Synthesis of terpene and steroid dimers and trimers having cyclobutadienyl-Co and aromatic tethers

Article abstract of DOI:10.1021/jo0703698

(Chemical Equation Presented) The reaction of natural product derived propargylic alcohols with CpCo(CO)₂ produces three new types of natural product hybrids having two or three terpene or steroid fragments. The tether joining the natural product subunits is built during the reaction. Type 1 hybrids have two terpene or steroid moieties joined by a CpCo-cyclobutadiene tether, with the two units disposed in a 1,2-arrangement (9, 14, 22). Type 2 hybrids have a Co-cyclopentadienone tether (10). Type 3 has three units of terpene or steroid joined to a benzene ring (11, 12, 15). An unusual Co-mediated β-carbon elimination pathway of propargylic alcohols leading to ketones (an unknown process in this chemistry) has been observed.

Full text of DOI:10.1021/jo0703698

Synthesis of Terpene and Steroid Dimers and Trimers Having
Cyclobutadienyl-Co and Aromatic Tethers
Miguel A. Sierra* and M. Rosario Torres†
Departamento de Qu´ımica Orga´nica and Laboratorio de Difraccio´n de Rayos X, Facultad de Qu´ımica,
UniVersidad Complutense, 28040-Madrid, Spain
Mar´ıa C. de la Torre* and Elsa AÄ lvaro
Instituto de Qu´ımica Orga´nica, Consejo Superior de InVestigaciones Cient´ıficas (CSIC),
Juan de la CierVa 3, 28006-Madrid, Spain
iqot310@iqog.csic.es
ReceiVed February 22, 2007
The reaction of natural product derived propargylic alcohols with CpCo(CO)2 produces three new types
of natural product hybrids having two or three terpene or steroid fragments. The tether joining the natural
product subunits is built during the reaction. Type 1 hybrids have two terpene or steroid moieties joined
by a CpCo-cyclobutadiene tether, with the two units disposed in a 1,2-arrangement (9, 14, 22). Type 2
hybrids have a Co-cyclopentadienone tether (10). Type 3 has three units of terpene or steroid joined to
a benzene ring (11, 12, 15). An unusual Co-mediated â-carbon elimination pathway of propargylic alcohols
leading to ketones (an unknown process in this chemistry) has been observed.
Introduction
several ferrocenyl-â-lactams 14 and, among other derivatives,
the dicobalthexacarbonyl complexes from alkaloid- and steroid-
terpene hybrids 2 and 3 as bio-organometallic natural product
derivatives.5 An alternate approach to the building of bio-
organometallic natural product hybrids is to join two moieties
by an organometallic tether. To the best of our knowledge, the
single example of this approach is the stepwise preparation of
dimeric terpene 4 recently reported by us.6
The preparation of bio-organometallic compounds1 and
natural product hybrids2 share the common goal of preparing
new molecular entities having structural diversity. The merge
of both approaches open doors to prepare bio-organometallic
natural product hybrids within the idea of diversity oriented
synthesis.3 In this field we have reported the preparation of
† Laboratorio de Difraccio´n de Rayos X. To whom inquires regarding the
determination of the structure of compounds 9 and 10 should be addressed.
(1) For an overview of this field, see: (a) Fish, R. H.; Jaouen, G.
Organometallics 2003, 22, 36. (b) Dagani, R. Chem. Eng. News 2002, 80,
23. (c) Special issue on bioorganometallic chemistry: J. Organomet. Chem.
1999, 589, Issue 1.
(2) (a) Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Angew. Chem., Int.
Ed. 2003, 42, 3996. (b) Mehta, G.; Singh, V. Chem. Soc. ReV. 2002, 31,
324.
(3) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Schreiber, S. L.
Chem. Eng. News 2003, 81, 51. (c) Burke, M. D.; Schreiber, S. L. Angew.
Chem., Int. Ed. 2004, 43, 46.
(4) Sierra, M. A.; Manchen˜o, M. J.; Vicente, R.; Go´mez-Gallego, M. J.
Org. Chem. 2001, 66, 8920.
(5) AÄ lvaro, E.; de la Torre, M. C.; Sierra, M. A. Chem.sEur. J. 2006,
12, 6403.
(6) de la Torre, M. C.; Deometrio, A. M.; AÄ lvaro, E.; Garc´ıa, I.; Sierra,
A. M. Org. Lett. 2006, 8, 593.
10.1021/jo0703698 CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/04/2007
J. Org. Chem. 2007, 72, 4213-4219
4213

Sierra et al.
SCHEME 2
TABLE 1. Reaction of 7 with CpCo(CO)2
yielda (%)
alkyne/Co
solvent
entry
1
equivalents
(T)
9
10
11+12
1:1
toluene
(120 °C)
xylenes
(140 °C)
xylenes
(140 °C)
decalin
21
5
30
2
3
4
2:1
39
3
3
1
4
28
18
35
The metal catalyzed [2+2+2] cycloaddition of alkynes
(Reppe’s reaction)7 offers a paramount opportunity to create
either hybrids incorporating three units of natural product across
an aromatic nucleus or two units across a cyclobutadieneCoCp
spacer, depending on the reaction conditions. This approach is
different from the one reported before by us because now the
organometallic tether is built during the joining of the fragments.
The CpCoL2-catalyzed [2+2+2] cycloaddition of alkynes has
been used to synthesize different natural products like, for
example, morphinanes,8 sesqui- and diterpenes,9 and strych-
nine.10 Furthermore, the use of nitriles as components of the
cycloadditions allowed the access to different pyridine contain-
ing heterocyclic natural products like LSD and lysergenes.11
However, the synthesis of natural product trimers tethered to
an aromatic nucleus is restricted to the synthesis of sugar
derivatives 5 by cyclotrimerization of alkynyl sugars 6 (Scheme
1).12
1:0.05
2:1
38
(160 °C)
a Isolated yield of chromatographically pure product.
