A convenient route to alkaloid lipids: Application for the synthesis of a leptophylline A analogue

Article abstract of DOI:10.1055/s-2002-19302

A synthetic route for efficient access to alkaloid lipids, using the chiral 2,3,6-trisubstituted piperidine acetaldehyde 9 as an intermediate, is reported. The utility of the synthetic route was demonstrated in the asymmetric synthesis of an unnatural analogue of Cassia leptophylla alkaloid lipid, leptophyllin A, in 16 steps and 15% overall yield starting from D-glucal.

Full text of DOI:10.1055/s-2002-19302

PAPER
111
A Convenient Route to Alkaloid Lipids: Application for the Synthesis of a
Leptophylline A Analogue
A
Convenient
o
R
oute to Alk
f
aloid
L
ip
i
ids a D. Koulocheri,a Emmanuel N. Pitsinos,b Serkos A. Haroutounian*a
a
Chemistry Laboratory, Agricultural University of Athens, Iera Odos 75, Athens 11855, Greece
Fax +30(1)5294265; E-mail: sehar@aua.gr
b
Laboratory of Organic and Bioorganic Chemistry, Institute of Physical Chemistry, NCSR “Demokritos”, P.O. Box 60228, Athens 15310,
Greece
Received 31 July 2001; revised 17 October 2001
OH
OH
OH
Abstract: A synthetic route for efficient access to alkaloid lipids,
using the chiral 2,3,6-trisubstituted piperidine acetaldehyde 9 as an
intermediate, is reported. The utility of the synthetic route was dem-
onstrated in the asymmetric synthesis of an unnatural analogue of
Cassia leptophylla alkaloid lipid, leptophyllin A, in 16 steps and
15% overall yield starting from D-glucal.
8
8
OH
N
N
H
H
O
O
(−)-prosopinine (1)
(−)-prosopine (2)
(−)-prosophylline (3)
OR
OH
Key words: piperidines, alkaloids, asymmetric synthesis
9
n
Y
HO
N
N
H
H
OH
O
n = 12, Y = CH3 (−)-spectalline (4)
n = 10, Y = OH leptophylline B (5)
R = H leptophylline A (6)
R = Ac 3-acetylleptophylline A (7)
Alkaloid lipids are natural compounds isolated from the
leaves, stems and roots of various Prosopis, and Cassia
species.1 Their structural framework consists of a polar Figure 1
head group (a 2,6-disubstituted-3-piperidinol) and a lipid
tail group (Figure 1, compounds 1–7). Besides their
thermore, this compound is easily obtained by diasterose-
lective transformation of the corresponding 6-hydroxy-
2S-hydroxymethyl-dihydropyridone 10, which can be
prepared efficiently from the readily available D-glucal
according to our recently reported synthetic route.7
unique structural features, these compounds and their syn-
thetic analogues were also found to possess a wide range
of antibiotic, anesthetic and CNS stimulating properties.2
Consequently, they have attracted increasing scientific in-
terest.3 Intense research activity directed towards the effi-
cient and stereoselective synthesis of these compounds
and their derivatives has been initiated, producing a large
number of biologically active compounds.4
4
OR1
R2
OBn
OR
O
3
5
9
6
2
N
Ts
HO
N
Ts
HO
N
Recently, bioassay-guided fractionation of a bioactive
leaf extract of the Brazilian legume Cassia leptophylla5
led to the isolation and structure elucidation of three new
alkaloid lipids named leptophylline B (5), leptophylline A
(6), and 3-acetylleptophylline (7). These new structures
represent the first example of alkaloid lipids that display
significant anticancer activity5 and differ from other Pros-
opis and Cassia alkaloid lipids in the length and unusual
dihydroxy functionality of their aliphatic side chains.
H
CHO
OR
OH
6. R1 = H, R2 = H
7. R1 = Ac, R2 = H
8. R1 = H, R2 = OH
9
10
R = TBDPS
Scheme 1
OR2
O
3 steps
73%
5 steps
61%
As part of our ongoing studies on the asymmetric synthe-
sis of biologically interesting piperidine alkaloid deriva-
tives,6 these intriguing molecules have attracted our
attention. Aiming to develop a general synthetic route for
the preparation of such compounds, our retrosynthetic
strategy envisioned the use of the chiral 2,6-disubstituted-
piperidin-3-ol 9 as a key intermediate (Scheme 1). This
molecule has the desired all cis-configuration and an ace-
taldehyde functionality on carbon atom C-6 that allows
for the facile attachment of various lipid side chains. Fur-
D-Glucal
EtO
N
Ts
HO
N
Ts
OTBDPS
11. R2=H
OTBDPS
a
91%
10
12. R2=Bn
OBn
OBn
b
c
OHC
N
N
96%
87%
Ts
Ts
OTBDPS
OTBDPS
9
13
Scheme 2 Reagents and conditions: (a) NaH, BnBr, Bu4NI, THF;
(b) allyltrimethylsilane, TiCl4, CH2Cl2, 78 °C; (c) i. K3Fe(CN)6,
K2CO3, K2OsO2(OH)2, CH3SO2NH2, t-BuOH H2O (1:1), ii. NaIO4,
H2O EtOH (1:1).
