Enantioselective synthesis of jaspine B (pachastrissamine) and Its C-2 and/or C-3 epimers

Article abstract of DOI:10.1002/ejoc.201001477

Jaspine B and its C-2 and/or C3 epimers have been enantioselectively prepared from butadiene monoepoxide through a synthetic procedure consisting of allylic amination by palladium-catalyzed dynamic kinetic asymmetric transformation, cross metathesis, and

Full text of DOI:10.1002/ejoc.201001477

FULL PAPER
DOI: 10.1002/ejoc.201001477
Enantioselective Synthesis of Jaspine B (Pachastrissamine) and Its C-2 and/or
C-3 Epimers
Josep Llaveria,[a] Yolanda Díaz,[a] M. Isabel Matheu,*[a] and Sergio Castillón*[a]
Dedicated to Professor Cármen Nájera on the occasion of her 60th birthday
Keywords: Natural products / Enantioselectivity / Metathesis / Dihydroxylation
Jaspine B and its C-2 and/or C3 epimers have been enantio-
selectively prepared from butadiene monoepoxide through a
synthetic procedure consisting of allylic amination by palla-
dium-catalyzed dynamic kinetic asymmetric transformation,
cross metathesis, and stereoselective dihydroxylation as key
steps.
Since its isolation in 2002, and in view of its interesting
biological activity, different synthetic methods have been re-
ported for the total synthesis of aspine B (1),[6] its isomers
2–4, and other analogues (Scheme 1). Thus, jaspine B and
its derivatives have been prepared by using starting materi-
als from the chiral pool, such as l-serine,[7] Garner’s alde-
hyde,[8–11] d-xylose,[4,12,13] d-glucose,[13–15] tri-O-benzyl-d-
galactal,[16] d-ribo-phytosphingosine,[3,17,18] (R)-glycidol,[19]
and l-tartaric acid[20,21] (Scheme 1).
Introduction
Jaspine B, also known as pachastrissamine (1; Figure 1),
is a cyclic anhydrosphingosine isolated by Higa and co-
workers in 2002 from the marine sponge Pachastrissa sp.
(family Calthropellidae), which is found in the Okinawan
islands.[1] Simultaneously, Debitus and co-workers[2] re-
ported the isolation of jaspine B from the marine sponge
Jaspis sp. This compound has shown submicromolar cyto-
toxic activity against P388, A549, MT29 and MEL28,
MDA231, and HeLa and CNE cell lines, indicating poten-
tial usage in various cancer treatments.[2–4] This biological
activity could act in synergy with classical antitumor mole-
cules, as has been shown for phytosphingosine.[5]
Scheme 1. Published approaches to jaspine B.
A few enantioselective catalytic procedures have been re-
ported that are based on: (i) Sharpless asymmetric epoxid-
ation of 4-benzyloxy-(2E)-butene-1-ol (Scheme 1a),[22]
(ii) Sharpless asymmetric dihydroxylation of ethyl (2E)-hep-
tadecenoate (Scheme 1b),[23] and (iii) methyl (2E)-5-p-meth-
oxybenzyloxy-2-pentanoate (Scheme 1c).[24] Recently, an
asymmetric organocatalytic method that uses a proline-cat-
alyzed aldol[25] or oxidation[26] reaction as a key step and a
diastereoselective synthesis based on the tandem conjugate
Figure 1. Jaspine B (1) and its isomers 2–4.
[a] Departament de Química Analítica i Química Orgànica,
Facultat de Química, Universitat Rovira i Virgili,
C/Marcel.lí Domingo s/n, 43007 Tarragona, Spain
Fax: 34-977-558446
E-mail: sergio.castillon@urv.cat
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001477.
1514
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1514–1519

Enantioselective Synthesis of Jaspine B and Its C-2 and/or C-3 Epimers
addition of a chiral lithium amide to a triisopropylsilyloxy- ence of the second generation Grubbs catalyst to afford
α,β-unsaturated methyl ester followed by enolate oxidation compound 7 in excellent yield (99%) and stereoselectivity,
1
have been described (Scheme 1d).[27]
with only the E isomer being detected by H NMR spec-
troscopy.
We have described the substrate-controlled dihydrox-
ylation of compound 7 by using osmium catalysis, which
provides a separable mixture of 8 and 9 in a 3.3:1 ratio.[29]
The diastereomeric ratio was further improved by using
(DHQ)2PYR as a ligand. Under these conditions, the reac-
tion was quantitative, and the ratio 8/9 was improved to
5.2:1, which allowed the isolation of compound 8 in an 80%
yield over three steps (Scheme 4). To promote the formation
of mismatched product 9, from which isomers 3 and 4 can
be obtained, the pseudoenantiomeric ligands (DHQD)2-
PYR and (DHQD)2AQN were tested in the osmium-cata-
lyzed dihydroxylation reaction. Both ligands afforded a
mixture of products 8 and 9 with excellent conversion
(Ͼ98%), and an 8/9 ratio of 1:1.3 was obtained when
(DHQD)2PYR was used. This allowed the recovery of com-
pound 9 in a 47% yield (Scheme 4).
Results and Discussion
Herein we report a catalytic enantioselective route to the
synthesis of jaspine B (1) and its epimers 2–4 (Figure 1),
starting from racemic butadiene monoepoxide (5). In the
proposed retrosynthesis, compounds 1–4 can be obtained
from common intermediate A (Scheme 2), which in turn
can be obtained from 5 by an enantioselective palladium-
catalyzed allylic amination, followed by a cross-metathesis
reaction with a ruthenium catalyst.
