Tetrahydrofuran-mediated radical processes: Stereoselective synthesis of d,l-hexestrol

Article abstract of DOI:10.1016/S0022-328X(03)00539-4

The highly stereoselective synthesis of d,l-hexestrol (1), an inhibitor of microtubule assembly, is developed by using, as a key step, an intermolecular coupling of Co₂(CO)₆-complexed propargyl radicals. The latter are generated by novel complementary processes involving an interaction of tetrahydrofuran with Co₂ (CO)₆-complexed propargyl alcohols and cations. An isomerically pure d,l-μ-η²-[3,4-di(4-methoxyphenyl)-1, 5-hexadiyne]-bis-dicobalthexacarbonyl (d,l-6) is isolated in 69-91% yield with intermolecular coupling reactions exhibiting an excellent chemo-(0.5-7%) and d,l-diastereoselectivity (90-94%). The structure of d,l-6 is determined by X-ray diffraction. The subsequent steps include BBr₃-induced demethylation of 4-methoxyaryl groups, demetalation with cerium(IV) ammonium nitrate, and hydrogenation of acetylenic termini affording d,l-hexestrol (1).

Full text of DOI:10.1016/S0022-328X(03)00539-4

Journal of Organometallic Chemistry 683 (2003) 324ꢀ330
/
www.elsevier.com/locate/jorganchem
Tetrahydrofuran-mediated radical processes: stereoselective synthesis
of -hexestrol
D,L
Gagik G. Melikyan a,*, Steve Sepanian a, Bobby Riahi a, Ferdinand Villena a,
John Jerome a, Brian Ahrens a, Randolph McClain a, John Matchett a,
Stephanie Scanlon a, Edwin Abrenica a, Kevin Paulsen a, Kenneth I. Hardcastle b
a Department of Chemistry, California State University Northridge, 18111 Nordhoff Street, Northridge, CA 91330, USA
b Department of Chemistry, Emory University, Atlanta, GA 30322, USA
Received 6 March 2003; received in revised form 31 May 2003; accepted 6 June 2003
Abstract
The highly stereoselective synthesis of
an intermolecular coupling of Co2(CO)6-complexed propargyl radicals. The latter are generated by novel complementary processes
involving an interaction of tetrahydrofuran with Co2(CO)6-complexed propargyl alcohols and cations. An isomerically pure
-m-
h2-[3,4-di(4-methoxyphenyl)-1,5-hexadiyne]-bis-dicobalthexacarbonyl (
-6) is isolated in 69ꢀ91% yield with intermolecular
coupling reactions exhibiting an excellent chemo- (0.5ꢀ7%) and -diastereoselectivity (90ꢀ94%). The structure of -6 is
determined by X-ray diffraction. The subsequent steps include BBr3-induced demethylation of 4-methoxyaryl groups, demetalation
D,L-hexestrol (1), an inhibitor of microtubule assembly, is developed by using, as a key step,
D,L
D
,
L
/
/
D
,
L
/
D,L
with cerium(IV) ammonium nitrate, and hydrogenation of acetylenic termini affording D,L-hexestrol (1).
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: Propargyl radical; Propargyl cation; Cobalt; X-ray structure; Hexestrol
1. Introduction
proven to be effective inhibitors of microtubule assem-
bly of proteins leading to the formation of twisted
ribbon structures [7]. Further studies of D,L-hexestrol (1)
are hampered by its inaccessibility: the synthetic meth-
ods utilizing, in particular, a reduction of diethylstilbes-
trol or radical coupling reactions feature a low
stereoselectivity, and attendant with it, a tedious isola-
tion of target compounds [8]. Herein, we report the
Last decade, the inhibitors of microtubule assembly
have become a hot commodity on the pharmaceutical
market. They are best represented by an antimitotic
agent colchicine [1], alkaloids vinblastine [1b,2] and
vincristine [3], an antitumor agent taxol [1b,2,4], and
methyl [5-(2-thienylcarbonyl)-1H-benzimidazol-2-yl]car-
bamate, a disruptor of mitotic spindle function [5]. The
current trend represents an ever increasing interest
stereoselective synthesis of D,L-hexestrol (1) utilizing, as
a key step, novel tetrahydrofuran (THF)-mediated
dimerization of cobalt-complexed propargyl alcohols
and cations [9].
toward small organic molecules (MWB
interact, and structurally alter, complex biological
systems, such as enzymes. -Hexestrol (1), along
/800) which can
D,L
with its meso-counterpart, belongs to a family of
nonsteroidal hormones. The latter, due to its availabil-
ity, has been thoroughly tested to exhibit an astonishing
range of biological activities [6]. Both isomers are
2. Results and discussion
Propargyl alcohol 2, synthesized by the condensation
of sodium acetylide with anisaldehyde, was complexed
with dicobaltoctacarbonyl [10] to afford a key substrate
3 in 53.1% overall yield (Scheme 1). Both electronic and
steric parameters of the metal core are crucial to the
subsequent radical reaction. First, the stability of the
* Corresponding author. Tel.: ꢁ
4068.
