A gold-catalyzed domino process to the steroid framework

Article abstract of DOI:10.1021/jo060606r

The facile formation of the B and C ring of rac-desoxyequilenin and of a chrysenone derivative in just one preparative step is demonstrated, applying a gold-catalyzed domino process, which involves a benzopyrylium cation as the key intermediate and an int

Full text of DOI:10.1021/jo060606r

A Gold-Catalyzed Domino Process to the Steroid Framework
Dirk Hildebrandt and Gerald Dyker*
/lp;&-5q;1Fakulta¨t fu¨r Chemie, Ruhr-UniVersita¨t Bochum, UniVersita¨tsstrasse 150,
D-44780 Bochum, Germany
gerald.dyker@rub.de
ReceiVed March 20, 2006
The facile formation of the B and C ring of rac-desoxyequilenin and of a chrysenone derivative in just
one preparative step is demonstrated, applying a gold-catalyzed domino process, which involves a
benzopyrylium cation as the key intermediate and an intramolecular [3 + 2] cycloaddition as the key
step.
Introduction
up in a single preparative step. Ring D was planned to be
introduced via cyclopentanone 5, substituted with an ethynyl
and a propargyl group. Ring A is derived from bromobenzal-
dehyde 4. Since both diastereoisomers of 2 should lead to the
natural product 1 in the final transformation, we decided to use
a mixture of the diastereoisomers of 5 for the approach to
racemic 3-desoxyequilenin (rac-1).
The bisalkyne coupling component 5 was efficiently synthe-
sized in three steps from cyclopentadione 6 (Scheme 2). The
C-alkylation with propargyl bromide proceeded smoothly in
80% yield, in accord with a known procedure.6 Trimethylsilyl
acetylene was metalated with n-BuLi and classically added to
one of the chemically equivalent keto groups to give 7 in 84%
Gold as precious metal is known for being rather inert, a fact
that might have somewhat hampered the development of gold
catalysts. This has dramatically changed in recent years, and
meanwhile it is clearly justified to claim that an eldorado for
homogeneous catalysis has been found:1 gold salts are now
established as highly active catalysts, especially as soft and
carbophilic Lewis acids. We became interested in a domino
process, which transforms o-alkynyl-substituted aromatic alde-
hydes and ketones to annulated ring systems via intermediary
benzopyrylium cations, featuring a fascinating 1,5-migration of
the carbonyl oxygen. Initially found to proceed under Brønsted
acid catalysis,2 this process became broadly applicable under
the moderate reaction conditions with gold, platinum, and copper
salts as catalysts.3 Recently, we succeeded in the total synthesis
of heliophenanthrone,4 a tricyclic ring system, prompting us to
extend this synthetic method to the steroid framework. Herein
we report on the synthesis of angular fused tetracyclic rings,
including 3-desoxyequilenin (1), a steroid isolated from the urine
of pregnant mares in 1945 by Prelog and Fuehrer and possessing
a moderate estrogenic activity.5
(3) (a) Antoniotti, S.; Genin, E.; Michelet, V.; Geneˆt, J. P. J. Am. Chem.
Soc. 2005, 127, 9976-9977. (b) Zhang, L.; Kozmin, S. A. J. Am. Chem.
Soc. 2005, 127, 6962-6963. (c) Yang, C.-G.; He, C. J. Am. Chem. Soc.
2005, 127, 6966-6977. (d) Zhu, J.; Grigoriadis, N. P.; Lee, J. P.; Porco, J.
A., Jr. J. Am. Chem. Soc. 2005, 127, 9342-9343. (e) Markham, J. P.; Staben,
S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 9708-9709. (f) Asao, N.;
Sato, K.; Menggenbateer; Yamamoto, Y. J. Org. Chem. 2005, 70, 3682-
3685. (g) Sato, K.; Asao, N.; Yamamoto, Y. J. Org. Chem. 2005, 70, 8977-
8981. (h) Kim, N.; Kim, Y.; Park, W.; Sung, D.; Gupta, A. K.; Oh, C. H.
Org. Lett. 2005, 7, 5289-5291. (i) Kusawa, H.; Miyashita, Y.; Takaya, J.;
Iwasawa, N. Org. Lett. 2006, 8, 289-292. (j) Lo, C. Y.; Kumar, M. P.;
Chang, H.-K.; Lush, S.-F.; Liu, R.-S. J. Org. Chem. 2005, 70, 10482-
10487. (k) Soriano, E.; Marco-Contelles, J. J. Org. Chem. 2005, 70, 9345-
9353. (l) Fuerstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024-
15025. (m) Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem.
Soc. 2005, 127, 15022-15023. (n) Nevado, C.; Echavarren, A. M. Chem.s
Eur. J. 2005, 11, 3155-3164. (o) Mun˜oz, M. P.; Adrio, J.; Carretero, J.
C.; Echavarren, A. M. Organometallics 2005, 24, 1293-1300. (p) Bajra-
charya, G. B.; Nakamura, I.; Yamamoto, Y. J. Org. Chem. 2005, 70, 892-
897. (q) Soriano, E.; Marco-Contelles, J. Chem.sEur. J. 2005, 11, 521-
533.
