The supertristeroids: Large, chiral, molecular bowls prepared by trimerization of pentacyclic steroidal ketones

Article abstract of DOI:10.1021/jo070458k

(Chemical Equation Presented) Robinson annulation of coprostanone (1) at the 2,3- and 3,4-positions gave two pentacyclic enones (7 and 10) that contain A/B-cis-fused ring junctions. Reduction of these enones gave the pentacyclic steroidal ketones 2α,3β- (8) and 2α,3α-(3′- oxocyclohexano)-5β-cholestane (9) and 4α,3β- (11) and 4α,3α-(3′-oxocyclohexano)-5β-cholestane (12). The structures of compounds 8, 9, and 11 were unambiguously established by X-ray analysis. TiCl₄-promoted trimerization of compounds 8 and 11 gave the "supertristeroids" 4 and 5, respectively: large (C₉₃) chiral, hydrocarbon clefts with C₃-symmetric pockets approximately 12 A in diameter.

Full text of DOI:10.1021/jo070458k

The Supertristeroids: Large, Chiral, Molecular Bowls Prepared by
Trimerization of Pentacyclic Steroidal Ketones
Qiuling Song, Douglas M. Ho, and Robert A. Pascal, Jr.*
Department of Chemistry, Princeton UniVersity, Princeton, New Jersey 08544
snake@chemVax.princeton.edu
ReceiVed March 5, 2007
Robinson annulation of coprostanone (1) at the 2,3- and 3,4-positions gave two pentacyclic enones (7
and 10) that contain A/B-cis-fused ring junctions. Reduction of these enones gave the pentacyclic steroidal
ketones 2R,3â- (8) and 2R,3R-(3′-oxocyclohexano)-5â-cholestane (9) and 4R,3â- (11) and 4R,3R-(3′-
oxocyclohexano)-5â-cholestane (12). The structures of compounds 8, 9, and 11 were unambiguously
established by X-ray analysis. TiCl4-promoted trimerization of compounds 8 and 11 gave the
“supertristeroids” 4 and 5, respectively: large (C93) chiral, hydrocarbon clefts with C3-symmetric pockets
approximately 12 Å in diameter.
Introduction
We have previously reported the synthesis and structure of the
chiral molecular cleft 3 by the trimerization of coprostanone (1).1
Provided that an enantiomerically pure ketone is used as the star-
ting material, the inherent directionality of the triple aldol conden-
sation (2) assures that only a single trimeric product is formed.
It has been argued that an ideal enantioselective host should
not only contain a chiral cavity complementary to only one
enantiomer of the guest but also possess a single minimum
energy conformation.2-5 Bowl-shaped steroid trimers such as
3 are conformationally homogeneous3-5 and might be excel-
lent scaffolds from which to construct such hosts, and they
have the practical advantage of very short syntheses. How-
ever, ab initio calculations of the structure of 3 indicate that
the central cleft is only large enough to hold an n-alkane, and
in the crystal structure of 3, the cleft is slightly compressed by
packing forces and contains no guest of any kind.1 In order to
accommodate guests of reasonable size, the steroid frame-
work must be expanded. Thus we report herein the synthesis
of the two “supertristeroids” 4 and 5 (Scheme 1), hydrocarbon
frameworks containing large, C3-symmetric, chiral cavities,
formed by the trimerization of homologated steroidal penta-
cyclic ketones.
(1) Pascal, R. A., Jr.; Mathai, M. S.; Shen, X.; Ho, D. M. Angew. Chem.,
Int. Ed. 2001, 40, 4746-4748.
(2) Cram, D. J. Angew. Chem., Int. Ed. Engl. 1988, 27, 1009-
1020.
(3) Wang, X.; Erickson, S. D.; Iimori, T.; Still, W. C. J. Am. Chem.
Soc. 1992, 114, 4129-4137.
(4) Hong, J.-I.; Namgoong, S. K.; Bernardi, A.; Still, W. C. J. Am. Chem.