E-mail address: hcchm025@csun.edu (G.G. Melikyan).
/
1-818-677-2565; fax: ꢁ1-818-677-
/
0022-328X/03/$ - see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-328X(03)00539-4

G.G. Melikyan et al. / Journal of Organometallic Chemistry 683 (2003) 324ꢀ
/330
325
Scheme 1. Synthesis of D,L-hexestrol (1) utilizing, as a key step, cobalt-templated radical coupling reactions.
cation 4 is enhanced, and isolation facilitated, due to the
charge delocalization over metal cluster and structural
changes attendant with it [11,12]. Second, the stereo-
selectivity of the dimerization step itself is favorably
influenced by a bulky metal core that decreases con-
formational flexibility of radical 5 and creates the space
constraints at the reaction site. The conversion of
alcohol 3 to bis-cluster 6, via cobalt-complexed species
4 and 5, was effected, first, by a tandem action of HBF4
and THF (path a) [9]. Although the mechanism of this
process is still under investigation [13], a ‘one-step
protocol’ for dimerization of metal-complexed propar-
90%), the former is more feasible from the practical
viewpoint: it does not require an isolation of the
intermediate cation, and also the higher yield of
D,L-6
was achieved (90.6 vs. 69.0%) [13]. The chemoselectivity,
represented by a ratio of dimeric and HAA products, 6/
7, is relatively high with only 0.5ꢀ7% of H-atom transfer
/
taking place. Although the intimate details of ‘THF
magic’ remain to be understood, the formation of
scarcely investigated cobalt-complexed propargyl radi-
cal, 5, and subsequent stereoselective dimerization are
implied. It is worthy to mention that coupling of organic
and organometallic radicals usually occur with low, if
any, diastereoselectivity [14].
gyl alcohols represents a viable synthetic method:
a major product, can be easily isolated, as a pure
diastereomer, from the mixture of -6, meso-6 and
H-atom abstraction product, [HCÅCCH2C6H4(4-
D,L-6,
The configuration of D,L-6 was determined by X-ray
crystallography. It adopts a non-imposed C2-symmetric
D,
L
/
conformation (Fig. 1; Tables 1 and 2) with noticeably
OMe)]Co2(CO)6 (7). An alternative approach is repre-
sented by a ‘two-step protocol’ that includes an isolation
of cation 4 followed by its treatment with a two-fold
excess of THF (Scheme 1, path b). While diastereos-
electivity is comparable for both procedures (94 and
distorted gauche-orientation of phenyl groups (C7Ã
C4ÃC13, 44.38) and nearly ideal disposition of Co-
alkyne units (C2ÃC3ÃC4ÃC5, 62.08). Atoms H3A and
H4A are disposed anti to each other thus confirming the
stereochemical assignment for this diastereomer (H3AÃ
/
C3Ã
/
/
/
/
/
/

326
G.G. Melikyan et al. / Journal of Organometallic Chemistry 683 (2003) 324ꢀ330
/
Fig. 1. X-ray determined molecular structure of complex
D
,
L
-6 with 30% probability ellipsoids.
