On the origin of diastereoselectivity in [2 + 2 + 2] cycloisomerization of chiral triynes: Controlling helicity of helicene-like compounds by thermodynamic factors

Article abstract of DOI:10.1021/jo701997p

(Chemical Equation Presented) Diastereoselective Co^I-mediated [2 + 2 + 2] cycloisomerization of CH₃O-substituted optically pure aromatic triynes to obtain nonracemic functionalized helicene-like compounds (comprising a penta-, hexa-,

Full text of DOI:10.1021/jo701997p

On the Origin of Diastereoselectivity in [2 + 2 + 2]
Cycloisomerization of Chiral Triynes: Controlling Helicity of
Helicene-like Compounds by Thermodynamic Factors
Petr Sehnal,†,‡ Zuzana Krausova´,†,‡ Filip Teply´,† Irena G. Stara´,*,†,‡ Ivo Stary´,*,†,‡
Lubom´ır Rul´ısˇek,*,†,‡ David Sˇaman,† and Ivana C´ısarˇova´§
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, FlemingoVo
na´m. 2, 166 10 Prague 6, Czech Republic, and Department of Inorganic Chemistry, Charles UniVersity,
AlbertoV 2030, 128 40 Prague 2, Czech Republic
stara@uochb.cas.cz; stary@uochb.cas.cz; rulisek@uochb.cas.cz
ReceiVed October 14, 2007
Diastereoselective CoI-mediated [2 + 2 + 2] cycloisomerization of CH3O-substituted optically pure
aromatic triynes to obtain nonracemic functionalized helicene-like compounds (comprising a penta-, hexa-,
and heptacyclic helical scaffold) was studied. The stereochemical outcome of the reaction at 140 °C
using CpCo(CO)2 was controlled by thermodynamic factors yielding diastereomeric ratios up to 91:9.
Using CpCo(ethylene)2 at room temperature, a kinetic control took place leading to the loss of
stereoselectivity. Barriers to epimerization for selected helicene-like compounds were measured indicating
their lower configurational stability in comparison to the parent carbohelicenes. Free energy differences
between corresponding pairs of diastereomers (calculated at the DFT B3LYP/TZV+P level) were in
excellent agreement with the experimental data and allowed for the prediction of the stereochemical
outcome of the reaction. An optically pure hexacyclic helicene-like alcohol was prepared on a multigram
scale. Its X-ray structure confirmed the previous helicity assignments being based on 1H-1H correlations
1
in ROESY H NMR spectra.
Introduction
some of them might be identified as highly promising because
remarkable progress in obtaining nonracemic helicenes has
already been achieved. Carren˜o and Urbano successfully
developed an asymmetric version of the Diels-Alder approach
(originally invented by Katz as a nonstereoselective process)3
providing helicene quinones with excellent optical purities.4 A
remarkable stereocontrol in the synthesis of [5]helicenes was
achieved by Karikomi, who used a completely diastereoselective
Asymmetric synthesis of helicenes1 and their congeners is
envisioned to be the most straightforward and efficient route to
single enantiomers of these attractive, helically chiral com-
pounds. Various concepts have emerged2 demonstrating basic
principles rather than generally useful methodologies. However,
† IOCB Prague.
‡ Center for Biomolecules and Complex Molecular Systems (supported by
the Ministry of Education, Youth, and Sports of the Czech Republic).
§ Charles University.
(2) In the past, asymmetric synthesis of helicenes was successfully
accomplished using photochemical as well as nonphotochemical methods.
For pioneering works, see: (a) Stara´, I. G.; Stary´, I.; Tichy´, M.; Za´vada, J.;
Hanusˇ, V. J. Am. Chem. Soc. 1994, 116, 5084. (b) Katz, T. J.; Sudhakar,
A.; Teasley, M. F.; Gilbert, A. M.; Geiger, W. E.; Robben, M. P.; Wuensch,
M.; Ward, M. D. J. Am. Chem. Soc. 1993, 115, 3182. (c) Vanest, J.; Martin,
R. H. Recl. TraV. Chim. (Pays-Bas) 1979, 98, 113. (d) Bestmann, H. J.;
Both, W. Chem. Ber. 1974, 107, 2923.
(1) For selected reviews, see: (a) Urbano, A. Angew. Chem., Int. Ed.
2003, 42, 3986. (b) Hopf, H. Classics in Hydrocarbon Chemistry: Syntheses,
Concepts, PerspectiVes; VCH: Weinheim, 2000; Chapter 12.2, p 323. (c)
Katz, T. J. Angew. Chem., Int. Ed. 2000, 39, 1921. (d) Oremek, G.; Seiffert,
U.; Janecka, A. Chem.-Ztg. 1987, 111, 69. (e) Vo¨gtle, F. Fascinating
Molecules in Organic Chemistry; Wiley: New York 1992; p 156. (f) Meurer,
K. P.; Vo¨gtle, F. Top. Curr. Chem. 1985, 127, 1. (g) Laarhoven, W. H.;
Prinsen, W. J. C. Top. Curr. Chem. 1984, 125, 63.
(3) (a) Willmore, N. D.; Liu, L. B.; Katz, T. J. Angew. Chem., Int. Ed.
1992, 31, 1093. (b) Liu, L.; Katz, T. J. Tetrahedron Lett. 1990, 31, 3983.
10.1021/jo701997p CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/20/2008
2074
J. Org. Chem. 2008, 73, 2074-2082

Helicene-like Compounds
aromatic oxy-Cope rearrangement as a key step.5 An original
approach was published by Genet, who took advantage of
chirality transfer from an enantiopure tether to a flexible [5]-
helicene backbone under thermal conditions, making it con-
figurationally locked.6 Nozaki described a stereospecific syn-
thesis of hetero[7]helicenes via Pd-catalyzed N- or O-arylation
of axially chiral substrates derived from optically pure 4,4′-
biphenanthryl-3,3′-diol.7 Very recently, Tanaka has demon-
strated enatioselective Rh-catalyzed [2 + 2 + 2] cyclotrimer-
ization of triynes in the synthesis of helicene-like compounds.8
In addition to that, the past decade has witnessed other attempts
at asymmetric synthesis of helicenes, but stereocontrol observed
has been moderate rather than high as published by Rajca,9
Tanaka,10 Pe´rez and Guitia´n,11 and our laboratory.12 In spite of
the above-mentioned achievements, practical asymmetric syn-
thesis of helical aromatics has so far remained a challenging
task.
Recently, we have contributed to solving this problem by
synthesizing nonracemic [7]helicene-like scaffolds using dias-
tereoselective [2 + 2 + 2] cycloisomerization of centrally chiral
aromatic triynes.13 Herein, we report the utilization of this
methodology in the synthesis of functionalized penta-, hexa-,
and heptacyclic aromatics in a nonracemic form. We also
provide a detailed view of the origin of diastereoselectivity of
the cyclization.
FIGURE 1. Model triynes for diastereoselective [2 + 2 + 2]
cycloisomerization.
have been used throughout. The calculations were expedited by
expanding the Coulomb integrals in an auxiliary basis set, the
resolution-of-identity (RI) approximation.17,18 All of the geometry
optimizations were carried out using the RI-PBE method and 6-31G-
(d) basis set,19 whereas the single-point energies were recomputed
in larger basis set TZV+P (triple-ú valence with one polarization
function on each atom),20 using the B3LYP method. To account
for solvation effects, the conductor-like screening model (COSMO)
method21,22 was used with the dielectric constant corresponding to
acetonitrile (ꢀr ) 36.6). Gibbs free energy was then calculated as
the sum of these contributions (eq 1)
Methods
Quantum Chemical Calculations. All density functional theory
(DFT) calculations reported in the study were carried out using
Turbomole 5.7 program.14 The PBE and B3LYP functionals15,16
(4) (a) Carren˜o, M. C.; Enr´ıquez, AÄ .; Garc´ıa-Cerrada, S.; Sanz-Cuesta,
M. J.; Urbano, A.; Maseras, F.; Nonell-Canals, A. Chem. Eur. J. 2008, 14,
603. (b) Carren˜o, M. C.; Gonzales-Lopez, M.; Urbano, A. Chem. Commun.
2005, 611. (c) Carren˜o, M. C.; Garcia-Cerrada, S.; Urbano. A. Chem. Eur.
J. 2003, 9, 4118. (d) Carren˜o, M. C.; Garcia-Cerrada, S.; Urbano, A. J.
Am. Chem. Soc. 2001, 123, 7929.
(5) Ogawa, Y.; Toyama, M.; Karikomi, M.; Seki, K.; Haga, K.; Uyehara,
T. Tetrahedron Lett. 2003, 44, 2167.
(6) El Abed, R.; Ben Hassine, B.; Genet, J. P.; Gorsane, M.; Madec, J.;
Ricard, L.; Marinetti, A. Synthesis 2004, 2513.
