Palladium-catalyzed potassium enoxyborate alkylation of enantiopure Hajos-Parrish indenone to construct rearranged steroid ring systems

Article abstract of DOI:10.1021/jo070530e

(Chemical Equation Presented) Here we report the stereo- and regiospecific C-6 alkylation of a trans-inden-5-one (from optically pure Hajos-Parrish ketone) with allylic electrophiles. Use of this alkylation procedure has led to an improved synthesis of th

Full text of DOI:10.1021/jo070530e

Palladium-Catalyzed Potassium Enoxyborate Alkylation of
Enantiopure Hajos-Parrish Indenone To Construct Rearranged
Steroid Ring Systems
Izabella Jastrzebska,†,| Jamie B. Scaglione,†,| Gregory T. DeKoster,§ Nigam P. Rath,‡ and
Douglas F. Covey*,†
Department of Molecular Biology and Pharmacology and Department of Biochemistry and
Molecular Biophysics, Washington UniVersity School of Medicine, St. Louis, Missouri 63110, and
Department of Chemistry and Biochemistry, UniVersity of MissourisSt. Louis, St. Louis, Missouri 63121
dcoVey@wustl.edu
ReceiVed March 14, 2007
Here we report the stereo- and regiospecific C-6 alkylation of a trans-inden-5-one (from optically pure
Hajos-Parrish ketone) with allylic electrophiles. Use of this alkylation procedure has led to an improved
synthesis of the benz[f]indene ring system and the first enantiospecific total syntheses of the cyclopenta-
[b]anthracene and cyclopenta[b]phenanthrene ring systems (two synthetic routes).
Introduction
To expand our structure-activity studies of neuroactive
steroids acting at γ-aminobutyric acid type A receptors, we are
interested in constructing enantiopure, rearranged steroid ring
systems. Specifically, we want to make cyclopenta[b]anthracene
and cyclopenta[b]phenanthrene neurosteroid analogues (Figure
1). Very few synthetic attempts for either ring system exist in
the literature. The only reference to the cyclopenta[b]anthracene
system is a very complicated series of two papers from a
Japanese group on the synthesis of linear progesterone and
testosterone analogues.1,2 By their method, the steroid hecogenin
is degraded to a cyclodecatrione framework, the cyclopenta[b]-
anthracene system is reconstructed through an intramolecular
condensation, and then unwanted functionalities are eliminated.
* To whom correspondence should be addressed. Tel.: 314-362-1726. Fax:
314-362-7058.
FIGURE 1. Structure and numbering of the steroid, benz[f]indene,
cyclopenta[b]anthracene, and cyclopenta[b]phenanthrene ring systems.
† Department of Molecular Biology and Pharmacology, Washington University
School of Medicine.
§ Department of Biochemistry and Molecular Biophysics, Washington
University School of Medicine.
The synthesis is long and riddled with byproducts, and the
stereochemistries are unclear.
There are three previously published synthetic routes to the
cyclopenta[b]phenanthrene system. All are racemic, and all were
‡ University of MissourisSt. Louis.
| These authors contributed equally to this work.
(1) Aoyama, S.; Sasaki, K. Chem. Pharm. Bull. 1970, 18, 481-89.
(2) Aoyama, S.; Sasaki, K. Chem. Pharm. Bull. 1970, 18, 1310-26.
10.1021/jo070530e CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/27/2007
J. Org. Chem. 2007, 72, 4837-4843
4837

Jastrzebska et al.
SCHEME 1. Benz[f]indenone System
done with the goal of obtaining cyclopenta[b]phenanthrene
estradiol analogues, so the A-rings are aromatic. Pitt and Handy
first synthesized cyclopenta[b]phenanthrene estradiol by two
different routes. Their first route was very convoluted, involving
the synthesis and ring contraction of a D-homo analogue of
cyclopenta[b]phenanthrene estradiol.3 Their second route was
shorter, involving a Michael addition of the anion of 2-methyl-
1,3-cyclopentanedione with 5-(3-methoxyphenyl)-3-methylene-
2-pentanone, but still not useful to us because the products are
racemates.3,4
In the final example by Collins et al., the key step in their
cyclopenta[b]phenanthrene estradiol synthesis is the conjugation
of a 6-methylene derivative of indenone 1 with 3-methoxyben-
zylmagnesium chloride.5 While the authors use racemic inde-
none as starting material, the same sequence could be carried
out with optically pure indenone. However, the scheme is
complicated by the propensity for the 6-methylene compound
to rapidly dimerize at room temperature. In fact, to carry out
the synthesis, the authors had to cleave the dimer by flash
vacuum pyrolysis at 500 °C and trap the monomer at liquid-
nitrogen temperature.
The original aim of Collins et al. was to assemble the
cyclopenta[b]phenanthrene ring system by alkylating indenone
1 at C-6 with 2-(3′-methoxyphenyl)ethyl halides, but they found
the indenone piece resistant to all alkylation attempts. We have
also observed this in our previous synthesis of the benz[f]indene
ring system (Figure 1).6 However, we recently came across a
previously reported method for the R-alkylation of ketones via
potassium enoxyborates with allylic electrophiles in the presence
of a catalytic amount of a palladium complex.7-9 We have found
that by this method, indenone 1, derived from optically pure
Hajos-Parrish ketone, is alkylated regio- and stereoselectively
at C-6 in high yield. In this paper, we describe how this reaction
has afforded us a much shorter route to the benz[f]indene ring
system, the first total synthesis route to the optically pure
cyclopenta[b]anthracene ring system, and two different paths
to the optically pure cyclopenta[b]phenanthrene ring system.
diketone 3 gave the two previously reported benz[f]indene
isomers, enone 4a (73%) and tetrasubstituted olefin 4b (24%).6
With the discovery of this alkylation method, this route to the
benz[f]indene skeleton represents a vast improvement over our
previous protracted method (previously seven steps from
indenone 1 to 4a, now three steps from indenone 1 to 4a).6
Enone 4a was then protected to give silyl ether 5 (100%,
Scheme 2). As expected, lithium liquid ammonia reduction of
5 gave exclusively the trans ring fusion product 6 (67%). The
alkylation procedure used for indenone 1 was repeated on
compound 6. However, whereas alkylation of the indenone
system resulted in a single regio- and stereoisomer, 13C NMR
and TLC indicated that alkylation of the benz[f]indene system
yielded a complex mixture of regio- and stereoisomers 7a and
7b (total yield, 76%) that could not be separated by column
chromatography. The uncharacterized mixture was immediately
subjected to the same mercury(II) trifluoroacetate hydration
procedure. Because the hydration yielded 8a and 8b as a single
spot by TLC, the mixture of diketones was taken together
through the aldol condensation.
