Asymmetric synthesis of [7]helicene-like molecules

Article abstract of DOI:10.1021/ol047311p

(Chemical Equation Presented) A new approach to nonracemic [7]helicene-like molecules has been developed. Stereoselective Co^I-mediated [2 + 2 + 2] cycloisomerization of aromatic triynes containing an asymmetric carbon atom produces [7]helicene-

Full text of DOI:10.1021/ol047311p

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2547-2550
Asymmetric Synthesis of
[7]Helicene-Like Molecules†
Irena G. Stara´,* Zuzana Alexandrova´, Filip Teply´, Petr Sehnal, Ivo Stary´,*
David Sˇaman, Milosˇ Budeˇsˇ´ınsky´, and Josef Cvacˇka
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech
Republic, FlemingoVo na´m. 2, 166 10 Prague 6, Czech Republic
stara@uochb.cas.cz; stary@uochb.cas.cz
Received December 30, 2004 (Revised Manuscript Received May 3, 2005)
ABSTRACT
A new approach to nonracemic [7]helicene-like molecules has been developed. Stereoselective CoI-mediated [2
+ 2 + 2] cycloisomerization
of aromatic triynes containing an asymmetric carbon atom produces [7]helicene-like scaffolds in diastereomeric ratios up to 100:0. This
central-to-helical chirality transfer can be controlled by the absolute configuration at the asymmetric center and by the presence of carbon
substituents.
Helicenes1 possess two primary attributes: they are both
unique nonplanar aromatic systems and inherently chiral
molecules. While the former feature is expected to be
beneficial primarily within the realm of future molecular
devices,2 the latter requires dealing with nonracemic heli-
cenes in many areas of their recent3 or proposed use.
Focusing mostly on chirality aspects and utilization, π-con-
jugation over the whole molecule might not be essential
provided that a not fully aromatic helicene congener mimics
the helicene scaffold.
Many different routes have already been explored to
produce enantiomerically enriched or pure helicenes.4 Even
classical photodehydrocyclization of stilbene-type precursors
can be carried out in an amazing stereoselective fashion. This
was successfully demonstrated by the pioneering works of
Martin5 and Katz6 who used stereocenter(s) external or
internal to the helix to control the stereoselectivity of helicene
(4) For recent leading references, see: (a) Laleu, B.; Mobian, P.; Herse,
C.; Laursen, B. W.; Hopfgartner, G.; Bernardinelli, G.; Lacour, J. Angew.
Chem., Int. Ed. 2005, 44, 1879. (b) Carreno, M. C.; Gonzales-Lopez, M.;
Urbano, A. Chem. Commun. 2005, 611. (c) Miyasaka, M.; Rajca, A.; Pink,
M.; Rajca, S. Chem. Eur. J. 2004, 10, 6531. (d) Rajca, A.; Miyasaka, M.;
Pink, M.; Wang, H.; Rajca, S. J. Am. Chem. Soc. 2004, 126, 15211. (e) El
Abed, R.; Ben Hassine, B.; Genet, J. P.; Gorsane, M.; Madec, J.; Ricard,
L.; Marinetti, A. Synthesis 2004, 2513. (f) Nakano, D.; Hirano, R.;
Yamaguchi, M.; Kabuto, C. Tetrahedron Lett. 2003, 44, 3683. (g) Ogawa,
Y.; Toyama, M.; Karikomi, M.; Seki, K.; Haga, K.; Uyehara, T. Tetrahedron
Lett. 2003, 44, 2167. (h) Carreno, M. C.; Garcia-Cerrada, S.; Urbano, A.
Chem. Eur. J. 2003, 9, 4118. (i) Carreno, M. C.; Garcia-Cerrada, S.; Urbano,
A. J. Am. Chem. Soc. 2001, 123, 7929. (j) Reetz, M. T.; Sostmann, S.
Tetrahedron 2001, 57, 2515. (k) Thongpanchang, T.; Paruch, K.; Katz, T.
J.; Rheingold, A. L.; Lam, K. C.; Liablesands, L. J. Org. Chem. 2000, 65,
1850. (l) Tanaka, K.; Osuga, H.; Suzuki, H.; Shogase, Y.; Kitahara, Y. J.
