), 39.1 (C-2), 47.1 (NCH2), 58.1 (C-50), 65.8
(C-100), 67.3 (C-40), 75.1 (C-60), 99.5 (C-80), 127.4 (CHPh), 127.9
(2 ꢃ CHPh), 128.3 (2 ꢃ CHPh), 138.2 (Ci), 158.5 (C-20), 201.4 (C-1).
Anal. Calcd for C18H23NO5: C, 64.85; H, 6.95; N, 4.20. Found: C,
64.90; H, 6.99; N, 4.18.
0
0
(83%) of compound 18 as a colourless oil. ½a D25
ꢄ
¼ ꢁ34:3 (c 0.30,
CHCl3). 1H NMR1H NMR (400 MHz, CDCl3):
d
1.27 (3H, t,
J = 7.1 Hz, CH3), 1.41 (3H, s, CH3), 1.49 (3H, s, CH3), 1.62–1.71
(1H, m, H-3), 1.94 (1H, m, H-3), 2.47 (2H, m, 2 ꢃ H-2), 3.69 (1H,
4.11. (5R,6S)-1-Benzyl-6-[(30E)-100-(200-hexyl-100,300-dioxolan-200-yl)
dec-30-en-10-yl]-8,8-dimethyl-3,7,9-trioxa-1-azaspiro[4.5]decan-2-
one (E)-20 and (5R,6S)-1-benzyl-6-[(30Z)-100-(200-hexyl-100,300-dioxo
lan-200-yl)dec-30-en-10-yl]-8,8-dimethyl-3,7,9-trioxa-1-azaspiro [4.5]-
decan-2-one (Z)-20
d, J4 ,4 = 9.4 Hz, H-40), 3.70 (1H, J10 ,10 = 12.4 Hz, H-100), 3.74 (1H,
0
0
0
0
J10 ,10 = 12.4 Hz, H-100), 3.86 (1H, dd, J6 ,3 = 1.9 Hz, J6 ,3 = 10.6 Hz,
0
0
0
0
H-60), 4.03 (1H, d, J4 ,4 = 9.4 Hz, H-40), 4.14 (2H, q, J = 7.1 Hz, CH2),
4.74 (1H, d, JH,H = 15.3 Hz, NCH2), 4.89 (1H, d, JH,H = 15.3 Hz,
NCH2), 7.26–7.34 (3H, m, Ph), 7.46–7.48 (2H, m, Ph). 13C NMR
(100 MHz, CDCl3): d 14.2 (CH3), 18.5 (CH3), 23.8 (C-3), 28.6 (CH3),
29.2 (C-2), 47.1 (NCH2), 58.1 (CH2), 60.9 (C-100), 65.9 (C-40), 67.3
(C-50), 75.0 (C-60), 99.5 (C-80), 127.4 (2 ꢃ CHPh), 128.0 (CHPh),
128.4 (2 ꢃ CHPh), 138.3 (Ci), 158.5 (C-20), 173.1 (C-1). Anal. Calcd
for C20H27NO6: C, 63.64; H, 7.21; N, 3.71. Found: C, 63.67; H,
7.18; N, 3.75.
0
0
To
a solution of 1,1,1,3,3,3-hexamethyldisilazane (0.76 mL,
3.60 mmol) in dry THF (3.8 mL) was added n-BuLi (2.25 mL,
3.60 mmol, a 1.6 M solution in hexane) at room temperature. The
solution of lithium hexamethyldisilazide (LHMDS) thus generated
was treated with a solution of 811 (2.51 g, 4.20 mmol) in dry THF
(7.5 mL), and the resulting dark mixture was stirred for 5 min at
room temperature. Next, aldehyde 6 (0.50 g, 1.50 mmol) dissolved
in dry THF (3.8 mL) was added. After stirring for 30 min, the mix-
4.9. (5R,6S)-1-Benzyl-6-(30-hydroxypropyl)-8,8-dimethyl-3,7,9-
trioxa-1-azaspiro[4.5]decan-2-one 19
ture was poured into
a saturated aqueous NH4Cl solution
(26.7 mL) and extracted with EtOAc (3 ꢃ 45 mL). The combined or-
ganic layers were dried over Na2SO4, the solvent was removed, and
the residue was purified by flash chromatography on silica gel hex-
ane/EtOAc (3:1) to afford 0.69 g (81%) of an inseparable mixture of
alkenes 20 as a colourless oil (Z:E ꢂ 3.5:1 ratio, determined by 1H
NMR analysis). From the obtained 1H NMR spectrum of 20, we
were able to find selected data for both geometrical isomers.
Diisobutylaluminum hydride (19.1 mL, a 1.0 M solution in THF)
was added to a solution of 18 (2.40 g, 6.36 mmol) in dry CH2Cl2
(12.9 mL) that was pre-cooled to ꢁ15 °C, and the resulting mixture
was stirred at ꢁ15 °C for 2 h. After decomposition of the excess hy-
dride with CH3OH (3 mL), a saturated aqueous NH4Cl solution
(17 mL) was added and the mixture was stirred for 30 min at room
temperature. The solid parts were filtered off, the filtrate was di-
luted with EtOAc (45 mL) and the separated aqueous phase was ex-
tracted with further portions of EtOAc (2 ꢃ 45 mL). The combined
organic layers were dried over Na2SO4, the solvent was evaporated
in vacuo and the residue was chromatographed on silica gel hex-
ane/EtOAc (1:2) to afford 1.45 g (68%) of compound 19 as a colour-
Alkene (Z)-20: 1H NMR (600 MHz, C6D6):
J4,4 = 9.3 Hz, H-4), 2.94 (1H, d, J10,10 = 12.6 Hz, H-10), 3.09 (1H, d,
d 2.76 (1H, d,
0
0
J4,4 = 9.3 Hz, H-4), 3.25 (1H, d, J6,1 = 2.0 Hz, J6,1 = 10.4 Hz, H-6),
3.28 (1H, d, J10,10 = 12.6 Hz, H-10), 4.74 (1H, d, JH,H = 15.1 Hz,
NCH2), 4.99 (1H, d, JH,H = 15.1 Hz, NCH2), 5.21–5.27 (1H, m, H-30),
5.41–5.48 (1H, m, H-40).
Alkene (E)-20: 1H NMR (600 MHz, C6D6):
d 2.82 (1H, d,
less oil. ½a 2D5
ꢄ
¼ ꢁ11:8 (c 0.55, CHCl3). 1H NMR (400 MHz, CDCl3): d
J4,4 = 9.3 Hz, H-4), 2.97 (1H, d, J10,10 = 12.6 Hz, H-10), 3.12 (1H, d,
J4,4 = 9.3 Hz, H-4), 3.28–3.30 (1H, m, H-6), 3.31 (1H, d,
J10,10 = 12.6 Hz, H-10), 4.73 (1H, d, JH,H = 15.1 Hz, NCH2), 4.98 (1H,
d, JH,H = 15.1 Hz, NCH2), 5.21–5.27 (1H, m, H-30), 5.41–5.48 (1H,
m, H-40).
1.44 (3H, s, CH3), 1.46–1.51 (4H, m, CH3, H-10), 1.59–1.82 (3H, m,
H-10, 2 ꢃ H-20), 3.62–3.65 (2H, m, 2 ꢃ H-30), 3.67 (1H, d,
J4,4 = 9.4 Hz, H-4), 3.73 (2H, s, 2 ꢃ H-10), 3.79 (1H, dd,
0
0
J6,1 = 1.3 Hz, J6,1 = 10.3 Hz, H-6), 3.94 (1H, d, J4,4 = 9.4 Hz, H-4),
4.77 (1H, d, JH,H = 15.4 Hz, NCH2), 4.87 (1H, d, JH,H = 15.4 Hz,
NCH2), 7.24–7.33 (3H, m, Ph), 7.45–7.47 (2H, m, Ph). 13C NMR
(100 MHz, CDCl3): d 18.6 (CH3), 25.0 (C-10), 28.5 (C-20), 28.6
(CH3), 47.1 (NCH2), 58.2 (C-5), 62.0 (C-30), 65.8 (C-10), 67.4 (C-4),
76.3 (C-6), 99.4 (C-8), 127.3 (CHPh), 127.9 (2 ꢃ CHPh), 128.3
(2 ꢃ CHPh), 138.3 (Ci), 158.6 (C-2). Anal. Calcd for C18H25NO5: C,
64.46; H, 7.51; N, 4.18. Found: C, 64.50; H, 7.49; N, 4.20.
4.12. (5R,6S)-6-[100-(200-Hexyl-100,300-dioxolan-200-yl)decyl]-8,8-
dimethyl-3,7,9-trioxa-1-azaspiro[4.5]decan-2-one 21
To a solution of 20 (0.69 g, 1.21 mmol) in t-BuOH (6.0 mL)
which was pre-cooled to 0 °C was added liquid EtNH2 (28.3 mL).
Next, several pieces of lithium (0.18 g) were added at ꢁ78 °C to this
solution. The resulting mixture was stirred for 15 min at ꢁ78 °C
and then for a further 22 h at ꢁ20 °C. After this period, another
portion of EtNH2 (9.4 mL) and Li (0.18 g) was added at ꢁ78 °C
and the mixture stirred for a further 22 h at ꢁ20 °C. The reaction
was then quenched with a saturated aqueous NH4Cl solution
(40 mL) and the mixture was extracted with CH2Cl2 (2 ꢃ 50 mL).
The combined organic layers were dried over Na2SO4, the solvent
removed and the residue was chromatographed on silica gel hex-
ane/EtOAc (2:1) to afford 0.45 g (77%) of an inseparable mixture
of olefins as a colourless oil, which was used immediately in the
next step.
