Two versatile and parallel approaches to highly symmetrical open and closed natural product-based structures

Article abstract of DOI:10.1002/chem.200903264

Two parallel approaches for preparing diverse and highly symmetrical homohybrids derived from a series of mono- and diterpenes, steroids, and alkaloids are reported. Both procedures are based on the mono-addition of bis(alkynyl) dilithium reagents to natural products having a carbonyl group to produce the corresponding al-kynyl derivatives. The Glaser-Hay Cu-promoted homocoupling of these al-kynyl natural product mono-adducts as well as the Huisgen Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction resulted in the synthesis of ste-roid-, terpene-, and alkaloid-based ho-mohybrid derivatives incorporating di-verse spacers to join the natural product scaffolds. Straightforward entries to novel closed highly symmetrical and complex estrone-based macrocyclic and cage architectures by means of the Glaser-Eglinton homocoupling and the CuAAC reaction have been devised.

Full text of DOI:10.1002/chem.200903264

DOI: 10.1002/chem.200903264
Two Versatile and Parallel Approaches to Highly Symmetrical Open and
Closed Natural Product-Based ACTHUNRTGNESGNU tructures
Hꢀctor E. Montenegro,[a, b] Pedro Ramꢁrez-Lꢂpez,*[a] Marꢁa C. de la Torre,*[a]
Marꢁa Asenjo,[a] and Miguel A. Sierra*[b]
Dedicated to Professor Antonio Garcꢀa-Martꢀnez (UCM) on the occasion of his retirement
Abstract: Two parallel approaches for
preparing diverse and highly symmetri-
cal homohybrids derived from a series
of mono- and diterpenes, steroids, and
alkaloids are reported. Both proce-
dures are based on the mono-addition
promoted homocoupling of these al-
kynyl natural product mono-adducts as
well as the Huisgen Cu-catalyzed
azide–alkyne cycloaddition (CuAAC)
reaction resulted in the synthesis of ste-
roid-, terpene-, and alkaloid-based ho-
mohybrid derivatives incorporating di-
verse spacers to join the natural prod-
uct scaffolds. Straightforward entries to
novel closed highly symmetrical and
complex estrone-based macrocyclic and
cage architectures by means of the
Glaser–Eglinton homocoupling and the
CuAAC reaction have been devised.
Keywords: alkyne homocoupling ·
click chemistry · diversity-oriented
synthesis (DOS) · molecular cages ·
natural products
of bis
ACHTUNGTRENNUNG
natural products having
a
group to produce the corresponding al-
kynyl derivatives. The Glaser–Hay Cu-
Introduction
versity-oriented synthesis (DOS) concept.[3] The main ad-
vantage of this strategy is the preparation of an unlimited
number of highly diverse molecular entities without relying
on the isolation of natural products from their natural sour-
ces. In order to implement this approach, general and effi-
cient methodologies are required. Thus, procedures based
on metathesis (cross-metathesis, CM[4a–c] and ring-closing
metathesis, RCM[4d–f]) and on the Huisgen Cu-catalyzed
azide–alkyne cycloaddition (CuAAC) “click” reaction have
been used to prepare natural product hybrids.[5] In our ongo-
ing research devoted to the development of methodologies
for preparing natural product hybrids by using transition
metal catalysts and reagents, we have recently shown that
natural product-based homodimers and homotrimers can be
built by creating the tether joining the monomeric subunits
by metathesis, as in the case of compound 1,[6] through the
Co-promoted cyclodimerization and cyclotrimerization of
appropriately functionalized natural product monomers, as
in the case of dimer 2,[7] and by means of the Nicholas ap-
proach, as exemplified by product 3[8] (Figure 1).
Although in the last decades there has been growing interest
in the development of methods for preparing large libraries
of new compounds, it has recently been recognized that the
number of compounds does not determine the quality of a
library; rather, among other factors, the quality is deter-
mined by the diversity.[1] In this context, one of the current
tendencies is the preparation of small focused collections of
synthetic natural product hybrids,[2] made as combinations
of fragments from different natural products within the di-
[a] Dr. H. E. Montenegro, Dr. P. Ramꢀrez-Lꢁpez, Dr. M. C. de la Torre,
M. Asenjo
Instituto de Quꢀmica Orgꢂnica General
Consejo Superior de Investigaciones Cientꢀficas (CSIC)
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax : (+34)915-644-853
E-mail: pedror@iqog.csic.es
ctorre@iqog.csic.es
[b] Dr. H. E. Montenegro, Prof. M. A. Sierra
Departamento de Quꢀmica Orgꢂnica, Facultad de Quꢀmica
Universidad Complutense, 28040 Madrid (Spain)
Fax : (+34)913944310
In parallel, we have also reported methodologies for the
synthesis of complex natural product-based macrocycles
through the Nicholas approach[9] and by sequential
CuAAC–Glaser–Eglinton homocoupling.[10] The prepara-
tions of highly symmetrical natural product-based macrocy-
cles such as 4 and 5 exemplify the versatility of these ap-
E-mail: sierraor@quim.ucm.es
Homepage: http://www.ucm.es/info/biorgmet/ingles/indexing.html
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903564.
3798
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3798 – 3814

FULL PAPER
Cu-promoted homocoupling or the Huisgen Cu-catalyzed
azide–alkyne cycloaddition (CuAAC) processes. In addition,
these methodologies conform to the diversity-oriented syn-
thesis concept (DOS).[3] It is remarkable to note that in
spite of the increasing number of applications of Cu-promot-
ed acetylenic coupling[11] and of the click[12] methodology in
organic synthesis, they have been scarcely employed to pre-
pare natural product homohybrids.
Thus, the Cu-promoted homocoupling of terminal alkynes
has been used to prepare only a few naturally occurring di-
and polyacetylenes,[11d] despite the fact that the first steroid-
based dimers[13] were synthesized nearly 50 years ago. On
the other hand, the CuAAC reaction has been profusely em-
ployed for the modification of primary metabolites.[14,15]
However, the use of this click methodology for the synthesis
of natural product hybrids remains little studied.[5] The syn-
thesis of dimer 6[16] by reaction of ethynylestradiol (7) with
azide 8, together with the preparation of bile acid dimers
and oligomers,[17] are two of the rare examples of the prepa-
ration of natural product homohybrids by using a click ap-
proach (Scheme 1).
Figure 1. Natural product-based homodimers.
proaches (Figure 2). Therefore, our work has shown how the
attachment of an alkynyl group to a natural product pro-
vides a key appendage for generating new structures, in
which the diversity may be variously introduced in the natu-
ral product scaffold, in the structure of the alkyne, or in a
reaction to which the terminal alkyne is later submitted.[7–10]
With these premises in hand, we devised two approaches
to access symmetrical open, macrocyclic, and eventually
cage structures based on natural products, by switching the
reactivity of the terminal alkynyl groups by means of either
Scheme 1. Steroid dimer 6 derived from ethynylestradiol (7).
We report herein the mono-addition of bisACTHNUTRGENU(GN alkynyl) di-
lithium reagents to various natural products bearing a car-
bonyl group to produce the scaffolds needed for accessing
diverse natural product hybrids, either by Cu-promoted oxi-
dative homocoupling or by Huisgen Cu-catalyzed azide–
alkyne cycloaddition (CuAAC). In this way, highly symmet-
rical homohybrids having novel complex open and closed es-
trone-based architectures could be accessed. These selective,
efficient, and versatile procedures should prove useful for
obtaining remarkable diverse and complex structures having
defined geometries.
Results and Discussion
Preparation of alkynyl natural product-derived scaffolds:
The preparation of alkynyl natural product derivatives was
first pursued by using robust natural products such as the
monoterpenes (1R)-(+)-camphor (9) and (R)-(À)-carvone
(10), as well as the steroid 3-O-methylestrone (11)
(Scheme 2). After tuning the reaction conditions 9, 10, and
Figure 2. Tetrameric natural product-based macrocycles obtained by the
Nicholas approach and through sequential CuAAC–Glaser–Eglinton ho-
mocoupling.
Chem. Eur. J. 2010, 16, 3798 – 3814
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3799

P. Ramꢀrez-Lꢁpez, M. C. de la Torre, M. A. Sierra et al.
11 were each reacted with an excess of the aromatic bis-
ACHTUNGTRENNUNG(alkynyl) dilithium reagent derived from 1,3- or 1,4-diethy-
nylbenzene to selectively afford the corresponding mono-ad-
ducts 12,[18] 13,[19] and 14[20] as the sole reaction products in
isolated yields of 81–99%.
Scheme 3. Preparation of terminal alkynyl derivatives from 19-acetylgna-
phalin (15).
in the presence of NaH in DMF. Regioisomers 19 and 20
were obtained in isolated yields of 30 and 63%, respectively
(Scheme 4).
The structures of reaction products 19 and 20 were estab-
lished by comparison of their NMR spectra with those of re-
lated derivatives; complete assignments of their 1H and
13C NMR spectra were made on the basis of 2D NMR ex-
periments (gHSQC and gHMBC).[26] In the case of the C-al-
kylated derivative 19, the stereochemistry at the newly
formed quaternary center C-7 was determined on the basis
of NOE experiments. Irradiation of proton H-3b at d=
4.05 ppm produced an enhancement of the intensity of the
signals attributable to H-21b (d=3.28 ppm) and the propar-
gylic methylene protons at d=2.84 and 2.23 ppm. Enhance-
ment of the overlapped signals at d=2.10 ppm was also ob-
served. This fact places proton H-3b and the propargylic
CH2 carbon on the same side of the molecule.
Scheme 2. Preparation of the alkynyl natural product derivatives 12–14.
The compatibility of this protocol with highly functional-
ized and sensitive natural products was then investigated. In
this context, we chose the diterpene 19-acetylgnaphalin
(15),[21] since it bears an impressive array of functionalities
and is extremely prone to rearrangement to montanin A.[22]
Prior to the use of a bisACHTUNRGTNE(NUG alkynyl) lithium reagent, we reacted
19-acetylgnaphalin (15) with one equivalent of TMS-acety-
lide in THF at À788C. Treatment of the reaction product
with tetrabutylammonium fluoride (TBAF) produced the al-
kynyl derivative 16 in 65% isolated yield (two steps)
(Scheme 3). Analogously, reaction of 19-acetylgnaphalin
(15) with the lithium reagent prepared “in situ” by deproto-
nation of 1,3-diethynylbenzene with lithium hexamethyldisi-
lazanide (LiHMDS) in THF at À788C produced 17 as the
sole reaction product in 65% yield (Scheme 3).[23] Analytical
and spectroscopic data for the reaction products 16 and 17
were in agreement with the proposed structures,[24] establish-
ing that the addition of the organolithium reagent at the C-6
position of the diterpene framework took place at the b face
of the decalin system.[25] Therefore, the addition of the orga-
nolithium reagents derived from TMS-acetylene and 1,3-di-
ethynylbenzene allows the efficient introduction of the re-
quired alkyne terminus in 19-acetylgnaphalin (15).
Having developed the synthetic methodology for obtain-
ing the natural product derivatives bearing the required
alkyne termini, we undertook the synthesis of natural prod-
uct oligomeric homohybrids, macrocycles, and molecular
cages by making use of the alkyne reactivity.
We first examined the synthesis of dimeric homohybrids
through the Cu-mediated oxidative homocoupling of the
natural product-derived terminal alkynes 12–14. Thus, reac-
tions of 12–14 with CuCl/TMEDA (TMEDA=N,N,N’,N’-
tetramethylethylenediamine) yielded the corresponding
dimers 21, 22, and 23 in isolated yields of 94%, 84%, and
88%, respectively (Scheme 5). The structures of the reaction
products 21–23 were established on spectroscopic grounds.
Finally, the terminal alkynyl moiety was appended to the
alkaloid reserpine (18) by reaction with propargyl bromide
1
In all cases, the H and 13C NMR spectra were devoid of the
3800
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3798 – 3814

Cu–Alkyne Chemistry
FULL PAPER
TMEDA under the standard
conditions to afford dimer 24 in
88% isolated yield (Scheme 6).
In the same manner, the C- and
N-alkylated reserpine deriva-
tives 19 and 20 produced
dimers 25 and 26 in isolated
yields of 61 and 43%, respec-
tively. The 1H and 13C NMR
data for homohybrids 24–26
were in agreement with the
proposed structures,[28] as were
the mass spectra, which showed
peaks at m/z 1077.3 [M+Na]+
for 24 (ESI) and 1291 [M+H]+
for 25 and 26 (APCI), establish-
ing that they were dimers of the
starting alkynes 17, 19, and 20,
respectively. From a structural
point of view, it has to be men-
tioned that all of the dimeric
compounds synthesized in the course of this work have one
Scheme 4. Preparation of terminal alkynyl derivatives from reserpine (18).
characteristic pattern of signals due to a terminal alkyne
fragment.[27] Instead, signals attributable to a symmetrically
substituted 1,3-butadiyne framework appeared. In addition,
the mass spectra of 21 (ESI), 22 (APCI), and 23 (ESI)
showed peaks at m/z 537.5 [MÀH2O+H]+, 533
[M+HÀH2O]+, and 783 [M+HÀ2H2O]+, respectively, con-
firming that these products were indeed dimers of the corre-
sponding starting alkynes 12–14.
1
binary symmetry axis, so that their H and 13C NMR spectra
account for half of the molecule, thus featuring a single set
of signals for the two natural product fragments. These re-
sults demonstrate the usefulness of our two-step protocol
for preparing functionalized polyalkynyl-tethered homodi-
meric natural product derivatives. This methodology allows
the preparation of C2-symmetric dimers having either a rigid
bis(diethynyl)benzene motif (compounds 21–24, Schemes 5
and 6) or a shorter 1,3-butadiyne bridge (compounds 25 and
26, Scheme 6).
Next, the CuAAC reaction was tested as a parallel ap-
proach to natural product-based homodimers. This protocol
allows the introduction of different tethers by varying the
nature of the azide, thereby providing a point for introduc-
ing structural diversity. The Cu-catalyzed cycloaddition reac-
tion was first tested with the commercially available and
robust steroid mestranol (27). Reactions of one equivalent
of azides 28a–c with two equivalents of 27, in the presence
of catalytic amounts of CuSO4·5H2O (10–30 mol%) and
sodium l-ascorbate (20–60 mol%) in DMF at RT, gave com-
pounds 29a–c in excellent yields (Scheme 7). Treatment of
mestranol (27) with the ferrocene-bis
ACHTUNGTREN(NUNG azide) 28b required a
higher loading of CuSO4·5H2O (30 mol%) and a longer re-
action time (6.5 h) to form the corresponding bisACHTUNGTRENNUNG(steroid)
29b in 90% isolated yield.
Next, we turned our attention to the more functionalized
reserpine derivative 20. Reaction of alkyne 20 with diazides
28a,b, in the presence of catalytic amounts of CuSO4·5H2O
(10–30 mol%) and sodium l-ascorbate (20–60 mol%) in
DMF at RT, yielded dimeric alkaloids 30a and 30b[29] in
good isolated yields (Scheme 8). Analogously, submitting
the C-propargyl reserpine derivative 19 to the same reaction
conditions with azide 28a led to the alkaloid-based dimer
31. In all cases, the structural and stereochemical integrity
of the reserpine nucleus was maintained (Scheme 8).
Scheme 5. C2-symmetric bisACTHNUGRTNEUNG(alkynyl)-tethered homohybrids derived from
(1R)-(+)-camphor (9), (R)-(À)-carvone (10), and 3-O-methylestrone
(11).
We proceeded to investigate the compatibility of these re-
action conditions with more functionalized scaffolds. Thus,
the 19-acetylgnaphalin derivative 17 was treated with CuCl/
Chem. Eur. J. 2010, 16, 3798 – 3814
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3801

