Crystal engineering of hydroxy group hydrogen bonding: Design and synthesis of new diol lattice inclusion hosts

Article abstract of DOI:10.1021/jo010787r

The diols 7-11 have been synthesized, and their X-ray crystal structures determined, to learn how to influence and control lattice hydroxy group hydrogen bonding using crystal engineering ideas. To obtain new lattice inclusion hosts precise structural rules can be defined which enable the necessary supramolecular interactions to be duplicated. In this manner the helical tubuland 10 and ellipsoidal clathrate 11 hosts were obtained for the first time and their chloroform inclusion compounds characterized. New synthetic routes were utilized to obtain the bicyclo[3.3.2]decane and 9-thiatricyclo[4.3.1.1^3,8] undecane frameworks present in these compounds. The solid-state conformations of bicyclo[3.3.2]decane derivatives 9 and 10 are compared with prior predictions and studies made on this uncommon ring system.

Full text of DOI:10.1021/jo010787r

J . Org. Chem. 2002, 67, 3221-3230
3221
Cr ysta l En gin eer in g of Hyd r oxy Gr ou p Hyd r ogen Bon d in g:
Design a n d Syn th esis of New Diol La ttice In clu sion Hosts
Sungho Kim, Roger Bishop,* Donald C. Craig, Ian G. Dance, and Marcia L. Scudder
School of Chemistry, The University of New South Wales, Sydney 2052, New South Wales, Australia
r.bishop@unsw.edu.au
Received August 2, 2001
The diols 7-11 have been synthesized, and their X-ray crystal structures determined, to learn
how to influence and control lattice hydroxy group hydrogen bonding using crystal engineering
ideas. To obtain new lattice inclusion hosts precise structural rules can be defined which enable
the necessary supramolecular interactions to be duplicated. In this manner the helical tubuland
10 and ellipsoidal clathrate 11 hosts were obtained for the first time and their chloroform inclusion
compounds characterized. New synthetic routes were utilized to obtain the bicyclo[3.3.2]decane
and 9-thiatricyclo[4.3.1.13,8]undecane frameworks present in these compounds. The solid-state
conformations of bicyclo[3.3.2]decane derivatives 9 and 10 are compared with prior predictions
and studies made on this uncommon ring system.
In tr od u ction
Crystal engineering seeks to uncover the roles played
by noncovalent interactions in self-assembly and packing
and then to apply this information in obtaining solids
with designed properties and characteristics.1,2 For some
time we have been developing the helical tubuland family
of alicyclic diols (currently comprising 12 examples and
typified by 1-4), all of which crystallize in the same
crystal space group P3121 (or its enantiomorph P3221).3
Each crystal consists of chirally pure material despite
commencing with a racemic mixture. Hydroxy group
hydrogen bonding results in formation of a network of
helical arrays of diol molecules which enclose parallel
tubes whose contours and dimensions vary considerably
from case to case (Figure 1). These large tubes4 make
these diols potent inclusion hosts capable of trapping a
wide range of guest species which only interact with the
host molecules through van der Waals forces.
We are interested in the design and synthesis of new
members of the helical tubuland family, the investigation
(1) (a) Desiraju, G. R. Crystal Engineering: The Design of Organic
Solids; Elsevier: Amsterdam, 1989. (b) The Crystal as a Supramo-
lecular Entity; Desiraju, G. R., Ed.; Wiley: New York, 1996. (c)
Comprehensive Supramolecular Chemistry; Atwood, J . L., Davies, J .
E. D., MacNicol, D. D., Vo¨gtle, F., Eds.; Pergamon, Oxford, U.K., 1996;
Vols. 1-11. (d) Nangia, A.; Desiraju, G. R. Top. Curr. Chem. 1998,
F igu r e 1. Diagrams a-d represent partial lattice structures
of the typical helical tubuland diols 1-4, respectively. For each,
a slice is shown through one empty tube projected in the ab
plane. Oxygen atoms are stippled, and the van der Waals radii
of selected hydrogen atoms (shown in black) define the empty
tube cross-sectional areas (also colored black).
198, 58.
(2) (a) Aakero¨y, C. B.; Seddon, K. R. Chem. Soc. Rev. 1993, 22, 397.
(b) Mascal, M. Contemp. Org. Synth. 1994, 1, 31. (c) Aakero¨y, C. B.
Acta Crystallogr., Sect. B 1997, 53, 569. (d) Fuhrhop, J .-H.; Rosengar-
ten, B. Synlett 1997, 1015. (e) Zaworotko, M. J . Chem. Commun. 2001,
1.
(3) (a) Bishop, R.; Dance, I. G. Top. Curr. Chem. 1988, 149, 137. (b)
Bishop, R. In Comprehensive Supramolecular Chemistry, Vol. 6: Solid-
state Supramolecular Chemistry: Crystal Engineering; MacNicol, D.
D., Toda, F., Bishop, R., Eds.; Pergamon: Oxford, U.K., 1996; Chapter
4, pp 85-115.
(4) For other tubular assemblies formed using weak forces between
small molecules, see, for example: (a) Allcock, H. R. In Inclusion
Compounds; Atwood, J . L., Davies, J . E. D., MacNicol, D. D., Eds.;
Academic Press: London, 1984; Vol. 1, Chapter 8, pp 351-374. (b)
Hollingsworth, M. D.; Harris, K. D. M. In Comprehensive Supramo-
lecular Chemistry, Vol. 6: Solid-state Supramolecular Chemistry:
Crystal Engineering; MacNicol, D. D., Toda, F., Bishop, R., Eds.;
Pergamon: Oxford, U.K., 1996; Chapter 7, pp 177-237. (c) Pe´rez, C.;
Espinola, C. G.; Foces-Foces, C.; Nun˜ez-Coello, P.; Carrasco, H.; Martin,
J . D. Org. Lett. 2000, 1185.
of their inclusion properties, and understanding the
supramolecular chemistry underpinning their unusual
behavior.5,6 Since the hydroxy group is a particularly
versatile hydrogen-bonding group,7 it is unsurprising that
many other alicyclic diols closely related in structure,
(5) (a) Dance, I. G.; Bishop, R.; Hawkins, S. C.; Lipari, T.; Scudder,
M. L.; Craig, D. C. J . Chem. Soc., Perkin Trans. 2 1986, 1299. (b) Dance,
I. G.; Bishop, R.; Scudder, M. L. J . Chem. Soc., Perkin Trans. 2 1986,
1309. (c) Bishop, R.; Craig, D. C.; Dance, I. G.; Scudder, M. L.;
Marchand, A. P.; Wang, Y. J . Chem. Soc., Perkin Trans. 2 1993, 937.
10.1021/jo010787r CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/11/2002

3222 J . Org. Chem., Vol. 67, No. 10, 2002
Kim et al.
Sch em e 1
receptor (as for familiar host types such as crown ethers,
calixarenes, or cyclodextrins).11 Hence, while this work
involves conventional organic synthesis, it extends be-
yond this to duplicate the precise intermolecular contacts
necessary for formation of a specific crystal space group.
Syn th esis a n d Str u ctu r e of Diol 7. The alicyclic
skeleton of all helical tubulands exhibits a small degree
of twisting about the C2 axis in the solid state. This is
believed to encourage development of hydrogen bonding
in a helical manner. Twist can be attained by conforma-
tional means (e.g. 1-3) or built into the ring skeleton
itself (e.g. 4). In marked contrast, the rigid adamantane
diol 5 forms a layer structure without inclusion proper-
ties.8 The rigid norbornane diol 6 does form a few
unstable inclusion compounds whose structures remain
unknown due to crystal twinning difficulties, but we do
not believe that these are helical tubulates on the basis
of their appearance and behavior.9 Target 7 was selected
since its degree of ring twisting lies between 1 and 6,
and thus, its crystal structure should help define the
limits of rule ii.
The synthesis of diol 7 (Scheme 1) commenced with
the diketone 12.12 Mercuric acetate hydration13 of diene
13 yielded the unsymmetrical diol 14 and the C2-
symmetric isomer 15, whose crystals suffered from twin-
ning disorder and were unsuitable for X-ray structure
determination. The required C2-symmetric diol 7 was
obtained instead by reacting 12 with methyllithium.
