Rac-9-ethyl-12a-hydroxy-tetra-deca-hydro-triphenyl-ene-1,5(2H,4bH)-dione: Stabilization of a new isomer of a functionalized perhydro-triphenyl-ene through a tandem Michael addition-aldol reaction

Article abstract of DOI:10.1107/S0108270108011876

The title compound, C20H30O3, is a new functionalized perhydro-triphenyl- ene derivative formed via a tandem Michael addition-aldol reaction. The structural study reveals that the system of fused rings approximates a C 2 point symmetry, with trans-cis-cis ring junctions, while highly symmetric all-trans perhydro-triphenyl-ene, previously characterized, approximates a D 3 symmetry. The perhydro-triphenyl-ene nucleus of the title compound corresponds to the third stable stereo-isomer isolated for this polycyclic system. Considering that the C s isomer was obtained recently through a similar tandem reaction, a general strategy is proposed which may help to obtain other stable stereoisomers of perhydro-triphenyl-ene. International Union of Crystallography 2008.

Full text of DOI:10.1107/S0108270108011876

organic compounds
Acta Crystallographica Section C
Crystal Structure
PHTP clathrates are severely complicated due to a tendency
towards disorder, with diffraction patterns including incom-
Communications
È
mensurate satellites (Weber et al., 2001; Burgi et al., 2005). For
ISSN 0108-2701
these reasons, very few PHTP derivatives have been char-
acterized in the solid state. On the other hand, to the best of
our knowledge, the possibility of stabilizing other isomers of
PHTP has not been addressed, neither through accurate ab
initio calculations nor by crystallizing such isomers.
The matter may be probed, at least partially, through the
synthesis of PHTP derivatives, provided that the starting
materials do not include fused rings. With the exception of the
abovementioned naked D3-PHTP, only one guest-free PHTP
derivative has been characterized crystallographically to date,
rac-9-Ethyl-12a-hydroxytetradeca-
hydrotriphenylene-1,5(2H,4bH)-
dione: stabilization of a new isomer of
a functionalized perhydrotriphenylene
through a tandem Michael addition±
aldol reaction
namely
9-benzyl-12a-hydroxytetradecahydrotriphenylene-
1,5(2H,4bH)-dione. This derivative was synthesized (Blake et
al., 2007) through an original triple cascade reaction involving
two Michael additions followed by an intramolecular aldol
reaction. The main dif®culty for the study of this compound by
X-ray diffraction was the very small size of the single crystals
available (0.08 Â 0.01 Â 0.01 mm).
a
b
Á
Â
Luis Arturo Garcõa, Sylvain Bernes * and Cecilia Anaya
de Parrodia
a
Â
Â
Universidad de las Americas Puebla, Departamento de Ciencias Quõmico-
Biologicas, Santa Catarina Martir S/N, Cholula, 72820 Puebla, Mexico, and bDEP,
Â
Â
Â
Facultad de Ciencias Quõmicas, UANL, Guerrero y Progreso S/N, Col. Trevino,
Ä
During our work on the copper-catalyzed conjugate addi-
tion of Et2Zn to enones in the presence of chiral phosphor-
amidites (Feringa, 2000), we found that cyclohex-2-en-1-one,
(3), behaves as expected, affording 3-ethylcyclohexanone, (4),
but a by-product, the title compound, rac-(I), was also
produced in a low 6% yield (see Scheme 1 and Experimental).
Analytical data indicated that (I) is the 9-ethyl analogue of
Blake and co-workers' functionalized PHTP. In fact, these
authors also detected (I) in their oligomeric mixture, but were
unable to isolate it as a pure crystalline solid. We surmise that
the formation of rac-(I) under our conditions occurred by
trapping the enolate of 3-ethylcyclohexanone with cyclohex-2-
en-1-one, which afforded the enolate of trans-3-ethyl-2-(3-
hydroxycyclohex-2-enyl)cyclohexanone. This step was
followed by a Michael addition reaction with another
equivalent of cyclohex-2-en-1-one, and ®nally the ring closure
proceeded by an aldol reaction, leading to a functionalized-
PHTP enolate. Protonation ®nally afforded the title alcohol,
rac-(I).
64570 Monterrey NL, Mexico
Correspondence e-mail: sylvain_bernes@hotmail.com
Received 1 March 2008
Accepted 24 April 2008
Online 14 May 2008
The title compound, C20H30O3, is a new functionalized
perhydrotriphenylene derivative formed via a tandem Michael
addition±aldol reaction. The structural study reveals that the
system of fused rings approximates a C2 point symmetry, with
trans±cis±cis ring junctions, while highly symmetric all-trans
perhydrotriphenylene, previously characterized, approximates
a D3 symmetry. The perhydrotriphenylene nucleus of the title
compound corresponds to the third stable stereoisomer
isolated for this polycyclic system. Considering that the Cs
isomer was obtained recently through a similar tandem
reaction, a general strategy is proposed which may help to
obtain other stable stereoisomers of perhydrotriphenylene.
Comment
Perhydrotriphenylene (C18H30, abbreviated as PHTP herein-
after) has a complex stereochemistry. There are six enantio-
meric pairs and four meso forms, as determined by Farina &
Audisio (1970a). These authors were able to resolve into
antipodes the highly symmetrical isomer belonging to the D3
point group, in which all rings have a chair conformation and
all fused-ring junctions have a trans con®guration (Farina &
Audisio, 1970b). Following Farina's nomenclature, the D3
isomer may be described as anti±trans±anti±trans±anti±trans,
shortened to ATATAT. The trans descriptors apply to endo
CÐC bonds of the central ring (bonds shared by two rings),
while the anti descriptors are for CÐC exo bonds.
The molecular structure of compound (I) is illustrated in
Fig. 1. The relative stereochemistry at the six chiral C atoms of
the central A ring is 1aRS,4aRS,5aSR,8aRS,9aRS,12aSR. This
con®guration corresponds to ring junctions trans±cis±cis for
A/C, A/B and A/D, respectively (Scheme 2 and Fig. 1). All the
Racemic D3-PHTP has been characterized crystal-
lographically (Harlow & Desiraju, 1990). This isomer gener-
ally forms inclusion compounds with small organic molecules
È
(Konig et al., 1997). In most cases, crystallographic studies of
Acta Cryst. (2008). C64, o319±o321
DOI: 10.1107/S0108270108011876
# 2008 International Union of Crystallography o319