Synthesis 2002, No. 1, 28 12 2001. Article Identifier:
1437-210X,E;2002,0,01,0111,0115,ftx,en;T07101SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

112
S. D. Koulocheri et al.
PAPER
The synthesis of compound 9 was accomplished as depict- aliphatic side of leptophylline A with the polar head group
ed in Scheme 2. Enantioselective transformation of D-glu- of Prosopis alkaloids. To this end, the chiral aliphatic sub-
cal to the trisubstituted piperidine 11 was achieved by an strate 18 was derived from the readily available 1,9-
8-step synthetic sequence in high yield, via the intermedi- nonandiol, according to the reaction sequence outlined in
ate 6-hydroxy-2S-hydroxymethyl-dihydropyridone 10.7 Scheme 3. The 1,9-nonandiol 14 was transformed to the
Protection of the hydroxyl group and reaction with allyl- corresponding bromoalcohol and oxidized to aldehyde 15.
trimethylsilane in the presence of a catalytic amount of ti- Subsequent Wittig olefination afforded the bromo-alkene
tanium tetrachloride at 78 °C resulted in the exclusive 16. Asymmetric dihydroxylation and subsequent acetal-
formation of the all cis-diastereomer of 6-allyl-piperidine ization provided the desired substrate 18 in very good
13. The diastereoselectivity of this transformation can be chemical yield (85%) with 80% ee.
rationalised, assuming an N-acyliminum ion intermediate
(Figure 2).8 The strong A(1,2) strain between the tert-butyl-
a, b
c
Br
CHO
Br
HO
OH
diphenyl-silyloxymethyl group on carbon atom C-2 and
the N-tosyl group favors conformer II over conformer I.
Exclusive formation of the 2,6-cis-isomer was revealed by
HPLC and 1H NMR analysis and could be attributed to the
stereoelectronically preferred axial attack by the silane
nucleophile on II.8
7
6
16
6
65%
75%
14
15
Br
O
Br
OH
d
e
6
6
O
85 %
OH
17
90%
18
Scheme 3 Reagents and conditions: (a) HBr, PhCH3; (b) PCC,
CH2Cl2; (c) CH3PPh3Br, n-BuLi, THF; (d) (DHQD)2-PYR,
K3Fe(CN)6, K2OsO2(OH)2, K2CO3, t-BuOH H2O (1:1); (e)
(CH3)2C(OCH3)2, p-TSA, acetone.
Ts
OTBDPS
N
BnO
N
Ts
BnO
TBDPSO
SiMe3
I
II
Introduction of the aliphatic side chain onto the piperidine
ring was performed via Wittig reaction of aldehyde 9 with
the enantiomerically enriched triphenylphosphonium
ylide. This ylide was derived from bromide 18, furnishing
the corresponding alkene 19, which was purified by chro-
matography and selective crystallization.
Figure 2
The stereochemistry of carbon atom C-6 in aldehyde 9
was assigned on the basis of 2D COSY and NOESY NMR
spectroscopic studies. The aldehyde 9 was obtained in ex-
cellent yield after dihydroxylation and subsequent perio-
date cleavage of olefin 13. Thus, the strong NOE
correlation among the CH2 protons of acetaldehyde, H-5eq
and the methylenic protons of the silyloxymethyl group
are indicative of the -axial orientation of the acetalde-
hyde moiety at carbon atom C-6 (Figure 3). Furthermore,
the small coupling constants observed between H-6 and
the two protons H-5 are consistent with the -equatorial
orientation of H-6, reinforcing the previous assignment.
Subsequent sequential removal of the silyl protective
group, catalytic hydrogenation-hydrogenolysis and cleav-
age of the acetonide and tosyl protective groups provided
the desired synthetic alkaloid lipid 8 in 16 steps and 15%
overall yield (from D-Glucal).
OBn
H
b
a
9
N
Ts
O
93%
90%
7
O
H
OTBDPS
19
OBn
OH
OH
H
7
9
c
N
Ts
N
Ts
O
O
85%
O
H
OH
O
H
SO2
H
H
N
20
21
O
H
H
H
H
H
H
H
H
H
OH
OH
H
O
CHO
9
Ph
d
e
8
Si
HO
N
Ts
97%
64%
(H3C)3C
Ph
OH
9
22
Figure 3
Scheme 4 Reagents and conditions: (a) PPh3, 18, n-BuLi; (b)
TBAF, THF; (c) H2, Pd/C, MeOH; (d) HCl, EtOH; (e) Na, naphtha-
lene, DME.
The all cis aldehyde 9 was envisioned to be the key inter-
mediate for the preparation of a broad variety of natural
and unnatural alkaloid lipids.9 To demonstrate the syn-
thetic utility and versatility of this aldehyde, we targeted
the novel chimeric alkaloid lipid analog 8 (Scheme 1).
This compound would combine in a single molecule, the
In conclusion, we have described the efficient and stereo-
selective preparation of the all cis-aldehyde 9, a useful and
versatile intermediate for the synthesis of alkaloid lipids.
In addition, the convenient preparation of a novel alkaloid
Synthesis 2002, No. 1, 111–115 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convenient Route to Alkaloid Lipids
113
(2S, 3S, 6R)-6-Allyl-3-benzyloxy-2-(tert-butyl-diphenyl-silyl-
oxymethyl)-1-tosyl piperidine (13)
lipid analog, incorporating in a single molecule the ali-
phatic tail chain of leptophylline A and the polar head
group of a Prosopis alkaloid, is presented. The described
approach is highly convergent and is generally applicable
since the side chain at carbon atom C-6 can be easily mod-
ified to provide access to a broad variety of natural and
synthetic alkaloid lipids of structural and biological im-
portance.
