Synthesis of a chiral helical molecular template based on trans-5,6,6a,7,8,12b-hexahydro-1,12-dimethylbenzo[c]phenanthrene-5,8-d ione

Article abstract of DOI:10.1021/jo961254z

Reduction of trans-5,5,6a,7,8,12b-hexahydro-1,12-dimethylbenzo[c]phenanthrene-5,8-d ione (1, R₁ = R₄ = H, R₂ = R₃ = CH₃) with lithium aluminum hydride yielded stereoselectively (5RS,8RS)-trans-5,6,6a,7,8,12b-hexahydro-1,12-dimethylbenzo[c]phenanth rene-5,8-diols 2, X = H. These diols proved to be configurationally stable chiral molecular templates capable of straightforward modification by attachment of molecular elements of different length and kind. The structures of the diacetate 2, X = COCH₃, and (5R,8R)-(-)-trans-5,6,6a,7,8,12b-hexahydro-1,12-dimethylbenzo[c]phenan threne-5,8-diyl di-p-bromobenzoate (2a, X = p-BrC₆H₄CO), as well as the absolute configuration of the latter were obtained by X-ray crystallography.

Full text of DOI:10.1021/jo961254z

62
J . Org. Chem. 1997, 62, 62-66
Syn th esis of a Ch ir a l Helica l Molecu la r Tem p la te Ba sed on
tr a n s-5,6,6a ,7,8,12b-Hexa h yd r o-1,12-d im eth ylben zo[c]p h en a n th r en e-
5,8-d ion e
J ulie Cheung,1a Leslie D. Field,1a Trevor W. Hambley,1b and Sever Sternhell*,1a
Department of Organic Chemistry and Department of Inorganic Chemistry, The University of Sydney,
New South Wales 2006, Australia
Received J uly 2, 1996X
Reduction of trans-5,5,6a,7,8,12b-hexahydro-1,12-dimethylbenzo[c]phenanthrene-5,8-dione (1, R1
) R4 ) H, R2 ) R3 ) CH3) with lithium aluminum hydride yielded stereoselectively (5RS,8RS)-
trans-5,6,6a,7,8,12b-hexahydro-1,12-dimethylbenzo[c]phenanthrene-5,8-diols 2, X ) H. These diols
proved to be configurationally stable chiral molecular templates capable of straightforward
modification by attachment of molecular elements of different length and kind. The structures of
the diacetate 2, X ) COCH3, and (5R,8R)-(-)-trans-5,6,6a,7,8,12b-hexahydro-1,12-dimethylbenzo-
[c]phenanthrene-5,8-diyl di-p-bromobenzoate (2a , X ) p-BrC6H4CO), as well as the absolute
configuration of the latter were obtained by X-ray crystallography.
In tr od u ction
We have previously described2 the synthesis of a series
of helical ketones 1 and have shown that trans-5,6,-
6a,7,8,12b-hexahydro-1,12-dimethylbenzo[c]phenanthrene-
5,8-dione (1, R1 ) R4 ) H, R2 ) R3 ) CH3) was
indefinitely stable at ambient temperature, i.e., that the
inversion 1a a 1b is very slow.3 We now wish to report
the preparation of a chiral molecular template based on
this compound.
F igu r e 1. ORTEP plot of (5R,8R)-trans-(-)-5,6,6a,7,8,12b-
hexahydro-1,12-dimethylbenzo[c]phenanthrene-5,8-diyl di-
acetate (2, X ) COCH3) showing atomic labels (30% thermal
ellipsoids).
diastereomers may be formed. For each sense of the
helix, the hydroxy groups on C5 and C8 could be either
both R, both â, or one R and the other â. The latter case
would give rise to two diastereomers. The four diaster-
eomers of one sense of the helix are each enantiomerically
related to those of the other helical sense; thus, in total,
there are four possible diastereomers of the diol 2, X )
H.
However, according to the 1H NMR spectrum (400
MHz) of the crude reaction product, the reaction pro-
ceeded to give exclusively one of the diastereomers. The
stereoselectivity of lithium aluminum hydride reduction
meant that only one of the four possible diastereomers
was generated and the reaction proceeded in essentially
quantitative yield. The diol 2 (X ) H) forms the desired
helical template, and esterification of this diol using
acetic anhydride and various acyl chlorides would allow
systematic variation of the molecular rods.
Our basic design aim was to incorporate the chiral
helical entity into a rodlike molecule in which we could
control (a) the length of the rods and (b) the nature of
the rods. This implies an attachment of molecular
elements to the carbonyl groups of 1. We have explored
a number of possibilities of which the stereoselective
reduction with lithium aluminum hydride was by far the
most successful.
