Synthesis of pachastrissamine (jaspine B) and its derivatives by the late-stage introduction of the C-2 alkyl side-chains using olefin cross metathesis

Article abstract of DOI:10.1016/j.tet.2013.03.091

An improved divergent synthesis of the four diastereomers of pachastrissamine from Garner's aldehyde has been reported. The common intermediate was synthesized by an indium-mediated acetoxyallylation reaction. The long alkyl side chain was introduced in t

Full text of DOI:10.1016/j.tet.2013.03.091

Tetrahedron 69 (2013) 4211e4220
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of pachastrissamine (jaspine B) and its derivatives by the
late-stage introduction of the C-2 alkyl side-chains using olefin cross
metathesis
*
*
Yuji Yoshimitsu, Jun Miyagaki, Shinya Oishi, Nobutaka Fujii , Hiroaki Ohno
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An improved divergent synthesis of the four diastereomers of pachastrissamine from Garner’s aldehyde
has been reported. The common intermediate was synthesized by an indium-mediated acetoxyallylation
reaction. The long alkyl side chain was introduced in the late stage of the synthesis using an olefin cross
metathesis reaction. Biological evaluation of the chain modified analogs of the (2S,3S,4R)-isomer dem-
onstrated that biological activity was highly dependent on the chain length.
Received 20 February 2013
Received in revised form 22 March 2013
Accepted 23 March 2013
Available online 28 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Pachastrissamine
Jaspine B
Divergent synthesis
Olefin cross metathesis
1. Introduction
that pachastrissamine inhibits sphingomyelin synthase to increase
the intracellular level of ceramide, inducing apoptotic cell death by
Pachastrissamine (Fig. 1, 1a),
a
naturally occurring anhy-
a caspase-dependent pathway.1d Due to its impressive biological
activity, and simple and unique structure, many total syntheses of
pachastrissamine,2,3 and its stereoisomers (Fig.1, 2ae4a)3h,j,k,4 have
been reported. Previously, we have developed a stereoselective
divergent synthesis of four pachastrissamine diastereomers3h and
identified that all eight isomers of pachastrissamine exhibit mod-
erate to high inhibitory activity against sphingosine kinase (SphK) 1
and 2.5 This promising biological activity prompted us to establish
a more divergent synthetic route to compounds of this structural
class. For the structureeactivity relationships associated with the
C-2 position1d,6 to be effectively investigated, a variety of alkyl side-
chain should be introduced in the late stage of the synthesis. Herein
we report an improved stereoselective and divergent strategy de-
veloped for the synthesis of four diastereomers of pachastrissamine
involving a late-stage olefin cross metathesis reaction.3a,j,o,p
drophytosphingosine derivative, was isolated from the Okinawan
marine sponge, Pachastrissa sp.1a Shortly after this discovery,
a French research group isolated the same compound from the
Vanuatuan marine sponge, Jaspis sp. and named the compound
jaspine B.1b Pachastrissamine exhibits marked sub-micromolar
cytotoxicity against several cancer cell lines. Delgado et al. re-
ported that the potency of cytotoxicity is dependent on the ste-
reochemistry of the tetrahydrofuran moiety.1c Salma et al. revealed
2. Results and discussion
Our strategy for an improved divergent synthesis of pachas-
trissamine derivatives is outlined in Scheme 1. It was envisaged that
the diol 6 could be used as a common intermediate for the syn-
thesis of four isomers. Compound 6 itself could be readily
prepared from (S)-Garner’s aldehyde 57 via an indium-mediated
acetoxyallylation.8 Removal of the acetonide group from 6 would
provide the amino triol 7a. The stereocenter at the C-3 position of
Fig. 1. Structures of pachastrissamine and its diastereomers.
* Corresponding authors. E-mail addresses: nfujii@pharm.kyoto-u.ac.jp (N. Fujii),
hohno@pharm.kyoto-u.ac.jp (H. Ohno).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.091

4212
Y. Yoshimitsu et al. / Tetrahedron 69 (2013) 4211e4220
indium-mediated reductive coupling of 5 with 3-bromoprop-1-
enyl acetate followed by solvolysis provided the common in-
termediate 6 in 77% yield. We initially examined the synthesis of
natural pachastrissamine 1a. The diol 6 was converted to the cor-
responding bis-tosylate 12 by the treatment with TsCl, Et3N, and
Me3N$HCl.9 The treatment of 12 with TsOH$H2O in MeOH under
reflux successfully produced the desired tetrahydrofuran 13 bear-
ing a vinyl group at the C-2-position in 79% yield.10 Following the
cleavage of the tosyl group of 13 with Mg and MeOH, the resulting
amino group was protected with the Cbz group.11 The introduction
of the alkyl chain through the olefin cross metathesis reaction with
tetradec-1-ene in the presence of the HoveydaeGrubbs second
generation catalyst,12 followed by concomitant reduction of the
double bond and removal of the Cbz group provided pachastriss-
amine 1a.
The (2R,3S,4S)-isomer 2a was then prepared in analogy with the
reported procedure (Scheme 3).13 The regioselective tosylation of
the primary hydroxy group of 7a, followed by treatment of the
resulting tosylate with K2CO3 to give the cyclization product 15.
Following a carbon chain elongation sequence involving the olefin
cross metathesis reaction with tetradec-1-ene, followed by hydro-
genation, and removal of the Boc group with TFA provided the
desired (2R,3S,4S)-isomer 2a.
Scheme 1. Strategy for stereoselective divergent synthesis of the four diastereomers of
pachastrissamine and their C-2-modified derivatives.
7a could be inverted via a Boc-mediated orthoester ring opening
reaction to produce 7b.3h However, this stereoinversion process of
7a would require fine-tuning of the reaction conditions and/or
protecting/activating groups for selective activation of the C-3 po-
sition in the presence of the highly active allylic hydroxy group. It
was anticipated that the amino triol derivatives 7a and 7b would
constitute suitable precursors for the tetrahydrofurans 8e11. Thus,
the selective activation of the C-4 hydroxy group in 7a or 7b would
lead to nucleophilic attack by the C-1 hydroxy group to give 8 or 10,
respectively (Scheme 1, path A). In contrast, the conversion of the C-
1 hydroxy group in 7a or 7b to a suitable leaving group would give 9
or 11, respectively (Scheme 1, path B). Following the cyclization
step, a variety of different alkyl chains could be introduced at the C-
2 position using the olefin cross metathesis reaction. Subsequent
functional group modification steps would lead to the pachas-
trissamine derivatives 1e4.
Scheme 3. Synthesis of the (2R,3S,4S)-isomer 2a. Reagents and conditions: (a)
TsOH$H2O, MeOH, rt; (b) TsCl, Et3N, Me3N$HCl, CH2Cl2, ꢁ78 ꢀC; (c) K2CO3, MeOH, rt;
(d) tetradec-1-ene, HoveydaeGrubbs II catalyst, CH2Cl2, reflux; (e) Pd/C, H2, EtOH, rt;
(f) TFA, CH2Cl2, rt.
Next, the synthesis of the (2S,3R,4S)-isomer 3a was attempted,
which required the regioselective inversion of the stereogenic
center at the C-3 position (Scheme 4). It was envisaged that this
transformation could be accomplished via the regio- and stereo-
specific ring-opening reaction of the orthoester A at the C-3
The synthesis started with the acetoxyallylation of (S)-Garner’s
aldehyde 5 (Scheme 2). According to Trombini’s protocol,8 the
TBDPSCl
imidazole
OH
OH
4
4
3
3
HO
Boc
TBDPSO
Boc
16
CH2Cl2, 0 ºC
91%
NH OH
NH OH
7a
TBDPSO
1
BF3·OEt2
4
MeC(OMe)3
3
HN
t-BuO
O
CH2Cl2 or
benzene
O
O
A
TBDPSO
TBDPSO
1
1
4
3
OAc
3
OAc
HN
O
HN
O
O
4
O
18
17
Scheme 2. Synthesis of natural pachastrissamine 1a. Reagents and conditions: (a) 3-
bromoprop-1-enyl acetate, In, DMF, 0 ꢀC; (b) K2CO3, MeOH/H2O (4:1), rt; (c) TsCl,
Et3N, Me3N$HCl, CH2Cl2, rt; (d) TsOH$H2O, MeOH, reflux; (e) Mg, MeOH, rt; (f) CbzCl,
NaHCO3, THF/H2O (1:1), rt; (g) tetradec-1-ene, HoveydaeGrubbs II catalyst, CH2Cl2,
reflux; (h) Pd/C, H2, EtOH, rt.
(via C-3 attack)
(via C-4 attack)
in CH2Cl2
44%
66%
36%
14%
in benzene
Scheme 4. The stereoinversion of the C-3 position of the 7a by orthoester formation.

Y. Yoshimitsu et al. / Tetrahedron 69 (2013) 4211e4220
4213
position, based on our previous synthetic strategy.3h Thus, the
stereoinversion of the C-3 position of 7a would be achieved
through orthoester formation and intramolecular nucleophilic at-
tack of the carbonyl oxygen of the Boc group. Following silyl pro-
tection of the primary hydroxy group in 7a, the resulting silyl ether
16 was subjected to the stereoinversion conditions. The treatment
of 16 with MeC(OMe)3 in the presence of a catalytic amount of
BF3$OEt2 in CH2Cl2 afforded the desired oxazolidinone 17 (44%).
Unfortunately, however, the product was also accompanied by
a considerable amount of the undesired regioisomer 18 (36%). The
low level of regioselectivity observed in this particular case was
attributed to the enhanced reactivity at the allylic position toward
the nucleophilic attack of the Boc oxygen to promote the formation
of the six-membered ring. A series of other reaction conditions
were then evaluated with a view to improving the selectivity. When
the reaction was conducted in the presence of BF3$OEt2 in benzene,
a moderate improvement in the selectivity was observed, with the
cyclized products 17 and 18 being obtained in 66% and 14% yields,
respectively. In contrast, when the reaction was conducted in the
presence of Me2AlCl or Zn(OTf)2, none of the cyclized product was
formed.
