The use of symmetry in enantioselective synthesis: Four pairs of chrysene enantiomers prepared from 19-nortestosterone

Article abstract of DOI:10.1039/c1ob05385j

Expansion of the D-ring of 19-norsteroids with incorporation of the steroid C-18 methyl group into a newly formed six-membered ring provides easy access to the chrysene ring system. By taking advantage of the symmetry of the chrysene ring system and avoiding meso chrysene intermediates, four optically pure 2,8-difunctionalized (C-2 hydroxyl group and C-8 oxo group) hexadecahydrochrysene diastereomers, and their corresponding optically pure enantiomers were prepared from 19-nortestosterone. The eight chrysene stereoisomers are of interest as starting materials for preparing chrysene analogues of physiologically important neurosteroids.

Full text of DOI:10.1039/c1ob05385j

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PAPER
The use of symmetry in enantioselective synthesis: Four pairs of chrysene
enantiomers prepared from 19-nortestosterone†
Eva Stastna,a Nigam P. Rathb and Douglas F. Covey*a
Received 11th March 2011, Accepted 28th March 2011
DOI: 10.1039/c1ob05385j
Expansion of the D-ring of 19-norsteroids with incorporation of the steroid C-18 methyl group into a
newly formed six-membered ring provides easy access to the chrysene ring system. By taking advantage
of the symmetry of the chrysene ring system and avoiding meso chrysene intermediates, four optically
pure 2,8-difunctionalized (C-2 hydroxyl group and C-8 oxo group) hexadecahydrochrysene
diastereomers, and their corresponding optically pure enantiomers were prepared from
19-nortestosterone. The eight chrysene stereoisomers are of interest as starting materials for preparing
chrysene analogues of physiologically important neurosteroids.
studies to include enantioselectivity studies in closely related ring
Introduction
systems. In this regard, the chrysene ring system substituted at
Some endogenous steroids in the androgen and pregnane classes
the C-2 and C-8 positions is one such option (Chart 1). This is a
and their analogues are known to be potent modulators of g-
aminobutyric acid type A (GABAA) receptors.1 Among the an-
drogens, the non-naturally occurring enantiomers of androsterone
and etiocholanolone, ent-androsterone and ent-etiocholanolone,
were found to be better modulators of GABAA receptors than
their natural enantiomers2,3 (Chart 1).
particularly attractive ring system for an analogue enantioselec-
tivity study because, as described herein, optically pure chrysene
diastereomers differing in the configurations of their A,B and C,D
ring fusions as well as their optically pure enantiomers can all
be readily prepared from optically pure 19-nortestosterone. The
synthetic strategy used to prepare diastereomers 1–4 and their
corresponding enantiomers ent-1-ent-4 19-nortestosterone (5) is
outlined in Scheme 1.
Chart 1
By contrast, the unnatural enantiomers of several other steroids
in the pregnane class are not more active than their natural
enantiomers.4,5 Currently, the molecular basis for these enantiose-
lectivity differences between the androgen and pregnane classes is
not fully understood. One way to gain a further understanding of
these previous enantioselectivity findings is to enlarge the steroid
aDepartment of Developmental Biology, Campus Box 8103, Washington
University in St. Louis, School of Medicine, 660 S. Euclid Ave., St. Louis,
MO, 63110, USA. E-mail: dcovey@wustl.edu; Fax: +1 314 362 7058;
Tel: +1 314 362 1726
bDepartment of Chemistry and Biochemistry and Center for Nanoscience,
University of Missouri St. Louis, One University Boulevard, St. Louis,
63121, USA
Scheme 1 Stereochemical plan.
† Electronic supplementary information (ESI) available: 1H NMR and 13
C
For chrysenes 1–4, the appropriate choice of reaction conditions
for reduction of the D4-double bond of steroid 5 will establish the
stereochemistry of the A,B ring fusion. Li/liquid NH3 reduction
NMR spectra. Crystal data for the structure shown in Fig. 1, CCDC
reference number 814522. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1ob05385j
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will lead ultimately to the trans A,B-ring fused chrysenes 1 and
2, whereas Pd/C catalyzed hydrogenation in pyridine will lead
ultimately to the cis A,B-ring fused chrysenes 3 and 4. A series
of reactions is then used to first convert the 3-oxo groups of
steroids 6 and 27 into MOM-protected 3a-hydroxyl groups and
then subsequently to expand the steroid five-membered D-ring
into the six-membered D-ring of chrysene enones 16 and 33.
The double bond of these enones is then either reduced using
Li/liquid NH3 to give chrysenes 1 and 3 which have the trans
C,D-ring fusion or reduced using Pd/C catalyzed hydrogenation
in pyridine to give chrysenes 2 and 4 which have the cis C,D-ring
fusion. The corresponding 2,8-diketones formed by oxidation of
the hydroxyl groups of chrysenes 1 and 4 have a center of symmetry
at the mid-point of the C-4b,C-10b bond and are therefore non-
optically active meso structures. Because of this symmetry, we
reasoned that chrysenes 1 and 4 could be converted to their
corresponding enantiomers ent-1 and ent-4 by interchanging the
positions of the hydroxyl (axial for chrysenes 1 and 2, equatorial
for chrysenes 3 and 4) and oxo groups of these chrysenes as long as
meso structures (e.g., the 2,8-diketones or diaxial-2,8-diols) were
avoided. We accomplished this by using protection/deprotection
reactions in combination with oxidation/reduction reactions to
switch the relative positions of the hydroxyl and oxo groups.
The 2,8-diketones derived from chrysenes 2 and 3 do not have
a center of symmetry and are not meso structures. Consequently,
use of the same strategy to switch the relative positions of the
hydroxyl and oxo groups does not lead to their corresponding
enantiomers. However, this same chemistry will convert chrysene
2 to ent-3, the enantiomer of chrysene 3, and chrysene 3 to ent-
2, the enantiomer of chrysene 2. Thus, we planned to convert
chrysenes 1–4 to their corresponding enantiomers by simple
procedures that preclude any degree of racemization of the
previously established stereocenters at C-4a, C-4b, C-6a, C-10a,
C-10b or C-12a.
Scheme 2 Synthesis of chrysenes 1 and 2.
hydroxyl group, compound 12 was treated with acetic anhydride in
pyridine in the presence of DMAP at room temperature to afford
the 3-acetate derivative 13 in 90% y◦ield. Compound 13 then gave
upon ozonolysis in CH2Cl2 at -78 C and subsequent reduction
with Zn/AcOH of the intermediate cyclic ozonide, diketone 14 in
79% yield. Diketone 14 was then cyclized using aqueous NaOH
in MeOH to the desired enone 15 in 75% yield. Since enone 15
was sparingly soluble in most solvents (e.g. hexanes, EtOAc),
it was treated with MOMCl and N,N-diisopropylethylamine at
room temperature overnight to afford the more soluble MOM
derivative 16 in 79% yield. Reduction of the double bond of enone
16 with Li/liquid NH3 gave chrysene 17 (79% yield) having the
trans C,D-ring fusion, and reduction of this double bond with
Pd/C in pyridine gave chrysene 18 (75%) having the cis C,D-ring
fusion. Finally, the MOM groups of compounds 17 and 18 were
removed using 6 N aqueous HCl in MeOH. Compounds 1 and
2 were prepared in 13 steps from 19-nortestosterone (5) in total
yields of 4.5% and 4.6%, respectively.
Results and discussion
Synthesis of chrysenes 1 and 2
Commercially available 19-nor-testosterone (5) was converted by
Li/liquid NH3 reduction followed by Jones oxidation to (5a)-
estrane-3,20-dione (7) in two steps in 63% overall yield6 (Scheme
2). The 3-oxo group was then selectively reduced by K-Selectride
in THF at -78 ◦C to afford the axial-3-alcohol derivative 8 in 55%
yield. Treatment of compound 8 with acetic anhydride in pyridine
in the presence of DMAP at room temperature gave the axial-3-
acetate derivative 9 in 91% yield. NaBH4 reduction of the 17-oxo
group in EtOH gave the 17b-alcohol derivative 10 in 87% yield.
Compound 10 was then treated with p-toluenesulfonyl chloride in
the presence of DMAP in pyridine at 90 ◦C to give the 17b-tosylate
11 in 90% yield. The Ka¨gi-Miescher rearrangement7,8,9 (1,2 shift
of the C-18 methyl group) was accomplished by following the
modified procedure of Engel et al.10 by refluxing of 17b-tosylate
11 in toluene with methylmagnesium bromide to afford the desired
Synthesis of chrysenes ent-1 and ent-3
A reaction sequence which utilized protection/deprotection chem-
istry in combination with oxidation/reduction chemistry was used
for the synthesis of compound ent-1 from compound 17 (Scheme
3). The 2-oxo group of compound 17 was selectively reduced by K-
Selectride in THF at -78 ◦C to afford the axial-alcohol 19 in 79%
yield. Treatment of compound 19 with BnBr/KH in THF gave the
benzyl derivative 20 in 75% yield. Acidic hydrolysis of compound
20 with aqueous HCl in MeOH gave compound 21 which was
then subsequently oxidized with Jones reagent to compound 22
(77% yield in each step). Overnight hydrogenation of chrysene 22
using Pd/C in EtOAc did not lead to the desired product and
only starting material was recovered. If EtOH was used instead of
EtOAc as solvent, a mixture of desired compound ent-1 and other
side products were obtained. A characteristic broad multiplet at
1
D13(17)-ene derivative 12 in 76% yield. The H NMR spectrum of
1
compound 12 displayed a singlet for the migrated methyl group at
d 1.61 and the 13C NMR of the compound showed resonances at d
136.8 and d 127.8 for the D13(17)-double bond. Since the conditions
of the Ka¨gi-Miescher rearrangement led to deprotection of the 3-
d 3.59 ppm in the H NMR spectrum of the major side product
indicated that reduction of the oxo group had occurred when
EtOH was the solvent. Finally, hydrogenation using a mixture of
Pd/C and Pd(OH)2 (4 : 1) in EtOH afforded the desired compound
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Scheme 4 Synthesis of chrysenes 3 and 4.
the D13(17)-ene derivative 30 was carried out in 98% yield. This
product’s structure was confirmed by its 1H NMR and 13C NMR
spectra which showed a resonance for the migrated 18-methyl
group as a singlet at d 1.60 in the 1H NMR spectrum and
resonances at d 136.7 and d 127.9 for the D13(17)-double bond in
the 13C NMR spectrum. To avoid potential solubility issues in the
subsequent ozonolysis and D-ring closure reactions, compound
30 was first converted to MOM-derivative 31 (99%). Ozonolysis
of compound 31 gave compound 32 in 65% yield, and ring closure
of this product under basic conditions afforded compound 33
(83% yield). Reduction of the double bond of compound 33 using
Li/liquid NH3 gave product 34 (51%) which had the trans C,D
ring fusion. Reduction of the double bond of compound 33 by
catalytic hydrogenation using Pd/C in pyridine gave product 35
(53%) which had the cis C,D ring fusion. Finally, the MOM groups
of compounds 34 and 35 were removed under acidic conditions
using aqueous 6 N HCl in MeOH. Compound 3 and compound 4
were each prepared in 9 steps from 19-nortestosterone (5) in total
yields of 5.5% and 6%, respectively.