P r ep a r a tion of Com p ou n d s
The dione 1, R1 ) R4 ) H, R2 ) R3 ) CH3, was reduced
using lithium aluminum hydride to give the diol 2, X )
H. Depending on the directions of attack of the nucleo-
phile on C5 and C8 (axial or equatorial), four possible
The diacetate 2, X ) COCH3, was synthesized by the
acetylation of the diol 2, X ) H, with acetic anhydride in
pyridine. The X-ray crystal structure of this compound
was obtained, and the ORTEP plot is given in Figure 1.
X Abstract published in Advance ACS Abstracts, December 1, 1996.
(1) (a) Department of Organic Chemistry. (b) Department of Inor-
ganic Chemistry.
(2) Cheung, J .; Field, L. D.; Regaglia, F.; Sternhell, S. Aust. J . Chem.
1995, 48, 1707.
(3) Cheung, J .; Field, L. D.; Hambley, T. W.; Sternhell, S. Aust. J .
Chem. 1995, 48, 1727.
The ORTEP plot and the structural data (see the
Supporting Information) indicated that the ester chains
are in pseudoequatorial positions in relation to the helical
S0022-3263(96)01254-6 CCC: $14.00 © 1997 American Chemical Society

Synthesis of a Chiral Helical Molecular Template
J . Org. Chem., Vol. 62, No. 1, 1997 63
Sch em e 1
F igu r e 2. Values of the experimental vicinal coupling con-
stants of the diol 2, X ) H (O), and the diacetate 2, X ) COCH3
(b), and the dihedral angles (φ) obtained from the X-ray data
of the diacetate 2, X ) COCH3, fitted onto the Karplus plot.4
framework and are approximately coplanar, thus giving
1
an elongated shape. Detailed analysis of the H NMR
spectra, in particular, the vicinal coupling constants of
protons on C5, C6, C6a, C7, and C8, of the diol 2, X ) H,
and the diacetate 2, X ) COCH3, also indicate that H5
and H8 in both compounds are pseudoaxial. The con-
Ta ble 1. Sp ecific Rota tion s a n d Mola r Differ en tia l
Dich r oic Absor p tion s for th e Diols 2, X ) H, a n d Th eir
Der iva tives
1
formations of these two compounds derived from the H
NMR data are remarkably similar to the conformation
depicted in the ORTEP plot of the diacetate 2, X )
COCH3, indicating the conformation of these helical
molecules is the same in solution and in crystal form.
This was established by plotting the dihedral angles
between these vicinal C-H bonds, obtained from the
X-ray structural data, against the observed vicinal
coupling constants (Figure 2). It was found that the
experimental data agreed well with the Karplus plot
calculated for this type of molecules.4
compd
[R]23
D
∆ꢀ (CHCl3)
2a , X ) Ha
-307 (c ) 0.5, CHCl3)g
+305 (c ) 0.2, CHCl3)g
+270 (c ) 0.1, CHCl3)g
-251 (c ) 0.3, CHCl3)g
+231 (c ) 0.9, CHCl3)g
2b, X ) Hb
2b, X ) Hc
d
d
e
f
2a , X ) COCH3
2b, X ) COCH3
2a , X ) COCH3
2b, X ) COCH3
-1.1 (283 nm)
+1.1 (282 nm)
-1.0 (285 nm)
+1.0 (285 nm)
a
b
Obtained from hydrolysis of the diester 5a . Obtained from
hydrolysis of the diester 5b. c Obtained from hydrolysis of the
d
diester 2b, X ) p-BrC6H6CO. Resolved by HPLC on a chiral
column. e Obtained from acetylation of the resolveda diol 2a , X )
The stereochemistry of the diol implies that the reduc-
tion of the dione 1, R1 ) R4 ) H, R2 ) R3 ) CH3, with
lithium aluminum hydride is the result of axial attacks
by the incoming nucleophiles generating pseudoequato-
rial alcohols and thus complying with the general rule
of stereoselectivity of the reduction of cyclohexanones.5-7
Resolu tion of Der iva tives of th e Diol 2 a n d th e
Deter m in a tion of Absolu te Con figu r a tion s of th e
En a n tiom er s. The diactete 2, X ) COCH3, was resolved
directly using HPLC with a chiral column (see Experi-
mental Section) in high enantiomeric purity (determined
H. f Obtained from acetylation of the resolvedb diol 2b, X ) H.
g
These values were determined on samples weighing between
0.9-5 mg and are therefore significant to approximately (10%.
sis product of the acyl chloride 4 and an authentic sample
of the acid 3 were found to be identical. The diastereo-
meric diesters 5a and 5b could be easily separated on a
silica column and, by hydrolysis, gave the resolved diols
2a , X ) H, and 2b, X ) H. The enantiomers of the
diactete 2, X ) COCH3, were prepared from the resolved
diols 2a , X ) H, and 2b, X ) H (Scheme 1). The
diacetates 2a , X ) COCH3, and b, X ) COCH3, were
found to be identical on the basis of their CD data to the
pair of diacetates resolved by HPLC (Table 1).