Wood and Woo have proposed a solution equilibrium
between two conformers of 12, both of which contain a
twist-boat cyclohexane-1,4-dione ring.12 Their favored
major conformation had a particularly exposed face
opposite to the propano bridge. Our results are in accord
since steric blocking by the propano bridge favored
reagent attack from the opposite side in both the above
reactions.
such as 58 and 6,9 behave quite differently. For a given
diol to form the helical tubuland lattice precise supramo-
lecular requirements must be met. To allow prediction
we have identified those structural features which are
essential to diols forming this lattice and also those
optional features which might be modified or omitted in
designing new examples:10
(i) The diol molecules must have C2 rotational sym-
metry or be capable of achieving this in the solid state
through crystallographic disorder.
(ii) The alicyclic structure should have a small degree
of twist.
(iii) Substituent groups around the periphery are
usually deleterious, but small substituents protruding
into the canal may be permitted.
(iv) A bridge on the opposite side of the hydroxy groups
is optional.
(v) The two hydroxy groups must be syn and be
separated by a molecular bridge.
(vi) The tertiary alcohol groups must have methyl
substituents.
Molecules satisfying all six of these structural require-
ments have a high probability of crystallizing with the
helical tubuland lattice, subject to its formation being
sterically reasonable. If just one rule is broken, then
different lattice packing will occur.
Resu lts
In this paper we present some of the experimental
evidence which was used to determine and validate the
above rules. Each of the diols 7-11, whose syntheses and
crystal structures are described here, were chosen care-
fully to probe specific structural aspects. It should be
emphasized that the targeted inclusion properties depend
on the entire lattice arrangement of diol molecules, not
simply on a molecule interacting with a single guest
Diol 7 failed to include any of the standard test solvents
(see Experimental Section) and also butanone and ethyl
propionate. From the latter solvent it gave needlelike
crystals in the tetragonal space group I41cd.14 Each
hydroxy group forms hydrogen bonds with two neighbors
forming continuous O-H‚‚‚O-H‚‚‚O-H spiral chains
surrounding 41 (or 43) axes along c [Etter graph set15
C(2)]. Eight molecules comprise one helical turn (Figure
(6) (a) Ung, A. T.; Bishop, R.; Craig, D. C.; Dance, I. G.; Rae, A. D.;
Scudder, M. L. J . Inclusion Phenom. 1993, 15, 385. (b) Ung, A. T.;
Gizachew, D.; Bishop, R.; Scudder, M. L.; Dance, I. G.; Craig, D. C. J .
Am. Chem. Soc. 1995, 117, 8745. (c) Yue, W.; Bishop, R.; Scudder, M.
L.; Craig, D. C. Chem. Lett. 1998, 803. (d) Yue, W.; Bishop, R.; Craig,
D. C.; Scudder, M. L. Tetrahedron 2000, 56, 6667.
(7) J effrey, G. A.; Saenger, W. Hydrogen Bonding in Biological
Systems; Springer-Verlag: Berlin, 1994.
(8) Hawkins, S. C.; Scudder, M. L.; Craig, D. C.; Rae, A. D.; Abdul
Raof, R. B.; Bishop, R.; Dance, I. G. J . Chem. Soc., Perkin Trans. 2
1990, 855.
(11) Inclusion Compounds; Atwood, J . L., Davies, J . E. D., MacNicol,
D. D., Eds.; Academic Press: London, 1984; Vols. 1-3. Inclusion
Compounds; Atwood, J . L., Davies, J . E. D., MacNicol, D. D., Eds.;
Oxford University Press: Oxford, U.K., 1991; Vols. 4 and 5.
(12) Wood, G.; Woo, E. P. Can. J . Chem. 1968, 46, 3713.
(13) Brown, H. C.; Geohegan, P. J . J . Org. Chem. 1970, 35, 1844.
(14) Crystal structure of 7: C11H20O2 (Mr ) 184.3); I41cd; a, b 15.054-
(3), c 18.240(4) Å; V 4134(1) Å3; Z 16; R 0.039; Rw 0.038 for 413 observed
reflections.
(9) Bishop, R. Unpublished results.
(10) (a) Bishop, R.; Dance, I. G.; Hawkins, S. C.; Scudder, M. L. J .
Inclusion Phenom. 1987, 5, 229. (b) Bishop, R.; Craig, D. C.; Scudder,
M. L.; Marchand, A. P.; Liu, Z. J . Chem. Soc., Perkin Trans. 2 1995,
1295.
(15) (a) Etter, M. C. Acc. Chem. Res. 1990, 23, 120. (b) Etter, M. C.
J . Phys. Chem. 1991, 95, 4601.

Diol Lattice Inclusion Hosts
J . Org. Chem., Vol. 67, No. 10, 2002 3223
F igu r e 3. Space-filling representations of (a) diol 1 and (b)
diol 8. Note the similar environments around their hydroxy
groups but the large difference in their central regions.
Sch em e 2
with pairs of opposite handedness (B) in the sequence
-A-A-B-B-A-A-B-B-. In crystalline 7 the enanti-
omers simply alternate -A-B-A-B- along the helix.
F igu r e 2. 8-fold repeat helical hydroxy group hydrogen-
bonding arrangement present in solid diol 7, showing hydrogen
bonds as dashed lines: (a) drawn with the c axis vertical, with
hydrogen atoms omitted for clarity; (b) unit cell viewed down
c showing the recurved nature of the hydrogen bonding motif.
Here the diol molecules are abbreviated to hollow spacer rods
attached to two oxygen atoms (stippled).
Syn th esis a n d Str u ctu r e of Diol 8. Space-filling
models of diol 1 indicated that additional methyl substi-
tution at most ring positions would result in unacceptable
steric bulk around the hydroxy groups. The one exception,
preserving C2 symmetry, was the endo-4,endo-8-dimethyl
derivative 8 (Figure 3), which therefore was synthesized
(Scheme 2) to test the substitution rule iii.
2a). The second diol hydroxy groups contribute to further
helices giving a three-dimensional network lattice where
each hydrogen bonded helix is surrounded by four
equivalent helices of the opposite handedness. Diols
which are involved in four neighboring helices abut and
interact through hydrocarbon dispersion forces. Unlike
the helical tubulands, however, there is insufficient
interhelical space for guest inclusion.
The view down c (Figure 2b) shows the hydrogen-
bonded helices to have a complex recurved projection. We
have previously reported recurved helices in the struc-
tures of diols 16 and 17.16 The former has a 4-fold diol
repeat, while 17 has an 8-fold repeat unit. In both
instances pairs of diols of one handedness (A) alternate
Reduction of dione 1817,18 (hydrogenation followed by
J ones’ oxidation)19 gave endo-4,endo-8-dimethylbicyclo-
[3.3.1]nonane-2,6-dione (19).20 Since the exo faces of the
bicyclo[3.3.1]nonane ring system are more exposed than
its endo faces, hydrogenation of 18 occurs stereoselec-
tively. Wittig reaction gave diene 20, which was then
epoxidized. Although Payne oxidation21 of the diene was
(19) Bowers, A.; Halsall, T. G.; J ones, E. R. H.; Lemin, A. J . J . Chem.
Soc. 1953, 2548.
(20) Hydrogenation of 18 to 19 has been carried out previously:
Doerner, T.; Gleiter, R.; Robbins, T. A.; Chayangkoon, P.; Lightner,
D. A. J . Am. Chem. Soc. 1992, 114, 3235. The product was tentatively
assigned the opposite stereochemistry on 1H NMR grounds but the
present endo, endo interpretation is now agreed.
(16) Hawkins, S. C.; Bishop, R.; Craig, D. C.; Dance, I. G.; Rae, A.
D.; Scudder, M. L. J . Chem. Soc., Perkin Trans. 2 1993, 1737.
(17) Knoevenagel, E.; Bialon, K.; Ruschhaupt, W.; Schneider, G.;
Croner, Fr.; Sa¨nger, W. Chem. Ber. 1903, 36, 2136.
(21) (a) Payne, G. B.; Deming, P. H.; Williams, P. H. J . Org. Chem.
1961, 26, 659. (b) Payne, G. B. Tetrahedron 1962, 18, 763.
(18) Knott, P. A.; Mellor, J . M. J . Chem. Soc. C 1971, 670.

3224 J . Org. Chem., Vol. 67, No. 10, 2002
Kim et al.
