Improved synthesis of fluorinated analogues of anticancer active ether lipids

Article abstract of DOI:10.1055/s-2002-23540

Racemic 2-fluoro-2-(hexadecyloxymethyl)-3-methoxy-propan-l-ol (15a) and its octadecyl homologue 15b were synthesized from ethyl 2-(hexadecyloxymethyl)acrylate (8a) and its homologue 8b, respectively, in five steps (20% or 19% overall yields) using a bromofluorination as the key step. The new compound 15b was transformed into 2′-(trimethylammonium)ethyl-2-methoxymethyl-3-(octadecyloxy)-l- ylphosphate (7b), a fluorinated analogue of anticancer active ether lipids. Enzyme-catalyzed deracemization of the fluorohydrins 15a and 15b using several lipases gave the corresponding enantiomers with low enantiomeric excess in all cases.

Full text of DOI:10.1055/s-2002-23540

648
PAPER
Improved Synthesis of Fluorinated Analogues of Anticancer Active Ether
Lipids
S
ynthesis of Fluor
ü
inate
d
A
nalo
n
gue
s
of Antic
t
a
nce
r
Active
E
the
r
r
L
ipids Haufe,* Annegret Burchardt
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany
E-mail: haufe@uni-muenster.de
Received 10 January 2002; revised 21 February 2002
Dedicated to Professor Dr. Hans J. Schäfer on the occasion of his 65th birthday
Recently, we reported the syntheses of fluorinated ana-
Abstract: Racemic 2-fluoro-2-(hexadecyloxymethyl)-3-methoxy-
logues 6 and 7a of such ether lipids. Both compounds
showed significant antitumor activity in an in vivo model
of the methylcholanthrene induced fibrosarcoma of mice.
propan-1-ol (15a) and its octadecyl homologue 15b were synthe-
sized from ethyl 2-(hexadecyloxymethyl)acrylate (8a) and its ho-
mologue 8b, respectively, in five steps (20% or 19% overall yields)
using a bromofluorination as the key step. The new compound 15b This activity, however, was lower than that of Cisplatin or
Ilmofosine (4) under identical conditions.4
was transformed into 2 -(trimethylammonium)ethyl-2-methoxyme-
thyl-3-(octadecyloxy)-1-ylphosphate (7b), a fluorinated analogue
of anticancer active ether lipids. Enzyme-catalyzed deracemization
This paper describes an improved access to the Ilmofosine
analogue 7a and the synthesis of the octadecyl homologue
7b (Scheme 1). Applying principally known proce-
dures,3a,5 the unsaturated long chain hydroxy ethers 9a
and 9b were synthesized from the corresponding ethyl
acrylates 8a and 8b by reduction with DIBAL. The free
hydroxy function of 9a and 9b was methylated with me-
thyl iodide and KOH in DMSO6 to give 10a and 10b. Sub-
sequently, the bromofluorination7 of 10a with NBS/
Et3N 3HF in dichloromethane at 25 °C after 16 hours, be-
sides 6% (GC) of starting material, gave 1-bromo-2-
fluoro-3-hexadecyloxy-2-(methoxymethyl)propane (11a)
(80%, GC), its regioisomer 12a (5%, GC) and 9% (GC) of
the dibromide 13a. From this mixture, the desired com-
pound 11a was isolated in 55% yield by column chroma-
tography. The dibromide 13a was also isolated in 5%
yield. The regioselectivity of bromofluorination increased
from 94:6 in the case of NBS/Et3N 3HF to 97:3 using the
slightly more acidic Me3N 3HF as the fluoride source un-
der identical conditions. The higher selectivity of the lat-
ter reagent has already been observed earlier.4a,8 Lowering
the temperature to –10 °C did not change the regioselec-
tivity, but increased the part of the dibromide 13a to 21%
(GC). The formation of dibromides under the conditions
of bromofluorination is due to a side reaction of NBS with
fluorinating reagents to form elemental bromine.9,10 This
process increases with decreasing reactivity of the double
bond and increasing nucleophilicity of the fluorinating
agent.11
of the fluorohydrins 15a and 15b using several lipases gave the cor-
responding enantiomers with low enantiomeric excess in all cases.
Key words: halofluorination, acylations, lipids, enzymes, kinetic
resolution
Ether lipids continue to attract considerable interest be-
cause of their important biological properties. Particularly
the platelet activating factor [mixture of (R)-1-O-hexade-
cyl-2-acetyl-sn-glycero-3-phosphocholine and its octade-
cyl homologue] 1 and analogues such as Edelfosine (1-O-
octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, 2)
were shown to exhibit significant cytotoxic effects against
numerous human and murine tumor cell strains both in
vitro and in vivo.1 Fluorinated analogues such as 3 also
showed antitumor activity.2 Variation of substituents at
the stereogenic center led to highly potent compounds
such as Ilmofosine (4), its oxygen analogue 5, and the oc-
tadecyl homologues of both compounds (Figure).3 The ac-
tivity of the enantiomers of compounds 4 and 5 was
different.1,3
Analogously, bromofluorination of 10b with NBS/
Me3N 3HF in dichloromethane at –10 °C after 96 hours
gave a 97:3 mixture of 11b and 12b besides the dibromide
13b (8% yield). From this mixture 11b was isolated in
55% yield by column chromatography.
The nucleophilic displacement of bromine by acetate oc-
curred by refluxing compounds 11 with KOAc in DMF in
accordance with the protocol used for similar compounds
earlier.4 The desired fluorohydrins 15 were obtained by
simple saponification of the acetates 14. The key interme-
diates 15a and 15b for the synthesis of fluorinated ether
Figure The structures of ether lipids 1–7.
