Syntheses of Fjord Region Bis-dihydrodiol and Bis-anti-diol Epoxide Metabolites of Benzo[s]picene

Article abstract of DOI:10.1021/jo971666n

Efficient syntheses of the trans-3,4-trans-9,10-tetrahydroxy-3,4,9,10-tetrahydro derivatives of benzo[s]picene and the corresponding bis-anti-diol epoxide derivatives in which the epoxide rings lie in the sterically crowded fjord regions are reported. Bis

Full text of DOI:10.1021/jo971666n

1168
J . Org. Chem. 1998, 63, 1168-1171
Syn th eses of F jor d Region Bis-d ih yd r od iol a n d Bis-a n ti-d iol
Ep oxid e Meta bolites of Ben zo[s]p icen e
Fang-J ie Zhang and Ronald G. Harvey*
Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637
Received September 8, 1997
Efficient syntheses of the trans-3,4-trans-9,10-tetrahydroxy-3,4,9,10-tetrahydro derivatives of
benzo[s]picene and the corresponding bis-anti-diol epoxide derivatives in which the epoxide rings
lie in the sterically crowded fjord regions are reported. Bis-dihydrodiols and bis-anti-diol epoxides
of this type are suspected as proximate and ultimate carcinogenic metabolites, respectively, of several
polycyclic aromatic hydrocarbons. These are the first examples of this class of molecules to be
synthesized. The syntheses entail in the key step double oxidative photocyclization of a
tetramethoxy-2,3-distyrylnaphthalene obtained from double Wittig reaction of naphthalene-2,3-
dialdehyde. The bis-dihydrodiols were obtained as a mixture of meso and racemic diastereomers
separable by HPLC on a reversed-phase ZORBAX ODS column. The bis-anti-diol epoxide
enantiomers derived from the latter were resolved by HPLC on a chiral column.
Benzo[s]picene (1) is a symmetrical six-ring polycyclic
aromatic hydrocarbon that has only recently become
conveniently available via a novel synthetic route.1 As
a consequence of its prior relative unavailability, virtually
nothing is known concerning the chemistry of benzo[s]-
picene.2 There are no reports of electrophilic substitution
or other types of reactions. Our interest was stimulated
by the potential carcinogenicity of 1, since it contains two
fjord regions, and fjord region-containing polyarenes,
such as dibenzo[a,l]pyrene3 and benzo[g]chrysene,4 are
among the most potent carcinogenic hydrocarbons known.
Like these polyarenes, 1 is likely to be distorted from
planarity due to steric interference between the fjord
region hydrogen atoms. Deviation from planarity is
associated with carcinogenicity, and it has been proposed
that this steric effect on bioactivity may result from
increased binding of the active diol epoxide metabolites
of 1 to deoxyadenosine sites in DNA.4-6
In connection with studies of the metabolism and
carcinogenicity of benzo[s]picene, we required samples
of its potential active metabolites, specifically the trans-
3,4-dihydrodiol (2) and the anti-diol epoxide (3) as well
as the more highly oxidized trans-3,4-trans-9,10-tetrahy-
drotetraol (4), referred to herein as the bis-dihydrodiol,
and the corresponding bis-anti-diol epoxide (5). Although
bis-dihydrodiols and the derived diol epoxides are impli-
cated as active metabolites of several carcinogenic hy-
drocarbons, such as dibenz[a,c]anthracene, dibenz[a,h]-
anthracene, dibenz[a,j]anthracene, and dibenzo[b,def]-
chrysene,7-10 practical methods for their synthesis are
lacking. The only bis-dihydrodiols whose syntheses have
been described are the 3,4,10,11- and 3,4,12,13-bis-
dihydrodiols of dibenz[a,h]anthracene; however, the over-
all yields are low (1.2% and 0.5%, respectively) and
minimal experimental details are provided.7 We now
report efficient syntheses of the bis-dihydrodiol and the
bis-anti-diol epoxide metabolites of benzo[s]picene (4 and
5).
(1) Tang, X.-Q.; Harvey, R. G. J . Org. Chem. 1995, 60, 3568.
(2) Harvey, R. G. Polycyclic Aromatic Hydrocarbons; Wiley-VCH:
New York, 1997.