Chem. Soc., Perkin Trans. 1 1998, 935. (m) Tanaka, K.; Suzuki, H.; Osuga,
H. J. Org. Chem. 1997, 62, 4465. See also refs 7a,d.
† Dedicated to Dr. J. Za´vada on the occasion of his 70th birthday.
(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.
(2) Treboux, G.; Lapstun, P.; Wu, Z. H.; Silverbrook, K. Chem. Phys.
Lett. 1999, 301, 493.
(3) For pioneering exploitations of helicenes in enantioselective catalysis,
see: (a) Nakano, D.; Yamaguchi, M. Tetrahedron Lett. 2003, 44, 4969. (b)
Sato, I.; Yamashima, R.; Kadowaki, K.; Yamamoto, J.; Shibata, T.; Soai,
K. Angew. Chem., Int. Ed. 2001, 40, 1096. (c) Dreher, S. D.; Katz, T. J.;
Lam, K. C.; Rheingold, A. L. J. Org. Chem. 2000, 65, 815. (d) Reetz, M.
T.; Sostmann, S. J. Organomet. Chem. 2000, 603, 105. (e) Reetz, M. T.;
Beuttenmuller, E. W.; Goddard, R. Tetrahedron Lett. 1997, 38, 3211.
(5) Vanest, J.; Martin, R. H. Recl. TraV. Chim. Pays-Bas 1979, 98, 113.
(6) 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.
10.1021/ol047311p CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/01/2005

cyclizations. Despite the astonishing results achieved so far,
there is a need for developing alternative methods for
obtaining optically pure helicenes or helicene-like molecules.
In this preliminary report, we describe a new approach to
nonracemic helical scaffolds that takes advantage of the
highly stereoselective CoI-mediated [2 + 2 + 2] cyclo-
isomerization of aromatic triynes.
Table 1. Diastereoselective [2 + 2 + 2] Cycloisomerization12
A similar alkyne cyclization method has already been
proven to be a reliable synthetic tool for constructing racemic
helicenes and helicene-like compounds,7 including Vollhardt
heliphenes.8 The first attempts at controlling helicity by
asymmetric catalysis have been described and moderate
enantioselectivities achieved,7a,d but this approach is still far
from practical. Accordingly, we have focused on asymmetric
synthesis using a chiral pool. Having been inspired by
helicene-related papers by Martin and Katz and, generally,
by papers by Lehn,9a Wulff,9b and Yashima,9c who described
successful intramolecular central-to-helical chirality transfers,
we proposed that the analogous stereocontrol in [2 + 2 +
2] cycloisomerization of aromatic triynes might result in
nonracemic helical targets. There are many examples of
intramolecular CoI-mediated [2 + 2 + 2] enediyne cyclo-
isomerizations or analogous intermolecular reactions of
related systems described in the literature manifesting good
to excellent diastereoselectivity.7e,10 However, to the best of
our knowledge, such a diastereoselective organometallic
approach to nonracemic helicene-like molecules has never
been systematically studied.
Initially, using the modular and convergent approach,11
we prepared a complementary set of unsubstituted/p-tolyl-
substituted triynes (1S)-(-)-1-4 (Figure 1). To assess the
a A: Ni(cod)2 (1.0 equiv), PPh3 (2.0 equiv), THF. B: CpCo(CO)2 (1.0
equiv), dioxane. C: CpCo(CO)2 (1.0 equiv), PPh3 (2.0 equiv), dioxane.
b Sense of optical rotation is indicated only if it was measured for a
diastereomerically pure or highly enriched compound; the values of optical
rotation measured for the diastereomer ratios are indicated. c Isolated.
d Irradiated with a halogen lamp.
(M,1S)-(-)-5 and minor (P,1S)-5, could be separated by a
careful flash chromatography on silica gel. However, such
a procedure would be impractical on a preparative scale, as
only the partial resolution of corresponding peaks can be
achieved by a single chromatography procedure. Therefore,
we aimed at further increasing the diastereoselectivity of the
cyclization.
