Synthesis of B,B-dinor-B-secosteroids as potential cardenolide analogues

Article abstract of DOI:10.1016/S0040-4020(02)01361-3

A novel chemical construction of B,B-dinor-B-secosteroids as simplified cardenolide analogs, starting from the Hajos-Parrish diketone was developed. The synthesis of the equivalent of the steroid A ring was carried out through a Diels-Alder reaction between an appropriate hydroindenyl acrylate derivative and Danishefsky's diene.

Full text of DOI:10.1016/S0040-4020(02)01361-3

Tetrahedron 58 (2002) 10103–10112
Synthesis of B,B-dinor-B-secosteroids as potential
cardenolide analogues
*
Luis G. Sevillano, Esther Caballero, Fernando Tome, Manuel Medarde and Arturo San Feliciano
´
´ ´ ´
Laboratorio de Quımica Organica y Farmaceutica, Facultad de Farmacia, Campus Miguel de Unamuno, E-37007 Salamanca, Spain
Dedicated to the memory of Dr Benedicto del Rey
Received 11 June 2002; revised 30 September 2002; accepted 25 October 2002
Abstract—A novel chemical construction of B,B-dinor-B-secosteroids as simplified cardenolide analogs, starting from the Hajos–Parrish
diketone was developed. The synthesis of the equivalent of the steroid A ring was carried out through a Diels–Alder reaction between an
appropriate hydroindenyl acrylate derivative and Danishefsky’s diene. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
compound I) showing a fairly positive inotropic effect
without modifying the heart rate.7
Digitalis glycosides, used for the treatment of dropsy more
than 200 years ago and for the treatment of congestive
cardiac failure since the beginning of the past century,1 have
as major problem in their clinical use their narrow
therapeutic index. The necessity of less toxic cardiotonic
agents has prompted much research on natural cardiotonics
and their synthetic analogues.2
After these results, we decided to broaden the study to B,B-
dinor-B-secosteroids depicted in Fig. 2 as mimics of the
genins of cardiac glycosides but lacking the whole steroid
skeleton.8 Starting from the Hajos–Parrish diketone 1
((3aS,7aS)-3a-hydroxy-7a-methylperhydroindene-1,5-
dione) the molecules already have the required absolute
stereochemistry and the 3a-bOH (14b of the steroid) group,
the major problem for the introduction of the A ring
equivalent being the control of the configuration at the C-5
position, that also controls the preferred conformation of the
hydroindenic derivatives. This question was solved by the
group from Praxis9 for compounds type B, in consequence
other strategies are needed for type A derivatives and for
type C derivatives.
As the genins of the CG are steroids that highly contribute to
the interaction with the digitalis binding site,3 previous
work from our group has been undertaken to investigate the
influence of the skeleton size on inotropic activity and
toxicity. Thus, we studied diterpenic cardenolide analogues4
and more simplified analogues, with only a cyclohexane5
ring. Afterwards, we prepared hydroindenic derivatives
(Fig. 1) which among other structural variations,6 have a D3a
unsaturation and an amidino hydrazono moiety at C-5 (see
In this paper we report the synthetic effort directed to the
Figure 1. Structure of digoxin compared to hydroindenic derivatives.
Keywords: digitalis glycosides; hydroindenes; secosteroids.
*
Corresponding author. Tel.: þ34-923-294528; fax: þ34-923-294515; e-mail: medarde@usal.es
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01361-3

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L. G. Sevillano et al. / Tetrahedron 58 (2002) 10103–10112
Figure 2. Structure of N-bonded piperidyl A, cyclohexyl B and C hydrindanic derivatives.
construction of the B,B-dinor-B-secosteroid skeleton from
the hydroindenic Hajos–Parrish diketone.
stereochemical-conformational assignments have been
based on the13C NMR shift of the methyl group at C-7a,
because many hydroindenic derivatives show a clear
difference in the chemical shift for equatorial C-7a methyl
(.17 ppm) and axial C-7a methyl (,16 ppm) groups,6b as it
can be appreciated for compounds 3a and 3b. These
assignments are in agreement with other observations for
compounds 6–9, as it is the nOe on the b-axial-H7 upon
irradiation of the equatorial C7a-methyl group and the
appearance of the H-5 signal as a broad multiplet
characteristic of an axial proton.
2. Results and discussion
We started with the study of the transformation of 1 into
N-substituted derivatives at C-5 and continued with the
synthesis of the C-substituted derivatives at this position.
Because of it is generally possible to chemoselectively
transform the C-5 ketone, we centred our efforts on the
construction of the A ring, independently of the substitution
at C-1.
To know the influence of a different substitution at C-1 on
the stereochemical course of the reductive amination at C-5,
the methylene ketone 11 was obtained from the previously
synthesized 10.13 Under standard conditions mixtures of
piperidyl nitriles 12a/12b and piperidines 13a/13b (Scheme
2), with a 3:1 prevalence of the a-piperidyl derivatives,
were produced. A subtle equilibrium between both confor-
mations in the intermediate iminium ions during the
reductive amination can be responsible for the mixtures
obtained from ketones 5 and 11 and the prevalence of the
unwanted a-substituted derivatives. Because of the diffi-
culties observed to prepare derivatives type A with the
requested stereochemistry, we decided to explore the other
planned target molecules of type C.
2.1. Hydroindenic derivatives N-substituted at C-5
A possibility for introducing a nitrogen atom with stereo-
chemical control is the Mitsunobu reaction, because a
nitrogen nucleophyle can replace the hydroxyl group with
inversion of the configuration at the OH supporting
carbon.10 For our purpose an a-OH is required, thus the
reduction of diketone 1 with lithium tri-tert-butoxy-
aluminiumhydride was carried out leading to a 2.6:1
mixture of the reduction products at C-5 3a/3b (39%) and
to a small amount of the C-1 reduction product 2 (3%)
(Scheme 1). When 3a was treated under Mitsunobu
conditions,11 the undesired dehydration product 4 (75%)
was obtained and this procedure was discarded for our
purposes.
2.2. Hydroindenic derivatives C-substituted at C-5
Several methods were assayed to obtain these compounds,
as it is shown in Scheme 3. Firstly, the malononitrile
derivative 14 (80%) was synthesized from the diketone 1 by
reaction with malononitrile14 and b-alanine15 as catalyst,
followed by reduction of the tetrasubstituted double bond.
The hydrogenation with H2/Pd(C)16 10% afforded a
complex mixture of products in which the C5a configur-
ation always predominated. The reduction with DIBALH17
yielded a 3:1 mixture of 15a/15b, respectively, in low yield
(27%).
The introduction of the nitrogen substituent with the
required b-stereochemistry was then tried by the reductive
amination of the C-5 keto group. The tertiary hydroxyl
group of 1 was protected (Scheme 2) as the trimethylsilyl-
ether 5 (79%) in order to avoid secondary reactions. The
reductive amination12 of 5 led to a 7:1 mixture (65%) of 6a/
6b, respectively, showing a marked preference towards the
5a-amino-derivative. Diketone 5 was also treated with
piperidine and sodium cyanoborohydride affording the
nitrile 7 (23%), the keto-hydroxy derivative 8 (14%) and
the ketopiperidine derivative 9 (33%) (Scheme 2). The
The condensation of compound 1 with nitromethane was
Scheme 1. Reagents and conditions: (a) LiAl(OtBu)3H, THF, 08C; (b) phthalimide, triphenylphosphine, DEAD, rt.