With the results of the poor regioselectivity in the stereo-
inversion process, our work proceeded toward the investigation of
an alternative strategy involving the use of thionyl chloride as an
activating agent (Scheme 5). The hydroxy groups at the C-1 and C-4
positions were selectively protected with TBDPSCl/imidazole at
ꢁ20 ꢀC to give the corresponding silyl ether 19 in 94% yield. The
desired C-3 stereoinversion product 20 was obtained in 83% yield
by the reaction of 19 with thionyl chloride. Subsequent protection
of the carbamate nitrogen with a nosyl group followed by cleavage
of the silyl ether and cyclic carbamate under strongly basic condi-
tions provided the free triol 7c. The cyclization of 7c was then
attempted using the hydroxy group at the C-4 position as a leaving
group. For this particular transformation, the construction of the
tetrahydrofuran ring via the orthoester was attempted according to
the conditions reported by Overkleeft et al.13 in their synthesis of
pachastrissamine using an azido-triol. The orthoesterification of 7c
using MeC(OMe)3 in the presence of BF3$OEt2 proceeded smoothly
to give the tetrahydrofuran cyclization product 22. The introduction
of the alkyl chain by olefin cross metathesis followed by sequential
removal of the Ns and Ac groups and hydrogenation of the alkene
provided the (2S,3R,4S)-isomer 3a.
followed by alcoholysis of the oxazolidinone successfully afforded
tetrahydrofuran 24. This compound was subjected to the olefin
cross metathesis reaction, followed by sequential hydrogenation
and deprotection reactions similar to those used for the other iso-
mers to produce the (2R,3R,4S)-isomer 4a. The spectroscopic and
optical rotation data for the synthetic materials 1ae4a matched
those reported previously in all respects.1e4
Scheme 6. Synthesis of the (2R,3R,4S)-isomer 4a. Reagents and conditions: (a) Boc2O,
Et3N, DMAP, THF, rt; (b) 3HF$Et3N, THF, reflux; (c) TsCl, Et3N, Me3N$HCl, CH2Cl2,
ꢁ78 ꢀC; (d) K2CO3, MeOH, rt; (e) tetradec-1-ene, HoveydaeGrubbs II catalyst, CH2Cl2,
reflux; (f) Pd/C, H2, EtOH, rt; (g) TFA, CH2Cl2, rt.
To conclude this work, the introduction of a variety of different
alkyl groups of different chain lengths at the C-2 position was
investigated using the established procedures. The protected vi-
nyl congener ent-24, the precursor of the (2S,3S,4R)-isomer ent-4,
was selected for this particular series of derivatization experi-
ments because it possessed the most potent SphK inhibitory ac-
tivity of the eight different stereoisomers.5 The ent-24 was
prepared starting from (R)-Garner’s aldehyde, according to the
same procedures used for the synthesis of 24. Reactions with
alkenes of different chain lengths followed by sequential re-
duction and deprotection afforded the desired products ent-4ael
(Table 1).
ent-4aee were then evaluated for their in vitro inhibitory ac-
tivity of SphK1 and SphK2 using LabChip3000 system (Table 2).14
For this series of compounds, the ent-4a, having an alkyl group
with the same chain length as natural pachastrissamine, exhibited
the most potent inhibitory activity. Side-chain elongated analog
ent-4b was slightly less potent than ent-4a. Chain truncated de-
rivatives ent-4cee showed a marked decrease in activity as the
alkyl chain length decreased, the similar trend as observed for the
inhibition of sphingomyelin synthase.6b
3. Conclusions
In conclusion, we have developed an improved stereoselective
divergent synthesis of four pachastrissamine diastereomers by the
late-stage olefin cross metathesis. The regioselectivity issue in the
stereoinversion step has been overcome by use of thionyl chloride-
mediated cyclization of the appropriately protected triol derivative
19. This strategy provides an efficient synthetic route to all
pachastrissamine stereoisomers and their side-chain derivatives.
Biological evaluations of the chain modified analogs of the
(2S,3S,4R)-isomer demonstrated that naturally occurring C14 alkyl
chain was most appropriate for the potent SphK inhibitory activity.
Scheme 5. Synthesis of the (2S,3R,4S)-isomer 3a. Reagents and conditions: (a)
TBDPSCl, imidazole, CH2Cl2, ꢁ20 ꢀC; (b) SOCl2, THF, reflux; (c) NsCl, NaH, THF, rt; (d)
TBAF, then KOH aq, THF, rt; (e) MeC(OMe)3, BF3$Et2O, CH2Cl2, rt; (f) tetradec-1-ene,
HoveydaeGrubbs II catalyst, CH2Cl2, reflux; (g) PhSH, Cs2CO3, then KOH aq, MeCN, rt;
(h) Pd/C, H2, EtOH, rt.
4. Experimental
With a successful strategy in hand, the stage was now set for the
synthesis of the (2R,3R,4S)-isomer 4a (Scheme 6). The protection of
20 with Boc2O, followed by desilylation provided the primary al-
cohol 23. Selective monotosylation of the primary hydroxy group,
4.1. General methods
All moisture-sensitive reactions were performed using syringe-
septum cap techniques under an argon atmosphere and all

4214
Y. Yoshimitsu et al. / Tetrahedron 69 (2013) 4211e4220
Table 1
4.2. tert-Butyl (S)-4-[(1S,2R)-1,2-dihydroxybut-3-enyl]-2,2-
dimethyloxazolidine-3-carboxylate (6)
Synthesis of the (2S,3S,4R)-isomer (ent-4a) and its side-chain derivatives (ent-4bel)
To a stirred solution of 5 (671 mg, 2.93 mmol) in DMF (15 mL)
were added 3-bromoprop-1-enyl acetate (1.06 mL, 8.76 mmol) and
indium (1.01 g, 8.80 mmol) at 0 ꢀC. After stirring for 6 h at this
temperature, H2O was added to the mixture, and the whole was
extracted with EtOAc. The extract was dried over MgSO4, and the
filtrate was concentrated under reduced pressure to give an oily
residue, which was dissolved in MeOH/H2O (15 mL, 4:1). To this
solution was added K2CO3 (810 mg, 5.86 mmol) at room tempera-
ture, and the mixture was stirred for 1 h at this temperature. The
mixture was quenched by addition of saturated aqueous NH4Cl at
0 ꢀC. MeOH was removed under reduced pressure and the aqueous
layer was extracted with EtOAc. The extract was dried over MgSO4,
and the filtrate was concentrated under reduced pressure to give an
oily residue, which was purified by flash chromatography over
silica gel with n-hexaneeEtOAc (9:1) to give 6 as a colorless oil
R
C
Yield (%)
14H29 (ent-4a)
44
51
46
C16H33 (ent-4b)
C12H25 (ent-4c)
C
10H21 (ent-4d)
52
C8H17 (ent-4e)
CH]CH2 (ent-4f)
44
89a
20
(644 mg, 77% yield): ½a D25
ꢂ
þ2.2 (c 0.97, CHCl3); IR (neat): 3413 (OH),
1690 (C]O); 1H NMR (500 MHz, CDCl3)
d
1.48 (s, 9H), 1.51 (s, 3H),
56
42
1.56 (s, 3H), 2.75e3.10 (br s, 1H), 3.66e3.74 (m, 1H), 3.75e3.90 (br s,
1H), 3.94e3.98 (m, 1H), 4.02e4.07 (m, 1H), 4.16e4.18 (m, 1H),
4.26e4.28 (m, 1H), 5.15e5.17 (m, 1H), 5.33e5.37 (m, 1H), 5.96 (ddd,
J¼17.2, 9.2, 4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 24.2, 27.0, 28.4
(3C), 58.8, 65.4, 74.5, 74.9, 81.4, 94.1, 114.9, 136.8, 153.9; HRMS (FAB)
calcd for C14H25NNaO5: [MþNa]þ, 310.1630; found: 310.1636.
53
4.3. tert-Butyl (S)-4-[(1S,2R)-1,2-bis(tosyloxy)but-3-enyl]-2,2-
dimethyloxazolidine-3-carboxylate (12)
49
52
To a stirred solution of 6 (77 mg, 0.268 mmol) in CH2Cl2 (1.3 mL)
were added TsCl (204 mg, 1.07 mmol), Et3N (300 mL, 2.16 mmol),
and Me3N$HCl (26 mg, 0.272 mmol) at room temperature. After
stirring for 6 h at this temperature, the mixture was quenched by
addition of saturated NH4Cl at 0 ꢀC, and the whole was extracted
with CH2Cl2. The extract was washed with H2O and brine, and dried
over MgSO4. The filtrate was concentrated under reduced pressure
to give an oily residue, which was purified by flash chromatography
over silica gel with n-hexaneeEtOAc (7:1) to give 12 as a pale yel-
a
The olefin cross metathesis and reduction were not carried out.
low oil (118 mg, 74% yield): ½a D25
ꢁ32.6 (c 1.90, CHCl3); IR (neat):
ꢂ
1692 (C]O), 1369 (OSO2), 1178 (OSO2); 1H NMR (500 MHz, CDCl3)
Table 2
SphK inhibitory activity of (2S,3S,4R)-isomer (ent-4a) and its side-chain derivatives
(ent-4bee)
d
1.32e1.46 (m, 6H), 1.48 (s, 9H), 2.43 (s, 3H), 2.45 (s, 3H), 3.87e3.90
(m, 1H), 3.96e4.10 (m, 2H), 5.17e5.30 (m, 1H), 5.19e5.21 (m, 3H),
5.72 (ddd, J¼16.0, 10.3, 5.7 Hz, 1H), 7.29 (d, J¼8.6 Hz, 2H), 7.32 (d,
J¼8.6 Hz, 2H), 7.69 (d, J¼8.0 Hz, 2H), 7.77 (d, J¼8.0 Hz, 2H); 13C NMR
Compound
IC50 (m
M)a
SphK1
SphK2
(125 MHz, CDCl3)
d 21.6 (2C), 24.9, 26.4, 28.3 (3C), 56.2, 63.0, 78.8,
ent-4a
ent-4b
ent-4c
ent-4d
ent-4e
1.0
1.2
8.2
>30
>30
0.52
2.1
1.9
7.7
>30
80.9, 81.6, 93.8, 120.6, 127.9 (2C), 128.2 (2C), 129.7 (4C), 129.8, 133.6
(2C), 144.9 (2C), 152.8; HRMS (FAB) calcd for C28H37NNaO9S2:
[MþNa]þ, 618.1807; found: 618.1805.
a
IC50 values are the concentrations for 50% inhibition of the sphingosine phos-
phorylation by SphK1 or SphK2. The data were derived from the doseeresponse
curves generated from duplicate data points.
4.4. (2S,3S,4S)-4-Amino-2-vinyltetrahydrofuran-3-yl 4-methyl
benzenesulfonate (13)
To a stirred solution of 12 (1.03 g, 1.73 mmol) in MeOH (58 mL)
was added TsOH$H2O (330 mg, 1.73 mmol) at room temperature.
After stirring for 6 h under reflux, the mixture was concentrated
under reduced pressure to give an oily residue, which was purified
by flash chromatography over silica gel with CHCl3eMeOHe28%
NH4OH (95:4:1) to give 13 as a white solid (386 mg, 79% yield): mp
glassware was dried in an oven for 2 h at 80 ꢀC prior to use. Re-
actions at ꢁ78 ꢀC employed a CO2eMeOH bath. Melting points
were measured by a hot stage melting point apparatus (un-
corrected). 1H NMR spectra were recorded at 500 or 400 MHz fre-
quency, and chemical shifts are reported in
d
(parts per million)
87e88 ꢀC; ½a 2D5
ꢂ
þ41.2 (c 1.01, CHCl3); IR (neat): 3395 (NH), 1367
relative to TMS (in CDCl3) as internal standard. 13C NMR spectra
were recorded at 125 or 100 MHz frequency and referenced to the
residual CHCl3 signal. 1H NMR spectra are tabulated as follows:
chemical shift, multiplicity (b¼broad, s¼singlet, d¼doublet,
t¼triplet, q¼quartet, br s¼broad singlet, m¼multiplet), number of
protons, and coupling constant(s).
