Synthesis of fluorinated steroids using a novel fluorinating reagent tetrabutylammonium difluorodimethylphenylsilicate (TAMPS)

Article abstract of DOI:10.1135/cccc20081825

Steroidal 3-fluoroderivatives were prepared from corresponding tosylates using tetrabutyl-ammonium difluorodimethylphenylsilicate as fluorinating agent. The reaction was tested on all four possible C-3 and C-5 stereoisomers of cholestane and 17-oxoandrostane skeletons. In this reaction only one isomer was always formed with opposite configuration at C-3 to starting tosylate. The reaction is accompanied by elimination which affords a mixture of corresponding olefines.

Full text of DOI:10.1135/cccc20081825

Synthesis of Fluorinated Steroids Using TAMPS
1825
SYNTHESIS OF FLUORINATED STEROIDS USING A NOVEL
FLUORINATING REAGENT TETRABUTYLAMMONIUM
DIFLUORODIMETHYLPHENYLSILICATE (TAMPS)
b
a2
Pavel HERRMANNa1, Jaroslav KVÍČALA , Vladimír POUZAR and
a3,
Hana CHODOUNSKÁ
*
a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i.,
Flemingovo nám. 2, 166 10 Prague 6, Czech Republic; e-mail: phermann@centrum.cz,
pouzar@uochb.cas.cz, hchod@uochb.cas.cz
Department of Organic Chemistry, Institute of Chemical Technology, Prague,
Technická 5, 166 28 Prague 6, Czech Republic; e-mail: jaroslav.kvicala@vscht.cz
1
2
3
b
Received July 31, 2008
Accepted August 4, 2008
Publish ed on lin e Decem ber 15, 2008
Dedicated to Professor Oldřich Paleta on the occasion of his 70th birthday.
Steroidal 3-fluoroderivatives were prepared from correspon din g tosylates usin g tetrabutyl-
am m on ium difluorodim eth ylph en ylsilicate as fluorin atin g agen t. Th e reaction was tested on
all four possible C-3 an d C-5 stereoisom ers of ch olestan e an d 17-oxoan drostan e skeleton s. In
th is reaction on ly on e isom er was always form ed with opposite con figuration at C-3 to start-
in g tosylate. Th e reaction is accom pan ied by elim in ation wh ich affords a m ixture of corre-
spon din g olefin es.
Keyw ord s: Steroidal fluoroderivatives; Stereoselective fluorin ation ; NMR spectroscopy;
SN reaction .
2
In th e course of previous research on n eurosteroids, a fluorin e atom was
foun d to effectively substitute a h ydroxy fun ction with out h arm in g th e bi-
ological activity1,2. Th is substitution m ay lead to im proved ph arm acologi-
cal ch aracteristics, such as an en h an ced m etabolic stability, wh ich seem ed
prom isin g. Besides th e 3α-h ydroxyl group, n eurosteroids an d th eir m etabo-
lites or precursors posses an oth er oxygen (carbon yl or h ydroxyl) fun ction al
group in position 17 of an drostan e an d 20 of pregn an e derivatives. Th e
question of regioselectivity an d ch em oselectivity of fluorin atin g agen ts h ad
to be con sidered.
Th e aim of our work was to com pare th e fluorin atin g ability of a n ucleo-
ph ilic fluorin atin g agen t3, tetrabutylam m on ium difluorodim eth ylph en yl-
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 12, pp. 1825–1834
© 2008 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20081825

1826
Herrmann, Kvíčala, Pouzar, Chodounská:
silicate (TAMPS; Ch art 1), in fluorin ation of selected secon dary steroidal
tosylates with m eth ods publish ed in literature (cf. Results an d Discussion ).
Procedures publish ed earlier utilise differen t fluorin atin g reagen ts to con -
vert a h ydroxyl group or a con ven ien t in term ediate, such as tosylate or
m esylate, in to a fluorin e atom . Tosylates an d m esylates react directly with a
fluorin e an ion or with fluorosilicate reagen ts. Both th e reaction s m en -
tion ed proceed in th e SN m ech an ism with elim in ation as a side reaction .
2
Th us th e reaction affords a m ixture of desired fluoro derivatives an d ole-
fin es in varyin g ratio. Ch iral m olecules m ake it possible to yield two stereo-
isom eric fluoro derivatives, th us stereolectivity of th e reaction is im portan t.