(7) Nakano, K.; Hidehira, Y.; Takahashi, K.; Hiyama, T.; Nozaki, K.
Angew. Chem., Int. Ed. 2005, 44, 7136.
(8) Tanaka, K.; Kamisawa, A.; Suda, T.; Noguchi, K.; Hirano, M. J.
Am. Chem. Soc. 2007, 129, 12078.
(9) For the synthesis of nonracemic thiaheterohelicenes via axially chiral
intermediates, see: (a) Rajca, A.; Miyasaka, M.; Pink, M.; Wang, H.; Rajca,
S. J. Am. Chem. Soc. 2004, 126, 15211. (b) Miyasaka, M.; Rajca, A.; Pink,
M.; Rajca, S. Chem. Eur. J. 2004, 10, 6531.
(10) For asymmetric synthesis of thiaheterohelicenes via diastereoselec-
tive biaryl cross-coupling, see: Tanaka, K.; Suzuki, H.; Osuga, H. J. Org.
Chem. 1997, 62, 4465.
G ) Eel + Gsolv + EZPE - RT ln(qtransqrotqvib
)
(1)
where Eel is the in vacuo energy of the system (at B3LYP/TZV+P
level, using the geometry optimized at the RI-PBE/6-31G(d) level
as described above), Gsolv is the solvation free energy (at the
RI-PBE/6-31G(d) level), EZPE is the zero-point energy, and
-RT lnqtransqrotqvib) accounts for the entropic terms and the thermal
correction to the enthalpy (obtained from a frequency calculation
with the same method and software as for the geometry optimiza-
tions at RI-PBE/6-31G(d) level, 298 K and 1 atm pressure, using
an ideal-gas approximation).23 The free energy calculated according
to eq 1 is a good approximation to ∆G in diluted solution.
Results and Discussion
Synthesis of optically pure aromatic triynes (S)-(-)-1-5 and
(R)-(-)-6 (Figure 1) containing an asymmetric carbon atom of
known absolute configuration was accomplished24 using the
general methodology we published previously.25
(11) Caeiro, J.; Pen˜a, D.; Cobas, A.; Pe´rez, D.; Guitia´n, E. AdV. Synth.
Catal. 2006, 348, 2466.
(12) For an enantioselective catalysis approach, see: (a) Alexandrova´,
Z.; Sehnal, P.; Stara´, I. G.; Stary´, I.; Sˇaman, D.; Urquhart, S. G.; Otero, E.
Collect. Czech. Chem. Commun. 2006, 71, 1256. (b) Teply´, F.; Stara´, I. G.;
Stary´, I.; Kolla´rovicˇ, A.; Sˇaman, D.; Fiedler, P.; Vyskocˇil, Sˇ. J. Org. Chem.
2003, 68, 5193. (c) Stara´, I. G.; Stary´, I.; Kolla´rovicˇ, A.; Teply´, F.; Vyskocˇil,
Sˇ.; Sˇaman, D. Tetrahedron Lett. 1999, 40, 1993.
(13) (a) Stary´, I.; Stara´, I. G.; Alexandrova´, Z.; Sehnal, P.; Teply´, F.;
Sˇaman, D.; Rul´ısˇek, L. Pure Appl. Chem. 2006, 78, 495. (b) Stara´, I. G.;
Alexandrova´, Z.; Teply´, F.; Sehnal, P.; Stary´, I.; Sˇaman, D.; Budeˇsˇ´ınsky´,
M.; Cvacˇka, J. Organic Lett. 2005, 13, 2547.
(17) Eichkorn, K.; Treutler, O.; O¨ hm, H.; Ha¨ser, M.; Ahlrichs, R. Chem.
Phys. Lett. 1995, 240, 283.
(18) Eichkorn, K.; Weigen, F.; Treutler, O.; Ahlrichs, R. Theor. Chim.
Acta 1997, 97, 119.
(19) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab initio
molecular orbital theory; Wiley-Interscience: New York, 1986.
(20) Scha¨fer, A.; Huber, C.; Ahlrichs, R. J. Chem. Phys. 1994, 100, 5829.
(21) Klamt, A.; Schuurmann, G. J. Chem. Soc., Perkin Trans. 2 1993,
799.
(14) Ahlrichs, R.; Ba¨r, M.; Ha¨ser, M.; Horn, H.; Ko¨lmel, C. Chem. Phys.
Lett. 1989, 162, 165.
(15) Perdew, J. P.; Burke, K.; Ernzerhof, M. Phys. ReV. Lett. 1996, 77,
3865.
(22) Scha¨fer, A.; Klamt, A.; Sattel, D.; Lohrenz, J. C. W.; Eckert, F.
Phys. Chem. Chem. Phys. 2000, 2, 2187.
(16) (a) Becke, A. D. Phys. ReV. A 1988, 38, 3098. (b) Lee, C. T.; Yang,
W. T.; Parr, R. G. Phys. ReV. B 1988, 37, 785. (c) Becke, A. D. J. Chem.
Phys. 1993, 98, 5648. (d) Stephens, P. J.; Devlin, F. J.; Chabalowski, C.
F.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623.
(23) Jensen, F. Introduction to Computational Chemistry; John Wiley
& Sons: New York, 1999.
(24) Krausova´, Z.; Sehnal, P.; Teply´, F.; Stara´, I. G.; Stary´, I.; Sˇaman,
D.; Fiedler, P. Collect. Czech. Chem. Commun. 2007, 72, 1499.
J. Org. Chem, Vol. 73, No. 6, 2008 2075

Sehnal et al.
TABLE 1. Diastereoselective [2 + 2 + 2] Cycloisomerization
Diastereoselective [2 + 2 + 2] Cycloisomerization of
Chiral Triynes 1-6. Triynes (S)-(-)-1-5 and (R)-(-)-6
bearing methoxy group(s) were subjected to [2 + 2 + 2]
cycloisomerization under uniform reaction conditions using
CpCo(CO)2 with PPh3 at 140 °C and visible light irradiation
(Table 1). The presence of a chiral center was proposed to
control the stereochemical outcome of the reaction giving rise
to (M) or (P) helix predominantly.26 In agreement with such an
expectation, triyne (S)-(--1 provided the pentacyclic product
(P,S)-(+)-7 with high diastereoselectivity (Table 1, entry 1).
Practically identical results were obtained with an analogous
triyne (S)-(-)-2, which afforded the major dimethoxy derivative
(P,S)-(+)-8 (Table 1, entry 2). Moreover, triyne (S)-(-)-3 was
cycloisomerized to hexacyclic (P,S)-(+)-9 with the same
stereochemical outcome (Table 1, entry 3). Triynes (S)-(-)-4
and (S)-(-)-5, differing only in the position of the methoxy
group, provided heptacyclic (P,S)-(+)-10 and (P,S)-(+)-11,
respectively, with slightly lower distereoselectivity than in the
previous runs (Table 1, entries 4 and 5). Thus, regardless of
the helical backbone length and the methoxy group position,
(S) configuration at the asymmetric center induced (P) helicity
of the product. For the sake of increased diastereoselectivity,
the methyl group at the chiral carbon was replaced with a more
bulky phenyl one. However, cyclization of (R)-(-)-627provided
(M,S)-(-)-12 with reversed diastereoselectivity (Table 1, cf.
entry 4 and 6).
Synthesis of Optically Pure Alcohol (P,S)-(+)-25. As [2
+ 2 + 2] cycloisomerization of the model functionalized triynes
exhibited a good and predictable stereochemical outcome, we
embarked upon a practical use of this reaction to prepare
optically pure helical alcohol (P,S)-(+)-25 on a gram scale
(Scheme 1). The convergent synthesis started from commercially
available o-vanillin 13 that was, upon transformation to nonaflate
14, ethynylated with (triisopropylsilyl)acetylene under PdII
catalysis. The presence of two ortho substituents did not hamper
the coupling reaction, which led smoothly to 15. The triisopro-
pylsilyl protecting group was chosen to survive basic conditions
in the following steps. To attach a chiral moiety, the aldehyde
group in 15 was reduced with diisobutylaluminum hydride to
afford benzylic alcohol 16, which was further reacted with
phosphorus tribromide providing benzylic bromide 17.
Afterward, 17 was treated with a sodium salt of (S)-(-)-18
(ref 25) to accomplish the synthesis of ether (S)-(-)-19, leaving
the triisopropylsilyl group untouched. To assemble a triyne
scaffold, (S)-(-)-19 was desilylated with tetrabutylammonium
fluoride and the resulting alkyne (S)-(-)-20 was coupled with
naphthyl iodide 21 (ref 28) under Pd0/CuI catalysis to provide
(S)-(-)-22. Deprotecting a pendant acetylene unit with tetrabu-
tylammonium fluoride, the triyne (S)-(-)-23 was obtained which
could undergo the key [2 + 2 + 2] cyclization step. Under CoI
catalysis, the helical products (P,S)-(+)- and (M,S)-24 were
obtained in a 87:13 ratio and in a good preparative yield.