L. G. Sevillano et al. / Tetrahedron 58 (2002) 10103–10112
10105
Scheme 2. Reagents and conditions: (a) TMSOTf, Et3N, CH2Cl2, rt; (b) NH4OAc, NaBH3CN, MeOH, rt; (c) piperidine, HCl/MeOH, NaBH3CN, rt.
carried out using ammonium acetate,18 potassium fluoride19
or ethylenediamine20 as catalysts. The best result was
obtained with the latter yielding the condensation product as
a clean 4.5:1 mixture of 16/160, respectively (Scheme 3),
TosMIC and KOtBu24 (Scheme 3). The crystal data of 18a
confirmed the stereochemical assignments of these
hydrindanes (3aR,5S,7aR in this compound) and the
preferred conformation in the crystalline state, which is
the same observed in solution, with the C7a-methyl in an
equatorial disposition (18.3 ppm). Its isomer 18b shows the
expected axial disposition for the methyl group (14.2 ppm).
whose reduction using H2/Ni Raney,21 H2/PtO2 and
22
hydrazine hydrate23 gave complex mixtures. Reaction
with H2/Pd(C) 10% yielded a 4:5 mixture of 17/170,
produced by hydrogenolysis of the allylic nitro group. The
disappearance of this group, required to further elaborate the
A ring, made this procedure useless for the construction of
B,B-dinor-B-secosteroids.
2.3. Synthesis of the B,B-dinor-B-secosteroids
Another way to introduce a moiety for the construction of A
ring and control the stereochemistry at C-5, is the
hydrogenation of an alkenyl residue produced by means of
the high yielding Wittig reaction. The treatment of diketone
The direct transformation of diketone 1 into a 2:1 mixture of
18a/18b (56%) was brought about by treatment with
Scheme 3. Reagents and conditions: (a) malononitrile, b-alanine, acetic acid, ethanol, rt; (b) DIBAL-H 1 M in hexane, THF, 08C; (c) CH3NO2,
ethylenediamine, D; (d) H2, Pd(C) 10%, EtOH, rt; (e) TosMIC, KtOBu, EtOH, 1,2-dimethoxyethane, rt.

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L. G. Sevillano et al. / Tetrahedron 58 (2002) 10103–10112
Scheme 4. Reagents and conditions: (a) Ph3PvCHCOOEt, benzene, D; (b) H2, Pd(C) 10%, EtOH, rt.
1 with ethoxycarbonylmethylenetriphenylphosphorane25
gave a 3:2 mixture (97%) of 19(Z)/20(E), respectively,
that upon hydrogenation using Pd(C) 10% as catalyst
quantitatively gave a 2:3 mixture of 21a/21b, respectively.
This two steps process leading to the ketoesters 21 (.95%
yield from 1) with predominance of the required C-5b
stereochemistry (Scheme 4), is a good methodology for
further elaborate the B,B-dinor-B-secosteroids.
22b were difficult to separate and we used the mixture in the
Diels–Alder reaction. Although four compounds can be
produced (23–26, two stereoisomers at the a-position of the
carboxylic esters for each, C5a and C5b derivatives),
they will be reduced again to the mixture of only the 5a
and 5b isomers (27 and 28) during the hydrogenation
step, because the stereogenicity at the a-position is
destroyed.
Among other approaches for the synthesis of A ring, we
choose the Diels–Alder methodology because it is straight-
forward, compatible with the hydroxy and keto functions at
C-3a and C-1, and allows the control of the regiochemistry
of final products. The designed strategy to complete this
process was the introduction of a dienophyllic moiety in the
a-position, followed by the Diels–Alder reaction with
the Danishefsky’s diene,0 which places a carbonyl group in
the position where the R substituent (see Fig. 2) should be
attached.
The 2:3 mixture of acrylates 22a/22b was reacted with
Danishefsky’s diene,28 affording the corresponding
cycloaddition products. After hydrolysis, both 5b–5a
diastereomeric mixtures were separated and the major
components (23 and 25) isolated. Although not important
for the whole process, the stereochemistry of these
compounds could be established by means of key nOes
observed between protons in A and C rings. The
hydrogenations of the 5b (23þ24) and 5a (25þ26)
diastereomeric mixtures, using Pd(C) 10% as catalyst and
absolute ethanol as solvent, led to the hydrogenated and
protected cyclohexanic ketones as diethyl ketals, 27
(89%) and 28 (82%), respectively (Scheme 5). When
the hydrogenation was carried out in ethylenglycol, the
mixture of 23þ24 gave the diketo derivative 29 in 80%
yield.
Due to the difficulties encountered for its resolution, the
mixture of 21a/21b was transformed into the corresponding
dienophiles 22a/22b via the Mannich26 reaction with the
Eschenmoser’s salt,27 alkylation with methyl iodide and
Hofmann elimination with NaHCO3. The acrylates 22a and
Scheme 5. Reagents and conditions: (a) (i) LDA, HMPTA, THF, 2788C, (ii) H2CvN(CH3)2I, THF, 2428C to rt, (iii) CH3I, p-dioxane, 908C, (iv) NaHCO3,
H2O/EtOAc, rt; (b) (i) Danishefsky’s diene, benzene, 958C, (ii) HCl c., CHCl3, rt; (c) H2, Pd(C) 10%, EtOH, rt; (d) H2, Pd(C) 10%, HOCH2CH2OH, rt.

L. G. Sevillano et al. / Tetrahedron 58 (2002) 10103–10112
10107
Figure 3. Comparison of compound 27 (two chairs conformations) with digitoxin.
Figure 4. Structure of products obtained by further transformations of 27.
By this procedure, the synthesis of the B,B-dinor-B-
secosteroid 27 and 29 was completed. These compounds
have the same stereochemistries at C-9, C-13 and C-14 as
the natural cardenolides, the 14bOH and key functionalities
at C-3 and C-17 to be converted into groupings conferring
good affinities to the digitalis receptor (Fig. 3). Other
structural characteristics of this compound are the symmetry
of ring A, that facilitates its conversion into single isomers,
and the presence of the carboxylate at C-19 that can be
maintained, converted into other functions (as presented in
several natural cardenolides) or removed to mimic the C-19
methyl of steroids.
4. Experimental
4.1. General
Solvents and reagents were used as purchased from Aldrich.
Chromatographic separations were performed on silica gel
columns by flash (Kieselgel 40, 0.040–0.063 mm; Merck)
or gravity column (Kieselgel 60, 0.063–0.200 mm; Merck)
chromatography. Reactions were monitored by thin-layer
chromatography (TLC precoated silica gel polyester plates,
0.25 mm thickness, with fluorescent indicator UV 254,
Polychrom SI F254). Solutions were dried with anhydrous
Na2SO4 and evaporated under reduced pressure. Melting
points were determined on a Buchi 510 apparatus and are
uncorrected. IR spectra were obtained in CH2Cl2 film in a
Further transformations (Fig. 4) of 27 were carried out to
check the possibilities of future transformations of these key
compounds into cardenolide analogues. These reactions
demonstrate the low reactivity of the ketone at C-1 of the
hydrindane system, as for example in the Wittig reaction of
28, taking place on the ester group rather than on the
free keto group at C-1 (compound 30). Only the reduction at
the C-1 carbonyl (yielding a and b-OH derivatives) was
readily produced with LiAlH4 (compound 31), although the
NaBH4 chemoselectively reduced the cyclohexanone
(compound 33 to 34, 35). The selective protection of the
hydroxymethyl group in the presence of a or bOH
functions at C-1 was also achieved (31 to 32). Compound
33, obtained by oxidation from 32, is an interesting
diketo derivative with two carbonyl groups of different
reactivity.