P. Ramꢀrez-Lꢁpez, M. C. de la Torre, M. A. Sierra et al.
(Scheme 9). Under the standard
conditions, the corresponding
dimers 32a and 33 were ob-
tained in isolated yields of 86
and 90% after 5 h and 1.5 h of
reaction, respectively. Further-
more, cycloaddition of com-
pound 16 and ferrocenyl azide
28b yielded the bioorganome-
tallic dimer 32b in 22% yield
(89% based on recovered start-
ing material). A higher catalyst
loading (30 mol%) and
a
longer reaction time (23 h)
were required in this case
(Scheme 9). It should be noted
that 76% of the 19-acetylgna-
phalin derivative 16 was recov-
ered unaltered.[31] The spectro-
scopic data for coupled com-
pounds 32a,b and 33 are in full
agreement with their proposed
structures.[32]
The obtained results prove
the compatibility of the Glaser–
Hay Cu-promoted oxidative ho-
mocoupling and CuAAC click
reactions with a range of natu-
ral products, from robust ste-
roids to sensitive, highly func-
tionalized diterpenes and alka-
loids. It is worth emphasizing
that diverse natural product ho-
modimers can be prepared ꢄ la
carte from a single alkyne by
choosing the coupling protocol.
Scheme 6. C2-symmetric bis
pine (18).
ACHTUNGTNER(NUNG alkynyl)-tethered homohybrids derived from 19-acetylgnaphalin (15) and reser-
Moreover, structural diversity
can be introduced by appropri-
The structures of compounds 29a–c, 30a,b, and 31 were
ate choice of the coupling reaction, the length of the tether
(by selecting the azide, the alkyne moiety, or both), and the
nature of the natural product scaffold. The fact that there is
a clear relationship between the structures of some dimeric
natural products and the induction of dimerization in pro-
teins may make this approach especially attractive.[33]
In addition to C2-symmetric dimers, the CuAAC reaction
provides a general entry to trimeric and tetrameric struc-
tures owing to the possibility of using tri- and tetra-azides.
Thus, mestranol (27) was independently reacted with tria-
zide 34a and tetraazide 35 under standard click conditions
to afford the corresponding trimeric and tetrameric homo-
hybrids 36 and 37 in excellent isolated yields (Scheme 10).
The structures of compounds 36 and 37 were established
by spectroscopic means. Electrospray MS analysis of 36
showed two signals at m/z 1196.6 and 1120.3 attributable to
the ions [M+Na]+ and [M+HÀ3H2O]+, respectively, consis-
tent with the attachment of three fragments derived from
mestranol (27) to spacer 34a. Likewise, tetramer 37 dis-
established by spectroscopic means. The 1H and 13C NMR
data for each of the dimers showed a single set of signals for
the two natural product fragments, as expected for mole-
cules having a C2 symmetry axis.[30] Likewise, the ESI mass
spectra of the coupled compounds 29a–c showed peaks at
m/z 797.5 [M+HÀH2O]+, 917 [M+H]+, and 773.3
[M+HÀH2O]+, respectively. Dimers 30a and 31 derived
from reserpine showed peaks at m/z 1505.6 [M+H]+ and
1506.2 [M+H]+, while compound 30b gave rise to a signal
at m/z 1589 [M+H]+. All of the above data are consistent
with the attachment of two natural product fragments to the
corresponding diazides 28a–c, in full accordance with the
proposed structures.
Clearly, the CuAAC protocol is an effective method for
preparing dimeric steroids and N- and C-linked dimeric al-
kaloids. To study the usefulness of this approach for prepar-
ing sensitive functionalized natural product-based dimers, al-
kynyl derivatives 16 and 17 were reacted with bisACTHNUTRGENUG(N azide) 28a
3802
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3798 – 3814

Cu–Alkyne Chemistry
FULL PAPER
played a signal at m/z 1562.8 corresponding to the ion
1
[M+Na]+. The H and 13C NMR data for 36 and 37 account
for one-third and one-quarter of the molecules, as expected
for compounds having one C3-symmetry axis and three C2-
symmetry axes, respectively (Scheme 10).[34]
Synthesis of closed oligomers—macrocycles and cages:
Having demonstrated that diverse dimeric and oligomeric
natural product-based structures can be easily obtained
from either commercial or readily available alkynyl deriva-
tives of natural products, we proceeded to investigate the
building of macrocyclic and cage-like steroid-derived archi-
tectures using either the Cu-mediated oxidative homocou-
pling or the CuAAC protocol.[35]
In our previous work,[10] it was established that the combi-
nation of rigid steroid scaffolds 38 with pre-organized tri-
AHCTUNGTREGaNNNU zole spacers produces semicavities 39 (Scheme 11). Com-
pounds 39 form macrocycles in good yields by dimerization
using the Glaser protocol, in spite of this reaction being ki-
netically controlled.[36] Evidently, effecting a second CuAAC
reaction on bisACHTUNTRGNEUNG(alkynyl) dimers 39 by using a series of cap-
Scheme 7. C2-symmetric homohybrids derived from mestranol (27).
ping diazides 28 will yield the desired C2-symmetric dimeric
macrocycles 40. Scaffold-based
diversity may be sequentially
introduced in both click reac-
tions by combining different di-
azides. Thus, semicavities 39a,
39b, and 39c were successfully
ring-closed to form macrocycles
40ab (42%), 40bc (44%), 40cc
(57%), and 40cd (38%) by re-
action with azides 28b, 28c, and
28d
as
appropriate
(Scheme 11).
The structures of the chiral
cavities 40 were established on
1
spectroscopic grounds. Their H
and 13C NMR data showed a
single set of signals for both ste-
roid fragments, as expected for
an architecture possessing a C2
symmetry axis. In addition, ESI
mass spectra of macrocycles
40ab, 40bc, 40cc, and 40cd
showed signals at m/z 1178,
1153, 1046, and 1047, corre-
sponding to the respective
[M+H]+ ions, thus confirming
the proposed structures.
Access to more rigid macro-
cycles having four estrone frag-
ments joined by four units of
1,3-butadiyne was devised by
using the Cu-promoted oxida-
tive coupling. This approach re-
quires the accomplishment of
two sequential Cu-promoted
Scheme 8. C2-symmetric homohybrids derived from reserpine (18).
Chem. Eur. J. 2010, 16, 3798 – 3814
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3803

P. Ramꢀrez-Lꢁpez, M. C. de la Torre, M. A. Sierra et al.
m/z 1294.8 [MÀ2H2O+H]+ and m/z 2682.5 [M+Na]+, re-
spectively. These results proved the proposed structures and
indicated the presence of eight steroid fragments in macro-
1
cycle 44. In addition, the H and 13C NMR data for macrocy-
cles 41 and 44 showed a single set of signals for the estrone
fragments, as expected for these highly symmetrical archi-
tectures possessing three C2-symmetry axes and one C4-sym-
metry axis, respectively. Efforts to modulate the size and the
functionality of the macrocycles are in progress in our labo-
ratories.
Finally, using both the acetylenic homocoupling and the
CuAAC protocols, the synthesis of natural product-based
C3-symmetric cages was pursued. The vast majority of the
reported cage-like architectures prepared through the acety-
lenic coupling have been based on rigid conjugated diynyl
and polyynyl aromatic chains or combinations thereof, and
have had little or no functionalization.[11d] As far as we are
aware, there have been no reports concerning the use of nat-
ural products as building blocks in the construction of such
architectures through these approaches.[39]
The scaffold to build a C3-symmetric cage required the in-
corporation of three identical terminal alkynyl moieties to
carry out either three simultaneous homocouplings or Cu-
mediated cycloadditions in the final decisive step. First, the
attachment of three alkynylestrone fragments to different
cores using the CuAAC protocol was pursued (Scheme 13).
Thus, monoprotected bisACHTNUTGRNEUNG
(alkynyl) building block 38[10] was
reacted with triazides 34a–c to afford trimers 45a (71%),
45b (75%), and 45c (72%), treatment of which with TBAF
produced tripods 46a (98%), 46b (91%), and 46c (88%).
Attempts to cap trimers 46a and 46c with triazides 34a or
34c under standard CuAAC conditions proved unsuccessful,
producing large amounts of polymeric materials. The failure
to generate molecular cages from trimers 46a and 46c could
be due to their lack of pre-organization. In contrast, tripod
46b, derived from bisACTHNUTRGNE(NUG alkynyl) building block 38 and 1,3,5-
tris(azidomethyl)-2,4,6-triethylbenzene (34b), produced the
desired molecular cage 47 in 25% isolated yield when sub-
mitted to the CuAAC protocol with triazide 34c
(Scheme 13). Evidently, the pre-organization imposed by the
1,3,5-triethylbenzene[40] core of azide 34b allows tripod 46b
to react with azide 34c in a productive way, resulting in clo-
sure of the cage. The structure of cage 47 was confirmed by
its ESI mass spectrum, which featured a peak at m/z 1527.3
corresponding to the [M+H]+ ion.
It is remarkable that, in contrast to the highly symmetrical
oligomeric homohybrids prepared throughout this work, the
1H and 13C NMR data for 47 did not show a single set of sig-
nals for the three steroid units (see the Experimental Sec-
tion). Nevertheless, its 13C NMR spectrum was devoid of sig-
nals attributable to any of the terminal alkyne moieties of
the precursor 46b.[41] It should be noted that a flexible tria-
zide like 34c is required for the capping of tripods 46 to
yield the corresponding cages. Thus, attempted reactions of
46 with azides 34a,b were unsuccessful.
Scheme 9. C2-symmetric homohybrids derived from 19-acetylgnaphalin
(15).
homocoupling reactions on a bis
ACHTUNGTNER(NUNG alkynyl)estrone derivative.
Bis(alkyne) 38, the starting material for the click macrocy-
ACHTUNGTRENNUNG
cles 40, has two differentiated alkyne termini and thus rep-
resents a suitable derivative for executing this strategy.
Thus, a sequential synthesis of the estrone-based macrocy-
cle 41 was accomplished (Scheme 12). Submission of 38 to
the Hay conditions for 16 h yielded the corresponding dimer
42 in 89% yield. Removal of the TMS groups by treatment
with TBAF afforded the semicavity 43 required to perform
the crucial macrocyclization step. The homocoupling of 43
under the Eglinton conditions (CuACHTNUTGRNEG(UN OAc)2·H2O/CH3CN-
Py)[37] nicely formed the expected tetrameric macrocycle 41
in a respectable 66% yield (Scheme 12), together with the
C4-symmetric oligomer 44 (Figure 3).[38] The macrocyclic
structures of compounds 41 and 44 were unequivocally con-
firmed by their ESI mass spectra, which showed peaks at
Finally, we developed an entry to steroid-based C3-sym-
metric cages by performing three simultaneous Cu-promot-
3804
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3798 – 3814

Cu–Alkyne Chemistry
FULL PAPER
lation of three equivalents of
estrone (49) with one equiva-
lent of 1,3,5-tris(bromomethyl)-
2,4,6-triethylbenzene[42] in the
presence of NaH in DMF at
708C (Scheme 14). Terminal
alkyne groups were then incor-
porated at the carbonyl groups
of estrone-based trimer 48 by
treatment with lithium TMS-
acetylide, yielding 50. Removal
of the TMS groups yielded
tripod 51 bearing three terminal
alkynyl groups. Compound 51
was ultimately submitted to the
Eglinton conditions, yielding
the desired C3-symmetric hex-
americ estrone-based cage 52 in
a remarkable 41% yield. Other
standard Cu–acetylene cou-
pling-based
methodologies
were tested, but without any
substantial improvement in
yield.[43]
Cage 52 possesses one C2-
and one C3-symmetry axis, and
its 1H and 13C NMR spectra
showed a single set of signals
for the six steroid fragments.
The structure of 52 was un-
equivocally confirmed by its
MALDI mass spectrum, which
showed two peaks at m/z 2191.3
[M+Na]+ and 2207.3 [M+K]+.
Scheme 10. Trimer 36 and tetramer 37 derived from mestranol (27).
As far as we are aware, this is
ed oxidative homocouplings on trialkynyl-based estrone
scaffolds (Scheme 14).
the first example of a natural product-based cage prepared
by acetylenic coupling.[39]
In the light of the discussed results, the C3-symmetric
tripod 48 bearing three estrone units was prepared by alky-
It is worth noting that while most efforts have been fo-
cused on the preparation of supramolecular cages, the effi-
Scheme 11. C2-symmetric macrocycles prepared from estrone-derived bisACTHUNTGRNEUNG(alkyne) 38.
Chem. Eur. J. 2010, 16, 3798 – 3814
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3805

P. Ramꢀrez-Lꢁpez, M. C. de la Torre, M. A. Sierra et al.
Scheme 12. Tetrameric macrocycle 41 from estrone-derived bisACTHNUGRTNEUNG(alkyne) 38.
Conclusion
Two parallel approaches for
preparing diverse and complex
C2- and C3-symmetric homohy-
brids derived from a series of
mono- and diterpenes, steroids,
and alkaloids have been report-
ed. Both procedures are based
on the mono-addition of bis-
AHCTUNGTRENGN(UN alkynyl) dilithium reagents to
natural products bearing a car-
bonyl group to produce the cor-
responding alkynyl derivatives.
Subjecting these alkynyl natural
product
mono-adducts
to
Glaser–Hay Cu-promoted ho-
mocoupling or the CuAAC re-
action resulted in the synthesis
of steroid-, terpene-, and alka-
loid-based homohybrid deriva-
tives
incorporating
diverse
spacers to join the natural prod-
uct scaffolds. The compatibility
of both approaches with dense-
ly functionalized natural prod-
ucts, such as the highly sensitive
diterpene 19-acetylgnaphalin,
Figure 3. C4-symmetric macrocycle prepared from bisACTHNUTRGENUG(N alkyne) 38.
cient covalent assembly of cage-like structures still remains
a challenge. In this context, the above described approach
to estrone-based cages 47 and 52 could be useful for applica-
tion to other natural products and represents an entry to
molecular architectures having very different structural de-
signs. The study of these chiral cavities as host molecules is
underway in our laboratories.
has also been studied. The use of ferrocenyl-bisACHTUNGTRENNUNG(azide)s
offers access to new bioorganometallic homohybrids having
two steroidal, two diterpenic, or two alkaloid moieties teth-
ered to the metallic nucleus through two triazole rings. Fur-
thermore, straightforward entries to novel closed highly
symmetrical and complex estrone-based macrocyclic and
cage architectures by means of the Glaser–Eglinton homo-
coupling and the CuAAC protocol have been devised. The
modular protocol developed here constitutes an excellent
means of preparing structurally diverse steroid-based macro-
3806
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3798 – 3814