Figure 1.
feasibility of the proposed stereoselective cyclization, triyne
(1S)-(-)-1 was treated with a stoichiometric amount of Ni0
complex (Table 1, entry 1). The expected product was formed
in low yield but with reasonable diastereoselectivity in favor
of (M,1S)-(-)-5. Application of a CoI complex slightly
improved the yield but led to a substantial decrease in the
diastereomeric ratio (Table 1, entry 2).
Interestingly, we observed high diastereoselectivity and
good chemical yield of the cyclization of triyne (1S)-(-)-1
when employing the CoI complex together with triphenyl-
phosphine (Table 1, entry 3). Both diastereomers, major
(7) For recent examples of [2 + 2 + 2] cycloisomerization of triynes
used in the synthesis of helicenes or helicene-like molecules, see: (a) Teply´,
F.; Stara´, I. G.; Stary´, I.; Kolla´rovicˇ, A.; Sˇaman, D.; Vyskocˇil, Sˇ.; Fiedler,
P. J. Org. Chem. 2003, 68, 5193. (b) Stara´, I. G.; Stary´, I.; Kolla´rovicˇ, A.;
Teply´, F.; Sˇaman, D.; Fiedler, P. Collect. Czech. Chem. Commun. 2003,
68, 917. (c) Teply´, F.; Stara´, I. G.; Stary´, I.; Kolla´rovicˇ, A.; Sˇaman, D.;
Rul´ısˇek, L.; Fiedler, P. J. Am. Chem. Soc. 2002, 124, 9175. (d) Stara´, I. G.;
Stary´, I.; Kolla´rovicˇ, A.; Teply´, F.; Vyskocˇil, Sˇ.; Sˇaman, D. Tetrahedron
Lett. 1999, 40, 1993. (e) Stara´, I. G.; Stary´, I.; Kolla´rovicˇ, A.; Teply´, F.;
Sˇaman, D.; Tichy´, M. J. Org. Chem. 1998, 63, 4046.
(8) (a) Han, S. D.; Bond, A. D.; Disch, R. L.; Holmes, D.; Schulman, J.
M.; Teat, S. J.; Vollhardt, K. P. C.; Whitener, G. D. Angew. Chem., Int.
Ed. 2002, 41, 3223. (b) Han, S. D.; Anderson, D. R.; Bond, A. D.; Chu, H.
V.; Disch, R. L.; Holmes, D.; Schulman, J. M.; Teat, S. J.; Vollhardt, K. P.
C.; Whitener, G. D. Angew. Chem., Int. Ed. 2002, 41, 3227.
2548
Org. Lett., Vol. 7, No. 13, 2005

We assumed that attaching more bulky substituents to
pendant acetylene units of (1S)-(-)-1 might lead to a more
congested transition state being decisive for the stereochem-
ical outcome. Actually, the cyclization of triyne (1S)-(-)-2
bearing two p-tolyl groups exclusively furnished diastereomer
(P,1S)-(+)-6 in good yield. To our surprise, its helicity was
opposite, although we maintained absolute stereochemistry
at the governing asymmetric center (Table 1, cf. entries 3
and 4).
of (M,1S)-(-)-5, a through-space interaction between 1-CH3
and 19-H was observed, but no interaction between 1-H and
19-H was observed (Figure 2). In contrast, (P,1S)-5 exhibited
The reactivity of the complementary triynes (1S)-(-)-3
and (1S)-(-)-4 told us which of the p-tolyl groups was
responsible for the stereoselectivity improvement and/or the
dramatic change of the helicity sense. While (1S)-(-)-3
behaved almost identically to (1S)-(-)-2, producing only
(P,1S)-(+)-7 (Table 1, cf. entries 4 and 5), (1S)-(-)-4
followed the reactivity of (1S)-(-)-1 (Table 1, cf. entries 3
and 6), giving major (M,1S)-(-)-8 along with minor (P,1S)-
8.
The helicity assignment of compounds 5-8 requires an
explanation. The absolute stereochemistry at the chiral center
was known, as the syntheses of 1-4 and, consequently, 5-8
started from optically pure commercially available (2S)-
(-)-11 (Scheme 1), leaving the chiral center untouched. The
Figure 2. Approximate distances (in Å) between protons relevant
for helicity assignment and observed 1H-1H correlations in ROESY
1H NMR spectra (indicated by arrows).13
Scheme 1
an interaction between 1-H and 19-H but no interaction
between 19-H and 1-CH3. This is in full agreement with
corresponding models and relevant proton distances. The
helicity of (M,1S)-(-)-8 was assigned in the same way.