Scheme 2. Retrosynthetic route to jaspine B (1) and its isomers 2–
4.
The strategy to 1–4 consists of performing the diastereo-
selective dihydroxylation of A to afford intermediates B and
C, from which compounds 1–4 can be obtained by cycliza-
tion involving routes a–d (Scheme 2).
Initially, butadiene monoepoxide (5) was treated with
phthalimide in the presence of Pd/(S,S)-DACH-naphthyl to
afford 2-N-phthalimido-3-buten-1-ol (6; Scheme 3) in excel-
lent yield and enantioselectivity through a palladium-cata-
lyzed DYKAT (dynamic kinetic asymmetric transforma-
tion) process described by Trost.[28] Compound 6 was
treated with an excess amount of 1-hexadecene in the pres-
Scheme 4. Synthesis of compounds 8 and 9 by osmium-catalyzed
dihydroxylation.
With 8 in hand, two strategies were studied to obtain
jaspine B and its C-2 epimer (epi-Jaspine). One pathway
was based on a cyclization involving a leaving group at the
primary hydroxy group (OX, Scheme 2a). Thus, when com-
pound 8 was treated with TsCl in TEA/DMAP, the isolated
tosyl derivative was obtained in a 42% yield, together with
the cyclization product in 25% yield. However, when the
crude reaction product was treated with Na2CO3 in meth-
anol, tetrahydrofuran derivative 10 was obtained in a 61%
yield over two steps as a consequence of intramolecular tos-
ylate displacement[3,17,19] and partial methanolysis of the
phthalimido group (Scheme 5). The phthalimido group was
then removed by treatment with MeNH2 to afford jaspine B
(1)[3,19,27a] in 93% yield.
Scheme 5. Synthesis of jaspine B (1) from triol 8.
The second strategy involved a reverse cyclization reac-
tion, where the leaving group is now present at the C-4 posi-
tion (OY, Scheme 2b) and the 1-OH is the nucleophile (X =
Scheme 3. Synthesis of compound 7 from racemic butadiene
monoepoxide (5).[29]
Eur. J. Org. Chem. 2011, 1514–1519
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1515

J. Llaveria, Y. Díaz, M. I. Matheu, S. Castillón
FULL PAPER
H, Scheme 2b). The 3,4-cyclic sulfate was selected as the
The synthesis of 3-epi-jaspine B (4)[3,11] was carried out
leaving group. The primary hydroxy group in 8 was pro- by initial silylation of 9 to give 14, which was then treated
tected as a tert-butyldimethylsilyl ether in 89% yield. Reac- with SOCl2 and RuO4 to afford cyclic sulfate 15. Com-
tion with thionyl chloride followed by oxidation with RuO4 pound 15 was treated with TBAF in THF at room tempera-
and NaIO4 afforded sulfate 11 in quantitative yield ture to afford protected tetrahydrofuran 16 through desi-
(Scheme 6). Treatment of reactive sulfate 11 with TBAF in lylative cyclization and sulfate hydrolysis in 93% yield over
THF at room temperature afforded protected tetra- two steps. Cyclization to give the oxetane was not detected
1
hydrofuran 12 in 86% yield over two steps through desi- by H NMR spectroscopy. Finally, removal of the phthal-
lylative cyclization and hydrolysis of the sulfate group. The imido group with methylamine afforded compound 4 in
4-exo-cyclization product was not detected in the reaction 85% yield (Scheme 8).
1
mixture by H NMR spectroscopy, as described by Kim et
al.[18] After deprotection of the phthalimido group, 2-epi-
jaspine B (2)[3,7,27] was obtained in 86% yield (Scheme 6).
Conclusions
In conclusion, we have developed a short and efficient
divergent enantioselective catalytic method to synthesize
the natural anhydrosphingosine jaspine B (Pachastrissam-
ine, 1) and three of its 2-, 3-, and 2,3-epimers (i.e., 2–4)
from racemic butadiene monoepoxide. Jaspine B was syn-
thesized in a 54% overall yield, and compounds 2, 3, and 4
were obtained in 55, 36, and 24% yield, respectively. A sim-
ilar methodology using the enantiomeric ligand (R,R)-
DACH-naphthyl could be used to obtain the corresponding
enantiomers.
Scheme 6. Synthesis of 2-epi-jaspine B (2) from triol 8.
Experimental Section
A similar strategy was followed to obtain C-2 and C-3 General Methods: All chemicals were reagent grade and used as
supplied unless otherwise specified. HPLC-grade dichloromethane
(CH2Cl2), tetrahydrofuran (THF), and dimethylformamide (DMF)
were dried by using a solvent purification system (Pure SOLV sys-
tem-4). 1H and 13C NMR spectra were recorded with a Varian
Mercury VX 400 (400 and 100.6 MHz, respectively) or Varian 400-
MR spectrometer in CDCl3 as solvent, with chemical shifts (δ) ref-
erenced to internal standards CDCl3 (δ = 7.26 ppm for 1H; δ =
77.23 ppm for 13C) or Me4Si as an internal reference (δ =
0.00 ppm). 2D correlation spectra (gCOSY, NOESY, gHSQC,
gHMBC) were visualized by using VNMR program (Varian). MS
(ESI) were run with an Agilent 1100 Series LC–MSD instrument.