Results and Discussion
The retrosynthetic analysis for the synthesis of 3-desoxy-
equilenin (1) is depicted in Scheme 1. In the key transformation
of this synthesissfrom 3 to 2srings B and C should be built
(1) For reviews on gold catalysis, see: (a) Dyker, G. Angew. Chem. 2000,
112, 4407-4409; Angew. Chem., Int. Ed. 2000, 39, 4237-4239. (b) Hashmi,
A. S. K. Gold Bull. 2004, 37, 51-65. (c) Hoffmann-Ro¨der, A.; Krause, N.
Org. Biomol. Chem. 2005, 3, 387-391.
(2) Dyker, G.; Stirner, W.; Henkel, G.; Ko¨ckerling, M. Tetrahedron Lett.
1999, 40, 7457-7458.
(4) Dyker, G.; Hildebrandt, D. J. Org. Chem. 2005, 70, 6093-6096.
(5) Prelog, V.; Fuehrer, J. HelV. Chim. Acta 1945, 28, 583-590.
(6) Brooks, D. W.; Mazdiyasni, H.; Grothaus, P. G. J. Org. Chem. 1987,
52, 3223-3232.
10.1021/jo060606r CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/09/2006
6728
J. Org. Chem. 2006, 71, 6728-6733

Au-Catalyzed Domino Process to the Steroid Framework
SCHEME 1. Retrosynthetic Analysis for the Synthesis of 3-Desoxyequilenin (1)
SCHEME 2. Preparation of Diyne 5a
a Conditions: (a) propargyl bromide, NaOH, H2O, rt, 80%; (b) TMS acetylene, n-BuLi, -70 °C, THF, 84%; (c) (AcO)2O, TEA, DMAP, rt, 85%.
SCHEME 3. Synthesis of Racemic 3-Desoxyequilenin (rac-1)a
a Conditions: (a) PdCl2(PPh3)2 (2 mol %), CuI (2 mol %), TEA, 80 °C, 88%; (b) KF, THF, MeOH, rt, 92%; (c) AuCl3 (3 mol %), MeCN, 80 °C,
rac-trans-2 (62%), rac-cis-8 (7%), 9 (22%); (d) K2CO3, THF, MeOH, rt, 86%; (e) KHSO4, (AcO)2O, 100 °C, 71%; (f) H2 (2.5 bar), Pd/C, EtOAc, rac-1
(57%), 10 (36%) (diastereomeric mixture of cis-10 and trans-10).
yield and a diastereomeric ratio of nearly 1:1 (determined by1H
NMR).7 Subsequent acetylation of the alcohol functionality gave
the desired coupling component 5 in 85% yield.8
Compound 5 was coupled with aryl bromide 4 in a Sono-
gashira reaction,9 followed by the cleavage of the TMS group
with KF in THF/methanol, resulting in an overall yield of 81%
of 3 (ratio of diastereoisomers 1:1.57).10 For the gold chloride
catalyzed cyclization of the functionalized aldehyde 3, we
anticipated the formation of a mixture of the two diastereoiso-
mers of tetracycle 2. Surprisingly, cis-2 was completely missing
1
in the crude product according to H NMR analysis. Instead,
the trans-annulated isomer rac-trans-2 was isolated as the main
product, accompanied by rac-cis-8sthe hydrolization product
of cis-2sand by the elimination product 9, reflecting subtle
steric or stereoelectronic influences on the reactivity of cis- and
trans-2. The trans-configuration of the latter isomer was crucial
for the identification of the subsequent products and therefore
(7) Chen, M.-J.; Lo, C.-Y.; Chin, C.-C.; Liu, R.-S. J. Org. Chem. 2000,
65, 6362-6367.
(8) (a) Fuhshuku, K.; Tomita, M.; Sugai, T. AdV. Synth. Catal. 2003,
345, 766-774. (b) Hoefle, G.; Steglich, W.; Vorbru¨ggen, H. Angew. Chem.
1978, 90, 602-615; Angew. Chem., Int. Ed. 1978, 17, 569-583.
(9) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
50, 4467-4470. (b) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67,
86-94.
(10) Saito, T.; Morimoto, M.; Akiyama, C.; Matsumoto, T.; Suzuki, K.
J. Am. Chem. Soc. 1995, 117, 10757-10758.
J. Org. Chem, Vol. 71, No. 18, 2006 6729

Hildebrandt and Dyker
SCHEME 4. Synthesis of rac-cis-15 and rac-trans-15a
a Conditions: (a) KOtBu, HOtBu, propargyl bromide, rt, 86%; (b) LiI‚2H2O, 2,4,6-trimethylpyridine, 180 °C, 54%; (c) TMS acetylene, n-BuLi, -70 °C,
MeI, THF, rt, 62%; (d) PdCl2(PPh3)2 (2 mol %), CuI (2 mol %), TEA, 80 °C, 85% (cis), 88% (trans); (e) K2CO3, THF, MeOH, rt, 91%; (f) AuCl3 (5 mol
%), MeCN, 80 °C, transformation of rac-cis-14 leads to rac-cis-15 (27%), 16 (13%), 17 (15%), rac-trans-14 leads to rac-trans-15 (52%), 16 (10%), 17
(17%); (g) AuCl3 (5 mol %), toluene, 120 °C (in a sealed tube), transformation of rac-cis-14 generates rac-cis-15 (77%), 16 (0%), 17 (0%), transformation
of rac-trans-14 generates rac-trans-15 (75%), 16 (0%), 17 (0%).
was confirmed by a NOESY experiment due to the correlations
observed between the methyl group and H-12 as well as H-15.
