Asymmetric synthesis of jaspine B (pachastrissamine) via an organocatalytic Aldol reaction as key step

Article abstract of DOI:10.1055/s-2008-1067142

The asymmetric synthesis of jaspine B (pachastrissamine) using a (R)-proline-catalyzed enantioselective aldol reaction as key step is described. Jaspine B was synthesized from the commercially available and inexpensive 1-pentadecanal and the dihydroxyacetone equivalent 2,2-dimethyl-1,3-dioxan-5-one in nine steps, good overall yield (23.6%) and excellent stereoselectivity (de >98%, ee = 95%). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067142

2278
PAPER
Asymmetric Synthesis of Jaspine B (Pachastrissamine) via an Organocatalytic
Aldol Reaction as Key Step
A
symmetric Synth
i
esis of
e
Jaspine
B
ter Enders,* Violeta Terteryan, Jiří Paleček
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 26 March 2008
Dedicated to Professor R. W. Hoffmann on the occasion of his 75th birthday
NH2 OH
OH
H2N
OH
Abstract: The asymmetric synthesis of jaspine B (pachastrissa-
mine) using a (R)-proline-catalyzed enantioselective aldol reaction
as key step is described. Jaspine B was synthesized from the com-
mercially available and inexpensive 1-pentadecanal and the dihy-
droxyacetone equivalent 2,2-dimethyl-1,3-dioxan-5-one in nine
steps, good overall yield (23.6%) and excellent stereoselectivity (de
>98%, ee = 95%).
HO
C13H27
C14H29
O
pachastrissamine
(Jaspine B)
(1)
D-ribo-phytosphingosine
(2)
Figure 1 Jaspine B (1) and D-ribo-phytosphingosine (2)
Key words: pachastrissamine (jaspine B), asymmetric synthesis,
aldol reaction, organocatalysis, proline
a non-polar aliphatic ‘tail’ and a polar aminoalcohol
‘head’ (Figure 1).
The naturally occurring, cyclic anhydrophytosphingosine
derivative jaspine B (pachastrissamine, 1) was first isolat-
ed from the Okinawan marine sponge Pachastrissa sp.
(family Calthropellidae) in 2002 by Higa et al.1 and later
from a different marine sponge, Jaspis sp., by Debitus and
co-workers.2
Recently reported syntheses of 1 and its analogues by the
groups of Overkleeft16 und Kim17 have taken advantage of
this structural similarity and transformed phytosphin-
gosine (2) into jaspine B.
Our research group has developed a proline-catalyzed al-
dol reaction that allows access to D- and L-phytosphin-
gosines (e.g 2) in a highly enantioselective manner.18
Herein we report an efficient asymmetric synthesis of jas-
pine B, which employs this diastereo- and enantioselec-
tive aldol reaction as a key step. Retrosynthetically, we
envisaged the preparation of the title compound by reduc-
tion of the cyclic azide 12, which could be traced back to
the tosylate 11 via a one-pot acid-catalyzed deprotection/
intramolecular nucleophilic substitution reaction
(Scheme 1). In turn, the tosylate 11 could be obtained
from the known acetonide and TBS-protected triol 7 in an
azidation/tosylation sequence. The asymmetric aldol re-
action of dioxanone 3 with 1-pentadecanal, catalyzed by
proline, would give access to the protected chiral anti-diol
5 that contains two of the required stereocenters of jaspine
B (1).18 Furthermore, the asymmetric organocatalytic al-
dol reaction of dioxanone 3 and 1-pentadecanal would as-
semble all 18 carbons of jaspine B in one synthetic step.
Due to the significant cytotoxic activity of jaspine B (IC50
0.01 mg/mL against P388, A549, HT29 and MEL28 tu-
mour cell lines), there is increasing interest within the
chemical community regarding its total synthesis.1
Indeed, several stereoselective syntheses of jaspine B
have been reported. Most of these routes are based on
chiral pool strategies and use L-serine,3 Garner’s alde-
hyde,4,5 D-xylose,6 L-xylose7 (to obtain a truncated pa-
chastrissamine), D-glucose,8 D-galactal9 and D-
tartaric acid as starting materials.10 The synthesis of jas-
pine B (1) derived from the chiral substrates (R)-
glycidol11 or other epoxides,12 generated by asymmetric
Sharpless epoxidation, have also been described. The re-
search groups of Yakura13 and Srinivasan14 have indepen-
dently disclosed the synthesis of 1 using the asymmetric
Sharpless dihydroxylation as a key step. Very recently
Davies et al. described an elegant asymmetric synthesis
via an aza-Michael addition/enolate oxidation sequence.15
To commence the synthesis of the jaspine B target, the si-
lyl ether 7 was prepared from dioxanone 319 using (R)-
proline for the organocatalytic aldol reaction (Scheme 2).