Nicolet (Impact 410) spectrophotometer. H and 13C NMR
1
spectra were recorded on a Bruker WP 200-SY spectrometer
at 200/50 MHz or on a Bruker DRX spectrometer at
400/100 MHz. Chemical shifts (d) are given in ppm
downfield from tetramethylsilane as an internal standard,
and coupling constants (J values) are in hertz. GC-MS
analyses were carried out with a Hewlett-Packard 5890
series II apparatus (70 eV). For HRMS analyses, a VG TS-
250 apparatus (70 eV) was used.
4.2. Method A: general procedure for hydrogenation
To a solution 0.13 M of the starting material in EtOH, Pd(C)
10% was added and stirred under H2 atmosphere (2 atm).
After disappearance of the starting material, the reaction
was filtered through a silica gel column and the solvent
evaporated to obtain the hydrogenation products.
3. Conclusion
4.2.1. (1R,7aS)-1-Hydroxy-7a-methyl-2,3,5,6,7,7a-hexa-
hydroinden-5-one (2), (3aS,5S,7aS)-3a,5-dihydroxy-7a-
methylperhydroinden-1-one (3b) and (3aS,5R,7aS)-3a,5-
dihydroxy-7a-methylperhydroinden-1-one (3a). A sus-
pension of lithium tri-tert-butoxyaluminohydride (792 mg,
3.0 mmol) in 5.5 mL of dry THF was heated to reflux under
Ar until it was completely dissolved. Next, it was cooled to
08C and 500 mg (2.75 mmol) of diketone 1 were added. The
mixture was stirred at 08C for 1.5 h, then an aqueous
solution of ammonium sulfate (1.5 g in 2.3 mL of H2O) was
added dropwise, with vigorous stirring and cooling. The
In conclusion, a straightforward methodology for the
preparation of B,B-dinor-B-secosteroids has been described
(in five steps from Hajos–Parrish ketone in 41% overall
yield: 25% overall of 9b ‘steroid like’ isomer 27 and 16%
overall of 9a ‘non-steroidal’ isomer 28). The synthesis of
more elaborated products could be carried out by this
procedure, although previous transformation of the C-1 keto
group is desirable due to its low reactivity. New cardenolide
analogues of this type will be synthesized by this procedure
and submitted for biological assays.

10108
L. G. Sevillano et al. / Tetrahedron 58 (2002) 10103–10112
reaction was extracted with EtOAc and washed with brine.
After column chromatography (hex/EtOAc 1:2) 60 mg
(12%) of starting material, 14 mg (3%) of an uncoloured
oil 2, 52 mg (10%) of 3b as a white crystalline product,
45 mg (9%) of a mixture of 3b/3a and 101 mg (20%) of 3a
as a colourless oil were obtained.
4.2.4. (3aS,5R,7aS)-5-Amino-7a-methyl-3a-trimethyl-
siloxyperhydroinden-1-one (6a). To a solution of diketone
5 (245 mg, 0.96 mmol), ammonium acetate (746 mg,
9.7 mmol) and sodium cyanoborohydride (64 mg,
1.0 mmol) in 3 mL of anhydrous MeOH were added.
After stirring for 48 h at room temperature, the mixture
was extracted with EtOAc and washed with brine. The crude
reaction was purified by column chromatography (hex/
EtOAc 1:2þ1% Et3N) yielding 160 mg (65%) of a 7:1
Compound 2: [a]D¼þ61.78 (c 0.41, CHCl3); IR (NaCl)
3425, 1650, 1220, 1075 cm21; 1H NMR (CDCl3) d 1.15 (s,
3H, H8), 1.6–2.9 (m, 8H), 3.86 (dd, 1H, J¼7.3, 10.6 Hz,
H1), 5.79 (dd, 1H, J¼1.8, 2.2 Hz, H4); 13C NMR (CDCl3) d
15.1, 26.5, 29.2, 33.3, 34.1, 45.3, 80.7, 123.5, 175.3, 199.4;
MS m/z 166 (Mþ, 33), 148 (Mþ2H2O, 4).
1
6a/6b mixture. 6a: IR (NaCl) 3370, 1742, 843 cm21; H
NMR (CDCl3) d 0.19 (s, 9H, –OTMS), 0.90 (s, 3H, H8),
0.9–2.7 (m, 10H), 3.0–3.3 (m, 1H, H5), 5.92 (bs, 2H, NH2);
13C NMR (CDCl3) d 2.3, 19.5, 27.2, 29.6, 32.4, 34.8, 42.5,
46.2, 53.6, 80.1, 217.7; MS m/z 255 (Mþ, 2).
3b: [a]D¼þ38.58 (c 0.65, CHCl3); IR (NaCl) 3440, 1740,
1
1180, 1090 cm21; H NMR (CDCl3) 400 MHz) d 1.01 (s,
4.2.5. (3aS,5R,7aS)-7a-Methyl-1-oxo-5-piperidyl-3a-tri-
methylsiloxyperhydroinden-5-carbonitrile (7), (3aS,
5R,7aS)-5-hydroxy-7a-methyl-3a-trimethylsiloxyper-
hydroinden-1-one (8) and (3aS,5R,7aS)-7a-methyl-5-
piperidyl-3a-trimethylsiloxyperhydroinden-1-one (9). To
a solution of piperidine (0.7 mL, 7.08 mmol) in MeOH
(5.5 mL), a solution HCl/MeOH 5N (2 equiv.) was added.
Then, 300 mg (1.18 mmol) of diketone 5 and NaBH3CN
(1 equiv.) were added. The mixture was stirred at room
temperature for 56 h. After usual work up and chromato-
graphy 95 mg (23%) of 7 (hex/EtOAc 5:1), 36 mg (14%) of 8
(hex/EtOAc 3:1) and 126 mg (33%) of 9 (hex/EtOAc 1:1)
were isolated.
3H, H8), 1.4–2.1 (m, 8H), 2.21 (ddd, 1H, J¼7.3, 9.4,
19.4 Hz, H2), 2.48 (ddd, 1H, J¼4.5, 10.1, 19.4 Hz, H2),
4.05 (tt, 1H, J¼2.9, 5.9 Hz, H5); 13C NMR (CD3OD) d 12.1,
27.1, 27.9, 29.4, 31.6, 40.0, 51.1, 65.8, 77.5, 220.8; MS m/z
184 (Mþ, 14), 166 (Mþ2H2O, 64).
3a: [a]D¼þ75.08 (c 0.26, CHCl3); IR (NaCl) 3410, 1726,
1
1172, 1094 cm21; H NMR (CDCl3 400 MHz) d 0.96 (s,
3H, H8), 1.08–1.25 (m, 1H, H6), 1.30 (tt, 1H, J¼3.9, 10.3,
19.6 Hz, H7), 1.39 (dd, 1H, J¼9.4, 13.8 Hz, H4), 1.70–1.80
(m, 1H, H6), 1.87–2.20 (m, 4H), 2.26 (td, 1H, J¼8.2,
19.6 Hz, H2), 2.48 (ddd, 1H, J¼3.9, 10.3, 19.6 Hz, H2),
3.89 (tt, 1H, J¼5.2, 9.2 Hz, H5); 13C NMR (CDCl3) d 17.5,
27.3, 31.2, 33.0, 34.4, 44.0, 52.7, 66.1, 78.5, 220.2; MS m/z
184 (Mþ, 8), 166 (Mþ2H2O, 34).
