Hydrogen atom transfer methodology for the synthesis of C-22, C-23, and C-25 stereoisomers of cephalostatin north 1 side chain from spirostan sapogenins

Article abstract of DOI:10.1016/j.tet.2005.01.077

A simple synthesis of all eight C-22, C-23, and C-25 diastereoisomers of the cephalostatin north 1 side chain has been accomplished from (25R)-5α-spirostan-3β-ol (tigogenin). The synthesis involves selective hydroxylations at C-23 and C-25 and reductive o

Full text of DOI:10.1016/j.tet.2005.01.077

Tetrahedron 61 (2005) 2803–2814
Hydrogen atom transfer methodology for the synthesis of C-22,
C-23, and C-25 stereoisomers of cephalostatin north 1 side chain
from spirostan sapogenins
b
Carmen Betancor, Raimundo Freire, Ines Perez-Martın, Thierry Prange and Ernesto Suarez
a
a
c
a,
*
´
´
´
´
´
a
´
Instituto de Productos Naturales y Agrobiologıa del C.S.I.C., Carretera de La Esperanza 3, 38206 La Laguna, Tenerife, Spain
b
´ ´
Departamento de Quımica Organica, Universidad de La Laguna, Tenerife, Spain
c
´
LURE, Universite Paris-Sud, Paris, 91405 Orsay Cedex, France
Received 12 November 2004; revised 18 January 2005; accepted 20 January 2005
Abstract—A simple synthesis of all eight C-22, C-23, and C-25 diastereoisomers of the cephalostatin north 1 side chain has been
accomplished from (25R)-5a-spirostan-3b-ol (tigogenin). The synthesis involves selective hydroxylations at C-23 and C-25 and reductive
opening of the 1,6-dioxaspiro[4.5]decane spirostan system to give a conveniently protected 5a-furostan-3b,23,25,26-tetrol. The construction
of the required 1,6-dioxaspiro[4.4]nonane system entailed an intramolecular hydrogen abstraction reaction promoted by the C-25 alkoxyl
radical as the key step. Acid-catalyzed isomerization of the spiroketal unit suggested that 22R isomers are the thermodynamic products while
the 22S isomers are the result of kinetic control. The acid-catalyzed equilibrium between 1,6-dioxaspiro[4.4]nonane and 1,6-
3
dioxaspiro[4.5]decane systems was also studied. In the 1,6-dioxaspiro[4.4]nonane units, the observed J23,24 coupling constants suggest
that the five-membered puckered ring-F undergoes substantial conformational changes on going from 22S to 22R isomers.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The syntheses of several of these natural products and
analogues have been achieved4 and during these studies
very interesting methodologies have been brought to light.5
Nevertheless, despite efforts by several research groups, the
mechanism of biological action remains unknown.6 The
structure-activity relationship between cephalostatins and
OSW-1 (Fig. 1), a related cholestane glycoside isolated
from a terrestrial plant (Ornithogalum saundersiae),7
supports the hypothesis that the bioactive intermediate
might be an oxocarbenium ion located at rings E or F and
originated by opening the dioxaspiro grouping.6,7b,8 We can
deduce from this that the stereochemistries at C-22, C-23,
and C-25, which doubtless have a strong influence on the
conformation and stability of the dioxaspiro[4.4]nonane
system, may also influence the activity of cephalostatins.
Cephalostatins1 and the structurally related ritterazines2
comprise a group of secondary metabolites isolated from
marine invertebrates (Cephalodiscus gilchristi and Ritter-
ella tokioka, respectively) which have attracted consider-
able attention from synthetic organic chemists and
pharmacologists due to their complex structures and
significant biological properties.3 They are alkaloids con-
stituted by two steroidal units linked through a pyrazine ring
involving the C2-C3 position of each monomeric unit and
are among the most potent cytotoxins ever isolated from a
natural source. In most of these substances the steroidal eight-
carbon side chain has been transformed into a 1,6-dioxaspiro
[4.4]nonane system. In particular, a polyoxygenated
(2S,4R,5S,9S)-2-hydroxymethyl-2,9-dimethyl-1,6-dioxaspiro
[4.4]nonan-4-ol substructure is found in the side chain of the
north unit in many cephalostatins (17 out of 19), and the
majority of ritterazines have a 2,2,9-trimethyl-1,6-diox-
aspiro[4.4]nonane system on one or other side of their
skeletons (Fig. 1).
With these ideas in mind, we decided to develop a simple
methodology to permit the synthesis of all eight possible
isomers of this system by modification of the steroidal side
chain of a commercially available spirostan sapogenin,9 the
key step being the formation of the spiroketal system by an
intramolecular hydrogen abstraction reaction (IHA) pro-
moted by alkoxyl radicals.10 In previous papers from this
laboratory we have demonstrated the utility of IHA
reactions in the synthesis of dioxaspiro[4.4]nonane ring
systems in the carbohydrate field.11 From this previous
Keywords: Cephalostatin; Radical reaction; Hydrogen abstraction; Alkoxyl
radical; Steroid; Spirostan sapogenin.
* Corresponding author. Tel.: C34 922 251004; fax: C34 922 260135;
e-mail: esuarez@ipna.csic.es
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.077

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C. Betancor et al. / Tetrahedron 61 (2005) 2803–2814
Scheme 1. Reagents and conditions: (a) NaNO2, BF3$Et2O, AcOH, rt, 1 h,
68%; (b) NaBH4, EtOH, rt, 1 h, 91% (3/4 ratio 5:95) or L-selectride, THF,
K20 8C, 1.5 h, 72% (3/4 ratio 63:37); (c) Ph2SiH2, TiCl4, CH2Cl2, K20 8C;
(d) pivaloyl chloride, Py, CH2Cl2, rt, 6-R 95%, 6-S 97%; (e) tBuMe2SiOTf,
CH2Cl2, Et3N, rt, 7-R 81%, 7-S 98%; (f) KOH, MeOH, rt, 8-R 92%, 8-S
91%; (g) o-NO2PhSeCN, n-Bu3P, THF, rt, 9-R 99%, 9-S 97%; (h) H2O2,
THF, rt, 10-R 92%, 10-S 82%; (i) OsO4, Py, CH2Cl2, rt; (j) Ac2O, Py, rt.
[For yields of the (i) and (j) reactions, see supplementary data section]. The
(R,S) designs the stereochemistry at C-23.
Figure 1. Examples of representative cephalostatins and reitterazines.
experience we were confident that both spiroketal isomers
could be obtained using this methodology. This is
synthetically important because in most of the ritterazines
both stereoisomers at the spiroketal center were obtained
from the natural source.12
those described (Scheme 1), the 23S isomer 4 was converted
into 10-S via 5-S, 6-S, 7-S, 8-S, and 9-S. Stoichiomeric
osmylation of the 10-R olefin afforded an inseparable
mixture of diols 11-R and 13-R which could be separated
after acetylation of the primary alcohol 12-R and 14-R in a
1:2 ratio (99%). In contrast, the osmylation of the 10-S
isomer afforded a separable mixture of diols 11-S and 13-S
in a 2:1 ratio (98%), which were subsequently and
separately acetylated to give 12-S and 14-S.
2. Results and discussion
The synthesis began with 3-methoxy-23-oxotigogenin (2)
(Scheme 1) prepared by using a previously described
procedure via oxidation of 3-methoxy-tigogenin (1) with
NaNO2/BF3$Et2O.13 The reduction of 2 with L-selectride
furnished a mixture of alcohols 3 and 4 (72%, 1.7:1) from
which the alcohol 3 with the correct natural orientation
(23R) could be obtained in moderate yield. The reduction of
2 with NaBH4 afforded preferentially the alcohol 4 (23S)
with the non-natural stereochemistry (91%, 19:1).
Initials attempts to asymmetrically dihydroxylate the 25-
olefin were unsuccessful.16 Using the Corey (1S,2S)-
N1,N2-bis(mesitylmethyl)-1,2-diphenyl-1,2-ethanediamine
reagent,17 the 10-R olefin gave the diols with similar yield
and diastereomeric ratio (11-R/13-R, 1:2, 97%) compared
with the uncatalyzed reaction. As both isomeric diols were
required for this study the uncatalyzed osmylation reaction
was preferred.
The two C-23 diastereoisomers 3 and 4 were taken through
the following steps of the synthesis separately (Scheme 1).
The tigogenin dioxaespiro[4.5]decane system present in 3
was regio- and stereoselectively reduced with Ph2SiH2/
TiCl4 to give the diol 5-R.14 Conversion of 5-R to the
monoprotected secondary alcohol 8-R was accomplished by
a three-step protection-deprotection sequence involving
formation of the primary pivalate 6-R, silylation of the 23-
alcohol with TBDMSOTf, and hydrolysis of pivalate 7-R
with KOH in methanol. Nitrophenylselenenylation of the
primary alcohol in 8-R followed by oxidative elimination
furnished alkene 10-R.15 In a series of reactions identical to
The IHA reaction was carried out by separately treating
compounds 12-R, 12-S, 14-R, and 14-S with (diacetoxyiodo)
benzene and iodine under irradiation with two 80 W
tungsten-filament lamps at 50 8C (Scheme 2). The alcohols
that possess the natural stereochemistry at C-23 (R) 12-R
and 14-R gave 1,6-dioxaspiro[4.4]nonane compounds 15

C. Betancor et al. / Tetrahedron 61 (2005) 2803–2814
2805
Scheme 2. Reagents and conditions: (a) PhI(OAc)2, I2, cyclohexane, hn, 70 8C, 15 23%, 16 60%; 20 28%, 21 55%; 25 23%, 26 74%; 30 28%, 31 47%; (b) (i)
TBAF, THF, rt, (ii) KOH, MeOH, rt (yields too steps: 17 62%, 18 73%, 22 74%, 23 70%, 27 67%, 28 87%, 32 99%, 33 91%); (c) HC, CH2Cl2, rt.
and 16 (83%, 28:72) and 20 and 21 (83%, 33:67), respec-
tively. On the other hand, the alcohols with the inverted
stereochemistry at C-23 (S) 12-S and 14-S afforded after the
IHA reaction dioxaspiro compounds 25, and 26 (97%,
24:76) and 30 and 31 (75%, 37:63), respectively. The
protecting groups of the alcohols at C-23 and C-25 were
selected to favor the 1,5-hydrogen atom transfer reaction. A
weak electron-withdrawing group (EWG) at C-23 (silyl
ether) should favor the hydrogen abstraction and the
subsequent oxidation of the C-22 radical to the oxocarbe-
nium ion intermediate.18 Also the stronger EWG at C-26
(acetyl ester) should prevent the competitive b-fragmentation
of the alkoxyl radical. The choice of the protecting group
could be critical and a hypothetical model where the two
protecting groups have been interchanged (acetyl at C-23
and silyl at C-26) should give significant amounts of the
methyl ketone from b-fragmentation.19 The desired diols
17, 18, 22, 23, 27, 28, 32, and 33 were obtained by
hydrolysis of the silyl and acetyl protective groups. The
structures of these eight stereoisomers of the cephalostatine
and HSQC experiments. Using 2D NOESY and DNOE, the
relative stereochemistry of the newly created stereogenic
centers (C-22 and C-25) with respect to the known
stereochemistry of the alcohol at C-23 may be assigned in
each case.20 As the flexibility of the 1,6-dioxaspiro system
(vide infra) may introduce some uncertainty in the NOE
results, the structure and stereochemistry were subsequently
confirmed by X-ray crystallographic analysis of compounds
18 and 23.21 The (22S,23R,25S)-diol 17 possesses the
stereochemistry of the natural cephalostatins. Compounds
17, 22, 27, and 32 appear to be the products of kinetic
control whereas 18, 23, 28, and 33 are the thermodynamic
products. The relative stability of these compounds was
determined by following the evolution of the acid-catalyzed
rearrangement through a C-22 oxocarbenium ion. Due to the
presence of the 25,26-glycol, dioxaspiro compounds of the
1,6-dioxaspiro[4.5]decane type (e.g. 19) may also be
formed.22
In a preliminary experiment, diol 17 was transformed into
the 22R-isomer 18 and both 17 and 18 finally led to the
dioxaspiro[4.5]decane 19 under prolonged acid treatment
north 1 side chain were determined by extensive 1H and 13
NMR 1D and 2D studies including DEPT, COSY, HMBC,
C