(OSO2), 1176 (OSO2); 1H NMR (500 MHz, CDCl3)
d 1.37 (s, 2H), 2.46
(s, 3H), 3.51 (dd, J¼8.3, 8.0 Hz, 1H), 3.75 (ddd, J¼8.3, 8.3, 4.6 Hz 1H),
4.06 (dd, J¼8.3, 8.0 Hz, 1H), 4.41 (dd, J¼5.7, 4.0 Hz, 1H), 4.87 (dd,
J¼4.6, 4.0 Hz, 1H), 4.99e5.01 (m, 1H), 5.17e5.21 (m, 1H), 5.55 (ddd,
J¼17.2, 10.3, 5.7 Hz, 1H), 7.34 (d, J¼8.0 Hz, 2H), 7.79 (d, J¼8.0 Hz,
2H); 13C NMR (125 MHz, CDCl3)
d 21.6, 55.2, 71.6, 81.6, 83.9, 118.4,

Y. Yoshimitsu et al. / Tetrahedron 69 (2013) 4211e4220
4215
127.9 (2C), 129.8 (2C), 132.5, 133.6, 145.1. Anal. Calcd for
C13H17NO4S: C, 55.11; H, 6.05; N, 4.94. Found: C, 54.89; H, 6.05;
N, 4.85.
CHCl3); IR (neat): 3331 (NH and OH), 1686 (C]O); 1H NMR
(500 MHz, CDCl3) 1.44 (s, 9H), 3.58e3.59 (m, 2H), 3.67 (d,
d
J¼5.7 Hz, 1H), 3.71e3.76 (m, 3H), 3.91e3.94 (m, 1H), 4.26e4.27 (m,
1H), 5.26e5.28 (m, 1H), 5.36e5.39 (m, 2H), 6.00 (ddd, J¼17.2, 10.9,
4.5. Benzyl [(3S,4S,5S)-4-hydroxy-5-vinyltetrahydrofuran-3-yl]
5.7 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 28.4 (3C), 52.6, 61.9, 73.9,
carbamate (14)
74.9, 80.1, 116.8, 136.5, 156.3. Anal. Calcd for C11H21NO5: C, 53.43; H,
8.56; N, 5.66. Found: C, 53.23; H, 8.37; N, 5.66.
To a stirred solution of 13 (251 mg, 0.886 mmol) in MeOH
(18 mL) was added Mg (215 mg, 8.84 mmol) at room temperature.
After stirring for 1 h at this temperature, the mixture was con-
centrated under reduced pressure followed by rapid filtration
through a short pad of silica gel with CHCl3eMeOHe28% NH4OH
(95:4:1) to give a crude amino alcohol, which was used without
further purification. To a stirred mixture of the above amino alcohol
4.8. tert-Butyl [(3S,4S,5R)-4-hydroxy-5-vinyltetrahydrofuran-
3-yl]carbamate (15)
To a stirred solution of 7a (69 mg, 0.279 mmol) and Et3N
(773 mL, 5.58 mmol) in CH2Cl2 (5.6 mL) were added TsCl (214 mg,
1.12 mmol) and Me3N$HCl (27 mg, 0.282 mmol) at ꢁ78 ꢀC. After
stirring for 30 min at this temperature, the mixture was quenched
by addition of saturated aqueous NH4Cl, and the whole was
extracted with CH2Cl2. The extract was washed with H2O and
brine, dried over MgSO4. The filtrate was concentrated under re-
duced pressure to give a white solid, which was purified by flash
chromatography over silica gel with n-hexaneeEtOAc (4:1) to give
the corresponding tosylate as a white solid. To a stirred solution
of the tosylate in MeOH (9.3 mL) was added K2CO3 (33 mg,
0.239 mmol) at room temperature, and the mixture was stirred for
30 min at this temperature. The mixture was quenched by addition
of saturated NH4Cl, and concentrated under reduced pressure. The
residue was extracted with EtOAc and dried over MgSO4. The fil-
trate was concentrated under reduced pressure to give a white
solid, which was purified by flash chromatography over silica gel
with n-hexaneeEtOAc (4:1) to give 15 as a white solid (51 mg, 80%
in THF/H2O (8.8 mL, 1:1) were added CbzCl (174 mL, 1.23 mmol) and
NaHCO3 (104 mg 1.24 mmol), and the mixture was stirred for
30 min at room temperature. THF was removed under reduced
pressure, and the residue was extracted with EtOAc and dried over
MgSO4. The filtrate was concentrated under reduced pressure to
give a white solid, which was purified by flash chromatography
over silica gel with n-hexaneeEtOAc (1:1) to give 14 as a white solid
a 25
ꢀ
(195 mg, 84% yield): mp 80e81 C; ½ ꢂD þ17.2 (c 0.94, CHCl3); IR
(neat): 3337 (NH and OH), 1718 (C]O); 1H NMR (500 MHz, CDCl3)
d
1.99 (br s, 1H), 3.65e3.68 (m, 1H), 4.14e4.16 (m, 2H), 4.45e4.57
(m, 2H), 5.10e5.12 (m, 2H), 5.38e5.40 (m, 2H), 5.46e5.49 (m, 1H),
5.55 (ddd, J¼17.2, 10.3, 5.2 Hz, 1H), 7.31e7.38 (m, 5H); 13C NMR
(125 MHz, CDCl3) d 54.5, 67.0, 70.3, 71.8, 82.4,119.1,128.1,128.2 (2C),
128.5 (2C),132.7,136.2, 156.1. Anal. Calcd for C14H17NO4: C, 63.87; H,
6.51; N, 5.32. Found: C, 63.71; H, 6.54; N, 5.30.
yield): mp 53e54 ꢀC; ½a D25
ꢂ
þ28.8 (c 0.93, CHCl3); IR (neat): 3438
4.6. (2S,3S,4S)-4-Amino-2-tetradecyltetrahydrofuran-3-ol (1a)
(NH and OH), 1692 (C]O); 1H NMR (500 MHz, CDCl3)
d 1.45 (s, 9H),
2.79 (br, s, 1H), 3.61e3.64 (m, 1H), 4.02e4.04 (m, 1H), 4.21e4.25
(m, 3H), 5.11 (br, s, 1H), 5.21e5.23 (m, 1H), 5.35e5.38 (m, 1H), 5.84
To a stirred solution of 14 (105 mg, 0.399 mmol) in CH2Cl2
(8.0 mL) were added tetradec-1-ene (1.01 mL, 3.99 mmol) and
second generation HoveydaeGrubbs catalyst (25 mg, 0.0399 mmol)
at room temperature. After stirring for 10 h under reflux, the
mixture was concentrated under reduced pressure to give an oily
residue, which was purified by flash chromatography over silica gel
with n-hexaneeEtOAc (4:1) to give the E/Z mixture of corre-
sponding metathesis product as a white solid. To a stirred solution
of the above metathesis product in EtOH (20 mL) was added 10%
Pd/C (42 mg, 0.0395 mmol) at room temperature, and the mixture
was stirred for 3 h at this temperature under H2. The mixture was
filtrated, and the filtrate was concentrated under reduced pressure
to give a white solid, which was purified by column chromatogra-
phy over silica gel with CHCl3eMeOHe28% NH4OH (100:3:1) to
give 1a as a white solid (82 mg, 69% yield): mp 94e95 ꢀC; IR (neat):
(ddd, J¼17.2, 10.3, 5.7 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 28.3
(3C), 52.5, 70.6, 74.9, 80.1, 85.4, 116.9, 135.6, 156.0. Anal. Calcd for
C11H19NO4: C, 57.62; H, 8.35; N, 6.11. Found: C, 57.36; H, 8.18;
N, 6.08.
4.9. (2R,3S,4S)-4-Amino-2-tetradecyltetrahydrofuran-3-ol (2a)
To a stirred solution of 15 (109 mg, 0.475 mmol) in CH2Cl2
(9.5 mL) were added tetradec-1-ene (1.20 mL, 4.74 mmol) and
second generation HoveydaeGrubbs catalyst (30 mg, 0.0479 mmol)
at room temperature. After stirring for 12 h under reflux, the
mixture was concentrated under reduced pressure to give an oily
residue, which was purified by flash chromatography over silica gel
with n-hexaneeEtOAc (4:1) to give the E/Z mixture of corre-
sponding metathesis product as a white solid. To a stirred solution
of the above metathesis product in EtOH (9.5 mL) was added 10%
Pd/C (51 mg, 0.0479 mmol) at room temperature, and the mixture
was stirred for 2 h at this temperature under H2. The mixture was
filtrated, and the filtrate was concentrated under reduced pressure
to give a white solid, which was dissolved in CH2Cl2 (9.5 mL). To this
solution was added TFA (9.5 mL) at 0 ꢀC, and the mixture was
stirred for 30 min at room temperature. The mixture was concen-
trated under reduced pressure to give an oily residue, which
was purified by column chromatography over silica gel with
CHCl3eMeOHe28% NH4OH (100:3:1) to give 2a as a white solid
3344 (NH and OH); ½a D25
ꢂ
þ15.6 (c 0.49, EtOH); 1H NMR (500 MHz,
CDCl3)
d
0.88 (t, J¼6.9 Hz, 3H), 1.20e1.48 (m, 26H), 1.59e1.73 (m,
2H), 3.51 (dd, J¼8.6, 6.9 Hz,1H), 3.64e3.68 (m, 1H), 3.73 (ddd, J¼7.4,
6.9, 3.7 Hz, 1H), 3.86 (dd, J¼4.9, 3.7 Hz, 1H), 3.92 (dd, J¼8.6, 7.4 Hz,
1H); 13C NMR (125 MHz, CDCl3)
d 14.1, 22.7, 26.3, 29.3, 29.4, 29.6,
29.7 (6C), 29.8, 31.9, 54.3, 71.8, 72.4, 83.2. Anal. Calcd for C18H37NO2:
C, 72.19; H, 12.45; N, 4.68. Found: C, 71.93; H, 12.68; N, 4.61.
