A rigid bicyclo[3.3.0]octane (octahydropentalene): a heavily constrained novel aliphatic template for molecular self-assembly

Article abstract of DOI:10.1016/j.tetlet.2008.03.062

This Letter reports the utility of a heavily constrained cis-fused bicyclo[3.3.0]octane (octahydropentalene) aliphatic template for effecting molecular self-assembly. An attractive feature of this system is its heavily constrained alicyclic backbone that would allow for the exploration of self-assembling systems with conformationally ordered features.

Full text of DOI:10.1016/j.tetlet.2008.03.062

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Tetrahedron Letters 49 (2008) 3056–3059
A rigid bicyclo[3.3.0]octane (octahydropentalene): a heavily
constrained novel aliphatic template for molecular self-assembly
Amol M. Kendhale a, Rajesh Gonnade b, P. R. Rajamohanan c, Gangadhar J. Sanjayan a,*
a Division of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
b Centre for Materials Characterization, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
c Central NMR Facility, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Received 9 January 2008; revised 6 March 2008; accepted 12 March 2008
Available online 15 March 2008
Abstract
This Letter reports the utility of a heavily constrained cis-fused bicyclo[3.3.0]octane (octahydropentalene) aliphatic template for
effecting molecular self-assembly. An attractive feature of this system is its heavily constrained alicyclic backbone that would allow
for the exploration of self-assembling systems with conformationally ordered features.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
This Letter reports the utility of a heavily constrained
cis-fused bicyclo[3.3.0]octane8 (octahydropentalene) ali-
phatic template for effecting molecular self-assembly. Such
self-assembling systems, based on heavily constrained
aliphatic templates, would be of use for the design and
development of novel self-assembling systems devoid of
p-stacking interferences commonly observed in their
aromatic counterparts.1a Bicyclo[3.3.0]octane, the parent
compound of polyquinanes,9 adopts a heavily constrained
structural framework with a preference for a cis-fused ring
junction, since the trans-fusion of two five-membered rings
would involve considerable torsional strain, with a very
large enthalpy difference (cis to trans ꢀ29.6 KJ/mole).10,11
Molecular self-assembly has emerged as a powerful tool
for the construction of well-defined supramolecular archi-
tectures and nano-scale materials with extensive structural
diversity and applications.1,2 During the past three dec-
ades, chemists have made considerable progress in under-
standing the fundamental rules of self-assembling
processes involving weak non-covalent interactions such
as Van der Waals, capillary, p–p and hydrogen bonds.3
Because of their directionality and specificity in recognition
processess,4 hydrogen bonds have been proved to be supe-
rior among other non-covalent forces for the programmed
self-assembly of smaller molecular components to generate
supramolecular ensembles with pre-defined structural fea-
tures. In order to further enhance the strength, directional-
ity and specificity of hydrogen bonding interactions, there
is currently intense research interest in the design and
development of novel self-assembling motifs having arrays
of hydrogen bond donor (D) and acceptor (A) sites,5–7
appended on various templates.
bicyclo[3.3.0]octane (octahydropentalene)
The possibility of quick access to heavily substituted
frameworks such as 3 in as little as three steps would
extend the application potential of such systems.
Compound 3 represents a simple example of a diverse
self-assembling system obtainable from a cis-fused bi-
cyclo[3.3.0]octane template by changing the stereochemistry
of the side chains attached to the bicyclo[3.3.0]octane
framework. The wide scope of the Weiss reaction to
*
Corresponding author. Tel./fax: +91 02025893153.
E-mail address: gj.sanjayan@ncl.res.in (G. J. Sanjayan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.062