To a stirred soln of TiCl4 (45 L, 0.41 mmol) in anhyd CH2Cl2 (1
mL) at –78 °C, a soln of 12 (256 mg, 0.39 mmol) and allyltrimeth-
ylsilane (0.12 mL, 0.75 mmol) in CH2Cl2 (1.5 mL) was added drop-
wise over a 5 min period. The soln was allowed to gradually warm
to 0 °C and stirred for a total period of 90 min. Then the reaction was
quenched with H2O (2 mL) and the aq layer was extracted with
CH2Cl2 (2 10 mL). The combined organic layers were washed
with brine, dried (MgSO4) and concentrated under reduced pressure
to give a colorless oil which was purified by chromatography
(EtOAc hexane, 1:4; Rf = 0.57) to give 13 as white crystals. Yield:
222 mg (87%).
All reactions were carried out under an argon atmosphere unless
otherwise noted. Solvents were distilled prior to use. THF was dis-
tilled from sodium-benzophenone, and CH2Cl2 was distilled over
CaH2 immediately prior to use. Starting materials and reagents were
purchased from Aldrich (analytical reagent grades) and used with-
out further purification. The (2S,3S,6R)-2-(tert-butyldiphenylsily-
loxymethyl)-6-ethoxy-1-tosylpiperidin-3-ol (11) ([ ]D22 = +60.4 (c
0.90, MeOH); mp 111–112 °C) was prepared according to literature
procedure.7 Melting points were determined on a Büchi apparatus
and are uncorrected. IR spectra were recorded on a Nicolet Magna
750, series II spectrometer. 1H NMR spectra were recorded in
CDCl3 on Bruker AM-250 or DRX-400 spectrometers (250 MHz
and 400 MHz, respectively) using TMS as internal standard. Optical
rotations were measured with a Perkin Elmer 241 polarimeter at
ambient temperature. Elemental analyses were provided by the Uni-
versity of Illinois microanalytical service laboratory. HPLC separa-
tions were performed using a Hewlett Packard 1100 series
instrument with a variable wavelength UV detector and coupled to
HP Chem-Station utilizing the manufacturer’s 5.01 software pack-
age. TLC was conducted on Merck glass plates coated with silica
gel 60 F254. Flash column chromatography was performed using
Merck silica gel 60 (230–400 mesh ASTM).
[ ]D22 = +20 (c 0.5, EtOAc); mp 90–92 °C.
IR: 1640 cm 1 (CH=CH2).
1H NMR (400 MHz, CDCl3): = 1.09 (s, 9 H, CCH3), 1.14–1.29
(m, 1 H, H-5), 1.45–1.62 (m, 3 H, H-4, H-5), 2.20–2.25 (m, 1 H,
CHHCH=CH2), 2.37 (s, 3 H, ArCH3), 2.43 (dt, J = 13.6, 5.3 Hz, 1
H, CHHCH=CH2), 3.25 (ddd, J = 11.5, 5.3 Hz, 1 H, H-3), 3.73–
3.82 (m, 1 H, H-6), 3.83 (dd, J = 11.2, 7.9 Hz, 1 H, CHHOTBDPS),
4.00 (dd, J = 11.2, 5.3 Hz, 1 H, CHHOTBDPS), 4.31 (d, J = 11.8
Hz, 1 H, CHHPh), 4.43 (d, J = 11.8 Hz, 1 H, CHHPh), 4.62 (dt,
J = 7.9, 5.3 Hz, 1 H, H-2), 4.87 (d, J = 17.1 Hz, 1 H, CHCH=CHH),
4.94 (d, J = 10.1 Hz, 1 H, CHCH=CHH), 5.60–5.75 (m, 1 H,
CHCH=CH2), 7.09–7.18 (m, 3 H, ArH), 7.27–7.32 (m, 4 H, ArH),
7.34–7.45 (m, 6 H, ArH), 7.65 (d, J = 7,9 Hz, 2 H, ArH), 7.72 (dd,
J = 7.9, 1.3 Hz, 2 H, ArH), 7.78 (dd, J = 7.9, 1.3 Hz, 2 H, ArH).
Anal. Calcd for C39H47NO4SSi (653.95): C, 71.63; H,7.24; N, 2.14.
Found: C, 71.50; H, 7.31; N, 2.11.
(2S, 3S, 6R)-[5-Benzyloxy-6-(tert-butyl-diphenyl-silyloxyme-
thyl)-1-tosylpiperidin-2-yl]-acetaldehyde (9)
A soln of K3Fe(CN)6 (181 mg, 0.549 mmol) and K2CO3 (75 mg,
0.549 mmol) in t-BuOH–H2O (1:1, 1.6 mL) was stirred for 15 min.
Then, K2OsO2(OH)2 (0.66 mg, 0.0018 mmol) was added and stir-
ring was continued for additional 15 min. The mixture was cooled
to 0 °C and CH3SO2NH2 (32 mg, 0.336 mmol) and 6-allyl-piperi-
dine 13 (120 mg, 0.183 mmol) were added at once. The heteroge-
neous slurry was allowed to reach r.t. and stirred vigorously for 1 h.