Table 1
Summary of the crystal structure data for complex 6
Table 2
˚
Selected bond lengths (A), bond and torsion angles (8) for complex 6
Formula
C
32H18O4Co4
Bond lengths
FW
862.18
100(2)
Co(1)Ã
Co(1B)Ã
/
Co(2)
Co(2B)
2.4642(4)
2.4703(4)
Co(3)Ã
Co(3B)Ã
/
Co(4)
2.4707(4)
2.4641(4)
Temperature (K)
Crystal color
Crystal dimension (mm)
Crystal system
/
/
Co(4B)
Dark-red
Co(1)Ã
Co(1)Ã
C(1)Ã
Co(2)Ã
Co(2)Ã
/
C(1)
C(2)
1.959(2)
1.9664(18)
1.334(3)
Co(3)Ã
Co(3)Ã
C(5)Ã
Co(4)Ã
Co(4)Ã
/
C(5)
1.9765(19)
1.9573(19)
1.332(3)
0.308ꢂ
Triclinic
/
0.300ꢂ0.092
/
/
/
C(6)
/C(2)
/C(6)
˚
a (A)
11.6715(8)
16.9534(14)
19.2353(13)
105.632(2)
90.736(2)
/
C(1)
C(2)
1.9640(18)
1.9902(19)
/
C(5)
1.9759(19)
1.9586(19)
˚
b (A)
/
/
C(6)
˚
c (A)
Bond angles
C(1)ÃC(2)Ã
C(6)ÃC(5)Ã
a (8)
b (8)
g (8)
/
/C(3)
142.08(18) C(2)Ã
141.67(18) C(5)Ã
/
C(1)Ã
/H(1A)
136.4
136.3
/
/C(4)
/
C(6)Ã
/H(6A)
109.416(1)
3434.8(4)
3
˚
V (A )
Dihedral angles
Co(1)ÃCo(2)Ã
C(1)ÃC(2)
C(1)ÃC(2)Ã
C(7)
¯
P1
Space group
Z
Dcalc (Mg mꢃ3
Ka) (mmꢃ1
m(Moꢀ )
Independent reflections
/
/
/
73.23(11) C(7)Ã
C(13)
C(13)Ã
C(6)
C(3)Ã
/
C(3)Ã
C(4)Ã
C(4)ÃC(5)Ã
C(3)Ã
C(1)Ã
C(6)Ã
/
C(4)Ã
/
ꢃ
/
44.3(2)
163.1(2)
69.9(3)
4
/
)
1.667
1.965
/
/
C(3)Ã
/
155.6(3)
/
/
C(5)Ã
/
/
20 492 [Riꢄ0.0218]
Semi-empirical from equiva-
lents
/
C(1)Ã
/
C(2)Ã
/
C(3)Ã
C(4)Ã
C(4)Ã
C(4)Ã
/
ꢃ77.3(3)
/
/
/
/
C(6)
ꢃ/
Absorption correction
C(4)
C(2)Ã
/
C(3)Ã
/
/
62.0(2)
H(3A)Ã
H(4A)
170.94(16) H(1A)Ã
C(3)
171.33(15) H(6A)Ã
C(4)
/
/
C(4)Ã
C(2)Ã
C(5)Ã
/
170.7
6.2
No. of data/restraints/params
Goodness-of-fit on F2
20 492/0/901
1.039
C(5)
C(7)Ã
/
C(3)Ã
/
/
ꢃ
/
/
/
/
Final R indices [I ꢀ2s(I)]
R1
/
C(5)
0.0434
0.1047
C(2)Ã
/
C(3)Ã
/
/
ꢃ/
/
/
/
7.7
wR2
C(13)
Largest difference peak, hole
ꢃ3
1.062, ꢃ0.489
/
˚
(e A
)
H6A) are remarkably proximate to each other with a
˚
separation distance of 2.46 A, close to the sum of the
˚
van der Waals radii (about 2.5 A). Other noteworthy
C3Ã
/
C4ÃH4A, 170.78). As molecular modeling shows,
/
the repulsion between CO-ligands pushes the metal
clusters away from each other, which in turn brings
structural features of
undistorted planarity of alkyne moieties (H1AÃ
C2ÃC3, 6.28, H6AÃC6ÃC5ÃC4, 7.78); (b) a bent
geometry [11] for coordinated alkyne unit (C6ÃC5Ã
D
,
L
-6 include: (a) an essentially
/
C1Ã
/
the CÃ
/
C triple bonds in close-to-parallel locations
/
/
/
/
(C1C2Ã
/
C5C6, 19.78). Acetylenic hydrogens (H1A,
/
/

G.G. Melikyan et al. / Journal of Organometallic Chemistry 683 (2003) 324ꢀ
/330
327
C4, 141.78, C1Ã
smaller angles for acetylenic termini (C2Ã
136.48, C5ÃC6ÃH6A, 136.38); and (c) a lengthened
coordinated CÃC triple bond (1.33 vs. 1.21 A for free
/
C2Ã
/
C3, 142.18) with substantially
Center on Mass-Spectroscopy, UC Riverside, Riverside,
CA (FAB, ZAB-SE; CI-NH3, 7070EHF; Micromass).