(3) Higginbotham, S.; Ramakrishna, N. V. S.; J ohansson, S. I.;
Rogan, E. G.; Cavalieri, E. L. Carcinogenesis 1993, 14, 875.
(4) Szeliga, J .; Lee, H.; Harvey, R. G.; Page, J . E.; Ross, H. L.;
Routledge, M. N.; Hilton, B. D.; Dipple, A. Chem. Res. Toxicol. 1994,
7, 420.
(5) Prakash, A. S.; Pigott, M. A.; Hilton, B. D.; Lee, H.; Harvey, R.
G.; Dipple, A. Carcinogenesis 1988, 9, 1721. Peltonen, K.; Cheng, S.
C.; Hilton, B. D.; Lee, H.; Cortez, C.; Harvey, R. G.; Dipple, A. J . Org.
Chem. 1991, 56, 4181.
(6) Dipple, A. In DNA Adducts: Identification and Biological
Significance; Hemminki, K., Dipple, A., Segerba¨ck, D., Kadlubar, F.
F., Shuker, D., Bartsch, H., Eds.; IARC: Lyon, France, 1994; pp 107-
129.
(7) Platt, K. L.; Schollmeier, M. Chem. Res. Toxicol. 1994, 7, 89.
(8) LeCoq, S.; Chalvet, O.; Strapelias, H.; Grover, P. L.; Phillips, D.
H.; Duquesne, M. Chem. Biol. Interact. 1991, 80, 532.
(9) Nair, R. V.; Nettikumara, A. N.; Cortez, C.; Harvey, R. G.;
DiGiovanni, J . Chem. Res. Toxicol. 1992, 5, 261.
(10) Marsch, G. A.; J ankowiak, R.; Small, G. J .; Hughes, N. C.;
Phillips, D. H. Chem. Res. Toxicol. 1992, 5, 765.
S0022-3263(97)01666-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/30/1998

Synthesis of Metabolites of Benzo[s]picene
J . Org. Chem., Vol. 63, No. 4, 1998 1169
Sch em e 1
Sch em e 2
Resu lts a n d Discu ssion
Our synthetic approach to the symmetrical terminal
ring-oxidized metabolites of benzo[s]picene entails in the
key step double photocyclization of a tetramethoxy-
substituted diolefin (7a ) (Scheme 1). This intermediate
is potentially accessible from double Wittig reaction
between an appropriate arylaldehyde and a phosphonium
salt, either through reaction of naphthalene-2,3-dialde-
hyde (6) with 2,3-dimethoxybenzyl triphenylphospho-
nium bromide or via reaction of the bis-benzyl triphen-
ylphosphonium salt of 2,3-bis(bromomethyl)naphthalene
with 2,3-dimethoxybenzaldehyde. However, all attempts
to obtain 7a via the latter route failed, possibly due to
the highly sterically hindered nature of the dibenzyltri-
phenylphosphonium salt. Naphthalene-2,3-dialdehyde
(6) required as the starting compound for the alternative
route is readily accessible from naphthalene-2,3-dicar-
boxylic acid by reduction to the corresponding dialcohol
with LiAlH4 followed by oxidation with oxalyl chloride
and dimethyl sulfoxide.11
Wittig reaction of 6 with the phosphonium salt pre-
pared from 2,3-dimethoxybenzyl bromide and triphenyl-
phosphine furnished a mixture of three isomeric diolefins
7a -c (87%) in an approximately equal ratio. Chroma-
tography on a silica gel column eluted with CH2Cl2-
hexane afforded the individual pure isomers distinguish-
1
able by their H NMR spectra. For two of the isomers,
the NMR spectra were relatively simple, indicative of the
symmetrical ZZ and EE olefin structures 7a and 7c.
However, the spectrum of the third isomer was relatively
complex, more consistent with the asymmetric ZE olefin
structure 7b. The relatively larger coupling constants
exhibited by the olefinic protons of 7a (J AB ) 16.2 Hz)
than 7c (J AB ) 12.3 Hz) suggest that the former has a
trans configuration with the EE structure while the latter
has a cis configuration with the ZZ structure. However,
these assignments should be regarded as only tentative.
