What can a metal catalyst do with allenes? One-step formation of steroid scaffolds from readily available starting materials

Article abstract of DOI:10.1002/anie.200501350

(Chemical Equation Presented) The beauty and power of transition-metal- catalyzed reactions has been demonstrated by the one-step synthesis of steroid scaffolds from readily available allenes. The best results (57-73% yield) were obtained using trans-[RhC

Full text of DOI:10.1002/anie.200501350

Angewandte
Chemie
Homogeneous Catalysis
DOI: 10.1002/anie.200501350
What Can a Metal Catalyst Do with Allenes?
One-Step Formation of Steroid Scaffolds from
Readily Available Starting Materials**
Shengming Ma,* Ping Lu, Lianghua Lu, Hairong Hou,
Jiemin Wei, Qiwen He, Zhenhua Gu, Xuefeng Jiang,
and Xing Jin
The diversity of available transition metals and organic
ligands for the formation of organometallic catalysts offers
the possibility of excellent selectivity and tunability in
homogeneous transformations.[1–4] Alkynes and alkenes are
two classes of well-studied compounds in organic chemistry
that have formed the basis of the petroleum industry and
modern organic chemistry.[5] It should be noted that 1–1.5%
of allene exists in propylene produced by the cracking of
hydrocarbons in petroleum.[6] The large amount of propylene
consumed means that the production of propadiene in
considerable quantities is thus possible. Although vanꢀt Hoff
predicted the correct structures of allenes and higher
cumulenes as early as 1874,[7] for a long period of time allenes
were considered to be highly unstable, which retarded the
demonstration of their synthetic potential. However, the
situation has changed dramatically during the last 8 to
10 years, and many new reactions have been developed
based on the chemistry of allenes.[8–13] Steroids are charac-
terized by a carbon skeleton with four fused rings, and their
presence in plants and animals illustrates their immense
biological importance.[14–17] Steroids are used for the treat-
ment of cancer, arthritis, allergies, and in birth control. Thus,
[*] Prof. S. Ma, P. Lu, L. Lu, H. Hou, J. Wei, Q. He, Z. Gu, X. Jiang, X. Jin
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (P.R. China)
Fax: (+86)21-6416-7510
E-mail: masm@mail.sioc.ac.cn
[**] Financial support from the National Natural Science Foundation of
China and the Major State Basic Research Development Program
(grant no. G2000077500) is greatly appreciated.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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efficient catalytic approaches to new steroid derivatives are
Furthermore, a clear relationship between yields and
concentrations was observed for this reaction (Table 2). It
should be noted that the yield was greatly improved when a
lower substrate concentration was used. We found that the
still of current interest.[18–25] Recently, during our study of
allene chemistry,[26] we identified a very efficient one-step
transition-metal-catalyzed transformation of simple 1,5-bisal-
lenes to steroid skeletons.
We prepared 5,5-bis(methoxycarbonyl)-1,2,7,8-nonate-
traene (1a)[27] from the bisallenylation of diethyl malonate
with 2,3-butadienyl bromide.[28] The reaction of 1a in the
presence of a catalyst of 5 mol% [RhCl(PPh3)3] and 10 mol%
AgSbF6 afforded a product with a complicated H NMR
spectrum (entry 1, Table 1). The structure of this product was
unambiguously established by X-ray diffraction studies to be
the 18,19-norsteroid derivative 2a (Figure 1).[30]
Table 2: Effect of the concentration of 1a in toluene on the trans-
[RhCl(CO)(PPh3)2]-catalyzed dimeric cycloisomerization of 1a.[a]
[29]
1
Entry
Concentration of 1a [m]
Yield of 2a [%]
1
2
3
4
5
0.25
42
55
69
73
72
Table 1: Dimeric cyclization of 1a in the presence of different catalysts.
0.125
0.0625
0.0417
0.0313
[a] The reaction was carried out using 1a (0.25 mmol) and trans-
[RhCl(CO)(PPh3)2] (5 mol%) in toluene under reflux.