This five-step procedure is similar to that reported previ-
ously which used (S)-proline.18,20 Thus, the aldol product
5 was prepared using the diastereo- and enantio-selective
(R)-proline-catalyzed aldol reaction of dioxanone 3 and 1-
pentadecanal (4). Next, protection of the alcohol as a tert-
butyldimethylsilyl (TBS) ether to form 6 and subsequent
diastereoselective reduction with L-Selectride afforded
the protected anti-1,3-diol 7 in multi-gram quantities. The
free hydroxy group of alcohol 7 was then transformed into
As a cyclic anhydrophytosphingosine derivative, the
structure of jaspine B is similar to that of phytosphin-
gosines, e.g. D-ribo-phytosphingosine (2), with character-
istic sub-units present in the ubiquitous sphingolipids.
Both 1 and 2 possess common structural elements, name-
ly, 18 carbon atoms, three contiguous stereogenic centers,
SYNTHESIS 2008, No. 14, pp 2278–2282
x
x.
x
x
.
2
0
0
8
Advanced online publication: 18.06.2008
DOI: 10.1055/s-2008-1067142; Art ID: C00708SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Synthesis of Jaspine B
2279
Amberlyst 15
THF, MeOH
24 h
N3
OTs
C14H29
N3
OH
H2N
OH
N3
OH
SN2
11
12
R
O
O
(– HOTs)
76%
C14H29
C14H29
HO OTs
O
O
Me Me
(R = C14H29)
1
12
13
11
Scheme 3 Acid-catalyzed intramolecular cyclization
9 steps
the synthesis, the azide group of the tetrahydrofuran 12
was subjected to a catalytic hydrogenation reaction, which
afforded jaspine B (1) in 98% yield.
OH OTBS
C14H29
O
O
OH
C14H29
O
O
O
O
O
O
In summary, we have developed an efficient asymmetric
synthesis of jaspine B (pachastrissamine, 1) using an or-
ganocatalytic aldol reaction as a key step. The title com-
pound was obtained in nine steps with a good overall yield
(23.6%) starting from the readily available achiral precur-
sors dioxanone 3 and 1-pentadecanal (4), in excellent di-
astereo- and enantiomeric excesses (de >98%, ee = 95%).
This method allows access to both enantiomers of jaspine
B depending on whether (R)- or (S)-proline is used as cat-
alyst. Furthermore, the pro-chiral ketone function of 6 can
be easily functionalized into epimeric amino groups.18 In
theory, this route allows access to various stereoisomers
of jaspine B, which is the subject of current investigations
in our laboratories.
Me Me
Me Me
Me Me
3
5
7
Scheme 1 Retrosynthetic analysis of jaspine B (1)
the mesylate 8 in 98% yield. Reaction of 8 with sodium
azide in the presence of 18-crown-6 proceeded with virtu-
ally complete inversion of configuration and gave the de-
sired TBS-protected syn-1,3-azido alcohol 9 in 79% yield
(de > 98% by NMR and GC). After deprotection of the si-
lyl ether 9 with tetra-butylammonium fluoride (TBAF),
the secondary alcohol of the syn-1,3-azido alcohol 10 was
tosylated to afford 11 in 81% yield. Treatment of this to-
sylate in a methanol/tetrahydrofuran solution with an
acidic resin (Amberlyst 15) at room temperature installed
the tetrahydrofuran ring present in jaspine B. Mechanisti-
cally, the one-pot, acid-catalyzed formation of tetrahydro-
furan 12 likely involves an initial acid-catalyzed acetal
solvolysis reaction within tosylate 11 to form the transient
All solvents were dried by conventional methods. Starting materials
and reagents were purchased from commercial suppliers and used
without further purification. THF was freshly distilled from Na–Pb
alloy under argon. CH2Cl2 was freshly distilled from CaH under ar-
gon. Preparative column chromatography was performed using sil-
diol intermediate 13 (Scheme 3). A subsequent intramo- ica gel 60, particle size 0.040–0.063 mm (230–240 mesh, flash).
Analytical TLC was carried out employing silica gel 60 F254 plates
lecular nucleophilic displacement reaction of intermediate
from Merck, Darmstadt. Visualization of the developed chromato-
grams was performed by staining with phosphomolybdic acid solu-
tion in EtOH. Optical rotation values were measured on a Perkin–
13 then affords the tetrahydrofuran 12 and sets the appro-
priate relative and absolute stereochemistry. To complete
O
OH
O
OTBS
C14H29
O
TBSOTf, 2,6-lutidine,
CH2Cl2, THF, –20 °C
L-Selectride,
THF, –78 °C, 2 h
O
(R)-proline (30 mol%),
CHCl3, r.t., 4 d
C14H29
+
H
C14H29
O
O
O
O
O
O
91%
95%
59%
4
Me Me
Me Me
Me Me
6
3
5
(de > 99%, ee = 95%)
OH OTBS
C14H29
OMs OTBS
C14H29
N3
OTBS
C14H29
MsCl, DMAP, CH2Cl2
0 °C to –10 °C, 15 h
TBAF, THF
0 °C to r.t., 24 h
NaN3, 18-crown-6
DMF, 100 °C, 48 h
O
O
O
O
O
O
83%
98%
79%
Me Me
Me Me
Me Me
7
8
9
(de > 98%)
H2, Pd/C
MeOH, CH2Cl2
r.t., 8 h
N3
OH
N3
OTs
H2N
OH
TsCl, DMAP
CH2Cl2, 0 °C, 4 h
N3
OH
Amberlyst 15
C14H29
C14H29 THF, MeOH, 24 h
98%
O
O
O
O
97%
76%
C14H29
C14H29
O
O
10
11
Me Me
Me Me
1
12
(de > 98%, ee = 95%)
Scheme 2 Asymmetric synthesis of jaspine B (pachastrissamine; 1)
Synthesis 2008, No. 14, 2278–2282 © Thieme Stuttgart · New York