However, the relative configurations of the diastereo-
meric diesters 5a and 5b could not be determined by
X-ray crystallography since neither of them produces
good quality crystals. In order to determine the absolute
configurations of the diols 2a , X ) H, and 2b, X ) H,
and their derivatives, the diester 2, X ) p-COC6H4Br,
was synthesized with the acyl chloride of 4-bromobenzoic
acid. This diester 2, X ) p-COC6H4Br, was then resolved
by HPLC with a chiral column. One of the enantiomers
2a , X ) p-COC6H4Br, was successfully recrystallized to
produce a good quality crystal for X-ray crystallography,
and the absolute configuration of this diester was deter-
mined. The ORTEP plot is shown in Figure 3. The other
enantiomer of the diester 2b, X ) p-COC6H4Br, was
1
by H NMR with the addition of a chiral shift reagent).8
It was also found to be possible to resolve the diol 2, X
) H, by converting it into a mixture of diastereomeric
diesters with the acyl chloride of (S)-R-methoxyphenyl-
acetic acid 39 according to Scheme 1. To show that
racemisation had not occurred when the acid 3 was
reacted with thionyl chloride, a portion of the product,
(S)-R-methoxyphenylacetyl chloride 4, was hydrolysed to
the acid with water. The optical rotations of the hydroly-
(4) Colucci, W. J .; J ungk, S. J .; Gandour, R. D. Magn. Reson. Chem.
1985, 23, 335.
(5) Anh, N. T.; Eisenstein, O. Nouv. J . Chim. 1976, 1(1), 61.
(6) Wigfield, D. C. Tetrahedron 1979, 35, 449.
(7) Che´rest, M.; Felkin, H. Tetrahedron Lett. 1968, 18, 2205.
(8) (SP)-tert-Butylphenylphosphinothioic acid was used as the chiral
shift reagent. For preparation, see: Haynes, R.; Freeman, R.; Mitchell,
C.; Vonwiller, S. C. J . Org. Chem. 1994, 59, 2919.
(9) McKenzie, A. J . Chem. Soc. 1899, 75, 761.

64 J . Org. Chem., Vol. 62, No. 1, 1997
Cheung et al.
threne-5,8-diol (2, X ) H) (98 mg, 98%) as colorless needles;
mp 238-240 °C (lit.12 mp 213-214 °C); UV (ethanol) 255.9
(log ꢀ, 2.81) nm; 1H NMR (600 MHz, CD2Cl2) δ 1.17 (ddd, J )
12.2, 11.4, 11.4 Hz, 1H), 1.32 (ddd, J ) 12.7, 9.3, 8.3 Hz, 1H),
1.43-1.56 (m, 1H), 1.53 (s, 3H), 1.93 (ddd, J ) 12.2, 4.1, 3.6
Hz), 1.96 (ddd, J ) 12.7, 9.5, 9.5 Hz, 1H), 2.07 (s, 3H), 3.49 (d,
J ) 11.2 Hz, 1H), 4.43 (dd, J ) 11.4, 3.6 Hz, 1H), 4.76 (dd, J
) 9.5, 9.3 Hz, 1H), 6.89 (dd, J ) 7.8, 1.3 Hz, 1H), 7.08 (dd, J
) 7.8, 1.1 Hz, 1H), 7.15 (dd, J ) 7.8, 7.8 Hz, 1H), 7.23 (dd, J
) 7.8, 7.8 Hz, 1H), 7.45 (dd, J ) 7.8, 1.3 Hz), 7.52 (dd, J )
7.8, 1.1, 1.1 Hz); MS m/ e 294 (M+, 30). Anal. Calcd for
C20H22O2: C, 81.6; H, 7.5. Found: C, 81.7; H, 7.5.
(5RS,8RS)-tr a n s-5,6,6a ,7,8,12b -H exa h yd r o-1,12-d im e-
t h ylb en zo[c]p h en a n t h r en e-5,8-d iyl Dia cet a t e (2, X )
COCH3). Acetic anhydride (87 mg) was added dropwise to a
solution of (5RS,8RS)-trans-5,6,6a,7,8,12b-hexahydro-1,12-
dimethylbenzo[c]phenanthrene-5,8-diol (2, X ) H) (128 mg, 0.4
mmol) in dry pyridine (10 mL) at rt. The solution was heated
at 40 °C for 1 h, poured into cold water, and stirred. The
mixture was filtered, and the residue of (5RS,8RS)-trans-5,6,-
6a,7,8,12b-hexahydro-1,12-dimethylbenzo[c]phenanthrene-5,8-
diyl diacetate (2, X ) COCH3) (108 mg, 72%) was collected.