Cu–Alkyne Chemistry
FULL PAPER
was added via a cannula at the same
temperature. The reaction mixture was
stirred at the temperature specified
below until completion of the reaction
(TLC analysis). After quenching with
saturated aqueous NH4Cl solution and
stirring for 30 min, the layers were
separated. The aqueous layer was ex-
tracted twice with AcOEt. The com-
bined organic layers were washed with
brine, dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo.
Pure reaction products were obtained
by chromatography on silica gel.
Compound 14: Following the general
procedure, a solution of 3-O-methyles-
trone (11) (112 mg, 0.39 mmol) in
THF (10 mL) was added to the orga-
nolithium reagent prepared from 1,3-
diethynylbenzene (100 mg, 0.79 mmol)
and LiHMDS (1.7 mL, 1.70 mmol,
1.0m in THF) in THF (20 mL). The re-
sulting mixture was stirred at À508C
for 3 h. Chromatography on silica gel
(hexanes/AcOEt 9:1) of the crude
product obtained following the general
work-up yielded 160 mg (99%) of
pure 14 as a yellow solid. M.p. 52–
568C (amorphous); [a]2D0 =À32.71 (c=
0.61 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.58 (brs, 1H; Ar), 7.43
(dd, J=7.9, 1.3 Hz, 2H; Ar), 7.26 (m,
2H, H-1; Ar), 6.72 (dd, J=8.5, 2.6 Hz, 1H; H-2), 6.64 (d, J=2.6 Hz, 1H;
Scheme 13. Synthesis of estrone-derived cage 47.
cycles and molecular cages. Investigations of the use of
these molecular architectures in different supramolecular
processes are underway in our laboratories.
ꢀ
H-4), 3.78 (s, 3H; OCH3), 3.05 (s, 1H; C CH), 2.87 (m, 2H), 2.50–1.26
(m, 14H), 0.93 ppm (s, 3H; H-18); 13C NMR (75 MHz, CDCl3): d=157.4
(C; C-3), 137.9 (C; C-5), 135.0 (CH; Ar), 132.5 (C; C-10), 131.9 (CH;
Ar), 131.7 (CH; Ar), 128.3 (CH; Ar), 126.3 (CH; C-1), 123.3 (C; Ar),
ꢀ
122.4 (C; Ar), 113.7 (CH; C-4), 111.5 (CH; C-2), 93.6 (C; C C), 84.9 (C;
Experimental Section
ꢀ
ꢀ
ꢀ
C C), 82.7 (C; C C), 80.2 (C; C-17), 77.8 (CH; C CH), 55.1 (OCH3),
49.8 (CH; C-14), 47.6 (C; C-13), 43.6 (CH; C-9), 39.4 (CH; C-8), 39.0
(CH2; C-16), 33.1 (CH2; C-12), 29.8 (CH2; C-6), 27.2 (CH2; C-7), 26.4
(CH2; C-11), 22.9 (CH2; C-15), 12.9 ppm (CH3; C-18); IR (KBr): n˜ =
3436, 3292, 2930, 1609, 1500, 1254, 895, 795 cmÀ1; MS (EI): m/z (%): 410
[M]+ (100), 395 (21), 316 (19), 284 (32), 267 (72), 242 (32), 227 (42), 174
(66), 147 (36), 126 (25), 115 (21), 91 (12); elemental analysis calcd (%)
for C29H30O2: C 84.84, H 7.37; found: C 85.02, H 7.08.
General procedures: Flame-dried glassware and standard Schlenk tech-
niques were used for moisture-sensitive reactions. DMF, MeCN, and
THF were dried by passage through solvent-purification columns con-
taining activated alumina. Other solvents were HPLC grade and were
used without further purification. All reagents were obtained from com-
mercial sources and were used without further purification, unless noted
otherwise. Flash column chromatography was performed using silica gel
(Merck, no. 9385, 230–400 mesh). Products were identified by means of
TLC (60 F254, Merck). UV light (l=254 nm) was used to develop the
plates. 1H and 13C NMR spectra were recorded at 300, 400, or 500 MHz
(1H NMR) and at 75 or 100 MHz (13C NMR) using CDCl3 as solvent,
with the residual solvent signal as the internal reference (CHCl3/CDCl3,
d=7.25 and 77.0 ppm). The following abbreviations are used to describe
peak patterns when appropriate: s (singlet), d (doublet), t (triplet), q
(quadruplet), m (multiplet), and br (broad). Mass spectra were recorded
using the electron impact (EI) technique with an ionization energy of
70 eV, atmospheric pressure chemical ionization (APCI), matrix-assisted
laser desorption/ionization (MALDI), or electrospray (ESI) chemical
ionization techniques in positive mode, unless noted otherwise. IR spec-
tra were obtained on a Perkin–Elmer 681 spectrophotometer. Optical ro-
tations were measured on a 241 MC polarimeter using light from a
sodium lamp. Melting points were determined on a Koffler block. Ele-
mental analyses were performed with a Carlo Erba EA 1108 apparatus.
Compound 16 from 19-acetylgnaphalin (15) and lithium TMS-acetylide:
tBuLi (0.17 mL, 0.28 mmol, 1.7m in hexanes) was added to a solution of
ethynyltrimethylsilane (42 mL, 0.30 mmol) in THF (5 mL) at À788C.
After stirring for 30 min, a solution of 19-acetylgnaphalin (26) (100 mg,
0.25 mmol) in THF (5 mL) was added via a cannula. The reaction mix-
ture was stirred for 30 min at À788C and then saturated aqueous NH4Cl
solution was added. The resulting mixture was extracted with AcOEt (3ꢅ
25 mL), and the combined layers were washed with brine, dried over an-
hydrous Na2SO4, filtered, and concentrated in vacuo. Chromatography on
silica gel (hexanes/AcOEt 7:3) of the crude product afforded 90 mg
(72%) of pure 16-TMS as a white solid. M.p. 65–678C (amorphous);
[a]2D0 =+31.16 (c=0.52 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.42
(m, 2H; H-15, H-16), 6.38 (dd, J=1.9, 0.9 Hz, 1H; H-14), 5.35 (t, J=
8.9 Hz, 1H; H-12), 5.10 (d, J=13.6 Hz, 1H; HB-19), 4.84 (d, J=13.6 Hz,
1H; HA-19), 4.69 (dd, J=3.6, 2.3 Hz, 1H; HB-18), 4.16 (s, 1H; OH),
2.42–2.10 (m, 7H), 2.07 (s, 3H; COCH3), 2.00–1.55 (m, 4H), 1.52 (qt, J=
13.1, 4.2 Hz, 1H), 1.04 (m overlapped, 1H), 1.02 (d, J=6.8 Hz, 3H; H-
17), 0.16 ppm (s, 9H; TMS); 13C NMR (75 MHz, CDCl3): d=175.9 (C=
O; C-20), 170.4 (C; COCH3), 144.1 (CH; C-15), 139.5 (CH; C-16), 125.0
General procedure for the addition of aromatic bisACHTNUTRGNEUNG(alkyne)s to natural
products—synthesis of compounds 12–14, 16, and 17: Lithium bis(trime-
thylsilyl)amide (LiHMDS, 1.0m in THF) was added dropwise to a solu-
ꢀ
ꢀ
(C; C-13), 109.7 (C; C C-Si), 107.9 (CH; C-14), 94.7 (C; C C-Si), 73.9
(C; C-6), 71.4 (CH; C-12), 64.9 (C; C-4), 62.9 (CH2; C-19), 52.3 (CH2; C-
18), 51.3 (CH; C-10), 50.8 (C; C-9), 47.2 (C; C-5), 44.9 (CH2; C-11), 41.0
(CH2; C-7), 37.4 (CH; C-8), 32.9 (CH2; C-3), 24.5 (CH2; C-2), 23.4 (CH2;
tion of the appropriate aromatic bis
argon. After stirring for 30 min, the resulting mixture was allowed to
G
reach À508C and then a solution of the requisite natural product in THF
Chem. Eur. J. 2010, 16, 3798 – 3814
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3807

P. Ramꢀrez-Lꢁpez, M. C. de la Torre, M. A. Sierra et al.
15.8 ppm (CH3; C-17); IR (film): n˜ =3466, 2950, 2873, 1753, 1739, 1444,
1250, 1187, 1154, 1025, 922, 873, 808 cmÀ1; MS (APCI): m/z: 429 [M+H]+
; elemental analysis calcd (%) for C24H28O7: C 67.28, H 6.59; found: C
67.50, H 6.75.
General procedure for the CuI-catalyzed oxidative coupling of terminal
alkynes—synthesis of compounds 21–26: CuCl (10 equiv) and freshly dis-
tilled TMEDA (10 equiv) were successively added to a solution of the ap-
propriate alkyne (1 equiv) in dry CH2Cl2 at room temperature. The dark-
green mixture was stirred at the same temperature under air until the
starting material was no longer detected (TLC analysis). The reaction
mixture was then partitioned between CH2Cl2 and H2O. The organic
layer was separated, washed with H2O until it became colorless, dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. Chromatog-
raphy on silica gel of the crude products afforded the desired pure com-
pounds.
Dimer 23 by coupling of alkyne 14: Following the general procedure,
dimer 23 was prepared from alkyne 14 (50 mg, 0.122 mmol), CuCl
(121 mg, 1.22 mmol), and TMEDA (183 mL, 1.22 mmol) in dry CH2Cl2
(10 mL). The reaction mixture was stirred for 2 h at room temperature.
Chromatography on silica gel (hexanes/AcOEt 9:1) of the crude product
obtained following the general work-up yielded 44 mg (88%) of pure 23
as a yellow solid. M.p. 104–1068C; [a]2D6 =À41.50 (c=0.56 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.59 (brs, 2H; Ar), 7.44 (dt, J=7.9,
1.6 Hz, 4H; Ar), 7.28 (t, J=7.9 Hz, 2H; Ar), 7.22 (d, J=8.6 Hz, 2H; H-
1), 6.72 (dd, J=8.6, 2.5 Hz, 2H; H-2), 6.63 (d, J=2.5 Hz, 2H; H-4), 3.78
(s, 6H; OCH3), 2.86 (m, 4H), 2.40 (m, 4H), 2.30–1.30 (m, 24H),
0.93 ppm (s, 6H; H-18); 13C NMR (100 MHz, CDCl3): d=157.4 (2C; C-
3), 137.9 (2C; C-5), 135.4 (2CH; Ar), 132.4 (2C; C-10), 132.3 (2CH;
Ar), 132.0 (2CH; Ar), 128.5 (2CH; Ar), 126.3 (2CH; C-1), 123.5 (2C;
ꢀ
Ar), 121.9 (2C; Ar), 113.7 (2CH; C-4), 111.4 (2CH; C-2), 93.8 (2C; C
ꢀ
ꢀ
ꢀ
C), 84.7 (2C; C C), 80.8 (2C; C-17), 80.2 (2C; C C), 74.3 (2C; C C),
55.1 (2OCH3), 49.8 (2CH; C-14), 47.6 (2C; C-13), 43.6 (2CH; C-9), 39.4
(2CH; C-8), 39.0 (2CH2; C-16), 33.0 (2CH2; C-12), 29.8 (2CH2; C-6),
27.2 (2CH2; C-7), 26.4 (2CH2; C-11), 22.9 (2CH2; C-15), 12.8 ppm
(2CH3; C-18); IR (KBr): n˜ =3460, 2930, 2865, 1610, 1591, 1499, 1254,
1041, 793, 684 cmÀ1
;
MS (ESI): m/z: 818.3 [M]+ (absent), 783
[MÀ2H2O+H]+; elemental analysis calcd (%) for C58H58O4: C 85.05, H
7.14; found: C 84.73, H 7.38.
Dimer 24 by coupling of alkyne 17: Following the general procedure,
dimer 24 was prepared from alkyne 17 (50 mg, 0.095 mmol), CuCl
(94 mg, 0.95 mmol), and TMEDA (142 mL, 0.95 mmol) in dry CH2Cl2
(10 mL). The reaction mixture was stirred for 2 h at room temperature.
Chromatography on silica gel (hexanes/AcOEt3:2) of the crude product
obtained following the general work-up yielded 44 mg (88%) of pure 24
as a white solid. M.p. 125–1278C; [a]2D6 =+80.54 (c=0.44 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.52 (m, 2H; Ar), 7.48 (dt, J=8.6,
1.3 Hz, 2H; Ar), 7.43 (m, 2H; Ar), 7.41 (m, 2H; Ar), 7.40 (dt, J=7.9,
1.4 Hz, 2H; Ar), 7.32 (t, J=7.7 Hz, 2H; Ar), 6.37 (dd, J=1.8, 0.9 Hz,
2H; H-14), 5.37 (t, J=8.6 Hz, 2H; H-12), 5.16 (d, J=13.7 Hz, 2H; HB-
19), 4.86 (d, J=13.7 Hz, 2H; HA-19), 4.62 (dd, J=3.6, 2.2 Hz, 2H; HB-
18), 4.28 (s, 2H; OH), 2.58–2.16 (overlapped, 14H), 2.08 (s, 6H;
COCH3), 2.04 (m, 2H), 1.92 (m, 2H), 1.81 (dd, J=13.9, 4.5 Hz, 2H), 1.75
(qd overlapped, J=13.2, 3.9 Hz, 2H), 1.56 (qt, J=13.4, 4.0 Hz, 2H), 1.07
(overlapped, 2H), 1.04 ppm (d, J=6.8 Hz, 6H; H-17); 13C NMR
(100 MHz, CDCl3): d=175.9 (2C; C-20), 170.5 (2C; COCH3), 144.2
(2CH; C-15), 139.5 (2CH; C-16), 134.9 (2CH; Ar), 132.5 (2CH; Ar),
132.0 (2CH; Ar), 128.8 (2CH; Ar), 125.0 (2C; C-13), 122.9 (2C; Ar),
Scheme 14. Synthesis of hexameric estrone-based cage 52.
C-1), 21.2 (CH3; COCH3), 15.8 (CH3; C-17), 0.3 ppm (3CH3; TMS); IR
(KBr): n˜ =3460, 2962, 2159, 1763, 1251, 1153, 1038, 925, 875, 844,
760 cmÀ1; MS (EI): m/z (%): 500 [M]+ (absent), 482 [MÀH2O]+ (1), 458
(2), 440 (5), 425 (5), 409 (11), 303 (26), 273 (54), 255 (41), 167 (48), 123
(90), 95 (51), 73 (100).
Solid nBu4NF·3H2O (95 mg, 0.30 mmol) was added in portions to a solu-
tion of alkyne 16-TMS (150 mg, 0.30 mmol) in THF (10 mL) at À788C
under argon. The resulting mixture was stirred for 30 min at the same
temperature. It was then filtered through a short pad of silica gel
(AcOEt) and the solvents were removed in vacuo to yield 16 (116 mg,
90%) as
a
white solid. M.p. 169–1708C; [a]3D0 =+28.24 (c=1.42 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.42 (m, 2H; H-15, H-16), 6.36
(dd, J=1.5 Hz, 0.9 Hz, 1H; H-14), 5.34 (t, J=8.7 Hz, 1H; H-12), 5.11 (d,
J=13.8 Hz, 1H; HB-19), 4.81 (d, J=13.8 Hz, 1H; HA-19), 4.66 (dd, J=
ꢀ
ꢀ
122.0 (2C; Ar), 107.9 (2CH; C-14), 94.2 (2C; C C), 88.1 (2C; C C),
ꢀ
ꢀ
ꢀ
3.3, 2.1 Hz, 1H; H-18), 4.23 (s, 1H; OH), 2.78 (s, 1H; C CH), 2.48–2.00
80.8 (2C; C C), 74.4 (2C; C C), 74.3 (2C; C-6), 71.5 (2CH; C-12), 65.1
(2C; C-4), 63.0 (2CH2; C-19), 52.3 (2CH2; C-18), 51.4 (2CH; C-10), 50.9
(2C; C-9), 47.6 (2C; C-5), 44.9 (2CH2; C-11), 41.4 (2CH2; C-7), 37.6
(2CH; C-8), 32.9 (2CH2; C-3), 24.5 (2CH2; C-2), 23.4 (2CH2; C-1), 21.3
(2CH3; COCH3), 15.9 ppm (2CH3; C-17); IR (KBr): n˜ =3454, 2964, 2932,
(m, 7H), 2.06 (s, 3H; COCH3), 2.00 (m, 1H), 1.91 (m, 1H), 1.72 (dd, J=
13.8, 3.9 Hz, 1H), 1.70 (m, 1H), 1.56 (qt overlapped, J=13.2, 4.4 Hz,
1H), 1.06 (m overlapped, 1H), 1.01 ppm (d, J=6.6 Hz, 3H; H-17);
13C NMR (75 MHz, CDCl3): d=176.0 (C=O; C-20), 170.4 (C; COCH3),
144.1 (CH; C-15), 139.5 (CH; C-16), 125.0 (C; C-13), 107.9 (CH; C-14),
2877, 2215, 1762, 1737, 1633, 1590, 1250, 1153, 1045, 925, 875, 796 cmÀ1
;
MS (ESI): m/z: 1077.3 [M+Na]+; elemental analysis calcd (%) for
ꢀ
ꢀ
87.7 (C; C C), 78.0 (CH; C CH), 73.8 (C; C-6), 71.5 (CH; C-12), 65.0
(C; C-4), 63.0 (CH2; C-19), 52.4 (CH2; C-18), 51.4 (CH; C-10), 50.5 (C;
C-9), 47.1 (C; C-5), 44.7 (CH2; C-11), 41.3 (CH2; C-7), 37.2 (CH; C-8),
32.9 (CH2; C-3), 24.4 (CH2; C-2), 23.4 (CH2; C-1), 21.2 (CH3; COCH3),
C64H62O14: C 72.85, H 5.92; found: C 73.19, H 5.66.
Dimer 25 by coupling of alkyne 19: Following the general procedure,
dimer 25 was prepared from alkyne 19 (30 mg, 0.046 mmol), CuCl
3808
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3798 – 3814