Synthesis 2002, No. 5, 08 04 2002. Article Identifier:
1437-210X,E;2002,0,05,0648,0654,ftx,en;T00702SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Synthesis of Fluorinated Analogues of Anticancer Active Ether Lipids
649
Scheme 1
lipids 7a and 7b were thus obtained in four steps each in cessful with Me3N 3HF in the presence of 20 mol% of
25% overall yield from 9a and 9b, respectively. The over- BF3 OEt2 analogous to a protocol used for acid-sensitive
all yield in the former six-step synthesis4a of 15a starting epoxides earlier.16 In this way the ring opening was almost
from 9a was 8%.
complete at 37 °C after 22 hours, but again oligomeric
products, hexadecanol (32%, GC), and other side products
were formed besides the desired fluorohydrin 15a (53%,
GC). Thus, there is no advantage in the yield of 15a of this
three-step procedure compared to the four-step sequence
described above.
For further shortening of the synthesis of 15a, the unsat-
urated bis-ether 10a was epoxidized with m-CPBA in
CH2Cl2 to yield 72% of the epoxide 16. Ring opening of
epoxides using different hydrofluorinating agents has
been reviewed.12a We applied Olah’s reagent (Py 9HF)
analogous to a procedure used earlier for a similar ep- Finally, the fluorohydrin 15b, analogously to 15a,4a was
oxide.12b A mixture of 15a (69%, GC) and hexadecanol transformed to the ether lipid 7b by treatment with a 3-
(31%, GC) was obtained besides oligomeric products.13,14 fold excess of 2-chloro-2-oxo-1,3-dioxa-2-phospholane
Signals for compounds with a primary fluorine substituent and triethylamine in THF and subsequent heating of the
at about 230 ppm in the 19F NMR spectrum of the crude intermediary phosphoric acid triester with trimethylamine
product mixture were not found, while several signals of in acetonitrile at 60 °C in a sealed tube for 72 hours. Com-
probably oligomeric side products with tertiary fluorine pound 7b was isolated in 52% yield over two steps. Thus,
substituents appeared between 170 and 175 ppm. The the overall yield over six steps from 8b was 13%.
oligomers were separated by column chromatography and
were not further analyzed. Separation of 15a from hexa-
decanol was incomplete. Thus, the crude product mixture
To obtain the enantiomers of 15a separately, enzymatic
deracemization of the acetate 14a using lipase from
Pseudomonas cepacia (PCL, Amano PS) in a 15:2 mix-
of another trial was acetylated with acetic anhydride in
ture of phosphate buffer (pH 7.0) and THF was carried
pyridine and the whole mixture was separated by column
out. After 4 hours a 58% conversion was observed and
chromatography to yield 30% of the acetate 14a
39% of the nontransformed acetate 14a (24% ee) and 43%
(Scheme 2).
of the fluorohydrin 15a (16% ee) were isolated.17 The
In order to minimize the oligomerization incorporating enantiomeric excess was determined by 19F NMR spectro-
the formed fluorohydrin 15a and also to avoid the forma- scopically after derivatization of the fluorohydrins (the
tion of hexadecanol by ether cleavage under the strongly acetate 14a was saponificated with KOH/MeOH at room
acidic conditions, the epoxide ring opening of 16 was tried temperature) with (R)-(+)-Mosher’s acid18 by DCC/
with the less acidic (compared to Olah’s reagent), but DMAP.19 Integration of the baseline-separated signals of
more nucleophilic15 Me3N 3HF at 100 °C without solvent the tertiary fluorine atoms of the diastereomeric Mosher
for 3 hours. Under these conditions, however, 16 was re- esters at = –172.16 and –172.20 ppm showed the ee of
covered almost completely. The ring opening was suc- the fluorohydrins.
Scheme 2
Synthesis 2002, No. 5, 648–654 ISSN 0039-7881 © Thieme Stuttgart · New York

650
G. Haufe, A. Burchardt
PAPER
carried out by the Mikroanalytisches Laboratorium, Organische
Chemie, University of Münster using a CHN-O analyzer. Starting
materials and NMR-shift reagents were purchased from Acros, Al-
drich, Fluka, or Merck, respectively, and were used without further
purification. PCL (Amano PS) was a gift of Amano Pharmaceutical
Co., Nagoya, Japan, CAL was donated by Novo Nordisk A/S,
Copenhagen, Denmark, CRL was purchased from Sigma, and PPL
was purchased from Serva.
Due to the low enantioselectivity of the lipase-catalyzed
hydrolysis of the acetate 14a and due to the frequently ob-
served higher enantioselectivity of lipase-catalyzed ester-
ifications of alcohols compared to the corresponding
hydrolyses of acetates, the acetylations with vinyl acetate
and lipases of Pseudomonas cepacia (PCL), Candida rug-
osa (CRL), Candida antarctica (CAL), and porcine pan-
creas lipase (PPL), of 15a and 15b were investigated.
These lipases have been used successfully for deracemi-
zation of other fluorohydrins.20 The results are given in
the Table.
2-(Hexadecyloxymethyl)prop-2-en-1-ol (9a) was prepared in 81%
yield according to the literature procedure.3
Ethyl 2-(Octadecyloxymethyl)acrylate (8b)
Analogous to the procedure given in Ref.,3a in a dried Schlenk ves-
sel under argon, octadecanol (6.80 g, 25.6 mmol) was dissolved in
anhyd THF (75 mL) and cooled down to 0 °C. At this temperature
The racemate cleavage of compounds 14 or 15, respec-
tively, did not allow the synthesis of highly enantiomeri-
cally enriched precursors of fluorinated ether lipids. BuLi (16.6 mL, 25.6 mmol of an 1.6 M solution in hexane) was add-
Engineered lipases might give better results.23
ed and the mixture was stirred for 15 min. After cooling down to
–78 °C, CuI (0.48 g, 38.0 mmol) was added and stirring was contin-
ued for 30 min. Then, ethyl 2-(bromomethyl)acrylate5 (7.20 g, 37.5
1H (300.1 MHz), 13C (75.5 MHz), and 19F NMR (282.4 MHz):
mmol) was added, the mixture was stirred at this temperature for
Bruker WM 300. Carbon multiplicities have been assigned by
DEPT experiments. Unless otherwise stated, the spectra were ob-
tained in CDCl3 solutions. TMS was used as internal standard for
1H, CDCl3 for 13C, and CFCl3 for 19F NMR spectroscopy. Mass
spectra (70 eV): GC/MS coupling: Varian GC 3400/MAT 8230 and
data system SS 300 of Finnigan MAT and Varian GC 3400/Varian
Saturn IT (Ion Trap) and data system NIST. The composition of
crude reaction products and the conversion of substrates during en-
zymatic transformations was followed by GC (Hewlett-Packard
additional 6 h and then allowed to slowly warm up to r.t. The reac-
tion mixture was poured into an 0.1 N NH3 solution (100 mL) of
10 °C. The organic layer was separated and the aqueous phase was
extracted with Et2O (3 50 mL). The combined organic layer was
washed with H2O (2 50 mL) and dried (MgSO4). After evapora-
tion of the solvent, the crude product was purified by column chro-
matography (pentane–Et2O, 20:1) to give 8b as a white solid; yield:
6.90 g (48%); mp 42 °C (pentane–Et2O, 20:1).