In form ation about toxicity, stability an d availability of th e reagen t is also a
im portan t factor in its ch oice.
CHART 1
In term ediate tosylates an d m esylates were prepared by th e reaction of th e
h ydroxyl substrates with sulfon yl ch lorides. Because th e m ajority of studies
publish ed were don e with th e tosylates, we used th em as well for easier
com parison of our fin din gs with data publish ed earlier.
RESULTS AND DISCUSSION
Tosylates used in th is paper were prepared accordin g publish ed proce-
dures4–7. Th e reagen t TAMPS itself h as been developed an d successfully
tested on aliph atic substrates by Kvíčala an d co-workers3.
Fluorosteroids (Sch em es 1–4) were obtain ed from th e correspon din g
tosylates after 4–20 h of reflux in aceton itrile un der an argon atm osph ere,
usin g two equivalen ts of TAMPS. Our results in dicate th at th e fluorin ation
in position 3 proceeds stereoselectively with in version of con figuration an d
furn ish es pure fluoro derivates (30–39%), accom pan ied by m ixture of corre-
spon din g 2-en e an d 3-en e olefin es (38–51%). Attem pts to in troduce fluo-
rin e in to position 17 by th is m eth od lead to elim in ation on ly. Th e reagen t
applied to 7β-tosylate 19 afforded th e 7α-fluoro derivative 20, too, th ough
in a lower yield (21%) an d th e m ixture of olefin es (43%). Structures of fluo-
1
ro derivatives obtain ed were con firm ed by th e H an d 19F NMR, m ass spec-
tra, an d com bustion an alysis. Ph ysical con stan ts (m .p., specific rotation ) of
kn own com poun ds were com pared with publish ed data.
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Synthesis of Fluorinated Steroids Using TAMPS
1827
Th e con figuration of th e fluorin e atom was con firm ed by th e 1H an d
19F NMR spectra. Th e sign al of th e h ydrogen atom in th e position 3 h as
a ch aracteristic ch em ical sh ift an d sh ape. Above all, th is sign al is spliced by
a stron g gem in al in teraction (2JH,F ≈ 50 Hz), as well as by oth er in teraction s
with proton s in th e m olecule. Really on ly 3J splittin g by vicin al proton s
in th e position s 2 an d 3 is observable. Resultin g sh ape of th e sign al is dou-
SCHEME 1
Reaction of ch olestan -3-yl tosylates with TAMPS
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1828
Herrmann, Kvíčala, Pouzar, Chodounská:
blet of m ultiplets, wh ereas th at m ultiplets width m atch es to th e axial
(W ≈ 32 Hz) or equatorial (W ≈ 12 Hz) orien tation . Ch em ical sh ifts of axial
an d equatorial proton s are very differen t, ca. 4.50 an d 4.85, respectively.
1
Th us in th e H NMR spectra it is possible to n otice occurren ce of th e oth er
isom er.
SCHEME 2
Reaction of an drostan -3-yl tosylates with TAMPS
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Synthesis of Fluorinated Steroids Using TAMPS
1829
Also th e 19F NMR spectra h ave th e ch aracteristic sh ape an d ch em ical sh ift
2
of th e sign al of fluorin e atom in th e position 3. Gem in al in teraction JH,F
(ca. 50 Hz) an d in teraction with th e oth er proton s in th e m olecule take ef-
fect. Really on ly 3J in teraction s with proton s in th e adjacen t position s 2
an d 4 are im portan t an d its size depen ds on th eir relative orien tation . In
th e case of an axial fluorin e atom two in teraction s with th e axial proton s
are observed, th eir size is com parable with th e gem in al in teraction con -
stan t, it m ean s about 50 Hz, an d con siderably low order in teraction s with
equatorial proton s. Com bin ation of all m en tion ed effects result in th e com -
plex m ultiplet (W ≈ 165 MHz).
SCHEME 3
Isom ers with equatorial orien tation of fluorin e h ave dih edral an gles be-
tween C–F an d C–H bon ds on th e n eigh bourin g carbon atom s of rough ly
3
th e sam e size, so th e JH,F is approxim ately equal size an d m arkedly lower
2
th an th e gem in al JH,F. Th us sign al of 3-H are two n arrow m ultiplets in th e
2
distan ce equal to JH,F, wh ich is 50 Hz. Ch em ical sh ifts of axial fluorin e at-
om s (ca. 178 ppm ) an d equatorial on es (ca. 164 ppm ) are also differen t.