7: [a]D¼þ50.38 (c 0.65, CHCl3); IR (NaCl) 2230, 1742,
1251, 842 cm21; 1H NMR (CDCl3) d 0.22 (s, 9H, –OTMS),
0.99 (s, 3H, H8), 1.1–2.7 (m, 20H); 13C NMR (CDCl3) d
2.4, 18.4, 24.1, 25.7, 26.1, 30.8, 32.5, 34.6, 42.6, 47.5, 53.2,
58.9, 79.7, 118.4, 218.2; MS m/z 321 (Mþ2CN, 13).
4.2.2. (3aS,7aS)-3a-Hydroxy-7a-methyl-2,3,3a,6,7,7a-
hexahydro-1H-inden-1-one (4). To an ice-cooled solution
of alcohol 3a (52 mg, 0.28 mmol), phthalimide (63 mg,
0.42 mmol) and triphenylphosphine (110 mg, 0.42 mmol) in
THF (3 mL); DEAD (0.07 mL, 0.42 mmol) was added
dropwise under argon. The mixture was stirred at room
temperature for 21 h. Then, THF was evaporated and the
residue solved in ethyl acetate and washed with brine,
dried (Na2SO4) and evaporated. The crude product
was chromatographied (hex/EtOAc 7:1) to yield 35 mg
(75%) of 4 as a colourless oil. [a]D¼þ183.18 (c 0.67,
8: [a]D¼þ23.88 (c 0.18, CHCl3); IR (NaCl) 3417, 1740,
1252, 842 cm21; 1H NMR (CDCl3) d 0.17 (s, 9H, –OTMS),
0.91 (s, 3H, H8), 1.0–2.5 (m, 10H), 3.86 (tt, 1H, J¼4.0,
9.5 Hz, H5); 13C NMR (CDCl3) d 2.3, 18.4, 27.3, 32.1, 32.9,
34.7, 44.8, 53.6, 66.7, 81.3, 219.0; MS m/z 256 (Mþ, 1)
9: [a]D¼þ55.88 (c 0.43, CHCl3); IR (NaCl) 1742, 1251,
841 cm21;1HNMR(CDCl3400 MHz)d0.14(s,9H, –OTMS),
0.85 (s, 3H, H8), 1.04 (ddd, 1H, J¼5.6, 11.3, 18.7 Hz, H2),
1.10–1.25 (m, 1H, H4), 1.31 (dt, 1H, J¼4.0, 13.6 Hz, H7),
1.32–2.59 (m, 5H), 1.6–1.7 (m, 1H, H6), 1.70–3.35 (m, 12H);
13CNMR(CDCl3)d2.3,19.6,24.6,25.9, 26.3,28.6,33.0,34.9,
38.5, 50.1, 53.9, 58.6, 81.0, 219.0; MS m/z 323 (Mþ, 6).
CHCl3); IR (NaCl) 3438, 1732, 1171 cm21 1H NMR
;
(CDCl3) d 1.05 (s, 3H, H8), 1.3–2.6 (m, 8H), 5.70 (td, 1H,
J¼1.8, 10.0 Hz, H4), 5.87 (td, 1H, J¼3.3, 10.0 Hz, H5); 13C
NMR (CDCl3) d 17.8, 22.0, 26.7, 33.3, 34.9, 51.9, 77.7,
131.2, 131.4, 220.5; MS m/z 166 (Mþ, 26), 148 (Mþ2H2O,
9).
4.2.6. (3aS,7aR)-7a-Methyl-1-methylen-3a-trimethyl-
siloxyperhydroinden-5-one (11). By the same procedure
previously described for 5, from 150 mg (0.83 mmol) of 10,
187 mg (90%) of 11 were obtained. [a]D¼þ1.48 (c 0.29,
4.2.3. (3aS,7aS)-7a-Methyl-3a-trimethylsiloxyper-
hydroinden-1,5-dione (5). To a solution of diketone 1
(200 mg, 1.1 mmol) in 10 mL of dry CH2Cl2 under Ar
atmosphere, dry Et3N (0.18 mL, 1.32 mmol) and TMSOTf
(0.25 mL, 1.32 mmol) were added. The mixture was stirred
at room temperature for 1 h. The reaction was quenched
with Et3N (0.54 mL), extracted with CH2Cl2, washed with
HCl 2N, NaHCO3 and brine. The organic solvent was dried
and evaporated to give 221 mg (79%) of 5. IR (NaCl) 1750,
1730, 850 cm21; 1H NMR (CDCl3) d 0.14 (s, 9H, –OTMS),
1.18 (s, 3H, H8); 13C NMR (CDCl3) d 2.9, 15.1, 29.2, 32.7,
33.7, 36.6, 50.5, 53.7, 84.2, 207.8, 217.8; MS m/z 254 (Mþ,
37).
1
CHCl3); IR (NaCl) 1723, 841 cm21; H NMR (CDCl3) d
0.03 (s, 9H, –OTMS), 0.95 (s, 3H, H8), 1.5–2.7 (m, 10H),
4.82 (t, 1H, J¼2.5 Hz, H9), 4.85 (t, 1H, J¼2.2 Hz, H9); 13C
NMR (CDCl3) d 2.0, 22.1, 27.5, 31.8, 34.8, 37.3, 48.8, 50.4,
86.4, 105.4, 154.5, 209.9; MS m/z 252 (Mþ, 23).
4.2.7. (3aS,5R,7aR)-7a-Methyl-1-methylen-5-piperidyl-
3a-trimethylsiloxyperhydroinden-5-carbonitrile (12a)
and N-[(3aS,5R,7aR)-7a-methyl-1-methylen-3a-tri-
methylsiloxyperhydroinden-5-yl] piperidine (13a). By

L. G. Sevillano et al. / Tetrahedron 58 (2002) 10103–10112
10109
the same procedure as previously described for 9, from
132 mg (0.52 mmol) of ketone 11, after column chroma-
tography (hex/EtOAc 5:1), 60 mg (33%) of a 2:1 (12a/12b)
mixture, 9 mg (5.3%) of 13a and 29 mg (17%) of a 2:1
(13a/13b) mixture were obtained.
2H, CH2NO2), 5.92 (s, 1H, H4); 13C NMR (CDCl3) d 17.0,
23.8, 26.9, 33.3, 34.7, 51.4, 76.4, 81.1, 131.5, 136.3, 219.7;
MS m/z 179 (Mþ2NO2, 53).
4.2.11. (3aS,7aS)-3a-Hydroxy-5,7a-dimethyl-2,3,3a,
6,7,7a-hexahydro-1H-inden-1-one
(17).
Following
12a: IR (NaCl) 2217, 1250, 1100, 841 cm21
;
1H NMR
method A, from 46 mg (0.2 mmol) of a 4.5:1 (16/160)
mixture, 36 mg (100%) of a 4.5:1 (17/170) mixture were
(CDCl3) d 0.19 (s, 9H, –OTMS), 0.94 (s, 3H, H8), 1.2–2.7
(m, 20H), 4.77 (t, 1H, J¼2.5 Hz, H9), 4.84 (t, 1H, J¼2.2 Hz,
H9); 13C NMR (CDCl3) d 2.3, 24.3, 24.8, 26.2, 27.4, 28.0,
30.4, 34.6, 42.7, 47.4, 48.0, 59.4, 81.8, 106.0, 119.1, 153.3;
MS m/z 320 (Mþ2CN, 2).
