1,1′-Linked cyclopropane derivatives: The helical conformation of quinquecyclopropanol

Article abstract of DOI:10.1002/anie.200702013

In a twist: 1,1′-Linked oligocyclopropanols have been obtained by an iterated reaction of a cyclopropaneboronate with in situ generated lithium bromocyclopropylidenoid and subsequent oxidation. As predicted by DFT computations for sexicyclopropane (shown

Full text of DOI:10.1002/anie.200702013

Angewandte
Chemie
DOI: 10.1002/anie.200702013
Oligocyclopropanols
1,1’-Linked Cyclopropane Derivatives: The Helical Conformation of
Quinquecyclopropanol**
Takuya Kurahashi, Sergei I. Kozhushkov, Heiko Schill, Kathrin Meindl, Stephan Rühl, and
Armin de Meijere*
Dedicated to Professor Kenneth B. Wiberg on the occasion of his 80th birthday
Single-, double-, and even triple-helical structures play
important roles for biological and synthetic macromolecules;
however, for relatively small organic compounds helical
arrangements are not common.[1] In most biological macro-
molecules such a helical structure is favored and maintained
by hydrogen bonds. Helical conformations of saturated
compounds without functional substituents is observed less
frequently. Aliphatic perfluorocarbon chains are known to
adopt a helical structure in the crystalline state and in solution
as a result of electrostatic repulsion of the fluorine substitu-
ents in the 1- and 3-positions,[2] poly(ethyleneglycol) adopts a
helical conformation in isobutyric acid solution,[3] and per-
methyldecasilane forms a helix in a helical schizophyllan
matrix.[4] As formally saturated hydrocarbons have no driving
forces to adopt helical conformations (apart from van der
Waals interactions), their conformations range from “zig-zag”
for linear hydrocarbons on one hand to helical for certain
enantiomerically pure [n]triangulanes (1)[5,6] on the other.
Helicity of the latter, however, is predetermined by their rigid
helical shape.
Thus, helical conformations were demonstrated for
[1,1’;2’,1’’]tercyclopropanedimethanol (2, n = 3, R1 = R2 =
CH2OH) and for [1,1’;2’,1’’;2’’,1’’’;2’’’,1’’’’]quinquecyclopro-
panedimethanol (2, n = 5, R1 = R2 = CH2OH) in solution as
well as in the solid state, while other compounds of this type
adopted different conformations, at least in the crystals.[8]
Based on an earlier observation that bicyclopropyl (3) in
the gaseous and the liquid state preferentially adopts a
synclinal (gauche) conformation,[9] one is intuitively led to
conceive that the higher 1,1’-linked oligocyclopropanes 4 (n ꢁ
3) would prefer helical arrangements in which all bicyclo-
propyl subunits have either (+)- or (ꢀ)-gauche conforma-
tions. This notion is indeed supported by density functional
theory (DFT) computations at the B3LYP/6-31G(d) level of
theory. Since the only known higher 1,1’-linked oligocyclo-
propanes 4, the 1,1-dicyclopropylcyclopropane 4a (n = 3,
R1 = R2 = H),[10] its derivatives 4b–d (n = 3, R1 = R2 = OH,[11]
OSiMe3,[11c,d]
and
OMs[11d]),
and
1,1’’’-dimethyl-
[1,1’;1’,1’’;1’’,1’’’]quatercyclopropane 4e (n = 4, R1 = R2 =
Me),[12] had not been structurally characterized at all, we set
out to prepare such [1,1’;1’,1’’;…;1nꢀ2,1nꢀ1]oligocyclopropanes
endowed with polar functionalities, in order to investigate
their structural features.
