An assisted solvolysis of 23-spirostanyl bromides and tosylates. A new rearrangement of spirostanes to the bisfuran systems

Article abstract of DOI:10.1021/jo020231j

Steroidal sapogenins bearing a good leaving group at C23 undergo a completely stereospecific rearrangement under a variety of conditions via a mechanism involving neighboring-group participation by the acetal oxygen atom in the departure of the nucleofuge from C23. The reactions of equatorial (23S)-23-bromo- or (23S)-23-tosyloxyspirostanes with either the α (25R) or β (25S) oriented 25-methyl group lead to the bisfuran products with inversion of configuration at C23. The reactions of the starting compounds with axial substituents (23R) at C23 require drastic conditions and result in the formation of the corresponding olefin accompanied by the rearranged product (in the case of the 25S isomer only).

Full text of DOI:10.1021/jo020231j

An Assisted Solvolysis of 23-Sp ir osta n yl Br om id es a n d Tosyla tes.
A New Rea r r a n gem en t of Sp ir osta n es to th e Bisfu r a n System s
Romana Anulewicz-Ostrowska,† Izabella J astrze¸bska,‡ J acek W. Morzycki,*,‡ and
J acek Wo´jcik§
Department of Chemistry, University of Warsaw, ul. Pasteura 1, 02-093 Warsaw, Poland, Institute of
Chemistry, University of Bialystok, al. Pilsudskiego 11/ 4, 15-443 Bialystok, Poland, and Institute of
Biochemistry and Biophysics, Polish Academy of Sciences, ul. Pawinskiego 5a, 02-106 Warsaw, Poland
morzycki@uwb.edu.pl
Received April 4, 2002
Steroidal sapogenins bearing a good leaving group at C23 undergo a completely stereospecific
rearrangement under a variety of conditions via a mechanism involving neighboring-group
participation by the acetal oxygen atom in the departure of the nucleofuge from C23. The reactions
of equatorial (23S)-23-bromo- or (23S)-23-tosyloxyspirostanes with either the R (25R) or â (25S)
oriented 25-methyl group lead to the bisfuran products with inversion of configuration at C23. The
reactions of the starting compounds with axial substituents (23R) at C23 require drastic conditions
and result in the formation of the corresponding olefin accompanied by the rearranged product (in
the case of the 25S isomer only).
In tr od u ction
Resu lts a n d Discu ssion
Steroidal saponins are widely distributed in plants.1
The steroid aglycones (sapogenins) are cholestane, furo-
stane, or spirostane derivatives. The latter compounds
with the two additional spiro connected rings (E and F)
are the most frequently found in plants. The naturally
occurring compounds always have an R configuration at
the spiro carbon atom. The 21-methyl group is usually
R-oriented (20S). However, the spirostanes differ in
configuration at C25. In compounds with an equatorial
27R-methyl group (e.g. hecogenin) it is R, while com-
pounds with an axial 27â-methyl group, such as sarsasa-
pogenin, have the 25S configuration. Of course, apart
from the spiro system there are further structural dif-
ferences between the saponins in the type of functional-
ization and stereochemistry at the ring junction (5R- and
5â-steroids).
The chemistry of spirostanes was intensively studied
during the last century.2 Plant sapogenins are relatively
cheap raw materials for the synthesis of a number of
medicinally important steroids.3 One of the major chal-
lenges for steroid chemists was to elaborate an efficient
route of spirostanol degradation to the C21 and C19
steroids.4,5 Recently, spirostanes have been enjoying a
renaissance, due to the intensive studies on cephalost-
atins and similar compounds by Fuchs and other chem-
ists.6
Bromination and oxidation of spirostanes occur at C23
(Schemes 1 and 2).7 In the case of the 25R spirostanes a
mixture of 23-bromides (e.g. 1a and 2a ) is formed with
the equatorial one prevailing; a 23,23-dibromide can also
be obtained with an excess of bromine. Contrary to this,
the 25S spirostanes yield exclusively the equatorial
bromide (such as 3a ) due to steric reasons (an axial
approach of a bromine atom toward C23 would result in
a strong 1,3-diaxial interaction with a 27â-methyl group).
Spirostanes can be easily transformed into their 23-oxo
derivatives by using the Barton’s procedure recently
improved by Cuban chemists.8 23-Oxo steroids obtained
(3) (a) Torgov, I. V. Chemistry of spirostanols (in Russian); Nauka:
Moscow, 1986. (b) Lazurievski, G. V., Ed. Stroenie i biologiczeskaya
aktivnost steroidnych glikozydov ryada spirostana i furostana. In Akad.
Nauk Moldav. SSR, Kishiniev 1987. (c) Tobari, A.; Teshima, M.;
Koyanagi, J .; Kawase, M.; Miyamae, H.; Yoza, K.; Takasaki, A.;
Nagamura, Y.; Saito, S. Eur. J . Med. Chem. 2000, 35, 511-552. (d)
Morzycki, J . W.; J astrze¸bska, I.; Katryn˜ski, K. S. Collect. Czech. Chem.
Commun. 2001, 66, 1746-1752.
(4) Gould, D. H.; Staeudle, H.;. Hershberg, E. B. J . Am. Chem. Soc.
1952, 74, 3685-3688.
(5) Fried, J .; Edwards, J . A. Organic Reactions in Steroid Chemistry;
van Nostrand Reinhold Company: New York, 1972; Vol. II, Chapter
11.
(6) (a) LaCour, T. G.; Guo, C.; Bhandaru, S.; Boyd, M. R.; Fuchs, P.
L. J . Am. Chem. Soc. 1998, 120, 692-707. (b) J eong, J . U.; Guo, C.;
Fuchs, P. L. J . Am. Chem. Soc. 1999, 121, 2071-2084. (c) Lee, S.;
LaCour, T. G.; Lantrip, D.; Fuchs, P. L. Org. Lett. 2002, 4, 313-316.
(d) Dro¨gemiller, M.; Flessner, T.; J autelat, R.; Scholz, U.; Winterfeldt,
E. Eur. J . Org. Chem. 1998, 2811-2831. (e) Betancor, C.; Freire, R.;
Pe´rez-Martin, I.; Prange´, T.; Sua´rez, E. Org. Lett. 2002, 4, 1295-1297.
(7) (a) Callow, R. K.; J ames, V. H. T.; Kennard, O.; Page, J . E.; Paton,
P. N.; Riva di Sanseverino, L. J . Chem. Soc. (C) 1966, 288-297. (b)
Wall, M. E.; J ones, H. W. J . Am. Chem. Soc. 1957, 79, 3222-3227. (c)
Dickson, D. H. W.; Page, J . E. J . Chem. Soc. (C) 1955, 447-450. (d)
Mueller, G. P.; Norton, L. L. J . Am. Chem. Soc. 1954, 76, 749-751.
(8) (a) Arteaga, M. A. I.; Gil, R. P.; Martinez, C. S. P.; Manchado, F.
