Synthesis of 1,10-dimethylbicyclo[8.8.8]hexacosane and 1,10- dihydroxybicyclo[8.8.8]hexacosane

Article abstract of DOI:10.1021/ol050714k

(Chemical Equation Presented) 1,10-Dimethylbicyclo[8.8.8]hexacosane (1) and 1,10-dihydroxybicyclo[8.8.8]hexacosane (2) were prepared in 4% yield over seven steps and in 18% yield over three steps, respectively, starting from 1,10-cyclooctadecanedione. The identities and out,out conformations of these compounds were established by single-crystal X-ray analysis.

Full text of DOI:10.1021/ol050714k

ORGANIC
LETTERS
2
005
Vol. 7, No. 14
841-2843
Synthesis of
,10-Dimethylbicyclo[8.8.8]hexacosane
and
2
1
1,10-Dihydroxybicyclo[8.8.8]hexacosane
Ian W. Jones, Yasunari Monguchi, Alice Dawson, Michael D. Carducci, and
Eugene A. Mash*
Department of Chemistry, UniVersity of Arizona, Tucson, Arizona 85721-0041
emash@u.arizona.edu
Received April 4, 2005
ABSTRACT
1
1
,10-Dimethylbicyclo[8.8.8]hexacosane (1) and 1,10-dihydroxybicyclo[8.8.8]hexacosane (2) were prepared in 4% yield over seven steps and in
8% yield over three steps, respectively, starting from 1,10-cyclooctadecanedione. The identities and out,out conformations of these compounds
were established by single-crystal X-ray analysis.
In 1972, Park and Simmons synthesized the diastereomers
1
of bicyclo[8.8.8]hexacosane (Figure 1). Diastereomerism
was due to different configurations at the bridgeheads. The
out,out and in,in structures represent possible conformer
subpopulations of the diastereomer of higher symmetry. The
in,in conformers were thought to predominate on the basis
of unpublished theoretical calculations and on the unreactivity
of this diastereomer to attack by bromine. Synthetic work
on other carbon bicycles capable of exhibiting in/out ster-
eoisomerism has been somewhat limited,2
,3
Figure 1. Representations of conformer subpopulations for the
diastereomers of bicyclo[8.8.8]hexacosane.
(
1) Park, C. H.; Simmons, H. E. J. Am. Chem. Soc. 1972, 94, 7184-
7
186.
(2) (a) Gassman, P. G.; Thummel, R. P. J. Am. Chem. Soc. 1972, 94,
7
9
183-7184. (b) Vinter, J. G.; Hoffmann, H. M. R. J. Am. Chem. Soc. 1974,
6, 5466-5478. (c) Gassman, P. G.; Korn, S. R.; Bailey, T. F.; Johnson,
In contrast with smaller out,out bicyclo[n.n.n]alkanes,
T. H.; Finer, J.; Clardy, J. Tetrahedron Lett. 1979, 20, 3401-3404. (d)
4
which are relatively inflexible, larger homologues should
McMurry, J. E.; Hodge, C. N. J. Am. Chem. Soc. 1984, 106, 6450-6451.
exhibit greater flexibility and conformational diversity.5
Flexibility might be important, for example, in the stepwise
(e) McMurry, J. E.; Lectka, T.; Hodge, C. N. J. Am. Chem. Soc. 1989, 111,
8
4
1
1
867-8872. (f) Kim, S.; Winkler, J. D. Chem. Soc. ReV. 1997, 26, 387-
00. (g) Saunders, M. Krause, N. J. Am. Chem. Soc. 1990, 112, 1791-
795. (h) McMurry, J. E.; Lectka, T. J. Am. Chem. Soc. 1993, 115, 10167-
0173. Considerable work on heteroatom-containing in/out bicyclic molecules
(4) (a) Zimmerman, H. E.; Goldman, T. D.; Hirzel, T. K.; Schmidt, S.
P. J. Org. Chem. 1980, 45, 3933-3951. (b) Kaszynski, P.; Michl, J. J. Am.
Chem. Soc. 1988, 110, 5225-5226.
(5) Saunders has used computational methods to investigate the conformer
populations of many unsubstituted bicyclic alkanes. See: Saunders, M. J.
Comput. Chem. 1989, 10, 203-208.
has also appeared. See: (i) Alder, R. W.; East, S. P. Chem. ReV. 1996, 96,
097-2111.
3) Recently a novel synthesis of bridgehead-substituted out/out bicyclo-
10.10.10]dotriacontanes was described. See: Kurata, H.; Rikitake, N.;
Okumura, A.; Oda, M. Chem. Lett. 2004, 33, 1018-1019.
2
(
[
1
0.1021/ol050714k CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/15/2005