Although diastereoselectivity of the cyclization was lower than
a A: CpCo(CO)2 (1.0 equiv), PPh3 (2.0 equiv), decane, irradiated with
a halogen lamp unless noted otherwise. b The optical rotations were
measured for the diastereomer ratios indicated unless noted otherwise. c The
1
ratios of diastereomers were inferred from H NMR spectra unless noted
otherwise. d Isolated yield of a mixture of both diastereomers. e The yield
of pure (P,S)-(+) diastereomer after crystallization of the mixture of
diastereomers. f Optical rotation of pure (P,S)-(+) diastereomer. g In dioxane.
h The ratio of diastereomers was determined by HPLC on a Chiralcel OD-H
column.
(25) Alexandrova´, Z.; Stara´, I. G.; Sehnal, P.; Teply´, F.; Stary´, I.; Sˇaman,
D.; Fiedler, P. Collect. Czech. Chem. Commun. 2004, 69, 2193.
(26) Helicity assignments are based on considering distances between
relevant protons and observed 1H-1H correlations in ROESY 1H NMR
spectra. Such an approach is described in ref 13b and exemplified here by
a structure analysis of (P,S)-(+)-24.
required, a single crystallization of the mixture led to the
optically pure (P,S)-(+)-24.
The helicity assignment of (P,S)-(+)-24 stems from a ROESY
1H NMR spectrum13b where a decisive through-space interaction
between proximal 3-H and 2′,6′-H of the 4-tolyl group (ca. 2.3
Å) was monitored. In contrast, such an interaction could not be
observed in (M,S)-24 possessing the opposite helicity and,
(27) Although the sense of absolute configuration at the chiral center
was conserved, the CIP notation denotes it contrariwise.
(28) Stara´, I. G.; Kolla´rovicˇ, A.; Teply´, F.; Stary´, I.; Sˇaman, D.; Fiedler,
P. Collect. Czech. Chem. Commun. 2000, 65, 577.
2076 J. Org. Chem., Vol. 73, No. 6, 2008

Helicene-like Compounds
SCHEME 1. Synthesis of Optically Pure Helical Alcohol
(P,S)-(+)-25
FIGURE 2. Single-crystal molecular structure of (P,S)-(+)-25.
FIGURE 3. UV absorption spectrum (top, ordinate on the right, red)
and CD spectrum (bottom, ordinate on the left, blue) of a 1.0 × 10-3
M solution of (P,S)-(+)-24 (solid line) and (P,S)-(+)-25 (dashed line)
in CH3CN.
1H NMR spectra (Figure 2). In addition, CD spectra of (P,S)-
(+)-24 and (P,S)-(+)-25 were measured (Figure 3). Throughout
the whole synthetic scheme, isolated yields ranged from good
to excellent ones and all steps were performed on a multigram
scale.
accordingly, having a significantly larger distance between the
above-mentioned protons (ca. 4.6 Å). Furthermore, the 3-CH3
signal of (P,S)-(+)-24 lies at 0.67 ppm while for diastereomer
(M,S)-24 at 0.92 ppm. It corresponds to a helicity-chemical
1
shift relation observed recently in H NMR spectra of a series
Thermodynamic versus Kinetic Control. Despite the fact
that a successful synthesis of optically pure (P,S)-(+)-25 was
developed, we decided to strive for higher diastereoselectivity
in the key [2 + 2 + 2] cycloisomerization step. Provided the
cyclization of (S)-(-)-23 proceeds at a lower temperature, a
better stereochemical outcome might be expected. Using Jonas
catalyst CpCo(ethylene)2,30 which exhibits generally higher
reactivity than CpCo(CO)2, the practically instantaneous cy-
clization of (S)-(-)-23 took place at room temperature. To our
surprise, the reaction yielded (P,S)-(+)- and (M,S)-24 in an
equimolar ratio (Scheme 2). In order to verify such an
unexpected result, the structurally related triyne (S)-(-)-2613b
was cyclized under the same reaction conditions to provide
(P,S)-(+)- and (M,S)-27 in a nearly equimolar ratio (44 : 56).31
Thus, diastereoselectivity was practically lost by lowering the
reaction temperature.
of analogous heptacyclic helicene-like compounds.13b In that
case, the CH3 groups were found to resonate within a 0.54-
0.62 ppm interval for (P)-helices and within a 1.58-1.67 ppm
interval for (M)-helices.
To accomplish the preparation of alcohol (P,S)-(+)-25, the
final demethylation step was examined. The use of boron
tribromide resulted in the formation of a complex mixture of
products. However, the treatment of (P,S)-(+)-24 with sodium
ethanethiolate at 130 °C led exclusively to the removal of the
methyl group leaving the benzylic moiety untouched, and
therefore, (P,S)-(+)-25 was isolated in good yield. It should be
noted that, starting from diastereomerically pure (P,S)-(+)-24,
partial epimerization took place obtaining (P,S)-(+)- and (M,S)-
25 in a 89:11 ratio. Similar to the above-mentioned purification
of (P,S)-(+)-24, a single crystallization provided the optically
pure product (P,S)-(+)-25. As suitable crystals for an X-ray
analysis were grown,29 the structure could be ultimately
confirmed as being in full accordance with that inferred from
This behavior raised a rather fundamental question whether
[2 + 2 + 2] cycloisomerization of chiral triynes (S)-(-)-1-5,
(R)-(-)-6, (S)-(-)-23, and (S)-(-)-26 is controlled by kinetic
(29) CCDC-625112 contains the supplementary crystallographic data for
(P,S)-(+)-25. These data can be obtained free of charge from Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_reguest/cif
or from the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44(1223) 336033; e-mail: deposit@
ccdc.cam.ac.uk.
(30) (a) Cammack, J. K.; Jalisatgi, S.; Matzger, A. J.; Negro´n, A.;
Vollhardt, K. P. C. J. Org. Chem. 1996, 61, 4798. (b) Jonas, K.; Deffense,
E.; Habermann, D. Angew. Chem. Int. Ed. 1983, 22, 716; Angew. Chem.
Suppl. 1983, 1005.
(31) It should be noted that utilizing CpCo(CO)2 at 140 °C resulted in
a preferential formation of (P,S)-(+)-27 (ref. 13b).
J. Org. Chem, Vol. 73, No. 6, 2008 2077

Sehnal et al.
SCHEME 2. [2 + 2 + 2] Cycloisomerization of Chiral
Triynes (S)-(-)-23 and 26 and Epimerization of the Helical
Products 24 and 27 under Thermal Conditions
(M,S) ) (M,S)eq + [(M,S)0 - (M,S)eq]
exp( - (kMfP + kPfM)t) (3)
kMfP 100 - (M,S)eq
)
(4)
(5)
kPfM
(M,S)eq
kBT
∆Gq ) RT ln
(
)
hk exp
By heating the mixtures of (M,S) and (P,S) diastereomers of
24 (initially 50:50, at 87 °C in heptane) and 27 (initially 56:44,
at 131 °C in decane) and monitoring continuously the diaste-
reomer ratios by HPLC (on a Chiralcel OD-H column), the
kinetic data could be acquired. After applying exponential
regression to the plotted time-dependent concentration of the
(M,S) diastereomer, the (M,S)eq concentration and the sum of
the rate constants (kMfP + kPfM) could be read. Using these
figures and eqs 4 and 5, the barriers to epimerization were
calculated along with other kinetic data (Table 2).
Thus, configurational stabilities of the helicene-like products
were found to be lower than originally expected. This is more
obvious from a comparison of the barrier to epimerization of
hexacyclic (P,S)-(+)-24 (27.7 kcal/mol) and heptacyclic (P,S)-
(+)-27 (31.9 kcal/mol) with the barriers to racemization of
parent fully aromatic hexahelicene (36.2 kcal/mol)33 and hep-
tahelicene (41.7 kcal/mol),33a respectively. It indicates that the
incorporation of more flexible dihydrobenzene and dihydroox-
epine rings results in a higher conformational flexibility of the
helical scaffold and, therefore, in lowering the barrier to
epimerization. Note that even the presence of the 1-methoxy
group in (P,S)-(+)-24 does not lead to its considerably higher
configurational stability as it is known from 1-substituted
helicenes.34
Quantum Chemical Calculations. Apparently, thermody-
namic factors may control the stereochemical outcome of the
studied triyne [2 + 2 + 2] cycloisomerization. To gain a deeper
insight into diastereoselectivity of the reaction, the differences
in Gibbs free energies between the (M,S) and (P,S) diastereomers
of helicene-like compounds 7-12, 24, and 27-3113b were
calculated at the DFT B3LYP/TZV+P level. The results are
summarized in Table 3 and compared with the experimental
values (Figure 4).