Soc. 1991, 113, 5111-5112.
(5) Li, G.; Still, W. C. J. Am. Chem. Soc. 1993, 115, 3804-3805.
10.1021/jo070458k CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/10/2007
J. Org. Chem. 2007, 72, 4449-4453
4449

Song et al.
SCHEME 1
Results and Discussion
cis) were failures. The initial formylation of coprostanone (1)
to give the 2-hydroxymethylene derivative 6 worked well, but
the subsequent Michael addition of methyl vinyl ketone (MVK)
was very sensitive to conditions. Frequently, the reactions
succeeded with model compounds but failed when applied to
6. Several traditional bases were examined, including KOtBu/
tBuOH,10 Triton B/MeOH,11 NaOEt/EtOH, and NaH/THF, but
without success. Ultimately, the use of a mixture of triethylamine
and KOH in ethyl acetate12 was found to give reasonable
amounts of the desired Michael adduct. The crude acyclic adduct
formed under these conditions readily closes upon treatment
with 1:1 6 N HCl-THF to give pentacyclic enone 7 in ca. 30%
overall yield from 1. This modest but easily reproducible yield
of 7 was sufficient for our purposes because of the easy
availability of coprostanone by the Raney nickel-catalyzed
isomerization of cholesterol.13
Synthesis of 2,3- and 3,4-Annulated Steroid Pentacycles.
The supertristeroid 4 (Scheme 1), a triple homologue of
compound 3, was our first target, and its synthesis from
pentacyclic ketone 8 was judged likely to succeed. However,
the construction of the precursor 8 with some confidence in
the regio- and stereochemistry of the additional ring was a more
challenging task. Pentacyclic steroid homologues with trans A/B
ring fusions have been known for almost 50 years,6-9 but we
know of no comparable A/B-cis-fused pentacycles such as 8.
(In this paper, the four original steroid rings are designated
A-D, as is conventional; the extra ring of the pentacycle that
is fused to ring A is designated E.)
Our first attempts to adapt the literature methods for Robinson
annulation of cholestanone (A/B-trans) to coprostanone (A/B-
(6) Urushibara, Y.; Inomata, J. Bull. Chem. Soc. Jpn. 1959, 32, 101-
102.
(10) Woodward, R. B.; Sondheimer, F.; Taub, D.; Heusler, K.; McLam-
ore, W. M. J. Am. Chem. Soc. 1952, 74, 4223-4251.
(11) Rajamannar, T.; Balasubramanian, K. K. Synth. Commun. 1994, 24,
279-292.
(7) Bloch, J. C.; Crabbe, P.; Kincl, F. A.; Ourisson, G.; Perez, J.; Zderic,
J. A. Bull. Soc. Chim. Fr. 1961, 559-560.
(8) Cooley, G.; Ducker, J. W.; Ellis, B.; Petrow, V.; Scott, W. P. J. Chem.
Soc. 1961, 4108-4110.
(9) Bloch, J. C.; Ourisson, G. Bull. Soc. Chim. Fr. 1964, 3011-3017
and 3018-3030.
(12) Jansen, B. J. M.; Hendrikx, C. C. J.; Masalov, N.; Stork, G. A.;
Meulemans, T. M.; Macaev, F. Z.; de Groot, A. Tetrahedron 2000, 56,
2075-2094.
(13) Forsek, J. Tetrahedron Lett. 1980, 21, 1071-1074.
4450 J. Org. Chem., Vol. 72, No. 12, 2007

The Supertristeroids
Pentacyclic enone 7 may be reduced by either of two methods.
Reduction by lithium in ammonia gives, as expected,14 the
desired 2R,3â (A/E-trans) isomer 8. Unfortunately, this reaction
is plagued by over-reduction of the ketone to give the corre-
sponding alcohol, and strict control of the amount of lithium
used invariably leaves unreacted starting material. In practice,
it is simpler to subject 7 to a 1 h catalytic hydrogenation, giving
a very clean mixture of A/E-trans 8 and A/E-cis 9 that is easily
resolved by column chromatography.