Scheme 3 Synthesis of chrysenes ent-1 and ent-3.
ent-1 in 61% yield. Chrysene ent-1 was prepared in 17 steps from
19-nortestosterone (5) in a total yield of 0.8%.
A benzoate ester instead of a benzyl ether protecting group was
used for the synthesis of chrysene ent-3 because of the difficulty
encountered with removal of the benzyl ether protecting group
in the synthesis of chrysene ent-1. Except for the changes in
hydroxyl group protection/deprotection reactions, the synthetic
strategy used to prepare compounds ent-3 and ent-1 were the same.
Thus, the 2-oxo group of compound 18 was selectively reduced by
lithium tri(tert-butoxy)aluminum hydride in THF at -40 ◦C to
afford equatorial-alcohol 23 in 65% yield. The hydroxyl group
stereochemical assignment was confirmed by 1H-NMR which
showed a resonance at d 3.64 that was a multiplet (W1/2 ~ 36 Hz)
as expected for an axial-proton at C-2 in chrysene 23. Treatment
of compound 23 with benzoyl chloride in the presence of DMAP
gave benzoate ester 24 in 99% yield. Acidic hydrolysis with aqueous
HCl in MeOH gave compound 25 (91% yield) and a subsequent
Jones oxidation gave intermediate 26 (73% yield). Basic hydrolysis
using aqueous NaOH in MeOH at room temperature afforded the
desired chrysene ent-3 in 92% yield. Compound ent-3 was prepared
in 17 steps from 19-nortestosterone (5) in total yield of 2.7%. The
increase in overall yield for the preparation of ent-3 relative to
the overall yield obtained for ent-1 is largely due to the improved
choice of the benzoate protecting group used for the synthesis of
ent-3.
Synthesis of chrysenes ent-2 and ent-4
Protecting groups used during the synthesis of compounds ent-
2 and ent-4 were the methoxymethyl and benzoate ester groups
(Scheme 5). The 2-oxo group of compound 34 was selectively
reduced using K-Selectride to afford derivative 36 in 76% yield.
Lithium tri(tert-butoxy)aluminum hydride reduction of com-
pound 35 was used to obtain compound 40 in 60% yield. Treatment
of compound 36 as well as compound 40 with benzoyl chloride in
the presence of DMAP gave ester 37 in 84% yield and ester 41 in
88% yield, respectively. Overnight acidic hydrolysis of compound
37 with aqueous HCl (Method A) was very slow and afforded
only a 42% yield of compound 38 (47% of starting material
was recovered). Therefore, acetylchloride in MeOH (Method B)
was used to carry out transesterification reactions to obtain
compounds 38 and 42 in yields of 91% and 80%, respectively.
Jones oxidation of compound 38 (75% yield) followed by basic
hydrolysis of oxidation product 39 using aqueous NaOH in MeOH
at 50 ◦C (92% yield) afforded chrysene ent-2. Similarly, compound
ent-4 was obtained by oxidation of compound 42 (96% yield)
and hydrolysis of compound 43 (86% yield). Compound ent-2
Synthesis of chrysenes 3 and 4
The experience gained in the synthesis of chrysenes 1 and 2
(Scheme 2) motivated us to modify the synthetic sequence to
decrease the number of reactions needed to prepare chrysenes 3
and 4 (Scheme 4). Catalytic hydrogenation of 19-nor-testosterone
(5) in pyridine using Pd/C gave (5b,17b)-17-hydroxyestrane-3-
one (27, 40% yield). Tosylation of the 17-hydroxyl group gave
compound 28, and subsequent selective reduction of the 3-
oxo group afforded intermediate 29 in yields of 78% and 88%,
respectively. Ka¨gi-Miescher rearrangement of compound 29 to
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derivative since its optical rotation as well as that of chrysene 2
were both negative.
Conclusions
Because of the symmetry of the chrysene ring system we were able
to develop efficient procedures for the preparation of four pairs
of 2,8-disubstituted hexadecahyrochrysene enantiomers from 19-
nortestosterone. These procedures provide each enantiomer in
any pair of chrysene enantiomers in optically pure form. To
our knowledge there are no previous reports in the literature of
enantiospecific routes to these optically active 2,8-disubstituted
hexadecahydrochrysenes. The successful development of the syn-
thetic routes to the reported chrysenes makes these compounds
available as starting materials for structure–activity studies of
chrysene modulation of GABAA receptors and other ligand-gated
ion channels known to be modulated by steroids.
Experimental
Scheme 5 Synthesis of chrysenes ent-2 and ent-4.
General
was prepared in 13 steps from 19-nortestosterone (5) in a total
yield of 3%. Compound ent-4 was prepared in 13 steps from 19-
nortestosterone (5) in a total yield of 2.9%.
Solvents were either used as purchased or dried and purified
by standard methodology. All extraction solvents were dried
with anhydrous Na2SO4. Flash chromatography was performed
using silica gel (32–63 mm) purchased from Scientific Adsorbents
(Atlanta, GA). Melting points were determined on Kofler micro
hot stage and are uncorrected. Infrared spectra were recorded
as films on a NaCl plate on a Perkin–Elmer Spectrum One FT-
IR spectrometer. Optical rotations were measured on a Perkin–
Elmer Model 341 Polarimeter in the solvent indicated. NMR
spectra were recorded on Varian NMR spectrometer in CDCl3
at ambient temperature operating at 300 MHz (1H) or 75 MHz
(13C). Chemical shifts are reported as d values relative to internal
chloroform (d = 7.27) for 1H and chloroform (d = 77.23) for 13C.
Summary
The enantiomeric relationship between chrysenes 1–4 and their
corresponding enantiomers ent-1-ent-4 was confirmed by compar-
ison of the physical and spectroscopic properties of the enantiomer
pairs. Optical rotations and melting points are summarized in
Table 1. Additional comparisons of IR and 1H-NMR spectra
for the enantiomer pairs can be made of this data as reported
in the Experimental Section. The near zero values for the
optical rotations of chrysenes 2 and 4 and their corresponding
enantiomers made determinations of their optical purity by optical
rotation measurements unreliable. Accordingly, the absolute con-
figuration of compound ent-2 was confirmed by an X-ray structure
determination (Fig. 1) of the compound’s 4-bromobenzoate ester
1
For the H NMR spectra, only the chemical shifts associated
with substituents are listed. The chemical shifts of the remaining
steroid or chrysene envelope protons can be found in the spectra
reported in the Supportive Information. Reactions were moni-
tored by thin layer chromatography (TLC) with 250 mm precoated
silica gel plates (Analtech). Elemental analyses were performed by
M-H-W Laboratories (Phoenix, AZ).
Table 1 Values of optical rotation and melting points for chrysenes 1–4
and their corresponding enantiomers
nat-Chrysenes
ent-Chrysenes
1
2
3
4
[a]2D0 -25.65
[a]2D0 -0.92
[a]2D0 -28.37
[a]2D0 -1.67
183–184 ◦
158–161 ◦
161–163 ◦
181–183 ◦
C
C
C
C
ent-1 [a]2D0 +26.51
ent-2 [a]2D0 -1.88
ent-3 [a]2D0 +29.7
ent-4 [a]2D0 +0.68
182–184 ◦
160–162 ◦
160–162 ◦
183–184 ◦
C
C
C
C
Experimental section
(4aR, 4bS, 6aS, 8R, 10aS, 10bR, 12aR) - 8 - Hydroxy - hexadeca -
hydro-chrysen-2-one (1). A solution of compound 17 (110 mg,
0.34 mmol) in MeOH (8 mL) was treated with 6 N HCl
(1 mL) at room temperature. After 15 h, it was poured into
water–ice and aqueous sat. NaHCO3 was added to pH 8. The
precipitated product was filtered off, dried at room temperature,
and recrystallized from EtOAc/hexanes to afford desired alcohol
◦
1 (82 mg, 86%): mp 183–184 C (EtOAc/hexanes); [a]2D0 -25.65
(c 0.11 in CHCl3). Found: C, 78.1; H, 10.3. Calc for C18H28O2: C,
78.2; H, 10.2%. IR (nmax/cm-1) 3438, 2946, 2914, 2850, 1702. dH
(300 MHz, CDCl3) 4.1 (1H, bs). dC (75 MHz, CDCl3) 212.3, 66.5,
48.8, 47.5, 46.9, 46.8, 46.4, 43.5, 41.5, 40.6, 35.7, 34.2, 33.7, 33.1,
30.5, 30.1, 29.4, 23.5.
Fig. 1 Projection plot showing the absolute configuration of the benzoate
derivative of chrysene ent-2.