A remarkable agreement between the experimental and
computed (M,S) vs (P,S) diastereomer ratios of helicene-like
compounds 7-12, 24, and 27-31 was found. The mean absolute
deviation (MAD) between the computed and experimental
values has been calculated as MAD(∆Gcalc - ∆Gexp) ) 0.63
kcal/mol. Therefore, the stereochemical outcome of chiral triyne
[2 + 2 + 2] cycloisomerization at higher temperature might be
fully predicted on the basis of thermodynamic stabilities of the
(M,S) and (P,S) diastereomeric pairs.
On the Origin of Diastereoselectivity. To address the origin
of diastereoselectivity in [2 + 2 + 2] cycloisomerization of
chiral triynes, the possible rationale for that can be clarified on
the example of the helicene-like compounds 28 and 29 (Figure
5). The difference in free energy content between (M,S) and
or thermodynamic factors. Hence, having in hand two helical
products 24 and 27, each of them in the form of two distinct
diastereomeric mixtures, their configurational stability was
examined under the cyclization reaction conditions (140 °C,
decane, 6 h). While the initial ratios of (P,S)/(M,S) ) 87:13
(for 24) and 81:19 (for 27) did not change over the course of
time, the initial ratios of (P,S)/(M,S) ) 50:50 (for 24) and 44:
56 (for 27) converged to the values of about 87:13 (for 24) and
81:19 (for 27). Obviously, both 24 and 27 undergo thermal
epimerization process during the CpCo(CO)2-mediated cycliza-
tion of the corresponding triynes at 140 °C in such a way that
the stereochemical outcome of the reactions reflects the
thermodynamic stability of the diastereomeric products. On the
other hand, the kinetic control apparently operates under the
CpCo(ethylene)2 catalysis at room temperature.32 Such observa-
tions indicate, moreover, that diastereoselective cyclizations of
triynes (S)-(-)-1-5 and (R)-(-)-6 (Table 1) at elevated
temperature proceeds under thermodynamic control.
Barriers to Epimerization. To characterize the dynamic
behavior of the helicene-like compounds 24 and 27 in detail,
their barriers to epimerization ∆Gq were measured. A purely
conformational process under the thermal conditions was
considered, leading to a mutual interconversion of the (P) and
(M) helices while conserving the (S) absolute configuration at
the asymmetric carbon atom (eq 2).
kMfP
(M,S) y z (P,S)
(2)
kPfM
Such a reversible monomolecular reaction can be described
by the first-order kinetic equation in an integrated form (eq 3)
considering the equilibrium conditions at the same time (eq 4).
Here, kMfP and kPfM are rate constants (s-1) for the (M)f(P)
and (P)f(M) helix interconversions, (M,S) represents a current
concentration (%) of (M,S) diastereomer, (M,S)eq represents its
equilibrium concentration (%), (M,S)0 represents its initial
concentration (%), and t is time (s).
(33) (a) Martin, R. H.; Marchant, M. J. Tetrahedron 1974, 30, 347. (b)
Martin, R. H.; Marchant, M. J. Tetrahedron Lett. 1972, 35, 3707.
(34) (a) Janke, R. H.; Haufe, G.; Wu¨rthwein, E.-U.; Borkent, J. H. J.
Am. Chem. Soc. 1996, 118, 6031. (b) Scheru¨bl, H.; Fritzsche, U.;
Mannschreck, A. Chem. Ber. 1984, 117, 336. (c) Borkent, J. H.; Laarhoven,
W. H. Tetrahedron 1978, 34, 2565.
(32) Diastereomerically pure (P,S)-(+)-24 and 27 were found to be
configurationally stable at room temperature.
2078 J. Org. Chem., Vol. 73, No. 6, 2008

Helicene-like Compounds
FIGURE 5. Steric repulsion in compounds 28 and 29 between 1-CH3
and a substituent at C-19 (H, tolyl) or the proximal naphthalene moiety
(aexperimental, bcalculated; relative energies computed by DFT B3LYP/
TZV+P method).
molecular models shows that an (M) helical arrangement brings
(1S)-CH3 and the substituent at C-19 to a steric interaction and,
vice versa, a (P) helical arrangement leads to a steric interaction
of (1S)-CH3 with the naphthalene unit. If the substituent at C-19
is small (e.g., hydrogen), then the interaction between it and
(1S)-CH3 is favored and, accordingly, (M,S) diastereomer is
more populated as evidenced by a ratio of (M,S)-28/(P,S)-28 )
92 : 8. In contrast, if the substituent at C-19 is larger (e.g., the
tolyl group), then its interaction with (1S)-CH3 is disfavored
and (P,S) diastereomer prevails as manifested by a ratio of
(M,S)-29/(P,S)-29 ) 0 : 100.
FIGURE 4. (M,S) to (P,S) diastereoisomer ratios of helical products
7-12, 24, and 27-31 (red bars, experimental results; blue bars,
computed).
TABLE 2. Kinetic Data for 24 and 27
24
27
403.8
T (K)
360.0
solvent
heptane
6.96 × 10-4
1.07 × 10-4
26.4
27.7
16.6
decane
1.98 × 10-4
4.63 × 10-5
30.7
31.9
58.3
k
k
MfP (s-1
)
Conclusions
PfM (s-1
)
∆GqMfP (kcal/mol)
In summary, most attention was paid to CpCo(CO)2-catalyzed
diastereoselective [2 + 2 + 2] cycloisomerization of CH3O-
substituted optically pure triynes to provide nonracemic func-
tionalized helicene-like compounds. Performing the cyclization
of p-tolyl-substituted triynes at 140 °C, diastereomer ratios
ranged from 27:73 to 9:91. The (S) configuration at the
asymmetric center of triynes induced predominantly (P) helicity
of the products regardless of the CH3O group position and the
helical backbone size. By contrast, cyclization of triyne without
the p-tolyl group displayed reversed diastereoselectivity. Per-
forming CpCo(ethylene)2 mediated [2 + 2 + 2] cycloisomer-
ization of chiral triynes at room temperature, no or marginal
diastereoselectivity was observed. Kinetic studies revealed that
(M,S) and (P,S) diastereomers of the helicene-like compounds
with a hexacyclic or heptacyclic backbone underwent thermal
equilibration, which led finally to the same ratios of (M,S) and
(P,S) diastereomers as those monitored in the corresponding [2
+ 2 + 2] cycloisomerizations at elevated temperature. Barriers
to epimerization were measured for both diastereomers of
selected compounds and found to be lower than those for parent
helicenes due to a higher flexibility of the not fully aromatic
helicene-like skeletons. It clearly indicated that diastereoselec-
tivity of [2 + 2 + 2] cycloisomerization of chiral triynes at
140 °C was controlled by thermodynamic factors whereas
kinetic factors operated at room temperature. Computing the
differences in free energies between the (M,S) and (P,S) pairs
∆GqPfM (kcal/mol)
t1/2 (min) for (M,S)
1/2 (min) for (P,S)
t
108.0
249.5
TABLE 3. Calculated Differences in Gibbs Free Energies (in
kcal/mol) between the (M,S) and (P,S) Pairs of Diastereomers
a,b
b
c
d
compd ∆Gcalc
(M,S)/(P,S)calc
(M,S)/(P,S)exp
∆Gcalc - ∆Gexp
7
8
9
2.04
1.00
1.48
2.16
1.65
-3.02
1.38
2.20
-1.99
4.18
2.05
-1.78
8:92
23:77
14:86
7:93
12:88
98:2
16:84
6:94
92:8
10:90
9:91
-0.23
0.91
0.33
-0.86
-0.83
1.65
0.18
-1.00
-0.02
10:90
17:83
27:73
84:16
13:87
19:81
92:8
0:100
0:100
86:14
10
11
12
24
27
28
29
30
31
1:99
8:92
90:10
0.29
a The positive value indicates the higher stability of (P,S) diastereomer.
b Calculated at the B3LYP/TZV+P//RI-PBE/6-31G* level. c The stereo-
chemical outcome of CpCo(CO)2 mediated [2 + 2 + 2] cycloisomerization
at 140 °C. d Mean absolute deviation (MAD) ) 0.63 kcal/mol.
