Unexpected fragmentation of 16β-acetoxy-22-oxocholestanes on the action of methylenetriphenylphosphorane

Article abstract of DOI:10.1016/j.mencom.2014.09.008

Treatment of 16β-acetoxy-22-oxocholestanes with methylenetriphenylphosphorane results in the cleavage of C²²-C²³ bond and formation of bisnorcholanic (22→16)-lactones. The analogous fragmentation also partially proceeds on Bu^tOK action.

Full text of DOI:10.1016/j.mencom.2014.09.008

Mendeleev
Communications
Mendeleev Commun., 2014, 24, 272–273
Unexpected fragmentation of 16b-acetoxy-22-oxocholestanes
on the action of methylenetriphenylphosphorane
Zuleykha R. Valiullina,a Lidiya S. Khasanova,a Natalya K. Selezneva,a
Fanuza A. Gimalova,a Kasimir K. Pivnitskyb and Mansur S. Miftakhov*a
a Institute of Organic Chemistry, Ufa Scientific Center of the Russian Academy of Sciences, 450054 Ufa,
Russian Federation. Fax: +7 347 235 6066; e-mail: bioreg@anrb.ru
b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5328; e-mail: kpiv@mail.ru
DOI: 10.1016/j.mencom.2014.09.008
Treatment of 16b-acetoxy-22-oxocholestanes with methylenetriphenylphosphorane results in the cleavage of C22–C23 bond and
formation of bisnorcholanic (22®16)-lactones. The analogous fragmentation also partially proceeds on ButOK action.
Methylenetriphenylphosphorane (CH2=PPh3) has wide syn-
thetic application for methylenation of ketones, aldehydes, esters,
etc.1,2 Olefination reactions usually proceed successfully under
mild conditions and in good yields, nevertheless, some difficulties
may be encountered in the case of enolisable and sterically hindered
ketones.3,4 Moreover, numerous ‘deviations’ from the normal
reaction course with the formation of abnormal products are
known for CH2=PPh3.5,6
Taking into account the necessity to generate the enolate in
the start of the fragmentation, we treated 2a with ButOK. As a
result, the same fragmentation was also observed with formation
of lactone 3a (10%). Competitive process was deacetylation of
hindered 16-OAc group primarily by 16®22 migration and then
O
Me
Me
Me
O
During the development of synthesis of anticancer steroid
saponin OSW-17 structural analogues from diosgenin 1a, we have
discovered the unexpected side-chain fragmentation of cholestanic
Me
Ac2O
BF3·Et2O
22-ketones 2a–c (Scheme 1).† The latter were derived from diosgeni
n
RO
1a (for the synthesis8 see Online Supplementary Materials).
1a R = H
1b R = Bn
When attempting olefination of ketones 2a–c with CH2=PPh3
under standard conditions the formation of bisnorcholanic lactones
3a,b as the single products was observed as a result of cleavage
of the (C23–C27) side chain fragment and loss of the 16-acetyl
group. Formation of lactone 3a (vespertilin acetate) with other
side-chain fragmentation of diosgenin derivatives has already been
reported.9,10
NaH, BnBr
O
Me
R'
Me
OAc Me
Me
Ph3P=CH2
†
3b-Benzyloxy-16b-hydroxydinorchol-5-enoic acid (22®16)-lactone
RO
3b. The 1.0 m solution of BuLi in hexane (0.32 ml, 0.32 mmol) was
added dropwise at –50 to –40°C under argon to a suspension of methyl-
triphenylphosphonium iodide (130 mg, 0.32 mmol) in anhydrous THF
(10 ml) and the mixture was stirred for 1 h at the same temperature. Then
a solution of ketone 2b (60 mg, 0.106 mmol) in THF (5 ml) was added.
The mixture was allowed to warm to room temperature and stirred for
2 h, then quenched with saturated NH4Cl solution. THF was removed from
the mixture in vacuo before the aqueous layer was extracted with EtOAc.
The extract was washed with brine, dried over Na2SO4 and concentrated
in vacuo. The crude product was purified by silica gel chromatography
using EtOAc–light petroleum (1:9) as the eluent to obtain lactone 3b
(25 mg, 56%), mp 232–233°C, [a]D20 –18 (c 1.00, CHCl3), Rf (EtOAc–
light petroleum, 3:7) 0.38. IR (Nujol, nmax/cm−1): 2930, 1763, 1462, 1456,
1377, 1366, 1307, 1239, 1188, 1180, 1113, 1102, 1075, 1035, 737. 1H NMR
(500 MHz, CDCl3) d: 0.78 (s, 3H, Me), 1.04 (s, 3H, Me), 1.33 (d, 3H, Me,
J 7.5 Hz), 1.57 (s, 3H, Me), 2.28 (m, 2H, C15H), 2.41–2.47 (m, 1H, CH),
2.59 (q, 1H, C20H, J 7.7 Hz), 3.28 (m, 1H, C3H), 4.57 (s, 2H, OCH2), 4.96
(dt, 1H, C16H, J 4.7 and 7.7 Hz), 5.35 (d, 1H, C6H, J 5.2 Hz), 7.34 (m, 5H, Ph).
13C NMR (125.77 MHz, CDCl3) d: 13.73 (Me), 18.02 (Me), 19.39 (Me),
20.34 (C11), 28.36 (C2), 31.24 (C8), 31.92 (C7), 33.10 (C15), 36.01 (C20),
36.98 (C10), 37.19 (C12), 38.22 (C4), 39.06 (C1), 41.46 (C13), 50.16 (C9),
54.83 (C14), 58.94 (C17), 69.92 (OCH2), 78.34 (C3), 82.70 (C16), 120.87 (C6),
127.42, 127.55, 128.35 and 138.97 (Ph), 141.09 (C5), 181.32 (C=O). MS (EI),
m/z (%): 434 (0.03, M+), 377 (1), 330 (3), 328 (100 [MH – OCH2Ph]+),
311 (30), 287 (22), 269 (8), 255 (6), 145 (13), 121 (14), 91 (36), 79 (8).
2a R = Ac, R' = OH
2b R = Bn, R' = OH
2c R = Ac, R' = Br
CBr4, Ph3P
Me
O
Me
O
Me
RO
3a R = Ac
3b R = Bn
OH
Me
Me
Me
OH
O
ButOK
SiO2
Me
2a
3a +
1a
RO
4a R = Ac
4b R = H
Scheme 1
© 2014 Mendeleev Communications. All rights reserved.
– 272 –