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C. Betancor et al. / Tetrahedron 61 (2005) 2803–2814
(Scheme 2). Subsequently, it was established that, in the
1,6-dioxaspiro[4.4]nonane system the 22S isomers 17, 22,
27, and 32 are easily transformed, under mild acid
conditions, into the 22R isomers 18, 23, 28, and 33,
respectively, confirming that the 22R are the most stable
compounds.
mol) and in consequence, an acid-catalyzed equilibrium
(ca. 60:40) is reached after extended periods of time.
Several other interesting features in the structure of these
compounds are shown in Table 1. For instance, compounds
with the same stereochemistry at C-23 display significantly
different coupling constants between the protons H23 and
H24 on changing from the 22R to the 22S series of
compounds (compare the coupling constant of 17 with 18
or 22 with 23 in which the stereochemistry at C-23 is always
R, or 27 with 28 and 32 with 33 where the stereochemistry is
23S). The small couplings (0, 5 Hz) suggest a pseudoaxial
orientation of the C-23 alcohol (e.g. 18) while the larger
couplings (8, 10 Hz) are more consistent with a pseudo-
equatorially disposed alcohol (e.g. 17).25 Nevertheless, a
reasonable explanation for this phenomenon is necessarily
associated with a change of the conformation of the
tetrahydrofuran F-ring on going from the 22S to 22R series
of compounds (Fig. 2). The study of the conformation of this
1,6-dioxaspiro ring system may not be an easy task due to
the significant flexibility of the puckered five-membered
rings, although, in this case, some conformational con-
straint, exerted by the substituents and the fused D-ring,
may be expected.26 In this approach we have determined the
conformations of the E- and F-rings of the eight different
The transformation from the dioxaspiro [4.4]nonane to the
[4.5]decane system deserves further comment.23 Although
compound 19 is obtained in moderate yield by acid-
catalyzed isomerization of diol 18, we observed that even
under prolonged reaction times neither 22 nor 23 yielded
the corresponding dioxaspiro[4.5]-compound 24 to any
appreciable extent. Furthermore, the reactions of 28 and 33
under similar conditions reach an equilibrium (28/29, 60:40
and 33/35, 66:34) after several hours at room temperature.
Aware that iodine is a Lewis acid, we also explored the
iodine-catalyzed isomerization of 22R-isomers and similar
results to those obtained with protic acids were achieved.
For example, reaction of diol 27 in cyclohexane with iodine
(10 mM) under the same conditions of the IHA reaction
afforded after 1 h at 70 8C the equilibrium mixture of 28 and
29 in a ratio of 60:40. Analogously, 32 was isomerized to a
mixture of 33 and 34 (60:40) under the same conditions.
These findings suggest that a possible iodine-catalyzed
partial isomerization between 22S and 22R isomers may
well have occurred during the IHA reaction. Partial
isomerization at the spirocenter may indeed be accom-
plished by treatment of fully protected compound 25 with
iodine under conditions emulating the IHA reaction, to give
a mixture of 25 and 26 (2:8) after 4 h at 70 8C.
These finding are in agreement with the results of a MM2
study (Table 1), compounds 17, 24, 27, and 32 being the
highest energy isomers in the respective series while 19, 23,
28, and 33 are the most stable.24 The isomeric pairs 28 and
29, and 33 and 34 have similar energy (DEZ0.4–0.6 Kcal/
Figure 2. Ring F conformations of 17 and 18, taken from the X-ray crystal
structures. For the sake of clarity only E and F rings are shown.
Table 1. Structural characteristics of dioxaspiro compounds
DEa (kcal/mol)
Pb (conformation)c
3J23,24 (Hz)
d
Compound
E-ring
F-ring
17
17 (X-ray)e
18
18 (X-ray)
19
6.8
—
3.4
—
134 (E16
)
)
)
146 (23T22
145 (23T22
)
)
8.1, 8.4
—
0.0, 5.7
—
2.8, 2.8
127 (E16
102 (oT16
93 (oE)
96 (oE)
339 (E23
332 (22T23
— (22C25
)
)
0.0
)
22
23
2.9
0.0
—
141 (17T16
)
)
)
155 (23E)
320 (22T23
324 (22T23
8.1, 9.8
0.0, 5.6
—
85 (oE)
)
)
23 (X-ray)
24
90 (oE)
4.3
99 (oE)
— (22C25
)
—
27
28
4.4
0.0
0.4
—
148 (17T16
144 (23T22
346 (E23)
)
0.0, 4.9
8.3, 10.5
5.3, 11.6
—
89 (oE)
29
29 (X-ray)
89 (oE)
— (22C25
)
)
80 (oT22
)
— (22C25
32
33
4.6
0.0
0.6
—
145 (17T16
153 (23T22
)
)
0.0, 4.6
8.5, 9.8
5.3, 11.7
—
85 (oE)
320 (22T23
34
34 (X-ray)
91 (oE)
— (22C25
— (22C25
)
)
72 (oT22
)
a Changes of the relative MM2 energy (in kcal/mol) with respect to the lowest energy isomer in the respective series.
b Altone-Sundaralingam phase angle (in degrees) as defined in Ref. 29c.
c An adaptation of the IUPAC nomenclature of carbohydrates is used (Ref. 30).
d Experimental 3JHH coupling from 500 MHz spectra.
e Data were taken from the X-ray analysis of (22S,23R,25S)-3b,12b-diacetoxy-22,25-epoxy-5a-furostan-23,26-diol (Ref. 27).

C. Betancor et al. / Tetrahedron 61 (2005) 2803–2814
2807
isomers over minimized structures (MM2) using the X-ray
structures 17,27 18, and 23 (X-ray) as starting geometry.28
With this study we are not attempting to make a complete
conformational analysis of the 1,6-dioxaspiro system, but
simply to explain the apparently anomalous coupling
constants observed for the proton at C-23.
biological activity, as occurs in other types of tetrahydro-
furan derivatives.29c,34 In any case, this should be taken into
consideration in the development of new biologically active
cephalostatin and ritterazin analogs.
Although we are aware that our conclusions regarding the
stability and conformation of the spiroketal side chain in the
different series of these simple monomers may not be fully
extrapolatable to the bioactive products, we believe that
they could help in designing such compounds.
The structures of lowest energy calculated by this
methodology have E- and F-ring conformations that were
very similar to those found in the crystallographic struc-
tures. A comparison of the conformations from the crystal
structure with those established by molecular mechanics
calculations is presented in Table 1 [compare 17 with 17
(X-ray), 18 with 18 (X-ray), and 23 with 23 (X-ray)]. The
ring conformations have been described by the Altone-
Sundaralingam phase angle29 and the IUPAC conformational
nomenclature for the furanose form of monosaccharides has
been adapted to these rings.30 The E-ring of the 22S-isomers
4. Experimental
4.1. General methods
Melting points were determined with a hot-stage apparatus
and are uncorrected. Optical rotations were measured at the
sodium line at ambient temperature in CHCl3 solutions. IR
spectra were recorded in CHCl3 solutions unless otherwise
(17, 22, 27, and 32) adopts a preferred conformation E16 or
17
T
16
(PZ134–1488) in the southern hemisphere of the
pseudorotational itinerary of the ring (Table 1).29 The E-ring
conformation in the 22R series of isomers (18, 23, 28, and
33) is located in the east oE (PZ102–858) of the
1
stated. NMR spectra were determined at 500 MHz for H
and 125.7 MHz for 13C in CDCl3 unless otherwise stated, in
the presence of TMS as internal standard. Mass spectra were
determined at 70 eV. Merck silica gel 60 PF (0.063–
0.2 mm) was used for column chromatography. Circular
layers of 1 mm of Merck silica gel 60 PF254 were used on a
Chromatotron for centrifugally assisted chromatography.
Commercially available reagents and solvents were ana-
lytical grade or were purified by standard procedures prior
to use. All reactions involving air- or moisture-sensitive
materials were carried out under a nitrogen atmosphere. The
spray reagents for TLC analysis were conducted with 0.5%
vanillin in H2SO4–EtOH (4:1) and further heating until
development of color.
pseudorotational wheel. On the other hand, the F-ring of
the 22S-isomers adopts a preferred conformation
23
T
22
or
23E (PZ144–1558) in the southern hemisphere, while,
22
conformations
T
or E23 (PZ320–3468) in the northern
hemisphere are found for the F-ring of the 22R-isomers.
23
3
The experimental J23,24 H-H coupling constants were
measured in 500 MHz spectra (Table 1), and are in agree-
ment with those calculated over minimized structures using
the HLA equation,31 the largest individual discrepancy
between experimental and calculated constants being
1.4 Hz.
4.1.1. (22S,23R,25S)-3b-Methoxy-23-tert-butyldimethyl-
silyloxy-26-acetoxy-22,25-epoxy-5a-furostan (15) and
(22R,23R,25S)-3b-methoxy-23-tert-butyldimethylsilyl-
oxy-26-acetoxy-22,25-epoxy-5a-furostan (16). A solution
of the alcohol 12-R (60 mg, 0.096 mmol) in cyclohexane
(10 mL) containing (diacetoxyiodo)benzene (40 mg,
0.124 mmol) and iodine (25 mg, 0.098 mmol) was irra-
diated with two 80 W tungsten-filament lamps at 50 8C for
3.5 h. The reaction mixture was then poured into aqueous
solution of sodium thiosulfate (10%) and extracted with
Et2O. The combined organic extracts were washed with
brine, dried (Na2SO4) and concentrated. Chromatotron
chromatography (hexanes–EtOAc, 95:5) of the residue
afforded compound compound 15 (14 mg, 0.022 mmol,
23.4%) and 16 (36 mg, 0.058 mmol, 60%). Compound 15:
In the 1,6-dioxa[4.5]decane compounds 19, 29 and 34, firm
22
evidence in favor of a
obtained by the J23,24 coupling constants. The alternative
C conformation for the F-ring was
25
3
25
C
22
chair conformation can be ruled out on the basis of the
same measurements (Table 1).32 X-ray diffraction analysis
confirmed the
and 34.21
22
C
25
conformation in the solid state for 29
3. Conclusion
In summary, we have demonstrated the usefulness of the
IHA reaction in the construction of the steroidal 1,6-
dioxaspiro[4.4]nonane ring system.33 Since thermodynami-
cally less stable isomers at the spirocenter can be obtained,
this methodology should be especially useful in the
synthesis of the natural products when both isomers are
isolated from nature, as described for several ritterazines.12
1
amorphous; [a]D K18 (c 0.23); IR 1746 cmK1; H NMR
0.07 (3H, s), 0.09 (3H, s), 0.64 (1H, m), 0.81 (3H, s), 0.87
(3H, s), 0.90 (9H, s), 1.06 (3H, d, JZ7.2 Hz), 1.32 (3H, s),
1.91 (1H, dd, JZ11.0, 11.4 Hz), 2.03 (1H, dd, JZ7.6,
11.6 Hz), 2.08 (3H, s), 2.30 (1H, dddd, JZ7.0, 7.0, 7.0,
7.0 Hz), 3.12 (1H, dddd, JZ4.6, 4.6, 10.9, 10.9 Hz), 3.35
(3H, s), 3.88 (2H, s), 4.30 (1H, dd, JZ7.8, 10.4 Hz), 4.62
(1H, ddd, JZ7.1, 7.1, 7.1 Hz); 13C NMR K5.4 (CH3), K4.0
(CH3), 12.3 (CH3), 16.1 (CH3), 16.6 (CH3), 17.8 (C), 20.9
(CH2), 21.1 (CH3), 25.8 (4!CH3), 27.9 (CH2), 28.8 (CH2),
32.3 (CH2), 32.4 (CH2), 34.3 (CH2), 35.0 (CH), 35.9 (C),
36.9 (CH2), 37.5 (CH), 40.2 (CH2), 40.3 (CH2), 41.1 (C),
44.8 (CH), 54.5 (CH), 55.5 (CH3), 55.6 (CH), 61.6 (CH),
The preparation of all eight possible isomers has led to the
discovery that the spirocenter stereochemistry can pro-
foundly influence the conformation of the F-ring. Taking
such an effect into account, the apparently anomalous
coupling constant for the proton at C-23, observed in the
NMR spectra of these compounds, can be readily explained.
From these findings the question that now arises is whether
the conformation of the F-ring might influence the