1H NMR: = 0.88 (t, 3 H, 3JH,H = 6.7 Hz, 18 -H), 1.23–1.39 (m, 33
5890 II) using quartz capillary columns, 25 m 0.33 mm, 0.52
m
3
H, JH,H = 6.6 Hz, 3 -H to 17 -H, 6-H), 1.55–1.64 (m, 2-H, 2 -H),
HP-1 and 30 m 0.32 mm, 0.25 m SPB-1 (Supelco), temperature
program, 40 °C 280 °C with a 10 °C/min heating rate, N2 as the
carrier gas. The ratio of compounds was determined by integration
of the peak areas. The products, including those of enzymatic trans-
formations, were separated by column chromatography (silica gel,
Merck 60, 70–230 mesh). Optical rotations were measured in
CDCl3 solution at the NaD line ( = 589 nm). Microanalyses were
3
3.48 (t, 2 H, JH,H = 6.6 Hz, 1 -H), 4.15–4.19 (m, 4 H, 5-H, 4-H),
5.84–5.86 (m, 1 H, 3-Ha), 6.27–6.28 (m, 1 H, 3-Hb).
13C NMR: = 14.1 (q, 18 -C), 14.2 (q, 6-C), 22.6 (t, 17 -C), 26.1 (t,
3 -C), 29.2, 29.3, 29.4, 29.6, 29.7 (11 t, 4 -C to16 -C), 31.9 (t, 2 -C),
60.6 (t, 5-C), 68.8 (t, 4-C), 71.1 (t, 1 -C), 125.1 (t, 3-C), 137.7 (s, 2-
C), 166.0 (s, 1-C).
Table Acetylation of Fluorohydrins 15a and 15b with Vinyl Acetate Catalyzed by Different Lipases
Entry
Substrate
(mg)
Vinyl
Acetate
(mg)
Enzyme
(mg)
Toluene
(mL)
Time
(h)
Conversion Product
(%)
Yield
(mg) (%)
eea
(%)
Eb
1
2
3
4
5
6
15a
150
36
immobil.c
PCL, 70
3
-
500
4
28d
54
13
58
60
57
15a
14a
85 (57)
35 (21)
11
26
2.0
1.9
15a
150
3
immobil.c
PCL, 20
15a
14a
50 (27)
65 (40)
23
32
1.8
2.7
15a
150
36
30
21
36
PPL
150
5
3
2
3
336
23.5
2.5
15a
14a
50 (40)
20 (12)
4
16
1.8
1.4
15a
125
CRL
29
15a
14a
50 (40)
80 (57)
11
10
1.1
1.3
15a
90
CAL
24
15a
14a
35 (38)
55 (55)
27
28
1.8
2.6
15b
162
CAL
3.25
15b
14b
65 (40)
80 (45)
24
16
1.8
1.5
a Determined by 19F NMR spectra of Mosher esters.
b The E value is a measure of the selectivity of an enzyme.21
c According to Ref.22
d No more reaction after 500 h.
Synthesis 2002, No. 5, 648–654 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Fluorinated Analogues of Anticancer Active Ether Lipids
651
MS (GC/MS): m/z (%) = 382 (M+, 5), 337 (M+ – C2H5O, 4), 269
(C18H37O+, 2), 129 (M+ – C18H37, 85), 114 (M+ – C18H36O, 100), 101
(M+ – C18H35 CH2, 19).
(t, 2 H, 3JH,H = 6.6 Hz, 1 -H), 3.92, 3.95 (2 s, 4 H, 3-H, 4-H), 5.15–
5.18 (m, 2 H, 1-H).
13C NMR: = 14.1 (q, 18 -C), 22.7 (t, 17 -C), 26.2 (t, 3 -C), 29.4,
29.5, 29.7 (each t, 13 C, 4 -C to 16 -C), 31.9 (t, 2 -C), 58.0 (t, 5-C),
70.6 (t, 3-C), 71.4 (t, 1 -C), 73.4 (t, 4-C), 113.5 (t, 1-C), 143.0 (s, 2-
C).
Anal. Calcd for C24H46O3 (382.6): C, 75.34; H, 12.12. Found: C,
75.10; H, 12.05.
2-(Octadecyloxymethyl)prop-2-en-1-ol (9b)
MS (GC/MS): m/z (%) = 354 (M+, 2), 322 (M+ – CH3OH, 6), 281
Following the procedure given in Ref.,3 8b (6.90 g, 18 mmol) was
dissolved in anhyd THF (100 mL) in a dried Schlenk vessel under
argon. After cooling to –78 °C, the stirred solution was treated drop-
wise with DIBAL (36 mL, 36 mmol of a 1 M solution in THF). The
stirring was continued at this temperature for further 6 h. The mix-
ture was allowed to warm slowly to r.t. while stirring was continued
for further 12 h. Then, first dropwise, ice-water (300 mL) was added
and the Al(OH)3 formed was dissolved in concd HCl. The clear,
slightly acidic mixture was extracted with Et2O (3 200 mL). The
combined ethereal layer was washed with H2O (2 200 mL) and
dried (MgSO4). The solvent was evaporated and the residue was
purified by column chromatography (pentane–Et2O, 1:1) to give 9b
as a white solid; yield: 4.50 g (74%); mp 42 °C (pentane–Et2O, 1:1).