9-12 was obtained (Scheme 2). Compounds 9 (21%) and 10
(5%) retain the Co moiety, while compounds 11 and 12 (30%
combined yield) were aromatic compounds derived from the
cyclotrimerization of alcohol 7. The structures of complexes 9
and 10 were unambiguously determined by X-ray diffraction
analysis as the CpCo-cyclobutadiene complex 9 and the
CpCo-cyclopentadienone complex 10, respectively (Figure 1).
The 1H and 13C NMR data of 10 showed signals characteristic
to the terpene fragment, together with new signals attributable
to the CpCo-cyclobutadiene moiety, instead of the signals
corresponding to the triple bond of alcohol 7. Extensive 2D-
NMR experiments allowed the assignment of signals at δC 85.2,
89.2, 56.3, and 60.0 to carbons C-1 to C-4 of the cyclobutadiene
fragment and two singlets, one proton each, at δH 3.67 and 4.02
to the cyclobutadiene protons H-3 and H-4, respectively.
Increasing the alkyne/CpCo(CO)2 ratio to 2:1 and the reaction
temperature (boiling xylenes or decalin, Table 1, entries 2 and
4, respectively) resulted in an increased yield of cyclobutadiene
complex 9, while the use of catalytic amounts of CoCp(CO)2
makes trimers 11 and 12 the main reaction products (Table 1,
entry 3).14
SCHEME 1
Mestranol 13 was used next as the substrate for these
reactions. Now a mixture of three compounds was obtained.
CpCo-cyclobutadiene complex 14 was identified as the minor
product (8-13%), while the 1,2,5-trisubstituted aromatic com-
pound 15 was the main product (30-44%) in all the conditions
tested (Scheme 3), even in the presence of high excesses (up to
10 equiv) of CpCo(CO)2 for each equivalent of mestranol (see
Table 2). Finally, methoxyestrone 16 was identified in all cases
in variable yields (7-12%).
Reported herein is the use of terpene- and steroid-derived
alkynes to prepare three novel classes of sophisticated terpene
or steroid dimers and trimers. Furthermore, the unusual frag-
mentation of a Co-coordinated propargyl alcohol complex to
yield a ketone has been discovered during these investigations.
Results and Discussion
Propargylic alcohol 7 was prepared by the reaction of (1R)-
(+)-camphor 8, following the procedure reported by Palomo et
al.13 Alcohol 7 was reacted with a stoichiometric amount of
CpCo(CO)2 in boiling toluene. A mixture of four compounds
The structure of the Co complex 14 was established by a
comparison of its spectroscopic data with those of CpCo-
cyclobutadiene 9, whose structure has been unambiguously
1
determined by X-ray diffraction analysis. H and 13C NMR
4214 J. Org. Chem., Vol. 72, No. 11, 2007

Synthesis of Terpene and Steroid Dimers and Trimers
FIGURE 1. ORTEP diagrams of the crystal structures of compounds 9 and 10.
SCHEME 3
signals, one methyl C-18 each (δH 1.03, 1.06, and 1.07). The
nonequivalence of the signals of the benzene ring and of the
steroidic fragment is consistent with a 1,2,5-substitution pattern
in the aromatic ring.15
Compounds 14 and 15 should arise from a common cobalt-
acyclopentadiene 17 having the bulky steroid groups farther
away. Because neither the 1,3-disubstituted cyclobutadiene
complex nor the 1,3,5-substituted benzene derivatives were
obtained, the formation of the alternate cobaltacyclopentadiene
18 should be strongly disfavored due in principle to steric
reasons (see below; Scheme 4).16
SCHEME 4
TABLE 2. Reaction of Mestranol 13 with CpCo(CO)2
yielda (%)
alkyne/Co
equivalents
solvent
(T)
time
(h)
entry
1
14
15
16
2:1
2:1
1:3
1:10
decalin
(160 °C)
decalin
(160 °C)
xylenes
(140 °C)
xylenes
(140 °C)
2
12
7
10
32
32
30
44
7
2
3
4
8
5
8
8
2.5
13
12
a Isolated yield of chromatographically pure product.
Results above pointed to steric hindrance as the controlling
factor for the regioselectivity of these processes. However, the
spectra of 14 showed signals attributable to the CpCo-1,2-
disubstituted cyclobutadiene moiety (δH 3.98 and 3.95, δC 59.3
and 57.1, one CH each, and 88.8 and 88.4, one C each). The
regiochemistry of 14 was confirmed by 2D-NMR spectroscopy.
The g-HMBC spectra showed cross-peaks between each cy-
clobutadiene hydrogen at 3.95 and 3.98 ppm, with just one single
C-17 steroid quaternary carbon at 81.8 and 82.8 ppm, respec-
tively. Should the obtained compound be the 1,3-isomer, the
aforementioned correlation would occur between each cyclo-
butadiene hydrogen with both C-17 steroid carbons.
(7) (a) Reppe, W.; Schlichting, O.; Klager, K.; Toepel, T. Liebigs Ann.
Chem. 1948, 560, 1. (b) Reppe, W.; Schwechendiek, W. J. Liebigs Ann.
Chem. 1948, 560, 104. For reviews, see: (c) Saito, S.; Yamamoto, Y. Chem.
ReV. 2000, 100, 2901. (d) Fru¨hauf, H.-W. Chem. ReV. 1997, 97, 523. (e)
Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96,
635. (f) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 46. (g)
Boese, R.; Sickle, A. P. V.; Vollhardt, K. P. C. Synthesis 1994, 1374. (h)
Schore, N. E. Chem. ReV. 1988, 88, 1081. (i) Vollhardt, K. P. C. Angew.
