Towards Stapling of Helical Alleno-Acetylene Oligomers - Synthesis of an Enantiopure Bis(ethynylvinylidene)-Substituted Cyclohexadeca-1,3,9,11-tetrayne

Article abstract of DOI:10.1002/ejoc.201301529

We are interested in developing strategies to bridge ("staple") enantiomerically pure acyclic alleno-acetylenic oligomers to enhance their conformational preferences for helical secondary structures, which are postulated to be at the origin of their exceptional chiroptical properties. We found that ring-closing metathesis (RCM), which has been used for the stapling of peptide helices, failed with an acyclic alleno-acetylene dimer decorated with lateral olefinic side chains. Instead, enyne RCM to an enantiomerically pure dienyne occurred. We switched to the introduction of diacetylene-containing bridges and report here the 15-step synthesis of a moderately strained, enantiomerically pure cyclohexa-1,3,9,11-tetrayne with an oxidative acetylenic coupling in the key step. The chiroptical properties of the new compounds are discussed. To stabilize the secondary helical structures and enhance the chiroptical properties of alleno-acetylenic oligomers by covalent linkage, two cyclization methods of enantiopure dimers (ring-closing metathesis and Hay coupling) were investigated. Olefin metathesis failed owing to concurrent enyne metathesis. Hay coupling afforded an enantiopure 16-membered macrocycle in 15 steps.

Full text of DOI:10.1002/ejoc.201301529

FULL PAPER
DOI: 10.1002/ejoc.201301529
Towards Stapling of Helical Alleno-Acetylene Oligomers – Synthesis of an
Enantiopure Bis(ethynylvinylidene)-Substituted Cyclohexadeca-1,3,9,11-tetrayne
I.-E. Sophie Müller,[a] Bruno Bernet,[a] Cagatay Dengiz,[a] W. Bernd Schweizer,[a] and
François Diederich*[a]
Keywords: Allenes / Alkynes / Enynes / Chirality / Circular dichroism / Macrocycles / Metathesis
We are interested in developing strategies to bridge
(“staple”) enantiomerically pure acyclic alleno-acetylenic
oligomers to enhance their conformational preferences for
helical secondary structures, which are postulated to be at
the origin of their exceptional chiroptical properties. We
found that ring-closing metathesis (RCM), which has been
used for the stapling of peptide helices, failed with an acyclic
alleno-acetylene dimer decorated with lateral olefinic side
chains. Instead, enyne RCM to an enantiomerically pure di-
enyne occurred. We switched to the introduction of diacetyl-
ene-containing bridges and report here the 15-step synthesis
of a moderately strained, enantiomerically pure cyclohexa-
1,3,9,11-tetrayne with an oxidative acetylenic coupling in the
key step. The chiroptical properties of the new compounds
are discussed.
alleno-acetylenic oligomers were supported by comparison
of the experimental ECD and optical rotatory dispersion
(ORD) profiles with those calculated by different computa-
tional methods (the preferred dihedral angle across buta-
1,3-diynediyl moieties 0ՅθՅ45° for all units suggests a he-
lical structure). By stapling the oligomers with pendant alk-
ene side chains through RCM (Scheme 1), we hoped to ri-
gidify the helical structure of the alleno-acetylene oligomers
and, thus, to amplify the chiroptical effects. Herein, we re-
port our first approaches to determine a methodology to
staple short optically active alleno-acetylenic oligomers.
Intrduction
Peptides and peptidomimetics are attracting increasing
interest as leads in drug discovery research.[1] Various stra-
tegies have been developed to stabilize their conformations,
in particular their helical secondary structures, as well as to
enhance their bioavailability and metabolic stability.
Grubbs and co-workers introduced ring-closing metathesis
(RCM) to prepare cyclic peptides with various ring sizes.[2]
Subsequently, they showed the stabilization of helical con-
formations by bridging (“stapling”) peptide helices through
RCM.[3] Since then, RCM has found wide application for
the stabilization of helical conformers in peptides.[4,5]
Optically pure oligomers derived from 3,5-di-tert-but-
ylhepta-3,4-dien-1,6-diyne [a 1,3-diethynylallene (DEA)]
showed a nonlinear increase in the intensity of their chir-
optical responses with increasing oligomeric length, and ex-
ceptionally high Cotton effects (Δε = Ϯ1360 m–1 cm–1 at λ
= 266 nm and Δε = Ϯ1690 m–1 cm–1 at λ = 212 nm) were
observed at the stage of the hexadecameric oligomer.[6] The
nonlinear changes in electronic circular dichroism (ECD)
with increasing oligomeric length were explained by an in-
creasing conformational preference for secondary helical
structures. Although a potential energy surface could not
be calculated owing to the low barriers of rotation about
the buta-1,3-diynediyl moieties connecting the chiral allene
moieties, the proposed helical conformations of the larger
Results and Discussion
Attempted Stapling by Ring-Closing Metathesis (RCM)
We decided to follow the leads from peptide chemistry
and apply RCM to conformationally stabilize acyclic oligo-
meric alleno-acetylenes. This versatile transformation[7] has
found widespread application in macrocyclizations of natu-
ral products[8] and in the construction of supramolecular
systems,[9] such as molecular knots and catenanes. Ruth-
enium-based carbene complexes are particularly popular
catalysts, owing to their high tolerance to functional groups,
stability in various media, and commercial availability.[10]
The optically active and partially protected DEA (P)-
(+)-1 (Figure 1) with stabilizing tert-butyl substituents on
both sides of the allene moiety[11,12] was used for the con-
struction of linear[6] and macrocyclic[13] oligomers by oxi-
dative acetylenic coupling. Allene (P)-(+)-2 with a 1,1-di-
methylbut-3-en-1-yl substituent has been initially investi-
gated,[14] but its derivatives undergo a remarkably facile
allenyl Cope rearrangement to give 2-allylbuta-1,3-dienes at
[a] Laboratorium für Organische Chemie, ETH Zürich,
Hönggerberg, HCI, Wolfgang-Pauli-Strasse 10, 8093 Zürich,
Switzerland
E-mail: diederich@org.chem.ethz.ch
http://www.diederich.chem.ethz.ch
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301529.
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Scheme 1. Proposed stapling (bridging) of optically active acyclic alleno-acetylenes by RCM.
50 °C.[14] The 1,1-dimethylpent-4-en-1-yl substituent of (P)- first-generation catalyst[19] have been reported. Rutjes and
(+)-3 precludes such a [3,3]-sigmatropic rearrangement, and co-workers attempted RCM of an olefinic allenamide but
RCM of the corresponding oxidatively coupled homodimer observed isomerization to an (E)-1,2-diene.[20a] Murakami
would lead to 14-membered (E)/(Z)-cyclotetradecenediynes et al. applied the ring-closing enyne metathesis to allenynes
with two attached ethynylvinylidene moieties. Compounds in the presence of the Schrock catalyst for the preparation
with this ring system are not known, but comparison with of 1,2,4-trienes.[20b] We have no hints that the targeted
crystal structures of related 14-membered paracyclophane- macrocyclization of dimerized (P)-(+)-3 can successfully
diynes[15] suggests that this macrocycle would only be compete with intramolecular enyne metathesis of the dialk-
slightly strained.
enylated buta-1,3-diyne.[21]
The synthesis of the target DEA (Ϯ)-3 followed a pre-
viously established strategy with a regioselective palladium-
mediated SN2Ј-type reaction as the key step for the genera-
tion of the allenyl moiety (Scheme 2).[14,22] The alkylation
of ethyl isobutyrate (4) with 4-bromobut-1-ene gave the un-
saturated ester 5,[23] which was saponified to acid 6[24] and
transformed into the Weinreb amide 7 in 70% yield. The
treatment of 7 with the lithium acetylide derived from 3,3-
dimethylbutyne afforded quantitatively ynone 8. This prop-
argylic ketone was treated with the lithium acetylide derived
from ethynyltriisopropylsilane followed by pentafluoro-
Figure 1. Monomeric 1,3-diethynylallenic precursors (DEAs).
Literature reports made us hopeful that RCM reactions benzoyl chloride to give bispropargylic benzoate (Ϯ)-9 in a
between the terminal alkenyl moieties of substituted alleno- one-pot reaction in 74% yield. The palladium-mediated
acetylene dimers would proceed without undesired inter- SN2Ј-type reaction of (Ϯ)-9 with 2-methyl-3-butyn-2-ol un-
ference of the allene moiety. Janssen and Krause reported der microwave irradiation afforded allene (Ϯ)-10 in 64%
the synthesis of macrocyclic allenes by ruthenium-catalyzed yield. The desilylation of (Ϯ)-10 with tetra-n-butylammo-
RCM of terminal olefins.[16] More recently, Katsumura and nium fluoride (TBAF) in tetrahydrofuran (THF) yielded
co-workers successfully applied homodimerization of all- the stable monomeric unit (Ϯ)-3, the enantiomers of which
enic olefins to the synthesis of mimulaxanthin, an allene- were separated by HPLC on a chiral stationary phase (Chi-
containing carotenoid.[17] On the other hand, the allene ralpak IA). The absolute configurations of the enantiomers
moiety could also participate in the metathesis reaction, as were assigned by ECD spectroscopy; (P)-configured op-
cross-metathesis of monosubstituted allenes[18a,18b] and tically active DEAs exhibit a positive Cotton effect, as es-
RCM of two terminal allenes[18c] in the presence of Grubbs tablished for monomer (P)-(+)-1.[22]
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Towards Stapling of Helical Alleno-Acetylene Oligomers
Scheme 2. Synthesis of (Ϯ)-3 and conditions for separation of enantiomers. Reagents and conditions: (a) iPr2NLi, ethyl isobutyrate, THF/
HMPA, –78 to 25 °C, 2 h, 74%; (b) LiOH·H2O, THF/MeOH/H2O, 40 °C, 12 h, 97%; (c) N,O-dimethylhydroxylamine, NEt3, methanesulf-
onyl chloride, THF, 0 °C, 2 h, 70%; (d) tBu–CϵC–Li, THF, –78 to 25 °C, 2 h, quant.; (e) i. TIPS–CϵC–Li, –78 to 25 °C, 1 h; ii. C6F5-
C(O)Cl, 0 °C, 2 h, 74%; (f) 2-methyl-3-butyn-2-ol, [PdCl2(PPh3)2], CuI, iPr2NEt, (CH2Cl)2, microwave, 80 °C, 20 min, 64%; (g) TBAF,
wet THF, 25 °C, 2 h, 61%; (h) HPLC on chiral stationary phase, Chiralpak IA with n-hexane/iPrOH (99.5:0.5) as eluent. HMPA =
hexamethylphosphoric triamide.