Through careful column chromatography and recrystallization,
cyclopenta[b]anthracenone 9a was isolated (31% from 6), and
a crystal structure confirmed the assignment of all stereocenters.
Cyclopenta[b]phenanthrenone 9b represented only a quarter of
the material (10% from 6). A portion of 9b could be separated
from 9a (∼30%), but a lot of the oily 9b was contaminated
with a small amount of 9a. We then began to look for an
alternate, higher yielding method for synthesizing the cyclo-
penta[b]phenanthrene system.
Results and Discussion
Cyclopenta[b]anthracene. Indenone 1 (prepared from opti-
cally pure Hajos-Parrish ketone as described previously),6 was
alkylated with a mixture of cis/trans-1,3-dichloro-2-butene
according to the previously described method to give compound
2 (Scheme 1, 88%).7-9 The stereochemistry of the chlorobutenyl
side chain was assigned based on the analogous alkylation of
indenone 1 with allyl bromide to yield compound 12, which is
described later for the synthesis of the cyclopenta[b]phenan-
threne ring system.
Cyclopenta[b]phenanthrene. Before describing the alterna-
tive method we established for synthesizing the cyclopenta[b]-
phenanthrene ring system, it should be noted that we made
several attempts to add different butanyl sidechains to enone 5
to obtain this ring system. One idea was to try a reductive
alkylation of 5 using Li/NH3 and 1,3-dichloro-2-butene. Despite
similar examples of this reaction in steroidal systems,11,12 this
yielded only the reduced product 6. A second plan was to
alkylate 5 using NaH and the cyclic ethylene ketal of 4-iodo-
2-butanone. We tested this reaction on the steroid 17-[[(1,1-
dimethylethyl)dimethylsilyl]oxy]estr-4-en-3-one and were able
to obtain the alkylated enone in 55% yield. However, when the
reaction was attempted on 5, the sole product was the silyl ether
derivative of compound 4b.
The mixture of cis/trans-chlorobutenyl isomers 2 was indi-
rectly hydrolyzed using mercury(II) trifluoroacetate to give a
single compound, diketone 3 (72%).10 Aldol condensation of
(3) Pitt, C. G.; Handy, R. W. Tetrahedron 1971, 27, 527-41.
(4) Wani, M. C.; Rector, D. H.; White, D. H.; Pitt, C. G.; Kimmel, G.
L. J. Med. Chem. 1977, 20, 547-51.
Therefore, we arrived at the following synthesis where,
utilizing the same potassium enoxyborate alkylation procedure,
indenone 1 was alkylated with allyl bromide to give the propenyl
indenone 12 (Scheme 3, 82%). Using Grubbs’ second-generation
(5) Collins, D. J.; Fallon, G. D.; Skene, C. E. Aust. J. Chem. 1992, 45,
71-97.
(6) Scaglione, J. B.; Rath, N. P.; Covey, D. F. J. Org. Chem. 2005, 70,
1089-92.
(7) Negishi, E.; Idacavage, M. J. Tetrahedron Lett. 1979, 10, 845-48.
(8) Negishi, E.; Matsushita, H.; Chatterjee, S.; John, R. J. Org. Chem.
1982, 47, 3188-90.
(11) Lin, H.; Rampersaud, A. A.; Archer, R. A.; Pawlak, J. M.; Beavers,
L. S.; Schmidt, R. J.; Kauffman, R. F.; Bensch, W. R.; Bumol, T. F.;
Apelgren, L. D.; Eacho, P. I.; Perry, D. N.; McClure, D. B.; Gadski, R. A.
J. Med. Chem. 1995, 38, 277-88.
(9) Negishi, E.; Luo, F. J. Org. Chem. 1983, 48, 2427-30.
(10) Nemoto, H.; Satoh, A.; Ando, M.; Fukumoto, K. J. Chem. Soc.
Perkin Trans. 1 1991, 1309-14.
(12) Graves, J.; Ringold, H. Steroids 1965, Supplement, 23-38.
4838 J. Org. Chem., Vol. 72, No. 13, 2007

Alkylation of trans-Inden-5-one
SCHEME 2. Cyclopenta[b]anthracenone and Cyclopenta[b]phenanthrenone Ring Systems
SCHEME 3. Side Chain Elongation by Cross Metathesis
catalyst, we then carried out a cross metathesis reaction between
12 and the heptenyl piece 11 (containing all the carbons for the
A and B rings) to give compound 13 (60%).
a quartet (1.89 δ) to a doublet of 6.3 Hz. The geminal 2-bond
coupling at C-7 is therefore 12.7 Hz. Two 3-bond vicinal
couplings between protons at C-7 to C-6 are 12.5 and 6.3 Hz.
These couplings indicate a large trans-diaxial coupling of the
methine proton at C-6 to one of the geminal protons at C-7.
The smaller coupling indicates an axial-equatorial stereochem-
ical relationship between the methine proton at C-6 and the
second geminal proton of C-7. This establishes the equatorial
configuration of the allyl substituent at C-6.
The next phase of the synthesis of the cyclopenta[b]-
phenanthrene ring system involved reactions needed to form
the third ring (Scheme 4). To avoid lactol formation while
functionalizing the double bond, compound 13 was protected
as the ketal to yield compound 14 (95%). Hydroboration of the
double bond in compound 14 yielded an uncharacterized mixture
of regio- and stereoisomers 15 that were immediately oxidized
to give the 3-octanone (16a, 37% from compound 14) and
The stereochemistry of the alkylation reaction yielding 12
was determined using a combination of proton two-dimensional
(2D) total correlation spectroscopy (TOCSY), proton (1D)
homodecoupling spectroscopy, and natural abundance two-
dimensional 13C-heteronuclear single-quantum coherence (HSQC)
NMR experiments. The protons in compound 12 were assigned
by 2D-TOCSY and natural-abundance 13C-HSQC. 1D homo-
decoupling experiments were used to determine the stereochem-
istry of protons attached to ring carbons 6 and 7. Selective
decoupling of the methine proton at C-6 (2.24 δ) collapses both
geminal protons at C-7 (1.89 and 0.91 δ) to a doublet of
12.7 Hz. Decoupling of one of the geminal protons at C-7 (1.89
δ) collapses a triplet centered at 0.91 δ to a doublet of 12.5 Hz,
while decoupling of the other geminal proton at 0.91 δ collapses
J. Org. Chem, Vol. 72, No. 13, 2007 4839

Jastrzebska et al.