Chem. 1984, 96, 525; Angew. Chem., Int. Ed. Engl. 1984, 23, 539. (j)
Grotjahn, D. B. In ComprehensiVe Organometallic Chemistry II; Abel, E.
W., Stone, F. G. A., Wilkinson, G., Hegedus L., Eds.; Pergamon: Oxford,
1995; Vol. 12, pp 741-770. (k) Shore, N. E. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
5, pp 1129-1162.
The structure of compound 15 as 1,2,5-trisubstituted benzene
was established by extensive NMR studies. 13C NMR spectra
of 15 showed signals for three aromatic CH carbons (δC 124.4,
128.3, and 128.4) and three quaternary carbons (δC 141.6, 142.2,
and 142.7), apart from the signals attributable to the three steroid
fragments, accounting for the formation of a trisubstituted
(8) Pe´rez, D.; Siesel, B. A.; Malaska, M. J.; David, E.; Vollhardt, K. P.
C. Synlett 2000, 306.
(9) (a) Johnson, E. P.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1991, 113,
381. (b) Germanas, J.; Aubert, C.; Vollhardt, K. P. C. J. Am. Chem. Soc.
1991, 113, 4006.
(10) Eichberg, M. J.; Dorta, R. L.; Grotjahn, D. B.; Lamottke, K.;
Schmidt, M.; Vollhardt, K. P. C. J. Am. Chem. Soc. 2001, 113, 9324.
(11) Saa´, C.; Crotts, D. D.; Hsu, G.; Vollhardt, K. P. C. Synlett 1999,
487.
1
benzene ring. In addition, H NMR spectra of compound 15
showed three singlet signals attributable to the three steroid
methoxy groups (δH 3.73, 3.76, and 3.78) and three singlet
(12) Kaufman, R. J.; Sidhu, R. S. J. Org. Chem. 1982, 47, 4941.
J. Org. Chem, Vol. 72, No. 11, 2007 4215

Sierra et al.
SCHEME 5
SCHEME 6
SCHEME 7
formation of methoxyestrone 16 together with compounds 14
and 15 deserves some additional comments relevant for the
mechanistic interpretation of these processes. First, the question
of the generality of formation of ketones from the propargylic
alcohols in the presence of CpCo(CO)2 was addressed. Camphor
was detected by GC-mass spectrometry in the crude reaction
mixtures of 7. Therefore, it can be concluded that the fragmen-
tation of the alkynyl group is general (see below for an additional
example). Second, the origin of methoxyestrone 16 is neither
the CpCo-cyclobutadiene complex 14 nor mestranol 13. This
was demonstrated by heating pure samples of both compounds
for 60 h under the conditions in which 16 is formed. Ketone 16
was not detected in these experiments. Therefore, the fragmen-
tation of the alkynyl moiety requires the presence of Co and
should occur before the intermediate cobaltacyclobutadiene 17
evolves to the final products. It is well-known that the
coordination to metals promotes the breakage of the propargylic
alcohols to form an organometal intermediate along with a
ketone.17 Therefore, it can be proposed that the coordination of
the alcohol to the CpCo(CO)2 leads to the formation of 19. This
process is followed by â-carbon elimination, with liberation of
either camphor or methoxyestrone, and competes with the
formation of cobaltacycle 17 and its further evolution to form
either trimers or Co-cyclobutadiene complexes (Scheme 5).
temperature and an increase in the amount of CoCp(CO)2.19
On the contrary, compound 21, having unblocked the C-17
hydroxyl group,18 produces complex 22 (9%) together with
methoxyestrone 16 as the main reaction product (48%; Scheme
6). The structure of cyclobutadiene-Co complex 22 was
1
established on spectroscopic grounds. Both H and 13C NMR
spectra are almost identical to those of CpCo-cyclobutadiene
14, except for the signals attributable to the cyclobutadiene
1
fragment. The H NMR spectrum of 22 showed one signal
singlet for only one cyclobutadiene proton at 4.27 ppm and one
signal singlet at 0.30 ppm, accounting for nine hydrogens
attributable to one trimethylsilyl group. The presence of the silyl
group is consistent with the low field shift observed for the
cyclobutadiene carbons (δC 93.5, 91.8, 61.8, and 66.0 for
carbons C-1 to C-4, respectively) compared with the 1,2-
disubstitued derivative 14 (Scheme 3). These data are in
accordance with structure 22.
Finally, to evaluate the role of the propargylic alcohol moiety
into the reactions, the alkyne was spaced from the carbinol
center. Thus, compound 23 was prepared by reacting the
Grignard compound derived from 24 with camphor and
subsequent treatment with TBAF/THF to remove the TMS-
group (Scheme 7). Alkyne 23 was submitted to a reaction with
1 equiv of CpCo(CO)2 in boiling toluene and simultaneous
irradiation (100W, W-lamp). An inseparable mixture of 1,3,5-
and 1,2,5-trisubstituted aromatic compounds 25 and 26 was
The importance of the coordination of the alcohol to the cobalt
and the steric bulkiness in the alkyne were additionally
evaluated. Reaction of the bis-TMS-derivative 20 of mestranol18
with CpCo(CO)2 resulted in recovery of starting material in all
the conditions assayed, including an increase in the reaction
(13) Palomo, C.; Gonza´lez, A.; Garc´ıa, J. M.; Landa, C.; Oiarbide, M.;
Rodr´ıguez, S.; Lynden, A. Angew. Chem., Int. Ed. 1998, 37, 180.
(14) This is congruent with the reported increment of cyclotrimerization/
cyclobutadiene complex ratio upon increasing the reaction temperature.
See: Sheppard, G. S.; Vollhardt, K. P. C. J. Org. Chem. 1986, 51, 5496.