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(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) - 8 - Hydroxy - hexadeca-
hydro-chrysen-2-one (ent-1). Compound 22 (103 mg, 0.28 mmol)
was dissolved in EtOH (50 mL). To this, 10% Pd/C (20 mg)
and Pd(OH)2 (5 mg) were added. The reaction mixture was
hydrogenated (60 psi, H2) for 3.5 h, then additional Pd(OH)2 (5 mg)
was added. After 2 h of hydrogenation, the reaction mixture was
filtered through a short column of silica gel to remove the catalyst,
washing with CH2Cl2. Solvents were removed under vacuo and
the residue was purified by column chromatography on silica gel
(5% EtOAc in CH2Cl2) to give compound ent-1 (47 mg, 61%) as a
white solid: mp 182–184 ◦C (EtOAc/hexanes), [a]2D0 +26.51 (c 0.23
in CHCl3). Found: C, 78.0; H, 10.1. Calc for C18H28O2 C, 78.2;
H, 10.2%. IR (nmax/cm-1) 3437, 2914, 2850, 1702. dH (300 MHz,
CDCl3) 4.1 (1H, m); dC (75 MHz, CDCl3) 212.3, 66.5, 48.8, 47.4,
46.96, 46.93, 46.45, 43.5, 41.5, 40.7, 35.7, 34.3, 33.8, 33.2, 30.5,
30.1, 29.4, 23.6.
(4aS, 4bR, 6aS, 8S, 10aR, 10bS, 12aS) - 8 - Hydroxy - hexadeca-
hydro-chrysen-2-one (ent-3).
A solution of compound 26
(250 mg, 0.65 mmol) in MeOH (36 mL) and water (1 mL) was
treated with NaOH (500 mg, 12.5 mmol) at 50 ◦C. After 1
h, the solution was poured into water (100 mL) and extracted
with CH2Cl2 (2 ¥ 100 mL). The combined extracts were washed
with brine and solvent dried over anhydrous Na2SO4. After
solvent evaporation, the oily residue was purified by column
chromatography on silica gel (20% EtOAc in hexanes) to afford
compound ent-3 (168 mg, 92%) as a white solid: mp 160–162 ◦C
(EtOAc/hexanes); [a]2D0 +29.7 (c 0.19 in CHCl3). Found: C, 78.3;
H, 10.5. Calc. for C18H28O2 calcd. C, 78.2; H, 10.2%. IR (nmax/cm-1)
3410, 2916, 2862, 1714. dH (300 MHz, CDCl3) 3.66 (1H, bm); dC
(75 MHz, CDCl3) 212.2, 71.8, 48.8, 47.3, 46.3, 43.5, 41.5, 40.4,
37.4, 36.3, 35.4, 34.2, 31.6, 30.5, 29.9, 29.5, 25.8, 25.3.
(4aR, 4bS, 6aR, 8R, 10aS, 10bR, 12aS) - 8 - Hydroxy - hexadeca-
hydro-chrysen-2-one (4). Compound 4 was prepared in the same
manner as compound 1. Starting from compound 35 (149 mg,
0.46 mmol), compound 4 (93 mg, 72%) was obtained as a white
solid after column chromatography on silica gel (20% EtOAc in
hexanes): mp 181–183 ◦C (EtOAc/hexanes); [a]2D0 -1.67 (c 0.21 in
CHCl3). Found: C, 78.0; H, 10.1. Calc. for C18H28O2 C, 78.2; H,
10.2%. IR (nmax/cm-1) 3464, 2929, 2907, 2857, 1697. dH (300 MHz,
CDCl3) 2.58 (1H, t, J = 14 Hz), 4.1 (1H, bs); dC (75 MHz, CDCl3)
213.2, 71.8, 43.0, 40.4, 40.3, 38.2, 37.9, 37.7, 36.7, 36.3, 35.5, 31.6,
30.8, 29.9, 27.6, 25.8, 25.1, 24.2.
(4aR, 4bS, 6aS, 8R, 10aS, 10bR, 12aS) - 8 - Hydroxy - hexadeca-
hydro-chrysen-2-one (2). Compound 2 was prepared in the same
manner as compound 1. Starting from compound 18 (221 mg,
0.69 mmol), compound 2 (146 mg, 76%) was obtained as a white
solid after column chromatography on silica gel (2% EtOAc in
◦
CH2Cl2): mp 158–161 C (EtOAc/hexanes); [a]2D0 -0.92 (c 0.26
in CHCl3). Found: C, 78.3; H, 10.1. Calc. for C18H28O2 C, 78.2;
H, 10.2%. IR (nmax/cm-1) 3401, 2914, 2857, 1706. dH (300 MHz,
CDCl3) 2.58 (1H, t, J = 13.5 Hz), 4.1 (1H, bs); dC (75 MHz, CDCl3)
213.4, 66.4, 47.4, 47.3, 43.0, 40.7, 40.5, 38.1, 37.5, 36.7, 35.6, 33.8,
33.1, 30.8, 29.8, 27.5, 24.1, 23.5.
(4aS, 4bR, 6aS, 8S, 10aR, 10bS, 12aR) - 8 - Hydroxy - hexadeca-
hydro-chrysen-2-one (ent-4). Compound ent-4 was prepared in
the same manner as compound ent-3. Starting from compound 43
(270 mg, 0.71 mmol), compound ent-4 (170 mg, 86%) was obtained
as a white solid after column ch◦romatography on silica gel (20%
EtOAc in hexanes): mp 183–184 C (EtOAc/hexanes); [a]2D0 +0.68
(c 0.29 in CHCl3). IR (nmax/cm-1) 3466, 2907, 2857, 1697, 1067.
dH (300 MHz, CDCl3) 2.57 (1H, t, J = 13.8 Hz), 3.66 (1H, bm);
dC (75 MHz, CDCl3) 213.0, 71.8, 43.0, 40.5, 40.4, 38.2, 38.0, 37.8,
36.6, 36.4, 35.5, 31.6, 30.8, 29.9, 27.6, 25.8, 25.1, 24.2. HRMS
(FAB) m/z Cacld for C18H29O2 [M]+ 277.2168, found: 277.2170.
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aR) - 8 - Hydroxy - hexadeca-
hydro-chrysen-2-one (ent-2).
A solution of compound 39
(317 mg, 0.83 mmol) in MeOH (50 mL) and water (1 mL) was
treated with NaOH (578 mg, 14.4 mmol) at 50 ◦C. After 1 h,
TLC indicated 90% starting material remained. NaOH (400 mg,
10.0 mmol) was added again and the reaction mixture was heated
at 50 ◦C. After 5 h, the solution was poured into water (100 mL)
and extracted with CH2Cl2 (2 ¥ 100 mL). The combined extracts
were washed with brine and the solvent dried over anhydrous
Na2SO4. After solvent evaporation, the oily residue was purified
by column chromatography on silica gel (20% EtOAc in hexanes)
to afford compound ent-2 (210 mg, 91%) as a white solid: mp 160–
162 ◦C (EtOAc/hexanes); [a]D20 -1.88 (c 0.25 in CHCl3). Found: C,
78.4; H, 10.2. Cacl. for C18H28O2 C, 78.2; H, 10.2%. IR (nmax/cm-1)
3411, 2914, 2857, 2822. dH (300 MHz, CDCl3) 4.09 (1H, m), 2.58
(1H, t, J = 13.8 Hz); dC (75 MHz, CDCl3) 213.1, 66.4, 47.4, 47.2,
42.9, 40.7, 40.4, 38.0, 37.5, 36.6, 35.6, 33.7, 33.1, 30.8, 29.8, 27.4,
24.0, 23.5.
(5a)-Estrane-3,17-dione (7). Compound 7 was prepared in two
steps from 19-nortestosterone (5) according to the literature11,12 as
a white solid: mp 99–100 ◦C (EtOAc/hexanes). Found: C, 79.0; H,
9.8. Calc. for C18H26O2 C, 78.8; H, 9.55%. dH (300 MHz, CDCl3)
0.90 (3H, s); dC (75 MHz, CDCl3) 221.0, 211.4, 50.6, 48.7, 48.1,
48.0, 45.9, 43.8, 41.4, 40.7, 36.0, 33.9, 31.7, 30.7, 29.7, 25.6, 21.8,
14.0.
(3a,5a)-3-Hydroxyestran-17-one (8). Compound 8 was p◦re-
pared according to the literature13 as a white solid: mp 160–161 C
(EtOAc/CHCl3). Found:C, 78.4; H, 9.9. Calc for C18H28O2 C, 78.2;
H, 10.2%. dH (300 MHz, CDCl3) 0.82 (3H, s), 2.34–2.43 (1H, m),
4.03 (1H, bm); dC (75 MHz, CDCl3) 221.6, 66.2, 50.7, 48.3, 47.9,
47.0, 40.8, 40.6, 36.0, 35.9, 33.5, 33.0, 31.6, 29.9, 24.9, 23.7, 21.7,
13.9.
(4aR, 4bS, 6aR, 8R, 10aS, 10bR, 12aR) - 8 - Hydroxy - hexadeca-
hydro-chrysen-2-one (3). Compound 3 was prepared in the same
manner as compound 1. Starting from compound 34 (156 mg,
0.48 mmol), compound 3 (100 mg, 75%) was obtained as a white
solid after column chromatography on silica gel (20% EtOAc in
hexanes): mp 161–163 ◦C (EtOAc/hexanes); [a]2D0 -28.37 (c 0.24 in
CHCl3). Found: C, 78.5; H, 10.0. Calc. for C18H28O2 calcd. C, 78.2;
H, 10.2%. IR (nmax/cm-1) 3409, 2916, 2862, 1714. dH (300 MHz,
CDCl3) 3.57 (1H, bm); dC (75 MHz, CDCl3) 212.2, 71.8, 48.8,
47.3, 46.3, 43.4, 41.4, 40.4, 37.3, 36.3, 35.3, 34.2, 31.6, 30.5, 29.9,
29.4, 25.8, 25.3.