SCHEME 5. Cyclopenta[b]phenanthrenone System
SCHEME 4. Substituted Benz[f]indenone and s-Indacenone
Ring Systems
We explored several oxidation conditions and found all to
result in at least some formation of the unwanted ketolactone
byproduct 21. The best yield of diketone 20 (30%) was obtained
with PCC oxidation. Aldol condensation of 20 gave 9b (80%),
with spectroscopic data identical to that of the sample obtained
from Scheme 2.
FIGURE 2. Ketolactone byproduct of hemiacetal oxidation.
Conclusions
In conclusion, we have found that indenone 1 can be alkylated
stereo- and regioselectively at C-6 with allylic electrophiles via
potassium enoxyborates in the presence of a catalytic amount
of palladium complex. Repeating this same reaction on the
resulting benz[f]indene system led, to our knowledge, to the
first reported total syntheses of enantiopure cyclopenta[b]-
anthracene and cyclopenta[b]phenanthrene systems in a ratio
of 3:1. These rearranged steroid ring systems can be converted
into a wide variety of steroid analogues.
Using this same potassium enoxyborate alkylation method
and a cross metathesis reaction, we explored an alternative
pathway to the cyclopenta[b]phenanthrene system, hoping to
increase the yield of this minor product. However, because of
the lack of regioselectivity for the hydroboration of olefin 14
(leading to 50% of the material going to the s-indacene system)
and the difficulty encountered in oxidation of hemiketal 19, the
pathway does not give a substantial increase in the yield of
cyclopenta[b]phenanthrenone 9b. Nevertheless, we have dem-
onstrated that cross metathesis of a steroid C,D ring piece and
an alkene is possible in relatively high yield. We expect this to
be very useful, as one can consider different alkenes for cross
metathesis that should lead to further improvements in the yield
of cyclopenta[b]phenanthrenes as well other ring systems.
2-octanone (16b, 35% from compound 14). The two regioiso-
mers were easily separable by column chromatography. Depro-
tection yielded the diketones 17a and 17b, which upon aldol
condensation, formed the substituted benz[f]indenone 18a (83%)
and s-indacenone 18b (86%) ring systems. At this time, we are
not interested in the s-indacene system, so this material was set
aside. However, there is only one synthetic example of a
carbocyclic s-indacene derivative in the literature, and the central
ring is aromatic.13 Consequently, this pathway may find some
utility in natural product synthesis.
Lithium liquid ammonia reduction of benz[f]indenone 18a
removed the enone double bond, cleaved the benzyl group, and
formed hemiketal 19 (Scheme 5, 63%). A crystal structure of
hemiketal 19 was obtained to confirm all the stereocenters and
is the basis for the stereochemical assignments in compound
9b. We first attempted to oxidize hemiketal 19 using Jones’
reagent. To our surprise, the product of this reaction was not
the desired diketone 20 but, based on the NMR and IR spectra,
ketolactone 21 (Figure 2). A similar hemiketal to ketolactone
conversion was reported in a 1971 total synthesis of the steroid
Norgestrel.14
Experimental Section
(1S,3aS,6R,7aS)-6-[(2E/Z)-3-Chloro-2-butenyl]-1-(1,1-dimeth-
ylethoxy)octahydro-7a-methyl-5H-inden-5-one (2). Indenone 1
(4 g, 0.02 mol), prepared as previously described,6 was dissolved
(13) Christoffers, J.; Zhang, Y.; Frey, W.; Fischer, P. Synlett 2006, 624-
26.
(14) Rosenberger, M.; Fraher, T. P.; Saucy, G. HelV. Chim. Acta 1971,
54, 2857-70.
4840 J. Org. Chem., Vol. 72, No. 13, 2007

Alkylation of trans-Inden-5-one
in dry THF (100 mL), and KHMDS (42 mL, 1.1 equiv of 0.5 M
solution in toluene, 0.021 mol) was added. After being stirred for
0.5 h, the reaction mixture was cooled to -78 °C, and BEt3
(21 mL, 1.1 equiv of 1.0 M solution in THF, 0.021 mol) was added.
This was followed by addition of a mixture of 1,3-dichloro-2-butene
(a mixture of cis and trans isomers, 2.3 mL, 1.1 equiv, 0.021 mol)
and Pd(PPh3)4 (1.1 g, 5 mol %) in dry THF (30 mL). The reaction
mixture was allowed to come to room temperature and was stirred
for 15 h. At this time, 3 N HCl (15 mL) was added. The reaction
was transferred to a separatory funnel, and the aqueous layer was
extracted with Et2O. The combined organic layers were washed
with saturated NaHCO3, dried, and evaporated. Chromatography
(silica gel, 5% EtOAc in hexanes) gave a mixture of cis and trans
vinyl chlorides as a yellow oil (5.45 g, 88%). Major isomer: 13C
NMR δ 212.0, 125.5, 123.7, 79.3, 72.6, 45.7, 45.3, 42.9, 42.7, 42.4,
42.2, 31.8, 28.6 (3 × C), 26.2, 25.7, 11.1; IR νmax 2973, 1709,
1362, 1193, 1062 cm-1. Anal. Calcd for C18H29ClO2: C, 69.10;
H, 9.34. Found: C, 69.28; H, 9.55.
neck flask fitted with a gas condenser and dropping funnel was
cooled to -78 °C, and ammonia (500 mL) was condensed. Lithium
(0.57 g, 82 mmol, 10 equiv) was added, and the resulting blue
solution was stirred for 0.5 h. To this was added a solution of
compound 5 (2.75 g, 8.20 mmol) in dry THF (75 mL). After 1 h
of stirring, saturated NH4Cl was added, and the reaction mixture
was allowed to come to room temperature overnight. The mixture
was extracted with CH2Cl2, and the combined organic fractions
were washed with brine and dried, and the solvent evaporated.
Column chromatography (silica gel, 20% EtOAc in hexanes) gave
compound 6 (1.8 g, 67%) as a colorless oil: [R]2D5 ) +68.0 (c )
1
0.51, CHCl3); H NMR δ 3.59 (1H, t, J ) 8.4 Hz), 2.39-2.30
(3H, m), 2.17-1.89 (3H, m), 1.77-1.62 (2H, m), 1.52-1.16 (7H,
m), 0.87 (9H, s), 0.77 (3H, s), 0.005 (3H, s), -0.005 (3H, s); 13C
NMR δ 211.6, 81.3, 48.6 (2 × C), 44.3, 44.1, 43.7, 41.6, 37.3,
33.5, 33.3, 30.9, 25.8 (3 × C), 25.3, 18.0, 11.6, -4.5, -4.8; IR
νmax 2955, 1716, 1472, 1130, 1074; HRMS (EI) m/z Calcd for
C20H36O2Si: 336.2485. Found: 336.2475.