The homodimerization of enantiopure (P)-(+)-3 and slow evaporation of n-hexane over three days. The crystal
(M)-(–)-3 under standard palladium-mediated oxidative structure (space group P43) corroborated the relative con-
conditions[25] gave buta-1,3-diynes (P,P)-11 and (M,M)-11 figuration of (M,M)-11 (Figure 2). No solvent molecules
in 89 and 83% yield, respectively (Scheme 3). Single crystals were incorporated in the crystal lattice. In one unit cell, four
of (M,M)-11 suitable for X-ray analysis were obtained by partly disordered molecules arrange in a helical array with
Scheme 3. Synthesis and proposed mechanism for the formation of (P,P)-12. Reagents and conditions: (a) [PdCl2(PPh3)2], CuI, TMEDA,
toluene, air, 50 °C, 2 h, 89%; (b) 0.4 equiv. of Stewart–Grubbs catalyst, benzene, 80 °C, 10 h, 34%. TMEDA = N,N,NЈ,NЈ-tetramethyleth-
ylenediamine.
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Figure 2. (a) ORTEP plot of (M,M)-11 at 100(2) K with vibrational ellipsoids shown at the 50% level. (b) Solid-state packing of (M,M)-
11 along the 43 screw axis (point represents axis). (c) Solid-state packing of (M,M)-11 along the b axis. Color code: C white, O red, H
dark gray. Hydrogen atoms are omitted for clarity, except OH involved in hydrogen bonding. The structure shows an interesting H-
bonding pattern along the 43 axis. Starting from an acceptor OH(2) group to the donor OH(17) [O18(2 – x, 2 – y, –0.5 + z)···O1(x, y, z)
2.57 Å] from a molecule related by a 21 operation in the opposite direction of the 43 screw axis, the same OH(17) group acts as a donor
to OH(2) [O1(y, 2 – x, 0.25 + z)···O18(2 – x, 2 – y, –0.5 + z) 2.63 Å] from a molecule generated by a 21 operation in the 43 screw axis
direction. This pattern is repeated once more and ends with a H bond to OH(17)(x, y, z) from the starting molecule.
the terminal alcohol groups forming strong intermolecular MS (liquid chromatography/mass spectrometry) and TLC
hydrogen bonds from HO(2) to HO(17) with O···O dis- (thin layer chromatography). The product (P,P)-12
tances of 2.57 and 2.62 Å. Three OH groups from sym- (Scheme 3) decomposed slowly in chlorinated solvents
metry-related molecules form H bonds until the second OH (CD2Cl2, CDCl3) at room temperature but was stable in
group from the starting molecule is involved. These helical acetonitrile for one day at that temperature. Nevertheless,
H-bonded tetramers finally assemble into infinite strands (P,P)-12 could be purified by recycling gel permeation
along the 43 screw axis that extends through crystals of chromatography (R-GPC) with CHCl3 as eluent, provided
(M,M)-11.
Dimeric (P,P)-11 proved to be inert at 80 °C in benzene an ultimate yield of 34% was obtained.
or 1,2-dichloroethane solution and in the presence of up to The spectroscopic data support the structural assignment
that the fractions were subjected to fast evaporation, and
1
0.6 equiv. of Grubbs first-generation[19] or second-genera- for C2-symmetric (P,P)-12. H and 13C NMR spectroscopy
tion catalysts.[26] However, in the presence of stoichiometric (25 °C, CD2Cl2) indicated the expected disappearance of
amounts of the Hoveyda–Grubbs second-generation[27] or the CH2 signals of the terminal alkenyl moieties but also
Stewart–Grubbs[28] catalysts in benzene at 80 °C, complete the disappearance of the buta-1,3-diynyl moiety and the ap-
conversion of (P,P)-11 to one product was observed by LC– pearance of an alkynyl unit (δ =77.12 ppm in the 13C NMR
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Towards Stapling of Helical Alleno-Acetylene Oligomers
spectrum), which suggests the sequence enyne RCM–[1,3]- For this purpose, an allene decorated with three differently
metallotropic shift–second RCM to afford the 1,2-di- protected terminal alkyne groups is required. We first trans-
(cyclohex-1-enyl)acetylene (P,P)-12 (Scheme 3).
formed the 2-hydroxyisopropyl-protected (P)-(+)-3 into the
There is literature precedence for such a mechanistic cas- methoxymethyl ether (P)-(+)-13 (Scheme 4). The C-sil-
cade. In elegant and comprehensive work, Lee and co- ylation of (P)-(+)-13 with triisopropylsilyl chloride
workers have shown that an enyne metathesis, followed by (TIPSCl) and nBuLi at –78 °C in THF gave diprotected (P)-
a [1,3]-metallotropic shift, transforms buta-1,3-diynes bear- (+)-14, which was dihydroxylated under standard condi-
ing a terminal alkenyl chain into monocyclic hexa-1,5-dien- tions with osmium tetroxide and N-methylmorpholine N-
3-ynes at 40 °C.[29] Van Otterlo and co-workers found that oxide (NMO)[34] to give a diastereoisomeric mixture of diols
the starting material with an additional terminal alkenyl (P,R/S)-15. A careful control of the reaction by TLC was
chain undergoes a second RCM involving the rearranged important to avoid overoxidation. To the best of our knowl-
intermediate ruthenium species and affords bicyclic dien- edge, this is the first example in which an alkenyl group
ynes similar to (P,P)-12.[30] These tandem enyne metathe- was selectively dihydroxylated in the presence of an allenyl
ses[29,30] were catalyzed by Grubbs second-generation cata- moiety, presumably because of the steric shielding of the
lyst, which, however, did not convert (P,P)-11 into (P,P)-12. latter by the tert-butyl groups. The oxidation of (P,R/S)-15
The 1H and 13C NMR spectroscopic data of (P,P)-12 are with sodium periodate afforded the thermally unstable and
in agreement with the proposed structure. The olefinic H acid-sensitive aldehyde (P)-(+)-16, which was directly con-
atom of (P,P)-12 appears as a triplet (J = 4.4 Hz; Figure verted by Seyferth–Gilbert homologation with the Ohira–
1
S24) at δ = 6.16 ppm in the H NMR spectrum, and the Bestmann reagent into the thermally stable terminal alkyne
allylic methylene group resonates downfield (triplet of dou- (P)-(+)-17. The enantiomer (M)-(–)-17 was obtained in a
blets at δ = 2.25 ppm, J = 6.3 and 4.5 Hz) from that of the similar manner from enantiopure (M)-(–)-3.
open-chain dimer (P,P)-11 (multiplet at δ = 2.00–2.09 ppm;
The Hay coupling of (P)-(+)-17 with CuCl in acetone at
Figure S22). In the 13C NMR spectrum, the ring closure 25 °C gave dimeric (P,P)-18 in 90% yield (Scheme 4). The
leads to a strong downfield shift for the allenic sp2 carbon use of high-grade anhydrous CuCl was crucial. The product
atom in the α-position to the gem-dimethyl group (δ was acid-sensitive and had to be purified over an alumina
=114.54 ppm, Δδ = 12.5 ppm; Figure S25). To date, the column. The desilylation of (P,P)-18 with TBAF in THF
preparation of (P,P)-12 is the only example of an enyne and chromatography on alumina afforded (P,P)-19 in 73%
metathesis occurring in the presence of an allenyl moiety yield. These two steps were also performed with racemic
and is the first one applied to an optically active chiral (Ϯ)-17 and led to a diastereoisomeric mixture of (M,M/
starting material.