Mendeleev Commun., 2014, 24, 272–273
removal to form lactol 4a (10%) and its 3-deacetylated analogue
4b (50%). The latter was unstable on silica gel, converting into
diosgenin 1a.
enolate Z-A, whereas strong base (ButOK) enolizes under kinetic
conditions, leading to less stable enolate E-A. Nucleophilic attack of
16-OAc group in enolate E-A is sterically hindered for the anionic
C23 center and is more preferable for anionic O22 center. There-
fore, for ButOK catalyzed reaction the main route is through
intermediates B' and E followed by the migration and removal of
acetyl group to form products 4.
In general, we have discovered a new fragmentation of 16b-
acetoxy-22-oxocholestanes with formation of bisnorcholanic
(22®16)-lactones, which proceeds under the action of methylene-
triphenylphosphorane reacting as a base.
Most likely, the unexpected reaction of ketones 2 is due to two
features of their structure – the well known sterically hindered
nature of 22-carbonyl group and its proximity to 16b-acetoxyl
group. As a result, the bulky phosphorane reagent is hardly able
to form a Wittig intermediate and provides instead an easier
reaction – enolization of 22-keto group, because CH2=PPh3 also
possesses the base properties (Scheme 2). Generated enolate Z-A
attacks closely located carbonyl group of C16-acetoxyl and the
resulting intermediate B fragmentizes to lactones 3 by retro-
Claisen mechanism. The distinction of ButOK (from CH2=PPh3
as the base) is that it is much more basic. Weak base (CH2=PPh3)
enolizes under thermodynamic conditions, producing a more stable
The study was supported by the Russian Foundation for
Basic Research (project no. 11-03-00780) and the Presidium of
the Russian Academy of Sciences (grant 2012–2013).
O
O
Online Supplementary Materials
Me
Me
Me
Me
Supplementary data associated with this article (syntheses and
characteristics for the starting compounds 1b and 2a–c) can be
found in the online version at doi:10.1016/j.mencom.2014.09.008.
R'
O
OAc Me
O
Ph3P=CH2
Me
References
2
Z-A
ButOK
1 A. Maereker, Org. React., 1965, 14, 270.
2 (a) B. E. Maryanoff and A. B. Reitz, Chem. Rev., 1989, 89, 863; (b) S. H.
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O
Me
Me
Me
Me
O
O
O
O
O
Me
Me
B
E-A
Me
Me
O
Me
Me
O
O
O
O
Me
3
8 M. A. Fernández-Herrera, H. López-Muñoz, J. M. V. Hernández-Vázquez,
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B'
OH
OH
Me
Me
Me
Me
O Me
Me
OH
O
O
Me
O
Received: 21st January 2014; Com. 14/4292
E
4a,b
Scheme 2
Reaction of ketone 2a with ButOK. Potassium tert-butoxide (43 mg,
0.38 mmol) was added to a stirred solution of the ketone 2a (100 mg,