Sch em e 3
Sch em e 4
dione, presumably the 2,7-isomer, was also formed. There
is evidence that exo-aminomethyl isomers show much
greater selectivity in such ring expansions than the
corresponding endo isomers.25
F igu r e 4. Edge-on view of two hydrogen-bonded bilayers
formed by diol 8 showing for each the interior where the
hydrogen bonds are located and the outer hydrocarbon sur-
faces. Oxygen atoms are stippled.
We therefore applied this concept to making 9 (Scheme
4). Bicyclo[2.2.2]oct-7-ene-2,5-dione (24)26 was reacted
with trimethylsilyl cyanide (TMSCN) to yield the bis(silyl
cyanohydrin) 25, which was then converted into the key
bis(amino alcohol) intermediate 26. The Momose27
TMSCN addition conditions were used here (whereby the
process is catalyzed by KCN-crown ether) rather than
the earlier Evans zinc iodide procedure.28 Double ring
expansion of 26 (using NaNO2-AcOH-H2O) afforded
bicyclo[3.3.2]dec-9-ene-2,6-dione (27), plus a small amount
of the 2,7-dione isomer. Finally, reaction of methyllithium
on the more exposed exo faces of 27 provided the target
9.
This compound showed no inclusion using the standard
test solvents but underwent self-resolution from chloro-
form solution yielding enantiomerically pure crystals in
tetragonal space group P41212 (and its enantiomorph).29
Figure 5a shows the molecular structure and conforma-
tion of 9 in the solid state. This ORTEP diagram, and
all others in this paper, are drawn at the 10% probability
level. The diol molecules once again form bilayers where
each -O-H takes part in one donor and one acceptor
hydrogen bond. In this case, however, the molecules
forming the bilayers are linked by (O-H)4 cycles (Figure
5b). This motif [graph set15 R44(8)] has been found to be
commonplace in other solid diol structures.30 The unit
cell contains parts of four stacked bilayers, with only
hydrocarbon contacts between these, related by a 41 (or
43) axis.
a slow reaction, we found this to be cleaner and higher
yielding than use of m-CPBA. Reaction again took place
mainly on the more exposed exo faces to yield the bis-
(epoxide) 21. Reductive ring opening then afforded the
target compound 8.
Diol 8 showed no inclusion behavior with any of the
test solvents and crystallized from chloroform in the
monoclinic space group P21/c. The X-ray determination22
confirmed the molecular structure and the proposed
stereochemistry and showed that the molecules were in
the usually favored twin-chair conformation with both
endo-methyl groups equatorial. As usual, each hydroxy
group participates in one donor and one acceptor hydro-
gen bond. The diol molecules assemble in the ac plane
as bilayers with hydrocarbon exterior surfaces as il-
lustrated in Figure 4. The hydroxy groups form parallel
hydrogen-bonded helical chains along c [graph set15 C(2)]
with the enantiomer ordering sequence -A-A-B-B-
A-A-B-B-. These chains also exhibit a recurved helical
projection.
Syn th esis a n d Str u ctu r e of Diol 9. Compound 9 is
an excellent probe for rule v, the requirement (or other-
wise) for a molecular bridge syn to the hydroxy substit-
uents. The bicyclo[3.3.2]decane ring system, with its two
conjoined seven-membered rings, has received sparse
attention compared to its common bicyclo[3.3.1]nonane
homologue, and no published synthetic routes provided
suitably functionalized C2 and C6 positions. In other
work, however, Borden had doubly ring-expanded the
diketone 12 into bicyclo[3.3.3]undecane-2,6-dione (23)
(Scheme 3).23 In this process the bis(amino alcohol) 22
was subjected to double Tiffeneau-Demjanov ring ex-
pansion during which the least-substituted carbons
migrated preferentially.24 A smaller amount of a second
Syn th esis a n d Str u ctu r e of Diol 10. A similar ring-
expansion sequence led from the saturated dione 2831 to
(25) This appears to be general; see for example: (a) Miyashita, M.;
Yoshikoshi, A. J . Am. Chem. Soc. 1974, 86, 1917. (b) Momose, T.;
Muraoka, O.; Shimada, N.; Tsujimoto, C.; Minematsu, T. Chem. Pharm.
Bull. 1989, 37, 1909.
(26) J efford, C. W.; Wallace, T. W.; Acar, M. J . Org. Chem. 1977,
42, 1654.
(27) Momose, T.; Yoshizawa, E.; Muraoka, O. Synth. Commun. 1985,
15, 17.
(28) (a) Evans, D. A.; Carroll, G. L.; Truesdale, L. K. J . Org. Chem.
1974, 39, 914. (b) Groutas, W. C.; Felker, D. Synthesis 1980, 861.
(22) Crystal structure of 8: C13H24O2 (Mr ) 212.3); P21/c; a 7.3920-
(4), b 18.8029(6), c 9.7706(5) Å; â 119.469(2)°; V 1182.3(1) Å3; Z 4; R
0.041; Rw 0.074 for 1959 observed reflections.
(23) (a) Greenhouse, R.; Borden, W. T.; Ravindranathan, T.; Hirotsu,
K.; Clardy, J . J . Am. Chem. Soc. 1977, 99, 6955. (b) Greenhouse, R.;
Ravindranathan, R.; Borden, W. T. J . Am. Chem. Soc. 1976, 98, 6738.
(24) For an overview of one carbon ring expansions of bicyclic
ketones, see: Krow, G. R. Tetrahedron 1987, 43, 3.
(29) Crystal structure of 9:
C12H20O2 (Mr ) 196.3); P41212; a, b
7.3548(3), c 41.500(3) Å; V 2244.9(2) Å3; Z 8; R 0.038; Rw 0.052 for
1123 observed reflections.
(30) Hawkins, S. C.; Scudder, M. L.; Craig, D. C.; Rae, A. D.; Abdul
Raof, R. B.; Bishop, R.; Dance, I. G. J . Chem. Soc., Perkin Trans. 1
1990, 855.
(31) Grob, C. A.; Weiss, A. Helv. Chim. Acta 1960, 43, 1390.

Diol Lattice Inclusion Hosts
J . Org. Chem., Vol. 67, No. 10, 2002 3225
F igu r e 6. ORTEP diagram of the molecular structure of 2,6-
dimethylbicyclo[3.3.2]decane-exo-2,exo-6-diol (10), showing its
twin twist-chair conformation in the solid state.
ring expansion afforded a crude product whose 13C NMR
data indicated formation of the diones 31:32 in a ratio of
1:4. Because of their different symmetry these compounds
exhibit 10 or 5 carbon peaks, respectively.
Wittig reaction on pure 32 gave the corresponding
diene which underwent Payne oxidation21 on its more
exposed exo faces to yield bis(epoxide) 33. Once again,
the use of m-CPBA was less satisfactory. Reductive ring
opening finally afforded the target diol 10. In this case,
the diene failed to react completely with mercuric acetate
so this method could not be used to generate 10 directly.
Steric retardation of Hg(OAc)2 addition reactions is well
documented.13
Crystals were grown by concentration of a chloroform
solution of 10. These were found to have the composition
(10)3‚1.5CHCl3 and belong to trigonal space group P31-
21.33 Figure 6 shows the molecular structure and con-
formation of diol 10 in this material. Host 10 is a new
member of the helical tubuland family, with lattice
symmetry identical to the examples 1-4 described briefly
in the Introduction and more fully in the literature.3 Once
again the hydrogen bonding graph set15 is C(2). Prior to
the synthesis of 10, we predicted the host canal topology
which it might assume. This model, based on the crystal
structure of 1 with homologation of the ring skeleton,
indicated a wide canal with nearly circular cross section.
The experimental result proved to be remarkably similar.
Its unobstructed canal cross-sectional area (Figure 7a)
is the largest so far observed (36.7 Å2) for the helical
tubuland family and has a maximum canal diameter of
9.13 Å. The chloroform guests are located near the canal
walls, with three guests every two unit cell lengths, hence
the 2:1 host-guest stoichiometry. Figure 7b shows a
projection view of a slice through four parallel canals
formed by helical tubuland 10.