P,P)-19 and (M,P)-19 (an enantiopair and a diastereoiso-
1
mer). The H and 13C NMR spectra of the diastereoiso-
meric (M,M/P,P)-18/(M,P)-18 and (M,M/P,P)-19/(M,P)-19
mixtures showed a single set of signals (Figures S36–
S39).[35] The crucial final step, an Eglinton–Galbraith
macrocyclization,[36] was first tried with diastereoisomeric
(M,M/P,P)- and (M,P)-19. Their reaction with CuCl and
Bridging Dimeric Alleno-Acetylene with Diacetylene
Chains – An Enantiopure Bis(ethynylvinylidene)-Substituted
Cyclohexadeca-1,3,9,11-tetrayne
We changed the synthetic strategy and targeted the CuCl2 at room temperature in dry pyridine under high di-
macrocyclic bridging of dimeric alleno-acetylenes by oxi- lution gave 75% yield of the desired cyclized (M,M/P,P)-
dative Hay coupling of an analogue of (P,P)-11 bearing two and (M,P)-20, which showed two sets of NMR signals for
terminal 1,1-dimethylpent-4-yn-1-yl chains (Figure S1). the diastereoisomers, presumably owing to restricted con-
This cyclization would lead to a divinylidene-substituted formational freedom in the macrocycle. According to R-
cyclohexadeca-1,3,9,11-tetrayne. In 1957, Sondheimer et al. GPC (with JAIGEL-1H then JAIGEL-2 H, CHCl3 as elu-
reported the synthesis of cyclohexadeca-1,3,9,11-tetrayne ent), (M,M/P,P)-20 and (M,P)-20 are the only products and
by Hay coupling,[31] and its crystal structure was published have the same retention time. High-resolution (MALDI)
much later by Gleiter et al. in 1999.[32] Stichler-Bonaparte mass spectrometry ascertained the presence of the cyclized
and Vasella transformed a 4-ethynyl-α-d-mannopyranosyl- product by the [M + NH4]+ peak at m/z = 694.4830. The
acetylene into a strained tricyclic cyclohexadeca-1,3,9,11- macrocyclization to (M,M/P,P)-20 and (M,P)-20 was cor-
tetrayne by oxidative coupling with Cu(OAc)2 in pyridine roborated by the disappearance of the signal of the terminal
1
at 100 °C.[33] Encouraged by these literature precedents, we alkyne (singlet at δ = 3.06 ppm) in the H NMR spectrum
wanted to convert (P,P)-11 into the corresponding bis(term- (CD2Cl2, 25 °C) and by two sets of buta-1,3-diyne signals
inal alkyne). Dihydroxylation and sodium periodate oxi- in 13C NMR spectrum. Compounds (P,P)-20 and (M,M)-
dation of (P,P)-11 to the dialdehyde was successful, but Sey- 20 were similarly obtained from (P)-(+)-17 and (M)-(–)-17
ferth–Gilbert homologation to the terminal dialkyne failed in overall yields of 49 and 44%, respectively.
owing to decomposition under the harsh reaction condi-
tions.
Decomposition of (M,M/P,P)- and (M,P)-20 occurred
during the NMR measurements and subsequent evapora-
Alternatively, the desired cyclohexadeca-1,3,9,11-tetra- tion of CD2Cl2 at 40 °C. The instability of (M,M/P,P)- and
yne should be accessible from an acetylenic analogue of (M,P)-20 could arise from the ring strain and from the
monomer 3 by two consecutive Hay couplings (Figure S1). proximity of the two butadiyne units within the macrocycle.
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Scheme 4. Synthesis of (P,P)-20. (A) Reagents and conditions: (a) MOMCl, NaI, iPr2NEt, DME, 25 °C, 16 h, 66%; (b) nBuLi, TIPSCl,
THF, –78 to 25 °C, 2 h, 94%; (c) 4% OsO4 in H2O, NMO, acetone/H2O (9:1), 25 °C, 90 min, 84%; (d) NaIO4, MeOH, 25 °C, 2 h, 92%;
(e) i. dimethyl(2-oxopropyl)phosphonate, p-toluenesulfonyl azide, K2CO3, MeCN, 2 h; ii. (P)-(+)-16 in MeOH, 25 °C, 12 h, 20%; (f) i.
TMEDA, dry CuCl, dry acetone, 30 min, 25 °C; ii. (P)-(+)-17 in acetone, air, 25 °C, 90 min, 90%; (g) TBAF, wet THF, 25 °C, 1 h, 73%;
(h) CuCl, CuCl2, pyridine, addition of (P,P)-19 for 20 h at 25 °C, 4 h, 75%. (B) Structure of the lowest free enthalpy conformer of (P,P)-
20 calculated at the B3LYP/6-31G(d) level of theory by using Gaussian 09. DME = 1,2-dimethoxyethane, MOMCl = chloromethyl methyl
ether.
To reduce the decomposition, the workup of enantiopure (P,P)-20D with relative stabilities 0, 0.96, 2.00, and
(P,P)-20 was performed at 25 °C. To our surprise, NMR 2.11 kcalmol–1 (for further details on the computational
measurements showed that pure (P,P)-20 had epimerized in methods see the Supporting Information, Table S3).[37] Cal-
CD2Cl2 within 48 h at room temperature to a 9:1 (P,P)/(M/ culations for (M,M)-20 led to the four mirror images of
P) mixture (Figures S42–S43). Furthermore, storage of a (M,M)-20A–(M,M)-20D (Table S5), whereas calculations
CD2Cl2 solution for one week at room temperature in day- for (M,P)-20 gave two twisted chair–chair [(M,P)-20A and
light also led to partial decomposition. However, a solution (M,P)-20B are mirror images] and two twisted boat–boat
of (P,P)-20 in CD2Cl2 was stable for one week at 5 °C (Fig- conformers [(M,P)-20C and (M,P)-20D are mirror images]
ure S44).
with relative free enthalpies
0
and 2.29 kcalmol–1
The analysis of the H and 13C NMR spectra of a 9:1 (Table S4). A comparison of the relative free enthalpies of
mixture of (P,P)-20 and of an approximately 1:1 mixture of the most stable conformers (P,P)-20A/(M,M)-20A and
(M,M/P,P)-20 and (M,P)-20 in CD2Cl2 allowed the assign- (M,P)-20A shows a negligible difference (0.03 kcalmol–1,
ment of the signals to the diastereoisomers (1H and 13C Table SI6). The global minimum of (P,P)-20, the twisted
NMR spectroscopic data in Tables S1 and S2, respectively). chair–chair conformer with crossed butadiynyl moieties
Calculations at the B3LYP/6-31G(d) level of theory gave (with a torsion angle of 23.2°), is similar to that of the solid-
four minima structures for (P,P)-20 within the range of state structure of the parent cyclohexadeca-1,3,9,11-tetra-
3 kcalmol–1 above the global minimum, namely, the two yne (torsion angles of 21.6 and 21.8°).[32] This evidences
twisted chair–chair conformers (P,P)-20A and (P,P)-20B only a weak influence of the two vinylidene substituents
and the two twisted boat–boat conformers (P,P)-20C and (two sp3-hybridized C atoms are replaced by two sp2-hy-
1
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Towards Stapling of Helical Alleno-Acetylene Oligomers
bridized C atoms) on the ring conformation. The transan- nitrile (Figure S5a); this indicates that the magnetic dipole
nular distance between the two buta-1,3-diyne moieties is moment contribution is smaller in this region for (P,P)-12.
shorter in (P,P)-20 than in the parent compound [3.57 vs. In other words, the intrinsic chiral properties of the two
4.25 Å between C(2) and C(11), see Table S7].
chromophores differ significantly from each other.
Similar conclusions were drawn when the UV/Vis and
ECD spectra were recorded in n-hexane and the corre-
sponding g factors were calculated (Figures S2b, S3, and
S5b). The ECD intensity of the monomer (P)-(+)-3 was
Chiroptical Properties
Circular dichroism is defined as a difference of the molar identical (Δε = +16 m–1 cm–1, λ = 225 nm) in both solvents.
decadic absorption coefficients for left and right circularly In contrast, the strength of the Cotton effect of dimer (P,P)-
polarized light. Electronic circular dichroism (ECD) arises 11 was significantly higher in the apolar solvent: Δε =
from electronic excitations, which dominate in the UV/Vis +140 m–1 cm–1, λ = 249 nm in n-hexane (Figure S2b) com-
region. ECD intensities capture angular correlations be- pared to Δε = +85 m–1 cm–1, λ = 246 nm in acetonitrile.
tween electric and magnetic transition moments. Therefore, Furthermore, the ECD intensity of the bicyclic dimer (P,P)-
ECD is a powerful tool in stereochemical analysis for the 12 also increases (Δε = –77 m–1 cm–1, λ = 235 nm; Figure S3)
determination of absolute configurations and conforma- in n-hexane in comparison to that in acetonitrile (Δε =
tional features of chiral compounds.[38]
–44 m–1 cm–1, λ = 231 nm). Such a strong solvent effect had
The ECD traces for (P,P)-11, (P,P)-12, and their corre- not been observed for the previously reported alleno-acetyl-
sponding (M)-configured enantiomers recorded in aceto- ene oligomers, which featured ECD spectra nearly indepen-
nitrile are mirror images (Figure 3). The ECD intensity (Δε dent of solvent polarity.[6]
in m–1 mol–1) in acetonitrile increases from the monomer
The comparison of the UV/Vis spectra of the differently
(P)-(+)-3 (Δε = +15 m–1 cm–1, λ = 224 nm; Figure S2a) to functionalized/protected monomeric DEAs prepared in this
the dimer (P,P)-11 (Δε = +85 m–1 cm–1, λ = 246 nm; Fig- study allows the assignment of the absorption bands of the
ure 3, left) and shifts bathochromically, as previously ob- two enyne chromophores, the traces of which are found in
served for dimeric alleno-acetylenes (comparison in Fig- the Supporting Information (Figure S4, bottom). The
ure S2).[6] In the UV/Vis spectrum of (P,P)-12, the three strongest band corresponds to the unprotected enyne unit
bands present in the spectrum of (P,P)-11 that correspond (λ = 224 nm) or silylated enyne unit (λ = 236 nm) and the
to vibronic coupling of the CϵC–CϵC bonds[13a] disap- weaker one to the 2-hydroxyisopropyl-protected second en-
pear, and this confirms the absence of the buta-1,3-diynyl yne unit (λ = 231 nm). The analysis of the ECD traces of
moiety (Figure 3, right). The ECD spectrum of the new these DEAs provides interesting information about the chir-
chromophore (P,P)-12 exhibits a negative Cotton effect (Δε optical contributions of the various substituents.[39] Table 1
= –44 m–1 cm–1) at 231 nm, the intensity of which is signifi- summarizes the data obtained in n-hexane, and the ECD
cantly lower than that of (P,P)-11 (Δε = +85 m–1 cm–1, λ = traces are also found in the Supporting Information (Fig-
246 nm). To obtain further insight into the origins of these ure S4, top). The addition of the olefinic substituents in (P)-
chiroptical responses, we calculated the g factors of these (+)-3 and (P)-(+)-13 enhances moderately the Δε value as
two compounds. The g factor is defined as the ratio between compared to that of the previously reported DEA (P)-(+)-
the molar circular dichroism Δε and the molar extinction 1 (Δε = 15–17 vs. 10 m–1 cm–1) with two tert-butyl groups.[6]
coefficient ε; it can be used to estimate the relative contri- A further enhancement of the Cotton effects is attributed
butions of electric and magnetic transition dipole moments to the TIPS alkyne-protecting groups of (P)-(+)-14 and (P)-
to the observed Cotton effect and is in general useful for (+)-17 (Δε = 32–33 m–1 cm–1). The most intense Cotton ef-
the comparison of chromophores with different molar ex- fect is exhibited by diols (P,R/S)-15 with Δε = 56 m–1 cm–1.