C. Synth. Commun. 2000, 30, 163-170. (b) Barton, D. H. R.; Sammes,
P. G.; Taylor, M. V.; Werstiuk, E. J . Chem. Soc. (C) 1970, 1977-1981.
* To whom correspondence should be addressed. Fax: +4885-
7457581.
† University of Warsaw.
‡ University of Bialystok.
§ Polish Academy of Sciences.
(1) Hostettmann, K.; Marston, A. Saponins; University Press:
Cambridge, UK, 1995.
(2) (a) Fieser, L.; Fieser, M. Sapogenins. In Steroids; Reinhold
Publishing Corporation: New York, 1959; Chapter 21. (b) Marker, R.
E.; Rohrmann, E. J . Am. Chem. Soc. 1940, 62, 518-520, 898-900.
10.1021/jo020231j CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/12/2002
6916
J . Org. Chem. 2002, 67, 6916-6924

Solvolysis of 23-Spirostanyl Bromides and Tosylates
SCHEME 1
SCHEME 2
in this way were reduced with hydrides to the corre-
sponding 23-alcohols (mixtures of C23 epimers). 25R-5R-
Spirostane-3â,12â-diol-23-one 3-acetate (8) when reduced
with sodium borohydride afforded a mixture of axial
(23R) and equatorial (23S) 23-alcohols in the ratio 10:1.
Analogous reduction of 23-oxosarsasapogenin acetate (9)
yielded the 7:5 mixture of 23 alcohols in favor of the
equatorial one. Relatively high amounts of axial alcohols
were formed during reduction of 23-oxo steroids due to
the easier approach of hydride from the R-side. 23S-
Hydroxyspirostane saponins are compounds occurring in
nature, e.g. they were found in the leaves of Sansevieria
trifasciata.9 Each of the four 23-alcohols obtained were
converted to the corresponding tosylates 1b, 2b, 3b, and
4b in order to study their solvolytic reactions along with
the bromide (1a , 1c, 2a , 2c, and 3a ) transformations.
Tosylhydrazones 5 and 6 were obtained in the usual way
from the ketones 8 and 9, respectively, and their decom-
position reactions were also studied.
In a preliminary communication the rearrangement of
equatorial 23-bromides to the bisfuran systems was
reported.10 Now, the results of a detailed study on
solvolytic reactions of spirostanes with a good leaving
group at C23 are presented (Table 1).
Bromide 1c was subjected to mild hydrolysis with
aqueous ammonia in n-butanol at reflux (Scheme 3). The
reaction afforded slowly but steadily a more polar product
10c. In a similar reaction of bromide 1a , an analogous
product 10a was formed accompanied by a minor product
10b with a free 3â-OH group. Compounds 10c and 10a
showed the O-H absorption bands in their IR spectra
and a characteristic pattern of fragmentation (M+
-
C5H10O) in MS. A similar fragmentation pathway was
previously reported for 23-alcohols.9 However, the 23-OH
structure for the products was excluded since 10c proved
to be different from both epimeric alcohols obtained by
1
reduction of the 23-ketone 8 (TLC, H NMR). Moreover,
attempts at acetylation of 10c and 10a failed, suggesting
(9) Gonzalez, A. G.; Freire, R.; Garcia-Estrada, M. G.; Salazar, J .
A.; Suarez, E. Tetrahedron 1972, 28, 1289-1297.
(10) Morzycki, J . W.; J astrze¸bska, I. Tetrahedron Lett. 2001, 42,
5989-5991.
J . Org. Chem, Vol. 67, No. 20, 2002 6917

Anulewicz-Ostrowska et al.
SCHEME 3
TABLE 1. Solvolytic Rea ction s of Com p ou n d s 1-6
faster than that in the 25R series and cleanly afforded
the rearranged product 11a . A similar reaction of the
corresponding tosylate 3b yielded the same product. Its
structure was unequivocally confirmed by an X-ray study
(see Supporting Information). In particular, the study
proved the configurations at the chiral centers C22 (S)
and C23 (R). The crystal structure showed no intra-
molecular hydrogen bonds. The ring E of 11a exists in a
slightly distorted 22R,Oâ-half-chair conformation, whereas
the ring F conformation is an intermediate between a
25â-envelope and a 24R,25â-half-chair. The oxygen atoms
in the “furanose” rings are approximately trans located
(the torsion angle O(16)-C22-C23-O(26) amounts to
75.0°). The conformation of the five-membered ring D is
a nearly pure 14R-envelope. The X-ray study proved
inversion of configuration at C23 during rearrangement.
This can be explained assuming participation of electrons
of the C22-O(26) bond in the bromide departure. It
should be added that an anti coplanar relationship of the
atoms O(26)-C22-C23-Br in the substrate is ideal for
such participation.
Bromide 1a was also subjected to solvolysis under
different conditions. When 1a was treated with silver
tetrafluoroborate in aqueous DMF, once again the rear-
ranged compound 10a was formed as the main product.
However, when DMF was replaced by glyme, the oxida-
tion to the ketone 7 took place instead. Compound 7 was
identified by comparison with the product of hecogenin
acetate 1d oxidation with sodium nitrite. The reaction
of 1a with AgBF4 performed in THF under anhydrous
entry substrate
conditionsa
products
yield, %
1
2
3
4
5
1a
1a
1a
1c
1a
a
b
c
14a
7
10a
79
72
63
c (no water added) 14b
d
27b
18b
43
10a
10b
6
7
8
1c
d
10c
no reaction
hydrolysis of
43b
2a or 2b a, b, c, or d
2a
e
3-acetate only
9
10
11
12
2a
3a
3a
3a
g
a
d
16a
15
11a
11b
34b
32
75b
23
12
44b
27
27
9b
e (K2CO3)
13b
13
14
3b
3b
d
f
11a
11b
13b
15
16
4b
5
g
f
17
18
10d
5
61
26
12
12d
16b
17
6
f
17 + products
not analyzed
a
Key: (a) AgBF4, THF, reflux; (b) AgBF4, glyme, H2O, reflux;
(c) AgBF4, DMF, H2O, reflux; (d) aq NH3, n-BuOH, reflux; (e)
Na2CO3, H2O, n-BuOH, reflux; (f) KOH, H2O, glycol, 120 °C; (g)
b
KOH, H2O, glycol, reflux. The unreacted starting material was
recovered (or product of its hydrolysis).
that the hydroxy group in these compounds is tertiary.11
The reaction of 23R-bromosarsasapogenin acetate (3a )
with aqueous ammonia in refluxing n-butanol was slightly
(11) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; J ohn Wileley & Sons: New York, 1991; Chapter 2.