2280
D. Enders et al.
PAPER
Elmer P241 polarimeter. Microanalyses were obtained with a Vario
EL element analyzer. Mass spectra were acquired on a Finnigan
SSQ7000 spectrometer (CI 100 eV; EI 70 eV). HRMS data were re-
corded on a Finnigan MAT95 spectrometer. IR spectra were mea-
26.0 (CH2), 29.4 (CH2), 29.6 (2 × CH2), 29.65 (2 × CH2), 29.7
(4 × CH2), 32.0 (CH2), 32.7 (CH2), 67.3 (CH2), 72.2 (CH), 78.5
(CH), 100.5 (C), 207.9 (C=O).
MS (CI): m/z (%) = 471 (2.1) [M+ + 1], 470 (0.5) [M+], 413 (10),
1
sured on a Perkin–Elmer FT-IR 1760 spectrophotometer. H and
343 (7), 342 (27), 341 (100), 339 (7), 129 (18).
13C NMR spectra were recorded on Varian Mercury 300, Gemini
300 or Inova 400 spectrometers with TMS as the internal standard.
Analytical HPLC was performed on Hewlett–Packard 1100 Series
chromatographs.
Anal. Calcd for C27H54O4Si: C, 68.88; H, 11.56. Found: C, 68.88;
H, 11.32.
(4S,5R)-4-[(R)-1-(tert-Butyldimethylsilyloxy)pentadecyl]-2,2-
dimethyl-1,3-dioxan-5-ol (7)
(R,R)-4-(1-Hydroxypentadecyl)-2,2-dimethyl-1,3-dioxan-5-one
(5)
To a solution of 6 (1.00 g, 2.12 mmol) in anhydrous THF (30 mL)
was added, dropwise, a solution of L-Selectride in THF (1 M,
2.3 mL, 2.34 mmol) at –78 °C. After 2 h the reaction mixture was
warmed to r.t. then quenched with aq NH4Cl (20 mL) and extracted
with Et2O (3 × 30 mL). The combined organic layers were washed
with brine (20 mL), dried over MgSO4 and concentrated under re-
duced pressure. The crude product was purified by flash chromatog-
raphy (silica gel, CH2Cl2–Et2O, 9:1) to afford the alcohol 7.
A suspension of the dioxanone 3 (1.00 g, 7.68 mmol) and 30 mol%
(R)-proline (0.27 g, 2.3 mmol) in CHCl3 (5 mL) was stirred for 30
min before aldehyde 4 (1.74 g, 7.7 mmol) was added in one portion.
The resulting mixture was stirred at r.t. under argon for 4 d. The re-
action mixture was quenched with sat. NH4Cl (10 mL), extracted
with Et2O (3 × 20 mL) and the combined organic phases were dried
over MgSO4, concentrated and the crude product was purified by
column chromatography (silica gel, CH2Cl2–Et2O, 9:1) to give the
aldol product 5.
22
Yield: 0.91 g (91%); colourless oil; de >98% (NMR); [a]D –7.9
(c 1.1, CHCl3).
Yield: 1.62 g (59%); colourless oil; de >99% (NMR, GC, HPLC);
IR (CHCl3): 3582, 3499, 2927, 2855, 1465, 1381, 1255, 1200, 1116,
1070, 836, 776 cm–1.
ee = 95% (HPLC, Daicel IA, n-heptane–i-PrOH, 95: 5; major iso-
22
mer 10.4 min, minor isomer 11.0 min); [a]D +112.8 (c 1.1,
1H NMR (400 MHz, CDCl3): d = 0.08 (s, 3 H, CH3Si), 0.09 (s, 3 H,
CH3Si), 0.85 (t, J = 6.9 Hz, 3 H, CH3), 0.92 [s, 9 H, (CH3)3CSi],
1.27 (m, 24 H, 12 × CH2), 1.43 (s, 3 H, CH3), 1.44 (s, 3 H, CH3),
1.58 (m, 2 H, CH2), 3.45 (br s, 1 H, OH), 3.65 (m, 2 H, 2 × CH),
3.85 (dd, J = 12.2, 1.7 Hz, 1 H, CH2), 3.91 (m, 1 H, CH), 3.98 (dd,
J = 12.2, 1.0 Hz, 1 H, CH2).