Cu–Alkyne Chemistry
FULL PAPER
(46 mg, 0.46 mmol), and TMEDA (69 mL, 0.46 mmol) in dry CH2Cl2
(10 mL). The reaction mixture was stirred for 5 h at room temperature.
Chromatography on silica gel (hexanes/AcOEt 1:1) of the crude product
obtained following the general work-up yielded 18 mg (61%) of pure 25
as an orange solid. M.p. 178–1808C; [a]2D0 =À261.06 (c=0.32 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.35 (d, J=8.2 Hz, 2H; H-9), 7.32 (s,
4H; H-25, H-29), 7.24 (d, J=2.3 Hz, 2H; H-12), 6.81 (dd, J=8.2, 2.3 Hz,
2H; H-10), 5.03 (ddd, J=11.9, 9.6, 5.1 Hz, 2H; H-18), 4.05 (brs, 2H; H-
3), 3.92 (s, 18H; OMe-30, OMe-32, OMe-31), 3.90 (m overlapped, 2H;
H-17), 3.87 (s, 6H; OMe-35), 3.83 (s, 6H; OMe-34), 3.52 (s, 6H; OMe-
33), 3.26 (t, J=12.8 Hz, 2H; H-21), 3.00 (m, 2H; H-15), 2.96 (d, J=
6H; H-9, H-25, H-29), 7.28 (s, 2H; N3C=CH), 6.96 (brs, 2H; H-12), 6.74
(d, J=8.4 Hz, 2H; H-10), 5.37 (d, J=17.2 Hz, 2H; CHHC=CN3), 5.16 (d,
J=17.2 Hz, 2H; CHHC=CN3), 5.10 (d, J=2.4 Hz, 4H; CH2N3), 5.02
(brdd, J=11.4, 4.8 Hz, 2H; H-18), 4.19 (brs, 2H; H-3), 4.07–4.04 (m
overlapped, 8H; Cp), 3.92 (s, 18H; OMe-30, OMe-32, OMe-31), 3.88–
3.84 (m, 2H; H-17), 3.77 (s, 6H; OMe-35), 3.72 (s, 6H; OMe-34), 3.49 (s,
6H; OMe-33), 3.16 (m overlapped, 6H; 2H-5, H-21), 2.94 (d, J=8.7 Hz,
2H; H-6), 2.68 (d, J=10.7 Hz, 2H; H-16), 2.47 (brm, 2H; H-6), 2.38 (m
overlapped, 8H; H-21, H-19, 2H-14), 2.21 (m overlapped, 2H; H-15),
2.01 (m, 2H; H-19), 1.98 ppm (m, 2H; H-20); 13C NMR (75 MHz,
CDCl3): d=172.3 (2C=O; C-22), 165.3 (2C=O; C-23), 156.5 (2C; C-11),
152.9 (4C; C-28, C-26), 144.8 (2C; N3C=CH), 142.2 (2C; C-27), 138.2
(2C; C-13), 132.1 (2C; C-2), 125.3 (2C; C-24), 121.6 (2C; C-8), 121.0
(2CH; N3C=CH), 118.6 (2CH; C-9), 109.9 (2C; C-7), 109.0 (2CH; C-10),
106.7 (4CH; C-25, C-29), 93.7 (2CH; C-12), 82.1 (2C; Cp), 77.8 (2CH;
C-17), 77.6 (2CH; C-18), 69.7 (4CH; Cp), 69.4 (2CH; Cp), 69.3 (2CH;
Cp), 60.8 (2OCH3; C-31), 60.6 (2OCH3; C-33), 56.2 (4OCH3; C-30, C-
32), 55.8 (2OCH3; C-35), 55.3 (2CH; C-3), 51.9 (2OCH3 + 2CH; C-16,
C-34), 51.4 (2CH2; C-5), 50.6 (2CH2; CH2N3), 49.4 (2CH2; C-21), 40.7
(2CH2; CH2C=CN3), 33.6 (2CH; C-20), 32.4 (2CH; C-15), 30.6 (2CH2;
C-19), 25.4 (2CH2; C-14), 17.9 ppm (2CH2; C-6); IR (KBr): n˜ =3435,
2936, 2837, 1716, 1622, 1589, 1504, 1493, 1458, 1415, 1333, 1255, 1224,
1179, 1154, 1127, 1043, 762 cmÀ1; MS (ESI): m/z: 1589 [M+H]+; elemen-
tal analysis calcd (%) for C84H96FeN10O18: C 63.47, H 6.09, N 8.81; found:
C 63.70, H 5.77, N 8.55.
ꢀ
16.7 Hz, 2H; CH2C C), 2.75 (dd, J=10.9, 4.7 Hz, 2H; H-16), 2.69 (dd,
J=14.0, 2.7 Hz, 2H; H-21), 2.62 (dd, J=11.7, 2.7 Hz, 2H; H-5), 2.40–2.00
(overlapped, 12H), 1.95 (brd overlapped, 2H; H-20), 1.90 (m, 2H; H-
19), 1.82 ppm (m, 2H; H-6); 13C NMR (100 MHz, CDCl3): d=182.8 (2C;
C-2), 172.6 (2C; C-22), 165.4 (2C; C-23), 160.3 (2C; C-11), 155.3 (2C; C-
13), 152.9 (4C; C-26, C-28), 142.2 (2C; C-27), 135.3 (2C; C-8), 125.4
(2C; C-24), 122.6 (2CH; C-9), 111.7 (2CH; C-10), 106.7 (4CH; C-25, C-
29), 106.6 (2CH; C-12), 78.0 (2CH; C-18), 77.9 (2CH; C-17), 73.4 (2C;
ꢀ
ꢀ
C C), 67.6 (2C; C C), 60.9 (2OCH3; C-31), 60.8 (2OCH3; C-33), 56.2
(4OCH3; C-30, C-32), 55.5 (2OCH3; C-35), 54.7 (2CH; C-3), 54.6 (2C;
C-7), 52.0 (2OCH3; C-34), 51.9 (2CH; C-16), 50.4 (2CH2; C-5), 49.3
(2CH2; C-21), 34.5 (2CH; C-20), 33.3 (2CH2; C-6), 31.2 (2CH; C-15),
ꢀ
29.6 (2CH2; C-19), 24.4 (2CH2; CH2C C), 22.6 ppm (2CH2; C-14); IR
(KBr): n˜ =3436, 2832, 1735, 1713, 1589, 1462, 1416, 1335, 1250, 1226,
1128, 1106, 982, 762 cmÀ1; MS (APCI): m/z: 1291 [M+H]+; elemental
analysis calcd (%) for C72H82N4O18: C 66.96, H 6.40, N 4.34; found: C
66.63, H 6.71, N 4.66.
Compound 31: Reaction of
a mixture of diazide 28a (11.0 mg,
0.052 mmol, 1.0 equiv), alkyne 19 (67.3 mg, 0.104 mmol, 2.0 equiv),
sodium l-ascorbate (2.0 mg, 0.010 mmol, 0.2 equiv), and CuSO4·5H2O
(1.2 mg, 0.005 mmol, 0.1 equiv) in DMF (3 mL) for 1 h, followed by pu-
rification (SiO2; AcOEt to AcOEt/MeOH 9:1), yielded pure 31 as a
yellow solid (59 mg, 75%). M.p. 150–1538C; [a]2D5 =À119.20 (c=0.60 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.32 (s, 6H; H-9, H-25, H-29),
7.12 (s, 2H; N3C=CH), 7.09 (d, J=2.4 Hz, 2H; H-12), 6.73 (dd, J=8.1,
2.4 Hz, 2H; H-10), 6.34 (s, 4H; CH2C=CN3), 5.01 (m, 2H; H-18), 4.36 (d,
J=5.1 Hz; 2H), 4.16 (d, J=14.1 Hz, 2H; CHHN3), 4.06 (d, J=14.1 Hz,
2H; CHHN3), 3.93 (s, 18H; OCH3-30, OCH3-31, OCH3-32), 3.92 (m over-
lapped, 4H; H-17, H-3), 3.81 (s, 6H; OCH3-35), 3.76 (s, 6H; OCH3-34),
3.56–3.46 (m overlapped, 2H), 3.51 (s, 6H; OCH3-33), 3.13 (d, J=
14.6 Hz, 2H; H-21), 2.92 (m, 2H; H-15), 2.68 (m, 6H; H-21, H-16, H-5),
2.35–2.00 (m, 6H; H-5, 2H-14), 1.98–1.78 (m, 8H; H-20, H-19, H-6),
General procedure for the synthesis of oligomers 29a–c, 30a,b, 31, 32a,b,
33, 36, 37, 40ab, 40bc, 40cc, 40 cd, 45a–c, and 47: A mixture of the requi-
site organic azide (1.0 equiv), the requisite alkyne (1.0 equiv per equiv of
N3), sodium l-ascorbate (0.10–2.00 equiv), and CuSO4·5H2O (0.05–
1.00 equiv) in DMF was stirred under Ar at RT for the period of time
specified below. The reaction was then quenched with water at 08C
(slightly exothermic) and the mixture was allowed to reach RT. It was
then extracted with AcOEt (three times) and the combined organic ex-
tracts were washed twice with water and once with brine. The organic
layer was dried over MgSO4 and filtered, and the solvent was removed in
vacuo to afford the respective reaction product, which was purified by
passage through a short pad of SiO2.
1.00 ppm (s, 6H; O2CACTHNUTRGNEUNG
(CH3)2); 13C NMR (75 MHz, CDCl3): d=184.1 (2C;
C-2), 172.4 (2C=O; C-22), 165.4 (2C=O; C-23), 160.2 (2C; C-11), 155.5
(2C; C-13), 152.9 (4C; C-26, C-28), 142.3 (2C; N3C=CH), 142.2 (2C; C-
27), 135.5 (2C; C-8), 125.4 (2C; C-24), 122.8 (2CH; C-9), 121.7 (2CH;
Compound 29b: Reaction of
a mixture of diazide 28b (28 mg,
0.090 mmol, 1.0 equiv), mestranol (27) (56 mg, 0.180 mmol, 2.0 equiv),
sodium l-ascorbate (11 mg, 0.054 mmol, 0.6 equiv), and CuSO4·5H2O
(7 mg, 0.027 mmol, 0.3 equiv) in DMF (4 mL) for 6.5 h, followed by pu-
rification (SiO2; AcOEt to AcOEt/MeOH 9:1), yielded pure 29b as an
orange solid (75 mg, 90%). M.p. 1908C (decomp.); [a]2D0 =+18.63 (c=
0.26 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.40 (s, 2H; N3C=CH),
7.12 (d, J=8.4 Hz, 2H; H-1), 6.67 (dd, J=8.4, 2.1 Hz, 2H; H-2), 6.61 (d,
J=2.1 Hz, 2H; H-4), 5.19 (s, 4H; CH2N3), 4.26 (s, 4H; Cp), 4.22 (s, 4H;
Cp), 3.76 (s, 6H; OCH3), 2.85 (m, 4H), 2.40–1.20 (m, 28H), 1.04 ppm (s,
6H; C-18); 13C NMR (75 MHz, [D6]DMSO): d=156.8 (2C; C-3), 154.0
(2C; N3C=CH), 137.3 (2C; C-5), 132.0 (2C; C-10), 126.0 (2CH; C-1),
122.1 (2CH; N3C=CH), 113.3 (2CH; C-4), 111.3 (2CH; C-2), 83.3 (2C;
Cp), 81.0 (2C; C-17), 69.4 (4CH; Cp), 69.1 (4CH; Cp), 54.7 (2OCH3),
48.3 (2CH2; CH2N3), 47.5 (2CH; C-14), 46.5 (2C; C-13), 43.1 (2CH; C-
9), 39.7 (2CH; C-8), 37.1 (2CH2; C-16), 32.5 (2CH2; C-12), 29.2 (2CH2;
C-6), 27.0 (2CH2; C-7), 25.9 (2CH2; C-11), 23.4 (2CH2; C-15), 14.3 ppm
(2CH3; C-18); IR (KBr): n˜ =3414, 2932, 2863, 1611, 1501, 1452, 1289,
1254, 1238, 1142, 1105, 1041, 843, 814, 491 cmÀ1; MS (ESI): m/z: 917
[M+H]+; elemental analysis calcd (%) for C54H64FeN6O4: C 70.73, H
7.03, N 9.17; found: C 70.50, H 6.90, N 8.93.
N3C=CH), 111.5 (2CH; C-10), 109.7 (C; O2CACTHNURGTNEG(UN CH3)2), 106.7 (4CH; C-25,
C-29), 106.4 (2CH; C-12), 78.1 (2CH; C-18), 77.9 (2CH; C-17), 74.5
(2CH; OCHCH2N3), 60.8 (2OCH3; C-31), 60.7 (2OCH3; C-33), 56.8
(2CH; C-3), 56.2 (4OCH3; C-30, C-32), 55.5 (2OCH3, C-35), 54.9 (2C;
C-7), 52.1 (2CH3; C-34), 51.7 (2CH; C-16), 50.2 (2CH2; C-5), 49.5
(2CH2; CH2N3), 49.2 (2CH2; C-21), 35.7 (2CH2; C-6), 34.6 (2CH; C-20),
31.3 (2CH; C-15), 30.3 (2CH2; CH2C=CN3), 29.6 (2CH2; C-19), 26.5
(2CH3; O2CACHTNUGRTNEUNG(CH3)2), 22.4 ppm (2CH2; C-14); IR (KBr): n˜ =3435, 2938,
2837, 1736, 1716, 1619, 1589, 1504, 1482, 1462, 1416, 1374, 1335, 1301,
1277, 1251, 1225, 1178, 1128, 1107, 1044, 1029, 998, 983, 763 cmÀ1; MS
(ESI): m/z: 1506.2 [M+H]+; elemental analysis calcd (%) for
C79H96N10O20: C 63.02, H 6.43, N 9.30; found: C 63.33, H 6.21, N 9.15.
Compound 33: Reaction of a mixture of diazide 28a (11 mg, 0.054 mmol,
1.0 equiv), alkyne 17 (60 mg, 0.114 mmol, 2.1 equiv), sodium l-ascorbate
(2 mg, 0.011 mmol, 0.2 equiv), and CuSO4·5H2O (1 mg, 0.005 mmol,
0.1 equiv) in DMF (4 mL) for 1.5 h, followed by purification (SiO2; hex-
anes/AcOEt 1:1 to AcOEt), yielded pure 33 as a white solid (62 mg,
90%). M.p. 187–1908C; [a]3D0 =+40.39 (c=1.03 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.94 (s, 2H; N3C=CH), 7.75 (m, 2H; Ar), 7.44–
7.38 (m, 10H; H-16, H-15, Ar), 6.38 (brs, 2H; H-14), 5.38 (t, J=8.4 Hz,
2H; H-12), 5.18 (d, J=13.5 Hz, 2H; HB-19), 4.88 (d, J=13.5 Hz, 2H;
HA-19), 4.71 (brs, 2H; H-18), 4.66 (brs, 4H; CH2N3), 4.31 (s, 2H; OH),
4.12 (brs, 2H; OCHC), 2.60–2.20 (m, 14H), 2.11 (s, 6H; COCH3), 2.00–
Compound 30b: Reaction of
a mixture of diazide 28b (15 mg,
0.051 mmol, 1.0 equiv), alkyne 20 (68 mg, 0.105 mmol, 2.1 equiv), sodium
l-ascorbate (6 mg, 0.030 mmol, 0.6 equiv), and CuSO4·5H2O (4 mg,
0.015 mmol, 0.3 equiv) in DMF (4 mL) for 3 h, followed by purification
(SiO2; hexanes/AcOEt 3:7 to AcOEt/MeOH 9:1), yielded pure 30b as an
orange solid (65 mg, 80%). M.p. 142–1448C (amorphous); [a]2D0 =À90.23
(c=0.35 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.32 (overlapped,
1.50 (m, 10H), 1.25 (s, 6H; O2C
ACHTUGNTERN(NUNG CH3)2), 1.10 (m overlapped, 2H),
1.06 ppm (d, J=6.6 Hz, 6H; H-17); 13C NMR (75 MHz, CDCl3): d=
Chem. Eur. J. 2010, 16, 3798 – 3814
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3809