(3a,5a)-3-(Acetyloxy)estran-17-one
(9). 4-Dimethylamino-
pyridine (114 mg, 0.9 mmol) and acetic anhydride (4.2 mL,
44.7 mmol) were added to a solution of steroid 8 (2.6 g, 9.4 mmol)
in pyridine (25 mL). After 2 h at room temperature, the reaction
mixture was poured into ice–water, stirred for 2 h, and then
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extracted with EtOAc (3 ¥ 70 mL). Combined extracts were
washed with an aqueous solution of KHCO3, brine, and dried
over anhydrous Na2SO4. After solvent evaporation, the oily
residue was purified by column chromatography on silica gel
(15% EtOAc in hexanes) to give compound 9 (2.74 g, 91%) as a
white solid: mp 96–98 ◦C (Et2O/hexanes). Found: C, 75.6; H, 9.3.
Calc. for C20H30O3 C, 75.4; H, 9.5%. dH (300 MHz, CDCl3) 0.85
(3H, s), 2.01 (3H, s), 5.02 (1H, bm); dC (75 MHz, CDCl3) 221.4,
170.7, 69.9, 50.8, 48.3, 48.0, 46.7, 40.9, 37.7, 36.9, 35.9, 33.4, 31.7,
30.2, 29.8, 25.0, 24.5, 21.7, 21.6, 13.9.
extracts were washed with brine, dried over anhydrous Na2SO4
and the solvents evaporated. Column chromatography on silica
gel (5% EtOAc in CH2Cl2) gave compound 12 (230 mg, 76%)
◦
as a white solid: mp 125–128 C (CH2Cl2/hexanes); [a]2D0 +4.30
(c 0.62 in CHCl3). Found: C, 82.9; H, 11.0. Calc for C18H28O
C, 83.0; H, 10.8%. IR (nmax/cm-1) 3350, 2920, 2848, 1595. dH
(300 MHz, CDCl3) 1.61 (3H, s), 2.47–2.57 (1H, m), 4.08 (1H, m).
dC (75 MHz, CDCl3) 136.8, 127.8, 66.7, 52.9, 51.3, 47.3, 46.4,
40.9, 37.4, 36.0, 33.8, 33.3, 31.5, 29.8, 28.2, 25.6, 23.9, 13.6.
(3a,5a)-3-(Acetyloxy)-17-methylgon-13(17)-ene (13). Com-
pound 13 was prepared in the same manner as compound 9.
Starting from compound 12 (6.9 g, 26.5 mmol), compound
13 (7.23 g, 90%) was obtained as a white solid after column
chromatography on silica gel (10% EtOAc in hexanes): mp
(3a,5a,17b)-Estrane-3,17,diol 3-acetate (10). Compound 9
(10 g, 31.4 mmol) was dissolved in EtOH (400 mL) and cooled
in an ice-bath. NaBH4 (1.2 g, 31.7 mmol) was added in small
portions to a stirred solution. After 1.5 h, the reaction mixture
was poured into a solution of brine (500 mL) and AcOH (7 mL)
and stirred for 1h. The precipitate was filtered off, dissolved in
CH2Cl2 (400 mL), and washed with brine. Solvent was dried over
anhydrous Na2SO4 and evaporated. Column chromatography on
silica gel (10% EtOAc in CH2Cl2) gave compound 10 (8.7 g, 87%)
◦
103–104 C (Et2O/hexanes); [a]2D0 +6.41 (c 0.88 in CHCl3).
Found: C, 79.5; H, 10.0. Calc. for C20H30O2 C, 79.4; H, 10.0%. IR
(nmax/cm-1) 3351, 2917, 2847, 1734, 1597. dH (300 MHz, CDCl3)
1.61 (3H, s), 2.06 (3H, s), 5.0 (1H, bs). dC (75 MHz, CDCl3) 170.9,
136.7, 127.9, 70.2, 53.0, 51.2, 46.9, 46.3, 37.8, 37.4, 36.8, 33.6,
31.4, 30.4, 29.8, 28.2, 25.6, 24.6, 21.7, 13.6.
◦
as a white solid: mp 219–221 C (CHCl3/hexanes); [a]2D0 +28.67
(c 0.75 in CHCl3). Found: C, 75.2; H, 9.9. Calc. for C20H32O3 C,
75.0; H, 10.1%. IR (nmax/cm-1) 3436, 2933, 2951, 2899, 2857, 2840,
1698. dH (300 MHz, CDCl3) 0.74 (3H, s), 2.04 (3H, s), 3.63 (1H,
t, J = 8.5 Hz), 5.03 (1H, bm); dC (75 MHz, CDCl3) 170.9, 82.2,
70.2, 50.4, 48.3, 46.8, 43.3, 41.5, 37.8, 37.0, 36.9, 33.6, 30.7 (2 ¥
C), 30.3, 25.4, 24.6, 23.4, 21.7, 11.7.
Acetic acid (1S,4aR,4bS,7R,8aS,10aR)-7-oxo-8-(3-oxo-butyl)-
tetradecahydro-phenanthren-2-yl ester (14). A solution of com-
pound 13 (4 g, 13.2 mmol) in CH2Cl2 (100 mL) was treated
with ozone at -78 ◦C until a blue color persisted (ca. 30 min).
Oxygen was passed through the solution for 30 min until the blue
color disappeared. AcOH (50 mL) was added and the CH2Cl2 was
evaporated under vacuum without heating. Then, AcOH (50 mL)
and Zn dust (8.6 g, 130 mmol) were added and the reaction mixture
was stirred at room temperature for 1h. Zn dust was filtered off
through cotton, washing with CH2Cl2 (100 mL). The Zn dust was
stirred with EtOAc (200 mL) for 1 h. The solids were filtered off, the
combined solvents were evaporated and the product was purified
by a column chromatography on silica gel (15% EtOAc in hexanes)
to give compound 14 (3.5 g, 79%) as a white solid: mp 71–73 ◦C
(Et2O/hexanes); [a]2D0 +22.92 (c 1.65 in CHCl3). Found: C, 72.0;
H, 8.9. Calc. for C20H30O4 C, 71.8; H, 9.0%. IR (nmax/cm-1) 3404,
2917, 2938, 2861, 1732, 1711, 1228, 1249. dH (300 MHz, CDCl3)
2.04 (3H, s), 2.11 (3H, s), 5.04 (1H, m); dC (75 MHz, CDCl3) 212.7,
209.3, 170.8, 69.8, 54.2, 47.9, 46.6, 46.2, 41.8, 41.1, 37.3, 36.2, 33.4,
31.2, 30.7, 30.1, 24.5, 21.6, 19.5.
(3a,5a,17b)-Estrane-3,17,diol 3-acetate, 17-tosylate (11).
A
solution of compound 10 (8.7 g, 31.4 mmol), 4-
dimethylaminopyridine (330 mg, 2.7 mmol), and p-TsCl
(7.5 g, 39.3 mmol) in anhydrous pyridine (75 mL) was heated
at 90 ◦C overnight. Then, 4-dimethylaminopyridine (60 mg,
0.49 mmol) and p-TsCl (1.3 g, 6.82 mmol) were added and
the reaction mixture was heated another 24 h. The reaction
mixture was poured into ice–water, extracted with CH2Cl2 (2 ¥
300 mL). The combined extracts were washed with aqueous HCl,
aqueous KHCO3, brine, and dried over anhydrous Na2SO4. After
solvent evaporation, the oily residue was purified by column
chromatography on silica gel (5% EtOAc in CH2Cl2) to give
compound 11 (11.6 g, 90%) as a white solid: mp 114–115 ◦C
(CH2Cl2/hexanes); [a]D20 +10.49 (c 0.51 in CHCl3). Found: C,
68.4; H, 8.2; S, 6.8. Calc. for C27H38O5S C, 68.3; H, 8.1; S, 6.8%.
IR (nmax/cm-1) 3306, 2919, 2861, 1732, 1598, 1445, 1361, 1176. dH
(300 MHz, CDCl3) 0.74 (3H, s), 2.04 (3H, s), 2.44 (1H, s), 4.27
(1H, m), 5.02 (1H, bm), 7.32 (2H, m), 7.78 (2H, d, J = 8.4 Hz);
dC (75 MHz, CDCl3) 170.8, 144.5, 134.6, 129.8, 128.0, 90.3, 70.0,
49.4, 48.1, 46.7, 43.3, 41.1, 37.7, 36.9, 36.3, 34.5, 30.5, 30.2, 27.8,
25.1, 24.5, 23.3, 21.8, 21.7, 11.9.
(4aS,4bR,6aS,8R,10aS,10bR)-8-Hydroxy-4,4a,4b,5,6,6a,7,8,-
9,10,10a,10b,11,12-tetradecahydro-3H-chrysen-2-one (15). A so-
lution of NaOH (10% w/v in MeOH/water (9 : 1), 30 mL) was
added to a solution of compound 14 (3.5 g, 10.5 mmol) in MeOH
(100 mL) and the mixture was stirred for 1 h at 40 ◦C. A few pieces
if crushed ice were added and the pH was adjusted to pH 1 by
adding aqueous 1 N HCl. Solids were filtered off, washed several
times with water and dried overnight at room temperature to give
15 (2.16 g, 75%) as a yellow solid, which was then crystallized
from MeOH/CHCl3 to afford white crystals. The aqueous phase
was extracted with CH2Cl2 (2 ¥ 100 mL), the organic extract was
washed with brine, dried over anhydrous Na2SO4, and the solvent
evaporated to afford additional, but slightly impure, oily product
15 (570 mg, 19%). Crystalline product 15 had: mp 250–251 ◦C
(MeOH/CHCl3), [a]2D0 -14.73 (c 0.27 in CHCl3). Found: C, 78.6;
H, 9.6. Calc. for C18H26O2 C, 78.8; H, 9.55%. IR (nmax/cm-1) 3403,
2928, 2856, 1648, 1611. dH (300 MHz, CDCl3) 4.12 (1H, m), 5.83
(3a,5a)-17-methylgon-13(17)-en-3-ol (12). Compound 11
(550 mg, 1.17 mmol) was dissolved in anhydrous toluene (8 mL)
and heated to 100 ◦C. Methylmagnesium bromide (3.0 M in Et2O,
2 mL, 6 mmol) was added to the stirring hot solution under an
N2 atmosphere dropwise as a white precipitate appeared. The
reaction mixture was heated for 2 h at 115 ◦C. The flask was
cooled, a few pieces of crushed ice were added, and the pH of
the solution was adjusted to pH 2 by dropwise addition of 2
N aqueous H2SO4. The toluene layer was separated and the
aqueous layer was extracted with EtOAc (80 mL). The combined
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(1H, s); dC (75 MHz, CDCl3) 200.3, 167.2, 124.3, 66.5, 48.9, 47.2,
46.4, 43.1, 40.5, 36.7, 35.8, 35.5, 33.6, 33.1, 30.5, 30.0, 26.4, 23.7.