Entry
Catalyst
t [h]
Yield of 2a [%]
reaction of 1a at a concentration of 0.0417m in toluene in the
presence of 5 mol% trans-[RhCl(CO)(PPh3)2] as the catalyst
under reflux was very clean and afforded 2a with a
cis conjunction at the C/D rings in 73% yield as the only
stereoisomer. It should be noted that no intermediate product
was observed during the reaction process and no other
stereoisomers were detected in the crude product by 1H NMR
spectroscopic analysis.
The effect of the solvent on this reaction are summarized
in Table 3. Among the solvents tested, the best results were
obtained in toluene (entry 1, Table 3). Furthermore, the yield
and reaction rate both dropped when the reaction was carried
out at a lower temperature (compare entries 2 and 1, Table 3).
1
2
[RhCl(PPh3)3]+AgSbF4[a]
[{RhCl(cod)}2]+P(OPh)3[b]
[RhH(CO)(PPh3)2]
3
12.5
2.5
12
2
2
12
4
10
15
31
38
38
42
–
3[c]
4
[d]
[{RhCl(cod)}2] +PPh3
5
6
7
8
[RhCl(PPh3)3]
trans-[RhCl(CO)(PPh3)2]
[Rh(cod)2]BF4
PtCl2
–
[a] 10 mol% AgSbF4 was added. [b] 10 mol% P(OPh)3 was added. [c] The
reaction was conducted at 0.125m 1a in toluene. [d] 10 mol% PPh3 was
added.
Table 3: Effect of the solvent on the trans-[RhCl(CO)(PPh3)2]-catalyzed
dimeric cycloisomerization of 1a.[a]
Entry
Solvent
t [h]
Yield of 2a [%][b]
1
toluene
toluene
CH3CN
THF
2
57
9.6
6
2.5
2.5
7
73
43
17
36
28
41
54
41
Figure 1. ORTEP representation of 2a.
2[c]
3
4
We screened a variety of catalysts using compound 1a as
the model, and some typical results are summarized in
Table 1. The yields were improved when we used [RhH(CO)-
(PPh3)2], [RhCl(cod)]2 + PPh3 (cod = cycloocta-1,5-diene),
and [RhCl(PPh3)3] without an Ag+ salt (entries 3–5,
Table 1). Further research showed that trans-[RhCl(CO)-
(PPh3)2] was the best catalyst (entry 6, Table 1) while neither
[Rh(cod)2]BF4 nor PtCl2 showed any activity in this trans-
formation (entries 7 and 8, Table 1).
5[d]
6
DMF
dioxane
benzene
xylene
7
8
2
[a] The reaction was carried out using 1a (0.0417m, 0.25 mmol) and
trans-[RhCl(CO)(PPh3)2] (5 mol%) in the specified solvent under reflux.
[b] Yields determined by NMR spectroscopy by using 1,3,5-trimethyl
benzene as the internal standard. [c] The reaction was conducted at
608C. [d] The reaction was conducted at 1108C.
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The reaction was also slow and the yield was quite low when
CH3CN was used as the solvent (entry 3, Table 3), while the
use of benzene, xylene, and dioxane led to the formation of 2a
in yields of 41–54% (entries 6–8, Table 3). It should be noted
1
that the H NMR spectrum of the crude products indicated
that only one stereoisomer was observed in all these cases.
With the optimized conditions in hand, we studied the
scope of this reaction, and found that it is general for
differently substituted bisallenes. 18,19-Norsteroid derivative
2c was readily prepared (1.086 g, 72%) from 1.5 g of bisallene
1c, which was prepared from CH2(SO2Ph)2, 2,3-butandienyl
bromide,[28] and NaH in quantitative yield. The nitrogen
analogue 2e can be prepared from the bis(2,3-allenyl)amine
1e. The dimeric cyclization of 1d resulted in a mixture of
2,16 epimers 2d in 67% yield (Scheme 1).
Scheme 2. A possible mechanism for the transition-metal-catalyzed
transformation of simple 1,5-bisallenes to steroid skeletons. (1) Cyclo-
metalation, (2) carbometalation, (3) reductive elimination, (4) Diels–
Alder reaction.
route to steroids with new structural and steric features. Thus,
this route may open up a new direction in steroid-related
science.
