Cobalt(I)-mediated [2 + 2 + 2] cyclization of allenediynes toward a diastereoselective approach to 11-aryl steroid skeletons

Article abstract of DOI:10.1021/ol0485060

(Chemical Equation Presented) An 11-aryl steroid skeleton has been built in one step with a simultaneous introduction of the substituents at both C11 and C10 in 48% overall yield from a trans-allenediyne, whereas a formal Alder ene reaction leading to a b

Full text of DOI:10.1021/ol0485060

ORGANIC
LETTERS
2004
Vol. 6, No. 22
3937-3940
Cobalt(I)-Mediated [2
+ 2 + 2]
Cyclization of Allenediynes toward a
Diastereoselective Approach to 11-Aryl
Steroid Skeletons
Marc Petit, Corinne Aubert,* and Max Malacria*
Laboratoire de Chimie Organique associe´ au CNRS, UniVersite´ Pierre et Marie Curie
(Paris 6), Tour 44-54, 2e`me e´tage, Case 229, 4 Place Jussieu,
F-75252 Paris Cedex 05, France
aubert@ccr.jussieu.fr; malacria@ccr.jussieu.fr
Received July 29, 2004
ABSTRACT
An 11-aryl steroid skeleton has been built in one step with a simultaneous introduction of the substituents at both C11 and C10 in 48% overall
yield from a trans-allenediyne, whereas a formal Alder ene reaction leading to a bicyclic yne-trienic compound becomes the major process
from the cis-allenediyne.
In the past 20 years, the synthesis, biological evaluation, and
clinical applications of an entirely new class of antiproges-
tational steroids have emerged.1 One of the primary structural
features of such steroids is the presence of an 11â-aryl
moiety.2 Due to their industrially relevant pharmacological
properties, a large number of synthetic efforts aimed at
producing new compounds has been reported.3 However, the
synthesis of 11â-aryl steroids is still very much in need of
the development of new methods.
explored the feasibility of building 11-aryl steroid frame-
works by using an intramolecular cobalt(I)-mediated [2 + 2
+ 2] cyclization of allenediynes.
The use of transition metal-mediated cyclizations5,6 is
certainly not new in the synthesis of the steroid nucleus.
Indeed, the cobalt(I) synthesis of racemic estrone is the
paramount illustration of the potency of this method.7 In
(3) (a) Be´langer, A.; Philibert, D.; Teutsch, G. Steroids 1981, 37, 361-
382. (b) Ottow, E.; Neef, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
1989, 28, 773-776. (c) Hazra, B. G.; Basu, S.; Pore, V. S.; Joshi, P. L.;
Pal, D.; Chakrabarti, P. Steroids 2000, 65, 157-162. (d) Rao, P. N.; Acosta,
C. K.; Bahr, M. L.; Burdett, J. E.; Cessac, J. W.; Morrison, P. A.; Kim, H.
K. Steroids 2000, 65, 395-400. (e) Geisler, J.; Cleve, A.; Harre, M. Steroids
2000, 56, 6489-6492. (f) Lecomte, V.; Foy, N.; Le Bideau, F.; Stephan,
E.; Jaouen, G. Tetrahedron Lett. 2001, 42, 5409-5411. (g) Prat, D.;
Benedetti, F.; Nait Bouda, L.; Franc Girard, G. Tetrahedron Lett. 2004,
45, 765-768.
(4) (a) Aubert, C.; Buisine, O.; Petit, M.; Slowinski, F.; Malacria, M.
Pure Appl. Chem. 1999, 71, 1463-1470. (b) Petit, M.; Chouraqui, G.;
Phansavath, P.; Aubert, C.; Malacria, M. Org. Lett. 2002, 4, 1027-1029.
(c) A¨ıssa, C.; Delouvrie´, B.; Dhimane, A. L.; Fensterbank, L.; Malacria,
M. Pure Appl. Chem. 2000, 72, 1605-1613.
In the course of our ongoing program based on metal-
catalyzed or radical cyclization cascades directed toward the
elaboration of basic skeletons of natural products,4 we have
(1) (a) Baulieu, E. E. In Clinical Applications of Mifepristone (RU486)
and Other Antiprogestins: Assessing the Science and Recommending a
Research Agenda; Donaldson, M. S., Dorflinger, L., Brown, S. S., Benet,
L. Z., Eds.; National Academic Press: Washington, DC, 1993; pp 71-
119. (b) Weigel, N. L. Ibid; pp 120-138. (c) Rao, P. N.; Wang, Z.; Cessac,
J. W.; Rosenberg, R. S.; Jenkins, D. J. A.; Diamandis, E. P. Steroids 1998,
63, 523-530. (d) Fuhrmann, U.; Hess-Stumpp, H.; Cleve, A.; Neef, G.;
Schwede, W.; Hoffmann, J.; Fritzemeier, K.-H.; Chwalisz, K. J. Med. Chem.
2000, 43, 5010-5016 and references therein.
(2) (a) Teutsch, G.; Ojasoo, T.; Raynaud, J. P. J. Steroid Biochem. 1988,
31, 549-565. (b) Cleve, A.; Frizmeier, K. H.; Heinrich, N.; Klar, U.; Mu¨ller-
Fahrnow, A.; Neef, G.; Ottow, E.; Schwede, W. Tetrahedron 1996, 52,
1529-1532.
(5) Su¨nnemann, H. W.; de Meijere, A. Angew. Chem., Int. Ed. 2004,
43, 895-897 and references therein.
(6) Vollhardt, K. P. C. Pure Appl. Chem. 1985, 57, 1819-1826.
(7) Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1980, 102, 5253-
5261.
10.1021/ol0485060 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/01/2004