Recrystallization from methanol gave an analytical sample
that melted at 208-211 °C. Extraction of the filtrate failed
to yield any additional product: UV (chloroform) 286.0 (log ꢀ,
F igu r e 3. ORTEP plot of (5R,8R)-(-)-trans-5,6,6a,7,8,12b-
hexahydro-1,12-dimethylbenzo[c]phenanthrene-5,8-diyl di-p-
bromobenzoate 2a , X ) p-BrC6H4CO, showing atomic labels
(30% thermal ellipsoids).
hydrolyzed to an enantiomer of the diol 2, X ) H, which
was correlated with the enantiomer of this diol obtained
from the hydrolysis of the diastereomeric diester 5b on
the basis of their specific rotations (Table 1). Thus, the
absolute configurations of the diols 2a , X ) H, and 2b, X
) H, and therefore the absolute configurations of the
diacetates 2a , X ) COCH3, and 2b, X ) COCH3,
synthesized from the diols were determined, and they are
shown in Scheme 1.
1
4.02), 238.5 (4.07) nm; H NMR (600 MHz, CDCl3) δ 1.53 (s,
3H), 1.59 (ddd, J ) 12.6, 11.5, 11.5 Hz, 1H), 1.74 (ddd, J )
13.1, 9.0, 8.3 Hz, 1H), 1.86-1.98 (m, 1H), 2.10 (s, 3H), 2.20 (s,
3H), 2.28 (s, 3H), 2.29 (ddd, J ) 12.6, 4.0, 3.6 Hz, 1H), 2.35
(ddd, J ) 13.1, 9.7, 9.7 Hz, 1H), 3.85 (d, J ) 11.2 Hz, 1H),
5.98 (dd, J ) 11.5, 3.6 Hz, 1H), 6.14 (dd, J ) 9.7, 9.0 Hz, 1H),
6.90 (dd, J ) 7.5, 1.3 Hz, 1H), 7.10 (dd, J ) 7.0, 1.3 Hz, 1H),
7.12 (dd, J ) 7.5, 7.5 Hz, 1H), 7.15 (dd, J ) 7.0, 1.3 Hz, 1H),
7.21 (dd, J ) 7.0, 7.0 Hz, 1H), 7.22 (dd, J ) 7.5, 1.3 Hz, 1H);
13C NMR (50 MHz, CDCl3) δ 20.1, 20.7, 21.3, 33.8, 35.2, 35.7,
43.3, 69.2, 71.5, 120.8, 122.7, 125.5, 126.5, 129.2, 130.8, 132.6,
135.2, 136.8, 137.3, 138.6, 138.6, 170.6, 171.0; MS m/ z 378
(M+, 19). Anal. Calcd for C24H26O4: C, 76.2; H, 6.9. Found:
C, 75.9; H, 6.9.
Con clu sion s
Clearly, esterification of the diols 2a , X ) H, and 2b,
X ) H, with a variety of acyl chlorides is straightforward
and leads to a series of chiral templates with rods of
variable type and length attached to it in a manner
shown in structure 6. It is apparent that these com-
pounds, which are now under investigation in these
laboratories, are similar in type to Cram’s binaphthyl
derivatives10 because their chirality involves a large steric
barrier to inversion of the helicene-like skeleton.
Resolu tion of (5RS,8RS)-tr a n s-5,6,6a ,7,8,12b-Hexa h y-
d r o-1,12-d im eth ylben zo[c]p h en a n th r en e-5,8-d iyl Dia c-
eta te (2, X ) COCH3). The resolution of the diacetates 2a ,
X ) COCH3, and 2b, X ) COCH3 (10 mg), was achieved by
preparative HPLC with a chiral stationary phase (eluant:
2-propanol (2.0%) in light petroleum). (5R,8R)-(-)-trans-5,6,-
6a,7,8,12b-Hexahydro-1,12-dimethylbenzo[c]phenanthrene-
5,8-diyl diacetate (2a , X ) COCH3) (4.5 mg, 45%) was obtained
as the first fraction: [R]20D -251.2 (c ) 0.3, CHCl3); UV
(chloroform) 282 (log ꢀ, 2.78) nm; CD (chloroform) [θ]295 0; [θ]270
-3630.
Exp er im en ta l Section
The second fraction consisted of (5S,8S)-(+)-trans-5,6,-
6a,7,8,12b-hexahydro-1,12-dimethylbenzo[c]phenanthrene-5,8-
diyl diacetate (2b, X ) COCH3) (4.0 mg, 40%): [R]20D +230.7
(c ) 0.9, CHCl3); UV (chloroform) 265 (log ꢀ, 2.79) nm; CD
Gen er a l Meth od s. The term worked up in the usual way
means that a solution of the product was washed with alkali
and/or acid (as indicated) and with saturated saly solution.