In accord with this result, the correlation between the methyl
group and the acetate functionality was missing.
nones rac-cis-15 and rac-trans-15 were isolated with satisfactory
yields above 75%. The relative configurations of both were
identified by NOE experiments with the methine proton.
However, the remarkable formation of 16, which obviously
involves a CO extrusion step, calls for a mechanistic interpreta-
tion (Scheme 5):
Saponification of rac-trans-2 with K2CO3 in THF/methanol
gave rac-trans-8 in 86% yield,11 confirming the identity of rac-
1
trans-8 by comparison of the H NMR spectra. The hydroxy
SCHEME 5. Proposed Mechanism for the Formation of 15
and 16
groups of rac-trans-8 and rac-cis-8 were eliminated with
KHSO4 in acetic anhydride as solvent to give the â,γ-unsaturated
ketone 9.12 Hydrogenation of 9 in ethyl acetate over palladium-
on-charcoal at 2.5 bar hydrogen pressure gave racemic 3-des-
oxyequilenin (rac-1) and a diastereomeric mixture of 10 in 57
and 36% yield, respectively.13
To demonstrate the generality of the annulation method, we
tested the synthesis of chrysenone rac-cis- and rac-trans-15 as
another tetracyclic product according to Scheme 4. C-Alkylation
of the cyclic â-ketoester 11 with propargyl bromide and
subsequent hydrolytic decarboxylation according to standard
procedures gave the cyclohexanone 12 in an overall yield of
46%,14 whereas the direct propargylation of cyclohexanone
proved to be unsuccessful in terms of synthetic utility.15
Preparation of the two diastereoisomers rac-cis-13 and rac-
trans-13 in a ratio of 1.76:1 was achieved with a one-pot
procedure by addition of lithiated trimethylsilyl acetylene to the
keto functionality and quenching with methyl iodide;7 the two
diastereoisomers rac-cis-13 and rac-trans-13 were separated by
flash column chromatography in 62% overall yield. The
Sonogashira coupling reaction with 2-bromobenzaldehyde (4)9
followed by cleavage of the TMS group with K2CO3 in THF/
methanol provided rac-cis-14 in 77% and rac-trans-14 in 80%
yield.16 Surprisingly, the gold-catalyzed domino process let to
the formation of three products when carried out in acetonitrile
at 80 °C; besides the expected annulation products rac-cis-15
and rac-trans-15 (with low to moderate yields of 27 and 52%),
phenolic compound 17 and the annulated fluorene 16 were
identified as byproducts.17 Changing to toluene as solvent and
increasing the reaction temperature to 120 °C completely
suppresses formation of these byproducts; instead, the chryse-
(11) Plattner, J. J.; Gless, R. D.; Rapoport, H. J. Am. Chem. Soc. 1972,
94, 8613-8615.
(12) St. Andre´, A. F.; MacPhillamy, H. B.; Nelson, J. A.; Shabica, A.
C.; Scholz, C. R. J. Am. Chem. Soc. 1952, 74, 5506-5510.
The double annulation process most probably proceeds through
the benzopyrylium cation I, which results from the nucleophilic
6730 J. Org. Chem., Vol. 71, No. 18, 2006

Au-Catalyzed Domino Process to the Steroid Framework
SCHEME 6. Synthesis of 19, rac-cis-20, and 21a
a AuCl3 (5 mol %), MeCN, 80°C, 19 (7%), rac-cis-20 (47%), 21 (4%).
attack of the carbonyl oxygen at the alkyne, activated by the
Lewis acidic gold salt. A subsequent intramolecular Huisgen-
type [3 + 2] cycloaddition of the second alkyne followed by a
rearrangement reaction leads to the aromatized final product
15, in analogy to the calculations of Straub.18 As a mechanistic
pathway to the fluorene derivative 16, we suggest an intramo-
lecular ring closure of the dipolar intermediate I to oxirane II
with a gold-carbene complex functionality.19 A somewhat
speculative rearrangement could lead to III, which should
liberate the active catalyst under formation of the o-quinoid
ketone IV. An intramolecular Diels-Alder reaction with the
second alkyne moiety would lead to cycloadduct V, which
should undergo the thermodynamically favorable extrusion of
carbon monoxide and the final elimination of methanol to the
observed byproduct 16. To confirm the regioselectivity of the
proposed mechanism, we synthesized model substrate rac-cis-
18, equipped with a diagnostic methyl group (Scheme 6). The
result of the gold-catalyzed annulation reaction corresponds to
the mechanistic Scheme 5 because the methyl group indeed ends
up at the 2-position of the fluorene derivative 19, proven by
two-dimensional NMR spectroscopy (HMBC correlation be-
tween the carbon of the methyl group at C-2 and H-1 and H-3
and by the absence of a cross signal between C-6 and H-11).