(15) The aromatic tether of compound 11, the 1,3,5-trisubstituted
regioisomer, possesses magnetically equivalent carbons and protons, show-
ing one signal for the three protons and two signals for the six aromatic
carbons.
(16) (a) Hardesty, J. H.; Koerner, J. B.; Albright, T. A.; Lee, G.-Y. J.
Am. Chem. Soc. 1999, 121, 6055. (b) Wakatsuki, Y.; Nomura, O.; Kitaura,
K.; Morokuma, K.; Yamazaki, H. J. Am. Chem. Soc. 1983, 105, 1907.
(17) Selected recent examples referred to Rh: (a) Funayama, A.; Satoh,
T.; Miura, M. J. Am. Chem. Soc. 2005, 127, 15354. (b) Terao, Y.; Wakui,
H.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2001, 123, 10407.
(c) Terao, Y.; Wakui, H.; Nomoto, N.; Satoh, T.; Miura, M.; Nomura, M.
J. Org. Chem. 2003, 68, 5236.
(19) The lack of reactivity of trimethylsilyl alkynyl carboranes has been
recognized; contrary to phenyl alkynyl carboranes that render the cobalta-
cyclobutadiene derivatives under analogous reaction conditions. Goswami,
A.; Nie, Y.; Oeser, T.; Siebert, W. Eur. J. Inorg. Chem. 2006, 566.
(18) Peters, R. H.; Crowe, D. F.; Tanabe, M.; Avery, M. A.; Chong, W.
K. M. J. Med. Chem. 1987, 30, 646.
4216 J. Org. Chem., Vol. 72, No. 11, 2007

Synthesis of Terpene and Steroid Dimers and Trimers
SCHEME 8
alcohols and are analogous to type 1, but having a Co-
cyclopentadienone tether (10). Type 1 and 2 are bio-organo-
metallic hybrid natural products. Type 3 has three units of
terpene or steroid joined to a benzene ring (11, 12, 15). A
reasonable mechanism based on the coordination of the pro-
pargyl alcohol to the Co center, followed by two competitive
reaction pathways from a common intermediate 27, is proposed.
Intermediate 28 may evolve mainly through the usual pathways
to cyclotrimerization or Co-cyclobutadiene products for mono-
substituted alkynes. The â-carbon elimination pathway leading
to ketones (an unknown process in this chemistry) competes
unfavorably in the above case, but it becomes the main reaction
pathway for disubstituted alkynes. Having established the
grounds to prepare three different types of natural product
hybrids, further work pursuing the synthesis of more complicated
structures is now in progress.
obtained in 58% yield (Scheme 7). Neither traces of the
corresponding CpCo-cyclobutadiene nor the CpCo-cyclo-
butadienone complexes were obtained. Camphor was not
detected in the crude reaction mixtures by GC-MS analysis.
Results above show that the coordination of the propargylic
alcohol to the CpCo(CO)2 is crucial to determine both the
composition of the reaction products and their regiochemistry.
Clearly, the separation of the triple bond and the alcohol moieties
as in 23 produces the usual outcome of these reactions, namely,
the cyclotrimerization products, as a nearly equimolar mixture
of regioisomers 25 and 26. The propargylic alcohols 7, 13, and
21 produce mixtures of cobalt complexes and cyclotrimers
together with the ketone derived from the breakage of the
propargyl moiety. Finally, the blockage of the propargyl alcohol
20 results in the inertia of this compound, at least in the
conditions investigated.
These experimental data may be rationalized by proposing
the initial coordination of the alcohol moiety to the CpCo(CO)2
to yield the key intermediate 27 (Scheme 8).20 The fate of this
intermediate is dictated by the bulkiness of the substituents
joined to the triple bond. Coordination of the triple bond to the
cobalt (route A, Scheme 8) competes favorably with the
â-carbon elimination in monosubstituted alkynes (route B,
Scheme 8). In this case, the additional stabilization of the 16-
electron intermediate cobaltacycle 28 allowed the formation of
cyclobutadiene-Co complexes (9, 14, 22) at the expense of
the cyclotrimerization compounds (11+12, 15). The regiochem-
istry in both cases is dictated by the steric hindrance of the
alkyne. Increasing the bulkiness of the substituents at the alkyne
(compound 21) results in an increased difficulty for the
coordination of the alkyne to the Co nucleus, and therefore,
the â-carbon elimination reaction leading to ketones (8, 16)
becomes the preferred pathway (Scheme 8). It should be noted
that, in this case, the Co-cyclobutadiene complex 22 is formed
in low yield and with the concomitant elimination of one TMS
group (Scheme 6).
Experimental Section
See Supporting Information for general methods and procedures.