The solution was then filtered and dried over anhydrous
magnesium sulfate and the solvent removed under reduced
pressure. Analytical instruments and general procedures used
in this work were previously described.2,3 Both analytical and
preparative chiral HPLC were carried out using a Regis Pirkle
type 1-A chiral column, 10 mm i.d. × 25 cm (5 µm partical
size), at a flow rate of 3.0 mL/min.
(5RS,8RS)-tr a n s-5,6,6a ,7,8,12b -H exa h yd r o-1,12-d im e-
th ylben zo[c]p h en a n th r en e-5,8-d iols (2, X ) H). A solution
of trans-5,6,6a,7,8,12b-hexahydro-1,12-dimethylbenzo[c]phenan-
threne-5,8-dione (1, R1 ) R4 ) H, R2 ) R3 ) CH3) (100 mg, 0.3
mmol) in dry THF (10 mL) was added gradually to a suspen-
sion of powdered lithium aluminum hydride (0.5 g) in dry THF
(50 mL). The mixture was heated at reflux under nitrogen
for 2 h, ether (50 mL) was added, and the excess lithium
aluminum hydride was decomposed with hydrochloric acid (3
M). The organic layer was worked up as usual, and the crude
product was recrystallized from chloroform to yield (5RS,8RS)-
trans-5,6,6a,7,8,12b-hexahydro-1,12-dimethylbenzo[c]phenan-
1
(chloroform) [θ]295 0; [θ]270 +3630. The H NMR spectra of the
racemic diacetate 2, X ) COCH3, and the resolved diacetates
2a , X ) COCH3, and 2b, X ) COCH3, were identical.
(S)-r-Meth oxyp h en yla cetyl Ch lor id e (4). Thionyl chlo-
ride (1 mL) was added dropwise to a solution of (S)-R-
methoxyphenylacetic acid (3) (200 mg, 1.87 mmol, [R]22D +143
(c ) 1.7, C2H5OH) (lit.13 [R]17D +150 (c ) 1, C2H5OH))) in dry
benzene (2 mL) at reflux and the reaction mixture stirred at
rt under nitrogen for 3 h. The excess thionyl chloride and
benzene were removed under reduced pressure to give (S)-R-
methoxyphenylacetyl chloride (4) (186 mg, 80%), which was
used in the next step without further purification: IR (chlo-
1
roform) 1743 (CdO) cm-1; H NMR (200 MHz, CDCl3) δ 3.53
(s, 3H), 5.01 (s, 1H), 7.30-7.60 (m, 5H).
A portion of this material (approximately 10 mg) was
hydrolyzed by stirring in water (5 mL) for 30 min. The
solution was extracted with ether; the ether layers were
worked up in the usual manner to yield (S)-R-methoxyphenyl-
acetic acid (3), [R]22D +145 (c ) 2.1, C2H5OH) showing that
(10) Cram, D. J . Angew. Chem., Int. Ed. Engl. 1988, 27(8), 1009.
(11) Newman, M. S.; Lednicer, D. J . Am. Chem. Soc. 1956, 78, 4765.
(12) Newman, M. S.; Wolf, M. J . Am. Chem. Soc. 1952, 74, 3225.
(13) McKenzie, A.; Walker, N. J . Chem. Soc. 1915, 107, 1700.

Synthesis of a Chiral Helical Molecular Template
J . Org. Chem., Vol. 62, No. 1, 1997 65
the formation of the acyl chloride 4 was not accompanied by
racemization.
anhydride (0.2 mL) was added and the mixture stirred at that
temperature for 1 h. The mixture was poured onto ice and
extracted with ether. The ether layers were washed with
dilute hydrochloric acid (3 M) and worked up in the usual
manner to give (5R,8R)-(-)-trans-5,6,6a,7,8,12b-hexahydro-1,-
12-dimethylbenzo[c]phenanthrene-5,8-diyl diacetate (2a , X )
COCH3) (2.9 mg, 60%): CD (chloroform) [θ]295 0; [θ]270 -3630.
The 1H NMR spectrum of this diacetate 2a , X)COCH3, was
identical to that of the racemic diacetate 2, X ) COCH3.
