A new route for synthesizing cholesterol analogs with fluorocarbon side chains and their liquid-crystalline aliphatic esters

Article abstract of DOI:10.1016/S0022-1139(01)00409-2

A new and efficient route has been developed to synthesize 17β-(1-methyl-3-perfluoroalkyl)propyl-3β-androsterol (1) in nine steps from hyodeoxycholic acid via selective addition of 1-perfluoroalkyl iodide to 24-norchola-5,22-dien-3β-ol. From (1), the first series of steroidal liquid crystalline aliphatic esters (smectic A) with fluorocarbon side chains has been prepared.

Full text of DOI:10.1016/S0022-1139(01)00409-2

Journal of Fluorine Chemistry 113 ꢀ2002) 13±15
A new route for synthesizing cholesterol analogs with ¯uorocarbon
side chains and their liquid-crystalline aliphatic esters
*
Yuehai Shen, Jianxun Wen
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Received 15 June 2000; received in revised form 23 April 2001; accepted 21 May 2001
Abstract
A new and ef®cient route has been developed to synthesize 17b-ꢀ1-methyl-3-per¯uoroalkyl)propyl-3b-androsterol ꢀ1) in nine steps from
hyodeoxycholic acid via selective addition of 1-per¯uoroalkyl iodide to 24-norchola-5,22-dien-3b-ol. From ꢀ1), the ®rst series of steroidal
liquid crystalline aliphatic esters ꢀsmectic A) with ¯uorocarbon side chains has been prepared. # 2002 Elsevier Science B.V. All rights
reserved.
Keywords: Steroid; Per¯uoroalkyl; Free radical; Liquid crystals
Besides their physiological and pharmaceutical activities
for example, 9a-¯uorohydrocortisone) [1], ¯uorinated ster-
groups needing repetitive and tedious experimental opera-
tions, as well as the precious ¯uorinated materials being
consumed heavily by undesired side reactions in the follow-
ing steps.
ꢀ
oids also exhibit interesting thermotropic liquid crystalline
properties ꢀfor a review on the liquid crystals derived from
non-¯uorinated steroids, see [2]; for our work on ¯uorinated
liquid crystals, see [3,4]). To study the structure±property
relationships of ¯uorinated steroidal liquid crystals, ef®cient
synthetic strategies are, therefore, in high demand to synthe-
size target compounds with various ¯uorine-substituents.
Herein, we report an improved route for the synthesis of
To address the aforementioned issues, a new strategy was
,22
5
developed, in which the D -steroid ꢀ2) was selected as the
substrate for per¯uoroalkyl radical addition ꢀFig. 1). From
2
2
literature precedent, chemoselective addition to the D -
double bond was expected. Selective dihydroxylation [14]
and borohydrogenation [15] at this position have been
5
1
7b-ꢀ1-methyl-3-per¯uoroalkyl)propyl-3b-androsterols ꢀ1).
reported. Furthermore, the D -double bond has been found
to be inert to per¯uoroalkyl radicals [16].
Retrosynthetically, ꢀ1) was traced back to an ole®n inter-
mediate ꢀ2) and further hyodeoxycholic acid ꢀ3) ꢀFig. 1).
From sterol ꢀ1), the ®rst series of steroid liquid crystals with
This new route was summarized in Scheme 1. Compound
ꢀ4) was prepared from hyodeoxycholic acid ꢀ3) in four steps
according to a reported method [9]. This procedure could be
carried out in large scale without separation. The crude
¯
uoro-carbon side chain has been obtained.
By the reaction of a steroidal terminal ole®n ꢀA) with a
3
,5
per¯uoroalkyl radical ꢀfor a review on reaction of per¯uor-
oalkyl halides with ole®ns, see [5±8]) and subsequent mod-
i®cation of the A,B-cis-fusion [9], Huang et al. have
prepared the sterol ꢀ1) bearing an iso-per¯uorobutyl terminal
mixture of ꢀ4) and a D -diene acid by-product ꢀcomes
from the substitution±elimination step ꢀKOAc, DMF±H O,
110 8C)) was easily puri®ed by recrystallization from hot
ethyl acetate to give pure material in 56% yield. After
2
1
group ꢀFig. 2) [10,12,13]. However, for the general pre-
protecting hydroxy as acetate, a decarboxylation ꢀPbꢀOAc) ,
4
5
,22
paration of steroids with different per¯uoroalkyl appen-
dages, this strategy proved to be inef®cient and costly
due to the early introduction of different per¯uoroalkyl
CuꢀOAc) , Py-PhH, re¯ux) produced D -steroid ꢀ5) in
2
90% yield based on recovered starting material. For ease of
puri®cation by ¯ash chromatography and recrystallization
from ethanol, the acetate ꢀ5) was then hydrolyzed to alcohol
ꢀ
6). Using sodium dithionite as an initiator in a chloroform±
*
Corresponding author. Tel.: ‡86-21-64163300;
water system, the terminal double bond of the alcohol ꢀ6)
was selectively reacted with 1-per¯uorobutyl and per¯uor-
ohexyl iodides, respectively. Due to the low reactivity of the
steroid substrate, these radical reactions proceeded slowly
fax: ‡86-21-64166128.
E-mail address: wenjianxun@pub.sioc.ac.cn ꢀJ. Wen).
1
G.J. Schroepfer et al. synthesized steroids with an iso-perfluoropropyl
terminal group by a similar strategy, see [12,13].
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ꢀ 0 1 ) 0 0 4 0 9 - 2