Reaction of Alcohol 7 with CpCo(CO)2. Compounds 9, 10,
11, and 12: CpCo(CO)2 (68 mg, 0.39 mmol) was added to a
solution of 7 (140 mg, 0.78 mmol) in degassed decaline (5.6 mL)
at 160 °C. The reaction mixture was boiled for 2.5 h, cooled to
room temperature, filtered through a pad of celite, and concentrated
in vacuo. Silica gel chromatography of the crude product (hexanes
f hexanes/AcOEt 4:1) afforded 9 (72 mg, 38%), 10 (8 mg , 4%),
and 11 and 12 (48 mg, 35%). Compound 9: Yellow syrup; IR
1
(nujol) νmax 3521, 3463, 2925, 1456, 1376, 1067, 813 cm-1; H
NMR (400 MHz, CDCl3) δ 4.97 (s, 5H), 4.02 (s, 1H), 3.67 (s,
2H), 3.12 (br s, 1H), 2.37 (dt, J ) 13.0, 3.7 Hz, 1H), 1.95 (dt, J )
13.6, 3.9 Hz, 1H), 1.74 (d, J ) 12.8 Hz, 1H), 1.67-1.49 (m, 6H),
1.35-1.21 (m, 2H), 1.34 (d, J ) 13.5 Hz, 1H), 1.08 (s, 3H), 1.04
(m, 1H), 1.07 (s, 3H), 1.03 (s, 3H), 0.92 (m, 1H), 0.90 (s, 3H),
0.82 (s, 3H), 0.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 89.2 (C),
85.2 (C), 81.5 (C), 80.2 (5CH), 78.9 (C), 60.0 (CH), 56.3 (CH),
54.3 (2C), 53.0 (CH2), 50.8 (C), 50.6 (C), 48.4 (CH2), 45.9 (CH),
45.5 (CH), 32.3 (CH2), 29.1 (CH2), 27.8 (CH2), 27.4 (CH2), 22.0
(CH3), 21.7 (CH3), 21.5 (CH3), 21.2 (CH3), 12.0 (CH3), 11.8 (CH3);
MS (EI) m/z (relative intensity) 480 [M+] (5), 462 [M+ - 18] (100),
447 [M+ - 15 - 18] (25), 419 (8), 338 (10), 311 (12), 124 (14).
Anal. Calcd for C29H41O2Co: C, 72.48; H, 8.60. Found: C, 72.25;
H, 8.38. Compound 10: Orange syrup; IR (KBr) νmax 3436, 2954,
1
1790, 1631, 1537, 1456, 1385, 1067, 720 cm-1; H NMR (400
MHz, CDCl3) δ 5.11 (s, 5H), 5.00 (d, J ) 3.1 Hz, 1H), 4.81 (d, J
) 3.3 Hz, 1H), 3.32 (d, J ) 13.0 Hz, 1H), 2.23 (dt, J ) 13.6, 3.9
Hz, 1H), 1.96 (ddd, J ) 13.0, 4.4, 2.9 Hz, 1H), 1.86-1.67 (m,
4H), 1.54 (m, 1H), 1.46 (d, J ) 13.4 Hz, 1H), 1.36-0.96 (m, 5H),
1.21 (s, 3H), 1.17 (s, 3H), 0.91 (s, 3H), 0.86 (s, 3H), 0.83 (s, 3H),
0.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.4 (C), 91.3 (C),
90.5 (C), 82.2 (5CH), 81.7 (C), 81.0 (C), 72.1 (CH), 71.5 (CH),
54.5 (C), 54.2 (C), 50.4 (C), 50.0 (C), 46.7 (CH2), 46.3 (CH), 45.4
(CH), 42.1 (CH2), 31.6 (CH2), 31.3 (CH2), 27.3 (CH2), 26.1 (CH2),
21.5 (CH3), 21.4 (2CH3), 21.2 (CH3), 11.6 (CH3), 10.1 (CH3); MS
(EI) m/z (relative intensity) 508 [M+] (28), 490 [M+ - 18] (100),
421 [M+ - 15 - 18] (15), 461 (10), 447 (11), 421 (39), 367 (40),
243 (36). Anal. Calcd for C30H41O3Co: C, 70.85; H, 8.13. Found:
C, 70.71; H, 7.89. Compound 11: Pale yellow oil; IR (KBr) νmax
In conclusion, the reaction of natural product derived pro-
pargylic alcohols with CpCo(CO)2 produces three new types
of natural product hybrids. These products contain two or three
terpene or steroid fragments and the tether joining the natural
product subunits is built during the reaction. Type 1 hybrids
have two terpene or steroid moieties joined by a CpCo-
cyclobutadiene tether, with the two units disposed in a 1,2-
arrangement (9, 14, 22). Type 2 hybrids have been obtained as
minor products in the reaction of camphor-derived propargylic
1
3436, 2957, 1631, 1478, 1458, 1388, 1065 cm-1; H NMR (200
MHz, CDCl3) δ 7.62 (s, 3H), 2.39-0.78 (overlapped m, 21H), 1.27
(s, 9H), 0.91 (s, 9H), 0.90 (s, 9H); 13C NMR (50 MHz, CDCl3) δ
144.3 (3C), 123.9 (3CH), 83.9 (3C), 53.6 (3C), 50.6 (3C), 45.8
(3CH2)*, 45.7 (3CH)*, 31.4 (3CH2), 26.6 (3CH2), 21.6 (6CH3),
9.9 (3CH3) (assignments marked with an asterisk may be inter-
changed); MS (EI) m/z (relative intensity) 534 [M+] (2), 516 [M+
- 18] (6), 425 (28), 406 (12), 315 (46), 204 (100), 108 (29), 95
(42). Anal. Calcd for C36H54O3: C, 80.85; H, 10.18. Found: C,
(20) A nitrogen coordinated cobaltacyclopentadiene has been proposed
by Saa´ et al. to explain regioselectivity in the synthesis of 3,3′-substituted
2,2′-bipyridines: Varela, J. A.; Castedeo, L.; Maestro, M.; Mah´ıa, J.; Saa´,
C. Chem.sEur. J. 2001, 7, 5203.
J. Org. Chem, Vol. 72, No. 11, 2007 4217

Sierra et al.
80.71; H, 10.41. Compound 12: Pale yellow oil; [R]22 -50.0 (c
(CH), 47.9 (C), 43.8 (CH), 40.5 (CH2), 39.5 (CH), 32.8 (CH2),
29.9 (CH2), 27.3 (CH2), 26.6 (CH2), 23.0 (CH2), 12.9 (CH3), 1.9
(3CH3), -0.1 (3CH3); MS (IE) m/z (relative intensity) 454 [M+]
(22), 439 (6), 381 (20), 364 (18), 268 (63), 242 (57), 225 (59), 174
(37), 147 (35), 73 (100). Anal. Calcd for C27H42O2Si2: C, 71.30;
H, 9.31. Found: C, 71.58; H, 9.04.