the same manner as compound 8. Starting from compound 17
(538 mg, 1.67 mmol), compound 19 (429 mg, 79%) was obtained
as a white solid after column chromatography on silica gel (10%
EtOAc in hexanes): mp 141–142 ◦C (EtOAc/hexanes); [a]D20 -5.59
(c 0.22 in CHCl3). Found: C, 74.2; H, 10.7. Calc. for C20H34O3
C, 74.5; H, 10.6%. IR (nmax/cm-1) 3293, 2915, 2848, 1050. dH
(300 MHz, CDCl3) 3.37 (3H, s), 3.88 (1H, bm), 4.09 (1H, m), 4.67
(2H, s); dC (75 MHz, CDCl3) 94.8, 71.7, 66.7, 55.3, 47.7, 47.6, 47.3
(2 ¥ C), 40.8, 38.6, 36.4, 35.8, 34.1, 34.0, 33.2, 30.6, 29.6 (2 ¥ C),
24.2, 23.6.
(4aS, 4bR, 6aS, 8R, 10aS, 10bR) - 8 - Methoxymethoxy - 4, 4a,-
4b,5,6,6a,7,8,9,10,10a,10b,11,12-tetradecahydro-3H-chrysen-2-
one (16). N,N-Diisopropylethylamine (0.52 mL, 2.9 mmol) was
added to a solution of compound 15 (410 mg, 1.49 mmol) in
◦
dry CH2Cl2 (40 mL). The solution was cooled to 0 C, MOMCl
(0.22 mL, 2.8 mmol) was added and the mixture was stirred under
Ar at room temperature. After 30 h, CH2Cl2 (50 mL) was added
and the organic layer was washed with the aqueous HCl (5%),
aqueous NaHCO3, and brine. Solvent was dried over anhydrous
Na2SO4 and evaporated. Column chromatography on silica gel
(10% EtOAc in hexane◦s) gave compound 16 (380 mg, 79%) as a
white solid: mp 64–65 C (EtOAc/hexanes); [a]2D0 -19.46 (c 0.35
in CHCl3). Found: C, 75.15; H, 9.5. Calc. for C20H30O3 C, 75.4;
H, 9.5%. IR (nmax/cm-1) 3332, 2915, 2858, 1673, 1621, 1045. dH
(300 MHz, CDCl3) 3.35 (3H, s), 3.86 (1H, bm), 4.64 (2H, s), 5.79
(1H, s). dC (75 MHz, CDCl3) 200.2, 167.1, 124.2, 94.7, 71.4, 55.3,
48.9, 46.9, 46.3, 43.0, 38.3, 36.6, 36.0, 35.7, 33.6, 30.4 (2 ¥ C), 29.9,
26.3, 24.2.
(2S,4aR,4bS,6aS,8R,10aS,10bR,12aR)-2-Benzyloxy-8-me-
thoxymethoxy-octadecahydro-chrysene (20). KH (106 mg, 30%
suspension in mineral oil, 0.82 mmol) was added to a solution
of compound 19 (75 mg, 0.23 mmol) in dry THF (12 mL). After
60 min reflux under an N2 atmosphere, the mixture was allowed
to attain room temperature. Then, BnBr (0.1 mL, 0.82 mmol) was
added and the resulting mixture was stirred at room temperature.
After 3 h, the reaction mixture was carefully quenched with
MeOH (2 mL), extracted with CH2Cl2 (50 mL). The organic
phase was washed with brine and dried over anhydrous Na2SO4.
Column chromatography on silica gel (2% EtOAc in CH2Cl2)
(4aR,4bS,6aS,8R,10aS,10bR,12aR)-8-Methoxymethoxy-hexa-
hydro-chrysen-2-one (17). Anhydrous NH3 (10 mL) was con-
densed with a gas condenser into a three-neck flask containing
Li metal (18 mg, 2.6 mmol) at -78 ◦C. Then, anhydrous THF
(12 mL) was added and the resulting blue solution was stirred
for 0.5 h. A solution of compound 16 (168 mg, 0.53 mmol) in
dry THF (6 mL) was added dropwise to the vigorously stirred
solution. After 3 h of stirring, the reaction color was discharged
by careful addition of solid NH4Cl in portions and left overnight
while the NH3 evaporated. The reaction was then acidified with
aqueous 1 N HCl up to pH <7 and the product was extracted
with EtOAc (2 ¥ 50 mL). The combined organic phases were
washed with sat. aqueous NaHCO3, brine, dried with anhydrous
Na2SO4, and the solvent evaporated. Purification by prep-TLC (4
plates, 40% EtOAc/hexanes)◦afforded ketone 17 (110 mg, 59%)
as a white solid: mp 103–105 C (hexanes), [a]2D0 -32.09 (c 0.21 in
CHCl3). Found: C, 75.1; H, 10.2. Calc. for C20H32O3 C, 75.0; H,
10.0%. IR (nmax/cm-1) 3368, 2952, 2910, 2848, 2836, 1721, 1042.
dH (300 MHz, CDCl3) 3.37 (3H, s), 3.87 (1H, bm), 4.66 (2H, s);
dC (75 MHz, CDCl3) 211.9, 94.7, 71.4, 55.2, 48.7, 47.2, 46.8, 46.8,
46.3, 43.4, 41.4, 38.4, 36.1, 34.2, 33.7, 30.43, 30.40, 29.9, 29.3, 24.1.
◦
gave compound 20 (72 mg, 75%) as a white solid: mp 95–97 C
(hexanes), [a]2D0 -2.85 (c 0.31 in CHCl3). Found: C, 78.9; H, 9.45.
Calc. for C27H40O3 C, 78.6; H, 9.7%. IR (nmax/cm-1) 3368, 2903,
2847, 1605, 1496, 1099, 1049. dH (300 MHz, CDCl3) 3.38 (3H, s),
3.69 (1H, bm), 3.88 (1H, m), 4.5 (2H, d, J = 3.3 Hz), 4.67 (2H,
s), 7.28–7.36 (5H, m); dH (75 MHz, CDCl3) 139.7, 128.5 (2 ¥ C),
127.5 (2 ¥ C), 127.4, 94.8, 73.3, 71.7, 69.8, 55.4, 47.8, 47.6, 47.3,
47.3, 38.6, 38.2, 36.4, 36.3, 34.1, 31.2, 30.6, 29.9, 29.6 (2 ¥ C), 24.2,
24.1.
(2S, 4aR, 4bS, 6aS, 8R, 10aS, 10bR, 12aR) - 8 - Benzyloxy - octa-
hydro-chrysen-2-ol (21). Compound 21 was prepared in the same
manner as compound 1. Starting from compound 20 (450 mg,
1.09 mmol), compound 21 (310 mg, 77%) was obtained as a white
solid after column chromatography on silica gel (10% EtOAc in
hexanes): mp 156–158 ◦C (EtOAc/hexanes); [a]2D0 -1.42 (c 0.15 in
CHCl3). Found: C, 81.4; H, 9.8. Calc. for C25H36O2 C, 81.5; H,
9.85%. IR (nmax/cm-1) 3271, 2916, 2850, 1595, 1094, 730, 694. dH
(300 MHz, CDCl3) 3.62 (1H, t, J = 2.7 Hz), 4.01 (1H, t, J = 2.7 Hz),
4.43 (2H, dd, J1 = 12 Hz, J2 = 15.3 Hz), 4.5 (2H, d, J = 3.3 Hz),
7.19–7.3 (5H, m); dC (75 MHz, CDCl3) 139.7, 128.5 (2 ¥ C), 127.6
(2 ¥ C), 127.4, 73.3, 69.8, 66.7, 47.8, 47.7, 47.3, 47.2, 40.8, 38.2,
36.3, 35.8, 34.1, 34.0, 33.2, 29.9, 29.64, 29.67, 27.1, 23.6.
(4aR,4bS,6aS,8R,10aS,10bR,12aS)-8-Methoxymethoxy-hexa-
decahydro-chrysen-2-one (18). A solution of compound 16
(200 mg, 0.63 mmol) in pyridine (25 ml) was hydrogenated in
the presence of Pd/C (5%, 30 mg) at 60 psi. After 12 h, the
catalyst was filtered through a short column of silica gel, washing
with CH2Cl2. The solvent was removed in vacuo to yield a white
solid. Column chromatography on silica gel (2% EtOAc in CH2Cl2)
gave compound 18 (153 mg, 76%) as a white solid: mp 94–96 ◦C
(hexanes), [a]2D0 -6.66 (c 0.195 in CHCl3). Found: C, 75.1; H, 10.0.
Calc. for C20H32O3 C, 75.0; H, 10.1%. IR (nmax/cm-1) 2909, 2856,
2823, 1710, 1034. dH (300 MHz, CDCl3) 2.58 (1H, t, J = 13.5 Hz),
3.37 (3H, s), 3.87 (1H, bs), 4.66 (2H, s); dC (75 MHz, CDCl) 213.3,
94.8, 71.5, 55.3, 47.3, 47.3, 43.0, 40.5, 38.6, 38.1, 37.5, 36.7, 36.3,
33.8, 30.9, 30.5, 29.8, 27.5, 24.1, 24.1.