(1S,3aS,6R,7aS)-1-(1,1-Dimethylethoxy)octahydro-7a-methyl-
6-(3-oxobutyl)-5H-inden-5-one (3). To a solution of mercury(II)
trifluoroacetate (30 g, 0.070 mol, 4 equiv) in nitromethane
(950 mL) was added the vinyl chloride mixture 2 (5.5 g, 0.017
mol) in dry THF (30 mL). The reaction mixture was stirred at room
temperature for 3 h, at which time 10% HCl (450 mL) was added
and the mixture was stirred for an additional 1 h. The mixture was
transferred to a separatory funnel and the aqueous layer extracted
with CH2Cl2. The combined organic fractions were washed with
brine and dried, and the solvent was evaporated to give a yellow
oil. Column chromatography (silica gel, 15% EtOAc in hexanes)
(1S,3aS,4aS,9aR,10aR,11aS)-1,2,3,3a,4,4a,5,8,9,9a,10,10a,11,-
11a-Tetradecahydro-1-hydroxy-11a-methyl-7H-cyclopenta[b]an-
thracen-7-one (9a) and (6aR,7aS,8S,10aS,11aR,11bS)-1,2,5,6,-
6a,7,7a,8,9,10,10a,11,11a,11b-Tetradecahydro-8-hydroxy-7a-
methyl-3H cyclopenta[b]phenanthren-3-one (9b). The procedure
detailed above for alkylation of indenone 1 was repeated on
compound 6 (1.8 g, 5.4 mmol). The reaction yielded a complex,
inseparable mixture of stereo- and regioisomers (7a and 7b).
Without further purification, this mixture of vinyl chlorides (1.7 g,
4 mmol) was taken through the oxymercuration procedure used on
vinyl chloride 2 and then immediately subjected to an intramolecular
aldol condensation to yield the two enones 9a (0.46 g, 31% from
6) and 9b (0.15 g, 10% from 6). Column chromatography (silica
gel, 40% EtOAc in hexanes) gave, after recrystallization, crystalline
enone 9a. Enone 9b was obtained as an oil.
yielded 3.7 g (72%) of diketone 3 as a colorless oil: [R]D25
)
1
+56.6 (c ) 1, CHCl3); H NMR δ 3.45 (1H, t, J ) 8.3), 2.58-
2.26 (5H, m), 2.13 (3H, s), 2.04-1.91 (3H, m), 1.67-1.14 (6H,
m), 1.13 (9H, s), 1.01 (3H, s); 13C NMR δ 212.2, 208.6, 79.2, 72.4,
45.7, 44.6, 42.9 (2 × C), 42.6, 41.4, 31.7, 29.6, 28.5 (3 × C), 25.6,
23.9, 11.0; IR νmax 2973, 1713, 1362, 1194, 1061. HRMS (EI) m/z
Calcd for C18H30O3: 294.2195. Found: 294.2200.
9a: [R]2D5 ) +54.8 (c ) 0.35, CHCl3); mp 156-158 °C
1
(acetone-hexanes); H NMR δ 5.80 (1H, bs), 3.65 (1H, t, J )
8.4, 8.1 Hz), 2.43-2.13 (3H, m), 2.11-1.90 (3H, m), 1.89-0.81
(15H, m), 0.78 (3H, s); 13C NMR δ 200.2, 166.7, 124.5, 81.7, 44.9,
44.5, 43.8, 43.7, 42.6, 41.9, 38.1, 37.6, 36.8, 32.8, 30.6, 29.3, 25.4,
11.4; IR νmax 3418, 2911, 1667, 1423, 1046. Anal. Calcd for
C18H26O2: C, 78.79; H, 9.55. Found: C, 79.00; H, 9.39.
(1S,3aS,8aR,9aS)-1,2,3,3a,4,7,8,8a,9,9a-Decahydro-1-hydroxy-
9a-methyl-6 H-benz[f]inden-6-one (4a) and (1S,3aS,9aS)-1,2,3,-
3a,4,5,7,8,9,9a-Decahydro-1-hydroxy-9a-methyl-6H-benz[f]inden-
6-one (4b). Diketone 3 (3.4 g, 0.012 mol) was dissolved in MeOH
(125 mL), and 3 N HCl (30 mL) was added. The reaction mix-
ture was refluxed overnight and then cooled to room temperature,
and the MeOH evaporated in vacuo. EtOAc and H2O were added
to the residue, and the aqueous layer was extracted with EtOAc.
The combined organic fractions were then washed with satu-
rated NaHCO3 and dried, and the solvent was removed. Chroma-
tography (silica gel, 35% EtOAc in hexanes) gave the previously
reported enone 4a (1.84 g, 73%) and the tetrasubstituted olefin 4b
(0.6 g, 24%). Spectroscopic data were in agreement with the
literature.6
9b: [R]2D5 ) -26.8 (c ) 1.4, CHCl3); 1H NMR δ 5.82 (1H, bs),
3.68 (1H, t, J ) 7.8 Hz), 2.48-2.03 (6H, m), 1.83-1.61 (4H, m),
1.60-1.02 (9H, m), 0.98-0.82 (2H, m), 0.79 (3H, s); 13C NMR δ
199.8, 166.7, 124.5, 81.5, 49.6, 44.8, 44.2, 43.0, 42.8, 37.4, 36.4,
35.9, 34.0, 30.5, 29.5, 26.1, 25.4, 11.2; IR νmax 3424, 2914, 1661,
1261, 1042 cm-1. HRMS (EI) m/z Calcd for C18H26O2: 274.1933.
Found: 274.1935.