The NMR data for compounds 8 and 9 shed no light on the
stereochemical assignments. Compound 8 was suspected to be
the A/E-trans isomer on the basis of its formation in the
dissolving metal reduction, but X-ray data were needed to
confirm this assignment. Fortunately, single crystals of both
compounds 8 and 9 were obtained, and their structures were
determined. Both the regio- and stereochemistry of the added
rings in 8 and 9 are as indicated in Scheme 1, that is, compound
8 possesses an A/E-trans ring junction (2R,3â) and compound
9 has an A/E-cis junction (2R,3R). The molecular structures of
both molecules are illustrated in the Supporting Information.
In the synthesis of the 2,3-annulated pentacycles 7-9, the
regiochemistry of Robinson annulation was determined by the
presence of the 2-hydroxymethylene group of compound 6. A
direct Robinson annulation of coprostanone might be expected
to give a mixture of pentacycles. In fact, when compound 1 is
treated with MVK, triethylamine, and KOH in ethyl acetate,
exactly as for the annulation of 6, the only pentacyclic enone
formed is the 3,4-adduct 10. The yield of this transformation
(35%) is, if anything, slightly higher than that for the synthesis
of 7, and thus we had easy access to the 3,4-annulated
pentacyclic ketones.
Lithium/ammonia reduction of 10 gives the A/E-trans ketone
11, and its structure was confirmed by X-ray analysis (the
structure is illustrated in the Supporting Information). However,
as before, it proved more convenient to hydrogenate compound
10 to the give a mixture of A/E-trans 11 and A/E-cis 12, which
were then separated chromatographically.
The crystal structures leave no doubt as to the structures of
the pentacyclic ketones and their enone precursors, but the easy
formation of the step-like, E/A/B-cis,cis isomers 9 and 12 is
somewhat surprising. The initial Michael additions give the
expected equatorial substitutions at C-2 and C-4 in enones 7
and 10, respectively. However, these pentacycles are bent by
roughly 60° at the cis A/B ring junction, and thus it is hard to
imagine how the R-faces of the enones approach the surface of
a heterogeneous hydrogenation catalyst in order to give the
ketones 9 and 12! One might have expected the essentially
unencumbered â-faces of the enones to be hydrogenated much
more rapidly than the R-faces, but the A/E-cis and A/E-trans
isomers are formed in roughly equal amounts in both hydro-
genation reactions.
FIGURE 1. Stereoviews of the calculated structures [B3LYP/6-31G-
(d)] of the polycyclic cores of supertristeroids 4 (top) and 5 (bottom).
The proton NMR spectra of the trimers 4 and 5 are relatively
uninformative, but the C3-symmetric supertristeroids are easily
identified by the presence of two (and only two) aromatic
resonances in their 13C NMR spectra near δ 132. The byproducts
of the trimerization, for which cyclization is incomplete, are
asymmetric and have very complicated 13C NMR spectra. The
strong molecular ions in the FAB mass spectra of 4 and 5
confirm their composition.
A great deal of effort was invested in the growth of crystals
of compounds 4 and 5, with the hope of determining their X-ray
crystal structures. Both compounds form relatively large hex-
agonal plates from solutions in chlorinated hydrocarbons, but
only inferior crystals are deposited from other solvents. X-ray
analysis of large crystals of compound 4 gave a trigonal unit
cell [a ) b ) 30.3934(5) Å, c ) 17.1086(3) Å] with P3 as the
likely space group. This large unit cell must contain at least
two independent molecules of 4, as well as several solvent
molecules. Several X-ray data sets were collected, but no
solution to the structure has been obtained. In addition, attempts
were made to brominate compounds 4 and 5 selectively at the
benzylic positions, as well as to displace the bromine atoms
with aromatic thiols, in order to generate derivatives that might
crystallize more satisfactorily, but only intractable mixtures were
obtained (data not shown).