Th us in th e 19F NMR spectra it is possible to n otice th e presen ce of th e
oth er isom er, too.
SCHEME 4
Th e com parison of presen ted fluorin atin g reagen t TAMPS with m eth ods
publish ed earlier is lim ited by th e fact th at papers discussed below do n ot
con tain results of fluorin atin g reaction for all four possible stereoisom ers in
th e position s 3 an d 5 on equal con dition s.
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1830
Herrmann, Kvíčala, Pouzar, Chodounská:
Th e m ost im portan t m eth ods described in literature are followin g. Re-
placem en t with fluoride ion on an ion exch an ge resin in refluxin g toluen e
was studied8. Mesylates on 5α-ch olestan e skeleton gave correspon din g
epim eric 3-fluoro derivatives 2 an d 4, th eir yields were 32 an d 20%, respec-
tively, side products was 2-en e derivative (31 an d 41%). 3β-Tosylate 1 un der
iden tical reaction con dition s gave lower yield (21%) of 3α-fluoro derivative
2 an d olefin (49%). 3-Fluoro derivatives 10 an d 12 were form ed in th e
5α-an drostan e series un der th e sam e con dition s. Th e yields are 41 an d 26%,
respectively. Th e oth er product is olefin (57 an d 37%, respectively). Reac-
tion with th e tetrabutylam m on ium fluoride (TBAF); 3β,5α-tosylate 9 gave
67% of 3α-fluoro derivative 10 an d 30% of olefin 9.
Tetrabutylam m on ium bifluoride in th e m ixture with m eth an esulfon yl
fluoride9 reacts directly with 3β-h ydroxy-5α-an drostan -17-on e to yield 82%
of a 3α-fluoro derivative 10 an d 12% of olefin . Th e yield of th is reaction is
h igh er com pared with dieth ylam in osulfur trioxide (DAST); isolated yields:
47% of th e 3α-fluoro derivative 10 an d 12% of olefin .
Reaction with tetrabutylph osph on ium h ydrogen bifluoride9; 3β,5α-
tosylate 9 afforded 77% of 3α-fluoro derivative 10 an d 15% of olefin , corre-
spon din g m esylate gave 80% of fluoro derivative 10 an d 16% of olefin .
Durin g th e reaction with DAST, h ydroxy derivatives react directly
with in version of con figuration at correspon din g reaction cen tres10
.
5α-Ch olestan -3β-ol afforded 43% of 3α-fluoro derivative 2 an d 32% of ole-
fin , n o 3β-fluoro derivative was recorded.
Ph en yltetraph osph oran e11 reacts directly with h ydroxy derivatives as
well. 5α-Ch olestan -3β-ol afforded 39% of 3α-fluoro derivative 2 an d 38% of
olefin . Epim eric 3α-h ydroxy derivative gave 20% of 3β-fluoro derivative 4
an d 76% of olefin . Th is reagen t can n ot be used in th e glass device.
To sum up, th e yields of th e reaction s steroid tosylates with TAMPS are
sim ilar to th e yields of publish ed earlier. In th is reaction on ly on e isom er
is always form ed an d its con figuration opposite to th e startin g tosylate.
Un fortun ately th is SN n ucleoph ilic substitution is accom pan ied by elim i-
2
n ation , wh ich affords a m ixture of 2-en e an d 3-en e olefin s with th e sign ifi-
can t prevalen ce of th e first isom er.
Som e of th e above discussed reaction s afford h igh er yields, but exh aus-
tive com parison with our results could n ot be don e because of publish ed
reaction s were n ot don e with all fours stereoisom ers un der th e sam e con -
dition s. On con trary, in th is work, th e possibility of th e preparation of
3-fluoro derivatives in all four con ceivable com bin ation s of con figuration s
in th e position s 3 an d 5 of steroid skeleton was exam in ed. Th e advan tage of
th e TAMPS reagen t is in its stereospecifity, furth erm ore th is reaction does
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 12, pp. 1825–1834

Synthesis of Fluorinated Steroids Using TAMPS
1831
n ot require an y special equipm en t, th e reagen t is safe an d n ot m oisture sen -
sitive.