(P,S) diastereomers is given by competing steric interactions
of (1S)-CH3 with either a naphthalene unit fused to the
dihydrooxepine ring or a substituent at C-19. The inspection of
J. Org. Chem, Vol. 73, No. 6, 2008 2079

Sehnal et al.
was added to decompose unreacted hydride, and the resulting
mixture was extracted with dichloromethane (4 × 200 mL). The
organic phase was dried over anhydrous Na2SO4, and the solvents
were removed in vacuo. Chromatography of the crude product on
silica gel (petroleum ether-ether-acetone 80:10:10) provided 16
(23.15 g, 97%) as a crystalline solid. Mp: 36-39 °C (petroleum
ether-ether-acetone). 1H NMR (500 MHz, CDCl3): δ 1.12-1.17
(21 H, m), 2.33 (1 H, m), 3.87 (3 H, s), 4.82 (2 H, bd, J ) 5.6 Hz),
6.82 (1 H, dd, J ) 8.3, 0.6 Hz), 7.01 (1 H, ddt, J ) 7.7, 1.0, 0.7,
0.7 Hz), 7.27 (1 H, dd, J ) 8.3, 7.7 Hz). 13C NMR (125 MHz,
CDCl3): δ 11.3 (d), 18.7 (q), 56.0 (q), 64.3 (t), 100.4 (s), 100.9
(s), 110.1 (d), 110.9 (s), 119.3 (d), 129.5 (d), 145.0 (s), 161.2 (s).
IR (CCl4): 3638 w, 3620 w, 3574 w, 3490 vw (br), 3070 w, 3028
w (sh), 3004 w, 2866 vs, 2839 m, 2150 s, 1597 w, 1577 s, 1473
vs, 1462 s, 1438 m, 1388 m, 1384 m, 1367 w, 1341 w, 1298 m,
1274 vs, 1252 w (sh), 1210 m, 1193 w, 1183 w (sh), 1152 vw,
1085 s, 1072 m (sh), 1041 s, 1018 s, 997 m, 920 w, 900 w, 883 s,
839 s, 722 m, 678 s, 662 s, 619 w, 582 w, 546 w, 498 w, 464 w.
EI MS: 318 (M+•, 35), 275 (47), 260 (5), 245 (94), 233 (100), 217
(26), 205 (95), 189 (30), 173 (19), 161 (10), 149 (33), 129 (32),
115 (73), 102 (43), 91 (26), 75 (39), 61 (55), 43 (78). HR EI MS:
calcd for C19H30O2Si 318.2015, found 318.2005.
of diastereomers at the DFT B3LYP/TZV+P level, an excellent
agreement was found between theory and experiment. Accord-
ingly, the stereochemical outcome of diastereoselective [2 + 2
+ 2] cycloisomerization of chiral triynes at elevated temperature
might be predicted on the theoretical basis. Stemming from these
findings, the preparation of optically pure helicene-like alcohol
(P,S)-(+)-25 was accomplished on a multigram scale. Finally,
the X-ray structure of it confirmed the previous helicity
1
1
assignments based on H-1H correlations in ROESY H NMR
spectra. Work is presently being done to utilize (P,S)-(+)-25
in enantioselective catalysis.
Experimental
2-Formyl-6-methoxyphenyl 1,1,2,2,3,3,4,4,4-Nonafluorobu-
tane-1-sulfonate (14). A 250 mL flask was charged with NaH (80%
suspension in mineral oil, 2.56 g, 85.40 mmol, 1.30 equiv) and put
under argon. Dry petroleum ether (10 mL) was added, and after
the mixture was stirred for 2 min, the liquid was removed via
syringe. DMF (23 mL) was added, and the stirred suspension was
cooled to 0 °C. A solution of 13 (10.00 g, 65.7 mmol) in DMF
(44 mL) was added dropwise, and the reaction mixture was stirred
at room temperature for 90 min. After the mixture was cooled again
to 0 °C, nonaflate fluoride (24.56 g, 81.3 mmol, 1.24 equiv) was
added, and the reaction mixture was stirred at room temperature
for 18 h. The solvent was removed in vacuo (60 °C, 20 mbar), and
the crude product was chromatographed on silica gel (petroleum
ether-ether-acetone 80:10:10) to provide 14 (26.46 g, 93%) as
{[2-(Bromomethyl)-6-methoxyphenyl]ethynyl}[tris(1-methyl-
ethyl)]silane (17). A 250 mL flask was charged with 16 (13.48 g,
42.32 mmol) and put under argon. THF (80 mL) was added, and
the resulting solution was cooled to 0 °C. Phosphorus tribromide
(12.60 g, 46.54 mmol, 1.10 equiv) was added dropwise, and the
reaction mixture was stirred at 0 °C for 1 h. Solvent was removed
in vacuo, and the crude product was chromatographed on silica
gel (petroleum ether-ether-acetone 80:10:10) to provide 17
1
an oil. H NMR (500 MHz, CDCl3): δ 3.92 (3 H, s), 7.28 (1 H,
1
dd, J ) 8.2, 1.7 Hz), 7.42 (1 H, ddd, J ) 8.2, 7.8, 0.8 Hz), 7.48 (1
H, dd, J ) 7.8, 1.7 Hz), 10.22 (1 H, m). 13C NMR (125 MHz,
CDCl3): δ 56.5 (q), 118.7 (d), 120.9 (d), 129.1 (d), 129.5 (s), 139.5
(s), 151.7 (s), 186.7 (d). IR (CCl4): 3081 vw, 3018 w, 2844 w,
1707 vs, 1682 w, 1609 w, 1583 s, 1481 s, 1459 m, 1439 s (sh),
1432 vs, 1393 m, 1353 s, 1313 s, 1285 vs, 1242 vvs, 1227 vs,
1208 vs, 1202 vs, 1147 vs, 1077 s, 1070 s, 1032 m, 1010 m, 912
m, 720 m, 594 m, 570 m, 530 m, 510 m. EI MS: 434 (M+•, 24),
151 (100), 136 (12), 108 (16), 93 (18). HR EI MS: calcd for
C12H7O5F9S 433.9871, found 433.9868.
(15.68 g, 97%) as an oil. H NMR (500 MHz, CDCl3): δ 1.12-
1.22 (21 H, m), 3.86 (3 H, s), 4.68 (2 H, s), 6.81 (1 H, dd, J ) 8.4,
1.0 Hz), 7.02 (1 H, dd, J ) 7.7, 1.0 Hz), 7.23 (1 H, dd, J ) 8.4,
7.7 Hz). 13C NMR (125 MHz, CDCl3): δ 11.4 (d), 18.7 (q), 31.8
(t), 56.0 (q), 99.5 (s), 101.9 (s), 110.8 (d), 113.0 (s), 121.7 (d),
129.3 (d), 141.2 (s), 161.2 (s). IR (CCl4): 3070 w, 3038 w (sh),
3005 m, 2866 vs, 2839 s, 2155 s, 1595 m, 1575 vs, 1473 vs, 1462
vs (sh), 1438 s, 1384 m, 1367 w, 1300 vs, 1275 vs, 1223 s, 1206
s, 1188 w, 1152 w, 1084 vs, 1071 vs, 1018 m, 997 s, 920 m, 883
vs, 835 s, 722 s, 677 vs, 660 vs, 624 s, 613 m (sh), 547 m, 512 w,
496 m, 463 m. EI MS: 380/382 (M+•, 8), 337/339 (17), 307/309
(8), 295 (8), 267 (8), 187 (8), 173 (8), 149 (15), 129 (8), 115 (14),
71 (8), 57 (17), 43 (100). HR EI MS: calcd for C19H29OSi 81Br
382.1151, found 382.1144; calcd for C19H29OSi 79Br 380.1171,
found 380.1157.
3-Methoxy-2-{[tris(1-methylethyl)silyl]ethynyl}benzal-
dehyde (15). A Teflon autoclave was charged with PdCl2(PPh3)2
(1.16 g, 1.65 mmol, 5 mol %) and put under argon. Via septum
and syringe, a solution of 14 (14.60 g, 33.60 mmol) in DMF (44
mL), (triisopropylsilyl)acetylene (7.36 g, 40.30 mmol, 1.20 equiv),
and triethylamine (17.42 g, 172 mmol, 5.12 equiv) were added,
and the autoclave was heated to 90 °C for 2 h. Solvents were
removed in vacuo, and the crude product was chromatographed on
silica gel (petroleum ether-ether-acetone 95:5:0 to 80:10:10) to
provide 15 (19.45 g, 90%) as an oil. 1H NMR (500 MHz, CDCl3):
δ 1.12-1.18 (21 H, m), 3.91 (3 H, s), 7.10 (1 H, dd, J ) 8.2, 1.1
Hz), 7.37 (1 H, dt, J ) 8.1, 8.1, 1.0 Hz), 7.51 (1 H, dd, J ) 7.8,
1.1 Hz), 10.62 (1H, d, J ) 1.0 Hz). 13C NMR (125 MHz, CDCl3):
δ 11.3 (d), 18.65 (q), 56.3 (q), 97.7 (s), 104.2 (s), 115.8 (d), 116.9
(s), 118.6 (d), 129.2 (d), 137.5 (s), 161.5 (s), 192.1 (d). IR (CCl4):
3069 w, 3006 m, 2866 vs, 2840 s (sh), 2826 m (sh), 2740 w, 2154
s, 1704 vs, 1678 m, 1593 s, 1573 s, 1472 vs, 1465 vs (sh), 1452 s
(sh), 1438 s, 1384 s, 1367 w, 1296 s, 1270 vs, 1244 vs, 1207 m,
1185 m, 1151 w, 1080 s, 1071 s, 997 s, 912 s, 883 s, 835 s, 735 m,
680 vs, 660 s, 619 m, 545 w, 498 m, 463 m. FAB MS: 317 ([M
+ H]+), 273, 249, 231, 217, 203, 181. HR FAB MS: calcd for
C19H29O2Si 317.1937, found 317.1904.