With no crystal structure in hand, the structures of the cores
of supertristeroids 4 and 5 (lacking the C8H17 side chains) were
calculated at the B3LYP/6-31G(d) level.15,16 Both molecules
possess chiral pockets some 12 Å in diameter, and the calculated
molecular structures are illustrated in Figure 1. The structures
(15) Hybrid density functional calculations were performed using Gauss-
ian 03;16 the built-in default thresholds for wave function and gradient
convergence were employed.
(16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.
Synthesis of the “Supertristeroids” 4 and 5. The trimer-
ization of ketones 8 and 11 to give supertristeroids 4 and 5,
respectively, was conducted in essentially the same manner as
the previously reported synthesis of 3.1 The ketone was dissolved
in hexanes in a screw-capped tube, 1 equiv of ZnCl2 and 3-4
equiv of TiCl4 were added, and the mixture was heated in an
oil bath at 140 °C overnight. Yields of the trimers were variable,
ranging from 10 to 50%. More highly polar solvents gave
inferior yields, and although lower temperatures gave poor
results, higher temperatures had little effect.
(14) Stork, G.; Darling, S. D. J. Am. Chem. Soc. 1964, 86, 1761-1768.
J. Org. Chem, Vol. 72, No. 12, 2007 4451

Song et al.
21.0, 22.5, 22.8, 23.1, 23.8, 24.1, 25.8, 26.2, 27.9, 28.2, 29.2, 32.8,
35.5, 35.7, 35.9, 36.1, 36.6, 39.4, 40.0, 41.0, 42.6, 43.7, 45.4, 56.3,
56.4, 124.0, 168.6, 199.8 (30 of 31 expected resonances); MS (EI)
m/z 438 (M+, 52), 423 (M - CH3, 19), 316 (37), 81 (100); exact
mass 438.3876, calcd for C31H50O 438.3862.
indicate that large, propeller-like guests should fit easily into
the clefts. For this reason, cocrystallization experiments with
triphenylphosphine, triphenylamine, tris(pentafluorophenyl)-
phosphine, and tris(pentafluorophenyl)borane were attempted,
but without success. Whether these molecules associate with
the supertristeroids in solution is the subject of future experi-
ments.
2R,3â- (8) and 2R,3R-(3′-Oxocyclohexano)-5â-cholestane (9)
by Hydrogenation of 7. Pentacyclic ketone 7 (70 mg, 0.16 mmol)
was dissolved in ethanol (20 mL), and 10% Pd on C (10 mg) was
added. The mixture was hydrogenated for 1 h at 45 psi. The catalyst
was filtered away, and the solvent was removed to give a colorless
solid. Silica gel column chromatography (solvent, 30:1 hexanes/
ether) gave two new pentacyclic ketones. Compound 8 (35 mg,
0.080 mmol, 50%) eluted first, followed by compound 9 (28 mg,
0.064 mmol, 40%). Subsequent X-ray analysis established the
structures of 8 and 9 as the 2R,3â (trans) and 2R,3R (cis) isomers,
respectively. Compound 8: mp 120-122 °C; 1H NMR (CDCl3) δ
0.65 (s, 3H), 0.86 (d, J ) 7 Hz, 6H), 0.90 (d, J ) 7 Hz, 3H), 0.95
(s, 3H), 0.99-1.70 (methylene envelope, 24H), 1.85 (m, 4H), 2.00
(d, J ) 12 Hz, 1H), 2.10 (t, J ) 14 Hz, 1H), 2.36 (m, 3H); 13C
NMR (CDCl3) δ 12.0, 18.7, 20.9, 22.5, 22.8, 23.8, 23.9, 24.2, 26.5,
26.9, 28.0, 28.3, 33.6, 35.0, 35.8, 35.9, 36.0, 36.2, 39.5, 40.3, 41.6,
41.7, 42.7, 42.8, 43.8, 44.0, 48.3, 56.4, 56.6, 211.8 (30 of 31
expected resonances); MS (EI) m/z 440 (M+, 29), 425 (M - CH3,
60), 285 (100); exact mass 440.4020, calcd for C31H52O 440.4018.