The Matteson homologation methodology[13] was consid-
ered to be employable as the key step. In this, an organyl
substituent migrates from the negatively charged boron to an
adjacent carbon in a borate complex with inversion of
configuration.[14] For example, intermediate 7, which is
formed upon treatment of a lithium halocarbenoid like 6
(prepared from dibromocyclopropane (5) and n-butylli-
thium)with a borane, is converted into the corresponding 1-
organocyclopropylborane 8 (Scheme 1). The latter can then
undergo the same transformation repeatedly upon treatment
with the in situ generated carbenoid 6, eventually leading to
1,1n-disubstituted oligocyclopropanes 4 (n ꢁ 2). Indeed, lith-
ium halocyclopropylidenoids upon treatment with organo-
boronates have been found to produce cyclopropaneboro-
nates in good yields.[13] Thus, when trimethylene methylbor-
onate (9) was treated with a solution of dibromocyclopropane
(5)[15] in tetrahydrofuran, to which n-butyllithium had been
[1,1’;2’,1’’;2’’,1’’’;…;2nꢀ2,1nꢀ1]Oligocyclopropanes
which have been discovered as substructures in two natural
products from different sources,[7] exhibit quite interesting
conformational properties depending on their substituents.
(2),
[*]Dr. T. Kurahashi, Dr. S. I. Kozhushkov, Dr. H. Schill,
Prof. Dr. A. de Meijere
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen (Germany)
Fax: (+49)551-399-475
E-mail: armin.demeijere@chemie.uni-goettingen.de
K. Meindl, Dr. S. Rühl
Institut für Anorganische Chemie
Georg-August-Universität Göttingen
Tammannstrasse 4, 37077 Göttingen (Germany)
[**]This work was supported by the State of Lower Saxony and the
Fonds der Chemischen Industrie. T.K. is indebted to the Alexander
von Humboldt Foundation for a research fellowship. The authors
are grateful to Yasuhide Inokuma for the X-ray structure analysis of
compound 18-DNB.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 1. Example of a Matteson-type homologation.
Angew. Chem. Int. Ed. 2007, 46, 6545 –6548
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6545

Communications
added at ꢀ1108C, and this treatment was iterated four more
times, a mixture of cyclopropylcyclopropaneboronates was
formed. Subsequent oxidation with hydrogen peroxide in the
presence of sodium hydroxide gave a mixture of the cyclo-
propylcyclopropanols 10–12 in good overall yield (Scheme 2).
Scheme 3. Synthesis of quinquecyclopropanol 18 and computed con-
formation of sexicyclopropane 19.
terminal cyclopropane moiety, has dihedral angles between
each two neighboring cyclopropanes of 52.9, 64.5, 60.3, and
ꢀ68.68, respectively (averages for the two independent
molecules in the asymmetric unit); this orientation is com-
pletely analogous to that calculated for the inner section of
the sexicyclopropane. In the crystals of the other three
dinitrobenzoates 10-DNB, 11-DNB, and 12-DNB the 1,1’-
linked cyclopropane moieties adopt analogous helical all-
gauche conformations.
Scheme 2. Facile synthesis of bis-, ter-, and quatercyclopropane deriv-
atives by a Matteson-type homologation of 1,1-dibromocyclopropane.