F igu r e 5. (a) ORTEP diagram of the molecular structure of
2,6-dimethylbicyclo[3.3.2]dec-9-ene-endo-2,endo-6-diol (9), show-
ing its eclipsed twin-chair conformation in the solid state. (b)
Hydrogen-bonded lattice present in solid 9 viewed down c and
showing the (O-H)4 cycles. For clarity, the diol molecules are
drawn as hollow spacer rods connecting two oxygen atoms
(stippled). Hydrogen bonds are indicated by dashed lines.
Sch em e 5
Syn th esis a n d Str u ctu r e of Diol 11. Our earlier
work on thiaadamantane diols had shown that the sulfur
atom did not intervene in the hydrogen-bonding network
if the hydroxy groups were anti but that intramolecular
-O-H‚‚‚S hydrogen bonds were produced in the syn
case.16 Hence, the stereochemistry of diol 11 was specif-
bicyclo[3.3.2]decane-2,6-dione (32) (Scheme 5). Some
difficulty was encountered removing the silyl groups of
intermediate 29, and the use of borane-dimethyl sul-
fide32 proved the most effective route to 30. The double
(32) Brown, H. C.; Choi, Y. M.; Narasimhan, S. J . Org. Chem. 1982,
47, 3153.
(33) Crystal structure of 10: (C12H22O2)3‚1.5CHCl3 (Mr ) 774.0); P31-
21; a, b 13.3834(6), c 7.0257(5) Å; V 1089.8(1) Å3; Z 1; R 0.066; Rw
0.078 for 1088 observed reflections.

3226 J . Org. Chem., Vol. 67, No. 10, 2002
Kim et al.
F igu r e 8. Lattice structure of the ellipsoidal clathrate (11)4‚
CHCl3 viewed down the canal axis c and showing the chloro-
form guest molecules. Hydrogen bonds are indicated by dashed
linkages, and host hydrogens are omitted for clarity. The
following atom coding is used: sulfur (black); oxygen (stip-
pling); chlorine (hatching); guest carbon (black); guest hydro-
gen (stippling).
Sch em e 6
group I41/acd and have the composition (11)4‚CHCl3.34
This new inclusion system is isostructural35 with that of
the ellipsoidal clathrate structure formed by diol 2 with
small guest molecules [graph set15 R44(8)]. The host
lattice is the outcome of two interpenetrating, but uncon-
nected, sublattices of hydrogen-bonded diol molecules.
Guest molecules occupy ellipsoidal cavities situated
between the two intertwined sublattices (Figure 8).
Adjacent guests are separated by c/2 along crystal-
lographic 2-fold axes parallel to c. In this structure the
sulfur atoms simply mimic the corresponding methylene
groups present in the compounds (2)4‚guest. They are
located away from the center of the cavity and thus avoid
any contact with the enclosed guest molecules.
F igu r e 7. (a) Projection view in the ab plane of just one of
the parallel tubes present in (10)3‚1.5CHCl3 showing a typical
orientation of the chloroform guest. The following atom coding
is used: oxygen (heavy stippling); chlorine (horizontal hatch-
ing); chloroform hydrogen (light stippling). (b) Section through
the helical tubuland lattice showing a projection in the ab
plane of four parallel host tubes with the guest molecules
omitted. Hydrogen atoms are colored black, and oxygens are
stippled. The van der Waals radii of the host atoms delineate
the tube walls producing a nearly circular cross section.
ically targeted to take advantage of this knowledge. This
compound extends the substituent rule iii since a het-
eroatom is incorporated within its ring skeleton.
Bicyclo[3.3.2]decane-2,6-dione (32) was converted into
its bis(pyrrolidino enamine) 34 and then reacted with
sulfur dichloride to give a modest yield of the tricyclic
dione 35 (Scheme 6). Attack by methylmagnesium chlo-
ride in THF took place from the side of the sulfur atom
to produce mainly the required diol 11. Selective alky-
lation from this direction would be expected on steric
grounds alone (as for the carbocyclic analogue 2) but
could be assisted further by coordination of the sulfur
and the organometallic reagent. Methyllithium was a less
satisfactory methylating reagent in this case. Compounds
11 and 35 are the first reported examples of the
9-thiatricyclo[4.3.1.13,8]undecane ring system.
Discu ssion
Con for m a tion s of th e Bicyclo[3.3.2]d eca n e Com -
p ou n d s 9 a n d 10. Parker,36 Engler,37 and Osawa38 have
(34) Crystal structure of 11: (C12H20O2S)4‚CHCl3 (Mr ) 1032.8); I41/
acd; a, b ) 23.042(3), c 19.022(3) Å; V 10099(2) Å3; Z 8; R 0.037; Rw
0.036 for 912 observed reflections.
(35) Hawkins, S. C.; Bishop, R.; Dance, I. G.; Lipari, T.; Craig, D.
C.; Scudder, M. L. J . Chem. Soc., Perkin Trans. 2 1993, 1729.
(36) Doyle, M.; Hafter, R.; Parker, W. J . Chem. Soc., Perkin Trans.
1 1977, 364.
(37) Engler, E. M.; Chang, L.; Schleyer, P. v. R. Tetrahedron Lett.
1972, 2525.
(38) Osawa, E.; Aigami, K.; Inamoto, Y. J . Chem. Soc., Perkin Trans.
2 1979, 172.
Crystals were grown by evaporation of a chloroform
solution of 11 and found to occupy the tetragonal space

Diol Lattice Inclusion Hosts
J . Org. Chem., Vol. 67, No. 10, 2002 3227
independently discussed the various conformers likely to
exist in bicyclo[3.3.2]decane ring compounds. The twist
twin-chair with a staggered ethano bridge and the boat-
chair with an eclipsed ethano bridge were determined
to be the lowest energy arrangements. For the parent
compound and simple derivatives these would probably
be in equilibrium in solution. As pointed out by Parker,36
introduction of a double bond in the two-carbon bridge
would markedly restrict the flexibility of the molecule
(by fixing the coplanarity of carbons 1, 5, 9, and 10) and
this would favor the boat-chair. Support for this is
available from the crystal structure of the quinoxaline
derivative 36.39 This is the only bicyclo[3.3.2]decane
derivative for which X-ray structural data have been
available up until now, so the new data on compounds 9
and 10 are of considerable interest.
In contradiction of the above, 9 adopts the classical
twin-chair conformation in the solid state (Figure 5). The
transannular C3‚‚‚C7 separation of 3.06 Å is identical
to that recorded for the flattened twin-chair conformation
adopted by 1-p-bromophenylsulfonyloxymethyl-5-meth-
ylbicyclo[3.3.1]nonan-9-ol.40 Engler,37 however, has al-
ready remarked that the conformation observed will
depend very much on the precise substitution pattern,
because the various conformers of the bicyclo[3.3.2]-
decane ring system are very close in energy. In both 9
and 10 the hydroxy group hydrogen bonding may also
play a role in conformational control. Compound 10
adopts the twist twin-chair arrangement with a stag-
gered ethano bridge (Figure 6) in its helical tubuland
lattice. The cross-ring C3‚‚‚C7 separation is 3.04 Å in this
structure.
cannot quite twist sufficiently to satisfy rule ii, which
encourages 3-fold hydrogen-bonding helicity to develop.
The unexpected behavior of 8 was entirely different
from that of diol 1. Figure 3 shows space-filling models
from which two observations can be made. First, the
immediate steric environment around the hydroxy groups
of both molecules is extremely similar so their minor
differences are unlikely to have caused this dramatic
change. However, the two additional methyl groups of 8
make the latter diol considerably wider and bulkier. Since
the diol molecules have to stack in eclipsed columns in
the helical tubuland lattice, this volume increase in the
alicyclic spacer molecule is critical. Hence substituent
groups should be avoided leading to rule iii.
If the syn-diol hydroxy groups are not separated by a
bridge, as in diol 9, then they can hydrogen bond easily
to give layer structures through use of (O-H)4 cycles.
This supramolecular motif is a very favorable one among
alicyclic diols,30 but the presence of a molecular bridge
can suppress its formation in favor of helical hydrogen-
bonded arrangements. Hence adherence to rule v is
crucial. During crystallization of diol 9 self-resolution did
take place to yield a conglomerate,41 where each crystal
is chirally pure. In this instance bilayers are produced,
and helicity is also present with four stacked bilayers
being related by a 41 axis (space group P41212) or a 43
axis (P43212), respectively.