Scheme 1. Dimeric cyclization of bisallenes 1 with a trans-[RhCl(CO)-
(PPh3)2] catalyst. Ts=toluene-4-sulfonyl.
Experimental Section
Typical procedure: A solution of 1c (1.509 g, 3.76 mmol) and trans-
[RhCl(CO)(PPh3)2] (130 mg, 0.19 mmol, 5 mol%) in dry toluene
(90 mL) was heated at reflux under Ar for 3 h. After the reaction was
complete, as monitored by TLC (eluent: CH2Cl2/MeOH 40:1),
removal of the solvent by rotary evaporation and flash chromatog-
raphy of the product on silica gel (eluent: CH2Cl2/MeOH 100:1)
afforded 1.086 g (72%) of 2c. M.p. 143–1458C (dichloromethane/
A possible mechanism was postulated on the basis of the
above results (Scheme 2). The reaction may proceed through
the cyclometalation[31] of 1a to afford 4a or 7a, which may
then undergo carbometalation with one of the two allene
moieties in 1a to afford 5a or 8a, respectively. Subsequent
reductive elimination would afford 6a or 9a, which could then
undergo a Diels–Alder reaction to form the 18,19-norsteroid
2a (Scheme 2). The results obtained illustrate that the
intramolecular Diels–Alder reaction between an allene
moiety and an alkene partner can proceed either in the
presence[31a] or absence[32] of a metal catalyst. The reaction
was conducted at a low temperature in an attempt to capture
any possible intermediate(s), but the reaction was very fast
and no intermediate product was detected.
In conclusion, we have reported an efficient route to
18,19-norsteroid derivatives from bisallenes by using a
catalytic amount of trans-[RhCl(CO)(PPh3)2]. Although
some steroids have been prepared from acyclic precursors
by long synthetic routes,[18–25] the availability of the starting
materials and the catalyst as well as the simplicity of the
current procedure makes this methodology a very efficient
1
diethyl ether); H NMR (300 MHz, CDCl3): d = 8.18–7.86 (m, 8H),
7.72–7.35 (m, 12H), 4.91 (brs, 1H), 4.75 (s, 1H), 4.71 (s, 1H), 3.02–
2.50 (m, 9H), 2.42–2.20 (m, 3H), 2.15–1.90 (m, 4H), 1.70–1.62 ppm
(m, 1H); 13C NMR (75.4 MHz, CDCl3): d = 26.1, 28.5, 30.2, 30.5, 31.9,
34.3, 36.1, 37.5, 46.4, 47.4, 87.9, 93.5, 110.7, 114.1, 126.9, 128.6(”2),
128.7, 128.8, 131.0, 131.2, 131.4(”3), 131.5, 134.3, 134.5, 134.6, 135.8,
136.0, 136.4, 136.7, 139.8, 142.3 ppm; IR (KBr): n˜ = 3066, 2906, 1447,
1328, 1309, 1144 cmÀ1; MALDI: m/z: 839 [M+K]+, 823 [M++Na];
HRMS calcd for C42H40O8S4Na [M+Na]+: 823.1498; found: 823.1497.
Elemental analysis calcd for C42H40O8S4: C 62.98, H 5.03; found: C
62.96, H 5.47%.
Received: April 19, 2005
Published online: July 20, 2005
Keywords: allenes · cyclization · homogeneous catalysis ·
.
rhodium · steroids
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5277

Communications
Chem. 2000, 112, 2382; Angew. Chem. Int. Ed. 2000, 39, 2285;
d) C. H. Oh, H. S. Yoo, S. H. Jung, Chem. Lett. 2001, 1288; e) R.
Grigg, N. Kongathip, B. Kongathip, S. Luangkamin, H. A.
Dondas, Tetrahedron 2001, 57, 9187; f) D. Hideura, H. Urabe,
F. Sato, Chem. Commun. 1998, 271; g) M. Arisawa, T. Sugihara,
M. Yamaguchi, Chem. Commun. 1998, 2615; h) M. Yoshida, T.
Gotou, M. Ihara, Tetrahedron Lett. 2003, 44, 7151; i) M.