These products could be separated by column chroma-
tography, and each cyclopropanol was individually trans-
formed to the corresponding 3,5-dinitrobenzoate—10-DNB
(81% yield), 11-DNB (70%), and 12-DNB (72%)—by
reaction with 3,5-dinitrobenzoyl chloride (13). Crystals of all
three dinitrobenzoates were grown and subjected to X-ray
diffraction analysis.[16]
In order to obtain an even higher 1,1’-linked oligocyclo-
propanol than 12, the same iterative homologation was
performed with cyclopropaneboronates 14[17] and 15
(Scheme 3).[18,19] Indeed, the [1,1’;1’,1’’;1’’,1’’’;1’’’,1’’’’]quinque-
cyclopropan-1-ol (18) was isolated in 32% (from 14) and 22%
yield (from 15) along with tercyclopropanol 16 (22% from 14,
6% from 15) and quatercyclopropanol 17 (28% from 14, 14%
from 15). The quinquecyclopropanol 18 was also converted to
its dinitrobenzoate 18-DNB, and the latter was analyzed by X-
ray diffraction.[16]
The chemical behavior of the 1,1’-oligocyclopropylcyclo-
propanols 16–18 is also noteworthy as it differs from that
commonly observed for 1-cyclopropyl-substituted cyclopro-
panols. Thus, an attempted conversion of the alcohols 17 and
18 to the corresponding bromides—which were desired for
reduction to the unsubstituted quatercyclopropane 4 f (n = 4,
R1 = R2 = H) and quinquecyclopropane 4g (n = 5, R1 = R2 =
H)—did neither occur with complete retention of their
cyclopropane moieties (cf. Ref. [26]) nor with iterative ring
enlargement by way of cascade rearrangements involving all
their cyclopropane moieties.[11c,d,27] Instead, in each case only
the cyclopropanol moiety itself underwent ring opening to a
b-bromoketone fragment (cf. Ref. [28]) to give the 3-bromo-
propionyl-1,1’-oligocyclopropanes 20 and 21 in 64 and 92%
yield, respectively, with retention of the other three-mem-
bered rings (Scheme 4).
The DFT computations[20–25] for [1,1’;1’,1’’;1’’,1’’’;1’’’,1’’’’;
1’’’’,1’’’’’]sexicyclopropane (19) in the gas phase predicted
dihedral angles of ꢀ55.0, + 60.6, + 62.5, + 59.4, and ꢀ52.58
(see the Supporting Information) along the chain for the
lowest energy conformer; in other words, the inner quatercy-
clopropane fragment in this molecule has an all-(+)-gauche
conformation, while the two outer cyclopropyl groups are
(ꢀ)-gauche oriented. In the crystal, the quinquecyclopropane
moiety of 18-DNB, on going from the cyclopropanol to the
Scheme 4. Ring opening of [1,1’;1’,1’’;1’’,1’’’]quatercyclopropan-1-ol
(17) and [1,1’;1’,1’’;1’’,1’’’;1’’’,1’’’’]quinquecyclopropan-1-ol (18) upon
attempted conversion into the corresponding bromides.
6546 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 6545 –6548

Angewandte
Chemie
Chem. 1999, 111, 3682 – 3685; Angew. Chem. Int. Ed. 1999, 38,
Thus, both the 1,1-linkage and the 1,2-linkage of oligocy-
clopropanes lead to helical structures of relatively small
molecules. The consequences of this preferred arrangement
of [1,1’;1’,1’’;…;1nꢀ2,1nꢀ1]oligocyclopropane units are currently
being studied.
3474 – 3477; b) A. de Meijere, A. F. Khlebnikov, S. I. Kozhush-
kov, R. R. Kostikov, P. R. Schreiner, A. Wittkopp, C. Rinder-
spacher, H. Menzel, D. S. Yufit, J. A. K. Howard, Chem. Eur. J.
2002, 8, 828 – 842; c) A. de Meijere, A. F. Khlebnikov, S. I.
Kozhushkov, K. Miyazawa, D. Frank, P. R. Schreiner, B. C.
Rinderspacher, D. S. Yufit, J. A. K. Howard, Angew. Chem.
2004, 116, 6715 – 6719; Angew. Chem. Int. Ed. 2004, 43, 6553 –
6557; d) A. de Meijere, A. F. Khlebnikov, S. I. Kozhushkov, D. S.
Yufit, O. V. Chetina, J. A. K. Howard, T. Kurahashi, K. Miya-
zawa, D. Frank, P. R. Schreiner, B. C. Rinderspacher, M.
Fujisawa, C. Yamamoto, Y. Okamoto, Chem. Eur. J. 2006, 12,
5697 – 5721.
