A straightforward synthesis of tetrameric estrone-based macrocycles

Article abstract of DOI:10.1021/ol801313g

(Chemical Equation Presented) A straightforward approach to macrocycles having four estrone-derived nuclei by the sequential Cu-catalyzed Huisgen azide-alkyne cycloaddition-Glaser-Eglington Cu homocoupling has been developed. Due to its efficiency and sim

Full text of DOI:10.1021/ol801313g

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3555-3558
A Straightforward Synthesis of
Tetrameric Estrone-Based Macrocycles
Pedro Ramírez-López,*,† Mar´ıa C. de la Torre,*,† Hector E. Montenegro,†,‡
Mar´ıa Asenjo,† and Miguel A. Sierra*,‡
Instituto de Qu´ımica Orga´nica, Consejo Superior de InVestigaciones Cient´ıficas
(CSIC), Juan de la CierVa 3, 28006-Madrid, Spain, and Departamento de Qu´ımica
Orga´nica, Facultad de Qu´ımica, UniVersidad Complutense, 28040-Madrid, Spain
pedror@iqog.csic.es; ctorre@iqog.csic.es; sierraor@quim.ucm.es
Received June 10, 2008
ABSTRACT
A straightforward approach to macrocycles having four estrone-derived nuclei by the sequential Cu-catalyzed Huisgen azide-alkyne
cycloaddition-Glaser-Eglington Cu homocoupling has been developed. Due to its efficiency and simplicity, this sequence is useful for
application to different natural product scaffolds.
Cu-promoted alkyne coupling1 and Huisgen 1,3-dipolar
cycloaddition chemistry2 have been widely applied to the
preparation of macrocycles.3,4 Nevertheless, since most of
these coupling-based methods are kinetically controlled
processes, they frequently lead irreversibly to the kinetic and
statistical distribution of products, including a large collection
of linear/cyclic oligomers and polymers of different chain
length, resulting inevitably in poor yields of the desired
macrocyclic structures. This fact contrasts with dynamic
covalent chemistry (DCC), the reversible nature of which
overcomes the formation of undesired linear/cyclic structures
allowing the preparation of the macrocyclic target molecule.3
In this context, during our search for new macrocyclic
entities, we used the DCC approach to prepare polymetallic
natural product based macrocycles employing the Nicholas
reaction5 and the reversible Michael addition of bisamines
to bisalkyne tethered group 6 biscarbene complexes to form
di- and tetrametallic macrocycles in a single step (Figure 1).6
† Consejo Superior de Investigaciones Cient´ıficas (CSIC).
‡ Universidad Complutense.
(1) (a) Hay, A. S. J. Org. Chem. 1962, 27, 3320. For an overview on
acetylenic homocoupling, see: (b) Siemsen, P.; Livingston, R. C.; Diederich,
F. Angew. Chem., Int. Ed. 2000, 39, 2632, and references therein.
(2) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. For a revision on the copper(I)-
catalyzed azide-alkyne reaction, see: (c) Bock, V. D.; Hiemstra, H.; van
Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51. (d) Tron, G. C.; Pirali, T.;
Billington, R. A.; Canonico, P. L.; Sorba, G.; Genazzani, A. A. Med. Res.
ReV. 2008, 28, 278. (e) Binder, W. H.; Sachsenhofer, R. Macromol. Rapid
Commun. 2007, 28, 15. (f) Nandivada, H.; Jiang, X.; Lahann, J. AdV. Mater.
2007, 19, 2197.
The common target of this research was to generate new
macrocyclic bio-organometallic scaffolds as well as co-
(3) Zhang, W.; Moore, J. S. Angew. Chem., Int. Ed. 2006, 45, 4416
.
(4) Recent examples on the use of the Huisgen catalyzed Cu azide-alkyne
cycloaddition to close macrocyclic rings: (a) Aher, N. G.; Pore, V. S.; Patil,
S. P. Tetrahedron 2007, 63, 12927. (b) Bodine, K. D.; Gin, D. Y.; Gin,
M. S. J. Am. Chem. Soc. 2004, 126, 1638. (c) Bodine, K. D.; Gin, D. Y.;
Gin, M. S. Org. Lett. 2005, 7, 4479. (d) Turner, R. A.; Oliver, A. G.; Lokey,
R. S. Org. Lett. 2007, 9, 5011. (e) Bock, V. D.; Perciaccante, R.; Jansen,
T. P.; Hiemstra, H.; van Maarseveen, J. H. Org. Lett. 2006, 8, 919. (f)
´
(5) Alvaro, E.; Sierra, M. A.; de la Torre, M. C. Chem. Commun. 2006,
985.
(6) (a) Ferna´ndez, I.; Sierra, M. A.; Manchen˜o, M. J.; Go´mez-Gallego,
M.; Ricart, S. Organometallics 2001, 20, 4304. (b) Ferna´ndez, I.; Manchen˜o,
M. J.; Go´mez-Gallego, M.; Sierra, M. A. Org. Lett. 2003, 5, 1237.
(7) Holliday, B. J.; Mirkin, C. A. Angew. Chem., Int. Ed. 2001, 40, 2022.
Laurent, B. A.; Grayson, S. M. J. Am. Chem. Soc. 2006, 128, 4238
.
10.1021/ol801313g CCC: $40.75
Published on Web 07/23/2008
2008 American Chemical Society