Similarly, in the case of 19-tolyl derivatives (P,1S)-(+)-6
and (P,1S)-(+)-7, helicity assignment relied on the presence
of a through-space interaction between 1-H and 2′,6′-H of
the tolyl group and the absence of one between 1-CH3 and
the tolyl group. Moreover, the chemical shift of the 1-CH3
signal was significant for (M)- and (P)-helicity. While
doublets of corresponding “exo” 1-CH3 groups appeared
within a 1.58-1.67 ppm interval for (M)-helices, shielding
the “endo” 1-CH3 with a proximal naphthalene unit (adjacent
to the dihydrooxepine ring) at the (P)-helices resulted in an
(9) (a) Zarges, W.; Hall, J.; Lehn, J. M.; Bolm C. HelV. Chim. Acta 1991,
74, 1843. (b) Vorogushin, A. V.; Wulff, W. D.; Hansen, H.-J. J. Am. Chem.
Soc. 2002, 124, 6512. This paper refers to central-to-axial chirality transfer.
However, products described therein can be regarded also as small helices.
(c) Maeda, K.; Morino, K.; Okamoto, Y.; Sato, T.; Yashima, E. J. Am.
Chem. Soc. 2004, 126, 4329 and refs 8 and 9 cited therein.
(10) (a) Slowinski, F.; Aubert, C.; Malacria, M. J. Org. Chem. 2003,
68, 378. (b) Slowinski, F.; Aubert, C.; Malacria, M. Eur. J. Org. Chem.
2001, 3491. (c) Pe´rez, D.; Siesel, B. A.; Malaska, M. J.; David, E.; Vollhardt,
K. P. C. Synlett 2000, 306. (d) Slowinski, F.; Aubert, C.; Malacria, M.
Tetrahedron Lett. 1999, 40, 5849. (e) Pelissier, H.; Rodriguez, J.; Vollhardt,
K. P. C. Chem. Eur. J. 1999, 5, 3549. (f) Germanas, J.; Aubert, C.; Vollhardt,
K. P. C. J. Am. Chem. Soc. 1991, 113, 4006. (g) Johnson, E. P.; Vollhardt,
K. P. C. J. Am. Chem. Soc. 1991, 113, 381. (h) Boese, R.; Rodriguez, J.;
Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1991, 30, 993. (i) Clinet,
J.-C.; Dun˜ach, E.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1983, 105, 6710.
(11) Syntheses of triynes 1-4 have been published recently; see:
Alexandrova´, Z.; Stara´, I. G.; Sehnal, P.; Teply´, F.; Stary´, I.; Sˇaman, D.;
Fiedler, P. Collect. Czech. Chem. Commun. 2004, 69, 2193. The preparation
of (P,1S)-(+)-18 (Scheme 1) illustrates in details the general synthesis
strategy.
task was to determine the diastereomeric relationship between
the asymmetric center and the helical backbone in 5-8. The
ROESY 1H NMR experiments enabled unequivocal handed-
ness assignment of helices further supported by CD spectra,
vide infra.
First, we compared the ROESY spectra of diastereomeri-
cally pure (M,1S)-(-)-5 and enriched (P,1S)-5. In the case
Org. Lett., Vol. 7, No. 13, 2005
2549

upfield shift of 1-CH3 signals appearing within a 0.54-0.62
ppm range. The opposite helicity of (M,1S)-(-)-5 versus
(P,1S)-(+)-6 is further shown by their CD spectra displaying
an obvious pseudoenantiomeric relationship (Figure 3).