organic compounds
exo central CÐC bonds are anti. All six-membered rings have
chair conformations, with small deviations from ideal
geometry, which can be attributed to polycyclic strain [puck-
ering parameters (Cremer & Pople, 1975) ꢀ = 177.67 (16),
5.31 (18), 176.33 (17) and 1.36 (17)ꢀ for rings A, B, C and D,
respectively]. Assuming ideal chair conformations for rings
A±D, the PHTP core structure of rac-(I) corresponds to the
rac-ATACAC isomer in Farina's nomenclature, and belongs to
point group C2.
Figure 1
Interestingly, Blake et al. (2007) isolated a third isomer for
the core PHTP structure, namely meso-STACAT, which
includes a syn C8aÐC9a exo bond and a trans C9aÐC12a A/D
ring junction (Scheme 2). The central A ring has a twist-boat
conformation (ꢀ = 89.9ꢀ and ' = 146.3ꢀ), as does ring B (ꢀ =
85.9ꢀ and ' = 153.6ꢀ). The other peripheral rings have
distorted chair conformations (ring C: ꢀ = 167.5ꢀ; ring D: ꢀ =
169.4ꢀ). The PHTP nucleus of this isomer approximates a Cs
symmetry, assuming ideal boat and chair conformations.
However, considering departures from ideal geometry, the
actual symmetry is rather C1 and the molecule is not a true
meso form.
As discussed above, a reasonable assumption is that both C2
and Cs isomers are produced following identical routes. The
stabilization of different isomers should then be related to the
nature of the functional group at C9 rather than to the reac-
tion conditions. If the proposed tandem mechanism is correct,
the differentiation takes place during the ®rst Michael addi-
tion, forming the C8aÐC9a bond. In the case of 3-benzyl-
cyclohexanone enolate addition, a syn±exo CÐC bond is
formed. The benzyl group is then equatorial, avoiding 1,3-
diaxial interactions. With the ethyl analogue, the opposite
enolate enantiomer is more favourably added, leading to an
axially oriented ethyl group. The second Michael addition,
forming the C4aÐC5a bond and the ®nal ring closure, is
identical regardless of the substituent at C9. In both cases, it
seems that the aldol reaction, forming the C1aÐC12a bond, is
assisted by the formation of a weak intramolecular hydrogen
bond involving the hydroxy and carbonyl functional groups at
C12a and C1, respectively. Other noncovalent interactions
seem to have very little in¯uence on the observed structure.
For (I), the crystal packing features centrosymmetric dimers
formed through weak C OÁ Á ÁH hydrogen bonds (Table 1).
NMR data [COSY (correlation spectroscopy) and HSQC
(heteronuclear single quantum coherence)] are consistent
with the con®guration observed in the solid state. We thus
consider that the stereochemistry of (I) is induced by the Zn
The molecular structure of compound (I), showing the atom-numbering
scheme. Displacement ellipsoids are drawn at the 40% probability level
and H atoms are shown as small spheres of arbitrary radii. The
intramolecular hydrogen bond is indicated as a dashed line (see also
Table 1).
catalyst formed in situ, and not by intermolecular interactions
in the solid state.
In conclusion, we propose that the MiMiRC tandem reac-
tion (Mi = Michael addition; RC = ring closure) may be
extended to libraries of substituted enones, allowing new
stereoisomers of PHTP derivatives to be stabilized. By using
suitable easily removable functional groups, new pure or
racemic PHTP stereoisomers would then be achievable.
Experimental
(1S,2S)-trans-N,N0-Bis[1-(S)-phenylethyl]-1,2-diaminocyclohexane,
(S,S,S,S)-(1) (18 mg, 2.2 mol%) (Anaya de Parrodi et al., 1998),
diethylaniline (13 ml, 32 mol%), CDCl3 (0.5 ml) and PCl3 (4.6 M
solution in CH2Cl2, 12 ml, 2.3 mol%) were placed with vigorous stir-
ring in a NMR tube and the reaction was followed by 31P NMR
analysis. After 5 min, the chlorodiazaphospholidine was formed in
situ. Immediately after, phenol or naphthol (2.2 mol%) were added to
the reaction mixture with vigorous stirring, 31P NMR spectra were
recorded, showing that the chiral phosphoramidite ligands (S,S,S,S)-
(2a) or (S,S,S,S)-(2b) were produced. Phosphoramidites (S,S,S,S)-
(2a) and (S,S,S,S)-(2b) were added directly from the NMR tube,
without puri®cation, to a solution of Cu(OAc)2 (7.7 mg, 1.7 mol%) in
toluene (3 ml). The solution was stirred under N2 at 298 K for 30 min
and then cooled to 273 K. Et2Zn (1.0 M solution in hexane, 3.8 ml,
3.8 mmol, 1.5 equivalents) and cyclohex-2-en-1-one, (3) (0.24 ml,
2.5 mmol, 1 equivalent), were added to the reaction mixture. After
5 h at 273 K, the reaction was quenched with aqueous NH4Cl and the
mixture was extracted with CH2Cl2 (2 Â 20 ml). The organic phases
were combined, dried over Na2SO4, ®ltered and concentrated. The
crude product was puri®ed by column chromatography on deacti-
vated silica gel (Et3N/SiO2, 2.5% v/v) with hexane as eluent, affording
rac-3-ethylcyclohexanone, (4) (47 mg, 15%), a mixture of non-
ꢁ
Â
o320 Garcõa et al. C20H30O3
Acta Cryst. (2008). C64, o319±o321