Optical rotations were measured at room temperature with a Per-
kin–Elmer 241 MC apparatus with 10-cm cells. IR spectra were
recorded with a JASCO FTIR–600 plus Fourier Transform Infra-
red Spectrometer ATR Specac Golden Gate. Melting points were
epimers 3 and 4 from the corresponding diastereoisomer 9
(Scheme 2, routes c and d). Thus, compound 9 was treated
with TsCl in CH2Cl2/pyridine to directly afford cyclization
product 13 in a 60% yield. Then, the phthalimido protect-
ing group was removed by reaction with methylamine to
provide 3[3,11] in an 88% yield (Scheme 7).
Scheme 7. Synthesis of 2,3-epi-jaspine (3) from 9.
Scheme 8. Synthesis of 3-epi-jaspine B (4) from 9.
1516
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1514–1519

Enantioselective Synthesis of Jaspine B and Its C-2 and/or C-3 Epimers
determined with a Reichert apparatus. Optical rotations were mea-
sured at 598 nm with a Jasco DIP-370 digital polarimeter by using
a 100-mm cell. Reactions were monitored by TLC carried out on
0.25 mm E. Merck silica gel 60 F254 glass or aluminum plates.
Developed TLC plates were visualized under a short-wave UV
lamp (250 nm) and by heating plates that were dipped in ethanol/
H2SO4 (15:1) and basic solution of potassium permanganate. Flash
column chromatography was carried out by using forced flow of
the indicated solvent on Merck silica gel 60 (230–400 mesh). Radial
chromatography was performed on 1- or 2-mm plates of Kieselgel
60 PF254 silica gel, depending on the amount of product. Flash
column chromatography (FCC) was performed by using flash silica
gel (32–63 μm) and employing a solvent polarity correlated with
TLC mobility.
(2R,3S,4S)-4-N-Phthalimido-2-tetradecyltetrahydrofuran-1-ol (12):
To a solution of sulfate 11 (0.09 mmol) dissolved in anhydrous
THF (1 mL) was dropwise added TBAF (1 m in THF, 117 mL,
0.117 mmol). The solution was stirred for 2 h at room temperature
and then a drop of water and H2SO4 were added to the solution.
The mixture was stirred at room temperature for another 2 h, and
the crude was then washed with an aqueous solution of NaHCO3
and brine. The organic layer was dried with anhydrous MgSO4, and
the solvent was removed under vacuum. The crude was purified by
silica gel chromatography (hexanes/ethyl acetate, 7:3) to afford 12
as a white solid (33 mg, 86%). [α]2D5 = +8.3 (c = 0.6, CHCl3). FTIR
1
(neat): ν = 3300, 2958, 2920, 2895, 1704, 1392, 1280, 720 cm–1. H
˜
NMR (400 MHz, CDCl3, 25 °C): δ = 7.85 (dd, J = 5.4, 3.2 Hz, 2
3
H, Ar), 7.74 (dd, J = 5.4, 3.2 Hz, 2 H, Ar), 4.95 (dd, JH,H = 8.0,
5.6 Hz, 1 H, 3-H), 4.91 (dt, 3JH,H = 8.4, 8.0 Hz, 1 H, 4-H), 4.59 (t,
(2S,3S,4S)-4-(2-Methylbenzoate)carbamoyl-2-tetradecyltetrahydro-
furan-3-ol (10): Compound 8 (276 mg, 0.6 mmol) was dissolved in
anhydrous dichloromethane (5 mL) and triethylamine (0.3 mL,
2.2 mmol). Then, DMAP (7 mg, 0.06 mmol) and tosyl chloride
(206 mg, 1.1 mmol) were added, and the mixture was stirred for
22 h at room temperature. The crude was acidified with HCl aque-
ous solution (10%) and then the organic layer was washed with
aqueous solution of NaHCO3 and brine. The organic layer was
dried with anhydrous MgSO4, and the solvent was removed under
vacuum. Then, Na2CO3 (125 mg, 1.5 mmol) was added, and the
mixture was dissolved in anhydrous methanol and it was stirred for
20 h at room temperature. The solvent was removed under vacuum,
and the crude was directly purified by silica gel chromatography
(hexanes/ethyl acetate, 7:3) to afford 10 as a white solid (165 mg,
3
3JH,H = 8.4 Hz, 1 H, 5-H), 4.21 (dd, JH,H = 8.4, 8.0 Hz, 1 H, 5Ј-
3
H), 4.15 (td, JH,H = 7.6, 5.6 Hz, 1 H, 2-H), 1.68–1.62 (m, 2 H),
3
1.57 (s, 1 H, OH), 1.34–1.25 (m, 24 H, alkyl chain), 0.86 (t, JH,H
= 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
168.1, 134.4, 131.6, 123.6, 82.5, 75.7, 66.3, 50.7, 33.6, 32.1, 29.9,
29.8, 29.7, 25.8, 22.9, 20.7, 14.4 ppm. HMRS (ESI): calcd. for
C16H39NO4Na+ 452.2777; found 452.2765.