4.7. tert-Butyl [(2S,3S,4R)-1,3,4-trihydroxyhex-5-en-2-yl]
carbamate (7a)
To a stirred solution of 6 (108 mg, 0.376 mmol) in MeOH (7.5 mL)
was added TsOH$H2O (7.2 mg, 0.0379 mmol) at 0 ꢀC, and the
mixture was warmed to room temperature. After stirring for 4 h at
this temperature, the mixture was quenched by addition of Et3N
(79 mg, 57% yield): mp 102e103 ꢀC; ½a D25
ꢂ
þ14.1 (c 0.35, EtOH); IR
(neat): 3342 (NH and OH); 1H NMR (500 MHz, CDCl3)
d
0.88 (t,
J¼6.9 Hz, 3H), 1.22e1.48 (m, 24H), 1.48e1.63 (m, 2H), 1.90e2.37 (br
s, 3H), 3.40 (dd, J¼8.6, 6.9 Hz, 1H), 3.46 (m, 1H), 3.58e3.64 (m, 2H),
(5.3
m
L, 0.0379 mmol) at 0 ꢀC, and concentrated under reduced
4.12 (dd, J¼8.6, 6.6 Hz, 1H);13C NMR (125 MHz, CDCl3)
d 14.1, 22.7,
pressure to give an oily residue, which was purified by flash chro-
matography over silica gel with n-hexaneeEtOAc (1:2) to give 7a as
25.8, 29.3, 29.5, 29.6, 29.7 (6C), 31.9, 33.7, 52.6, 73.2, 74.8, 85.2. Anal.
Calcd for C18H37NO2$0.2H2O: C, 71.33; H, 12.44; N, 4.62. Found: C,
71.57; H, 12.51, N 4.67.
a white solid (78 mg, 84% yield): mp 88e89 ꢀC; ½a D25
þ15.8 (c 1.27,
ꢂ

4216
Y. Yoshimitsu et al. / Tetrahedron 69 (2013) 4211e4220
4.10. tert-Butyl [(2S,3S,4R)-1-(tert-butyldiphenylsilyloxy)-
3,4-dihydroxyhex-5-en-2-yl]carbamate (16)
with n-hexaneetoluene (1:1) to give 19 as a colorless oil (6.86 g,
94% yield): ½a 2D5
ꢂ
þ11.5 (c 1.09, CHCl3); IR (neat): 3445 (NH and OH),
1714 (C]O); 1H NMR (500 MHz, CDCl3)
d
1.01 (s, 9H), 1.09 (s, 9H),
To a stirred solution of 7a (2.35 g, 9.50 mmol) in CH2Cl2 (95 mL)
were added imidazole (1.62 g, 23.8 mmol) and TBDPSCl (3.50 mL,
13.5 mmol) at 0 ꢀC. After stirring for 30 min at this temperature, the
mixture was quenched by addition of saturated NH4Cl, and the
whole was extracted with CH2Cl2. The extract was washed with
H2O and brine, and dried over MgSO4. The filtrate was concentrated
under reduced pressure to give an oily residue, which was purified
by flash chromatography over silica gel with n-hexaneeEtOAc (3:1)
1.36 (s, 9H), 2.38 (d, J¼3.4 Hz, 1H), 3.55 (m, 1H), 3.60e3.65 (m, 2H),
3.90 (m, 1H), 4.33 (m, 1H), 4.47 (d, J¼9.7 Hz, 1H), 5.20e5.24 (m,
2H), 5.96 (ddd, J¼17.2, 10.9, 6.3 Hz, 1H), 7.31e7.44 (m, 12H),
7.57e7.67 (m, 8H); 13C NMR (125 MHz, CDCl3)
d 19.3 (2C), 26.9
(3C), 27.0 (3C), 28.3 (3C), 52.1, 63.2, 74.0, 75.1, 79.1, 118.3, 127.5 (3C),
127.7 (3C), 129.7 (3C), 129.9 (3C), 133.1, 133.3, 133.4, 133.7, 135.1,
135.5 (2C), 135.6 (2C), 135.8 (2C), 135.9 (2C), 155.0. Anal. Calcd for
C43H57NO5Si2: C, 71.33; H, 7.93; N, 1.93. Found: C, 71.59; H, 7.97;
N, 1.98.
to give 16 as a colorless oil (4.22 g, 91% yield): ½a D25
þ16.9 (c 1.42,
ꢂ
CHCl3); IR (neat): 3442 (NH and OH), 1694 (C]O); 1H NMR
(500 MHz, CDCl3)
d
1.08 (s, 9H), 1.43 (s, 9H), 2.79e2.88 (m, 2H),
4.13. (4S,5R)-5-[(R)-1-(tert-Butyldiphenylsilyloxy)allyl]-4-
[(tert-butyldiphenylsilyloxy)methyl]oxazolidin-2-one (20)
3.72e3.81 (m, 3H), 4.03 (d, J¼10.3 Hz, 1H), 4.27e4.29 (m, 1H), 5.07
(d, J¼8.0 Hz, 1H), 5.20e5.22 (m, 1H), 5.32e5.35 (m, 1H), 6.00 (ddd,
J¼17.8, 10.3, 5.2 Hz, 1H), 7.38e7.46 (m, 6H), 7.64e7.68 (m, 4H); 13C
To a stirred solution of 19 (280 mg, 0.387 mmol) in THF (7.7 mL)
NMR (125 MHz, CDCl3)
d
19.2, 26.9 (3C), 28.4 (3C), 52.5, 63.8, 74.3,
was added SOCl2 (140 m
L, 1.93 mmol) at 0 ꢀC, and the mixture was
74.6, 79.9, 115.9, 127.9 (4C), 130.0 (2C), 132.6 (2C), 135.5 (2C), 135.6
(2C), 136.8, 155.9; HRMS (FAB) calcd for C27H40NO5Si: [MþH]þ,
486.2670; found: 486.2673.
stirred for 16 h under reflux. The mixture was concentrated under
reduced pressure to give an oily residue, which was purified by
flash chromatography over silica gel with n-hexaneeEtOAc (7:1) to
a 25
give 20 as a yellow oil (210 mg, 83% yield): ½ ꢂD ꢁ9.5 (c 1.11, CHCl3);
4.11. (R)-1-{(4S,5R)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2-
oxooxazolidin-5-yl}allyl acetate (17) and (4S,5S,6S)-4-[(tert-
butyldiphenylsilyloxy)methyl]-2-oxo-6-vinyl-1,3-oxazinan-5-
yl acetate (18)
IR (neat): 3280 (NH), 1759 (C]O); 1H NMR (500 MHz, CDCl3)
d 1.02
(s, 9H), 1.03 (s, 9H), 3.47 (dd, J¼10.3, 6.9 Hz, 1H), 3.56 (dd, J¼10.3,
3.4 Hz, 1H), 3.82e3.84 (m, 1H), 3.99 (dd, J¼4.9, 4.6 Hz, 1H), 4.37 (dd,
J¼6.0, 4.9 Hz, 1H), 5.05 (s, 1H), 5.18e5.25 (m, 2H), 6.00 (ddd, J¼17.2,
10.9, 6.0 Hz, 1H), 7.27e7.46 (m, 12H), 7.56e7.61 (m, 8H); 13C NMR
To a stirred solution of 16 (56 mg, 0.115 mmol) in CH2Cl2 (12 mL)
(125 MHz, CDCl3) d 19.2, 19.3, 26.7 (3C), 27.0 (3C), 30.9, 54.0, 66.1,
were added MeC(OMe)3 (86
m
L, 0.687 mmol) and BF3$OEt2 (2.8
m
L,
73.4, 78.8, 119.0, 127.6 (2C), 127.8 (2C), 127.9 (2C), 129.9 (2C), 130.0
(2C), 130.1, 132.7 (2C), 132.8, 133.1, 134.0, 135.4 (2C), 135.5 (2C),
135.7 (2C), 135.8 (2C), 158.2; HRMS (FAB) calcd for C39H48NO4Si2:
[MþH]þ 650.3116; found: 650.3113.
0.0227 mmol) at 0 ꢀC, and the mixture was warmed to room
temperature. After stirring for 1.5 h at this temperature, the mix-
ture was quenched by addition of MeOH at 0 ꢀC, and concentrated
under reduced pressure to give an oily residue, which was purified
by flash chromatography over silica gel with n-hexaneeEtOAc (4:1)
to give 17 (23 mg, 44% yield) and 18 (19 mg, 36% yield) both as
a colorless oil.
4.14. (4S,5R)-5-[(R)-1-(tert-Butyldiphenylsilyloxy)allyl]-4-
[(tert-butyldiphenylsilyloxy)methyl]-3-[(2-nitrophenyl)sulfo-
nyl]oxazolidin-2-one (21)
Compound 17: ½a 2D5
ꢂ
ꢁ33.1 (c 0.93, CHCl3); IR (neat): 3262 (NH),
1763 (C]O); 1H NMR (500 MHz, CDCl3)
d
1.05 (s, 9H), 2.05 (s, 3H),
To a stirred solution of 20 (460 mg, 0.708 mmol) in THF (3.5 mL)
was added NaH (56 mg, 1.41 mmol) at 0 ꢀC. After stirring for 30 min
at room temperature, NsCl (312 mg, 1.41 mmol) was added. The
mixture was stirred for 1 h at room temperature, and quenched by
addition of saturated NH4Cl at 0 ꢀC. The whole was extracted with
Et2O. The extract was washed with H2O and brine, and dried over
MgSO4. The filtrate was concentrated under reduced pressure to
give an oily residue, which was purified by flash chromatography
over silica gel with n-hexaneetoluene (1:1) to give 21 as a colorless
3.60 (d, J¼5.2 Hz, 2H), 3.68 (dd, J¼9.5, 5.2 Hz, 1H), 4.40e4.42 (m,
1H), 5.34e5.42 (m, 3H), 5.58 (s, 1H), 6.00 (ddd, J¼16.6, 10.9, 6.3 Hz,
1H), 7.38e7.42 (m, 4H), 7.43e7.49 (m, 2H), 7.62 (d, J¼5.2 Hz, 4H);
13C NMR (125 MHz, CDCl3)
d 19.1, 20.9, 26.7 (3C), 54.9, 65.1, 73.9,
78.0, 121.1, 127.9 (4C), 130.1 (2C), 130.5, 132.5 (2C), 135.5 (4C), 158.2,
169.6; HRMS (FAB) calcd for C25H32NO5Si: [MþH]þ, 454.2044;
found: 454.2046.