tinction coefficients. The plot of the g factors (Δε/ε) reveals This shows a clear dependence of the ECD spectra upon
a significantly smaller g factor in the region 225–300 nm for the substituents of the hepta-3,4-dien-1,6-diyne moiety.
dienyne (P,P)-12 than for buta-1,3-diyne (P,P)-11 in aceto- These observations are in agreement with the g-factor cal-
Figure 3. Left: ECD spectra (top) and UV/Vis spectra (bottom) of (P,P)-11 (black line) and (M,M)-11 (grey line) in MeCN. Right: ECD
spectra (top) and UV/Vis spectra (bottom) of (P,P)-12 (black line) and (M,M)-12 (grey line) in MeCN (c = 3.7–5.6ϫ10–5 molL–1).
Eur. J. Org. Chem. 2014, 941–953
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F. Diederich et al.
FULL PAPER
culations (Figure S6). The strong enhancement of the chir- To enhance the helical structure of acyclic oligomeric
optical properties by TIPS substitution confirms findings alleno-acetylenes, different types of bridging need to be ex-
from our earlier work.[13c,22]
plored in future work.
Table 1. Cotton effects of monomeric DEAs with different substitu-
ents measured in n-hexane (Δε is relative to the maximal value of
the unprotected or silylated enyne unit).
Conclusions
To stabilize the helical secondary structure of oligomeric
alleno-acetylenes by bridging and, thus, increase their ex-
ceptional chiroptical responses, we describe in this paper
the first investigations of the cyclization of dimeric alleno-
acetylenes. In a first approach, we prepared an optically
active dimeric alleno-acetylene with two laterally pendant
olefinic substituents to cyclize the all-carbon scaffold by
RCM. However, enyne metathesis was preferred, and a cas-
cade of enyne RCM–1,3-metallotropic shift–second RCM,
for which there was some precedent in the literature, led
to an optically pure 1,2-di(cyclohex-1-enyl)acetylene. This
genuinely new chiral chromophore features distinctly dif-
ferent chiroptical properties than the acyclic alleno-acetyle-
nic dimer. In a second approach, rigidification of the chiral
dimer was attempted by oxidative Hay coupling to form a
macrocyclic cyclohexadeca-1,3,9,11-tetrayne with two vinyl-
idene substituents. This ring closure was successful and pro-
vided an interesting new chiral chromophore. However, it
did not enhance the chiroptical properties. Clear leads for
future work were obtained: we are now bridging larger
alleno-acetylenic oligomers, in which the helical conforma-
tional preference is more pronounced, through coupling
acetylenic and phenylacetylenic side chains at different posi-
tions along the oligomeric backbone. The results of these
efforts will be reported in due course.
R1
R2
R3
Δε
λmax
[m–1 cm–1] [nm]
(P)-(+)-1[6] OH
CH3
C4H7
H
H
H
TIPS
10
15
17
33
56
32
225
224
223
232
237
236
(P)-(+)-3
OH
(P)-(+)-13 OMOM C4H7
(P)-(+)-14 OMOM C4H7
(P,R/S)-15 OMOM (CH2)2CHOHCH2OH TIPS
(P)-(+)-17 OMOM C4H5 TIPS
The ECD intensity in n-hexane increases threefold from
monomer (P)-(+)-17 (Δε = +32 m–1 cm–1, λ = 236 nm) to
the corresponding dimer (P,P)-18 (Δε = +93 m–1 cm–1, λ =
238 nm; Scheme 4 and Figure 4). Upon removal of the two
TIPS groups in (P,P)-19 (Δε = 40 m–1 cm–1, λ = 226 nm),
the intensity diminishes nearly to the level of monomer (P)-
(+)-17.
Experimental Section
Materials and General Methods: Compound 6 was synthesized ac-
cording to literature procedures.[22,23] For further details, see Sup-
porting Information.
(P,P)-5,14-Di-(tert-butyl)-2,17-dimethyl-7,12-bis(1,1-dimethylpent-
4-en-1-yl)octadeca-5,6,12,13-tetraen-3,8,10,15-tetrayne-2,17-diol
[(P,P)-11]: A solution of monomeric allene (P)-(+)-3 (128 mg,
0.43 mmol) in toluene (8.6 mL) under air was treated with
[Pd(PPh3)2Cl2] (30 mg, 0.04 mmol), CuI (8 mg, 0.04 mmol), and
N,N,NЈ,NЈ-tetramethylethylenediamine (TMEDA; 64 μL,
0.43 mmol), the mixture was stirred at 50 °C for 2 h, and the sol-
vents were evaporated. Flash chromatography (FC; n-hexane/
EtOAc 6:1) gave (P,P)-11 (114 mg, 89 %) as a yellowish solid.
Double crystallization from n-hexane gave white crystals of (P,P)-
11. Rf = 0.48 (SiO2; n-hexane/EtOAc 4:1). M.p. 109–111 °C. [α]2D0
= +660 (c = 0.1 in CHCl3). 1H NMR (400 MHz, CD2Cl2): δ = 1.10
and 1.12 [2s, 6 H, Me2C(1Ј)], 1.13 [s, 9 H, Me3C–C(5)], 1.50–1.57
[m, 2 H, H2C(2Ј)], 1.52 [s, 6 H, Me2C(2)], 2.00–2.09 [m, 3 H,
H2C(3Ј), OH], 4.93 [br dq, J = 10.2, 0.9 Hz, 1 H, HE–C(5Ј)], 5.03
[dq, J = 17.1, 1.5 Hz, 1 H, HZ–C(5Ј)], 5.85 [ddt, J = 16.8, 10.2,
6.6 Hz, 1 H, H–C(4Ј)] ppm. 13C NMR (101 MHz, CD2Cl2): δ =
27.04 and 27.41 [Me2C(1Ј)], 29.22 [Me3C–C(5)], 29.77 [C(3Ј)], 31.85
[Me2C(2)], 36.08 [Me3C–C(5)], 39.35 [C(1Ј)], 41.17 [C(2Ј)], 66.07
[C(2)], 75.30 and 75.74 [C(8,9)], 77.32 [C(4)], 99.29 [C(3)], 101.98
[C(7)], 104.62 [C(5)], 114.51 [C(5Ј)], 139.71 [C(4Ј)], 214.80 [C(6)]
Figure 4. UV/Vis spectra (bottom) and ECD spectra (top) of (P,P)-
18 (dark grey line), (P,P)-19 (grey line), and (P,P)-20 (black line) in
n-hexane (c = 1.0–6.2ϫ10–5 molL–1). The corresponding (M,M)-
enantiomers are in the same shade as the (P,P)-enantiomers but in
dashed lines.
A substantial bathochromic shift of the most intense UV/
Vis absorption is observed from acyclic (P,P)-19 (λmax
=
223 nm) to macrocyclic (P,P)-20 (λmax = 257 nm). Addition-
ally, the intensity of the characteristic vibrational fine struc-
ture of the buta-1,3-diynediyl moieties increases (Fig-
ure S2b). The highest-intensity Cotton effects for the
macrocycle (P,P)-20 were reached at 257 (Δε
=
+23 m–1 cm–1) and 219 nm (Δε = +17 m–1 cm–1). In other
words, the macrocyclization has not yielded an increase in
chiroptical intensity (for g-factor analysis, see Figure S7). ppm. IR (ATR): ν = 3299 (br), 3083 (w), 2965 (s), 2931 (m), 2867
˜
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Towards Stapling of Helical Alleno-Acetylene Oligomers
(w), 2162 (very w), 1927 (w), 1642 (m), 1469 (m), 1458 (m), 1411 4.92 [ddt, J = 10.2, 2.3, 1.3 Hz, 1 H, HE–C(1)], 5.02 [dq, J = 17.1,
(w), 1386 (s), 1375 (m), 1362 (s), 1312 (w), 1281 (w), 1249 (w), 1229
(m), 1164 (s), 1150 (s), 1109 (w), 1067 (w), 992 (w), 958 (s), 878 (s),
1.7 Hz, 1 H, HZ–C(1)], 5.83 [ddt, J = 16.8, 10.2, 6.6 Hz, 1 H, H–
C(2)] ppm. 13C NMR (101 MHz, CD2Cl2): δ = 26.99 and 27.22
863 (w), 834, 761 (m), 673 (m) cm–1. UV/Vis (n-hexane): λmax (ε, [Me2C(5)], 29.23 [Me3C–C(8)], 29.75 [C(3)], 30.52 and 30.55
m
–1 cm–1) = 316 (19420), 296 (23260), 278 (19428), 256 (68000),
248 (78180) nm. UV/Vis (MeCN): λmax (ε, m–1 cm–1) = 316 (17620), (OMe), 71.93 [C(11)], 77.63 (CϵCH), 78.30 [C(9)], 80.93 (CϵCH),
296 (20710), 278 (17200), 257 (62870), 248 (65660) nm. ECD (n- 93.70 (OCH2O), 95.84 [C(10)], 101.38 [C(6)], 104.03 [C(8)], 114.35
[Me2C(11)], 35.87 [Me3C–C(8)], 38.77 [C(5)], 40.90 [C(4)], 55.77
hexane): λ (Δε, m–1 cm–1) = 314 (8), 294 (12), 275 (23), 249 (140), [C(1)], 139.79 [C(2)], 213.24 [C(7)] ppm. IR (ATR): ν = 3312 (w),
˜
203 (–82) nm. ECD (MeCN): λ (Δε, m–1 cm–1) = 314 (6), 293 (10),
3286 (w), 2964 (m), 2931 (w), 2158 (very w), 1931 (very w), 1641
(w), 1460 (w), 1362 (m), 1144 (s), 1088 (m), 1033 (s), 1001 (m),
264 (28), 246 (85), 242 (82), 214 (–36) nm. HRMS (MALDI): calcd.