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C. Betancor et al. / Tetrahedron 61 (2005) 2803–2814
70.3 (CH2), 73.2 (CH), 79.0 (C), 79.8 (CH), 81.7 (CH),
117.9 (C), 170.6 (C); MS m/z (rel intensity) 618 (MC, !1),
561 (6), 475 (30), 287 (23); HRMS calcd for C36H62O6Si
618.4316; found 618.4255. Anal. Calcd for C36H62O6Si: C,
69.86; H, 10.10. Found: C, 69.01; H, 10.17. Compound 16:
2.02 (1H, ddd, JZ5.6, 7.3, 12.4 Hz), 2.20 (1H, br d, JZ
10.0 Hz), 2.29 (1H, dd, JZ8.1, 12.6 Hz), 2.34 (1H, dddd,
JZ4.0, 7.5, 7.5, 7.5 Hz), 3.12 (1H, dddd, JZ4.7, 4.7, 11.0,
11.0 Hz), 3.29 (1H, d, JZ11.3 Hz), 3.34 (3H, s), 3.38 (1H,
d, JZ11.3 Hz), 4.22 (1H, ddd, JZ8.4, 8.4, 8.4 Hz), 4.56
(1H, ddd, JZ7.0, 7.0, 8.7 Hz); 13C NMR 12.3 (CH3), 16.2
(CH3), 17.5 (CH3), 20.9 (CH2), 25.3 (CH3), 27.8 (CH2), 28.7
(CH2), 32.3 (CH2), 33.9 (CH2), 34.3 (CH2), 34.8 (CH), 35.9
(C), 36.9 (CH2), 39.4 (CH), 40.1 (CH2), 41.5 (C), 41.7
(CH2), 44.8 (CH), 54.5 (CH), 55.4 (CH3), 55.5 (CH), 63.4
(CH), 69.7 (CH2), 73.3 (CH), 79.8 (CH), 81.3 (C), 83.7
(CH), 118.6 (C); MS m/z (rel intensity) 461 (MCKH, !1),
431 (4), 287 (100); HRMS calcd for C28H45O5 461.3267;
found 461.3225. Anal. Calcd for C28H46O5: C, 72.69; H,
10.02. Found: C, 72.81; H, 10.19.
1
amorphous; [a]D K45 (c 0.24); IR 1745 cmK1; H NMR
0.07 (3H, s), 0.08 (3H, s), 0.62 (1H, m), 0.76 (3H, s), 0.80
(3H, s), 0.90 (9H, s), 1.06 (3H, d, JZ6.9 Hz), 1.33 (3H, s),
1.59 (1H, dd, JZ0.0, 13.3 Hz), 1.93 (1H, ddd, JZ5.7, 7.5,
12.4 Hz), 2.05 (3H, s), 2.22 (1H, dd, JZ5.4, 13.3 Hz), 2.32
(1H, dddd, JZ6.1, 6.1, 6.1, 6.1 Hz), 3.11 (1H, dddd, JZ4.5,
4.5, 10.8, 10.8 Hz), 3.33 (3H, s), 3.88 (1H, d, JZ10.9 Hz),
4.10 (1H, d, JZ10.9 Hz), 4.14 (1H, d, JZ4.6 Hz), 4.44 (1H,
ddd, JZ5.6, 7.8, 7.8 Hz); 13C NMR K5.1 (CH3), K5.0
(CH3), 12.3 (CH3), 16.3 (CH3), 16.8 (CH3), 17.9 (C), 20.9
(CH2), 21.0 (CH3), 25.0 (CH3), 25.7 (3!CH3), 27.9 (CH2),
28.7 (CH2), 32.0 (CH2), 32.2 (CH2), 34.3 (CH2), 35.3 (CH),
35.9 (C), 36.2 (CH), 36.9 (CH2), 39.8 (CH2), 41.0 (C), 42.3
(CH2), 44.7 (CH), 54.4 (CH), 55.5 (CH3), 56.3 (CH), 63.1
(CH), 70.8 (CH2), 78.5 (CH), 79.8 (CH), 81.3 (CH), 82.0
(C), 120.9 (C), 171.0 (C); MS m/z (rel intensity) 618 (MC,
!1), 561 (2), 545 (7), 475 (32), 287 (43); HRMS calcd for
C36H62O6Si 618.4316; found 618.4238. Anal. Calcd for
C36H62O6Si: C, 69.86; H, 10.10. Found: C, 69.93; H, 10.22.
4.1.3. (22R,23R,25S)-3b-Methoxy-22,25-epoxy-5a-furo-
stan-23,26-diol (18). To a solution of compound 16
(35 mg, 0.056 mmol) in THF (5 mL) was added TBAF
(0.3 mL, 0.3 mmol, 1.0 M in THF) and stirred at room
temperature for 3 h. The mixture was then poured into
aqueous saturated solution of NaHCO3 and extracted with
Et2O. The organic extracts were washed with brine, dried
(Na2SO4) and concentrated. Chromatotron chromato-
graphy (hexanes–EtOAc, 80:20) of the residue afforded
(22R,23R,25S)-3b-methoxy-26-acetoxy-22,25-epoxy-5a-
furostan-23-ol (23 mg, 0.045 mmol, 81%): mp 208.5–
209 8C (from EtOAc-n-hexane); [a]D K57 (c 1.03); IR
3516, 1723 cmK1; 1H NMR 0.62 (1H, m), 0.77 (3H, s), 0.80
(3H, s), 1.09 (3H, d, JZ6.9 Hz), 1.34 (3H, s), 1.93 (1H, ddd,
JZ5.8, 7.4, 12.6 Hz), 2.07 (3H, s), 2.28 (1H, dd, JZ5.6,
13.7 Hz), 2.39 (1H, dddd, JZ6.4, 6.4, 6.4, 6.4 Hz), 3.11
(1H, dddd, JZ4.6, 4.6, 10.9, 10.9 Hz), 3.33 (3H, s), 3.93
(1H, d, JZ10.9 Hz), 4.09 (1H, d, JZ10.9 Hz), 4.18 (1H, br
d, JZ4.9 Hz), 4.44 (1H, ddd, JZ5.7, 7.8, 7.8 Hz); 13C
NMR 12.3 (CH3), 16.1 (CH3), 16.8 (CH3), 20.9 (CH3), 21.0
(CH2), 25.5 (CH3), 27.9 (CH2), 28.7 (CH2), 31.9 (CH2), 32.2
(CH2), 34.3 (CH2), 35.2 (CH), 35.9 (C), 36.1 (CH), 36.9
(CH2), 39.7 (CH2), 41.0 (C), 42.0 (CH2), 44.8 (CH), 54.4
(CH), 55.5 (CH3), 56.3 (CH), 63.3 (CH), 70.9 (CH2), 78.1
(CH), 79.8 (CH), 81.2 (CH), 81.6 (C), 120.2 (C), 171.0 (C);
MS m/z (rel intensity) 504 (MC !1), 486 (11), 431 (6), 287
(100); HRMS calcd for C30H48O6 504.3451; found
504.3455. Anal. Calcd for C30H48O6: C, 71.39; H, 9.59.
Found: C, 71.06; H, 9.86. A solution of this acetate (20 mg,
0.0397 mmol) in MeOH (10 mL) containing KOH (0.35 g)
was stirred at room temperature for 4 h. The mixture was
poured into water and extracted with AcOEt. The combined
extracts were washed with brine, dried (Na2SO4) and
concentrated. Chromatotron chromatography (hexanes–
EtOAc, 7:3) of the residue afforded compound 18
(16.5 mg, 0.036 mmol, 90%): mp 211.5–213.5 8C (from
4.1.2. (22S,23R,25S)-3b-Methoxy-22,25-epoxy-5a-furo-
stan-23,26-diol (17). To a solution of compound 15
(13 mg, 0.021 mmol) in THF (3 mL) was added TBAF
(0.1 mL, 0.1 mmol, 1.0 M in THF) and stirred at room
temperature for 2 h. The mixture was then poured into
aqueous saturated solution of NaHCO3 and extracted with
AcOEt. The organic extracts were washed with brine,
dried (Na2SO4) and concentrated. Chromatotron chroma-
tography (benzene–EtOAc, 90:10) of the residue afforded
(22S,23R,25S)-3b-methoxy-26-acetoxy-22,25-epoxy-5a-
furostan-23-ol (8.6 mg, 0.017 mmol, 81%): mp 151–154 8C
(from EtOAc); IR 3447, 1744 cmK1; 1H NMR 0.64 (1H, m),
0.81 (3H, s), 0.91 (3H, s), 1.13 (3H, d, JZ7.5 Hz), 1.29 (3H,
s), 2.01 (1H, ddd, JZ5.7, 7.2, 12.3 Hz), 2.07 (3H, s), 2.27
(1H, dd, JZ7.8, 12.6 Hz), 2.34 (1H, dddd, JZ3.5, 7.4, 7.4,
7.4 Hz), 3.11 (1H, dddd, JZ4.6, 4.6, 10.9, 10.9 Hz), 3.33
(3H, s), 3.86 (2H, s), 4.25 (1H, ddd, JZ8.8, 8.8, 8.8 Hz),
4.54 (1H, ddd, JZ7.0, 7.0, 7.0 Hz); 13C NMR 12.3 (CH3),
16.1 (CH3), 17.5 (CH3), 20.9 (CH3), 20.9 (CH2), 25.8 (CH3),
27.9 (CH2), 28.8 (CH2), 32.4 (CH2), 34.0 (CH2), 34.3
(CH2), 34.8 (CH), 35.9 (C), 36.9 (CH2), 39.1 (CH), 40.1
(CH2), 41.5 (C), 41.9 (CH2), 44.8 (CH), 54.5 (CH), 55.48
(CH), 55.52 (CH3), 63.3 (CH), 70.2 (CH2), 73.0 (CH),
78.9 (C), 79.8 (CH), 83.7 (CH), 118.5 (C), 170.7 (C); MS m/
z (rel intensity) 486 (MCKH2O, 3), 471 (!1), 426 (4), 413
(4), 361 (39), 287 (100); HRMS calcd for C30H46O5
486.3345; found 486.3363. Anal. Calcd for C30H48O6: C,
71.39; H, 9.59. Found: C, 71.51; H, 9.71. A solution of this
acetate (8 mg, 0.0158 mmol) in MeOH (5 mL) containing
KOH (0.15 g) was stirred at room temperature for 4 h. The
mixture was poured into water and extracted with AcOEt.
The combined extracts were washed with brine, dried
(Na2SO4) and concentrated. Chromatotron chromatography
(hexanes–EtOAc, 7:3) of the residue afforded compound 17
(5.6 mg, 0.012 mmol, 76%): mp 187.5–190 8C (from
EtOAc-n-hexane); [a]D K55 (c 0.108); IR 3426, 1453 cmK1
;
1H NMR 0.63 (1H, m), 0.78 (3H, s), 0.81 (3H, s), 1.10 (3H,
d, JZ7.2 Hz), 1.30 (3H, s), 1.58 (1H, dd, JZ0.0, 13.8 Hz),
1.96 (1H, m), 2.46 (1H, dddd, JZ7.0, 7.0, 7.0, 7.0 Hz), 2.56
(1H, dd, JZ5.7, 13.8 Hz), 3.11 (1H, dddd, JZ4.5, 4.5, 10.7,
10.7 Hz), 3.31 (1H, d, JZ9.0 Hz), 3.33 (3H, s), 3.49 (1H, d,
JZ9.0 Hz), 4.21 (1H, d, JZ5.7 Hz), 4.53 (1H, ddd, JZ5.6,
7.5, 7.5 Hz); 13C NMR 12.3 (CH3), 16.0 (CH3), 17.0 (CH3),
20.9 (CH2), 25.2 (CH3), 27.9 (CH2), 28.7 (CH2), 31.9 (CH2),
32.2 (CH2), 34.3 (CH2), 35.2 (CH), 35.5 (CH), 35.9 (C),
36.9 (CH2), 39.5 (2!CH2), 41.1 (C), 44.7 (CH), 54.4 (CH),
1
EtOAc-n-hexane); [a]D C11 (c 0.19); IR 3417 cmK1; H
NMR 0.64 (1H, m), 0.81 (3H, s), 0.92 (3H, s), 1.13 (3H, d,
JZ7.4 Hz), 1.27 (3H, s), 1.69 (1H, dd, JZ8.4, 12.6 Hz),