6918 J . Org. Chem., Vol. 67, No. 20, 2002

Solvolysis of 23-Spirostanyl Bromides and Tosylates
SCHEME 4
TABLE 2. Ca lcu la ted Ster ic En er gies (k ca l/M) for Eigh t
Ster eom er s of Bisfu r a n s in th e Hecogen in (25R) a n d
Sa r sa sa p ogen in (25S) Ser iesa
conditions resulted in the formation of the fragmentation
product, lactone 14a .12
The solvolytic reactions of the equatorial bromides and
tosylates were also performed in the more alkaline
medium (sodium carbonate or potassium hydroxide was
used as a base). It was found that the reaction rates do
not depend on the basicity of the medium. However, when
a stronger base was used, a new product (12 or 13) was
formed in addition to the described earlier rearranged
products 10 or 11. In a separate experiment it was proved
that this slightly more polar product is formed by base-
catalyzed isomerization of the primary rearranged prod-
uct. Most likely the base forms the alkoxide of the
hemiacetal moiety of compounds 10 and 11, which opens
up (reversibly) to the corresponding 16-hydroxy-22-oxo
derivative allowing for epimerization at C22. Enolization
of the 22-ketone could then result in epimerization at C21
and/or C23. In the base-promoted equilibrium the most
stable product should prevail. A molecular modeling
performed for the compound 11b equilibration revealed
that of the eight isomeric structures taken into consid-
eration, the most stable are the 20S,22R,23R isomer 13b
and the starting compound 11b (Table 2). Similar results
were obtained for the 25R series with the hecogenin
skeleton. A conclusion could be drawn from these results
that the base-catalyzed epimerization took place at C23
during the reaction. To confirm this conclusion com-
pounds 11a and 13a were subjected to sodium borohy-
dride reduction (Scheme 4). In both cases mixtures of
epimers at C22 were obtained. However, the two pairs
of epimeric diols (19 + 20 and 21 + 22) were not identical,
proving that structures 11a and 13a differ in their
configurations at C20 or C23, not at C22. To distinguish
between these two possibilities both compounds were
stereomer
25R series
25S series
20R,22R,23R
20R,22R,23S
20R,22S,23R
20S,22R,23R
20R,22S,23S
20S,22R,23S
20S,22S,23R
20S,22S,23S
66.58
67.80
68.88
66.03
67.64
66.99
63.19 (10b)
63.28 (12b)
65.58
65.43
66.12
64.17
65.37
64.15
61.35 (11b)
60.31 (13b)
a
HyperChem, Release 5.01 for Windows from Hypercube, Inc.;
minimizations employed the MM+ force field and the Polak-
Ribiere algorithm with RMS gradient 0.001 kcal/Å‚M.
then oxidized with PCC. The reactions were highly
efficient (about 90% yield) and led to the same lactone
15. This proves that 11a and 13a have the same
configuration (S) at C20 and differ, by elimination, in
configuration at C23.
The solvolytic reactions of the axial 23-spirostanyl
bromides and tosylates were also studied (Scheme 5).
These compounds were found to be much less reactive
when compared with the equatorial 23-epimers, proving
that there is no assistance from electrons of the C22-
O(16) bond. Bromide 2a and tosylate 2b were recovered
unchanged from the reaction mixtures. Only when drastic
conditions were used (KOH, glycol, reflux) slow elimina-
tion to the olefin 16a was observed. In the case of the
axial tosylate 4b with a 25S configuration the reaction
also required forced conditions and the olefin 17 was
accompanied by a minor product, which was identified
as 18, an expected product of rearrangement. It was
formed by migration of the C22-O(16) bond to C23
followed by water addition. In this case the hemiketal
form is less stable than the open-chain hydroxy-ketone
18. However, this product was formed in 5% yield only
(12) Balakrishnan, P.; Bhattacharyya, S. C. Ind. J . Chem. 1975, 13,
212-214.
J . Org. Chem, Vol. 67, No. 20, 2002 6919

Anulewicz-Ostrowska et al.
SCHEME 5
and the reaction was much slower than that of the
equatorial tosylate 3b. The most likely explanation is
that the electrons of the C22-O(16) bond do not partici-
pate in the reaction and products are formed through a
carbocation at C23 (SN1 mechanism). The configuration
(S) of compound 18 at C20 was unequivocally established
reaction of tosylhydrazone 6 afforded a complex mixture
consisting of olefin 17 and several other products that
were not analyzed.
1
The H NMR spectra of compounds described in this
paper were briefly studied (Table 3). It is clear from the
spectra that the starting bromides and tosylates prefer-
ably exist in the usual “prone” conformation A (Scheme
6). The alternative “upright” conformation B suffers from
the strong interaction of the 20-methyl group and the
hydrogen atoms on C24 and C26.7a Molecular modeling
indicates that such a conformation is rather unlikely
(steric energy is at least 5 kcal/mol higher) and even in
the case of compound 4b there is no spectral evidence of
its occurrence. Both the 23-tosylate and the 27-methyl
group of 4b occupy axial (probably slightly disturbed)
positions despite the 1,3-diaxial interaction. Compounds
with rearranged structure (10-13) are relatively easy to
distinguish by the significant downfield shift of their
16R-H signals (they appear in the range of δ 4.59-4.67
ppm compared to δ 4.34-4.45 ppm for the starting
compounds). Geminal coupling constants of the 26-
protons for compounds with five-membered rings are
smaller (J gem ) 7.4-8.0 Hz) than those in the starting
bromides or tosylates (J gem ) 11.1-11.4 Hz). The signals
are well separated (∆δ ) 0.55-0.70 ppm) and resemble
triplets. The signals of 23-H appear in the narrow range
of δ 3.93-4.02 ppm as triplets or doublets of doublets.
1
by analysis of its H NMR spectra, particularly selective
1D NOE. Upon irradiation of 20-H, a 2.2% enhancement
of the 18-H singlet at δ 1.00 and a 0.9% enhancement of
the 21-H doublet at δ 0.96 were observed. This proved
that the 18-methyl protons are close to the proton at C20.
The proton occupies a pseudoaxial position as can be
concluded from its coupling constant J 17R,20 ) 9.8 Hz. The
molecular modeling of compound 18 shows that the six-
membered ring E exists in the boat form with the oxygen
and C20 atoms located above the plane. The four-carbon
atom side chain at C23 is presumably pseudoequatorial
(23R configuration) since it is more stable by about 2 kcal/
mol than the 23S epimer. The side chain rotates rapidly
around the C23-C24 bond and for this reason 23-H comes
out as a triplet at δ 3.79 with an averaged coupling
constant J 23,24 ) 6.2 Hz.
