A three-step route to a tricyclic steroid precursor

Article abstract of DOI:10.1021/jo801767n

(Chemical Equation Presented) 2-Alkyl cyclohexenones are useful intermediates for organic synthesis. The Wittig reaction of a series of aldehydes with (cyclopropylmethyl)triphenylphosphonium bromide delivered the corresponding alkenyl cyclopropanes. UV irradiation in the presence of Fe(CO)s converted the alkenyl cyclopropanes to the 2-substituted cyclohexenones. This approach enabled a three-step synthesis of the tricyclic core of estrone methyl ether.

Full text of DOI:10.1021/jo801767n

A Three-Step Route to a Tricyclic Steroid Precursor
Douglass F. Taber* and Ritesh B. Sheth
Department of Chemistry & Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
taberdf@udel.edu
ReceiVed August 7, 2008
2-Alkyl cyclohexenones are useful intermediates for organic synthesis. The Wittig reaction of a series of
aldehydes with (cyclopropylmethyl)triphenylphosphonium bromide delivered the corresponding alkenyl
cyclopropanes. UV irradiation in the presence of Fe(CO)5 converted the alkenyl cyclopropanes to the
2-substituted cyclohexenones. This approach enabled a three-step synthesis of the tricyclic core of estrone
methyl ether.
Introduction
Estrone 1 and estradiol 2 (eq 1), important hormones that
control the menstruation cycle of mammals, are an attractive
research area due to their high biological activity and many
pharmaceutical applications. A variety of synthetic strategies
have been published for the synthesis of estrone and its
derivatives.1 The first total synthesis of estrone was published
in 1948 by Anner and Miescher.1a The tricyclic phenanthrenone
core 3 played a key role in that synthesis and is a potentially
useful intermediate for steroid syntheses.2
We envisioned (Scheme 1) that aldehyde 4a could be
homologated to the corresponding alkenyl cyclopropane by
Wittig reaction with the commercially available (cyclopropyl-
methyl)triphenylphosphonium bromide 5.3 UV irradiation of the
alkenyl cyclopropane 6a so prepared in the presence of Fe(CO)5
under a CO atmosphere4 would then lead to the corresponding
cyclohexenone 7a. Acid-catalyzed cyclization would then deliver
the tricyclic ketone 3, in just three steps from the commercial
aldehyde 4a.
(1) For the Bachmann-Miescher estrone synthesis, see: (a) Anner, G.;
Miescher, K. HelV. Chim. Acta 1948, 31, 2173. (b) Bachmann, W. E.; Cole,
W.; Wilds, A. L. J. Am. Chem. Soc. 1940, 62, 824. (c) Bachmann, W. E.;
Kushner, A. C.; Stevenson, A. C. J. Am. Chem. Soc. 1942, 64, 976. For a review
of synthetic routes to estrone, see: (d) Quinkert, G.; Stark, H. Angew. Chem.,
Int. Ed. 1983, 22, 637. For more recent references, see: (e) Vollhardt, K. P. C.
Pure Appl. Chem. 1985, 57, 1819. (f) Lecker, S. H.; Nguyen, N. H.; Vollhardt,
K. P. C. J. Am. Chem. Soc. 1986, 108, 856. (g) Taber, D. F.; Raman, K.; Gaul,
M. D. J. Org. Chem. 1987, 52, 28. (h) Michellys, P.-Y.; Pelliser, H.; Santelli,
M. Tetrahedron Lett. 1993, 34, 1931. (i) Trost, B. M.; Shil, Y. J. Am. Chem.
Soc. 1993, 115, 9421. (j) Sakamoto, Y.; Yasuharu, H.; Takahashi, T. Synlett
1995, 231. (k) Quinkert, G.; Del Grosso, M.; Doring, A.; Doring, W.; Schenkel,
R. I.; Bauch, M.; Dambacher, G. T.; Bats, J. W.; Zimmerman, G.; Durner, G.
HelV. Chim. Acta 1995, 78, 1345. (l) Sugahara, T.; Ogasawara, K. Tetrahedron
Lett. 1996, 37, 7403. (m) Ouellet, L.; Langlois, P.; Deslongchamps, P. Synlett
1997, 689. (n) Tietze, L. F.; Nobel, T.; Spescha, M. J. Am. Chem. Soc. 1998,
120, 8971. (o) Hu, Q.-Y.; Rege, P. D.; Corey, E. J J. Am. Chem. Soc. 2004,
126, 5984. (p) Pattenden, G.; Gonzalez, M. A.; McCulloch, S.; Walter, A.;
Woodhead, S. J. Proc. Nat. Acad. Sci. 2004, 101, 12024. (q) Soorukram, D.;
Knochel, P. Org. Lett. 2007, 9, 1021.