for C42H58NaO2 [M + Na]+ 617.4329; found 617.4331 (44 %); 911 (m), 875 (w) cm–1. UV/Vis (n-hexane): λmax (ε, m–1 cm–1) = 231
calcd. for C42H58O2 [M]+ 594.4431; found 594.4433 (100 %). (33560), 224 (36000), 214 (24770) nm. ECD (n-hexane): λ (Δε,
C42H58O2 (594.44): calcd. C 84.80, H 9.83, O 5.38; found C 84.59,
H 9.62, O 5.51.
m
–1 cm–1) = 257 (–0.3), 223 (17) nm. HRMS (ESI): calcd. for
C23H34NaO2 [M + Na]+ 365.2451; found 365.2454 (22%); 229.1226
(23%); calcd. for C17H21 [M – C6H13O2]+ 225.1638; found 225.1637
(23%); 177.1274 (100%), 150.0372 (21%).
(P,P)-5,5Ј-{[(Ethynylene)bis(6,6-dimethylcyclohex-2-en-2-yl-1-
ylidene)]bis(methanediylidene)}bis(2,6,6-trimethylhept-3-yn-2-ol)
[(P,P)-12]: A solution of dimeric (P,P)-11 (40 mg, 0.07 mmol) in
benzene (6.7 mL) was degassed for 15 min with argon, and Ste-
wart–Grubbs catalyst[28] (19 mg, 0.03 mmol) was added. The mix-
ture was heated to 80 °C for 10 h, cooled to 25 °C, and the solvents
were evaporated. FC (n-hexane/EtOAc 6:1) gave (P,P)-12 (13 mg,
34%) as a yellowish solid. For ECD measurements, (P,P)-12 was
purified by R-GPC chromatography (JAIGEL-1 H, CHCl3, flow
rate: 4 mL/min). After each run (6 mg in 3 mL of CHCl3), the prod-
uct-containing fractions were evaporated to dryness, as decomposi-
tion was observed for CHCl3 solutions within hours. Rf = 0.23
(SiO2; n-hexane/EtOAc 4:1). M.p. 60.2 °C (dec.). [α]2D0 = +136 (c =
(P)-(+)-[5-(tert-Butyl)-8-(methoxymethoxy)-8-methyl-3-(1,1-dimeth-
ylpent-4-en-1-yl)nona-3,4-dien-1,6-diyn-1-yl]triisopropylsilane [(P)-
(+)-14]: A solution of MOM-protected allene (P)-(+)-13 (244 mg,
0.712 mmol) in THF (1 mL) was treated dropwise at –78 °C with
1.6 m nBuLi in n-hexane (0.6 mL). The mixture was stirred for
15 min at –78 °C, and for 30 min at 25 °C, cooled to –78 °C, and
treated with TIPSCl (0.23 mL, 1.07 mmol). The mixture was
warmed to 25 °C, stirred for 2 h at 25 °C, and diluted with Et2O
and H2O. The aqueous phase was extracted with Et2O (3ϫ 20 mL).
The combined organic phases were washed with brine and dried
with MgSO4, and the solvents were evaporated. FC (SiO2; n-hex-
0.1 in CHCl3). 1H NMR (400 MHz, CD2Cl2): δ = 1.07 and 1.08 [2s, ane/CH2Cl2 2:1Ǟ1:1) gave (P)-(+)-14 (334 mg, 94%) as a yellow-
6 H, Me2C(6Ј)], 1.12 [s, 9 H, Me3C–C(5)], 1.43–1.65 [m, 2 H, ish oil. Rf = 0.76 (SiO2; n-hexane/CH2Cl2 1:1). [α]2D0 = +183 (c =
H2C(5Ј)], 1.52 [s, 6 H, Me2C(2)], 2.07–2.17 (br s, 1 H, OH), 2.25
0.1 in CHCl3). 1H NMR (400 MHz, CD2Cl2): δ = 1.09 [br s, 24 H,
[td, J = 6.3, 4.5 Hz, 2 H, H2C(4Ј)], 6.16 [t, J = 4.4 Hz, 1 H, H– Si(CHMe2)3, MeC(1Ј)], 1.12 [s, 3 H, MeC(1Ј)], 1.13 [s, 9 H, Me3C–
C(3Ј)] ppm. 13C NMR (101 MHz, CD2Cl2): δ = 24.01 [C(4Ј)], 27.88
and 28.40 [Me2C(6Ј)], 29.42 [Me3C–C(5)], 31.98 and 32.03
C(5)], 1.53 [s, 6 H, Me2C(8)], 1.53–1.59 [m, 2 H, H2C(2Ј)], 2.05 [br
q, J = 7.8 Hz, 2 H, H2C(3Ј)], 3.35 (s, 3 H, OMe), 4.86 (s, 2 H,
[Me2C(2)], 33.65 [C(6Ј)], 35.65 [C(5Ј)], 35.74 [Me3C–C(5)], 66.08 OCH2O), 4.90 [ddt, J = 10.1, 2.3, 1.2 Hz, 1 H, HE–C(5Ј)], 5.00 [dq,
[C(2)], 77.12 [CϵC–C(2Ј)], 87.66 [C(4)], 97.14 [C(3)], 104.66 [C(5)], J = 17.1, 1.7 Hz, 1 H, HZ–C(5Ј)], 5.82 [ddt, J = 16.8, 10.1, 6.6 Hz,
114.54 [C(1Ј)], 118.40 [C(2Ј)], 135.12 [C(3Ј)], 206.80 (C=C=C) ppm. 1 H, H–C(4Ј)] ppm. 13C NMR (101 MHz, CD2Cl2): δ = 11.96
IR (ATR): ν = 3309 (br), 2964 (s), 2925 (s), 2863 (m), 2359 (w), [Si(CHMe2)3], 19.02 [Si(CHMe2)3], 27.09 and 27.47 [Me2C(1Ј)],
˜
2325 (w), 1985 (w), 1699 (w), 1456 (m), 1383 (m), 1362 (s), 1254
29.29 [Me3C–C(5)], 29.90 [C(3Ј)], 30.52 and 30.54 [Me2C(8)], 35.97
(m), 1228 (m), 1162 (s), 1139 (s), 1072 (m), 953 (s), 897 (m), 844 [Me3C–C(5)], 38.93 [C(1Ј)], 41.15 [C(2Ј)], 55.79 (OMe), 71.94
(m), 801 (m) cm–1. UV/Vis (n-hexane): λmax (ε, m–1 cm–1) = 287 [C(8)], 78.56 [C(6)], 93.69 (OCH2O), 94.87 [C(1)], 95.48 [C(7)],
(9170), 272 (13180), 231 (62840) nm. UV/Vis (MeCN): λmax (ε,
–1 cm–1) = 286 (9840), 272 (12590), 231 (61670) nm. ECD (n-hex-
100.60 [C(2)], 102.76 [C(3)], 103.31 [C(5)], 114.32 [C(5Ј)], 139.82
m
[C(4Ј)], 213.39 [C(4)] ppm. IR (ATR): ν = 2962 (m), 2942 (m), 2866
˜
ane): λ (Δε, m–1 cm–1) = 286 (7), 252 (40), 235 (–74), 232 (–73), 213
(64) nm. ECD (MeCN): λ (Δε, m–1 cm–1) = 278 (9), 246 (21), 231
(–44), 206 (48) nm. HRMS (ESI): calcd. for C40H54KO2 [M + K]+
605.3755; found 605.3757 (42 %); calcd. for C40H54NaO2
[M + Na]+ 589.4016; found 589.4015 (48%); calcd. for C40H58NO2
[M + NH4]+ 584.4462; found 584.4456 (100%).
(m), 2140 (w), 1927 (w), 1641 (w), 1462 (m), 1362 (m), 1145 (s),
1089 (m), 1034 (s), 996 (m), 881 (m), 721 (m), 675 (m) cm–1. UV/
Vis (n-hexane): λmax (ε, m–1 cm–1) = 236 (39800), 227 (33090) nm.
ECD (n-hexane): λ (Δε, m–1 cm–1) = 270 (0.3), 232 (33), 229 (32),
207 (15) nm. HRMS (ESI): calcd. for C32H54NaO2Si [M + Na]+
521.3785; found 521.3781 (70%); calcd. for C26H42O2NaSi [M –
C6H12 + Na]+ 437.2846; found 437.3591 (100%); 381.2965 (78%).