1
obtained. 17: IR (NaCl) 3451, 1733, 1145, 858 cm21; H
NMR (CDCl3) d 1.03 (s, 3H, H8), 1.68 (s, 3H, Me–C5),
0.8–2.6 (m, 9H), 5.42 (c, 1H, J¼1.5 Hz, H4); 13C NMR
(CDCl3) d 17.7, 23.6, 27.0 (£2), 33.5, 34.7, 51.4, 76.4,
126.2, 139.6, 220.7; MS m/z 180 (Mþ, 58).
13a: [a]D¼þ32.48 (c 0.29, CHCl3); IR (NaCl) 1250, 1091,
841 cm21; 1H NMR (CDCl3) d 0.12 (s, 9H, –OTMS), 0.84
(s, 3H, H8), 4.74 (t, 1H, J¼2.5 Hz, H9), 4.79 (t, 1H,
J¼2.2 Hz, H9); 13C NMR (CDCl3) d 2.4, 24.7, 24.8, 25.2,
26.3, 27.5, 30.4, 35.0, 37.2, 48.8, 50.3, 59.8, 83.1, 104.8,
154.2; MS m/z 321 (Mþ, 13).
4.2.12. (3aS,5R,7aS)-3a-Hydroxy-7a-methyl-1-oxoper-
hydroinden-5-carbonitrile (18a) and (3aS,5S,7aS)-3a-
hydroxy-7a-methyl-1-oxoperhydroinden-5-carbonitrile
(18b). To a cooled solution (08C) (500 mg, 2.75 mmol) of
diketone 1 and TosMIC (719 mg, 3.6 mmol) in 9.5 mL of
dry 1,2-dimethoxyethane and 0.25 mL of absolute EtOH,
312 mg (2.6 mmol) of KOtBu in small portions were added.
The solution got darker and after stirring for 6 h under Ar at
room temperature, the precipitate was removed by filtration.
The filtrate was extracted with ether, washed with brine and
dried (Na2SO4) yielding a yellow oil (5a/5b 1.7:1). The
crude was purified by column chromatography (hex/EtOAc
2:1) to give 90 mg (17%) of 18a as a white crystalline solid,
197 mg (37%) of a mixture of both epimers and 7 mg (1%)
of 18b.
4.2.8. (3aS,7aS)-3a-Hydroxy-7a-methyl-1-oxoperhydro-
inden-5-yliden]malononitrile (14). To a solution 0.4 M of
diketone 1 (50 mg, 0.27 mmol) in EtOH (0.7 mL) at room
temperature, 19.6 mg (0.30 mmol) of malononitrile, 0.2 mg
(0.0027 mmol) of b-alanine and 0.3 mL of acetic acid were
sequentially added. After stirring for 2 h at room tempera-
ture, the mixture was extracted with EtOAc and washed
with brine. The residue was chromatographed (hex/EtOAc
3:1) yielding 50 mg (80%) of 14 as a white solid.
[a]D¼þ27.08 (c 0.73, CHCl3); IR (NaCl) 3486, 2235,
1
1741 cm21; H NMR (CDCl3) d 1.14 (s, 3H, H8), 1.1–2.9
18a: mp 159–1608C (CH2Cl2). [a]D¼þ81.78 (c 0.29,
(m, 10H); 13C NMR (CDCl3) d 15.4, 30.6, 30.7, 32.3, 33.7,
43.6, 52.9, 81.6, 85.1, 111.2, 111.5, 179.9, 216.8; MS m/z
166 (Mþ2C(CN)2, 26). HRMS (EI) calcd for C13H14N2O2
230.1055; found 230.1057.
CHCl3); IR (NaCl) 3458, 2249, 1731, 1194 cm21 1H
;
NMR (CDCl3) d 1.00 (s, 3H, H8), 1.1–2.9 (m, 11H); 13C
NMR (CDCl3) d 18.3, 23.9, 26.1, 27.6, 32.5, 34.3, 38.7,
52.1, 76.2, 122.2, 217.6, MS m/z 193 (Mþ, 3). Anal. Calcd
for C11H15NO2: C, 68.37; H, 7.82; N, 7.25; Found: C, 68.72;
H, 8.09; N, 7.01.
4.2.9. (3aS,5R,7aS)-3a-Hydroxy-7a-methyl-1-oxoper-
hydroinden-5-yl]malononitrile (15a). To a cooled solution
(08C) of nitrile 14 (95 mg, 0.41 mmol) in 1.5 mL of dry
THF, 1.03 mL (1.03 mmol) of DIBAL-H 1 M in hexane
were dropwise added. After, stirring for 30 min, 0.3 mL of
NH4Cl sat and 0.37 mL of 10% H2SO4 were added and
stirred for 10 min. After usual work up and column
chromatography (hex/EtOAc 1:1) 26 mg (27%) of a 3:1
(15a/15b) mixture and 9 mg of more polar products.
18b: [a]D¼þ31.88 (c 0.27, CHCl3); IR (NaCl) 3436, 2252,
1
1736 cm21; H NMR (CDCl3) d 1.09 (s, 3H, H8), 1.3–2.8
(m, 11H); 13C NMR (CDCl3) d 14.2, 24.5, 25.9, 29.6, 30.9,
33.5, 36.6, 52.2, 77.7, 121.4, 218.7; MS m/z 193 (Mþ, 15).
4.2.13. Ethyl (Z)-[(3aS,7aS)-(3a-hydroxy-7a-methyl-1-
oxoperhydroinden-5-yliden)]acetate (19) and ethyl (E)-
[(3aS,7aS)-(3a-hydroxy-7a-methyl-1-oxoperhydroinden-
5-yliden)]acetate (20). A solution of diketone 1 (1.93 g,
15a/15b: IR (NaCl) 3468, 2257, 2226, 1732 cm21 1H
;
NMR (CDCl3) d 0.88 (s, 3H, H8, minor isomer), 1.02 (s, 3H,
H8, major isomer), 1.0–2.7 (m, 12H), 3.62 (dd, 1H, J¼4.4,
6.2 Hz, H5b, major), 3.9–4.1 (m, 1H, H5a, minor); 13C
NMR (CDCl3) (data for major isomer 15a) d 19.3, 27.0,
27.9, 28.8, 33.2, 34.6, 34.8, 40.0, 52.4, 81.3, 111.5, 111.6,
217.2; MS m/z 232 (Mþ, 3).
10.6 mmol)
and
ethoxycarbonylmethylen-triphenyl-
phosphorane (6.3 g, 18.02 mmol) in 42.4 mL of dry benzene
was heated to reflux for 3.5 h. After evaporating the solvent,
the residue was chromatographed (hex/EtOAc 1:1) yielding
2.6 g (97%) of a 3:2 (19/20) mixture. Both stereoisomers
were separated by new column chromatographies.
4.2.10. (3aS,7aS)-3a-Hydroxy-7a-methyl-5-nitromethyl-
2,3,3a,6,7,7a-hexahydro-1H-inden-1-one (16). To a sol-
ution of diketone 1 (100 mg, 0.55 mmol) in 5.4 mL of
freshly distilled nitromethane under Ar atmosphere, 8 mL of
ethylenediamine were added. The mixture was heated to
reflux for 13 h. After that time, the solvent was evaporated
and the crude of reaction purified by column chromato-
graphy (hex/EtOAc 1:4) yielding 89 mg (77%) of a 4.5:1
(16/160) mixture. 16: IR (NaCl) 3445, 1731, 1556 cm21; 1H
NMR (CDCl3) d 1.07 (s, 3H, H8), 1.2–2.7 (m, 9H), 4.85 (s,
19: [a]D¼þ58.28 (c 1.00, CHCl3); IR (NaCl) 3479, 1739,
1
1714, 1152 cm21; H NMR (CDCl3) d 1.11 (s, 3H, H8),
1.29 (t, 3H, J¼6.9 Hz, –COO–CH2–CH3), 1.4–2.7 (m,
9H), 2.83 (d, 1H, J¼13.0 Hz, H4), 3.19 (d, 1H, J¼13.0 Hz,
H4), 4.16 (c, 2H, J¼6.9 Hz, COO–CH2–CH3), 5.80 (s, 1H,
vCH–COOEt); 13C NMR (CDCl3) d 14.1, 14.8, 31.6, 32.0,
32.9, 33.6, 38.2, 53.1, 60.0, 80.8, 116.1, 158.1, 166.8, 219.7;
MS m/z 252 (Mþ, 16). Anal. Calcd for C14H20O4: C, 66.65;
H, 7.99; Found: C, 66.87; H, 8.12.