C. Betancor et al. / Tetrahedron 61 (2005) 2803–2814
2809
55.5 (CH3), 56.2 (CH), 63.5 (CH), 68.5 (CH2), 78.9 (CH),
79.8 (CH), 81.8 (CH), 85.3 (C), 120.3 (C); MS m/z (rel
intensity) 462 (MC, !1), 444 (1), 431 (28), 287 (100);
HRMS calcd for C28H46O5 462.3345; found 462.3338.
Anal. Calcd for C28H46O5: C, 72.69; H, 10.02. Found: C,
72.83; H, 9.78.
44.8 (CH), 54.5 (CH), 55.5 (CH3), 55.6 (CH), 61.9 (CH),
71.0 (CH2), 72.7 (CH), 78.5 (C), 79.8 (CH), 81.8 (CH),
118.0 (C), 170.9 (C); MS m/z (rel intensity) 618 (MC, !1),
617 (!1), 561 (6), 475 (31), 287 (20); HRMS calcd for
C36H62O6Si 618.4316; found 618.4335. Anal. Calcd for
C36H62O6Si: C, 69.86; H, 10.10. Found: C, 69.98; H, 10.22.
Compound 21: amorphous; [a]D K58.2 (c 0.5); IR
1
1745 cmK1; H NMR 0.06 (3H, s), 0.07 (3H, s), 0.63 (1H,
4.1.4. (22S,23R,25S)-3b-Methoxy-5a-spirostan-23,25-
diol (19). A solution of compound 18 (10 mg, 0.02 mmol)
in CHCl3 (10 mL) was treated with an undetermined
catalytic amount of HCl (some gas taken with a Pasteur
pipet from of a concd HCl bottle) and stirred at room
temperature for 24 h. The reaction mixture was poured into
aqueous saturated NaHCO3 and extracted with CHCl3.
Chromatotron chromatography (hexanes–EtOAc, 85:15) of
the residue afforded compound 19 (5 mg, 0.01 mmol, 50%):
mp 250.5–252.5 8C (from EtOAc-n-hexane); [a]D K80 (c
m), 0.76 (3H, s), 0.80 (3H, s), 0.89 (9H, s), 1.02 (3H, d, JZ
7.0 Hz), 1.29 (3H, s), 1.84 (1H, dd, JZ0.0, 13.5 Hz), 1.96
(1H, ddd, JZ5.7, 7.3, 12.7 Hz), 2.04 (1H, dd, JZ5.1,
13.5 Hz), 2.06 (3H, s), 2.33 (1H, dddd, JZ6.9, 6.9, 6.9,
6.9 Hz), 3.11 (1H, dddd, JZ4.5, 4.5, 10.9, 10.9 Hz), 3.33
(3H, s), 4.04 (1H, d, JZ10.6 Hz), 4.08 (1H, d, JZ10.6 Hz),
4.17 (1H, d, JZ4.4 Hz), 4.52 (1H, ddd, JZ5.7, 7.9, 7.9 Hz);
13C NMR K5.1 (CH3), K5.0 (CH3), 12.3 (CH3), 16.4
(CH3), 16.8 (CH3), 17.9 (C), 20.91 (CH2), 20.96 (CH3), 25.7
(3!CH3), 26.1 (CH3), 27.9 (CH2), 28.7 (CH2), 32.1 (CH2),
32.2 (CH2), 34.3 (CH2), 35.3 (CH), 35.9 (C), 36.4 (CH),
36.9 (CH2), 39.8 (CH2), 41.1 (C), 42.7 (CH2), 44.8 (CH),
54.4 (CH), 55.5 (CH3), 56.3 (CH), 63.2 (CH), 70.4 (CH2),
78.7 (CH), 79.8 (CH), 81.4 (CH), 81.8 (C), 122.0 (C), 170.9
(C); MS m/z (rel intensity) 618 (MC, 1), 603 (!1), 561
(43), 545 (23), 287 (68); HRMS calcd for C36H62O6Si
618.4316; found 618.4324. Anal. Calcd for C36H62O6Si: C,
69.86; H, 10.10. Found: C, 69.71; H, 9.98.
1
0.45); IR 3601, 3492 cmK1; H NMR 0.63 (1H, m), 0.77
(3H, s), 0.80 (3H, s), 1.12 (3H, s), 1.15 (3H, d, JZ6.9 Hz),
1.82 (1H, ddd, JZ2.8, 2.8, 14.3 Hz), 1.96 (1H, dd, JZ3.2,
14.3 Hz), 2.30 (1H, dddd, JZ6.9, 6.9, 6.9, 6.9 Hz), 3.11
(1H, dddd, JZ4.6, 4.6, 10.9, 10.9 Hz), 3.33 (3H, s), 3.39
(1H, dd, JZ2.8, 11.8 Hz), 3.63 (1H, dd, JZ2.8, 2.8 Hz),
3.77 (1H, d, JZ11.8 Hz), 4.47 (1H, ddd, JZ5.7, 7.8,
7.8 Hz); 13C NMR 12.3 (CH3), 16.2 (CH3), 16.7 (CH3), 20.9
(CH2), 26.2 (CH3), 27.8 (CH2), 28.7 (CH2), 32.0 (CH2), 32.2
(CH2), 34.3 (CH2), 35.2 (CH), 35.9 (C), 36.9 (CH2), 38.3
(CH2), 39.6 (CH2), 40.4 (CH), 41.0 (C), 44.8 (CH), 54.4
(CH), 55.5 (CH3), 56.4 (CH), 64.1 (CH), 68.8 (C), 69.2
(CH2), 70.9 (CH), 79.8 (CH), 81.8 (CH), 108.7 (C); MS m/z
(rel intensity) 462 (MC, 2), 444 (2), 426 (2), 411 (2), 361
(46), 287 (100); HRMS calcd for C28H46O5 462.3345; found
462.3401. Anal. Calcd for C28H46O5: C, 72.69; H, 10.02.
Found: C, 72.71; H, 10.13.
4.1.6. (22S,23R,25R)-3b-Methoxy-22,25-epoxy-5a-furo-
stan-23,26-diol (22). To a solution of compound 20
(38 mg, 0.061 mmol) in THF (8 mL) was added TBAF
(0.4 mL, 0.4 mmol, 1.0 M in THF) and stirred at room
temperature for 1.5 h. The mixture was then poured into
aqueous saturated solution of NaHCO3 and extracted with
Et2O. The organic extracts were washed with brine, dried
(Na2SO4) and concentrated. Chromatotron chromato-
graphy (benzene–EtOAc, 90:10) of the residue afforded
(22S,23R,25R)-3b-methoxy-26-acetoxy-22,25-epoxy-5a-
furostan-23-ol (28 mg, 0.055 mmol, 90%): amorphous; [a]D
C10 (c 0.39); IR 3443, 1745 cmK1; 1H NMR 0.62 (1H, m),
0.80 (3H, s), 0.89 (3H, s), 1.12 (3H, d, JZ7.5 Hz), 1.19 (3H,
s), 1.82 (1H, dd, JZ9.1, 12.4 Hz), 1.87 (1H, ddd, JZ5.7,
7.3, 12.2 Hz), 2.06 (3H, s), 2.36 (1H, dddd, JZ3.5, 7.4, 7.4,
7.4 Hz), 3.11 (1H, dddd, JZ4.5, 4.5, 10.6, 10.6, Hz), 3.33
(3H, s), 3.96 (1H, d, JZ10.8 Hz), 4.06 (1H, d, JZ10.8 Hz),
4.25 (1H, ddd, JZ8.8, 8.8, 8.8 Hz), 4.54 (1H, ddd, JZ7.0,
7.0, 7.0 Hz); 13C NMR 12.2 (CH3), 15.9 (CH3), 17.3 (CH3),
20.9 (CH3), 20.9 (CH2), 25.2 (CH3), 27.8 (CH2), 28.7 (CH2),
32.3 (CH2), 32.8 (CH2), 34.2 (CH2), 34.7 (CH), 35.9 (C),
36.8 (CH2), 39.1 (CH), 40.0 (CH2), 41.4 (C), 41.7 (CH2),
44.7 (CH), 54.5 (CH), 55.5 (CH), 55.5 (CH3), 63.3 (CH),
70.4 (CH2), 72.4 (CH), 78.5 (C), 79.7 (CH), 83.7 (CH),
128.3 (C), 170.8 (C); MS m/z (rel intensity) 505 (MC C H,
! 1), 486 (! 1), 471 (!1), 413 !1), 361 (83), 287 (100);
HRMS calcd for C30H46O5 486.3345; found 486.3335.
Anal. Calcd for C30H48O6: C, 71.39; H, 9.59. Found: C,
71.52; H, 9.71. A solution of this acetate (24 mg,
0.047 mmol) in MeOH (15 mL) containing KOH (0.3 g)
was stirred at room temperature for 8 h. The mixture was
poured into water and extracted with AcOEt. The combined
extracts were washed with brine, dried (Na2SO4) and concen-
trated. Chromatotron chromatography (hexanes–EtOAc, 7:3)
of the residue afforded compound 22 (18 mg, 0.039 mmol,
82%): mp 166.5–168 8C (from EtOAc-n-hexane); [a]D K4
4.1.5. (22S,23R,25R)-3b-Methoxy-23-tert-butyldimethyl-
silyloxy-26-acetoxy-22,25-epoxy-5a-furostan (20) and
(22R,23R,25R)-3b-methoxy-23-tert-butyldimethylsilyl-
oxy-26-acetoxy-22,25-epoxy-5a-furostan (21). A solution
of the alcohol 14-R (137 mg, 0.22 mmol) in cyclohexane
(25 mL) containing (diacetoxyiodo)benzene (84 mg,
0.264 mmol) and iodine (56 mg, 0.22 mmol) was irradiated
with two 80 W tungsten-filament lamps at 55 8C for 7 h. The
reaction mixture was then poured into aqueous solution of
sodium thiosulfate (10%) and extracted with Et2O. The
combined organic extracts were washed with brine, dried
(Na2SO4) and concentrated. Chromatotron chromatography
(hexanes–EtOAc, 95:5) of the residue afforded compound
20 (38 mg, 0.061 mmol, 27.8%) and compound 21 (76 mg,
0.122 mmol, 55.3%). Compound 20: amorphous; [a]D K27
(c 0.064); IR 1746 cmK1; 1H NMR 0.07 (3H, s), 0.10 (3H,
s), 0.63 (1H, m), 0.80 (3H, s), 0.85 (3H, s), 0.90 (9H, s), 1.06
(3H, d, JZ7.3 Hz), 1.20 (3H, s), 1.85 (1H, dd, JZ7.5,
11.1 Hz), 1.90 (1H, ddd, JZ6.0, 6.8, 12.3 Hz), 1.98 (1H, dd,
JZ11.2, 10.4 Hz), 2.05 (3H, s), 2.31 (1H, dddd, JZ6.9, 6.9,
6.9, 6.9 Hz), 3.10 (1H, dddd, JZ4.6, 4.6, 10.7, 10.7 Hz),
3.35 (3H, s), 4.01 (1H, d, JZ10.9 Hz), 4.10 (1H, d, JZ
10.9 Hz), 4.22 (1H, dd, JZ7.5, 10.4 Hz), 4.59 (1H, ddd, JZ
6.8, 6.8, 6.8 Hz); 13C NMR K5.3 (CH3), K4.0 (CH3), 12.3
(CH3), 16.0 (CH3), 16.5 (CH3), 17.8 (C), 21.0 (CH2), 21.0
(CH3), 25.0 (CH3), 25.8 (3!CH3), 27.9 (CH2), 28.8 (CH2),
32.3 (CH2), 33.4 (CH2), 34.3 (CH2), 35.0 (CH), 35.9 (C),
36.9 (CH2), 37.4 (CH), 40.1 (CH2), 40.2 (CH2), 41.2 (C),