(C18H35OCH2 , 2), 253 (C18H37+, 5), 71 (C5H11+; C4H7O+, 80), 57
+
+
(C4H9 ; C3H5O+, 100).
Anal. Calcd for C23H46O2 (354.6): C, 77.90; H, 13.07. Found: C,
78.22; H, 13.15.
Bromofluorination of 3-Hexadecyloxy-2-(methoxymethyl)
prop-1-ene (10a)
A solution of 10a (702 mg, 2.46 mmol) and Me3N 3HF (439 mg,
3.69 mmol) in CH2Cl2 (10 mL) was treated with NBS portionwise
(483 mg, 2.71 mmol) at –10 °C and stirred at this temperature for
120 h. Subsequently, the mixture was poured into ice-water (50 mL)
and neutralized with 26% aq NH3. The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (3 20 mL). The
combined organic layer was washed with 0.1 N HCl (10 mL) fol-
lowed by 5% aq NaHCO3 solution (10 mL) and dried (MgSO4). The
solvent was evaporated and the residue, after GC and 19F NMR
analysis, was purified by column chromatography (pentane–Et2O,
40:1).
1H NMR: = 0.88 (t, 3 H, 3JH,H = 6.4 Hz, 18 -H), 1.95–1.40 (m, 30
H, 3 -H to 17 -H), 1.51–1.60 (m, 2-H, 2 -H), 2.03 (s, 1 H, 1-OH),
3.42 (t, 2 H, 3JH,H = 6.7 Hz, 1 -H), 4.04 (s, 2 H, 4-H), 4.17 (s, 2 H,
1-H), 5.10 (s, 1 H, 3-Ha), 5.16 (s, 1 H, 3-Hb).
13C NMR: = 14.1 (q, 18 -C), 22.7 (t, 17 -C), 26.2 (t, 3 -C), 29.4,
29.5, 29.7, (13 t, 4 -C to 16 -C), 31.9 (t, 2 -C), 64.8 (t, 1-C), 70.8 (t,
4-C), 72.7 (t, 1 -C), 113.1 (t, 3-C), 145.3 (s, 2-C).
1-Bromo-2-fluoro-3-hexadecyloxy-2-(methoxymethyl)propane
(11a)
MS (GC/MS): m/z (%) = 340 (M+, 2), 322 (M+ – H2O, 3), 309 (M+
Colorless, viscous oil; yield: 586 mg (56%).
+
– CH2OH, 10), 281 (C18H35OCH2 , 10), 71 (C5H11+, C4H7O+, 70), 57
+
(C4H9 , C3H5O+, 100).
1H NMR: = 0.88 (t, 3 H, 3JH,H = 6.6 Hz, 16 -H), 1.22–1.40 (m, 26
H, 3 -H to 15’-H), 1.53–1.59 (m, 2 H, 2 -H), 3.40 (s, 3 H, 5-H), 3.49
(t, 2 H, 3JH,H = 6.6 Hz, 1 -H), 3.63, 3.65, 3.67 (3 d, 6 H, 3JH,F = 17.4
Hz, 3JH,F = 18.1 Hz, 1-H, 3-H, 4-H).
Anal. Calcd for C22H44O2 (340.6): C, 77.58; H, 13.02. Found: C,
77.44; H, 12.94.
3-Hexadecyloxy-2-(methoxymethyl)prop-1-ene (10a); Typical
Procedure3b
13C NMR: = 14.1 (q, 16 -C), 22.7 (t, 15 -C), 26.0 (t, 3 -C), 29.4,
29.5, 29.7 (11 t, 4 -C to 14 -C), 31.9 (t, 2 -C), 32.1 (dt, 2JC,F = 25.4
2
Powdered KOH (224 mg, 4 mmol) was dissolved in DMSO (2 mL)
and stirred for 10 min. To this solution 9a (312 mg, 1 mmol) and
subsequently MeI (284 mg, 2 mmol) was added while stirring. After
stirring for 90 min, sat. NaCl solution (15 mL) was added and the
solution was extracted with Et2O (3 10 mL). The combined ether-
eal layer was washed with H2O (2 10 mL) and dried (MgSO4). The
solvent was evaporated and the residue was purified by column
chromatography (pentane–Et2O, 10:1). Compound 10a was isolated
as a colorless, oily liquid; yield: 230 mg (71%).
1H NMR: = 0.88 (t, 3 H, 3JH,H = 6.7 Hz, 16 -H), 1.20–1.39 (m, 26
H, 3 -H to 15 -H), 1.53–1.62 (m, 2-H, 2 -H), 3.30 (s, 3 H, 5-H), 3.41
(t, 2 H, 3JH,H = 6.6 Hz, 1 -H), 3.92, 3.96 (2 s, 4 H, 3-H, 4-H), 5.15–
5.18 (m, 2 H, 1-H).
Hz, 1-C), 59.7 (q, 5-C), 70.4 (dt, JC,F = 25.4 Hz, 3-C), 72.2 (t, 1 -
C), 72.5 (dt, 2JC,F = 25.4 Hz, 4-C), 95.2 (ds, 1JC,F = 178.0 Hz, 2-C).
19F NMR: = –166.6 (ttt, 3JH,F = 17.2 Hz).
MS (GC/MS): m/z (%) = 424/426 (M+, 0.4/0.4), 345 (M+ – Br, 5),
+
325 (345 – HF, 60), 255 (C16H33OCH2 , 38), 225 (C16H33+, 31), 201/
203 (M+ – C16H31, 14), 85 (C6H13+, 100).
+
MS (GC/MS, CI): m/z = 442/444 (M + NH4 ).
Anal. Calcd for C21H42BrFO2 (425.46): C, 59.28; H, 9.95. Found: C,
59.43; H, 10.11.
2-Bromo-1-fluoro-3-hexadecyloxy-2-(methoxymethyl)propane
(12a)
19F NMR: = –220.2 (t, 2JFH = 47.6 Hz) (crude product mixture).