14
Y. Shen, J. Wen / Journal of Fluorine Chemistry 113 )2002ꢀ 13±15
Fig. 1.
Fig. 2.
Scheme 1. Reagents and conditions: ꢀa) MeOH, cat. H
2
SO
, Py-PhH, reflux, 71% ꢀ90%); ꢀg) KOH, MeOH, 98%; ꢀh) FꢀCF
5% ꢀtwo steps for n ˆ 4), 74% ꢀtwo steps for n ˆ 6).
4
; ꢀb) TsCl, Py; ꢀc) KOAc, DMF±H
2
O, 110 8C; ꢀd) KOH, MeOH, 56% ꢀfour steps); ꢀe) Ac O, Py,
4
I, Na ±NaHCO , CHCl ±H O, 40 8C; ꢀi) LiAlH , THF,
2
1
00%; ꢀf) PbꢀOAc)
4
, CuꢀOAc)
2
2
)
n
2
S
2
O
4
3
3
2
7
and the yields varied depending on the amount of per¯uor-
oalkyl iodides. Under optimized conditions, two equivalents
of per¯uoroalkyl iodide were added in four portions over
steps were required to obtain ꢀ1) in lower yield ꢀ<60%) from
the substrate ꢀA) by the previous route [10].
Lastly, the condensation of ꢀ1a) and ꢀ1b) with octanoic
acid gave two corresponding aliphatic esters ꢀ7 and 8)
2
ꢀScheme 2). Their phase transition properties were inves-
tigated by differential scanning calorimetry ꢀDSC) and
polarizing optical microscopy. The esters are enantiotropic
smectic ꢀTable 1, entry 1 and 2). To the best of our knowl-
edge, this is the ®rst series of steroid liquid crystals that
2
4 h to give about 80% yield of the desired iodides, which
were then reduced to afford the per¯uoroalkylated sterols
1a) and ꢀ1b). They were identi®ed by comparing the data
ꢀ
with those in literature [11].
The high ef®ciency of this strategy is worth highlighting.
Due to the per¯uoroalkylation at a later stage in the synth-
esis, only two steps were required to obtain the sterol ꢀ1) in
high yield ꢀꢀ75%) from the terminal ole®n ꢀ6). Whereas six
2
The structures of compounds ꢀ7) and ꢀ8) are supported by MS, IR,
1H and 19F NMR spectra and elemental analyses. Compound ꢀ7): MS
‡
À1
Table 1
ꢀm/z) 530 ꢀM À C
7
H
15CO
2
H), 408, 255, 213, 147; IR ꢀKBr) u ꢀcm
, 300 MHz, TMS) d ꢀppm) 5.41
, 282 MHz, TFA)
d ꢀppm) 3.5 ꢀm, 3F), 37.2 ꢀm, 2F), 46.9 ꢀm, 2F), 48.6 ꢀm, 2F); analysis
calcd. for C35 , C 62.30, H7.62; found C 62.69, H7.65.
Compound ꢀ8): MS ꢀm/z) 632 ꢀM À C
15CO
ester); 1H NMR ꢀCDCl
)
a
1
1
736 ꢀC=O, ester); H NMR ꢀCDCl
3
The phase transition temperatures
1
9
ꢀ
d, 1H, J ˆ 4:8 Hz), 4.68 ꢀm, 1H); F NMR ꢀCDCl
3
Entry
Compounds
Phase transition temperatures ꢀ8C)
51 9 2
H F O
1
2
3
4
7
Cr 132.3 S
Cr 124.6 S
Cr 138.6 I
A
A
134.0 I 133.0 S
159.3 I 156.4 S
A
A
102.3 Cr
103.2 Cr
‡
‡
7
H
15CO
2
H ‡ 2H), 631 ꢀM
À
8
À1
C
7
H
2
H ‡ 1H), 509, 255, 213, 147; IR ꢀKBr) u ꢀcm ) 1737 ꢀC=O,
1a
1b
3
, 300 MHz, TMS) d ꢀppm) 5.37 ꢀd, 1H,
Cr 161.0 I 151.5 Ch 150.3 Cr
1
9
J ˆ 4:8 Hz), 4.61 ꢀm, 1H); F NMR ꢀCDCl
3
, 282 MHz, TFA) d ꢀppm)
a
The phase transition temperatures were the peak values of the curves
3.82 ꢀm, 3F), 37.58 ꢀs, 2F), 45.05 ꢀs, 2F), 45.99 ꢀs, 2F), 46.51 ꢀs, 2F),
recorded by DSC ꢀwith a heating and cooling rate of 5 8C/min). Cr:
crystalline; S : smectic A; Ch: cholesteric; I: isotropic liquid.
A
53 13 2
49.24 ꢀs, 2F); analysis calcd. for C38H F O , C 57.36, H6.64; found
C 57.25, H6.71.

Y. Shen, J. Wen / Journal of Fluorine Chemistry 113 )2002ꢀ 13±15
15
Scheme 2. Reagents and conditions: ꢀj) C
7
H
13CO
2
2 2
H, DCC, cat. DMAP, CH Cl , 92% for ꢀ7), 69% for ꢀ8).
incorporate a per¯uorinated side chain. In comparison with
cholesteryl octanoate, which is enantiotropic cholesteric and
monotropic smectic [2], the esters ꢀ7) and ꢀ8) displayed only
a smectic phase, conceivable due to the ¯uorocarbon chain
increasing intermolecular lateral interactions. Compound
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[
1
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China for ®nancial support ꢀNo. 29974038).
The authors also wish to thank Daikin Co., Japan, for their
generous gift of per¯uoroalkyl iodides. Y.S. thanks Drs.
Ximin Chen, Hengfeng Li, Mr. Hao Chen and Kan Wang for
valuable discussions and Dr. Martin J. Lear for his correction
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