0.19 mmol) in anhydrous THF (6 ml) at 0°C. The reaction mixture was
allowed to warm to room temperature and stirred overnight, then quenched
with saturated NH4Cl solution. Further treatment as above afforded the
mixture which according to TLC contained one major product as the most
polar spot and several minor ones. This major product was identified as
most probably an unstable triol 4b because it completely converted into
diosgenin 1a (yield 50%) in the course of column chromatography on
silica gel. Lactone 3a (10%), lactol 4a (10%) and traces of vespertilin
(4%) were also isolated by chromatography.
3b-Acetoxy-16b-hydroxydinorchol-5-enoic acid (22®16)-lactone 3a.
Method A. Similarly, reaction of ketone 2a (108 mg, 0.209 mmol) with
CH2=PPh3 (0.836 mmol) produced lactone 3a, yield 43 mg (60%),
mp 216–217°C, [a]D20 –106 (c 1.0, CHCl3) [lit.,11 mp 212–215°C, [a]D20 –90
(CHCl3); lit.,10 mp 225–228°C], Rf (EtOAc–light petroleum, 3:7) 0.30.
IR (Nujol, nmax/cm−1): 2925, 2854, 1748, 1723, 1463, 1377, 1308, 1246,
1193, 1030, 963. 1H NMR (300 MHz, CDCl3) d: 0.77 (s, 3H, Me), 1.04
(s, 3H, Me), 1.32 (d, 3H, C21H, J 7.7 Hz), 2.04 (s, 3H, MeCO), 2.26 (m,
1H, C15H), 2.34 (m, 2H, CH), 2.59 (dq, 1H, C20H, J 7.7 and 0.9 Hz),
4.56–4.64 (m, 1H, C3H), 4.96 (td, 1H, C16H, J 4.6 and 7.7 Hz), 5.38 (d,
1H, C6H, J 5.0 Hz). 13C NMR (75.47 MHz, CDCl3) d: 13.73 (Me), 18.02
(Me), 19.33 (Me), 20.30 (C11), 21.43 (MeCO), 27.69 (C2), 31.21 (C8),
31.88 (C7), 33.11 (C15), 36.05 (C20), 36.68 (C10), 36.96 (C1), 38.03 (C4),
38.15 (C12), 41.47 (C13), 50.01 (C9), 54.75 (C14), 58.94 (C17), 73.74 (C3),
82.72 (C16), 121.94 (C6), 139.83 (C5), 170.59 (MeCO), 181.32 (C=O).
MS (EI), m/z (%): 326 (100, [M–AcOH]+), 311 (24), 255 (4), 237 (3),
145 (12), 121 (13), 107 (14), 91 (7), 43 (6). Method B. Analogously,
ketone 2c (140 mg, 0.24 mmol) and CH2=PPh3 (0.72 mmol) provided
lactone 3a in 40% yield at 71% conversion.
(25R)-3b-Acetoxyfurost-5-ene-22,26-diol 4a. 1H NMR (500 MHz, CDCl3)
d: 0.85 (s, 3H, Me), 0.88 (d, 3H, Me, J 7.0 Hz), 1.02 (d, 3H, Me, J 7.0 Hz),
1.07 (s, 3H, Me), 1.98 (s, 3H, MeCO), 3.35–3.42 (m, 1H, C26H), 3.50
(br.s, 1H, OH), 4.48 (m, 1H, C3H), 4.55 (m, 1H, C16H), 5.38 (d, 1H, C6H,
J 4.9 Hz). 13C NMR (125.77 MHz, CDCl3) d: 16.19 (Me), 16.73 (Me),
17.24 (Me), 19.64 (Me), 21.20 (Me), 21.54 (C11), 28.22 (C24), 28.49 (C2),
32.26 (C8), 32.70 (C7), 32.76 (C15), 37.08 (C25), 37.28 (C1), 37.49 (C10),
37.80 (C4), 38.88 (C12), 40.47 (C23), 40.48 (C13), 41.32 (C20), 51.02 (C9),
57.16 (C14), 64.10 (C17), 67.87 (C26), 74.23 (C3), 81.27 (C16), 110.83 (C22),
122.96 (C6), 140.78 (C5), 170.37 (MeCO).
– 273 –