/
C1ÃH1A,
/
/
/
˚
/
3.3. [1-(4-Methoxyphenyl)-prop-2-yn-1-
ol]dicobalthexacarbonyl (3)
ligand) attendant with complexation to the transition
metal.
The subsequent steps in total synthesis include BBr3-
Under an atmosphere of nitrogen, a solution of p-
anisaldehyde (1.36 g, 10 mmol) in dry THF (10 ml) was
added dropwise (10 min) to a suspension of sodium
acetylide (0.72 g, 15 mmol; 4 g, 18% suspension in
induced demethylation [15] of
demetalation of -8 with cerium(IV) ammonium
nitrate and hydrogenation of acetylenic termini in
9. An empirical ratio of -6:BBr3, 1:13, suggests that,
prior to deprotection of hydroxy groups, a donorꢀ
D,L-6, followed by
D,L
D,L-
D,L
xylene) in THF (30 ml) at ꢃ50 8C. The reaction mixture
/
/
was stirred for 5 h at 20 8C, diluted with saturated
aqueous ammonium chloride (40 ml) at 0 8C, extracted
acceptor coordination between CO-ligands and Lewis
acid takes place [15]. A moderate yield of decomplexa-
tion reaction (46.6%) reflects a relative lability of bis-
alkyne 9 in the presence of the oxidizing agents, such as
tetravalent cerium.
The synthetic strategy utilizing, as a key step, the
highly stereoselective, THF-mediated dimerization of
cobalt-complexed propargyl alcohols and cations, was
with ether (4ꢂ25 ml), and the combined ethereal
/
extracts were dried over Na2SO4. The filtrate was
evaporated to dryness, crude alcohol 2 was dissolved
in dry ether (50 ml), and a solution, under an atmo-
sphere of nitrogen, was added dropwise (60 min) to a
solution of Co2(CO)8 (3.76 g, 11 mmol) in degassed
ether (100 ml) at 20 8C. Upon stirring for 3 h (TLC
control), a solvent was stripped under reduced pressure,
developed for
D,L-hexestrol (1), an inhibitor of micro-
tubule assembly. Gram-quantities of the target com-
pound, as well as its structural and functional analogs,
will become available for an extensive biological probe.
and residue was fractionated on a Florisil column (60ꢀ
/
100 mesh, 200 g, PE, PE:E, 5:1, 2:1) to afford 3 (2.38 g,
53.1%) as dark-red crystals. M.p. 59.5 8C (sealed capil-
lary). TLC (PE:E, 2:1): Rf 0.42. H-NMR (200 MHz,
1
CDCl3, TMS): d 2.30 (1H, d, OH, Jꢄ
CH3), 5.86 (1H, d unresolved, OCH), 6.06 (1H, d, HCÅ
Jꢄ0.8), 6.83ꢀ6.94 (2H, m, aromatic H), 7.30ꢀ7.42 (2H,
m, aromatic H). MS FABꢁ
: m/z [Mꢁ] 448, 431 [Mꢁꢃ
OH], 420 [MꢁꢃCO], 403 [Mꢁꢃ CO], 392 [Mꢁꢃ
OHÃ
2CO), 364 [Mꢁꢃ3CO], 347 [Mꢁꢃ
OHÃ3CO], 336
[Mꢁꢃ4CO], 319 [Mꢁꢃ 4CO], 308 [Mꢁꢃ
OHÃ 5CO],
291 [Mꢁꢃ 5CO], 280 [Mꢁꢃ6CO], 145 [Mꢁꢃ
OHÃ
OHÃ6COÃ2Co]. Microanalysis: Found: C, 43.02; H,
2.20. C16H10O8Co2 requires: C, 42.88; H, 2.25%.
/
3.5), 3.80 (3H, s,
3. Experimental
/,
/
/
/
/
/
3.1. Materials and methods
/
/
/
/
/
/
/
All manipulations of air-sensitive materials were
carried out in flame-dried Schlenk-type glassware on a
dual-manifold Schlenk line interfaced to a vacuum line.
Argon and nitrogen (Airgas, ultra high purity) were
dried by passing through a Drierite tube (Hammond).
All solvents were distilled before use under dry nitrogen
over appropriate drying agents (ether, THF, from
sodium benzophenone ketyl; CH2Cl2, from CaH2).
/
/
/
/
/
/
/
/
/
/
3.4.