Experimental Section
Representative procedure: Synthesis of 18: n-Butyllithium in hexane
(2.2 mmol, 0.91 mL of a 2.42m solution in hexane) was added
dropwise under argon to a solution of 1,1-dibromocyclopropane (5)[15]
(440 mg, 2.2 mmol) in anhydrous THF (20 mL) at ꢀ1108C, and the
mixture was stirred at ꢀ1108C for 5 min. The mixture was then
treated with trimethylene cyclopropaneboronate (14) (252 mg,
2.0 mmol), and the resulting mixture was gradually warmed to room
temperature within approximately 12 h. After that, dibromide 5
(440 mg, 2.2 mmol) was added at 258C, and the mixture was cooled to
ꢀ1108C again. n-Butyllithium (2.2 mmol, 0.91 mL of a 2.42m solution
in hexane) was added at ꢀ1108C, and the mixture was gradually
warmed to room temperature again. This procedure was repeated
another three times. Finally, hydrogen peroxide (8 mmol, 908 mg,
820 mL of 30% aq. solution) and sodium hydroxide (5 mmol, 5 mL of
1n aq. solution) were added at 08C, and the reaction mixture was
stirred at 258C for 6 h. The resulting mixture was extracted
thoroughly with diethyl ether (6 ” 50 mL), and the combined organic
extracts were dried (MgSO4). The solution was concentrated under
reduced pressure, and the residue was separated and purified by
column chromatography (80 g of flash silica gel, 2 ” 60 cm column,
hexane/ether 10:1!4:1, Rf = 0.25 in hexane/ether 4:1) to yield
[7] Review: J. Pietruszka, Chem. Rev. 2003, 103, 1051 – 1070.
[8] A. G. M. Barrett, R. A. James, G. E. Morton, P. A. Procopiou, C.
Boehme, A. de Meijere, C. Griesinger, U. M. Reinscheid, J. Org.
Chem. 2006, 71, 2756 – 2759, and references [6,7] cited therein.
[9] A. de Meijere, W. Lüttke, F. Heinrich, Justus Liebigs Ann. Chem.
1974, 306 – 327.
[10] a) F. Effenberger, W. Podszun, Angew. Chem. 1969, 81, 1046 –
1047; Angew. Chem. Int. Ed. Engl. 1969, 8, 976; b) O. M. Nefe-
dov, I. E. Dolgii, I. B. Shvedova, R. N. Shafran, Bull. Acad. Sci.
USSR Div. Chem. Sci. 1972, 21, 1834 – 1836; Izv. Akad. Nauk
SSSR Ser. Khim. 1972, 21, 1885 – 1887; c) W. Weber, U. Behrens,
A. de Meijere, Chem. Ber. 1981, 114, 1196 – 1199.
[11] a) T. Imamoto, Y. Kamiya, T. Hatajima, H. Takahashi, Tetrahe-
dron Lett. 1989, 30, 5149 – 5152; b) T. Imamoto, T. Hatajima, N.
Takiyama, T. Takeyama, Y. Kamiya, T. Yoshizawa, J. Chem. Soc.
Perkin Trans. 1 1991, 3127 – 3135; c) N. S. Zefirov, S. I. Kozhush-
kov, T. S. Kuznetsova, Zh. Org. Khim. 1988, 24, 447 – 448; J. Org.
Chem. USSR 1988, 24, 395 – 396; d) N. S. Zefirov, K. A. Lukin,
S. I. Kozhushkov, T. S. Kuznetsova, A. M. Domarev, I. M.
Sosonkin, Zh. Org. Khim. 1989, 25, 312 – 319; J. Org. Chem.
USSR 1989, 25, 278 – 284.
quinquecyclopropan-1-ol 18 (139 mg, 32%) as
a colorless oil.