(5R ,8R )-(-)-t r a n s-5,6,6a ,7,8,12b -H e xa h yd r o-1,12-d i-
m eth ylben zo[c]p h en a n th r en e-5,8-d iyl Dia ceta te (2b, X
) COCH3). (5S,8S)-(+)-trans-5,6,6a,7,8,12b-Hexahydro-1,12-
dimethylbenzo[c]phenanthrene-5,8-diyl bis[(S)-R-methoxy-
phenylacetate] (5b) (10 mg was treated in the same manner
as (5R,8R)-(-)-trans-5,6,6a,7,8,12b-hexahydro-1,12-dimethyl-
(5R ,8R )-(-)-t r a n s-5,6,6a ,7,8,12b -H e xa h yd r o-1,12-d i-
m et h ylb en zo[c]p h en a n t h r en e-5,8-d iyl Bis[(S)-r-m et h -
oxyp h en yla ceta te] (5a ) a n d (5S,8S)-(+)-tr a n s-5,6,6a ,7,8,-
12b-Hexa h yd r o-1,12-d im eth ylben zo[c]p h en a n th r en e-5,8-
d iols Bis[(S)-r-m eth oxyp h en yla ceta te (5b). (5RS,8RS)-
tr a n s-5,6,6a ,7,8,12b-H exa h ydr o-1,12-dim et h ylben zo[c]-
phenanthrene-5,8-diol (2, X ) H) (120 mg, 0.37 mmol) was
dissolved in a mixture of dry pyridine (0.38 mL) and dry
benzene (12 mL) maintained at 40 °C. (S)-R-Methoxyphenyl-
acetyl chloride 4 (185 mg, 1.0 mmol) was added dropwise to
the solution and the mixture maintained at 40 °C for 1 h. The
solution was poured into cold water and extracted with ether.
The combined ether extracts were washed with saturated
sodium bicarbonate solution and worked up in the usual way
to give a white solid (164 mg, 75%) that was purified by flash
chromatography over silica (eluant: ethyl acetate (10%) in
light petroleum). The first major fraction, (5R,8R)-(-)-trans-
5,6,6a,7,8,12b-hexahydro-1,12-dimethylbenzo[c]phenanthrene-
5,8-diyl bis[(S)-R-methoxyphenylacetate] (5a ) (79 mg, 36%),
was recrystallized from methanol to give white needles: mp
163-165 °C; [R]23D -122 (c ) 0.3, CHCl3); UV (chloroform)
benzo[c]phenanthrene-5,8-diyl
bis[(S)-R-methoxyphenyl-
acetate] (5a ) to give (5R,8R)-(+)-trans-5,6,6a,7,8,12b-hexahy-
dro-1,12-dimethylbenzo[c]phenanthrene-5,8-diol (2b, X ) H)
(4.0 mg, 95%) as a white solid: [R]23D +305 (c ) 0.2, CHCl3).
The 1H NMR spectrum of this resolved diol was identical to
that of the racemic diol 2, X ) H.
Esterification of the resolved diol 2b, X ) H, with acetic
anhydride gave (5R,8R)-(+)-trans-5,6,6a,7,8,12b-hexahydro-
1,12-dimethylbenzo[c]phenanthrene-5,8-diyl diacetate (2b, X
1
240 (log ꢀ, 2.04) nm; H NMR (400 MHz, CDCl3) δ 1.40 (ddd,
J ) 12.0, 11.4, 11.4 Hz, 1H, H6R), 1.48 (s, 3H), 1.55 (ddd, J )
12.6, 9.0, 9.0 Hz, 1H), 1.71-1.82 (m, 1H), 1.95 (ddd, J ) 12.0,
3.6, 3.4 Hz, 1H), 2.02 (s, 3H), 2.12 (ddd, J ) 12.6, 9.8, 9.8 Hz,
1H), 3.49 (s, 3H), 3.54 (s, 3H), 3.75 (d, J ) 10.4 Hz, 1H), 4.89
(s, 1H), 4.98 (s, 1H), 5.97 (dd, J ) 11.4, 3.4 Hz, 1H), 6.11 (dd,
J ) 9.8, 9.0 Hz, 1H), 6.88 (dd, J ) 8.0, 0.8 Hz, 1H), 7.03 (d, J
) 8.0, 0.8 Hz, 1H), 7.08 (d, J ) 8.0, 0.8 Hz, 1H), 7.09 (dd, J )
8.0, 8.0 Hz, 1H), 7.15 (dd, J ) 8.0, 0.8 Hz, 1H), 7.17, dd, J )
8.0, 8.0 Hz, 1H), 7.34-7.52 (m, 10H); 13C NMR (100 MHz,
CDCl3) δ 20.0, 20.7, 33.2, 34.7, 35.2, 43.3, 57.4, 57.5, 69.8, 72.0,
82.7, 120.8, 122.7, 125.6, 126.5, 129.3, 130.9, 127.1, 128.6-
128.8, 132.6, 135.1, 135.1, 136.0, 136.3, 136.8, 138.4, 138.6,
170.2, 170.6. Anal. Calcd for C38H38O6: C, 77.3; H, 6.4.
Found: C, 77.2; H, 6.6.
) (2.9, 75%) as a white solid: CD (chloroform) [θ]295
) COCH3
0; [θ]270 +3630. The 1H NMR spectrum of this resolved
diacetate was identical to that of the racemic diacetate 2, X )
COCH3.