On measurement of the UV spectra of the individual pure
isomers, they underwent conversion to an equilibrium
mixture of diolefins.
7.60 assigned to the remaining eight aryl protons, and a
pair of singlets at δ 4.09 and 4.10, equivalent to six
protons each, for the methoxy protons. Demethylation
of 8a with BBr3 furnished the bis-catechol, tetrahydroxy-
benzo[s]picene (8b), which was isolated as its tetraacetate
(8c) because of the sensitivity of polycyclic catechols to
air oxidation.
Attempted reduction of 8c to the bis-dihydrodiol (4) by
treatment with NaBH4 in EtOH with oxygen bubbling
through the solution by the procedure employed previ-
ously for reduction of other polycyclic hydroquinones13
afforded a complex mixture of partially reduced products.
Since this apparent resistance to reduction is a likely
consequence of the poor solubility of 8b,c and the
partially reduced intermediate products in EtOH, similar
reaction was conducted with methylene chloride as
cosolvent. Reduction of 8c with NaBH4 in CH2Cl2-EtOH
(1:1) took place smoothly and stereospecifically under an
oxygen atmosphere to afford a mixture of two diastere-
omeric trans-3,4,9,10-tetrahydrotetraols (4a and 4b)
Photochemical cyclodehydrogenation of the mixture of
diolefins 7a -c conducted in dilute benzene solution in
the presence of iodine and propylene oxide12 gave a single
1
cyclized product (8a ) in 91% yield (Scheme 2). The H
NMR spectrum of 8a was consistent with its symmetrical
structure, exhibiting a doublet and a multiplet at char-
acteristic low field (δ 8.75 and 8.88, respectively) assigned
to the two pairs of fjord region protons, three additional
doublets at δ 8.63, 8.37, and 7.44 and a multiplet at δ
(11) Carlson, R. G.; Srinivasachar, K.; Givens, R. S.; Matuszewski,
B. K. J . Org. Chem. 1986, 51, 3978. Omura, K.; Swern, D. Tetrahedron
1991, 56, 3769.
(12) Propylene oxide serves to prevent competing reactions by
scavenging the HI produced: Liu, L. B.; Yang, B. W.; Katz, T. J .;
Poindexter, M. K. J . Org. Chem. 1991, 56, 3769.
(13) Dai, W.; Abu-Shqara, E.; Harvey, R. G. J . Org. Chem. 1995,
60, 4905. Platt, K.; Oesch, F. Synthesis 1982, 459.

1170 J . Org. Chem., Vol. 63, No. 4, 1998
Zhang and Harvey
separable by HPLC on a reversed-phase ZORBAX ODS
column eluted with a linear gradient of 50-100% metha-
nol/water. No trace of the corresponding cis-isomers was
detected by TLC, HPLC, or NMR analysis, consistent
with previous findings of trans-stereospecificity of these
types of reductions.14
for the synthesis of analogous oxidized derivatives of
other symmetical polycyclic aromatic ring systems. These
compounds are urgently required as standards for me-
tabolism studies to identify the more polar metabolites
that often accompany the less oxidized metabolites as
well as for studies to clarify their role in carcinogenesis.
The early- and late-eluting bis-dihydrodiol isomers
were assigned structures 4a and 4b, respectively, on the
basis of their 300 MHz 1H NMR spectra. As a conse-
quence of the asymmetry of 4a , it is anticipated to exist
as a pair of enantiomers, while 4b is a meso form
expected to be optically inactive. The resolution of 4a
was not attempted, but the existence of enantiomers was
confirmed indirectly by resolution of the corresponding
anti-diol epoxides on a chiral column described in the
following paragraph. The coupling constants for the
carbinol protons of 4a were in the range 8.0-8.2 Hz,
indicating the dihydrodiol to exist in solution in DMSO-
d6 predominantly as the diequatorial conformer. This is
consistent with previous findings for other related dihy-
drodiols free to adopt this conformation.14,15
Conversion of the individual bis-dihydrodiols 4a and
4b to the corresponding bis-anti-diol epoxides, 5a and 5b,
took place stereospecifically on treatment with m-chlo-
roperbenzoic acid (m-CPBA). It was previously demon-
strated that epoxidation with m-CPBA of trans-dihy-
drodiols that are free to adopt a diequatorial conformation
generally takes place with high stereoselectivity to afford
the corresponding anti-diol epoxide isomers.14 The HPLC
profiles of the bis-anti-diol epoxides 5a and 5b on a Regis
chiral column [PIRKLE Covalent (R,R) âGEM] eluted
isocratically with EtOH-hexane showed them to be
remarkably pure. The bis-anti-diol epoxide 5a was
resolved into two peaks on the chiral column, indicative
of its existence as a pair of enantiomers and consistent
with its assignment as a derivative of the racemic bis-
dihydrodiol 4a with the structure shown in Scheme 2.