The reaction was quenched by addition of Na2SO3 (70 mg, 0.55
mmol) and stirred for an additional 30 min. Then the mixture was
extracted with EtOAc (3 15 mL). The combined organic layers
were washed with brine, dried (MgSO4) and concentrated under re-
duced pressure. The colorless oil obtained was purified by chroma-
tography (EtOAc hexanes, 1:2) and the resulting dihydroxy
intermediate was dissolved in THF–H2O (1:1, 5 mL). NaIO4 (39
mg, 0.183 mmol) was added and after stirring for 30 min the reac-
tion mixture was extracted with Et2O (2 15 mL). The combined
organic layers were washed with brine, dried (MgSO4) and concen-
trated under reduced pressure to give a colorless oil which was pu-
rified by chromatography (EtOAc hexane, 1:4, Rf = 0.22) to
furnish aldehyde 9 as white crystals. Yield: 115 mg (96%).
(2S, 3S, 6R)-3-Benzyloxy-2-(tert-butyl-diphenyl-silyloxyme-
thyl)-6-ethoxy-1-tosyl piperidine (12)
To an ice-cold stirred soln of compound 11 (2.5 g, 4.4 mmol) in an-
hyd THF (7 mL), NaH was added in small quantities (126 mg, 5.28
mmol). The reaction mixture was allowed to reach r.t. and stirred for
30 min. A catalytic amount of Bu4NI (80 mg, 0.22 mmol) was added
followed by addition of BnBr (0.74 mL, 6.61 mmol). After stirring
for 2 h, the reaction was quenched with sat. aq NH4Cl (15 mL) and
extracted with EtOAc (3 15 mL). The combined organic extracts
were washed with brine, dried (MgSO4) and evaporated to give a
yellowish slurry which was purified by chromatography (EtOAc
hexane, 1:4; Rf = 0.55) to provide 12 in pure white crystalline form.
Yield: 2.1 g (91%).
[ ]D22 = +59.06 (c 1.06, EtOAc); mp 75–77 °C.
1H NMR (400 MHz, CDCl3):
= 1.03 (t, J = 7.1 Hz, 3 H,
CH3CH2O), 1.09 (s, 9 H, C-CH3), 1.15–1.27 (m, 1 H, H-4), 1.41–
1.51 (m, 1 H, H-4), 1.66–1.83 (m, 2 H, H-5), 2.34 (s, 3 H, ArCH3),
2.91–3.00 (m, 1 H, H-3), 3.42 (dq, J = 9.5, 7.1 Hz, 1 H,
OCHHCH3), 3.90 (dq, J = 9.5, 7.1 Hz, 1 H, OCHHCH3), 3.96 (dd,
J = 11.2, 5.0 Hz, 1 H, CHHOTBDPS), 4.01 (d, J = 12.2 Hz, 1 H,
CHHPh), 4.06–4.16 (dd, J = 11.2, 10.1 Hz, 1 H, CHHOTBDPS),
4.21 (d, J = 12.2 Hz, 1 H, CHHPh), 4.35 (m, 1 H, H-2), 5.07 (d,
J = 3.3 Hz, 1 H, H-6), 7.03 (dd, J = 7.5, 1.6 Hz, 2 H, ArH), 7.10 (d,
J = 8.3 Hz, 2 H, ArH), 7.21–7.28 (m, 3 H, ArH), 7.34–7.43 (m, 6 H,
ArH), 7.56 (d, J = 7.9 Hz, 2 H, ArH), 7.70 (dd, J = 7.5, 1.6 Hz, 2 H,
ArH), 7.82 (dd, J = 7.5, 1.6 Hz, 2 H, ArH).
[ ]D22 = +30 (c 0.3, EtOAc); mp 159–161 °C.
IR: 1724 cm 1 (C=O).
1H NMR (400 MHz, CDCl3): = 1.09 (s, 9 H, CCH3), 1.17–1.33 (m,
1 H, H-5ax), 1.34–1.45 (m, 1 H, H-5eq), 1.47–1.78 (m, 2 H, H-4),
2.34 (s, 3 H, ArCH3), 2.68 (dd, J = 17.8, 9.5 Hz, 1 H, CHHCHO),
2.91 (dd, J = 17.8, 4.1 Hz, 1 H, CHHCHO), 3.24 (m, 1 H, H-3), 3.82
(dd, J = 11.2, 9.5 Hz, 1 H, CHHOTBDPS), 3.97 (dd, J = 11.2, 5.4
Hz, 1 H, CHHOTBDPS), 4.24 (d, J = 12.0 Hz, 1 H, CHHPh), 4.29–
4.39 (m, 1 H, H-6), 4.35 (d, J = 12.0 Hz, 1 H, CHHPh), 4.57 (dt, J
= 9.4, 5.4 Hz, 1 H, H-2), 7.07–7.14 (m, 2 H, ArH), 7.15 (d, J = 8.3
Hz, 2 H, ArH), 7.26–7.33 (m, 3 H, ArH), 7.35–7.48 (m, 6 H, ArH),
7.60 (d, J = 8.3 Hz, 2 H, ArH), 7.73 (dd, J = 9.5, 5.4 Hz, 2 H, ArH),
7.78 (dd, J = 9.5, 5.4 Hz, 2 H, ArH), 9.64 (s, 1 H, CHO).
Anal. Calcd for C38H47NO5SSi (657.9): C, 69.37; H, 7.20; N, 2.13.
Found: C, 69.22; H, 7.10; N, 2.22.