1H NMR (250 MHz, CDCl3): d = 2.55 (brs, 1H; OH), 1.66–1.57 (m,
1H; CH), 0.71–0.66 (m, 2H; CH2), 0.56–0.51 (m, 2H; CH2), 0.49–0.44
(m, 2H; CH2), 0.39–0.31 (m, 2H; CH2), 0.29–0.21 (m, 6H; CH2), 0.12–
0.06 (m, 4H; CH2), ꢀ0.02 to ꢀ0.09 ppm (m, 2H; CH2); 13C NMR
(62.9 MHz, CDCl3): d = 59.9 (C-OH), 25.7 (C), 25.2 (C), 23.6 (C), 14.8
(CH), 12.4 (2CH2), 9.7 (2CH2), 8.0 (2CH2), 7.5 (2CH2), 1.9 ppm
(2CH2). The structure of 18 was proved by X-ray crystal structure
analysis of its 3,5-dinitrobenzoate 18-DNB.[16]
[12] a) J. L. Ripoll, J. C. Limasset, J. M. Conia, Tetrahedron 1971, 27,
2431 – 2452. For cyclic analogues of compounds of type 4 see also
a recent review (Ref. [5a]) and references therein.
[13] Reviews: a) A. Pelter, K. Smith, H. C. Brown, Borane Reagents,
Academic Press, New York, 1988; b) D. S. Matteson in Stereo-
directed Synthesis with Organoboranes, Vol. 32, Springer, Berlin,
1995. Recent applications: c) A. N. Thadani, R. A. Batey,
Tetrahedron Lett. 2003, 44, 8051 – 8055; d) P. R. Blakemore,
M. S. Burge, J. Am. Chem. Soc. 2007, 129, 3068 – 3069.
[14] a) D. S. Matteson, D. Majumdar, J. Am. Chem. Soc. 1980, 102,
7588 – 7590; b) M. Duraisamy, H. M. Walborsky, J. Am. Chem.
Soc. 1984, 106, 5035 – 5037; c) R. L. Danheiser, A. C. Savoca, J.
Org. Chem. 1985, 50, 2401 – 2403; d) R. Inoue, H. Shinokubo, K.
Oshima, Tetrahedron Lett. 1996, 37, 5377 – 5380.
Received: May 7, 2007
Published online: July 24, 2007
Keywords: borates · cyclopropane · helical structures · lithiation ·
.
rearrangement
[15] C. Blankenship, L. A. Paquette, Synth. Commun. 1984, 14, 983 –
987.
[1] For a highlight on this topic see: C. Schmuck, Angew. Chem.
2003, 115, 2552 – 2556; Angew. Chem. Int. Ed. 2003, 42, 2448 –
2452.
[16] CCDC 642257
(10-DNB),
CCDC 642256
(11-DNB),
CCDC 642258 (12-DNB), and CCDC 642255 (18-DNB) contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[2] K. Monde, N. Miura, M. Hashimoto, T. Taniguchi, T. Inabe, J.
Am. Chem. Soc. 2006, 128, 6000 – 6001, and references [2,3] cited
therein.
[3] a) M. L. Alessi, A. I. Norman, S. E. Knowlton, D. L. Ho, S. C.
Greer, Macromolecules 2005, 38, 9333 – 9340; See also: b) L.
Malysheva, A. Onipko, R. Valiokas, B. Liedberg, J. Phys. Chem.
A 2005, 109, 7788 – 7796.
[4] S. Haraguchi, T. Hasegawa, M. Numata, M. Fujiki, K. Uezu, K.
Sakurai, S. Shinkai, Org. Lett. 2005, 7, 5605 – 5608.
[5] Reviews: a) A. de Meijere, S. I. Kozhushkov, H. Schill, Chem.
Rev. 2006, 106, 4926 – 4996; b) A. de Meijere, S. I. Kozhushkov,
Chem. Rev. 2000, 100, 93 – 142; c) A. de Meijere, S. I. Kozhush-
kov in Advances in Strain in Organic Chemistry, Vol. 4 (Ed.: B.
Halton), JAI, London, 1995, pp. 225 – 282.