The CO extrusion was confirmed with an indicator paper, which
was soaked with an aqueous PdCl2 solution; its color turned
from brown to black upon contact with the gas phase above
the reaction mixture.
systems as important structural framework of natural products,
such as steroids.
Experimental Section
trans-14-Acetoxy-13-methyl-13,14,15,16-tetrahydro-12H-cy-
clopenta[a]phenanthrene-11,17-dione (rac-trans-2), cis-14-Hy-
droxy-13-methyl-13,14,15,16-tetrahydro-12H-cyclopenta[a]-
phenanthrene-11,17-dione (rac-cis-8), and 13-Methyl-13,16-
dihydro-12H-cyclopenta[a]phenanthrene-11,17-dione (9). In a
screw-capped flask, 385 mg (1.20 mmol) of 3 and 11 mg (36 µmol)
of AuCl3 were dissolved in 50 mL of acetonitrile. The mixture was
stirred at 80 °C for 3 h and, after cooling to room temperature,
filtered through a short pad of silica (eluent: ethyl acetate). After
evaporation of the solvents, the residue was fractionated by flash
chromatography (SiO2, petroleum ether/ethyl acetate 3:1); 1st
fraction (Rf ) 0.33): 70 mg (22%) of 9 as colorless crystals (mp
109-111 °C); 2nd fraction (Rf ) 0.19): 240 mg (62%) of rac-
trans-2 as colorless crystals (mp 55 °C); 3rd fraction (Rf ) 0.09):
30 mg (7%) of rac-cis-8 as colorless crystals (mp 170 °C). rac-
trans-2: IR (KBr) ν˜ 3056 (w), 2976 (w), 2935 (w), 1745 (vs), 1680
(s), 1430 (m), 1369 (m), 1236 (s), 1143 (m), 1078 (w), 1029 (m),
830 (m), 757 (m), 672 (w) cm-1; UV (acetonitrile) λmax (log ꢀ)
316 (3.75), 308 (3.84), 234 (4.18) nm; 1H NMR (CDCl3, 400 MHz)
δ 1.24 (s, 3H), 2.10 (s, 3H), 2.11 (m, 1H), 2.59 (m, 1H), 2.65-
2.79 (m, 2H), 3.00 (d, J ) 14.6 Hz, 1H), 3.10 (d, J ) 14.6 Hz,
1H), 7.55 (t, J ) 7.8 Hz, 1H), 7.63-7.67 (m, 2H), 7.82 (d, J ) 7.8
Hz, 1H), 8.08 (d, J ) 8.8 Hz, 1H), 9.25 (d, J ) 8.8 Hz, 1H); 13C
NMR {1H} (CDCl3, 100 MHz) δ 18.7, 21.6, 34.8, 35.2, 46.7, 53.4,
86.7, 123.0, 127.2, 127.3, 127.8, 128.2, 129.5, 129.8, 133.4, 135.5,
143.7, 169.9, 197.7, 215.3; MS (70 eV, EI) m/z (%) ) 322 [M+]
(100), 280 (36), 262 (55), 238 (67), 220 (63), 196 (29), 178 (24),
165 (24), 152 (16), 127 (13), 73 (19), 43 (66). Anal. Calcd for
C20H18O4: C, 74.52; H, 5.63. Found: C, 74.71; H, 5.49. rac-cis-8:
IR (KBr) ν˜ 3446 (s), 2951 (w), 2919 (w), 1750 (vs), 1648 (vs),
1590 (m), 1434 (m), 1209 (m), 1021 (m), 770 (m) cm-1; UV
(acetonitrile) λmax (log ꢀ) 318 (3.78), 308 (3.80), 242 (4.27), 224-
Conclusion
The total syntheses of rac-3-desoxyequilenin and of a
chrysenone derivative were accomplished via a gold-catalyzed
domino process, which achieves a high degree of complexity
in just one preparative step. This result demonstrates the
usefulness of this method for the construction of tetracyclic ring
1
(4.28) nm; H NMR (CDCl3, 400 MHz) δ 0.97 (s, 3H), 2.01 (s,
1H), 2.59-2.76 (m, 4H), 2.63 (d, J ) 18.4 Hz, 1H), 3.32 (dd, J )
18.3, 0.5 Hz, 1H), 7.52 (d, J ) 8.3 Hz, 1H), 7.56 (td, J ) 7.6, 1.0
Hz, 1H), 7.67 (td, J ) 8.0, 1.0 Hz, 1H), 7.89 (d, J ) 8.3 Hz, 1H),
8.12 (d, J ) 8.3 Hz, 1H), 9.18 (d, J ) 8.8 Hz, 1H); 13C NMR
{1H} (CDCl3, 100 MHz) δ 21.7, 29.8, 33.6, 42.4, 53.7, 79.5, 121.1,
126.7, 127.0, 127.4, 128.7, 129.5, 131.3, 134.5, 135.2, 142.7, 199.6,
216.0; MS (70 eV, EI) m/z (%) ) 280 [M+] (100), 262 (7), 221
(33), 207 (12), 197 (79), 178 (17), 165 (19), 152 (15), 127 (16).