4.10. 3-[(50R,60S)-10-Benzyl-80,80-dimethyl-20-oxo-30,70,90-trioxa-
10-azaspiro[40.50]decan-60-yl]propanal 6
To a stirred solution of alcohol 19 (1.40 g, 4.17 mmol) in CH3CN
(37.5 mL) was added IBX (1.75 g, 6.25 mmol) at room temperature.
After being heated at reflux for 30 min, the reaction mixture was
allowed to cool to room temperature, the solid parts were filtered
off, and the filtrate was evaporated in vacuo. The residue was puri-
fied by flash chromatography on silica gel hexane/EtOAc (2:1) to
give 1.39 g (80%) of aldehyde 6 as a colourless oil. ½a D25
¼ þ61:6
ꢄ
(c 0.35, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.39 (3H, s, CH3),

128
M. Martinková et al. / Tetrahedron: Asymmetry 24 (2013) 121–133
To a solution of the alkenes obtained (0.45 g, 0.93 mmol) in dry
(C@O). Anal. Calcd for C31H59NO7: C, 66.75; H, 10.66; N, 2.51.
EtOH (10.5 mL) was added 20% Pd(OH)2/C (32 mg). The resulting
mixture was stirred for 2 h under an atmosphere of hydrogen
and then filtered through a pad of Celite. The solvent was removed
under reduced pressure, and the residue was chromatographed on
silica gel hexane/EtOAc (2:1) to afford 447 mg (99%) of compound
Found: C, 66.80; H, 10.61; N, 2.56.
4.15. (4S,5S)-5-[(tert-Butoxycarbonyl)amino]-4-[100-(200-hexyl-
100,300-dioxolan-200-yl)decyl]-2,2-dimethyl-1,3-dioxane-5-carbox-
ylic acid 24
21 as a colourless oil. ½a D22
ꢄ
¼ ꢁ16:2 (c 0.52, CHCl3). 1H NMR
(400 MHz, CDCl3): d 0.88 (3H, t, J = 6.8 Hz, CH3), 1.27–1.36 (23H,
m, 11 ꢃ CH2, CH2), 1.41 (3H, s, CH3), 1.44 (3H, s, CH3), 1.49–1.53
(3H, m, CH2, CH2), 1.57–1.61 (4H, m, 2 ꢃ CH2), 3.64–3.67 (1H, m,
H-6), 3.73 (1H, d, J10,10 = 11.8 Hz, H-10), 3.82 (1H, d, J4,4 = 9.3 Hz,
H-4), 3.83 (1H, d, J10,10 = 11.8 Hz, H-10), 3.93 (4H, s, 2 ꢃ H-400,
2 ꢃ H-500), 4.03 (1H, d, J4,4 = 9.3 Hz, H-4), 5.84–5.86 (1H, m, NH).
13C NMR (100 MHz, CDCl3): d 14.1 (C-6000), 18.6 (CH3), 22.6 (CH2),
23.8 (CH2), 23.8 (CH2), 25.3 (CH2), 28.3 (CH2), 29.0 (CH2), 29.4
(CH3), 29.5 (3 ꢃ CH2), 29.6 (2 ꢃ CH2), 29.9 (CH2), 31.8 (CH2), 37.1
(C-100, C-1000), 57.0 (C-5), 64.8 (C-400, C-500), 67.8 (C-4), 67.9 (C-10),
74.0 (C-6), 99.4 (C-8), 111.9 (C-200), 157.9 (C-2). Anal. Calcd for
C27H49NO6: C, 67.05; H, 10.21; N, 2.90. Found: C, 67.09; H, 10.25;
N, 2.94.
To a solution of 23 (0.16 g, 0.29 mmol) in dry DMF (2.7 mL) was
added PDC (1.69 g, 4.49 mmol). After stirring at room temperature
for 2 h, the reaction mixture was poured into ice water (22 mL) and
extracted with Et2O (3 ꢃ 45 mL). The combined organic layers
were dried over Na2SO4, the solvent was removed, and the residue
was chromatographed through a short column of silica gel hexane/
EtOAc (9:1) to afford 138 mg (87%) of an aldehyde as a colourless
oil which was used immediately in the next step. A solution of Na-
ClO2 (0.20 g, 2.21 mmol) and NaH2PO4ꢀ2H2O (0.25 g, 1.60 mmol) in
water (1.1 mL) was added to the aldehyde obtained (0.13 g,
0.23 mmol) in a 4:4:1 mixture of CH3CN/t-BuOH/2-methylbut-2-
ene (5.1 mL) at 0 °C. After being stirred at 0 °C for 30 min, the
resulting mixture was poured into a saturated aqueous NaCl solu-
tion (3 mL) and extracted with EtOAc (2 ꢃ 10 mL). The combined
organic layers were dried over Na2SO4, the solvent was evaporated
in vacuo and the residue was purified by flash chromatography on
silica gel hexane/EtOAc (9:1) providing 127 mg (95%) of compound
24 as a colourless oil which was used in the next step after a rapid
1H NMR analysis. 1H NMR (400 MHz, CD3OD): d 0.87 (3H, t,
J = 7.0 Hz, CH3), 1.25 (26H, m, 13 ꢃ CH2), 1.35 (3H, s, CH3), 1.41
(9H, s, 3 ꢃ CH3), 1.43 (3H, s, CH3), 1.51–1.55 (4H, m, 2 ꢃ CH2),
3.87 (4H, s, 2 ꢃ H-400, 2 ꢃ H-500), 4.03 (1H, m, H-4), 4.10 (1H, d,
J6,6 = 11.9 Hz, H-6), 4.22 (1H, d, J6,6 = 11.9 Hz, H-6).
4.13. tert-Butyl (5R,6S)-6-[100-(200-hexyl-100,300-dioxolan-200-yl)decyl
]-8,8-dimethyl-2-oxo-3,7,9-trioxa-1-azaspiro[4.5]decan-1-carboxy-
late 22
To a solution of 21 (0.17 g, 0.35 mmol) in dry CH3CN (1 mL)
were successively added Boc2O (0.15 g, 0.69 mmol) and DMAP
(42.8 mg, 0.35 mmol). The resulting mixture was stirred for
30 min at room temperature and then concentrated in vacuo. The
residue was purified by flash chromatography on silica gel hex-
ane/EtOAc (3:1) to provide 195 mg (95%) of compound 22 as a col-
ourless oil. ½a 2D1
ꢄ
¼ ꢁ7:9 (c 0.62, CHCl3). 1H NMR (400 MHz, CDCl3):
4.16. (2S,3S)-2-Amino-3-hydroxy-2-(hydroxymethyl)-14-oxoico
sanoic acid hydrochloride 4ꢀHCl
d 0.87 (3H, t, J = 6.7 Hz, CH3), 1.25 (24H, m, 12 ꢃ CH2), 1.30 (3H, s,
CH3), 1.43 (3H, s, CH3), 1.52–1.65 (15H, m, 3 ꢃ CH3, 3 ꢃ CH2), 3.46–
3.48 (1H, m, H-6), 3.51 (1H, d, J10,10 = 11.1 Hz, H-10), 3.79 (1H, dd,
J10,4 = 1.5 Hz, J4,4 = 9.1 Hz, H-4), 3.91 (4H, s, 2 ꢃ H-400, 2 ꢃ H-500),
4.29 (1H, dd, J10,4 = 1.5 Hz, J10,10 = 11.0 Hz, H-10), 4.36 (1H, d,
Compound 24 (17 mg, 29.7 lmol) was treated with a 6 M aque-
ous HCl solution (1.4 mL), and the resulting mixture was stirred
and heated at 100 °C for 4 h. Removal of the solvent gave a residue
which was diluted with Et2O/hexane (1:5). The solid was filtered
off, washed several times with Et2O and dried on a pump for
10 h at room temperature. This procedure yielded 11 mg (87%) of
13
J4,4 = 9.1 Hz, H-4). C NMR (100 MHz, CDCl3): d 14.1 (C-6000), 22.6
(CH2), 23.0 (CH3), 23.8 (CH2), 23.8 (CH2), 24.3 (CH3), 26.3 (CH2),
27.4 (CH2), 28.0 (3 ꢃ CH3), 29.3 (CH2), 29.4 (CH2), 29.5 (2 ꢃ CH2),
29.5 (CH2), 29.6 (CH2), 29.9 (CH2), 31.8 (CH2), 37.1 (C-100, C-1000),
62.0 (C-10), 64.8 (C-400, C-500), 65.4 (C-5), 69.8 (C-4), 73.0 (C-6),
84.5 (Cq), 101.7 (C-8), 111.8 (C-200), 149.6 (C@O), 152.7 (C-2). Anal.
Calcd for C32H57NO8: C, 65.83; H, 9.84; N, 2.40. Found: C, 65.87; H,
9.88; N, 2.44.
4ꢀHCl as a white amorphous solid. ½a D23
¼ ꢁ3:5 (c 0.18, CH3OH).
ꢄ
1H NMR (600 MHz, CD3OD): d 0.88 (3H, t, J = 6.9 Hz, CH3), 1.24–
1.32 (20H, m, 10 ꢃ CH2), 1.48–1.54 (6H, m, 3 ꢃ CH2), 2.42 (4H, t,
J = 7.3 Hz, 2 ꢃ H-13, 2 ꢃ H-15), 3.80 (1H, m, H-3), 3.86 (1H, d,
JH,H = 11.0 Hz, CH2OH ), 4.00 (1H, d, JH,H = 11.0 Hz, CH2OH). 13C
0
NMR (150 MHz, CD3OD):
d 14.4 (C-20), 23.6 (CH2), 24.9
4.14. tert-Butyl {(4S,5S)-4-[100-(200-hexyl-100,300-dioxolan-200-yl)decyl
]-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl}carbamate 23
(3 ꢃ CH2), 30.0 (2 ꢃ CH2), 30.3 (2 ꢃ CH2), 30.6 (3 ꢃ CH2), 30.7
(CH2), 32.8 (CH2), 43.5 (C-13, C-15), 64.4 (CH2OH), 71.2 (C-2, C-
3), 214.4 (C-14), not seen (COOH). Anal. Calcd for C21H42ClNO5: C,
59.48; H, 9.98; N, 3.30. Found: C, 59.54; H, 9.92; N, 3.37.