overcome these problems. In fact, this rigidity makes steroids
exceptional building blocks for the synthesis of steroid-based
macrocyclic molecules.8 We report herein a straightforward
cyclodimerization of a bissteroid scaffold, prepared employ-
ing a “Click” reaction9 on a bisalkyne steroid, by using a
Cu-promoted Glaser-Eglinton homocoupling to furnish in
good overall yields a series of chiral, highly symmetric
tetrameric estrone-derived macrocycles (Scheme 1).
Scheme 1
.
Synthetic Strategy for the Cu-Catalyzed Synthesis of
Estrone-Based Macrocycles
Figure 1. Some polymetallic macrocycles prepared using the DCC
cyclooligomerization approach.
valently connected polymetallic macrocyclic rings (in con-
trast with macrocycles joined through a more flexible M-C
bond)7 to study the long-range interaction between metallic
centers.
In contrast with this previous work and according to
literature precedents, the sequential building of a macrocycle
in a limited number of steps will face relative overall low
yields and contamination with a large collection of linear/
cyclic oligomers and polymers of different chain length.3
However, the use of rigid steroid scaffolds may help to
(8) The review by Li and Dias compiles most of the different structural
types of steroid-based architectures reported: (a) Li, Y.; Dias, J. R. Chem.
ReV. 1997, 97, 283. (b) Wallimann, P.; Marti, T.; Fu¨rer, A.; Diederich, F.
Chem. ReV 1997, 97, 1567. For the use of esteroids in the preparation of
cholaphanes and cholaphane-based macrocycles, see: (c) Tamminen, J.;
Kolehmainen, E. Molecules 2001, 6, 21. (d) Rivera, D. G.; Wessjohann,
L. A. Molecules 2007, 12, 1890. (e) Virtanen, E.; Kolehmainen, E. Eur. J.
Org. Chem. 2004, 3385.
(9) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004. The head to tail cyclodimerization of peptides by the
copper(I)-catalyzed azide-alkyne reaction has been reported. See: (b) Punna,
S.; Kuzelka, J.; Wang, Q.; Finn, M. G. Angew. Chem., Int. Ed. 2005, 44,
2215. The following reference contains a nice selection of the state of the
art on the copper(I)-catalyzed azide-alkyne reaction: (c) Rodionov, V. O.;
Presolski, S. I.; Gardinier, S.; Lim, Y. H.; Finn, M. G. J. Am. Chem. Soc.
2007, 129, 12696.
Estrone 1 was propargylated at the oxygen and subse-
quently reacted with lithium TMS-acetylide, using standard
methodology to form 2, which was submitted to reaction
with bisazides 3a-f. The resulting dimers 4a-f were isolated
in 72-88% yields (Scheme 2), demonstrating the exceptional
efficiency of the Cu-catalyzed Huisgen reaction.10 Aromatic
(4a-c), heteroaromatic (4d), aliphatic (4e), and ferrocenyl
(4f) derived azides were fully compatible with this process.11
Having prepared half of the cavity, the TMS-group of the
alkyne of compounds 4 was removed (TBAF, THF), and
the terminal diyne 5 was submitted to the Glaser-Eglinton
coupling (Cu(OAc)2·H2O/MeCN,Py).12 The result of this
coupling strongly depends on the nature of the tether joining
both steroid nuclei. Thus, while compounds 5a and 5d,f
furnished the desired macrocycles 6, having four steroid
nuclei, four triazole, and two 1,3-diyne linkers disposed
(10) The synthesis of compound 4a is representative: A mixture of
diazide 3a (82.4 mg, 0.438 mmol, 1.0 equiv), alkyne 2 (356.6 mg, 0.877
mmol, 2.0 equiv), sodium (L)-ascorbate (17.4 mg, 0.088 mmol, 0.2 equiv),
and CuSO4·5H2O (11.0 mg, 0.044 mmol, 0.1 equiv) in DMF (10 mL) was
stirred under Ar at rt for 3 h. The reaction was quenched with water at 0
°C and allowed to reach rt. The mixture was extracted with AcOEt (3 ×
20 mL), and the organic extracts were washed with water (2 × 20 mL) and
once with brine (20 mL). The organic layer was dried over MgSO4 and
filtered, and the solvent was removed under vacuum. The resulting white
solid was purified through a short pad of SiO2 (Hex/AcOEt 2:1 to 1:3) to
yield 4a as a white solid (384.5 mg, 88%). M.p. 126-128 °C. 1H NMR
(300 MHz, CDCl3) δ 7.48 (s, 2H), 7.40-7.36 (m, 2H), 7.27-7.25 (m, 2H),
7.20 (d, J ) 8.7 Hz, 2H), 6.75 (dd, J1 ) 8.7 Hz, J2 ) 2.4 Hz, 2H), 6.67 (d,
J ) 2.4 Hz, 2H), 5.62 (s, 4H), 5.13 (s, 4H), 2.90-2.73 (m, 4H), 2.41-1.21
(m, 28H), 0.86 (s, 6H), 0.17 (s, 18H). 13CNMR (75 MHz, CDCl3) δ 156.0
(C), 145.0 (C), 138.0 (C), 133.1 (C), 130.4 (CH), 129.8 (CH), 126.4 (CH),
122.8 (CH), 122.7 (C), 114.7 (CH), 112.2 (CH), 109.5 (C), 89.9 (C), 80.0
(C), 62.0 (2CH2), 51.2 (3CH2), 49.5 (CH), 47.1 (C), 43.7 (CH), 39.3 (CH),
38.9 (CH2), 32.8 (CH2), 29.7 (CH2), 27.2 (CH2), 26.4 (CH2), 22.8 (CH2),
12.7 (CH3), 0.0 (CH3). IR (KBr) νmax 3435, 3139, 2160, 1609, 1498, 1456,
1250, 1047, 843 cm-1. [R]D30 -15.15 (c 0.858, CHCl3). MS (ES) m/z 1001.3
[M + H]+. Anal. Calcd. for C60H76N6O4Si2: C, 71.96; H, 7.65; N, 8.39.
Found: C, 72.23; H, 7.83; N, 8.13.
(11) The structure of all new compounds fully satisfies their spectro-
scopic data. See the Supporting Information.
(12) Cloninger, M. J.; Whitlock, H. W. J. Org. Chem. 1998, 63, 6153.
3556
Org. Lett., Vol. 10, No. 16, 2008