D,L
-, meso-m-h2-[3,4-Di(4-methoxyphenyl)-1,5-
hexadiyne]-bis-dicobalthexacarbonyl (
and [3-(4-methoxyphenyl)-1-
propyne]dicobalthexacarbonyl (7)
D,L-6, meso-6)
The reagents*
/
HBF4×
/
Me2O, anisaldehyde, BBr3, Ce
were purchased from Aldrich
and used as received. Co2(CO)8 was received from
(NH4)2(NO3)6, Pd/C*
/
Strem.
3.4.1. One-step protocol (path a)
Under an atmosphere of nitrogen, HBF4×
mg, 2.50 mmol) was added dropwise to a solution of
alcohol 3 (560 mg, 1.25 mmol) and THF (180 mg, 2.50
/
Me2O (335
3.2. Physical and analytical measurements
NMR spectra were recorded on Bruker ACF-200 (1H,
200 MHz). Chemical shifts were referenced to internal
solvent resonances and are reported relative to tetra-
methylsilane. Elemental analyses were performed by
Desert Analytics (Tucson, AZ). Melting temperatures
(uncorrected) were measured on Mel-Temp II (Labora-
tory Devices) apparatus. Thin-layer and column chro-
matography were conducted on Silica gel 60 F254 (EM
mmol) in dry CH2Cl2 (12.5 ml) at ꢃ5 8C. The reaction
mixture was stirred for 5 h at 20 8C (TLC control),
diluted with Et2O (25 ml), then, at 0 8C, with water (20
/
ml). The organic layer was washed with water (4ꢂ5 ml),
/
dried (MgSO4), and solvents were stripped off under
reduced pressure. By NMR, the crude mixture con-
tained
94%). Fractionation on a silica gel column (250 g,
degassed, ꢁ5 8C, PE:E, 15:1) afforded -6 (244 mg,
90.6% [13]) along with meso-6 and HAA-7.
D,L-6, meso-6 and 7 in the ratio of 96.7:2.8:0.5 (de
Science) and Silica Gel S733-1 (200ꢀ/425 mesh; Fisher),
/
D,L
respectively. Mass spectra were run at the Regional

328
G.G. Melikyan et al. / Journal of Organometallic Chemistry 683 (2003) 324ꢀ330
/
D
,
L
-6: dark-brown crystals. M.p. 136 8C (sealed
and LS-DF syntheses, refinement against F2 (SHELXTL
[16d]) with all H atoms included in idealized positions.
All non-H atoms refined anisotropically with hydrogens
capillary). TLC (PE:E, 7:1): Rf 0.36. 1H-NMR (200
MHz, CDCl3, TMS): d 3.71 (6H, s, CH3), 4.28 (2H, s,
CH), 6.28 (2H, s, HCÅ
8.0), 7.00 (4H, d, aromatic H). MS FABꢁ
[MHꢁ], 778 [Mꢁꢃ3CO], 750 [Mꢁꢃ4CO], 722 [Mꢁꢃ
5CO], 694 [Mꢁꢃ6CO], 666 [Mꢁꢃ7CO], 638 [Mꢁꢃ
8CO], 610 [Mꢁꢃ9CO], 582 [Mꢁꢃ10CO], 554 [Mꢁꢃ
11CO], 526 [Mꢁꢃ12CO], 436 [Mꢁꢃ
11COÃ2Co].
/
), 6.69 (4H, d, aromatic H, Jꢄ
/
as riding atoms; final residual electron density of 1.054
0.490 e Aꢃ1. Structure solution, refinements,
˚
and ꢃ
/
: m/z 863
/
/
/
/
graphics and tables calculations performed with
SHELXTL. Further details of the structural refinement
are given in Tables 1 and 2. The Crystallographic
Information File (CIF, no. 185838) can be obtained
from the Cambridge Crystallographic Data Centre,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK:
/
/
/
/
/
/
/
/
/
Anal. Found: C, 44.64; H, 2.34. C32H18O14Co4 requires:
C, 44.59; H, 2.10%. X-ray quality crystals were obtained
-
by ethanol vapor diffusion into heptane solution of
6 (Fig. 1).
Meso-6: dark-red oil. TLC (PE:E, 7:1): Rf 0.53. H-
D
,L
Fax: ꢁ
/
44-1223-336033, World Wide Web: http://
www.ccdc.cam.ac.uk).