(2R,3S,4S)-4-Amino-2-tetradecyltetrahydrofuran-3-ol [2-epi-Jaspine
(2)]: Compound 12 (25 mg, 0.055 mmol) was dissolved in aqueous
solution of MeNH2 (0.2 mmol, 0.2 mL, 40%), and the resulting
mixture was stirred in an open flask for 1.5 h at 50 °C. The reaction
was cooled to room temperature, and methylamine was removed,
first by bubbling argon through the reaction mixture for 30 min
and then by placing the mixture under vacuum for 1 h. The crude
was purified by silica gel chromatography (CH2Cl2/MeOH/
61%). [α]2D5 = –8.3 (c = 0.25, CHCl ). FTIR (neat): ν = 3453, 3279,
˜
3
2970, 2922, 2852, 2361, 1727, 1633, 1547, 1464, 1292, 772 cm–1. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 7.97 (d, JH,H = 7.6 Hz, 1 H,
NH4OH, 96:3:1) to afford 2 as a white solid (13 mg, 86%). [α]2D5
=
3
3
Ar), 7.58 (t, 3JH,H = 7.6 Hz, 1 H, Ar), 7.49 (t, JH,H = 7.6 Hz, 1 H, +9.1 (c = 0.1, CHCl3) {ref.[7] [α]2D5 = +9.6 (c = 0.11, CH3Cl); ref.[27a]
Ar), 7.44 (d, JH,H = 7.6 Hz, 1 H, Ar), 6.13 (d, JH,H = 8.0 Hz, 1
[α]2D5 = +11.7 (c = 0.65, CH3Cl); ref.[3] [α]2D5 = +14.8 (c = 0.97,
3
3
3
1
3
H, NH), 4.72 (tdd, JH,H = 8.4, 8.0, 4.0 Hz, 1 H, 4-H), 4.43 (dd,
CH3Cl)}. H NMR (400 MHz, CDCl3, 25 °C): δ = 4.12 (dd, JH,H
3JH,H = 4.0, 3.6 Hz, 1 H, 3-H), 4.13 (dd, JH,H = 8.4, 8.0 Hz, 1 H, = 9.1, 6.8 Hz, 1 H, 5-H) 3.61 (m, 2 H, 3-H, 2-H), 3.45 (m, 1 H, 4-
3
3
3
5-H), 3.91 (s, 3 H, OCH3), 3.87 (td, JH,H = 6.8, 3.6 Hz, 1 H, 2- H), 3.40 (dd, JH,H = 9.1, 6.8 Hz 1 H,5Ј-H), 2.10–1.49 (m, 5 H,
H), 3.72 (dd, 3JH,H = 8.4, 8.0 Hz, 1 H, 5Ј-H), 3.13 (br. s, 1 H, OH),
NH2, OH, CH2), 1.34–1.25 (m, 24 H, alkyl chain), 0.86 (t, JH,H =
3
3
1.70 (m, 2 H), 1.45–1.25 (m, 24 H, alkyl chain), 0.88 (t, JH,H
=
6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 85.5,
6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 170.2, 74.5, 73.4, 52.7, 32.1, 30.0, 29.9, 29.8, 29.6, 26.5, 22.9, 14.4 ppm.
+
167.0, 138.7, 132.7, 130.4, 129.7, 127.6, 82.6, 70.9, 69.2, 54.4, 52.9,
31.9, 29.8, 29.7, 29.6, 29.5, 29.4, 29.0, 26.2, 22.7, 14.2 ppm. HMRS
(ESI): calcd. for C27H43NO5SNa+ 484.3039; found 484.3048.
HMRS (ESI): calcd. for C18H38NO2 300.2903; found 300.2910.
(2R,3R,4S)-4-N-Phthalimido-2-tetradecyltetrahydrofuran-3-ol (13):
Alcohol
9 (200 mg, 0.44 mmol) and tosyl chloride (92 mg,
(2S,3S,4S)-4-Amino-2-tetradecyltetrahydrofuran-3-ol [Pachastrissa-
mine or Jaspine B (1)]: Compound 10 (23 mg, 0.051 mmol) was dis-
solved in an aqueous solution of MeNH2 (40%, 0.15 mmol), and
the resulting mixture was stirred in an open flask for 1 h at 50 °C).