D
0.09, CHCl3); IR (KBr) νmax 3430, 2934, 1630, 1477, 1459, 1390,
1
1062 cm-1; H NMR (200 MHz, CDCl3) 7.62 (m, 1H), 7.44 (d, J
) 8.6 Hz, 1H), 7.26 (d, J ) 8.6 Hz, 1H), 2.45-0.82 (overlapped
m), 1.27, 0.91, 0.89 (3s, 27H); 13C NMR (50 MHz, CDCl3) δ 142.2
(3C), 131.1 (CH), 130.7 (CH), 123.5 (CH), 83.7 (3C), 55.1, 53.6,
51.3, 51.1 and 50.6 (6C), 45.7 (3CH2)*, 45.5 (3CH)*, 31.7 (CH2),
31.6 (CH2), 31.3 (CH2), 26.8 (3CH2), 22.3, 21.7 and 21.6 (6CH3),
10.0 (3CH3) (assignments marked with asterisk may be inter-
changed); MS (EI) m/z (relative intensity) 516 [M+ - 18] (54),
501 [M+ - 18 - 15] (7), 445 (96), 407 (31), 335 (21), 296 (23),
186 (64), 95 (100). Anal. Calcd for C36H54O3: C, 80.85; H, 10.18.
Found: C, 80.57; H, 10.42.
Preparation of Compound 21. To a solution of compound 20
(160 mg, 0.35 mmol) in MeOH (20 mL) were added dropwise 0.4
mL of concd HCl. The mixture was stirred for 5 h at this
temperature and for 72 h at -20 °C until compound 20 was
consumed. NaHCO3 saturated aqueous solution was added to the
reaction mixture, most of the methanol was removed under vacuum,
and the residue was extracted with AcOEt. The combined organic
layers were washed with brine and dried over anhydrous Na2SO4.
Removal of the solvents afforded a residue that was chromato-
graphed on silica gel with hexanes/AcOEt mixtures 25:1 f 10:1,
yielding pure 21(123 mg, 91%): 1H NMR (300 MHz, CDCl3) δ
7.24 (d, J ) 8.5 Hz, 1H), 6.73 (dd, J ) 8.5, 2.4 Hz, 1H), 6.64 (d,
J ) 2.4 Hz, 1H), 3.78 (s, 3H), 2.87 (m, 2H), 2.40-1.10 (m, 14H),
0.88 (s, 3H), 0.19 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 157.4
(C), 137.9 (C), 132.4 (C), 126.3 (CH), 113.7 (CH), 111.5 (CH),
109.5 (C), 90.0 (C), 80.0 (C), 55.1, (CH3), 49.5 (CH), 47.2 (C),
43.7 (CH), 39.4 (CH2), 38.9 (CH), 32.8 (CH2), 29.8 (CH2), 27.3
(CH2), 26.4 (CH2), 22.8 (CH2), 12.8 (CH3), 0.02 (3 CH3).
Reaction of Mestranol 13 with CpCo(CO)2. Compounds 14
and 15: CpCo(CO)2 (5.6 mmol, 1.0 g) was added to a solution of
mestranol (215 mg, 0.56 mmol) in xylenes at 140 °C. The reaction
mixture was refluxed for 2.5 h until no starting material was left
(TLC analysis), cooled to room temperature, and filtered through
a pad of celite. The solvent was removed under reduced pressure.
Silica gel chromatography of the residue yielded, in increasing order
of polarity, 3-O-methylstrone 16 (19 mg, 12%), cyclobutadiene-
Co complex 14 (28 mg, 135), and trimer 15 (77 mg, 44%).
Compound 14: Yellow oil; IR (KBr) νmax 3435, 2928, 1610, 1500,
1
1453, 1255, 1038 cm-1; H NMR (200 MHz, CDCl3) δ 7.11 (m,
4H), 6.56 (m, 6H), 4.99 (s, 5H), 3.98 (br s, 1H), 3.95 (br s, 1H),
3.71 (s, 3H), 3.70 (s, 3H), 2.77-1.18 (overlapped m), 0.89 (s, 3H),
0.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.5, 157.4, 138.1,
138.0, 132.6, 132.5, 126.4, 113.8, 111.6, 111.5, 88.7, 88.3, 82.8,
81.1, 80.2, 59.3, 57.1, 55.2, 53.8, 49.7, 49.5, 48.5, 47.7, 43.6, 43.5,
39.9, 39.3, 37.4, 35.3, 33.6, 31.7, 29.9, 29.7, 27.5, 27.4, 26.9, 26.6,
23.5, 23.1, 15.2, 14.8; MS (EI) m/z (relative intensity) 744 [M+]
(12), 726 [M+ - 18] (100), 708 (73), 497 (23), 460 (17), 443 (17),
173 (46), 147 (35), 124 (22). Anal. Calcd for C47H57O4Co: C, 75.78;
H, 7.71. Found: C, 75.53; H, 7.44. Compound 15: Pale yellow
solid; mp 205-208 °C; [R]20D +64.15 (c 0.132, CHCl3); IR (film)
Reaction of Alcohol 21 with CpCo(CO)2. Compound 22:
CpCo(CO)2 (931 mg, 5.17 mmol) was added to a solution of alcohol
21 (198 mg, 0.52 mmol) in degassed xylenes (4 mL) at 140 °C.