2810
C. Betancor et al. / Tetrahedron 61 (2005) 2803–2814
(c 0.55); IR 3408 cmK1; H NMR 0.62 (1H, m), 0.80 (3H,
s), 0.89 (3H, s), 1.13 (3H, s), 1.16 (3H, d, JZ7.5 Hz), 1.96
(1H, dd, JZ8.1, 12.3 Hz), 2.04 (1H, ddd, JZ7.3, 7.3,
7.3 Hz), 2.15 (1H, dd, JZ9.8, 12.4 Hz), 2.39 (1H, dddd, JZ
3.3, 7.3, 7.3, 7.3 Hz), 3.11 (1H, dddd, JZ4.5, 4.5, 10.7,
10.7 Hz), 3.25 (1H, d, JZ11.4 Hz), 3.33 (3H, s), 3.45 (1H,
d, JZ11.5 Hz), 4.26 (1H, dd, JZ9.0, 9.0 Hz), 4.58 (1H,
ddd, JZ7.3, 7.3, 7.3 Hz); 13C NMR 12.2 (CH3), 16.1 (CH3),
17.2 (CH3), 20.8 (CH2), 24.9 (CH3), 27.8 (CH2), 28.7 (CH2),
32.2 (CH2), 34.0 (CH2), 34.2 (CH2), 34.8 (CH), 35.9 (C),
36.9 (CH2), 38.5 (CH), 38.5 (CH2), 39.7 (CH2), 41.5 (C),
44.7 (CH), 54.4 (CH), 55.4 (CH3), 55.6 (CH), 63.8 (CH),
68.1 (CH2), 73.4 (CH), 79.7 (CH), 81.7 (C), 83.8 (CH),
118.2 (C); MS m/z (rel intensity) 444 (MCKH2O, 2), 431
(6), 426 (9), 411 (4), 287 (100); HRMS calcd for C28H44O4
444.3240; found 444.3221. Anal. Calcd for C28H46O5: C,
72.69; H, 10.02. Found: C, 72.71; H, 10.14.
C21.2 (c 0.08); IR 1745 cmK1; 1H NMR 0.07 (3H, s), 0.08
(3H, s), 0.64 (1H, m), 0.81 (3H, s), 0.86 (3H, s), 0.90 (9H, s),
1.13 (3H, d, JZ7.2 Hz), 1.33 (3H, s), 1.89 (1H, dd, JZ3.3,
13.1 Hz), 2.01 (1H, dd, JZ5.2, 13.1 Hz), 2.07 (3H, s), 3.11
(1H, dddd, JZ4.7, 4.7, 11.0, 11.0 Hz), 3.33 (3H, s), 4.02
(1H, d, JZ10.7 Hz), 4.11 (1H, d, JZ10.4 Hz), 4.26 (1H, dd,
JZ3.4, 5.1 Hz), 4.38 (1H, ddd, JZ7.5, 7.5, 9.4 Hz); NOE
correlation from 23-H to 21-Me and to 27-Me; 13C NMR
(100.6 MHz) K5.2 (CH3), K3.8 (CH3), 12.3 (CH3), 16.2
(CH3), 17.0 (CH3), 17.8 (C), 20.9 (CH3), 21.2 (CH2), 25.6
(CH3), 25.9 (3!CH3), 27.9 (CH2), 28.8 (CH2), 32.5 (CH2),
33.1 (CH2), 34.3 (CH2), 34.4 (CH), 36.0 (C), 36.9 (CH2),
39.4 (CH), 41.0 (CH2), 41.1 (C), 42.6 (CH2), 44.9 (CH),
54.6 (CH), 54.9 (CH), 55.5 (CH3), 62.1 (CH), 70.5 (CH2),
77.7 (CH), 79.8 (CH), 80.5 (C), 81.7 (CH), 120.6 (C), 170.8
(C); MS m/z (rel intensity) 618 (MC, !1), 561 (3), 545 (2),
198 (100); HRMS calcd for C36H62O6Si 618.4316; found
618.4317. Anal. Calcd for C36H62O6Si: C, 69.86; H, 10.10.
Found: C, 69.92; H, 10.04. Compound 26: mp 135.0–
1
4.1.7. (22R,23R,25R)-3b-Methoxy-22,25-epoxy-5a-furo-
stan-23,26-diol (23). To a solution of compound 21 (23 mg,
0.037 mmol) in THF (5 mL) was added TBAF (0.2 mL,
0.2 mmol, 1.0 M in THF) and stirred at room temperature
for 3 h. The mixture was then poured into aqueous saturated
solution of NaHCO3 and extracted with Et2O. The organic
extracts were washed with brine, dried (Na2SO4) and con-
centrated. The crude residue was saponified with methanolic
KOH (10 mL, 3%) for 4 h at room temperature. Chromato-
tron chromatography (benzene–EtOAc, 75:25) of the
residue afforded compound 23 (12 mg, 0.026 mmol, 70%):
mp 269.5–270 8C (from MeOH); [a]D K72 (c 0.122); IR
3317 cmK1; 1H NMR 0.63 (1H, m), 0.79 (3H, s), 0.80 (3H,
s), 1.11 (3H, d, JZ6.7 Hz), 1.27 (3H, s), 1.93 (1H, dd, JZ
0.0, 14.0 Hz), 1.96 (1H, ddd, JZ5.8, 7.4, 12.4 Hz), 2.28
(1H, dd, JZ5.5, 14.0 Hz), 2.53 (1H, dddd, JZ7.0, 7.0, 7.0,
7.0 Hz), 3.11 (1H, dddd, JZ4.5, 4.5, 10.7, 10.7 Hz), 3.33
(3H, s), 3.39 (1H, d, JZ11.2 Hz), 3.65 (1H, d, JZ11.2 Hz),
4.02 (1H, d, JZ5.5 Hz), 4.51 (1H, ddd, JZ5.7, 7.9, 7.9 Hz);
13C NMR 12.3 (CH3), 16.1 (CH3), 17.1 (CH3), 20.9 (CH2),
26.2 (CH3), 27.8 (CH2), 28.7 (CH2), 32.0 (CH2), 32.2 (CH2),
34.3 (CH2), 35.1 (CH), 35.9 (C), 36.3 (CH), 36.9 (CH2),
39.8 (CH2), 41.1 (C), 42.4 (CH2), 44.8 (CH), 54.4 (CH),
55.5 (CH3), 56.3 (CH), 63.6 (CH), 68.9 (CH2), 77.0 (CH),
79.8 (CH), 81.0 (CH), 83.2 (C), 120.6 (C); MS m/z (rel
intensity) 444 (MCKH2O, !1), 413 (2), 287 (45); HRMS
calcd for C28H44O4 444.3240; found 444.3268. Anal.
Calcd for C28H46O5: C, 72.69; H, 10.02. Found: C, 72.69;
H, 9.90.
136.0 8C (from EtOAc); [a]D K34 (c 0.10); IR 1745 cmK1
;
1H NMR 0.06 (3H, s), 0.07 (3H, s), 0.60 (1H, m), 0.77 (3H,
s), 0.78 (3H, s), 0.88 (9H, s), 0.92 (3H, d, JZ6.9 Hz), 1.17
(3H, s), 1.89 (1H, dd, JZ7.9, 11.8 Hz), 2.05 (3H, s), 2.14
(1H, m), 3.10 (1H, dddd, JZ4.6, 4.6, 10.9, 10.9 Hz), 3.32
(3H, s), 3.97 (1H, d, JZ10.8 Hz), 4.01 (1H, dd, JZ7.8,
10.6 Hz), 4.04 (1H, d, JZ10.8 Hz), 4.43 (1H, ddd, JZ7.4,
7.4, 7.4 Hz); NOE correlation from 23-H to 21-Me and to
27-Me; 13C NMR (100.6 MHz) K4.8 (CH3), K4.7 (CH3),
12.3 (CH3), 14.0 (CH3), 16.6 (CH3), 18.2 (C), 20.9 (CH2),
20.9 (CH3), 25.1 (CH3), 25.8 (3! CH3), 27.9 (CH2), 28.7
(CH2), 31.8 (CH2), 32.2 (CH2), 34.3 (CH2), 34.9 (CH),
35.0 (CH), 35.8 (C), 36.9 (CH2), 40.1 (CH2), 40.5 (CH2),
40.9 (C), 44.7 (CH), 54.4 (CH), 55.5 (CH3), 56.2 (CH),
61.4 (CH), 70.6 (CH), 71.1 (CH2), 78.0 (C), 79.8 (CH),
80.8 (CH), 116.7 (C), 170.8 (C); MS m/z (rel intensity)
618 (MC, !1), 562 (3), 545 (2), 287 (100); HRMS calcd
for C36H62O6Si 618.4316; found 618.4317. Anal. Calcd
for C36H62O6Si: C, 69.86; H, 10.10. Found: C, 69.84; H,
10.26.
4.1.9. (22S,23S,25S)-3b-Methoxy-22,25-epoxy-5a-furo-
stan-23,26-diol (27). To a solution of compound 25 (96 mg,
0.15 mmol) in THF (22 mL) was added TBAF (0.75 mL,
0.75 mmol, 1.0 M in THF) and stirred at room temperature
for 2 h. The mixture was then poured into aqueous saturated
solution of NaHCO3 and extracted with CH2Cl2. The
organic extracts were washed with brine, dried (Na2SO4)
and concentrated. A solution of the residue in MeOH
(46 mL) containing KOH (1.5 g) was stirred at room
temperature for 0.5 h. The mixture was poured into water
and extracted with EtOAc. The combined extracts were
washed with brine, dried (Na2SO4) and concentrated.
Chromatotron chromatography (hexanes–EtOAc, 7:3)
afforded compound 27 (48 mg, 0.10 mmol, 67%): mp
172.5–173.2 8C (from n-hexane-EtOAc); [a]D C30.8 (c
0.12); IR 3352 cmK1; 1H NMR 0.62 (1H, m), 0.79 (3H, s),
0.94 (3H, s), 1.19 (3H, d, JZ7.3 Hz), 1.25 (3H, s), 1.89 (1H,
dd, JZ0.0, 13.6 Hz), 2.19 (1H, dd, JZ4.9, 13.7 Hz), 2.36
(1H, dddd, JZ2.0, 7.2, 7.2, 7.2 Hz), 3.11 (1H, dddd, JZ4.6,
4.6, 11.0, 11.0 Hz), 3.32 (3H, s), 3.33 (1H, d, JZ11.2 Hz),
3.53 (1H, d, JZ11.2 Hz), 3.93 (1H, dd, JZ0.0, 4.8 Hz),
4.54 (1H, ddd, JZ7.8, 7.8, 7.8 Hz); NOE correlation from
23-H to 21-Me; 13C NMR (100.6 MHz) 12.2 (CH3), 16.1
4.1.8. (22S,23S,25S)-3b-Methoxy-23-tert-butyldimethyl-
silyloxy-26-acetoxy-22,25-epoxy-5a-furostan (25) and
(22R,23S,25S)-3b-methoxy-23-tert-butyldimethylsilyl-
oxy-26-acetoxy-22,25-epoxy-5a-furostan (26). A solution
of the alcohol 12-S (420 mg, 0.68 mmol) in cyclohexane
(70 mL) containing (diacetoxyiodo)benzene (437 mg,
1.36 mmol) and iodine (172 mg, 0.68 mmol) was irradiated
with a 80 W tungsten-filament lamp at 70 8C for 1 h. The
reaction mixture was then poured into aqueous solution of
sodium thiosulfate (10%) and extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried
(Na2SO4) and concentrated. Flash-chromatography(hexanes–
EtOAc, 93:7) of the residue afforded compound 25 (96 mg,
0.15 mmol, 23%) and compound 26 (310 mg, 0.50 mmol,
74%). Compound 25: mp 62.4–63.7 8C (from EtOAc); [a]D