binding to cell surface receptors of two or more bioactive
ligands joined by out,out bicyclo[n.n.n]alkane linkers.
Development of such linkers depends on the availability of
large out,out bicyclo[n.n.n]alkane derivatives. We report
herein syntheses of 1,10-dimethylbicyclo[8.8.8]hexacosane
The 13C NMR spectrum of 9 showed nine peaks for sp3
6
2
carbons and one peak for sp carbon consistent with either
1
1
an in,in or an out,out isomer. Hydrogenation of 9 was
sluggish but proceeded using 10% Pd/C under 90 psi of H
2
and, after 6 days, produced alkane 1 in 97% yield. The
structure of 1 was supported by NMR data, and the out,out
conformation was established by X-ray crystallography (Vide
infra).
(1) and 1,10-dihydroxybicyclo[8.8.8]hexacosane (2), the first
examples of out,out bicyclo[8.8.8]hexacosanes.
The syntheses of 1 and 2 follow a pathway similar to that
established by Park and Simmons but employ modern
synthetic methodology. 1,10-Cyclooctadecanedione (com-
pound 3, Scheme 1) was prepared from sebacoyl chloride
For the synthesis of 2, dione 3 was treated with pente-
1
2
13
nylmagnesium bromide in the presence of CeCl
3
to give
a 1:1 mixture of diols 10 and 11 in 80% yield (Scheme 2).
Scheme 1. Synthesis of
,10-Dimethylbicyclo[8.8.8]hexacosane (1)
Scheme 2. Synthesis of
1,10-Dihydroxybicyclo[8.8.8]hexacosane (2)
1
These diols were separated by flash chromatography and
were independently subjected to olefin metathesis using the
Grubbs first generation catalyst. Although the less polar diol
10 afforded no bicyclic products, the more polar diol 11 gave
bicyclic alkene 12 (double bond geometry unknown) in 42%
1
4
13
yield. The C NMR spectrum of 12 showed eight peaks
3
2
for sp carbons and one peak for sp carbon consistent with
1
5
either an in,in or an out,out isomer. Hydrogenation of 12
was again sluggish but proceeded under forcing conditions
to give alkanediol 2 in quantitative yield. The structure of 2
was supported by NMR data, and the out,out conformation
was established by X-ray crystallography (Vide infra).
Crystals of compounds 1 and 2 were obtained from
pentane and methanol, respectively, and were subjected to
7
by the method of Blomquist. Reaction of 3 with the lithium
enolate derived from trimethyl phosphonoacetate gave an
inseparable 1:1 mixture of diene-diesters 4 in 75% yield.
Copper-mediated conjugate addition of methyllithium pro-
8
ceeded in methylene chloride to give an inseparable 1:1
mixture of diesters 5 in 82% yield. Reduction of 5 to the
corresponding diols 6 (62%), conversion of 6 to the ditosy-
lates 7 (67%), and coupling of 7 with allylmagnesium
bromide gave the dienes 8 (60%). Dienes 8 were inseparable
and were carried forward as a mixture.
1
6,17
single-crystal X-ray analysis.
conformer 1A and its enantiomer were observed in the crystal
of 1, four chiral conformers 2A-D, each possessing C
Whereas a single chiral
2
11) An in,out bicyclic alkene would be distinguished in the 13C NMR
by its lower symmetry.
12) Ashby, E. C.; DePriest, R. N.; Goel, A. B.; Wenderoth, B.; Pham,
(
Ring-closing olefin metathesis using the Grubbs first
(
9
generation catalyst, (Cy
P)
3 2
Cl
2
RudCHPh, produced bicyclic
T. N. J. Org. Chem. 1984, 49, 3545-3556.
1
0
alkene 9 (double bond geometry unknown) in 30% yield.
(13) Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett. 1984,
2
5, 4233-4236.
(
14) The byproduct 1,10,19,28-tetrahydroxytricyclo[26.8.8.810,19]dopenta-
(
6) Maison, W.; Frangioni, J. V.; Pannier, N. Org. Lett. 2004, 6, 4567-
conta-5,23-diene from cyclodimerization of 11 may have been produced
but, being a tetrol, would have been lost during chromatographic purification
of 12.
4
7
4
569.
(7) Blomquist, A. T.; Prager, J.; Wolinsky, J. J. Am. Chem. Soc. 1955,
7, 1804-1806.
(15) Cyclization of trans isomer 10 might have afforded an in,out bicyclic
alkene diol distinguished in the 13C NMR by its lower symmetry, but did
not.
(
8) Asao, N.; Lee, S.; Yamamoto, Y. Tetrahedron Lett. 2003, 44, 4265-
266.
9) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
(
(16) Crystal data for 1: C28H54; M ) 390.71 g mol-1, monoclinic, P21/
c, colorless prism measuring 0.34 mm × 0.21 mm × 0.07 mm, T ) 173(2)
K, a ) 10.639(3), b ) 27.103(8), c ) 10.096(3) Å, â ) 116.417(5)°, V )
Chem., Int. Ed. Engl. 1995, 34, 2039-2041. (b) Grubbs, R. H.; Miller, S.
J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446-452.
3
-3
-1
(10) A minor byproduct believed to be 1,10,19,28-tetramethyltricyclo-
2607.3(14) Å , Z ) 4, Dc ) 0.995 Mg m , µ ) 0.055 mm , Tmax )
10,19
2
[
26.8.8.8
]dopentaconta-5,23-diene from cyclodimerization of 8 was also
0.996, Tmin ) 0.943, GOF on F ) 1.007, R1 ) 0.0688 and wR2 ) 0.1433
produced and was carried forward along with 9.
([I > 2σ(I)), R1 ) 0.1754 and wR2 ) 0.1856 (all data).
Org. Lett., Vol. 7, No. 14, 2005
2
842