(R)-Hept-6-en-2-ol (10). Compound 10 was prepared as de-
scribed previously, with slight modification.15 Briefly, a solution
of 3-butenylmagnesium bromide (750 g, 4.7 mol) was added slowly
to a suspension of (R)-propylene oxide (25 g, 0.43 mol) and CuCN
(3.6 g, 0.040 mol) in THF at -78 °C. The mixture was stirred
overnight, warming to ambient temperature. The reaction was
quenched by addition of saturated aqueous NH4Cl (500 mL), and
the aqueous layer was extracted with Et2O. The organic extracts
were combined, dried, and filtered. The solvent was removed to
yield 10 as a colorless oil (36 g, 73%) that was used without further
purification. Spectroscopic data were in agreement with the
literature.15
(1S,3aS,8aR,9aS)-1-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-
1,2,3,3a,4,7,8,8a,9,9a-decahydro-9a-methyl-6H-benz[f]inden-6-
one (5). To enone 4a (1.8 g, 8.2 mmol) dissolved in DMF
(90 mL) were added imidazole (1.1 g, 16 mmol), TBDMSCl (2.5
g, 17 mmol), and DMAP. The reaction was stirred for 20 h at room
temperature, and then DMF was removed under high vacuum. The
residue was redissolved in CH2Cl2, washed with water and brine,
and dried, and the solvent was removed. Chromatography (silica
gel, 20% EtOAc in hexanes) gave compound 5 as a colorless oil
(2.75 g, 100%): [R]2D5 ) +70.7 (c ) 1, CHCl3); H NMR δ 5.83
1
(R)-[[(1-Methyl-5-hexenyl)oxy]methyl]-benzene (11). To a
suspension of 60% NaH (15 g, 0.38 mol) in THF (500 mL) was
added compound 10 (36 g, 0.31 mol) dropwise. After 15 min,
benzyl bromide (75 g, 0.44 mol) was added dropwise, followed by
tetrabutylammonium iodide (17 g, 0.048 mol), and the reaction was
refluxed for 4 h. At this time, the reaction was cooled to room
(1H, s), 3.64 (1H, t, J ) 7.8, 8.4 Hz), 2.56-2.27 (5H, m), 2.09-
1.92 (3H, m), 1.68-1.26 (6H, m) 0.90 (9H, s), 0.88 (3H, s), 0.15
(6H, bs); 13C NMR δ 200.0, 166.5, 125.7, 80.9, 44.6, 44.1, 43.7,
37.4, 35.9, 34.4, 31.0, 30.4. 25.8 (3 × C), 25.4, 18.0, 10.7, -4.5,
-4.9; IR νmax 2954, 1674, 1463, 1136, 1068. HRMS (EI) m/z Calcd
for C20H34O2Si: 334.2328. Found: 334.2328.
(1S,3aS,4aS,8aR,9aS)-1-[[(1,1-Dimethylethyl)dimethylsilyl]-
oxy]dodecahydro-9a-methyl-6H-benz[f]inden-6-one (6). A three-
(15) Furstner, A.; Thiel, O. R.; Ackermann, L. Org. Lett. 2001, 3, 449-
51.
J. Org. Chem, Vol. 72, No. 13, 2007 4841

Jastrzebska et al.
temperature, and saturated NH4Cl (250 mL) was added. The
aqueous layer was extracted with Et2O (3 × 100 mL). The organic
layers were combined, dried, filtered, and concentrated in vacuo
to give 11 as a yellow oil. Chromatography (silica gel, 5% EtOAc
in hexanes) yielded product 11 as a pale yellow oil (47 g, 80%):
(3H, d, J ) 6 Hz), 1.11 (9H, s), 0.77 (3H, s); 13C NMR δ 139.2,
131.3, 130.5, 129.4, 128.3, 127.6, 127.3, 111.8, 80.1, 74.7, 72.2,
70.3, 64.9, 64.7, 42.3, 42.1, 40.6, 40.1, 36.1, 35.5, 32.6, 31.8, 31.6,
28.7 (3 × C), 27.3, 25.6, 25.2, 19.6, 10.9; IR νmax 2972, 1361,
1194, 1133, 1062 cm-1. Anal. Calcd for C31H48O4: C, 76.82; H,
9.98. Found: C, 76.61; H, 9.77.
[R]2D5 ) -24.4 (c ) 1.2, CHCl3); H NMR δ 7.34-7.21 (5H, m),
1
5.86 (1H, ddt, J ) 17.0, 9.8, 6.7 Hz), 5.02-4.91 (2H, m), 4.56
(2H, q, J ) 12.0, 24.0 Hz), 3.54-3.46 (1H, m), 2.07-2.00 (2H,
m), 1.65-1.38 (4H, m), 1.18 (3H, d, J ) 6.0 Hz); 13C NMR δ
139.1, 138.7, 128.2 (2 × C), 127.5 (2 × C), 127.2, 114.4, 74.6,
70.2, 36.1, 33.7, 24.8, 19.5; IR νmax 2970, 1641, 1454, 1093,
734 cm-1. Anal. Calcd for C14H20O: C, 82.30; H, 9.87. Found: C,
82.55; H, 10.04.
(1′S,3′aS,6′R,7′aS)-1′-(1,1-Dimethylethoxy)octahydro-7′a-methyl-
r-[(4R)-4-(phenylmethoxy)pentyl]-spiro[1,3-dioxolane-2,5′-[5H]-
indene]-6′-propanol and (1′S,3′aS,6′S,7′aS)-1′-(1,1-Dimethyl-
ethoxy)octahydro-7′a-methyl-r-[(5R)-5-(phenylmethoxy)hexyl]-
spiro[1,3-dioxolane-2,5′-[5H]indene]-6′-ethanol (15). Compound
14 (9.0 g, 0.019 mol) was dissolved in dry THF (80 mL). To this
was added a 1.0 M solution of borane-tetrahydrofuran complex
in THF (60 mL, 60 mmol). The reaction was stirred at room
temperature for 2 h. After 2 h, the reaction was cooled to 0 °C,
and 10% NaOH (75 mL) was carefully added dropwise, followed
by 30% H2O2 (75 mL). The reaction was stirred at room temperature
for 1 h, at which time the reaction was transferred to a separatory
funnel and the aqueous layer was extracted with EtOAc. The
combined organic layers were washed with brine, dried, filtered,
and concentrated in vacuo to give a colorless oil. The uncharac-
terized mixture of regio- and stereoisomers (15, 7.5 g) was carried
forward without further purification.
(1S,3aS,6R,7aS)-1-(1,1-Dimethylethoxy)octahydro-7a-methyl-
6-(2-propenyl)-5H-inden-5-one (12). To a solution of indenone 1
(10 g, 0.04 mol) in dry THF (500 mL) was added KHMDS
(100 mL, 1.1 equiv of 0.5 M solution in toluene, 0.05 mol). After
0.5 h, the reaction mixture was cooled to -78 °C, and BEt3
(50 mL, 1.1 equiv of 1.0 M solution in THF, 0.05 mol) was added.