addition, intramolecular cyclizations of enediynes that allow
the simultaneous formation of either the BCD or ABCD ring
systems have been proposed.8 Although 11-trimethylsilyl-
substituted steroid frameworks have been described,9 only
one example of a low-yielding access to the 11-R-hetero-
substituted steroid skeleton has been reported. Our retrosyn-
thetic plan is depicted in Scheme 1.
cyclization. Exposure of 4b-e to a stoichiometric amount
of CpCo(CO)2 in refluxing xylenes under irradiation led to
the complexed tricyclic compounds 5b-e in 60-65% yield
as a nearly 1:1 mixture of endo/exo diastereomers (Scheme
2).11
Several features in these cyclizations are noteworthy: (i)
they are totally regioselective and lead only to the (6,6,6)-
tricyclic cycloadducts; (ii) the yields are higher compared
to the cyclization of 4a due to an increase in the stability of
the isolated complexes since they could be purified with
nondegassed solvents on silica gel; (iii) the endo/exo dia-
stereoselectivity is independent of the substitution on the
allene; (iv) the cyclization is compatible with an oxy-
functionality at C3.
Scheme 1
Since an aryl group was compatible with the conditions
of the cyclization, we undertook the synthesis of 3b (R )
H) starting from the commercially available 2-methyl-2-
cyclopenten-1-one. Conjugate addition of (trimethylsilyl)-
ethynyl copper(I) reagent in the presence of iodotrimethyl-
silane12 provided the corresponding silyl enol ether 6 in 95%
yield. Subsequent acid hydrolysis furnished the ketone 7 in
85% yield.
We envisioned reaching the tetracyclic complex 2 from
an intramolecular [2 + 2 + 2] cyclization of a judiciously
substituted allenediyne 3 starting from an already preexisting
D ring. This novel strategy would have allowed the creation
in one step of the ABC ring system and, most interestingly,
the simultaneous introduction of the substituents at both C11
and C10. Subsequent manipulation of 2 might lead to the
11â-aryl corticosteroids 1.
Different methods for effecting the alkylation of 6 were
quite unsuccessful; the use of MeLi or NaNH2 in THF
/HMPA resulted in decomposition of the starting material,
whereas the use of NaH led to a complex mixture of the
ketone 7 and mono- and trialkylated adducts albeit in low
yields (10-12%). The expected alkylated adduct was
obtained from 6 with a slightly modified Nicholas reaction13
(Scheme 3).
We previously reported that the cobalt-mediated [2 + 2
+ 2] cycloaddition of allenediynes bearing the allene moiety
at the terminal position is a completely regio-, chemo-,
diastereoselective high-yielding process and one that can be
performed with a total transfer of chirality.10 However, under
the same conditions, the allenediyne 4a, having a tetrasub-
stituted internal allene, led to the η4-complexed tricyclic
structures as a 7:3 diastereomeric mixture in moderate yield
(42%, see Scheme 2).10a,b
Indeed the following sequence (addition of 6 at room
temperature to a solution of (propargyl)dicobalt hexacarbonyl
cation, demetalation,14 and acetalization15 of the correspond-
ing adducts) furnished a 2:1 mixture of the ketals 10cis/trans.
The cis relationship between the alkynyl and ethynyl chain
for the major diastereomer was assigned by NOE NMR
experiments. Alkylation of the lithium acetylide of 10cis/
trans with 8-trimethylsilyl-oct-7-yn-2-one provided the cor-
responding alcohols 11cis/trans in 66 and 50% yield,
respectively. Almost all attempts at generating the allenes
Scheme 2a
(8) (a) Sternberg, E. D.; Vollhardt, K. P. C. J. Org. Chem. 1984, 49,
1574-1583. (b) Lecker, S. H.; Nguyen, N. H.; Vollhardt, K. P. C. J. Am.
Chem. Soc. 1986, 108, 856-858.
(9) Clinet, J. C.; Dun˜ach, E.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1983,
105, 6710-6712.
(10) (a) Aubert, C.; Llerena, D.; Malacria, M. Tetrahedron Lett. 1994,
35, 2341-2344. (b) Llerena, D.; Buisine, O.; Aubert, C.; Malacria, M.
Tetrahedron 1998, 54, 9373-9392. (c) Buisine, O.; Aubert, C.; Malacria,
M. Synthesis 2000, 985-989.
(11) endo/exo stereochemical assigments and ratio were determined by
1H NMR on the basis of the chemical shift and integration of the angular
CH3 (δCH3 endo ) 1.80 ppm; δCH3 exo ) 1.20 ppm), Cp- and dienic
protons, see ref 9b, and for parent compounds: Sternberg, E. D.; Vollhardt,
K. P. C. J. Org. Chem. 1984, 49, 1564-1573.
(12) Eriksson, M.; Iliefski, T.; Nilsson, M.; Olsson, T. J. Org. Chem.
1997, 62, 182-187.
a Conditions: CpCo(CO)2 (1 equiv), xylenes, hν, ∆.
(13) (a) Nicholas, K. M.; Mulvaney, M.; Bayer, M. J. Am. Chem. Soc.
1980, 102, 2508-2510. (b) Nicholas, K. M. Acc. Chem. Res. 1987, 20,
207-214.
Thus, before starting the synthesis of 2, we initially decided
to investigate the behavior of different allenediynes 4b-e
bearing an aryl group on the allene and to evaluate the
influence of such a substituent on the course of the
(14) Seyferth, D.; Wehman, A. T. J. Am. Chem. Soc. 1970, 92, 5520-
5522.
(15) The reaction proceeded in excellent yield only if the following
conditions are respected: 10
ethylene glycol.
-2
M in benzene, 5% PTSA, and 2 equiv of
3938
Org. Lett., Vol. 6, No. 22, 2004