Compound 9: mp 155-157 °C; 1H NMR (CDCl3) δ 0.65 (s, 3H),
0.87 (d, J ) 7 Hz, 6H), 0.89 (d, J ) 7 Hz, 3H), 1.01 (s, 3H),
0.95-2.03 (methylene envelope, 32H), 2.20 (m, 3H), 2.37 (td, J
) 14, 7 Hz, 1H), 2.66 (t, J ) 14 Hz, 1H); 13C NMR (CDCl3) δ
12.0, 18.7, 20.8, 22.5, 22.8, 23.8, 24.2, 24.4, 26.4, 26.5, 28.0, 28.3,
28.5, 31.7, 31.8, 35.5, 35.77, 35.81, 36.2, 36.6, 36.8, 38.0, 39.5,
40.2, 40.7, 42.4, 42.7, 56.4, 56.6, 213.3 (30 of 31 expected
resonances); MS (EI) m/z 440 (M+, 27), 425 (M - CH3, 58), 285
(100); exact mass 440.4003, calcd for C31H52O 440.4018.
2R,3â-(3′-Oxocyclohexano)-5â-cholestane (8) by Li/NH3 Re-
duction of 7. Lithium (23 mg, 3.3 mmol) was added to liquid
ammonia (∼25 mL) in a three-necked flask topped by a dry ice
condenser and a CaCl2 drying tube. After the solution turned dark
blue, a solution of pentacyclic ketone 7 (180 mg, 0.411 mmol) in
THF (2 mL) was added over 1 h. The solution was stirred for
another 2 h, and then solid NH4Cl was added to quench the reaction.
After the ammonia had evaporated, water was added, and the
mixture was extracted three times with CH2Cl2. The combined
organic layers were washed successively with water, saturated
NaHCO3, and brine, and then dried over Na2SO4. The solution was
concentrated to dryness, and the residue was purified by silica gel
column chromatography to give compound 8 (90 mg, 50%),
identical to that prepared by hydrogenation of 7.
Conclusion
We have reported very short syntheses (3-4 steps) of two
large (C93), chiral, hydrocarbon clefts, containing C3-symmetric
cavities big enough to accommodate guests of moderate
complexity. If one employed a similar synthetic strategy with
precursors containing polar functionalitysperhaps an A/B-cis-
fused polyhydroxy steroid such as cholic acidsthen chiral clefts
with multiple, internally directed polar groups might be prepared.
Experimental Section
Coprostanone (5â-cholestan-3-one), mp 56-58 °C (lit.17 60-
61 °C) was prepared by the method of Forsek.13
2-Hydroxymethylene-5â-cholestan-3-one (6). Sodium (247 mg,
10.7 mmol) and ethyl formate (0.89 mL, 10.7 mmol) were added
to a solution of coprostanone (2.08 g, 5.37 mmol) in dry ether (40
mL). The flask was placed in an ice bath, the reaction was initiated
by the addition of ethanol (0.4 mL), and the mixture was stirred
overnight. Ethanol was added to destroy any excess sodium, and
after stirring for 0.5 h, water and 3 N HCl were added. The acidic
solution was extracted three times with ether. The combined organic
layers were washed twice with brine, dried over Na2SO4, and
concentrated to give compound 6 (2.21 g, 5.33 mmol, 99%): mp
1
98-100 °C; H NMR (CDCl3) δ 0.63 (s, 3H), 0.84 (d, J ) 7 Hz,
6H), 0.86 (d, J ) 7 Hz, 3H), 1.03 (s, 3H), 0.90-1.99 (methylene
envelope, 26H), 2.29 (dd, J ) 20, 8 Hz, 1H), 2.32 (d, J ) 16 Hz,
1H), 2.52 (dd, J ) 20, 10 Hz, 1H), 8.24 (s, 1H), 14.31 (br s, 1H);
13C NMR (CDCl3) δ 12.0, 18.6, 20.9, 22.2, 22.5, 22.8, 23.7, 24.1,
25.2, 25.3, 27.9, 28.2, 33.8, 34.7, 35.06, 35.14, 35.7, 36.0, 38.4,
39.4, 39.8, 40.4, 42.6, 56.1, 56.2, 107.3, 181.7, 189.3 (28 of 28
expected resonances); MS (EI) m/z 414 (M+, 10), 386 (M - CO,
22), 316 (53), 81 (100); exact mass 414.3494, calcd for C28H46O2
414.3498.