P. Ramꢀrez-Lꢁpez, M. C. de la Torre, M. A. Sierra et al.
176.0 (2C=O; C-20), 170.5 (2C; COCH3), 146.9 (2C; N3C=CH), 144.1
(2CH; C-15), 139.5 (2CH; C-16), 131.1 (2CH; Ar), 130.7 (2C; Ar), 129.0
(2CH; Ar), 128.2 (2CH; Ar), 125.9 (2CH; N3C=CH), 125.0 (2C; C-13),
40ab as a yellow solid (28.7 mg, 42%). M.p. 193–1958C; [a]2D7 =+10.45
(c=0.44 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.55 (s, 2H; N3C=
CH), 7.45 (s, 2H; N3C=CH), 7.01 (d, J=8.4 Hz, 2H; H-1), 6.68–6.64 (m,
4H; H-2 + H-4), 5.30–5.17 (m, 8H), 4.51 (d, J=14.4 Hz, 2H), 4.40 (d,
J=14.4 Hz, 2H), 4.20 (s, 6H; Cp), 4.13 (s, 2H; Cp), 3.88 (m, 2H; OCH),
2.77 (m, 4H), 2.37 (m, 2H), 2.08 (m, 4H), 1.90 (m, 6H), 1.64–1.25 (m,
14H), 1.01 (s, 6H), 0.98 (s, 6H), 0.68 ppm (brt, J=12.0 Hz, 2H);
13C NMR (75 MHz, CDCl3): d=155.6 (2C; C-3), 153.8 (2C; N3C=CH),
145.1 (2C; N3C=CH), 138.0 (2C; C-5), 133.0 (2C; C-10), 126.3 (2CH; C-
1), 124.2 (2CH; N3C=CH), 121.2 (2CH; N3C=CH), 115.1 (2CH; C-4),
123.0 (2C; Ar), 121.8 (2CH; Ar), 110.5 (C; O2CACHTNUTRGNEG(UN CH3)2), 108.0 (2CH; C-
ꢀ
ꢀ
14), 93.5 (2C; C C), 89.0 (2C; C C), 75.4 (2CH; OCHCH2N3), 74.3
(2C; C-6), 71.5 (2CH; C-12), 65.1 (2C; C-4), 63.1 (2CH2; C-19), 52.4
(2CH2; C-18), 51.5 (2CH; C-10), 50.8 (2CH2; CH2N3), 50.2 (2C; C-9),
47.6 (2C; C-5), 44.8 (2CH2; C-11), 41.4 (2CH2; C-7), 37.5 (2CH; C-8),
33.0 (2CH2; C-3), 26.7 (2CH3; O2CACHTUNTRGNEUNG(CH3)2), 24.4 (2CH2; C-2), 23.4
(2CH2; C-1), 21.3 (2CH3; COCH3), 16.0 ppm (2CH3; C-17); IR (KBr):
n˜ =3454, 2965, 2879, 1762, 1738, 1609, 1458, 1368, 1250, 1180, 1153, 1113,
1043, 924, 875, 795, 601 cmÀ1; MS (ESI): m/z: 1291.3 [M+Na]+, 1269.6
[M+H]+; elemental analysis calcd (%) for C71H76N6O16: C 67.18, H 6.03,
N 6.62; found: C 66.95, H 5.84, N 6.38.
112.2 (2CH; C-2), 110.3 (2C; O2CACHTNUGTRNEUNG(CH3)2), 83.2 (2C; Cp), 82.4 (2C; C-
17), 75.2 (2CH; OCH), 69.5 (4CH; Cp), 69.2 (2CH; Cp), 69.0 (2CH;
Cp), 61.7 (2CH2), 49.9 (2CH2), 49.3 (2CH2), 48.6 (2CH; C-14), 47.3 (2C;
C-13), 43.5 (2CH; C-9), 39.4 (2CH; C-8), 38.1 (2CH2; C-16), 33.0
(2CH2; C-12), 29.8 (2CH2; C-6), 27.3 (2CH2; C-7), 26.4 (2CH3), 26.3
(2CH2; C-11), 23.4 (2CH2; C-15), 14.2 ppm (2CH3; C-18); IR (KBr): n˜ =
3436, 2929, 1609, 1497, 1456, 1381, 1232, 1049, 815 cmÀ1; MS (ES): m/z:
1177.9 [M+H]+; elemental analysis calcd (%) for C65H76FeN12O6 (%): C
66.32, H 6.51, N 14.28; found: C 66.54, H 6.78, N 14.42.
Dimer 42 by coupling of alkyne 38:[10] Following the general procedure,
dimer 42 was prepared from alkyne 38 (200 mg, 0.492 mmol), CuCl
(487 mg, 4.92 mmol), and TMEDA (0.74 mL, 4.92 mmol) in dry CH2Cl2
(10 mL). The reaction mixture was stirred for 16 h at room temperature.
Chromatography on silica gel (hexanes/AcOEt 9:1) of the crude product
obtained following the general work-up yielded 178 mg (89%) of pure 42
Compound 36: Reaction of
a mixture of triazide 34a (28.0 mg,
0.115 mmol, 1.0 equiv), mestranol (27) (107.1 mg, 0.345 mmol, 3.0 equiv),
sodium l-ascorbate (6.9 mg, 0.035 mmol, 0.30 equiv), and CuSO4·5H2O
(4.5 mg, 0.018 mmol, 0.15 equiv) in DMF (4 mL) for 1 h, followed by pu-
rification (SiO2; hexanes/AcOEt 1:1 to AcOEt), yielded pure 36 as a
white solid (125.0 mg, 93%). M.p. 179–1818C; [a]2D5 =+37.07 (c=0.74 in
1
CHCl3); H NMR (300 MHz, CDCl3): d=7.36 (s, 3H; N3C=CH), 7.12 (d,
J=8.7 Hz, 3H; H-1), 7.08 (s, 3H; Ar), 6.66 (dd, J=8.7, 2.7 Hz, 3H; H-2),
6.61 (d, J=2.7 Hz, 3H; H-4), 5.49 (s, 6H; CH2N3), 3.75 (s, 9H; OCH3),
2.92 (brs, 3H; OH), 2.88–2.83 (m, 6H), 2.44–2.34 (m, 3H), 2.20–2.05 (m,
6H), 2.01–1.90 (m, 9H), 1.62–1.33 (m, 18H), 1.03 (s, 9H; H-18),
0.68 ppm (td, J=12.9, 3.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=157.4
(3C; C-3), 154.5 (3C; N3C=CH), 138.0 (3C; Ar), 137.0 (3C; C-5), 132.5
(3C; C-10), 127.0 (3CH; Ar), 126.2 (3CH; C-1), 121.5 (3CH; N3C=CH),
113.8 (3CH; C-4), 111.4 (3CH; C-2), 82.4 (3C; C-17), 55.2 (3OCH3),
53.3 (3CH2; CH2N3), 48.4 (3CH; C-14), 47.3 (3C; C-13), 43.4 (3CH; C-
9), 39.4 (3CH; C-8), 37.9 (3CH2; C-16), 33.0 (3CH2; C-12), 29.8 (3CH2;
C-6), 27.4 (3CH2; C-7), 26.2 (3CH2; C-11), 23.5 (3CH2; C-15), 14.2 ppm
(3CH3; C-18); IR (KBr): n˜ =3436, 3133, 2930, 2867, 1610, 1576, 1500,
1454, 1255, 1235, 1129, 1043 cmÀ1; MS (ESI): m/z: 1196.6 [M+Na]+,
1120.3 [MÀ3H2O+H]+; elemental analysis calcd (%) for C72H87N9O6: C
73.63, H 7.47, N 10.73; found: C 73.29, H 7.28, N 10.48.
as
a
white solid. M.p. 88–908C; [a]2D6 =À16.80 (c=0.36 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.24 (d, J=8.5 Hz, 2H; H-1), 6.74 (dd,
J=8.5, 2.5 Hz, 2H; H-2), 6.66 (d, J=2.5 Hz, 2H; H-4), 4.72 (s, 4H;
OCH2), 2.82 (m, 4H), 2.40–1.20 (m, 28H), 0.87 (s, 6H; H-18), 0.19 ppm
(s, 18H; TMS); 13C NMR (75 MHz, CDCl3): d=155.3 (2C; C-3), 138.1
(2C; C-5), 133.7 (2C; C-10), 126.4 (2CH; C-1), 114.9 (2CH; C-4), 112.2
ꢀ
ꢀ
(2CH; C-2), 109.4 (2C; C C), 90.1 (2C; C C), 80.1 (2C; C-17), 74.8
ꢀ
ꢀ
(2C; C C), 70.9 (2C; C C), 56.2 (2OCH2), 49.6 (2CH; C-14), 47.2 (2C;
C-13), 43.7 (2CH; C-9), 39.3 (2CH; C-8), 38.9 (2CH2; C-16), 32.8
(2CH2; C-12), 29.8 (2CH2; C-6), 27.2 (2CH2; C-7), 26.4 (2CH2; C-11),
22.8 (2CH2; C-15), 12.7 (2CH3; C-18), 0.00 ppm (6CH3; TMS); IR
(KBr): n˜ =3437, 2932, 2865, 2159, 1608, 1497, 1249, 1029, 889, 843,
760 cmÀ1; MS (APCI): m/z: 793 [MÀH2O+H]+, 775 [MÀ2H2O+H]+.
Compound 37: Reaction of
a mixture of tetraazide 35 (17.6 mg,
0.059 mmol, 1.0 equiv), mestranol (27) (72.3 mg, 0.236 mmol, 4.0 equiv),
sodium l-ascorbate (4.8 mg, 0.024 mmol, 0.4 equiv), and CuSO4·5H2O
(3.0 mg, 0.012 mmol, 0.2 equiv) in DMF (3 mL) for 1 h, followed by pu-
rification (SiO2; hexanes/AcOEt 1:1 to AcOEt), yielded pure 37 as a
white solid (86.3 mg, 95%). M.p. 201–2038C; [a]2D5 =+44.90 (c=1.02 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.28 (s, 4H; N3C=CH), 7.16 (s,
2H; Ar), 7.10 (d, J=8.5 Hz, 4H; H-1), 6.66 (dd, J=8.5, 2.7 Hz, 4H; H-
2), 6.60 (d, J=2.7 Hz, 4H; H-4), 5.69 (d, J=15.0 Hz, 4H; CHHN3), 5.52
(d, J=15.0 Hz, 4H; CHHN3), 3.75 (s, 12H; OCH3), 2.83–2.82 (m, 12H),
2.45 (m, 4H), 2.17–1.96 (m, 20H), 1.63–1.27 (m, 24H), 1.02 (s, 12H; H-
18), 0.66 ppm (m, 4H); 13C NMR (75 MHz, CDCl3): d=157.3 (4C; C-3),
154.6 (4C; N3C=CH), 137.9 (4C; C-5), 134.7 (4C; Ar), 132.4 (4C; C-10),
131.7 (2CH; Ar), 126.1 (4CH; C-1), 122.1 (4CH; N3C=CH), 113.7
(4CH; C-4), 111.3 (4CH; C-2), 82.3 (4C; C-17), 55.1 (4OCH3), 50.4
(4CH2; CH2N3), 48.3 (4CH; C-14), 47.2 (4C; C-13), 43.2 (4CH; C-9),
39.4 (4CH; C-8), 37.8 (4CH2; C-16), 33.0 (4CH2; C-12), 29.7 (4CH2; C-
6), 27.3 (4CH2; C-7), 26.2 (4CH2; C-11), 23.5 (4CH2; C-15), 14.2 ppm
(4CH3; C-18); IR (KBr): n˜ =3436, 2930, 2867, 1610, 1576, 1500, 1454,
1254, 1232, 1143, 1042 cmÀ1; MS (ESI): m/z: 1562.8 [M+Na]+; elemental
analysis calcd (%) for C94H114N12O8: C 73.31, H 7.46, N 10.91; found: C
73.15, H 7.67, N 10.72.
Desilylation of compound 42 to afford 43: Solid nBu4NF·3H2O (151 mg,
0.48 mmol) was added to a solution of 42 (178 mg, 0.22 mmol) in THF
(10 mL) at room temperature under argon. The resulting solution was
stirred for 10 min until completion of the reaction (TLC analysis). The
reaction mixture was then filtered through a short pad of silica gel using
CH2Cl2 as eluent. Chromatography on silica gel (hexanes/AcOEt 4:1) of
the residue obtained afforded 103 mg (70%) of pure 43 as a white solid.
M.p. 128–1308C; [a]2D0 =+4.73 (c=0.34 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.22 (d, J=8.5 Hz, 2H; H-1), 6.74 (dd, J=8.5, 2.7 Hz, 2H;
H-2), 6.66 (d, J=2.7 Hz, 2H; H-4), 4.71 (s, 4H; OCH2), 2.84 (m, 4H),
ꢀ
2.61 (s, 2H; C CH), 2.40–1.25 (m, 28H), 0.88 ppm (s, 6H; H-18);
13C NMR (75 MHz, CDCl3): d=155.2 (2C; C-3), 138.1 (2C; C-5), 133.6
(2C; C-10), 126.4 (2CH; C-1), 114.8 (2CH; C-4), 112.2 (2CH; C-2), 87.5
ꢀ
ꢀ
ꢀ
(2C; C C), 79.8 (2C; C-17), 74.8 (2C; C C), 74.1 (2CH; C CH), 70.9
ꢀ
(2C; C C), 56.1 (2OCH2), 49.4 (2CH; C-14), 47.1 (2C; C-13), 43.5
(2CH; C-9), 39.2 (2CH; C-8), 38.9 (2CH2; C-16), 32.7 (2CH2; C-12),
29.7 (2CH2; C-6), 27.1 (2CH2; C-7), 26.3 (2CH2; C-11), 22.8 (2CH2; C-
15), 12.6 ppm (2CH3; C-18); IR (KBr): n˜ =3417, 3287, 2932, 2869, 1605,
1498, 1229, 1026, 753 cmÀ1
;
MS (APCI): m/z: 667 [M+H]+, 649
[MÀH2O+H]+, 631 [MÀ2H2O+H]+; elemental analysis calcd (%) for
C46H50O4: C 82.85, H 7.56; found: C 83.11, H 7.40.
Compound 40ab:
A mixture of diazide 28b (17.2 mg, 0.058 mmol,
1.0 equiv), bis(alkyne) 39a (51.1 mg, 0.058 mmol, 1.0 equiv), sodium l-as-
G
Macrocycles 41 and 44: A mixture of pyridine (8 mL) and CH3CN
(25 mL) was heated at reflux for 1 h. Dimer 43 (50 mg, 0.075 mmol,
1.0 equiv) and CuACHTNUTRGNEUNG(OAc)2·H2O (75 mg, 0.375 mmol, 5.0 equiv) were then
successively added, and the mixture was refluxed for a further 1 h. It was
then allowed to cool to room temperature, quenched with ice, diluted
with CH2Cl2 (40 mL), and washed with H2O (4ꢅ50 mL). The organic
layer was dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. Chromatography on silica gel (hexanes/AcOEt 4:1) of the residue
afforded 31 mg (66%) of the desired pure macrocycle 41 together with
corbate (23.0 mg, 0.116 mmol, 2.0 equiv), and CuSO4·5H2O (7.2 mg,
0.029 mmol, 0.5 equiv) in DMF (80 mL) was stirred under Ar at RT for
3 days. The reaction was then quenched with water, the resulting mixture
was extracted with AcOEt (100 mL), and the organic extracts were
washed with water (2ꢅ100 mL) and brine (1ꢅ100 mL). The organic layer
was dried over MgSO4, filtered, and the solvent was removed in vacuo.
The resulting yellow solid was purified by passage through a short pad of
SiO2 (6ꢅ1.5 cm, hexane/AcOEt 1:3 to AcOEt/MeOH 200:1) to afford
3810
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3798 – 3814