This was followed by addition of a mixture of allyl bromide
(4.3 mL, 1.1 equiv, 0.05 mol) and Pd(PPh3)4 (2.6 g, 5 mol %) in
dry THF (30 mL). The reaction mixture was allowed to come to
room temperature and was stirred for 15 h. At this time, 3 N HCl
(30 mL) was added. The organic layer was separated, and the
aqueous layer was extracted with Et2O. The combined organic layers
were washed with saturated NaHCO3, dried, and evaporated.
Chromatography (silica gel, 5% EtOAc in hexanes) gave compound
12 (9.7 g, 82%) as a colorless oil: [R]2D5 ) +49.6 (c ) 1.3,
CHCl3); 1H NMR δ 5.75-5.64 (1H, m), 4.98-4.91 (2H, m), 3.42
(1H, t, J ) 8.1 Hz), 2.53-2.45 (1H, m), 2.39-2.22 (3H, m), 2.04-
1.87 (3H, m), 1.65-1.46 (4H, m), 1.41-1.09 (1H, m), 1.08 (9H,
s), 0.96 (3H, s); 13C NMR δ 211.4, 136.5, 115.9, 79.2, 72.3, 45.5,
45.0, 42.7, 42.5, 42.0, 33.8, 31.7, 28.5 (3 × C), 25.6, 11.0; IR νmax
2973, 1706, 1641, 1193, 1062 cm-1. HRMS (EI) m/z Calcd for
C17H28O2: 264.2089. Found: 264.2074.
(7R)-1-[(1′S,3a′S,6′R,7a′S)-1′-(1,1-Dimethylethoxy)octahydro-
7′a-methylspiro[1,3-dioxolane-2,5′-[5H]inden]-6′-yl]-7-(phenyl-
methoxy)-3-octanone (16a) and (7R)-1-[(1′S,3a′S,6′S,7a′S)-1′-
(1,1-Dimethylethoxy)octahydro-7′a-methylspiro[ 1,3-dioxolane-
2,5′-[5H]inden]-6′-yl]-7-(phenylmethoxy)-2-octanone (16b). Mixture
15 (7.5 g, 0.015 mol) was dissolved in CH2Cl2. To this was added
NaOAc (3.8 g, 0.045 mol), followed by PCC (6.6 g, 0.030 mol),
and the solution was stirred under N2 at room temperature for 3 h.
The reaction mixture was then filtered through a short stack of silica
gel, and the solvent was removed in vacuo to yield a pale yellow
oil. Column chromatography (silica gel, 10% EtOAc in hexanes)
gave product 16a (3.4 g, 37% from compound 14) and product
16b (3.3 g, 35% from compound 14) as colorless oils.
(1S,3aS,6R,7aS)-1-(1,1-Dimethylethoxy)octahydro-7a-methyl-
6-[(2E/Z,7R)-7-(phenylmethoxy)-2-octenyl]-5H-inden-5-one (13).
In a three-neck flask equipped with condenser, second-generation
Grubbs’ catalyst (1.4 g, 5 mol %) was dissolved in CH2Cl2
(500 mL). To this were added compounds 11 (41 g, 0.36 mol) and
12 (9.0 g, 0.034 mol) simultaneously via syringe, and the reaction
was refluxed overnight. The reaction was then cooled to room
temperature, and the solvent was removed in vacuo to yield a
brownish-red oil. Column chromatography (silica gel, 5% EtOAc
in hexanes) gave compound 13 (9.0 g, 60%) as a colorless oil:
16a: [R]2D5 ) -8.3 (c ) 1.5, CHCl3); H NMR δ 7.34-7.24
1
(5H, m), 4.58 (2H, q, J ) 11.7, 27 Hz), 3.95-3.90 (4H, m), 3.54-
3.39 (2H, m), 2.49-2.28 (4H, m), 1.94-1.23 (16H, m), 1.20 (3H,
d, J ) 6.3 Hz), 1.12 (9H, s), 0.77 (3H, s); 13C NMR δ 211.3, 138.9,
128.2 (2 × C), 127.6 (2 × C), 127.3, 111.6, 79.9, 74.5, 72.2, 70.2,
64.8, 64.5, 42.5, 42.2, 41.8, 41.2, 40.0, 39.9, 36.1, 35.1, 31.5, 28.7
(3 × C), 25.1, 22.6, 19.8, 19.5, 10.9 ; IR νmax 2929, 1712, 1454,
1134, 1064 cm-1. Anal. Calcd for C31H48O5: C, 74.36; H, 9.66.
Found: C, 74.10; H, 9.58.
[R]2D5 ) +16.5 (c ) 1.2, CHCl3); H NMR δ 7.34-7.24 (5H, m),
1
16b: [R]2D5 ) -12.9 (c ) 1.4, CHCl3); H NMR δ 7.35-7.23
1
5.43-5.34 (2H, m), 4.58 (2H, q, J ) 11.7, 21.3 Hz), 3.53-3.40
(2H, m), 2.52-2.27 (2H, m), 2.07-1.88 (6H, m), 1.69-1.26 (10H,
m), 1.19 (3H, d, J ) 6.3 Hz), 1.13 (9H, s), 1.00 (3H, s); 13C NMR
δ 212.1, 139.2, 132.2, 131.2, 128.3, 128.0, 127.6, 127.3, 79.4, 74.7,
72.5, 70.3, 45.6, 45.5, 42.9, 42.6, 42.2, 36.1, 32.7, 32.6, 31.8, 31.6,
28.7 (3 × C), 25.7, 25.4, 19.6, 11.2; IR νmax 2972, 1708, 1362,
1193, 1062 cm-1. Anal. Calcd for C29H44O3: C, 79.04; H, 10.06.
Found: C, 78.88; H, 9.95.
(5H, m), 4.58 (2H, q, J ) 12, 24 Hz), 3.96-3.82 (4H, m), 3.53-
3.38 (2H, m), 2.60-2.32 (4H, m), 2.16-1.88 (2H, m), 1.71-1.20
(14H, m), 1.19 (3H, d, J ) 6 Hz), 1.10 (9H, s), 0.85 (3H, s); 13C
NMR δ 210.6, 139.1, 128.3 (2 × C), 127.6 (2 × C), 127.3, 111.1,
79.8, 74.7, 72.2, 70.3, 64.6, 64.3, 43.1, 42.6, 42.5, 42.0, 41.0, 36.8,
36.5, 34.7, 31.6, 28.7 (3 × C), 25.2, 25.1, 23.9, 19.6, 10.9; IR νmax
2971, 1712, 1194, 1134, 1063 cm-1. Anal. Calcd for C31H48O5:
C, 74.36; H, 9.66. Found: C, 74.12, H, 9.44.