In isomer 4a , the hydroxyl groups in both terminal rings
are trans, and the hydroxyl groups in the 4- and 9-posi-
tions are on opposite faces of the molecule as are the
hydroxyl groups in the 3- and 10-positions. The bis-anti-
diol epoxide 5b exhibited a single sharp peak on the
chiral HPLC column, consistent with its origin from the
meso bis-dihydrodiol 4b. In this isomer the hydroxyl
groups in the 4- and 9-positions are on the same face of
the molecule and trans to the hydroxyl groups in the 3-
and 10-positions.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. Naphthalene-2,3-dialdehyde was
synthesized from naphthalene-2,3-dicarboxylic acid (Aldrich)
by the published method.11 (2,3-Dimethoxybenzyl)triphenyl-
phosphonium bromide was prepared by heating an equimolar
solution of 2,3-dimethoxybenzyl bromide and PPh3 in a mini-
mum volume of benzene at reflux for 5 h. The solution was
cooled, and the solid precipitate was filtered, dried, and used
directly. m-Chloroperbenzoic acid (Aldrich) was purified by
washing with pH 7.4 phosphate buffer and drying under
reduced pressure. THF was distilled from sodium benzophe-
1
none ketyl. The H NMR spectra were recorded on a QE-300
MHz spectrometer in CDCl3 with tetramethylsilane as internal
standard unless stated otherwise. The UV spectra were
measured on a Perkin-Elmer Lamda 6 spectrometer. All
melting points are uncorrected. Ca u tion : Although benzo-
[s]picene is not an established carcinogen, it and its dihydrodiol
and diol epoxide metabolites are potentially hazardous and
should be handled in accordance with “NIH Guidlines for the
Laboratory Use of Chemical Carcinogens”.
2,3-Bis(2,3-d im eth oxystyr yl)n a p h th a len e (7). Naph-
thalene-2,3-dialdehyde (552 mg, 3 mmol) and (2,3-dimethoxy-
benzyl)triphenylphosphonium bromide (4.43 g, 9 mmol) were
dissolved in CH2Cl2 (70 mL), and to this solution was added
50% NaOH (14 g). The mixture was stirred under argon at
room temperature for 15 h and then diluted with ice-water.
The organic layer was separated, and the aqueous layer was
extracted with CH2Cl2. The extracts were combined, washed
with water, dried (Na2SO4), and evaporated to dryness, and
the residue was chromatographed on a silica gel column.