Cu–Alkyne Chemistry
FULL PAPER
ꢀ
ꢀ
9 mg (18%) of pure 44, both as white solids. 41: M.p. 2608C (decomp.);
[a]2D0 =À64.43 (c=0.39 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.25
(d, J=8.6 Hz, 4H; H-1), 6.70 (dd, J=8.6, 2.8 Hz, 4H; H-2), 6.65 (d, J=
2.8 Hz, 4H; H-4), 4.75 (d, J=7.0 Hz, 4H; OCH2), 4.72 (d, J=7.0 Hz, 4H;
OCH2), 2.81 (m, 8H), 2.39–2.30 (m, 8H), 2.18–1.92 (m, 12H), 1.90–1.64
(m, 16H), 1.62–1.22 (m, 20H), 0.92 ppm (s, 12H; H-18); 13C NMR
(100 MHz, CDCl3): d=154.3 (4C; C-3), 138.1 (4C; C-5), 132.4 (4C; C-
10), 126.9 (4CH; C-1), 116.7 (4CH; C-4), 110.4 (4CH; C-2), 83.0 (4C;
(3CH; C-2), 87.5 (3Csp; C C), 79.8 (3C; C-17), 74.0 (3Csp; C CH), 62.0
(3CH2), 53.3 (3CH2), 49.4 (3CH; C-14), 47.1 (3C; C-13), 43.5 (3CH; C-
9), 39.3 (3CH; C-8), 38.9 (3CH2; C-16), 32.7 (3CH2; C-12), 29.8 (3CH2;
C-6), 27.2 (3CH2; C-7), 26.3 (3CH2; C-11), 22.8 (3CH2; C-15), 12.7 ppm
(3CH3; C-18); IR (KBr): n˜ =3435, 3299, 2931, 2870, 1609, 1576, 1497,
1252, 1233, 1051, 1016 cmÀ1; MS (ES): m/z: 1247.2 [M+H]+; elemental
analysis calcd (%) for C78H87N9O6: C 75.15, H 7.03, N 10.11; found: C
74.90, H 6.88, N 10.33.
ꢀ
ꢀ
ꢀ
ꢀ
C C), 80.4 (4C; C-17), 74.5 (4C; C C), 71.1 (4C; C C), 69.8 (4C; C
C), 55.0 (4OCH2), 50.4 (4CH; C-14), 48.2 (4C; C-13), 44.7 (4CH; C-9),
39.1 (4CH; C-8), 38.6 (4CH2; C-16), 33.4 (4CH2; C-12), 29.9 (4CH2; C-
6), 27.1 (4CH2; C-7), 26.1 (4CH2; C-11), 22.7 (4CH2; C-15), 13.0 ppm
(4CH3; C-18); IR (KBr): n˜ =3447, 2930, 2867, 1609, 1498, 1260,
1024 cmÀ1; MS (ESI): m/z: 1294.8 [MÀ2H2O+H]+; elemental analysis
calcd (%) for C92H96O8: C 83.10, H 7.28; found: C 83.41, H 7.51. 44: M.p.
Compound 46b: A solution of nBu4NF·3H2O (335.1 mg, 1.062 mmol) in
THF (5 mL) was added dropwise to a solution of TMS-protected trial-
kyne 45b (457.2 mg, 0.295 mmol) in THF (15 mL) at 08C. The resulting
mixture was stirred for 30 min at the same temperature. The solvent was
then removed in vacuo and the concentrated mixture was filtered
through a short pad of silica gel (10ꢅ2 cm, AcOEt) to yield terminal tri-
alkyne 46b as a white solid (355.6 mg, 91%). M.p. 148–1508C; [a]D25
=
1
3108C (decomp.); [a]2D0 =À36.19 (c=0.84 in CHCl3); H NMR (400 MHz,
À3.53 (c=0.17 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.36 (s, 3H;
N3C=CH), 7.16 (d, J=8.4 Hz, 3H; H-1), 6.73 (dd, J=8.4, 2.4 Hz, 3H; H-
2), 6.67 (d, J=2.4 Hz, 3H; H-4), 5.64 (s, 6H), 5.12 (s, 6H), 2.79 (m,
CDCl3): d=7.20 (d, J=8.5 Hz, 8H; H-1), 6.76 (dd, J=8.5, 2.4 Hz, 8H;
H-2), 6.64 (d, J=2.4 Hz, 8H; H-4), 4.72 (s, 16H; OCH2), 2.84 (m, 16H),
2.39–2.20 (m, 16H), 2.03 (brt, J=11.9 Hz, 8H), 1.90–1.60 (m, 40H),
1.50–1.20 (m, 48H), 0.88 ppm (s, 24H; H-18); 13C NMR (100 MHz,
CDCl3): d=155.0 (8C; C-3), 138.1 (8C; C-5), 133.5 (8C; C-10), 126.3
ꢀ
12H), 2.61 (s, 3H; C CH), 2.38–2.29 (m, 6H), 2.24–2.17 (brt, J=12.0 Hz,
3H; CH2CH3), 2.07–1.30 (m, 33H), 0.95 (t, J=7.2 Hz, 9H; CH2CH3),
0.88 ppm (s, 9H; H-18); 13C NMR (75 MHz, CDCl3): d=156.0 (3C; C-3),
146.5 (3C; Ar), 144.7 (3C; N3C=CH), 138.0 (3C; C-5), 133.2 (3C; C-10),
129.6 (3C; Ar), 126.4 (3CH; C-1), 122.0 (3CH; N3C=CH), 114.7 (3CH;
ꢀ
ꢀ
(8CH; C-1), 115.4 (8CH; C-4), 111.8 (8CH; C-2), 83.4 (8C; C C), 80.7
ꢀ
ꢀ
ꢀ
(8C; C-17), 74.9 (8C; C C), 71.1 (8C; C C), 70.4 (8C; C C), 55.8
(8OCH2), 49.8 (8CH; C-14), 47.9 (8C; C-13), 43.4 (8CH; C-9), 39.3
(8CH; C-8), 38.8 (8CH2; C-16), 33.0 (8CH2; C-12), 29.7 (8CH2; C-6),
27.2 (8CH2; C-7), 26.3 (8CH2; C-11), 22.9 (8CH2; C-15), 12.8 ppm
(8CH3; C-18); IR (KBr): n˜ =3436, 2927, 2856, 1610, 1497, 1453, 1228,
1028, 874 cmÀ1; MS (ESI): m/z: 2682.5 [M+Na]+; elemental analysis
calcd (%) for C184H192O16: C 83.10, H 7.28; found: C 82.88, H 7.02.
C-4), 112.2 (3CH; C-2), 87.5 (3Csp; C C), 79.8 (3C; C-17), 74.0 (3Csp
;
ꢀ
C CH), 62.0 (3CH2), 49.4 (3CH; C-14), 47.9 (3CH2), 47.1 (3C; C-13),
43.5 (3CH; C-9), 39.3 (3CH; C-8), 38.9 (3CH2; C-16), 32.7 (3CH2; C-
12), 29.7 (3CH2; C-6), 27.2 (3CH2; C-7), 26.3 (3CH2; C-11), 23.6 (3CH2),
22.8 (3CH2; C-15), 15.3 (3CH3), 12.7 ppm (3CH3; C-18); IR (KBr): n˜ =
3436, 2931, 2871, 1609, 1497, 1454, 1380, 1280, 1232, 1145, 1047 cmÀ1; MS
(ES): m/z: 1330.9 [M+H]+, 1352.9 [M+Na]+; elemental analysis calcd
(%) for C84H99N9O6: C 75.81, H 7.50, N 9.47; found: C 75.55, H 7.38, N
9.60.
Compound 45b:
A mixture of triazide 34b (145.5 mg, 0.444 mmol,
1.0 equiv), bis(alkyne) 38 (541.6 mg, 1.322 mmol, 3.0 equiv), sodium l-as-
ACHTUNGTRENNUNG
corbate (26.3 mg, 0.133 mmol, 0.6 equiv), and CuSO4·5H2O (16.7 mg,
0.067 mmol, 0.3 equiv) in DMF (20 mL) was stirred under Ar at RT for
1.5 h. The reaction was then quenched with water, the resulting mixture
was extracted with AcOEt (150 mL), and the organic extract was washed
with water (2ꢅ150 mL) and brine (1ꢅ150 mL). The organic layer was
dried over MgSO4, filtered, and the solvent was removed in vacuo. The
resulting white solid was purified by passage through a short pad of SiO2
(hexane/AcOEt 2:1 to 1:1) to yield 45b as a white solid (516.4 mg, 75%).
M.p. 155–1568C; [a]2D5 =À10.21 (c=0.48 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.37 (s, 3H; N3C=CH), 7.20 (d, J=8.7 Hz, 3H; H-1), 6.75
(dd, J=8.7, 2.4 Hz, 3H; H-2), 6.68 (d, J=2.4 Hz, 3H; H-4), 5.64 (s, 6H),
5.13 (s, 6H), 2.80 (m, 12H), 2.36–2.26 (m, 6H), 2.17 (m, 3H), 2.04–1.62
(m, 21H), 1.50–1.26 (m, 12H), 0.94 (t, J=7.2 Hz, 9H; CH2CH3), 0.86 (s,
9H; H-18), 0.17 ppm (s, 27H; TMS); 13C NMR (75 MHz, CDCl3): d=
156.0 (3C; C-3), 146.5 (3C; Ar), 144.7 (3C; N3C=CH), 138.1 (3C; C-5),
133.2 (3C; C-10), 129.6 (3C; Ar), 126.4 (3CH; C-1), 122.0 (3CH; N3C=
ꢀ
Compound 46c: A solution of nBu4NF·3H2O (188.7 mg, 0.598 mmol) in
THF (4 mL) was added dropwise to a solution of TMS-protected trial-
kyne 45c (234.8 mg, 0.166 mmol) in THF (6 mL) at 08C. The resulting
mixture was stirred for 30 min at the same temperature. The solvent was
then removed in vacuo and the concentrated mixture was filtered
through a short pad of silica gel (10ꢅ2 cm, AcOEt/hexane 1:2 to 1:5) to
yield terminal trialkyne 46c as a white solid (175.4 mg, 88%). M.p. 123–
1258C; [a]2D5 =+2.16 (c=0.37 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=8.03 (s, 3H; N3C=CH), 7.21 (d, J=8.7 Hz, 3H; H-1), 6.79 (dd, J=8.7,
2.4 Hz, 3H; H-2), 6.72 (d, J=2.4 Hz, 3H; H-4), 5.20 (s, 6H), 4.41 (s, 6H),
ꢀ
2.83 (m, 6H), 2.60 (s, 3H; C CH), 2.38–2.30 (m, 6H), 2.25–2.17 (m, 3H),
2.07–1.65 (m, 21H), 1.55–1.32 (m, 12H), 0.88 (s, 9H; H-18), 0.84 ppm (s,
3H; CH3); 13C NMR (75 MHz, CDCl3): d=156.0 (3C; C-3), 144.5 (3C;
N3C=CH), 138.1 (3C; C-5), 133.4 (3C; C-10), 126.4 (3CH; C-1), 125.6
ꢀ
(3CH; N3C=CH), 114.9 (3CH; C-4), 112.3 (3CH; C-2), 87.5 (3Csp; C
CH), 114.8 (3CH; C-4), 112.3 (3CH; C-2), 109.4 (3Csp; C C), 90.1 (3Csp
;
ꢀ
C), 79.8 (3C; C-17), 74.0 (3Csp; C CH), 61.9 (3CH2), 53.4 (3CH2), 49.4
ꢀ
C C), 80.1 (3C; C-17), 62.0 (3CH2), 49.6 (3CH; C-14), 47.9 (3CH2), 47.2
(3C; C-13), 43.7 (3CH; C-9), 39.4 (3CH; C-8), 38.9 (3CH2; C-16), 32.8
(3CH2; C-12), 29.8 (3CH2; C-6), 27.2 (3CH2; C-7), 26.4 (3CH2; C-11),
23.6 (3CH2), 22.8 (3CH2; C-15), 15.2 (3CH3), 12.8 (3CH3; C-18),
0.03 ppm (9CH3; TMS); IR (KBr): n˜ =3436, 2933, 2872, 2159, 1609, 1498,
1455, 1381, 1250, 1046, 843 cmÀ1; MS (ES): m/z: 1548.2 [M+H]+.
(3CH; C-14), 47.1 (3C; C-13), 43.5 (3CH; C-9), 41.6 (C), 39.3 (3CH; C-
8), 39.0 (3CH2; C-16), 32.7 (3CH2; C-12), 29.8 (3CH2; C-6), 27.2 (3CH2;
C-7), 26.4 (3CH2; C-11), 22.8 (3CH2; C-15), 19.2 (CH3), 12.7 ppm
(3CH3; C-18); IR (KBr): n˜ =3435, 3298, 3145, 2932, 2870, 1608, 1497,
1455, 1234, 1049, 755 cmÀ1; MS (ES): m/z: 1199.2 [M+H]+; elemental
analysis calcd (%) for C74H87N9O6: C 74.16, H 7.32, N 10.52; found: C
74.30, H 7.15, N 10.37.
Compound 46a: A solution of nBu4NF·3H2O (118.6 mg, 0.376 mmol) in
THF (3 mL) was added dropwise to a solution of TMS-protected trial-
kyne 45a (166.3 mg, 0.114 mmol) in THF (9 mL) at 08C. The resulting
mixture was stirred for 30 min at the same temperature. The solvent was
then removed in vacuo and the concentrated mixture was filtered
through a short pad of silica gel (10ꢅ2 cm, hexanes/AcOEt 1:2 to 1:4) to
yield terminal trialkyne 46a as a white solid (139.2 mg, 98%). M.p. 165–
1678C; [a]2D9 =+2.50 (c=0.60 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=7.56 (s, 3H; N3C=CH), 7.19 (d, J=8.7 Hz, 3H; H-1), 7.13 (s, 3H; Ar),
6.75 (dd, J=8.7, 2.7 Hz, 3H; H-2), 6.69 (d, J=2.7 Hz, 3H; H-4), 5.47 (s,
Compound 47:
A mixture of triazide 34c (15.0 mg, 0.077 mmol,
1.0 equiv), alkyne 46b (102.0 mg, 0.077 mmol, 1.0 equiv), sodium l-ascor-
bate (30.5 mg, 0.154 mmol, 2.0 equiv), and CuSO4·5H2O (19.2 mg,
0.077 mmol, 1.0 equiv) in DMF (150 mL) was stirred under Ar at RT for
3 days. The reaction was then quenched with water, the resulting mixture
was extracted with AcOEt (150 mL), and the organic extract was washed
with water (2ꢅ150 mL) and brine (1ꢅ150 mL). The organic layer was
dried over MgSO4, filtered, and the solvent was removed in vacuo. The
resulting white solid was purified by column chromatography (15ꢅ
1.5 cm, SiO2; AcOEt to AcOEt/MeOH 5:1) to yield 47 as a white solid
(29.4 mg, 25%). M.p. 2458C (decomp.); [a]2D8 =+14.44 (c=0.27 in
CHCl3); 1H NMR (400 MHz, CDCl3/CD3OD): d=7.99 (brs), 7.83 (brs),
7.69 (brs), 7.60 (brs), 7.40 (brs), 7.30–7.22 (m), 6.89 (d, J=9.2 Hz), 6.78
ꢀ
6H), 5.15 (s, 6H), 2.81 (m, 6H), 2.60 (s, 3H; C CH), 2.36–2.17 (m, 9H),
2.06–1.65 (m, 21H), 1.53–1.26 (m, 12H), 0.87 ppm (s, 9H; H-18);
13C NMR (75 MHz, CDCl3): d=156.0 (3C; C-3), 145.3 (3C; N3C=CH),
138.1 (3C; C-5), 136.8 (3C; Ar), 133.3 (3C; C-10), 127.5 (3CH; Ar),
126.4 (3CH; C-1), 122.8 (3CH; N3C=CH), 114.7 (3CH; C-4), 112.1
Chem. Eur. J. 2010, 16, 3798 – 3814
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3811