(1′S,3a′S,6′R,7a′S)-1′-(1,1-Dimethylethoxy)octahydro-7′a-methyl-
6′-[(2E Z,7R)-7-(phenylmethoxy)-2-octenyl]-spiro[1,3-dioxolane-
2,5′-[5H]indene] (14). In a round-bottom flask equipped with a
Dean-Stark trap and reflux condenser, compound 13 (8.7 g,
0.020 mol) was dissolved in 200 mL of benzene. To this were added
ethylene glycol (11 mL, 0.20 mol) and PPTS (2.6 g, 10 mmol).
The reaction was heated to reflux for 14 h. At this time, the pale
yellow reaction was cooled to ambient temperature. The organic
layer was washed with H2O and brine, dried, filtered, and
concentrated in vacuo to give a yellow oil. Chromatography (silica
gel, 5% EtOAc in hexanes) gave compound 14 as a colorless oil
(1S,3aS,6R,7aS)-1-(1,1-Dimethylethoxy)octahydro-7a-methyl-
6-[(7R)-3-oxo-7-(phenylmethoxy)octyl]-5H-inden-5-one (17a) and
(1S,3aS,6S,7aS)-1-(1,1-Dimethylethoxy)octahydro-7a-methyl-6-
[(7R)-2-oxo-7-(phenylmethoxy)octyl]-5H-inden-5-one (17b). Com-
pound 16a (3.3 g, 6.6 mmol) was dissolved in acetone (200 mL),
and p-TsOH (25% w/w, 825 mg) was added. The reaction was
stirred for 24 h, at which time the acetone was removed and the
residue was redissolved in EtOAc. The organic layer was washed
with H2O and brine, dried, and filtered, and the solvent was removed
in vacuo. The product was purified by column chromatography
(silica gel, 10% EtOAc in hexanes) to yield product 17a as a
colorless oil (2.5 g, 86%). This procedure was repeated on
compound 16b (3.2 g, 6.4 mmol) to give the colorless oil 17b
(2.6 g, 88%).
(9.1 g, 95%): [R]2D5 ) -3.3 (c ) 1.7, CHCl3); H NMR δ 7.36-
1
7.25 (5H, m), 5.37-5.33 (2H, m), 4.58 (2H, q, J ) 12, 20 Hz)
3.96-3.91 (4H, m), 3.50-3.40 (2H, m), 2.01-1.21 (18H, m), 1.19
4842 J. Org. Chem., Vol. 72, No. 13, 2007

Alkylation of trans-Inden-5-one
17a: [R]2D5 ) +20.6 (c ) 1.2, CHCl3); H NMR δ 7.35-7.24
(5H, m), 4.58 (2H, q, J ) 11.7, 26.7 Hz), 3.54-3.40 (2H, m), 2.56-
2.25 (6H, m), 2.04-1.90 (3H, m), 1.78-1.23 (11H, m), 1.20 (3H,
d, J ) 6.3 Hz), 1.13 (9H, s), 1.01 (3H, s); 13C NMR δ 212.4, 210.9,
138.9, 128.2 (2 × C), 127.6 (2 × C), 127.3, 79.2, 74.5, 72.5, 70.2,
45.8, 44.7, 43.0, 42.9, 42.7, 42.5, 40.5, 36.1, 31.8, 28.6 (3 × C),
25.7, 23.9, 19.8, 19.5, 11.1; IR νmax 2971, 1709, 1362, 1194, 1063
cm-1. HRMS (EI) m/z Calcd for C29H44O4: 456.3240. Found:
456.3234.
1
room temperature overnight. The solution was extracted with CH2-
Cl2, the combined organic fractions were washed with brine and
dried, and the solvent evaporated. Column chromatography (silica
gel, 25% EtOAc in hexanes) gave compound 19 (1.0 g, 63%) as a
white solid: [R]2D5 ) +22.4 (c ) 1.2, CHCl3); mp 157-159 °C;
1H NMR δ 4.07-4.02 (1H, m), 3.38 (1H, t, J ) 7.2 Hz), 1.90-
1.62 (7H, m), 1.59-1.16 (11H, m), 1.13 (3H, m), 1.12 (9H, s),
1.05-0.75 (3H, m), 0.71 (3H, s); 13C NMR δ 97.0, 80.7, 72.1,
65.6, 47.1, 44.9, 44.7, 43.8, 42.7, 39.6, 38.5, 33.8, 31.2, 30.6, 28.8
(3 × C), 28.4, 25.9, 21.9, 21.5, 11.8; IR νmax 3463, 2932, 1362,
17b: [R]2D5 ) +16.1 (c ) 1.2, CHCl3); H NMR δ 7.34-7.24
1
1059, 904 cm-1
.
(5H, m), 4.57 (2H, q, J ) 11.7, 22.5 Hz), 3.52-3.40 (2H, m), 2.99-
2.78 (2H, m), 2.51-2.18 (5H, m), 1.99-1.93 (2H, m), 1.81-1.19
(1S,3aS,4aR,5S,8aR,9aS)-1-(1,1-Dimethylethoxy)dodecahydro-
9a-methyl-5-(3-oxobutyl)-6H-benz[f]inden-6-one (20). Compound
19 (1.0 g, 2.9 mmol) was dissolved in CH2Cl2. To this was added
NaOAc (2.8 g, 34 mmol), followed by PCC (4.9 g, 23 mmol), and
the reaction was stirred under N2 at room temperature overnight.
The reaction was then filtered through a short stack of silica gel,
and the solvent was removed in vacuo to yield a pale yellow oil.
Column chromatography (silica gel, 10% EtOAc in hexanes) gave
diketone 20 (0.30 g, 30%) as a colorless oil. [R]2D5 ) +27.0 (c )
2.2, CHCl3); 1H NMR δ 3.41 (1H, t, J ) 7.8 Hz), 2.59-2.34 (4H,
m), 2.24-2.16 (1H, m), 2.13 (3H, s), 2.08-1.82 (3H, m), 1.79-
1.63 (5H, m), 1.57-1.15 (7H, m), 1.13 (9H, s), 0.79 (3H, s); 13C
NMR δ 212.3, 208.9, 80.4, 72.1, 54.1, 48.5, 44.4, 44.1, 42.5, 42.0,
41.0, 37.5, 34.3, 31.2, 30.2, 29.7, 28.7 (3 × C), 25.5, 19.3, 11.7;
IR νmax 2972, 1712, 1361, 1196, 1066 cm-1. HRMS (EI) m/z Calcd
for C22H36O3: 348.2664. Found: 348.2676.