10110
L. G. Sevillano et al. / Tetrahedron 58 (2002) 10103–10112
20: mp 92–948C (CH2Cl2). [a]D¼þ22.78 (c 1.06, CHCl3);
IR (NaCl) 3472, 1736, 1714, 1147 cm21; 1H NMR (CDCl3)
d 1.18 (s, 3H, H8), 1.31 (t, 3H, J¼7.3 Hz, –COO–CH2–
CH3), 1.4–2.7 (m, 10H), 3.34 (td, 1H, J¼5.7 Hz, 14.3, H6),
4.17 (c, 2H, J¼7.3 Hz, COO–CH2–CH3), 5.74 (s, 1H,
vCH–COOEt); 13C NMR (CDCl3) d 14.1, 14.2, 24.6, 31.0,
31.5, 33.6, 45.9, 53.2, 60.0, 80.7, 116.5, 157.3, 166.2, 219.5;
MS m/z 252 (Mþ, 8). Anal. Calcd for C14H20O4: C, 66.65;
H, 7.99; Found: C, 66.79; H, 8.10.
(Mþ2H2O, 11). Anal. Calcd for C15H22O4: C, 67.64; H,
8.33; Found: C, 67.87; H, 8.55.
22b: [a]D¼þ6.48 (c 0.86, CHCl3); IR (NaCl) 3469, 1729,
864 cm21; 1H NMR (CDCl3) d 1.14 (s, 3H, H8), 1.27 (t, 3H,
J¼7.3 Hz, –COO–CH2–CH3), 1.1–2.6 (m, 10H), 3.05 (dt,
1H, J¼3.3, 17.2 Hz, H4), 4.15 (c, 2H, J¼7.3 Hz, COO–
CH2–CH3), 5.46 (dd, 1H, J¼1.1, 2.6 Hz, vCH2), 6.20 (dd,
1H, J¼1.5 Hz, 3.3, vCH2); 13C NMR (CDCl3) d 12.9, 14.3,
26.9, 32.2, 32.6, 38.8, 39.5, 41.2, 53.1, 60.5, 77.7, 120.3,
141.9, 172.4, 208.2; MS m/z 266 (Mþ, 2), 248 (Mþ2H2O,
7). Anal. Calcd for C15H22O4: C, 67.64; H, 8.33; Found: C,
67.96; H, 8.80.
4.2.14. Ethyl [(3aS,5R,7aS)-2-(3a-hydroxy-7a-methyl-1-
oxoperhydroinden-5-yl)]acetate (21a). Following method
A, from 6 g (23.8 mmol) of a 3:1 (19/20) mixture, after
column chromatography (hex/EtOAc 2:1) a quantitative
mixture 1:1.4 (21a/21b) was obtained. Only compound 21a
was isolated from the mixture. [a]D¼þ74.08 (c 0.20,
4.2.16. Ethyl (1S)-1-[(3aS,5S,7aS)-(3a-hydroxy-7a-
methyl-1-oxoperhydroinden-5-yl)]-4-oxocyclohex-2-ene
carboxylate (23) and ethyl (1R)-1-[(3aS,5R,7aS)-(3a-
hydroxy-7a-methyl-1-oxoperhydroinden-5-yl)]-4-oxo-
cyclohex-2-enecarboxylate (25). To a solution of 2:3
(22a/22b) mixture (829 mg, 3.11 mmol) in 4 mL of dry
benzene, 4.9 mL (21.8 mmol) of Danishefsky’s diene were
added and heated to 958C under Ar for 26 h. After that time,
the solvent was evaporated and the residue was solved in
40 mL of CHCl3, adding 28 drops of concentrated HCl. The
mixture was stirred for 1 h at room temperature. It was
extracted with CH2Cl2, and washed with brine, to give an oil
crude that was purified by column chromatography
(hex/EtOAc 2:1) yielding 334 mg (37%) of a 3.5:1 (23/24)
mixture and 263 mg (25%) of 2:1 (25/26) mixture. These
fractions were again chromatographed allowing the separ-
ation of the major products of these mixtures.
CHCl3); IR (NaCl) 3469, 1738, 1732, 1201 cm21 1H
;
NMR (CDCl3) d 0.99 (s, 3H, H8), 1.25 (t, 3H, J¼6.9 Hz,
–COO–CH2–CH3), 0.7–2.7 (m, 14H), 4.12 (c, 2H,
J¼6.9 Hz, COO–CH2–CH3); 13C NMR (CDCl3) d 14.3,
19.6, 28.7, 29.4, 29.6, 32.9, 34.7, 41.2, 43.1, 52.8, 60.5,
79.6, 172.9, 219.1; MS m/z 254 (Mþ, 5). Anal. Calcd for
C14H22O4: C, 66.12; H, 8.72; Found: C, 66.72; H, 8.53.
4.2.15. Ethyl 2-[(3aS,5R,7aS)-(3a-hydroxy-7a-methyl-1-
oxoperhydroinden-5-yl)]acrylate (22a) and ethyl 2-
[(3aS,5S,7aS)-(3a-hydroxy-7a-methyl-1-oxoperhydro-
inden-5-yl)]acrylate (22b). To a solution of LDA (4 equiv.,
62.8 mmol) in 200 mL of dry THF at 2788C, 4 g
(15.7 mmol) of 3:2 (21b/21a) mixture in 360 mL of dry
THF and 15.6 mL (86.3 mmol) of HMPTA were slowly
added. After the addition, the solution was stirred at 2788C
for 15 min, the temperature was raised to 2428C and then
kept for 15 min. In another reaction flask, 30 g (162 mmol)
of the Eschenmoser’s salt (previously dried at 808C and high
vacuum) were suspended in THF (300 mL). The enolate
solution was passed via canule to the Eschenmoser’s salt
flask at 2428C. The mixture was stirred at 2428C for
45 min, and then allowed to reach the room temperature for
14 h. HCl 2N until acid pH and solid Na2CO3 until basic pH
were added. The organic layer was extracted five times with
EtOAc, dried and evaporated to give an oil.
23: IR (NaCl) 3469, 1732, 1667, 1182 cm21 1H NMR
;
(CDCl3 400 MHz) d 1.09 (s, 3H, H8), 1.24 (t, 3H,
J¼7.2 Hz, –COO–CH2–CH3), 1.1–2.5 (m, 15H), 2.83
(ddd, 1H, J¼4.8, 10.5, 16.9 Hz, H50), 4.12 (c, 2H,0J¼7.2 Hz,
COO–CH2–CH3), 05.93 (d, 1H, J¼10.1 Hz, H3 ), 6.91 (d,
1H, J¼10.1 Hz, H2 ); 13C NMR (CDCl3) d 13.5, 14.2, 26.8,
32.5, 32.7, 34.2, 35.1, 40.1, 41.0, 44.6, 50.0, 53.9, 60.4,
78.5, 128.3, 152.9, 172.0, 198.5, 219.9; MS m/z 334 (Mþ,
12).