The reactions of tosylhydrazones 5 and 6 were also
briefly examined. Decomposition of 5 under basic condi-
tions afforded olefin 16b and both rearranged products
of different configuration at C23: 10d and 12d . The olefin
that is probably formed via a carbene intermediate
becomes the main product under aprotic conditions
(diglyme), the yield falling as the solvent becomes more
hydroxylic in character. In hydroxylic solvents tosyl-
hydrazone decomposes to afford the C23 carbocation that
undergoes rearrangement to the more stable C22 car-
bocation. The primary product 10d partially isomerizes
to 12d under the basic reaction conditions. The analogous
Con clu sion s
Equatorial 23-bromides and 23-tosylates are much
more reactive than their axial epimers and readily
undergo the highly stereoselective rearrangement to the
bisfuran products. A concerted mechanism is suggested
6920 J . Org. Chem., Vol. 67, No. 20, 2002

Solvolysis of 23-Spirostanyl Bromides and Tosylates
TABLE 3. P r oton Ch em ica l Sh ifts δ (p p m ) a n d Cou p lin g Con sta n ts J (Hz) Mea su r ed in CDCl3 a t 25 °C Ca r r yin g
Str u ctu r a lly Releva n t In for m a tion
proton
compd
16-H
18-H
19-H
21-H
23-H
26-H (ax)
26-H (eq)
3.49 (dd)
J gem ) 11.2; J ea ) 5.0
3.58 (dd)
J gem ) 11.4; J ea ) 5.0
3.29 (dd)
27-H
1a
4.34 (m) 1.17 (s) 0.93 (s) 1.03 (d) 4.10 (dd)
3.41 (t)
J gem ) J aa ) 11.2
3.45 (t)
J gem ) J aa ) 11.4
3.99 (dd)
J gem ) 11.1; J ae ) 2.6
3.85 (dd)
J gem ) 11.2; J ae ) 2.8
3.95 (dd)
0.83 (d)
J ) 6.6
0.82 (d)
J ) 6.7
1.13 (d)
J ) 6.9
J aa ) 12.3; J ae ) 4.5
2a
4.44 (m) 1.10 (s) 0.93 (s) 1.31 (d) 4.09 (t)
J ) 7.0 J ea ) J ee ) 3.1
4.41 (m) 0.88 (s) 0.99 (s) 0.97 (d) 4.31 (dd)
J ) 7.0 J aa ) 12.8; J ae ) 4.7
4.38 (m) 0.75 (s) 0.98 (s) 0.83 (d) 4.60 (dd)
3a
J gem ) 11.1; J ee ) ∼1.2 J ) 7.2
3b
3.18 (br d)
J gem ) 11.2
3.34 (br d)
J gem ) 11.2
3.91 (t)
1.06 (d)
J ) 7.3
1.15 (d)
J ) 7.2
1.05 (d)
J ) 6.5
1.06 (d)
J ) 6.7
1.02
J ) 6.8
1.04 (d)
J ) 6.9
1.07 (d)
J ) 6.7
J ) 7.0
J aa ) 12.3; J ae ) 5.2
4b
4.43 (m) 0.54 (s) 0.97 (s) 1.01 (d) 4.36 (t)
J ) 7.0 J ea ) J ee ) 3.0
4.60 (m) 1.06 (s) 0.90 (s) 1.13 (d) 3.99 (dd)
J ) 6.9
4.67 (m) 0.78 (s) 0.84 (s) 1.11 (d) 4.01 (dd)
J ) 6.7 J trans ) 8.9; J cis ) 6.7 J trans ) 9.3; J gem ) 7.8
4.63 (m) 0.78 (s) 0.98 (s) 1.03 (d) 4.02 (t) 4.01 (dd)
J ) 6.9 J trans ) J cis ) 8.7
4.59 (m) 1.09 (s) 0.91 (s) 1.19 (d) 3.96 (t)
J gem ) 11.2; J ae ) 3.2
3.35 (dd)
10b
10d
11a
12b
13b
J trans ) 9.0; J cis ) 6.7 J trans ) 9.5; J gem ) 7.8
3.37 (dd)
J gem ) J cis ) 7.8
3.92 (t)
J gem ) J cis ) 7.8
3.31 (dd)
J trans ) 10.4; J gem ) 8.0 J gem ) 8.0; J cis ) 7.1
4.02 (t)
J gem ) J trans ) 7.4
3.36 (dd)
3.42 (dd)
J gem ) 7.4; J cis ) 5.9
4.02 (t)
J ) 6.9
J trans ) J cis ) 7.7
4.65 (m) 0.78 (s) 0.98 (s) 1.06 (d) 3.93 (dd)
J ) 7.0
J trans)10.7; J cis ) 5.2 J trans ) 9.0; J gem ) 8.0
J gem ) J cis ) 8.0
SCHEME 6
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. Routine
NMR spectra were taken at 200 MHz in CDCl3. Spectra
available as Supporting Information were measured at 25 °C
at 500 MHz. Infrared spectra were recorded in chloroform.
Mass spectra were obtained at 70 eV. The reaction products
were isolated by column chromatography performed on 70-
230 mesh silica gel. Thin-layer chromatograms were developed
on aluminum TLC sheets precoated with silica gel F254 and
visualized with 50% sulfuric acid after heating. All solvents
were dried and freshly distilled prior to use.
Determination of the crystal structure of 11a was performed
on a diffractometer applying graphite-monochromated Mo KR
radiation. The details of X-ray measurements, structural
computations, and crystal data are given in the Supporting
Information.
Br om in a tion P r oced u r e (Syn th esis of 1a , 2a , a n d 3a ).
To a stirred solution of hecogenin acetate 1d (about 5 g; 12
mmol) in glacial acetic acid (150 mL) was added dropwise a 1
M solution of bromine in glacial acetic acid (12 mL) at room
temperature. After completion of bromination (disappearance
of a bromine color) the reaction mixture was poured into water,
neutralized with NaHCO3, and extracted with chloroform. The
extract was dried over magnesium sulfate and solvent was
evaporated in vacuo. The reaction resulted in the formation
of a mixture of bromides 1a and 2a in the ratio 3:1 (81%),
respectively. Bromides 1a and 2a were separated by fractional
crystallization of the mixture from hexane/dichloromethane.
The products were identical with respective bromides described
in the literature.7 A full characterization of these compounds
is given therein, including melting points, IR and 1H NMR;
also X-ray crystallographic data of their close relatives are
available.7a
Similar bromination of sarsasapogenin acetate 3c was
performed at slightly higher temperature (35 °C). A single
bromide 3a was obtained in 78% yield, identical in all respects
with the compound described in the literature.7a
Syn th esis of Tosyla tes (1b, 2b, 3b, a n d 4b). 23-Oxo-
sarsasapogenin acetate (9; 1.04 g, 2.2 mmol) was reduced with
0.4 g of sodium borohydride in methanol (8 mL) and dioxane
(6 mL). The crude reaction product was dissolved in anhydrous
pyridine (20 mL) and p-tosyl chloride (0.5 g, 2.6 mmol) was
added. The reaction mixture was stirred overnight at room
temperature, poured into an aqueous solution of cupric sulfate,
and extracted with chloroform. The extract was dried over
for bisfuran formation consisting of simultaneous depar-
ture of a leaving group and shift of an oxygen atom from
C20 to C22, followed by addition of water to the stabilized
carbocation. Most likely the migration of the neighboring
C22-O(26) bond commences when the leaving group is
still weakly bonded. This mechanism implies inversion
of configuration at C23. In the case of axial tosylate 4b
involvement of the neighboring electrons begins only
when the positive charge at C23 reaches a value greater
than in the transition state, so that although no anchi-
meric assistance is observed, the product 18 is formed
by migration of the C22-O(16) bond placed trans to the
leaving group. The described rearrangement is fully
stereoselective but the primary products may undergo
equilibration under the basic reaction conditions. The
rearrangement also takes place when a highly reactive
carbocation is generated at C23 by the tosylhydrazone
decomposition.