13C NMR: = 14.1 (q, 16 -C), 22.7 (t, 15 -C), 26.2 (t, 3 -C), 29.4,
29.5, 29.6, 29.7, 29.8 (11 t, 4 -C to 14 -C), 31.9 (t, 2 -C), 58.0 (t, 5-
C), 70.6 (t, 3-C), 71.4 (t, 1 -C), 73.4 (t, 4-C), 113.5 (t, 1-C), 143.0
(s, 2-C).
1,2-Dibromo-3-hexadecyloxy-2-(methoxymethyl)propane (13a)
Colorless, viscous oil; yield: 60 mg (5%).
1H NMR: = 0.88 (t, 3 H, 3JH,H = 6.7 Hz, 16 -H), 1.22–1.39 (m, 26
H, 3 -H to 15 -H), 1.54–1.63 (m, 2 H, 2 -H), 3.44 (s, 3 H, 5-H), 3.51
(t, 2 H, 3JH,H = 6.6 Hz, 1 -H), 3.72, 3.76 (2 s, 4 H, 3-H, 4-H), 3.88 (s,
2 H, 1-H).
MS (GC/MS): m/z (%) = 326 (M+, 2), 294 (M+ – CH3OH, 23), 253
+
+
(C16H31OCH2 , 5), 241 (C16H33O+, 2), 225 (C16H33+, 8), 71 (C5H11
,
C4H7O+, 100).
13C NMR: = 14.1 (q, 16 -C), 22.7 (t, 15 -C), 26.0 (t, 3 -C), 29.4,
29.5, 29.6, 29.7 (11 t, 4 -C to 14 -C), 31.9 (t, 2 -C), 36.2 (t, 1-C),
59.5 (q, 5-C), 66.8 (s, 2-C), 71.9 (t, 1 -C), 74.3 (t, 3-C), 75.4 (t, 4-C).
2-Methoxymethyl-3-(octadecyloxy)prop-1-ene (10b)
According to the procedure given above, powdered KOH (526 mg,
9.3 mmol) in DMSO (6 mL) was reacted with 9b (800 mg, 2.4
mmol) and MeI (650 mg, 4.7 mmol) to give, after chromatographic
purification, 10b as a colorless, oily liquid; yield: 570 mg (69%).
1H NMR: = 0.88 (t, 3 H, 3JH,H = 6.7 Hz, 18 -H), 1.24–1.35 (m, 30
H, 3 -H to 17 -H), 1.53–1.62 (m, 2-H, 2 -H), 3.30 (s, 3 H, 5-H), 3.41
MS (GC/MS): m/z (%) = 405/407 (M+ – Br, 6/6), 373/375 (405/407
+
– CH3OH, 8/8), 325 (405/407 – HBr, 17), 255 (C16H33OCH2 , 42),
+
225 (C16H33+, 31), 57 (C4H9 , 100).
+
MS (GC/MS, CI): m/z = 502/504/506 (M + NH4 ).
Synthesis 2002, No. 5, 648–654 ISSN 0039-7881 © Thieme Stuttgart · New York

652
G. Haufe, A. Burchardt
PAPER
Bromofluorination of 2-Methoxymethyl-3-(octadecyloxy)prop-
1-ene (10b)
2), 225 (C16H33+, 5), 181 (M+ – C16H31, 33), 100 (324 – C16H32, 98),
43 (C3H7 ; C2H3O+, 100).
+
According to the typical procedure given above for 11a, compound
10b (1.00 g, 2.85 mmol) was reacted with Me3N 3HF (0.66 g, 5.5
mmol) and NBS (0.55 g, 3.1 mmol) in CH2Cl2 (10 mL) at –10 °C
for 96 h to give a 11:79:10 mixture (GC) of 10b, 11b and 1,2-dibro-
mo-3-octadecyloxy-2-(methoxymethyl)propane (13b).
Anal. Calcd for C23H45FO4 (404.6): C, 68.28; H 11.21. Found: C,
68.57; H, 11.26.
1-Acetoxy-2-fluoro-2-methoxymethyl-3-(octadecyloxy)pro-
pane (14b)
Following the typical procedure given for 14a, compound 11b (0.70
g, 1.58 mmol) and KOAc (0.62 g, 6.30 mmol) in anhyd DMF (20
mL) was refluxed for 24 h to give 14b as a colorless, viscous oil;
yield: 510 mg (75%).
1H NMR: = 0.88 (t, 3 H, 3JH,H = 6.7 Hz, 18 -H), 1.21–1.38 (m, 30
H, 3 -H to 17 -H), 1.47–1.63 (m, 2 H, 2 -H), 2.09 (s, 3 H, 7-H), 3.39
(s, 3 H, 5-H), 3.46 (t, 2 H, 3JH,H = 6.6 Hz, 1 -H), 3.52–3.67 (m, 4 H,
3-H, 4-H), 4.30 (d, 3JH,F = 20.3 Hz, 2 H, 1-H).
1-Bromo-2-fluoro-2-methoxymethyl-3-(octadecyloxy)propane
(11b)
Colorless, viscous oil; yield: 0.70 g (55%).
1H NMR: = 0.88 (t, 3 H, 3JH,H = 6.8 Hz, 18 -H), 1.21–1.38 (m, 30
H, 3 -H to 17 -H), 1.52–1.60 (m, 2 H, 2 -H), 3.41 (s, 3 H, 5-H), 3.49
(t, 2 H, 3JH,H = 6.6 Hz, 1 -H), 3.63, 3.64, 3.66 (3 d, 6 H, 3JH,F = 17.4
Hz, 3JH,F = 18.1 Hz, 1-H, 3-H, 4-H).
13C NMR: = 14.1 (q, 18 -C), 22.7 (t, 17 -C), 26.0 (t, 3 -C), 29.3,
29.4, 29.6, 29.7 (13 t, 4 -C to 16 -C), 31.9 (t, 2 -C), 32.1 (dt,
2JC,F = 25.4 Hz, 1-C), 59.7 (q, 5-C), 70.4 (dt, 2JC,F = 25.4 Hz, 3-C),
72.2 (t, 1 -C), 72.5 (dt, 2JC,F = 22.9 Hz, 4-C), 95.2 (ds,1JC,F = 180.6
Hz, 2-C).