To a solution of 22 (0.19 g, 0.32 mmol) in dry CH3OH (4.4 mL)
was added Cs2CO3 (32.6 mg, 0.10 mmol). After being stirred at
room temperature for 1.5 h, the solvent was removed, and the res-
idue was subjected to flash chromatography through a short col-
umn of silica gel hexane/EtOAc (5:1) to give 0.17 g (94%) of
4.17. 8-Oxotetradecyl acetate 26
To a solution of 2511 (5.0 g, 21.9 mmol) in dry pyridine (163 mL)
were successively added Ac2O (3.10 mL, 32.8 mmol) and DMAP
(0.27 g, 2.21 mmol). After stirring at room temperature for
45 min, the resulting mixture was poured into ice water
(500 mL) and extracted with Et2O (3 ꢃ 200 mL). The combined or-
ganic layers were dried over Na2SO4, the solvent was removed and
the residue was subjected to flash chromatography on silica gel
hexane/EtOAc (9:1) to give 5.8 g (98%) of compound 26 as a colour-
less oil. 1H NMR (400 MHz, CDCl3): d 0.83 (3H, t, J = 6.9 Hz, CH3),
1.23–1.30 (12H, m, 6 ꢃ CH2), 1.50–1.60 (6H, m, 3 ꢃ CH2), 2.00
(3H, s, CH3CO), 2.32–2.36 (4H, m, 2 ꢃ H-7, 2 ꢃ H-9), 4.00 (2H, t,
J = 6.7 Hz, 2 ꢃ H-1). 13C NMR (100 MHz, CDCl3): d 13.9 (C-14),
20.9 (CH3CO), 22.4 (CH2), 23.6 (CH2), 23.7 (CH2), 25.6 (CH2), 28.4
compound 23 as a colourless oil. ½a D22
ꢄ
¼ þ22:2 (c 0.52, CHCl3). 1H
NMR (400 MHz, CDCl3): d 0.88 (3H, t, J = 6.8 Hz, CH3), 1.26–1.39
(26H, m, 13 ꢃ CH2), 1.43 (6H, br s, 2 ꢃ CH3), 1.46 (9H, s, 3 ꢃ CH3),
1.57–1.60 (4H, m, 2 ꢃ CH2), 3.40–3.48 (1H, m, CH2OH), 3.64–3.67
(1H, m, H-4), 3.77 (1H, d, J6,6 = 12.3 Hz, H-6), 3.92–3.97 (5H, m,
2 ꢃ H-400, 2 ꢃ H-500, CH2OH), 4.00 (1H, d, J6,6 = 12.3 Hz, H-6), 4.79
(1H, dd, JH,OH = 2.9 Hz, JH,OH = 11.0 Hz, OH), 5.36 (1H, br s, NH).
13C NMR (100 MHz, CDCl3): d 14.1 (C-6000), 18.6 (CH3), 22.6 (CH2),
23.8 (CH2), 23.8 (2 ꢃ CH2), 25.5 (CH2), 28.3 (3 ꢃ CH3), 28.7 (CH2),
29.3 (CH3), 29.4 (CH2), 29.5 (2 ꢃ CH2), 29.6 (2 ꢃ CH2), 29.9 (CH2),
31.8 (CH2), 37.1 (C-100, C-1000), 55.7 (C-5), 64.8 (C-400, C-500, CH2OH),
65.0 (C-6), 74.7 (C-4), 80.3 (Cq), 98.8 (C-2), 111.9 (C-200), 157.2

M. Martinková et al. / Tetrahedron: Asymmetry 24 (2013) 121–133
129
(CH2), 28.8 (CH2), 28.9 (CH2), 29.0 (CH2), 31.5 (CH2), 42.6 (C-7 or C-
9), 42.7 (C-7 or C-9), 64.4 (C-1), 171.1 (CH3CO), 211.4 (C-8). Anal.
Calcd for C16H30O3: C, 71.07; H, 11.18. Found: C, 71.01; H, 11.12.
4.21. Ethyl (2Z)-9-(20-hexyl-10,30-dioxolan-20-yl)non-2-enoate
(Z)-30 and ethyl (2E)-9-(20-hexyl-10,30-dioxolan-20-yl)non-2-
enoate (E)-30
4.18. 7-(20-Hexyl-10,30-dioxolan-20-yl)heptyl acetate 27
To a solution of 29 (5.1 g, 18.9 mmol) in dry CH2Cl2 (71 mL) was
added stabilized ylide (Ph3P@CHCO2Et, 7.87 g, 22.6 mmol). The
mixture was stirred at room temperature for 30 min, and then fur-
ther portions of ylide (2 ꢃ 2 g, 5.74 mmol) were added at 30 min
intervals. One hour after the last addition, the solvent was evapo-
rated in vacuo, and the residue was chromatographed on silica gel
hexane/EtOAc (20:1) to afford 5.97 g (93%) of a mixture of esters 30
as a colourless oil.
To a solution of 26 (5.70 g, 21.1 mmol) in dry CH2Cl2 (135 mL)
which was pre-cooled to 0 °C were successively added
(TMSOCH2)2 (19.6 g, 94.9 mmol) and TMSOTf (1.02 mL,
5.28 mmol). After being stirred at 0 °C for 2 h, Et3N (34.6 mL)
was added, and the resulting mixture was poured into a saturated
aqueous NaHCO3 solution (100 mL) and extracted with CH2Cl2
(2 ꢃ 250 mL). The combined organic layers were dried over
Na2SO4, the solvent was evaporated in vacuo and the residue
was chromatographed on silica gel hexane/EtOAc (9:1) to afford
A small amount of the mixture of 30 was separated by column
chromatography on silica gel hexane/EtOAc (20:1) to provide each
isomer in pure form.
6.56 g (99%) of compound 27 as
a
colourless oil. 1H NMR
Ester (Z)-30: 1H NMR (400 MHz, CDCl3): d 0.88 (3H, t, J = 6.8 Hz,
CH3), 1.26–1.36 (19H, m, 8 ꢃ CH2, CH3), 1.56–1.60 (4H, m,
2 ꢃ CH2), 2.64 (2H, m, 2 ꢃ H-4), 3.92 (4H, s, 2 ꢃ H-40, 2 ꢃ H-50),
4.16 (2H, q, J = 7.2 Hz, CH2), 5.75 (1H, td, J4,2 = 1.7 Hz, J4,2 = 1.7 Hz,
J3,2 = 11.5 Hz, H-2), 6.21 (1H, td, J4,3 = 7.5 Hz, J4,3 = 7.5 Hz,
J3,2 = 11.5 Hz, H-3). 13C NMR (100 MHz, CDCl3): d 14.1 (CH3), 14.3
(CH3), 22.6 (CH2), 23.8 (CH2), 23.8 (CH2), 29.0 (2 ꢃ CH2), 29.3
(CH2), 29.6 (CH2), 29.7 (CH2), 31.8 (CH2), 37.1 (C-9, C-100), 59.7
(CH2), 64.9 (C-40, C-50), 110.0 (C-20), 111.9 (C-3), 150.6 (C-2),
166.5 (C-1). Anal. Calcd for C20H36O4: C, 70.55; H, 10.66. Found:
C, 70.50; H, 10.70.
(400 MHz, CDCl3): d 0.86 (3H, t, J = 6.6 Hz, CH3), 1.26–1.30 (16H,
m, 8 ꢃ CH2), 1.55–1.62 (6H, m, 3 ꢃ CH2), 2.03 (3H, s, CH3CO),
3.91 (4H, s, 2 ꢃ H-40, 2 ꢃ H-50), 4.03 (2H, t, J = 6.8 Hz, 2 ꢃ H-1).
13C NMR (100 MHz, CDCl3): d 14.1 (C-600), 21.0 (CH3CO), 22.6
(CH2), 23.7 (CH2), 23.8 (CH2), 25.8 (CH2), 28.5 (CH2), 29.2 (CH2),
29.6 (CH2), 29.8 (CH2), 31.8 (CH2), 37.1 (C-7, C-100), 64.6 (C-1),
64.8 (H-40, H-50), 111.8 (C-20), 171.2 (CH3CO). Anal. Calcd for
C18H34O4: C, 68.75; H, 10.90. Found: C, 68.71; H, 10.94.