organic compounds
isolated oligomers, and rac-(I) as colourless crystals (48 mg, 6%),
which were recrystallized from hexane±CH2Cl2 (10:1 v/v). Analytical
data for rac-(I) are available in the archived CIF.
included in calculated positions and treated as riding atoms, with CÐ
Ê
H = 0.96±0.98 A and Uiso(H) = 1.2 or 1.5Ueq(C).
Data collection: XSCANS (Siemens, 1996); cell re®nement:
XSCANS; data reduction: XSCANS; program(s) used to solve
structure: SHELXTL-Plus (Sheldrick, 2008); program(s) used to
re®ne structure: SHELXTL-Plus; molecular graphics: SHELXTL-
Plus; software used to prepare material for publication: SHELXTL-
Plus.
Crystal data
C20H30O3
ꢃ = 67.681 (9)ꢀ
V = 858.41 (18) A
Z = 2
3
Ê
Mr = 318.44
Triclinic, P1
a = 8.6898 (10) A
Ê
Ê
Mo Kꢁ radiation
1
b = 9.2312 (12) A
ꢄ = 0.08 mm
T = 298 (2) K
Ê
c = 12.3633 (14) A
ꢁ = 72.377 (11)ꢀ
ꢂ = 73.574 (10)ꢀ
Â
Â
SB is grateful to Benemerita Universidad Autonoma de
Puebla (BUAP) for diffractometer time. The authors
acknowledge CONACyT (project No. 55802) for ®nancial
support.
0.60 Â 0.44 Â 0.18 mm
Data collection
Bruker P4 diffractometer
6729 measured re¯ections
3878 independent re¯ections
2728 re¯ections with I > 2ꢅ(I)
Rint = 0.018
3 standard re¯ections
every 97 re¯ections
intensity decay: 1%
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: SU3020). Services for accessing these data are
described at the back of the journal.
Re®nement
R[F2 > 2ꢅ(F2)] = 0.042
wR(F2) = 0.118
S = 1.05
3878 re¯ections
213 parameters
H atoms treated by a mixture of
independent and constrained
re®nement
References
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3
Ê
Áꢆmax = 0.21 e A
3
Ê
0.16 e A
Áꢆmin
=
È
Burgi, H.-B., Hauser, J., Weber, T. & Neder, R. B. (2005). Cryst. Growth Des. 5,
2073±2083.
Table 1
Hydrogen-bond geometry (A, ).
ꢀ
Ê
Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354±1358.
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DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
O3ÐH3Á Á ÁO1
0.82 (2)
0.98
2.01 (2)
2.52
2.7081 (16)
3.4381 (18)
143 (2)
156
C8aÐH8aAÁ Á ÁO2i
È
È
Konig, O., Burgi, H.-B., Armbruster, T., Hulliger, J. & Weber, T. (1997).
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Symmetry code: (i) x ‡ 1; y; z ‡ 1.
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ments Inc., Madison, Wisconsin, USA.
Hydroxyl atom H3 was located in a difference Fourier map and
Ê
re®ned freely, with OÐH = 0.82 (2) A. The remaining H atoms were
È
Weber, T., Estermann, M. A. & Burgi, H.-B. (2001). Acta Cryst. B57, 579±590.
ꢁ
Â
Acta Cryst. (2008). C64, o319±o321
Garcõa et al. C20H30O3 o321