Takimoto, M. Kawamura, M. Mori, Org. Lett. 2003, 5, 2599.
[28] 2,3-Butadienyl bromide was prepared from the bromination of
2,3-butadienol, see: J. Pornet, M. L. B. Randrianoelina, J.
Organomet. Chem. 1979, 174, 1.
[1] Applied Homogeneous Catalysis with Organometallic Com-
pounds (Ed.: B. Cornils, W. A. Herrmann), Wiley-VCH, Wein-
heim, 2002.
[2] A. Mortreux, F. Petit, Industrial Applications of Homogeneus
Catalysis, D. Reidel, Dordrecht, 1988.
[3] J. Tsuji, Transition Metal Reagents and Catalysts, Wiley, Ciches-
ter, 2000.
[4] S. Bhaduri, D. Mukesh, Homogeneous Catalysis, Wiley-Inter-
science, New York, 2000.
[5] M. M. Green, H. A. Wittcoff, Organic Chemistry Principles and
Industrial Practice, Wiley-VCH, Weinheim, 2003.
[6] For a review, see: K. Griesbaum, Angew. Chem. 1966, 78, 953;
Angew. Chem. Int. Ed. Engl. 1966, 5, 933.
[29] a) P. A. Evans, J. E. Robinson, E. W. Baum, A. N. Fazal, J. Am.
Chem. Soc. 2002, 124, 8782; b) S. R. Gilbertson, B. DeBoef, J.
Am. Chem. Soc. 2002, 124, 8784.
[30] Crystal data for compound 2a: C26H32O8, Mr = 472.52, ortho-
[7] For a review, see: A. Hoffmann-Röder, N. Krause, Angew.
Chem. 2004, 116, 1216; Angew. Chem. Int. Ed. 2004, 43, 1196.
[8] S. Patai, The Chemistry of Ketenes, Allenes, and Related
Compounds, Part 1, Wiley, New York, 1980.
[9] S. R. Landor, The Chemistry of Allenes, Vols. 1–3, Academic
Press, New York, 1982.
[10] H. F. Schuster, G. M. Coppola, Allenes in Organic Synthesis,
Wiley, New York, 1984.
[11] S. Ma in Handbook of Organopalladium Chemistry for Organic
Synthesis (Eds.: E. Negishi, A. de Meijer), Wiley, New York,
2002, p. 1491.
rhombic, space group P2(1)2(1)2(1), 293 K, MoKa
, a =
8.6778(12), b = 9.7305(13), c = 28.671(4) Š, V= 2421.0(6) Š3,
Z = 4, final R indices [I > 2s(I)], R1 0.0507, wR2 = 0.1035, no.
of reflection measured/unique 14786/5647 (Rint = 0.1486). No.
observations (I > 2.00s(I)) 4180, no. variable 190, GOF = 0.898.
Absolute structure parameter 0.1(10). CCDC-262016 contains
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[31] a) P. A. Wender, T. E. Jenkins, S. Suzuki, J. Am. Chem. Soc. 1995,
117, 1843; b) B. M. Trost, J. M. Tour, J. Am. Chem. Soc. 1988,
110, 5231; c) P. A. Wender, F. Glorius, C. O. Husfeld, E.
Langkopf, J. A. Love, J. Am. Chem. Soc. 1999, 121, 5348;
d) K. M. Brummond, H. Chen, P. Sill, L. You, J. Am. Chem. Soc.
2002, 124, 15186; e) T. Shibata, Y. Takesue, S. Kadowaki, K.
Takagi, Synlett 2003, 268; f) T. Makino, K. Itoh, Tetrahedron Lett.
2003, 44, 6335; g) T. Makino, K. Itoh, J. Org. Chem. 2004, 69, 395.
[32] a) M. E. Jung, N. Nishimura, J. Am. Chem. Soc. 1999, 121, 3529;
b) C. Spino, S. FrØchette, Tetrahedron Lett. 2000, 41, 8033;
c) M. E. Jung, N. Nishimura, Org. Lett. 2001, 3, 2113; d) D.