A. M. Kendhale et al. / Tetrahedron Letters 49 (2008) 3056–3059
3057
provide bicyclo[3.3.0]octane (octahydropentalene) analogs
of diverse architectures, substituents and stereochemistries
means that the bicyclo[3.3.0]octane framework may be
used as a versatile template on which self-assembling sys-
tems of diverse structural architectures can be designed
and developed.
The self-assembling system 3 can be readily obtained in
good yield starting from glyoxal using the Weiss proto-
col.12 Reaction of glyoxal with diacetyl acetone in the
presence of a base affords the bicyclo[3.3.0]octane-derived
bis-b-keto ester 1, which was subjected to reduction using
NaBH4 in methanol to afford the dihydroxy bicyclic ester
2. The self-assembling system 3 was obtained in excellent
yield by amidation of 2 with saturated methylamine
solution in methanol at room temperature (Scheme 1).
Self-assembling system 3 crystallized in the monoclinic
space group C2/c from hot water. The hydrogen bonding
interactions in 3 according to crystal structure studies are
shown in Figure 1.
The analysis of the crystal structure showed that the
D/A self-complementary hydrogen bonding codes
(D = donor, A = acceptor) in 3 are clearly projected for
intermolecular hydrogen bonding interactions, a pre-requi-
site for efficient self-assembling.1 The self-complementary
individual strands undergo self-assembly through inter-
molecular N–Hꢁ ꢁ ꢁO@C hydrogen bonding interactions.
The hydrogen-bonds in 3 are fairly strong with D–Hꢁ ꢁ ꢁA
˚
distances [d(N–Hꢁ ꢁ ꢁO)] in the range 1.99–2.0 A. The
N-methyl groups of the adjacent self-assembling strands
˚
of 3 are uniformly separated by 4.88 A, an observation that
could provide insight for developing such templates into
potential protein-b-sheet nucleators.13 It is noteworthy that
the extended sheet structures have been disclosed recently
Fig. 1. Crystal structure of the bicyclo[3.3.0]octane-derived self-assem-
bling system 3 showing intermolecular hydrogen bonding interactions.
Crystal structure and intermolecular arrangement (top), side view of the
intermolecular hydrogen bonding interactions (middle), and supramole-
cular structure formation involving the amide and hydroxyl groups
(bottom).
O
O
O
O
O
O
O
MeO
HO
OMe
OH
MeO
O
OMe
O
H
in certain cyclopropane. c-Peptides stabilized by C–
H. . .O hydrogen bonds,14 and also in isotactic acrylamide
oligomers.15 The individual strands in protein b-sheets
are in close proximity, involving extensive intermolecular
hydrogen bonding interactions; an observation that has
been explored in the design of novel synthetic b-sheet
nucleators/scaffolds. It should be emphasized that synthetic
b-sheet scaffolds have considerable relevance in the under-
standing and development of potential therapies for
Alzheimer’s disease, a leading cause of dementia in the
elderly, which is pathologically defined by the occurrence
of amyloid plaques, composed of the amyloid b-protein,
and neurofibrillary tangles.16 Closer inspection of the crys-
tal structure further reveals that 3 undergoes yet another
mode of self-assembly via the hydroxyl groups, appended
on the periphery of the octahydropentalene framework
(Fig. 1, bottom) leading to the formation of a supramole-
cular structural architecture. The hydroxyl groups partici-
pate in intermolecular O. . .H. . .O@C hydrogen bonding
i
CHO
CHO
+
+
H
MeO
OMe
MeO
OMe
O
ii
1
CH3
CH3
O
O
O
O
O
O
N
N
H
MeO
HO
OMe
OH
H
H
H
iii
HO
OH
H
H
N
H
H
N
MeO
OMe
O
O
CH3
CH3
2
3
Scheme 1. Synthesis of 3. Reagents and conditions: (i) (a) NaOH, MeOH,
reflux; (b) de-ionized H2O, 1 M HCl (89%); (ii) NaBH4, MeOH, rt, 4 h
(62%); (iii) MeOH, MeNH2, rt, 24 h (96%).
˚
patterns with D–Hꢁ ꢁ ꢁA distance [d(O–Hꢁ ꢁ ꢁO@C)] of 2.0 A.