4.19. 7-(20-Hexyl-10,30-dioxolan-20-yl)heptan-1-ol 286,11a
Ester (E)-30: 1H NMR (400 MHz, CDCl3): d 0.86–0.90 (3H, m,
CH3), 1.27–1.31 (19H, m, 8 ꢃ CH2, CH3), 1.57–1.60 (4H, m,
2 ꢃ CH2), 2.16–2.22 (2H, m, 2 ꢃ H-4), 3.92 (4H, s, 2 ꢃ H-40, 2 ꢃ H-
50), 4.18 (2H, q, J = 7.2 Hz, CH2), 5.81 (1H, td, J4,2 = 1.5 Hz,
J4,2 = 1.5 Hz, J3,2 = 15.6 Hz, H-2), 6.96 (1H, td, J4,3 = 6.9 Hz,
J4,3 = 6.9 Hz, J3,2 = 15.6 Hz, H-3). 13C NMR (100 MHz, CDCl3): d
14.1 (CH3), 14.2 (CH3), 22.6 (CH2), 23.7 (CH2), 23.8 (CH2), 27.9
(CH2), 29.1 (CH2), 29.6 (CH2), 29.6 (CH2), 31.8 (CH2), 32.1 (CH2),
37.0 (C-9 or C-100), 37.1 (C-9 or C-100), 60.1 (CH2), 64.9 (C-40, C-50),
111.8 (C-20), 121.2 (C-3), 149.3 (C-2), 166.7 (C-1). Anal. Calcd for
To a solution of 27 (6.50 g, 20.7 mmol) in CH3OH (228 mL)
which was pre-cooled to 0 °C was added K2CO3 (1.43 g,
10.3 mmol). The mixture was stirred for 10 min at 0 °C and then
for a further 3 h at room temperature. Next, Et2O (650 mL) and so-
lid Na2SO4 were added and the resulting suspension was stirred
vigorously for 15 min. The insoluble parts were removed by filtra-
tion, the filtrate was concentrated and the residue was chromato-
graphed on silica gel hexane/EtOAc (2:1) to afford 5.58 g (99%) of
compound 28 as a colourless oil. 1H NMR (400 MHz, CDCl3): d
0.86 (3H, t, J = 6.8 Hz, CH3), 1.26–1.31 (16H, m, 8 ꢃ CH2), 1.52–
1.59 (6H, m, 3 ꢃ CH2), 3.61 (2H, t, J = 6.7 Hz, 2 ꢃ H-1), 3.91 (4H, s,
C20H36O4: C, 70.55; H, 10.66. Found: C, 70.59; H, 10.62.
13
2 ꢃ H-40, 2 ꢃ H-50). C NMR (100 MHz, CDCl3): d 14.0 (C-600), 22.6
4.22. Ethyl 9-(20-hexyl-10,30-dioxolan-20-yl)nonanoate 31
(CH2), 23.7 (CH2), 23.8 (CH2), 25.6 (CH2), 29.3 (CH2), 29.6 (CH2),
29.8 (CH2), 31.8 (CH2), 31.7 (CH2), 37.0 (C-7 or C-100), 37.1 (C-7 or
C-100), 62.9 (C-1), 64.8 (C-40, C-50), 111.8 (C-20). Anal. Calcd for
C16H32O3: C, 70.54; H, 11.84. Found: C, 70.50; H, 11.88.
To a solution of 30 (5.90 g, 17.3 mmol) in dry EtOH (187 mL)
was added 20% Pd(OH)2/C (0.59 g). The resulting mixture was stir-
red under an atmosphere of hydrogen for 1 h, and then filtered
through a pad of Celite. Evaporation of the solvent and chromatog-
raphy of the residue on silica gel hexane/EtOAc (20:1) gave 5.64 g
(95%) of compound 31 as a colourless oil. 1H NMR (400 MHz,
CDCl3): d 0.84 (3H, t, J = 6.7 Hz, CH3), 1.19–1.31 (21H, m, 9 ꢃ CH2,
CH3), 1.52–1.59 (6H, m, 3 ꢃ CH2), 2.24 (2H, t, J = 7.5 Hz, 2 ꢃ H-2),
3.88 (4H, s, 2 ꢃ H-40, 2 ꢃ H-50), 4.08 (2H, q, J = 7.1 Hz, CH2). 13C
NMR (100 MHz, CDCl3): d 14.0 (CH3), 14.2 (CH3), 22.5 (CH2), 23.7
(2 ꢃ CH2), 24.9 (CH2), 29.0 (CH2), 29.1 (CH2), 29.3 (CH2), 29.5
(CH2), 29.8 (CH2), 31.8 (CH2), 34.3 (CH2), 37.0 (C-9 or C-100), 37.1
(C-9 or C-100), 60.0 (CH2), 64.8 (C-40, C-50), 111.8 (C-20), 173.7 (C-
1). Anal. Calcd for C20H38O4: C, 70.13; H, 11.18. Found: C, 70.18;
H, 11.13.
4.20. 7-(20-Hexyl-10,30-dioxolan-20-yl)heptanal 296,17
To a solution of DMSO (3.2 mL, 45.0 mmol) in dry CH2Cl2
(39.5 mL) which was pre-cooled to ꢁ78 °C was added (COCl)2
(1.94 mL, 22.6 mmol) in dry CH2Cl2 (39.5 mL), and the resulting
mixture was stirred for 1 h at ꢁ78 °C. To this mixture was added
dropwise a solution of 28 (5.55 g, 20.4 mmol) in dry CH2Cl2
(39.5 mL) at the same temperature. After stirring at ꢁ78 °C for
3 h, Et3N (39.5 mL) and then
a saturated NaHCO3 solution
(113 mL) were added. The aqueous phase was extracted with fur-
ther portions of CH2Cl2 (2 ꢃ 250 mL). The combined organic layers
were dried over Na2SO4, the solvent was evaporated in vacuo and
the residue was chromatographed on silica gel hexane/EtOAc (2:1)
to give 5.12 g (93%) of compound 29 as a colourless oil. 1H NMR
(400 MHz, CDCl3): d 0.88 (3H, t, J = 6.8 Hz, CH3), 1.28–1.33 (14H,
m, 7 ꢃ CH2), 1.56–1.65 (6H, m, 3 ꢃ CH2), 2.42 (2H, m, 2 ꢃ H-2),
3.92 (4H, s, 2 ꢃ H-40, 2 ꢃ H-50), 9.74 (1H, t, J2,1 = 1.8 Hz,
4.23. 9-(20-Hexyl-10,30-dioxolan-20-yl)nonan-1-ol 32
Lithium aluminum hydride (1.24 g, 32.7 mmol) was added por-
tionwise to a solution of 31 (5.60 g, 16.3 mmol) in dry Et2O (96 mL)
which was pre-cooled to 0 °C. The resulting mixture was stirred at
0 °C for 15 min and then for another 45 min at room temperature.
Water (5.2 mL) was then added and the solid parts were removed
by filtration. The filtrate obtained was dried over Na2SO4, the sol-
vent was taken down, and residue was chromatographed on silica
gel hexane/EtOAc (20:1) to provide 4.81 g (98%) of compound 32 as
13
J2,1 = 1.8 Hz, H-1). C NMR (100 MHz, CDCl3): d 14.0 (C-600), 21.9
(CH2), 22.5 (CH2), 23.6 (CH2), 23.8 (CH2), 29.1 (CH2), 29.6
(2 ꢃ CH2), 31.8 (CH2), 37.0 (C-7 or C-100), 37.1 (C-7 or C-100), 43.8
(C-2), 64.8 (C-40, C-50), 111.8 (C-20), 202.8 (C-1). Anal. Calcd for
C16H30O3: C, 71.07; H, 11.18. Found: C, 71.01; H, 11.12.

130
M. Martinková et al. / Tetrahedron: Asymmetry 24 (2013) 121–133
a colourless oil. 1H NMR (400 MHz, CDCl3): d 0.86–0.90 (3H, m,
CH3), 1.29–1.35 (20H, m, 10 ꢃ CH2), 1.52–1.61 (6H, m, 3 ꢃ CH2),
3.63 (2H, t, J = 7.5 Hz, 2 ꢃ H-1), 3.92 (4H, s, 2 ꢃ H-40, 2 ꢃ H-50).
NH), 9.56 (1H, s, CHO). 13C NMR (100 MHz, CDCl3): d 18.7 (CH3),
28.4 (CH3), 56.0 (C-5), 66.7 (C-4), 67.6 (C-10), 76.4 (C-6), 100.0
(C-8), 157.8 (C-2), 200.7 (CHO). Anal. Calcd for C9H13NO5: C,
50.23; H, 6.09; N, 6.51. Found: C, 50.29; H, 6.02; N, 6.58.
13C NMR (100 MHz, CDCl3):
d
14.0 (C-600), 22.5 (CH2), 23.8
(2 ꢃ CH2), 25.7 (CH2), 29.4 (CH2), 29.5 (2 ꢃ CH2), 29.6 (CH2), 29.9
(CH2), 31.8 (CH2), 32.7 (CH2), 37.1 (C-9, C-100), 62.9 (C-1), 64.8 (C-
40, C-50), 111.9 (C-20). Anal. Calcd for C18H36O3: C, 71.95; H, 12.08.
Found: C, 71.90; H, 12.03.
4.27. (5S,6R)-6-[100-(200-Hexyl-100,300-dioxolan-200-yl)decyl]-8,8-
dimethyl-3,7,9-trioxa-1-azaspiro[4.5]decan-2-one ent-21
Using the same procedure as described for the preparation of
20, compound 9 (0.50 g, 2.32 mmol) and phosphonium salt 11
(4.07 g, 6.51 mmol) afforded, after flash chromatography on silica
gel hexane/EtOAc (1:1), 0.65 g (58%) of an inseparable mixture of
isomers 34 as a colourless oil.