{[2-Methoxy-6-({[(1S)-1-methyl-3-(4-methylphenyl)prop-2-
yn-1-yl]oxy}methyl)phenyl]ethynyl}[tris(1-methylethyl)]silane
(19). A 250 mL three-neck flask was charged with NaH (80%
suspension in mineral oil, 517 mg, 17.20 mmol, 1.21 equiv) and
put under argon. Dry petroleum ether (10 mL) was added, and after
the mixture was stirred for 2 min, the liquid was removed via
syringe. THF (8 mL) was added, and the stirred suspension was
cooled to 0 °C. A solution of (S)-(-)-18 (2.73 g, 17.00 mmol, 1.20
equiv) in THF (50 mL) was added dropwise. The reaction mixture
was stirred at room temperature for 1 h and then warmed to 40 °C
until all NaH dissolved. A solution of 17 (5.42 g, 14.20 mmol) in
THF (50 mL) was added and the reaction was heated to 60 °C for
8 h. Solvent was removed in vacuo, and the crude product was
chromatographed on silica gel (petroleum ether-ether 100:0 to 98:
2) to provide (S)-(-)-19 (4.86 g, 74%) as an oil. Optical rotation:
1
[R]22 -93 (c 0.006, CH2Cl2). H NMR (500 MHz, CDCl3): δ
D
1.07-1.16 (21 H, m), 1.58 (3 H, d, J ) 6.6 Hz), 2.34 (3 H, s),
3.85 (3 H, s), 4.51 (1 H, q, J ) 6.6 Hz), 4.82 (1 H, d, J ) 13.3
Hz), 4.91 (1 H, d, J ) 13.3 Hz), 6.78 (1 H, dd, J ) 8.2, 0.9 Hz),
7.10 (2 H, m), 7.14 (1 H, dq, J ) 7.9, 0.9, 0.9, 0.9 Hz), 7.27 (1 H,
t, J ) 8.1 Hz), 7.31 (2 H, m). 13C NMR (125 MHz, CDCl3): δ
11.4 (d), 18.7 (q), 21.4 (q), 22.3 (q), 56.0 (q), 65.8 (d), 68.8 (t),
85.2 (s), 88.3 (s), 100.1 (s), 100.6 (s), 109.6 (d), 111.2 (s), 119.1
(d), 119.8 (s), 128.9 (d), 129.1 (d), 131.7 (d), 138.2 (s), 142.5 (s),
(3-Methoxy-2-{[tris(1-methylethyl)silyl]ethynyl}phenyl)-
methanol (16). A 750 mL flask was charged with 15 (23.60 g,
74.56 mmol) and put under argon. Toluene (250 mL) was added,
and the resulting solution was cooled to -78 °C. Via syringe, a
diisobutylaluminium hydride solution (1.5 M in toluene, 52.2 mL,
78.30 mmol, 1.05 equiv) was added dropwise. The reaction mixture
was stirred at -78 °C for 1 h. A saturated NaCl solution (200 mL)
2080 J. Org. Chem., Vol. 73, No. 6, 2008

Helicene-like Compounds
160.9 (s). IR (CCl4): 3071 w, 3052 w, 3031 w, 2987 m, 2866 vs,
2838 m, 2228 w, 2153 m, 1597 w, 1579 m, 1511 s, 1473 vs, 1462
s, 1438 s, 1408 w, 1384 m, 1371 m, 1328 s, 1313 m, 1275 vs,
1209 m, 1184 w, 1152 w (sh), 1116 s, 1106 s, 1087 s, 1063 vs,
1031 m, 1019 m, 996 m, 919 m, 883 s, 839 s, 818 s, 730 w, 723
w (sh), 709 w, 677 s, 663 s, 648 m (sh), 621 w, 546 w, 522 w, 498
w, 463 w. EI MS: 417 ([M - CH(CH3)2]+, 8), 390 (3), 373 (4),
289 (10), 259 (6), 239 (4), 227 (5), 185 (13), 157 (9), 143 (100),
128 (27), 115 (17), 59 (14). HR EI MS: calcd for C27H33O2Si [M
- CH(CH3)2] 417.2250, found 417.2254.
628 m, 617 m, 456 w, 405 w. EI MS: 638 (M+•, 8), 595 (6), 429
(23), 321 (11), 289 (8), 239 (7), 173 (13), 159 (21), 149 (26), 143
(100), 128 (42), 115 (50), 73 (36), 59 (42). HR EI MS: calcd for
C44H50O2Si 638.3580, found 638.3595.
2-But-3-yn-1-yl-1-{[2-methoxy-6-({[(1S)-1-methyl-3-(4-meth-
ylphenyl)prop-2-yn-1-yl]oxy}methyl)phenyl]ethynyl}-
naphthalene (23). A 250 mL three-neck flask was charged with a
solution of (S)-(-)-22 (11.99 g, 18.80 mmol) in THF (160 mL)
under argon. A tetrabutylammonium fluoride solution (1.072 M in
THF, 21 mL, 22.50 mmol, 1.20 equiv) was added, and the reaction
mixture was stirred at room temperature for 1 h. Solvent was
removed in vacuo, and the crude product was chromatographed on
silica gel (petroleum ether-ether-acetone 90:10:0 to 80:10:10).
The obtained product was triturated with petroleum ether (3 × 150
2-Ethynyl-1-methoxy-3-({[(1S)-1-methyl-3-(4-methylphenyl)-
prop-2-yn-1-yl]oxy}methyl)benzene (20). A 250 mL flask was
charged with (S)-(-)-19 (13.10 g, 28.43 mmol) and put under argon.
THF (125 mL) was added, and the resulting solution was treated
with a tetrabutylammonium fluoride solution (1.072 M in THF, 32
mL, 34.30 mmol, 1.21 equiv). The reaction mixture was stirred at
room temperature for 40 min. Solvent was removed in vacuo, and
the crude product was chromatographed on silica gel (petroleum
ether-ether 95:5) to provide (S)-(-)-20 (7.91 g, 91%) as a
mL) to provide (S)-(-)-23 (7.80 g, 86%) as an amorphous solid.
1
Optical rotation: [R]22 -134 (c 0.005, CH2Cl2). H NMR (500
D
MHz, CDCl3): δ 1.61 (3 H, d, J ) 6.6 Hz), 1.98 (1 H, t, J ) 2.6
Hz), 2.29 (3 H, s), 2.69 (2 H, dt, J ) 7.7, 7.7, 2.6 Hz), 3.34 (2 H,
t, J ) 7.7 Hz), 4.00 (3 H, s), 4.59 (1 H, q, J ) 6.6 Hz), 5.04 (2 H,
d, J ) 12.7 Hz), 5.19 (2 H, d, J ) 12.7 Hz), 6.90 (1 H, dd, J )
8.3, 1.1 Hz), 6.98 (2 H, m), 7.23 (1 H, dd, J ) 7.7, 1.1 Hz), 7.23
(2 H, m), 7.35 (1 H, dd, J ) 8.3, 7.7 Hz), 7.41 (1 H, d, J ) 8.4
Hz), 7.43 (1 H, ddd, J ) 8.1, 6.8, 1.3 Hz), 7.49 (1 H, ddd, J ) 8.3,
6.8, 1.4 Hz), 7.75 (1 H, bd, J ) 8.4 Hz), 7.80 (1 H, ddt, J ) 8.1,
1.4, 0.6, 0.6 Hz), 8.61 (1 H, ddt, J ) 8.3, 1.3, 0.8, 0.8 Hz). 13C
NMR (125 MHz, CDCl3): δ 19.6 (t), 21.4 (q), 22.3 (q), 34.6 (t),
56.0 (q), 65.6 (d), 68.8 (d), 69.0 (t), 84.3 (s), 85.5 (s), 88.4 (s),
92.9 (s), 95.2 (s), 109.5 (d), 111.4 (s), 119.6 (s), 119.8 (d), 120.0
(s), 125.8 (d), 126.5 (d), 126.9 (d), 127.4 (d), 127.9 (d), 128.2 (d),
128.9 (d), 129.3 (d), 131.6 (d), 132.0 (s), 133.7 (s), 138.2 (s), 141.2
(s), 141.5 (s), 160.6 (s). IR (CCl4): 3313 s, 3294 w, 3088 w (sh),
3056 m, 3031 w, 2838 m, 2227 w, 2205 vw (sh), 2119 w, 1620 w,
1596 w, 1578 m, 1569 w, 1510 s, 1473 vs, 1459 m, 1438 m, 1430
m (sh), 1407 vw, 1389 w, 1371 m, 1313 w, 1300 w (sh), 1272 vs,
1186 w, 1116 s, 1105 s (sh), 1099 s (sh), 1087 s, 1063 vs, 1026 m,
865 w, 836 w, 722 w, 708 w, 635 s, 522 w, 457 w, 442 w. EI MS:
482 (M+•, 2), 467 (8), 439 (20), 429 (25), 407 (9), 323 (15), 279
(21), 252 (24), 239 (45), 226 (25), 191 (25), 171 (30), 143 (59),
128 (100), 115 (38), 91 (35), 55 (27), 43 (93). HR EI MS: calcd
for C35H30O2 482.2246, found 482.2251.