Self-resolution of racemic 10 took place on its crystal-
lization, chloroform was included, the space group was
P3121, and its crystal structure proved this diol to be a
further example of the helical tubuland family. The
molecular structure of 10 satisfied all five of the molec-
ular rules, and molecular modeling enabled a sound
prediction of its tubular dimensions to be made in
advance of its preparation.42
Similarly, diol 11 satisfied all the molecular rules and
proved to be a further example of the diol inclusion
family. It should be noted that diol 2 forms ellipsoidal
clathrates (containing both diol enantiomers in space
group I41/acd) with small guests and helical tubulates
(containing one enantiomer only in space group P3121)
with large guests.35 This dual nature has not been
observed for the other helical tubuland diols.3 From a
solution of 11 in chloroform, the ellipsoidal clathrate
structure (11)4‚CHCl3 results where the sulfur atom
effectively mimics a methylene group in 2. It is probable
that 11 will show similar structural duality, and further
investigation is in progress. Furthermore, we expect diol
11 to exhibit distinctive inclusion behavior when con-
fronted by guests potentially able to coordinate with
sulfur.
The apparent transannular C3-H‚‚‚H-C7 hydrogen
separations in 9 and 10 are only 1.83 and 1.86 Å,
respectively. These short contact distances between the
two endo-hydrogen atoms will be inaccurate, however,
since we used only calculated hydrogen positions in our
X-ray determinations. The true separations are almost
certainly larger, and a value of 2.05 Å has been calculated
by Osawa for the parent hydrocarbon.37
Helica l Tu bu la n d Str u ctu r a l Ru les
Formation of the helical tubuland lattice requires
formation of a helical hydrogen-bonded structure and also
self-resolution of the diol molecules to give a crystalline
conglomerate.41 Very special supramolecular conditions
are required to bring about these ends, but the structural
membership rules allow us to design molecules close to,
or within, this window of opportunity. Hence prediction
and control of the hydrogen-bonding and lattice packing
can be achieved.
It should also be noted that 11 is the first heterocyclic
example of these diol inclusion hosts. An earlier approach
to such a compound had failed, since the ether oxygen
atom of diol 37 was found to participate in the hydroxy
hydrogen-bonding network, and therefore, a totally dif-
ferent structure without inclusion properties resulted.43
The key conclusion here is that a heteroatom can be
placed within a molecular bridge, provided that C2
symmetry is retained and that it cannot interfere with
the hydrogen-bonding network. The validity of the struc-
Solid diol 7 is unresolved and the net lattice structure
is achiral, but its molecules do hydrogen bond in a helical
manner. In structural terms the bridged cyclohexane ring
(39) (a) Hafter, R.; Murray-Rust, J .; Murray-Rust, P.; Parker, W.
J . Chem. Soc., Chem. Commun. 1972, 1127. (b) Murray-Rust, J .;
Murray-Rust, P. Acta Crystallogr., Sect. B 1975, 31, 310.
(40) Brown, W. A. C.; Martin, J .; Sim, G. A. J . Chem. Soc. 1965,
1844.
(41) J acques, J .; Collet, A.; Wilen, S. H. Enantiomers, Racemates,
and Resolutions; Wiley: New York, 1981.
(42) Bishop, R.; Craig, D. C.; Dance, I. G.; Kim, S.; Mallick, M. A.
I.; Pich, K. C.; Scudder, M. L. Supramol. Chem. 1993, 1, 171.
(43) Pich, K. C.; Bishop, R.; Craig, D. C.; Dance, I. G.; Rae, A. D.;
Scudder, M. L. Struct. Chem. 1993, 4, 41.

3228 J . Org. Chem., Vol. 67, No. 10, 2002
Kim et al.
dried (Na2SO4). Evaporation of solvent from the filtrate yielded
a yellow oil from which solid formed. Filtration, followed by
recrystallization from CHCl3, gave the exo,exo-diol 7 as fine
needles (0.33 g, 46%), mp 126-129 °C: IR (paraffin mull) 3350
tural rules has been considerably strengthened by these
results. They confirm the value of using defined struc-
tural requirements as part of synthetic strategy toward
a required supramolecular outcome, and two improve-
ments can be made.
First, substitution can be tolerated within the carbocy-
clic framework provided the heteroatom does not inter-
fere with the hydrogen-bonding network. A series of
heteroatom helical tubuland hosts now must be consid-
ered as being potentially possible.
Second, increasing the width of the alicyclic moiety
may result in a diol which simply cannot pack properly
in the 3-fold hydrogen-bonded spine structure of the
helical tubuland lattice. Hence, steric problems may
override the other structural factors.
1
s cm-1; H NMR (500 MHz, CDCl3) δ 1.34 (s, 6H), 1.44-1.51
(m, 4H), 1.70-1.81 (m, 6H), 1.91-1.96 (m, 2H), 2.14-2.21 (m,
2H); 13C NMR (126 MHz, CDCl3) δ 21.7 (CH2), 29.6 (CH2), 33.1
(CH3), 42.0 (CH2), 44.0 (CH), 71.7 (C). Anal. Calcd for
C
11H20O2: C, 71.70; H, 10.94. Found: C, 71.53; H, 11.17.
en d o-4,en d o-8-Dim et h ylb icyclo[3.3.1]n on a n e-2,6-d i-
on e (19). Diketone 1817,18 (1.00 g, 5.7 mmol) was dissolved in
methanol (20 mL). Adams catalyst (20 mg) and perchloric acid
(70%; 3 drops) were added, and the mixture was hydrogenated
at room temperature and 1 atm. After filtration and removal
of solvent, the residual mixture was subjected to the standard
J ones’ oxidation procedure.19 The final CHCl3 extract was
evaporated to give the diketone 1920 as a colorless oil (0.78 g,
76%), bp ca. 250 °C: IR (neat) 1715 s cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.74-0.83 (m, 6H), 1.71-1.86 (m, 2H), 1.99-2.16 (m,
4H), 2.35-2.49 (m, 2H), 2.51-2.57 (m, 2H); 13C NMR (126
MHz, CDCl3) δ 19.6 (CH3), 32.9 (CH2), 34.3 (CH), 47.6 (CH2),
49.9 (CH), 210.2 (C). Anal. Calcd for C11H16O2: C, 73.30; H,
8.95. Found: C, 73.15; H, 9.21.
Exp er im en ta l Section
General procedures have been described.16 Elemental analy-
ses were carried out at UNSW by Dr. H. P. Pham. Petroleum
ether refers to bp 60-80 °C material. Dry THF and DME
solvents were freshly distilled from LiAlH4, and dry DMSO
was freshly distilled under reduced pressure from CaH2.
6,8-Bis(m eth ylid en e)bicyclo[3.2.2]n on a n e (13). Dike-
tone 1212 (6.08 g, 0.04 mol) was added to a stirred solution of
methylidenetriphenylphosphorane (0.082 mol) in dry DMSO
under N2, following the Corey procedure and workup.44 Mi-
crodistillation gave the diene 13 (2.98 g, 50%), bp 195-198
en d o-2,en d o-4,en d o-6,en d o-8-Tetr a m eth ylbicyclo[3.3.1]-
n on a n e-exo-2,exo-6- d iol (8). Dione 19 (1.50 g, 8.33 mmol)
was reacted with methylidenetriphenylphosphorane (18.3
mmol) in dry DMSO by following the Corey procedure.44 After
4 h of stirring at room temperature, the reaction was worked
up in the usual manner. Microdistillation gave diene 20 as a
colorless oil (0.72 g, 49%), bp 200-203 °C: IR (neat) 3080 m,
2980 s, 2950 s, 2920 s, 2900 s, 1640 s, 1475 m, 1460 s, 1455 s,
°C: IR (neat) 3070 m, 1645 m, 890 s, 870 s cm-1 1H NMR
;
1380 m, 1110 s, 1010 m, 895 s cm-1 13C NMR (126 MHz,
;
(500 MHz, CDCl3) δ 1.50-1.56 (m, 2H), 1.66-1.70 (m, 4H),
2.43-2.45 (m, 4H) 2.61-2.63 (m, 2H), 4.71-4.72 (m, 2H),
4.77-4.79 (m, 2H); 13C NMR (25 MHz, CDCl3) δ 21.1 (CH2),
34.7 (CH2), 35.6 (CH2), 39.4 (CH), 108.0 (CH2), 150.8 (C). Anal.