Note, the use of potassium salt in THF was key to our
success, as analogous lithium or sodium salts exhibited poor
reactivity under various conditions. The Sonogashira cou-
pling of (1S)-(-)-14 with 157a under Pd0/CuI catalysis
allowed us to assemble triyne (1S)-(-)-16 that subsequently,
on reaction with TBAF, produced unprotected triyne
(1S)-(-)-17. In the final step of the synthesis sequence, this
key intermediate was cycloisomerized in the presence of
CpCo(CO)2/PPh3 to get the target [7]helicene-like compound
(P,1S)-(+)-18. The reaction proceeded with good diastereo-
selectivity and could be mediated by a stoichiometric or
catalytic amount of CoI complex.15 Diastereomerically pure
(P,1S)-(+)-18 was obtained after crystallization.
The helicity assignment was done in the same way as for
(P,1S)-(+)-6 and 7, vide supra. In ROESY 1H NMR
spectrum, a through-space interaction between 1-H and
2′,6′-H of the 1,4-phenylene group and the absence of one
between 1-CH3 and the 1,4-phenylene group was obvious.
Furthermore, the chemical shift of 1-CH3 at 0.57 ppm lying
within the 0.54-0.62 ppm interval indicated an “endo”
position of 1-CH3 and, accordingly, (P)-helicity of the
backbone.
In summary, we have developed highly stereoselective [2
+ 2 + 2] cycloisomerization of aromatic triynes producing
a [7]helicene-like scaffold in diastereomeric ratios up to 100:
0. This efficient central-to-helical chirality transfer can be
controlled by an absolute configuration at the asymmetric
center and by the position of carbon substituents. Synthetic
studies on the transformation to parent helicenes and on the
preparation of nonracemic, functionalized derivatives are in
progress.
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 pseudoenantiomers (M,1S)-(-)-5 (solid line)
and (P,1S)-(+)-6 (dashed line) in CH3CN.
Encouraged by the high stereocontrol in the [2 + 2 + 2]
cycloisomerization step, we decided to synthesize the
[7]helicene-like compound (P,1S)-(+)-18, representing a new
structural type of possible liquid-crystalline materials (Scheme
1).
Acknowledgment. The financial support from the Grant
Agency of the Czech Republic (Reg. No. 203/02/0248) is
gratefully acknowledged. We thank the group of Dr. K. Ubik
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). We also thank Dr. E. Poetsch (Merck,
Darmstadt) for initializing the synthesis of (P,1S)-(+)-18 and
providing the starting material 9.
The synthesis was started from commercially available
phenylbromide 9 that was converted into the corresponding
iodide 10 using the routine lithiation/iodination protocol. The
following Sonogashira coupling with propargylic alcohol
(2S)-(-)-11 (being commercially available in both enantio-
meric forms) under PdII/CuI catalysis created alcohol (2S)-
(-)-12. Its potassium salt was treated with benzylic bromide
1314 to afford functionalized naphthyliodide (1S)-(-)-14.
Supporting Information Available: Experimental pro-
cedures for cyclization of 1-4 and 17, experimental details
for the synthesis of 18 from 9, characterization data and 1H
NMR spectra for cyclic products 5-8 and 18 and compounds
9, 10, 12, 14, 16, and 17, and UV and CD spectra for cyclic
products 5-8 and 18. This material is available free of charge
via the Internet at http://pubs.acs.org.
(12) Diastereomeric ratios were inferred from 1H NMR spectra by
integrating the signals of the methyl groups attached to the dihydrooxepine
ring of both diastereomers. The prolonged reaction periods did not affect
the diastereomeric ratios of the products.
OL047311P
(13) Optimized structures were obtained using Quantum CAChe for
Windows 3.0 (Oxford Molecular Group/Fujitsu) at the semiempirical AM1
level. The nature of the R group (H or p-tolyl) did not substantially affect
the distances between the protons discussed. In the case of the 1-CH3 and
19-tolyl groups we were aware of their rotation (only the closest distances
taken from the optimized “frozen” structures are displayed).
(14) Stara´, I. G.; Kolla´rovicˇ, A.; Teply´, F.; Stary´, I.; Sˇaman, D.; Fiedler,
P. Collect. Czech. Chem. Commun. 2000, 65, 577.
(15) Use of substoichiometric amounts of CpCo(CO)2 (40 mol %) and
PPh3 (40 mol %) led to a substantially prolonged reaction period (25 h)
and lower yield (64%).
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Org. Lett., Vol. 7, No. 13, 2005