P. Ramꢀrez-Lꢁpez, M. C. de la Torre, M. A. Sierra et al.
(m), 6.70 (d, J=8.8 Hz), 6.51–6.40 (m), 5.62–5.54 (m), 4.91–4.83 (m), 4.63
(d, J=14.4 Hz), 4.54 (d, J=14.4 Hz), 4.33 (m), 4.22 (m), 4.10–4.07 (m),
3.91 (brs), 2.57 (m), 2.32 (m), 2.19 (m), 2.04 (m), 1.82–1.67 (m), 1.56–1.44
(m), 1.35–1.04 (m), 0.92 (s), 0.88 (s), 0.76 (m), 0.51–0.35 ppm (m);
13C NMR (75 MHz, CDCl3/CD3OD): d=156.0, 155.9, 155.9, 155.8, 155.7
(C; C-3), 153.9, 153.5, 153.4, 152.9 (C; N3C=CH), 146.8, 146.7, 146.6 (C;
Ar), 144.5, 144.3, 144.2, 144.1 (C; N3C=CH), 138.0, 137.9, 137.7, 137.6 (C;
C-5), 133.1, 133.0, 132.8 (C; C-10), 129.5, 129.4, 129.3, 129.2 (C; Ar),
126.0, 125.7 (CH; C-1), 124.9, 124.8 (ꢅ2), 124.6 (ꢅ2), 124.5 (CH; N3C=
CH), 121.8, 121.7, 121.1 (CH; N3C=CH), 114.7, 114.2, 113.9 (CH; C-4),
113.0, 112.3 (CH; C-2), 82.1, 81.9, 81.7, 81.6 (C; C-17), 62.1, 61.8, 61.7
(CH2), 53.5 (CH2), 48.5 (ꢅ2) (CH; C-14), 47.6 (CH2), 47.4, 47.2, 47.1 (C;
C-13), 43.4, 43.3, 43.1 (CH; C-9), 42.2, 41.6 (CH3C), 39.3, 39.0 (CH; C-8),
37.7, 37.4 (CH2; C-16), 33.0 (ꢅ2), 32.9 (ꢅ2) (CH2; C-12), 29.6, 29.5, 29.0
(CH2; C-6), 27.5, 27.2 (CH2; C-7), 25.9, 25.8, 25.7 (CH2; C-11), 23.4, 23.2,
(3CH2; C-16), 32.8 (3CH2; C-12), 29.9 (3CH2; C-6), 27.3 (3CH2; C-7),
26.4 (3CH2; C-11), 22.8 (6CH2; C-15
+ ArCH2), 16.5 (3CH3), 12.8
(3CH3; C-18), 0.02 ppm (9CH3; TMS); IR (KBr): n˜ =3437, 2951, 2932,
2872, 2160, 1608, 1575, 1496, 1249, 1017, 843 cmÀ1; MS (ESI): m/z: 1287.2
[M+HÀH2O]+.
Desilylation of compound 50—preparation of compound 51: A solution
of nBu4NF·3H2O (202 mg, 0.640 mmol) in THF (3 mL) was added drop-
wise to a solution of TMS-protected tripod 50 (253 mg, 0.194 mmol) in
THF (7 mL) at 08C. The resulting mixture was stirred for 30 min at this
temperature. The solvent was then removed in vacuo and the concentrat-
ed mixture was filtered through a short pad of silica gel (10ꢅ2 cm, hex-
anes/AcOEt 1:1 to 1:2) to yield 207 mg (98%) of pure tripod 51 as a
white solid. M.p. 173–1758C; [a]2D6 =+5.00 (c=0.12 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.30 (d, J=8.7 Hz, 3H; H-1), 6.89 (brd, J=
8.7 Hz, 3H; H-2), 6.81 (brs, 3H; H-4), 5.08 (s, 6H; OCH2), 2.92–2.85 (m,
12H), 2.64 (s, 3H), 2.44–2.26 (m, 9H), 2.01–1.71 (m, 21H), 1.61–1.39 (m,
12H), 1.27 (t, J=7.2 Hz, 9H; CH3), 0.92 ppm (s, 9H; H-18); 13C NMR
(75 MHz, CDCl3): d=156.8 (3C; C-3), 146.0 (3C), 138.0 (3C; C-5), 132.8
(3C; C-10), 131.1 (3C), 126.4 (3CH; C-1), 114.2 (3CH; C-4), 112.1
23.1, 23.0 (CH2; C-15
+ CH2Ar), 19.4, 19.2 (CH3C), 15.7, 15.6, 15.5
(CH3Ar), 14.3, 14.1, 14.0 ppm (CH3; C-18); IR (KBr): n˜ =3436, 2930,
2872, 1609, 1497, 1455, 1380, 1281, 1232, 1047, 754 cmÀ1; MS (ES): m/z:
1527.3 [M+H]+; elemental analysis calcd (%) for C89H108N18O6: C 70.05,
H 7.13, N 16.52; found: C 69.80, H 6.84, N 16.21.
ꢀ
ꢀ
(3CH; C-2), 87.5 (3Csp; C C), 79.8 (3C; C-17), 74.0 (3Csp; C C), 63.9
(3OCH2), 49.4 (3CH; C-14), 47.1 (3C; C-13), 43.5 (3CH; C-9), 39.4
(3CH; C-8), 38.9 (3CH2; C-16), 32.7 (3CH2; C-12), 29.9 (3CH2; C-6),
27.2 (3CH2; C-7), 26.4 (3CH2; C-11), 22.9 (3CH2; ArCH2), 22.8 (3CH2;
C-15), 16.5 (3CH3), 12.7 ppm (3CH3; C-18); IR (KBr): n˜ =3437, 3303,
2932, 2871, 1607, 1574, 1495, 1229, 1145, 1047, 1014 cmÀ1; MS (ESI): m/z:
1069.9 [M+HÀH2O]+, 1087.2 [M+H]+; elemental analysis calcd (%) for
C75H90O6: C 82.83, H 8.34; found: C 82.69, H 8.57.
Tripod 48: NaH (458 mg, 11.44 mmol, 60% in mineral oil) was added in
one portion to a solution of estrone (49) (1.00 g, 3.70 mmol) in dry DMF
(100 mL) at 08C under argon. After stirring for 10 min, the mixture was
allowed to warm to RT and then stirred for a further 10 min. It was then
cooled to 08C once more, whereupon 1,3,5-tris(bromomethyl)-2,4,6-tri-
ACHTUNGTRENNUNG
ethylbenzene[42] (542 mg, 1.23 mmol) was added in one portion. The mix-
ture was allowed to warm to room temperature and was then heated at
708C for 12 h. Thereafter, the reaction was quenched with H2O at 08C.
After neutralizing the diluted mixture with 0.1m HCl, it was extracted
with CH2Cl2 (3ꢅ100 mL). The combined organic layers were washed
twice with brine, dried over anhydrous Na2SO4, filtered, and concentrated
in vacuo. Filtration of the crude residue through a short pad of silica gel
(CH2Cl2/MeOH 100:1 to 25:1) yielded 956 mg (77%) of pure 48 as a
white solid. M.p. 178–1808C; [a]2D4 =+123.74 (c=0.91 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.30 (d, J=8.7 Hz, 3H; H-1), 6.90 (dd,
J=8.7, 2.4 Hz, 3H; H-2), 6.83 (d, J=2.4 Hz, 3H; H-4), 5.09 (s, 6H;
OCH2), 2.98 (m, 6H), 2.86 (m, 6H), 2.59–2.44 (m, 6H), 2.32–1.99 (m,
15H), 1.71–1.47 (m, 18H), 1.28 (t, J=7.2 Hz, 9H; CH3), 0.95 ppm (s, 9H;
H-18); 13C NMR (75 MHz, CDCl3): d=220.8 (3C=O; C-17), 156.8 (3C;
C-3), 146.0 (3C), 137.8 (3C; C-5), 132.2 (3C; C-10), 131.0 (3C), 126.4
(3CH; C-1), 114.3 (3CH; C-4), 112.1 (3CH; C-2), 63.8 (3OCH2), 50.3
(3CH; C-14), 47.9 (3C; C-13), 43.9 (3CH; C-9), 38.3 (3CH; C-8), 35.8
(3CH2; C-16), 31.5 (3CH2; C-12), 29.6 (3CH2; C-6), 26.5 (3CH2; C-7),
25.8 (3CH2; C-11), 22.9 (3CH2; ArCH2), 21.5 (3CH2; C-15), 16.5 (3CH3),
13.8 ppm (3CH3; C-18); IR (KBr): n˜ =3436, 2930, 1740, 1607, 1574, 1496,
1454, 1373, 1279, 1229, 1006 cmÀ1; MS (ESI): m/z: 1010.0 [M+H]+; ele-
mental analysis calcd (%) for C69H84O6: C 82.10, H 8.39; found: C 82.45,
H 8.17.
Compound 52: A solution of tripod 51 (50.0 mg, 0.046 mmol) in dry pyri-
dine (14 mL)/CH3CN (42 mL) was heated at reflux for 30 min under
argon. CuACHTNUGTRENUNG(OAc)2·H2O (68.9 mg, 0.345 mmol) was added and the mixture
was refluxed for a further 1 h. The reaction mixture was then allowed to
cool to RT, quenched with ice, diluted with AcOEt, and washed three
times with H2O. The organic layer was dried over anhydrous Na2SO4 and
the solvents were removed in vacuo. Column chromatography (hexanes/
AcOEt 10:1 to 1:1) of the resulting residue yielded 20.4 mg (41%) of
pure estrone-based cage 52 as a white solid. M.p. 3008C (decomp.);
[a]2D8 =+3.27 (c=0.55 in CHCl3); 1H NMR (300 MHz, CDCl3/CD3OD):
d=7.04 (d, J=8.7 Hz, 6H), 6.76 (brd, J=8.7 Hz, 6H), 6.72 (brs, 6H),
5.04 (d, J=9.9 Hz, 6H), 4.89 (d, J=9.9 Hz, 6H), 2.84–2.77 (m, 24H), 2.39
(s, 6H; OH), 2.23–2.15 (m, 18H), 1.93–1.66 (m, 36H), 1.48–1.30 (m,
24H), 1.18 (t, J=7.5 Hz, 18H), 0.84 ppm (s, 18H; H-18); 13C NMR
(75 MHz, CDCl3/CD3OD): d=156.7 (6C; C-3), 145.9 (6C), 137.4 (6C; C-
5), 131.6 (6C; C-10), 130.8 (6C), 127.0 (6CH; C-1), 113.9 (6CH; C-4),
ꢀ
ꢀ
112.4 (6CH; C-2), 85.5 (6Csp; C C), 79.7 (6C; C-17), 69.7 (6Csp; C C),
63.5 (6OCH2), 49.8 (6CH; C-14), 48.9 (6C; C-13), 44.7 (6CH; C-9), 39.4
(6CH; C-8), 37.8 (6CH2; C-16), 33.0 (6CH2; C-12), 30.1 (6CH2; C-6),
27.1 (6CH2; C-7), 26.8 (6CH2; C-11), 22.7 (12CH2; C-15 + ArCH2), 16.5
(6CH3), 12.7 ppm (6CH3; C-18); IR (KBr): n˜ =3437, 2930, 2871, 1608,
1575, 1496, 1454, 1279, 1229, 1138, 1047, 1011 cmÀ1; MS (MALDI): m/z:
2191.3 [M+Na]+, 2207.3 [M+K]+; elemental analysis calcd (%) for
C150H174O12: C 83.06, H 8.09; found: C 83.38, H 7.75.
Compound 50: LiHMDS (4.46 mmol, 4.5 mL, 1.0m in THF) was added
dropwise to a solution of ethynyltrimethylsilane (438 mg, 4.46 mmol) in
THF (100 mL) at À788C. The mixture was stirred at the same tempera-
ture for 30 min and then warmed to 08C, whereupon a solution of tripod
48 (0.50 g, 0.495 mmol) in THF (20 mL) was added dropwise via a cannu-
la. The reaction mixture was allowed to reach room temperature, stirred
overnight, and subsequently quenched at 08C with saturated aqueous
NH4Cl solution. The resulting mixture was extracted with AcOEt (3ꢅ
25 mL), and the combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. Chromatog-
raphy on silica gel (25ꢅ3 cm, hexanes/AcOEt 10:1 to 4:1) of the crude
residue yielded 342 mg (53%) of pure 50 as a white solid. M.p. 158–
1608C; [a]2D5 =À10.36 (c=0.28 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=7.34 (d, J=8.7 Hz, 3H; H-1), 6.92 (brd, J=8.7 Hz, 3H; H-2), 6.84
(brs, 3H; H-4), 5.11 (s, 6H; OCH2), 2.91 (m, 12H), 2.47–2.33 (m, 9H),
2.16–1.71 (m, 21H), 1.63–1.45 (m, 12H), 1.30 (t, J=6.9 Hz, 9H; CH3),
0.94 (s, 9H; H-18), 0.25 ppm (s, 27H; TMS); 13C NMR (75 MHz, CDCl3):
d=156.7 (3C; C-3), 146.0 (3C), 138.0 (3C; C-5), 132.7 (3C; C-10), 131.1
(3C), 126.4 (3CH; C-1), 114.2 (3CH; C-4), 112.1 (3CH; C-2), 109.5
Acknowledgements
Support of this work through 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 Minis-
terio de Educaciꢁn y Ciencia (Spain) is acknowledged. H.M. thanks the
Alban-EU Program for a predoctoral grant. P.R.-L. is a Juan de la Cierva
Fellow. M.A. thanks the CSIC-JAE Program for a predoctoral grant.
[1] a) R. Breinbauer, I. R. Vetter, H. Waldmann, Angew. Chem. 2002,
114, 3002; Angew. Chem. Int. Ed. 2002, 41, 2878; b) I. Paterson,
E. A. Anderson, Science 2005, 310, 451; c) D. J. Newman, G. M.
ꢀ
ꢀ
(3Csp; C C), 89.9 (3Csp; C C), 80.0 (3C; C-17), 63.8 (3OCH2), 49.5
(3CH; C-14), 47.2 (3C; C-13), 43.7 (3CH; C-9), 39.4 (3CH; C-8), 38.9
3812
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3798 – 3814