13C NMR: = 14.0 (q, 18 -C), 20.7 (q, 7-C), 22.6 (t, 17 -C), 26.0 (t,
3 -C), 29.3, 29.4, 29.5, 29.7 (13 t, 4 -C to 16 -C), 31.9 (t, 2 -C), 59.7
(q, 5-C), 63.6 (dt, 2JC,F = 25.4 Hz, 1-C), 69.6 (dt, 2JC,F = 25.4 Hz, 3-
2
C), 71.7 (dt, JC,F = 25.4 Hz, 4-C), 72.2 (t, 1 -C), 95.5 (ds,
1JC,F = 178.0 Hz, 2-C), 170.3 (s, 6-C).
19F NMR: = –166.5 (ttt, 3JH,F = 17.2 Hz).
19F NMR: = –173.5 (ttt, 3JH,F = 19.1 Hz).
MS (GC/MS): m/z (%) = 452/454 (M+, 1/1), 432/434 (M+ – HF, 0.5/
MS (GC/MS): m/z (%) = 433 (M+ + 1, 0.5), 432 (M+, 3), 390 (M+ –
C2H2O, 1), 352 (M+ – CH3CO2H, – HF, 40), 338 (390 – HF –
CH3OH, 10), 321 (352 – CH3O, 35), 253 (C18H37+, 1), 181 (M+ –
0.5), 373 (M+ – Br, 11), 353 (M+ – Br – HF, 11), 283 (C18H37OCH2 ,
+
74), 267 (C18H35O+, 5), 253 (C18H37+, 18), 201/203 (M+ – C18H35,
14/14), 85 (C6H13+, 100).
C18H35, 33), 163 (M+ – C18H37O, 22), 43 (C3H7 , C2H3O+, 100).
+
+
MS (GC/MS, CI): m/z = 470/472 (M + NH4 ).
Anal. Calcd for C25H49FO4 (432.7): C, 69.40; H, 11.42. Found: C,
69.59; H, 11.55.
Anal. Calcd for C23H46BrFO2 (453.5): C, 60.91; H, 10.22. Found: C,
61.08; H, 10.10.
2-Fluoro-2-(hexadecyloxymethyl)-3-methoxypropan-1-ol(15a);
Typical Procedure
1,2-Dibromo-2-methoxymethyl-3-(octadecyloxy)propane (13b)
Colorless, viscous oil; yield: 0.11 g (8%).
MS (GC/MS): m/z (%) = 433/435 (M+ – Br, 3/3), 401/403 (433/435
To a solution of KOH (0.80 g, 14.0 mmol) in MeOH (15 mL) was
added 14a (0.90 g, 2.23 mmol) and stirred at r.t. for 2 h. The mixture
was poured into H2O (25 mL) and extracted with Et2O (4 10 mL).
The combined organic layers were washed with H2O (2 10 mL)
and dried (MgSO4). After evaporation of the solvent, the residue
was purified by column chromatography (pentane–Et2O, 3:1) to
give 15a as a white solid; yield: 0.76 g (94%); mp 45 °C (pentane–
Et2O, 3:1). The spectroscopic data agree with the literature values.4a
+
– CH3OH, 3/3), 353 (433/435 – HBr, 6), 283 (C18H37OCH2 , 16),
+
253 (C18H37+, 8), 57 (C4H9 ,100).
+
MS (GC/MS, CI): m/z = 530/532/534 (M + NH4 ).
1-Acetoxy-2-fluoro-2-hexadecyloxy-3-(methoxymethyl)pro-
pane (14a); Typical Procedure
A mixture of 11a (170 mg, 0.4 mmol) and KOAc (157 mg, 1.6
mmol) in anhyd DMF (5 mL) was refluxed for 24 h. After cooling
the reaction mixture to r.t., a 1:1 mixture of cyclohexane–EtOAc (5
mL) was added and the precipitated KBr was separated by filtration.
The organic layer was washed with H2O, dried (MgSO4), and the
solvent was evaporated. The residue was purified by column chro-
matography (pentane–Et2O, 5:1) to give 14a as a colorless, viscous
oil; yield: 110 mg (68%).
1H NMR: = 0.88 (t, 3 H, 3JH,H = 6.7 Hz, 16 -H), 1.20–1.39 (m, 26
H, 3 -H to 15 -H), 1.50–1.60 (m, 2 H, 2 -H), 2.09 (s, 3 H, 7-H), 3.39
(s, 3 H, 5-H), 3.46 (t, 2 H, 3JH,H = 6.6 Hz, 1 -H), 3.55–3.63 (m, 4 H,
3-H, 4-H), 4.30 (d, 2 H, 3JH,F = 20.3 Hz, 1-H).
2-Fluoro-2-methoxymethyl-3-(octadecyloxy)propan-1-ol (15b)
Analogous to the above typical procedure, compound 14b (0.50 g,
1.16 mmol) was hydrolyzed with KOH (0.40 g, 7.0 mmol) in MeOH
(10 mL). After chromatographic purification (pentane–Et2O, 3:1),
15b was isolated as a white solid; yield: 0.40 g (89%); mp 48 °C
(pentane–Et2O, 3:1).
1H NMR: = 0.88 (t, 3 H, 3JH,H = 6.6 Hz, 18 -H), 1.21–1.38 (m, 30
H, 3 -H to 17 -H), 1.53–1.58 (m, 2 H, 2 -H), 2.23 (br s, 1 H, 1-OH),
3.40 (s, 3 H, 5-H), 3.48 (t, 2 H, 3JH,H = 76.6 Hz, 1 -H), 3.61 and 3.64
(2 d, 4 H, 3JH,F = 19.1 Hz, 3-H, 3JH,F = 18.4 Hz, 4 H), 3.80 (d, 2 H,
3JH,F = 16.9 Hz, 1-H).