Anal. Calcd for C13H16O3: C, 77.12; H, 5.75. Found: C, 77.41; H,
5.89. 9: IR (KBr) ν˜ 3062 (w), 2967 (w), 2928 (w), 1747 (vs), 1664
(vs), 1612 (m), 1590 (m), 1508 (m), 1428 (m), 1362 (m), 1213 (s),
1195 (m), 1149 (m), 1053 (m), 988 (m), 839 (m), 808 (s), 780
(m), 767 (m) cm-1; UV (acetonitrile) λmax (log ꢀ) 327 (3.69), 277
(13) (a) Marker, R. E.; Rohrmann, E. J. Am. Chem. Soc. 1939, 61, 3314-
3317. (b) Johnson, W. S.; Petersen, J. W.; Gutsche, C. D. J. Am. Chem.
Soc. 1947, 69, 2942-2955.
(14) Magatti, C. V.; Kaminski, J. J.; Rothberg, I. J. Org. Chem. 1991,
56, 3102-3108.
(15) Miller, R. B. Synth. Commun. 1972, 2, 267-272.
(16) Scott, L. T.; Cooney, M. J.; Johnels, D. J. Am. Chem. Soc. 1990,
112, 4054-4055.
(17) Frenton, S. W.; Arnold, R. T.; Fritz, H. E. J. Am. Chem. Soc. 1955,
77, 5983-5986.
(18) Straub, B. F. Chem. Commun. 2004, 1726-1728.
(19) (a) Padwa, A.; Hornbuckle, S. F. Chem. ReV. 1991, 91, 263-309.
(b) Lu, C.-D.; Chen, Z.-Y.; Liu, H.; Hu, W.-H.; Mi, A.-Q. Org. Lett. 2004,
6, 3071-3074.
J. Org. Chem, Vol. 71, No. 18, 2006 6731

Hildebrandt and Dyker
1
(4.22), 267 (4.25), 256 (4.26), 229 (4.25) nm; H NMR (CDCl3,
1335 (w), 1208 (m), 1132 (w), 1111 (w), 1038 (w), 1010 (w), 958
(w), 840 (m), 822 (m), 764 (m) cm-1; UV (acetonitrile) λmax (log
400 MHz) δ 1.32 (s, 3H), 2.83 and 2.95 (d, J ) 15.2 Hz, 2H),
3.21 and 3.42 (dd, J ) 23.7, 2.5 Hz, 2H), 6.62 (t, J ) 2.5 Hz, 1H),
7.53 (td, J ) 7.3, 1.0 Hz, 1H), 7.66 (td, J ) 7.8, 1.5 Hz, 1H), 7.72
(d, J ) 8.6 Hz, 1H), 7.83 (d, J ) 8.1 Hz, 1H), 8.04 (d, J ) 8.6 Hz,
1H), 9.40 (d, J ) 8.8 Hz, 1H); 13C NMR {1H} (CDCl3, 100 MHz)
δ 21.6, 42.7, 47.5, 52.6, 121.5, 121.8, 124.7, 126.9, 127.3, 128.6,
129.6, 131.2, 134.1, 135.4, 136.2, 144.6, 198.4, 216.5; MS (70 eV,
EI) m/z (%) ) 262 [M+] (100), 234 (74), 219 (34), 206 (36), 191
(34), 178 (13), 165 (24), 117 (9), 101 (7), 89 (10). Anal. Calcd for
C18H14O2: C, 82.42; H, 5.38. Found: C, 82.43; H, 5.77.
1
ꢀ) 317 (3.83), 308 (3.82), 246 (4.31), 220 (4.44) nm; H NMR
(CDCl3, 400 MHz) double set of signals because of diastereoisomers
(ratio 3:2) δ 0.86 and 1.29 (s, 3H), 2.12-2.24 (m, 1H), 2.39-2.77
(m, 4H), 2.92 and 2.94 (d, J ) 13.8, 18.2 Hz, 1H), 2.35-3.44 (m,
1H), 7.38 and 7.41 (d, J ) 8.6, 8.4 Hz, 1H), 7.53 (“t”, 1H), 7.67
(“t”, 1H), 7.83 and 7.87 (d, J ) 7.6, 8.4 Hz, 1H), 8.03 and 8.09 (d,
J ) 8.3, 8.4 Hz, 1H), 9.30 and 9.31 (d, J ) 8.8, 8.6 Hz, 1H); 13C
NMR {1H} (CDCl3, 100 MHz) δ 15.3, 20.4, 22.1, 28.5, 35.9, 37.7,
43.2, 49.0, 46.4, 48.4, 49.0, 50.4, 123.1, 126.7, 125.8, 127.0, 126.3,
126.5, 126.4, 126.6, 128.5, 128.7, 129.4, 129.5, 130.9, 131.4, 133.1,
133.4, 135.4, 135.4, 143.3, 145.6, 197.6, 198.7, 217.3, 218.0; MS
(70 eV, EI) m/z (%) ) 264 [M+] (100), 236 (10), 221 (10), 208
(48), 196 (40), 178 (23), 165 (37), 152 (13), 76 (5).