J . Org. Chem, Vol. 67, No. 20, 2002 6921

Anulewicz-Ostrowska et al.
magnesium sulfate and solvent was evaporated in vacuo. Silica
gel column chromatography with hexane-ethyl acetate (93:
7) elution afforded 23R,25S-5â-spirostane-3â,23-diol 3-acetate
23-tosylate (4b ; 0.44 g, 32%) and 23S,25S-5â-spirostane-
3â,23-diol 3-acetate 23-tosylate (3b; 0.65 g, 47%).
hexane-ethyl acetate (93:7), mp 279-283 °C; IR, νmax 1728,
1708, 1255, 1026, 965 cm-1; 1H NMR, δ 4.62 (1H, m), 4.53 (1H,
m), 3.77 (1H, def. t, J ) 10.9 Hz), 3.63 (1H, m), 2.78 (1H, m),
2.03 (3H, s), 1.06 (3H, s), 1.03 (3H, d, J ) 6.9 Hz), 0.94 (3H, d,
J ) 6.7 Hz), 0.92 (3H, s); 13C NMR, δ 212.9 (C), 201.6 (C), 170.6
(C), 109.8 (C), 81.7 (CH), 73.1 (CH), 65.7 (CH2), 55.8 (CH), 55.5
(C), 55.4 (CH), 53.1 (CH), 45.2 (CH2), 44.5 (CH), 37.6 (CH2),
36.3 (CH2), 36.1 (C), 35.5 (CH), 35.4 (CH), 34.3 (CH), 33.8
(CH2), 31.4 (CH2), 31.1 (CH2), 28.1 (CH2), 27.2 (CH2), 21.4
(CH3), 17.1 (CH3), 15.8 (CH3), 13.0 (CH3), 11.9 (CH3); EI-MS,
m/z (%) 458 (M+ - H2O, 49), 404 (95), 386 (100), 357 (17); HR
ES-MS calcd for C29H42O6Na 509.2879, found 509.2853.
Compound 4b: mp 177-178 °C; IR, νmax 1724, 1450, 1178,
1027 cm-1; 1H NMR, δ 7.80 (2H, d, J ) 8.3 Hz), 7.34 (2H, d, J
) 8.3 Hz), 5.06 (1H, m), 4.43 (1H, m), 4.36 (1H, t, J ) 3.0 Hz),
3.95 (1H, dd, J ) 11.2, 3.2 Hz), 3.34 (1H, d, J ) 11.2 Hz), 2.44
(3H, s), 2.03 (3H, s), 1.15 (3H, d, J ) 7.2 Hz), 1.01 (3H, d, J )
7.0 Hz), 0.97 (3H, s), 0.54 (3H, s); 13C NMR, δ 213.3 (C), 170.6
(C), 129.9 (CH × 2), 128.1 (CH × 2), 81.8 (CH), 73.5 (CH), 70.9
(CH), 70.8 (C), 64.1 (CH2), 61.6 (CH), 56.6 (CH), 40.4 (CH2),
40.2 (CH), 37.5 (CH), 36.2 (CH), 35.5 (CH), 32.6 (CH2), 31.8
(CH2), 30.99 (CH2), 30.8 (CH2), 30.6 (C), 30.1 (CH), 29.9 (C),
26.6 (CH2 × 2), 25.2 (CH2), 24.1 (CH3), 21.9 (CH3), 21.8 (C),
21.7 (CH3), 21.1 (CH2), 17.2 (CH3), 16.6 (CH3), 13.7 (CH3); EI-
MS, m/z (%) 456 (M+ - TsOH, 100), 396 (4), 389 (16), 255 (34),
141 (54).
En tr y 3: To a solution of 1a (250 mg, 0.45 mmol) in DMF
(15 mL) and water (3 mL) was added silver tetrafluoroborate
(174 mg, 0.9 mmol). The mixture was refluxed for 4 days,
poured into water, and extracted with chloroform. Pure
bisfuran 10a (140 mg, 63%) was obtained by silica gel column
chromatography with hexane-ethyl acetate (65:35) elution, mp
1
151-154 °C; IR, νmax 3392, 1723, 1706, 1254, 1033 cm-1; H
Compound 3b: mp 154-156 °C; IR, νmax 1724, 1451, 1176,
NMR, δ 4.63 (2H, m), 3.98 (1H, dd, J ) 8.8, 6.6 Hz), 3.91 (1H,
t, J ) 7.4 Hz), 3.34 (1H, dd, J ) 9.3, 8.0 Hz), 3.20 (1H, bs),
2.54 (1H, dd, J ) 8.8, 6.5 Hz), 2.02 (3H, s), 1.13 (3H, d, J )
1
969 cm-1; H NMR, δ 7.80 (2H, d, J ) 8.3 Hz), 7.34 (2H, d, J
) 8.3 Hz), 5.06 (1H, m), 4.60 (1H, dd, J ) 12.3, 5.2 Hz), 4.38
(1H, m), 3.85 (1H, dd, J ) 11.2, 2.8 Hz), 3.18 (1H, d, J ) 11.2
Hz), 2.45 (3H, s), 2.04 (3H, s), 1.06 (3H, d, J ) 7.3 Hz), 0.98
(3H, s), 0.83 (3H, d, J ) 7.0 Hz), 0.75 (3H, s); 13C NMR, δ 213.3
(C), 170.6 (C), 129.9 (CH × 2), 128.2 (CH × 2), 82.3 (CH), 79.5
(CH), 70.9 (CH), 70.8 (C), 64.8 (CH2), 64.1 (CH), 56.7 (CH),
40.7 (CH), 40.2 (CH), 39.8 (CH2), 39.7 (C), 37.5 (CH), 35.6 (CH),
32.0 (CH2), 31.2 (CH2), 30.9 (CH2), 30.85 (C), 30.8 (CH2), 26.6
(CH2 × 2), 25.9 (CH), 25.2 (CH2), 24.1 (CH3), 21.8 (CH3), 21.75
(C), 21.7 (CH3), 20.9 (CH2), 19.4 (CH3), 16.1 (CH3 × 2); EI-
MS, m/z (%) 456 (M+ - TsOH, 100), 396 (9), 390 (7), 255 (36),
141 (90).