(6aR,7aS,8S,10aS,11aR,11bS)-1,2,5,6,6a,7,7a,8,9,10,10a,11,-
11a,11b-Tetradecahydro-8-hydroxy-7a-methyl-3H cyclopenta-
[b]phenanthren-3-one (9b). Compound 20 (298 mg, 0.86 mmol)
was dissolved in MeOH (50 mL), and 3 N HCl (2.5 mL) was added.
The reaction was heated to 81 °C and allowed to reflux for 12 h.
At this time, the reaction was cooled to room temperature, and the
methanol was removed under reduced pressure. EtOAc (20 mL)
and H2O (10 mL) were added to the dark yellow oil, and the
aqueous layer was extracted with EtOAc. The organic fractions
were washed with 15% NaHCO3 and brine, dried, filtered, and
concentrated in vacuo to give a yellow oil. Chromatography (33%
EtOAc in hexanes) gave 188 mg (80%) of 9b as a colorless oil.
Spectroscopic data were in agreement with the previously synthe-
sized 9b.
(11H, m), 1.19 (3H, d, J ) 5.4 Hz), 1.12 (9H, s), 1.05 (3H, s); 13
C
NMR δ 211.3, 209.4, 139.0, 128.2 (2 × C), 127.5 (2 × C), 127.3,
79.2, 74.6, 72.4, 70.2, 45.4, 43.1, 42.8, 42.7, 42.4, 42.3, 41.8, 36.4,
31.7, 28.6 (3 × C), 25.6, 25.0, 23.7, 19.5, 10.9; IR νmax 2971, 1707,
1362, 1193, 1063 cm-1. HRMS (EI) m/z Calcd for C29H44O4:
456.3240. Found: 456.3228.
(1S,3aS,8aR,9aS)-1-(1,1-Dimethylethoxy)-1,2,3,3a,4,7,8,8a,9,-
9a-decahydro-9a-methyl-5-[(3R)-3-(phenylmethoxy)butyl]-6H-
benz[f]inden-6-one (18a) and (4aS,7S,7aS)-7-(1,1-Dimethylethoxy)-
4,4a,5,6,7,7a,8,8a-octahydro-7a-methyl-3 -[(4S)-4-(phenylmethoxy)-
pentyl]-s-indacen-2(1H)-one (18b). Compound 17a (2.5 g, 5.5
mmol) was dissolved in ethanol (200 mL), and 3 N KOH (5 mL)
was added. The reaction was stirred for 15 h, at which time the
methanol was removed, and the residue was redissolved in EtOAc.
The organic layer was washed with H2O, 10% HCl, and brine. It
was then dried and filtered, and the solvent was removed in vacuo.
Column chromatography (silica gel, 10% EtOAc in hexanes) gave
18a as a colorless oil (2.0 g, 83%). This procedure was repeated
on compound 17b (2.6 g, 5.7 mmol) to give the colorless oil 18b
(2.1 g, 86%).
18a: [R]2D5 ) +61.6 (c ) 1.3, CHCl3); H NMR δ 7.36-7.25
1
(5H, m), 4.58 (2H, q, J ) 11.7, 20.1 Hz), 3.55-3.36 (2H, m), 2.77-
2.24 (6H, m), 2.04-1.61 (4H, m), 1.59-1.25 (8H, m), 1.22 (3H,
d, J ) 6 Hz), 1.14 (9H, s), 0.86 (3H, s); 13C NMR δ 199.3, 159.4,
139.2, 134.5, 128.2 (2 × C), 127.4 (2 × C), 127.2, 80.0, 74.8,
72.3, 70.1, 45.4, 44.5, 42.2, 37.6, 36.1, 34.9, 31.2, 30.9, 30.0, 28.7
(3 × C), 25.8, 21.2, 19.5, 10.9; IR νmax 2971, 1667, 1361, 1196,
1062 cm-1. HRMS (EI) m/z Calcd for C29H42O3: 438.3134.
Found: 438.3114.
18b: [R]2D5 ) -11.4 (c ) 2.1, CHCl3); H NMR δ 7.33-7.25
1
Acknowledgment. This work was supported by NIH Grant
GM47969 (D.F.C.), Chemical Biology Interface Training Grant
NIH 5 T32 GM08785 (J.B.S.), a Lucille P. Markey Predoctoral
Fellowship (J.B.S.), a Kauffman Life Science Entrepreneur
Fellowship (J.B.S.), and an NSF Shared Instrument Grant CHE-
0420497. We thank Prof. Philip L. Fuchs for a helpful discussion
of oxidation methods for the conversion of lactol 19 to
compound 20.
(5H, m), 4.57 (2H, q, J ) 12, 22.8 Hz), 3.54-3.36 (2H, m), 2.86-
2.51 (2H, m), 2.19-1.85 (7H, m), 1.60-1.20 (9H, m), 1.18 (3H,
d, J ) 6 Hz), 1.13 (9H, s), 0.93 (3H, s); 13C NMR δ 208.8, 175.9,
139.0, 137.9, 128.2 (2 × C), 127.5 (2 × C), 127.3, 79.4, 74.7,
72.3, 70.3, 45.2, 44.7, 43.4, 41.5, 36.4, 36.1, 31.4, 29.1, 28.6 (3 ×
C), 25.8, 24.7, 22.6, 19.6, 11.0; IR νmax 2972, 1698, 1645, 1362,
1066 cm-1. HRMS (EI) m/z Calcd for C29H42O3: 438.3134.
Found: 438.3117.
(3R,4aS,6aR,7aS,8S,10aS,11aR,11bS)-8-(1,1-Dimethylethoxy)-
tetradecahydro-3,7a-dimethyl-cyclopenta[6,7]naphtho[2,1-b]py-
ran-4a(1H)-ol (19). A three-neck flask fitted with a gas condenser
and dropping funnel was cooled to -78 °C, and ammonia
(100 mL) was condensed. Lithium (0.26 g, 37 mmol, 8 equiv) was
added, and the resulting blue solution was stirred for 0.5 h. To this
was added a solution of compound 18a (2.0 g, 4.6 mmol) in dry
THF (20 mL). After the mixture was stirred for 1 h, saturated NH4-
Cl was added, and the reaction mixture was allowed to come to
Supporting Information Available: 1H NMR spectra for
compounds 2, 3, 5, 6, 9a, 9b, 11-14, and 16a-20, 13C NMR
spectra for compounds 3, 5, 6, 9b, 11, 12, and 17a-20, and X-ray
crystallographic data and projection views of compounds 9a and
19. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO070530E
J. Org. Chem, Vol. 72, No. 13, 2007 4843