Results and Discussion
2-Alkyl cyclohexenones are important intermediates for
target-directed synthesis.5 While several methods have been
(3) For the preparation of (cyclopropylmethyl)triphenylphosphonium bromide,
see: (a) Maercker, A. Angew. Chem., Int. Ed. 1967, 6, 557. (b) Schweizer, E. E.;
Thompson, J. G.; Ulrich, T. A. J. Org. Chem. 1968, 33, 3082. For the utility of
(cyclopropylmethyl)triphenylphosphonium bromide, see: (c) Kataoka, F.; Shimi-
zu, N.; Nishida, S. J. Am. Chem. Soc. 1980, 102, 711. (d) Cavasotto, C. N.; Liu,
G.; James, S. Y.; Hobbs, P. D.; Peterson, V. J.; Bhattacharya, A. A.; Kolluri,
S. K.; Zhang, X.; Leid, M.; Abagyan, R.; Liddington, R. C.; Dawson, M. I.
J. Med. Chem. 2004, 47, 4360.
(2) For previous preparations of the tricyclic ketones 3 and 8, see: (a) Birch,
A. J.; Smith, H.; Thornton, R. E Chem. Ind. 1956, 1310. (b) Birch, A. J.; Smith,
H.; Thornton, R. E. J. Chem. Soc. 1957, 1339. (c) Ansell, M. F.; Ducker, J. W.
J. Chem. Soc. 1961, 206. (d) Wiley, R. H.; Crawford, T. H.; Bray, N. F. J.
Polym. Sci., Part B: Polym. Lett. 1965, 3, 99. (e) Nagata, W.; Terasawa, T.;
Tori, K. J. Am. Chem. Soc. 1964, 86, 3746. (f) Sundar, N. S.; Subba Rao, G. S.
J. Chem. Res., Synop. 1982, 1381. (g) Varech, D.; Lacombe, L.; Jacques, J.
New J. Chem. 1984, 8, 445. (h) Thompson, H. W.; Long, D. J. J. Org. Chem.
1988, 53, 4201.
(4) For the development of Fe-mediated cyclocarbonylation, see: (a) Taber,
D. F.; Kanai, K.; Jiang, Q.; Bui, G. J. Am. Chem. Soc. 2000, 122, 6807. (b)
Taber, D. F.; Bui, G.; Chen, B. J. Org. Chem. 2001, 66, 3423. (c) Taber, D. F.;
Joshi, P. V.; Kanai, K. J. Org. Chem. 2004, 69, 2268.
(5) For examples of the utility of 2-alkyl cyclohexenones in target-directed
synthesis, see: (a) Hauser, F. M.; Caringal, Y. J. Org. Chem. 1990, 55, 555. (b)
Majetich, G.; Liu, S.; Fang, J.; Siesel, D.; Zhang, Y. J. Org. Chem. 1997, 62,
6928. (c) Iwamatsu, S.; Matsubara, K.; Nagashima, H. J. Org. Chem. 1999, 64,
9625. (d) Coelho, F.; Diaz, G. Tetrahedron 2002, 58, 1647.
8030 J. Org. Chem. 2008, 73, 8030–8032
10.1021/jo801767n CCC: $40.75 2008 American Chemical Society
Published on Web 09/25/2008

Three-Step Route to a Tricyclic Steroid Precursor
TABLE 1. Witting Reaction and Carbonylation
SCHEME 1
developed to prepare such cyclohexenones, these routes tend
to be either low-yielding or multistepped.6 There were two
challenges to be overcome in developing the route to 2-alkyl-
cyclohexenones outlined in Scheme 1: development of the
Wittig reaction and optimization of the Fe-mediated cyclocar-
bonylation.
Development of the Wittig Reaction. We initially performed
the Wittig reaction utilizing 1 equiv of commercial (cyclopro-
pylmethyl)triphenylphosphonium bromide and 1 equiv of potas-
sium tert-butoxide at cryogenic temperatures. This protocol led
to modest yields, with some unreacted aldehyde. During
optimization, we found that increasing both base and phospho-
nium salt to a slight excess increased conversion. While
maintaining the slight excess of phosphonium bromide, we
doubled the amount of base, which led to complete conversion
and high yields. Finally, we found that the reaction could be
carried out at room temperature. The products (Table 1) were
isolated as a mixture of both the Z and E isomers of the alkenyl
cyclopropane, which was of no consequence for the subsequent
cyclocarbonylation.