13C NMR (100 MHz, CDCl3): d = –4.7 (CH3), –4.6 (CH3), 14.1
(CH3), 18.1 (C), 18.5 (CH3), 22.7 (CH2), 24.1 (CH2), 25.2
(2 × CH3), 29.4 (CH2), 29.6 (3 × CH2), 29.7 (4 × CH2), 29.9 (CH2),
32.1 (CH2), 33.1 (CH2), 63.3 (CH), 66.1 (CH2), 72.2 (CH), 72.3
(CH), 98.7 (C).
CHCl3).
IR (CHCl3): 3540, 2925, 2855, 1741, 1463, 1378, 1223, 1092, 722
cm–1.
1H NMR (400 MHz, CDCl3): d = 0.88 (t, J = 6.9 Hz, 3 H, CH3), 1.28
(m, 26 H, 13 × CH2), 1.44 (s, 3 H, CH3), 1.48 (s, 3 H, CH3), 2.97 (br
s, 1 H, OH), 3.89 (m, 1 H, CH), 4.02 (d, J = 17.3 Hz, 1 H, CH2),
4.09 (dd, J = 6.9, 1.4 Hz, 1 H, CH), 4.27 (dd, J = 17.3, 1.4 Hz, 1 H,
CH2).
13C NMR (100 MHz, CDCl3): d = 14.1 (CH3), 22.7 (CH2), 23.5
(CH3), 23.9 (CH3), 25.0 (CH2), 29.4 (CH2), 29.6 (3 × CH2), 29.7
(2 × CH2), 29.8 (3 × CH2), 31.9 (CH2), 32.3 (CH2), 66.7 (CH2), 70.6
(CH), 76.0 (CH), 100.9 (C), 211.2 (C=O).
MS (CI): m/z (%) = 473 (100) [M+ + 1], 472 (2) [M+], 471 (4) [M+
– 1], 416 (13).
MS (CI): m/z (%) = 340 (22) [M+ – 16], 339 (100) [M+ – 17], 338
(8).
Anal. Calcd for C27H56O4Si: C, 68.59; H, 11.94. Found: C, 68.45;
H, 11.43.
Anal. Calcd for C21H40O4: C, 70.74; H, 11.31. Found: C, 71.02; H,
11.36.
(4R,5R)-4-[(R)-1-(tert-Butyldimethylsilyloxy)pentadecyl]-2,2-
dimethyl-1,3-dioxan-5-yl Methanesulfonate (8)
To a stirred solution of 7 (0.90 g, 1.90 mmol) in CH2Cl2 (20 mL)
was added DMAP (2.32 g, 19.0 mmol) at 0 °C. After 10 min the re-
action mixture was cooled to –10 °C and methanesulfonyl chloride
(1.09 g, 9.50 mmol) was added dropwise. After 4 h the reaction
mixture was warmed to r.t. and stirred for an additional 11 h then
poured into H2O (18 mL) and extracted with CH2Cl2 (3 × 20 mL).
The combined organic layers were washed with brine (15 mL) and
dried over MgSO4. Evaporation of the solvent followed by column
chromatography (silica gel, n-pentane–Et2O, 3:1) of the crude prod-
uct afforded 8.
(R,R)-4-[1-(tert-Butyldimethylsilyloxy)pentadecyl]-2,2-dimeth-
yl-1,3-dioxan-5-one (6)
To a solution of the aldol product 5 (1.50 g, 4.21 mmol) in CH2Cl2
(15 mL) at –20 °C was added sequentially, 2,6-lutidine (2.0 mL,
16.8 mmol) and TBSOTf (2.9 mL, 12.6 mmol) dropwise via sy-
ringe. After 2 h the reaction mixture was quenched with sat.
NaHCO3 solution (10 mL) and warmed to r.t. The aqueous phase
was extracted with CH2Cl2 (3 × 30 mL) and the combined organic
layers were dried over MgSO4 and the solvent was removed under
reduced pressure. Purification by flash chromatography (silica gel,
n-pentane–CH2Cl2, 1:1) afforded the desired product 6.
Yield: 1.03 g (98%); colourless oil; de >98% (NMR); [a]D23 –26.4
(c 1.25, CHCl3).
Yield: 1.88 g (95%); colourless oil; de >99% (NMR); [a]D21 +88.5
(c 2.4, CHCl3).
IR (CHCl3): 2927, 2856, 1465, 1357, 1258, 1176, 1119, 962, 906,
836, 778, 528 cm–1.
IR (CHCl3): 2926, 2856, 1750, 1465, 1378, 1252, 1225, 1096, 838,
763 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.10 (s, 3 H, CH3Si), 0.14 (s, 3 H,
CH3Si), 0.88 (t, J = 6.9 Hz, 3 H, CH3), 0.90 [s, 9 H, (CH3)3CSi],
1.26 (m, 24 H, 12 × CH2), 1.43 (s, 3 H, CH3), 1.46 (s, 3 H, CH3),
1.64 (m, 2 H, CH2), 3.13 (s, 3 H, OSO2CH3), 3.77 (dd, J = 1.0, 8.7
Hz, 1 H, CH), 3.97 (m, 1 H, CH), 4.00 (dd, J = 13.9, 1.0 Hz, 1 H,
CH2), 4.37 (dd, J = 13.9, 1.8 Hz, 1 H, CH2), 4.64 (m, 1 H, CH).