trans-14-Hydroxy-13-methyl-13,14,15,16-tetrahydro-12H-cy-
clopenta[a]phenanthrene-11,17-dione (rac-trans-8). A solution
of 104 mg (0.75 mmol) of K2CO3 in 10 mL of methanol was added
to 240 mg (0.75 mmol) of rac-trans-2 in 10 mL of THF, and the
mixture was stirred for 16 h. Fifteen milliliters of aqueous 1 N
NH4Cl was added, and the water layer was extracted three times
with 20 mL of MTBE. The combined organic extract was dried
over sodium sulfate. Evaporation of the solvents and flash chro-
matography of the residue (SiO2, petroleum ether/ethyl acetate 2:1;
Rf ) 0.26) resulted in 180 mg (86%) of rac-trans-8 as colorless
crystals (mp 212 °C): IR (KBr) ν˜ 3465 (s), 2977 (w), 2927 (w),
1727 (vs), 1654 (vs), 1591 (m), 1508 (m), 1362 (m), 1330 (m),
trans-10a-Methoxy-6a,7,8,9,10,10a-hexahydro-6H-chrysen-5-
one (rac-trans-15), 8,9,10,11-Tetrahydro-7H-benzo[a]fluorene
(16), and 7,8,9,10-Tetrahydrochrysen-5-ol (17). In a screw-capped
flask, 135 mg (0.48 mmol) of rac-trans-14 and 7.0 mg (23 µmol)
of AuCl3 were dissolved in 20 mL of acetonitrile. The mixture was
stirred at 80 °C for 3 h and, after cooling to room temperature,
filtered through a short pad of silica (eluent: ethyl acetate). After
evaporation of the solvents, the residue was fractionated by flash
chromatography (SiO2, petroleum ether/ethyl acetate 20:1); 1st
fraction (Rf ) 0.73): 11 mg (10%) of 16 as colorless crystals (mp
81 °C); 2nd fraction (Rf ) 0.30): 70 mg (52%) of rac-trans-15 as
colorless crystals (mp 105-107 °C); 3rd fraction (Rf ) 0.13): 20
mg (17%) of 17 as colorless crystals (mp 189-190 °C). rac-trans-
15: IR (KBr) ν˜ 2929 (s), 2855 (s), 2823 (m), 1668 (vs), 1590 (m),
1460 (m), 1448 (m), 1367 (m), 1341 (m), 1231 (s), 1220 (s), 1199
(m), 1115 (s), 1071 (s), 1059 (s), 927 (m), 838 (s), 828 (s), 812
(s), 753 (vs) cm-1; UV (acetonitrile) λmax (log ꢀ) 312 (3.91), 308
1218 (s), 1183 (m), 1067 (s), 971 (m), 828 (m), 759 (m) cm-1
UV (acetonitrile) λmax (log ꢀ) 317 (3.76), 308 (3.82), 244 (4.21),
227 (4.23) nm; H NMR (CDCl3, 400 MHz) δ 1.26 (s, 3H), 2.11
;
1
(s, 1H), 2.44-2.81 (m, 4H), 2.56 (d, J ) 15.1 Hz, 1H), 2.94 (d, J
) 14.9 Hz, 1H), 7.57 (td, J ) 7.6, 1.0 Hz, 1H), 7.68 (td, J ) 7.8,
1.5 Hz, 1H), 7.85 (“d”, 1H), 7.89 (d, J ) 8.8 Hz, 1H), 8.15 (d, J
) 8.6 Hz, 1H), 9.34 (d, J ) 8.8 Hz, 1H); 13C NMR {1H} (CDCl3,
100 MHz) δ 14.6, 35.4, 35.5, 47.0, 57.2, 80.0, 123.4, 125.0, 127.0,
127.1, 128.5, 129.7, 130.3, 133.6, 136.2, 147.0, 196.6, 216.5; MS
(70 eV, EI) m/z (%) ) 280 [M+] (100), 262 (6), 224 (87), 209
(16), 197 (34), 181 (17), 165 (17), 152 (17), 127 (25). Anal. Calcd
for C13H16O3: C, 77.12; H, 5.75. Found: C, 77.37; H, 5.70.
Elimination Reaction of 8 to 9. Ninety milligrams (0.32 mmol)
of a mixture of rac-trans-8 and rac-cis-8 was dissolved in 4 mL of
acetic anhydride; 109 mg (0.80 mmol) of KHSO4 was added and
the mixture was heated at 100 °C for 1 h. Ten milliliters of 5%
aqueous KHCO3 was added, and the water layer was extracted with
MTBE. The combined organic extract was washed with brine and
dried over sodium sulfate. Evaporation of the solvents and flash
chromatography of the residue (SiO2, petroleum ether/ethyl acetate
3:1; Rf ) 0.35) gave 60 mg (71%) of 9 as colorless crystals (mp
109-111 °C).
rac-3-Desoxyequilenin (rac-1) and 13-Methyl-13,14,15,16-
tetrahydro-12H-cyclopenta[a]phenanthrene-11,17-dione (10).