[17] According to Beilstein X-fire, boronate 14 (chemical name: 2-
cyclopropyl-[1,3,2]dioxaborinane) is not known (see also the
Supporting Information).
[18] 1-Cyclopropylcyclopropaneboronate 15 [chemical name: 2-
(bicyclopropyl-1-yl)-[1,3,2]dioxaborinane] was prepared from
bicyclopropylidene[19] in 27% yield adopting a published proto-
col: K. Utimoto, M. Tamura, M. Tanouti, K. Sisido, Tetrahedron
1972, 28, 5697 – 5702. For details see the Supporting Information.
[19] For reviews on bicyclopropylidenes see: a) A. de Meijere, S. I.
Kozhushkov, A. F. Khlebnikov, Zh. Org. Khim. 1996, 32, 1607 –
1626; Russ. J. Org. Chem. 1996, 32, 1555 – 1575; b) A. de Meijere,
[6] a) A. de Meijere, A. F. Khlebnikov, R. R. Kostikov, S. I. Koz-
hushkov, P. R. Schreiner, A. Wittkopp, D. S. Yufit, Angew.
Angew. Chem. Int. Ed. 2007, 46, 6545 –6548
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6547

Communications
S. I. Kozhushkov, A. F. Khlebnikov, Top. Curr. Chem. 2000, 207,
[25] Gaussian 03 (Revision C.02): M. J. Frisch et al., see the
Supporting Information.
[26] a) A. de Meijere, S. I. Kozhushkov, T. Spꢀth, N. S. Zefirov, J.
Org. Chem. 1993, 58, 502 – 505; b) A. de Meijere, S. I. Kozhush-
kov, T. Spꢀth, Org. Synth. 2000, 78, 142 – 151.
89 – 147; c) A. de Meijere, S. I. Kozhushkov, Eur. J. Org. Chem.
2000, 3809 – 3822; d) A. de Meijere, S. I. Kozhushkov, T. Spꢀth,
M. von Seebach, S. Lꢁhr, H. Nüske, T. Pohlmann, M. Es-Sayed,
S. Brꢀse, Pure Appl. Chem. 2000, 72, 1745 – 1756.
[20] Geometries were optimized by density functional theory (DFT)
computations employing Beckeꢂs three-parameter functional
with the Lee–Yang–Parr correlation functional (B3LYP)[21–24]
utilizing the 6-31G(d) basis set[24] as implemented in Gaussian
03.[25]
[27] L. Fitjer, D. Wehle, M. Noltemeyer, E. Egert, G. M. Sheldrick,
Chem. Ber. 1984, 117, 203 – 221.
[28] a) O. G. Kulinkovich, S. V. Sviridov, D. A. Vasilevskii, A. I. Sav-
chenko, T. S. Pritytskaya, Zh. Org. Khim. 1991, 27, 294 – 298; J.
Org. Chem. USSR 1991, 27, 250 – 253; b) M. V. Raiman, A. V.
Pukin, V. I. Tyvorskii, N. De Kimpe, O. G. Kulinkovich, Tetrahe-
dron 2003, 59, 5265 – 5272; c) S. Baktharaman, S. Selvakumar,
V. K. Singh, Tetrahedron Lett. 2005, 46, 7527 – 7529; d) J. Jiao,
L. X. Nguyen, D. R. Patterson, R. A. Flowers II, Org. Lett. 2007,
9, 1323 – 1326.
[21] A. D. Becke, Phys. Rev. A 1988, 38, 3098 – 3100.
[22] C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785 – 789.
[23] R. G. Parr, W. Yang, Density Functional Theory of Atoms and
Molecules, Oxford University Press, New York, 1989.
[24] W. J. Hehre, L. Radom, P. v. R. Schleyer, J. A. Pople, Ab Initio
Molecular Orbital Theory, Wiley-Interscience, New York, 1986.
6548 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 6545 –6548