Calcd for C11H16: C, 89.12; H, 10.88. Found: C, 89.53; H, 11.08.
6,8-Dim eth ylbicyclo[3.2.2]n on an e-en do-6,exo-8-diol (14).
A solution of 13 (2.87 g, 29.4 mmol) in dry THF (20 mL) was
reacted with a solution of mercuric acetate (12.5 g, 38.8 mmol)
in water (250 mL) and dry THF (250 mL) following Brown’s
procedure.13 Evaporation of ethyl acetate solvent gave a gum
which was heated with EtOAc and filtered, and the solvent
was evaporated from the filtrate. 13C NMR indicated two diol
products. The mixture was chromatographed on activated
alumina using petroleum ether, followed by increasing amounts
of diethyl ether and then increasing amounts of chloroform.
The endo, exo isomer 14 was obtained (95:5 Et2O/CHCl3) (0.57
g, 16%), mp 94-96 °C: IR (paraffin mull) 3330 s cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.34 (s, 3H), 1.52 (s, 3H), 1.38-1.82 (m,
11H, reduced to 9H on D2O exchange), 1.94-2.01 (m, 1H),
2.09-2.20 (m, 1H), 2.27-2.35 (m, 1H); 13C NMR (126 MHz,
CDCl3) δ 21.1 (CH2), 28.7 (CH2), 30.7 (CH3), 30.9 (CH2), 32.7
(CH3), 40.6 (CH2), 40.9 (CH2), 42.5 (CH), 44.5 (CH), 71.9 (C),
72.2 (C). Anal. Calcd for C11H20O2: C, 71.70; H, 10.94. Found:
C, 71.42; H, 11.04.
6,8-Dim et h ylb icyclo[3.2.2]n on a n e-en d o-6,en d o-8-d iol
(15). Further elution of the above column (Et2O/CHCl3 80:20)
gave the endo,endo-diol 15 (0.49 g, 14%), mp 98-100 °C: IR
(paraffin mull) 3270 s cm-1; 1H NMR (300 MHz, CDCl3) δ 1.27
(s, 6H), 1.45-1.69 (m, 8H), 1.86-1.89 (m, 2H), 2.15-2.22 (dd,
2H, J 15.4, 7.5), 3.76 (br s, 2H, exchd with D2O); 13C NMR
(126 MHz, CDCl3) δ 20.4 (CH2), 28.4 (CH3), 29.8 (CH2), 39.6
(CH2), 41.6 (CH), 72.1 (C). Anal. Calcd for C11H20O2: C, 71.70;
H, 10.94. Found: C, 71.85; H, 11.16.
6,8-Dim eth ylbicyclo[3.2.2]n on a n e-exo-6,exo-8-d iol (7).
Diketone 12 (0.61 g, 4.0 mmol) was dissolved in dry THF (25
mL) and stirred under N2. MeLi solution in diethyl ether (1.4
M; 7.1 mL, 0.01 mol) was added by syringe, and then the
reaction was refluxed overnight. Wet Et2O was added, followed
by H2O, and the ether layer separated. The aqueous layer was
extracted with CHCl3, and the combined organic extracts were
CDCl3) δ 20.3 (CH3), 35.9 (CH), 38.3 (CH2), 40.6 (CH2), 43.9
(CH), 109.9 (CH2), 148.9 (C).
The diene (0.70 g, 4.0 mmol) was added to a mixture of
methanol (30 mL), acetonitrile (0.60 g), and KHCO3 (0.14 g),
which was stirred at 0 °C. Hydrogen peroxide (27.5% w/w, 1.04
g) was added dropwise. After addition was complete, the
mixture was refluxed for 90 h. After cooling, brine was added
and organic material extracted using CH2Cl2. The combined
extracts were washed with water, then dried (Na2SO4). Evapo-
ration of solvent from the filtrate gave bis(epoxide) 21 as an
oil (0.50 g, 60%): IR (neat) 3050 w, 2980 s, 2950 s, 2920 s,
2890 s, 1470 s, 1380 w, 1115 m, 935 s, 925 s, 780 m, 760 m
cm-1
.
Crude 21 (0.50 g) was dissolved in dry THF (10 mL), and
the solution was added dropwise to a suspension of LiAlH4
(0.76 g, 20 mmol) in dry THF (30 mL) at 0 °C. After stirring
at room temperature overnight, wet Et2O and then aqueous
Na2SO4 solution were added. The ethereal solution was
decanted, the aqueous phase was extracted with further Et2O,
and the extracts were dried (Na2SO4). Evaporation of solvent
from the filtrate gave dialcohol 8 as a white solid (0.43 g, 84%),
mp 205-206 °C (from Et2O): IR (paraffin mull) 3430 s cm-1
;
1
MS m/z 194 [(M - 18), 7%]; H NMR [300 MHz, (CD3)2SO] δ
0.94 (d, 6H, J 6.81), 1.13 (s, 6H), 1.34-1.39 (m, 6H), 1.92 (t,
2H, J 3.14), 2.07-2.16 (m, 2H), 3.91 (s, 2H, exchd with D2O);
13C NMR [126 MHz, (CD3)2SO] δ 22.5 (CH3), 31.7 (CH2), 31.8
(CH), 31.9 (CH3), 44.8 (CH2), 45.6 (CH), 71.6 (C). Anal. Calcd
for C13H24O2: C, 73.54; H, 11.39. Found: C, 73.82; H, 11.74.
2,5-Bis(tr im eth ylsilyloxy)bicyclo[2.2.2]oct-7-en e-2,5-d i-
ca r bon itr ile (25). Bicyclo[2.2.2]oct-7-ene-2,5-dione (24)26,45
(3.00 g, 22.0 mmol), dicyclohexyl-18-crown-6 (0.50 g), and KCN
(0.25 g) were mixed in dry DME (30 mL), and trimethylsilyl
cyanide (TMSCN; 5.0 g, 50.5 mmol) was added. After the initial
warming had subsided, the mixture was stirred at room
temperature for 4 h and then solvent evaporated to give an
oil. After washing several times with petroleum ether, the silyl
cyanohydrin 25 was obtained as a pale red-orange oil (6.93 g,
1
94%): IR (neat) 3080 w, 2240 w, 860 vs cm-1; H NMR (500
MHz, CDCl3) (mixture of all three epimers) δ 0.21 (s), 0.28
(s), 1.56-1.60 (dd, J 14.3, 3.4), 1.71-1.74 (dd, J 15.1, 3.6),
(44) Greenwald, B. R.; Chaykovsky, M.; Corey, E. J . J . Org. Chem.
1963, 28, 1128.
(45) Cookson, R. C.; Wariyar, N. S. J . Chem. Soc. 1957, 327.

Diol Lattice Inclusion Hosts
J . Org. Chem., Vol. 67, No. 10, 2002 3229
2.03-2.07 (dd, J 14.8, 2.0), 2.18-2.22 (dd, J 14.8, 3.9), 2.62-
2.66 (dd, J 15.1, 2.3), 2.73-2.76 (dd, J 14.3, 2.5), 2.90-2.93
(m), 2.98-3.00 (m), 6.18-6.26 (m), 6.37-6.40 (m); 13C NMR
(126 MHz, CDCl3) δ 1.07 (CH3), 1.13 (CH3), 1.16 (CH3), 1.3
(CH3), 34.5 (CH2), 37.5 (CH2), 39.2 (CH2), 40.2 (CH2), 41.4 (CH),
41.8 (CH), 42.0 (CH), 68.2 (C), 69.3 (C), 69.7 (C), 69.8 (C), 121.6
(C), 121.8 (C), 122.4 (C), 122.6 (C), 130.0 (CH), 131.1 (CH),
132.4 (CH), 133.2 (C), one bridgehead CH obscured, probably
two signals at δ 41.4. Anal. Calcd for C16H26N2O2Si2: C, 57.44;
H, 7.83; N, 8.37. Found: C, 57.35; H, 8.06; N, 8.46.
Meth od A. The silyl cyanohydrin 29 (7.25 g, 21.54 mmol)
was dissolved in dry Et2O and added dropwise to a stirred
suspension of LiAlH4 (1.70 g, 44.85 mmol) in dry Et2O (60 mL).