The reaction was allowed to cool to room temperature, and methyl-
amine was removed, first by bubbling argon through the reaction
mixture for 30 min and then by placing the mixture under vacuum
for 1 h. The crude was purified by silica gel chromatography
(CH2Cl2/MeOH/NH4OH, 96:3:1) to afford 1 as a white solid
(13 mg, 93%). [α]2D5 = +7.7 (c = 0.6, CHCl3) {ref.[3] [α]2D5 = +8.7 (c
0.48 mmol) were dissolved in anhydrous dichloromethane (1 mL),
and the solution was cooled to 0 °C. Pyridine (1 mL) was added,
and the mixture was stirred at 0 °C for 1 h. Then, the mixture was
warmed to room temperature for 10 h, tosyl chloride (40 mg,
0.24 mmol) was added, and the mixture was stirred for another
10 h. The mixture was treated with HCl aqueous solution (10%),
the aqueous layer was washed with dichloromethane, and the com-
bined organic layers were washed with NaHCO3 saturated aqueous
solution and brine. The organic layer was dried with anhydrous
MgSO4, and the solvent was removed under vacuum. The mixture
was purified by radial chromatography (hexanes/ethyl acetate, 7:3)
to afford 13 as a white solid (190 mg, 60%). [α]2D5 = +11.5 (c = 1.6,
= 1.1, CH3Cl); ref.[19] [α]2D5 = +9.0 (c = 1.5, CH3Cl); ref.[2] [α]2D5
=
1
+7.0 (c = 0.1, CH3Cl); ref.[27a] [α]2D5 = +6.5 (c = 0.45, CH3Cl)}. H
NMR (400 MHz, CDCl3, 25 °C): δ = 3.86 (dd, 3JH,H = 8.5, 7.2 Hz,
CH Cl ). FTIR (neat): ν = 3350, 2963, 2910, 2845, 1697, 1392,
˜
2
2
3
1 H, 5-H), 3.80 (dd, 3JH,H = 4.8, 3.4 Hz, 1 H, 3-H), 3.66 (td, JH,H
720 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.78 (dd, J =
5.2, 3.0 Hz, 2 H, Ar), 7.67 (dd, J = 5.2, 3.0 Hz, 2 H, Ar), 4.67 (ddd,
3JH,H = 7.6, 6.0, 1.6 Hz, 1 H, 3-H), 4.53 (m, 1 H, 4-H), 4.25–4.20
3
= 7.2, 3.4 Hz, 1 H, 2-H), 3.60 (dt, JH,H = 7.2, 4.8 Hz, 1 H, 4-H),
3
3.45 (dd, JH,H = 8.5, 7.2 Hz, 1 H, 5-H), 1.80 (br. s, 3 H, NH2 and
3
OH), 1.65–1.52 (m, 2 H), 1.38–1.18 (m, 24 H, alkyl chain), 0.81 (t,
(m, 2 H, 5-H and 5Ј-H), 3.56 (t, JH,H = 6.8 Hz, 1 H, 2-H), 2.27
3JH,H = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ (d, JH,H = 6.0 Hz, 1 H, OH), 1.70–1.60 (m, 2 H), 1.41–1.25 (m,
3
3
= 83.4, 72.5, 71.9, 54.4, 32.1, 30.0, 29.9, 29.8, 29.6, 26.5, 26.5, 22.9,
24 H, alkyl chain), 0.792 (t, JH,H = 6.8 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 168.2, 134.5, 131.9, 123.6, 82.9, 76.4,
67.6, 59.8. 32.1, 30.0, 29.9, 29.8, 26.6, 28.7, 26.4, 22.9, 14.3 ppm.
+
14.5 ppm. HMRS (ESI): calcd. for C18H38NO2 300.2903; found
300.3000.
Eur. J. Org. Chem. 2011, 1514–1519
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1517

J. Llaveria, Y. Díaz, M. I. Matheu, S. Castillón
FULL PAPER
HMRS (ESI): calcd. for C26H39NO4Na+ 452.2777; found 452.2779.
fied and directly used in the next reaction. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 7.87 (dd, J = 5.6, 3.2 Hz, 2 H, Ar), 7.80 (dd, J
= 5.6, 3.0 Hz, 2 H, Ar), 7.50 (d, J = 6.6 Hz, 2 H, Ar), 7.45 (d, J =
6.6 Hz, 2 H, Ar), 7.41–1.36 (m, 4 H, Ar), 7.30 (t, J = 8.0 Hz, 2 H,
(2R,3R,4S)-4-Amino-2-tetradecyltetrahydrofuran-3-ol [C-2,C-3-epi-
Jaspine B (3)]: Compound 13 was dissolved in aqueous solution of
MeNH2 (0.17 mmol, 15 mL, 40%), and the resulting mixture was
stirred in an open flask for 1 h at 50 °C. The reaction is allowed to
cool to room temperature, and methylamine was removed, first by
bubbling argon through the reaction for 30 min and then by placing
the mixture under vacuum for 1 h. The crude was purified by silica
gel chromatography (CH2Cl2/MeOH/NH4OH, 96:4:1) to afford 3
as a white solid (17 mg, 88%). [α]2D5 = –0.7 (c = 1.0, CH3Cl) {ref.[3]
[α]2D5 = –2.5 (c = 0.7, CH3Cl); ref.[11] [α]2D5 = –1.11 (c = 0.99,
3
3
Ar), 5.92 (dd, JH,H = 11.4, 5.0 Hz, 1 H, 3-H), 4.86 (ddd, JH,H
=
3
11.4, 5.0, 2.8 Hz, 1 H, 4-H), 4.76 (ddd, JH,H = 8.6, 5.0, 4.2 Hz, 1
3
3
H, 2-H), 4.16 (dd, JH,H = 10.6, 8.6 Hz, 1 H, 1-H), 3.95 (dd, JH,H
= 10.6, 4.2 Hz, 1 H, 1Ј-H), 1.52–1.39 (m, 2 H), 1.28–1.15 (m, 24
3
H, alkyl chain), 0.88 (t, JH,H = 6.8 Hz, 3 H), 0.58 [s, 9 H, Si-
(CH3)3] ppm. 13C NMR (100 MHz, 25 °C): δ = 168.5, 135.6, 134.9,
132.5, 131.6, 130.2, 130.1, 128.2, 128.0, 124.0, 85.6, 79.8, 61.4, 51.0,
32.1, 30.1, 29.9, 29.8, 29.7, 29.6, 29.3, 28.9, 27.9, 26.9, 26.7, 25.9,
25.0, 22.9, 19.1, 14.4 ppm. HMRS (ESI): calcd. for
C42H57NO7SNa+ 770.3523; found 770.3551.