(P)-(+)-8-(tert-Butyl)-6-ethynyl-11-(methoxymethoxy)-5,5,11-tri-
methyldodeca-1,6,7-trien-9-yne [(P)-(+)-13]: A solution of alcohol
(P,R/S)-8-(tert-Butyl)-11-(methoxymethoxy)-5,5,11-trimethyl-6-[(tri-
(P)-(+)-3 (400 mg, 1.3 mmol) in 1,2-dimethoxyethane (DME; isopropylsilyl)ethynyl]dodeca-6,7-dien-9-yne-1,2-diol [(P,R/S)-15]: A
0.2 mL) was treated with NaI (804 mg, 5.4 mmol), iPr2NEt
solution of allene (P)-(+)-14 (596 mg, 1.2 mmol) in acetone/H2O
(1.3 mL, 7.4 mmol), and dropwise with chloromethyl methyl ether
(9:1, 12 mL) was treated with NMO (162 mg, 1.2 mmol) and 4%
(MOMCl; 0.5 mL, 6.7 mmol). The mixture was stirred for 16 h at aqueous OsO4 (0.38 mL, 0.06 mmol), and the mixture was stirred
25 °C, diluted with a saturated Na2CO3 solution, and extracted
with CH2Cl2 (3 ϫ 20 mL). The combined organic phases were
washed with brine and dried with MgSO4, and the solvents were
at 25 °C for 90 min and diluted with 10% aqueous NaHSO3 solu-
tion (120 mL). The phases were separated, and the aqueous phase
was extracted with Et2O (3 ϫ 70 mL). The combined organic
evaporated. FC (SiO2; CH2Cl2) gave (P)-(+)-13 (302 mg, 66%) as phases were washed with brine, dried with MgSO4, and evaporated
a yellowish oil. Rf = 0.64 (SiO2; CH2Cl2). [α]2D0 = +96 (c = 0.1 in
at 25 °C. FC (SiO2; CH2Cl2/MeOH 97:3) gave (P,R/S)-15 (535 mg,
CHCl3). 1H NMR (400 MHz, CD2Cl2): δ = 1.08 and 1.12 [2s, 6 H, 84%, 1:1 mixture of diastereoisomers) as a yellowish oil. An ana-
Me2C(5)], 1.13 [s, 9 H, Me3C–C(8)], 1.47–1.61 [m, 2 H, H2C(4)], lytic sample for UV/Vis, ECD, and [α]2D0 measurements was ob-
1.52 [s, 6 H, Me2C(11)], 2.03 [br qt, J = 7.9, 1.4 Hz, 2 H, H2C(3)],
tained by preparative HPLC on a Chiralpak® IA stationary phase
3.05 (s, 1 H, CϵCH), 3.34 (s, 3 H, OMe), 4.86 (s, 2 H, OCH2O), (Daicel Chemical Industries Ltd., n-hexane/iPrOH 98:2, flow rate:
Eur. J. Org. Chem. 2014, 941–953
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F. Diederich et al.
FULL PAPER
20 mLmin–1). Under these conditions, a solution of crude (P,R/S)-
15 (50 mg, 0.1 mmol) in n-hexane (25 mL, injections of 3 mL) gave
pure (P,R/S)-15 (37 mg, 69%, 1:1 mixture of diastereoisomers, tR
= 10.6 min). Rf = 0.59 (SiO2; CH2Cl2/MeOH 9:1). [α]2D0 = +230 (c
= 0.1 in CHCl3). 1H NMR (400 MHz, CD2Cl2, 1:1 mixture of dia-
stereoisomers): δ = 1.07/1.08 [2s, 3 H, Me–C(5)], 1.09 [s, 21 H,
Si(CHMe2)3], 1.12 [s, 9 H, Me3C–C(8)], 1.13/1.15 [2s, 3 H, Me–
2.0 mmol), and the mixture was stirred for 2 h at 25 °C and treated
dropwise with a solution of aldehyde (P)-(+)-16 (420 mg,
0.84 mmol) in MeOH (3 mL). This mixture was stirred for 12 h,
and the solvents were evaporated. The residue was diluted with
Et2O und H2O. The phases were separated, and the aqueous phase
was extracted with E2O (3ϫ 20 mL). The combined organic phases
were washed with brine and dried with MgSO4, and the solvents
C(5)], 1.42–1.53 [m, 4 H, H2C(3,4)], 1.53 [s, 6 H, Me2C(11)], 2.14 were evaporated. FC (SiO2; CH2Cl2) gave (P)-(+)-17 (83 mg, 20%)
and 2.15 [2 br s, 1 H, HO–C(2)], 2.24 and 2.25 [2 br s, 1 H, HO–
C(1)], 3.36 (s, 3 H, OMe), 3.36–3.38 [m, 1 H, Ha–C(1)], 3.56–3.60
as a colorless oil. Rf = 0.79 (SiO2; CH2Cl2). [α]2D0 = +168 (c = 0.1
1
in CHCl3). H NMR (400 MHz, CD2Cl2): δ = 1.09 [s, 24 H, Me–
[m, 2 H, Hb–C(1), H–C(2)], 4.87/4.88 (2s, 2 H, OCH2O) ppm. 13C C(1Ј), Si(CHMe2)3], 1.11 [s, 3 H, Me–C(1Ј)], 1.12 [s, 9 H, Me3C–
NMR (101 MHz, CD2Cl2, 1:1 mixture of diastereoisomers): δ =
11.94 [Si(CHMe2)3], 19.01 [Si(CHMe2)3], 27.08/27.14 [Me–C(5)],
27.51/27.58 [Me–C(5)], 29.24/29.26 [Me3C–C(8)], 29.34/29.44
C(5)], 1.53 [s, 6 H, Me2C(8)], 1.73–1.81 [m, 2 H, H2C(2Ј)], 1.93 [t,
J = 2.6 Hz, 1 H, H–C(5Ј)], 2.17 [td with virtual coupling,[40] J =
8.3, 2.7 Hz, 2 H, H2C(3Ј)], 3.35 (s, 3 H, OMe), 4.86 (s, 2 H,
[C(4)], 30.53/30.55/30.56 [Me2C(11)], 35.93/35.95 [Me3C–C(8)], OCH2O) ppm. 1 3C NMR (101 MHz, CD2 Cl2): δ = 11.93
37.52/37.54 [C(3)], 38.77/38.79 [C(5)], 55.78 (OMe), 67.19/67.22 [Si(CHMe2)3], 14.79 [C(3Ј)], 19.01 [Si(CHMe2)3], 26.82 and 27.19
[C(1)], 72.06/72.08 [C(11)], 73.26/73.31 [C(2)], 78.74/78.75 [C(9)],
93.59 (OCH2O), 94.98/95.00 (CϵC–TIPS), 95.44/95.49 [C(10)],
[Me2C(1Ј)], 29.25 [Me3C–C(5)], 30.48 and 30.51 [Me2C(8)], 35.99
[Me3C–C(5)], 38.84 [C(1Ј)], 40.86 [C(2Ј)], 55.79 (OMe), 68.22
100.57/100.59 (CϵC–TIPS), 102.47/102.55 [C(6)], 103.29 [C(8)], [C(5Ј)], 71.91 [C(8)], 78.30 [C(6)], 85.36 [C(4Ј)], 93.68 (OCH2O),
213.48/213.51 [C(7)] ppm. IR (ATR): ν = 3415 (br s), 2961 (m),
95.33 (CϵC–TIPS), 95.75 [C(7)], 100.15 (CϵC–TIPS), 102.02
˜
2942 (m), 2896 (m), 2865 (m), 2139 (w), 1929 (very w), 1462 (m),
1384 (w), 1362 (m), 1238 (m), 1145 (m), 1088 (m), 1073 (m), 1025
(s), 998 (m), 829 (w), 882 (m), 815 (w), 765 (w), 720 (m), 665 (s),
[C(3)], 103.71 [C(5)], 213.42 [C(4)] ppm. IR (ATR): ν = 3315 (w),
˜
2962 (m), 2943 (m), 2866 (m), 2140 (w), 1925 (very w), 1462 (m),
1386 (w), 1362 (m), 1259 (m), 1238 (w), 1213 (w), 1145 (s), 1113
635 (m) cm–1. UV/Vis (n-hexane): λmax (ε, m–1 cm–1) = 236 (43690), (w), 1088 (m), 1034 (s), 1000 (m), 920 (m), 882 (m), 854 (w), 817
227 (35800), 210 (15720) nm. ECD (n-hexane): λ (Δε, m–1 cm–1) =
269 (–2), 237 (56), 229 (47), 211 (16), 206 (18) nm. HRMS (ESI):
calcd. for C32H56NaO4Si [M + Na]+ 555.3840; found 555.3840
(17%); calcd. for C30H51O2Si [M – OCH2OMe]+ 471.3653; found
471.3651 (100%).
(w), 766 (w), 720 (m), 676 (s), 664 (s), 630 cm–1 (s). UV/Vis (n-
hexane): λmax (ε, m–1 cm–1) = 296 (5830), 236 (45510), 228 (40800),
210 (21413) nm. ECD (n-hexane): λ (Δε, m–1 cm–1) = 236 (32), 228
(28), 211 (11), 206 (13) nm. HRMS (ESI): calcd. for C32H52NaO2Si
[M]+ 519.3629; found 519.3623 (26%); calcd. for C30H47Si [M –
OCH2OMe]+ 435.3442; found 435.3441 (100%).
(P)-(+)-7-(tert-Butyl)-10-(methoxymethoxy)-4,4,10-trimethyl-5-[(tri-
isopropylsilyl)ethynyl]undeca-5,6-dien-8-ynal [(P)-(+)-16]: A solu-
tion of (P,R/S)-15 (485 mg, 0.91 mmol) in MeOH (34 mL) was
treated with NaIO4 (195 mg, 0.91 mmol), the mixture was stirred
for 2 h at 25 °C, and the solvents were evaporated. A solution of
the residue in H2O was extracted with Et2O (3ϫ 20 mL). The com-
bined organic phases were washed with brine and dried with
MgSO4, and the solvents were evaporated. Drying of the solid over-
night under vacuum gave (P)-(+)-16 (421 mg, 92%) as a yellowish
oil, which was used for the next step without further purification.