2R,3-(3′-Oxocyclohex-4′-eno)-5â-cholestane (7). Triethylamine
(2.2 mL, 15.3 mmol) and methyl vinyl ketone (1.9 mL, 23 mmol)
were added to a solution of ketone 6 (1.58 g, 3.82 mmol) in ethyl
acetate (20 mL). Two pellets of solid KOH were then added, and
the reaction mixture was stirred under argon for 24 h at room
temperature. Water was added, and the mixture was acidified to
pH 2 with 3 N HCl. The aqueous mixture was extracted four times
with ether, and the combined organics were washed three times
with brine. After drying over Na2SO4, removal of the solvent gave
a sticky, yellow solid (the crude initial Michael adduct). This
material was dissolved in a 1:1 mixture of THF and 6 N HCl (48
mL), and the solution was heated at reflux for 2 h. After cooling,
water was added, and the resulting mixture was extracted three times
with CH2Cl2. The combined organic layers were washed three times
with water, and the combined aqueous layers were back extracted
with CH2Cl2. The combined organics were then washed twice with
brine, dried over Na2SO4, and concentrated to give a yellow oil.
Purification of this material by silica gel column chromatography
(solvent, 10:1 hexanes/ethyl acetate) gave pentacyclic ketone 7 (545
4R,3-(3′-Oxocyclohex-4′-eno)-5â-cholestane (10). Coprostanone
(1.38 g, 3.58 mmol) was subjected to the same two-step procedure
used for the preparation of compound 7 from 6. The crude cyclized
product was purified by preparative TLC (solvent, 10:1 hexanes/
ethyl acetate) to give pure compound 10 (549 mg, 1.25 mmol,
1
35%): mp 82-85 °C; H NMR (CDCl3) δ 0.64 (s, 3H), 0.84 (d,
J ) 7 Hz, 6H), 0.88 (d, J ) 7 Hz, 3H), 0.96 (s, 3H), 1.20-2.43
(methylene envelope, 33H), 2.65 (t, J ) 9 Hz, 1H), 5.82 (s, 1H);
13C NMR (CDCl3) δ 12.0, 18.6, 21.1, 22.0, 22.5, 22.7, 23.6, 23.7,
24.0, 25.6, 27.2, 27.9, 28.2, 30.6, 35.1, 35.5, 35.67, 35.71, 36.0,
36.7, 36.9, 39.4, 40.0, 41.7, 42.6, 50.3, 56.2, 56.4, 124.5, 168.6,
199.9 (31 of 31 expected resonances); MS (EI) m/z 438 (M+, 79),
423 (M - CH3, 36), 329 (47), 175 (100); exact mass 438.3867,
calcd for C31H50O 438.3862.
4R,3â- (11) and 4R,3R-(3′-Oxocyclohexano)-5â-cholestane (12)
by Hydrogenation of 10. Pentacyclic ketone 10 (90 mg, 0.21
mmol) was hydrogenated and fractionated as described for the
preparation of compounds 8 and 9, to give the saturated ketones
11 (42 mg, 0.095 mmol, 45%) and 12 (37 mg, 0.084 mmol, 40%).