1
NMR (200 MHz, CDCl3, TMS): only signals different
3.6.
hexadiyne]-bis-dicobalthexacarbonyl (D,L
D,
L
-m-h2-[3,4-Di(4-hydroxyphenyl)-1,5-
-8)
from those of
(2H, s, HCÅ). MS FABꢁ
[Mꢁꢃ4CO], 694 [Mꢁꢃ6CO], 666 [Mꢁꢃ
[Mꢁꢃ8CO], 610 [Mꢁꢃ9CO], 582 [Mꢁꢃ
10CO], 554
[Mꢁꢃ11CO], 526 [Mꢁꢃ12CO], 436 [Mꢁꢃ
11COÃ
2Co].
D,
L
-6 are shown, d 4.31 (2H, s, CH), 5.06
: m/z 778 [Mꢁꢃ
3CO], 750
7CO], 638
/
/
/
/
/
/
Under an atmosphere of nitrogen, a solution of BBr3
(8.81 g, 35.10 mmol) in CH2Cl2 (35.10 ml, 1 M) was
/
/
/
/
/
/
/
slowly added to a solution of
D,
L
-6 (2.33 g, 2.70 mmol)
in dry CH2Cl2 (250 ml) at ꢃ
/
78 8C (45 min). The cold
1
HAA-7: dark-red oil. TLC (PE:E, 7:1): Rf 0.59. H-
NMR (200 MHz, CDCl3, TMS): d 3.79 (3H, s, CH3),
bath was removed and the mixture was stirred for 4 h
(TLC control), poured into the mixture of ice water (250
ml), CH2Cl2 (50 ml) and ether (50 ml), stirred an hour,
and saturated with NaCl. Aqueous layer was extracted
with CH2Cl2 (50 ml), and combined organic extracts
were dried over Na2SO4. The solvents were stripped off
under reduced pressure, and the residue was fractio-
4.04 (2H, d, CH2), 6.07 (1H, t, HCÅ
/
, Jꢄ 1.1) 6.87 (2H,
/
dt, aromatic H, Jꢄ 8.6, 2.1), 7.18 (2H, dt, aromatic H).
/
An authentic sample of 7 was synthesized in a high yield
(86.1%) by quenching cation 4 with tributyltinhydride.
3.4.2. Two-step protocol (path b)
nated on Florisil (125 g, degassed, ꢁ
affording -8 (980 mg, 43.5%) as dark-red crystals.
Tdec. 80ꢀ92 8C (sealed capillary). TLC (PE:E, 1:3): Rf
0.68. 1H-NMR (200 MHz, CDCl3, TMS): d 4.25 (2H, s,
CH), 4.58 (2H, s, OH), 6.29 (2H, s, HCÅ), 6.63 (4H, d,
aromatic H, Jꢄ 8.4), 6.97 (4H, d, aromatic H). MS
FABꢁ 3CO], 722
: m/z 806 [MꢁꢃCO], 750 [Mꢁꢃ
[Mꢁꢃ4CO], 694 [Mꢁꢃ5CO], 666 [Mꢁꢃ
[Mꢁꢃ7CO], 610 [Mꢁꢃ8CO], 582 [Mꢁꢃ
[Mꢁꢃ
C30H14O14Co4 requires: C, 43.17; H, 1.68%.
/
5 8C, PE:E, 2:1)
Under an atmosphere of nitrogen, complex 3 (112 mg,
0.25 mmol) was placed in a flame-dried flask and
dissolved in dry diethyl ether (20 ml). The solution
D,L
/
was cooled (ꢃ
ml, 134 mg, 1.00 mmol). After stirring for 1 h at ꢃ
an ethereal layer was removed, and cation 4 was washed
with dry ether (3ꢂ15 ml) at ꢃ20 8C. Residual amount
/
20 8C) and treated with HBF4×
/
Me2O (122
/
/
20 8C,
/
/
/
/
/
/
/
/
/
6CO], 638
9CO], 554
of ether was stripped under reduced pressure, dry
methylene chloride (2.5 ml) was added, followed by
THF (36 mg, 0.5 mmol). The reaction mixture was
/
/
/
/
10CO]. Anal. Found: C, 43.73; H, 1.76.
stirred 2 h, at ꢁ
/
20 8C (TLC control). By NMR, the
crude mixture contained
of 88:5:7 (de 90%). Fractionation of the crude mixture
D
,
L
-6, meso-6 and 7 in the ratio
3.7. D,L-3,4-Di(4-hydroxyphenyl)-1,5-hexadiyne (D,L-
9)
on the preparative TLC plate (silica gel, PE:E, 7:1)
afforded
isomer (by NMR).