EXPERIMENTAL
Meltin g poin ts were determ in ed on a Koefler m eltin g poin t m icroapparatus Boetius (Ger-
m an y) an d are un corrected. An alytical sam ples were dried over ph osph orus pen toxide at
50 °C/100 Pa. Proton NMR spectra were m easured on spectrom eter Varian UNITY-200 (at
200 MHz) in CDCl3 with tetram eth ylsilan e as in tern al referen ce. 19F NMR spectra were m ea-
sured on a Bruker Avan ce II-500 spectrom eter (at 470.3 MHz) in CDCl3. Hexafluoroben zen e
(δ –163.0) was used as extern al stan dard. Ch em ical sh ifts are given in ppm (δ-scale), cou-
plin g con stan ts J an d width s of m ultiplets W in Hz. Un less oth erwise stated, th e data were
in terpreted as th e first-order spectra. Mass spectra were m easured on spectrom eter ZAB-EQ
(VG An alytical), EI (70 eV). Th in -layer ch rom atograph y (TLC) was perform ed on silica gel
(ICN Bioch em icals). Preparative TLC (PLC) was carried out on 200 × 200 m m plates coated
with a 0.7 m m th ick layer of th e sam e m aterial. For colum n ch rom atograph y, 60–120 µm
silica gel was used (Merck). Wh en ever aqueous solution s of h ydroch loric acid were used,
con cen tration was 5% (v/v). Solven ts were evaporated on a rotatory evaporator in vacuo
(0.25 kPa, bath tem perature 40 °C).
Preparation of Fluoro Derivatives. Gen eral Meth od
To th e solution of tosylate in th e m in im um am oun t of absolute aceton itrile was added,
th rough a septum , a solution of TAMPS in aceton itrile. Th e reaction m ixture was refluxed in
an argon atm osph ere for 4–20 h . Th e reaction course was m on itored by TLC. After com ple-
tion th e m ixture was cooled to room tem perature an d poured in to th e water (200 m l). Prod-
ucts were extracted to th e eth er (100 m l, 3 tim es). Collected extracts were wash ed with
saturated solution of sodium ch loride (250 m l) an d dried usin g an h ydrous sodium sulfate,
an d th e solven ts evaporated. Th e residue was ch rom atograph ed on four preparative silica gel
plates.
3α-Fluoro-5α-ch olestan e (2)
Mixture of tosylate4 1 (150 m g, 0.28 m m ol), aceton itrile (20 m l) an d 0.59 M TAMPS in ace-
ton itrile (0.95 m l, 0.56 m m ol) was refluxed for 16 h . PLC: ligh t petroleum –eth er (95:5);
yield 32 m g (30%) of crystallin e product 2; m .p. 100–101 °C (lit.8 gives 103–104 °C).
1H NMR: 0.65 (3 H, s, H-18); 0.78 (3 H, s, H-19); 0.87 (6 H, d, J = 6.1, H-26 an d H-27); 0.90
(3 H, d, J = 6.1, H-21); 4.81 (1 H, dm , JF,H-3 = 49, H-3). 19F NMR: –176.96 (1 F, m , JF,H-3β
≈
JF,H-2β ≈ JF,H-4b ≈ 48, JF,H-2α ≈ JF,H-4α ≈ 12, F-3α). EI MS, m/z (rel. in t.): 390 (46, M), 375 (13,
M – CH3), 250 (12), 235 (94), 221 (17), 167 (33), 149 (21), 135 (12), 123 (22), 107 (28), 95
(46), 81 (53), 69 (70), 55 (84), 43 (100). For C27H47F (390.7) calculated: 83.01% C, 12.13% H,
4.86% F; foun d: 82.79% C, 12.37% H, 4.68% F. In addition to th e above, a m ixture of
olefin s (45 m g, 43%) an d startin g m aterial 1 (14 m g, 9%) were obtain ed.