Compound 18: ½a 2D5
ꢂ
ꢁ40.2 (c 1.75, CHCl3); IR (neat): 3249 (NH),
1714 (C]O); 1H NMR (500 MHz, CDCl3)
d
1.07 (s, 9H), 2.07 (s, 3H),
oil (502 mg, 85% yield): ½a D25
þ154.6 (c 0.63, CHCl3); IR (neat): 1783
ꢂ
3.53e3.57 (m, 1H), 3.65 (dd, J¼10.6, 5.4 Hz, 1H), 3.71 (dd, J¼10.6,
6.0 Hz, 1H), 4.83e4.85 (m, 1H), 5.15e5.16 (m, 1H), 5.32e5.34 (m,
1H), 5.42e5.45 (m, 1H), 5.72e5.79 (m, 2H), 7.39e7.42 (m, 4H),
7.43e7.47 (m, 2H), 7.62e7.65 (m, 4H); 13C NMR (125 MHz, CDCl3)
(C]O), 1371 (NO2 and NSO2), 1138 (NSO2); 1H NMR (500 MHz,
CDCl3)
d
1.00 (s, 9H), 1.08 (s, 9H), 3.61 (dd, J¼11.5, 1.7 Hz, 1H),
4.19e4.24 (m, 2H), 4.41 (dd, J¼6.9, 2.9 Hz, 1H), 4.50e4.51 (m, 1H),
4.81e4.83 (m,1H), 5.04e5.08 (m,1H), 5.60 (ddd, J¼17.8,10.3, 7.4 Hz,
1H), 7.15e7.18 (m, 1H), 7.22e7.26 (m, 3H), 7.30e7.33 (m, 1H),
7.37e7.47 (m, 6H), 7.52e7.54 (m, 4H), 7.65e7.68 (m, 4H), 7.70e7.72
(m,1H), 7.74e7.77 (m, 1H), 7.80e7.83 (m,1H), 8.47 (dd, J¼8.0,1.1 Hz,
d
19.1, 20.7, 26.8 (3C), 55.8, 64.9, 65.7, 75.5, 119.3, 128.0 (4C), 130.1,
130.2, 130.8, 132.2, 132.3, 135.5 (2C), 135.6 (2C), 153.0, 169.9; HRMS
(FAB) calcd for C25H32NO5Si: [MþH]þ, 454.2044; found: 454.2049.
1H); 13C NMR (125 MHz, CDCl3)
d 19.2, 19.3, 26.7 (3C), 26.9 (3C),
4.12. tert-Butyl [(2S,3S,4R)-1,4-bis(tert-butyldiphenylsilyloxy)-
3-hydroxyhex-5-en-2-yl]carbamate (19)
59.4, 64.8, 74.2, 79.0, 121.0, 124.2, 127.4 (2C), 127.5 (2C), 127.8 (2C),
127.9 (2C), 129.7, 129.8, 130.0 (2C), 131.1, 132.0, 132.2, 132.7 (2C),
133.0, 133.3, 134.3, 134.9, 135.6 (2C), 135.8 (4C), 135.9 (2C), 147.8,
151.3; HRMS (FAB) calcd for C45H50N2NaO8SSi2: [MþH]þ 857.2724;
found: 857.2729.
To a stirred solution of 7a (2.50 g, 10.1 mmol) in CH2Cl2
(100 mL) were added imidazole (2.75 g, 40.4 mmol) and TBDPSCl
(7.86 mL, 30.2 mmol) at ꢁ20 ꢀC. After stirring for 19 h at this
temperature, the mixture was quenched by addition of saturated
NH4Cl, and the whole was extracted with CH2Cl2. The extract was
washed with H2O and brine, and dried over MgSO4. The filtrate
was concentrated under reduced pressure to give an oily residue,
which was purified by column chromatography over NH silica gel
4.15. 2-Nitro-N-[(2S,3R,4R)-1,3,4-trihydroxyhex-5-en-2-yl]
benzenesulfonamide (7c)
To a stirred solution of 21 (142 mg, 0.518 mmol) in THF (5.2 mL)
was added TBAF (1.0 M in THF; 2.07 mL, 2.07 mmol) at 0 ꢀC. After

Y. Yoshimitsu et al. / Tetrahedron 69 (2013) 4211e4220
4217
stirring for 2 h at room temperature, 1 N KOH (5.2 mL, 5.20 mmol)
was added. The mixture was stirred for 1 h at room temperature,
and quenched by addition of saturated NH4Cl at 0 ꢀC. The mixture
was concentrated under reduced pressure, and the residue was
extracted with EtOAc. The extract was dried over MgSO4. The fil-
trate was concentrated under reduced pressure to give an oily
residue, which was purified by flash chromatography over silica gel
with CHCl3eMeOH (20:1) to give 7c as a yellow solid (142 mg, 82%
(neat cmꢁ1): 3442 (NH and OH); 1H NMR (500 MHz, CDCl3)
d
0.88
(t, J¼6.9 Hz, 3H), 1.22e1.52 (m, 25H), 1.54e1.70 (m, 3H), 1.70e1.85
(br s, 3H), 3.30e3.33 (m, 1H), 3.57e3.62 (m, 3H), 4.01 (dd, J¼9.2,
6.3 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 14.1, 22.7, 26.0, 29.3, 29.5,
29.6, 29.7 (6C), 31.9, 34.0, 60.3, 73.7, 83.7, 85.1. Anal. Calcd for
C18H37NO2: C, 72.19; H, 12.45; N, 4.68. Found: C, 72.08; H, 12.25;
N, 4.76.
yield): mp 148e149 ꢀC; ½a D25
ꢂ
þ13.8 (c 0.33, MeCN); IR (neat): 3370
4.18. tert-Butyl (4S,5R)-5-[(R)-1-hydroxyallyl]-4-(hydroxy
methyl)-2-oxooxazolidine-3-carboxylate (23)
(NH and OH), 1363 (NO2 and NSO2), 1168 (NSO2); 1H NMR
(500 MHz, acetone-d6)
d 3.58e3.68 (m, 3H), 3.72e3.73 (m, 1H),
4.02e4.04 (m, 2H), 4.22e4.26 (m, 2H), 5.06e5.08 (m, 1H), 5.11e5.15
(m, 1H), 5.83 (ddd, J¼17.2, 11.5, 5.8 Hz,1H), 6.25 (br s,1H), 7.88e7.93
(m, 2H), 7.98e8.02 (m, 1H), 8.15e8.20 (m, 1H); 13C NMR (125 MHz,
To a stirred solution of 20 (1.91 g, 2.94 mmol) in THF (29 mL)
were added Et3N (407 mL, 2.94 mmol), Boc2O (890 mg, 4.08 mmol),
and DMAP (718 mg, 5.88 mmol) at 0 ꢀC, and the mixture was
warmed to room temperature. After stirring for 1 h at this tem-
perature, the mixture was quenched by addition of saturated
NH4Cl at 0 ꢀC, and the whole was extracted with Et2O. The extract
was washed with H2O and brine, and dried over MgSO4. The fil-
trate was concentrated under reduced pressure to give an oily
residue, which was dissolved in THF (29 mL). 3HF$Et3N (4.79 mL,
29.4 mmol) was added to this solution at room temperature, the
mixture was stirred for 6 h under reflux. The mixture was
quenched by addition of saturated NaHCO3 at 0 ꢀC and THF was
removed under reduced pressure. The whole was extracted with
EtOAc, and dried over MgSO4. The filtrate was concentrated under
reduced pressure to give an oily residue, which was purified by
flash chromatography over silica gel with n-hexaneeEtOAc (1:2) to
acetone-d6)
d 57.3, 62.8, 73.1, 73.2, 117.0, 126.0, 131.2, 133.8, 134.7,
135.7, 138.6, 148.8. Anal. Calcd for C12H16N2O7S: C, 43.37; H, 4.85; N,
8.43. Found: C, 43.26; H, 4.67; N, 8.41.
4.16. (2S,3R,4S)-4-(2-Nitrobenzenesulfonylamido)-2-vinyltetra
hydofuran-3-yl acetate (22)
To a stirred solution of 7c (133 mg, 0.400 mmol) in CH2Cl2
(8.0 mL) were added MeC(OMe)3 (300
mL, 2.40 mmol) and BF3$OEt2
(9.9 L, 0.0802 mmol) at room temperature, and the mixture was
m
stirred for 18 h at this temperature. The mixture was quenched by
addition of saturated NaHCO3 at 0 ꢀC, and the whole was extracted
with CH2Cl2. The extract was washed with H2O and brine, and dried
over MgSO4. The filtrate was concentrated under reduced pressure
to give an oily residue, which was purified by flash chromatography
over silica gel with n-hexaneeEtOAc (2:1) to give 22 as a yellow oil
give 23 as a colorless oil (765 mg, 95% yield): ½a D25
ꢁ6.6 (c 0.80,
ꢂ
CHCl3); IR (neat): 3442 (OH), 1731 (C]O); 1H NMR (500 MHz,
CDCl3)
d
1.53 (s, 9H), 3.13e3.26 (m, 2H), 3.73 (dd, J¼11.7, 3.2 Hz,
(122 mg, 86% yield): ½a D25
ꢂ
ꢁ101.1 (c 1.75, CHCl3); IR (neat): 3334 (NH
1H), 3.91 (dd, J¼11.7, 4.3 Hz, 1H), 4.18e4.20 (m, 1H), 4.29 (dd, J¼5.7,
4.6 Hz, 1H), 4.46 (dd, J¼4.6, 4.0 Hz, 1H), 5.33e5.37 (m, 1H),
5.45e5.51 (m, 1H), 5.89 (ddd, J¼17.2, 10.9, 5.7 Hz, 1H); 13C NMR
and OH), 1742 (C]O), 1365 (NO2 and NSO2), 1170 (NSO2); 1H NMR
(500 MHz, CDCl3)
d
2.02 (s, 3H), 3.91 (dd, J¼12.3, 4.9 Hz, 1H),
4.06e4.10 (m, 2H), 4.27e4.28 (m, 1H), 4.79e4.80 (m, 1H), 5.23 (dd,
J¼9.2, 1.7 Hz, 1H), 5.41 (dd, J¼17.2, 1.7 Hz, 1H), 5.84e5.91 (m, 2H),
7.75e7.79 (m, 2H), 7.89e7.94 (m, 1H), 8.15e8.19 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 27.9 (3C), 57.6, 61.9, 72.4, 77.3, 84.4, 119.1, 134.0,
149.4, 152.6; HRMS (FAB) calcd for C12H19NNaO6: [MþNa]þ,
296.1110; found: 296.1115.
(125 MHz, CDCl3)
d 20.7, 59.6, 72.1, 81.1, 83.5, 117.1, 125.5, 130.9,
133.0, 133.9, 134.1, 134.5, 147.8, 169.8; HRMS (FAB) calcd for
4.19. tert-Butyl [(3S,4R,5R)-4-hydroxy-5-vinyltetrahydrofuran-
3-yl]carbamate (24)
C14H15N2O7S: [MþH]þ, 355.0605; found: 355.0603.