(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-Benzyloxy-hexadeca-
hydro-chrysen-2-one (22). Jones reagent was added dropwise
to a solution of compound 21 (320 mg, 0.87 mmol) in acetone
(20 mL) at 0 ◦C until an orange color persisted. The course
of the reaction was checked by TLC. Then, 2-propanol was
added dropwise until the reaction mixture turned green. After
30 min, the reaction mixture was poured into water–ice. The
product was extracted with EtOAc (2 ¥ 50 mL) and the water
phase was partially evaporated (1/3) and extracted with EtOAc
(50 mL). The combined extracts were washed with brine, dried
over anhydrous Na2SO4, and the solvent was evaporated. Column
chromatography on silica gel (10% EtOAc in hexanes) gave
compound 22 (247 mg, 77%) as a white solid: mp 109–110 ◦C
(Et2O); [a]2D0 +17.88 (c 0.34 in CHCl3). Found: C, 82.0; H, 9.3.
(2S,4aR,4bS,6aS,8R,10aS,10bR,12aR)-8-Methoxymethoxy-
octadecahydro-chrysen-2-ol (19). Compound 19 was prepared in
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Calc. for C25H34O2 C, 81.9; H, 9.35%. IR (nmax/cm-1) 3407, 2948,
2913, 2847, 1715, 1096, 1068. dH (300 MHz, CDCl3) 3.60 (1H,
bm), 4.41 (2H, dd, J = 12 Hz, J = 15.9 Hz), 7.17–7.26 (5H, m);
dC (75 MHz, CDCl3) 212.3, 139.6, 128.5 (2 ¥ C), 127.5 (2 ¥ C),
127.4, 73.1, 69.8, 48.8, 47.5, 46.94, 46.97, 46.5, 43.5, 41.5, 38.1,
36.2, 34.3, 33.9, 30.5, 30.1, 29.9, 29.4, 24.1.
131.1, 129.7 (2 ¥ C), 128.4 (2 ¥ C), 75.2, 66.6, 47.61, 47.58, 40.8,
40.6, 37.6, 35.7, 35.4, 33.9, 33.2, 32.5, 31.6, 29.7, 26.2, 25.6, 24.7,
23.6.
Benzoic acid (4aS, 4bR, 6aS, 8S, 10aR, 10bS, 12aS) - 8 - Oxo -
octadecahydro-chrysen-2-yl ester (26). Compound 26 was pre-
pared in the same manner as compound 22. Starting from
compound 25 (400 mg, 1.04 mmol), compound 26 (289 mg, 73%)
was obtained as a solidified foam after column chromatography
on silica gel (10% EtOAc in hexanes): [a]2D0 +1.3 (c 0.16 in CHCl3);
IR (nmax/cm-1) 2914, 2866, 1714, 1274. dH (300 MHz, CDCl3) 5.02
(1H, bm), 7.41–7.47 (2H, m), 7.53–7.59 (1H, m), 8.04–8.07 (2H,
m). dC (75 MHz, CDCl3) 212.0, 166.3, 132.9, 131.1, 129.7 (2 ¥ C),
128.5 (2 ¥ C), 74.9, 48.8, 47.3, 46.3, 43.4, 41.5, 40.4, 37.4, 35.3,
34.2, 32.4, 31.5, 30.5, 29.5, 26.2, 25.7, 25.3. HRMS (EI) m/z Calcd
for C25H32O3 [M]+ 380.2351, found: 380.2355.
(2S,4aR,4bS,6aS,8R,10aS,10bR,12aS)-8-Methoxymethoxy-
octahexahydro-chrysen-2-ol (23). Lithium tri(tert-butoxy)-
aluminum hydride (1 M solution in THF, 4.8 mL) was added
dropwise to a cooled solution (-40 ◦C) of compound 18 (860 mg,
2.68 mmol) in anhydrous THF (200 mL) under an N2 atmosphere.
After 2 h at -40 ◦C, aqueous 1 N HCl (50 mL) was carefully
added and the mixture was allowed to attain room temperature.
The product was extracted with CH2Cl2 (2 ¥ 150 mL), combined
extracts were washed with sat. aqueous NaHCO3, brine, dried
over anhydrous Na2SO4. After solvent evaporation, the residue
was purified by column chromatography on silica gel (10% EtOAc
in hexanes) to affor◦d compound 23 (570 mg, 65%) as a white
solid: mp 118–119 C (EtOAc/hexanes), [a]2D0 -4.0 (c 0.15 in
CHCl3); IR (nmax/cm-1) 3306, 2915, 2864, 1049. dH (300 MHz,
CDCl3) 3.37 (3H, s), 3.64 (1H, bm), 3.87 (1H, bs), 4.66 (2H, s).
dC (75 MHz, CDCl3) 94.8, 72.1, 71.6, 55.4, 47.7, 47.5, 40.6, 38.6,
37.6, 36.5, 36.4, 35.5, 34.0, 31.8, 30.6, 30.0, 29.7, 25.8, 24.8, 24.2.
HRMS (FAB) m/z Calcd for C20H34O3 [M]+ 332.2508, found:
332.2495.
(5b,17b)-17-Hydroxyestran-3-one (27). Compound 27 was
prepared in the same manner as compound 18. Starting from
compound 5 (6 g, 21.8 mmol), pure 5b-isomer 27 (2.39 g,
40%) and a mixture of 5b/5a-isomers (95 : 5, 1.98 g, 33%) were
obtained after column chromatography on silica gel (15% EtOAc
in hexanes): mp 105–106 ◦C (EtOAc, hexanes). dH (300 MHz,
CDCl3) 0.77 (3H, s), 2.57 (1H, t, J = 13.9 Hz), 3.66 (1H, t, J =
8.4 Hz); dC (75 MHz, CDCl3) 213.2, 82.1, 50.2, 43.4, 43.1, 41.7,
39.9, 38.6, 38.5, 36.8, 36.6, 30.68, 30.72, 27.9, 25.7, 25.2, 23.4, 11.3.
HRMS (FAB) m/z Calcd for C18H29O2 [M + H]+ 277.2168, found:
277.2168.
Benzoic acid (2S, 4aR, 4bS, 6aS, 8R, 10aS, 10bR, 12aS) - 8 -
methoxymethoxy-octadecahydro-chrysen-2-yl ester (24). A so-
lution of compound 23 (520 mg, 1.61 mmol) and 4-
dimethylaminopyridine (10 mg, 0.01 mmol) in dry pyridine
(45 mL) was cooled in an ice-bath. Then, BzCl (0.9 mL, 8.06 mmol)
was added dropwise while stirring. After 15 h at room temperature,
the reaction mixture was poured into water and extracted with
CH2Cl2 (2 ¥ 150 mL). The combined extracts were washed
with aqueous HCl, sat. aqueous NaHCO3, brine, and dried over
anhydrous Na2SO4. After solvent evaporation, the oily residue was
purified by column chromatography on silica gel (10% EtOAc in
hexanes) to afford compound 24 (683 mg, 99%)as a white solid:
[a]D20 -15.85 (c 0.2 in CHCl3); IR (nmax/cm-1) 2915, 2867, 1715,
1275, 1039. dH (300 MHz, CDCl3) 3.38 (3H, s), 3.88 (1H, bs),
4.67 (2H, s), 5.01 (1H, bm), 7.41–7.46 (2H, m), 7.52–7.57 (1H, m),
8.03–8.06 (2H, m); dC (75 MHz, CDCl3) 166.3, 132.8, 131.1, 129.7
(2 ¥ C), 128.4 (2 ¥ C), 94.8, 75.22, 71.6, 55.3, 47.6, 47.5, 40.6, 38.7,
37.6, 36.3, 35.4, 34.0, 32.5, 31.6, 30.6, 29.7, 26.2, 25.7, 24.7, 24.2.
HRMS (FAB) m/z Calcd for C27H38O4Na [M + Na]+ 449.2668,
found: 449.2664.
(5b,17b)-17-hydroxyestran-3-one 17-tosylate (28). Compound
28 was prepared in the same manner as compound 11. Starting
from compound 27 (5.8 g, 20.1 mmol), compound 28 (7.03 g,
78%) was obtained after column chromatography on silica gel
(10% EtOAc in hexanes): mp 130–132 ◦C (EtOAc/hexanes); [a]2D0
+7.49 (c 0.25 in CHCl3). Found: C, 69.6; H, 8.25; S, 7.3. Calc.
for C25H34O4S C, 69.4; H, 8.4; S, 7.4%. IR (nmax/cm-1) 3400, 2920,
2871, 1708, 1357, 1175. dH (300 MHz, CDCl3) 0.83 (3H, s), 2.45
(3H, s), 2.53 (1H, t, J = 14 Hz), 4.28 (1H, t, J = 9 Hz), 7.31–7.35
(2H, m), 7.77–7.79 (2H, m); dC (75 MHz, CDCl3) 212.8, 144.6,
134.4, 129.8 (2 ¥ C), 128.0 (2 ¥ C), 90.0, 49.2, 43.4, 43.0, 41.3,
39.8, 38.4, 38.3, 36.5, 36.3, 30.6, 27.87, 27.82, 25.3, 25.0, 23.3,
21.8, 11.9.
(3a,5a,17b)-estrane-3,17-diol 17-tosylate (29). Compound 29
was prepared in the same manner as compound 23. Starting from
compound 28 (6.94 g, 16.1 mmol), compound 29 (6.19 g, 88%) was
obtained as a white solid after column chromatography on silica
◦
gel (20% EtOAc in hexanes): mp 174–176 C (EtOAc/hexanes);
[a]2D0 +7.89 (c 0.38 in CHCl3). Found: C, 69.6; H, 8.25; S, 7.3. Calc.
for C25H36O4S C, 69.4; H, 8.4; S, 7.4%. IR (nmax/cm-1) 3418, 2923,
2861, 1644, 1356, 1175. dH (300 MHz, CDCl3) 0.77 (3H, s), 2.44
(3H, s), 3.60 (1H, bm), 4.23 (1H, t, J = 8 Hz), 7.33 (2H, d, J =
8.4 Hz), 7.78 (2H, d, J = 8.7 Hz); dC (75 MHz, CDCl3) 144.5,
134.3, 129.8 (2 ¥ C), 127.9 (2 ¥ C), 90.3, 71.7, 49.2, 43.3, 41.6,
39.9, 384, 36.4, 36.3, 35.6, 31.4, 29.7, 27.8, 26.1, 25.7, 25.0, 23.3,
21.8, 11.9.