Rf = 0.60 (SiO2; CH2Cl2/MeOH 95.5:0.5). 1H NMR (400 MHz,
CD2Cl2): δ = 1.08 [s, 21 H, Si(CHMe2)3], 1.12 and 1.13 [2s, 6 H,
Me2C(4)], 1.13 [s, 9 H, Me3C–C(7)], 1.53 [s, 6 H, Me2C(10)], 1.74–
1.82 [m, 2 H, H2C(3)], 2.42 [td, J = 8.0, 1.7 Hz, 2 H, H2C(2)], 3.35
(s, 3 H, OMe), 4.86 (s, 2 H, OCH2O), 9.74 (t, J = 1.6 Hz, 1 H, CHO)
ppm. 13C NMR (101 MHz, CD2Cl2): δ = 11.92 [Si(CHMe2)3], 18.99
[Si(CHMe2)3], 27.03 and 27.31 [Me2C(4)], 29.25 [Me3C–C(7)],
30.52 and 30.53 [Me2C(10)], 33.44 [C(2)], 36.02 [Me3C–C(7)], 38.47
[C(4)], 40.57 [C(3)], 55.79 (OMe), 71.94 [C(10)], 78.31 [C(8)], 93.67
(OCH2O), 95.43 (CϵC–TIPS), 95.86 [C(9)], 100.13 (CϵC–TIPS),
102.05 [C(5)], 103.76 [C(7)], 202.56 (CHO), 213.45 [C(6)] ppm. IR
{(P,P)-3,14-Bis[2-(tert-butyl)-5-(methoxymethoxy)-5-methylhex-1-
en-3-yn-1-ylidene]-4,4,13,13-tetramethylhexadeca-1,7,9,15-tetrayne-
1,16-diyl}bis(triisopropylsilane) [(P,P)-18]: A suspension of anhy-
drous CuICl (Ն99.99%, 48 mg, 0.48 mmol) in dry acetone (0.8 mL)
was treated with TMEDA (60 μL, 0.40 mmol), and the mixture was
stirred under argon for 30 min at 25 °C. The resulting blue-green
suspension of the CuCl–TMEDA complex was filtered through a
syringe filter directly into a solution of (P)-(+)-17 (10 mg,
0.02 mmol) in acetone (1 mL). The mixture was stirred under air
at 25 °C for 90 min and diluted with a saturated NH4Cl solution
and E2O. The phases were separated, and the aqueous phase was
extracted with Et2O (3ϫ 20 mL). The combined organic phases
were washed with brine and dried with MgSO4, and the solvents
were evaporated. FC (Alox B with 6% H2O; n-hexane/CH2Cl2 7:3)
gave (P,P)-18 (9 mg, 90 %) as a yellowish oil. Rf = 0.26 (SiO2;
CH2Cl2). [α]2D0 = +155 (c = 0.1 in CHCl3). 1H NMR (400 MHz,
CD2Cl2): δ = 1.08 [s, 3 H, Me–C(4)], 1.09 [s, 21 H, Si(CHMe2)3],
1.10 [s, 3 H, Me–C(4)], 1.12 [s, 9 H, Me3C–C(2Ј)], 1.53 [s, 6 H,
Me2C(5Ј)], 1.68–1.88 [m, 2 H, H2C(5)], 2.21–2.25 [m, 2 H, H2C(6)],
3.35 (s, 3 H, OMe), 4.86 (s, 2 H, OCH2O) ppm. 13C NMR
(101 MHz, CD2Cl2): δ = 11.93 [Si(CHMe2)3], 15.60 [C(6)], 19.00
[Si(CHMe2)3], 26.77 and 27.20 [Me2C(4)], 29.25 [Me3C–C(2Ј)],
30.49 and 30.51 [Me2C(5Ј)], 36.00 [Me3C–C(2Ј)], 38.85 [C(4)], 40.53
[C(5)], 55.79 (OMe), 65.62 [C(8)], 71.91 [C(5Ј)], 78.00 [C(7)], 78.26
[C(3Ј)], 93.68 (OCH2O), 95.43 [C(1)], 95.81 [C(4Ј)], 100.07 [C(2)],
(ATR): ν = 3452 (br), 2961 (m), 2945 (m), 2865 (m), 2140 (w), 1927
˜
(w), 1728 (m), 1672 (w), 1462 (m), 1385 (w), 1362 (w), 1259 (w),
1238 (w), 1215 (w), 1145 (m), 1088 (m), 1032 (s), 999 (m), 941 (w),
920 (w), 881 (m), 816 (w), 767 (w), 721 (w), 675 (m), 664 (m),
634 (m) cm–1. HRMS (ESI): calcd. for C31H56NO3Si [M + NH4]+
518.4013; found 518.4024 (trace); calcd. for C30H51O2Si [M –
CHO]+ 471.3653; found 471.3650 (100%); calcd. for C29H47OSi
[M – C2H5O2]+ 439.3391; found 439.3393 (54%).
101.90 [C(3)], 103.78 [C(2Ј)], 213.43 [C(1Ј)] ppm. IR (ATR): ν =
˜
2962 (m), 2942 (m), 2865 (m), 2139 (w), 1929 (w), 1462 (m), 1362
(m), 1259 (m), 1238 (m), 1144 (s), 1088 (m), 1034 (s), 999 (m), 920
(m), 882 (s), 817 (w), 720 (m), 675 (s), 664 (s) cm–1. UV/Vis (n-
(P)-(+)-[5-(tert-Butyl)-8-(methoxymethoxy)-8-methyl-3-(1,1-dimeth-
ylpent-4-yn-1-yl)nona-3,4-dien-1,6-diyn-1-yl]triisopropylsilane [(P)- hexane): λmax (ε, m–1 cm–1) = 339 (3203), 323 (3890), 308 (3406),
(+)-17]: A solution of dried K2CO3 (695 mg, 5.0 mmol) and p-tolu-
237 (103520), 227 (85960), 211 (42130) nm. ECD (n-hexane): λ (Δε,
m
enesulfonyl azide (397 mg, 2.0 mmol) in MeCN (30 mL) was
–1 cm–1) = 272 (–4), 238 (93), 230 (77), 211 (16), 206 (20) nm.
treated with dimethyl(2-oxopropyl)phosphonate (0.28 mL, HRMS (MALDI): calcd. for C64H102NaO4Si2 [M + Na]+
950
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 941–953

Towards Stapling of Helical Alleno-Acetylene Oligomers
1013.7209; found 1013.7210 (11%); calcd. for C64H102O4Si2 [M]+
990.7311; found 990.7310 (100 %); calcd. for C62H97O2Si2 [M –
OCH2OMe]+ 929.7022; found 929.7018 (12%).
36.10 [Me3C–C(2Ј), (M,P)], 40.22 [C(7), (M,P)], 40.26 [C(7), (M,M/
P,P)], 40.70/40.74 [C(6)], 55.79 (OMe), 67.26 [C(10), (M,M/P,P)],
67.32 [C(10), (M,P)], 71.93 [C(5Ј)], 77.65 [C(9), (M,M/P,P)], 77.69
[C(9), (M,P)], 77.93 [C(3Ј)], 79.12 [C(3), (M,M/P,P)], 79.15 [C(3),
(M,P)], 80.86 [C(4), (M,P)], 80.93 [C(4), (M,M/P,P)], 93.73
(OCH2O), 96.33 [C(4Ј), (M,P)], 96.41 [C(4Ј), (M,M/P,P)], 101.15
[C(5), (M,M/P,P)], 101.23 [C(5), (M,P)], 104.67 [C(4Ј), (M,M/P,P)],
104.69 [C(2Ј), (M,P)], 215.51 [C(1Ј), (M,P)], 215.56 [C(1Ј), (M,M/
(P,P)-5,20-Di-tert-butyl-7,18-diethynyl-2,23-bis(methoxymethoxy)-
2,8,8,17,17,23-hexamethyltetracosa-5,6,18,19-tetraen-3,11,13,21-tet-
rayne [(P,P)-19]: A solution of (P,P)-18 (30 mg, 0.03 mmol) in THF
(0.3 mL) was treated with 1 m TBAF in THF (76 μL, 0.08 mmol),
the mixture was stirred at 25 °C for 1 h, and the solvents were evap-
orated. FC (Alox B with 6 % H2O, n-hexane/CH2Cl2 7:3) gave
(P,P)-19 (15 mg, 73%) as a yellowish oil. Rf = 0.12 (SiO2; CH2Cl2).
[α]2D0 = +75 (c = 0.1 in CHCl3). 1H NMR (400 MHz, CD2Cl2): 1.07
and 1.10 [2s, 6 H, Me2C(8)], 1.12 [s, 9 H, Me3C–C(5)], 1.52 [s, 6
H, Me2C(2)], 1.71 and 1.76 [2 dt, J = 14.0, 7.8 Hz, 2 H, H2C(9)],
2.22 [t, J = 8.1 Hz, 2 H, H2C(10)], 3.06 (s, 1 H, CϵCH), 3.35 (s, 3
H, OMe), 4.86 (s, 2 H, OCH2O) ppm. 13C NMR (101 MHz,
CD2Cl2): δ = 15.53 [C(10)], 26.74 and 26.84 [Me2C(8)], 29.20
[Me3C–C(5)], 30.51 and 30.52 [Me2C(2)], 35.90 [Me3C–C(5)], 38.72
[C(8)], 40.30 [C(9)], 55.79 (OMe), 65.59 [C(12)], 71.90 [C(2)], 77.16
(CϵCH), 78.01 [C(11)], 78.14 [C(4)], 81.31 (CϵCH), 93.71
(OCH2O), 96.17 [C(3)], 100.53 [C(7)], 104.49 [C(5)], 213.30 [C(6)
P,P)] ppm. IR (ATR): ν = 2959 (m), 2923 (m), 2852 (m), 1738 (m),
˜
1461 (w), 1377 (m), 1362 (m), 1259 (m), 1088 (m), 1034 (m), 796
(m), 631 (s) cm–1. HRMS (MALDI): calcd. for C46H60KO4 [M +
K]+ 715.4114; found 715.4114 (4%); calcd. for C46H60NaO4 [M +
Na]+ 699.4384; found 699.4375 (8%); calcd. for C46H64NO4 [M +
NH4]+ 694.4830; found 694.4830 (100%).