13C NMR: = 14.1 (q, 18 -C), 22.6 (t, 17 -C), 26.0 (t, 3 -C), 29.3,
29.4, 29.5, 29.7 (13 t, 4 -C to 16 -C), 31.9 (t, 2 -C), 59.7 (q, 5-C),
63.5 (dt, 2JC,F = 25.4 Hz, 1-C), 70.6 (dt, 2JC,F = 25.4 Hz, 3-C), 72.2
(t, 1 -C), 72.6 (dt, 2JC,F = 25.4 Hz, 4-C), 96.5 (ds, 1JC,F = 175.5 Hz,
2-C).
13C NMR: = 14.0 (q, 16 -C), 20.7 (q, 7-C), 22.6 (t, 15 -C), 26.0 (t,
3 -C), 29.3, 29.4, 29.5, 29.6 (11t, 4 -C to 14 -C), 31.9 (t, 2 -C), 59.6
(q, 5-C), 63.5 (dt, 2JC,F = 22.9 Hz, 1-C), 69.6 (dt, 2JC,F = 25.4 Hz, 3-
2
C), 71.6 (dt, JC,F = 25.4 Hz, 4-C), 72.1 (t, 1 -C), 95.2 (ds,
1JC,F = 178.0 Hz, 2-C), 170.3 (s, 6-C).
19F NMR: = –172.7 (ttt, 3JH,F = 19.1 Hz).
19F NMR: = –173.5 (ttt, 3JH,F = 19.1 Hz).
MS (GC/MS): m/z (%) = 390 (M+, 6), 370 (M+ – HF, 16), 339 (M+,
MS (GC/MS): m/z (%) = 405 (M+ + 1, 0.5), 404 (M+, 0.7), 385 (405
+
– HF, – CH3O, 88), 325 (370 – CH3OCH2, 32), 281 (C18H35OCH2 ,
– HF, 0.1), 324 (M+ – CH3CO2H, – HF, 30), 310 (M+ – C2H2O, –
+
6), 268 (C18H36O+, 5), 121 (M+ – C18H37O, 23), 57 (C4H9 , 100).
+
HF, – CH3OH, 12), 255 (C16H33OCH2 , 2), 251 (6), 239 (C16H31O+,
Anal. Calcd for C23H47FO3 (390.6): C, 70.72; H, 12.13. Found: C,
70.82; H, 12.18.
Synthesis 2002, No. 5, 648–654 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Fluorinated Analogues of Anticancer Active Ether Lipids
653
2 -(Trimethylammonium)ethyl 2-Fluoro-2-methoxymethyl-3-
(octadecyloxy)-1-ylphosphate (7b)
perature. Then, the reaction mixture was poured into ice-cold 2 N
aq NH3 (30 mL) and the organic layer was separated. The aqueous
phase was extracted with CH2Cl2 (3 5 mL). The aqueous phase
Analogous to the literature procedure,3a a mixture of fluorohydrin
15b (214 mg, 0.55 mmol) and Et3N (0.25 mL, 1.73 mmol) in anhyd
THF (20 mL) was prepared in an argon-flushed, dried Schlenk ves-
sel. A solution of 2-chloro-2-oxo-1,3,2-dioxaphospholane (0.16
mL), 1.7 mmol) in anhyd THF (8 mL) was added to this flask at
0 °C, and the resulting mixture was stirred at this temperature for 30
min. Then, the mixture was allowed to warm to r.t. and stirred for
an additional 22 h. The precipitated Et3N HCl was filtered through
silica gel (2 cm, THF as eluent) under argon, and the solvent was
evaporated in vacuum. Under argon the residue was dissolved in an-
hyd MeCN (20 mL), placed in a pressure vessel, and cooled to
–78 °C. Me3N (about 2.5 mL) was condensed into the vessel, which
was sealed and heated at 60 °C for 68 h. The resulting liquid was
separated and maintained at –20 °C for 24 h. The precipitated
brown waxy material was purified by column chromatography
(CHCl3–MeOH–H2O, 65:25:4) to obtain, besides some starting ma-
terial, the desired ether lipid 7b as a light brownish solid; yield: 160
mg (52%).
was saturated with NaCl and extracted again with CH2Cl2 (2
mL). The combined organic layers were washed with brine (2
5
5
mL) and dried (MgSO4). The solvent was evaporated and the crude
residue (1.23 g) was analyzed by 19F NMR spectroscopy and GC.
Compound 15a was identified ( = 174.7 in 19F NMR spectrum) as
the main fluorinated product, besides several unidentified traces of
other fluorine containing compounds. Compound 15a amounted
69% of the volatile products. Hexadecanol (31%, GC) was also
identified. Because these two compounds could not be separated by
column chromatography, the product mixture was treated with
Ac2O (510 mg, 5.0 mmol) and pyridine (395 mg, 5.0 mmol) and
stirred at r.t. for 20 h. Then, ice-water (10 mL) was added and the
mixture was extracted with CH2Cl2 (4 3 mL). The combined or-
ganic layers were washed with 10% aq HCl (2 2 mL) and H2O (2
mL) and dried (MgSO4). The solvent was evaporated and the resi-
due was purified by column chromatography (pentane–, 10:1) to
give 14a as a colorless, viscous liquid, which solidified in the refrig-
erator (about +4 °C); yield: 450 mg (30%) over two steps.The spec-
troscopic data agree with those obtained above.
1H NMR: = 0.84 (t, 3 H, 3JH,H = 6.6 Hz, 18 -H), 1.23–1.37 (m, 30
H, 3 -H to 17 -H), 1.48–1.56 (m, 2 H, 2 -H), 3.18 (s, 9 H, 8-H to 10-
H), 3.34 (s, 3 H, 5-H), 3.43 (t, 2 H, 3JH,H = 6.5 Hz, 1 -H), 3.55–3.64
(m, 6 H, 3-H, 4-H, 7-H), 3.97–4.05 (m, 2 H, 1-H), 4.18 - 4.27 (m, 2
H, 6-H).