25: IR (NaCl) 3469, 1732, 1674, 1186 cm21 1H NMR
;
Methyl iodide (200 mL) and 100 mL of dioxane were added
to the crude product. The mixture was vigorously stirred and
heated at 908C under Ar atmosphere for 19 h. After
evaporating the solvent, the solid was dissolved in 50 mL
of water. NaHCO3 in excess and 200 mL of ethyl acetate
were added and the reaction mixture was vigorously stirred
for 30 min. The organic layer was dried and evaporated
yielding a 6 g residue that was chromatographed (hex/
EtOAc 3:1) to give 3.42 g (77%) of a 2:3 (22a/22b) mixture.
Both stereoisomers were separated for characterization by
new column chromatographies.
(CDCl3 400 MHz) d 1.11 (s, 3H, H8), 1.24 (t, 3H,
J¼7.2 Hz, –COO–CH2–CH3), 0.7–2.9 (m, 16H), 4.11 (c,
2H, J¼7.2 Hz, COO–CH2–CH3), 5.97 (d, 1H, J¼10.0 Hz,
H30), 6.61 (d, 1H, J¼10.0 Hz, H20); 13C NMR (CDCl3) d
14.2, 20.1, 29.2, 29.5, 29.6, 33.7, 34.0, 40.8, 45.1, 47.1,
50.4, 54.4, 60.4, 75.6, 129.1, 151.9, 172.3, 198.1, 217.2; MS
m/z 334 (Mþ, 11).
4.2.17. Ethyl 4,4-diethoxy-1-[(3aS,5S,7aS)-3a-hydroxy-
7a-methyl-1-oxoperhydroinden-5-yl)] cyclohexanecar-
boxylate (27). Following method A, from 240 mg
(0.72 mmol) of a 3.5:1 (23/24) mixture, 242 mg (82%) of
27 as a colourless oil were obtained. IR (NaCl) 3500, 1738,
22a: [a]D¼þ37.58 (c 0.87, CHCl3); IR (NaCl) 3469, 1731,
1182, 858 cm21; 1H NMR (CDCl3) d 1.02 (s, 3H, H8), 1.24
(t, 3H, J¼7.3 Hz, –COO–CH2–CH3), 1.0–2.6 (m, 10H),
2.80 (dt, 1H, J¼3.3, 16.1 Hz, H4), 4.11 (c, 2H, J¼7.3 Hz,
COO–CH2–CH3), 5.39 (dd, 1H, J¼1.5, 2.9 Hz, vCH2),
6.13 (dd, 1H, J¼1.8, 3.3 Hz, vCH2); 13C NMR (CDCl3) d
14.3, 19.8, 28.8, 29.5, 41.1, 41.1, 41.4, 43.8, 52.8, 60.4,
75.2, 119.7, 142.8, 172.7, 206.6; MS m/z 266 (Mþ, 5), 248
1
1732, 1152 cm21; H NMR (CDCl3) d 1.06 (s, 3H, H8),
1.1–1.3 (m, 9H, –COO–CH2–CH3 and 2·OCH2CH3), 1.0–
2.5 (m, 20H), 3.3–3.5 (m, 4H, J¼6.9 Hz, 2·OCH2CH3),
4.17 (c, 2H, J¼7.3 Hz, COO–CH2–CH3); 13C NMR
(CDCl3) d 13.3, 14.3, 15.3, 15.5, 26.8, 29.7, 30.1, 30.9,
32.5, 32.5, 34.7, 40.6, 41.1, 41.5, 48.0, 53.9, 54.8, 55.0,
60.3, 78.0, 98.8, 172.4, 224.7; MS m/z 364 (Mþ2EtO, 12).

L. G. Sevillano et al. / Tetrahedron 58 (2002) 10103–10112
10111
4.2.18. Ethyl 4,4-diethoxy-1-[(3aS,5R,7aS)-3a-hydroxy-
7a-methyl-1-oxoperhydroinden-5-yl)] cyclohexanecar-
boxylate (28). Following method A, from 70 mg
(0.21 mmol) of a 2:1 (25/26) mixture, 77 mg (89%) of 28
as a colourless oil were obtained. [a]D¼þ40.68 (c 1.34,
evaporated yielding 109 mg (52%) of a mixture of the a and
b triols. The major product 31 was isolated by chromato-
graphy (hex/EtOAc 1:2þ1% Et3N) as a white foaming
solid. IR (NaCl) 3419, 1177 cm21; 1H NMR (CDCl3) d 1.05
(s, 3H, H8), 1.1–1.3 (m, 6H, 2·OCH2CH3), 0.8–2.1 (m,
21H), 3.3–3.5 (m, 4H, OCH2CH3), 3.6–3.7 (m, 2H,
CH2OH), 3.80 (bs, 1H, H1); 13C NMR (CDCl3) d 15.5,
15.7, 17.4, 27.8, 29.8, 30.2, 31.3, 31.6, 32.0, 36.3, 39.8,
41.3, 44.9, 48.0, 55.1, 55.1, 60.3, 80.2, 89.4, 99.5, C7a not
obs; MS m/z 324 (Mþ2EtO, 34).
CHCl3); IR (NaCl) 3469, 1732, 1163 cm21 1H NMR
;
(CDCl3) d 1.08 (s, 3H, H8), 1.1–1.3 (m, 9H, –COO–CH2–
CH3 and 2·OCH2CH3), 0.7–2.4 (m, 20H), 3.41 (c, 2H,
J¼6.9 Hz, OCH2CH3), 4.12 (c, 2H, J¼6.9 Hz, COO–CH2–
CH3); 13C NMR (CDCl3) d 14.3, 15.4, 15.6, 21.6, 29.7, 29.7,
30.0, 30.0, 31.2, 35.6, 41.1, 41.1, 44.8, 45.6, 49.0, 53.8,
55.1, 55.3, 60.4, 77.8, 98.7, 172.7, 222.7; MS m/z 364
(Mþ2EtO, 39). Anal. Calcd for C23H38O6: C, 67.29; H,
9.33; Found: C, 67.61; H, 9.62.
4.2.22. (1R,3aS,5S,7aR)-5-[(1-tert-Butyldimethylsiloxy-
methyl-4,4-diethoxy)cyclohexyl]-7a-methyl perhydro-
inden-1,3a-diol (32). To a solution of 31 (105 mg
0.28 mmol) in 10 mL of dry CH2Cl2, 0.21 mL of Et3N
and 0.14 mL (0.6 mmol) of tert-butyldimethylsilyl trifluoro-
methanesulfonate were added. The mixture was stirred
under Ar for 3 h, after that time it was diluted with CH2Cl2,
washed with NaHCO3 and brine. After habitual process, the
residue was chromatographed (hex/EtOAc 1:1þ1% Et3N)
and 32 was quantitatively isolated as a white solid. IR
4.2.19. Ethyl 1-[(3aS,5S,7aS)-3a-hydroxy-7a-methyl-1-
oxoperhydroinden-5-yl)]-4-oxocyclohexane carboxylate
(29). To a solution of 49 mg (0.15 mmol) of a 3.5:1 (23/24)
mixture, in HOCH2CH2OH, 10 mg Pd(C) 10% were added
and stirred under H2 atmosphere (2 atm). After disappear-
ance of the starting material (36 h), the reaction was filtered
through a silica gel column and the solvent evaporated to
obtain 40 mg (80%) of 29. [a]D¼þ13.48 (c 0.51, CHCl3);
IR (NaCl) 3500, 1732, 1716, 1150 cm21; 1H NMR (CDCl3)
d 1.10 (s, 3H, H8), 1.28 (t, 3H, J¼7.3 Hz, –COO–CH2–
CH3), 4.16 (c, 2H, J¼7.3 Hz, COO–CH2–CH3); 13C NMR
(CDCl3) d 13.5, 14.3, 27.0, 32.7, 33.0, 34.9, 37.9 (£2), 38.2,
40.9, 41.2, 42.0, 47.1, 54.4, 60.6, 78.5, 172.4, 210.7, 223.3;
MS m/z 336 (Mþ, 4). HRMS (EI) calcd for C19H28O5
336.1937; found 336.1940.