(P,P)-5,16-Bis[2-(tert-butyl)-5-(methoxymethoxy)-5-methylhex-1-en-
3-yn-1-ylidene]-6,6,15,15-tetramethylcyclohexadeca-1,3,9,11-tetra-
yne [(P,P)-20]: A suspension of CuCl (234 mg, 2.36 mmol) and
CuCl2 (32 mg, 0.24 mmol) in dry pyridine (60 mL) was degassed
for 60 min and treated with a solution of (P,P)-19 (27 mg,
0.04 mmol) in dry, degassed pyridine (15 mL) over 20 h at 25 °C.
The mixture was stirred for 4 h at 25 °C, diluted with saturated
NH4Cl solution, and extracted with n-pentane (3ϫ). The combined
organic phases were washed with saturated CuSO4 solution (5ϫ)
and brine, dried with MgSO4, and evaporated at 25 °C. FC (Alox
B with 15% H2O, n-pentaneǞn-pentane/CH2Cl2 1:1) gave (P,P)-
20 (6 mg, 75%) as a yellowish oil. Rf = 0.71 (Alox; CH2Cl2). [α]2D0
= +181 (c = 0.1 in CHCl3). 1H NMR [600 MHz, CD2Cl2, (P,P)/
(M,P) ≈ 9:1]: δ = 1.03 and 1.12 [2s, 5.4 H, Me2C(6,15), (P,P)], 1.05
and 1.10 [2s, 0.6 H, Me2C(6,15), (M,P)], 1.15 [s, 9 H, Me3C–C(2Ј)],
1.5327 and 1.5369 [2s, 6 H, Me2C(5Ј)], 1.82 [ddd, J = 14.1, 8.6,
2.9 Hz, 0.9 H, Ha–C(7), (P,P)], 1.85–1.90 [m, 0.2 H, H2C(7), (P,M)],
1.92 [ddd, J = 14.1, 8.6, 3.0 Hz, 0.9 H, Hb–C(7), (P,P)], 2.14 [ddd,
J ≈ 18.5, 8.0, 3.0 Hz, 0.9 H, Ha–C(8), (P,P)], 2.13–2.20 [m, 0.2 H,
H2C(8), (M,P)], 2.23 [ddd, J ≈ 18.0, 8.6, 3.0 Hz, 0.9 H, Hb–C(8),
(P,P)], 3.353 (s, 3 H, OMe), 4.87 (s, 2 H, OCH2O) ppm. 13C NMR
(151 MHz, CD2Cl2): δ = 15.32 [C(8)], 27.26 and 28.43 [Me2C(6)],
29.20 [Me3C–C(2Ј)], 30.49 and 30.51 [Me2C(5Ј)], 36.07 [Me3C–
C(2Ј)], 40.25 [C(7)], 40.72 [C(6)], 55.79 (OMe), 67.24 [C(10)], 71.93
[C(5Ј)], 77.64 [C(9)], 77.91 [C(3Ј)], 79.11 [C(3)], 80.92 [C(4)], 93.72
(OCH2O), 96.40 [C(4Ј)], 101.13 [C(5)], 104.65 [C(2Ј)], 215.55 [C(1Ј)]
ppm. UV/Vis (n-hexane): λmax (ε, m–1 cm–1) = 319 (5670), 300
(8450), 282 (9100), 260 (18450), 248 (28860), 238 (23500) nm. ECD
(n-hexane): λ (Δε, m–1 cm–1) = 324 (–2), 302 (–3), 285 (–1), 275 (3),
257 (23), 243 (11), 234 (4), 230 (4), 219 (17), 214 (15) nm.
ppm]. IR (ATR): ν = 3310 (w), 3287 (w), 2964 (m), 2929 (m), 2097
˜
(very w), 1933 (very w), 1461 (m), 1362 (m), 1259 (m), 1237 (m),
1144 (s), 1088 (m), 1032 (s), 1001 (m), 920 (m), 875 (w), 818 (w),
754 (w) cm–1. UV/Vis (n-hexane): λmax (ε, m–1 cm–1) = 329 (1710),
313 (2700), 299 (2300), 231 (77110), 223 (82700) nm. ECD (n-hex-
ane): λ (Δε, m–1 cm–1) = 278 (1), 259 (–1), 231 (35), 226 (40) nm.
HRMS (ESI): calcd. for C46H62KO4 [M + K]+ 717.4280; found
717.4281 (19 %); calcd. for C46H62NaO4 [M + Na]+ 701.4540;
found 701.4541 (100%); calcd. for C46H62O4 [M]+ 678.4643; found
678.4644 (81%); calcd. for C44H57O2 [M – OCH2OMe]+ 617.4353;
found 617.4355 (30%).
(M,M/P,P)- and (M,P)-5,16-Bis[2-(tert-butyl)-5-(methoxymethoxy)-
5-methylhex-1-en-3-yn-1-ylidene]-6,6,15,15-tetramethylcyclohexa-
deca-1,3,9,11-tetrayne [(M,M/P,P)- and (M,P)-20]: A suspension of
CuCl (787 mg, 8 mmol) and CuCl2 (107 mg, 0.8 mmol) in dry pyr-
idine (60 mL) was degassed for 60 min and treated with a solution
of (M,M/P,P)- and (M,P)-19 (27 mg, 0.04 mmol) in dry, degassed
pyridine (15 mL) over 20 h at 25 °C. The mixture was stirred for
4 h at 25 °C. After evaporation of pyridine at 40 °C, the mixture
was diluted with saturated NH4Cl solution and n-pentane. The
phases were separated, and the aqueous phase was extracted with
n-pentane (3ϫ). The combined organic phases were washed with
brine, dried with MgSO4, and evaporated at 40 °C. An analytic
sample of (M,M/P,P)- and (M,P)-20 (5 mg) as a yellowish oil was
obtained by preparative R-GPC with JAIGEL-1 H, followed by
JAIGEL-2H as the stationary phase (Japan Analytical Industries,
CHCl3, flow rate: 4 mL/min). Decomposition was observed at
40 °C. Rf = 0.13 (SiO2; CH2Cl2). 1H NMR [400 MHz, CD2Cl2,
(M,M/P,P)/(M,P) 48:52]: δ = 1.03/1.12 [2s, 2.88 H, Me2C(6,15),
(M,M/P,P)], 1.06/1.10 [2s, 3.12 H, Me2C(6,15), (M,P)], 1.15 [s, 4.32
H, Me3C–C(2Ј), (M,M/P,P)], 1.16 [s, 4.68 H, Me3C–C(2Ј), (M,P)],
1.53 [s, 6 H, 2 Me2C(5Ј)], 1.82 [ddd, J ≈ 14.0, 8.2, 3.3 Hz, 0.48 H,
Ha–C(7), (M,M/P,P)], 1.83–1.90 [m, 1.04 H, H2C(7), (M,P)], 1.92
[ddd, J = 14.3, 7.8, 3.3 Hz, 0.48 H, Hb–C(7), (M,M/P,P)], 2.14
[ddd, J ≈ 18.4, 7.4, 2.9 Hz, 0.48 H, Ha–C(8), (M,M/P,P)], 2.12–2.22
[m, 1.04 H, H2C(8), (M,P)], 2.23 [ddd, J ≈ 17.9, 8.4, 3.4 Hz, 0.48
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterizations for the precur-
sors to the DEAs and all enantiomers with (M) chirality. Plots of
NMR spectra, UV/Vis, ECD, and g factors. DFT calculations of
the conformers of cyclohexadeca-1,3,9,11-tetrayne macrocycle
(P,P)-20.
Acknowledgments
This work was supported by the European Research Council
H, Hb–C(8), (M,M/P,P)], 3.350 [s, 1.56 H, OMe, (M,P)], 3.353 [s, (ERC) Advanced Grant 246637 (“OPTELOMAC”). The authors
1.44 H, OMe, (M,M/P,P)], 4.86 [s, 1.04 H, OCH2O, (M,P)], 4.87
[s, 0.96 H, OCH2O, (M,M/P,P)] ppm. 13C NMR (101 MHz,
CD2Cl2): δ = 15.33 [C(8), (M,M/P,P)], 15.38 [C(8), (M,P)], 27.27
thank Dr. Pablo Rivera-Fuentes for critically reading the manu-
script. Prof. H. Wennemers is thanked for access to a Chirascan
instrument for ECD measurements. The authors are grateful to Dr.
[Me–C(6), (M,M/P,P)], 27.88 [Me2C(6), (M,P)], 28.43 [Me–C(6), Adam R. Lacy and Dr. Emmanouil Tzirakis for reading the manu-
(M,M/P,P)], 29.21 [Me3C–C(2Ј), (M,M/P,P)], 29.23 [Me3C–C(2Ј), script and fruitful discussions during the development of this pro-
(M,P)], 30.50/30.52 [Me2C(5Ј)], 36.07 [Me3C–C(2Ј), (M,M/P,P)], ject.
Eur. J. Org. Chem. 2014, 941–953
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
951

F. Diederich et al.
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