6.9 Hz), 1.06 (3H, s), 1.04 (3H, d, J ) 6.4 Hz), 0.91 (3H, s); 13
C
NMR, δ 213.2 (C), 170.6 (C), 109.6 (C), 81.8 (CH), 80.1 (CH),
74.9 (CH2), 73.1 (CH), 55.5 (C), 55.4 (CH), 55.3 (CH), 53.4 (CH),
44.4 (CH), 38.9 (CH), 37.6 (CH2), 36.2 (CH2), 36.1 (C), 34.9
(CH), 34.6 (CH2), 34.3 (CH), 33.8 (CH2), 31.4 (CH2), 31.1 (CH2),
28.1 (CH2), 27.2 (CH2), 21.4 (CH3), 16.4 (CH3), 16.0 (CH3), 14.2
(CH3), 11.8 (CH3); EI-MS, m/z (%) 470 (M+ - H2O, 100), 455
(6), 403 (14), 385 (10). Anal. Calcd for C29H44O6: C, 71.28; H,
9.08. Found: C, 70.98; H, 9.10.
En tr y 4: To a solution of 23S,25R-23-bromo-5R-spirostane-
3â,12â-diol diacetate (1c; 40 mg, 0.067 mmol) in DMF (10 mL)
was added silver tetrafluoroborate (25 mg, 0.13 mmol). The
mixture was refluxed for 3 days, poured into water, and
extracted with chloroform. Pure product 14b (8 mg, 27%) was
eluted from a silica gel column with hexane-ethyl acetate (82:
18).
Similar reduction of 25R-5R-spirostane-3â,12â-diol-23-one
diacetate (8) with sodium borohydride followed by tosylation
yielded compounds 2b and 1b in the ratio of 10:1.
Syn th esis of Tosylh yd r a zon es (5 a n d 6). To a solution
of 25R-5R-spirostane-3â,12â-diol-23-one diacetate (8; 1.25 g;
2.3 mmol) in anhydrous ethanol (36 mL) was added tosyl-
hydrazine (0.55 g; 2.9 mmol). The reaction mixture was
refluxed for 1.5 h, poured into water, and extracted with
benzene. The extract was dried over magnesium sulfate and
solvent was evaporated in vacuo. Pure tosylhydrazone (5; 1.26
g, 77%), mp 105-107 °C, was obtained by silica gel column
chromatography with hexane-ethyl acetate (82.5:17.5) elution.
Tosylhydrazone 6 was obtained from 23-oxo-sarsasapogenin
acetate (9) in a similar way.
En tr y 5: To a solution of 1a (200 mg, 0.36 mmol) in
n-butanol (50 mL) was added aqueous ammonia (7 mL). The
mixture was refluxed for 7 days. A 5-mL portion of aqueous
ammonia was added every day. The solvents were evaporated
in vacuo. Pure products 10a (310 mg, 18%) and 10b (70 mg,
43%), mp 169-172 °C, were eluted from a silica gel column
with hexane-ethyl acetate 65:35 and 20:80, respectively.
En tr y 6: Compound 1c yielded 10c (43%), mp 152-154 °C,
under similar conditions.
Solvolytic Rea ction s of 23S,25R-23-Br om id es 1a a n d
1c. En tr y 1: To a solution of 23S,25R-23-bromo-5R-spirostan-
3â-ol-12-one acetate (1a ; 250 mg, 0.45 mmol) in dry THF (15
mL) was added silver tetrafluoroborate (174 mg, 0.9 mmol).
The mixture was refluxed for 24 h, poured into water, and
extracted with chloroform. The extract was dried over mag-
nesium sulfate and solvent was evaporated in vacuo. Pure
lactone 14a (144 mg, 79%) was obtained by silica gel column
chromatography with hexane-ethyl acetate (75:25) elution, mp
220-223 °C; IR, νmax 1765, 1720 (shoulder), 1708, 1255, 1182,
Solvolyt ic R ea ct ion s of 23R,25R-23-Br om id e 2a a n d
Tosyla te 2b. En tr y 7: There was no reaction of 2a or 2b with
silver tetrafluoroborate or aqueous ammonia (conditions a-d).
En tr y 8: Reaction of 2a with a solution of sodium carbonate
in n-butanol-water at reflux resulted in hydrolysis of the
3-acetate group only.
En tr y 9: Compound 2a (126 mg) was dissolved in ethylene
glycol (20 mL) and a solution of KOH (20 mg) in 3 mL of water
was added. The reaction mixture was heated for 3 days at
reflux. Then it was poured into water and extracted with
dichloromethane. The extract was washed with water several
times, dried (anhydrous MgSO4), and evaporated in vacuo.
Chromatography of the crude product afforded olefin 16a
eluted with hexane-ethyl acetate 60:40, in addition to the
hydrolyzed starting bromide. Compound 16a : mp 245-247 °C;
1
1031 cm-1; H NMR, δ 4.89 (1H, m), 4.67 (1H, m), 2.59 (2H,
m), 2.02 (3H, s), 1.39 (3H, d, J ) 7.5 Hz,), 1.06 (3H, s), 0.92
(3H, s); 13C NMR, δ 212.3 (C), 180.7 (C), 170.6 (C), 80.8 (CH),
73.0 (CH), 55.7 (C), 55.5(CH), 53.9 (CH), 50.8 (CH), 44.4 (CH),
37.2 (CH2), 36.6 (CH), 36.2 (CH2), 36.1 (C), 34.1 (CH), 33.7
(CH2), 32.4 (CH2), 31.3 (CH2), 27.9 (CH2), 27.1 (CH2), 21.3
(CH3), 17.2 (CH3), 13.8 (CH3), 11.8 (CH3); EI-MS m/z (%) 402
(M+, 6), 342 (100), 288 (16). HR-MS calcd for C24H34O5
402.2406, found 402.2390. Anal. Calcd for C24H34O5: C, 71.61;
H, 8.51. Found: C, 71.45; H, 8.40.
En tr y 2: To a solution of 1a (250 mg, 0.45 mmol) in glyme
(15 mL) and water (3 mL) was added silver tetrafluoroborate
(174 mg, 0.9 mmol). The mixture was refluxed for 4 days,
poured into water, and extracted with chloroform. Pure ketone
7 (160 mg, 72%) was eluted from silica gel column with
1
IR, νmax 3605, 3455, 1703, 1077, 1043, 979 cm-1; H NMR, δ
5.88 (1H, d, J ) 10.0 Hz), 5.54 (1H, dd, J ) 10.0, 2.5 Hz), 4.45
(1H, m), 3.69 (1H, m), 3.60 (1H, m), 3.45 (1H, t, J ) 10.9 Hz),
2.61 (1H, dd, J ) 8.7, 7.0 Hz), 1.09 (3H, s), 1.02 (d, J ) 7.0
Hz), 0.91 (3H, s), 0.89 (d, J ) 7.2 Hz); 13C NMR, δ 213.2 (C),
137.2 (CH), 126.1 (CH), 107.1 (C), 80.1 (CH), 70.9 (CH), 65.4
(CH2), 55.7 (CH), 55.5 (CH), 55.2 (C), 53.6 (CH), 44.6 (CH),
42.4 (CH), 37.82 (CH2), 37.78 (CH2), 36.5 (CH2), 36.1 (C), 34.3
(CH), 31.5 (CH2), 31.2 (CH2), 31.1 (CH2), 29.0 (CH), 28.2 (CH2),
6922 J . Org. Chem., Vol. 67, No. 20, 2002

Solvolysis of 23-Spirostanyl Bromides and Tosylates
16.0 (CH3), 15.7 (CH3), 13.2 (CH3), 11.9 (CH3). Anal. Calcd for
× 2), 23.9 (CH3), 20.9 (CH2), 18.0 (CH3), 16.5 (CH3), 14.3 (CH3).