(5RS,8RS)-tr a n s-5,6,6a ,7,8,12b -H exa h yd r o-1,12-d im e-
th ylben zo[c]p h en a n th r en e-5,8-d iyl Di-p-br om oben zoa te
(2, X ) p-Br C6H4CO). p-Bromobenzoyl chloride, prepared
from p-bromobenzoic acid (400 mg, 2.0 mmol), was added to a
solution of (5RS,8RS)-trans-5,6,6a,7,8,12b-hexahydro-1,12-
dimethylbenzo[c]phenanthrene-5,8-diol (2, X ) H) (200 mg, 0.7
mmol) in dry pyridine (4 mL) held at 40 °C. The reaction
mixture was heated at that temperature for 1 h, at which time
it was poured into cold water. The mixture was filtered, and
the solid collected was purified by column chromatography
over silica (eluant: dichlorometane (10%) in light petroleum)
to give (5RS,8RS)-trans-5,6,6a,7,8,12b-hexahydro-1,12-dim-
ethylbenzo[c]phenanthrene-5,8-diyl di-p-bromobenzoate (2, X
) p-BrC6H4CO) (180 mg, 42%). It was recrystallized from
chloroform/methanol to give pale yellow crystals: mp 230 °C;
1H NMR (400 MHz, CDCl3) δ 1.59 (s, 3H), 1.75 (ddd, J ) 12.3,
11.1, 11.1 Hz, 1H), 1.93 (ddd, J ) 12.7, 8.7, 8.7 Hz, 1H), 2.03-
2.10 (m, 1H), 2.12 (s, 3H), 2.44 (ddd, J ) 12.3, 3.6, 3.6 Hz,
1H), 2.49 (ddd, J ) 12.7, 9.6, 9.6 Hz, 1H), 3.98 (d, J ) 11.0
Hz, 1H), 6.26 (dd, J ) 11.1, 4.1 Hz, 1H), 6.42 (dd, J ) 8.8, 8.7
Hz, 1H), 6.95 (d, J ) 7.6, 1.0 Hz, 1H), 7.14-7.16 (m, 4H), 7.31
(d, J ) 7.6 Hz, 1H), 7.62 and 7.99 (AA′ΒΒ′, J ) 8.6 Hz, 4H),
7.67 and 8.08 (AA′BB′, J ) 8.6 Hz, 4H); 13C NMR (100 MHz,
CDCl3) δ 19.7, 20.7, 33.7, 35.0, 35.3, 43.3, 70.0, 72.7, 120.5,
122.7, 125.4, 126.4, 128.4, 129.1, 129.4, 130.7, 131.7, 132.0,
132.5, 135.4, 135.7, 137.4, 138.6, 139.1, 166.3, 166.7.
The second major fraction, (5S,8S)-(+)-trans-5,6,6a,7,8,12b-
hexahydro-1,12-dimethylbenzo[c]phenanthrene-5,8-diyl bis-
[(S)-R-methoxyphenylacetate] (5b) (75 mg, 34%) was obtained
as a white foam that was recrystallized from benzene/light
petroleum to give white crystals: mp 79-80 °C; [R]23D +130
(c ) 0.5, CHCl3); UV (chloroform) 265.2 (log ꢀ 1.48), 259.8
1
(1.48), 239.2 (1.74) nm; H NMR (400 MHz, CDCl3) δ 1.42 (s,
3H), 1.59 (ddd, J ) 12.0, 11.2, 11.2 Hz, 1H), 1.74 (ddd, J )
12.8, 8.4, 8.4 Hz, 1H), 1.82-1.94 (m, 1H), 1.96 (s, 3H), 2.29
(ddd, J ) 12.0, 3.6, 3.6 Hz, 1H), 2.35 (ddd, J ) 12.8, 9.6, 9.6
Hz, 1H), 3.47 (s, 3H), 3.51 (s, 3H), 3.75 (d, J ) 11.0 Hz, 1H),
4.85 (s, 1H), 4.97 (s, 1H), 5.97 (dd, J ) 11.3, 4.1 Hz, 1H), 6.11
(dd, J ) 8.6, 8.2 Hz, 1H), 6.34 (dd, J ) 7.8, 1.0 Hz, 1H), 6.65
(dd, J ) 7.8, 1.0 Hz, 1H), 6.79, dd, J ) 7.8, 1.0 Hz, 1H), 6.87
(dd, J ) 7.8, 7.8 Hz, 1H), 6.89 (dd, J ) 7.8, 7.8 Hz, 1H), 6.99
(dd, J ) 7.8, 1.0 Hz, 1H), 7.39-7.58 (m, 10H); 13C NMR (100
MHz, CDCl3) δ 20.0, 20.6, 33.8, 35.1, 35.4, 43.2, 57.3, 57.3,
69.6, 72.0, 82.7, 82.8, 120.6, 122.6, 125.5, 126.3, 127.6, 128.8-
129.2, 130.8, 132.5, 134.9, 136.2, 136.3, 136.5, 136.9, 138.3,
138.5, 170.1, 170.5. Anal. Calcd for C38H38O6: C, 77.3; H, 6.4.