Scheme 2
.
Synthesis of Semicavities 4 and 5
Scheme 3
.
Cyclooligomerization Reactions to Prepare
Estrone-Based Macrocycles 6
symmetrically (it should be noted that the structures have a
macrocyclic symmetry plane) in good to excellent yields,13
compounds 5b and 5c did not yield the desired macrocycles
(Scheme 3).
The structure of highly symmetric compounds 6 was
ascertained by spectroscopic means (NMR studies and MS
1
analysis). The H and 13C NMR for macrocycles 6 account
for one-fourth of the molecule and were almost identical to
those of the corresponding dimers 5a and 5d,f, except for
the presence of signals attributable to the symmetrically 1,4-
disubstituted-1,3-dialkyne bridge and the lack of the signals
corresponding to the terminal alkyne moiety. The possible
formation of highly symmetric [2 + 2], [3 + 3], or [4 + 4]
products was discarded by ESI-MS. Thus, compound 6a
showed a signal at m/z 1732.8 corresponding to [M + Na]+;
compound 6b showed a signal at m/z 1713.2 corresponding
to [M + H]+; and compound 6c showed two signals at m/z
1780.2 and m/z 1758.7 attributable to the ions [M + Na]+
and [M + H]+, respectively. Finally, compound 6d showed
a molecular peak at m/z 1926.9 [M + H]+ in agreement with
the proposed macrocyclic structure. Therefore, the formation
of lower or higher macrocyclic homologues was discarded.
The behavior of semicavities 5b,c contrasts with those of
compounds 5a and 5d having 1,2-phenyl and 2,6-pyridyl
bridges, respectively. Compounds 5b,c gave rise to the
formation of variable amounts of insoluble polymeric mate-
rial, which may be attributed to the relative m- and
p-disposition of the bridging aromatic ring, compared to the
o-disposition of the compound 5a. The ability of compound
5d to form the macrocyclic ring may be attributed to the
chelating effect of the pyridine and triazole nitrogens which
may template the Cu-promoted alkyne dimerization.14
It should be noted that compound 6d has two ferrocene
nuclei in its macrocyclic structure. The simultaneous presence
(13) The synthesis of macrocycle 6a is representative: To a mixture of
dry pyridine (7 mL)/CH3CN (21 mL), heated at reflux for 1 h, dimer 5a
(50.0 mg, 0.058 mmol, 1.0 equiv) and Cu(OAc)2·H2O (57.9 mg, 0.290 mmol,
5.0 equiv) were successively added. After refluxing for 1 h, the reaction
mixture was allowed to reach rt, quenched with ice, diluted with AcOEt
(40 mL), and washed with H2O (3 × 50 mL). The organic layer was dried
over anhydrous Na2SO4, and solvents were removed under vacuum. The
resulting residue was purified through a short pad of SiO2 (10.2 cm, Hex/
AcOEt 1:2 to 1:4) to yield 6a as a white solid (38.2 mg, 77%). M. p. )
1
260-262 °C. H NMR (300 MHz, CDCl3) δ 7.47-7.43 (m, 4H), 7.34 (s,
4H), 7.35-7.32 (m, 4H), 7.04 (d, J ) 8.7 Hz, 4H), 6.66 (dd, J1 ) 8.7 Hz,
J2 ) 2.4 Hz, 4H), 6.58 (d, J ) 2.4 Hz, 4H), 5.65 (s, 8H), 5.23 (s, 8H),
2.89-2.67 (m, 8H), 2.44-2.35 (m, 8H), 2.19-2.02 (m, 8H), 1.96-1.27
(m, 40H), 0.95 (s, 12H). 13C NMR (75 MHz, CDCl3) δ 155.4 (C), 145.3
(C), 137.7 (C), 132.9 (C), 132.3 (C), 130.6 (CH), 129.9 (CH), 126.0 (CH),
122.5 (CH), 115.3 (CH), 112.0 (CH), 84.5 (C), 80.4 (C), 70.1 (C), 61.7
(CH2), 51.1 (CH2), 49.9 (CH), 48.4 (C), 44.1 (CH), 39.1 (CH), 38.5 (CH2),
33.1 (CH2), 29.6 (CH2), 27.3 (CH2), 26.3 (CH2), 22.8 (CH2), 12.8 (CH3).
IR (KBr) νmax 3436, 2929, 1609, 1498, 1452, 1250, 1232, 1051, 1023 cm-1
.
(14) (a) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M.
Chem.-Eur. J. 2004, 10, 5607. (b) Jia, W. L.; McCormick, T. M.; Tao,
Y.; Lu, J.-P.; Wang, S. Inorg. Chem. 2005, 44, 5706. (c) McCormick, T. M.;
Liu, Q.; Wang, S. Org. Lett. 2007, 9, 4087.
30
[R]D -62.72 (c 0.220, CHCl3). MS (ES) m/z 1732.8 [M + Na]+. Anal.
Calcd. for C108H116N12O8: C, 75.85; H, 6.84; N, 9.83. Found: C, 75.54; H,
7.01; N, 9.62.
Org. Lett., Vol. 10, No. 16, 2008
3557