C. Betancor et al. / Tetrahedron 61 (2005) 2803–2814
2811
(CH3), 19.3 (CH3), 21.1 (CH2), 26.1 (CH3), 27.8 (CH2), 28.8
(CH2), 32.5 (CH2), 33.7 (2!CH2), 34.3 (CH), 35.9 (C),
36.8 (CH2), 38.6 (CH), 41.0 (CH2), 41.4 (C), 42.2 (CH2),
44.8 (CH), 54.6 (2!CH), 55.5 (CH3), 64.2 (CH), 68.3
(CH2), 74.8 (CH), 79.8 (CH), 82.4 (C), 83.8 (CH), 121.7
(C); MS m/z (rel intensity) 462 (MC, !1), 444 (7), 426
(16), 287 (100); HRMS calcd for C28H46O5 462.3345; found
462.3326. Anal. Calcd for C28H46O5: C, 72.69; H, 10.02.
Found: C, 72.77; H, 10.03.
(CH2), 34.3 (CH2), 34.9 (CH), 35.7 (CH), 35.9 (C), 36.9
(CH2), 40.1 (CH2), 41.1 (C), 42.6 (CH2), 44.8 (CH), 54.4
(CH), 55.5 (CH3), 56.3 (CH), 61.5 (CH), 64.3 (CH), 68.4
(CH2), 70.3 (C), 79.8 (CH), 82.1 (CH), 110.5 (C); MS m/z
(rel intensity) 462 (MC, 6), 444 (3), 426 (3), 287 (100);
HRMS calcd for C28H46O5 462.3345; found 462.3324.
Anal. Calcd for C28H46O5: C, 72.69; H, 10.02. Found: C,
72.67; H, 10.17.
4.1.12.
(22S,23S,25R)-3b-Methoxy-23-tert-butyldi-
4.1.10. (22R,23S,25S)-3b-Methoxy-22,25-epoxy-5a-furo-
stan-23,26-diol (28). To a solution of compound 26 (83 mg,
0.13 mmol) in THF (19 mL) was added TBAF (0.65 mL,
0.65 mmol, 1.0 M in THF) and stirred at room temperature
for 1 h. The mixture was then poured into aqueous saturated
solution of NaHCO3 and extracted with EtOAc. The organic
extracts were washed with brine, dried (Na2SO4) and
concentrated. A solution of the residue in MeOH (40 mL)
containing KOH (1.3 g) was stirred at room temperature for
0.5 h. The mixture was poured into water and extracted with
EtOAc. The combined extracts were washed with brine,
dried (Na2SO4) and concentrated. Chromatotron chromato-
graphy (hexanes–EtOAc, 6:4) afforded compound 28
(54 mg, 0.12 mmol, 87%): mp 183.8–184.2 8C (from n-
methylsilyloxy-26-acetoxy-22,25-epoxy-5a-furostan (30)
and (22R,23S,25R)-3b-methoxy-23-tert-butyldimethyl-
silyloxy-26-acetoxy-22,25-epoxy-5a-furostan (31). A solu-
tion of the alcohol 14-S (49 mg, 0.08 mmol) in cyclohexane
(8.6 mL) containing (diacetoxyiodo)benzene (52 mg,
0.16 mmol) and iodine (21 mg, 0.08 mmol) was irradiated
with a 80 W tungsten-filament lamp at 70 8C for 1 h. The
reaction mixture was then poured into aqueous solution of
sodium thiosulfate (10%) and extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried
(Na2SO4) and concentrated. Chromatotron chromatography
(hexanes–EtOAc, 93:7) of the residue afforded compound
30 (14 mg, 0.02 mmol, 28%) and compound 31 (23 mg,
0.04 mmol, 47%). Compound 30: mp 144.0–144.7 8C (from
EtOAc); [a]D C24 (c 0.10); IR 1745 cmK1; 1H NMR 0.07
(3H, s), 0.08 (3H, s), 0.62 (1H, m), 0.80 (3H, s), 0.89 (3H, s),
0.91 (9H, s), 1.13 (3H, d, JZ7.3 Hz), 1.34 (3H, s), 1.67 (1H,
dd, JZ2.3, 13.1 Hz), 2.06 (3H, s), 2.12 (1H, dd, JZ5.12,
13.0 Hz), 2.33 (1H, m), 3.10 (1H, dddd, JZ4.6, 4.6, 10.9,
10.9 Hz), 3.33 (3H, s), 3.98 (1H, d, JZ10.7 Hz), 4.03 (1H,
d, JZ10.7 Hz), 4.18 (1H, dd, JZ2.3, 5.0 Hz), 4.37 (1H,
ddd, JZ7.4, 7.4, 7.4 Hz); NOE correlation from 23-H to
21-Me and to 26-H2; 13C NMR (100.6 MHz) K5.2 (CH3),
K3.7 (CH3), 12.3 (CH3), 16.1 (CH3), 17.7 (CH3), 17.8 (C),
20.9 (CH3), 21.1 (CH2), 25.2 (CH3), 25.9 (3! CH3), 27.9
(CH2), 28.8 (CH2), 32.5 (CH2), 33.1 (CH2), 34.3 (CH2), 34.5
(CH), 35.1 (C), 36.9 (CH2), 39.2 (CH), 40.9 (CH2), 41.2 (C),
42.7 (CH2), 44.8 (CH), 54.6 (CH), 54.9 (CH), 55.5 (CH3),
62.8 (CH), 71.4 (CH2), 76.9 (CH), 79.8 (CH), 80.5 (C), 81.9
(CH), 121.1 (C), 171.0 (C); MS m/z (rel intensity) 618 (MC,
!1), 561 (5), 198 (100); HRMS calcd for C36H62O6Si
618.4316; found 618.4321. Anal. Calcd for C36H62O6Si: C,
69.86; H, 10.10. Found: C, 69.80; H, 10.07. Compound 31:
mp 157.0–157.8 8C (from EtOAc); [a]D K37.5 (c 0.12); IR
1746 cmK1; 1H NMR 0.04 (6H, s), 0.60 (1H, m), 0.76 (3H,
s), 0.77 (3H, s), 0.85 (3H, d, JZ5.3 Hz), 0.87 (9H, s), 1.28
(3H, s), 1.91 (1H, dd, JZ10.6, 11.9 Hz), 2.02 (3H, s), 2.11
(1H, m), 3.07 (1H, dddd, JZ4.5, 4.5, 10.8, 10.8 Hz), 3.29
(3H, s), 3.77 (1H, d, JZ11.2 Hz), 3.93 (1H, d, JZ11.2 Hz),
4.04 (1H, dd, JZ8.1, 10.4 Hz), 4.48 (1H, ddd, JZ7.3, 7.3,
7.3 Hz); NOE correlation from 23-H to 21-Me and to 20-H;
13C NMR (100.6 MHz) K4.9 (CH3), K4.8 (CH3), 12.2
(CH3), 13.9 (CH3), 16.6 (CH3), 18.2 (C), 20.8 (CH3), 20.9
(CH2), 25.8 (3!CH3), 26.0 (CH3), 27.8 (CH2), 28.7 (CH2),
31.8 (CH2), 32.2 (CH2), 34.2 (CH2), 35.0 (2!CH), 35.8
(C), 36.9 (CH2), 40.1 (CH2), 40.4 (CH2), 40.9 (C), 44.7
(CH), 54.3 (CH), 55.4 (CH3), 56.2 (CH), 61.6 (CH), 70.3
(CH2), 71.2 (CH), 78.3 (C), 79.7 (CH), 80.8 (CH), 116.5
(C), 170.5 (C); MS m/z (rel intensity) 618 (MC, !1), 561
(6), 545 (1), 75 (100); HRMS calcd for C36H62O6Si
618.4316; found 618.4303. Anal. Calcd for C36H62O6Si:
C, 69.86; H, 10.10. Found: C, 69.95; H, 10.13.
hexane-EtOAc); [a]D K46.7 (c 0.06); IR 3571, 3466 cmK1
;
1H NMR 0.63 (1H, m), 0.77 (3H, s), 0.78 (3H, s), 0.94 (3H,
d, JZ7.0 Hz), 1.14 (3H, s), 1.97 (1H, dd, JZ8.3, 12.3 Hz),
2.12 (1H, dd, JZ10.5, 12.4 Hz), 2.31 (1H, dddd, JZ6.9,
6.9, 6.9, 6.9 Hz), 3.10 (1H, dddd, JZ4.6, 4.6, 10.9,
10.9 Hz), 3.29 (1H, d, JZ10.3 Hz), 3.32 (3H, s), 3.44
(1H, d, JZ11.3 Hz), 4.04 (1H, m), 4.55 (1H, ddd, JZ7.1,
7.1, 8.7 Hz); NOE correlation from 23-H to 21-Me, to 20-H
and to 27-Me; 13C NMR (100.6 MHz) 12.2 (CH3), 14.3
(CH3), 16.4 (CH3), 20.9 (CH2), 24.6 (CH3), 27.8 (CH2), 28.6
(CH2), 31.8 (CH2), 32.2 (CH2), 34.2 (CH2), 34.9 (CH), 35.0
(CH), 35.8 (C), 36.8 (CH2), 38.1 (CH2), 39.9 (CH2), 41.1
(C), 44.7 (CH), 54.3 (CH), 55.5 (CH3), 56.0 (CH), 61.7
(CH), 68.3 (CH2), 72.2 (CH), 79.7 (CH, C-3), 82.0 (C), 82.3
(CH), 116.8 (C); MS m/z (rel intensity) 431 (MCKCH2OH,
26), 413 (11), 287 (100); HRMS calcd for C27H43O4
431.3161; found 431.3106. Anal. Calcd for C28H46O5: C,
72.69; H, 10.02. Found: C, 72.75; H, 9.92.
4.1.11. (22S,23S,25S)-3b-Methoxy-5a-spirostan-23,25-
diol (29). A solution of compound 28 (47 mg, 0.1 mmol)
in CHCl3 (2.4 mL) was treated with p-TsOH (5 mg
dissolved in 0.5 mL CHCl3) and stirred at room temperature
for 1 h. The reaction mixture was neutralized with Amberjet
4400 OH, filtered and concentrated. Chromatotron chromato-
graphy (toluene-EtOAc, 60:40) of the residue afforded
starting material 28 (30 mg, 0.06 mmol, 60%) and com-
pound 29 (15 mg, 0.03 mmol, 30%). Compound 29: mp
214–216 8C (from acetone); [a]D K92.2 (c 0.09); IR
3579 cmK1 1H NMR 0.64 (1H, m), 0.80 (6H, s), 1.00
;
(3H, d, JZ7.0 Hz), 1.13 (3H, s), 1.56 (1H, dd, JZ12.3,
12.3 Hz), 2.05 (1H, ddd, JZ2.7, 5.3, 12.7 Hz), 2.56 (1H,
dddd, JZ6.9, 6.9, 6.9, 6.9 Hz), 3.11 (1H, dddd, JZ4.7, 4.7,
10.9, 10.9 Hz), 3.23 (1H, dd, JZ2.7, 11.6 Hz), 3.33 (3H, s),
3.62 (1H, d, JZ11.5 Hz), 3.75 (1H, dd, JZ5.3, 11.6 Hz),
4.45 (1H, ddd, JZ7.1, 7.1, 7.1 Hz); NOE correlation from
23-H to 20-H, to 21-H3 and from 26-Hb to 24-Ha; 13C NMR
(100.6 MHz) 12.3 (CH3), 14.0 (CH3), 16.6 (CH3), 21.0
(CH2), 24.8 (CH3), 27.8 (CH2), 28.7 (CH2), 31.7 (CH2), 32.3