Found: C, 77.5; H, 6.6.
R esolu t ion of (5RS,8RS)-tr a n s-5,6,6a ,7,8,12b -H exa -
h yd r o-1,12-d im eth ylben zo[c]p h en a n th r en e-5,8-d iols Di-
p-br om oben zoa te (2, X ) p-Br C6H4CO). The resolution of
the diesters 2a , X ) p-BrC6H4CO, and 2b, X ) p-BrC6H4CO
(40 mg), was achieved by preparative HPLC with a chiral
stationary phase (eluant: 2-propanol (0.4%) in light petro-
leum). (5R,8R)-(-)-trans-5,6,6a,7,8,12b-hexahydro-1,12-di-
methylbenzo[c]phenanthrene-5,8-diyl di-p-bromobenzoate (2a ,
X ) p-BrC6H4CO) (15 mg) was obtained as the first fraction,
(5R ,8R )-(-)-t r a n s-5,6,6a ,7,8,12b -H e xa h yd r o-1,12-d i-
m eth ylben zo[c]p h en a n th r en e-5,8-d iyl Dia ceta te (2a , X
) COCH3). Potassium hydroxide (3.0 mg) was added to a
solution of (5R,8R)-(-)-trans-5,6,6a,7,8,12b-hexahydro-1,12-
dimethylbenzo[c]phenanthrene-5,8-diyl bis[(S)-R-methoxy-
phenylacetate] (5a ) (10.0 mg) in 90% aqueous ethanol (4 mL).
The reaction mixture was heated at reflux for 1 h, cooled, and
diluted with brine. The mixture was extracted with ether, and
the combined ether layers were worked up in the usual manner
to give (5R,8R)-(-)-trans-5,6,6a,7,8,12b-hexahydro-1,12-di-
methylbenzo[c]phenanthrene-5,8-diol (2a , X ) H) (3.7 mg,
88%) as a white solid: [R]23D -307 (c ) 0.5, CHCl3). This
resolved diol 2a , X ) H, had an 1H NMR spectrum identical
to that of the racemic diol 2, X ) H.
[R]23
D -198 (c ) 0.3, CHCl3). A sample was recrystallized from
chloroform/methanol, mp 211 °C, and the X-ray crystal struc-
ture was obtained.
The second fraction consisted of (5S,8S)-(+)-trans-5,6,-
6a,7,8,12b-hexahydro-1,12-dimethylbenzo[c]phenanthrene-5,8-
diyl di-p-bromobenzoate (2b, X ) p-BrC6
H4CO) (10 mg), [R]23
D
1
+200 (c ) 0.2, CHCl3). The H NMR of the racemic diester 2,
X ) p-BrC6H4CO, and the resolved diesters 2a , X ) p-BrC6H4-
CO, and 2b, X ) p-BrC6H4CO, were identical.
Hyd r olysis of (5S,8S)-(+)-tr a n s-5,6,6a ,7,8,12b-Hexa h y-
d r o-1,12-d im et h ylb en zo[c]p h en a n t h r en e-5,8-d iyl Di-p -
br om oben zoa te (2b, X ) p-Br C6H4CO). (5S,8S)-(+)-trans-
5,6,6a,7,8,12b-Hexahydro-1,12-dimethylbenzo[c]phenanthrene-
Acetic anhydride (0.2 mL) was added to a solution of the
diol 2a , X ) H (3.7 mg), in dry pyridine (1 mL). The mixture
was stirred at 50 °C for 15 min. A second portion of acetic

66 J . Org. Chem., Vol. 62, No. 1, 1997
Cheung et al.
5,8-diyl di-p-bromobenzoate (2b, X ) p-BrC6H4CO) (6.3 mg,
0.01 mmol) was added to a 90% aqueous ethanol solution of
sodium hydroxide (3 mg in 4 mL). The reaction mixture was
treated in a similar manner as for the base hydrolysis of
diester 5a to give (5S,8S)-(+)-trans-5,6,6a,7,8,12b-hexahydro-
1,12-dimethylbenzo[c]phenanthrene-5,8-diol (2b, X ) H) (1 mg,
36%), [R]23D +270 (c ) 0.1, CHCl3). This resolved diol has an
1H NMR spectrum identical to that of the racemic diol 2, X )
H.
3 with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, upon request, from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK.
Ack n ow led gm en t. We thank the Australian Re-
search Council for financial support (to S.S., L.D.F., and
T.W.H.) and the Australian Government for an Austra-
lian Postgraduate Research Award (to J .C.).
Str u ctu r e Deter m in a tion . The authors have deposited
atomic coordinates for the structures depicted in Figures 1 and
J O961254Z