Subsequent X-ray analysis established the structure of 11 as the
1
mg, 1.24 mmol, 33%): mp 84-87 °C; H NMR (CDCl3) δ 0.66
(s, 3H), 0.86 (d, J ) 7 Hz, 6H), 0.90 (d, J ) 7 Hz, 3H), 0.98 (s,
3H), 1.01-2.07 (methylene envelope, 30H), 2.37 (m, 3H), 2.75 (t,
J ) 14 Hz, 1H), 5.83 (s, 1H); 13C NMR (CDCl3) δ 12.0, 18.6,
1
4R,3â (trans) isomer. Compound 11: mp 125-127 °C; H NMR
(17) Rubin, M.; Armbrecht, B. H. J. Am. Chem. Soc. 1953, 75, 3513-
3516.
(CDCl3) δ 0.65 (s, 3H), 0.86 (d, J ) 7 Hz, 6H), 0.90 (d, J ) 7 Hz,
4452 J. Org. Chem., Vol. 72, No. 12, 2007

The Supertristeroids
3H), 0.95 (s, 3H), 0.99-1.62 (methylene envelope, 26H), 1.70 (m,
2H), 1.82 (m, 3H), 1.98 (d, J ) 11 Hz, 1H), 2.14 (t, J ) 13 Hz,
1H), 2.30 (m, 4H); 13C NMR (CDCl3) δ 12.1, 18.6, 21.0, 22.1,
22.5, 22.8, 23.8, 24.2, 24.4, 26.0, 28.0, 28.3, 28.8, 30.8, 35.8, 35.9,
36.0, 36.2, 37.0, 37.5, 39.5, 40.3, 41.4, 41.9, 42.7, 44.2, 48.5, 48.7,
56.4, 56.6, 211.9 (31 of 31 expected resonances); MS (EI) m/z 440
(M+, 33), 425 (M - CH3, 70), 285 (100); exact mass 440.4005,
calcd for C31H52O 440.4018. Compound 12: mp 100-102 °C; 1H
NMR (CDCl3) δ 0.65 (s, 3H), 0.86 (d, J ) 7 Hz, 6H), 0.89 (d, J
) 7 Hz, 3H), 1.02 (s, 3H), 1.03-1.65 (methylene envelope, 26H),
1.80 (m, 3H), 2.00 (m, 2H), 2.13 (m, 2H), 2.25 (m, 3H), 2.68 (t, J
) 14 Hz, 1H); 13C NMR (CDCl3) δ 12.1, 18.6, 21.1, 21.7, 22.5,
22.8, 23.8, 24.2, 24.8, 25.4, 25.5, 27.6, 28.0, 28.3, 30.2, 30.9, 35.8,
35.9, 36.0, 36.2, 36.3, 38.0, 38.6, 39.5, 40.3, 41.1, 42.5, 42.8, 56.4,
56.6, 213.2 (31 of 31 expected resonances); MS (EI) m/z 440 (M+,
31), 425 (M - CH3, 56), 386 (16), 285 (75), 81 (100); exact mass
440.4010, calcd for C31H52O 440.4018.
Trimerization of Compound 11 to Give the “3,4-Supertris-
teroid” 5. Pentacyclic ketone 11 (85 mg, 0.193 mmol) was
trimerized by treatment with ZnCl2 (26 mg, 0.19 mmol) and TiCl4
(0.07 mL, 0.6 mmol) as described above to give compound 5 as a
white solid (38 mg, 47%): mp >300 °C; 1H NMR (CDCl3) δ 0.65
(s, 9H), 0.85 (3 overlapping d’s, 27H), 0.98 (s, 9H), 0.94-1.60
(methylene envelope, 81H), 1.70-2.02 (m, 15H), 2.26 (m, 3H),
2.64 (d, J ) 16 Hz, 3H), 2.83 (d, J ) 16 Hz, 3H); 13C NMR
(CDCl3) δ 12.1, 18.7, 21.0, 22.0, 22.6, 22.8, 23.8, 24.2, 24.5, 26.1,
28.0, 28.3, 29.7, 33.2, 34.1, 35.8, 35.9, 36.2, 36.8, 38.4, 39.5, 40.2,
41.9, 42.8, 50.0, 56.3, 56.7, 131.86, 131.89 (29 of 31 expected
resonances); MS (FAB) m/z 1268 (M+ [13C2], 20), 447 (100).