1
3
CH3Cl)}. H NMR (400 MHz, CDCl3, 25 °C): δ = 4.22 (dd, JH,H
3
= 9.4, 5.6 Hz, 1 H, 5-H), 3.89 (dt, JH,H = 7.2, 3.6 Hz, 1 H, 4-H),
3.82–3.79 (m, 1 H, 3-H), 3.49–3.47 (m, 1 H, 2-H), 3.38 (dd, JH,H
3
(2S,3R,4S)-4-N-Phthalimido-2-tetradecyltetrahydrofuran-3-ol (16):
To a solution of 15 (0.052 mmol) dissolved in anhydrous dichloro-
methane (2 mL) was added a solution of TBAF (1 m in THF,
57 mL, 0.057 mmol). The solution was stirred for 2 h at room tem-
perature and then a drop of water and H2SO4 were added to the
solution. The mixture was stirred at room temperature for another
2 h, and the crude was then washed with an aqueous solution of
NaHCO3 and brine. The crude was purified by radial chromatog-
raphy (hexanes/ethyl acetate, 5:2) to afford 16 as a white solid
= 9.4, 3.6 Hz, 1 H, 5-H), 1.62–1.52 (m, 5 H), 1.33–1.25 (m, 24 H,
3
alkyl chain), 0.87 (t, JH,H = 6.8 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 80.9, 80.0, 74.0, 60.1, 32.1, 30.0,
29.9, 29.8, 29.7, 29.6, 28.7, 26.6, 22.9, 14.4 ppm. HMRS (ESI):
calcd. for C18H37NO2Na+ 322.2722; found 322.2720.
(2S,3R,4R)-1-tert-Butyldiphenylsilyloxy-2-N-phthalimidooctadecane-
3,4-diol (14): Alcohol 9 (107 mg, 0.24 mmol) was dissolved in
dichloromethane (2 mL) and DMF (0.5 mL). DMAP (1.5 mg,
0.012 mmol) and triethylamine (0.1 mL, 0.6 mmol) were added,
and then the solution was cooled to 0 °C and TBDPSCl (0.07 mL,
0.3 mmol) was added dropwise. After 1 h, the mixture was warmed
to room temperature and it was stirred for 18 h, at which point
TLC showed complete conversion. The crude was quenched with
a NH4Cl aqueous saturated solution, the aqueous layer was washed
with dichloromethane, and the combined organic layers were
washed with brine and dried with anhydrous MgSO4. The solvent
was removed under vacuum, and the crude was purified by radial
chromatography (hexanes/ethyl acetate, 6:4) to afford 14 as a color-
less oil (163 mg, 77%). [α]2D5 = –20.2 (c = 0.9, CH3Cl). FTIR (neat):
(20 mg, 92%). [α]2D5 = +8.9 (c = 1.4, CHCl ). FTIR (neat): ν =
˜
3
3530, 3414, 2952, 2915, 2848, 2361, 2334, 1695, 1467, 1397,
720 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.81 (dd, J =
5.6, 3.2 Hz, 2 H, Ar), 7.71 (dd, J = 5.6, 3.2 Hz, 2 H, Ar), 4.64 (ddd,
3
3JH,H = 8.6, 8.0, 7.6 Hz, 1 H, 4-H), 4.53 (dd, JH,H = 7.6, 6.8 Hz,
1 H, 3-H), 4.24 (dd, 3JH,H = 8.8, 8.6 Hz, 1 H, 5-H), 4.12 (dd, 3JH,H
3
= 8.8, 8.0 Hz, 1 H, 5Ј-H), 3.75 (td, JH,H = 7.6, 4.8 Hz, 1 H, 2-H),
2.74 (br. s, 1 H, OH), 1.77–1.68 (m, 2 H), 1.53–1.24 (m, 24 H, alkyl
3
chain), 0.86 (t, JH,H = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 168.6, 134.5, 131.9, 123.6, 83.4, 77.8, 67.2, 59.3,
33.3, 32.1, 29.9, 29.8, 29.7, 29.6, 26.0, 22.9, 14.3 ppm. HMRS
(ESI): calcd. for C26H39NO4Na+ 452.2777; found 452.2763.
ν = 3424, 3123, 2924, 2853, 2361, 1706, 1465, 1430, 1389, 1213,
˜
1
1111, 751 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 7.85 (dd,
(2S,3R,4S)-4-Amino-2-tetradecyltetrahydrofuran-3-ol
[3-epi-Jas-
J = 5.4, 3.2 Hz, 2 H, Ar), 7.75 (dd, J = 5.4, 3.2 Hz, 2 H, Ar), 7.61
(dd, J = 8.0, 1.4 Hz, 2 H, Ar), 7.51 (dd, J = 8.0, 1.4 Hz, 2 H, Ar),
7.41–7.32 (m, 4 H, Ar), 7.27 (t, J = 8.0 Hz, 2 H, Ar), 4.77 (ddd,
pine B (4)]: Compound 16 (36 mg, 0.085 mol) was dissolved in an
aqueous solution of MeNH2 (0.20 mmol, 0.25 mL, 40%) and the
resulting mixture was stirred in an open flask for 1 h at 50 °C. The
reaction was allowed to cool at room temperature, and methyl-
amine was removed, first by bubbling argon through the reaction
for 30 min and then by placing the mixture under vacuum for 1 h.