Fifty-five milligrams (0.21 mmol) of 9 was hydrogenated within
2.5 h at 2.5 bar of hydrogen pressure in ethyl acetate (10 mL) using
50 mg of 10% palladium-on-charcoal as catalyst. The mixture was
filtrated, the solvent evaporated, and the residue was fractionated
by flash chromatography (SiO2, petroleum ether/ethyl acetate 3:1);
1st fraction (Rf ) 0.52): 20 mg (36%) of 10 in the ratio 1:1.58 as
colorless crystals (mp 146-149 °C); 2nd fraction (Rf ) 0.20): 30
mg (57%) of rac-1 as colorless crystals (mp 180 °C). rac-1: IR
(KBr) ν˜ 3046 (w), 2930 (s), 2865 (m), 1735 (vs), 1509 (m), 1459
(m), 1428 (m), 1369 (m), 1349 (m), 1287 (m), 1251 (m), 1063
(m), 1033 (m), 1014 (m), 820 (s), 764 (s) cm-1; 1H NMR (CDCl3,
400 MHz) δ 0.82 (s, 3H), 1.91 (m, 1H), 2.04 (m, 1H), 2.24 (m,
1H), 2.42 (dd, J ) 18.7, 9.1 Hz, 1H), 2.58 (m, 1H), 2.71 (dd, J )
19.2, 8.6 Hz, 1H), 3.21 (dd, J ) 12.6, 6.0 Hz, 1H), 3.31-3.37 (m,
2H), 7.32 (d, J ) 8.6 Hz, 1H), 7.46 (t, J ) 7.8 Hz, 1H), 7.53 (td,
J ) 8.3, 1.3 Hz, 1H), 7.74 (d, J ) 8.3 Hz, 1H), 7.84 (d, J ) 7.8
Hz, 1H), 7.97 (d, J ) 8.3 Hz, 1H); 13C NMR {1H} (CDCl3, 100
MHz) δ 13.4, 22.0, 24.1, 29.3, 36.7, 47.1, 47.7, 123.4, 123.9, 125.2,
126.3, 126.8, 128.8, 131.0, 132.1, 132.6, 134.6, 219.9; MS (70 eV,
EI) m/z (%) ) 250 [M+] (100), 235 (4), 207 (20), 193 (37), 178
(27), 165 (25), 113 (12), 98 (17), 89 (16), 76 (7). 10: IR (KBr) ν˜
3021 (w), 2970 (w), 1745 (vs), 1662 (vs), 1594 (m), 1512 (m),-
1
(3.98), 240 (4.52), 222 (4.57) nm; H NMR (CDCl3, 400 MHz) δ
1.34 (m, 1H), 1.56 (m, 1H), 1.60-1.84 (m, 5H), 2.13 (m, 1H),
2.66 (dd, J ) 18.1, 7.0 Hz, 1H), 2.79 (dd, J ) 18.1, 10.6 Hz, 1H),
2.85 (m, 1H), 2.87 (s, 3H), 7.53 (td, J ) 7.5, 1.0 Hz, 1H), 7.60-
7.64 (m, 2H), 7.85 (d, J ) 8.0 Hz, 1H), 8.00 (d, J ) 8.5 Hz, 1H),
9.04 (d, J ) 9.0 Hz, 1H); 13C NMR {1H} (CDCl3, 100 MHz) δ
21.5, 25.5, 28.7, 29.2, 41.4, 42.5, 49.9, 73.8, 122.8, 126.6, 126.8,
128.1, 128.6, 129.6, 130.8, 132.5, 133.6, 145.8, 201.0; MS (70 eV,
EI) m/z (%) ) 280 [M+] (100), 265 (15), 249 (67), 237 (14), 221
(33), 207 (20), 181 (79), 165 (25), 152 (20), 141 (12). Anal. Calcd
for C19H20O2: C, 81.40; H, 7.19. Found: C, 81.06; H, 7.25. 16:
IR (KBr) ν˜ 3051 (m), 2929 (s), 2852 (m), 2826 (m), 1615 (w),
1513 (w), 1435 (m), 1397 (m), 1257 (m), 1209 (w), 1139 (m), 1022
(w), 943 (w), 820 (vs), 810 (vs), 744 (vs) cm-1; UV (acetonitrile)
λmax (log ꢀ) 316 (3.69), 304 (3.89), 296 (3.80), 248 (4.17), 218
1
(4.14) nm; H NMR (CDCl3, 400 MHz) δ 1.85 (m, 4H), 2.52 (s,
4H), 3.56 (s, 2H), 7.34 (td, J ) 7.5, 1.2 Hz, 1H), 7.44 (m, 2H),
7.76 (d, J ) 8.4 Hz, 1H), 7.84 (d, J ) 8.4 Hz, 1H), 7.89 (d, J )
8.3 Hz, 1H); 13C NMR {1H} (CDCl3, 100 MHz) δ 22.6, 22.9, 23.5,
26.1, 39.6, 117.9, 123.5, 123.9, 126.0, 127.0, 129.0, 130.2, 131.4,
136.6, 138.7, 141.0, 143.7; MS (70 eV, EI) m/z (%) 220 [M+] (100),
202 (6), 192 (51), 178 (15), 165 (12), 96 (5). Anal. Calcd for
C17H16: C, 92.68; H, 7.32. Found: C, 92.30; H, 7.41. 17: IR (KBr)
ν˜ 3520 (vs), 2929 (s), 2855 (m), 1621 (w), 1422 (w), 1391 (m),
1307 (m), 1221 (m), 1188 (m), 1111 (m), 850 (m), 807 (s), 755 (s)
cm-1; UV (acetonitrile) λmax (log ꢀ) 362 (3.62), 345 (3.53), 329
(3.30), 308 (3.93), 301 (3.94), 276 (4.28), 245 (4.29) nm; 1H NMR
(CDCl3, 400 MHz) δ 1.87 (m, 2H), 1.99 (m, 2H), 2.89 (t, J ) 6.3
Hz, 2H), 3.11 (t, J ) 6.3 Hz, 2H), 5.49 (s, 1H), 6.72 (s, 1H), 7.56
(td, J ) 7.2, 1.2 Hz, 1H), 7.63 (td, J ) 7.8, 1.5 Hz, 1H), 7.77 (d,
J ) 9.4 Hz, 1H), 7.88 (dd, J ) 7.8, 1.3 Hz, 1H), 7.92 (d, J ) 9.1
Hz, 1H), 9.64 (d, J ) 8.6 Hz, 1H); 13C NMR {1H} (CDCl3, 100
MHz) δ 22.9, 23.8, 26.3, 30.4, 114.5, 118.2, 122.1, 125.4, 125.6,
126.5, 128.2, 128.6, 128.6, 130.9, 132.0, 133.3, 135.9, 152.2; MS
(70 eV, EI) m/z (%) ) 248 [M+] (100), 231 (5), 220 (26), 191
(10), 165 (7), 124 (7), 101 (12).