Scheme 3a
Scheme 4a
a Conditions: (a) n-BuLi, MsCl, THF, -78 °C. (b) CuBr‚SMe2,
PhMgBr, LiBr, -50 °C. (c) cat PTSA, MeOH, rt. (d) Et3N, cat
4-DMAP, MsCl, CH2Cl2, -40 °C. (e) KHMDS, -15 °C, THF;
-50 °C, 16, THF. (f) K2CO3, MeOH.
a Conditions: (a) n-BuLi, Me3SiCtCH, TMSI, CuI, THF, -78°
to -30 °C, 95%. (b) MeOCH2-CtCH‚o2(CO)6, BF3‚OEt2,
CH2Cl2, rt, 95%. (c) CAN, acetone, rt, 78%. (d) 5 mol % PTSA,
ethylene glycol (2 equiv), benzene (0.01 M), 10cis/trans: 95%.
(e) n-BuLi, -78 °C, THF, CH3C(O)(CH2)4CtCSiMe3, 11cis: 60%;
11trans: 50%. (f) n-BuLi; MsCl, THF, -78 °C. (g) CuBr‚SMe2,
PhMgCl, LiBr, THF, -50 °C, 10%. (h) K2CO3, MeOH, rt, 13cis:
quant.
irradiation (300W visible lamp, 50% of its power). Surpris-
ingly, after 20 min, the allenediyne 13cis afforded the
bicyclic yne-trienic compound 17 in 66% yield,17 which
could result from a formal Alder ene reaction between the
triple bond attached to the five-membered ring and the double
bond of the allene bearing the methyl group (Scheme 5).
through a sequence of mesylation of the alcohols followed
by a SN2′ with copper(I) reagents were unsuccessful. Only
the addition of phenylcopper(I) reagent [generated from
PhMgCl and CuBr‚SMe2 in the presence of LiBr] on 11cis
furnished the corresponding allene in 10% yield, whereas
under the same conditions 11trans (or the mesylate) was
recovered. Subsequent quantitative deprotection of the triple
bonds afforded the allenediyne 13cis. Since the allene
formation occurred only for the cis adduct in poor yield, we
decided to study another synthetic path to the allene 13. As
alkylation of the ketone 7 with propargyl bromide furnished
the corresponding adduct in 60% yield, we checked the
feasibility of such an alkylation with the mesylate 16 derived
from the alcohol 15.
Scheme 5a
The starting material of this sequence was the alcohol 14,
which was generated from the condensation of the lithium
derivative of the tetrahydropyranyl propargyl ether with
8-trimethylsilyl-oct-7-yn-2-one. Smooth formation of the
allene and acid hydrolysis of the ether provided the alcohol
15 in 94% overall yield. The addition of the corresponding
mesylate 16 to the potassium enolate of 7 afforded, after
desilylation of the triple bonds, the allenediyne 13trans as a
5:4 mixture of two diastereomers in 50% yield over the three
steps (mesylation, alkylation, desilylation). The assigned
stereochemistry of the major 13trans, which was obtained
pure after flash chromatography and crystallization, was
unambiguously established by X-ray analysis.16 In addition,
NMR experiments showed also the trans relationship between
the two unsaturated chains for the minor 13trans diastere-
omer.
a Conditions: (a) CpCo(CO)2 (1 equiv), xylenes, hν, ∆.
Such an Alder ene reaction has already been observed by
our group with some allenediynes and allenynes18 and occurs
competitively with the [2 + 2 + 2] cyclization when the
latter is disfavored usually for geometric reasons. In the case
of 13cis, molecular models showed that the allene and the
triple bond are quite close to each other and allow the
complexation of these two unsaturations with the cobalt
moiety. After oxidative coupling, â-elimination followed by
reductive elimination furnish the cycloadduct 17.
The cobalt(I)-mediated cyclizations were carried out in the
presence of a stoichiometric amount of η5-cyclopentadienyl-
dicarbonyl cobalt(I) [CpCo(CO)2] in boiling xylenes under
On the contrary, when the major diastereomer 13trans was
exposed to CpCo(CO)2 in the same conditions as above, we
(16) Crystal structures have been deposited at the Cambridge Crystal-
lographic Data Centre with the following deposition numbers: 13trans:
CCDC 245955; 18: CCDC 245954. See Supporting Information for the
ORTEP representation of major 13 trans.
(17) 17 is obtained as a mixture of isomers and is quite unstable.
(18) (a) Llerena, D.; Aubert, C.; Malacria, M. Tetrahedron Lett. 1996,
37, 7027-7030. (b) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002,
102, 813-834.
Org. Lett., Vol. 6, No. 22, 2004
3939