Cu–Alkyne Chemistry
FULL PAPER
Cragg, J. Nat. Prod. 2007, 70, 461; d) F. E. Koehn, G. T. Carter, Nat.
Rev. Drug. Discovery 2005, 4, 206.
[17] These compounds facilitate the dissolution of the hydrophilic dye
cresol red in nonpolar organic solvents; see: N. G. Aher, V. S. Pore,
S. P. Patil, Tetrahedron 2007, 63, 12927.
[2] Natural product hybrids are a combination of parts of natural prod-
uct fragments. See: a) L. F. Tietze, H. P. Bell, S. Chandrasekhar,
Angew. Chem. 2003, 115, 4128; Angew. Chem. Int. Ed. 2003, 42,
3996; b) G. Mehta, V. Singh, Chem. Soc. Rev. 2002, 31, 324.
[3] Diversity-oriented synthesis concept (DOS): a) S. L. Schreiber, Sci-
ence 2000, 287, 1964; b) S. L. Schreiber, Chem. Eng. News 2003, 81,
51; c) M. D. Burke, S. L. Schreiber, Angew. Chem. 2004, 116, 48;
Angew. Chem. Int. Ed. 2004, 43, 46. For recent reviews on DOS,
see: d) R. J. Spandl, A. Bender, D. R. Spring, Org. Biomol. Chem.
2008, 6, 1149; e) R. J. Spandl, M. Dꢀaz-Gavilꢂn, K. M. G. OꢆConnell,
G. L. Thomas, D. R. Spring, Chem. Rec. 2008, 8, 129; f) C. Cordier,
D. Morton, S. Murrison, A. Nelson, C. OꢆLeary-Steele, Nat. Prod.
Rep. 2008, 25, 719; g) T. E. Nielsen, S. L. Schreiber, Angew. Chem.
2008, 120, 52; Angew. Chem. Int. Ed. 2008, 47, 48; h) D. S. Tan, Nat.
Chem. Biol. 2005, 1, 74.
[4] a) S. T. Diver, S. L. Schreiber, J. Am. Chem. Soc. 1997, 119, 5106;
b) F. Grellepois, B. Crousse, D. Bonnet-Delpon, J. P. Bꢇguꢇ, Org.
Lett. 2005, 7, 5219; c) J. P. Sestelo, A. MouriÇo, L. A. Sarandeses,
Org. Lett. 1999, 1, 1005; d) A. Fꢈrstner, T. Gastner, H. Weintritt, J.
Org. Chem. 1999, 64, 2361; e) P. E. Harrington, M. A. Tius, Org.
Lett. 1999, 1, 649; f) A. B. Smith III, C. M. Adams, S. A. Kozmin,
D. V. Paone, J. Am. Chem. Soc. 2001, 123, 5925.
[5] G. C. Tron, T. Pirali, R. A. Billington, P. L. Canonico, G. Sorba,
A. A. Genazzani, Med. Res. Rev. 2008, 28, 278.
[6] M. C. de La Torre, A. M. Deometrio, E. ꢉlvaro, I. Garcꢀa, M. A.
Sierra, Org. Lett. 2006, 8, 593.
[7] M. A. Sierra, R. M. Torres, M. C. de la Torre, E. ꢉlvaro, J. Org.
Chem. 2007, 72, 4213.
[8] E. ꢉlvaro, M. C. de la Torre, M. A. Sierra, Chem. Eur. J. 2006, 12,
6403.
[9] E. ꢉlvaro, M. C. de la Torre, M. A. Sierra, Chem. Commun. 2006,
985.
[10] P. Ramꢀrez-Lꢁpez, M. C. de la Torre, H. Montenegro, M. Asenjo,
M. A. Sierra, Org. Lett. 2008, 10, 3555.
[11] a) C. Glaser, Ber. Dtsch. Chem. Ges. 1869, 2, 422; b) A. S. Hay, J.
Org. Chem. 1962, 27, 3320; c) G. Eglinton, A. R. Galbraith, Chem.
Ind. 1956, 737; for an overview of acetylenic homo-coupling, see:
d) P. Siemsen, R. C. Livingston, F. Diederich, Angew. Chem. 2000,
112, 2740; Angew. Chem. Int. Ed. 2000, 39, 2632, and references
therein. For a review on copper-mediated couplings, see: e) G.
Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008, 108, 3054.
[12] a) C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67,
3057; b) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. 2002, 114, 2708; Angew. Chem. Int. Ed. 2002, 41,
2596; for selected reviews on the copper(I)-catalyzed azide–alkyne
reaction, see: c) M. Meldal, C. W. Tornøe, Chem. Rev. 2008, 108,
2952; d) V. D. Bock, H. Hiemstra, J. H. van Maarseveen, Eur. J. Org.
Chem. 2006, 51; e) W. H. Binder, R. Sachsenhofer, Macromol. Rapid
Commun. 2007, 28, 15; f) H. Nandivada, X. Jiang, J. Lahann, Adv.
Mater. 2007, 19, 2197.
[13] P. Crabbe, J. A. Zderic, Bull. Soc. Chim. Belg. 1961, 70, 403.
[14] Selected examples in oligo- and polysaccharide chemistry: a) S. Mu-
thana, H. Yu, S. Huang, X. Chen, J. Am. Chem. Soc. 2007, 129,
11918; b) A. Dondoni, A. Marra, J. Org. Chem. 2006, 71, 7546; c) E.
Fernꢂndez-Megia, J. Correa, R. Riguera, Biomacromolecules 2006,
7, 3104; d) K. D. Bodine, D. Y. Gin, M. S. Gin, J. Am. Chem. Soc.
2004, 126, 1638; for a review on the Huisgen CuI-catalyzed azide–
alkyne 1,3-dipolar cycloaddition reaction in nucleoside, nucleotide,
and oligonucleotide chemistry, see: e) F. Amblard, J. H. Cho, R. F.
Schinazi, Chem. Rev. 2009, 109, 4207.
[18] Comparison of the 13C NMR signals of the terpenic domain of 12
with those of a related camphor derivative, the structure of which
was determined by X-ray diffraction analysis, allowed us to establish
the stereochemistry at the carbinol center; see: M. Czugler, P. P.
Korkas, P. Bombicz, W. Seichter, E. Weber, Chirality 1997, 9, 203.
[19] The stereochemistry at the formed tertiary carbinol center of alkyne
13 was established by comparison of the 13C NMR data of the ter-
penic domain with those of related derivatives, see: L. Zhao, D. J.
Burnell, Tetrahedron Lett. 2006, 47, 3291.
[20] Comparison of the 13C NMR signals of the steroid domain of com-
pound 14 with those reported for mestranol allowed us to establish
the stereochemistry at the carbinol center, see: a) A. G. J. Sedee,
G. M. J. B. van Henegouwen, M. E. de Vries, C. Erkelens, Steroids
1985, 45, 101; b) M. I. Choudhary, S. G. Musharraf, Z. A. Siddiqui,
N. T. Khan, R. A. Ali, Atta-Ur-Rahman, Chem. Pharm. Bull. 2005,
53, 1011.
[21] G. Savona, M. P. Paternostro, F. Piozzi, B. Rodrꢀguez, Tetrahedron
Lett. 1979, 20, 379.
[22] G. Domꢀnguez, M. C. de la Torre, B. Rodrꢀguez, J. Org. Chem. 1991,
56, 6595.
[23] A full account of the addition of organolithium reagents to 19-ace-
tylgnaphalin and related compounds will be disclosed in due course.
[24] The 13C NMR spectra of derivatives 16 and 17 are devoid of signals
attributable to the carbonyl groups, showing instead signals due to
new methyne carbons geminal to the oxygen atom (16: dC-6 =73.8;
17: dC-6 =74.2 ppm).
[25] Concerning the stereochemical outcome of the reaction, it has to be
mentioned that the signals of the H18B-endo protons are shifted to
low field (16: dHÀ18B =4.66; 17: dHÀ18B =4.64 ppm) with respect to the
6a-hydroxy derivative teucjaponin B (dHÀ18B =3.25 ppm) as a conse-
quence of the triple-bond effect of the substituent at the 6b-axial po-
sition. See: J. Fayos, F. Fernꢂndez-Gadea, C. Pascual, A. Perales, F.
Piozzi, M. Rico, B. Rodrꢀguez, G. Savona, J. Org. Chem. 1984, 49,
1789. The deshielding effect of the b-alkyne group is stronger than
the effect of a C-6b-hydroxyl group as in teucjaponin A, the H18B
signal of which appeared at d=3.78 ppm). See: G. Y. Papanov, P. Y.
Malakov, Phytochemistry 1983, 22, 2787.
[26] For NMR data of related derivatives, see: D. V. C. Awang, B. A.
Dawson, M. Girard, A. Vincent, I. Ekiel, J. Org. Chem. 1990, 55,
4443.
[27] The 1H NMR spectra of precursors 12, 13, and 14 each featured a
singlet at d=3.05–3.07 ppm attributable to the alkynyl proton. As
expected, these signals were no longer seen in the spectra of the cor-
responding dimers 21, 22, and 23.
[28] The 13C NMR signals corresponding to the terminal alkynyl carbons
in precursors 17, 19, and 20 at d=78.3, 71.0, and 73.2 ppm are re-
placed by signals attributable to the new quaternary sp carbons in
24, 25, and 26 at d=74.4, 67.6, and 68.6 ppm, respectively.
[29] It should be noted that compounds 29b and 30b are new bioorgano-
metallic derivatives, which have a ferrocene–triazole tether joining
the two natural fragments. For the use of ferrocene derivatives in
bioorganometallic chemistry, see: a) N. Metzler-Nolte, M. Salmain,
“The Bioorganometallic Chemistry of Ferrocene”, in Ferrocene Li-
gands, Materials and Biomolecules (Ed.: P. Stepnicka), Wiley-VCH,
Weinheim, 2008, pp. 499–639. A recent example: b) L. Tebben, B.
Bussmann, M. Hegemann, G. Kehr, R. Frçhlich, G. Erker, Organo-
metallics 2008, 27, 4269, and references therein.
[30] The 1H and 13C NMR spectra of dimers 29a–c, 30a,b, and 31 were
almost identical to those of their precursors, except for the absence
of the alkynyl proton signal and the appearance of signals attributa-
ble to the tether and the newly formed triazole rings.
[15] Selected examples concerning glycopeptides: a) Q. Wan, J. Chen, G.
Chen, S. J. Danishefsky, J. Org. Chem. 2006, 71, 8244; b) H. Lin,
C. T. Walsh, J. Am. Chem. Soc. 2004, 126, 13998; c) C. Palomo, J. M.
Aizpurua, E. Balentovꢂ, I. Azcune, J. I. Santos, J. Jimꢇnez-Barbero,
J. CaÇada, J. I. Miranda, Org. Lett. 2008, 10, 2227.
[31] No traces of montanin A were detected in the experiments carried
out in the course of this work. See ref. [22].
[32] As in the case of the mestranol and reserpine dimers, the 1H NMR
spectra of the 19-acetylgnaphalin dimers 32a, 32b, and 33 showed a
single set of signals for the two natural product fragments, as expect-
[16] V. O. Rodionov, S. I. Presolski, S. Gardinier, Y.-H. Lim, M. G. Finn,
J. Am. Chem. Soc. 2007, 129, 12696.
Chem. Eur. J. 2010, 16, 3798 – 3814
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3813

P. Ramꢀrez-Lꢁpez, M. C. de la Torre, M. A. Sierra et al.
ed for molecules having a C2 symmetry axis. Consequently, the 1H
and 13C NMR spectra are almost identical to those of their precur-
sors 16 and 17, except for the disappearance of the alkynyl proton
signal and the appearance of signals attributable to the tether and
the newly formed triazole rings. ESI mass spectra for dimers 32a,
32b, and 33 showed signals at m/z=1069, 1153, and 1270, corre-
sponding to the respective [M+H]+ ions, in agreement with the pro-
posed structures.
tions that form macrocycles under equilibrium conditions. In these
cases, the thermodynamic stability allows the preparation of the
macrocyclic target molecule, overcoming the formation of undesired
by-products (dynamic covalent chemistry (DCC)), see: W. Zhang,
J. S. Moore, Angew. Chem. 2006, 118, 4524; Angew. Chem. Int. Ed.
2006, 45, 4416.
[37] M. J. Cloninger, H. W. Whitlock, J. Org. Chem. 1998, 63, 6153.
[38] The 13C NMR spectrum of semicavity 43 featured three signals cor-
responding to the internal alkynyl carbons at d=87.5, 74.8, and
70.9 ppm and a signal at d=74.1 ppm attributable to the terminal al-
kynyl carbons. In contrast, the 13C NMR spectra of compounds 41
and 44 showed four signals corresponding to the internal sp carbons
at d=83.0, 74.5, 71.1, and 69.8 ppm and at d=83.4, 74.9, 71.1, and
70.4 ppm, respectively, confirming their identity as closed oligomeric
structures of the precursor 43.
[39] A cholic acid-based triply-bridged cyclophane showing moderate
binding of organic guest molecules has been reported, see: S. Koh-
moto, D. Fukui, T. Nagashima, K. Kishikawa, M. Yamamoto, K. J.
Yamada, J. Chem. Soc. Chem. Commun. 1996, 1869.
[33] For dimeric compounds as ligands for proteins, see: a) P. A. Clem-
ons, Curr. Opin. Chem. Biol. 1999, 3, 112; b) S. T. Diver, S. L.
Schreiber, J. Am. Chem. Soc. 1997, 119, 5106; c) K. C. Nicolaou, R.
Hughes, S. Y. Cho, N. Wissinger, C. Smethurst, R. Enderman,
Angew. Chem. 2000, 112, 3981; Angew. Chem. Int. Ed. 2000, 39,
3823; for reviews on dimeric steroids, see: d) L. Nahar, A. B. Turner,
Curr. Med. Chem. 2007, 14, 1349; e) Y. X. Li, J. R. Dias, Chem. Rev.
1997, 97, 283; for ring-connected dimeric steroids, see: f) V. C.
Edelsztein, P. H. Di Chenna, G. Burton, Tetrahedron 2009, 65, 3615;
g) J. F. Templeton, H. Magjier-Baranowska, K. Marat, Steroids 2000,
65, 219; h) M. DellaGreca, M. R. Iesce, L. Previtera, F. Temussi, A.
À
Zarrelli, C. A. Mattia, R. Puliti, J. Org. Chem. 2002, 67, 9011; for C
C-connected dimeric steroids, see: i) J. W. Morzycki, S. Kalinowski,
Z. Lotowski, J. Rabiczko, Tetrahedron 1997, 53, 10579.
[40] Tripodal species containing a trisubstituted triethylbenzene core ex-
hibit a preference of 10–15 kJmolÀ1 for an alternating (3-up, 3-
down) conformation and, therefore, are partially pre-organized, with
the three arms oriented in the same direction. See: K. J. Wallace,
W. J. Belcher, D. R. Turner, K. F. Syed, J. W. Steed, J. Am. Chem.
Soc. 2003, 125, 9699, and references therein.
[34] The synthesis of some star-shaped amphiphilic derivatives of cholic
acid using a click reaction has recently been reported: a) J. Luo, Y.
Chen, X. X. Zhu, Synlett 2007, 2201; for a recent review on the use
of bile acids in synthesis, supramolecular/materials chemistry, and
nanoscience, including molecular umbrellas, see: b) Nonappa, U.
Maitra, Org. Biomol. Chem. 2008, 6, 657.
[35] Hybrid macrocyclic scaffolds based on steroids are of special inter-
est due to their structural pre-organization and flexibility; see:
a) A. L. Sisson, J. P. Clare, A. P. Davis, Chem. Commun. 2005, 5263;
b) A. P. Davis, R. S. Wareham, Angew. Chem. 1999, 111, 3160;
Angew. Chem. Int. Ed. 1999, 38, 2978; c) P. Wallimann, T. Marti, A.
Fꢈrer, F. Diederich, Chem. Rev. 1997, 97, 1567; d) J. Tamminen, E.
Kolehmainen, Molecules 2001, 6, 21.
[41] The 13C NMR spectrum of precursor 46b featured one signal corre-
sponding to the internal alkynyl carbons at d=87.5 ppm and one
signal at d=74.0 ppm attributable to the terminal alkynyl carbons.
No significant simplification of the signals of compound 47 was ob-
served in the 1H and 13C NMR spectra recorded in [D6]DMSO at
908C.
[42] A. Vacca, C. Nativi, M. Cacciarini, R. Pergoli, S. Roelens, J. Am.
Chem. Soc. 2004, 126, 16456.
[43] High-dilution techniques using a syringe pump did not improve this
result. CuCl/CuCl2-Py afforded the target molecule in only 6%
yield, while Hay conditions (CuCl/TMEDA/O2, RT) did not gener-
ate the target product.
[36] It is known that kinetically controlled processes frequently lead irre-
versibly to the kinetic and statistical distribution of products, includ-
ing a collection of linear/cyclic oligomers and polymers of different
chain lengths, thus inevitably resulting in poor yields of the desired
macrocyclic structures. This is in contrast with the reversible reac-
Received: November 29, 2009
Published online: February 16, 2010
3814
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3798 – 3814