1H NMR (400 MHz, CDCl3): d = 0.08 (s, 3 H, CH3Si), 0.10 (s, 3 H,
CH3Si), 0.88 (t, J = 6.9 Hz, 3 H, CH3), 0.89 [s, 9 H, (CH3)3CSi],
1.26 (m, 24 H, 12 × CH2), 1.29 (m, 2 H, CH2), 1.45 (s, 3 H, CH3),
1.46 (s, 3 H, CH3), 3.91 (d, J = 15.8 Hz, 1 H, CH2), 4.07 (m, 1 H,
CH), 4.20 (dd, J = 15.8, 1.5 Hz, 1 H, CH2), 4.23 (m, 1 H, CH).
13C NMR (100 MHz, CDCl3): d = –4.8 (CH3), –4.2 (CH3), 14.1
(CH3), 18.1 (C), 18.5 (CH3), 21.7 (CH2), 22.7 (CH2), 26.0 (CH3),
29.2 (CH3), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2), 29.7 (CH2), 29.8
13C NMR (100 MHz, CDCl3): d = –4.6 (CH3), –4.4 (CH3), 14.1
(CH3), 18.1 (C), 22.7 (CH2), 23.4 (CH3), 24.5 (CH3), 25.9 (CH3),
Synthesis 2008, No. 14, 2278–2282 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Jaspine B
2281
(4 × CH2), 29.9 (CH2), 31.9 (CH2), 32.0 (CH2), 40.2 (OSO2CH3),
62.3 (CH2), 68.7 (CH), 72.0 (CH), 72.9 (CH), 99.1 (C).
(R)-1-[(4S,5S)-5-Azido-2,2-dimethyl-1,3-dioxan-4-yl]penta-
decyl p-Toluenesulfonate (11)
To a solution of 10 (0.20 g, 0.52 mmol) in CH2Cl2 (5 mL) was added
DMAP (127 mg, 1.04 mmol) and p-toluenesulfonyl chloride
(148 mg, 0.78 mmol) at 0 °C. The reaction was stirred at r.t. for 4 h
then quenched with H2O (5 mL), extracted with CH2Cl2 (3 × 10
mL) and dried over MgSO4. Evaporation of the solvent gave the
crude product, which was purified by flash chromatography (silica
gel, CH2Cl2–Et2O, 9:1) to give 11.
MS (CI): m/z (%) = 551 (100) [M+ + 1], 493 (25), 419 (21), 341 (19).
Anal. Calcd for C28H58O6SSi: C, 61.05; H, 10.61. Found: C, 60.76;
H, 10.69.
(R)-1-[(4S,5S)-5-Azido-2,2-dimethyl-1,3-dioxan-4-yl)penta-
decyloxy]-tert-butyldimethylsilane (9)
To a solution of 8 (1.00 g, 1.81 mmol) in DMF (20 mL) were added
18-crown-6 (0.95 g, 3.62 mmol) and NaN3 (1.17 g, 18.1 mmol).
The reaction mixture was heated to 100 °C and stirred under argon
for 48 h then DMF was distilled off and the crude residue was dis-
solved in H2O–Et2O (1:1, 70 mL). The aqueous phase was extracted
with Et2O (3 × 25 mL) and the combined organic layers were dried
over MgSO4. Evaporation of the solvent followed by column chro-
matography (silica gel, n-pentane–Et2O, 9:1) of the crude residue
afforded 9.
Yield: 0.27 g (97%); de >98% (NMR); [a]D22 +30.0 (c 2.4, CHCl3).
IR (film): 2925, 2856, 2106, 1598, 1461, 1370, 1269, 1180, 1099,
920, 814, 766, 672, 557 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.8 Hz, 3 H, CH3-18),
1.26 (m, 24 H, 12 × CH2), 1.32 (s, 6 H, 2 × CH3), 1.55 (m, 1 H,
CH2-5a), 1.78 (m, 1 H, CH2-5b), 2.44 (s, 3 H, Ar-CH3), 3.37 (m,
1 H, CH-2), 3.69 (dd, J = 11.8, 7.8 Hz, 1 H, CH2-1a), 3.80 (dd,
J = 9.4, 2.5 Hz, 1 H, CH-3), 3.92 (dd, J = 11.6, 5.2 Hz, 1 H, CH2-
1b), 4.67 (m, 1 H, TsOCH), 7.34 (d, J = 8.0 Hz, 2 H, ArH), 7.81 (d,
J = 8.2 Hz, 2 H, ArH).
Yield: 0.71 g (79%); colourless oil; de >98% (NMR); [a]D23 +24.9
(c 1.0, CHCl3).
IR (CHCl3): 2927, 2856, 2109, 1465, 1380, 1258, 1224, 1100, 1029,
836, 777 cm–1.