After stirring of the mixture at room temperature overnight,
water was added carefully, followed by aqueous NaOH. The
ether solution was decanted and dried (Na2SO4), and solvent
was evaporated from the filtrate to give the silylamine as a
colorless oil (6.68 g, 90%): IR (neat) 3450 s, 2950 s, 1440 m,
1365 m, 1245 s, 1175 m, 1115 m, 1080 m, 1040 s, 835 s, 750 m
cm-1. This material (6.34 g, 18 mmol) was dissolved in ethanol
(30 mL), NaOH solution (3.75 M, 3 mL) was added, and the
mixture was refluxed overnight. Solvent was evaporated,
organic material was extracted with Et2O, and the extracts
were dried (Na2SO4). Evaporation of solvent from the filtrate
gave the amino alcohol 30 (2.58 g, 70%) as a viscous syrup:
IR (neat) 3350 s, 3280 s, 1645 m, 1595 m, 1440 m, 1360 m,
1080 m, 1025 s, 960 m cm-1. Alternatively, the silylamine (2.10
g, 6.1 mmol) was dissolved in THF (60 mL), HCl (6.0 M, 20
mL) was added, and the mixture was refluxed for 2 h. Sodium
hydroxide (6.00 g in 10 mL water) was added, and the reaction
was saturated with K2CO3. Extraction using ethyl acetate gave
30 (0.56 g, 46%) as a colorless oil.
Meth od B. 29 (2.0 g, 6.0 mmol) was dissolved in dry THF
(15 mL) and brought to reflux under N2. Borane-dimethyl
sulfide in CH2Cl2 (1.0 M, 13.1 mL, 0.013 mol) was added and
the Me2S distilled off. Hydrochloric acid (6.0 M, 10 mL) was
added and the mixture refluxed for a further 30 min. After
cooling of the mixture to 0 °C, NaOH (2.0 g) was added followed
by excess K2CO3 to saturate the aqueous phase. The water-
soluble organic product was best extracted from a hot aqueous
solution saturated with NaCl using EtOAc. The combined
extracts were dried (Na2SO4), and solvent was evaporated from
the filtrate to give the amino alcohol 30 (0.97 g, 82%).
Bicyclo[3.3.2]d ec-9-en e-2,6-d ion e (27). Crude 25 (2.02 g,
6.0 mmol) dissolved in dry Et2O (10 mL) was added dropwise
to a suspension of LiAlH4 (0.28 g, 7.4 mmol) in Et2O. After
stirring of the mixture for 2 h at room temperature, water (5
mL) and then NaOH solution (2 M; 5 mL) and more water (15
mL) were added. The reaction was extracted using CHCl3, and
the combined extracts were dried (Na2SO4). Evaporation of
solvent from the filtrate gave a viscous yellow oil (1.59 g). A
sample (0.29 g) was dissolved in ethanol (18 mL) and NaOH
solution (3.75 M; 2 mL) added. The mixture was refluxed and
stirred overnight. Water was added and organic material
extracted using Et2O. After drying (Na2SO4), solvent was
evaporated from the filtrate to give amino alcohol 26 as a
colorless syrup (0.11 g, 66%): IR (neat) 3370 s, 3060 m, 1595
s cm-1
.
Crude 26 (0.10 g, 0.51 mmol) was dissolved in acetic acid (1
mL) and water (10 mL) and then cooled in ice. Sodium nitrite
(0.5 g) was added and the reaction stirred at 0 °C for 2 h.
Saturated NaHCO3 solution (20 mL) was added, organic
material extracted with Et2O, and the extract dried (Na2SO4).
Evaporation of solvent from the filtrate gave an oil which was
purified by preparative TLC to afford diketone 27 (0.045 g,
54%), mp 129-130 °C (from petroleum ether): IR (paraffin
mull) 3050 w, 1695 s cm-1; MS m/z 164 (M, 52%); 1H NMR
(500 MHz, CDCl3) δ 2.08-2.15 (m, 2H), 2.38-2.44 (m, 2H),
2.46-2.51 (m, 2H), 2.88-2.94 (m, 2H), 3.02-3.06 (m, 2H),
6.24-6.28 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 29.4 (CH2),
40.0 (CH2), 49.4 (CH), 130.7 (CH), 212.7 (C). Anal. Calcd for
30 (4.35 g, 20.3 mmol) was dissolved in methanol (90 mL),
and the solution was then cooled in ice. Concentrated HCl (45
mL) was added slowly with stirring. After the initial vigorous
reaction had subsided, the mixture was refluxed for 90 min
and then evaporated to dryness under reduced pressure. The
resulting frothy brown hydrochloride salt was pumped under
vacuum for 12 h to remove excess HCl. It was then dissolved
in water (50 mL) and acetic acid (5.5 mL), after which NaOAc
(4.6 g) and benzene (90 mL) were added. The solution was
cooled in ice, and a solution of sodium nitrite (6.30 g) in water
(24 mL) was added in portions with vigorous stirring over 30
min. It was then stirred for a further 18 h. The organic layer
was separated, the aqueous phase was extracted with C6H6,
and the combined extracts were dried (Na2SO4). Evaporation
of solvent from the filtrate gave an orange oil, which was
chromatographed on alumina to separate diketone 31 (0.32 g,
8%) [13C NMR (126 MHz, CDCl3) δ 21.1 (CH2), 23.3 (CH2), 25.8
(CH2), 29.7 (CH2), 38.1 (CH2), 40.3 (CH2), 45.1 (CH), 45.8 (CH),
208.9 (C), 213.3 (C)] from the required isomeric diketone 32
C
10H12O2: C, 73.15; H, 7.37. Found: C, 73.15; H, 7.60.
2,6-Dim eth ylbicyclo[3.3.2]d ec-9-en e-en d o-2,en d o-6-d i-
ol (9). Diketone 27 (0.29 g, 1.76 mmol) was dissolved in dry
THF (10 mL) and stirred under N2. MeLi in diethyl ether (1.4
M; 5 mL, 7.0 mmol) was added by syringe. The mixture was
stirred at room temperature for 30 min and then refluxed for
2 h. Wet Et2O (20 mL) was added, followed by water (30 mL).
Organic material was extracted using CHCl3, and the extracts
were dried (Na2SO4). Evaporation of solvent from the filtrate
gave a pale orange semisolid material which, on addition of a
small amount of Et2O, gave dialcohol 9 as a white solid (0.20
g, 58%), mp 152-155 °C (from petroleum ether): IR (paraffin
mull) 3335 s, 3040 m cm-1; MS m/z 178 [(M - 18), 5%]; 1H
NMR (300 MHz, CDCl3) δ 1.27 (s, 6H), 1.48 (br s, 2H, exchd.
with D2O), 1.58-1.70 (m, 2H), 1.74-1.82 (m, 2H), 1.98-2.08
(m, 2H), 2.19-2.24 (m, 2H), 2.29-2.39 (m, 2H), 5.83-5.86 (m,
2H); 13C NMR (126 MHz, CDCl3) δ 23.4 (CH2), 30.9 (CH3), 39.9
(CH2), 46.7 (CH), 72.8 (C), 132.8 (CH). Anal. Calcd for
(1.30 g, 32%), mp 143-145 °C: IR (paraffin mull) 1690 s cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.77-2.04 (m, 4H), 2.18-2.45
(m, 6H), 2.69-2.80 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 24.4
(CH2), 27.1 (CH2), 39.1 (CH2), 47.8 (CH), 215.9 (C). Anal. Calcd
for C10H14O2: C, 72.26; H, 8.49. Found: C, 71.98; H, 8.76.
2,6-Dim eth ylbicyclo[3.3.2]d eca n e-exo-2,exo-6-d iol (10).
Diketone 32 (1.00 g, 6.0 mmol) was added to a stirred solution
of methylidenetriphenylphosphorane (12.6 mmol) in dry DMSO
under N2 using the Corey procedure.44 After heating for 2 h
at 60 °C, the cooled product was worked up in the usual
manner with water and petroleum ether. The crude product
was eluted through a short column of alumina using petroleum
ether to remove traces of triphenylphosphine oxide and keto
olefin. Solvent was removed by distillation to give 2,6-bis-
(methylidene)bicyclo[3.3.2]decane (0.44 g, 45%) as an oil, bp
177-180 °C: IR (neat) 3070 m, 2930 s, 2860 s, 1635 m, 1440
C
12H20O2: C, 73.43; H, 10.27. Found: C, 73.48; H, 10.32.