of four steroid nuclei and two iron metal nuclei makes
macrocycle 6d a bio-organometallic derivative.15 Reported
examples of this class of compounds are scarce, and their
biological relevance remains to be determined.
required to avoid the formation of linear oligomers. Progress
in these laboratories to achieve the synthesis of higher
macrocyclic homologues as well as to study the behavior of
these chiral rich cavities is underway.
To conclude, the straightforward access to macrocycles
having four estrone-derived nuclei by the sequential Cu-
catalyzed Huisgen azide-alkyne cycloaddition-Glaser-
Eglington Cu-homocoupling has been developed. The ap-
proach uses two differentiated triple bonds attached to the
steroid nucleus; it is tunable in both the tether and the
scaffold; and due to its efficiency and simplicity, it is useful
for application to different natural product scaffolds. The
success of this approach probably rests in the rigidity of the
estrone nucleus, which overcomes the kinetically unfavorable
cyclodimerization process by providing the preorganization
Acknowledgment. Support for this work under grants
CTQ2007-67730-C02-01/BQU, CAM-UCM-910762 (to
M.A.S.), CTQ2007-67730-C02-02/BQU (to M.C.T.), and
Consolider-Ingenio 2010 (CSD 2007-00006) from the Min-
isterio de Educacio´n y Ciencia (Spain) is acknowledged.
H.M. thanks the Alꢀan-EU Program for a predoctoral grant.
P.R.L. is a Juan de la Cierva Fellow.
Supporting Information Available: Full experimental
and listed spectroscopic data for the compounds 3, 4, 5, and
1
6 described in the paper as well as copies of their H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) For an overview of this field, see: (a) Dagani, R. Chem. Eng. News.
2002, 80, 23–29. (b) Special issue on bioorganometallic chemistry: J.
Organomet. Chem. 1999, 589, 1.
OL801313G
3558
Org. Lett., Vol. 10, No. 16, 2008