Elution with EtOAc-hexane (1:4) afforded a mixture of 7a -c
(1.18 g, 87%) in approximately equal ratio as a semisolid. TLC
of the mixture on silica gel with CH2Cl2 gave Rf values for
7a -c of 0.65, 0.52, and 0.38, respectively. Chromatography
on a silica gel column using CH2Cl2-hexane (1:1) to CH2Cl2
as the eluting solvent gave the pure isomers. 7a : mp 138-
1
139 °C (MeOH); H NMR δ 3.86 (s, 6), 3.90 (s, 6), 6.86 (dd, 2,
J ) 8.0, 1.0 Hz), 7.08 (t, 2, J ) 8.0 Hz), 7.29 (br d, 2, J ) 7.9
Hz), 7.40-7.50 (m, 2), 7.45 (d, 2, J ) 16.2 Hz), 7.60 (d, 2, J )
16.2 Hz), 7.82-7.90 (m, 2), 8.06 (s, 2); FAB MS m/z 453 ([M +
H]+); UV λmax 303 (ꢀ 94 260) nm. Anal. Calcd for C30H28O4:
C, 79.62; H, 6.24. Found: C, 79.35; H, 6.28. 7b: mp 125-
1
126 °C (MeOH); H NMR δ 3.82 (s, 3), 3.85 (s, 3), 3.89 (s, 3),
3.90 (s, 3), 6.55-6.72 (m, 3), 6.85 (dd, 1, J ) 8.1, 0.9 Hz), 6.90-
7.10 (m, 3), 7.23 (dd, 1, J ) 7.1, 1.0 Hz), 7.32-7.48 (m, 2),
7.49 (s, 1), 7.50 (s, 1), 7.60 (d, 1, J ) 7.1 Hz), 7.61 (s, 1), 7.86
(d, 1, J ) 8.1 Hz), 8.13 (s, 1); FAB MS m/z 453 ([M + H]+); UV
λmax 292 (ꢀ 58 290) nm. Anal. Calcd for C30H28O4: C, 79.62;
H, 6.24. Found: C, 79.46; H, 6.31. 7c: mp 167-168 °C
(MeOH); 1H NMR δ 3.85 (s, 6), 3.92 (s, 6), 6.59 (dd, 2, J ) 7.6,
1.7 Hz), 6.66 (t, 2, J ) 7.8 Hz), 6.72 (dd, 2, J ) 8.0, 1.8 Hz),
6.84 (d, 2, J ) 12.3 Hz), 6.90 (d, 2, J ) 12.3 Hz), 7.28-7.38
(m, 2), 7.53-7.60 (m, 2), 7.67 (s, 2); FAB MS m/z 453 ([M +
H]+); UV λmax 303 (ꢀ 94 260) nm. Anal. Calcd for C30H28O4:
C, 79.62; H, 6.24. Found: C, 79.67; H, 6.26.
The bis-anti-diol epoxides (5a and 5b) of benzo[s]picene
whose syntheses are reported are the first examples of
this class of higher oxidized metabolites of carcinogenic
hydrocarbons to be synthesized. Recent biological studies
indicate that bis-dihydrodiol and bis-anti-diol epoxide
metabolites may play a potentially important role in the
mechanism of tumorigenesis of some polycyclic aromatic
hydrocarbons. The syntheses described are efficient,
affording the bis-dihydrodiols (4a and 4b) in 61% overall
yield in four steps and the bis-anti-diol epoxides (5a and
5b) in 58% overall yield in five steps from readily
available precursors. In principle, this synthetic ap-
proach may be employed with appropriate modification
3,4,9,10-Tetr a m eth oxyben zo[s]p icen e (8a ). Argon was
bubbled through a solution of the mixture of diolefins 7a -c
(1.2 g, 2.65 mmol) and I2 (3.57 g, 5.3 mmol) in benzene (1.5 L)
for 15 min, and then propylene oxide (15 mL) was added. The
mixture was irradiated with a Hanovia 450 W medium-
pressure mercury lamp through a Pyrex filter for 5 h. TLC
showed the reaction to be complete. The solvent was removed,
the residue was dissolved in CHCl3, and the solution was
washed with 10% Na2S2O3 and H2O and dried over MgSO4.
Evaporation of the solvent followed by recrystallization of the
solid residue from CHCl3 gave 8a (1.08 g, 91%) as a white
(14) Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry
and Carcinogenicity; Cambridge University Press: Cambridge, U.K.,
1991; Chapter 13, pp 306-329.
(15) Harvey, R. G. In The Conformational Analysis of Cyclohexenes,
Cyclohexadienes, and Related Hydroaromatic Compounds; Rabideau,
P. W., Ed.; VCH Publishers: New York, 1989; pp 267-298.

Synthesis of Metabolites of Benzo[s]picene
J . Org. Chem., Vol. 63, No. 4, 1998 1171
1
solid: mp 303-304 °C dec; H NMR δ 4.09 (s, 6), 4.10 (s, 6),
Hz), 8.15-8.28 (m, 2), 8.51 (d, 2, J ) 8.4 Hz); UV (THF) λmax
283 (ꢀ 64 150) nm; FAB MS m/z 396 (M+); HRMS calcd for
7.44 (d, 2, J ) 9.2 Hz), 7.58-7.65 (m, 2), 8.37 (d, 2, J ) 9.2
Hz), 8.63 (d, 2, J ) 9.2 Hz), 8.88-8.95 (m, 2), 8.75 (d, 2, J )
9.3 Hz); FAB MS m/z 448 (M+); UV (THF) λmax 320 (ꢀ 83 630),
285 (137 390) nm. Anal. Calcd for C30H24O4: C, 80.34; H, 5.39.