Synthesis 2002, No. 1, 111–115 ISSN 0039-7881 © Thieme Stuttgart · New York

114
S. D. Koulocheri et al.
PAPER
Anal. Calcd for C38H45NO5SSi (655.9): C, 69.58; H, 6.92; N, 2.14.
Found: C, 69.38; H, 7.01; N, 2.10.
CH2CH2Br), 3.76–3.79 (m, 1 H, CHOH), 4.30–4.33 (m, 2 H,
CH2OH).
Anal. Calcd for C10H21BrO2 (253.18): C, 47.44; H, 8.36. Found: C,
47.57; H, 8.51.
9-Bromo-nonanal (15)
A soln of 1,9-nonandiol (8 g, 50 mmol) and 48% HBr (6 mL) in ben-
zene (100 mL) was refluxed for 24 h in a Dean Stark apparatus. The
resulting soln was washed successively with NaOH (6 N, 50 mL),
HCl (10%, 50 mL) and H2O (2 150 mL). The organic layer was
separated, washed with brine, dried (MgSO4) and evaporated to a
colorless oil which was purified by chromatography (Et2O hexane,
1:4) to yield 15 (7.8 g). The latter was dissolved in CH2Cl2 (75 mL)
and PCC (16.2 g, 75 mmol) was added. After 30 min of stirring, the
supernated was decanted and filtered through a short pad of silica
gel. The insoluble residue remaining in the reaction vessel was
washed several times with Et2O and the combined washings were
passed through the same silica gel pad. The combined filtrates were
washed with brine, dried (MgSO4) and concentrated under reduced
pressure to give a colorless oil which was further purified by flash
chromatography (EtOAc hexane, 1:9; Rf = 0.58). Yield: 7.18 g
(65%).
The ratio of enantiomers was determined by reacting the diol
17 with R-(+)-MTPA and subsequent HPLC analysis [kromasil
100-5, C-18, H2 MeOH CH3CN gradient elution from
40:40:20 0:10:90, flow = 2 mL/min, UV detection at 254 nm]; Rt
major 22.1 min (90%); and Rt minor 20.3 (of other enantiomer
10%).
(4R)-4-(8-Bromo-octyl)-2,2-dimethyl-[1,3]dioxolane (18)
To a stirred soln of 10-bromo-decane-1,2-diol (17) (400 mg, 1.36
mmol) and 2,2-dimethoxypropane (0.84 ml, 6.8 mmol) in anhyd ac-
etone (2 mL), p-TsOH (5 mg, 0.02 mmol) was added. After stirring
for 5 h, the reaction was quenched with sat. aq NaHCO3 (5 mL) and
extracted with EtOAc (2 15 mL). The combined organic layers
were washed with brine, dried (MgSO4) and concentrated under re-
duced pressure to give a colorless oil which was purified by chro-
matography (EtOAc hexane, 1:9; Rf = 0.64) to furnish 18 as
colorless oil. Yield: 359 mg (90%).
[ ]D22 = +9.2 (c 0.9, EtOAc).
IR: 1320, 980 cm 1 (COC).
1H NMR (250 MHz, CDCl3): = 1.23–1.45 (m, 12 H, CH2), 1.34 (s,
3 H, CH3), 1.39 (s, 3 H, CH3), 1.83 (quint, J = 6.7 Hz, 2 H,
CH2CH2Br), 3.39 (t, J = 6.7 Hz, 2 H, CH2CH2Br), 3.45–3.51 (m, 1
H, CHO), 4.03–4.07 (m, 2 H, CH2O).
IR (KBr): 1720 cm 1 (C=O), 2923, 2855, 1462 (CH2).
1H NMR (250 MHz, CDCl3): = 1.23–1.45 (m, 8 H, CH2), 1.51–
1.71 (m, 2 H, CH2CH2CHO), 1.84 (dt, J = 13.4, 6.7 Hz, 2 H,
CH2CH2Br), 2.42 (td, J = 7.5, 2.0 Hz, 2 H, CH2CHO) 3.40 (t, J =
6.7 Hz, 2 H, CH2CH2Br), 9.8 (t, J = 2.0 Hz, 1 H, CHO).
Anal. Calcd for C9H17BrO (221.13): C, 48.88; H, 7.55. Found: C,
49.05; H, 7.61.
10-Bromo-dec-1-ene (16)
Anal. Calcd for C13H25BrO2 (293.24): C, 47.44; H, 8.36. Found: C,
47.63; H, 8.23.
To a suspension of methyltriphenylphosphonium bromide (14.3 g,
40 mmol) in anhyd THF (50 mL), n-BuLi (1.6 M in hexane, 21.9
mL, 35 mmol) was added. The resulting orange colored mixture
was stirred for 1 h, cooled to –78 °C and a soln of aldehyde 15 (5 g,
22.6 mmol) in THF (10 mL) was added. The reaction was allowed
to reach r.t. and stirred for an additional 1 h. The mixture was ex-
tracted with EtOAc (2 60 mL) and the combined organic layers
were washed with brine, dried (MgSO4) and concentrated under re-
duced pressure. The resulting colorless oil was purified by chroma-
tography (EtOAc hexane, 5:95; Rf = 0.7) to afford alkene 16 as a
colorless oil. Yield: 3.7 g (75%).