1
9
symmetry, were observed in the crystal of 2. Conformers
A and 2C are very nearly enantiomeric except for differ-
determined using MMFF in Spartan ’02 v1.0.4e. Also listed
are the measured values for κ, the bridgehead-to-bridgehead
distance, and γ, the angles formed by the atom attached to
a bridgehead and the two bridgehead atoms. Differences in
κ provide a measure of the flexibility of the bicyclo[8.8.8]-
hexacosane ring. Comparisons of the values of γ provide a
measure of the colinearity of the methyl and bridgehead
carbon atoms of 1 or the oxygen and bridgehead carbon
2
ences in the orientations of the hydroxyl groups. ORTEP
drawings of these conformers are shown in Table 1 along
1
8
with their relative energies after geometry optimization
Table 1. Conformers of 1 and 2 Observed in the Crystals
atoms of 2 (when γ
1
) γ ) 180° the four atoms are
2
colinear). For compound 2 the largest difference in inter-
bridgehead distance, ∆κ, is 0.8 Å (a difference of 15%)
observed for 2A or 2C and 2D. A Monte Carlo search5
for conformations of 2 within 25 kJ of the global minimum
gave a maximum ∆κ of 1.8 Å (a difference of 30%). Close
matches to conformers 2A or 2C and 2D were found within
,20
2
2
.6 and 2.8 kJ of the global energy minimum conformer,
B, respectively. A similar search for conformations of 1
5
,20
within 25 kJ of the global minimum gave a maximum ∆κ
of 1.8 Å (a difference of 29%). The global minimum located
2
1
in this search was a close match to 1A.
Conformer 1A very nearly possesses C
and γ are both close to 180°, indicating near linearity of
the methyl and bridgehead carbon atoms. Conformers 2A-D
possess C symmetry, so γ ) γ for each. The values of γ
2
symmetry, and
γ
1
2
2
1
2
for 2A-D range from 166° to 176°, indicating near linearity
of the oxygen and bridgehead carbon atoms.
In summary, a workable synthesis of bridgehead-substi-
tuted bicyclo[8.8.8]hexacosanes has been demonstrated by
the preparation of compounds 1 and 2. X-ray crystallographic
analyses have confirmed the out,out conformations of these
compounds. Although 1 and 2 resemble smaller homologues
in the near linearity of their bridgehead substituents, they
differ in that they possess considerable flexibility. This fea-
ture is expected to afford utility to bicyclo[8.8.8]hexacosane
derivatives as linkers in biomedical and other applications.
Acknowledgment. This work was supported by grants
R33 CA 95944 and RO1 CA 97360 from the National Cancer
Institute, by grant CHE9610374 from the NSF, and by the
University of Arizona. We thank Matthew A. Lynn for
assistance with computational studies.
Supporting Information Available: Experimental pro-
cedures, spectral characterizations of new compounds, copies
1
13
of the H and C NMR spectra of new compounds, and
X-ray crystallographic information files in CIF format for
compounds 1 and 2. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL050714K
(
17) Crystal data for 2: C26H50O2; M ) 394.66 g mol-1, tetragonal, P41-
2, colorless block measuring 0.21 mm × 0.23 mm × 0.28 mm, T ) 170-
2
(
2) K, a ) 19.4695(10), b ) 19.4695(10), c ) 26.580(2) Å, R ) â ) γ )
3
-3
-1
9
0°, V ) 10075.5(12) Å , Z ) 16, Dc ) 1.041 Mg m , µ ) 0.063 mm ,
2
Tmax ) 0.987, Tmin ) 0.855, GOF on F ) 1.028, R1 ) 0.0945, wR2 )
.2439([I > 2σ(I)), R1 ) 0.1470 and wR2 ) 0.3052 (all data).
18) The authors thank a reviewer for pointing out the proper way to
0
(
perform these calculations.
(19) Halgren, T. A. J. Comput. Chem. 1996, 17, 490 and following papers
in this issue.
(20) The details of this search will appear in a full paper to follow.
(21) The lowest energy in,in conformer of 1 was found 208.4 kJ above
the out,out global minimum. The lowest energy in,out conformer was 72.3
kJ above the out,out global minimum.
a
b
ORTEP structures showing 50% thermal elipsoids. Determined using
c
MMFF in Spartan ’02 v1.0.4e. na ) not applicable. κ is the bridgehead-
d
to-bridgehead distance observed in the crystal structure. γ is the angle
formed by the atom attached to a bridgehead and the two bridgehead atoms
observed in the crystal structure.
Org. Lett., Vol. 7, No. 14, 2005
2843