The crude was purified by silica gel chromatography (CH2Cl2/
MeOH/NH4OH, 96:4:1) to afford 4 as a white solid (30 mg, 85%).
[α]2D5 = –1.8 (c = 0.8, CHCl3) {ref.[3] [α]2D5 = –3.8 (c = 0.7, CHCl3);
ref.[11] [α]2D5 = –1.55 (c = 0.4, CHCl3)}. 1H NMR (400 MHz, CDCl3,
3
3JH,H = 8.8, 5.8, 3.2 Hz, 1 H, 2-H), 4.17 (dd, JH,H = 10.8, 5.8 Hz,
3
1 H, 1-H), 4.15 (dd, JH,H = 10.8, 8.8 Hz, 1 H, 1Ј-H), 4.08 (m, 1
H, 3-H), 3.91–3.88 (m, 1 H, 4-H), 3.55 (br. s, 1 H, OH), 1.93 (br.
s, 1 H, OH), 1.43–1.38 (m, 2 H), 1.25–1.22 (m, 24 H, alkyl chain),
0.89 (t, 3JH,H = 6.8 Hz, 3 H), 0.89 [s, 9 H, (CH3)3] ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 169.5 135.9, 135.7, 134.4, 133.2,
133.1, 132.0, 130.0, 129.9, 127.9, 127.9, 123.7, 75.4, 72.7, 60.8, 54.6,
32.6, 32.1, 29.9, 29.8, 29.7, 29.6, 26.8, 25.8, 22.9, 19.1, 14.3 ppm.
HRMS (ESI): calcd. for C42H59NO5SiNa+ 708.4060; found
708.4021.
3
25 °C): δ = 4.00 (dd, JH,H = 9.2, 6.0 Hz, 1 H, 5-H), 3.59–3.56 (m,
3
3 H, 5Ј–H, 3-H, 4-H), 3.29 (ddd, JH,H = 8.0, 4.4, 3.6 Hz, 1 H, 2-
H), 1.94 (br. s, 3 H, NH2 and OH), 1.68–1.57 (m, 2 H), 1.49–1.14
3
(m, 24 H, alkyl chain), 0.87 (t, JH,H = 6.4 Hz, 3 H) ppm. 13C
(2S,3R,4R)-1-(tert-Butyldiphenylsilyloxy)-2-N-phthalimido-3,4-O-
sulfuryloctadecane (15): To a solution of diol 14 (0.16 g, 0.23 mmol)
in dichloromethane (2 mL) was added triethylamine (90 μL,
0.68 mmol) and thionyl chloride (20 μL, 0.27 mmol) at 0 °C. After
stirring for 40 min, the reaction mixture was poured into brine and
extracted with ethyl acetate. The organic layer was dried with anhy-
drous MgSO4 and concentrated in vacuo. The crude was dried in
vacuo for one night and then dissolved in CCl4/CH3CN/H2O
(1:1:1 mL). RuCl3·3H2O (6 mg, 0.011 mmol) and NaIO4 (0.14 g,
0.68 mmol) were added. After 2.5 h, no starting material was ob-
served by TLC. The reaction mixture was diluted with AcOEt and
washed with a saturated solution of Na2SO3, and the organic layer
was dried with anhydrous MgSO4 and concentrated under reduced
pressure to afford compound 15 as a beige oil, which was not puri-
NMR (100 MHz, CDCl3, 25 °C): δ = 85.1, 83.7, 73.7, 60.4, 34.0,
31.9, 29.7, 29.6, 29.5, 29.4, 26.1, 22.7, 14.1 ppm. HMRS (ESI):
+
calcd. for C18H38NO2 300.2903; found 300.2906.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of compounds 1–4 and 10–16.
Acknowledgments
Financial support of the Ministerio de Ciencia y Tecnología, Spain,
through DGI (CTQ2008-01569-BQU), Consolider Ingenio 2010
(CSD2006-0003) and technical assistance from the Servei de Re-
cursos Cientifics (URV) are gratefully acknowledged. J. L. thanks
1518
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1514–1519

Enantioselective Synthesis of Jaspine B and Its C-2 and/or C-3 Epimers
[17] R. J. B. H. N. Van der Berg, T. J. Boltje, C. P. Verhagen,
R. E. J. N. Litjens, G. A. Van der Marel, H. S. Overkleeft, J.
Org. Chem. 2006, 71, 836–839.
[18] T. Lee, S. Lee, Y. S. Kwak, D. Kim, S. Kim, Org. Lett. 2007, 9,
429–932.
MICINN for a fellowship. We also thank Dr. Christopher Cobley,
Dr. Reddy’s Custom Pharmaceutical Services, Chirotech Technol-
ogy, Ltd., for the generous gift of a sample of the starting material.
[19] C. Ribes, E. Falomir, M. Carda, J. A. Marco, Tetrahedron 2006,
[1]
[2]
[3]
[4]
[5]
I. Kuroda, M. Musman, I. I. Ohtani, T. Ichiba, J. Tanaka, D.
Garcia-Gravalos, T. Higa, J. Nat. Prod. 2002, 65, 1505–1506.
V. Ledroit, C. Debitus, C. Lavaud, G. Massiot, Tetrahedron
Lett. 2003, 44, 225–228.