Anal. Calcd for C27H42O3: C, 78.21; H, 10.21. Found: C, 77.95;
H, 10.20. Compound 18: mp 136-139 °C;1H NMR, δ 4.12 (2H,
m), 3.92 (1H, dd, J ) 14.6, 8.1 Hz), 3.78 (1H, t, J ) 6.2 Hz),
3.53 (1H, dd, J ) 11.1, 5.0 Hz), 3.45 (1H, dd, J ) 11.1, 6.5
Hz), 2.81 (1H, dq, J ) 10.3, 6.4 Hz), 2.22 (1H, m), 1.07 (3H, d,
J ) 6.4 Hz), 1.00 (3H, s), 0.99 (3H, s), 0.96 (3H, d, J ) 6.9
Hz,); 13C NMR, δ 217.6 (C), 81.6 (CH), 78.8 (CH), 67.5 (CH2),
67.0 (CH), 57.4 (CH), 53.1 (CH), 43.0 (C), 40.4 (CH2), 39.8 (CH),
39.3 (CH), 36.5 (CH2), 36.4 (CH), 35.2 (CH), 33.5 (CH2), 32.9
(CH2), 32.7 (CH and C), 29.9 (CH2), 27.8 (CH2), 26.52 (CH2),
26.48 (CH2), 23.9 (CH3), 20.9 (CH2), 16.9 (CH3), 14.8 (CH3),
12.5 (CH3). Anal. Calcd for C27H44O4: C, 74.96; H, 10.25.
Found: C, 75.09; H, 10.20.
Solvolysis of 25R-23-Tosylh yd r a zon e 5. En tr y 16: (25R)-
3â,12â-Diacetoxy-5R-spirostan-23-one tosylhydrazone (5; 322
mg) was dissolved in ethylene glycol and a 10% aqueous
solution of KOH (6 mL) was added. The reaction mixture was
heated 1 h under reflux at 120 °C, poured into water, and
extracted with benzene. The extract was washed with water,
dried with anhydrous MgSO4, and evaporated in vacuo and
the residue was chromatographed on a silica gel column with
hexane-ethyl acetate (from 50% to 70%) elution. Olefin 16b
(mp 78-79 °C, yield 12%) and rearranged products of different
configuration at C23, 10d (mp 149-151 °C, yield 61%) and
12d (mp 69-70 °C, yield 26%), were consecutively eluted.
Oxid a tion of Bisfu r a n s to th e La cton es. To a solution
of 10a (24.7 mg, 0.05 mmol) in dry CH2Cl2 was added
pyridinium chlorochromate (105 mg, 0.5 mmol). The reaction
mixture was stirred 3 days at room temperature and filtered
through a silica gel column with hexane-ethyl acetate (75:
25) elution. Lactone 14a obtained in 95% yield was proved
identical with compound 14a described in entry 1.
C
27H40O4: C, 75.66; H, 9.41. Found: C, 75.55; H, 9.40.
Solvolytic Rea ction s of 23S,25S-23-Br om id e 3a a n d
Tosyla te 3b. En tr y 10: The reaction of 3a with silver
tetrafluoroborate in THF at reflux was performed in the same
way as described for 1a (entry 1). Lactone 15, mp 163-165
°C, was obtained in 32% yield in addition to the unreacted
starting material. Compound 15: IR, νmax 1759, 1724, 1263,
1027 cm-1; 1H NMR, δ 5.07 (1H, m), 4.94 (1H, dt, J ) 7.7, 4.6
Hz), 2.58 (1H, q, J ) 7.6 Hz), 2.27 (1H, m).
En tr y 11: To a solution of 3a (160 mg, 0.29 mmol) in
n-butanol (50 mL) was added aqueous ammonia (7 mL). The
mixture was refluxed for 7 days. An additional portion of
aqueous ammonia (5 mL) was added every second day. The
solvents were evaporated in vacuo. The silica gel column
chromatography afforded pure 11a (105 mg, 75%) eluted with
hexane-ethyl acetate (80:20), mp 138-140 °C. IR, νmax 3538,
1
1724, 1264, 1239, 1025, 980 cm-1; H NMR, δ 5.04 (1H, m),
4.60 (1H, m), 4.01 (2H, m), 3.30 (2H, bs and t, J ) 7.6 Hz),
2.38 (1H, m), 2.00 (3H, s), 1.00 (6H, d, J ) 6.8 Hz), 0.96 (3H,
s), 0.75 (3H, s); 13C NMR, δ 170.6 (C), 109.6 (C), 81.6 (CH),
80.6 (CH), 75.3 (CH2), 70.6 (CH), 62.0 (CH), 56.2 (CH), 41.0
(C), 40.1 (CH2), 39.9 (CH), 38.2 (CH), 37.2 (CH), 35.2 (CH),
34.9 (CH2), 34.4 (CH), 33.8 (C), 31.7 (CH2), 30.7 (CH2), 30.5
(CH2), 26.3 (CH2 × 2), 24.9 (CH2), 23.8 (CH3), 21.4 (CH3), 20.8
(CH2), 17.7 (CH3), 16.4 (CH3), 15.4 (CH3); EI-MS, m/z (%) 456
(M+ - H2O, 9), 389 (35), 329 (100), 255 (87). Anal. Calcd for
C
29H46O5: C, 73.38; H, 9.77. Found: C, 73.15; H, 9.59.
En tr y 12: A solution of bromide 3a (178 mg) in 2 mL of
dichloromethane and 15 mL of n-butanol was treated with a
10% aqueous solution (5 mL) of potassium carbonate. The
reaction mixture was heated at reflux for 4 days. Then solvents
were evaporated in vacuo and the residue was chromato-
graphed on a silica gel column. Pure compounds 11b (36 mg,
23%), mp 145-147 °C, and 13b (19 mg, 12%), mp 75-77 °C,
were eluted with hexane-ethyl acetate (2:1). Compound 13b:
Oxidation of 12a with PCC afforded the same product.