4.17. (2S,3R,4S)-4-Amino-2-tetradecyltetrahydrofuran-3-ol (3a)
To a stirred solution of 23 (146 mg, 0.534 mmol) and Et3N
(1.48 mL, 10.7 mmol) in CH2Cl2 (11 mL) were added TsCl (408 mg,
2.14 mmol) and Me3N$HCl (51 mg, 0.534 mmol) at ꢁ78 ꢀC. After
stirring for 1 h at this temperature, the mixture was quenched by
addition of saturated NH4Cl, and the whole was extracted with
CH2Cl2. The extract was washed with H2O and brine, and dried over
MgSO4. The filtrate was concentrated under reduced pressure to
give a white solid, which was purified by flash chromatography
over silica gel with n-hexaneeEtOAc (4:1) to give the correspond-
ing tosylate as a white solid. To a stirred solution of the above
tosylate in MeOH (11 mL) was added K2CO3 (149 mg, 1.08 mmol),
and the mixture was stirred for 30 min at room temperature. The
mixture was quenched by addition of saturated NH4Cl, and con-
centrated under reduced pressure. The residue was extracted with
EtOAc and dried over MgSO4. The filtrate was concentrated under
reduced pressure to give a white solid, which was purified by flash
chromatography over silica gel with n-hexaneeEtOAc (4:1) to give
To a stirred solution of 22 (220 mg, 0.617 mmol) in CH2Cl2
(12 mL) were added tetradec-1-ene (1.56 mL, 6.16 mmol) and
second generation HoveydaeGrubbs catalyst (39 mg, 0.0622 mmol)
at room temperature. After stirring for 10 h under reflux, the
mixture was concentrated under reduced pressure followed by
rapid filtration through a short pad of silica gel with n-hex-
aneeEtOAc (4:1) to give a crude metathesis product, which was
dissolved in MeCN (6.2 mL). To this solution were added PhSH
(125
mL, 1.23 mmol) and Cs2CO3 (401 mg, 1.23 mmol) at room
temperature. After stirring for 1 h at this temperature, 1 N KOH
(6.2 mL, 6.20 mmol) was added. After stirring for 12 h at room
temperature, MeCN was removed under reduced pressure. The
residue was extracted with EtOAc, and dried over Na2SO4. The fil-
trate was concentrated under reduced pressure to give an oily
residue, which was purified by flash chromatography over silica gel
with CHCl3eMeOHe28% NH4OH (95:4:1) to give the corresponding
amino alcohol as a white solid. To a stirred solution of this amino
alcohol in EtOH (12 mL) was added 10% Pd/C (66 mg, 0.0620 mmol)
at room temperature, and the mixture was stirred for 12 h at this
temperature under H2. The mixture was filtrated, and the filtrate
was concentrated under reduced pressure to give a white solid,
which was purified by column chromatography over silica gel with
CHCl3eMeOHe28% NH4OH (100:3:1) to give 3a as a white solid
24 as a white solid (81 mg, 66% yield): mp 120e121 ꢀC; ½a D25
ꢁ37.3
ꢂ
(c 0.81, CHCl3); IR (neat): 3380 (NH and OH), 1684 (C]O); 1H NMR
(500 MHz, CDCl3)
d
1.46 (s, 9H), 2.34 (br s, 1H), 3.60 (dd, J¼9.2,
3.4 Hz, 1H), 4.08e4.16 (m, 2H), 4.29 (dd, J¼9.2, 6.0 Hz, 1H),
4.46e4.48 (m, 1H), 4.68 (br s 1H), 5.35e5.37 (m, 1H), 5.43e5.47 (m,
1H), 5.93 (ddd, J¼17.8, 10.9, 5.7 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d
28.3 (3C), 59.2, 70.8, 77.6, 80.2, 81.8, 118.4, 132.9, 155.5. Anal. Calcd
for C11H19NO4: C, 57.62; H, 8.35; N, 6.11. Found: C, 57.38; H, 8.36;
N, 5.97.
(109 mg 59% yield): mp 69e70 ꢀC; ½a D25
ꢁ2.66 (c 0.50, CHCl3); IR
ꢂ

4218
Y. Yoshimitsu et al. / Tetrahedron 69 (2013) 4211e4220
4.20. (2R,3R,4S)-4-Amino-2-tetradecyltetrahydrofuran-3-ol (4a)
86e87 ꢀC; ½a 2D5
þ2.7 (c 0.33, CHCl3); IR (neat): 3312 (NH and OH);
ꢂ
1H NMR (500 MHz, CDCl3)
d
0.88 (t, J¼6.9 Hz, 3H), 1.24e1.48 (m,
To a stirred solution of 24 (221 mg, 0.964 mmol) in CH2Cl2
(19 mL) were added tetradec-1-ene (2.44 mL, 9.64 mmol) and
second generation HoveydaeGrubbs catalyst (60 mg, 0.0964 mmol)
at room temperature. After stirring for 6 h under reflux, the mixture
was concentrated under reduced pressure to give an oily residue,
which was purified by flash chromatography over NH silica gel with
n-hexaneeEtOAc (6:1) to give the E/Z mixture of corresponding
metathesis product. To a stirred solution of the above metathesis
product in EtOH (32 mL) was added 10% Pd/C (51 mg, 0.0479 mmol)
at room temperature, and the mixture was stirred for 1 h at this
temperature under H2. The mixture was filtrated through a short
pad of Celite, and the filtrate was concentrated under reduced
pressure to give a white solid, which was dissolved in CH2Cl2
(19 mL). To this solution was added TFA (19 mL) at 0 ꢀC, and the
mixture was stirred for 30 min at room temperature. The mixture
was concentrated under reduced pressure to give an oily residue,
which was purified by column chromatography over silica gel with
CHCl3eMeOHe28% NH4OH (95:4:1) to give 4a as a white solid
31H), 1.54e1.67 (m, 2H), 3.39 (dd, J¼9.2, 3.2 Hz, 1H), 3.47e3.49 (m,
1H), 3.80e3.81 (m, 1H), 3.88e3.91 (m, 1H), 4.22 (dd, J¼9.2, 5.7 Hz,
1H); 13C NMR (125 MHz, CDCl3)
d 14.1, 22.7, 26.4, 28.5, 29.3, 29.6
(2C), 29.7 (7C), 29.8, 31.9, 60.0, 73.7, 79.7, 80.8. Anal. Calcd for
C20H41NO2$0.2H2O: C, 72.54; H, 12.60; N, 4.23. Found: C, 72.63; H,
12.51; N, 4.16.
4.24. (2S,3S,4R)-4-Amino-2-dodecyltetrahydrofuran-3-ol
(ent-4c)
By a procedure identical with that described for the preparation
of 4a, ent-24 (122 mg, 0.532 mmol) was reacted with dodec-1-ene
(1.18 mL, 5.31 mmol), followed by reduction and N-Boc depro-
tection to give ent-4c (66 mg, 46% yield) as a white solid: mp
77e78 ꢀC; ½a 2D5
þ3.3 (c 0.39, CHCl3); IR (neat): 3364 (NH and OH);
ꢂ
1H NMR (500 MHz, CDCl3)
d
0.88 (t, J¼6.9 Hz, 3H), 1.24e1.48 (m,
21H), 1.54e1.67 (m, 2H), 3.39 (dd, J¼9.2, 3.4 Hz, 1H), 3.47e3.49 (m,
1H), 3.80e3.81 (m, 1H), 3.88e3.91 (m, 1H), 4.22 (dd, J¼9.2, 6.3 Hz,
(153 mg, 53% yield): mp 80e81 ꢀC; ½a D25
ꢂ
ꢁ3.0 (c 0.98, CHCl3); IR
1H); 13C NMR (125 MHz, CDCl3)
d 14.1, 22.7, 26.4, 28.5, 29.3, 29.5,
(neat): 3422 (NH and OH); 1H NMR (500 MHz, CDCl3)
d
0.88 (t,
29.6 (4C), 29.8, 31.9, 60.0, 73.8, 79.8, 80.7. Anal. Calcd for
C16H33NO2: C, 70.80; H, 12.25; N, 5.16. Found: C, 70.52; H, 12.40;
N, 5.25.
J¼6.9 Hz, 3H), 1.23e1.48 (m, 27H), 1.54e1.67 (m, 2H), 3.39 (dd,
J¼9.2, 3.4 Hz, 1H), 3.47e3.49 (m, 1H), 3.80 (dd, J¼3.4, 1.1 Hz, 1H),
3.88e3.91 (m, 1H), 4.22 (dd, J¼9.2, 6.3 Hz, 1H); 13C NMR (125 MHz,
CDCl3)
d
14.1, 22.7, 26.4, 28.5, 29.3, 29.6 (2C), 29.7 (5C), 29.8, 31.9,
4.25. (2S,3S,4R)-4-Amino-2-decyltetrahydrofuran-3-ol (ent-4d)
59.9, 73.8, 79.8, 80.7. Anal. Calcd for C18H37NO2: C, 72.19; H, 12.45;
N, 4.68. Found: C, 71.90; H, 12.68; N, 4.87.
By a procedure identical with that described for the preparation
of 4a, ent-24 (146 mg, 0.637 mmol) was reacted with dec-1-ene
(1.21 mL, 6.39 mmol), followed by reduction and N-Boc depro-
tection to give ent-4d (81 mg, 52% yield) as a white solid: mp
4.21. tert-Butyl [(3R,4S,5S)-4-hydroxy-5-vinyltetrahydrofuran-
3-yl]carbamate (ent-24)
70e71 ꢀC; ½a 2D5
þ3.4 (c 0.39, CHCl3); IR (neat): 3362 (NH and OH);
ꢂ
By a procedure identical with that described for the preparation
1H NMR (500 MHz, CDCl3)
d
0.88 (t, J¼6.9 Hz, 3H), 1.24e1.48 (m,
of 24, (R)-Garner’s aldehyde was converted into ent-24: mp
19H), 1.54e1.67 (m, 2H), 3.39 (dd, J¼9.2, 3.2 Hz, 1H), 3.47e3.49 (m,
1H), 3.80e3.81 (m, 1H), 3.88e3.92 (m, 1H), 4.21 (dd, J¼9.2, 5.7 Hz,
120e121 ꢀC; ½a 2D5
ꢂ
þ39.8 (c 0.30, CHCl3) IR (neat): 3378 (NH and
OH),1685 (C]O); 1H NMR (500 MHz, CDCl3)
d
1.45 (s, 9H), 2.59 (br s
1H); 13C NMR (125 MHz, CDCl3)
d 14.1, 22.7, 26.4, 28.5, 29.3, 29.5,
1H), 3.60 (dd, J¼9.2, 3.4 Hz, 1H), 4.08e4.16 (m, 2H), 4.29 (dd, J¼9.5,
6.0 Hz, 1H), 4.46 (dd, J¼5.7, 4.6 Hz, 1H), 4.75 (d, J¼5.7 Hz, 1H), 5.35
(d, J¼10.9 Hz, 1H), 5.44 (d, J¼17.2 Hz, 1H), 5.93 (ddd, J¼17.2, 10.9,
29.6 (2C), 29.8, 31.9, 60.0, 73.8, 79.8, 80.8. Anal. Calcd for
C14H29NO2$0.2H2O: C, 68.08; H, 12.00; N, 5.67. Found: C, 68.03; H,
11.95; N, 5.54.
5.7 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 28.3 (3C), 59.2, 70.8, 77.6,
80.2, 81.8, 118.4, 132.9, 155.5. Anal. Calcd for C11H19NO4: C, 57.62; H,
8.35; N, 6.11. Found: C, 57.81; H, 8.65; N, 5.92.