6732 J. Org. Chem., Vol. 71, No. 18, 2006

Au-Catalyzed Domino Process to the Steroid Framework
cis-10a-Methoxy-6a,7,8,9,10,10a-hexahydro-6H-chrysen-5-
one (rac-cis-15), 8,9,10,11-Tetrahydro-7H-benzo[a]fluorene (16),
and 7,8,9,10-Tetrahydrochrysen-5-ol (17). In a screw-capped
flask, 135 mg (0.48 mmol) of rac-cis-14 and 7.0 mg (23 µmol) of
AuCl3 were dissolved in 20 mL of acetonitrile. The mixture was
stirred at 80 °C for 3 h and, after cooling to room temperature,
filtered through a short pad of silica (eluent: ethyl acetate). After
evaporation of the solvents, the residue was fractionated by flash
chromatography (SiO2, petroleum ether/ethyl acetate 20:1); 1st
fraction (Rf ) 0.73): 14 mg (13%) of 16 as colorless crystals (mp
81 °C); 2nd fraction (Rf ) 0.23): 37 mg (27%) of rac-cis-15 as
colorless crystals (mp 112 °C); 3rd fraction (Rf ) 0.13): 18 mg
(15%) of 17 as colorless crystals (mp 189-190 °C). rac-cis-15:
IR (KBr) ν˜ 2930 (s), 2858 (s), 2823 (m), 1665 (vs), 1616 (m),
1502 (m), 1446 (m), 1429 (m), 1357 (m), 1343 (m), 1267 (m),
1243 (m), 1223 (m), 1214 (m), 1181 (m), 1166 (m), 1098 (m),
1079 (s), 1066 (s), 839 (s), 799 (m), 757 (s) cm-1; UV (acetonitrile)
3.07 (dd, J ) 15.6, 13.5 Hz, 1H), 7.53 (t, J ) 7.0 Hz, 1H), 7.64
(td, J ) 8.5, 1.5 Hz, 1H), 7.70 (d, J ) 9.0 Hz, 1H), 7.84 (d, J )
8.0 Hz, 1H), 8.05 (d, J ) 9.0 Hz, 1H), 9.39 (d, J ) 8.5 Hz, 1H);
13C NMR {1H} (CDCl3, 100 MHz) δ 19.9, 21.7, 26.6, 34.8, 35.5,
43.7, 50.0, 78.0, 123.7, 126.6, 127.0, 128.0, 128.3, 128.9, 131.0,
133.3, 134.9, 149.9, 200.6; MS (70 eV, EI) m/z (%) ) 280 [M+]
(100), 265 (12), 249 (52), 237 (27), 223 (38), 209 (25), 181 (59),
165 (29), 152 (24), 127 (13). Anal. Calcd for C19H20O2: C, 81.40;
H, 7.19. Found: C, 81.06; H, 7.25.
Acknowledgment. We gratefully acknowledge financial
support from Fonds der Chemischen Industrie and of the
Deutsche Forschungsgemeinschaft (DFG-project DY 12/7-2).
Supporting Information Available: Experimental details of the
syntheses of 3, 5, 7, 13, 14, 18-21 as well as additional
characterization data and spectra of all products. This material is
available free of charge via Internet at http://pubs.acs.org.
1
λmax (log ꢀ) 312 (3.37), 308 (3.41), 245 (3.88), 215 (4.15) nm; H
NMR (CDCl3, 400 MHz) δ 1.45-1.62 (m, 4H), 1.84-1.96 (m,
4H), 2.75 (dd, J ) 15.6, 4.0 Hz, 1H), 2.84 (m, 1H), 3.06 (s, 3H),
JO060606R
J. Org. Chem, Vol. 71, No. 18, 2006 6733