Regµs, J. M. Ruiz, M. M. Afonso, A. Galindo, J. A. Palenzuela,
Tetrahedron Lett. 2003, 44, 8471; e) J. D. Winkler, K. J. Quinn,
C. H. MacKinnon, S. D. Hiscock, E. C. McLaughlin, Org. Lett.
2003, 5, 1805.
[12] Modern Allene Chemistry (Eds.: N. Krause, A. S. K. Hashmi),
Wiley-VCH, Weinheim, 2004.
[13] For reviews, see: a) Y. Yamamoto, U. Radhakrishnan, Chem.
Soc. Rev. 1999, 28, 199; b) R. C. Larock, J. Organomet. Chem.
1999, 576, 111; c) R. Grigg, V. Sridharan, J. Organomet. Chem.
1999, 576, 65; d) R. Zimmer, C. U. Dinesh, E. Nandanan, F. A.
Khan, Chem. Rev. 2000, 100, 3067; e) A. S. K. Hashmi, Angew.
Chem. 2000, 112, 3737; Angew. Chem. Int. Ed. 2000, 39, 3590;
f) H. U. Reissig, S. Hormuth, W. Schade, M. O. Amombo, T.
Watanabe, R. Pulz, A. Hausherr, R. Zimmer, J. Heterocycl.
Chem. 2000, 37, 597; g) S. Ma, L. Li, Synlett 2001, 1206; h) H. U.
Reissig, W. Schade, M. O. Amombo, R. Pulz, A. Hausherr, Pure
Appl. Chem. 2002, 74, 175.
[14] K. Nakanishi in Natural Products Chemistry, Vol. 1 (Eds.: K.
Nakanishi, T. Goto, S. Ito, S. Nastori, S. Nozoe), Kodansha,
Tokyo, 1974, chap. 6.
[15] J. B. Dence, Steroids and Peptides, Wiley, New York, 1980.
[16] J. R. Sabine, Cholesterol, Marcel Dekker, New York, 1977.
[17] Steroid-biochemistry (Ed.: R. Hobkirk), CRC, Boca Raton, FL,
1979.
[18] A. A. Akhrem, Y. A. Tltov, Total Steroid Synthesis, Plenum, New
York, 1970.
[19] W. S. Johnson, M. F. Semmelhack, M. U. S. Sultanbawa, L. A.
Dolak, J. Am. Chem. Soc. 1968, 90, 2994.
[20] R. L. Funk, K. P. C. Vollhardt, J. Am. Chem. Soc. 1977, 99, 5483.
[21] E. E. van Tamelen, J. R. Hwu, J. Am. Chem. Soc. 1983, 105, 2490.
[22] Y. Zhang, G. Wu, G. Angel, E. Negishi, J. Am. Chem. Soc. 1990,
112, 8590.
[23] E. J. Corey, H. B. Wood, J. Am. Chem. Soc. 1996, 118, 11982.
[24] a) L. F. Tietze, T. Nöbel, M. Spescha, J. Am. Chem. Soc. 1998,
120, 8971; b) L. F. Tietze, G. Schneider, J. Wölfling, A. Fecher, T.
Nöbel, S. Petersen, I. Schuberth, C. Wulff, Chem. Eur. J. 2000, 6,
3755; c) L. F. Tietze, J. Matthias, C. Vock, J. Organomet. Chem.
2003, 687, 346.
[25] R. Thoma, T. Schulz-Gasch, B. DꢀArcy, J. Benz, J. Aebi, H.
Dehmlow, M. Hennig, M. Stihle, A. Ruf, Nature 2004, 432, 118.
[26] S. Ma, Acc. Chem. Res. 2003, 36, 701.
[27] For some typical reports on the reactions between two allenes,
see: a) A. S. K. Hashmi, Angew. Chem. 1995, 107, 1749; Angew.
Chem. Int. Ed. Engl. 1995, 34, 1581; b) A. S. K. Hashmi, T. L.
Ruppert, T. Knöfel, J. W. Bats, J. Org. Chem. 1997, 62, 7295;
c) A. S. K. Hashmi, L. Schwarz, J.-H. Choi, T. M. Frost, Angew.
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