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 19.7 (Ar-CH3), 21.6
(CH3), 22.7 (CH2), 25.1 (CH2), 27.4 (CH3), 29.2, 29.4, 29.5, 29.6,
29.69, 29.7 (9 × CH2), 31.9 (2 × CH2), 55.1 (CH), 62.1 (CH2), 72.6
(CH), 82.6 (CH), 99.6 (C), 128.0 (CHAr), 129.7 (CHAr), 134.4 (CAr),
144.7 (CArCH3).
MS (EI): m/z (%) = 522 (23) [M+ – 15], 239 (11), 173 (29), 156 (28),
155 (100), 137 (13), 123 (23), 109 (38), 98 (52), 97 (40), 95 (60), 91
(86), 84 (64), 72 (41), 69 (57), 57 (62).
1H NMR (400 MHz, CDCl3): d = 0.08 (s, 3 H, CH3Si), 0.10 (s, 3 H,
CH3Si), 0.88 (t, J = 6.9 Hz, 3 H, CH3), 0.92 [s, 9 H, (CH3)3CSi],
1.26 (m, 24 H, 12 × CH2), 1.35 (s, 3 H, CH3), 1.40 (s, 3 H, CH3),
1.58 (m, 2 H, CH2), 3.57 (d, J = 7.2 Hz, 1 H, CH), 3.68 (dd,
J = 14.1, 6.9 Hz, 1 H, CH2), 3.73 (m, 2 H, 2 × CH), 3.92 (dd,
J = 14.5, 7.9 Hz, 1 H, CH2).
13C NMR (100 MHz, CDCl3): d = –4.9 (CH3), –4.1 (CH3), 14.0
(CH3), 18.1 (C), 20.3 (CH3), 22.6 (CH2), 25.8 (CH3), 26.1 (CH2),
27.15 (CH3), 29.2 (CH2), 29.4 (3 × CH2), 29.5 (2 × CH2), 29.55
(3 × CH2), 31.8 (CH2), 33.9 (CH2), 55.1 (CH), 62.4 (CH2), 73.9
(CH), 74.4 (CH), 99.3 (C).
HRMS: m/z calcd for [C28H47N3O5S – CH3]: 522.3001; found:
522.3002.
(2S,3S,4S)-4-Azido-2-tetradecyltetrahydrofuran-3-ol (12)
To a solution of 11 (0.16 g, 0.30 mmol) in THF (2 mL) and MeOH
(2 mL) was added Amberlyst 15 (0.15 g) and the mixture was stirred
for 24 h. After filtration of the resin, the solvent was removed under
reduced pressure. Purification by flash chromatography (silica gel,
CH2Cl2–Et2O, 9:1) afforded the desired product 12.
MS (ESI): m/z (%) = 471 (33) [M+ – 26], 470 (100) [M+ – 27].
Anal. Calcd for C27H55N3O3Si: C, 65.14; H, 11.14; N, 8.44. Found:
C, 64.90; H, 10.96; N, 8.74.
23
Yield: 74 mg (76%); colourless solid; de >98% (NMR); [a]D
(R)-1-[(4S,5S)-5-Azido-2,2-dimethyl-1,3-dioxan-4-yl]penta-
decan-1-ol (10)
+15.9 (c 1.1, CHCl3) {Lit.17 [a]D +16.7 (c 1.0, CHCl3), Lit.10 [a]D
+17 (c 1.0, CHCl3)}.
To a solution of 9 (0.70 g, 1.41 mmol) in THF (30 mL) was added
TBAF (1 M in THF, 2.8 mL, 2.80 mmol) at 0 °C. The reaction was
stirred at r.t. for 24 h then the solvent was removed under reduced
pressure followed by filtration through a short pad of silica gel using
Et2O (20 mL) as eluent to give 10.
Yield: 0.45 g (83%); colourless oil; de >98% (NMR); [a]D21 +22.7
(c 1.9, CHCl3).
IR (CHCl3): 3332, 2920, 2852, 2106, 1467, 1340, 1261, 1121, 759
cm–1.
1H NMR (CDCl3, 400 MHz,): d = 0.88 (t, J = 6.9 Hz, 3 H, CH3),
1.25–1.44 (m, 24 H, 12 × CH2), 1.64 (m, 2 H, CH2-5), 2.04 (d,
J = 5.2 Hz, 1 H, OH), 3.76 (ddd, J = 3.6, 6.9, 6.9 Hz, 1 H, H-4), 3.85
(dd, J = 6.6, 9.1 Hz, 1 H, H-1a), 3.98 (dd, J = 7.4, 9.1 Hz, 1 H, H-
1b), 4.11 (ddd, J = 4.9, 6.6, 7.1 Hz, 1 H, H-2), 4.21 (dd, J = 4.4, 4.7
Hz, 1 H, H-3).
13C NMR (100 MHz, CDCl3): d = 14.1 (CH3), 22.7, 26.0, 28.8, 29.3,
29.49, 29.53, 29.61, 29.64 (CH2, C6-17), 31.9 (CH2, C-5), 63.6
(CH, C-2), 68.3 (CH2, C-1), 72.4 (CH, C-3), 82.0 (CH, C-4).