Optimization of the Fe-Mediated Cyclocarbonylation. We
initiated carbonylation studies using the conditions that we had
previously developed.6 We found that using less than 1 equiv
of Fe(CO)5 reduced the conversion rate, while adding greater
than 2 equiv did not lead to significantly higher conversions.
Increasing the concentration of the solution typically lowered
conversion. We did find that the conversion and yield improved
when the mixture was agitated periodically, providing for an
exchange between the product and starting material forming the
thin film that was being irradiated. We maintained a CO
atmosphere in each of the runs, even though CO is formed
during the irradiation of the Fe(CO)5.
a Autocooling in Rayonet was turned off. b For a previous preparation
of 3d, see ref 8.
SCHEME 2
During the carbonylation of 6d, we observed a significantly
lower conversion of the alkenyl cyclopropane to the cyclohex-
enone 7d. It was our hypothesis that the steric bulk of the
molecule hindered the carbonylation. When we ran the pho-
tolysis without autocooling and so warmer, the conversion
improved significantly. This two-step conversion appears to be
a versatile and convenient way to prepare 2-alkyl cyclohex-
enones from the corresponding aldehydes.7
(6) For previous preparations of 2-alkyl cyclohexenones, see: (a) Taber, D. F.;
Gunn, B. P.; Bruce, P. J. Org. Chem. 1979, 44, 450. (b) Johnson, C. R.; Braun,
M. P. J. Am. Chem. Soc. 1993, 115, 11014. (c) Armitage, M. A.; Lathbury,
D. C.; Mitchell, M. B. J. Chem. Soc., Perkin Trans. 1 1994, 12, 1551. (d) Abbas,
A. A.; Kobayashi, Y. Tetrahedron Lett. 2003, 44, 119. (e) Takeishi, K.;
Sugishima, K.; Sasaki, K.; Tanaka, K. Chem. Eur. J. 2005, 10, 5681.
(7) This approach is not useful for 2-aryl cyclohexenones. The iron reactions
proceed with >90% yield but only to about 20% conversion. We believe that
the lower conversion is a result of the competing absorption of UV radiation by
the aryl enone. For practical routes to 2-aryl cyclohexenones, see: (a) Bosse, F.;
Tunoori, A. R.; Niestro, A. J.; Gronwald, O.; Maier, M. E. Tetrahedron 1996,
52, 9485. (b) Prasad, A. S. B.; Knochel, P. Tetrahedron 1997, 53, 16711. (c)
Kim, J.; Kulawiec, R. Tetrahedron Lett. 1998, 39, 3107. (d) Felpin, F. J. Org.
Chem. 2005, 70, 8575.
Cyclization of the Enone. We envisioned (Scheme 2) that a
variety of Lewis acids could effect the cyclization of the enone
3.5b,9 We initiated our studies with BF3 ·OEt2 and TiCl4. While
both Lewis acids were efficient in forming the tricyclic ring,
BF3 ·OEt2 was milder in its reaction with the cyclohexenone,
leading to less decomposition and thus higher yield. We found
(9) For previous examples of acid-mediated cyclization of cyclohexenones
onto arenes, see: (a) Pepin, J. J.; Andre-Louisfert, J.; Bisagni, E Bull. Soc. Chim.
Fr. 1970, 8-9, 3038. (b) Hauser, F. M.; Caringal, Y. J. Org. Chem. 1990, 55,
555. (d) Bie, P. Y.; Zhang, C. L.; Peng, X. J.; Chen, B.; Yang, Y.; Pan, X. F.
Chem. J. Chin. UniV. 2003, 24, 1219.
(8) Reetz, M. T.; Heimbach, H. Chem. Ber. 1983, 116, 3702.