4.24. 2-(90-Bromononyl)-2-hexyl-1,3-dioxolane 33
To a solution of 32 (4.80 g, 16.0 mmol) in dry DMF (27.0 mL)
was added Ph3P (6.50 g, 24.8 mmol) at room temperature. The
resulting mixture was allowed to cool to 10 °C after which NBS
(4.40 g, 24.8 mmol) was added in portions. After stirring at 10 °C
for 30 min, the mixture was poured into ice water (170 mL) and ex-
tracted with Et2O (3 ꢃ 300 mL). The combined organic layers were
dried over Na2SO4, the solvent evaporated in vacuo and the residue
was chromatographed on silica gel hexane/EtOAc (35:1) to afford
To a solution of 34 (0.65 g, 1.35 mmol) in dry EtOH (14.3 mL)
was added 20% Pd(OH)2/C (46 mg) at room temperature. After
being stirred for 2 h, the resulting mixture was filtered through a
pad of Celite, the filtrate was concentrated in vacuo, and the resi-
due was subjected to flash chromatography on silica gel hexane/
EtOAc (1:1) to give 0.64 g (98%) of compound ent-21 as a colourless
5.0 g (86%) of compound 33 as
a
colourless oil. 1H NMR
oil.½a 2D3
ꢄ
¼ 17:6 (c 0.76, CHCl3). 1H NMR (400 MHz, CDCl3): d 0.88
(400 MHz, CDCl3): d 0.86–0.90 (3H, m, CH3), 1.29–1.36 (20H, m,
10 ꢃ CH2), 1.56–1.61 (4H, m, 2 ꢃ CH2), 1.81–1.89 (2H, m, CH2),
3.40 (2H, t, J = 6.9 Hz, 2 ꢃ H-90), 3.92 (4H, s, 2 ꢃ H-4, 2 ꢃ H-5). 13C
NMR (100 MHz, CDCl3): d 14.1 (C-600), 22.6 (CH2), 23.8 (2 ꢃ CH2),
28.1 (CH2), 28.7 (CH2), 29.3 (CH2), 29.4 (CH2), 29.6 (CH2), 29.8
(CH2), 31.8 (CH2), 32.8 (CH2), 34.0 (C-90), 37.1 (C-10, C-100), 64.8
(C-4, C-5), 111.8 (C-2). Anal. Calcd for C18H35BrO2: C, 59.50; H,
9.71. Found: C, 59.56; H, 9.77.
(3H, t, J = 6.8 Hz, CH3), 1.27–1.33 (23H, m, 11 ꢃ CH2, CH2), 1.42
(3H, s, CH3), 1.44 (3H, s, CH3), 1.47–1.53 (3H, m, CH2, CH2), 1.57–
1.61 (4H, m, 2 ꢃ CH2), 3.65–3.67 (1H, m, H-6), 3.74 (1H, d,
J10,10 = 11.8 Hz, H-10), 3.82 (1H, d, J4,4 = 9.4 Hz, H-4), 3.83 (1H, d,
J10,10 = 11.8 Hz, H-10), 3.93 (4H, s, 2 ꢃ H-400, 2 ꢃ H-500), 4.03 (1H,
d, J4,4 = 9.4 Hz, H-4), 6.04 (1H, br s, NH). 13C NMR (100 MHz, CDCl3):
d 14.0 (C-6000), 18.6 (CH3), 22.5 (CH2), 23.8 (CH2), 23.8 (CH2), 25.3
(CH2), 28.3 (CH2), 28.9 (CH2), 29.3 (CH3), 29.5 (3 ꢃ CH2), 29.5
(2 ꢃ CH2), 29.9 (CH2), 31.8 (CH2), 37.1 (C-100, C-1000), 57.0 (C-5),
64.8 (C-400, C-500), 67.8 (C-10), 67.8 (C-4), 74.0 (C-6), 99.4 (C-2),
111.8 (C-200), 158.0 (C-2). Anal. Calcd for C27H49NO6: C, 67.05; H,
10.21; N, 2.90. Found: C, 67.10; H, 10.16; N, 2.95.
4.25. [9-(20-Hexyl-10,30-dioxolan-20-yl)nonyl]triphenylphospho-
nium bromide 11
To a solution of 33 (5.00 g, 13.8 mmol) in dry CH3CN (55.3 mL)
were successively added Ph3P (4.51 g, 17.2 mmol) and anhydrous
Na2CO3 (0.29 g, 2.75 mmol). The resulting mixture was stirred
and heated at reflux for 72 h. After cooling to room temperature,
the solvent was evaporated in vacuo and the mixture was washed
repeatedly with Et2O to remove Ph3P. The phosphonium salt was
precipitated after the addition of anhydrous Et2O (200 mL) to the
glassy material obtained. The precipitate was allowed to settle
overnight, after which the clear solution was decanted, and the res-
idue was dried on a pump for 3 days at room temperature. This
procedure yielded 6.54 g (76%) of compound 11 as a white hygro-
scopic powder. 1H NMR (400 MHz, CDCl3): d 0.87 (3H, t, J = 6.7 Hz,
CH3), 1.20–1.27 (18H, m, 9 ꢃ CH2), 1.53–1.63 (8H, m, 4 ꢃ CH2),
3.73–3.82 (2H, m, 2 ꢃ H-1), 3.91 (4H, s, 2 ꢃ H-40, 2 ꢃ H-50), 7.69–
7.74 (6H, m, Ph), 7.78–7.88 (9H, m, Ph). 13C NMR (100 MHz, CDCl3):
d 14.0 (C-600), 22.5 (CH2), 23.0 (CH2), 23.7 (2 ꢃ CH2), 29.1 (CH2), 29.2
(CH2), 29.4 (CH2), 29.5 (CH2), 29.8 (CH2), 30.3 (CH2), 30.4 (CH2),
31.8 (CH2), 37.0 (C-9 or C-100), 37.1 (C-9 or C-100), 64.8 (C-40, C-50),
111.8 (C-20), 117.9 (2 ꢃ Ci), 118.8 (Ci), 130.4 (3 ꢃ CHPh), 130.5
(3 ꢃ CHPh), 133.6 (3 ꢃ CHPh), 133.7 (3 ꢃ CHPh), 134.9 (CHPh),
134.9 (CHPh), 134.9 (CHPh). Anal. Calcd for C36H50BrO2P: C, 69.11;
H, 8.06. Found: C, 69.18; H, 8.12.
4.28. tert-Butyl (5S,6R)-6-[100-(200-hexyl-100,300-dioxolan-200-yl)decyl
]-8,8-dimethyl-2-oxo-3,7,9-trioxa-1-azaspiro[4.5]decan-1-
carboxylate ent-22
According to the procedure described for the preparation of 22,
compound ent-21 (0.30 g, 0.62 mmol), Boc2O (0.27 g, 1.24 mmol)
and DMAP (76 mg, 0.62 mmol) provided, after flash chromatogra-
phy on silica gel hexane/EtOAc (3:1), 0.34 g (94%) of ent-22 as a col-
ourless oil. ½a 2D0
ꢄ
¼ þ8:9 (c 0.78, CHCl3). 1H NMR (400 MHz, CDCl3):
d 0.88 (3H, t, J = 6.8 Hz, CH3), 1.26 (24H, m, 12 ꢃ CH2), 1.31 (3H, s,
CH3), 1.44 (3H, s, CH3), 1.51–1.67 (15H, m, 3 ꢃ CH3, 3 ꢃ CH2), 3.47–
3.50 (1H, m, H-6), 3.52 (1H, d, J10,10 = 11.1 Hz, H-10), 3.80 (1H, dd,
J10,4 = 1.8 Hz, J4,4 = 9.2 Hz, H-4), 3.92 (4H, s, 2 ꢃ H-400, 2 ꢃ H-500),
4.30 (1H, dd, J10,4 = 1.8 Hz, J10,10 = 11.1 Hz, H-10), 4.37 (1H, d,
13
J4,4 = 9.2 Hz, H-4). C NMR (100 MHz, CDCl3): d 14.0 (C-6000), 22.6
(CH2), 23.0 (CH3), 23.8 (CH2), 23.8 (CH2), 24.3 (CH3), 26.3 (CH2),
27.5 (CH2), 28.0 (3 ꢃ CH3), 29.3 (CH2), 29.4 (CH2), 29.5 (2 ꢃ CH2),
29.5 (CH2), 29.6 (CH2), 29.9 (CH2), 31.8 (CH2), 37.1 (C-100, C-1000),
62.0 (C-10), 64.8 (C-400, C-500), 65.4 (C-5), 69.8 (C-4), 73.0 (C-6),
84.5 (Cq), 101.7 (C-8), 111.8 (C-200), 149.6 (C@O), 152.7 (C-2). Anal.
Calcd for C32H57NO8: C, 65.83; H, 9.84; N, 2.40. Found: C, 65.87; H,
9.88; N, 2.44.