Bicyclo[3.3.2]d eca n e-2,6-d ion e (32). Bicyclo[2.2.2]octane-
2,5-dione (28)31,46 (3.40 g, 0.025 mol), KCN (0.25 g), and
dicyclohexyl-18-crown-6 (0.40 g) were dissolved in dry DME
(50 mL). TMSCN (5.00 g, 0.05 mol) was added, and the mixture
was stirred for 4 h. The dark orange colored oil obtained on
evaporation of the solvent was washed with petroleum ether
several times and then eluted through a column of alumina
using petroleum ether/Et2O (1:1). The silyl cyanohydrin 29 was
obtained as a colorless oil (7.53 g, 91%) containing all three
epimers: IR (neat) 2230 w, 850 vs cm-1 13C NMR (126 MHz,
;
CDCl3) δ 1.06 (CH3), 1.11 (CH3), 1.18 (CH3), 1.4 (CH3), 16.7
(CH2), 16.9 (CH2), 19.8 (CH2), 35.9 (CH), 36.2 (CH), 36.3 (CH),
36.5 (CH), 36.8 (CH2), 37.2 (CH2), 39.6 (CH2), 40.8 (CH2), 67.8
(C), 68.0 (C), 68.2 (C), 68.4 (C), 121.87 (C), 121.92 (C), 122.1
(C), 122.6 (C), one CH2 signal obscured.
m, 880 s cm-1 13C NMR (126 MHz, CDCl3) δ 29.4 (CH2), 32.5
;
(CH2), 33.7 (CH2), 42.0 (CH), 109.8 (CH2), 155.3 (C).
The diene (1.70 g, 10.5 mmol) was stirred with methanol
(30 mL), acetonitrile (1.57 g), and KHCO3 (0.37 g) at 0 °C.
Hydrogen peroxide solution (27.5% w/w; 2.72 g) was added
dropwise. After addition the reaction was refluxed for 40 h.
Brine was added and then CH2Cl2 used to extract organic
(46) Guha, P. C.; Krishnamurthy, C. Chem Ber. 1939, 72, 1359.

3230 J . Org. Chem., Vol. 67, No. 10, 2002
Kim et al.
material. The combined extracts were washed and then dried
(Na2SO4). Evaporation of solvent from the filtrate gave the
crude bis(epoxide) 33 (1.50 g, 74%) as a pale yellow oil: IR
(neat) 3020 m, 2930 s, 2850 s, 1450 m, 1280 m, 880 s, 800 m,
730 m cm-1. This product was dissolved in dry THF (20 mL),
and the solution was added to a suspension of LiAlH4 (1.18 g,
31 mmol) in dry THF (40 mL) at 0 °C. The mixture was stirred
overnight at room temperature, and then excess LiAlH4 was
destroyed by addition of aqueous Na2SO4 solution. The THF
layer was separated, and then organic material was extracted
using EtOAc. The combined extracts were dried (Na2SO4), and
solvent was evaporated from the filtrate to yield a viscous
colorless oil (1.52 g), which was dissolved in a small volume
of Et2O/petroleum ether (3:1) and cooled to yield the solid diol
10 (0.83 g, 40%). Recrystallization from chloroform gave the
inclusion compound, mp 156-158 °C: IR (paraffin mull) 3375
orange oil which partly crystallized on standing. This solid was
filtered off and recrystallized from acetone to give the diketone
35 (0.51 g, 12.5%), mp 143-148 °C: IR (neat) 1700 s cm-1
;
13C NMR (126 MHz, CDCl3) δ 25.3 (CH2), 36.3 (CH2), 43.9 (CH),
46.1 (CH), 206.5 (C). Anal. Calcd for C10H12O2S: C, 61.20; H,
6.16. Found: C, 61.10; H, 6.42.
2,7-Dim et h yl-9-t h ia t r icyclo[4.3.1.13,8]u n d eca n e-a n ti-
2,a n ti-7-d iol (11). A solution of methylmagnesium chloride
(3.0 M in THF, 1.8 mL, 5.4 mmol) was added by syringe to a
stirred solution of diketone 35 (0.35 g, 1.8 mmol) in dry THF
(10 mL) at 0 °C. After 4 h of reflux a saturated solution of
NH4Cl was added and the organic layer separated. The
aqueous phase was extracted further using Et2O. The com-
bined extracts were dried (Na2SO4), and evaporation of solvent
from the filtrate gave a yellow solid. Recrystallization from
chloroform gave fine needles of the diol 11 as an inclusion
compound (0.26 g, 64%), mp 153-155 °C: IR (paraffin mull,
cm-1) 3405 s; 1H NMR (300 MHz, CDCl3) δ 1.62 (s, 6H), 1.52-
1.65 (m, 2H), 2.08-2.48 (m, 10H), 4.78 (br s, 2H, exchanged
with D2O); 13C NMR (126 MHz, CDCl3) δ 28.3 (CH2), 31.3
(CH3), 35.7 (CH2), 43.6 (CH), 43.7 (CH), 74.8 (C). Anal. Calcd
for (C12H20O2S)4‚CHCl3: C, 56.99; H, 7.91. Found: C, 57.28;
H, 8.35.
1
s, 1110 s, 1080 s, 770 s cm-1; H NMR (300 MHz, CDCl3) δ
1.25 (s, 6H), 1.43 (br s, 2H, exchanged with D2O), 1.44-1.54
(m, 2H), 1.61-1.91 (m, 10H), 2.19-2.31 (m, 2H); 13C NMR (126
MHz, CDCl3) δ 24.5 (CH2), 24.8 (CH2), 30.9 (CH3), 38.1 (CH2),
46.2 (CH), 75.6 (C). Sublimation under reduced pressure (ca.
120 °C, 15 mmHg) yielded solvent-free 10, mp 156-157 °C:
IR (paraffin mull) 770 cm-1, absorption due to CHCl3 now
absent. Anal. Calcd for C12H22O2: C, 72.68; H, 11.18. Found:
C, 73.03; H, 11.50.
In clu sion Beh a vior a n d Cr ysta l Str u ctu r es of th e
Diols 7-11. Compounds 7-9 were screened for potential
inclusion properties by recrystallization from a standard set
of solvents (acetone, acetonitrile, benzene, dichloromethane,
diethyl ether, chloroform, ethyl acetate, and chloroform) fol-
lowed by examination of their IR (paraffin mull) spectra. All
cases tested negative. In contrast, both 10 and 11 showed
inclusion properties.
9-Th ia tr icyclo[4.3.1.13,8]u n d eca n e-2,7-d ion e (35). Dione
32 (3.47 g, 0.021 mol), pyrrolidine (5.3 mL, 0.064 mol), and
p-toluenesulfonic acid (20 mg) were mixed with C6H6 (100 mL)
and heated under reflux using a Dean-Stark trap. After water
separation was complete, solvent was evaporated to give the
crude bis(enamine) 34 as a dark brown oil, which was dissolved
in CH2Cl2 (40 mL). Freshly distilled triethylamine (10 mL) was
added and the mixture brought to reflux. A solution of freshly
purified sulfur dichloride47 (1.5 mL, 0.023 mol) in CH2Cl2 (10
mL) was added in portions over 15 min. The reaction was
refluxed for a further 1 h and then stirred overnight at room
temperature. Excess HCl (2.5 M) was added with stirring and
then the CH2Cl2 solution separated. The aqueous phase was
extracted several times with CHCl3. The combined organic
extracts were washed several times with water and then dried
(Na2SO4). Evaporation of solvent from the filtrate gave a dark
Ack n ow led gm en t. We thank the Australian Re-
search Council for financial support of this work.
Su p p or tin g In for m a tion Ava ila ble: Listings of IR and
MS peaks, figures showing the X-ray molecular structures and
conformations of diols 7, 8, and 11, details of the solution and
refinement of the five crystal structures, including numerical
data, and tables listing fractional coordinates, thermal pa-
rameters, interatomic distances and angles, and dimensions
associated with the hydrogen bonding. This material is avail-
able free of charge via Internet at http://pubs.acs.org.
(47) Brauer, G.; Ed. Handbook of Preparative Inorganic Chemistry,
2nd English ed.; Academic Press: New York, 1963; Vol. 1, pp 370-
371.
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