General X-ray Crystallographic Procedures. X-ray data for
compounds 8, 9, and 11 were collected at 200 K using graphite
monochromated Mo KR radiation (λ ) 0.71073 Å) on a Nonius
KappaCCD diffractometer. All diffraction data were processed using
the program DENZO.18 All structures were solved by direct methods
using Siemens SHELXTL,19 and all were refined by full-matrix
least-squares on F2 using SHELXTL. All non-hydrogen atoms were
refined anisotropically, and hydrogens were included with a riding
model. Specific crystal, reflection, and refinement data are contained
in the CIF files in the Supporting Information.
4R,3â-(3′-Oxocyclohexano)-5â-cholestane (11) by Li/NH3
Reduction of 10. Compound 10 (73 mg, 0.167 mmol) was subjected
to Li/NH3 reduction, as described above for the reduction of 7, to
yield compound 11 (38 mg, 0.087 mmol, 52%), identical to that
prepared by hydrogenation of 10.
Trimerization of Compound 8 to Give the “2,3-Supertris-
teroid” 4. Pentacyclic ketone 8 (247 mg, 0.56 mmol) was dissolved
in hexanes (15 mL) in a 15 mm × 150 mm screw-capped tube.
Anhydrous ZnCl2 (76 mg, 0.56 mmol) and TiCl4 (0.2 mL, 1.8
mmol) were added to give a brown mixture. The bottom of the
tube was placed in an oil bath heated to 140 °C, and it was left
overnight. After cooling, water was added, and the mixture was
extracted three times with CH2Cl2. The combined organic layers
were washed three times with water, dried over Na2SO4, and
concentrated to give a light yellow solid. Purification by silica gel
column chromatography (solvent, hexanes) gave trimer 4 as a white
Acknowledgment. This work was supported by National
Science Foundation Grants CHE-0314873 and CHE-0614879,
which are gratefully acknowledged.
Supporting Information Available: NMR spectra of com-
pounds 4-12; Cartesian coordinates of the DFT-computed struc-
tures; three crystallographic information files (CIF); and three Ortep
drawings for compounds 8, 9, and 11. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
solid (43 mg, 18%): mp >300 °C; H NMR (CDCl3) δ 0.68 (s,
9H), 0.85 (3 overlapping d’s, 27H), 0.97 (s, 9H), 0.94-1.62
(methylene envelope, 81H), 1.76-2.04 (m, 15H), 2.18 (m, 3H),
2.51 (d, J ) 16 Hz, 3H), 2.63 (d, J ) 16 Hz, 3H); 13C NMR
(CDCl3) δ 12.2, 18.7, 19.1, 20.8, 22.5, 22.8, 23.8, 24.0, 24.3, 26.8,
27.3, 28.0, 28.4, 32.0, 35.0, 35.78, 35.84, 35.9, 36.2, 36.3, 38.5,
39.5, 41.6, 42.8, 42.9, 45.1, 56.0, 56.8, 131.6, 132.1 (30 of 31
expected resonances); MS (FAB) m/z 1267 (M+ [13C1], 38), 460
(100).
JO070458K
(18) Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307-
326.
(19) Sheldrick, G. M. SHELXTL, version 5; Siemens Analytical X-ray
Instruments: Madison, WI, 1996.
J. Org. Chem, Vol. 72, No. 12, 2007 4453