1
(NaCl) 3466, 1256, 1095, 837 cm21; H NMR (CDCl3) d
0.03 (s, 6H, OSiMe2), 0.84 (s, 9H, OSitBu), 0.98 (s, 3H, H8),
1.0–1.2 (m, 6H, 2·OCH2CH3), 0.8–2.0 (m, 21H), 3.3–3.5
(m, 4H, OCH2CH3), 3.55–3.65 (m, 2H, CH2O–), 3.75 (bs,
1H, H1); 13C NMR (CDCl3) d 25.3, 15.5, 15.6, 17.4, 18.3,
25.9, 27.8, 30.1, 31.2, 31.6, 32.1, 36.3, 39.8, 41.2, 44.9,
45.9, 48.0, 55.0, 55.0, 60.8, 80.2, 89.4, 99.4, C7a not obs;
MS m/z 438 (Mþ2OEt, 1).
4.2.23. (3aS,5S,7aS)-5-[(1-tert-Butyldimethylsiloxy-
methyl-4-oxo)cyclohexyl]-3a-hydroxy-7a-methyl per-
hydroinden-1-one (33). To a suspension of 350 mg
4.2.20. (3aS,5R,7aS)-5-(4,4-Diethoxy-1-isopropenylcyclo-
hexyl)-3a-hydroxy-7a-methylperhydroinden-1-one (30).
To a suspension of 0.2 g (0.42 mmol) of methyltriphenyl-
phosphonium iodide in 3.3 mL of dry benzene under Ar, a
solution of NaOtAm 4.5N (87.4 mg, 0.42 mmol) in benzene
was added at room temperature and the bright-yellow
phosphorane was immediately formed. The mixture was
heated to reflux and a solution of 28 (58 mg, 0.14 mmol) in
0.4 mL of benzene was added and the mixture was gently
refluxed for 1 h 30 min. After cooling and filtration, the
solution was diluted with EtOAc and washed with brine.
After purification by column chromatography (hex/EtOAc
5:1) 11 mg (21%) of 30 and 2 mg of deprotected starting
material were obtained. [a]D¼þ55.98 (c 0.32, CHCl3); IR
˚
(1.6 mmol) of CCP, 200 mg of 4 A molecular sieves and
0.26 mL (3.2 mmol) of dry pyridine in 48 mL of dry
CH2Cl2, a solution of 32 (130 mg, 0.27 mmol) in 15 mL of
dry CH2Cl2 was added. The reaction mixture was stirred at
room temperature for 45 min and the mixture was passed
through a column (hex/EtOAc 2:1þ1% Et3N) and the
diketone 33 was obtained quantitatively. [a]D¼21.938 (c
1.09, CHCl3); IR (NaCl) 3480, 1731, 1716, 1255, 1166,
838 cm21; 1H NMR (CDCl3) d 0.07 (s, 6H, OSiMe2), 0.90
(s, 9H, OSitBu), 1.11 (s, 3H, H8), 1.0–2.7 (m, 20H), 3.6–
3.7 (m, 2H, CH2OTBDMS); 13C NMR (CDCl3) d 25.2,
13.6, 18.4, 26.0, 27.3, 33.3, 33.3, 34.8, 37.7, 37.9, 38.2,
39.5, 41.3, 42.1, 47.0, 54.8, 60.6, 78.6, 211.0, 223.8; MS m/z
393 (Mþ215, 1). Anal. Calcd for C23H40O4Si: C, 67.60; H,
9.87; Found: C, 68.01; H, 10.12.
1
(NaCl) 3500, 1731, 1162, 887 cm21; H NMR (CDCl3) d
1.07 (s, 3H, H8), 1.10–1.25 (m, 6H, 2·OCH2CH3), 1.60 (s,
3H, CH3CvCH2), 0.5–2.2 (m, 20H), 3.41 (c, 2H, J¼
6.9 Hz, OCH2CH3), 3.50 (c, 2H, J¼6.9 Hz, OCH2CH3),
4.62 (s, 1H, vCH2), 4.73 (d, 1H, J¼1.5 Hz, vCH2); 13C
NMR (CDCl3) d 15.5, 15.7, 21.6, 22.5, 29.8, 30.1 (£2), 30.3,
30.4, 31.3, 35.6, 45.1, 45.2, 46.0, 49.1, 54.1, 55.1, 55.3,
76.5, 98.8, 111.9, 143.6, 222.8; MS m/z 378 (Mþ, 2). HRMS
(EI) calcd for C23H38O4 378.2770; found 378.2771.
4.2.24. (3aS,5S,7aS)-5-[(1-tert-Butyldimethylsiloxy-
methyl-4-hydroxy)cyclohexyl]-3a-hydroxy-7a-methyl
perhydroinden-1-one (34). To a solution of 64 mg
(0.16 mmol) of diketone 33 in 4 mL of dry MeOH at
2158C, 2 mg (0.043 mmol) of NaBH4 were added. After
stirring at 2158C for 15 min, the reaction mixture was
quenched with water, extracted with EtOAc, washed with
brine, to yield 64 mg (98%) of a 2:1 (34/35) mixture. 34: IR
(NaCl) 3445, 1724, 1098 cm21; 1H NMR (CDCl3) d 0.03 (s,
6H, OSiMe2), 0.88 (s, 9H, OSitBu), 1.03 (s, 3H, H8), 3.6–
3.7 (m, 2H, CH2OTBDMS); 13C NMR (CDCl3) d 25.3,
13.5, 18.3, 25.9, 27.3, 31.6, 31.9, 32.3, 32.4, 33.0, 36.6,
39.5, 41.4, 41.8, 48.0, 54.3, 60.6, 69.8, 78.6, 225.4; MS m/z
353 (Mþ257, 61).
4.2.21. (1R,3aS,5S,7aR)-5-(4,4-Diethoxy-1-hydroxy-
methylcyclohexyl)-7a-methylperhydroinden-1,3a-diol
(31). To a solution of 27 (235 mg, 0.57 mmol) in 3 mL of
dry ether, 2 equiv. of LiAlH4 were added at room
temperature. After stitting under Ar atmosphere for
45 min, ether saturated of water was added. The mixture
was filtrated under vacuum and the precipitate washed with
hot THF several times. The organic layer was dried and

10112
L. G. Sevillano et al. / Tetrahedron 58 (2002) 10103–10112
10. (a) Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127–164.
Acknowledgements
(b) Roush, W. R.; Straub, J. A.; Brown, J. R. J. Org. Chem.
1987, 52, 5127–5136.
´
Financial support came from Junta de Castilla y Leon
(SA-02/99, the Consejeria de Educacion y Cultura and the
European Social Fund). L. G. S. thanks the Spanish Ministry
of Education for a predoctoral grant.
´
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