2812
C. Betancor et al. / Tetrahedron 61 (2005) 2803–2814
4.1.13. (22S,23S,25R)-3b-Methoxy-22,25-epoxy-5a-furo-
stan-23,26-diol (32). To a solution of compound 30 (55 mg,
0.09 mmol) in THF (12.6 mL) was added TBAF (0.42 mL,
0.42 mmol, 1.0 M in THF) and stirred at room temperature
for 3 h. The mixture was then poured into aqueous saturated
solution of NaHCO3 and extracted with CH2Cl2. The
organic extracts were washed with brine, dried (Na2SO4)
and concentrated. A solution of the residue in MeOH
(26 mL) containing KOH (0.9 g) was stirred at room
temperature for 1.5 h. The mixture was poured into water
and extracted with EtOAc. The combined extracts were
washed with brine, dried (Na2SO4) and concentrated.
Chromatotron chromatography (hexanes–EtOAc, 7:3)
afforded compound 32 (41 mg, 0.09 mmol, 99%): mp
145.1–146.7 8C (from AcOEt); [a]D C7.8 (c 0.09); IR
3629, 3448 cmK1; 1H NMR 0.62 (1H, m), 0.79 (3H, s), 0.93
(3H, s), 1.25 (3H, d, JZ7.3 Hz), 1.31 (3H, s), 1.55 (1H, dd,
JZ0.0, 13.5 Hz), 2.46 (1H, dddd, JZ3.1, 7.3, 7.3, 7.3 Hz),
2.56 (1H, dd, JZ4.6, 13.6 Hz), 3.11 (1H, dddd, JZ4.6, 4.6,
11.0, 11.0 Hz), 3.31 (1H, d, JZ10.3 Hz), 3.32 (3H, s), 3.54
(1H, d, JZ11.3 Hz), 4.15 (1H, dd, JZ0.0, 4.5 Hz), 4.53
(1H, ddd, JZ7.1, 7.1, 9.3 Hz); NOE correlation from 23-H
to 21-H3; 13C NMR 12.2 (CH3), 15.9 (CH3), 18.7 (CH3),
20.9 (CH2), 25.8 (CH3), 27.8 (CH2), 28.6 (CH2), 32.3 (CH2),
33.5 (CH2), 34.2 (CH2), 34.4 (CH), 35.8 (C), 36.8 (CH2),
38.4 (CH), 39.1 (CH2), 40.5 (CH2), 41.4 (C), 44.7 (CH),
54.5 (CH), 55.0 (CH), 55.4 (CH3), 64.6 (CH), 68.3 (CH2),
76.7 (CH), 79.8 (CH), 83.1 (CH), 84.4 (C), 120.6 (C); MS
m/z (rel intensity) 444 (MC-H2O, 5), 426 (34), 287 (100);
HRMS calcd for C28H44O4 444.3240; found 444.3239.
Anal. Calcd for C28H46O5: C, 72.69; H, 10.02. Found: C,
72.85; H, 9.74.
C28H44O4 444.3240; found 444.3252. Anal. Calcd for
C28H46O5: C, 72.69; H, 10.02. Found: C, 72.72; H, 9.98.
4.1.15. (22S,23S,25R)-3b-Methoxy-22,26-epoxy-5a-
spirostan-23,25-diol (34). A solution of compound 33
(46 mg, 0.1 mmol) in CHCl3 (2.5 mL) was treated with p-
TsOH (5 mg dissolved in 0.5 mL CHCl3) and stirred at room
temperature for 24 h. The reaction mixture was neutralized
with Amberjet 4400 OH, filtered and concentrated.
Chromatotron chromatography (toluene-EtOAc, 65:35) of
the residue afforded starting material 33 (31 mg, 0.06 mmol,
60%) and compound 34 (13 mg, 0.03 mmol, 30%).
Compound 34: mp 263–263.5 8C (from acetone); [a]D
1
K132.8 (c 0.07); IR 3576 cmK1; H NMR 0.64 (1H, m),
0.79 (3H, s), 0.80 (3H, s), 0.95 (3H, d, JZ7.0 Hz), 1.30 (3H,
s), 1.99 (1H, ddd, JZ5.5, 7.6, 12.3 Hz), 2.07 (1H, ddd, JZ
2.5, 5.2, 11.6 Hz), 2.50 (1H, dddd, JZ7.0, 7.0, 7.0, 7.0 Hz),
3.11 (1H, dddd, JZ4.6, 4.6, 10.9, 10.9 Hz), 3.19 (1H, dd,
JZ2.5, 10.4 Hz), 3.33 (3H, s), 3.49 (1H, dd, JZ5.3,
11.7 Hz), 3.50 (1H, d, JZ10.2 Hz), 4.46 (1H, ddd, JZ7.1,
7.1, 8.7 Hz); NOE correlation from 23-H to 20-H, to 21-H3;
13C NMR (100.6 MHz) 12.3 (CH3), 13.9 (CH3), 16.6 (CH3),
21.0 (CH2), 25.0 (CH3), 27.8 (CH2), 28.7 (CH2), 31.6 (CH2),
32.3 (CH2), 34.3 (CH2), 34.9 (CH), 35.6 (CH), 35.9 (C),
36.9 (CH2), 40.1 (CH2), 41.0 (C), 44.6 (CH2), 44.8 (CH),
54.4 (CH), 55.5 (CH3), 56.2 (CH), 61.5 (CH), 65.8 (CH),
68.2 (CH2), 68.9 (C), 79.8 (CH), 82.0 (CH), 110.0 (C); MS
m/z (rel intensity) 462 (MC, 1), 444 (2), 426 (5), 287 (100);
HRMS calcd for C28H46O5 462.3345; found 462.3336.
Anal. Calcd for C28H46O5: C, 72.69; H, 10.02. Found: C,
72.89; H, 10.13.
4.1.16. (22S,23S,25R)-3b-Methoxy-23-acetoxy-5a-spiro-
stan-23,25-diol (35). The compound 34 (4 mg, 8.6!
10K3 mmol) was acetylated with Ac2O and pyridine to give
after chromatography (hexanes–EtOAc, 85:15) compound
35 (3 mg, 5.9!10K3 mmol, 68%): amorphous; [a]D K72.0
(c 0.05); IR 3434, 1745 cmK1; 1H NMR 0.64 (1H, m), 0.78
(3H, s), 0.80 (3H, s), 0.96 (3H, d, JZ7.0 Hz), 1.37 (3H, s),
2.04 (3H, s), 2.07 (1H, m), 3.12 (1H, dddd, JZ4.6, 4.6, 10.9,
10.9 Hz), 3.22 (1H, dd, JZ2.0, 10.5 Hz), 3.33 (3H, s), 3.60
(1H, d, JZ10.6 Hz), 4.45 (1H, ddd, JZ7.7, 7.7, 7.7 Hz),
4.84 (1H, dd, JZ5.3, 11.9 Hz); NOE correlation from 23-H
to 20-H, to 21-H3 and to 27-H3; 13C NMR (100.6 MHz) 12.3
(CH3), 13.9 (CH3), 16.1 (CH3), 20.9 (CH2), 21.0 (CH3), 25.3
(CH3), 27.9 (CH2), 28.7 (CH2), 31.6 (CH2), 32.3 (CH2), 34.3
(CH2), 35.2 (CH), 35.9 (C), 36.0 (CH), 36.9 (CH2), 39.9
(CH2), 40.3 (CH2), 41.1 (C), 44.8 (CH), 54.4 (CH), 55.5
(CH3), 56.3 (CH), 61.5 (CH), 66.7 (CH), 68.1 (CH2), 69.0
(C), 79.8 (CH), 81.6 (CH), 108.2 (C), 170.4 (C); MS m/z (rel
intensity) 504 (MC, 3), 486 (6), 444 (31), 287 (100); HRMS
calcd for C30H48O6 504.3451; found 504.3418. Anal. Calcd
for C30H48O6: C, 71.39; H, 9.59. Found: C, 71.27; H, 9.84.
4.1.14. (22R,23S,25R)-3b-Methoxy-22,25-epoxy-5a-furo-
stan-23,26-diol (33). To a solution of compound 31
(108 mg, 0.17 mmol) in THF (25 mL) was added TBAF
(0.84 mL, 0.84 mmol, 1.0 M in THF) and stirred at room
temperature for 1 h. The mixture was then poured into
aqueous saturated solution of NaHCO3 and extracted with
CH2Cl2. The organic extracts were washed with brine, dried
(Na2SO4) and concentrated. A solution of the residue in
MeOH (50 mL) containing KOH (1.7 g) was stirred at room
temperature for 5 h. The mixture was poured into water and
extracted with EtOAc. The combined extracts were washed
with brine, dried (Na2SO4) and concentrated. Chromatotron
chromatography (hexanes–EtOAc, 7:3) afforded compound
33 (74 mg, 0.16 mmol, 91%): mp 198.5–199.7 8C (from n-
hexane-EtOAc); [a]D K47.7 (c 0.13); IR 3567 mmolcmK1
;
1H NMR 0.64 (1H, m), 0.77 (3H, s), 0.79 (3H, s), 0.95 (3H,
d, JZ7.0 Hz), 1.26 (3H, s), 1.69 (1H, dd, JZ9.8, 12.4 Hz),
2.32 (1H, dd, JZ8.5, 12.4 Hz), 3.10 (1H, dddd, JZ4.6, 4.6,
11.0, 11.0 Hz), 3.30 (1H, d, JZ11.0 Hz), 3.32 (3H, s), 3.39
(1H, d, JZ11.3 Hz), 4.03 (1H, ddd, JZ9.0, 9.0, 9.0 Hz),
4.55 (1H, ddd, JZ6.6, 6.6, 8.7 Hz); NOE correlation from
23 to 21-Me, to 20-H and to 26-H2; 13C NMR (100.6 MHz)
12.2 (CH3), 14.3 (CH3), 16.4 (CH3), 20.9 (CH2), 25.6 (CH3),
27.8 (CH2), 28.7 (CH2), 31.8 (CH2), 32.2 (CH2), 34.3 (CH2),
34.9 (CH), 35.5 (CH), 35.8 (C), 36.8 (CH2), 40.0 (CH2),
41.0 (C), 41.3 (CH2), 44.7 (CH), 54.3 (CH), 55.5 (CH3),
56.1 (CH), 61.8 (CH), 69.8 (CH2), 72.2 (CH), 79.7 (CH),
81.3 (CH), 81.3 (C), 116.7 (C); MS m/z (rel intensity) 444
(MC-H2O, 5), 426 (27), 287 (100); HRMS calcd for
Acknowledgements
This work was supported by the Investigation Programmes
´
nos. BQU2000-0650 and BQU2001-1665 of the Direccion
General de Investigacion Cientıfica y Tecnica, Spain. I.P.-
´
´
´
M. thanks the I3P-CSIC Program for a fellowship.