4.26. (2S,3S,4R)-4-Amino-2-octyltetrahydrofuran-3-ol (ent-4e)
By a procedure identical with that described for the preparation
of 4a, ent-24 (190 mg, 0.829 mmol) was reacted with oct-1-ene
(1.29 mL, 8.29 mmol), followed by reduction and N-Boc depro-
tection to give ent-4e (78 mg, 44% yield) as a white solid: mp
4.22. (2S,3S,4R)-4-Amino-2-tetradecyltetrahydrofuran-3-ol
(ent-4a)
By a procedure identical with that described for the preparation
of 4a, ent-24 (102 mg, 0.445 mmol) was reacted with tetradec-1-
ene (1.13 mL, 4.46 mmol), followed by reduction and N-Boc
deprotection to give ent-4a (58 mg, 44% yield) as a white solid: mp
63e64 ꢀC; ½a 2D5
þ3.2 (c 0.44, CHCl3); IR (neat): 3356 (NH and OH);
ꢂ
1H NMR (500 MHz, CDCl3)
d
0.88 (t, J¼6.9 Hz, 3H), 1.21e1.68 (m,
17H), 3.39 (dd, J¼9.2, 3.4 Hz,1H), 3.47e3.49 (m, 1H), 3.81 (dd, J¼3.4,
1.1 Hz, 1H), 3.88e3.92 (m, 1H), 4.21 (dd, J¼9.2, 5.7 Hz, 1H); 13C NMR
81e82 ꢀC; ½a 2D5
ꢂ
þ3.6 (c 0.20, CHCl3); IR (neat): 3350 (NH and OH);
(125 MHz, CDCl3) d 14.1, 22.6, 26.4, 28.5, 29.2, 29.5, 29.8, 31.8, 60.0,
1H NMR (500 MHz, CDCl3)
d
0.88 (t, J¼6.9 Hz, 3H), 1.24e1.48 (m,
73.8, 79.7, 80.8. Anal. Calcd for C12H25NO2$0.2H2O: C, 65.83; H,
11.69; N, 6.40. Found: C, 65.96; H, 11.59; N, 6.27.
27H), 1.54e1.66 (m, 2H), 3.39 (dd, J¼9.2, 3.2 Hz, 1H), 3.47e3.49 (m,
1H), 3.80e3.81 (m, 1H), 3.88e3.91 (m, 1H), 4.22 (dd, J¼9.2, 5.7 Hz,
1H); 13C NMR (125 MHz, CDCl3)
d
14.1, 22.7, 26.4, 28.5, 29.3, 29.6
4.27. (2S,3S,4R)-4-Amino-2-vinyltetrahydrofuran-3-ol (ent-4f)
(2C), 29.7 (5C), 29.8, 31.9, 60.0, 73.8, 79.8, 80.7. Anal. Calcd for
C18H37NO2: C, 72.19; H, 12.45; N, 4.68. Found: C, 72.04; H, 12.57;
N, 4.69.
To a stirred solution of ent-24 (120 mg, 0.523 mmol) in CH2Cl2
(10 mL) was added TFA (10 mL) at 0 ꢀC, and the mixture was stirred
for 30 min at room temperature. The mixture was concentrated
under reduced pressure to give an oily residue, which was purified
by flash chromatography over silica gel with CHCl3eMeOHe28%
NH4OH (95:4:1) to give ent-4f (60 mg, 89% yield) as a white solid:
4.23. (2S,3S,4R)-4-Amino-2-hexadecyltetrahydrofuran-3-ol
(ent-4b)
By a procedure identical with that described for the preparation
of 4a, ent-24 (86 mg, 0.735 mmol) was reacted with hexadec-1-ene
(1.07 mL, 3.73 mmol), followed by reduction and N-Boc depro-
tection to give ent-4b (63 mg, 51% yield) as a white solid: mp
mp 53e54 ꢀC; ½a 2D5
ꢂ
þ23.6 (c 0.35, CHCl3); IR (neat): 3355 (NH and
OH); 1H NMR (500 MHz, CDCl3)
d
1.48 (s, 3H), 3.53e3.57 (m, 2H),
3.88 (dd, J¼3.7, 1.4 Hz, 1H), 4.25e4.28 (m, 1H), 4.59e4.61 (m, 1H),
5.37e5.40 (m, 1H), 5.48e5.52 (m, 1H), 5.91 (ddd, J¼17.2, 10.5,

Y. Yoshimitsu et al. / Tetrahedron 69 (2013) 4211e4220
4219
5.7 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d
59.2, 73.8, 79.5, 81.4, 118.4,
CDCl3) d 25.9 (2C), 26.2, 26.4, 26.7, 28.5, 29.5 (5C), 29.6, 29.7, 29.8,
133.3. Anal. Calcd for C6H11NO2: C, 55.80; H, 8.58; N, 10.84. Found:
C, 55.53; H, 8.76; N, 10.77.
30.2, 38.0, 60.0, 71.1, 73.8, 76.8, 79.8, 80.7. Anal. Calcd for C22H43NO3:
C, 71.50; H, 11.73; N, 3.79. Found: C, 71.22; H, 11.97; N, 3.75.
4.28. (2S,3S,4R)-4-Amino-2-(4-octylphenethyl)tetrahydrofu-
ran-3-ol (ent-4g)
4.32. (2S,3S,4R)-4-Amino-2-(10-phenoxydecyl)tetrahydrofu-
ran-3-ol (ent-4k)
By a procedure identical with that described for the preparation
of 4a, ent-24 (100 mg, 0.436 mmol) was reacted with 1-octyl-4-
vinylbenzene (196 mg, 0.906 mmol), followed by reduction and
N-Boc deprotection to give ent-4g (37 mg, 20% yield) as a white
By a procedure identical with that described for the preparation
of 4a, ent-24 (90 mg, 0.393 mmol) was reacted with (dec-9-en-1-
yloxy)benzene (630 mg, 2.71 mmol), followed by reduction and
N-Boc deprotection to give ent-4k (65 mg, 49% yield) as a white
solid: mp 93e94 ꢀC; ½a D25
ꢂ
ꢁ10.2 (c 0.23, CHCl3); IR (neat): 3320 (NH
solid: mp 62e63 ꢀC; ½a D25
ꢂ
þ2.0 (c 0.45, CHCl3); 1H NMR (500 MHz,
and OH); 1H NMR (500 MHz, CDCl3)
d
0.88 (t, J¼6.9 Hz, 3H),
CDCl3) d 1.26e1.48 (m, 17H), 1.54e1.66 (m, 2H), 1.75e1.80 (m, 2H),
1.24e1.34 (m, 13H), 1.56e1.62 (m, 2H), 1.86e1.93 (m, 1H), 1.96e2.03
(m,1H), 2.56 (t, J¼7.7 Hz, 2H), 2.63e2.69 (m,1H), 2.77e2.83 (m,1H),
3.40 (dd, J¼9.2, 3.4 Hz, 1H), 3.45e3.47 (m, 1H), 3.77e3.79 (m, 1H),
3.91e3.95 (m, 1H), 4.22 (dd, J¼9.2, 5.7 Hz, 1H), 7.12 (dd, J¼18.3,
3.39 (dd, J¼9.2, 3.4 Hz, 1H), 3.47e3.49 (m, 1H), 3.80e3.81 (m, 1H),
3.90 (td, J¼6.7, 3.1 Hz, 1H), 3.95 (t, J¼6.6 Hz, 2H), 4.22 (dd, J¼9.2,
5.7 Hz, 1H), 6.89e6.94 (m, 3H), 7.26e7.29 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 26.0, 26.4, 28.5, 29.3, 29.4, 29.5 (3C), 29.8, 60.0,
8.0 Hz, 4H); 13C NMR (125 MHz, CDCl3)
d
14.1, 22.7, 29.3, 29.4, 29.5,
67.9, 73.8, 79.9, 80.7, 114.5 (2C), 120.4, 129.4 (2C), 159.1. Anal. Calcd
for C20H33NO3$0.2H2O: C, 70.84; H, 9.93; N, 4.13. Found: C, 70.62; H,
10.06; N, 4.03.
30.4, 31.6, 31.9, 32.1, 35.6, 60.1, 73.7, 79.8, 80.2, 128.2 (2C), 128.5
(2C), 138.9, 140.6. Anal. Calcd for C20H33NO2: C, 75.19; H, 10.41; N,
4.38. Found: C, 75.02; H, 10.46; N, 4.40.
4.33. (2S,3S,4R)-4-Amino-2-(11-phenoxyundecyl)tetrahydro-
furan-3-ol (ent-4l)
4.29. (2S,3S,4R)-4-Amino-2-(11-ethoxyundecyl)tetrahydrofu-
ran-3-ol (ent-4h)
By a procedure identical with that described for the preparation
of 4a, ent-24 (80 mg, 0.349 mmol) was reacted with (undec-10-en-
1-yloxy)benzene (667 mg, 2.71 mmol), followed by reduction and
N-Boc deprotection to give ent-4l (64 mg, 52% yield) as a white
By a procedure identical with that described for the preparation
of 4a, ent-24 (100 mg, 0.436 mmol) was reacted with 11-
ethoxyundec-1-ene (595 mg, 3.00 mmol), followed by reduction
and N-Boc deprotection to give ent-4h (67 mg, 56% yield) as a white
solid: mp 74e75 ꢀC; ½a D25
ꢂ
þ1.6 (c 0.70, CHCl3); IR (neat): 3321 (NH
solid: mp 59e60 ꢀC; ½a D25
ꢂ
þ2.8 (c 0.70, CHCl3); IR (neat): 3372 (NH
and OH); 1H NMR (500 MHz, CDCl3)
d 1.27e1.48 (m, 16H), 1.52e1.66
and OH); 1H NMR (500 MHz, CDCl3)
d
1.20 (t, J¼7.2 Hz, 3H),
(m, 5H), 1.75e1.80 (m, 2H), 3.39 (dd, J¼9.2, 3.4 Hz, 1H), 3.47e3.49
(m, 1H), 3.80e3.82 (m, 1H), 3.90 (td, J¼6.7, 2.7 Hz, 1H), 3.95 (t,
J¼6.6 Hz, 2H), 4.22 (dd, J¼9.2, 5.7 Hz, 1H), 6.89e6.94 (m, 3H),
1.25e1.47 (m, 19H), 1.54e1.67 (m, 4H), 3.38e3.41 (m, 3H),
3.45e3.49 (m, 3H), 3.80e3.81 (m, 1H), 3.90 (td, J¼7.0, 2.7 Hz, 1H),
4.22 (dd, J¼9.2, 6.3 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d
15.2, 26.2,
7.26e7.29 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 26.0, 26.4, 28.5,
26.4, 28.5, 29.5 (5C), 29.7, 29.8, 60.0, 66.0, 70.8, 73.7, 79.7, 80.7. Anal.
Calcd for C17H35NO3: C, 67.73; H, 11.70; N, 4.65. Found: C, 67.49; H,
11.81; N, 4.54.
29.3, 29.4, 29.5 (4C), 29.8, 60.0, 67.9, 73.8, 79.8, 80.7, 114.5 (2C),
120.4, 129.4 (2C), 159.1. Anal. Calcd for C21H35NO3$0.2H2O: C, 71.43;
H, 10.10; N, 3.97. Found: C, 71.34; H, 10.03; N, 3.87.