3β-Fluoro-5α-ch olestan e (4)
Mixture of tosylate4 3 (200 m g, 0.37 m m ol), aceton itrile (30 m l) an d 0.59 M TAMPS in ace-
ton itrile (1.25 m l, 0.74 m m ol) was refluxed for 5.5 h . PLC: ligh t petroleum ; yield 43 m g
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 12, pp. 1825–1834

1832
Herrmann, Kvíčala, Pouzar, Chodounská:
(30%) of crystallin e product 4; m .p. 75–77 °C (lit.8 gives m .p. 78–80 °C). 1H NMR: 0.66 (3 H,
s, H-18); 0.83 (3 H, s, H-19); 0.87 (6 H, d, J = 6.1, H-26 an d H-27); 0.91 (3 H, d, J = 6.1,
H-21); 4.48 (1 H, dm , JF,H-3 = 50, H-3). 19F NMR: –163.67 (1 F, dm , JF,H-3α = 50, F-3). EI MS,
m/z (rel. in t.): 390 (60, M), 375 (16, M – CH3), 250 (15), 235 (100), 221 (13), 167 (12), 149
(16), 135 (10), 123 (15), 107 (25), 95 (35), 81 (40), 69 (26), 55 (49), 43 (57). For C27H47
F
(390.7) calculated: 83.01% C, 12.13% H, 4.86% F; foun d: 82.73% C, 12.29% H, 5.02% F. In
addition to th e above, a m ixture of olefin s (49 m g, 47%) was obtain ed.
3α-Fluoro-5β-ch olestan e (6)
Mixture of tosylate5 5 (150 m g, 0.28 m m ol), aceton itrile (20 m l) an d 0.59 M TAMPS in ace-
ton itrile (1.0 m l, 0.59 m m ol) was refluxed for 6 h . PLC: ligh t petroleum ; yield 33 m g (31%)
of oily product 6. 1H NMR: 0.65 (3 H, s, H-18); 0.86 (6 H, d, J = 6.1, H-26 an d H-27); 0.90
(3 H, d, J = 6.1, H-21); 0.96 (3 H, s, H-19); 4.87 (1 H, dm , JF,H = 50, ∑JH,H = 32, H-3).
19F NMR: –163.22 (1 F, dm , JF,H-3β = 50, F-3). EI MS, m/z (rel. in t.): 390 (82, M), 375 (28, M –
CH3), 250 (10), 235 (100), 221 (13), 167 (15), 149 (22), 135 (13), 123 (18), 107 (34), 95 (50), 81
(55), 69 (38), 55 (75), 43 (94). For C27H47F (390.7) calculated: 83.01% C, 12.13% H, 4.86% F;
foun d: 82.96% C, 12.02% H, 4.77% F. In addition to th e above, a m ixture of olefin s (53 m g,
51%) was obtain ed.
3β-Fluoro-5β-ch olestan e (8)
Mixture of tosylate5 7 (150 m g, 0.28 m m ol), aceton itrile (20 m l) an d 0.59 M TAMPS in ace-
ton itrile (1.0 m l, 0.59 m m ol) was refluxed for 6 h . PLC: ligh t petroleum ; yield 38 m g (35%)
of oily product 8. 1H NMR: 0.64 (3 H, s, H-18); 0.84 (3 H, s, H-19); 0.87 (6 H, d, J = 6.1,
H-26 an d H-27); 0.91 (3 H, d, J = 6.1, H-21); 4.51 (1 H, dm , JF,H-3 = 50, H-3). 19F NMR:
–178.18 (1 F, m , JF,H-3β ≈ JF,H-2β ≈ JF,H-4β ≈ 48, JF,H-2α ≈ JF,H-4α ≈ 12, F-3). EI MS, m/z (rel. in t.):
390 (55, M), 375 (15, M – CH3), 250 (12), 235 (100), 221 (16), 167 (20), 149 (18), 135 (13),
123 (17), 107 (31), 95 (50), 81 (52), 69 (39), 55 (70), 43 (91). For C27H47F (390.7) calculated:
83.01% C, 12.13% H, 4.86% F; foun d: 82.79% C, 11.96% H, 5.06% F. In addition to th e
above, a m ixture of olefin s (49 m g, 47%) was obtain ed.
3α-Fluoro-5α-an drostan -17-on e (10)
Mixture of tosylate4 9 (160 m g, 0.36 m m ol), aceton itrile (20 m l) an d 0.59 M TAMPS in ace-
ton itrile (1.2 m l, 0.72 m m ol) was refluxed for 11 h . PLC: ligh t petroleum –aceton e; yield
34 m g (32%) of crystallin e product 10; m .p. 112–116 °C (lit.12 gives m .p. 114–115 °C).