crystalline solid. Mp: 80-82 °C (petroleum ether-ether). Optical
1
rotation: [R]22 -125 (c 0.012, CH2Cl2). H NMR (500 MHz,
D
CDCl3): δ 1.57 (3 H, d, J ) 6.6 Hz), 2.34 (3 H, s), 3.53 (1 H, s),
3.90 (3 H, s), 4.50 (1 H, q, J ) 6.6 Hz), 4.79 (1 H, d, J ) 12.8
Hz), 4.97 (1 H, d, J ) 12.8 Hz), 6.83 (1 H, dd, J ) 8.3, 1.0 Hz),
7.11 (2 H, m), 7.16 (1 H, dq, J ) 7.8, 0.9, 0.9, 0.9 Hz), 7.32 (1 H,
t, J ) 8.0 Hz), 7.33 (2 H, m). 13C NMR (125 MHz, CDCl3): δ
21.4 (q), 22.2 (q), 56.0 (q), 65.7 (d), 68.6 (t), 77.5 (s), 85.3 (s),
86.1 (d), 88.4 (s), 109.5 (d), 109.8 (s), 119.8 (s), 120.0 (d), 129.0
(d), 129.7 (d), 131.6 (d), 138.3 (s), 142.8 (s), 160.8 (s). IR (CCl4):
3316 s, 3085 w, 3072 w, 3053 w, 3030 m, 2838 s, 2227 w, 2188
vw, 2106 w, 1598 m, 1581 s, 1510 vs, 1473 vs, 1460 vs, 1438 s,
1408 w, 1328 vs, 1312 s, 1300 s, 1277 vs, 1258 s (sh), 1210 w,
1184 w, 1152 w (sh), 1115 vs, 1100 vs, 1088 vs, 1063 vs, 1022 m,
835 m, 709 m, 647 s, 606 s, 461 w, 408 m. EI MS: 303 ([M -
H]+, 11), 289 (53), 276 (14), 261 (63), 245 (22), 229 (16), 213
(12), 173 (16), 143 (40), 129 (62), 115 (100). HR EI MS: calcd
for C21H19O2 [M - H] 303.1385, found 303.1387.
[4-(1-{[2-Methoxy-6-({[(1S)-1-methyl-3-(4-methylphenyl)-
prop-2-yn-1-yl]oxy}methyl)phenyl]ethynyl}naphthalen-2-yl)but-
1-yn-1-yl][tris(1-methylethyl)]silane (22). A 750 mL flask was
charged with 21 (13.10 g, 28.31 mmol, 1.09 equiv), Pd(PPh3)4 (1.62
g, 1.41 mmol, 5 mol %), and CuI (495 mg, 2.60 mmol, 10 mol %)
and put under argon. A solution of (S)-(-)-20 (7.91 g, 25.98 mmol)
in diisopropylamine (360 mL) was added, and the reaction was
stirred at room temperature for 5 min and then heated at 80 °C for
60 min. Solvent was removed in vacuo, and the crude product was
chromatographed on silica gel (petroleum ether-ether 95:5) to
(P,3S)-14-Methoxy-3-methyl-4-(4-methylphenyl)-1,3,6,7-
tetrahydrobenzo[c]benzo[5,6]phenanthro[4,3-e]oxepine (24). (S)-
(-)-23 (3.10 g, 6.43 mmol), PPh3 (1.35 g, 5.13 mmol, 80 mol %),
and CpCo(CO)2 (340 µL, 2.57 mmol, 40 mol %) were subjected
to general cyclization procedure A in decane (280 mL). Eluent:
petroleum ether-ether 100:0 to 93:7. Yield: 2.59 g (82%, (M,S)-
24/(P,S)-24 ) 13:87). Crystallization from boiling heptane (800
mL) provided pure (P,S)-24 (1.97 g, 63%) as a white solid. Mp:
303-304 °C. Optical rotation: [R]22D +465 (c 0.007, CH2Cl2) for
provide (S)-(-)-22 (11.99 g, 72%) as an oil. Optical rotation: [R]22
D
1
-97 (c 0.002, CH2Cl2). H NMR (500 MHz, CDCl3): δ 0.95-
1
1.04 (21 H, m), 1.61 (3 H, d, J ) 6.5 Hz), 2.29 (3 H, s), 2.77 (2
H, t, J ) 7.2 Hz), 3.32 (2 H, t, J ) 7.2 Hz), 4.00 (3 H, s), 4.57 (1
H, q, J ) 6.5 Hz), 5.02 (1 H, d, J ) 12.8 Hz), 5.18 (1 H, d, J )
12.8 Hz), 6.89 (1 H, dd, J ) 8.4, 1.0 Hz), 6.98 (2 H, m), 7.24 (1
H, dd, J ) 7.7, 1.0 Hz), 7.24 (2 H, m), 7.34 (1 H, dd, J ) 8.4, 7.7
Hz), 7.42 (1 H, ddd, J ) 8.1, 6.8, 1.3 Hz), 7.47 (1 H, d, J ) 8.4
Hz), 7.48 (1 H, ddd, J ) 8.5, 6.8, 1.5 Hz), 7.72 (1 H, bd, J ) 8.4
Hz), 7.80 (1 H, ddt, J ) 8.1, 1.5, 0.6, 0.6 Hz), 8.60 (1 H, ddt, J )
8.5, 1.3, 0.8, 0.8 Hz). 13C NMR (125 MHz, CDCl3): δ 11.3 (d),
18.6 (q), 21.1 (t), 21.4 (q), 22.3 (q), 34.7 (t), 56.0 (q), 65.5 (d),
69.0 (t), 80.9 (s), 85.5 (s), 88.3 (s), 92.7 (s), 95.3 (s), 108.5 (s),
109.5 (d), 111.6 (s), 119.6 (s), 119.80 (s), 119.82 (d), 125.6 (d),
126.5 (d), 126.7 (d), 127.82 (d), 127.84 (d), 128.0 (d), 128.9 (d),
129.2 (d), 131.6 (d), 132.0 (s), 133.6 (s), 138.2 (s), 141.4 (s), 141.5
(s), 160.6 (s). IR (CCl4): 3088 w (sh), 3056 m, 3031 m, 2990 s
(sh), 2865 vs, 2839 s, 2227 w, 2200 vw, 2169 s, 1620 w, 1596 w,
1577 m, 1568 w (sh), 1510 s, 1472 vs, 1463 vs, 1438 s, 1388 m,
1383 m, 1371 m, 1328 s, 1314 m, 1302 m, 1272 vs, 1257 m (sh),
1240 w (sh), 1185 w, 1117 s, 1100 s, 1088 vs, 1063 vs, 1025 m,
996 m, 952 w, 919 m, 884 s, 865 w, 835 w, 708 w, 677 s, 660 s,
pure (P,S)-24. H NMR (500 MHz, CDCl3): δ 0.67 (3 H, d, J )
7.1 Hz), 2.43 (3 H, s), 2.72 (3 H, s), 2.77 (1 H, dddd, J ) 15.7,
14.5, 4.5, 1.4 Hz), 2.88-2.95 (2 H, m), 3.04 (1 H, dt, J ) 15.0,
15.0, 1.3 Hz), 4.72 (1 H, d, J ) 11.4 Hz), 5.00 (1 H, d, J ) 11.4
Hz), 5.32 (1 H, q, J ) 7.1 Hz), 6.09 (1 H, dd, J ) 7.8, 1.6 Hz),
6.73 (1 H, ddd, J ) 8.5, 6.7, 1.5 Hz), 6.92 (1 H, t, J ) 7.6 Hz),
6.95 (1 H, dd, J ) 7.4, 1.6 Hz), 7.03 (1 H, ddd, J ) 8.1, 6.7, 1.3
Hz), 7.20 (1 H, bdq, J ) 8.5, 0.9, 0.9, 0.9 Hz), 7.27 (2 H, m), 7.38
(2 H, m), 7.38 (1 H, d, J ) 1.2 Hz), 7.46 (1 H, d, J ) 8.1 Hz),
7.54 (1 H, dd, J ) 8.1, 1.5 Hz), 7.60 (1 H, bd, J ) 8.1 Hz). 13C
NMR (125 MHz, CDCl3): δ 21.2 (q), 22.4 (q), 30.6 (t), 30.7 (t),
54.4 (q), 67.9 (t), 72.4 (d), 110.2 (d), 121.4 (d), 123.5 (d), 123.9
(d), 125.8 (d), 125.9 (d), 126.7 (d), 126.9 (d), 128.7 (s), 129.0 (d),
129.10 (d), 129.13 (d), 130.0 (d), 130.1 (s), 132.3 (s), 133.2 (s),
133.3 (s), 134.1 (s), 135.6 (s), 136.6 (s), 137.9 (s), 138.0 (s), 138.9
(s), 140.1 (s), 141.5 (s), 154.7 (s). IR (CCl4): 3050 w, 3024 w,
2835 m, 1620 vw, 1594 w, 1587 w, 1580 w (sh), 1568 vw (sh),
1514 m, 1475 s, 1436 m, 1368 m, 1340 w, 1317 w, 1300 w, 1272
vs, 1260 s, 1214 w, 1185 w, 1111 w (sh), 1097 s, 1085 s, 1075 m
(sh), 1061 w, 1023 w, 863 w, 844 w, 821 vs, 728 w, 701 w, 529
J. Org. Chem, Vol. 73, No. 6, 2008 2081

Sehnal et al.