(2S, 3S, 6S, 4 R)-[3-Benzyloxy-2-(tert-butyl-diphenyl-silyloxy-
methyl)-6-[10 -(2 ,2 -dimethyl-[1 ,3 ]dioxolan-4 -yl)-dec-2 -
enyl]-1-tosylpiperidine (19)
A soln of 4-(8-bromo-octyl)-2,2-dimethyl-[1,3]dioxolane (18) (250
mg, 0.88 mmol) and Ph3P (250 mg, 0.94 mmol) in anhyd CH3CN (1
mL) was heated in a sealed tube for 24 h. The solvent was evaporat-
ed under reduced pressure and the resulting viscous liquid was
washed several times with hexane and Et2O to yield 0.86 g of triph-
enylphosphonium ylide as an amorphous solid (0.44 g, 90%). To an
ice-cold suspension of Wittig reagent (250 mg, 0.45 mmol) in THF
(3 mL), n-BuLi (1.6 M in hexane, 0.28 mL, 0.45 mmol) was added
and the orange colored mixture was stirred at 0 ºC for an additional
30 min. To this mixture, an ice-cold soln of aldehyde 9 (148 mg,
0.23 mmol) in THF (1 mL) was cannulated. The reaction was al-
lowed to reach r.t. and stirred for 1 h. After the reaction was
quenched with sat. aq NaHCO3 (5 mL) and Et2O (15 mL), the or-
ganic phase was separated and the aq layer was extracted with Et2O
(2 10 mL). The combined organic layers were washed with brine,
dried (MgSO4) and concentrated under reduced pressure to give a
pale yellow oil which was purified by chromatography (EtOAc
hexane, 1:4; Rf = 0.41) to furnish 19 as a white solid which was re-
crystallized from Et2O. Yield: 173 mg (90%).
IR: 1645 cm 1 (CH=CH2).
1H NMR (400 MHz, CDCl3): = 1.23–1.45 (m, 8 H, CH2), 1.84
(quint, J = 6.7 Hz, 2 H, CH2CH2Br), 2.01–2.09 (m, 2 H,
CH2CH=CH2), 3.40 (t, J = 6.7 Hz, 2 H, CH2CH2Br), 4.93 (ddt,
J=10.1, 2.0, 1.0 Hz, 1 H, CH2CH=CHH), 4.99 (ddt, J = 17.1, 2.0,
1.0 Hz, 1 H, CH2CH=CHH), 5.80 (ddt, J = 17.1, 10.1, 6.7 Hz, 1 H,
CH2CH=CH2).
(2R)-10-Bromo-decane-1,2-diol (17)
To an ice-cold stirred soln of (DHQD)2-PYR (16 mg, 1.83 mol%),
K3Fe(CN)6 (1.81 g, 5.49 mmol), K2CO3 (0.75 g, 5.49 mmol) and
K2OsO2(OH)2 (6.6 mg, 0.018 mmol) in t-BuOH–H2O (1:1, 15 mL),
alkene 16 (0.40 g, 1.83 mmol) was added. The mixture was stirred
at 0 °C for 10 h, quenched with Na2SO3 (70 mg, 0.55 mmol) and
stirred for 30 min at r.t. The mixture was extracted with CH2Cl2 (30
mL) and the aq layer was extracted with EtOAc (2 30 mL). The
combined organic layers were washed with brine, dried (MgSO4)
and concentrated under reduced pressure. The colorless oil was pu-
rified by chromatography (EtOAc hexane, 2:3; Rf 0.2) to furnish
the dihydroxylation product 17 as a colorless oil. Yield: 394 mg
(85%).
[ ]D22 = +10.7 (c 1.1, EtOH).
IR: 3391 cm 1 (OH).
1H NMR (250 MHz, CDCl3): = 1.23–1.45 (m, 12 H, CH2), 1.84
(quint, J = 6.7 Hz, 2 H, CH2CH2Br), 3.40 (t, J = 6.7 Hz, 2 H,
[ ]D22 = +1.5 (c 0.55, hexane); mp = 78–80 °C.
IR: 1320, 980 cm–1 (COC).
1H NMR (400 MHz, CDCl3): = 1.09 (s, 9 H, CCH3), 1.20–1.35 (m,
11 H, H-5, CH2), 1.33 (s, 3 H, CCH3), 1.38 (s, 3 H, CCH3), 1.45–
1.70 (m, 5 H, H-4, CH2), 1.85–1.95 (m, 2 H, CH2CH2CH), 2.34 (s,
3 H, ArCH3), 2.37–2.43 (m, 2 H, CHCH2CH), 3.26–3.33 (m, 1 H,
H-3), 3.48–3.54 (m, 1 H, OCH), 3.67–3.77 (m, 1 H, H-6), 3.88 (dd,
J = 10.8, 8.3 Hz, 1 H, CHHOTBDPS), 3.98–4.13 (m, 3 H, OCH2,
CHHOTBDPS), 4.35 (d, J = 12.0 Hz, 1 H, CHHPh), 4.47 (d, J =
12.0 Hz, 1 H, CHHPh), 4.72 (dt, J = 8.3, 5.7, 1 H, H-2), 5.28 (dt, J
= 10.6, 6.8 Hz, 1 H, CH), 5.4 (dt, J = 10.6, 7.2 Hz, 1 H, CH), 7.10–
7.20 (m, 4 H, ArH), 7.23–7.33 (m, 3 H, ArH), 7.33–7.49 (m, 6 H,
Synthesis 2002, No. 1, 111–115 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convenient Route to Alkaloid Lipids
115
ArH), 7.65 (d, J = 8.3 Hz, 2 H, ArH), 7.73 (d, J = 6.5 Hz, 2 H, ArH),
7.78 (d, J = 6.5 Hz, 2 H, ArH).