Benzoic acid (2S, 4aR, 4bS, 6aS, 8R, 10aS, 10bR, 12aS) - 8 -
Hydroxy-octadecahydro-chrysen-2-yl ester (25). Compound 25
was prepared in the similar fashion as compound 1, wherein
MeOH (60 mL) and 6 N HCl (4 mL) were used to carry out
the hydrolysis. Starting from compound 24 (550 mg, 1.28 mmol),
compound 25 (450 mg, 91%) was obtained as a white solid after
column chro◦matography on silica gel (10% EtOAc in hexanes):
mp 164–166 C (EtOAc/hexanes); [a]2D0 -17.81 (c 0.16 in CHCl3).
Found: C, 78.6; H, 8.8. Calc. for C25H34O3 C, 78.5; H, 9.0%.
IR (nmax/cm-1) 3364, 2913, 2865, 1715,1275, 772. dH (300 MHz,
CDCl3) 4.1 (1H, bs), 5.01 (1H, bm), 7.41–7.46 (2H, m), 7.52–7.58
(1H, m), 8.04–8.07 (2H, m); dC (75 MHz, CDCl3) 166.3, 132.8,
(3a,5b)-17-methylgon-13(17)-en-3-ol (30). Compound 30 was
prepared in the same manner as compound 12. Starting from
compound 29 (2.9 g, 6.7 mmol), compound 30 (1.71 g, 98%) was
obtained as a white solid after column chromatography on silica
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◦
gel (20% EtOAc in hexanes): mp 130–131 C (EtOAc/hexanes);
(4aR, 4bS, 6aR, 8R, 10aS, 10bR, 12aS) - 8 - Methoxymethoxy -
hexadecahydro-chrysen-2-one (35). Compound 35 was prepared
in the same manner as compound 18. Starting from compound 33
(400 mg, 1.25 mmol), cis-isomer 35 (214 mg, 53%), trans-isomer 34
(99 mg, 24%) and a mixture of 34 and 35 (1 : 1, 52 mg, 13%) were
obtained after column chromatography on silica gel (10% EtOAc
[a]2D0 -7.05 (c 0.105 in CHCl3). Found: C, 83.0; H, 10.7. Calc. for
C18H28O C, 83.0; H, 10.8%. IR (nmax/cm-1) 3368, 2923, 2861, 1638,
1068, 1034. dH (300 MHz, CDCl3) 1.60 (3H, s), 2.48–2.55 (1H, m),
3.64 (1H, bm); dC (75 MHz, CDCl3) 136.7, 127.9, 72.0, 52.8, 51.6,
40.2, 37.4, 36.8, 36.5, 35.8, 31.6, 30.1, 30.1, 28.2, 26.6, 26.1, 25.7,
13.6.
◦
in hexanes): mp 102–103 C (ether/hexanes); [a]2D0 +6.06 (c 0.21
in CHCl3). Found: C, 75.1; H, 9.9. Calc. for C20H32O3 C, 75.0; H,
10.1%. IR (nmax/cm-1) 2925, 2869, 2849, 1712, 1039. dH (300 MHz,
CDCl3) 2.58 (1H, t, J = 13.8 Hz), 3.37 (3H, s), 3.56 (1H, bm), 4.69
(2H, s); dC (75 MHz, CDCl3) 213.1, 94.7, 76.8, 55.3, 43.0, 40.6,
40.3, 38.1, 37.9, 37.7, 36.6, 35.4, 33.5, 31.6, 30.8, 27.6, 27.1, 25.8,
25.0, 24.2.
(3a,5b)-3-Methoxymethoxy-17-methylgon-13(17)-ene
(31).
Compound 31 was prepared in the same manner as compound
16. Starting from compound 30 (5.28 g, 20.2 mmol), compound
31 (6.11 g, 99%) was obtained as an oily material after column
chromatography on silica gel (5% EtOAc in hexanes). Compound
31 had: [a]2D0 +1.35 (c 0.17 in CHCl3); IR (nmax/cm-1) 2926, 2865,
1454, 1444, 1043. dH (300 MHz, CDCl3) 1.60 (3H, s), 2.48–2.55
(1H, m), 3.38 (3H, s), 3.56 (1H, bm), 4.70 (2H, s); dC (75 MHz,
CDCl3) 136.7, 127.9, 94.7, 77.01, 55.3, 52.8, 51.6, 40.4, 37.4, 36.8,
35.8, 33.6, 31.7, 30.1, 28.2, 27.3, 26.5, 26.2, 25.7, 13.6. HRMS
(FAB) m/z Calcd for C20H32O2Na [M + Na]+ 327.2300, found:
327.2297.
(2S,4aR,4bS,6aR,8R,10aS,10bR,12aR)-8-Methoxymethoxy-
octadecahydro-chrysen-2-ol (36). Compound 36 was prepared in
the same manner as compound 8. Starting from compound 34
(860 mg, 2.68 mmol), compound 36 (660 mg, 76%) was obtained
as a white solid after chromatography on silica gel (15% EtOAc
in hexanes): mp 150–151 ◦C (Et2O); [a]D20 +4.7 (c 0.27 in CHCl3).
Found: C, 74.6; H, 10.8. Calc. for C20H34O3 C, 74.5; H, 10.6%. IR
(nmax/cm-1) 3275, 2914, 2866, 2845. dH (300 MHz, CDCl3) 3.37
(3H, s), 3.54 (1H, bm), 4.07 (1H, bs), 4.69 (2H, s); dC (75 MHz,
CDCl3) 94.7, 76.8, 66.6, 55.3, 47.7, 47.6, 40.8 (2 ¥ C), 37.5, 35.8,
35.5, 33.9, 33.6, 33.2, 31.8, 29.7, 27.1, 25.8, 24.7, 23.6.
(1S, 4aR, 4bS, 7R, 8aR, 10aR)-7-Methoxymethoxy-1-(3-oxo-
butyl)-dodecahydro-phenanthren-2-one (32). Compound 32 was
prepared in the same manner as compound 14. Starting from
compound 31 (6.11 g, 20.06 mmol), compound 32 (4.43 g, 65%)
was obtained as an oily material after column chromatography
on silica gel (10% EtOAc in hexanes): [a]2D0 +22.6 (c 0.29 in
CHCl3); IR (nmax/cm-1) 2935, 2869, 1711, 1041. dH (300 MHz,
CDCl3) 2.10 (3H, s), 3.36 (3H, s), 3.56 (1H, bm), 4.68 (2H, s); dC
(75 MHz, CDCl3) 212.7, 209.2, 94.7, 76.6, 55.3, 54.1, 48.4, 42.0,
41.1, 40.3, 36.9, 35.0, 33.4, 31.6, 31.0, 30.0, 27.1, 26.7, 26.0, 19.5.
HRMS (FAB) m/z Calcd for C20H33O4 [M + H]+ 337.2379, found:
337.2376.
Benzoic acid (2S, 4aR, 4bS, 6aR, 8R, 10aS, 10bR, 12aR) - 8 -
methoxymethoxy-octadecahydro-chrysen-2-yl ester (37). Com-
pound 37 was prepared in the same manner as compound 24.
Starting from compound 36 (610 mg, 1.89 mmol), compound
37 (680 mg, 84%) was obtained as a white solid after column
chromatography on silica gel (10% EtOAc in hexanes): mp 130–
131 ◦C (Et2O/hexanes); [a]D20 +5.52 (c 0.39 in CHCl3). Found: C,
76.25; H, 9.1. Calc. for C27H38O4 C, 76.0; H, 9.0%. IR (nmax/cm-1)
2930, 2865, 1715, 1450, 1275, 1040, 714. dH (300 MHz, CDCl3)
3.38 (3H, s), 3.56 (1H, bm), 4.70 (2H, s), 5.31 (1H, m), 7.42–
7.47 (2H, m), 7.53–7.59 (1H, m), 8.04–8.08 (2H, m); dC (75 MHz,
CDCl3) 166.1, 132.8, 1631.3, 129.7 (2 ¥ C), 128.5 (2 ¥ C), 94.7,
77.0, 70.7, 55.3, 47.6, 47.2, 40.8, 37.9, 37.5, 36.9, 35.5, 33.8, 33.6,
31.8, 30.5, 29.6, 27.1, 25.8, 24.7, 24.5.
(4aS,4bR,6aR,8R,10aS,10bR)-8-Methoxymethoxy-4,4a,4b,-
5,6,6a,7,8,9,10,10a,11,12-tetradecahydro-3H-chrysen-2-one (33).
Compound 32 was prepared in the same manner as compound
15. Starting from compound 32 (4.37 g, 12.9 mmol), compound
33 (3.45 g, 83%) was obtained as an low melting solid after column
chromatography on silica gel (20% EtOAc in hexanes): mp <65 ◦C
(hexanes); [a]2D0 -13.77 (c 0.39 in CHCl3). Found: C, 75.5; H, 9.4.
Calc. for C20H30O3 C, 75.4; H, 9.5%. IR (nmax/cm-1) 3382, 2931,
2865, 1671, 1040. dH (300 MHz, CDCl3) 3.36 (3H, s), 3.56 (1H,
bm), 4.68 (2H, s), 5.81 (1H, bs); dC (75 MHz, CDCl3) 200.1, 166.9,
124.3, 94.7, 76.7, 55.3, 49.3, 42.9, 40.3, 36.8, 36.6, 35.7, 35.1, 33.5,
31.5, 30.2, 27.2, 26.4, 25.8, 25.6.