J. Org. Chem. Vol. 73, No. 20, 2008 8031

Taber and Sheth
subsequently concentrated. The residue was chromatographed to
give 2 mg of unreacted 2a and 202 mg of 7a (89% yield based on
6a not recovered) as an oil. TLC Rf ) 0.17 (9:1 hexanes/EtOAc);
1H NMR δ 7.16 (t, J ) 8.4 Hz, 1H), 7.07 (d, J ) 9.2 Hz, 1H),
6.81 (t, J ) 9.2 Hz, 1H), 6.73 (m, 1H), 6.61 (m, 1H), 3.78 (s, 3H),
2.68 (m, 2H), 2.45 (m, 4H), 2.28 (m, 2H), 1.98 (m, 2H); 13C NMR
δ CH3: 55.4, CH2: 38.7, 35.1, 31.7, 26.1, 23.1, CH: 149.6, 129.2,
121.0, 114.1, 111.2, C: 199.4, 159.5, 143.7, 139.2; IR 3442, 2960,
1734, 1206, 1099 cm-1; MS m/z (%) 230 (M, 8), 221 (7), 163 (15),
135 (95), 107 (100); HRMS calcd for C15H18O2 231.1385, obsd
231.1391.
that by adding the Lewis acid slowly at 0 °C, we could also
minimize decomposition.
The tricyclic ketone was approximately a 1:1 mixture of trans
and cis diastereomers 3 and 8. As had been described,2 the trans
diastereomer 3 could be separated by fractional crystallization.
Alternatively, the two diastereomers could be efficiently sepa-
rated by column chromatography. The isolated cis diastereomer
8 could then be epimerized to the 1:1 mixture by heating to
reflux with K2CO3 in THF. Using this approach, one could
prepare gram quantities of the crystalline trans ketone 3.
7-Methoxy-2,3,4,4a,10,10a-hexahydrophenanthren-1(9H)-
one 3 and 8. BF3 ·OEt2 (1.0 M solution in CH2Cl2, 2 mL, 2 mmol)
was added over 5 min to cyclohexenone 7a (230 mg, 1.0 mmol) in
5 mL of dry CH2Cl2 (0.20 M) at 0 °C. The solution was stirred at
room temperature for 3 h, quenched with water (5 mL), and then
partitioned between water and methylene chloride. The combined
organic extract was dried (MgSO4) and concentrated. The residue
was chromatographed using 80:20 PE/MTBE as an elution solvent
to give the phenanthrenone 3 (92 mg, 40% yield) as a solid and
phenanthrenone 8 (90 mg, 38% yield, 78% yield overall) as an oil.
The cis diastereomer 8 (85 mg, 0.37 mmol) was then heated to
reflux with a suspension of K2CO3 (690 mg, 5 mmol) in dry THF
(2 mL) overnight to epimerize the phenanthrenone to a 1:1 mixture
of diastereomers. For phenanthreone 3: mp ) 106-109 °C; TLC
Conclusion
We expect that the aldehyde to 2-alkyl cyclohexenone
conversion described here will make such cyclohexenones more
readily available as intermediates for target-directed synthesis.
We also envision that this facile new preparation of the ketone
3 will facilitate future steroid syntheses.
Experimental Section
1-(4-Cyclopropylbut-3-enyl)-3-methoxybenzene 6a. Potassium
tert-butoxide (1.0 M solution in THF, 50 mL, 50 mmol) was added
over 20 min to a suspension of (cyclopropylmethyl)triphe-
nylphosphonium bromide (10.0 g, 25 mmol) in 25 mL of dry THF
at 0 °C. The external cooling was removed, and the mixture was
stirred for 30 min. The aldehyde 4a (3.28 g, 20 mmol) was added,
and the solution was stirred at room temperature for 1 h. The
mixture was quenched with 1 N HCl (50 mL) and then partitioned
between water and EtOAc (3 × 100 mL). The combined organic
extract was dried (MgSO4) and concentrated. The residue was
chromatographed to give the alkenyl cyclopropane 6a (3.76 g, 93%
yield, 77:23 Z/E) as an oil. TLC Rf ) 0.62 (9:1 hexanes/EtOAc);
1H NMR (Z) δ 7.19 (t, J ) 7.8 Hz, 1H), 6.72-6.84 (m, 3H),
5.33-5.38 (m, 1H), 4.76 (t, J ) 10.8 Hz, 1H), 3.79 (s, 3H),
2.61-2.72 (m, 2H), 2.44-2.52 (m, 2H), 1.44-1.53 (m, 1H),
0.63-0.72 (m, 2H), 0.27-0.31 (m, 2H); 13C NMR (Z) δ CH3: 55.1
CH2: 36.2, 29.4, 6.8 CH: 134.5, 129.2, 127.0, 120.9, 114.2, 111.0,
1
Rf ) 0.45 (8:2 hexanes/EtOAc (double elution)); H NMR δ 7.23
(d, J ) 9 Hz, 1H), 6.75 (dd, J ) 9, 3 Hz, 1H), 6.66 (d, J ) 3 Hz,
1H), 3.78 (s, 3H), 2.84 (m, 2H), 2.73 (td, J ) 12, 3 Hz, 1H), 2.61
(m, 1H), 2.41-2.53 (m, 2H), 2.35 (td, J ) 12, 3 Hz, 1H), 2.18-2.30
(m, 2H), 1.86 (tdd, J ) 13, 5, 4 Hz, 1H), 1.61-1.77 (m, 2H); 13
C
NMR δ CH3: 55.2, CH2: 44.3, 30.5, 29.3, 26.3, 21.7, CH: 138.0,
113.8, 112.0, 52.7, 44.3, C: 212.0, 157.8, 138.0, 131.2, 126.9; IR
1720, 1615 cm-1; MS m/z (%) 230 (M, 100), 213 (55), 187 (30),
160 (25), 135 (43); HRMS calcd for C14H18O 230.1307, obsd.