1 H, OH), 2.85 (s br, 1 H, OH), 3.34–3.49 (m, 2 H, H-5 , CHOH),
3.58–3.72 (m, 3 H, CHHOH, CH2OH), 3.82–3.96 (m, 1 H, H-2 ),
4.04–4.13 (m, 2 H, H-6 , CHHOH), 7.24 (d, J = 8.3 Hz, 2 H, ArH),
7.67 (d, J = 8.1 Hz, 2 H, ArH).
Anal. Calcd for C51H69NO6SSi (852.25): C, 71.87; H, 8.16; N, 1.64.
Found: C, 72.04; H, 8.31; N, 1.51.
Anal. Calcd for C25H43NO6S (485.68): C, 61.82; H, 8.92; N, 2.88.
Found: C, 62.11; H, 8.82; N, 2.71.
(2S, 3S, 6S, 4 R)-{3-Benzyloxy-6-[10 -(2 ,2 -dimethyl-[1 ,3 ]di-
oxolan-4 -yl)-dec-2 -enyl]-1-tosylpiperidin-2-yl}-methanol (20)
To a soln of olefin 19 (145 mg, 0.17 mmol) in THF (2 mL), TBAF
(1.0 M soln in THF, 0.25 mL) was added. The mixture was stirred
at 40 °C for 12 h, then the solvent was evaporated under reduced
pressure to yield a yellowish slurry which was purified by chroma-
tography (EtOAc hexane, 3:2; Rf = 0.67) to give alcohol 20 as a
colorless oil. Yield: 97 mg (93%)
(2R, 2 R, 5 S, 6 S)-12-(5 -Hydroxy-6 -hydroxymethyl-piperidin-
2 -yl)-dodecane-1,2-diol (8)
To a soln of naphthalene (50 mg, 0.39 mmol) in freshly distilled
DME (2 mL), sodium (9 mg, 0.38 mmol) was added. The mixture
was stirred at ambient temperature for 45 min (dark-green color),
cooled to –78 °C and a soln of 22 (30 mg, 0.062 mmol) in DME (1
mL) was added. The reaction mixture was stirred at –78 °C for 30
[ ]D22 = +2.7 (c 0.7, EtOAc).
IR: 3445 cm 1 (OH), 1351, 980 (COC).
min, quenched with brine (2 mL) and extracted with EtOAc (3
5
mL). The combined organic layers were washed with brine, dried
(MgSO4) and concentrated under reduced pressure to give a color-
less oil which was purified by chromatography (EtOAc MeOH,
10:1; Rf = 0.63) to furnish the desired product 8. Yield: 16 mg
(64%).
[ ]D22 = +4.7 (c 1.2, EtOAc).
IR: 3407 cm 1 (OH).
1H NMR (250 MHz, CDCl3): = 1.15–1.69 (m, 22 H, CH2), 2.07 (s
br, 1 H, OH), 2.25 (s br, 1 H, OH), 2.63 (s br, 1 H, OH), 2.85 (s br,
1 H, OH), 3.15 (m, 2 H, H-2 , H-5 ), 3.32–3.37 (m, 2 H, H-6 ,
CHOH), 3.55 3.72 (m, 4 H, CH2OH, CH2OH).
1H NMR (400 MHz, CDCl3): = 1.20–1.35 (m, 11 H, H-5, CH2),
1.33 (s, 3 H, CCH3), 1.38 (s, 3 H, CCH3), 1.45–1.70 (m, 5 H, H-4,
CH2), 1.98–2.11 (m, 2 H CH2CH2CH), 2.33–2.42 (m, 2 H
CHCH2CH), 2.43 (s, 3 H, ArCH3), 2.62 (t, J = 7.0 Hz, 1 H, OH),
3.17–3.25 (m, 1 H, H-3), 3.47–3.55 (m, 1 H, OCH), 3.64–3.74 (m,
1 H, CHHOH), 3.98–4.14 (m, 4 H, H-6, OCH2, CHHOH), 4.31 (dd,
J = 13.1, 6.8 Hz, 1 H, H-2), 4.43 (d, J = 11.9 Hz, 1 H, CHHPh), 4.48
(d, J = 11.9 Hz, 1 H, CHHPh), 5.38 (dt, J = 10.6, 6.8 Hz, 1 H, CH),
5.51 (dt, J = 10.6, 7.2 Hz, 1 H, CH), 7.23 (d, J = 8.3 Hz, 2 H, ArH),
7.25–7.30 (m, 2 H, ArH), 7.34–7.41 (m, 3 H, ArH), 7.63 (d, J = 8.3
Hz, 2 H, ArH).
Anal. Calcd for C35H51NO6S (613.9): C, 68.48; H, 8.37; N, 2.28.
Found: C, 68.38; H, 8.21; N, 2.25.
Anal. Calcd for C18H37NO4 (331.49): C, 65.22; H, 11.25; N, 4.23.
Found: C, 65.44; H, 11.38; N, 4.19.