Similar oxidation of compounds 11a and 13a to the corre-
sponding lactone 15 was also performed.
IR, νmax 3614, 3539, 1036, 1002 cm-1 1H NMR, δ 4.64 (1H,
;
Sod iu m Bor oh yd r id e Red u ction of Bisfu r a n s. Com-
pound 11a (67 mg, 0.14 mmol) was dissolved in dry THF and
NaBH4 (26 mg, 0.68 mmol) was added. The reaction mixture
was refluxed 3 h, poured into water, and extracted with
chloroform. Solvent was removed in vacuo from the dried
(anhydrous MgSO4) extract and the residue (a mixture of
products 19 and 20) was subjected to the chromatographic
separation on a silica gel column. Elution with ethyl acetate-
hexane (38:62) mixture afforded 20.6 mg (30.6%) of a less polar
product and 37.3 mg (55.4%) of a more polar product. Less
polar product: mp 197-200 °C; IR, νmax 3469, 1724, 1265, 1023
cm-1; 1H NMR, δ 5.07 (1H, narrow m), 4.43 (1H, m), 4.16 (1H,
dt, J ) 7.5, 3.1 Hz), 4.03 (1H, dd, J ) 8.3, 6.6 Hz), 3.70 (1H,
dd, J ) 8.7, 3.1 Hz), 3.31 (1H, dd, J ) 8.3, 7.4 Hz), 2.05 (3H,
s), 1.05 (3H, d, J ) 6.7 Hz), 0.97 (3H, s), 0.95 (3H, d, J ) 7.4
Hz), 0.90 (3H, s). More polar product: mp 170-171 °C; IR,
m), 4.08 (1H, m), 4.01 (1H, t, J ) 7.6 Hz), 3.91 (1H, dd, J )
10.7, 5.3 Hz), 3.34 (1H, m), 2.96 (1H, bs), 2.35 (1H, m), 1.05
(6H, d, J ) 6.6), 0.96 (3H, s), 0.79 (3H, s); 13C NMR, δ 108.6
(C), 83.8 (CH), 81.5 (CH), 75.3 (CH2), 66.9 (CH), 63.9 (CH),
56.4 (CH), 41.1 (C), 39.9 (CH2), 39.8 (CH), 37.7 (CH), 36.4 (CH),
35.8 (CH2), 35.3 (C), 35.1 (CH), 34.5 (CH2), 33.4 (CH2), 31.8
(CH2), 29.9 (CH2), 27.7 (CH2), 26.44 (CH2), 26.37 (CH2), 23.8
(CH3), 20.7 (CH2), 16.5 (CH3), 16.1 (CH3), 15.6 (CH3); EI-MS,
m/z (%) 414 (M+ - H2O, 99), 329 (20), 255 (51).
En tr y 13: The reaction of 3b with ammonia was performed
under conditions analogous to these described in entry 11.
Compound 11b was obtained in 44% yield in addition to the
unreacted starting material.
En tr y 14: To a solution of tosylate 3b (80 mg, 0.13 mmol)
in ethylene glycol (20 mL) was added a 10% solution of
potassium hydroxide in water. The reaction mixture was
stirred 1 h at 120 °C. Then it was poured into water and
extracted with dichloromethane. The reaction products were
separated by silica gel column chromatography to afford 11b
(19 mg, 27%) and 13b (19 mg, 27%).
ν
max 3435, 1724, 1265, 1023 cm-1; 1H NMR, δ 5.06 (1H, narrow
m), 4.37 (1H, m), 4.03 (1H, m), 3.95 (1H, dd, J ) 8.3, 3.1 Hz),
3.59 (1H, dd, J ) 7.3, 1.8 Hz), 3.33 (1H, dd, J ) 8.3, 6.1 Hz),
2.04 (3H, s), 1.04 (6H, d, J ) 6.9 Hz), 0.97 (3H, s), 0.89 (3H,
s).
Similar reduction of 13a with NaBH4 led to the mixture of
21 and 22.
Solvolysis of 23R,25S-23-Tosyla te 4b. En tr y 15: To a
solution of tosylate 4b (96 mg, 0.15 mmol) in ethylene glycol
(20 mL) was added a solution of potassium hydroxide (10%)
in water. The mixture was stirred 24 h at reflux. Compounds
17 (6 mg, 9%) and 18 (3.5 mg, 5%) were obtained by silica gel
column chromatography with hexane-ethyl acetate elution
(75:25 and 60:40, respectively). Compound 17: mp 144-146
Isom er iza tion of Bisfu r a n s. To a solution of 11b (60.8
mg; 0.14 mmol) in n-butanol (5 mL) was added a 10% aqueous
solution (5 mL) of potassium carbonate. The reaction mixture
was heated 6 days at reflux. After removal of the solvent in
vacuo, a residue was subjected to chromatographic separation
on a silica gel column. Compounds 11b (42.6 mg, 70%) and
13b (18.1 mg, 30%) were eluted with a hexane-ethyl acetate
(2:1) mixture.
1
°C; H NMR, δ 6.03 (1H, ddd, J ) 9.9, 4.2, 1.1 Hz), 5.53 (1H,
dd, J ) 9.9, 1.1 Hz), 4.53 (1H, m), 4.12 (1H, m), 4.05 (1H, dd,
J ) 11.1, 3.5 Hz), 3.48 (1H, d, J ) 11.1 Hz), 1.09 (3H, d, J )
7.0 Hz), 0.99 (3H, s), 0.94 (3H, d, J ) 4.3 Hz), 0.81 (3H, s); 13
C
Ack n ow led gm en t. Financial support from the State
Committee for Scientific Research, Poland (Grant No.
4 T09A 146 22), is gratefully acknowledged. We also
thank Mrs. M. Zdanowicz for skillful technical as-
NMR, δ 135.6 (CH), 126.5 (CH), 107.3 (C), 81.9 (CH), 67.1
(CH), 64.3 (CH2), 62.3 (CH), 56.5 (CH), 41.8 (CH), 40.9 (C),
40.3 (CH2), 39.8 (CH), 36.5 (CH), 35.3 (C), 35.2 (CH), 33.6
(CH2), 31.8 (CH2), 29.9 (CH2), 28.9 (CH), 27.8 (CH2), 26.5 (CH2
J . Org. Chem, Vol. 67, No. 20, 2002 6923

Anulewicz-Ostrowska et al.
pounds 1a , 2a , 3a , 3b, 4b, 10b, 10d , 11a , 12b, and 13b, crystal
data and structure refinement parameters for 11a , and an
ORTEP view of molecule 11a . This material is available free
of charge via the Internet at http://pubs.acs.org.
sistance and Mrs. J . Maj for help in preparation of the
manuscript.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra
recorded at 500 MHz, 1D TOCSY13 and 1D NOE14 measured
with selective excitation pulse, 2D TOCSY15 spectra of com-
J O020231J
6924 J . Org. Chem., Vol. 67, No. 20, 2002