were very pleased to observe the formation of the η4-cobalt-
complexed tetracyclic compound 18 in 60% yield as a single
diastereomer that crystallizes from a mixture of pentane/CH2-
Cl2 (Scheme 6).
Scheme 6a
Figure 1.
a Conditions: (a) CpCo(CO)2 (1 equiv), xylenes, hν, ∆. (b) SiO2,
13trans. This new synthetic route highlights the high
performance of the cobalt(I)-mediated cycloadditions in the
synthesis of complex polycyclic molecules. Further manipu-
lations either of the complex 18 or the free ligand 19,
especially the reduction of the double-bond ∆9-11, are
currently being investigated. As we have already observed
both the compatibility of an oxy-functionality at C3 and the
transfer of axial chirality to a centered one,10c the access to
compound 2 in an enantiomerically pure form should be
straightforward. On the contrary, we have observed another
behavior for the allenediyne 13cis. Probably because of
geometrical restrictions, a formal Alder ene reaction that is
competitive to the [2 + 2 + 2] cyclization becomes the major
process and leads to a bicyclic yne-trienic compound.
CH2Cl2, rt.
The free ligand 19 can be easily obtained in 90% yield
by a simple treatment of the complex with silica gel in
dichloromethane. Therefore, the cyclization/decomplexation
sequence can also be carried out without purifying the
complex 18 and allowed the formation of the 11-aryl steroid
framework in 48% overall yield.
On the basis of the 1H NMR spectrum, the cis relationship
between the cobalt moiety and the A/B angular methyl was
established (δ ) 1.75 ppm). The assigned structure was
secured by a single-crystal X-ray analysis.16 The ORTEP
representation (Figure 1) showed, in addition to the endo
stereochemistry of the complex, the trans relationship
between the two angular methyl groups and the nonconju-
gation of the phenyl group with the ∆9-11 double bond
Acknowledgment. M.M. is a member of IUF. Financial
support was provided by CNRS, MRES, and IUF. M.P.
thanks Aventis-CNRS for his fellowship.
In summary, depending on the stereochemical relationship
(cis or trans) between the ethynyl group and the allene, we
have noticed two different trends occurring in the cobalt(I)-
mediated cyclization of allenediynes that incorporate a five-
membered ring. Indeed, we have been able to build the 11-
aryl steroid skeleton in 48% yield from the allenediyne
Supporting Information Available: Experimental pro-
cedures and characterization data of all the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0485060
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Org. Lett., Vol. 6, No. 22, 2004