IR (film): 3531, 2925, 2856, 2106, 1461, 1377, 1265, 1220, 1163,
1098, 866, 771 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.88 (t, J = 6.9 Hz, 3 H, aliph.
CH3), 1.26 (m, 24 H, 12 × CH2), 1.37 (s, 3 H, CH3), 1.43 (s, 3 H,
CH3), 1.53 (m, 2 H, CH2), 2.22 (d, J = 4.4 Hz, 1 H, OH), 3.62 (m,
1 H, CH), 3.72 (m, 1 H, CH), 3.75 (m, 1 H, CH2), 3.95 (t, J = 2.4
Hz, 1 H, CH), 3.97 (dd, J = 11.8, 4.4 Hz, 1 H, CH2).
MS (EI): m/z (%) = 268 (7) [M+ – 57], 250 (5), 97 (11), 85 (8), 83
(14), 72 (16), 71 (100), 69 (29), 57 (66), 55 (28).
13C NMR (100 MHz, CDCl3): d = 14.1 (CH3), 20.4 (CH3), 22.7
(CH2), 25.6 (CH3), 25.9 (CH2), 27.4 (CH3), 29.35, 29.4, 29.57,
29.59, 29.6, 29.7 (6 × CH2), 31.6 (CH2), 31.9 (CH2), 55.1 (CH),
62.3 (CH2), 72.3 (CH), 74.1 (CH), 99.3 (C).
Anal. Calcd for C18H35N3O2: C, 66.42; H, 10.84; N, 12.91. Found:
C, 66.56; H, 11.03; N, 12.89.
Jaspine B (Pachastrissamine; 1)
To a solution of 12 (158 mg, 0.48 mmol) in MeOH (5 mL) and
CH2Cl2 (6 mL) were added 5% Pd/C (158 mg). The reaction mix-
ture was stirred for 8 h under an H2 atmosphere at r.t. then filtered
through a short pad of Celite and washed with CH2Cl2–MeOH (1:1,
20 mL). Evaporation of the solvent followed by flash chromatogra-
phy (silica gel, CH2Cl2–MeOH, 9:1, including 1% NH4OH), afford-
ed the title compound 1.
MS (EI): m/z (%) = 368 (17) [M+ – 15], 156 (7), 114 (8), 99 (9), 84
(47), 72 (24), 71 (22), 69 (79), 59 (100), 57 (31).
HRMS: m/z [C21H41N3O3 – CH3] calcd for: 368.2913; found:
368.2915.
Synthesis 2008, No. 14, 2278–2282 © Thieme Stuttgart · New York

2282
D. Enders et al.
PAPER
23
Yield: 144 mg (98%); de >98% (NMR); ee = 95%; [a]D +20.2
(c 0.55, MeOH) {Lit.1 [a]D +18 (c 0.1, EtOH), Lit.10 [a]D +17.5 (c
0.4, EtOH), Lit.15 [a]D23 +17.5 (c 0.3, EtOH)}.
(10) Prasad, K. R.; Chandrakumar, A. J. Org. Chem. 2007, 72,
6312.
(11) Ribes, C.; Falomir, E.; Carda, M.; Marco, J. A. Tetrahedron
2006, 62, 5421.
(12) Génisson, Y.; Lamandé, L.; Salma, Y.; Andrieu-Abadie, N.;
André, C.; Baltas, M. Tetrahedron: Asymmetry 2007, 18,
857.
(13) Yakura, T.; Sato, S.; Yoshimoto, Y. Chem. Pharm. Bull.
2007, 55, 1284.
IR (KBr): 3343, 3284, 2923, 2852, 2742, 1584, 1471, 1383, 1037,
719 cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.88 (t, J = 6.8 Hz, 3 H, CH3), 1.25
(m, 24 H, 12 × CH2), 1.65 (m, 2 H, CH2-5), 2.08 (br s, 3 H, NH2,
OH), 3.51 (dd, J = 8.4, 6.7 Hz, 1 H, H-1a), 3.61–3.68 (br m, 1 H, H-
2), 3.74 (ddd, J = 3.7, 6.9, 6.9 Hz, 1 H, H-4), 3.85–3.96 (m, 2 H, H-
3, H-1b).
(14) Venkatesan, K.; Srinivasan, K. V. Tetrahedron: Asymmetry
2008, 19, 209.
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 22.7, 26.3, 29.3, 29.4,
29.6, 29.7, 29.8 (CH2, C6-17), 31.9 (CH2, C-5), 54.4 (CH, C-2),
71.8 (CH, C-3), 72.4 (CH2, C-1), 83.2 (CH, C-4).
MS (EI): m/z (%) = 299 (5) [M+], 252 (2), 226 (4), 83 (4), 71 (6), 60
(100), 59 (46), 57 (9).
(15) Abraham, E.; Candela-Lena, J. I.; Davies, S. G.; Georgiou,
M.; Nicholson, R. L.; Roberts, P. M.; Russell, A. J.;
Sánchez-Fernández, E. M.; Smith, A. D.; Thomson, J. E.