4.30. (2S,3S,4R)-4-Amino-2-(10-propoxydecyl)tetrahydrofu-
ran-3-ol (ent-4i)
4.34. Sphingosine kinase assay
SphK inhibitory activities were evaluated by the off-chip mo-
bility shift assay by the QuickScoutÒ service from Carna Bioscience
(Kobe, Japan). SphK1 (1e384) and SphK2 (1e618) were expressed
as N-terminal GST-fusion proteins using a baculovirus expression
system. They were purified using glutathione sepharose chroma-
tography. Each chemical in DMSO at different concentrations was
diluted fourfold with reaction buffer [20 mM HEPES (pH 7.5), 0.01%
Triton X-100, 2 mM DTT]. For SphK reactions, a combination of the
By a procedure identical with that described for the preparation
of 4a, ent-24 (90 mg, 0.393 mmol) was reacted with 10-
propoxydec-1-ene (350 mg, 1.76 mmol), followed by reduction
and N-Boc deprotection to give ent-4i (50 mg, 42% yield) as a white
solid: mp 55e56 ꢀC; ½a D25
þ1.6 (c 0.45, CHCl3); IR (neat): 3361 (NH
ꢂ
and OH); 1H NMR (500 MHz, CDCl3)
d
0.92 (t, J¼7.4 Hz, 3H),
1.25e1.46 (m, 17H), 1.53e1.66 (m, 6H), 3.35e3.41 (m, 5H),
3.47e3.49 (m, 1H), 3.80e3.81 (m, 1H), 3.88e3.91 (m, 1H), 4.22 (dd,
compound, 1
for SphK2) in reaction buffer (20
SphK in 384-well plates at room temperature for 1 h (n¼2). The
reaction was terminated by addition of 60 L of termination buffer
mM Sph, 5 mM MgCl2, ATP (25
mM for SphK1; 600 mM
J¼9.5, 6.0 Hz,1H); 13C NMR (125 MHz, CDCl3)
d
10.6, 22.9, 26.2, 26.4,
mL) were incubated with each
28.5, 29.5 (4C), 29.7, 29.8, 60.0, 70.9, 72.5, 73.8, 79.8, 80.7. Anal.
Calcd for C17H35NO3$0.25H2O: C, 66.73; H, 11.69; N, 4.58. Found: C,
66.47; H, 11.80; N, 4.52.
m
(Carna Biosciences). Substrate and product were separated by
electrophoretic means using the LabChip3000 system. The kinase
reaction was evaluated by the product ratio, which was calculated
from the peak heights of the substrate (S) and product (P): [P/
(PþS)]. Inhibition data were calculated by comparing with no-
enzyme controls for 100% inhibition and no-inhibitor reactions
for 0% inhibition. IC50 values were calculated using GraphPad Prism
4 software (GraphPad Software, Incorporated, La Jolla, CA, USA).
4.31. (2S,3S,4R)-4-Amino-2-[11-(cyclohexylmethoxy)undecyl]
tetrahydrofuran-3-ol (ent-4j)
By a procedure identical with that described for the preparation
of 4a, ent-24 (80 mg, 0.349 mmol) was reacted with [(undec-10-en-
1-yloxy)methyl]cyclohexane (595 mg, 3.00 mmol), followed by re-
duction and N-Boc deprotection to give ent-4j (69 mg, 53% yield) as
a white solid: mp 63e64 ꢀC; ½a D25
ꢂ
þ1.8 (c 1.29, CHCl3); IR (neat):
Acknowledgements
3365 (NH and OH); 1H NMR (500 MHz, CDCl3)
d
0.87e0.95 (m, 2H),
1.14e1.48 (m, 22H), 1.52e1.77 (m, 10H), 3.19 (d, J¼6.3 Hz, 2H),
3.36e3.41 (m, 3H), 3.46e3.48 (m, 1H), 3.80e3.81 (m, 1H), 3.90 (td,
J¼6.7, 3.1 Hz, 1H), 4.22 (dd, J¼9.2, 6.3 Hz, 1H); 13C NMR (125 MHz,
This work was supported by a Grant-in-Aid for Encouragement
of Young Scientists (A) (H.O.); and Platform for Drug Discovery,
Informatics, and Structural Life Science from the Ministry of

4220
Y. Yoshimitsu et al. / Tetrahedron 69 (2013) 4211e4220
Jin, X.; Park, S. H.; Joo, J. E.; Ham, W. H. Synthesis 2012, 44, 2340; (p) Lee, D.
Synlett 2012, 2840.
4. (a) Jayachitra, G.; Sudhakar, N.; Anchoori, R. K.; Rao, B. V.; Roy, S.; Banerjee, R.
Education, Culture, Sports, Science and Technology of Japan. Y.Y. is
grateful for Research Fellowships from the Japan Society for the
Promotion of Science (JSPS) for Young Scientists.
Synthesis 2010, 115; (b) Rao, G. S.; Sudhakar, N.; Rao, B. V.; Basha, S. J. Tetra-
ꢀ
hedron: Asymmetry 2010, 21, 1963; (c) Sanchez-Eleuterio, A.; Quintero, L.; Sar-
tillo-Piscil, F. J. Org. Chem. 2011, 76, 5466; (d) Prasad, K. R.; Penchalaiah, K.
Tetrahedron: Asymmetry 2011, 22, 1400; (e) Rao, G. S.; Rao, B. V. Tetrahedron Lett.
2011, 52, 4861; (f) Rao, G. S.; Chandrasekhar, B.; Rao, B. V. Tetrahedron: Asym-
metry 2012, 23, 564.
5. Yoshimitsu, Y.; Oishi, S.; Miyagaki, J.; Inuki, S.; Ohno, H.; Fujii, N. Bioorg. Med.
Chem. 2011, 19, 5402.
References and notes
1. (a) Kuroda, I.; Musman, M.; Ohtani, I.; Ichiba, T.; Tanaka, J.; Garcia-Gravalos, D.;
Higa, T. J. Nat. Prod. 2002, 65, 1505; (b) Ledroit, V.; Debitus, C.; Lavaud, C.;
Massoit, G. Tetrahedron Lett. 2003, 44, 225; (c) Canals, D.; Mormeneo, D.; Fab-
ꢀ
rias, G.; Llebaria, A.; Casas, J.; Delgado, A. Bioorg. Med. Chem. 2009, 17, 235; (d)
6. For the structureeactivity relationships associated with the C-2 position, see:
ꢁ
ꢁ
ꢁ
ꢁ
Salma, Y.; Lafont, E.; Therville, N.; Carpentier, S.; Bonnafe, M. J.; Levade, T.;
(a) Genisson, Y.; Lamande, L.; Salma, Y.; Andrieu-Abadie, N.; Andre, C.; Baltas,
ꢁ
Genisson, Y.; Abadie, N. A. Biochem. Pharmacol. 2009, 78, 477.
M. Tetrahedron: Asymmetry 2007, 18, 857; (b) Salma, Y.; Ballereau, S.; Ladeira, S.;
ꢁ
2. For a review, see: Abraham, E.; Davies, S. G.; Roberts, P. M.; Russell, A. J.;
Lepetit, C.; Chauvin, R.; Andrieu-Abadie, N.; Genisson, Y. Tetrahedron 2011, 67,
Thomson, J. E. Tetrahedron: Asymmetry 2008, 19, 1027.
4253.
3. For recent syntheses, see: (a) Passiniemi, M.; Koskinen, A. M. P. Tetrahedron Lett.
2008, 49, 980; (b) Ichikawa, Y.; Matsunaga, K.; Masuda, T.; Kotsuki, H.; Nakano,
K. Tetrahedron 2008, 64, 11313; (c) Reddipalli, G.; Venkataiah, M.; Mishra, M. K.;
Fadnavis, N. W. Tetrahedron: Asymmetry 2009, 20, 1802; (d) Inuki, S.; Yoshi-
mitsu, Y.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2009, 11, 4478; (e) Salma, Y.;
7. (a) Garner, P. Tetrahedron Lett. 1984, 25, 5855; (b) Campbell, A. D.; Raynham, T.
M.; Taylor, R. J. K. Synthesis 1998, 1707.
8. (a) Lombardo, M.; Licciulli, S.; Trombini, C. Tetrahedron Lett. 2003, 44, 9147; (b)
Lombardo, M.; Gianotti, K.; Licciulli, S.; Trombini, C. Tetrahedron 2004, 60,
11725.
ꢁ
Ballereau, S.; Maaliki, C.; Ladeira, S.; Andrieu-Abadie, N.; Genisson, Y. Org. Bi-
9. Tanabe, Y.; Yamamoto, H.; Yoshida, Y.; Miyawaki, T.; Utsumi, N. Bull. Chem. Soc.
Jpn. 1995, 68, 297.
omol. Chem. 2010, 8, 3227; (f) Urano, H.; Enomoto, M.; Kuwahara, S. Biosci.
Biotechnol. Biochem. 2010, 74, 152; (g) Inuki, S.; Yoshimitsu, Y.; Oishi, S.; Fujii, N.;
Ohno, H. J. Org. Chem. 2010, 75, 3831; (h) Yoshimitsu, Y.; Inuki, S.; Oishi, S.; Fujii,
N.; Ohno, H. J. Org. Chem. 2010, 75, 3843; (i) Vichare, P.; Chattopadhyay, A.
Tetrahedron: Asymmetry 2010, 21, 1983; (j) Passiniemi, M.; Koskinen, A. M. P.
Org. Biomol. Chem. 2011, 9, 1774; (k) Llaveria, J.; Díaz, Y.; Matheu, M. I.; Castillon,
S. Eur. J. Org. Chem. 2011, 1514; (l) Rao, G. S.; Rao, B. V. Tetrahedron Lett. 2011, 52,
6076; (m) Cruz-Gregorio, S.; Espinoza-Rojas, C.; Quintero, L.; Sartillo-Piscil, F.
Tetrahedron Lett. 2011, 52, 6370; (n) Zhao, M. L.; Zhang, E.; Gao, J.; Zhang, Z.;
Zhao, Y. T.; Qu, W.; Liu, H. M. Carbohydr. Res. 2012, 351, 126; (o) Mu, Y.; Kim, J. Y.;
€
10. For a related THF formation under acidic conditions, see: Borner, A.; Holz, J.;
Ward, J.; Kagan, H. B. J. Org. Chem. 1993, 58, 6814.
11. Although the amino-unprotected derivative was subjected to various olefin
cross metathesis conditions, none of which were suitably unsuccessful.
12. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 8168.
13. van den Berg, R.; Boltje, T.; Verhagen, C.; Litjens, R.; van der Marel, G.; Over-
kleeft, H. J. Org. Chem. 2006, 71, 836.
ꢁ
14. Perrin, D.; Fremaux, C.; Scheer, A. J. Biomol. Screen. 2006, 11, 359.