w. EI MS: 482 (M+•, 100), 467 (44), 439 (35), 424 (7), 149 (7),
95 (12), 83 (13), 69 (16), 57 (32), 43 (20). HR EI MS: calcd for
C35H30O2 482.2246, found 482.2239. Cyclization with CpCo-
(ethylene)2: (S)-(-)-23 (50 mg, 0.104 mmol) and CpCo(C2H4)2
(27 mg, 0.150 mmol, 1.45 equiv) were subjected to general
cyclization procedure B in THF (4 mL). Eluent: petroleum ether-
ether 92:8. Yield 28 mg (56%, (M,S)-24/(P,S)-24 ) 50:50,
diastereomers not separated).
m, 822 vs, 730 m, 701 w. EI MS: 468 (M+•, 46), 453 (18), 425
(15), 279 (18), 167 (40), 149 (96), 129 (17), 113 (20), 97 (29), 83
(40), 71 (64), 57 (100), 43 (87). HR EI MS: calcd for C34H28O2
468.2089, found 468.2076.
General Cyclization Procedure A. A Schlenk flask was charged
with the starting triyne and triphenylphosphine (2.00 equiv or 80
mol %) and put under argon. The degassed solvent was added via
syringe and the reaction mixture was warmed to 140 °C. CpCo-
(CO)2 (1.00 equiv or 40 mol %) was added via Hamilton syringe,
and the reaction mixture was heated to 140 °C with concomitant
irradiation with a halogen lamp for 1-36 h. The solvent was
removed in vacuo (80 °C, 20 mbar), and the crude product was
chromatographed on silica gel to provide an equilibrium mixture
of (P,S) and (M,S) diastereoisomers of the respective cyclized
product.
General Cyclization Procedure B. A Schlenk flask was charged
with a solution of the starting triyne in THF under argon. A solution
of CpCo(C2H4)2 (typically 150 mol %) in THF was added and the
reaction mixture was stirred at room temperature for 15 min. The
solvent was removed in vacuo, and the crude product was
chromatographed on silica gel to provide a mixture of (P,S) and
(M,S) diastereoisomers of the respective cyclized product.
(P,3S)-3-Methyl-4-(4-methylphenyl)-1,3,6,7-tetrahydrobenzo-
[c]benzo[5,6]phenanthro[4,3-e]oxepin-14-ol (25). A 250 mL three-
neck flask was charged with NaH (80% suspension in mineral oil,
3.13 g, 104 mmol, 20.00 equiv) and put under argon. Dry petroleum
ether (25 mL) was added, and after the mixture was stirred for 2
min, the liquid was removed via syringe. DMF (25 mL) was added,
and the stirred suspension was cooled to 0 °C. Ethanethiol (7.5
mL, 101 mmol, 19.40 equiv) was added dropwise, and the reaction
mixture was stirred at 0 °C until all NaH dissolved. A solution of
24 (2.51 g, 5.21 mmol) in DMF (200 mL) was added, and the
reaction was heated to 130 °C for 15 h. The reaction mixture was
diluted with water (250 mL), acidified with concd HCl to pH 1,
and extracted with dichloromethane (3 × 300 mL). The organic
phase was dried over anhydrous Na2SO4, and the solvents were
removed in vacuo. Chromatography of the crude product on silica
gel (petroleum ether-acetone 95:5 to 80:20) provided an equilibrium
mixture of (P,S)-25 and (M,S)-25 (2.16 g, 89%, (M,S)/(P,S) ) 11:
89). 1.11 g of this mixture was crystallized twice from heptane-
toluene-ethanol to provide pure (P,S)-(+)-25 (791 mg, 72%) as a
white crystalline solid. Mp: 278-280 °C (heptane-n-propanol)
for pure (P,S)-(+)-25. Optical rotation: [R]22D +469 (c 0.009, CH2-
Acknowledgment. This research was supported by the
Ministry of Education (Center for Biomolecules and Complex
Molecular Systems, project LC512, and the Barrande project
2005-06-041-1), Zentiva, and the Ministry of Industry and Trade
(Grant No. FI-IM/073), the Grant Agency of the Czech Republic
(Grant No. 203/07/1664), and the Institute of Organic Chemistry
and Biochemistry (the work is a part of research project Z4
055 0506). We are very grateful to Prof. K. Jonas (Max-Planck-
Institut fu¨r Kohlenforschung, Mu¨lheim, Germany) for providing
CpCo(ethylene)2. We thank the group of Dr. J. Cvacˇka for the
mass spectra, Dr. H. Dlouha´ and Dr. P. Malonˇ for the CD
spectra, and Dr. P. Fiedler for the IR spectra (all from the IOCB).
1
Cl2) for pure (P,S)-(+)-25. H NMR (500 MHz, CDCl3): δ 0.63
(3 H, d, J ) 7.1 Hz), 2.44 (3 H, s), 2.80 (1 H, dddd, J ) 14.6,
10.7, 8.6, 1.2 Hz), 2.92-3.02 (1 H, m), 2.92-3.02 (2 H, m), 4.29
(1 H, s), 4.73 (1 H, d, J ) 11.4 Hz), 5.00 (1 H, d, J ) 11.4 Hz),
5.30 (1 H, q, J ) 7.1 Hz), 6.18 (1 H, dd, J ) 8.0, 1.3 Hz), 6.81 (1
H, ddd, J ) 8.4, 6.8, 1.4 Hz), 6.87 (1 H, dd, J ) 8.0, 7.4 Hz), 6.94
(1 H, dd, J ) 7.4, 1.3 Hz), 7.09 (1 H, ddd, J ) 8.1, 6.8, 1.2 Hz),
7.26 (1 H, dq, J ) 8.4, 1.0, 1.0, 1.0 Hz), 7.29 (2 H, m), 7.37 (2 H,
m), 7.45 (1 H, d, J ) 1.2 Hz), 7.47 (1 H, d, J ) 8.2 Hz), 7.60 (1
H, bdd, J ) 8.1, 1.4 Hz), 7.74 (1 H, bd, J ) 8.2 Hz). 13C NMR
(125 MHz, CDCl3): δ 21.3 (q), 22.2 (q), 30.5 (t), 30.7 (t), 68.1 (t),
72.3 (d), 116.1 (d), 121.7 (d), 124.0 (d), 124.5 (d), 125.6 (d), 126.2
(d), 127.2 (d), 127.8 (s), 128.8 (d), 128.9 (s), 129.1 (d, 2 × C),
129.6 (d), 129.7 (d), 130.4 (s), 132.1 (s), 132.4 (s), 132.6 (s), 136.7
(s), 137.0 (s), 137.6 (s), 138.4 (s), 138.6 (s), 141.3 (s), 142.8 (s),
151.6 (s). IR (CCl4): 3604 w, 3558 m, 1612 w, 1595 w, 1588 w,
1578 w, 1514 m, 1465 s, 1438 m, 1369 m, 1181 m, 1090 s, 1073
Supporting Information Available: General experimental data
for compounds 7-12 and 27, crystallographic data for (P,S)-(+)-
25, kinetic and thermodynamic data for epimerization of 24 and
1
27, H NMR spectra for the new compounds 7-12, 14-17, 19,
20, and 22-25, CIF file for (P,S)-(+)-25, and xyz geometries and
molecular energies for 7-12, 24, and 27-31. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO701997P
2082 J. Org. Chem., Vol. 73, No. 6, 2008