The reaction mixture was boiled for 12 h, cooled to room
temperature, filtered through a pad of celite, and concentrated in
vacuo. Silica gel chromatography of the residue (hexanes f
hexanes/AcOEt 15:1) yielded in increasing order of polarity pure
methoxyestrone 16 (53 mg, 48%) and 22 (19 mg, 9%) as yellow
oil: IR (KBr) νmax 3436, 2932, 1703, 1610, 1500, 1280, 1256, 1037
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.06 (d, J ) 8.5 Hz, 1H),
6.79 (d, J ) 8.8 Hz, 1H), 6.58 (m, 3H), 6.49 (dd, J ) 8.5, 2.7 Hz,
1H), 5.02 (s, 5H), 4.27 (s, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 2.83 (m,
4H), 2.17-1.28 (m overlapped), 0.93 (s, 3H,), 0.91 (s, 3H), 0.3 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 157.4 (2C), 137.8 (2C), 132.1
(C), 132.0 (C), 126.9 (CH), 126.8 (CH), 113.7 (CH), 113.6 (CH),
111.7 (CH), 111.6 (CH), 93.5 (C), 91.8 (C), 82.7 (C), 82.6 (C),
79.3 (5CH), 66.0 (CH), 61.8 (C), 55.2 (2CH3, OCH3), 48.7 (2CH),
46.7 (C), 46.2 (C), 44.6 (CH), 44.1 (CH), 39.4 (CH), 39.2 (CH),
38.1 (CH2), 37.1 (CH2), 35.3 (CH2), 35.1 (CH2), 30.0 (2CH2), 27.6
(CH2), 27.1 (CH2), 26.8 (CH2), 26.5 (CH2), 23.9 (CH2), 23.4 (CH2),
14.3 (CH3), 14.1 (CH3), 2.8 (3CH3); MS (ES) m/z 816.4 [M+]. Anal.
Calcd for C50H65O4SiCo: C, 73.50; H, 8.02. Found: C, 73.66; H,
8.32.
νmax 3360, 2930, 1610, 1500, 1255, 1237, 1050, 1038, 755 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.32 (br s, 1H), 7.18-7.03 (m, 4H),
6.81 (d, J ) 8.5 Hz, 1H), 6.79-6.52 (m, 6H), 3.78 (s, 3H), 3.76
(s, 3H), 3.73 (s, 3H), 2.87-1.14 (overlapped m), 1.07 (s, 3H), 1.06
(s, 3H), 1.03 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.2 (3C),
142.7 (C), 142.2 (C), 141.6 (C), 137.8, 137.6 (3C), 132.7, 132.2
(3C), 128.4 (CH), 128.3 (CH), 126.3, 126.2 (3CH), 124.4 (CH),
113.6 (3CH), 111.3 (3CH), 89.4 (C), 89.1 (C), 85.7 (C), 55.1
(3CH3), 49.8 (CH), 49.6 (CH), 48.8 (C), 48.7 (C), 48.2 (CH), 47.4
(C), 43.4, 43.3 (3CH), 43.0, 42.7 (2CH2), 39.9, 39.7, 39.4 (3CH),
39.1 (CH2), 34.6, 34.5, 34.2 (3CH2), 29.9, 29.7 (3CH2), 27.5, 27.4
(3CH2), 26.8, 26.7, 26.1 (3CH2), 24.2, 24.0, 23.9 (3CH2), 15.4, 14.7
(3CH3); MS (API-ES) m/z 953 [M+ + Na]. Anal. Calcd for
C63H78O6: C, 81.25; H, 8.44. Found: C, 81.07; H, 8.41.
Preparation of Compound 20. To a solution of mestranol (300
mg, 0.97 mmol) in THF (10 mL) at 0 °C, n-BuLi (0.90 mL, 1.16
mmol) was added. The mixture was allowed to reach room
temperature and stirred for 30 min. The reaction mixture was cooled
again at 0 °C, and trimethylsilylchloride was added (0.14 mL, 1.06
mmol). After 30 min, the process was repeated by cooling the
mixture at 0 °C, adding n-BuLi (0.90 mL, 1.16 mmol) and
trimethylsilylchloride (0.14 mL, 1.06 mmol). Finally, after 1 h of
stirring at room temperature, 10% HCl aqueous solution was added
and the reaction mixture was extracted with AcOEt. The combined
organic layers were washed with brine and dried over anhydrous
Na2SO4. Removal of the solvents under vacuum afforded a residue
that was chromatographed on silica gel with hexanes, yielding pure
20 (420 mg, 95%) as a white solid: IR (KBr) νmax 2954, 2928,
2158, 1610, 1499, 1249, 1092, 903, 841 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.24 (d, J ) 8.4 Hz, 1H), 6.72 (dd, J ) 8.4, 2.7 Hz, 1H),
6.63 (d, J ) 2.6 Hz, 1H), 3.79 (s, 3H), 2.85 (m, 2H), 2.40-1.32
(m, 13H), 0.81 (s, 3H), 0.19 (s, 9H), 0.18 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 157.3 (C), 138.0 (C), 132.8 (C), 126.4 (CH), 113.7
(CH), 111.4 (CH), 110.2 (C), 90.6 (C), 80.9 (C), 55.2 (CH3), 48.4
Preparation of Compound 24. A solution of [(4-bromophenyl)-
ethynyl](trimethyl)silane (1.66 g, 4.44 mmol) in THF (13 mL) was
added dropwise to a suspension of Mg (0.31 g, 12.9 mmol) in THF
(3 mL), which had been previously treated with a small amount of
I2. The mixture was refluxed for 1.5 h and cooled to room
temperature. Then it was treated with a solution of (R)-(+)-camphor
(0.50 g, 3.22 mmol) in THF (4 mL) and stirred for 8 h. After
quenching with NH4Cl (saturated aqueous solution), the mixture
was extracted with Et2O. The combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. Silica gel chromatography (hexanes f hexanes/
AcOEt 9:1) of the crude product afforded pure 24 (0.47 g, 45%)
as a clear oil: [R]20D -22.9 (c 0.14, CHCl3); IR (nujol) νmax 3468,
1
2957, 2158, 1502, 1457, 1249, 1064 cm-1; H NMR (500 MHz,
CDCl3) δ 7.45 (d, J ) 8.3 Hz, 2H), 7.41 (d, J ) 8.3 Hz, 2H), 2.28
(d, J ) 14.1 Hz, 1H), 2.18 (dt, J ) 13.7, 3.9 Hz, 1H), 1.90 (t, J )
3.9 Hz, 1H), 1.72 (m, 1H), 1.29-1.12 (m, 2H), 1.25 (s, 3H), 0.89
(s, 3H), 0.87 (s, 3H), 0.76 (m, 1H), 0.24 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 146.5 (C), 131.1 (2CH), 126.7 (2CH), 121.5 (C),
104.9 (C), 94.2 (C), 83.5 (C), 53.6 (C), 50.4 (C), 45.5 (CH), 45.4
(CH2), 31.1 (CH2), 26.5 (CH2), 21.6 (2CH3), 9.7 (CH3), 0.0 (3CH3);
MS (EI) m/z (relative intensity) 326 [M+] (5), 311 [M+ - 15] (9),
4218 J. Org. Chem., Vol. 72, No. 11, 2007

Synthesis of Terpene and Steroid Dimers and Trimers
216 (100), 201 (88), 158 (11), 95 (11). Anal. Calcd for C21H30OSi:
C, 77.24; H, 9.26. Found: C, 77.02; H, 9.43.