4.26. (5S,6S)-8,8-Dimethyl-2-oxo-3,7,9-trioxa-1-azaspiro[4.5]-
decane-6-carbaldehyde 9
4.29. tert-Butyl {(4R,5R)-4-[100-(200-hexyl-100,300-dioxolan-200-yl)
decyl]-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl}carba
mate ent-23
Using the same procedure as described for the preparation of
compound 6, alcohol 1010g 0.60 g, 2.76 mmol) and IBX (1.16 g,
4.14 mmol) gave after flash chromatography on silica gel (EtOAc)
0.56 g (94%) of crystalline aldehyde 9. Mp 148–150 °C,
Using the same procedure as described for the preparation of
derivative 23, ent-22 (0.34 g, 0.58 mmol) and Cs2CO3 (57 mg,
0.17 mmol) afforded, after flash chromatography on silica gel hex-
ane/EtOAc (5:1), 0.30 g (92%) of compound ent-23 as a colourless
½
a 2D5
ꢄ
¼ ꢁ72:1 (c 0.42, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.50
(3H, s, CH3), 1.55 (3H, s, CH3), 3.78 (1H, d, J10,10 = 12.0 Hz, H-10),
3.89 (1H, d, J10,10 = 12.0 Hz, H-10), 3.93 (1H, d, J4,4 = 9.4 Hz, H-4),
4.14 (1H, s, H-6), 4.62 (1H, d, J4,4 = 9.4 Hz, H-4), 6.63 (1H, br s,
oil. ½a 2D0
ꢄ
¼ ꢁ21:1 (c 0.62, CHCl3). 1H NMR (400 MHz, CDCl3): d
0.87 (3H, t, J = 6.8 Hz, CH3), 1.25–1.30 (26H, m, 13 ꢃ CH2), 1.42

M. Martinková et al. / Tetrahedron: Asymmetry 24 (2013) 121–133
131
(6H, br s, 2 ꢃ CH3), 1.45 (9H, s, 3 ꢃ CH3), 1.56–1.60 (4H, m,
2 ꢃ CH2), 3.39–3.45 (1H, m, CH2OH), 3.63–3.66 (1H, m, H-4), 3.76
(1H, d, J6,6 = 12.3 Hz, H-6), 3.91–3.96 (5H, m, 2 ꢃ H-400, 2 ꢃ H-500,
CH2OH), 3.99 (1H, d, J6,6 = 12.3 Hz, H-6), 4.77 (1H, dd, JH,OH = 2.9 Hz,
JH,OH = 10.0 Hz, OH), 5.35 (1H, br s, NH). 13C NMR (100 MHz, CDCl3):
d 14.1 (C-6000), 18.6 (CH3), 22.6 (CH2), 23.8 (CH2), 23.8 (2 ꢃ CH2),
25.5 (CH2), 28.3 (3 ꢃ CH3), 28.7 (CH2), 29.3 (CH3), 29.4 (CH2),
29.5 (2 ꢃ CH2), 29.6 (2 ꢃ CH2), 29.9 (CH2), 31.8 (CH2), 37.1 (C-100,
C-1000), 55.7 (C-5), 64.9 (C-400, C-500, CH2OH), 65.0 (C-6), 74.7 (C-4),
80.3 (Cq), 98.9 (C-2), 111.9 (C-200), 157.2 (C@O). Anal. Calcd for
(CH2OH), 71.1 (C-2, C-3), 171.8 (C-1), 214.4 (C-14). Anal. Calcd
for C21H42ClNO5: C, 59.48; H, 9.98; N, 3.30. Found: C, 59.41; H,
9.91; N, 3.25.
4.32. (4S)-4-[(10R)-10-Hydroxy-120-oxooctadecyl]-4-(hydroxymeth-
yl)oxazolidin-2-one 35
A solution of 21 (0.27 g, 0.56 mmol) in a mixture of 7:3 AcOH/
H2O (55 mL) was heated for 6 h at 80 °C, and then for a further
16 h at 40 °C before evaporation of the solvent. The residue was
chromatographed on silica gel hexane/EtOAc (1:1) to afford
136 mg (79%) of crystalline compound 35. Mp 57–59 °C,
C31H59NO7: C, 66.75; H, 10.66; N, 2.51. Found: C, 66.80; H, 10.61;
N, 2.56.
½
a 2D5
ꢄ
¼ þ9:3 (c 0.54, CHCl3). 1H NMR (400 MHz, CDCl3): d 0.87
4.30. (4R,5R)-5-[(tert-Butoxycarbonyl)amino]-4-[100-(200-hexyl-
100,300-dioxolan-200-yl)decyl]-2,2-dimethyl-1,3-dioxane-5-carbox-
ylic acid ent-24
(3H, t, J = 6.8 Hz, CH3), 1.24–1.42 (20H, m, 10 ꢃ CH2), 1.52–1.55
(6H, m, 3 ꢃ CH2), 2.38 (4H, t, J = 7.5 Hz, 2 ꢃ H-110, 2 ꢃ H-130),
3.61–3.71 (1H, m, H-10), 3.62 (1H, d, JH,H = 11.7 Hz, CH2OH), 3.69
(1H, d, JH,H = 11.7 Hz, CH2OH), 4.21 (1H, d, J5,5 = 8.7 Hz, H-5), 4.30
(1H, d, J5,5 = 8.7 Hz, H-5), 6.91 (1H, br s, NH). 13C NMR (100 MHz,
CDCl3): d 14.0 (C-180), 22.5 (CH2), 23.8 (3 ꢃ CH2), 26.0 (CH2), 28.9
(CH2), 29.2 (CH2), 29.4 (2 ꢃ CH2), 29.5 (2 ꢃ CH2), 30.7 (CH2), 31.6
(CH2), 42.8 (C-110, C-130), 64.3 (CH2OH), 65.9 (C-4), 68.8 (C-5),
72.5 (C-10), 161.0 (C-2), 212.1 (C-120). Anal. Calcd for C22H40NO5:
C, 66.13; H, 10.34; N, 3.51. Found: C, 66.18; H, 10.29; N, 3.56.
To a solution of DMSO (0.13 mL, 1.83 mmol) in dry CH2Cl2
(1 mL) which was pre-cooled to ꢁ78 °C, was added (COCl)2
(0.76 mL, 8.84 mmol) in dry CH2Cl2 (1 mL), and the resulting mix-
ture was stirred for 1 h at ꢁ78 °C. To this mixture was added drop-
wise a solution of ent-23 (0.30 g, 0.54 mmol) in CH2Cl2 (2 mL) at
the same temperature. After stirring at ꢁ78 °C for 3 h, Et3N
(1.55 mL) and then a saturated NaHCO3 solution (13 mL) were
added successively. The aqueous phase was extracted with further
portions of CH2Cl2 (2 ꢃ 48 mL). The combined organic layers were
dried over Na2SO4, the solvent removed and the residue was chro-
matographed on silica gel hexane/EtOAc (5:1) to provide 0.27 g
(93%) of an aldehyde as a colourless oil which was used immedi-
ately in the next reaction.
4.33. (4S)-4-[(10R)-10-Hydroxy-120-oxooctadecyl]-4-(trityloxymeth-
yl)oxazolidin-2-one 36
To a solution of 35 (0.13 g, 0.42 mmol) in dry pyridine (3.4 mL)
were successively added TrCl (0.45 g, 1.61 mmol) and DMAP
(80 mg, 0.65 mmol). After stirring at 60 °C for 24 h, the resulting
mixture was poured into ice water (15 mL) and extracted with
Et2O (3 ꢃ 30 mL). The combined organic layers were dried over
Na2SO4, the solvent was removed, and the residue was chromato-
graphed on silica gel hexane/EtOAc (1:1) to afford 0.24 g (88%) of
To a solution of the aldehyde obtained (0.27 g, 0.49 mmol) in a
mixture of 4:4:1 CH3CN/t-BuOH/2-methylbut-2-ene (11.0 mL) was
added a solution of NaClO2 (0.42 g, 4.64 mmol) and NaH2PO4ꢀ2H2O
(0.52 g, 3.33 mmol) in water (2.5 mL) at 0 °C. After being stirred at
0 °C for 30 min, the mixture was poured into a saturated NaCl solu-
tion (6.5 mL) and extracted with EtOAc (2 ꢃ 21 mL). The combined
organic layers were dried over Na2SO4, the solvent was evaporated
in vacuo, and the residue was subjected to flash chromatography
on silica gel hexane/EtOAc (1:1) to give 244 mg (88%) of ent-24
compound 36 as a colourless oil. ½a D23
ꢄ
¼ þ20:0 (c 0.12, CHCl3). 1H
NMR (400 MHz, CDCl3): d 0.88 (3H, t, J = 6.8 Hz, CH3), 1.13–1.32
(20H, m, 10 ꢃ CH2), 1.52–1.57 (6H, m, 3 ꢃ CH2), 2.38 (4H, t,
J = 7.5 Hz, 2 ꢃ H-110, 2 ꢃ H-130), 2.62 (1H, d, J1 ,OH = 4.3 Hz, OH),
0
3.21 (1H, d, JH,H = 9.5 Hz, CH2O), 3.38 (1H, d, JH,H = 9.5 Hz, CH2O),
3.76–3.78 (1H, m, H-10), 3.99 (1H, d, J5,5 = 8.9 Hz, H-5), 4.28 (1H,
d, J5,5 = 8.9 Hz, H-5), 6.06 (1H, br s, NH), 7.21–7.31 (9H, m, Ph),
as
a
colourless oil.
½
a 2D0
ꢄ
¼ þ12:1 (c 0.24, CHCl3). 1H NMR
(400 MHz, CD3OD): d 0.89 (3H, t, J = 6.9 Hz, CH3), 1.28–1.34 (24H,
m, 12 ꢃ CH2), 1.35–1.36 (2H, m, CH2), 1.37 (3H, s, CH3), 1.44 (9H,
s, 3 ꢃ CH3), 1.45 (3H, s, CH3), 1.54–1.57 (4H, m, 2 ꢃ CH2), 3.89
(4H, s, 2 ꢃ H-400, 2 ꢃ H-500), 4.04–4.07 (1H, m, H-4), 4.13 (1H, d,
J6,6 = 11.8 Hz, H-6), 4.24 (1H, d, J6,6 = 11.8 Hz, H-6). 13C NMR
(100 MHz, CD3OD): d 14.5 (C-6000), 19.2 (CH3), 23.7 (CH2), 24.9
(2 ꢃ CH2), 26.8 (CH2), 28.8 (3 ꢃ CH3), 29.3 (CH3), 30.4 (CH2), 30.6
(CH2), 30.7 (CH2), 30.7 (2 ꢃ CH2), 30.8 (CH2), 31.0 (CH2), 33.0
(CH2), 38.1 (C-100, C-1000), 61.1 (C-5), 64.9 (C-6), 65.9 (C-400, C-500),
74.6 (C-4), 80.7 (Cq), 100.4 (C-2), 113.0 (C-200), 157.0 (C@O), 173.3
(C-1). Anal. Calcd for C31H57NO8: C, 65.12; H, 10.05; N, 2.45. Found:
C, 65.18; H, 10.12; N, 2.51.