230.1302. For phenanthrenone 8: TLC Rf ) 0.42 (8:2 hexanes/
EtOAc (double elution)); 1H NMR δ 7.05 (d, J ) 9 Hz, 1H), 6.75
(dd, J ) 9, 3 Hz, 1H), 6.62 (d, J ) 3 Hz, 1H), 3.78 (s, 3H), 2.84
(m, 2H), 2.73 (td, J ) 12, 3 Hz, 1H), 2.61 (m, 1H), 2.41-2.53 (m,
2H), 2.35 (td, J ) 12, 3 Hz, 1H), 2.18-2.30 (m, 2H), 1.86 (tdd, J
) 13, 5, 4 Hz, 1H), 1.61-1.77 (m, 2H); 13C NMR δ CH3: 55.6,
CH2: 38.8, 30.7, 29.0, 24.5, 22.6, CH: 129.7, 113.6, 112.7, 50.6,
1
9.5 C: 159.6, 143.8; H NMR (E) δ 7.19 (t, J ) 7.8 Hz, 1H)
6.72-6.84 (m, 3H), 5.52-5.57 (m, 1H), 5.01 (dd, J ) 15.2, 8.4
Hz, 1H), 3.79 (s, 3H), 2.61-2.72 (m, 2H), 2.25-2.32 (m, 2H),
1.30-1.36 (m, 1H), 0.63-0.72 (m, 2H), 0.27-0.31 (m, 2H); 13C
NMR (Z) δ CH3: 55.1, CH2: 36.1, 29.4, 6.4, CH: 134.4, 129.2,
127.2, 120.9, 114.2, 111.0, 9.5 C: 159.6, 143.8; IR 2935, 1598,
1487, 1455, 1258 cm-1; MS m/z (%) 202 (M, 30), 137 (65), 121
(100); HRMS calcd for C14H18O 202.1358, obsd 202.1360.
2-(3-Methoxyphenethyl)cyclohex-2-enone 7a. To the alkenyl
cyclopropane 6a (202 mg, 1.0 mmol) in 15 mL of 2-propanol (0.075
M) was added Fe(CO)5 (392 mg, 2.0 mmol). The reaction vessel
was purged with CO, a CO balloon was attached, and the mixture
was photolyzed for 8 h at room temperature in a Rayonet apparatus
(300 nm) set for autocooling. The reaction was halted every 2 h to
agitate the tube inside the larger tube, after which photolysis was
restarted. At the end of the irradiation, DBU (304 mg, 2.0 mmol)
was added, and the mixture was stirred at room temperature for
1 h under nitrogen. The mixture was diluted with 40 mL of EtOAc,
filtered through a small pad of packed silica gel, and then
40.4, C: 214.4, 157.8, 137.0, 131.2, 126.9; IR 1720, 1615 cm-1
;
MS m/z (%) 230 (M, 100), 213 (4), 187 (40), 159 (35), 147 (31),
121 (19); HRMS calcd for C14H18O 230.1307, obsd 230.1302.
Acknowledgment. This work is dedicated to E. E. Schweizer,
in recognition of his many contributions to organic chemistry.
WethankDuPontAgriculturalProductsandtheNIH(GM060287)
for financial support of this work.
Supporting Information Available: General experimental
procedures, experimental procedures for 2b-2f and 3b-3f,
details of the photochemical apparatus, and spectroscopic data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801767N
8032 J. Org. Chem. Vol. 73, No. 20, 2008