for an additional 3.5 h period. After cooling to room temperature,
it was filtered through a pad of celite and concentrated in vacuo.
The crude product was purified by silica gel chromatography
(hexanes f hexanes/AcOEt 10:1), which provided a mixture of
25 and 26 (24 mg, 58%) as a yellow solid: IR (nujol) νmax 3461,
2923, 1458, 1376, 1063 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.80
(s), 7.69-7.59 (m), 7.52 (d, J ) 8.1 Hz), 7.35 (m), 7.12 (m), 2.24-
14 (m), 1.94-1.67 (m), 1.29 (s), 1.25 (s), 0.96 (s), 0.95 (s), 0.93
(s), 0.90 (s), 0.88 (s); 13C NMR (50 MHz, CDCl3) δ 145.5, 145.4,
144.3, 144.2, 141.8, 140.7, 140.0, 139.8, 139.6, 139.5, 139.2, 138.9,
130.8, 129.1, 127.3, 126.4, 126.2, 126.0, 124.8, 83.5, 83.4, 53.6,
53.5, 50.5, 50.3, 45.6, 45.2, 31.2, 26.6, 26.4, 21.7, 21.6, 9.9, 9.8;
MS (ESI) m/z 785.3 [M+ + Na], 801.4 [M+ + K]. Anal. Calcd for
C54H66O3: C, 84.99; H, 8.72. Found: C, 85.23; H, 8.66.
Preparation of Compound 23: A solution of TBAF (250 mg,
0.77 mmol) in THF (11 mL) was added dropwise to a solution of
24 (252 mg, 0.77 mmol) in THF (15 mL). After 10 min of stirring
at room temperature, a saturated aqueous solution of NH4Cl (10
mL) was added. The mixture was extracted with AcOEt and washed
with brine. The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure. Silica gel
chromatography (hexanes/AcOEt 9:1) of the crude product gave
23 (88 mg, 67%) as a white solid: [R]20 -31.4 (c 0.21, CHCl3);
D
mp 207-210 °C; IR (nujol) νmax 3498, 3298, 2925, 2103, 1502,
1457, 1388, 1371, 1060 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.48
(d, J ) 8.9 Hz, 2H), 7.41 (d, J ) 8.9 Hz, 2H), 3.06 (s, 1H), 2.28
(d, J ) 13.9 Hz, 1H), 2.18 (dt, J ) 13.9, 4.1 Hz, 1H), 1.90 (t, J )
4.3 Hz, 1H), 1.72 (m, 1H), 1.24-1.15 (m, 2H), 1.26 (s, 3H), 0.90
(s, 3H), 0.88 (s, 3H), 0.78 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
146.9 (C), 131.2 (2CH), 126.8 (2CH), 120.4 (C), 83.5 (CH), 83.4
(C), 77.2 (C), 53.5 (C), 50.4 (C), 45.5 (CH, CH2), 31.1 (CH2), 26.5
(CH2), 21.6 (2CH3), 9.7 (CH3); MS (EI) m/z (relative intensity)
254 [M+] (2), 239 [M+ - 15] (1), 144 (100), 129 (26), 101 (11),
95 (24). Anal. Calcd for C18H22O: C, 84.99; H, 8.72. Found: C,
85.22; H, 8.50.
Acknowledgment. Financial support by the Spanish Min-
isterio de Ciencia y Tecnolog´ıa [Grants CTQ2004-06250-C02-
02/BQU (M.C.T.) and CTQ2004-06250-C02-01/BQU (M.A.S.)]
are gratefully acknowledged. E.AÄ . thanks the MEC (Spain) for
a FPU-predoctoral fellowship.
Supporting Information Available: Copies of the 1D- and 2D-
NMR spectra of new compounds prepared through this work as
well as X-ray characterization of compounds 9 and 10. This material
is available free of charge via the Internet at http://pubs.acs.org.
Reaction of 23 with CpCo(CO)2. Compounds 25 and 26:
CpCo(CO)2 (29 mg, 0.16 mmol) was added to a solution of 23 (41
mg, 0.16 mmol) in degassed toluene (5 mL) at 110 °C. The reaction
mixture was irradiated (100 W, W lamp) for 30 min and then boiled
JO0703698
J. Org. Chem, Vol. 72, No. 11, 2007 4219