13
7.39–7.41 (6H, m, Ph). C NMR (100 MHz, CDCl3): d 14.0 (C-180),
22.5 (CH2), 23.8 (2 ꢃ CH2), 26.1 (CH2), 28.9 (CH2), 29.2 (CH2),
29.3 (2 ꢃ CH2), 29.4 (CH2), 29.4 (2 ꢃ CH2), 30.2 (CH2), 31.6 (CH2),
42.8 (C-110, C-130), 64.1 (C-4), 65.5 (CH2O), 69.1 (C-5), 72.7 (C-10),
87.1 (CqTr), 127.3 (3 ꢃ CHPh), 128.0 (6 ꢃ CHPh), 128.5 (6 ꢃ CHPh),
142.9 (3 ꢃ Ci), 159.6 (C-2), 211.9 (C-120). Anal. Calcd For
C41H55NO5: C, 76.72; H, 8.64; N, 2.18. Found: C, 76.77; H, 8.59;
N, 2.12.
4.34. (1R)-12-Oxo-1-[(40S)-20-oxo-40-(trityloxymethyl)oxazolidin-
40-yl]octadecyl benzoate 37
4.31. (2R,3R)-2-Amino-3-hydroxy-2-(hydroxymethyl)-14-oxoicosa
noic acid hydrochloride ent-4ꢀHCl
To a solution of 36 (0.24 g, 0.37 mmol) in dry pyridine (3.6 mL)
were successively added BzCl (0.26 mL, 2.24 mmol) and DMAP
(4.6 mg, 37.6 lmol). After being stirred at room temperature for
According to the same procedure described for the preparation
4.5 h, the resulting mixture was poured into ice water (11 mL)
and extracted with Et2O (3 ꢃ 15 mL). The combined organic layers
were dried over Na2SO4, the solvent was evaporated in vacuo, and
the residue was chromatographed on silica gel hexane/EtOAc (3:1,
then 1:1) to provide 0.22 g (80%) of compound 37 as a colourless
of mycestericin FꢀHCl 4ꢀHCl, compound ent-24 (36 mg, 63.0
lmoI)
was transformed into ent-4ꢀHCl (18 mg 64%, white amorphous so-
lid). ½a 2D4
ꢄ
¼ þ4:4 (c 0.16, CH3OH). 1H NMR (600 MHz, CD3OD): d
0.87 (3H, t, J = 6.9 Hz, CH3), 1.23–1.31 (20H, m, 10 ꢃ CH2), 1.48–
1.54 (6H, m, 3 ꢃ CH2), 2.41 (4H, t, J = 7.3 Hz, 2 ꢃ H-13, 2 ꢃ H-15),
3.80 (1H, m, H-3), 3.86 (1H, d, JH,H = 11.2 Hz, CH2OH), 4.00 (1H, d,
JH,H = 11.2 Hz, CH2OH). 13C NMR (150 MHz, CD3OD): d 14.4 (C-
20), 23.6 (CH2), 24.9 (3 ꢃ CH2), 30.0 (2 ꢃ CH2), 30.3 (2 ꢃ CH2),
30.6 (3 ꢃ CH2), 30.7 (CH2), 32.8 (CH2), 43.5 (C-13, C-15), 64.4
oil. ½a 2D0
ꢄ
¼ ꢁ1:4 (c 0.72, CHCl3). 1H NMR (400 MHz, CDCl3): d 0.87
(3H, t, J = 6.9 Hz, CH3), 1.18–1.27 (20H, m, 10 ꢃ CH2), 1.32–1.33
(1H, m, CH2), 1.41–1.46 (1H, m, CH2), 1.51–1.57 (4H, m, 2 ꢃ CH2),
2.34–2.39 (4H, m, 2 ꢃ H-110, 2 ꢃ H-130), 3.19 (1H, d, JH,H = 9.6 Hz,
0
0
CH2O), 3.42 (1H, d, JH,H = 9.6 Hz, CH2O), 3.96 (1H, d, J5 ,5 = 9.0 Hz,

132
M. Martinková et al. / Tetrahedron: Asymmetry 24 (2013) 121–133
H-50), 4.36 (1H, d, J5 ,5 = 9.0 Hz, H-50), 5.55 (1H, dd, J2,1 = 1.7 Hz,
J2,1 = 10.7 Hz, H-1), 5.71–5.75 (1H, br s, NH), 7.21–7.30 (10H, m,
PhTr), 7.40–7.42 (5H, m, PhTr), 7.44–7.46 (2H, m, PhBz), 7.56–7.60
(1H, m, PhBz), 7.95–7.97 (2H, m, PhBz). 13C NMR (100 MHz, CDCl3):
d 14.0 (C-18), 22.5 (CH2), 23.8 (2 ꢃ CH2), 25.7 (CH2), 28.8 (CH2),
28.9 (CH2), 29.2 (CH2), 29.2 (CH2), 29.3 (CH2), 29.3 (2 ꢃ CH2),
29.4 (CH2), 31.6 (CH2), 42.7 (C-11 or C-13), 42.8 (C-11 or C-13),
63.6 (C-40), 65.3 (CH2O), 68.5 (C-50), 73.9 (C-1), 87.2 (CqTr), 127.4
(4 ꢃ CHTr), 128.0 (6 ꢃ CHTr), 128.5 (7 ꢃ CHTr, 2 ꢃ CHBz) 129.3 (Ci-
Bz), 129.7 (2 ꢃ CHBz), 133.3 (CHBz), 142.8 (3 ꢃ Ci-Tr), 158.3 (C-20),
166.2 (C@O), 211.7 (C-12). Anal. Calcd for C48H59NO6: C, 77.28;
H, 7.97; N, 1.88. Found: C, 77.21; H, 7.90; N, 1.81.
(2 ꢃ CH2), 30.5 (2 ꢃ CH2), 32.8 (CH2), 43.5 (C-110, C-130), 69.7 (C-
4), 70.1 (C-5), 76.9 (C-10), 129.7 (2 ꢃ CHPh), 130.9 (2 ꢃ CHPh),
131.2 (Ci), 134.5 (CHPh), 161.2 (C-2), 167.6 (C@O), 176.8 (C-1),
214.4 (C-120). Anal. Calcd for C29H43NO7: C, 67.29; H, 8.37; N,
2.71. Found: C, 67.23; H, 8.31; N, 2.76.
0
0
4.37. (2S,3R)-2-Amino-3-hydroxy-2-(hydroxymethyl)-14-oxoi-
cosanoic acid hydrochloride 5ꢀHCl
To a solution of 39 (25 mg, 48.3 lmol) in CH3OH (1.7 mL) was
added 10% aqueous NaOH solution (1.7 mL) at room temperature.
The mixture was stirred at 80 °C for 3 h, and then a 6 M aqueous
HCl was added to pH 1–2. After being stirred and heated at 80 °C
for another 30 min, the solvents were removed under reduced
pressure. The solid parts obtained were washed several times with
water, then with a mixture hexane/Et2O (5:1), and dried on a pump
for 10 h at room temperature. This procedure yielded 12.6 mg
(62%) of mycestericin GꢀHCl 5ꢀHCl as a white amorphous solid.
4.35. (1R)-1-[(40S)-40-(Hydroxymethyl)-20-oxooxazolidin-40-yl)-
12-oxooctadecyl benzoate 38
To a solution of 37 (0.20 g, 0.27 mmol) in a mixture of 2:1
CH2Cl2/CH3OH (3.3 mL) was added p-TsOH (51 mg, 0.27 mmol).
After stirring at room temperature for 1.5 h, another portion of p-
TsOH (102 mg, 0.54 mmol) was added. Twenty two hours after
the last addition, the reaction was quenched with Et3N (0.15 mL).
The solvent was removed under reduce pressure, and the residue
was subjected to flash chromatography through a short column
of silica gel hexane/EtOAc (1:1) to afford 122 mg (91%) of com-
½
a 2D4
ꢄ
¼ þ10:5 (c 0.24, CH3OH). 1H NMR (600 MHz, CD3OD): d 0.87
(3H, t, J = 6.9 Hz, CH3), 1.22–1.38 (20H, m, 10 ꢃ CH2), 1.49–1.61
(6H, m, 3 ꢃ CH2), 2.41 (4H, t, J = 7.3 Hz, 2 ꢃ H-13, 2 ꢃ H-15), 3.74
(1H, d, JH,H = 11.2 Hz, CH2OH), 3.90 (1H, m, H-3), 3.98 (1H, d,
JH,H = 11.2 Hz, CH2OH). 13C NMR (150 MHz, CD3OD): d 14.4 (C-
20), 23.6 (CH2), 24.9 (3 ꢃ CH2), 30.0 (2 ꢃ CH2), 30.3 (CH2), 30.4
(CH2), 30.6 (2 ꢃ CH2), 30.7 (2 ꢃ CH2), 32.8 (2 ꢃ CH2), 43.5 (C-13,
C-15), 62.1 (CH2OH), 70.7 (C-2), 71.7 (C-3), 171.7 (C-1), 214.5 (C-
14). Anal. Calcd for C21H42ClNO5: C, 59.48; H, 9.98; N, 3.30. Found:
C, 59.55; H, 9.94; N, 3.35.