1H NMR: 0.81 (3 H, s, H-18); 0.86 (3 H, s, H-19); 4.83 (1 H, dm , JF,H = 50, H-3). 19F NMR:
–177.24 (1 F, m , JF,H-3β ≈ JF,H-2β ≈ JF,H-4β ≈ 48, JF,H-2α ≈ JF,H-4α ≈ 12, F-3). EI MS, m/z (rel. in t.):
292 (80, M), 277 (15, M – CH3), 248 (36), 235 (17), 221 (30), 167 (15), 149 (16), 121 (15),
108 (40), 91 (50), 79 (65), 67 (80), 55 (78), 41 (100). For C19H29FO (292.4) calculated:
78.04% C, 10.00% H, 6.50% F; foun d: 77.85% C, 10.13% H, 6.58% F. In addition to th e
above, a m ixture of olefin s (27 m g, 28%) an d startin g m aterial 9 (27 m g, 18%) were obtain ed.
3β-Fluoro-5α-an drostan -17-on e (12)
Mixture of tosylate4 11 (150 m g, 0.34 m m ol), aceton itrile (15 m l) an d 0.59 M TAMPS in ace-
ton itrile (1.15 m l, 0.67 m m ol) was refluxed for 4 h . PLC: ligh t petroleum –aceton e (9:1);
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Synthesis of Fluorinated Steroids Using TAMPS
1833
yield 38 m g (39%) of crystallin e product 12; m .p. 135–138 °C (lit.12 gives m .p. 132–135 °C).
1H NMR: 0.86 (6 H, s, H-18 an d H-19); 4.48 (1 H, dm , JF,H = 50, ∑JH,H = 32, H-3). 19F NMR:
–163.99 (1 F, dm , JF,H-3α = 49.6, F-3). EI MS, m/z (rel. in t.): 292 (100, M), 277 (13, M – CH3),
248 (37), 235 (15), 221 (20), 167 (12), 149 (11), 121 (23), 108 (60), 91 (46), 79 (52), 67 (65),
55 (45), 41 (54). For C19H29FO (292.4) calculated: 78.04% C, 10.00% H, 6.50% F; foun d:
77.89% C, 10.17% H, 6.34% F. In addition to th e above, a m ixture of olefin s (39 m g, 40%)
was obtain ed.
3α-Fluoro-5β-an drostan -17-on e (14)
Mixture of tosylate6 13 (200 m g, 0.46 m m ol), aceton itrile (30 m l) an d 0.59 M TAMPS in ace-
ton itrile (1.6 m l, 0.92 m m ol) was refluxed for 4 h . PLC: ligh t petroleum –aceton e (95:5);
yield 40 m g (33%) of crystallin e product 14; m .p. 123–125 °C. 1H NMR: 0.85 (3 H, s, H-18);
0.95 (3 H, s, H-19); 4.52 (1 H, dm , JF,H = 50, ∑JH,H = 32, H-3). 19F NMR: –163.47 (1 F, dm ,
JF,H-3 = 49.3, F-3). EI MS, m/z (rel. in t.): 292 (45, M), 277 (10, M – CH3), 248 (22), 235 (11),
221 (12), 167 (10), 149 (100), 121 (15), 108 (23), 91 (35), 79 (33), 67 (52), 55 (70), 41 (96). For
C
19H29FO (292.4) calculated: 78.04% C, 10.00% H, 6.50% F; foun d: 77.75% C, 10.11% H,
6.37% F. In addition to th e above, a m ixture of olefin s (54 m g, 43%) was obtain ed.
3β-Fluoro-5β-an drostan -17-on e (16)
Mixture of tosylate6 15 (170 m g, 0.38 m m ol), aceton itrile (20 m l) an d 0.76 M TAMPS in ace-
ton itrile (1.3 m l, 0.92 m m ol) was refluxed for 5 h . PLC: ligh t petroleum –aceton e (95:5);
yield 35 m g (31%) of crystallin e product 16; m .p. 123–126 °C (lit.10 gives m .p. 131 °C).