Benzoic acid (2S, 4aR, 4bS, 6aR, 8R, 10aS, 10bR, 12aR) - 8 -
hydroxy-octadecahydro-chrysen-2-yl ester (38). Method A: Com-
pound 38 was prepared in the same manner as compound 1.
Starting from compound 37 (600 mg, 1.4 mmol), compound
38 (228 mg, 42%) and starting material 37 (286 mg, 47%) were
obtained after column chromatography on silica gel (20% EtOAc
in hexanes). Method B: To a solution of compound 37 (286 mg,
0.67 mmol) in MeOH (18 mL) and benzene (6 mL) was added
dropwise AcCl (0.8 mL, 11.2 mmol) at 0 ◦C and the reaction
mixture was allowed to stir overnight at room temperature. Then,
a few pieces of crushed ice were added and the pH was adjusted
with sat. aqueous NaHCO3 to pH 6. The product was extracted
with CH2Cl2 (2 ¥ 80 mL) and the combined extracts were washed
with brine and dried over anhydrous Na2SO4. After solvent
evaporation, the residue was purified by a column chromatography
(20% EtOAc/hexanes) to afford compound 38 (233 mg, 91%): mp
(4aR, 4bS, 6aR, 8R, 10aS, 10bR, 12aR) - 8 - Methoxymethoxy -
hexadecahydro-chrysen-2-one (34). Compound 34 was prepared
in the same manner as compound 17. Starting from compound 33
(500 mg, 1.57 mmol), compound 34 (260 mg, 51%) and starting
material 33 (140 mg, 28%) were obtained as white solids after
column chromatography on si◦lica gel (20% EtOAc in hexanes).
Compound 34 had: mp 83–84 C (hexanes); [a]2D0 -19.9 (c 0.31 in
CHCl3). Found: C, 75.2; H, 10.0. Calc. for C20H32O3 C, 75.0; H,
10.1%. IR (nmax/cm-1) 2931, 2910, 2862, 1717, 1035. dH (300 MHz,
CDCl3) 3.36 (3H, s), 3.54 (1H, bm), 4.68 (2H, s); dC (75 MHz,
CDCl3) 212.1, 94.7, 76.8, 55.3, 48.8, 47.3, 46.3, 43.4, 41.4, 40.6,
37.3, 35.4, 34.2, 33.5, 31.6, 30.5, 29.4, 27.1, 25.8, 25.3.
◦
196–198 C (EtOAc); [a]D20 -0.92 (c 0.24 in CHCl3). Found: C,
78.3; H, 9.0. Calc. for C25H34O3 C, 78.5; H, 9.0%. IR (nmax/cm-1)
3377, 2922, 2862, 1714, 1450, 1275, 713. dH (300 MHz, CDCl3)
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3.65 (1H, m), 5.32 (1H, m), 7.42–7.48 (2H, m), 7.53–7.59 (1H, m),
8.04–8.07 (2H, m); dC (75 MHz, CDCl3) 166.1, 132.8, 131.4, 129.7
(2 ¥ C), 128.5 (2 ¥ C), 72.0, 70.7, 47.7, 47.3, 40.7, 37.9, 37.6, 36.9,
36.5, 35.5, 33.8, 31.8, 30.5, 30.1, 29.7, 25.8, 24.8, 24.6.
chro◦matography on silica gel (25% EtOAc in hexanes): mp 173–
174 C (EtOAc); [a]2D0 -15.15 (c 0.2 in CHCl3). Found: C, 78.7;
H, 8.9. Calc. for C25H34O3 C, 78.5; H, 9.0%. IR (nmax/cm-1) 3292,
2917, 2867, 1714, 1451, 1275, 711. dH (300 MHz, CDCl3) 3.65 (1H,
m), 5.00 (1H, m), 7.40–7.46 (2H, m), 7.52–7.57 (1H, m), 8.04–8.07
(2H, m); dC (75 MHz, CDCl3) 166.3, 132.8, 131.2, 129.7 (2 ¥ C),
128.4 (2 ¥ C), 75.2, 71.9, 40.5, 38.1 (2 ¥ C), 36.5, 35.6, 35.5, 32.5,
31.7, 31.6, 30.0, 26.2, 25.9, 25.7, 24.98, 24.92.
Benzoic acid (4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aR) - 8 - Oxo -
octadecahydro-chrysen-2-yl ester (39). Compound 39 was pre-
pared in the same manner as compound 22. Starting from
compound 38 (447 mg, 1.16 mmol), compound 39 (335 mg, 75%)
was obtained as a white solid after column chromatography on
silica gel (15% EtOAc in hexanes): mp 115–117 ◦C (EtOAc);
[a]2D0 +1.84 (c 0.39 in CHCl3). Found: C, 78.8; H, 8.6. Calc. for
C25H32O3 C, 78.9; H, 8.5%. IR (nmax/cm-1) 2916, 2862, 1712, 1274.
dH (300 MHz, CDCl3) d 2.60 (1H, t, J = 13.8 Hz), 5.33 (1H,
m), 7.43–7.49 (2H, m), 7.54–7.59 (1H, m), 8.05–8.09 (2H, m); dC
(75 MHz, CDCl3) 212.9, 166.1, 132.9, 131.3, 129.7 (2 ¥ C), 128.5
(2 ¥ C), 70.5, 47.3, 47.3, 43.0, 40.5, 38.1, 37.9, 37.5, 36.9, 36.7,
33.7, 30.9, 30.5, 29.8, 27.6, 24.5, 24.1.
Benzoic acid (4aS, 4bR, 6aS, 8S, 10aR, 10bS, 12aR) - 8 - Oxo -
octadecahydro-chrysen-2-yl ester (43). Compound 43 was pre-
pared in the same manner as compound 22. Starting from
compound 42 (357 mg, 0.93 mmol), compound 43 (342 mg, 96%)
was obtained as a white solid after column chromatography on
silica gel (15% EtOAc in hexanes): mp 116–117 ◦C (hexanes),
[a]2D0 -16.3 (c 0.24 in CHCl3). Found: C, 79.0; H, 8.4. Calc. for
C25H32O3 C, 78.9; H, 8.5%. IR (nmax/cm-1) 2916, 2868, 1711, 1274.
dH (300 MHz, CDCl3) 2.60 (1H, t, J = 13.8 Hz), 5.02 (1H, bm),
7.41–7.46 (2H, m), 7.52–7.58 (1H, m), 8.04–8.08 (2H, m); dC
(75 MHz, CDCl3) 212.8, 166.2, 132.9, 131.1, 129.7 (2 ¥ C), 128.4
(2 ¥ C), 74.9, 43.0, 40.5, 40.4, 38.2, 38.0, 37.8, 36.6, 35.4, 32.4,
31.5, 30.8, 27.6, 26.2, 25.7, 25.1, 24.3.
(2S,4aR,4bS,6aR,8R,10aS,10bR,12aS)-8-Methoxymethoxy-
octadecahydro-chrysen-2-ol (40). Compound 40 was prepared in
the same manner as compound 23. Starting from compound 35
(264 mg, 0.823 mmol), compound 40 (160 mg, 60%) and starting
material 35 (42 mg, 16%) were obtained as white solids after
column chromatography on silica◦gel (15% EtOAc in hexanes).
Compound 40 had: mp 151–152 C (Et2O); [a]2D0 +6.75 (c 0.24
in CHCl3). Found: C, 74.4; H, 10.6. Calc. for C20H34O3 C, 74.5;
H, 10.6%. IR (nmax/cm-1) 3272, 2934, 2911, 2869, 2845, 1058. dH
(300 MHz, CDCl3) 3.37 (3H, s), 3.52–3.65 (2H, m), 4.68 (2H, s);
dC (75 MHz, CDCl3) 94.7, 76.8, 71.9, 55.3, 40.6, 40.4, 38.0 (2 ¥
C), 36.4, 35.6, 35.5, 33.6, 31.8, 31.7, 29.9, 27.1, 25.9, 25.8, 24.9
(2 ¥ C).
Acknowledgements
The authors thank Dr Achintya K. Bandyopadhyaya for his
preliminary studies on methods for expansion of the steroid D-
ring. This work was supported by NIH Grant GM47969 to DFC.
The X-ray structure determinations were made possible by NSF
Shared Instrument Grant No. CHE-042097.
Notes and references
Benzoic acid (2S, 4aR, 4bS, 6aR, 8R, 10aS, 10bR, 12aS) - 8 -
Methoxymethoxy-octadecahydro-chrysen-2-yl ester (41). Com-
pound 41 was prepared in the same manner as compound 24.
Starting from compound 40 (480 mg, 1.48 mmol), compound
41 (560 mg, 88%) was obtained as a white solid after column
chromatography on silica gel (5% EtOAc in hexanes): mp 126–
128 ◦C (EtOAc/hexanes); [a]D20 -8.71 (c 0.28 in CHCl3). Found: C,
76.1; H, 8.8. Calc. for C27H38O4 C, 76.0; H, 9.0%. IR (nmax/cm-1)
2932, 2869, 1719, 1450, 1273, 1044, 712. dH (300 MHz, CDCl3) 3.38
(3H, s), 3.55 (1H, m), 4.70 (2H, s), 5.00 (1H, m), 7.40–7.46 (2H,
m), 7.52–7.57 (1H, m), 8.03–8.07 (2H, m); dC (75 MHz, CDCl3)
166.3, 132.8, 131.2, 129.7 (2 ¥ C), 128.4 (2 ¥ C), 94.8, 76.8, 75.1,
55.3, 40.7, 40.5, 38.10, 38.07, 35.6, 35.5, 33.6, 32.5, 31.8, 31.6, 27.2,
26.2, 25.9, 25.7, 24.95, 24.91.
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B. Starting from compound 41 (530 mg, 1.24 mmol), compound
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4694 | Org. Biomol. Chem., 2011, 9, 4685–4694
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