D. Canals, D. Mormeneo, G. Fabriàs, A. Llebaria, J. Casas, A.
Delgado, Bioorg. Med. Chem. 2009, 17, 235–241.
J. Liu, Y. Du, X. Dong, S. Meng, J. Xiao, L. Cheng, Carbohydr.
Res. 2006, 341, 2653–2687.
Y. Salma, E. Lafont, N. Therville, S. Carpentier, M.-J. Bonnafé,
T. Levade, Y. Génisson, N. Andrieu-Abadie, Biochem. Pharma-
col. 2009, 78, 477–485.
E. Abraham, S. G. Davies, P. M. Roberts, A. J. Russel, J. E.
Thomson, Tetrahedron: Asymmetry 2008, 19, 1027–1047.
P. Bhaket, K. Morris, C. S. Stauffer, A. Datta, Org. Lett. 2005,
7, 875–876.
M. Passiniemi, A. M. P. Koskinen, Tetrahedron Lett. 2008, 49,
980–983.
62, 5421–5425.
[20] Y. Ichikawa, K. Matsunaga, T. Masuda, H. Kotsuki, K. Nak-
ano, Tetrahedron 2008, 64, 11313–11318.
[21] a) K. R. Prasad, A. Chandrakumar, J. Org. Chem. 2007, 72,
6312–6315; b) G. Reddipalli, M. Venkataiah, M. K. Mishra,
N. W. Fadnavis, Tetrahedron: Asymmetry 2009, 20, 1802–1805.
[22] a) Y. Génisson, L. Lamandé, Y. Salma, N. Andrieu-Abadie, C.
André, M. Baltas, Tetrahedron: Asymmetry 2007, 18, 857; b) Y.
Salma, S. Ballereau, C. Maaliki, S. Ladeira, N. Andrieu-Aba-
die, Y. Génisson, Org. Biomol. Chem. 2010, 8, 3227–3243.
[23] K. Venkatesan, K. V. Srinivasan, Tetrahedron: Asymmetry
2008, 19, 209–215.
[6]
[7]
[8]
[24] T. Yakura, S. Sato, Y. Yoshimoto, Chem. Pharm. Bull. 2007,
55, 1284–1286.
[25] D. Enders, V. Terteryan, J. Palecek, Synthesis 2008, 14, 2278–
2282.
[26] H. Urano, M. Enamoto, S. Kuwahara, Biosci. Biotechnol. Bio-
chem. 2010, 74, 152–157.
[9] N. Sudhakar, A. R. Kumar, A. Prabhakar, B. Jagadeesh, B. V.
Rao, Tetrahedron Lett. 2005, 46, 325–327.
[10] a) S. Inuki, Y. Yoshimitsu, S. Oishi, N. Fujii, H. Ohno, J. Org.
Chem. 2010, 75, 3831–3842; b) S. Inuki, Y. Yoshimitsu, S.
Oishi, N. Fujii, H. Ohno, Org. Lett. 2009, 11, 4478–4481.
[11] Y. Yoshimitsu, S. Inuki, S. Oishi, N. Fujii, H. Ohno, J. Org.
Chem. 2010, 75, 3843–3846.
[27] a) E. Abraham, J. I. Candela-Lena, S. G. Davies, M. Georgiou,
R. L. Nicholson, P. M. Roberts, A. J. Russell, E. M. Sánchez-
Fernández, A. D. Smith, J. E. Thomson, Tetrahedron: Asym-
metry 2007, 18, 2510–2513; b) E. Abraham, E. A. Brock, J. I.
Candela-Lena, S. G. Davies, M. Georgiou, R. L. Nicholson,
J. H. Perkins, P. M. Roberts, A. J. Russell, E. M. Sánchez-
Fernández, P. M. Scott, A. D. Smith, J. E. Thomson, Org. Bio-
mol. Chem. 2008, 6, 1665–1673.
[12] Y. Du, J. Liu, R. J. Linhardt, J. Org. Chem. 2006, 71, 1251–
1253.
[28] a) B. M. Trost, D. B. Horne, M. J. Woltering, Angew. Chem.
Int. Ed. 2003, 42, 5987–5990; b) B. M. Trost, R. C. Nunt, R. C.
Lemoine, T. L. Calkins, J. Am. Chem. Soc. 2000, 122, 5968–
5976; c) B. M. Trost, D. B. Horne, M. J. Woltering, Chem. Eur.
J. 2006, 12, 6607–6620.
[13] S. Chandrasekhar, B. Tiwari, S. J. Prakash, ARKIVOC 2006,
11, 155–161.
[14] C. V. Ramana, A. G. Giri, S. B. Suryawanshi, R. G. Gonnade,
Tetrahedron Lett. 2007, 48, 265–268.
[15] G. Jayachitra, N. Sudhakar, R. K. Anchoori, R. Vankateswara,
S. Roy, R. Banerjee, Synthesis 2010, 1, 115–119.
[16] L. V. R. Reddy, P. V. Reddy, A. K. Shaw, Tetrahedron: Asym-
metry 2007, 18, 542–546.
[29] J. Llaveria, Y. Díaz, M. I. Matheu, S. Castillón, Org. Lett. 2009,
11, 205–208.
Received: October 30, 2010
Published Online: January 26, 2011
Eur. J. Org. Chem. 2011, 1514–1519
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1519