1H NMR: 0.86 (3 H, s, H-18); 0.99 (3 H, s, H-19); 4.88 (1 H, dm , JF,H = 50, H-3). 19F NMR:
–178.45 (1 F, m , JF,H-3α ≈ JF,H-2α ≈ JF,H-4α ≈ 48, JF,H-2β ≈ JF,H-4β ≈ 12, F-3). EI MS, m/z (rel. in t.):
292 (95, M), 277 (10, M – CH3), 248 (37), 235 (15), 221 (18), 167 (10), 149 (30), 121 (23), 108
(52), 91 (46), 79 (55), 67 (76), 55 (72), 41 (100). For C19H29FO (292.4) calculated: 78.04% C,
10.00% H, 6.50% F; foun d: 77.81% C, 10.21% H, 6.29% F. In addition to th e above, a m ix-
ture of olefin s (49 m g, 51%) was obtain ed.
3α-Fluoro-5β-pregn an -20-on e (18)
Mixture of tosylate6 17 (150 m g, 0.32 m m ol), aceton itrile (20 m l) an d 0.76 M TAMPS in ace-
ton itrile (1.1 m l, 0.64 m m ol) was refluxed for 6 h . PLC: ligh t petroleum –aceton e (9:1); yield
35 m g (34%) of crystallin e product 18; m .p. 104–106 °C (lit.2 gives 107–108 °C). 1H NMR:
0.60 (3 H, s, H-18); 0.93 (3 H, s, H-19); 2.12 (3 H, s, H-21); 2.54 (1 H, dd, J1 = J2 = 9, H-17);
4.53 (1 H, dm , JF,H = 50, H-3). 19F NMR: –163.30 (1 F, dm , JF,H-3β = 50, F-3). EI MS, m/z
(rel. int.): 320 (52, M), 302 (48), 250 (13), 235 (70), 149 (20), 121 (35), 107 (37), 95 (46), 84 (90),
67 (42), 55 (35), 43 (100). For C21H33FO (320.5) calculated: 78.70% C, 10.38% H, 5.93% F;
foun d: 78.81% C, 10.25% H, 5.82% F. In addition to th e above, a m ixture of olefin s (46 m g,
48%) was obtain ed.
7α-Fluoro-5α-ch olestan -3β-yl Acetate (20)
Mixture of tosylate7 19 (150 m g, 0.25 m m ol), aceton itrile (20 m l) an d 0.76 M TAMPS in ace-
ton itrile (0.9 m l, 0.53 m m ol) was refluxed for 16 h . PLC: ligh t petroleum –aceton e (9:1);
yield 24 m g (21%) of crystallin e product 20; m .p. 110–113 °C. 1H NMR: 0.64 (3 H, s, H-18);
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Herrmann, Kvíčala, Pouzar, Chodounská:
0.82 (3 H, s, H-19); 0.87 (6 H, d, J = 6.1, H-26 an d H-27); 0.91 (3 H, d, J = 6.1, H-21); 2.02
(3 H, s, OAc); 4.63 (1 H, dm , JF,H = 50, H-7); 4.75 (1 H, m , W = 32, H-3). 19F NMR: –176.53
(1 F, m , JF,H-7β ≈ JF,H-6β ≈ JF,H-8β ≈ 48, JF,H-6α ≈ 12, F-3α). EI MS, m/z (rel. in t.): 448 (90, M),
428 (35), 388 (50), 368 (30), 294 (20), 248 (30), 234 (55), 149 (50), 121 (22), 107 (55), 95 (60),
81 (80), 69 (80), 55 (43), 43 (100). For C29H49FO2 (448.7): 77.63% C, 11.01% H, 4.23% F;
foun d: 77.49% C, 10.96% H, 4.14% F. In addition to th e above, a m ixture of 6(7) an d 7(8)
olefin s (46 m g, 43%) an d startin g m aterial 19 (18 m g, 12%) were obtain ed.
W e are indebted to Dr P. Fiedler for the measurement and interpretation of IR spectra and
Dr M. Dračínský for the measurement and interpretation of NMR spectra. Our thanks are due to
Dr L. Holasová for elemental analyses. This work was supported by the Czech Science Foundation
(203/08/1498, Research Project of the Academy of Sciences of the Czech Republic Z4 005 0506).
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