Tetrahedron: Asymmetry 2007, 18, 2510.
(16) van den Berg, R. J. B. H. N.; Boltje, T. J.; Verhagen, C. P.;
Litjens, R. E. J. N.; van der Marel, G. A.; Overkleeft, H. S.
J. Org. Chem. 2006, 71, 836.
HRMS: m/z calcd for C18H37NO2: 299.2824; found: 299.2826.
(17) Lee, T.; Lee, S.; Kwak, Y. S.; Kim, D.; Kim, S. Org. Lett.
2007, 9, 429.
(18) Enders, D.; Paleček, J.; Grondal, C. Chem. Commun. 2006,
Acknowledgment
655.
This work was supported by the Fonds der Chemischen Industrie
and the Deutsche Forschungsgemeinschaft (Schwerpunktpro-
gramm 1179 Organokatalyse). We thank the companies Bayer AG,
BASF AG, Wacker Chemie and Degussa AG for the donation of
chemicals.
(19) 2,2-Dimethyl-1,3-dioxan-5-one was prepared in two steps
from tris(hydroxymethyl)aminomethane hydrochloride,
see: (a) For a review: Enders, D.; Voith, M.; Lenzen, A.
Angew. Chem. Int. Ed. 2005, 44, 1304; Angew. Chem. 2005,
117, 1330. (b) Enders, D.; Voith, M.; Ince, S. J. Synthesis
2002, 1775. (c) Enders, D.; Whitehouse, D. L.; Runsink, J.
Chem. Eur. J. 1995, 1, 382.
References
(20) (a) Enders, D.; Grondal, C. Angew. Chem. Int. Ed. 2005, 44,
1210; Angew. Chem. 2005, 117, 1235. (b) Enders, D.;
Grondal, C.; Vrettou, M.; Raabe, G. Angew. Chem. Int. Ed.
2005, 44, 4079; Angew. Chem. 2005, 117, 4147.
(c) Grondal, C.; Enders, D. Tetrahedron 2006, 62, 329..
(d) Enders, D.; Vrettou, M. Synthesis 2006, 2155.
(e) Enders, D.; Grondal, C.; Vrettou, M. Synthesis 2006,
3597. (f) Grondal, C.; Enders, D. Synlett 2006, 3507.
(g) Grondal, C.; Enders, D. Adv. Synth. Catal. 2007, 349,
694. For related publications, see: (h) Westermann, B.;
Neuhaus, C. Angew. Chem. Int. Ed. 2005, 44, 4077; Angew.
Chem. 2005, 117, 4145. (i) Suri, J. T.; Ramachary, D. B.;
Barbas, C. F. III Org. Lett. 2005, 7, 1383. (j) Suri, J. T.;
Mitsumori, S.; Albertshofer, K.; Tanaka, F.; Barbas, C. F. III
J. Org. Chem. 2006, 71, 3822. (k) Ibrahem, I.; Córdova, A.
Tetrahedron Lett. 2005, 46, 3363. (l) Ibrahem, I.; Zou, W.;
Casas, J.; Sundén, H.; Córdova, A. Tetrahedron 2006, 62,
357. (m) Ibrahem, I.; Zou, W.; Xu, Y.; Córdova, A. Adv.
Synth. Catal. 2006, 348, 211. (n) Majewski, M.; Niewczas,
I.; Palyam, N. Synlett 2006, 2387.
(1) Kuroda, I.; Musman, M.; Ohtani, I. I.; Ichiba, T.; Tanaka, J.;
Garcia-Gravalos, D.; Higa, T. J. Nat. Prod. 2002, 65, 1505.
(2) Ledroit, V.; Debitus, C.; Lavaud, C.; Massiot, G.
Tetrahedron Lett. 2003, 44, 225.
(3) Bhaket, P.; Morris, K.; Stauffer, C. S.; Datta, A. Org. Lett.
2005, 7, 875.
(4) Sudhakar, N.; Ravi Kumar, A.; Prabhakar, A.; Jagadeesh,
B.; Venkateswara Rao, B. Tetrahedron Lett. 2005, 46, 325.
(5) Passiniemi, M.; Koskinen, A. M. P. Tetrahedron Lett. 2008,
49, 980.
(6) (a) Du, Y.; Liu, J.; Linhardt, R. J. J. Org. Chem. 2006, 71,
1251. (b) Liu, J.; Du, Y.; Dong, X.; Meng, S.; Xiao, J.;
Cheng, L. Carbohydr. Res. 2006, 341, 2653.
(7) Chandrasekhar, S.; Tiwari, B.; Prakash, S. J. ARKIVOC
2006, (xi), 155.
(8) Ramana, C. V.; Giri, A. G.; Suryawanshi, S. B.; Gonnade, R.
G. Tetrahedron Lett. 2007, 48, 265.
(9) Reddy, L. V. R.; Reddy, P. V.; Shaw, A. K. Tetrahedron:
Asymmetry 2007, 18, 542.
Synthesis 2008, No. 14, 2278–2282 © Thieme Stuttgart · New York