Found: C, 80.26; H, 5.42.
C
26H20O4 396.1362, found 396.1363. The late-eluting isomer
4b was a white solid: mp 252-255 °C (THF-hexane); 1H NMR
(DMSO-d6) δ 4.51 (br s, 4), 5.38 (br s, 2, exchangeable with
D2O), 5.72 (br s, 2, exchangeable with D2O), 6.18 (d, 2, J )
10.1 Hz), 6.98 (d, 2, J ) 10.1 Hz), 7.50-7.60 (m, 2), 7.83 (d, 2,
J ) 8.3 Hz), 8.15-8.25 (m, 2), 8.53 (d, 2, J ) 8.4 Hz); UV (THF)
λmax 282 (ꢀ 67 240) nm; FAB MS m/z 396 (M+); HRMS calcd
for C26H20O4 396.1362, found 396.1363.
3,4,9,10-Tetr a a cetoxyben zo[s]p icen e (8c). To a solution
of 8a (1.0 g, 2.23 mmol) in dry CH2Cl2 (150 mL) at -20 °C
was added a solution of BBr3 in CH2Cl2 (1 M, 30 mL). The
resulting yellowish solution was stirred at the same temper-
ature for 30 min and then at room temperature for 3 h. Ice
was added, and the CH2Cl2 was removed at reduced pressure.
The aqueous suspension was extracted with EtOAc, and the
combined EtOAc solution was washed with brine, dried over
Na2SO4, and evaporated to dryness. The solid thus obtained
was dissolved in pyridine (60 mL) and Ac2O (42 mL) and
stirred at ambient temperature for 48 h. The mixture was
poured into ice-water and extracted with CHCl3. The organic
layer was washed with 1 N HCl and brine in turn and dried
over Na2SO4. After removal of the solvent, the residue was
recrystallized from CH2Cl2-MeOH to afford 8c (1.15 g, 92%)
Bis-a n ti-d iol Ep oxid es of Ben zo[s]p icen e (5a a n d 5b).
To a solution of 4a (50 mg, 0.13 mmol) in 10 mL of dry THF
was added freshly recrystallized m-CPBA (434 mg, 2.52 mmol).
The solution was stirred at room temperature under argon for
2 h and then concentrated under vacuum without heating, and
the residue was dissolved in 6 mL of THF. Addition of 24 mL
of hexane gave a precipitate that was collected by filtration
and washed twice with a mixture of THF (3 mL) and hexane
(12 mL). Pure 5a (47.5 mg, 88%) was a gray solid: mp 223-
1
225 °C; H NMR δ 3.81 (d, 2, J ) 4.5 Hz), 3.85-3.97 (m, 2)
[after addition of D2O changed to 3.90 (d, 2, J ) 8.7 Hz)], 4.40-
4.52 (m, 2) [after addition of D2O changed to 4.49 (d, 2, J )
8.7 Hz)], 4.82 (d, 2, J ) 4.4 Hz), 5.65 (d, 2, J ) 5.2 Hz,
exchangeable with D2O), 5.78 (d, 2, J ) 6.7 Hz, exchangeable
with D2O), 7.55-7.70 (m, 2), 7.84 (d, 2, J ) 8.3 Hz), 8.15-
8.25 (m, 2), 8.58 (d, 2, J ) 8.6 Hz); UV (THF) λmax 273 (ꢀ 74 700)
nm; FAB MS m/z 427 (M - H+); HRMS calcd for C26H19O6
427.1182, found 427.1182. Pure 5b (48 mg, 89%) was a gray
solid: mp 225-227 °C; 1H NMR δ 3.70-3.82 (m, 4), 4.50-
4.70 (m, 4), 5.68 (d, 2, J ) 5.1 Hz, exchangeable with D2O),
5.84 (d, 2, J ) 6.5 Hz, exchangeable with D2O), 7.64-7.75 (m,
2), 7.88 (d, 2, J ) 8.4 Hz), 8.30-8.45 (m, 2), 8.64 (d, 2, J ) 8.6
Hz); UV (THF) λmax 274 (ꢀ 80 200) nm; FAB MS m/z 429 (M +
H+); HRMS calcd for C26H21O6 429.1338, found 429.1336.