D
,
L
-6 (37 mg, 69.0% [13]), as a pure stereo-
Under a N2 atmosphere, a solution of Ce(N-
H4)2(NO3)6 (1.21 g, 2.20 mmol) in dry acetone (15 ml;
degassed) was slowly added to a solution of
mg, 0.22 mmol) in dry acetone (10 ml; degassed) at ꢃ
78 8C (25 min). Upon addition, the reaction mixture was
warmed up to ꢃ40 8C, stirred for 25 min, then warmed
D,L-8 (183
3.5. X-ray crystallography of
D
,
L
-6
/
A total of 30 362 reflections were measured on a
Bruker D8 diffractometer with APEX CCD detector
and graphite monochromator by 8 and v scans; unit
cell determination using 3288 reflections. Data collec-
tion, data reduction, Lorentz and polarization correc-
tions carried out using SMART [16a] and SAINT [16b]; a
multi-scan absorption correction was applied using
SADABS [16c]. Structure solution by direct methods
/
up to 0 8C, and poured into saturated NaCl solution (20
ml). Aqueous-acetone layer was extracted with ether
˚
(6ꢂ7 ml) and dried (mol. sieves, 4 A). The solvents were
/
evaporated, and the residue was chromatographed on
Florisil (15 g, ꢁ5 8C, degassed, P:E, 2:1) affording -9
(27 mg, 46.6%) as a white solid (benzene dried, 2ꢂ
ml). Tdec. 170ꢀ175 8C (melting observed at 178ꢀ179 8C;
/
D,L
/
2
/
/

G.G. Melikyan et al. / Journal of Organometallic Chemistry 683 (2003) 324ꢀ
/330
329
[4] (a) H. Parekh, H. Simpkins, Gen. Pharmacol. 29 (1997) 167;
sealed capillary); lit. data: [8e] m.p. 178ꢀ
/
179 8C dec.
TLC (PE:E, 1:2): Rf 0.39. H-NMR (200 MHz, CDCl3,
TMS): d 2.37 (2H, d, HCÅ, Jꢄ1.0), 3.91 (2H, d, CH),
6.74 (4H, d, aromatic H, Jꢄ 6.6), 7.13 (4H, d, aromatic
1
(b) S.S. Rai, J. Wolff, Proc. Natl. Acad. USA 95 (1998) 4253.
[5] R.F. Luduena, M.C. Roach, Pharmacol. Ther. 49 (1991) 133.
[6] (a) A.G. Reznikov, S.V. Varga, L.V. Chaikovskaya, L.V.
Tarasenko, L.I. Polyakova, J. Endocrinol. Invest. 19 (1996) 654;
(b) A. Miglietta, C. Bocca, A. Rampa, A. Bisi, L. Gabriel,
Anticancer Drug Des. 12 (1997) 607;
/
/
/
H). MS DIP: m/z 262 (9%), 131 (100%). HR-MS/CI-
NH3: Calc. for C18H15O2 MHꢁ 263.107 205. Found:
263.107 290. Anal. Found: C, 82.78; H, 5.21. C18H14O2
requires: C, 82.44; H, 5.34%.
(c) G.G. Kuiper, B. Carlsson, K. Grandien, E. Enmark, J.
Haggblad, S. Nilsson, J.A. Gustafsson, Endocrinology 138
¨
(1997) 863;
(d) N. Inazu, N. Inaba, T. Satoh, Biochem. Pharmacol. 40 (1990)
2495;
3.8.
D,L-3,4-Di(4-hydroxyphenyl)hexane (D,L-1)
(e) N. Inazu, T. Satoh, Biochem. Pharmacol. 47 (1994) 1489;
(f) K.E. Bergmann, K.E. Carlson, J.A. Katzenellenbogen, Bio-
conjug. Chem. 5 (1994) 141;
Under an atmosphere of hydrogen, a solution of
D,L-9
(42 mg, 0.16 mmol) in ethyl acetate (8 ml) was stirred
over 5% Pd/C (28 mg) for 48 h at 20 8C. The reaction
mixture was filtered off on a short bed of celite,
evaporated to dryness, then fractionated on a Florisil
(g) K.E. Bergmann, S.W. Landvatter, P.G. Rocque, K.E.
Carlson, M.J. Welch, J.A. Katzenellenbogen, Nucl. Med. Biol.