(2S, 3S, 6R, 4 R)-{6-[10 -(2 ,2 -Dimethyl-[1 ,3 ]dioxolan-4 -
yl)-decyl]-2-hydroxymethyl}-1-tosylpiperidin-3-ol (21)
Olefin 20 (62 mg, 0.1 mmol) was dissolved in MeOH (2 mL) and
hydrogenated over 10% Pd/C (13 mg) under 1 bar pressure for 2 h.
The mixture was filtered through celite and concentrated in vacuo
to give a yellowish oil which was purified by chromatography
(EtOAc hexane, 3:2; Rf = 0.16) to furnish 21 as a colorless oil.
Yield: 46 mg (85%).
References
(1) Schneider, M. J. In Alkaloids: Chemical and Biological
Perspectives, Vol. 10; Pelletier, S. W., Ed.; Pergamon Press:
Oxford, 1996, 155-299.
(2) (a) Astudillo, S. L.; Jürgens, S. K.; Schmeda-Hirschman, G.;
Griffith, G. A.; Holt, D. H.; Jenkins, P. R. Planta Med. I
1999, 65, 161. (b) Jones, T. H.; Blum, M. S.; Robertson, H.
G. J. Nat. Prod. 1990, 53, 429. (c) Roth, H. J.; Kleemann,
A. In Pharmaceutical Chemistry; John Wiley & Sons: New
York, 1988. (d) Strunz, G. M.; Findlay, J. A. In Alkaloids,
Vol 26; Brossi, A., Ed.; Academic Press: New York, 1985,
89-183.
(3) For a comprehensive recent review on stereoselective
synthesis of Prosopis and Cassia piperidine alkaloids see:
Laschat, S.; Dickner, T. Synthesis 2000, 1781.
(4) Some representative recent articles: (a) Datta, A.; Kumar, J.
S. R.; Roy, S. Tetrahedron 2001, 57, 1169. (b) Enders, D.;
Kirchhoff, J. H. Synthesis 2000, 2099. (c) Herdeis, C.;
Telser, J. Eur. J. Org. Chem. 1999, 1407. (d) Herdeis, C.;
Schiffer, T. Tetrahedron 1999, 55, 1043. (e) Ojima, I.;
Vidal, E. S. J. Org. Chem. 1998, 63, 7999.
[ ]D22 = +3.8 (c 0.65, EtOAc).
IR: 3450 cm 1 (OH), 1354, 982 (COC).
1H NMR (400 MHz, CDCl3): = 1.17–1.76 (m, 22 H, H-5, H-4,
CH2), 1.35 (s, 3 H, CCH3), 1.41 (s, 3 H, CCH3), 2.42 (s, 3 H,
ArCH3), 2.51 (s br, 1 H, OH), 2.61 (s br, 1 H, OH), 3.46–3.57 (m, 2
H, H-3, OCH), 3.72 (dd, 1 H, J = 10.6, 4.4 Hz, CHHOH), 3.89–3.99
(m, 1 H, H-6), 4.01–4.16 (m, 3 H, OCH2, CHHOH), 4.16–4.25 (m,
1 H, H-2), 7.29 (d, J = 8.3 Hz, 2 H, ArH), 7.72 (d, J = 8.3 Hz, 2 H,
ArH).
Anal. Calcd for C28H47NO6S (525.7): C, 63.97; H, 9.01; N, 2.66.
Found: C, 64.15; H, 8.88; N, 2.71.
(2R, 2 R, 5 S, 6 S)-12-(5 -Hydroxy-6 -hydroxymethyl-1 -tosyl-
piperidin-2 -yl)-dodecane-1,2-diol (22)
(5) Bolzani, V. S.; Gunatilaka, A. A. L.; Kingston, D. G. I.
Tetrahedron 1995, 51, 5929.
(6) (a) Koulocheri, S. D.; Haroutounian, S. A. Tetrahedron Lett.
1999, 40, 6869. (b) Koulocheri, S. D.; Magiatis, P.;
Skaltsounis, A.-L.; Haroutounian, S. A. Tetrahedron 2000,
56, 6135.
To a stirred soln of 21 (40 mg, 0.076 mmol) in MeOH (2 mL), p-
TsOH (0.2 mg, 0.008 mmol) was added. After 1 h, the reaction was
quenched with sat. aq NaHCO3 and extracted with EtOAc (2 10
mL). The combined organic layers were washed with brine, dried
(MgSO4) and concentrated under reduced pressure to give a color-
less oil which was purified by chromatography (EtOAc; Rf = 0.3) to
furnish 22 as a colorless oil. Yield: 36 mg (97%).
(7) Koulocheri, S. D.; Haroutounian, S. A. Synthesis 1999,
1889.
(8) For a recent review on this subject see: Speckamp, W. N.;
Moolenaar, M. J. Tetrahedron 2000, 56, 3817.
(9) (a) Cook, G. R.; Beholz, L. G.; Stille, J. R. J. Org. Chem.
1994, 59, 3575. (b) Cook, G. R.; Beholz, L. G.; Stille, J. R.
Tetrahedron Lett. 1994, 35, 1669.
[ ]D22 = +3.3 (c 0.3, EtOAc).
IR: 3448 cm 1 (OH).
1H NMR (400 MHz, CDCl3): = 1.15–1.69 (m, 22 H, CH2), 2.05 (s
br, 1 H, OH), 2.22 (s br, 1 H, OH), 2.38 (s, 3 H, ArCH3), 2.63 (s br,
Synthesis 2002, No. 1, 111–115 ISSN 0039-7881 © Thieme Stuttgart · New York