C. Betancor et al. / Tetrahedron 61 (2005) 2803–2814
2813
J. Am. Chem. Soc. 2002, 124, 4548–4549. (g) Lee, S.; Fuchs,
P. L. Org. Lett. 2002, 3, 317–318. (h) LaCour, T. G.; Tong, Z.;
Fuchs, P. L. Org. Lett. 1999, 1, 1815–1818.
Supplementary data
Detailed experimental procedures, and spectral and analy-
tical data for compounds 6-R, 6-S, 7-R, 7-S, 8-R, 8-S, 9-R, 9-
S, 10-R, 10-S, 11-S, 12-R, 12-S, 13-S, 14-R, and 14-S (15
pages) are provided. A figure with the pseudorotational
wheels for E and F-rings is also included.
6. LaCour, T. G.; Guo, C.; Boyd, M. R.; Fuchs, P. L. Org. Lett.
2000, 2, 33–36.
7. Isolation (a) : Kubo, S.; Mimaki, Y.; Terao, M.; Sashida, Y.;
Nikaido, T.; Ohmoto, T. Phytochemistry 1992, 31, 3969–3973.
Synthesis (b): Guo, C.; Fuchs, P. L. Tetrahedron Lett. 1998,
39, 1099–1102. (c) Deng, S.; Yu, B.; Lou, Y.; Hui, Y. J. Org.
Chem. 1999, 64, 202–208. (d) Morzycki, J. W.; Gryszkiewicz,
A.; Jastrzebska, I. Tetrahedron Lett. 2000, 41, 3751–3754.
(e) Yu, W.; Jin, Z. J. Am. Chem. Soc. 2001, 123, 3369–3370.
(f) Yu, W.; Jin, Z. J. Am. Chem. Soc. 2002, 124, 6576–6583.
8. Guo, C.; LaCour, T. G.; Fuchs, P. L. Bioorg. Med. Chem. Lett.
1999, 9, 419–424.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2005.01.
077
9. Part of this work was previously published as a preliminary
´ ´
communication: Betancor, C.; Freire, R.; Perez-Martın, I.;
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it is strongly supported by previous results on related models.
For examples of the influence of the polarity of the substituents
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20. For example, irradiation at H-23 in each of the different

2814
C. Betancor et al. / Tetrahedron 61 (2005) 2803–2814
diastereoisomers results in enhancement of the following
C24–H24aZ154.4 and H23–C23–C24–H24bZ34.88) and 18 (H23–
C23–C24–H24aZ29.7 and H23–C23–C24–H24bZ90.68).
26. (a) Fuchs, B. Top. Stereochem. 1978, 10, 1–94. (b) Romers, C.;
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protons: 17 (21-Me and 26-H2), 18 (18-Me and 20-H), 22 (21-
Me and 27-Me), 23 (18-Me, 20-H, and 27-Me), 27 (21-Me), 28
(20H, 21-Me, and 27-Me), 32 (21-Me), 33 (21-Me and 26-H2).
21. Crystallographic data (excluding structure factors) for the
structures 18, 23, 29, and 34 in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC-176076, CCDC-176077,
CCDC-243668, CCDC-243669 respectively. Copies of the
data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [fax: C44 (0) 1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
27. Data were taken from the X-ray analysis of (22S,23R,25S)-
3b,12b-diacetoxy-22,25-epoxy-5a-furostan-23,26-diol.Jeong,
J. U.; Fuchs, P. L. J. Am. Chem. Soc. 1994, 116, 773–774.
28. The five endocyclic dihedral angles fj (JZ0–4) were obtained
from the X-ray cif files using Mercury v. 1.2.1 (Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK) (http://www.ccdc.cam.ac.uk/mercury/).
29. (a) Houseknecht, J. B.; Altona, C.; Hadad, C. M.; Lowary,
T. L. J. Org. Chem. 2002, 67, 4647–4651. (b) Altona, C.;
Sundaralingam, M. J. Am. Chem. Soc. 1973, 95, 2333–2344.
(c) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1972, 94,
8205–8212.
22. Acid-catalyzed spiroketal equilibration in 23-deoxy compounds:
(a) Thompson, M. J.; Scheer, I.; Mosettig, E. J. Am. Chem. Soc.
1959, 81, 5222–5224. (b) Thompson, M. J.; Scheer, I.; Mosettig,
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E. J. Am. Chem. Soc. 1959, 81, 5225–5230. (c) Gonzalez, A. G.;
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Freire, R.; Salazar, J. A.; Suarez, E. Phytochemistry 1971, 10,
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1339–1346. (d) Gonzalez, A. G.; Freire, R.; Salazar, J. Anal.
Quim. 1972, 68, 1021–1027. (e) Jeong, J. U.; Fuchs, P. L.
Tetrahedron Lett. 1994, 35, 5385–5388.
30. IUPAC: Nomenclature of Carbohydrates, IUPAC, (http://
www.chem.qmul.ac.uk/iupac/2carb/). Rule 2-Carb-7.1.
31. Coupling constants were measured using the HLA equation as
implemented in MacroModel v. 7.0: Haasnoot, C. A. G.; de
Leeuw, F. A. A. M.; Altona, C. Tetrahedron 1980, 36,
2783–2792.
23. No compounds of the 1,6-dioxaspiro[4.5]decane type belong-
ing to the (22S)-spirostan, (20R,22R)-spirostan (cyclopseudo-
iso), or (20R,22S)-spirostan (cyclopseudoneo) series of
spirostan sapogenins, which are theoretically possible
through an oxocarbenium ion via an intermediate of furost-
20(22)-en sapogenin, were detected during these acid-
catalyzed experiments. (a) Fieser, L. F.; Fieser, M. In Steroids;
Reinhold Publishing Corp: New York, 1959. (b) IUPAC-IUB
Revised Tentative Rule for Nomenclature of Steroids Verkade,
P. E.; Hoffmann-Ostenhof, O. J. Org. Chem. 1969, 34, 1517–
1532.
32. For an early conformational study of the F-ring of natural
spirostan sapogenins deoxygenated at C-23 see: Callow, R. K.;
James, V. H. T.; Kennard, O.; Page, J. E.; Paton, P. N.; Riva di
Sanseverino, L. J. Chem. Soc. (C) 1966, 288–297.
33. Shortly before submitting our preliminary communication
(Ref. 9) we became aware of the studies by Prof. P.L. Fuchs in
the ASAP section of Organic Letters (Refs. 5g, 19b, see also
Ref. 5c) where IHA reactions are used to prepare related
dioxaspiro compounds.
24. CS Chem3D Ultra v. 6.0, CambridgeSoft Corp.: Cambridge,
MA.
34. (a) Westhof, E.; Sundaralingam, M. J. Am. Chem. Soc. 1983,
105, 970–976. (b) Levitt, M.; Warshel, A. J. Am. Chem. Soc.
1978, 100, 2607–2613.
25. Dihedral angles consistent with these configurations are observed
in the X-ray crystallographic structures of 17 (X-ray) (H23–C23–