pound 38 as a colourless oil. ½a D23
ꢄ
¼ þ35:2 (c 0.44, CHCl3). 1H
NMR (400 MHz, CDCl3): d 0.87 (3H, t, J = 6.8 Hz, CH3), 1.21–1.38
(20H, m, 10 ꢃ CH2), 1.51–1.57 (4H, m, 2 ꢃ CH2), 1.68–1.75 (2H,
m, CH2), 2.35–2.39 (4H, m, 2 ꢃ H-11, 2 ꢃ H-13), 3.44–3.47 (1H,
0
0
m, OH), 3.61–3.70 (2H, m, CH2OH), 4.31 (1H, d, J5 ,5 = 9.1 Hz, H-
50), 4.39 (1H, d, J5 ,5 = 9.1 Hz, H-50), 5.38 (1H, dd, J2,1 = 3.4 Hz,
J2,1 = 9.8 Hz, H-1), 6.27–6.32 (1H, m, NH), 7.43–7.47 (2H, m, Ph),
7.57–7.61 (1H, m, Ph), 8.02–8.04 (2H, m, Ph). 13C NMR (100 MHz,
CDCl3): d 14.0 (C-18), 22.5 (CH2), 23.8 (2 ꢃ CH2), 25.7 (CH2), 28.9
(CH2), 29.2 (2 ꢃ CH2), 29.3 (2 ꢃ CH2), 29.3 (CH2), 29.7 (CH2), 31.6
(CH2), 42.8 (C-11, C-13), 64.4 (CH2OH), 67.5 (C-40), 68.9 (C-50),
74.2 (C-1), 128.6 (2 ꢃ CHPh), 129.0 (CHPh), 129.8 (CHPh), 133.7
(Ci), 159.4 (C-20), 166.8 (C@O), 211.9 (C-12). Anal. Calcd for
Acknowledgements
0
0
The present work was supported by the Grant Agency (Nos. 1/
0568/12 and 1/0433/11) of the Ministry of Education, Slovak
Republic.
References
1. (a) Sasaki, S.; Hashimoto, R.; Kiuchi, M.; Inoue, K.; Ikumoto, T.; Hirose, R.; Chiba,
K.; Hoshino, Y.; Okumoto, T.; Fujita, T. J. Antibiot. 1994, 47, 420–433; (b) Fujita,
T.; Hamamichi, N.; Kiuchi, M.; Matsuzaki, T.; Kitao, Y.; Inoue, K.; Hirose, R.;
Yoneta, M.; Sasaki, S.; Chiba, K. J. Antibiot. 1996, 49, 846–853.
C
29H45NO6: C, 69.15; H, 9.01; N, 2.78. Found: C, 69.16; H, 9.07;
N, 2.72.
4.36. (4S)-4-[(10R)-10-(Benzoyloxy)-120-oxooctadecyl]-2-oxooxa-
zolidine-4-carboxylic acid 39
2. Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki, S.; Toyama, R.; Chiba, K.;
Hoshino, Y.; Okumoto, T. J. Antibiot. 1994, 47, 208–215.
3. For recent reviews on the synthesis of natural products possessing an
a-
substituted serine scaffold, see: (a) Brunner, M.; Koskinen, A. M. P. Curr. Org.
Chem. 2004, 8, 1629–1645; (b) Kang, S. H.; Kang, S. Y.; Lee, H.-S.; Buglass, A. J.
Chem. Rev. 2005, 105, 4537–4558; (c) Ohflune, Y.; Shinada, T. Eur. J. Org. Chem
2005, 5127–5134; (d) Byun, H.-S.; Lu, X.; Bittman, R. Synthesis 2006, 2447–
2474.
To a stirred solution of 38 (0.12 g, 0.24 mmol) in CH3CN
(4.6 mL) was added IBX (0.10 g, 0.36 mmol) at room temperature.
After being heated at reflux for 1 h, the reaction mixture was al-
lowed to cool to room temperature and the insoluble parts were
removed by filtration. The filtrate was concentrated in vacuo, and
the residue was used immediately in the next reaction.
To a solution of the crude aldehyde (0.12 g, 0.24 mmol) in a
mixture of 4:4:1 CH3CN/t-BuOH/2-methylbut-2-ene (5.1 mL) was
added at 0 °C a solution of NaH2PO4ꢀ2H2O (0.25 g, 1.60 mmol)
and NaClO2 (0.20 g, 2.21 mmol) in water (1.2 mL). After stirring
for 30 min at the same temperature, the mixture was poured into
4. (a) Sato, H.; Sato, K.; Iida, M.; Yamanaka, H.; Oishi, T.; Chida, N. Tetrahedron Lett.
2008, 49, 1943–1947; (b) Yamanaka, H.; Sato, K.; Sato, H.; Iida, M.; Oishi, T.;
Chida, N. Tetrahedron 2009, 65, 9188–9201.
5. (a) Shibata, K.; Shingu, K.; Vassilev, V. P.; Nishide, K.; Fujita, T.; Node, M.;
Kajimoto, T.; Wong, C.-H. Tetrahedron Lett. 1996, 37, 2791–2794; (b) Nishide,
K.; Shibata, K.; Fujita, T.; Kajimoto, T.; Wong, C.-H.; Node, M. Heterocycles 2000,
52, 1191–1201.
6. Fujita, T.; Hamamichi, N.; Matsuzaki, T.; Kitao, Y.; Kiuchi, M.; Node, M.; Hirose,
R. Tetrahedron Lett. 1995, 36, 8599–8602.
7. Iwabuchi, Y.; Furukawa, M.; Esumi, T.; Hatakeyama, S. Chem. Commun. 2001,
2030–2031.
8. Berhal, F.; Takechi, S.; Kumagai, N.; Shibasaki, M. Chem. Eur. J. 2011, 17, 1915–
1921.
9. Fairhurst, N. W. G.; Mahon, M. F.; Munday, R. H.; Carbery, D. R. Org. Lett. 2012,
14, 756–759.
10. (a) Gonda, J.; Martinková, M.; Raschmanová, J.; Balentová, E. Tetrahedron:
Asymmetry 2006, 17, 1875–1882; (b) Martinková, M.; Gonda, J.; Raschmanová,
J. Molecules 2006, 11, 564–573; (c) Martinková, M.; Gonda, J.; Raschmanová, J.;
a
saturated NaCl solution (3 mL) and extracted with EtOAc
(2 ꢃ 10 mL). The combined organic layers were dried over Na2SO4,
the solvent was removed, and the residue was chromatographed
on silica gel CH2Cl2/CH3OH (7:1) to give 0.10 g (84%) of compound
39 as a colourless oil, ½a D21
ꢄ
¼ þ24:7 (c 0.38, CD3OD). 1H NMR
(400 MHz, CDCl3): d 0.88 (3H, t, J = 6.9 Hz, CH3), 1.22–1.36 (20H,
m, 10 ꢃ CH2), 1.49–1.53 (4H, m, 2 ꢃ CH2), 1.70 (2H, m, CH2),
2.38–2.43 (4H, m, 2 ꢃ H-110 2 ꢃ H-130), 4.54 (1H, d, J5,5 = 9.0 Hz,
H-5), 4.73 (1H, d, J5,5 = 8.9 Hz, H-5), 5.60–5.62 (1H, m, H-10),
7.45–7.49 (2H, m, Ph), 7.58–7.62 (1H, m, Ph), 8.04–8.06 (2H, m,
ˇ
Vojtícková, M. Tetrahedron 2007, 63, 10603–10607; (d) Martinková, M.; Gonda,
J.; Raschmanová, J.; Uhríková, A. Tetrahedron: Asymmetry 2008, 19, 1879–1885;
(e) Martinková, M.; Gonda, J.; Špaková Raschmanová, J.; Slaninková, M.;
Kuchár, J. Carbohydr. Res. 2010, 345, 2427–2437; (f) Martinková, M.; Gonda, J.;
ˇ
Uhríková, A.; Kovácová, M. Chem. Pap. 2011, 65, 527–535; (g) Martinková, M.;
Gonda, J.; Uhríková, A.; Špaková, Raschmanová, J.; Kuchár, J. Carbohydr. Res.
2012, 352, 23–36; (h) Martinková, M.; Gonda, J.; Špaková Raschmanová, J.;
13
Ph). C NMR (100 MHz, CDCl3): d 14.4 (C-180), 23.6 (CH2), 24.9
ˇ
Kozíšek, J.; Kuchár, J. Tetrahedron: Asymmetry 2012, 23, 536–546.
(2 ꢃ CH2), 27.0 (CH2), 30.0 (CH2), 30.3 (CH2), 30.4 (2 ꢃ CH2), 30.5

M. Martinková et al. / Tetrahedron: Asymmetry 24 (2013) 121–133
133
11. (a) Payette, D. R.; Just, G. Can. J. Chem. 1981, 59, 269–282; (b) Sano, S.;
Kobayashi, Y.; Kondo, T.; Takebayashi, M.; Maruyama, S.; Fujita, T.; Nagao, Y.
Tetrahedron Lett. 1995, 36, 2097–2100.
12. (a) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001–3003; (b) Satam, V.; Harad,
A.; Rajule, R.; Pati, H. Tetrahedron 2010, 66, 7659–7706 and references cited
therein.
14. King, A. O.; Shinkai, I. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: Chichester, 1995; pp 3888–3889.
15. Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 4185–4188.
16. Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.; Chida, N. Bull. Chem. Soc. Jpn.
2002, 75, 1927–1947.
17. Hayes, C. J.; Bradley, D. M.; Thomson, N. M. J. Org. Chem. 2006, 71, 2661–2665.
13. (a) Honda, M.; Ueda, Y.; Sugiyama, S.; Komori, T. Chem. Pharm. Bull. 1991, 39,
1385–1391; (b) Julina, R.; Herzig, T.; Bernet, B.; Vasella, A. Helv. Chim. Acta
1986, 69, 368–373.