21 (1994) 25;
(h) H. Wiseman, B. Halliwell, FEBS Lett. 332 (1993) 159;
(i) H. Ohishi, M. Ogawa, Chem. Pharm. Bull. (Tokyo) 41 (1993)
1157;
column (P, P:E, 2:1, 1:1) to yield
a white solid. M.p. 124ꢀ124.5 8C (sealed capillary); lit.
data: m.p. 126ꢀ128 8C [8a]; 123ꢀ124 8C [8c]. TLC
(PE:E, 1:2): Rf 0.52. H-NMR (200 MHz, [d6]acetone,
TMS): d 0.69 (6H, t, CH3, Jꢄ7.3), 1.38ꢀ1.58 (2H, m,
CH2), 1.73ꢀ1.92 (2H, m, CH2), 2.63 (2H, m, CH), 6.57ꢀ
D,L-1 (37 mg, 86.0%) as
/
(j) F. Martinez-Azorin, J.A. Teruel, F. Fernandez-Belda, J.C.
Gomez-Fernandez, J. Biol. Chem. 267 (1992) 11923;
(k) Y. Inamori, M. Ogawa, H. Amino, M. Tsuboi, S. Yamaguchi,
H. Tsujibo, S. Takemura, Chem. Pharm. Bull. (Tokyo) 38 (1990)
2045;
/
/
1
/
/
/
/
(l) J.E. Hart, Toxicology 61 (1990) 185.
[7] (a) Y. Sato, T. Murai, T. Oda, H. Saito, M. Kodama, A. Hirata,
J. Biochem. 101 (1987) 1247;
6.75 (8H, m, aromatic H), 7.93 (2H, s, OH). MS DIP: m/
z 270 (3%), 135 (100%). HR-MS/CI-NH3: Calc. for
C18H26NO2 MNH4ꢁ 288.196 354. Found: 288.195 968.
(b) Y. Sakakibara, K. Hasegawa, T. Oda, H. Saito, M. Kodama,
A. Hirata, M. Matsuhashi, Y. Sato, Biochem. Pharmacol. 39
(1990) 167;
(c) T. Oda, M. Watanuki, Y. Sakakibara, Y. Sato, Biol. Pharm.
Bull. 18 (1995) 1435.
[8] For nonstereoselective synthesis of D,L-1 see:
4. Supplementary material
(a) E. Schwenk, D. Papa, B. Whitman, H.F. Ginsberg, J. Org.
Chem. 9 (1944) 175;
Tables of crystallographic details, bond distances and
angles, atomic coordinates and equivalent isotropic
displacement parameters, as well as torsion angles for
(b) N.P. Buu-Hoi, N. Noan, J. Org. Chem. 14 (1949) 1023;
(c) D.J. Collins, J.J. Hobbs, Aust. J. Chem. 23 (1970) 1605;
(d) H.H. Inhoffen, D. Kopp, S. Maric, J. Bekurdts, R. Selimoglu,
Tetrahedron Lett. (1970) 999;
D,L-6; data are also available as files in CIF format.
For the adaptation of the synthetic method previously developed
by us, see:
Acknowledgements
(e) M.J. Meyers, J. Sun, K.E. Carlson, G.A. Marriner, B.S.
Katzenellenbogen, J.A. Katzenellenbogen, J. Med. Chem. 44
(2001) 4230.
Acknowledgment is made to the donors of the
American Chemical Society Petroleum Research Fund
for support of this research (Grant #39104ꢀB1). The
authors are greatly indebted to Hewlett Packard and
Office of Graduate Studies, Research and International
Programs, College of Science and Mathematics and
University Corporation, California State University
Northridge for generous support.
[9] G.G. Melikyan, A. Deravakian, S. Myer, S. Yadegar, K.I.
Hardcastle, J. Ciurash, P. Toure, J. Organomet. Chem. 578
(1999) 68.
/
[10] H. Greenfield, H.W. Sternberg, R.A. Friedel, J.H. Wotiz, R.
Markby, I. Wender, J. Am. Chem. Soc. 78 (1956) 120.
[11] (a) M.J. McGlinchey, L. Girard, R. Ruffolo, Coord. Chem. Rev.
143 (1995) 331;
(b) G.G. Melikyan, K.M. Nicholas, in: P.J. Stang, F. Diederich
(Eds.), Modern Acetylene Chemistry, VCH, Weinheim, 1995, p.
99;
(c) H.E. Amouri, M. Gruselle, Chem. Rev. 96 (1996) 1077.
[12] (a) G.G. Melikyan, S. Bright, T. Monroe, K.M. Hardcastle, J.
Ciurash, Angew.Chem. 110 (1998) 170;
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