1
as a white solid: mp 314-316 °C dec; H NMR δ 2.43 (s, 6),
2.57 (s, 6), 7.55 (d, 2, J ) 9.2 Hz), 7.65-7.75 (m, 2), 8.07 (d, 2,
J ) 9.0 Hz), 8.65 (d, 2, J ) 9.2 Hz), 8.82-8.90 (m, 2), 8.91 (d,
2, J ) 9.0 Hz); FAB MS m/z 560 (M+); UV (THF) λmax 309 (ꢀ
96 140), 289 (67 580), 280 (126 760) nm. Anal. Calcd for C34
24O8: C, 72.85; H, 4.32. Found: C, 72.97; H, 4.32.
tr a n s-3,4-tr a n s-9,10-Tetr a h yd r oxy-3,4,9,10-tetr a h yd r o-
-
H
ben zo[s]p icen e (4a a n d 4b). A mixture of 8c (840 mg, 1.5
mmol) and NaBH4 (2.27 g, 60 mmol) in 200 mL of EtOH-
CH2Cl2 (1:1) was stirred under an oxygen atmosphere at room
temperature for 16 h. The solvent was removed under reduced
pressure without heating, 200 mL of cold water was added,
and the suspension was extracted with EtOAc. The organic
layer was washed with brine, 1 N HCl, and brine in turn and
dried over Na2SO4. The solvent was removed in vacuo, and
the residue was recrystallized from EtOAc to afford a mixture
of 4a and 4b (540 mg, 91%) as a white solid, mp 192-195 °C.
Anal. Calcd for C26H20O4: C, 78.77; H, 5.09. Found: C, 78.50;
H, 5.20. The isomers 4a and 4b were separated by HPLC on
a ZORBAX ODS column (9.4 mm × 25 cm) eluted with a linear
gradient of 50-100% MeOH/H2O with a flow rate of 4 mL/
min. Retention times of 4a and 4b were 7.0 and 8.0 min,
respectively. The early-eluting isomer 4a was a white solid
that softened at 205 °C and melted at 250 °C (THF-hexane):
1H NMR (DMSO-d6) δ 4.28-4.40 (m, 2) [after addition of D2O
changed to 4.35 (br d, 2, J ) 8.0 Hz)], 4.56-4.70 (m, 2) [after
addition of D2O changed to 4.61 (br d, 2, J ) 8.2 Hz)], 5.29 (d,
2, J ) 5.0 Hz, exchangeable with D2O), 5.54 (d, 2, J ) 5.6 Hz,
exchangeable with D2O), 6.17 (dd, 2, J ) 10.1 and 3.2 Hz),
7.14 (d, 2, J ) 10.1 Hz), 7.50-7.62 (m, 2), 7.77 (d, 2, J ) 8.4
HPLC of the bis-anti-diol epoxides 5a and 5b on a Regis
chiral column [PIRKLE Covalent (R,R) âGEM, 250 × 4.6 mm,
5 µm] eluted isocratically with EtOH-hexane (40:60) at a flow
rate of 1 mL/min confirmed their purity. The 5a isomer
showed two peaks on the chiral column (retention times 7.5
and 8.5 min), indicative of its existence as a racemate and
consistent with origin from the racemic bis-dihydrodiol 4a . The
5b isomer appeared as a single sharp peak eluted at 7.0 min
on the chiral column, consistent with its origin from the meso
bis-dihydrodiol 4b.
Ack n ow led gm en t. This research was supported by
grants from the American Cancer Society (CN-22) and
the National Cancer Institute (CA 67937).
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