3058
A. M. Kendhale et al. / Tetrahedron Letters 49 (2008) 3056–3059
In summary, we have demonstrated the utility of a cis-
1159, 1091, 1051, 954; MALDI-TOF MS: 371.42 (M+1),
393.38 (M+Na), 409.34 (M+K); Anal. Calcd for
C16H26N4O6: C, 51.88; H, 7.08; N, 15.13. Found: C,
51.63; H, 6.81; N, 15.37.
fused rigid bicyclo[3.3.0]octane (octahydropentalene)
template for effecting molecular self-assembly. The striking
feature of this system is its heavily constrained alicyclic
backbone coupled with the possibility of stereochemical
alterations on the pentalene periphery that would allow
for the exploration of self-assembling systems with diverse
structural architectures. We are currently exploring the
possibility of stereochemical alterations on the bicyclo-
[3.3.0]octane template to investigate their self-assembling
propensity, and will report the results in due course.
2.3. Crystallographic data for 3
(C16H26N4O6): M = 370.41, crystal dimensions 0.78 ꢂ
0.04 ꢂ 0.04 mm3, monoclinic, space group C2/c, a =
˚
21.191(8), b = 4.8840(19), c = 17.271(7) A, b = 93.389(6)°;
3
V = 1784.4(12) A ; Z = 4; qcalcd = 1.379 g cmꢃ3, l (Mo-
˚
Ka) = 0.106 mmꢃ1, F(000) = 792, 2hmax = 50.00°, 7770
reflections collected, 1559 unique, 1039 observed
(I > 2r(I)) reflections, 121 refined parameters, R value
0.0820, wR2 = 0.2117 (all data R = 0.1195, wR2 =
0.2370), S = 1.041, minimum and maximum transmissions
0.9218 and 0.9963, respectively, maximum and minimum
2. Experimental
2.1. Tetramethyl 3,7-dihydroxy-bicyclo[3.3.0]octane-
2,4,6,8-tetracarboxylate ð2Þ
ꢃ3
˚
To an ice cooled solution of tetramethyl bicyclo[3.3.0]-
octane-3,7-dione-2,4,6,8-tetracarboxylate 112 (2 g, 5.405
mmol) in methanol (10 ml), sodium borohydride (0.408 g,
10.81 mmol) was added at 0 °C and the resulting reaction
mixture was stirred at room temperature for 4 h. The reac-
tion mixture was diluted with ethyl acetate (10 ml) and
quenched via dropwise addition of 1 N HCl (20 ml). The
product was extracted with ethyl acetate (3 ꢂ 250 ml).
The organic layer was washed with NaHCO3, followed
by water and brine, then dried over anhydrous Na2SO4,
concentrated and the product was purified by column chro-
matography providing 2 as a low melting white semi-solid
1.27 g (yield: 62.6%) Rf = 0.25, 50% EtOAc/pet. ether; mp
residual electron densities +0.743 and ꢃ0.341 e A
.
Crystallographic data of 3 have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication no. CCDC 656550.
Acknowledgements
AMK thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi, for a research fellowship.
This work was funded partly by the International Founda-
tion for Science (IFS), Sweden; Grant No. F/4193-1, and
the Department of Science and Technology (DST), New
Delhi.
1
82–84 °C; H NMR (200 MHz, CDCl3, ppm) d 4.65 (1H,
m) 4.38 (1H, t, J = 13 Hz) 3.72 (3H, s) 3.71 (3H, s) 3.66
(3H, s) 3.65 (3H, s) 3.25–2.92 (8H, m); 13C NMR
(50 MHz, CDCl3, ppm) d 173.9–172.5, 77.6, 77.1, 56.0,
55.2, 54.0, 51.9–50.0, 44.9, 42.7; IR (CHCl3), m (cmꢃ1):
3508, 3020, 2954, 2360, 1731, 1436, 1267, 1215, 1176,
757, 667; LCMS: 375.07 (M+1), 397.04 (M+Na); Anal.
Calcd for C16H22O10: C, 51.34; H, 5.92; Found: C, 51.58;
H, 5.62.
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˜