Lipase-Catalyzed Hydrolysis of ( )-1-Acetoxy-2-fluoro-2-hexa-
decyloxy-3-(methoxymethyl)propane (14a)
A solution of the acetate 14a (168 mg, 0.416 mmol) in THF (2 mL)
was added to the phosphate buffer (12 mL, 0.1 M, pH = 7.0) con-
taining Pseudomonas cepacia lipase (Lipase Amano PS, 15 mg),
and stirred at r.t. for 4 h. The reaction was stopped by the addition
of a small amount of NaCl, Celite 577 (2 g) and EtOAc (10 mL).
The solid particles were removed by filtration. The filtrate was dried
(MgSO4) and concentrated under reduced pressure. The crude resi-
due was passed through a short column (3 cm silica gel, eluent:
EtOAc) and analyzed by GC. A 42:58 ratio of 14a and 15a was de-
tected (not corrected). After evaporation of the solvent, the residue
was separated by column chromatography (pentane–Et2O, 5:1
3:1); yields: 65 mg (39%) of 14a (16% ee); 65 mg (43%) of 15a
(24% ee).
13C NMR (CDCl3/CD3OD, 1:1, 90 MHz): = 13.2 (q, 18 -C), 22.0
(t, 17 -C), 25.4 (t, 3 -C), 28.7, 28.8, 28.9, 29.0 (13 t, 4 -C to 16 -C),
31.3 (t, 2 -C), 53.4 (3 q, 8-C to 10-C), 58.4 (dt, 2JC,P = 4.2 Hz, 6-C),
2
58.7 (q, 5-C), 64.6 (ddt, 2JC,F = 25.0 Hz, JC,P = 5.6 Hz, 1-C), 65.9
(br t, 7-C), 69.0 (dt, 2JC,F = 25.0 Hz, 4-C), 70.8 (dt, 2JC,F = 23.6 Hz,
3-C), 71.6 (t, 1 -C), 95.5 (dds, 1JC,F = 177.6 Hz, 3JC,P = 8.3 Hz, 2-C).
19F NMR: = –173.6 (ttt, 3JH,F = 19.1 Hz).
31P NMR (CDCl3/CD3OD, 1:1): = 4.15 (m).
MS (Maldi-TOF): m/z = 555 0.05% (M+).
1,2-Epoxy-3-hexadecyloxy-2-(methoxymethyl)propane (16)
To a solution of m-CPBA (330 mg, 1.5 mmol, 75%) in CH2Cl2 (5
mL) was added compound 10a (200 mg, 0.65 mmol) at 0 °C and
stirred for 4 h, while the mixture was allowed to warm up to r.t. The
precipitated m-chlorobenzoic acid was separated by filtration and
the filtrate was washed with 10% aq Na2SO3 solution (2 1 mL) and
10% aq NaHCO3 solution (6 1 mL) and H2O (1 mL). The organic
layer was dried (MgSO4), the solvent was evaporated, and the resi-
due was purified by column chromatography (pentane–Et2O, 10:1);
colorless, viscous oil; yield: 160 mg (72%).
1H NMR: = 0.88 (t, 3 H, 3JH,H = 6.6 Hz, 16 -H), 1.22–1.40 (m, 26
H, 3 -H to 15 -H), 1.52–1.60 (m, 2 H, 2 -H), 2.76 (s, 2 H, 1-H), 3.40
(s, 3 H, 5-H), 3.46 (t, 2 H, 3JH,H = 6.4 Hz, 1 -H), 3.51–3.61 (m, 4 H,
3-H, 4-H).
Lipase-Catalyzed Acetylation of ( )-2-Fluoro-2-hexadecyloxy-
3-(methoxymethyl)propan-1-ol (15a) and ( )-2-Fluoro-2-meth-
oxymethyl-3-(hexadecyloxy)propan-1-ol (15b)
The fluorohydrins 15a or 15b and vinyl acetate (molar ratio about
1:1) were dissolved in toluene and the enzyme (occasionally immo-
bilized) was added. This mixture was stirred at r.t. for the length of
time given in the Table. The reaction was stopped by filtration of the
mixture through a short column with silica gel (3 cm, EtOAc as elu-
ent). The mixture was analyzed by GC, the solvent was evaporated,
and the residue was separated by column chromatography (pen-
tane–Et2O, 5:1 3:1). The exact parameters of the experiments and
the results are given in the Table.
13C NMR: = 14.0 (q, 16 -C), 22.7 (t, 15 -C), 26.1 (t, 3 -C), 29.4,
29.5, 29.7, (11 t, 4 -C to 14 -C), 31.9 (t, 2 -C), 48.5 (t, 1-C), 57.6 (q,
5-C), 59.3 (s, 2-C), 70.6 (t, 3-C), 71.8 (t, 1 -C), 72.4 (t, 4-C).
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. We thank the Bayer AG,
Leverkusen, the Hoechst AG, Frankfurt, the Amano Pharmaceutical
Co., Ltd., Nagoya, Japan, and the Novo Nordisk A/S, Copenhagen,
Denmark, for kind donation of chemicals or lipases.
MS (GC/MS): m/z (%) = 342 (M+, 0.5), 311 (M+ – CH3O, 35), 297
+
(M+ – C2H5O, 6), 253 (C16H31OCH2 , 10), 241 (C16H33O+, 5), 225
(C16H33+, 2), 102 (M+ – C16H32O, 41), 71 (C5H11+, C4H7O+, 100).
Anal. Calcd for C21H42O3 (342.6): C, 73.63; H, 12.36. Found: C,
73.81; H, 12.61.
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1-Acetoxy-2-fluoro-3-hexadecyloxy-2-(methoxymethyl)pro-
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Synthesis 2002, No. 5, 648–654 ISSN 0039-7881 © Thieme Stuttgart · New York

654
G. Haufe, A. Burchardt
PAPER
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Angew. Chem., Int. Ed. 2001, 40, 284; Angew. Chem. 2001,
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Synthesis 2002, No. 5, 648–654 ISSN 0039-7881 © Thieme Stuttgart · New York